Indolizine derivatives and their application in medicine

Abstract

This invention relates to indolizine derivatives and their use in medicine. In particular, the present invention discloses novel substituted indolizine derivatives of formula I, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. The invention also relates to the use of these compounds in medicine. ##STR00001##

Claims

1. A method of treating a disease associated with hypoxia inducible factors, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, ##STR00282## or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof in which R.sup.1 and R.sup.2 are each independently selected from the group consisting of cyano, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, amino, R.sup.9O—, R.sup.9S—, R.sup.9(O═)S—, and R.sup.9(O═).sub.2S—, wherein R.sup.9 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl or heteroaryl; and wherein the alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, and amino are optionally substituted by one or more substituents wherein the substituents are independently selected from the group consisting of halo, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, ═O, ═S, —SH, R.sup.10O—, R.sup.10S—, R.sup.10(O═)S—, and R.sup.10(O═).sub.2S—, and wherein R.sup.10 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl; or R.sup.1 and R.sup.2 are taken together to form a ring; R.sup.3, R.sup.4 and R.sup.5 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, R.sup.11O—, R.sup.11S—, R.sup.11 (O═)S—, and R.sup.11 (O═).sub.2S—, wherein R.sup.11 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl or heteroaryl; wherein the alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, and amino are optionally substituted by one or more substituents wherein the substituents are independently selected from the group consisting of halogen, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, ═O, ═S, —SH, R.sup.12O—, R.sup.12S—, R.sup.12(O═)S—, and R.sup.12(O═).sub.2S—, and wherein R.sup.12 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl; R.sup.6 and R.sup.6′ are each independently selected from the group consisting of hydrogen and optionally substituted alkyl; R.sup.7 is selected from the group consisting of hydrogen, alkyl and acyl; wherein the alkyl and acyl are optionally substituted by the following groups: halogen, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, ═O, ═S, —SH, R.sup.13O—, R.sup.13S—, R.sup.13(O═)S—, and/or R.sup.13(O═).sub.2S—, wherein R.sup.13 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl; R.sup.8 is selected from the group consisting of hydrogen, alkyl and —OC(O)R.sup.14, wherein R.sup.14 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl or heteroaryl; wherein the alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl group is optionally substituted with the following groups: halogen, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, ═O, ═S, —SH, R.sup.15O—, R.sup.15S—, R.sup.15(O═)S—, and/or R.sup.15(O═).sub.2S—; wherein R.sup.15 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl; and X is an oxygen atom or a sulfur atom or NH, wherein the disease associated with hypoxia-inducing factors is selected from the group consisting of anemia, cardiovascular disease, neurological diseases, HIV infections, rheumatoid arthritis, surgery-related ischemia, fetal suffocation, cancer and diseases associated with cancer, eye diseases, central nervous system diseases, chronic kidney disease, renal insufficiency and acute renal failure, sexual dysfunction, diabetes and its complications selected from diabetic macroangiopathy and microangiopathy, diabetic nephropathy, neurodegenerative diseases, ischemic diseases and fibrotic diseases.

2. The method according to claim 1, wherein R.sup.1 and R.sup.2 are independently selected from the group consisting of cyano, C1-C12 acyclic alkyl, C2-C12 acyclic alkenyl, C2-C12 acyclic alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, heteroaryl containing 5 to 14 ring members, C1-C12 acyclic alkyl —C(═O)—, C2-C12 acyclic alkenyl-C(═O)—, amino, R.sup.9O—, R.sup.9S—, R.sup.9(O═)S—, and R.sup.9(O═).sub.2S—, wherein R.sup.9 is C1-C12 acyclic alkyl, C2-C12 acyclic alkenyl, C2-C12 acyclic alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members; wherein the above C1-C12 acyclic alkyl group, C2-C12 acyclic alkenyl group, C2-C12 acyclic alkynyl group, C6-C14 aryl group, C3-C8 cycloalkyl group, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, heteroaryl having 5 to 14 ring members, C1-C12 acyclic alkyl-C(═O)—, C2-C12 acyclic alkenyl-C(═O)—, and amino group are optionally substituted by 1 to 3 substituents wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C2-C6 acyclic alkenyl-, C2-C6 acyclic alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl having 5 to 14 ring members, C1-C6 acyclic alkyl-O—, C3-C8 cycloalkyl-O—, C2-C6 acyclic alkenyl-O—, C2-C6 acyclic alkynyl-O—, C3-C8 cycloalkenyl-O—, C6-C14 aryl-O—, heteroaryl-O— having 5 to 14 ring members, C1-C6 acyclic alkyl-S—, C3-C8 cycloalkyl-S—, C2-C6 acyclic alkenyl-S—, C2-C6 acyclic alkynyl —S—, C3-C8 cycloalkenyl-S—, C6-C14 aryl-S—, heteroaryl-S— having 5 to 14 ring members, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, ═O, ═S, —SH, —CF.sub.3, —CO.sub.2C.sub.1-C.sub.6 acyclic alkyl, C1-C6 acyclic alkyl-S—, C1-C6 acyclic alkyl (O═)S— and C1-C6 acyclic alkyl (O═).sub.2S—; or R.sup.1 and R.sup.2 are taken together to form an optionally substituted cycloalkane ring, cycloalkylene ring, heterocycloalkane ring, or heterocycloalkylene ring having 3 to 8 ring members; R.sup.3, R.sup.4 and R.sup.5 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, C1-C12 acyclic alkyl, C2-C12 acyclic alkenyl, C2-C12 acyclic alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, heteroaryl having 5 to 14 ring members, C1-C12 acyclic alkyl-C(═O)—, C2-C12 acyclic alkenyl-C(═O)—, amino, R.sup.11O—, R.sup.11S—, R.sup.11(O═)S—, and R.sup.11(O═).sub.2S— wherein R.sup.11 is C1-C12 acyclic alkyl, C2-C12 acyclic alkenyl, C2-C12 acyclic alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3-8 ring members, or heterocycloalkenyl having 3 to 8 ring members; wherein the above C1-C12 acyclic alkyl, C2-C12 acyclic alkenyl, C2-C12 acyclic alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, heteroaryl having 5 to 14 ring members, C1-C12 acyclic alkyl-C(═O)—, C2-C12 acyclic alkenyl-C(═O)—, and amino are optionally substituted with from 1 to 3 substituents wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C2-C6 acyclic alkenyl-, C2-C6 acyclic alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl having 5 to 14 ring members, C1-C6 acyclic alkyl-O—, C3-C8 cycloalkyl-O—, C2-C6 acyclic alkenyl-O—, C2-C6 acyclic alkynyl-O—, C3-C8 cycloalkenyl-O—, C6-C14 aryl-O—, heteroaryl-O— having 5 to 14 ring members, C1-C6 acyclic alkyl-S—, C3-C8 cycloalkyl-S—, C2-C6 acyclic alkenyl-S—, C2-C6 acyclic alkynyl-S—, C3-C8 cycloalkenyl-S—, C6-C14 aryl-S—, heteroaryl-S— having 5 to 14 ring members, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, ═O, ═S, —SH, —CF.sub.3, —CO.sub.2C.sub.1-C.sub.6 acyclic alkyl group, C1-C6 acyclic alkyl-S—, C1-C6 acyclic alkyl (O═)S— and C1-C6 acyclic alkyl (O═).sub.2S—; R.sup.6 and R.sup.6′ are each independently selected from the group consisting of hydrogen, C1-C6 acyclic alkyl and C3-C8 cycloalkyl; the above C1-C6 acyclic alkyl and C3-C8 cycloalkyl are optionally substituted by 1 to 3 substituents wherein the substituents are independently selected from the group consisting of hydroxy, halogen, cyano, amino, carboxy, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C2-C6 acyclic alkenyl-, C2-C6 acyclic alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl having 5 to 14 ring members, C1-C6 acyclic alkyl-O—, C3-C8 cycloalkyl-O—, C2-C6 acyclic alkenyl-O—, C2-C6 acyclic alkynyl-O—, C3-C8 cycloalkenyl-O—, C6-C14 aryl-O—, and heteroaryl-O-having 5 to 14 ring members; R.sup.7 is selected from the group consisting of hydrogen, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C1-C6 acyclic alkyl-C(═O)—, and C2-C6 acyclic alkenyl-C(═O)—; wherein the C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C1-C6 acyclic alkyl-C(═O)—, and C2-C6 acyclic alkenyl-C(═O)— are optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C2-C6 acyclic alkenyl-, C2-C6 acyclic alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl having 5 to 14 ring members, C1-C6 acyclic alkyl-O—, C3-C8 cycloalkyl-O—, C2-C6 acyclic alkenyl-O—, C2-C6 acyclic alkynyl-O—, C3-C8 cycloalkenyl-O—, C6-C14 aryl-O—, and heteroaryl-O-having 5 to 14 ring members; R.sup.8 is selected from the group consisting of hydrogen, C1-C12 acyclic alkyl, C3-C8 cycloalkyl and —OC(O)—C1-C12 acyclic alkyl; wherein the C1-C12 acyclic alkyl, C3-C8 cycloalkyl and —OC(O)—C1-C12 acyclic alkyl group are optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C2-C6 acyclic alkenyl-, C2-C6 acyclic alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl having 5 to 14 ring members, C1-C6 acyclic alkyl-O—, C3-C8 cycloalkyl-O—, C2-C6 acyclic alkenyl-O—, C2-C6 acyclic alkynyl-O—, C3-C8 cycloalkenyl-O—, C6-C14 aryl-O—, and heteroaryl-O— having 5 to 14 ring members; and X is an oxygen atom or a sulfur atom or NH.

3. The method according to claim 1, wherein R.sup.1 and R.sup.2 are each independently selected from the group consisting of cyano, amino, and unsubstituted C1-C6 acyclic alkyl; or R1 and R2 are taken together to form an optionally substituted cycloalkane ring or heterocycloalkane ring having 3-8 ring members.

4. The method according to claim 1, wherein R.sup.3, R.sup.4 and R.sup.5 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, C1-C6 acyclic alkyl, C6-C14 aryl, C3-C8 cycloalkyl, C1-C6 acyclic alkyl —O—, and heteroaryl having 5 to 14 ring members; wherein the above C1-C6 acyclic alkyl, C6-C14 aryl, C3-C8 cycloalkyl, C1-C6 acyclic alkyl-O—, heteroaryl having 5 to 14 ring members and amino are optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C6-C14 aryl and C1-C6 acyclic alkyl.

5. The method according to claim 1, wherein R.sup.6 and R.sup.6′ are each independently selected from hydrogen, unsubstituted C1-C6 acyclic alkyl, unsubstituted C3-C8 cycloalkyl, and C1-C6 acyclic alkyl substituted by 1-3 halogens.

6. The method according to claim 1, wherein R.sup.7 is selected from the group consisting of hydrogen, unsubstituted C1-C6 acyclic alkyl, unsubstituted C1-C6 acyclic alkyl-C(═O)— and unsubstituted C2-C6 acyclic alkenyl-C(═O)—.

7. The method according to claim 1, wherein R.sup.8 is selected from the group consisting of hydrogen, C1-C6 acyclic alkyl, and —OC(O)—C1-C12 acyclic alkyl; wherein the C1-C6 acyclic alkyl and —OC(O)—C1-C12 acyclic alkyl are optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from hydroxy, halo, cyano, amino, carboxy, C1-C6 acyclic alkyl and C1-C6 acyclic alkyl-O—.

8. The method according to claim 1, wherein X is an oxygen atom.

9. The method according to claim 1, wherein the compound is selected from the group consisting of: (6′-hydroxy-8′-oxo-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)-D-alanine; (6-hydroxy-5,5-dimethyl-8-oxo-5,8-dihydroindolizin-7-carbonyl)glycine; (6-hydroxy-5,5-dimethyl-8-oxo-5,8-dihydroindolizin-7-carbonyl)-L-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine methyl ester; (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine ethyl ester; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-D-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (3′-cyclobutyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (3′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (6′-hydroxy-3′-methyl-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (3′-(tert-butyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (3′-cyclopentyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine, (3′-cyclohexyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine, (6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine ethyl ester; (((6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycyloxy)) methyl pivalate; (6′-hydroxy-8′-oxo-3′-(pyridin-3-yl)-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (3′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine (3′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine (3′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6′-hydroxy-3′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl glycine; (6′-hydroxy-8′-oxo-3′-(4-methylphenyl)-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine (3′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (3′-tert-butyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-3′-methyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (3′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-D-alanine; (3′-cyclobutyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (3′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (3′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (6′-hydroxy-3′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)glycine; (6-hydroxy-5,5-dimethyl-8-oxo-3-phenyl-5,8-dihydroindolizin-7-carbonyl)glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6-hydroxy-8-oxo-3-phenyl-2′,3′,5′,6′-tetrahydro-8H-spiro[indolizin-5,4′-pyran]-7-carbonyl)glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-D-alanine; (6-hydroxy-8-oxo-2′,3′,5′,6′-tetrahydro-8H-spiro[indolizin-5,4′-pyran]-7-carbonyl)glycine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine ethyl ester; (3′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-previous]-7′-carbonyl) glycine ethyl ester (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine-2,2-dideuterium (6′-Hydroxy-8′-oxo-3′-(phenyl-4-hydra)-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (3′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine methyl ester; (3′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine methyl ester; (1′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine; (2′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine; (6′-hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-2′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (1′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (2′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (1′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (2′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (6′-hydroxy-1′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl glycine; (6′-hydroxy-2′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl glycine; (1′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (2′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (6′-hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-2′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cycloheptane-1,5′-indolizine]-7′-carbonyl)glycine; ((1,4-trans)-6′-hydroxy-4-methyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; ((1,4-cis)-6′-hydroxy-4-methyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-2′-phenyl-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine-2,2-di-deuterium (6′-hydroxy-3′-(4-hydroxyphenyl)-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-3′-(2-methoxyphenyl)-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl glycine; and (6′-hydroxy-3′-(3-methoxyphenyl)-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl glycine.

10. The method according to claim 1, wherein the compound is be administered to the patient at dosage levels in the range of about 0.01 to about 4,000 mg per day or 0.05 to 2000 mg per day, or 0.1 to 1000 mg per day or 0.1 to 500 mg per day.

11. The method according to claim 10, wherein the daily dosage is administered continuously.

12. A method of increasing hematocrit, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, ##STR00283## or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof in which R.sup.1 and R.sup.2 are each independently selected from the group consisting of cyano, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, amino, R.sup.9O—, R.sup.9S—, R.sup.9(O═)S—, and R.sup.9(O═).sub.2S—, wherein R.sup.9 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl or heteroaryl; and wherein the alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, and amino are optionally substituted by one or more substituents wherein the substituents are independently selected from the group consisting of halo, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, ═O, ═S, —SH, R.sup.10O—, R.sup.10S—, R.sup.10(O═)S—, and R.sup.10(O═).sub.2S—, and wherein R.sup.10 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl; or R.sup.1 and R.sup.2 are taken together to form a ring; R.sup.3, R.sup.4 and R.sup.5 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, R.sup.11O—, R.sup.11S—, R.sup.11 (O═)S—, and R.sup.11 (O═).sub.2S—, wherein R.sup.11 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl or heteroaryl; wherein the alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, and amino are optionally substituted by one or more substituents wherein the substituents are independently selected from the group consisting of halogen, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, ═O, ═S, —SH, R.sup.12O—, R.sup.12S—, R.sup.12(O═)S—, and R.sup.12(O═).sub.2S—, and wherein R.sup.12 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl; R.sup.6 and R.sup.6′ are each independently selected from the group consisting of hydrogen and optionally substituted alkyl; R.sup.7 is selected from the group consisting of hydrogen, alkyl and acyl; wherein the alkyl and acyl are optionally substituted by the following groups: halogen, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, ═O, ═S, —SH, R.sup.13O—, R.sup.13S—, R.sup.13(O═)S—, and/or R.sup.13(O═).sub.2S—, wherein R.sup.13 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl; R.sup.8 is selected from the group consisting of hydrogen, alkyl and —OC(O)R.sup.14, wherein R.sup.14 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl or heteroaryl; wherein the alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl group is optionally substituted with the following groups: halogen, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, ═O, ═S, —SH, R.sup.15O—, R.sup.15S—, R.sup.15(O═)S—, and/or R.sup.15(O═).sub.2S—; wherein R.sup.15 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl; and X is an oxygen atom or a sulfur atom or NH, wherein the disease is selected from the group consisting of anemia, cardiovascular disease, neurological diseases, HIV infections, rheumatoid arthritis, surgery-related ischemia, fetal suffocation, cancer and diseases associated with cancer, eye diseases, central nervous system diseases, chronic kidney disease, renal insufficiency and acute renal failure, sexual dysfunction, diabetes and its complications selected from diabetic macroangiopathy and microangiopathy, diabetic nephropathy, neurodegenerative diseases, ischemic diseases and fibrotic diseases.

13. The method according to claim 12, wherein R.sup.1 and R.sup.2 are independently selected from the group consisting of cyano, C1-C12 acyclic alkyl, C2-C12 acyclic alkenyl, C2-C12 acyclic alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, heteroaryl containing 5 to 14 ring members, C1-C12 acyclic alkyl —C(═O)—, C2-C12 acyclic alkenyl-C(═O)—, amino, R.sup.9O—, R.sup.9S—, R.sup.9(O═)S—, and R.sup.9(O═).sub.2S—, wherein R.sup.9 is C1-C12 acyclic alkyl, C2-C12 acyclic alkenyl, C2-C12 acyclic alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members; wherein the above C1-C12 acyclic alkyl group, C2-C12 acyclic alkenyl group, C2-C12 acyclic alkynyl group, C6-C14 aryl group, C3-C8 cycloalkyl group, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, heteroaryl having 5 to 14 ring members, C1-C12 acyclic alkyl-C(═O)—, C2-C12 acyclic alkenyl-C(═O)—, and amino group are optionally substituted by 1 to 3 substituents wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C2-C6 acyclic alkenyl-, C2-C6 acyclic alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl having 5 to 14 ring members, C1-C6 acyclic alkyl-O—, C3-C8 cycloalkyl-O—, C2-C6 acyclic alkenyl-O—, C2-C6 acyclic alkynyl-O—, C3-C8 cycloalkenyl-O—, C6-C14 aryl-O—, heteroaryl-O— having 5 to 14 ring members, C1-C6 acyclic alkyl-S—, C3-C8 cycloalkyl-S—, C2-C6 acyclic alkenyl-S—, C2-C6 acyclic alkynyl —S—, C3-C8 cycloalkenyl-S—, C6-C14 aryl-S—, heteroaryl-S— having 5 to 14 ring members, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, ═O, ═S, —SH, —CF.sub.3, —CO.sub.2C.sub.1-C.sub.6 acyclic alkyl, C1-C6 acyclic alkyl-S—, C1-C6 acyclic alkyl (O═)S— and C1-C6 acyclic alkyl (O═).sub.2S—; or R.sup.1 and R.sup.2 are taken together to form an optionally substituted cycloalkane ring, cycloalkylene ring, heterocycloalkane ring, or heterocycloalkylene ring having 3 to 8 ring members; R.sup.3, R.sup.4 and R.sup.5 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, C1-C12 acyclic alkyl, C2-C12 acyclic alkenyl, C2-C12 acyclic alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, heteroaryl having 5 to 14 ring members, C1-C12 acyclic alkyl-C(═O)—, C2-C12 acyclic alkenyl-C(═O)—, amino, R.sup.11O—, R.sup.11S—, R.sup.11(O═)S—, and R.sup.11(O═).sub.2S— wherein R.sup.11 is C1-C12 acyclic alkyl, C2-C12 acyclic alkenyl, C2-C12 acyclic alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3-8 ring members, or heterocycloalkenyl having 3 to 8 ring members; wherein the above C1-C12 acyclic alkyl, C2-C12 acyclic alkenyl, C2-C12 acyclic alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, heteroaryl having 5 to 14 ring members, C1-C12 acyclic alkyl-C(═O)—, C2-C12 acyclic alkenyl-C(═O)—, and amino are optionally substituted with from 1 to 3 substituents wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C2-C6 acyclic alkenyl-, C2-C6 acyclic alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl having 5 to 14 ring members, C1-C6 acyclic alkyl-O—, C3-C8 cycloalkyl-O—, C2-C6 acyclic alkenyl-O—, C2-C6 acyclic alkynyl-O—, C3-C8 cycloalkenyl-O—, C6-C14 aryl-O—, heteroaryl-O— having 5 to 14 ring members, C1-C6 acyclic alkyl-S—, C3-C8 cycloalkyl-S—, C2-C6 acyclic alkenyl-S—, C2-C6 acyclic alkynyl-S—, C3-C8 cycloalkenyl-S—, C6-C14 aryl-S—, heteroaryl-S— having 5 to 14 ring members, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, ═O, ═S, —SH, —CF.sub.3, —CO.sub.2C.sub.1-C.sub.6 acyclic alkyl group, C1-C6 acyclic alkyl-S—, C1-C6 acyclic alkyl (0=)S— and C1-C6 acyclic alkyl (O═).sub.2S—; R.sup.6 and R.sup.6′ are each independently selected from the group consisting of hydrogen, C1-C6 acyclic alkyl and C3-C8 cycloalkyl; the above C1-C6 acyclic alkyl and C3-C8 cycloalkyl are optionally substituted by 1 to 3 substituents wherein the substituents are independently selected from the group consisting of hydroxy, halogen, cyano, amino, carboxy, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C2-C6 acyclic alkenyl-, C2-C6 acyclic alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl having 5 to 14 ring members, C1-C6 acyclic alkyl-O—, C3-C8 cycloalkyl-O—, C2-C6 acyclic alkenyl-O—, C2-C6 acyclic alkynyl-O—, C3-C8 cycloalkenyl-O—, C6-C14 aryl-O—, and heteroaryl-O-having 5 to 14 ring members; R.sup.7 is selected from the group consisting of hydrogen, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C1-C6 acyclic alkyl-C(═O)—, and C2-C6 acyclic alkenyl-C(═O)—; wherein the C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C1-C6 acyclic alkyl-C(═O)—, and C2-C6 acyclic alkenyl-C(═O)— are optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C2-C6 acyclic alkenyl-, C2-C6 acyclic alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl having 5 to 14 ring members, C1-C6 acyclic alkyl-O—, C3-C8 cycloalkyl-O—, C2-C6 acyclic alkenyl-O—, C2-C6 acyclic alkynyl-O—, C3-C8 cycloalkenyl-O—, C6-C14 aryl-O—, and heteroaryl-O-having 5 to 14 ring members; R.sup.8 is selected from the group consisting of hydrogen, C1-C12 acyclic alkyl, C3-C8 cycloalkyl and —OC(O)—C1-C12 acyclic alkyl; wherein the C1-C12 acyclic alkyl, C3-C8 cycloalkyl and —OC(O)—C1-C12 acyclic alkyl group are optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C2-C6 acyclic alkenyl-, C2-C6 acyclic alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl having 5 to 14 ring members, C1-C6 acyclic alkyl-O—, C3-C8 cycloalkyl-O—, C2-C6 acyclic alkenyl-O—, C2-C6 acyclic alkynyl-O—, C3-C8 cycloalkenyl-O—, C6-C14 aryl-O—, and heteroaryl-O— having 5 to 14 ring members; and X is an oxygen atom or a sulfur atom or NH.

14. The method according to claim 12, wherein the compound is selected from the group consisting of: (6′-hydroxy-8′-oxo-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)-D-alanine; (6-hydroxy-5,5-dimethyl-8-oxo-5,8-dihydroindolizin-7-carbonyl)glycine; (6-hydroxy-5,5-dimethyl-8-oxo-5,8-dihydroindolizin-7-carbonyl)-L-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine methyl ester; (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine ethyl ester; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-D-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (3′-cyclobutyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (3′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (6′-hydroxy-3′-methyl-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (3′-(tert-butyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (3′-cyclopentyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (3′-cyclohexyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine ethyl ester; (((6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycyloxy)) methyl pivalate; (6′-hydroxy-8′-oxo-3′-(pyridin-3-yl)-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (3′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine (3′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine (3′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6′-hydroxy-3′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl glycine; (6′-hydroxy-8′-oxo-3′-(4-methylphenyl)-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine (3′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (3′-tert-butyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-3′-methyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (3′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-D-alanine; (3′-cyclobutyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (3′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (3′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (6′-hydroxy-3′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)glycine; (6-hydroxy-5,5-dimethyl-8-oxo-3-phenyl-5,8-dihydroindolizin-7-carbonyl)glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6-hydroxy-8-oxo-3-phenyl-2′,3′,5′,6′-tetrahydro-8H-spiro[indolizin-5,4′-pyran]-7-carbonyl)glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-D-alanine; (6-hydroxy-8-oxo-2′,3′,5′,6′-tetrahydro-8H-spiro[indolizin-5,4′-pyran]-7-carbonyl)glycine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine ethyl ester; (3′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-previous]-7′-carbonyl) glycine ethyl ester (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine-2,2-dideuterium (6′-Hydroxy-8′-oxo-3′-(phenyl-4-hydra)-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (3′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine methyl ester; (3′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine methyl ester; (1′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine; (2′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine; (6′-hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-2′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (1′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (2′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (1′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (2′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (6′-hydroxy-1′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl glycine; (6′-hydroxy-2′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl glycine; (1′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (2′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (6′-hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-2′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cycloheptane-1,5′-indolizine]-7′-carbonyl)glycine; ((1,4-trans)-6′-hydroxy-4-methyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; ((1,4-cis)-6′-hydroxy-4-methyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-2′-phenyl-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine-2,2-di-deuterium (6′-hydroxy-3′-(4-hydroxyphenyl)-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-3′-(2-methoxyphenyl)-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl glycine; and (6′-hydroxy-3′-(3-methoxyphenyl)-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl glycine.

15. The method according to claim 12, wherein the compound is be administered to the patient at dosage levels in the range of about 0.01 to about 4,000 mg per day or 0.05 to 2000 mg per day, or 0.1 to 1000 mg per day or 0.1 to 500 mg per day.

16. The method according to claim 15, wherein the daily dosage is administered continuously.

17. A method of treating a disease associated with a HIF prolyl hydroxylase inhibitor, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I (or a preferred compound of Formula I), ##STR00284## or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof in which R.sup.1 and R.sup.2 are each independently selected from the group consisting of cyano, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, amino, R.sup.9O—, R.sup.9S—, R.sup.9(O═)S—, and R.sup.9(O═).sub.2S—, wherein R.sup.9 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl or heteroaryl; and wherein the alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, and amino are optionally substituted by one or more substituents wherein the substituents are independently selected from the group consisting of halo, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, ═O, ═S, —SH, R.sup.10O—, R.sup.10S—, R.sup.10(O═)S—, and R.sup.10(O═).sub.2S—, and wherein R.sup.10 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl; or R.sup.1 and R.sup.2 are taken together to form a ring; R.sup.3, R.sup.4 and R.sup.5 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, amino, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, R.sup.11O—, R.sup.11S—, R.sup.11 (O═)S—, and R.sup.11 (O═).sub.2S—, wherein R.sup.11 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl or heteroaryl; wherein the alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, and amino are optionally substituted by one or more substituents wherein the substituents are independently selected from the group consisting of halogen, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, ═O, ═S, —SH, R.sup.12O—, R.sup.12S—, R.sup.12(O═)S—, and R.sup.12(O═).sub.2S—, and wherein R.sup.12 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl; R.sup.6 and R.sup.6′ are each independently selected from the group consisting of hydrogen and optionally substituted alkyl; R.sup.7 is selected from the group consisting of hydrogen, alkyl and acyl; wherein the alkyl and acyl are optionally substituted by the following groups: halogen, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, ═O, ═S, —SH, R.sup.13O—, R.sup.13S—, R.sup.13(O═)S—, and/or R.sup.13(O═).sub.2S—, wherein R.sup.13 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl; R.sup.8 is selected from the group consisting of hydrogen, alkyl and —OC(O)R.sup.14, wherein R.sup.14 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl or heteroaryl; wherein the alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl group is optionally substituted with the following groups: halogen, cyano, hydroxy, amino, carboxy, acyl, alkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, ═O, ═S, —SH, R.sup.15O—, R.sup.15S—, R.sup.15(O═)S—, and/or R.sup.15(O═).sub.2S—; wherein R.sup.15 is alkyl, heterocyclyl, alkenyl, alkynyl, aryl, or heteroaryl; and X is an oxygen atom or a sulfur atom or NH, wherein the disease is selected from the group consisting of anemia, cardiovascular disease, neurological diseases, HIV infections, rheumatoid arthritis, surgery-related ischemia, fetal suffocation, cancer and diseases associated with cancer, eye diseases, central nervous system diseases, chronic kidney disease, renal insufficiency and acute renal failure, sexual dysfunction, diabetes and its complications selected from diabetic macroangiopathy and microangiopathy, diabetic nephropathy, neurodegenerative diseases, ischemic diseases and fibrotic diseases.

18. The method according to claim 17, wherein R.sup.1 and R.sup.2 are independently selected from the group consisting of cyano, C1-C12 acyclic alkyl, C2-C12 acyclic alkenyl, C2-C12 acyclic alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, heteroaryl containing 5 to 14 ring members, C1-C12 acyclic alkyl —C(═O)—, C2-C12 acyclic alkenyl-C(═O)—, amino, R.sup.9O—, R.sup.9S—, R.sup.9(O═)S—, and R.sup.9(O═).sub.2S—, wherein R.sup.9 is C1-C12 acyclic alkyl, C2-C12 acyclic alkenyl, C2-C12 acyclic alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members; wherein the above C1-C12 acyclic alkyl group, C2-C12 acyclic alkenyl group, C2-C12 acyclic alkynyl group, C6-C14 aryl group, C3-C8 cycloalkyl group, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, heteroaryl having 5 to 14 ring members, C1-C12 acyclic alkyl-C(═O)—, C2-C12 acyclic alkenyl-C(═O)—, and amino group are optionally substituted by 1 to 3 substituents wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C2-C6 acyclic alkenyl-, C2-C6 acyclic alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl having 5 to 14 ring members, C1-C6 acyclic alkyl-O—, C3-C8 cycloalkyl-O—, C2-C6 acyclic alkenyl-O—, C2-C6 acyclic alkynyl-O—, C3-C8 cycloalkenyl-O—, C6-C14 aryl-O—, heteroaryl-O— having 5 to 14 ring members, C1-C6 acyclic alkyl-S—, C3-C8 cycloalkyl-S—, C2-C6 acyclic alkenyl-S—, C2-C6 acyclic alkynyl —S—, C3-C8 cycloalkenyl-S—, C6-C14 aryl-S—, heteroaryl-S— having 5 to 14 ring members, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, ═O, ═S, —SH, —CF.sub.3, —CO.sub.2C.sub.1-C.sub.6 acyclic alkyl, C1-C6 acyclic alkyl-S—, C1-C6 acyclic alkyl (O═)S— and C1-C6 acyclic alkyl (O═).sub.2S—; or R.sup.1 and R.sup.2 are taken together to form an optionally substituted cycloalkane ring, cycloalkylene ring, heterocycloalkane ring, or heterocycloalkylene ring having 3 to 8 ring members; R.sup.3, R.sup.4 and R.sup.5 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, C1-C12 acyclic alkyl, C2-C12 acyclic alkenyl, C2-C12 acyclic alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, heteroaryl having 5 to 14 ring members, C1-C12 acyclic alkyl-C(═O)—, C2-C12 acyclic alkenyl-C(═O)—, amino, R.sup.11O—, R.sup.11S—, R.sup.11(O═)S—, and R.sup.11(O═).sub.2S— wherein R.sup.11 is C1-C12 acyclic alkyl, C2-C12 acyclic alkenyl, C2-C12 acyclic alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3-8 ring members, or heterocycloalkenyl having 3 to 8 ring members; wherein the above C1-C12 acyclic alkyl, C2-C12 acyclic alkenyl, C2-C12 acyclic alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, heteroaryl having 5 to 14 ring members, C1-C12 acyclic alkyl-C(═O)—, C2-C12 acyclic alkenyl-C(═O)—, and amino are optionally substituted with from 1 to 3 substituents wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C2-C6 acyclic alkenyl-, C2-C6 acyclic alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl having 5 to 14 ring members, C1-C6 acyclic alkyl-O—, C3-C8 cycloalkyl-O—, C2-C.sub.6 acyclic alkenyl-O—, C2-C6 acyclic alkynyl-O—, C3-C8 cycloalkenyl-O—, C6-C14 aryl-O—, heteroaryl-O— having 5 to 14 ring members, C1-C6 acyclic alkyl-S—, C3-C8 cycloalkyl-S—, C2-C6 acyclic alkenyl-S—, C2-C6 acyclic alkynyl-S—, C3-C8 cycloalkenyl-S—, C6-C14 aryl-S—, heteroaryl-S— having 5 to 14 ring members, heterocycloalkyl having 3 to 8 ring members, heterocycloalkenyl having 3 to 8 ring members, ═O, ═S, —SH, —CF.sub.3, —CO.sub.2C.sub.1-C.sub.6 acyclic alkyl group, C1-C6 acyclic alkyl-S—, C1-C6 acyclic alkyl (O═)S— and C1-C6 acyclic alkyl (O═).sub.2S—; R.sup.6 and R.sup.6′ are each independently selected from the group consisting of hydrogen, C1-C6 acyclic alkyl and C3-C8 cycloalkyl; the above C1-C6 acyclic alkyl and C3-C8 cycloalkyl are optionally substituted by 1 to 3 substituents wherein the substituents are independently selected from the group consisting of hydroxy, halogen, cyano, amino, carboxy, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C2-C6 acyclic alkenyl-, C2-C6 acyclic alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl having 5 to 14 ring members, C1-C6 acyclic alkyl-O—, C3-C8 cycloalkyl-O—, C2-C6 acyclic alkenyl-O—, C2-C6 acyclic alkynyl-O—, C3-C8 cycloalkenyl-O—, C6-C14 aryl-O—, and heteroaryl-O-having 5 to 14 ring members; R.sup.7 is selected from the group consisting of hydrogen, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C1-C6 acyclic alkyl-C(═O)—, and C2-C6 acyclic alkenyl-C(═O)—; wherein the C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C1-C6 acyclic alkyl-C(═O)—, and C2-C6 acyclic alkenyl-C(═O)— are optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C2-C6 acyclic alkenyl-, C2-C6 acyclic alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl having 5 to 14 ring members, C1-C6 acyclic alkyl-O—, C3-C8 cycloalkyl-O—, C2-C6 acyclic alkenyl-O—, C2-C6 acyclic alkynyl-O—, C3-C8 cycloalkenyl-O—, C6-C14 aryl-O—, and heteroaryl-O-having 5 to 14 ring members; R.sup.8 is selected from the group consisting of hydrogen, C1-C12 acyclic alkyl, C3-C8 cycloalkyl and —OC(O)—C1-C12 acyclic alkyl; wherein the C1-C12 acyclic alkyl, C3-C8 cycloalkyl and —OC(O)—C1-C12 acyclic alkyl group are optionally substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxyl, halogen, cyano, amino, carboxyl, C1-C6 acyclic alkyl, C3-C8 cycloalkyl, C2-C6 acyclic alkenyl-, C2-C6 acyclic alkynyl-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, heteroaryl having 5 to 14 ring members, C1-C6 acyclic alkyl-O—, C3-C8 cycloalkyl-O—, C2-C6 acyclic alkenyl-O—, C2-C6 acyclic alkynyl-O—, C3-C8 cycloalkenyl-O—, C6-C14 aryl-O—, and heteroaryl-O— having 5 to 14 ring members; and X is an oxygen atom or a sulfur atom or NH.

19. The method according to claim 17, wherein the compound is selected from the group consisting of: (6′-hydroxy-8′-oxo-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)-D-alanine; (6-hydroxy-5,5-dimethyl-8-oxo-5,8-dihydroindolizin-7-carbonyl)glycine; (6-hydroxy-5,5-dimethyl-8-oxo-5,8-dihydroindolizin-7-carbonyl)-L-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine methyl ester; (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine ethyl ester; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-D-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (3′-cyclobutyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (3′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (6′-hydroxy-3′-methyl-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (3′-(tert-butyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (3′-cyclopentyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (3′-cyclohexyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine ethyl ester; (((6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycyloxy)) methyl pivalate; (6′-hydroxy-8′-oxo-3′-(pyridin-3-yl)-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (3′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine (3′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine (3′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6′-hydroxy-3′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl glycine; (6′-hydroxy-8′-oxo-3′-(4-methylphenyl)-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine (3′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (3′-tert-butyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-3′-methyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (3′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-D-alanine; (3′-cyclobutyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (3′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (3′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (6′-hydroxy-3′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)glycine; (6-hydroxy-5,5-dimethyl-8-oxo-3-phenyl-5,8-dihydroindolizin-7-carbonyl)glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6-hydroxy-8-oxo-3-phenyl-2′,3′,5′,6′-tetrahydro-8H-spiro[indolizin-5,4′-pyran]-7-carbonyl)glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-D-alanine; (6-hydroxy-8-oxo-2′,3′,5′,6′-tetrahydro-8H-spiro[indolizin-5,4′-pyran]-7-carbonyl)glycine; (6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine ethyl ester; (3′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-previous]-7′-carbonyl) glycine ethyl ester (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine-2,2-dideuterium (6′-Hydroxy-8′-oxo-3′-(phenyl-4-hydra)-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (3′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine methyl ester; (3′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine methyl ester; (1′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine, (2′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine, (6′-hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-2′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (1′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (2′-(4-fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (1′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (2′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (6′-hydroxy-1′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl glycine; (6′-hydroxy-2′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl glycine; (1′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (2′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine; (6′-hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-2′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine; (6′-hydroxy-8′-oxo-8′H-spiro[cycloheptane-1,5′-indolizine]-7′-carbonyl)glycine; ((1,4-trans)-6′-hydroxy-4-methyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; ((1,4-cis)-6′-hydroxy-4-methyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-2′-phenyl-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine-2,2-di-deuterium (6′-hydroxy-3′-(4-hydroxyphenyl)-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine; (6′-hydroxy-3′-(2-methoxyphenyl)-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl glycine; and (6′-hydroxy-3′-(3-methoxyphenyl)-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl glycine.

20. The method according to claim 1, wherein the disease associated with hypoxia-inducing factors is selected from the group consisting of idiopathic anemia, renal anemia, anemia associated with neoplastic diseases, chemotherapy-induced anemia, hemorrhagic anemia, anemia caused by women's menorrhagia, iron deficiency anemia, vitamin deficiency anemia, cell hypoplastic and aplastic anemia, hemolytic anemia, anemia caused by iron disease or anemia caused by hypothyroidism; heart dysfunction, coronary heart disease, angina pectoris, myocardial infarction, stroke, arteriosclerosis, spontaneous hypertension, pulmonary hypertension, malignant hypertension, and peripheral arterial obstructive disease; damage to health conditions that occur after application of cytostatics, antibiotics, and radiation, glaucoma, dementia, chronic pain, loss of libido, Alzheimer's disease, Parkinson's disease, ischemic cerebrovascular disease, ischemicrenaldisease, ischemic cardiomyopathy, and fibrosis of heart, lung and liver.

21. The method according to claim 12, wherein the disease associated with hypoxia-inducing factors is selected from the group consisting of idiopathic anemia, renal anemia, anemia associated with neoplastic diseases, chemotherapy-induced anemia, hemorrhagic anemia, anemia caused by women's menorrhagia, iron deficiency anemia, vitamin deficiency anemia, cell hypoplastic and aplastic anemia, hemolytic anemia, anemia caused by iron disease or anemia caused by hypothyroidism; heart dysfunction, coronary heart disease, angina pectoris, myocardial infarction, stroke, arteriosclerosis, spontaneous hypertension, pulmonary hypertension, malignant hypertension, and peripheral arterial obstructive disease; damage to health conditions that occur after application of cytostatics, antibiotics, and radiation, glaucoma, dementia, chronic pain, loss of libido, Alzheimer's disease, Parkinson's disease, ischemic cerebrovascular disease, ischemicrenaldisease, ischemic cardiomyopathy, and fibrosis of heart, lung and liver.

22. The method according to claim 17, wherein the disease associated with hypoxia-inducing factors is selected from the group consisting of idiopathic anemia, renal anemia, anemia associated with neoplastic diseases, chemotherapy-induced anemia, hemorrhagic anemia, anemia caused by women's menorrhagia, iron deficiency anemia, vitamin deficiency anemia, cell hypoplastic and aplastic anemia, hemolytic anemia, anemia caused by iron disease or anemia caused by hypothyroidism; heart dysfunction, coronary heart disease, angina pectoris, myocardial infarction, stroke, arteriosclerosis, spontaneous hypertension, pulmonary hypertension, malignant hypertension, and peripheral arterial obstructive disease; damage to health conditions that occur after application of cytostatics, antibiotics, and radiation, glaucoma, dementia, chronic pain, loss of libido, Alzheimer's disease, Parkinson's disease, ischemic cerebrovascular disease, ischemicrenaldisease, ischemic cardiomyopathy, and fibrosis of heart, lung and liver.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

(1) The invention is further illustrated by the following examples; however, these examples do not limit the scope of the invention.

(2) The structures of compounds were determined by liquid chromatography-mass spectrometry (LCMS) or nuclear magnetic resonance (NMR). The NMR chemical shift (δ) is expressed in units of 10.sup.−6 (ppm). The NMR spectra were measured by Bruker-500 nuclear magnetic resonance apparatus in which deuterated dimethyl sulfoxide (dmso-d6), deuterated chloroform (CDCl.sub.3) and the like were used as solvent, and tetramethylsilane (TMS) was used as an internal standard. LCMS was determined using Shimadzu LCMS-2020 or Thermo UltiMate 3000.

(3) Silica gel plates Huanghai HSGF254 available from Yantai, Shandong, China or plates GF254 from Qingdao, Shandong, China were used as thin-layer chromatography silica gel plates. Generally, Huanghai silica gel with 200 to 300 mesh available from Yantai, Shandong was used as a carrier for column chromatography.

(4) All starting materials used in the present invention were purchased from chemical suppliers or can be synthesized by methods known in literatures.

(5) The abbreviations used in the description of this article are as follows:

(6) DMSO-d6: dimethyl sulfoxide in which six hydrogen atoms are replaced by deuterium

(7) CDCl.sub.3: Deuterated chloroform

(8) CAS: Chemical Abstracts Accession Number

(9) NMR: Nuclear Magnetic Resonance

(10) LCMS: Liquid Chromatography-Mass Spectrometry

(11) ESI: Electrospray ionization

(12) ppm: one part per million

(13) δ: chemical shift of nuclear magnetic resonance

(14) TMS: tetramethylsilane

(15) s: nuclear magnetic single peak

(16) d: nuclear magnetic double peak

(17) t: nuclear magnetic triplet peak

(18) br: nuclear magnetic broad peak

(19) CDI: carbonyl diimidazole

(20) DCC: N,N′-dicyclohexylcarbodiimide

(21) NBS: N-bromocyclosuccinimide

Example 1: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl) glycine (1)

(22) ##STR00008##

Step 1: 1-(1H-pyrrol-1-yl)cyclopropane-1-carboxylic acid (1a)

(23) ##STR00009##

(24) 1 ml of concentrated hydrochloric acid was added to a mixture of 2,5-dimethoxytetrahydrofuran (3.16 g, 24 mmol) and 20 ml of water, the resulting mixture was stirred at RT for 1 hour, and then to the reaction mixture sodium acetate solid (3.28 g, 40 mmol) and 1-aminocyclopropane-1-carboxylic acid (2.02 g, 20 mmol) were added successively. The reaction mixture was stirred at RT overnight; then diluted with water, neutralized with 1 M hydrochloric acid to pH 4, and extracted with ethyl acetate. The ethyl acetate layer was separated, and then washed twice with dilute aqueous sodium chloride. The separated ethyl acetate phase was dried over anhydrous sodium sulfate; filtered to remove the desiccant and then evaporated to dryness on a rotary evaporator. The resulting residue was purified by column chromatograph to yield 1 g of compound 1a. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 12.64 (1H, s), 6.78 (2H, t), 5.96 (2H, t), 1.58-1.55 (2H, m), 1.43-1.40 (2H, m).

Step 2: 2-(1-(1H-pyrrol-1-yl)cyclopropane-1-acyl)malonate diethyl ester (1b)

(25) ##STR00010##

(26) Compound 1a (1.55 g, 10.26 mmol), 1H-benzo[d][1,2,3]triazole-1-ol (1.73 g, 11.29 mmol) and DCC (2.33 g, 11.29 mmol) were mixed in tetrahydrofuran (30 ml) and the resulting mixture was stirred at RT for 16 hours. The solid was removed by filtration, and washed with a small amount of anhydrous tetrahydrofuran. The filtrate and washings were combined.

(27) In a separate reaction flask, diethyl malonate (2.46 g, 15.39 mmol) was dissolved in anhydrous tetrahydrofuran (30 ml), then cooled at an ice water bath, and to this a mixture of mineral oil with purity of 60% and sodium hydride (616 mg) was carefully added under a nitrogen stream and then the resulting reaction mixture was stirred for half an hour. The above combined filtrate and washings were then added to the second reaction flask. The reaction was stirred for 1 hour. The resulting mixture was diluted with water, acidified carefully with 1 M dilute aqueous hydrochloric acid to pH 4, and then extracted with ethyl acetate. The ethyl acetate layer was separated, then washed twice with dilute aqueous sodium chloride. The separated ethyl acetate phase was dried over anhydrous sodium sulfate; filtered to remove the desiccant and then evaporated to dryness on a rotary evaporator. The resulting residue was purified by column chromatograph to yield 2.6 g of compound 1b (with a small amount of diethyl malonate). .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 6.84 (2H, t), 6.13 (2H, t), 4.27 (1H, s), 4.12-4.09 (4H, m), 1.70-1.69 (4H, m), 1.19-1.17 (6H, m).

Step 3: Ethyl 6′-Hydroxy-8′-oxo-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carboxylate (1c)

(28) ##STR00011##

(29) Compound 1b (500 mg) was dissolved in 4 ml of dichloromethane, and 2 ml of methanesulfonic acid was slowly added dropwise at RT. The reaction was stirred for 1 hour. The resulting mixture was extracted with dichloromethane. The dichloromethane layer was separated, then washed twice with diluted aqueous sodium chloride. The separated dichloromethane phase was dried over anhydrous sodium sulfate; filtered to remove the desiccant and then evaporated to dryness on a rotary evaporator. The resulting residue was purified by column chromatograph to yield 240 mg of compound 1c. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 7.32-7.31 (1H, m), 6.70-6.98 (1H, m), 6.44-6.42 (1H, m), 4.32-4.27 (2H, m), 1.78-1.76 (2H, m), 1.69-1.67 (2H, m), 1.31-1.27 (3H, m).

Step 4: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)glycine (1)

(30) ##STR00012##

(31) Compound 1c (124 mg), glycine (225 mg) and 0.5 M sodium methoxide solution in methanol (5 mL) were combined and evaporated to dryness. Then, n-propyl alcohol (4 ml) was added with refluxing until the reaction was complete. After cooling, the reaction solution was diluted with water, and then carefully acidified to a pH of about 4 with a 1 M diluted aqueous solution of hydrochloric acid. Solid was precipitated, collected by filtration, and then washed with water; and then dried to give 84 mg of compound 1. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.06 (1H, s), 12.94 (1H, s), 9.99 (1H, s), 7.34 (1H, s), 6.97 (1H, s), 6.44 (1H, s), 4.09-4.08 (2H, d), 1.87 (2H, s), 1.78 (2H, s). LCMS ESI(+): 277 (M+1).sup.+.

Example 2: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)-L-alanine (2)

(32) ##STR00013##

Step 1: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)-L-alanine (2)

(33) ##STR00014##

(34) Compound 1c (124 mg), L-alanine (250 mg) and 0.5 M sodium methoxide solution in methanol (5 mL) were combined and evaporated to dryness. Then, n-propyl alcohol (4 ml) was added with refluxing until the reaction was complete. After cooling, the reaction solution was diluted with water, and then carefully acidified to a pH of about 4 with a 1 M diluted aqueous solution of hydrochloric acid. Solid was precipitated, collected by filtration, and then washed with water; and then dried to give 98 mg of compound 2. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.99 (1H, s), 13.14 (1H, s), 10.14 (1H, d), 7.36 (1H, s), 6.98 (1H, s), 6.46 (1H, s), 4.53-4.46 (1H, m), 1.89 (2H, s), 1.79 (2H, s), 1.44 (3H, d). LCMS ESI(+): 291 (M+1).sup.+.

Example 3: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)-D-alanine (3)

(35) ##STR00015##

Step 1: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)-D-alanine (3)

(36) ##STR00016##

(37) Compound 1c (90 mg), D-alanine (192 mg) and 0.5 M sodium methoxide solution in methanol (3.6 mL) were combined and evaporated to dryness. Then, n-propyl alcohol (4 ml) was added with refluxing until the reaction was complete. After cooling, the reaction solution was diluted with water, and then carefully acidified to a pH of about 4 with a 1 M diluted aqueous solution of hydrochloric acid. Solid was precipitated, collected by filtration, washed with water, and then dried to give 98 mg of compound 3. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.99 (1H, s), 13.16 (1H, s), 10.14 (1H, d), 7.35 (1H, s), 6.98 (1H, s), 6.45 (1H, s), 4.51-4.45 (1H, m), 1.88 (2H, s), 1.78 (2H, s), 1.43-1.42 (3H, d). LCMS ESI(+): 291 (M+1).sup.+.

Example 4: (6-Hydroxy-5,5-dimethyl-8-oxo-5,8-dihydroindolizin-7-carbonyl) glycine (4)

(38) ##STR00017##

Step 1: 2-methyl-2-(1H-pyrrol-1-yl)propionic acid (4a)

(39) ##STR00018##

(40) 2.9 ml of concentrated hydrochloric acid was added to a mixture of 2,5-dimethoxytetrahydrofuran (7.69 g) and 50 ml of water, the resulting mixture was stirred at RT for 1 hour; and then to the reaction mixture sodium acetate solid (13.2 g) and 2-amino-2-methylpropionic acid (5 g) were added successively. The reaction mixture was stirred at RT overnight; then diluted with water, neutralized with 1 M hydrochloric acid to pH 4; and then extracted with ethyl acetate. The ethyl acetate layer was separated, and then washed twice with dilute aqueous sodium chloride. The separated ethyl acetate phase was dried over anhydrous sodium sulfate; filtered to remove the desiccant and then evaporated to dryness on a rotary evaporator. The resulting residue was purified by column chromatograph to yield 5 g of compound 4a. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 12.78 (1H, s), 6.87 (1H, t), 6.02 (1H, t), 1.68 (6H, s).

Step 2: Dimethyl 2-(2-methyl-2-(1H-pyrrol-1-yl)propanoyl)malonate (4b)

(41) ##STR00019##

(42) Compound 4a (1.5 g) and CDI (1.9 g) were mixed in tetrahydrofuran (35 ml) and the resulting mixture was stirred at RT for 1 hour. Then dimethyl malonate sodium salt (2.26 g) was added and was stirred for one hour. The resulting mixture was diluted with water and acidified with 1 M diluted hydrochloric acid aqueous solution to pH 4; and then extracted with ethyl acetate. The ethyl acetate layer was separated, and then washed twice with diluted aqueous sodium chloride. The separated ethyl acetate phase was dried over anhydrous sodium sulfate; filtered to remove the desiccant and then evaporated to dryness on a rotary evaporator. The resulting residue was purified by column chromatograph to yield 1.03 g of compound 4b. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 6.89 (2H, t), 6.12 (2H, t), 4.75 (1H, s), 3.60 (6H, s), 1.69 (6H, s).

Step 3: Methyl 6-hydroxy-5,5-dimethyl-8-oxo-5,8-dihydroindolizin-7-carboxylate (4c)

(43) ##STR00020##

(44) Compound 4b (830 mg) was dissolved in 8 ml of dichloromethane, and 4 ml of methanesulfonic acid was slowly added dropwise at RT. The reaction was stirred for 1 hour. The resulting mixture was extracted with dichloromethane. The dichloromethane layer was separated, then washed twice with diluted aqueous sodium chloride. The separated dichloromethane phase was dried over anhydrous sodium sulfate; filtered to remove the desiccant and then evaporated to dryness on a rotary evaporator. The resulting residue was purified by column chromatograph to yield 550 mg of compound 4c. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 13.97 (1H, br s), 7.73-7.72 (1H, m), 6.70-6.99 (1H, m), 6.47-6.46 (1H, m), 3.81 (3H, s), 1.58 (6H, s).

Step 4: (6-Hydroxy-5,5-dimethyl-8-oxo-5,8-dihydroindolizin-7-carbonyl) glycine (4)

(45) ##STR00021##

(46) Compound 4c (150 mg), glycine (270 mg) and 0.5 M sodium methoxide solution in methanol (6 mL) were combined and evaporated to dryness. Then, n-propyl alcohol (5 ml) was added with refluxing until the reaction was complete. After cooling, the reaction solution was diluted with water, and then carefully acidified to a pH of about 4 with a 1 M diluted aqueous solution of hydrochloric acid. Solid was precipitated, collected by filtration, washed with water, and then dried to give 84 mg of compound 4. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.19 (1H, s), 12.99 (1H, s), 9.99 (1H, s), 7.76 (1H, s), 6.97 (1H, s), 6.48 (1H, s), 4.10 (1H, d), 1.65 (6H, s). LCMS ESI(+): 279 (M+1).sup.+.

Example 5: (6-Hydroxy-5,5-dimethyl-8-oxo-5,8-dihydroindolizin-7-carbonyl)-L-alanine (5)

(47) ##STR00022##

Step 1: (6-Hydroxy-5,5-dimethyl-8-oxo-5,8-dihydroindolizin-7-carbonyl)-L-alanine (5)

(48) ##STR00023##

(49) Compound 4c (150 mg), L-alanine (320 mg) and 0.5 M sodium methoxide solution in methanol (6 mL) were combined and evaporated to dryness. Then, n-propyl alcohol (5 ml) was added with refluxing until the reaction was complete. After cooling, the reaction solution was diluted with water, and then carefully acidified to a pH of about 4 with a 1 M diluted aqueous solution of hydrochloric acid. Solid was precipitated, collected by filtration, washed with water, and then dried to give 141 mg of compound 5. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.10 (1H, s), 13.19 (1H, s), 10.13 (1H, d), 7.76 (1H, s), 6.97 (1H, s), 6.48 (1H, s), 4.51-4.46 (1H, m), 1.64 (6H, s), 1.45 (3H, d). LCMS ESI(+): 293 (M+1).sup.+.

Example 6: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine (6)

(50) ##STR00024##

Step 1: 1-(1H-pyrrol-1-yl)cyclobutane-1-carboxylic acid (6a)

(51) ##STR00025##

(52) 0.8 ml of concentrated hydrochloric acid was added to a mixture of 2,5-dimethoxytetrahydrofuran (2.09 g) and water; the resulting mixture was stirred at RT for 1 hour; and then sodium acetate solid (5.38 g) and 1-amino-cyclobutane-1-carboxylic acid (2 g) were successively added to the reaction mixture. The reaction mixture was stirred at RT overnight; then diluted with water, neutralized with 1 M hydrochloric acid to pH 4; and then extracted with ethyl acetate. The ethyl acetate layer was separated, and then washed twice with dilute aqueous sodium chloride. The separated ethyl acetate phase was dried over anhydrous sodium sulfate; filtered to remove the desiccant and then evaporated to dryness on a rotary evaporator. The resulting residue was purified by column chromatograph to yield 2 g of compound 6a. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 12.81 (1H, s), 6.75 (2H, t), 6.03 (2H, t), 2.76-2.71 (2H, m), 2.58-2.51 (2H, m), 2.01-1.93 (2H, m).

Step 2: 2-(1-(1H-pyrrol-1-yl)cyclobutane-1-acyl)malonate dimethyl ester (6b)

(53) ##STR00026##

(54) Compound 6a (2 g) and CDI (2.36 g) were mixed in tetrahydrofuran (35 ml) and the resulting mixture was stirred at RT for 1 hour. Then dimethyl malonate sodium salt (2.8 g) was added and was stirred for one hour. The resulting mixture was diluted with water and acidified carefully with 1 M diluted hydrochloric acid aqueous solution to pH 4; and then extracted with ethyl acetate. The ethyl acetate layer was separated, and then washed twice with diluted aqueous sodium chloride. The separated ethyl acetate phase was dried over anhydrous sodium sulfate; filtered to remove the desiccant and then evaporated to dryness on a rotary evaporator. The resulting residue was purified by column chromatograph to yield 1.25 g of compound 6b (with a small amount of dimethyl malonate). .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 6.80 (2H, t), 6.15 (2H, t), 4.44 (1H, s), 3.59 (6H, s), 2.78-2.72 (2H, m), 2.61-2.55 (2H, m), 1.96-1.90 (2H, m).

Step 3: Ethyl 6′-Hydroxy-8′-oxo-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carboxylate (6c)

(55) ##STR00027##

(56) Compound 6b (650 mg) was dissolved in 6 ml of dichloromethane, and 3 ml of methanesulfonic acid was slowly added dropwise at RT. The reaction was stirred for 1 hour. The resulting mixture was extracted with dichloromethane. The dichloromethane layer was separated, then washed twice with diluted aqueous sodium chloride. The separated dichloromethane phase was dried over anhydrous sodium sulfate; filtered to remove the desiccant and then evaporated to dryness on a rotary evaporator. The resulting residue was purified by column chromatograph to yield 300 mg of compound 6c. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 13.93 (1H, s), 7.96-7.95 (1H, m), 6.99-6.98 (1H, m), 6.52-6.50 (1H, m), 3.82 (3H, s), 2.77-2.72 (2H, m), 2.48-2.43 (2H, m), 2.12-2.04 (2H, m).

Step 4: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine (6)

(57) ##STR00028##

(58) Compound 6c (150 mg), glycine (270 mg) and 0.5 M sodium methoxide solution in methanol (6 mL) were combined and evaporated to dryness. Then, n-propyl alcohol (5 ml) was added with refluxing until the reaction was complete. After cooling, the reaction solution was diluted with water, and then carefully acidified to a pH of about 4 with a 1 M diluted aqueous solution of hydrochloric acid. Solid was precipitated, collected by filtration, washed with water, and then dried to give 142 mg of compound 6. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.09 (1H, s), 12.95 (1H, s), 10.07 (1H, s), 7.99 (1H, s), 6.96 (1H, s), 6.52 (1H, s), 4.11 (2H, d), 2.82-2.78 (2H, m), 2.59-2.55 (2H, m), 2.15-2.09 (2H, m). LCMS ESI(+): 291 (M+1).sup.+.

Example 7: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)-L-alanine (7)

(59) ##STR00029##

Step 1: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)-L-alanine (7)

(60) ##STR00030##

(61) Compound 6c (150 mg), L-alanine (320 mg) and 0.5 M sodium methoxide solution in methanol (6 mL) were combined and evaporated to dryness. Then, n-propyl alcohol (54 ml) was added with refluxing until the reaction was complete. After cooling, the reaction solution was diluted with water, and then carefully acidified to a pH of about 4 with a 1 M diluted aqueous solution of hydrochloric acid. Solid was precipitated, collected by filtration, washed with water, and then dried to give 140 mg of compound 7. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.05 (1H, s), 13.05 (1H, s), 10.21 (1H, d), 7.98 (1H, s), 6.95 (1H, s), 6.52 (1H, s), 4.51-4.46 (1H, m), 2.84 (2H, br s), 2.60-2.54 (2H, m), 2.17-2.10 (2H, m), 1.45 (2H, d). LCMS ESI(+): 305 (M+1).sup.+.

Example 8: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (8)

(62) ##STR00031##

Step 1: 1-(1H-pyrrol-1-yl)cyclopentane-1-carboxylic acid (8a)

(63) ##STR00032##

(64) The synthetic route of the first step of Example 6 was repeated, wherein the starting material 1-aminocyclobutane-1-carboxylic acid was replaced with 1-aminocyclopentane-1-carboxylic acid to obtain the compound 8a. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 6.82 (2H, t, J=3 Hz), 5.99 (2H, t, J=3 Hz), 2.45-2.37 (2H, m), 2.25-2.16 (2H, m), 1.79-1.60 (4H, m).

Step 2: 2-(1-(1H-pyrrol-1-yl)cyclopentan-1-acyl)malonate diethyl ester (8b)

(65) ##STR00033##

(66) Compound 8a (1.17 g), 1H-benzo[d][1,2,3]triazole-1-ol (1.20 g) and DCC (1.61 g) were mixed in tetrahydrofuran (20 ml) and the resulting mixture was stirred at RT for 1 hour. The solid was removed by filtration, and washed with a small amount of anhydrous tetrahydrofuran. The filtrate and washings were combined.

(67) In a separate reaction flask, diethyl malonate (1.57 g) was dissolved in anhydrous tetrahydrofuran (30 ml), then cooled at an ice water bath, and to this a mixture of mineral oil with purity of 60% and sodium hydride (392 mg) was carefully added under a nitrogen stream and then the resulting reaction mixture was stirred for one hour. The above combined filtrate and washings were then added to the second reaction flask. The reaction was stirred for 1 hour. The resulting mixture was diluted with water, acidified carefully with 1 M dilute aqueous hydrochloric acid to pH 4; and then extracted with ethyl acetate. The ethyl acetate layer was separated, then washed twice with diluted aqueous sodium chloride. The separated ethyl acetate phase was dried over anhydrous sodium sulfate; filtered to remove the desiccant and then evaporated to dryness on a rotary evaporator. The resulting residue was purified by column chromatograph to yield 2.25 g of compound 8b (with a small amount of diethyl malonate). .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 6.845 (2H, t, J=2.5 Hz), 6.12 (2H, t, J=2.5 Hz), 4.51 (1H, s), 4.07-4.00 (4H, m), 2.44-2.34 (2H, m), 2.32-2.25 (2H, m), 1.78-1.63 (4H, m).

Step 3: Ethyl 6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carboxylate (8c)

(68) ##STR00034##

(69) Compound 8b (1.7 g) was dissolved in 6 ml of dichloromethane, and 3.5 ml of methanesulfonic acid was slowly added dropwise at RT. The reaction was stirred for 1 hour. The resulting mixture was extracted with dichloromethane. The dichloromethane layer was separated, then washed twice with diluted aqueous sodium chloride. The separated dichloromethane phase was dried over anhydrous sodium sulfate; filtered to remove the desiccant and then evaporated to dryness on a rotary evaporator. The resulting residue was purified by column chromatograph to yield 373 mg of compound 8c. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 14.06 (1H, s), 7.57-7.53 (1H, m), 7.03-6.96 (1H, m), 6.47-6.42 (1H, m), 4.29 (2H, q, J=9 Hz), 2.43-2.31 (2H, m), 2.02-1.90 (2H, m), 1.90-1.75 (4H, m), 1.29 (3H, t, J=9 Hz).

Step 4: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine (8)

(70) ##STR00035##

(71) The synthetic route of the fourth step of Example 6 was repeated, wherein the starting material 6c was replaced with 8c to afford compound 8. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.12 (1H, s), 12.99 (1H, s), 9.95 (1H, s), 7.59 (1H, s), 6.98 (1H, d, J=6 Hz), 6.47 (1H, s), 4.07 (2H, d, J=6 Hz), 2.45-2.37 (1H, m), 2.05-1.96 (2H, m), 1.94-1.82 (4H, m). LCMS ESI(+): 305 (M+1).sup.+.

Example 9: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine methyl ester (9)

(72) ##STR00036##

Step 1: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine methyl ester (9)

(73) ##STR00037##

(74) Compound 8 (150 mg) was dissolved in 4 mL of methanol, and then to this thionyl chloride (233 mg) was slowly added dropwise. After the addition, the reaction was refluxed for 3 hours. After cooling, the resulting mixture was diluted with water and then extracted with dichloromethane. The organic phase was washed successively with water and diluted aqueous sodium chloride. The organic phase was dried over anhydrous sodium sulfate; filtered and concentrated. The resulting residue was purified by column chromatograph to yield 140 mg of compound 9. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.92 (1H, s), 9.95 (1H, br s), 7.59 (1H, s), 7.00 (1H, s), 6.48 (1H, s), 4.19 (1H, d), 3.70 (3H, s), 2.45-2.39 (2H, m), 2.04-2.00 (2H, m), 1.94-1.85 (4H, m). LCMS ESI(+): 319 (M+1).sup.+.

Example 10 (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine ethyl ester (10)

(75) ##STR00038##

Step 1: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine ethyl ester (10)

(76) ##STR00039##

(77) The synthetic route of the first step of Example 9, the solvent methanol was replaced with ethanol to afford Compound 10. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.95 (1H, s), 9.96 (1H, br s), 7.59 (1H, s), 7.00 (1H, s), 6.48 (1H, s), 4.18 (1H, d), 2.46-2.39 (2H, m), 2.06-2.02 (2H, m), 1.95-1.90 (4H, m), 1.25-1.21 (3H, m). LCMS ESI(+): 333 (M+1).sup.+.

Example 11: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine (11)

(78) ##STR00040##

Step 1: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine (11)

(79) ##STR00041##

(80) The synthetic route of the first step of Example 2 was repeated, wherein the starting material 1c was replaced with 8c to afford Compound 11. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.02 (1H, s), 13.12 (1H, s), 10.09 (1H, d), 7.59 (1H, s), 6.99 (1H, s), 6.48 (1H, s), 4.51-4.46 (1H, m), 2.42-2.37 (2H, m), 2.02 (2H, br s), 1.89 (4H, br s), 1.45 (3H, d). LCMS ESI(+): 319 (M+1).sup.+.

Example 12: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-D-alanine (12)

(81) ##STR00042##

Step 1: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-D-alanine (12)

(82) ##STR00043##

(83) The synthetic route of the first step of Example 3 was repeated, wherein the starting material 1c was replaced with 8c to afford Compound 12. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.03 (1H, s), 13.19 (1H, s), 10.09 (1H, d), 7.59 (1H, s), 6.99 (1H, s), 6.48 (1H, s), 4.51-4.46 (1H, m), 2.43-2.38 (2H, m), 2.03-2.01 (2H, m), 1.89 (4H, br s), 1.45 (3H, d). LCMS ESI(+): 319 (M+1).sup.+.

Example 13: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (13)

(84) ##STR00044##

Step 1: 1-(1H-pyrrol-1-yl)cyclohexane-1-carboxylic acid (13a)

(85) ##STR00045##

(86) The synthetic route of the first step of Example 6 was repeated, wherein the starting material 1-aminocyclobutane-1-carboxylic acid was replaced with 1-aminocyclohexane-1-carboxylic acid to afford the compound 13a. .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 6.87 (t, 2H), 6.22 (t, 2H), 2.40˜2.33 (m, 2H), 2.22˜2.16 (m, 2H), 1.64˜1.58 (m, 4H), 1.54˜1.42 (m, 2H).

Step 2: 2-(1-(1H-pyrrol-1-yl)cyclohexane-1-acyl)malonate diethyl ester (13b)

(87) ##STR00046##

(88) The synthetic route of the second step of Example 8 was repeated, wherein the starting material 8a was replaced with 13a to afford the compound 13b. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 6.92 (t, 2H), 6.15 (t, 2H), 4.49 (s, 1H), 4.06˜3.99 (m, 4H), 2.34 (d, 2H), 1.97 (t, 2H), 1.62 (t, 2H), 1.48 (t, 2H), 1.31 (t, 2H), 1.13 (t, 6H).

Step 3: 6′-Hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carboxylic acid ethyl ester (13c)

(89) ##STR00047##

(90) The synthetic route of the third step of Example 8 was repeated, wherein the starting material 8b was replaced with 13b to afford the compound 13c. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 13.78 (s, 1H), 7.75 (dd, 1H), 6.99 (dd, 1H), 6.44 (dd, 1H), 4.29 (q, 2H), 2.00˜1.96 (m, 2H), 1.86˜1.78 (m, 4H), 1.66˜1.61 (m, 3H), 1.44˜1.40 (m, 1H), 1.29 (t, 3H).

Step 4: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (13)

(91) ##STR00048##

(92) The synthetic route of the fourth step of Example 6 was repeated, wherein the starting material 6c was replaced with 13c to afford the compound 13. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.12 (s, 1H), 13.02 (s, 1H), 10.01 (s, 1H), 7.90 (s, 1H), 7.07 (d, 1H), 6.57 (t, 1H), 4.16 (d, 2H), 1.82˜1.74 (m, 10H). LCMS ESI(+): 319 (M+1).sup.+.

Example 14: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)-L-alanine (14)

(93) ##STR00049##

Step 1: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)-L-alanine (14)

(94) ##STR00050##

(95) The synthetic route of the first step of Example 2 was repeated, wherein the starting material 1c was replaced with 13c to afford the compound 14. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.00 (s, 1H), 13.15 (br, 1H), 10.07 (s, 1H), 7.81 (s, 1H), 6.98 (s, 1H), 6.48 (s, 1H), 4.50˜4.44 (m, 1H), 2.04˜1.88 (m, 10H), 1.44 (d, 3H). LCMS ESI(+): 333 (M+1).sup.+.

Example 15: (3′-Cyclobutyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (15)

(96) ##STR00051##

Step 1: 1-(2-cyclobutyl-1H-pyrrol-1-yl)cyclopentane-1-carboxylic acid (15a)

(97) ##STR00052##

(98) 1-cyclobutyl-3-(1,3-dioxan-2-yl)propan-1-one (1 eq.; prepared according to the method described in the patent document WO/2011/042477) and 1-amino-cyclopentane-1-carboxylic acid (1.2 eq.) were suspended in acetic acid (4 vol.) and then stirred under reflux overnight. After cooling, most of acetic acid was evaporated to dryness on a rotary evaporator. The resulting residue was diluted with water, extracted with ethyl acetate. The ethyl acetate layer was separated, then washed twice with diluted aqueous sodium chloride. The separated ethyl acetate phase was dried over anhydrous sodium sulfate; filtered to remove the desiccant and then evaporated to dryness on a rotary evaporator. The resulting residue was purified by column chromatograph to yield compound 15a. LCMS ESI(+): 234 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(2-cyclobutyl-1H-pyrrol-1-yl)cyclopentane-1-carbonyl)malonate (15b)

(99) ##STR00053##

(100) The synthetic route of the second step for compound 8b of Example 8 was repeated, wherein the starting materials 8a and diethyl malonate were respectively replaced with 15a and dimethyl malonate to afford compound 15b. LCMS ESI(+): 348 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 6.90 (dd, J=3.0, 1.7 Hz, 1H), 6.14 (dd, J=3.6, 1.7 Hz, 1H), 6.06 (t, J=3.3 Hz, 1H), 4.48 (s, 1H), 3.54 (d, J=3.2 Hz, 6H), 2.93-2.82 (m, 1H), 2.17 (dd, J=9.8, 7.2 Hz, 2H), 2.10-1.89 (m, 4H), 1.80-1.69 (m, 4H), 1.59 (s, 2H).

Step 3: 3′-Cyclobutyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carboxylic acid methyl ester (15c)

(101) ##STR00054##

(102) The synthetic route of the third step of Example 8 was repeated, wherein the starting material 8 was replaced with 15b to afford compound 15c. LCMS ESI(+): 316 (M+1).sup.+.

Step 4: (3′-Cyclobutyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (15)

(103) ##STR00055##

(104) The synthetic route of the fourth step of Example 1 was repeated, wherein the starting material 1c was replaced with 15c to afford compound 15. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 17.79 (s, 1H), 12.96 (s, 1H), 9.90 (t, J=5.6 Hz, 1H), 6.99 (d, J=4.2 Hz, 1H), 6.65 (d, J=4.3 Hz, 1H), 4.05 (d, J=5.5 Hz, 2H), 3.63 (q, J=8.5 Hz, 2H), 2.42-2.30 (m, 6H), 2.23-2.08 (m, 6H), 1.85 (dd, J=10.8, 8.2 Hz, 2H).

Example 16: (3′-Cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (16)

(105) ##STR00056##

Step 1: 1-(2-cyclopropyl-1H-pyrrol-1-yl)cyclopentane-1-carboxylic acid (16a)

(106) ##STR00057##

(107) The synthetic route of the first step for compound 15a of Example 15 was repeated, wherein the starting material 1-cyclobutyl-3-(1,3-dioxan-2-yl)propan-1-one was replaced with 1-cyclopropyl-3-(1,3-dioxan-2-yl)propan-1-one which was prepared according to the method described in the patent document WO/2011/042477 to afford compound 16a. LCMS ESI(+): 220 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(2-cyclopropyl-1H-pyrrol-1-yl)cyclopentane-1-carbonyl)malonate (16b)

(108) ##STR00058##

(109) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 16a to afford compound 16b. LCMS ESI(+): 334 (M+1).sup.+.

Step 3: Methyl 3′-Cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carboxylate (16c)

(110) ##STR00059##

(111) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 16b was used to afford compound 16c. LCMS ESI(+): 302 (M+1).sup.+.

Step 4: (3′-Cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (16)

(112) ##STR00060##

(113) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 16c was used to afford compound 16. LCMS ESI(+): 345 (M+1).sup.+.

Example 17: (6′-Hydroxy-3′-methyl-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (17)

(114) ##STR00061##

Step 1: 1-(2-methyl-1H-pyrrol-1-yl)cyclopentane-1-carboxylic acid (17a)

(115) ##STR00062##

(116) The synthetic route of the first step for compound 15a of Example 15 was repeated, wherein the starting material 1-cyclobutyl-3-(1,3-dioxan-2-yl)propan-1-one was replaced with 4-(1,3-dioxan-2-yl)butan-2-one which was prepared according to the method described in the patent document WO/2011/042477 to afford compound 17a. LCMS ESI(+): 194 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(2-methyl-1H-pyrrol-1-yl)cyclopentane-1-carbonyl)malonate (17b)

(117) ##STR00063##

(118) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 17a to afford compound 17b. LCMS ESI(+): 308 (M+1).sup.+.

Step 3: Methyl 6′-Hydroxy-3′-methyl-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carboxylate (17c)

(119) ##STR00064##

(120) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 17b was used to afford compound 17c. LCMS ESI(+): 276 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 13.90 (1H, s), 6.94 (1H, d, J=3.5 Hz), 6.29 (1H, d, J=4.0 Hz), 3.80 (3H, s), 2.48 (3H, s), 2.25-2.32 (2H, m), 2.05-2.11 (3H, m), 1.92-1.98 (2H, m), 1.68-1.75 (1H, m).

Step 4: (3′-Methyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (17)

(121) ##STR00065##

(122) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 17c was used to afford compound 17. LCMS ESI(+): 319 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.78 (1H, s) 12.92 (1H, s), 9.92 (1H, t, J=5.5 Hz), 6.93 (1H, d, J=4.0 Hz), 6.31 (1H, d, J=4.0 Hz), 4.06 (2H, d, J=6.0 Hz), 2.49 (3H, s), 2.28-2.39 (4H, m), 2.13-2.19 (2H, m), 2.01-2.08 (2H, m).

Example 18: (3′-(tert-butyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (18)

(123) ##STR00066##

Step 1: 1-(2-(tert-butyl)-1H-pyrrol-1-yl)cyclopentane-1-carboxylic acid (18a)

(124) ##STR00067##

(125) The synthetic route of the first step for compound 15a of Example 15 was repeated, wherein the starting material 1-cyclobutyl-3-(1,3-dioxan-2-yl)propan-1-one was replaced with 1-(1,3-dioxan-2-yl)-4,4-dimethylpentan-3-one which was prepared according to the method described in the patent document WO/2011/042477 to afford compound 18a. LCMS ESI(+): 236 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(2-(tert-butyl)-1H-pyrrol-1-yl)cyclopentane-1-carbonyl)malonate (18b)

(126) ##STR00068##

(127) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 18a to afford compound 18b. LCMS ESI(+): 350 (M+1).sup.+.

Step 3: Methyl 3′-(tert-Butyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carboxylate (18c)

(128) ##STR00069##

(129) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 18b was used to afford compound 18c. LCMS ESI(+): 318 (M+1).sup.+.

Step 4: (3′-(tert-butyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (18)

(130) ##STR00070##

(131) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 18c was used to afford compound 18. LCMS ESI(+): 361 (M+1).sup.+.

Example 19: (3′-Cyclopentyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (19)

(132) ##STR00071##

Step 1: 1-(2-cyclopentyl-1H-pyrrol-1-yl)cyclopentane-1-carboxylic acid (19a)

(133) ##STR00072##

(134) The synthetic route of the first step for compound 15a of Example 15 was repeated, wherein the starting material 1-cyclobutyl-3-(1,3-dioxan-2-yl)propan-1-one was replaced with 1-cyclopentyl-3-(1,3-dioxan-2-yl)-propan-3-one which was prepared according to the method described in the patent document WO/2011/042477 to afford compound 19a. LCMS ESI(+): 248 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(2-cyclopentyl-1H-pyrrol-1-yl)cyclopentane-1-carbonyl)malonate (19b)

(135) ##STR00073##

(136) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 19a to afford compound 19b. LCMS ESI(+): 362 (M+1).sup.+.

Step 3: Methyl 3′-Cyclopentyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carboxylate (19c)

(137) ##STR00074##

(138) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 19b was used to afford compound 19c. LCMS ESI(+): 330 (M+1).sup.+.

Step 4: (3′-Cyclopentyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (12)

(139) ##STR00075##

(140) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 19c was used to afford compound 19. LCMS ESI(+): 373 (M+1).sup.+.

Example 20: (3′-Cyclohexyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (20)

(141) ##STR00076##

Step 1: 1-(2-cyclohexyl-1H-pyrrol-1-yl)cyclopentane-1-carboxylic acid (20a)

(142) ##STR00077##

(143) The synthetic route of the first step for compound 15a of Example 15 was repeated, wherein the starting material 1-cyclobutyl-3-(1,3-dioxan-2-yl)propan-1-one was replaced with 1-cyclohexyl-3-(1,3-dioxocyclo-2-yl)propan-1-one, which was prepared according to the method described in the patent document WO/2011/042477 and exhibited the following NMR data: .sup.1H NMR (500 MHz, DMSO-d6) δ 4.47 (t, J=5.1 Hz, 1H), 4.0-3.93 (m, 2H), 3.70-3.61 (m, 2H), 2.48 (d, J=7.5 Hz, 2H), 2.39-2.32 (m, 1H), 1.88-1.77 (m, 1H), 1.77-1.71 (m, 2H), 1.71-1.62 (m, 4H), 1.61-1.55 (m, 1H), 1.34-1.26 (m, 2H), 1.26-1.16 (m, 4H), to afford compound 20a. LCMS ESI(+): 262 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(2-cyclohexyl-1H-pyrrol-1-yl)cyclopentane-1-carbonyl)malonate (20b)

(144) ##STR00078##

(145) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 20a to afford compound 20b. LCMS ESI(+): 376 (M+1).sup.+.

Step 3: Methyl 3′-Cyclohexyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carboxylate (20c)

(146) ##STR00079##

(147) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 20b was used to afford compound 20c. LCMS ESI(+): 344 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ 13.90 (s, 1H), 7.00 (d, J=4.2 Hz, 1H), 6.43 (d, J=4.2 Hz, 1H), 3.80 (s, 3H), 2.72 (m, 1H), 2.44-2.37 (m, 2H), 2.08-1.96 (m, 4H), 1.94-1.87 (m, 2H), 1.84-1.78 (m, 4H), 1.73-1.69 (m, 1H), 1.50-1.43 (m, 2H), 1.34-1.26 (m, 3H).

Step 4: (3′-Cyclohexyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (20)

(148) ##STR00080##

(149) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 20c was used to afford compound 20. LCMS ESI(+): 387 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ 12.92 (s, 1H), 9.91 (t, J=6 Hz, 1H), 6.97 (d, J=4.2 Hz, 1H), 6.42 (d, J=4.2 Hz, 1H), 4.06 (d, J=5.6 Hz, 2H), 2.73 (t, J=11.7 Hz, 1H), 2.48-2.38 (m, 2H), 2.17-2.04 (m, 4H), 2.03-1.93 (m, 2H), 1.88-1.78 (m, 4H), 1.74-1.68 (m, 1H), 1.52-1.42 (m, 2H), 1.34-1.26 (m, 3H).

Example 21: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine ethyl ester (21)

(150) ##STR00081##

Step 1: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine ethyl ester (21)

(151) ##STR00082##

(152) The synthetic route of the first step of Example 9, the solvent methanol was replaced with ethanol and the starting material was replaced with 11 to afford compound 21. LCMS ESI(+): 347 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.82 (1H, s), 10.05 (1H, d), 7.61 (1H, s), 7.00 (1H, s), 6.48 (1H, s), 4.58-4.52 (1H, m), 4.18-4.16 (2H, m), 2.42-2.37 (2H, m), 2.03-2.01 (2H, m), 1.89-1.88 (4H, m), 1.45 (3H, d), 1.22 (3H, d).

Example 22: (((6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycyloxy) methyl) pivalate (22)

(153) ##STR00083##

Step 1: (((6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycyloxy) methyl) pivalate (22)

(154) ##STR00084##

(155) Compound 13 (515 mg) was dissolved in N,N-dimethylformamide (8 ml), and then to this potassium carbonate (560 mg) and chloromethyl pivalate (488 mg) were added successively. The reaction was stirred at RT for 2 days. Then, the resulting mixture was diluted with water and ethyl acetate, and acidified with 2 M hydrochloric acid. The organic phase was separated, washed twice with diluted aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified by column chromatography to afford compound 22 (70 mg). .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.77 (s, 1H), 9.92 (t, J=6.0 Hz, 1H), 7.82 (t, J=2.0 Hz, 1H), 6.99 (dd, J=4.0 Hz, 1.5 Hz, 1H), 6.49 (t, 1H), 5.76 (s, 2H), 4.20 (d, J=6.0 Hz, 2H), 2.05-1.60 (m, 10H), 1.15 (s, 9H). LCMS ESI(+): 433 (M+1).sup.+.

Example 23: (6′-Hydroxy-8′-oxo-3′-(pyridin-3-yl)-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (23)

(156) ##STR00085##

Step 1: 1-(2-(pyridin-3-yl)-1H-pyrrol-1-yl)cyclopentane-1-carboxylic Acid (23a)

(157) ##STR00086##

(158) The synthetic route of the first step for compound 15a of Example 15 was repeated, wherein the starting material 1-cyclobutyl-3-(1,3-dioxan-2-yl)propan-1-one was replaced with 3-(1,3-dioxan-2-yl)-1-(pyridin-3-yl)propan-1-one which was prepared according to the method described in the patent document WO/2011/042477 to afford compound 23a. LCMS ESI(+): 257 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(2-(pyridin-3-yl)-1H-pyrrol-1-yl)cyclopentane-1-carbonyl)malonate (23b)

(159) ##STR00087##

(160) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 23a to afford compound 23b. LCMS ESI(+): 371 (M+1).sup.+.

Step 3: Methyl 6′-Hydroxy-8′-oxo-3′-(pyridin-3-yl)-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carboxylate (23c)

(161) ##STR00088##

(162) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 23b was used to afford compound 23c. LCMS ESI(+): 339 (M+1).sup.+.

Step 4: (6′-Hydroxy-8′-oxo-3′-(pyridin-3-yl)-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (23)

(163) ##STR00089##

(164) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 23c was used to afford compound 23.

Example 24: (6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (24)

(165) ##STR00090##

Step 1: 1-(2-phenyl-1H-pyrrol-1-yl)cyclopentane-1-carboxylic acid (24a)

(166) ##STR00091##

(167) 3-(1,3-dioxan-2-yl)-1-phenylpropan-1-one which was prepared according to the method described in the patent document WO/2011/042477 (500 mg) and 1-amino-cyclopentane-1-carboxylic acid (421 mg) were refluxed in 8 mL of acetic acid for 16 hours. After cooling, acetic acid was evaporated to dryness on a rotary evaporator. The resulting residue was diluted with water and ethyl acetate. The organic phase was separated, then washed twice with diluted aqueous sodium chloride solution until water phase was close to neutral. The separated ethyl acetate phase was dried over anhydrous sodium sulfate; filtered, concentrated and then purified by column chromatograph to yield compound 24a. LCMS ESI(+): 256 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ (ppm): 12.95 (br, s, 1H), 7.35-7.33 (m, 3H), 7.25-7.22 (m, 2H), 7.00-6.99 (m, 1H), 6.04 (m, 1H), 5.95 (m, 1H), 2.14-2.11 (m, 2H), 2.01-1.97 (m, 2H), 1.60-1.57 (m, 4H).

Step 2: Dimethyl 2-(1-(2-phenyl-1H-pyrrol-1-yl)cyclopentane-1-carbonyl)malonate (24b)

(168) ##STR00092##

(169) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 24a to afford compound 24b. LCMS ESI(+): 370 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.28-7.22 (m, 3H), 7.20-7.15 (m, 2H), 7.11 (dd, J=3.2, 1.8 Hz, 1H), 6.15 (t, J=3.3 Hz, 1H), 5.93 (dd, J=3.5, 1.7 Hz, 1H), 5.13 (s, 1H), 3.56 (s, 6H), 2.06 (d, J=8.0 Hz, 2H), 1.59 (t, J=12.2 Hz, 2H), 1.33 (s, 2H), 1.16 (s, 2H).

Step 3: Methyl 6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carboxylate (24c)

(170) ##STR00093##

(171) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 24b to afford compound 24c. LCMS ESI(+): 338 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ 13.84 (s, 1H), 7.54-7.43 (m, 5H), 7.09 (d, J=4.0 Hz, 1H), 6.35 (d, J=4.0 Hz, 1H), 3.81 (s, 3H), 2.30-2.21 (m, 2H), 2.10-2.01 (m, 2H), 1.48-1.38 (m, 2H), 1.00-0.89 (m, 2H).

Step 4: (6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (24)

(172) ##STR00094##

(173) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 24c to afford compound 24. LCMS ESI(+): 381 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ (ppm) 17.96 (s, 1H), 12.97 (s, 1H), 9.89-9.87 (d, J=5.5 Hz, 1H), 7.53-7.46 (m, 5H), 7.08-7.07 (d, 1H), 6.37-6.36 (d, 1H), 4.08-4.07 (d, J=5.5 Hz, 2H), 2.35-2.20 (m, 2H), 2.18-2.10 (m, 2H), 1.60-1.46 (m, 2H), 0.98-0.85 (m, 2H).

Example 25: (3′-(4-Fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine (25)

(174) ##STR00095##

(175) Step 1: 1-(2-(4-Fluorophenyl)-1H-pyrrol-1-yl)cyclopentane-1-carboxylicacid (25a)

(176) ##STR00096##

(177) The synthetic route of the first step for compound 24a of Example 24 was repeated, wherein the starting material 3-(1,3-dioxan-2-yl)-1-phenylpropan-1-one was replaced by 3-(1,3-dioxan-2-yl)-1-(4-fluorophenyl)propan-1-one which was prepared according to the method described in the patent document WO/2011/042477 to afford compound 25a. LCMS ESI(+): 274 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 12.90 (s, 1H), 7.28-7.24 (m, 2H), 7.20-7.15 (m, 2H), 6.99 (dd, J=1.8, 3.0 Hz, 1H), 6.03 (t, J=3.0 Hz, 1H), 5.95 (dd, J=1.8, 3.0 Hz, 1H), 2.18-2.09 (m, 2H), 1.64-1.55 (m, 4H).

Step 2: Dimethyl 2-(1-(2-(4-fluorophenyl)-1H-pyrrol-1-yl)cyclopentane-1-carbonyl)malonate (25b)

(178) ##STR00097##

(179) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 25a to afford compound 25b. LCMS ESI(+): 388 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 7.28-7.24 (m, 2H), 7.22-7.13 (m, 3H), 6.16 (t, J=3.3 Hz, 1H), 6.03 (dd, J=1.8, 3.6 Hz, 1H), 5.26 (s, 1H), 3.59 (s, 6H), 2.34-2.26 (m, 2H), 1.90-1.80 (m, 2H), 1.65-1.55 (m, 2H), 1.44-1.36 (m, 2H).

Step 3: Methyl 3′-(4-Fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carboxylate (25c)

(180) ##STR00098##

(181) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 25b to afford compound 25c. LCMS ESI(+): 356 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 7.55-7.50 (m, 2H), 7.28-7.24 (m, 2H), 6.79 (d, J=3.9 Hz, 1H), 6.18 (d, J=3.9 Hz, 1H), 3.67 (s, 3H), 2.28-2.20 (m, 2H), 1.99-1.93 (m, 2H), 1.50-1.43 (m, 2H), 0.93-0.84 (m, 2H).

Step 4: (3′-(4-Fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine (25)

(182) ##STR00099##

(183) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 25 c to afford compound 25. LCMS ESI(+): 399 (M+1).sup.+. H NMR (500 MHz, dmso-d6) δ (ppm): 18.00 (s, 1H), 13.00 (s, 1H), 9.89 (s, 1H), 7.63-7.55 (m, 2H), 7.36-7.26 (m, 2H), 7.07 (m, 1H), 6.37 (m, 1H), 4.07 (d, J=5.6 Hz, 2H), 2.35-2.26 (m, 2H), 2.16-2.06 (m, 2H), 1.63-1.50 (m, 2H), 1.00-0.90 (m, 2H).

Example 26: (3′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine (26)

(184) ##STR00100##

Step 1: 1-(2-(4-Chlorophenyl)-1H-pyrrol-1-yl)cyclopentane-1-carboxylicacid (26a)

(185) ##STR00101##

(186) The synthetic route of the first step for compound 24a of Example 24 was repeated, wherein the starting material 3-(1,3-dioxan-2-yl)-1-phenylpropan-1-one was replaced by 3-(1,3-dioxan-2-yl)-1-(4-chlorophenyl)propan-1-one which was prepared according to the method described in the patent document WO/2011/042477 to afford compound 26a. LCMS ESI(+): 290 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 12.97 (1H, s), 7.42-7.39 (2H, m), 7.27-7.24 (2H, m), 7.02-7.01 (1H, m), 6.05 (1H, t, J=3.5 Hz), 5.98-5.97 (1H, m), 2.19-2.13 (2H, m), 1.99-1.96 (2H, m), 1.62-1.60 (4H, m).

Step 2: Dimethyl 2-(1-(2-(4-chlorophenyl)-1H-pyrrol-1-yl)cyclopentane-1-carbonyl)malonate (26b)

(187) ##STR00102##

(188) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 26a to afford compound 26b. LCMS ESI(+): 404 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 7.42-7.40 (2H, m), 7.25-7.24 (3H, m), 6.17 (1H, t, J=3.0 Hz), 6.06-6.05 (1H, m), 5.39 (1H, s), 3.58 (6H, s), 2.35 (2H, br, s), 1.83 (2H, br s), 1.63-1.60 (2H, m), 1.41-1.39 (2H, m).

Step 3: Methyl 3′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carboxylate (26c)

(189) ##STR00103##

(190) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 26b to afford compound 26c. LCMS ESI(+): 372 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 13.85 (1H, s), 7.55 (4H, s), 7.09 (1H, d, J=4.0 Hz), 6.37 (1H, d, J=4.0 Hz), 3.82 (3H, s), 2.30-2.25 (2H, m), 2.03-1.97 (2H, m), 1.50-1.46 (2H, m), 1.01-0.97 (2H, m).

Step 4: (3′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine (26)

(191) ##STR00104##

(192) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 26c to afford compound 2. LCMS ESI(+): 415 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.99 (1H, s), 13.03 (1H, br s), 9.87 (1H, s), 7.58-7.54 (4H, m), 7.07 (1H, d, J=2.5 Hz), 6.37 (1H, d, J=3.0 Hz), 4.08 (1H, d, J=5.0 Hz), 2.37-2.30 (2H, m), 2.10-2.09 (2H, m), 1.58 (2H, br, s), 1.02-0.97 (2H, m).

Example 27: (3′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine (2)

(193) ##STR00105##

Step 1: (3′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine (27)

(194) ##STR00106##

(195) The synthetic route of the fourth step for compound 26 of Example 26 was repeated, wherein the starting material glycine was replaced with L-alanine to afford compound 27. LCMS ESI(+): 429 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.88 (1H, s), 13.14 (1H, br s), 9.99 (1H, s), 7.57-7.53 (4H, m), 7.06 (1H, s), 6.36 (1H, d, J=3.0 Hz), 4.51-4.45 (1H, m), 2.36-2.31 (2H, m), 2.12-2.08 (2H, m), 1.58 (2H, br, s), 1.43 (2H, d, J=7.0 Hz), 1.02-0.97 (2H, m).

Example 28: (6′-Hydroxy-3′-(4-methoxyphenyl)-8′-oxo-8′H-spiro [cyclopentane-1,5′-indolizine]-7′-carbonyl glycine (28)

(196) ##STR00107##

Step 1: 1-(2-(4-methoxyphenyl)-1H-pyrrol-1-yl)cyclopentane-1-carboxylic acid (28a)

(197) ##STR00108##

(198) The synthetic route of the first step for compound 24a of Example 24 was repeated, wherein the starting material 3-(1,3-dioxan-2-yl)-1-phenylpropan-1-one was replaced by 3-(1,3-dioxan-2-yl)-1-(4-methoxyphenyl)propan-1-one which was prepared according to the method described in the patent document WO/2011/042477 to afford compound 28a. LCMS ESI(+): 286 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 12.55 (1H, s), 7.14 (2H, d, J=9.0 Hz), 6.87-6.95 (3H, m), 5.99-6.00 (1H, m), 5.87-5.88 (1H, m), 2.10-2.15 (2H, m), 1.96-1.99 (2H, m), 1.57-1.61 (4H, m).

Step 2: Dimethyl 2-(1-(2-(4-methoxyphenyl)-1H-pyrrol-1-yl)cyclopentane-1-carbonyl)malonate (28b)

(199) ##STR00109##

(200) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 28a to afford compound 28b. LCMS ESI(+): 400 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 7.12-7.15 (3H, m), 6.88 (2H, d, J=9.0 Hz), 6.14 (1H, t, J=9.0 Hz), 5.97-6.98 (1H, m), 3.77 (3H, s), 3.59 (6H, s), 2.24-2.33 (2H, m), 1.77-1.84 (2H, m), 1.58-1.63 (2H, m), 1.35-1.43 (2H, m).

Step 3: Methyl 6′-Hydroxy-3′-(4-methoxyphenyl)-8′-oxo-8′H-spiro [cyclopentane-1,5′-indolizine]-7′-carboxylate (28c)

(201) ##STR00110##

(202) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 28b to afford compound 28c. LCMS ESI(+): 368 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 13.88 (1H, s), 7.40 (2H, d, J=8.5 Hz), 7.07 (1H, d, J=4.0 Hz), 7.00 (1H, d, J=8.5 Hz), 6.31 (1H, d, J=4.0 Hz), 3.81 (6H, s), 2.22-2.27 (2H, m), 2.00-2.07 (2H, m), 1.41-1.49 (2H, m), 0.95-1.02 (2H, m).

Step 4: (6′-Hydroxy-3′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl glycine (28)

(203) ##STR00111##

(204) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 28c to afford compound 28. LCMS ESI(+): 411 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.97 (1H, s) 12.94 (1H, s), 9.89 (1H, s), 7.42 (2H, d, J=8.5 Hz), 7.04 (1H, s), 7.01 (2H, d, J=8.5 Hz), 6.30 (1H, d, J=3.5 Hz) 4.07 (2H, d, J=5.5 Hz), 2.28-2.31 (2H, m), 2.15 (2H, s), 1.50-1.60 (2H, m), 0.94-1.02 (2H, m).

Example 29: (6′-Hydroxy-8′-oxo-3′-(4-methylphenyl)-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine (29)

(205) ##STR00112##

Step 1: 1-(2-(4-methylphenyl)-1H-pyrrol-1-yl)cyclopentane-1-carboxylic Acid (29a)

(206) ##STR00113##

(207) The synthetic route of the first step for compound 24a of Example 24 was repeated, wherein the starting material 3-(1,3-dioxan-2-yl)-1-phenylpropan-1-one was replaced by 3-(1,3-dioxan-2-yl)-1-(4-methylphenyl)propan-1-one which was prepared according to the method described in the patent document WO/2011/042477 to afford compound 29a. LCMS ESI(+): 270 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(2-(4-methylphenyl)-1H-pyrrol-1-yl)cyclopentane-1-carbonyl)malonate (29b)

(208) ##STR00114##

(209) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 29a to afford compound 29b. LCMS ESI(+): 384 (M+1).sup.+.

Step 3: Methyl 6′-hydroxy-8′-oxo-3′-(4-methylphenyl)-8′H-spiro [cyclopentane-1,5′-indolizine]-7′-carboxylate (29c)

(210) ##STR00115##

(211) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 29b to afford compound 29c. LCMS ESI(+): 352 (M+1).sup.+.

Step 4: (6′-Hydroxy-8′-oxo-3′-(4-methylphenyl)-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine (29)

(212) ##STR00116##

(213) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 29c to afford compound 29. LCMS ESI(+): 395 (M+1).sup.+.

Example 30: (3′-Cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (30)

(214) ##STR00117##

Step 1: 1-(2-cyclopropyl-1H-pyrrol-1-yl)cyclohexane-1-carboxylic acid (30a)

(215) ##STR00118##

(216) The synthetic route of the first step for compound 24a of Example 24 was repeated, wherein the starting materials 3-(1,3-dioxan-2-yl)-1-phenylpropan-1-one and 1-amino-cyclopentane-1-carboxylic acid were respectively replaced by 1-cyclopentyl-3-(1,3-dioxan-2-yl) propan-1-one, which was prepared according to the method described in the patent document WO/2011/042477, and 1-amino-cyclohexane-1-carboxylic acid to afford compound 30a. LCMS ESI(+): 234 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ 12.35 (s, 1H), 6.84 (dd, 1H), 5.82 (t, 1H), 5.66 (dd, 1H), 2.39˜2.35 (m, 2H), 2.14˜2.09 (m, 2H), 1.73˜1.69 (m, 1H), 1.62˜1.56 (m, 4H), 1.39˜1.36 (m, 2H), 0.79˜0.74 (m, 2H), 0.55˜0.52 (m, 2H).

Step 2: Dimethyl 2-(1-(2-cyclopropyl-1H-pyrrol-1-yl)cyclohexane-1-carbonyl)malonate (30b)

(217) ##STR00119##

(218) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 30a to afford compound 30b. LCMS ESI(+): 348 (M+1).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 6.86 (td, 1H), 6.16 (t, 1H), 5.85˜5.84 (m, 1H), 4.27 (s, 1H), 3.68 (s, 6H), 2.60˜2.57 (m, 2H), 2.21 (t, 2H), 1.69˜1.67 (m, 1H), 1.50˜1.42 (m, 2H), 1.39˜1.30 (m, 2H), 1.18˜1.07 (m, 2H), 0.82˜0.80 (m, 2H), 0.69˜0.66 (m, 2H).

Step 3: Methyl 3′-Cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[methylcyclo-1,5′-indolizine]-7′-carboxylate (30c)

(219) ##STR00120##

(220) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 30b to afford compound 30c. LCMS ESI(+): 316 (M+1).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 14.20 (s, 1H), 6.98 (d, 1H), 6.01 (d, 1H), 3.95 (s, 3H), 2.59˜2.56 (m, 2H), 2.20˜2.18 (m, 2H), 1.85˜1.82 (m, 1H), 1.50˜1.45 (m, 2H), 1.34˜1.30 (m, 2H), 1.16˜1.12 (m, 2H), 0.88 (dd, 2H), 0.82 (dd, 2H).

Step 4: (6′-Hydroxy-3′-cyclopropyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (30)

(221) ##STR00121##

(222) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 30c to afford compound 30. LCMS ESI(+): 359 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ 17.81 (s, 1H), 12.94 (s, 1H), 9.90 (s, 1H), 6.88 (d, 1H), 6.15 (d, 1H), 4.02 (br, 2H), 2.59˜2.57 (m, 2H), 2.25˜2.24 (m, 2H), 2.07˜2.04 (m, 2H), 1.96˜1.91 (m, 2H), 1.76˜1.71 (m, 3H), 1.14 (dt, 2H), 0.85 (dt, 2H).

Example 31: (3′-tert-Butyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (31)

(223) ##STR00122##

Step 1: 1-(2-tert-Butyl-1H-pyrrol-1-yl)cyclohexane-1-carboxylic acid (31a)

(224) ##STR00123##

(225) The synthetic route of the first step for compound 30a of Example 30 was repeated, wherein the starting material 1-cyclopropyl-3-(1,3-dioxan-2-yl)propan-1-one was replaced by 1-(1,3-dioxan-2-yl)-4,4-dimethylpentan-3-one which was prepared according to the method described in the patent document WO/2011/042477 to afford compound 31a. LCMS ESI(+): 250 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(2-tert-butyl-1H-pyrrol-1-yl)cyclohexane-1-carbonyl)malonate (31b)

(226) ##STR00124##

(227) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 31a to afford compound 31b. LCMS ESI(+): 364 (M+1).sup.+.

Step 3: Methyl 3′-tert-Butyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carboxylate (31c)

(228) ##STR00125##

(229) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 31b to afford compound 31c. LCMS ESI(+): 332 (M+1).sup.+.

Step 4: (6′-Hydroxy-3′-tert-butyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (31)

(230) ##STR00126##

(231) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 31c to afford compound 31. LCMS ESI(+): 375 (M+1).sup.+.

Example 32: (6′-Hydroxy-3′-methyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (32)

(232) ##STR00127##

Step 1: 1-(2-methyl-1H-pyrrol-1-yl)cyclohexane-1-carboxylic acid (2a)

(233) ##STR00128##

(234) The synthetic route of the first step for compound 30a of Example 30 was repeated, wherein the starting material 1-cyclopropyl-3-(1,3-dioxan-2-yl)propan-1-one was replaced by 4-(1,3-dioxan-2-yl)butan-2-one which was prepared according to the method described in the patent document WO/2011/042477 to afford compound 32a. LCMS ESI(+): 208 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 12.90 (1H, s), 6.85 (1H, t, J=3.0 Hz), 5.86 (1H, t, J=3.0 Hz), 5.76 (1H, s), 2.25-2.32 (2H, m), 2.16 (3H, s), 1.50-1.61 (6H, m), 1.29-1.38 (2H, m).

Step 2: Dimethyl 2-(1-(2-methyl-1H-pyrrol-1-yl)cyclohexane-1-carbonyl)malonate (32b)

(235) ##STR00129##

(236) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 32a to afford compound 32b. LCMS ESI(+): 322 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 6.97 (1H, t, J=2.5 Hz), 6.03 (1H, t, J=3.0 Hz), 5.86 (1H, s), 4.97 (1H, s), 2.16 (3H, s), 3.56 (6H, s), 2.20-2.30 (2H, m), 2.02-2.12 (2H, m), 1.55-1.63 (2H, m), 1.40-1.55 (4H, m).

Step 3: Methyl 6′-Hydroxy-3′-methyl-8′-oxo-8′H-spiro[methylcyclo-1,5′-indolizine]-7′-carboxylate (32c)

(237) ##STR00130##

(238) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 32b to afford compound 32c. LCMS ESI(+): 290 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 13.73 (1H, s), 6.95 (1H, d, J=4.0 Hz), 6.28 (1H, d, J=4.0 Hz), 3.80 (3H, s), 3.80 (3H, s), 2.10-2.18 (2H, m), 1.84-1.93 (4H, m), 1.60-1.74 (4H, m).

Step 4: (6′-Hydroxy-3′-methyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (32)

(239) ##STR00131##

(240) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 32c to afford compound 32. LCMS ESI(+): 333 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.78 (1H, s) 12.92 (1H, s), 9.89 (1H, s), 6.92 (1H, d, J=4.0 Hz), 6.30 (1H, d, J=4.0 Hz), 4.05 (2H, d, J=5.0 Hz), 2.63 (3H, s), 2.16-2.24 (2H, m), 1.96-2.05 (4H, m), 1.65-1.78 (4H, m), 1.41-1.46 (1H, m).

Example 33: (3′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-D-alanine (33)

(241) ##STR00132##

Step 1: (3′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-D-alanine (33)

(242) ##STR00133##

(243) The synthetic route of the first step for compound 27 of Example 27 was repeated, wherein the starting material L-alanine was replaced by D-alanine to afford compound 33. LCMS ESI(+): 429 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.89 (1H, s), 13.14 (1H, br s), 10.00 (1H, s), 7.57-7.53 (4H, m), 7.06 (1H, s), 6.37 (1H, d, J=3.0 Hz), 4.51-4.45 (1H, m), 2.36-2.31 (2H, m), 2.12-2.08 (2H, m), 1.58 (2H, br s), 1.43 (2H, d, J=7.0 Hz), 1.02-0.97 (2H, m).

Example 34: (3′-Cyclobutyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (3)

(244) ##STR00134##

Step 1: 1-(2-Cyclobutyl-1H-pyrrol-1-yl)cyclohexane-1-carboxylic acid (34a)

(245) ##STR00135##

(246) The synthetic route of the first step for compound 30a of Example 30 was repeated, wherein the starting material 1-cyclopropyl-3-(1,3-dioxan-2-yl)propan-1-one was replaced by 1-cyclobutyl-3-(1,3-dioxan-2-yl)propan-2-one which was prepared according to the method described in the patent document WO/2011/042477 to afford compound 34a. LCMS ESI(+): 248 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(2-cyclobutyl-1H-pyrrol-1-yl)cyclohexane-1-carbonyl)malonate (34b)

(247) ##STR00136##

(248) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 34a to afford compound 34b. LCMS ESI(+): 362 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 6.98 (dd, J=3.1, 1.8 Hz, 1H), 6.17 (dd, J=3.7, 1.7 Hz, 1H), 6.12 (t, J=3.3 Hz, 1H), 4.36 (s, 1H), 3.54 (d, J=2.1 Hz, 6H), 2.95 (m, J=8.2 Hz, 1H), 2.27-2.13 (m, 4H), 2.04-1.91 (m, 4H), 1.78 (dtd, J=16.4, 8.6, 3.5 Hz, 2H), 1.65-1.56 (m, 2H), 1.43 (d, 4H).

Step 3: Methyl 3′-Cyclobutyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carboxylate (34c)

(249) ##STR00137##

(250) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 34b to afford compound 34c. LCMS ESI(+): 330 (M+1).sup.+.

Step 4: (3′-Cyclobutyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (34)

(251) ##STR00138##

(252) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 34c to afford compound 34. LCMS ESI(+): 373 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 17.77 (s, 1H), 12.93 (s, 1H), 9.88 (s, 1H), 6.98 (d, J=4.3 Hz, 1H), 6.67 (d, J=4.3 Hz, 1H), 4.05 (d, J=5.4 Hz, 2H), 3.95 (t, J=8.6 Hz, 1H), 2.44-2.38 (m, 2H), 2.17 (t, J=9.9 Hz, 2H), 2.07-1.93 (m, 6H), 1.88-1.74 (m, 4H), 1.51 (s, 2H).

Example 35: (6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (35)

(253) ##STR00139##

Step 1: 1-(2-phenyl-1H-pyrrol-1-yl)cyclohexane-1-carboxylic acid (35a)

(254) ##STR00140##

(255) The synthetic route of the first step for compound 30a of Example 30 was repeated, wherein the starting material 1-cyclopropyl-3-(1,3-dioxan-2-yl)propan-1-one was replaced by 3-(1,3-dioxan-2-yl)-1-phenylpropan-1-one which was prepared according to the method described in the patent document WO/2011/042477 to afford compound 35a. LCMS ESI(+): 270 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ (ppm): 12.92 (1H, s) 7.34-7.30 (3H, m), 7.25-7.21 (2H, m), 7.04 (1H, m), 6.07 (1H, t), 5.92 (1H, dd), 2.05-1.23 (10H, m).

Step 2: Dimethyl 2-(1-(2-phenyl-1H-pyrrol-1-yl)cyclohexane-1-carbonyl)malonate (35b)

(256) ##STR00141##

(257) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 35a to afford compound 35b. LCMS ESI(+): 384 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 7.33-7.30 (m, 3H), 7.24-7.22 (m, 2H), 7.18-7.17 (m, 1H), 6.22-6.20 (t, 1H), 5.98-6.00 (m, 1H), 5.19 (s, 1H), 3.62 (s, 6H), 2.13-1.22 (m, 10H).

Step 3: Methyl 6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[methylcyclo-1,5′-indolizine]-7′-carboxylate (35c)

(258) ##STR00142##

(259) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 35b to afford compound 35c. LCMS ESI(+): 352 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ (ppm): 13.53 (1H, s), 7.49-7.44 (5H, m), 7.10-7.09 (1H, d), 6.30-6.31 (1H, d), 3.81 (3H, s), 2.0-1.3 (10H, m).

Step 4: (6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (35)

(260) ##STR00143##

(261) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 35c to afford compound 35. LCMS ESI(+): 395 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ (ppm): 12.92 (1H, s, OH), 9.79 (1H, t, NH), 7.51-7.47 (5H, m), 7.09-7.08 (1H, d), 6.34-6.33 (1H, d), 4.07-4.06 (2H, d), 2.14-1.79 (10H, m).

Example 36: (3′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (36)

(262) ##STR00144##

Step 1: 1-(2-(4-Chlorophenyl)-1H-pyrrol-1-yl)cyclohexane-1-carboxylic Acid (36a)

(263) ##STR00145##

(264) The synthetic route of the first step for compound 30a of Example 30 was repeated, wherein the starting material 1-cyclopropyl-3-(1,3-dioxan-2-yl)propan-1-one was replaced by 3-(1,3-dioxan-2-yl)-1-(4-chlorophenyl)propan-1-one which was prepared according to the method described in the patent document WO/2011/042477 to afford compound 36a. LCMS ESI(+): 304 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(2-(4-chlorophenyl)-1H-pyrrol-1-yl)cyclohexane-1-carbonyl)malonate (36b)

(265) ##STR00146##

(266) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 36a to afford compound 36b. LCMS ESI(+): 418 (M+1).sup.+.

Step 3: Methyl 3′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carboxylate (36c)

(267) ##STR00147##

(268) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 36b to afford compound 36c. LCMS ESI(+): 386 (M+1).sup.+.

Step 4: (3′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (36)

(269) ##STR00148##

(270) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 36c to afford compound 36. LCMS ESI(+): 429 (M+1).sup.+.

Example 37: (3′-(4-Fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (37)

(271) ##STR00149##

Step 1: 1-(2-(4-Fluorophenyl)-1H-pyrrol-1-yl)cyclohexane-1-carboxylic Acid (37a)

(272) ##STR00150##

(273) The synthetic route of the first step for compound 30a of Example 30 was repeated, wherein the starting material 1-cyclopropyl-3-(1,3-dioxan-2-yl)propan-1-one was replaced by 3-(1,3-dioxan-2-yl)-1-(4-fluorophenyl)propan-1-one which was prepared according to the method described in the patent document WO/2011/042477 to afford compound 37a. LCMS ESI(+): 288 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(2-(4-fluorophenyl)-1H-pyrrol-1-yl)cyclohexane-1-carbonyl)malonate (37b)

(274) ##STR00151##

(275) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 37a to afford compound 37b. LCMS ESI(+): 402 (M+1).sup.+.

Step 3: Methyl 3′-(4-Fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[methylcyclo-1,5′-indolizine]-7′-carboxylate (37c)

(276) ##STR00152##

(277) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 37b to afford compound 37c. LCMS ESI(+): 370 (M+1).sup.+.

Step 4: (3′-(4-Fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (37)

(278) ##STR00153##

(279) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 37c to afford compound 37. LCMS ESI(+): 413 (M+1).sup.+.

Example 38: (6′-Hydroxy-3′-(4-methoxyphenyl)-8′-oxo-8′H-spiro [cyclohexane-1,5′-indolizine]-7′-carbonyl glycine (38)

(280) ##STR00154##

Step 1: 1-(2-(4-methoxyphenyl)-1H-pyrrol-1-yl)cyclohexane-1-carboxylic acid (38a)

(281) ##STR00155##

(282) The synthetic route of the first step for compound 30a of Example 30 was repeated, wherein the starting material 1-cyclopropyl-3-(1,3-dioxan-2-yl)propan-1-one was replaced by 3-(1,3-dioxan-2-yl)1-(4-methoxyphenyl)propan-1-one which was prepared according to the method described in the patent document WO/2011/042477 to afford compound 38a. LCMS ESI(+): 300 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(2-(4-methoxyphenyl)-1H-pyrrol-1-yl)cyclohexane-1-carbonyl)malonate (38b)

(283) ##STR00156##

(284) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 38a to afford compound 38b. LCMS ESI(+): 414 (M+1).sup.+.

Step 3: Methyl 6′-Hydroxy-3′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carboxylate (38c)

(285) ##STR00157##

(286) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 38b to afford compound 38c. LCMS ESI(+): 382 (M+1).sup.+.

Step 4: (6′-Hydroxy-3′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl glycine (38)

(287) ##STR00158##

(288) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 38c to afford compound 38. LCMS ESI(+): 425 (M+1).sup.+.

Example 39: (6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine (39)

(289) ##STR00159##

Step 1: 1-(2-phenyl-1H-pyrrol-1-yl)cyclobutane-1-carboxylic acid (39a)

(290) ##STR00160##

(291) The synthetic route of the first step for compound 24a of Example 24 was repeated, wherein the starting material 1-amino-cyclopentane-1-carboxylic acid was replaced by 1-amino-cyclobutane-1-carboxylic acid to afford compound 39a. LCMS ESI(+): 242 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(2-phenyl-1H-pyrrol-1-yl)cyclobutane-1-carbonyl)malonate (39b)

(292) ##STR00161##

(293) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 39a to afford compound 39b. LCMS ESI(+): 356 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.36-7.28 (m, 3H), 7.23-7.16 (m, 2H), 7.08 (dd, J=3.0, 1.9 Hz, 1H), 6.19 (t, J=3.2 Hz, 1H), 6.13 (dd, J=3.5, 1.8 Hz, 1H), 5.14 (s, 1H), 3.59 (s, 6H), 2.45 (s, 2H), 2.31 (s, 2H), 1.78-1.59 (m, 2H).

Step 3: Methyl 6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carboxylate (19c)

(294) ##STR00162##

(295) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 39b to afford compound 39c. LCMS ESI(+): 324 (M+1).sup.+.

Step 4: (6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine (39)

(296) ##STR00163##

(297) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 39c to afford compound 39. LCMS ESI(+): 367 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 17.92 (s, 1H), 12.99 (s, 1H), 9.98 (d, J=6.9 Hz, 1H), 7.68-7.62 (m, 2H), 7.55-7.50 (m, 3H), 7.08 (d, J=4.0 Hz, 1H), 6.41 (d, J=4.1 Hz, 1H), 4.09 (d, J=5.5 Hz, 2H), 2.59 (td, J=18.7, 18.3, 6.3 Hz, 4H), 1.71 (q, J=9.4 Hz, 1H), 1.09-0.99 (m, 1H).

Example 40: (6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)glycine (40)

(298) ##STR00164##

Step 1: 1-(2-phenyl-1H-pyrrol-1-yl)cyclopropane-1-carboxylic acid (40a)

(299) ##STR00165##

(300) The synthetic route of the first step for compound 24a of Example 24 was repeated, wherein the starting material 1-amino-cyclopentane-1-carboxylic acid was replaced by 1-amino-cyclopropane-1-carboxylic acid to afford compound 40a. LCMS ESI(+): 228 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ 12.97 (s, 1H), 7.40˜7.35 (m, 4H), 7.30˜7.26 (m, 1H), 6.93 (dd, 1H), 6.13 (dd, 1H), 6.06 (t, 1H), 1.90˜1.85 (m, 4H).

Step 2: Dimethyl 2-(1-(2-phenyl-1H-pyrrol-1-yl)cyclopropane-1-carbonyl)malonate (40b)

(301) ##STR00166##

(302) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 40a to afford compound 40b. LCMS ESI(+): 342 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ 7.41˜7.29 (m, 5H), 6.84 (dd, 1H), 6.33 (dd, 1H), 6.20 (t, 1H), 4.51 (s, 1H), 3.71 (s, 3H), 3.60 (s, 3H), 1.90˜1.85 (m, 4H).

Step 3: Methyl 6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carboxylate (40c)

(303) ##STR00167##

(304) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 40b to afford compound 40c. LCMS ESI(+): 310 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ 13.91 (s, 1H), 7.52˜7.12 (m, 5H), 6.33 (s, 1H), 6.32 (d, 1H), 3.80 (s, 3H), 1.40˜1.32 (m, 4H).

Step 4: (6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopropane-1,5′-indolizine]-7′-carbonyl)glycine (40)

(305) ##STR00168##

(306) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 40c to afford compound 40. LCMS ESI(+): 353 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ 17.95 (s, 1H), 12.96 (s, 1H), 9.92 (s, 1H), 7.54˜7.44 (m, 5H), 7.10 (s, 1H), 6.33 (s, 1H), 4.07 (d, 2H), 1.50˜1.46 (m, 4H).

Example 41: (6-Hydroxy-5,5-dimethyl-8-oxo-3-phenyl-5,8-dihydroindolizin-7-carbonyl)glycine (41)

(307) ##STR00169##

Step 1: 2-methyl-2-(2-phenyl-1H-pyrrol-1-yl)propionic acid (41a)

(308) ##STR00170##

(309) The synthetic route of the first step for compound 24a of Example 24 was repeated, wherein the starting material 1-amino-cyclopentane-1-carboxylic acid was replaced by 2-amino-isobutane-1-carboxylic acid to afford compound 41a. LCMS ESI(+): 230 (M+1).sup.+.

Step 2: Dimethyl 2-(2-methyl-2-(2-phenyl-1H-pyrrol-1-yl)propanoyl)malonate (41b)

(310) ##STR00171##

(311) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 41a to afford compound 41b. LCMS ESI(+): 344 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.33 (dt, J=4.6, 2.9 Hz, 3H), 7.23 (dd, J=6.5, 3.0 Hz, 2H), 7.00 (dd, J=3.0, 1.9 Hz, 1H), 6.15 (t, J=3.3 Hz, 1H), 6.00 (dd, J=3.5, 1.8 Hz, 1H), 5.04 (s, 1H), 3.63 (s, 6H), 1.49 (s, 6H).

Step 3: Methyl 6-hydroxy-5,5-dimethyl-8-oxo-3-phenyl-5,8-dihydroindolizin-7-carboxylate (4c)

(312) ##STR00172##

(313) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 41b to afford compound 41c. LCMS ESI(+): 312 (M+1).sup.+.

Step 4: (6-Hydroxy-5,5-dimethyl-8-oxo-3-phenyl-5,8-dihydroindolizin-7-carbonyl)glycine (41)

(314) ##STR00173##

(315) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 41c to afford compound 41. LCMS ESI(+): 355 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 18.02 (s, 1H), 12.97 (s, 1H), 9.90 (t, J=5.6 Hz, 1H), 7.55-7.43 (m, 5H), 7.14-7.04 (m, 1H), 6.34 (d, J=4.1 Hz, 1H), 4.09 (d, J=5.5 Hz, 2H), 1.46 (s, 6H).

Example 42: (6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine (42)

(316) ##STR00174##

Step 1: (6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine (42)

(317) ##STR00175##

(318) The synthetic route of the first step for compound 24 of Example 15 was repeated, wherein the starting material glycine was replaced with L-alanine to afford compound 42. LCMS ESI(+): 395 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ ppm 17.96-17.79 (m, 1H), 13.11 (s, 1H), 9.99 (s, 1H), 7.49 (tdd, J=8.4, 6.2, 3.2 Hz, 5H), 7.07 (d, J=3.8 Hz, 1H), 6.35 (d, J=3.8 Hz, 1H), 4.47 (q, J=7.1 Hz, 1H), 2.29 (s, 2H), 2.14 (s, 2H), 1.53 (s, 2H), 1.43 (d, J=7.2 Hz, 3H), 0.91 (dt, J=12.1, 6.4 Hz, 2H).

Example 43: (6-Hydroxy-8-oxo-3-phenyl-2′,3′,5′,6′-tetrahydro-8H-spiro [indolizin-5,4′-pyran]-7-carbonyl)glycine (43)

(319) ##STR00176##

Step 1: 4-(2-phenyl-1H-pyrrol-1-yl)tetrahydro-2H-pyran-4-carboxylic acid (43a)

(320) ##STR00177##

(321) The synthetic route of the first step for compound 24a of Example 24 was repeated, wherein the starting material 1-amino-cyclopentane-1-carboxylic acid was replaced by 4-aminotetrahydro-2H-pyran-4-carboxylic acid to afford compound 43a. LCMS ESI(+): 272 (M+1).sup.+.

Step 2: dimethyl 2-(4-(2-phenyl-1H-pyrrol-1-yl)tetrahydro-2H-pyran-4-carbonyl) malonate (43b)

(322) ##STR00178##

(323) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 43a to afford compound 43b. LCMS ESI(+): 386 (M+1).sup.+.

Step 3: Methyl 6-Hydroxy-8-oxo-3-phenyl-2′,3′,5′,6′-tetrahydro-8H-spiro[indolizin-5,4′-pyran]-7-carboxylate (43c)

(324) ##STR00179##

(325) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 43b to afford compound 43c. LCMS ESI(+): 354 (M+1).sup.+.

Step 4: (6-Hydroxy-8-oxo-3-phenyl-2′,3′,5′,6′-tetrahydro-8H-spiro[indolizin-5,4′-pyran]-7-carbonyl)glycine (43)

(326) ##STR00180##

(327) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 43c to afford compound 43. LCMS ESI(+): 397 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 17.88 (s, 1H), 12.95 (s, 1H), 9.74 (t, J=5.4 Hz, 1H), 7.49 (s, 5H), 7.13 (d, J=4.0 Hz, 1H), 6.36 (d, J=4.0 Hz, 1H), 4.08 (d, J=5.6 Hz, 2H), 3.83 (td, J=11.8, 2.5 Hz, 2H), 3.57 (dd, J=11.3, 5.7 Hz, 2H), 2.33 (td, J=13.1, 5.9 Hz, 2H), 1.88 (d, J=13.7 Hz, 2H).

Example 44: (6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-D-alanine (44)

(328) ##STR00181##

Step 1: (6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-D-alanine (44)

(329) ##STR00182##

(330) The synthetic route of the first step for compound 24 of Example 24 was repeated, wherein the starting material glycine was replaced with D-alanine to afford compound 44. LCMS ESI(+): 395 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.85 (br s, 1H), 13.11 (s, 1H), 9.99 (s, 1H), 7.49 (m, J=8.4, 6.2, 3.2 Hz, 5H), 7.07 (d, J=3.8 Hz, 1H), 6.35 (d, J=3.8 Hz, 1H), 4.47 (q, J=7.1 Hz, 1H), 2.29 (br s, 2H), 2.14 (br s, 2H), 1.53 (s, 2H), 1.43 (d, J=7.2 Hz, 3H), 0.91 (m, 2H).

Example 45: (6-Hydroxy-8-oxo-2′,3′,5′,6′-tetrahydro-8H-spiro[indolizin-5,4′-pyran]-7-carbonyl)glycine (45)

(331) ##STR00183##

Step 1: 4-(1H-pyrrol-1-yl)tetrahydro-2H-pyran-4-carboxylic acid (45a)

(332) ##STR00184##

(333) The synthetic route of the first step of Example 6 was repeated, wherein the starting material 1-aminocyclobutane-1-carboxylic acid was replaced with 4-aminotetrahydro-2H-pyran-4-carboxylic acid to afford compound 45a. LCMS ESI(+): 196 (M+1).sup.+.

Step 2: Dimethyl 2-(4-(1H-pyrrol-1-yl)tetrahydro-2H-pyran-4-carbonyl) malonate (45b)

(334) ##STR00185##

(335) The synthetic route of the second step of Example 8 was repeated, wherein the starting materials diethyl malonate and 8a were replaced with dimethyl malonate and 45a to afford compound 45b. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 6.98 (t, J=2.2 Hz, 2H), 6.18 (t, J=2.2 Hz, 2H), 4.71 (s, 1H), 3.75 (dt, J=11.8, 4.2 Hz, 2H), 3.42-3.38 (m, 2H), 2.40-2.34 (m, 2H), 2.22 (ddd, J=14.1, 9.6, 4.0 Hz, 2H). LCMS ESI(+): 319 (M+1).sup.+.

Step 3: Methyl 6-Hydroxy-8-oxo-2′,3′,5′,6′-tetrahydro-8H-spiro[indolizin-5,4′-pyran]-7-carboxylate (45)

(336) ##STR00186##

(337) The synthetic route of the third step of Example 8 was repeated, wherein the starting material 8b was replaced with 45b to afford compound 45c. LCMS ESI(+): 278 (M+1).sup.+.

Step 4: (6-Hydroxy-8-oxo-2′,3′,5′,6′-tetrahydro-8H-spiro[indolizin-5,4′-pyran]-7-carbonyl)glycine (45)

(338) ##STR00187##

(339) The synthetic route of the fourth step of Example 6 was repeated, wherein the starting material 6c was replaced with 45c to afford compound 45. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.14 (s, 1H), 12.97 (s, 1H), 9.89 (s, 1H), 7.84 (s, 1H), 7.07-6.97 (m, 1H), 6.51 (t, J=3.3 Hz, 1H), 4.13-4.00 (m, 4H), 3.87 (ddd, J=12.0, 5.2, 2.5 Hz, 2H), 2.17-2.01 (m, 4H). LCMS ESI(+): 321 (M+1).sup.+.

Example 46: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine ethyl ester (46)

(340) ##STR00188##

Step 1: (6′-Hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine ethyl ester (46)

(341) ##STR00189##

(342) The synthetic route of the first step of Example 10 was repeated, wherein the starting material 8 was replaced with 13 to afford compound 46. LCMS ESI(+): 347 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.90 (s, 1H), 9.93 (t, J=5.7 Hz, 1H), 7.82 (s, 1H), 6.99 (dd, J=1.5, 4.2 Hz, 1H), 6.51-6.46 (m, 1H), 4.19-4.10 (m, 4H), 2.05-1.83 (m, 6H), 1.74-1.61 (m, 3H), 1.55-1.43 (m, 1H), 1.21 (t, J=7.1 Hz, 3H).

Example 47: (3′-(4-Fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine Ethyl ester (47)

(343) ##STR00190##

Step 1: (3′-(4-Fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine Ethyl ester (47)

(344) ##STR00191##

(345) The synthetic route of the first step of Example 46 was repeated, wherein the starting material 13 was replaced with 25 to afford compound 47. LCMS ESI(+): 427 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.82 (s, 1H), 9.88 (s, 1H), 7.63-7.54 (m, 2H), 7.35-7.28 (m, 2H), 7.07 (d, J=4.0 Hz, 1H), 6.37 (d, J=4.1 Hz, 1H), 4.20-4.08 (m, 4H), 2.34-2.23 (m, 2H), 2.16-2.05 (m, 2H), 1.63-1.49 (m, 2H), 1.21 (t, J=7.1 Hz, 3H), 1.02-0.90 (m, 2H).

Example 48: (6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine-2,2-dideuterium (48)

(346) ##STR00192##

Step 1: (6′-Hydroxy-8′-oxo-3′-phenyl-8H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine-2,2-dideuterium (48)

(347) ##STR00193##

(348) The synthetic route of the fourth step of Example 35 was repeated, wherein the starting material glycine was replaced with glycine-2,2-dideuterium to afford compound 48. LCMS ESI(+): 397 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ (ppm): 12.9 (1H, s), 9.8 (1H, t, NH), 7.5-7.4 (5H, m), 7.09 (1H, d), 6.34-6.33 (1H, d), 2.14-1.79 (10H, m).

Example 49: (6′-Hydroxy-8′-oxo-3′-(phenyl-4-deuterium)-8′H-spiro [cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (49)

(349) ##STR00194##

Step 1: (6′-Hydroxy-8′-oxo-3′-(phenyl-4-deuterium)-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (49)

(350) ##STR00195##

(351) For the synthesis of compound 49, reference can be made to the literature (Org. Lett. 2004, vol 6, 3521): A 100 ml round bottom flask filled with atmospheric pressure of hydrogen was charged with a mixture of heavy water (3 ml) and 10% palladium on carbon (7.4 mg). The mixture was stirred at RT for 24 hours to which a solution of compound 36 (0.5 mmol) and triethylamine (0.6 mmol) in tetrahydrofuran (5 mL) was then added. The reaction was stirred at RT for further 24 hours. The reaction mixture was diluted with ethyl acetate and water, acidified with 2 mol/L of hydrochloric acid. The ethyl acetate phase was separated; washed twice with diluted aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to afford Compound 49. LCMS ESI(+): 396 (M+1).sup.+.

Example 50: (3′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine methyl ester (50)

(352) ##STR00196##

Step 1: (3′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine methyl ester (50)

(353) ##STR00197##

(354) Compound 26 (50 mg) was suspended in MeOH (2 mL) to which thionyl chloride (0.2 ml) was added carefully dropwise. The reaction was allowed to continue with refluxing until the reaction was complete. It was cooled to RT naturally and then cooled with an ice water bath. The solid was collected by filtration and washed with cold methanol to give Compound 50. LCMS ESI(+): 429 (M+1).sup.+.

Example 51: (3′-(4-Fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine methyl ester (51)

(355) ##STR00198##

Step 1: (3′-(4-Fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl) glycine methyl ester (51)

(356) ##STR00199##

(357) Compound 25 (50 mg) was suspended in MeOH (2 mL) to which thionyl chloride (0.2 ml) was added carefully dropwise. The reaction was allowed to continue with refluxing until the reaction was complete. It was cooled to RT naturally and then cooled with an ice water bath. The solid was collected by filtration and washed with cold methanol to give Compound 51. LCMS ESI(+): 413 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ 17.78 (s, 1H), 9.88 (t, J=5.7 Hz, 1H), 7.63-7.55 (m, 2H), 7.34-7.28 (m, 2H), 7.08 (d, J=4.0 Hz, 1H), 6.37 (d, J=4.0 Hz, 1H), 4.16 (d, J=5.8 Hz, 2H), 3.68 (s, 3H), 2.35-2.27 (m, 2H), 2.16-2.06 (m, 2H), 1.60-1.52 (m, 2H), 1.01-0.92 (m, 2H).

Examples 52 and 53: (1′-Cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (52) and (2′-Cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (53)

(358) ##STR00200##

Step 1: 1-(3-bromo-1H-pyrrole-1-yl)cyclohexane-1-carboxylic acid (52-Br)

(359) ##STR00201##

(360) Compound 52-Br was prepared according to the procedure similar to those in the literature of Synlett, 2002, (7), 1152-1154: Compound 13a (1 eq.) was dissolved in tetrahydrofuran (5 vol.) and cooled to −78° C. with dry ice acetone bath to which phosphorus tribromide (0.05 eq.) was added. With stirring, ground solid N-bromosuccinimide (1.15 eq.) was added and the resulting mixture was stirred at −78° C. for 2 hr then stirred at RT overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was separated, and then washed twice with diluted aqueous sodium chloride solution. The ethyl acetate phase was dried over anhydrous sodium sulfate and spin-dried on an evaporator. The residue was purified by column chromatography to afford product 52-Br. LCMS ESI(+): 272 (M+1).sup.+.

Step 2: 1-(3-cyclopropyl-1H-pyrrol-1-yl)cyclohexane-1-carboxylic acid (52a)

(361) ##STR00202##

(362) Compound 52a was prepared by Suzuki coupling reaction: compound 52-Br (1 eq.), cyclopropylborate (1.5 eq.), Pd(OAc).sub.2 (0.05 eq.), 2′,6′-methoxybiphenyl-dicyclohexyl phosphine (CAS #: 657408-07-6, 0.1 eq.) and potassium phosphate (3 eq.) were mixed in toluene (10 vol.) and refluxed overnight under nitrogen. After cooling, the reaction solution was diluted with water, acidified with diluted aqueous hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was separated, washed twice with dilute aqueous sodium chloride, dried over anhydrous sodium sulfate, and filtered to remove the desiccant and then dried on a rotary evaporator. The residue was purified by column chromatography to afford product 52a. LCMS ESI(+): 234 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 12.80 (1H, br s), 6.73 (1H, t), 6.67 (1H, t), 5.75-5.74 (1H, m), 2.24-2.10 (3H, m), 1.67-1.62 (1H, m), 1.48-1.44 (7H, m), 0.73-0.69 (2H, dd), 0.41-0.38 (2H, dd).

Step 3: Dimethyl 2-(1-(3-cyclopropyl-1H-pyrrol-1-yl)cyclohexane-1-carbonyl)malonate (52b)

(363) ##STR00203##

(364) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 52a to afford compound 52b. LCMS ESI(+): 348 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 6.77 (1H, t), 6.67 (1H, t), 4.57 (1H, s), 3.63 (6H, s), 2.32-2.29 (2H, m), 1.92-1.86 (2H, m), 1.67-1.65 (1H, m), 1.61-1.58 (2H, m), 1.48-1.47 (2H, m), 0.75-0.73 (2H, dd), 0.44-0.43 (2H, dd).

Step 4: Methyl 1′-Cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carboxylate (52c1) and Methyl 2′-Cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carboxylate (52c2)

(365) ##STR00204##

(366) Compounds 52c1 and 52c2 were obtained via purification by column chromatography of two isomers obtained by cyclization of 52b as a starting material with methanesulfonic acid, under the conditions similar to those for the preparation of compound 1c. 52c1: LCMS ESI(+): 316 (M+1).sup.+; .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 14.48 (1H, s), 7.66 (1H, d), 6.03 (1H, d), 3.81 (3H, s), 2.02-1.96 (8H, m), 1.62-1.60 (3H, m), 0.98-0.97 (2H, dd), 0.66-0.65 (2H, dd). 52c2: LCMS ESI(+): 316 (M+1).sup.+.

Step 5: (1′-Cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (52)

(367) ##STR00205##

(368) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 52c1 to afford compound 52. LCMS ESI(+): 359 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.40 (1H, s), 12.96 (1H, s), 10.04 (1H, d), 7.66 (1H, d), 6.03 (1H, d), 4.07 (2H, d), 2.01-1.96 (5H, m), 1.86-1.85 (2H, m), 1.65-1.64 (2H, m), 1.47-1.45 (2H, m), 0.96-0.95 (2H, dd), 0.65-0.64 (2H, dd).

Step 6: (2′-Cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (5)

(369) ##STR00206##

(370) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 52c2 to afford compound 53. LCMS ESI(+): 359 (M+1).sup.+.

Examples 54 and 55: (6′-Hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (54) and (6′-Hydroxy-8′-oxo-2′-phenyl-8′H-spiro [cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (55)

(371) ##STR00207##

Step 1: 1-(3-phenyl-1H-pyrrol-1-yl)cyclohexane-1-carboxylic acid (54a)

(372) ##STR00208##

(373) The synthetic route of the second step for compound 52a of Examples 52 and 53 was repeated, wherein the starting material cyclopropylborate was replaced with phenylborate to afford compound 54a. LCMS ESI(+): 270 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 12.67 (1H, s), 7.53-7.56 (2H, m), 7.39 (1H, t, J=2.0 Hz), 7.29 (2H, t, J=8.0 Hz), 7.10 (1H, t, J=8.0 Hz), 6.95 (2H, t, J=3.0 Hz), 6.47 (1H, dd, J=1.6 Hz) 2.25-2.35 (2H, m), 2.10-2.17 (2H, m), 1.43-1.55 (6H, m).

Step 2: Dimethyl 2-(1-(3-phenyl-1H-pyrrol-1-yl)cyclohexane-1-carbonyl)malonate (54b)

(374) ##STR00209##

(375) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 54a to afford compound 54b. LCMS ESI(+): 384 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 7.58-7.56 (2H, m), 7.33-7.30 (2H, m), 7.27-7.25 (1H, m), 7.15-7.11 (1H, m), 7.00-6.99 (1H, s), 6.58-6.57 (1H, m), 4.85 (1H, s), 3.52 (6H, s), 2.46-2.43 (2H, m), 1.99-1.95 (2H, m), 1.64-1.62 (2H, m), 1.52-1.49 (2H, m), 1.42-1.30 (2H, m).

Step 3: Methyl 6′-Hydroxy-8′-oxy-1′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7-carboxylate (54c1), and Methyl 6′-Hydroxy-8′-oxy-2′-phenyl-8′H-spiro [cyclohexane-1,5′-indolizine]-7′-carboxylate (54c2)

(376) ##STR00210##

(377) Compounds 54c1 and 54c2 were obtained via purification by column chromatography of two isomers obtained by cyclization of 54b as a starting material with methanesulfonic acid, under the conditions similar to those for the preparation of compound 1c. 54c1: LCMS ESI(+): 352 (M+1).sup.+; .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 14.24 (1H, s) 7.83 (1H, s), 7.52-7.50 (2H, m), 7.37 (2H, t), 7.33-7.31 (1H, m), 6.50 (1H, d), 3.80 (3H, s), 2.10-1.95 (2H, m), 1.89-1.83 (4H, m), 1.69-1.64 (2H, m), 1.48-1.40 (2H, m). 54c2: LCMS ESI(+): 352 (M+1).sup.+.

Step 4: (6′-Hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (54)

(378) ##STR00211##

(379) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 54c1 to afford compound 54. LCMS ESI(+): 395 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.30 (1H, s), 12.97 (1H, s), 10.07 (1H, s), 7.83 (1H, s), 7.53-7.52 (2H, m), 7.36 (2H, t), 7.33-7.31 (1H, m), 6.53 (1H, br s), 4.06 (2H, d), 2.12-2.07 (2H, m), 2.01-1.93 (4H, m), 1.69-1.64 (2H, m), 1.48-1.40 (2H, m).

Step 5: (6′-Hydroxy-8′-oxo-2′-phenyl-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (55)

(380) ##STR00212##

(381) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 54c2 to afford compound 55. LCMS ESI(+): 395 (M+1).sup.+.

Examples 56 and 57: (1′-(4-Fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (56) and (2′-(4-Fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (57)

(382) ##STR00213##

Step 1: 1-(3-(4-Fluorophenyl)-1H-pyrrol-1-yl)cyclohexane-1-carboxylic Acid (56a)

(383) ##STR00214##

(384) The synthetic route of the second step for compound 52a of Examples 52 and 53 was repeated, wherein the starting material cyclopropylborate was replaced with 4-fluorophenylborate to afford compound 56a. LCMS ESI(+): 288 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(3-(4-fluorophenyl)-1H-pyrrol-1-yl)cyclohexane-1-carbonyl)malonate (56b)

(385) ##STR00215##

(386) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 56a to afford compound 56b. LCMS ESI(+): 402 (M+1).sup.+.

Step 3: Methyl 1′-(4-Fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[methyl hexane-1,5′-indolizine]-7′-carboxylate (56c1) and Methyl 2′-(4-Fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[methyl hexane-1,5′-indolizine]-7′-carboxylate (56c2)

(387) ##STR00216##

(388) Compounds 56c1 and 56c2 were obtained via purification by column chromatography of two isomers obtained by cyclization of 56b as a starting material with methanesulfonic acid, under the conditions similar to those for the preparation of compound 1c. 56c1: LCMS ESI(+): 370 (M+1).sup.+; 56c2: LCMS ESI(+): 370 (M+1).sup.+.

Step 4: (1′-(4-Fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (56)

(389) ##STR00217##

(390) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 56c1 to afford compound 56. LCMS ESI(+): 413 (M+1).sup.+.

Step 5: (2′-(4-Fluorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (57)

(391) ##STR00218##

(392) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 56c2 to afford compound 57. LCMS ESI(+): 413 (M+1).sup.+.

Examples 58 and 59: (1′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (58) and (2′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (59)

(393) ##STR00219##

Step 1: 1-(3-(4-Chlorophenyl)-1H-pyrrol-1-yl)cyclohexane-1-carboxylic Acid (58a)

(394) ##STR00220##

(395) The synthetic route of the second step for compound 52a of Examples 52 and 53 was repeated, wherein the starting material cyclopropylborate was replaced with 4-chlorophenylborate to afford compound 58a. LCMS ESI(+): 304 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(3-(4-chlorophenyl)-1H-pyrrol-1-yl)cyclohexane-1-carbonyl)malonate (58b)

(396) ##STR00221##

(397) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 58a to afford compound 58b. LCMS ESI(+): 418 (M+1).sup.+.

Step 3: Methyl 1′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[methyl hexane-1,5′-indolizine]-7′-carboxylate (58c1) and Methyl 2′-(4-chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carboxylate (58c2)

(398) ##STR00222##

(399) Compounds 58c1 and 58c2 were obtained via purification by column chromatography of two isomers obtained by cyclization of 58b as a starting material with methanesulfonic acid, under the conditions similar to those for the preparation of compound 1c. 58c1: LCMS ESI(+): 386 (M+1).sup.+; 58c2: LCMS ESI(+): 386 (M+1).sup.+.

Step 4: (1′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (58)

(400) ##STR00223##

(401) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 58c1 to afford compound 58. LCMS ESI(+): 429 (M+1).sup.+.

Step 5: (2′-(4-Chlorophenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl) glycine (59)

(402) ##STR00224##

(403) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 58c2 to afford compound 59. LCMS ESI(+): 429 (M+1).sup.+.

Examples 60 and 61: (6′-Hydroxy-1′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl glycine (60) and (6′-hydroxy-2′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (61)

(404) ##STR00225##

Step 1: 1-(3-(4-methoxyphenyl)-1H-pyrrol-1-yl)cyclohexane-1-carboxylic acid (60a)

(405) ##STR00226##

(406) The synthetic route of the second step for compound 52a of Examples 52 and 53 was repeated, wherein the starting material cyclopropylborate was replaced with 4-methoxyphenylborate to afford compound 60a. LCMS ESI(+): 300 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(3-(4-methoxyphenyl)-1H-pyrrol-1-yl)cyclohexane-1-carbonyl)malonate (60b)

(407) ##STR00227##

(408) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 60a to afford compound 60b.

Step 3: Methyl 1′-(4-Methoxyphenyl)-6′-hydroxy-8′-oxo-8′H-spiro [cyclohexane-1,5′-indolizine]-7′-carboxylate (60c1) and Methyl 2′-(4-methoxyphenyl)-6′-hydroxy-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7-carboxylate (60c2)

(409) ##STR00228##

(410) Compounds 60c1 and 60c2 were obtained via purification by column chromatography of two isomers obtained by cyclization of 60b as a starting material with methanesulfonic acid, under the conditions similar to those for the preparation of compound 1c. 60c1: LCMS ESI(+): 382 (M+1).sup.+; 60c2: LCMS ESI(+): 382 (M+1).sup.+.

Step 4: (6′-Hydroxy-1′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl glycine (60)

(411) ##STR00229##

(412) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 60c1 to afford compound 60. LCMS ESI(+): 425 (M+1).sup.+.

Step 5: (6′-Hydroxy-2′-(4-methoxyphenyl)-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl glycine (61)

(413) ##STR00230##

(414) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 60c2 to afford compound 61. LCMS ESI(+): 425 (M+1).sup.+.

Examples 62 and 63: (1′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro [cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (62) and (2′-Cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (63)

(415) ##STR00231##

Step 1: 1-(3-bromo-1H-pyrrole-1-yl)cyclopentane-1-carboxylic acid (62-Br)

(416) ##STR00232##

(417) The synthetic route of the first step for compound 52-Br of Examples 52 and 53 was repeated, wherein the starting material 13a was replaced with 8a to afford compound 62-Br. LCMS ESI(+): 258 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 12.9 (br s, 1H), 7.0 (m, 1H), 6.88 (m, 1H), 6.1 (m, 1H), 2.4-2.2 (m, 4H), 1.9-1.6 (m, 4H).

Step 2: 1-(3-cyclopropyl-1H-pyrrol-1-yl)cyclopentane-1-carboxylic acid (62a)

(418) ##STR00233##

(419) The synthetic route of the second step for compound 52a of Examples 52 and 53 was repeated, wherein the starting material 52-Br was replaced with 62-Br to afford compound 62a. LCMS ESI(+): 220 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 12.63 (1H, br s), 6.67 (1H, t), 6.61 (1H, t), 5.72 (1H, t), 2.45-2.34 (4H, m), 2.24-2.20 (1H, m), 2.19-2.14 (2H, m), 1.74-1.67 (2H, m), 0.71-0.69 (2H, m), 0.40-0.38 (2H, m).

Step 3: Dimethyl 2-(1-(3-Cyclopropyl-1H-pyrrol-1-yl)cyclopentane-1-carbonyl) malonate (62b)

(420) ##STR00234##

(421) The synthetic route of the second step for compound 52b of Examples 52 and 53 was repeated, wherein the starting material 52a was replaced with 62a to afford compound 62b. LCMS ESI(+): 334 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 6.72 (1H, t), 6.61 (1H, t), 5.88 (1H, t), 4.58 (1H, s), 3.58 (6H, s), 2.37-2.23 (5H, m), 1.73-1.62 (4H, m), 0.75-0.72 (2H, m), 0.43-0.40 (2H, m).

Step 4: Methyl 1′-cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7-carboxylate (62c1) and Methyl 2′-Cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro [cyclopentane-1,5′-indolizine]-7′-carboxylate (62c2)

(422) ##STR00235##

(423) Compounds 62c1 and 62c2 were obtained via purification by column chromatography of two isomers obtained by cyclization of 62b as a starting material with methanesulfonic acid, under the conditions similar to those for the preparation of compound 1c. 62c1: LCMS ESI(+): 302 (M+1).sup.+; .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 14.75 (1H, s), 7.46 (1H, d), 6.04 (1H, d), 3.82 (3H, s), 2.34-2.30 (2H, m), 2.02-1.97 (1H, m), 1.84-1.74 (6H, m), 0.98-0.96 (2H, m), 0.66-0.65 (2H, m). 62c2: LCMS ESI(+): 302 (M+1).sup.+.

Step 5: (1′-Cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (62)

(424) ##STR00236##

(425) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 62c1 to afford compound 62. LCMS ESI(+): 345 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.45 (1H, s), 13.01 (1H, s), 10.06 (1H, t), 7.44 (1H, d), 6.03 (1H, d), 5.77 (1H, s), 4.08 (2H, d), 2.39-2.36 (2H, m), 1.97-1.96 (6H, m), 1.85-1.84 (6H, m), 0.97-0.95 (2H, m), 0.66-0.62 (2H, m).

Step 6: (2′-Cyclopropyl-6′-hydroxy-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (63)

(426) ##STR00237##

(427) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 62c2 to afford compound 63. LCMS ESI(+): 345 (M+1).sup.+.

Examples 64-65: (6′-Hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (64) and (6′-Hydroxy-8′-oxo-2′-phenyl-8′H-spiro [cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (65)

(428) ##STR00238##

Step 1: 1-(3-phenyl-1H-pyrrol-1-yl)cyclopentane-1-carboxylic acid (64a)

(429) ##STR00239##

(430) Compound 64a was prepared by Suzuki coupling reaction: compound 62-Br (1 eq.), phenylborate (1.5 eq.), Pd(PPh.sub.3).sub.2Cl.sub.2 (0.05 eq.), and 2M aqueous sodium carbonate solution (3 eq.) were mixed in n-propanol (4 vol.) and refluxed for 3 hours under nitrogen. After cooling, the reaction solution was diluted with water, acidified with diluted aqueous hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was separated, then washed twice with dilute aqueous sodium chloride, dried over anhydrous sodium sulfate, and filtered to remove the desiccant and then dried on a rotary evaporator. The residue was purified by column chromatography to afford product 64a. LCMS ESI(+): 256 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 7.47-7.50 (2H, m), 7.26 (2H, t, J=8.0 Hz), 7.22 (1H, t, J=2.0 Hz), 7.05 (1H, t, J=7.5 Hz), 6.81 (1H, t, J=2.5 Hz), 6.31-6.33 (1H, m), 2.42-2.48 (2H, m), 2.02-2.07 (2H, m), 1.65-1.72 (2H, m), 1.58-1.63 (2H, m).

Step 2: Dimethyl 2-(1-(3-phenyl-1H-pyrrol-1-yl)cyclopentane-1-carbonyl)malonate (64b)

(431) ##STR00240##

(432) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 64a to afford compound 64b. LCMS ESI(+): 370 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 7.56 (2H, d, J=7.0 Hz), 7.36 (1H, t, J=2.0 Hz), 7.31 (2H, t, J=7.5 Hz), 7.13 (1H, t, J=7.5 Hz), 6.93 (1H, t, J=2.5 Hz), 6.54-6.55 (1H, m), 4.88 (1H, s), 3.53 (3H, s), 2.35-2.44 (4H, m), 1.66-1.78 (4H, m).

Step 3: Methyl 6′-Hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7-carboxylate (64c1) and Methyl 6′-Hydroxy-8′-oxy-2′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carboxylate (64c)

(433) ##STR00241##

(434) Compounds 64c1 and 64c2 were obtained via purification by column chromatography of two isomers obtained by cyclization of 64b as a starting material with methanesulfonic acid, under the conditions similar to those for the preparation of compound 1c. 64c1: LCMS ESI(+): 338 (M+1).sup.+; .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 14.44 (1H, s), 7.65 (2H, s), 7.50-7.53 (2H, m), 7.37 (2H, t, J=7.5 Hz), 7.30-7.33 (1H, m), 6.51 (1H, d, J=4.5 Hz), 3.80 (3H, s), 2.40-2.45 (2H, m), 1.89-1.98 (4H, m), 1.80-1.84 (2H, m). 64c2: LCMS ESI(+): 338 (M+1).sup.+; .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 14.10 (1H, s), 8.12 (1H, d), 7.80 (2H, d), 7.44 (3H, d), 7.29 (1H, t), 3.88 (3H, s), 2.48-2.43 (2H, m), 2.13-2.10 (2H, m), 2.09-2.00 (2H, m), 1.99-1.85 (2H, m).

Step 4: (6′-Hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (64)

(435) ##STR00242##

(436) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 64c1 to afford compound 64. LCMS ESI(+): 381 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.36 (1H, s), 12.95 (1H, s), 10.11 (1H, s), 7.64 (1H, s), 7.53 (2H, d, J=7.5 Hz), 7.29-7.39 (3H, m), 6.52 (1H, s), 4.07 (2H, d, J=5.5 Hz), 2.44-2.48 (2H, m), 1.89-2.04 (6H, m).

Step 5: (6′-Hydroxy-8′-oxo-2′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (65)

(437) ##STR00243##

(438) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 64c2 to afford compound 65. LCMS ESI(+): 381 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.21 (1H, s), 13.05 (1H, s), 10.03 (1H, s), 8.12 (1H, d), 7.80 (2H, d), 7.43 (3H, d), 7.29 (1H, t), 4.16 (2H, d), 2.51 (2H, br, s), 2.16-1.96 (6H, m).

Example 66: (6′-Hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine (66)

(439) ##STR00244##

Step 1: (6′-Hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)-L-alanine (66)

(440) ##STR00245##

(441) The synthetic route of the first step of Example 2 was repeated, wherein the starting material 1c was replaced with 64c1 to afford compound 66. LCMS ESI(+): 381 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.36 (1H, s) 12.95 (1H, s), 10.11 (1H, s), 7.64 (1H, s), 7.53 (2H, d, J=7.5 Hz), 7.29-7.39 (3H, m) 6.52 (1H, s) 4.07 (2H, d, J=5.5 Hz), 2.44-2.48 (2H, m), 1.89-2.04 (6H, m).

Example 67: (6′-Hydroxy-8′-oxo-8′H-spiro[cycloheptane-1,5′-indolizine]-7′-carbonyl)glycine (67)

(442) ##STR00246##

Step 1: 1-(1H-pyrrol-1-yl)cycloheptane-1-carboxylic acid (67a)

(443) ##STR00247##

(444) The synthetic route of the first step of Example 6 was repeated, wherein the starting material 1-aminocyclobutane-1-carboxylic acid was replaced by 1-aminocycloheptane-1-carboxylic acid, which was prepared according to the literature ACS Combinatorial Sciences, 2016, 18(6), 330-336, to afford compound 67a. .sup.1H NMR (400 MHz, dmso-d6) δ (ppm): 12.80 (br, 1H), 6.82 (t, 2H), 6.00 (t, 2H), 2.4-2.2 (m, 4H), 1.7-1.4 (m, 8H). LC MS ESI(+): 208 (M+H).sup.+.

Step 2: Dimethyl 2-(1-(1H-pyrrol-1-yl)cycloheptane-1-yl)malonate (67)

(445) ##STR00248##

(446) The synthetic route of the second step of Example 8 was repeated, wherein the starting materials diethyl malonate and 8a were respectively replaced with dimethyl malonate and 67a to afford compound 67b. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 6.85 (t, 2H), 6.13 (t, 2H), 4.50 (s, 1H), 3.56 (s, 6H), 2.4-2.1 (m, 4H), 1.7-1.4 (m, 8H). LC MS ESI(+): 322 (M+H).sup.+.

Step 3: Ethyl 6′-Hydroxy-8′-oxo-8′H-spiro[cycloheptane-1,5′-indolizine]-7′-carboxylate (67c)

(447) ##STR00249##

(448) The synthetic route of the third step of Example 8 was repeated, wherein the starting material 8b was replaced with 67b to afford compound 67c. LC MS ESI(+): 290 (M+H).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 12.8 (br, 1H), 7.71 (dd, 1H, J=1.5 Hz, 2.5 Hz), 7.03 (dd, 1H, J=1.6 Hz, J=4.0 Hz), 6.45 (dd, 1H, J=2.6 Hz, J=4.1 Hz), 3.81 (s, 3H), 2.3-1.5 (m, 12H).

Step 4: (6′-Hydroxy-8′-oxo-8′H-spiro[cycloheptane-1,5′-indolizine]-7′-carbonyl)glycine (67)

(449) ##STR00250##

(450) The synthetic route of the fourth step of Example 6 was repeated, wherein the starting material 6c was replaced with 67c to afford compound 67. LCMS ESI(+): 333 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.01 (s, 1H), 12.98 (br, s, 1H), 9.91 (br, s, 1H), 7.73 (br s, 1H), 7.00 (d, 1H, J=3.6 Hz), 6.47 (t, 1H), 4.07 (d, 2H, J=5.4 Hz), 2.35-1.50 (m, 12H).

Example 68: ((1,4-trans)-6′-hydroxy-4-methyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (68)

(451) ##STR00251##

Step 1: (1,4-trans)-4-methyl-1-(1H-pyrrol-1-yl)cyclohexane-1-carboxylic Acid (68a)

(452) ##STR00252##

(453) The synthetic route of the fourth step of Example 6 was repeated, wherein the starting material 1-aminocyclobutane-1-carboxylic acid was replaced by (1,4-trans)-1-amino-4-methyl cyclohexane-1-carboxylic acid (CAS: 32958-46-6; which was prepared according to J. Chem. Soc. 1961, 4372-9) to afford compound 68a. .sup.1H NMR (400 MHz, dmso-d6) δ (ppm): 12.94 (s, 1H), 6.88 (t, 2H), 6.01 (t, 2H), 2.7-2.6 (m, 2H), 1.8-1.6 (m, 4H), 1.6-1.3 (br, m, 1H), 1.10 (t, 2H, J=11.6 Hz), 0.88 (d, 3H, J=6.2 Hz). LC MS ESI(+): 208 (M+H).sup.+.

Step 2: dimethyl 2-((1,4-trans)-4-methyl-1-(1H-pyrrol-1-yl)cyclohexane-1-yl)malonate (68b)

(454) ##STR00253##

(455) The synthetic route of the second step of Example 8 was repeated, wherein the starting materials diethyl malonate and 8a were respectively replaced with dimethyl malonate and 68a to afford compound 68b. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 6.86 (t, 2H), 6.10 (t, 2H), 4.78 (s, 1H), 3.54 (s, 6H), 2.59 (br, 1H), 2.0-1.2 (m, 8H), 0.90 (d, 3H, J=6.4 Hz). LC MS ESI(+): 322 (M+H).sup.+.

Step 3: Methyl (1,4-trans)-6′-hydroxy-4-methyl-8′-oxo-8′H-spiro [cyclohexane-1,5′-indolizine]-7′-carboxylate (68c)

(456) ##STR00254##

(457) The synthetic route of the third step of Example 8 was repeated, wherein the starting material 8b was replaced with 68b to afford compound 68c. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 13.70 (br, s, 1H), 7.74 (br s, 1H), 6.99 (d, 1H), 6.46 (t, 1H), 3.81 (s, 3H), 1.99 (m, 4H), 1.57 (m, 5H), 0.93 (br s, 3H). LC MS ESI(+): 290 (M+H).sup.+.

Step 4: ((1,4-trans)-6′-hydroxy-4-methyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (68)

(458) ##STR00255##

(459) The synthetic route of the fourth step of Example 6 was repeated, wherein the starting material 6c was replaced with 68c to afford compound 68. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.06 (s, 1H), 12.90 (br s, 1H), 9.89 (t, 1H), 7.79 (br s, 1H), 6.96 (d, 1H, J=3.2 Hz), 6.48 (t, 1H), 4.07 (d, 2H, J=5.8 Hz), 2.2-1.5 (m, 9H), 0.97 (br, 1H). LCMS ESI(+): 333 (M+1).sup.+.

Example 69: ((1,4-cis)-6′-hydroxy-4-methyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (69)

(460) ##STR00256##

Step 1: (1,4-cis)-4-methyl-1-(1H-pyrrol-1-yl)cyclohexane-1-carboxylic Acid (69a)

(461) ##STR00257##

(462) The synthetic route of the fourth step of Example 6 was repeated, wherein the starting material 1-aminocyclobutane-1-carboxylic acid was replaced by (1,4-cis)-1-amino-4-methyl cyclohexane-1-carboxylic acid (CAS: 32958-45-5; which was prepared according to J. Chem. Soc. 1961, 4372-9) to afford compound 69a. .sup.1H NMR (400 MHz, dmso-d6) δ (ppm): 12.66 (br s, 1H), 6.88 (t, 2H), 6.03 (t, 2H), 2.54 (m, 1H), 2.1-1.9 (m, 2H), 1.65-1.36 (m, 3H), 1.0-0.84 (m, 3H), 0.76 (d, 3H, J=6.4 Hz). LC MS ESI(+): 208 (M+H).sup.+.

Step 2: dimethyl 2-((1,4-cis)-4-methyl-1-(1H-pyrrol-1-yl)cyclohexane-1-yl)malonate (69b)

(463) ##STR00258##

(464) The synthetic route of the second step of Example 8 was repeated, wherein the starting materials diethyl malonate and 8a were respectively replaced with dimethyl malonate and 69a to afford compound 69b. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 6.93 (t, 2H), 6.15 (t, 2H), 4.54 (s, 1H), 3.57 (s, 6H), 2.5 (m, 1H), 2.0-1.8 (m, 2H), 1.7-1.35 (m, 3H), 1.0-0.80 (m, 3H), 0.75 (d, 3H, J=6.4 Hz). LC MS ESI(+): 322 (M+H).sup.+.

Step 3: Methyl (1,4-cis)-6′-hydroxy-4-methyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carboxylate (69c)

(465) ##STR00259##

(466) The synthetic route of the third step of Example 8 was repeated, wherein the starting material 8b was replaced with 69b to afford compound 69c. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 13.8 (br, s, 1H), 7.77 (dd, 1H, J=1.4 Hz, 2.4 Hz), 7.06 (dd, 1H, J=1.6 Hz, J=4.0 Hz), 6.44 (dd, 1H, J=2.4 Hz, J=4.0 Hz), 3.80 (s, 3H), 2.2-2.0 (m, 2H), 1.85-1.65 (m, 4H), 1.65-1.20 (m, 3H), 1.00 (d, 3H, J=6.2 Hz). LC MS ESI (+): 290 (M+H).sup.+.

Step 4: ((1,4-cis)-6′-hydroxy-4-methyl-8′-oxo-8′H-spiro[cyclohexane-1,5′-indolizine]-7′-carbonyl)glycine (69)

(467) ##STR00260##

(468) The synthetic route of the fourth step of Example 6 was repeated, wherein the starting material 6c was replaced with 69c to afford compound 69. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 18.04 (s, 1H), 12.98 (br, s, 1H), 9.93 (br, 1H), 7.81 (br, s, 1H), 7.05 (d, 1H, J=3.8 Hz), 6.46 (d, 1H, J=3.4 Hz), 4.07 (d, 2H, J=5.6 Hz), 2.3-1.3 (m, 9H), 1.04 (d, 3H, J=6.2 Hz). LCMS ESI(+): 333 (M+1).sup.+.

Examples 70 and 71: (6′-Hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine (70) and (6′-Hydroxy-8′-oxo-2′-phenyl-8′H-spiro [cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine (71)

(469) ##STR00261##

Step 1: 1-(3-bromo-1H-pyrrol-1-yl)cyclobutane-1-carboxylic acid (70-Br)

(470) ##STR00262##

(471) The synthetic route of the first step for compound 52-Br of Examples 52 and 53 was repeated, wherein the starting material 13a was replaced with 6a to afford compound 70-Br. LCMS ESI(+): 244 (M+1).sup.+.

Step 2: 1-(3-phenyl-1H-pyrrol-1-yl)cyclobutane-1-carboxylic acid (70a)

(472) ##STR00263##

(473) The synthetic route of the second step for compound 52a of Examples 52 and 53 was repeated, wherein the starting materials cyclopropylborate and 52-Br were respectively replaced with phenylborate and 70-Br to afford compound 70a. LCMS ESI(+): 242 (M+1).sup.+.

Step 3: Dimethyl 2-(1-(3-phenyl-1H-pyrrol-1-yl)cyclobutane-1-carbonyl) malonate (70b)

(474) ##STR00264##

(475) The synthetic route of the second step for compound 52b of Examples 52 and 53 was repeated, wherein the starting material 52a was replaced with 70a to afford compound 70b. LCMS ESI(+): 356 (M+1).sup.+.

Step 4: Methyl 6′-Hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carboxylate (70c1) and Methyl 6′-Hydroxy-8′-oxy-2′-phenyl-8′H-spiro [cyclobutane-1,5′-indolizine]-7′-carboxylate (70c2)

(476) ##STR00265##

(477) Compounds 70c1 and 70c2 were obtained via purification by column chromatography of two isomers obtained by cyclization of 70b as a starting material with methanesulfonic acid, under the conditions similar to those for the preparation of compound 1c. 70c1: LCMS ESI(+): 324 (M+1).sup.+; 70c2: LCMS ESI(+): 324 (M+1).sup.+.

Step 5: (6′-Hydroxy-8′-oxo-1′-phenyl-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine (70)

(478) ##STR00266##

(479) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 70c1 to afford compound 70. LCMS ESI(+): 367 (M+1).sup.+.

Step 6: (6′-Hydroxy-8′-oxo-2′-phenyl-8′H-spiro[cyclobutane-1,5′-indolizine]-7′-carbonyl)glycine (71)

(480) ##STR00267##

(481) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 70c2 to afford compound 71. LCMS ESI(+): 367 (M+1).sup.+.

Example 72: (6′-Hydroxy-8′-oxo-3′-phenyl-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine-2,2-dideuterium (72)

(482) ##STR00268##

Step 1: (6′-Hydroxy-8′-oxo-3′-phenyl-8H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine-2,2-dideuterium (72)

(483) ##STR00269##

(484) The compound of Example 24, glycine-2,2-dideuterium and 0.5 M NaOMe solution in methanol were combined, and then dried under reduced pressure to give a residue, to which 2-methoxyethanol was added. The resulting reaction mixture was refluxed for 1.5 hours. The reaction solution was then cooled, diluted with water, and then acidified to pH 2-3 with 2 M aqueous hydrochloric acid to give solid. The solid was filtered under reduced pressure and washed with water to afford the product, i.e. the compound 72. LCMS ESI(+): 383 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.95 (s, 1H), 12.93 (s, 1H), 9.86 (s, 1H), 7.49 (m, 5H), 7.07 (d, J=3.6 Hz, 1H), 6.35 (d, J=3.6 Hz, 1H), 2.29 (m, br, 2H), 2.15 (m, br, 2H), 1.53 (m, br, 2H), 0.93 (m, br, 2H).

Example 73: (6′-Hydroxy-3′-(4-hydroxyphenyl)-8′-oxo-8′H-spiro [cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (7)

(485) ##STR00270##

Step 1: (6′-Hydroxy-3′-(4-hydroxyphenyl)-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl)glycine (73)

(486) ##STR00271##

(487) The compound 28 of Example (100 mg) was dissolved in dichloromethane (1.5 ml), and cooled with ice-water bath, to which a solution of boron tribromide in dichloromethane (0.96 ml, concentration: 1 M) was added. The resulting mixture was then stirred at RT for 1.5 hours. After reaction, an aqueous solution of sodium carbonate was added and the solution was extracted twice with ethyl acetate. The aqueous phase was acidified to pH=3-4 with 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase was washed twice with dilute aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Crystallization of residue from ethanol gave the solid product as Compound 73 (64 mg). LCMS ESI(+): 397 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.88 (s, 1H), 12.92 (s, 1H), 9.88 (s, 1H), 9.78 (s, 1H), 7.35-7.23 (m, 2H), 7.04 (d, J=4.0 Hz, 1H), 6.88-6.78 (m, 2H), 6.29 (d, J=4.1 Hz, 1H), 4.07 (d, J=5.5 Hz, 2H), 2.34-2.21 (m, 2H), 2.15 (m, 2H), 1.56 (m, 2H), 1.03 (m, 2H).

Example 74: (6′-Hydroxy-3′-(2-methoxyphenyl)-8′-oxo-8′H-spiro [cyclopentane-1,5′-indolizine]-7′-carbonyl glycine (74)

(488) ##STR00272##

Step 1: 1-(2-(2-methoxyphenyl)-1H-pyrrol-1-yl)cyclopentane-1-carboxylic acid (74a)

(489) ##STR00273##

(490) The synthetic route of the first step for compound 24a of Example 24 was repeated, wherein the starting material 3-(1,3-dioxane-2-yl)-1-phenylpropan-1-one was replaced by 3-(1,3-dioxane-2-yl)-1-(2-methoxyphenyl)propan-1-one, which was prepared according to the method described in Liebis Annalen der Chemie, 1989, (9), 863-881, to afford compound 74a. LCMS ESI(+): 286 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(2-(2-methoxyphenyl)-1H-pyrrol-1-yl)cyclopentane-1-carbonyl)malonate (74b)

(491) ##STR00274##

(492) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 74a to afford compound 74b. LCMS ESI(+): 400 (M+1).sup.+.

Step 3: Methyl 6′-Hydroxy-3′-(2-methoxyphenyl)-8′-oxo-8′H-spiro [cyclopentane-1,5′-indolizine]-7′-carboxylate (74c)

(493) ##STR00275##

(494) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 74b to afford compound 74c. LCMS ESI(+): 368 (M+1).sup.+.

Step 4: (6′-Hydroxy-3′-(2-methoxyphenyl)-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl glycine (74)

(495) ##STR00276##

(496) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 74c to afford compound 74. LCMS ESI(+): 411 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 17.9 (1H, s), 12.94 (1H, s), 9.89 (1H, s), 7.53-7.50 (1H, m), 7.39-7.37 (1H, m), 7.16-7.14 (1H, m), 7.07-7.04 (1H, m), 6.29 (1H, d), 4.08 (2H, d), 3.75 (3H, s), 2.3-2.1 (4H, br), 1.6-1.48 (2H, br), 1.0-0.8 (2H, br).

Example 75: (6′-Hydroxy-3′-(3-methoxyphenyl)-8′-oxo-8′H-spiro [cyclopentane-1,5′-indolizine]-7′-carbonyl glycine (75)

(497) ##STR00277##

Step 1: 1-(2-(3-methoxyphenyl)-1H-pyrrol-1-yl)cyclopentane-1-carboxylic acid (75a)

(498) ##STR00278##

(499) The synthetic route of the first step for compound 24a of Example 24 was repeated, wherein the starting material 3-(1,3-dioxane-2-yl)-1-phenylpropan-1-one was replaced by 3-(1,3-dioxane-2-yl)-1-(3-methoxyphenyl)propan-1-one, which was prepared according to the method described in Liebis Annalen der Chemie, 1989, (9), 863-881, to afford compound 75a. LCMS ESI(+): 286 (M+1).sup.+.

Step 2: Dimethyl 2-(1-(2-(3-methoxyphenyl)-1H-pyrrol-1-yl)cyclopentane-1-carbonyl)malonate (75b)

(500) ##STR00279##

(501) The synthetic route of the second step for compound 15b of Example 15 was repeated, wherein the starting material 15a was replaced with 75a to afford compound 75b. LCMS ESI(+): 400 (M+1).sup.+.

Step 3: Methyl 6′-Hydroxy-3′-(3-methoxyphenyl)-8′-oxo-8′H-spiro [cyclopentane-1,5′-indolizine]-7′-carboxylate (74c)

(502) ##STR00280##

(503) The synthetic route of the third step for compound 15c of Example 15 was repeated, wherein the starting material 15b was replaced with 75b to afford compound 75c. LCMS ESI(+): 368 (M+1).sup.+.

Step 4: (6′-Hydroxy-3′-(3-methoxyphenyl)-8′-oxo-8′H-spiro[cyclopentane-1,5′-indolizine]-7′-carbonyl glycine (75)

(504) ##STR00281##

(505) The synthetic route of the fourth step for compound 15 of Example 15 was repeated, wherein the starting material 15c was replaced with 75c to afford compound 75. LCMS ESI(+): 411 (M+1).sup.+. .sup.1H NMR (500 MHz, dmso-d6) δ (ppm): 12.98 (1H, s), 9.88 (1H, s), 7.40-7.36 (1H, m), 7.08-7.02 (4H, m), 6.36 (1H, d), 4.08 (2H, d), 3.79 (3H, s), 2.29-2.19 (4H, br), 1.57 (2H, br), 1.06-1.01 (2H, br).

(506) Evaluation of Pharmacological Activity

(507) 1. Effect of Compounds on Activities of HIF Prolyl Hydroxylase-2

(508) Activities of HIF prolyl hydroxylase was determined according to the method as described in Anal Biochem, 2004, 330: 74-80, which was slightly modified. A 96-well plate was pretreated with blocker casein and 1 mM biotin for 30 minutes, and then biotin-linked HIF-1α556-574 (biotinyl-DLDLEMLAPYIPMDDDFQL) was immobilized on the 96-well plate. The 96-well plate was then filled with an appropriate amount of HIF-PHD2-containing buffer (20 mM Tris (pH 7.5), 5 mM KCl, 1.5 mM MgCl.sub.2, 20 mM 2-oxoglutarate, 10 mM FeSO.sub.4, 2 mM ascorbic acid, 4% EDTA-free protease inhibitor) and was incubated for 1 to 60 minutes at RT. The reaction mixture also contained different concentrations of HIF prolyl hydroxylase inhibitors to be tested. The reaction was stopped by rinsing the 96-well plate three times with washing buffer. In 100 μl binding buffer (50 mM tris(hydroxymethyl)-aminomethane, pH 7.5, 120 mM NaCl), hydroxylated HIF-1α556-574 was reacted with Eu-VBC protein in the binding buffer at RT for 60 minutes. The reaction solution was aspirated, and the unbound Eu-VBC protein was washed away by washing 3 times with an elution buffer. Subsequently, 10 μl of rabbit anti-Eu-VBC polyclonal antibody was added. After further 30 minutes, 10 μl of anti-rabbit polyclonal antibody immunoglobulin coupled to horseradish peroxidase was added to the binding buffer. To determine the amount of bound Eu-VBC protein, it was incubated with TMB for 15 minutes. The color reaction was terminated by addition of 100 μl of 1 M sulfuric acid. The amount of bound Eu-VBC protein was determined by measuring optical density at 450 nm, which was proportional to the amount of hydroxylated proline in the peptide substrate.

(509) The IC.sub.50 data in the table below are representative data. These values represent only the data measured by the applicant at the time of filing the application. Due to variations in reagents, measurement conditions, and mode of operation in the methods given above, the IC.sub.50 data obtained may show some variations. Therefore, these values should be regarded as relative ones rather than absolute ones.

(510) TABLE-US-00001 PHD2 Examples IC.sub.50 (μM) 1 0.9 2 2.5 3 >10 4 0.8 5 2.7 6 0.5 7 1.5 8 0.5 9 >10 10 >10 11 2.1 16 0.6 17 0.5 21 >10 22 >10 30 0.8 32 0.7 45 1.1 46 >10 52 0.6 53 0.7 67 1.2 68 0.7 69 0.8

(511) The above IC.sub.50 data indicates that compounds of the present invention can effectively inhibit HIF prolyl hydroxylase.

(512) 2. Effect of Compounds of Examples on Hemoglobin in Mice

(513) Male C57Bl/6 mice of 8-10 weeks (Shanghai Slack Laboratory Animals Co., Ltd.) were administrated orally the test compounds in 30 mg/kg for 2 weeks, 3 times each week and Roxadustat (CAS: 808118-40-3) was administrated in an amount of 60 mg/kg as a positive control. Before the first administration and 6 hours after the last administration, about 30 μl of blood was taken from the mandibular vein, and the hemoglobin content was measured by Hemocue hemoglobin analyzer. The hemoglobin elevation was calculated as the value obtained by subtracting the first hemoglobin content from the hemoglobin content after the last administration.

(514) In addition, hemoglobin elevation was also tested in the same manner for Roxadustat as a positive control. Roxadustat was purchased from Selleckchem, which was known to be a potent inhibitor of HIF prolyl hydroxylase in the art and be able to increase hemoglobin production.

(515) The hemoglobin elevation caused by representative compounds of the invention are given in the table below.

(516) TABLE-US-00002 Hemoglobin Examples elevation (g/dL) 1 1.0 2 0.6 4 0.8 5 1.0 6 0.9 7 0.7 8 3.1 9 2.0 10 1.9 11 2.0 12 0.8 13 4.3 14 1.0 21 1.8 24 4.0 35 2.5 39 4.8 62 0.1 67 0.8 68 5.2 69 0.7 Roxadustat 1.7

(517) As can be seen from the above table, compounds of the present invention showed comparable or even better hemoglobin elevation compared to Roxadustat under the same measurement conditions. The results showed that compounds of the present invention may stabilize HIFs by inhibiting prolyl hydroxylase, and thus can be used as medicine for treating and/or preventing diseases associated with HIFs such as anemia through, among others, increasing erythropoietin production and elevating hemoglobin content.

(518) While embodiments of the present invention have been illustrated and described, it is not intended that all possible embodiments of the invention have been illustrated and described. Rather, the words used in the specification are merely illustrative and not restrictive, and it shall be understood that various changes may be made without departing from the spirit and scope of the invention.