Carboxylic acid derivatives that inhibit the binding of integrins to their receptors

专利摘要:
a method of inhibiting α 4 β 1 integrins from binding to their receptors such as VCAM-1 (vascular cell adsorption molecule-1) and fibronectin; Compounds which inhibit this binding; Pharmaceutically active compositions containing such compounds; And the use of such compounds or formulations for the inhibition or prevention of disease states involving α 4 β 1 is described herein.
公开号:KR20020035471A
申请号:KR1020010069008
申请日:2001-11-06
公开日:2002-05-11
发明作者:비디거로날드제이；천치；덱커이래드포드；홀랜드조지더블유；카시르야말엠；리원；마켓로버트브이；스코트아이안엘；우청더；리잔
申请人:데이비드 비. 맥윌리암스；텍사스 바이오테크놀로지 코포레이션；
IPC主号:

专利说明:

Carboxylic acid derivatives that inhibit the binding of integrins to their receptors
[1] The present invention generally relates to inhibiting α ₄ β ₁ integrins from binding to their receptors such as VCAM-1 (vascular cell adsorption molecule-1) and fibronectin. The present invention also relates to compounds which inhibit such binding, pharmaceutically active compositions containing these compounds and the use of such compounds or formulations for controlling or preventing disease conditions involving α ₄ β ₁ .
[2] If tissue is infected or damaged by microorganisms, white blood cells play a major role in the inflammatory response. One of the most important aspects of the inflammatory response is the cellular adsorption phenomenon. In general, white blood cells have been found to circulate through the bloodstream. However, when tissue is infected or damaged, white blood cells recognize the infected or damaged tissue, bind to the capillary wall, and then migrate through the capillary to the infected or damaged tissue. This phenomenon is mediated by a class of proteins called cell adsorption molecules.
[3] White blood cells fall into three categories: granulocytes, monocytes and lymphocytes. Integrin α ₄ β ₁ (also called VLA-4 (Very Late Antigen-4)) is heterologous expressed on the surface of monocytes, lymphocytes and granulocytes (eosinophilic and basophils) of two subclasses It is a dimeric protein. This protein plays a key role in cell adsorption through its ability to recognize and bind VCAM-1 and fibronectin (proteins that bind to endothelial cells that form the inner walls of the capillaries).
[4] Following infection or injury around capillary tissue, endothelial cells express a series of adsorption molecules, including VCAM-1, which are important for binding to the white blood cells needed to fight infection. Leukocytes first bind to specific adsorption molecules to slow down their flow and "roll" along the activated endothelial prior to binding to VCMA-1 or fibronectin. Monocytes, lymphocytes, basophils and eosinophils can bind strongly to VCAM-1 or fibronectin on the vessel wall via α ₄ β ₁ integrin. In addition, there is evidence that this interaction is related to the initial rolling phenomenon itself, as well as the migration of these white blood cells to damaged tissues.
[5] Although leukocyte migration to the wound site may help fight infection and destroy foreign material, in many cases this migration cannot be controlled while leukocytes flock to these sites causing extensive tissue damage. Thus, compounds that can block this process may be useful as therapeutic agents. In this regard, it may be beneficial to develop inhibitors that inhibit the binding of white blood cells to VCAM-1 and fibronectin.
[6] Some of the diseases that can be treated by inhibition of α ₄ β ₁ binding include, but are not limited to, atherosclerosis, rheumatoid arthritis, asthma, allergies, multiple sclerosis, lupus, inflammatory bowel disease, transplant rejection, contact hypersensitivity, and Type I diabetes is included. In addition to being found in some leukocytes, α ₄ β ₁ is also found in various cancer cells, including leukemia, melanoma, lymphoma and sarcoma cells. It has been suggested that α ₄ β ₁ related cell adsorption is associated with metastasis of certain cancers. Thus, α ₄ β ₁ binding inhibitors may be useful for the treatment of some cancer types.
[7] Isolation and purification of peptides that inhibit the binding of α ₄ β ₁ to proteins is described in US Pat. No. 5,510,332. Peptides that inhibit binding are described in WO 95/15973, EP 0 341 915, EP 0 422 938 A1, USP 5,192,746 and WO 96/06108. Novel compounds useful for the inhibition and prevention of cell adsorption and cell adsorption-mediated pathology are described in WO 96/22966, WO 98/04247 and WO 98/04913.
[8] It is an object of the present invention to provide novel compounds which are α ₄ β ₁ binding inhibitors and pharmaceutical compositions comprising such new compounds.
[9] The present invention relates to a compound of formula (1) or a pharmaceutically acceptable salt thereof.
[10]
[11] In the above formula,
[12] Each Y is independently selected from the group consisting of C (O), N, CR ¹ , C (R ² ) (R ³ ), NR ⁵ , CH, O and S;
[13] q is an integer from 3 to 10;
[14] A is selected from the group consisting of O, S, C (R ¹⁶ ) (R ¹⁷ ) and NR ⁶ ;
[15] E is selected from the group consisting of CH ₂ , O, S and NR ⁷ ;
[16] J is selected from the group consisting of O, S and NR ⁸ ;
[17] T is selected from the group consisting of C (O) and (CH ₂ ) _b , wherein b is an integer from 0 to 3;
[18] M is selected from the group consisting of C (R ⁹ ) (R ¹⁰ ) and (CH ₂ ) _u , wherein u is an integer from 0 to 3;
[19] L is selected from the group consisting of O, NR ¹¹ , S and (CH ₂ ) _n , where n is an integer of 0 or 1;
[20] X is CO ₂ B, PO ₃ H ₂ , SO ₃ H, SO ₂ NH ₂ , SO ₂ NHCOR ¹² , OPO ₃ H ₂ , C (O) NHC (O) R ¹³ , C (O) NHSO ₂ R ¹⁴ , Selected from the group consisting of hydroxyl, tetrazolyl and hydrogen;
[21] W is selected from the group consisting of C, CR ¹⁵ and N;
[22] B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and Each R ¹⁷ is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl ), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) -NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ ( C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl , -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , Haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, bi Aryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO _2- (C ₁ -C ₃ alkyl),- Is selected from the group consisting of SO ₃ — (C ₁ -C ₃ alkyl), sulfonamido, carbamate, aryloxyalkyl, and —C (O) NH (benzyl) group; B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ is unsubstituted or substituted with one or more electron donating groups or electron withdrawing groups; When L is NR ¹¹ , R ⁴ and R ¹¹ may form a ring together, when M is C (R ⁹ ) (R ¹⁰ ), R ⁹ and R ¹⁰ may form a ring together, A When NR ⁶ and at least one Y is CR ¹ , R ¹ and R ⁶ together may form a ring;
[23] Provided that when A is C (R ¹⁶ ) (R ¹⁷ ) then E is not NR ⁷ .
[24] In formula 1, preferred compounds are those in which A is NR ⁶ ; E is NR ⁷ ; J is O; M is C (R ⁹ ) (R ¹⁰ ), q is 4 or 5; T is (CH ₂ ) _b , where b is 0; L is (CH ₂ ) _n where n is 0; X is CO ₂ B; W is C or CR ¹⁵ ; R ⁴ is aryl, alkylaryl, aralkyl, heterocyclyl, alkylheterocyclyl or heterocyclylalkyl; R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and R ¹⁵ are independently hydrogen or lower alkyl.
[25] More specifically, the compound of the present invention may be a compound of Formula 2 or a pharmaceutically acceptable salt thereof:
[26]
[27] In the above formula,
[28] Each Y is independently selected from the group consisting of C (O), N, CR ¹ , C (R ² ) (R ³ ), NR ⁵ , CH, O and S;
[29] q is an integer from 3 to 7;
[30] T is selected from the group consisting of C (O) and (CH ₂ ) _b , wherein b is an integer from 0 to 3;
[31] L is selected from the group consisting of O, NR ¹¹ , S and (CH ₂ ) _n , where n is an integer of 0 or 1;
[32] W is selected from the group consisting of C, CR ¹⁵ and N;
[33] B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁵ are independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy , Alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxy Carbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O ) -NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkyl Amino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloal Kenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, hete Rosa cycle reel, alkylaryl, aralkyl, alkenyl, aralkyl, alkyl, heterocyclyl, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 Alkyl), sulfonamido, carbamate, aryloxyalkyl, and -C (O) NH (benzyl) group; B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁵ are unsubstituted or substituted with one or more electron donating groups or electron withdrawing groups ; When L is NR ¹¹ , R ⁴ and R ¹¹ may form a ring together, R ⁹ and R ¹⁰ may form a ring together, and when one or more Y is CR ¹ , R ¹ and R ⁶ may be Together, they may form a ring.
[34] Preferred compounds of formula 2 have q of 4 or 5; W is C or CR ¹⁵ ; T is (CH ₂ ) _b , where b is 0; L is (CH ₂ ) _n where n is 0; R ⁴ is aryl, alkylaryl, aralkyl, heterocyclyl, alkylheterocyclyl or heterocyclylalkyl; R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and R ¹⁵ are independently hydrogen or lower alkyl.
[35] More specifically, the compound of the present invention may be a compound of Formula 3 or a pharmaceutically acceptable salt thereof:
[36]
[37] In the above formula,
[38] Each Y is independently selected from the group consisting of C (O), N, CR ¹ , C (R ² ) (R ³ ), NR ⁵ , CH, O and S;
[39] q is an integer from 2 to 5;
[40] T is selected from the group consisting of C (O) and (CH ₂ ) _b , wherein b is an integer from 0 to 3;
[41] L is selected from the group consisting of O, NR ¹¹ , S and (CH ₂ ) _n , where n is an integer of 0 or 1;
[42] R ⁵ , R ⁶ , R ⁷ , R ¹¹ and R ¹⁸ are independently alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, halo Alkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, hetero Cyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen, and -C (O) -NH (benzyl) group;
[43] B, R ¹ , R ² , R ³ , R ⁴ , R ⁹ and R ¹⁰ are independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl , Aliphatic acyl, -CF ₃ , -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C _1- C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) -NH (C ₁ -C ₃ alkyl), -NHC ( O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino , -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ ,- CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, Aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, Reual alkenyl, aralkyl, alkyl, heterocyclyl, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbazole Mate, aryloxyalkyl, and -C (O) NH (benzyl) group; B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁸ are unsubstituted or substituted with one or more electron donating groups or electron withdrawing groups; When L is NR ¹¹ , R ⁴ and R ¹¹ together may form a ring; R ⁹ and R ¹⁰ together may form a ring; When at least one Y is CR ¹ , R ¹ and R ⁶ together may form a ring.
[44] Preferred compounds of formula 3 are those wherein R ¹⁸ is hydrogen, alkyl, aryl, aralkyl, cycloalkyl, alkylheterocyclyl, heterocyclylalkyl or heterocyclyl; T is (CH ₂ ) _b , where b is 0; L is (CH ₂ ) _n where n is 0; Y is CR ¹ and C (R ² ) (R ³ ); q is 2 or 3.
[45] In Formula 3, the molecule The part of may be a molecule of the formula and a pharmaceutically acceptable salt thereof:
[46]
[47] In the above formula,
[48] R ¹⁹ , R ²⁰ , R ²¹ and R ²⁸ are each independently halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ ,- OH, -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) -NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ Alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- ( C ₁ -C ₃ ) alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, Thioaryl, diarylamino, heterocyclyl, alkylaryl, aralke , Aralkyl, alkyl, heterocyclyl, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbamate, Aryloxyalkyl and -C (O) NH (benzyl) group;
[49] R ¹⁸ is alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cyclo Alkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyl Heterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen, and -C (O) -NH (benzyl) group;
[50] R ²² is hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl),- NHC (O) N (C ₁ -C ₃ alkyl) C (O) -NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C _1- C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH— (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, Alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl , Alkylaryl, aralkenyl, aralkyl, alkylheterocyclo Keulril, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbamate, aryloxyalkyl and -C ( O) NH (benzyl) group;
[51] c is an integer from 0 to 2;
[52] d is an integer from 0 to 3;
[53] e is an integer from 0 to 4;
[54] i is an integer from 0 to 2.
[55] In one embodiment, R ¹⁸ is aralkyl; R ⁴ is aryl; T is (CH ₂ ) _b , where b is 0; L is (CH ₂ ) _n where n is 0; B, R ⁶ , R ⁷ , R ⁹ and R ¹⁰ are each independently hydrogen.
[56] More specifically, the compound of the present invention may be a compound of formula 4 or a pharmaceutically acceptable salt thereof.
[57]
[58] In the above formula,
[59] T is selected from the group consisting of C (O) and (CH ₂ ) _b , wherein b is an integer from 0 to 3;
[60] L is selected from the group consisting of O, NR ¹¹ , S and (CH ₂ ) _n , where n is an integer of 0 or 1;
[61] g is an integer from 0 to 7;
[62] B, R ⁴ , R ⁹ , R ¹⁰ and R ²³ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl,- CF ₃ , -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl)- C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , —OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, Biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, ar Alkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO _2- (C ₁ -C ₃ alkyl), -SO _3- (C ₁ -C ₃ alkyl), sulfonamido, carba Mate, aryloxyalkyl, and -C (O) NH (benzyl) group;
[63] R ⁶ , R ⁷ , R ¹¹ and R ¹⁸ are each independently alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, Alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl , Alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and —C (O) NH (benzyl) group; B, R ⁴ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹⁸ and R ²³ are unsubstituted or substituted with one or more electron donating groups or electron withdrawing groups; When L is NR ¹¹ , R ⁴ and R ¹¹ together may form a ring; R ⁹ and R ¹⁰ may form a ring together.
[64] Preferred compounds of the present invention may be a compound of formula (5) or a pharmaceutically acceptable salt thereof.
[65]
[66] In the above formula,
[67] h is an integer from 0 to 5;
[68] B, R ⁹ , R ¹⁰ , R ²⁴ and R ²⁵ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl,- CF ₃ , -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl)- C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , —OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, Biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, ah Alkenyl, aralkyl, alkyl, heterocyclyl, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbazole Mate, aryloxyalkyl, and -C (O) NH (benzyl) group;
[69] Each R ²⁷ is independently halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH , -CN, -NO ₂ , -NH ₂ , alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C _1- C ₃ alkyl), -NHSO ₂ (aryl), -N (C ₁ -C ₃ alkyl) SO ₂ (C ₁ -C ₃ alkyl), -N (C ₁ -C ₃ alkyl) SO ₂ (aryl), alkoxy Alkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl , -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl , Cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, dia Arylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO _2- (C ₁ -C ₃ alkyl), -SO _3- (C ₁ -C ₃ alkyl), sulfonamido, carbamate, aryloxyalkyl and -C (O) NH (benzyl) group;
[70] R ⁶ , R ⁷ and R ¹⁸ are each independently alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkoxy, Carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl , Aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and —C (O) NH (benzyl) group;
[71] R ²⁶ is hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, -CF ₃ , alkoxycarbonyl, heterocycloyl, carboxy, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -PO ₃ H ₂ , haloalkyl, carboxamide, cycloalkyl, cycloal Kenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, biaryl, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO _2- ( C ₁ -C ₃ alkyl), sulfonamido, aryloxyalkyl, and —C (O) NH (benzyl) group; B, R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹⁸ , R ²⁴ , R ²⁵ , R ²⁶ and R ²⁷ are unsubstituted or substituted with one or more electron donating groups or electron withdrawing groups; R ¹⁸ and R ²⁴ may form a ring together; R ²⁴ and R ²⁵ together may form a ring; R ²⁵ and R ²⁶ together may form a ring; R ⁹ and R ¹⁰ may form a ring together.
[72] Preferred compounds of formula (5) are aralkyl wherein B, R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ²⁴ , R ²⁵ and R ²⁶ are each independently hydrogen and R ¹⁸ is substituted or unsubstituted.
[73] Other preferred compounds of the present invention may be a compound of formula (6) or a pharmaceutically acceptable salt thereof.
[74]
[75] In the above formula,
[76] Z are each independently selected from the group consisting of C (O), N, CR ³⁰ , C (R ³¹ ) (R ³² ), NR ³³ , CH, O and S;
[77] z is an integer from 3 to 6;
[78] k is an integer from 0 to 5;
[79] T is selected from the group consisting of C (O) and (CH ₂ ) _b , wherein b is an integer from 0 to 3;
[80] L is selected from the group consisting of O, NR ¹¹ , S and (CH ₂ ) _n , where n is an integer of 0 or 1;
[81] R ⁶ , R ⁷ , R ¹¹ , R ¹⁸ and R ³³ are each independently alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, Haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, Heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen, and -C (O) NH (benzyl) group;
[82] B, R ⁴ , R ⁹ , R ¹⁰ , R ³⁰ , R ³¹ and R ³² are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxy Alkyl, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH, -OH, -CN, -NO ₂ , -NH ₂ , alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (C ₁ -C ₃ alkyl), -NHC ( O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino , -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ ,- CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, Aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkyl Aryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO _2- (C ₁ -C ₃ alkyl), -SO _3- (C ₁ -C ₃ alkyl), sulfonami In addition, it is selected from the group consisting of carbamate, aryloxyalkyl, and -C (O) NH (benzyl) group;
[83] Each R ²⁹ is independently halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH, -CN , -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C _1- C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH— (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, Alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl , Alkylaryl, aralkenyl, aralkyl, alkyl Interrogating heterocyclyl, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbamate, aryloxyalkyl and- Is selected from the group consisting of C (O) NH (benzyl) groups; B, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² and R ³³ are unsubstituted or one or more electron donating groups or Substituted with an electron withdrawing group; When L is NR ¹¹ , R ⁴ and R ¹¹ together may form a ring; R ⁹ and R ¹⁰ may form a ring together.
[84] Some compounds of Formulas 1-6 may be prepared from novel intermediates of Formulas 7 and 8 below.
[85]
[86] In the above formula,
[87] R ²⁴ and R ²⁵ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -SH, -OH , -CO ₂ H, -CN, -NO ₂ , -NH ₂ , alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C _1- C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) Alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diaryl Amino, heterocyclyl, alkylaryl, aralkenyl, sub Alkyl, heterocyclyl, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbamate, aryloxyalkyl Selected from the group consisting of alkyl and -C (O) NH (benzyl) groups;
[88] R ¹⁸ and R ³⁴ are each independently alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde , Carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aral Kenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and -C (O) NH (benzyl) group; R ¹⁸ , R ²⁴ , R ²⁵ and R ³⁴ are unsubstituted or substituted with one or more electron donating groups or electron withdrawing groups; R ²⁴ and R ²⁵ together may form a ring; Provided that when R ²⁴ and R ²⁵ together form a ring, the formed ring is not benzene.
[89] Preferred compounds of formula 7 are those wherein R ³⁴ is hydrogen; R ¹⁸ is alkyl; R ²⁴ and R ²⁵ are each independently hydrogen, lower alkyl, or lower alkyl wherein R ²⁴ and R ²⁵ together may form a ring.
[90] Formula 8 is a preferred novel intermediate.
[91]
[92] In the above formula,
[93] R ²⁴ and R ²⁵ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -SH, -OH , -CO ₂ H, -CN, -NO ₂ , -NH ₂ , alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C _1- C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) Alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diaryl Amino, heterocyclyl, alkylaryl, aralkenyl, sub Alkyl, heterocyclyl, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbamate, aryloxyalkyl Selected from the group consisting of alkyl and -C (O) NH (benzyl) groups;
[94] R ³⁴ is alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cyclo Alkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyl Heterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen, and -C (O) NH (benzyl) group;
[95] Each R ³⁵ is independently halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH , -CN, -NO ₂ , -NH ₂ , alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C _1- C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH— (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, Alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl , Alkylaryl, aralkenyl, aral Kyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO _2- (C ₁ -C ₃ alkyl), -SO _3- (C ₁ -C ₃ alkyl), sulfonamido, carbamate, aryloxy Selected from the group consisting of alkyl and -C (O) NH (benzyl) groups; R ²⁴ , R ²⁵ , R ³⁴ and R ³⁵ are unsubstituted or substituted with one or more electron donating groups or electron withdrawing groups; m is an integer of 0-5.
[96] Preferred compounds of formula (8) are those in which R ³⁴ is hydrogen; m is an integer from 1 to 3; Each R ³⁵ is independently alkyl, halogen, alkoxy, haloalkyl, sulfonyl, —OH or —CN.
[97] Preferred compounds of formula 1 include the following compounds:
[98] (3S) -3-[({[2-methyl-4- (2-methylpropyl) -6-oxo-1- (phenylmethyl) -1,6-dihydro-5-pyrimidinyl] amino} carbo Yl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 [({[2-oxo-1- (phenylmethyl) -4-propyl-1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4 -Ethyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1- [ (2-chlorophenyl) methyl] -2-oxo-4-propyl-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- ( 4-methylphenyl) propanoic acid, (3S) -3-{[({6-methyl-2-oxo-1- (phenylmethyl) -4-[(phenylmethyl) oxy] -1,2-dihydro-3 -Pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophene ) Methyl] -2,4-dimethyl-6-oxo-1,6-dihydro-5-pyrimidinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3 -{[({4-amino-1-[(2-chlorophenyl) methyl] -6-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3 -(4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl } Amino) carbonyl] amino} -3- [4- (methyloxy) phenyl] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-methyl-2 -Oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3,4-dimethylphenyl) propanoic acid, (3S) -3-{[({4-amino- 1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S)- 3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- ( 4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4- ( 1,4-oxazinan-4-yl) -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S)- 3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-4- (propylamino) -1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3 -(4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-bromophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyri Diyl] amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo -1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [3-methyl-4- (methyloxy) phenyl] propanoic acid, (3S) -3-{[({1 -[(2-chlorophenyl) methyl] -2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl] amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, ( 3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[(2-{[2- (methyloxy) ethyl] oxy} ethyl) oxy] -2-oxo-1, 2-dihydro-3-pyridinyl] amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[(1,1-dimethylethyl) amino] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl] propanoic acid, (3S) -3-{[({1-[(2 -Chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino} carbonyl) amino} -3-phenylpropanoic acid, (3S) -3-{[ ({1-[(2-chlorophenyl) methyl] -4- [4-methyltetrahydro-1 (2H) -pyrazinyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino} Carbonyl) amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2 -Dihydro-3-pyridinyl} amino) carbonyl) amino} -3- [4- (methyloxy) phenyl] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) Methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} ami } Carbonyl] amino} -3- (3,5-dimethylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo -1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) Methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [3- (methyloxy) phenyl] propanoic acid, (3S)- 3- [3,5-bis (methyloxy) phenyl] -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3 -Pyridinyl} amino} carbonyl) amino} propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-di Hydro-3-quinolinyl} amino) carbonyl) amino} -3- [4-methylphenyl] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4- Hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [3- (trifluoromethyl) phenyl] propanoic acid, (3S) -3- { [({1-[(2-chlorophenyl) methyl] -4-[({ethyl [(ethyla No) carbonyl] amino) carbonyl] amino} -2-oxo-1,2-dihydro-3-pyridinyl} amino} carbonyl) amino} -3- (4-methylphenyl] propanoic acid, (3S) -3-{[({4- (1-Azetanyl) -1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] Amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-({2-[(2-{[2- ( Methyloxy) ethyl] oxy} ethyl) oxy] ethyl} oxy) -2-oxo-1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-fluorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino } -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chloro-6-fluorophenyl) methyl] -4-hydroxy-2-oxo-1, 2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl]- 5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo ] Amino} -3- (4-methylphenyl) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3-((((2-oxo-1-((4- (Trifluoromethyl) phenyl) methyl) -1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) propanoic acid, (3S) -3-((((1-((2-chloro Phenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- (4-methylphenyl) propanoic acid, (3S) -3-(((((1 -((2-fluorophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- (4-methylphenyl) propanoic acid, (3S)- 3-((((1-((2-bromophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- (4-methylphenyl) Propanoic acid, (3S) -3-((((1-((2,4-dichlorophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- (4-methylphenyl) propanoic acid, (3S) -3-((((1-((2-chloro-6-fluorophenyl) methyl) -2-oxo-1,2-dihydro-3 -Pyridinyl) amino) carbonyl) amino) -3- (4-methylphenyl) propanoic acid, (3S) -3-((((1-(( 2-chlorophenyl) methyl) -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- (4-trifluoromethyl) oxy) phenyl ) Propanoic acid, (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid, 4-{[3-[({[(1S) -2-carboxy-1- (4-methylphenyl) ethyl] amino} carbonyl) amino] -1- ( 2-chlorobenzyl) -2-oxo-1,2-dihydropyridin-4-yl] amino} benzoic acid, (3S) -3-{[({1- (2-chlorobenzyl) -4-[(2 , 2-dimethylpropanoyl) amino] -2-oxo-1,2-dihydropyridin-3-yl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3 -[({[4-{[(tert-butylamino) carbonyl] amino} -1- (2-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbo Yl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-cyanobenzyl) -4-hydroxy-2-oxo-1,2-dihydro Pyridin-3-yl] amino} carbonyl) amino] -3- (4 -Methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl ) Amino] -3- (2,3-dihydro-1,4-benzodioxin-6-yl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4- Hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (7-methoxy-1,3-benzodioxol-5-yl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxy-4-methoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridine -3-yl] amino} carbonyl) amino] -3- (3,4-dimethoxyphenyl) propanoic acid, (3S) -3-[({[1- (4-chlorobenzyl) -4-hydroxy -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2- Chloro-6-methoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridine-3- ] Amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo -1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2,6-difluoro Lobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3- [ ({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3 , 5-dimethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] Amino} carbonyl) amino] -3- (3,4-diethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo- 1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] Mino} carbonyl) amino] -3- (3-methoxy-4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo -1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,5-dimethoxy-4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,4-dimethylphenyl) propanoic acid, ( 3S) -3-[({[1- (2-chlorobenzyl) -5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1- [2-chloro-5- (trifluoromethyl) benzyl] -4-hydroxy-2-oxo-1, 2-dihydropyridin-3-yl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-methoxybenzyl ) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-methylphenyl) propanoic acid, (3S) -3-[({ [1- (2-Chloro-6-methylbenzyl) -4-hydroxy-5- Methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2 -Chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (4 -Methylphenyl) propanoic acid, (3S) -3-[({[1- (2,6-dimethoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-di Hydropyridin-3-yl] amino} carbonyl) amino] -3- (3-propoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy -2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid, (3S) -3-[({ [1- (2-chlorobenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4- Methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro Benzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,4-diethoxyphenyl) propanoic acid, (3S) -3- (3-butoxyphenyl) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] Amino} carbonyl) amino] propanoic acid, (3S) -3-{[({1- [2-chloro-5- (methylsulfonyl) benzyl] -4-hydroxy-2-oxo-1,2- Dihydropyridin-3-yl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy- 2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- [3- (2-methoxyethoxy) phenyl] propanoic acid, (3S) -3-[( {[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,4-dipropoxy Phenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- [3- (difluoromethoxy) phenyl ] Propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} Carbonyl) amino] -3- (3,4-diethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2- Oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro -6-methylbenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,4-die Methoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-cyanobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl ] Amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, 3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridine -3-yl] amino} carbonyl) amino] -3- (2-naphthyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5, 6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (3,4-diethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-5-methyl- 2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,4-diethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid, ( 3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-2-oxo-2,5,6 , 7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid, (3S) -3-[({[1 -(2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl Propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine- 3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4- Hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (1-methyl-1H-indol-5-yl) propanoic acid, ( 3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} Carbonyl) amino] -3- (2,3-dihydro-1-benzofuran-5-yl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl ) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (3,5- Diethoxyphenyl) propanoic acid, (3S) -3-[({[5-chloro-1- (2-chloro- 6-ethoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid, (3S ) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5 , 6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (3-propoxyphenyl) propanoic acid, (3S) -3-[({ [1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} Carbonyl) amino] -3-phenylpropanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro -1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5 -Yl) propanoic acid, (3S) -3-[({[1- (2- Chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-trifluorome Methoxy) phenyl] propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2- Dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4- Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (1-methyl-1H-indole- 5-yl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -5-cyclopropyl-4-hydroxy-2-oxo-1,2-di Hydropyridin-3-yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl ) -5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S)- 3-[({[1- (2 -Chloro-5-methoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) Propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3- Yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydro Hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (1-methyl-1H-indol-6-yl) propanoic acid, (3S ) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl] amino} carbonyl) amino] -3- [3- (cyclopropyloxy) phenyl] propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydro Roxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- [3- (cyclopropylmethoxy) phenyl ] Propanoic acid, (3S) -3-[( {[1- (2-Chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino } Carbonyl) amino] -3- [3- (cyclopropylmethoxy) phenyl] propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo -2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (3,5-dimethylphenyl) propanoic acid, (3S)- 3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl } Amino) carbonyl] amino} -3- {3-[(difluoromethyl) oxy] phenyl} propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl]- 4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl} amino) carbonyl] amino} -3- {3-[(1, 1,2,2-tetrafluoroethyl) oxy] phenyl} propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2 , 5,6,7-tetrahydro-1H-cyclo Ta [b] pyridin-3-yl} amino) carbonyl] amino} -3- (1-ethyl-1H-indol-5-yl) propanoic acid, (3S) -3-{[({1-[( 2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl} amino) carbonyl] amino} -3 -[3- (diethylamino) phenyl] propanoic acid, (3S) -3-[({[1-((2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2 -Dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1-((2-chlorobenzyl) -4-hydro Roxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S ) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino]- 3- [3- (diethylamino) phenyl] propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2- Oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1 , 2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl)- 4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl ) Propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridine-3 -Yl] amino} carbonyl) amino] -3- (6-methoxy) -2-naphthyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydro Roxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (3-methylphenyl) propanoic acid, (3S ) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] Pyridin-3-yl} amino) carbonyl] amino} -3- (1-methyl-1H-yne -5-yl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro- 1H-cyclopenta [b] pyridin-3-yl} amino) carbonyl] amino} -3- {3-[(methylsulfonyl) amino] phenyl} propanoic acid, (3S) -3-{[((1 -[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl} amino) carbo Nil] amino} -3- {3-[(methylsulfonyl) amino] phenyl} propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy- 2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl} amino) carbonyl] amino} -3- {3- [methyl (methylsulfonyl) amino] Phenyl} propanoic acid, (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro- 1H-cyclopenta [b] pyridin-3-yl} amino) carbonyl] amino} -3- {3- [methyl (methylsulfonyl) amino] phenyl} propanoic acid, (3S) -3-{[({ 1-[(2-chlorophenyl) methyl] -4-hydroxy Cy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl} amino) carbonyl] amino} -3- {3- [ethyl (methylsulfonyl) Amino] phenyl} propanoic acid, (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetra Hydro-1H-cyclopenta [b] pyridin-3-yl} amino) carbonyl] amino} -3- {3- [ethyl (methylsulfonyl) amino] phenyl} propanoic acid, and (3S) -3- { [({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl } Amino) carbonyl] amino} -3- (1H-indol-5-yl) propanoic acid and pharmaceutically acceptable salts of said compounds.
[99] Preferred compounds of formula 7 include the following compounds:
[100] 5- (2-chlorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -6-methyl- 3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-fluorobenzyl) -3,5-dihydro [1,3] oxa Solo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-6-fluorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] Pyridine-2,4-dione, 5-benzyl-6-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5-benzyl-3, 5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2,5-dimethylbenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-methylbenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4- Dione, 5- (2,4-dichlorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-methoxybenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2,5-difluorobenzyl) -3,5-dihydro [1 , 3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [2-chloro-5- ( Ylthio) benzyl] -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (4-fluorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-5-methoxybenzyl) -3,5-dihydro [1,3] oxazolo [ 4,5-c] pyridine-2,4-dione, 5- [3,5-bis (trifluoromethyl) benzyl] -3,5-dihydro [1,3] oxazolo [4,5-c ] Pyridine-2,4-dione, 5- (4-tert-butylbenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5 -(3-chlorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (4-chlorobenzyl) -3,5-di Hydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [3- (trifluoromethyl) benzyl] -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-bromobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4 -Dione, 5- (3,4-dichlorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (4-methylbenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyrid -2,4-dione, 5- (2-chloro-6-methoxybenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5 -[4- (trifluoromethyl) benzyl)]-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (3-methylbenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (pyridin-2-ylmethyl) -3,5-dihydro [1,3 ] Oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c ] Pyridine-2,4-dione, 5- (2,4-difluorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2,6-difluorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [3- (trifluorome Methoxy) benzyl] -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [4- (trifluoromethoxy) benzyl] -3,5 -Dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [2- (trifluoromethyl) benzyl] -3,5-dihydro [1,3] Oxazolo [4,5-c] pyridine-2,4-dione, 5- (3-methoxybenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2,3-dichlorobenzyl) -3 , 5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (3,5-dimethylbenzyl) -3,5-dihydro [1,3] oxa Zolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -7-pentyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine -2,4-dione, 5- (2,4-dichlorobenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -7-ethyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 7-butyl-5- (2- Chlorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [2-chloro-5- (trifluoromethyl) benzyl]- 3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2,6-dichlorobenzyl) -3,5-dihydro [1,3] Oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-5-fluorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c ] Pyridine-2,4-dione, 5- (2-chloro-6-methylbenzyl)- 7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (4-chlorobenzyl) -7-methyl-3,5-di Hydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -5,6,7,8-tetrahydro-2H-cyclopenta [b] [1,3] oxazolo [5,4-d] pyridine-2,4 (3H) -dione, 7-methyl-5- [4- (methylsulfonyl) benzyl] -3,5-dihydro [1 , 3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (4-methoxybenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] Pyridine-2,4-dione, 5- (2-chlorobenzyl) -7-propyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 4 -[(2,4-dioxo-2,3-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl) methyl] -N, N-dimethylbenzenesulfonamide , 5- (methylmethyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -3,5, 6,7,8,9-hexahydro [1,3] oxazolo [4,5-c] quinoline-2,4-dione, 5- (2-chlorobenzyl) -7-ethyl-6-methyl-3 , 5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-di , 5- [2- (methylthio) benzyl] -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 2-[(2,4-di Oxo-2,3-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl) methyl] -N, N-dimethylbenzenesulfonamide, 5- (2,6- Dimethoxybenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [2- (trifluoromethoxy) benzyl] -3,5 -Dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -6,7-dimethyl-3,5-dihydro [1,3 ] Oxazolo [4,5-c] pyridine-2,4-dione, 5- [2-chloro-5- (methylsulfonyl) benzyl] -3,5-dihydro [1,3] oxazolo [4 , 5-c] pyridine-2,4-dione, 5- (4-chloro-2-methoxybenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2 , 4-dione, 5- (2-chlorobenzyl) -5,6,7,8,9,10-hexahydro-2H-cyclohepta [b] [1,3] oxazolo [5,4-d] Pyridine-2,4 (3H) -dione, 5- [2- (difluoromethoxy) benzyl] -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4 -Dione, 7-methyl-5-[(1R) -1-phenylethyl] -3,5- Dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (4-chlorobenzyl) -7-propyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [2- (methylsulfonyl) benzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine- 2,4-dione, 5- (2,6-dimethylbenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 3-chloro-2 -[(2,4-dioxo-2,3-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl) methyl] benzonitrile, 5- (2-chloro -6-methylbenzyl) -6,7-dimethyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 2-[(2,4-di Oxo-2,3-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl) methyl] benzonitrile, 5- (2-chloro-6-methoxybenzyl)- 7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [3- (methylthio) benzyl] -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -7-cyclopropyl-3,5-dihydro [1,3] oxazolo [ 4,5-c] pyridine-2,4-dione, 5- (3-chloro Benzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2,6-dichlorobenzyl) -7-methyl- 3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 7-methyl-5- (4-methylbenzyl) -3,5-dihydro [1, 3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (3,5-dimethoxybenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4 , 5-c] pyridine-2,4-dione, 5- (2,6-difluorobenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] Pyridine-2,4-dione, 5- [3- (methylsulfonyl) benzyl] -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5 -(2-chloro-6-ethoxybenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-6- Ethoxybenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-fluoro-6-methoxybenzyl ) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-6-methoxybenzyl) -7- Propyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4 -Dione, 5- (5-chloro-2-fluorobenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5 -(2-chlorobenzyl) -7-isopropyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (5-fluoro-2 -Methylbenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 7-methyl-5-[(1S) -1- Phenylethyl] -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-5-isopropoxybenzyl) -7-methyl -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (5-acetyl-2-methoxybenzyl) -3,5-dihydro [ 1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4, 5-d] pyridazine-2,4-dione, 5- [2-fluoro-6- (trifluoromethyl) benzyl] -7-methyl-3,5-dihydro [1,3] oxazolo [ 4,5-c] pyridine-2,4-dione, 5- (2-chloro-6-methylbenzyl) -5,6,7,8-tetrahydro-2H-cyclopenta [b] [1,3] Oxazolo [5,4-d] pyridine-2,4 (3 H) -dione, 5- (2-chloro-6-ethoxybenzyl) -7-ethyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione , 5- (2-chloro-6-propoxybenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- ( 2-chloro-6-isobutoxybenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro- 6-ethoxybenzyl) -5,6,7,8-tetrahydro-2H-cyclopenta [b] [1,3] oxazolo [5,4-d] pyridine-2,4 (3H) -dione, 5- (2-chloro-6-isopropoxybenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- ( 2-chloro-6- (2,2,2-trifluoroethoxy) benzyl] -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2, 4-dione, 5- (2-chloro-6-ethoxybenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-d] pyridazine-2,4-dione , 5- [2-chloro-6- (2-methoxyethoxy) benzyl] -5,6,7,8-tetrahydro-2H-cyclopenta [b] [1,3] oxazolo [5,4 -d] pyridine-2,4 (3H) -dione, 5- (2 -Chloro-6-ethoxybenzyl) -6,7-dimethyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro -6-ethoxybenzyl) -7-ethyl-6-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro Benzyl) -7-ethyl-3,5-dihydro [1,3] oxazolo [4,5-d] pyridazine-2,4-dione, 5- (2-chloro-6-ethoxybenzyl)- 7-propyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-6-ethoxybenzyl) -7-cyclopropyl -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-5-propoxybenzyl) -7-methyl-3,5 -Dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-5-methoxybenzyl) -7-methyl-3,5-dihydro [ 1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-6-ethoxybenzyl) -6-methyl-3,5-dihydro [1,3] Oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-5-ethoxybenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4 , 5-c] pyridine-2,4-dione, 5- [2- Roro-5- (piperidin-1-ylsulfonyl) benzyl] -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5 -[2-chloro-5- (pyrrolidin-1-ylsulfonyl) benzyl] -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4 -Dione, 5- [2-chloro-6- (cyclopentylmethoxy) benzyl] -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4 -Dione, 5- [2- (benzyloxy) -6-chlorobenzyl] -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione , 5- (2,3-dichloro-6-ethoxybenzyl) -5,6,7,8-tetrahydro-2H-cyclopenta [b] [1,3] oxazolo [5,4-d] pyridine -2,4 [3H] -dione, 5- [2-chloro-5- (trifluoromethyl) benzyl] -7-methyl-3,5-dihydro [1,3] oxazolo [4,5- c] pyridine-2,4-dione and 5- (2-chloro-5-fluorobenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine- 2,4-dione.
[101] Also included are derivatives such as esters, carbamates, aminos, amides, optical isomers and prodrugs.
[102] The invention also relates to pharmaceutical compositions comprising a physiologically acceptable diluent and at least one compound of the invention.
[103] In addition, the present invention discloses that α ₄ β ₁ integrin binds to VCAM-1, including exposing cells expressing α ₄ β ₁ integrin to a VCAM-1 expressing cell in the presence of an inhibitory effective amount of a compound of the present invention. It is about how to suppress doing. VCAM-1 may be present on the surface of vascular endothelial cells, antigen presenting cells or other types of cells. α ₄ β ₁ is white blood cells such as monocytes, lymphocytes, granulocytes; Stem cells; Or on the surface of other cells that naturally express α ₄ β ₁ .
[104] The invention also provides a method of treating a disease state mediated by α ₄ β ₁ binding, including administering an effective amount of a compound of the invention alone or in a formulation to a diseased patient.
[105] Term Definition
[106] As used herein, alone or in combination with another term, the term "alkyl" refers to a C ₁ -C ₁₂ straight or branched chain derived from a saturated hydrocarbon by removal of one hydrogen atom, unless specifically indicated as C _x -C _y , Substituted or unsubstituted, saturated chain radical. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, secondary-butyl, iso-butyl and t-butyl.
[107] The term "alkenyl" as used herein, alone or in combination, refers to a substituted or unsubstituted straight or substituted or unsubstituted branched alkenyl radical containing 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to, ethenyl, E- and Z-pentenyl, decenyl, and the like.
[108] The term "alkynyl" as used herein, alone or in combination, refers to a substituted or unsubstituted straight or substituted or unsubstituted branched alkynyl radical containing 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to, ethynyl, propynyl, propargyl, butynyl, hexynyl, decinyl, and the like.
[109] The term "lower" used before "alkyl", "alkenyl", "alkynyl" or "alkoxy" refers to a C ₁ -C ₆ unit for each functional group. For example, lower alkyl means C ₁ -C ₆ alkyl.
[110] The term "aliphatic acyl" as used herein, alone or in combination with another, refers to the formulas alkyl-C (O)-, alkenyl-C (O)-and alkynyl-C (derived from alkanes, alkenes, or alkyncarboxylic acids). O), where "alkyl", "alkenyl" and "alkynyl" are as defined above. Examples of such aliphatic acyl radicals include, but are not limited to, propionyl, butyryl, valeryl, 4-methylvaleryl, acryloyl, crotyl, propionyl and methylpropionyl.
[111] As used herein, the term “cycloalkyl” refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, norbornyl and acryl Dandelion is included. Cycloalkyl groups are groups consisting of lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide It may be substituted or unsubstituted with one, two or three substituents independently selected from among.
[112] "Cycloalkyl" includes cis or trans forms. Also, the substituent may be at the endo or exo position of the bridged bicyclic system.
[113] The term "cycloalkenyl" as used herein, alone or in combination, refers to a cyclic carbocycle containing 4 to 8 carbon atoms and one or more double bonds. Examples of such cycloalkenyl radicals include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclopentadienyl, and the like.
[114] As used herein, the term “cycloalkylalkyl” refers to a cycloalkyl group bonded to a lower alkyl radical, for example cyclohexylmethyl.
[115] As used herein, the term "halo" or "halogen" refers to I, Br, Cl or F.
[116] The term "haloalkyl" as used herein refers to a lower alkyl radical to which one or more halogen substituents are attached, examples of which include, in particular, chloromethyl, fluoroethyl, trifluoromethyl and pentafluoromethyl.
[117] The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term "alkyl" is as defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, secondary-butoxy, t-butoxy and the like. This includes.
[118] As used herein, the term "alkoxyalkyl" refers to R _y -OR _z where R _y is lower alkyl as defined above and R _z is alkylene (-(CH ₂ ) _w- ), where w is 0 to Is an integer of 6). Representative examples include especially methoxymethyl, methoxyethyl, and ethoxyethyl.
[119] The term "alkenoxy" as used herein, alone or in combination, refers to a radical of the formula alkenyl-O, wherein "alkenyl" is as defined above, provided that the radical is not an enol ether. Examples of suitable alkenoxy include, but are not limited to, allyloxy, E- and Z-3-methyl-2-propenoxy and the like.
[120] The term "alkynoxy" as used herein refers to a radical of the formula alkynyl-O-, provided that the radical is not -inol ether. Examples of suitable alkynyl include, but are not limited to, propargyloxy, 2-butynyloxy and the like.
[121] The term "carboxy" as used herein, means -C (O) O-.
[122] The term "thioalkoxy" refers to a thioether radical of the formula alkyl-S-, where "alkyl" is as defined above.
[123] The term "sulfonamido" as used herein refers to -SO ₂ NH ₂ .
[124] As used herein, the term “carboxaldehyde” refers to —C (O) R, wherein R is hydrogen.
[125] As used herein, the term “carboxamide” or “amide” refers to —C (O) NR _a R _b where R _a and R _b are each independently hydrogen, alkyl or other suitable substituent.
[126] The term "alkoxyalkoxy" as used herein refers to R _c OR _d O [where R _c is lower alkyl as defined above and R _d is alkylene-(CH ₂ ) _{n '} -(where n' is 1-6). Is an integer). Representative examples of alkoxyalkoxy include, in particular, methoxymethoxy, ethoxymethoxy, t-butoxymethoxy.
[127] As used herein, the term “alkylamino” refers to R _e NH—, where R _e is a lower alkyl group, and examples include, in particular, ethylamino, butylamino.
[128] The term "alkenylamino" as used herein, alone or in combination, refers to the formula alkenyl-NH- or (alkenyl) ₂ N-, wherein the term "alkenyl" is as defined above, provided that the radical is Is not an enamine. Examples of such alkenylamine radicals include allylamino radicals.
[129] The term "alkynylamino" as used herein, alone or in combination, refers to the formula alkynyl-NH- or (alkynyl) ₂ N-, wherein the term "alkynyl" is as defined above, provided that the radical is Is not an amine. Examples of such alkynylamino radicals include propargylamino radicals.
[130] The term "dialkylamino" as used herein refers to R _f R _g N-, wherein R _f and R _g are independently selected from lower alkyl, and examples include, in particular, diethylamino and methyl propylamino. have.
[131] The term "alkoxycarbonyl" as used herein, alone or in combination, refers to an alkoxy group as defined above which is attached to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include, in particular, methoxycarbonyl, ethoxycarbonyl and isopropoxycarbonyl.
[132] The term "aryl" or "aromatic" as used herein alone or in combination with another, refers to a substituted or unsubstituted carboxylic aromatic group having about 6 to 12 carbon atoms (e.g., phenyl, naphthyl, indenyl, indanyl) , Azulenyl, fluorenyl and anthracenyl) or heterocyclic aromatic groups containing one or more endocyclic N, O or S atoms (e.g. furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thia Zolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3, 4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-tritianyl, indolinyl, indolyl, isoindoleyl, 3H-indole Reel, indolinyl, benzo [b] furanyl, 2,3-dihydrobenzofuranyl, benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, furinyl, 4H-qui Zinnilyl, isoquinolinyl, cinnaolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthridinyl, pterridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, Phenoxyazinyl, pyrazolo [1,5-c] triazinyl, etc.). "Aralkyl" and "alkylaryl" use the term "alkyl" as defined above. The ring may be substituted in plural.
[133] The term "aralkyl" as used herein, alone or in combination, refers to an aryl substituted alkyl radical, wherein the terms "alkyl" and "aryl" are as defined above. Examples of suitable aralkyl radicals include, but are not limited to, phenylmethyl, phenylethyl, phenylhexyl, diphenylmethyl, pyridylmethyl, tetrazolyl methyl, furylmethyl, imidazolyl methyl, indolylmethyl, thienylpropyl, and the like. This includes.
[134] The term "aralkenyl" as used herein, alone or in combination, refers to an aryl substituted alkenyl radical, wherein the terms "aryl" and "alkenyl" are as defined above.
[135] The term "arylamino" as used herein, alone or in combination, refers to a radical of the formula aryl-NH-, where "aryl" is as defined above. Examples of arylamino radicals include, but are not limited to, phenylamino (anilide), naphthylamino, 2-, 3- and 4-pyridylamino, and the like.
[136] As used herein, "benzyl" refers to C ₆ H ₅ -CH _2- .
[137] As used herein, alone or in combination, the term “biaryl” refers to a radical of the formula aryl-aryl, wherein “aryl” is as defined above.
[138] As used herein, alone or in combination, the term "thioaryl" refers to a radical of the formula aryl-S-, where aryl is as defined above. Examples of thioaryl radicals include thiophenyl radicals.
[139] As used herein, alone or in combination, the term “aroyl” refers to a radical of the formula aryl-CO—, where “aryl” is as defined above. Examples of suitable aromatic acyl radicals include, but are not limited to, benzoyl, 4-halobenzoyl, 4-carboxybenzoyl, niptoyl, pyridylcarbonyl, and the like.
[140] The term "heterocyclyl" as used herein, alone or in combination, refers to a non-aromatic 3- to 10-membered ring containing one or more endocyclic N, O, or S atoms. Heterocycles may be optionally aryl-fused. In addition, heterocycles are especially hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl It may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of oxo, arylsulfonyl and aralkylaminocarbonyl.
[141] As used herein, the term "alkylheterocyclyl" refers to the alkyl group attached to the parent moiety through a heterocyclyl group, examples of which are 2-methyl-5-thiazolyl, 2-methyl-1-pyrrolyl and 5-ethyl-2-thienyl includes, but is not limited to.
[142] As used herein, the term “heterocyclylalkyl” refers to the heterocyclyl group attached to the parent molecular moiety through an alkyl group, examples of which are 2-thienylmethyl, 2-pyridinylmethyl and 2- (1- Piperidinyl) ethyl, including but not limited to.
[143] The term "heterocycloyl" as used herein refers to a radical of the formula heterocyclyl-C (O)-, wherein the term "heterocyclyl" is as defined above.
[144] As used herein, the term "amino" refers to hemi acetals of the formula R _h C (NR _i R _j ) (NR _k R _l )-wherein R _h , R _i , R _j , R _k and R _l are independently Hydrogen, alkyl or other suitable substituent).
[145] The term “ester” as used herein is —C (O) R _m where R _m is hydrogen, alkyl or other suitable substituent.
[146] The term "carbamate" as used herein is a compound based on carbamic acid NH ₂ C (O) OH.
[147] As used herein, the term “optical isomer” refers to compounds that differ only in the stereochemistry of one or more atoms, such as enantiomers, diastereomers and racemates.
[148] Use of the term includes substituted and unsubstituted residues. Substituents include alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyls, nitros, cyanos, carboxys, amines, heteroatoms, lower alkyls, lower alkoxys, lower alkoxycarbonyls, alkoxyalkoxy, acyloxy, halogen, trifluoro Methoxy, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocycle It may be one or more groups such as arylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl or any of the substituents described in the paragraphs above or any of the substituents directly bonded or bound by a suitable linker. Linkers are typically of -C-, -C (O)-, -NH-, -S-, -S (O)-, -O-, -C (O) O- or -S (O) O- It is a short chain of 1 to 3 atoms, in which any combination is included. The ring may be substituted in plural.
[149] The term "electron attraction" or "electron donation" refers to the ability of a substituent to attract or donate electrons relative to hydrogen, if hydrogen is present at the same position in the molecule. These terms are well understood by those skilled in the art and are described in Advanced Organic Chemistry by J. March, 1985, pp. 16-18. The contents of this document are incorporated herein by reference. Examples of electron withdrawing groups include, in particular, halo, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde, carboxamido, aryl, quaternary ammonium, trifluoromethyl, sulfonyl and aryl lower alkanoyl. do. Examples of electron donating groups include, in particular, hydroxy, lower alkyl, amino, lower alkylamino, di (lower alkyl) amino, aryloxy, mercapto, lower alkylthio, lower alkyl mercapto and disulfide. Those skilled in the art will appreciate that such substituents may have electron donating or valence attraction properties under different chemical conditions. In addition, the present invention includes any combination of substituents selected from the above groups.
[150] Most preferred electron donating or electron withdrawing substituents are halo, nitro, alkanoyl, carboxaldehyde, arylalkanoyl, aryloxy, carboxyl, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclyl, guanidine, quaternary Ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di (lower alkyl) amino, amine lower alkyl mercapto, mercaptoalkyl, alkylthio, carboxy Lower alkyl, arylalkoxy, alkanoylamino, alkanoyl (lower alkyl) amino, lower alkylsulfonylamino, arylsulfonylamino, alkylsulfonyl (lower alkyl) amino, arylsulfonyl (lower alkyl) amino, lower alkylcar Voxamide, di (lower alkyl) carboxamide, sulfonamide, lower alkylsulfonamide, di (lower alkyl) sulfonamide, lower alkylsulfonyl, arylsulfonyl and alkyldithio.
[151] As used herein, the term “composition” includes not only products containing a certain amount of a particular ingredient, but also products formed by combining certain ingredients directly or indirectly in a particular amount.
[152] The term "mammal" as used herein includes humans and other animals.
[153] Rings defined as Y in Formulas 1, 2 and 3 may be mono-cyclic heterocycle or aromatic rings or bicyclic rings.
[154] The dotted lines used in Formulas 1, 2, 3, 4 and 6 indicate that the bond at that position may be a single or double bond. For example, the bond between atoms Y and W may be a double bond or a single bond when Y and / or W are substituents such as N, C or CH. Thus, the ring defined by Y in the above formula may be saturated or unsaturated depending on the choice of W and / or Y. In formulas (4) and (6), dashed lines indicate that the nitrogen-containing ring contains a double bond at the optionally indicated position.
[155] In the above formulae, certain R groups potentially substitute several of their linking rings. R ¹⁹ , R ²⁰ , R ²¹ , R ²³ , R ²⁷ , R ²⁸ , R ²⁹ and R ²⁵ each substitute one or more of these linking rings. For example, for R ¹⁹ , when c is 0, the linking ring is unsubstituted and has a hydrogen atom in the C-2 and C-4 position; In the case of R ²³ , hydrogen is located at C-2-C-5 when g is zero.
[156] Suitable substituents for the aryl, alkyl, cycloalkyl, heterocyclyl groups or for the ring defined by Y and W in the formulas above are alcohols, amines which, when present, are bonded directly or via suitable linkers , Heteroatoms or any combination of aryl, alkoxy, alkoxyalkoxy, alkyl, cycloalkyl or heterocyclyl groups. The linker is typically one to three, including all combinations of C, C═O, CO ₂ , O, N, S, S═O, SO ₂ such as ether, amide, amine, urea, sulfamide, sulfonamide It is a short chain of atoms.
[157] For example, in the above formula, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are not limited to, but independently hydrogen, alkyl, phenyl, thienylmethyl, isobutyl, n -Butyl, 2-thienylmethyl, 1,3-thiazol-2-yl-methyl, benzyl, thienyl, 3-pyridinylmethyl, 3-methyl-1-benzothiophen-2-yl, allyl, 3 -Methoxybenzyl, propyl, 2-ethoxyethyl, cyclopropylmethyl, benzylsulfanylmethyl, benzylsulfonylmethyl, phenylsulfanylmethyl, phenethylsulfanylmethyl, 3-phenylpropylsulfanylmethyl, 4-(( 2-toluidinocarbonyl) amino) benzyl, 2-pyridinylethyl, 2- (1H-indol-3-yl) ethyl, 1H-benzylimidazol-2-yl, 4-piperidinylmethyl, 3 -Hydroxy-4-methoxybenzyl, 4-hydroxyphenethyl, 4-aminobenzyl, phenylsulfonylmethyl, 4- (acetylamino) phenyl, 4-methoxyphenyl, 4-aminophenyl, 4-chlorophenyl , (4- (benzylsulfonyl) amino) phenyl, 4- (methylsulfonyl) amino) phenyl, 2-aminophenyl, 2-methylphenyl, Isopropyl, 2-oxo-1-pyrrolidinyl, 3- (methylsulfanyl) propyl, (propylsulfanyl) methyl, octylsulfanylmethyl, 3-aminophenyl, 4-((2-toluidinocarbonyl ) Amino) phenyl, 2-((methylbenzyl) amino) benzyl, methylsulfanylethyl, hydroxy, chloro, fluoro, bromo, ureido, amino, methanesulfonylamino, acetylamino, ethylsulfanylmethyl, 2-chlorobenzyl, 2-bromobenzyl, 2-fluorobenzyl, 2-chloro-6-fluorobenzyl, 2-chloro-4-fluorobenzyl, 2,4-dichlorobenzyl, 2-chloro-6- Methoxybenzyl, 2-cyanobenzyl, 2,6-difluorobenzyl, 2-chloro-5- (trifluoromethyl) benzyl, 2-chloro-6-methylbenzyl, 2,6-dimethoxybenzyl, 2-chloro-5- (methylsulfonyl) benzyl, 2-chloro-6-cyanobenzyl, 2-chloro-6-ethoxybenzyl, 2-chloro-5-methoxybenzyl, 2-chloro-5-fluor Lobenzyl, 5-chloro-2-fluorobenzyl, ethyl, propyl, butyl, pentyl, cyclopropyl, tert-butyl Mino, propylamino, 4-methyl-1-piperazinyl, 1-azetidinyl, 4-morpholino, (4-carboxyphenyl) amino, pivaloylamino, ((tert-butylamino) carbonyl ) Amino, trifluoromethyl, benzyloxy, 2- (2-methoxyethoxy) ethoxy, 2- (2- (2-methoxyethoxy) ethoxy and 2- (2- (2- (2) -Methoxyethoxy) ethoxy) ethoxy) ethoxy.
[158] R ⁴ substituents in the above formulas include, but are not limited to, 1,3-benzodioxol-5-yl, 1-naphthyl, thienyl, 4-isobutoxyphenyl, 2,6-dimethylphenyl, allyloxyphenyl, 3-bromo-4-methoxyphenyl, 4-butoxyphenyl, 1-benzofuran-2-yl, 2-thienylmethyl, phenyl, methylsulfanyl, phenylsulfanyl, phenethylsulfanyl, 4-bro Mo-2-thienyl, 3-methyl-2-thienyl, 4-methylphenyl, 3,5-bis (methyloxy) phenyl, 4- (methyloxy) phenyl, 4-fluorophenyl, 3- (methyloxy ) Phenyl, 3,4,5-tris (methyloxy) phenyl, 2,3-dihydro-1-benzofuran-5-yl, 3-fluorophenyl, 4- (trifluoromethyl) phenyl, 4- Fluoro-3- (trifluoromethyl) phenyl, 4- (1,1-dimethylethyl) phenyl, 3,5-dimethylphenyl, 4-hydroxyphenyl, 3,4-dimethylphenyl, 3-methyl-4 -(Methyloxy) phenyl, 4-hydroxy-3-methylphenyl, 3-methylphenyl, 2,3-dihydro-inden-5-yl, 2-methylphenyl, 2,6-bis (methyloxy) phenyl, 2, 6-dihydrophenyl, 4- Lorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 4-((trifluoromethyl) oxy) phenyl, 4-ethylphenyl, 4- (ethyloxy) phenyl, methyl, 2-propyl, 4,5 -Dihydro-1,3-oxazol-2-yl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethoxy) phenyl, 2,3-dihydro-1,4-benzodioxine- 6-yl, 7-methoxy-1,3-benzodioxol-5-yl, 3-ethoxy-4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 3- Ethoxyphenyl, 3-methoxy-4-methylphenyl, 3,5-dimethoxy-4-methylphenyl, 3-propoxyphenyl, 3-butoxyphenyl, 3- (2-methoxyethoxy) phenyl, 3, 4-dipropoxyphenyl, 3- (difluoromethoxy) phenyl, 2-naphthyl, 3-isopropoxyphenyl, 1-methyl-1H-indol-5-yl, 2,3-dihydro-1- Benzofuran-5-yl, 1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl, 3- (trifluoromethoxy) phenyl, 1-methyl-1H -Indol-6-yl, 3- (cyclopropoxy) phenyl, 3- (cyclopropylmethoxy) phenyl, 3- (difluoro Methoxy) phenyl, 3- (1,1,2,2-tetrafluoroethoxy) phenyl, 1-ethyl-1H-indol-5-yl, 3- (diethylamino) phenyl, 6-methoxy- 2-naphthyl, 3-[(methylsulfonyl) amino] phenyl, 3- [methyl (methylsulfonyl) amino] phenyl, 3- [ethyl (methylsulfonyl) amino] phenyl, 1H-indol-5-yl , 3-fluoro4-methoxyphenyl, and 3- (difluoromethyl) phenyl.
[159] Two independent R ¹ , R ² , R ³ or R ⁵ groups can be linked together to form a ring.
[160] R ⁴ and R ¹¹ are joined to form rings, in particular 1-pyrrolidino, 1-piperidino, 4-methyl-1-piperazino, 4-acetyl-1-piperazino and 4-morpholino can do.
[161] R ⁹ and R ¹⁰ may be linked to form rings, in particular cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[162] Abbreviation
[163] The meanings of the abbreviations used in the following schemes and examples are as follows:
[164] BOC: t-butyloxycarbonyl; DMF: dimethylformamide; THF: tetrahydrofuran; DME: dimethoxyethane; DMSO: dimethyl sulfoxide; NMM: N-methylmorpholine; DIPEA: diisopropylethylamine; CDI: 1,1′-carbonyldiimidazole, TBS: tris-buffered saline; Ms: methanesulfonyl; TMEDA: N, N, N ', N'-tetramethylethylenediamine; DCE: 1,2-dichloroethane; NCS: N-chlorosuccinimide; NBS: N-bromosuccinimide; DPPA: diphenylphosphoryl azide; DEAD: diethyl azodicarboxylate; m-CPBA: 3-gloperoxybenzoic acid; TFAA: trifluoroacetic anhydride; DCM: dichloromethane; LHMDS: lithium bis (trimethylsilyl) amide; And Cbz: benzyloxycarbonyl. The abbreviations for amino acids are as follows: C: L-cysteine; D: L-aspartic acid; E: L-glutamic acid; G: glycine; H: L-histidine; I: L-isoleucine; L: L-leucine; N: L-asparagine; P: L-proline; Q: L-glutamine; S: L-serine; T: L-threonine; V: L-valine; And W: L-tryptophan.
[165] Examples of processes that can be used to synthesize the compounds of the formulas described above can be shown in the following schemes. Details of representative compounds according to the invention are described in the Examples below.
[166] Scheme 1 below depicts the process described in Example 1.
[167]
[168] Scheme 2 depicting the process of Example 2 is as follows:
[169]
[170] Scheme 3 depicting the process of Example 3 is as follows:
[171]
[172] Scheme 4 depicting the process of Example 4 is as follows:
[173]
[174] Scheme 5 depicting the process of Example 5 is as follows:
[175]
[176] Scheme 6 depicting the process of Example 6 is as follows:
[177]
[178] Scheme 7 depicting the process of Example 7 is as follows:
[179]
[180] Scheme 8 depicting the process of Example 8 is as follows:
[181]
[182] Scheme 9 depicting the process of Example 9 is as follows:
[183]
[184] Scheme 10 depicting the process of Example 10 is as follows:
[185]
[186] Scheme 11 depicting the process of Example 11 is as follows:
[187]
[188] Scheme 12 depicting the process of Example 12 is as follows:
[189]
[190] Scheme 13 depicting the process of Example 13 is as follows:
[191]
[192] Scheme 14 depicting the process of Example 14 is as follows:
[193]
[194] Scheme 15 depicting the process of Example 15 is as follows:
[195]
[196] Scheme 16 depicting the process of Example 16 is as follows:
[197]
[198] Scheme 17 depicting the process of Example 17 is as follows:
[199]
[200] Scheme 18 depicting the process of Example 18 is as follows:
[201]
[202] Scheme 19 depicting the process of Example 19 is as follows:
[203]
[204] Scheme 20 depicting the process of Example 20 is as follows:
[205]
[206] Scheme 21 depicting the process of Example 21 is as follows:
[207]
[208] Scheme 22 depicting the process of Example 22 is as follows:
[209]
[210] Scheme 23 depicting the process of Example 23 is as follows:
[211]
[212] Scheme 24 depicting the process of Example 24 is as follows:
[213]
[214] Scheme 25 depicting the process of Example 25 is as follows:
[215]
[216] Scheme 26 depicting the process of Example 26 is as follows:
[217]
[218] Scheme 27 depicting the process of Example 27 is as follows:
[219]
[220] Scheme 28 depicting the process of Example 28 is as follows:
[221]
[222] Scheme 29 depicting the process of Example 29 is as follows:
[223]
[224] Scheme 30 depicting the process of Example 30 is as follows:
[225]
[226] Scheme 31 depicting the process of Example 31 is as follows:
[227]
[228]
[229]
[230]
[231]
[232]
[233]
[234]
[235]
[236]
[237]
[238]
[239] The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The term "pharmaceutically acceptable salts" means salts that are suitable for use in contact with human and lower animal tissues without inducing excessive toxicity, irritation, allergic reactions, etc. under pure medical judgment, and with a reasonable benefit / risk ratio. do. Pharmaceutically acceptable salts are well known in the art. See, eg, S. M. Berge et al., J. Pharmaceutical Sciences, 1977, 66: 1], describe in detail the pharmaceutically acceptable salts. Salts can be prepared in situ during the final separation and purification of the compounds of the invention or separately by reacting the free base functional groups with a suitable organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerol Lophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothionate), lactate, maleate, methanesulfonate , Nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate , Phosphate, glutamate, bicarbonate, p-toluenesulfonate and udecanoate Included. In addition, basic nitrogen-containing groups include lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; Dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; Long chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide; Quaternized with agents such as arylalkyl halides such as benzyl and phenethyl bromide. This gives a water soluble or oil soluble or dispersible product. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid.
[240] Basic addition salts may be selected from the group containing a carboxylic acid-containing moiety in situ during the final separation and purification of a compound of the invention in a suitable base (e.g., a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation) or ammonia or It can be prepared by reaction with an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal cations such as lithium, sodium, potassium, calcium, magnesium and aluminum salts, and nontoxic quaternary ammonia and amine cations (especially ammonium, in particular Tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium and ethylammonium). Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.
[241] Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and aspirants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and other necessary preservatives, buffers or propellants. Eye drops, eye ointments, powders and solutions also fall within the scope of the present invention.
[242] The actual dosage of the active ingredient contained in the pharmaceutical composition of the present invention may vary depending on the amount of the active compound, the composition, and the mode of administration effective to achieve the desired therapeutic response in a particular patient. The dosage chosen depends on the activity of the particular compound, the route of administration, the severity of the disease condition, and the condition and medical history of the patient. However, it is common in the art to establish a dosage of a compound at a level lower than necessary to achieve the desired therapeutic effect and then gradually increase until the desired effect is achieved.
[243] The therapeutically effective amounts of the compounds according to the invention for use in these and other treatments may be used in pure form or, if present in such form, in pharmaceutically acceptable salt, ester or prodrug form. Alternatively, the compound may be administered as a pharmaceutical composition containing the compound together with one or more pharmaceutically acceptable excipients. By "therapeutically effective amount" of a compound of the present invention is meant an amount of the compound sufficient to treat the disease at a reasonable benefit / risk ratio applicable to medical treatment. However, it will be understood by those skilled in the art that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician under reasonable medical judgment. Specific therapeutically effective dosages for certain patients include the disease and its severity; The activity of the specific compound employed; The specific composition used; The age, body weight, general health, sex and diet of the patient; The time of administration, route of administration, and rate of excretion of the specific compound employed; Duration of treatment; It will be determined according to various factors, including drugs used with or concurrently with the specific compound used, and other factors well known in the medical arts. For example, in the art, it is common to set a dose of a compound at a level lower than necessary to achieve the desired therapeutic effect and then gradually increase until the desired effect is achieved.
[244] The total daily dose of a compound according to the invention administered to a human or lower animal is from about 0.0001 to about 1000 mg / kg / day. More preferred dosages for the purpose of oral administration are from about 0.001 to about 5 mg / kg / day. If desired, the effective daily dose may be divided into several doses for the purpose of administration. As a result, a single dosage composition may contain divided doses that make up the daily dosage.
[245] The present invention also provides pharmaceutical compositions containing a compound of the invention formulated with one or more pharmaceutically acceptable non-toxic carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
[246] The pharmaceutical compositions of the present invention may be administered to humans or other mammals orally, rectally, parenterally, subretinal, intravaginal, intraperitoneal, topical (powders, ointments or drops), oral, oral or nasal. have. As used herein, the term “parenteral” means a mode of administration, including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
[247] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a physiologically acceptable diluent. The present invention particularly relates to compositions with one or more physiologically acceptable diluents, carriers, adjuvants or vehicles (collectively referred to as diluents) for parenteral injection, intranasal delivery, oral administration in solid or liquid form, rectal or topical administration. One or more compounds as formulated therein.
[248] The composition may also be delivered via a catheter for topical delivery to the target site via an intra-tubular stent (tubular device consisting of a fine wire network) or a biodegradable polymer. In addition, the compositions may complex with ligands such as antibodies for targeted delivery.
[249] Compositions suitable for parenteral injection can include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), vegetable oils (olive oils), injectable organic esters (e.g. ethyl oleate) and these Suitable mixtures of are included.
[250] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. Various antibacterial and antifungal agents (eg, parabens, chlorobutanol, phenol, sorbic acid, etc.) can inhibit the action of microorganisms. It may also be desirable to include osmotic agents such as sugars, sodium chloride, and the like. Absorption delaying agents (eg, aluminum monostearate and gelatin) may be used to delay absorption of the injectable drug.
[251] Suspending agents, in addition to the active compounds, suspending agents (e.g., ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof And the like).
[252] In some cases, to sustain the effect of the drug, it may be desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with low water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, will depend upon crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered drug form is achieved by dissolving or suspending the drug in an oil vehicle.
[253] Injectable depot forms are prepared by forming the microcapsule matrix of the drug into a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of release of the drug can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with the body tissue.
[254] Injectable formulations can be sterilized, for example, by filtration through bacterial-bearing filters or by incorporation of the sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable media immediately prior to use. have.
[255] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is one or more inert pharmaceutically acceptable excipients or carriers (eg sodium citrate or dicalcium phosphate) and / or a) fillers or extenders (eg starch, lactose, sucrose, Glucose, mannitol and silicic acid), b) binders (e.g. carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic), c) humectants (e.g. glycerol), d) disintegrants (e.g. , Agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate), e) liquid retardants (e.g. paraffin), f) absorption accelerators (e.g. quaternary ammonium compounds), g) wetting agents (e.g. Cetyl alcohol and glycerol monostearate), h) absorbents (eg kaolin and bentonite clay) and i) lubricants (eg talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and It may be mixed with a mixture of). In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
[256] Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.
[257] Solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as coatings well known in enteric skin and other pharmaceutical fields. They may optionally contain a clouding agent and may also be formulated to release only the active ingredient or preferentially release the active ingredient in a randomly delayed manner at certain sites of the intestine. Examples of embedding compositions that can be used include polymeric substances and waxes.
[258] The active compound may also be present in microcapsule form with one or more of the aforementioned excipients as required.
[259] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solvents, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may be water or other solvents, solubilizers and emulsifiers (e.g. ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol Dimethyl formamide, oils (especially cottonseed oil, peanuts, corn oil, germ oil, olive oil, castor oil and sesame oil), fatty acid esters of glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan and mixtures thereof It may contain inert diluents commonly used in the art.
[260] In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents and fragrances.
[261] Compositions for rectal or vaginal administration are preferably suitable non-irritating adjuvants or carriers (e.g. cocoa butter, polyethylene glycol or suppositories) which release the active compound by dissolving the compound of the invention in a solid at room temperature or liquid at body temperature to release the active compound. And waxes that can be prepared by mixing.
[262] The compounds of the present invention can also be administered in the form of liposomes. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by single- or multi-lamellae hydrated liquid crystals dispersed in an aqueous medium. Physiologically acceptable, non-toxic and acid-degradable lipids capable of forming liposomes are also available. The present compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidyl choline (lecithin) used separately or together.
[263] Methods for forming liposomes are described, for example, in Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33et seq.].
[264] As used herein, the term “pharmaceutically acceptable prodrug” is suitable for use in contact with tissues of humans and lower animals without rational toxicities, irritation and allergic reactions, and reasonable benefit / risk ratios under reasonable medical judgment. In addition to the prodrugs of the compounds of the invention effective for the intended use, the zwitterion forms of the compounds of the invention, where possible, are indicated. The prodrugs of the present invention can be rapidly converted into the parent compound of the above formula in vivo, for example by hydrolysis in the blood. For details, see T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). The contents of this document are incorporated herein by reference.
[265] Compounds of the invention formed by in vivo conversion of different compounds administered to a mammal are also within the scope of the invention.
[266] The compounds of the present invention may exist as stereoisomers in which asymmetric or chiral centers exist. These stereoisomers are R or S depending on the arrangement of the peripheral substituents of chiral carbon atoms. The present invention includes several stereoisomers and mixtures thereof. Stereoisomers include enantiomers, diastereomers and mixtures of enantiomers and diastereomers. Individual stereoisomers of the compounds of the present invention can be prepared by synthesis from commercially available starting materials having asymmetric or chiral centers, or by preparing racemic mixtures and then separating as known to those skilled in the art. These separation methods include (1) separation of the resulting diastereomeric mixture by linkage, recrystallization or chromatography of the enantiomeric mixture, and free of the optically pure product from the auxiliary or (2) chiral chromatography columns. It can be exemplified by the direct separation of the mixture of optical enantiomers in the phase.
[267] Mixtures of the present invention may exist in unsolvated as well as solvated forms and include hydrated forms such as hemi-hydrates. In general, solvated forms with pharmaceutically acceptable solvents such as water and ethanol are equivalent to unsolvated forms for the purposes of the present invention.
[268] In another aspect, the present invention includes a method of inhibiting the binding of α ₄ β ₁ to VCAM-1. The method of the invention can be used in vivo or in vitro. According to the method of the present invention, cells expressing α ₄ β ₁ integrin are exposed to cells expressing VCAM-1 in the presence of an effective inhibitory amount of a compound of the present invention.
[269] Cells expressing α ₄ β ₁ integrins may be native leukocytes, mast cells, or other cell types that naturally express α ₄ β ₁ integrins on the cell surface, or polynucleotides encoding α ₄ β ₁ integrins, such as genomes. Cells transfected with an expression vector containing DNA or cDNA). In a particularly preferred embodiment, α ₄ β ₁ integrin is present on the surface of leukocytes such as monocytes, lymphocytes or granulocytes (eg basophils or eosinophils).
[270] Cells expressing VCAM-1 may be natural cells (eg endothelial cells) or cells transfected with an expression vector containing polynucleotides encoding VCAM-1. Methods of preparing transfected cells expressing VCAM-1 are well known in the art.
[271] When VCAM-1 is present on the cell surface, expression of VCAM-1 is preferably induced by inflammatory cytokines such as tumor necrosis factor-α, interleukin-4 and interleukin-1β.
[272] When cells expressing α ₄ β ₁ integrin and VCAM-1 are present in a living organism, the compounds of the present invention are administered to the living organism in an effective amount. Preferably the compound is present in the pharmaceutical composition of the present invention. The methods of the invention are particularly useful for treating diseases associated with unregulated migration of leukocytes to damaged tissue. Such diseases include, but are not limited to, asthma, atherosclerosis, rheumatoid arthritis, allergies, multiple sclerosis, lupus, inflammatory bowel disease, transplant rejection, contact hypersensitivity, type I diabetes, leukemia and brain cancer. Administration is preferably accomplished via intravascular, subcutaneous, intranasal, transdermal or oral delivery.
[273] In addition, the present invention provides a method for selectively inhibiting the binding of α ₄ β ₁ integrin to a protein comprising exposing the α ₄ β ₁ integrin in the presence of the compounds of the invention of an effective inhibiting amount of a protein. In a preferred embodiment, α ₄ β ₁ integrins are expressed on the surface of natural cells or cells transformed to express α ₄ β ₁ integrins.
[274] The protein to which the α ₄ β ₁ integrin binds may be expressed on the cell surface or part of an extracellular matrix. Particularly preferred proteins are fibronectin or invacin.
[275] The ability of the compounds of the invention to inhibit binding is described in detail in the Examples below. These examples are presented to describe preferred embodiments and usefulness of the present invention and should not be construed as limiting the invention as described in the claims appended hereto.
[276] Example 1
[277] (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-ethyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- Synthesis of 3- (4-methylphenyl) propanoic acid (10)
[278] Step 1 : Compound 1 (20.8 g, 135 mmol) was dissolved in methanol (270 mL) and palladium on carbon (10% Pd dry weight, degussa type E101 NE / W, about 50% water content, 5.75 g, 2.7 mmol Pd) Was added. The atmosphere was replaced with hydrogen (repeated hydrogen in vacuum and balloon five times) and the mixture was stirred overnight and then filtered. The filtrate was concentrated in vacuo and the residue was taken in a 1: 1 hexane: ethyl acetate mixture and washed with a 4: 1 mixture of water and saturated NaHCO ₃ , saturated NaHCO ₃ and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 2 (12.43 g, 74%) as a white solid. This material was used without further purification.
[279] Step 2 : Compound 2 (2.64 g, 21.3 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0 ° C. The cold solution was treated sequentially with triethylamine (3.6 mL, 25.6 mmol) and trimethylacetyl chloride (2.90 mL, 23.4 mmol). The solution was stirred at rt for 6 h and then refluxed overnight. The mixture was partitioned between dichloromethane and aqueous NaOH (2N). The organic layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate was concentrated to give compound 3 (3.33 g, 75%).
[280] Step 3 : Compound 3 (0.50 g, 2.4 mmol) was dissolved in anhydrous THF (9.6 mL) and TMEDA (1.1 mL, 7.2 mmol) under anhydrous nitrogen atmosphere. The resulting solution was cooled to −20 to −10 ° C. and n-butyllithium (1.6M in hexanes, 2.25 mL) and t-butyllithium (1.7M in pentane, 2.1 mL) were added dropwise successively by syringe. After 30 minutes the bath temperature was raised to -5 to 0 ° C. and ethyl iodide (0.77 mL, 9.6 mmol) was treated with a syringe. The solution was stirred at 0 ° C. for 2 hours and then at room temperature overnight. The mixture was quenched with methanol and concentrated to dryness. The residue was purified by filtration through silica gel, eluting with 3: 1 hexanes: ethyl acetate, and recrystallized from hexanes to give compound 4 (0.32 g, 56%).
[281] Step 4 : Compound 4 (0.32 g, 1.3 mmol) was dissolved in glacial acetic acid (4.5 mL) and treated with potassium iodide (0.65 g, 3.9 mmol). The resulting mixture was heated for 1.0 h in an oil bath adjusted to 115 ° C. The mixture was cooled, diluted with water and then adjusted to pH 6 with 2N NaOH and 2N HCl. The mixture was extracted with chloroform (4 times). The combined extracts were washed with aqueous sodium thiosulfate, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 5 (0.25 g, 86%) as a white solid. This material was used without further purification.
[282] Step 5 : Compound 5 (0.25 g, 1.1 mmol) was dissolved in THF (45 mL) and a solution of potassium bis (trimethylsilyl) amide (0.5 M in toluene, 2.7 mL) was added dropwise at 0 ° C. The resulting solution was treated with 2-chlorobenzylbromide (0.16 mL, 1.2 mmol) and the solution was warmed to room temperature overnight. The mixture was partitioned between 2N HCl and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was chromatographed (SiO ₂ , hexane: ethyl acetate from elution gradient 4: 1 to 2: 1) to afford compound 6 (0.16 g, 41%).
[283] Step 6 : Compound 6 (0.16 g, 0.46 mmol) was suspended in 1: 1 water: concentrated HCl (4.6 mL). The suspension was refluxed for 4 hours to dissolve the compound. The mixture was cooled down, diluted with water and then extracted with diethyl ether. The aqueous layer was basified with excess saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 7 (0.081 g, 67%).
[284] Step 7 : Compound 7 (0.080 g, 0.30 mmol) was dissolved in 1,2-dichloroethane (1.2 mL) and DIPEA (0.115 mL, 0.66 mmol) and cooled to 0 ° C. The cold solution was quickly treated with a phosgene solution (1.93 M in toluene, 0.170 mL, 0.33 mmol). After 30 minutes a solution of compound 8 (0.068 g, 0.33 mmol) in 1,2-dichloroethane (0.5 mL) was quickly added by syringe. The resulting mixture was heated to 55 ° C. for 1 hour. The mixture was partitioned between dichloromethane and 2N HCl. The organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to give compound 9 (0.110 g, 74%).
[285] Step 8 : Compound 9 (0.11 g, 0.22 mmol) was dissolved in 2: 1 THF: water (0.88 mL) and treated with 2N NaOH solution (0.33 mL). Methanol was added dropwise until a homogeneous solution was obtained. The mixture was stirred for 20 minutes, diluted with water and washed with ethyl ether. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to give (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-ethyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Amino} -3- (4-methylphenyl) propanoic acid (10, 0.095 g, 92%) was obtained.
[286] Example 2
[287] (3S) -3-{[({6-methyl-2-oxo-1- (phenylmethyl) -4-[(phenylmethyl) oxy] -1,2-dihydro-3-pyridinyl} amino) carbo Synthesis of Nyl] amino} -3- (4-methylphenyl) propanoic acid (15)
[288] Step 1 : Benzyl bromide (2.31 g, 13.5 mmol) was added to a suspension of compound 11 (1.0 g, 5.9 mmol) and K ₂ CO ₃ (2.40 g, 17.6 mmol) in acetone (50 mL). After refluxing overnight the reaction was cooled and the mixture was partitioned between ethyl acetate and saturated NaHCO ₃ . The organic layer was washed with dilute HCl and brine, dried over magnesium sulfate, filtered and the filtrate was concentrated to give compound 12 (1.60 g, 80%).
[289] Step 2 : Compound 12 (0.30 g, 0.86 mmol), zinc powder (0.30 g, 4.6 mmol) and saturated aqueous NH ₄ Cl (0.30 mL) were mixed in MeOH (18 mL). The mixture was stirred for 1 h at rt before further zinc (0.30 g, 4.6 mmol) was added. The resulting heterogeneous mixture was refluxed overnight. The hot mixture was filtered and the filtrate was concentrated under reduced pressure, then the residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO ₃ and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 13 (0.18 g, 66%).
[290] Step 3 : Compound 13 (0.30 g, 0.94 mmol) and DIPEA (0.40 mL, 2.3 mmol) were dissolved in CH ₂ Cl ₂ and the mixture was cooled to 0 ° C. To this solution was added dropwise phosgene (1.9 M in toluene, 0.55 ml, 1.0 mmol). The reaction mixture was stirred at 0 ° C. for 15 min and then compound 8 (0.19 g, 0.94 mmol) in CH ₂ Cl ₂ (2 mL) was added. The resulting solution was stirred at rt overnight then poured into ethyl acetate and washed with saturated aqueous NaHCO ₃ , 1N HCl and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with hexanes: ethyl acetate, increasing from 1: 1 to 1: 2 to give compound 14 (0.33 g, 64%).
[291] Step 4 : A solution of compound 14 (0.33 g, 0.6 mmol) in THF (6 mL) was treated with 2N NaOH (2 mL). MeOH was added until a homogeneous solution was obtained. The reaction mixture was stirred at rt for 30 min and poured into water (50 mL). The aqueous layer was washed with diethyl ether (twice) and then acidified with 1N HCl. The aqueous layer was extracted with ethyl acetate (twice). The combined ethyl acetate extracts were washed with brine (twice), dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (3S) -3-{[({6-methyl-2-oxo-1- (phenylmethyl) -4-[(phenylmethyl) oxy] -1,2-dihydro-3- Pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid (15, 0.26 g, 90%) was obtained as a gray solid. Melting point: 124-126 ° C.
[292] Example 3
[293] (3S) -3-{[({4-amino-1-[(2-chlorophenyl) methyl] -6-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Synthesis of amino} -3- (4-methylphenyl) propanoic acid (22)
[294] Step 1 : To a solution of compound 11 (10.00 g, 58.8 mmol) in anhydrous DMF (120 mL) at 0 ° C. was added NaH (60% dispersion in mineral oil, 5.40 g, 135 mmol). The mixture was stirred at 0 ° C. for 15 minutes before 2-chlorobenzylchloride (12.3 g, 76.4 mmol) was added. After stirring at 55 ° C. overnight, the mixture was poured into ice water and washed twice with ethanol. The aqueous layer was acidified and the resulting precipitate was filtered to yield compound 16 (14.7 g, 85%).
[295] Step 2 : In a flask containing Compound 16 (8.00 g, 28.6 mmol) sealed with a rubber stopper, POCl ₃ (30.0 ml, 322 mmol) was added by syringe at room temperature under anhydrous nitrogen atmosphere. The nitrogen line was removed and the reaction mixture was stirred at 70 ° C. overnight, then poured onto ice (300 ml) and stirred for 30 minutes. The resulting mixture was extracted with dichloromethane (300 ml) and the organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 17 (7.3 g, 86%) as a dark brown solid.
[296] Step 3 : A solution of compound 17 (2.1 g, 7.05 mmol), methanol (55 ml) and aqueous ammonium hydroxide (28-30%, 70.0 ml, 1.14 mol) was added to a 250 ml flask equipped with a rubber stopper with a balloon and a condenser. Was added. The reaction mixture was heated to 65 [deg.] C. for 60 hours only by opening the balloon. The mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 18 (1.5 g, 76%) as a brown solid.
[297] Step 4 : To a solution of compound 18 (0.3 g, 1.02 mmol) in methanol (50 ml) at room temperature was added saturated aqueous ammonium chloride (2 ml) and zinc dust (0.30 g, 4.6 mmol) successively. After stirring for 30 minutes at room temperature additional zinc was added (0.30 g, 4.6 mmol) and the reaction mixture was refluxed overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 1N NaOH. The solution was filtered and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford compound 19 (0.21 g, 78%) as a brown solid.
[298] Step 5 : A solution of compound 19 (0.10 g, 0.38 mmol), NMM (0.040 mL, 0.38 mmol) and compound 20 (0.14 g, 0.38 mmol) in anhydrous DMF (5 mL) was heated to 50 ° C. overnight. The mixture was cooled and diluted with ethyl acetate (60 mL). The organic layer was washed with 0.5N NaOH (3 × 30 mL) and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel, eluting with CHCl ₃ : MeOH, increasing from 9: 1 to 17: 3 to give compound 21 (0.120 g, 65%) as a yellow foam.
[299] Step 6 : A solution of compound 21 (0.120 g, 0.25 mmol) in THF (6 mL) was treated with 2N NaOH (2 mL). Methanol was added until a homogeneous solution was obtained. The reaction mixture was stirred at room temperature for 30 minutes and poured into water (50 ml). The aqueous layer was washed with diethyl ether (twice) and then acidified with 1N HCl. The aqueous layer was extracted with ethyl acetate (twice). The combined ethyl acetate extracts were washed with brine (twice), dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (3S) -3-{[({4-amino-1-[(2-chlorophenyl) methyl] -6-methyl-oxo-1,2-dihydro-3-pyridinyl} Amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid (22, 0.100 g, 89%) was obtained as a gray solid. Melting point: 145-147 ° C.
[300] Example 4
[301] (3S) -3-[({[1-[(2-chlorophenyl) methyl] -4- (methyloxy) -2-oxo-1,2-dihydro-3-pyridinyl] amino} carbonyl) Synthesis of Amino] -3- (4-methylphenyl) propanoic acid
[302] Step 1 : To a solution of compound 23 (10.00 g, 64.0 mmol) in dry DMF (130 mL) at 0 ° C. was added NaH (60% dispersion in mineral oil, 5.90 g, 147 mmol). The mixture was stirred at 0 ° C. for 15 minutes before 2-chlorobenzylchloride (13.4 g, 83.3 mmol) was added. After stirring at 55 ° C. overnight, the mixture was poured into ice water and washed with ethanol (twice). The aqueous layer was acidified and the resulting precipitate was filtered to give compound 24 (13.5 g, 75%).
[303] Step 2 : A suspension of compound 24 (1.0 g, 3.6 mmol), K ₂ CO ₃ (0.85 g, 6.2 mmol) and MeI (1.18 g, 8.3 mmol) in acetone (20 mL) was refluxed overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO ₃ , 1N HCl and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 25 (0.74 g, 70%).
[304] (3S) -3-[({[1-[(2-chlorophenyl) methyl] -4- (methyloxy) -2-oxo-1,2-di from Compound 25 according to the procedure described in Example 3 Hydro-3-pyridinyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid was prepared. MS: calculated: (M + H) ⁺ = 469.93; Found: (M + H) ⁺ = 470.01.
[305] Example 5
[306] (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-fluoro-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} Synthesis of -3- (4-methylphenyl) propanoic acid
[307] Step 1 : Compound 3 (0.65 g, 3.1 mmol) was dissolved in dry THF (12.4 mL) and TMEDA (0.90 mL, 6 mmol) under anhydrous nitrogen atmosphere. The resulting solution was cooled to −15 to −10 ° C. and n-butyllithium (1.6M in hexanes, 7.75 mL, 12.4 mmol) was added dropwise by syringe. After 1.5 h, a solution of N-fluorobenzenesulfonimide (1.07 g, 3.4 mmol) in THF (5 mL) was added dropwise to the cooling solution by syringe. The solution was stirred at 0 ° C. for 1 hour and then at room temperature for 3 hours. The mixture was quenched with water and extracted with chloroform (4 times). The combined organic extracts were washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography (SiO ₂ , plug gel, 4: 1 to 3: 1 hexanes: ethyl acetate) to give compound 26 (0.177 g, 25%).
[308] (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-fluoro-2-oxo-1,2-dihydro- from Compound 26 according to the procedure described in Example 1 3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid was prepared. MS: calculated: (M + H) ⁺ = 458.12; Found: (M + H) ⁺ = 458.01.
[309] Example 6
[310] (3S) -4-chloro-3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- Synthesis of 3- (4-methylphenyl) propanoic acid
[311] Step 1 : Compound 3 (0.65 g, 3.1 mmol) was dissolved in THF (21 mL) and TMEDA (1.20 mL, 7.75 mmol) and cooled to -15 ° C. The solution was treated with n-butyllithium (1.6 M in hexanes, 4.8 mL, 7.8 mmol). The mixture was kept between -20 and -10 ° C for 1 hour and cooled to -78 ° C. The instrument was placed under a positive outflow of nitrogen and solid N-chlorosuccinimide (0.45 g, 3.4 mmol) was added. The reaction was slowly warmed to room temperature and then stirred overnight. The mixture was quenched with water and extracted with chloroform (4 times). The organic layers were combined, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from hexane to give compound 27 (0.25 g, 33%).
[312] (3S) -4-chloro-3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3 from Compound 27 according to the procedure described in Example 1 -Pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid was prepared.
[313] Example 7
[314] (3S) -4-bromo-3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} Synthesis of -3- (4-methylphenyl) propanoic acid
[315] Step 1 : Compound 3 (2.00 g, 9.6 mmol) was dissolved in dry THF (32 mL) and TMEDA (2.20 mL, 14.4 mmol) under anhydrous nitrogen atmosphere. The resulting solution was cooled to −20 to −10 ° C. and n-butyl lithium (1.60 M in hexanes, 18.0 mL, 28.8 mmol) was added dropwise by syringe. After the addition was complete, the solution was cooled to -78 ° C and bromine (0.49 mL, 10.5 mmol) was added dropwise by syringe. The solution was slowly warmed to room temperature overnight, then quenched with water and extracted with chloroform. The organic layer was dried over MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane to give compound 28 (1.32 g, 48%) as a tan white solid.
[316] (3S) -4-bromo-3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro- from compound 28 according to the procedure described in Example 1 3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid was prepared.
[317] Example 8
[318] (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} Synthesis of 3- (4-methylphenyl) propanoic acid (32)
[319] Step 1 : A saturated ammonium chloride (1.5 mL) and zinc dust (1.5 g, 23 mmol) were added successively to a solution of compound 24 (1.5 g, 5.3 mmol) in methanol (50 mL) at room temperature. After stirring for 30 minutes at room temperature additional zinc dust (1.5 g, 23 mmol) was added and the reaction mixture was refluxed overnight. The reaction mixture was filtered while heating and the filtrate was concentrated under reduced pressure. HCl (IN) was added to the resulting residue until the pH became about 4, and the resulting precipitate was collected by filtration to obtain Compound 29 (0.80 g, 57%) as a brown solid.
[320] Step 2 : A solution of compound 29 (0.26 g, 1.0 mmol) and CDI (0.25 g, 1.6 mmol) in DMF (10 mL) was heated to 70 ° C. overnight. After cooling to room temperature the mixture was diluted with ethyl acetate and washed with 1N HCl (3 times) and brine. The organic layer was dried over MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure to give compound 30 (0.14 g, 50%) as a brown solid.
[321] Step 3 : A solution of compound 30 (0.1 g, 0.36 mmol) and compound 8 (0.082 g, 0.40 mmol) in anhydrous DMF (5 mL) was heated to 70 ° C. overnight. The mixture was cooled, diluted with ethyl acetate and washed with 1N HCl (3 times) and brine. The organic layer was dried over MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ ), eluting with 9: 1 CHCl ₃ : MeOH to give compound 31 (0.17 g, 97%).
[322] Step 4 : A solution of compound 31 (0.170 g, 0.35 mmol) in THF (3 mL) was treated with 2N NaOH (1 mL). Methanol was added until a homogeneous solution was formed. The reaction mixture was stirred for 30 minutes at room temperature and poured into H ₂ O (50 mL). The aqueous layer was washed with diethyl ether (twice) and then acidified with 1N HCl. The aqueous layer was extracted with ethyl acetate (twice). The combined ethyl acetate extracts were washed with brine (twice), dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino ) Carbonyl] amino} -3- (4-methylphenyl) propanoic acid (32, 0.150 g, 94%) was obtained as a gray solid. Melting point: 113-115 ° C.
[323] Example 9
[324] (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- Synthesis of 3- (4-methylphenyl) propanoic acid
[325] Step 1 : Compound 33 (prepared from Compound 28 according to the procedure described in Example 1, 0.20 g, 0.50 mmol) was dissolved in DMF (1.8 mL) and water (0.7 mL) and K ₃ PO ₄ (0.39 g, 1.86 mmol) and phenyl boronic acid (0.113 g, 0.93 mmol). The resulting mixture was oxygen glass (5 times conversion between vacuum and nitrogen) followed by addition of tetrakis (triphenylphosphine) palladium (0) (8.7 mg, 0.050 mmol). The mixture was oxygenated as before and heated to 90 ° C. overnight. The mixture was cooled down, diluted with water and then extracted with ethyl acetate (twice). The combined extracts were washed with brine, dried over magnesium sulfate, filtered through silica gel and concentrated under reduced pressure. The residue was suspended in 1: 1 water: concentrated HCl (2 mL) and acetonitrile (0.5 mL). The suspension was refluxed for 1 hour and cooled, then partitioned between ethyl acetate and saturated aqueous NaHCO ₃ . The ethyl acetate layer was washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by flash chromatography (SiO ₂ , 3: 1 hexanes / ethyl acetate) to give compound 34 (0.115 g, 94%). This material was used without further purification.
[326] (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-4-phenyl-1,2-dihydro-3 from compound 34 according to the procedure described in Example 1 -Pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid was prepared.
[327] ¹ H NMR (400 MHz, CD ₃ OD): δ 2.25 (s, 3H), 2.50 (m, 2H), 4.89 (t, J = 5.9 Hz, 1H), 5.34 (s, 2H), 6.40 (d, J = 7.0Hz, 1H), 7.0 (d, J = 8.0Hz, 2H), 7.10 (d, J = 8.0Hz, 2H), 7.18 (m, 1H), 7.28 (m, 2H), 7.35 (m, 3H ), 7.43 (m, 1 H), 7.49 (m, 3 H).
[328] Example 10
[329] (3S) -3-[({[2-methyl-4- (2-methylpropyl) -6-oxo-1- (phenylmethyl) -1,6-dihydro-5-pyrimidinyl] amino} carbo Synthesis of Nyl) amino] -3- (4-methylphenyl) propanoic acid (43)
[330] Step 1 : Compound 35 (2.00 g, 18.2 mmol) was dissolved in 30 mL of absolute methanol. To this solution benzylamine (1.97 g, 18.2 mmol) and triethylamine (2.0 g, 20.0 mmol) were added. The reaction mixture was stirred at 50 ° C. for 3 hours and concentrated under reduced pressure. The residue was partitioned between water and CH ₂ Cl ₂ . The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 36 (2.3 g, 82%).
[331] Step 2 : To a solution of compound 37 (3.50 g, 26.5 mmol) in ethanol (10 mL) and pyridine (5 mL), isovaleraldehyde (2.8 mL, 27 mmol) and piperidine (1 mL) were added. The reaction mixture was heated to reflux for 3 hours and concentrated under reduced pressure. The residue was partitioned between 2N HCl (15 mL) and ethyl acetate (30 mL). The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 2: 1 hexanes: ethyl acetate to give 38 (3.6 g, 67%).
[332] Step 3 : A solution of compound 38 (2.5 g, 12.48 mmol) and compound 36 (2.52 g, 13.7 mmol) in anhydrous methanol (25 mL) was vigorously heated to reflux for 3 hours, cooled, and then concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 2: 1 hexanes: ethyl acetate, to afford compound 39 (2.75 g, 69%).
[333] Step 4 : NBS (1.4 g, 8.0 mmol), K ₂ CO ₃ (11.0 g, 80.0 mmol) and benzoyl peroxide (50 mg, 0.20 mmol) in a solution of compound 39 (2.5 g, 7.9 mmol) in CCl ₄ (15 mL) ) Was added. The reaction mixture was heated to reflux for 1 hour, cooled to room temperature, diluted with water and extracted with CH ₂ Cl ₂ . The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 3: 1 hexanes: ethyl acetate to afford compound 40 (0.62 g, 25%).
[334] Step 5 : Compound 40 (0.60 g, 1.9 mmol) was treated with 2N NaOH (5 mL) and THF (3 mL). The resulting mixture was stirred at rt for 2 h, acidified with 2N HCl and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 41 (560 mg, 98%).
[335] Step 6 : To a solution of compound 41 (0.56 g, 1.86 mmol) in anhydrous benzene (10 mL) was added diphenylphosphoryl azide (0.56 g, 2.0 mmol) and triethylamine (2.02 g, 2.0 mmol). The reaction mixture was heated to 90 ° C. for 1 h and then a solution of compound 8 (0.39 g, 1.9 mmol) in benzene (2 mL) was added. The reaction was further stirred at 90 ° C. for 1 h, cooled to rt, diluted with 10% aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 7: 3 ethyl acetate: hexanes to afford compound 42 (0.38 g, 40%).
[336] Step 7 : 2N NaOH (8 mL) was added to a solution of compound 42 (0.35 g, 0.7 mmol) in a 1: 1 mixture of THF: MeOH (8 mL). The reaction was stirred at rt for 3 h, acidified with 2N HCl (10 mL) and then extracted with ethyl acetate (20 mL). The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give (3S) -3-[({[2-methyl-4- (2-methylpropyl-6-oxo-1- (phenylmethyl)- 1,6-dihydro-5-pyridinyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid (43, 250 mg, 75%) was obtained MS: Calculated: (M + H) ⁺ = 477.25 m / z; found: (M + H) ⁺ = 477.17 m / z
[337] Example 11
[338] (3S) -3-[({[2-methyl-6-oxo-1- (phenylmethyl) -1,6-dihydro-5-pyrimidinyl] amino} carbonyl) amino] -3- (4 Synthesis of -methylphenyl) propanoic acid
[339] Step 1 : A solution of compound 36 (2.3 g, 15.5 mmol) and compound 44 (3.36 g, 15.5 mmol) in dry ethanol (35 mL) was refluxed for 3 hours and concentrated. The residue was chromatographed on silica gel, eluting with 1: 1 ethyl acetate: hexanes to afford compound 45 (1.87 g, 55% yield).
[340] (3S) -3-{[({[2-methyl-6-oxo-1- (phenylmethyl) -1,6-dihydro-5-pyrimidinyl from Compound 45 according to the procedure described in Example 10 ] Amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid was obtained.
[341] ¹ H NMR (400 MHz, CD ₃ OD) δ 2.28 (s, 3H), 2.35 (s, 3H), 2.57 (m, 2H), 5.16 (m, 1H), 5.30 (s, 2H), 7.13 (m, 4H), 7.30 (m, 5H), 8.50 (s, 1H).
[342] Example 12
[343] (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[({ethyl [(ethylamino) carbonyl] amino} carbonyl) amino] -2-oxo-1, Synthesis of 2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid
[344] Step 1 : A solution of Compound 46 (0.50 g, 1.8 mmol, prepared according to the procedure described in Example 3) in THF (10 mL) at 0 ° C. was added NaH (60% dispersion in mineral oil, 0.23 g, 5.1 mmol). Added. The mixture was stirred at 0 ° C. for 10 minutes and then ethyl isocyanate (0.65 g, 9.15 mmol) was added. The mixture was stirred at rt over the weekend, sodium borohydride with 1N HCl and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 47 (0.60 g). This material was used without purification.
[345] (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[({ethyl [(ethylamino) carbonyl] amino} from Compound 47 according to the procedure described in Example 3 Carbonyl) amino] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid. Melting point: 128-130 ° C.
[346] Example 13
[347] (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl} amino) carbonyl] amino Synthesis of 3- (4-methylphenyl) propanoic acid
[348] Step 1 : To a solution of Compound 48 (2.00 g, 9.70 mmol) in dry DMF (25 mL) at 0 ° C. was added NaH (60% dispersion in mineral oil, 0.89 g, 22 mmol). The mixture was stirred at 0 ° C. for 15 minutes before 2-chlorobenzylchloride (2.03 g, 12.6 mmol) was added. After stirring at 55 ° C. overnight, the mixture was poured into ice water and washed with Et ₂ O (twice). The aqueous layer was acidified and the resulting precipitate was filtered to yield 49 (3.45 g). This material was used without further purification.
[349] (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro- from compound 49 according to the procedure described in Example 8 3-quinolinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid was prepared. Melting point: 134-136 ° C.
[350] Example 14
[351] (3S) -3-{[({1-[(2-chlorophenyl) methyl] -5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- Synthesis of 3- (4-methylphenyl) propanoic acid (56)
[352] Step 1 : 2-chlorobenzylamine (1.30 mL, 10.8 mmol) and EDCl (2.35 g, 12.3 mmol) in a suspension of compound 51 (1.67 g, 9.81 mmol) in DMF (33 mL) at room temperature under anhydrous nitrogen atmosphere Added. The resulting mixture was stirred vigorously at room temperature for 5 hours, diluted with ethyl acetate and washed with 2N HCl, water (3 times), saturated aqueous NaHCO ₃ and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 52 (2.55 g, 100%) as a pale yellow solid.
[353] Step 2 : A solution of compound 52 (555 mg, 2.17 mmol) and 3-dimethylamino-2-methylpropenal (738 mg, 6.5 mmol) in anhydrous ethanol (4.3 mL) and glacial acetic acid (0.22 mL) was heated to reflux overnight. The resulting mixture was cooled to rt, diluted with ethyl acetate and washed with 2N HCl (twice), water and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The concentrate was eluted with increasing hexane: ethyl acetate ratio from 7: 3 to 1: 1 and finally chromatographed on silica gel eluting with 19: 19: 2 hexane: ethyl acetate: methanol to give compound 53 (182 mg, 27%) was obtained as a yellow oil.
[354] Step 3 : To a solution of compound 53 (167 mg, 0.55 mmol) in THF (3 mL) was added 2N NaOH (1 mL) and methanol (2 mL). The resulting mixture was stirred for 15 minutes, diluted with water and extracted with ethyl acetate. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield compound 54 (139 mg, 91%) as a white solid.
[355] Step 4 : DPPA (0.29 mL, 1.34 mmol) was added by syringe to a suspension of compound 54 (175 mg, 0.63 mmol) in THF (6.7 mL) and DIPEA (0.23 mL, 1.34 mmol) at room temperature under anhydrous nitrogen atmosphere. The resulting mixture was stirred at rt for 15 min and then heated to reflux for 3.5 h. The mixture was cooled to room temperature and a solution of compound 8 (278 mg, 1.34 mmol) in THF (6.0 mL) was added via cannula with THF (0.7 mL) rinse. The resulting mixture was stirred at rt overnight, diluted with ethyl acetate and washed with 2N HCl (twice), saturated aqueous NaHCO ₃ and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting sequentially with 7: 3, 3: 2 and 1: 1 hexanes: ethyl acetate to give 55 (60 mg, 20%) as a colorless oil.
[356] Step 5 : 0.192 N NaOH (0.65 mL, 0.12 mmol) and methanol (2 mL) were added to a solution of compound 55 (60 mg, 0.12 mmol) in THF (3 mL). The resulting mixture was stirred at rt for 24 h and then diluted with water. The organic solvent was removed under reduced pressure and the resulting aqueous mixture was extracted with ethyl ether. The aqueous layer was lyophilized to afford (3S) -3-{[({1-[(2-chlorophenyl) methyl] -5-methyl-2-oxo-1,2-dihydro-3-pyridinyl as gray solid. } Amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, sodium salt (56, 56 mg, 95%) was obtained. _{MS: (C 24 H 23 ClN} 3 O 4) - Calcd: 452.14 m / z; Found 451.99 m / z.
[357] Example 15
[358] (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[2-oxo-1- (2-thienylmethyl) -1,2-dihydro-3-pyri Synthesis of diyl] amino} carbonyl) amino] propanoic acid (62)
[359] Step 1 : Triethylamine (2.98 ml, 21.4 mmol) and methanesulfonyl in a solution of 2-thiophenmethanol (1.015 g, 8.89 mmol) in CH ₂ Cl ₂ (17.8 ml) cooled to 0 ° C. under anhydrous nitrogen atmosphere. Chloride (0.69 ml, 8.9 mmol) was added continuously by syringe. The resulting mixture was stirred at 0 ° C. for 15 minutes, then 2-hydroxy-3-nitropyridine (1.496 g, 10.7 mmol) and 4-dimethylaminopyridine (catalyst) were added. The mixture was slowly warmed to room temperature and stirred overnight. The mixture was diluted with ethyl acetate and diluted with 2N HCl, water, saturated NaHCO ₃ and brine. The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 58 (395 mg) as a yellow waxy solid.
[360] Step 2 : Iron (154 mg, 2.8 mmol, -325 mesh) was added to a solution of compound 58 (330 mg, 1.40 mmol) in glacial acetic acid (6.6 ml) at room temperature under anhydrous nitrogen atmosphere. The resulting solution was heated at 60 ° C. for 20 minutes with vigorous stirring in an oil bath. The mixture was cooled to rt, diluted with ethyl acetate and then filtered through celite. The filtrate was washed with water, saturated NaHCO ₃ and brine. The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel, eluting with hexanes: ethyl acetate, increasing from 1: 1 to 1: 3 ratio to give compound 59 (188 mg, 12% for two steps) as a green solid.
[361] Step 3 : N, N-diisopropylethylamine (0.23 ml, 1.30 mmol) and phosgene in a solution of compound 59 (111 mg, 0.54 mmol) in CH ₂ Cl ₂ (2.7 ml) cooled to 0 ° C. under anhydrous nitrogen atmosphere. (0.31 ml, 1.9 M in toluene, 0.59 mmol) were added continuously by syringe. The resulting mixture was stirred at 0 ° C. for 15 minutes and a solution of β-amino ester 60 (167 mg, 0.70 mmol) in CH ₂ Cl ₂ (2.7 ml) was passed through the cannula with CH ₂ Cl ₂ rinse (1.0 ml). Added. The resulting mixture was allowed to warm to rt and stirred for 2 h then diluted with ethyl acetate and washed with 2N HCl, water, saturated NaHCO ₃ and brine. The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1: 1 hexanes: ethyl acetate to give compound 61 (231 mg, 91%) as purple foam.
[362] Step 4 : To a solution of ester 61 (227 mg, 0.48 mmol) in THF (6 ml) at room temperature was added NaOH (2 ml, 2N in water, 4 mmol) and methanol (a sufficient amount to make a clear solution, about 2 ml). The resulting mixture was stirred for 15 minutes, then diluted with water and extracted with ether. The aqueous phase was acidified with HCl (2N) and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 62 (191 mg, 90%) as a white solid.
[363] ¹ H NMR (400 MHz, CD ₃ SOCD ₃ ) δ 2.63 (d, J = 7.3 Hz, 2H), 4.99 (dt, J = 8.4, 7.3 Hz, 1H), 5.30 (s, 2H), 5.98 (m, 2H ), 6.21 (dd, J = 7.5, 7.0 Hz, 1H), 6.78 (dd, J = 8.1, 1.6 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 1.6 Hz , 1H), 6.97 (dd, J = 5.1, 3.5Hz, 1H), 7.17 (dd, J = 3.5, 1.1Hz, 1H), 7.35 (dd, J = 7.0, 1.8Hz, 1H), 7.44 (dd, J = 5.1, 1.1 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.94 (dd, J = 7.5, 1.8 Hz, 1H), 8.40 (s, 1H).
[364] Example 16
[365] (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[(3S) -2-oxo-1- (2-thienylmethyl) hexahydro-3-pyridinyl ] Amino} carbonyl) amino] propanoic acid (68)
[366] Step 1 : N-α-t-butoxycarbonyl-N-δ-benzyloxycarbonyl-L-ornithine 63 (1.00 g, 2.73 mmol) and cesium carbonate (1.33 g, 4.1 mmol) at room temperature under anhydrous nitrogen atmosphere To the solution of iodomethane (0.22 ml, 3.3 mmol) was added by syringe. The resulting mixture was stirred at rt for 18 h, then diluted with ethyl acetate and washed with water, 10% Na ₂ S ₂ O ₅ , saturated NaHCO ₃ and brine. The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give ester 64 (1.21 g) as a pale yellow oil. This material contained DMF but was used without purification.
[367] Step 2 : Palladium on charcoal (300 mg, 10% Pd, degussa type E101 NE) in a solution of Compound 64 (0.86 g crude, theoretically 1.94 mmol) in methanol (10 ml) at 0 ° C. under anhydrous nitrogen atmosphere. / W, wet, 50% by weight of water) was added. Replace the nitrogen atmosphere with hydrogen (5 times repeated hydrogen supply to vacuum and balloon) and stir the mixture at 0 ° C. for 30 minutes and then into a flask containing 2-thiophenecarboxaldehyde (177 mg, 1.58 mmol). It was filtered directly. The mixture was concentrated (water bath at room temperature) and the residue was taken up in dichloroethane (6 ml). To this solution was added sodium triacetoxyborohydride (479 mg, 2.26 mmol) and the mixture was stirred for 2 hours, then diluted with ethyl acetate and washed with saturated NaHCO ₃ (twice) and brine. The organic phase was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel eluting with 7: 3 hexanes: ethyl acetate to give lactam 65 (75 mg, 12% in two steps) as a colorless oil.
[368] Step 3 : HCl (7.2 ml, 4.0 M in dioxane, 28.8 mmol) was added by syringe to a flask containing Compound 65 (89 mg, 0.29 mmol) sealed with a rubber stopper at room temperature under anhydrous nitrogen atmosphere. The nitrogen needle was removed and the mixture in the sealed flask was stirred overnight. The mixture was diluted with CH ₂ Cl ₂ and washed with saturated NaHCO ₃ . The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give amine 66 (60 mg, 100%) as a pale yellow oil. This material was used without purification.
[369] Step 4 : Carbonyldiimidazole (51 mg, 0.32 mmol) was added to a solution of β-amino ester 60 (75 mg, 0.32 mmol) in CH ₂ Cl ₂ (0.6 ml) at room temperature under anhydrous nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 minutes and a solution of amine 66 (60 mg, 0.29 mmol) in CH ₂ Cl ₂ (0.6 ml) was added via cannula with a CH ₂ Cl ₂ (0.2 ml) rinse. The resulting mixture was stirred for 3 days at room temperature, diluted with ethyl acetate and washed with 2N NCl (twice), water, saturated NaHCO ₃ and brine. The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel, eluting with hexanes: ethyl acetate, increasing the ratio from 1: 1 to 2: 3 to give urea 67 (110 mg, 80%).
[370] Step 5 : To a solution of urea 67 (108 mg, 0.23 mmol) in THF (3 ml) at room temperature was added NaOH (1 ml, 2N in water, 2 mmol) and methanol (a sufficient amount to make a clear solution, about 2 ml). The resulting mixture was stirred for 15 minutes, then diluted with water and extracted with ether. The aqueous phase was acidified with HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 68 (92 mg, 90%) as a white foam.
[371] ¹ H NMR (400 MHz, CD ₃ SOCD ₃ ) δ 1.45 (m, 1H), 1.76 (m, 2H), 2.62 (m, 2H), 3.25 (m overlapping H ₂ O, 2H), 4.01 (m, 1H ), 4.59 (d, J = 15.0 Hz, 1H), 4.68 (d, J = 15.0 Hz, 1H), 4.96 (m, 1H), 5.97 (s, 2H), 6.24 (d, J = 6.6 Hz, 1H ), 6.71 (d, J = 8.4 Hz, 1H), 6.75 (dd, J = 8.1, 1.5 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 1.5 Hz, 1H ), 6.97 (dd, J = 5.1, 3.3 Hz, 1H), 7.03 (dd, J = 3.3, 1.5 Hz, 1H), 7.42 (dd, J = 5.1, 1.5 Hz, 1H), 12.06 (br.s, 1H).
[372] Example 17
[373] (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[(3S) -2-oxo-1- (2-thienylmethyl) tetrahydro-1H-pyrrole- Synthesis of 3-yl] amino} carbonyl) amino] propanoic acid (74)
[374] Step 1 : To a solution of Nt-butoxycarbonyl-L-aspartic acid α-benzyl ester (2.10 g, 6.5 mmol) in dimethoxyethane (15 ml) cooled to −15 ° C. (bath temperature) under anhydrous nitrogen atmosphere. 4-methylmorpholine (0.71 ml, 6.5 mmol) and isobutyl chloroformate (0.84 ml, 6.5 mmol) were added sequentially using a syringe. The resulting mixture was stirred for 2 minutes, filtered and the solid cake was washed with dimethoxyethane (10 ml). The filtrate was recooled to −15 ° C. (bath temperature) and a solution of sodium borohydride (370 mg, 9.7 mmol) in water (3 ml) was added immediately after the addition of water (100 ml). The mixture was extracted with ethyl acetate (3 times) and the organic layers combined and washed with cold (0 ° C) HCl (0.2N), water, saturated NaHCO ₃ and brine. The resulting organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 69 (2.50 g) as a colorless oil. This material contained some of the non-reduced mixed anhydrides but was used without purification.
[375] Step 2 : A solution of oxalyl chloride (2.4 ml, 2.0 M in CH ₂ Cl ₂ , 4.8 mmol) in CH ₂ Cl ₂ (30 ml) cooled to −65 ° C. under anhydrous nitrogen atmosphere in CH ₂ Cl ₂ (8 ml) A solution of methylsulfoxide (0.55 ml, 7.8 mmol) was added using a syringe. The resulting mixture was stirred at -65 ℃ for 15 minutes and then CH ₂ Cl ₂ (29ml) was added via cannula with a solution of alcohol 69 (1.00g, 3.2mmol) and CH ₂ Cl ₂ (3ml) rinse. The mixture was stirred at -65 ° C for 3 hours and then warmed to -20 ° C (bath temperature). Triethylamine (0.96 ml, 6.9 mmol) was added followed by water (20 ml). The aqueous layer was extracted with CH ₂ Cl ₂ and the combined organic phases were dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give aldehyde 70 as a white solid. This material was used immediately without purification.
[376] Step 3 : Sodium triacetoxyborohydride (959 mg, 4.5) in a solution of crude aldehyde 70 (3.2 mmol in theory) and 2-aminomethylthiophene (402 mg, 3.55 mmol) in dichloroethane (13 ml) at room temperature under anhydrous nitrogen atmosphere. mmol) was added. The resulting mixture was stirred at rt overnight, diluted with ethyl acetate and washed with saturated NaHCO ₃ and brine. The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 1: 1 hexanes: ethyl acetate to give lactam 71 (220 mg, 23% for three steps) as a white solid.
[377] Step 4 : HCl (1.50 ml, 4.0 M in dioxane, 6.0 mmol) in compound 71 (220 mg, 0.74 mmol) in dioxane (1.5 ml) sealed with a rubber stopper at room temperature under anhydrous nitrogen atmosphere was added by syringe. The nitrogen needle was removed and the mixture in the sealed flask was stirred for 5 hours. The mixture was diluted with CH ₂ Cl ₂ and washed with saturated NaHCO ₃ . The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give amine 72 (129 mg, 89%) as a pale yellow oil. This material was used without purification.
[378] Step 5 : Carbonyldiimidazole (112 mg, 0.69 mmol) was added to a solution of amine 72 (123 mg, 0.63 mmol) in CH ₂ Cl ₂ (1.5 ml) at room temperature under anhydrous nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 minutes and a solution of β-amino ester 60 (164 mg, 0.69 mmol) in CH ₂ Cl ₂ (0.8 ml) was added via cannula with a CH ₂ Cl ₂ (0.2 ml) rinse. . The resulting mixture was stirred at rt overnight, diluted with ethyl acetate and washed with 2N NCl (twice), water, saturated NaHCO ₃ and brine. The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel, eluting with 49: 1 chloroform: methanol to give urea 73 (230 mg, 80%) as a colorless oil. This oil solidified slowly upon standing.
[379] Step 6 : To a solution of urea 73 (230 mg, 0.50 mmol) in THF (3 ml) at room temperature was added NaOH (1 ml, 2N in water, 2 mmol) and methanol (1 ml). The resulting mixture was stirred for 1 hour and then diluted with water and extracted with ether. The aqueous phase was acidified with HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 74 (181 mg, 84%) as a white foam.
[380] ¹ H NMR (400MHz, CD ₃ SOCD ₃ ) δ 1.64 (m, 1H), 2.30 (m, 1H), 2.64 (m, 2H), 3.20 (m, 2H), 4.17 (dd, J = 8.8, 8.4Hz , 1H), 4.56 (s, 2H), 4.96 (m, 1H), 5.97 (s, 2H), 6.30 (d, J = 7.0 Hz, 1H), 6.58 (d, J = 8.8 Hz, 1H), 6.77 (m, 1H), 6.80-6.90 (m, 2H), 6.96-7.04 (m, 2H), 7.45 (dd, J = 5.1, 0.7 Hz, 1H), 12.10 (br.s, 1H).
[381] Example 18
[382] Synthesis of (3S) -3-[({[5-chloro-2-hydroxy-3- (phenylmethyl) phenyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid
[383] Step 1 : KNO ₃ (2.30 g, 22.9 mmol) and NaNO ₂ (20 mg, catalyst) in a mixture of 2-phenylmethyl-3-chlorophenol (5.00 g, 22.9 mmol) in ethanol (20 mL) and 6N HCl (50 mL). Was added continuously. The resulting mixture was stirred for 2 hours, diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 99 (6.0 g, 100%).
[384] Step 2 : To a solution of compound 99 (6.0 g, 22.8 mmol) in methanol (360 mL) was added zinc powder (6.0 g, 92 mmol) and saturated aqueous NH ₄ Cl (6 mL). The resulting homogeneous mixture was refluxed overnight. The hot mixture was filtered and the filtrate was concentrated under reduced pressure, then the residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO ₃ and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 100 (2.93 g, 55%).
[385] Step 3 : To a solution of compound 25 (0.20 g, 0.96 mmol) in CH ₂ Cl ₂ at 0 ° C. was added successively DIPEA (0.40 mL, 2.4 mmol) and phosgene (1.93 M in toluene, 0.60 mL, 1.2 mmol). It was. The resulting mixture was allowed to warm to room temperature, stirred for 20 minutes and then recooled to 0 ° C. To this mixture was added dropwise a solution of compound 100 (0.25 g, 1.1 mmol) in CH ₂ Cl ₂ . The resulting mixture was warmed to rt overnight, diluted with water and then extracted with CH ₂ Cl ₂ . The organic layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with hexanes: ethyl acetate, increasing from 9: 1 to 5: 1 to give compound 101 (60 mg, 12%).
[386] (3S) -3-[({[5-chloro-2-hydroxy-3- (phenylmethyl) phenyl] amino} carbonyl) amino] -3- (from Compound 101 according to the procedure described in Example 1). 4-Methylphenyl) propanoic acid was prepared.
[387] ¹ H NMR (400 MHz, CD ₃ SO ₂ CD ₃ ) δ 2.26 (s, 3H), 2.58 (dd, J = 15.8, 6.6 Hz, 1H), 2.67 (dd, J = 15.8, 8.4 Hz, 1H), 3.49 (s, 2H), 4.88 (m, 1H), 7.00-7.70 (m, 1H), 11.95 (br.s, 1H).
[388] Example 19
[389] (3S) -3- (1,3-benzodioxol-5-yl) -3-[({butyl [2,5-dioxo-1- (phenylmethyl) tetrahydro-1H-pyrrol-3-yl ] Amino} carbonyl) amino] propanoic acid
[390] Step 1 : A solution of N-benzylmaleimide (2.60 g, 13.9 mmol) and n-butylamine (1.00 g, 13.7 mmol) in THF (15 mL) was stirred at rt overnight and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes: ethyl acetate, increasing the ratio from 4: 1 to 2: 1 to give compound 102 (3.25 g, 90%).
[391] (3S) -3- (1,3-benzodioxol-5-yl) -3-[({butyl [2,5-dioxo-1- (phenyl) from Compound 102 according to the procedure described in Example 1 Methyl) tetrahydro-1H-pyrrole-3-yl] amino} carbonyl) amino] propanoic acid was prepared: melting point 80-85 ° C.
[392] Example 20
[393] (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[1- (cyclopentylmethyl) -2-oxo-1,2-dihydro-3-pyridinyl] Synthesis of amino} carbonyl) amino] propanoic acid
[394] Step 1 : Cyclopentanmethanol (178 mg, 1.78 mmol) was added to a solution of 2-hydroxy-3-nitropyridine (200 mg, 1.4 mmol) in CH ₂ Cl ₂ (14 mL) at 0 ° C. under nitrogen atmosphere, followed by triphenyl Phosphine (551 mg, 2.1 mmol) was added. The solution was stirred at 0 ° C. for 15 minutes and diethyl azodicarboxylate (366 mg, 2.1 mmol) was added dropwise by syringe. The reaction was stirred for 1 h at 0 ° C. and then overnight at rt. The mixture was quenched with methanol (20 mL) and washed with water (twice). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over magnesium sulfate and then filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography eluting with 1: 1 hexanes: ethyl acetate to afford compound 103 (299 mg, 96% yield) as a yellow solid.
[395] (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[1- (cyclopentylmethyl) -2-oxo- from compound 103 according to the procedure described in Example 1 1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] propanoic acid was prepared.
[396] ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.2-1.7 (m, 8H), 2.34 (m, 1H), 2.81 (dd, J =, 1H), 2.95 (dd, J =, 1H), 3.92 (d, J = 7.7 Hz, 2H), 5.30 (m, 1H), 5.92 (m, 2H), 6.30 (t, J = 7.1 Hz, 1H), 6.68-7.00 (m, 5H), 8.33 (d, J = 7.7 Hz, 1H), 8.89 (s, 1H).
[397] Example 21
[398] (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({3-[(2-thiophenylmethyl) amino] phenyl} amino) carbonyl] amino} propanoic acid
[399] Step 1 : 3-nitroaniline (0.51 g, 3.7 mmol) was added to a solution of 2-thiophenecarboxaldehyde (0.48 g, 4.0 mmol) in dichloromethane. The solution was concentrated to dryness and placed in 1,2-dichloroethane (16 mL). Molecular sieves (3x, 1.1 g) were added followed by NaBH (OAc) ₃ (1.01 g, 4.8 mmol). The solution was stirred at rt overnight, diluted with chloroform and washed with water. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 104 (0.72 g, 84%).
[400] Step 2 : Trifluoroacetic anhydride (0.193 mL, 1.4 mmol) in a solution of compound 104 (0.30 g, 1.3 mmol) in CH ₂ Cl ₂ (5.2 mL) and triethylamine (0.215 mL, 1.5 mmol) at 0 ° C. Was added. The solution was stirred at 0 ° C. for 15 minutes, the ice bath was removed and the mixture was stirred for an additional 15 minutes. The mixture was diluted with CH ₂ Cl ₂ and washed with 2N HCl, water and brine. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to yield compound 105 (0.38 g, 100%) as a yellow solid.
[401] Step 3 : Add Fe powder (0.36 g, 6.5 mmol) to a solution of compound 105 (0.38 g, 1.4 mmol) in ethanol (2.6 mL) and acetic acid (2.6 mL) at room temperature and TLC to indicate complete disappearance of compound 105 The suspension was stirred vigorously at 40 ° C. until. The mixture was filtered through celite and washed with chloroform. The filtrate was diluted with saturated sodium bicarbonate and the chloroform layer was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel (elute gradient 6: 1 to 4: 1 hexanes: ethyl acetate) to give compound 106 (0.102 g, 25%).
[402] (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({3-[(2-thiophenylmethyl) amino] from Compound 106 according to the procedure described in Example 1 Phenyl} amino) carbonyl] amino} propanoic acid.
[403] ¹ H NMR (400 MHz, CD ₃ SO ₂ CD ₃ ) δ 2.50 (m, 2H overlapping DMSO), 4.37 (d, J = 5.9 Hz, 2H), 4.94 (m, 1H), 5.94 (m, 2H), 6.06 (t, J = 5.8 Hz, 1H), 6.16 (m, 1H), 6.59 (d, J = 8.8 Hz, 1H), 6.78 (m, 3H), 6.85 (dd, J = 8.8, 7.7 Hz, 1H ), 6.90 (s, 1H), 6.94 (dd, J = 5.2, 3.7 Hz, 1H), 7.00 (d, J = 3.3 Hz, 1H), 7.33 (dd, J = 5.1, 1.1 Hz, 1H), 8.5 (s, 1 H).
[404] Example 22
[405] 3- (1,3-benzodioxol-5-yl) -2,2-difluoro-3-[({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro Synthesis of -3-pyridinyl] amino} carbonyl) amino] propanoic acid
[406] Step 1 : Lithium bis () in a solution of (1S, 2R, 5S)-(+)-mentyl (R) -p-toluenesulfinate (3.00 g, 10.2 mmol) in THF (25.5 mL) cooled to -78 ° C. Trimethylsilyl) amide (1.0 M in THF, 15.3 mL) was added dropwise over 15 minutes. The resulting mixture was stirred at rt for 6 h and then cooled to 0 ° C. Piperonal (3.06 g, 20.4 mmol) and CsF (3.10 g, 20.4 mmol) were added dropwise quickly and the suspension was stirred at rt for 36 h. The reaction was quenched with saturated NH ₄ Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane and dichloromethane to give compound 108 (1.36 g, 46%).
[407] Step 2 : Ethyl bromodifluoroacetate (0.78 mL, 6.1 mmol) was added to a suspension of Zn powder (2.00 g, 30.5 mmol) in THF (20.2 mL) and refluxed for 15 minutes. The suspension was cooled to 0 ° C. and compound 108 (0.87 g, 3.0 mmol) was added. The suspension was warmed to rt and stirred overnight. The mixture was quenched with minimal amount of saturated NH ₄ Cl and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel (elute gradient 6: 1 to 4: 1 hexanes: ethyl acetate) to afford compound 109 (0.607 g, 61% to 80% conversion).
[408] Step 3 : To a solution of compound 109 (0.700 g, 1.70 mmol) in methanol (4.3 mL) at 0 ° C. was added trifluoroacetic acid (0.26 mL, 3.4 mmol). The solution was stirred at 0 ° C. for 2 hours and then concentrated to dryness under reduced pressure, keeping the external temperature below 30 ° C. The residue was taken up in diethyl ether and washed with 2N HCl (twice). The combined aqueous layers were carefully basified with excess saturated NaHCO ₃ and extracted with diethyl ether. The ether layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 110 (0.326 g, 80%).
[409] 3- (1,3-benzodioxol-5-yl) -2,2-difluoro-3-[({[2-oxo-1- (2) from Compound 110 following the procedure described in Example 1 -Thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] propanoic acid was prepared. MS: calcd (MH) ^- = 476.07; Found (MH) ^- = 476.00.
[410] Example 23
[411] (3S) -3- (1,3-benzodioxol-5-yl) -3-({[9-oxo-8- (phenylmethyl) -2,3,4,5,8,9-hexahydro Synthesis of -1H-pyrido [3,4-b] azin-1-yl] carbonyl} amino) propanoic acid
[412] Step 1 : n-butyllithium (1.6M in hexane, 3.4 mL, 5.4 mmol) in a solution of compound 3 (0.74 g, 3.6 mmol) in THF (14.4 mL) and TMEDA (1.60 mL, 10.8 mmol) at −20 ° C. ) And t-butyllithium (1.7 M in pentane, 2.5 mL, 4.3 mmol) were added dropwise successively by syringe. The temperature was warmed to −10 to 0 ° C. and maintained for 2 hours. 1,4-Dibromobutane (1.75 mL, 14.7 mmol) was added quickly to the resulting mixture and the solution was allowed to warm to room temperature and stirred for 4 days. The reaction was quenched with water and extracted with CHCl ₃ (3 times). The combined extracts were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel, eluting with 4: 1 hexanes: ethyl acetate to afford compound 111 (0.41 g, 44%). (3S) -3- (1,3-benzodioxol-5-yl) -3-({[9-oxo-8- (phenylmethyl) -2, from Compound 111 according to the procedure described in Example 4 3,4,5,8,9-hexahydro-1H-pyrido [3,4-b] azin-1-yl] carbonyl} amino) propanoic acid was prepared. MS: calcd (MH) ^- = 488.18; Found (MH) ⁻ = 488.21.
[413] Example 24
[414] (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4 Synthesis of -hydroxyphenyl) propanoic acid
[415] Step 1 : In a solution of compound 112 (0.19 g, 0.39 mmol, prepared according to the procedure described in Example 15, in CH ₂ Cl ₂ at 0 ° C. under nitrogen), BBr ₃ (1.0 M in CH ₂ Cl ₂ , 1.2 mL, 1.2 mmol) was added by syringe. The mixture was slowly warmed to room temperature and then stirred overnight. The mixture was diluted with water and stirred for 30 minutes and further diluted with saturated aqueous NaHCO ₃ . The organic layer was washed with water, the aqueous layers were combined and then acidified with 2N HCl and extracted with ethyl acetate (3 times). The combined ethyl acetate layers were dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2 -Dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-hydroxyphenyl) propanoic acid (113, 120 mg, 70%) was obtained.
[416] ¹ H NMR (400 MHz, CD ₃ SO ₂ CD ₃ ) δ 2.95 (d, J = 5.2 Hz, 2H), 5.28 (s, 2H), 5.35 (ddd, J = 9.2, 4.8, 4.4 Hz, 1H), 6.33 (t, J = 7.1Hz, 1H), 6.60 (d, J = 8.8Hz, 2H), 7.04 (m, 5H), 7.22 (m, 3H), 7.37 (dd, J = 7.7, 1.5Hz, 1H) , 8.35 (dd, J = 7.6, 1.5 Hz, 1 H), 8.80 (s, 1 H).
[417] Example 25
[418] (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid (119)
[419] Step 1 : TMEDA (13.2 mL, 87.5 mmol) was added to a suspension of sodium hydride (3.6 g of 60% dispersion in mineral oil, 90 mmol) in THF (300 mL) under anhydrous nitrogen atmosphere and the mixture was cooled to -20 ° C. . Methyl propionyl acetate (9.60 mL, 76.5 mmol) was added dropwise and the solution was stirred for an additional 15 minutes. A solution of n-butyllithium (90 mL, 1.6 M in hexanes, 144 mmol) was added dropwise and the resulting mixture was stirred at −20 ° C. for 15 minutes. Methyl formate (6.0 mL, 97 mmol) was added quickly and the mixture was stirred for 15 minutes and then quenched with HCL (2N, 250 mL). The reaction solution was diluted with diethyl ether (150 mL) and the organic layer was washed twice with water. The aqueous layers were combined and sodium chloride was added until saturated. This mixture was extracted with ethyl acetate (3 times). The first ether layer was washed with saturated sodium bicarbonate solution and water. The combined aqueous washes were acidified with excess HCl (2N), saturated with sodium chloride and extracted with ethyl acetate (3 times). All ethyl acetate extracts were combined and dried over magnesium sulfate. The resulting mixture was vacuum filtered through silica gel and the filtrate was concentrated under reduced pressure to give compound 114 (8.27 g, 68%) as a pale yellow oil. This material was used without further purification.
[420] Step 2 : A solution of 2-chlorobenzylamide (4.2 g, 30 mmol) in anhydrous methanol (25 mL) was added dropwise from a funnel to a suspension of compound 114 (3.95 mg, 25.0 mmol) in anhydrous methanol (225 mL) at room temperature. It was. The solution was heated at 45 ° C. overnight and then refluxed for 2 hours. The reaction mixture was cooled to rt and concentrated to dryness. The residue was taken up in dichloromethane and filtered, the solids were collected and dried in vacuo to yield 115 (2.20 g, 35%) as a pale yellow solid.
[421] Step 3 : In a suspension of compound 115 (840 mg, 3.4 mmol) in glacial acetic acid (11 mL) at room temperature, NaNO ₂ (46 mg, 0.67 mmol), water (0.92 mL) and HNO ₃ (70%, 0.85 mL, 13.4 mmol). ) Were added sequentially. The resulting pale yellow solution was stirred overnight at room temperature and then diluted with CH ₂ Cl ₂ and water. The aqueous phase was extracted with CH ₂ Cl ₂ and the organic layers combined and washed with water (3 times) and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 116 (910 mg, 92%) as a pale yellow solid. This material was used without purification.
[422] Step 4 : Zn powder (909 mg, 13.9 mmol) and triethylamine hydrochloride (2340 mg, 17.0 mmol) were added to a solution of compound 116 (910 mg, 3.1 mmol) in DMF (10.3 mL) at room temperature under anhydrous nitrogen atmosphere. Added. The resulting mixture was heated to 55 ° C. for 2 hours and then cooled to room temperature. To the resulting mixture was added CDI (1002 mg, 6.18 mmol) as a solid. When added, gas was generated. The mixture was heated to 80 ° C. for 1 h, cooled to rt and diluted with CH ₂ Cl ₂ and HCl (2N). The aqueous phase was extracted with CH ₂ Cl ₂ and the organic layers combined and washed with water (4 times) and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 117 (920 mg) as a yellow solid. This material contained a small amount of DMF and was used without purification.
[423] Step 5 : A suspension of Compound 117 (920 mg crude, theoretical 3.1 mmol) and Compound 8 (800 mg, 3.86 mmol) in 21 mL of THF under anhydrous nitrogen atmosphere was heated to 55 ° C. overnight, cooled to room temperature and then ethyl acetate Diluted with. The resulting mixture was washed twice with HCl (2N) and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography, eluting with 7: 3 hexanes: ethyl acetate to afford compound 118 (1098 mg, 71% in two steps) as light yellow foam.
[424] Step 6 : To a solution of compound 118 (1091 mg, 2.19 mmol) in THF (18 mL) at room temperature was added sodium hydroxide (2 N, 6 mL) and methanol (12 mL). The mixture was stirred for 20 minutes, then diluted with water and extracted with ethyl ether. The aqueous phase was acidified with HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylphenyl) propanoic acid 119 (1045 g) was obtained as white foam. MS: calcd (MH) ^- = 468.13 m / z; Found (MH) ^- = 467.99 m / z.
[425] Example 26
[426] (3S) -3-[({[4-hydroxy-2-oxo-1- (pyridin-2-ylmethyl) -1,2-dihydropyridin-3-yl] amino} carbonyl) amino]- Preparation of 3- (4-methylphenyl) propanoic acid
[427] Step 1 : To a solution of compound 23 (0.50 g, 3.2 mmol) in DMSO (12.5 ml) at room temperature was added KOH powder (0.89 g, 16 mmol) and the mixture was stirred for 1.5 h. To the resulting mixture, 2-picolylchloride hydrochloride (0.63 g, 3.8 mmol) was added as a solid and the mixture was stirred overnight. At this point, triethylamine hydrochloride (3.52 g, 25.6 mmol) and DMF (5 mL) were added followed by zinc powder (1.04 g, 16.0 mmol). The mixture was heated to 80 ° C. for 2 hours and then cooled to room temperature. To this mixture, CDI (1.00 g, 6.2 mmol) was added and the resulting mixture was heated to 80 ° C overnight. The mixture was diluted with ethyl acetate and saturated aqueous NaHCO ₃ . The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was filtered through a pad of silica gel, eluting with 9: 1 CHCl ₃ : CH ₃ OH to afford compound 120 (0.14 g, 18%).
[428] (3S) -3-[({[4-hydroxy-2-oxo-1- (pyridin-2-ylmethyl) -1,2-dihydropyridine-) from compound 120 according to the method described in Example 25. 3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid was prepared. MS: calcd (MH) ^- = 421.15 m / z; Found (MH) ^- = 421.06 m / z.
[429] Example 27
[430] (3S) -3-{[({1- [2-chloro-5- (methylsulfonyl) benzyl] -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl} amino) Preparation of Carbonyl] Amino} -3- (4-methylphenyl) propanoic acid
[431] Step 1 : m-to a solution of compound 121 (prepared from compound 23, 220 mg, 0.67 mmol) in anhydrous CH ₂ Cl ₂ (14 mL) cooled to 0 ° C. under anhydrous nitrogen atmosphere, according to the method described in Example 4. CPBA (610 mg, 3.6 mmol) was added. The resulting mixture was allowed to warm to rt and stirred for 4 h. The reaction was diluted with water (50 mL) and the aqueous phase extracted with CH ₂ Cl ₂ (twice). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 9: 1 CHCl ₃ : MeOH to afford compound 122 (219 mg, 91% yield) as a yellow solid.
[432] (3S) -3-{[({1- [2-chloro-5- (methylsulfonyl) benzyl] -4-hydroxy-2-oxo-1, from compound 122 according to the method described in Example 25, 2-dihydropyridin-3-yl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid was prepared. MS: calcd (MH) ^- = 532.10 m / z; found (MH) ^- = 531.94 m / z.
[433] Example 28
[434] (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Preparation of Amino] -3- (3-methylphenyl) propanoic acid
[435] Step 1: ZnBr ₂ (200 mg, 0.82 mmol) was added to a solution of compound 123 (70 mg, 0.13 mmol) in anhydrous CH ₂ Cl ₂ (3 mL) with stirring under nitrogen atmosphere. The solution was stirred at 0 ° C. for 1 h. The reaction mixture was allowed to warm to room temperature and stirred overnight. At this point water (50 mL) was added and the mixture was stirred for an additional 3 hours. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (twice). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-2-oxo-1 , 2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-methylphenyl) propanoic acid 124 (60 mg, 95% yield) was obtained. MS: calcd (MH) ^- = 484.13 m / z; Found (MH) ^- = 484.00 m / z.
[436] Example 29
[437] (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid
[438] Step 1 : A mixture of malonyl dichloride (25.0 g, 177 mmol) and valeronitrile (25.0 g, 300.7 mmol) was stirred vigorously for 24 hours at room temperature under anhydrous atmosphere. Diethyl ether (50 mL) was added to the resulting heterogeneous mixture. The precipitate was collected and washed with diethyl ether to give compound 125.HCl as a white solid (20.2 g, 64%).
[439] Step 2 : Triethylamine (5.8 g, 57.3 mmol) and palladium on carbon (10% Pd dry weight, degussa type E101 NE /) in a suspension of 125.HCl (6.10 g, 27.2 mmol) in ethanol (100 mL). W, about 50% water content, 3.5 g, 1.6 mmol Pd) was added. The atmosphere was replaced with hydrogen (toggle 5 times between hydrogen and vacuum from the balloon) and the mixture was stirred overnight and then filtered. The filtrate was concentrated under reduced pressure to give 126.2Et ₃ NHCl (11.0 g, 94%). This material was used without further purification.
[440] (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-5-propyl-1,2 from 126.2Et ₃ NHCl according to the method described in Example 25 -Dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-methylphenyl) propanoic acid was prepared. MS: calcd (MH) ^- = 496.16 m / z; Found (MH) ⁻ = 495.94 m / z.
[441] Example 30
[442] (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Preparation of I] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid
[443] Step 1 : To a solution of ethyl 2-oxocyclopentanecarboxylate (3.30 g, 21.1 mmol) in toluene (45 ml) was added 4-chlorobenzylamine (2.56 mL, 21.1 mmol). The resulting mixture was refluxed overnight with azeotropic removal of water through a Dean-Stark trap. The reaction mixture was concentrated under reduced pressure to give compound 127 (5.90 g, 99%) as a red oil. This material was used without purification.
[444] Step 2 : To a solution of compound 127 (11.0 g, 39.3 mmol) in dry THF (75 mL) cooled to 0 ° C. under anhydrous nitrogen atmosphere was added NaH (60% dispersion in mineral oil, 1.73 g, 43.2 mmol). The reaction was stirred for 10 min at 0 ° C. and then acetyl chloride (3.9 mL, 55 mmol) was added. The reaction mixture was slowly warmed to room temperature and then stirred overnight. The resulting mixture was concentrated under reduced pressure and a mixture of ice water (200 mL) and HCl (1N, 200 mL) was added to the residue. The mixture was extracted with ethyl acetate (300 mL) and the ethyl acetate layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 128 (13.4 g) as a brown oil. This material contained mineral oil but was used without purification.
[445] Step 3 : To a solution of crude compound 128 (13.4 g, theoretical 39.3 mmol) in dry THF (50 mL) cooled to 0 ° C. under anhydrous nitrogen atmosphere (1.0 M in THF, 125 mL, 125 in THF) mmol) was slowly added by syringe. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The mixture was concentrated under reduced pressure and the residue was triturated with ethyl acetate / hexanes and filtered. The solid was washed with HCl (IN, 250 mL) and water (500 mL) to give compound 129 (5.48 g, 48% in two steps) as a brown solid.
[446] (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro from compound 129 according to the method described in Example 25 -1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid was prepared. MS: calculated (M + H) ⁺ = 496.16 m / z; Found (M + H) ⁺ = 495.99 m / z.
[447] Example 31
[448] (3S) -3-[({[4-{[(tert-butylamino) carbonyl] amino} -1- (2-chlorobenzyl) -2-oxo-1,2-dihydropyridine-3- Preparation of I] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid
[449] Step 1 : To a solution of Compound 46 (500 mg, 1.79 mmol) in dry THF (10 mL) cooled to 0 ° C. under anhydrous nitrogen atmosphere was added NaH (60% dispersion in mineral oil, 210 mg, 5.37 mmol) and produced. The resulting mixture was stirred for 20 minutes. To this mixture t-butyl isocyanate (0.31 mL, 2.68 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 2 days. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 130 (660 mg, 97%) as a brown solid.
[450] (3S) -3-[({[4-{[(t-butylamino) carbonyl] amino} -1- (2-chlorobenzyl) -2-oxo from compound 130 according to the method described in Example 3 -1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid was prepared. MS: calcd (MH) ^- = 552.20 m / z; Found (MH) ^- = 551.89 m / z.
[451] Synthetic methods similar to those described above can be used to obtain the compounds of Tables 2, 3, 4 and 5.
[452] Example 32
[453] (3S) -3-[({[5-chloro-1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid
[454] Step 1 : Sulfurylchloride (1.0 M in CH ₂ Cl ₂ , 0.65 mL, 0.65 mmol) was added by syringe to a solution of compound 31 (350 mg, 0.72 mmol) in CH ₂ Cl ₂ at room temperature under anhydrous nitrogen atmosphere. The resulting mixture was stirred at rt for 1 h and then partitioned between CH ₂ Cl ₂ and water. The organic layer was washed with brine, dried over magnesium sulfate and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 8: 1 then 4: 1 and finally with 1: 1 hexanes: ethyl acetate to give Compound 131 (240 mg, 64%).
[455] (3S) -3-[({[5-chloro-1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydro from Compound 131 according to the method described in Example 1 Pyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid was synthesized. MS: calcd (MH) ^- = 488.08 m / z; Found (MH) ⁻ = 487.97 m / z.
[456] Example 33
[457] (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (2 ', 6'-dimethoxy-1,1'-biphenyl-4-yl) propanoic acid
[458] Step 1 : solution of (R)-(+)-N-benzyl-α-methylbenzyl amine (5.07 g, 24 mmol) in THF (85 mL) under nitrogen in a flame-dried flask cooled to -78 ° C. To butyl lithium (1.3 M solution in cyclohexane, 18.0 mL, 24.4 mmol) was added dropwise over 30 minutes. The mixture was stirred for an additional 30 minutes at -78 ° C, then a solution of t-butyl 4-bromoscinnamate (5.1 g, 20 mmol) in THF (20 mL) was added dropwise and the mixture was allowed to warm to room temperature overnight. The reaction solution was quenched by addition of saturated ammonium chloride (about 50 mL), and then the organic layer was washed with saturated sodium chloride, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was eluted with hexane and then purified by silica gel chromatography eluting with 3: 1 hexanes: ethyl acetate to give compound 132 (4.33 g, 47%) as a pale yellow oil.
[459] Step 2 : Finely divided potassium phosphate (8.0 g) in a solution of compound 132 (7.4 g, 15 mmol) and 2,6-dimethoxyphenylboric acid (4.9 g, 27 mmol) in DME (100 mL) at room temperature under anhydrous nitrogen atmosphere. , 37.5 mM) and dichlorobis (triphenylphosphine) palladium (0) (0.5 g, 0.75 mmol) were added. The mixture was deoxygenated (5 toggles between vacuum and nitrogen gas) and heated to reflux for 8 hours. The mixture was cooled and Celite ^(R Celite) the filtrate was concentrated and then filtered through a 521 under reduced pressure. The residue was purified by silica gel chromatography, eluting with 3: 1 hexanes: ethyl acetate to give compound 133 (7.8 g, 95% yield).
[460] Step 3 : A solution of compound 133 (3.39 g, 6.1 mmol) in ethanol (80 mL) in 250 mL flask with acetic acid (0.5 mL) and palladium on carbon (10% Pd dry weight, water content about 50%, degussa) Form E101 NE / W, 2.5 g, 1.2 mmol Pd) was added sequentially. The mixture was stirred for 36 h under hydrogen atmosphere from the balloon. The mixture was filtered through Celite ^R 521 and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give compound 134.HOAc (1.0 g, 71%) as a white solid.
[461] (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-di from 134 · HOAc according to the method described in Example 25 Hydropyridin-3-yl] amino} carbonyl) amino] -3- (2 ', 6'-dimethoxy-1,1'-biphenyl-4-yl) propanoic acid. MS: calculated (M + H) ⁺ = 592.04 m / z; Found (M + H) ⁺ = 592.19 m / z.
[462] Example 34
[463] (3S) -3-[({[2- (2-chloro-6-ethoxybenzyl) -5-hydroxy-6-methyl-3-oxo-2,3-dihydropyridazin-4-yl] Preparation of amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid
[464] Step 1 : Ethanol (250 mL, 5.35 mol) was added dropwise over 10 minutes to a solution of sodium t-botoxide (65 g, 0.642 mol) in THF (1 L) at room temperature under anhydrous nitrogen atmosphere. To the resulting solution was added 2-chloro-6-fluorobenzonitrile (100 g, 0.642 mol) in portions. The reaction mixture was stirred at rt for 30 min and then reduced to a volume of about 250 mL under reduced pressure. The resulting mixture was poured into chloroform and water and the layers separated. The organic layer was washed with water (twice) and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a pale yellow solid. This material was recrystallized from hexanes to give 2-chloro-6-ethoxybenzonitrile 135 (101 g, 87% yield) as a white crystalline solid.
[465] Step 2 : To a solution of 2-chloro-6-ethoxybenzonitrile 135 (93.2 g, 0.513 mol) in THF (350 mL) at room temperature under anhydrous nitrogen atmosphere was added borane (1.0 M, 620 mL, 0.62 mol) in THF. Added. The resulting mixture was heated to reflux for 3 hours and cooled to room temperature. Water (250 mL) was added very slowly to the solution to generate hydrogen. Concentrated HCl (50 mL) was added over several minutes and the solution was heated to 50 ° C. for 2 hours. The mixture was cooled and partitioned between chloroform and water. The aqueous layer was washed six times with chloroform. The combined organic fractions were washed with HCl (1 M) and this organic layer was discarded. Chloroform was added to the combined aqueous layers and solid KOH was added until the aqueous phase became basic (pH> 9). The aqueous layer was washed five more times with chloroform. The organic fractions were combined, washed with water and brine and dried over magnesium sulfate and silica gel (2 g). The mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-chloro-6-ethoxybenzylamine 136 (60.1 g, 64% yield) as a pale yellow oil.
[466] Step 3 : A small amount of sodium nitrate (6.00 g, 85.7 mmol) was added to a solution of 2-chloro-6-ethoxybenzylamine 136 (7.30 g, 39.3 mmol) in glacial acetic acid (50 mL) and acetic anhydride (50 mL) at room temperature. Add in portions. The resulting mixture was stirred at rt overnight then poured into ice water and extracted with ethyl acetate. The organic layer was washed with aqueous NaOH (1N, 2X100 mL) and brine (twice). The organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to give compound 137 (9.00 g, 100%) as a pale yellow solid.
[467] Step 4 : Slowly adding aqueous NaOH (2N, 50 mL, 100 mmol) to a solution of compound 137 (9.00 g, 39.3 mmol) and tetrabutylammonium bromide (1.0 g, 3.1 mmol) in THF (50 mL) at room temperature The mixture was heated to 45 ° C. overnight. The reaction mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to give compound 138 (7.08 g, 96% yield).
[468] Step 5 : A solution of SOCl ₂ (9.0 mL, 120 mmol) in CH ₂ Cl ₂ (30 mL) in a solution of compound 138 (7.08 g, 37.9 mmol) in CH ₂ Cl ₂ (55 mL) at room temperature under anhydrous nitrogen atmosphere. Was added drop wise. The resulting mixture was stirred at rt overnight and then poured into ice water. The aqueous layer was extracted with CH ₂ Cl ₂ and the combined organic layers were washed with aqueous NaOH (1 N, 2 times), water (3 times) and brine (2 times). The organic layer was dried over Na ₂ S0 ₄ , filtered and the filtrate was concentrated under reduced pressure to give 2-chloro-6-ethoxybenzylchloride 139 (6.69 g, 86% yield).
[469] Step 6 : A solution of 2-chloro-6-ethoxybenzylchloride 139 (6.90, 33.7 mmol) and hydrazine (21.60 g, 673 mmol) in MeOH (22 mL) was stirred at room temperature for 3 hours. The mixture was partitioned between CH ₂ Cl ₂ and water. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 140 (6.18 g, 92%).
[470] Step 7 : A solution of compound 140 (6.14 g, 30.6 mmol) in CHCl ₃ (30 mL) was slowly added to a suspension of ethyl pyruvate (3.85 mL, 33.7 mmol) and MgSO ₄ in CHCl ₃ (65 mL). The resulting mixture was stirred at rt overnight. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 141 (8.43 g, 92%). This material was used in the next step without purification.
[471] Step 8 : Add sodium hydride (60% dispersion in mineral oil, 1.88 g, 47.1 mmol) in one portion to a solution of compound 141 (8.43 g, 28.2 mmol) in dry THF (110 mL) cooled to 0 ° C. under anhydrous nitrogen atmosphere. It was. The resulting mixture was stirred at 0 ° C. for 30 minutes and then methyl malonylchloride (6.63 g, 47.10 mmol) was added slowly. The mixture was allowed to warm to rt and stirred overnight, then carefully quenched with water and extracted with ethyl acetate (twice). The organic layers were combined, washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford compound 142 (14.29 g). This material was used in the next step without further purification.
[472] Step 9 : To a solution of crude compound 142 (14.29 g) in anhydrous DMF (60 mL) cooled to 0 ° C. under anhydrous nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil, 2.90 g, 72.2 mmol) in one portion. The solution was heated to 60 ° C. overnight, cooled in an ice bath and shaken with hexanes. The layers were separated and the DMF layer was poured into ice water. The mixture was acidified (pH 1) by addition of HCl (2N). The precipitate was collected by filtration and dissolved in ethyl acetate. The organic solution was dried over magnesium sulfate, filtered and the filtrate was concentrated to give compound 143 (8.42 g, 85% yield in two steps).
[473] Step 10 : A solution of compound 143 (8.42 g, 23.9 mmol) in dioxane (100 mL) and aqueous HCl (60 mL, 5.2 N) was refluxed overnight. The mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 1: 1 ethyl acetate: hexanes and then with ethyl acetate and finally with 9: 1 acetyl acetate: methanol to give compound 144 (2.0 g, 28%). Obtained.
[474] (3S) -3-[({[2- (2-chloro-6-ethoxybenzyl) -5-hydroxy-6-methyl-3-oxo-2 from compound 144 according to the method described in Example 25 , 3-dihydropyridazin-4-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid was prepared. MS: calcd (M + H) ⁺ = 545.05 m / z; Found (M + H) ⁺ = 545.18 m / z.
[475] Example 35
[476] (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Preparation of I] amino} carbonyl) amino] -3- (1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) propanoic acid
[477] Step 1 : Slowly warm the ice water mixture of sodium hydride (8.00 g, 60% dispersion in mineral oil, 200 mmol) and compound 145 (8.94 g, 66.6 mmol) in DMF (250 mL) under anhydrous nitrogen atmosphere to room temperature under nitrogen atmosphere. It was. Ioethane (16 ml, 200 mmol) was added to the resulting mixture and the mixture was stirred at rt overnight. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in hexane and filtered. The resulting brown solid was dried under reduced pressure to afford compound 146 (9.00 g, 71% yield). This material was used without purification.
[478] Step 2 : A mixture of DMF (3.6 g, 49 mmol) and POCl ₃ (9.6 mL, 100 mmol) was stirred for 1 hour at room temperature under anhydrous nitrogen atmosphere. The flask containing this mixture was placed in a 45 ° C. oil bath and compound 146 (7.6 g, 40 mmol) was added in portions. The temperature of the oil bath was raised to 70 ° C. and the mixture was stirred overnight and then cooled to room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give a 7: 3 mixture (6.69 g) of compound 147: compound 146. This material was used without purification.
[479] Step 3 : To the solution of the obtained 147: 146 mixture (2.2 g) in ethanol (2.2 mL) was added sequentially malonic acid (1.16 g, 11.2 mmol), pyridine (0.44 mL) and piperidine (0.99 mL). It was. The resulting mixture was heated to reflux for 6 hours and cooled to room temperature. The mixture was diluted with aqueous NaOH (IN) and extracted four times with ethyl acetate. The aqueous phase was acidified to pH 3 with HCl (IN) and the resulting suspension was filtered and the solid was washed with water. The white solid was collected and dried under reduced pressure to afford compound 148 (1.69 g, 49% for two steps).
[480] (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7- from Compound 148 according to the methods described in Examples 33 and 25 Tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazole -5-yl) propanoic acid was prepared. MS: found (M + H) ⁺ = 594.05 m / z; Calculated (M + H) ⁺ = 594.21 m / z.
[481] Example 36
[482] (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylphenyl) propanoic acid (153)
[483] Step 1 : 2-chloro-6-ethoxybenzylamine 136 (31.1 g, 168 mmol) was added to a solution of compound 114 (20.3 g, 129 mmol) at room temperature under anhydrous nitrogen atmosphere. The solution was heated to 45 ° C. for 1 h and then refluxed overnight. The reaction mixture was cooled to rt and concentrated to dryness. The residue was taken up in dichloromethane and filtered. The solid was collected and dried in vacuo resulting in compound 149 (14.7 g, 39%).
[484] Step 2 : In a suspension of compound 149 (11.02 g, 37.8 mmol) in glacial acetic acid (126 mL) at room temperature, NaNO ₂ (522 mg, 7.6 mmol), water (10.5 mL) and HNO ₃ (70%, 9.6 mL, 151.2 mmol). ) Were added sequentially. The resulting pale yellow solution was stirred overnight at room temperature and then diluted with CH ₂ Cl ₂ and water. The aqueous phase was extracted with CH ₂ Cl ₂ and the organic layers combined and washed with water (3 times) and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from CH ₂ Cl ₂ / ethyl acetate to give compound 150 (10.9 g, 85%) as a pale yellow solid.
[485] Step 3 : Zn powder (9.48 g, 145 mmol) and triethylamine hydrochloride (24.4 g, 177 mmol) were added to a solution of compound 150 (10.9 g, 32.2 mmol) in DMF (107 mL) at room temperature under anhydrous nitrogen atmosphere. Added. The resulting mixture was heated to 55 ° C. for 1 hour and then cooled to room temperature. To the resulting mixture was added CDI (10.4 g, 64.4 mmol) as a solid. Upon addition, gas was generated. The mixture was heated to 80 ° C. for 2 hours, cooled to room temperature and poured into HCl (2N, 1L). The resulting suspension was stirred for 20 minutes, then diluted with water (1 L) and filtered. The solid was resuspended in water (1 L) and then filtered. The solid was dried under vacuum to afford compound 151 (10.78 g, 100% yield) as a white powder.
[486] Step 4 : A mixture of compound 151 (10.68 g, 31.9 mmol) and compound 8 (8.27 g, 39.3 mmol) in DMF (64 mL) under anhydrous nitrogen atmosphere was heated to 55 ° C. overnight, cooled to room temperature and diluted with ethyl acetate It was. The resulting mixture was washed with HCl (2N), water (4 times) and brine and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography, eluting with 7: 3 hexanes: ethyl acetate to give compound 152 (14.2 g, 82%) as light yellow foam.
[487] Step 5 : To a solution of compound 152 (11.60 g, 21.4 mmol) in THF (138 mL) at room temperature was added aqueous sodium hydroxide (2N, 46 mL) and methanol (92 mL). The mixture was stirred for 20 minutes, then diluted with water and extracted with ethyl ether. The aqueous phase was acidified with HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridine -3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid 153 (10.82 g, 98% yield) was obtained as light brown foam. MS: calcd (MH) ^- = 512.16 m / z; Found (MH) ^- = 512.03 m / z.
[488] Example 37
[489] (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid 156
[490] Step 1 : A mixture of compound 151 (8.40 g, 28.8 mmol) and compound 154 (8.2 g, 35 mmol) in DMF (100 mL) under anhydrous nitrogen atmosphere was heated to 55 ° C. overnight, cooled to room temperature and diluted with ethyl acetate It was. The resulting mixture was washed with HCl (2N), water (4 times) and brine and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography, eluting with hexanes: ethyl acetate, increasing from 8: 2 to 1: 1 to give compound 155 (11.1 g, 67% yield).
[491] Step 2 : To a solution of compound 155 (9.12 g, 15.9 mmol) in THF (100 mL) at room temperature was added aqueous sodium hydroxide (1N, 88 mL) and methanol (63 mL). The mixture was stirred for 20 minutes, then diluted with water and extracted with ethyl ether. This ether layer was discarded. The aqueous phase was acidified with HCl (2N) and extracted with ethyl ether (4 times). The organic layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridine -3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid 156 (8.13 g, 93%) was obtained as a white foam. MS: calculated (M + H) ⁺ = 544.19 m / z; Found (M + H) ⁺ = 544.04 m / z.
[492] Example 38
[493] (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (6-methoxy-2-naphthyl) propanoic acid 159
[494] Step 1 : A mixture of compound 151 (110 mg, 0.29 mmol), compound 157 (130 mg, 0.34 mmol) and NMM (0.50 mL, 4.5 mmol) in DMF (1.0 mL) under anhydrous nitrogen atmosphere was heated to 55 ° C. overnight. After cooling to room temperature it was diluted with ethyl acetate. The resulting mixture was washed with HCl (2N), water (4 times) and brine and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography eluting with 1: 1 hexanes: ethyl acetate to give compound 158 (130 mg, 73% yield).
[495] Step 2 : To a solution of compound 158 (130 mg, 0.21 mmol) in THF (3 mL) at room temperature was added aqueous sodium hydroxide (2N, 1 mL) and methanol (2 mL). The mixture was stirred for 20 minutes, then diluted with water and extracted with ethyl ether. The aqueous phase was acidified with HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridine -3-yl] amino} carbonyl) amino] -3- (6-methoxy-2-naphthyl) propanoic acid 159 (90 mg, 74% yield) was obtained. MS: found (M + H) ⁺ = 580.07 m / z; Calculated (M + H) ⁺ = 580.19 m / z.
[496] Example 39
[497] (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Preparation of I] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid 164
[498] Step 1 : In a suspension of compound 129 (5.30 g, 19.2 mmol) in glacial acetic acid (64 mL) at room temperature, NaNO ₂ (266 mg, 3.9 mmol), water (5.3 mL) and HNO ₃ (70%, 4.9 mL, 77 mmol). ) Were added sequentially. The resulting pale yellow solution was stirred overnight at room temperature, poured into water, filtered and washed with water. The yellow solid was dried under reduced pressure to give compound 160 (5.35 g, 87%).
[499] Step 2 : Zn powder (4.88 g, 74.7 mmol) and triethylamine hydrochloride (1.26 g, 91.5 mmol) were added to a solution of compound 160 (5.35 g, 16.7 mmol) in DMF (56 mL) at room temperature under anhydrous nitrogen atmosphere. Added. The resulting mixture was heated to 55 ° C. for 1 hour and then cooled to room temperature. To the resulting mixture was added CDI (5.41 g, 33.4 mmol) as a solid. Upon addition, gas was generated. The mixture was heated to 80 ° C. for 2 hours, cooled to room temperature and poured into HCl (2N, 500 mL). The resulting suspension was stirred for 20 minutes, then diluted with water (500 mL) and filtered. The solid was resuspended in water (500 mL) and then filtered. The solid was dried under vacuum to afford compound 161 (5.0 g, 95% yield) as a white powder.
[500] Step 3 : A mixture of compound 161 (6.14 g, 19.4 mmol) and compound 162 (5.12 g, 20.3 mmol) in DMF (90 mL) under anhydrous nitrogen atmosphere was heated to 80 ° C. overnight, then cooled to room temperature and diluted with ethyl acetate. It was. The resulting mixture was washed with HCl (2N), water (4 times) and brine and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography eluting with 7: 3 hexanes: ethyl acetate to give compound 163 (8.90 g, 81%) as light yellow foam.
[501] Step 4 : To a solution of compound 163 (8.69 g, 15.3 mmol) in THF (35 mL) at room temperature was added aqueous sodium hydroxide (2N, 30 mL) and methanol (30 mL). The mixture was stirred overnight then diluted with water and extracted with ethyl ether. The aqueous phase was acidified with HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid 164 (7.50 g, 91% yield) was obtained. MS: found (M + H) ⁺ = 540.09 m / z; Calculated (M + H) ⁺ = 540.19 m / z.
[502] Example 40
[503] (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Preparation of I] amino} carbonyl) amino] -3- (4-chloro-3-isopropoxyphenyl) propanoic acid
[504] Step 1 : A mixture of compound 162 (200 mg, 0.80 mmol) in glacial acetic acid (1.65 mL) cooled to 0 ° C. under anhydrous nitrogen atmosphere was added a mixture of SO ₂ Cl ₂ (1.2 mL, 15 mmol) in glacial acetic acid (1.0 mL). Added by syringe. The resulting mixture was stirred at 0 ° C. for 30 minutes and then warmed to room temperature. After stirring for a further 4 hours, the mixture was recooled to 0 ° C. and quenched by careful addition of saturated aqueous NaHCO ₃ . The mixture was extracted with ethyl acetate and the organic layer was washed with saturated aqueous NaHCO ₃ , dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 2: 1 hexanes: ethyl acetate to give compound 165 (148 mg, 65%).
[505] (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7- from Compound 165 according to the methods described in Examples 25 and 30 Tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (4-chloro-3-isopropoxyphenyl) propanoic acid was synthesized. MS: calcd (MH) ^- = 586.15 m / z; Found (MH) ⁻ = 585.92 m / z.
[506] Example 41
[507] (3S) -3-({[(1-{[2-chloro-6-tetrahydro-1 (2H) -pyridinylphenyl] methyl} -4-hydroxy-5-methyl-2-oxo-1, Preparation of 2-dihydro-3-pyridinyl) amino] carbonyl} amino) -3- (4-methylphenyl) propanoic acid
[508] Step 1 : Glacial acetic acid (189 μL, in a suspension of compound 166 (0.35 g, 1.06 mmol, prepared according to the methods described in Examples 34 and 25) in methanol (7 mL) and water (3.4 mL) cooled to 0 ° C. 3.2 mmol) and sodium nitrate (178 mg, 2.65 mmol) were added sequentially. The mixture was allowed to slowly warm to rt overnight then diluted with chloroform and water. Check the pH of the aqueous phase to bring it to pH 4-5. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 167 (0.35 g, 92%) as a yellow solid.
[509] (3S) -3-({[(1-{[2-chloro-6-tetrahydro-1 (2H) -pyridinylphenyl] methyl} -4-hydroxy from compound 167 according to the method described in Example 25 Roxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl) amino] carbonyl} amino) -3- (4-methylphenyl) propanoic acid was synthesized. MS: calcd (MH) ^- = 551.21 m / z; Found (MH) ^- = 551.06 m / z.
[510] Example 42
[511] (3S) -3-({[(1-{[2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Preparation of Nyl] amino} -3- [3- (difluoromethyl) phenyl] propanoic acid
[512] Step 1 : Palladium acetate (73 mg, 0.32 mmol), tri-0-tolylphosphine (197 mg) in a solution of 3-bromobenzaldehyde 168 (3.00 g, 16.2 mmol) in DMF (69 mL) under anhydrous nitrogen atmosphere. , 0.65 mmol), ethyl acrylate (2.20 mL, 20.3 mmol) and triethylamine (4.50 mL, 32.4 mmol) were added. The system was deoxygenated (five toggles between vacuum and nitrogen) and the mixture was heated to 125 ° C. for 19 hours and then cooled to room temperature. The reaction solution was poured into water and extracted with ether. The organic layer was washed with HCl (4N) and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 169 (2.74 g, 83%). This material was used without further purification.
[513] Step 2 : (dimethylamino) sulfur trifluoride (0.96 mL, 9.8 mmol) was added by syringe to a flask containing compound 169 (1.00 g, 4.9 mmol) under anhydrous nitrogen atmosphere. The mixture was heated to 90 ° C. with a windscreen for 25 minutes and then cooled to room temperature. The resulting mixture was diluted with CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ and water. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 1: 5 ethyl acetate: hexanes to give compound 170 (0.62 g, 56%).
[514] Step 3 : Second-BuLi in a solution of (R)-(+)-N-benzyl-α-methylbenzylamine (0.70 g, 3.3 mmol) in THF (6.7 mL) cooled to -78 ° C under anhydrous nitrogen atmosphere. (4.22 mL, 1.3 M in cyclohexane, 5.5 mmol) was added dropwise. The resulting mixture was stirred at −78 ° C. for 30 minutes and then a solution of compound 170 (0.62 g, 2.74 mmol) in THF (3.4 mL) was added dropwise by syringe. The mixture was stirred at −78 ° C. for 5 hours and then quenched with glacial acetic acid (2 mL) in THF (5 mL). The reaction mixture was warmed to room temperature and poured into a 1: 1 mixture of saturated aqueous NaHCO ₃ : EtOAc. The organic layer was washed with water (twice) and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 1: 5 ethyl acetate: hexanes to give compound 171 (1.2 g, 100%). This material contained a small amount of impurities but was used without further purification.
[515] Step 4 : Pd / C (10% Pd dry weight, 50% by weight, degussa type E101 NE / W, in a solution of compound 171 (0.50 g, 1.14 mmol) in EtOH (10 mL) at room temperature under anhydrous nitrogen atmosphere 0.25 g) and glacial acetic acid (0.5 mL) were added. The atmosphere was replaced with hydrogen (5 toggles between hydrogen and vacuum from the balloon) and the mixture was heated to 35 ° C. for 6 hours. The reaction was cooled to room temperature, filtered through a plug of Celite ^R 521 and the filtrate was concentrated under reduced pressure. The residue was diluted with CHCl ₃ and washed with saturated aqueous NaHCO ₃ . The aqueous layer was extracted with CHCl ₃ (twice) and the combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 1:10 MeOH: CHCl ₃ to give compound 172 (180 mg, 67%).
[516] (3S) -3-({[(1-{[2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2 from compound 172 according to the method described in Example 25 -Dihydro-3-pyridinyl} amino) carbonyl] amino}-[3- (difluoromethyl) phenyl] propanoic acid was synthesized. MS: calcd (MH) ^- = 504.11 m / z; Found (MH) ^- = 503.96 m / z.
[517] Example 43
[518] While changing the starting materials, several compounds of Formula 7 and Formula 8 were synthesized using the method described in Examples 3, 4, 8, 25, 26, 27, 29, 30, 34, 36, 39 and 41. Compounds synthesized therefrom and their physical data are reported in Table 1 below.
[519]
[520]
[521]
[522]
[523]
[524]
[525]
[526]
[527]
[528]
[529]
[530]
[531]
[532]
[533] Example 42
[534] The efficacy of the synthesized compounds can be determined using a method of linking a 26-amino acid peptide (CDELPQLVTLPHPNLHGPEILDVPST) containing the CS1 sequence of fibronectin with N-terminal Cys to maleimide activated ovalbumin. Bovine serum albumin (BSA) and CS1 linked ovalbumin were coated on 96-well polystyrene plates with 0.5 μg / ml in TBS for 16 hours at 4 ° C. Plates were washed three times with TBS and blocked with TBS containing 3% BSA for 4 hours at room temperature. Blocked plates were washed three times with binding buffer (TBS; 1 mM MgCl ₂ ; 1 mM CaCl ₂ ; 1 mM MnCl ₂ ) before assay. Ramos cells fluorescently labeled with calcein AM were resuspended in binding buffer (10 ⁷ cells / ml) and diluted 1: 2 with the same buffer with or without compound. 100 μM compound was added. The cells were immediately added to wells (2.5 × 10 ⁵ cells / well) and incubated at 37 ° C. for 30 minutes. After washing three times with binding buffer, adherent cells were lysed and quantified by fluorimeter. The results are listed in Tables 2-7. IC ₅₀ values are defined as the dose (μM) required to induce 50% inhibition. The lower the IC ₅₀ value and the higher the inhibition rate, the higher the efficiency of the compound for the inhibition of cell adhesion.
[535] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[(3S) -2-oxo-1- (2-thienylmethyl) hexahydro-3-pyridinyl ] Amino} carbonyl) amino] propanoic acid0.2Calculated (MH) ^- = 444.12; found (MH) ^- = 444.08. (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[(3S) -2-oxo-1- (2-thienylmethyl) tetrahydro-1H-pyrrole- 3-yl] amino} carbonyl) amino] propanoic acid15Calculated (MH) ^- = 430.11; found (MH) ^- = 430.06 (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[(3R) -2-oxo-1- (2-thienylmethyl) hexahydro-3-pyridinyl ] Amino} carbonyl) amino] propanoic acid2Calculated (MH) ^- = 444.12; found (MH) ^- = 444.05 (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[2-oxo-1- (2-thienylmethyl) -1,2-dihydro-3-pyri Diyl] amino} carbonyl) amino] propanoic acid0.9Calculated (MH) ^- = 440.09; found (MH) ^- = 439.98. (3S) -3- (1,3-benzodioxol-5-yl) -3-({[((3S) -2-oxo-1- {4-[(2-toluidinocarbonyl) amino ] Benzyl} hexahydro-3-pyridinyl] amino} carbonyl} amino) propanoic acid0.0003Calculated (MH) ^- = 586.23; found (MH) ^- = 586.17. (3S) -3- (1,3-benzodioxol-5-yl) -3-({[2-oxo-1- {4-[(2-toluidinocarbonyl) amino] benzyl} -1 , 2-dihydro-3-pyridinyl] amino} carbonyl} amino) propanoic acid0.001Calculated (MH) ^- = 582.20; found (MH) ^- = 582.20. (3S) -3- (1,3-benzodioxol-5-yl) -3-({[((3S) -1- {4-[(2-methylbenzyl) amino] benzyl} -2-oxo Hexahydro-pyridinyl] amino] carbonyl) amino] propanoic acidnonenone (3S) -3- (1,3-benzodioxol-5-yl) -3-[({butyl [2-oxo-1- (2-thienylmethyl) -1,2-dihydro-3- Pyridinyl] amino} carbonyl) amino] propanoic acid20Calculated (MH) ^- = 496.15; found (MH) ^- = 496.10. (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[(3S) -2-oxo-1- (2-thienylmethyl) azpanyl] amino} carbonyl ) Amino] propanoic acid0.015Calculated (MH) ^- = 458.13; found (MH) ^- = 458.09.
[536] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[2-methyl-4- (2-methylpropyl) -6-oxo-1- (phenylmethyl) -1,6-dihydro-5-pyrimidinyl] amino} carbo Yl) amino] -3- (4-methylphenyl) propanoic acid10Calculated (MH) ^- = 475.23; found (MH) ^- = 475.02. (3S) -3- (1,3-benzodioxol-5-yl) -3-({[2-oxo-1- (phenylmethyl) -4-propyl-1,2-dihydro-3-pyri Diyl] amino} carbonyl) amino] propanoic acid10Calculated (MH) ^- = 476.18; found (MH) ^- = 475.99. (3S) -3- (1,3-benzodioxol-5-yl) -3-({[9-oxo-8- (phenylmethyl) -2,3,4,5,8,9-hexahydro -1H-pyrido [3,4-b] azin-1-yl] carbonyl} amino) propanoic acid4000Calculated (MH) ^- = 488.18; found (MH) ^- = 488.19. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-ethyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid10Calculated (MH) ^- = 466.15; found (MH) ^- = 465.95. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-4-propyl-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid4Calculated (MH) ^- = 480.17; found (MH) ^- = 480.00. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid5Calculated (MH) ^- = 454.15; found (MH) ^- = 454.09. (3S) -3-{[({6-methyl-2-oxo- (phenylmethyl) -4-[(phenylmethyl) oxy] -1,2-dihydro-3-pyridinyl} amino) carbonyl] Amino} -3- (4-methylphenyl) propanoic acid5Calculated (MH) ^- = 524.22; found (MH) ^- = 524.02. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2,4-dimethyl-6-oxo-1,6-dihydro-5-pyrimidinyl} amino) carbonyl] Amino} -3- (4-methylphenyl) propanoic acid10Calculated (MH) ^- = 467.15; found (MH) ^- = 467.00.
[537] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-{[({1-[(2,4-dichlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino } -3- (4-methylphenyl) propanoic acid30Calculated (MH) ^- = 486.10; found (MH) ^- = 485.95. (3S) -3-{[({4-amino-1-[(2-chlorophenyl) methyl] -6-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Amino} -3- (4-methylphenyl) propanoic acid10Calculated (MH) ^- = 467.15; found (MH) ^- = 467.14. (3S) -3-[({[1-[(2-chlorophenyl) methyl] -4- (methyloxy) -2-oxo-1,2-dihydro-3-pyridinyl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid20Calculated (MH) ^- = 468.13 found (MH) ^- = 467.97. (3S) -3-{[({4-chloro-1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid20Calculated (MH) ^- = 472.08; Found (MH) ^- = 471.91. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- [3-methyl-4- (methyloxy) phenyl] propanoic acid15Calculated (MH) ^- = 482.15; found (MH) ^- = 481.93. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- [4- (methyloxy) phenyl] propanoic acid3Calculated (MH) ^- = 470.15; found (MH) ^- = 470.01. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (3,4-dimethylphenyl] propanoic acid10Calculated (MH) ^- = 468.17; found (MH) ^- = 468.05. (3S) -3-{[({4-amino-1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid10Calculated (MH) ^- = 453.13; found (MH) ^- = 453.01. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-fluoro-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid15Calculated (MH) ^- = 456.12; found (MH) ^- = 455.94.
[538] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1-[(2-chlorophenyl) methyl] -2-oxo-4- (phenylamino) -1,2-dihydro-3-pyridinyl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid20Calculated (MH) ^- = 529.16; found (MH) ^- = 529.02. (3S) -3-[({[1-[(2-chlorophenyl) methyl] -2-oxo-4- (2-pyridinylamino) -1,2-dihydro-3-pyridinyl] amino} Carbonyl) amino] -3- (4-methylphenyl) propanoic acid15Calculated (MH) ^- = 530.16; found (MH) ^- = 529.99. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid10Calculated (MH) ^- = 454.11; found (MH) ^- = 454.05. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-4-[(2-pyridinylmethyl) amino] -1,2-dihydro-3-pyridinyl } Amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid15Calculated (MH) ^- = 544.17; found (MH) ^- = 544.03. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-4-[(3-pyridinylmethyl) amino] -1,2-dihydro-3-pyridinyl } Amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid20Calculated (MH) ^- = 544.17; found (MH) ^- = 544.02. (3S) -3-[({[1-[(2-chlorophenyl) methyl] -4- (1,4-oxazinan-4-yl) -2-oxo-1,2-dihydro-3- Pyridinyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acidOneCalculated (MH) ^- = 523.17; found (MH) ^- = 523.02. (3S) -3-[({[1-[(2-chlorophenyl) methyl] -2-oxo-4- (propylamino) -1,2-dihydro-3-pyridinyl} amino) carbonyl] Amino} -3- (4-methylphenyl) propanoic acid10Calculated (MH) ^- = 495.18; found (MH) ^- = 495.04. (3S) -3-{[({1-[(2-fluorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid20Calculated (MH) ^- = 436.17; found (MH) ^- = 435.99. (3S) -3-{[({1-[(2,6-dichlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino } -3- (4-methylphenyl) propanoic acid20Calculated (MH) ^- = 486.10; found (MH) ^- = 485.95.
[539] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3R) -3-{[({1-[(2-chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} moiety Carbonic acid300Calculated (MH) ^- = 376.11; Found (MH) ^- = 376.00. (3S) -3-{[({1-[(2-bromophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid10Calculated (MH) ^- = 496.09; found (MH) ^- = 495.87. (3S) -3-[({[4-methyl-2-oxo-1- (phenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] -3- (4- Methylphenyl) propanoic acid30Calculated (MH) ^- = 418.17; found (MH) ^- = 417.96. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [3-methyl-4- (methyloxy) phenyl] propanoic acid8Calculated (MH) ^- = 484.12 found (MH) ^- = 484.03. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid10Calculated (MH) ^- = 514.15; found (MH) ^- = 514.00. (3S) -3-{[({4-bromo-1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid20Calculated (MH) ^- = 516.03; found (MH) ^- = 515.90. (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2 -Dihydro-3-pyridinyl} amino) carbonyl] amino} propanoic acid20Calculated (MH) ^- = 484.09; found (MH) ^- = 484.03. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[(2-{[2- (methyloxy) ethyl] oxy} ethyl) oxy] -2-oxo-1 , 2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid2Calculated (MH) ^- = 556.18 Found (MH) ^- = 556.03. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] amino} -3- (4-methylphenyl) propanoic acid15Calculated (MH) ^- = 468.13; found (MH) ^- = 468.05.
[540] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[(1,1-dimethylethyl) amino] -2-oxo-1,2-dihydro-3-pyri Diyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid3Calculated (MH) ^- = 509.20; found (MH) ^- = 509.06. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} 3-phenylpropanoic acid10Calculated (MH) ^- = 440.10; found (MH) ^- = 440.04. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4- [4-methyltetrahydro-1 (2H) -pyrazinyl] -2-oxo-1,2-dihydro -3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid3Calculated (MH) ^- = 536.20; found (MH) ^- = 536.12. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [4- (methyloxy) phenyl] propanoic acid5Calculated (MH) ^- = 470.11; found (MH) ^- = 470.05. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [3,4,5-tris (methyloxy) phenyl] propanoic acid20Calculated (MH) ^- = 530.13; found (MH) ^- = 530.05. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3,5-dimethylphenyl) propanoic acid15Calculated (MH) ^- = 468.13; found (MH) ^- = 468.08. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[(3-methyl-5-isoxazolyl) amino] -2-oxo-1,2-dihydro- 3-pyridinyl} amino) carbonyl] amino} -3- (4- (methyl) phenyl) propanoic acid15Calculated (MH) ^- = 534.15; found (MH) ^- = 534.01. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3-methylphenyl] propanoic acid20Calculated (MH) ^- = 454.17; found (MH) ^- = 454.04. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [3- (methyloxy) phenyl] propanoic acid5Calculated (MH) ^- = 470.11; found (MH) ^- = 470.03.
[541] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3- [3,5-bis (methyloxy) phenyl] -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2- Dihydro-3-pyridinyl} amino) carbonyl] amino} propanoic acid3Calculated (MH) ^- = 500.12; found (MH) ^- = 500.07. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl} amino) carbonyl] amino } -3- (4-methylphenyl) propanoic acid8Calculated (MH) ^- = 504.13; found (MH) ^- = 504.06. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [3- (trifluoromethyl) phenyl] propanoic acid20Calculated (MH) ^- = 508.04; found (MH) ^- = 508.09. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[({ethyl [(ethylamino) carbonyl] amino} carbonyl) amino] -2-oxo-1, 2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid2Calculated (MH) ^- = 595.21; found (MH) ^- = 594.97. (3S) -3-{[({4- (1-azanthyl) -1-[(2-chlorophenyl) methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] amino} -3- (4-methylphenyl) propanoic acid5Calculated (MH) ^- = 493.16; found (MH) ^- = 493.05. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-fluorophenyl) propanoic acid30Calculated (MH) ^- = 458.09; found (MH) ^- = 458.03. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3-fluorophenyl) propanoic acid40Calculated (MH) ^- = 458.09; found (MH) ^- = 458.06. (3S) -3-[({[1-[(2-chlorophenyl) methyl] -4-({2-[(2-{[2- (methyloxy) ethyl] oxy} ethyl) oxy] ethyl} Oxy) -2-oxo-1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid2Calculated (MH) ^- = 600.21; found (MH) ^- = 600.10. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [4- (trifluoromethyl) phenyl] propanoic acid25Calculated (MH) ^- = 508.09; found (MH) ^- = 508.02.
[542] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-{[({1-[(2-fluorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino } -3- (4-methylphenyl) propanoic acid30Calculated (MH) ^- = 438.15; found (MH) ^- = 438.07. (3S) -3-{[({1-[(2-chloro-6-fluorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) Carbonyl] amino} -3- (4-methylphenyl) propanoic acid10Calculated (MH) ^- = 472.11; found (MH) ^- = 472.06. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [4- (1,1-dimethylethyl) phenyl] propanoic acid400Calculated (MH) ^- = 496.16; found (MH) ^- = 496.11. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- [4- (methylphenyl) propanoic acid70Calculated (MH) ^- = 452.14; found (MH) ^- = 451.99. 3- (4-chlorophenyl) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) Carbonyl] amino} propanoic acid30Calculated (MH) ^- = 474.06; found (MH) ^- = 474.07. (3S) -3-[({[1-[(2-methyl-6-oxo-1- (phenylmethyl) -4- (2-pyridinyl) -1,6-dihydro-5-pyrimidinyl ] Amino} carbonyl) amino] -3- [4- (methylphenyl) propanoic acid25Calculated (M + H) ⁺ = 498.22; found (M + H) ⁺ = 498.10. 3- (3-chlorophenyl) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) Carbonyl] amino} propanoic acid30Calculated (MH) ^- = 474.06; found (MH) ^- = 474.03. 3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- ( 3,4-dichlorophenyl) propanoic acid40Calculated (MH) ^- = 508.02; Found (MH) ^- = 507.97.
[543] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[2-oxo-1- (phenylmethyl) -3-azpanyl] amino} carbonyl) amino] propane mountain0.015Calculated (MH) ^- = 452.18; found (MH) ^- = 452.10. (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({1-[(3-cyanophenyl) methyl] -2-oxo-3-azpanyl} amino) Carbonyl] amino} propanoic acid0.04Calculated (MH) ^- = 477.18; found (MH) ^- = 477.14. (3S) -3- (4-methylphenyl) -3-[({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino Propanoic acid0.6Calculated (MH) ^- = 410.11; found (MH) ^- = 410.00. (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[2-oxo-1- (phenylmethyl) -1,2-dihydro-3-pyridinyl] amino } Carbonyl) amino] propanoic acid0.5Calculated (MH) ^- = 434.13; found (MH) ^- = 434.05. (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({1-[(4-methylphenyl) methyl] -2-oxo-1,2-dihydro-3- Pyridinyl} amino) carbonyl] amino} propanoic acidOneCalculated (MH) ^- = 448.14; found (MH) ^- = 448.02. (3S) -3- (1,3-benzodioxol-5-yl) -3-({[(1-{[4- (methyloxy) phenyl] methyl} -2-oxo-1,2-di Hydro-3-pyridinyl) amino] carbonyl} amino) propanoic acid3Calculated (MH) ^- = 464.14; found (MH) ^- = 464.03. (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({1-[(3-methylphenyl) methyl] -2-oxo-1,2-dihydro-3- Pyridinyl} amino) carbonyl] amino} propanoic acid1.5Calculated (MH) ^- = 448.15; found (MH) ^- = 448.04. (3S) -3- [3,5-bis (methyloxy) phenyl] -3-[({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3-pyridinyl ] Amino} carbonyl) amino] propanoic acid0.7Calculated (MH) ^- = 456.12; found (MH) ^- = 456.00.
[544] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3- [4- (methyloxy) phenyl] -3-[({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} Carbonyl) amino] propanoic acid0.8Calculated (MH) ^- = 426.11; found (MH) ^- = 426.00. (3S) -3-[({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] -3- [3- ( Trifluoromethyl) phenyl] propanoic acid2.5Calculated (MH) ^- = 464.09; found (MH) ^- = 463.99. (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[3- (phenyloxy) phenyl] amino} carbonyl) amino] propanoic acid50Calculated (MH) ^- = 419.12; found (MH) ^- = 418.97. (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({3-[(2-thiophenylmethyl) amino] phenyl} amino) carbonyl] amino} propanoic acid5Calculated (MH) ^- = 438.11; found (MH) ^- = 438.00. (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({1-[(3-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3 -Pyridinyl} amino) carbonyl] amino} propanoic acid0.8Calculated (MH) ^- = 468.09; found (MH) ^- = 468.01. (3S) -3- (1,3-benzodioxol-5-yl) -3-({[(2-oxo-1-{[3- (trifluoromethyl) phenyl] methyl} -1,2 -Dihydro-3-pyridinyl) amino] carbonyl} amino) propanoic acid0.8Calculated (MH) ^- = 502.12; found (MH) ^- = 502.03. (3S) -3- (4-fluorophenyl) -3-[({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl ) Amino] propanoic acid1.6Calculated (MH) ^- = 414.09; found (MH) ^- = 414.01. (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({1-[(4-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3 -Pyridinyl} amino) carbonyl] amino} propanoic acid3Calculated (MH) ^- = 468.09; found (MH) ^- = 467.99.
[545] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3- (1,3-benzodioxol-5-yl) -3-({[(1-{[2- (methyloxy) phenyl] methyl} -2-oxo-1,2-di Hydro-3-pyridinyl) amino] carbonyl} amino) propanoic acid0.5Calculated (MH) ^- = 464.14; found (MH) ^- = 464.04. (3S) -3- [3- (methyloxy) phenyl] -3-[({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} Carbonyl) amino] propanoic acid1.4Calculated (MH) ^- = 426.11; found (MH) ^- = 426.02. (3S) -3-[({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] -3-phenylpropanoic acidOneCalculated (MH) ^- = 396.10; found (MH) ^- = 396.01. (3S) -3-[({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] -3- [3,4 , 5-tris (methyloxy) phenyl] propanoic acid0.3Calculated (MH) ^- = 486.13; found (MH) ^- = 485.98. (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3 -Pyridinyl} amino) carbonyl] amino} propanoic acid0.3Calculated (MH) ^- = 468.08; found (MH) ^- = 468.03. (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({1-[(4-fluorophenyl) methyl] -2-oxo-1,2-dihydro- 3-pyridinyl} amino) carbonyl] amino} propanoic acid2Calculated (MH) ^- = 452.12; found (MH) ^- = 452.00. 3- (1,3-benzodioxol-5-yl) -2,2-difluoro-3-[({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro -3-pyridinyl] amino} carbonyl) amino] propanoic acid> 100Calculated (MH) ^- = 476.07; found (MH) ^- = 476.00. (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({2-oxo-1- [3- (phenyloxy) propyl] -1,2-dihydro-3 -Pyridinyl} amino) carbonyl] amino} propanoic acid14Calculated (MH) ^- = 478.16; found (MH) ^- = 478.09.
[546] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({1-[(3,5-dichlorophenyl) methyl] -2-oxo-1,2-dihydro -3-pyridinyl} amino) carbonyl] amino} propanoic acid5Calculated (MH) ^- = 502.05; found (MH) ^- = 501.94. (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[1- (cyclopentylmethyl) -2-oxo-1,2-dihydro-3-pyridinyl] Amino} carbonyl) amino] propanoic acid6Calculated (MH) ^- = 426.16; found (MH) ^- = 426.09. (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({2-oxo-1- [2- (2-thiophenyl) ethyl] -1,2-dihydro -3-pyridinyl} amino) carbonyl] amino} propanoic acid15Calculated (MH) ^- = 454.09; found (MH) ^- = 453.99. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4 -Methylphenyl) propanoic acid0.1Calculated (M + H) ⁺ = 440.14; found (M + H) ⁺ = 440.09. (3S) -3- (2,3-dihydro-1-benzofuran-5-yl) -3-[({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro -3-pyridinyl] amino} carbonyl) amino] propanoic acid0.14Calculated (MH) ^- = 438.11; found (MH) ^- = 437.99. (3S) -3- (3-fluorophenyl) -3-[({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl ) Amino] propanoic acid3Calculated (MH) ^- = 414.09; found (MH) ^- = 413.99. (3S) -3-[({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] -3- [4- ( Trifluoromethyl) phenyl] propanoic acid1.5Calculated (MH) ^- = 464.09; found (MH) ^- = 463.99. (3S) -3- (1,3-benzodioxol-5-yl) -3-[({[6-oxo-1- (phenylmethyl) -1,6-dihydro-3-pyridinyl] amino } Carbonyl) amino] propanoic acid0.5Calculated (MH) ^- = 434.13; found (MH) ^- = 434.02. (3S) -3- [4-fluoro-3- (trifluoromethyl) phenyl] -3-[({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro- 3-pyridinyl] amino} carbonyl) amino] propanoic acid0.35Calculated (MH) ^- = 482.08; found (MH) ^- = 481.97.
[547] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3- [4- (1,1-dimethylethyl) phenyl-3-[({[2-oxo-1- (2-thiophenylmethyl) -1,2-dihydro-3-pyridinyl ] Amino} carbonyl) amino] propanoic acid2Calculated (MH) ^- = 452.16; found (MH) ^- = 452.02. (3S) -3- (1,3-benzodioxol-5-yl) -3-[({butyl [2,5-dioxo-1- (phenylmethyl) tetrahydro-1H-pyrrol-3-yl ] Amino} carbonyl) amino] propanoic acid70Calculated (MH) ^- = 494.19; found (MH) ^- = 494.12. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [3 , 4,5-tris (methoxyoxy) phenyl] propanoic acid0.04Calculated (M + H) ⁺ = 516.16; found (M + H) ⁺ = 516.02. (3S) -3-{[({1-[(2,6-dichlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid0.2Calculated (M + H) ⁺ = 474.10; found (M + H) ⁺ = 474.04. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [4 -Fluoro-3- (trifluoromethyl) phenyl] propanoic acid0.2Calculated (M + H) ⁺ = 512.10; found (M + H) ⁺ = 512.04. (3S) -3-{[({1-[(2-fluorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- ( 4-methylphenyl) propanoic acid0.1Calculated (MH) ^- = 422.15; found (MH) ^- = 422.01. (3S) -3- (4-methylphenyl) -3-{[({1-[(2-methylphenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] Amino} propanoic acid0.1Calculated (MH) ^- = 418.18; found (MH) ^- = 418.02. (3S) -3-{[({1-[(2-bromophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- ( 4-methylphenyl) propanoic acid0.05Calculated (M + H) ⁺ = 484.09; found (M + H) ⁺ = 484.03. (3S) -3-{[({1-[(2,4-dichlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid0.4Calculated (M + H) ⁺ = 474.10; found (M + H) ⁺ = 474.05.
[548] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [2 , 3-dihydro-1-benzofuran-5-yl) propanoic acid0.04Calculated (MH) ^- = 466.11; found (MH) ^- = 466.00. (3S) -3- (1,3-benzodioxol-5-yl) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3 -Pyridinyl} amino) carbonyl] amino} propanoic acid2Calculated (MH) ^- = 468.09; found (MH) ^- = 467.97. (3S) -3- (4-methylphenyl) -3-({[(2-oxo-1-{[2- (trifluoromethyl) phenyl] methyl} 1,2-dihydro-3-pyridinyl) Amino] carbonyl} amino) propanoic acidOneCalculated (M + H) ⁺ = 474.10; found (M + H) ⁺ = 474.09. (3S) -3-{[({1-[(2,5-dichlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid0.15Calculated (M + H) ⁺ = 474.10; found (M + H) ⁺ = 474.04. (2R) -2-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3-phenylpropane mountain50Calculated (MH) ^- = 424.10; found (MH) ^- = 423.99. (2R) -2-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -2-phenyl Carbonic acid80Calculated (MH) ^- = 410.08; found (MH) ^- = 409.95. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3 , 5-dimethylphenyl) propanoic acid0.1Calculated (MH) ^- = 452.14; found (MH) ^- = 451.96. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3-phenylpropane mountain0.1Calculated (MH) ^- = 424.10; found (MH) ^- = 424.07. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [4 -(Methyloxy) phenyl] propanoic acid0.1Calculated (MH) ^- = 454.11; found (MH) ^- = 454.01.
[549] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4 Hydroxyphenyl) propanoic acid0.1Calculated (MH) ^- = 440.10; found (MH) ^- = 440.00. (3S) -3-({[(1-{[3- (methyloxy) phenyl] methyl} -2-oxo-1,2-dihydro-3-pyridinyl) amino] carbonyl} amino) -3 -(4-methylphenyl) propanoic acid0.2Calculated (MH) ^- = 434.17; found (MH) ^- = 434.01. (3S) -3-{[({1-[(2-bromophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [ 3,4,5-tris (methyloxy) phenyl] propanoic acid0.08Calculated (MH) ^- = 558.09; found (MH) ^- = 557.87. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3 , 4-dimethylphenyl) propanoic acid0.09Calculated (M + H) ⁺ = 454.15; found (M + H) ⁺ = 454.07. (3S) -3-[({[5-chloro-2-hydroxy-3- (phenylmethyl) phenyl] amino) carbonyl) amino] -3- (4-methylphenyl) propanoic acid8Calculated (MH) ^- = 437.12; found (MH) ^- = 437.06. (3S) -3- (4-methylphenyl) -3-[({[3- (phenylmethyl) phenyl] amino} carbonyl) amino] propanoic acid10Calculated (MH) ^- = 387.17; found (MH) ^- = 387.00. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [3 -Methyl-4- (methyloxy) phenyl] propanoic acid0.04Calculated (MH) ^- = 468.13; found (MH) ^- = 468.01. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4 -Hydroxy-3-methylphenyl) propanoic acid0.07Calculated (MH) ^- = 454.11; found (MH) ^- = 454.00. (3S) -3-{[({1-[(2,3-dichlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid0.35Calculated (MH) ^- = 472.08; found (MH) ^- = 471.94.
[550] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1-([1,1'-biphenyl] -2-ylmethyl) -2-oxo-1,2-dihydro-3-pyridinyl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid2.5Calculated (MH) ^- = 480.19; found (MH) ^- = 480.05. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3 -Methylphenyl) propanoic acid0.2Calculated (MH) ^- = 438.12; found (MH) ^- = 438.00. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (2 -Methylphenyl) propanoic acid3Calculated (MH) ^- = 438.12; found (MH) ^- = 437.99. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (2 , 3-dihydro-1H-inden-5-yl) propanoic acid0.3Calculated (MH) ^- = 464.13; found (MH) ^- = 464.03. (3S) -3-{[({1-[(2-cyanophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- ( 4-methylphenyl) propanoic acid0.1Calculated (M + H) ⁺ = 431.18; found (M + H) ⁺ = 431.09. (3S) -3- [2,6-bis (methyloxy) phenyl] -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3- Pyridinyl} amino) carbonyl] amino} propanoic acid6Calculated (MH) ^- = 484.14; found (MH) ^- = 483.96. (3S) -3-{[({1-[(3-hydroxyphenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- ( 4-methylphenyl) propanoic acid0.2Calculated (M + H) ⁺ = 420.18; found (M + H) ⁺ = 422.05. (3S) -3-[({[2-methyl-6-oxo-1- (phenylmethyl) -1,6-dihydro-5-pyridinyl] amino} carbonyl) amino] -3- (4- Methylphenyl) propanoic acid0.1Calculated (MH) ^- = 419.17; found (MH) ^- = 419.03. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-oxo-1,4-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4 -Methylphenyl) propanoic acid0.1Calculated (MH) ^- = 438.12; found (MH) ^- = 438.10.
[551] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3- (4-methylphenyl) -3-{[({1-[(2-nitrophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Amino} propanoic acidOneCalculated (M + H) ⁺ = 451.17; found (M + H) ⁺ = 451.07. (3S) -3- (4-methylphenyl) -3-{[({1-[(4-nitrophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Amino} propanoic acidOneCalculated (M + H) ⁺ = 451.17; found (M + H) ⁺ = 451.09. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (2 , 6-dihydroxyphenyl) propanoic acid3Calculated (MH) ^- = 456.10; found (MH) ^- = 456.04. (3S) -3-{[({1-[(2,6-difluorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid0.3Calculated (MH) ^- = 440.14; found (MH) ^- = 440.00. (3S) -3-{[({1-[(2,4-difluorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid1.3Calculated (MH) ^- = 440.14; Found (MH) ^- = 439.96. (3S) -3-{[({1-[(2,5-difluorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid0.8Calculated (MH) ^- = 440.14; Found (MH) ^- = 439.96. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-methyl-6-oxo-1,6-dihydro-5-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid0.09Calculated (MH) ^- = 453.13; found (MH) ^- = 453.00. (3S) -3-{[({1-[(2-chloro-6-fluorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid0.1Calculated (MH) ^- = 456.11; Found (MH) ^- = 455.94. (3S) -3-{[({1-[(2-bromo-5-fluorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino } -3- (4-methylphenyl) propanoic acid0.5Calculated (MH) ^- = 500.06; found (MH) ^- = 499.91.
[552] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-{[({1-[(2-chloro-4-fluorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid0.35Calculated (MH) ^- = 456.11; Found (MH) ^- = 455.93. (3S) -3-{[({1-[(2-bromophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [ 3-methyl-4- (methyloxy) phenyl] propanoic acid0.2Calculated (MH) ^- = 512.08 found (MH) ^- = 511.96. (3S) -3-{[({1-[(3,5-dimethyl-4-isoxazole) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino } -3- (4-methylphenyl) propanoic acid3Calculated (MH) ^- = 423.17 found (MH) ^- = 423.02. (3S) -3- (4-methylphenyl) -3-{[({2-oxo-1-[(2,4,6-trimethylphenyl) methyl] -1,2-dihydro-3-pyridinyl} Amino) carbonyl] amino} propanoic acid2.5Calculated (MH) ^- = 446.21; found (MH) ^- = 446.08. (3S) -3- (4-methylphenyl) -3-{[({1-[(2-methyl-1,3-thiazol-4-yl) methyl] -2-oxo-1,2-dihydro -3-pyridinyl} amino) carbonyl] amino} propanoic acidOneCalculated (MH) ^- = 425.13; found (MH) ^- = 424.99. (3S) -3-({[(1-{[4- (1,1-dimethylethyl) phenyl] methyl} -2-oxo-1,2-dihydro-3-pyridinyl) amino] carbonyl} Amino) -3- (4-methylphenyl) propanoic acid6Calculated (MH) ^- = 460.22; found (MH) ^- = 460.07. (3S) -3-[({[1- (1,3-benzoxazol-2-ylmethyl) -2-oxo-1,2-dihydro-3-pyridinyl] amino} carbonyl) amino]- 3- (4-methylphenyl) propanoic acid> 10Calculated (MH) ^- = 445.15; found (MH) ^- = 445.01. (3S) -3-({[(1- {2-[(2-hydroxyphenyl) amino] -2-oxoethyl} -2-oxo-1,2-dihydro-3-pyridinyl) amino] Carbonyl} amino) -3- (4-methylphenyl) propanoic acid> 10Calculated (MH) ^- = 463.16; found (MH) ^- = 463.06. (3S) -3-{[({1-[(2-chloro-6-nitrophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid4Calculated (MH) ^- = 483.11; found (MH) ^- = 483.01.
[553] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-{[({1-[(5-chloro-2-fluorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid2.5Calculated (MH) ^- = 456.11; Found (MH) ^- = 456.00. (3S) -3-{[({1-[(2-amino-6-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid2Calculated (MH) ^- = 453.13; found (MH) ^- = 453.02. (3S) -3-({[(1-{[2-fluoro-4- (trifluoromethyl) phenyl] methyl} -2-oxo-1,2-dihydro-3-pyridinyl) amino] Carbonyl} amino) -3- (4-methylphenyl) propanoic acid3Calculated (MH) ^- = 490.14; found (MH) ^- = 489.99. (3S) -3-{[({1-[(5-chloro-2-thiophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-methylphenyl) propanoic acid1.3Calculated (MH) ^- = 440.08; found (MH) ^- = 443.97. (3S) -3-{[({1-[(2-bromo-5-nitrophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid2Calculated (MH) ^- = 527.06; found (MH) ^- = 526.95. 3- (4-chlorophenyl) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) Carbonyl] amino} propanoic acid0.03Calculated (MH) ^- = 474.06; found (MH) ^- = 474.07. (3S) -3-[({[2-methyl-6-oxo-1- (phenylmethyl) -4- (2-pyridinyl) -1,6-dihydro-5-pyrimidinyl] amino} carbo Yl) amino] -3- (4-methylphenyl) propanoic acid0.025Calculated (M + H) ⁺ = 498.22; found (M + H) ⁺ = 498.10. (3S) -3-{[({1-[(5-amino-2-bromophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid0.08Calculated (MH) ^- = 497.08; found (MH) ^- = 497.02. (3S) -3-{[({1-[(2,5-dimethylphenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid0.15Calculated (MH) ^- = 432.19; found (MH) ^- = 432.04.
[554] compoundIC ₅₀ (nM)Mass spectral data (m / z) 3- (3-chlorophenyl) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) Carbonyl] amino} propanoic acid0.03Calculated (MH) ^- = 474.06; found (MH) ^- = 474.03. 3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- ( 3,4-dichlorophenyl) propanoic acid0.04Calculated (MH) ^- = 508.02; found (MH) ^- = 507.97. (3S) -3-({[(1-{[5- (acetylamino) -2-bromophenyl] methyl} -2-oxo-1,2-dihydro-3-pyridinyl) amino] carbonyl } Amino) -3- (4-methylphenyl) propanoic acid0.2Calculated (MH) ^- = 539.09; found (MH) ^- = 539.02. (3S) -3-[({[1-({2-bromo-5-[(methylsulfonyl) amino] phenyl} methyl) -2-oxo-1,2-dihydro-3-pyridinyl] Amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.25Calculated (MH) ^- = 575.06; found (MH) ^- = 575.01. 3- (4-chlorophenyl) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} Propanoic acid0.4Calculated (MH) ^- = 458.07; found (MH) ^- = 457.96. 3- (3-chlorophenyl) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} Propanoic acidOneCalculated (MH) ^- = 458.07; found (MH) ^- = 457.93. 3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3,4-dichloro Phenyl) propanoic acidOneCalculated (MH) ^- = 492.03; found (MH) ^- = 491.85. (3S) -3-{[({1-[(2-bromo-4-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acidOneCalculated (MH) ^- = 516.03; found (MH) ^- = 515.91. (3S) -3-{[({1-[(4-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4 -Methylphenyl) propanoic acid2Calculated (MH) ^- = 438.12; found (MH) ^- = 437.88.
[555] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [2,3-dimethyl-4- (methyloxy) phenyl] propanoic acid0.035Calculated (MH) ^- = 498.14; found (MH) ^- = 498.05. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- {4-[(trifluoromethyl) oxy] phenyl} propanoic acid0.015Calculated (MH) ^- = 524.08; found (MH) ^- = 524.03. (3R) -3-[({[1-[(2-chlorophenyl) methyl] -4- (1,4-oxazinan-4-yl) -2-oxo-1,2-dihydro-3- Pyridinyl] amino} carbonyl) amino] -5-methylhexanoic acid0.1Calculated (MH) ^- = 489.19; found (MH) ^- = 489.13. (3S) -3-[({[4-hydroxy-6-methyl-2-oxo-1- (phenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino]- 3- (4-methylphenyl) propanoic acid0.035Calculated (MH) ^- = 434.17; found (MH) ^- = 434.08. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-4-[(propylsilfonyl) amino] -1,2-dihydro-3-pyridinyl} amino ) Carbonyl] amino} -3- (4-methylphenyl) propanoic acid0.030Calculated (MH) ^- = 559.14; found (MH) ^- = 559.04. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-ethylphenyl) propanoic acid0.025Calculated (MH) ^- = 468.13; found (MH) ^- = 468.06. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [4- (ethyloxy) phenyl] propanoic acid0.02Calculated (MH) ^- = 484.13; found (MH) ^- = 484.06. (3S) -3-[({[4-hydroxy-2-oxo-1- (phenylmethyl) -1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] -3- (4 -Methylphenyl) propanoic acid0.030Calculated (MH) ^- = 420.16; found (MH) ^- = 420.08.
[556] compoundIC ₅₀ (μM)Mass spectral data (m / z) (3S) -3-[({[1- (3-tert-butyl-3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid2.5Calculated (MH) ^- = 490.23; found (MH) ^- = 490.11. (3S) -3-[({[1- (4-fluorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl Propanoic acid2Calculated (MH) ^- = 422.12; found (MH) ^- = 422.00. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- [4-fluoro-3- (trifluoromethyl) methyl] propanoic acid0.025Calculated (MH) ^- = 526.08; found (MH) ^- = 526.01. (3S) -3-[({[1- (2,5-dimethylbenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino]- 3- (4-methylphenyl) propanoic acid0.02Calculated (MH) ^- = 448.19; found (MH) ^- = 448.00. (3S) -3-[({[4-hydroxy-1- (2-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.02Calculated (MH) ^- = 434.17; found (MH) ^- = 434.05. (3S) -3-[({[1- (2-hydroxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl Propanoic acid0.2Calculated (MH) ^- = 426.16; found (MH) ^- = 420.09.
[557] compoundIC ₅₀ (μM)Mass spectral data (m / z) (3S) -3-[({[1- (3-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) Propanoic acid0.5Calculated (MH) ^- = 438.12; found (MH) ^- = 438.01. (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.1Calculated (MH) ^- = 468.13; found (MH) ^- = 468.08. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methoxy-3,5-dimethylphenyl) propanoic acid0.035Calculated (MH) ^- = 498.14; found (MH) ^- = 497.94. 4-{[3-[({[(1S) -2-carboxy-1- (4-methylphenyl) ethyl] amino} carbonyl) amino] -1- (2-chlorobenzyl) -2-oxo-1, 2-dihydropyridin-4-yl] amino} propanoic acid0.004Calculated (MH) ^- = 573.15; found (MH) ^- = 572.92. (3S) -3-{[({1- (2-chlorobenzyl) -4-[(2,2-dimethylpropanoyl) amino] -2-oxo-1,2-dihydropyridin-3-yl } Amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid0.01Calculated (MH) ^- = 537.19; found (MH) ^- = 536.88. (3S) -3-[({[1- (2-chloro-5-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.09Calculated (MH) ^- = 468.13; found (MH) ^- = 467.99. (3R) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] butanoic acid0.19Calculated (MH) ^- = 378.09; found (MH) ^- = 378.01. (3S) -3-[({[4-{[tert-butylamino) carbonyl] amino} -1- (2-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl ] Amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.01Calculated (MH) ^- = 552.20; found (MH) ^- = 551.89. (3S) -3-[({[1- (2-chloro-5-hydroxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.25Calculated (MH) ^- = 454.12; found (MH) ^- = 454.03. (3S) -3-[({[1- (2-cyanobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3 -(4-methylphenyl) propanoic acid0.009Calculated (MH) ^- = 445.15; found (MH) ^- = 445.01. (3S) -3-[({[1- (2,4-dichlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino]- 3- (4-methylphenyl) propanoic acid0.06Calculated (MH) ^- = 488.08; found (MH) ^- = 487.96.
[558] compoundIC ₅₀ (μM)Mass spectral data (m / z) (3S) -3-[({[4-hydroxy-1- (2-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3 -(4-methylphenyl) propanoic acid0.08Calculated (MH) ^- = 450.17; found (MH) ^- = 450.02. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methoxy-2,5-dimethylphenyl) propanoic acid0.08Calculated (MH) ^- = 498.14; found (MH) ^- = 497.95. (3S) -3-[({[1- (2-chloro-6-hydroxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.1Calculated (MH) ^- = 454.12; found (MH) ^- = 454.05. (3S) -3-[({[1- (3-tert-butyl-2-hydroxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid4Calculated (MH) ^- = 476.02; found (MH) ^- = 476.00. (3R) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.3Calculated (MH) ^- = 454.17; found (MH) ^- = 454.05. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethylphenyl) propanoic acid0.015Calculated (MH) ^- = 468.13; found (MH) ^- = 467.95. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (2,3-dihydro-1,4-benzodioxin-6-yl) propanoic acid0.01Calculated (MH) ^- = 498.10; found (MH) ^- = 497.85. (3S) -3-[({[1- (2,5-difluorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid0.015Calculated (MH) ^- = 456.14; found (MH) ^- = 455.96. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -4- (4-methylphenyl) butanoic acid30Calculated (MH) ^- = 468.13; found (MH) ^- = 467.87. (3S) -3-{[({1- [2-chloro-5- (methylthio) benzyl] -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl} amino) carbo Nil] amino} -3- (4-methylphenyl) propanoic acid0.015Calculated (MH) ^- = 500.10; found (MH) ^- = 499.92. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (7-methoxy-1,3-benzodioxol-5-yl) propanoic acid0.005Calculated (MH) ^- = 514.10; found (MH) ^- = 513.86. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxy-4-methoxyphenyl) propanoic acid0.002Calculated (MH) ^- = 514.13; found (MH) ^- = 513.90.
[559] compoundIC ₅₀ (μM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-fluoro-4-methoxyphenyl) propanoic acid0.015Calculated (MH) ^- = 488.10; Found (MH) ^- = 487.92. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,4-dimethoxyphenyl) propanoic acid0.002Calculated (MH) ^- = 500.12; found (MH) ^- = 500.01. (3S) -3-[({[1- (4-fluorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3 -(4-methylphenyl) propanoic acid0.022Calculated (MH) ^- = 438.18; found (MH) ^- = 438.00. (3S) -3-[({[1- (2-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl Propanoic acid0.25Calculated (MH) ^- = 434.17; found (MH) ^- = 433.95. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (2,5-dimethylphenyl) propanoic acid0.05Calculated (MH) ^- = 468.13; found (MH) ^- = 467.94. (3S) -3-[({[1- (2-chloro-5-methoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid0.012Calculated (MH) ^- = 484.13; found (MH) ^- = 484.03. (3S) -3-[({[1- (3,5-bis (trifluoromethyl) benzyl] -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} Carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.3Calculated (MH) ^- = 556.13; found (MH) ^- = 555.95. (3S) -3-[({[1- (4-tert-butylbenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.03Calculated (MH) ^- = 476.22; found (MH) ^- = 476.05. (3S) -3-[({[1- (3-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.015Calculated (MH) ^- = 454.12; found (MH) ^- = 453.99. (3S) -3-[({[1- (4-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.007Calculated (MH) ^- = 454.12; found (MH) ^- = 454.00. (3S) -3-{[({4-hydroxy-2-oxo-1- [3- (trifluoromethyl) benzyl] -1,2-dihydropyridin-3-yl} amino) carbonyl] Amino} -3- (4-methylphenyl) propanoic acid0.017Calculated (MH) ^- = 488.14; found (MH) ^- = 487.99.
[560] compoundIC ₅₀ (μM)Mass spectral data (m / z) (3S) -3-[({[1- (2-bromobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3 -(4-methylphenyl) propanoic acid0.015Calculated (MH) ^- = 498.07; found (MH) ^- = 497.97. (3S) -3-[({[1- (3,4-dichlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino]- 3- (4-methylphenyl) propanoic acid0.045Calculated (MH) ^- = 488.08; found (MH) ^- = 487.96. (3S) -3-[({[4-hydroxy-1- (4-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.025Calculated (MH) ^- = 434.17; found (MH) ^- = 434.05. (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid0.003Calculated (MH) ^- = 484.13; found (MH) ^- = 484.02. (3S) -3-{[({4-hydroxy-2-oxo- [4- (trifluoromethyl) benzyl] -1,2-dihydropyridin-3-yl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid0.02Calculated (MH) ^- = 488.14; found (MH) ^- = 487.99. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- [3- (trifluoromethoxy) phenyl] propanoic acid0.02Calculated (MH) ^- = 524.08; found (MH) ^- = 523.91. (3S) -3-[({[4-hydroxy-1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3 -(4-methylphenyl) propanoic acid0.055Calculated (MH) ^- = 434.17; found (MH) ^- = 433.99. (3S) -3-[({[4-hydroxy-2-oxo-1- (pyridin-2-ylmethyl) -1,2-dihydropyridin-3-yl] amino} carbonyl) amino]- 3- (4-methylphenyl) propanoic acid0.045Calculated (MH) ^- = 421.15; found (MH) ^- = 421.06. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid0.005Calculated (MH) ^- = 468.13; found (MH) ^- = 467.99. (3S) -3-[({[1- (2,4-difluorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid0.03Calculated (MH) ^- = 456.14; found (MH) ^- = 456.01. (3S) -3-[({[1- (2,6-difluorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid0.008Calculated (MH) ^- = 456.14; found (MH) ^- = 456.01.
[561] compoundIC ₅₀ (μM)Mass spectral data (m / z) (3S) -3-{[({4-hydroxy-2-oxo-1- [3- (trifluoromethoxy) benzyl] -1,2-dihydropyridin-3-yl} amino) carbonyl] Amino} -3- (4-methylphenyl) propanoic acid0.045Calculated (MH) ^- = 504.14; found (MH) ^- = 503.98. (3S) -3-{[({4-hydroxy-2-oxo- [4- (trifluoromethoxy) benzyl] -1,2-dihydropyridin-3-yl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid0.025Calculated (MH) ^- = 504.14; found (MH) ^- = 503.98. (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (3,5-dimethoxyphenyl) propanoic acid0.0015Calculated (MH) ^- = 530.13; found (MH) ^- = 529.91. 3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (2-furyl Propanoic acid0.05Calculated (MH) ^- = 430.08; found (MH) ^- = 429.94. (3S) -3-{[({4-hydroxy-2-oxo-1- [2- (trifluoromethyl) benzyl] -1,2-dihydropyridin-3-yl} amino) carbonyl] Amino} -3- (4-methylphenyl) propanoic acid0.02Calculated (MH) ^- = 488.14; found (MH) ^- = 487.96. (3R) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -4- (4-methylphenyl) butanoic acid0.15Calculated (MH) ^- = 468.13; found (MH) ^- = 467.99. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,4-diethoxyphenyl) propanoic acid0.0008Calculated (MH) ^- = 528.15; found (MH) ^- = 527.96. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid0.003Calculated (MH) ^- = 484.12; found (MH) ^- = 483.94. (3S) -3-[({[4-hydroxy-1- (3-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3 -(4-methylphenyl) propanoic acid0.04Calculated (MH) ^- = 450.17; found (MH) ^- = 450.00. (3S) -3-[({[1- (2,3-dichlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino]- 3- (4-methylphenyl) propanoic acid0.13Calculated (MH) ^- = 488.08; found (MH) ^- = 487.92. (3S) -3-[({[1-benzyl-2-oxo-5- (trifluoromethyl) -1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- ( 4-methylphenyl) propanoic acid1.5Calculated (MH) ^- = 472.15; found (MH) ^- = 471.89.
[562] compoundIC ₅₀ (μM)Mass spectral data (m / z) (3S) -3-[({[1- (3,5-dimethylbenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino]- 3- (4-methylphenyl) propanoic acid0.06Calculated (MH) ^- = 448.19; Found (MH) ^- = 448.02. (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- [4- (trifluoromethoxy) phenyl] propanoic acid0.04Calculated (MH) ^- = 554.09; found (MH) ^- = 553.98. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-methoxy-4-methylphenyl) propanoic acid0.003Calculated (MH) ^- = 484.13; found (MH) ^- = 483.95. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,5-dimethoxy-4-methylphenyl) propanoic acid0.003Calculated (MH) ^- = 514.14; found (MH) ^- = 513.95. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-5-pentyl-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid0.04Calculated (MH) ^- = 524.20; found (MH) ^- = 523.98. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,4-dimethoxyphenyl) propanoic acid0.005Calculated (M + H) ⁺ = 468.13; found (M + H) ⁺ = 467.99. (3S) -3-[({[1- (2,4-dichlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl ) Amino] -3- (4-methylphenyl) propanoic acid0.02Calculated (MH) ^- = 502.09; found (MH) ^- = 501.89. [2-({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) -1- (4-methylphenyl) high Drazino] acetic acid> 10Calculated (MH) ^- = 455.11; found (MH) ^- = 454.97. (3S) -3-[({[1- (2-chlorobenzyl) -5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid0.01Calculated (MH) ^- = 482.15; found (MH) ^- = 482.00. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- Pyridin-3-ylpropanoic acid0.05Calculated (MH) ^- = 441.09; found (MH) ^- = 441.00. (3S) -3-[({[5-butyl-1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid0.025Calculated (MH) ^- = 510.18; found (MH) ^- = 509.98.
[563] compoundIC ₅₀ (μM)Mass spectral data (m / z) (3S) -3-{[({1- [2-chloro-5- (trifluoromethyl) benzyl] -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl} amino ) Carbonyl] amino} -3- (4-methylphenyl) propanoic acid0.01Calculated (MH) ^- = 522.10; found (MH) ^- = 521.97. (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (3-methylphenyl) propanoic acid0.005Calculated (MH) ^- = 487.13; found (MH) ^- = 484.00. (3S) -3-[({[1- (2,6-dichlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino]- 3- (4-methylphenyl) propanoic acid0.013Calculated (MH) ^- = 488.08; found (MH) ^- = 487.91. (3S) -3-[({[1- (2-chloro-5-fluorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid0.014Calculated (MH) ^- = 477.11; found (MH) ^- = 471.96. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} Carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.01Calculated (MH) ^- = 482.15; found (MH) ^- = 481.98. (3S) -3-[({[1- (4-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid0.02Calculated (MH) ^- = 468.13; found (MH) ^- = 467.94. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.003Calculated (M + H) ⁺ = 496.16; found (M + H) ⁺ = 495.99. (3S) -3-{[({4-hydroxy-5-methyl-1- [4- (methylsulfonyl) benzyl] -2-oxo-1,2-dihydropyridin-3-yl} amino) Carbonyl] amino} -3- (4-methylphenyl) propanoic acid0.02Calculated (MH) ^- = 512.15; found (MH) ^- = 511.96. (3S) -3-[({[4-hydroxy-1- (4-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3 -(4-methylphenyl) propanoic acid0.02Calculated (MH) ^- = 450.17; found (MH) ^- = 449.99. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid0.02Calculated (MH) ^- = 496.16; found (MH) ^- = 495.94.
[564] compoundIC ₅₀ (μM)Mass spectral data (m / z) (3S) -3-({[(1- {4-[(dimethylamino) sulfonyl] benzyl} -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl) amino] carbo Nyl} amino) -3- (4-methylphenyl) propanoic acid0.035Calculated (MH) ^- = 527.16; found (MH) ^- = 526.96. (3S) -3-[({[4-hydroxy-1- (mesitylmethyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- ( 4-methylphenyl) propanoic acid0.06Calculated (MH) ^- = 462.20; found (MH) ^- = 462.02. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinolin-3-yl] amino} Carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.02Calculated (MH) ^- = 508.16; found (MH) ^- = 507.96. (3S) -3-[({[1- (2-chlorobenzyl) -5-ethyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} Carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.025Calculated (MH) ^- = 496.16; found (MH) ^- = 495.96. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.4Calculated (MH) ^- = 468.13; found (MH) ^- = 467.85. (3S) -3-{[({4-hydroxy-1- [2- (methylthio) benzyl] -2-oxo-1,2-dihydropyridin-3-yl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid0.02Calculated (MH) ^- = 466.14; found (MH) ^- = 465.97. (3S) -3-({[(1- {2-[(dimethylamino) sulfonyl] benzyl} -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl) amino] carbo Nil} amino)]-3- (4-methylphenyl) propanoic acid0.03Calculated (MH) ^- = 527.16; found (MH) ^- = 526.97. (3S) -3-[({[1- (2,6-dimethoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.01Calculated (MH) ^- = 480.18; found (MH) ^- = 480.00. (3S) -3-{[({4-hydroxy-2-oxo-1- [2- (trifluoromethoxy) benzyl] -1,2-dihydropyridin-3-yl} amino) carbonyl] Amino} -3- (4-methylphenyl) propanoic acid0.025Calculated (MH) ^- = 504.14; found (MH) ^- = 503.96. (3R) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -4- [3- (trifluoromethyl) phenyl] butanoic acid0.35Calculated (MH) ^- = 522.10; found (MH) ^- = 521.95.
[565] compoundIC ₅₀ (μM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-propoxyphenyl) propanoic acid0.003Calculated (MH) ^- = 498.14; found (MH) ^- = 497.97. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (3-ethoxyphenyl) propanoic acid0.003Calculated (M + H) ⁺ = 528.19; found (M + H) ⁺ = 528.02. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl] carbonyl) amino ] -3- (4-methylphenyl) propanoic acid0.006Calculated (MH) ^- = 482.15; found (MH) ^- = 481.95. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (3,4-diethoxyphenyl) propanoic acid0.005Calculated (MH) ^- = 570.20; found (MH) ^- = 569.98. (3S) -3- (3-butoxyphenyl) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] Amino} carbonyl) amino] propanoic acid0.005Calculated (M + H) ⁺ = 514.17; found (M + H) ⁺ = 514.00. (3S) -3-{[({1- [2-chloro-5- (methylsulfonyl) benzyl] -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl} amino) Carbonyl] amino} -3- (4-methylphenyl) propanoic acid0.003Calculated (MH) ^- = 532.10; found (MH) ^- = 531.94. (3R) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -4- (2-methylphenyl) butanoic acid0.08Calculated (MH) ^- = 468.13; found (MH) ^- = 468.03. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- [3- (2-methoxyethoxy) phenyl] propanoic acid0.003Calculated (MH) ^- = 514.14; found (MH) ^- = 513.95. (3S) -3-[({[1- (4-chloro-2-methoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid0.025Calculated (MH) ^- = 484.13; found (MH) ^- = 483.93. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,4-dipropoxyphenyl) propanoic acid0.003Calculated (MH) ^- = 556.18; found (MH) ^- = 555.94.
[566] compoundIC ₅₀ (μM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7,8,9-hexahydro-1H-cyclohepta [b] Pyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.12Calculated (MH) ^- = 522.18; found (MH) ^- = 521.98. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -4, 4-diphenylbutanoic acid12Calculated (MH) ^- = 530.15; found (MH) ^- = 529.92. (3S) -3-{[({1- [2- (difluoromethoxy) benzyl] -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl} amino) carbonyl] Amino} -3- (4-methylphenyl) propanoic acid0.075Calculated (MH) ^- = 486.15; found (MH) ^- = 486.00. (3S) -3-{[({4-hydroxy-5-methyl-2-oxo-1-[(1R) -1-phenylethyl] -1,2-dihydropyridin-3-yl} amino) Carbonyl] amino} -3- (4-methylphenyl) propanoic acid4Calculated (MH) ^- = 448.19; Found (MH) ^- = 447.99. (3S) -3-[({[1- (4-chlorobenzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid0.03Calculated (MH) ^- = 496.16; found (MH) ^- = 495.96. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,4-diethylphenyl) propanoic acid0.05Calculated (MH) ^- = 496.16; found (MH) ^- = 495.98. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,5-difluorophenyl) propanoic acid0.05Calculated (MH) ^- = 476.08; found (MH) ^- = 475.93. 3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (2-naph Acetyl) propanoic acid0.02Calculated (MH) ^- = 490.12; found (MH) ^- = 489.97. 3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (5-methyl 2-furyl) propanoic acid0.025Calculated (M + H) ⁺ = 446.11; found (M + H) ⁺ = 446.08. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,4-dibutoxyphenyl) propanoic acid0.025Calculated (MH) ^- = 584.21; found (MH) ^- = 583.98. (3S) -3-{[({4-hydroxy-1- [2- (methylsulfonyl) benzyl] -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid0.035Calculated (M + H) ⁺ = 500.15; found (M + H) ⁺ = 500.01.
[567] compoundIC ₅₀ (μM)Mass spectral data (m / z) 3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (1-naph Acetyl) propanoic acid0.2Calculated (MH) ^- = 490.12; found (MH) ^- = 489.91. (3S) -3-[({[1- (4-chlorobenzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (3-ethoxyphenyl) propanoic acid0.03Calculated (MH) ^- = 526.17; found (MH) ^- = 525.95. (3S) -3-[({[1- (4-chlorobenzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (3,4-diethoxyphenyl) propanoic acid0.015Calculated (MH) ^- = 570.20; found (MH) ^- = 569.97. (3S) -3-[({[1- (2,6-dimethylbenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino]- 3- (4-methylphenyl) propanoic acid0.035Calculated (MH) ^- = 448.19; Found (MH) ^- = 448.02. (3S) -3- [3,5-bis (trifluoromethyl) phenyl] -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-di Hydropyridin-3-yl] amino} carbonyl) amino] propanoic acid0.22Calculated (MH) ^- = 576.08; found (MH) ^- = 575.91. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- [3- (difluoromethoxy) phenyl] propanoic acid0.006Calculated (MH) ^- = 506.09; found (MH) ^- = 505.93. (3R) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -4- Pyridine-2-ylbutanoic acid0.225Calculated (MH) ^- = 455.11; found (MH) ^- = 455.09. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (3,4-diethoxyphenyl) propanoic acid0.0006Calculated (MH) ^- = 542.17; found (MH) ^- = 542.06. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (3-ethoxyphenyl) propanoic acid0.002Calculated (MH) ^- = 499.15; found (MH) ^- = 498.07. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (3-methoxy-4-methylphenyl) propanoic acid0.020Calculated (M + H) ⁺ = 500.16; found (M + H) ⁺ = 500.02.
[568] compoundIC ₅₀ (μM)Mass spectral data (m / z) 3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (2-naphthyl) propanoic acid0.030Calculated (MH) ^- = 504.13; found (MH) ^- = 504.04. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl] Amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid0.015Calculated (MH) ^- = 526.17; found (MH) ^- = 525.95. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl] Amino} carbonyl) amino] -3- (3-methoxy-4-methylphenyl) propanoic acid0.025Calculated (MH) ^- = 526.17; found (MH) ^- = 525.97. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl] Amino} carbonyl) amino] -3- (3,4-diethoxyphenyl) propanoic acid0.004Calculated (MH) ^- = 570.20; found (MH) ^- = 570.00. (3S) -3-[({[1- (2-chloro-6-cyanobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid0.007Calculated (MH) ^- = 479.11; found (MH) ^- = 478.90. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl] Amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid0.03Calculated (MH) ^- = 496.16; found (MH) ^- = 495.97. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl Amino] -3- (3-methoxy-4-methylphenyl) propanoic acid0.015Calculated (MH) ^- = 512.16; found (MH) ^- = 511.95. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl ) Amino] -3- (3,4-diethoxyphenyl) propanoic acid0.003Calculated (MH) ^- = 556.18; found (MH) ^- = 555.99.
[569] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3R) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -4- (1-naphthyl) butanoic acid2500Calculated (MH) ^- = 504.13; found (MH) ^- = 503.97. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl ) Amino] -3- (3-ethoxyphenyl) propanoic acid30Calculated (MH) ^- = 512.16; found (MH) ^- = 511.99. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl ) Amino] -3- (3,4-dimethylphenyl) propanoic acid40Calculated (MH) ^- = 496.16; found (MH) ^- = 496.05. (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylphenyl) propanoic acid5Calculated (MH) ^- = 498.15; found (MH) ^- = 497.91. (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3,4-diethoxyphenyl) propanoic acid2Calculated (MH) ^- = 572.18; found (MH) ^- = 571.96. (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3-methoxy-4-methylphenyl) propanoic acid6Calculated (MH) ^- = 528.15; found (MH) ^- = 527.95. (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid3Calculated (MH) ^- = 528.15; found (MH) ^- = 527.99. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propanoic acid15Calculated (MH) ^- = 556.09; found (MH) ^- = 555.97. (3R) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -4- (2-chlorophenyl) butanoic acid700Calculated (MH) ^- = 488.08; found (MH) ^- = 487.96.
[570] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-{[({4-hydroxy-1- [3- (methylthio) benzyl] -2-oxo-1,2-dihydropyridin-3-yl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid20Calculated (MH) ^- = 466.14; found (MH) ^- = 466.04. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (3,4-dimethylphenyl) propanoic acid15Calculated (MH) ^- = 482.15; found (MH) ^- = 482.02. (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3,4-dimethylphenyl) propanoic acid3Calculated (MH) ^- = 512.16; found (MH) ^- = 512.03. (3S) -3-[({[1- (2-chlorobenzyl) -5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid20Calculated (M + H) ⁺ = 496.16; found (M + H) ⁺ = 496.05. (3S) -3-[({[1- (4-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid50Calculated (MH) ^- = 494.15; found (MH) ^- = 494.02. (3S) -3-[({[1- (3-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid20Calculated (MH) ^- = 468.13; found (MH) ^- = 468.02. (3S) -3-[({[1- (2,6-dichlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl ) Amino] -3- (4-methylphenyl) propanoic acid20Calculated (MH) ^- = 502.09; found (MH) ^- = 501.92. (3S) -3-[({[4-hydroxy-5-methyl-1- (4-methylbenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid150Calculated (MH) ^- = 448.19; Found (MH) ^- = 448.05. 3- (1-benzofuran-2-yl) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] propanoic acid140Calculated (MH) ^- = 480.10; found (MH) ^- = 479.96. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid3Calculated (MH) ^- = 524.16; found (MH) ^- = 523.95.
[571] compoundIC ₅₀ (nM)Mass spectral data (m / z) 3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (6-meth Methoxy-2-naphthyl) propanoic acid15Calculated (MH) ^- = 520.13; found (MH) ^- = 520.00. (3S) -3-[({[1- (3,5-dimethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbo Yl) amino] -3- (4-methylphenyl) propanoic acid70Calculated (MH) ^- = 494.19; found (MH) ^- = 494.04. (3S) -3-[({[1- (2,6-difluorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} Carbonyl) amino] -3- (4-methylphenyl) propanoic acid25Calculated (MH) ^- = 470.15; found (MH) ^- = 470.03. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Ill] amino} carbonyl) amino] -3- (3,4-diethoxyphenyl)3Calculated (M + H) ⁺ = 570.20; found (M + H) ⁺ = 570.00. (3S) -3-{[({4-hydroxy-1- [3- (methylsulfonyl) benzyl] -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid25Calculated (MH) ^- = 498.13; found (MH) ^- = 498.01. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} Carbonyl) amino] -3- (3,4-diethoxyphenyl) propanoic acid3Calculated (MH) ^- = 556.19; found (MH) ^- = 556.02. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} Carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid4Calculated (MH) ^- = 512.16; found (MH) ^- = 512.02. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} Carbonyl) amino] -3- (3,4-dimethylphenyl) propanoic acid45Calculated (MH) ^- = 496.16; found (MH) ^- = 496.01. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} Carbonyl) amino] -3- (3-methoxy-4-methylphenyl) propanoic acid25Calculated (MH) ^- = 512.16; found (MH) ^- = 511.97. 3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4,5 Dimethyl-2-furyl) propanoic acid115Calculated (MH) ^- = 458.11; found (MH) ^- = 457.99.
[572] compoundIC ₅₀ (nM)Mass spectral data (m / z) 3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-meth Methoxy-1-naphthyl) propanoic acid160Calculated (MH) ^- = 520.13; found (MH) ^- = 519.97. (3R) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -5- Phenylpentanoic acid115Calculated (MH) ^- = 468.13; found (MH) ^- = 467.98. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid12Calculated (MH) ^- = 534.14; found (MH) ^- = 533.94. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (3,4-dimethylphenyl) propanoic acid18Calculated (M + H) ⁺ = 510.18; found (M + H) ⁺ = 510.06. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid7Calculated (M + H) ⁺ = 500.16; found (M + H) ⁺ = 500.06. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylphenyl) propanoic acid3Calculated (MH) ^- = 512.16; found (MH) ^- = 512.03. (3S) -3-[({[1- (2-chlorobenzyl) -5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (3-ethoxyphenyl) propanoic acid14Calculated (M + H) ⁺ = 526.17; found (M + H) ⁺ = 526.01. (3S) -3-[({[1- (2-chlorobenzyl) -5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (3,4-diethoxyphenyl) propanoic acid6Calculated (M + H) ⁺ = 570.20; found (M + H) ⁺ = 570.04. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- [4- (difluoromethoxy) phenyl] propanoic acid30Calculated (MH) ^- = 506.09; found (MH) ^- = 505.96. 3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3-quinoline-2- Ilpropanoic acid105Calculated (MH) ^- = 491.11; found (MH) ^- = 490.96.
[573] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1- (2-fluoro-6-methoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] Amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid10Calculated (MH) ^- = 482.17; found (MH) ^- = 482.02. (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylphenyl) propanoic acid15Calculated (M + H) ⁺ = 528.19; found (M + H) ⁺ = 528.04. (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3-ethoxypetyl) propanoic acid7Calculated (M + H) ⁺ = 558.20; found (M + H) ⁺ = 558.07. (3S) -3-[({[1- (5-chloro-2-fluorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylfetyl) propanoic acid15Calculated (MH) ^- = 486.12; found (MH) ^- = 486.00. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl] amino} carbonyl) amino] -3- (3-methoxy-4-methylfetyl) propanoic acid14Calculated (MH) ^- = 534.14; found (MH) ^- = 533.95. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl] amino} carbonyl) amino] -3- (3,4-diethoxypetyl) propanoic acid4Calculated (MH) ^- = 578.17; found (MH) ^- = 577.99. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl] amino} carbonyl) amino] -3- (3,4-dimethylphenyl) propanoic acid25Calculated (MH) ^- = 518.15; found (MH) ^- = 517.56. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- Pyridin-2-ylpropanoic acid150Calculated (M + H) ⁺ = 443.11; found (M + H) ⁺ = 443.03. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid3Calculated (MH) ^- = 498.14; found (MH) ^- = 498.04. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,5-diethoxyphenyl) propanoic acid7Calculated (MH) ^- = 528.15; found (MH) ^- = 528.02.
[574] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-isopropyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid60Calculated (M + H) ⁺ = 498.18; found (M + H) ⁺ = 498.05. (3S) -3-[({[1- (5-fluoro-2-methylbenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylphenyl) propanoic acid20Calculated (M + H) ⁺ = 468.19; found (M + H) ⁺ = 468.07. (3S) -3-{[({4-hydroxy-5-methyl-2-oxo-1-[(1S) -1-phenylethyl] -1,2-dihydropyridin-3-yl} amino) Carbonyl] amino} -3- (4-methylphenyl) propanoic acid1500Calculated (M + H) ⁺ = 450.20; found (M + H) ⁺ = 450.07. (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3,4-diethoxyphenyl) propanoic acid3Calculated (M + H) ⁺ = 602.23; found (M + H) ⁺ = 602.04. (3S) -3-[({[1- (2-chloro-5-isopropoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] Amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid7Calculated (MH) ^- = 526.17; found (MH) ^- = 526.04. (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3-methoxy-4-methylphenyl) propanoic acid15Calculated (M + H) ⁺ = 558.20; found (M + H) ⁺ = 558.05. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid2Calculated (M + H) ⁺ = 544.19; found (M + H) ⁺ = 544.04. (3S) -3-[({[1- (5-acetyl-2-methoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid33Calculated (MH) ^- = 492.18; found (MH) ^- = 492.04. 3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (6-methoxy-2-naphthyl) propanoic acid35Calculated (MH) ^- = 548.16; found (MH) ^- = 548.01. (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3,4-dimethylphenyl) propanoic acid17Calculated (M + H) ⁺ + = 542.21; found (M + H) ⁺ = 542.05.
[575] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (1-Methyl-1H-indol-5-yl) propanoic acid3Calculated (MH) ^- = 493.13; found (MH) ^- = 492.95. (3S) -3-[({[2- (2-chlorobenzyl) -5-hydroxy-6-methyl-3-oxo-2,3-dihydropyridazin-4-yl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid18Calculated (M + H) ⁺ = 471.14; found (M + H) ⁺ = 471.00. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (6-methoxy-2-naphthyl) propanoic acid5Calculated (MH) ^- = 534.14; found (MH) ^- = 533.91. (3S) -3-[({[2- (2-chlorobenzyl) -5-hydroxy-6-methyl-3-oxo-2,3-dihydropyridazin-4-yl] amino} carbonyl) Amino] -3- (3-ethoxyphenyl) propanoic acid5Calculated (M + H) ⁺ = 501.15; found (M + H) ⁺ = 501.01. 3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3-thien-2- Ilpropanoic acid30Calculated (M + H) ⁺ = 448.07; found (M + H) ⁺ = 447.97. (3S) -3-[({[5-chloro-1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methylphenyl) propanoic acid6Calculated (MH) ^- = 488.08; found (MH) ^- = 487.97. (3S) -3- (3-butoxyphenyl) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H -Cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] propanoic acid20Calculated (MH) ^- = 552.19; found (MH) ^- = 552.01. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- [3- (cyclopentyloxy) phenyl] propanoic acid5Calculated (MH) ^- = 524.16; found (MH) ^- = 542.00. (3S) -3-[({[2- (2-chlorobenzyl) -5-hydroxy-6-methyl-3-oxo-2,3-dihydropyridazin-4-yl] amino} carbonyl) Amino] -3- (3,4-diethoxyphenyl) propanoic acid3Calculated (M + H) ⁺ = 545.18; found (M + H) ⁺ = 544.98. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (1-methyl-1H-indol-5-yl) propanoic acid3Calculated (MH) ^- = 507.14; found (MH) ^- = 506.94.
[576] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[2- (2-chlorobenzyl) -5-hydroxy-6-methyl-3-oxo-2,3-dihydropyridazin-4-yl] amino} carbonyl) Amino] -3- (3,5-diethoxyphenyl) propanoic acid10Calculated (M + H) ⁺ = 545.18; found (M + H) ⁺ = 545.01. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- [4- (trifluoromethoxy) phenyl] propanoic acid70Calculated (MH) ^- = 538.10; found (MH) ^- = 537.95. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- [3- (trifluoromethoxy) phenyl] propanoic acid10Calculated (MH) ^- = 538.10; found (MH) ^- = 537.95. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methoxyphenyl) propanoic acid4Calculated (M + H) ⁺ = 486.14; found (M + H) ⁺ = 486.04. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (6-methoxy-2-naphthyl) propanoic acid15Calculated (MH) ^- = 520.13; found (MH) ^- = 520.03. (3S) -3-{[({1- [2-fluoro-6- (trifluoromethyl) benzyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridine- 3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid100Calculated (MH) ^- = 520.15; found (MH) ^- = 519.97. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- [3- (trifluoromethyl) phenyl] propanoic acid10Calculated (MH) ^- = 522.10; found (MH) ^- = 521.96. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (3-methoxyphenyl) propanoic acid3Calculated (MH) ^- = 484.13; found (MH) ^- = 484.00. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] Pyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid20Calculated (M + H) ⁺ = 510.18; found (M + H) ⁺ = 510.05. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] Pyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid4Calculated (M + H) ⁺ = 540.19; found (M + H) ⁺ = 540.10.
[577] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid3Calculated (M + H) ⁺ = 540.19; found (M + H) ⁺ = 540.09. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (3,5-diethoxyphenyl) propanoic acid3Calculated (MH) ^- = 542.17; found (MH) ^- = 542.00. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid4Calculated (MH) ^- = 556.19; found (MH) ^- = 556.01. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (3-ethoxyphenyl) propanoic acid3Calculated (M + H) ⁺ = 530.17; found (M + H) ⁺ = 530.04. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- [3- (cyclopentyloxy) phenyl) propanoic acid15Calculated (MH) ^- = 538.17; found (MH) ^- = 538.03. 3- (1,1'-biphenyl-4-yl) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydro Pyridin-3-yl] amino} carbonyl) amino] propanoic acid130Calculated (MH) ^- = 530.15; found (MH) ^- = 529.96. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- [3- (2,2,2-trifluoroethoxy) phenyl] propanoic acid30Calculated (M + H) ⁺ 580.15; found (M + H) ⁺ = 580.02. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- [3- (2,2,2-trifluoroethoxy) phenyl] propanoic acid15Calculated (M + H) ⁺ = 554.13; found (M + H) ⁺ = 554.00. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (3-isopropoxyphenyl) propanoic acid3Calculated (M + H) ⁺ = 514.17; found (M + H) ⁺ = 514.05. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid4Calculated (M + H) ⁺ = 558.20; found (M + H) ⁺ = 558.05.
[578] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4-methoxy-3-methylphenyl) propanoic acid9Calculated (M + H) ⁺ = 500.16; found (M + H) ⁺ = 500.01. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] Pyridin-3-yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid10Calculated (M + H) ⁺ = 554.21; found (M + H) ⁺ = 554.06. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (6-methoxy-2-naphthyl) propanoic acid3Calculated (M + H) ⁺ = 580.19; found (M + H) ⁺ = 580.07. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (3,5-dimethoxy-4-methylphenyl) propanoic acid12Calculated (M + H) ⁺ = 530.17; found (M + H) ⁺ = 530.00. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] Pyridin-3-yl] amino} carbonyl) amino] -3- (3-propoxyphenyl) propanoic acid12Calculated (M + H) ⁺ = 554.21; found (M + H) ⁺ = 554.05. (3S) -3-[({[1- (2-chloro-6-propoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylphenyl) propanoic acid10Calculated (M + H) ⁺ = 528.19; found (M + H) ⁺ = 528.06. (3S) -3-[({[1- (2-chloro-6-isobutoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylphenyl) propanoic acid22Calculated (M + H) ⁺ = 542.21; found (M + H) ⁺ = 542.06. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (3-propoxyphenyl) propanoic acid15Calculated (M + H) ⁺ = 540.19; found (M + H) ⁺ = 540.07. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b ] Pyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid3Calculated (M + H) ⁺ = 540.19; found (M + H) ⁺ = 540.04. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b ] Pyridin-3-yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid4Calculated (M + H) ⁺ = 584.22; found (M + H) ⁺ = 584.05.
[579] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (2 ', 6'-dimethoxy-1,1'-biphenyl-4-yl) propanoic acid40Calculated (M + H) ⁺ = 592.19; found (M + H) ⁺ = 592.04. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (1-methyl-1H-indol-7-yl) propanoic acid30Calculated (M + H) ⁺ = 509.16; found (M + H) ⁺ = 509.03. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b ] Pyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid2Calculated (M + H) ⁺ = 570.20; found (M + H) ⁺ = 570.09. (3S) -3-[({[1- (2-chloro-6-propoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid5Calculated (M + H) ⁺ = 558.20; found (M + H) ⁺ = 558.03. (3S) -3-[({[1- (2-chloro-6-isobutoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid14Calculated (M + H) ⁺ = 572.22; found (M + H) ⁺ = 572.05. (3S) -3-[({[1- (2-chloro-6-isopropoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] Amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid7Calculated (M + H) ⁺ = 558.20; found (M + H) ⁺ = 558.03. (3S) -3-{[({1- (2-chloro-6- (2,2,2-trifluoroethoxy) benzyl] -4-hydroxy-5-methyl-2-oxo-1, 2-dihydropyridin-3-yl} amino) carbonyl] amino} -3- (3-ethoxyphenyl) propanoic acid4Calculated (M + H) ⁺ = 598.16; found (M + H) ⁺ = 597.99. 3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- [4- (methylthio) phenyl] propanoic acid15Calculated (M + H) ⁺ = 502.12; found (M + H) ⁺ = 501.98. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b ] Pyridin-3-yl] amino} carbonyl) amino] -3- (6-methoxy-2-naphthyl) propanoic acid2Calculated (M + H) ⁺ = 606.20; found (M + H) ⁺ = 606.04. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (2,3-dihydro-1-benzofuran-5-yl) propanoic acid6Calculated (M + H) ⁺ = 498.14; found (M + H) ⁺ = 498.02. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (1-methyl-1H-indol-5-yl) propanoic acid3Calculated (M + H) ⁺ = 513.19; found (M + H) ⁺ = 553.05.
[580] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (2,3-dihydro-1-benzofuran-5-yl) propanoic acid2Calculated (M + H) ⁺ = 542.17; found (M + H) ⁺ = 542.06. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b ] Pyridin-3-yl] amino} carbonyl) amino] -3- (3,5-diethoxyphenyl) propanoic acid3Calculated (M + H) ⁺ = 614.22; found (M + H) ⁺ = 614.11. (3S) -3-[({[1- (2-chloro-6-isopropoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] Amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid4Calculated (M + H) ⁺ = 558.20; found (M + H) ⁺ = 588.02. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3-propoxyphenyl) propanoic acid3Calculated (M + H) ⁺ = 558.20; found (M + H) ⁺ = 558.07. (3S) -3- (3-butoxyphenyl) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2 -Dihydropyridin-3-yl] amino} carbonyl) amino] propanoic acid4Calculated (M + H) ⁺ = 572.22; found (M + H) ⁺ = 572.07. (3S) -3-[({[5-chloro-1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid3Calculated (M + H) ⁺ = 564.13; found (M + H) ⁺ = 563.99. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (3-isopropoxyphenyl) propanoic acid3Calculated (M + H) ⁺ = 544.19; found (M + H) ⁺ = 544.06. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenter [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (2,3-dihydro-1-benzofuran-5-yl) propanoic acid2Calculated (M + H) ⁺ = 524.16; found (M + H) ⁺ = 524.03. (3S) -3-[({[2- (2-chloro-6-ethoxybenzyl) -5-hydroxy-6-methyl-3-oxo-2,3-dihydropyridazin-4-yl] Amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid7Calculated (M + H) ⁺ = 515.19; found (M + H) ⁺ = 515.05.
[581] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b ] Pyridin-3-yl] amino} carbonyl) amino] -3- (3-propoxyphenyl) propanoic acid3Calculated (M + H) ⁺ = 584.21; found (M + H) ⁺ = 584.10. (3S) -3-[({[2- (2-chloro-6-ethoxybenzyl) -5-hydroxy-6-methyl-3-oxo-2,3-dihydropyridazin-4-yl] Amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid3Calculated (M + H) ⁺ = 545.18; found (M + H) ⁺ = 545.05. (3S) -3-[({[2- (2-chloro-6-ethoxybenzyl) -5-hydroxy-6-methyl-3-oxo-2,3-dihydropyridazin-4-yl] Amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid2Calculated (M + H) ⁺ = 559.20; found (M + H) ⁺ = 559.04. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b ] Pyridin-3-yl] amino} carbonyl) amino] -3- [3- (cyclopentyloxy) phenyl] propanoic acid6Calculated (M + H) ⁺ = 610.23; found (M + H) ⁺ = 610.14. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- [3- (cyclopentyloxy) phenyl] propanoic acid7Calculated (M + H) ⁺ = 566.21; found (M + H) ⁺ = 566.09. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b ] Pyridin-3-yl] amino} carbonyl) amino] -3-phenylpropanoic acid2Calculated (M + H) ⁺ = 526.17; found (M + H) ⁺ = 526.07. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3-phenylpropanoic acid8Calculated (M + H) ⁺ = 482.15; found (M + H) ⁺ = 482.07. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} Carbonyl) amino] -3- (2,3-dihydro-1-benzofuran-5-yl) propanoic acid5Calculated (M + H) ⁺ = 512.16; found (M + H) ⁺ = 512.03. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Il] amino} carbonyl) amino] -3- (1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) propanoic acid4Calculated (M + H) ⁺ = 594.21; found (M + H) ⁺ = 594.05. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- [3- (trifluoromethyl) phenyl] propanoic acid3Calculated (M + H) ⁺ = 568.15; found (M + H) ⁺ = 568.00
[582] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- [3- (trifluoromethoxy) phenyl] propanoic acid4Calculated (M + H) ⁺ = 584.14; found (M + H) ⁺ = 584.01. (3S) -3-{[({1- [2-chloro-6- (2-methoxyethoxy) benzyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro- 1H-cyclopeta [b] pyridin-3-yl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid6Calculated (MH) ^- = 568.18; found (MH) ^- = 568.03. (3S) -3-{[({1- [2-chloro-6- (2-methoxyethoxy) benzyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro- 1H-cyclopeta [b] pyridin-3-yl} amino) carbonyl] amino} -3- (3-ethoxyphenyl) propanoic acid4Calculated (MH) ^- = 598.19; found (MH) ^- = 598.01. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- [3- (cyclopropyloxy) phenyl] propanoic acid4Calculated (M + H) ⁺ = 538.17; found (M + H) ⁺ = 538.09. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl ] Amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid4Calculated (MH) ^- = 556.19; found (MH) ^- = 556.02 (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl ] Amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid4Calculated (MH) ^- = 526.17; found (MH) ^- = 526.02. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -5-ethyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3 -Yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid4Calculated (MH) ^- = 570.20; found (MH) ^- = 570.04. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -5-ethyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3 -Yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid4Calculated (MH) ^- = 540.19; found (MH) ^- = 540.05. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (2'-methoxy-1,1'-biphenyl-4-yl) propanoic acid25Calculated (M + H) ⁺ = 562.19; found (M + H) ⁺ = 562.05. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl ] Amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid3Calculated (MH) ^- = 570.20; found (MH) ^- = 570.00. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl ] Amino} carbonyl) amino] -3-phenylpropanoic acid4Calculated (MH) ^- = 512.16; found (MH) ^- = 512.01.
[583] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -5-ethyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3 -Yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid5Calculated (MH) ^- = 584.22; found (MH) ^- = 584.03. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -5-ethyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3 -Yl] amino} carbonyl) amino] -3-phenylpropanoic acid4Calculated (MH) ^- = 526.17; found (MH) ^- = 526.00. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (6-ethoxy-2-naphthyl) propanoic acid6Calculated (MH) ^- = 592.19; found (MH) ^- = 592.00. (3S) -3-[({[2- (2-chlorobenzyl) -6-ethyl-5-hydroxyoxy-3-oxo-2,3-dihydropyridazin-4-yl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid22Calculated (MH) ^- = 483.14; found (MH) ^- = 483.03. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (3-isobutylphenyl) propanoic acid15Calculated (MH) ^- = 536.20; found (MH) ^- = 536.99. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (1-methyl-1H-indol-6-yl) propanoic acid4Calculated (M + H) ⁺ = 509.16; found (M + H) ⁺ = 509.05. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] Pyridin-3-yl] amino} carbonyl) amino] -3- [3- (cyclopropyloxy) phenyl] propanoic acid4Calculated (MH) ^- = 550.17; found (MH) ^- = 550.01 (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (6-ethoxy-2-naphthyl) propanoic acid15Calculated (MH) ^- = 574.17; found (MH) ^- = 574.02 (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3-phenylpropanoic acid23Calculated (MH) ^- = 526.17; found (MH) ^- = 526.04. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid22Calculated (MH) ^- = 584.22; found (MH) ^- = 584.09. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylphenyl) propanoic acid20Calculated (MH) ^- = 540.09; found (MH) ^- = 540.05.
[584] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid6Calculated (MH) ^- = 570.20; found (MH) ^- = 570.04. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4'-methyl-1,1'-biphenyl-4-yl) propanoic acid40Calculated (MH) ^- = 530.15; found (MH) ^- = 530.02. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Il] amino} carbonyl) amino] -3- (1-methyl-1H-indol-5-yl) propanoic acid4Calculated (MH) ^- = 533.16; found (MH) ^- = 533.00. (3S) -3-{({[1- (2-chloro-6-ethoxybenzyl) -5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] Amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid3Calculated (MH) ^- = 582.20; found (MH) ^- = 582.07. (3S) -3-{({[1- (2-chloro-6-ethoxybenzyl) -5-cyclopropyl-4-hydroxy-2-oxo1,2-hydropyridin-3-yl] amino} Carbonyl) amino] -3- (4-methylphenyl) propanoic acid3Calculated (MH) ^- = 538.17; found (MH) ^- = 538.06. (3S) -3-{({[1- (2-chloro-5-propoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylphenyl) propanoic acid6Calculated (MH) ^- = 526.17; found (MH) ^- = 526.05. (3S) -3-{({[1- (2-chloro-5-methoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylphenyl) propanoic acid3Calculated (MH) ^- = 498.14; found (MH) ^- = 498.01. 3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (2-naphthyl) propanoic acid13Calculated (MH) ^- = 548.16; found (MH) ^- = 548.01. 3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- [4- (methylsulfonyl) phenyl] propanoic acid8Calculated (MH) ^- = 576.12; found (MH) ^- = 576.00. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3'-ethoxy-1,1'-biphenyl-4-yl) propanoic acid27Calculated (MH) ^- = 560.16; found (MH) ^- = 560.04. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] Pyridin-3-yl] amino} carbonyl) amino] -3- [3- (cyclobutyloxy) phenyl] propanoic acid20Calculated (MH) ^- = 564.19; found (MH) ^- = 564.00.
[585] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- [3- (cyclobutyloxy) phenyl] propanoic acid17Calculated (MH) ^- = 550.17; found (MH) ^- = 550.02. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid3Calculated (MH) ^- = 556.19; found (MH) ^- = 556.05. 3-{({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-pyrrolidin-1-ylphenyl) propanoic acid10Calculated (MH) ^- = 523.17; found (MH) ^- = 522.99. 3-{({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-piperidin-1-ylphenyl) propanoic acid22Calculated (MH) ^- = 537.19; found (MH) ^- = 537.08. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] Pyridin-3-yl] amino} carbonyl) amino] -3- [3- (1-ethylpropoxy) phenyl] propanoic acid22Calculated (MH) ^- = 580.22 'found (MH) ^- = 580.04. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- [3- (1-ethylpropoxy) phenyl] propanoic acid20Calculated (MH) ^- = 566.20; found (MH) ^- = 566.01. (3S) -3- (4-chloro-3-isopropoxyphenyl) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-2-oxo-2,5 , 6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] propanoic acid23Calculated (MH) ^- = 586.15; found (MH) ^- = 586.92. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (4-chloro-3-isopropoxyphenyl) propanoic acid38Calculated (MH) ^- = 572.14; found (MH) ^- = 572.00. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3'-methyl-1,1'-biphenyl-4-yl) propanoic acid30Calculated (MH) ^- = 530.15; found (MH) ^- = 530.02. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Il] amino} carbonyl) amino] -3- (1-methyl-1H-indol-6-yl) propanoic acid3Calculated (MH) ^- = 533.16; found (MH) ^- = 532.97. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (1-methyl-1H-indol-6-yl) propanoic acid3Calculated (MH) ^- = 551.17; found (MH) ^- = 551.02.
[586] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (4'-methoxy-1,1'-biphenyl-4-yl) propanoic acid23Calculated (MH) ^- = 560.16; found (MH) ^- = 560.01. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (2'-methyl-1,1'-biphenyl-4-yl) propanoic acid55Calculated (M + H) ⁺ = 546.18; found (M + H) ⁺ = 546.11. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (6-methoxy-2-naphthyl) propanoic acid3Calculated (MH) ^- = 560.16; found (MH) ^- = 560.00. (3S) -3- (4-chloro-3-ethoxyphenyl) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-2-oxo-2,5, 6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] propanoic acid25Calculated (MH) ^- = 572.14; found (MH) ^- = 571.94. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (4-chloro-3-ethoxyphenyl) propanoic acid30Calculated (MH) ^- = 558.12; found (MH) ^- = 557.77. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b ] Pyridin-3-yl] amino} carbonyl) amino] -3- (3-isobutylphenyl) propanoic acid4Calculated (M + H) ⁺ = 582.24; found (M + H) ⁺ = 582.10. (3S) -3-[({[1- (2-chloro-5-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylphenyl) propanoic acid4Calculated (M + H) ⁺ = 514.17; found (M + H) ⁺ = 514.08. 3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl} amino] -3- [4- (methylsulfonyl) phenyl] propanoic acid134Calculated (M + H) ⁺ = 534.11; found (M + H) ⁺ = 534.07. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Il] amino} carbonyl) amino] -3- (2,4-dichloro-3-ethoxyphenyl) propanoic acid225Calculated (M + H) ⁺ = 594.09; found (M + H) ⁺ = 593.98. (3S) -3-{[({1- [2-chloro-5- (piperidin-1-ylsulfonyl) benzyl] -4-hydroxy-5-methyl-2-oxo-1,2-di Hydropyridin-3-yl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid27Calculated (MH) ^- = 615.17; found (MH) ^- = 615.04. (3S) -3-{[({1- [2-chloro-5- (pyrrolidin-1-ylsulfonyl) benzyl] -4-hydroxy-5-methyl-2-oxo-1,2-di Hydropyridin-3-yl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid15Calculated (MH) ^- = 601.15; found (MH) ^- = 601.03.
[587] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b ] Pyridin-3-yl] amino} carbonyl) amino] -3- [3- (cyclopropyloxy) phenyl] propanoic acid2Calculated (M + H) ⁺ = 582.20; found (M + H) ⁺ = 582.10. (3S) -3-{[({1- [2-chloro-6- (cyclopentylmethoxy) benzyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridine-3 -Yl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid20Calculated (MH) ^- = 566.20; found (MH) ^- = 566.09. (3S) -3-{[({1- [2- (benzyloxy) -6-chlorobenzyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl } Amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid10Calculated (MH) ^- = 574.17; found (MH) ^- = 574.01. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (3-chloro-4,5-diethoxyphenyl) propanoic acid3Calculated (M + H) ⁺ = 604.16; found (M + H) ⁺ = 604.02. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] Pyridin-3-yl] amino} carbonyl} amino] -3- (2,4-dichloro-3,5-diethoxyphenyl) propanoic acid500Calculated (M + H) ⁺ = 652.14; found (M + H) ⁺ = 651.98. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Il] amino} carbonyl} amino] -3- (2,4-dichloro-3,5-diethoxyphenyl) propanoic acid450Calculated (M + H) ⁺ = 638.12; found (M + H) ⁺ = 637.97. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl} amino] -3- [3- (cyclopropylmethoxy) phenyl] propanoic acid9Calculated (M + H) ⁺ = 552.19; found (M + H) ⁺ = 552.10. (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl] amino} carbonyl) amino] -3- [3- (cyclopropylmethoxy) phenyl] propanoic acid4Calculated (M + H) ⁺ = 596.21; found (M + H) ⁺ = 596.11. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] Pyridin-3-yl] amino} carbonyl) amino] -3- [3- (cyclopropylmethoxy) phenyl] propanoic acid10Calculated (M + H) ⁺ = 566.20; found (M + H) ⁺ = 566.12. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (2,4-diethoxypyrimidin-5-yl) propanoic acid13Calculated (MH) ^- = 544.16; found (MH) ^- = 544.00.
[588] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1- (2,3-dichloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid5Calculated (MH) ^- = 572.13; found (MH) ^- = 571.97. (3S) -3- [3- (cyclopropylmethoxy) phenyl] -3-[({[1- (2,3-dichloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2 , 5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] propanoic acid7Calculated (MH) ^- = 628.16; found (MH) ^- = 628.98. (3S) -3-[({[1- (2,3-dichloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid3Calculated (MH) ^- = 602.15; found (MH) ^- = 601.99. (3S) -3-[({[1- (2,3-dichloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid5Calculated (MH) ^- = 616.16; found (MH) ^- = 616.01. (3S) -3-({[[1- (2-chlorobenzyl) -4-methoxy-2-oxo-1,2-dihydropyridin-3-yl] (methyl) amino] carbonyl} amino) -3- (4-methylphenyl) propanoic acid2000Calculated (MH) ^- = 482.14; found (MH) ^- = 482.07. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- (2'-methoxy-1,1'-biphenyl-3-yl) propanoic acid15Calculated (MH) ^- = 560.16; found (MH) ^- = 559.98. 3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (5-methyl-2-furyl) propanoic acid20Calculated (MH) ^- = 458.11; found (MH) ^- = 457.99. 3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- [4- (methylsulfonyl) phenyl] propanoic acid43Calculated (M + H) ⁺ = 548.13; found (M + H) ⁺ = 548.07. 3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} Carbonyl) amino] -3- (2-furyl) propanoic acid5Calculated (MH) ^- = 470.11; found (MH) ^- = 469.91. 3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (2-furyl Propanoic acid4Calculated (MH) ^- = 444.10; found (MH) ^- = 443.91. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- [4- (trifluoromethyl) phenyl] propanoic acid18Calculated (MH) ^- = 548.12; found (MH) ^- = 548.00.
[589] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (3-methylphenyl) propanoic acid5Calculated (MH) ^- = 494.15; found (MH) ^- = 494.02. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- [3- (trifluoromethyl) phenyl] propanoic acid10Calculated (MH) ^- = 548.12; found (MH) ^- = 547.99. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (3,5-dimethylphenyl) propanoic acid9Calculated (MH) ^- = 508.16; found (MH) ^- = 508.02. (3S) -3- [3,5-bis (trifluoromethyl) phenyl] -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6 , 7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] propanoic acid130Calculated (MH) ^- = 615.11; found (MH) ^- = 615.99. (3S) -3-{[({1- [2-chloro-5- (trifluoromethyl) benzyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridine-3 -Yl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid6Calculated (MH) ^- = 536.12; found (MH) ^- = 535.99. (3S) -3-[({[1- (2-chloro-5-fluorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylphenyl) propanoic acid5Calculated (MH) ^- = 486.12; found (MH) ^- = 485.97. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- [3- (diethylamino) phenyl] propanoic acid2Calculated (MH) ^- = 525.19; found (MH) ^- = 525.00. 3- (1,1'-biphenyl-4-yl) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro -1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] propanoic acid30Calculated (MH) ^- = 556.16; found (MH) ^- = 555.99. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Il] amino} carbonyl) amino] -3- (2,3-dihydro-1H-inden-5-yl) propanoic acid8Calculated (M + H) ⁺ = 522.17; found (M + H) ⁺ = 522.03. (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] Pyridin-3-yl] amino} carbonyl) amino] -3- (2,3-dihydro-1H-inden-5-yl) propanoic acid10Calculated (M + H) ⁺ = 536.19; found (M + H) ⁺ = 536.08.
[590] compoundIC ₅₀ (nM)Mass spectral data (m / z) N- {1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} -N '-[1 (S)- 1- (4-methylphenyl) -2- (1H-1,2,3,4-tetrazol-5-yl) ethyl] urea6000Calculated (M + H) ⁺ = 494.17; found (M + H) ⁺ = 494.01. (3S) -3- [1,1'-biphenyl] -3-yl-3-{[({1- [2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5, 6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl} amino) carbonyl] amino} propanoic acid17Calculated (MH) ^- = 556.16; found (MH) ^- = 556.01. (3S) -3-{[({1- [2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine- 3-yl} amino) carbonyl] amino} -3- {4-[(trifluoromethyl) oxy] phenyl} propanoic acid13Calculated (MH) ^- = 564.11; found (MH) ^- = 564.01. (3S) -3-{[({1- [2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine- 3-yl} amino) carbonyl] amino} -3- {4-[(difluoromethyl) oxy] phenyl} propanoic acid13Calculated (MH) ^- = 546.12; found (MH) ^- = 546.97. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl} amino) carbonyl] amino} -3- {3-[(trifluoromethyl) oxy] phenyl} propanoic acid10Calculated (MH) ^- = 564.11; found (MH) ^- = 563.98. (3S) -3-{[({1- [2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine- 3-yl} amino) carbonyl] amino} -3- {3-[(difluoromethyl) oxy] phenyl} propanoic acid5Calculated (MH) ^- = 546.12; found (MH) ^- = 546.01. (3S) -3-{[({1- [2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine- 3-yl} amino) carbonyl] amino} -3- {3-[(1,1,2,2-tetrafluoroethyl) oxy] phenyl} propanoic acid4Calculated (MH) ^- = 596.12; found (MH) ^- = 596.02. (3S) -3-{[({1- [2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine- 3-yl} amino) carbonyl] amino} -3- [3,5-dimethyl-4- (methyloxy) phenyl] propanoic acid11Calculated (MH) ^- = 538.17; found (MH) ^- = 538.04. (3S) -3-{[({1- [2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine- 3-yl} amino) carbonyl] amino} -3- (1-ethyl-1H-indol-5-yl) propanoic acid5Calculated (M + H) ⁺ = 549.19; found (M + H) ⁺ = 549.02. (3S) -3-{[({1- [2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine- 3-yl} amino) carbonyl] amino} -3- (3,5-difluorophenyl) propanoic acid7Calculated (MH) ^- = 516.11; found (MH) ^- = 516.01.
[591] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl} amino) carbonyl] amino} -3- [3-fluoro-4- (methyloxy) phenyl] propanoic acid3Calculated (MH) ^- = 528.13; found (MH) ^- = 528.00. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl} amino) carbonyl] amino} -3- (4-propylphenyl) propanoic acid17Calculated (MH) ^- = 522.18; found (MH) ^- = 522.04. (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl} amino) carbonyl] amino} -3- (4-propylphenyl) propanoic acid20Calculated (MH) ^- = 536.20; found (MH) ^- = 536.06. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] amino} -3- (2-methylphenyl) propanoic acid267Calculated (MH) ^- = 468.13; found (MH) ^- = 468.00. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl} amino) carbonyl] amino} -3- (4-cyclopropylphenyl) propanoic acid25Calculated (M + H) ⁺ = 522.18; found (M + H) ⁺ = 522.04. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Yl] amino} -3- (3-quinolinyl) propanoic acid22Calculated (MH) ^- = 505.13; found (MH) ^- = 504.98. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl} amino) carbonyl] amino} -3- (3-quinolinyl) propanoic acid22Calculated (MH) ^- = 531.14; found (MH) ^- = 530.99. 3-({[(1-{[2-chloro-6- (ethoxy) phenyl] methyl} -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl) Amino] carbonyl} amino) -3- (2-furanyl) propanoic acid8Calculated (MH) ^- = 488.12; found (MH) ^- = 487.98. (3S) -3- [2,4-bis (ethyloxy) -5-pyrimidinyl] -3-{[{1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo- 2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl} amino) carbonyl] amino} propanoic acid15Calculated (MH) ^- = 570.18; found (MH) ^- = 570.14. (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl} amino) carbonyl] amino} -3- (4-cyclopropylphenyl) propanoic acid19Calculated (M + H) ⁺ = 536.20; found (M + H) ⁺ = 536.07.
[592] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3R) -3-{[({1- [2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine- 3-yl} amino) carbonyl] amino} butanoic acid15Calculated (MH) ^- = 418.12; found (MH) ^- = 418.00. (3S) -3-{[({1- [2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine- 3-yl} amino) carbonyl] amino} -3- (4-ethylphenyl) propanoic acid8Calculated (MH) ^- = 508.16; measured (MH) ^- = 508.06. (3S) -3-{[({1- [2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine- 3-yl} amino) carbonyl] amino} -3- [4- (1-methylethyl) phenyl] propanoic acid17Calculated (MH) ^- = 522.17; found (MH) ^- = 522.06. (3S) -3-{[({1- [2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Amino} -3- (4-ethylphenyl) propanoic acid30Calculated (MH) ^- = 482.14; found (MH) ^- = 482.00. (3S) -3-{[({1- [2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Amino} -3- [4- (1-methylethyl) phenyl] propanoic acid175Calculated (MH) ^- = 496.16; found (MH) ^- = 496.01. (3S) -3-{[({1- [2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Amino} -3- [4- (cyclopropyloxy) phenyl] propanoic acid6Calculated (MH) ^- = 510.14; found (MH) ^- = 510.00. (3S) -3-{[({1- [2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl ] Amino} -3- (4-propylphenyl) propanoic acid12Calculated (MH) ^- = 496.16; found (MH) ^- = 495.99.
[593] compoundIC ₅₀ (nM)Mass spectral data (m / z) 3-{[({1- [2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino}- 3- (4-cyclopropylphenyl) propanoic acid35Calculated (MH) ^- = 494.15; found (MH) ^- = 494.01. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Yl] amino} -3- (2,3-dihydro-1H-inden-5-yl) propanoic acid18Calculated (MH) ^- = 494.15; found (MH) ^- = 494.02. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl} amino) carbonyl] amino} -3- (9-ethyl-9H) carbazol-3-yl_propanoic acid13Calculated (MH) ^- = 597.19; found (MH) ^- = 597.01. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] amino} -3- (9-ethyl-9H-carbazol-3-yl) propanoic acid23Calculated (MH) ^- = 571.17; found (MH) ^- = 570.99. (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl} amino) carbonyl] amino} -3- (1-methyl-1H-indol-5-yl) propanoic acid3Calculated (MH) ^- = 547.17; found (MH) ^- = 547.04. (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl} amino) carbonyl] amino} -3- {3-[(difluoromethyl) oxy] phenyl} propanoic acid3Calculated (MH) ^- = 560.14; found (MH) ^- = 560.03. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] amino} -3- [2- (ethyloxy) [1,1'-biphenyl] -4-yl] propanoic acid25Calculated (MH) ^- = 574.17; found (MH) ^- = 574.00. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl} amino) carbonyl] amino} -3- [2- (ethyloxy) [1,1'-biphenyl] -4-yl] propanoic acid20Calculated (MH) ^- = 600.19; found (MH) ^- = 600.01. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] amino} -3- (2'-methyl [1,1'-biphenyl] -3-yl) propanoic acid20Calculated (MH) ^- = 544.16; found (MH) ^- = 544.04. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] amino} -3- (3'-methyl [1,1'-biphenyl] -3-yl) propanoic acid18Calculated (MH) ^- = 544.16; found (MH) ^- = 544.00.
[594] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-({[(1-{[2-chloro-6-tetrahydro-1 (2H) -pyridinylphenyl] methyl} -4-hydroxy-5-methyl-2-oxo-1, 2-dihydro-3-pyridinyl) amino] carbonyl} amino) -3- (4-methylphenyl) propanoic acid90Calculated (MH) ^- = 551.21; found (MH) ^- = 551.06. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] amino} -3- (4'-methyl [1,1'-biphenyl] -3-yl) propanoic acid23Calculated (MH) ^- = 544.16; found (MH) ^- = 543.99. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl} amino) carbonyl] amino} -3- [3- (diethylamino) phenyl] propanoic acid3Calculated (MH) ^- = 551.21; found (MH) ^- = 551.05. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] amino} -3- [3- (difluoromethyl) phenyl] propanoic acid20Calculated (MH) ^- = 504.11; found (MH) ^- = 503.96. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl} amino) carbonyl] amino} -3- (3-fluorophenyl) propanoic acid16Calculated (MH) ^- = 498.12; found (MH) ^- = 498.02. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl} amino) carbonyl] amino} -3- (4-fluorophenyl) propanoic acid9Calculated (MH) ^- = 498.12; found (MH) ^- = 498.01. N- {1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl-N '-[(R) -phenyl ( 1H-1,2,3,4-tetrazol-5-yl) methyl] urea> 10000Calculated (MH) ^- = 464.12; found (MH) ^- = 464.01. (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} Amino) carbonyl] amino} -3- (1-methyl-1H-indol-5-yl) propanoic acid4Calculated (MH) ^- = 521.16; found (MH) ^- = 521.00. (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl} amino) carbonyl] amino} -3- [3- (diethylamino) phenyl] propanoic acid10Calculated (MH) ^- = 565.14; found (MH) ^- = 565.04. (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl} amino) carbonyl] amino} -3- (3-methylphenyl) propanoic acid4Calculated (MH) ^- = 508.16; found (MH) ^- = 508.03.
[595] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl} amino) carbonyl] amino} -3-phenylpropanoic acid17Calculated (MH) ^- = 494.15; found (MH) ^- = 494.09. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl} amino) carbonyl] amino} -3- (3-hydroxyphenyl) propanoic acid8Calculated (MH) ^- = 496.13; found (MH) ^- = 495.99. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] amino} -3- (3-hydroxyphenyl) propanoic acid9Calculated (MH) ^- = 470.11; found (MH) ^- = 469.98. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Yl] amino} -3- (3 ', 5'-dimethyl [1,1'-biphenyl] -3-yl) propanoic acid50Calculated (MH) ^- = 558.18; found (MH) ^- = 558.00. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] amino} -3-phenylpropanoic acid15Calculated (MH) ^- = 455.12; found (MH) ^- = 454.00. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl} amino) carbonyl] amino} -3- {3-[(methylsulfonyl) amino] phenyl} propanoic acid3Calculated (MH) ^- = 573.12; found (MH) ^- = 572.98. (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl} amino) carbonyl] amino} -3- {3-[(methylsulfonyl) amino] phenyl} propanoic acid3Calculated (MH) ^- = 587.14; found (MH) ^- = 586.98. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl} amino) carbonyl] amino} -3- [3- (difluoromethyl) phenyl] propanoic acid4Calculated (MH) ^- = 530.13; found (MH) ^- = 530.03. (2S, 3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino ) Carbonyl] amino} -2-methyl-3- (4-methylphenyl) propanoic acid1500Calculated (MH) ^- = 482.15; found (MH) ^- = 481.99. (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl} amino) carbonyl] amino} -3- (4-ethylphenyl) propanoic acid15Calculated (MH) ^- = 522.18; found (MH) ^- = 522.04.
[596] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl} amino) carbonyl] amino} -3- (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl) propanoic acid3Calculated (MH) ^- = 550.17; found (MH) ^- = 550.05. (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl} amino) carbonyl] amino} -3- [3-fluoro-4- (methyloxy) phenyl] propanoic acid3Calculated (MH) ^- = 542.15; found (MH) ^- = 542.00. (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl} amino) carbonyl] amino} -3- {3-[(trifluoromethyl) oxy] phenyl} propanoic acid11Calculated (MH) ^- = 578.13; found (MH) ^- = 578.02. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl} amino) carbonyl] amino} -3- {3- [methyl (methylsulfonyl) amino] phenyl} propanoic acid1.6Calculated (MH) ^- = 587.14; found (MH) ^- = 586.99. (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl} amino) carbonyl] amino} -3- {3- [methyl (methylsulfonyl) amino] phenyl} propanoic acid1.3Calculated (MH) ^- = 601.15; found (MH) ^- = 601.00. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine -3-yl} amino) carbonyl] amino} -3- {3- [ethyl (methylsulfonyl) amino] phenyl} propanoic acidOneCalculated (MH) ^- = 601.15; found (MH) ^- = 601.00. (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl} amino) carbonyl] amino} -3- {3- [ethyl (methylsulfonyl) amino] phenyl} propanoic acidOneCalculated (MH) ^- = 615.17; found (MH) ^- = 615.04. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] amino} -3- (2'-fluoro [1,1'-biphenyl-3-yl) propanoic acid25Calculated (MH) ^- = 548.14; found (MH) ^- = 547.96. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Yl] amino} -3- [2 '-(trifluoromethyl) [1,1'-biphenyl] -3-yl] propanoic acid157Calculated (MH) ^- = 597.14; found (MH) ^- = 597.97. (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nyl] a (mino) -3- (2-fluorophenyl) propanoic acid10Calculated (MH) ^- = 472.11; found (MH) ^- = 471.98.
[597] compoundIC ₅₀ (nM)Mass spectral data (m / z) (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl} amino) carbonyl] amino} -3- (1H-indol-5-yl) propanoic acid2Calculated (MH) ^- = 533.16; found (MH) ^- = 533.01. (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [ b] pyridin-3-yl} amino) carbonyl] amino} -3- (3,5-difluorophenyl) propanoic acid11Calculated (MH) ^- = 530.13; found (MH) ^- = 530.00.
[598] All references cited are incorporated herein by reference.
[599] The invention is understood by the foregoing detailed description and examples. As many variations are apparent to those skilled in the art, the foregoing detailed description is considered as non-limiting examples. All such modifications within the scope and spirit of the appended claims are considered to be included in the claims.
[600] Changes may be made in the construction, processes and arrangements of the methods of the invention described herein without departing from the spirit and scope of the invention as defined in the claims that follow.
[601] The compounds of the present invention inhibit the binding of α ₄ β ₁ integrins to their receptors such as VCAM-1 (vascular cell adsorption molecule-1) and fibronectin. In addition, the compounds of the present invention are used to control or prevent disease symptoms involving α ₄ β ₁ .

权利要求:
Claims (31)
[1" claim-type="Currently amended] A compound of Formula 1 or a pharmaceutically acceptable salt thereof.
Formula 1

In the above formula,
Each Y is independently selected from the group consisting of C (O), N, CR ¹ , C (R ² ) (R ³ ), NR ⁵ , CH, O and S;
q is an integer from 3 to 10;
A is selected from the group consisting of O, S, C (R ¹⁶ ) (R ¹⁷ ) and NR ⁶ ;
E is selected from the group consisting of CH ₂ , O, S and NR ⁷ ;
J is selected from the group consisting of O, S and NR ⁸ ;
T is selected from the group consisting of C (O) and (CH ₂ ) _b , wherein b is an integer from 0 to 3;
M is selected from the group consisting of C (R ⁹ ) (R ¹⁰ ) and (CH ₂ ) _u , wherein u is an integer from 0 to 3;
L is selected from the group consisting of O, NR ¹¹ , S and (CH ₂ ) _n , where n is an integer of 0 or 1;
X is CO ₂ B, PO ₃ H ₂ , SO ₃ H, SO ₂ NH ₂ , SO ₂ NHCOR ¹² , OPO ₃ H ₂ , C (O) NHC (O) R ¹³ , C (O) NHSO ₂ R ¹⁴ , Selected from the group consisting of hydroxyl, tetrazolyl and hydrogen;
W is selected from the group consisting of C, CR ¹⁵ and N;
B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and Each R ¹⁷ is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl ), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) -NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ ( C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl , -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , Haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, bi Aryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO _2- (C ₁ -C ₃ alkyl),- Is selected from the group consisting of SO ₃ — (C ₁ -C ₃ alkyl), sulfonamido, carbamate, aryloxyalkyl, and —C (O) NH (benzyl) group; B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ is unsubstituted or substituted with one or more electron donating groups or electron withdrawing groups; When L is NR ¹¹ , R ⁴ and R ¹¹ may form a ring together, when M is C (R ⁹ ) (R ¹⁰ ), R ⁹ and R ¹⁰ may form a ring together, A When NR ⁶ and at least one Y is CR ¹ , R ¹ and R ⁶ together may form a ring;
Provided that when A is C (R ¹⁶ ) (R ¹⁷ ) then E is not NR ⁷ .
[2" claim-type="Currently amended] The compound of claim 1, wherein A is NR ⁶ ; E is NR ⁷ ; J is O; M is C (R ⁹ ) (R ¹⁰ ); q is 4 or 5; T is (CH ₂ ) _b , where b is 0; L is (CH ₂ ) _n where n is 0; X is CO ₂ B; W is C or CR ¹⁵ ; R ⁴ is selected from the group consisting of aryl, alkylaryl, aralkyl, heterocyclyl, alkylheterocyclyl and heterocyclylalkyl; R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and R ¹⁵ are independently selected from the group consisting of hydrogen and lower alkyl.
[3" claim-type="Currently amended] The compound of claim 1, which is a derivative selected from the group consisting of esters, carbamates, aminos, amides, optical isomers and prodrugs.
[4" claim-type="Currently amended] A compound of Formula 2 or a pharmaceutically acceptable salt thereof:
Formula 2

In the above formula,
Each Y is independently selected from the group consisting of C (O), N, CR ¹ , C (R ² ) (R ³ ), NR ⁵ , CH, O and S;
q is an integer from 3 to 7;
T is selected from the group consisting of C (O) and (CH ₂ ) _b , wherein b is an integer from 0 to 3;
L is selected from the group consisting of O, NR ¹¹ , S and (CH ₂ ) _n , where n is an integer of 0 or 1;
W is selected from the group consisting of C, CR ¹⁵ and N;
B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁵ are independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy , Alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxy Carbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O ) -NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkyl Amino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloal Kenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, hete Rosa cycle reel, alkylaryl, aralkyl, alkenyl, aralkyl, alkyl, heterocyclyl, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 Alkyl), sulfonamido, carbamate, aryloxyalkyl, and -C (O) NH (benzyl) group; B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁵ are unsubstituted or substituted with one or more electron donating groups or electron withdrawing groups ; When L is NR ¹¹ , R ⁴ and R ¹¹ may form a ring together, R ⁹ and R ¹⁰ may form a ring together, and when one or more Y is CR ¹ , R ¹ and R ⁶ may be Together, they may form a ring.
[5" claim-type="Currently amended] The compound of claim 4, wherein q is 4 or 5; W is C or CR ¹⁵ ; T is (CH ₂ ) _b , where b is 0; L is (CH ₂ ) _n where n is 0; R ⁴ is selected from the group consisting of aryl, alkylaryl, aralkyl, heterocyclyl, alkylheterocyclyl and heterocyclylalkyl; R ⁶ , R ⁷ , R ⁹ , R ¹⁰ and R ¹⁵ are independently selected from the group consisting of hydrogen and lower alkyl.
[6" claim-type="Currently amended] A compound according to claim 4 which is a derivative selected from the group consisting of esters, carbamates, aminos, amides, optical isomers and prodrugs.
[7" claim-type="Currently amended] A compound of Formula 3 or a pharmaceutically acceptable salt thereof:
Formula 3

In the above formula,
Each Y is independently selected from the group consisting of C (O), N, CR ¹ , C (R ² ) (R ³ ), NR ⁵ , CH, O and S;
q is an integer from 2 to 5;
T is selected from the group consisting of C (O) and (CH ₂ ) _b , wherein b is an integer from 0 to 3;
L is selected from the group consisting of O, NR ¹¹ , S and (CH ₂ ) _n , where n is an integer of 0 or 1;
R ⁵ , R ⁶ , R ⁷ , R ¹¹ and R ¹⁸ are independently alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, halo Alkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, hetero Cyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen, and -C (O) -NH (benzyl) group;
B, R ¹ , R ² , R ³ , R ⁴ , R ⁹ and R ¹⁰ are independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl , Aliphatic acyl, -CF ₃ , -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C _1- C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) -NH (C ₁ -C ₃ alkyl), -NHC ( O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino , -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ ,- CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, Aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, Reual alkenyl, aralkyl, alkyl, heterocyclyl, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbazole Mate, aryloxyalkyl, and -C (O) NH (benzyl) group; B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁸ are unsubstituted or substituted with one or more electron donating groups or electron withdrawing groups ; When L is NR ¹¹ , R ⁴ and R ¹¹ together may form a ring and R ⁹ and R ¹⁰ together may form a ring; When at least one Y is CR ¹ , R ¹ and R ⁶ together may form a ring.
[8" claim-type="Currently amended] 8. The compound of claim 7, wherein R ¹⁸ is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, alkylheterocyclyl, heterocyclylalkyl and heterocyclyl; T is (CH ₂ ) _b , where b is 0; L is (CH ₂ ) _n where n is 0; Y is selected from the group consisting of CR ¹ and C (R ² ) (R ³ ); and q is 2 or 3.
[9" claim-type="Currently amended] 8. A compound according to claim 7, which is a derivative selected from the group consisting of esters, carbamates, aminos, amides, optical isomers and prodrugs.
[10" claim-type="Currently amended] The method of claim 7, wherein Part of

[In the above formula,
R ¹⁹ , R ²⁰ , R ²¹ and R ²⁸ are each independently halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ ,- OH, -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) -NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ Alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- ( C ₁ -C ₃ ) alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, Thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl , Aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO _2- (C ₁ -C ₃ alkyl), -SO _3- (C ₁ -C ₃ alkyl), sulfonamido, carbamate, Aryloxyalkyl and -C (O) NH (benzyl) group;
R ¹⁸ is alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cyclo Alkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyl Heterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen, and -C (O) -NH (benzyl) group;
R ²² is hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl),- NHC (O) N (C ₁ -C ₃ alkyl) C (O) -NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C _1- C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH— (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, Alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl , Alkylaryl, aralkenyl, aralkyl, alkylheterocyclo Keulril, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbamate, aryloxyalkyl and -C ( O) NH (benzyl) group;
c is an integer from 0 to 2;
d is an integer from 0 to 3;
e is an integer from 0 to 4;
i is an integer from 0 to 2].
[11" claim-type="Currently amended] 8. A compound according to claim 7, wherein R ¹⁸ is aralkyl; R ⁴ is aryl; T is (CH ₂ ) _b , where b is 0; L is (CH ₂ ) _n where n is 0; B, R ⁶ , R ⁷ , R ⁹ and R ¹⁰ are each independently hydrogen.
[12" claim-type="Currently amended] A compound of formula 4 or a pharmaceutically acceptable salt thereof.
Formula 4

In the above formula,
T is selected from the group consisting of C (O) and (CH ₂ ) _b , wherein b is an integer from 0 to 3;
L is selected from the group consisting of O, NR ¹¹ , S and (CH ₂ ) _n , where n is an integer of 0 or 1;
g is an integer from 0 to 7;
B, R ⁴ , R ⁹ , R ¹⁰ and R ²³ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl,- CF ₃ , -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl)- C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , —OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, Biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, ar Alkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO _2- (C ₁ -C ₃ alkyl), -SO _3- (C ₁ -C ₃ alkyl), sulfonamido, carba Mate, aryloxyalkyl, and -C (O) NH (benzyl) group;
R ⁶ , R ⁷ , R ¹¹ and R ¹⁸ are each independently alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, Alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl , Alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and —C (O) NH (benzyl) group; B, R ⁴ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹⁸ and R ²³ are unsubstituted or substituted with one or more electron donating groups or electron withdrawing groups; When L is NR ¹¹ , R ⁴ and R ¹¹ together may form a ring; R ⁹ and R ¹⁰ may form a ring together.
[13" claim-type="Currently amended] 13. The compound of claim 12, which is a derivative selected from the group consisting of esters, carbamates, aminos, amides, optical isomers and prodrugs.
[14" claim-type="Currently amended] A compound of formula 5 or a pharmaceutically acceptable salt thereof.
Formula 5

In the above formula,
h is an integer from 0 to 5;
B, R ⁹ , R ¹⁰ , R ²⁴ and R ²⁵ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl,- CF ₃ , -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl)- C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , —OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, Biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, ah Alkenyl, aralkyl, alkyl, heterocyclyl, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbazole Mate, aryloxyalkyl, and -C (O) NH (benzyl) group;
Each R ²⁷ is independently halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH , -CN, -NO ₂ , -NH ₂ , alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C _1- C ₃ alkyl), -NHSO ₂ (aryl), -N (C ₁ -C ₃ alkyl) SO ₂ (C ₁ -C ₃ alkyl), -N (C ₁ -C ₃ alkyl) SO ₂ (aryl), alkoxy Alkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl , -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl , Cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, dia Arylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO _2- (C ₁ -C ₃ alkyl), -SO _3- (C ₁ -C ₃ alkyl), sulfonamido, carbamate, aryloxyalkyl and -C (O) NH (benzyl) group;
R ⁶ , R ⁷ and R ¹⁸ are each independently alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkoxy, Carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl , Aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and —C (O) NH (benzyl) group;
R ²⁶ is hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, -CF ₃ , alkoxycarbonyl, heterocycloyl, carboxy, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -PO ₃ H ₂ , haloalkyl, carboxamide, cycloalkyl, cycloal Kenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, biaryl, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO _2- ( C ₁ -C ₃ alkyl), sulfonamido, aryloxyalkyl, and —C (O) NH (benzyl) group; B, R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹⁸ , R ²⁴ , R ²⁵ , R ²⁶ and R ²⁷ are unsubstituted or substituted with one or more electron donating groups or electron withdrawing groups; R ¹⁸ and R ²⁴ may form a ring together; R ²⁴ and R ²⁵ together may form a ring; R ²⁵ and R ²⁶ together may form a ring; R ⁹ and R ¹⁰ may form a ring together.
[15" claim-type="Currently amended] The compound of claim 14, wherein B, R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ²⁴ , R ²⁵ and R ²⁶ are each independently hydrogen and R ¹⁸ is substituted or unsubstituted aralkyl.
[16" claim-type="Currently amended] 15. The compound of claim 14, which is a derivative selected from the group consisting of esters, carbamates, aminos, amides, optical isomers and prodrugs.
[17" claim-type="Currently amended] A compound of formula 6 or a pharmaceutically acceptable salt thereof.
Formula 6

In the above formula,
Z are each independently selected from the group consisting of C (O), N, CR ³⁰ , C (R ³¹ ) (R ³² ), NR ³³ , CH, O and S;
z is an integer from 3 to 6;
k is an integer from 0 to 5;
T is selected from the group consisting of C (O) and (CH ₂ ) _b , wherein b is an integer from 0 to 3;
L is selected from the group consisting of O, NR ¹¹ , S and (CH ₂ ) _n , where n is an integer of 0 or 1;
R ⁶ , R ⁷ , R ¹¹ , R ¹⁸ and R ³³ are each independently alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, Haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, Heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen, and -C (O) NH (benzyl) group;
B, R ⁴ , R ⁹ , R ¹⁰ , R ³⁰ , R ³¹ and R ³² are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxy Alkyl, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH, -OH, -CN, -NO ₂ , -NH ₂ , alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (C ₁ -C ₃ alkyl), -NHC ( O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino , -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ ,- CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, Aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkyl Aryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO _2- (C ₁ -C ₃ alkyl), -SO _3- (C ₁ -C ₃ alkyl), sulfonami In addition, it is selected from the group consisting of carbamate, aryloxyalkyl, and -C (O) NH (benzyl) group;
Each R ²⁹ is independently halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH, -CN , -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C _1- C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH— (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, Alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl , Alkylaryl, aralkenyl, aralkyl, alkyl Interrogating heterocyclyl, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbamate, aryloxyalkyl and- Is selected from the group consisting of C (O) NH (benzyl) groups; B, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² and R ³³ are unsubstituted or one or more electron donating groups or Substituted with an electron withdrawing group; When L is NR ¹¹ , R ⁴ and R ¹¹ together may form a ring; R ⁹ and R ¹⁰ may form a ring together.
[18" claim-type="Currently amended] 18. The compound of claim 17, which is a derivative selected from the group consisting of esters, carbamates, aminos, amides, optical isomers and prodrugs.
[19" claim-type="Currently amended] 18. The compound of claim 17, wherein z is 3 or 4.
[20" claim-type="Currently amended] A compound of formula
Formula 7

In the above formula,
R ²⁴ and R ²⁵ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -SH, -OH , -CO ₂ H, -CN, -NO ₂ , -NH ₂ , alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C _1- C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) Alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diaryl Amino, heterocyclyl, alkylaryl, aralkenyl, sub Alkyl, heterocyclyl, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbamate, aryloxyalkyl Selected from the group consisting of alkyl and -C (O) NH (benzyl) groups;
R ¹⁸ and R ³⁴ are each independently alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde , Carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aral Kenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and -C (O) NH (benzyl) group; R ¹⁸ , R ²⁴ , R ²⁵ and R ³⁴ are unsubstituted or substituted with one or more electron donating groups or electron withdrawing groups; R ²⁴ and R ²⁵ together may form a ring; Provided that when R ²⁴ and R ²⁵ together form a ring, the formed ring is not benzene.
[21" claim-type="Currently amended] The compound of claim 20, wherein R³⁴Is hydrogen; R¹⁸Is aralkyl; R²⁴And R²⁵Is Each independently hydrogen, lower alkyl, and R²⁴And R²⁵Is selected from the group consisting of lower alkyl which together may form a ring.
[22" claim-type="Currently amended] The compound of formula 20 according to claim 20.
Formula 8

In the above formula,
R ²⁴ and R ²⁵ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -SH, -OH , -CO ₂ H, -CN, -NO ₂ , -NH ₂ , alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C _1- C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) Alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diaryl Amino, heterocyclyl, alkylaryl, aralkenyl, sub Alkyl, heterocyclyl, heterocyclylalkyl, _{sulfonyl, -SO 2 - (C 1 -C} 3 _{alkyl), -SO 3 - (C 1} -C 3 alkyl), sulfonamido, carbamate, aryloxyalkyl Selected from the group consisting of alkyl and -C (O) NH (benzyl) groups;
R ³⁴ is alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cyclo Alkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyl Heterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen, and -C (O) NH (benzyl) group;
Each R ³⁵ is independently halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH , -CN, -NO ₂ , -NH ₂ , alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (C ₁ -C ₃ alkyl), -NHC (O) NH (C ₁ -C ₆ alkyl), -NHSO ₂ (C _1- C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C ₁ -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O) NH— (C ₁ -C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, Alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl , Alkylaryl, aralkenyl, aral Kyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO _2- (C ₁ -C ₃ alkyl), -SO _3- (C ₁ -C ₃ alkyl), sulfonamido, carbamate, aryloxy Selected from the group consisting of alkyl and -C (O) NH (benzyl) groups; R ²⁴ , R ²⁵ , R ³⁴ and R ³⁵ are unsubstituted or substituted with one or more electron donating groups or electron withdrawing groups; m is an integer of 0-5.
[23" claim-type="Currently amended] The compound of claim 22, wherein R ³⁴ is hydrogen; m is an integer from 1 to 3; R ³⁵ is each selected from the group consisting of alkyl, halogen, alkoxy, haloalkyl, sulfonyl, -OH and -CN.
[24" claim-type="Currently amended] The method of claim 20,
5- (2-chlorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -6-methyl- 3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-fluorobenzyl) -3,5-dihydro [1,3] oxa Solo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-6-fluorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] Pyridine-2,4-dione, 5-benzyl-6-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5-benzyl-3, 5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2,5-dimethylbenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-methylbenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4- Dione, 5- (2,4-dichlorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-methoxybenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2,5-difluorobenzyl) -3,5-dihydro [1 , 3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [2-chloro-5- ( Ylthio) benzyl] -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (4-fluorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-5-methoxybenzyl) -3,5-dihydro [1,3] oxazolo [ 4,5-c] pyridine-2,4-dione, 5- [3,5-bis (trifluoromethyl) benzyl] -3,5-dihydro [1,3] oxazolo [4,5-c ] Pyridine-2,4-dione, 5- (4-tert-butylbenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5 -(3-chlorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (4-chlorobenzyl) -3,5-di Hydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [3- (trifluoromethyl) benzyl] -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-bromobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4 -Dione, 5- (3,4-dichlorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (4-methylbenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyrid -2,4-dione, 5- (2-chloro-6-methoxybenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5 -[4- (trifluoromethyl) benzyl)]-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (3-methylbenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (pyridin-2-ylmethyl) -3,5-dihydro [1,3 ] Oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c ] Pyridine-2,4-dione, 5- (2,4-difluorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2,6-difluorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [3- (trifluorome Methoxy) benzyl] -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [4- (trifluoromethoxy) benzyl] -3,5 -Dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [2- (trifluoromethyl) benzyl] -3,5-dihydro [1,3] Oxazolo [4,5-c] pyridine-2,4-dione, 5- (3-methoxybenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2,3-dichlorobenzyl) -3 , 5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (3,5-dimethylbenzyl) -3,5-dihydro [1,3] oxa Zolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -7-pentyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine -2,4-dione, 5- (2,4-dichlorobenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -7-ethyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 7-butyl-5- (2- Chlorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [2-chloro-5- (trifluoromethyl) benzyl]- 3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2,6-dichlorobenzyl) -3,5-dihydro [1,3] Oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-5-fluorobenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c ] Pyridine-2,4-dione, 5- (2-chloro-6-methylbenzyl)- 7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (4-chlorobenzyl) -7-methyl-3,5-di Hydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -5,6,7,8-tetrahydro-2H-cyclopenta [b] [1,3] oxazolo [5,4-d] pyridine-2,4 (3H) -dione, 7-methyl-5- [4- (methylsulfonyl) benzyl] -3,5-dihydro [1 , 3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (4-methoxybenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] Pyridine-2,4-dione, 5- (2-chlorobenzyl) -7-propyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 4 -[(2,4-dioxo-2,3-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl) methyl] -N, N-dimethylbenzenesulfonamide , 5- (methylmethyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -3,5, 6,7,8,9-hexahydro [1,3] oxazolo [4,5-c] quinoline-2,4-dione, 5- (2-chlorobenzyl) -7-ethyl-6-methyl-3 , 5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-di , 5- [2- (methylthio) benzyl] -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 2-[(2,4-di Oxo-2,3-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl) methyl] -N, N-dimethylbenzenesulfonamide, 5- (2,6- Dimethoxybenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [2- (trifluoromethoxy) benzyl] -3,5 -Dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -6,7-dimethyl-3,5-dihydro [1,3 ] Oxazolo [4,5-c] pyridine-2,4-dione, 5- [2-chloro-5- (methylsulfonyl) benzyl] -3,5-dihydro [1,3] oxazolo [4 , 5-c] pyridine-2,4-dione, 5- (4-chloro-2-methoxybenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2 , 4-dione, 5- (2-chlorobenzyl) -5,6,7,8,9,10-hexahydro-2H-cyclohepta [b] [1,3] oxazolo [5,4-d] Pyridine-2,4 (3H) -dione, 5- [2- (difluoromethoxy) benzyl] -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4 -Dione, 7-methyl-5-[(1R) -1-phenylethyl] -3,5- Dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (4-chlorobenzyl) -7-propyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [2- (methylsulfonyl) benzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine- 2,4-dione, 5- (2,6-dimethylbenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 3-chloro-2 -[(2,4-dioxo-2,3-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl) methyl] benzonitrile, 5- (2-chloro -6-methylbenzyl) -6,7-dimethyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 2-[(2,4-di Oxo-2,3-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl) methyl] benzonitrile, 5- (2-chloro-6-methoxybenzyl)- 7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- [3- (methylthio) benzyl] -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -7-cyclopropyl-3,5-dihydro [1,3] oxazolo [ 4,5-c] pyridine-2,4-dione, 5- (3-chloro Benzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2,6-dichlorobenzyl) -7-methyl- 3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 7-methyl-5- (4-methylbenzyl) -3,5-dihydro [1, 3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (3,5-dimethoxybenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4 , 5-c] pyridine-2,4-dione, 5- (2,6-difluorobenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] Pyridine-2,4-dione, 5- [3- (methylsulfonyl) benzyl] -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5 -(2-chloro-6-ethoxybenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-6- Ethoxybenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-fluoro-6-methoxybenzyl ) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-6-methoxybenzyl) -7- Propyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2, 4-dione, 5- (5-chloro-2-fluorobenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -7-isopropyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (5-fluoro- 2-methylbenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 7-methyl-5-[(1S) -1 -Phenylethyl] -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-5-isopropoxybenzyl) -7- Methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (5-acetyl-2-methoxybenzyl) -3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chlorobenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4 , 5-d] pyridazine-2,4-dione, 5- [2-fluoro-6- (trifluoromethyl) benzyl] -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-6-methylbenzyl) -5,6,7,8-tetrahydro-2H-cyclopenta [b] [1,3 ] Oxazolo [5,4-d] pyridine-2,4 ( 3H) -dione, 5- (2-chloro-6-ethoxybenzyl) -7-ethyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione , 5- (2-chloro-6-propoxybenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- ( 2-chloro-6-isobutoxybenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro- 6-ethoxybenzyl) -5,6,7,8-tetrahydro-2H-cyclopenta [b] [1,3] oxazolo [5,4-d] pyridine-2,4 (3H) -dione, 5- (2-chloro-6-isopropoxybenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- ( 2-chloro-6- (2,2,2-trifluoroethoxy) benzyl] -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2, 4-dione, 5- (2-chloro-6-ethoxybenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-d] pyridazine-2,4-dione , 5- [2-chloro-6- (2-methoxyethoxy) benzyl] -5,6,7,8-tetrahydro-2H-cyclopenta [b] [1,3] oxazolo [5,4 -d] pyridine-2,4 (3H) -dione, 5- ( 2-chloro-6-ethoxybenzyl) -6,7-dimethyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2- Chloro-6-ethoxybenzyl) -7-ethyl-6-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2- Chlorobenzyl) -7-ethyl-3,5-dihydro [1,3] oxazolo [4,5-d] pyridazine-2,4-dione, 5- (2-chloro-6-ethoxybenzyl) -7-propyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-6-ethoxybenzyl) -7-cyclo Propyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-5-propoxybenzyl) -7-methyl-3, 5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-5-methoxybenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-6-ethoxybenzyl) -6-methyl-3,5-dihydro [1,3 ] Oxazolo [4,5-c] pyridine-2,4-dione, 5- (2-chloro-5-ethoxybenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [ 4,5-c] pyridine-2,4-dione, 5- [2- Roro-5- (piperidin-1-ylsulfonyl) benzyl] -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione, 5 -[2-chloro-5- (pyrrolidin-1-ylsulfonyl) benzyl] -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4 -Dione, 5- [2-chloro-6- (cyclopentylmethoxy) benzyl] -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4 -Dione, 5- [2- (benzyloxy) -6-chlorobenzyl] -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine-2,4-dione , 5- (2,3-dichloro-6-ethoxybenzyl) -5,6,7,8-tetrahydro-2H-cyclopenta [b] [1,3] oxazolo [5,4-d] pyridine -2,4 [3H] -dione, 5- [2-chloro-5- (trifluoromethyl) benzyl] -7-methyl-3,5-dihydro [1,3] oxazolo [4,5- c] pyridine-2,4-dione and 5- (2-chloro-5-fluorobenzyl) -7-methyl-3,5-dihydro [1,3] oxazolo [4,5-c] pyridine- A compound selected from the group consisting of 2,4-dione.
[25" claim-type="Currently amended] (3S) -3-[({[2-methyl-4- (2-methylpropyl) -6-oxo-1- (phenylmethyl) -1,6-dihydro-5-pyrimidinyl] amino} carbo Yl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 [({[2-oxo-1- (phenylmethyl) -4-propyl-1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4 -Ethyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1- [ (2-chlorophenyl) methyl] -2-oxo-4-propyl-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- ( 4-methylphenyl) propanoic acid, (3S) -3-{[({6-methyl-2-oxo-1- (phenylmethyl) -4-[(phenylmethyl) oxy] -1,2-dihydro-3 -Pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophene ) Methyl] -2,4-dimethyl-6-oxo-1,6-dihydro-5-pyrimidinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3 -{[({4-amino-1-[(2-chlorophenyl) methyl] -6-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3 -(4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyridinyl } Amino) carbonyl] amino} -3- [4- (methyloxy) phenyl] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-methyl-2 -Oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3,4-dimethylphenyl) propanoic acid, (3S) -3-{[({4-amino- 1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S)- 3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- ( 4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4- ( 1,4-oxazinan-4-yl) -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S)- 3-{[({1-[(2-chlorophenyl) methyl] -2-oxo-4- (propylamino) -1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3 -(4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-bromophenyl) methyl] -4-methyl-2-oxo-1,2-dihydro-3-pyri Diyl] amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo -1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [3-methyl-4- (methyloxy) phenyl] propanoic acid, (3S) -3-{[({1 -[(2-chlorophenyl) methyl] -2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl] amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, ( 3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[(2-{[2- (methyloxy) ethyl] oxy} ethyl) oxy] -2-oxo-1, 2-dihydro-3-pyridinyl] amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo Nil] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-[(1,1-dimethylethyl) amino] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl] propanoic acid, (3S) -3-{[({1-[(2 -Chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino} carbonyl) amino} -3-phenylpropanoic acid, (3S) -3-{[ ({1-[(2-chlorophenyl) methyl] -4- [4-methyltetrahydro-1 (2H) -pyrazinyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino} Carbonyl) amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2 -Dihydro-3-pyridinyl} amino) carbonyl) amino} -3- [4- (methyloxy) phenyl] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) Methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} ami } Carbonyl] amino} -3- (3,5-dimethylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo -1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (3-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) Methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [3- (methyloxy) phenyl] propanoic acid, (3S)- 3- [3,5-bis (methyloxy) phenyl] -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3 -Pyridinyl} amino} carbonyl) amino} propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-1,2-di Hydro-3-quinolinyl} amino) carbonyl) amino} -3- [4-methylphenyl] propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4- Hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- [3- (trifluoromethyl) phenyl] propanoic acid, (3S) -3- { [({1-[(2-chlorophenyl) methyl] -4-[({ethyl [(ethylami No) carbonyl] amino) carbonyl] amino} -2-oxo-1,2-dihydro-3-pyridinyl} amino} carbonyl) amino} -3- (4-methylphenyl] propanoic acid, (3S) -3-{[({4- (1-Azetanyl) -1-[(2-chlorophenyl) methyl] -2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] Amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-({2-[(2-{[2- ( Methyloxy) ethyl] oxy} ethyl) oxy] ethyl} oxy) -2-oxo-1,2-dihydro-3-pyridinyl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-fluorophenyl) methyl] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbonyl] amino } -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chloro-6-fluorophenyl) methyl] -4-hydroxy-2-oxo-1, 2-dihydro-3-pyridinyl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl]- 5-methyl-2-oxo-1,2-dihydro-3-pyridinyl} amino) carbo ] Amino} -3- (4-methylphenyl) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3-((((2-oxo-1-((4- (Trifluoromethyl) phenyl) methyl) -1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) propanoic acid, (3S) -3-((((1-((2-chloro Phenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- (4-methylphenyl) propanoic acid, (3S) -3-(((((1 -((2-fluorophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- (4-methylphenyl) propanoic acid, (3S)- 3-((((1-((2-bromophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- (4-methylphenyl) Propanoic acid, (3S) -3-((((1-((2,4-dichlorophenyl) methyl) -2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- (4-methylphenyl) propanoic acid, (3S) -3-((((1-((2-chloro-6-fluorophenyl) methyl) -2-oxo-1,2-dihydro-3 -Pyridinyl) amino) carbonyl) amino) -3- (4-methylphenyl) propanoic acid, (3S) -3-((((1-((2 -Chlorophenyl) methyl) -4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl) amino) carbonyl) amino) -3- (4-trifluoromethyl) oxy) phenyl) Propanoic acid, (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, 4-{[3-[({[(1S) -2-carboxy-1- (4-methylphenyl) ethyl] amino} carbonyl) amino] -1- (2 -Chlorobenzyl) -2-oxo-1,2-dihydropyridin-4-yl] amino} benzoic acid, (3S) -3-{[({1- (2-chlorobenzyl) -4-[(2, 2-dimethylpropanoyl) amino] -2-oxo-1,2-dihydropyridin-3-yl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3- [({[4-{[(tert-butylamino) carbonyl] amino} -1- (2-chlorobenzyl) -2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl ) Amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-cyanobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridine -3-yl] amino} carbonyl) amino] -3- (4- Methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (2,3-dihydro-1,4-benzodioxin-6-yl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydro Oxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (7-methoxy-1,3-benzodioxol-5-yl) propanoic acid, ( 3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- ( 3-ethoxy-4-methoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridine- 3-yl] amino} carbonyl) amino] -3- (3,4-dimethoxyphenyl) propanoic acid, (3S) -3-[({[1- (4-chlorobenzyl) -4-hydroxy- 2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro -6-methoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl ] Amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo -1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2,6-difluoro Lobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3- [ ({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3 , 5-dimethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] Amino} carbonyl) amino] -3- (3,4-diethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo- 1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] a Mino} carbonyl) amino] -3- (3-methoxy-4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo -1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,5-dimethoxy-4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,4-dimethylphenyl) propanoic acid, ( 3S) -3-[({[1- (2-chlorobenzyl) -5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-{[({1- [2-chloro-5- (trifluoromethyl) benzyl] -4-hydroxy-2-oxo-1, 2-dihydropyridin-3-yl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-methoxybenzyl ) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-methylphenyl) propanoic acid, (3S) -3-[({ [1- (2-Chloro-6-methylbenzyl) -4-hydroxy-5-meth Methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2 -Chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (4 -Methylphenyl) propanoic acid, (3S) -3-[({[1- (2,6-dimethoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-di Hydropyridin-3-yl] amino} carbonyl) amino] -3- (3-propoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy -2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid, (3S) -3-[({ [1- (2-chlorobenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4- Methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro Benzyl) -4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,4-diethoxyphenyl) propanoic acid, (3S) -3- (3-butoxyphenyl) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] Amino} carbonyl) amino] propanoic acid, (3S) -3-{[({1- [2-chloro-5- (methylsulfonyl) benzyl] -4-hydroxy-2-oxo-1,2- Dihydropyridin-3-yl} amino) carbonyl] amino} -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy- 2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- [3- (2-methoxyethoxy) phenyl] propanoic acid, (3S) -3-[( {[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,4-dipropoxy Phenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- [3- (difluoromethoxy) phenyl] Ropanic Acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbo Yl) amino] -3- (3,4-diethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo -1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro- 6-methylbenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,4-diethoxy Phenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-cyanobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] Amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, 3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridine- 3-yl] amino} carbonyl) amino] -3- (2-naphthyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5,6 -Dimethyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Mino] -3- (3,4-diethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-methoxybenzyl) -4-hydroxy-5-methyl- 2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3,4-diethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid, ( 3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-methylbenzyl) -4-hydroxy-2-oxo-2,5,6 , 7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid, (3S) -3-[({[1 -(2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl Propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4 -Hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid, (3S) -3 -[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3- Yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy -5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (1-methyl-1H-indol-5-yl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl ) Amino] -3- (2,3-dihydro-1-benzofuran-5-yl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl)- 4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (3,5-diethoxy Phenyl) propanoic acid, (3S) -3-[({[5-chloro-1- (2-chloro-6- Ethoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid, (3S)- 3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3 -(3-isopropoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6 , 7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (3-propoxyphenyl) propanoic acid, (3S) -3-[({[1 -(2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl ) Amino] -3-phenylpropanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H -Cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl Propanoic acid, (3S) -3-[({[1- (2- Roro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-trifluorome Methoxy) phenyl] propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5,6-dimethyl-2-oxo-1,2- Dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4- Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (1-methyl-1H-indole- 5-yl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -5-cyclopropyl-4-hydroxy-2-oxo-1,2-di Hydropyridin-3-yl] amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl ) -5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S)- 3-[({[1- (2- Roro-5-methoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propane Acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl ] Amino} carbonyl) amino] -3- (3-isopropoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy -5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (1-methyl-1H-indol-6-yl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine- 3-yl] amino} carbonyl) amino] -3- [3- (cyclopropyloxy) phenyl] propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy -2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- [3- (cyclopropylmethoxy) phenyl] Propanoic acid, (3S) -3-[({[ 1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbo Yl) amino] -3- [3- (cyclopropylmethoxy) phenyl] propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2 , 5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (3,5-dimethylphenyl) propanoic acid, (3S) -3- {[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl} amino ) Carbonyl] amino} -3- {3-[(difluoromethyl) oxy] phenyl} propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4- Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl} amino) carbonyl] amino} -3- {3-[(1,1, 2,2-tetrafluoroethyl) oxy] phenyl} propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5 , 6,7-tetrahydro-1H-cyclophene Ta [b] pyridin-3-yl} amino) carbonyl] amino} -3- (1-ethyl-1H-indol-5-yl) propanoic acid and (3S) -3-{[({1-[( 2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl} amino) carbonyl] amino} -3 A compound selected from the group consisting of [3- (diethylamino) phenyl] propanoic acid, and a pharmaceutically acceptable salt thereof.
[26" claim-type="Currently amended] (3S) -3-[({[1-((2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid and pharmaceutically acceptable salts thereof.
[27" claim-type="Currently amended] (3S) -3-[({[1-((2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3 -Yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid and pharmaceutically acceptable salts thereof.
[28" claim-type="Currently amended] (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino ] -3- [3- (diethylamino) phenyl] propanoic acid and pharmaceutically acceptable salts thereof.
[29" claim-type="Currently amended] (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino } Carbonyl) amino] -3- (4-methylphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl- 2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (3-ethoxyphenyl) propanoic acid, (3S) -3-[({[1- (2 -Chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (3 Isopropoxyphenyl) propanoic acid, (3S) -3-[({[1- (2-chloro-6-ethoxybenzyl) -4-hydroxy-5-methyl-2-oxo-1,2- Dihydropyridin-3-yl] amino} carbonyl) amino] -3- (6-methoxy) -2-naphthyl) propanoic acid, (3S) -3-[({[1- (2-chlorobenzyl ) -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (3-methylphenyl) Propanoic acid, (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4- Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl} amino) carbonyl] amino} -3- (1-methyl-1H-indole- 5-yl) propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H -Cyclopenta [b] pyridin-3-yl} amino) carbonyl] amino} -3- {3-[(methylsulfonyl) amino] phenyl} propanoic acid, (3S) -3-{[((1- [(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl} amino) carbonyl ] Amino} -3- {3-[(methylsulfonyl) amino] phenyl} propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4-hydroxy-2 -Oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl} amino) carbonyl] amino} -3- {3- [methyl (methylsulfonyl) amino] phenyl } Propanoic acid, (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H -Cyclopenta [b] pyridin-3-yl} Mino) carbonyl] amino} -3- {3- [methyl (methylsulfonyl) amino] phenyl} propanoic acid, (3S) -3-{[({1-[(2-chlorophenyl) methyl] -4 -Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl} amino) carbonyl] amino} -3- {3- [ethyl (methylsul Ponyl) amino] phenyl} propanoic acid, (3S) -3-{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7 -Tetrahydro-1H-cyclopenta [b] pyridin-3-yl} amino) carbonyl] amino} -3- {3- [ethyl (methylsulfonyl) amino] phenyl} propanoic acid, and (3S) -3 -{[({1-[(2-chloro-6-methylphenyl) methyl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridine-3 -Yl} amino) carbonyl] amino} -3- (1H-indol-5-yl) propanoic acid and a pharmaceutically acceptable salt thereof.
[30" claim-type="Currently amended] A pharmaceutical composition comprising the compound of claim 1 in a pharmaceutically acceptable carrier.
[31" claim-type="Currently amended] A method of selectively inhibiting α ₄ β ₁ integrin binding in a mammal, comprising administering to the mammal a therapeutic amount of the compound of claim 1.

类似技术:

---

公开号 | 公开日 | 专利标题

---

US9790183B2|2017-10-17|Pyridyl inhibitors of hedgehog signalling

---

JP5627574B2|2014-11-19|Compounds and methods for treating inflammatory and fibrotic diseases

---

KR101643781B1|2016-07-28|Pyridyl inhibitors of hedgehog signalling

---

DE69728685T2|2005-04-14|New substituted imidazol compounds

---

US5629325A|1997-05-13|3-pyridyloxymethyl heterocyclic ether compounds useful in controlling chemical synaptic transmission

---

EP1024138B1|2007-04-25|Pyrazole derivatives

---

AU735901B2|2001-07-19|Substituted pyrimidinone and pyridone compounds and methods of use

---

JP3981398B1|2007-09-26|Substituted pyrimidinones

---

FI120397B|2009-10-15|New sulfonamides

---

ES2327940T3|2009-11-05|3- | -n-aril-benzamidas in quality of inhibitors of the production of citocines for the treatment of chronic inflammatory diseases.

---

TWI344955B|2011-07-11|Heterocyclic rinf having nitrogen atom derivatives and medicament containing the derivatives as active ingredient

---

AU654372B2|1994-11-03|Cyclic imino derivatives

---

CN101018783B|2012-11-21|Quinoxaline inhibitors of the HEDGEHOG signalling pathway

---

DE60309739T2|2007-10-31|Pyridine derivatives as modulators of the CB2 receptor

---

JP4394442B2|2010-01-06|Spiro-hydantoin compounds useful as anti-inflammatory agents

---

US7064142B2|2006-06-20|Imidazonline compounds

---

CA2702647C|2016-03-22|Thiopyrimidine-based compounds and uses thereof

---

AU742442B2|2002-01-03|Substituted pyridine compounds as anti-inflammatory agents

---

KR100484331B1|2005-09-30|3-pyridyloxyalkylheterocyclic ether compounds useful for modulating chemical synaptic transmission

---

JP4606161B2|2011-01-05|Substituted heterocyclic compounds and methods of use

---

AU2002334205B8|2003-05-06|Dihydroxypyrimidine carboxamide inhibitors of HIV integrase

---

AU2002219555B2|2006-11-30|VLA-4 Inhibitors

---

US6610698B2|2003-08-26|Substituted pyrimidine compounds and methods of use

---

DE60305061T2|2006-12-07|2-pyridone derivatives as inhibitors of neutrophiler elastase

---

JP6574435B2|2019-09-11|Human plasma kallikrein inhibitor

同族专利:

---

公开号 | 公开日

---

NZ515252A|2004-01-30|

---

US20060276476A1|2006-12-07|

---

KR100851766B1|2008-08-13|

---

EP1203766A3|2004-12-08|

---

AT547406T|2012-03-15|

---

EP1203766B8|2012-04-11|

---

ES2379945T3|2012-05-07|

---

NO20015394L|2002-05-07|

---

EP1203766B1|2012-02-29|

---

IL146313A|2010-12-30|

---

IL146313D0|2002-07-25|

---

US6972296B2|2005-12-06|

---

DK1203766T3|2012-04-10|

---

US7812038B2|2010-10-12|

---

NO324496B1|2007-10-29|

---

US20040063955A1|2004-04-01|

---

TR200103179A2|2002-06-21|

---

EP1203766A2|2002-05-08|

---

NO20015394D0|2001-11-05|

---

HK1046275A1|2003-01-03|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

法律状态:
2000-11-06|Priority to US70706800A

---

2000-11-06|Priority to US09/707,068

---

2001-10-09|Priority to US09/973,142

---

2001-10-10|Priority to US09/973,142

---

2001-11-06|Application filed by 데이비드 비. 맥윌리암스, 텍사스 바이오테크놀로지 코포레이션

---

2002-05-11|Publication of KR20020035471A

---

2008-08-13|Application granted

---

2008-08-13|Publication of KR100851766B1

优先权:

---

申请号 | 申请日 | 专利标题

---

US70706800A| true| 2000-11-06|2000-11-06|

---

US09/707,068|2000-11-06|

---

US09/973,142|US6972296B2|1999-05-07|2001-10-09|Carboxylic acid derivatives that inhibit the binding of integrins to their receptors|

---

US09/973,142|2001-10-10|