DNA POLYMERASE THETA INHIBITOR AND USE THEREOF

Abstract

A DNA polymerase theta inhibitor and use thereof are provided. Specifically, a compound of formula I or formula II, or a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of any of the above, or a solvate of any of the above has a better inhibitory effect on Pol.

##STR00001##

Claims

1. A compound of formula II or III, or a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or a solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt, ##STR00119## wherein Z is C(R.sub.9) or N; ring B is a 6-membered heteroaromatic ring containing at least one N; X.sub.1 is C(R.sub.1a) or N(R.sub.1b); X.sub.2 is C(R.sub.2a), N(R.sub.2b), or N; X.sub.3 is C(R.sub.3a), N(R.sub.3b), or N; X.sub.4 is C(R.sub.4a), N(R.sub.4b), or N; X.sub.5 is C(R.sub.5a), N(R.sub.5b), or N; R.sub.1a and R.sub.2a, R.sub.1a and R.sub.2b, R.sub.1b and R.sub.2b, or R.sub.1b and R.sub.2a join to form ring A, X.sub.3 is C(R.sub.3a) or N, X.sub.4 is C(R.sub.4a) or N, X.sub.5 is C(R.sub.5a) or N, and R.sub.3a, R.sub.4a, and R.sub.5a are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, C.sub.1-6 alkyl substituted with one or more R.sup.X1, C.sub.1-6 alkoxy substituted with one or more R.sup.X1, C.sub.3-8 cycloalkyl substituted with one or more R.sup.X1, C.sub.3-8 cycloalkyl, C.sub.2-6 alkenyl, CN, or NR.sup.xR.sup.y; or, R.sub.1a and R.sub.5a, R.sub.1a and R.sub.5b, R.sub.1b and R.sub.5b, or R.sub.1b and R.sub.5a join to form ring A, X.sub.2 is C(R.sub.2a) or N, X.sub.3 is C(R.sub.3a) or N, X.sub.4 is C(R.sub.4a) or N, and R.sub.2a, R.sub.3a, and R.sub.4a are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, C.sub.1-6 alkyl substituted with one or more R.sup.X1, C.sub.3-8 cycloalkyl, CN, C.sub.1-6 alkoxy substituted with one or more R.sup.X1, C.sub.3-8 cycloalkyl substituted with one or more R.sup.X1, SO.sub.2R.sub.2aa, SOR.sub.2aa, SO(NH)R.sub.2aa, PO(C.sub.1-6 alkyl).sub.2, SF.sub.5, SR.sub.2aa, or NR.sup.xR.sup.y; or, R.sub.4a and R.sub.5a, R.sub.4a and R.sub.5b, R.sub.4b and R.sub.5b, or R.sub.4b and R.sub.5a join to form ring A, X.sub.1 is C(R.sub.1a), X.sub.2 is C(R.sub.2a) or N, X.sub.3 is C(R.sub.3a) or N, and R.sub.1a, R.sub.2a, and R.sub.3a are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, C.sub.1-6 alkyl substituted with one or more R.sup.X1, C.sub.1-6 alkoxy substituted with one or more R.sup.X1, C.sub.3-8 cycloalkyl substituted with one or more R.sup.X1, C.sub.3-8 cycloalkyl, CN, or NR.sup.xR.sup.y; or, R.sub.2a and R.sub.3a, R.sub.2a and R.sub.3b, R.sub.2b and R.sub.3b, or R.sub.2b and R.sub.3a join to form ring A, X.sub.1 is C(R.sub.1a), X.sub.4 is C(R.sub.4a) or N, X.sub.5 is C(R.sub.5a) or N, and R.sub.1a, R.sub.4a, and R.sub.5a are each independently hydrogen; R.sub.2aa is C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl substituted with one or more R.sup.X1, C.sub.1-6 alkyl, or C.sub.1-6 alkyl substituted with one or more R.sup.X1; R.sup.x and R.sup.y are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with 1, 2, or 3 R.sup.X1, C.sub.3-8 cycloalkyl, 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, C(O)C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl substituted with 1, 2, or 3 R.sup.X2, C(O)C.sub.1-6 alkyl substituted with 1, 2, or 3 R.sup.X3, 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with 1, 2, or 3 R.sup.X4, C(O)C.sub.3-8 cycloalkyl substituted with 1, 2, or 3 R.sup.X5, or C(O)C.sub.1-6 alkyl; R.sup.X1, R.sup.X2, R.sup.X3, and R.sup.XS are each independently halogen, hydroxyl, amino, or sulfonyl; each of the 1, 2, or 3 R.sup.X4 is independently oxo (O), hydroxyl, C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups, C.sub.1-6 alkoxy substituted with 1, 2, or 3 hydroxyl groups, or C(O)C.sub.1-6 alkyl; or, R.sup.x and R.sup.y together with a N atom join to form a 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, R.sup.x and R.sup.y are attached to the N atom; ring A is a 3- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic carbon ring, a 3- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic carbon ring substituted with one or more R.sub.1-1, a 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, or a 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with one or more R.sub.1-2; R.sub.1-1 and R.sub.1-2 are each independently oxo (O), hydroxyl, CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.3-8 cycloalkyl, halogen, nitro, amino, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, SO.sub.2(C.sub.1-6 alkyl), SCF.sub.3, S(C.sub.1-6 alkyl), PO(C.sub.1-6 alkyl).sub.2, CO(C.sub.1-6 alkyl), COOH, CONH.sub.2, CONR.sup.xR.sup.y, NR.sup.xR.sup.y, C.sub.1-6 alkoxy substituted with one or more halogens, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl substituted with one or more halogens, SO.sub.2(C.sub.3-8 cycloalkyl), SO(NH)(C.sub.1-6 alkyl), SO(NH)(C.sub.3-8 cycloalkyl), SCHF.sub.2, S(C.sub.3-8 cycloalkyl), SO(C.sub.3-8 cycloalkyl), CO(C.sub.3-8 cycloalkyl), COCHF.sub.2, or 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se; R.sub.5 is oxo (O), hydrogen, cyano, C.sub.1-6 alkyl substituted with one or more halogens, SO.sub.2C.sub.1-6 alkyl, SO.sub.2(C.sub.3-8 cycloalkyl), P(O)(C.sub.1-6 alkyl).sub.2, P(O)(C.sub.3-8 cycloalkyl).sub.2, or CH.sub.2R.sup.z; X is CHR.sub.6-1, NR.sub.6-2, Se, S, S(O), SO.sub.2, SO(NH), or O; R.sub.6-1 is hydrogen, hydroxyl, halogen, CN, NR.sup.mR.sup.n, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with one or more R.sub.16-1, C.sub.1-6 alkoxy substituted with one or more R.sub.16-1, SO.sub.2(C.sub.3-8 cycloalkyl), SO(NH)(C.sub.1-6 alkyl), SO(NH)(C.sub.3-8 cycloalkyl), C.sub.3-8 cycloalkyl, cyano, -L-(C.sub.6-C.sub.10 aryl), -L-(C.sub.6-C.sub.10 aryl substituted with one or more R.sub.6-1-1), -L-4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, -L-4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with one or more R.sub.6-1-2, or SO.sub.2C.sub.1-6 alkyl; L represents a single link bond or C.sub.1-6 alkylene optionally in which 1, 2, or 3 methylene groups are replaced by O; R.sub.6-1-1 and R.sub.6-1-2 are each independently oxo, hydroxyl, C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups, COC.sub.1-6 alkyl, or C.sub.00C.sub.1-6 alkyl; R.sub.6-2 is hydrogen, hydroxyl, halogen, CN, NR.sup.mR.sup.n, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with one or more R.sub.16-1, C.sub.1-6 alkoxy substituted with one or more R.sub.16-1, SO.sub.2(C.sub.3-8 cycloalkyl), SO(NH)(C.sub.1-6 alkyl), SO(NH)(C.sub.3-8 cycloalkyl), C.sub.3-8 cycloalkyl, oxa-C.sub.3-8 cycloalkyl, cyano, or SO.sub.2C.sub.1-6 alkyl; R.sub.8a is hydrogen, NR.sup.xR.sup.y, CH.sub.2R.sup.z, or hydroxyl; or, R.sub.6-1 and R.sub.6-2 are each independently OR.sub.15a; R.sub.8a is OR.sub.15b; R.sub.15a and R.sub.15b together with an atom join to form a 3- to 8-membered saturated monocyclic, spirocyclic, or fused cyclic carbon ring, a 3- to 8-membered saturated monocyclic, spirocyclic, or fused cyclic carbon ring substituted with one or more C.sub.1-6 alkyl, or a 4- to 8-membered saturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring containing one heteroatom N, R.sub.15a and R.sub.15b are attached to the atom; each of the one or more R.sub.16-1 is independently halogen, hydroxyl, NR.sup.mR.sup.n, oxo (O), hydroxyl, C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups, C(O)C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, C.sub.1-6 alkoxy substituted with 1, 2, or 3 hydroxyl groups, or C(O)OC.sub.1-6 alkyl; R.sup.m and R.sup.n are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl substituted with one or more halogens, CO(C.sub.1-6 alkyl), CO(C.sub.3-8 cycloalkyl), CO(C.sub.3-8 cycloalkyl substituted with one or more halogens), 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, C.sub.1-6 alkyl substituted with 1, 2, or 3 R.sup.m-1, CO(C.sub.1-6 alkyl) substituted with 1, 2, or 3 R.sup.m-2, or 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with 1, 2, or 3 R.sup.m-3; R.sup.m-1 and R.sup.m-2 are each independently hydroxyl, halogen, amino, or sulfonyl; each of the 1, 2, or 3 R.sup.m-3 is independently oxo (O), hydroxyl, CO(C.sub.1-6 alkyl), C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy substituted with 1, 2, or 3 hydroxyl groups, or C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups; R.sup.z is hydrogen, C.sub.1-6 alkyl, hydroxyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, C.sub.1-6 alkoxy substituted with 1, 2, or 3 hydroxyl groups, or C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups; R.sub.8b is hydrogen or hydroxyl; R.sub.8 is C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl substituted with one or more R.sub.8-1, or C.sub.1-6 alkyl substituted with one or more R.sub.8-1; each of the one or more R.sub.8-1 is independently halogen or deuterium; R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are each independently hydrogen, C.sub.1-6 alkyl, hydroxyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, NR.sup.mR.sup.n, halogen, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.2-6 alkenyl, C.sub.6-C.sub.10 aryl, C.sub.1-6 alkoxy substituted with one or more halogens, C.sub.3-8 cycloalkyl substituted with one or more halogens, 8- to 10-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, C.sub.6-C.sub.10 aryl substituted with one or more R.sub.9-1, or 8- to 10-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with one or more R.sub.9-2; R.sub.9-1 and R.sub.9-2 are each independently C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, halogen, CN, C(O)N(C.sub.1-6 alkyl).sub.2, CH.sub.2N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl substituted with one or more R.sub.9-a, or C.sub.1-6 alkoxy substituted with one or more R.sub.9-b; R.sub.9-a and R.sub.9-b are each independently hydroxyl or halogen; or, two adjacent groups of the R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 join to form a 4- to 8-membered saturated or unsaturated monocyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se; R.sub.14 is C.sub.6-C.sub.10 aryl, 8- to 10-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, C.sub.6-C.sub.10 aryl substituted with one or more R.sub.14-1, or 8- to 10-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with one or more R.sub.14-2; R.sub.14-1 and R.sub.14-2 are each independently C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups, C.sub.3-8 cycloalkyl, halogen, CN, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.1-6 alkoxy substituted with one or more halogens, C.sub.3-8 cycloalkyl substituted with one or more halogens, CONR.sup.mR.sup.n, or CH.sub.2NR.sup.mR.sup.n; R.sub.15 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy substituted with one or more R.sub.15-1, C.sub.3-8 cycloalkyl substituted with one or more R.sub.15-1, or C.sub.1-6 alkyl substituted with one or more R.sub.15-1; each of the one or more R.sub.15-1 is independently halogen or deuterium; Y is C(R.sub.16) or N; and R.sub.16 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, or halogen.

2. The compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 1, wherein: Z is C(R.sub.9) or N; ring B is a 6-membered heteroaromatic ring containing at least one N; X.sub.1 is C(R.sub.1a) or N(R.sub.1b); X.sub.2 is C(R.sub.2a), N(R.sub.2b), or N; X.sub.3 is C(R.sub.3a), N(R.sub.3b), or N; X.sub.4 is C(R.sub.4a), N(R.sub.4b), or N; X.sub.5 is C(R.sub.5a), N(R.sub.5b), or N; R.sub.1a and R.sub.2a, R.sub.1a and R.sub.2b, R.sub.1b and R.sub.2b, or R.sub.1b and R.sub.2a join to form ring A, R.sub.3a, R.sub.4a, and R.sub.5a are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.3-8 cycloalkyl, CN, or NR.sup.xR.sup.y; or, R.sub.1a and R.sub.5a, R.sub.1a and R.sub.5b, R.sub.1b and R.sub.5b, or R.sub.1b and R.sub.5a join to form ring A, R.sub.2a, R.sub.3a, and R.sub.4a are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.3-8 cycloalkyl, CN, C.sub.1-6 alkoxy substituted with one or more halogens, SF.sub.5, SR.sub.2aa, or NR.sup.xR.sup.y; or, R.sub.4a and R.sub.5a, R.sub.4a and R.sub.5b, R.sub.4b and R.sub.5b, or R.sub.4b and R.sub.5a join to form ring A, R.sub.1a, R.sub.2a, and R.sub.3a are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.3-8 cycloalkyl, CN, or NR.sup.xR.sup.y; R.sub.2aa is C.sub.1-6 alkyl or C.sub.1-6 alkyl substituted with one or more halogens; R.sup.x and R.sup.y are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with 1, 2, or 3 R.sup.X1, C.sub.3-8 cycloalkyl, 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, C(O)C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl substituted with 1, 2, or 3 R.sup.X2, C(O)C.sub.1-6 alkyl substituted with 1, 2, or 3 R.sup.X3, 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with 1, 2, or 3 R.sup.X4, C(O)C.sub.3-8 cycloalkyl substituted with 1, 2, or 3 R.sup.X5, or C(O)C.sub.1-6 alkyl; each of the 1, 2, or 3 R.sup.X1 is independently halogen, hydroxyl, amino, or SO.sub.3H; R.sup.X2, R.sup.X3, and R.sup.X5 are each independently halogen, hydroxyl, amino, or sulfonyl; each of the 1, 2, or 3 R.sup.X4 is independently oxo (O), hydroxyl, C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups, or C(O)C.sub.1-6 alkyl; or, R.sup.x and R.sup.y together with a N atom join to form a 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, R.sup.x and R.sup.y are attached to the N atom; ring A is a 3- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic carbon ring, a 3- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic carbon ring substituted with one or more R.sub.1-1, a 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, or a 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with one or more R.sub.1-2; R.sub.1-1 and R.sub.1-2 are each independently oxo (O), hydroxyl, CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.3-8 cycloalkyl, halogen, nitro, amino, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, SO.sub.2(C.sub.1-6 alkyl), SCF.sub.3, S(C.sub.1-6 alkyl), PO(C.sub.1-6 alkyl).sub.2, CO(C.sub.1-6 alkyl), COOH, CONH.sub.2, CONR.sup.xR.sup.y, NR.sup.xR.sup.y, C.sub.1-6 alkoxy substituted with one or more halogens, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, or 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se; R.sub.5 is oxo (O), hydrogen, cyano, C.sub.1-6 alkyl substituted with one or more halogens, SO.sub.2C.sub.1-6 alkyl, P(O)(C.sub.1-6 alkyl).sub.2, or CH.sub.2R.sup.z; X is CHR.sub.6-1, NR.sub.6-2, or O; R.sub.61 and R.sub.6-2 are each independently hydrogen, hydroxyl, halogen, CN, NR.sup.mR.sup.n, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with one or more R.sub.16-1, C.sub.3-8 cycloalkyl, oxa-C.sub.3-8 cycloalkyl, cyano, or SO.sub.2C.sub.1-6 alkyl; or, R.sub.6-1 and R.sub.6-2 are each independently OR.sub.15a; R.sub.8a is OR.sub.15b; R.sub.15a and R.sub.15b together with an atom join to form a 3- to 8-membered saturated monocyclic, spirocyclic, or fused cyclic carbon ring, or a 4- to 8-membered saturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring containing one heteroatom N, R.sub.15a and R.sub.15b are attached to the atom; each of the one or more R.sub.16-1 is independently halogen, hydroxyl, NR.sup.mR.sup.n, oxo (O), hydroxyl, C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups, C(O)C.sub.1-6 alkyl, or C(O)OC.sub.1-6 alkyl; R.sup.m and R.sup.n are each independently hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, CO(C.sub.1-6 alkyl), 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, C.sub.1-6 alkyl substituted with 1, 2, or 3 R.sup.m-1, CO(C.sub.1-6 alkyl) substituted with 1, 2, or 3 R.sup.m-2, or 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with 1, 2, or 3 R.sup.m-3; R.sup.m-1 and R.sup.m-2 are each independently hydroxyl, halogen, amino, or sulfonyl; each of the 1, 2, or 3 R.sup.m-3 is independently oxo (O), hydroxyl, CO(C.sub.1-6 alkyl), or C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups; R.sub.8a is hydrogen, CH.sub.2R.sup.z, or hydroxyl; R.sup.z is hydrogen, C.sub.1-6 alkyl, hydroxyl, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups; R.sub.8b is hydrogen or hydroxyl; R.sub.8 is C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, or C.sub.1-6 alkyl substituted with one or more R.sub.8-1; each of the one or more R.sub.8-1 is independently halogen or deuterium; R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are each independently hydrogen, C.sub.1-6 alkyl, hydroxyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, NR.sup.mR.sup.n, halogen, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.2-6 alkenyl, C.sub.6-C.sub.10 aryl, 8- to 10-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, C.sub.6-C.sub.10 aryl substituted with one or more R.sub.9-1, or 8- to 10-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with one or more R.sub.9-2; R.sub.9-1 and R.sub.9-2 are each independently C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, halogen, CN, C(O)N(C.sub.1-6 alkyl).sub.2, CH.sub.2N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl substituted with one or more R.sub.9-a, or C.sub.1-6 alkoxy substituted with one or more R.sub.9-b; R.sub.9-a and R.sub.9-b are each independently hydroxyl or halogen; or, two adjacent groups of the R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 join to form a 4- to 8-membered saturated or unsaturated monocyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se; R.sub.14 is C.sub.6-C.sub.10 aryl, 8- to 10-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, C.sub.6-C.sub.10 aryl substituted with one or more R.sub.14-1, or 8- to 10-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with one or more R.sub.14-2; R.sub.14-1 and R.sub.14-2 are each independently C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups, C.sub.3-8 cycloalkyl, halogen, CN, C.sub.1-6 alkyl substituted with one or more halogens, CONR.sup.mR.sup.n, or CH.sub.2NR.sup.mR.sup.n; R.sub.15 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, or C.sub.1-6 alkyl substituted with one or more R.sub.15-1; each of the one or more R is 1 is independently halogen or deuterium; Y is C(R.sub.16) or N; and R.sub.16 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or halogen.

3. The compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 2, wherein the compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt, satisfies one or more of the following conditions: (1) the compound of formula III is a compound of formula I as follows, ##STR00120## in the formula I, ring B is a 6-membered heteroaromatic ring containing at least one N; X.sub.1 is C(R.sub.1a) or N(R.sub.1b); X.sub.2 is C(R.sub.2a), N(R.sub.2b), or N; X.sub.3 is C(R.sub.3a), N(R.sub.3b), or N; X.sub.4 is C(R.sub.4a), N(R.sub.4b), or N; X.sub.5 is C(R.sub.5a), N(R.sub.5b), or N; R.sub.1a and R.sub.2a, R.sub.1a and R.sub.2b, R.sub.1b and R.sub.2b, or R.sub.1b and R.sub.2a join to form ring A, R.sub.3a, R.sub.4a, and R.sub.5a are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.3-8 cycloalkyl, CN, or NR.sup.xR.sup.y; or, R.sub.1a and R.sub.5a, R.sub.1a and R.sub.5b, R.sub.1b and R.sub.5b, or R.sub.1b and R.sub.5a join to form ring A, R.sub.2a, R.sub.3a, and R.sub.4a are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.3-8 cycloalkyl, CN, or NR.sup.xR.sup.y; or, R.sub.4a and R.sub.5a, R.sub.4a and R.sub.5b, R.sub.4b and R.sub.5b, or R.sub.4b and R.sub.5a join to form ring A, R.sub.1a, R.sub.2a, and R.sub.3a are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.3-8 cycloalkyl, CN, or NR.sup.xR.sup.y; R.sup.x and R.sup.y are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with 1, 2, or 3 R.sup.X1, C.sub.3-8 cycloalkyl, or C(O)C.sub.1-6 alkyl; each of the 1, 2, or 3 R.sup.X1 is independently halogen, hydroxyl, amino, or SO.sub.3H; ring A is a 3- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic carbon ring, a 3- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic carbon ring substituted with one or more R.sub.1, a 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, or 3 heteroatoms selected from 1, 2, or 3 of N, O, and S, or a 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, or 3 heteroatoms selected from 1, 2, or 3 of N, O, and S substituted with one or more R.sub.1-2; R.sub.1-1 and R.sub.1-2 are each independently oxo (O), hydroxyl, CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.3-8 cycloalkyl, or halogen; R.sub.5 is oxo (O) or hydrogen; X is CHR.sub.6-1, NR.sub.6-2, or O; R.sub.6-1 and R.sub.6-2 are each independently hydrogen, hydroxyl, halogen, CN, NR.sup.mR.sup.n, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl substituted with one or more R.sub.16-1; each of the one or more R.sub.16-1 is independently halogen, hydroxyl, or NR.sup.mR.sup.n; R.sup.m and R.sup.n are each independently hydrogen or C.sub.1-6 alkyl; R.sub.8a is hydrogen, CH.sub.2R.sup.z, or hydroxyl; R.sup.z is hydrogen, C.sub.1-6 alkyl, hydroxyl, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups; R.sub.8b is hydrogen or hydroxyl; R.sub.8 is C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, or C.sub.1-6 alkyl substituted with one or more R.sub.8-1; each of the one or more R.sub.8-1 is independently halogen or deuterium; and R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are each independently hydrogen, C.sub.1-6 alkyl, hydroxyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, NR.sup.mR.sup.n, halogen, or C.sub.1-6 alkyl substituted with one or more halogens; (2) in the formula II, ring B is a 6-membered heteroaromatic ring containing at least one N; X.sub.1 is C(R.sub.1a) or N(R.sub.1b); X.sub.2 is C(R.sub.2a), N(R.sub.2b), or N; X.sub.3 is C(R.sub.3a), N(R.sub.3b), or N; X.sub.4 is C(R.sub.4a), N(R.sub.4b), or N; X.sub.5 is C(R.sub.5a), N(R.sub.5b), or N; R.sub.1a and R.sub.2a, R.sub.1a and R.sub.2b, R.sub.1b and R.sub.2b, or R.sub.1b and R.sub.2a join to form ring A, R.sub.3a, R.sub.4a, and R.sub.5a are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.3-8 cycloalkyl, CN, or NR.sup.xR.sup.y; or, R.sub.1a and R.sub.5a, R.sub.1a and R.sub.5b, R.sub.1b and R.sub.5b, or R.sub.1b and R.sub.5a join to form ring A, R.sub.2a, R.sub.3a, and R.sub.4a are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.3-8 cycloalkyl, CN, or NR.sup.xR.sup.y; or, R.sub.4a and R.sub.5a, R.sub.4a and R.sub.5b, R.sub.4b and R.sub.5b, or R.sub.4b and R.sub.5a join to form ring A, R.sub.1a, R.sub.2a, and R.sub.3a are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.3-8 cycloalkyl, CN, or NR.sup.xR.sup.y; R.sup.x and R.sup.y are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with 1, 2, or 3 R.sup.X1, C.sub.3-8 cycloalkyl, or C(O)C.sub.1-6 alkyl; each of the 1, 2, or 3 R.sup.X1 is independently halogen, hydroxyl, amino, or SO.sub.3H; ring A is a 3- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic carbon ring, a 3- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic carbon ring substituted with one or more R.sub.1-1, a 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, or 3 heteroatoms selected from 1, 2, or 3 of N, O, and S, or a 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, or 3 heteroatoms selected from 1, 2, or 3 of N, O, and S substituted with one or more R.sub.1-2; R.sub.1-1 and R.sub.1-2 are each independently oxo (O), hydroxyl, CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.3-8 cycloalkyl, or halogen; R.sub.5 is oxo (O) or hydrogen; X is CHR.sub.6-1, NR.sub.6-2, or O; R.sub.6-1 and R.sub.6-2 are each independently hydrogen, hydroxyl, halogen, CN, NR.sup.mR.sup.n, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl substituted with one or more R.sub.16-1; each of the one or more R.sub.16-1 is independently halogen, hydroxyl, or NR.sup.mR.sup.n; R.sup.m and R.sup.n are each independently hydrogen or C.sub.1-6 alkyl; R.sub.8a is hydrogen, CH.sub.2R.sup.z, or hydroxyl; R.sup.z is hydrogen, C.sub.1-6 alkyl, hydroxyl, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups; R.sub.8b is hydrogen or hydroxyl; R.sub.14 is C.sub.6-C.sub.10 aryl, 8- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms selected from 1, 2, or 3 of N, O, and S, C.sub.6-C.sub.10 aryl substituted with one or more R.sub.14-1, or 8- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms selected from 1, 2, or 3 of N, O, and S substituted with one or more R.sub.14-2; R.sub.14-1 and R.sub.14-2 are each independently C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups, C.sub.3-8 cycloalkyl, halogen, CN, or C.sub.1-6 alkyl substituted with one or more halogens; R.sub.15 is hydrogen, halogen, or C.sub.1-6 alkyl; Y is C(R.sub.16) or N; and R.sub.16 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or halogen.

4. The compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 2, wherein the compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt, satisfies one or more of the following conditions: (1) when R.sub.1a and R.sub.5a, R.sub.1a and R.sub.5b, R.sub.1b and R.sub.5b, or R.sub.1b and R.sub.5a join to form ring A, R.sub.2a, R.sub.3a, and R.sub.4a are each independently C.sub.1-6 alkoxy substituted with one or more halogens, SF.sub.5, or SR.sub.2aa; R.sub.2aa is C.sub.1-6 alkyl or C.sub.1-6 alkyl substituted with one or more halogens; (2) R and R.sup.y are each independently 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, C(O)C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl substituted with 1, 2, or 3 R.sup.X2, C(O)C.sub.1-6 alkyl substituted with 1, 2, or 3 R.sup.X3, 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with 1, 2, or 3 R.sup.X4, or C(O)C.sub.3-8 cycloalkyl substituted with 1, 2, or 3 R.sup.X5; R.sup.X2, R.sup.X3, and R.sup.X5 are each independently halogen, hydroxyl, amino, or sulfonyl; each of the 1, 2, or 3 R.sup.X4 is independently oxo (O), hydroxyl, C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups, or C(O)C.sub.1-6 alkyl; or, R.sup.x and R.sup.y together with a N atom join to form a 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, R.sup.x and R.sup.y are attached to the N atom; (3) each of the 1, 2, or 3 R.sup.X1 is independently sulfonyl; (4) R.sub.1-1 and R.sub.1-2 are each independently nitro, amino, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, SO.sub.2(C.sub.1-6 alkyl), SCF.sub.3, S(C.sub.1-6 alkyl), PO(C.sub.1-6 alkyl).sub.2, CO(C.sub.1-6 alkyl), COOH, CONH.sub.2, CONR.sup.xR.sup.y, NR.sup.xR.sup.y, C.sub.1-6 alkoxy substituted with one or more halogens, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, or 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se; (5) R.sub.5 is cyano, C.sub.1-6 alkyl substituted with one or more halogens, SO.sub.2C.sub.1-6 alkyl, P(O)(C.sub.1-6 alkyl).sub.2, or CH.sub.2R.sup.z; (6) X is S, S(O), SO.sub.2, or Se; (7) R.sub.6-1 and R.sub.6-2 are each independently C.sub.3-8 cycloalkyl, oxa-C.sub.3-8 cycloalkyl, cyano, or SO.sub.2C.sub.1-6 alkyl; or, R.sub.61 and R.sub.6-2 are each independently OR.sub.15a; R.sub.8a is OR.sub.15b; R.sub.15a and R.sub.15b, together with an atom, join to form a 3- to 8-membered saturated monocyclic, spirocyclic, or fused cyclic carbon ring, or a 4- to 8-membered saturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring containing one heteroatom N, R.sub.6-1 and R.sub.6-2 are attached to the atom; (8) each of the one or more R.sub.16-1 is independently C.sub.6-C.sub.10 aryl substituted with one or more R.sub.16-a, or 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with one or more R.sub.16-b; R.sub.16-a and R.sub.16-b are each independently oxo (O), hydroxyl, C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups, C(O)C.sub.1-6 alkyl, or C(O)OC.sub.1-6 alkyl; (9) R.sup.m and R.sup.n are each independently C.sub.3-8 cycloalkyl, CO(C.sub.1-6 alkyl), 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, C.sub.1-6 alkyl substituted with 1, 2, or 3 R.sup.m-1, CO(C.sub.1-6 alkyl) substituted with 1, 2, or 3 R.sup.m-2, or 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with 1, 2, or 3 R.sup.m-3; R.sup.m-1 and R.sup.m-2 are each independently hydroxyl, halogen, amino, or sulfonyl; each of the 1, 2, or 3 R.sup.m-3 is independently oxo (O), hydroxyl, CO(C.sub.1-6 alkyl), or C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups; (10) R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are each independently C.sub.2-6 alkenyl, C.sub.6-C.sub.10 aryl, 8- to 10-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, C.sub.6-C.sub.10 aryl substituted with one or more R.sub.9-1, or 8- to 10-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with one or more R.sub.9-2; R.sub.9-1 and R.sub.9-2 are each independently C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, halogen, CN, C(O)N(C.sub.1-6 alkyl).sub.2, CH.sub.2N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl substituted with one or more R.sub.9-a, or C.sub.1-6 alkoxy substituted with one or more R.sub.9-b; R.sub.9-a and R.sub.9-b are each independently hydroxyl or halogen; or, two adjacent groups of the R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 join to form a 4- to 8-membered saturated or unsaturated monocyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se; (11) R.sub.14-1 and R.sub.14-2 are each independently CONR.sup.mR.sup.n or CH.sub.2NR.sup.mR.sup.n; and (12) R.sub.15 is C.sub.3-8 cycloalkyl or C.sub.1-6 alkyl substituted with one or more R.sub.15-1; each of the one or more R.sub.15-1 is independently halogen or deuterium.

5. The compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer any of the above, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 1, wherein the compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt, satisfies one or more of the following conditions: (1) R.sub.2a and R.sub.3a, R.sub.2a and R.sub.3b, R.sub.2b and R.sub.3b, or R.sub.2b and R.sub.3a join to form ring A, X.sub.1 is C(R.sub.1a), X.sub.4 is C(R.sub.4a) or N, X.sub.5 is C(R.sub.5a) or N, and R.sub.1a, R.sub.4a, and R.sub.5a are each independently hydrogen; (2) when R.sub.1a and R.sub.2a, R.sub.1a and R.sub.2b, R.sub.1b and R.sub.2b, or R.sub.1b and R.sub.2a join to form ring A, X.sub.3 is C(R.sub.3a) or N, X.sub.4 is C(R.sub.4a) or N, X.sub.5 is C(R.sub.5a) or N, and R.sub.3a, R.sub.4a, and R.sub.5a are each independently C.sub.1-6 alkoxy substituted with one or more R.sup.X1, C.sub.3-8 cycloalkyl substituted with one or more R.sup.X1, or C.sub.2-6 alkenyl; (3) when R.sub.1a and R.sub.5a, R.sub.1a and R.sub.5b, R.sub.1b and R.sub.5b, or R.sub.1b and R.sub.5a join to form ring A, X.sub.2 is C(R.sub.2a) or N, X.sub.3 is C(R.sub.3a) or N, X.sub.4 is C(R.sub.4a) or N, and R.sub.2a, R.sub.3a, and R.sub.4a are each independently C.sub.3-8 cycloalkyl substituted with one or more R.sup.X1, SO.sub.2R.sub.2aa, SOR.sub.2aa, SO(NH)R.sub.2aa, or PO(C.sub.1-6 alkyl).sub.2; (4) when R.sub.4a and R.sub.5a, R.sub.4a and R.sub.5b, R.sub.4b and R.sub.5b, or R.sub.4b and R.sub.5a join to form ring A, X.sub.1 is C(R.sub.1a), X.sub.2 is C(R.sub.2a) or N, X.sub.3 is C(R.sub.3a) or N, and R.sub.1a, R.sub.2a, and R.sub.3a are each independently C.sub.1-6 alkoxy substituted with one or more R.sup.X1 or C.sub.3-8 cycloalkyl substituted with one or more R.sup.X1; (5) when R.sub.1a and R.sub.5a, R.sub.1a and R.sub.5b, R.sub.1b and R.sub.5b, or R.sub.1b and R.sub.5a join to form ring A, R.sub.2a, R.sub.3a, and R.sub.4a are each independently SO.sub.2R.sub.2aa, SOR.sub.2aa, or SO(NH)R.sub.2aa; R.sub.2aa is C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkyl substituted with one or more R.sup.X1; (6) R.sub.2aa is C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkyl substituted with one or more R.sup.X1; (7) each of the one or more R.sup.X1 is independently sulfonyl; (8) each of the 1, 2, or 3 R.sup.X4 is independently C.sub.1-6 alkoxy substituted with 1, 2, or 3 hydroxyl groups; (9) R.sub.1-1 and R.sub.1-2 are each independently C.sub.3-8 cycloalkyl substituted with one or more halogens, SO.sub.2(C.sub.3-8 cycloalkyl), SO(NH)(C.sub.1-6 alkyl), SO(NH)(C.sub.3-8 cycloalkyl), SCHF.sub.2, S(C.sub.3-8 cycloalkyl), SO(C.sub.3-8 cycloalkyl), CO(C.sub.3-8 cycloalkyl), or COCHF.sub.2; (10) R.sub.5 is SO.sub.2(C.sub.3-8 cycloalkyl) or P(O)(C.sub.3-8 cycloalkyl).sub.2; (11) X is Se, S, S(O), SO.sub.2, or SO(NH); (12) when X is S, R.sub.5 is oxo; (13) R.sub.6-1 is C.sub.1-6 alkoxy substituted with one or more R.sub.16-1, SO.sub.2(C.sub.3-8 cycloalkyl), SO(NH)(C.sub.1-6 alkyl), SO(NH)(C.sub.3-8 cycloalkyl), -L-C.sub.6-C.sub.10 aryl, or -L-4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se; L is a single link bond or C.sub.1-6 alkylene optionally substituted with an oxygen atom; (14) R.sub.6-2 is C.sub.1-6 alkoxy substituted with one or more R.sub.16-1, SO.sub.2(C.sub.3-8 cycloalkyl), SO(NH)(C.sub.1-6 alkyl), or SO(NH)(C.sub.3-8 cycloalkyl); (15) R.sub.6, and R.sub.6-2 are each independently OR.sub.15a; R.sub.8a is OR.sub.15b; and R.sub.15a and R.sub.15b, together with an atom, join to form a 3- to 8-membered saturated monocyclic, spirocyclic, or fused cyclic carbon ring substituted with one or more C.sub.1-6 alkyl, R.sub.6-1 and R.sub.6-2 are attached to the atom; (16) each of the one or more R.sub.16-1 is independently C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, or C.sub.1-6 alkoxy substituted with 1, 2, or 3 hydroxyl groups; (17) R.sup.m and R.sup.n are each independently C.sub.1-6 alkyl substituted with one or more halogens, C.sub.3-8 cycloalkyl substituted with one or more halogens, CO(C.sub.3-8 cycloalkyl), or CO(C.sub.3-8 cycloalkyl substituted with one or more halogens); (18) each of the 1, 2, or 3 R.sup.m-3 is independently C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or C.sub.1-6 alkoxy substituted with 1, 2, or 3 hydroxyl groups; (19) R.sup.z is C.sub.3-8 cycloalkyl or C.sub.1-6 alkoxy substituted with 1, 2, or 3 hydroxyl groups; (20) R.sub.8 is C.sub.3-8 cycloalkyl substituted with one or more R.sub.8-1; (21) R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are each independently C.sub.1-6 alkoxy substituted with one or more halogens or C.sub.3-8 cycloalkyl substituted with one or more halogens; (22) R.sub.14-1 and R.sub.14-2 are each independently C.sub.1-6 alkoxy substituted with one or more halogens or C.sub.3-8 cycloalkyl substituted with one or more halogens; (23) R.sub.15 is C.sub.1-6 alkoxy, C.sub.1-6 alkoxy substituted with one or more R.sub.15-1, or C.sub.3-8 cycloalkyl substituted with one or more R.sub.15-1; and (24) R.sub.16 is C.sub.3-8 cycloalkyl.

6. The compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 1, wherein the compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt, satisfies one or more of the following conditions: (1) when R.sub.1a and R.sub.2a, R.sub.1a and R.sub.2b, R.sub.1b and R.sub.2b, or R.sub.1b and R.sub.2a join to form ring A, R.sub.3a, R.sub.4a, and R.sub.5a are each independently hydrogen, C.sub.1-6 alkyl, or halogen; (2) when R.sub.1a and R.sub.5a, R.sub.1a and R.sub.5b, R.sub.1b and R.sub.5b, or R.sub.1b and R.sub.5a join to form ring A, R.sub.2a, R.sub.3a, and R.sub.4a are each independently hydrogen, C.sub.3-8 cycloalkyl, SF.sub.5, SR.sub.2aa, PO(C.sub.1-6 alkyl).sub.2, or C.sub.1-6 alkyl substituted with one or more halogens; R.sub.2aa is C.sub.1-6 alkyl or C.sub.1-6 alkyl substituted with one or more halogens; (3) when R.sub.4a and R.sub.5a, R.sub.4a and R.sub.5b, R.sub.4b and R.sub.5b, or R.sub.4b and R.sub.5a join to form ring A, R.sub.1a, R.sub.2a, and R.sub.3a are each independently hydrogen or C.sub.1-6 alkyl substituted with one or more halogens; (4) R.sub.1-1 and R.sub.1-2 are each independently oxo (O), hydroxyl, CN, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with one or more halogens, carboxyl, amino, CONH.sub.2, CONR.sup.xR.sup.y, or halogen; (5) R.sub.6-1 and R.sub.6-2 are each independently hydrogen, hydroxyl, or C.sub.1-6 alkyl substituted with one or more R.sub.16-1; (6) each R.sub.16-1 is independently hydroxyl or NR.sup.mR.sup.n; (7) R.sup.m and R.sup.n are each independently C.sub.1-6 alkyl; (8) R.sub.8a is hydrogen or hydroxyl; (9) R.sub.8b is hydrogen; (10) R.sub.8 is C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, or C.sub.1-6 alkyl substituted with one or more R.sub.8-1; (11) each of the one or more R.sub.8-1 is independently deuterium; (12) R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are each independently hydrogen, C.sub.1-6 alkyl, or halogen; (13) R.sub.14 is C.sub.6-C.sub.10 aryl substituted with one or more R.sub.14-1, or 8- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms selected from 1, 2, or 3 of N, O, and S substituted with one or more R.sub.14-2; (14) R.sub.14-1 and R.sub.14-2 are each independently C.sub.1-6 alkyl or halogen; (15) R.sub.15 is hydrogen or methyl; (16) Y is C(R.sub.16)=; (17) R.sub.16 is hydrogen or halogen; (18) ring A is a 5- to 6-membered saturated or unsaturated monocyclic carbon ring, a 5- to 6-membered saturated or unsaturated monocyclic carbon ring substituted with one or more R.sub.1-1, a 5-membered saturated or unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms selected from 1 or 2 of N, O, and S, a 5-membered saturated or unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms selected from 1 or 2 of N, O, and S substituted with one or more R.sub.1-2, or a 6-membered saturated or unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms selected from 1 or 2 of N, O, and S; and (19) when X is NR.sub.6-2 or O, R.sub.5 is oxo (O).

7. The compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 1, wherein the compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt-, satisfies one or more of the following conditions: (1) R.sub.1-1 and R.sub.1-2 are each independently oxo (O), hydroxyl, C.sub.1-6 alkyl, or halogen; (2) R.sub.5 is oxo (O); (3) X is CHR.sub.6-1 or NR.sub.6-2; (4) R.sub.6-1 and R.sub.6-2 are each independently hydrogen or hydroxyl; (5) R.sub.8 is C.sub.1-6 alkyl; (6) ##STR00121## is ##STR00122## (7) R.sub.2a is halogen, C.sub.3-8 cycloalkyl, C.sub.1-6 alkoxy substituted with one or more halogens, SF.sub.5, SR.sub.2aa, C.sub.1-6 alkyl, or C.sub.1-6 alkyl substituted with one or more halogens.

8. The compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 1, wherein the compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt, satisfies one or more of the following conditions: (1) R.sub.1-1 and R.sub.1-2 are each independently halogen; (2) R.sub.6-1 is hydroxyl, and R.sub.6-2 is hydrogen; (3) R.sub.2a is C.sub.1-6 alkyl substituted with one or more halogens; and (4) a compound of formula I has a structure of formula I-A or formula I-B: ##STR00123##

9. The compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 1, wherein ##STR00124## is ##STR00125## ring A is a 5-membered saturated or unsaturated monocyclic carbon ring, a 5-membered saturated or unsaturated monocyclic carbon ring substituted with one or more halogens, or a 4- to 8-membered saturated or unsaturated monocyclic heterocyclic ring having 1, 2, or 3 heteroatoms selected from 1, 2, or 3 of N, O, and S; R.sub.2a is C.sub.1-6 alkyl substituted with one or more halogens; R.sub.5 is oxo (O); X is NH or CH(OH); R.sub.5a is hydrogen or hydroxyl; R.sub.8b is hydrogen; R.sub.8 is C.sub.1-6 alkyl; and R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are each independently hydrogen or halogen.

10. The compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 1, wherein the compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt, satisfies one or more of the following conditions: (1) when R.sub.1a and R.sub.2a, R.sub.1a and R.sub.2b, R.sub.1b and R.sub.2b, or R.sub.1b and R.sub.2a join to form ring A, in R.sub.3a, R.sub.4a, and R.sub.5a, the C.sub.1-6 alkyl groups of the C.sub.1-6 alkyl substituted with one or more halogens, the C.sub.1-6 alkyl substituted with one or more R.sup.X1, and the C.sub.1-6 alkyl are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (2) when R.sub.1a and R.sub.2a, R.sub.1a and R.sub.2b, R.sub.1b and R.sub.2b, or R.sub.1b and R.sub.2a join to form ring A, in R.sub.3a, R.sub.4a, and R.sub.5a, the C.sub.1-6 alkoxy groups of the C.sub.1-6 alkoxy and the C.sub.1-6 alkoxy substituted with one or more R.sup.X1 are each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; (3) when R.sub.1a and R.sub.2a, R.sub.1a and R.sub.2b, R.sub.1b and R.sub.2b, or R.sub.1b and R.sub.2a join to form ring A, in R.sub.3a, R.sub.4a, and R.sub.5a, the halogen groups of the C.sub.1-6 alkyl substituted with one or more halogens and the halogen are each independently fluorine, chlorine, bromine, or iodine; (4) when R.sub.1a and R.sub.5a, R.sub.1a and R.sub.5b, R.sub.1b and R.sub.5b, or R.sub.1b and R.sub.5a join to form ring A, in R.sub.2a, R.sub.3a, and R.sub.4a, the C.sub.1-6 alkyl groups of the C.sub.1-6 alkyl substituted with one or more halogens, the C.sub.1-6 alkyl substituted with one or more R.sup.X1, the PO(C.sub.1-6 alkyl).sub.2, and the C.sub.1-6 alkyl are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (5) when R.sub.1a and R.sub.5a, R.sub.1a and R.sub.5b, R.sub.1b and R.sub.5b, or R.sub.1b and R.sub.5a join to form ring A, in R.sub.2a, R.sub.3a, and R.sub.4a, the C.sub.1-6 alkoxy groups of the C.sub.1-6 alkoxy and the C.sub.1-6 alkoxy substituted with one or more R.sup.X1 are each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; (6) when R.sub.1a and R.sub.5a, R.sub.1a and R.sub.5b, R.sub.1b and R.sub.5b, or R.sub.1b and R.sub.5a join to form ring A, in R.sub.2a, R.sub.3a, and R.sub.4a, the halogen groups of the C.sub.1-6 alkyl substituted with one or more halogens and the halogen are each independently fluorine, chlorine, bromine, or iodine; (7) when R.sub.4a and R.sub.5a, R.sub.4a and R.sub.5b, R.sub.4b and R.sub.5b, or R.sub.4b and R.sub.5a join to form ring A, in R.sub.1a, R.sub.2a, and R.sub.3a, the C.sub.1-6 alkyl groups of the C.sub.1-6 alkyl substituted with one or more halogens, the C.sub.1-6 alkyl substituted with one or more R.sup.X1, and the C.sub.1-6 alkyl are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (8) when R.sub.4a and R.sub.5a, R.sub.4a and R.sub.5b, R.sub.4b and R.sub.5b, or R.sub.4b and R.sub.5a join to form ring A, in R.sub.1a, R.sub.2a, and R.sub.3a, the C.sub.1-6 alkoxy groups of the C.sub.1-6 alkoxy and the C.sub.1-6 alkoxy substituted with one or more R.sup.X1 are each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; (9) when R.sub.4a and R.sub.5a, R.sub.4a and R.sub.5b, R.sub.4b and R.sub.5b, or R.sub.4b and R.sub.5a join to form ring A, in R.sub.1a, R.sub.2a, and R.sub.3a, the halogen groups of the C.sub.1-6 alkyl substituted with one or more halogens and the halogen are each independently fluorine, chlorine, bromine, or iodine; (10) in R.sup.x, R.sup.y, R.sub.1-1, R.sub.1-2, R.sub.6-1, R.sub.6-2, R.sup.m, R.sup.n, R.sup.z, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14-1, R.sub.14-2, R.sub.15, R.sub.5, R.sub.2aa, R.sub.16-a, R.sub.16-b, R.sub.9-1, R.sup.m-3, R.sub.9-2, R.sup.X4, R.sub.16, R.sub.6-1-1, and R.sub.6-1-2, the C.sub.1-6 alkyl groups of the C.sub.1-6 alkyl, the C.sub.1-6 alkyl substituted with 1, 2, or 3 R.sup.X1, the C(O)C.sub.1-6 alkyl, the C.sub.1-6 alkyl substituted with one or more halogens, the C.sub.1-6 alkyl substituted with one or more R.sup.X1, the C.sub.1-6 alkyl substituted with one or more R.sub.16-1, the C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups, the C.sub.1-6 alkyl substituted with one or more R.sub.8-1, the SO(NH)(C.sub.1-6 alkyl), the C(O)C.sub.1-6 alkyl substituted with 1, 2, or 3 R.sup.X3, the C.sub.1-6 alkyl substituted with one or more R.sub.9-a, the C(O)OC.sub.1-6 alkyl, the C(O)N(C.sub.1-6 alkyl).sub.2, the CH.sub.2N(C.sub.1-6 alkyl).sub.2, the SO.sub.2C.sub.1-6 alkyl, the P(O)(C.sub.1-6 alkyl).sub.2, the NH(C.sub.1-6 alkyl), the N(C.sub.1-6 alkyl).sub.2, the S(C.sub.1-6 alkyl), the C.sub.1-6 alkyl substituted with 1, 2, or 3 R.sup.m-1, the CO(C.sub.1-6 alkyl) substituted with 1, 2, or 3 R.sup.m-2, and the C.sub.1-6 alkyl substituted with one or more R.sub.15-1 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (11) in R.sup.X1, R.sub.1-1, R.sub.1-2, R.sub.6-1, R.sub.6-2, R.sub.16-1, R.sub.8-1, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14-1, R.sub.14-2, R.sub.15, R.sub.5, R.sub.9-1, R.sub.9-2, R.sub.2a, R.sub.3a, R.sub.4a, R.sub.2aa, R.sub.9-a, R.sub.9-b, R.sup.X2, R.sup.X3, R.sup.X5, R.sup.m-1, R.sup.m-2, R.sub.15-1, and R.sub.16, the halogen groups of the halogen, the C.sub.1-6 alkoxy substituted with one or more halogens, and the C.sub.1-6 alkyl substituted with one or more halogens are each independently fluorine, chlorine, bromine, or iodine; (12) in R.sup.X4, R.sub.16-1, R.sup.m-3, R.sup.z, R.sub.15, R.sub.1-1, R.sub.1-2, R.sub.6-1, R.sub.6-2, R.sup.z, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14-1, R.sub.14-2, R.sub.9-1, R.sub.9-2, R.sub.2a, R.sub.3a, R.sub.4a, and R.sub.16, the C.sub.1-6 alkoxy groups of the C.sub.1-6 alkoxy, the C.sub.1-6 alkoxy substituted with one or more halogens, the C.sub.1-6 alkoxy substituted with 1, 2, or 3 hydroxyl groups, the C.sub.1-6 alkoxy substituted with one or more R.sub.16-1, the C.sub.1-6 alkoxy substituted with one or more R.sub.15-1, and the C.sub.1-6 alkoxy substituted with one or more R.sub.9-b are each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; (13) in R.sub.6-1, R.sub.14, R.sub.16-1, R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13, the C.sub.6-C.sub.10 aryl groups of the C.sub.6-C.sub.10 aryl substituted with one or more R.sub.14-1, the C.sub.6-C.sub.10 aryl substituted with one or more R.sub.16-a, the C.sub.6-C.sub.10 aryl substituted with one or more R.sub.9-1, the -L-C.sub.6-C.sub.10 aryl, the -L-(C.sub.6-C.sub.10 aryl substituted with one or more R.sub.6-1-1), and the C.sub.6-C.sub.10 aryl are each independently phenyl; (14) in ring A, the 3- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic carbon ring groups of the 3- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic carbon ring and the 3- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic carbon ring substituted with one or more R.sub.1-1 are each independently a 5- to 6-membered saturated or unsaturated monocyclic ring; (15) in ring A, the 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se groups of the 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se and the 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with one or more R.sub.1-2 are each independently a 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, or 3 heteroatoms selected from 1, 2, or 3 of N, O, and S, preferably a 5-membered unsaturated monocyclic ring having 1 or 2 heteroatoms selected from 1, 2, or 3 of N, O, and S; (16) in R.sub.2aa, R.sub.5, R.sub.16-1, R.sup.z, R.sub.16, R.sub.1-1, R.sub.1-2, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14-1, R.sub.6-1, R.sub.6-2, R.sub.9-1, R.sub.9-2, R.sup.m, R.sup.n, R.sup.x, R.sup.y, R.sub.15, and R.sub.14-2, the C.sub.3-8 cycloalkyl groups of the C.sub.3-8 cycloalkyl, the C.sub.3-8 cycloalkyl substituted with one or more R.sup.X1, the C.sub.3-8 cycloalkyl substituted with one or more halogens, the SO.sub.2(C.sub.3-8 cycloalkyl), the SO(NH)(C.sub.3-8 cycloalkyl), the S(C.sub.3-8 cycloalkyl), the SO(C.sub.3-8 cycloalkyl), the P(O)(C.sub.3-8 cycloalkyl).sub.2, the CO(C.sub.3-8 cycloalkyl substituted with one or more halogens), the C.sub.3-8 cycloalkyl substituted with one or more R.sub.8-1, the C.sub.3-8 cycloalkyl substituted with one or more R is 1, the C(O)C.sub.3-8 cycloalkyl, the C.sub.3-8 cycloalkyl substituted with 1, 2, or 3 R.sup.X2, and the C.sub.3-8 cycloalkyl substituted with 1, 2, or 3 R.sup.X5 are each independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (17) when R.sub.1a and R.sub.2a, R.sub.1a and R.sub.2b, R.sub.1b and R.sub.2b, or R.sub.1b and R.sub.2a join to form ring A, in R.sub.3a, R.sub.4a, and R.sub.5a, the C.sub.3-8 cycloalkyl groups of the C.sub.3-8 cycloalkyl and the C.sub.3-8 cycloalkyl substituted with one or more R.sup.X1 are each independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (18) when R.sub.1a and R.sub.5a, R.sub.1a and R.sub.5b, R.sub.1b and R.sub.5b, or R.sub.1b and R.sub.5a join to form ring A, in R.sub.2a, R.sub.3a, and R.sub.4a, the C.sub.3-8 cycloalkyl groups of the C.sub.3-8 cycloalkyl and the C.sub.3-8 cycloalkyl substituted with one or more R.sup.X1 are each independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (19) when R.sub.4a and R.sub.5a, R.sub.4a and R.sub.5b, R.sub.4b and R.sub.5b, or R.sub.4b and R.sub.5a join to form ring A, in R.sub.1a, R.sub.2a, and R.sub.3a, the C.sub.3-8 cycloalkyl groups of the C.sub.3-8 cycloalkyl and the C.sub.3-8 cycloalkyl substituted with one or more R.sup.X1 are each independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (20) in R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, and R.sub.14, the 8- to 10-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se groups of the 8- to 10-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, the 8- to 10-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with one or more R.sub.9-2, and the 8- to 10-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and S substituted with one or more R.sub.14-2 are each independently 8- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms selected from 1, 2, or 3 of N, O, and S, preferably a heteroaryl group having 2 heteroatoms N formed by a fusion of a 5-membered heteroaromatic ring and a 5- to 6-membered heteroaromatic ring; (21) in R.sub.6-1 and R.sub.6-2, the oxa-C.sub.3-8 cycloalkyl groups are oxiranyl, oxetanyl, oxolanyl, or oxacyclohexyl; (22) in R.sub.6-1, R.sup.x, R.sup.y, R.sub.16-1, R.sup.m, and R.sup.n, the -L-(4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se) groups of the -L-(4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se), the -L-(4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with one or more R.sub.6-1-2), the 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, the 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with 1, 2, or 3 R.sup.X4, the 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with one or more R.sub.16-b, and the 4- to 8-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with 1, 2, or 3 R.sup.m-3 are each independently 4- to 8-membered heterocycloalkyl having 1, 2, or 3 heteroatoms selected from 1, 2, or 3 of N, O, and S, preferably 5-membered heterocycloalkyl having 1 or 2 heteroatoms selected from N or S; (23) in R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.1-1, and R.sub.1-2, the C.sub.2-6 alkenyl groups are ethenyl or propenyl; (24) in R.sub.1-1 and R.sub.1-2, the C.sub.2-6 alkynyl groups are ethynyl or propynyl; (25) when R.sup.x and R.sup.y together with a N atom join to form a 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, the heterocyclic ring is a 4- to 8-membered saturated monocyclic heterocyclic ring containing one heteroatom N, R and R.sup.y are attached to the N atom; (26) when two adjacent groups of R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 join to form a 4- to 8-membered saturated or unsaturated monocyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se, the heterocyclic ring is a 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, or 3 heteroatoms selected from 1, 2, or 3 of N, O, and S; (27) when R.sub.1a and R.sub.2a, R.sub.1a and R.sub.2b, R.sub.1b and R.sub.2b, or R.sub.1b and R.sub.2a join to form ring A, in R.sub.3a, R.sub.4a, and R.sub.5a, the C.sub.2-6 alkenyl groups are ethenyl or propenyl; and (28) in L, the C.sub.1-6 alkylene group of the C.sub.1-6 alkylene optionally substituted with an oxygen atom is methylene or ethylene.

11. The compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 1, wherein the compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt, satisfies one or more of the following conditions: (1) when R.sub.1a and R.sub.2a, R.sub.1a and R.sub.2b, R.sub.1b and R.sub.2b, or R.sub.1b and R.sub.2a join to form ring A, in R.sub.3a, R.sub.4a, and R.sub.5a, the C.sub.1-6 alkyl groups of the C.sub.1-6 alkyl substituted with one or more halogens and the C.sub.1-6 alkyl are methyl; (2) when R.sub.1a and R.sub.2a, R.sub.1a and R.sub.2b, R.sub.1b and R.sub.2b, or R.sub.1b and R.sub.2a join to form ring A, in R.sub.3a, R.sub.4a, and R.sub.5a, the halogen groups of the C.sub.1-6 alkyl substituted with one or more halogens and the halogen are fluorine; (3) when R.sub.1a and R.sub.5a, R.sub.1a and R.sub.5b, R.sub.1b and R.sub.5b, or R.sub.1b and R.sub.5a join to form ring A, in R.sub.2a, R.sub.3a, and R.sub.4a, the C.sub.1-6 alkyl groups of the C.sub.1-6 alkyl substituted with one or more halogens and the C.sub.1-6 alkyl are methyl; (4) when R.sub.1a and R.sub.5a, R.sub.1a and R.sub.5b, R.sub.1b and R.sub.5b, or R.sub.1b and R.sub.5a join to form ring A, in R.sub.2a, R.sub.3a, and R.sub.4a, the halogen groups of the C.sub.1-6 alkyl substituted with one or more halogens and the halogen are fluorine; (5) when R.sub.4a and R.sub.5a, R.sub.4a and R.sub.5b, R.sub.4b and R.sub.5b or R.sub.4b and R.sub.5a join to form ring A, in R.sub.1a, R.sub.2a, and R.sub.3a, the C.sub.1-6 alkyl groups of the C.sub.1-6 alkyl substituted with one or more halogens and the C.sub.1-6 alkyl are methyl; (6) when R.sub.4a and R.sub.5a, R.sub.4a and R.sub.5b, R.sub.4b and R.sub.5b, or R.sub.4b and R.sub.5a join to form ring A, in R.sub.1a, R.sub.2a, and R.sub.3a, the halogen groups of the C.sub.1-6 alkyl substituted with one or more halogens and the halogen are each independently fluorine or chlorine; (7) in R.sup.x, R.sup.y, R.sub.1-1, R.sub.1-2, R.sub.6-1, R.sub.6-2, R.sup.m, R.sup.n, R.sup.z, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14-1, R.sub.14-2, R.sub.15, R.sub.5, R.sub.2aa, R.sub.16-a, R.sub.16-b, R.sub.9-1, R.sup.m-3, R.sub.9-2, R.sup.X4, and R.sub.16, the C.sub.1-6 alkyl groups of the C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with 1, 2, or 3 R.sup.X1, C(O)C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with one or more halogens, C.sub.1-6 alkyl substituted with one or more R.sub.16-1, C.sub.1-6 alkyl substituted with 1, 2, or 3 hydroxyl groups, C.sub.1-6 alkyl substituted with one or more R.sub.8-1, the C(O)C.sub.1-6 alkyl substituted with 1, 2, or 3 R.sup.X.sub.3, the C.sub.1-6 alkyl substituted with one or more R.sub.9-a, the C(O)OC.sub.1-6 alkyl, the C(O)N(C.sub.1-6 alkyl).sub.2, the CH.sub.2N(C.sub.1-6 alkyl).sub.2, the SO.sub.2C.sub.1-6 alkyl, the P(O)(C.sub.1-6 alkyl).sub.2, the NH(C.sub.1-6 alkyl), the N(C.sub.1-6 alkyl).sub.2, the S(C.sub.1-6 alkyl), the C.sub.1-6 alkyl substituted with 1, 2, or 3 R.sup.m-1, the CO(C.sub.1-6 alkyl) substituted with 1, 2, or 3 R.sup.m-2, and the C.sub.1-6 alkyl substituted with one or more R.sub.15-1 are methyl; (8) in R.sup.X1, R.sub.1-1, R.sub.1-2, R.sub.6-1, R.sub.6-2, R.sub.16-1, R.sub.8-1, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14-1, R.sub.14-2, R.sub.15, R.sub.5, R.sub.9-1, R.sub.9-2, R.sub.2a, R.sub.3a, R.sub.4a, R.sub.2aa, R.sub.9-a, R.sub.9-b, R.sup.X2, R.sup.X3, R.sup.X5, R.sup.m-1, R.sup.m-2, R.sub.15-1, and R.sub.16, the halogen groups of the halogen, the C.sub.1-6 alkoxy substituted with one or more halogens, and the C.sub.1-6 alkyl substituted with one or more halogens are fluorine; (9) in ring A, the 3- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic carbon ring groups of the 3- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic carbon ring and the 3- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic carbon ring substituted with one or more R.sub.1-1 are each independently ##STR00126## (10) in ring A, the 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se groups of the 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se and the 4- to 8-membered saturated or unsaturated monocyclic, spirocyclic, or fused cyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from 1, 2, 3, or 4 of N, O, S, and Se substituted with one or more R.sub.1-2 are each independently ##STR00127## (11) when R.sub.1a and R.sub.5a, R.sub.1a and R.sub.5b, R.sub.1b and R.sub.5b, or R.sub.1b and R.sub.5a join to form ring A, in R.sub.2a, R.sub.3a, and R.sub.4a, the C.sub.3-8 cycloalkyl groups of the C.sub.3-8 cycloalkyl and the C.sub.3-8 cycloalkyl substituted with one or more R.sup.X1 are each independently cyclopropyl; and (12) in R.sub.2aa, R.sub.5, R.sub.16-1, R.sup.z, R.sub.16, R.sub.1-1, R.sub.1-2, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14-1, R.sub.6-1, R.sub.6-2, R.sub.9-1, R.sub.9-2, R.sup.m, R.sup.n, R.sup.x, R.sup.y, R.sub.15, and R.sub.14-2, the C.sub.3-8 cycloalkyl groups of the C.sub.3-8 cycloalkyl, the C.sub.3-8 cycloalkyl substituted with one or more R.sup.X1, the C.sub.3-8 cycloalkyl substituted with one or more halogens, the SO.sub.2(C.sub.3-8 cycloalkyl), the SO(NH)(C.sub.3-8 cycloalkyl), the S(C.sub.3-8 cycloalkyl), the SO(C.sub.3-8 cycloalkyl), the P(O)(C.sub.3-8 cycloalkyl).sub.2, the CO(C.sub.3-8 cycloalkyl substituted with one or more halogens), the C.sub.3-8 cycloalkyl substituted with one or more R.sub.8-1, the C.sub.3-8 cycloalkyl substituted with one or more R.sub.15-1, the C(O)C.sub.3-8 cycloalkyl, the C.sub.3-8 cycloalkyl substituted with 1, 2, or 3 R.sup.X2, and the C(O)C.sub.3-8 cycloalkyl substituted with 1, 2, or 3 R.sup.X5 are each independently cyclopropyl.

12. The compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 1, wherein the compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt, satisfies one or more of the following conditions: (1) when R.sub.1a and R.sub.2a, R.sub.1a and R.sub.2b, R.sub.1b and R.sub.2b, or R.sub.1b and R.sub.2a join to form ring A, R.sub.3a, R.sub.4a, and R.sub.5a are each independently hydrogen, methyl, or chlorine; (2) when R.sub.1a and R.sub.5a, R.sub.1a and R.sub.5b, R.sub.1b and R.sub.5b, or R.sub.1b and R.sub.5a join to form ring A, R.sub.2a, R.sub.3a, and R.sub.4a are each independently hydrogen, trifluoromethyl, cyclopropyl, SMe, SF.sub.5, or P(O)(CH.sub.3).sub.2; (3) when R.sub.4a and R.sub.5a, R.sub.4a and R.sub.5b, R.sub.4b and R.sub.5b, or R.sub.4b and R.sub.5a join to form ring A, R.sub.1a, R.sub.2a, and R.sub.3a are each independently hydrogen or trifluoromethyl; (4) R.sub.1-1 and R.sub.1-2 are each independently oxo (O), hydroxyl, amino, CONH.sub.2, CONHMe, CN, methyl, fluorine, or trifluoromethyl; (5) R.sup.m and R.sup.n are methyl; (6) X is NH, CH(OH), O or ##STR00128## (7) R.sub.8 is methyl, cyclopropyl, or CD.sub.3; (8) R.sub.9, R.sub.10, R.sub.11, R.sub.12, and R.sub.13 are each independently hydrogen, fluorine, methyl, or chlorine; (9) R.sub.14-1 and R.sub.14-2 are each independently methyl, fluorine, or chlorine; (10) R.sub.15 is hydrogen or methyl; and (11) Y is C(F)=, C(Cl)=, or C(H)=.

13. The compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 1, wherein the compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt, satisfies one or more of the following conditions: (1) R.sub.1-1 and R.sub.1-2 are each independently fluorine; (2) X is NH or CH(OH); (3) each R.sub.16-1 is independently hydroxyl or ##STR00129## (4) R.sub.8 is methyl; and (5) R.sub.14 is ##STR00130##

14. The compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 1, wherein ##STR00131## is one of the following structural fragments: ##STR00132## ##STR00133## ##STR00134##

15. The compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 1, wherein the compound of formula II or III is one of the following: ##STR00135## ##STR00136## ##STR00137## ##STR00138## ##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152##

16. The compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 1, wherein the compound of formula III is any-one of the following: a compound having a retention time of 1.57 min under the following conditions and being one of stereoisomers of ##STR00153## chromatographic column CHIRALPAK ID-3 4.6*50 mm, 3 um; mobile phase A: (0.1% diethylamine) n-hexane, mobile phase B: ethanol, mobile phase A:mobile phase B=70:30; flow rate: 1.0 mL/min; temperature: 25 C.; a compound having a retention time of 1.92 min under the following conditions and being one of the stereoisomers of ##STR00154## chromatographic column CHIRALPAK ID-3 4.6*50 mm, 3 um; mobile phase A: (0.1% diethylamine) n-hexane, mobile phase B: ethanol, mobile phase A:mobile phase B=70:30; flow rate: 1.0 mL/min; temperature: 25 C.; a compound having a retention time of 1.64 min under the following conditions and being one of the stereoisomers of ##STR00155## chromatographic column: CHIRALPAK IA-3 Column 4.6*50 mm, 3 um; mobile phase A: (0.1% diethylamine) n-hexane, mobile phase B: ethanol; mobile phase A:mobile phase B=80:20; flow rate: 1 mL/min; temperature: 25 C.; a compound having a retention time of 2.67 min under the following conditions and being one of the stereoisomers of ##STR00156## chromatographic column: CHIRALPAK IA-3 Column 4.6*50 mm, 3 um; mobile phase A: (0.1% diethylamine) n-hexane, mobile phase B: ethanol; mobile phase A:mobile phase B=80:20; flow rate: 1 mL/min; temperature: 25 C.; a compound having a retention time of 3.52 min under the following conditions one of rotamers of ##STR00157## chromatographic column CHIRAL Cellulose-SB 4.6*100 mm, 3 um; mobile phase A: (0.1% formic acid) n-hexane, mobile phase B: ethanol; mobile phase A:mobile phase B=80:20; flow rate: 1 mL/min; temperature: 25 C.; a compound having a retention time of 3.94 min under the following conditions and being one of the rotamers of ##STR00158## chromatographic column CHIRAL Cellulose-SB 4.6*100 mm, 3 um; mobile phase A: (0.1% formic acid) n-hexane, mobile phase B: ethanol; mobile phase A:mobile phase B=80:20; flow rate: 1 mL/min; temperature: 25 C.; a compound having a retention time of 6.30 min under the following conditions and being one of the stereoisomers of ##STR00159## chromatographic column: XBridge Prep OBD C18 column, 30*150 mm, 5 m; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 32% B to 63% B within 8 min; wavelength: 220 nm; and a compound having a retention time of 7.58 min under the following conditions and being one of the stereoisomers of ##STR00160## chromatographic column: XBridge Prep OBD C18 column, 30*150 mm, 5 m; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 32% B to 63% B within 8 min; wavelength: 220 nm.

17. A pharmaceutical composition comprising: (1) the compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 1, and (2) a pharmaceutically acceptable excipient.

18. A method of preparing a Pol inhibitor, comprising using the compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 1.

19. The method according to claim 18, wherein the Pol inhibitor is used in a mammalian organism and/or in vitro, mainly for experimental purposes.

20. A method of a treatment and/or a prevention of a cancer, comprising using the compound of formula II or III, or the tautomer thereof, the stereoisomer thereof, the pharmaceutically acceptable salt of the compound, the tautomer, or the stereoisomer, or the solvate of the compound, the tautomer, the stereoisomer, or the pharmaceutically acceptable salt according to claim 1.

21. (canceled)

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0337] The present disclosure is further illustrated by way of the following examples without limiting the present disclosure to the scope of the described examples. The experimental methods in the following examples, which are not specified with specific conditions, are generally selected according to conventional methods and conditions, or according to the product manual.

Intermediate 1: Synthesis of (3aS,4S,6aS)-2,2-dimethyl-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxylic acid

##STR00055## ##STR00056##

Step 1: Synthesis of (R)-3-(benzyloxy)-2-(tert-butoxycarbonyl)amino)propanoic(methyl carbonic)anhydride

[0338] O-benzyl-N-(tert-butoxycarbonyl)-D-serine (100.00 g, 338.60 mmol) and 4-methylmorpholine (3.77 g, 37.25 mmol) were dissolved in tetrahydrofuran (1000 mL) and cooled to 20 C. Methyl chloroformate (3.36 g, 35.55 mmol) was then added dropwise and stirred at 20 C. for 1 h. The suspension was filtered. The filter cake was washed with tetrahydrofuran (50 mL*2), and the filtrate was used directly in the next step. LCMS (ESI) m/z: 354 [M+H]+.

Step 2: Synthesis of tert-butyl (S)-(1-(benzyloxy)-3-hydroxypropan-2-yl)carbamate

[0339] To water (1000 mL) cooled to 0 C. was added sodium borohydride (32.00 g, 845.89 mmol) in batches, followed by a solution of (R)-3-(benzyloxy)-2-(tert-butoxycarbonyl)amino)propanoic(methyl carbonic)anhydride in tetrahydrofuran (1100 mL) obtained in the previous step. The mixture was stirred at room temperature overnight and filtered. The filtrate was extracted with ethyl acetate (1 L*2). The combined organic phase was washed with saturated salt water (1.5 L), dried over anhydrous sodium sulfate, and concentrated to give a residue. The obtained crude product was purified on a silica gel column (ethyl acetate:petroleum ether=33:67) to give tert-butyl (S)-(1-(benzyloxy)-3-hydroxypropan-2-yl)carbamate (55.00 g, 195.49 mmol, two-step yield: 58%) as a colorless oil. LCMS (ESI) m/z: 282[M+H]+.

Step 3: Synthesis of tert-butyl (R)-(1-(benzyloxy)-3-oxopropan-2-yl)carbamate

[0340] Oxalyl chloride (30 mL, 355.43 mmol) was dissolved in dichloromethane (750 mL) and cooled to 78 C. in the presence of protective nitrogen. Dimethyl sulfoxide (5.55 g, 71.09 mmol) was then slowly added dropwise. The mixture was stirred at 78 C. for half an hour. Tert-butyl (S)-(1-(benzyloxy)-3-hydroxypropan-2-yl)carbamate (50 g, 177.71 mmol) was dissolved in dichloromethane (250 mL) and then slowly added dropwise to the reaction system. The obtained mixture was stirred at 78 C. for another half an hour. N,N-Diisopropylethyl amine (17.5 mL, 106.63 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h, warmed to 40 C., and then stirred for another 2 h. The mixture was diluted with water (1000 mL) and extracted with dichloromethane (1000 mL*2). The combined organic phase was washed with saturated salt water (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product tert-butyl (R)-(1-(benzyloxy)-3-oxopropan-2-yl)carbamate (32.60 g) as a colorless oil. LCMS (ESI) m/z: 280[M+H]+.

Step 4: Synthesis of methyl 5-(benzyloxy)-4-(tert-butoxycarbonyl)amino)pentyl-2-enoate

[0341] Methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (34.85 g, 109.55 mmol) was dissolved in tetrahydrofuran (400 mL). 18-Crown-6 (28.96 g, 109.55 mmol) was added to the mixture and then cooled to 78 C. in the presence of protective nitrogen. Potassium bis(trimethylsilyl)amide (1 mol/L in tetrahydrofuran) (110 mL, 110 mmol) was then added dropwise. Finally, tert-butyl (R)-(1-(benzyloxy)-3-oxopropan-2-yl)carbamate (30.60 g, 109.55 mmol) was dissolved in tetrahydrofuran (300 mL) and added to the reaction system. The obtained mixture was stirred at 78 C. for 2 h. The mixture was quenched with 1 mol/L hydrochloric acid (107 mL) and extracted with ethyl acetate (600 mL*2). The combined organic phase was washed with saturated salt water (500 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue. The obtained crude product was purified on a silica gel column (ethyl acetate:petroleum ether=25:75) to give methyl 5-(benzyloxy)-4-(tert-butoxycarbonyl)amino)pentyl-2-enoate (22.50 g, 67.08 mmol, yield: 61%) as a colorless oil. LCMS (ESI) m/z: 336[M+H]+.

Step 5: Synthesis of methyl (S,Z)-4-amino-5-(benzyloxy)pent-2-enoate hydrochloride

[0342] Methyl 5-(benzyloxy)-4-(tert-butoxycarbonyl)amino)pentyl-2-enoate (21.80 g, 65.00 mmol) was dissolved in a mol/L solution of hydrogen chloride in 1,4-dioxane (60 mL), and the mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure to give the crude product methyl (S,Z)-4-amino-5-(benzyloxy)pent-2-enoate hydrochloride (19.60 g) as a yellow solid. LCMS (ESI) m/z: 236[M+H]+.

Step 6: Synthesis of methyl 5-(benzyloxy)-4-(diphenylmethylene)amino)pentyl-2-enoate

[0343] Methyl (S,Z)-4-amino-5-(benzyloxy)pent-2-enoate hydrochloride (19.30 g, 71.02 mmol) was dissolved in dichloromethane (200 mL). Benzophenone imine (12.87 g, 71.02 mmol) was added to the mixture and stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated under reduced pressure to give a residue. The obtained crude product was purified on a silica gel column (ethyl acetate:petroleum ether=25:75) to give methyl 5-(benzyloxy)-4-(diphenylmethylene)amino)pentyl-2-enoate (23 g, 57.57 mmol, yield: 81%) as a yellow oil. LCMS (ESI) m/z: 400[M+H]+.

Step 7: Synthesis of methyl (2S,3S,4R)-5-(benzyloxy)-4-(diphenylmethylene)amino)-2,3-dihydroxyvalerate

[0344] The methyl (S,Z)-5-(benzyloxy)-4-(diphenylmethylene)amino)pentyl-2-enoate (21 g, 52.57 mmol) was dissolved in tetrahydrofuran (210 mL). Water (210 mL), potassium osmate dihydrate (0.82 g, 2.63 mmol), and N-methylmorpholine oxide (15.40 g, 131.42 mmol) were added to the mixture, heated to 35 C., and stirred for 6 h. The mixture was diluted with ethyl acetate (300 mL) and water (300 mL) and extracted with ethyl acetate (300 mL*2). The combined organic phase was washed with saturated salt water (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product methyl (2S,3S,4R)-5-(benzyloxy)-4-(diphenylmethylene)amino)-2,3-dihydroxyvalerate (23.50 g) as a brown oil. LCMS (ESI) m/z: 434[M+H]+.

Step 8: Synthesis of methyl (4S,5S)-5-((R)-2-(benzyloxy)-1-((diphenylmethylene)amino)ethyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate

[0345] Methyl (2S,3S,4R)-5-(benzyloxy)-4-(diphenylmethylene)amino)-2,3-dihydroxypentanoate (23.50 g, 54.21 mmol) and 2,2-dimethoxypropane (28.23 g, 271.05 mmol) were dissolved in toluene (250 mL). Pyridinium p-toluenesulfonate (3.41 g, 13.55 mmol) was added to the mixture, heated to 100 C., and stirred for 12 h. The mixture was cooled to room temperature and then concentrated under reduced pressure. The obtained crude product was purified on a silica gel column (ethyl acetate:petroleum ether=15:85) to give methyl (4S,5S)-5-((R)-2-(benzyloxy)-1-((diphenylmethylene)amino)ethyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (14.30 g, 30.20 mmol, yield: 56%) as a yellow solid. LCMS (ESI) m/z: 474[M+H]+.

Step 9: Synthesis of (3aS,6R,6aS)-6-(hydroxymethyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxo[4,5-c]pyrrol-4-one

[0346] Methyl (4S,5S)-5-((R)-2-(benzyloxy)-1-((diphenylmethylene)amino)ethyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (5 g, 10.56 mmol) was dissolved in methanol (50 mL). 20% Palladium hydroxide/carbon (0.74 g, 1.06 mmol) and 10% Hydrous Palladium/Carbon (1.12 g, 1.06 mmol) were added to the mixture. The reaction system was replaced with hydrogen three times and then stirred at 40 C. under hydrogen (4 MPa) for 60 h. The mixture was filtered. The filter cake was washed with methanol (10 mL*2), and the obtained filtrate was concentrated under reduced pressure to give a residue. The residue was slurried with n-hexane (20 mL) for 30 min, filtered, and then washed with n-hexane (5 mL*2). The filter cake was dried under a vacuum to give (3aS,6R,6aS)-6-(hydroxymethyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxo[4,5-c]pyrrol-4-one (1.57 g, 8.39 mmol, yield: 79%) as a white solid. LCMS (ESI) m/z: 188[M+H]+.

Step 10: Synthesis of (3aS,4S,6aS)-2,2-dimethyl-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxylic acid

[0347] (3aS,6R,6aS)-6-(Hydroxymethyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxo[4,5-c]pyrrol-4-one (1.00 g, 5.34 mmol) was dissolved in acetonitrile (9 mL). Carbon tetrachloride (9 mL), H.sub.2O (13 mL), ruthenium trichloride (0.11 g, 0.53 mmol), and sodium periodate (3.43 g, 16.03 mmol) were added to the mixture and stirred in the presence of protective nitrogen for 2 h. The mixture was filtered. The filter cake was washed with methanol (10 mL*2), and the obtained filtrate was concentrated under reduced pressure to give a residue. The residue was dissolved in methanol (20 mL), filtered, and then washed with methanol (5 mL*2). The filtrate was concentrated under reduced pressure to give a crude product (560 mg). The crude product was slurried with water (2.5 mL) for 30 min, filtered, and then washed with water (0.5 mL). The filter cake was dried under a vacuum to give (3aS,4S,6aS)-2,2-dimethyl-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxylic acid (0.25 g, 1.24 mmol, yield: 23%) as an off-white solid. LCMS (ESI) m/z: 202[M+H]+.

Intermediate 2: Synthesis of di-tert-butyl (S)-2-oxoimidazolidine-1,4-dicarboxylate

##STR00057##

Step 1: Synthesis of (S)-3-((benzyloxy)carbonyl)-2-oxoimidazolidine-4-carboxylic acid

[0348] Sodium hydroxide (14.87 g, 371.83 mmol) was dissolved in (300 mL), and the mixture was cooled to 0 C. Bromine (18.01 g, 112.68 mmol) was then slowly added dropwise over 30 min, followed by ((benzyloxy)carbonyl)-L-asparagine (30.0 g, 112.68 mmol) in batches. The obtained colorless solution was heated to 55 C. and stirred for 3 h. The mixture was cooled to room temperature and then extracted with methyl tert-butyl ether (300 mL*2). The aqueous layer was acidified to pH=2 with 6 mol/L hydrochloric acid at 0 C. The suspension was stirred at 0 C. for 2 h and filtered to give (S)-3-((benzyloxy)carbonyl)-2-oxoimidazolidine-4-carboxylic acid (21.0 g, 79.47 mmol, yield: 71%) as a white solid. LCMS (ESI) m/z: 265[M+H]+.

Step 2: Synthesis of 1-benzyl 5-(tert-butyl)(thio)-2-oxoimidazolidine-1,5-dicarboxylate

[0349] (S)-3-((Benzyloxy)carbonyl)-2-oxoimidazolidine-4-carboxylic acid (1.08 g, 4.08 mmol) was dissolved in chloroform (20 mL). Tert-butanol (1.21 g, 16.33 mmol) and pyridine (1.94 g, 24.49 mmol) were added to the mixture and cooled to 15 C. Phosphorus oxychloride (0.72 g, 4.69 mmol) was then added dropwise. The mixture was stirred at room temperature for 2 h. The mixture was washed with 1 mol/L hydrochloric acid (30 mL), saturated aqueous sodium bicarbonate solution (30 mL), and finally saturated salt water (30 mL), dried over NaSO4, filtered, and then concentrated under reduced pressure to give the crude product 1-benzyl 5-(tert-butyl)(thio)-2-oxoimidazolidine-1,5-dicarboxylate (1.3 g) as a yellow solid. LCMS (ESI) m/z: 321[M+H]+.

Step 3: Synthesis of 3-benzyl 1,4-di-tert-butyl (S)-2-oxoimidazolidine-1,3,4-tricarboxylate

[0350] A mixture of 1-benzyl 5-(tert-butyl)(S)-2-oxoimidazolidine-1,5-dicarboxylate (1.30 g, 4.06 mmol), di-tert-butyl dicarbonate (17.71 g, 81.16 mmol), and 4-dimethylaminopyridine (0.05 g, 0.41 mmol) was heated to 60 C. and stirred for 2 h. The mixture was cooled to room temperature, then diluted with dichloromethane (30 mL), washed with saturated aqueous sodium bicarbonate solution (30 mL*3) and saturated salt water (30 mL), and finally dried over anhydrous sodium, and concentrated to give a residue. The obtained crude product was purified on a silica gel column (ethyl acetate:petroleum ether=27:73) to give 3-benzyl 1,4-di-tert-butyl (S)-2-oxoimidazolidine-1,3,4-tricarboxylate (1.37 g, 3.26 mmol, yield: 80%) as an off-white solid. LCMS (ESI) m/z: 421[M+H]+.

Step 4: Synthesis of di-tert-butyl (S)-2-oxoimidazolidine-1,4-dicarboxylate

[0351] 3-Benzyl 1,4-di-tert-butyl (S)-2-oxoimidazolidine-1,3,4-tricarboxylate (1.26 g, 3.00 mmol) was dissolved in tetrahydrofuran (20 mL). Platinum dioxide (0.17 g, 0.75 mmol) was added to the mixture. The reaction system was replaced with hydrogen three times and then stirred at room temperature for 1 h. The mixture was filtered through diatomaceous earth and washed with tetrahydrofuran (10 mL). The filtrate was concentrated under reduced pressure to give the crude product di-tert-butyl (S)-2-oxoimidazolidine-1,4-dicarboxylate (0.92 g) as a white solid. LCMS (ESI) m/z: 287[M+H]+.

Intermediate 3: Synthesis of (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-N,2,2-trimethyl-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxamide

##STR00058##

Step 1: Synthesis of 5-chloro-2,4-difluoro-N-methylaniline

[0352] Sodium methoxide (6.61 g, 122.29 mmol) was dissolved in methanol (60 mL). 5-Chloro-2,4-difluoroaniline (2.00 g, 12.23 mmol) and aqueous formaldehyde (1.36 mL, 18.34 mmol) were added to the mixture and stirred at room temperature for 16 h. The mixture was cooled to 0 C. Sodium borohydride (0.93 g, 24.46 mmol) was then slowly added in batches. The mixture was returned to room temperature and stirred for 2 h. The mixture was concentrated under reduced pressure to remove the solvent and then diluted with ethyl acetate (30 mL) and water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL*2). The combined organic phase was washed with saturated salt water (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=20:80) to give 5-chloro-2,4-difluoro-N-methylaniline (1.37 g, 7.71 mmol, yield: 63%) as a colorless oil. LCMS (ESI) m/z: 178[M+H]+.

Step 2: Synthesis of (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-N,2,2-trimethyl-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxamide

[0353] (3aS,4S,6aS)-2,2-Dimethyl-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxylic acid (Intermediate 1, 150 mg, 0.75 mmol) was dissolved in N,N-dimethylacetamide (3 mL). 5-Chloro-2,4-difluoro-N-methylaniline (199 mg, 1.12 mmol) and pyridine (0.18 mL, 2.24 mmol) were added to the mixture and then cooled to 0 C. Phosphorus oxychloride (114 mg, 0.75 mmol) was then slowly added dropwise, and the obtained mixture was stirred at room temperature for 1 h. The mixture was directly purified by reverse phase column chromatography (acetonitrile:0.05% ammonium bicarbonate aqueous solution=30:70) to give (3aS,4S,6As)N-(5-chloro-2,4-difluorophenyl)-N,2,2-trimethyl-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxamide (137 mg, 0.38 mmol, yield: 51%) as a white solid. LCMS (ESI) m/z: 361[M+H]+.

Intermediate 4: Synthesis of (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-2,2-dimethyl-N-(deuterated methyl)-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxamide

##STR00059##

Step 1: Synthesis of tert-butyl (5-chloro-2,4-difluorophenyl)carbamate

[0354] 5-Chloro-2,4-difluoroaniline (10 g, 61.14 mmol) was dissolved in 1,4-dioxane (50 mL). Water (50 mL), di-tert-butyl dicarbonate (40 g, 183.43 mmol), and sodium bicarbonate (30.82 g, 366.86 mmol) were added to the mixture and stirred at 40 C. for 24 h. The mixture was extracted with ethyl acetate (100 mL*3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=20:80) to give tert-butyl (5-chloro-2,4-difluorophenyl)carbamate (6.80 g, 25.79 mmol, yield: 42%) as a pink solid. LCMS (ESI) m/z: 264[M+H]+.

Step 2: Synthesis of tert-butyl (5-chloro-2,4-difluorophenyl)(deuterated methyl)carbamate

[0355] Tert-butyl (5-chloro-2,4-difluorophenyl)carbamate (900 mg, 3.41 mmol) was dissolved in N,N-dimethylformamide (10 mL) and cooled to 0 C. 60% Sodium hydride (205 mg, 5.12 mmol) was then added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 C. again. Perdeuteroiodomethane (594 mg, 4.10 mmol) was then slowly added dropwise to the reaction system, and the obtained mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=20:80) to give tert-butyl (5-chloro-2,4-difluorophenyl)(deuterated methyl)carbamate (882 mg, 3.14 mmol, yield: 92%) as a yellow oil. LCMS (ESI) m/z: 281[M+H]+.

Step 3: Synthesis of 5-chloro-2,4-difluoro-N-(deuterated methyl)aniline

[0356] Tert-butyl (5-chloro-2,4-difluorophenyl)(deuterated methyl)carbamate (800 mg, 2.85 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added to the mixture and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give a residue. The obtained crude product was purified by reverse phase column chromatography (acetonitrile:0.05% ammonium bicarbonate aqueous solution=30:70) to give 5-chloro-2,4-difluoro-N-(deuterated methyl)aniline (450 mg, 2.49 mmol, yield: 87%) as a yellow oil. LCMS (ESI) m/z: 181[M+H]+.

Step 4: Synthesis of (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-2,2-dimethyl-N-(deuterated methyl)-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxamide

[0357] (3aS,4S,6aS)-2,2-Dimethyl-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxylic acid (Intermediate 1, 280 mg, 1.39 mmol) was dissolved in N,N-dimethylacetamide (5 mL). 5-Chloro-2,4-difluoro-N-(deuterated methyl)aniline (377 mg, 2.09 mmol) and pyridine (0.34 mL, 4.18 mmol) were added to the mixture and then cooled to 0 C. Phosphorus oxychloride (213 mg, 1.39 mmol) was then slowly added dropwise, and the obtained mixture was stirred at room temperature for 1 h. The mixture was directly purified by reverse phase column chromatography (acetonitrile:0.05% ammonium bicarbonate aqueous solution=30:70) to give (3aS,4S,6As)N-(5-chloro-2,4-difluorophenyl)-2,2-dimethyl-N-(methyl-D3)-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxamide (405 mg, 1.11 mmol, yield: 80%) as a white solid. LCMS (ESI) m/z: 364[M+H]+.

Intermediate 5: Synthesis of (3aS,4S,6aS)N-(3-chloro-2,4-difluorophenyl)-2,2-dimethyl-N-(deuterated methyl)-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxamide

##STR00060##

Step 1: Synthesis of tert-butyl (3-chloro-2,4-difluorophenyl)carbamate

[0358] 3-Chloro-2,4-difluoroaniline (10 g, 61.14 mmol) was dissolved in 1,4-dioxane (50 mL). Water (50 mL), di-tert-butyl dicarbonate (26.69 g, 122.29 mmol), and sodium bicarbonate (20.55 g, 244.57 mmol) were added to the mixture and stirred at 40 C. for 24 h. The mixture was extracted with ethyl acetate (100 mL*3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=20:80) to give tert-butyl (3-chloro-2,4-difluorophenyl)carbamate (8.60 g, 32.62 mmol, yield: 53%) as an off-white solid. LCMS (ESI) m/z: 264[M+H]+.

Step 2: Synthesis of tert-butyl (3-chloro-2,4-difluorophenyl)(deuterated methyl)carbamate

[0359] Tert-butyl (3-chloro-2,4-difluorophenyl)carbamate (1.00 g, 3.79 mmol) was dissolved in N,N-dimethylformamide (10 mL) and cooled to 0 C. 60% Sodium hydride (0.14 g, 5.69 mmol) was then added. The mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 C. again. Perdeuteroiodomethane (0.66 g, 4.55 mmol) was then slowly added dropwise to the reaction system, and the obtained mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL*3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified on a silica gel column (ethyl acetate:petroleum ether=10:90) to give tert-butyl (3-chloro-2,4-difluorophenyl)(deuterated methyl)carbamate (0.95 g, 3.38 mmol, yield: 89%) as a colorless oil. LCMS (ESI) m/z: 281[M+H]+.

Step 3: Synthesis of 3-chloro-2,4-difluoro-N-(deuterated methyl)aniline

[0360] Tert-butyl (3-chloro-2,4-difluorophenyl)(deuterated methyl)carbamate (850 mg, 3.03 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (2 mL) was added to the mixture and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give a residue. The obtained crude product was purified by reverse phase column chromatography (acetonitrile:0.05% ammonium bicarbonate aqueous solution=30:70) to give 3-chloro-2,4-difluoro-N-(deuterated methyl)aniline (510 mg, 2.82 mmol, yield: 93%) as a yellow oil. LCMS (ESI) m/z: 181[M+H]+.

Step 4: Synthesis of (3aS,4S,6aS)N-(3-chloro-2,4-difluorophenyl)-2,2-dimethyl-N-(deuterated methyl)-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxamide

[0361] (3aS,4S,6aS)-2,2-Dimethyl-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxylic acid (Intermediate 1, 130 mg, 0.65 mmol) was dissolved in N,N-dimethylacetamide (3 mL). 3-Chloro-2,4-difluoro-N-(deuterated methyl)aniline (117 mg, 0.65 mmol) and pyridine (0.16 mL, 1.94 mmol) were added to the mixture and then cooled to 0 C. Phosphorus oxychloride (99 mg, 0.65 mmol) was then slowly added dropwise, and the obtained mixture was stirred at room temperature for 1 h. The mixture was directly purified by reverse phase column chromatography (acetonitrile:0.05% ammonium bicarbonate aqueous solution=30:70) to give (3aS,4S,6aS)N-(3-chloro-2,4-difluorophenyl)-2,2-dimethyl-N-(methyl-D3)-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxamide (86 mg, 0.24 mmol, yield: 37%) as a white solid. LCMS (ESI) m/z: 364[M+H]+.

Intermediate 6: Synthesis of tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate

Step 1: Synthesis of 3-chloro-2,4-difluoro-N-methylaniline

##STR00061##

[0362] Sodium methoxide (33 g, 611.43 mmol) was added to methanol (300 mL) at 0 C. 3-Chloro-2,4-difluoroaniline (10 g, 61.14 mmol) and aqueous formaldehyde (7 mL, 91.72 mmol, 37%) were then added to the system. The mixed solution was allowed to return to room temperature, stirred for 12 h, and then cooled to 0 C. Sodium borohydride (4.63 g, 122.29 mmol) was added and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, added with water (30 mL), and extracted with ethyl acetate (30 mL*2). The organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The obtained crude product was purified on a silica gel column (petroleum ether:ethyl acetate=10:90) to give 3-chloro-2,4-difluoro-N-methylaniline (8.50 g, 476.91 mmol, yield: 78%) as a yellow oil. LCMS (ESI) m/z: 178[M+H]+.

Step 2: Synthesis of benzyl (S)-5-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate

[0363] To dichloromethane (40 mL) was added (S)-3-(benzyloxy) carbonyl)-2-oxoimidazolidine-4-carboxylic acid (3.77 g, 14.27 mmol), followed by N,N-dimethylformamide (2 drops). The mixed solution was cooled to 0 C. Oxalyl chloride (2.42 mL, 28.53 mmol) was slowly added dropwise. The mixed solution was allowed to return to room temperature and stirred for 1 h. The mixture was concentrated under reduced pressure at 0 C. The residue was dissolved in dichloromethane (25 mL) and added dropwise to a solution of 3-chloro-2,4-difluoro-N-methylaniline (3.04 g, 17.12 mmol), pyridine (3.5 mL, 42.80 mmol), and DMAP (0.17 g, 1.43 mmol) in dichloromethane (25 mL) at 0 C. The mixed solution was allowed to return to room temperature and stirred for 1 h. After completion of the reaction, the mixed solution was cooled to 0 C., added dropwise with ice water (50 mL), and then extracted with dichloromethane (50 mL*3). The organic layer was collected, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The obtained crude product was purified on a silica gel column (petroleum ether:ethyl acetate=50:50) to give benzyl (S)-5-(3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (1.85 g, 4.42 mmol, yield: 31%) as a yellow oil. LCMS (ES, m/z): 424 [M+H]+.

Step 3: Synthesis of 3-benzyl 1-(tert-butyl) (S)-4-(3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1,3-dicarboxylate

[0364] Benzyl (S)-5-(3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (0.64 g, 1.51 mmol), Boc-anhydride (6.57 g, 30.11 mmol), and 4-dimethylaminopyridine (0.02 g, 0.15 mmol) were added to a reaction flask and refluxed at 50 C. for 2 h. After completion of the reaction, the reaction solution was cooled to room temperature and poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated to give the crude product 3-benzyl 1-(tert-butyl) (S)-4-(3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1,3-dicarboxylate (1.45 g) as a yellow oily solid, which was used in the next step without purification. LCMS (ES, m/z): 524 [M+H]+.

Step 4: Synthesis of tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate

[0365] 3-Benzyl 1-(tert-butyl) (S)-4-(3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1,3-dicarboxylate (1.30 g, 2.48 mmol) was dissolved in tetrahydrofuran (25 mL). Platinum dioxide (0.14 g, 0.62 mmol) was added to the mixture and stirred at room temperature under a hydrogen atmosphere for 1 h. The reaction solution was filtered through a Buchner funnel. The filter cake was washed with methanol (20 mL*2). The filtrate was concentrated to give the crude product tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (0.36 g, 37%) as a white solid, which was used in the next step without purification. LCMS (ESI) m/z: 390[M+H]+.

Intermediate 7: Synthesis of 7-bromo-5-chlorothiazolo[5,4-b]pyridine

##STR00062##

[0366] Step 1: 4-bromo-2,6-dichloropyridin-3-amine (10 g, 41.69 mmol) and phenylcyanosulfuric anhydride (10 g, 62.53 mmol) were dissolved in 1,4-dioxane (200 mL) and reacted at 100 C. overnight. After completion of the reaction, the reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=20:80) to give N-(7-bromo-5-chlorothiazolo[5,4-b]pyridin-2-yl)benzamide (10 g, 27.25 mmol, yield: 65%) as a light yellow solid. LCMS (ESI) m z: 368 [M+H]+.

[0367] Step 2: N-(7-bromo-5-chlorothiazolo[5,4-b]pyridin-2-yl)benzamide (10 g, 27.25 mmol) was dissolved in 98% concentrated sulfuric acid (200 mL) and reacted at 100 C. overnight. After completion of the reaction, the reaction solution was slowly dropped into an excess amount of 5% sodium hydroxide solution and suction filtered under a vacuum. The solid phase was washed with water to give 7-bromo-5-chlorothiazolo[5,4-b]pyridin-2-amine (5 g, 19.02 mmol, yield: 70%) as a white solid. LCMS (ESI) m z: 266 [M+H].sup.+.

[0368] Step 3: 7-bromo-5-chlorothiazolo[5,4-b]pyridin-2-amine (5 g, 19.02 mmol) and tert-butyl nitrite (2.94 g, 28.53 mmol) were dissolved in tetrahydrofuran (100 mL) and refluxed at 70 C. overnight. After completion of the reaction, the reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=20:80) to give 7-bromo-5-chlorothiazolo[5,4-b]pyridine (2.7 g, 10.89 mmol, yield: 57%) as a light yellow solid. LCMS (ESI) m z: 249 [M+H].sup.+.

Example 1: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-4-carboxamide (Compound 1)

##STR00063## ##STR00064##

Step 1: Synthesis of 2-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one

[0369] Cyclopentane-1,3-dione (10.00 g, 101.94 mmol) was added to 1,2-dichloroethane (100 mL), followed by ethyl 4,4,4-trifluoro-3-oxobutanoate (28.15 g, 152.91 mmol), ammonium acetate (39.29 g, 509.68 mmol), and 4-dimethylaminopyridine (2.49 g, 20.39 mmol). The mixture was stirred at 140 C. for 16 h. After completion of the reaction, the system was cooled to room temperature, poured into water (200 mL), and then extracted with dichloromethane (50 mL*3). The combined organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=90:10) to give 2-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one (5.00 g, 23.44 mmol, yield: 23%) as a white solid. LCMS (ESI) m/z: 218 (M+H).sup.+.

Step 2: Synthesis of 4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-ol

[0370] 2-Hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one (2.00 g, 9.21 mmol) was added to tetrahydrofuran (20 mL), followed by borane (2.76 mL, 27.63 mmol, 10 mol/L in dimethyl sulfide). The mixture was stirred in a sealed tube at 80 C. for 16 h. After completion of the reaction, the system was cooled to room temperature and quenched with methanol (20 mL). The mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile:water=40:60) to give 4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-ol (0.35 g, 1.75 mmol, yield: 19%) as a yellow solid. LCMS (ESI) m/z: 204 (M+H).sup.+.

Step 3: Synthesis of 4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl triflate

[0371] 4-(Trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-ol (100 mg, 0.49 mmol) was added to dichloromethane (5 mL), followed by triethylamine (149 mg, 1.48 mmol). The mixture was cooled to 45 C., and triflic anhydride (416 mg, 1.48 mmol) was added dropwise. The system was stirred at room temperature for 16 h. After completion of the reaction, the reaction solution was poured into water (20 mL) and extracted with dichloromethane (10 mL*2). The combined organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=80:20) to give 4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl triflate (40 mg, 0.12 mmol, yield: 24%) as a colorless oil. LCMS (ESI) m/z: 336 (M+H).sup.+.

Step 4: Synthesis of tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-1-carboxylate

[0372] 4-(Trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl triflate (25 mg, 0.07 mmol) was added to 1,4-dioxane (2 mL), followed by tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (Intermediate 6, 32 mg, 0.08 mmol), bis(dibenzylideneacetone)palladium (5 mg, 0.01 mmol), 1,1-bis(diphenylphosphino)ferrocene (4 mg, 0.01 mmol), and potassium carbonate (21 mg, 0.15 mmol). The mixture was stirred at 100 C. for 2 h. After completion of the reaction, the system was cooled to room temperature, poured into water (10 mL), and extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=80:20) to give tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-1-carboxylate (30 mg, 0.04 mmol, yield: 70%) as a yellow oil. LCMS (ESI) m/z: 575 (M+H).sup.+.

Step 5: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-4-carboxamide

[0373] Tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-1-carboxylate (25 mg, 0.04 mmol) was added to dichloromethane (2 mL), followed by trifluoroacetic acid (0.4 mL). The mixture was stirred at room temperature for 1 h. After completion of the reaction, the system was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (column type: Xsele CSH C18 OBD column 30*150 mm, 5 m, mobile phase A: 0.05% formic acid in water, mobile phase B: acetonitrile; flow rate: 60 mL/min; elution gradient: mobile phase B from 15% to 76% within 8 min, wavelength: 220 nm, retention time: 7.02 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-4-carboxamide (10.95 mg, 0.02 mmol , yield: 53%) as a white solid. LCMS (ESI) m/z: 474.95 (M+H).sup.+. HNMR (400 MHz, DMSO-d6): ppm 8.40-8.14 (m, 1H), 7.79-7.60 (m, 1H), 7.59-7.35 (m, 2H), 5.69-4.73 (m, 1H), 3.89-3.41 (m, 2H), 3.22-3.10 (m, 3H), 3.10-2.76 (m, 4H), 2.19-2.06 (m, 2H).

Example 2: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-3-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide (Compound 2)

##STR00065##

Step 1: Synthesis of tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-2-oxoimidazolidine-1-carboxylate

[0374] Tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (Intermediate 6, 100 mg, 0.26 mmol) was added to 1,4-dioxane (2.5 mL), followed by 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (59 mg, 0.38 mmol), palladium acetate (6 mg, 0.03 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (15 mg, 0.03 mmol), and potassium carbonate (106 mg, 0.77 mmol). The mixture was stirred at 80 C. in the presence of protective nitrogen for 2 h. After completion of the reaction, the system was cooled to room temperature, poured into water (20 mL), and then extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=55:45) to give tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-2-oxoimidazolidine-1-carboxylate (82 mg, 0.16 mmol, yield: 63%) as a yellow solid. LCMS (ESI) m/z: 507 (M+H).sup.+.

Step 2: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-3-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide

[0375] Tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-2-oxoimidazolidine-1-carboxylate (82 mg, 0.16 mmol) was added to dichloromethane (3 mL), followed by trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 1 h. After completion of the reaction, the system was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (column: Xsele CSH C18 OBD column 30*150 mm, 5 m, mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; elution gradient: mobile phase B from 30% to 70% within 8 min, wavelength: 220 nm, retention time: 7.17 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-3-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide (33.80 mg, 0.08 mmol, yield: 51%) as a white solid. LCMS (ESI) m/z: 407.10 (M+H).sup.+. HNMR (400 MHz, DMSO-d6): ppm 7.98-7.83 (m, 1H), 7.82-7.35 (m, 3H), 7.29-7.07 (m, 1H), 5.69-4.64 (m, 1H), 3.85-3.35 (m, 2H), 3.19-3.04 (m, 3H), 3.00-2.88 (m, 1H), 2.87-2.72 (m, 3H), 2.12-1.95 (m, 2H).

Example 3: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-4-carboxamide (Compound 3)

##STR00066##

Step 1: Synthesis of 2-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one

[0376] Cyclopentane-1,3-dione (10 g, 101.936 mmol), ethyl 4,4,4-trifluoro-3-oxobutanoate (28.15 g, 152.904 mmol), ammonium acetate (39.29 g, 509.680 mmol), and 4-dimethylaminopyridine (2.49 g, 20.387 mmol) were dissolved in 1,2-dichloroethane (100 mL) and reacted at 140 C. overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=80:20) to give 2-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one (8.50 g, 39.143 mmol, yield: 38.40%) as a pink solid. LCMS (ESI): 218 [M+H].sup.+.

Step 2: Synthesis of 5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl triflate

[0377] 2-Hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one (200 mg, 0.921 mmol) was dissolved in dichloromethane (4 mL). Triethylamine (0.28 g, 2.763 mmol) was added at room temperature, and then triflic anhydride (0.47 mL, 2.763 mmol) was added dropwise at 45 C. The system was allowed to return to room temperature for 2 h. After completion of the reaction, the reaction solution was poured into water (10 mL) and extracted with dichloromethane (10 mL*2). The combined organic layer was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=70:30) to give 5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-2-yl triflate (120 mg, 0.343 mmol, yield: 37.31%) as a bright yellow solid. LCMS (ESI): 350 [M+H].sup.+.

Step 3: Synthesis of tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-2-yl) imidazolidine-1-carboxylate

[0378] In the presence of protective nitrogen, 5-oxo-4-(trifluoromethyl)-6H,7H-cyclopenta[b]pyridin-2-yl triflate (50 mg, 0.143 mmol), tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (Intermediate 6, 61 mg, 0.157 mmol), tris(dibenzylideneacetone)dipalladium (13 mg, 0.014 mmol), 1,1-bis(diphenylphosphino)ferrocene (8 mg, 0.014 mmol), and potassium carbonate (40 mg, 0.286 mmol) were dissolved in 1,4-dioxane (3 mL) solution, and the mixture was reacted at 100 C. for 2 h. After completion of the reaction, the system was cooled to room temperature. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL*2). The combined organic layer was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=50:50) to give tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-1-carboxylate (50 mg, 0.085 mmol, yield: 59.29%) as a white solid. LCMS (ESI): 589 [M+H].sup.+.

Step 4: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopentyl[b]pyridin-2-yl)imidazolidine-4-carboxamide

[0379] Tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-2-yl)imidazolidine-1-carboxylate (50 mg, 0.085 mmol) and trifluoroacetic acid (63 L, 0.850 mmol) were dissolved in dichloromethane (1 mL), and the system was stirred at room temperature in the presence of nitrogen for 1 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (column: CSH Xsele C18 OBD column 30*150 mm, 5 m; mobile phase A: 0.05% formic acid in water, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 15% B to 68% B within 8 min; wavelength: 220 nm; retention time: 7.70 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-4-carboxamide (10.35 mg, 0.021 mmol, yield: 24.94%) as a white solid. LCMS (ESI): 489.00 [M+H].sup.+. HNMR (400 MHz, DMSO-d6): ppm 8.71-8.52 (m, 1H), 8.51-8.13 (m, 1H), 7.92-7.56 (m, 1H), 7.56-7.32 (m, 1H), 5.12-4.38 (m, 1H), 4.38-4.20 (m, 1H), 4.19-3.82 (m, 2H), 3.30-3.28 (m, 1H), 3.15-3.10 (s, 3H), 2.75-2.66 (m, 2H).

Example 4: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)imidazoline-4-carboxamide (Compound 4)

##STR00067##

Step 1: Synthesis of 7-(trifluoromethyl)thieno[3,2-b]pyridin-5-ol

[0380] 3-Aminothiophene hydrochloride (2.0 g, 14.75 mmol) was added to ethyl trifluoroacetoacetate (10.86 g, 58.99 mmol). The mixture was stirred at 130 C. overnight. The mixture was concentrated, and methyl tert-butyl ether (20 mL) was added. Solid was precipitated and filtered. The filter cake was washed with methyl tert-butyl ether (20 mL*2) and dried to give 7-(trifluoromethyl)thieno[3,2-b]pyridin-5-ol (1.51 g, 6.84 mmol, yield: 34%) as a yellow solid. LCMS (ESI) m/z: 220[M+H].sup.+.

Step 2: Synthesis of 7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl triflate

[0381] 7-(Trifluoromethyl)thieno[3,2-b]pyridin-5-ol (550 mg, 2.51 mmol) was added to dichloromethane (5 mL), followed by triethylamine (762 mg, 7.53 mmol). The system was controlled at 0 C., and triflic anhydride (1.06 g, 3.76 mmol) was added dropwise. The mixed system was warmed to room temperature and reacted overnight. The mixture was poured into water (20 mL) and extracted with dichloromethane (10 mL*2). The combined organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=80:20) to give 7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl triflate (580 mg, 1.65 mmol, yield: 65%) as a yellow oil. LCMS (ESI) m/z: 352 [M+H].sup.+.

Step 3: Synthesis of tert-butyl (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)imidazoline-4-carboxamide

[0382] Tert-butyl (S)-4-(3-chloro-2,4-difluorophenyl)methylcarbamoyl-2-oxoimidazoline-1-carboxylate (Intermediate 6, 50 mg, 0.13 mmol) and 7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl triflate (68 mg, 0.19 mmol) were added to dioxane (1 mL), followed by tris(dibenzylideneacetone)dipalladium (8 mg, 0.012 mmol), 1,1-bis(diphenylphosphino)ferrocene (7 mg, 0.012 mmol), and potassium carbonate (3 mg, 0.26 mmol). The mixture was stirred at 110 C. under a nitrogen atmosphere for 2 h. After completion of the reaction, the system was cooled to room temperature. The mixture was added to water (2 mL) and extracted with ethyl acetate (2 mL*2). The combined organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=85:15) to give tert-butyl (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)imidazoline-4-carboxamide (65 mg, 0.11 mmol, yield: 85%) as a yellow oil. LCMS (ESI) m/z: 591[M+H].sup.+.

Step 4: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)imidazoline-4-carboxamide

[0383] Tert-butyl (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)imidazoline-4-carboxamide (65 mg, 0.11 mmol) was added to a mixed solution of dichloromethane (0.8 mL) and trifluoroacetic acid (0.2 mL). The mixture was stirred at room temperature for 1 h and concentrated. The crude product was purified by high-performance liquid chromatography (column: CSH C18 OBD column 30150 mm, 5 m; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 30% B to 90% B within 8 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)imidazoline-4-carboxamide (26.66 mg, 0.054 mmol, yield: 49%) as a white solid. LCMS (ESI) m/z: 490.85[M+H].sup.+. HNMR (400 MHz, DMSO-d6): ppm 8.76-8.67 (m, 1H), 8.41-8.29 (m, 1H), 8.01-7.33 (m, 4H), 5.86-4.84 (m, 1H), 3.96-3.39 (m, 2H), 3.27-3.07 (m, 3H).

Example 5: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-2-yl)imidazolidine-4-carboxamide (Compound 5)

##STR00068## ##STR00069##

Step 1: Synthesis of 2-hydroxy-4-(trifluoromethyl)-7,8-dihydroquinolin-5(6H)-one

[0384] Cyclohexane-1,3-dione (35 g, 0.31 mol) was dissolved in 1,2-dichloroethane (700 mL). Ethyl 4,4,4-trifluoro-3-oxobutanoate (86.25 g, 0.46 mol), ammonium acetate (120.36 g, 1.55 mol), and 4-dimethylaminopyridine (7.56 g, 0.06 mol) were added to the solution, and the mixture was stirred at 140 C. for 16 h. After completion of the reaction, the system was cooled to room temperature, poured into ice water, and extracted with dichloromethane (300 mL*2). The combined organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=80:20) to give 2-hydroxy-4-(trifluoromethyl)-7,8-dihydroquinolin-5(6H)-one (12.24 g, 0.05 mol, yield: 16%) as a yellow solid. LCMS (ESI) m/z: 232[M+H].sup.+.

Step 2: Synthesis of 4-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-2,5-diol

[0385] 2-Hydroxy-4-(trifluoromethyl)-7,8-dihydroquinolin-5(6H)-one (12.23 g, 0.05 mol) was dissolved in methanol (200 mL), and sodium borohydride (18.91 g, 0.5 mol) was added at 0 C. The mixture was stirred at room temperature for 6 h. After completion of the reaction, the mixture was poured into ice water and extracted with dichloromethane (200 mL*2). The organic layer was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product 4-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-2,5-diol (3.43 g) as a yellow oil, which was used in the next step without purification. LCMS (ESI) m/z: 234[M+H].sup.+.

Step 3: Synthesis of 4-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-2-ol

[0386] 4-(Trifluoromethyl)-5,6,7,8-tetrahydroquinolin-2,5-diol (3.43 g, 14.7 mmol) was placed into a 1 L reaction flask. Trifluoroacetic acid (400 mL) was added, followed by triethylsilane (3.41 g, 29.4 mmol) at 0 C. The mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure and extracted with water (50 mL) and ethyl acetate (30 mL*2). The combined organic layer was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=40:60) to give 4-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-2-ol (1.33 g, 5.9 mmol, yield: 40%) as a yellow solid. LCMS (ESI) m/z: 218[M+H].sup.+.

Step 4: Synthesis of 4-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-2-yl triflate

[0387] 4-(Trifluoromethyl)-5,6,7,8-tetrahydroquinolin-2-ol (1.31 g, 5.9 mmol) was dissolved in dichloromethane (200 mL), and triflic anhydride (3.31 g, 11.8 mmol) and triethylamine (1.78 g, 17.7 mmol) were added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was extracted with water (50 mL) and dichloromethane (50 mL*2). The combined organic layer was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=30:70) to give 4-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-2-yl triflate (600 mg, 1.7 mmol, yield: 28%) as a yellow oil. LCMS (ESI) m/z: 218[M+H].sup.+.

Step 5: Synthesis of tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-2-yl)imidazolidine-1-carboxylate

[0388] 4-(Trifluoromethyl)-5,6,7,8-tetrahydroquinolin-2-yl triflate (600 mg, 1.7 mmol) was dissolved in dioxane (20 mL). Bis(dibenzylideneacetone)palladium (96 mg, 0.17 mmol), 1,1-bis(diphenylphosphino)ferrocene (94 mg, 0.17 mmol), potassium carbonate (46 mg, 0.34 mmol), and tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (Intermediate 6, 661 mg, 1.7 mmol) was added and stirred at 100 C. in the presence of protective nitrogen for 2 h. After completion of the reaction, the mixture was extracted with water (20 mL) and ethyl acetate (20 mL*2). The combined organic layer was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=30:70) to give tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-2-yl)imidazolidine-1-carboxylate (160 mg, 0.27 mmol, yield: 16%) as a yellow solid. LCMS (ESI) m/z: 589[M+H].sup.+.

Step 6: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-2-yl)imidazolidine-4-carboxamide

[0389] Tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-2-yl)imidazolidine-1-carboxylate (160 mg, 0.27 mmol) was placed into a 100 mL reaction flask, and a solution of hydrogen chloride in dioxane (20 mL, 4 mol/L) was added. The mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (column: XBridge Prep OBD C18, 30150 mm, 5 um, mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile, flow rate: 60 mL/min, elution gradient: mobile phase B increased from 15% to 45% within 8 min, detection wavelength: 220 nm, retention time: 7.90 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-2-yl)imidazolidine-4-carboxamide (8.22 mg, 0.016 mmol, yield: 5.9%) as a white solid. LCMS (ESI) m/z: 489.10[M+H].sup.+. HNMR (400 MHz, DMSO-d.sub.6): ppm 8.38-8.28 (m, 1H), 7.83-7.33 (m, 3H), 5.70-4.71 (m, 1H), 3.91-3.35 (m, 2H), 3.19-3.06 (m, 3H), 2.96-2.85 (m, 1H), 2.83-2.71 (m, 3H), 1.89-1.73 (m, 4H).

Examples 6a and 6b: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-3-(R)-5-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-2-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide and (S)N-(3-chloro-2,4-difluorophenyl)-3-(S)-5-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-2-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide

##STR00070##

[0390] (S)N-(3-Chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-4-carboxamide (Compound 3, 100 mg, 0.20 mmol) and sodium borohydride (16 mg, 0.41 mmol) were added to methanol (10.00 mL) and stirred at room temperature for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The obtained crude product was purified by high-performance liquid chromatography (column: YMC-Actus Triart C18, 30*150 mm, 5 m; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 62% B within 10 min; wavelength: 220 nm; retention time: 8.45 min and 9.28 min) to give Compound 6a (8.84 mg, 0.0180 mmol, yield: 8.75%) as a white solid and Compound 6b (11.72 mg, 0.0239 mmol, yield: 11.47%) as a white solid.

Compound 6a: Earlier Peak.

[0391] LCMS (ESI) m/z: 491.15[M+H].sup.+; HNMR (400 MHz, DMSO-d.sub.6): ppm 8.38-8.28 (m, 1H), 7.81-7.64 (m, 1H), 7.62-7.35 (m, 2H), 5.31-5.22 (m, 2H), 4.87-4.74 (m, 1H), 3.53-3.47 (m, 2H), 3.19-2.96 (m, 4H), 2.95-2.72 (m, 1H), 2.42-2.32 (m, 1H), 1.95-1.90 (m, 1H). Chiral HPLC: column CHIRALPAK ID-3 4.6*50 mm, 3 um; mobile phase A: (0.1% diethylamine) n-hexane, mobile phase B: ethanol, mobile phase A:mobile phase B=70:30; flow rate: 1.0 mL/min; temperature: 25 C.; retention time: 1.57 min.

Compound 6b: Later Peak.

[0392] LCMS (ESI) m/z: 491.15[M+H].sup.+; 1HNMR (400 MHz, DMSO-d.sub.6): ppm 8.38-8.28 (m, 1H), 7.79-7.65 (m, 1H), 7.63-7.39 (m, 2H), 5.33-5.28 (m, 1H), 5.21-5.17 (m, 1H), 4.88-4.77 (m, 1H), 3.53-3.48 (m, 1H), 3.42-3.37 (m, 1H), 3.29-3.07 (m, 4H), 2.88-2.64 (m, 1H), 2.36-2.27 (m, 1H), 2.01-1.93 (m, 1H). Chiral HPLC: column CHIRALPAK ID-3 4.6*50 mm, 3 um; mobile phase A: (0.1% diethylamine) n-hexane, mobile phase B: ethanol, mobile phase A:mobile phase B=70:30; flow rate: 1.0 mL/min; temperature: 25 C.; retention time: 1.92 min.

Example 7: Synthesis of (2S,3S,4S)N-(5-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-methyl-5-oxo-1-(4-(trifluoromethyl)-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-2-yl)pyrrolidine-2-carboxamide (Compound 7)

##STR00071##

Step 1: Synthesis of (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-N,2,2-trimethyl-6-oxo-5-(4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)tetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxamide

[0393] 4-(Trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl triflate (40 mg, 0.12 mmol) was stirred with (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-N,2,2-trimethyl-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxamide (Intermediate 3, 43 mg, 0.12 mmol), tris(dibenzylideneacetone)dipalladium (7 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (14 mg, 0.02 mmol), and cesium carbonate (78 mg, 0.24 mmol) in toluene (4 mL) at 100 C. for 12 h. The mixture was then filtered, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=12:88) to give (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-N,2,2-trimethyl-6-oxo-5-(4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)tetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxamide (20 mg, 0.03 mmol, yield: 31%) as a yellow solid. LCMS (ESI) m/z: 546 (M+H).sup.+.

Step 2: Synthesis of (2S,3S,4S)N-(5-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-methyl-5-oxo-1-(4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)pyrrolidine-2-carboxamide

[0394] A mixture of (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-N,2,2-trimethyl-6-oxo-5-(4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)tetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxamide (0.02 g, 0.04 mmol) in dichloromethane (2 mL) was added to boron trichloride (0.01 g 0.18 mmol). The mixture was stirred at 20 C. for 2 h, poured into saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by high-performance liquid chromatography (column type: Xsele CSH C18 OBD column 30*150 mm, 5 m, mobile phase A: 0.05% formic acid in water, mobile phase B: acetonitrile; flow rate: 60 mL/min; elution gradient: mobile phase B from 15% to 76% within 8 min, wavelength: 220 nm, retention time: 7.73 min) to give (2S,3S,4S)N-(5-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-methyl-5-oxo-1-(4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)pyrrolidine-2-carboxamide (1.77 mg, 0.01 mmol, yield: 9%) as a white solid. LCMS (ESI) m/z: 506.05 (M+H).sup.+. 1H NMR (400 MHz, DMSO-d6) 8.45-8.17 (m, 1H), 7.99-7.54 (m, 1H), 5.68-5.61 (m, 1H), 5.17-5.03 (m, 1H), 4.86-4.74 (m, 2H), 4.24-4.20 (m, 1H), 4.08-4.03 (m, 1H), 3.15-3.01 (m, 4H), 2.95-2.85 (m, 1H), 2.25-2.08 (m, 2H).

Examples 8a and 8b: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-3-(S)-5-hydroxy-5-methyl-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide and (S)N-(3-chloro-2,4-difluorophenyl)-3-(R)-5-hydroxy-5-methyl-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide

##STR00072##

[0395] (S)N-(3-Chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-4-carboxamide (Compound 3, 40 mg, 0.07 mmol) was dissolved in anhydrous ethyl ether (1 mL), and methylmagnesium bromide (2.8 mol/L in 2-methyltetrahydrofuran, 0.1 mL, 0.28 mmol) was added dropwise at 0 C. The mixture was stirred at 0 C. for 2 h. After completion of the reaction, the mixture was quenched with ice water (10 mL) and filtered. The filtrate was extracted with ethyl acetate (5 mL*2). The organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The obtained crude product was purified by high-performance liquid chromatography (column: Xselect CSH C18 OBD Column 30*150 mm, 5 m; mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 20% B to 64% B within 10 min; wavelength: 220 nm; retention time 1: 7.02 min, retention time 2: 8.83 min) to give a compound earlier peak Compound 8a (1.91 mg, 0.003 mmol, yield: 5.38%) as a white solid and a compound later peak Compound 8b (2.55 mg, 0.005 mmol, yield: 7.30%) as a white solid.

Compound 8a: Earlier Peak.

[0396] LCMS (ESI) m/z: 505.00[M+H].sup.+; HNMR (400 MHz, DMSO-d.sub.6): ppm 8.36-8.32 (m, 1H), 7.75-7.61 (m, 1H), 7.60-7.38 (m, 2H), 5.28-5.22 (m, 1H), 4.88-4.75 (m, 1H), 3.53-3.47 (m, 1H), 3.39-3.37 (m, 1H), 3.19-3.11 (m, 3H), 3.03-2.91 (m, 1H), 2.87-2.83 (m, 1H), 2.15-2.11 (m, 2H), 1.47-1.45 (m, 3H). Chiral HPLC: CHIRALPAK IA-3 4.6*50 mm, 3 um; mobile phase A: (0.1% diethylamine) n-hexane, mobile phase B: ethanol; mobile phase A:mobile phase B=80:20; flow rate: 1 mL/min; temperature: 25 C.; retention time: 1.64 min.

Compound 8b: Later Peak.

[0397] LCMS (ESI) m/z: 505.00[M+H].sup.+; HNMR (400 MHz, DMSO-d.sub.6): ppm 8.36-8.33 (m, 1H), 7.80-7.62 (m, 1H), 7.60-7.36 (m, 2H), 5.30-5.26 (m, 1H), 4.85-4.75 (m, 1H), 3.91-3.79 (m, 0.5H), 3.53-3.46 (m, 1.5H), 3.17-3.09 (m, 3H), 3.05-2.90 (m, 1H), 2.88-2.74 (m, 1H), 2.21-2.12 (m, 2H), 1.44-1.35 (m, 3H). Chiral HPLC: CHIRALPAK IA-3 4.6*50 mm, 3 um; mobile phase A: (0.1% diethylamine) n-hexane, mobile phase B: ethanol; mobile phase A:mobile phase B=80:20; flow rate: 1 mL/min; temperature: 25 C.; retention time: 2.67 min.

Examples 9a and 9b: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-7H-cyclopenta[b]pyridin-2-yl)imidazolidine-4-carboxamide and (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-7H-cyclopenta[b]pyridin-2-yl)imidazolidine carboxamide

##STR00073##

Step 1: Synthesis of tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(5-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-2-yl)imidazolidine-1-carboxylate

[0398] Tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-2-yl)imidazolidine-1-carboxylate (500 mg, 0.85 mmol) was dissolved in methanol (10 mL), and sodium borohydride (48 mg, 1.27 mmol) was then added. The mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was poured into water (30 mL) and extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=40:60) to give tert-butyl (4S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(5-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-2-oxoimidazolidine-1-carboxylate (360 mg, 0.60 mmol, yield: 71%) as a yellow solid. LCMS (ESI) m/z: 591[M+H].sup.+;

Step 2: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-7H-cyclopenta[b]pyridin-2-yl)imidazolidine-4-carboxamide (Compound 9a) and (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-7H-cyclopenta[b]pyridin-2-yl)imidazolidine-4-carboxamide (Compound 9b)

[0399] Tert-butyl (4S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(5-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-2-oxoimidazolidine-1-carboxylate (200 mg, 0.34 mmol) and pyridinium p-toluenesulfonate (170 mg, 0.38 mmol) were dissolved in 1,2-dichloroethane (10 mL) and stirred at 100 C. for 6 h. After completion of the reaction, the system was cooled to room temperature. Water (20 mL) was added, and the mixture was extracted with dichloromethane (5 mL*2). The organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The obtained crude product was purified by high-performance liquid chromatography (column: XBridge Shield RP18 OBD Column, 19*150 mm, 5 m; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 30% B to 70% B within 10 min; wavelength: 220 nm; retention time: 9.12 min) to give 40 mg of a mixture of rotamers, which was subjected to chiral resolution (chiral column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 m; mobile phase A: 0.1% diethylamine in n-hexane, mobile phase B: ethanol; flow rate: 20 mL/min; gradient: 20% B to 20% B within 11 min; wavelength: 220 nm; retention time 1: 9 min, retention time 2: 10.3 min) to give rotamer 1 (Compound 9a) (4.95 mg, 0.01 mmol, yield: 3.09%) as a white solid and rotamer 2 (Compound 9b) (14.95 mg, 0.03 mmol, yield: 9.34%) as a white solid.

Compound 9a: Rotamer 1, Earlier Peak.

[0400] LCMS (ESI) m/z: 473.00[M+H].sup.+; HTEM (400 MHz, DMSO-d.sub.6): ppm: 8.42-8.25 (m, 1H), 8.11-7.41 (m, 2H), 7.40-7.14 (m, 2H), 7.13-6.80 (m, 1H), 5.44-4.72 (m, 1H), 3.72-3.48 (m, 3H), 3.39-3.14 (m, 4H).

[0401] Chiral HPLC: CHIRAL Cellulose-SB 4.6*100 mm, 3 um; mobile phase A: (0.1% formic acid) n-hexane, mobile phase B: ethanol; mobile phase A:mobile phase B=80:20; flow rate: 1 mL/min; temperature: 25 C.; retention time: 3.52 min.

Compound 9b: Rotamer 2, Later Peak.

[0402] LCMS (ESI) m/z: 472.95[M+H].sup.+; HNMR (400 MHz, DMSO-d.sub.6): ppm: 8.38-8.24 (m, 1H), 7.81-7.34 (m, 2H), 7.33-7.04 (m, 2H), 7.03-6.78 (m, 1H), 5.32-4.51 (m, 1H), 3.73-3.44 (m, 3H), 3.41-3.09 (m, 4H).

[0403] Chiral HPLC: CHIRAL Cellulose-SB 4.6*100 mm, 3 um; mobile phase A: (0.1% formic acid) n-hexane, mobile phase B: ethanol; mobile phase A:mobile phase B=80:20; flow rate: 1 mL/min; temperature: 25 C.; retention time: 3.94 min.

Example 10: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(1-methyl-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-5-yl)-2-oxoimidazolidine-4-carboxamide (Compound 10)

##STR00074## ##STR00075##

Step 1: Synthesis of 2-chloro-N-methyl-4-(trifluoromethyl)pyridin-3-amine

[0404] 2-Chloro-3-fluoro-4-(trifluoromethyl)pyridine (10.00 g, 0.05 mol) was weighed into a reaction flask, and a solution of methylamine in water (20.00 mL, 25%-30% content) was added. The mixture was stirred at room temperature for 8 h. After completion of the reaction, water (100 mL) was added, and the mixture was extracted with dichloromethane (50 mL*3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and concentrated to give the crude product 2-chloro-N-methyl-4-(trifluoromethyl)pyridin-3-amine (6.52 g) as a yellow oil, which was used in the next step without purification. LCMS (ESI) m/z: 2112[M+H]+.

Step 2: Synthesis of N.SUP.2.-(4-methoxybenzyl)-N.SUP.3.-methyl-4-(trifluoromethyl)pyridine-2,3-diamine

[0405] 2-Chloro-N-methyl-4-(trifluoromethyl)pyridin-3-amine (6.32 g, 30.01 mmol) was taken into a reaction flask, and p-methoxybenzylamine (12.00 mL) was added. The mixture was stirred at 140 C. overnight. After completion of the reaction, the system was cooled to room temperature. Water (100 mL) was added, and the mixture was extracted with dichloromethane (50 mL*3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=50:50) to give N.sup.2-(4-methoxybenzyl)-N.sup.3-methyl-4-(trifluoromethyl)pyridine-2,3-diamine (3.58 g, 11.47 mmol, yield: 38%) as a yellow oil. LCMS (ESI) m/z: 312[M+H]+.

Step 3: Synthesis of N.SUP.3.-methyl-4-(trifluoromethyl)pyridine-2,3-diamine

[0406] The N.sup.2-(4-methoxybenzyl)-N.sup.3-methyl-4-(trifluoromethyl)pyridine-2,3-diamine (2.00 g, 10.47 mmol) was dissolved in a mixed solution of trifluoroacetic acid (1.00 mL) and dichloromethane (5.00 mL), and the mixture was stirred at 60 C. overnight. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent, added with dichloromethane (20 mL) to slurry for 30 min, and filtered. The filter cake was washed with dichloromethane (10 mL*3) and dried to give the crude product N.sup.3-methyl-4-(trifluoromethyl)pyridine-2,3-diamine (2.2 g) as a white solid, which was used in the next step without purification. LCMS (ESI) m/z: 192[M+H]+.

Step 4: Synthesis of 1-methyl-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine

[0407] N.sup.3-Methyl-4-(trifluoromethyl)pyridine-2,3-diamine (1.35 g, 6.71 mmol) was weighed into a reaction flask, and formic acid (10.00 mL) was added for dissolution. The mixture was stirred at 100 C. overnight. After completion of the reaction, the system was cooled to room temperature. Water (50 mL) was added, and the mixture was extracted with dichloromethane (20 mL*3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give the crude product 1-methyl-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine (1.35 g) as a yellow oil, which was used in the next step without purification. LCMS (ESI) m/z: 202[M+H]+.

Step 5: Synthesis of 1-methyl-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine 4-oxide

[0408] 1-Methyl-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine (1.00 g, 4.97 mmol) was weighed into a reaction flask, and dichloromethane (10.00 mL) was added for dissolution. m-Chloroperoxybenzoic acid (1.72 g, 9.94 mmol) was added to the system, and the mixture was stirred at room temperature for 6 h. After completion of the reaction, the crude product was purified by silica gel column chromatography (dichloromethane:methanol=65:35) to give 1-methyl-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine 4-oxide (0.52 g, 2.38 mmol, yield: 48%) as a white solid. LCMS (ESI) m/z: 218[M+H]+.

Step 6: Synthesis of 5-chloro-1-methyl-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine

[0409] 1-Methyl-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine 4-oxide (400 mg, 1.84 mmol) was weighed into a reaction flask. N,N-Dimethylformamide (10.00 mL) was added for dissolution, followed by methanesulfonyl chloride (211 mg, 1.84 mmol). The mixture was stirred at 80 C. for 2 h. After completion of the reaction, the system was cooled to room temperature. Saturated aqueous ammonium bicarbonate solution (30 mL) was added, and the mixture was extracted with dichloromethane (10 mL*3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give the crude product 5-chloro-1-methyl-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine (350 mg) as a yellow oil, which was used in the next step without purification. LCMS (ESI) m/z: 236[M+H]+.

Step 7: Synthesis of tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(1-methyl-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-5-yl)-2-oxoimidazolidine-1-carboxylate

[0410] 5-Chloro-1-methyl-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine (100 mg, 0.42 mmol) was weighed into a reaction flask. 1,4-Dioxane (1.00 mL) was added for dissolution, followed by tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(1-methyl-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-5-yl)-2-oxoimidazolidine-1-carboxylate (165 mg, 0.42 mmol), tris(dibenzylideneacetone)dipalladium (51 mg, 0.08 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (26 mg, 0.08 mmol), and cesium carbonate (211 mg, 1.84 mmol). The mixture was stirred at 80 C. under a nitrogen atmosphere for 2 h. After completion of the reaction, the system was cooled to room temperature. Water (30 mL) was added, and the mixture was extracted with dichloromethane (10 mL*3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give the crude product tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(1-methyl-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-5-yl)-2-oxoimidazolidine-1-carboxylate (350 mg) as a yellow oil, which was used in the next step without purification. LCMS (ESI) m/z: 589[M+H]+.

Step 8: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(1-methyl-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-5-yl)-2-oxoimidazolidine-4-carboxamide

[0411] Tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(1-methyl-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-5-yl)-2-oxoimidazolidine-1-carboxylate (350 mg, 0.59 mmol) was dissolved in a mixed solution of trifluoroacetic acid (1.00 mL) and dichloromethane (5.00 mL) and stirred at room temperature for 2 h. The mixture was concentrated under a vacuum to give a crude product. The crude product was purified by high-performance liquid chromatography (column: Xbridge Shield RP18 OBD Column, 19*150 mm, m, mobile phase A: 10 mmol/L formic acid in water, mobile phase B: acetonitrile, flow rate: 60 mL/min, elution gradient: mobile phase B increased from 20% to 50% within 9.33 min, detection wavelength: 220 nm, retention time: 7.58 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(1-methyl-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-5-yl)-2-oxoimidazolidine-4-carboxamide (84.70 mg, 0.173 mmol, yield: 29%) as a white solid. LCMS (ESI) m/z: 489.05[M+H]+; HNMR (400 MHz, DMSO-d.sub.6): ppm 8.57 (s, 1H), 8.47 (s, 1H), 8.37 (brs, 1H), 7.45 (brs, 1H), 7.24 (s, 1H), 5.85-4.75 (m, 1H), 3.92 (s, 3H), 3.72-3.32 (m, 2H), 3.31-3.12 (m, 3H).

Example 11: (S)N-(3-chloro-2,4-difluorophenyl)-3-(5,5-difluoro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-2-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide (Compound 11)

##STR00076##

Step 1: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-6,7-dihydrospiro[cyclopentadienyl[b]pyridine-5, 2-[1,3]dithiolane]-2-yl)imidazolidine-4-carboxamide

[0412] Tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-2-yl)imidazolidine-1-carboxylate (100 mg, 0.17 mmol) was taken into a reaction flask. Acetic acid (2.00 mL) was added for dissolution, followed by ethane-1,2-dithiol (24 mg, 0.25 mmol) and aluminum trichloride (5 mg, 0.03 mmol). The mixture was stirred at 100 C. overnight. After completion of the reaction, the system was cooled to room temperature. Water (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL*3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=35:65) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-6,7-dihydrospiro[cyclopenta[b]pyridine-5,2-[1,3]dithiolane]-2-yl)imidazolidine-4-carboxamide (80 mg, 0.14 mmol, yield: 83%) as a yellow solid. LCMS (ESI) m/z: 565[M+H]+.

Step 2: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-3-(5,5-difluoro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopentadienyl[b]pyridin-2-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide

[0413] Iodosuccinimide (35 mg, 0.18 mmol) was dissolved in dichloromethane (5.00 mL), and the mixture was cooled to 78 C. (S)N-(3-Chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-6,7-dihydrospiro[cyclopenta[b]pyridine-5,2-[1,3]dithiolane]-2-yl)imidazolidine-4-carboxamide (50 mg, 0.08 mmol) was then added, and at this temperature, pyridinium hydrofluoride (5 mg, 0.18 mmol) was added. The mixture was stirred at 78 C. for 1 h. After completion of the reaction, water (10 mL) was added to the system, and the mixture was extracted with dichloromethane (5 mL*3). The organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by high-performance liquid chromatography (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 m; mobile phase A: 0.05% formic acid in water, mobile phase B: acetonitrile; flow rate: 60 mL; elution gradient: mobile phase B increased from 35% to 70% within 8 min; detection wavelength: 220 nm; retention time: 7.67 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-3-(5,5-difluoro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide (4.66 mg, 0.008 mmol, yield: 10%) as a white solid. LCMS (ESI) m/z: 511.20 (M+H).sup.+; HNMR (400 MHz, DMSO-d.sub.6): ppm 8.56 (s, 1H), 7.78-7.35 (m, 3H), 5.01-4.75 (m, 1H), 3.62-3.41 (m, 2H), 3.33-3.11 (m, 5H), 2.80-2.53 (m, 2H).

Example 12: (S)N-(3-chloro-2,4-difluorophenyl)-3-(7,7-difluoro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide (Compound 12)

##STR00077## ##STR00078##

Step 1: Synthesis of 2-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one

[0414] 1,3-Cyclopentanedione (100.00 g, 1.02 mol), ethyl 4,4,4-trifluoro-3-oxobutanoate (281.50 g, 1.53 mol), ammonium acetate (392.00 g, 5.09 mol), and 4-dimethylaminopyridine (24.91 g, 0.20 mol) were dissolved in dichloroethane (1 L) and stirred in an autoclave at 140 C. overnight. After completion of the reaction, the system was cooled to room temperature. The mixture was poured into water (500 mL) and extracted with dichloromethane (500 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=80:20) to give 2-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one (30.00 g, 0.14 mol, yield: 14%) as a pink solid. LCMS(ESI) m/z: 218[M+H].sup.+.

Step 2: Synthesis of 4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-2,5-diol

[0415] 2-Hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one (30.00 g, 138.15 mmol) was dissolved in methanol (600 mL) solution. Sodium borohydride (26.13 g, 690.77 mmol) was added and stirred at room temperature for 12 h. After completion of the reaction, the obtained mixture was concentrated under reduced pressure, poured into water (500 mL), and extracted with dichloromethane (500 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product 4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-2,5-diol (35.00 g) as a white solid. The crude product was directly used in the next step without purification. LCMS(ESI) m/z: 220[M+H].sup.+.

Step 3: Synthesis of 4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-ol

[0416] 4-(Trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-2,5-diol (30.00 g, 0.13 mol) was dissolved in a mixed solution of triethylsilane (60 mL) and trifluoroacetic acid (300 mL), and the mixture was stirred at 50 C. for 2 h. After completion of the reaction, the system was cooled to room temperature. The obtained mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=55:45) to give 4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-ol (15.02 g, 0.07 mmol, yield: 54%) as a yellow oil. LCMS(ESI) m/z: 204[M+H].sup.+.

Step 4: Synthesis of 2-chloro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine

[0417] 4-(Trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-ol (10.00 g, 49.21 mmol) was added to phosphorus oxychloride (200 mL) solution at room temperature. The mixture was stirred at 60 C. for 12 h. After completion of the reaction, the system was cooled to room temperature. The obtained mixture was concentrated under reduced pressure to give the crude product 2-chloro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (10.01 g) as a yellow oil. The crude product was directly used in the next step without purification. LCMS(ESI) m/z: 222[M+H].sup.+.

Step 5: Synthesis of 2-chloro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-1-oxide

[0418] 2-Chloro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (1.00 g, 4.52 mmol) was dissolved in dichloromethane (20 mL) solution. m-Chloroperoxybenzoic acid (3.12 g, 18.04 mmol, 85% content) was added at room temperature. The mixture was stirred at 40 C. overnight. After completion of the reaction, the system was cooled to room temperature. The mixture was poured into water (10 mL) and extracted with dichloromethane (10 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=45:55) to give 2-chloro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-1-oxide (350 mg, 1.47 mmol, yield: 34%) as a yellow oil. LCMS(ESI) m/z: 238[M+H].sup.+.

Step 6: Synthesis of 2-chloro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate

[0419] 2-Chloro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-1-oxide (350 mg, 1.47 mmol) was dissolved in acetic anhydride (10 mL). The mixture was stirred at 100 C. for 2 h. After completion of the reaction, the system was cooled to room temperature and directly concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=70:30) to give 2-chloro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (350 mg, 1.25 mmol, yield: 85%) as a yellow oil. LCMS(ESI) m/z: 280[M+H].sup.+.

Step 7: Synthesis of 2-chloro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

[0420] 2-Chloro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (350 mg, 1.25 mmol) and potassium hydroxide (350 mg, 6.26 mmol) were dissolved in a solution of ethanol (10 mL) and water (1 mL), and the mixture was stirred at room temperature for 1 h. After completion of the reaction, the aqueous phase was adjusted to pH 4 with 2 mol/L aqueous hydrochloric acid solution. The mixture was extracted with dichloromethane (10 mL*2). The combined organic layer was dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure. The crude product was eluted by silica gel column chromatography (petroleum ether:ethyl acetate=90:10) to give 2-chloro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (200 mg, 0.84 mmol, yield: 67%) as a yellow oil. LCMS(ESI) m/z: 238[M+H].sup.+.

Step 8: Synthesis of 2-chloro-4-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one

[0421] 2-Chloro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (200 mg, 0.84 mmol) and Dess-Martin periodinane (714 mg, 1.68 mmol) were dissolved in dichloromethane (4 mL) solution, and the mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate solution (10 mL) and saturated sodium bisulfite solution (10 mL). The mixture was extracted with dichloromethane (10 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=90:10) to give 2-chloro-4-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (150 mg, 0.63 mmol, yield: 76%) as a yellow oil. LCMS(ESI) m/z: 236[M+H].sup.+.

Step 9: Synthesis of (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(7-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-1-carboxylate

[0422] 2-Chloro-4-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (150 mg, 0.64 mmol), (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (Intermediate 6, 198 mg, 0.51 mmol), palladium acetate (14 mg, 0.06 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (14 mg, 0.06 mmol), and potassium carbonate (263 mg, 1.91 mmol) was dissolved in dioxane (3 mL) solution and reacted at 80 C. for 2 h. After completion of the reaction, the system was cooled to room temperature. The reaction solution was poured into water (10 mL). The obtained mixture was extracted with ethyl acetate (10 mL2). The combined organic layer was washed with saturated salt water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=60:40) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(7-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-1-carboxylate (140 mg, 0.23 mmol, yield: 37%) as a yellow oil. LCMS(ESI) m/z: 590[M+H].sup.+.

Step 10: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[b]pyridine-7,2-[1,3]dithiolane]-2-yl)imidazolidine-4-carboxamide

[0423] (S)-Tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(7-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-1-carboxylate (70 mg, 0.12 mmol) was dissolved in glacial acetic acid (5 mL). Ethanedithiol (33 mg, 0.30 mmol) was then added, and the reaction system was replaced with nitrogen three times. The obtained mixture was stirred at 100 C. overnight. After completion of the reaction, the system was cooled to room temperature. The reaction solution was poured into water (10 mL). The obtained mixture was extracted with ethyl acetate (5 mL3). The combined organic layer was washed with saturated salt water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=60:40) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[b]pyridine-7,2-[1,3]dithiolane]-2-yl)imidazolidine-4-carboxamide (60 mg, 0.11 mmol, yield: 89%) as a yellow solid. LCMS(ESI) m/z: 565[M+H].sup.+.

Step 11: Synthesis of (S)N-(3-chloro-2,4-difluorophenyl)-3-(7,7-difluoro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide

[0424] N-Bromosuccinimide (16 mg, 0.09 mmol) was dissolved in dichloromethane (2.00 mL). Pyridine hydrofluorate (5 mg, 0.05 mmol) was added, and the obtained mixture was stirred at 78 C. for 0.5 h. (S)N-(3-Chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[b]pyridine-7,2-[1,3]dithiolane]-2-yl)imidazolidine-4-carboxamide (25 mg, 0.04 mmol) was then added at 78 C. The obtained mixture was stirred at 40 C. for 2 h. After completion of the reaction, the mixture was poured into water (10 mL) and extracted with dichloromethane (10 mL*2). The combined organic phase was dried over anhydrous sodium sulfate and suction filtered. The filtrate was spin-dried. The crude product was purified by high-performance liquid chromatography (column: Xselect CSH OBD Column 30*150 mm, 5 um; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; elution gradient: mobile phase B increased from 40% to 60% within 10 min; detection wavelength: 220 nm; retention time: 8.93 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-3-(7,7-difluoro-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide (3.15 mg, 0.006 mmol, yield: 14%) as a white solid. HNMR (400 MHz, CDCl.sub.3): ppm 8.71 (s, 1H), 7.94-7.88 (m, 1H), 7.18-7.13 (m, 1H), 4.99-4.95 (m, 1H), 3.66-3.56 (m, 2H), 3.26 (s, 3H), 3.16-3.10 (m, 2H), 2.74-2.63 (m, 2H). LCMS(ESI) m/z: 510.80[M+H].sup.+.

Example 13: (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(7-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-4-carboxamide (Compound 13)

##STR00079##

[0425] (S)-Tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(7-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-1-carboxylate (50 mg, 0.08 mmol) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (5 mL), and the system was stirred at room temperature for 1 h. After completion of the reaction, the obtained mixture was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (column: XBridge Shield RP18 OBD column, 30150 mm, m; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 70% B within 8 min; wavelength: 220 nm; retention time: 7.53 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(7-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-4-carboxamide (10.68 mg, 0.02 mmol, yield: 26%) as a white solid. HNMR (400 MHz, DMSO-d.sub.6): ppm 8.78 (s, 1H), 8.59-8.53 (m, 1H), 7.80 (s, 1H), 7.53-7.47 (m, 1H), 4.89-4.86 (m, 1H), 3.52-3.49 (m, 1H), 3.24-3.03 (m, 6H), 2.81-2.67 (m, 2H). LCMS (ESI) m/z: 488.80 [M+H].sup.+.

Example 14: (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)imidazolidine-4-carboxamide (Compound 14)

##STR00080## ##STR00081##

[0426] Step 1: a reaction system of ethyl 4,4,4-trifluoro-3-oxobutanoate (10.00 g, 54.32 mmol), trifluoroacetic acid (3.10 g, 27.16 mmol), and concentrated sulfuric acid (1.33 g, 13.58 mmol) was reacted at 90 C. overnight in the presence of protective nitrogen. After completion of the reaction, the system was cooled to room temperature. The mixture was added dropwise to saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (25 mL). The aqueous phase was adjusted to pH 4 with 2 mol/L aqueous hydrochloric acid solution and extracted with ethyl acetate (25 mL*2). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product 4,4,4-trifluoro-3-oxobutanoic acid (5.00 g) as a colorless oil. The crude product was directly used in the next step without purification. LCMS (ESI) m/z: 157 [M+H].sup.+.

[0427] Step 2: 4,4,4-trifluoro-3-oxobutanoic acid (5.00 g, 32.04 mmol) and methyl 5-aminothiophene-2-carboxylate (5.04 g, 32.04 mmol) were added to glacial acetic acid (100.00 mL) and reacted at 80 C. for 2 h. After completion of the reaction, the obtained mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=70:30) to give methyl 6-hydroxy-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate (1.10 g, 3.95 mmol, yield: 25%) as a yellow solid. LCMS (ESI) m/z: 278[M+H].sup.+.

[0428] Step 3: methyl 6-hydroxy-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate (1.01 g, 3.61 mmol) was dissolved in a solution of methanol (16 mL) and water (2 mL), and potassium hydroxide (606 mg, 10.83 mmol) was added. The mixture was stirred at 50 C. for 2 h. After completion of the reaction, the system was cooled to room temperature. The mixture was adjusted to pH 4 with 2 mol/L aqueous hydrochloric acid solution and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=80:20) to give 6-hydroxy-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylic acid (900 mg, 3.4 mmol, yield: 95%) as a yellow solid. LCMS (ESI) m/z: 264 [M+H].sup.+.

[0429] Step 4: 6-hydroxy-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylic acid (600 mg, 2.28 mmol) and cuprous oxide (652 mg, 4.56 mmol) were dissolved in N,N-dimethylformamide (12 mL) solution, and the mixture was stirred at 140 C. for 12 h. After completion of the reaction, the system was cooled to room temperature. The reaction solution was poured into water (20 mL). The mixture was extracted with ethyl acetate (20 mL*2). The combined organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=85:15) to give 4-(trifluoromethyl)thieno[2,3-b]pyridin-6-ol (300 mg, 1.36 mmol, yield: 60%) as a light yellow solid. LCMS(ESI) m/z: 220[M+H]+.

[0430] Step 5: 4-(trifluoromethyl)thieno[2,3-b]pyridin-6-ol (200 mg, 0.91 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (808 mg, 8 mmol) was added. Triflic anhydride (772 mg, 2.74 mmol) was added to the solution at 45 C. The mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was poured into water (10 mL) and extracted with dichloromethane (10 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=85:15) to give 4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl triflate (240 mg, 0.68 mmol, yield: 75%) as a colorless oil. LCMS(ESI) m/z: 352[M+H].sup.+.

[0431] Step 6: 4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl triflate (100 mg, 0.28 mmol), (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (Intermediate 6, 110 mg, 0.28 mmol), tris(dibenzylideneacetone)dipalladium (26 mg, 0.03 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (16 mg, 0.03 mmol), and potassium carbonate (117 mg, 0.85 mmol) was dissolved in toluene (3 mL), and the mixture was reacted at 80 C. under a nitrogen atmosphere for 2 h. After completion of the reaction, the system was cooled to room temperature. The reaction solution was poured into water (20 mL). The obtained mixture was extracted with ethyl acetate (10 mL2). The combined organic layer was washed with saturated salt water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=50:50) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)imidazolidine-1-carboxylate (100 mg, 0.17 mmol, yield: 59%) as a colorless oil. LCMS (ESI) m/z: 591 [M+H].sup.+.

[0432] Step 7: (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)imidazolidine-1-carboxylate (100 mg, 0.17 mmol) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (5 mL), and the system was stirred at room temperature for 1 h. After completion of the reaction, the obtained mixture was directly concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (column: Xselect CSH C18 OBD column 30*150 mm, 5 m; mobile phase A: 0.05% formic acid in water, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 50% B to 90% B within 8 min; wavelength: 220 nm; retention time: 6.22 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)imidazolidine-4-carboxamide (52.37 mg, 0.11 mmol, yield: 63%) as a white solid. HNMR (400 MHz, DMSO-d.sub.6): ppm 8.71-8.66 (m, 1H), 7.96-7.89 (m, 1H), 7.82-7.65 (m, 2H), 7.52-7.41 (m, 2H), 5.82-4.67 (m, 1H), 3.58-3.48 (m, 1H), 3.42-3.37 (m, 1H), 3.23-3.10 (m, 3H). LCMS (ESI) m/z: 490.95 [M+H].sup.+.

Example 15: (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)furo[2,3-b]pyridin-6-yl)imidazolidine-4-carboxamide (Compound 15)

##STR00082## ##STR00083##

[0433] Step 1: 2-chloro-4-(trifluoromethyl)pyridine (20.00 g, 110 mmol) was dissolved in tetrahydrofuran (400 mL) and cooled to 78 C. A solution of lithium diisopropylamide in tetrahydrofuran (110 mL, 220 mmol, 2 mol/L) was added dropwise. After stirring the mixture at 78 C. for 2 h, carbon dioxide gas was continuously introduced for 15 min. After completion of the reaction, saturated ammonium chloride solution (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL*2). The aqueous phase was retained, adjusted to about pH 3 with 2 mol/L aqueous hydrochloric acid solution, and extracted with ethyl acetate (50 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product 2-chloro-4-(trifluoromethyl)nicotinic acid (19.00 g) as a white solid. LCMS (ESI) m/z: 226[M+H].sup.+.

[0434] Step 2: 2-chloro-4-(trifluoromethyl)nicotinic acid (19.00 g, 85 mmol) was dissolved in N,N-dimethylformamide (400 mL). Potassium carbonate (23.50 g, 170 mmol) and iodoethane (14.58 g, 93.5 mmol) were added and stirred at room temperature for 6 h. After completion of the reaction, water (800 mL) was added, and the mixture was extracted with ethyl acetate (400 mL*3). The combined organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=70:30) to give ethyl 2-chloro-4-(trifluoromethyl)nicotinate (21.01 g, 83 mmol, yield: 97.6%) as a yellow solid. LCMS (ESI) m/z: 254[M+H].sup.+.

[0435] Step 3: ethyl 2-hydroxyacetate (21.61 g, 208 mmol) was dissolved in ethylene glycol dimethyl ether (400 mL) solution and cooled to 0 C. Sodium hydride (6.66 g, 166 mmol, 60% content) was added. The mixture was stirred at 0 C. for 1 h and gradually warmed to room temperature. Ethyl 2-chloro-4-(trifluoromethyl)nicotinate (21.01 g, 83 mmol) was then added. The system was warmed to 75 C. and stirred for 3 h. After completion of the reaction, the system was cooled to room temperature, and water (300 mL) was added. The mixture was extracted with ethyl acetate (300 mL*3). The organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=55:45) to give ethyl 3-hydroxy-4-(trifluoromethyl)furo[2,3-b]pyridine-2-carboxylate (20.31 g, 73.9 mmol, yield: 89.1%) as a yellow solid. LCMS (ESI) m/z: 276[M+H].sup.+.

[0436] Step 4: ethyl 3-hydroxy-4-(trifluoromethyl)furo[2,3-b]pyridine-2-carboxylate (20.31 g, 73.9 mmol) was dissolved in 4 mol/L aqueous hydrochloric acid solution (200 mL). The system was warmed to 100 C. and stirred for 12 h. After completion of the reaction, the system was cooled to room temperature, adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate (200 mL*3). The organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=60:40) to give 4-(trifluoromethyl)furo[2,3-b]pyridin-3(2H)-one (4.05 g, 19.95 mmol, yield: 27.1%) as a light yellow oil. LCMS (ESI) m/z: 204[M+H].sup.+.

[0437] Step 5: 4-(trifluoromethyl)furo[2,3-b]pyridin-3(2H)-one (4.01 g, 19.7 mmol) was dissolved in methanol (80 mL), and sodium borohydride (1.52 g, 40 mmol) was added. The mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was slowly added to water (100 mL) with stirring and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product 4-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-ol (4.21 g) as a white oil. The crude product was directly used in the next step without purification. LCMS (ESI) m/z: 206[M+H].sup.+.

[0438] Step 6: 4-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-ol (4.02 g, 19.5 mmol) was dissolved in dichloromethane (80 mL). Triflic anhydride (11.02 g, 39 mmol) was added dropwise and stirred at room temperature for 6 h. After completion of the reaction, the reaction solution was poured into water (100 mL) and extracted with dichloromethane (50 mL*2). The combined organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give 4-(trifluoromethyl)furo[2,3-b]pyridine (1.21 g, 6.5 mmol, yield: 33%) as a yellow oil. LCMS (ESI) m/z: 188[M+H].sup.+.

[0439] Step 7: 4-(trifluoromethyl)furo[2,3-b]pyridine (0.80 g, 4.28 mmol) was dissolved in dichloromethane (10.00 mL), and m-chloroperoxybenzoic acid (1.56 g, 8.56 mmol) was added. The mixture was stirred at 40 C. for 36 h. After completion of the reaction, saturated aqueous sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL*2). The combined organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol=90:10) to give 4-(trifluoromethyl)furo[2,3-b]pyridine-7-oxide (0.40 g, yield: 46%, 1.9 mmol) as a brown solid. LCMS (ESI) m/z: 204[M+H].sup.+.

[0440] Step 8: 4-(trifluoromethyl)furo[2,3-b]pyridine-7-oxide (300 mg, 1.48 mmol) was dissolved in acetic anhydride (6.00 mL). The mixture was stirred at 100 C. for 1 h. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure. The obtained crude product was purified by reverse phase chromatography (10% ammonium bicarbonate aqueous solution:acetonitrile=50:50) to give 4-(trifluoromethyl)furo[3,2-e]pyridin-6-yl acetate (120 mg, 0.48 mmol, yield: 33%) as a yellow oil. LCMS (ESI) m/z: 246[M+H].sup.+.

[0441] Step 9: 4-(trifluoromethyl)furo[3,2-e]pyridin-6-yl acetate (120 mg, 0.48 mmol) and potassium carbonate (202 mg, 1.47 mmol) were dissolved in ethanol (5 mL) and water (0.50 mL). The mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was extracted with dichloromethane (10 mL*2). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=50:50) to give 4-(trifluoromethyl)furo[2,3-b]pyridin-6-ol (55 mg, 0.26 mmol, yield: 55%) as a yellow oil. LCMS (ESI) m/z: 204[M+H].sup.+.

[0442] Step 10: 4-(trifluoromethyl)furo[2,3-b]pyridin-6-ol (50 mg, 0.25 mmol) was dissolved in dichloromethane (2.00 mL) at 45 C., and triflic anhydride (104 mg, 0.37 mmol) and triethylamine (49 mg, 0.49 mmol) were added. The mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was poured into water (10 mL) and extracted with dichloromethane (5 mL*3). The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=75:25) to give 4-(trifluoromethyl)furo[2,3-e]pyridin-6-yl triflate (70 mg, 0.21 mmol, yield: 85%) as a yellow solid. LCMS (ESI) m/z: 336[M+H].sup.+.

[0443] Step 10: 4-(trifluoromethyl)furo[2,3-e]pyridin-6-yl triflate (70 mg, 0.21 mmol), (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (Intermediate 6, 65 mg, 0.17 mmol), tris(dibenzylideneacetone)dipalladium (19 mg, 0.02 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (12 mg, 0.02 mmol), and potassium carbonate (86 mg, 0.63 mmol) was dissolved in dioxane (3 mL) solution, and the mixture was reacted at 80 C. under a nitrogen atmosphere for 2 h. After completion of the reaction, the system was cooled to room temperature. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (5 mL*3). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=25:75) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)furo[2,3-b]pyridin-6-yl)imidazolidine-1-carboxylate (55 mg, 0.09 mmol, yield: 46%) as a yellow oil. LCMS (ESI) m/z: 575[M+H].sup.+.

[0444] Step 12: (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)furo[2,3-b]pyridin-6-yl)imidazolidine-1-carboxylate (50 mg, 0.09 mmol) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (5 mL), and the system was stirred at room temperature for 1 h. After completion of the reaction, the obtained mixture was directly concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (column: Kinetex EVO prep C18, 30*150, 5 m; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 65% B within 10 min; wavelength: 220 nm; retention time: 9.03 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)furo[2,3-b]pyridin-6-yl)imidazolidine-4-carboxamide (12.35 mg, 0.03 mmol, yield: 30%) as a white solid. HNMR (400 MHz, DMSO-d.sub.6): ppm 8.64 (s, 1H), 8.04-8.01 (m, 1H), 7.68 (s, 1H), 7.26-7.20 (m, 1H), 6.85 (s, 1H), 5.04-4.90 (m, 2H), 3.62-3.47 (m, 2H), 3.30 (s, 3H). LCMS (ESI) m/z: 474.80[M+H].sup.+.

Example 16: (2S,3S,4S)N-(5-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-(methyl-D3)-5-oxo-1-(4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)pyrrolidine-2-carboxamide (Compound 16)

##STR00084##

[0445] Step 1: (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-2,2-dimethyl-N-(methyl-D3)-6-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide (Intermediate 4, 90 mg, 0.24 mmol), 4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl triflate (14-5, 84 mg, 0.24 mmol), potassium carbonate (99 mg, 0.72 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (14 mg, 0.024 mmol) were dissolved in toluene (5 mL), and then tris(dibenzylideneacetone)dipalladium (22 mg, 0.024 mmol) was added. The mixture was reacted at 80 C. under a nitrogen atmosphere for 2 h. After completion of the reaction, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=50:50) to give (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-N,2,2-trimethyl-6-oxo-5-(4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)tetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide (100 mg, 0.19 mmol, yield: 79.16%) as a yellow solid. LCMS(ESI) m/z: 562[M+H].sup.+.

[0446] Step 2: (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-N,2,2-trimethyl-6-oxo-5-(4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)tetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide (100 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), and then a solution of boron trichloride in dichloromethane (0.28 mL, 0.28 mmol, 1 mol/L) was added. The mixture was reacted at 0 C. for 1 h. After completion of the reaction, the reaction solution was poured into saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (10 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated to give a crude product. The crude product was purified by high-performance liquid chromatography (column: XBridge Prep OBD C18, 30150 mm, 5 um, mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile, flow rate: 60 mL/min, elution gradient: mobile phase B increased from 20% to 60% within 10 min, detection wavelength: 220 nm, retention time: 8.12 min) to give (2S,3S,4S)N-(5-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-(methyl-D3)-5-oxo-1-(4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)pyrrolidine-2-carboxamide (26.36 mg, 0.05 mmol, yield: 26.31%) as a white solid. HNMR (400 MHz, DMSO-d.sub.6): ppm 8.56-8.53 (s, 1H), 8.11-8.04 (m, 1H), 7.95-7.54 (m, 2H), 7.51-7.49 (m, 1H), 5.84-5.62 (m, 2H), 5.30-4.93 (m, 1H), 4.83-4.03 (m, 2H). LCMS (ESI) m/z: 525.30 [M+H].sup.+.

Example 17: (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)quinolin-2-yl)imidazolidine-4-carboxamide (Compound 17)

##STR00085##

[0447] Step 1: to a solution of 4-(trifluoromethyl)quinolin-2-ol (1.00 g, 4.69 mmol) in dichloromethane (10.00 mL) was added triflic anhydride (1.59 g, 5.63 mmol), pyridine (0.74 g, 9.38 mmol), and 4-dimethylaminopyridine (0.06 g, 0.47 mmol) at 0 C. The mixture was stirred at room temperature for 3 h. After completion of the reaction, the mixture was poured into water (20 mL) and extracted with dichloromethane (10 mL2). The organic layers were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, suction filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=80:20) to give 4-(trifluoromethyl)quinolin-2-yl triflate (0.98 g, 2.8 mmol, yield: 61%) as a white solid. LCMS (ESI) m/z: 346[M+H].sup.+.

[0448] Step 2: to a solution of 4-(trifluoromethyl)quinolin-2-yl triflate (200 mg, 0.58 mmol) in dioxane (5.00 mL) was added (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (Intermediate 6, 225 mg, 0.58 mmol), potassium carbonate (159 mg, 1.16 mmol), tris(dibenzylideneacetone)dipalladium (53 mg, 0.06 mmol), and 1,1-bis(diphenylphosphino)ferrocene (320 mg, 0.06 mmol). The mixture was stirred at 80 C. under a nitrogen atmosphere for 2 h. After completion of the reaction, the mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL2). The organic layers were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=60:40) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)quinolin-2-yl)imidazolidine-1-carboxylate (160 mg, 0.27 mmol, yield: 47%) as a white solid. LCMS(ESI) m/z: 585[M+H].sup.+.

[0449] Step 3: (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)quinolin-2-yl)imidazolidine-1-carboxylate (22 mg, 0.17 mmol) was added to a mixed solution of trifluoroacetic acid (1.00 mL) and dichloromethane (5.00 mL), and the system was stirred at room temperature for 2 h. After completion of the reaction, the system was directly concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (column: XBridge Prep OBD C18, 30150 mm, 5 um, mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile, flow rate: 60 mL/min, elution gradient: mobile phase B increased from 30% to 60% within 10 min, detection wavelength: 220 nm, retention time: 9.21 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)quinolin-2-yl)imidazolidine-4-carboxamide (22.78 mg, 0.05 mmol, yield: 28%) as a white solid. HNMR (400 MHz, DMSO-d.sub.6): ppm 9.00-8.94 (m, 1H), 8.05-7.81 (m, 4H), 7.79-7.49 (m, 3H), 5.86-4.97 (m, 1H), 3.96-3.58 (m, 1H), 3.56-3.38 (m, 1H), 3.36-3.16 (m, 3H). LCMS (ESI) m/z: 485.00 [M+H].sup.+.

Example 18: (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-oxoimidazolidine-4-carboxamide (Compound 18)

##STR00086## ##STR00087##

[0450] Step 1: to a solution of 4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (820 mg, 4.40 mmol) in N,N-dimethylformamide (10.00 mL) was added sodium hydride (440 mg, 11.00 mmol, 600 content) and iodomethane (687 mg, 4.84 mmol) at 0 C. The mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL2). The organic layers were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, suction filtered, and concentrated. The crude product was purified by silica gel chromatography column (petroleum ether:ethyl acetate=80:20) to give 1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (450 mg, 2.25 mmol, yield: 513) as a yellow solid. LCMS (ESI) m/z: 201[M+H].sup.+.

[0451] Step 2: to a solution of the 1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (200 mg, 1.00 mmol) in dichloromethane (5 mL) was added m-chloroperoxybenzoic acid (860 mg, 5.00 mmol). The mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was quenched with saturated sodium sulfite solution (10 mL) and saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (20 mL2). The organic layers were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=60:40) to give 1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (66 mg, 0.30 mmol, yield: 30%) as a white solid. LCMS(ESI) m/z: 2175[M+H].sup.+.

[0452] Step 3: 1-methyl-4-(trifluoromethyl)pyrrolo[2,3-b]pyridin-7-one (300 mg, 1.39 mmol) was added to acetic anhydride (6.00 mL) at room temperature. The mixture was stirred at 100 C. for 1 h. After completion of the reaction, the system was concentrated under reduced pressure. The obtained crude product was purified by reverse phase chromatography (acetonitrile:5% ammonium bicarbonate aqueous solution=50:50) to give 1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl acetate (150 mg, 0.58 mmol, yield: 42%) as a yellow oil. LCMS (ESI) m/z: 259[M+H].sup.+.

[0453] Step 4: 1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl acetate (140 mg, 0.54 mmol) and potassium carbonate (224 mg, 1.63 mmol) were dissolved in ethanol (5.00 mL) and water (0.50 mL). The mixture was stirred at room temperature for 1 h. After completion of the reaction, the system was extracted with dichloromethane (10 mL*2). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=50:50) to give 1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-ol (110 mg, 0.50 mmol, yield: 94%) as a yellow oil. LCMS (ESI) m/z: 217[M+H]+.

[0454] Step 5: 1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-ol (110 mg, 0.51 mmol) was dissolved in dichloromethane (2 mL) at 0 C., and triflic anhydride (287 mg, 1.02 mmol) and triethylamine (103 mg, 1.02 mmol) were added. The mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was poured into water (10 mL) and extracted with dichloromethane (5 mL*3). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=20:80) to give 1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl triflate (70 mg, 0.19 mmol, yield; 39%) as a yellow solid. LCMS (ESI) m/z: 349[M+H]+.

[0455] Step 6: 1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl triflate (35 mg, 0.10 mmol), (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (Intermediate 6, 47 mg, 0.12 mmol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (5 mg, mmol), and potassium carbonate (41 mg, 0.30 mmol) were dissolved in dioxane (3 mL) solution, and the system was reacted at 80 C. under a nitrogen atmosphere for 2 h. After completion of the reaction, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (3 mL*3). The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=50:50) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-oxoimidazolidine-1-carboxylate (30 mg, 0.051 mmol, yield: 50%) as a yellow oil. LCMS (ESI) m/z: 588[M+H]+.

[0456] Step 7: (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-oxoimidazolidine-1-carboxylate (30 mg, 0.05 mmol) was dissolved in a solution of trifluoroacetic acid (1 mL) and dichloromethane (5 mL), and the system was stirred at room temperature for 1 h. After completion of the reaction, the obtained mixture was directly concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (column: Kinetex EVO prep C18, 30*150, m; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 65% B within 10 min; wavelength: 220 nm; retention time: 9.12 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-oxoimidazolidine-4-carboxamide (1.79 mg, 0.003 mmol, yield: 7%) as a white solid. HNMR (400 MHz, DMSO-d6): ppm 8.37-8.42 (s, 1H), 7.60 (m, 1H), 7.14 (s, 1H), 7.05 (m, 1H), 6.56 (s, 1H), 5.22 (m, 1H), 4.71 (m, 1H), 3.83-3.87 (m, 3H), 3.44-3.63 (m, 2H), 3.27-3.30 (m, 3H). LCMS(ESI) m/z: 487.80[M+H]+.

Example 19: (2S,3S,4S)N-(5-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-(methyl-D3)-5-oxo-1-(4-(trifluoromethyl)-7H-cyclopenta[b]pyridin-2-yl)pyrrolidine-2-carboxamide (Compound 19)

##STR00088## ##STR00089##

[0457] Step 1: (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-2,2-dimethyl-N-(methyl-D3)-6-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide (Intermediate 4, 100 mg, 0.27 mol), 5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl triflate (112 mg, 0.32 mol), potassium carbonate (75 mg, 0.54 mol), and 1,1-bis(diphenylphosphino)ferrocene (11 mg, 0.02 mol) was dissolved in dioxane (2 mL), and then tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mol) was added. The system was replaced with nitrogen three times and reacted at 80 C. for about 5 h. After completion of the reaction, the reaction solution was poured into saturated aqueous sodium chloride solution (20 mL) and extracted with ethyl acetate (10 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=50:50) to give (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-2,2-dimethyl-N-(methyl-D3)-6-oxo-5-(5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)tetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide (110 mg, 0.19 mmol, yield: 70%) as a yellow solid. LCMS (ESI): 563 [M+H].sup.+.

[0458] Step 2: (3aS, 4S, 6aS)N-(5-chloro-2,4-difluorophenyl)-2,2-dimethyl-N-(methyl-D3)-6-oxo-5-(5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)tetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide (110 mg, 0.19 mmol) and sodium borohydride (7 mg, 0.19 mmol) were dissolved in anhydrous methanol solution (5 mL) and reacted at 0 C. for 5 h. After completion of the reaction, the reaction solution was poured into water (5 mL) and extracted with ethyl acetate (5 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=60:40) to give (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-5-(5-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-2,2-dimethyl-N-(methyl-D3)-6-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide (60 mg, 0.10 mmol, yield: 52%) as a yellow solid. LCMS (ESI): 565 [M+H].sup.+.

[0459] Step 3: (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-5-(5-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-2,2-dimethyl-N-(methyl-D3)-6-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide (110 mg, 0.19 mmol), methanesulfonyl chloride (43 mg, 0.38 mmol), and triethylamine (57 mg, 0.57 mmol) were dissolved in dichloromethane solution (2 mL) and reacted at room temperature for 5 h. After completion of the reaction, the reaction solution was poured into water (10 mL) and extracted with dichloromethane (10 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=40:60) to give 2-((3aS,4S,6aS)-4-((5-chloro-2,4-difluorophenyl)(methyl-d3)carbamoyl)-2,2-dimethyl-6-oxotetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl)-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl methanesulfonate (45 mg, 0.07 mmol, yield: 36.8%) as a yellow solid. LCMS (ESI): 643 [M+H].sup.+.

[0460] Step 4: 2-((3aS,4S,6aS)-4-((5-chloro-2,4-difluorophenyl)(methyl-d3)carbamoyl)-2,2-dimethyl-6-oxotetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl)-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl methanesulfonate (45 mg, 0.07 mmol) and triethylamine (14 mg, 0.14 mmol) were dissolved in dichloromethane (2 mL) and reacted at 40 C. for 2 h. After completion of the reaction, the reaction solution was poured into water (10 mL) and extracted with dichloromethane (5 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated to give the crude product (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-5-(5-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-2,2-dimethyl-N-(methyl-D3)-6-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide (60 mg) as a white solid, which was directly used in the next step without purification. LCMS (ESI) m/z: 547[M+H].sup.+.

[0461] Step 5: (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-5-(5-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-2,2-dimethyl-N-(methyl-D3)-6-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide (60 mg, 0.109 mmol) was dissolved in dichloromethane (5 mL) and then cooled to 20 C. Boron trichloride (0.22 mL, 0.22 mmol, 1 mol/L in dichloromethane) was added, and the reaction system was reacted at room temperature for 1 h. After completion of the reaction, the reaction solution was poured into water (10 mL) and extracted with dichloromethane (5 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated to give a crude product. The crude product was purified by high-performance liquid chromatography (column: XBridge Prep OBD C18, 30150 mm, 5 um, mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile, flow rate: 60 mL/min, elution gradient: mobile phase B increased from 35% to 70% within 10 min, detection wavelength: 220 nm, retention time: 9.15 min) to give (2S,3S,4S)N-(5-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-(methyl-D3)-5-oxo-1-(4-(trifluoromethyl)-7H-cyclopenta[b]pyridin-2-yl)pyrrolidine-2-carboxamide (40 mg, 0.07 mmol, yield: 64.2%) as a white solid. LCMS (ESI) m/z: 507.05[M+H].sup.+, HNMR (400 MHz, DMSO-d.sub.6): ppm 8.33-8.14 (m, 1H), 8.11-7.50 (m, 2H), 7.31-7.12 (m, 1H), 7.11-6.83 (m, 1H), 5.80-5.48 (m, 2H), 5.20-4.72 (m, 1H), 4.50-4.18 (m, 1H), 4.15-4.01 (m, 1H), 3.76-3.60 (m, 2H).

Example 20: (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-6-yl)imidazolidine-4-carboxamide (Compound 20)

##STR00090##

[0462] (S)N-(3-Chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)furo[2,3-b]pyridin-6-yl)imidazolidine-4-carboxamide (Compound 15) (10 mg, 0.0209 mmol) was dissolved in ethanol (3 mL), and then rhodium on carbon (25 mg) was added. The reaction system was replaced with hydrogen three times and stirred at room temperature under a hydrogen atmosphere (4 atm) for 4 h. After completion of the reaction, the mixture was filtered. The filtrate was concentrated. The crude product was purified by high-performance liquid chromatography (column: Kinetex EVO C18 column, 30*150, 5 um; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 20% B to 60% B within 10 min; wavelength: 220 nm; retention time: 9.48 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-6-yl)imidazolidine-4-carboxamide (4.47 mg, 0.0093 mmol, yield: 44.4%) as a white solid. LCMS (ESI) m/z: 476.75[M+H].sup.+, HNMR (400 MHz, CDCl.sub.3): ppm 8.06 (s, 1H), 7.97-7.88 (m, 1H), 7.21-7.15 (m, 1H), 4.90-4.80 (m, 2H), 4.75-4.65 (m, 2H), 3.61-3.50 (m, 2H), 3.41-3.34 (m, 2H), 3.29 (s, 3H).

Example 21: (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-4-carboxamide (Compound 21)

##STR00091##

[0463] Step 1: (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(7-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-1-carboxylate (50 mg, 0.085 mmol) was dissolved in methanol (1 mL), and sodium borohydride (3.21 mg, 0.085 mmol) was added at 0 C. The reaction system was stirred at room temperature for 1 h. After completion of the reaction, the reaction was quenched with water (1 mL). The obtained mixture was concentrated under reduced pressure to give the crude product tert-butyl (4S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(7-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-2-oxoimidazolidine-1-carboxylate (45 mg) as a white solid. LCMS (ESI) m/z: 591[M+H].sup.+.

[0464] Step 2: tert-butyl (4S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(7-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-2-oxoimidazolidine-1-carboxylate (45 mg, 0.076 mmol) was dissolved in dichloroethane (2 mL), and pyridinium p-toluenesulfonate (38 mg, 0.15 mmol) was added. The reaction system was stirred at 80 C. for 3 h. After completion of the reaction, the system was poured into water (10 mL) and extracted with dichloromethane (10 mL*2). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=75:25) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-1-carboxylate (40 mg, 0.069 mmol, yield: 90.7%) as a yellow oil. LCMS (ESI) m/z: 573[M+H].sup.+.

[0465] Step 3: (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-1-carboxylate (40 mg, 0.069 mmol) was dissolved in trifluoroacetic acid (0.20 mL) and dichloromethane (0.50 mL). The reaction system was reacted at room temperature for 2 h. After completion of the reaction, the system was directly concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (column: Kinetex EVO C18 column, 30*150, 5 um; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 35% B to 60% B within 10 min; wavelength: 220 nm; retention time: 8.55 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)-5H-cyclopenta[b]pyridin-2-yl)imidazolidine-4-carboxamide (3.34 mg, 0.0070 mmol, yield: 10.1%) as a white solid. LCMS (ESI) m/z: 472.70[M+H].sup.+, HNMR (400 MHz, DMSO-d6): ppm 8.53-8.20 (m, 1H), 8.00-7.64 (m, 1H), 7.64-7.32 (m, 2H), 7.32-7.09 (s, 1H), 7.08-6.73 (m, 1H), 5.75-4.40 (m, 1H), 3.88-3.60 (m, 2H), 3.55-3.50 (m, 1H), 3.45-3.40 (m, 1H), 3.22-3.10 (m, 3H).

Example 22: (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)pyrrolo[1,2-a]pyrimidin-2-yl)imidazolidine-4-carboxamide (Compound 22)

##STR00092##

[0466] Step 1: to a solution of 2,4-dichloro-6-(trifluoromethyl) pyrimidine (200 mg, 0.92 mmol) in dichloromethane (5.00 mL) was added tert-butyl (4S)-4-[N-(3-chloro-2,4-difluorophenyl)-N-methylcarbamoyl]-2-oxoimidazolidine carboxylate (179 mg, 0.46 mmol), tris(dibenzylideneacetone)dipalladium (84 mg, 0.09 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (53 mg, 0.09 mmol), and the reaction system was replaced with nitrogen three times. The obtained mixture was stirred at 80 C. for 1 h. The reaction showed 80% product by LC-MS on a TLC plate (Rf=0.6, petroleum ether:ethyl acetate=1:1). The reaction solution was poured into water (10 mL) and extracted with dichloromethane (10 mL2). The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under a vacuum. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=20:80) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-2-oxoimidazolidine-1-carboxylate (305 mg, yield: 58%) as a yellow solid. LCMS (ESI) m/z: 570[M+H].sup.+.

[0467] Step 2: to a solution of (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-2-oxoimidazolidine-1-carboxylate (150 mg, 0.26 mmol) in dioxane (5.00 mL) was added bis(triphenylphosphine)palladium(II) chloride (18 mg, 0.03 mmol) and tributylstannane (173 mg, 0.53 mmol), and the obtained mixture was stirred at 80 C. for 2 h. After completion of the reaction monitored by LC-MS, the reaction solution was poured into water and extracted with dichloromethane (10 mL*2). The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under a vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=70:30) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(2-(prop-1-yn-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)imidazolidine-1-carboxylate (90 mg, yield: 60%) as a yellow solid. LCMS (ESI) m/z: 574[M+H].sup.+.

[0468] Step 3: to a solution of tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(2-(prop-1-yn-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)imidazolidine-1-carboxylate (60 mg, 0.10 mmol) in N,N-dimethylacetamide (1.00 mL) was added cuprous bromide (0.86 mg, 0.01 mmol) and triethylamine (211 mg, 2.00 mmol), and the obtained mixture was stirred at 140 C. After 12 h, after completion of the reaction monitored by LC-MS, the reaction solution was poured into water (5 mL) and extracted with ethyl acetate (5 mL*2). The combined organic phase was dried over anhydrous sodium sulfate, suction filtered, and then spin-dried. The residue was purified by high-performance liquid chromatography (column: XBridge Prep OBD C18 column, 30*150 mm, 5 m; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 32% B to 65% B within 10 min; wavelength: 220 nm; retention time: 8.45 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)pyrrolo[1,2-a]pyrimidin-2-yl)imidazolidine-4-carboxamide (6.66 mg, 0.014 mmol, yield: 11%) as a yellow solid.

[0469] LCMS (ESI) m/z: 473.80[M+H].sup.+, HNMR (400 MHz, DMSO-d6): ppm 8.30-8.25 (m, 1H), 7.90-7.61 (m, 2H), 7.50-7.35 (m, 2H), 7.04-7.01 (m, 1H), 6.61-6.32 (m, 1H), 4.90-4.76 (m, 1H), 3.55-3.50 (m, 1H), 3.47-3.38 (m, 1H), 3.22-3.09 (m, 3H).

Example 23: (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(7-(trifluoromethyl)thiazolo[5,4-b]pyridin-2-yl)imidazolidine-4-carboxamide (Compound 23)

##STR00093##

[0470] Step 1: a mixture of 2,6-dichloro-4-(trifluoromethyl)-3-pyridinamine (5.00 g, 21.65 mmol) and potassium thiocyanate (6.30 g, 64.94 mmol) in ethanol (50.00 mL) and hydrochloric acid (100.00 mL) was stirred at 100 C. overnight, and the reaction was monitored by LCMS for completion. The reaction solution was poured into water (100 mL) and extracted with dichloromethane (100 mL*2). The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under a vacuum. The concentrate was purified by silica gel column chromatography (ethyl acetate:petroleum ether=50:50) to give 5-chloro-7-(trifluoromethyl)-1,3-thiazolo[5,4-b]pyridin-2-ylamine (2.0 g, 7.9 mmol, yield: 36%) as a yellow oil. LCMS (ESI) m/z: 253 [M+H].sup.+.

[0471] Step 2: a mixture of 5-chloro-7-(trifluoromethyl)-1,3-thiazolo[5,4-b]pyridin-2-ylamine (2.00 g, 7.89 mmol) and tert-butoxy (1.87 mL, 15.77 mmol) in tetrahydrofuran (10.00 mL) was stirred at 0 C. for 30 min. The reaction mixture was then stirred at 90 C., and the reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was poured into water (20 mL) and extracted with ethyl acetate (20 mL*2). The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under a vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=80:20) to give 5-chloro-7-(trifluoromethyl)-1,3-thiazolo[5,4-b]pyridine (500.00 mg, 2.1 mmol, yield: 27%) as a red solid. LCMS (ESI) m/z: 238[M+H].sup.+.

[0472] Step 3: to a solution of 5-chloro-7-(trifluoromethyl)-1,3-thiazolo[5,4-b]pyridine (250 mg, 1.05 mmol) in dioxane (5.00 mL) was added (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (326 mg, 0.84 mmol), tris(dibenzylideneacetone)dipalladium (95 mg, 0.86 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (60 mg, 0.10 mmol), and potassium carbonate (433 mg, 3.14 mmol), and the reaction solution was stirred at 80 C. overnight. After completion of the reaction monitored by LC-MS, the reaction solution was poured into water (20 mL) and extracted with dichloromethane (10 mL*2). The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under a vacuum. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=30:70) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(7-(trifluoromethyl)thiazolo[5,4-b]pyridin-5-yl)imidazolidine-1-carboxylate (220.00 mg, 0.37 mmol, yield: 35%) as a yellow oil. LCMS (ESI) m/z: 592 [M+H].sup.+.

[0473] Step 4: to a solution of (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(7-(trifluoromethyl)thiazolo[5,4-b]pyridin-5-yl)imidazolidine-1-carboxylate (Intermediate 6, 200 mg, 0.34 mmol) in dichloromethane (5.00 mL) and trifluoroacetic acid (0.1 mL), the reaction solution was reacted at room temperature for 0.5 h and was monitored by LC-MS. After completion of the reaction, the reaction solution was spin-dried. The residue was purified by high-performance liquid chromatography (XBridge Shield RP18 OBD column, 30*150 mm, 5 um; mobile phase A: water (10 mmol/L ammonium bicarbonate aqueous solution), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 62% B within 10 min, wavelength: 220 nm; peak time: 9.37 min) to give {(4S)-2-oxo-3-[7-(trifluoromethyl)(1,3-thiazolo[4,5-e]pyridin-5-yl)]imidazolidin-4-yl}-N-(3-chloro-2,4-difluorophenyl)-N-methylformamide (81.82 mg, 0.166 mmol, yield: 49%) as a white solid.

[0474] LCMS (ESI) m/z: 491.85 [M+H].sup.+.

[0475] HNMR (400 MHz, DMSO-d.sub.6): ppm 9.54-9.49 (m, 1H), 8.84-8.78 (m, 1H), 7.88-7.63 (m, 2H), 7.51-7.36 (m, 1H), 5.82-4.85 (m, 1H), 3.95-3.52 (m, 1H), 3.49-3.40 (m, 1H), 3.21-3.17 (m, 3H).

Example 24: (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)thieno[2,3-d]pyridin-2-yl)imidazolidine-4-carboxamide (Compound 24)

##STR00094##

[0476] Step 1: methyl 2-aminothiophene-3-carboxylate (11.00 g, 0.07 mol) and urea (21.01 g, 0.35 mol) were reacted at 150 C. for about 2.5 h. After completion of the reaction, the reaction solution was poured into saturated aqueous sodium chloride solution (30 mL) and extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=50:50) to give thienopyrimidine-2,4-diol (2 g, crude product) as a yellow solid, which was directly used in the next step. LCMS(ESI): 169[M+H].sup.+.

[0477] Step 2: thienopyrimidine-2,4-diol (2 g, 0.01 mol) and phosphorus oxychloride (20 mL) were reacted at 80 C. for 12 h. After completion of the reaction, phosphorus oxychloride was concentrated, and then the mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=40:60) to give 2,4-dichlorothieno[2,3-d]pyrimidine (1.40 g, 0.006 mol, yield: 60%) as a yellow solid. LCMS (ESI): 205[M+H].sup.+.

[0478] Step 3: 2,4-dichlorothieno[2,3-d]pyrimidine (2.10 g, 0.01 mol), [PPh4].sup.+[Cu(CF3)2].sup. (10.81 g, 0.02 mol), cuprous iodide (1.91 g, 0.01 mol), and N-methylpyrrolidinone (10 mL) were reacted at 110 C. for 10 h. After completion of the reaction, the reaction solution was poured into water (20 mL) and extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=20:80) to give 2-chloro-4-(trifluoromethyl)thieno[2,3-d]pyrimidine (0.31 g, 0.001 mol, yield: 13%) as a white solid. LCMS (ESI): 239[M+H].sup.+.

[0479] Step 4: 2-chloro-4-(trifluoromethyl)thieno[2,3-d]pyrimidine (315 mg, 1.32 mmol), (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (Intermediate 6, 513 mg, 1.32 mmol), tris(dibenzylideneacetone)dipalladium (120 mg, 0.132 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (76 mg, 0.132 mmol), and potassium carbonate (546 mg, 3.96 mmol) were dissolved in dioxane (5 mL) and reacted at 80 C. for 12 h. After completion of the reaction, the reaction solution was poured into water (5 mL) and extracted with dichloromethane (5 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=60:40) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)thieno[2,3-d]pyrimidin-2-yl)imidazolidine-1-carboxylate (270 mg, 0.45 mmol, yield: 34.6%) as a white solid. LCMS (ESI) m/z: 592[M+H].sup.+.

[0480] Step 5: (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)thieno[2,3-d]pyrimidin-2-yl)imidazolidine-1-carboxylate (270 mg, 0.45 mmol) was added to a mixed solution of trifluoroacetic acid (4 mL) in dichloromethane (20 mL) and then reacted at room temperature for 10 h. After completion of the reaction, the reaction solution was poured into water (5 mL) and extracted with dichloromethane (5 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated to give a crude product. The crude product was purified by high-performance liquid chromatography (column: XBridge Prep OBD C18, 30150 mm, 5 um, mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile, flow rate: 60 mL/min, elution gradient: mobile phase B increased from 35% to 70% within 10 min, detection wavelength: 220 nm, retention time: 9.15 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)thieno[2,3-d]pyrimidin-2-yl)imidazolidine-4-carboxamide (114 mg, 0.23 mmol, yield: 51.1%) as a white solid.

[0481] LCMS (ESI) m/z: 491.60[M+H]+.

[0482] HNMR (400 MHz, DMSO-d6): ppm 8.01-7.95 (m, 1H), 7.74-7.59 (m, 1H), 7.55-7.39 (m, 3H), 5.79-4.85 (m, 1H), 3.93-3.36 (m, 2H), 3.20-3.16 (m, 3H).

Example 25: ((S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(7-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)imidazolidine-4-carboxamide (Compound 25)

##STR00095##

[0483] Step 1: 6-chloro-4-(trifluoromethyl)pyridin-2-amine (2.01 g, 0.01 mol), di-tert-butyl dicarbonate (6.67 g, 0.03 mol), 4-dimethylaminopyridine (0.21 g, 0.002 mol), and triethylamine (3.70 g, 0.03 mol) were dissolved in dichloromethane (10 mL) and reacted at room temperature for about 10 h. After completion of the reaction, the reaction solution was poured into saturated aqueous sodium chloride solution (20 mL) and extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=20:80) to give tert-butyl (6-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamate (1.91 g, 0.006 mol, yield: 60%) as a yellow solid. LCMS(ESI): 297[M+H].sup.+.

[0484] Step 2: tert-butyl (6-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamate (360 mg, 1.21 mmol), (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (Intermediate 6, 513 mg, 1.32 mmol), tris(dibenzylideneacetone)dipalladium (110 mg, 0.121 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (69.93 mg, 0.121 mmol), and potassium carbonate (500 mg, 3.63 mmol) were dissolved in dioxane solution (10 mL) and reacted at 80 C. for 10 h. After completion of the reaction, the reaction solution was poured into water (5 mL) and extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=50:50) to give (S)-tert-butyl 3-(6-((tert-butoxycarbonyl)amino)-4-(trifluoromethyl)pyridin-2-yl)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (264 mg, 0.40 mmol, yield: 33%) as a yellow solid. LCMS (ESI): 650 [M+H].sup.+.

[0485] Step 3: (S)-tert-butyl 3-(6-((tert-butoxycarbonyl)amino)-4-(trifluoromethyl)pyridin-2-yl)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (259 mg, 0.39 mmol) and dichloromethane (20 mL) were dissolved in trifluoroacetic acid (4 mL) and reacted at room temperature for 10 h. After completion of the reaction, the reaction solution was poured into water (5 mL) and extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=50:50) to give (S)-3-(6-amino-4-(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxoimidazolidine-4-carboxamide (45 mg, 0.07 mmol, yield: 36.8%) as a yellow solid. LCMS (ESI): 450 [M+H].sup.+.

[0486] Step 4: (S)-3-(6-amino-4-(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxoimidazolidine-4-carboxamide (60 mg, 0.13 mmol) and chloroacetaldehyde (10.14 mg, 0.13 mmol) were dissolved in anhydrous ethanol (2 mL) and reacted at 90 C. for 16 h. After completion of the reaction, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (15 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(7-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)imidazolidine-4-carboxamide (4.16 mg, 0.008 mmol, yield: 6%) as a white solid.

[0487] LCMS (ESI) m/z: 473.80 [M+H].sup.+.

[0488] HNMR (400 MHz, DMSO-d6): ppm 8.05-8.01 (m, 1H), 7.98-7.93 (m, 1H), 7.79-7.78 (m, 1H), 7.77-7.62 (m, 1H), 7.49-7.27 (m, 2H), 7.16-7.08 (m, 1H), 5.21-5.11 (m, 1H), 4.17-3.52 (m, 1H), 3.47-3.38 (m, 1H), 3.21-2.94 (m, 3H).

Example 26: (2S,3S,4S)N-(5-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-(methyl-D3)-5-oxo-1-(7-(trifluoromethyl)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-2-carboxamide (Compound 26)

##STR00096##

[0489] The same synthetic method as Compound 16 using 5-chloro-7-(trifluoromethyl)-1,3-thiazolo[5,4-b]pyridine (Intermediate 23-2) and Intermediate 4 as the starting materials and high-performance liquid chromatography (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 m; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 50% B within 8 min; wavelength: 220 nm; retention time: 7.83 min) were performed to give (2S,3S,4S)N-(5-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-(methyl-D3)-5-oxo-1-(7-(trifluoromethyl)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-2-carboxamide (4.67 mg, yield: 10%, 0.008 mmol) as a white solid.

[0490] LCMS (ESI): 525.80[M+H].sup.+.

[0491] HNMR (400 MHz, DMSO-d6): ppm 9.66-9.62 (m, 1H), 8.68-8.64 (m, 1H), 7.96-7.90 (m, 1H), 7.87-7.56 (m, 1H), 5.85-5.32 (m, 2H), 5.13-4.80 (m, 1H), 4.50-4.29 (m, 1H), 4.10-4.05 (m, 1H).

Example 27: (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)pyrrolo[1,2-b]pyridazin-2-yl)imidazolidine-4-carboxamide (Compound 27)

##STR00097##

[0492] Step 1: 3,6-dichloro-4-(trifluoromethyl)pyridazine (1.01 g, 4.61 mmol), (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (Intermediate 6, 538 mg, 1.38 mmol), palladium acetate (103.24 mg, 0.46 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (266 mg, 0.46 mmol), and potassium carbonate (1.91 g, 13.83 mmol) were dissolved in 1,4-dioxane (20 mL) solution and reacted at 80 C. for 2 h. The desired product can be detected by LCMS. The obtained mixture was extracted with dichloromethane (35 mL). The combined organic layer was washed with salt water (33 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate in petroleum ether) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(6-chloro-5-(trifluoromethyl)pyridazin-3-yl)-2-oxoimidazolidine-1-carboxylate (500 mg, 0.87 mmol, yield: 19%) as a yellow solid. LCMS (ESI): 570 [M+H].sup.+.

[0493] Step 2: (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(6-chloro-5-(trifluoromethyl)pyridazin-3-yl)-2-oxoimidazolidine-1-carboxylate (450 mg, 0.79 mmol) was dissolved in 1,4-dioxane (10 mL), and 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (55 mg, 0.08 mmol) and tributylstannane (520 mg, 1.58 mmol) were added at room temperature. The system was then warmed to 80 C. and reacted for 4 h. The desired product can be detected by LCMS. The obtained mixture was extracted with dichloromethane (310 mL). The combined organic layer was washed with saturated salt water (35 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (30% ethyl acetate in petroleum ether) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(6-(prop-1-yn-1-yl)-5-(trifluoromethyl)pyridazin-3-yl)imidazolidine-1-carboxylate (300 mg, 0.56 mmol, yield: 60%) as a yellow oil. LCMS (ESI): 574 [M+H].sup.+.

[0494] Step 3: (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(6-(prop-i-yn-1-yl)-5-(trifluoromethyl)pyridazin-3-yl)imidazolidine-1-carboxylate (150 mg, 0.26 mmol), cuprous chloride (25 mg, 0.26 mmol), and triethylamine (726 L, 5.23 mmol) were dissolved in N,N-dimethylacetamide (5 mL) and reacted at 140 C. overnight. The desired product can be detected by LCMS. The obtained mixture was extracted with ethyl acetate (35 mL). The combined organic layer was washed with salt water (33 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. After concentration, the concentrate was purified on a column: XBridge Prep OBD C18 column, 30*150 mm, 5 m; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 39% to 65% B within 10 min; wavelength: 220 nm; retention time: 9.5 min, to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)pyrrolo[1,2-b]pyridazin-2-yl)imidazolidine-4-carboxamide (16.38 mg, 0.034 mmol, yield: 13%) as a light yellow solid.

[0495] LCMS (ESI): 473.75[M+H].sup.+.

[0496] HNMR (400 MHz, DMSO-d6): ppm 8.25-8.22 (m, 1H), 8.06-7.85 (m, 1H), 7.78-7.62 (m, 2H), 7.60-7.38 (m, 1H), 6.95-6.91 (m, 1H), 6.68-6.62 (m, 1H), 5.68-4.75 (m, 1H), 3.54-3.50 (m, 1H), 3.48-3.40 (m, 1H), 3.24-3.11 (m, 3H).

Example 28a and Example 28b: (S)N-(3-chloro-2,4-difluorophenyl)-3-((R)-7-hydroxy-7-methyl-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide and (R)N-(3-chloro-2,4-difluorophenyl)-3-((R)-7-hydroxy-7-methyl-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide

##STR00098##

[0497] The same synthetic method as Compound 8a using Compound 13 as the starting material and high-performance liquid chromatography (column: XBridge Prep OBD C18 column, 30*150 mm, 5 m; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 32% B to 63% B within 8 min; wavelength: 220 nm) were performed to give a earlier peak with peak time of 6.30 min as a yellow solid and a later peak with peak time of 7.58 min as a yellow solid.

[0498] Compound 28a: earlier peak.

[0499] LCMS (ESI): 504.75[M+H].sup.+.

[0500] HNMR (400 MHz, DMSO-d6): ppm 8.56-8.39 (m, 1H), 8.34-7.49 (m, 2H), 7.41-7.21 (m, 1H), 5.80-4.77 (m, 2H), 3.93-3.51 (m, 2H), 3.18-3.09 (m, 3H), 3.05-2.97 (m, 1H), 2.87-2.83 (m, 1H), 2.25-2.12 (m, 2H), 1.48-1.36 (m, 3H).

[0501] Compound 28b: later peak.

[0502] LCMS (ESI): 504.80[M+H].sup.+.

[0503] HNMR (400 MHz, DMSO-d6): ppm 8.58-8.52 (m, 1H), 8.42-8.38 (m, 1H), 7.70-7.58 (m, 1H), 7.52-7.28 (m, 1H), 5.75-4.77 (m, 2H), 3.93-3.45 (m, 2H), 3.18-3.09 (m, 3H), 3.05-2.94 (m, 1H), 2.83-2.78 (m, 1H), 2.25-2.12 (m, 2H), 1.48-1.36 (m, 3H).

Example 29: (S)-6-(5-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylic acid (Compound 29)

##STR00099##

[0504] Step 1: triflic anhydride (1.22 g, 4.33 mmol) was added to a mixture of methyl 6-hydroxy-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate (1.01 g, 3.61 mmol) and triethylamine (721 mg, 7.21 mmol) in dichloromethane (10.00 mL) at 0 C. and reacted at room temperature for 2 h. After completion of the reaction, the mixture was poured into water and extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, suction filtered, spin-dried, and purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to give methyl 4-(trifluoromethyl)-6-(((trifluoromethyl)sulfonyl)oxy)thieno[2,3-b]pyridine-2-carboxylate (1.00 g, 1.8 mmol, yield: 68%). LCMS (ESI): 410[M+H].sup.+.

[0505] Step 2: methyl 4-(trifluoromethyl)-6-[(trifluoromethyl)sulfonyloxy]thieno[2,3-b]pyridine-2-carboxylate (0.20 g, 0.49 mmol), tert-butyl (4S)-4-[N-(3-chloro-2,4-difluorophenyl)-N-methylcarbamoyl]-2-oxoimidazolidine carboxylate (Intermediate 6, 0.19 g, 0.49 mmol), tris(dibenzylideneacetone)dipalladium (0.04 g, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.03 g, 0.06 mmol), and potassium carbonate (0.13 g, 0.98 mmol) were stirred in dioxane (5.00 mL) at 80 C. for 12 h. After completion of the reaction, the mixture was poured into water, extracted with ethyl acetate (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (30% ethyl acetate in petroleum ether) to give (S)-6-(3-(tert-butoxycarbonyl)-5-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate (0.16 g, 0.24 mmol, yield: 50%) as a white solid, LCMS (ESI): 649[M+H].sup.+.

[0506] Step 3: a mixture of (S)-methyl 6-(3-(tert-butoxycarbonyl)-5-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate (200 mg, 0.31 mmol) and sodium hydroxide (24.65 mg, 0.62 mmol) in methanol (2.00 mL) was stirred at room temperature for 2 h. After completion of the reaction, the mixture was spin-dried to give 6-{(5S)-3-[(tert-butyl)oxycarbonyl]-5-[N-(3-chloro-2,4-difluorophenyl)-N-methylcarbamoyl]-2-oxoimidazolidinyl}-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylic acid (120 mg, yield: 61%, 0.192 mmol) as a white solid. LCMS (ESI): 635[M+H].sup.+.

[0507] Step 4: (S)-6-(3-(tert-butoxycarbonyl)-5-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylic acid (100 mg, 0.16 mmol) was dissolved in dichloromethane (10.00 mL), and then trifluoroacetic acid (2.00 mL) was added dropwise to the reaction. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the organic phase was spin-dried and subjected to high-performance liquid chromatography (column: Xselect CSH C18 OBD column 30150 mm, 5 m; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 45% B to 75% B within 8 min; wavelength: 220 nm; retention time: 6.93 min) to give (S)-6-(5-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylic acid (17.92 mg, 21%, 0.033 mmol) as a white solid.

[0508] LCMS (ESI): 535.25[M+H].

[0509] HNMR (400 MHz, DMSO-d6): ppm 9.66-9.62 (m, 1H), 8.89-8.66 (m, 3H), 7.51-7.40 (m, 1H), 5.00-4.86 (m, 1H), 3.56-3.42 (m, 2H), 3.18-3.09 (m, 3H).

Example 30: (R)-4-(1-(3-chloro-4-fluorophenyl)-4-fluoro-1H-imidazol-2-yl)-3-(4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)oxazolidin-2-one (Compound 30)

##STR00100##

[0510] A mixture of (R)-4-(1-(3-chloro-4-fluorophenyl)-4-fluoro-1H-imidazol-2-yl)oxazolidin-2-one (synthesized according to the method reported in the patent WO2021123785) (70 mg, 0.23 mmol), 4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl triflate (98 mg, 0.28 mmol), potassium carbonate (96 mg, 0.70 mmol), tris(dibenzylideneacetone)dipalladium (21 mg, 0.02 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (13 mg, 0.02 mol) in dioxane (5 mL) was stirred at 80 C. under a nitrogen atmosphere for 4 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (35 mL). The combined organic layer was washed with salt water, dried over anhydrous sodium sulfate, filtered, and concentrated under a vacuum to give a crude product. The crude product was purified by high-performance liquid chromatography (column: Xselect CSH C18 OBD column 30*150 mm, 5 m, mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 50% B to 80% B within 8 min, wavelength: 220 nm; retention time: 7.55 min) to give (R)-4-(1-(3-chloro-4-fluorophenyl)-4-fluoro-1H-imidazol-2-yl)-3-(4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)oxazolidin-2-one (19.76 mg, yield: 17%, 0.039 mmol) as a white solid.

[0511] LCMS (ESI): 501.15[M+H].sup.+.

[0512] HNMR (400 MHz, DMSO-d6): ppm 8.45 (s, 1H), 8.04 (d, J=4 Hz, 1H), 7.99 (dd, J=6.4 Hz, 1H), 7.80-7.71 (m, 2H), 7.47-7.45 (m, 1H), 7.25 (d, J=8 Hz, 1H), 5.82-5.79 (m, 1H), 4.82 (t, J=8.4 Hz, 1H), 4.69-4.66 (m, 1H).

Example 31: [(4S)-3-(7-cyclopropyl (1,3-thiazolo[4,5-e]pyridin-5-yl))-2-oxoimidazolidin-4-yl]-N-(3-chloro-2,4-difluorophenyl)-N-methylformamide (Compound 31)

##STR00101##

[0513] Step 1: 7-bromo-5-chloro-1,3-thiazolo[5,4-b]pyridine (Intermediate 7, 500.00 mg, 2.00 mmol), cyclopropylboronic acid (688.52 mg, 8.02 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (145.41 mg, 0.20 mmol), and potassium carbonate (553.90 mg, 4.01 mmol) were reacted in 1,4-dioxane (1.00 mL) at 140 C. for 12 h. The mixture was poured into water with stirring, extracted with ethyl acetate (5 mL), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate=60:40) to give 5-chloro-7-cyclopropyl-1,3-thiazolo[5,4-b]pyridine (300.00 mg, 2 mmol, yield: 71%) as a colorless oil. LCMS (ESI): 210[M+H]+.

[0514] Step 2: 5-chloro-7-cyclopropyl-1,3-thiazolo[5,4-b]pyridine (0.10 g, 0.47 mmol) was reacted with tert-butyl 4-[N-(3-chloro-2,4-difluorophenyl)-N-methylcarbamoyl]-2-oxoimidazolidine carboxylate (Intermediate 6, 0.15 g, 0.38 mmol), tris(dibenzylideneacetone)dipalladium ((0.03 g, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.01 g, 0.06 mmol), and potassium carbonate (0.20 g, 1.42 mmol) in 1,4-dioxane (10 mL) at 100 C. for 2 h. After completion of the reaction, the mixture was poured into water with stirring, extracted with ethyl acetate (5 mL), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate=80:20) to give 5-chloro-7-cyclopropyl-1,3-thiazolo[5,4-b]pyridine (300 mg, 2 mmol, yield: 71%) as a colorless oil, LCMS (ESI): 564[M+H]+.

[0515] Step 3: a mixture of tert-butyl (4S)-4-[N-(3-chloro-2-fluoro-4-methylphenyl)-N-methylcarbamoyl]-3-(7-cyclopropyl (1,3-thiazolo[4,5-e]pyridin-5-yl))-2-oxoimidazolidine carboxylate (85 mg, 0.15 mmol) in trifluoroacetic acid (0.2 mL) and dichloromethane (1.00 mL) was stirred at room temperature for 2 h. After completion of the reaction, the mixture was spin-dried and purified by high-performance liquid chromatography (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 m; mobile phase A: water (10 mmol/L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 60% B within 10 min; wavelength: 220 nm; retention time (min): 8.62) to give [(4S)-3-(7-cyclopropyl (1,3-thiazolo[4,5-e]pyridin-5-yl))-2-oxoimidazolidin-4-yl]-N-(3-chloro-2,4-difluorophenyl)-N-methylformamide (14.25 mg, 0.15 mmol, yield: 14%) as a white solid.

[0516] LCMS (ESI): 464.05[M+H].sup.+.

[0517] HNMR (400 MHz, DMSO-d6): ppm 9.28-9.22 (m, 1H), 8.00-7.93 (m, 1H), 7.74-7.64 (m, 1H), 7.54-7.39 (m, 2H), 5.72-4.78 (m, 1H), 3.84-3.38 (m, 2H), 3.15-3.13 (m, 3H), 1.22-1.69 (m, 1H), 1.01-0.99 (m, 2H).

Example 32: {(4S)-3-[7-(dimethylcarbonyl) (1,3-thiazolo[4,5-e]pyridin-5-yl)]-2-oxoimidazolidin-4-yl}-N-(3-chloro-2,4-difluorophenyl)-N-methylformamide (Compound 32)

##STR00102##

[0518] Step 1: a solution of 7-bromo-5-chloro-1,3-thiazolo[5,4-b]pyridine (200 mg, 0.80 mmol), tris(dibenzylideneacetone)dipalladium (57 mg, 0.08 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (46 mg, 0.08 mmol), potassium phosphate (255 mg, 1.20 mmol), and dimethylphosphine oxide (7 mg, 0.96 mmol) in dioxane (5 mL) was reacted at 100 C. for 4 h. After completion of the reaction, the system was cooled to room temperature, and saturated aqueous sodium bicarbonate solution (15 mL) was added. The mixture was extracted with ethyl acetate (25 mL). The aqueous phases were combined, acidified with 2M aqueous hydrochloric acid solution (5 mL), and extracted 5 times with 5 mL of ethyl acetate each. The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=70:30) to give 1,4(5-chloro(1,3-thiazolo[5,4-b]pyridin-7-yl))dimethylphosphin-1-one (150 mg, 0.8 mmol, yield: 76%) as a colorless oil. LCMS (ESI): 246 [M+H].sup.+.

[0519] Step 2: 5-chloro-7-cyclopropyl-1,3-thiazolo[5,4-b]pyridine (0.10 g, 0.47 mmol), tert-butyl 4-[N-(3-chloro-2,4-difluorophenyl)-N-methylcarbamoyl]-2-oxoimidazolidine carboxylate (Intermediate 6, 0.3 g, 0.76 mmol), tris(dibenzylideneacetone)dipalladium (53 mg, 0.08 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (43 mg, 0.08 mmol), cesium carbonate (733 mg, 2.25 mmol), and 5-chloro(1,3-thiazolo[5,4-b]pyridin-7-yl))dimethylphosphin-1-one (185 mg, 0.75 mmol) were refluxed in dioxane (5 mL) for 2-4 h. After completion of the reaction, the obtained mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate=80:20) to give tert-butyl 6(4S)-3-[7-(dimethylcarbonyl)(1,3-thiazolo[4,5-e]pyridin-5-yl)]-4-[N-(3-chloro-2,4-difluorophenyl)-N-methylcarbamoyl]-2-oxoimidazolidine carboxylate (40 mg, 0.75 mmol, yield: 9%) as a yellow solid. LCMS (ESI): 600 [M+H]+.

[0520] Step 3: a mixture of tert-butyl (4S)-3-[7-(dimethylcarbonyl)(1,3-thiazolo[4,5-e]pyridin-5-yl)]-4-[N-(3-chloro-2,4-difluorophenyl)-N-methylcarbamoyl]-2-oxoimidazolidine carboxylate (80 mg, 0.13 mmol) in trifluoroacetic acid (0.5 mL) and dichloromethane (2.00 mL) was stirred at room temperature for 0.5 h. After completion of the reaction, the combined organic layer was washed with salt water, dried over anhydrous sodium sulfate, filtered, concentrated under a vacuum, and purified by high-performance liquid chromatography (column: XBridge Prep OBD C18 column, 30*150 mm, 5 m; mobile phase A: water (10 mmol/L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 37% B to 67% B within 10 min; wavelength: 220 nm; retention time (min): 8.53) to give {(4S)-3-[7-(dimethylcarbonyl)(1,3-thiazolo[4,5-e]pyridin-5-yl)]-2-oxoimidazolidin-4-yl}-N-(3-chloro-2,4-difluorophenyl)-N-methylformamide (2.70 mg, 0.13 mmol, yield: 4%) as a white solid.

[0521] LCMS (ESI): 500.20 [M+H].sup.+.

[0522] HNMR (400 MHz, DMSO-d6): ppm 9.48-9.42 (m, 1H), 8.90-8.78 (m, 1H), 7.79-7.64 (m, 2H), 7.49-7.42 (m, 1H), 5.79-4.23 (m, 2H), 3.92-3.91 (m, 1H), 3.16 (s, 3H), 1.87 (s, 6H).

Example 33: (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)selenobenzo[2,3-b]pyridin-6-yl)imidazolidine-4-carboxamide (Compound 33)

##STR00103## ##STR00104##

[0523] Step 1: 2-chloro-4-(trifluoromethyl)pyridine (20.00 g, 110 mmol) was dissolved in tetrahydrofuran (200 mL) and cooled to 78 C. A solution of lithium diisopropylamide in tetrahydrofuran (110 mL, 220 mmol, 2 mol/L) was added dropwise. The mixture was stirred at room temperature for 30 min and then cooled again to 78 C. Anhydrous N,N-dimethylformamide (10.96 g, 150 mmol) was added in one portion. After completion of the reaction, saturated ammonium chloride solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=70:30) to give 2-chloro-4-(trifluoromethyl)nicotinaldehyde (6.50 g, yield: 280, 31 mmol) as a yellow oil. LCMS (ESI) m/z: 210[M+H].sup.+, .sup.1H NMR (400 MHz, DMSO-d6) 10.42 (q, J=1.8 Hz, 1H), 8.89-8.88 (m, 1H), 8.00 (d, J=5.2 Hz, 1H).

[0524] Step 2: 2-chloro-4-(trifluoromethyl)nicotinaldehyde (6.00 g, 29 mmol) was dissolved in N,N-dimethylformamide (60 mL). Sodium selenide (3.58 g, 29 mmol) was added and stirred at room temperature for 2 h. After completion of the reaction, the crude reaction solution was directly used in the next step without post-processing. LCMS(ESI) 256[M+H].sup.+.

[0525] Step 3: ethyl 2-chloroacetate (7.10 g, 58 mmol) and sodium acetate (5.68 g, 58 mmol) were added to the above crude reaction solution and stirred at room temperature for 2 h. After completion of the reaction, water (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL*3). The combined organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product ethyl 2-((3-formyl-4-(trifluoromethyl)pyridin-2-yl)seleno)acetate (7.00 g) as a yellow oil, which was directly used in the next step without further purification. LCMS (ESI) m/z: 342[M+H].sup.+.

[0526] Step 4: the crude product ethyl 2-((3-formyl-4-(trifluoromethyl)pyridin-2-yl)seleno)acetate (7.00 g) was dissolved in anhydrous N,N-dimethylformamide (50 mL). Potassium carbonate (8.28 g, 60 mmol) was added and stirred at room temperature for 2 h. After completion of the reaction, the mixture was filtered to remove the potassium carbonate solid. The filtrate was added with water (50 mL) and extracted with ethyl acetate (60 mL*3). The combined organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=70:30) to give ethyl 4-(trifluoromethyl)selenobenzo[2,3-b]pyridine-2-carboxylate (3.50 g, 11 mmol, yield: 55%) as a light yellow solid. LCMS(ESI) 324[M+H].sup.+, 1H NMR (400 MHz, DMSO-d6) 8.23 (t, J=1.8 Hz, 1H), 8.14 (d, J=0.8 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).

[0527] Step 5: ethyl 4-(trifluoromethyl)selenobenzo[2,3-b]pyridine-2-carboxylate (2.00 g, 6 mmol) was dissolved in acetic acid (20 mL), and 30% aqueous hydrogen peroxide solution (4 mL, 30 mmol) was added. The system was warmed to 80 C. and stirred for 2 h. After completion of the reaction, the reaction solution was concentrated to give the crude product 2-(ethoxycarbonyl)-4-(trifluoromethyl)selenobenzo[2,3-b]pyridine 7-oxide (2.00 g) as a light yellow solid, which was used in the next step without purification. LCMS (ESI) m/z: 340[M+H].sup.+.

[0528] Step 6: the crude product 2-(ethoxycarbonyl)-4-(trifluoromethyl)selenobenzo[2,3-b]pyridine 7-oxide (2.00 g) was added to phosphorus oxychloride (20 mL) solution at room temperature. The mixture was stirred at 120 C. for 2 h. After completion of the reaction, the system was cooled to room temperature. The obtained mixture was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=70:30) to give ethyl 6-chloro-4-(trifluoromethyl)selenobenzo[2,3-b]pyridine-2-carboxylate (1.80 g, 5 mmol, yield: 84.75%) as a light yellow solid. LCMS (ESI) m/z: 358[M+H].sup.+.

[0529] Step 7: ethyl 6-chloro-4-(trifluoromethyl)selenobenzo[2,3-b]pyridine-2-carboxylate (150 mg, 0.42 mmol), (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (Intermediate 6, 163 mg, 0.42 mmol), tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (23 mg, 0.04 mmol), and potassium carbonate (174 mg, 1.26 mmol) were dissolved in dioxane (15 mL) solution and reacted at 80 C. for 1 h. After completion of the reaction, the system was cooled to room temperature. The reaction solution was poured into water (10 mL). The obtained mixture was extracted with ethyl acetate (20 mL2). The combined organic layer was washed with saturated salt water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=60:40) to give (S)-ethyl 6-(3-(tert-butoxycarbonyl)-5-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)selenobenzo[2,3-b]pyridine-2-carboxylate (130 mg, 0.18 mmol, yield: 44%) as a light yellow solid. LCMS (ESI) m/z: 711[M+H].sup.+.

[0530] Step 8: ethyl (S)-6-(3-(tert-butoxycarbonyl)-5-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)selenobenzo[2,3-b]pyridine-2-carboxylate (130 mg, 0.18 mmol) was dissolved in methanol (3 mL) solution. Sodium hydroxide (72 mg, 1.8 mmol) was dissolved in water (1 mL) and added to the above methanol solution. The system was warmed to 70 C. and stirred for 1 h. After the completion of the reaction, the system was cooled to room temperature. The reaction solution was poured into water (5 mL). The obtained mixture was extracted with ethyl acetate (20 mL2). The aqueous phase was retained, adjusted to about pH 3 with 2 mol/L aqueous hydrochloric acid solution, and extracted with ethyl acetate (20 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product (S)-6-(5-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)selenobenzo[2,3-b]pyridine-2-carboxylic acid (90 mg) as a white solid. LCMS (ESI) m/z: 583[M+H].sup.+.

[0531] Step 9: the crude product (S)-6-(5-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)selenobenzo[2,3-b]pyridine-2-carboxylic acid (90 mg, 15.46 mmol), silver carbonate (1.7 mg, 0.006 mmol), and acetic acid (0.7 mg, 0.012 mmol) were dissolved in dimethyl sulfoxide (4 mL) solution. The system was warmed to 100 C. and stirred for 4 h. After completion of the reaction, the obtained mixture was directly filtered to give a crude product. The crude product was purified by high-performance liquid chromatography (column: Kinetex EVO prep C18, 30*150, 5 m; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 37% B to 67% B within 10 min; wavelength: 220 nm; retention time: 8.53 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)selenobenzo[2,3-b]pyridin-6-yl)imidazolidine-4-carboxamide (3.88 mg, 0.007 mmol, yield: 4.8%) as a white solid.

[0532] LCMS(ESI) 538.85[M+H].sup.+.

[0533] HNMR (400 MHz, DMSO-d6): ppm 8.67-8.64 (m, 1H), 8.45-8.36 (m, 1H), 7.83-7.70 (m, 1H), 7.66-7.37 (m, 3H), 5.82-4.86 (m, 1H), 5.81-4.86 (m, 1H), 3.95-3.65 (m, 2H), 3.25-3.12 (m, 3H).

Example 34: (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(2-methyl-7-(trifluoromethyl)thiazolo[5,4-b]pyridin-5-yl)-2-oxoimidazolidine-4-carboxamide (Compound 34)

##STR00105##

[0534] Step 1: 5-chloro-7-(trifluoromethyl)thiazolo[5,4-b]pyridin-2-amine (500 mg, 1.97 mmol) was dissolved in acetonitrile (20 mL) and cooled to 0 C. Tert-butyl nitrite (0.35 mL) was added at 0 C., and the system was reacted at 0 C. for 10 min. Copper bromide (660.46 mg, 2.96 mmol) was then added, and the system was reacted at 0 C. for 30 min and then at room temperature for 2 h. The desired product can be detected by LCMS. The obtained mixture was extracted with dichloromethane (310 mL). The combined organic layer was washed with salt water (35 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (5:1) to give 2-bromo-5-chloro-7-(trifluoromethyl)thiazolo[5,4-b]pyridine (435 mg, yield: 70%) as a yellow solid. LCMS (ESI): 317 [M+H]+.

[0535] Step 2: 2-bromo-5-chloro-7-(trifluoromethyl)thiazolo[5,4-b]pyridine (300 mg, 0.94 mmol) was dissolved in 1,4-dioxane (10 mL) solution. Trimethylboroxine (0.32 mL, 1.13 mmol) and potassium carbonate (195.58 mg, 1.42 mmol) were added at room temperature, followed by tetrakis(triphenylphosphine)palladium (109.13 mg, 0.09 mmol) under a nitrogen atmosphere. The reaction was reacted at 100 C. for 4 h. The desired product can be detected by LCMS. The obtained mixture was extracted with dichloromethane (310 mL). The combined organic layer was washed with saturated salt water (5 mL3) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (3:1) to give 5-chloro-2-methyl-7-(trifluoromethyl)thiazolo[5,4-b]pyridine (145 mg, yield: 61%) as a yellow solid.

[0536] LCMS (ESI): 253 [M+H]+.

[0537] Step 3: 5-chloro-2-methyl-7-(trifluoromethyl)thiazolo[5,4-b]pyridine (130 mg, 0.51 mmol), (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (Intermediate 6, 160.45 mg, 0.41 mmol), tris(dibenzylideneacetone)dipalladium (47.08 mg, 0.05 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (29.74 mg, 0.05 mmol), and potassium carbonate (213.00 mg, 1.54 mmol) were dissolved in 1,4-dioxane (5 mL) solution and reacted at 80 C. for 2 h. The desired product can be detected by LCMS. The obtained mixture was extracted with dichloromethane (35 mL). The combined organic layer was washed with salt water (31 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (1:1) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(2-methyl-7-(trifluoromethyl)thiazolo[5,4-b]pyridin-5-yl)-2-oxoimidazolidine-1-carboxylate (200 mg, yield: 64%) as a yellow solid. LCMS (ESI): 606 [M+H]+.

[0538] Step 4: (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(2-methyl-7-(trifluoromethyl)thiazolo[5,4-b]pyridin-5-yl)-2-oxoimidazolidine-1-carboxylate (180 mg, 0.30 mmol) was dissolved in 5 mL of trifluoroacetic acid:dichloromethane (1:5) and reacted at room temperature for 0.5 h. The desired product can be detected by LCMS. After distillation under reduced pressure, the mixture was passed through a column: XBridge Prep OBD C18 column, 30*150 mm, 5 m; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 33% B to 65% B within 8 min; wavelength: 220 nm; retention time 7.42 min; run times: 0, to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(2-methyl-7-(trifluoromethyl)thiazolo[5,4-b]pyridin-5-yl)-2-oxoimidazolidine-4-carboxamide (101.44 mg, yield: 68%) as a white solid.

[0539] LCMS (ESI): 505.80 [M+H]+.

[0540] HNMR (400 MHz, DMSO-d6): ppm 8.70-8.69 (s, 1H), 7.85-7.73 (m, 1H), 7.73-7.63 (m, 1H), 7.52-7.39 (m, 1H), 5.80-4.83 (m, 1H), 3.90-3.41 (m, 2H), 3.24-3.11 (s, 3H), 2.90-2.93 (s, 3H).

Example 35: {(4S)-3-[2-amino-7-(trifluoromethyl)(1,3-thiazolo[4,5-e]pyridin-5-yl)]-2-oxoimidazolidin-4-yl}-N-(3-chloro-2,4-difluorophenyl)-N-methylformamide (Compound 35)

##STR00106##

[0541] Step 1: a mixture of 5-chloro-7-(trifluoromethyl)-1,3-thiazolo[5,4-b]pyridin-2-ylamine (100.00 mg, 0.39 mmol), di-tert-butyl dicarbonate (257.86 mg, 1.18 mmol), and dimethylaminopyridine (0.12 mg, 0.00 mmol) in dichloromethane (3.00 mL) was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with salt water, dried over anhydrous sodium sulfate, filtered, and concentrated under a vacuum. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=90:10) to give the product tert-butyl {bis(tert-butoxy)-N-[5-chloro-7-(trifluoromethyl)(1,3-thiazolo[5,4-b]pyridin-2-yl)]carbonylamino}carboxylate (170 mg, 0.37 mmol, yield: 60%) as a colorless oil. LCMS (ESI): 454 [M+H].sup.+.

[0542] Step 2: tert-butyl {bis(tert-butoxy)-N-[5-chloro-7-(trifluoromethyl)(1,3-thiazolo[5,4-b]pyridin-2-yl)]carbonylamino}carboxylate (100.00 mg, 0.22 mmol), (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (Intermediate 6, 85.88 mg, 0.22 mmol), tris(dibenzylideneacetone)dipalladium (20.18 mg, 0.02 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12.76 mg, 0.02 mmol), and potassium carbonate (91.22 mg, 0.66 mmol) were reacted in dioxane (10.00 mL) at 100 C. for 1 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with salt water, dried over anhydrous sodium sulfate, filtered, and concentrated under a vacuum. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=70:30) to give the product {(4S)-tris(tert-butoxy)-3-[2-amino-7-(trifluoromethyl)(1,3-thiazolo[4,5-e]pyridin-5-yl)]-2-oxoimidazolidin-4-yl}-N-(3-chloro-2,4-difluorophenyl)-N-methylformamide (200 mg, 0.24 mmol, yield: 80%) as a yellow solid. LCMS (ESI): 807[M+H].sup.+.

[0543] Step 3: a mixture of {(4S)-tris(tert-butoxy)-3-[2-amino-7-(trifluoromethyl)(1,3-thiazolo[4,5-e]pyridin-5-yl)]-2-oxoimidazolidin-4-yl}-N-(3-chloro-2,4-difluorophenyl)-N-methylformamide (200.00 mg, 0.25 mmol) and trifluoroacetic acid (2.00 mL) in dichloromethane (10.00 mL) was stirred at room temperature for 1 h. After completion of the reaction, the reaction was quenched with saturated salt and extracted with ethyl acetate. The combined organic layer was washed with salt water, dried over anhydrous sodium sulfate, filtered, and concentrated under a vacuum. The crude product was purified by high-performance liquid chromatography (column: Xselect CSH C18 OBD column 30*150 mm, 5 m; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 50% B within 8 min; wavelength: 220 nm; retention time: 7.15 min) to give {(4S)-3-[2-amino-7-(trifluoromethyl)(1,3-thiazolo[4,5-e]pyridin-5-yl)]-2-oxoimidazolidin-4-yl}-N-(3-chloro-2,4-difluorophenyl)-N-methylformamide (20.22 mg, yield: 16%) as a white solid.

[0544] LCMS (ESI): 507.25[M+H],

[0545] HNMR (400 MHz, DMSO-d6): ppm 8.40-8.34 (s, 1H), 8.13-8.06 (m, 2H), 7.68-7.57 (m, 1H), 7.55-7.38 (m, 2H), 5.70-4.75 (m, 1H), 3.86-3.45 (m, 2H), 3.22-3.16 (m, 3H).

Example 36: (S)N-(3-chloro-2,4-difluorophenyl)-3-(2-cyano-7-(trifluoromethyl)thiazolo[5,4-b]pyridin-5-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide (Compound 36)

##STR00107##

[0546] A solution of cuprous cyanide (26.64 mg, 0.30 mmol) and tert-butyl nitrite (30.48 mg, 0.30 mmol) in acetonitrile (10.00 mL) was stirred at 50 C. for 10 min. Then, {(4S)-3-[2-amino-7-(trifluoromethyl) (1,3-thiazolo[4,5-e]pyridin-5-yl)]-2-oxoimidazolidin-4-yl}-N-(3-chloro-2,4-difluorophenyl)-N-methylformamide (Compound 35, 100.00 mg, 0.20 mmol) in acetonitrile (5.00 mL) was added to the mixture at the same temperature. The reaction solution was concentrated. The crude product was purified by prep-HPLC: column: XBridge Prep OBD C18 column, 30*150 mm, 5 m; mobile phase A: water (10 mmol/L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 37% B to 67% B within 10 min; wavelength: 220 nm; RT1 (min): 8.53, to give (S)N-(3-chloro-2,4-difluorophenyl)-3-(2-cyano-7-(trifluoromethyl)thiazolo[5,4-b]pyridin-5-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide (3.57 mg, yield: 3%) as a yellow solid.

[0547] LCMS (ESI): 517.20[M+H]+.

[0548] HNMR (400 MHz, DMSO-d6): ppm 9.03-8.97 (m, 1H), 8.13-8.05 (m, 1H), 7.74-7.68 (m, 1H), 7.52-7.48 (m, 1H), 5.07-4.86 (m, 1H), 3.62-3.58 (m, 1H), 3.51-3.49 (m, 1H), 3.22-3.17 (m, 3H).

Example 37: {(2S,3S,4S)-1-[7,7-difluoro-4-(trifluoromethyl)(5,6,7-trihydrocyclopenta[1,2-e]pyridin-2-yl)]-3,4-dihydroxy-5-oxopyrrolidin-2-yl}-N-(5-chloro-2,4-difluorophenyl)-N-methylformamide (Compound 37)

##STR00108##

[0549] Step 1: a solution of ((1S,2S,5S)-7,7-dimethyl-4-oxo-6,8-dioxa-3-azabicyclo[3.3.0]octan-2-yl)-N-(5-chloro-2,4-difluorophenyl)-N-methylformamide (Intermediate 4, 400.00 mg, 1.10 mmol), 2-chloro-4-(trifluoromethyl)-5,6-dihydrocyclopenta[2,1-b]pyridin-7-one (Compound 12-5, 388.59 mg, 1.65 mmol), potassium carbonate (455.25 mg, 3.30 mmol), tris(dibenzylideneacetone)dipalladium (100.70 mg, 0.0.11 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (63.67 mg, 0.11 mmol) in dioxane (20.00 mL) was stirred at 80 C. for 2 h. After completion of the reaction, the system was cooled to room temperature, and saturated aqueous sodium bicarbonate solution (15 mL) was added. The mixture was extracted with ethyl acetate (25 mL). The aqueous phases were combined and extracted 5 times with 5 mL of ethyl acetate each. The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give {(1S,2S,5S)-7,7-dimethyl-4-oxo-3-[7-oxo-4-(trifluoromethyl)(5,6-dihydrocyclopenta[1,2-e]pyridin-2-yl)]-6,8-dioxa-3-azabicyclo[3.3.0]octan-2-yl}-N-(5-chloro-2,4-difluorophenyl)-N-methylformamide (140.00 mg, 1.09 mmol, yield: 23%) as a colorless oil. LCMS (ESI): 563[M+H].sup.+.

[0550] Step 2: to a solution of {(1S,2S,5S)-7,7-dimethyl-4-oxo-3-[7-oxo-4-(trifluoromethyl)(5,6-dihydrocyclopenta[1,2-e]pyridin-2-yl)]-6,8-dioxa-3-azabicyclo[3.3.0]octan-2-yl}-N-(5-chloro-2,4-difluorophenyl)-N-methylformamide (140.00 mg, 0.25 mmol) in acetic acid (8.00 mL) was added ethane-1,2-dithiol (70.29 mg, 0.75 mmol) and aluminum trichloride (13.27 mg, 0.10 mmol). The reaction system was then replaced with nitrogen three times. The obtained mixture was stirred at 80 C. overnight for 2 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with salt water, dried over anhydrous sodium sulfate, filtered, and concentrated under a vacuum. The crude product was purified by reverse phase low-pressure chromatography (5% to 60% ammonium bicarbonate aqueous solution/acetonitrile, yield: 30%) to give {(2S,3S,4S)-3,4-dihydroxy-5-oxo-1-[9-(trifluoromethyl)spiro[1,3-dithiolane-2,7-5,6,7-trihydrocyclopenta[2,1-e]pyridin]-7-yl]pyrrolidin-2-yl}-N-(5-chloro-2,4-difluorophenyl)-N-methylformamide (60.00 mg, 0.24 mmol, yield: 40%), LCMS (ESI): 599 [M+H]+.

[0551] Step 3: to a solution of N-bromosuccinimide (35.66 mg, 0.20 mmol) in dichloromethane (6.00 mL) was added pyridine hydrofluoride (0.60 mL) at 78 C. The mixture was stirred for 0.5 h. {(2S,3S,4S)-3,4-Dihydroxy-5-oxo-1-[9-(trifluoromethyl)spiro[1,3-dithiolane-2,7-5,6,7-trihydrocyclopenta[1,2-e]pyridin]-7-yl]pyrrolidin-2-yl}-N-(5-chloro-2,4-difluorophenyl)-N-methylformamide (90.00 mg, 0.02 mmol) in dichloromethane (0.5 mL) was then added. After completion, the reaction mixture was diluted with ice water and extracted with dichloromethane. The combined organic layer was washed with salt water, dried over anhydrous sodium sulfate, filtered, and concentrated under a vacuum. The reaction solution was concentrated. The residue was purified by reverse phase low-pressure chromatography (5% to 60% ammonium bicarbonate aqueous solution/acetonitrile, yield: 45%) to give a crude product (60 mg). The crude product was purified by high-performance liquid phase: column: Xselect CSH C18 OBD column 30*150 mm 5 m; mobile phase A: water (0.05% FA), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 50% B within 8 min; wavelength: 220 nm; retention time: 7.15 min, to give {(2S,3S,4S)-1-[7,7-difluoro-4-(trifluoromethyl)(5,6,7-trihydrocyclopenta[1,2-e]pyridin-2-yl)]-3,4-dihydroxy-5-oxopyrrolidin-2-yl}-N-(5-chloro-2,4-difluorophenyl)-N-methylformamide (11.18 mg, 0.1 mmol, yield: 20%) as a white solid.

[0552] LCMS (ESI): 545.00[M+H].sup.+.

[0553] HNMR (400 MHz, DMSO-d6): ppm 8.60-8.52 (m, 1H), 7.94-7.43 (m, 2H), 5.74-5.25 (m, 2H), 5.04-4.79 (m, 1H), 4.48-4.33 (m, 1H), 4.09-3.98 (m, 1H), 3.20-3.19 (m, 2H), 2.79-2.74 (m, 2H).

Example 38: 6{(5S)-5-[N-(3-chloro-2,4-difluorophenyl)-N-methylcarbamoyl]-2-oxoimidazolidinyl}-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (Compound 38)

##STR00109##

[0554] Step 1: methyl 4-(trifluoromethyl)-6-(((trifluoromethyl)sulfonyl)oxy)thieno[2,3-b]pyridine-2-carboxylate (800 mg, 1.96 mmol) and (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (Intermediate 6, 768 mg, 1.96 mmol) were dissolved in 1,4-dioxane (50 mL). Tris(dibenzylideneacetone)dipalladium (44 mg, 0.20 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.14 g, 0.20 mmol), and anhydrous potassium carbonate (4.08 g, 3.88 mmol) were then added. The mixture was reacted at 80 C. for 1 h. After completion of the reaction, the reaction solution was poured into saturated aqueous sodium bicarbonate solution (60 mL) and extracted with ethyl acetate (60 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=20:80) to give (S)-methyl 6-(3-(tert-butoxycarbonyl)-5-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate (780 mg, 1.20 mmol, yield: 61%) as a light yellow solid powder. LCMS (ESI) m z: 649 [M+H].sup.+.

[0555] Step 2: methyl (S)-6-(3-(tert-butoxycarbonyl)-5-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate (350 mg, 0.54 mmol) was dissolved in ammonia-methanol (7M, 30 mL) solution and reacted at 80 C. for 2 h. After completion of the reaction, the reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=30:70) to give (S)-tert-butyl 3-(2-carbamoyl-4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (250 mg, 0.40 mmol, yield: 73%) as a light yellow solid powder. LCMS (ESI) m z: 634 [M+H].sup.+.

[0556] Step 3: (S)-tert-butyl 3-(2-carbamoyl-4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (125 mg, 0.20 mmol) was dissolved in trifluoroacetic acid (5 mL) and dichloromethane (25 mL). The mixture was reacted at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated to give a crude product. The crude product was purified by preparative liquid chromatography (column: Kinetex EVO prep C18, 30*150, 5 m; mobile phase A: water (10 mmol/L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 20% B to 50% B within 8 min; wavelength: 220 nm; RT1 (min): 7.97; run times: 0) to give 29.86 mg of 6-{(5S)-5-[N-(3-chloro-2,4-difluorophenyl)-N-methylcarbamoyl]-2-oxoimidazolidinyl}-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide as a white solid.

[0557] LCMS(ESI) 534.20 [M+H].sup.+.

[0558] .sup.1H NMR (400 MHz, DMSO-d6) 8.77-8.70 (m, 1H), 8.45-8.42 (m, 1H), 8.19-8.16 (m, 1H), 7.90-7.82 (m, 1H), 7.77-7.73 (m, 1H), 7.72-7.67 (m, 1H), 7.51-7.47 (m, 1H), 5.65-4.66 (m, 1H), 3.60-3.41 (m, 2H), 3.23-3.20 (m, 3H).

Example 39: (S)N-(3-chloro-2,4-difluorophenyl)-3-(2-cyano-4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide (Compound 39)

##STR00110##

[0559] Step 1: a mixture of tert-butyl (4S)-3-[2-carbamoyl-4-(trifluoromethyl) thieno [3, 2-e]pyridin-6-yl]-4-[N-(3-chloro-2, 4-difluorophenyl)-N-methylcarbamoyl]-2-oxoimidazolidine carboxylate (500.00 mg, 0.79 mmol), pyridine (7.5 mg, 9.46 mmol), and trifluoroacetic anhydride (198.77 mg, 0.95 mmol) in dichloromethane (0.50 mL) were stirred at room temperature for 12 h. The mixture was then concentrated and purified by column chromatography (petroleum ether:ethyl acetate=70:30) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(2-cyano-4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)-2-oxoimidazolidine-1-carboxylate (200 mg, yield: 59%) as a colorless oil. LCMS (ESI): 616 [M+H].sup.+.

[0560] Step 2: (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(2-cyano-4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)-2-oxoimidazolidine-1-carboxylate (100 mg, 0.17 mmol) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (5 mL), and the system was stirred at room temperature for 1 h. After completion of the reaction, the obtained mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative high performance liquid chromatography under the following conditions: column: Xselect CSH C18 OBD column 30*150 mm, 5 m; mobile phase A: water (0.05% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 50% B to 90% B within 8 min; wavelength: 220 nm; RT1 (min): 6.22; run times: 0, to give (S)N-(3-chloro-2,4-difluorophenyl)-3-(2-cyano-4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide (4.94 mg, 0.009 mmol, yield: 63%) as a white solid.

[0561] LCMS (ESI): 516.25 [M+H]+.

[0562] HNMR (400 MHz, DMSO-d6): ppm 8.87-8.81 (m, 1H), 8.45-8.42 (m, 1H), 8.05-7.96 (m, 1H), 7.76-7.69 (m, 1H), 7.47-7.39 (m, 1H), 5.82-4.86 (m, 1H), 3.61-3.55 (m, 1H), 3.42-3.40 (m, 1H), 3.25-3.18 (m, 3H).

Example 40: (6-{(5S)-5-[N-(3-chloro-2,4-difluorophenyl)-N-methylcarbamoyl]-2-oxoimidazolidinyl}-4-(trifluoromethyl)thieno[2,3-b]pyridin-2-yl)-N-methylformamide (Compound 40)

##STR00111##

[0563] Step 1: a mixture of methyl 6-{(5S)-3-[(tert-butyl)oxycarbonyl]-5-[N-(3-chloro-2,4-difluorophenyl)-N-methylcarbamoyl]-2-oxoimidazolidinyl}-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate (500 mg, 0.77 mmol) and sodium hydroxide (61 mg, 1.54 mmol) in methanol (10.00 mL) was stirred at room temperature for 5 h, adjusted to acidic (pH=3) with dilute hydrochloric acid, and then filtered to give 6-{(5S)-3-[(tert-butyl)oxycarbonyl]-5-[N-(3-chloro-2,4-difluorophenyl)-N-methylcarbamoyl]-2-oxoimidazolidinyl}-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylic acid (300 mg, 0.77 mmol, yield: 61%) as a colorless oil. LCMS (ESI): 634 [M+H].sup.+.

[0564] Step 2: (S)-6-(3-(tert-butoxycarbonyl)-5-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylic acid (300 mg, 0.47 mmol), methylamine (27 mg, 0.94 mmol), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (303 mg, 0.94 mmol), and N,N-diisopropylethyl amine (182 mg, 1.42 mmol) were stirred in dimethylformamide (5.00 mL) for 2 h. The mixture was then poured into water (10 mL), extracted with ethyl acetate (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was then purified by column chromatography (petroleum ether:ethyl acetate=70:30) to give tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(2-(methylcarbamoyl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl 2-oxoimidazolidine-1-carboxylate (200.00 mg, 0.47 mmol, yield: 65%) as a yellow solid. LCMS (ESI): 648[M+H]+.

[0565] Step 3: a mixture of tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(2-(methylcarbamoyl)-4-(trifluoromethyl)thieno[2,3-b]pyridin-6-yl 2-oxoimidazolidine-1-carboxylate (250 mg, 0.39 mmol) in trifluoroacetic acid (2 mL) and dichloromethane (6 mL) was stirred at room temperature for 2 h. The mixture was spin-dried and purified by high-performance liquid chromatography (column: XBridge Shield RP18 OBD column, 30150 mm, m; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 30% B to 60% B within 10 min; wavelength: 220 nm; retention time (min): 8.62) to give (6-{(5S)-5-[N-(3-chloro-2,4-difluorophenyl)-N-methylcarbamoyl]-2-oxoimidazolidinyl}-4-(trifluoromethyl)thieno[2,3-b]pyridin-2-yl)-N-methylformamide (30.73 mg, 0.38 mmol, yield: 14%) as a white solid.

[0566] LCMS (ESI): 548.25 [M+H].sup.+.

[0567] HNMR (400 MHz, DMSO-d6): ppm 8.96-8.92 (m, 1H), 8.76-8.72 (m, 1H), 8.14-8.10 (m, 1H), 7.90-7.75 (m, 1H), 7.74-7.68 (m, 1H), 7.51-7.39 (m, 1H), 5.81-4.86 (m, 1H), 3.58-3.48 (m, 2H), 3.27-3.23 (m, 3H), 2.83-2.82 (m, 3H).

Example 41: (S)N-(3-chloro-2,4-difluorophenyl)-3-(imidazo[1,2-a]pyrazin-8-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide (Compound 41)

##STR00112##

[0568] Step 1: a solution of 8-chloro-4-hydroimidazo[1,2-a]pyrazine (100 mg, 0.65 mmol), tert-butyl (4S)-4-[N-(3-chloro-2,4-difluorophenyl)-N-methylcarbamoyl]-2-oxoimidazolidine carboxylate (Intermediate 6, 253 mg, 0.65 mmol), potassium carbonate (269 mg, 1.95 mmol), palladium acetate (14 mg, 0.07 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (37 mg, 0.07 mmol) in dioxane (10 mL) was reacted at 80 C. for 12 h. After completion of the reaction, the mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL), dried, concentrated, and then purified by column chromatography (petroleum ether:ethyl acetate=70:30) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(imidazo[1,2-a]pyrazin-8-yl)-2-oxoimidazolidine-1-carboxylate (60 mg, 0.118 mmol, yield: 18%) as a colorless oil. LCMS (ESI): 506 [M+H]+.

[0569] Step 2: (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(imidazo[1,2-a]pyrazin-8-yl)-2-oxoimidazolidine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (5 mL), and the system was stirred at room temperature for 1 h. After completion of the reaction, the obtained mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative high performance liquid chromatography under the following conditions: column: Xselect CSH C18 OBD column 30*150 mm, 5 m; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 15% B to 40% B within 8 min; wavelength: 220 nm; retention time (min): 7.23 min, to give (S)N-(3-chloro-2,4-difluorophenyl)-3-(imidazo[1,2-a]pyrazin-8-yl)-N-methyl-2-oxoimidazolidine-4-carboxamide (59 mg, 0.10 mmol, yield: 63%) as a white solid.

[0570] LCMS (ESI): 406.80 [M+H].sup.+.

[0571] HNMR (400 MHz, DMSO-d6): ppm 8.40-8.30 (m, 1H), 8.10-8.05 (m, 1H), 7.80-7.70 (m, 1H), 7.68-7.50 (m, 2H), 7.48-7.28 (m, 2H), 6.28-5.35 (m, 1H), 3.93-3.42 (m, 2H), 3.20-3.05 (m, 3H).

Example 42: (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-6-yl)imidazolidine-4-carboxamide (Compound 42)

##STR00113##

[0572] Step 1: a mixture of isoxazol-5-ylamine (50.00 mg, 0.59 mmol) and ethyl 4,4,4-trifluoro-3-oxobutanoate (109.49 mg, 0.59 mmol) in acetic acid (1.00 mL) was stirred at 120 C. for 12 h. After completion of the reaction, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=80:20) to give 4-(trifluoromethyl)-7-hydroisoxazolo[5,4-b]pyridin-6-one (30.00 mg, yield: 25%, 0.146 mmol) as a yellow oil. LCMS (ESI): 205 [M+H].sup.+.

[0573] Step 2: a solution of 4-(trifluoromethyl)-7-hydroisoxazolo[5,4-b]pyridin-6-one (300 mg, 1.46 mmol) in phosphorus oxychloride (2 mL) was stirred at 150 C. under microwave for 2 h. After the reaction, the reaction solution was concentrated, poured into water, extracted with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was then concentrated and purified by column chromatography (petroleum ether:ethyl acetate=50:50) to give 6-chloro-4-(trifluoromethyl)isoxazolo[5,4-b]pyridine (300 mg, yield: 55%, 1.4 mmol) as a white solid. LCMS (ESI): 223 [M+H].sup.+.

[0574] Step 3: a solution of 6-chloro-4-(trifluoromethyl)isoxazolo[5,4-b]pyridine (40 mg, 0.18 mmol), (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (70 mg, 0.18 mmol), potassium carbonate (70 mg, 0.54 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg, 0.02 mmol) in dioxane (4.00 mL) was stirred at 80 C. for 12 h. The mixture was poured into water (5 mL), extracted with ethyl acetate (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol=80:20) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-6-yl)imidazolidine-1-carboxylate (50 mg, yield: 48%, 0.086 mmol) as a yellow oil. LCMS (ESI): 576 [M+H].sup.+.

[0575] Step 4: to a solution of (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-6-yl)imidazolidine-1-carboxylate (210.00 mg, 0.36 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated. The crude product was purified by chiral__HPLC: column: CHIRALPAK-IA 2*25 cm, 5 m; mobile phase A: n-hexane (0.1% formic acid), mobile phase B: ethanol:dichloromethane=1:1; flow rate: 20 mL/min; gradient: isocratic 20; wavelength: 254/220 nm; RT1 (min): 7.44; sample solvent: ethanol; injection volume: 2.0 mL; run times: 3 times, to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(4-(trifluoromethyl)isoxazolo[5,4-b]pyridin-6-yl)imidazolidine-4-carboxamide (18.53 mg, yield: 10%, 0.038 mmol) as a white solid.

[0576] LCMS (ESI): 475.90 [M+H].sup.+.

[0577] 1H NMR (400 MHz, DMSO-d6) ppm 8.78-8.76 (m, 1H), 7.41-7.39 (m, 2H), 7.20-6.95 (m, 2H), 5.55-4.67 (m, 1H), 3.21-3.20 (m, 1H), 3.11 (s, 3H), 3.01-2.92 (m, 1H).

Example 43: (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(7-(methylthio)thiazolo[5,4-b]pyridin-5-yl)-2-oxoimidazolidine-4-carboxamide (Compound 43)

##STR00114##

[0578] Step 1: 7-bromo-5-chlorothiazolo[5,4-b]pyridine (500 mg, 2.02 mmol) was dissolved in tetrahydrofuran (50 mL), and sodium methanethiolate (141 mg, 2.02 mmol) was then added. The system was reacted at 60 C. for 2 h. After completion of the reaction, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=75:25) to give 5-chloro-7-(methylthio)thiazolo[5,4-b]pyridine (350 mg, 1.62 mmol, yield: 80%) as a white solid. LCMS (ESI): 217 [M+H].sup.+.

[0579] Step 2: 5-chloro-7-(methylthio)thiazolo[5,4-b]pyridine (350 mg, 1.62 mmol) was dissolved in 1,4-dioxane (30 mL) and added to tert-butyl (S)-4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (535 mg, 1.37 mmol). Tris(dibenzylideneacetone)dipalladium (126 mg, 0.14 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (79 mg, 0.14 mmol), and anhydrous potassium carbonate (569 mg, 4.12 mmol) were then added and stirred at 80 C. overnight. After completion of the reaction, the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=85:15) to give (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(7-(methylthio)thiazolo[5,4-b]pyridin-5-yl)-2-oxoimidazolidine-1-carboxylate (210 mg, 0.37 mmol, yield: 24.67%) as a white solid. LCMS (ESI): 570 [M+H].sup.+.

[0580] Step 3: (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-3-(7-(methylthio)thiazolo[5,4-b]pyridin-5-yl)-2-oxoimidazolidine-1-carboxylate (210 mg, 0.37 mmol) was dissolved in dichloromethane:trifluoroacetic acid (10 mL:2 mL) and reacted at room temperature for 2 h. After completion of the reaction, the mixture was spin-dried. The crude product was purified by high-performance liquid chromatography (column: ultimate XBC18; mobile phase A: water (10 mmol/L ammonium bicarbonate aqueous solution), mobile phase B: acetonitrile; flow rate: 100 mL/min; gradient: 30% B to 60% B within 20 min; wavelength: 254 nm/220 nm; retention time: 19 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-3-(7-(methylthio)thiazolo[5,4-b]pyridin-5-yl)-2-oxoimidazolidine-4-carboxamide (73 mg, 0.16 mmol, yield: 43%) as a white solid.

[0581] LCMS (ESI): 470.20 [M+H].sup.+.

[0582] 1H NMR (400 MHz, DMSO-d6) ppm 9.24-9.18 (m, 1H), 8.32-8.28 (m, 1H), 7.65-7.60 (m, 1H), 7.52 (s, 1H), 7.47-7.42 (m, 1H), 5.72-4.92 (m, 1H), 3.87-3.45 (m, 2H), 3.14-3.11 (m, 3H), 2.53-2.48 (m, 3H).

Example 44: (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(7-((trifluoromethyl)thio)thiazolo[5,4-b]pyridin-5-yl)imidazolidine-4-carboxamide (Compound 44)

##STR00115##

[0583] Step 1: a mixture of trimethylsilyl chloride (43 mg, 0.4 mmol), sodium iodide (44 mg, 0.4 mmol), and 7-bromo-5-chloro-1,3-thiazolo[5,4-b]pyridine (50 mg, 0.2 mmol) in acetonitrile (1.00 mL) was stirred at 80 C. for 3 h. After completion of the reaction, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL3). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=15:75) to give 7-iodo-5-chloro-1,3-thiazolo[5,4-b]pyridine (20 mg, yield: 40%, 0.058 mmol) as a yellow oil. LCMS (ESI): 342 [M+H].sup.+.

[0584] Step 2: a mixture of thiotrifluoromethyl copper salt (64 mg, 0.2 mmol) and 7-iodo-5-chloro-1,3-thiazolo[5,4-b]pyridine (50 mg, 0.2 mmol) in dioxane (1.00 mL) was stirred at 100 C. overnight. After the reaction, the reaction solution was concentrated, poured into water, extracted with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was then concentrated and purified by column chromatography (petroleum ether:ethyl acetate=30%) to give 5-chloro-7-(trifluoromethylthio)-1,3-thiazolo[5,4-b]pyridine (27 mg, 0.1 mmol, yield: 50%) as a white solid. LCMS (ESI): 272 [M+H].sup.+.

[0585] Step 3: 5-chloro-7-(trifluoromethylthio)-1,3-thiazolo[5,4-b]pyridine (200 mg, 0.74 mmol), tert-butyl (4S)-4-[N-(3-chloro-2,4-difluorophenyl)-N-methylcarbamoyl]-2-oxoimidazolidine carboxylate (290 mg, 0.74 mmol), potassium carbonate (310 mg, 2.22 mmol), tris(dibenzylideneacetone)dipalladium (30 mg, 0.07 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.07 mmol) were reacted in dioxane (1.00 mL) at 80 C. for 12 h. The mixture was poured into water (2 mL), extracted with ethyl acetate (5 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=45:55) to give tert-butyl (4S)-4-[N-(3-chloro-2,4-difluorophenyl)-N-methylcarbamoyl]-2-oxo-3-[7-(trifluoromethylthio)(1,3-thiazolo[4,5-e]pyridin-5-yl)]imidazolidine carboxylate (50 mg, yield: 48%, 0.086 mmol) as a yellow oil. LCMS (ESI): 624 [M+H].sup.+.

[0586] Step 4: to a solution of (S)-tert-butyl 4-((3-chloro-2,4-difluorophenyl)(methyl)carbamoyl)-2-oxo-3-(7-((trifluoromethyl)thio)thiazolo[5,4-b]pyridin-5-yl)imidazolidine-1-carboxylate (50 mg, 0.086 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated and purified by high-performance liquid chromatography (column: XB-C18; mobile phase A: water (10 mmol/L ammonium bicarbonate aqueous solution), mobile phase B: acetonitrile; flow rate: 100 mL/min; gradient: 30% B to 60% B within 20 min; wavelength: 254 nm/220 nm; retention time: 16 min) to give (S)N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-oxo-3-(7-((trifluoromethyl)thio)thiazolo[5,4-b]pyridin-5-yl)imidazolidine-4-carboxamide (1.77 mg, yield: 4, 0.003 mmol) as a white solid.

[0587] LCMS (ESI): 524 [M+H].sup.+.

[0588] HNMR (400 MHz, DMSO-d6): ppm 9.46-9.34 (m, 1H), 8.85-8.73 (m, 1H), 7.80-7.63 (m, 2H), 7.51-7.39 (m, 1H), 5.78-4.83 (m, 1H), 4.12-3.52 (m, 2H), 3.18-2.97 (m, 3H).

Example 45: (2S,3S,4S)N-(5-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-(methyl-D3)-5-oxo-1-(7-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)pyrrolidine-2-carboxamide (Compound 45)

##STR00116##

[0589] To a solution of (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-2,2-dimethyl-N-(methyl-D3)-6-oxo-5-(7-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)tetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide (80 mg, 0.142 mmol) in acetic acid (8.00 mL) was added anhydrous aluminum chloride (8 mg, 0.056 mmol), and the mixture was stirred at 80 C. for 2 h. The reaction solution was concentrated. The crude product was purified by high-performance liquid chromatography: column: Kinetex 5 m EVO C18, 30 mm*150 mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: 20 mm sodium hydroxide+10% acetonitrile; flow: 60 mL/min; gradient: 20% B to 50% B within 8 min; wavelength: 254 nm/220 nm; retention time (min): 7.55, to give (2S,3S,4S)N-(5-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-(methyl-D3)-5-oxo-1-(7-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)pyrrolidine-2-carboxamide (10 mg, yield: 13%, 0.019 mmol) as a white solid.

[0590] LCMS (ESI): 523.30 [M+H].sup.+.

[0591] 1H NMR (400 MHz, DMSO-d6) ppm 8.73-8.69 (m, 1H), 8.67 (s, 1H), 7.89-7.83 (m, 1H), 5.79-5.56 (m, 2H), 5.24-5.23 (m, 1H), 5.00-4.97 (m, 1H), 4.31-4.26 (m, 1H), 4.11-4.05 (m, 1H), 3.23-3.17 (m, 2H), 2.83-2.82 (m, 1H).

Example 46: (2S,3S,4S)N-(5-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-(methyl-D3)-5-oxo-1-(4-(trifluoromethyl)selenophenyl[2,3-b]pyridin-6-yl)pyrrolidine-2-carboxamide (Compound 46)

##STR00117## ##STR00118##

[0592] Step 1: ethyl 6-chloro-4-(trifluoromethyl)selenobenzo[2,3-b]pyridine-2-carboxylate (200 mg, 0.56 mmol), (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-2,2-dimethyl-N-(methyl-D3)-6-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide (203 mg, 0.56 mmol), tris(dibenzylideneacetone)dipalladium (55 mg, 0.06 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35 mg, 0.06 mmol), and potassium carbonate (232 mg, 1.68 mmol) were dissolved in dioxane (15 mL) and reacted at 80 C. for 1 h. After completion of the reaction, the system was cooled to room temperature. The reaction solution was poured into water (10 mL). The obtained mixture was extracted with ethyl acetate (20 mL2). The combined organic layer was washed with saturated salt water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=60:40) to give ethyl 6-((3aS,4S,6aS)-4-((5-chloro-2,4-difluorophenyl)(methyl-d3)carbamoyl)-2,2-dimethyl-6-oxotetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl)-4-(trifluoromethyl)selenobenzo[2,3-b]pyridine-2-carboxylate (250 mg, 0.37 mmol, yield: 65%) as a light yellow solid. LCMS (ESI) m/z: 685 [M+H].sup.+.

[0593] Step 2: ethyl 6-((3aS,4S,6aS)-4-((5-chloro-2,4-difluorophenyl)(methyl-d3)carbamoyl)-2,2-dimethyl-6-oxotetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl)-4-(trifluoromethyl)selenobenzo[2,3-b]pyridine-2-carboxylate (250 mg, 0.37 mmol) was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL). Potassium hydroxide (414 mg, 7.4 mmol) was dissolved in water (3 mL) and added to the above solution at 0 C. The system was warmed to room temperature and stirred for 2 h. After completion of the reaction, the reaction solution was poured into water (10 mL). The obtained mixture was extracted with ethyl acetate (20 mL2). The aqueous phase was retained, adjusted to about pH 5 with formic acid, and extracted with ethyl acetate (20 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product 6-((3aS,4S,6aS)-4-((5-chloro-2,4-difluorophenyl)(methyl-d3)carbamoyl)-2,2-dimethyl-6-oxotetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl)-4-(trifluoromethyl)selenobenzo[2,3-b]pyridine-2-carboxylic acid (200 mg) as a white solid. LCMS (ESI) m/z: 657 [M+H].sup.+.

[0594] Step 3: the crude product 6-((3aS,4S,6aS)-4-((5-chloro-2,4-difluorophenyl)(methyl-d3)carbamoyl)-2,2-dimethyl-6-oxotetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl)-4-(trifluoromethyl)selenobenzo[2,3-b]pyridine-2-carboxylic acid (200 mg), silver carbonate (2.8 mg, 0.01 mmol), and acetic acid (1.2 mg, 0.02 mmol) were dissolved in dimethyl sulfoxide (4 mL) solution. The system was warmed to 100 C. and reacted overnight. After completion of the reaction, the reaction solution was poured into water (4 mL). The obtained mixture was extracted with ethyl acetate (10 mL3). The combined organic layer was washed with saturated salt water (5 mL3) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-2,2-dimethyl-N-(methyl-D3)-6-oxo-5-(4-(trifluoromethyl)selenophenyl[2,3-b]pyridin-6-yl)tetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide (150 mg) as a black solid. LCMS (ESI) m/z: 613 [M+H].sup.+.

[0595] Step 4: the crude product (3aS,4S,6aS)N-(5-chloro-2,4-difluorophenyl)-2,2-dimethyl-N-(methyl-D3)-6-oxo-5-(4-(trifluoromethyl)selenophenyl[2,3-b]pyridin-6-yl)tetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrole-4-carboxamide (150 mg) and anhydrous aluminum chloride (13.2 mg, 0.1 mmol) was dissolved in acetic acid. The system was warmed to 80 C. and reacted overnight. Part of the solvent was removed by concentration under reduced pressure to give a crude product. The crude product was purified by high-performance liquid chromatography (column: Kinetex EVO prep C18, 30*150, 5 m; mobile phase A: 10 mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 60% B within 10 min; wavelength: 254 nm/220 nm; retention time: 8.87 min) to give (2S,3S,4S)N-(5-chloro-2,4-difluorophenyl)-3,4-dihydroxy-N-(methyl-D3)-5-oxo-1-(4-(trifluoromethyl)selenophenyl[2,3-b]pyridin-6-yl)pyrrolidine-2-carboxamide (24.93 mg, 0.04 mmol, yield: 16.3%) as a light pink solid.

[0596] LCMS (ESI) m/z: 573 [M+H].sup.+.

[0597] HNMR (400 MHz, DMSO-d6): ppm 8.58-8.52 (m, 2H), 7.98-7.68 (m, 2H), 7.67-7.55 (m, 1H), 5.75-5.63 (m, 2H), 5.29-4.92 (m, 1H), 4.83-4.05 (m, 2H).

Effect Example 1

Pol Polymerase Activity Assay

[0598] The ability of compounds to inhibit Pol 0 polymerase activity was determined by the PicoGreen method in vitro.

[0599] The His-TEV-SUMO-tagged Pol protein (amino acids 1792-2590) expressed in E. coli was purified and stored in aliquots at 80 C.

[0600] The composition of the assay buffer is 25 mM Tris HCl pH 7.5, 12.5 mM NaCl, 0.5 mM MgCl.sub.2, 5% glycerol, 0.01% Triton X-100, 0.01% BSA, and 1 mM DTT.

[0601] Test compounds were diluted in 100% DMSO and diluted three-fold into 10 concentration points in a dilution plate (Greiner-781280) using Bravo (Agilent) according to concentration requirements. The compounds diluted in DMSO were then diluted 20-fold in the assay buffer using Bravo. Further, 2 l of diluted compounds were transferred to the assay plate (Corning-4512) using Bravo. The purified Pol 0 enzyme and primers ((primer strand: 5-GCGGCTGTCATAAG-3, SEQ ID NO: 1):(template strand: 5-GCTACATTGACAATGGCATCAAATCTCAGATTGCGTCTTATGACAGCCGCG-3, SEQ ID NO: 2)=1:1.1) were prepared at a working concentration of 2.5 (1.5 nM Pol and 50 nM PTD) in the assay buffer, transferred to the assay plate at 4 l per well using an E1-CLIPTIP 12-channel pipette (Thermo, 1-30 l), and incubated at room temperature for 30 min. dNTP (Sigma-D7295) was diluted with the assay buffer to a working concentration of 2.5 (40 uM dNTP), transferred to the assay plate at 4 l per well (final DMSO concentration of 1%) using an El-CLIPTIP 12-channel pipette (Thermo, 1-30 l), and incubated at room temperature for 60 min. A mixture containing 10 mM EDTA, 25 mM Tris pH 7.5, and a 1:200 diluted PicoGreen dye (Invitrogen-P7581) was added to the assay plate at 6 l per well to stop the reaction. After 30 min of reaction at room temperature in the dark, fluorescence values were read on EnVision 2105 (PerkinElmer) using the Ex480 nm Em520 nm program, and the raw data was analyzed using XLfit to generate IC50 values. The results are shown in the table below.

TABLE-US-00001 Compound No. Pol IC.sub.50 1 A 2 C 3 D 4 B 5 C 6a C 7 A 8a C 9a A 9b A 10 D 11 B 12 A 13 A 14 A 15 B 16 A 17 B 18 B 19 A 20 B 21 A 22 A 23 A 24 A 26 A 27 A 30 A 31 A 33 A 37 A 41 D 43 B 44 B 45 A 46 A A: IC.sub.50 50 nM; B: 50 nM < IC.sub.50 500 nM; C: 500 nM < IC.sub.50 5000 nM, D: IC.sub.50 > 5000 nM.