Chemical compounds and pharmaceutical compositions as cathepsin S inhibitors

专利摘要:
The present invention relates to compounds of formula (I) useful as selective cathepsin S inhibitors, pharmaceutically acceptable salts thereof and N-oxides thereof, their use as therapeutics and methods for their preparation. Formula I In Formula I above, X 1 is —NH (CR 1 ) (R 2 ) X 3 or —NHR 4 , The remaining radicals are as defined in the claims.
公开号:KR20040015725A
申请号:KR10-2003-7015739
申请日:2002-06-03
公开日:2004-02-19
发明作者:그라우페미하엘；리자야오；링크존오；지펠쉐일라；팀안드레아스파이；앨더스데이비드제이；투라이랏남스칸티니
申请人:액시스 파마슈티컬스 인코포레이티드；아벤티스 파마슈티칼스 인크.；
IPC主号:

专利说明:

Chemical compounds and pharmaceutical compositions as cathepsin S inhibitors}
[1] invent
[2] This patent application is based on U.S. Provisional Patent Application No. 60 / 295,301, filed Jun. 1, 2001, which is incorporated herein by reference, which is claimed as a priority.
[3] This patent application relates to compounds and compositions for the treatment of diseases associated with cysteine protease activity, in particular diseases associated with the activity of cathepsin S.
[4] Cysteine proteases are a class of peptidase characterized by the presence of cysteine residues at the catalytic sites of the enzyme. Cysteine proteases are involved in the normal degradation and processing of proteins. However, for example, as a result of increased expression or enhanced activation, aberrant activity of cysteine proteases can lead to pathological consequences. In this regard, certain cysteine proteases are associated with a number of disease states, such as arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease and discolored white matter atrophy. Increased cathepsin S activity contributes to the pathology and / or symptoms of many diseases. Thus, molecules that inhibit the activity of cathepsin S protease are useful as therapeutic agents in the treatment of such diseases.
[5] The gist of the invention
[6] The present patent application discloses compounds of formula (I), N-oxide derivatives thereof, prodrug derivatives thereof, protected derivatives thereof, individual isomers and mixtures thereof, and compounds of formula (I), N-oxide derivatives thereof, prodrug derivatives thereof And pharmaceutically acceptable salts and solvates of the protected derivatives thereof, the individual isomers thereof, and mixtures thereof.
[7]
[8] In Formula I above,
[9] X ¹ is —NHC (R ¹ ) (R ² ) X ³ or -NHX ⁴ ,
[10] X ² is hydrogen, fluoro, —OH, —OR ⁴ , —NHR ¹⁵ or —NR ¹⁷ R ¹⁸ , X ⁷ is hydrogen, X ² and X ⁷ are both fluoro,
[11] X ³ is cyano, -C (R ⁷ ) (R ⁸ ) R ¹⁶ , -C (R ⁶ ) (OR ⁶ ) ₂ , -CH ₂ C (O) R ¹⁶ , -CH = CHS (O) ₂ R ⁵ , -C (O) CF ₂ C (O) NR ⁵ R ⁵ , -C (O) C (O) NR ⁵ R ⁶ , -C (O) C (O) OR ⁵ , -C (O) CH ₂ OR ⁵ , -C (O) CH ₂ N (R ⁶ ) SO ₂ R ⁵ or -C (O) C (O) R ⁵ , R ⁵ is hydrogen, (C _1-4 ) alkyl, (C _{3 -10)} cycloalkyl (C _0-6) alkyl, hetero (C _3-10) cycloalkyl (C _0-3) alkyl, (C _6-10) aryl (C _0-6) alkyl, hetero (C _5-10 ) Aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl, R ⁶ is hydrogen , Hydroxy or (C _1-6 ) alkyl, or when X ³ contains an —NR ⁵ R ⁶ group, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are hetero (C _3-10 ) cycloalkyl, Forms hetero (C _5-10 ) aryl or hetero (C _8-10 ) bicycloaryl, R ⁷ is hydrogen or (C _1-4 ) alkyl, R ⁸ is hydroxy, or R ⁷ and R ⁸ are Together form oxo, R ¹⁶ is hydrogen, -X ⁴ , -CF ₃ , -CF ₂ CF ₂ R ⁹ or —N (R ⁶ ) OR ⁶ , R ⁹ is hydrogen, halo, (C _1-4 ) alkyl, (C _5-10 ) aryl (C _0-6 ) alkyl or (C _5-10 ) hetero Aryl (C _0-6 ) alkyl provided that when X ³ is cyano, then X ² is hydrogen, fluoro, —OH, —OR ⁴ or —NR ¹⁷ R ¹⁸ , X ⁷ is hydrogen, or X ² and X ⁷ is both fluoro,
[12] X ⁴ is a heteromonocyclic ring containing 4 to 7 ring atoms or a fused heterobicyclic ring system containing 8 to 14 ring atoms and carbocyclic ketones, iminoketones or thioketone derivatives thereof Provided that -2 is a ring other than a heteromonocyclic ring containing five ring atoms wherein up to two of the ring atoms containing -X ⁴ are a hetero atom, X ² is fluoro, -OH, -OR ⁴ , -NHR ¹⁵ or -NR ¹⁷ R ¹⁸ , X ⁷ is hydrogen, X ² and X ⁷ are both fluoro,
[13] The alicyclic or aromatic ring system in R ⁵ , X ³ or X ⁴ is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _{1- 4} ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² ,- X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ and -X ⁵ 1 to 5 radicals independently selected from S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S ( O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S ( ^{_{O) 2 R 14, -X 5}} NR 12 C (O) NR 14 R 12 and ^{-X 5 NR 12 C (NR 12} ) NR 14 R ¹² selected from one LA Being further substituted by a knife, X ⁵ is a bond or (C _1-6) alkylene, R ¹² are each independently hydrogen, (C _1-6) alkyl or halo-substituted (C _1-6) alkyl R ¹³ is (C _1-6 ) alkyl or halo-substituted (C _1-6 ) alkyl, R ¹⁴ is (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _{3- 10} ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) ratio _Cycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl,
[14] R ¹ is hydrogen or (C _1-6 ) alkyl, R ² is hydrogen, cyano, -X ⁵ NR ¹² R ¹² , X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -R ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² (where X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, or R ¹ and R ² together with the carbon atom to which they are attached are (C _3-8 ) cycloalkylene or (C _3-8) form a heterocycloalkyl alkylene, and R ² in the heteroaryl, aryl, cycloalkyl, heterocycloalkyl, cycloalkylene or heterocyclic cycloalkylene is optionally substituted with (C _1-6) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1-4 ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² ,- X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² Further by 1 to 3 radicals independently selected from C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ and -X ⁵ C (O) R ¹³ Substituted, X ⁵ , R ¹² and R ¹³ are as defined above,
[15] R ³ is (C _1-6 ) alkyl or —C (R ⁶ ) (R ⁶ ) X ⁶ , R ⁶ is hydrogen or (C _1-6 ) alkyl, X ⁶ is —X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C ( O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , wherein X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
[16] R ⁴ is -X ⁸ NR ¹² R ¹² , -X ⁸ NR ¹² C (O) R ¹² , -X ⁸ NR ¹² C (O) OR ¹² , -X ⁸ NR ¹² C (O) NR ¹² R ¹² ,- X ⁸ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁸ OR ¹² , -X ⁸ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁸ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁸ S (O) ₂ NR ¹² R ¹² , -X ⁸ NR ¹² S (O) ₂ R ¹² , -X ⁸ P (O ) (OR ¹² ) OR ¹² , -X ⁸ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁸ NR ¹² C (O) R ¹³ , -X ⁸ S (O ) R ¹³ , -X ⁸ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁸ OR ¹⁴ , -X ⁸ SR ¹⁴ , -X ⁸ S (O) R ¹⁴ , -X ⁸ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁸ OC (O) R ¹⁴ , -X ⁸ NR ¹⁴ R ¹² , -X ⁸ NR ¹² C (O) R ¹⁴ , -X ⁸ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁸ S (O) ₂ NR ¹⁴ R ¹² , -X ⁸ NR ¹² S (O) ₂ R ¹⁴ , —X ⁸ NR ¹² C (O) NR ¹⁴ R ¹² and ^—8 NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , X ⁸ is (C _1-6 ) alkylene, X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, provided that when X ³ is cyano and X ² is -OR ⁴ , where R ⁴ is -R ¹⁴ , then R ¹⁴ is (C _3-10 ) cyclo alkyl (C _1-6) alkyl, hetero (C _3-10) Alkyl cycle (C _1-3) alkyl, (C _6-10) aryl (C _1-6) alkyl, hetero (C _5-10) aryl (C _1-6) alkyl, (C _9-10) bicyclo Aryl (C _1-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _1-6 ) alkyl,
[17] R ¹⁵ is (C _6-10 ) aryl, hetero (C _5-10 ) aryl, (C _9-10 ) _bicycloaryl or hetero (C _8-10 ) _bicycloaryl ,
[18] R ¹⁷ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) Aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) ratio _Cycloaryl (C _0-6 ) alkyl provided that when X ³ is cyano, then R ¹⁷ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, (C _6-10 ) aryl (C _1-6 ) alkyl, hetero (C _5-10 ) aryl (C _1-6 ) alkyl, (C _9-10 ) Bicycloaryl (C _1-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _1-6 ) alkyl,
[19] R ¹⁸ is hydrogen, (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, (C _{6- 10} ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) _Bicycloaryl (C _0-6 ) alkyl provided that when X ³ is cyano, R ¹⁸ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, hetero (C _3-10) cycloalkyl (C _1- 6) alkyl, (C _6-10) aryl (C _1-6) alkyl, hetero (C _5-10) aryl (C _1-6) alkyl, (C _{9 -10} ) bicycloaryl (C _1-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _1-6 ) alkyl,
[20] In R ³ , R ⁴ , R ¹⁵ , R ¹⁷ and R ¹⁸ , the alicyclic or aromatic ring system is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo- Substituted (C _1-4 ) alkyl, nitro, —X ⁵ NR ¹² R ¹² , —X ⁵ NR ¹² C (O) R ¹² , —X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C ( O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) 1 to 5 radicals independently selected from R ¹³ , -X ⁵ C (O) R ¹³ and -X ⁵ S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² in Emitter is further substituted by a selected one radical, the aliphatic moiety in the R ³ and R ⁴ is unsubstituted or substituted with cyano, halo, ^{cyano, -NR 12 R 12, -NR 12} C (O) R 12, - NR ¹² C (O) OR ¹² , -NR ¹² C (O) NR ¹² R ¹² , -NR ¹² C (NR ¹² ) NR ¹² R ¹² , -OR ¹² , -SR ¹² , -C (O) OR ¹² , -C (O) R ¹² , -OC (O) R ¹² , -C (O) NR ¹² R ¹² , -S (O) ₂ NR ¹² R ¹² , -NR ¹² S (O) ₂ R ¹² , -P (O) (OR ¹² ) OR ¹² , -OP (O) (OR ¹² ) OR ¹² , -NR ¹² C (O) R ¹³ , -S (O) R ¹³ and -S (O) ₂ R ¹³ Further substituted by 1 to 5 radicals selected from X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, provided that X ³ is cyano and X ² is —OR ⁴ (where R ⁴ is -R ¹⁴ ) or -NHR ¹⁸ , the aromatic ring system present in R ¹⁴ or R ¹⁸ is halo, (C _3-10 ) cycloalkyl, hetero (C _3-10 ) cycloalkyl, (C _{6 -10)} aryl, hetero (C _5-10) aryl, (C _9-10) bicyclo aryl or hetero (C _8-10) bicyclo aryl Not substituted,
[21] Provided that only one bicyclic ring structure is present in R ³ , R ⁴ or R ¹⁵ .
[22] A second aspect of the invention is a pharmaceutical composition containing a compound of formula (I), an N-oxide derivative thereof, an individual isomer thereof or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof with one or more suitable excipients.
[23] A third aspect of the invention provides cathepsin S comprising administering to a animal a therapeutically effective amount of a compound of formula (I), an N-oxide derivative thereof, an individual isomer thereof, or a mixture of isomers thereof or a pharmaceutically acceptable salt thereof. Inhibition of is a method of treating a disease in an animal that prevents, inhibits or alleviates the pathology and / or symptoms of the disease.
[24] A fourth aspect of the invention is a process for preparing a compound of formula (I), an N-oxide derivative thereof, a prodrug derivative thereof, a protected derivative thereof, an individual isomer thereof or a mixture of isomers thereof and a pharmaceutically acceptable salt thereof.
[25] Justice:
[26] Unless stated otherwise, the following terms used in the specification and claims are defined for the purposes of this patent application and have the following meanings.
[27] A "cycloaliphatic" is a moiety characterized by the arrangement of carbon atoms in a non-aromatic closed ring structure whose properties resemble aliphatic, which may be saturated or partially unsaturated by two or more double or triple bonds.
[28] An "aliphatic" is a moiety characterized by a straight or branched chain configuration of constituent carbon atoms, which may be saturated or partially unsaturated by two or more double or triple bonds.
[29] "Alkyl" refers to a straight or branched chain, saturated or unsaturated, aliphatic radical having a number of carbon atoms per se, such as (C _1-6 ) alkyl is methyl, ethyl, propyl, isopropyl, butyl, secondary-butyl, iso Butyl, tert - butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl and 2- Propynyl, and the like. Alkyl (e.g. arylalkyl) together with another radical may be a straight or branched chain having the indicated carbon number, a saturated or unsaturated aliphatic divalent calacal or a bond when no carbon number is indicated [e.g. (C _6-10 ) aryl (C _0-3) alkyl is, and the like, phenyl, benzyl, phenethyl, 1-phenylethyl and 3-phenylpropyl.
[30] Unless stated otherwise, "alkylene" refers to a straight or branched chain, saturated or unsaturated, aliphatic divalent radical, such as indicated by carbon number [e.g. (C _1-6 ) alkylene is methylene (-CH _2- ), ethylene (- CH ₂ CH ₂ -), trimethylene _{(-CH 2 CH 2 CH 2 -} ), tetramethylene _{(-CH 2 CH 2 CH 2 CH} 2 -), 2- butenylene _{(-CH 2 CH = CHCH 2 -} ), 2-methyltetramethylene (-CH ₂ CH (CH ₃ ) CH ₂ CH _2- ), pentamethylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH _2- ), and the like.
[31] "Alkylidene" refers to a straight or branched chain saturated or unsaturated, aliphatic divalent radical, indicated as carbon number [e.g., (C _1-6 ) alkylidene is methylidene (= CH ₂ ), ethylidene (= CHCH ₃ ), Leadide (= C (CH ₃ ) ₂ ), propylidene (= CHCH ₂ CH ₃ ), allylidene (= CH-CH = CH ₂ ), and the like.
[32] "Amino" is a radical -NH ₂ . Unless stated otherwise, compounds of the invention containing amino moieties include protected derivatives thereof. Suitable protecting groups for amino residues include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like.
[33] "Animals" include humans, non-human mammals (eg dogs, cats, rabbits, cows, horses, sheep, goats, pigs, and deer, etc.) and non-mammals (eg birds, etc.).
[34] An "aromatic" is a moiety that constitutes an unsaturated ring system in which the constituent atoms are sp ² hybridized and the total number of pi atoms is 4n + 2.
[35] "Aryl" is a monocyclic or fused acyclic ring assemblage having the indicated total ring carbon number, each ring consisting of six ring carbon atoms and, when aromatic or fused with a second ring, represents an aromatic ring assembly Form. For example, optionally substituted (C _6-10 ) aryl used in this patent application is biphenyl-2-yl, 2-bromophenyl, 2-bromocarbonylphenyl, 2-bromo-5-fluoro Phenyl, 4 - tert-butylphenyl, 4-carbamoylphenyl, 4-carboxy-2-nitrophenyl, 2-chlorophenyl, 4-chlorophenyl, 3-chlorocarbonylphenyl, 4-chlorocarbonylphenyl, 2 -Chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 4-chloro-2-nitrophenyl, 6-chloro-2-nitrophenyl, 2,6-dibromophenyl, 2,3- Dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-difluoromethoxyphenyl, 3,5-dimethylphenyl, 2-ethoxycarbonylphenyl, 2-fluorophenyl, 2-iodo Phenyl, 4-isopropylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 5-methyl-2-nitrophenyl, 4-methylsulfonylphenyl, naft 2-yl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,3,4,5,6-pentafluorophenyl, phenyl, 2-triflu Romethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethylsulfanylphenyl And 4-trifluoromethylsulfanylphenyl and the like, but are not limited thereto. The optionally substituted (C _6-10 ) aryl used in this patent application is 3-acetylphenyl, tert - butoxycarbonylaminomethylphenyl, biphenyl-4-yl, 3-hydroxyphenyl, 4-hydroxy Oxyphenyl, 3-methoxyphenyl, naphth-2-yl, 3-phenoxyphenyl, phenyl and the like.
[36] "Bicycloaryl" is a bicyclic ring assemblage of the indicated ring carbon number, the rings are bonded or fused by a single bond, and at least one of the rings comprising the asmblylic is aromatic and its carbocyclic ketones, thioketones or Noketone derivatives such as (C _9-10 ) bicycloaryl are cyclohexylphenyl, 1,2-dihydronaphthyl, 2,4-dioxo-1,2,3,4-tetrahydronaphthyl, Nil, indenyl and 1,2,3,4-tetrahydronaphthyl and the like.
[37] "Carbamoyl" is a radical -C (O) NH ₂ . Unless stated otherwise, compounds of the invention containing carbamoyl moieties include protected derivatives thereof. Suitable protecting groups for carbamoyl moieties include acetyl, tert - butoxycarbonyl, benzyloxycarbonyl and the like, and include both unprotected and protected derivatives within the scope of the present invention.
[38] A "carbocyclic ketone derivative" is a derivative containing the residue -C (O)-.
[39] "Carboxy" is a radical -C (O) OH. Unless stated otherwise, compounds of the invention containing carboxy moieties include protected derivatives thereof. Suitable protecting groups for carboxy moieties include benzyl and tert - butyl and the like.
[40] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly and the carbocyclic ketone, thioketone or iminoketone derivatives of the indicated ring carbohydrates [eg : (C _3-10 ) cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo [2.2.2] octyl, adamantane-1- One, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl and 2-oxobicyclo [2.2.1] hept-1-yl and the like].
[41] "Cycloalkylene" is a divalent saturated or partially unsaturated, monocyclic ring or bridged polycyclic ring assembly with the indicated carbon number and carbocyclic ketone, thioketone or iminoketone derivatives thereof. For example, when "R ¹ and R ² together with the carbon atom to which they are attached form (C _3-8 ) cycloalkylene" , And It includes, but is not limited to.
[42] A "disease" specifically includes an unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused or caused by medical or veterinary treatment applied to the animal, ie the "side effects" of such treatment.
[43] "Halo" is fluoro, chloro, bromo or iodo.
[44] "Halo-substituted alkyl" as part of an isolated group or larger group is "alkyl" substituted by one or more "halo" atoms, as such terms are defined in this patent application. Halo-substituted alkyls include haloalkyl, dihaloalkyl, trihaloalkyl and perhaloalkyl and the like [eg halo-substituted (C _1-3 ) alkyl may be selected from chloromethyl, dichloromethyl, difluoromethyl, trifluoro Chloromethyl, 2,2,2-trifluoroethyl, perfluoroethyl and 2,2,2-trifluoro-1,1-dichloroethyl, and the like.
[45] “Hetero atomic moiety” includes —N═, —NR—, —O—, —S— or —S (O) ₂ —, wherein R is hydrogen, (C _1-6 ) alkyl or a protecting group .
[46] "Heterocycloalkylene" is a cycloalkylene as defined in this patent application, wherein one or more ring carbon atoms indicated is from -N =, -NR-, -O-, -S- and -S (O) _2- . May be replaced by a selected hetero atom residue, and R is hydrogen or (C _1-6 ) alkyl. For example, when "R ¹ and R ² together with the carbon atom to which they are attached form a hetero (C _3-8 ) cycloalkyl" , , And Wherein R is hydrogen, (C _1-6 ) alkyl or a protecting group], but is not limited thereto.
[47] "Heteroaryl" is aryl as defined in this patent application, wherein one or more of the ring carbon atoms indicated is replaced by a hetero atom residue selected from -N =, -NR-, -O-, and -S-, and R is hydrogen , (C _1-6 ) alkyl, a protecting group or a free valency serving as a point of attachment to ring nitrogen, each ring consisting of 5 or 6 ring atoms. For example, optionally substituted hetero (C _5-10 ) aryl used in this patent application is 4-amino-2-hydroxypyrimidin-5-yl, benzothiazol-2-yl, 1H-benzoimidazole. 2-yl, 2-bromopyrid-5-yl, 5-bromopyrid-2-yl, 4-carbamoylthiazol-2-yl, 3-carboxypyrid-4-yl, 5-carboxy- 2,6-dimethylpyrid-3-yl, 3,5-dimethylisoxazol-4-yl, 5-ethoxy-2,6-dimethylpyrid-3-yl, 5-fluoro-6-hydro Roxypyrimidin-4-yl, fur-2-yl, fur-3-yl, 5-hydroxy-4,6-dimethylpyrid-3-yl, 8-hydroxy-5,7-dimethylquinoline-2 -Yl, 5-hydroxymethylisoxazol-3-yl, 3-hydroxy-6-methylpyrid-2-yl, 3-hydroxypyrid-2-yl, 1H-imidazol-2-yl , 1H-imidazol-4-yl, 1H-indol-3-yl, isothiazol-4-yl, isoxazol-4-yl, 2-methylfur-3-yl, 5-methylfur-2-yl , 1-methyl-1H-imidazol-2-yl, 5-methyl-3H-imidazol-4-yl, 5-methylisoxazol-3-yl, 5-methyl-2H-pyrazol-3-yl , 3-mer Tilpyrid-2-yl, 4-methylpyrid-2-yl, 5-methylpyrid-2-yl, 6-methylpyrid-2-yl, 2-methylpyrid-3-yl, 2-methyl Thiazol-4-yl, 5-nitropyrid-2-yl, 2H-pyrazol-3-yl, 3H-pyrazol-4-yl, pyridazin-3-yl, pyrid-2-yl, blood Lead-3-yl, pyrid-4-yl, 5-pyrid-3-yl-2H- [1,2,4] triazol-3-yl, pyrimidin-4-yl, pyrimidin-5- 1, 1H-pyrrole-3-yl, quinolin-2-yl, 1H-tetrazol-5-yl, thiazol-2-yl, thiazol-5-yl, thien-2-yl, thien-3-yl , 2H- [1,2,4] triazol-3-yl, 3H- [1,2,3] triazol-4-yl, 5-trifluoromethylpyrid-2-yl and the like, It is not limited to this. Suitable protecting groups include tert - butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl and 2-nitrobenzyl and the like. The optionally substituted hetero (C _5-10 ) aryl used in this patent application to define R ⁴ is benzofur-2-yl, fur-2-yl, fur-3-yl, pyrid-3-yl, Pyrid-4-yl, quinol-2-yl, quinol-3-yl, thien-2-yl and thien-3-yl and the like.
[48] "Heterobicycloaryl" is a bicycloaryl and carbocyclic ketone, thioketone or iminoketone derivative thereof as defined in this patent application, wherein one or more ring carbon atoms indicated is -N =, -NR-, -O- and Substituted by a hetero atom residue selected from -S-, R is the free valency serving as a point of attachment to hydrogen, (C _1-6 ) alkyl, a protecting group or ring nitrogen. For example, optionally substituted hetero (C _8-10 ) _bicycloaryl , as used in this patent application, includes 2-amino-4-oxo-3,4-dihydropteridin-6-yl and the like, It is not limited to this. In general, the term heterobicycloaryl as used in this patent application is, for example, benzo [1,3] dioxol-5-yl, 3,4-dihydro-2H- [1,8] naphthyridinyl, 3,4-dihydro-2H-quinolinyl, 2,4-dioxo-3,4-dihydro-2H-quinazolinyl, 1,2,3,4,5,6-hexahydro [2, 2 '] bipyridinylyl, 3-oxo-2,3-dihydrobenzo [1,4] oxazinyl and 5,6,7,8-tetrahydroquinolinyl and the like.
[49] “Heterocycloalkyl” refers to cycloalkyls and carbocyclic ketones, thioketones or iminoketone derivatives as defined in this patent application [eg, the term hetero (C _5-10 ) cycloalkyl refers to imidazolidinyl, morpholinyl, Piperazinyl, piperidyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, and the like], and one or more ring carbon atoms indicated are selected from -N =, -NR-, -O-, and -S-. Replaced by hetero atom residues, R is a free valency that acts as a point of attachment to hydrogen, (C _1-6 ) alkyl, a protecting group or ring nitrogen. Suitable protecting groups include tert - butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl and 2-nitrobenzyl and the like. Both unprotected and protected derivatives are included within the scope of this invention.
[50] "Heteromonocyclic ring" is a saturated or partially unsaturated monocyclic ring assembly containing a specified number of ring carbon atoms as defined in this patent application, wherein the one or more ring carbon atoms indicated are -N =, Substituted by one or more hetero atoms selected from -NY ^3- , -O-, and -S-, Y ³ is hydrogen, alkyl, aryl, arylalkyl, -C (= 0) -R ¹⁴ , -C (= 0 ) -OR ¹⁴ or -SO ₂ R ¹⁴ .
[51] "Heterobicyclic ring" is a saturated or partially unsaturated fused bicyclic or bridged polycyclic ring assembly containing the indicated number of ring carbon atoms as defined in this patent application, wherein the one or more rings indicated The carbon atom is replaced by one or more hetero atoms selected from -N =, -NY ^3- , -O- and -S-, and Y ³ is hydrogen, alkyl, aryl, arylalkyl, -C (= O) -R ¹⁴ , -C (= 0) -OR ¹⁴ or -SO ₂ R ¹⁴ .
[52] "Hydroxy" is a radical -OH. Unless stated otherwise, compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for hydroxy moieties include benzyl and the like.
[53] "Iminoketone derivative" is a derivative containing the residue -C (NR)-, where R is hydrogen or (C _1-6 ) alkyl.
[54] "Isomers" are compounds of formula (I) which have the same molecular formula but differ in the bonding properties or order or space of their atoms in their atoms. Isomers that differ in their atomic arrangement in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are referred to as "partial stereoisomers" and non-excessible enantiomeric stereoisomers are referred to as "enantiomers" or sometimes "optical isomers". Carbon atoms bonded to four nonidentical substituents are referred to as "chiral centers". When a compound having one chiral center has two enantiomeric forms of opposite chirality, it is referred to as a "racemic mixture". Compounds having at least one chiral center have 2 ^n-1 enantiomeric pairs, where n is the number of chiral centers. Compounds having one or more chiral centers may exist as individual diastereomers or as mixtures of diastereomers called "diastereomeric mixtures". If one chiral center is present, the stereoisomer may be characterized by the absolute configuration of the chiral center. Absolute coordination refers to the arrangement in space of substituents attached to chiral centers. Enantiomers are characterized by the absolute configuration of chiral centers and are described by the R- and S-order rules of Cahn, Ingold and Prelog (Cahn, Ingold and Prelog). Stereochemistry naming conventions, stereochemical measurement methods, and stereoisomer separation are well known in the art ("Advanced Organic Chemistry", 4th edition, March, Jerry, John Wiley & Sons, New York, 1992). The names and descriptions used in this patent application to describe compounds of formula (I) are meant to include all possible stereoisomers. Thus, for example, N- [1- (1-benzothiazol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenylmethanesulfonyl-propionamide is (S) -N- [1- (1-Benzothiazol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenylmethanesulfonyl-propionamide, (R) -N- [1- (1-benzothia Zol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenylmethanesulfonyl-propionamide, (R) -N-[(S) -1- (1-benzothiazol-2- Yl-methanoyl) -propyl] -2-hydroxy-3-phenylmethanesulfonyl-propionamide, (S) -N-[(R) -1- (1-benzothiazol-2-yl-methanoyl ) -Propyl] -2-hydroxy-3-phenylmethanesulfonyl-propionamide, (R) -N-[(R) -1- (1-benzothiazol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenylmethanesulfonyl-propionamide, N-[(S) -1- (1-benzothiazol-2-yl-methanoyl) -propyl] -2-hydroxy-3- Phenylmethanesulfonyl-propionamide, N-[(R) -1- (1-benzothiazol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenylmethanesul Nyl-propionamide, (S) -N-[(S) -1- (1-benzothiazol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenylmethanesulfonyl-propionamide And mixtures thereof or racemics.
[55] "Ketone derivatives" are derivatives containing residues -C (O)-. For example, in this patent application X ³ may be 2-acetoxy-azetidin-3-yl. A “carbocyclic ketone derivative” of this example of X ³ is 2-acetoxy-4-oxo-azetidin-3-yl (see Table 3, C32).
[56] "Nitro" is a radical -NO ₂ .
[57] “Any” or “optionally” means that a result or situation described later occurs or does not occur, and such description includes when a result or situation appears and when it does not appear. For example, "R ³ and R ⁴ is an alicyclic or aromatic ring system in which may be substituted further by 1 to 5 radicals" is optionally substituted in the sphere R ³ and R ⁴ range been invention that substituted It can be.
[58] "Oxoalkyl" is an alkyl as defined above wherein one of the indicated carbon atoms is replaced by an oxygen group (-O-), for example, oxo (C _2-6 ) alkyl includes methoxymethyl and the like.
[59] "N-oxide derivative" means a derivative of a compound of formula I which is in an oxidized state of nitrogen (ie O-N) and has the desired pharmacological activity.
[60] "Pathology" of a disease refers to structural and functional changes resulting from the disease process as well as the essential nature, cause and development of the disease.
[61] "Pharmaceutically acceptable" means generally useful for preparing safe, non-toxic and biologically or otherwise desired pharmaceutical compositions, including those acceptable for veterinary and human pharmaceutical use.
[62] "Pharmaceutically acceptable salt" means a salt of a compound of formula (I) having the pharmaceutically acceptable and desired pharmacological activity as defined above. Such salts may be inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid , Malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, madeelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane Disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] oct- 2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl Acids formed using sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid It includes a salt.
[63] Pharmaceutically acceptable salts also include base addition salts which may be formed when the acidic protons present react with an inorganic or organic base. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
[64] "Prodrug" means a compound that can be converted in vivo to a compound of formula I by metabolic methods (eg hydrolysis). For example, esters of compounds of formula (I) containing hydroxy groups can be converted to the parent molecule in vivo by hydrolysis. Alternatively, esters of compounds of formula (I) containing a carboxy group can be converted to the parent molecule by hydrolysis in vivo. Suitable esters of compounds of formula I containing hydroxy groups include, for example, acetates, citrate, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, Maleate, methylene-bis-b-hydroxynaphthoate, gentisate, isethionate, di-p-toluoyl tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclo Hexylsulfamate and quinate. Suitable esters of compounds of formula I containing a carboxy group are described, for example, in F. J. Leinweber, Drug Metab. Res., 1987, 18, page 379. Esters of a particularly useful class of compounds of formula I containing hydroxy groups are described in Bundgaard et al., J. Med. Chem., 1989, 32, page 2503-2507, which may be formed from acid residues selected from compounds and include substituted (aminomethyl) benzoates such as dialkylamino-methylbenzoate, Two alkyl groups may be bonded together and / or interrupted by an oxygen atom or an optionally substituted nitrogen atom, for example an alkylated nitrogen atom, and more particularly (morpholino-methyl) benzoate, for example 3- or 4- (morpholinomethyl) -benzoate and (4-alkylpiperazin-1-yl) benzoate, for example 3- or 4- (4-alkylpiperazin-1-yl) benzo It is eight.
[65] "Protected derivative" means a derivative of the compound of formula I in which the reactive site (s) are blocked with a protecting group. Protected derivatives of compounds of formula (I) may be useful in the preparation of compounds of formula (I) or may themselves be active cathepsin S inhibitors. For a comprehensive list of suitable protection groups, see T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999].
[66] By "therapeutically effective amount" is meant an amount sufficient to affect the treatment of such a disease when administered to an animal to treat the disease.
[67] "Tioketone derivative" means a derivative containing the residue -C (S)-.
[68] "Treatment or treating" means administration of a compound of the present invention (1) to prevent a disease that occurs in an animal that is susceptible to disease or has not yet experienced or exhibited the pathology or symptoms of the disease, or (2) Inhibiting the disease (ie, inhibiting further development of the pathology and / or symptoms) in an animal experiencing or exhibiting the pathology or symptom, or (3) alleviating the disease (ie, in an animal experiencing or exhibiting the pathology or symptom of the disease) , Undoing the pathology and / or symptoms).
[69] denomination:
[70] The compounds of formula (I) and the intermediates and starting materials used in their preparation are named according to the IUPAC rules of the nomenclature in which the characteristic groups have reduced cited properties as base groups, acids, esters or amides, etc. as follows. Alternatively, the compound is named by AutoNom 4.0 (Beilstein Information Systems, Inc.). For example, X ² is hydroxy, R ³ is phenylmethanesulfonylmethyl, X ¹ is —NHC (R ¹ ) (R ² ) X ³ (wherein R ¹ is hydrogen and R ² is ethyl , X ³ is 1-benzothiazol-2-yl-methanoyl), i.e. The compound of is called (R) -N-[(S) -1- (1-benzothiazol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenylmethanesulfonylpropionamide.
[71] Preferred Aspects:
[72] While the scope of the invention is as shown in the subject matter of the invention, certain aspects of the invention are preferred. For example, compounds of formula (I), N-oxide derivatives thereof, prodrug derivatives thereof, protected derivatives thereof, individual isomers and mixtures thereof, and compounds of formula (I), N-oxide derivatives thereof, prodrug derivatives thereof Preference is given to pharmaceutically acceptable salts and solvates of, protected derivatives thereof, individual isomers thereof and mixtures thereof.
[73] Formula I
[74]
[75] In Formula I above,
[76] X ¹ is —NHC (R ¹ ) (R ² ) X ³ or —NHCH (R ¹⁹ ) C (O) R ²⁰ ,
[77] X ² is hydrogen, fluoro, —OH, —OR ⁴ , —NHR ¹⁵ or —NR ¹⁷ R ¹⁸ , X ⁷ is hydrogen, X ² and X ⁷ are both fluoro,
[78] X ³ is cyano, -C (R ⁷ ) (R ⁸ ) R ¹⁶ , -C (R ⁶ ) (OR ⁶ ) ₂ , -CH ₂ C (O) R ¹⁶ , -CH = CHS (O) ₂ R ⁵ , -C (O) CF ₂ C (O) NR ⁵ R ⁵ , -C (O) C (O) NR ⁵ R ⁶ , -C (O) C (O) OR ⁵ , -C (O) CH ₂ OR ⁵ , -C (O) CH ₂ N (R ⁶ ) SO ₂ R ⁵ or -C (O) C (O) R ⁵ , R ⁵ is hydrogen, (C _1-4 ) alkyl, (C _{3 -10} ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _{5- 10} ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl, R ⁶ is When hydrogen, hydroxy or (C _1-6 ) alkyl or X ³ contains a —NR ⁵ R ⁶ group, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are hetero (C _3-10 ) cycloalkyl , Hetero (C _5-10 ) aryl or hetero (C _8-10 ) bicycloaryl, R ⁷ is hydrogen or (C _1-4 ) alkyl, R ⁸ is hydroxy, or R ⁷ and R ⁸ Together form oxo, R ¹⁶ is hydrogen, -X ⁴ , -CF ₃ , -CF ₂ CF ₂ R ⁹ or —N (R ⁶ ) OR ⁶ , R ⁹ is hydrogen, halo, (C _1-4 ) alkyl, (C _5-10 ) aryl (C _0-6 ) alkyl or (C _5-10 Heteroaryl (C _0-6 ) alkyl provided that when X ³ is cyano, then X ² is hydrogen, fluoro, —OH, —OR ⁴ or —NR ¹⁷ R ¹⁸ , and X ⁷ is hydrogen or X ² and X ⁷ are both fluoro,
[79] X ⁴ is a heteromonocyclic ring containing 4 to 7 ring atoms or a fused heterobicyclic ring system containing 8 to 14 ring atoms and carbocyclic ketones, iminoketones or thioketone derivatives thereof Provided that, when -X ⁴ is a ring other than a heteromonocyclic ring containing five ring atoms in which two or less of the ring containing a ring is a hetero atom, X ² is fluoro, -OH, -OR ⁴ , -NHR ¹⁵ or -NR ¹⁷ R ¹⁸ , X ⁷ is hydrogen, X ² and X ⁷ are both fluoro,
[80] The alicyclic or aromatic ring system in R ⁵ , X ³ or X ⁴ is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _{1- 4} ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² ,- X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ and -X ⁵ 1 to 5 substituents independently selected from S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S ( O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S ( ^{_{O) 2 R 14, -X 5}} NR 12 C (O) NR 14 R 12 and ^{-X 5 NR 12 C (NR 12} ) NR 14 R ¹² selected from one LA Being further substituted by a knife, X ⁵ is a bond or (C _1-6) alkylene, R ¹² are each independently hydrogen, (C _1-6) alkyl or halo-substituted (C _1-6) alkyl R ¹³ is (C _1-6 ) alkyl or halo-substituted (C _1-6 ) alkyl, R ¹⁴ is (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _{3- 10} ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) ratio _Cycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl,
[81] R ¹ is hydrogen or (C _1-6 ) alkyl, R ² is hydrogen, cyano, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O ) OR ¹² , -R ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² ,- X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O ) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² (where X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, or R ¹ and R ² together with the carbon atom to which they are attached are (C _3-8 ) cycloalkylene or (C _3-8) heterocycloalkyl to form a alkylene, heteroaryl, aryl, cycloalkyl in R ^2, heterocycloalkyl, cycloalkylene or heterocyclic cycloalkylene is optionally substituted with (C _1-6) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1-4 ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ By 1 to 3 substituents independently selected from NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ and -X ⁵ C (O) R ¹³ Substituted, X ⁵ , R ¹² and R ¹³ are as defined above,
[82] R ³ is (C _1-6 ) alkyl or —C (R ⁶ ) (R ⁶ ) X ⁶ , R ⁶ is hydrogen or (C _1-6 ) alkyl, X ⁶ is —X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C ( O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , wherein X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
[83] R ⁴ is -X ⁸ NR ¹² R ¹² , -X ⁸ NR ¹² C (O) R ¹² , -X ⁸ NR ¹² C (O) OR ¹² , -X ⁸ NR ¹² C (O) NR ¹² R ¹² ,- X ⁸ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁸ OR ¹² , -X ⁸ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁸ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁸ S (O) ₂ NR ¹² R ¹² , -X ⁸ NR ¹² S (O) ₂ R ¹² , -X ⁸ P (O ) (OR ¹² ) OR ¹² , -X ⁸ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁸ NR ¹² C (O) R ¹³ , -X ⁸ S (O ) R ¹³ , -X ⁸ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁸ OR ¹⁴ , -X ⁸ SR ¹⁴ , -X ⁸ S (O) R ¹⁴ , -X ⁸ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁸ OC (O) R ¹⁴ , -X ⁸ NR ¹⁴ R ¹² , -X ⁸ NR ¹² C (O) R ¹⁴ , -X ⁸ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁸ S (O) ₂ NR ¹⁴ R ¹² , -X ⁸ NR ¹² S (O) ₂ R ¹⁴ , —X ⁸ NR ¹² C (O) NR ¹⁴ R ¹² and —N ⁸ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , X ⁸ is (C _1-6 ) alkylene and X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, provided that X ³ is cyano and X ² is -OR ⁴ , where R ⁴ is -R ¹⁴ , and R ¹⁴ is (C _{3- 10} ) cycloalkyl (C _1-6 ) alkyl, hetero (C _3-10 ) Cycloalkyl (C _1-3 ) alkyl, (C _6-10 ) aryl (C _1-6 ) alkyl, hetero (C _5-10 ) aryl (C _1-6 ) alkyl, (C _9-10 ) bicycloaryl (C _1-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _1-6 ) alkyl,
[84] R ¹⁵ is (C _6-10 ) aryl, hetero (C _5-10 ) aryl, (C _9-10 ) _bicycloaryl or hetero (C _8-10 ) _bicycloaryl ,
[85] R ¹⁷ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) Aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) ratio _Cycloaryl (C _0-6 ) alkyl provided that when X ³ is cyano, then R ¹⁷ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, (C _6-10 ) aryl (C _1-6 ) alkyl, hetero (C _5-10 ) aryl (C _1-6 ) alkyl, (C _9-10 ) Bicycloaryl (C _1-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _1-6 ) alkyl,
[86] R ¹⁸ is hydrogen, (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, (C _{6- 10} ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) _Bicycloaryl (C _0-6 ) alkyl, provided that when X ³ is cyano, R ¹⁸ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, (C _6-10 ) aryl (C _1-6 ) alkyl, hetero (C _5-10 ) aryl (C _1-6 ) alkyl, (C _{9 -10} ) bicycloaryl (C _1-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _1-6 ) alkyl,
[87] R ¹⁹ and R ²⁰ together with the atoms to which they are attached form a (C _4-8 ) heterocycloalkylene wherein at least one of the ring atoms comprising the ring is a hetero atom selected from —NR ²¹ — and —O—, and the ring is is unsubstituted or is substituted by R ^2, R ² is as defined above, R ²¹ is ^{hydrogen, -C (O) oR 12,} -C (O) R 12, -C (O) NR 12 R 12, - S (O) ₂ NR ¹² R ¹² , -S (O) R ¹³ , -S (O) ₂ R ¹³ , -S (O) R ¹⁴ , -S (O) ₂ R ¹⁴ , -C (O) R ¹⁴ , -C (O) OR ¹⁴ , -C (O) NR ¹² R ¹² and -S (O) ₂ NR ¹⁴ R ^12, wherein R ¹² , R ¹³ and R ¹⁴ are as defined above,
[88] In R ³ , R ⁴ , R ¹⁵ , R ¹⁷ and R ¹⁸ , the alicyclic or aromatic ring system is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo- Substituted (C _1-4 ) alkyl, nitro, —X ⁵ NR ¹² R ¹² , —X ⁵ NR ¹² C (O) R ¹² , —X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C ( O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) 1 to 5 radicals independently selected from R ¹³ , -X ⁵ C (O) R ¹³ and -X ⁵ S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² in Emitter is further substituted by a selected one radical, R ³ and R ⁴ in the aliphatic moiety is unsubstituted or substituted with cyano, halo, ^{nitro, -NR 12 R 12, -NR 12} C (O) R 12, -NR ¹² C (O) OR ¹² , -NR ¹² C (O) NR ¹² R ¹² , -NR ¹² C (NR ¹² ) NR ¹² R ¹² , -OR ¹² , -SR ¹² , -C (O) OR ¹² ,- C (O) R ¹² , -OC (O) R ¹² , -C (O) NR ¹² R ¹² , -S (O) ₂ NR ¹² R ¹² , -NR ¹² S (O) ₂ R ¹² , -P ( O) (OR ¹² ) OR ¹² , -OP (O) (OR ¹² ) OR ¹² , -NR ¹² C (O) R ¹³ , -S (O) R ¹³ and -S (O) ₂ R ¹³ independently Further substituted by 1 to 5 radicals selected, wherein X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, provided that X ³ is cyano and X ² is —OR ⁴ wherein R ⁴ is -R ¹⁴ ) or -NHR ¹⁸ , the aromatic ring system present in R ¹⁴ or R ¹⁸ is halo, (C _3-10 ) cycloalkyl, hetero (C _3-10 ) cycloalkyl, (C _6-10 ) Aryl, hetero (C _5-10 ) aryl, (C _9-10 ) _bicycloaryl or hetero (C _8-10 ) _bicycloaryl Not substituted by
[89] Provided that only one bicyclic ring structure is present in R ³ , R ⁴ or R ¹⁵ .
[90] Compounds of Formula I, N-oxide derivatives thereof, prodrug derivatives thereof, protected derivatives thereof, individual isomers thereof and mixtures thereof, and compounds of Formula I, N-oxide derivatives thereof, prodrug derivatives thereof, protected Preference is given to pharmaceutically acceptable salts and solvates of derivatives, individual isomers thereof and mixtures of isomers thereof.
[91] Formula I
[92]
[93] In Formula I above,
[94] X ¹ is —NHC (R ¹ ) (R ² ) X ³ or —NHCH (R ¹⁹ ) C (O) R ²⁰ ,
[95] X ² is hydrogen, fluoro, —OH, —OR ⁴ , —NHR ¹⁵ or —NR ¹⁷ R ¹⁸ , X ⁷ is hydrogen, X ² and X ⁷ are both fluoro,
[96] X ³ is -C (R ⁷ ) (R ⁸ ) R ¹⁶ , -C (R ⁶ ) (OR ⁶ ) ₂ , -CH ₂ C (O) R ¹⁶ , -CH = CHS (O) ₂ R ⁵ ,- C (O) CF ₂ C (O) NR ⁵ R ⁵ , -C (O) C (O) NR ⁵ R ⁶ , -C (O) C (O) OR ⁵ , -C (O) CH ₂ OR ⁵ , -C (O) CH ₂ N (R ⁶ ) SO ₂ R ⁵ or -C (O) C (O) R ⁵ , R ⁵ is hydrogen, (C _1-4 ) alkyl, (C _3-10 ) Cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl, R ⁶ is hydrogen, hydrogen If oxy or (C _1-6 ) alkyl or X ³ contains a -NR ⁵ R ⁶ group, then R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are hetero (C _3-10 ) cycloalkyl, hetero ( C _5-10 ) aryl or hetero (C _8-10 ) bicycloaryl, R ⁷ is hydrogen or (C _1-4 ) alkyl, R ⁸ is hydroxy, or R ⁷ and R ⁸ together are oxo forming, and R ¹⁶ is _{^{hydrogen, -X 4, -CF 3, -CF}} 2 CF 2 R 9 Is -N (R ⁶⁾ is OR ^6, R ⁹ is hydrogen, halo, (C _1-4) alkyl, (C _5-10) aryl (C _0-6) alkyl or (C _5-10) heteroaryl ( C _0-6 ) alkyl,
[97] X ⁴ is a heteromonocyclic ring containing 4 to 7 ring atoms or a fused heterobicyclic ring system containing 8 to 14 ring atoms and carbocyclic ketones, iminoketones or thioketone derivatives thereof Provided that -2 is a ring other than a heteromonocyclic ring containing five ring atoms wherein up to two of the ring atoms containing -X ⁴ are a hetero atom, X ² is fluoro, -OH, -OR ⁴ , -NHR ¹⁵ or -NR ¹⁷ R ¹⁸ , X ⁷ is hydrogen, X ² and X ⁷ are both fluoro,
[98] The alicyclic or aromatic ring system in R ⁵ , X ³ or X ⁴ is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _{1- 4} ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² ,- X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ and -X ⁵ 1 to 5 radicals independently selected from S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S ( O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S ( ^{_{O) 2 R 14, -X 5}} NR 12 C (O) NR 14 R 12 and ^{-X 5 NR 12 C (NR 12} ) NR 14 R ¹² selected from one LA Being further substituted by a knife, X ⁵ is a bond or (C _1-6) alkylene, R ¹² are each independently hydrogen, (C _1-6) alkyl or halo-substituted (C _1-6) alkyl R ¹³ is (C _1-6 ) alkyl or halo-substituted (C _1-6 ) alkyl, R ¹⁴ is (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _{3- 10} ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) ratio _Cycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl,
[99] R ¹ is hydrogen or (C _1-6 ) alkyl, R ² is hydrogen, cyano, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O ) OR ¹² , -X ⁵ R ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² where X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, or R ¹ and R ² together with the carbon atom to which they are attached are (C _3-8 ) cycloalkylene or It is (C _3-8) heterocycloalkyl to form a alkylene, heteroaryl, aryl, cycloalkyl in R ^2, heterocycloalkyl, cycloalkylene or heterocyclic cycloalkylene is optionally substituted with (C _1-6) alkyl , (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1-4 ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² ,- X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O ) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ and -X ⁵ C (O) R ¹³ independently selected from 1 to 3 radicals Substituted by X ⁵ , R ¹² and R ¹³ are as defined above,
[100] R ³ is —C (R ⁶ ) (R ⁶ ) X ⁶ , R ⁶ is hydrogen or (C _1-6 ) alkyl, X ⁶ is —X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O ) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² ,- X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C ( O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , wherein X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
[101] R ⁴ is -X ⁸ NR ¹² R ¹² , -X ⁸ NR ¹² C (O) R ¹² , -X ⁸ NR ¹² C (O) OR ¹² , -X ⁸ NR ¹² C (O) NR ¹² R ¹² ,- X ⁸ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁸ OR ¹² , -X ⁸ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁸ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁸ S (O) ₂ NR ¹² R ¹² , -X ⁸ NR ¹² S (O) ₂ R ¹² , -X ⁸ P (O ) (OR ¹² ) OR ¹² , -X ⁸ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁸ NR ¹² C (O) R ¹³ , -X ⁸ S (O ) R ¹³ , -X ⁸ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁸ OR ¹⁴ , -X ⁸ SR ¹⁴ , -X ⁸ S (O) R ¹⁴ , -X ⁸ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁸ OC (O) R ¹⁴ , -X ⁸ NR ¹⁴ R ¹² , -X ⁸ NR ¹² C (O) R ¹⁴ , -X ⁸ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁸ S (O) ₂ NR ¹⁴ R ¹² , -X ⁸ NR ¹² S (O) ₂ R ¹⁴ , —X ⁸ NR ¹² C (O) NR ¹⁴ R ¹² and —X ⁸ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , X ⁸ is (C _1-6 ) alkylene, X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
[102] R ¹⁵ is (C _6-10 ) aryl, hetero (C _5-10 ) aryl, (C _9-10 ) _bicycloaryl or hetero (C _8-10 ) _bicycloaryl ,
[103] R ¹⁷ is hydrogen, (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-3 ) alkyl, (C _{6- 10} ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) _Bicycloaryl (C _0-6 ) alkyl,
[104] R ¹⁸ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, (C _6-10 ) Aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) ratio _Cycloaryl (C _0-6 ) alkyl,
[105] R ¹⁹ and R ²⁰ together with the atoms to which they are attached form a (C _4-8 ) heterocycloalkylene wherein at least one of the ring atoms comprising the ring is a hetero atom selected from —NR ²¹ — and —O—, and the ring is is unsubstituted or is substituted by R ^1, R ¹ is as defined above, R ²¹ is ^{hydrogen, -C (O) oR 12,} -C (O) R 12, -C (O) NR 12 R 12, - S (O) ₂ NR ¹² R ¹² , -S (O) R ¹³ , -S (O) ₂ R ¹³ , -S (O) R ¹⁴ , -S (O) ₂ R ¹⁴ , -C (O) R ¹⁴ , -C (O) OR ¹⁴ , -C (O) NR ¹² R ¹² and -S (O) ₂ NR ¹⁴ R ^12, wherein R ¹² , R ¹³ and R ¹⁴ are as defined above,
[106] In R ³ , R ⁴ , R ¹⁵ , R ¹⁷ and R ¹⁸ , the alicyclic or aromatic ring system is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo- Substituted (C _1-4 ) alkyl, nitro, —X ⁵ NR ¹² R ¹² , —X ⁵ NR ¹² C (O) R ¹² , —X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C ( O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) 1 to 5 radicals independently selected from R ¹³ , -X ⁵ C (O) R ¹³ and -X ⁵ S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² in Emitter is further substituted by a selected one radical, a cycloaliphatic moiety is unsubstituted or substituted in the R ³ and R ^4, cyano, halo, ^{nitro, -NR 12 R 12, -NR 12} C (O) R 12, - NR ¹² C (O) OR ¹² , -NR ¹² C (O) NR ¹² R ¹² , -NR ¹² C (NR ¹² ) NR ¹² R ¹² , -OR ¹² , -SR ¹² , -C (O) OR ¹² , -C (O) R ¹² , -OC (O) R ¹² , -C (O) NR ¹² R ¹² , -S (O) ₂ NR ¹² R ¹² , -NR ¹² S (O) ₂ R ¹² , -P (O) (OR ¹² ) OR ¹² , -OP (O) (OR ¹² ) OR ¹² , -NR ¹² C (O) R ¹³ , -S (O) R ¹³ and -S (O) ₂ R ¹³ Further substituted by 1 to 5 substituents selected from X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
[107] Provided that only one bicyclic ring structure is present in R ³ , R ⁴ or R ¹⁵ .
[108] Compounds of Formula I, N-oxide derivatives thereof, prodrug derivatives thereof, protected derivatives thereof, individual isomers thereof and mixtures thereof, and compounds of Formula I, N-oxide derivatives thereof, prodrug derivatives thereof, protected Preference is given to pharmaceutically acceptable salts and solvates of derivatives, individual isomers thereof and mixtures of isomers thereof.
[109] Formula I
[110]
[111] In Formula I above,
[112] X ¹ is —NHC (R ¹ ) (R ² ) X ³ or —NHCH (R ¹⁹ ) C (O) R ²⁰ ,
[113] X ² is hydrogen, fluoro, —OH, —OR ⁴ or —NR ¹⁷ R ¹⁸ , X ⁷ is hydrogen, X ² and X ⁷ are both fluoro,
[114] X ³ is cyano,
[115] The alicyclic or aromatic ring system within X ³ is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1-4 ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ and -X ⁵ S (O) ₂ R 1 to 5 substituents independently selected from ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , by one radical selected from ^{-X 5 NR 12 C (O)} NR 14 R 12 and ^{-X 5 NR 12 C (NR 12} ) NR 14 R 12 Horizontal substituted, X ⁵ is a bond or (C _1-6) alkylene, R ¹² are each independently hydrogen, (C _1-6) alkyl or halo-substituted (C _1-6) alkyl, R ¹³ Is (C _1-6 ) alkyl or halo-substituted (C _1-6 ) alkyl, R ¹⁴ is C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl ( C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _{0 -6} ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl,
[116] R ¹ is hydrogen or (C _1-6 ) alkyl, R ² is hydrogen, cyano, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O ) OR ¹² , -X ⁵ R ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² where X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, or R ¹ and R ² together with the carbon atom to which they are attached are (C _3-8 ) cycloalkylene or It is (C _3-8) heterocycloalkyl to form a alkylene, heteroaryl, aryl, cycloalkyl in R ^2, heterocycloalkyl, cycloalkylene or heterocyclic cycloalkylene is optionally substituted with (C _1-6) alkyl , (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1-4 ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² ,- X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O ) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ and -X ⁵ C (O) R ¹³ independently selected from 1 to 3 radicals Substituted by X ⁵ , R ¹² and R ¹³ are as defined above,
[117] R ³ is —C (R ⁶ ) (R ⁶ ) X ⁶ , R ⁶ is hydrogen or (C _1-6 ) alkyl, X ⁶ is —X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O ) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² ,- X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C ( O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , wherein X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
[118] R ⁴ is -X ⁸ NR ¹² R ¹² , -X ⁸ NR ¹² C (O) R ¹² , -X ⁸ NR ¹² C (O) OR ¹² , -X ⁸ NR ¹² C (O) NR ¹² R ¹² ,- X ⁸ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁸ OR ¹² , -X ⁸ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁸ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁸ S (O) ₂ NR ¹² R ¹² , -X ⁸ NR ¹² S (O) ₂ R ¹² , -X ⁸ P (O ) (OR ¹² ) OR ¹² , -X ⁸ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁸ NR ¹² C (O) R ¹³ , -X ⁸ S (O ) R ¹³ , -X ⁸ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁸ OR ¹⁴ , -X ⁸ SR ¹⁴ , -X ⁸ S (O) R ¹⁴ , -X ⁸ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁸ OC (O) R ¹⁴ , -X ⁸ NR ¹⁴ R ¹² , -X ⁸ NR ¹² C (O) R ¹⁴ , -X ⁸ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁸ S (O) ₂ NR ¹⁴ R ¹² , -X ⁸ NR ¹² S (O) ₂ R ¹⁴ , —X ⁸ NR ¹² C (O) NR ¹⁴ R ¹² and X ⁸ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , X ⁸ is (C _1-6 ) alkylene, X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, provided that when X ³ is cyano and X ² is -OR ⁴ , where R ⁴ is -R ¹⁴ , then R ¹⁴ is (C _3-10 Cycloalkyl (C _1-6 ) alkyl, hetero (C _3-10 ) Cycloalkyl (C _1-3 ) alkyl, (C _6-10 ) aryl (C _1-6 ) alkyl, hetero (C _5-10 ) aryl (C _1-6 ) alkyl, (C _9-10 ) bicycloaryl (C _1-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _1-6 ) alkyl,
[119] R ¹⁵ is (C _6-10 ) aryl, hetero (C _5-10 ) aryl, (C _9-10 ) _bicycloaryl or hetero (C _8-10 ) _bicycloaryl ,
[120] R ¹⁷ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, (C _6-10 ) Aryl (C _1-6 ) alkyl, hetero (C _5-10 ) aryl (C _1-6 ) alkyl, (C _9-10 ) bicycloaryl (C _1-6 ) alkyl or hetero (C _8-10 ) ratio Cycloaryl (C _1-6 ) alkyl,
[121] R ¹⁸ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, (C _6-10 ) Aryl (C _1-6 ) alkyl, hetero (C _5-10 ) aryl (C _1-6 ) alkyl, (C _9-10 ) bicycloaryl (C _1-6 ) alkyl or hetero (C _8-10 ) ratio Cycloaryl (C _1-6 ) alkyl,
[122] R ¹⁹ and R ²⁰ together with the atoms to which they are attached form a (C _4-8 ) heterocycloalkylene wherein at least one of the ring atoms comprising the ring is a hetero atom selected from —NR ²¹ — and —O—, and the ring is is unsubstituted or is substituted by R ^1, R ¹ is as defined above, R ²¹ is ^{hydrogen, -C (O) oR 12,} -C (O) R 12, -C (O) NR 12 R 12, - S (O) ₂ NR ¹² R ¹² , -S (O) R ¹³ , -S (O) ₂ R ¹³ , -S (O) R ¹⁴ , -S (O) ₂ R ¹⁴ , -C (O) R ¹⁴ , -C (O) OR ¹⁴ , -C (O) NR ¹² R ¹² and -S (O) ₂ NR ¹⁴ R ^12, wherein R ¹² , R ¹³ and R ¹⁴ are as defined above,
[123] In R ³ , R ⁴ , R ¹⁵ , R ¹⁷ and R ¹⁸ , the alicyclic or aromatic ring system is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo- Substituted (C _1-4 ) alkyl, nitro, —X ⁵ NR ¹² R ¹² , —X ⁵ NR ¹² C (O) R ¹² , —X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C ( O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) 1 to 5 radicals independently selected from R ¹³ , -X ⁵ C (O) R ¹³ and -X ⁵ S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² in Emitter is further substituted by a selected one radical, R ³ and R ⁴ in the aliphatic moiety is unsubstituted or substituted with cyano, halo, ^{nitro, -NR 12 R 12, -NR 12} C (O) R 12, -NR ¹² C (O) OR ¹² , -NR ¹² C (O) NR ¹² R ¹² , -NR ¹² C (NR ¹² ) NR ¹² R ¹² , -OR ¹² , -SR ¹² , -C (O) OR ¹² ,- C (O) R ¹² , -OC (O) R ¹² , -C (O) NR ¹² R ¹² , -S (O) ₂ NR ¹² R ¹² , -NR ¹² S (O) ₂ R ¹² , -P ( O) (OR ¹² ) OR ¹² , -OP (O) (OR ¹² ) OR ¹² , -NR ¹² C (O) R ¹³ , -S (O) R ¹³ and -S (O) ₂ R ¹³ independently Further substituted by 1 to 5 radicals selected, wherein X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, provided that X ² is -OR ⁴ where R ⁴ is -R ¹⁴ or In the case of —NHR ¹⁸ , the aromatic ring system present in R ¹⁴ or R ¹⁸ is halo, (C _3-10 ) cycloalkyl, hetero (C _3-10 ) cycloalkyl, (C _6-10 ) aryl, hetero (C _5-10 ) unsubstituted by aryl, (C _9-10 ) _bicycloaryl or hetero (C _8-10 ) bicycloaryl High,
[124] Provided that only one bicyclic ring structure is present in R ³ , R ⁴ or R ¹⁵ .
[125] Compounds of Formula I, N-oxide derivatives thereof, prodrug derivatives thereof, protected derivatives thereof, individual isomers thereof and mixtures thereof, and compounds of Formula I, N-oxide derivatives thereof, prodrug derivatives thereof, protected Preference is given to pharmaceutically acceptable salts and solvates of derivatives, individual isomers thereof and mixtures of isomers thereof.
[126] Formula I
[127]
[128] In Formula I above,
[129] X ¹ is —NHC (R ¹ ) (R ² ) X ³ or —NHCH (R ¹⁹ ) C (O) R ²⁰ ,
[130] X ² is —OH, —OC (O) NR ¹² R ¹² or —OC (O) R ¹⁴ , wherein R ¹² and R ¹⁴ are as defined below,
[131] X ³ is cyano, -C (R ⁷ ) (R ⁸ ) R ¹⁶ , -C (R ⁶ ) (OR ⁶ ) ₂ , -CH ₂ C (O) R ¹⁶ , -CH = CHS (O) ₂ R ⁵ , -C (O) CF ₂ C (O) NR ⁵ R ⁵ , -C (O) C (O) NR ⁵ R ⁶ , -C (O) C (O) OR ⁵ , -C (O) CH ₂ OR ⁵ , -C (O) CH ₂ N (R ⁶ ) SO ₂ R ⁵ or -C (O) C (O) R ⁵ , R ⁵ is hydrogen, (C _1-4 ) alkyl, (C _{3 -10} ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _{5- 10} ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl, R ⁶ is When hydrogen, hydroxy or (C _1-6 ) alkyl or X ³ contains a —NR ⁵ R ⁶ group, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are hetero (C _3-10 ) cycloalkyl , Hetero (C _5-10 ) aryl or hetero (C _8-10 ) bicycloaryl, R ⁷ is hydrogen or (C _1-4 ) alkyl and R ⁸ is hydroxy or R ⁷ and R ⁸ Together form oxo, R ¹⁶ is hydrogen, -X ⁴ , -CF ₃ , -CF ₂ CF ₂ R ⁹ or —N (R ⁶ ) OR ⁶ , R ⁹ is hydrogen, halo, (C _1-4 ) alkyl, (C _5-10 ) aryl (C _0-6 ) alkyl or (C _5-10 Heteroaryl (C _0-6 ) alkyl,
[132] X ⁴ comprises a heteromonocyclic ring containing 4 to 7 ring atoms or a heterobicyclic ring system containing 8 to 14 ring atoms and carbocyclic ketone, iminoketone or thioketone derivatives thereof and,
[133] The alicyclic or aromatic ring system in R ⁵ , X ³ or X ⁴ is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _{1- 4} ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² ,- X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ and -X ⁵ 1 to 5 radicals independently selected from S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S ( O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S ( ^{_{O) 2 R 14, -X 5}} NR 12 C (O) NR 14 R 12 and ^{-X 5 NR 12 C (NR 12} ) NR 14 R ¹² selected from one LA Being further substituted by a knife, X ⁵ is a bond or (C _1-6) alkylene, R ¹² are each independently hydrogen, (C _1-6) alkyl or halo-substituted (C _1-6) alkyl R ¹³ is (C _1-6 ) alkyl or halo-substituted (C _1-6 ) alkyl, R ¹⁴ is (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _{3- 10} ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) ratio _Cycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl,
[134] R ¹ is hydrogen or (C _1-6 ) alkyl, R ² is hydrogen, cyano, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O ) OR ¹² , -X ⁵ R ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² where X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, or R ¹ and R ² together with the carbon atom to which they are attached are (C _3-8 ) cycloalkylene or It is (C _3-8) heterocycloalkyl to form a alkylene, heteroaryl, aryl, cycloalkyl in R ^2, heterocycloalkyl, cycloalkylene or heterocyclic cycloalkylene is optionally substituted with (C _1-6) alkyl , (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1-4 ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² ,- X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O ) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ and -X ⁵ C (O) R ¹³ independently selected from 1 to 3 radicals Substituted by X ⁵ , R ¹² and R ¹³ are as defined above,
[135] R ³ is —C (R ⁶ ) (R ⁶ ) X ⁶ , R ⁶ is hydrogen or (C _1-6 ) alkyl, X ⁶ is —X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O ) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² ,- X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C ( O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , wherein X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
[136] R ¹⁹ and R ²⁰ together with the atoms to which they are attached form a (C _4-8 ) heterocycloalkylene wherein at least one of the ring atoms comprising the ring is a hetero atom selected from —NR ²¹ — and —O—, and the ring is is unsubstituted or is substituted by R ^1, R ¹ is as defined above, R ²¹ is ^{hydrogen, -C (O) oR 12,} -C (O) R 12, -C (O) NR 12 R 12, - S (O) ₂ NR ¹² R ¹² , -S (O) R ¹³ , -S (O) ₂ R ¹³ , -S (O) R ¹⁴ , -S (O) ₂ R ¹⁴ , -C (O) R ¹⁴ , -C (O) OR ¹⁴ , -C (O) NR ¹² R ¹² and -S (O) ₂ NR ¹⁴ R ^12, wherein R ¹² , R ¹³ and R ¹⁴ are as defined above,
[137] In R ³ , R ⁴ , R ¹⁵ , R ¹⁷ and R ¹⁸ , the alicyclic or aromatic ring system is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo- Substituted (C _1-4 ) alkyl, nitro, —X ⁵ NR ¹² R ¹² , —X ⁵ NR ¹² C (O) R ¹² , —X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C ( O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) 1 to 5 radicals independently selected from R ¹³ , -X ⁵ C (O) R ¹³ and -X ⁵ S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² in Emitter is further substituted by a selected one radical, R ³ and R ⁴ in the aliphatic moiety is unsubstituted or substituted with cyano, halo, ^{nitro, -NR 12 R 12, -NR 12} C (O) R 12, -NR ¹² C (O) OR ¹² , -NR ¹² C (O) NR ¹² R ¹² , -NR ¹² C (NR ¹² ) NR ¹² R ¹² , -OR ¹² , -SR ¹² , -C (O) OR ¹² ,- C (O) R ¹² , -OC (O) R ¹² , -C (O) NR ¹² R ¹² , -S (O) ₂ NR ¹² R ¹² , -NR ¹² S (O) ₂ R ¹² , -P ( O) (OR ¹² ) OR ¹² , -OP (O) (OR ¹² ) OR ¹² , -NR ¹² C (O) R ¹³ , -S (O) R ¹³ and -S (O) ₂ R ¹³ independently Further substituted by 1 to 5 radicals selected, X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
[138] Provided that only one bicyclic ring structure is present in R ³ , R ⁴ or R ¹⁵ .
[139] Compounds of Formula I, N-oxide derivatives thereof, prodrug derivatives thereof, protected derivatives thereof, individual isomers thereof and mixtures thereof, and compounds of Formula I, N-oxide derivatives thereof, prodrug derivatives thereof, protected Preference is given to pharmaceutically acceptable salts and solvates of derivatives, individual isomers thereof and mixtures of isomers thereof.
[140] Formula I
[141]
[142] In Formula I above,
[143] X ¹ is —NHC (R ¹ ) (R ² ) C (O) C (O) NR ⁵ R ⁶ , R ⁵ is hydrogen, (C _1-4 ) alkyl, (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _{0- 6} ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl, R ⁶ is hydrogen, hydroxy or (C _1-6 ) alkyl, or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached hetero (C _3-10 ) cycloalkyl, hetero (C _5-10 ) aryl or hetero (C _8-10 ) bicycloaryl Forming,
[144] X ² is hydrogen,
[145] The alicyclic or aromatic ring system within X ¹ is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1-4 ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ and -X ⁵ S (O) ₂ R 1 to 5 radicals independently selected from ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , by one radical selected from ^{-X 5 NR 12 C (O)} NR 14 R 12 and ^{-X 5 NR 12 C (NR 12} ) NR 14 R 12 Horizontal substituted, X ⁵ is a bond or (C _1-6) alkylene, R ¹² are each independently hydrogen, (C _1-6) alkyl or halo-substituted (C _1-6) alkyl, R ¹³ Is (C _1-6 ) alkyl or halo-substituted (C _1-6 ) alkyl, R ¹⁴ is (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl,
[146] R ¹ is hydrogen, R ² is (C _1-6 ) alkyl,
[147] R ³ is —CH ₂ X ⁶ , X ⁶ is —X ⁵ NR ¹² S (O) ₂ R ¹² or —X ⁵ S (O) ₂ R ¹⁴ , and X ⁵ , R ¹² and R ¹⁴ are as defined above. Equal,
[148] The alicyclic or aromatic ring system in R ³ is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1-4 ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ C (O) R ¹³ And further substituted by 1 to 5 radicals independently selected from —X ⁵ S (O) ₂ R ¹³ , wherein the aliphatic residues in R ³ are unsubstituted or substituted with cyano, halo, nitro, —NR ¹² R ¹² , -NR ¹² C (O) R ¹² , -NR ¹² C (O) OR ¹² , -NR ¹² C (O) NR ¹² R ¹² , -NR ¹² C (NR ¹² ) NR ¹² R ¹² , -OR ¹² ,- SR ¹² , -C (O) OR ¹² , -C (O) R ¹² , -OC (O) R ¹² , -C (O) NR ¹² R ¹² , -S (O) ₂ NR ¹² R ¹² , -NR ¹² S (O) ₂ R ¹² , -P (O) (OR ¹² ) OR ¹² , By 1 to 5 radicals independently selected from -OP (O) (OR ¹² ) OR ¹² , -NR ¹² C (O) R ¹³ , -S (O) R ¹³ and -S (O) ₂ R ¹³ Further substituted, X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
[149] Provided that only one bicyclic ring structure is present in R ³ .
[150] X ¹ is —NHC (R ¹ ) (R ² ) X ³ or —NHCH (R ¹⁹ ) C (O) R ²⁰ , R ¹ is hydrogen or (C _1-6 ) alkyl, R ² is hydrogen, ( C _1-6 ) alkyl, -X ⁵ OR ¹² , -X ⁵ S (O) R ¹³ , -X ⁵ OR ¹⁴ , (C _6-10 ) aryl (C _0-6 ) alkyl or hetero (C _5-10 ) Aryl (C _0-6 ) alkyl, or R ¹ and R ² together with the carbon atom to which they are attached form (C _3-6 ) cycloalkylene or (C _3-6 ) heterocycloalkylene, and R ² Heteroaryl, aryl, cycloalkylene or heterocycloalkylene is unsubstituted or substituted by (C _1-6 ) alkyl or hydroxy, in particular X ³ is cyano, -C (O) R ¹⁶ ,- C (R ⁶ ) (OR ⁶ ) ₂ , -CH = CHS (O) ₂ R ⁵ , -CH ₂ C (O) R ¹⁶ , -C (O) CF ₂ C (O) NR ⁵ R ⁵ , -C (O) C (O) NR ⁵ R ⁶ , -C (O) C (O) OR ⁵ , -C (O) CH ₂ OR ⁵ , -C (O) CH ₂ N (R ⁶ ) SO ₂ R ⁵ Or —C (O) C (O) R ⁵ , R ⁵ , R ⁶ and R ¹⁶ are as defined above and R ¹⁹ and R ²⁰ together with the atoms to which they are attached (C _4-8 ) heterocycloalkylene Form , At least one of the ring atoms comprising the ring is a hetero atom selected from -NR ²¹ -and -O-, in particular the ring being unsubstituted or substituted by (C _1-6 ) alkyl or -X ⁵ C (O) OR ¹² R ²¹ is hydrogen, (C _1-6 ) alkyl, -X ⁵ C (O) R ¹² , -X ⁵ C (O) OR ¹² , -R ¹⁴ , -X ⁵ C (O) R ¹⁴ or- Preferred are compounds of the invention that are C (O) OR ¹⁴ .
[151] X ³ is cyano, -C (O) X ⁴ , -C (O) H, -C (O) N (CH ₃ ) OCH ₃ , -CH (OCH ₃ ) ₂ , -C (O) CF ₃ , -C (O) CF ₂ CF ₃ , -CH ₂ C (O) R ¹⁶ , (E) -2-benzenesulfonyl-vinyl, 2-dimethylcarbamoyl-2,2-difluoro-acetyl, 2- Oxo-2-pyrrolidin-1-yl-acetyl, 2-morpholin-4-yl-2-oxo-acetyl, 2-oxo-2-piperazin-1-yl-acetyl, 2- (4-methane Sulfonyl-piperazin-1-yl) -2-oxo-acetyl, 2- (1,1-dioxo-1λ ⁶ -thiomorpholin-4-yl) -2-oxo-acetyl, dimethylaminooxalyl, Tetrahydro-pyran-4-ylaminooxalyl, 2-morpholin-4-yl-ethylaminooxalyl, cyclopentyl-ethyl-aminooxalyl, pyridin-3-ylaminooxalyl, phenylaminooxalyl, 1 -Benzoyl-piperidin-4-ylaminooxalyl, 1-benzylcarbamoyl-methanoyl, 1-benzyloxy (oxalyl), 2-benzyloxy-acetyl, 2-benzenesulfonylamino-ethanoyl, 2 -Oxo-2-phenyl-ethanoyl, 3H-oxazole-2-carbonyl, 5-trifluoromethyl-oxazole-2-carbonyl, 3-triflu Rhomethyl- [1,2,4] oxadiazole-5-carbonyl, 2,2,3,3,3-pentafluoro-propionyl, hydroxyaminooxalyl, oxalyl, 2- (1, 3-dihydro-isoindol-2-yl) -2-oxo-acetyl, benzothiazol-2-ylaminooxalyl, 2-oxo-ethyl, 2-oxazol-2-yl-2-oxo-ethyl Or 2-benzooxazol-2-yl-2-oxo-ethyl, in particular X ⁴ is 1H-benzoimidazol-2-yl, pyrimidin-2-yl, benzoxazol-2-yl, benzothiazole -2-yl, pyridazin-3-yl, 3-phenyl- [1,2,4] oxadiazol-5-yl, 5-ethyl- [1,3,4] -oxazol-2-yl, 5-ethyl- [1,2,4] -oxazol-3-yl or 3-ethyl- [1,2,4] oxadiazol-5-yl, R ¹⁹ and R ²⁰ are the atoms to which they are attached Together 1-benzoyl-3-oxo-piperidin-4-yl, 1-benzoyl-3-oxo-azpan-4-yl, 2-methyl-4-oxo-tetrahydro-furan-3-yl, 2 -Ethyl-4-oxo-tetrahydro-furan-3-yl, 4-oxo-1- (1-phenyl-methanoyl) -pyrrolidin-3-yl or (S) -2-acetoxy-4- The present invention is oxo-azetidin-3-yl Compounds are particularly preferred.
[152] X ³ is —C (O) X ⁴ , in particular 1H-benzoimidazol-2-ylcarbonyl, pyrimidin-2-ylcarbonyl, benzoxazol-2-ylcarbonyl, benzothiazol-2-yl Carbonyl, pyridazin-3-ylcarbonyl, 3-phenyl- [1,2,4] oxadiazole-5-ylcarbonyl, 5-ethyl- [1,2,4] -oxadiazole-3 -Ylcarbonyl, 5-ethyl [1,3,4] -oxadiazole-2-ylcarbonyl or 3-ethyl- [1,2,4] oxadiazole-5-ylcarbonyl, or -C (O) C (O) NR ⁵ R ⁶ , in particular 2-oxo-2-pyrrolidin-1-yl-acetyl, 2-morpholin-4-yl-2-oxo-acetyl, 2-oxo-2-piperazine -1-yl-acetyl, 2- (4-methanesulfonyl-piperazin-1-yl) -2-oxo-acetyl, 2- (1,1-dioxo-1λ ⁶ -thiomorpholin-4-yl ) -2-oxo-acetyl, dimethylaminooxalyl, tetrahydro-pyran-4-ylaminooxalyl, 2-morpholin-4-yl-ethylaminooxalyl, cyclopentyl-ethyl-aminooxalyl, pyridine- Most preferred compounds of the invention are 3-ylaminooxalyl, phenylaminooxalyl or 1-benzoyl-piperidin-4-ylaminooxalyl Particularly preferred.
[153] X ² is —OH or —OC (O) NR ¹² R ¹² , wherein each R ¹² is independently hydrogen or (C _1-6 ) alkyl and the alkyl is unsubstituted or substituted by hydroxy or methoxy , -OC (O) NHR ¹⁴ , wherein R ¹⁴ is (C _3-10 ) cycloalkyl (C _0-6 ) alkyl or hetero (C _3-10 ) cycloalkyl (C _1-3 ) alkyl OC (O) R ¹⁴ , wherein R ¹⁴ is —NR ²² R ²³ , and R ²² and R ²³ together with the nitrogen atom to which they are attached form a hetero (C _4-6 ) cycloalkyl ring, the ring being unsubstituted or Hydroxy), in particular X ² is -OH, dimethylcarbamoyloxy, morpholin-4-ylcarbonyloxy, piperidin-1-yl-carbonyloxy, pyrrolidine-1- Mono-carbonyloxy, pyrimidin-2-ylamino, tetrahydro-pyran-4-ylamino, 1-methyl-piperidin-4-ylamino, N- (2-methoxyethyl) -N- ( Tetrahydro-pyran-4-yl) amino, isopropylamino and cyclohexylamino, 4-tert-butoxycarbonyl-piperazin-1-yl-oxy-carbonyl, N- benzyl-carbamoyl-oxy, pyrrolidin-1-yl-oxy-carbonyl, N, N- dimethyl-carbamoyl-oxy, P Ferridin-1-yl-carbonyloxy, 4-methanesulfonyl-piperazin-1-yl-carbonyloxy, 4-ethoxycarbonylpiperazin-1-ylcarbonyloxy, N-cyclohexyl-carba Moyloxy, N-phenyl-carbamoyloxy, N- (5,6,7,8-tetrahydro-naphthalen-1-yl) -carbamoyloxy, N-butyl-N-methyl-carbamoyloxy, N- Pyridin-3-yl-carbamoyloxy, N-isopropyl-carbamoyloxy, N-pyridin-4-yl-carbamoyloxy, N-cyanomethyl-N-methyl-carbamoyloxy, N, N-bis -(2-methoxy-ethyl) -carbamoyloxy, N-phenethyl-carbamoyloxy, piperazine-carbonyloxy, N-naphthalen-2-yl-carbamoyloxy, 4-benzyl-piperazine-1 -Carbamoyloxy, 4- (1-furan-2-yl-carbonyl) -piperazin-1-carbamoyloxy, thiomorpholin-4-yl-carbonyloxy, 1,1-dioxo-1λ ⁶ Thiomorpholin-4-yl) -Carbonyloxy, bis- (2-methoxy-ethyl) -carbamoyloxy, morpholin-4-ylcarbonyloxy, 2-methoxyethylcarbamoyloxy, diethylcarbamoyloxy, pyrrolidine-1 -yl-carbonyl-oxy, 2-hydroxyethyl carbamoyl oxy, tetrahydro-furan-2-ylmethyl-carbamoyl oxy, cyclopropyl carbamoyl-oxy, 3-tert-butyl-carbamoyl-oxy, 3-hydroxy-pyrrolidine -1-yl-carbonyloxy and carbamoyloxy, more particularly morpholin-4-ylcarbonyloxy, 2-methoxyethylcarbamoyloxy, diethylcarbamoyloxy, pyrrolidin-1-ylcarbonyloxy , 2-hydroxyethylcarbamoyloxy, tetrahydro-furan-2-ylmethylcarbamoyloxy, cyclopropylcarbamoyloxy, tert - butylcarbamoyloxy, 3-hydroxy-pyrrolidin-1-yl- Most particularly preferred are compounds of the invention that are carbonyloxy and carbamoyloxy.
[154] X ² is —NHR ¹⁵ where R ¹⁵ is (C _6-10 ) aryl, hetero (C _5-10 ) aryl, (C _9-10 ) _bicycloaryl or hetero (C _8-10 ) _bicycloaryl ) Or —NR ¹⁷ R ¹⁸ , wherein R ¹⁷ is hetero (C _3-10 ) cycloalkyl, R ¹⁸ is hydrogen, or R ¹⁷ and R ¹⁸ are independently (C _6-10 ) aryl (C _1-6 ) Alkyl or hetero (C _5-10 ) aryl (C _1-6 ) alkyl, wherein the alicyclic or aromatic ring system in R ¹⁵ , R ¹⁷ and R ¹⁸ is unsubstituted or (C _1-6 ) alkyl, Cyano, halo, nitro, halo-substituted (C _1-4 ) alkyl, -X ⁵ OR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁵ C ( O) NR ¹² R ¹² and -X ⁵ 1 to 5 radicals independently selected from NR ¹² S (O) ₂ R ¹² and / or -R ¹⁴ , -X ⁵ OR ¹⁴ and -X ⁵ C (O) NR ¹⁴ Further substituted by one radical selected from R ¹² , in particular X ² is 5-nitrothiazol-2-ylamino, 2-nitrophenylamino, pyrimidin-2-ylamino, tetrahydro-pyran-4 - Amino, N- (2-methoxyethyl) -N- (tetrahydro-pyran-4-yl) amino, 1-methyl-piperidin-4-ylamino, isopropylamino, di (thien-2-yl Preferred are compounds of the invention selected from methyl) amino or di (benzyl) amino.
[155] X ² is —OR ⁴ where R ⁴ is 4-methoxy-phenyl, 4′-hydroxymethyl-phenyl, methoxymethyl, phenyl-methanoyl, 1- (4-phenoxy-phenyl) -methanoyl , 3-biphenyl, 4-biphenyl, 1-biphenyl-4-yl-methanoyl, naphthalen-2-yl-methanoyl, benzo [1,3] dioxol-5-yl-methanoyl, (4 Methanesulfonylamino-phenyl) -methanoyl, benzo [b] thien-2-yl-methanoyl, 4'-chloro-4-biphenyl, 4-hydroxy-phenyl-methanoyl, 3-chloro-benzo [b] thien-2-yl-methanoyl, thien-2-yl-methanoyl, thien-3-yl-methanoyl, 3-chloro-thien-2-yl-methanoyl, 5-methyl-thien-2 -Yl-methanoyl, 4-methoxy-phenyl metanoyl, 4-trifluoromethoxy-phenyl metanoyl, 4-chloro-phenyl-methanoyl, 3-bromo-phenyl, cyclohexylmethyl, 3,4- Dimethoxy-phenyl-methanoyl, 3,4-difluorophenyl-methanoyl, 3-fluoro, 4-methoxy-phenyl-methanoyl, 4-fluorophenyl-methanoyl, 4-trifluoromethyl -Phenyl-methanoyl, 4-foam Ryl-phenyl-formyl, 3-formyl-phenyl-formyl, 4-methyl-pentanoyl, tetrahydro-pyran-4-ylmethyl 2-morpholin-4-yl-2-oxo-ethyl) Preferred are the compounds of the present invention.
[156] X ² is —OH, dimethylcarbamoyloxy, morpholin-4-ylcarbonyloxy, piperidin-1-yl-carbonyloxy, pyrrolidin-1-yl-carbonyloxy, pyrimidine-2- Monoamino, tetrahydro-pyran-4-ylamino, 1-methyl-piperidin-4-ylamino, N- (2-methoxyethyl) -N- (tetrahydro-pyran-4-yl) amino, Most particularly preferred are compounds of the invention selected from isopropylamino and cyclohexylamino.
[157] R ¹ is hydrogen or (C _1-6 ) alkyl, R ² is hydrogen, —X ⁵ OR ¹² , —X ⁵ R ¹² , (C _5-10 ) heteroaryl (C _0-6 ) alkyl, (C _{5 -10} ) aryl (C _0-6 ) alkyl, (C _5-10 ) cycloalkyl (C _0-6 ) alkyl, (C _5-10 ) heterocycloalkyl (C _0-6 ) alkyl or (C _1-6 ) Is alkyl, or R ¹ and R ² together with the carbon atom to which they are attached form (C _3-8 ) cycloalkylene or (C _3-8 ) heterocycloalkylene and heteroaryl, aryl, in R ² , Cycloalkyl, heterocycloalkyl, cycloalkylene or heterocycloalkylene is optionally selected by one to three radicals independently selected from (C _1-6 ) alkyl and hydroxy, in particular R ¹ is hydrogen or methyl, R ² is hydrogen, methoxymethyl, (C _1-6 ) alkyl, phenethyl, thien-2-yl or 5-methyl-furan-2-yl, or R ¹ and R ² together with the carbon atom to which they are attached Cyclopropylene, tetrahydro-pyran-4-ylene or Preference is given to compounds of the invention which form methyl-piperidin-4-ylene.
[158] R ³ is -CH ₂ X ⁶ , X ⁶ is -X ⁵ SR ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ R ¹³ , -X ⁵ C (O) R ¹³ , -X ⁵ OR ¹² , -X ⁵ SR ¹⁴ , -X ⁵ R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ and -X ⁵ C (O) NR ¹⁴ Is selected from R ¹² , X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, in particular R ³ is thiophen-2-sulfonyl-methyl, 3-chloro-2-fluoro-phenyl-methane- Sulfonyl-methyl, benzene-sulfonyl-methyl, phenyl-methane-sulfonyl-methyl, 2- (1,1-difluoro-methoxy) -phenyl-methane-sulfonyl-methyl, 2-benzene-sul Phenyl-ethyl, 2- (pyridine-2-sulfonyl) -ethyl, 2- (pyridine-4-sulfonyl) -ethyl, 2-phenyl-methanesulfonyl-ethyl, oxy-pyridin-2-yl-methane- Sulfonyl-methyl, prop-2-ene-1-sulfonyl-methyl, 4-methoxy-phenyl-methane-sulfonyl-methyl, p-tolyl-methane-sulfonyl-methyl, 4-chloro-phenyl- Methane-sulfonyl-methyl, o-tolyl-methane-sulfonyl-methyl, 3,5-dimethyl-phenyl-methane-sulfonyl-methyl, 4-trifluoro-methyl-phenyl-methane-sulfonyl-methyl, 4-tree Luoro-methoxy-phenyl-methane-sulfonyl-methyl, 2-bromo-phenyl-methane-sulfonyl-methyl, pyridin-2-yl-methane-sulfonyl-methyl, pyridin-3-yl-methane- Sulfonyl-methyl, pyridin-4-yl-methane-sulfonyl-methyl, naphthalen-2-yl-methane-sulfonyl-methyl, 3-methyl-phenyl-methane-sulfonyl-methyl, 3-trifluoro- Methyl-phenyl-methane-sulfonyl-methyl, 3-trifluoro-methoxy-phenyl-methane-sulfonyl-methyl, 4-fluoro-2-trifluoromethoxy-phenyl-methane-sulfonylmethyl, 2 -Fluoro-6-trifluoromethyl-phenylmethanesulfonylmethyl, 3-chloro-phenylmethanesulfonylmethyl, 2-fluoro-phenylmethanesulfonylmethyl, 2-trifluoro-phenylmethanesulfonylmethyl, 2-cyano-phenylmethanesulfonylmethyl, 4-tert-butyl-phenylmethanesulfonylmethyl, 2-fluoro-3-methyl-phenyl-methane-sulfonyl-methyl, 3-fluoro-phenylmethanesul Ponylmethyl, 4-fluoro-phenylmethane-sulfonylmethyl, 2-chloro-phenylmethanesulfonylmethyl, 2,5-difluoro- Phenylmethane-sulfonylmethyl, 2,6-difluoro-phenylmethanesulfonylmethyl, 2,5-dichloro-phenyl-methane-sulfonylmethyl, 3,4-dichloro-phenylmethanesulfonylmethyl, 2- ( 1,1-difluoro-methoxy) -phenyl-methanesulfonylmethyl, 2-cyano-phenyl-methane-sulfonyl-methyl, 3-cyano-phenylmethanesulfonylmethyl, 2-trifluoro- Methoxy-phenyl-methane-sulfonylmethyl, 2,3-difluoro-phenylmethanesulfonylmethyl, 2,5-difluoro-phenyl-methanesulfonylmethyl, biphenyl-2-ylmethanesulfonylmethyl , Cyclohexylmethyl, 3-fluoro-phenyl-methanesulfonylmethyl, 3,4-difluoro-phenyl-methanesulfonylmethyl, 2,4-difluoro-phenylmethanesulfonylmethyl, 2,4, 6-trifluoro-phenylmethanesulfonylmethyl, 2,4,5-trifluoro-phenylmethanesulfonylmethyl, 2,3,4-trifluoro-phenylmethanesulfonylmethyl, 2,3,5- Trifluoro-phenyl-methane-sulfonylmethyl, 2,5,6-trifluoro-phenylmethanesulfonylmethyl, 2-chloro-5-trifluoro-meth Phenylmethanesulfonylmethyl, 2-methyl-propane-1-sulfonyl, 2-fluoro-3-trifluoro-methylphenylmethanesulfonylmethyl, 2-fluoro-4-trifluoro-methylphenylmethanesulfonylmethyl , 2-fluoro-5-trifluoro-methyl-phenyl-methane-sulfonyl-methyl, 4-fluoro-3-trifluoro-methylphenylmethanesulfonylmethyl, 2-methoxy-phenyl-methanesulfonyl Methyl, 3,5-bis-trifluoromethyl-phenylmethanesulfonylmethyl, 4-difluoromethoxy-phenylmethanesulfonylmethyl, 2-difluoro-methoxy-phenyl-methanesulfonylmethyl, 3- Difluoromethoxy-phenylmethanesulfonylmethyl, 2,6-dichloro-phenylmethanesulfonylmethyl, biphenyl-4-ylmethanesulfonylmethyl, 3,5-dimethyl-isoxazol-4-ylmethanesulfonylmethyl , 5-chloro-thien-2-yl-methane-sulfonylmethyl, 2- [4- (1,1-difluoro-methoxy) -benzenesulfonyl] -ethyl, 2- [2- (1, 1-difluoro-methoxy) -benzenesulfonyl] -ethyl, 2- [3- (1,1-difluoro-methoxy) -benzenesulfonyl] -ethyl , 2- (4-trifluoromethoxy-benzenesulfonyl) -ethyl, 2- (3-trifluoromethoxy-benzenesulfonyl) -ethyl, 2- (2-trifluoro-methoxy-benzene-sul Phonyl) -ethyl, (cyanomethyl-methyl-carbamoyl) -methyl, biphenyl-3-ylmethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, 2-benzenesulfonyl-ethyl, Isobutylsulfanylmethyl, 2-phenylsulfanyl-ethyl, cyclohexylmethanesulfonylmethyl, 2-cyclohexyl-ethanesulfonyl, benzyl, naphthalen-2-yl, benzylsulfanylmethyl, 2-trifluoromethyl- Benzylsulfanylmethyl, phenylsulfanyl-ethyl, cyclopropyl-methanesulfonylmethyl, 5-bromo-thien-2-ylmethyl, 3-phenyl-propyl, 2,2-difluoro-3-phenyl-propyl , 3,4,5-trimethoxy-phenylmethanesulfonylmethyl, 2,2-difluoro-3-thien-2-yl-propyl, cyclohexylethyl, cyclohexylmethyl, tert - butylmethyl, 1 -Methylcyclohexylmethyl, 1-methylcyclopentylmethyl, 2,2-difluoro-3-phenylpropyl, 2,2-dimethyl-3- Phenylpropyl, 1-benzylcyclopropylmethyl, -X ⁵ S (O) ₂ R ¹³ and -X ⁵ S (O) ₂ R ¹⁴ , R ¹³ is alkyl, R ¹⁴ is phenyl, phenyl is unsubstituted Substituted compounds of the invention are preferred.
[159] R ³ is cyclohexylethyl, cyclohexylmethyl, tert - butylmethyl, 1-methylcyclohexylmethyl, 1-methylcyclopentylmethyl, 2,2-difluoro-3-phenylpropyl, 2,2-dimethyl- 3-phenylpropyl, 1-benzylcyclopropylmethyl, -X ⁵ S (O) ₂ R ¹³ or -X ⁵ S (O) ₂ R ¹⁴ , R ¹³ is alkyl, R ¹⁴ is phenyl, phenyl is substituted Preferred are compounds of the invention which are unsubstituted or substituted.
[160] The following table is intended to provide better guidance in carrying out the invention. However, it is not intended that the scope of the invention be limited thereto. One skilled in the art will combine O ^* , NH ^* or H ^* in the fractions (A1 to A62) shown in Table 1 to one methine carbon atom ( ^* CH ^* ) in the fractions (B1 to B93) shown in Table 2, A specific compound is selectively selected by binding a methine carbon atom ( ^* CH ^* or ^* CF ^* ) in the fractions (B1 to B93) shown in Table 2 to an acyl carbon atom (C ^* ) in the fraction (C1 intrinsic C91) shown in Table 3. It can manufacture.
[161]
[162]
[163]
[164]
[165]
[166]
[167]
[168]
[169]
[170]
[171]
[172] For convenience, the compounds of the present invention may be referred to as a combination of "A", "B" and "C" fractions. Thus, for example, the compound referred to as A7-B4-C13 is a combination product of group A7 in Table 1 and B4 in Table 2 and C13 in Table 3, ie pyrrolidine-1-carboxylic acid (R) -1- [ (S) -1- (1-Benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester to be.
[173] Further preferred compounds of formula (I) include:
[174] (R) -N-cyanomethyl-2-hydroxy-3-phenylmethanesulfonyl-propionamide;
[175] (R) -N- (1-cyano-1-thiophen-2-yl-methyl) -2-hydroxy-3-phenylmethanesulfonyl-propionamide;
[176] (R) -N- (1-cyano-1-thiophen-2-yl-methyl) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2- Hydroxy-propionamide;
[177] (R) -N-cyanomethyl-3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxy-propionamide;
[178] Morpholine-4-carboxylic acid (R) -1- (cyanomethyl-carbamoyl) -2-phenylmethanesulfonyl-ethyl ester;
[179] Morpholine-4-carboxylic acid (R) -1- (cyanomethyl-carbamoyl) -2- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester;
[180] (R)-(2-methoxy-ethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-phenylmethanesulfonyl-ethyl ester;
[181] (S) -diethyl-carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
[182] (S) -pyrrolidine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
[183] (S) -morpholine-4-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
[184] (S) -4-ethyl-piperazine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
[185] (S) -2-hydroxymethyl-pyrrolidine-1-carboxylic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
[186] (S)-(2,2,2-trifluoro-ethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
[187] (S)-(2-hydroxyethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
[188] (Tetrahydrofuran-2-ylmethyl) -carbamic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
[189] (S) -azetidine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
[190] (S) -cyclopropyl-carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
[191] (S) -piperidine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
[192] (S)-(2-methoxy-ethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethylester;
[193] (R) -3-hydroxy-pyrrolidine-1-carboxylic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
[194] (S) -3-hydroxy-pyrrolidine-1-carboxylic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
[195] (S) -morpholine-4-carboxylic acid 1- (cyanomethyl-carbamoyl) -3-cyclohexyl-propyl ester;
[196] Morpholine-4-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester;
[197] Morpholin-4-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2- [2- (1,1-di Fluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester;
[198] Morpholin-4-carboxylic acid (R) -1-[(S) -1- (1-benzothiazol-2-yl-methanoyl) -propylcarbamoyl] -2- [2- (1,1-di Fluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester;
[199] Pyrrolidine-1-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester;
[200] Dimethyl-carbamic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester;
[201] Morpholine-4-carboxylic acid (R) -1-[(S) -1- (1-benzylcarbamoyl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester;
[202] Morpholine-4-carboxylic acid (S) -1-[(S) -1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester;
[203] Morpholine-4-carboxylic acid (S) -1-[(S) -1- (5-ethyl- [1,3,4] oxadiazole-2-carbonyl) -propylcarbamoyl] -2-phenylmethane Sulfonyl-ethyl esters;
[204] (S) -2-{(R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxy-propanoylamino} -N-methoxy -N-methyl-butyramide;
[205] (R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -N-((S) -1-formyl-propyl) -2-hydroxy-propionamide ;
[206] (R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenyl-methanesulfonyl-propionamide;
[207] (S) -3- {3- [2- (1,1-Difluoro-methoxy) -phenylmethanesulfonyl] -propanoylamino} -2-oxo-pentanoic acid benzylamide;
[208] N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propyl] -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] Propionamide;
[209] N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -3-phenyl-propyl] -3-p-tolylmethanesulfonyl-propionamide;
[210] 3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- (1-ethyl-2,3-dioxo-3-pyrrolidin-1-yl-propyl) -propionamide;
[211] 3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- (1-ethyl-3-morpholin-4-yl-2,3-dioxo-propyl) -propionamide;
[212] 3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- (1-ethyl-2,3-dioxo-3-piperazin-1-yl-propyl) -propionamide;
[213] 3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- [3- (1,1-dioxo-1λ ⁶ -thiomorpholin-4-yl) -1-ethyl-2,3-di Oxo-propyl] -propionamide;
[214] 3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- [1-ethyl-3- (4-methyl-sulfonyl-piperazin-1-yl) -2,3-dioxo-propyl] Propionamide;
[215] 3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid dimethylamide;
[216] 3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid cyclopentyl-ethyl-amide;
[217] 3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid phenylamide;
[218] 3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid pyridin-3-ylamide;
[219] 3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid (tetrahydro-pyran-4-yl) -amide;
[220] 3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid (1-benzoyl-piperidin-4-yl) -amide;
[221] 3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid (2-morpholin-4-yl-ethyl) -amide;
[222] (R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -2- (2-nitro-phenylamino) -3-phenylmethanesulfonyl-propion amides;
[223] N- [1- (benzooxazole-2-carbonyl) -propyl] -3-phenylmethanesulfonyl-2- (pyrimidin-2-ylamino) -propionamide.
[224] (R) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -butyl] -2- (5-nitro-thiazol-2-ylamino) -3-phenyl Methanesulfonyl-propionamide;
[225] (2S) (4,4-Difluoro-2-hydroxy-5-phenyl-pentanoic acid (1 (S) -cyano-3-phenyl-propyl) -amide;
[226] N- (1 (S) -Cyano-3-phenyl-propyl) -2- (S)-(2-morpholin-4-yl-2-oxo-ethoxy) -4-phenyl-butyramide;
[227] N- (1- (S) -Cyano-3-phenyl-propyl) -2- (S) -fluoro-4-phenyl-butyramide;
[228] N- (1- (S) -cyano-3-phenyl-propyl) -2,2-difluoro-4-phenyl-butyramide;
[229] N- (1- (S) -Cyano-3-phenyl-propyl) -2- (S) -hydroxy-4-phenyl-butyramide;
[230] N- (1- (S) -Cyano-3-phenyl-propyl) -2- (R) -hydroxy-4-phenyl-butyramide;
[231] N- (1- (S) -cyano-3-phenyl-propyl) -2- (R) -methoxy-4-phenyl-butyramide;
[232] 2,2-difluoro-5-phenyl-pentanoic acid (1-cyano-cyclopropyl) -amide;
[233] N- (1- (S) -cyano-3-phenyl-propyl) -4-phenyl-butyramide;
[234] 2,2-difluoro-5-phenyl-pentanoic acid ((S) -1-cyano-3-phenyl-propyl) -amide;
[235] N- (4-cyano-1-ethyl-piperidin-4-yl) -3-cyclohexyl-propionamide;
[236] N- (4-cyano-1-ethyl-piperidin-4-yl) -3- (2-difluoromethoxy-phenylmethanesulfonyl) -propionamide;
[237] (S) -tert-butyl-carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
[238] (R) -carbamic acid 1- (cyanomethyl-carbamoyl) -2- (2-difluoromethoxy-phenylmethanesulfonyl) -ethyl ester;
[239] (S) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
[240] (R) -morpholine-4-carboxylic acid 1- (1-cyano-cyclopropylcarbamoyl) -2-phenylmethanesulfonyl-ethyl ester;
[241] (R) -morpholine-4-carboxylic acid 1- (4-cyano-tetrahydro-pyran-4-ylcarbamoyl) -2-phenylmethanesulfonyl-ethyl ester;
[242] 3-cyclohexyl-2-hydroxy-N- [1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propyl] -propionamide;
[243] (R) -N- [1- (benzothiazole-2-carbonyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide;
[244] (R) -N- [1- (benzothiazol-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide;
[245] (R) -N- [1- (benzothiazole-2-carbonyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide;
[246] (R) -N- [1- (benzothiazole-2-carbonyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide;
[247] (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide ;
[248] (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2- (1-methyl-piperidin-4-ylamino) -3-phenylmethanesulfonyl Propionamide;
[249] (R) -N-[(S) -1- (Benzooxazole-2-carbonyl) -butyl] -2- (bis-thiophen-2-ylmethyl-amino) -3-phenylmethanesulfonyl- Propionamide;
[250] (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide;
[251] (S) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2- (tetrahydro-pyran-4-ylamino) -3-thiophen-2-yl- Propionamide;
[252] (S) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-isopropylamino-3-thiophen-2-yl-propionamide;
[253] (R) -N- [1- (benzothiazol-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide;
[254] (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide ;
[255] (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide;
[256] (R) -N-[(S) -1- (benzooxazol-2-carbonyl) -butyl] -2-[(2-methoxy-ethyl)-(tetrahydro-pyran-4-yl)- Amino] -3-phenylmethanesulfonyl-propionamide;
[257] (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-cyclohexylamino-3-phenylmethanesulfonyl-propionamide;
[258] (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide;
[259] (1S) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2- (S) -fluoro-4-phenyl-butyramide;
[260] 2,2-difluoro-5-phenyl-pentanoic acid [(S) -1- (benzooxazole-2-carbonyl) -butyl] -amide;
[261] Morpholine-4-carboxylic acid (S) -1-[(S) -1- (benzooxazole-2-carbonyl) -propylcarbamoyl] -2-cyclohexyl-ethyl ester;
[262] Morpholine-4-carboxylic acid (S) -2-cyclohexyl-1-[(S) -1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propylcarbamoyl] -ethyl ester;
[263] Morpholine-4-carboxylic acid (S) -2-cyclohexyl-1-[(S) -1- (5-ethyl- [1,3,4] oxadiazole-2-carbonyl) -propylcarbamoyl] Ethyl esters;
[264] Morpholine-4-carboxylic acid (S) -2-cyclohexyl-1-[(S) -1- (5-phenyl- [1,3,4] oxadiazole-2-carbonyl) -propylcarbamoyl] Ethyl esters;
[265] Morpholine-4-carboxylic acid (S) -1-[(S) -1- (benzooxazole-2-carbonyl) -propylcarbamoyl] -3-cyclohexyl-propyl ester;
[266] 4- [4,4-dimethyl-2- (morpholine-4-carbonyloxy) -pentanoylamino] -3-oxo-azepane-1-carboxylic acid benzyl ester;
[267] (R) -N-[(S) -1- (Benzooxazole-2-carbonyl) -butyl] -3-cyclopropylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propion amides;
[268] (R) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2-cyclohexylamino-3-cyclopropylmethanesulfonyl-propionamide;
[269] (R) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2-cycloheptylamino-3-cyclopropylmethanesulfonyl-propionamide;
[270] (R) -3-phenylmethanesulfonyl-N-[(S) -3-phenyl-1- (thiazole-2-carbonyl) -propyl] -2- (tetrahydro-pyran-4-ylamino) Propionamide;
[271] (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -3-phenyl-propyl] -3-cyclopropylmethanesulfonyl-2- (tetrahydro-pyran-4-yl Amino) -propionamide;
[272] (R) -3-cyclopropylmethanesulfonyl-N- [1- (5-ethyl-1,2,4-oxadiazole-3-carbonyl) -propyl] -2- (tetrahydro-pyran-4 -Ylamino) -propionamide;
[273] (R) -3-phenylmethanesulfonyl-N- [1- (3-phenyl-1,2,4-oxadiazole-5-carbonyl) -propyl] -2- (tetrahydro-pyran-4- Monoamino) -propionamide;
[274] (R) -N- [1- (3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl) -propyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4 -Ylamino) -propionamide;
[275] {(R) -1- [1- (benzothiazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
[276] {(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
[277] {(S) -1-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-thiophen-2-yl-ethyl} -carbamic acid tertiary Butyl ester;
[278] {(R) -1- [1- (benzothiazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
[279] {(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
[280] {(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -carbamic acid tertiary- Butyl esters;
[281] (R) -1- {1- [hydroxy- (3-phenyl-1,2,4-oxadiazol-5-yl) -methyl] -propylcarbamoyl} -2-phenylmethanesulfonyl-ethyl) Carbamic acid tert-butyl ester;
[282] ((R) -2-cyclopropylmethanesulfonyl-1-{(S) -1-[(5-ethyl-1,2,4-oxadiazol-3-yl) -hydroxy-methyl] -propyl Carbamoyl} -ethyl) -carbamic acid tert-butyl ester;
[283] {(R) -1- [1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
[284] {(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -3-phenyl-propylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -car Chest acid tert-butyl ester;
[285] {(R) -1-[(S) -1- (hydroxy-thiazol-2-yl-methyl) -3-phenyl-propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid 3 Tert-butyl ester;
[286] {(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -carbamic acid tertiary- Butyl esters;
[287] (R) -1- {1- [hydroxy- (3-phenyl-1,2,4-oxadiazol-5-yl) -methyl] -propylcarbamoyl} -2-phenylmethanesulfonyl-ethyl) Carbamic acid tert-butyl ester;
[288] ((R) -2-cyclopropylmethanesulfonyl-1-{(S) -1-[(5-ethyl-1,2,4-oxadiazol-3-yl) -hydroxy-methyl] -propyl Carbamoyl} -ethyl) -carbamic acid tert-butyl ester;
[289] {(R) -1- [1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
[290] {(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -3-phenyl-propylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -car Chest acid tert-butyl ester;
[291] {(R) -1-[(S) -1- (hydroxy-thiazol-2-yl-methyl) -3-phenyl-propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid 3 Tert-butyl ester;
[292] (R) -2-phenylmethanesulfonyl-1-{(S) -1-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl) -hydroxy-methyl] -propylcarba Moyl} -ethyl) -carbamic acid tert-butyl ester;
[293] (R) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2- [cyclopropylmethyl- (tetrahydro-pyran-4-ylmethyl) -amino] -3-phenylmethanesul Ponyl-propionamide;
[294] (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide;
[295] (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide ;
[296] (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide;
[297] (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide;
[298] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino ) -Propionamide;
[299] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2- (1-methyl-piperidin-4-ylamino) -3- Phenylmethanesulfonyl-propionamide;
[300] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2- (bis-thiophen-2-ylmethyl-amino) -3-phenyl Methanesulfonyl-propionamide;
[301] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide;
[302] (S) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2- (tetrahydro-pyran-4-ylamino) -3-thiophene- 2-yl-propionamide;
[303] S) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-isopropylamino-3-thiophen-2-yl-propionamide;
[304] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide;
[305] (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide ;
[306] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino ) -Propionamide;
[307] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino ) -Propionamide;
[308] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-[(2-methoxy-ethyl)-(tetrahydro-pyran-4 -Yl) -amino] -3-phenylmethanesulfonyl-propionamide;
[309] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-cyclohexylamino-3-phenylmethanesulfonyl-propionamide;
[310] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide;
[311] N-cyanomethyl-3-cyclohexyl-propionamide;
[312] N-cyanomethyl-3- (2-difluoromethoxy-phenylmethanesulfonyl) -propionamide;
[313] 3- (3-cyclohexyl-propionylamino) -2-oxo-5-phenyl-pentanoic acid thiazol-2-ylamide;
[314] 3-cyclohexyl-N- (1-formyl-3-phenyl-propyl) -propionamide;
[315] 3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N-[(S) -1- (5-ethyl- [1,3,4] oxadiazole-2-carbonyl) -propyl]- Propionamide;
[316] N-[(S) -1- (benzooxazole-2-carbonyl) -propyl] -2- (2-cyano-phenylamino) -3-cyclohexyl-propionamide;
[317] N-cyanomethyl-3-cyclohexyl-2- (4-methoxy-phenoxy) -propionamide;
[318] 2-benzyloxy-N-cyanomethyl-3-cyclohexyl-propionamide;
[319] (R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -butyl] -2-benzyloxy-3-phenylmethanesulfonyl-propionamide;
[320] (R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -2-methoxymethoxy-3-phenylmethanesulfonyl-propionamide;
[321] (S) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -butyl] -2-hydroxy-3-phenyl-propionamide;
[322] (R) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propyl] -3-phenylmethanesulfonyl-2-triisopropylsilanyloxy-propionamide;
[323] (R) -N-[(S) -1- (1-benzothiazol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenylmethanesulfonyl-propionamide;
[324] (R) -2-hydroxy-3-phenylmethanesulfonyl-N-[(S) -1- (1-pyridazin-3-yl-methanoyl) -butyl] -propionamide;
[325] (S) -3-((R) -2-hydroxy-3-phenylmethanesulfonyl-propanoylamino) -2-oxo-pentanoic acid benzylamide;
[326] (R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -3- [2- (1,1-difluoro-methoxy) -phenyl Methanesulfonyl] -2-hydroxy-propionamide;
[327] (R) -N-[(S) -1- (1-Benzothiazol-2-yl-methanoyl) -propyl] -3- [2- (1,1-difluoro-methoxy) -phenyl Methanesulfonyl] -2-hydroxy-propionamide;
[328] (2R, 5S) -2- [2- (1,1-Difluoro-methoxy) -phenylmethanesulfonylmethyl] -6-ethoxy-5-ethyl-morpholin-3-one and their corresponding N-oxides, their prodrugs, their protected derivatives, their individual isomers and mixtures of their isomers, said compounds, their corresponding N-oxides, their prodrugs, their protected derivatives, these Pharmaceutically acceptable salts and solvates (eg hydrates) of the individual isomers of and mixtures of these isomers.
[329] Pharmacology and usability:
[330] The compounds of the present invention are selective inhibitors of cathepsin S and are useful in treating diseases in which cathepsin S activity contributes to the pathology and / or symptoms of the disease. For example, the compounds of the present invention include autoimmune diseases, asthma, including, but not limited to, pediatric diabetes, multiple sclerosis, vulgaris, graves' disease, myasthenia gravis, systemic lupus erythematosis, rheumatoid arthritis and Hashimoto's thyroiditis. It may be useful for the treatment of allergic diseases including but not limited to allogeneic immune responses, including but not limited to organ transplantation or tissue grafts.
[331] Cathepsin S can also be used to treat excess airway elastic tissue breakdown, pneumonia and cardiovascular disease, for example in diseases involving excess elastic tissue breakdown, such as chronic obstructive pulmonary disease (eg emphysema), bronchiolitis, asthma and bronchitis. Related to plug rupture and atherosclerosis. Since cathepsin S is involved in fibril formation, inhibitors of cathepsin S are used for the treatment of systemic hereditary disease.
[332] Cysteine protease inhibitory activity of the compounds of the present invention can be measured by methods known to those skilled in the art. In vitro assays suitable for measuring protease activity and inhibition thereof by test compounds are known. Typically, the assay measures protease induced hydrolysis of peptide based substrates. Detailed descriptions of assays for measuring protease inhibitory activity are given in the following enzyme assay examples.
[333] Administration and Pharmaceutical Compositions:
[334] In general, the compounds of formula (I) may be administered in therapeutically effective amounts either alone or in combination with one or more therapeutic agents through useful and acceptable methods known in the art. The therapeutically effective amount can vary depending on the severity of the disease, the age and relative health of the individual, the potency of the compound used and other factors. For example, a therapeutically effective amount of a compound of formula (I) may be about 1 μg / kg body weight / day to about 60 mg / kg body weight / day, and typically about 1 μg / kg / day to about 20 mg / kg / day. Thus, a therapeutically effective amount can be from about 80 μg / day to about 4.8 g / day, typically from about 80 μg / day to about 1.6 g / day in an 80 kg patient. In general, one skilled in the art can trust personal judgment and the techniques of this patent application to identify therapeutically effective amounts of compounds of formula (I) for the treatment of a given disease.
[335] The compounds of formula (I) can be administered as pharmaceutical compositions in one of the following routes: oral, systemic (eg transdermal, nasal or suppository) or parenteral (eg intramuscular, intravenous or subcutaneous). The composition may be in the form of tablets, pills, capsules, semisolids, powders, sustained releases, solutions, suspensions, elixirs, aerosols or other suitable compositions, generally in the form of a compound of formula (I) together with one or more pharmaceutically acceptable excipients Is done. Acceptable excipients are nontoxic, assist in administration and do not adversely affect the therapeutic effect of the active ingredient. Such excipients may be solid, liquid or semisolid or, in the case of aerosol compositions, gaseous excipients which are generally useful in the art.
[336] Solid excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride and dry skim milk And the like. Liquid and semisolid excipients can be selected from water, ethanol, glycerol, propylene glycol and various oils such as petroleum, animal, vegetable or synthetic (eg peanut oil, soybean oil, inorganic oil and sesame oil, etc.). Preferred liquid carriers, in particular carriers for injections, include water, saline, aqueous dextrose and glycols.
[337] The amount of the compound of formula (I) in the composition can vary depending on the form of the formulation, the size of the unit dose, the type of excipient and other factors known to those skilled in the pharmaceutical sciences. In general, the composition of the compound of formula (I) for the treatment of a given disease comprises from 0.01 to 10% by weight, preferably from 0.3 to 1% by weight, with the remainder being the excipient (s). Preferably, the pharmaceutical composition is optionally administered in a single unit dose form for continuous treatment or in a single unit dose form where special relief of symptoms is desired. Representative pharmaceutical formulations containing a compound of Formula (I) are described in Example 15 below.
[338] chemistry:
[339] Process for preparing compound of formula (I):
[340] The compounds of the present invention can be prepared by applying the methods used to date or known methods described, for example, in R. C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.
[341] In the reactions described below, when described in the final product, reactive functional groups such as hydroxy, amino, imino, thio or carboxy groups can be protected to avoid unwanted involvement in the reaction. Conventional protection groups can be used according to standard methods (see T. W. Greene and P. G. M. Wuts in "Protectiveg Groups in Organic Chemistry" John Wiley and Sons, 1991).
[342] Compounds of formula (I) wherein X ¹ is -NHC (R ¹ ) (R ² ) X ³ can be prepared by the method shown in Scheme 1.
[343]
[344] In Scheme 1 above,
[345] X ² , X ³ , X ⁷ , R ¹ , R ² and R ³ are each as defined in formula I in the gist of the invention.
[346] Compounds of formula I can be prepared by condensing the acid of formula II with an amino compound of formula NH ₂ CR ¹ R ² X ³ . The condensation reaction can be carried out at ambient temperature by a suitable coupling agent such as benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP ^R ), tetra-methyluronium hexafluorophosphate (HATU), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), O-benzotriazol-1-yl-N, N, N ', N' - tetramethyluronium hexafluorophosphate (HBTU ), 1,3-dicyclohexylcarbodiimide (DCC), N-cyclohexylcarbodiimide or N'-methylpolystyrene, etc.) and optionally suitable catalysts (eg 1-hydroxybenzotriazole (HOBt), 1 -Hydroxy-7-azabenzotriazole (HOAt) or O- (7-azabenzotrizol-1-yl) -1,1,3,3 and the like) and non-nucleophilic bases such as triethylamine And N-methylmorpholine or the like, or a suitable combination thereof), and 5 to 10 hours are required to complete the reaction.
[347] If desired, the oxidation step can be carried out at an ambient temperature using an oxidizing agent (e.g., oxone ^R or metachloroperbenzoic acid, etc.) in a suitable solvent (e.g. methanol or water, or a suitable combination thereof), 16 to 24 hours are required to complete the reaction. A more detailed description of the synthesis of compounds of formula (I) by the method of Scheme 1 is given in Examples 1-10 below.
[348] Compounds of formula (I) wherein X ¹ is -NHX ⁴ can be prepared by the method shown in Scheme 2.
[349]
[350] In Scheme 2 above,
[351] X ² , X ⁴ , X ⁷ and R ³ are each as defined in formula (I) in the gist of the invention.
[352] Compounds of formula (I) can be prepared by condensing an acid of formula (II) with an amino compound of formula NH ₂ X ⁴ . The condensation reaction can be carried out at ambient temperature by a suitable coupling agent such as benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP ^R ), O- (7-azabenzotrizol-1-yl)- 1,1,3,3, tetra-methyluronium hexafluorophosphate (HATU), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), O-benzotriazole-1 -Yl-N, N, N ', N' - tetramethyluronium hexafluorophosphate (HBTU), 1,3-dicyclohexylcarbodiimide (DCC), N-cyclohexylcarbodiimide and N'- Methylpolystyrene, etc.) and optionally suitable catalysts such as 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt, etc.) and non-nucleophilic bases such as triethylamine And N-methylmorpholine or the like, or a suitable combination thereof), 5 to 10 hours are required to complete the reaction.
[353] If desired, the oxidation step is carried out at an ambient temperature in an appropriate solvent (e.g. methanol or water, or a suitable combination thereof), for example oxone Or metachloroperbenzoic acid, etc.), and 16 to 24 hours are required to complete the reaction.
[354] Compounds of formula I, wherein X ² is -OR ⁴ , can be prepared by reacting a compound of formula 3 with a compound of formula R ⁴ L according to the method according to Scheme 3.
[355]
[356] In Scheme 3 above,
[357] L is an exit group,
[358] X ¹ , R ³ and R ⁴ are as defined in the summary of the invention.
[359] A more detailed description of the synthesis of compounds of formula (I) in the manner described above is given in Example 4 below.
[360] Compounds of formula I, wherein X ² is —NHR ¹⁵ may be prepared by reacting a compound of formula 4 with a compound of formula R ¹⁵ L according to Scheme 4.
[361]
[362] In Scheme 4 above,
[363] L is an exit group,
[364] X ¹ , R ³ and R ¹⁵ are as defined in the subject matter of the invention.
[365] A more detailed description of the synthesis of compounds of formula (I) by the process described above is given below.
[366] Additional Processes for the Preparation of Compounds of Formula (I)
[367] Compounds of formula (I) may be prepared as pharmaceutically acceptable acid addition salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, pharmaceutically acceptable base addition salts of compounds of formula (I) can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of compounds of formula I are shown in the definition of this patent application. Alternatively, the salt forms of the compounds of formula (I) can be prepared using salts of the starting materials or intermediates.
[368] The free acid or free base form of the compound of formula (I) can be prepared from the corresponding base addition salt or acid addition salt form. For example, in the acid addition salt form, the compound of formula I can be converted to the corresponding free base by treatment with a suitable base such as ammonium hydroxide solution and sodium hydroxide and the like. Compounds of formula (I) in the form of base addition salts can be converted to the corresponding free acids by treatment with a suitable acid, such as hydrochloric acid.
[369] N-oxides of compounds of formula (I) can be prepared by methods known to those skilled in the art. For example, N-oxides can be used to prepare an oxidized form of a compound of formula I in an inert organic solvent such as a halogenated hydrocarbon such as dichloromethane at about 0 ° C., such as trifluoroperacetic acid, Maleic acid, perbenzoic acid, peracetic acid or meta-chloroperoxybenzoic acid). Alternatively, N-oxides of compounds of formula I can be prepared from N-oxides of suitable starting materials.
[370] Compounds of formula (I) in their unoxidized form may be used in a suitable inert organic solvent (e.g. acetonitrile, ethanol or aqueous dioxane, etc.) at 0-80 ° C. for reducing agents (e.g. sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, Sodium borohydride, phosphorus trichloride or phosphorus tribromide, etc.) to prepare from N-oxides of compounds of formula (I).
[371] Prodrug derivatives of the compounds of formula I can be prepared by methods known to those skilled in the art . See Saulnier et al . ( 1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985]. For example, suitable prodrugs may be prepared by reacting an underivatized compound of formula I with a suitable carbamylating agent, such as 1,1-acyloxyalkylcarbon chloride or para-nitrophenyl carbonate, for example. .
[372] Protected derivatives of compounds of formula I can be prepared by methods known to those skilled in the art. Detailed description of a suitable technique to generate and removal of the protective group are to be found in reference: TW Greene, Protecting Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons, Inc. 1999].
[373] Compounds of the invention are conveniently prepared or formed as solvates (eg hydrates) during the course of the invention. Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous / organic solvent mixture using organic solvents such as dioxin, tetrahydrofuran or methanol.
[374] The compound of formula (I) reacts a racemic mixture of compounds with an optically active dissolving agent to form pairs of diastereomeric compounds, separate diastereomers, and then recover the optically pure enantiomers as individual stereoisomers. It can manufacture. Decomposition of the enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of formula (I), but dissociable complexes are preferred (eg crystalline diastereomeric salts). Diastereomers have distinct physical properties (eg melting point, boiling point, solubility or reactivity) and can be easily separated by the advantage of these differences. Diastereoisomers may be separated by chromatography or preferably by separation / degradation techniques based on solubility differences. Optically pure enantiomers are recovered with the disintegrant in a practical manner that does not result in racemization. A more detailed description of techniques suitable for the resolution of stereoisomers of compounds from racemic mixtures can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
[375] In summary, the compounds of formula (I)
[376] (A) reacting a compound of Formula II with a compound of Formula NH ₂ CR ¹ R ² X ³ , wherein R ¹ , R ² and X ³ are as defined in the subject matter of Formula I to
[377] (B) reacting a compound of Formula II with a compound of Formula NH ₂ X ⁴ , wherein X ⁴ is as defined in the subject matter of the invention with respect to Formula I, or
[378] (C) reacting a compound of Formula 3 with a compound of Formula R ⁴ L, wherein L is a leaving group and R ⁴ is as defined in the subject matter of Formula I to
[379] (D) reacting a compound of formula 4 with a compound of formula R ¹⁵ L, wherein L is a leaving group and R ¹⁵ is as defined in the subject matter of formula (I) with respect to formula (I)
[380] (E) optionally converting the compound of formula I into a pharmaceutically acceptable salt,
[381] (F) optionally converting the salt form of the compound of formula I to the non-salt form,
[382] (G) optionally converting the unoxidized form of the compound of formula (I) into a pharmaceutically acceptable N-oxide,
[383] (H) optionally converting the N-oxide form of the compound of Formula I to its non-oxidized form,
[384] (I) optionally, from a mixture of isomers to individual isomers of the compound of formula (I),
[385] (J) optionally converting the underivatized compound of Formula I into a pharmaceutical prodrug derivative,
[386] (K) optionally, a method comprising converting a prodrug derivative of a compound of formula (I) to its underivatized form.
[387]
[388]
[389]
[390] In Formulas II, 3 and 4 above,
[391] R ³ , R ⁴ and X ¹ are as defined in the subject matter of formula (I).
[392] The invention is further illustrated, but is not limited to, the following examples which illustrate the preparation of compounds (Examples) and intermediates (reference examples) of the formulas (I) and (II) according to the invention.
[393] LC / MS-Methods:
[394] LC / MS (Method A):
[395] Mass Spectrometer (MS)-LCT Time-of-Flight (Micromass UK Ltd) Serial No. KA014
[396] Ionization Mode: Electrospray (Positive Ion)
[397] Scan: Tof MS (full scan m / z 100-1200, sum for 0.4 sec at 50 Hz / scan) Centroid mode
[398] Liquid Chromatograph (LC): Hewlett Packard HP1100 Series Dual Pump (Serial # US80301343) and Degasser (Serial # JP73008973)
[399] Mobile phase:
[400] A = water + 0.05% TFA (trifluoroacetic acid) buffer
[401] B = acetonitrile + 0.05% TFA buffer
[402] Gradient: 5% B to 100% B, 5 minutes
[403] Column: Hypersil BDS C-18, 3μ, 4.6mm x 50mm Reversed Phase
[404] Injection volume: 5 μl
[405] Flow rate: 1 ml / min column and UV detector, flow rate separation after UV detector, 0.75 ml / min ELS detector and 0.25 ml / min mass spectrometer.
[406] Secondary detector:
[407] (i) Hurek Packard Model HP1100 Series UV Detector (Serial # JP73704703) Wavelength = 220 nm
[408] (ii) Sedere (France) Model SEDEX 75 Evaporative Light Scattering (ELS) Detector (Serial # 9970002A)
[409] Temperature = 46 ° C, nitrogen pressure = 4bar
[410] Autosampler / injector: Gilson model 215 liquid handler, equipped with model 819 injection valve (serial # 259E8280)
[411] LC / MS (Method B):
[412] Same as Method A, gradient: 5% B to 90% B 3 minutes, 90% B to 100% B 2 minutes
[413] LC / MS (Method C):
[414] Mass Spectrometer (MS)-LCT Flight Time (Micromass UK Ltd) Serial No. KA014
[415] Ionization Mode: Electrospray (Positive Ion)
[416] Scan: Tof MS (full scan m / z 100-1200, sum for 0.4 sec at 50 Hz / scan) Centroid mode
[417] Liquid Chromatograph (LC): Hewlett Packard HP1100 Series Binary Pump (Serial # US80301343) and Degasser (Serial # JP73008973)
[418] Mobile phase:
[419] A = water + 0.1% formic acid buffer
[420] B = acetonitrile + 0.1% formic acid buffer
[421] Gradient: 5% B to 90% B 3 minutes, 90% B to 100% B 2 minutes
[422] Column: Phenomenex Synergi C-18, 2μ, 4.mm x 20mm Reversed Phase
[423] Injection volume: 5 μl
[424] Flow rate: 1 ml / min column and UV detector, flow rate separation after UV detector, 0.75 ml / min ELS detector and 0.25 ml / min mass spectrometer.
[425] Secondary detector:
[426] (i) Hurek Packard Model HP1100 Series UV Detector (Serial # JP73704703) Wavelength = 220 nm
[427] (ii) France Model Cedex 75 Evaporative Light Scattering (ELS) Detector (Serial # 9970002A)
[428] Temperature = 46 ° C, nitrogen pressure = 4bar
[429] Autosampler / injector: Gilson model 215 liquid handler, equipped with model 819 injection valve (serial # 259E8280)
[430] Reference Example 1
[431] (a) (R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxypropionic acid
[432]
[433] (R) -2-tert - butoxycarbonylamino-3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -propionic acid (5.19) in CH ₂ Cl ₂ (20 ml) The solution of g) is treated with trifluoroacetic acid (20 ml) at room temperature. After 2 hours, the reaction mixture is concentrated under reduced pressure. The white solid obtained is dissolved in 1M H ₂ SO ₄ (100 ml) and dioxane (30 ml). The solution is cooled to 0 ° C. and NaNO ₂ (1.95 g in 50 ml of water) is added with stirring for 1 hour. The reaction mixture is stirred overnight at ambient temperature. The product was concentrated, extracted with ethyl acetate, dried over anhydrous MgSO ₄ , filtered, concentrated and recrystallized with ethyl acetate to give (R) -3- [2- (1,1-difluoro-meth). Methoxy) -phenylmethanesulfonyl] -2-hydroxy-propionic acid (2.36 g) is obtained.
[434] (b) (R) -2-hydroxy-3-phenylmethanesulfonyl-propionic acid
[435]
[436] (R) -2-tert - butoxycarbonylamino-3- [henylmethanesulfonyl] -propionic acid to react in a similar manner as in Reference Example 1 (a) to (R) -2-hydroxy Prepare 3-Phenylmethanesulfonyl-propionic acid.
[437] Reference Example 2
[438] (R) -2-Amino-N-methoxy-N-methyl-butyramide
[439] To a solution of [(R) -1- (methoxy-methyl-carbamoyl) -propyl] -carbamic acid tert - butylester (4.92 g, 20 mmol) in CH ₂ Cl ₂ (20 ml) at room temperature TFA (10 ml) Add. After stirring for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure to give (R) -2-amino-N-methoxy-N-methyl-butyamide TFA salt (5.4 g).
[440] Reference Example 3
[441] (R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-triisopropylsilanyloxy-propionic acid
[442] (R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxypropionic acid (7.0 g, 22.58 mmol) in CH ₂ Cl ₂ (50 ml). React with 2,6-lutidine (12.09 g, 112.9 mmol) and triisopropylsilyl-trifluoro-methanesulfonate (20.75 g, 67.74 mmol) at -78 ° C for 1 hour. The reaction mixture is allowed to warm to room temperature and quenched by addition of saturated ammonium chloride solution. The product is extracted with ethyl acetate, the solvent is removed under reduced pressure, and the oil residue is dissolved in EtOH: THF: H ₂ O (3: 1: 1, 60 ml). Solid K ₂ CO ₃ (24 g) was added at room temperature, the mixture was stirred for 1 hour, then filtered, extracted with ethyl acetate, dried over anhydrous MgSO ₄ , filtered and concentrated to give (R) -3- [ 2- (1,1-Difluoro-methoxy) -phenylmethanesulfonyl] -2-triisopropylsilanyloxy-propionic acid (8.58 g) is obtained.
[443] The following intermediates were prepared following Reference Example 3:
[444] (R) -3-phenylmethanesulfonyl-2-triisopropylsilanyloxy-propionic acid.
[445] Reference Example 4
[446] 3- [2- (1,1-Difluoro-methoxy) -phenylmethanesulfonyl] -propionic acid
[447] [2- (1,1-Difluoro-methoxy) -phenyl] -methanethiol (190 mg, 1.0 mmol), acrylic acid (69 μl, 1.0 mmol), diisopropylethylamine (440 μl, 1.1 mmol) and A mixture of 0.5 ml of dimethylformamide is stirred at 45 ° C. for 4 hours. Diethyl ether (5 ml) and 1N HCl (2 ml) are added. The layers are separated and the organic layer is washed with 1N HCl (2 ml), then dried over MgSO ₄ and concentrated. The resulting oil is dissolved in methanol (5 ml), treated with an aqueous solution of oxone (921 mg, 1.5 mmol) (5 ml) and then stirred for 1 hour. Methanol is removed under reduced pressure and 20 ml of water are added. The mixture was extracted with 60 ml fractions of two ethyl acetate, dried over MgSO ₄ and concentrated to 3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -propionic acid (160 mg, 0.54 mmol, 54% yield).
[448] Reference Example 5
[449] 3-benzylsulfanyl-2- (2-nitro-phenylamino) -propionic acid
[450] S-benzylcysteine (1.06 g, 5.0 mmol), 2-fluoronitrobenzene (1.05 ml, 10.0 mmol), potassium carbonate (1.38 g, 10.0 mmol) and dimethylformamide (3 ml) were combined and 100 ° C. for 4 hours. Stir in The mixture is diluted with 40 ml of water and washed with 15 ml fractions of two diethyl ether. The aqueous layer is acidified to pH 4 with 6N HCl and extracted with 30 ml fractions of two ethyl acetate. The ethyl acetate layer is dried over MgSO ₄ and concentrated. Diethyl ether is added and decanted to afford 3-benzylsulfanyl-2- (2-nitro-phenylamino) -propionic acid (541 mg, 1.63 mmol, 33% yield).
[451] Reference Example 6
[452] (R) -3-benzylsulfanyl-2- (5-nitro-thiazol-2-ylamino) -propionic acid
[453] S-benzylcysteine (0.845 g, 4 mmol) and bis (trimethylsilyl) acetamide (3 ml, 16 mmol) are stirred at 75 ° C. for 1 hour. 2-bromo-5-nitrothiazole (837 mg, 4 mmol) and toluene (8 ml) are added and the mixture is stirred at 100 ° C. for 1 day. Toluene is removed under reduced pressure. The residue is stirred with 5 ml of dioxane and 5 ml of 1N HCl for 30 minutes. Dioxane is removed under reduced pressure, the mixture is basified with saturated NaHCO ₃ and washed with 50 ml of ethyl acetate. The aqueous layer was acidified with 6N HCl, extracted with two 25 ml portions of two ethyl acetate, dried over MgSO ₄ , concentrated and chromatographed using a gradient of 5-10% methanol in methylene chloride (R) -3 -Benzylsulfanyl-2- (5-nitro-thiazol-2-ylamino) -propionic acid (42.7 mg, 0.123 mmol, 3% yield) is obtained.
[454] Reference Example 7
[455] (2S) -4,4-Difluoro-2-hydroxy-5-phenyl-pentanoic acid
[456]
[457] To a suspension of (S) -2-amino-4,4-difluoro-5-phenyl-pentanoic acid (1.0 mmol, 230 mg) in water (3 ml) was added dropwise 2M sulfuric acid (about 3 ml) until the solid was dissolved. . A solution of sodium nitrite (1.5 equiv, 1.5 mmol, 104 mg) in 1 ml of water is added dropwise. The mixture is stirred at rt for 21 h and extracted twice with ether (30 ml). The organic layer is dried over MgSO ₄ and concentrated in vacuo to give (2S) -4,4-difluoro-2-hydroxy-5-phenyl-pentanoic acid (90 mg, 39%) as a white solid. ¹ H NMR (CDCl ₃ ) 7.3 (m, 5H), 5.6 (b, 1H), 4.61 (dd, J = 8.5, 2.9 Hz, 1H), 3.3 (t, J = 16.8 Hz, 2H), 2.45 (m , 1H), 2.2 (m, 2H).
[458] Reference Example 8
[459] 2- (S)-(2-Morpholin-4-yl-2-oxo-ethoxy) -4-phenyl-butyric acid
[460]
[461] Step (i): ethyl (2R) 2-hydroxy-4-phenylbutyrate (1.81 g, 8.71 mmol), 4-nitro-benzoic acid (1.1 equiv, 9.56 mmol, 1.598 g) and triphenyl in dry THF (80 ml) To a cooled (0 ° C.) solution of phosphine (1.1 equiv, 9.5 mmol, 2.50 g) was slowly added diethyl azodicarboxylate (1.1 equiv, 9.56 mmol, 1.67 g) under nitrogen. The mixture is stirred at 0 ° C. for 2.5 h and concentrated in vacuo. The residue is triturated with a mixture of ethyl acetate and heptane (1: 3, 150 ml) and the resulting solid is filtered off. The filtrate was concentrated in vacuo and purified on 110 g of silica gel, eluting with a mixture of ethyl acetate and heptane (1: 4, v / v) to give 4-nitro-benzoic acid (S) -1-ethoxycarbonyl-3-phenyl- Obtain propyl ester (3.4 g, 98%).
[462] Step (ii): Potassium carbonate in a cooled (0 ° C.) solution of 4-nitro-benzoic acid (S) -1-ethoxycarbonyl-3-phenyl-propyl ester (2.04 g, 5.83 mmol) in MeOH (30 ml). 1.5 equivalents, 8.75 mmol, 1.21 g) is added. The mixture is stirred for 5 minutes at 0 ° C., 1.5 hours at room temperature and concentrated in vacuo. The residue is partitioned between water (40 ml) and ethyl acetate (40 ml). The organic layer is dried over MgSO ₄ and concentrated in vacuo. The residue was purified on 35 g of silica gel eluting with dichloromethane to afford methyl- (2S) -2-hydroxy-4-phenyl-butyrate (933 mg, 82%) as a colorless oil.
[463] Step (iii): sodium hydride (60%, 1.5 equiv., 2.32 mmol, 92.7 mg) in a solution of methyl- (2S) -2-hydroxy-4-phenyl-butyrate (300 mg, 1.54 mmol) in anhydrous DMF (3 ml) ) After 5 minutes, 4- (2-chloroacetyl) morpholine (1.1 equiv, 1.69 mmol, 277 mg) is added and the mixture is stirred at rt for 24 h, then diluted with water (60 ml) and neutralized with 1N HCl. . The aqueous solution is extracted twice with ethyl acetate (40 ml). The organic layer is washed with water (50 ml), dried over MgSO ₄ and concentrated in vacuo. The residue was purified on 35 g of silica gel eluting with ethyl acetate and 5% MeOH in ethyl acetate to give (S) -2- (2-morpholin-4-yl-2-oxo-ethoxy) -4-phenyl-butyrate methyl Obtain ester (117 mg, 24%).
[464] Step (iv): (S) -2- (2-morpholin-4-yl-2-oxo-ethoxy) -4-phenyl-butyric acid methyl ester in MeOH: H ₂ O (2: 1 volume, 3 ml) To a solution of (117 mg, 0.36 mmol) add lithium hydroxide hydrate (2.0 equiv, 0.73 mmol, 30.5 mg). The mixture is stirred for 5 hours at room temperature, diluted with water (30 ml) and then extracted with ether (30 ml). The aqueous layer is acidified with 1N HCl and extracted twice with ether (30 ml). The acidic extract was dried over MgSO ₄ and concentrated in vacuo to afford (S) -2- (2-morpholin-4-yl-2-oxo-ethoxy) -4-phenyl-butyric acid (85.5 mg, 77%) as a colorless oil. Obtained as ¹ H NMR (CDCl ₃ ) 10.5 (b, 1H), 7.2 (m, 5H), 4.55 (d, J = 15.2 Hz, 1H), 4.14 (d, J = 15.2 Hz, 1H), 3.9 (dd, J = 7.6, 4.2 Hz, 1H), 4.6 (m, 6H), 3.4 (m, 2H), 2.8 (m, 2H), 2.3 (m, 1H), 2.15 (m, 1H). LC / MS 96% (M + l) 308.
[465] Reference Example 9
[466] (2S) -2-fluoro-4-phenyl-butyric acid
[467]
[468] Step (i): DAST (3.0 equiv, 14.4 mmol) in a cooled (0 ° C.) solution of methyl- (2R) -2-hydroxy-4-phenyl-butyrate (1.00 g, 4.80 mmol) in anhydrous dichloromethane (3 ml) , 2.32 g). The mixture is stirred at rt for 18 h, diluted with dichloromethane (20 ml) and then quenched carefully with saturated sodium bicarbonate (150 ml). The aqueous layer is extracted with dichloromethane (30 ml) and the organic layer is dried over MgSO ₄ and then concentrated in vacuo. The residue was purified on 90 g of silica gel, eluting with a mixture of dichloromethane and heptane (1: 2 then 1: 1, v / v) to give methyl-2S-fluoro-4-phenyl-butyrate (578 mg, 57%). Obtained as a pale yellow oil.
[469] Step (ii): Lithium hydroxide monohydrate (1.5 equiv., In a solution of methyl-2S-fluoro-4-phenyl-butyrate (577 mg, 2.74 mmol) in a mixture of MeOH: H ₂ O (2: 1 volume, 6 ml) 4.11 mmol, 173 mg) is added. The mixture is stirred at rt for 5 h and concentrated in vacuo. The residue is diluted with water (30 ml) and extracted with ether (20 ml). The aqueous layer is acidified with HCl and extracted with ether (30 ml). The acidic extract is dried over MgSO ₄ and concentrated in vacuo to give 2 (S) -fluoro-4-phenyl-butyric acid (486 mg, 97%) as a yellow oil. ¹ H NMR (CDCl ₃ ) 7.5 (b, 1H), 7.3 (m, 5H), 4.95 (ddd, J = 48.9, 6.9, 5.4Hz, 1H), 2.85 (m, 2H), 2.25 (m, 2H) . MS (CI) M + 1 183.
[470] Reference Example 10
[471] 2 (R) -methoxy-4-phenyl-butyric acid
[472]
[473] Step 1: Sodium hydride (60%, 2.0 equiv, 4.80 mmol, 192 mg) under nitrogen in a solution of ethyl- (2R) -2-hydroxy-4-phenyl-butyrate (500 mg, 2.40 mmol) in anhydrous DMF (4 mL). And methyl iodide (3.0 equiv, 7.20 mmol, 1.02 g) is added. The mixture is stirred at rt for 22 h, diluted with NH ₄ Cl (100 ml) and then extracted with ethyl acetate (50 ml). The organic layer is dried over MgSO ₄ and concentrated in vacuo. The residue was purified on 35 g of silica gel, eluting with ethyl acetate and heptane (1: 3, v / v) to afford (R) -2-methoxy-4-phenyl-butyric acid ethyl ester (480 mg, 90%).
[474] Step 2: Lithium hydroxide hydrate (2.0 equiv, 4.32) in a solution of (R) -2-methoxy-4-phenyl-butyric acid ethyl ester (480 mg, 2.8 mmol) in MeOH: H ₂ O (2: 1 volume, 9 ml) mmol, 181 mg) is added. The mixture is stirred at rt for 2.5 h, diluted with water (20 ml) and then extracted with ether (20 ml). The aqueous layer is acidified with 1N HCl and extracted twice with ether (30 ml). The combined extracts are dried over MgSO ₄ and concentrated in vacuo to give 2 (R) -methoxy-4-phenyl-butyric acid (426 mg, quant.) As a colorless solid. ¹ H NMR (CDCl ₃ ) 7.25 (m, 5H), 3.8 (dd, J = 6.8, 5.2 Hz, 1H), 3.48 (s, 3H), 2.78 (t, J = 7.3 Hz, 2H), 2.1 (m , 2H). MS (CI) M 194.
[475] Using benzyl bromide in step 2 to obtain the following intermediates according to Reference Example 10:
[476] 2 (R) -benzyloxy-4-phenyl-butyric acid.
[477] Reference Example 11
[478] (a) (R) -2-Amino-N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-propionamide
[479]
[480] {(R) -1- [1- (benzothiazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tertiary in dichloromethane (5 ml) The solution of -butyl ester (888 mg, 1.58 mmol, Example 27 (a)) is treated with trifluoroacetic acid (5 ml). The mixture is stirred at rt for 1 h and evaporated. The residue is dissolved in dichloromethane (20 ml) and the solution is treated with silycycle triamine (4.3 g, 16 mmol). The mixture is stirred for 2 hours at room temperature and filtered. Evaporate the filtrate to give the title compound (692 mg, 94%). LC / MS mlz = 562 (M + H).
[481] (b) (S) -2-amino-N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-thiophen-2-yl-propionamide
[482]
[483] {(S) -1-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-thiophen-2-yl-ethyl} -carbamic acid tertiary -Butyl ester (790 mg, 1.67 mmol, Example 27 (c)) and the reaction product flash flash chromatography on silica eluting with a mixture of ethyl acetate and methanol (9: 1, v / v) in the Reference Example. (S) -2-amino-N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-thiophene by reaction in a similar manner as in 11 (a) Obtain 2-yl-propionamide (415 mg, 66%). LC / MS mlz = 374 (M + H).
[484] (c) (R) -2-Amino-N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-propionamide
[485]
[486] {(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl Reaction was carried out in the same manner as in Reference Example 11 (a) using ester {908 mg, 1.66 mmol, Example 27 (b)} to give (R) -2-amino-N-[(S) -1- (benzo Oxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-propionamide (726 mg, 98%) is obtained. LC / MS mlz = 446 (M + H).
[487] (d) (R) -2-Amino-N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-propionamide
[488]
[489] {(R) -1- [1- (benzothiazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester {0.63 mmol , Example 27 (d)}, was reacted in a similar manner as in Reference Example 11 (a) to give (R) -2-amino-N- [1- (benzothiazol-2-yl-hydroxy- Methyl) -butyl] -3-phenylmethanesulfonyl-propionamide (212 mg, 73%) is obtained. LC / MS mlz = 462 (M + H).
[490] (e) (R) -2-amino-N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-propionamide
[491]
[492] {(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl (R) -2-amino-N-[(S) -1- (benzoxazole) by reaction in the same manner as in Reference Example 11 (a) using ester {1.7 mmol, Example 27 (e)} 2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-propionamide (726 mg, 98%) is obtained. LC / MS mlz = 446 (M + H).
[493] (f) (R) -2-amino-N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-cyclopropylmethanesulfonyl-propionamide
[494]
[495] {(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -carbamic acid tertiary- Reaction was carried out in the same manner as in Reference Example 11 (a) using butyl ester (450 mg, 0.88 mmol, Example 27 (f)) to give (R) -2-amino-N-[(S) -1- ( Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-cyclopropylmethanesulfonyl-propionamide (360 mg, 0.879 mmol, 100%) is obtained. LC / MS m / z = 410 (M + H).
[496] (g) (R) -2-Amino-N- {1- [hydroxy- (3-phenyl-1,2,4-oxadiazol-5-yl) -methyl] -propyl} -3-phenylmethane Sulfonyl-propionamide
[497]
[498] (R) -1- {1- [hydroxy- (3-phenyl-1,2,4-oxadiazol-5-yl) -methyl] -propylcarbamoyl} -2-phenylmethanesulfonyl-ethyl) -Carbamic acid tert-butyl ester {Example 27 (g)} to react in a similar manner as in Reference Example 11 (a) to (R) -2-amino-N- {1- [hydroxy- (3-phenyl-1,2,4-oxadiazol-5-yl) -methyl] -propyl} -3-phenylmethanesulfonyl-propionamide is obtained. LC / MS mlz = 481 (M + Na), 459 (M + H).
[499] (h) (R) -2-Amino-3-cyclopropylmethanesulfonyl-N-{(S) -1-[(5-ethyl-1,2,4-oxadiazol-3-yl) -hydr Roxy-methyl] -propyl} -propionamide
[500]
[501] ((R) -2-cyclopropylmethanesulfonyl-1-{(S) -1-[(5-ethyl-1,2,4-oxadiazol-3-yl) -hydroxy-methyl] -propyl Carbamoyl} -ethyl) -carbamic acid tert-butyl ester {Example 27 (i)} was used to react in a similar manner as in Reference Example 11 (a) to (R) -2-amino-3-cyclo Propylmethanesulfonyl-N-{(S) -1-[(5-ethyl-1,2,4-oxadiazol-3-yl) -hydroxy-methyl] -propyl} -propionamide is obtained. LC / MS mlz = 375 (M + H).
[502] (i) (R) -2-Amino-N- [1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-propionamide
[503]
[504] {(R) -1- [1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester {Example 27 (j)} to react in a similar manner as in Reference Example 11 (a) to give (R) -2-amino-N- [1- (benzooxazol-2-yl-hydroxy-methyl)- Butyl] -3-phenylmethanesulfonyl-propionamide is obtained. LC / MS mlz = 446 (M + H).
[505] (j) (R) -2-Amino-N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -3-phenyl-propyl] -3-cyclopropylmethanesulfonyl- Propionamide
[506]
[507] {(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -3-phenyl-propylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -car (R) -2-amino-N-[(S) -1- (benzo) was reacted in a similar manner as in Reference Example 11 (a) using the chest acid tert-butyl ester {Example 27 (k)} Oxazol-2-yl-hydroxy-methyl) -3-phenyl-propyl] -3-cyclopropylmethanesulfonyl-propionamide is obtained. LC / MS mlz = 472 (M + H).
[508] (k) (R) -2-Amino-N-[(S) -1- (hydroxy-thiazol-2-yl-methyl) -3-phenyl-propyl] -3-phenylmethanesulfonyl-propionamide
[509]
[510] {(R) -1-[(S) -1- (hydroxy-thiazol-2-yl-methyl) -3-phenyl-propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid 3 By reaction in a similar manner as in Reference Example 11 (a) using a tert-butyl ester {Example 27 (l)} (R) -2-amino-N-[(S) -1- (hydroxy- Thiazol-2-yl-methyl) -3-phenyl-propyl] -3-phenylmethanesulfonyl-propionamide is obtained.
[511] (l) (R) -2-amino-3-phenylmethanesulfonyl-N-{(S) -1-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl) -hydr Roxy-methyl] -propyl} -propionamide
[512]
[513] ((R) -2-phenylmethanesulfonyl-1-{(S) -1-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl) -hydroxy-methyl] -propyl Carbamoyl} -ethyl) -carbamic acid tert-butyl ester {Example 27 (s)} was used to react in a similar manner as in Reference Example 11 (a) to give (R) -2-amino-3-phenyl Methanesulfonyl-N-{(S) -1-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl) -hydroxy-methyl] -propyl} -propionamide is obtained.
[514] (m) 2-amino-1- (5-ethyl- [1,3,4] oxadiazol-2-yl-butan-1-ol
[515]
[516] {1-[(5-ethyl- [1,3,4] oxadiazol-2-yl) -hydroxy-methyl] -propyl} -carbamic acid tert - butyl ester (Reference Example 16) Reaction in a similar manner as in Reference Example 11 (a) affords 2-amino-1- (5-ethyl- [1,3,4] oxadiazol-2-yl-butan-1-ol.
[517] Reference Example 12
[518] [(S) -1- (hydroxy-thiazol-2-yl-methyl) -3-phenyl-propyl] -carbamic acid tert-butyl ester
[519]
[520] n-butyllithium (4.2 ml, 10.5 mmol, 2.5 M solution in hexane) is mixed with 16 ml of diethyl ether and the resulting solution is cooled to -78 ° C. 2-bromothiazole (1.64 g, 10 mmol) is dissolved in a mixture in 2 ml of diethyl ether and 1 ml of THF. The solution is added dropwise to the n-butyllithium solution. The resulting reaction mixture is stirred for 15 minutes. A solution of [(S) -1- (methoxy-methyl-carbamoyl) -3-phenyl-propyl] -carbamic acid tert-butyl ester (1.4 g, 4.3 mmol) in 20 ml of THF is added dropwise to the reaction mixture. Stirring is continued for 1 hour, and 50 ml of water is added to quench the reaction mixture. After warming to room temperature, the phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine and dried over magnesium sulfate. The solvent is evaporated under vacuum to afford 1.4 g of [(S) -3-phenyl-1- (thiazole-2-carbonyl) -propyl] -carbamic acid tert-butyl ester as a brown solid. [(S) -3-phenyl-1- (thiazole-2-carbonyl) -propyl] -carbamic acid tert-butyl ester (1.41 g, 4.1 mmol) was dissolved in 50 ml of ethanol and the solution was brought to 0 ° C. Cool. Sodium borohydride (155 mg, 4.1 mmol) is added and the reaction mixture is stirred for 90 minutes. Water is added and the aqueous phase is acidified by addition of 1M hydrochloric acid. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine and dried over magnesium sulfate. The solvent is evaporated under reduced pressure (1.32, 3.8 mmol, 88%). LC / MS mlz = 271 (M + H-isobutene), 249 (M + H-Boc).
[521] Reference Example 13
[522] (S) -2-amino-4-phenyl-1-thiazol-2-yl-butan-1-ol
[523]
[524] [(S) -1- (hydroxy-thiazol-2-yl-methyl) -3-phenyl-propyl] -carbamic acid tert-butyl ester (1.32 g, 3.8 mmol, Reference Example 12) was converted to dichloromethane. Dissolve in 10 ml. Trifluoroacetic acid is added and the resulting reaction mixture is stirred for 2 hours. The solvent is evaporated under reduced pressure and saturated sodium bicarbonate solution is added. The solution is extracted with ethyl acetate. The combined organic phases are washed with brine and dried over magnesium sulfate. The solvent was evaporated and the crude product was flash chromatography (eluted with ethyl acetate followed by 10% methanol in ethyl acetate) to give (S) -2-amino-4-phenyl-1-thiazol-2-yl-butane-1 -Ol (466 mg, 1.87 mmol, 49%) is obtained. LC / MS mlz = 249 (M + H).
[525] Reference Example 14
[526] (S) -2-amino-1- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -butan-1-ol
[527]
[528] A solution of Boc-3S-amino-2-hydroxypentanoic acid (2.00 g, 8.57 mmol) and cyclopropanecarboxamide oxime (1.03 g, 10.29 mmol) in 20 ml of dichloromethane was stirred at 0 ° C. with N-cyclo 1.25 equivalents of hexylcarbodiimide-N'-methyl polystyrene (1.70 mmol / g, 6.30 g, 10.72 mmol) are added in portions and the reaction mixture is warmed to 15 ° C. with stirring under nitrogen for 3 hours. The reaction mixture is filtered and the resin is washed with dichloromethane. Evaporate to dryness in vacuo [LC / MS m / z = 338 (M + H + Na)]. The residue is dissolved in 20 ml of tetrahydrofuran and heated in a microwave reactor at 160 ° C. for 3 minutes. Evaporate to dryness in vacuo [LC / MS m / z = 320 (M + H + Na)]. The residue is dissolved in 50 ml of dichloromethane and 50 ml of a solution of 50% trifluoroacetic acid in dichloromethane is added dropwise with stirring at room temperature. After 3 hours, the reaction is evaporated to dryness in vacuo and dissolved in 50 ml of dichloromethane. 3 equivalents of Silycyl Triamine-3 are added and the mixture is stirred overnight at room temperature. The mixture is filtered and washed with dichloromethane. Evaporation in vacuo affords 1.04 g (61% total) of (S) -2-amino-1- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -butan-1-ol. [LC / MS m / z = 198 (M + H)].
[529] Reference Example 15
[530] Ethyl-1,3,4-oxadiazole:
[531] A mixture of formic acid hydrazide (60 g, 1 mole), triethylorthopropionate (176.26 g, 1 mole) and p-toluenesulfonic acid (250 mg) is stirred at 120 ° C. for 12 hours. Ethanol was removed under vacuum and the residue was distilled under vacuum to yield 24 g of ethyl-1,3,4-oxadiazole. H ¹ NMR (DMSO-δ): 9.34 (1H, s), 2.86 (2H, q), 1.25 (3H, t).
[532] Reference Example 16
[533] {1-[(5-ethyl- [1,3,4] oxadiazol-2-yl) -hydroxy-methyl] -propyl} -carbamic acid tert-butyl ester
[534]
[535] To a stirred solution of ethyl-1,3,4-oxadiazole (4.66 g, 48 mmol, Reference Example 15) in THF (50 ml) was added n-BuLi (1.6 M solution in 30 ml of hexane) at −78 ° C. under N ₂ . Add it down. After 1 h, MgBr.Et ₂ O (12.38 g, 48 mmol) was added and the reaction mixture was warmed to −45 ° C. for 1 h and treated with 2-Boc-Nlu-aldehyde (3.2 g, 24 mmol) in THF (20 ml). do. The reaction mixture is stirred for 1 h, quenched with saturated NH ₄ Cl and then extracted with ethyl acetate. The organic layer is washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography to obtain {1 - [(5-ethyl- [1,3,4] oxadiazol-2-yl) -hydroxy-methyl] -propyl} -carbamic acid tert- Butyl ester (2.13 g) is obtained. ¹ H NMR (DMSO-δ): 6.65, 6.52 (1H, d, d, J = 9.2 Hz, J = 9.2 Hz, NH, diastereomer), 6.14, 5.95 (1H, d, d, J = 5.6 Hz , J = 5.6 Hz, OH, diastereomer), 4.758, 4.467 (1H, m, diastereomer), 3.7-3.55 (1H, m), 2.8 (2H, q), 1.33 (12H, t), 1.25 -1.21 (2H, m), 0.82 (3H, m). MS: 284.1 (M-1), 286 (M + l), 308 (M + Na).
[536] Reference Example 17
[537] (a) (S) -2-amino-1-benzooxazol-2-yl-butan-1-ol
[538]
[539] Step 1. Cool benzoxazole (600 mg, 5 mmol) in 20 ml THF and add isopropyl magnesium chloride (2M in THF, 2.5 ml, 5 mmol). After stirring at −5 ° C. for 1 hour, (S)-(1-formyl-propyl) -carbamic acid tert-butyl ester prepared according to Reference Example 15 in 10 ml of THF {561 mg, 3 mmol, Reference Example 18 (a)}. The reaction is stirred for 2 hours while warming to room temperature. The reaction is quenched with saturated ammonium chloride solution and excess THF solvent is removed. The residue is extracted with EtOAc, washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated. The crude residue is purified by chromatography to give 688 mg (75%) of product. LC-MS: 305.2 (M-1), 307.0 (M + l).
[540] Step 2. Mix (S)-[1- (benzooxazol-2-yl-hydroxy-methyl) -propyl] -carbamic acid tert - butyl ester (275 mg, 0.89 mmol) and MeCl ₂ (5 ml) TFA (1 ml) is added at room temperature. After stirring for 1 hour, the solvent and excess TFA are removed under vacuum to afford 260 mg of (S) -2-amino-1-benzooxazol-2-yl-butan-1-ol TFA salt.
[541] (b) (S) -2-amino-1-benzothiazol-2-yl-butan-1-ol
[542]
[543] Reaction in step 1 using benzothiazole in a similar manner as in Example 17 (a) to afford the (S) -2-amino-1-benzothiazol-2-yl-butan-1-ol TFA salt .
[544] (c) (S) -2-amino-1-benzooxazol-2-yl-pentan-1-ol
[545]
[546] In a similar manner as in Example 17 (a) using (S)-(1-formyl-butyl) -carbamic acid tert-butyl ester (561 mg, 3 mmol, Reference Example 18 (b)) in Step 1 Reaction gives (S) -2-amino-1-benzooxazol-2-yl-pentan-1-ol.
[547] (d) 2-amino-1-benzothiazol-2-yl-pentan-1-ol
[548]
[549] In Example 17 (a) using benzothiazole and (S)-(1-formyl-butyl) -carbamic acid tert-butyl ester (561 mg, 3 mmol, Reference Example 18 (b)) in Step 1 Reaction in a similar manner to yield 2-amino-1-benzothiazol-2-yl-pentan-1-ol.
[550] Reference Example 18
[551] (a) (S)-(1-formyl-propyl) -carbamic acid tert-butyl ester
[552] (S)-(+)-2-amino-1-butanol (50 g, 561 mmol) in 200 ml of water and 200 ml of dioxane was cooled to 0 ° C., NaOH (26.9 g, 673 mmol) and di-tert-butyl-di Mix with carbonate (146.96 g, 673 mmol). After addition, the reaction is allowed to warm to room temperature. The reaction mixture is stirred for 2 hours. After removal of the dioxane, the residue is extracted with EtOAc, washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated. Without further purification, the crude product (120 g) is used in the next step reaction.
[553] A solution of oxylyl chloride (40.39 g, 265 mmol) in 700 ml of MeCl ₂ is stirred and cooled to -60 ° C. Dimethylsulfoxide (51.7 g, 663 mmol) in 100 ml of MeCl ₂ was added dropwise. After 10 minutes, a solution of (S) -2-Boc-amino-1-butanol (50 g, 265 mmol) in 100 ml of MeCl ₂ was added dropwise at −70 ° C. The reaction mixture is warmed to -40 ° C for 10 minutes and cooled to -70 ° C. A solution of triethylamine (74.9 g, 742 mmol) in 100 ml of MeCl ₂ is added. The reaction mixture is warmed over 2 hours at room temperature. 100 ml of saturated sodium dihydrogen phosphate are added and the organic layer is washed with brine and then dried over MgSO ₄ . Remove the solvent to afford 45 g of (S)-(1-formyl-propyl) -carbamic acid tert-butyl ester. ¹ H NMR (DMSO-δ): 9.4 (1H, s), 7.29 (1H, br.), 3.72 (1H, m), 1.69 (2H, m), 1.4-1.2 (9H, s), 0.86 (3H , t).
[554] (b) reaction with (S)-(+)-2-amino-1-pentanol in a similar manner as in Reference Example 18 (a) to (S)-(1-formyl-butyl) -car Obtains chest acid tert-butyl ester.
[555] Reference Example 19
[556] (S) -3-Amino-2-hydroxy-pentanoic acid benzylamide
[557]
[558] Step 1. Dissolve (1S)-(2-cyano-1-ethyl-2-hydroxyethyl) carbamic acid tert-butyl ester (10 g, 46.7 mmol) in 1,4-dioxane (100 ml). Anisole (5 ml) is added and concentrated HCl (100 ml) is added. The mixture is heated at reflux for 24 h. The mixture is evaporated to dryness in vacuo and redissolved in 100 ml of water. The solution is washed with ether and neutralized with saturated aqueous NaHCO ₃ . Di-tert - butyl dicarbonate (10 g, 46 mmol) is added together with 1,4-dioxane (200 ml) and the mixture is stirred at ambient temperature for 24 hours. Dioxane is removed in vacuo and the remaining aqueous solution is washed with ether. The solution is acidified with 1N HCl and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over magnesium sulfate and evaporated to afford 3-tert-butoxycarbonylamino-2-hydroxy-pentanoic acid (4.5 g) as a yellow oil.
[559] Step 2. Combine 3-tert-butoxycarbonylamino-2-hydroxy-pentanoic acid (300 mg, 1.29 mmol) with EDC (400 mg, 2.1 mmol) and HOBt (400 mg, 2.6 mmol). A solution of benzylamine (0.22 ml) and 4-methylmorpholine (0.5 ml) in dichloromethyl (4 ml) is added in one portion. The mixture is stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (150 ml), the solution is washed with 1N aqueous HCl, water, saturated aqueous NaHCO ₃ and brine. The resulting mixture was dried over magnesium sulfate and evaporated in vacuo to give (S) -3-amino-2-hydroxy-pentanoic acid benzylamide (380 mg) as a white solid.
[560] Step 3. (S) -3-Amino-2-hydroxy-pentanoic acid benzylamide is dissolved in a mixture of TFA / dichloromethyl (1: 1, 6 ml), stirred for 1 hour and then evaporated to dryness. (3S) -3-Amino-2-hydroxy-pentanoic acid benzylamide is obtained as a TFA salt and used without further purification.
[561] Reference Example 20
[562] (S) -2-amino-1-oxazolo [4,5-b] pyridin-2-yl-butan-1-ol
[563]
[564] Step 1. A mixture of 2-amino-3-hydroxy pyridine (25 g, 227 mmol), triethylorthoformate (75 ml) and p-toluenesulfonic acid (61 mg) is heated at 140 ° C. for 8 hours. Excess triethylorthoformate is removed under vacuum. The product is crystallized from ethyl acetate to give 22.5 g of pyridyloxazole. H ¹ NMR (DMSO-δ): 9.26 (1H, s), 8.78 (1H, d), 8.45 (1H, d), 7.7 (1H, dd); MS: 120.8 (M + 1).
[565] Step 2. Pyridyloxazole (600 mg, 5 mmol) in 30 ml THF is cooled to 0 ° C. and isopropanyl magnesium chloride (2M in THF, 2.5 ml, 5 mmol) is added. After stirring at 0 ° C. for 1 hour, (S)-(1-formyl-propyl) -carbamic acid tert-butyl ester (573 mg, 3 mmol, Reference Example 18) in 20 ml of THF is added. The ice bath is removed and the reaction is allowed to warm to room temperature. The reaction mixture is stirred for 2 hours and quenched with saturated ammonium chloride solution. Excess THF is removed and the residue is extracted with EtOAc, washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated. The crude residue is purified by chromatography to give [1- (hydroxy-oxazolo [4,5-b] pyridin-2-yl-methyl) -propyl] -carbamic acid tert - butyl ester (383 mg). . ¹ H NMR (DMSO-δ): 8.42 (1H, m), 8.18 (1H, m), 7.3 (1H, m), 6.8, 6.6 (1H, dd, d, OH, diastereoisomeric), 6.3, 6.02 (1H, d, d, NH, diastereoisomers), 4.82, 4.5 (1H, m, m, diastereoisomers), 1.8-1.3 (2H, m), 1.2, 1.05 (9H, s, s , Diastereoisomers), 0.89 (3H, m). MS: 306.2 (M-1), 308.6 (M + l).
[566] Step 3. Stirring of [1- (hydroxy-oxazolo [4,5-b] pyridin-2-yl-methyl) -propyl] -carbamic acid tert - butyl ester (12 g, 100 mmol) in THF (300 ml) To the solution is added dropwise n-BuLi (1.6M solution in 62.5 ml of hexane) at −78 ° C. under N ₂ . After 1 h, MgBr.Et ₂ O (25.8 g, 100 mmol) was added and the reaction mixture was warmed to −45 ° C. for 1 h and 2-Boc-amino-butyl-aldehyde (11.46 g, 60 mmol) in THF (50 ml) To be processed. The reaction mixture is stirred for 1 h, quenched with saturated NH ₄ Cl and then extracted with ethyl acetate. The organic layer is washed with brine, dried over MgSO ₄ and concentrated. The residue is purified by silica gel column chromatography to give 2-Boc-amino-1- (5-pyridyloxazol-2-yl) -1-butanol (14.1 g).
[567] Step 4. 2-Boc-amino-1- (5-pyridyloxazol-2-yl) -1-butanol (311 mg, 1 mmol) and MeCl ₂ (5 ml) were mixed and TFA (1 ml) was added at room temperature. do. After stirring for 1 hour, the solvent and excess TFA are removed under vacuum to yield 355 mg of 2-amino-1-oxazolo [4,5-b] pyridin-2-yl-butan-1-ol TFA salt.
[568] Reference Example 21
[569] (S) -2-amino-1- (3-phenyl- [1,2,4] oxadiazol-5-yl) -butan-1-ol
[570]
[571] 3-tert - butoxycarbonylamino-2-hydroxy-pentanoic acid (500 mg, 2.14 mmol) with EDC (600 mg, 3.14 mmol), HOBt (600 mg, 3.92 mmol) and N-hydroxy-benzamidine ( 292 mg, 2.14 mmol). Dichloromethyl (10 ml) is added and 4-methylmorpholine (1 ml) is added. The mixture is stirred at ambient temperature for 16 hours. After dilution with ethyl acetate (200 ml), the solution is washed with water (30 ml), saturated aqueous NaHCO ₃ and brine, dried over MgSO ₄ and then evaporated in vacuo. The crude product is dissolved in pyridine (10 ml) and heated at 80 ° C. for 15 hours. Pyridine is evaporated in vacuo and the residue is purified by flash chromatography on silica gel (eluant: ethyl acetate) to give 290 mg (0.83 mmol). Oxadiazole (145 mg, 0.41 mmol) is dissolved in CH ₂ Cl ₂ (4 ml) and TFA (4 ml) is added. After stirring for 1 hour, the mixture was evaporated to dryness to afford (S) -2-amino-1- (3-phenyl- [1,2,4] oxadiazol-5-yl) -butan-1-ol do.
[572] Reference Example 22
[573] (R) -2-tert-butoxycarbonylamino-3-cyclopropylmethanesulfonyl-propionic acid
[574]
[575] Step 1. Sodium hydroxide (2.16 g, 54 mmol) was dissolved in 27 ml of water and the solution was (R) -2-tert-butoxycarbonylamino-3-mercapto-propionic acid (8.2 g, 37 mmol) in 54 ml of methanol. Is added to the suspension. After the clear solution is formed, bromomethyl-cyclopropane (5 g, 37 mmol) is added and the resulting reaction mixture is stirred for 3 days. Methanol is removed under reduced pressure. The residue is treated with 200 ml of 1 M hydrochloric acid and extracted three times with 200 ml of dichloromethane. The combined organic phases are washed with brine and dried over magnesium sulfate. The solvent is evaporated under reduced pressure to afford 2-3-butoxycarbonylamino-3-cyclopropylmethylsulfanyl-propionic acid (7.94 g).
[576] Step 2. Dissolve sodium hydroxide (2.32 g, 58 mmol) in 75 ml of water. 2-3-butoxycarbonylamino-3-cyclopropylmethylsulfanyl-propionic acid (7.94 g, 29 mmol) is added. A solution of oxone in 100 ml of water is slowly added. The pH is adjusted to 3 by addition of sodium bicarbonate and the reaction mixture is stirred for 30 minutes. Extract three times with 200 ml of ethyl acetate. The combined organic phases are washed with 100 ml brine and dried over magnesium sulfate. Remove the solvent to afford (R) -2-tert-butoxycarbonylamino-3-cyclopropylmethanesulfonyl-propionic acid (4.64 g, 15 mmol, 31%).
[577] Reference Example 23
[578] (S) -2-Amino-1- (5-ethyl-1,2,4-oxadiazol-3-yl) -butan-1-ol trifluoro-acetic acid salt
[579]
[580] Step 1. Cool a solution of (2-cyano-1-ethyl-2-hydroxy-ethyl) -carbamic acid tert-butyl ester (1, 9.53 g, 44 mmol) in methanol (80 ml), Continuous treatment with hydroxylamine hytrochloride (3.05, 44 mmol) in methanol (80 ml) and 25% sodium methoxide (10.2 ml) in methanol (10.2 ml). Stir at 0 ° C. for 5 minutes, remove the cold bath and then stir the reaction mixture at room temperature for 5 hours. Methanol is evaporated under reduced pressure and the crude product is partitioned between ethyl acetate and water. The organic layer is separated, dried (MgSO ₄ ) and then evaporated under reduced pressure to yield a yellow oil. Purification by MPLC, eluting with a mixture of ethyl acetate-heptane, yielded {(S) -1- [hydroxy- (N'-hydroxycarbamimidoyl) -methyl] -propyl} -carbamic acid tert-butyl ester ( 3.5 g) is obtained as a white solid. MS: M (H ⁺ ) 248.
[581] Step 2. {(S) -1- [Hydroxy- (N'-hydroxycarbamimidoyl) -methyl] -propyl} -carbamic acid tert-butyl ester in dioxane (5 ml) (525 mg, 2.16 mmol) , A mixture of propionic anhydride (0.3 ml, 2.37 mmol) is heated in a microwave (Smith Creator, S00219) at 150 ° C. for 35 minutes. The crude product was evaporated under reduced pressure and purified by flash column chromatography to afford {(S) -1-[(5-ethyl-1,2,4-oxadiazol-3-yl) -hydroxy-methyl]- Propyl} -carbamic acid tert-butyl ester (0.8 g, 67%) is obtained as a yellow solid. ¹ H NMR (CDCl ₃ ): 4.88-4.80 (2H, m), 4.01-3.84 (1H, 2 broad m), 3.64-3.45 (1H, 2bs), 2.95-2.86 (2H, dq, J = 4.2 Hz, 7.6 Hz), 1.73-1.62 (1H, m), 1.6-1.32 (13H, m), 1.02-0.94 (3H, q, J = 7.5 Hz). MS: 304 (M + 1).
[582] Step 3. {(S) -1-[(5-ethyl-1,2,4-oxadiazol-3-yl) -hydroxy-methyl] -propyl} -carbamic acid tertiary in dichloromethane (3 ml) Butyl ester (214 mg, 0.75 mmol) was treated with trifluoroacetic acid at room temperature for 3 hours. The solvent was evaporated under reduced pressure to give (S) -2-amino-1- (5-ethyl-1,2,4-oxadiazol-3-yl) -butan-1-ol trifluoro-acetic acid salt (0.3 g ) Is obtained as a brown oil. ¹ H NMR (CDCl ₃ ): 7.9-7.4 (3H, 2bs), 5.07 & 5.24 (1H, 2xd, J = 3.5 Hz & 5.5 Hz), 3.8-3.6 (1H, 2bs), 2.96-2.87 (2H, dq , J = 2.4 Hz, 7.5 Hz), 1.8-1.4 (2H, m), 1.40-1.34 (3H, dt, J = 1.4 Hz, 7.5 Hz), 1.06-0.98 (3H, dt, J = 7.5 Hz, 10.5 Hz). MS: 186 (M + 1).
[583] Example 1
[584] (a) (R) -N-cyanomethyl-2-hydroxy-3-phenylmethanesulfonyl-propionamide (Compound 4)
[585]
[586] DMF (5 ml) was converted to 2-hydroxy-3-phenylmethanesulfonyl-propionic acid [200 mg, 0.82 mmol, Reference Example 1 (b)], EDC (300 mg, 1.57 mmol), HOBt (300 mg, 1.96 mmol) and amino. To a mixture of acetonitrile hydrochloride (200 mg, 2.1 mmol) is added. 4-methylmorpholine (0.5 ml) is added and the mixture is stirred at ambient temperature for 2 hours. The mixture is diluted with ethyl acetate (200 ml) and washed with 1N HCl, brine, saturated aqueous NaHCO ₃ and brine, then dried over MgSO ₄ and evaporated in vacuo. (R) -N-cyanomethyl-2-hydroxy-3-phenylmethanesulfonyl-propionamide is crystallized from ethyl acetate / hexanes to give 154 mg (0.55 mmol). ¹ H NMR: (DMSO) 8.89-8.77 (m, 1 H), 7.46-7.37 (m, 5 H), 6.71-6.62 (m, 1 H), 4.60-4.45 (m, 3 H), 4.17-4.08 (m, 2 H) ), 3.39-3.28 (m, 2 H). MS: (M ⁺ +1) 283.
[587] (b) (R) -N- (1-cyano-1-thiophen-2-yl-methyl) -2-hydroxy-3-phenylmethanesulfonyl-propionamide (Compound 7)
[588]
[589] Similar to Example 1 (a) using (R) -2-hydroxy-3-phenylmethanesulfonyl-propionic acid [Reference Example 1 (b)] and DL-α-amino-2-thiopheneacetic acid Reaction is carried out to give (R) -N- (1-cyano-1-thiophen-2-yl-methyl) -2-hydroxy-3-phenylmethanesulfonyl-propionamide. ¹ H NMR (DMSO): 9.55 (d, J = 6.5 Hz, 1H), 7.58 (d, J = 5.21 Hz, 1H), 7.42-7.39 (m, 5H), 7.23 (m, 1H), 7.05 (dd , J = 3.51Hz, J = 5.21Hz, 1H), 6.58 (dd, J = 3.45Hz, J = 6.66Hz, 1H), 6.41 (s, 1H), 4.59-4.50 (m, 3H), 3.29 (s , 2H). MS: 362.6 (M ⁻¹ ), 365 (M ⁺¹ ).
[590] (c) (R) -N- (1-cyano-1-thiophen-2-yl-methyl) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] 2-Hydroxy-propionamide (Compound 8)
[591]
[592] (R) -3- [2- (1,1-Difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxy-propionic acid [Reference Example 1 (a)] and DL-α-amino- Reaction was carried out in a similar manner as in Example 1 (a) using 2-thiophenacetic acid to give (R) -N- (1-cyano-1-thiophen-2-yl-methyl) -3- [2- (1,1-Difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxy-propionamide is obtained. ¹ H NMR (CD ₃ Cl): δ 7.6-7.2 (m, 7H), 7.01 (t, J = 73.6 Hz, 1H), 6.62 (s, 1H), 6.21 (d, J = 8.15, 1H), 4.71 -4.67 (m, 1H), 4.46 (s, 2H), 3.68 (s, 2H), 3.22-3.18 (m, 1H). MS: 428.6 (M-1), 453 (M + 23).
[593] (d) (R) -N-cyanomethyl-3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxy-propionamide (Compound 17)
[594]
[595] Example 1 was prepared using (R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxypropionic acid [Reference Example 1 (a)]. Reaction was carried out in a similar manner as in a) to (R) -N-cyanomethyl-3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxypropionamide To obtain. ¹ H NMR (DMSO): 8.81 (t, J = 5.67 Hz, 1H), 7.55-7.4 (m, 2H), 7.35-7.2 (m, 2H), 7.13 (t, J = 73.68 Hz, 1H), 6.62 (d, J = 6.67 Hz, 1H), 4.58 (s, 2H), 4.52-4.45 (m, 1H), 4.12 (d, J = 5.94 Hz, 2H), 3.45-3.4 (m, 2H). MS: 347.4 (M-1), 371 (M + 23).
[596] Example 2
[597] Morpholine-4-carboxylic acid (R) -1- (cyanomethyl-carbamoyl) -2-phenylmethanesulfonyl-ethyl ester (Compound 6)
[598]
[599] A phosgene solution (0.77 ml, 1.93 M, in toluene) is added to CH ₂ Cl ₂ (5 ml) and cooled to 0 ° C. under nitrogen. Quinoline (0.12 ml, 1.0 mmol) was added, followed by (R) -N-cyanomethyl-2-hydroxy-3-phenylmethanesulfonyl-propionamide [100 mg, 0.354 mmol, Example 1 (a)]. do. The mixture is stirred at ambient temperature for 3 hours. Morpholine (1 mmol) was added and stirring continued for 3 hours. The mixture is diluted with ethyl acetate (200 ml) and washed continuously with 1N HCl, brine, saturated aqueous NaHCO ₃ and brine. The product was dried over MgSO ₄ , evaporated in vacuo and then crystallized from ethyl acetate / hexane solution to morpholine-4-carboxylic acid (R) -1- (cyanomethyl-carbamoyl) -2-phenylmethanesulfonyl-ethyl Ester (85 mg; 0.215 mmol) is obtained. ¹ H NMR: (DMSO) 8.99-8.88 (m, 1H), 7.46-7.37 (m, 5H), 5.42-5.32 (m, 1H), 4.60-4.45 (m, 2H), 4.20-4.13 (m, 2H) ), 3.70-3.28 (m, 10 H). MS: (M ⁺ +1) 396.
[600] Example 3
[601] (a) Morpholine-4-carboxylic acid (R) -1- (cyanomethyl-carbamoyl) -2- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester (Compound 31)
[602]
[603] (R) -N-cyanomethyl-3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxy-propionamide [100 mg, 0.287 mmol, Example 1 (d)] is dissolved in CH ₂ Cl ₂ (2 ml). Pyridine (32.4 μl, 0.4 mmol) and trichloromethylchloroformate (36.2 μl, 0.3 mmol) are added. The mixture is stirred at ambient temperature for 3 hours. Morpholine (0.5 ml) is added and stirring is continued for 3 hours. The mixture is diluted with ethyl acetate (200 ml) and washed with 1N HCl, brine, saturated aqueous NaHCO ₃ and brine. The product was dried over MgSO ₄ , evaporated in vacuo and then crystallized from a solution of ethyl acetate / hexanes to give morpholine-4-carboxylic acid (R) -1- (cyanomethyl-carbamoyl) -2- [2- ( 1,1-difluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester (60 mg; 0.130 mmol) is obtained. ¹ H NMR: (DMSO) δ8.95 (t, J = 5.2 Hz, 1H), 7.51-7.44 (m, 2H), 7.32-7.22 (m, 2H), 7.14 (t, J _{H, F} = 73 Hz, 1H), 5.39-5.35 (m, 1H), 4.67-4.53 (m, 2H), 4.19-4.15 (m, 2H), 3.83-3.28 (m, 10H). MS: (M ⁺ +1) 462.
[604] (b) (R)-(2-methoxy-ethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-phenylmethanesulfonyl-ethyl ester
[605]
[606] In Example 3 (a) using (R) -N-cyanomethyl-2-hydroxy-3-phenylmethanesulfonyl-propionamide [Example 1 (a)] and 2-methoxyethylamine Reaction in a similar manner affords (R)-(2-methoxy-ethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-phenylmethanesulfonyl-ethyl ester. ¹ H NMR: (DMSO) 8.91 (t, J = 5.6 Hz, 1H), 7.64 (t, J = 5.6 Hz, 1H), 7.40-7.32 (m, 5H), 5.30-5.25 (m, 1H), 4.59 -4.50 (m, 2H), 4.17-4.13 (m, 2H), 3.58 (dd, J = 9.2 Hz, J = 14.8 Hz, 1H), 3.43 (d, 14.8 Hz, 1H), 3.33 (s, 3H) , 3.38-3. 12 (m, 4H). MS: (M + H) ⁺ 384.
[607] (c) (S) -diethyl-carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester
[608]
[609] Reaction was carried out in a similar manner as in Example 3 (a) using (R) -N-cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide and diethylamine to (S) -diethyl-car Obtain acetic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester. ¹ H NMR: (DMSO) 8.62 (t, J = 5.6 Hz, 1H), 4.87-4.82 (m, 1H), 4.12 (d, J = 5.6, 2H), 3.42-3.10 (m, 4H), 1.72- 0.82 (m, 19 H). MS: (M + H) ⁺ 310.
[610] (d) (S) -pyrrolidine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester
[611]
[612] (R) -N-cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide and pyrrolidine were reacted in a similar manner as in Example 3 (a) to (S) -pyrrolidine- 1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester is obtained. ¹ H NMR: (DMSO) 8.59 (t, J = 4.8 Hz, 1H), 4.86-4.81 (m, 1H), 4.11 (d, J = 4.8, 2H), 3.48-3.19 (m, 4H), 1.87- 0.82 (m, 17 H). MS: (M + H) ⁺ 308.
[613] (e) (S) -morpholine-4-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester
[614]
[615] (R) -N-cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide and morpholine were reacted in a similar manner as in Example 3 (a) to (S) -morpholine-4- Obtain carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester. ¹ H NMR: (DMSO) 8.66 (t, J = 5.2 Hz, 1H), 4.88-4.83 (m, 1H), 4.13 (d, J = 4.8, 2H), 3.60-3.26 (m, 8H), 1.71- 0.82 (m, 13 H). MS: (M + H) ⁺ 324.
[616] (f) (S) -4-ethyl-piperazine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester
[617]
[618] Reaction was carried out in a similar manner as in Example 3 (a) using (R) -N-cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide and 4-ethylpiperazine (S) -4- Ethyl-piperazine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester is obtained. LC-MS: Elution time = 2.08 min, 349.2 (M-1), 351.3 (M + 1). (MS: API 150EX. LC: HP Agilent 1100 Series, Column: Phenomenex, 5μ ODS3 100A 100X3mm; Flow: 2ml / min.Two solvent gradients: Solvent A, 99% water, 1% acetonitrile, 0.1% Solvent B, 99% acetonitrile, 1% water, 0.1% AcOH.gradient 100% A, 0% B to 0% A, 100% B t = 0 to 6 min.Gradient: 100% A, 0% B t = 7-15 minutes).
[619] (g) (S) -2-hydroxymethyl-pyrrolidine-1-carboxylic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester
[620]
[621] In a similar manner as in Example 3 (a) using (R) -N-cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide and (S) -2-hydroxymethyl-pyrrolidine Reaction gives (S) -2-hydroxymethyl-pyrrolidine-1-carboxylic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester. LC-MS: Elution time = 3.73 min, 336.5 (M-1), 338.2 (M + 1). (MS: API 150EX. LC: HP Agilent 1100 Series, Column: Phenomenex, 5μ ODS3 100A 100X3mm; Flow: 2ml / min.Two solvent gradients: Solvent A, 99% water, 1% acetonitrile, 0.1% Solvent B, 99% acetonitrile, 1% water, 0.1% AcOH.gradient 100% A, 0% B to 0% A, 100% B t = 0 to 6 min.gradient 100% A, 0% B t = 7-15 minutes).
[622] (h) (S)-(2,2,2-Trifluoro-ethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester
[623]
[624] By reaction in a similar manner as in Example 3 (a) using (R) -N-cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide and 2,2,2-trifluoroethylamine (S)-(2,2,2-Trifluoro-ethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester is obtained. LC-MS: Elution time = 4.07 min, 334.1 (M-1), 336.2 (M + 1). (MS: API 150EX. LC: HP Agilent 1100 Series, Column: Phenomenex, 5μ ODS3 100A 100X3mm; Flow: 2ml / min.Two solvent gradients: Solvent A, 99% water, 1% acetonitrile, 0.1% Solvent B, 99% acetonitrile, 1% water, 0.1% AcOH.gradient 100% A, 0% B to 0% A, 100% B t = 0 to 6 min.gradient 100% A, 0% B t = 7-15 minutes).
[625] (i) (S)-(2-hydroxyethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethylester
[626]
[627] (R) -N-cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide and 2-hydroxyethylamine were reacted in a similar manner as in Example 3 (a) to (S)-( 2-hydroxyethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester is obtained. ¹ H NMR: (DMSO) 8.65 (t, J = 5.2 Hz, 1H), 7.16 (t, J = 5.2 Hz, 1H), 4.85-4.80 (m, 1H), 4.62 (t, J = 5.6 Hz, 1H ), 4.12 (d, J = 5.6 Hz, 2H), 3.45-3.33 (m, 2H), 3.12-2.96 (m, 2H), 1.74-0.80 (m, 13H). MS: (M + H) ⁺ 298.
[628] (j) (tetrahydrofuran-2-ylmethyl) -carbamic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester
[629]
[630] (R) -N-cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide and tetrahydrofurfurylamine were reacted in a similar manner as in Example 3 (a) (tetrahydrofuran-2 -Ylmethyl) -carbamic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester is obtained as a 1: 1 mixture of diastereomers. ¹ H NMR: (DMSO) 8.66 (t, J = 5.2 Hz, 1H), 7.28 (t, J = 5.2 Hz, 1H), 4.86-4.81 (m, 1H), 4.12 (d, J = 5.2 Hz, 2H ), 3.83-3.54 (m, 3H), 3.09-2.92 (m, 2H), 1.89-0.80 (m, 17H). MS: (M + H) ⁺ 338.
[631] (k) (S) -azetidine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester
[632]
[633] (R) -N-cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide and azetidine were reacted in a similar manner as in Example 3 (a) to (S) -azetidine-1- Obtain carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester. ¹ H NMR: (DMSO) 8.59 (t, J = 5.2 Hz, 1H), 4.82-4.77 (m, 1H), 4.11 (d, J = 5.2 Hz, 2H), 4.13-3.81 (m, 4H), 2.18 (quint, J = 7.6 Hz, 2H), 1.71-0.80 (m, 13H). MS: (M + H) ⁺ 294.
[634] (l) (S) -cyclopropyl-carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester
[635]
[636] (R) -N-cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide and cyclopropylamine were reacted in a similar manner as in Example 3 (a) to (S) -cyclopropyl-car Obtain acetic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester. ¹ H NMR: (DMSO) 8.64 (t, J = 5.2 Hz, 1H), 7.44 (br, 1H), 4.83-4.78 (m, 1H), 4.11 (d, J = 5.2 Hz, 2H), 2.50-2.40 (m, 1 H), 1.72-0.78 (m, 13 H), 0.58-0.30 (m, 4H). MS: (M + H) ⁺ 294.
[637] (m) (S) -piperidine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester
[638]
[639] (R) -N-cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide and piperidine were reacted in a similar manner as in Example 3 (a) to (S) -piperidine- 1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester is obtained. ¹ H NMR: (DMSO) 8.63 (t, J = 5.2 Hz, 1H), 4.86-4.81 (m, 1H), 4.11 (d, J = 5.6 Hz, 2H), 3.48-3.20 (m, 4H), 1.70 -0.82 (m, 19 H). MS: (M + H) ⁺ 322.
[640] (n) (S)-(2-methoxy-ethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester
[641]
[642] (R) -N-cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide and 2-methoxyethylamine were reacted in a similar manner as in Example 3 (a) to (S)-( 2-methoxy-ethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester is obtained. ¹ H NMR: (DMSO) 8.66 (t, J = 5.6 Hz, 1H), 7.27 (t, J = 5.6 Hz, 1H), 4.85-4.80 (m, 1H), 4.12 (d, J = 5.6 Hz, 2H ), 3.40-3.03 (m, 4H), 3.32 (s, 3H), 1.74-0.80 (m, 13H). MS: (M + H) ⁺ 312.
[643] (o) (R) -3-hydroxy-pyrrolidine-1-carboxylic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester
[644]
[645] Reaction in a similar manner as in Example 3 (a) using (R) -N-cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide and (R) -3-hydroxy-pyrrolidine To give (R) -3-hydroxy-pyrrolidine-1-carboxylic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester. ¹ H NMR: (DMSO) 8.64-8.56 (m, 1H), 4.98-4.80 (m, 2H), 4.29-4.20 (m, 1H), 4.11 (d, J = 5.2 Hz, 2H), 3.57-3.12 ( m, 4H), 1.91-0.82 (m, 15H). MS: (M + H) ⁺ 324.
[646] (p) (S) -3-hydroxy-pyrrolidine-1-carboxylic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester
[647]
[648] Reaction in a similar manner as in Example 3 (a) using (R) -N-cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide and (S) -3-hydroxy-pyrrolidine To give (S) -3-hydroxy-pyrrolidine-1-carboxylic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester. ¹ H NMR: (DMSO) 8.63-8.55 (m, 1H), 4.98-4.90 (m, 1H), 4.85-4.80 (m, 1H), 4.28-4.19 (m, 1H), 4.13-4.09 (m, 2H) ), 3.54-3.09 (m, 4H), 1.93-0.81 (m, 15H). MS: (M + H) ⁺ 324.
[649] (q) (S) -morpholine-4-carboxylic acid 1- (cyanomethyl-carbamoyl) -3-cyclohexyl-propyl ester
[650]
[651] (R) -N-cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide and morpholine were reacted in a similar manner as in Example 3 (a) to (S) -morpholine-4- Obtain carboxylic acid 1- (cyanomethyl-carbamoyl) -3-cyclohexyl-propyl ester. ¹ H NMR: (DMSO) 8.61 (t, J = 5.6 Hz, 1H), 4.79 (t, J = 5.6 Hz, 1H), 4.13 (d, J = 5.2 Hz, 2H), 3.59-3.26 (m, 8H ), 1.73-1.55 (m, 7H), 1.23-1.06 (m, 6H), 0.88-0.76 (m, 2H). MS: (M + H) ⁺ 338.
[652] Example 4
[653] (a) morpholine-4-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl Ester (Compound 11)
[654]
[655] Step 1. Dissolve (R) -2-hydroxy-3-phenylmethanesulfonyl-propionic acid {2 g, 8.19 mmol, Reference Example 1 (b)} in CH ₂ Cl ₂ (20 ml). 4-methylmorpholine (3.8 ml) and chloromethyl methyl ether (1.52 ml, 20 mmol) are added. After stirring for 30 minutes at ambient temperature, the reaction is quenched with water (50 ml) and extracted with ethyl acetate. The combined organic layers are washed with saturated aqueous NaHCO ₃ solution and brine. The product is dried over MgSO ₄ , evaporated in vacuo and then crystallized from ethyl acetate / hexanes to give 2-hydroxy-3-phenylmethanesulfonyl-propionic acid methoxymethyl ester (1.2 g; 4.16 mmol).
[656] Step 2. Add phosgene solution (2.07 ml, 1.93 M, in toluene) to CH ₂ Cl ₂ (10 ml) and cool to 0 ° C. under nitrogen. Quinoline (0.95 ml) is added and 2-hydroxy-3-phenylmethanesulfonyl-propionic acid methoxymethyl ester (250 mg, 0.87 mmol) is added. The mixture is stirred for 3 hours at ambient temperature. Morpholine (0.35 ml, 4 mmol) is added and stirring is continued for 3 hours. The mixture is dissolved in ethyl acetate (200 ml) and washed successively with 1N HCl, brine, saturated aqueous NaHCO ₃ and brine. The crude product is dried over MgSO ₄ , evaporated in vacuo and then dissolved in 1,4-dioxane (20 ml). 1N HCl (10 ml) is added and the mixture is stirred at ambient temperature for 3 hours. Dioxane is evaporated in vacuo and the product is extracted with ethyl acetate. The combined ethyl acetate layers are washed with saturated aqueous NaHCO ₃ ( ₃ × ₂₀ ml). The NaHCO ₃ solution is acidified with 6N HCl and extracted with ethyl acetate. The combined ethyl acetate layers are washed with brine, dried over MgSO ₄ and evaporated in vacuo to afford (R) -morpholine-4-carboxylic acid 1-carboxy-2-phenylmethanesulfonyl-ethyl ester.
[657] Step 3. (R) -Morpholin-4-carboxylic acid 1-carboxy-2-phenylmethanesulfonyl-ethyl ester with EDC (250 mg, 1.3 mmol), HOBt (250 mg, 1.6 mmol) and (2S) -2-amino 1-benzooxazol-2-yl-butan-1-ol {250 mg, 1.2 mmol, Reference Example 17 (a)}. Dichloromethane (4 ml) is added and 4-methylmorpholine (0.5 ml) is added. The mixture is stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (150 ml), the solution is washed with 1N aqueous HCl, water, saturated aqueous NaHCO ₃ and brine, dried over MgSO ₄ and evaporated in vacuo. The crude product is dissolved in anhydrous dichloromethane (10 ml) and Dess Martin periodinan (500 mg, 1.2 mmol) is added. After stirring for 1 h at ambient temperature, the mixture is diluted with ethyl acetate (150 ml) and treated with a 0.26 M Na ₂ S ₂ O ₃ solution in saturated aqueous NaHCO ₃ . The organic phase is washed with saturated aqueous NaHCO ₃ and brine, dried over MgSO ₄ and then evaporated. The product was crystallized from ethyl acetate / hexanes to give morpholine-4-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2- Phenylmethanesulfonyl-ethyl ester (190 mg; 0.35 mmol) is obtained. ¹ H NMR: (DMSO) 8.95 (d, J = 6.6 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.40-7.34 (m, 5H), 5.44-5.35 (m 1H), 5.26-5.16 (m, 1H), 4.60 (d, J = 13.6 Hz, 1H), 4.47 (d, J = 13.6 Hz, 1H), 3.71-3.28 (m, 10H), 2.10-1.94 (m, 1H), 1.81-1.65 (m, 1H), 0.98 (t, J = 7.2 Hz, 3H). MS: (M ⁺ +1) 544.
[658] (b) morpholine-4-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2- [2- (1, 1-difluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester (compound 14)
[659]
[660] In step 1 using (R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxy-propionic acid {Reference Example 1 (a)} Reaction in a similar manner as in Example 4 (a) to give morpholine-4-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] Obtain 2- [2- (1,1-Difluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester. ¹ H NMR: (DMSO) 8.95 (d, J = 6.4 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.52-7.43 (m, 2H), 7.31-7.21 (m, 2H), 7.11 (t, J _{H, F} = 73 Hz, 1H), 5.43 -5.37 (m 1H), 5.27-5.17 (m, 1H), 4.63 (d, J = 13.5 Hz, 1H), 4.54 (d, J = 13.5 Hz, 1H), 3.88-3.28 (m, 10H), 2.10 -1.94 (m, 1H), 1.81-1.65 (m, 1H), 0.98 (t, J = 7.6 Hz, 3H); MS: (M ⁺ +1) 610.
[661] (c) morpholine-4-carboxylic acid (R) -1-[(S) -1- (1-benzothiazol-2-yl-methanoyl) -propylcarbamoyl] -2- [2- (1, 1-difluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester (compound 15)
[662]
[663] In step 1 (R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxy-propionic acid {see Example 1 (a)} and in step 3 (2S) -2-amino-1-benzothiazol-2-yl-butan-1-ol {Reference Example 17 (b)} to react in a similar manner as in Example 4 (a) to give morpholine 4-carboxylic acid (R) -1-[(S) -1- (1-benzothiazol-2-yl-methanoyl) -propylcarbamoyl] -2- [2- (1,1-difluoro -Methoxy) -phenylmethanesulfonyl] -ethyl ester is obtained. ¹ H NMR: (DMSO) 8.93 (d, J = 6.4 Hz, 1H), 8.30-8.24 (m, 2H), 7.72-7.62 (m, 2H), 7.51-7.44 (m, 2H), 7.32-7.22 ( m, 2H), 7.12 (t, JH _{, F} = 73 Hz, 1H), 5.49-5.35 (m 2H), 4.64 (d, J = 13.5 Hz, 1H), 4.55 (d, J = 13.5 Hz, 1H) , 3.91-3.28 (m, 10H), 2.08-1.94 (m, 1H), 1.84-1.68 (m, 1H), 0.99 (t, J = 7.6 Hz, 3H). MS: (M ⁺ +1) 626.
[664] (d) Pyrrolidine-1-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl- Ethyl ester (compound 19)
[665]
[666] Reaction with pyrrolidin in step 2 in a similar manner as in Example 4 (a) to give pyrrolidine-1-carboxylic acid (R) -1-[(S) -1- (1-benzooxazole-2 -Yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester. ¹ H NMR: (DMSO) 8.90 (d, J = 6.4 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.40-7.33 (m, 5H), 5.41-5.33 (m 1H), 5.26-5.15 (m, 1H), 4.59 (d, J = 13.5 Hz, 1H), 4.47 (d, J = 13.5 Hz, 1H), 3.66-3.17 (m, 6H), 2.10-1.64 (m, 6H), 0.97 (t, J = 7.2 Hz, 3H); MS: (M ⁺ +1) 528.
[667] (e) Dimethyl-carbamic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester Compound 20)
[668]
[669] Reaction in step 2 using dimethylamine in a similar manner as in Example 4 (a) to give dimethyl-carbamic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-meta Noyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester. ¹ H NMR: (DMSO) 8.91 (d, J = 6.4 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.40-7.33 (m, 5H), 5.39-5.33 (m 1H), 5.26-5.15 (m, 1H), 4.59 (d, J = 13.5 Hz, 1H), 4.47 (d, J = 13.5 Hz, 1H), 3.63 (dd, J = 14.8 Hz, J = 10.6 Hz, 1H), 3.42 (dd, J = 14.8 Hz, J = 2.5 Hz, 1H) , 2.89 (s, 3H), 2.79 (s, 3H), 2.10-1.94 (m, 1H), 1.81-1.64 (m, 1H), 0.97 (t, J = 7.2 Hz, 3H); MS: (M ⁺ +1) 502.
[670] (f) Morpholine-4-carboxylic acid (R) -1-[(S) -1- (1-benzylcarbamoyl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester (Compound 25 )
[671]
[672] In step 3, (R) -3-amino-2-hydroxy-pentanoic acid benzylamide TFA salt (Reference Example 19) was reacted in a similar manner as in Example 4 (a) to give morpholine-4-carboxylic acid (R) -1-[(S) -1- (1-benzylcarbamoyl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester is obtained. ¹ H NMR: (DMSO) 9.27 (t, J = 5.5 Hz, 1H), 8.67 (d, J = 8.1 Hz, 1H), 7.40-7.20 (m, 10H), 5.42-5.34 (m 1H), 4.96- 4.85 (m, 1H), 4.64-4.24 (m, 4H), 3.66-3.28 (m, 10H), 1.90-1.72 (m, 1H), 1.63-1.46 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H); MS: (M ⁺ +1) 560.
[673] (g) morpholine-4-carboxylic acid (S) -1-[(S) -1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propylcarbamoyl] -2-phenylmethanesulphate Phenyl-ethyl ester
[674]
[675] Similar to Example 4 (a) using (S) -2-amino-1-oxazolo [4,5-b] pyridin-2-yl-butan-1-ol TFA salt (Reference Example 20) Reaction by morpholine-4-carboxylic acid (S) -1-[(S) -1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propylcarbamoyl] -2-phenylmethane Sulfonyl-ethyl ester is obtained. ¹ H NMR: (DMSO) 9.00 (d, J = 6.4 Hz, 1H), 8.73 (m, 1H), 8.39 (d, J = 8.4 Hz, 1H), 7.69-7.64 (m, 1H), 7.45-7.30 (m, 5H), 5.37 (d, J = 10.4 Hz, 1H), 5.19-5.13 (m, 1H), 4.57 (d, J = 13.6 Hz, 1H), 4.46 (d, J = 13.6 Hz, 1H) , 3.67-3.23 (m, 10H), 2.10-1.98 (m, 1H), 1.80-1.69 (m, 1H), 0.99 (t, J = 7.0 Hz, 3H). MS: (M + H) ⁺ 545.
[676] (h) Morpholine-4-carboxylic acid (S) -1-[(S) -1- (5-ethyl- [1,3,4] oxadiazole-2-carbonyl) -propylcarbamoyl] -2 -Phenylmethanesulfonyl-ethyl ester
[677]
[678] In Example 4 (a) using 2-amino-1- (5-ethyl- [1,3,4] oxadiazol-2-yl-butan-1-ol {Reference Example 11 (m)} Reaction in a similar manner to morpholine-4-carboxylic acid (S) -1-[(S) -1- (5-ethyl- [1,3,4] oxadiazole-2-carbonyl) -propylcarbamoyl ] -2-phenylmethanesulfonyl-ethyl ester ¹ H NMR: (DMSO) 8.95 (d, J = 6.0 Hz, 1H), 7.41-7.33 (m, 5H), 5.35 (d, J = 10.0) Hz, 1H), 4.97-4.91 (m, 1H), 4.63-4.45 (m, 2H), 3.64-3.23 (m, 10H), 2.96 (q, J = 7.2 Hz, 2H), 1.99-1.89 (m, 1H), 1.75-1.64 (m, 1H), 1.30 (t, J = 7.6 Hz, 3H), 0.94 (t, J = 7.2 Hz, 3H). MS: (M + H) ⁺ 523.
[679] Example 5
[680] (S) -2-{(R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxy-propanoylamino} -N-methoxy -N-methyl-butyramide (Compound 32)
[681]
[682] (R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxypropionic acid in CH ₂ Cl ₂ (20 ml) {1.24g, 4mmol, Reference Practice HOBt (0.74 g, 4.8 mmol), EDC (1.15 g, 6 mmol), (R) -2-amino-N-methoxy-N-, prepared as in Reference Example 2 in the solution of Example 1 (a)} Methyl-butyramide TFA salt (1.04 g, 4 mmol) and NMM (1.6 g, 16 mmol) are added. After stirring for 14 hours at room temperature, the reaction mixture is diluted with 150 ml of ethyl acetate. The mixture is washed with saturated NaHCO ₃ and brine and dried over anhydrous MgSO ₄ . The crude product was filtered, concentrated and purified by flash column chromatography on silica gel using hexanes / acetate as eluent to give (S) -2-{(R) -3- [2- (1,1- Difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxy-propanoylamino} -N-methoxy-N-methyl-butyrylamide (1.45 g) is obtained. ¹ H NMR (CD ₃ Cl): 7.6-7.5 (d, J = 7.67 Hz, 1H), 7.5-7.35 (m, 2H), 7.31-7.15 (m, 2H), 6.63 (t, J = 73.4 Hz, 1H), 5.0-4.85 (br., 1H), 4.7-4.6 (m, 1H), 4.55-4.48 (m, 2H), 4.45-4.35 (m, 1H), 3.80 (s, 3H), 3.6-3.8 (m, 1H), 3.35-3.2 (m, 1H), 1.78 (s, 3H), 2.0-1.5 (m, 2H), 0.93 (t, J = 6.9 Hz, 3H); MS: 437.4.4 (M-1), 439.4 (M + 1).
[683] Example 6
[684] (R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -N-((S) -1-formyl-propyl) -2-hydroxy-propionamide (Compound 23)
[685]
[686] (S) -2-{(R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxy in ethyl ether (50 ml) at 0 ° C. under N _2. To a solution of oxy-propanoylamino} -N-methoxy-N-methyl-butyramide (1.3 g, 3 mmol, Example 5) is added 1N LAH solution of ethyl ether (3 ml). After 3 h stirring at 0 ° C., 1 ml of ethyl acetate and saturated NH ₄ Cl solution are added. The crude product is extracted with ether, washed with brine, dried over MgSO ₄ , filtered and concentrated. The residue was purified by flash column chromatography on silica gel using hexane / acetate as eluent to give (R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl]-. N-((S) -1-formyl-propyl) -2-hydroxy-propionamide (0.66 g) is obtained. ¹ H NMR (DMSO): 9.43 (s, 1H), 8.42 (d, J = 7.45 Hz, 1H), 7.6-7.0 (m, 4H), 7.12 (t, J = 73.93 Hz, 1H), 6.52 (d , J = 6.45 Hz, 1H), 5.2-5.17 (m, 1H), 4.65-4.53 (m, 2H), 4.12-4.0 (m, 1H), 3.63-3.55 (m, 2H), 1.7-1.4 (m , 2H), 0.89 (t, J = 6.8 Hz, 3H); MS: 378.2 (M-1), 380.4 (M + l).
[687] Example 7
[688] (R) -N-[( S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenyl-methanesulfonyl-propionamide (Compound 5)
[689]
[690] Step 1.HOBt (183 mg) at room temperature in a solution of (R) -3-phenylmethanesulfonyl-2-triisopropylsilanyloxy-propionic acid {556 mg, 1 mmol, Reference Example 3} in CH ₂ Cl ₂ (10 ml). , 1.2 mmol), EDC (288 mg, 15 mmol), (S) -2-amino-1-benzooxazol-2-yl-butanol (206 mg, 1 mmol) and NMM (202 mg, 2 mmol) are added. The mixture is stirred at rt overnight, diluted with ethyl acetate (100 ml), washed with saturated NaHCO ₃ , brine, dried over anhydrous MgSO ₄ , filtered and concentrated. The crude product is purified by flash column chromatography on silica gel using hexanes / acetate as eluent (180 mg product obtained). This compound is dissolved in CH ₂ Cl ₂ , Dess Martin periodinan (196 mg, 0.46 mmol) is added at room temperature, and the mixture is stirred for 2 hours. Na ₂ S ₂ O ₃ -NaHCO ₃ saturated solution (5 ml) is added, stirred for an additional 30 minutes, extracted with ethyl acetate, and washed successively with saturated NaHCO ₃ solution and brine. The crude product was dried over anhydrous MgSO ₄ , filtered, concentrated and purified by flash column chromatography on silica gel using hexanes / acetate as eluent (R) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propyl] -3-phenylmethanesulfonyl-2-triisopropylsilanyloxy-propionamide is obtained.
[691] Step 2. (R) -N-[(S) -1- (1-Benzooxazol-2-yl-Methanoyl) -propyl] -3-phenylmethanesulfonyl-2- in CH ₃ CN (10 ml) Triisopropylsilanyloxy-propionamide (120 mg, 0.2 mmol) is mixed with 48% HF / water solution (1 ml) and stirred for 16 hours at room temperature. The pH is adjusted between 8-9 by careful addition of saturated NaHCO ₃ solution. The product is extracted with ethyl acetate (100 ml), washed with brine and dried over magnesium sulfate. The solvent was removed and the product crystallized from acetate and hexane to give (R) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propyl] -2-hydroxy-3- Phenyl-methanesulfonyl-propionamide is obtained as a white solid (85% yield). ¹ H NMR: (DMSO) 8.29 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.59 (t, J = 8.1 Hz, 1H), 7.46-7.35 (m, 7H ), 6.52 (d, J = 6.6 Hz, 1H), 5.08-4.99 (m, 1H), 4.58-4.47 (m, 3H), 3.35-3.28 (m, 2H), 2.05-1.90 (m, 1H), 1.81-1.65 (m, 1 H), 0.91 (t, J = 7.2 Hz, 3H); MS: (M ⁺ +1) 431.
[692] Example 8
[693] (a) (S) -3- {3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -propanoylamino} -2-oxo-pentanoic acid benzylamide (compound 27)
[694]
[695] Step 1. (R) -3-Amino-2-hydroxy-pentanoic acid benzylamide TFA salt (70 mg, 0.22 mmol), 3- [2- (1,1-difluoro-methoxy) -phenylmethanesulphate Phonyl] -propionic acid (64 mg, 0.22 mmol, Reference Example 19), HOBT (33 mg, 0.22 mmol), EDC (63 mg, 0.325 mmol), 1 ml of dichloromethane and N-methyl morpholine (48 μl, 0.434 mmol) do. The mixture is stirred for 16 hours. The product was extracted with 60 ml of ethyl acetate, washed with two 10 ml fractions of 1N HCl, 10 ml water and two 10 ml fractions of saturated NaHCO ₃ , dried over MgSO ₄ and concentrated to crude (R) -3- {3- [ 105 mg (0.21 mmol, 100% yield) of 2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -propanoylamino} -2-hydroxy-pentanoic acid benzylamide are obtained.
[696] Step 2. (R) -3- {3- [2- (1,1-Difluoro-methoxy) -phenylmethanesulfonyl] -propanoylamino} -2-hydroxy-phene in 1 ml of dichloromethane To a solution of 105 mg of benzyl carbonate (0.21 mmol) is added Dess Martin periodinan (179 mg, 0.42 mmol). The mixture was stirred for 16h, saturated NaHCO ₃ Na ₂ S ₂ O was added in a 0.26M ₃ 10ml, the mixture was extracted with two 30ml ethyl acetate fractions were washed with three 15ml saturated NaHCO ₃ fractions. The organic layer Dry with MgSO ₄ and concentrate. The product was purified by silica gel chromatography using 3: 1 hexanes: ethyl acetate eluent and crystallized from diethyl ether and hexane to give (S) -3- {3- [2- (1,1-difluoro). -Methoxy) -phenylmethanesulfonyl] -propanoylamino} -2-oxo-pentanoic acid benzylamide (28 mg, 0.054 mmol, 26% yield) is obtained. ¹ H NMR: (CDCl ₃ ) 7.0-7.47 (m, 9H), 6.49 (m, 1H), 6.24 (m, 1H), 5.22 (m, 1H), 4.40 (m, 2H), 4.30 (m, 3H ), 3.23 (m, 2H), 2.70 (m, 2H), 2.01 (m, 1H), 1.68 (m, 1H), 0.85 (m, 3H); MS: (M ⁺ +1) 499.4, 496.53.
[697] The following compounds are prepared by the method of Example 8:
[698] N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propyl] -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] Propionamide (compound 26); ¹ H NMR: (CDCl ₃ ) 7.85 (d, J = 7.6 Hz, 1H), 7.7-7.0 (m, 7H), 6.51 (m, 2H), 5.60 (m, 1H), 4.34 (m, 3H), 3.29 (m, 2H), 2.80 (m, 2H), 2.13 (m, 1H), 1.87 (m, 1H), 0.96 (m, 3H); MS: (M ⁺ +1) 481, 480.48;
[699] N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -3-phenyl-propyl] -3-p-tolylmethanesulfonyl-propionamide (Compound 30); ¹ H NMR: (CDCl ₃ ) 7.9 (m, 1H), 7.62 (m, 1H), 7.56 (td, J = 6.9,1.2 Hz, 1H), 7.47 (td, J = 7.1,1.2 Hz, 1H), 7.3-7.1 (m, 9H), 6.47 (d, J = 7.7 Hz, 1H), 5.71 (m, 1H), 4.22 (s, 2H), 3.20 (m, 2H), 2.71 (m, 4H), 2.47 (m, 1 H), 2.33 (s, 3 H), 2.21 (m, 1 H); MS: (M ⁺ +1) 505.2, 504.60.
[700] 3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- (1-ethyl-2,3-dioxo-3-pyrrolidin-1-yl-propyl) -propionamide;
[701] 3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- (1-ethyl-3-morpholin-4-yl-2,3-dioxo-propyl) -propionamide;
[702] 3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- (1-ethyl-2,3-dioxo-3-piperazin-1-yl-propyl) -propionamide;
[703] 3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- [3- (1,1-dioxo-1λ ⁶ -thiomorpholin-4-yl) -1-ethyl-2,3-di Oxo-propyl] -propionamide;
[704] 3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- [1-ethyl-3- (4-methyl-sulfonyl-piperazin-1-yl) -2,3-dioxo-propyl] Propionamide;
[705] 3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid dimethylamide;
[706] 3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid cyclopentyl-ethyl-amide;
[707] 3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid phenylamide;
[708] 3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid pyridin-3-ylamide;
[709] 3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid (tetrahydro-pyran-4-yl) -amide;
[710] 3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid (1-benzoyl-piperidin-4-yl) -amide and
[711] 3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid (2-morpholin-4-yl-ethyl) -amide.
[712] Example 9
[713] (R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -2- (2-nitro-phenylamino) -3-phenylmethanesulfonyl-propion Amide (Compound 28)
[714]
[715] Step 1. Dissolve 3-benzylsulfanyl-2- (2-nitro-phenylamino) -propionic acid (350 mg, 1.05 mmol, Reference Example 5) in 20 ml of methanol and 20 ml of an aqueous solution of oxone (970 mg, 0.12 mmol). After treatment, it is stirred for 72 hours. Water (300 ml) is added and the precipitate is filtered and dried to afford 2- (2-nitro-phenylamino) -3-phenylmethanesulfonyl-propionic acid (215 mg, 0.59 mmol, 56% yield).
[716] Step 2. 2- (2-Nitro-phenylamino) -3-phenylmethanesulfonyl-propionic acid (215 mg, 0.59 mmol), HOBT (136 mg, 0.148 mmol), EDC (408 mg, 2.13 mmol), (S) -2 -Amino-1-benzooxazol-2-yl-butan-1-ol (122 mg, 0.59 mmol, {Example 17 (a)}, 2.4 ml of dichloromethane and N-methyl morpholine (97 μl, 0.89 mmol ) Is stirred for 16 hours The product is extracted with 20 ml of ethyl acetate and washed with ₃ ml of ₃ 1N HCl and 1 ml of saturated NaHCO ₃ , dried over MgSO ₄ , concentrated to (R) -N -[(S) -1- (1-Benzooxazol-2-yl-1-hydroxy-methyl) -propyl] -2- (2-nitro-phenylamino) -3-phenylmethane-sulfonyl-propion Obtained amide (223 mg, 0.40 mmol, 45% yield).
[717] Step 3. (R) -N-[(S) -1- (1-Benzooxazol-2-yl-1-hydroxy-methyl) -propyl] -2- (2-nitro-phenylamino) -3 Phenylmethane-sulfonyl-propionamide (223 mg, 0.4 mmol) is dissolved in 1.6 ml of dichloromethane and treated with des martin periodinan (342 mg, 0.80 mmol). The mixture was stirred for 16h, saturated NaHCO ₃ Na ₂ S ₂ O was added in a 0.26M ₃ 20ml, the mixture was extracted with two 30ml ethyl acetate fractions were washed with saturated NaHCO ₃ three 5ml fractions. The organic layer is dried over MgSO ₄ and concentrated. The crude product is dissolved in a minimum amount of hot ethyl acetate and crystallized by addition of anhydrous diethyl ether. This crystallization was repeated to give clear (R) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propyl] -2- (2-nitro-phenylamino) -3- Phenylmethanesulfonyl-propionamide (97 mg, 0.176 mmol, 44% yield) is obtained. ¹ H NMR: (DMSO) 8.67 (m, 1H), 8.12 (m, 1H), 7.81 (m, 1H), 7.65-7.35 (m, 10H), 6.78 (m, 2H), 5.51 (m, 1H) , 4.68 (m, 1H), 4.37 (s, 2H), 3.62 (m, 1H), 3.38 (m, 1H), 2.15 (m, 1H), 1.91 (m, 1H), 0.98 (m, 3H); MS: (M ⁺ +1) 551.0, 550.58.
[718] The following compounds are prepared by the method of Example 9:
[719] N- [1- (benzooxazole-2-carbonyl) -propyl] -3-phenylmethanesulfonyl-2- (pyrimidin-2-ylamino) -propionamide.
[720] Example 10
[721] (R) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -butyl] -2- (5-nitro-thiazol-2-ylamino) -3-phenyl Methanesulfonyl-propionamide (Compound 29)
[722]
[723] Step 1. (R) -3-benzylsulfanyl-2- (5-nitro-thiazol-2-ylamino) -propionic acid (42 mg, 0.123 mmol, Reference Example 6), HOBT (28 mg, 0.148 mmol), EDC (29 mg, 0.148 mmol), (S) -2-amino-1-benzooxazol-2-yl-pentan-1-ol {27 mg, 0.123 mmol, Reference Example 17 (c)}, 1 ml of dichloromethane and A mixture of N-methyl morpholine (14 μl, 0.123 mmol) is stirred for 16 hours. The product was extracted with 60 ml of ethyl acetate, washed with one 30 ml fraction of 1N HCl and one 30 ml fraction of saturated NaHCO ₃ , dried over MgSO ₄ and concentrated to (R) -N-[(S) -1- ( 1-benzooxazol-2-yl-1-hydroxy-methyl) -butyl] -3-benzylsulfanyl-2- (5-nitro-thiazol-2-ylamino) -propionamide (41.8 mg, 0.077 mmol, 63% yield).
[724] Step 2. (R) -N-[(S) -1- (1-Benzooxazol-2-yl-1-hydroxy-methyl) -butyl] -3-benzylsulfanyl-2- (5-nitro -Thiazol-2-ylamino) -propionamide (41.8 mg, 0.077 mmol) is dissolved in 0.5 ml of methanol, treated with 0.5 ml of an aqueous solution of oxone (43 mg, 0.069 mmol) and stirred for 1 hour. Methanol is removed under reduced pressure and 2 ml of water are added. The mixture is extracted with two 10 ml fractions of ethyl acetate, dried over MgSO ₄ and concentrated. It is dissolved in 0.5 ml of dichloromethane and treated with des martin periodinane (65 mg, 0.154 mmol). The mixture was stirred for 16h, was added a 0.26M Na ₂ S ₂ O ₃ 5ml of saturated NaHCO _3, and then the mixture was extracted with two 10ml ethyl acetate fractions were washed with saturated NaHCO ₃ three 5ml fractions. The organic phase is dried over MgSO ₄ and concentrated. The product was purified by polishing with diethyl ether to give (R) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -butyl] -2- (5-nitro-thiazole 2-ylamino) -3-phenylmethanesulfonyl-propionamide (28 mg, 054 mmol, 26% yield) is obtained. ¹ H NMR: (CDCl ₃ ) 7.96 (s, 1H), 7.87 (m, 1H), 7.7-7.3 (m, 9H), 5.57 (m, 1H), 5.06 (m, 1H), 4.47 (m, 2H ), 3.75 (m, 1H), 3.48 (m, 1H), 2.09 (m, 1H), 1.85 (m, 1H), 1.43 (m, 1H), 1.24 (m, 1H), 0.94 (m, 3H) ; MS: (M ⁺ +1) 572.2, 571.63.
[725] Example 11
[726] (a) (2S) (4,4-Difluoro-2-hydroxy-5-phenyl-pentanoic acid (1 (S) -cyano-3-phenyl-propyl) -amide (Compound 33)
[727]
[728] Amino-acetonitrile hydrochloride (0.37 mmol, 72.6 mg) in dichloromethane anhydrous (4 ml), (2S) -4,4-difluoro-2-hydroxy-5-phenyl-pentanoic acid (1.0 equiv, 0.37 mmol , 85.0 mg, Reference Example 7) and N, N-diisopropylethylamine (2.2 equiv, 0.81 mmol, 105.2 mg) are added PyBOP ^R (1.1 equiv, 0.41 mmol, 212 mg) under nitrogen. The mixture is stirred at rt for 15.5 h and concentrated in vacuo. The residue is diluted with ethyl acetate (30 ml) and the mixture is washed with water (30 ml), sodium bicarbonate (30 ml) and water (30 ml). The organic layer is dried over MgSO ₄ and concentrated in vacuo. The residue was purified on 10 g of silica gel, eluting with a mixture of ethyl acetate and heptane (1: 2, v / v) to give (2S) (4,4-difluoro-2-hydroxy-5-phenyl-pentanoic acid ( 1 (S) -cyano-3-phenyl-propyl) -amide (67.4 mg, 48.9%) is obtained as a pale tan solid ¹ H NMR (CDCl ₃ ) 7.3 (m, 10H), 7.1 (d, J = 7 Hz, 1H), 4.8 (q, J = 7.4 Hz, 1H), 4.53 (bd, J = 9.5 Hz, 1H), 3.2 (dt, J = 16.2, 4.2 Hz, 2H), 2.96 (s, 1H ), 2.85 (m, 2H), 2.5 (m, 1H), 2.3-0.9 (m, 3H) LC / MS 89% parent (M + 1).
[729] (b) N- (1 (S) -cyano-3-phenyl-propyl) -2- (S)-(2-morpholin-4-yl-2-oxo-ethoxy) -4-phenyl-part Tyramide (Compound 34)
[730]
[731] (S) -2-Amino-4-phenyl-butyronitrile hydrochloride and 2- (S)-(2-morpholin-4-yl-2-oxo-ethoxy) -4-phenyl-butyric acid Example 8] was reacted in a similar manner as in Example 11 (a) to give N- (1 (S) -cyano-3-phenyl-propyl) -2- (S)-(2-morpholine-4 -Yl-2-oxo-ethoxy) -4-phenyl-butyramide is obtained as an oil. ¹ H NMR (CDCl ₃ ) 9.4 (d, J = 8.2 Hz, 1H), 7.3 (m, 10H), 4.75 (q, J = 7.5 Hz, 1H), 4.63 (d, J = 15.1 Hz, 1H), 3.95 (d, J = 15.3 Hz, 1H), 3.87 (dd, J = 8.2, 3.9 Hz, 1H), 3.7 (m, 6H), 3.32 (m, 2H), 2.85 (m, 4H), 2.1 (m , 3H), 2.05 (m, 1H). LC / MS 100% (M + l) 450.
[732] (c) N- (1- (S) -cyano-3-phenyl-propyl) -2- (S) -fluoro-4-phenyl-butyramide (Compound 35)
[733]
[734] Similar to Example 11 (a) using (S) -2-amino-4-phenyl-butyronitrile hydrochloride and (2S) -2-fluoro-4-phenyl-butyric acid (Reference Example 9) Reaction by the method affords N- (1- (S) -cyano-3-phenyl-propyl) -2- (S) -fluoro-4-phenyl-butyrylamide as a pale tan solid. ¹ H NMR (CDCl ₃ ) 7.3 (m, 10H), 6.6 (bs, 1H), 4.95 (ddd, J = 49.2, 8.2, 3.5 Hz, 1H), 4.8 (m, 1H), 3.8 (m, 4H) , 2.3 (m, 1H), 2.2 (m, 3H). MS (CI, M + 1) 325.
[735] (d) N- (1- (S) -cyano-3-phenyl-propyl) -2,2-difluoro-4-phenyl-butyramide (Compound 36)
[736]
[737] (S) -2-amino-4-phenyl-butyronitrile hydrochloride and 2,2-difluoro-4-phenyl-butyric acid were reacted in a similar manner as in Example 11 (a) to give N- ( 1- (S) -cyano-3-phenyl-propyl) -2,2-difluoro-4-phenyl-butyramide is obtained as a white solid. ¹ H NMR (CDCl ₃ ) 7.3 (m, 10H), 6.6 (d, J = 8.1 Hz, 1H), 4.83 (q, J = 7.4 Hz, 1H), 2.88 (dt, J = 7.5, 2.5 Hz, 2H ), 2.79 (t, J = 8 Hz, 2H), 2.4 (m, 2H), 2.2 (q, J = 7.5 Hz, 2H). LC / MS 50% (M + l) 343.
[738] (e) N- (1- (S) -cyano-3-phenyl-propyl) -2- (S) -hydroxy-4-phenyl-butyramide (Compound 37)
[739]
[740] (S) -2-amino-4-phenyl-butyronitrile hydrochloride and (2S) -2-hydroxy-4-phenyl-butyric acid were reacted in a similar manner as in Example 11 (a) to give N- (1- (S) -Cyano-3-phenyl-propyl) -2- (S) -hydroxy-4-phenyl-butyramide is obtained as a white solid. ¹ H NMR (CDCl ₃ ) 7.3 (m, 10H), 6.9 (d, J = 8.4 Hz, 1H), 4.86 (q, J = 7.4 Hz, 1H), 4.2 (m, 1H), 2.84 (t, J = 7.1 Hz, 2H), 2.77 (t, J = 7.8 Hz, 2H), 2.5 (d, J = 4.7 Hz, H), 2.2 (m, 3H), 1.95 (m, 1H). LC / MS 49% (M + l) 323.
[741] (f) N- (1- (S) -cyano-3-phenyl-propyl) -2- (R) -hydroxy-4-phenyl-butyramide (Compound 38)
[742]
[743] (S) -2-amino-4-phenyl-butyronitrile hydrochloride and (2R) -2-hydroxy-4-phenyl-butyric acid were reacted in a similar manner as in Example 11 (a) to give N- (1- (S) -Cyano-3-phenyl-propyl) -2- (R) -hydroxy-4-phenyl-butyramide is obtained as a white solid. ¹ H NMR (CDCl ₃ ) 7.4-7.1 (m, 10H), 6.9 (d, J = 8.7 Hz, 1H), 4.87 (q, J = 7.3 Hz, 1H), 4.1 (m, 1H), 2.85 (t , J = 7.5 Hz, 2H), 2.77 (t, J = 8.4 Hz, 2H), 2.3 (d, J = 5.1 Hz, 1H), 2.2 (m, 3H), 2.0 (m, 1H). LC / MS 94% (M + l) 323.
[744] (g) N- (1- (S) -cyano-3-phenyl-propyl) -2- (R) -methoxy-4-phenyl-butyramide (Compound 39)
[745]
[746] Example 11 using (S) -2-amino-4-phenyl-butyronitrile hydrochloride (0.407 mmol, 80 mg) and 2 (R) -methoxy-4-phenyl-butyric acid (Reference Example 10) Reaction was carried out in a similar manner as in a) to N- (1-S) -cyano-3-phenyl-propyl) -2- (R) -methoxy-4-phenyl-butyramide (91.8 mg, 67%) Is obtained as a white solid. ¹ H NMR (CDCl ₃ ) 7.2 (m, 10H), 6.8 (d, J = 8.5 Hz, 1H), 4.86 (q, J = 7.5 Hz, 1H), 3.67 (dd, J = 6.5, 4.5 Hz, 1H ), 3.35 (s, 3H), 2.85 (m, 2H), 2.68 (t, J = 8.0 Hz, 2H), 2.2-2.0 (m, 4H). LC / MS 84% (M ⁺ 1) 337.
[747] (h) 2,2-difluoro-5-phenyl-pentanoic acid (1-cyano-cyclopropyl) -amide (compound 40)
[748]
[749] 2,2-difluoro-5 by reaction in a similar manner as in Example 11 (a) using 2,2-difluoro-5-phenyl-pentanoic acid and 1-amino-cyclopropanecarbonitrile hydrochloride Obtain phenyl-pentanoic acid (1-cyano-cyclopropyl) -amide. ¹ H NMR (CDCl ₃ ) δ 1.32 (m, 2H), 1.64 (m, 2H), 1.82 (m, 2H), 2.12 (m, 2H), 2.8-2.56 (m, 2H), 6.82 (m, 1H ), 7.36-7.15 (m, 5H). MS (ES-) 277.
[750] (i) N- (1- (S) -cyano-3-phenyl-propyl) -4-phenyl-butyramide (Compound 41)
[751]
[752] (S) -2-amino-4-phenyl-butyronitrile hydrochloride and 4-phenylbutyric acid were reacted in a similar manner as in Example 11 (a) to give N- (1- (S) -cyano- 3-phenyl-propyl) -4-phenyl-butyramide is obtained as a colorless oil. ¹ H NMR (CDCl ₃ ): d 7.3 (m, 10H), 6.0 (d, J = 8.3 Hz, 1H), 4.9 (q, J = 7.4 Hz, 1H), 2.8 (m, 2H), 2.65 (t , J = 7.4 Hz, 2H), 2.15 (m, 4H), 1.95 (m, 2H). LC / MS 100% (M + l) 307.
[753] Example 12
[754] 2,2-Difluoro-5-phenyl-pentanoic acid ((S) -1-cyano-3-phenyl-propyl) -amide (Compound 42)
[755]
[756] 2,2-difluoro-5-phenyl-pentanoic acid (109 mg, 0.509 mmol) in DMF (4 ml), (S) -2-amino-4-phenyl-butyronitrile hydrochloride (103 mg, 0.523 mmol) and The mixture of HATU (206 mg, 0.542 mmol) is stirred at room temperature for 5 hours and evaporated under reduced pressure. The residue is dissolved in ethyl acetate and washed with 1N HCl, sodium bicarbonate and water. The organic extract is dried over Na ₂ S0 ₄ and evaporated in vacuo to give an orange oil. The residue was treated with MPLC, eluting with a mixture of ethyl acetate and heptane (1: 9, v / v) to give 2,2-difluoro-5-phenyl-pentanoic acid ((S) -1-cyano-3- Phenyl-propyl) -amide (82 mg) is obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) 7.3-7.1 (m, 10H), 6.9 (bs, 1H), 4.80 (q, J = 7.5 Hz, 1H), 2.80 (dt, J = 7.3, 2.7 Hz, 2H), 2.65 (t, J = 7.5 Hz, 2H), 2.2-2.0 (m, 4H), 1.8 (m, 2H). MS 357 (MH <^+> ), 379 (M + Na).
[757] Example 13
[758] (a) N- (4-cyano-1-ethyl-piperidin-4-yl) -3-cyclohexyl-propionamide
[759]
[760] Step 1. To a stirred solution of 1-ethyl-4-piperidone (25 g, 0.197 mol) in 300 ml diethyl ether and NH ₄ Cl (22.3 g, 0.41 mol) was added NaCN (14.5 g, 0.295 mol, in 70 ml water). Dropwise at room temperature. After stirring for 24 hours, the diethyl ether is separated and the aqueous phase is extracted with n-BuOH, then washed with brine and dried. Most of n-BuOH is removed under reduced pressure, and the residue is diluted with 50 ml of diethyl ether and acidified at 0 ° C. with 2N HCl in diethyl ether solution. The solid is dried under vacuum to afford 45 g of 4-amino-1-ethyl-piperidine-4-carbonitrile HCl salt.
[761] Step 2. 3-cyclohexyl-propionic acid (156 mg, 1 mmol), 4-amino-1-ethyl-piperidine-4-carbonitrile HCl salt (227, 1 mmol, prepared in step 1) in MeCl ₂ (5 ml) ) And HATU (570 mg, 1.5 mmol) are added N, N-diisopropylethylamine (516 mg, 4 mmol) at room temperature. After stirring for 14 hours, the reaction mixture is extracted with ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , brine, dried over MgSO ₄ and concentrated to N- (4-cyano-1-ethyl-piperidin-4-yl) -3-cyclohexyl-propionamide (170 mg ). LC-MS: Elution time = 2.25 min, 290.2 (M-1), 292.2 (M + 1). (MS: API 150EX. LC: HP Agilent 1100 Series, Column: Phenomenex, 5μ ODS3 100A 100X3mm; Flow: 2ml / min.Two solvent gradients: Solvent A, 99% water, 1% acetonitrile, 0.1% Solvent B, 99% acetonitrile, 1% water, 0.1% AcOH.gradient 100% A, 0% B to 0% A, 100% B t = 0 to 6 min.gradient 100% A, 0% B t = 7-15 minutes).
[762] (b) N- (4-cyano-1-ethyl-piperidin-4-yl) -3- (2-difluoromethoxy-phenylmethanesulfonyl) -propionamide
[763]
[764] 3- (2-difluoromethoxy-phenylmethanesulfonyl) -propionic acid (294 mg, 1 mmol) and 4-amino-1-ethyl-piperidine-4-carbonitrile HCl salt (227, 1 mmol) Reaction was carried out in a similar manner as in Example 13 (a) to N- (4-cyano-1-ethyl-piperidin-4-yl) -3- (2-difluoromethoxy-phenylmethanesulfonyl) -propion Obtain amide (260 mg). LC-MS: R _T = 1.96 min, 428.2 (M-1), 430.3 (M + 1). MS: API 150EX. (LC: Agilent 1100 series, column: Phenomenex, 5μ ODS3 100A 100X3mm.Flow rate: 2ml / min.Two solvent gradients: Solvent A, 99% water, 1% acetonitrile, 0.1% AcOH.Solvent B, 99% Acetonitrile, 1% water, 0.1% AcOH.gradient 100% A, 0% B-0% A, 100% B t = 0-6 min. Gradient 100% A, 0% B t = 7-15 min).
[765] Example 14
[766] (S) -tert-butyl-carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester
[767]
[768] (S) -N-cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide (53 mg, 0.252 mmol) is dissolved in dichloromethane (1 ml). Triethylamine (0.1 ml) is added and tert-butyl isocyanate (0.034 ml, 0.3 mmol) is added. The mixture is stirred brown at room temperature. After dilution with ethyl acetate (100 ml), the solution is washed with 1N aqueous HCl, brine, saturated aqueous NaHCO ₃ and brine, dried over MgSO ₄ and evaporated in vacuo. Flash chromatography on silica gel (hexane / ethyl acetate 1: 1) to give (S) -tert-butyl-carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester (63 mg, 0.204 mmol) is obtained as a white solid.
[769] Example 15
[770] (a) (R) -carbamic acid 1- (cyanomethyl-carbamoyl) -2- (2-difluoromethoxy-phenylmethanesulfonyl) -ethyl ester
[771]
[772] (R) -N-cyanomethyl-3- (2- (1,1-difluoromethoxy) -phenylmethanesulfonyl) -2-hydroxy-propionamide {100 mg, 0.287 mmol, Example 1 (a) ) Is dissolved in dichloromethane (2 ml) and THF (1 ml). Trichloroacetyl isocyanate (0.051 ml, 0.43 mmol) is added and the mixture is stirred for 1 hour. The solvent is removed in vacuo and the residue is dissolved in 1,4-dioxane (10 ml). 1N aqueous HCl (5 ml) is added and the mixture is heated at 70 ° C. for 4 h. After cooling to room temperature, the mixture is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO ₄ and evaporated in vacuo. Flash chromatography on silica gel (hexanes / ethyl acetate 1: 3) to give (R) -carbamic acid 1- (cyanomethyl-carbamoyl) -2- (2-difluoromethoxy-phenylmethanesulfonyl) -ethyl Ester (35 mg, 0.089 mmol) is obtained as a white solid. ¹ H NMR: (DMSO) 8.90 (t, J = 4.8 Hz, 1H), 7.48-7.43 (m, 2H), 7.30-7.21 (m, 2H), 7.11 (t, J _{H, F} = 73.6 Hz, 1H ), 6.98-6.76 (br, 2H), 5.28-5.23 (m, 1H), 4.60 (s, 2H), 4.15 (d, J = 4.8 Hz, 2H), 3.70 (dd, J = 10.0 Hz, J = 14.8 Hz, 1H), 3.54 (d, J = 14.4 Hz, 1H). MS: (M + H) ⁺ 392.
[773] (b) (S) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester
[774]
[775] (R) -N -cyanomethyl-3-cyclohexyl-2-hydroxy-propionamide was reacted in a similar manner as in Example 8 (a) to (S) -carbamic acid 1- (cyanomethyl-carba Moyl) -2-cyclohexyl-ethyl ester. ¹ H NMR: (DMSO) 8.63 (t, J = 5.6 Hz, 1H), 6.63 (br, 2H), 4.81-4.77 (m, 1H), 4.11 (d, J = 5.2 Hz, 2H), 1.74-0.81 (m, 13 H). MS: (M + H) ⁺ 254.
[776] Example 16
[777] (a) (R) -Morpholine-4-carboxylic acid 1- (1-cyano-cyclopropylcarbamoyl) -2-phenylmethanesulfonyl-ethyl ester
[778]
[779] DMF was added to (R) -morpholine-4-carboxylic acid 1-carboxy-2-phenylmethanesulfonyl-ethyl ester {from step 2 in Example 4 (a)} (60 mg, 0.168 mmol), HATU (200 mg, 0.52 mmol ) And 1-amino-cyclopropanecarbonitrile hydrochloride (100 mg, 0.84 mmol). 4-methylmorpholine (0.5 ml) is added and the mixture is stirred overnight. The mixture is diluted with ethyl acetate (100 ml), washed with 1N aqueous HCl, brine, saturated aqueous NaHCO ₃ , brine, dried over MgSO ₄ and evaporated in vacuo. Flash chromatography on silica gel (hexane / ethyl acetate 1: 2) gave (R) -morpholine-4-carboxylic acid 1- (1-cyano-cyclopropylcarbamoyl) -2-phenylmethanesulfonyl-ethyl ester ( 7 mg, 0.017 mmol) is obtained. ¹ H NMR: (DMSO) 9.16 (s, 1H), 7.40-7.32 (m, 5H), 5.24-5.19 (m, 1H), 4.55 (d, J = 13.2 Hz, 1H), 4.48 (d, J = 13.2 Hz, 1H), 3.63-3.25 (m, 10H), 1.51-1.39 (m, 2H), 1.20-1.07 (m, 2H). MS: (M + H) ⁺ 422.
[780] (b) (R) -Morpholine-4-carboxylic acid 1- (4-cyano-tetrahydro-pyran-4-ylcarbamoyl) -2-phenylmethanesulfonyl-ethyl ester
[781]
[782] Similar to Example 16 (a) using 4-amino-tetrahydropyran-4-carbonitrile hydrochloride (prepared according to step 1 of Example 13 (a) using tetrahydropyran-4-one) Reaction by the method affords (R) -morpholine-4-carboxylic acid 1- (4-cyano-tetrahydro-pyran-4-ylcarbamoyl) -2-phenylmethanesulfonyl-ethyl ester. LC-MS: Elution time = 3.20 min, 464.4 (M-1), 466.2 (M + 1). (MS: API 150EX. LC: HP Agilent 1100 Series, Column: Phenomenex, 5μ ODS3 100A 100X3mm; Flow: 2ml / min.Two solvent gradients: Solvent A, 99% water, 1% acetonitrile, 0.1% Solvent B, 99% acetonitrile, 1% water, 0.1% AcOH.gradient 100% A, 0% B to 0% A, 100% B t = 0 to 6 min.gradient 100% A, 0% B t = 7-15 minutes).
[783] Example 17
[784] 3-cyclohexyl-2-hydroxy-N- [1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propyl] -propionamide
[785]
[786] Step 1. [1- (Hydroxy-oxazolo [4,5-b] pyridin-2-yl-methyl) -propyl] -carbamic acid tert - butyl ester (3.11 g, 10 mmol, in dioxane (4 ml) To a stirred solution of (prepared as described in step 2 of Reference Example 20) HCl (4N solution in 5 ml of dioxane) is added at room temperature. After 2 h ethyl ether (50 ml) is added and the reaction mixture is filtered. The resulting solid is washed with 20 ml of ethyl ether and dried under vacuum to afford 3 g of 2-amino-1-oxazolo [4,5-b] pyridin-2-yl-butan-1-ol HCl salt.
[787] Step 2. 3-Cyclohexyl-2-hydroxy-propionic acid (155 mg, 0.9 mmol), 2-amino-1-oxazolo [4,5-b] pyridin-2-yl-butane-1 in MeCN (5 ml) To a stirred mixture of -ol HCl salt and HOBt (168 mg, 1.1 mmol) was added EDC (270 mg, 1.4 mmol) and N-methylmorpholine (0.45 ml) at 23 ° C. After stirring for 14 hours, the reaction mixture is extracted with ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , brine, dried over MgSO ₄ and concentrated to 3-cyclohexyl-2-hydroxy-N- [1- (hydroxy-oxazolo [4,5-b] pyridine-2 293 mg of -yl-methyl) -propyl] -propionamide are obtained and used in step 3 without further purification. MS: 360.3 (M-1), 362.3 (M + 1), 384.2 (M + Na).
[788] Step 3. 3-cyclohexyl-2-hydroxy-N- [1- (hydroxy-oxazolo [4,5-b] pyridin-2-yl-methyl) -propyl] -propion in MeCl ₂ (20 ml) To a stirred solution of amide (300 mg, 0.83 mmol) MnO ₂ (1.44 g, 16.6 mmol) is added at room temperature. After stirring for 30 minutes, the mixture is filtered to remove MnO ₂ and washed with 20 ml of MeCl ₂ . The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give 3-cyclohexyl-2-hydroxy-N- [1- (oxazolo [4,5-b] pyridine-2-carbonyl)- Propyl] -propionamide (40 mg) is obtained. ¹ H NMR (DMSO-δ): 8.71 (1H, dd, NH, diastereomer), 8.38 (1H, dd,), 8.28 (1H, m), 7.7-7.6 (1H, m), 5.5-5.4 ( 1H, m), 5.2-5.1 (1H, m), 3.95-3.991H, br., OH), 2.1-1.95 (1H, m), 1.85-1.75 (1, m), 1.7-0.8 (16H, m ). MS: 358.1 (M-1), 360.1 (M + 1), 382 (M + Na).
[789] Example 18
[790] (a) (R) -N- [1- (benzothiazole-2-carbonyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide
[791]
[792] (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide {30 mg in dichloromethane (10 ml) , 0.06 mmol, Example 30 (a)} is treated with Dess Martin periodinan (51 mg, 0.12 mmol). The mixture is stirred at room temperature for 45 minutes, treated with resin bound thiosulfate (400 mg, 0.6 mmol) and then stirred for an additional 24 hours, and the mixture is treated with AP-trisamine (270 mg, 0.6 mmol). . After stirring for an additional 24 hours, the reaction mixture is filtered and the filtrate is evaporated to (R) -N- [1- (benzothiazole-2-carbonyl) -butyl] -2-isopropylamino-3- Phenylmethanesulfonyl-propionamide (23 mg, 75%) is obtained as a mixture of diastereomers. ¹ H NMR (CDCl ₃ , 300 MHz): 8.29-8.27 (m, 1H), 8.23-8.19 (m, 1H), 8.01-7.98 (m, 1H), 7.63-7.36 (m, 7H), 5.80-5.74 ( m, 1H), 4.36-4.31 (m, 2H), [3.79 (dd, J = 9.5 Hz, 3 Hz), 3.73 (dd, J = 9 Hz, 2.5 Hz) 1H], 3.41-3.34 (m, 1H), 3.20-3.01 (m, 1H), 2.89-2.85 (m, 1H), 2.17-2.06 (m, 1H), 1.88-1.78 (m, 1H), 1.52-1.25 (m, 3H), 1.12-1.06 (m , 6H), [0.96 (t, J = 7.5 Hz) 0.95 (t, J = 7.5 Hz) 1H]. LC / MS mlz = 502 (M + H).
[793] (b) (R) -N- [1- (benzothiazol-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide
[794]
[795] (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide {0.11 mmol, Example 29 (b)} and the crude product were treated by HPLC and reacted in a similar manner as in Example 18 (a) to give (R) -N- [1- (benzothiazole-2- Carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide (10 mg, 16%) is obtained. LC / MS retention time 2.92 min (TIC), m / z = 544 (M + H) (as measured by Method A).
[796] (c) (R) -N- [1- (benzothiazole-2-carbonyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide
[797]
[798] (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide {0.11 mmol, Example 29 ( a)} and the crude product was treated by HPLC and reacted in a similar manner as in Example 18 (a) to give (R) -N- [1- (benzothiazole-2-carbonyl) -butyl] -2 -Dibenzylamino-3-phenylmethanesulfonyl-propionamide (4 mg) is obtained as a mixture of diastereomers. ¹ H NMR (CDCl ₃ , 300 MHz): 8.33-7.89 (m, 3H), 7.61-7.55 (m, 2H), 7.47-7.29 (m, 15H), 5.75 (m, 1H), [4.54 (d, J) = 14 Hz), 4.51 (d, J = 13.5 Hz), 1H], [4.27 (d, J = 14 Hz), 4.25 (d, J = 13.5 Hz), 1H], 4.11-3.95 (m, 2H), [ 3.78 (d, J = 13 Hz), 3.76 (d, J = 13 Hz), 2H], [3.51 (d, J = 13 Hz), 3.50 (d, J = 13 Hz), 2H], 3.19-3.13 (m, 1H ), 2.10-1.77 (m, 2H), 1.51-1.37 (m, 2H), 0.91-084 (m, 3H). LC / MS m / z = 640 (M + H).
[799] (d) (R) -N- [1- (benzothiazole-2-carbonyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide
[800]
[801] (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide {30 mg, 0.06 mmol, Example 30 (b)} and the crude product was treated by HPLC to react in a similar manner as in Example 18 (a) to give (R) -N- [1- (benzothiazole-2-carbonyl) -butyl]- 2-dimethylamino-3-phenylmethanesulfonyl-propionamide (11 mg, 38%) is obtained. LC / MS retention time 2.98 min (TIC), m / z = 488 (M + H) (measured by Method A).
[802] Example 19
[803] (a) (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) Propionamide
[804]
[805] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-) in dichloromethane (10 ml) A solution of pyran-4-ylamino) -propionamide {0.22 mmol, Example 31 (a)} is treated with des martin periodinan (187 mg, 0.44 mmol). The mixture is stirred overnight at room temperature, treated with resin bound thiosulfate (1.47 g, 2.2 mmol), then stirring is continued for an additional 24 hours, and the mixture is treated with silicyl triamine (611 mg, 2.2 mmol). After stirring for 24 hours, the reaction mixture is filtered. The filtrate was evaporated and the residue was treated by HPLC to give (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro Pyran-4-ylamino) -propionamide (9 mg, 8%) is obtained. LC / MS retention time 3.0 min (TIC), m / z = 528 (M + H) (measured by Method B).
[806] (b) (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2- (1-methyl-piperidin-4-ylamino) -3-phenyl Methanesulfonyl-propionamide
[807]
[808] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2- (1-methyl-piperidin-4-ylamino) -3- Reaction was carried out in a similar manner as in Example 19 (a) using phenylmethanesulfonyl-propionamide {0.22 mmol, Example 31 (b)} to give (R) -N-[(S) -1- (benzooxa Sol-2-carbonyl) -butyl] -2- (1-methyl-piperidin-4-ylamino) -3-phenylmethanesulfonyl-propionamide (7 mg, 6%) is obtained. LC / MS retention time 2.7 min (TIC), m / z = 541 (M + H) (as measured by Method A).
[809] (c) (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2- (bis-thiophen-2-ylmethyl-amino) -3-phenylmethane Sulfonyl-propionamide
[810]
[811] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2- (bis-thiophen-2-ylmethyl-amino) -3-phenyl Reaction was carried out in a similar manner as in Example 19 (a) using methanesulfonyl-propionamide {0.22 mmol, Example 31 (c)} to give (R) -N-[(S) -1- (benzoxazole 2-carbonyl) -butyl] -2- (bis-thiophen-2-ylmethyl-amino) -3-phenylmethanesulfonyl-propionamide (5.3 mg, 4%) is obtained. LC / MS retention time 3.7 min (TIC), m / z = 636 (M + H) (measured by Method A).
[812] (d) (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide
[813]
[814] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide {0.22 mmol, Example 31 (d)} was reacted in a similar manner as in Example 19 (a) to give (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl]- 2-dibenzylamino-3-phenylmethanesulfonyl-propionamide (3.8 mg, 3%) is obtained. LC / MS retention time 4.14 min (TIC), m / z = 624 (M + H) (as measured by Method B).
[815] (e) (S) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2- (tetrahydro-pyran-4-ylamino) -3-thiophene-2 -Yl-propionamide
[816]
[817] (S) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2- (tetrahydro-pyran-4-ylamino) -3-thiophene- Reaction was carried out in a similar manner as in Example 19 (a) using 2-yl-propionamide {0.22mmol, Example 31 (e)} to give (S) -N-[(S) -1- (benzooxazole -2-carbonyl) -butyl] -2- (tetrahydro-pyran-4-ylamino) -3-thiophen-2-yl-propionamide (6.5 mg, 6%). LC / MS retention time 2.92 min (TIC), m / z = 456 (M + H) (measured by Method B).
[818] (f) (S) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-isopropylamino-3-thiophen-2-yl-propionamide
[819]
[820] (S) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-isopropylamino-3-thiophen-2-yl-propionamide {0.22 (S) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl by reaction in the same manner as in Example 19 (a) using mmol, Example 31 (f)} ] -2-isopropylamino-3-thiophen-2-yl-propionamide (10.6 mg, 12%) is obtained. LC / MS retention time 2.99 min (TIC), m / z = 414 (M + H) (as measured by Method B).
[821] Example 20
[822] (a) (R) -N- [1- (benzothiazol-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide
[823]
[824] (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4- in dichloromethane (10 ml) A solution of monoamino) -propionamide {0.22 mmol, Example 32 (a)} is treated with des martin periodinan (187 mg, 0.44 mmol). After stirring at room temperature for 30 minutes, the reaction mixture is treated with saturated sodium thiosulfate solution (50 ml) and saturated sodium bicarbonate solution (50 ml). The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried over magnesium sulphate and evaporated. The residue was flash chromatographed using a silica gel cartridge to give (R) -N- [1- (benzothiazole-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran- 4-ylamino) -propionamide (46 mg, 38%) is obtained as a mixture of diastereomers. The two diastereomers are separated by silica gel column chromatography, eluting with a 1: 1 v / v heptane-ethyl acetate mixture.
[825] Diastereomer A: ¹ H NMR (CDCl ₃ , 300 MHz): 8.23-8.20 (m, 2H), 8.00 (dd, J = 7 Hz, 2 Hz, 1H), 7.63-7.53 (m, 2H), 7.48-7.40 ( m, 5H), 5.80 (m, 1H), 4.38 (d, J = 14 Hz, 1H), 4.32 (d, J = 14 Hz, 1H), 3.97-3.90 (m, 2H), 3.80 (dd, J = 9.5 Hz, 3 Hz, 1H), 3.43-3.30 (m, 3H), 3.13 (dd, J = 14.5 Hz, 9.5 Hz, 1H), 2.70 (m, 1H), 2.27 (m, 1H), 2.09 (m, 1H ), 1.91-1.76 (m, 3H), 1.52-1.37 (m, 4H), 0.95 (t, J = 7.5 Hz, 3H). LC / MS mlz = 544 (M + H).
[826] Diastereomer B: ¹ H NMR (CDCl ₃ , 300 MHz): 8.22-8.19 (m, 2H), 8.01-7.98 (m, 1H), 7.63-7.53 (m, 2H), 7.44-7.37 (m, 5H) , 5.74 (m, 1H), 4.35-4.31 (m, 2H), 3.99-3.94 (m, 2H), 3.86 (dd J = 9.5 Hz, 3 Hz, 1H), 3.49-3.33 (m, 3H), 3.08 ( dd, J = 14.5 Hz, 9.5 Hz), 2.75-2.70 (m, 1H), 2.22 (m, 1H), 2.15-2.06 (m, 1H), 1.91-1.75 (m, 3H), 1.53-1.37 (m , 4H), 0.96 (t, J = 7.5 Hz, 3H). LC / MS mlz = 544 (M + H).
[827] (b) (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) Propionamide
[828]
[829] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino (R) -N-[(S) -1- (benzooxazole-2) by reaction in a similar manner as in Example 20 (a) using) -propionamide {0.22 mmol, Example 32 (b)} -Carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide (48 mg, 41%) is obtained. ¹ H NMR (CDCl ₃ , 300 MHz): 8.22 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.60-7.40 (m , 7H), 5.68-5.61 (m, 1H), 4.37 (d, J = 14HZ, 1H), 4.31 (d, J = 14 Hz, 1H), 3.97-3.91 (m, 2H), 3.80 (dd, J = 9.5 Hz, 3 Hz, 1H), 3.43-3.32 (m, 3H), 3.12 (dd, J = 14.5 Hz, 9.5 Hz, 1H), 2.73-2.66 (m, 1H), 2.26 (m, 1H), 2.13- 2.05 (m, 1H), 1.89-1.77 (m, 3H), 1.52-1.39 (m, 4H), 0.97 (t, J = 7.5 Hz, 3H). LC / MS mlz = 528 (M + H).
[830] Example 21
[831] (a) ( R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide
[832]
[833] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl- in dichloromethane (10 ml) A solution of propionamide {30 mg, 0.063 mmol, Example 31 (g)} was treated with des martin piperiodinan (53 mg, 0.126 mmol), and the mixture was stirred at room temperature for 1 hour, and METTLER as follows. Post-treatment of the Mettler-Toledo Allex ^R liquid handler:
[834] Dichloromethane (15 ml) is added to the reaction mixture, and a 1: 1 mixture (8 ml) of saturated sodium thiosulfate solution and saturated sodium bicarbonate solution is added. The phases are separated and the organic phase is washed with 5 ml of thiosulfate / bicarbonate solution. The organic phase is washed with brine and dried over magnesium sulfate. The crude product was flash chromatographed using a silica gel cartridge to give (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-isopropylamino-3-phenylmethane Sulfonyl propionamide (6.2 mg, 20%) is obtained. LC / MS retention time 2.7 min (TIC), m / z = 486 (M + H) (measured by Method C).
[835] (b) (R) -N-[(S) -1- (Benzooxazole-2-carbonyl) -butyl] -2-[(2-methoxy-ethyl)-(tetrahydro-pyran-4- Yl) -amino] -3-phenylmethanesulfonyl-propionamide
[836]
[837] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-[(2-methoxy-ethyl)-(tetrahydro-pyran-4 -Yl) -amino] -3-phenylmethanesulfonyl-propionamide {80 mg, 0.136 mmol, Example 32 (d)} to react in a similar manner as in Example 21 (a) (R) -N -[(S) -1- (Benzoxazol-2-carbonyl) -butyl] -2-[(2-methoxy-ethyl)-(tetrahydro-pyran-4-yl) -amino] -3- Phenylmethanesulfonyl-propionamide (7 mg, 9%) is obtained. LC / MS retention time 3.5 min (TIC), m / z = 586 (M + H) (measured by Method C).
[838] (c) (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-cyclohexylamino-3-phenylmethanesulfonyl-propionamide
[839]
[840] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-cyclohexylamino-3-phenylmethanesulfonyl-propionamide {48 mg, 0.091 mmol, Example 32 (e)} and reacted in a similar manner as in Example 21 (a) to give (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl ] -2-cyclohexylamino-3-phenylmethanesulfonyl-propionamide (7.9 mg, 16%) is obtained. LC / MS retention time 2.99-3.02 min (TIC), m / z = 526 (M + H) (measured by Method C).
[841] (d) (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide
[842]
[843] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide {10 mg, 0.021 mmol (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] in a similar manner as in Example 21 (a) using Example 32 (f) 2-Dimethylamino-3-phenylmethanesulfonyl-propionamide (2.5 mg, 24%) is obtained. LC / MS retention time 2.82 min (TIC), m / z = 472 (M + H) (as measured by Method C).
[844] Example 22
[845] (1S) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2- (S) -fluoro-4-phenyl-butyramide
[846]
[847] Step 1. (S) -2-Amino-1-benzooxazol-2-yl-pentan-1-ol {0.549 mmol, 121 mg, Reference Example 17 (c)} in anhydrous dichloromethane (5 ml) under nitrogen. To a mixture of (S) -2-fluoro-4-phenyl-butyric acid (1.0 equiv, 0.549 mmol, 100 mg, Reference Example 9) and N, N-diisopropylethylamine (1.1 equiv, 0.604 mmol, 78 mg) PyBOP ^R (1.1 equiv, 0.603 mmol, 285 mg) is added. The mixture is stirred at rt for 23.5 h and concentrated in vacuo. The residue is diluted with ethyl acetate (20 ml) and washed with sodium bicarbonate (30 ml) and water (30 ml). The organic layer is dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate and heptane (1: 2) to give (S) -N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -Butyl] -2-fluoro-4-phenyl-butyramide (167.8 mg, 79.5%) is obtained as a mixture of diastereomers.
[848] Step 2. (S) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-fluoro-4- in anhydrous dichloromethane (5 ml) under nitrogen. 15% (by weight in dichloromethane, 2.0 equiv, 0.863 mmol, 2.44 g) in 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodine in a solution of phenyl-butyrylamide Oxol-3 (1H) -one (des-martin piperiodinan) is added. The mixture is stirred for 2 hours at room temperature and quenched by addition of a solution of Na ₂ S ₂ O ₃ (4.0 equiv, 1.73 mmol, 273 mg) in saturated sodium bicarbonate solution (30 ml). The organic layer is dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified on 10 g of silica gel, eluting with ethyl acetate and heptane (1: 3) to give (1S) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2- (S) -fluoro Rho-4-phenyl-butyramide (156 mg, 94%) is obtained as a pale yellow solid. ¹ H NMR (CDCl ₃ ) 7.95 (d, J = 7.9 Hz, 1H), 7.7 (d, J = 8.2 Hz, 1H), 7.6 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.2 (m, 6H), 5.8 (m, 1H), 4.95 (ddd, J = 49.4, 8, 3.5 Hz, 1H), 2.8 (m, 2H), 2.4 (m, 1H), 2.2 (m, 2H), 1.85 (m, 1H), 1.5 (m, 2H), 1.0 (t, J = 7.3 Hz, 3H). LC / MS 86% (M + l) 383.
[849] Example 23
[850] 2,2-difluoro-5-phenyl-pentanoic acid [(S) -1- (benzooxazole-2-carbonyl) -butyl] -amide
[851]
[852] Step 1. A solution of 2,2-difluoro-5-phenyl-pentanoic acid (182 mg, 0.85 mmol) in DMF (10 ml) was added to (S) -2-amino-1-benzooxazol-2-yl-pentane. Treat with -1-ol (187 mg, 0.85 mmol), HATU (323 mg, 0.85 mmol) and N, N-diisopropylethylamine (0.162 ml) and stir at room temperature for 5 hours 30 minutes. DMF is evaporated and the crude product is dissolved in ethyl acetate and washed with 1N HCl, saturated NaHCO ₃ and brine. Dry with Na ₂ SO ₄ and evaporate under reduced pressure to give an oil. Purification by column chromatography eluting with a 1: 1 mixture of ethyl acetate and heptane to yield 2,2-difluoro-5-phenyl-pentanoic acid [(S) -1- (benzooxazol-2-yl-hydride Roxy-methyl) -butyl] -amide (216 mg) is obtained as an orange oil. MS 417 (MH ⁺ ).
[853] Step 2. 2,2-Difluoro-5-phenyl-pentanoic acid [(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -amide in dichloromethane (10 ml) 216 mg, 0.52 mmol) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodeoxol-3 (1H) -one (des-martin piperiodinan) (220 mg , 0.52 mmol) at room temperature for 1 hour. The reaction mixture is washed with 0.5M Na ₂ S ₂ O ₃ , saturated NaHCO ₃ and water and dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography, eluting with a mixture of ethyl acetate and heptanes to give 2,2-difluoro-5-phenyl-pentanoic acid [(S) -1- (benzooxa Sol-2-carbonyl) -butyl] -amide (90 mg) is obtained as off-white solid. ¹ H NMR (CDCl ₃ ) 7.93 (d, J = 8 Hz, 1H), 7.68 (d, J = 8 Hz, 1H), 7.59 (t, J = 8 Hz, 1H), 7.49 (t, J = 8 Hz, 1H), 7.3-7.11 (m, 5H), 5.72 (m, 1H), 2.67 (t, J = 7.5 Hz, 2H), 2.22-2.07 (m, 3H), 1.92-1.77 (m, 3H) , 1.55-1.26 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). LC / MS 415 (M + l).
[854] Example 24
[855] (a) morpholine-4-carboxylic acid (S) -1-[(S) -1- (benzooxazole-2-carbonyl) -propylcarbamoyl] -2-cyclohexyl-ethyl ester
[856]
[857] Step 1. Dissolve (S) -3-cyclohexyl-2-hydroxy-propionic acid (3 g, 17.4 mmol) in methanol (30 ml). Trimethylorthopromate (5 ml) and p-toluenesulfonic acid monohydrate (100 mg) are added. The mixture is stirred at ambient temperature overnight. Water (50 ml) is added and stirring is continued for 2 hours. Methanol is removed in vacuo and the aqueous residue is extracted with ethyl acetate (3x50 ml). The combined organic layers are washed with saturated aqueous NaHCO ₃ and brine, dried over MgSO ₄ and evaporated. (S) -3-cyclohexyl-2-hydroxy-propionic acid methyl ester (3.1 g, 16.7 mmol) is obtained as a colorless liquid.
[858] Step 2. Dissolve (S) -3-cyclohexyl-2-hydroxy-propionic acid methyl ester (1 g, 5.37 mmol) in dichloromethane (20 ml). Pyridine (0.57 ml, 7 mmol) is added and the solution is cooled to 0 ° C. under nitrogen. Trichloromethylchloroformate (0.66 ml, 5.5 mmol) is added and the mixture is stirred at room temperature for 30 minutes. Morpholine (0.5 ml) is added and stirring is continued for 2 hours. After dilution with ethyl acetate (200 ml), the solution is washed with 1N aqueous HCl and brine, dried over MgSO ₄ and evaporated in vacuo. The residue is dissolved in methanol (50 ml) and 1N NaOH aqueous solution (20 ml) is added. The mixture is stirred at rt for 4 h. Methanol is removed in vacuo and the aqueous residue is washed with diethyl ether. The aqueous layer is acidified with 1N aqueous HCl and extracted with ethyl acetate (3 × 100 ml). The combined organic layers are washed with brine, dried over MgSO ₄ and evaporated in vacuo. Crude (S) -morpholine-4-carboxylic acid 1-carboxy-2-cyclohexyl-ethyl ester is used without further purification.
[859] Step 3. Reaction in a manner similar to that described in Step 3 of Example 4 (a) using (S) -morpholine-4-carboxylic acid 1-carboxy-2-cyclohexyl-ethyl ester Carboxylic acid (S) -1-[(S) -1- (benzooxazole-2-carbonyl) -propylcarbamoyl] -2-cyclohexyl-ethyl ester is obtained. ¹ H NMR: (DMSO) 8.61 (d, J = 6.4 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 5.15-5.09 (m, 1H), 4.91-4.86 (m, 1H), 3.56-3.20 (m, 8H), 2.05-1.93 (m, 1H), 1.79-0.78 (m, 14H), 0.96 (t, J = 7.2 Hz, 3H). MS: (M + H) ⁺ 472.
[860] Reaction was carried out in a similar manner as in Example 24 (a), to prepare:
[861] (b) morpholine-4-carboxylic acid (S) -2-cyclohexyl-1-[(S) -1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propylcarbamoyl]- Ethyl ester
[862]
[863] ¹ H NMR: (DMSO) 8.73-8.69 (m, 2H), 8.38 (d, J = 8.0 Hz, 1H), 7.67-7.62 (m, 1H), 5.08-5.02 (m, 1H), 4.88-4.83 ( m, 1H), 3.57-3.20 (m, 8H), 2.07-1.95 (m, 1H), 1.79-0.75 (m, 14H), 0.97 (t, J = 7.2 Hz, 3H). MS: (M + H) ⁺ 473;
[864] (c) morpholine-4-carboxylic acid (S) -2-cyclohexyl-1-[(S) -1- (5-ethyl- [1,3,4] oxadiazole-2-carbonyl) -propyl Carbamoyl] -ethyl ester
[865]
[866] ¹ H NMR: (DMSO) 8.62 (d, J = 4.8 Hz, 1H), 4.94-4.84 (m, 2H), 3.57-3.20 (m, 8H), 2.95 (q, J = 7.2 Hz, 2H), 1.98 -1.87 (m, 1H), 1.74-0.82 (m, 14H), 1.29 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H). MS: (M + H) ⁺ 451;
[867] (d) Morpholine-4-carboxylic acid (S) -2-cyclohexyl-1-[(S) -1- (5-phenyl- [1,3,4] oxadiazole-2-carbonyl) -propyl Carbamoyl] -ethyl ester
[868]
[869] ¹ H NMR: (DMSO) 8.69 (d, J = 6.0 Hz, 1H), 8.07 (d, J = 8 Hz, 2H), 7.70-7.59 (m, 3H), 4.99-4.92 (m, 1H), 4.88- 4.83 (m, 1H), 3.57-3.20 (m, 8H), 2.03-1.92 (m, 1H), 1.77-0.77 (m, 14H), 0.96 (t, J = 7.2 Hz, 3H). MS: (M + H) ⁺ 499;
[870] (e) Morpholine-4-carboxylic acid (S) -1-[(S) -1- (benzooxazole-2-carbonyl) -propylcarbamoyl] -3-cyclohexyl-propyl ester
[871]
[872] ¹ H NMR: (DMSO) 8.60 (d, J = 6.8 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 5.13-5.06 (m, 1H), 4.81-4.76 (m, 1H), 3.56-3.21 (m, 8H), 2.05-1.93 (m, 1H), 1.79-1.46 (m, 8H), 1.19-0.90 (m, 6H), 0.96 (t, J = 7.2 Hz, 3H), 0.77-0.62 (m, 2H). MS: (M + H) ⁺ 486;
[873] Example 25
[874] 4- [4,4-Dimethyl-2- (morpholine-4-carbonyloxy) -pentanoylamino] -3-oxo-azepane-1-carboxylic acid benzyl ester
[875]
[876] Sodium hydride (60% in mineral oil, 10 g, 250 mmol) is suspended in anhydrous DMF. Allyl-carbamic acid benzyl ester (19.1 g, 100 mmol) is added dropwise at ambient temperature. After stirring for 5 minutes, 5-bromo-1-pentene (25 g, 168 mmol) is added dropwise. Stirring is continued at 50 ° C. for 1 hour. The reaction is quenched with water and partitioned between diethyl ether and water. The ether layer is washed with water and brine, dried over MgSO ₄ and evaporated in vacuo. Flash chromatography (ethyl acetate / hexane 1: 9) yields 15.5 g of allyl-pent-4-enyl-carbamic acid benzyl ester.
[877] Allyl-pent-4-enyl-carbamic acid benzyl ester (15.5 g, 59.8 mmol) is dissolved in dichloromethane and bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (1 g) is added. The mixture is refluxed under a nitrogen atmosphere until TLC analysis indicates complete reaction. The solvent is evaporated in vacuo and the residue is purified by flash chromatography (ethyl acetate / hexane 1: 9). Yield: 7.8 g of 2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester.
[878] To a solution of 2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester (4.5 g, 19.45 mmol) in dichloromethane (50 ml) is added m-chloroperbenzoic acid (60 mmol). The mixture is stirred at ambient temperature for 16 hours. Saturated aqueous K ₂ CO ₃ solution is added and the mixture is extracted with dichloromethane. The combined organic layers are washed with saturated aqueous NaHCO ₃ and brine, dried over MgSO ₄ and evaporated in vacuo. The crude epoxide is dissolved in an 8: 1 methanol / water mixture (100 ml). Ammonium chloride (3.2 g, 60 mmol) and sodium azide (3.9 g, 60 mmol) are added and the mixture is heated to 60 ° C. for 48 h. Most solvents are removed in vacuo. The residue is extracted with ethyl acetate. The combined organic layers are washed with saturated aqueous NaHCO ₃ (200 ml) and brine (200 ml), dried over MgSO ₄ and evaporated in vacuo. The residue was flash chromatographed (hexane / ethyl acetate 3: 1) to give 3.3 g of 4-azido-3-hydroxy-azepane-1-carboxylic acid benzyl ester.
[879] Triethylamine (5 ml) and 1,3-propanedithiol (3.42 ml) in a solution of 4-azido-3-hydroxy-azepane-1-carboxylic acid benzyl ester (3.3 g, 11.37 mmol) in methanol (50 ml) , 35 mmol). The mixture is stirred at ambient temperature until TLC analysis shows complete consumption of starting material. The white precipitate is filtered off and the filtrate is evaporated to dryness. The residue is triturated with a 1: 1 hexane / diethylether mixture to remove excess dithiol and dried under vacuum.
[880] Crude 4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester (150 mg, 0.57 mmol), morpholine-4-carboxylic acid 1-carboxy-3,3-dimethyl-butyl ester (120 mg, 0.46 mmol), Combine EDC (400 mg, 2.1 mmol) and HOBt (400 mg, 2.5 mmol). Dichloromethane (5 ml) is added and 4-methylmorpholine (0.5 ml) is added. The mixture is stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (100 ml), the solution is washed with 1N HCl, saturated aqueous NaHCO ₃ and brine, dried over MgSO ₄ and evaporated in vacuo. The residue is dissolved in DMSO (5 ml). Triethylamine (0.3 ml) and SO ₃ pyridine complex (150 mg) are added and the mixture is stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (100 ml), the solution is washed with water (50 ml) and brine, dried over MgSO ₄ and evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give 4- [4,4-dimethyl-2- (morpholine-4-carbonyloxy) -pentanoylamino] -3-oxo-azepane-1-carboxylic acid benzyl Ester (95 mg, 0.189 mmol) is obtained as a white solid. 2: 1 mixture of diastereomers. ¹ H NMR: (DMSO) 8.14-8.08 (m, 1H), 7.40-7.25 (m, 5H), 5.18-4.89 (m, 3H), 4.51-4.33 (m, 2H), 4.01-3.76 (m, 2H ), 3.60-3.25 (m, 8H), 2.95-2.79 (m, 1H), 1.84-1.54 (m, 6H), 0.92 / 0.91 (s, 9H). MS: (M + H) ⁺ 504. LC / MS m / z = 474 (M + H).
[881] Example 26
[882] (a) (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -3-cyclopropylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino ) -Propionamide
[883]
[884] Step 1. (R) -2-Amino-N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-cyclopropylmethanesulfonyl-propionamide {90 mg 0.22 mmol, Reference Example 11 (f)} is dissolved in 5% acetic acid in acetonitrile (10 ml). Tetrahydro-4H-pyran-4-one (110 mg, 1.1 mmol) is added, followed by (polystyrylmethyl) trimethylammonium cyanoborohydride (107 mg, 1.1 mmol). The resulting reaction mixture is stirred for 4 hours and suction filtered. The solvent is evaporated under high vacuum. The residue is dissolved in 5 ml of dichloromethane, silicyl triamine (940 mg, 2.2 mmol) is added and the reaction mixture is stirred for 4 hours. Suction filtration and the filtrate was concentrated under reduced pressure to afford (R) -N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-cyclopropylmethanesulfonyl-2- (Tetrahydro-pyran-4-ylamino) -propionamide (89 mg, 0.18 mmol, 82%) is obtained.
[885] Step 2. (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-cyclopropylmethanesulfonyl-2- (tetrahydro-pyran- 4-ylamino) -propionamide (89 mg, 0.18 mmol) is dissolved in 10 ml of dichloromethane. Dess-Martin-Piperiodinan (153 mg, 0.36 mmol) is added and the resulting reaction mixture is stirred for 2 hours. The reaction mixture is poured into a 1: 1 mixture of saturated sodium bicarbonate solution and saturated sodium thiosulfate solution. The aqueous phase is extracted with dichloromethane. The combined organic phases are washed with saturated sodium bicarbonate solution and brine. The organic phase is dried over magnesium sulfate and dichloromethane is evaporated under reduced pressure. The crude product was purified via flash chromatography (heptane / ethyl acetate 1/1 eluting) to afford (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -3-cyclo Propylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide (24 mg, 0.049 mmol, 27%) is obtained. ¹ H NMR (CDCl ₃ , 300 MHz): 8.29 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 8 Hz, 1H), 7.68 (d, J = 8 Hz, 1H), 7.59-7.46 (m, 2H), 5.67 (m, 1H), 3.99-3.93 (m, 2H), 3.84 (dd, J = 9.5 Hz, 2.5 Hz, 1H), 3.56 (dd, J = 14.5 Hz, 2.5 Hz, 1H), 3.42 -3.33 (m, 2H), 3.24 (dd, J = 14.5 Hz, 9.5 Hz, 1H), 3.02-2.99 (m, 2H), 2.78-2.71 (m, 1H), 2.13-2.07 (m, 1H), 1.95-1.78 (m, 3H), 1.55-1.41 (m, 5H), 1.23-1.16 (m, 1H), 1.00 (t, J = 7.5 Hz, 3H), 0.81-0.74 (m, 2H), 0.48- 0.43 (m, 2 H). LC / MS m / z = 492 (M + H).
[886] (b) (R) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2-cyclohexylamino-3-cyclopropylmethanesulfonyl-propionamide
[887]
[888] Reaction was carried out in a similar manner as in Example 26 (a) using cyclohexanone to give (R) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2-cyclohexylamino-3- Cyclopropylmethanesulfonyl-propionamide (primarily as one diastereoisomer) is obtained. ¹ H NMR (CDCl ₃ , 300 MHz): 8.37 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8 Hz, 1H), 7.67 (d, J = 8 Hz, 1H), 7.59-7.36 (m, 2H), 5.65 (m, 1H), 3.79 (dd, J = 9.5 Hz, 2.5 Hz, 1H), 3.54 (dd, J = 14.25 Hz, 2.5 Hz, 1H), 3.24 (dd, J = 14.25 Hz, 9.5 Hz, 1H), 3.02-2.95 (m, 2H), 2.49 (m, 1H), 2.12-2.07 (m, 1H), 1.96-1.17 (m, 15H), 0.98 (t, J = 7 Hz, 3H), 0.80-0.72 (m, 2H), 0.48-0.43 (m, 2H). LC / MS mlz = 490 (M + H).
[889] (c) (R) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2-cycloheptylamino-3-cyclopropylmethanesulfonyl-propionamide
[890]
[891] Reaction was carried out in a similar manner as in Example 26 (a) using cycloheptanone to give (R) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2-cycloheptylamino-3- Cyclopropylmethanesulfonyl-propionamide is obtained. ¹ H NMR (CDCl ₃ , 300 MHz): [8.36 (d, J = 8.5 Hz), 8.28 (d, J = 8.5 Hz), 1H], [8.05 (dd, J = 8 Hz, 1 Hz), 7.97 (dd, J = 8.5 Hz, 1.5 Hz), 1H], [7.92 (d, J = 8.5 Hz), 7.67 (d, J = 8 Hz), 1H], 7.59-7.48 (m, 1H), [7.44 (ddd, J) = 8 Hz, 7.5 Hz, 1 Hz), 7.19 (ddd, J = 8 Hz, 7.5 Hz, 1 Hz), 1H], [5.65 (m), 5.62 (m), 1H], [3.82 (dd, J = 10 Hz, 3 Hz) ), 3.75 (dd, J = 9 Hz, 3 Hz), 1H], [3.55 (dd, J = 14.5 Hz, 3 Hz), 3.49 (dd, J = 14.5 Hz, 3 Hz), 1H], 3.27 (dd, J = 14.5 Hz, 9 Hz, 1H), 3.03-2.96 (m, 2H), 2.72 (m, 1H), 2.14-2.05 (m, 1H), 1.91-1.39 (m, 16H), 1.23-1.17 (m, 1H) , [0.99 (t, J = 7.25 Hz), 0.98 (t, J = 7.25 Hz), 1H], 0.79-0.7 (m, 2H), 0.48-0.44 (m, 2H). LC / MS mlz = 504 (M + H).
[892] (d) (R) -3-phenylmethanesulfonyl-N-[(S) -3-phenyl-1- (thiazole-2-carbonyl) -propyl] -2- (tetrahydro-pyran-4- Monoamino) -propionamide
[893]
[894] (R) -2-Amino-N-[(S) -1- (hydroxy-thiazol-2-yl-methyl) -3-phenyl-propyl] -3-phenylmethanesulfonyl-propionamide {Reference Practice Example 11 (k)} to react in a similar manner as in Example 26 (a) to give (R) -3-phenylmethanesulfonyl-N-[(S) -3-phenyl-1- (thiazole- 2-carbonyl) -propyl] -2- (tetrahydro-pyran-4-ylamino) -propionamide is obtained. ¹ H NMR (CDCl ₃ , 300 MHz): 8.27 (d, J = 9 Hz, 1H), 8.06 (d, J = 3 Hz, 1H), 7.73 (d, J = 3 Hz, 1H), 7.47-7.39 (m, 5H ), 7.25-7.11 (m, 5H), 5.72 (m, 1H), 4.36 (d, J = 14 Hz, 1H), 4.31 (d, J = 14 Hz, 1H), 3.97-3.90 (m, 2H), 3.76 (dd, J = 9.5 Hz, 3 Hz, 1H), 3.40-3.31 (m, 3H), 3.01 (dd, J = 14.5 Hz, 9.5 Hz, 1H), 2.76-2.62 (m, 3H), 2.51-2.40 ( m, 1H), 2.22-2.09 (m, 1H), 1.87-1.75 (m, 2H), 1.53-1.38 (m, 3H). LC / MS mlz = 556 (M + H).
[895] (e) (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -3-phenyl-propyl] -3-cyclopropylmethanesulfonyl-2- (tetrahydro-pyran- 4-ylamino) -propionamide
[896]
[897] (R) -2-Amino-N-[(S) -1- (hydroxy-thiazol-2-yl-methyl) -3-phenyl-propyl] -3-phenylmethanesulfonyl-propionamide {Reference Practice Example 11 (j)} to react in a similar manner as in Example 26 (a) to give (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -3-phenyl- Propyl] -3-cyclopropylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide is obtained. ¹ H NMR (CDCl ₃ , 300 MHz): 8.36 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8 Hz, 1H), 7.67 (d, J = 8 Hz, 1H), 7.60-7.46 (m, 2H), 7.25-7.16 (m, 5H), 5.72 (m, 1H), 3.99-3.93 (m, 2H), 3.81 (dd, J = 9.5 Hz, 3 Hz, 1H), 3.52 (dd, J = 14 Hz, 3 Hz, 1H), 3.41-3.33 (m, 2H), 3.15 (dd, J = 14 Hz, 9.5 Hz, 1H), 3.01-2.70 (m, 2H), 2.81-2.70 (m, 3H), 2.53 (m, 1H), 2.27-2.23 (m, 1H), 1.94-1.44 (m, 5H), 1.22-1.17 (m, 1H), 0.80-0.74 (m, 2H), 0.47-0.42 (m, 2H). LC / MS mlz = 554 (M + H).
[898] (f) (R) -3-cyclopropylmethanesulfonyl-N- [1- (5-ethyl-1,2,4-oxadiazole-3-carbonyl) -propyl] -2- (tetrahydro- Pyran-4-ylamino) -propionamide
[899]
[900] (R) -2-Amino-3-cyclopropylmethanesulfonyl-N-{(S) -1-[(5-ethyl-1,2,4-oxadiazol-3-yl) -hydroxy-methyl ] -Propyl} -propionamide {see Example 11 (h)} to react in a similar manner as in Example 26 (a) to (R) -3-cyclopropylmethanesulfonyl-N- [1- ( 5-Ethyl-1,2,4-oxadiazole-3-carbonyl) -propyl] -2- (tetrahydro-pyran-4-ylamino) -propionamide is obtained. ¹ H NMR (CDCl ₃ , 300 MHz): [8.28 (d, J = 8.5 Hz), 8.15 (d, J = 8 Hz), 1H], [5.40 (m), 5.33 (m), 1H], 3.99-3.95 (m, 2H), [3.90 (dd, J = 10 Hz, 3 Hz), 3.84 (dd, J = 9.5 Hz, 3 Hz), 1H], [3.55 (dd, J = 14 Hz, 3 Hz), 3.47 (dd, J = 14 hz, 11 Hz), 1H], 3.45-3.33 (m, 2H), 3.23 (dd, 14 Hz, 10 Hz, 1H), 3.07-2.94 (m, 4H), 2.82-2.71 (m, 1H), 2.19-2.08 (m, 1H), 1.95-1.77 (m, 5H), 1.58-1.43 (m, 1H), 1.45 (t, J = 7.5 Hz, 3H), 1.23-1.14 (m, 1H), [1.00 (t, J = 7.5 Hz), 0.97 (t, J = 7.5 Hz), 3H], 0.81-0.73 (m, 2H), 0.48-0.41 (m, 2H). LC / MS mlz = 457 (M + H).
[901] (g) (R) -3-phenylmethanesulfonyl-N- [1- (3-phenyl-1,2,4-oxadiazole-5-carbonyl) -propyl] -2- (tetrahydro-pyran -4-ylamino) -propionamide
[902]
[903] (R) -2-Amino-N- {1- [hydroxy- (3-phenyl-1,2,4-oxadiazol-5-yl) -methyl] -propyl} -3-phenylmethanesulfonyl- Reaction was carried out in a similar manner as in Example 26 (a) using propionamide (see Example 11 (g)) to give (R) -3-phenylmethanesulfonyl-N- [1- (3-phenyl-1, 2,4-oxadiazole-5-carbonyl) -propyl] -2- (tetrahydro-pyran-4-ylamino) -propionamide is obtained. ¹ H NMR (CDCl ₃ , 300 MHz): [8.15 (d, J = 8 Hz), 8.14 (d, J = 8 Hz), 1H], 7.61-7.39 (m, 10H), [5.46 (m), 5.40 (m) ), 1H], 4.34-4.28 (m, 2H), 4.09-3.93 (m, 2H), [3.87 (dd, J = 9.5 Hz, 3 Hz), 3.81 (dd, J = 9.5 Hz, 3 Hz), 1H] , 3.41-3.32 (m, 3H), [3.16 (dd, J = 13.5 Hz, 10 Hz), 3.11 (dd, J = 14 Hz, 9.5 Hz), 1H], 2.75-2.68 (m, 1H), 2.23-2.13 (m, 1 H), 1.96-1.43 (m, 6 H), 1.06-0.99 (m, 3H). LC / MS m / z = 541 (M + H).
[904] (h) (R) -N- [1- (3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl) -propyl] -3-phenylmethanesulfonyl-2- (tetrahydro- Pyran-4-ylamino) -propionamide
[905]
[906] (R) -2-Amino-3-phenylmethanesulfonyl-N-{(S) -1-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl) -hydroxy-methyl ] -Propyl} -propionamide {see Example 11 (l)} to react in a similar manner as in Example 26 (a) to (R) -N- [1- (3-cyclopropyl-1,2 , 4-oxadiazole-5-carbonyl) -propyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide is obtained. ¹ H NMR (CDCl ₃ , 300 MHz): [8.19 (d, J = 8.5 Hz), 8.11 (d, J = 7.5 Hz), 1H], 7.46-7.40 (m, 5H), [5.33 (m), 5.27 (m), 1H], 4.55-4.35 (m, 2H), 3.99-3.95 (m, 2H), [3.88 (dd, J = 10 Hz, 3 Hz), 3.83 (dd, J = 9.5 Hz, 3 Hz), 1H ], 3.44-3.34 (m, 3H), 3.18-3.07 (m, 1H), 2.78-2.67 (m, 1H), 2.24-2.17 (m, 1H), 2.15-2.08 (m, 1H), 1.89-1.72 (m, 3H), 1.55-1.43 (m, 2H), 1.20-1.11 (m, 4H), [0.98 (t, J = 7.5 Hz), 0.97 (t, J = 7.5 Hz), 3H]. LC / MS mlz = 505 (M + H).
[907] Example 27
[908] (a) {(R) -1- [1- (Benzothiazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester
[909]
[910] N-cyclohexylcarbodiimide, N'-methyl polystyrene (1.74 g, 3.4 mmol) suspended in a mixture of dichloromethane (10 ml) and dimethylformamide (2 ml) was added to hydroxybenzotriazole (391 mg, 2.89 mmol) and Treatment with LN-Boc-benzylsulfonylalanine (876 mg, 2.55 mmol). The mixture was stirred for 30 minutes at room temperature, treated with 2-amino-1-benzothiazol-2-yl-pentan-1-ol {400 mg, 1.7 mmol, Reference Example 17 (d)}, and further After stirring for 2 h, the mixture is treated with silicyl-triamine (2.36 g, 8.5 mmol). The reaction mixture is stirred for 2 hours and filtered. Evaporate the filtrate to give the title compound (888 mg, 93%). LC / MS m / z = 562.
[911] (b) {(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid 3 Class-butyl ester
[912]
[913] LN-Boc-benzylsulfonylalanine (876 mg, 2.55 mmol) and (2S) -2-amino-1-benzooxazol-2-yl-pentan-1-ol {374 mg, 1.7 mmol, Reference Example 17 (c )} In the same manner as in Example 27 (a) to react {(R) -1-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl ] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester (908 mg, 98%) is obtained.
[914] (c) {(S) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-thiophen-2-yl-ethyl} -car Chest acid tert-butyl ester
[915]
[916] Resin bound diimide (1.76 g, 3.4 mmol) suspended in dichloromethane (10 ml), hydroxybenzotriazole (391 mg, 2.89 mmol), (2S) -2-tert-butoxycarbonylamino-3- Thiophen-2-yl-propionic acid (692 mg, 2.55 mmol), (2S) -2-amino-1-benzooxazol-2-yl-pentan-1-ol {374 mg, 1.7 mmol, Reference Example 17 (c )} And silicyl-triamine (2.36 g, 8.5 mmol) were reacted in a similar manner as in Example 27 (a) to {(S) -1-[(S) -1- (benzooxazole- 2-yl-hydroxy-methyl) -butylcarbamoyl] -2-thiophen-2-yl-ethyl} -carbamic acid tert-butyl ester (790 mg (1.67 mmol, 98%) is obtained. LC / MS m / z = 562 (M + H).
[917] (d) {(R) -1- [1- (Benzothiazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester
[918]
[919] Resin-bound diimide (741 mg, 1.26 mmol), hydroxybenzotriazole (144 mg, 1.07 mmol), LN-Boc-benzylsulfonylalanine (326 mg, 0.95 mmol), 2-amino-1-benzothiazole-2 Reaction in a similar manner as in Example 27 (a) using -yl-pentan-1-ol {150 mg, 0.63 mmol, Reference Example 17 (d)} and silicyl-triamine (2.36 g, 8.5 mmol) To give {(R) -1- [1- (benzothiazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester It is used without further purification. LC / MS mlz = 562 (M + H).
[920] (e) {(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid 3 Class-butyl ester
[921]
[922] Resin bound diimide (1.76 g, 3.4 mmol), hydroxybenzotriazole (391 mg, 2.89 mmol), LN-Boc-benzylsulfonylalanine (876 mg, 2.55 mmol), (2S) -2-amino-1- In Example 27 (a) using benzooxazol-2-yl-pentan-1-ol {374 mg, 1.7 mmol, Reference Example 17 (c)} and silicyl-triamine (2.36 g, 8.5 mmol) In a similar manner to {(R) -1-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl}- Carbamic acid tert-butyl ester is obtained and used directly in the next step. LC / MS mlz = 546 (M + H), 490 (M = H-butene).
[923] (f) {(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -carbamic acid Tert-butyl ester
[924]
[925] Suspension of resin bound diimide (1.07 g, 1.82 mmol) in dichloromethane (20 ml), hydroxybenzotriazole (209 mg, 1.55 mmol) and (R) -2-tert-butoxycarbonylamino-3- Cyclopropylmethanesulfonyl-propionic acid (420 mg, 1.365 mmol, Reference Example 22), (S) -2-amino-1-benzooxazol-2-yl-pentan-1-ol {200 mg 0.91 mmol, Reference Example 17 (c)} and silicyl-triamine (2.8 g, 9.1 mmol) were reacted in a similar manner as in Example 27 (a) to {(R) -1-[(S) -1- (benzo Oxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester (450 mg, 97%) is obtained. LC / MS mlz = 532 (M + Na), 510 (M + H), 454 (M + H-isobutene).
[926] (g) (R) -1- {1- [hydroxy- (3-phenyl-1,2,4-oxadiazol-5-yl) -methyl] -propylcarbamoyl} -2-phenylmethanesulfonyl -Ethyl) -carbamic acid tert-butyl ester
[927]
[928] LN-Boc-benzylsulfonylalanine and (R) -2-tert-butoxycarbonylamino-3-phenylmethanesulfonyl-propionic acid and (S) -2-amino-1- (3-phenyl- [1 , 2,4] oxadiazol-5-yl) -butan-1-ol (see Example 21), followed by reaction in a similar manner as in Example 27 (f) to give (R) -1- {1- [Hydroxy- (3-phenyl-1,2,4-oxadiazol-5-yl) -methyl] -propylcarbamoyl} -2-phenylmethanesulfonyl-ethyl) -carbamic acid tert-butyl ester To obtain. LC / MS mlz = 545 (M + Na), 467 (M + H-isobutene), 423 (M + H-Boc).
[929] (i) ((R) -2-cyclopropylmethanesulfonyl-1-{(S) -1-[(5-ethyl-1,2,4-oxadiazol-3-yl) -hydroxy-methyl ] -Propylcarbamoyl} -ethyl) -carbamic acid tert-butyl ester
[930]
[931] Similar to Example 27 (f) using 2-amino-1- (5-ethyl- [1,2,4] -oxadiazol-3-yl-butan-1-ol (see Example 23) Reacted by the method ((R) -2-cyclopropylmethanesulfonyl-1-{(S) -1-[(5-ethyl-1,2,4-oxadiazol-3-yl) -hydroxy- Methyl] -propylcarbamoyl} -ethyl) -carbamic acid tert-butyl ester LC / MS m / z = 497 (M + Na), 419 (M + H-isobutene), 375 (M + H-Boc).
[932] (j) {(R) -1- [1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester
[933]
[934] Example 27 (f) using LN-Boc-benzylsulfonylalanine and (S) -2-amino-1-benzooxazol-2-yl-pentan-1-ol {Reference Example 17 (c)} Reaction in a similar manner as in {(R) -1- [1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid 3 To give a tert-butyl ester. LC / MS mlz = 546 (M + H), 490 (M + H-isobutene).
[935] (k) {(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -3-phenyl-propylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl } -Carbamic acid tert-butyl ester
[936]
[937] (2S) -2-amino-4-phenyl-1-benzooxazol-2-yl-butan-1-ol was reacted in a similar manner as in Example 27 (f) to give {(R) -1- [(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -3-phenyl-propylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester To obtain. LC / MS mlz = 572 (M + H), 516 (M + H-isobutene).
[938] (l) {(R) -1-[(S) -1- (hydroxy-thiazol-2-yl-methyl) -3-phenyl-propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl}- Carbamic acid tert-butyl ester
[939]
[940] Example 27 (f) using LN-Boc-benzylsulfonylalanine and (2S) -2-amino-4-phenyl-1-thiazol-2-yl-butan-1-ol (Reference Example 13) Reaction in a similar manner as in {(R) -1-[(S) -1- (hydroxy-thiazol-2-yl-methyl) -3-phenyl-propylcarbamoyl] -2-phenylmethanesulfonyl -Ethyl} -carbamic acid tert-butyl ester is obtained. LC / MS mlz = 574 (M + H).
[941] (m) {(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -carbamic acid Tert-butyl ester
[942]
[943] Dichloromethane (20ml) of N- cyclohexyl Dorsett suspended in a carbodiimide, N '- methyl polystyrene (1.07g, 1.82mmol), hydroxybenzotriazole (209mg, 1.55mmol), (R ) -2-3 -class Butoxycarbonylamino-3-cyclopropylmethanesulfonyl-propionic acid (420 mg, 1.365 mmol, see Example 22), (S) -2-amino-1-benzooxazol-2-yl-pentane-1- All {200mg 0.91mmol, Reference Example 17 (c)} and silyl-triamine (2.8g, 9.1mmol) were reacted in a similar manner as in Example 27 (f) to {(R) -1- [(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester (450 mg, 0.88 mmol) , 97%). LC / MS mlz = 532 (M + Na), 510 (M + H), 454 (M + H-isobutene).
[944] (n) (R) -1- {1- [hydroxy- (3-phenyl-1,2,4-oxadiazol-5-yl) -methyl] -propylcarbamoyl} -2-phenylmethanesulfonyl -Ethyl) -carbamic acid tert-butyl ester
[945]
[946] LN-Boc-benzylsulfonylalanine and (S) -2-amino-1- (3-phenyl- [1,2,4] oxadiazol-5-yl) -butan-1-ol (see Example 21 ) And (R) -1- {1- [hydroxy- (3-phenyl-1,2,4-oxadiazol-5-yl)-to react in a similar manner as in Example 27 (m). Methyl] -propylcarbamoyl} -2-phenylmethanesulfonyl-ethyl) -carbamic acid tert-butyl ester is obtained. LC / MS mlz = 545 (M + Na), 467 (M + H-isobutene), 423 (M + H-Boc).
[947] (o) ((R) -2-cyclopropylmethanesulfonyl-1-{(S) -1-[(5-ethyl-1,2,4-oxadiazol-3-yl) -hydroxy-methyl ] -Propylcarbamoyl} -ethyl) -carbamic acid tert-butyl ester
[948]
[949] In a similar manner as in Example 27 (m) using (S) -2-amino-1- (5-ethyl- [1,2,4] oxadiazol-3-yl) -butan-1-ol To react ((R) -2-cyclopropylmethanesulfonyl-1-{(S) -1-[(5-ethyl-1,2,4-oxadiazol-3-yl) -hydroxy-methyl] -Propylcarbamoyl} -ethyl) -carbamic acid tert-butyl ester is obtained. LC / MS mlz = 497 (M + Na), 419 (M + H-isobutene), 375 (M + H-Boc).
[950] (p) {(R) -1- [1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester
[951]
[952] Example using LN-Boc-benzylsulfonylalanine and (S) -2-amino-1-benzooxazol-2-yl-pentan-1-ol {200 mg 0.91 mmol, Reference Example 17 (c)} Reaction was carried out in a similar manner as in 27 (m), to give {(R) -1- [1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -Carbamic acid tert-butyl ester is obtained. LC / MS mlz = 546 (M + H), 490 (M + H-isobutene).
[953] (q) {(R) -1-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -3-phenyl-propylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl } -Carbamic acid tert-butyl ester
[954]
[955] (2S) -2-amino-4-phenyl-1-benzooxazol-2-yl-butan-1-ol was reacted in a similar manner as in Example 27 (m) to give {(R) -1- [(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -3-phenyl-propylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester To obtain. LC / MS mlz = 572 (M + H), 516 (M + H-isobutene).
[956] (r) {(R) -1-[(S) -1- (hydroxy-thiazol-2-yl-methyl) -3-phenyl-propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl}- Carbamic acid tert-butyl ester
[957]
[958] Example 27 (m) using LN-Boc-benzylsulfonylalanine and (2S) -2-amino-4-phenyl-1-thiazol-2-yl-butan-1-ol (Reference Example 13) Reaction in a similar manner as in {(R) -1-[(S) -1- (hydroxy-thiazol-2-yl-methyl) -3-phenyl-propylcarbamoyl] -2-phenylmethanesulfonyl -Ethyl} -carbamic acid tert-butyl ester is obtained. LC / MS mlz = 574 (M + H).
[959] (s) ((R) -2-phenylmethanesulfonyl-1-{(S) -1-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl) -hydroxy-methyl ] -Propylcarbamoyl} -ethyl) -carbamic acid tert-butyl ester
[960]
[961] LN-Boc-benzylsulfonylalanine and (S) -2-amino-1- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -butan-1-ol (see Example 14 Reaction was carried out in a similar manner as in Example 27 (m) using (). -Oxadiazol-5-yl) -hydroxy-methyl] -propylcarbamoyl} -ethyl) -carbamic acid tert-butyl ester is obtained.
[962] Example 28
[963] (R) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2- [cyclopropylmethyl- (tetrahydro-pyran-4-ylmethyl) -amino] -3-phenylmethanesul Phenyl-propionamide
[964]
[965] Step 1. (R) -2-Amino-N- [1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-propionamide {200 mg, 0.448 mmol, see Example 11 (i)} is dissolved in 5% acetic acid in acetonitrile (10 ml). Tetrahydro-pyran-4-carbaldehyde (51 mg, 0.448 mmol) is added and the reaction mixture is stirred for 16 h. (Polytyrylmethyl) trimethylammonium cyanoborohydride (218 mg, 0.896 mmol) is added and the reaction mixture is stirred for 3 hours. Cyclopropanecarbaldehyde (157 mg, 2.24 mmol) is added and stirring is continued for 3 hours. The mixture is suction filtered and the filtrate is concentrated under high vacuum.
[966] Step 2. The residue is dissolved in 10 ml of dichloromethane. Dess-Martin-Piperiodinan (380 mg, 0.896 mmol) is added and the resulting reaction mixture is stirred for 2 hours. The reaction mixture is poured into a 1/1 mixture of saturated sodium bicarbonate solution and saturated sodium thiosulfate solution. The aqueous phase is extracted with dichloromethane. The combined organic phases are washed with saturated sodium bicarbonate solution and brine. The organic phase is dried over magnesium sulfate and dichloromethane is evaporated under reduced pressure. The crude product was purified via flash chromatography (heptane / ethyl acetate 2/1 followed by heptane / ethyl acetate 1/1) to give (R) -N- [1- (benzooxazole-2-carbonyl) -butyl ] -2- [cyclopropylmethyl- (tetrahydro-pyran-4-ylmethyl) -amino] -3-phenylmethanesulfonyl-propionamide (83 mg, 0.139 mmol, 31%) as a mixture of diastereomers do. LC / MS mlz = 596 (M + H) retention time 3.84 (method C).
[967] Example 29
[968] (a) (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide
[969]
[970] (R) -2-Amino-N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-propionamide {50 mg, 0.11 mmol, Reference Example 11 (a)} is dissolved in a mixture of acetonitrile (5 ml) and acetic acid (1 ml). Benzaldehyde (56 μl, 0.55 mmol, 5 equiv) and resin bound cyanoborohydride (54 mg, 0.22 mmol, 2 equiv) were added. The reaction mixture is stirred overnight, filtered off with suction and the filtrate is evaporated to (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-dibenzylamino-3- Phenylmethanesulfonyl-propionamide is obtained and used in the preparation of example 18 (c) without further purification.
[971] (b) (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) Propionamide
[972]
[973] Tetrahydro-4H-pyran-4-one (51 μl, 0.55 mmol, 5 equiv) was reacted in a similar manner as in Example 29 (a) to give (R) -N- [1- (benzothiazole- 2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide is obtained. LC / MS mlz = 546 (M + H).
[974] Example 30
[975] (a) (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide
[976]
[977] (R) -2-Amino-N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-propionamide {50 mg, 0.11 mmol, Reference Example 11 (a)} is dissolved in a mixture of acetonitrile (5 ml) and acetic acid (1 ml). Acetone (500 μl) and resin bound cyanoborohydride (54 mg, 0.22 mmol, 2 equiv) are added. The reaction mixture is stirred overnight, filtered off with suction and concentrated in vacuo. The residue is dissolved in dichloromethane and AP Arsnaut Technology (550 mg, 1.2 mmol) is added. The mixture was stirred for 2 hours, suction filtered and the filtrate was concentrated in vacuo to give (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-isopropylamino 3-Phenylmethanesulfonyl-propionamide (30 mg, 0.06 mmol, 54%) is obtained. LC / MS mlz = 504 (M + H).
[978] (b) (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide
[979]
[980] (R) -N- [1- (benzothiazol-2-yl-hydroxy was reacted in a similar manner as in Example 30 (a) using formaldehyde solution (75 μl, 1 mmol, 37 wt% aqueous solution). -Methyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide (30 mg, 54%) is obtained. LC / MS mlz = 490 (M + H).
[981] Example 31
[982] (a) (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4 -Ylamino) -propionamide
[983]
[984] (R) -2-amino-N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -3- in a mixture of acetonitrile (5 ml) and acetic acid (1 ml) A solution of phenylmethanesulfonyl-propionamide {100 mg, 0.22 mmol, Reference Example 11 (c)} is treated with tetrahydro-4H-pyran-4-one (101 μl, 1.1 mmol). After stirring for 3 hours at room temperature, the mixture is treated with resin bound cyanoborohydride (108 mg, 0.44 mmol) and stirring is continued overnight. The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in dichloromethane (10 ml) and the solution is treated with silyl triamine (611 mg, 2.2 mmol), stirred for 2 hours and filtered. (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino A solution of) -propionamide is used directly in the preparation of Example 20 (b).
[985] (b) (R) -N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -2- (1-methyl-piperidin-4-ylamino) 3-phenylmethanesulfonyl-propionamide
[986]
[987] Reaction was carried out in a similar manner as in Example 31 (a) using 1-methyl-4-piperidone (136 μl, 1.1 mmol) to give (R) -N-[(S) -1- (benzooxazole-2 -Yl-hydroxy-methyl) -butyl] -2- (1-methyl-piperidin-4-ylamino) -3-phenylmethanesulfonyl-propionamide, preparing Example 19 (b) Use directly on
[988] (c) (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2- (bis-thiophen-2-ylmethyl-amino)- 3-phenylmethanesulfonyl-propionamide
[989]
[990] Reaction was carried out in a similar manner as in Example 31 (a) using 2-thiophenecarboxaldehyde (20 μl, 0.22 mmol) to give (R) -N-[(S) -1- (benzooxazole-2- Obtained 1-hydroxy-methyl) -butyl] -2- (bis-thiophen-2-ylmethyl-amino) -3-phenylmethanesulfonyl-propionamide and used directly in the preparation of example 19 (c). do.
[991] (d) (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide
[992]
[993] Reaction was performed in the same manner as in Example 31 (a) using benzaldehyde (22 μl, 0.22 mmol) to give (R) -N-[(S) -1- (benzooxazol-2-yl-hydroxy- Methyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide is obtained and used directly in the preparation of example 19 (d).
[994] (e) (S) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2- (tetrahydro-pyran-4-ylamino) -3- Thiophen-2-yl-propionamide
[995]
[996] (S) -2-amino-N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-thiophen-2-yl-propionamide {82 mg, 0.22 mmol, Reference Example 11 (b)} and tetrahydro-4H-pyran-4-one (101 μl, 1.1 mmol) were reacted in a similar manner as in Example 317 (a) to give (S) -N- [(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2- (tetrahydro-pyran-4-ylamino) -3-thiophen-2-yl-propionamide Was obtained and used directly in the preparation of Example 19 (e).
[997] (f) (S) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-isopropylamino-3-thiophen-2-yl-propion amides
[998]
[999] (S) -2-amino-N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-thiophen-2-yl-propionamide {82 mg, 0.22 mmol, reference Example 11 (b)} and acetone (100 μl) were reacted in a similar manner as in Example 31 (a) to give (S) -N-[(S) -1- (benzooxazole- 2-yl-hydroxy-methyl) -butyl] -2-isopropylamino-3-thiophen-2-yl-propionamide is obtained and used directly in the preparation of example 19 (f).
[1000] (g) (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide
[1001]
[1002] (R) -N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl was reacted in a similar manner as in Example 31 (a) using acetone (500 μl). ] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide (30.5 mg, 29%) is obtained. LC / MS mlz = 488 (M + H).
[1003] Example 32
[1004] (a) (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) Propionamide
[1005]
[1006] (R) -2-amino-N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -3 in a mixture of acetonitrile and acetic acid (10 ml, 95: 5, v / v) A solution of -phenylmethanesulfonyl-propionamide {100 mg, 0.22 mmol, Reference Example 11 (a)} was added to tetrahydro-4H-pyran-4-one (101 [mu] l, 1.1 mmol) and resin bound cyanoborohydride. Treated with Ride (108 mg, 0.44 mmol). The mixture is stirred at rt overnight and evaporated. The residue is dissolved in dichloromethane and the solution is treated with silyl triamine (611 mg, 2.2 mmol), stirred at room temperature for 2 hours and filtered. The filtrate was evaporated to give (R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino ) -Propionamide is obtained and used directly in the preparation of Example 18 (b). LC / MS mlz = 546 (M + H).
[1007] (b) (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4 -Ylamino) -propionamide
[1008]
[1009] (R) -2-amino-N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-propionamide {98 mg, 0.22 mmol, Reaction was carried out in a similar manner as in Example 32 (a) using Reference Example 11 (c)} to give (R) -N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl ) -Butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide is obtained and used directly in the preparation of example 19 (a). LC / MS mlz = 530 (M + H).
[1010] (c) (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4 -Ylamino) -propionamide
[1011]
[1012] (R) -2-Amino-N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-propionamide {Reference Example 11 ( c)} to react in a similar manner as in Example 32 (a) to give (R) -N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl]- 3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide (106 mg, 91%) is obtained. LC / MS mlz = 530 (M + H).
[1013] (d) (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-[(2-methoxy-ethyl)-(tetrahydro- Pyran-4-yl) -amino] -3-phenylmethanesulfonyl-propionamide
[1014]
[1015] (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino ) -Propionamide {53 mg, 0.1 mmol, Reference Example 32 (c)} and 2-methoxyethanal (53 mg, 0.55 mmol) were reacted in a similar manner as in Example 32 (a) (R) -N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-[(2-methoxy-ethyl)-(tetrahydro-pyran-4-yl) -Amino] -3-phenylmethanesulfonyl-propionamide (56 mg, 95%) is obtained. LC / MS mlz = 588 (M + H).
[1016] (e) (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-cyclohexylamino-3-phenylmethanesulfonyl-propionamide
[1017]
[1018] (R) -2-amino-N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-propionamide {49 mg, 0.11 mmol, Reference Example 11 (c)} and cyclohexanone (52 μl, 0.5 mmol) were reacted in a similar manner as in Example 32 (a) to give (R) -N-[(S) -1- (benzo Oxazol-2-yl-hydroxy-methyl) -butyl] -2-cyclohexylamino-3-phenylmethanesulfonyl-propionamide (48 mg, 83%) is obtained.
[1019] (f) (R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide
[1020]
[1021] (R) -2-amino-N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-propionamide {49 mg, 0.11 mmol, Reference Example 11 (c)} and formaldehyde (75 μl, 1 mmol, 37% by weight in water) were reacted in a similar manner as in Example 32 (a) to give (R) -N-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide (10 mg, 19%) is obtained. LC / MS mlz = 474 (M + H).
[1022] Example 33
[1023] The following compounds of formula (I) are provided by the methods described in this patent application:
[1024] (a) N-cyanomethyl-3-cyclohexyl-propionamide
[1025]
[1026] ¹ H NMR: (CDCl ₃ ) 6.22 (br s, 1H), 4.20 (s, 2H), 2.23 (m, 2H), 1.65 (m, 5H), 1.50 (m, 2H), 1.10-1.30 (m, 4H), 0.90 (m, 2H); LC-MS: t = 3.67 min, 193.0 (M-1), 195.1 (M + 1). MS: API 150EX. (LC: Agilent 1100 series, column: Phenomenex, 5μ ODS3 100A 100X3mm.Flow rate: 2ml / min.Two solvent gradients: Solvent A, 99% water, 1% acetonitrile, 0.1% AcOH.Solvent B, 99% Acetonitrile, 1% water, 0.1% AcOH.gradient 100% A, 0% B to 0% A, 100% B t = 0 to 6 minutes gradient 100% A, 0% B t = 7 to 15 minutes);
[1027] (b) N-cyanomethyl-3- (2-difluoromethoxy-phenylmethanesulfonyl) -propionamide
[1028]
[1029] ¹ H NMR: (CDCl ₃ ) 7.52 (d, 1H, J = 8Hz), 7.43 (t, 1H, J = 8Hz), 7.29 (d, 1H, J = 8Hz), 7.20 (d, 1H, J = 8Hz ), 6.40 (m, 1H), 4.41 (s, 2H), 4.16 (d, 2H, J = 6 Hz), 3.72 (s, 1H), 3.34 (t, 2H, J = 8 Hz), 2.77 (t, 2H) , J = 8 Hz); LC-MS: t = 3.02 min, 331.1 (M-1), 333.1 (M + l). MS: API 150EX. (LC: Agilent 1100 series, column: Phenomenex, 5μ ODS3 100A 100X3mm.Flow rate: 2ml / min.Two solvent gradients: Solvent A, 99% water, 1% acetonitrile, 0.1% AcOH.Solvent B, 99% Acetonitrile, 1% water, 0.1% AcOH.gradient from 100% A, 0% B to 0% A, 100% B t = 0 to 6 minutes.gradient 100% A, 0% B t = 7 to 15 minutes) .
[1030] (c) 3- (3-cyclohexyl-propionylamino) -2-oxo-5-phenyl-pentanoic acid thiazol-2-ylamide
[1031]
[1032] Data for the depicted compound and its enol and hydrate forms: LC-MS: t = 4.74 min. 426.4 (M-1), 428.2 (M + l); 4.97 min, 426.2 (M-1), 428.2 (M + l); 5.57 min, 426.3 (M-1), 427.9 (M + 1). MS: API 150EX. (LC: Agilent 1100 series, column: Phenomenex, 5μ ODS3 100A 100X3mm.Flow rate: 2ml / min.Two solvent gradients: Solvent A, 99% water, 1% acetonitrile, 0.1% AcOH.Solvent B, 99% Acetonitrile, 1% water, 0.1% AcOH.gradient 100% A, 0% B to 0% A, 100% B t = 0 to 6 minutes.gradient 100% A, 0% B t = 7 to 15 minutes)
[1033] (d) 3-cyclohexyl-N- (1-formyl-3-phenyl-propyl) -propionamide
[1034]
[1035] LC-MS: t = 4.57 min, 300.4 (M-1), 302.3 (M + 1). MS: API 150EX. (LC: Agilent 1100 series, column: Phenomenex, 5μ ODS3 100A 100X3mm.Flow rate: 2ml / min.Two solvent gradients: Solvent A, 99% water, 1% acetonitrile, 0.1% AcOH.Solvent B, 99% Acetonitrile, 1% water, 0.1% AcOH.gradient 100% A, 0% B to 0% A, 100% B t = 0 to 6 minutes.gradient 100% A, 0% B t = 7 to 15 minutes)
[1036] (f) 3- (2-difluoromethoxy-phenylmethanesulfonyl) -N-[(S) -1- (5-ethyl- [1,3,4] oxadiazole-2-carbonyl)- Propyl] -propionamide
[1037]
[1038] LC-MS: R _T = 2.32 min, 460.3 (M + 1) 482.2 (M + 23) MS: API 150EX. (LC: Agilent 1100 series, column: Phenomenex, 5μ ODS3 100A 100X3mm.Flow rate: 2ml / min.Two solvent gradients: Solvent A, 99% water, 1% acetonitrile, 0.1% AcOH.Solvent B, 99% Acetonitrile, 1% water, 0.1% AcOH.gradient 100% A, 0% B to 0% A, 100% B t = 0 to 2.5 minutes Gradient 100% A, 0% B t = 3.0 to 3.5 minutes 100% A, 0% B t = 3.5 to 5 minutes)
[1039] (g) N-[(S) -1- (benzooxazole-2-carbonyl) -propyl] -2- (2-cyano-phenylamino) -3-cyclohexyl-propionamide
[1040]
[1041] ¹ H NMR: (CDCl ₃ ) 7.83 (d, 1H, J = 8 Hz), 7.59 (d, 1H, J = 8 Hz), 7.43-7.58 (m, 2H), 7.02-7.25 (m, 4H), 6.59 ( t, 1H, J = 8 Hz, 6.49 (d, 1H, J = 8 Hz), 5.40-5.47 (m, 1H), 4.77 (m, 1H), 3.83-3.88 (m, 1H), 2.12-2.22 (m , 1H), 1.85-2.00 (m, 2H), 1.55-1.83 (m. 8H), 1.12-1.35 (m, 4H), 0.95-1.10 (m, 3H); LC-MS: t = 2.97 min, 457.5 (M-1), 459.3 (M + 1), 481.4 (M + 23) MS: API 150EX. (LC: Agilent 1100 series, column: Phenomenex, 5μ ODS3 100A 100X3mm.Flow rate: 2ml / min.Two solvent gradients: Solvent A, 99% water, 1% acetonitrile, 0.1% AcOH.Solvent B, 99% Acetonitrile, 1% water, 0.1% AcOH.gradient 100% A, 0% B to 0% A, 100% B t = 0 to 2.5 minutes gradient 100% A, 0% B t = 3.0 to 3.5 minutes 100% A, 0% B t = 3.5 to 5 minutes)
[1042] (h) N-cyanomethyl-3-cyclohexyl-2- (4-methoxy-phenoxy) -propionamide (Compound 1)
[1043] ¹ H NMR: (CDCl ₃ ) 7.42-7.36 (m, 5H), 6.90 (t, 1H), 4.55 (d, 1H), 4.51 (d, 1H), 4.22 (dd, 1H), 4.16 (dd, 1H ), 4.00 (t, 1 H), 1.70-0.80 (m, 13 H). MS: (M ⁺ +1) 301;
[1044] (i) 2-benzyloxy-N-cyanomethyl-3-cyclohexyl-propionamide (Compound 2)
[1045]
[1046] 2 (R) -benzyloxy-4-phenyl-butyric acid is used as starting material. ¹ H NMR: (CDCl ₃ ) δ 6.84-6.80 (m, 4H), 6.75 (t, 1H), 4.55 (dd, 1H), 4.24 (dd, 1H), 4.12 (dd, 1H), 3.78 (s, 3H), 1.80-0.85 (m, 13H). MS: (M-1) 315.
[1047] (j) (R) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -butyl] -2-benzyloxy-3-phenylmethanesulfonyl-propionamide (compound 3)
[1048] ¹ H NMR: (CDCl ₃ ) 7.89 (d, 1H), 7.68 (d, 1H), 7.60-7.32 (m, 13H), 5.70 (m, 1H), 4.79 (d, 1H), 4.77 (d, 1H ), 4.53 (dd, 1H), 4.33 (d, 1H), 4.30 (d, 1H), 3.38 (dd, 1H), 3.25 (dd, 1H), 2.15-2.05 (m, 1H), 1.84-75 ( m, 1H), 1.45-1.30 (m, 2H), 0.93 (t, 3H). MS: (M ⁺⁺ 1) 535, (M-1) 533.
[1049] (k) (R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -2-methoxymethoxy-3-phenylmethanesulfonyl-propionamide (Compound 9)
[1050] ¹ H NMR (DMSO): 8.87 (d, J = 6.91 Hz, 1H), 7.99 (d, J = 7.91 Hz, 1H), 7.89 (d, J = 8.15 Hz, 1H), 7.64 (t, J = 8.1 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.4-7.3 (m, 5H), 5.3-5.2 (m, 1H), 4.7-4.65 (m, 1H), 4.65-4.63 (m, 2H), 4.55-4.50 (m, 2H), 3.53-3.26 (m, 2H), 3.34 (s, 3H), 2.11-1.98 (m, 1H), 1.81-1.69 (m, 1H), 0.97 (t, J = 7.15 Hz, 3H). MS: 473 (M-1), 497 (M + 23).
[1051] (l) (S) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -butyl] -2-hydroxy-3-phenyl-propionamide (Compound 10)
[1052] (m) (R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -3-phenylmethanesulfonyl-2-triisopropylsilanyloxy- Propionamide (Compound 12)
[1053] ¹ H NMR (CD ₃ Cl): 7.93 (d, J = 8.15 Hz, 1H), 7.6 (d, J = 8.1 Hz, 1H), 7.6-7.4 (m, 3H), 7.4-7.3 (m, 5H) , 5.85-5.73 (m, 1H), 4.85-4.74 (m, 1H), 4.5-4.3 (m, 2H), 3.47-3.35 (m, 2H), 2.35-2.15 (m, 1H), 2.15-1.95 ( m, 1H), 1.3-0.8 (m, 24H). MS: 609.4 (M + 23).
[1054] (n) (R) -N-[(S) -1- (1-Benzothiazol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenylmethanesulfonyl-propionamide (compound 13)
[1055] ¹ H NMR (CD ₃ Cl): 8.21 (d, J = 8.67 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.7-7.55 (m, 3H), 7.45-7.3 (m, 5H) , 5.8-5.7 (m, 1H), 4.75-4.6 (m, 1H), 4.4-4.3 (m, 2H), 4.08 (br, 1H), 3.62-3.5 (m, 1H), 3.3-3.1 (m, 1H), 2.3-2.15 (m, 1H), 2.05-1.9 (m, 1H), 0.997 (t, J = 7.4 Hz, 3H). MS: 469.2 (M + 23).
[1056] (o) (R) -2-hydroxy-3-phenylmethanesulfonyl-N-[(S) -1- (1-pyridazin-3-yl-methanoyl) -butyl] -propionamide (Compound 16 )
[1057] ¹ H NMR (CD ₃ Cl): 9.35 (dd, J = 4.93 Hz, J = 1.72 Hz, 1H), 8.14 (dd, J = 1.72 Hz, J = 8.39 Hz, 1H), 7.69 (dd, J = 4.93 Hz, J = 8.39 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.5-7.36 (m, 5H), 6.04-5.96 (m, 1H), 4.75-4.63 (m, 1H), 4.45 -4.3 (m, 3H), 3.53 (dd, J = 2.48 Hz, J = 14.85 Hz, 1H), 3.22 (dd, J = 14.82 Hz, J = 2.48 Hz, 1H), 2.2-2.07 (m, 1H) , 1.81-1.65 (m, 1H), 1.6-1.2 (m, 2H), 0.93 (t, J = 7.18 Hz, 3H). MS: 403.6 (M-1), 428 (M + 23).
[1058] (p) (S) -3-((R) -2-hydroxy-3-phenylmethanesulfonyl-propanoylamino) -2-oxo-pentanoic acid benzylamide (Compound 18)
[1059] ¹ H NMR (CD ₃ Cl): 7.45-7.25 (m, 10H), 5.34-5.26 (m, 1H), 4.7-4.6 (m, 1H), 4.47 (d, J = 6.18 Hz, 2H), 4.4- 4.3 (m, 2H), 4.15-4.05 (m, 1H), 3.55-3.45 (m, 1H), 3.25-3.13 (m, 1H), 22.2-2.0 (m, 1H), 1.8-1.6 (m, 1H ), 1.61 (s, 2H), 0.95 (t, J = 6.91 Hz, 3H); MS: 469.2 (M + 23).
[1060] (q) (R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -3- [2- (1,1-difluoro-methoxy ) -Phenylmethanesulfonyl] -2-hydroxypropionamide (Compound 21)
[1061] ¹ H NMR (CD ₃ Cl): 7.91 (d, J = 7.91 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.7-7.2 (m, 6H), 6.63 (t, J = 73.41 Hz , 1H), 5.7-5.58 (m, 1H), 5.4-5.29 (m, 1H), 4.7-4.6 (m, 1H), 4.51 (s, 2H), 4.19 (br, 1H), 3.72-3.63 (m , 1H), 3.35-3.2 (m, 1H), 2.3-2.0 (m, 1H), 2.0-1.7 (m, 1H), 0.99 (t, J = 6.9 Hz, 3H); MS: 495.5 (M-1), 497.2 (M + 1).
[1062] (r) (R) -N-[(S) -1- (1-Benzothiazol-2-yl-methanoyl) -propyl] -3- [2- (1,1-difluoro-methoxy ) -Phenylmethanesulfonyl] -2-hydroxy-propionamide (Compound 22)
[1063] ¹ H NMR (CD ₃ Cl): 8.21 (d, J = 8.15 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.73-7.2 (m, 6H), 6.63 (t, J = 73.4 Hz , 1H), 5.85-5.75 (m, 1H), 5.3 (s, 1H), 4.78-4.7 (m, 1H), 4.56-4.4 (m, 2H), 4.19-4.09 (m, 1H), 3.7-3.6 (m, 1H), 3.35-3.2 (m, 1H), 2.28 (s, 2H), 1.27 (t, J = 6.9 Hz, 3H). MS; 511.4 (M-1), 513.6 (M + 1).
[1064] (s) (2R, 5S) -2- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonylmethyl] -6-ethoxy-5-ethyl- monopolin-3-one ( Compound 24).
[1065] Enzyme Assay Example
[1066] Cathepsin S Analysis
[1067] Solutions of test compounds at various concentrations are prepared in 1 μl of dimethyl sulfoxide (DMSO) and diluted in assay buffer (40 μl, MES, 50 mM, pH 6.5); EDTA, 2.5 mM and NaCl, including 100 mM. Human cathepsin S (0.158 p Moles, in 25 μl assay buffer) is added to the dilution. The assay solution is mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at ambient temperature. Z-Val-Val-Arg-AMC (9 n Moles, in 25 μl of assay buffer) is added to the assay solution and hydrolyzed spectrophotometrically at (λ 460 nm) for 5 minutes. The apparent inhibition constant (K _i ) is calculated from the enzyme progression curve using the standard mathematical model.
[1068] Enzyme Assay Example
[1069] Cathepsin B Assay
[1070] Solutions of test compounds at various concentrations were prepared in 10 μl of dimethyl sulfoxide (DMSO) and assay buffer (40 μl, N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid (BES), 50 mM ( pH 6); polyoxyethylene sorbitan monolaurate, 0.05%; and dithiothritol (DTT), including 2.5 mM). Human cathepsin B (0.025 pMoles, in 25 μl assay buffer) is added to the dilution. The assay solution is mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at ambient temperature. Z-FR-AMC (20 n Moles, in 25 μl of assay buffer) is added to the assay solution and hydrolyzed spectrophotometrically at (λ460 nm) for 5 minutes. The apparent inhibition constant (K _i ) is calculated from the enzyme progression curve using the standard mathematical model.
[1071] Enzyme Assay Example
[1072] Cathepsin K Analysis
[1073] Solutions of test compounds at various concentrations are prepared in 10 μl of dimethyl sulfoxide (DMSO) and diluted in assay buffer (40 μl, MES, 50 mM pH 5.5; EDTA, 2.5 mM and DTT, 2.5 mM). Human cathepsin K (0.0906 p Moles, in 25 μl assay buffer) is added to the dilution. The assay solution is mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at ambient temperature. Z-Phe-Arg-AMC (4 n Moles, in 25 μl of assay buffer) is added to the assay solution and hydrolyzed spectrophotometrically at (λ460 nm) for 5 minutes. The apparent inhibition constant (K _i ) is calculated from the enzyme progression curve using the standard mathematical model.
[1074] Enzyme Assay Example
[1075] Cathepsin L Assay
[1076] Solutions of test compounds at various concentrations are prepared in 10 μl of dimethyl sulfoxide (DMSO) and diluted in assay buffer (40 μl, MES, 50 mM pH 5.5; EDTA, 2.5 mM and DTT, 2.5 mM). Human cathepsin L (0.05 pMoles, 25 μl assay buffer) is added to the dilution. The assay solution is mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at ambient temperature. Z-Phe-Arg-AMC (1 n Moles, in 25 μl of assay buffer) is added to the assay solution and hydrolyzed spectrophotometrically at (λ460 nm) for 5 minutes. The apparent inhibition constant (K _i ) is calculated from the enzyme progression curve using the standard mathematical model.
[1077] According to Applicants' analysis performed as described above, the apparent inhibition constant (K _i ) of the following compounds of the present invention is about 0.01 μM or less for cathepsin S:
[1078] Morpholine-4-carboxylic acid (R) -1- (cyanomethyl-carbamoyl) -2- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester ), Example 3 (a);
[1079] Morpholin-4-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester (compound 11), Example 4 (a);
[1080] Morpholin-4-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2- [2- (1,1-di Fluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester (Compound 14), Example 4 (b);
[1081] Morpholin-4-carboxylic acid (R) -1-[(S) -1- (1-benzothiazol-2-yl-methanoyl) -propylcarbamoyl] -2- [2- (1,1-di Fluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester (Compound 15), Example 4 (c);
[1082] Pyrrolidine-1-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester ( Compound 19), Example 4 (d);
[1083] Dimethyl-carbamic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester (Compound 20) Example 4 (e);
[1084] Morpholin-4-carboxylic acid (R) -1-[(S) -1- (1-benzylcarbamoyl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester (Compound 25). Example 4 (f);
[1085] Morpholine-4-carboxylic acid (S) -1-[(S) -1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl Ester, Example 4 (g);
[1086] Morpholine-4-carboxylic acid (S) -1-[(S) -1- (5-ethyl- [1,3,4] oxadiazole-2-carbonyl) -propylcarbamoyl] -2-phenylmethane Sulfonyl-ethyl ester, Example 4 (h);
[1087] (R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -N-((S) -1-formyl-propyl) -2-hydroxy-propionamide (Compound 23), Example 6;
[1088] (R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenyl-methanesulfonyl-propionamide (Compound 5) , Example 7;
[1089] (S) -3- {3- [2- (1,1-Difluoro-methoxy) -phenylmethanesulfonyl] -propanoylamino} -2-oxo-pentanoic acid benzylamide (Compound 27), Example 8 (a);
[1090] (R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -2- (2-nitro-phenylamino) -3-phenylmethanesulfonyl-propion Amide (Compound 28), Example 9;
[1091] (R) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -butyl] -2- (5-nitro-thiazol-2-ylamino) -3-phenyl Methanesulfonyl-propionamide (Compound 29), Example 10;
[1092] (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide Example 19 (a);
[1093] (R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl propionamide, Example 21 (a);
[1094] (R) -N-[(S) -1- (benzooxazol-2-carbonyl) -butyl] -2-[(2-methoxy-ethyl)-(tetrahydro-pyran-4-yl)- Amino] -3-phenylmethanesulfonyl-propionamide, Example 21 (b);
[1095] (R) -N-[(S) -1- (Benzooxazole-2-carbonyl) -butyl] -2-cyclohexylamino-3-phenylmethanesulfonyl-propionamide, Example 21 (c);
[1096] Morpholine-4-carboxylic acid (S) -2-cyclohexyl-1-[(S) -1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propylcarbamoyl] -ethyl ester, Example 24 (b);
[1097] 3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N-[(S) -1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propyl] -propionamide, practice Example 33 (e);
[1098] (S) -3-((R) -2-hydroxy-3-phenylmethanesulfonyl-propanoylamino) -2-oxo-pentanoic acid benzylamide (Compound 18), Example 33 (p);
[1099] (R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -3- [2- (1,1-difluoro-methoxy) -phenyl Methanesulfonyl] -2-hydroxy-propionamide (Compound 21), Example 33 (q);
[1100] In addition, the compounds of the present invention were observed to have varying degrees of selective inhibitory action against cathepsin S protease. For example, these 22 compounds have been found to inhibit cathepsin S protease activity at concentrations less than 75 times the concentration required to achieve equivalent activity inhibition against cathepsin K protease.
[1101] Representative Pharmaceutical Formulation Examples Containing a Compound of Formula (I)
[1102] Oral formulation
[1103] Compound of Formula I: 10-100mg
[1104] Citric Acid Monohydrate: 105mg
[1105] Sodium Hydroxide: 18mg
[1106] Flavor
[1107] Water: suitable amount to make 100ml
[1108] Intravenous Formulation
[1109] Compound of Formula I: 0.1-10mg
[1110] Dextrose monohydrate: the right amount to make isotonic
[1111] Citric Acid Monohydrate: 1.05mg
[1112] Sodium Hydroxide: 0.18mg
[1113] Water for injection: suitable amount to make 1.0ml
[1114] Tablet formulation
[1115] Compound of Formula I: 1%
[1116] Microcrystalline Cellulose: 73%
[1117] Stearic acid: 25%
[1118] Colloidal Silica: 1%

权利要求:
Claims (20)
[1" claim-type="Currently amended] Agents of compounds of formula (I), N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomeric mixtures thereof, and agents of the compounds, N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomeric mixtures thereof Scholarly acceptable salts and solvates.
Formula I

In Formula I above,
X ¹ is —NHC (R ¹ ) (R ² ) X ³ or -NHX ⁴ ,
X ² is hydrogen, fluoro, —OH, —OR ⁴ , —NHR ¹⁵ or —NR ¹⁷ R ¹⁸ , X ⁷ is hydrogen, X ² and X ⁷ are both fluoro,
X ³ is cyano, -C (R ⁷ ) (R ⁸ ) R ¹⁶ , -C (R ⁶ ) (OR ⁶ ) ₂ , -CH ₂ C (O) R ¹⁶ , -CH = CHS (O) ₂ R ⁵ , -C (O) CF ₂ C (O) NR ⁵ R ⁵ , -C (O) C (O) NR ⁵ R ⁶ , -C (O) C (O) OR ⁵ , -C (O) CH ₂ OR ⁵ , -C (O) CH ₂ N (R ⁶ ) SO ₂ R ⁵ or -C (O) C (O) R ⁵ , R ⁵ is hydrogen, (C _1-4 ) alkyl, (C _{3 -10} ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _{5- 10} ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl, R ⁶ is When hydrogen, hydroxy or (C _1-6 ) alkyl or X ³ contains a —NR ⁵ R ⁶ group, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are hetero (C _3-10 ) cycloalkyl , Hetero (C _5-10 ) aryl or hetero (C _8-10 ) bicycloaryl, R ⁷ is hydrogen or (C _1-4 ) alkyl and R ⁸ is hydroxy or R ⁷ and R ⁸ Together form oxo, R ¹⁶ is hydrogen, -X ⁴ , -CF ₃ , -CF ₂ CF ₂ R ⁹ or —N (R ⁶ ) OR ⁶ , R ⁹ is hydrogen, halo, (C _1-4 ) alkyl, (C _5-10 ) aryl (C _0-6 ) alkyl or (C _5-10 Heteroaryl (C _0-6 ) alkyl provided that when X ³ is cyano, then X ² is hydrogen, fluoro, —OH, —OR ⁴ or —NR ¹⁷ R ¹⁸ , and X ⁷ is hydrogen or X ² and X ⁷ are both fluoro,
X ⁴ is a heteromonocyclic ring containing 4 to 7 ring atoms or a fused heterobicyclic ring system containing 8 to 14 ring atoms and carbocyclic ketones, iminoketones or thioketone derivatives thereof Provided that -2 is a ring other than a heteromonocyclic ring containing five ring atoms wherein up to two of the ring atoms containing -X ⁴ are a hetero atom, X ² is fluoro, -OH, -OR ⁴ , -NHR ¹⁵ or -NR ¹⁷ R ¹⁸ , X ⁷ is hydrogen, X ² and X ⁷ are both fluoro,
The alicyclic or aromatic ring system in R ⁵ , X ³ or X ⁴ is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _{1- 4} ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² ,- X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ and -X ⁵ 1 to 5 radicals independently selected from S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S ( O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S ( O) ₂ R ^14, 1 one selected from ^{-X 5 NR 12 C (O)} NR 14 R 12 and ^{-X 5 NR 12 C (NR 12} ) NR 14 R 12 Being further substituted by a radical, X ⁵ is a bond or (C _1-6) alkylene, R ¹² are each independently hydrogen, (C _1-6) alkyl or halo-substituted (C _1-6) alkyl R ¹³ is (C _1-6 ) alkyl or halo-substituted (C _1-6 ) alkyl, R ¹⁴ is (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _{3- 10} ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) ratio _Cycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl,
R ¹ is hydrogen or (C _1-6 ) alkyl, R ² is hydrogen, cyano, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O ) OR ¹² , -R ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² ,- X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O ) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² (where X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, or R ¹ and R ² together with the carbon atom to which they are attached are (C _3-8 ) cycloalkylene or (C _3-8) heterocycloalkyl to form a alkylene, heteroaryl, aryl, cycloalkyl in R ^2, heterocycloalkyl, cycloalkylene or heterocyclic cycloalkylene is optionally substituted with (C _1-6) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1-4 ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ and -X ⁵ C (O) R ¹³ , where X ⁵ , R ¹² and R ¹³ Is further defined by one to three radicals independently selected from
R ³ is (C _1-6 ) alkyl or —C (R ⁶ ) (R ⁶ ) X ⁶ , R ⁶ is hydrogen or (C _1-6 ) alkyl, X ⁶ is —X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C ( O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and —X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , wherein X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
R ⁴ is -X ⁸ NR ¹² R ¹² , -X ⁸ NR ¹² C (O) R ¹² , -X ⁸ NR ¹² C (O) OR ¹² , -X ⁸ NR ¹² C (O) NR ¹² R ¹² ,- X ⁸ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁸ OR ¹² , -X ⁸ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁸ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁸ S (O) ₂ NR ¹² R ¹² , -X ⁸ NR ¹² S (O) ₂ R ¹² , -X ⁸ P (O ) (OR ¹² ) OR ¹² , -X ⁸ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁸ NR ¹² C (O) R ¹³ , -X ⁸ S (O ) R ¹³ , -X ⁸ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁸ OR ¹⁴ , -X ⁸ SR ¹⁴ , -X ⁸ S (O) R ¹⁴ , -X ⁸ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁸ OC (O) R ¹⁴ , -X ⁸ NR ¹⁴ R ¹² , -X ⁸ NR ¹² C (O) R ¹⁴ , -X ⁸ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁸ S (O) ₂ NR ¹⁴ R ¹² , -X ⁸ NR ¹² S (O) ₂ R ¹⁴ , -X ⁸ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁸ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , wherein X ⁸ is (C _1-6 ) alkylene and X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, provided that when X ³ is cyano and X ² is -OR ⁴ , where R ⁴ is -R ¹⁴ , then R ¹⁴ is ( C _3-10 ) cycloalkyl (C _1-6 ) alkyl, hete (C _3-10 ) cycloalkyl (C _1-3 ) alkyl, (C _6-10 ) aryl (C _1-6 ) alkyl, hetero (C _5-10 ) aryl (C _1-6 ) alkyl, (C _9-10 ) bicycloaryl (C _1-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _1-6 ) alkyl,
R ¹⁵ is (C _6-10 ) aryl, hetero (C _5-10 ) aryl, (C _9-10 ) _bicycloaryl or hetero (C _8-10 ) _bicycloaryl ,
R ¹⁷ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) Aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) ratio _Cycloaryl (C _0-6 ) alkyl provided that when X ³ is cyano, then R ¹⁷ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, (C _6-10 ) aryl (C _1-6 ) alkyl, hetero (C _5-10 ) aryl (C _1-6 ) alkyl, (C _9-10 ) Bicycloaryl (C _1-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _1-6 ) alkyl,
R ¹⁸ is hydrogen, (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, (C _{6- 10} ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) _Bicycloaryl (C _0-6 ) alkyl provided that when X ³ is cyano, R ¹⁸ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, (C _6-10 ) aryl (C _1-6 ) alkyl, hetero (C _5-10 ) aryl (C _1-6 ) alkyl, (C _{9 -10} ) bicycloaryl (C _1-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _1-6 ) alkyl,
In R ³ , R ⁴ , R ¹⁵ , R ¹⁷ and R ¹⁸ , the alicyclic or aromatic ring system is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo- Substituted (C _1-4 ) alkyl, nitro, —X ⁵ NR ¹² R ¹² , —X ⁵ NR ¹² C (O) R ¹² , —X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C ( O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) 1 to 5 radicals independently selected from R ¹³ , -X ⁵ C (O) R ¹³ and -X ⁵ S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² in Emitter is further substituted by a selected one radical, R ³ and R ⁴ in the aliphatic moiety is unsubstituted or substituted with cyano, halo, ^{nitro, -NR 12 R 12, -NR 12} C (O) R 12, -NR ¹² C (O) OR ¹² , -NR ¹² C (O) NR ¹² R ¹² , -NR ¹² C (NR ¹² ) NR ¹² R ¹² , -OR ¹² , -SR ¹² , -C (O) OR ¹² ,- C (O) R ¹² , -OC (O) R ¹² , -C (O) NR ¹² R ¹² , -S (O) ₂ NR ¹² R ¹² , -NR ¹² S (O) ₂ R ¹² , -P ( O) (OR ¹² ) OR ¹² , -OP (O) (OR ¹² ) OR ¹² , -NR ¹² C (O) R ¹³ , -S (O) R ^13, and -S (O) ₂ R ¹³ , wherein X ⁵ , R ¹² , R ¹³ and R ¹⁴ are further substituted with 1 to 5 substituents independently selected from: provided that X ³ is cyano and X ² is -OR ⁴ , wherein , R ⁴ is —R ¹⁴ ) or —NHR ¹⁸ , the aromatic ring system present at R ¹⁴ or R ¹⁸ is halo, (C _3-10 ) cycloalkyl, hetero (C _3-10 ) cycloalkyl, ( C _6-10 ) aryl, hetero (C _5-10 ) aryl, (C _9-10 ) _bicycloaryl or hetero (C _8-10 ) bicyclo Not further substituted by aryl,
Provided that only one bicyclic ring structure is present in R ³ , R ⁴ or R ¹⁵ .
[2" claim-type="Currently amended] The compound of claim 1, wherein
Chemical formula

In the above formula,
X ² is hydrogen, fluoro, —OH, —OR ⁴ or —NHR ¹⁵ ,
R ³ , R ⁴ , R ¹⁵ and X ¹ are as defined in claim 1.
[3" claim-type="Currently amended] The method according to claim 1 or 2,
X ¹ is -NHC (R ¹ ) (R ² ) X ³ or -NHCH (R ¹⁹ ) C (O) R ²⁰ ,
X ² is hydrogen, fluoro, —OH, —OR ⁴ , —NHR ¹⁵ or —NR ¹⁷ R ¹⁸ , X ⁷ is hydrogen, X ² and X ⁷ are both fluoro,
X ³ is cyano, -C (R ⁷ ) (R ⁸ ) R ¹⁶ , -C (R ⁶ ) (OR ⁶ ) ₂ , -CH ₂ C (O) R ¹⁶ , -CH = CHS (O) ₂ R ⁵ , -C (O) CF ₂ C (O) NR ⁵ R ⁵ , -C (O) C (O) NR ⁵ R ⁶ , -C (O) C (O) OR ⁵ , -C (O) CH ₂ OR ⁵ , -C (O) CH ₂ N (R ⁶ ) SO ₂ R ⁵ or -C (O) C (O) R ^5, wherein R ⁵ is hydrogen, (C _1-4 ) alkyl, (C _{3 -10} ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _{5- 10} ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl, R ⁶ is When hydrogen, hydroxy or (C _1-6 ) alkyl or X ³ contains a —NR ⁵ R ⁶ group, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are hetero (C _3-10 ) cycloalkyl , Hetero (C _5-10 ) aryl or hetero (C _8-10 ) bicycloaryl, wherein R ⁷ is hydrogen or (C _1-4 ) alkyl and R ⁸ is hydroxy or R ⁷ and R ⁸ Together form oxo, and R ¹⁶ is hydrogen, -X ⁴ , -CF ₃ , -CF ₂ CF ₂ R ⁹ or —N (R ⁶ ) OR ⁶ , R ⁹ is hydrogen, halo, (C _1-4 ) alkyl, (C _5-10 ) aryl (C _0-6 ) alkyl or (C _5-10 Heteroaryl (C _0-6 ) alkyl provided that when X ³ is cyano, then X ² is hydrogen, fluoro, —OH, —OR ⁴ or —NR ¹⁷ R ¹⁸ , and X ⁷ is hydrogen or X ² and X ⁷ are both fluoro,
X ⁴ is a cyclic fused heterocyclic non containing a hetero monocyclic ring or 8 to 14 ring atoms containing 4 to 7 ring atoms ring system and cyclic thereof carbonyl ketones, imino ketone or thio ketone derivative Provided that, when -X ⁴ is a ring other than a heteromonocyclic ring containing five ring atoms wherein up to two of the ring atoms containing the ring are hetero atoms, X ² is fluoro, -OH, -OR ⁴ , -NHR ¹⁵ or -NR ¹⁷ R ¹⁸ , X ⁷ is hydrogen, X ² and X ⁷ are both fluoro,
Unsubstituted or substituted (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1- ) alicyclic or aromatic ring systems in R ⁵ , X ³ or X ⁴ ₄ ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² ,- X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ and -X ⁵ 1 to 5 radicals independently selected from S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S ( O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S ( ^{_{O) 2 R 14, -X 5}} NR 12 C (O) NR 14 R 12 and ^{-X 5 NR 12 C (NR 12} ) NR 14 R ¹² selected from one LA Being further substituted by a knife, X ⁵ is a bond or (C _1-6) alkylene, R ¹² are each independently hydrogen, (C _1-6) alkyl or halo-substituted (C _1-6) alkyl R ¹³ is (C _1-6 ) alkyl or halo-substituted (C _1-6 ) alkyl, R ¹⁴ is (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _{3- 10} ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) ratio _Cycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl,
R ¹ is hydrogen or (C _1-6 ) alkyl, R ² is hydrogen, cyano, —X ⁵ NR ¹² R ¹² , —X ⁵ NR ¹² C (O) R ¹² , —X ⁵ NR ¹² C (O ) OR ¹² , -R ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² ,- X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O ) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² (where X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, or R ¹ and R ² together with the carbon atom to which they are attached are (C _3-8 ) cycloalkylene or (C _3-8) heterocycloalkyl form an alkylene group, and R ² in the heteroaryl, aryl, cycloalkyl, heterocycloalkyl, cycloalkylene or heterocyclic cycloalkylene is unsubstituted or substituted by (C _1-6) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1-4 ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ and -X ⁵ C (O) R ¹³ , where X ⁵ , R ¹² and R ¹³ Is further defined by one to three radicals independently selected from
R ³ is (C _1-6 ) alkyl or —C (R ⁶ ) (R ⁶ ) X ⁶ , R ⁶ is hydrogen or (C _1-6 ) alkyl, X ⁶ is —X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C ( O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and —X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , wherein X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
R ⁴ is -X ⁸ NR ¹² R ¹² , -X ⁸ NR ¹² C (O) R ¹² , -X ⁸ NR ¹² C (O) OR ¹² , -X ⁸ NR ¹² C (O) NR ¹² R ¹² ,- X ⁸ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁸ OR ¹² , -X ⁸ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁸ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁸ S (O) ₂ NR ¹² R ¹² , -X ⁸ NR ¹² S (O) ₂ R ¹² , -X ⁸ P (O ) (OR ¹² ) OR ¹² , -X ⁸ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁸ NR ¹² C (O) R ¹³ , -X ⁸ S (O ) R ¹³ , -X ⁸ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁸ OR ¹⁴ , -X ⁸ SR ¹⁴ , -X ⁸ S (O) R ¹⁴ , -X ⁸ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁸ OC (O) R ¹⁴ , -X ⁸ NR ¹⁴ R ¹² , -X ⁸ NR ¹² C (O) R ¹⁴ , -X ⁸ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁸ S (O) ₂ NR ¹⁴ R ¹² , -X ⁸ NR ¹² S (O) ₂ R ¹⁴ , —X ⁸ NR ¹² C (O) NR ¹⁴ R ¹² and —X ⁸ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , X ⁸ is (C _1-6 ) alkylene, X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, provided that X ³ is cyano and X ² is -OR ⁴ , where R ⁴ is -R ¹⁴ , and R ¹⁴ is (C _{3- 10} ) cycloalkyl (C _1-6 ) alkyl, hetero (C _3-10 ) Cycloalkyl (C _1-3 ) alkyl, (C _6-10 ) aryl (C _1-6 ) alkyl, hetero (C _5-10 ) aryl (C _1-6 ) alkyl, (C _9-10 ) bicyclo Aryl (C _1-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _1-6 ) alkyl,
R ¹⁵ is (C _6-10 ) aryl, hetero (C _5-10 ) aryl, (C _9-10 ) _bicycloaryl or hetero (C _8-10 ) _bicycloaryl ,
R ¹⁷ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) Aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) ratio _Cycloaryl (C _0-6 ) alkyl, provided that when X ³ is cyano, then R ¹⁷ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, (C _6-10 ) aryl (C _1-6 ) alkyl, hetero (C _5-10 ) aryl (C _1-6 ) alkyl, (C _9-10 ) Bicycloaryl (C _1-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _1-6 ) alkyl,
R ¹⁸ is hydrogen, (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, (C _{6- 10} ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) _Bicycloaryl (C _0-6 ) alkyl, provided that when X ³ is cyano, R ¹⁸ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, (C _6-10 ) aryl (C _1-6 ) alkyl, hetero (C _5-10 ) aryl (C _1-6 ) alkyl, (C _{9 -10} ) bicycloaryl (C _1-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _1-6 ) alkyl,
And R ¹⁹ and R ²⁰ together with the atoms to which they are attached form (C _4-8 ) heterocycloalkylene wherein at least one of the ring atoms comprising the ring is a hetero atom selected from —NR ²¹ — and —O— and the ring is Unsubstituted or substituted by R ² , wherein R ² is as defined above, R ²¹ is hydrogen, —C (O) OR ¹² , —C (O) R ¹² , —C (O) NR ¹² R ¹² , -S (O) ₂ NR ¹² R ¹² , -S (O) R ¹³ , -S (O) ₂ R ¹³ , -S (O) R ¹⁴ , -S (O) ₂ R ¹⁴ , -C ( O) R ¹⁴ , -C (O) OR ¹⁴ , -C (O) NR ¹² R ¹² and -S (O) ₂ NR ¹⁴ R ¹² , wherein R ¹² , R ¹³ and R ¹⁴ are as defined above ego,
In R ³ , R ⁴ , R ¹⁵ , R ¹⁷ and R ¹⁸ the alicyclic or aromatic ring system is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo- Substituted (C _1-4 ) alkyl, nitro, —X ⁵ NR ¹² R ¹² , —X ⁵ NR ¹² C (O) R ¹² , —X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C ( O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) 1 to 5 radicals independently selected from R ¹³ , -X ⁵ C (O) R ¹³ and -X ⁵ S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² in Emitter is further substituted by a selected one radical, R ³ and R ⁴ in the aliphatic moiety is unsubstituted or substituted from cyano, halo, ^{nitro, -NR 12 R 12, -NR 12} C (O) R 12, -NR ¹² C (O) OR ¹² , -NR ¹² C (O) NR ¹² R ¹² , -NR ¹² C (NR ¹² ) NR ¹² R ¹² , -OR ¹² , -SR ¹² , -C (O) OR ¹² ,- C (O) R ¹² , -OC (O) R ¹² , -C (O) NR ¹² R ¹² , -S (O) ₂ NR ¹² R ¹² , -NR ¹² S (O) ₂ R ¹² , -P ( O) (OR ¹² ) OR ¹² , -OP (O) (OR ¹² ) OR ¹² , -NR ¹² C (O) R ¹³ , -S (O) R ¹³ and -S (O) ₂ R ¹³ independently Further substituted by 1 to 5 radicals selected, wherein X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, provided that X ³ is cyano and X ² is —OR ⁴ where R ⁴ Is -R ¹⁴ ) or -NHR ¹⁸ , the aromatic ring system present in R ¹⁴ or R ¹⁸ is halo, (C _3-10 ) cycloalkyl, hetero (C _3-10 ) cycloalkyl, (C _{6- 10)} aryl, hetero (C _5-10) aryl, (C _9-10) bicyclo aryl or hetero (C _8-10) of the bicyclo aryl It is not further substituted,
Provided that only one acyclic ring structure is present at R ³ , R ⁴ or R ¹⁵ , N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomer mixtures thereof, and the compounds, N thereof Pharmaceutically acceptable salts and solvates of oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomer mixtures.
[4" claim-type="Currently amended] The method according to claim 1 or 2,
X ¹ is -NHC (R ¹ ) (R ² ) X ³ or -NHCH (R ¹⁹ ) C (O) R ²⁰ ,
X ² is hydrogen, fluoro, —OH, —OR ⁴ , —NHR ¹⁵ or —NR ¹⁷ R ¹⁸ , X ⁷ is hydrogen, X ² and X ⁷ are both fluoro,
X ³ is -C (R ⁷ ) (R ⁸ ) R ¹⁶ , -C (R ⁶ ) (OR ⁶ ) ₂ , -CH ₂ C (O) R ¹⁶ , -CH = CHS (O) ₂ R ⁵ ,- C (O) CF ₂ C (O) NR ⁵ R ⁵ , -C (O) C (O) NR ⁵ R ⁶ , -C (O) C (O) OR ⁵ , -C (O) CH ₂ OR ⁵ , -C (O) CH ₂ N (R ⁶ ) SO ₂ R ⁵ or -C (O) C (O) R ⁵ , R ⁵ is hydrogen, (C _1-4 ) alkyl, (C _3-10 ) Cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl, R ⁶ is hydrogen, hydrogen Oxy or (C _1-6 ) alkyl, or when X ³ contains a -NR ⁵ R ⁶ group, then R ⁵ and R ⁶ together with the nitrogen atom to which they are attached hetero (C _3-10 ) cycloalkyl, hetero ( C _5-10 ) aryl or hetero (C _8-10 ) bicycloaryl, wherein R ⁷ is hydrogen or (C _1-4 ) alkyl and R ⁸ is hydroxy or R ⁷ and R ⁸ together are oxo forming, and R ¹⁶ is _{^{hydrogen, -X 4, -CF 3, -CF}} 2 CF 2 R 9 Is -N (R ⁶⁾ is OR ^6, R ⁹ is hydrogen, halo, (C _1-4) alkyl, (C _5-10) aryl (C _0-6) alkyl or (C _5-10) heteroaryl ( C _0-6 ) alkyl,
X ⁴ is a cyclic fused heterocyclic non containing a hetero monocyclic ring or 8 to 14 ring atoms containing 4 to 7 ring atoms ring system and cyclic thereof carbonyl ketones, imino ketone or thio ketone derivative Provided that, when -X ⁴ is a ring other than a heteromonocyclic ring containing five ring atoms wherein up to two of the ring atoms containing the ring are hetero atoms, X ² is fluoro, -OH, -OR ⁴ , -NHR ¹⁵ or -NR ¹⁷ R ¹⁸ , X ⁷ is hydrogen, X ² and X ⁷ are both fluoro,
Unsubstituted or substituted (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1- ) alicyclic or aromatic ring systems in R ⁵ , X ³ or X ⁴ ₄ ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² ,- X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ and -X ⁵ 1 to 5 radicals independently selected from S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S ( O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S ( ^{_{O) 2 R 14, -X 5}} NR 12 C (O) NR 14 R 12 and ^{-X 5 NR 12 C (NR 12} ) NR 14 R ¹² selected from one LA Being further substituted by a knife, X ⁵ is a bond or (C _1-6) alkylene, R ¹² are each independently hydrogen, (C _1-6) alkyl or halo-substituted (C _1-6) alkyl R ¹³ is (C _1-6 ) alkyl or halo-substituted (C _1-6 ) alkyl, R ¹⁴ is (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _{3- 10} ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) ratio _Cycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl,
R ¹ is hydrogen or (C _1-6 ) alkyl, R ² is hydrogen, cyano, —X ⁵ NR ¹² R ¹² , —X ⁵ NR ¹² C (O) R ¹² , —X ⁵ NR ¹² C (O ) OR ¹² , -R ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² ,- X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O ) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² (where X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, or R ¹ and R ² together with the carbon atom to which they are attached are (C _3-8 ) cycloalkylene or (C _3-8) heterocycloalkyl form an alkylene group, and R ² in the heteroaryl, aryl, cycloalkyl, heterocycloalkyl, cycloalkylene or heterocyclic cycloalkylene is unsubstituted or substituted by (C _1-6) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1-4 ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ and -X ⁵ C (O) R ¹³ , where X ⁵ , R ¹² and R ¹³ Is further defined by one to three radicals independently selected from
R ³ is (C _1-6 ) alkyl or —C (R ⁶ ) (R ⁶ ) X ⁶ , R ⁶ is hydrogen or (C _1-6 ) alkyl, X ⁶ is —X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C ( O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , wherein X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
R ⁴ is -X ⁸ NR ¹² R ¹² , -X ⁸ NR ¹² C (O) R ¹² , -X ⁸ NR ¹² C (O) OR ¹² , -X ⁸ NR ¹² C (O) NR ¹² R ¹² ,- X ⁸ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁸ OR ¹² , -X ⁸ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁸ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁸ S (O) ₂ NR ¹² R ¹² , -X ⁸ NR ¹² S (O) ₂ R ¹² , -X ⁸ P (O ) (OR ¹² ) OR ¹² , -X ⁸ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁸ NR ¹² C (O) R ¹³ , -X ⁸ S (O ) R ¹³ , -X ⁸ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁸ OR ¹⁴ , -X ⁸ SR ¹⁴ , -X ⁸ S (O) R ¹⁴ , -X ⁸ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁸ OC (O) R ¹⁴ , -X ⁸ NR ¹⁴ R ¹² , -X ⁸ NR ¹² C (O) R ¹⁴ , -X ⁸ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁸ S (O) ₂ NR ¹⁴ R ¹² , -X ⁸ NR ¹² S (O) ₂ R ¹⁴ , —X ⁸ NR ¹² C (O) NR ¹⁴ R ¹² and —X ⁸ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , X ⁸ is (C _1-6 ) alkylene, X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
R ¹⁵ is (C _6-10 ) aryl, hetero (C _5-10 ) aryl, (C _9-10 ) _bicycloaryl or hetero (C _8-10 ) _bicycloaryl ,
R ¹⁷ is hydrogen, (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, (C _{6- 10} ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) _Bicycloaryl (C _0-6 ) alkyl,
R ¹⁸ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, (C _6-10 ) Aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) ratio _Cycloaryl (C _0-6 ) alkyl,
Or one of R ¹⁹ and R ²⁰ together with the atoms to which they are attached to form a ring (C _4-8 ) heterocycloalkylene wherein one or more of the ring atoms containing the ring is a hetero atom selected from —NR ²¹ — and —O— and the ring is Unsubstituted or substituted by R ² , wherein R ² is as defined above, R ²¹ is hydrogen, —C (O) OR ¹² , —C (O) R ¹² , —C (O) NR ¹² R ¹² , -S (O) ₂ NR ¹² R ¹² , -S (O) R ¹³ , -S (O) ₂ R ¹³ , -S (O) R ¹⁴ , -S (O) ₂ R ¹⁴ , -C ( O) R ¹⁴ , -C (O) OR ¹⁴ , -C (O) NR ¹² R ¹² and -S (O) ₂ NR ¹⁴ R ^12, wherein R ¹² , R ¹³ and R ¹⁴ are as defined above,
In R ³ , R ⁴ , R ¹⁵ , R ¹⁷ and R ¹⁸ the alicyclic or aromatic ring system is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo- Substituted (C _1-4 ) alkyl, nitro, —X ⁵ NR ¹² R ¹² , —X ⁵ NR ¹² C (O) R ¹² , —X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C ( O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) 1 to 5 radicals independently selected from R ¹³ , -X ⁵ C (O) R ¹³ and -X ⁵ S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² in Emitter is further substituted by a selected one radical, a cycloaliphatic moiety is unsubstituted or substituted in the R ³ and R ^4, cyano, halo, ^{nitro, -NR 12 R 12, -NR 12} C (O) R 12, - NR ¹² C (O) OR ¹² , -NR ¹² C (O) NR ¹² R ¹² , -NR ¹² C (NR ¹² ) NR ¹² R ¹² , -OR ¹² , -SR ¹² , -C (O) OR ¹² , -C (O) R ¹² , -OC (O) R ¹² , -C (O) NR ¹² R ¹² , -S (O) ₂ NR ¹² R ¹² , -NR ¹² S (O) ₂ R ¹² , -P (O) (OR ¹² ) OR ¹² , -OP (O) (OR ¹² ) OR ¹² , -NR ¹² C (O) R ¹³ , -S (O) R ¹³ and -S (O) ₂ R ¹³ Further substituted by 1 to 5 radicals selected from X ⁵ , R ¹² , R ¹³ and R ¹⁴ as defined above,
Provided that only one acyclic ring structure is present in R ³ , R ⁴ or R ¹⁵ , N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomer mixtures thereof, and the compounds, N thereof Pharmaceutically acceptable salts and solvates of oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomer mixtures.
[5" claim-type="Currently amended] The method according to claim 1 or 2,
X ¹ is -NHC (R ¹ ) (R ² ) X ³ or -NHCH (R ¹⁹ ) C (O) R ²⁰ ,
X ² is hydrogen, fluoro, —OH, —OR ⁴ or —NR ¹⁷ R ¹⁸ , X ⁷ is hydrogen, X ² and X ⁷ are both fluoro,
X ³ is cyano,
Unsubstituted or substituted (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1-4 ) alkyl, nitro, in X ³ , -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ and -X ⁵ S (O) ₂ R 1 to 5 radicals independently selected from ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , by one radical selected from ^{-X 5 NR 12 C (O)} NR 14 R 12 and ^{-X 5 NR 12 C (NR 12} ) NR 14 R 12 Horizontal is selected, X ⁵ is a bond or (C _1-6) alkylene, R ¹² are each independently hydrogen, (C _1-6) alkyl or halo-substituted (C _1-6) alkyl, R ¹³ Is (C _1-6 ) alkyl or halo-substituted (C _1-6 ) alkyl, R ¹⁴ is (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl,
R ¹ is hydrogen or (C _1-6 ) alkyl, R ² is hydrogen, cyano, —X ⁵ NR ¹² R ¹² , —X ⁵ NR ¹² C (O) R ¹² , —X ⁵ NR ¹² C (O ) OR ¹² , -R ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² ,- X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O ) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² (where X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, or R ¹ and R ² together with the carbon atom to which they are attached are (C _3-8 ) cycloalkylene or (C _3-8) heterocycloalkyl form an alkylene group, and R ² in the heteroaryl, aryl, cycloalkyl, heterocycloalkyl, cycloalkylene or heterocyclic cycloalkylene is unsubstituted or substituted by (C _1-6) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1-4 ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ By 1 to 3 radicals independently selected from NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ and -X ⁵ C (O) R ¹³ Further substituted, X ⁵ , R ¹² and R ¹³ are as defined above,
R ³ is (C _1-6 ) alkyl or —C (R ⁶ ) (R ⁶ ) X ⁶ , R ⁶ is hydrogen or (C _1-6 ) alkyl, X ⁶ is —X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C ( O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , wherein X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
R ⁴ is -X ⁸ NR ¹² R ¹² , -X ⁸ NR ¹² C (O) R ¹² , -X ⁸ NR ¹² C (O) OR ¹² , -X ⁸ NR ¹² C (O) NR ¹² R ¹² ,- X ⁸ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁸ OR ¹² , -X ⁸ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁸ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁸ S (O) ₂ NR ¹² R ¹² , -X ⁸ NR ¹² S (O) ₂ R ¹² , -X ⁸ P (O ) (OR ¹² ) OR ¹² , -X ⁸ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁸ NR ¹² C (O) R ¹³ , -X ⁸ S (O ) R ¹³ , -X ⁸ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁸ OR ¹⁴ , -X ⁸ SR ¹⁴ , -X ⁸ S (O) R ¹⁴ , -X ⁸ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁸ OC (O) R ¹⁴ , -X ⁸ NR ¹⁴ R ¹² , -X ⁸ NR ¹² C (O) R ¹⁴ , -X ⁸ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁸ S (O) ₂ NR ¹⁴ R ¹² , -X ⁸ NR ¹² S (O) ₂ R ¹⁴ , —X ⁸ NR ¹² C (O) NR ¹⁴ R ¹² and —X ⁸ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , X ⁸ is (C _1-6 ) alkylene, X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, provided that X ³ is cyano and X ² is -OR ⁴ , where R ⁴ is -R ¹⁴ , and R ¹⁴ is (C _{3- 10} ) cycloalkyl (C _1-6 ) alkyl, hetero (C _3-10 ) Cycloalkyl (C _1-3 ) alkyl, (C _6-10 ) aryl (C _1-6 ) alkyl, hetero (C _5-10 ) aryl (C _1-6 ) alkyl, (C _9-10 ) bicyclo Aryl (C _1-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _1-6 ) alkyl,
R ¹⁵ is (C _6-10 ) aryl, hetero (C _5-10 ) aryl, (C _9-10 ) _bicycloaryl or hetero (C _8-10 ) _bicycloaryl ,
R ¹⁷ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, (C _6-10 ) Aryl (C _1-6 ) alkyl, hetero (C _5-10 ) aryl (C _1-6 ) alkyl, (C _9-10 ) bicycloaryl (C _1-6 ) alkyl or hetero (C _8-10 ) ratio Cycloaryl (C _1-6 ) alkyl,
R ¹⁸ is (C _1-6 ) alkyl, (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _1-6 ) alkyl, (C _6-10 ) Aryl (C _1-6 ) alkyl, hetero (C _5-10 ) aryl (C _1-6 ) alkyl, (C _9-10 ) bicycloaryl (C _1-6 ) alkyl or hetero (C _8-10 ) ratio Cycloaryl (C _1-6 ) alkyl,
One or more of R ¹⁹ and R ²⁰ together with the atom to which they are attached form a ring (C _4-8 ) heterocycloalkylene wherein the ring is a hetero atom selected from —NR ²¹ — and —O— and the ring is Unsubstituted or substituted by R ² , wherein R ² is as defined above, R ²¹ is hydrogen, —C (O) OR ¹² , —C (O) R ¹² , —C (O) NR ¹² R ¹² , -S (O) ₂ NR ¹² R ¹² , -S (O) R ¹³ , -S (O) ₂ R ¹³ , -S (O) R ¹⁴ , -S (O) ₂ R ¹⁴ , -C ( O) R ¹⁴ , -C (O) OR ¹⁴ , -C (O) NR ¹² R ¹² and -S (O) ₂ NR ¹⁴ R ^12, wherein R ¹² , R ¹³ and R ¹⁴ are as defined above,
In R ³ , R ⁴ , R ¹⁵ , R ¹⁷ and R ¹⁸ the alicyclic or aromatic ring system is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo- Substituted (C _1-4 ) alkyl, nitro, —X ⁵ NR ¹² R ¹² , —X ⁵ NR ¹² C (O) R ¹² , —X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C ( O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) 1 to 5 radicals independently selected from R ¹³ , -X ⁵ C (O) R ¹³ and -X ⁵ S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² in Emitter is further substituted by a selected one radical, R ³ and R ⁴ in the aliphatic moiety is unsubstituted or substituted from cyano, halo, ^{nitro, -NR 12 R 12, -NR 12} C (O) R 12, -NR ¹² C (O) OR ¹² , -NR ¹² C (O) NR ¹² R ¹² , -NR ¹² C (NR ¹² ) NR ¹² R ¹² , -OR ¹² , -SR ¹² , -C (O) OR ¹² ,- C (O) R ¹² , -OC (O) R ¹² , -C (O) NR ¹² R ¹² , -S (O) ₂ NR ¹² R ¹² , -NR ¹² S (O) ₂ R ¹² , -P ( O) (OR ¹² ) OR ¹² , -OP (O) (OR ¹² ) OR ¹² , -NR ¹² C (O) R ¹³ , -S (O) R ¹³ and -S (O) ₂ R ¹³ independently Further substituted by 1 to 5 radicals selected, wherein X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, provided that X ² is —OR ⁴ where R ⁴ is —R ¹⁴ or In the case of —NHR ¹⁸ , the aromatic ring system present in R ¹⁴ or R ¹⁸ may be halo, (C _3-10 ) cycloalkyl, hetero (C _3-10 ) cycloalkyl, (C _6-10 ) aryl, hetero (C _5-10) aryl, (C _9-10) bicyclo aryl or hetero (C _8-10) further substituted by an aryl bicyclo Not
Provided that only one acyclic ring structure is present in R ³ , R ⁴ or R ¹⁵ , N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomer mixtures thereof, and the compounds, N thereof Pharmaceutically acceptable salts and solvates of oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomer mixtures.
[6" claim-type="Currently amended] The method according to claim 1 or 2,
X ¹ is -NHC (R ¹ ) (R ² ) X ³ or -NHCH (R ¹⁹ ) C (O) R ²⁰ ,
X ² is —OH, —OC (O) NR ¹² R ¹² or —OC (O) R ¹⁴ , wherein R ¹² and R ¹⁴ are as defined below,
X ³ is cyano, -C (R ⁷ ) (R ⁸ ) R ¹⁶ , -C (R ⁶ ) (OR ⁶ ) ₂ , -CH ₂ C (O) R ¹⁶ , -CH = CHS (O) ₂ R ⁵ , -C (O) CF ₂ C (O) NR ⁵ R ⁵ , -C (O) C (O) NR ⁵ R ⁶ , -C (O) C (O) OR ⁵ , -C (O) CH ₂ OR ⁵ , -C (O) CH ₂ N (R ⁶ ) SO ₂ R ⁵ or -C (O) C (O) R ⁵ , R ⁵ is hydrogen, (C _1-4 ) alkyl, (C _{3 -10} ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _{5- 10} ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl, R ⁶ is When hydrogen, hydroxy or (C _1-6 ) alkyl or X ³ contains a —NR ⁵ R ⁶ group, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are hetero (C _3-10 ) cycloalkyl , Hetero (C _5-10 ) aryl or hetero (C _8-10 ) bicycloaryl, wherein R ⁷ is hydrogen or (C _1-4 ) alkyl and R ⁸ is hydroxy or R ⁷ and R ⁸ Together form oxo, and R ¹⁶ is hydrogen, -X ⁴ , -CF ₃ , -CF ₂ CF ₂ R ⁹ or —N (R ⁶ ) OR ⁶ , R ⁹ is hydrogen, halo, (C _1-4 ) alkyl, (C _5-10 ) aryl (C _0-6 ) alkyl or (C _5-10 Heteroaryl (C _0-6 ) alkyl,
X ⁴ is a cyclic fused heterocyclic non containing a hetero monocyclic ring or 8 to 14 ring atoms containing 4 to 7 ring atoms ring system and cyclic thereof carbonyl ketones, imino ketone or thio ketone derivative Including,
Unsubstituted or substituted (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1- ) alicyclic or aromatic ring systems in R ⁵ , X ³ or X ⁴ ₄ ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² ,- X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ and -X ⁵ 1 to 5 radicals independently selected from S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S ( O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S ( ^{_{O) 2 R 14, -X 5}} NR 12 C (O) NR 14 R 12 and ^{-X 5 NR 12 C (NR 12} ) NR 14 R ¹² selected from one LA Being further substituted by a knife, X ⁵ is a bond or (C _1-6) alkylene, R ¹² are each independently hydrogen, (C _1-6) alkyl or halo-substituted (C _1-6) alkyl R ¹³ is (C _1-6 ) alkyl or halo-substituted (C _1-6 ) alkyl, R ¹⁴ is (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _{3- 10} ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) ratio _Cycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl,
R ¹ is hydrogen or (C _1-6 ) alkyl, R ² is hydrogen, cyano, —X ⁵ NR ¹² R ¹² , —X ⁵ NR ¹² C (O) R ¹² , —X ⁵ NR ¹² C (O ) OR ¹² , -R ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² ,- X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O ) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² (where X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above, or R ¹ and R ² together with the carbon atom to which they are attached are (C _3-8 ) cycloalkylene or ( C _3-8) heterocycloalkyl form an alkylene group, and R ² in the heteroaryl, aryl, cycloalkyl, heterocycloalkyl, cycloalkylene or heterocyclic cycloalkylene is unsubstituted or substituted by (C _1-6) alkyl, ( C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1-4 ) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ and -X ⁵ C (O) R ¹³ substituted by 1 to 3 radicals independently selected from X ⁵ , R ¹² and R ¹³ are as defined above,
R ³ is (C _1-6 ) alkyl or —C (R ⁶ ) (R ⁶ ) X ⁶ , R ⁶ is hydrogen or (C _1-6 ) alkyl, X ⁶ is —X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C ( O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ S (O) ₂ R ¹³ , -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² , wherein X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
Or one of R ¹⁹ and R ²⁰ together with the atoms to which they are attached to form a ring (C _4-8 ) heterocycloalkylene wherein one or more of the ring atoms containing the ring is a hetero atom selected from —NR ²¹ — and —O— and the ring is Unsubstituted or substituted by R ² , wherein R ² is as defined above, R ²¹ is hydrogen, —C (O) OR ¹² , —C (O) R ¹² , —C (O) NR ¹² R ¹² , -S (O) ₂ NR ¹² R ¹² , -S (O) R ¹³ , -S (O) ₂ R ¹³ , -S (O) R ¹⁴ , -S (O) ₂ R ¹⁴ , -C ( O) R ¹⁴ , -C (O) OR ¹⁴ , -C (O) NR ¹² R ¹² and -S (O) ₂ NR ¹⁴ R ^12, wherein R ¹² , R ¹³ and R ¹⁴ are as defined above,
In R ³ , R ⁴ , R ¹⁵ , R ¹⁷ and R ¹⁸ the alicyclic or aromatic ring system is unsubstituted or (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo- Substituted (C _1-4 ) alkyl, nitro, —X ⁵ NR ¹² R ¹² , —X ⁵ NR ¹² C (O) R ¹² , —X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C ( O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) 1 to 5 radicals independently selected from R ¹³ , -X ⁵ C (O) R ¹³ and -X ⁵ S (O) ₂ R ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹⁴ R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² in Emitter is further substituted by a selected one radical, R ³ and R ⁴ in the aliphatic moiety is unsubstituted or substituted from cyano, halo, ^{nitro, -NR 12 R 12, -NR 12} C (O) R 12, -NR ¹² C (O) OR ¹² , -NR ¹² C (O) NR ¹² R ¹² , -NR ¹² C (NR ¹² ) NR ¹² R ¹² , -OR ¹² , -SR ¹² , -C (O) OR ¹² ,- C (O) R ¹² , -OC (O) R ¹² , -C (O) NR ¹² R ¹² , -S (O) ₂ NR ¹² R ¹² , -NR ¹² S (O) ₂ R ¹² , -P ( O) (OR ¹² ) OR ¹² , -OP (O) (OR ¹² ) OR ¹² , -NR ¹² C (O) R ¹³ , -S (O) R ¹³ and -S (O) ₂ R ¹³ independently Further substituted by 1 to 5 radicals selected, X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
Provided that only one acyclic ring structure is present in R ³ , R ⁴ or R ¹⁵ , N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomer mixtures thereof, and the compounds, N thereof Pharmaceutically acceptable salts and solvates of oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomer mixtures.
[7" claim-type="Currently amended] The method according to claim 1 or 2,
X ¹ is —NHC (R ¹ ) (R ² ) C (O) C (O) NR ⁵ R ⁶ , R ⁵ is hydrogen, (C _1-4 ) alkyl, (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cycloalkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _{0- 6} ) alkyl, (C _9-10 ) bicycloaryl (C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl, R ⁶ is hydrogen, hydroxy or (C _1-6 ) alkyl, or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached hetero (C _3-10 ) cycloalkyl, hetero (C _5-10 ) aryl or hetero (C _8-10 ) bicycloaryl Forming,
X ² is hydrogen,
Unsubstituted or substituted (C _1-6 ) alkyl, (C _1-6 ) alkylidene, cyano, halo, halo-substituted (C _1-4 ) alkyl, nitro, in X ¹ -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ and -X ⁵ S (O) ₂ R 1 to 5 radicals independently selected from ¹³ and / or -R ¹⁴ , -X ⁵ OR ¹⁴ , -X ⁵ SR ¹⁴ , -X ⁵ S (O) R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ , -X ⁵ C (O) OR ¹⁴ , -X ⁵ OC (O) R ¹⁴ , -X ⁵ NR ¹⁴ R ¹² , -X ⁵ NR ¹² C (O) R ¹⁴ , -X ⁵ NR ¹² C (O) OR ¹⁴ , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹⁴ R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹⁴ , By one radical selected from -X ⁵ NR ¹² C (O) NR ¹⁴ R ¹² and -X ⁵ NR ¹² C (NR ¹² ) NR ¹⁴ R ¹² Further substituted, X ⁵ is a bond or (C _1-6 ) alkylene, each R ¹² is independently hydrogen, (C _1-6 ) alkyl or halo-substituted (C _1-6 ) alkyl, R ¹³ is (C _1-6 ) alkyl or halo-substituted (C _1-6 ) alkyl, R ¹⁴ is (C _3-10 ) cycloalkyl (C _0-6 ) alkyl, hetero (C _3-10 ) cyclo Alkyl (C _0-3 ) alkyl, (C _6-10 ) aryl (C _0-6 ) alkyl, hetero (C _5-10 ) aryl (C _0-6 ) alkyl, (C _9-10 ) bicycloaryl ( C _0-6 ) alkyl or hetero (C _8-10 ) bicycloaryl (C _0-6 ) alkyl,
R ¹ is hydrogen, R ² is (C _1-6 ) alkyl,
R ³ is -CH ₂ X ⁶ , X ⁶ is -X ⁵ NR ¹² S (O) ₂ R ¹² or -X ⁵ S (O) ₂ R ¹⁴ , and X ⁵ , R ¹² and R ¹⁴ are as defined above; Equal,
R ³ in the alicyclic or aromatic ring system is optionally substituted with (C _1-6) alkyl, (C _1-6) alkylidene, cyano, halo, halo-substituted (C _1-4) alkyl, nitro, -X ⁵ NR ¹² R ¹² , -X ⁵ NR ¹² C (O) R ¹² , -X ⁵ NR ¹² C (O) OR ¹² , -X ⁵ NR ¹² C (O) NR ¹² R ¹² , -X ⁵ NR ¹² C (NR ¹² ) NR ¹² R ¹² , -X ⁵ OR ¹² , -X ⁵ SR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹² , -X ⁵ OC (O) R ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ NR ¹² R ¹² , -X ⁵ NR ¹² S (O) ₂ R ¹² , -X ⁵ P (O) (OR ¹² ) OR ¹² , -X ⁵ OP (O) (OR ¹² ) OR ¹² , -X ⁵ NR ¹² C (O) R ¹³ , -X ⁵ S (O) R ¹³ , -X ⁵ C (O) R ¹³ And further substituted by 1 to 5 radicals independently selected from —X ⁵ S (O) ₂ R ¹³ , wherein no aliphatic residues are substituted in R ³ or cyano, halo, nitro, —NR ¹² R ¹² , -NR ¹² C (O) R ¹² , -NR ¹² C (O) OR ¹² , -NR ¹² C (O) NR ¹² R ¹² , -NR ¹² C (NR ¹² ) NR ¹² R ¹² , -OR ¹² ,- SR ¹² , -C (O) OR ¹² , -C (O) R ¹² , -OC (O) R ¹² , -C (O) NR ¹² R ¹² , -S (O) ₂ NR ¹² R ¹² , -NR ¹² S (O) ₂ R ¹² , -P (O) (OR ¹² ) OR ¹² , By 1 to 5 radicals independently selected from -OP (O) (OR ¹² ) OR ¹² , -NR ¹² C (O) R ¹³ , -S (O) R ¹³ and -S (O) ₂ R ¹³ Further substituted, X ⁵ , R ¹² , R ¹³ and R ¹⁴ are as defined above,
Provided that only one acyclic ring structure is present in R ³ , N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomeric mixtures thereof, and the compound, N-oxide derivatives thereof, prodrugs thereof Pharmaceutically acceptable salts and solvates of derivatives, protected derivatives, individual isomers and isomer mixtures.
[8" claim-type="Currently amended] The method of claim 3,
X ¹ is —NHC (R ¹ ) (R ² ) X ³ or —NHCH (R ¹⁹ ) C (O) R ²⁰ , R ¹ is hydrogen or (C _1-6 ) alkyl, R ² is hydrogen, ( C _1-6 ) alkyl, -X ⁵ OR ¹² , -X ⁵ S (O) R ¹³ , -X ⁵ OR ¹⁴ , (C _6-10 ) aryl (C _0-6 ) alkyl or hetero (C _5-10 ) Aryl (C _0-6 ) alkyl, or R ¹ and R ² together with the carbon atom to which they are attached form (C _3-6 ) cycloalkylene or (C _3-6 ) heterocycloalkylene, and R ² Heteroaryl, aryl, cycloalkylene or heterocycloalkylene is unsubstituted or substituted by (C _1-6 ) alkyl or hydroxy and X ³ is cyano, -C (O) R ¹⁶ , -C (R ⁶ ) (OR ⁶ ) ₂ , -CH = CHS (O) ₂ R ⁵ , -CH ₂ C (O) R ¹⁶ , -C (O) CF ₂ C (O) NR ⁵ R ⁵ , -C ( O) C (O) NR ⁵ R ⁶ , -C (O) C (O) OR ⁵ , -C (O) CH ₂ OR ⁵ , -C (O) CH ₂ N (R ⁶ ) SO ₂ R ⁵ or -C (O) C (O) R ^5, wherein R ¹⁹ and R ²⁰ are one or less of the ring atoms containing a ring together with the atoms to which they are attached a hetero atom selected from -NR ²¹ -and -O- _4-8) Forming an interrogating cycloalkylene, and ring is optionally substituted with (C _1-6) alkyl, or is substituted by ^{-X 5 C (O) OR 12} , R 21 is hydrogen, (C _1-6) alkyl, -X ⁵ C (O) R ¹² , -X ⁵ C (O) OR ¹² , -R ¹⁴ , -X ⁵ C (O) R ¹⁴ or -C (O) OR ¹⁴ ,
X ² is —OH or —OC (O) NR ¹² R ¹² , wherein each R ¹² is independently hydrogen or (C _1-6 ) alkyl and alkyl is unsubstituted or substituted by hydroxy or methoxy , -OC (O) NHR ¹⁴ , wherein R ¹⁴ is (C _3-10 ) cycloalkyl (C _0-6 ) alkyl or hetero (C _3-10 ) cycloalkyl (C _1-3 ) alkyl OC (O) R ¹⁴ , wherein R ¹⁴ is —NR ²² R ²³ , and R ²² and R ²³ together with the nitrogen atom to which they are attached form a hetero (C _4-6 ) cycloalkyl ring and the ring is unsubstituted Substituted by hydroxy),
R ³ is -CH ₂ X ⁶ , X ⁶ is -X ⁵ SR ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ R ¹³ , -X ⁵ C (O) R ¹³ , -X ⁵ OR ¹² , -X ⁵ SR ¹⁴ , -X ⁵ R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ and -X ⁵ C (O) NR ¹⁴ Compounds selected from R ¹² , N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomeric mixtures thereof, and compounds, N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomeric mixtures thereof Pharmaceutically acceptable salts and solvates of.
[9" claim-type="Currently amended] The method of claim 8,
X ³ is cyano, -C (O) X ⁴ , -C (O) H, -C (O) N (CH ₃ ) OCH ₃ , -CH (OCH ₃ ) ₂ , -C (O) CF ₃ , -C (O) CF ₂ CF ₃ , -CH ₂ C (O) R ¹⁶ , (E) -2-benzenesulfonyl-vinyl, 2-dimethylcarbamoyl-2,2-difluoro-acetyl, 2- Oxo-2-pyrrolidin-1-yl-acetyl, 2-morpholin-4-yl-2-oxo-acetyl, 2-oxo-2-piperazin-1-yl-acetyl, 2- (4-methane Sulfonyl-piperazin-1-yl) -2-oxo-acetyl, 2- (1,1-dioxo-1λ ⁶ -thiomorpholin-4-yl) -2-oxo-acetyl, dimethylaminooxalyl, Tetrahydro-pyran-4-ylaminooxalyl, 2-morpholin-4-yl-ethylaminooxalyl, cyclopentyl-ethyl-aminooxalyl, pyridin-3-ylaminooxalyl, phenylaminooxalyl, 1 -Benzoyl-piperidin-4-ylaminooxalyl, 1-benzylcarbamoyl-methanoyl, 1-benzyloxy (oxalyl), 2-benzyloxy-acetyl, 2-benzenesulfonylamino-ethanoyl, 2 -Oxo-2-phenyl-ethanoyl, 3H-oxazole-2-carbonyl, 5-trifluoromethyl-oxazole-2-carbonyl, 3-triflu Rhomethyl- [1,2,4] oxadiazole-5-carbonyl, 2,2,3,3,3-pentafluoro-propionyl, hydroxyaminooxalyl, oxalyl, 2- (1, 3-dihydro-isoindol-2-yl) -2-oxo-acetyl, benzothiazol-2-ylaminooxalyl, 2-oxo-ethyl, 2-oxazol-2-yl-2-oxo-ethyl Or 2-benzooxazol-2-yl-2-oxo-ethyl,
X ² is —OH, dimethylcarbamoyloxy, morpholin-4-ylcarbonyloxy, piperidin-1-yl-carbonyloxy, pyrrolidin-1-yl-carbonyloxy, pyrimidine-2- Monoamino, tetrahydro-pyran-4-ylamino, 1-methyl-piperidin-4-ylamino, N- (2-methoxyethyl) -N- (tetrahydro-pyran-4-yl) amino, Isopropylamino and cyclohexylamino; 4-tert-butoxycarbonyl-piperazin-1-yl-oxy-carbonyl, N- benzyl-carbamoyl-oxy, pyrrolidin-1-yl-oxy-carbonyl, N, N- dimethyl-carbamoyl-oxy, P Ferridin-1-yl-carbonyloxy, 4-methanesulfonyl-piperazin-1-yl-carbonyloxy, 4-ethoxycarbonylpiperazin-1-ylcarbonyloxy, N-cyclohexyl-carba Moyloxy, N-phenyl-carbamoyloxy, N- (5,6,7,8-tetrahydro-naphthalen-1-yl) -carbamoyloxy, N-butyl-N-methyl-carbamoyloxy, N- Pyridin-3-yl-carbamoyloxy, N-isopropyl-carbamoyloxy, N-pyridin-4-yl-carbamoyloxy, N-cyanomethyl-N-methyl-carbamoyloxy, N, N-bis -(2-methoxy-ethyl) -carbamoyloxy, N-phenethyl-carbamoyloxy, piperazine-carbonyloxy, N-naphthalen-2-yl-carbamoyloxy, 4-benzyl-piperazine-1 -Carbamoyloxy, 4- (1-furan-2-yl-carbonyl) -piperazin-1-carbamoyloxy, thiomorpholin-4-yl-carbonyloxy, 1,1-dioxo-1λ ⁶ -Thiomorpholin-4-yl)- Carbonyloxy, bis- (2-methoxy-ethyl) -carbamoyloxy, morpholin-4-ylcarbonyloxy, 2-methoxyethylcarbamoyloxy, diethylcarbamoyloxy, pyrrolidine-1- Ilcarbonyloxy, 2-hydroxyethylcarbamoyloxy, tetrahydro-furan-2-ylmethylcarbamoyloxy, cyclopropylcarbamoyloxy, tert - butylcarbamoyloxy, 3-hydroxy-pyrrolidine- 1-yl-carbonyloxy and carbamoyloxy,
R ³ is thiophene-2-sulfonyl-methyl, 3-chloro-2-fluoro-phenyl-methane-sulfonyl-methyl, benzene-sulfonyl-methyl, phenyl-methane-sulfonyl-methyl, 2- ( 1,1-Difluoro-methoxy) -phenyl-methane-sulfonyl-methyl, 2-benzene-sulfonyl-ethyl, 2- (pyridine-2-sulfonyl) -ethyl, 2- (pyridine-4- Sulfonyl) -ethyl, 2-phenyl-methanesulfonyl-ethyl, oxy-pyridin-2-yl-methane-sulfonyl-methyl, prop-2-en-1-sulfonyl-methyl, 4-methoxy- Phenyl-methane-sulfonyl-methyl, p-tolyl-methane-sulfonyl-methyl, 4-chloro-phenyl-methane-sulfonyl-methyl, o -tolyl-methane-sulfonyl-methyl, 3,5-dimethyl- Phenyl-methane-sulfonyl-methyl, 4-trifluoro-methyl-phenyl-methane-sulfonyl-methyl, 4-trifluoro-methoxy-phenyl-methane-sulfonyl-methyl, 2-bromo-phenyl Methane-sulfonyl-methyl, pyridin-2-yl-methane-sulfonyl-methyl, pyridin-3-yl-methane-sulfonyl-methyl, pyridin-4-yl-methane-sulfonyl-methyl, naphthalene-2 -Yl-methane-sulfonyl-methyl, 3-methyl-phenyl-methane-sulfo -Methyl, 3-trifluoro-methyl-phenyl-methane-sulfonyl-methyl, 3-trifluoro-methoxy-phenyl-methane-sulfonyl-methyl, 4-fluoro-2-trifluoromethoxy- Phenyl-methane-sulfonylmethyl, 2-fluoro-6-trifluoromethyl-phenylmethanesulfonylmethyl, 3-chloro-phenylmethanesulfonylmethyl, 2-fluoro-phenylmethanesulfonylmethyl, 2-tri Fluoro-phenylmethanesulfonylmethyl, 2-cyano-phenylmethanesulfonylmethyl, 4 - tert-butyl-phenylmethanesulfonylmethyl, 2-fluoro-3-methyl-phenyl-methane-sulfonyl-methyl , 3-fluoro-phenylmethanesulfonylmethyl, 4-fluoro-phenylmethane-sulfonylmethyl, 2-chloro-phenylmethanesulfonylmethyl, 2,5-difluoro-phenylmethane-sulfonylmethyl, 2 , 6-difluoro-phenylmethanesulfonylmethyl, 2,5-dichloro-phenyl-methane-sulfonylmethyl, 3,4-dichloro-phenylmethanesulfonylmethyl, 2- (1,1-difluoro- Methoxy) -phenyl-methanesulfonylmethyl, 2-cyano-phenyl-methane-sulfonyl-methyl, 3-cyano- Phenylmethanesulfonylmethyl, 2-trifluoro-methoxy-phenyl-methane-sulfonylmethyl, 2,3-difluoro-phenylmethanesulfonylmethyl, 2,5-difluoro-phenyl-methanesulfonyl Methyl, biphenyl-2-ylmethanesulfonylmethyl, cyclohexylmethyl, 3-fluoro-phenyl-methanesulfonylmethyl, 3,4-difluoro-phenyl-methanesulfonylmethyl, 2,4-difluoro Rho-phenylmethanesulfonylmethyl, 2,4,6-trifluoro-phenylmethanesulfonylmethyl, 2,4,5-trifluoro-phenylmethanesulfonylmethyl, 2,3,4-trifluoro- Phenylmethanesulfonylmethyl, 2,3,5-trifluoro-phenyl-methane-sulfonylmethyl, 2,5,6-trifluoro-phenylmethanesulfonylmethyl, 2-chloro-5-trifluoro- Methylphenylmethanesulfonylmethyl, 2-methyl-propane-1-sulfonyl, 2-fluoro-3-trifluoro-methylphenylmethanesulfonylmethyl, 2-fluoro-4-trifluoro-methylphenylmethanesulfonylmethyl , 2-fluoro-5-trifluoro-methyl-phenyl-methane-sulfonyl-methyl, 4-fluoro 3-trifluoro-methylphenylmethanesulfonylmethyl, 2-methoxy-phenyl-methanesulfonylmethyl, 3,5-bis-trifluoromethyl-phenylmethanesulfonylmethyl, 4-difluoromethoxy-phenyl Methanesulfonylmethyl, 2-difluoro-methoxy-phenyl-methanesulfonylmethyl, 3-difluoromethoxy-phenylmethanesulfonylmethyl, 2,6-dichloro-phenylmethanesulfonylmethyl, biphenyl-4 -Ylmethanesulfonylmethyl, 3,5-dimethyl-isoxazol-4-ylmethanesulfonylmethyl, 5-chloro-thien-2-yl-methane-sulfonylmethyl, 2- [4- (1,1- Difluoro-methoxy) -benzenesulfonyl] -ethyl, 2- [2- (1,1-difluoro-methoxy) -benzenesulfonyl] -ethyl, 2- [3- (1,1- Difluoro-methoxy) -benzenesulfonyl] -ethyl, 2- (4-trifluoromethoxy-benzenesulfonyl) -ethyl, 2- (3-trifluoromethoxy-benzenesulfonyl) -ethyl, 2 -(2-Trifluoro-methoxy-benzene-sulfonyl) -ethyl, (cyanomethyl-methyl-carbamoyl) -methyl, biphenyl-3-ylmethyl, 2-oxo-2-pyrrolidine- 1-yl-ethyl, 2-benzene Sulfonyl-ethyl, isobutylsulfanylmethyl, 2-phenylsulfanyl-ethyl, cyclohexylmethanesulfonylmethyl, 2-cyclohexyl-ethanesulfonyl, benzyl, naphthalen-2-yl, benzylsulfanylmethyl, 2- Trifluoromethyl-benzylsulfanylmethyl, phenylsulfanyl-ethyl, cyclopropyl-methanesulfonylmethyl, 5-bromo-thien-2-ylmethyl, 3-phenyl-propyl, 2,2-difluoro- 3-phenyl-propyl, 3,4,5-trimethoxy-phenylmethanesulfonylmethyl, 2,2-difluoro-3-thien-2-yl-propyl, cyclohexylethyl, cyclohexylmethyl, tertiary -butyl methyl, 1-methyl-cyclohexylmethyl, 1-methyl-cyclopentylmethyl, 2,2-difluoro-3-phenylpropyl, 2,2-dimethyl-3-phenylpropyl, 1-benzyl-cyclopropylmethyl, - X ⁵ S (O) ₂ R ¹³ and -X ⁵ S (O) ₂ R ¹⁴ , R ¹³ is alkyl, R ¹⁴ is unsubstituted or substituted phenyl, N-oxide derivatives, prodrug derivatives thereof, Protected derivatives, individual isomers and isomers Mixture, and the compound, and its N- oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and salts and solvates of pharmaceutically acceptable isomer mixture.
[10" claim-type="Currently amended] The method of claim 9,
X ³ is 1H-benzoimidazol-2-ylcarbonyl, pyrimidin-2-ylcarbonyl, benzoxazol-2-ylcarbonyl, benzothiazol-2-ylcarbonyl, pyridazin-3-yl Carbonyl, 3-phenyl- [1,2,4] oxadiazole-5-ylcarbonyl or 3-ethyl- [1,2,4] oxadiazole-5-ylcarbonyl, 2-oxo-2 -Pyrrolidin-1-yl-acetyl, 2-morpholin-4-yl-2-oxo-acetyl, 2-oxo-2-piperazin-1-yl-acetyl, 2- (4-methanesulfonyl- Piperazin-1-yl) -2-oxo-acetyl, 2- (1,1-dioxo-1λ ⁶ -thiomorpholin-4-yl) -2-oxo-acetyl, dimethylaminooxalyl, tetrahydro- Pyran-4-ylaminooxalyl, 2-morpholin-4-yl-ethylaminooxalyl, cyclopentyl-ethyl-aminooxalyl, pyridin-3-ylaminooxalyl, phenylaminooxalyl or 1-benzoyl- Piperidin-4-ylaminooxalyl,
X ² is —OH, dimethylcarbamoyloxy, morpholin-4-ylcarbonyloxy, piperidin-1-yl-carbonyloxy, pyrrolidin-1-yl-carbonyloxy, pyrimidine-2- Monoamino, tetrahydro-pyran-4-ylamino, 1-methyl-piperidin-4-ylamino, N- (2-methoxyethyl) -N- (tetrahydro-pyran-4-yl) amino, Isopropylamino and cyclohexylamino,
R ³ is cyclohexylethyl, cyclohexylmethyl, tert - butylmethyl, 1-methylcyclohexylmethyl, 1-methylcyclopentylmethyl, 2,2-difluoro-3-phenylpropyl, 2,2-dimethyl- 3-phenylpropyl, 1-benzylcyclopropylmethyl, -X ⁵ S (O) ₂ R ¹³ or -X ⁵ S (O) ₂ R ¹⁴ , R ¹³ is alkyl, R ¹⁴ is unsubstituted or substituted phenyl Phosphorus compounds, N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomeric mixtures, and pharmaceutical compounds of the compounds, N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomer mixtures Acceptable salts and solvates.
[11" claim-type="Currently amended] The method of claim 3,
X ¹ is —NHC (R ¹ ) (R ² ) X ³ or —NHCH (R ¹⁹ ) C (O) R ²⁰ , R ¹ is hydrogen or (C _1-6 ) alkyl, R ² is hydrogen, ( C _1-6 ) alkyl, -X ⁵ OR ¹² , -X ⁵ S (O) R ¹³ , -X ⁵ OR ¹⁴ , (C _6-10 ) aryl (C _0-6 ) alkyl or hetero (C _5-10 ) Aryl (C _0-6 ) alkyl, or R ¹ and R ² together with the carbon atom to which they are attached form (C _3-6 ) cycloalkylene or (C _3-6 ) heterocycloalkylene, and R ² Heteroaryl, aryl, cycloalkylene or heterocycloalkylene is unsubstituted or substituted by (C _1-6 ) alkyl or hydroxy and X ³ is cyano, -C (O) R ¹⁶ , -C (R ⁶ ) (OR ⁶ ) ₂ , -CH = CHS (O) ₂ R ⁵ , -CH ₂ C (O) R ¹⁶ , -C (O) CF ₂ C (O) NR ⁵ R ⁵ , -C ( O) C (O) NR ⁵ R ⁶ , -C (O) C (O) OR ⁵ , -C (O) CH ₂ OR ⁵ , -C (O) CH ₂ N (R ⁶ ) SO ₂ R ⁵ or -C (O) C (O) R ^5, wherein R ¹⁹ and R ²⁰ are one or more of the ring atoms containing a ring together with the atoms to which they are attached, a hetero atom selected from -NR ²¹ -and -O- _4-8 ) Forms a heterocycloalkylene, ring is unsubstituted or substituted by (C _1-6 ) alkyl or —X ⁵ C (O) OR ¹² , wherein R ²¹ is hydrogen, (C _1-6 ) alkyl, —X ⁵ C (O) R ¹² , -X ⁵ C (O) OR ¹² , -R ¹⁴ , -X ⁵ C (O) R ¹⁴ or -C (O) OR ¹⁴ ,
X ² is —NHR ¹⁵ wherein R ¹⁵ is (C _6-10 ) aryl, hetero (C _5-10 ) aryl, (C _9-10 ) _bicycloaryl or hetero (C _8-10 ) _bicycloaryl ) Or —NR ¹⁷ R ¹⁸ , wherein R ¹⁷ is hetero (C _3-10 ) cycloalkyl, R ¹⁸ is hydrogen, or R ¹⁷ and R ¹⁸ are independently (C _6-10 ) aryl (C _1-6 ) Alkyl or hetero (C _5-10 ) aryl (C _1-6 ) alkyl, and no alicyclic or aromatic ring system is substituted in R ¹⁵ , R ¹⁷ and R ¹⁸ or (C _1-6 ) alkyl, Furnace, halo, nitro, halo-substituted (C _1-4 ) alkyl, -X ⁵ OR ¹² , -X ⁵ C (O) OR ¹² , -X ⁵ C (O) R ¹³ , -X ⁵ C (O NR ¹² R ¹² and -X ⁵ 1 to 5 radicals independently selected from NR ¹² S (O) ₂ R ¹² and / or -R ¹⁴ , -X ⁵ OR ¹⁴ and -X ⁵ C (O) NR ¹⁴ R Further substituted by one radical selected from ¹² ,
R ³ is -CH ₂ X ⁶ , X ⁶ is -X ⁵ SR ¹² , -X ⁵ C (O) NR ¹² R ¹² , -X ⁵ S (O) ₂ R ¹³ , -X ⁵ C (O) R ¹³ , -X ⁵ OR ¹² , -X ⁵ SR ¹⁴ , -X ⁵ R ¹⁴ , -X ⁵ S (O) ₂ R ¹⁴ , -X ⁵ C (O) R ¹⁴ and -X ⁵ C (O) NR ¹⁴ Compounds selected from R ¹² , N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomeric mixtures thereof, and compounds, N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomeric mixtures thereof Pharmaceutically acceptable salts and solvates of.
[12" claim-type="Currently amended] The method of claim 11,
X ³ is cyano, -C (O) X ⁴ , -C (O) H, -C (O) N (CH ₃ ) OCH ₃ , -CH (OCH ₃ ) ₂ , -C (O) CF ₃ , -C (O) CF ₂ CF ₃ , -CH ₂ C (O) R ¹⁶ , (E) -2-benzenesulfonyl-vinyl, 2-dimethylcarbamoyl-2,2-difluoro-acetyl, 2- Oxo-2-pyrrolidin-1-yl-acetyl, 2-morpholin-4-yl-2-oxo-acetyl, 2-oxo-2-piperazin-1-yl-acetyl, 2- (4-methane Sulfonyl-piperazin-1-yl) -2-oxo-acetyl, 2- (1,1-dioxo-1λ ⁶ -thiomorpholin-4-yl) -2-oxo-acetyl, dimethylaminooxalyl, Tetrahydro-pyran-4-ylaminooxalyl, 2-morpholin-4-yl-ethylaminooxalyl, cyclopentyl-ethyl-aminooxalyl, pyridin-3-ylaminooxalyl, phenylaminooxalyl, 1 -Benzoyl-piperidin-4-ylaminooxalyl, 1-benzylcarbamoyl-methanoyl, 1-benzyloxy (oxalyl), 2-benzyloxy-acetyl, 2-benzenesulfonylamino-ethanoyl, 2 -Oxo-2-phenyl-ethanoyl, 3H-oxazole-2-carbonyl, 5-trifluoromethyl-oxazole-2-carbonyl, 3-triflu Rhomethyl- [1,2,4] oxadiazole-5-carbonyl, 2,2,3,3,3-pentafluoro-propionyl, hydroxyaminooxalyl, oxalyl, 2- (1, 3-dihydro-isoindol-2-yl) -2-oxo-acetyl, benzothiazol-2-ylaminooxalyl, 2-oxo-ethyl, 2-oxazol-2-yl-2-oxo-ethyl Or 2-benzooxazol-2-yl-2-oxo-ethyl,
X ² is 5-nitrothiazol-2-ylamino, 2-nitrophenylamino, pyrimidin-2-ylamino, tetrahydro-pyran-4-ylamino, N- (2-methoxyethyl) -N- (Tetrahydro-pyran-4-yl) amino, 1-methyl-piperidin-4-ylamino, isopropylamino, di (thien-2-ylmethyl) amino and di (benzyl) amino,
R ³ is thiophene-2-sulfonyl-methyl, 3-chloro-2-fluoro-phenyl-methane-sulfonyl-methyl, benzene-sulfonyl-methyl, phenyl-methane-sulfonyl-methyl, 2- ( 1,1-Difluoro-methoxy) -phenyl-methane-sulfonyl-methyl, 2-benzene-sulfonyl-ethyl, 2- (pyridine-2-sulfonyl) -ethyl, 2- (pyridine-4- Sulfonyl) -ethyl, 2-phenyl-methanesulfonyl-ethyl, oxy-pyridin-2-yl-methane-sulfonyl-methyl, prop-2-en-1-sulfonyl-methyl, 4-methoxy- Phenyl-methane-sulfonyl-methyl, p-tolyl-methane-sulfonyl-methyl, 4-chloro-phenyl-methane-sulfonyl-methyl, o-tolyl-methane-sulfonyl-methyl, 3,5-dimethyl- Phenyl-methane-sulfonyl-methyl, 4-trifluoro-methyl-phenyl-methane-sulfonyl-methyl, 4-trifluoro-methoxy-phenyl-methane-sulfonyl-methyl, 2-bromo-phenyl Methane-sulfonyl-methyl, pyridin-2-yl-methane-sulfonyl-methyl, pyridin-3-yl-methane-sulfonyl-methyl, pyridin-4-yl-methane-sulfonyl-methyl, naphthalene-2 -Yl-methane-sulfonyl-methyl, 3-methyl-phenyl-methane-sulfonyl -Methyl, 3-trifluoro-methyl-phenyl-methane-sulfonyl-methyl, 3-trifluoro-methoxy-phenyl-methane-sulfonyl-methyl, 4-fluoro-2-trifluoromethoxy- Phenyl-methane-sulfonylmethyl, 2-fluoro-6-trifluoromethyl-phenylmethanesulfonylmethyl, 3-chloro-phenylmethanesulfonylmethyl, 2-fluoro-phenylmethanesulfonylmethyl, 2-tri Fluoro-phenylmethanesulfonylmethyl, 2-cyano-phenylmethanesulfonylmethyl, 4 - tert-butyl-phenylmethanesulfonylmethyl, 2-fluoro-3-methyl-phenyl-methane-sulfonyl-methyl , 3-fluoro-phenylmethanesulfonylmethyl, 4-fluoro-phenylmethane-sulfonylmethyl, 2-chloro-phenylmethanesulfonylmethyl, 2,5-difluoro-phenylmethane-sulfonylmethyl, 2 , 6-difluoro-phenylmethanesulfonylmethyl, 2,5-dichloro-phenyl-methane-sulfonylmethyl, 3,4-dichloro-phenylmethanesulfonylmethyl, 2- (1,1-difluoro- Methoxy) -phenyl-methanesulfonylmethyl, 2-cyano-phenyl-methane-sulfonyl-methyl, 3-cyano- Nylmethanesulfonylmethyl, 2-trifluoro-methoxy-phenyl-methane-sulfonylmethyl, 2,3-difluoro-phenylmethanesulfonylmethyl, 2,5-difluoro-phenyl-methanesulfonyl Methyl, biphenyl-2-ylmethanesulfonylmethyl, cyclohexylmethyl, 3-fluoro-phenyl-methanesulfonylmethyl, 3,4-difluoro-phenyl-methanesulfonylmethyl, 2,4-difluoro Rho-phenylmethanesulfonylmethyl, 2,4,6-trifluoro-phenylmethanesulfonylmethyl, 2,4,5-trifluoro-phenylmethanesulfonylmethyl, 2,3,4-trifluoro- Phenylmethanesulfonylmethyl, 2,3,5-trifluoro-phenyl-methane-sulfonylmethyl, 2,5,6-trifluoro-phenylmethanesulfonylmethyl, 2-chloro-5-trifluoro- Methylphenylmethanesulfonylmethyl, 2-methyl-propane-1-sulfonyl, 2-fluoro-3-trifluoro-methylphenylmethanesulfonylmethyl, 2-fluoro-4-trifluoro-methylphenylmethanesulfonylmethyl , 2-fluoro-5-trifluoro-methyl-phenyl-methane-sulfonyl-methyl, 4-fluoro 3-trifluoro-methylphenylmethanesulfonylmethyl, 2-methoxy-phenyl-methanesulfonylmethyl, 3,5-bis-trifluoromethyl-phenylmethanesulfonylmethyl, 4-difluoromethoxy-phenyl Methanesulfonylmethyl, 2-difluoro-methoxy-phenyl-methanesulfonylmethyl, 3-difluoromethoxy-phenylmethanesulfonylmethyl, 2,6-dichloro-phenylmethanesulfonylmethyl, biphenyl-4 -Ylmethanesulfonylmethyl, 3,5-dimethyl-isoxazol-4-ylmethanesulfonylmethyl, 5-chloro-thien-2-yl-methane-sulfonylmethyl, 2- [4- (1,1- Difluoro-methoxy) -benzenesulfonyl] -ethyl, 2- [2- (1,1-difluoro-methoxy) -benzenesulfonyl] -ethyl, 2- [3- (1,1- Difluoro-methoxy) -benzenesulfonyl] -ethyl, 2- (4-trifluoromethoxy-benzenesulfonyl) -ethyl, 2- (3-trifluoromethoxy-benzenesulfonyl) -ethyl, 2 -(2-Trifluoro-methoxy-benzene-sulfonyl) -ethyl, (cyanomethyl-methyl-carbamoyl) -methyl, biphenyl-3-ylmethyl, 2-oxo-2-pyrrolidine- 1-yl-ethyl, 2-benzene Phenyl-ethyl, isobutylsulfanylmethyl, 2-phenylsulfanyl-ethyl, cyclohexylmethanesulfonylmethyl, 2-cyclohexyl-ethanesulfonyl, benzyl, naphthalen-2-yl, benzylsulfanylmethyl, 2-tri Fluoromethyl-benzylsulfanylmethyl, phenylsulfanyl-ethyl, cyclopropyl-methanesulfonylmethyl, 5-bromo-thien-2-ylmethyl, 3-phenyl-propyl, 2,2-difluoro-3 phenyl-propyl, 3,4,5-trimethoxy-phenyl-methanesulfonyl-methyl, 2,2-difluoro-3-thien-2-yl-propyl, cyclohexyl-ethyl, cyclohexylmethyl, tert- Butylmethyl, 1-methylcyclohexylmethyl, 1-methylcyclopentylmethyl, 2,2-difluoro-3-phenylpropyl, 2,2-dimethyl-3-phenylpropyl, 1-benzylcyclopropylmethyl, -X ⁵ S (O) ₂ R ¹³ and-X ⁵ S (O) ₂ R ¹⁴ , R ¹³ is alkyl, R ¹⁴ is unsubstituted or substituted phenyl, N-oxide derivatives, prodrug derivatives thereof, protection Derivatives, individual isomers and isomers Mixtures, and pharmaceutically acceptable salts and solvates of the compounds, their N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomeric mixtures.
[13" claim-type="Currently amended] The method of claim 12,
X ³ is 1H-benzoimidazol-2-ylcarbonyl, pyrimidin-2-ylcarbonyl, benzoxazol-2-ylcarbonyl, benzothiazol-2-ylcarbonyl, pyridazin-3-yl Carbonyl, 3-phenyl- [1,2,4] oxadiazole-5-ylcarbonyl or 3-ethyl- [1,2,4] oxadiazole-5-ylcarbonyl, 2-oxo-2 -Pyrrolidin-1-yl-acetyl, 2-morpholin-4-yl-2-oxo-acetyl, 2-oxo-2-piperazin-1-yl-acetyl, 2- (4-methanesulfonyl- Piperazin-1-yl) -2-oxo-acetyl, 2- (1,1-dioxo-1λ ⁶ -thiomorpholin-4-yl) -2-oxo-acetyl, dimethylaminooxalyl, tetrahydro- Pyran-4-ylaminooxalyl, 2-morpholin-4-yl-ethylaminooxalyl, cyclopentyl-ethyl-aminooxalyl, pyridin-3-ylaminooxalyl, phenylaminooxalyl or 1-benzoyl- Piperidin-4-ylaminooxalyl,
X ² is —OH, dimethylcarbamoyloxy, morpholin-4-ylcarbonyloxy, piperidin-1-yl-carbonyloxy, pyrrolidin-1-yl-carbonyloxy, pyrimidine-2- Monoamino, tetrahydro-pyran-4-ylamino, 1-methyl-piperidin-4-ylamino, N- (2-methoxyethyl) -N- (tetrahydro-pyran-4-yl) amino, Isopropylamino and cyclohexylamino,
R ³ is cyclohexylethyl, cyclohexylmethyl, tert - butylmethyl, 1-methylcyclohexylmethyl, 1-methylcyclopentylmethyl, 2,2-difluoro-3-phenylpropyl, 2,2-dimethyl- 3-phenylpropyl, 1-benzylcyclopropylmethyl, -X ⁵ S (O) ₂ R ¹³ or -X ⁵ S (O) ₂ R ¹⁴ , R ¹³ is alkyl, R ¹⁴ is unsubstituted or substituted phenyl Phosphorus compounds, N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomeric mixtures, and pharmaceutical compounds of the compounds, N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and isomeric mixtures thereof Acceptable salts and solvates.
[14" claim-type="Currently amended] The method of claim 1,
(R) -N-cyanomethyl-2-hydroxy-3-phenylmethanesulfonyl-propionamide;
(R) -N- (1-cyano-1-thiophen-2-yl-methyl) -2-hydroxy-3-phenylmethanesulfonyl-propionamide;
(R) -N- (1-cyano-1-thiophen-2-yl-methyl) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2- Hydroxy-propionamide;
(R) -N-cyanomethyl-3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxy-propionamide;
Morpholine-4-carboxylic acid (R) -1- (cyanomethyl-carbamoyl) -2-phenylmethanesulfonyl-ethyl ester;
Morpholine-4-carboxylic acid (R) -1- (cyanomethyl-carbamoyl) -2- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester;
(R)-(2-methoxy-ethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-phenylmethanesulfonyl-ethyl ester;
(S) -diethyl-carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -pyrrolidine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -morpholine-4-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -4-ethyl-piperazine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -2-hydroxymethyl-pyrrolidine-1-carboxylic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S)-(2,2,2-trifluoro-ethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S)-(2-hydroxyethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(Tetrahydrofuran-2-ylmethyl) -carbamic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -azetidine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -cyclopropyl-carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -piperidine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S)-(2-methoxy-ethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(R) -3-hydroxy-pyrrolidine-1-carboxylic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -3-hydroxy-pyrrolidine-1-carboxylic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -morpholine-4-carboxylic acid 1- (cyanomethyl-carbamoyl) -3-cyclohexyl-propyl ester;
Morpholine-4-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester;
Morpholin-4-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2- [2- (1,1-di Fluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester;
Morpholin-4-carboxylic acid (R) -1-[(S) -1- (1-benzothiazol-2-yl-methanoyl) -propylcarbamoyl] -2- [2- (1,1-di Fluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester;
Pyrrolidine-1-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester;
Dimethyl-carbamic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester;
Morpholine-4-carboxylic acid (R) -1-[(S) -1- (1-benzylcarbamoyl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester;
Morpholine-4-carboxylic acid (S) -1-[(S) -1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester;
Morpholine-4-carboxylic acid (S) -1-[(S) -1- (5-ethyl- [1,3,4] oxadiazole-2-carbonyl) -propylcarbamoyl] -2-phenylmethane Sulfonyl-ethyl esters;
(S) -2-{(R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxy-propanoylamino} -N-methoxy -N-methyl-butyramide;
(R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -N-((S) -1-formyl-propyl) -2-hydroxy-propionamide ;
(R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenyl-methanesulfonyl-propionamide;
(S) -3- {3- [2- (1,1-Difluoro-methoxy) -phenylmethanesulfonyl] -propanoylamino} -2-oxo-pentanoic acid benzylamide;
N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propyl] -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] Propionamide;
N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -3-phenyl-propyl] -3-p-tolylmethanesulfonyl-propionamide;
3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- (1-ethyl-2,3-dioxo-3-pyrrolidin-1-yl-propyl) -propionamide;
3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- (1-ethyl-3-morpholin-4-yl-2,3-dioxo-propyl) -propionamide;
3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- (1-ethyl-2,3-dioxo-3-piperazin-1-yl-propyl) -propionamide;
3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- [3- (1,1-dioxo-1λ ⁶ -thiomorpholin-4-yl) -1-ethyl-2,3-di Oxo-propyl] -propionamide;
3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- [1-ethyl-3- (4-methyl-sulfonyl-piperazin-1-yl) -2,3-dioxo-propyl] Propionamide;
3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid dimethylamide;
3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid cyclopentyl-ethyl-amide;
3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid phenylamide;
3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid pyridin-3-ylamide;
3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid (tetrahydro-pyran-4-yl) -amide;
3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid (1-benzoyl-piperidin-4-yl) -amide;
3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid (2-morpholin-4-yl-ethyl) -amide;
(R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -2- (2-nitro-phenylamino) -3-phenylmethanesulfonyl-propion amides;
N- [1- (benzooxazole-2-carbonyl) -propyl] -3-phenylmethanesulfonyl-2- (pyrimidin-2-ylamino) -propionamide;
(R) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -butyl] -2- (5-nitro-thiazol-2-ylamino) -3-phenyl Methanesulfonyl-propionamide;
(2S) (4,4-Difluoro-2-hydroxy-5-phenyl-pentanoic acid (1 (S) -cyano-3-phenyl-propyl) -amide;
N- (1 (S) -Cyano-3-phenyl-propyl) -2- (S)-(2-morpholin-4-yl-2-oxo-ethoxy) -4-phenyl-butyramide;
N- (1- (S) -Cyano-3-phenyl-propyl) -2- (S) -fluoro-4-phenyl-butyramide;
N- (1- (S) -cyano-3-phenyl-propyl) -2,2-difluoro-4-phenyl-butyramide;
N- (1- (S) -Cyano-3-phenyl-propyl) -2- (S) -hydroxy-4-phenyl-butyramide;
N- (1- (S) -Cyano-3-phenyl-propyl) -2- (R) -hydroxy-4-phenyl-butyramide;
N- (1- (S) -cyano-3-phenyl-propyl) -2- (R) -methoxy-4-phenyl-butyramide;
2,2-difluoro-5-phenyl-pentanoic acid (1-cyano-cyclopropyl) -amide;
N- (1- (S) -cyano-3-phenyl-propyl) -4-phenyl-butyramide;
2,2-difluoro-5-phenyl-pentanoic acid ((S) -1-cyano-3-phenyl-propyl) -amide;
N- (4-cyano-1-ethyl-piperidin-4-yl) -3-cyclohexyl-propionamide;
N- (4-cyano-1-ethyl-piperidin-4-yl) -3- (2-difluoromethoxy-phenylmethanesulfonyl) -propionamide;
(S) -tert-butyl-carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(R) -carbamic acid 1- (cyanomethyl-carbamoyl) -2- (2-difluoromethoxy-phenylmethanesulfonyl) -ethyl ester;
(S) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(R) -morpholine-4-carboxylic acid 1- (1-cyano-cyclopropylcarbamoyl) -2-phenylmethanesulfonyl-ethyl ester;
(R) -morpholine-4-carboxylic acid 1- (4-cyano-tetrahydro-pyran-4-ylcarbamoyl) -2-phenylmethanesulfonyl-ethyl ester;
3-cyclohexyl-2-hydroxy-N- [1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propyl] -propionamide;
(R) -N- [1- (benzothiazole-2-carbonyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N- [1- (benzothiazol-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide;
(R) -N- [1- (benzothiazole-2-carbonyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N- [1- (benzothiazole-2-carbonyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide ;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2- (1-methyl-piperidin-4-ylamino) -3-phenylmethanesulfonyl Propionamide;
(R) -N-[(S) -1- (Benzooxazole-2-carbonyl) -butyl] -2- (bis-thiophen-2-ylmethyl-amino) -3-phenylmethanesulfonyl- Propionamide;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide;
(S) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2- (tetrahydro-pyran-4-ylamino) -3-thiophen-2-yl- Propionamide;
(S) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-isopropylamino-3-thiophen-2-yl-propionamide;
(R) -N- [1- (benzothiazol-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide ;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (benzooxazol-2-carbonyl) -butyl] -2-[(2-methoxy-ethyl)-(tetrahydro-pyran-4-yl)- Amino] -3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-cyclohexylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide;
(1S) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2- (S) -fluoro-4-phenyl-butyramide;
2,2-difluoro-5-phenyl-pentanoic acid [(S) -1- (benzooxazole-2-carbonyl) -butyl] -amide;
Morpholine-4-carboxylic acid (S) -1-[(S) -1- (benzooxazole-2-carbonyl) -propylcarbamoyl] -2-cyclohexyl-ethyl ester;
Morpholine-4-carboxylic acid (S) -2-cyclohexyl-1-[(S) -1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propylcarbamoyl] -ethyl ester;
Morpholine-4-carboxylic acid (S) -2-cyclohexyl-1-[(S) -1- (5-ethyl- [1,3,4] oxadiazole-2-carbonyl) -propylcarbamoyl] Ethyl esters;
Morpholine-4-carboxylic acid (S) -2-cyclohexyl-1-[(S) -1- (5-phenyl- [1,3,4] oxadiazole-2-carbonyl) -propylcarbamoyl] Ethyl esters;
Morpholine-4-carboxylic acid (S) -1-[(S) -1- (benzooxazole-2-carbonyl) -propylcarbamoyl] -3-cyclohexyl-propyl ester;
4- [4,4-dimethyl-2- (morpholine-4-carbonyloxy) -pentanoylamino] -3-oxo-azepane-1-carboxylic acid benzyl ester;
(R) -N-[(S) -1- (Benzooxazole-2-carbonyl) -butyl] -3-cyclopropylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propion amides;
(R) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2-cyclohexylamino-3-cyclopropylmethanesulfonyl-propionamide;
(R) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2-cycloheptylamino-3-cyclopropylmethanesulfonyl-propionamide;
(R) -3-phenylmethanesulfonyl-N-[(S) -3-phenyl-1- (thiazole-2-carbonyl) -propyl] -2- (tetrahydro-pyran-4-ylamino) Propionamide;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -3-phenyl-propyl] -3-cyclopropylmethanesulfonyl-2- (tetrahydro-pyran-4-yl Amino) -propionamide;
(R) -3-cyclopropylmethanesulfonyl-N- [1- (5-ethyl-1,2,4-oxadiazole-3-carbonyl) -propyl] -2- (tetrahydro-pyran-4 -Ylamino) -propionamide;
(R) -3-phenylmethanesulfonyl-N- [1- (3-phenyl-1,2,4-oxadiazole-5-carbonyl) -propyl] -2- (tetrahydro-pyran-4- Monoamino) -propionamide;
(R) -N- [1- (3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl) -propyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4 -Ylamino) -propionamide;
{(R) -1- [1- (benzothiazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
{(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
{(S) -1-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-thiophen-2-yl-ethyl} -carbamic acid tertiary Butyl ester;
{(R) -1- [1- (benzothiazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
{(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
{(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -carbamic acid tertiary- Butyl esters;
(R) -1- {1- [hydroxy- (3-phenyl-1,2,4-oxadiazol-5-yl) -methyl] -propylcarbamoyl} -2-phenylmethanesulfonyl-ethyl) Carbamic acid tert-butyl ester;
((R) -2-cyclopropylmethanesulfonyl-1-{(S) -1-[(5-ethyl-1,2,4-oxadiazol-3-yl) -hydroxy-methyl] -propyl Carbamoyl} -ethyl) -carbamic acid tert-butyl ester;
{(R) -1- [1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
{(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -3-phenyl-propylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -car Chest acid tert-butyl ester;
{(R) -1-[(S) -1- (hydroxy-thiazol-2-yl-methyl) -3-phenyl-propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid 3 Tert-butyl ester;
{(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -carbamic acid tertiary- Butyl esters;
(R) -1- {1- [hydroxy- (3-phenyl-1,2,4-oxadiazol-5-yl) -methyl] -propylcarbamoyl} -2-phenylmethanesulfonyl-ethyl) Carbamic acid tert-butyl ester;
((R) -2-cyclopropylmethanesulfonyl-1-{(S) -1-[(5-ethyl-1,2,4-oxadiazol-3-yl) -hydroxy-methyl] -propyl Carbamoyl} -ethyl) -carbamic acid tert-butyl ester;
{(R) -1- [1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
{(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -3-phenyl-propylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -car Chest acid tert-butyl ester;
{(R) -1-[(S) -1- (hydroxy-thiazol-2-yl-methyl) -3-phenyl-propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid 3 Tert-butyl ester;
(R) -2-phenylmethanesulfonyl-1-{(S) -1-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl) -hydroxy-methyl] -propylcarba Moyl} -ethyl) -carbamic acid tert-butyl ester;
(R) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2- [cyclopropylmethyl- (tetrahydro-pyran-4-ylmethyl) -amino] -3-phenylmethanesul Ponyl-propionamide;
(R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide ;
(R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino ) -Propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2- (1-methyl-piperidin-4-ylamino) -3- Phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2- (bis-thiophen-2-ylmethyl-amino) -3-phenyl Methanesulfonyl-propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide;
(S) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2- (tetrahydro-pyran-4-ylamino) -3-thiophene- 2-yl-propionamide;
(S) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-isopropylamino-3-thiophen-2-yl-propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide ;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino ) -Propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino ) -Propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-[(2-methoxy-ethyl)-(tetrahydro-pyran-4 -Yl) -amino] -3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-cyclohexylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide;
N-cyanomethyl-3-cyclohexyl-propionamide;
N-cyanomethyl-3- (2-difluoromethoxy-phenylmethanesulfonyl) -propionamide;
3- (3-cyclohexyl-propionylamino) -2-oxo-5-phenyl-pentanoic acid thiazol-2-ylamide;
3-cyclohexyl-N- (1-formyl-3-phenyl-propyl) -propionamide;
3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N-[(S) -1- (5-ethyl- [1,3,4] oxadiazole-2-carbonyl) -propyl]- Propionamide;
N-[(S) -1- (benzooxazole-2-carbonyl) -propyl] -2- (2-cyano-phenylamino) -3-cyclohexyl-propionamide;
N-cyanomethyl-3-cyclohexyl-2- (4-methoxy-phenoxy) -propionamide;
2-benzyloxy-N-cyanomethyl-3-cyclohexyl-propionamide;
(R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -butyl] -2-benzyloxy-3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -2-methoxymethoxy-3-phenylmethanesulfonyl-propionamide;
(S) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -butyl] -2-hydroxy-3-phenyl-propionamide;
(R) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propyl] -3-phenylmethanesulfonyl-2-triisopropylsilanyloxy-propionamide;
(R) -N-[(S) -1- (1-benzothiazol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenylmethanesulfonyl-propionamide;
(R) -2-hydroxy-3-phenylmethanesulfonyl-N-[(S) -1- (1-pyridazin-3-yl-methanoyl) -butyl] -propionamide;
(S) -3-((R) -2-hydroxy-3-phenylmethanesulfonyl-propanoylamino) -2-oxo-pentanoic acid benzylamide;
(R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -3- [2- (1,1-difluoro-methoxy) -phenyl Methanesulfonyl] -2-hydroxy-propionamide;
(R) -N-[(S) -1- (1-Benzothiazol-2-yl-methanoyl) -propyl] -3- [2- (1,1-difluoro-methoxy) -phenyl Methanesulfonyl] -2-hydroxy-propionamide and
From the group consisting of (2R, 5S) -2- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonylmethyl] -6-ethoxy-5-ethyl-morpholin-3-one Pharmaceutical Compounds of the Compounds, N-oxide Derivatives, Prodrug Derivatives, Protected Derivatives, Individual Isomers, and Isomer Mixtures of Selection, and Compounds, N-oxide Derivatives, Prodrug Derivatives, Protected Derivatives, Individual Isomers, and Isomer Mixtures Acceptable salts and solvates.
[15" claim-type="Currently amended] The method of claim 14,
(R) -N-cyanomethyl-2-hydroxy-3-phenylmethanesulfonyl-propionamide;
(R) -N- (1-cyano-1-thiophen-2-yl-methyl) -2-hydroxy-3-phenylmethanesulfonyl-propionamide;
(R) -N- (1-cyano-1-thiophen-2-yl-methyl) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2- Hydroxy-propionamide;
(R) -N-cyanomethyl-3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxy-propionamide;
Morpholine-4-carboxylic acid (R) -1- (cyanomethyl-carbamoyl) -2-phenylmethanesulfonyl-ethyl ester;
Morpholine-4-carboxylic acid (R) -1- (cyanomethyl-carbamoyl) -2- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester;
(R)-(2-methoxy-ethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-phenylmethanesulfonyl-ethyl ester;
(S) -diethyl-carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -pyrrolidine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -morpholine-4-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -4-ethyl-piperazine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -2-hydroxymethyl-pyrrolidine-1-carboxylic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S)-(2,2,2-trifluoro-ethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S)-(2-hydroxyethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(Tetrahydrofuran-2-ylmethyl) -carbamic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -azetidine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -cyclopropyl-carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -piperidine-1-carboxylic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S)-(2-methoxy-ethyl) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(R) -3-hydroxy-pyrrolidine-1-carboxylic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -3-hydroxy-pyrrolidine-1-carboxylic acid (S) -1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(S) -morpholine-4-carboxylic acid 1- (cyanomethyl-carbamoyl) -3-cyclohexyl-propyl ester;
Morpholine-4-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester;
Morpholin-4-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2- [2- (1,1-di Fluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester;
Morpholin-4-carboxylic acid (R) -1-[(S) -1- (1-benzothiazol-2-yl-methanoyl) -propylcarbamoyl] -2- [2- (1,1-di Fluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester;
Pyrrolidine-1-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester;
Dimethyl-carbamic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester;
Morpholine-4-carboxylic acid (R) -1-[(S) -1- (1-benzylcarbamoyl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester;
Morpholine-4-carboxylic acid (S) -1-[(S) -1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester;
Morpholine-4-carboxylic acid (S) -1-[(S) -1- (5-ethyl- [1,3,4] oxadiazole-2-carbonyl) -propylcarbamoyl] -2-phenylmethane Sulfonyl-ethyl esters;
(S) -2-{(R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -2-hydroxy-propanoylamino} -N-methoxy -N-methyl-butyramide;
(R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -N-((S) -1-formyl-propyl) -2-hydroxy-propionamide ;
(R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenyl-methanesulfonyl-propionamide;
(S) -3- {3- [2- (1,1-Difluoro-methoxy) -phenylmethanesulfonyl] -propanoylamino} -2-oxo-pentanoic acid benzylamide;
N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propyl] -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] Propionamide;
N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -3-phenyl-propyl] -3-p-tolylmethanesulfonyl-propionamide;
3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- (1-ethyl-2,3-dioxo-3-pyrrolidin-1-yl-propyl) -propionamide;
3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- (1-ethyl-3-morpholin-4-yl-2,3-dioxo-propyl) -propionamide;
3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- (1-ethyl-2,3-dioxo-3-piperazin-1-yl-propyl) -propionamide;
3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- [3- (1,1-dioxo-1λ ⁶ -thiomorpholin-4-yl) -1-ethyl-2,3-di Oxo-propyl] -propionamide;
3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N- [1-ethyl-3- (4-methyl-sulfonyl-piperazin-1-yl) -2,3-dioxo-propyl] Propionamide;
3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid dimethylamide;
3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid cyclopentyl-ethyl-amide;
3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid phenylamide;
3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid pyridin-3-ylamide;
3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid (tetrahydro-pyran-4-yl) -amide;
3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid (1-benzoyl-piperidin-4-yl) -amide;
3- [3- (2-Difluoromethoxy-phenylmethanesulfonyl) -propionylamino] -2-oxo-pentanoic acid (2-morpholin-4-yl-ethyl) -amide;
(R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -2- (2-nitro-phenylamino) -3-phenylmethanesulfonyl-propion amides;
N- [1- (benzooxazole-2-carbonyl) -propyl] -3-phenylmethanesulfonyl-2- (pyrimidin-2-ylamino) -propionamide.
(R) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -butyl] -2- (5-nitro-thiazol-2-ylamino) -3-phenyl Methanesulfonyl-propionamide;
(2S) (4,4-Difluoro-2-hydroxy-5-phenyl-pentanoic acid (1 (S) -cyano-3-phenyl-propyl) -amide;
N- (1 (S) -Cyano-3-phenyl-propyl) -2- (S)-(2-morpholin-4-yl-2-oxo-ethoxy) -4-phenyl-butyramide;
N- (1- (S) -Cyano-3-phenyl-propyl) -2- (S) -fluoro-4-phenyl-butyramide;
N- (1- (S) -cyano-3-phenyl-propyl) -2,2-difluoro-4-phenyl-butyramide;
N- (1- (S) -Cyano-3-phenyl-propyl) -2- (S) -hydroxy-4-phenyl-butyramide;
N- (1- (S) -Cyano-3-phenyl-propyl) -2- (R) -hydroxy-4-phenyl-butyramide;
N- (1- (S) -cyano-3-phenyl-propyl) -2- (R) -methoxy-4-phenyl-butyramide;
2,2-difluoro-5-phenyl-pentanoic acid (1-cyano-cyclopropyl) -amide;
N- (1- (S) -cyano-3-phenyl-propyl) -4-phenyl-butyramide;
2,2-difluoro-5-phenyl-pentanoic acid ((S) -1-cyano-3-phenyl-propyl) -amide;
N- (4-cyano-1-ethyl-piperidin-4-yl) -3-cyclohexyl-propionamide;
N- (4-cyano-1-ethyl-piperidin-4-yl) -3- (2-difluoromethoxy-phenylmethanesulfonyl) -propionamide;
(S) -tert-butyl-carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(R) -carbamic acid 1- (cyanomethyl-carbamoyl) -2- (2-difluoromethoxy-phenylmethanesulfonyl) -ethyl ester;
(S) -carbamic acid 1- (cyanomethyl-carbamoyl) -2-cyclohexyl-ethyl ester;
(R) -morpholine-4-carboxylic acid 1- (1-cyano-cyclopropylcarbamoyl) -2-phenylmethanesulfonyl-ethyl ester;
(R) -morpholine-4-carboxylic acid 1- (4-cyano-tetrahydro-pyran-4-ylcarbamoyl) -2-phenylmethanesulfonyl-ethyl ester;
3-cyclohexyl-2-hydroxy-N- [1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propyl] -propionamide;
(R) -N- [1- (benzothiazole-2-carbonyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N- [1- (benzothiazol-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide;
(R) -N- [1- (benzothiazole-2-carbonyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N- [1- (benzothiazole-2-carbonyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide ;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2- (1-methyl-piperidin-4-ylamino) -3-phenylmethanesulfonyl Propionamide;
(R) -N-[(S) -1- (Benzooxazole-2-carbonyl) -butyl] -2- (bis-thiophen-2-ylmethyl-amino) -3-phenylmethanesulfonyl- Propionamide;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide;
(S) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2- (tetrahydro-pyran-4-ylamino) -3-thiophen-2-yl- Propionamide;
(S) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-isopropylamino-3-thiophen-2-yl-propionamide;
(R) -N- [1- (benzothiazol-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide ;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (benzooxazol-2-carbonyl) -butyl] -2-[(2-methoxy-ethyl)-(tetrahydro-pyran-4-yl)- Amino] -3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-cyclohexylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide;
(1S) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2- (S) -fluoro-4-phenyl-butyramide;
2,2-difluoro-5-phenyl-pentanoic acid [(S) -1- (benzooxazole-2-carbonyl) -butyl] -amide;
Morpholine-4-carboxylic acid (S) -1-[(S) -1- (benzooxazole-2-carbonyl) -propylcarbamoyl] -2-cyclohexyl-ethyl ester;
Morpholine-4-carboxylic acid (S) -2-cyclohexyl-1-[(S) -1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propylcarbamoyl] -ethyl ester;
Morpholine-4-carboxylic acid (S) -2-cyclohexyl-1-[(S) -1- (5-ethyl- [1,3,4] oxadiazole-2-carbonyl) -propylcarbamoyl] Ethyl esters;
Morpholine-4-carboxylic acid (S) -2-cyclohexyl-1-[(S) -1- (5-phenyl- [1,3,4] oxadiazole-2-carbonyl) -propylcarbamoyl] Ethyl esters;
Morpholine-4-carboxylic acid (S) -1-[(S) -1- (benzooxazole-2-carbonyl) -propylcarbamoyl] -3-cyclohexyl-propyl ester;
4- [4,4-dimethyl-2- (morpholine-4-carbonyloxy) -pentanoylamino] -3-oxo-azepane-1-carboxylic acid benzyl ester;
(R) -N-[(S) -1- (Benzooxazole-2-carbonyl) -butyl] -3-cyclopropylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propion amides;
(R) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2-cyclohexylamino-3-cyclopropylmethanesulfonyl-propionamide;
(R) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2-cycloheptylamino-3-cyclopropylmethanesulfonyl-propionamide;
(R) -3-phenylmethanesulfonyl-N-[(S) -3-phenyl-1- (thiazole-2-carbonyl) -propyl] -2- (tetrahydro-pyran-4-ylamino) Propionamide;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -3-phenyl-propyl] -3-cyclopropylmethanesulfonyl-2- (tetrahydro-pyran-4-yl Amino) -propionamide;
(R) -3-cyclopropylmethanesulfonyl-N- [1- (5-ethyl-1,2,4-oxadiazole-3-carbonyl) -propyl] -2- (tetrahydro-pyran-4 -Ylamino) -propionamide;
(R) -3-phenylmethanesulfonyl-N- [1- (3-phenyl-1,2,4-oxadiazole-5-carbonyl) -propyl] -2- (tetrahydro-pyran-4- Monoamino) -propionamide;
(R) -N- [1- (3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl) -propyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4 -Ylamino) -propionamide;
{(R) -1- [1- (benzothiazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
{(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
{(S) -1-[(S) -1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-thiophen-2-yl-ethyl} -carbamic acid tertiary Butyl ester;
{(R) -1- [1- (benzothiazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
{(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
{(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -carbamic acid tertiary- Butyl esters;
(R) -1- {1- [hydroxy- (3-phenyl-1,2,4-oxadiazol-5-yl) -methyl] -propylcarbamoyl} -2-phenylmethanesulfonyl-ethyl) Carbamic acid tert-butyl ester;
((R) -2-cyclopropylmethanesulfonyl-1-{(S) -1-[(5-ethyl-1,2,4-oxadiazol-3-yl) -hydroxy-methyl] -propyl Carbamoyl} -ethyl) -carbamic acid tert-butyl ester;
{(R) -1- [1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
{(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -3-phenyl-propylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -car Chest acid tert-butyl ester;
{(R) -1-[(S) -1- (hydroxy-thiazol-2-yl-methyl) -3-phenyl-propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid 3 Tert-butyl ester;
{(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -carbamic acid tertiary- Butyl esters;
(R) -1- {1- [hydroxy- (3-phenyl-1,2,4-oxadiazol-5-yl) -methyl] -propylcarbamoyl} -2-phenylmethanesulfonyl-ethyl) Carbamic acid tert-butyl ester;
((R) -2-cyclopropylmethanesulfonyl-1-{(S) -1-[(5-ethyl-1,2,4-oxadiazol-3-yl) -hydroxy-methyl] -propyl Carbamoyl} -ethyl) -carbamic acid tert-butyl ester;
{(R) -1- [1- (benzooxazol-2-yl-hydroxy-methyl) -butylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid tert-butyl ester;
{(R) -1-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -3-phenyl-propylcarbamoyl] -2-cyclopropylmethanesulfonyl-ethyl} -car Chest acid tert-butyl ester;
{(R) -1-[(S) -1- (hydroxy-thiazol-2-yl-methyl) -3-phenyl-propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbamic acid 3 Tert-butyl ester;
(R) -2-phenylmethanesulfonyl-1-{(S) -1-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl) -hydroxy-methyl] -propylcarba Moyl} -ethyl) -carbamic acid tert-butyl ester;
(R) -N- [1- (benzooxazole-2-carbonyl) -butyl] -2- [cyclopropylmethyl- (tetrahydro-pyran-4-ylmethyl) -amino] -3-phenylmethanesul Ponyl-propionamide;
(R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide ;
(R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino ) -Propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2- (1-methyl-piperidin-4-ylamino) -3- Phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2- (bis-thiophen-2-ylmethyl-amino) -3-phenyl Methanesulfonyl-propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-dibenzylamino-3-phenylmethanesulfonyl-propionamide;
(S) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2- (tetrahydro-pyran-4-ylamino) -3-thiophene- 2-yl-propionamide;
S) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-isopropylamino-3-thiophen-2-yl-propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N- [1- (benzothiazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide ;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino ) -Propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino ) -Propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-[(2-methoxy-ethyl)-(tetrahydro-pyran-4 -Yl) -amino] -3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-cyclohexylamino-3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (Benzooxazol-2-yl-hydroxy-methyl) -butyl] -2-dimethylamino-3-phenylmethanesulfonyl-propionamide;
N-cyanomethyl-3-cyclohexyl-propionamide;
N-cyanomethyl-3- (2-difluoromethoxy-phenylmethanesulfonyl) -propionamide;
3- (3-cyclohexyl-propionylamino) -2-oxo-5-phenyl-pentanoic acid thiazol-2-ylamide;
3-cyclohexyl-N- (1-formyl-3-phenyl-propyl) -propionamide;
3- (2-Difluoromethoxy-phenylmethanesulfonyl) -N-[(S) -1- (5-ethyl- [1,3,4] oxadiazole-2-carbonyl) -propyl]- Propionamide;
N-[(S) -1- (benzooxazole-2-carbonyl) -propyl] -2- (2-cyano-phenylamino) -3-cyclohexyl-propionamide;
N-cyanomethyl-3-cyclohexyl-2- (4-methoxy-phenoxy) -propionamide;
2-benzyloxy-N-cyanomethyl-3-cyclohexyl-propionamide;
(R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -butyl] -2-benzyloxy-3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -2-methoxymethoxy-3-phenylmethanesulfonyl-propionamide;
(S) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -butyl] -2-hydroxy-3-phenyl-propionamide;
(R) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propyl] -3-phenylmethanesulfonyl-2-triisopropylsilanyloxy-propionamide;
(R) -N-[(S) -1- (1-benzothiazol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenylmethanesulfonyl-propionamide;
(R) -2-hydroxy-3-phenylmethanesulfonyl-N-[(S) -1- (1-pyridazin-3-yl-methanoyl) -butyl] -propionamide;
(S) -3-((R) -2-hydroxy-3-phenylmethanesulfonyl-propanoylamino) -2-oxo-pentanoic acid benzylamide;
(R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -3- [2- (1,1-difluoro-methoxy) -phenyl Methanesulfonyl] -2-hydroxy-propionamide;
(R) -N-[(S) -1- (1-Benzothiazol-2-yl-methanoyl) -propyl] -3- [2- (1,1-difluoro-methoxy) -phenyl Methanesulfonyl] -2-hydroxy-propionamide and
From the group consisting of (2R, 5S) -2- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonylmethyl] -6-ethoxy-5-ethyl-morpholin-3-one Compound selected.
[16" claim-type="Currently amended] The method of claim 15,
Morpholine-4-carboxylic acid (R) -1- (cyanomethyl-carbamoyl) -2- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester );
Morpholin-4-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester (compound 11);
Morpholin-4-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2- [2- (1,1-di Fluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester (compound 14);
Morpholin-4-carboxylic acid (R) -1-[(S) -1- (1-benzothiazol-2-yl-methanoyl) -propylcarbamoyl] -2- [2- (1,1-di Fluoro-methoxy) -phenylmethanesulfonyl] -ethyl ester (Compound 15);
Pyrrolidine-1-carboxylic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester ( Compound 19);
Dimethyl-carbamic acid (R) -1-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester (Compound 20) ;
Morpholine-4-carboxylic acid (R) -1-[(S) -1- (1-benzylcarbamoyl-methanoyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester (Compound 25);
Morpholine-4-carboxylic acid (S) -1-[(S) -1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl ester;
Morpholine-4-carboxylic acid (S) -1-[(S) -1- (5-ethyl- [1,3,4] oxadiazole-2-carbonyl) -propylcarbamoyl] -2-phenylmethane Sulfonyl-ethyl esters;
(R) -3- [2- (1,1-difluoro-methoxy) -phenylmethanesulfonyl] -N-((S) -1-formyl-propyl) -2-hydroxy-propionamide ;
(R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -2-hydroxy-3-phenyl-methanesulfonyl-propionamide;
(S) -3- {3- [2- (1,1-Difluoro-methoxy) -phenylmethanesulfonyl] -propanoylamino} -2-oxo-pentanoic acid benzylamide;
(R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -2- (2-nitro-phenylamino) -3-phenylmethanesulfonyl-propion amides;
(R) -N-[(S) -1- (1-benzooxazol-2-yl-methanoyl) -butyl] -2- (5-nitro-thiazol-2-ylamino) -3-phenyl Methanesulfonyl-propionamide;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -3-phenylmethanesulfonyl-2- (tetrahydro-pyran-4-ylamino) -propionamide ;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-isopropylamino-3-phenylmethanesulfonyl propionamide;
(R) -N-[(S) -1- (benzooxazol-2-carbonyl) -butyl] -2-[(2-methoxy-ethyl)-(tetrahydro-pyran-4-yl)- Amino] -3-phenylmethanesulfonyl-propionamide;
(R) -N-[(S) -1- (benzooxazole-2-carbonyl) -butyl] -2-cyclohexylamino-3-phenylmethanesulfonyl-propionamide;
Morpholine-4-carboxylic acid (S) -2-cyclohexyl-1-[(S) -1- (oxazolo [4,5-b] pyridine-2-carbonyl) -propylcarbamoyl] -ethyl ester;
(S) -3-((R) -2-hydroxy-3-phenylmethanesulfonyl-propanoylamino) -2-oxo-pentanoic acid benzylamide and
(R) -N-[(S) -1- (1-Benzooxazol-2-yl-methanoyl) -propyl] -3- [2- (1,1-difluoro-methoxy) -phenyl Methanesulfonyl] -2-hydroxy-propionamide.
[17" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable excipient.
[18" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 2 and a pharmaceutically acceptable excipient.
[19" claim-type="Currently amended] A therapeutically effective amount of a compound according to claim 1 or 2 is administered to an animal wherein the inhibition of cathepsin S can prevent, inhibit or alleviate the pathology and / or symptoms of the disease. Treatment method.
[20" claim-type="Currently amended] Use of a compound according to claim 1 or 2 for the manufacture of a medicament for the treatment of a disease in an animal in which kadipsin S activity contributes to the pathology and / or symptoms of the disease.