SUBSTITUTED ARYL COMPOUND

Abstract

The present application describes a substituted aryl compound used as an RAD51 inhibitor and a pharmaceutically acceptable salt thereof. The compound has the structure as represented by Formula (I) and has the substituents and structural features as described in the present application. Furthermore, the present application describes a pharmaceutical composition containing the compound as represented by Formula (I) or the pharmaceutically acceptable salt thereof, and the use of the compound as represented by Formula (I) or the pharmaceutically acceptable salt thereof and the pharmaceutical composition containing same in the preparation of a drug for preventing or treating RAD51 mediated diseases.

##STR00001##

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, ##STR00384## wherein R.sup.1 is ##STR00385## R.sup.7 is ##STR00386## C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl, said C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R.sup.7a; R.sup.7a is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, or the following group optionally substituted with one or more R.sup.7b: NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; R.sup.7b is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, or the following group optionally substituted with one or more R.sup.7c: NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; R.sup.7c is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl; R.sup.8 is H, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl, said C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R.sup.8a; R.sup.8a is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, or the following group optionally substituted with one or more R.sup.8b: NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; R.sup.8b is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, or the following group optionally substituted with one or more R.sup.8c: NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; R.sup.8c is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl; R.sup.9 is C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl, said C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R.sup.9a; R.sup.9a is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, or the following group optionally substituted with one or more R.sup.9b: NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; R.sup.9b is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, or the following group optionally substituted with one or more R.sup.9c: NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; R.sup.9c is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl; R.sup.10 is C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl, said C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R.sup.10a; R.sup.10a is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, or the following group optionally substituted with one or more R.sup.10b: NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; R.sup.10b is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, or the following group optionally substituted with one or more R.sup.10c: NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; R.sup.10c is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl; R.sup.11, R.sup.12, and R.sup.13 are independently C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl, said C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R.sup.11a; or R.sup.11 and R.sup.12, together with an atom to which they are linked, form 3- to 10-membered heterocyclyl, said 3- to 10-membered heterocyclyl is optionally substituted with one or more R.sup.11a; R.sup.11a is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, or the following group optionally substituted with one or more R.sup.11b: NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; R.sup.11b is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, or the following group optionally substituted with one or more R.sup.11c: NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; R.sup.11c is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl; R.sup.2, R.sup.3, and R.sup.4 are independently H, F, Cl, Br, I, OH, CN, NO.sub.2, or the following group optionally substituted with one or more R.sup.a: NH.sub.2, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; R.sup.a is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; L is ##STR00387## X.sub.1, X.sub.2, X.sub.3, Y.sub.2, Y.sub.3, and Z.sub.1 are independently CR.sup.15 or N; Y.sub.1, Z.sub.2, and Z.sub.3 are independently O, NH, or S; m is 0, 1, or 2; R.sup.15 is H, F, Cl, Br, I, OH, CN, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl, said C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R.sup.15a; said R.sup.15a is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; L.sub.1 is phenyl, C.sub.7-C.sub.12 spirocyclyl, C.sub.6-C.sub.12 fused cyclyl, C.sub.5-C.sub.12 bridged cyclyl, 7- to 12-membered spiroheterocyclyl, 6- to 12-membered fused heterocyclyl, 3- to 10-membered monocyclic heterocyclyl, or 5- to 12-membered bridged heterocyclyl, said 7- to 12-membered spiroheterocyclyl, 6- to 12-membered fused heterocyclyl, 3- to 10-membered monocyclic heterocyclyl, or 5- to 12-membered bridged heterocyclyl contains 1 to 3 heteroatoms selected from O, N, or S; said C.sub.7-C.sub.12 spirocyclyl, C.sub.6-C.sub.12 fused cyclyl, C.sub.5-C.sub.12 bridged cyclyl, 7- to 12-membered spiroheterocyclyl, 6- to 12-membered fused heterocyclyl, 3- to 10-membered monocyclic heterocyclyl, or 5- to 12-membered bridged heterocyclyl is optionally substituted with one or more R.sup.28; said R.sup.28 is F, Cl, Br, I, OH, CN, NO.sub.2, or the following group optionally substituted with one or more R.sup.28a: NH.sub.2, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; R.sup.28a is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl; W.sub.1 and W.sub.4 are independently a chemical bond, NR.sup.16, or O; R.sup.16 is H, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl, said C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R.sup.16a; said R.sup.16a is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; R.sup.5 is ##STR00388## 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; said 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl is optionally substituted with one or more R.sup.20a; n is 0 or 1; X.sub.5 is N or CR.sup.21; Y.sub.5 and Y.sub.6 are independently a chemical bond, NH, or CR.sup.22; Z.sub.5 and Z.sub.6 are independently O or NR.sup.23; R.sup.17, R.sup.18, R.sup.25, and R.sup.26 are independently H, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy, said C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy is optionally substituted with one or more R.sup.17a; R.sup.17a is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, or the following group optionally substituted with one or more R.sup.17b: NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; R.sup.17b is F, Cl, Br, I, OH, CN, or the following group optionally substituted with one or more R.sup.17c: C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, or C.sub.6-C.sub.10 aryl; R.sup.17c is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl; or R.sup.17 and R.sup.18, together with an atom X.sub.5 to which they are linked, form 3- to 10-membered heterocyclyl or C.sub.3-C.sub.10 cycloalkyl, said 3- to 10-membered heterocyclyl or C.sub.3-C.sub.10 cycloalkyl is optionally substituted with one or more R.sup.17a; R.sup.20 is the following group optionally substituted with one or more R.sup.20a: 5- to 10-membered heteroaryl, —C(O)-5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or —C(O)—C.sub.6-C.sub.10 aryl; R.sup.20a is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl; said C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R.sup.20b; R.sup.20b is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, NH.sub.2, SH, or C.sub.3-C.sub.10 cycloalkyl; R.sup.21, R.sup.22, and R.sup.27 are independently H, C.sub.1-C.sub.10 alkyl, or C.sub.6-C.sub.10 aryl, said C.sub.1-C.sub.10 alkyl or C.sub.6-C.sub.10 aryl is optionally substituted with one or more R.sup.21a; R.sup.21a is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl; R.sup.23 is H, CN, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl, said C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R.sup.23a; R.sup.23a is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; or R.sup.4 and R.sup.5, together with an atom to which they are linked, form 4- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, said 4- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with one or more R.sup.24a; R.sup.24a is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, or the following group optionally substituted with one or more R.sup.24b: NH.sub.2, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; R.sup.24b is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, or the following group optionally substituted with one or more R.sup.24c: NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy; R.sup.24c is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, NH.sub.2, SH, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl; R.sup.6 is H or the following group optionally substituted with one or more R.sup.6a: NH.sub.2, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, or 5- to 10-membered heteroaryl; R.sup.6a is F, Cl, Br, I, OH, CN, ═O, NO.sub.2, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, 3- to 10-membered heterocyclyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-C.sub.10 cycloalkyloxy, 3- to 10-membered heterocyclyloxy, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.6-C.sub.10 aryl, 5- to 10-membered heteroaryl, C.sub.6-C.sub.10 aryloxy, or 5- to 10-membered heteroaryloxy, provided that when L.sub.1 is phenyl, or when R.sup.5 is 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, R.sup.7 is not ##STR00389##

2. The compound or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, ##STR00390## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are as defined in claim 1, L is ##STR00391## X.sub.1, X.sub.3, Y.sub.1, Y.sub.3, Z.sub.1, Z.sub.3, W.sub.1, and m are as defined in claim 1; said ##STR00392## provided that when L.sub.1 is 3- to 10-membered monocyclic heterocyclyl optionally substituted with R.sup.28, W.sub.4 is not a chemical bond, wherein R.sup.28 is as defined in claim 1.

3. The compound or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, ##STR00393## wherein L is ##STR00394## R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, X.sub.2, Y.sub.2, and Z.sub.2 are as defined in claim 1, provided that when R.sup.1 is tert-butylsulfamoyl, R.sup.5 is ##STR00395## wherein R.sup.20 is 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, or C(O)—C.sub.6-C.sub.10 aryl, said 5- to 10-membered heteroaryl is pyrazolyl, isoxazolyl, 1,2,3-triazolyl, pyridazinyl, benzopyrazolyl, or pyridopyrazolyl, said 5- to 10-membered heterocyclyl is dihydropyridinyl, and said C.sub.6-C.sub.10 aryl is phenyl.

4. The compound or the pharmaceutically acceptable salt thereof according to claim 3, wherein the compounds of formula (Ia) do not comprise ##STR00396##

5. The compound or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, ##STR00397## wherein R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are as defined in claim 1; R.sup.1 is ##STR00398## R.sup.7 is ##STR00399## C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, or C.sub.6-C.sub.10 aryl, said C.sub.1-C.sub.10 alkyl is optionally substituted with one or more R.sup.7a; wherein R.sup.7a, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are as defined in claim 1, provided that R.sup.1 is not tert-butylsulfamoyl.

6. The compound or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (II) or a pharmaceutically acceptable salt thereof, ##STR00400## wherein L is ##STR00401## X.sub.2, Y.sub.2, Z.sub.2, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as defined in claim 1, provided that when R.sup.1 is tert-butylsulfamoyl and X.sub.2 is CR.sup.15 together with Y.sub.2 is N, Z.sub.2 is not S, and R.sup.15 is as defined in claim 1.

7. The compound or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (IIa) or a pharmaceutically acceptable salt thereof, ##STR00402## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and L are as defined in claim 1; R.sup.20 is 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, or C(O)—C.sub.6-C.sub.10 aryl, said 5- to 10-membered heteroaryl is pyrazolyl, isoxazolyl, 1,2,3-triazolyl, pyridazinyl, benzopyrazolyl, or pyridopyrazolyl, said 5- to 10-membered heterocyclyl is dihydropyridinyl, and said C.sub.6-C.sub.10 aryl is phenyl, provided that R.sup.1 is not tert-butylsulfamoyl.

8. The compound or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, ##STR00403## wherein R.sup.1 is ##STR00404## R.sup.7 is C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, or C.sub.6-C.sub.10 aryl, said C.sub.1-C.sub.10 alkyl is optionally substituted with one or more R.sup.7a; R.sup.2, R.sup.3, R.sup.4, R.sup.8, R.sup.9, R.sup.11, and R.sup.12 are as defined in claim 1, L is ##STR00405## X.sub.2, Y.sub.2, and Z.sub.2 are as defined in claim 1; R.sup.5 is ##STR00406## and R.sup.20 is as defined in claim 1.

9. The compound or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (IV) or a pharmaceutically acceptable salt thereof, ##STR00407## wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as defined in claim 1; said ##STR00408## is ##STR00409##

10. The compound or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, ##STR00410## wherein ring Q is 4- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, said 4- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with one or more R.sup.24a; and R.sup.1, R.sup.2, R.sup.3, L, and R.sup.24a are as defined in claim 1.

11. The compound or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula I-1, formula I-7 or formula I-11, or a pharmaceutically acceptable salt thereof, ##STR00411## wherein L, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.8, R.sup.9, R.sup.11, R.sup.12, and R.sup.13 are as defined in claim 1.

12. The compound or the pharmaceutically acceptable salt thereof according to claim 1, being a compound of formula I-13, formula I-23 or formula I-27, or a pharmaceutically acceptable salt thereof, ##STR00412## wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.8, R.sup.9, R.sup.11, R.sup.12, R.sup.13, X.sub.2, Z.sub.2, and Y.sub.2 are as defined in claim 1.

13. The compound or the pharmaceutically acceptable salt thereof according to claim 1, being the following compound or a pharmaceutically acceptable salt thereof, ##STR00413## ##STR00414## ##STR00415## ##STR00416## ##STR00417## ##STR00418## ##STR00419## ##STR00420## ##STR00421## ##STR00422## ##STR00423## ##STR00424## ##STR00425## ##STR00426## ##STR00427## ##STR00428## ##STR00429## ##STR00430##

14. A pharmaceutical composition, comprising the compound or the pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable excipient.

15. A method for treating an RAD51-associated disease, comprising administering a therapeutically effective dose of the compound or the pharmaceutically acceptable salt thereof according to claim 1 to a subject in need thereof.

16. The method according to claim 15, wherein the RAD51-associated disease is a tumor or an autoimmune disease.

17. A pharmaceutical composition, comprising the compound or the pharmaceutically acceptable salt thereof according to claim 13 and a pharmaceutically acceptable excipient.

18. A method for treating an RAD51-associated disease, comprising administering a therapeutically effective dose of the pharmaceutical composition according to claim 14 to a subject in need thereof.

19. The method according to claim 18, wherein the RAD51-associated disease is a tumor or an autoimmune disease.

Description

DETAILED DESCRIPTION

[0355] The technical solutions of the present disclosure will be illustrated in detail by way of the Examples below. However, the protection scope of the present disclosure includes but is not limited thereto.

[0356] The solvents used in the present disclosure are commercially available. The commercially available compounds are referred to as the names in the catalogs of suppliers.

[0357] The structure of a compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The unit of NMR shift is 10.sup.−6 (ppm). Solvents for NMR assay are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS). “IC50” refers to a half maximal inhibitory concentration, i.e. the concentration at which half of the maximal inhibitory effect is achieved. The eluent described below may be a mixed eluent formed by two or more solvents, and the percentage is the volume ratio of the solvents. For example, “tetrahydrofuran/petroleum ether=0% to 20%” means that during the gradient elution, the volume ratio of the amount of tetrahydrofuran to the amount of petroleum ether in the mixed eluent is 0:100 to 20:100.

[0358] The following abbreviations are used in the present disclosure:

TABLE-US-00001 Abbreviation Chemical Name Abbreviation Chemical Name BPin 4,4,5,5-Tetramethyl-1,3,2- B.sub.2Pin.sub.2 4,4,5,5-Tetramethyl-2-(4,4,5,5- dioxaborolan-2-yl tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane HATU O-(7-azabenzotriazol-1-yl)- EDCI 1-(3-Dimethylaminopropyl)- N,N,N,N-tetramethyluronium 3-ethylcarbodiimide hexafluorophosphate DMAP 4-Dimethylaminopyridine 2-Me—THF 2-Methyltetrahydrofuran DCM Dichloromethane DMA N,N-dimethylacetamide EtOH Ethanol AcOH Acetic acid Pd(dppf)Cl.sub.2 1,1-Bis(diphenylphosphino) DMSO Dimethyl sulfoxide ferrocene dichloropalladium KOAc Potassium acetate TFA Trifluoroacetic acid THF Tetrahydrofuran MeCN Acetonitrile TEA Triethylamine T.sub.3P Tri-n-propylphosphoric anhydride M Mole per liter MeB(OH).sub.2 Methylboronic acid mCPBA m-Chloroperoxybenzoic acid Cu(OAc).sub.2 Copper acetate DMF N,N-dimethylformamide Ti(OiPr).sub.4 Titanium tetraisopropoxide TsOH p-Toluenesulfonic acid tBuONO tert-Butyl nitrite (R)-(S)- (R)-1-[(S)-2-(dicyclohexyl- BrettPhos Methanesulfonato(2-dicyclohexyl- cy.sub.2PF-PtBU.sub.2 phosphino)ferrocenyl]ethyl-tert- Pd G.sub.3 phosphino)-3,6-dimethoxy-2,4,6- butylphosphorus trihydride triisopropyl-1,1-biphenyl)(2-amino- 1,1-biphenyl-2-yl) palladium (II) Pd(PPh.sub.3).sub.4 Tetrakis(triphenylphosphine) Et.sub.2O Ethyl ether palladium Boc tert-Butyloxycarbonyl NBS N-bromosuccinimide DIEA N,N-diisopropylethylamine DME Glycol dimethyl ether PhI(OAc).sub.2 Iodobenzene diacetate LiHMDS Lithium bis(trimethylsilyl)amide MeOH Methanol THP Tetrahydropyranyl MW Microwave Boc.sub.2O Di-tert-butyl dicarbonate Xphos-Pd G.sub.2 Chloro(2-dicyclohexylphosphino- t-BuBrettPhos- Methanesulfonato-2-(di-tert-butyl- 2,4,6-triisopropyl-1,1-biphenyl)[2- Pd G.sub.3 phosphino)-3,6-dimethoxy-2,4,6- (2-amino-1,1-biphenyl)] triisopropyl-1,1-biphenyl(2-amino- palladium (II) 1,1-biphenyl-2-yl) palladium (II) xantphos 4,5-Bis(diphenylphosphino)-9, DMEDA N,N-dimethylethylenediamine 9-dimethylxanthene Pd.sub.2(dba).sub.3 Tris(dibenzylideneacetone) NIS N-iodosuccinimide dipalladium Xphos 2-Dicyclohexylphosphino-2,4,6- Pd(AmPhos) Bis[di-tert-butyl-(4-dimethyl- triisopropylbiphenyl Cl.sub.2 aminophenyl)phosphine]dichloro- palladium (II) Pd(OAc).sub.2 Palladium acetate n-BuOH n-Butanol

Intermediate 1: Synthesis of 5-amino-N-tert-butyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

[0359] ##STR00151##

Synthetic Method

[0360] ##STR00152##

Step 1: Synthesis of 2-bromo-5-nitro-benzenesulfonyl chloride

[0361] 2-Bromobenzenesulfonyl chloride (50.0 g, 195.7 mmol) was dissolved in sulfuric acid (750 mL), and a solution of nitric acid (37.0 g, 587.1 mmol, 26.5 mL) in sulfuric acid (750 mL) was slowly added. The whole dropwise addition process took 30 minutes. The temperature of the system was kept at 0° C. in an ice-salt bath environment. After the dropwise addition, the clear reaction solution was stirred and reacted at 10° C. for 2 hours. After the completion of the reaction was detected, the reaction solution was slowly added into ice water (2.5 L) while stirring. A white solid precipitated with stirring. The white solid was filtered, washed with 1.5 L (0.5 L×3) of water, and then dried to obtain 2-bromo-5-nitro-benzenesulfonyl chloride (48.0 g).

Step 2: Synthesis of 2-bromo-N-tert-butyl-5-nitrobenzenesulfonamide

[0362] Tert-butylamine (5.9 g, 79.9 mmol) was dissolved in dichloromethane (0.2 L), and 2-bromo-5-nitro-benzenesulfonyl chloride (8.0 g, 26.6 mmol) was added in batches at 0° C. Triethylamine (5.4 g, 53.3 mmol) was added into the reaction solution. The light yellow reaction solution was stirred and reacted at 20° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was added with dilute hydrochloric acid (1M, 200 mL) and subjected to the liquid-liquid separation. Then, a saturated sodium carbonate solution (200 mL) was added into the organic phase. The organic phase was dried over anhydrous sodium sulfate and filtered. Thereafter, the organic phase was concentrated to dryness under reduced pressure. Methanol (50 mL) was added, a white solid precipitated with stirring, and the solid was slurried to obtain 2-bromo-N-tert-butyl-5-nitrobenzenesulfonamide (8.0 g).

[0363] .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 8.69 (d, J=2.75 Hz, 1H), 8.29 (dd, J=8.63, 2.75 Hz, 1H), 8.18-8.04 (m, 2H), 1.22-1.07 (m, 9H).

Step 3: Synthesis of 5-amino-2-bromo-N-tert-butylbenzenesulfonamide

[0364] 2-Bromo-N-tert-butyl-5-nitrobenzenesulfonamide (5.0 g, 14.8 mmol) was dissolved in ethanol (0.2 L), and zinc powder (4.9 g, 74.1 mmol) and ammonium chloride (4.0 g, 74.1 mmol) were added. The reaction solution was stirred and reacted at 40° C. for 1 hour. The reaction solution was subjected to suction filtration to remove zinc powder. The mother liquor was concentrated to dryness under reduced pressure, water (200 mL) was added thereto, and the resulting mixture was extracted with 600 mL (300 mL×2) of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness via rotary evaporation under reduced pressure to obtain a crude product of 5-amino-2-bromo-N-tert-butylbenzenesulfonamide (4.9 g).

[0365] MS m/z (ESI): 307.1, 309.1 [M+H].sup.+;

Step 4: Synthesis of 5-amino-N-tert-butyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

[0366] 5-Amino-2-bromo-N-tert-butylbenzenesulfonamide (1.0 g, 3.3 mmol) was dissolved in tetrahydrofuran (100 mL), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.3 g, 13.0 mmol) and potassium acetate (958.4 mg, 9.8 mmol) were added. Under the protection of nitrogen, a mixture of 1,1-bis(diphenylphosphino)ferrocenedichloropalladium and dichloromethane (132.9 mg, 162.8 μmol) was added into the reaction solution. Under the protection of nitrogen, the dark red reaction solution was stirred and reacted at 100° C. for 2 hours. The reaction solution was subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, tetrahydrofuran/petroleum ether=0% to 20%) to obtain 5-amino-N-tert-butyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (0.6 g).

[0367] MS m/z (ESI): 355.2 [M+H].sup.+.

Intermediate 2: Synthesis of isopropyl trans-N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0368] ##STR00153##

Synthetic Method

[0369] ##STR00154##

Step 1: Synthesis of tert-butyl trans-N-(4-carbamoylcyclohexyl)carbamate

[0370] Trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (20.0 g, 82.2 mmol) was dissolved in N,N-dimethylformamide (1.0 L), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (117.2 g, 308.3 mmol), ammonium chloride (66.0 g, 1.2 mol) and N,N-diisopropylethylamine (31.4 mg, 242.6 μmol, 42.3 μL) were added. The reaction solution was stirred and reacted at 25° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure. Methanol (0.2 L) and water (1.0 L) were added, and a white solid precipitated, followed by stirring at room temperature for 30 minutes. The resultant was filtered and then washed with 0.9 L (0.3 L×3) of water to obtain tert-butyl trans-N-(4-carbamoylcyclohexyl)carbamate (13.0 g).

[0371] MS m/z (ESI): 187.1 [M-55].sup.+;

Step 2: Synthesis of tert-butyl trans-N-(4-carbamothioylcyclohexyl)carbamate

[0372] Tert-butyl trans-N-(4-carbamoylcyclohexyl)carbamate (12.0 g, 49.5 mmol) was dissolved in tetrahydrofuran (0.5 L), and Lawesson reagent (20.0 g, 49.5 mmol) was added. The reaction solution was stirred and reacted at 80° C. for 30 minutes. The reaction solution was added with a saturated aqueous sodium carbonate solution (0.8 L) so that the pH of the mixture was adjusted to 8˜9, and the resulting mixture was extracted with ethyl acetate (1.6 L) three times. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, tetrahydrofuran/petroleum ether=0% to 50%) to obtain tert-butyl trans-N-(4-carbamothioylcyclohexyl)carbamate (6.0 g).

[0373] MS m/z (ESI): 203.1 [M-55].sup.+;

Step 3: Synthesis of trans-4-thiazol-2-ylcyclohexylamine

[0374] Tert-butyl trans-N-(4-carbamothioylcyclohexyl)carbamate (2.0 g, 7.7 mmol) and bromoacetaldehyde diethyl acetal (3.1 g, 15.5 mmol, 2.4 mL) were dissolved in anhydrous ethanol (80 mL), and p-toluenesulfonic acid (2.7 g, 15.5 mmol) was added. The clear reaction solution was stirred and reacted at 80° C. for 1 hour. The reaction solution was added with a saturated aqueous sodium carbonate solution (100 mL) so that the pH of the mixture was adjusted to 8˜9, and the resulting mixture was extracted with dichloromethane (300 mL) three times. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure to obtain a crude product of trans-4-thiazol-2-ylcyclohexylamine (1.5 g).

[0375] MS m/z (ESI): 183.1 [M+H].sup.+;

Step 4: Synthesis of isopropyl trans-N-(4-thiazol-2-ylcyclohexyl)carbamate

[0376] Trans-4-thiazol-2-ylcyclohexylamine (1.4 g, 7.7 mmol) and isopropyl chloroformate (2.9 g, 23.3 mmol, 3.3 mL) were dissolved in dichloromethane (200 mL), and N,N-diisopropylethylamine (2.0 g, 15.5 mmol, 2.7 mL) and 4-dimethylaminopyridine (472.8 mg, 3.9 mmol) were added. The reaction solution was stirred and reacted at 20° C. for 30 minutes. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, ethyl acetate/petroleum ether=0% to 15%) to obtain isopropyl trans-N-(4-thiazol-2-ylcyclohexyl)carbamate (0.3 g).

[0377] MS m/z (ESI): 269.1 [M+H].sup.+;

Step 5: Synthesis of isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate

[0378] Isopropyl trans-N-(4-thiazol-2-ylcyclohexyl)carbamate (0.3 g, 1.1 mmol) was dissolved in N,N-dimethylformamide (1.5 mL), and N-bromosuccinimide (0.4 g, 2.3 mmol) was added. The reaction solution was stirred and reacted at 50° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, tetrahydrofuran/petroleum ether=0% to 10%) to obtain isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (0.1 g).

[0379] MS m/z (ESI): 347.0, 349.0 [M+H].sup.+;

Step 6: Synthesis of isopropyl trans-N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl] thiazol-2-yl]cyclohexyl]carbamate

[0380] 5-Amino-N-tert-butyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (61.0 mg, 172.8 μmol) and isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (0.1 g, 288.0 μmol) were dissolved in a mixture of ethanol (2.0 mL), toluene (2.0 mL) and water (0.7 mL), and sodium carbonate (30.5 mg, 288.0 μmol), potassium fluoride (16.7 mg, 288.0 μmol) and tetrakis(triphenylphosphine)palladium (16.6 mg, 14.4 μmol) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 100° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with water (2 mL) and extracted with dichloromethane (6 mL) three times. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure to obtain a crude product of isopropyl trans-N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (60.0 mg).

[0381] MS m/z (ESI): 495.3 [M+H].sup.+.

Intermediate 3: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]-3-(methylsulfonimidoyl)phenyl]carbamate

[0382] ##STR00155##

Synthetic Method

[0383] ##STR00156##

Step 1: Synthesis of isopropyl N-(3-methylsulfanylphenyl)carbamate

[0384] 3-Methylthioaniline (806 mg, 5.79 mmol) as a reactant was dissolved in anhydrous tetrahydrofuran (20 mL), and N,N-diisopropylethylamine (1.50 g, 11.58 mmol, 2.02 mL) and 4-dimethylaminopyridine (353.65 mg, 2.89 mmol) were added at 0° C. Thereafter, isopropyl chloroformate (2.13 g, 17.37 mmol, 2.41 mL) was added into the reaction system at 0° C. The reaction solution was stirred and reacted at 25° C. for 3 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated under reduced pressure to remove the solvent tetrahydrofuran, added with 20 mL of dichloromethane, and extracted three times with a saturated aqueous sodium chloride solution (20 mL×3). The organic phase was separated, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate=10:1) to obtain isopropyl N-(3-methylsulfanylphenyl)carbamate (1.16 g) as a yellow liquid.

[0385] MS m/z (ESI): 226.1 [M+H].sup.+.

Step 2: Synthesis of isopropyl N-(4-bromo-3-methylsulfanyl-phenyl)carbamate

[0386] Isopropyl N-(3-methylsulfanylphenyl)carbamate (50 mg, 221.92 μmol) as a reactant was dissolved in dichloromethane (2 mL), and N-bromosuccinimide (39.50 mg, 221.92 μmol) was added into the reaction system. The reaction solution was stirred at −70° C. for 3 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate=10:1) to obtain isopropyl N-(4-bromo-3-methylsulfanyl-phenyl)carbamate as a white solid (50 mg).

[0387] MS m/z (ESI): 262.0 [M+H-iPr].sup.+;

[0388] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.75 (s, 1H) 7.50-7.45 (m, 2H) 7.20 (dd, J=8.57, 1.94 Hz, 1H) 4.97-4.87 (m, 1H) 2.44 (s, 3H) 1.27 (d, J=6.25 Hz, 6H).

Step 3: Synthesis of isopropyl N-[3-methylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[0389] Isopropyl N-(4-bromo-3-methylsulfanyl-phenyl)carbamate (153 mg, 0.51 mmol) and bis(pinacolato)diboron (510.88 mg, 2.01 mmol) as reactants were dissolved in anhydrous tetrahydrofuran (3 mL). Under the protection of nitrogen, potassium acetate (148.08 mg, 1.51 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (20.54 mg, 25.15 μmol) were added. The reaction solution was stirred at 80° C. for 2 hours. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was purified by column chromatography (silica, petroleum ether:ethyl acetate=10:1) to obtain isopropyl N-[3-methylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (141 mg) as a yellow solid.

[0390] MS m/z (ESI): 352.2 [M+H].sup.+.

Step 4: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]-3-methylsulfanyl-phenyl]carbamate

[0391] Isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (100 mg, 287.96 μmol), isopropyl N-[3-methylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (121.38 mg, 345.55 μmol) and sodium carbonate (61.04 mg, 575.92 μmol) were dissolved in water (600 μL) and 1,4-dioxane (6 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (23.52 mg, 28.80 μmol) was added. The reaction solution was stirred at 80° C. for 6 hours. LCMS showed that the reaction was complete. The reaction solution was filtered. The filtrate was evaporated to dryness via rotary evaporation to remove 1,4-dioxane. The resultant was added with water (10 mL), and the resulting mixture was extracted three times with dichloromethane (10 mL×3). After dried over anhydrous sodium sulfate, the resultant was purified by thin-layer chromatography (silica, dichloromethane/methanol=15:1) to obtain isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-methylsulfanyl-phenyl]carbamate (133 mg) as a brown solid.

[0392] MS m/z (ESI): 492.3 [M+H].sup.+.

Step 5: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl] thiazol-5-yl]-3-(methylsulfonimidoyl)phenyl]carbamate

[0393] Isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-methylsulfanyl-phenyl]carbamate (140 mg, 284.75 μmol), ammonium carbamate (444.60 mg, 5.69 mmol) and iodobenzene diacetate (917.17 mg, 2.85 mmol) were added into a 4-mL microwave reaction flask, and anhydrous methanol (1 mL) was added. The reaction was carried out under microwave irradiation at 100° C. for 3 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to remove methanol, added with water (4 mL), extracted with dichloromethane (4 mL×3), and subjected to the liquid-liquid separation. The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness via rotary evaporation under reduced pressure, and purified by thin-layer chromatography (silica, dichloromethane/methanol=15:1) to obtain isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(methylsulfonimidoyl) phenyl]carbamate (47.4 mg) as a yellow solid compound.

[0394] MS m/z (ESI): 523.2 [M+H].sup.+.

Example 1: Synthesis of isopropyl trans-N-[3-dimethylphosphoryl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0395] ##STR00157##

Synthetic Method

[0396] ##STR00158##

Step 1: Synthesis of (2-bromophenyl)dimethylphosphine oxide

[0397] 1-Bromo-2-iodobenzene (5.0 g, 17.6 mmol), potassium phosphate (5.6 g, 26.5 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (613.6 mg, 1.06 mmol) were dissolved in N,N-dimethylformamide (50 mL), and dimethylphosphine oxide (1.7 g, 21.2 mmol) and palladium acetate (198.4 mg, 0.88 mmol) were added. The reaction solution was stirred and reacted at 110° C. for 16 hours. The reaction solution was filtered. The filtrate was collected and concentrated to dryness under reduced pressure, and then purified by column chromatography (silica, dichloromethane/methanol=20/1) to obtain (2-bromophenyl)dimethylphosphine oxide as the product (2.3 g).

[0398] MS m/z (ESI): 233.0, 235.0 [M+H].sup.+;

Step 2: Synthesis of (2-bromo-5-nitrophenyl)dimethylphosphine oxide

[0399] (2-Bromophenyl)dimethylphosphine oxide (1.0 g, 4.3 mmol) was dissolved in concentrated sulfuric acid (15 mL), and concentrated nitric acid (876.6 mg, 13.2 mmol, 626.1 μL) was added. The reaction solution was stirred and reacted at 25° C. for 1 hour. The reaction solution was dissolved in water (200 mL) and extracted with ethyl acetate (100 mL) three times. The organic phase was concentrated to dryness under reduced pressure to obtain (2-bromo-5-nitrophenyl)dimethylphosphine oxide as the product (1.0 g).

[0400] MS m/z (ESI): 277.9, 279.9 [M+H].sup.+;

Step 3: Synthesis of (5-amino-2-bromophenyl)dimethylphosphine oxide

[0401] (2-Bromo-5-nitrophenyl)dimethylphosphine oxide (0.9 g, a crude product) was dissolved in ethanol (10 mL), and iron powder (903.8 mg, 16.2 mmol) and ammonium chloride (865.7 mg, 16.2 μmol) were added. The reaction solution was stirred and reacted at 90° C. for 1 hour. The reaction solution was filtered. The filtrate was concentrated to dryness under reduced pressure, and then purified by column chromatography (silica, dichloromethane/methanol=20/1) to obtain (5-amino-2-bromophenyl)dimethylphosphine oxide as the product (0.15 g).

[0402] MS m/z (ESI): 248.0, 250.0 [M+H].sup.+;

Step 4: Synthesis of isopropyl (4-bromo-3-(dimethylphosphoryl)phenyl)carbamate

[0403] (5-Amino-2-bromophenyl)dimethylphosphine oxide (130 mg, 524.1 μmol) was dissolved in dichloromethane (10 mL), and isopropyl chloroformate (192.7 mg, 1.6 mmol, 218.2 μL) was added. Thereafter, 4-dimethylaminopyridine (32.1 mg, 262.1 μmol) and triethylamine (106.1 mg, 1.05 mmol, 145.9 μL) were added at 0° C. The reaction solution was stirred and reacted at 25° C. for 2 hours. The reaction solution was filtered. The filtrate was concentrated to dryness under reduced pressure, and then purified by column chromatography (silica, dichloromethane/methanol=20/1) to obtain isopropyl (4-bromo-3-(dimethylphosphoryl) phenyl)carbamate as the product (0.12 g).

[0404] MS m/z (ESI): 334.1, 336.1 [M+H].sup.+;

Step 5: Synthesis of isopropyl trans-N-[3-dimethylphosphoryl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0405] Isopropyl (4-bromo-3-(dimethylphosphoryl)phenyl)carbamate (60 mg, 179.56 μmol), isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (62.36 mg, 179.56 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (182.39 mg, 718.25 μmol) were dissolved in tetrahydrofuran (6 mL). Under the protection of nitrogen, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (4.5 mg, 9.0 μmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)] palladium (II) (7.1 mg, 9.0 μmol), tris(dibenzylideneacetone)dipalladium (8.2 mg, 9.0 μmol) and potassium acetate (35.3 mg, 359.1 μmol) were added. The reaction solution was stirred and reacted at 80° C. for 16 hours. The reaction solution was filtered. The filtrate was concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (Phenomenex Gemini-NX column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[3-dimethylphosphoryl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate (10.4 mg).

[0406] MS m/z (ESI): 522.3 [M+H].sup.+;

[0407] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.88 (s, 1H), 8.03 (dd, J=14.26, 2.13 Hz, 1H), 7.82 (s, 1H), 7.69 (d, J=8.50 Hz, 1H), 7.44-7.30 (m, 1H), 7.00 (d, J=7.38 Hz, 1H), 4.92 (dt, J=12.51, 6.25 Hz, 1H), 4.74 (dt, J=12.41, 6.11 Hz, 1H), 3.40-3.25 (m, 1H), 2.99-2.85 (m, 1H), 2.12 (d, J=12.13 Hz, 2H), 1.91 (d, J=10.26 Hz, 2H), 1.63-1.49 (m, 2H), 1.44 (d, J=13.26 Hz, 6H), 1.40-1.29 (m, 2H), 1.27 (d, J=6.25 Hz, 6H), 1.16 (d, J=6.25 Hz, 6H).

Example 2: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]-3-isopropylsulfonyl-phenyl]carbamate

[0408] ##STR00159##

Synthetic Method

[0409] ##STR00160##

Step 1: Preparation of 3-isopropylsulfanylaniline

[0410] 3-Aminothiophenol (1 g, 7.99 mmol) as a reactant was dissolved in N,N-dimethylformamide (10 mL), and isopropyl bromide (1.18 g, 9.59 mmol) and potassium carbonate (1.66 g, 11.98 mmol) were added. The reaction solution was stirred and reacted at 25° C. for 3 hours. After the reaction was complete, the solvent N,N-dimethylformamide was evaporated to dryness by using a rotary evaporator, and then 5 mL of dichloromethane was added into the mixture to dissolve the mixture. The resulting mixture was added with 5 mL of water and extracted twice with dichloromethane (5 mL×2) to separate the organic layer. The organic phase was dried over anhydrous sodium sulfate. The organic layer was concentrated to dryness under reduced pressure, and purified by column chromatography (silica, dichloromethane/methanol=10:1) to obtain 3-isopropylsulfanylaniline as the product (1.4 g).

[0411] MS m/z (ESI): 168.0 [M+H].sup.+

Step 2: Synthesis of isopropyl N-(3-isopropylsulfanylphenyl)carbamate

[0412] 3-Isopropylsulfanylaniline (0.1 g, 597.83 μmol) as a reactant was dissolved in anhydrous tetrahydrofuran (1 mL), and N,N-diisopropylethylamine (154.53 mg, 1.20 mmol) and 4-dimethylaminopyridine (36.52 mg, 298.92 μmol) were added. Thereafter, isopropyl chloroformate (87.92 mg, 717.40 μmol) was added into the reaction system. The reaction solution was stirred and reacted at 25° C. for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent dichloromethane, added with 1 mL of water, and extracted three times with dichloromethane (1 mL×3) to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate=3:1) to obtain isopropyl N-(3-isopropylsulfanylphenyl)carbamate (0.08 g).

[0413] MS m/z (ESI): 254.1 [M+H].sup.+

Step 3: Synthesis of isopropyl N-(4-bromo-3-isopropylsulfanyl-phenyl)carbamate

[0414] Isopropyl N-(3-isopropylsulfanylphenyl)carbamate (1.22 g, 4.82 mmol) as a reactant was dissolved in dichloromethane (15 mL). N-bromosuccinimide (857.03 mg, 4.82 mmol) was added into the reaction system. The reaction solution was stirred at −20° C. for 3 hours. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography to obtain isopropyl N-(4-bromo-3-isopropylsulfanyl-phenyl)carbamate as the product (500 mg).

[0415] MS m/z (ESI): 332.0, 334.0 [M+H].sup.+

Step 4: Synthesis of isopropyl N-[3-isopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[0416] Isopropyl N-(4-bromo-3-isopropylsulfanyl-phenyl)carbamate (450 mg, 1.35 mmol) and bis(pinacolato)diboron (1.38 g, 5.42 mmol) as reactants were dissolved in anhydrous tetrahydrofuran (5 mL). Under the protection of nitrogen, potassium acetate (398.77 mg, 4.06 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (55.30 mg, 67.72 μmol) were added. The reaction solution was stirred at 80° C. for 2 hours. After the reaction was complete, the system was evaporated to dryness via rotary evaporation and the resultant was purified by column chromatography (silica, petroleum ether:ethyl acetate=5% to 15%) to obtain isopropyl N-[3-isopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (350 mg).

[0417] MS m/z (ESI): 380.1 [M+H].sup.+

Step 5: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]-3-isopropylsulfanyl-phenyl]carbamate

[0418] Isopropyl N-[3-isopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]carbamate (50 mg, 131.81 μmol) and isopropyl N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (50.35 mg, 145.00 μmol) as reactants were dissolved in 1,4-dioxane (1 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (5.38 mg, 6.59 μmol) and sodium carbonate (2M, 131.81 μL) were added. The reaction solution was stirred at 80° C. for 2 hours. The reaction system was evaporated to dryness via rotary evaporation to remove 1,4-dioxane, added with water (2 mL), and extracted three times with dichloromethane (2 mL×3). The resultant was dried over anhydrous sodium sulfate, and then purified by thin-layer chromatography (silica, petroleum ether/tetrahydrofuran=3:1) to obtain isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfanyl-phenyl]carbamate (33 mg).

[0419] MS m/z (ESI): 520.1 [M+H].sup.+

Step 6: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfonyl-phenyl] carbamate

[0420] Isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfanyl-phenyl]carbamate (0.02 g, 38.48 μmol) was dissolved in anhydrous dichloromethane (1 mL), and m-chloroperoxybenzoic acid (15.63 mg, 76.96 μmol) was added at −25° C. The reaction solution was reacted at 20° C. for 1 hour. The reaction solution was subjected to rotary evaporation to remove dioxane, added with water (2 mL), extracted three times with dichloromethane (2 mL×3), and subjected to liquid-liquid separation to separate dichloromethane phase. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. 0.5 mL of methanol was added as a solvent to dissolve the resultant, and the resulting mixture was then purified. The resultant was purified by preparative high-performance liquid chromatography (YMCTriartC18 column, 7 μm silica, 50 mm in diameter, 250 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (38% to 78%) as eluents) to obtain the compound isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfonyl-phenyl]carbamate (5.20 mg).

[0421] MS m/z (ESI): 552.2 [M+H].sup.+

[0422] .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ ppm 10.13 (s, 1H), 8.32 (d, J=2.25 Hz, 1H), 7.76 (dd, J=8.44, 2.19 Hz, 1H), 7.69 (s, 1H), 7.49 (d, J=8.38 Hz, 1H), 7.00 (br d, J=7.75 Hz, 1H), 4.93 (quin, J=6.22 Hz, 1H), 4.74 (dt, J=12.44, 6.28 Hz, 1H), 3.27 (br d, J=3.75 Hz, 1H), 3.01-2.78 (m, 2H), 2.12 (d, J=12.01 Hz, 2H), 1.91 (d, J=10.51 Hz, 2H), 1.64-1.46 (m, 2H), 1.41-1.30 (m, 2H), 1.27 (d, J=6.25 Hz, 6H), 1.16 (d, J=6.25 Hz, 6H), 1.05 (d, J=6.75 Hz, 6H).

Example 3: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]-3-(isopropylsulfonimidoyl)phenyl]carbamate

[0423] ##STR00161##

Synthetic Method

[0424] ##STR00162##

[0425] Isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfanyl-phenyl]carbamate (30 mg, 57.72 μmol), ammonium carbamate (90.13 mg, 1.15 mmol) and iodobenzene diacetate (185.93 mg, 577.24 μmol) were added into a 4-mL microwave reaction flask, and 1 mL of anhydrous methanol was added. The reaction was carried out under microwave irradiation at 100° C. for 2 hours. The reaction solution was concentrated under reduced pressure to remove methanol, added with water (2 mL), extracted with dichloromethane (2 mL×3), and subjected to liquid-liquid separation. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness via rotary evaporation under reduced pressure. The resultant was purified by preparative high-performance liquid chromatography (Phenomenex Gemini-NX C18 column, 3 μm silica, 30 mm in diameter, 75 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (30% to 70%) as eluents) to obtain isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(isopropylsulfonimidoyl)phenyl] carbamate (6.18 mg).

[0426] MS m/z (ESI): 551.3 [M+H].sup.+

[0427] .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ ppm 10.04 (s, 1H), 8.34 (d, J=2.13 Hz, 1H), 7.75-7.65 (m, 2H), 7.39 (d, J=8.38 Hz, 1H), 7.00 (br d, J=7.50 Hz, 1H), 4.93 (dt, J=12.48, 6.33 Hz, 1H), 4.81-4.70 (m, 1H), 4.35 (s, 1H), 3.26 (br s, 1H), 2.96-2.88 (m, 1H), 2.87-2.79 (m, 1H), 2.12 (br d, J=13.01 Hz, 2H), 1.92 (br d, J=10.51 Hz, 2H), 1.62-1.49 (m, 2H), 1.40-1.31 (m, 2H), 1.28 (d, J=6.25 Hz, 6H), 1.17 (d, J=6.25 Hz, 6H), 1.08 (d, J=6.75 Hz, 3H), 0.99 (d, J=6.75 Hz, 3H).

Example 4: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]-3-(isopropyl-N-prop-2-enoyl-sulfonimidoyl)phenyl]carbamate

[0428] ##STR00163##

Synthetic Method

[0429] ##STR00164##

[0430] Isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(isopropylsulfonimidoyl)phenyl]carbamate (0.01 g, 18.16 μmol) and acrylic acid (1.44 mg, 19.97 μmol, 1.37 μL) were dissolved in anhydrous dichloromethane (1 mL). 4-Dimethylaminopyridine (1.11 mg, 9.08 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.18 mg, 21.79 μmol) were added into the reaction system. The reaction solution was stirred at 25° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by preparative high-performance liquid chromatography (Phenomenex Gemini-NX C18 column, 3 μm silica, 30 mm in diameter, 75 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (36% to 76%) as eluents) to obtain isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(isopropyl-N-prop-2-enoyl-sulfonimidoyl) phenyl]carbamate (0.84 mg).

[0431] MS m/z (ESI): 627.2 [M+Na].sup.+;

[0432] .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ ppm 10.18 (s, 1H), 8.33 (d, J=2.32 Hz, 1H), 7.75 (dd, J=8.56, 2.08 Hz, 1H), 7.54 (s, 1H), 7.42 (d, J=8.31 Hz, 1H), 7.02 (br d, J=8.31 Hz, 1H), 6.09-5.90 (m, 2H), 5.68 (dd, J=9.41, 2.69 Hz, 1H), 4.93 (quin, J=6.36 Hz, 1H), 4.83-4.67 (m, 1H), 3.27-3.23 (m, 1H), 2.99-2.79 (m, 1H), 2.09 (br d, J=9.78 Hz, 2H), 1.90 (br d, J=9.78 Hz, 2H), 1.59-1.45 (m, 2H), 1.35 (d, J=6.72 Hz, 5H), 1.28 (d, J=6.24 Hz, 6H), 1.23 (br s, 1H), 1.16 (d, J=6.24 Hz, 6H), 0.99 (d, J=6.85 Hz, 3H).

Example 5: Synthesis of isopropyl trans-N-[3-(tert-butylsulfamoyl)-4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]phenyl]carbamate

[0433] ##STR00165##

Synthetic Method

[0434] ##STR00166##

Step 1: Synthesis of tert-butyl trans-N-[4-(formamidocarbamoyl)cyclohexyl]carbamate

[0435] Trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (5 g, 20.55 mmol) and formylhydrazine (1.60 g, 26.72 mmol) were dissolved in N,N-dimethylformamide (80 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (9.38 g, 24.66 mmol) and N,N-diisopropylethylamine (6.91 g, 53.43 mmol, 9.31 mL) were added. The reaction solution was stirred and reacted at 25° C. for 0.5 hours. After the reaction was complete, the solvent N,N-dimethylformamide (80 mL) was evaporated to dryness by using a rotary evaporator. Thereafter, 400 mL of water and 4 mL of methanol were added into the mixture. The resultant was filtered to obtain tert-butyl trans-N-[4-(formamidocarbamoyl)cyclohexyl]carbamate as the product (3 g, 10.51 mmol).

[0436] MS m/z (ESI): 230.2 [M-55].sup.+;

Step 2: Synthesis of tert-butyl trans-N-[4-(1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate

[0437] Tert-butyl trans-N-[4-(formamidocarbamoyl)cyclohexyl]carbamate (750 mg, 2.63 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). Afterwards, Lawesson reagent (1.28 g, 3.15 mmol) and Burgess reagent (626.37 mg, 2.63 mmol) were added into the reaction system. The reaction solution was stirred and reacted at 80° C. for 16 hours. The reaction solution was subjected to rotary evaporation under reduced pressure to remove tetrahydrofuran. The remaining organic phase was added with water (30 mL) and extracted three times with ethyl acetate (10 mL×3) to separate the organic phase. The organic phase was concentrated to dryness under reduced pressure, and purified by column chromatography (silica, ethyl acetate:petroleum ether=2/1 to 3/1) to obtain tert-butyl trans-N-[4-(1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate as the product (280 mg).

[0438] MS m/z (ESI): 227.9 [M-55].sup.+;

Step 3: Synthesis of tert-butyl N-[4-(5-bromo-1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate

[0439] Tert-butyl trans-N-[4-(1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate (0.1 g, 352.87 μmol) as a reactant was dissolved in N,N-dimethylformamide (3 mL), and N-bromosuccinimide (188.42 mg, 1.06 mmol) was added into the reaction system. The reaction solution was stirred at 60° C. for 10 hours. The reaction solution was concentrated under reduced pressure to remove the solvent N,N-dimethylformamide (3 mL). The mixture was added with 3 mL of water and extracted with dichloromethane (3 mL×2) to separate the organic layer. The organic phase was dried over anhydrous sodium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (silica, petroleum ether:ethyl acetate=0% to 20%) to obtain tert-butyl trans-N-[4-(5-bromo-1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate as the product (0.030 g).

[0440] MS m/z (ESI): 307.8 [M-55].sup.+

Step 4: Synthesis of isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-(tert-butylsulfamoyl)phenyl]carbamate

[0441] Tert-butyl trans-N-[4-(5-bromo-1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate (0.02 g, 55.21 μmol) and isopropyl (3-(N-(tert-butyl)sulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (24.31 mg, 55.21 μmol) as reactants were dissolved in dioxane (1 mL). Under the protection of nitrogen, sodium carbonate (2M, 82.81 μL) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (4.51 mg, 5.52 μmol) were added. The reaction solution was stirred at 80° C. for 2 hours. The reaction system was evaporated to dryness via rotary evaporation, and the resultant was then purified by thin-layer chromatography (silica, petroleum ether:tetrahydrofuran=3:1) to obtain isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-(tert-butyl sulfamoyl)phenyl]carbamate (27 mg).

[0442] MS m/z (ESI): 596.3 [M+H].sup.+

Step 5: Synthesis of isopropyl trans-(4-(5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl)-3-(N-(tert-butyl)sulfamoyl)phenyl)carbamate

[0443] Isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-(tert-butylsulfamoyl)phenyl]carbamate (0.027 g, 45.32 μmol) as a reactant was dissolved in anhydrous methanol (2 mL). A solution of hydrochloric acid in methanol (4M, 113.30 μL) was added. The reaction solution was stirred at 15° C. for 1 hour. The reaction system was evaporated to dryness via rotary evaporation to obtain isopropyl trans-(4-(5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl)-3-(N-(tert-butyl)sulfamoyl)phenyl)carbamate (0.02 g).

[0444] MS m/z (ESI): 496.2 [M+H].sup.+;

Step 6: Synthesis of isopropyl trans-N-[3-(tert-butylsulfamoyl)-4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]phenyl]carbamate

[0445] Isopropyl trans-N-[4-[5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl]-3-(tert-butylsulfamoyl) phenyl]carbamate (22 mg, 44.39 μmol) as a reactant was dissolved in dichloromethane (1 mL), and pyridine (35.11 mg, 443.86 μmol) and isopropyl chloroformate (16.32 mg, 133.16 μmol) were added. The reaction solution was stirred at 20° C. for 3 hours. The reaction system was evaporated to dryness via rotary evaporation. The resultant was purified by preparative high-performance liquid chromatography (Phenomenex Gemini-NX C18 column, 3 μm silica, 30 mm in diameter, 75 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (36% to 76%) as eluents) to obtain isopropyl trans-N-[3-(tert-butylsulfamoyl)-4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]phenyl]carbamate (2.78 mg).

[0446] MS m/z (ESI): 582.3 [M+H].sup.+;

[0447] .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.47-9.5 (m, 1H), 8.36 (d, J=2.25 Hz, 1H), 7.74 (dd, J=8.50, 2.13 Hz, 1H), 7.64 (d, J=8.50 Hz, 1H), 7.30 (s, 1H), 7.03 (d, J=8.50 Hz, 1H), 4.94 (quin, J=6.28 Hz, 1H), 4.75 (dt, J=12.32, 6.35 Hz, 1H), 3.25-3.03 (m, 2H), 2.16 (d, J=12.38 Hz, 2H), 1.93 (br d, J=10.26 Hz, 2H), 1.71-1.56 (m, 2H), 1.41-1.31 (m, 2H), 1.28 (d, J=6.25 Hz, 6H), 1.17 (d, J=6.25 Hz, 6H), 1.14 (s, 9H).

Example 6: Synthesis of isopropyl 2-[2-(2-tert-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylate

[0448] ##STR00167##

Synthetic Method

[0449] ##STR00168##

Step 1: Synthesis of 2-[2-(tert-butylsulfamoyl)-4-(isopropoxycarbonylamino) phenyl]tert-butyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylate

[0450] Isopropyl (3-(N-(tert-butyl)sulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)carbamate (100 mg, 313.27 μmol) and tert-butyl 2-bromo-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylate (137.95 mg, 313.27 μmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), and sodium carbonate (66.41 mg, 626.53 μmol) and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (II)-dichloromethane complex (25.58 mg, 31.33 μmol) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 80° C. for 1 hour. The reaction solution was added with water (1 mL), and extracted with dichloromethane (2 mL) three times. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (silica, petroleum ether/ethyl acetate=1/1) to obtain 2-[2-(tert-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]tert-butyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylate as the product (120 mg).

[0451] MS m/z (ESI): 553.1 [M+H].sup.+;

Step 2: Synthesis of isopropyl N-[3-(tert-butylsulfamoyl)-4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)phenyl]carbamate

[0452] 2-[2-(Tert-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]tert-butyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylate (60 mg, 108.56 μmol) was dissolved in hydrochloric acid-methanol (5 mL, 4 mol/L). The reaction solution was stirred and reacted at 25° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain isopropyl N-[3-(tert-butylsulfamoyl)-4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl) phenyl]carbamate as the product (45 mg).

[0453] MS m/z (ESI): 453.3 [M+H].sup.+

Step 3: Synthesis of isopropyl 2-[2-(2-tert-butylsulfamoyl)-4-(isopropoxycarbonylamino) phenyl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylate

[0454] Isopropyl N-[3-(tert-butylsulfamoyl)-4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl) phenyl]carbamate (60 mg, 132.57 μmol) and isopropyl chloroformate (81.23 mg, 662.85 μmol, 92.00 μL) were dissolved in anhydrous dichloromethane (4 mL), and pyridine (314.59 mg, 3.98 mmol, 321.01 μL) was added under the condition of ice bath. The reaction solution was stirred and reacted at 25° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (column: YMCTriartC18; 5 μm silica, 25 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (65% to 85%) as eluents) to obtain the compound isopropyl 2-[2-(2-tert-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]-6,7-dihydro-4H-thiazolo[5, 4-c]pyridine-5-carboxylate (5.26 mg).

[0455] MS m/z (ESI): 539.3 [M+H].sup.+

[0456] .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ ppm 10.18 (s, 1H), 8.35 (d, J=2.3 Hz, 1H), 7.88 (br s, 1H), 7.76-7.71 (m, 1H), 7.70-7.65 (m, 1H), 4.94 (quin, J=6.2 Hz, 1H), 4.84 (td, J=12.4, 6.2 Hz, 1H), 4.72 (s, 2H), 3.75 (t, J=5.6 Hz, 2H), 2.84 (br s, 2H), 1.28 (d, J=6.0 Hz, 6H), 1.23 (d, J=6.3 Hz, 6H), 1.20 (s, 9H).

Example 7: Synthesis of isopropyl (3-(5-(4-(isopropoxycarbonyl)amino-2-(N-(tert-butyl) sulfamoyl)phenyl)thiazol-2-yl)bicyclo[1.1.1]pent-1-yl)carbamate

[0457] ##STR00169##

Synthetic Method

[0458] ##STR00170##

Step 1: Synthesis of tert-butyl (3-carbamoylbicyclo[1.1.1]pent-1-yl)carbamate

[0459] 3-((Tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (250 mg, 1.10 mmol) was dissolved in N,N-dimethylformamide (10 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (627.42 mg, 1.65 mmol), ammonium chloride (176.53 mg, 3.30 mmol) and triethylamine (333.95 mg, 3.30 mmol, 459.36 μL) were added. The reaction solution appeared as a yellow suspension and was stirred and reacted at 30° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and diluted by adding dichloromethane (50 mL). The organic layer was washed with water (20 mL), and a solid precipitated. The resultant was filtered to obtain tert-butyl (3-carbamoylbicyclo[1.1.1]pent-1-yl)carbamate (210 mg).

[0460] MS m/z (ESI): 227.0 [M+H].sup.+;

Step 2: Synthesis of tert-butyl (3-carbamothioylbicyclo[1.1.1]pent-1-yl)carbamate

[0461] Tert-butyl (3-carbamoylbicyclo[1.1.1]pent-1-yl)carbamate (230 mg, 1.02 mmol) was dissolved in 2-methyltetrahydrofuran (5.00 mL), and Lawesson reagent (411.13 mg, 1.02 mmol) was added. The reaction solution was stirred and reacted at 80° C. for 1 hour. The reaction solution was added with a saturated aqueous sodium carbonate solution (10 mL) so that the pH of the mixture was adjusted to 8˜9, and the resulting mixture was extracted with ethyl acetate (20 mL) three times. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether/ethyl acetate=2/1) to obtain tert-butyl (3-carbamothioylbicyclo[1.1.1]pent-1-yl)carbamate (170 mg).

[0462] MS m/z (ESI): 186.9 [M-55].sup.+;

Step 3: Synthesis of 3-(thiazol-2-yl)bicyclo[1.1.1]pentyl-1-amino

[0463] Tert-butyl (3-carbamothioylbicyclo[1.1.1]pent-1-yl)carbamate (170 mg, 701.50 μmol) and bromoacetaldehyde diethyl acetal (276.49 mg, 1.40 mmol, 211.06 μL) were dissolved in anhydrous ethanol (2 mL), and p-toluenesulfonic acid monohydrate (266.88 mg, 1.40 mmol) was added. The reaction solution was stirred and reacted at 80° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was added with a saturated aqueous sodium carbonate solution (10 mL) so that the pH of the mixture was adjusted to 8˜9, and the resulting mixture was extracted with ethyl acetate (5 mL) six times. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure to obtain 3-(thiazol-2-yl)bicyclo[1.1.1]pentyl-1-amino (80 mg).

[0464] MS m/z (ESI): 167.0 [M+H].sup.+;

Step 4: Synthesis of isopropyl (3-(thiazol-2-yl)bicyclo[1.1.1]pent-1-yl)carbamate

[0465] 3-(Thiazol-2-yl)bicyclo[1.1.1]pentyl-1-amino (80 mg, 481.22 μmol) and isopropyl chloroformate (117.95 mg, 962.45 μmol, 133.58 μL) were dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (124.39 mg, 962.45 μmol, 167.64 μL) and 4-dimethylaminopyridine (29.40 mg, 240.61 μmol) were added. The reaction solution was stirred and reacted at 25° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, petroleum ether/ethyl acetate=2/1) to obtain isopropyl (3-(thiazol-2-yl)bicyclo[1.1.1]pent-1-yl)carbamate (31 mg).

[0466] MS m/z (ESI): 253.1 [M+H].sup.+;

Step 5: Synthesis of isopropyl (3-(5-bromothiazol-2-yl)bicyclo[1.1.1]pent-1-yl)carbamate

[0467] Isopropyl (3-(thiazol-2-yl)bicyclo[1.1.1]pent-1-yl)carbamate (31 mg, 122.85 μmol) was dissolved in N,N-dimethylformamide (4 mL), and N-bromosuccinimide (65.60 mg, 368.56 μmol) was added. The reaction solution was stirred and reacted at 50° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, petroleum ether/ethyl acetate=1/1) to obtain isopropyl (3-(5-bromothiazol-2-yl)bicyclo[1.1.1]pent-1-yl)carbamate (34 mg).

[0468] MS m/z (ESI): 331.1, 333.1 [M+H].sup.+;

Step 6: Synthesis of isopropyl (3-(5-(4-(isopropoxycarbonyl)amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)bicyclo[1.1.1]pent-1-yl)carbamate

[0469] Isopropyl (3-(5-bromothiazol-2-yl)bicyclo[1.1.1]pent-1-yl)carbamate (50 mg, 150.95 μmol) and isopropyl (3-(N-(tert-butyl)sulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (66.47 mg, 150.95 μmol) were dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL), and sodium carbonate (32.00 mg, 301.91 μmol) and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (II)-dichloromethane complex (12.33 mg, 15.10 μmol) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 80° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with water (1 mL) and extracted with dichloromethane (2 mL) three times. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm in diameter, 250 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl (3-(5-(4-(isopropoxycarbonyl)amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)bicyclo[1.1.1]pent-1-yl)carbamate (11.3 mg).

[0470] MS m/z (ESI): 565.1 [M+H].sup.+

[0471] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.10 (s, 1H), 8.32 (d, J=2.0 Hz, 1H), 7.94 (br s, 1H), 7.69-7.59 (m, 2H), 7.39 (d, J=8.5 Hz, 1H), 7.17 (s, 1H), 4.93 (m, J=6.3 Hz, 1H), 4.76 (m, J=6.1 Hz, 1H), 2.34-2.32 (m, 1H), 2.33 (s, 5H), 1.28 (d, J=6.3 Hz, 6H), 1.18 (br d, J=5.8 Hz, 6H), 1.10 (s, 9H).

Example 8: Synthesis of isopropyl 7-(5-(2-(N-(tert-butyl)sulfamoyl)-4-((isopropoxycarbonyl)amino)phenyl)thiazol-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0472] ##STR00171##

Synthetic Method

[0473] ##STR00172##

Step 1: Synthesis of N-(tert-butyl)-5-nitro-2-(thiazol-5-yl)benzenesulfonamide

[0474] 2-Bromo-N-(tert-butyl)-5-nitrobenzenesulfonamide (2.0 g, 5.93 mmol) as a reactant was dissolved in N,N-dimethylacetamide (20 mL), and thiazole (1.51 g, 17.97 mmol), palladium acetate (133.16 mg, 593.14 μmol) and potassium acetate (1.75 g, 17.79 mmol) were added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 140° C. for 16 hours. The reaction solution was dissolved in water (200 mL) and the resulting mixture was filtered. The filter cake was collected and concentrated to dryness under reduced pressure, and then purified by column chromatography (silica, petroleum ether/tetrahydrofuran=3/1) to obtain N-(tert-butyl)-5-nitro-2-(thiazol-5-yl)benzenesulfonamide (0.9 g).

[0475] MS m/z (ESI): 342.1 [M+H].sup.+;

Step 2: Synthesis of 2-(2-bromothiazol-5-yl)-N-(tert-butyl)-5-nitrobenzenesulfonamide

[0476] N-(tert-butyl)-5-nitro-2-(thiazol-5-yl)benzenesulfonamide (0.8 g, 2.34 mmol) was dissolved in acetic acid (10.00 mL), and potassium acetate (1.15 g, 11.72 mmol) and liquid bromine (1.87 g, 11.72 mmol) were added. The reaction solution was stirred and reacted at 80° C. for 3 hours. The reaction solution was added with a saturated aqueous sodium carbonate solution (100 mL) so that the pH of the mixture was adjusted to 8˜9, and the resulting mixture was extracted with ethyl acetate (100 mL) three times. The organic phase was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The resulting crude 2-(2-bromothiazol-5-yl)-N-(tert-butyl)-5-nitrobenzenesulfonamide (1.4 g, crude product) was directly used in the next reaction step.

[0477] MS m/z (ESI): 420.0, 422.0 [M+H].sup.+;

Step 3: Synthesis of 5-amino-2-(2-bromothiazol-5-yl)-N-(tert-butyl)benzenesulfonamide

[0478] 2-(2-Bromothiazol-5-yl)-N-(tert-butyl)-5-nitrobenzenesulfonamide (1.4 g, 3.33 mmol) was dissolved in anhydrous ethanol (15 mL), and iron powder (1.86 g, 33.31 mmol) and ammonium chloride (1.78 g, 33.31 mmol) were added. The reaction solution was stirred and reacted at 80° C. for 2 hours. The reaction solution was filtered. The filtrate was concentrated to dryness under reduced pressure, and then purified by column chromatography (silica, dichloromethane/methanol=20/1) to obtain 5-amino-2-(2-bromothiazol-5-yl)-N-(tert-butyl)benzenesulfonamide (0.9 g).

[0479] MS m/z (ESI): 390.0, 392.0 [M+H].sup.+;

Step 4: Synthesis of tert-butyl 7-(5-(4-amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0480] 5-Amino-2-(2-bromothiazol-5-yl)-N-(tert-butyl)benzenesulfonamide (20 mg, 51.24 μmol) was dissolved in dimethyl sulfoxide (2 mL), and sodium bicarbonate (12.91 mg, 153.72 μmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (23.19 mg, 102.48 μmol) were added. The reaction solution was stirred and reacted under microwave irradiation at 120° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and purified by thin-layer chromatography (silica, dichloromethane/methanol=20/1) to obtain tert-butyl 7-(5-(4-amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (18 mg).

[0481] MS m/z (ESI): 536.3 [M+H].sup.+;

Step 5: Synthesis of 2-(2-(2,7-diazaspiro[3.5]nonan-7-yl)thiazol-5-yl)-5-amino-N-(tert-butyl)benzenesulfonamide

[0482] Tert-butyl 7-(5-(4-amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (18 mg, 33.60 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (180 mg, 1.58 mmol, 116.88 μL) was added. The reaction solution was stirred and reacted at 25° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain 2-(2-(2,7-diazaspiro[3.5]nonan-7-yl)thiazol-5-yl)-5-amino-N-(tert-butyl)benzenesulfonamide (0.14 g).

[0483] MS m/z (ESI): 436.2 [M+H].sup.+;

Step 6: Synthesis of isopropyl 7-(5-(2-(N-(tert-butyl)sulfamoyl)-4-((isopropoxycarbonyl) amino)phenyl)thiazol-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0484] 2-(2-(2,7-Diazaspiro[3.5]nonan-7-yl)thiazol-5-yl)-5-amino-N-(tert-butyl)benzenesulfonamide (0.14 g, crude product) was dissolved in dichloromethane (10 mL), and pyridine (254.22 mg, 3.21 mmol, 259.41 μL) and isopropyl chloroformate (157.55 mg, 1.29 mmol, 178.42 μL) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 25° C. for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (Phenomenex GeminiNX C18 column, 5 μm silica, 30 mm in diameter, 150 mm in length) (using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (45% to 65%) as eluents) to obtain the compound isopropyl 7-(5-(2-(N-(tert-butyl)sulfamoyl)-4-((isopropoxycarbonyl) amino)phenyl)thiazol-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (3.8 mg).

[0485] MS m/z (ESI): 608.1 [M+H].sup.+

[0486] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 10.00 (s, 1H), 8.28 (d, J=2.2 Hz, 1H), 7.60 (dd, J=8.3, 2.3 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.18 (s, 1H), 6.95 (s, 1H), 4.99-4.68 (m, 2H), 3.65 (br s, 4H), 3.39 (br s, 4H), 1.79 (br t, J=5.6 Hz, 4H), 1.31-1.05 (m, 21H).

Example 9 and Example 10: Synthesis of isopropyl endo-N-[3-(tert-butylsulfamoyl)-4-[2-[6-(isopropoxycarbonylamino)-3-azabicyclo[3.1.0]hex-3-yl]thiazol-5-yl]phenyl]carbamate and isopropyl exo-N-[3-(tert-butylsulfamoyl)-4-[2-[6-(isopropoxycarbonylamino)-3-azabicyclo[3.1.0]hex-3-yl] thiazol-5-yl]phenyl]carbamate

[0487] ##STR00173##

Synthetic Method

[0488] ##STR00174##

Step 1: Synthesis of tert-butyl (3-(5-(4-amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate

[0489] 5-Amino-2-(2-bromothiazol-5-yl)-N-(tert-butyl)benzenesulfonamide (40 mg, 102.48 μmol) was dissolved in dimethyl sulfoxide (2 mL), and sodium bicarbonate (25.83 mg, 307.44 μmol) and tert-butyl 3-azabicyclo[3.1.0]hexyl-6-carbamate (60.95 mg, 307.44 μmol) were added. The reaction solution was stirred and reacted under microwave irradiation at 120° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, dichloromethane/methanol=20/1) to obtain tert-butyl (3-(5-(4-amino-2-(N-(tert-butyl) sulfamoyl)phenyl)thiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate as the product (80 mg).

[0490] MS m/z (ESI): 508.3 [M+H].sup.+;

Step 2: Synthesis of 5-amino-2-(2-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)thiazol-5-yl)-N-(tert-butyl)benzenesulfonamide

[0491] Tert-butyl (3-(5-(4-amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)-3-azabicyclo [3.1.0]hex-6-yl)carbamate (120 mg, 236.37 μmol) was dissolved in dichloromethane (12 mL), and trifluoroacetic acid (1.2 g, 10.52 mmol, 779.22 μL) was added. The reaction solution was stirred and reacted at 25° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure to obtain 5-amino-2-(2-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)thiazol-5-yl)-N-(tert-butyl)benzenesulfonamide as the product (0.1 g, crude product).

[0492] MS m/z (ESI): 408.1 [M+H].sup.+;

Step 3: Synthesis of isopropyl N-[3-(tert-butylsulfamoyl)-4-[2-[6-(isopropoxycarbonylamino)-3-azabicyclo[3.1.0]hex-3-yl]thiazol-5-yl]phenyl]carbamate

[0493] 5-Amino-2-(2-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)thiazol-5-yl)-N-(tert-butyl) benzenesulfonamide (0.1 g, crude product) was dissolved in dichloromethane (10 mL), and pyridine (194.09 mg, 2.45 mmol, 198.05 μL) and isopropyl chloroformate (180.42 mg, 1.47 mmol, 204.32 μL) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 25° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Phenomenex GeminiNX C18 column, 5 μm silica, 30 mm in diameter, 150 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia and 10 mM ammonium bicarbonate) and acetonitrile (50% to 70%) as eluents) to obtain two products, i.e. isopropyl endo-N-[3-(tert-butylsulfamoyl)-4-[2-[6-(isopropoxycarbonylamino)-3-azabicyclo[3.1.0]hex-3-yl]thiazol-5-yl]phenyl]carbamate and isopropyl exo-N-[3-(tert-butylsulfamoyl)-4-[2-[6-(isopropoxycarbonylamino)-3-azabicyclo [3.1.0]hex-3-yl]thiazol-5-yl]phenyl]carbamate (17.0 mg/17.0 mg) respectively, the correspondence of specific configurations was unknown.

[0494] Product 1:

[0495] MS m/z (ESI): 580.3 [M+H].sup.+

[0496] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.01 (s, 1H), 8.27 (d, J=2.3 Hz, 1H), 7.59 (dd, J=8.4, 2.1 Hz, 1H), 7.38-7.08 (m, 3H), 7.00-6.82 (m, 1H), 4.99-4.67 (m, 2H), 3.67-3.55 (m, 2H), 3.46 (br d, J=10.3 Hz, 2H), 2.69-2.59 (m, 1H), 2.06-1.92 (m, 2H), 1.29-1.05 (m, 21H).

[0497] Product 2:

[0498] MS m/z (ESI): 580.3 [M+H].sup.+;

[0499] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.01 (s, 1H), 8.27 (d, J=2.2 Hz, 1H), 7.60 (dd, J=8.4, 2.3 Hz, 1H), 7.43-7.29 (m, 2H), 7.19 (s, 1H), 6.96 (s, 1H), 4.96-4.68 (m, 2H), 3.60-3.47 (m, 4H), 2.30 (br s, 1H), 1.83 (br s, 2H), 1.28-1.07 (m, 21H).

Example 11: Synthesis of isopropyl N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)azepan-1-yl]thiazol-5-yl]phenyl]carbamate

[0500] ##STR00175##

Synthetic Method

[0501] ##STR00176##

Step 1: Synthesis of tert-butyl N-[1-[1-[5-[4-amino-2-(tert-butylsulfamoyl)tert-butyl] phenyl]thiazol-2-yl]aza-4-yl]carbamate

[0502] 5-Amino-2-(2-bromothiazol-5-yl)-N-tert-butylbenzenesulfonamide (0.03 g, 76.86 μmol), tert-butyl azepan-4-ylcarbamate (49.41 mg, 230.58 μmol) and sodium bicarbonate (19.37 mg, 230.58 μmol, 8.97 μL) as reactants were added into a 4-mL microwave reaction flask, dimethyl sulfoxide (1 mL) was added, and the mixture was reacted under microwave irradiation at 120° C. for 5 hours. The reaction system was added with 2 mL of water, and extracted twice with dichloromethane (2 mL×2) to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (silica, dichloromethane/methanol=95:5) to obtain tert-butyl N-[1-[1-[5-[4-amino-2-(tert-butylsulfamoyl)tert-butyl]phenyl]thiazol-2-yl]aza-4-yl]carbamate as the product (40 mg).

[0503] MS m/z (ESI): 524.3 [M+H].sup.+;

Step 2: Synthesis of 5-amino-2-[2-(4-aminoaza-1-yl)thiazol-5-yl]-N-tert-butylbenzenesulfonamide

[0504] Tert-butyl N-[1-[1-[5-[4-amino-2-(tert-butylsulfamoyl)tert-butyl]phenyl]thiazol-2-yl]aza-4-yl]carbamate (0.04 g, 76.38 μmol) as a reactant was dissolved in anhydrous dichloromethane (5 mL), and trifluoroacetic acid (383.19 mg, 3.36 mmol, 248.82 μL) was added. The reaction solution was stirred and reacted at 25° C. for 1 hour. The completion of the reaction was detected by LCMS. The resultant was concentrated under reduced pressure to remove the solvent dichloromethane to obtain crude 5-amino-2-[2-(4-aminoaza-1-yl)thiazol-5-yl]-N-tert-butylbenzenesulfonamide (80 mg, crude product).

[0505] MS m/z (ESI): 424.1 [M+H].sup.+;

Step 3: Synthesis of isopropyl N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)azepan-1-yl]thiazol-5-yl]phenyl]carbamate

[0506] 5-Amino-2-[2-(4-aminoaza-1-yl)thiazol-5-yl]-N-tert-butylbenzenesulfonamide (32 mg, 75.54 μmol) as a reactant was dissolved in anhydrous dichloromethane (2 mL). Pyridine (3.92 g, 49.56 mmol, 4 mL) and isopropyl chloroformate (55.55 mg, 453.26 μmol, 62.91 μL) were added into the reaction system. The reaction solution was stirred at 25° C. for 5 hours. LCMS showed that the reaction was complete. The resulting mixture was concentrated under reduced pressure to remove dichloromethane. The resultant was purified by preparative high-performance liquid chromatography (YMCTriartC18 column, 7 μm silica, 50 mm in diameter, 250 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (35% to 75%) as eluents) to obtain the compound isopropyl N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)azepan-1-yl]thiazol-5-yl]phenyl]carbamate (6.42 mg).

[0507] MS m/z (ESI): 596.3 [M+H].sup.+;

[0508] .sup.1H-NMR: (400 MHz, DMSO-d.sub.6) δ 9.98 (s, 1H), 8.27 (d, J=2.20 Hz, 1H), 7.59 (dd, J=8.38, 2.26 Hz, 1H), 7.35 (d, J=8.44 Hz, 1H), 7.18 (s, 1H), 7.09 (br d, J=7.58 Hz, 1H), 6.84 (s, 1H), 4.92 (spt, J=6.22 Hz, 1H), 4.80-4.64 (m, 1H), 3.79-3.65 (m, 1H), 3.61-3.47 (m, 2H), 3.46-3.36 (m, 2H), 2.01-1.85 (m, 2H), 1.84-1.70 (m, 2H), 1.69-1.59 (m, 1H), 1.51-1.35 (m, 1H), 1.27 (d, J=6.24 Hz, 6H), 1.15 (d, J=6.24 Hz, 6H), 1.10 (s, 9H).

Example 12: Synthesis of isopropyl trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(3,4-dihydro-1H-isoquinoline-2-carbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0509] ##STR00177##

Synthetic Method

[0510] ##STR00178##

Step 1: Synthesis of 4-nitrophenyl trans-N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0511] The above-mentioned intermediate 2, i.e. isopropyl trans-N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (100 mg, 202.16 μmol) was dissolved in dichloromethane (6 mL). At 0° C., 4-nitrophenyl chloroformate (65.20 mg, 323.45 μmol) was added, and 4-dimethylaminopyridine (12.35 mg, 101.08 μmol) and pyridine (47.97 mg, 606.47 μmol, 48.95 μL) were added. The reaction solution was stirred and reacted at 20° C. for 0.5 hours. The reaction solution was concentrated to dryness under reduced pressure and no further purification was conducted, so as to obtain 4-nitrophenyl trans-N-[3-(tert-butyl sulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate as the product (130 mg).

[0512] MS m/z (ESI): 660.3 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(3,4-dihydro-1H-isoquinoline-2-carbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0513] 4-Nitrophenyl trans-N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]phenyl]carbamate (133 mg, 201.58 μmol) and 1,2,3,4-tetrahydroisoquinoline (80.55 mg, 604.75 μmol, 75.99 μL) were dissolved in acetonitrile (4 mL), and N,N-diisopropylethylamine (65.13 mg, 503.96 μmol, 87.78 μL) was added. The reaction solution was stirred and reacted at 80° C. for 1 hour. The reaction solution was cooled to 20° C. and concentrated to dryness under reduced pressure. A solution of sodium carbonate (30 mg) in water (3 mL) was added to the residue and the resulting mixture was stirred for 3 minutes. The extracted organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. The resultant was purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm in diameter, 250 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain isopropyl trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(3,4-dihydro-1H-isoquinoline-2-carbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate as the product (36 mg).

[0514] MS m/z (ESI): 654.1 [M+H].sup.+;

[0515] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.05 (s, 1H), 8.33 (d, J=2.25 Hz, 1H), 7.78 (dd, J=8.50, 2.13 Hz, 1H), 7.66 (s, 1H), 7.34 (d, J=8.50 Hz, 1H), 7.20 (s, 4H), 7.03 (br d, J=7.50 Hz, 1H), 6.80 (s, 1H), 4.74 (dt, J=12.44, 6.28 Hz, 1H), 4.67 (s, 2H), 3.73 (t, J=5.88 Hz, 2H), 3.31 (br s, 1H), 2.95-2.84 (m, 3H), 2.13 (br d, J=11.63 Hz, 2H), 1.91 (br d, J=10.01 Hz, 2H), 1.66-1.49 (m, 2H), 1.42-1.28 (m, 2H), 1.16 (d, J=6.25 Hz, 6H), 1.04 (s, 9H).

Example 13: Synthesis of isopropyl trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(1,2,3,4-tetrahydroisoquinoline-3-carbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0516] ##STR00179##

Synthetic Method

[0517] ##STR00180##

[0518] Isopropyl trans-N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate (20 mg, 40.43 μmol) and 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (21.49 mg, 121.29 μmol) were dissolved in acetonitrile (0.5 mL), and tri-n-propylphosphoric anhydride (0.5 mL) was added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 80° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (column: BostonPrimeC18; 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (43% to 73%) as eluents) to obtain the compound isopropyl trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(1,2,3,4-tetrahydroisoquinoline-3-carbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate (11.87 mg).

[0519] MS m/z (ESI): 654.2 [M+H].sup.+;

[0520] .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.37 (s, 1H), 8.56 (d, J=2.3 Hz, 1H), 7.88 (dd, J=8.4, 2.4 Hz, 1H), 7.69 (s, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.34-7.22 (m, 1H), 7.18-6.96 (m, 6H), 4.80-4.70 (m, 1H), 4.06-3.90 (m, 2H), 3.66 (br s, 1H), 3.41 (br d, J=4.0 Hz, 1H), 3.05-2.81 (m, 3H), 2.14 (br d, J=10.0 Hz, 2H), 1.92 (br d, J=10.5 Hz, 2H), 1.65-1.50 (m, 2H), 1.41-1.27 (m, 2H), 1.17 (d, J=6.3 Hz, 6H), 1.06 (s, 9H).

Example 14: Synthesis of isopropyl trans-N-[4-[5-[4-[[(E)-N-benzyl-N′-cyanocarbamoylamino]amino]-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0521] ##STR00181##

Synthetic Method

[0522] ##STR00182##

Step 1: Synthesis of isopropyl trans-N-[4-[5-[4-(benzylaminomethylthioamino)-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0523] Isopropyl trans-N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (75.0 mg, 151.6 μmol) was dissolved in N,N-dimethylformamide (5.0 mL), and benzyl isothiocyanate (33.9 mg, 227.4 μmol, 30.0 μL) and N,N-diisopropylethylamine (39.2 mg, 303.2 μmol, 52.8 μL) were added. The reaction solution was stirred and reacted at 20° C. for 0.5 hours. The reaction solution was directly concentrated to dryness under reduced pressure and purified by column chromatography (silica, methanol/dichloromethane=1:10) to obtain isopropyl trans-N-[4-[5-[4-(benzylaminomethylthioamino)-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate (18.0 mg).

[0524] MS m/z (ESI): 644.3 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-N-[4-[5-[4-[[N-benzyl-N′-cyanocarbamoylamino] amino]-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0525] Isopropyl trans-N-[4-[5-[4-(benzylaminomethylthioamino)-2-(tert-butylsulfamoyl)phenyl] thiazol-2-yl]cyclohexyl]carbamate (66.0 mg, 105.1 μmol) and cyanamide (113.6 mg, 2.7 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.2 mg, 157.7 μmol) and N,N-diisopropylethylamine (27.2 mg, 210.3 μmol, 36.6 μl) were added. The reaction solution was stirred and reacted at 40° C. for 16 hours. The reaction solution was concentrated to dryness under reduced pressure and separated by high-performance liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm in diameter, 250 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (48% to 68%) as eluents) to obtain isopropyl trans-N-[4-[5-[4-[[N-benzyl-N′-cyanocarbamoylamino]amino]-2-(tert-butylsulfamoyl)phenyl] thiazol-2-yl]cyclohexyl]carbamate (1.58 mg).

[0526] MS m/z (ESI): 652.2 [M+H].sup.+

[0527] .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 9.48 (br s, 1H), 8.20-8.09 (m, 1H), 8.04-7.95 (m, 1H), 7.72-7.64 (m, 1H), 7.54-7.47 (m, 1H), 7.45-7.40 (m, 1H), 7.39-7.32 (m, 5H), 7.07-6.95 (m, 1H), 7.14-6.95 (m, 1H), 4.82-4.65 (m, 1H), 4.49 (br s, 2H), 2.91 (tt, J=11.8, 3.5 Hz, 1H), 2.56-2.52 (m, 1H), 2.20-2.07 (m, 2H), 1.91 (br d, J=10.27 Hz, 2H), 1.57 (qd, J=12.72, 2.81 Hz, 2H), 1.40-1.27 (m, 2H), 1.16 (d, J=6.24 Hz, 6H), 1.05 (s, 9H).

Example 15: Synthesis of isopropyl trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-[(2-phenoxyacetyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0528] ##STR00183##

Synthetic Method

[0529] ##STR00184##

[0530] Isopropyl trans-N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate (60.0 mg, 121.3 μmol) was dissolved in dichloromethane (6.0 mL), and 2-phenoxyacetyl chloride (20.7 mg, 121.3 μmol, 16.7 μL) and N,N-diisopropylethylamine (31.4 mg, 242.6 μmol, 42.3 μl) were added. The reaction solution was stirred and reacted at 20° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMCTriartC18 column, 5 μm silica, 25 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain isopropyl trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-[(2-phenoxyacetyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (22.3 mg).

[0531] MS m/z (ESI): 629.1 [M+H].sup.+

[0532] .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.55 (s, 1H), 8.48 (d, J=2.00 Hz, 1H), 7.88 (dd, J=8.44, 2.06 Hz, 1H), 7.68 (s, 1H), 7.44 (d, J=8.38 Hz, 1H), 7.32 (t, J=7.94 Hz, 2H), 7.10-6.86 (m, 5H), 4.84-4.60 (m, 3H), 3.40-3.25 (m, 1H), 2.91 (br t, J=11.94 Hz, 1H), 2.13 (br d, J=11.51 Hz, 2H), 1.92 (br d, J=9.63 Hz, 2H), 1.64-1.49 (m, 2H), 1.41-1.26 (m, 2H), 1.16 (d, J=6.25 Hz, 6H), 1.05 (s, 9H).

Example 16: Synthesis of isopropyl trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(cyclopropylmethoxycarbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0533] ##STR00185##

Synthetic Method

[0534] ##STR00186##

[0535] 4-Nitrophenyl trans-N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]phenyl]carbamate (50 mg, 75.78 μmol) prepared in Example 12 and cyclopropylmethanol (54.64 mg, 757.84 μmol, 59.92 μL) were dissolved in acetonitrile (4 mL), and N,N-diisopropylethylamine (24.49 mg, 189.46 μmol, 33.00 μL) was added. The reaction solution was stirred and reacted at 80° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure at 20° C. and extracted with an aqueous sodium carbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm in diameter, 250 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain isopropyl trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(cyclopropylmethoxycarbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate as the product (9.2 mg).

[0536] MS m/z (ESI): 615.1 [M+Na].sup.+;

[0537] .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.20 (s, 1H), 10.27-10.13 (m, 1H), 8.33 (d, J=2.01 Hz, 1H), 7.68-7.60 (m, 2H), 7.39 (d, J=8.53 Hz, 1H), 7.62-7.09 (m, 2H), 4.80-4.62 (m, 1H), 3.96 (d, J=7.28 Hz, 2H), 3.33-3.30 (m, 1H), 2.90 (br t, J=12.17 Hz, 1H), 2.13 (br d, J=11.54 Hz, 2H), 1.92 (br d, J=10.54 Hz, 2H), 1.63-1.51 (m, 2H), 1.40-1.28 (m, 2H), 1.17 (d, J=6.02 Hz, 6H), 1.10-1.06 (m, 1H), 1.07 (s, 7H), 1.09-1.05 (m, 1H), 0.60-0.52 (m, 2H), 0.37-0.29 (m, 2H).

Example 17: Synthesis of isopropyl trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-[(1-phenylcyclopropyl)carbamoylamino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0538] ##STR00187##

Synthetic Method

[0539] ##STR00188##

[0540] 4-Nitrophenyl trans-N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]phenyl]carbamate (50 mg, 75.78 μmol) and 1-phenylcyclopropanamine (20.19 mg, 151.57 μmol, 59.92 μL) were dissolved in acetonitrile (4 mL), and N,N-diisopropylethylamine (24.49 mg, 189.46 μmol, 33.00 μL) was added. The reaction solution was stirred and reacted at 80° C. for 1 hour. The completion of the reaction was detected by LC-MS. The reaction solution was concentrated to dryness under reduced pressure at 20° C. The residue was extracted with an aqueous sodium carbonate solution/dichloromethane, and the resulting mixture was subjected to liquid-liquid separation. The resulting organic phase was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtrate was concentrated to dryness and purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm in diameter, 250 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain isopropyl trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-[(1-phenylcyclopropyl)carbamoylamino]phenyl]thiazol-2-yl]cyclohexyl]carbamate as the product (6.18 mg).

[0541] MS m/z (ESI): 654.3 [M+H].sup.+;

[0542] .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 8.97 (br s, 1H), 8.21 (d, J=2.26 Hz, 1H), 7.64 (s, 1H), 7.60 (dd, J=8.41, 2.13 Hz, 1H), 7.30 (dd, J=14.56, 7.78 Hz, 3H), 7.25-7.20 (m, 2H), 7.19-7.10 (m, 2H), 7.03 (br d, J=7.78 Hz, 1H), 6.86 (s, 1H), 4.81-4.65 (m, 1H), 3.49-3.39 (m, 1H), 3.32-3.29 (m, 2H), 2.97-2.81 (m, 1H), 2.13 (br d, J=12.05 Hz, 2H), 1.92 (br d, J=10.04 Hz, 2H), 1.65-1.48 (m, 2H), 1.23 (br d, J=6.02 Hz, 4H), 1.17 (d, J=6.27 Hz, 6H), 1.04 (s, 9H).

Example 18: Synthesis of isopropyl trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-[(2-phenylcyclopropanecarbonyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0543] ##STR00189##

Synthetic Method

[0544] ##STR00190##

[0545] Isopropyl trans-N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate (40 mg, 80.86 μmol) and 2-phenylcyclopropanecarboxylic acid (15.74 mg, 97.03 μmol) were dissolved in acetonitrile (1 mL). Under the protection of nitrogen, tri-n-propylphosphoric anhydride (1.07 g, 3.36 mmol, 1 mL) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 80° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was added with water (15 mL) and extracted with dichloromethane (15 mL) twice. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and methanol as eluents) to obtain the compound isopropyl trans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-[(2-phenylcyclopropanecarbonyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (18.19 mg).

[0546] MS m/z (ESI): 639.1 [M+H].sup.+;

[0547] .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.68 (s, 1H), 8.42 (d, J=2.13 Hz, 1H), 7.82 (dd, J=8.44, 2.06 Hz, 1H), 7.68 (s, 1H), 7.42 (d, J=8.13 Hz, 1H), 7.34-7.28 (m, 2H), 7.24-7.19 (m, 3H), 7.02 (s, 1H), 6.93 (s, 1H), 4.82-4.71 (m, 1H), 3.29 (s, 2H), 2.91 (s, 1H), 2.17-2.07 (m, 3H), 1.93 (br d, J=12.88 Hz, 2H), 1.63-1.51 (m, 3H), 1.45-1.31 (m, 3H), 1.17 (d, J=6.25 Hz, 6H), 1.06 (s, 9H).

Example 19: Synthesis of isopropyl trans-N-[3-(tert-butylsulfonylamino)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0548] ##STR00191##

Synthetic Method

[0549] ##STR00192##

Step 1: Synthesis of isopropyl N-(4-bromo-3-nitro-phenyl)-N-isopropoxycarbonyl-carbamate

[0550] 4-Bromo-3-nitroaniline (5 g, 23.04 mmol) and isopropyl chloroformate (5.65 g, 46.08 mmol, 6.40 mL) were dissolved in anhydrous dichloromethane (100 mL), and N,N-diisopropylethylamine (5.96 g, 46.08 mmol, 8.03 mL) and pyridine (9.11 g, 115.20 mmol, 9.30 mL) were added. The reaction solution appeared as a dark brown suspension, and was stirred and reacted at 20° C. for 0.5 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, tetrahydrofuran:petroleum ether=1:6) to obtain isopropyl N-(4-bromo-3-nitro-phenyl)-N-isopropoxycarbonyl-carbamate (5.6 g, 14.39 mmol).

[0551] MS m/z (ESI): 411/413 [M+Na].sup.+;

Step 2: Synthesis of isopropyl N-(3-amino-4-bromophenyl)carbamate

[0552] Isopropyl N-(4-bromo-3-nitro-phenyl)-N-isopropoxycarbonyl-carbamate (1 g, 2.57 mmol) was dissolved in anhydrous methanol (10 mL), and iron trichloride hexahydrate (891.75 mg, 3.30 mmol) was added. The reaction solution was stirred and reacted at 70° C. for 12 min. Thereafter, hydrazine hydrate (1.98 g, 39.59 mmol) was added. The yellow reaction solution was stirred and reacted at 70° C. for 3 h. The completion of the reaction was detected by LCMS. The reaction solution was filtered, evaporated to dryness via rotary evaporation, and extracted with ethyl acetate (30 mL), water (30 mL) and saturated saline (30 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, ethyl acetate/petroleum ether=1:4) to obtain isopropyl N-(3-amino-4-bromophenyl)carbamate (300 mg, 1.10 mmol).

[0553] MS m/z (ESI): 273/275 [M+H].sup.+;

Step 3: Synthesis of isopropyl N-[4-bromo-3-(tert-butylsulfinylamino)phenyl]carbamate

[0554] Isopropyl N-(3-amino-4-bromophenyl)carbamate (300 mg, 1.10 mmol) was dissolved in anhydrous dichloromethane (3 mL), and pyridine (260.65 mg, 3.30 mmol, 265.97 μL) was added. Under the protection of nitrogen, tert-butylsulfinyl chloride (185.36 mg, 1.32 mmol, 162.60 μL) was added dropwise. The reaction solution was stirred and reacted at 20° C. for 7 h. The completion of the reaction was detected by LCMS. The resultant was purified by column chromatography (silica, ethyl acetate/petroleum ether=1:4) to obtain isopropyl N-[4-bromo-3-(tert-butylsulfinylamino)phenyl]carbamate (160 mg, 424.07 μmol).

[0555] MS m/z (ESI): 377/379 [M+H].sup.+;

Step 4: Synthesis of isopropyl N-[4-bromo-3-(tert-butylsulfonylamino)phenyl]carbamate

[0556] Isopropyl N-[4-bromo-3-(tert-butylsulfinylamino)phenyl]carbamate (150 mg, 397.57 μmol) was dissolved in anhydrous dichloromethane (1 mL). Under the protection of nitrogen, m-chloroperoxybenzoic acid (171.52 mg, 993.91 μmol) was added. The reaction solution was stirred and reacted at 20° C. for 3 h. The completion of the reaction was detected by LCMS. The reaction solution was poured into ammonium chloride in ice-water bath, and extracted with dichloromethane (2×15 mL) and saturated saline (15 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness via rotary evaporation. The resultant was purified by column chromatography (silica, ethyl acetate/petroleum ether=1:4) to obtain isopropyl N-[4-bromo-3-(tert-butylsulfonylamino)phenyl]carbamate (100 mg, 254.26 μmol).

[0557] MS m/z (ESI): 410/412 [M+H.sub.2O].sup.+;

Step 5: Synthesis of isopropyl N-[3-(tert-butylsulfonylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[0558] Isopropyl N-[4-bromo-3-(tert-butylsulfonylamino)phenyl]carbamate (50 mg, 127.13 μmol) and bis(pinacolato)diboron (129.13 mg, 508.52 μmol) were dissolved in anhydrous tetrahydrofuran (5 mL). Under the protection of nitrogen, potassium acetate (37.43 mg, 381.39 μmol) and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (II)-dichloromethane complex (10.38 mg, 12.71 μmol) were added. The red reaction solution was stirred and reacted at 80° C. for 7 h. The completion of the reaction was detected by LCMS. The resultant was purified by thin-layer chromatography (silica, petroleum ether/tetrahydrofuran=3/1) to obtain isopropyl N-[3-(tert-butylsulfonylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]carbamate (30 mg, 68.13 μmol).

[0559] MS m/z (ESI): 458 [M+H.sub.2O].sup.+;

Step 6: Synthesis of isopropyl trans-N-[3-(tert-butylsulfonylamino)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0560] Isopropyl N-[3-(tert-butylsulfonylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]carbamate (30 mg, 68.13 μmol) and isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (23.66 mg, 68.13 μmol) were dissolved in 1,4-dioxane (4 mL) and water (0.4 mL). Under the protection of nitrogen, sodium carbonate (14.44 mg, 136.25 μmol) and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (II)-dichloromethane complex (5.56 mg, 6.81 μmol) were added. The reaction solution was stirred and reacted at 80° C. for 7 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with water (15 mL) and extracted with dichloromethane (15 mL) twice. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (Boston Prime C18 column; 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain isopropyl trans-N-[3-(tert-butylsulfonylamino)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate.

[0561] MS m/z (ESI): 581.1 [M+H].sup.+;

[0562] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.81 (br s, 1H) 8.80-8.91 (m, 1H) 7.86 (s, 1H) 7.73 (s, 1H) 7.32-7.44 (m, 2H) 7.04 (br d, J=7.53 Hz, 1H) 4.86-4.96 (m, 1H) 4.69-4.81 (m, 1H) 3.32-3.32 (m, 1H) 2.90 (br t, J=11.80 Hz, 1H) 2.08 (br s, 2H) 1.91 (br d, J=9.54 Hz, 2H) 1.48-1.61 (m, 2H) 1.31-1.40 (m, 2H) 1.26 (d, J=6.27 Hz, 6H) 1.13-1.20 (m, 15H).

Example 20: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]-3-(isopropyl-N-methyl-sulfonimidoyl)phenyl]carbamate

[0563] ##STR00193##

Synthetic Method

[0564] ##STR00194##

[0565] Isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(isopropylsulfonimidoyl)phenyl]carbamate (20 mg, 36.32 μmol) as a reactant was dissolved in 1,4-dioxane (2 mL). Anhydrous copper acetate (9.89 mg, 54.47 μmol) and pyridine (6.89 mg, 87.16 μmol, 7.03 μL) were added at 20° C. The reaction solution was stirred at 20° C. for 5 minutes, and methylboronic acid (4.35 mg, 72.63 μmol) was added. The reaction solution was stirred at 100° C. for 12 hours. The completion of the reaction was detected by LC-MS. The reaction solution was filtered under reduced pressure. The filtrate was concentrated to dryness under reduced pressure and purified by preparative high-performance liquid chromatography (Phenomenex Gemini-NX C18 column, 5 μm silica, 30 mm in diameter, 100 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (50% to 70%) as eluents) to obtain isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(S-isopropyl-N-methyl-sulfonimidoyl)phenyl] carbamate (1.5 mg).

[0566] MS m/z (ESI): 565.3 [M+H].sup.+

[0567] .sup.1H NMR: (400 MHz, METHANOL-d.sub.4) δ ppm 8.23 (d, J=2.26 Hz, 1H), 7.83-7.77 (m, 1H), 7.63 (s, 1H), 7.44 (d, J=8.53 Hz, 1H), 5.05-5.00 (m, 1H), 4.92-4.80 (m, 1H), 3.55-3.45 (m, 1H), 3.17-3.09 (m, 1H), 3.06-2.96 (m, 1H), 2.26-2.21 (m, 2H), 2.15-2.02 (m, 2H), 1.74-1.63 (m, 2H), 1.49-1.40 (m, 2H), 1.35-1.32 (m, 12H), 1.24 (br d, J=6.27 Hz, 6H), 1.11 (d, J=6.78 Hz, 3H).

Example 21: Synthesis of isopropyl N-[3-(tert-butylsulfamoyl)-4-[2-[8-(isopropoxycarbonylamino)-3-bicyclo[3.2.1]octyl]thiazol-5-yl]phenyl]carbamate

[0568] ##STR00195##

Synthetic Method

[0569] ##STR00196##

Step 1: Synthesis of methyl 8-oxobicyclo[3.2.1]octane-3-carboxylate

[0570] Methyl 2-(bromomethyl)acrylate (19.57 g, 109.31 mmol) was dissolved in acetonitrile (135 mL). At room temperature, a solution of 1-pyrrolidinyl-1-cyclopentene (15 g, 109.31 mmol) in acetonitrile (135 mL) was slowly added dropwise, and then triethylamine (17.81 g, 175.99 mmol) was added. The reaction solution was stirred and reacted at 90° C. for 5 hours. Afterwards, acetic acid (77.46 g, 64.49 mmol) was added. The reaction solution was continued to be stirred and reacted at 90° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (silica, dichloromethane:methanol=15:1) to obtain methyl 8-oxobicyclo[3.2.1]octane-3-carboxylate (12 g).

[0571] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 3.70 (s, 3H) 2.76 (t, J=7.82 Hz, 1H) 2.58-2.69 (m, 2H) 2.03-2.22 (m, 4H) 1.75-1.85 (m, 2H) 1.59-1.70 (m, 2H).

Step 2: Synthesis of isopropyl 8-((tert-butylsulfinyl)imino)bicyclo[3.2.1]octane-3-carboxylate

[0572] Methyl 8-oxobicyclo[3.2.1]octane-3-carboxylate (8 g, 43.90 mmol) and 2-methyl-2-propanesulfinamide (15.96 g, 131.71 mmol) were dissolved in tetrahydrofuran (160 mL), and then titanium tetraisopropoxide (37.43 g, 131.71 mmol) was added. The reaction solution was stirred and reacted at 60° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction product undergone transesterification and became an isopropyl ester product. The reaction solution was used directly in the next reaction step without treatment.

[0573] MS m/z (ESI): 314.3 [M+28].sup.+;

Step 3: Synthesis of isopropyl 8-(tert-butylsulfinylamino)bicyclo[3.2.1]octane-3-carboxylate

[0574] Sodium borohydride (4.98 g, 131.71 mmol) was slowly added into the reaction solution obtained in Step 2. The reaction solution was stirred and reacted at 30° C. for 4 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with a saturated sodium carbonate solution (100 mL), stirred at room temperature for 30 minutes, and then extracted with dichloromethane (100 mL) twice. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (silica, dichloromethane:methanol=15:1) to obtain isopropyl 8-(tert-butylsulfinylamino)bicyclo[3.2.1] octane-3-carboxylate (7.7 g).

[0575] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 4.95-4.88 (m, 1H) 3.20-3.13 (m, 1H) 2.50-2.45 (m, 1H) 2.40-1.93 (m, 6H) 1.63-1.60 (m, 2H) 1.49-1.47 (m, 2H) 1.20-1.08 (m, 15H).

Step 4: Synthesis of isopropyl 8-aminobicyclo[3.2.1]octane-3-carboxylate

[0576] Isopropyl 8-(tert-butylsulfinylamino)bicyclo[3.2.1]octane-3-carboxylate (2.31 g, 8.05 mmol) was dissolved in methanol (18 mL), and hydrochloric acid/dioxane (22 mL) was added. The reaction solution was stirred and reacted at 30° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure to obtain isopropyl 8-aminobicyclo[3.2.1]octane-3-carboxylate (1.2 g, crude product).

[0577] MS m/z (ESI): 212.2 [M+H].sup.+

Step 5: Synthesis of isopropyl 8-((isopropoxycarbonyl)amino)bicyclo[3.2.1]octane-3-carboxylate

[0578] Methyl 8-aminobicyclo[3.2.1]octane-3-carboxylate (547 mg, 2.99 mmol) and isopropyl chloroformate (438.98 mg, 3.58 mmol) were dissolved in dichloromethane (26 mL), and N,N-diisopropylethylamine (1.93 g, 14.93 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. The reaction solution was added with water (10 mL), and then extracted with ethyl acetate (30 mL) twice. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (silica, petroleum ether:tetrahydrofuran=3:1) to obtain isopropyl 8-((isopropoxycarbonyl)amino)bicyclo[3.2.1] octane-3-carboxylate (416 mg, 1.54 mmol).

[0579] MS m/z (ESI): 298.3 [M+H].sup.+

Step 6: Synthesis of 8-(isopropoxycarbonylamino)bicyclo[3.2.1]octane-3-carboxylic acid

[0580] Isopropyl 8-((isopropoxycarbonyl)amino)bicyclo[3.2.1]octane-3-carboxylate (416 mg, 1.54 mmol) was dissolved in methanol (4 mL), and sodium hydroxide (2 M, 2.32 mL) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. Hydrochloric acid (2 M, 4 mL) was added and the pH of the mixture was adjusted to 3. The reaction solution was added with 3 mL of dichloromethane (1 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain 8-(isopropoxycarbonylamino)bicyclo[3.2.1]octane-3-carboxylic acid (360 mg, crude product).

[0581] MS m/z (ESI): 256.2 [M+H].sup.+

[0582] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.95 (s, 1H) 7.12 (br d, J=3.51 Hz, 1H) 4.70-4.80 (m, 1H) 3.33-3.34 (m, 1H) 2.36-2.48 (m, 1H) 2.10-2.04 (m, 2H) 1.79 (br t, J=12.80 Hz, 2H) 1.63-1.72 (m, 2H) 1.42-1.52 (m, 2H) 1.33-1.41 (m, 2H) 1.13-1.22 (m, 6H).

Step 7: Synthesis of isopropyl (3-carbamoylbicyclo[3.2.1]oct-8-yl)carbamate

[0583] 8-(Isopropoxycarbonylamino)bicyclo[3.2.1]octane-3-carboxylic acid (1.6 g, 6.27 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (2.62 g, 6.89 mmol) were dissolved in N,N-dimethylformamide (100 mL), and ammonium chloride (1.68 g, 31.33 mmol) and N,N-diisopropylethylamine (4.05 g, 31.33 mmol) were added. The reaction solution was stirred and reacted at 30° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran=3:1) to obtain isopropyl (3-carbamoylbicyclo[3.2.1]oct-8-yl)carbamate (500 mg, crude product).

[0584] MS m/z (ESI): 255.2 [M+H].sup.+

[0585] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 7.17 (br s, 1H) 7.02 (br d, J=5.13 Hz, 1H) 6.65 (br s, 1H) 4.81-4.72 (m, 1H) 3.40-3.30 (m, 1H) 2.30-2.45 (m, 1H) 2.15-2.06 (m, 2H) 1.63-1.81 (m, 4H) 1.41-1.50 (m, 2H) 1.23-1.32 (m, 2H) 1.18 (d, J=6.25 Hz, 6H).

Step 8: Synthesis of isopropyl (3-aminomethylthiobicyclo[3.2.1]oct-8-yl)carbamate

[0586] Isopropyl (3-carbamoylbicyclo[3.2.1]oct-8-yl)carbamate (500 mg, 1.97 mmol) was dissolved in tetrahydrofuran (25 mL), and Lawesson reagent (397.59 mg, 983.00 μmol) was added. The reaction solution was stirred and reacted at 80° C. for 0.5 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with a saturated aqueous sodium carbonate solution (50 mL) so that the pH of the mixture was adjusted to 8˜9, and the resulting mixture was extracted with ethyl acetate (50 mL) three times. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran=3:1) to obtain isopropyl (3-aminomethylthiobicyclo[3.2.1]oct-8-yl)carbamate (270 mg, 998.56 μmol).

[0587] MS m/z (ESI): 271.1 [M+H].sup.+

Step 9: Synthesis of isopropyl (3-(thiazol-2-yl)bicyclo[3.2.1]oct-8-yl)carbamate

[0588] Isopropyl (3-aminomethylthiobicyclo[3.2.1]oct-8-yl)carbamate (278 mg, 1.03 mmol) and bromoacetaldehyde diethyl acetal (607.85 mg, 3.08 mmol) were dissolved in ethanol (4 mL), and p-toluenesulfonic acid monohydrate (391.14 mg, 2.06 mmol) was added. The reaction solution was stirred and reacted at 80° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with a saturated aqueous sodium carbonate solution (20 mL) so that the pH of the mixture was adjusted to 8-9, and the resulting mixture was extracted with dichloromethane (50 mL) three times. The organic layer was dried over anhydrous magnesium sulfate, subjected to suction filtration, and concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (silica, petroleum ether:tetrahydrofuran=2:1) to obtain isopropyl (3-(thiazol-2-yl)bicyclo[3.2.1]oct-8-yl)carbamate (100 mg).

[0589] MS m/z (ESI): 295.2 [M+H].sup.+

[0590] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.69 (d, J=3.26 Hz, 1H) 7.20 (d, J=3.51 Hz, 1H) 5.05 (br s, 1H) 4.84-4.99 (m, 1H) 3.78 (br s, 1H) 3.30-3.46 (m, 1H) 2.30 (br s, 2H) 1.83-1.90 (m, 4H) 1.64-1.69 (m, 2H) 1.24 (d, J=6.27 Hz, 6H).

Step 10: Synthesis of isopropyl (3-(5-bromothiazol-2-yl)bicyclo[3.2.1]oct-8-yl)carbamate

[0591] Isopropyl (3-(thiazol-2-yl)bicyclo[3.2.1]oct-8-yl)carbamate (52 mg, 176.62 μmol) was dissolved in N,N-dimethylformamide (3 mL), and then the mixture was slowly added dropwise into a solution of N-bromosuccinimide (62.87 mg, 353.25 μmol) in N,N-dimethylformamide (3 mL). The reaction solution was stirred and reacted at 50° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran=2:1) to obtain isopropyl (3-(5-bromothiazol-2-yl)bicyclo[3.2.1]oct-8-yl)carbamate (50 mg).

[0592] MS m/z (ESI): 373.1 & 375.1 [M+H].sup.+

[0593] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.55 (s, 1H) 4.95-4.90 (m, 2H) 3.76 (br s, 1H) 3.23-3.37 (m, 1H) 2.30 (br s, 2H) 1.95-1.76 (m, 6H) 1.70-1.63 (m 2H) 1.24 (d, J=6.27 Hz, 6H).

Step 11: Synthesis of isopropyl N-[3-(tert-butylsulfamoyl)-4-[2-[8-(isopropoxycarbonylamino)-3-bicyclo[3.2.1]octyl]thiazol-5-yl]phenyl]carbamate

[0594] Isopropyl (3-(5-bromothiazol-2-yl)bicyclo[3.2.1]oct-8-yl)carbamate (30 mg, 80.36 μmol) and isopropyl (3-(N-(tert-butyl)sulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (42.47 mg, 96.44 μmol) were dissolved in water (240 μl) and dioxane (3 mL). Afterwards, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (6.56 mg, 8.04 μmol) and sodium carbonate (25.55 mg, 241.09 μmol) were added under the condition where nitrogen gas was introduced. The reaction solution was stirred and reacted at 80° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with water (2 mL) and extracted with ethyl acetate (6 mL) three times. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC Triart C18 column, 7 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl N-[3-(tert-butylsulfamoyl)-4-[2-[8-(isopropoxycarbonylamino)-3-bicyclo[3.2.1]octyl] thiazol-5-yl]phenyl]carbamate (30 mg).

[0595] MS m/z (ESI): 607.4 [M+H].sup.+

[0596] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 10.07 (s, 1H) 8.31 (d, J=2.25 Hz, 1H) 7.55-7.72 (m, 2H) 7.37 (d, J=8.38 Hz, 1H) 7.23 (br s, 1H) 6.98 (s, 1H) 4.96-4.89 (m, 1H) 4.80-4.75 (m, 1H) 3.40 (br s, 1H) 3.37-3.46 (m, 1H) 2.26 (br s, 2H) 1.99 (br t, J=12.07 Hz, 2H) 1.82-1.55 (m, 6H) 1.27 (d, J=6.25 Hz, 6H) 1.17 (d, J=6.25 Hz, 6H) 1.09 (s, 9H).

Example 22: Synthesis of isopropyl trans-(4-(5-(4-((1H-pyrazol-3-yl)amino)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0597] ##STR00197##

Synthetic Method

[0598] ##STR00198##

Step 1: Synthesis of isopropyl trans-(4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl) phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0599] Isopropyl trans-(4-(5-(4-amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (1.4 g, 2.83 mmol) was dissolved in acetonitrile (30 mL). Under the protection of nitrogen, tert-butyl nitrite (437.77 mg, 4.25 mmol, 504.93 μL) was added. The reaction solution was stirred at 0° C. for 1 hour. Cuprous bromide (487.19 mg, 3.40 mmol) was added into the reaction solution under the protection of nitrogen. The reaction solution was stirred at 25° C. for 15 hours. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was purified by column chromatography (silica, tetrahydrofuran/petroleum ether=0% to 20%) to obtain isopropyl trans-(4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (0.9 g, 1.46 mmol).

[0600] MS m/z (ESI): 558.2, 560.2 [M+H].sup.+;

Step 2: Synthesis of tert-butyl trans-3-((3-(N-(tert-butyl)sulfamoyl)-4-(2-(4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)amino)-1H-pyrazole-1-carboxylate

[0601] Isopropyl trans-(4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (250 mg, 447.59 μmol) and tert-butyl 3-amino-1H-pyrazole-1-carboxylate (123.00 mg, 671.38 μmol) were dissolved in anhydrous tetrahydrofuran (6 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (40.57 mg, 44.76 μmol) and potassium acetate (131.78 mg, 1.34 mmol) were added. The reaction solution was stirred at 80° C. for 1 hour. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was extracted with ethyl acetate (40 mL×3) to obtain tert-butyl trans-3-((3-(N-(tert-butyl)sulfamoyl)-4-(2-(4-((isopropoxycarbonyl) amino)cyclohexyl)thiazol-5-yl)phenyl)amino)-1H-pyrazole-1-carboxylate (235 mg, crude product).

[0602] MS m/z (ESI): 661.4 [M+H].sup.+;

Step 3: Synthesis of isopropyl trans-(4-(5-(4-((1H-pyrazol-3-yl)amino)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0603] Tert-butyl trans-3-((3-(N-(tert-butyl)sulfamoyl)-4-(2-(4-((isopropoxycarbonyl)amino) cyclohexyl)thiazol-5-yl)phenyl)amino)-1H-pyrazole-1-carboxylate (200 mg, 302.64 μmol) was dissolved in methanol (5 mL), and p-toluenesulfonic acid monohydrate (156.35 mg, 907.93 μmol) was added. The reaction solution was stirred at 30° C. for 2 hours. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation. The resultant was purified by preparative high-performance liquid chromatography (Phenomenex Gemini-NX C18 column, 5 μm silica, 30 mm in diameter, 150 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia and 10 mmol ammonium bicarbonate) and acetonitrile (45% to 65%) as eluents) and lyophilized to obtain isopropyl trans-(4-(5-(4-((1H-pyrazol-3-yl)amino)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (36.79 mg).

[0604] MS m/z (ESI): 561.3 [M+H].sup.+;

[0605] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 12.17 (s, 1H) 9.02 (s, 1H) 8.16 (d, J=2.32 Hz, 1H) 7.69-7.57 (m, 2H) 7.53 (dd, J=8.44, 2.32 Hz, 1H) 7.25 (d, J=8.31 Hz, 1H) 7.01 (br d, J=7.70 Hz, 1H) 6.71 (s, 1H) 5.86 (t, J=2.08 Hz, 1H) 4.83-4.70 (m, 1H) 3.31-3.27 (m, 1H) 2.95-2.83 (m, 1H) 2.17-2.05 (m, 2H) 1.95-1.83 (m, 2H) 1.65-1.47 (m, 2H) 1.42-1.26 (m, 2H) 1.16 (d, J=6.24 Hz, 6H) 1.07 (s, 9H).

Example 23: Synthesis of isopropyl trans-N-[3-diethylphosphoryl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0606] ##STR00199##

Synthetic Method

[0607] ##STR00200##

Step 1: Synthesis of (2-bromophenyl)diethylphosphine oxide

[0608] O-bromoiodobenzene (1 g, 3.53 mmol, 454.55 μL), potassium phosphate (1.50 g, 7.07 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (409.06 mg, 706.95 μmol) were dissolved in N,N-dimethylformamide (15 mL). Under the protection of nitrogen, diethylphosphine oxide (750.10 mg, 7.07 mmol) and palladium acetate (158.72 mg, 706.95 μmol) were added. The reaction solution appeared as a light yellow suspension, and was stirred and reacted at 100° C. for 1 h. The completion of the reaction was detected by LCMS. The reaction solution was added with water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=20:1) to obtain the compound (2-bromophenyl)diethylphosphine oxide (900 mg).

[0609] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.05-7.92 (m, 1H) 7.81-7.70 (m, 1H) 7.64-7.45 (m, 2H) 2.27-2.01 (m, 4H) 1.01-0.88 (m, 6H).

Step 2: Synthesis of (2-bromo-5-nitrophenyl)diethylphosphine oxide

[0610] (2-Bromophenyl)diethylphosphine oxide (900 mg, 3.45 mmol) was dissolved in concentrated sulfuric acid (10 mL), and fuming nitric acid (651.62 mg, 10.34 mmol, 465.44 μL) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 30° C. for 1 h. The completion of the reaction was detected by LCMS. The reaction solution was added with water (20 mL), and then extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure to obtain crude (2-bromo-5-nitrophenyl)diethylphosphine oxide (840 mg).

[0611] MS m/z (ESI): 306.0, 308.0 [M+H].sup.+;

Step 3: Synthesis of (5-amino-2-bromophenyl)diethylphosphine oxide

[0612] (2-Bromo-5-nitrophenyl)diethylphosphine oxide (840 mg, 2.74 mmol) was dissolved in anhydrous ethanol (3 mL). Under the protection of nitrogen, reduced iron powder (919.52 mg, 16.47 mmol) and ammonium chloride (1.47 g, 27.44 mmol) were added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 80° C. for 12 h. The completion of the reaction was detected by LCMS. The reaction solution was filtered while it was still hot. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=20:1) to obtain the compound (5-amino-2-bromophenyl)diethylphosphine oxide (360 mg).

[0613] MS m/z (ESI): 276.0, 278.0 [M+H].sup.+;

Step 4: Synthesis of isopropyl (4-bromo-3-(diethylphosphoryl)phenyl)carbamate

[0614] (5-Amino-2-bromophenyl)diethylphosphine oxide (180 mg, 651.92 μmol) was dissolved in anhydrous dichloromethane (3 mL). Under the protection of nitrogen, pyridine (309.40 mg, 3.91 mmol, 315.71 μL) and isopropyl chloroformate (239.68 mg, 1.96 mmol, 271.43 μL) were added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 1 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain the compound isopropyl (4-bromo-3-(diethylphosphoryl)phenyl)carbamate (180 mg, 496.97 μmol).

[0615] MS m/z (ESI): 362.0, 364.0 [M+H].sup.+;

Step 5: Synthesis of isopropyl trans-N-[3-diethylphosphoryl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0616] Isopropyl (4-bromo-3-(diethylphosphoryl)phenyl)carbamate (80 mg, 220.87 μmol), isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (76.70 mg, 220.87 μmol) and bis(pinacolato)diboron (224.35 mg, 883.49 μmol) were dissolved in anhydrous tetrahydrofuran (6 mL). Under the protection of nitrogen, tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (10.11 mg, 11.04 μmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (5.26 mg, 11.04 μmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (8.69 mg, 11.04 μmol) and potassium acetate (43.35 mg, 441.75 μmol) were added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 80° C. for 16 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was added with water (5 mL) and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[3-diethylphosphoryl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate (10.35 mg).

[0617] MS m/z (ESI): 550.0 [M+H].sup.+;

[0618] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.92 (s, 1H) 8.14-8.00 (m, 1H) 7.75-7.68 (m, 2H) 7.40-7.30 (m, 1H) 7.08-6.97 (m, 1H) 4.98-4.86 (m, 1H) 4.80-4.67 (m, 1H) 3.32-3.27 (m, 1H) 3.00-2.86 (m, 1H) 2.19-2.06 (m, 2H) 1.97-1.85 (m, 2H) 1.76-1.63 (m, 2H) 1.63-1.50 (m, 4H) 1.40-1.30 (m, 2H) 1.27 (d, J=6.27 Hz, 6H) 1.17 (d, J=6.27 Hz, 6H) 0.95-0.83 (m, 6H).

Example 24: Synthesis of isopropyl trans-N-[3-(2,2-dimethylpropylsulfonyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0619] ##STR00201##

Synthetic Method

[0620] ##STR00202##

Step 1: Synthesis of 3-(neopentylthio)aniline

[0621] 3-Aminobenzenethiol (400 mg, 3.20 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 1-bromo-2,2-dimethylpropane (579.12 mg, 3.83 mmol) and potassium carbonate (662.38 mg, 4.79 mmol) were added. The reaction solution was stirred and reacted at 25° C. for 3 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (15 mL) four times. The organic phase was dried, filtered, concentrated to dryness, and then purified by column chromatography (silica, petroleum ether/ethyl acetate=5/1) to obtain 3-(neopentylthio)aniline as the product (230 mg).

[0622] MS m/z (ESI): 196.2 [M+H].sup.+;

[0623] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 7.01 (t, J=8.0 Hz, 1H), 6.75 (s, 1H), 6.78 (d, J=6.8 Hz, 1H), 6.53 (d, J=1.6 Hz, 1H), 2.88 (s, 2H), 1.03 (s, 9H).

Step 2: Synthesis of isopropyl (3-(neopentylthio)phenyl)carbamate

[0624] Diisopropylethylamine (880.04 mg, 6.81 mmol), 4-dimethylaminopyridine (207.97 mg, 1.70 mmol) and isopropyl chloroformate (677.28 mg, 5.53 mmol) were added into a solution of 3-(neopentylthio)aniline (665 mg, 3.40 mmol) in tetrahydrofuran (10 mL) at room temperature. The reaction solution was stirred overnight at room temperature. The reaction solution was poured into ice water (20 mL), and the resulting mixture was extracted with ethyl acetate (20 mL) three times. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and then purified by column chromatography (silica, petroleum ether/ethyl acetate=10/1) to obtain isopropyl (3-(neopentylthio)phenyl)carbamate as the product (794 mg).

[0625] MS m/z (ESI): 282.2 [M+H].sup.+;

Step 3: Synthesis of isopropyl (4-bromo-3-(neopentylthio)phenyl)carbamate

[0626] At −20° C., N-bromosuccinimide (126.49 mg, 710.7 μmol) was added into a solution of isopropyl (3-(neopentylthio)phenyl)carbamate (200 mg, 710.7 μmol) in dichloromethane (5 mL). The reaction solution was stirred at −20° C. for 3 hours. The resulting mixture was diluted with dichloromethane (15 mL). The organic phase was washed with saturated saline (5 mL), dried, filtered, and concentrated to dryness. Thereafter, the resultant was purified by column chromatography (silica, petroleum ether/ethyl acetate=20/1) to obtain isopropyl (4-bromo-3-(neopentylsulfonyl)phenyl)carbamate as the product (85 mg).

[0627] MS m/z (ESI): 361.1 [M+H].sup.+.

Step 4: Synthesis of isopropyl (4-bromo-3-(neopentylsulfonyl)phenyl)carbamate

[0628] At 0° C., m-chloroperoxybenzoic acid (95.79 mg, 471.82 μmol) was added into a solution of isopropyl (4-bromo-3-(neopentylthio)phenyl)carbamate (85 mg, 235.91 μmol) in dichloromethane (5 mL). The reaction solution was stirred overnight at room temperature. The resulting mixture was diluted with dichloromethane (20 mL), washed with a saturated sodium sulfite solution (5 mL), dried, filtered, and concentrated to obtain isopropyl (4-bromo-3-(neopentylsulfonyl)phenyl)carbamate as the product (85 mg).

[0629] MS m/z (ESI): 392.0, 394.0 [M+H].sup.+;

Step 5: Synthesis of isopropyl trans-N-[3-(2,2-dimethylpropylsulfonyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0630] Under the nitrogen atmosphere, a solution of isopropyl (4-bromo-3-(neopentylsulfonyl)phenyl)carbamate (40 mg, 101.96 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (38.84 mg, 152.94 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (3.73 mg, 5.10 μmol) and potassium acetate (15.01 mg, 152.94 μmol) in tetrahydrofuran (2 mL) was heated to 80° C., and was stirred and reacted for 2 hours. Afterwards, isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl] carbamate (42.49 mg, 122.35 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (3.73 mg, 5.10 μmol), potassium phosphate (43.29 mg, 203.92 μmol) and water (0.5 mL) were added into the above reaction solution. The reaction solution was reacted overnight at 80° C. The reaction solution was filtered and concentrated. The resultant was purified by preparative liquid chromatography (Agela DuraShell C18 column: 5 μm silica, 25 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.04% aqueous ammonia and 10 mm NH.sub.4CO.sub.3) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[3-(2,2-dimethylpropylsulfonyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl] phenyl]carbamate (3.25 mg).

[0631] MS m/z (ESI): 580.1 [M+H].sup.+;

[0632] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 8.34 (s, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.67 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 5.06-5.00 (m, 1H), 4.99-4.83 (m, 1H), 3.51-3.47 (m, 1H), 3.08-3.02 (m, 1H), 2.91 (s, 2H), 2.23 (d, J=12.0 Hz, 2H), 2.08 (d, J=10.0 Hz, 2H), 1.74-1.69 (m, 2H), 1.48-1.41 (m, 2H), 1.34 (d, J=6.0 Hz, 6H), 1.24 (d, J=6.0 Hz, 6H), 1.02 (s, 9H).

Example 25: Synthesis of isopropyl trans-N-[4-[5-[4-(isopropoxycarbonylamino) cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylsulfonyl-phenyl]carbamate

[0633] ##STR00203##

Synthetic Method

[0634] ##STR00204##

Step 1: Synthesis of isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylmercapto-phenyl]carbamate

[0635] [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (4.51 mg, 5.52 μmol) was added into a solution of isopropyl N-[3-isopropylmercapto-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (50.26 mg, 132.49 μmol), tert-butyl trans-N-[4-(5-bromo-1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate (40 mg, 110.41 μmol) and potassium phosphate (46.87 mg, 220.82 μmol) in tetrahydrofuran (2 mL) and water (0.5 mL). Under the protection of nitrogen, the reaction solution was stirred overnight at 80° C. The completion of the reaction was monitored by LCMS. The reaction solution was concentrated to dryness, and then the resultant was purified by column chromatography (silica, petroleum ether/ethyl acetate=1/1) to obtain isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylmercapto-phenyl] carbamate as the product (35 mg).

[0636] MS m/z (ESI): 535.2 [M+H].sup.+;

Step 2: Synthesis of trans-N-[4-[5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl]-3-isopropylmercapto-phenyl]carbamate

[0637] At room temperature, hydrochloric acid/dioxane (4M, 0.35 mL) was added into a solution of isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylmercapto-phenyl]carbamate (35 mg, 65.45 μmol) in dioxane (1 mL). The reaction solution was stirred at room temperature for 4 hours. The completion of the reaction was monitored by LCMS. The reaction solution was concentrated to dryness to obtain isopropyl trans-N-[4-[5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl]-3-isopropylmercapto-phenyl]carbamate as the product (28 mg).

[0638] MS m/z (ESI): 435.1 [M+H].sup.+;

Step 3: Synthesis of isopropyl trans-N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylmercapto-phenyl]carbamate

[0639] Isopropyl chloroformate (9.47 mg, 77.31 μmol) and diisopropylethylamine (24.98 mg, 193.27 μmol) were added into a solution of isopropyl trans-N-[4-[5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl]-3-isopropylmercapto-phenyl]carbamate (28 mg, 64.42 μmol) in dichloromethane (3 mL). The reaction solution was stirred overnight at room temperature. The completion of the reaction was monitored by LCMS. The reaction solution was concentrated to dryness and purified by thin-layer chromatography (silica, petroleum ether/ethyl acetate=1/1) to obtain isopropyl trans-N-[4-[5-[4-(isopropoxycarbonylamino) cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylmercapto-phenyl]carbamate as the product (23.5 mg).

[0640] MS m/z (ESI): 521.2 [M+H].sup.+;

Step 4: Synthesis of isopropyl trans-N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylsulfonyl-phenyl]carbamate

[0641] At 0° C., m-chloroperoxybenzoic acid (10.99 mg, 54.16 μmol) was added into a solution of isopropyl trans-N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylmercapto-phenyl]carbamate (23.5 mg, 45.13 μmol) in dichloromethane (3 mL). The reaction solution was stirred at room temperature for 4 hours. The resulting mixture was diluted with dichloromethane (20 mL) and then washed with a saturated aqueous sodium sulfite solution (5 mL, twice). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resultant was purified by preparative liquid chromatography (Agela DuraShell C18 column: 5 μm silica, 25 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.04% aqueous ammonia and 10 mM NH.sub.4CO.sub.3) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylsulfonyl-phenyl] carbamate (1.52 mg).

[0642] MS m/z (ESI): 553.1 [M+H].sup.+;

[0643] .sup.1H NMR (400 MHz, MeOD) δ ppm 8.31 (d, J=2.4 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 5.06-5.01 (m, 2H), 4.06-4.02 (m, 1H), 3.50-3.49 (m, 1H), 3.25-3.22 (m, 1H), 2.36-2.25 (m, 2H), 2.20-2.07 (m, 2H), 1.79-1.72 (m, 2H), 1.48-1.44 (m, 2H), 1.35 (d, J=6.4 Hz, 6H), 1.29 (d, J=6.4 Hz, 6H), 1.25 (d, J=6.4 Hz, 6H).

Example 26: Synthesis of isopropyl trans-(4-(5-(4-(3-benzylureido)-2-(dimethylphosphoryl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0644] ##STR00205##

Synthetic Method

[0645] ##STR00206##

Step 1: Synthesis of isopropyl trans-(4-(5-(4-amino-2-(dimethylphosphoryl)phenyl) thiazol-2-yl)cyclohexyl)carbamate

[0646] (5-Amino-2-bromophenyl)dimethylphosphine oxide (60 mg, 241.88 μmol), isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (84 mg, 241.88 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (245.69 mg, 967.52 μmol) were dissolved in tetrahydrofuran (6 mL). Under the protection of nitrogen, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (5.97 mg, 12.09 μmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)] palladium (II) (9.52 mg, 12.09 μmol), tris(dibenzylideneacetone)dipalladium (11.07 mg, 12.09 μmol) and potassium acetate (47.48 mg, 483.76 μmol) were added. The reaction solution was stirred and reacted at 80° C. for 16 hours. The reaction solution was filtered. The filtrate was concentrated to dryness under reduced pressure. The resultant was added with water (5 mL), and the mixture was extracted with 15 mL of ethyl acetate (5 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a black oily compound, which was further purified by column chromatography (silica, petroleum ether:ethyl acetate=1:2) to obtain isopropyl trans-(4-(5-(4-amino-2-(dimethylphosphoryl) phenyl)thiazol-2-yl)cyclohexyl)carbamate (23 mg).

[0647] MS m/z (ESI): 436.2 [M+H].sup.+.

Step 2: Synthesis of isopropyl trans-(4-(5-(4-(3-benzylureido)-2-(dimethylphosphoryl) phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0648] Isopropyl trans-(4-(5-(4-amino-2-(dimethylphosphoryl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (20 mg, 45.92 μmol) and benzyl isocyanate (12.23 mg, 91.84 μmol) were dissolved in dichloromethane (4 mL), and N,N-diisopropylethylamine (11.87 mg, 91.84 μmol, 16.00 μL) and 4-dimethylaminopyridine (2.81 mg, 22.96 μmol) were added. The reaction solution was stirred at 45° C. for 2 hours. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was purified by preparative liquid chromatography (Phenomenex Gemini column: 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (35% to 55%) as eluents) to obtain the compound isopropyl trans-(4-(5-(4-(3-benzylureido)-2-(dimethylphosphoryl)phenyl)thiazol-2-yl)cyclohexyl) carbamate as a white solid (4.75 mg).

[0649] MS m/z (ESI): 569.1 [M+H].sup.+;

[0650] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.02 (s, 1H) 7.91 (dd, J=14.31, 2.32 Hz, 1H) 7.80 (s, 1H) 7.71 (dd, J=8.44, 1.47 Hz, 1H) 7.39-7.28 (m, 5H) 7.27-7.22 (m, 1H) 7.03 (br d, J=7.70 Hz, 1H) 6.76 (t, J=5.93 Hz, 1H) 4.82-4.70 (m, 1H) 4.32 (d, J=5.99 Hz, 2H) 3.30-3.26 (m, 1H) 3.02-2.85 (m, 1H) 2.12 (br d, J=11.25 Hz, 2H) 1.91 (br d, J=9.66 Hz, 2H) 1.63-1.49 (m, 2H) 1.43 (d, J=13.20 Hz, 6H) 1.39-1.26 (m, 2H) 1.16 (d, J=6.24 Hz, 6H).

Example 27: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]-3-(1-oxophospholan-1-yl)phenyl]carbamate

[0651] ##STR00207##

Synthetic Method

[0652] ##STR00208##

Step 1: Synthesis of 1-phenylphospholane-1-oxide

[0653] Phenylphosphonic dichloride (4 g, 20.51 mmol) was dissolved in diethyl ether (15 mL). Under the protection of nitrogen, butyl di(magnesium bromide) (5.43 g, 20.51 mmol) was added at −30° C. The reaction solution appeared as a gray suspension, and was stirred and reacted at 25° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with saturated ammonium chloride solution (30 mL), and extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=20:1) to obtain the compound 1-phenylphospholane-1-oxide (830 mg, 4.61 mmol) as a yellow oil.

[0654] MS m/z (ESI): 181.1 [M+H].sup.+

Step 2: Synthesis of 1-(3-nitrophenyl)phospholane-1-oxide

[0655] 1-Phenylphospholane-1-oxide (700 mg, 3.88 mmol) was dissolved in concentrated sulfuric acid (10 mL), and fuming nitric acid (734.40 mg, 11.65 mmol, 524.57 μL) was added at 0° C. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with water (30 mL), and then extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure to obtain crude 1-(3-nitrophenyl)phospholane-1-oxide (800 mg) as a yellow oil.

[0656] MS m/z (ESI): 226.1 [M+H].sup.+

Step 3: Synthesis of 1-(3-aminophenyl)phospholane-1-oxide

[0657] 1-(3-Nitrophenyl)phospholane-1-oxide (800 mg, 3.55 mmol) was dissolved in anhydrous ethanol (3 mL) and water (600 μL). Under the protection of nitrogen, reduced iron powder (1.19 g, 21.32 mmol) and ammonium chloride (1.90 g, 35.53 mmol) were added. The reaction solution appeared as a black suspension, and was stirred and reacted at 80° C. for 3 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered while it was still hot. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=10:1) to obtain the compound 1-(3-aminophenyl)phospholane-1-oxide (230 mg, 1.18 mmol) as a yellow oil.

[0658] MS m/z (ESI): 196.1 [M+H].sup.+

Step 4: Synthesis of isopropyl (3-(1-oxidophospholan-1-yl)phenyl)carbamate

[0659] 1-(3-Aminophenyl)phospholane-1-oxide (230 mg, 1.18 mmol) was dissolved in anhydrous dichloromethane (3 mL). Under the protection of nitrogen, pyridine (559.22 mg, 7.07 mmol, 570.63 μL) and isopropyl chloroformate (433.20 mg, 3.53 mmol, 490.60 μL) were added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=10:1) to obtain the compound isopropyl (3-(1-oxidophospholan-1-yl)phenyl)carbamate (260 mg, 924.32 μmol) as a yellow solid.

[0660] MS m/z (ESI): 282.2 [M+H].sup.+

Step 5: Synthesis of isopropyl (4-bromo-3-(1-oxidophospholan-1-yl)phenyl)carbamate

[0661] Isopropyl (3-(1-oxidophospholan-1-yl)phenyl)carbamate (260 mg, 924.32 μmol) was dissolved in N,N-dimethylformamide (5 mL), and N-bromosuccinimide (493.54 mg, 2.77 mmol) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 50° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:tetrahydrofuran=1:1) to obtain the compound isopropyl (4-bromo-3-(1-oxidophospholan-1-yl)phenyl)carbamate (300 mg, 832.91 μmol) as a white solid.

[0662] MS m/z (ESI): 360.1, 362.0 [M+H].sup.+

Step 6: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl] thiazol-5-yl]-3-(1-oxophospholan-1-yl)phenyl]carbamate

[0663] Isopropyl (4-bromo-3-(1-oxidophospholan-1-yl)phenyl)carbamate (200 mg, 555.27 μmol), isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (192.83 mg, 555.27 μmol) and bis(pinacolato)diboron (564.02 mg, 2.22 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL). Under the protection of nitrogen, tris(dibenzylideneacetone)dipalladium(0) (25.42 mg, 27.76 μmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (13.24 mg, 27.76 μmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)] palladium (II) (21.84 mg, 27.76 μmol) and potassium acetate (108.99 mg, 1.11 mmol) were added. The reaction solution appeared as a black suspension, and was stirred and reacted at 80° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was added with water (10 mL) and the mixture was extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(1-oxophospholan-1-yl) phenyl]carbamate (65.22 mg) as a white solid.

[0664] MS m/z (ESI): 548.1 [M+H].sup.+;

[0665] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.92 (s, 1H), 8.09-8.02 (m, 1H), 7.94 (s, 1H), 7.76-7.70 (m, 1H), 7.49-7.44 (m, 1H), 7.08-7.01 (m, 1H), 5.00-4.89 (m, 1H), 4.83-4.70 (m, 1H), 3.36-3.33 (m, 1H), 3.02-2.89 (m, 1H), 2.19-2.09 (m, 2H), 1.98-1.78 (m, 6H), 1.69-1.50 (m, 6H), 1.43-1.32 (m, 2H), 1.29 (d, J=6.3 Hz, 6H), 1.18 (d, J=6.3 Hz, 6H).

Example 28: Synthesis of isopropyl trans-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0666] ##STR00209##

Synthetic Method

[0667] ##STR00210##

Step 1: Synthesis of tert-butyl trans-3-((3-(N-(tert-butyl)sulfamoyl)-4-(2-4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)amino)-5-methyl-1H-pyrazole-1-carboxylate

[0668] Isopropyl trans-N-[4-[5-[4-bromo-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate (250 mg, 447.59 μmol) (an intermediate synthesized in Example 22) and tert-butyl 3-amino-5-methyl-pyrazole-1-carboxylate (264.84 mg, 1.34 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (20.29 mg, 22.38 μmol) and potassium acetate (131.78 mg, 1.34 mmol) were added. The reaction solution was stirred at 80° C. for 16 hours. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was subjected to liquid-liquid extraction (extracted with 120 mL of ethyl acetate three times) to obtain tert-butyl trans-3-((3-(N-(tert-butyl)sulfamoyl)-4-(2-4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)amino)-5-methyl-1H-pyrazole-1-carboxylate (280 mg, crude product).

[0669] MS m/z (ESI): 674.9 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0670] Tert-butyl trans-3-((3-(N-(tert-butyl)sulfamoyl)-4-(2-4-((isopropoxycarbonyl)amino) cyclohexyl)thiazol-5-yl)phenyl)amino)-5-methyl-1H-pyrazole-1-carboxylate (235 mg, 348.21 μmol) was dissolved in methanol (5 mL), and p-toluenesulfonic acid (179.89 mg, 1.04 mmol) was added. The reaction solution was stirred at 50° C. for 2 hours. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation. The resultant was added with 2M sodium hydroxide (10 mL), and then the mixture was extracted with dichloromethane (120 mL) three times. The resultant was purified by preparative high-performance liquid chromatography (Phenomenex Gemini-NX column, 5 μm silica, 30 mm in diameter, 150 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia and 10 mmol of ammonium bicarbonate) and acetonitrile (45% to 65%) as eluents) and lyophilized to obtain isopropyl trans-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (32.73 mg).

[0671] MS m/z (ESI): 575.2 [M+H].sup.+;

[0672] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.82 (s, 1H) 8.91 (s, 1H) 8.14 (d, J=2.32 Hz, 1H) 7.60 (s, 1H) 7.50 (dd, J=8.44, 2.32 Hz, 1H) 7.23 (d, J=8.31 Hz, 1H) 7.01 (br d, J=7.46 Hz, 1H) 6.70 (s, 1H) 5.63 (s, 1H) 4.81-4.69 (m, 1H) 3.35-3.25 (m, 1H) 2.92-2.80 (m, 1H) 2.19 (s, 3H) 2.12 (br d, J=11.62 Hz, 2H) 1.91 (br d, J=10.15 Hz, 2H) 1.63-1.49 (m, 2H) 1.41-1.26 (m, 2H) 1.16 (d, J=6.24 Hz, 6H) 1.07 (s, 9H).

Example 29: Synthesis of isopropyl trans-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(isoxazol-5-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0673] ##STR00211##

##STR00212##

[0674] Isopropyl trans-N-[4-[5-[4-bromo-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate (120 mg, 214.84 μmol) and isoxazol-5-amine (72.25 mg, 859.37 μmol) were dissolved in tetrahydrofuran (5 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (9.74 mg, 10.74 μmol) and potassium acetate (63.26 mg, 644.52 μmol) were added. The reaction solution was stirred at 90° C. for 1 hour. TLC (dichloromethane:methanol=15:1) showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was purified twice by thin-layer chromatography (silica, dichloromethane:methanol=10:1) to obtain isopropyl trans-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(isoxazol-5-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (2.35 mg).

[0675] MS m/z (ESI): 562.1 [M+H].sup.+;

[0676] .sup.1HNMR: (400 MHz, DMSO-d.sub.6) δ ppm 10.74 (s, 1H) 8.35 (d, J=2.25 Hz, 1H) 7.78 (dd, J=8.44, 2.19 Hz, 1H) 7.68 (s, 1H) 7.46 (d, J=8.25 Hz, 1H) 7.17-6.95 (m, 2H) 4.80-4.70 (m, 1H) 3.97 (d, J=4.13 Hz, 1H) 3.31-3.25 (m, 1H) 2.99-2.86 (m, 1H) 2.19-2.05 (m, 2H) 1.92-1.87 (m, 2H) 1.68-1.50 (m, 2H) 1.43-1.27 (m, 2H) 1.16 (d, J=6.25 Hz, 6H) 1.05 (s, 9H).

Example 30: Synthesis of isopropyl trans-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(isoxazol-3-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0677] ##STR00213##

##STR00214##

[0678] Isopropyl trans-N-[4-[5-[4-bromo-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate (300 mg, 537.10 μmol) and isoxazol-3-amine (135.47 mg, 1.61 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (24.34 mg, 26.86 μmol) and potassium acetate (158.14 mg, 1.61 mmol) were added. The reaction solution was stirred at 80° C. for 0.5 hours. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was purified by preparative high-performance liquid chromatography (Phenomenex Gemini-NX column, 5 μm silica, 30 mm in diameter, 150 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia and 10 mmol of ammonium bicarbonate) and acetonitrile (45% to 65%) as eluents) and lyophilized to obtain isopropyl trans-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(isoxazol-3-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (32.79 mg).

[0679] MS m/z (ESI): 562.2 [M+H].sup.+;

[0680] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.76 (s, 1H) 8.67 (d, J=1.59 Hz, 1H) 8.26 (d, J=2.45 Hz, 1H) 7.71-7.57 (m, 2H) 7.40 (d, J=8.44 Hz, 1H) 7.08-6.98 (m, 1H) 6.92 (br s, 1H) 6.25 (d, J=1.71 Hz, 1H) 4.80-4.70 (m, 1H) 3.31-3.24 (m, 1H) 2.97-2.82 (m, 1H) 2.13 (br d, J=11.74 Hz, 2H) 1.92 (br d, J=10.15 Hz, 2H) 1.66-1.49 (m, 2H) 1.43-1.26 (m, 2H) 1.16 (d, J=6.11 Hz, 6H) 1.08 (s, 9H).

Example 31: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]-3-[isopropyl(methyl)phosphoryl]phenyl]carbamate

[0681] ##STR00215##

Synthetic Method

[0682] ##STR00216##

Step 1: Synthesis of ethyl methyl(phenyl)phosphinate

[0683] Iodobenzene (800 mg, 3.92 mmol, 437.16 μL), potassium phosphate (1.66 g, 7.84 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (453.80 mg, 784.28 μmol) were dissolved in N,N-dimethylformamide (2 mL). Under the protection of nitrogen, methyldiethoxyphosphine (1.07 g, 7.84 mmol) and palladium acetate (176.08 mg, 784.28 μmol) were added. The reaction solution appeared as a light yellow suspension, and was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:tetrahydrofuran=3:1) to obtain the compound ethyl methyl(phenyl)phosphinate (540 mg, 2.93 mmol).

[0684] MS m/z (ESI): 185.1 [M+H].sup.+;

Step 2: Synthesis of isopropyl(methyl)(phenyl)phosphine oxide

[0685] Ethyl methyl(phenyl)phosphinate (200 mg, 1.09 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL). Under the protection of nitrogen, a solution (2M, 3.26 mL) of isopropylmagnesium chloride (2.0M) in tetrahydrofuran was added at −30° C. The reaction solution appeared as a brown suspension, and was stirred and reacted at 40° C. for 16 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was added with saturated ammonium chloride (10 mL), and the mixture was extracted with ethyl acetate (20 mL) twice. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:tetrahydrofuran=1:2) to obtain the compound isopropyl(methyl)(phenyl)phosphine oxide (115 mg, 631.18 μmol).

[0686] MS m/z (ESI): 183.2 [M+H].sup.+;

Step 3: Synthesis of isopropyl(methyl)(3-nitrophenyl)phosphine oxide

[0687] Isopropyl(methyl)(phenyl)phosphine oxide (115 mg, 631.18 μmol) was dissolved in concentrated sulfuric acid (2 mL), and fuming nitric acid (119.32 mg, 1.89 mmol, 85.23 μL) was added at 0° C. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 2 h. The completion of the reaction was detected by LCMS. The reaction solution was added with water (10 mL) and then extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure to obtain crude isopropyl(methyl)(3-nitrophenyl)phosphine oxide (70 mg).

[0688] MS m/z (ESI): 228.1 [M+H].sup.+;

Step 4: Synthesis of (3-aminophenyl)(isopropyl)(methyl)phosphine oxide

[0689] Isopropyl(methyl)(3-nitrophenyl)phosphine oxide (70 mg, 308.10 μmol) was dissolved in anhydrous ethanol (3 mL) and water (600 μL). Under the protection of nitrogen, reduced iron powder (103.24 mg, 1.85 mmol) and ammonium chloride (164.80 mg, 3.08 mmol) were added. The reaction solution appeared as a black suspension, and was stirred and reacted at 90° C. for 12 h. The completion of the reaction was detected by LCMS. The reaction solution was filtered while it was still hot. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=10:1) to obtain the compound (3-aminophenyl)(isopropyl)(methyl)phosphine oxide (45 mg, 228.18 μmol).

[0690] MS m/z (ESI): 198.2 [M+H].sup.+;

Step 5: Synthesis of isopropyl (3-(isopropyl(methyl)phosphoryl)phenyl)carbamate

[0691] (3-Aminophenyl)(isopropyl)(methyl)phosphine oxide was dissolved in anhydrous dichloromethane (3 mL). Under the protection of nitrogen, pyridine (108.29 mg, 1.37 mmol, 110.50 μL) and isopropyl chloroformate (83.89 mg, 684.54 μmol, 95.01 μL) were added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 30° C. for 1 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (dichloromethane:methanol=10:1) to obtain the compound isopropyl (3-(isopropyl(methyl)phosphoryl)phenyl)carbamate (30 mg, 105.89 μmol).

[0692] MS m/z (ESI): 284.2 [M+H].sup.+;

Step 6: Synthesis of isopropyl (4-bromo-3-(isopropyl(methyl)phosphoryl)phenyl) carbamate

[0693] Isopropyl (3-(isopropyl(methyl)phosphoryl)phenyl)carbamate (30 mg, 105.89 μmol) was dissolved in N,N-dimethylformamide (2 mL). N-bromosuccinimide (56.54 mg, 317.68 μmol) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 50° C. for 16 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain the compound isopropyl (4-bromo-3-(isopropyl(methyl)phosphoryl)phenyl)carbamate (30 mg, 82.83 μmol).

[0694] MS m/z (ESI): 362.1, 364.1 [M+H].sup.+;

Step 7: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]-3-[isopropyl(methyl)phosphoryl]phenyl]carbamate

[0695] Isopropyl (4-bromo-3-(isopropyl(methyl)phosphoryl)phenyl)carbamate (25 mg, 69.02 μmol), isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (23.97 mg, 69.02 μmol) and bis(pinacolato)diboron (70.11 mg, 276.09 μmol) were dissolved in anhydrous tetrahydrofuran (3 mL). Under the protection of nitrogen, tris(dibenzylideneacetone)dipalladium(0) (3.16 mg, 3.45 μmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (1.65 mg, 3.45 μmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (2.72 mg, 3.45 μmol) and potassium acetate (13.55 mg, 138.05 μmol) were added. The reaction solution appeared as a black suspension, and was stirred and reacted at 80° C. for 16 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was added with water (10 mL), and the mixture was extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-[isopropyl (methyl)phosphoryl]phenyl]carbamate (5.44 mg, 9.89 μmol).

[0696] MS m/z (ESI): 550.1 [M+H].sup.+;

[0697] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.93 (s, 1H), 8.14-8.03 (m, 1H), 7.75-7.68 (s, 2H), 7.41-7.33 (m, 1H), 7.09-7.01 (m, 1H), 5.00-4.88 (m, 1H), 4.81-4.71 (m, 1H), 3.35-3.34 (m, 1H), 3.02-2.89 (m, 1H), 2.19-2.08 (m, 2H), 1.98-1.88 (m, 2H), 1.75-1.64 (m, 1H), 1.61-1.54 (m, 2H), 1.35-1.45 (m, 3H), 1.38-1.32 (m, 2H), 1.29 (d, J=6.3 Hz, 6H), 1.18 (d, J=6.3 Hz, 6H), 1.00-0.83 (m, 5H).

Example 32: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]-3-isopropylsulfinyl-phenyl]carbamate

[0698] ##STR00217##

Synthetic Method

[0699] ##STR00218##

Step 1: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]-3-isopropylsulfanyl-phenyl]carbamate

[0700] Isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (100 mg, 287.96 μmol), isopropyl N-[3-isopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] carbamate (131.08 mg, 345.55 μmol) and sodium carbonate (61.04 mg, 575.92 μmol) were dissolved in water (600 μL) and 1,4-dioxane (6 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (23.52 mg, 28.80 μmol) was added. The reaction solution was stirred at 80° C. for 6 hours. LCMS showed that the reaction was complete. The reaction solution was filtered. The filtrate was evaporated to dryness via rotary evaporation to remove 1,4-dioxane. The resultant was added with water (10 mL), and the mixture was extracted three times with ethyl acetate (10 mL×3). After dried over anhydrous sodium sulfate, the resultant was purified by thin-layer chromatography (silica, petroleum ether/ethyl acetate=2:1) to obtain isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfanyl-phenyl]carbamate (84.8 mg).

[0701] MS m/z (ESI): 520.3 [M+H].sup.+

Step 2: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]-3-isopropylsulfinyl-phenyl]carbamate

[0702] Isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfanyl-phenyl]carbamate (75 mg, 144.31 μmol) was dissolved in dichloromethane (2 mL), and m-chloroperoxybenzoic acid (19.92 mg, 115.45 μmol) was added at 20° C. The reaction solution was reacted at 20° C. for 2 hours. LCMS showed that the reaction was complete. The reaction solution was filtered. The filtrate was evaporated to dryness via rotary evaporation to remove dichloromethane. The resultant was added with water (2 mL), and the mixture was extracted three times with ethyl acetate (2 mL×3). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness via rotary evaporation under reduced pressure. The resultant was purified by preparative high-performance liquid chromatography (Phenomenex Gemini-NX C18 column, 5 μm silica, 30 mm in diameter, 150 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (0% to 70%) as eluents) to obtain isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfinyl-phenyl]carbamate (16.14 mg).

[0703] MS m/z (ESI): 536.0 [M+H].sup.+

[0704] .sup.1H NMR: (400 MHz, METHANOL-d.sub.4) δ ppm 8.02 (d, J=2.26 Hz, 1H) 7.77-7.71 (m, 2H) 7.48 (d, J=8.53 Hz, 1H) 5.05-4.95 (m, 1H) 4.88-4.82 (m, 1H) 3.52-3.44 (m, 1H) 3.08-2.98 (m, 1H) 2.82-2.73 (m, 1H) 2.24 (br d, J=11.80 Hz, 2H) 2.09 (br d, J=10.04 Hz, 2H) 1.77-1.66 (m, 2H) 1.48-1.38 (m, 2H) 1.34 (d, J=6.27 Hz, 6H) 1.26-0.98 (m, 12H).

Example 33: Synthesis of isopropyl trans-N-[3-cyclopropylsulfonyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0705] ##STR00219##

Synthetic Method

[0706] ##STR00220##

Step 1: Synthesis of 3-cyclopropylsulfanylaniline

[0707] 3-Aminothiophenol (6 g, 47.93 mmol) was dissolved in N,N-dimethylformamide (60 mL). Under the protection of nitrogen, sodium hydride (2.01 g, 50.30 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. Thereafter, cyclopropyl bromide (6.09 g, 50.30 mmol) was added into the reaction solution. The reaction solution was stirred and refluxed at 100° C. for 5 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, dichloromethane/methanol=20/1) to obtain 3-cyclopropylsulfanylaniline (1.35 g).

[0708] MS m/z (ESI): 166.0 [M+H].sup.+;

Step 2: Synthesis of isopropyl N-(3-cyclopropylsulfanylphenyl)carbamate

[0709] 3-Cyclopropylsulfanylaniline (1.28 g, 7.75 mmol) and isopropyl chloroformate (1.42 g, 11.62 mmol) were dissolved in dichloromethane (400 mL), and pyridine (3.68 g, 46.47 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, and then the resultant was purified by column chromatography (silica, dichloromethane/methanol=20/1) to obtain isopropyl N-(3-cyclopropylsulfanylphenyl) carbamate (1.6 g).

[0710] MS m/z (ESI): 252 [M+H].sup.+;

[0711] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.59 (s, 1H) 7.56 (s, 1H) 7.31-7.14 (m, 2H) 6.95 (dt, J=7.47, 1.41 Hz, 1H) 4.88 (spt, J=6.27 Hz, 1H) 2.20 (tt, J=7.40, 4.27 Hz, 1H) 1.27-1.22 (m, 1H) 1.24 (s, 3H) 1.11-1.02 (m, 2H) 0.66-0.50 (m, 2H).

Step 3: Synthesis of isopropyl N-(4-bromo-3-cyclopropylsulfanyl-phenyl)carbamate

[0712] Isopropyl N-(3-cyclopropylsulfanylphenyl)carbamate (300 mg, 1.19 mmol) was dissolved in dichloromethane (20 mL), and then a solution of N-bromosuccinimide (212.44 mg, 1.19 mmol) in dichloromethane (10 mL) was slowly added dropwise into the reaction solution. The reaction solution was stirred and reacted at −20° C. for 3 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:dichloromethane=1:2) to obtain isopropyl N-(4-bromo-3-cyclopropylsulfanyl-phenyl) carbamate (201 mg).

[0713] MS m/z (ESI): 330.1, 332.1 [M+H].sup.+.

Step 4: Synthesis of isopropyl N-[3-cyclopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[0714] Isopropyl N-(4-bromo-3-cyclopropylsulfanyl-phenyl)carbamate (600 mg, 1.82 mmol) and bis(pinacolato)diboron (1.85 g, 7.27 mmol) were dissolved in tetrahydrofuran (6 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (148.37 mg, 181.69 μmol) and potassium acetate (534.93 mg, 5.45 mmol) were added. The reaction solution was stirred and reacted at 80° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of dichloromethane (3 mL×3) and 4 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:ethyl acetate=5:1) to obtain isopropyl N-[3-cyclopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] carbamate (400 mg).

[0715] MS m/z (ESI): 378 [M+H].sup.+;

Step 5: Synthesis of isopropyl trans-N-[3-cyclopropylsulfanyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0716] Isopropyl N-[3-cyclopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]carbamate (400 mg, 1.06 mmol) and isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (306.80 mg, 883.46 μmol) were dissolved in water (2.3 mL) and dioxane (24 mL). Thereafter, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (72.15 mg, 88.35 μmol) and sodium carbonate (280.91 mg, 2.65 mmol) were added under the condition where nitrogen gas was introduced. The reaction solution was stirred and reacted at 80° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran=2:1) to obtain isopropyl trans-N-[3-cyclopropylsulfanyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl] phenyl]carbamate (300 mg).

[0717] MS m/z (ESI): 518.3 [M+H].sup.+;

Step 6: Synthesis of isopropyl trans-N-[3-cyclopropylsulfonyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0718] Isopropyl trans-N-[3-cyclopropylsulfanyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl] thiazol-5-yl]phenyl]carbamate (150 mg, 289.74 μmol) was dissolved in dichloromethane (2 mL), and then a solution of m-chloroperoxybenzoic acid (117.65 mg, 579.48 μmol) in dichloromethane (3 mL) was slowly added dropwise into the reaction solution. The reaction solution was stirred and reacted at 30° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. A saturated sodium carbonate solution (3 mL) and 9 mL of dichloromethane (3 mL×3) were added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Phenomenex gemini C18 column, 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[3-cyclopropylsulfonyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl] phenyl]carbamate (33.3 mg).

[0719] MS m/z (ESI): 5503 [M+H].sup.+;

[0720] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.14 (s, 1H) 8.29 (d, J=2.32 Hz, 1H) 7.84-7.66 (m, 2H) 7.48 (d, J=8.44 Hz, 1H) 7.04 (br d, J=7.82 Hz, 1H) 4.98-4.87 (m, 1H) 4.80-4.68 (m, 1H) 3.33-3.26 (m, 1H) 3.01-2.85 (m, 1H) 2.45-2.37 (m, 1H) 2.14 (br d, J=11.86 Hz, 2H) 1.92 (br d, J=10.27 Hz, 2H) 1.65-1.50 (m, 2H) 1.41-1.30 (m, 2H) 1.28 (d, J=6.24 Hz, 6H) 1.17 (d, J=6.24 Hz, 6H) 1.01-0.94 (m, 2H) 0.91-0.85 (m, 2H).

Example 34: Synthesis of isopropyl trans-N-[3-tert-butylsulfonyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0721] ##STR00221##

Synthetic Method

[0722] ##STR00222##

Step 1: Synthesis of 3-tert-butylsulfanylaniline

[0723] 3-Bromoaniline (4 g, 23.25 mmol, 2.53 mL) and a solution (2M, 27.90 mL) of lithium bis(trimethylsilyl)amide (2M) in tetrahydrofuran were dissolved in ethylene glycol dimethyl ether (100 mL). Under the protection of nitrogen, palladium acetate (261.02 mg, 1.16 mmol), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-tert-butylphosphine (644.74 mg, 1.16 mmol) and tert-butyl mercaptan (2.10 g, 23.25 mmol, 2.62 mL) were added. The reaction solution appeared as a black suspension, and was stirred and reacted at 110° C. for 48 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane=1) to obtain the compound 3-tert-butylsulfanylaniline (3.68 g, 20.30 mmol).

[0724] MS m/z (ESI): 182.1 [M+H].sup.+;

Step 2: Synthesis of isopropyl N-(3-tert-butylsulfanylphenyl)carbamate

[0725] 3-Tert-butylsulfanylaniline (2 g, 11.03 mmol) was dissolved in anhydrous dichloromethane (30 mL). Under the protection of nitrogen, pyridine (5.24 g, 66.19 mmol, 5.34 mL) and isopropyl chloroformate (4.06 g, 33.09 mmol, 4.59 mL) were added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 2 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:dichloromethane=1:2) to obtain the compound isopropyl N-(3-tert-butylsulfanylphenyl)carbamate (2 g, 7.48 mmol).

[0726] MS m/z (ESI): 268.2 [M+H].sup.+;

Step 3: Synthesis of isopropyl N-(4-bromo-3-tert-butylsulfanyl-phenyl)carbamate

[0727] Isopropyl N-(3-tert-butylsulfanylphenyl)carbamate (2 g, 7.48 mmol) was dissolved in anhydrous dichloromethane (30 mL), and a solution of N-bromosuccinimide (1.33 g, 7.48 mmol) in anhydrous dichloromethane (30 mL) was added dropwise. The reaction solution appeared as a yellow suspension, and was stirred and reacted at −30° C. for 2 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to obtain the compound isopropyl N-(4-bromo-3-tert-butylsulfanyl-phenyl)carbamate (360 mg, 1.04 mmol).

[0728] MS m/z (ESI): 347.0 [M+H].sup.+.

Step 4: Synthesis of isopropyl N-(4-bromo-3-tert-butylsulfonyl-phenyl)carbamate

[0729] Isopropyl N-(4-bromo-3-tert-butylsulfanyl-phenyl)carbamate (200 mg, 577.56 μmol) was dissolved in anhydrous dichloromethane (3 mL), and m-chloroperoxybenzoic acid (299.00 mg, 1.73 mmol) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 20° C. for 3 h. The completion of the reaction was detected by LCMS. The reaction solution was added with saturated sodium carbonate solution (15 mL) and extracted with dichloromethane (30 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to obtain the compound isopropyl N-(4-bromo-3-tert-butylsulfonyl-phenyl)carbamate (130 mg, 343.66 μmol).

[0730] MS m/z (ESI): 400.0, 402.0 [M+Na].sup.+;

Step 5: Synthesis of isopropyl N-[3-tert-butylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[0731] Isopropyl N-(4-bromo-3-tert-butylsulfonyl-phenyl)carbamate (130 mg, 343.66 μmol) and bis(pinacolato)diboron (349.07 mg, 1.37 mmol) were dissolved in anhydrous tetrahydrofuran (4 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino) ferrocene]dichloropalladium-dichloromethane (28.06 mg, 34.37 μmol) and potassium acetate (101.18 mg, 1.03 mmol) were added. The reaction solution appeared as a red suspension, and was stirred and reacted at 80° C. for 7 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to obtain the compound isopropyl N-[3-tert-butylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]carbamate (100 mg, 235.10 μmol).

[0732] MS m/z (ESI): 426.2 [M+H].sup.+;

Step 6: Synthesis of isopropyl trans-N-[3-tert-butylsulfonyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0733] Isopropyl N-[3-tert-butylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] carbamate (100 mg, 235.10 μmol) and isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (81.64 mg, 235.10 μmol) were dissolved in anhydrous dioxane (3 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino) ferrocene]dichloropalladium-dichloromethane (19.20 mg, 23.51 μmol), sodium carbonate (49.84 mg, 470.21 μmol) and water (300 μL) were added. The reaction solution appeared as a black suspension, and was stirred and reacted at 80° C. for 7 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was added with water (10 mL), and the mixture was extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[3-tert-butylsulfonyl-4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]phenyl]carbamate (32.94 mg, 58.22 μmol).

[0734] MS m/z (ESI): 566.1 [M+H].sup.+;

[0735] 1H NMR (400 MHz, DMSO-d6) δ ppm 10.13 (s, 1H), 8.31-8.24 (m, 1H), 7.81-7.74 (m, 1H), 7.62-7.57 (m, 1H), 7.47-7.41 (m, 1H), 7.05-6.99 (m, 1H), 4.97-4.89 (m, 1H), 4.79-4.70 (m, 1H), 3.32-3.31 (m, 1H), 2.96-2.86 (m, 1H), 2.16-2.07 (m, 2H), 1.96-1.87 (m, 2H), 1.62-1.48 (m, 2H), 1.40-1.30 (m, 2H), 1.28 (d, J=6.3 Hz, 6H), 1.17 (d, J=6.3 Hz, 6H), 1.11 (s, 9H).

Example 35: Synthesis of isopropyl trans-N-[4-[5-[2-isopropylsulfonyl-4-[(2-oxo-1H-pyridin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0736] ##STR00223##

[0737] The intermediate isopropyl trans-N-[4-[5-(4-bromo-2-isopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate (50 mg, 94.43 μmol) in Example 36 was dissolved in tetrahydrofuran (1 mL). 3-Amino-1H-pyridin-2-one (12.48 mg, 113.31 μmol) was added. Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (4.28 mg, 4.72 μmol) and cesium carbonate (92.30 mg, 283.28 μmol) were added. The reaction solution was stirred at 100° C. for 2 hours. LCMS showed that the reaction was complete. The reaction solution was filtered. The filtrate was evaporated to dryness via rotary evaporation to remove tetrahydrofuran. The resultant was added with water (15 mL), and the mixture was extracted three times with ethyl acetate (15 mL×3). The organic phase was dried over anhydrous sodium sulfate, and evaporated to dryness via rotary evaporation under reduced pressure. The resultant was purified by preparative high-performance liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm in diameter, 150 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (38% to 58%) as eluents) to obtain isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfinyl-phenyl]carbamate (1.02 mg).

[0738] MS m/z (ESI): 559.0 [M+H].sup.+;

[0739] .sup.1H NMR: (400 MHz, METHANOL-d.sub.4) δ ppm 7.91 (d, J=1.96 Hz, 1H) 7.74 (s, 1H) 7.50-7.44 (m, 3H) 7.07 (d, J=6.60 Hz, 1H) 6.42 (t, J=6.97 Hz, 1H) 5.42-5.35 (m, 1H) 3.49-3.40 (m, 1H) 3.12-2.90 (m, 2H) 2.28-2.23 (m, 2H) 2.15-2.05 (m, 2H) 1.78-1.68 (m, 2H) 1.50-1.42 (m, 2H) 1.35-1.20 (m, 6H) 1.19 (d, J=12.00 Hz, 6H).

Example 36: Synthesis of isopropyl trans-(4-(5-(4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0740] ##STR00224##

Synthetic Method

[0741] ##STR00225##

Step 1: Synthesis of tert-butyl (3-(isopropylthio)phenyl)carbamate

[0742] 3-Isopropylsulfanylaniline (15 g, 44.88 mmol) was dissolved in anhydrous dichloromethane (500 mL), and di-tert-butyl dicarbonate (30.81 g, 141.18 mmol, 32.43 mL), pyridine (18.85 g, 235.31 mmol, 18.48 mL) and 4-dimethylaminopyridine (14.37 g, 117.65 mmol) were added at 0° C. The reaction solution was stirred and reacted at 25° C. for 5 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated under reduced pressure to remove the solvent dichloromethane, and purified by column chromatography (silica, petroleum ether:ethyl acetate=10:1) to obtain tert-butyl (3-(isopropylthio)phenyl)carbamate (15 g).

[0743] MS m/z (ESI): 212.1 [M+H-t-Bu].sup.+;

Step 2: Synthesis of tert-butyl (4-bromo-3-(isopropylthio)phenyl)carbamate

[0744] Tert-butyl (3-(isopropylthio)phenyl)carbamate (5.0 g, 18.70 mmol) was dissolved in dichloromethane (200 mL), and N-bromosuccinimide (3.33 g, 18.70 mmol) was added into the reaction system. The reaction solution was stirred at −30° C. for 3 hours. The completion of the reaction was detected by LCMS. The fraction was concentrated to dryness under reduced pressure, and the resultant was purified by column chromatography (silica, petroleum ether:ethyl acetate=20:1) to obtain tert-butyl (4-bromo-3-(isopropylthio)phenyl)carbamate (2.3 g).

[0745] MS m/z (ESI): 290.0, 292.0 [M+H-t-Bu].sup.+;

[0746] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.51 (s, 1H), 7.58 (d, J=2.3 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.25 (dd, J=2.3, 8.5 Hz, 1H), 3.43 (spt, J=6.5 Hz, 1H), 1.47 (s, 9H), 1.31 (d, J=6.8 Hz, 6H).

Step 3: Synthesis of tert-butyl (4-bromo-3-(isopropylsulfonyl)phenyl)carbamate

[0747] Tert-butyl (4-bromo-3-(isopropylthio)phenyl)carbamate (1.0 g, 2.89 mmol) was dissolved in anhydrous dichloromethane (25 mL), and a solution of m-chloroperoxybenzoic acid (996.68 mg, 5.78 mmol, purity: 85%) in anhydrous dichloromethane (25 mL) was added at −30° C. The reaction solution was reacted at −30° C. for 3 hours. LCMS showed that the reaction was complete. A saturated aqueous sodium carbonate solution (50 mL) was added into the reaction solution, and then the reaction solution was extracted with dichloromethane (100 mL) twice. The dichloromethane phases were combined, dried over anhydrous sodium sulfate and subjected to suction filtration. The resultant was purified by column chromatography (silica, petroleum ether:ethyl acetate=20:1) to obtain tert-butyl (4-bromo-3-(isopropylsulfonyl)phenyl)carbamate (0.8 g).

[0748] MS m/z (ESI): 322.0, 324.0 [M+H-t-Bu].sup.+;

[0749] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.90 (s, 1H), 8.31 (d, J=2.6 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.61 (dd, J=2.6, 8.7 Hz, 1H), 3.82-3.75 (m, 1H), 1.48 (s, 9H), 1.18 (d, J=6.9 Hz, 6H).

Step 4: Synthesis of tert-butyl (3-(isopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate

[0750] Tert-butyl (4-bromo-3-(isopropylsulfonyl)phenyl)carbamate (800 mg, 2.11 mmol) and bis(pinacolato)diboron (2.69 g, 10.57 mmol) were dissolved in anhydrous tetrahydrofuran (25 mL). Under the protection of nitrogen, potassium acetate (207.55 mg, 2.11 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (863.52 mg, 1.06 mmol) were added. The reaction solution was stirred at 80° C. for 16 hours. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was purified by column chromatography (silica, petroleum ether:ethyl acetate=10:1) to obtain tert-butyl (3-(isopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (560 mg).

[0751] MS m/z (ESI): 443.3 [M+H+NH.sub.3].sup.+;

Step 5: Synthesis of isopropyl trans-N-[4-[2-[4-(tert-butoxycarbonylamino)-2-isopropylsulfonyl-phenyl]thiazol-5-yl]cyclohexyl]carbamate

[0752] Isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (961.18 mg, 2.77 mmol) and tert-butyl (3-(isopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)carbamate (1.18 g, 2.77 mmol) were dissolved in an aqueous sodium carbonate solution (2M, 4.15 mL, 8.30 mmol) and 1,4-dioxane (30 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (113.01 mg, 138.39 μmol) was added. The reaction solution was stirred at 100° C. for 16 hours. LCMS showed that the reaction was complete. The reaction solution was filtered. The filtrate was evaporated to dryness via rotary evaporation to remove 1,4-dioxane, added with water (10 mL), and extracted three times with dichloromethane (10 mL×3). The resultant was dried over anhydrous sodium sulfate and then purified by thin-layer chromatography (silica, petroleum ether/ethyl acetate=5:1) to obtain isopropyl trans-N-[4-[2-[4-(tert-butoxycarbonylamino)-2-isopropylsulfonyl-phenyl]thiazol-5-yl]cyclohexyl]carbamate (0.8 g).

[0753] MS m/z (ESI): 566.3 [M+H].sup.+;

Step 6: Synthesis of isopropyl trans-(4-(5-(4-amino-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0754] Isopropyl trans-N-[4-[2-[4-(tert-butoxycarbonylamino)-2-isopropylsulfonyl-phenyl] thiazol-5-yl]cyclohexyl]carbamate (0.8 g, 1.41 mmol) was dissolved in anhydrous methanol (20 mL). Hydrochloric acid/dioxane (4M, 3.54 mL, 14.14 mmol) was added. The reaction solution was stirred at 25° C. for 1 hour. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was added with 1M aqueous sodium hydroxide solution (10 mL), followed by liquid-liquid extraction (extraction with 120 mL of ethyl acetate three times) to obtain the compound isopropyl trans-(4-(5-(4-amino-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (560 mg).

[0755] MS m/z (ESI): 466.2 [M+H].sup.+;

Step 7: Synthesis of isopropyl trans-(4-(5-(4-bromo-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0756] Isopropyl trans-(4-(5-(4-amino-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (0.5 g, 1.07 mmol) was dissolved in anhydrous acetonitrile (50 mL). Under the protection of nitrogen, tert-butyl nitrite (166.1 mg, 1.61 mmol) was slowly added at 0° C. The reaction solution was stirred at 25° C. for 30 minutes. Under the protection of nitrogen, cuprous bromide (184.85 mg, 1.29 mmol) was added. The reaction solution was continued to be stirred at 25° C. for 16 hours. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was added with a saturated ammonium chloride solution, followed by liquid-liquid extraction (extraction with 120 mL of dichloromethane three times). The dichloromethane phases were combined, dried over anhydrous sodium sulfate, and subjected to suction filtration. The resultant was purified by column chromatography (silica, dichloromethane/methanol=20/1) to obtain isopropyl trans-(4-(5-(4-bromo-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (350 mg).

[0757] MS m/z (ESI): 529.2, 531.2 [M+H].sup.+;

Step 8: Isopropyl trans-(4-(5-(4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0758] Isopropyl trans-(4-(5-(4-bromo-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (50 mg, 94.43 μmol) and 1,5-dimethyl-1H-pyrazol-3-amine (26.24 mg, 236.07 μmol) were dissolved in anhydrous tetrahydrofuran (4 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (4.28 mg, 4.72 μmol) and potassium acetate (27.8 mg, 283.28 μmol) were added. The reaction solution was stirred at 85° C. for 16 hours. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was purified by preparative high-performance liquid chromatography (Phenomenex Gemini-NX column, 10 μm silica, 50 mm in diameter, 250 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (50% to 70%) as eluents) and lyophilized to obtain isopropyl trans-(4-(5-(2-(isopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl) cyclohexyl)carbamate (4.34 mg).

[0759] MS m/z (ESI): 560.1 [M+H].sup.+;

[0760] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.07 (s, 1H), 7.95 (d, J=2.6 Hz, 1H), 7.74 (dd, J=2.4, 8.5 Hz, 1H), 7.64 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.02 (br d, J=7.9 Hz, 1H), 5.66 (s, 1H), 4.80-4.68 (m, 1H), 3.64 (s, 3H), 3.31-3.20 (m, 1H), 2.97-2.81 (m, 2H), 2.21 (s, 3H), 2.12 (br d, J=12.7 Hz, 2H), 1.91 (br d, J=10.5 Hz, 2H), 1.62-1.48 (m, 2H), 1.39-1.27 (m, 2H), 1.16 (d, J=6.2 Hz, 6H), 1.05 (d, J=6.7 Hz, 6H).

Example 37: Synthesis of isopropyl trans-(4-(5-(2-(isopropylsulfonyl)-4-((5-methylisoxazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0761] ##STR00226##

[0762] Isopropyl trans-(4-(5-(4-bromo-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (50 mg, 94.43 μmol) and 3-amino-5-methylisoxazole (23.16 mg, 236.07 μmol) were dissolved in anhydrous 1,4-dioxane (4 mL). Under the protection of nitrogen, tris(dibenzylideneacetone)dipalladium (4.32 mg, 4.72 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.73 mg, 4.72 μmol) and cesium carbonate (92.3 mg, 283.28 μmol) were added. The reaction solution was stirred at 85° C. for 1 hour. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was subjected to liquid-liquid extraction (extraction with 12 mL of ethyl acetate three times) to obtain a yellow solid compound. The resultant was purified by preparative high-performance liquid chromatography (Phenomenex Gemini-NX column, 10 μm silica, 50 mm in diameter, 250 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (45% to 65%) as eluents) and lyophilized to obtain isopropyl trans-(4-(5-(2-(isopropylsulfonyl)-4-((5-methylisoxazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (15.85 mg).

[0763] MS m/z (ESI): 547.1 [M+H].sup.+;

[0764] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.77 (s, 1H), 8.14 (d, J=2.4 Hz, 1H), 7.80 (dd, J=2.5, 8.5 Hz, 1H), 7.72-7.65 (m, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.02 (br d, J=7.7 Hz, 1H), 5.96 (d, J=0.7 Hz, 1H), 4.80-4.70 (m, 1H), 3.32-3.25 (m, 1H), 3.01-2.81 (m, 2H), 2.37 (s, 3H), 2.13 (br d, J=11.7 Hz, 2H), 1.91 (br d, J=10.0 Hz, 2H), 1.65-1.50 (m, 2H), 1.41-1.26 (m, 2H), 1.16 (d, J=6.2 Hz, 6H), 1.06 (d, J=6.7 Hz, 6H).

Example 38: Synthesis of isopropyl trans-N-[4-[5-[2-isopropylsulfonyl]-4-[(3-methylisothiazol-5-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0765] ##STR00227##

[0766] Isopropyl trans-N-[4-[5-(4-bromo-2-isopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (20 mg, 37.77 μmol) and 3-methyl-5-aminoisothiazole (10.78 mg, 94.43 μmol) were dissolved in anhydrous dioxane (4 mL). Under the protection of nitrogen, tris(dibenzylideneacetone)dipalladium (1.73 mg, 1.89 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.09 mg, 1.89 μmol) and cesium carbonate (36.92 mg, 113.31 μmol) were added. The reaction solution appeared as a black suspension, and was stirred and reacted at 100° C. for 16 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with water (10 mL), and extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[5-[2-isopropylsulfonyl]-4-[(3-methylisothiazol-5-yl)amino]phenyl] thiazol-2-yl]cyclohexyl]carbamate (2.62 mg, 4.66 μmol).

[0767] MS m/z (ESI): 563.1 [M+H].sup.+;

[0768] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.50 (s, 1H), 7.81-7.76 (m, 1H), 7.72 (s, 1H), 7.57-7.53 (m, 1H), 7.45-7.40 (m, 1H), 7.08-7.01 (m, 1H), 6.74 (s, 1H), 4.81-4.69 (m, 1H), 3.33-3.31 (m, 1H), 3.00-2.85 (m, 2H), 2.33 (s, 3H), 2.20-2.09 (m, 2H), 1.97-1.87 (m, 2H), 1.64-1.50 (m, 2H), 1.41-1.27 (m, 2H), 1.17 (d, J=6.2 Hz, 6H), 1.08 (d, J=6.7 Hz, 6H).

Example 39: Synthesis of isopropyl trans-(4-(5-(2-(isopropylsulfonyl)-4-((1-methyl-1H-1,2,3-triazol-4-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0769] ##STR00228##

[0770] Isopropyl trans-(4-(5-(4-bromo-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (50 mg, 94.43 μmol) and 1-methyl-1H-1,2,3-triazol-4-amine (236.07 mg, 236.07 μmol) were dissolved in anhydrous tetrahydrofuran (4 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (4.28 mg, 4.72 μmol) and potassium acetate (27.8 mg, 283.28 μmol) were added. The reaction solution was stirred at 85° C. for 16 hours. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was added with water (3 mL), followed by liquid-liquid extraction (extraction with 12 mL of ethyl acetate three times) to obtain a yellow solid compound. The resultant was purified by preparative high-performance liquid chromatography (Phenomenex Gemini-NX column, 10 μm silica, 30 mm in diameter, 100 mm in length) (using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (26% to 66%) as eluents) and lyophilized to obtain isopropyl trans-(4-(5-(2-(isopropylsulfonyl)-4-((1-methyl-1H-1,2,3-triazol-4-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (8.4 mg).

[0771] MS m/z (ESI): 547.1 [M+H].sup.+;

[0772] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.22 (s, 1H), 7.87-7.80 (m, 2H), 7.65 (s, 1H), 7.47 (dd, J=2.5, 8.5 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.02 (br d, J=7.7 Hz, 1H), 4.80-4.70 (m, 1H), 4.03 (s, 3H), 3.35-3.28 (m, 1H), 2.98-2.80 (m, 2H), 2.12 (br d, J=12.0 Hz, 2H), 1.91 (br d, J=9.9 Hz, 2H), 1.62-1.49 (m, 2H), 1.41-1.27 (m, 2H), 1.16 (d, J=6.2 Hz, 6H), 1.05 (d, J=6.7 Hz, 6H).

Example 40: Synthesis of isopropyl trans-(4-(5-(2-(isopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0773] ##STR00229##

Synthetic Method

[0774] ##STR00230##

Step 1: Synthesis of tert-butyl trans-3-((4-(2-(4-((isopropoxycarbonyl)amino)cyclohexyl) thiazol-5-yl)-3-(isopropylsulfonyl)phenyl)amino)-5-methyl-1H-pyrazole-1-carboxylate

[0775] Isopropyl trans-(4-(5-(4-bromo-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (50 mg, 94.43 μmol) and tert-butyl 3-amino-5-methyl-pyrazole-1-carboxylate (46.56 mg, 236.07 μmol) were dissolved in anhydrous tetrahydrofuran (4 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (4.28 mg, 4.72 μmol) and potassium acetate (27.8 mg, 283.28 μmol) were added. The reaction solution was stirred at 85° C. for 16 hours. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was subjected to liquid-liquid extraction (extraction with 12 mL of ethyl acetate three times) to obtain tert-butyl trans-3-((4-(2-(4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)-3-(isopropylsulfonyl) phenyl)amino)-5-methyl-1H-pyrazole-1-carboxylate (50 mg, crude product).

[0776] MS m/z (ESI): 646.3 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-(4-(5-(2-(isopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0777] Tert-butyl trans-3-((4-(2-(4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)-3-(isopropylsulfonyl)phenyl)amino)-5-methyl-1H-pyrazole-1-carboxylate (50 mg, 77.42 μmol) was dissolved in methanol (3 mL), and p-toluenesulfonic acid (73.63 mg, 387.10 μmol) was added. The reaction solution was stirred at 50° C. for 2 hours. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation. The resultant was added with saturated sodium bicarbonate solution (5 mL), and then the mixture was extracted with dichloromethane (15 mL) three times. The dichloromethane phases were combined, dried over anhydrous sodium sulfate, and subjected to suction filtration. The resultant was purified by preparative high-performance liquid chromatography (Phenomenex Gemini-NX column, 5 μm silica, 30 mm in diameter, 150 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia and 10 mmol of ammonium bicarbonate) and acetonitrile (45% to 65%) as eluents) and lyophilized to obtain isopropyl trans-(4-(5-(2-(isopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl) cyclohexyl)carbamate (5.47 mg).

[0778] MS m/z (ESI): 546.1 [M+H].sup.+;

[0779] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.88 (s, 1H), 9.08 (s, 1H), 8.10 (s, 1H), 7.71-7.62 (m, 2H), 7.34 (d, J=8.5 Hz, 1H), 7.03 (br d, J=7.5 Hz, 1H), 5.63 (s, 1H), 4.81-4.68 (m, 1H), 3.32-3.26 (m, 1H), 2.98-2.78 (m, 2H), 2.20 (s, 3H), 2.12 (br d, J=11.8 Hz, 2H), 1.91 (br d, J=9.8 Hz, 2H), 1.62-1.47 (m, 2H), 1.40-1.27 (m, 2H), 1.16 (d, J=6.3 Hz, 6H), 1.05 (d, J=6.8 Hz, 6H).

Example 41: Synthesis of isopropyl trans-N-[4-[5-[4-(isopropoxycarbonylamino) cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-(isopropylsulfonimidoyl)phenyl]carbamate

[0780] ##STR00231##

Synthetic Method

[0781] ##STR00232##

Step 1: Synthesis of tert-butyl trans-N-[4-(1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate

[0782] Tert-butyl trans-N-[4-(formamidocarbamoyl)cyclohexyl]carbamate (10 g, 35.05 mmol) was dissolved in anhydrous tetrahydrofuran (250 mL), and then Lawesson reagent (17.01 g, 42.06 mmol) and methyl N-(triethylammoniosulfonyl)carbamate (8.35 g, 35.05 mmol) were added. The reaction solution was stirred and reacted at 80° C. for 16 hours. The complete reaction of the raw materials was detected. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:tetrahydrofuran=2:1) to obtain tert-butyl trans-N-[4-(1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate as the product (5.5 g).

[0783] MS m/z (ESI): 228.1 [M+H-tBu].sup.+;

[0784] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.49 (s, 1H), 6.83 (br d, J=7.6 Hz, 1H), 3.29 (br dd, J=3.7, 8.1 Hz, 1H), 3.11 (tt, J=3.5, 12.0 Hz, 1H), 2.14-2.06 (m, 2H), 1.89 (br d, J=10.1 Hz, 2H), 1.63-1.51 (m, 2H), 1.39 (s, 9H), 1.36-1.26 (m, 2H).

Step 2: Synthesis of tert-butyl trans-N-[4-(5-bromo-1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate

[0785] Tert-butyl trans-N-[4-(1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate (2 g, 7.06 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL), and then N-bromosuccinimide (3.77 g, 21.17 mmol) was added. The reaction solution was stirred and reacted at 60° C. for 16 hours. The complete reaction of the raw materials was detected. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:tetrahydrofuran=2:1) to obtain tert-butyl trans-N-[4-(5-bromo-1,3,4-thiadiazol-2-yl) cyclohexyl]carbamate as the product (1.5 g).

[0786] MS m/z (ESI): 305.8, 307.8 [M+H-tBu].sup.+;

[0787] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 6.88-6.76 (m, 1H), 3.58-3.58 (m, 1H), 3.55 (t, J=6.8 Hz, 1H), 3.42 (t, J=6.3 Hz, 1H), 2.08 (br d, J=12.0 Hz, 2H), 1.92-1.85 (m, 2H), 1.62-1.53 (m, 2H), 1.39 (s, 9H), 1.42-1.21 (m, 2H).

Step 3: Synthesis of isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylsulfanyl-phenyl]carbamate

[0788] Tert-butyl trans-N-[4-(5-bromo-1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate (150 mg, 414.04 μmol) and isopropyl N-[3-isopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (188.46 mg, 496.85 μmol) were dissolved in tetrahydrofuran (7 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (33.81 mg, 41.40 μmol) and an aqueous potassium phosphate solution (2M, 621.06 μL) were added. The reaction solution was stirred and reacted at 80° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran=2:1) to obtain isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino) cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylsulfanyl-phenyl]carbamate (120 mg).

[0789] MS m/z (ESI): 535 [M+H].sup.+;

Step 4: Synthesis of isopropyl trans-N-[4-[5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl]-3-isopropylsulfanyl-phenyl]carbamate

[0790] Isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylsulfanyl-phenyl]carbamate (220 mg, 411.42 μmol) was dissolved in methanol (2 mL), and hydrochloric acid/dioxane (1.13 mL) was added. The reaction solution was stirred and reacted at 30° C. for 3 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure to obtain isopropyl trans-N-[4-[5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl]-3-isopropylsulfanyl-phenyl]carbamate (178 mg).

[0791] MS m/z (ESI): 435.3 [M+H].sup.+;

Step 5: Synthesis of isopropyl trans-N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylsulfanyl-phenyl]carbamate

[0792] Isopropyl trans-N-[4-[5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl]-3-isopropylsulfanyl-phenyl]carbamate (178 mg, 409.56 μmol) and isopropyl chloroformate (60.23 mg, 491.47 μmol) were dissolved in dichloromethane (4 mL), and N,N-diisopropylethylamine (264.66 mg, 2.05 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:ethyl acetate=1:1) to obtain isopropyl trans-N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylsulfanyl-phenyl]carbamate (120 mg).

[0793] MS m/z (ESI): 521.3 [M+H].sup.+;

Step 6: Synthesis of isopropyl trans-N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-(isopropylsulfonimidoyl)phenyl]carbamate

[0794] Isopropyl trans-N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylsulfanyl-phenyl]carbamate (38 mg, 72.98 μmol) was dissolved in a solution of ammonia in methanol (2 mL), and iodobenzene diacetate (352.59 mg, 1.09 mmol) was added. The reaction solution was stirred and reacted at 60° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (Boston Prime C18 column: 5 μm silica, 25 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain isopropyl trans-N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-(isopropylsulfonimidoyl)phenyl]carbamate (20 mg).

[0795] MS m/z (ESI): 552.1 [M+H].sup.+;

[0796] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.18 (s, 1H), 8.33 (d, J=2.1 Hz, 1H), 7.76 (br d, J=8.5 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.04 (br d, J=8.0 Hz, 1H), 4.98-4.90 (m, 1H), 4.80-4.68 (m, 1H), 4.11 (s, 1H), 3.74-3.64 (m, 1H), 3.28-3.22 (m, 1H), 3.16-3.06 (m, 1H), 2.15 (br d, J=11.0 Hz, 2H), 1.92 (br d, J=15.0 Hz, 2H), 1.68-1.53 (m, 2H), 1.42-1.32 (m, 2H), 1.28 (d, J=6.3 Hz, 6H), 1.19-1.09 (m, 12H).

Example 42: Synthesis of isopropyl trans-N-[4-[2-[2-(isopropylsulfonimidoyl)]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-5-yl]cyclohexyl]carbamate

[0797] ##STR00233##

Synthetic Method

[0798] ##STR00234##

Step 1: Synthesis of tert-butyl N-(3-isopropylsulfanylphenyl)carbamate

[0799] 3-Isopropylsulfanylaniline (10 g, 59.78 mmol) as a reactant was dissolved in anhydrous methanol (400 mL), and di-tert-butyl dicarbonate (195.71 g, 896.75 mmol, 206.01 mL) was added at 25° C. The reaction solution was stirred and reacted at 25° C. for 12 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated under reduced pressure to remove the solvent methanol, added with 400 mL of aqueous ammonia, and extracted three times with dichloromethane (300 mL×3) to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (silica, petroleum ether:ethyl acetate=10:1) to obtain tert-butyl N-(3-isopropylsulfanylphenyl)carbamate as a white solid (13.38 g, 50.04 mmol).

[0800] MS m/z (ESI): 212.1 [M-tBu+H].sup.+

Step 2: Synthesis of tert-butyl N-(4-bromo-3-isopropylsulfanyl-phenyl)carbamate

[0801] Tert-butyl N-(3-isopropylsulfanylphenyl)carbamate (13.38 g, 50.04 mmol) as a reactant was dissolved in dichloromethane (500 mL). N-bromosuccinimide (8.91 g, 50.04 mmol) was added into the reaction system. The reaction solution was stirred at −20° C. for 3 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:ethyl acetate=10:1) to obtain tert-butyl N-(4-bromo-3-isopropylsulfanyl-phenyl)carbamate as the product (5.32 g, 15.36 mmol), which was a white solid.

[0802] MS m/z (ESI): 290.0 [M-tBu+H].sup.+

Step 3: Synthesis of tert-butyl N-[3-isopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[0803] Tert-butyl N-(4-bromo-3-isopropylsulfanyl-phenyl)carbamate (2 g, 5.78 mmol) and bis(pinacolato)diboron (5.87 g, 23.10 mmol) as reactants were dissolved in anhydrous tetrahydrofuran (50 mL). Under the protection of nitrogen, potassium acetate (1.70 g, 17.33 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (235.83 mg, 288.78 μmol) were added. The reaction solution was stirred at 80° C. for 2 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to remove the solvent tetrahydrofuran, added with 50 mL of dichloromethane, and extracted three times with water (50 mL×3) to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (silica, petroleum ether:ethyl acetate=10:1) to obtain tert-butyl N-[3-isopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate as a white solid (2.2 g, 5.59 mmol).

[0804] MS m/z (ESI): 394.3 [M+H].sup.+

Step 4: Synthesis of isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-isopropylsulfanyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0805] Tert-butyl N-[3-isopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]carbamate (2 g, 5.08 mmol), isopropyl trans-N-[4-(5-bromothiazol-2-yl) cyclohexyl]carbamate (1.68 g, 4.84 mmol) and sodium carbonate (1.54 g, 14.53 mmol) were dissolved in water (600 μL) and 1,4-dioxane (6 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (395.45 mg, 484.24 μmol) was added. The reaction solution was stirred at 100° C. for 16 hours. The reaction solution was filtered. The filtrate was evaporated to dryness via rotary evaporation to remove 1,4-dioxane. The resultant was added with water (30 mL), and the mixture was extracted three times with dichloromethane (30 mL×3). The resultant was dried over anhydrous sodium sulfate and then purified by column chromatography (silica, petroleum ether/tetrahydrofuran=2/1) to obtain isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-isopropylsulfanyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate as a yellow solid (1 g, 1.87 mmol).

[0806] MS m/z (ESI): 534.1 [M+H].sup.+

Step 5: Synthesis of isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-isopropylsulfinyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0807] Isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-isopropylsulfanyl-phenyl] thiazol-2-yl]cyclohexyl]carbamate (1.03 g, 1.93 mmol) was dissolved in dichloromethane (50 mL). m-Chloroperoxybenzoic acid (333.01 mg, 1.93 mmol) was added at 0° C. The reaction was carried out at 100° C. for 3 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:ethyl acetate=2:1) to obtain isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-isopropylsulfinyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate as the product (725 mg, 1.32 mmol), which was a white solid with a yield of 68.34%.

[0808] MS m/z (ESI): 550.3 [M+H].sup.+

Step 6: Synthesis of isopropyl trans-N-[4-[5-(4-amino-2-isopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate

[0809] Isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-isopropylsulfinyl-phenyl] thiazol-2-yl]cyclohexyl]carbamate (200 mg, 363.81 μmol) was dissolved in methanol (4 mL). Hydrochloric acid/1,4-dioxane (4M, 909.51 μL) was added at 25° C. The reaction was carried out at 25° C. for 12 hours. LCMS showed that the reaction was complete. The reaction solution was evaporated to dryness via rotary evaporation to remove methanol, added with water (5 mL), and extracted three times with dichloromethane (5 mL×3). The resultant was dried over anhydrous sodium sulfate and purified by column chromatography (silica, dichloromethane:methanol=15:1) to obtain isopropyl trans-N-[4-[5-(4-amino-2-isopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate as the product (116 mg, 257.99 μmol), which was a white solid.

[0810] MS m/z (ESI): 450.1 [M+H].sup.+

Step 7: Synthesis of isopropyl trans-N-[4-[5-(4-bromo-2-isopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate

[0811] Isopropyl trans-N-[4-[5-(4-amino-2-isopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (238 mg, 529.33 μmol) was dissolved in acetonitrile (6 mL). At 0° C., tert-butyl nitrite (163.75 mg, 1.59 mmol, 188.87 μL) was added and the mixture was stirred for 1 hour, and cuprous bromide (189.83 mg, 1.32 mmol) was added at 25° C. The reaction solution was reacted at 25° C. for 15 hours. LCMS showed that the reaction was complete. The reaction solution was evaporated to dryness via rotary evaporation to remove acetonitrile, added with saturated ammonium chloride solution (20 mL), and extracted three times with dichloromethane (20 mL×3). The resultant was dried over anhydrous sodium sulfate and purified by column chromatography (silica, dichloromethane:methanol=15:1) to obtain isopropyl trans-N-[4-[5-(4-bromo-2-isopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate as the product (198 mg, 385.58 μmol), which was a yellow solid.

[0812] MS m/z (ESI): 515.1 [M+H].sup.+

Step 8: Synthesis of isopropyl trans-N-[4-[5-[2-isopropylsulfinyl]-4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0813] Isopropyl trans-N-[4-[5-(4-bromo-2-isopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (212 mg, 412.84 μmol) was dissolved in tetrahydrofuran (6 mL). 5-Methyl-1-tetrahydropyran-2-yl-pyrazol-3-amine (82.30 mg, 454.13 μmol) was added at 25° C. Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (37.42 mg, 41.28 μmol) and potassium acetate (40.52 mg, 412.84 μmol) were added. The reaction was carried out at 100° C. for 1 hour. LCMS showed that the reaction was complete. The reaction solution was concentrated to dryness and purified by column chromatography (silica, dichloromethane:methanol=15:1) to obtain isopropyl trans-N-[4-[5-[2-isopropylsulfinyl]-4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate as the product (226 mg, 368.18 μmol), which was a yellow solid.

[0814] MS m/z (ESI): 614.4 [M+H].sup.+

Step 9: Synthesis of isopropyl trans-N-[4-[2-[2-isopropylsulfinyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-5-yl]cyclohexyl]carbamate

[0815] Isopropyl trans-N-[4-[5-[2-isopropylsulfinyl]-4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (90 mg, 146.62 μmol) was dissolved in methanol (2 mL). p-Toluenesulfonic acid (126.24 mg, 733.10 μmol) was added at 25° C. The reaction was carried out at 50° C. for 2 hours. LCMS showed that the reaction was complete. The reaction solution was evaporated to dryness via rotary evaporation to remove methanol, added with saturated sodium bicarbonate solution (5 mL), and stirred for 5 minutes. The aqueous phase was extracted three times with dichloromethane (5 mL×3). The resultant was dried over anhydrous sodium sulfate and purified by thin-layer chromatography (silica, dichloromethane:methanol=15:1) to obtain isopropyl trans-N-[4-[2-[2-isopropylsulfinyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-5-yl]cyclohexyl]carbamate as the product (30 mg, 56.63 μmol), which was a white solid.

[0816] MS m/z (ESI): 530.3 [M+H].sup.+

Step 10: Synthesis of isopropyl trans-N-[4-[2-[2-(isopropylsulfonimidoyl)]-4-][(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-5-yl]cyclohexyl]carbamate

[0817] Isopropyl trans-N-[4-[2-[2-isopropylsulfinyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl] thiazol-5-yl]cyclohexyl]carbamate (30 mg, 56.63 μmol), ammonium carbamate (88.43 mg, 1.13 mmol) and iodobenzene diacetate (182.42 mg, 566.34 μmol) were charged into a microwave vial containing methanol (0.5 mL). The reaction was carried out under microwave irradiation at 100° C. for 2 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, dichloromethane:methanol=15:1) to obtain a crude product. Then, the crude product was further purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain isopropyl trans-N-[4-[2-[2-(isopropylsulfonimidoyl)]-4-[(5-methyl-1H-pyrazol-3-yl)amino] phenyl]thiazol-5-yl]cyclohexyl]carbamate as the product (1.21 mg), which was a white solid.

[0818] MS m/z (ESI): 545.3 [M+H].sup.+

[0819] .sup.1H NMR: (400 MHz, METHANOL-d.sub.4) δ ppm 8.01 (s, 1H) 7.67 (s, 1H) 7.49 (br d, J=7.28 Hz, 1H) 7.31 (d, J=8.53 Hz, 1H) 5.82 (s, 1H) 4.82-4.70 (m, 1H) 3.55-3.42 (m, 1H) 2.98-3.13 (m, 2H) 2.30 (s, 3H) 2.25 (br d, J=9.03 Hz, 2H) 2.09 (br d, J=10.54 Hz, 2H) 1.78-1.65 (m, 2H) 1.38-1.54 (m, 2H) 1.32 (d, J=6.2 Hz, 6H) 1.24 (d, J=6.2 Hz, 6H).

Example 43: Synthesis of isopropyl trans-N-[3-(N-cyclopropyl-S-methyl-sulfonimidoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0820] ##STR00235##

[0821] Isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(methylsulfonimidoyl)phenyl]carbamate (40 mg, 76.53 μmol) was dissolved in 1,4-dioxane (1 mL), and copper acetate (20.85 mg, 114.79 μmol) and pyridine (14.53 mg, 183.67 μmol, 14.82 μL) were added. The reaction mixture was stirred at 20° C. for 5 minutes, and cyclopropylboronic acid (13.15 mg, 153.06 μmol) was added. The reaction solution was stirred at 100° C. for 12 hours. LCMS showed that the reaction was complete. The reaction solution was filtered. The filtrate was evaporated to dryness via rotary evaporation to remove 1,4-dioxane, added with water (15 mL), and extracted three times with ethyl acetate (15 mL×3). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness via rotary evaporation under reduced pressure. The resultant was purified by preparative high-performance liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm in diameter, 150 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (48% to 68%) as eluents) to obtain isopropyl trans-N-[3-(N-cyclopropyl-S-methyl-sulfonimidoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl] thiazol-5-yl]phenyl]carbamate (14.12 mg, 25.09 μmol).

[0822] MS m/z (ESI): 563.3 [M+H].sup.+

[0823] .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ ppm 10.10 (s, 1H) 8.37 (d, J=2.32 Hz, 1H) 7.74-7.68 (m, 2H) 7.43 (d, J=8.31 Hz, 1H) 7.03 (br d, J=7.70 Hz, 1H) 4.97-4.88 (m, 1H) 4.80-4.71 (m, 1H) 2.97-2.89 (m, 1H) 2.87 (s, 3H) 2.55-2.51 (m, 1H) 2.32-2.26 (m, 1H) 2.12 (br d, J=12.35 Hz, 2H) 1.91 (br d, J=10.15 Hz, 2H) 1.62-1.51 (m, 2H) 1.39-1.31 (m, 2H) 1.28 (d, J=6.24 Hz, 6H) 1.17 (d, J=6.24 Hz, 6H) 0.44-0.33 (m, 2H) 0.33-0.20 (m, 2H).

Example 44: Synthesis of isopropyl trans-N-[4-[5-[2-isopropylsulfonyl-4-(pyridazin-3-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0824] ##STR00236##

[0825] Isopropyl trans-N-[4-[5-(4-bromo-2-isopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (20 mg, 37.77 μmol) and 3-aminopyridazine (8.98 mg, 94.43 μmol) were dissolved in dioxane (2 mL). Afterwards, tris(dibenzylideneacetone)dipalladium (1.73 mg, 1.89 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.09 mg, 1.89 μmol) and cesium carbonate (36.92 mg, 113.31 μmol) were added under the condition where nitrogen gas was introduced. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 4 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Phenomenex Gemini C18 column: 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain isopropyl trans-N-[4-[5-[2-isopropylsulfonyl-4-(pyridazin-3-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate (7 mg).

[0826] MS m/z (ESI): 544.1 [M+H].sup.+;

[0827] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.91 (s, 1H), 8.77 (d, J=4.4 Hz, 1H), 8.45-8.26 (m, 2H), 7.72 (s, 1H), 7.61-7.46 (m, 2H), 7.19 (d, J=8.8 Hz, 1H), 7.03 (br d, J=7.6 Hz, 1H), 4.77-4.66 (m, 1H), 3.30-3.24 (m, 1H), 3.00-2.84 (m, 2H), 2.13 (br d, J=12.0 Hz, 2H), 1.92 (br d, J=9.6 Hz, 2H), 1.64-1.50 (m, 2H), 1.41-1.28 (m, 2H), 1.16 (d, J=6.3 Hz, 6H), 1.08 (d, J=6.8 Hz, 6H).

Example 45: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-isopropylsulfonyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0828] ##STR00237##

Synthetic Method

[0829] ##STR00238##

Step 1: Synthesis of tert-butyl trans-5-cyclopropyl-3-[4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]-3-isopropylsulfonyl-anilino]pyrazole-1-carboxylate

[0830] Isopropyl trans-N-[4-[5-(4-bromo-2-isopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (40 mg, 75.54 μmol) and tert-butyl 3-amino-5-cyclopropyl-pyrazole-1-carboxylate (18.55 mg, 83.10 μmol) were dissolved in tetrahydrofuran (5 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6.85 mg, 7.55 μmol) and potassium acetate (7.41 mg, 75.54 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 4 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, dichloromethane:methanol=15:1) to obtain tert-butyl trans-5-cyclopropyl-3-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfonyl-anilino]pyrazole-1-carboxylate as a yellow substance (30 mg).

[0831] MS m/z (ESI): 672.3 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-isopropylsulfonyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0832] Tert-butyl trans-5-cyclopropyl-3-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfonyl-anilino]pyrazole-1-carboxylate (63 mg, 93.77 μmol) was dissolved in methanol (5 mL), and then p-toluenesulfonic acid monohydrate (80.74 mg, 468.84 μmol) was added into the reaction solution. The reaction solution was stirred and reacted at 50° C. for 2 hours. The completion of the reaction was detected by LCMS. The resultant was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Phenomenex Gemini-NX column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile as eluents) to obtain isopropyl trans-N-[4-[5-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-isopropylsulfonyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate as a white substance (2.9 mg).

[0833] MS m/z (ESI): 572.1 [M+H].sup.+;

[0834] 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93 (s, 1H), 9.06 (s, 1H), 8.13 (s, 1H), 7.70-7.58 (m, 2H), 7.34 (d, J=8.4 Hz, 1H), 7.02 (br d, J=7.8 Hz, 1H), 5.54 (s, 1H), 4.82-4.70 (m, 1H), 3.31-3.27 (m, 1H), 2.98-2.79 (m, 2H), 2.12 (br d, J=11.5 Hz, 2H), 1.96-1.88 (m, 2H), 1.88-1.82 (m, 1H), 1.63-1.47 (m, 2H), 1.41-1.25 (m, 2H), 1.16 (d, J=6.2 Hz, 6H), 1.05 (d, J=6.8 Hz, 6H), 0.96-0.88 (m, 2H), 0.74-0.64 (m, 2H).

Example 46: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfinyl]-4-[(5-methyl-lH-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0835] ##STR00239##

[0836] Isopropyl trans-N-[4-[5-(4-bromo-2-isopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (50 mg, 94.43 μmol) and tert-butyl 3-amino-5-(trifluoromethyl)pyrazole-1-carboxylate (28.46 mg, 113.31 μmol) were dissolved in tetrahydrofuran (5 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8.56 mg, 9.44 μmol) and potassium acetate (9.27 mg, 94.43 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, dichloromethane:methanol=10:1) to obtain isopropyl trans-N-[4-[5-[2-cyclopropylsulfinyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl] cyclohexyl]carbamate as a white substance (2.3 mg).

[0837] MS m/z (ESI): 600.2 [M+H].sup.+;

[0838] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 13.80-13.39 (m, 1H), 9.58-9.12 (m, 1H), 8.24-8.04 (m, 1H), 7.72-7.58 (m, 2H), 7.41 (d, J=8.3 Hz, 1H), 7.21 (br s, 1H), 7.02 (br d, J=7.5 Hz, 1H), 6.49 (br s, 1H), 4.82-4.70 (m, 1H), 3.40-3.33 (m, 1H), 3.00-2.80 (m, 2H), 2.12 (br d, J=11.8 Hz, 2H), 1.91 (br d, J=9.8 Hz, 2H), 1.63-1.47 (m, 2H), 1.40-1.27 (m, 2H), 1.16 (d, J=6.3 Hz, 6H), 1.05 (d, J=6.8 Hz, 6H).

Example 47: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0839] ##STR00240##

Synthetic Method

[0840] ##STR00241##

Step 1: Synthesis of tert-butyl (3-(1-oxidophospholan-1-yl)phenyl)carbamate

[0841] 1-(3-Aminophenyl)phospholane-1-oxide (340 mg, 1.74 mmol) was dissolved in methanol (10 mL), and BOC anhydride (3.80 g, 17.42 mmol, 4.00 mL) was added at 25° C. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 16 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. Aqueous ammonia (10 mL) was added into the reaction solution. The reaction solution was stirred and reacted at 25° C. for 2 h, and then extracted with dichloromethane (20 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=10:1) to obtain the compound tert-butyl (3-(1-oxidophospholan-1-yl)phenyl)carbamate (400 mg, 1.35 mmol) as a white solid.

[0842] MS m/z (ESI): 296.2 [M+H].sup.+;

Step 2: Synthesis of tert-butyl N-[4-bromo-3-(1-oxidophospholan-1-yl)phenyl]carbamate

[0843] Tert-butyl (3-(1-oxidophospholan-1-yl)phenyl)carbamate (360 mg, 1.22 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-bromosuccinimide (650.91 mg, 3.66 mmol) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 50° C. for 16 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (dichloromethane:methanol=10:1) to obtain the compound tert-butyl N-[4-bromo-3-(1-oxidophospholan-1-yl)phenyl)carbamate (320 mg, 855.14 μmol) as a yellow oil.

[0844] MS m/z (ESI): 374.0, 376.0 [M+H].sup.+;

[0845] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.68 (s, 1H), 8.13-8.05 (m, 1H), 7.65 (d, J=4.0 Hz, 1H), 7.63-7.58 (m, 1H), 2.30-2.17 (m, 2H), 2.05-1.86 (m, 6H), 1.50 (s, 9H).

Step 3: Synthesis of isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0846] Tert-butyl N-[4-bromo-3-(1-oxidophospholan-1-yl)phenyl]carbamate (220 mg, 587.91 μmol), isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (204.16 mg, 587.91 μmol) and bis(pinacolato)diboron (597.17 mg, 2.35 mmol) were dissolved in anhydrous tetrahydrofuran (4 mL). Under the protection of nitrogen, tris(dibenzylideneacetone)dipalladium(0) (26.92 mg, 29.40 μmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (14.01 mg, 29.40 μmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)] palladium (II) (23.13 mg, 29.40 μmol) and potassium acetate (115.40 mg, 1.18 mmol) were added. The reaction solution appeared as a dark yellow suspension, and was stirred and reacted at 80° C. for 16 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with water (10 mL), and extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=10:1) to obtain the compound isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl]cyclohexyl] carbamate (160 mg, 284.86 μmol) as a yellow oil.

[0847] MS m/z (ESI): 562.2 [M+H].sup.+;

Step 4: Synthesis of isopropyl trans-N-[4-[5-[4-amino-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0848] Isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(1-oxidophospholan-1-yl)phenyl] thiazol-2-yl]cyclohexyl]carbamate (160 mg, 284.86 μmol) was dissolved in anhydrous methanol (2.5 mL), and hydrochloric acid/dioxane (4M, 2.5 mL) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 2 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with a saturated sodium carbonate solution (10 mL), and extracted with dichloromethane (20 mL) twice. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure to obtain crude isopropyl trans-N-[4-[5-[4-amino-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (110 mg) as a white solid.

[0849] MS m/z (ESI): 462.2 [M+H].sup.+;

Step 5: Synthesis of isopropyl trans-N-[4-[5-[4-bromo-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0850] Isopropyl trans-N-[4-[5-[4-amino-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl] cyclohexyl]carbamate (110 mg, 238.32 μmol) was dissolved in acetonitrile (3 mL). Under the protection of nitrogen, tert-butyl nitrite (73.73 mg, 714.97 μmol, 85.04 μL) was added at −30° C. The reaction solution was stirred and reacted for 1 h. Under the protection of nitrogen, cuprous bromide (85.47 mg, 595.81 μmol, 18.15 μL) was added at −30° C. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 16 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with saturated ammonium chloride solution (10 mL), and extracted with dichloromethane (20 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=10:1) to obtain the compound isopropyl trans-N-[4-[5-[4-bromo-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (70 mg, 133.22 μmol) as a white solid.

[0851] MS m/z (ESI): 525.1, 527.1 [M+H].sup.+;

Step 6: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0852] Isopropyl trans-N-[4-[5-[4-bromo-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl] cyclohexyl]carbamate (35 mg, 66.61 μmol) and 1-Boc-3-amino-5-methylpyrazole (13.28 mg, 73.27 μmol) were dissolved in anhydrous tetrahydrofuran (3 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6.04 mg, 6.66 μmol) and potassium acetate (6.54 mg, 66.61 μmol) were added. The reaction solution appeared as a black suspension, and was stirred and reacted at 100° C. for 1 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (dichloromethane:methanol=10:1) to obtain the compound isopropyl trans-N-[4-[5-[4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (20 mg, 31.96 μmol) as a white solid.

[0853] MS m/z (ESI): 626.3 [M+H].sup.+;

Step 7: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0854] Isopropyl trans-N-[4-[5-[4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (20 mg, 31.96 μmol) was dissolved in anhydrous methanol (3 mL), and p-toluenesulfonic acid monohydrate (27.52 mg, 159.81 μmol) was added. The reaction solution appeared as a black suspension, and was stirred and reacted at 50° C. for 1 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with saturated sodium carbonate solution (5 mL), and extracted with dichloromethane (10 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[5-[4-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (1.12 mg, 2.07 μmol) as a white solid.

[0855] MS m/z (ESI): 542.2 [M+H].sup.+;

[0856] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (s, 1H), 8.86-8.78 (m, 1H), 7.99-7.91 (m, 1H), 7.86 (s, 1H), 7.59-7.53 (m, 1H), 7.34-7.28 (m, 1H), 7.06-7.00 (m, 1H), 5.69 (s, 1H), 4.83-4.66 (m, 1H), 3.35-3.29 (m, 1H), 2.97-2.85 (m, 1H), 2.20 (s, 3H), 2.16-2.07 (m, 2H), 1.96-1.78 (m, 6H), 1.67-1.48 (m, 6H), 1.40-1.29 (m, 2H), 1.17 (d, J=6.3 Hz, 6H).

Example 48: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0857] ##STR00242##

Synthetic Method

[0858] ##STR00243##

Step 1: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0859] The intermediate isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (150 mg, 284.36 μmol) in Example 55 and 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (56.69 mg, 312.8 μmol) were dissolved in anhydrous tetrahydrofuran (6 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (25.78 mg, 428.44 μmol) and potassium acetate (83.72 mg, 853.09 μmol) were added. The reaction solution was stirred at 100° C. for 1 hour. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was subjected to liquid-liquid extraction (extraction with 12 mL of ethyl acetate three times) to obtain isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino) phenyl)thiazol-2-yl)cyclohexyl)carbamate as a yellow solid compound (150 mg, crude product).

[0860] MS m/z (ESI): 628.3 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0861] Isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (150 mg, 238.92 μmol) was dissolved in methanol (5 mL), and p-toluenesulfonic acid (205.72 mg, 1.19 mmol) was added. The reaction solution was stirred at 50° C. for 30 minutes. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation. The resultant was added with saturated sodium bicarbonate solution (20 mL), and then the mixture was extracted with dichloromethane (60 mL) three times. The dichloromethane phases were combined, dried over anhydrous sodium sulfate, and subjected to suction filtration. The resultant was purified by preparative high-performance liquid chromatography (Phenomenex Gemini-NX column, 10 μm silica, 30 mm in diameter, 100 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (35% to 55%) as eluents) and lyophilized to obtain isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (55.59 mg).

[0862] MS m/z (ESI): 544.2 [M+H].sup.+;

[0863] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.86 (s, 1H), 9.04 (s, 1H), 8.09 (d, J=2.1 Hz, 1H), 7.67-7.58 (m, 2H), 7.32 (d, J=8.4 Hz, 1H), 7.02 (br d, J=7.6 Hz, 1H), 5.64 (s, 1H), 4.80-4.69 (m, 1H), 3.31-3.23 (m, 1H), 2.98-2.88 (m, 1H), 2.42-2.32 (m, 1H), 2.20 (s, 3H), 2.13 (br d, J=12.3 Hz, 2H), 1.91 (br d, J=10.1 Hz, 2H), 1.65-1.47 (m, 2H), 1.42-1.25 (m, 2H), 1.16 (d, J=6.1 Hz, 6H), 1.00-0.90 (m, 2H), 0.90-0.83 (m, 2H).

Example 49: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0864] ##STR00244##

[0865] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (40 mg, 75.83 μmol) and 1,5-dimethyl-1H-pyrazol-3-amine (10.11 mg, 91.0 μmol) were dissolved in anhydrous tetrahydrofuran (5 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6.87 mg, 7.58 μmol) and potassium acetate (22.33 mg, 227.49 μmol) were added. The reaction solution was stirred at 100° C. for 1 hour. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was subjected to liquid-liquid extraction (extraction with 12 mL of ethyl acetate three times) to obtain a yellow solid compound. The compound was purified by preparative high-performance liquid chromatography (Phenomenex Gemini-NX column, 10 μm silica, 30 mm in diameter, 100 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (40% to 60%) as eluents) and lyophilized to obtain isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (4.55 mg).

[0866] MS m/z (ESI): 558.2 [M+H].sup.+;

[0867] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.04 (s, 1H), 7.97 (br s, 1H), 7.75-7.58 (m, 2H), 7.33 (br d, J=8.4 Hz, 1H), 7.02 (br d, J=6.1 Hz, 1H), 5.66 (s, 1H), 4.85-4.64 (m, 1H), 3.63 (s, 3H), 3.28-3.22 (m, 1H), 3.00-2.84 (m, 1H), 2.46-2.35 (m, 1H), 2.21 (s, 3H), 2.13 (br d, J=11.3 Hz, 2H), 1.91 (br d, J=10.4 Hz, 2H), 1.66-1.47 (m, 2H), 1.42-1.26 (m, 2H), 1.16 (br d, J=6.0 Hz, 6H), 1.02-0.76 (m, 4H).

Example 50: Synthesis of isopropyl trans-N-[4-[5-[2-(cyclopropylsulfonimidoyl)-4-]((5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0868] ##STR00245##

Synthetic Method

[0869] ##STR00246##

Step 1: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfanyl]-4-[(3-methyl-2-tetrahydropyran-2-yl-2H-pyrrol-5-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0870] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfanyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (20 mg, 40.36 μmol) and 5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-amine (8.05 mg, 44.40 μmol) were dissolved in tetrahydrofuran (4 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (3.66 mg, 4.04 μmol) and potassium acetate (3.96 mg, 40.36 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by thin-layer chromatography (silica, dichloromethane:methanol=15:1) to obtain isopropyl trans-N-[4-[5-[2-cyclopropylsulfanyl]-4-[(3-methyl-2-tetrahydropyran-2-yl-2H-pyrrol-5-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate as the product (20 mg).

[0871] MS m/z (ESI): 596.3 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-N-[4-[5-[2-(cyclopropylsulfonimidoyl)-4-]((5-methyl-1-tetrahydropyran-2-ylpyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0872] Isopropyl trans-N-[4-[5-[2-cyclopropylsulfanyl]-4-[(3-methyl-2-tetrahydropyran-2-yl-2H-pyrrol-5-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (33 mg, 55.39 μmol) was dissolved in a solution of ammonia in methanol (3 mL), and diacetoxyiodobenzene (267.59 mg, 830.79 μmol) was added. The reaction solution was stirred and reacted at 60° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by thin-layer chromatography (silica, dichloromethane:methanol=15:1) to obtain isopropyl trans-N-[4-[5-[2-(cyclopropylsulfonimidoyl)-4-]((5-methyl-1-tetrahydropyran-2-ylpyrazol-3-yl)amino]phenyl] thiazol-2-yl]cyclohexyl]carbamate as the product (20 mg).

[0873] MS m/z (ESI): 627.3 [M+H].sup.+;

Step 3: Synthesis of isopropyl trans-N-[4-[5-[2-(cyclopropylsulfonimidoyl)-4-]((5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0874] Isopropyl trans-N-[4-[5-[2-(cyclopropylsulfonimidoyl)-4-]((5-methyl-1-tetrahydropyran-2-ylpyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (20 mg, 31.91 μmol) was dissolved in methanol (2 mL), and p-toluenesulfonic acid monohydrate (27.47 mg, 159.53 μmol) was added. The reaction solution was stirred and reacted at 50° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with 9 mL of dichloromethane (3 mL×3) and 5 mL of a saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Phenomenex Gemini C18 column: 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[5-[2-(cyclopropylsulfonimidoyl)-4-]((5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (2.46 mg).

[0875] MS m/z (ESI): 543.3 [M+H].sup.+;

[0876] .sup.1H NMR (400 MHz, DMSO-d6) δ 11.81 (br s, 1H), 8.93 (s, 1H), 8.03 (s, 1H), 7.70-7.55 (m, 2H), 7.24 (d, J=8.5 Hz, 1H), 7.01 (br d, J=7.8 Hz, 1H), 5.63 (s, 1H), 4.80-4.69 (m, 1H), 4.20 (s, 1H), 3.32-3.31 (m, 1H), 2.95-2.83 (m, 1H), 2.31-2.23 (m, 1H), 2.19 (s, 3H), 2.17-2.06 (m, 2H), 1.95-1.83 (m, 2H), 1.63-1.47 (m, 2H), 1.41-1.25 (m, 2H), 1.16 (d, J=6.3 Hz, 6H), 0.94-0.73 (m, 4H).

Example 51: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0877] ##STR00247##

Synthetic Method

[0878] ##STR00248##

Step 1: Synthesis of tert-butyl (3-((trifluoromethyl)thio)phenyl)carbamate

[0879] 3-(Trifluoromethylthio)aniline (1 g, 5.18 mmol) was dissolved in methanol (20 mL), and BOC anhydride (16.95 g, 77.64 mmol, 17.84 mL) was added at 25° C. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 16 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. Aqueous ammonia (60 mL) was added into the reaction solution. The reaction solution was stirred and reacted at 25° C. for 2 h, and then extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the compound tert-butyl (3-((trifluoromethyl)thio)phenyl)carbamate (600 mg, 2.05 mmol) as a white solid.

[0880] MS m/z (ESI): 238.0 [M+H-tert-butyl].sup.+;

Step 2: Synthesis of tert-butyl N-[4-bromo-3-(trifluoromethylsulfanyl)phenyl]carbamate

[0881] Tert-butyl (3-((trifluoromethyl)thio)phenyl)carbamate (560 mg, 1.91 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-bromosuccinimide (679.64 mg, 3.82 mmol) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 16 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the compound tert-butyl N-[4-bromo-3-(trifluoromethylsulfanyl)phenyl]carbamate (470 mg, 1.26 mmol) as a yellow oil.

[0882] MS m/z (ESI): 318.0, 316.0 [M+H-tert-butyl].sup.+;

Step 3: Synthesis of tert-butyl N-[4-bromo-3-(trifluoromethylsulfonyl)phenyl]carbamate

[0883] Tert-butyl N-[4-bromo-3-(trifluoromethylsulfanyl)phenyl]carbamate (450 mg, 1.21 mmol) and anhydrous ruthenium trichloride (2.51 mg, 12.09 μmol) were dissolved in acetonitrile (2 mL), tetrachloromethane (2 mL) and water (4 mL), and sodium periodate (775.80 mg, 3.63 mmol, 200.98 μL) was added. The reaction solution appeared as a black suspension, and was stirred and reacted at 25° C. for 16 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with water (10 mL), and extracted with dichloromethane (20 mL). The organic layer was washed with saturated saline (10 mL), dried over anhydrous magnesium sulfate, and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to obtain the compound tert-butyl N-[4-bromo-3-(trifluoromethylsulfonyl)phenyl]carbamate (360 mg, 890.65 μmol) as a yellow oil.

[0884] MS m/z (ESI): 426.0, 428.0 [M+Na].sup.+;

Step 4: Synthesis of tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethylsulfonyl)phenyl]carbamate

[0885] Tert-butyl N-[4-bromo-3-(trifluoromethylsulfonyl)phenyl]carbamate (360 mg, 890.65 μmol) and bis(pinacolato)diboron (904.68 mg, 3.56 mmol) were dissolved in anhydrous tetrahydrofuran (3 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (72.73 mg, 89.06 μmol) and potassium acetate (262.23 mg, 2.67 mmol) were added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 80° C. for 16 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to obtain the compound tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethylsulfonyl)phenyl]carbamate (300 mg, 664.80 μmol) as a white solid.

[0886] MS m/z (ESI): 469.2 [M+H.sub.2O].sup.+;

Step 5: Synthesis of isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0887] Tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethylsulfonyl) phenyl]carbamate (300 mg, 664.80 μmol) and isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (230.86 mg, 664.80 μmol) were dissolved in anhydrous dioxane (3 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino) ferrocene]dichloropalladium-dichloromethane (54.29 mg, 66.48 μmol), sodium carbonate (140.92 mg, 1.33 mmol) and water (400 μL) were added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 80° C. for 16 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=10:1) to obtain the compound isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (300 mg, 507.05 μmol) as a white solid.

[0888] MS m/z (ESI): 592.3 [M+H].sup.+;

Step 6: Synthesis of isopropyl trans-N-[4-[5-[4-amino-2-(trifluoromethylsulfonyl) phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0889] Isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(trifluoromethylsulfonyl)phenyl] thiazol-2-yl]cyclohexyl]carbamate (300 mg, 507.05 μmol) was dissolved in anhydrous methanol (3 mL), and hydrochloric acid/dioxane (4M, 3 mL) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 2 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with a saturated sodium carbonate solution (10 mL), and extracted with dichloromethane (20 mL) twice. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure to obtain crude isopropyl trans-N-[4-[5-[4-amino-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (230 mg) as a white solid.

[0890] MS m/z (ESI): 492.2 [M+H].sup.+;

Step 7: Synthesis of isopropyl trans-N-[4-[5-[4-bromo-2-(trifluoromethylsulfonyl) phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0891] Isopropyl trans-N-[4-[5-[4-amino-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl] cyclohexyl]carbamate (230 mg, 467.91 μmol) was dissolved in acetonitrile (5 mL). Under the protection of nitrogen, tert-butyl nitrite (144.75 mg, 1.40 mmol, 166.96 μL) was added at −30° C. The reaction solution was stirred and reacted for 1 h. Under the protection of nitrogen, cuprous bromide (167.80 mg, 1.17 mmol, 35.63 μL) was added at −30° C. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 16 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with saturated ammonium chloride solution (10 mL), and extracted with dichloromethane (20 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain the compound isopropyl trans-N-[4-[5-[4-bromo-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (20 mg, 36.01 μmol) as a white solid.

[0892] MS m/z (ESI): 555.0, 557.0 [M+H].sup.+;

Step 8: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0893] Isopropyl trans-N-[4-[5-[4-bromo-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl] cyclohexyl]carbamate (10 mg, 18.00 μmol) and 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (3.59 mg, 19.80 μmol) were dissolved in anhydrous tetrahydrofuran (2 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (1.63 mg, 1.80 μmol) and potassium acetate (1.77 mg, 18.00 μmol) were added. The reaction solution appeared as a black suspension, and was stirred and reacted at 100° C. for 1 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (dichloromethane:methanol=10:1) to obtain the compound isopropyl trans-N-[4-[5-[4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (10 mg, 15.25 μmol) as a white solid.

[0894] MS m/z (ESI): 656.3 [M+H].sup.+;

Step 9: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0895] Isopropyl trans-N-[4-[5-[4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (20 mg, 30.50 μmol) was dissolved in anhydrous methanol (3 mL), and p-toluenesulfonic acid monohydrate (26.26 mg, 152.50 μmol) was added. The reaction solution appeared as a black suspension, and was stirred and reacted at 50° C. for 1 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with saturated sodium carbonate solution (5 mL), and extracted with dichloromethane (10 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[5-[4-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (1.08 mg, 1.89 μmol) as a white solid.

[0896] MS m/z (ESI): 572.1 [M+H].sup.+;

[0897] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 8.14 (br s, 1H), 7.70 (br d, J=8.5 Hz, 1H), 7.55 (s, 1H), 7.43 (d, J=8.5 Hz, 1H), 5.79 (s, 1H), 4.82-4.70 (m, 1H), 3.55-3.42 (m, 1H), 3.07-2.96 (m, 1H), 2.31 (s, 3H), 2.24 (br d, J=12.0 Hz, 2H), 2.12-2.05 (m, 2H), 1.76-1.63 (m, 2H), 1.48-1.34 (m, 2H), 1.24 (br d, J=6.3 Hz, 6H).

Example 52: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfinyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0898] ##STR00249##

Synthetic Method

[0899] ##STR00250##

Step 1: Synthesis of 3-cyclopropylsulfanylaniline

[0900] 3-Aminothiophenol (10 g, 79.88 mmol) was dissolved in N,N-dimethylformamide (60 mL). Under the protection of nitrogen, sodium hydride (3.19 g, 79.88 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. Thereafter, cyclopropyl bromide (9.66 g, 79.88 mmol) was added into the reaction solution. The reaction solution was stirred under reflux at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, dichloromethane/methanol=20/1) to obtain 3-cyclopropylsulfanylaniline (10 g).

[0901] MS m/z (ESI): 165.9 [M+H].sup.+;

Step 2: Synthesis of tert-butyl N-(3-cyclopropylsulfanylphenyl)carbamate

[0902] 3-Cyclopropylsulfanylaniline (21 g, 127.08 mmol) was dissolved in methanol (315 mL), and Boc anhydride (416.01 g, 1.91 mol) was added. The reaction solution was stirred and reacted at 30° C. for 16 hours. Aqueous ammonia (250 mL) was added into the reaction solution. The reaction solution was stirred and reacted at 0° C. for 2 hours. The reaction solution was extracted with dichloromethane (300 mL) three times. The organic phase was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether/ethyl acetate=20/1) to obtain tert-butyl N-(3-cyclopropylsulfanylphenyl)carbamate as the product (25 g).

[0903] MS m/z (ESI): 210.1 [M+H-tert-butyl].sup.+;

[0904] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.37 (s, 1H), 7.52 (s, 1H), 7.25-7.13 (m, 2H), 6.94 (dd, J=1.5, 7.3 Hz, 1H), 2.26-2.14 (m, 1H), 1.47 (s, 9H), 1.14-1.01 (m, 2H), 0.62-0.50 (m, 2H).

Step 3: Synthesis of tert-butyl N-(4-bromo-3-cyclopropylsulfanyl-phenyl)carbamate

[0905] Tert-butyl N-(3-cyclopropylsulfanylphenyl)carbamate (25 g, 94.21 mmol) was dissolved in dichloromethane (1 L), and then a solution of N-bromosuccinimide (16.77 g, 94.21 mmol) in dichloromethane (1 L) was slowly added dropwise into the reaction solution. The reaction solution was stirred and reacted at −20° C. for 3 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:ethyl acetate=10:1) to obtain tert-butyl N-(4-bromo-3-cyclopropylsulfanyl-phenyl)carbamate as a white solid (10 g).

[0906] MS m/z (ESI): 289.9 [M+H-tert-butyl].sup.+;

[0907] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.55 (s, 1H), 7.80 (d, J=2.3 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.24 (dd, J=2.3, 8.8 Hz, 1H), 2.25-2.01 (m, 1H), 1.47 (s, 9H), 1.21-1.12 (m, 2H), 0.66-0.59 (m, 2H).

Step 4: Synthesis of tert-butyl N-(4-bromo-3-cyclopropylsulfinyl-phenyl)carbamate

[0908] Tert-butyl N-(4-bromo-3-cyclopropylsulfanyl-phenyl)carbamate (5 g, 14.52 mmol) was dissolved in dichloromethane (85 mL), and then a solution of m-chloroperoxybenzoic acid (2.95 g, 14.52 mmol) in dichloromethane (80 mL) was slowly added dropwise into the reaction solution. The reaction solution was stirred and reacted at 30° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with saturated sodium carbonate solution (30 mL), and extracted with 90 mL of dichloromethane (30 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=5:1) to obtain tert-butyl N-(4-bromo-3-cyclopropylsulfinyl-phenyl)carbamate as the product (700 mg).

[0909] MS m/z (ESI): 305.9 [M+H-tert-butyl].sup.+;

Step 5: Synthesis of tert-butyl N-[3-cyclopropylsulfinyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[0910] Tert-butyl N-(4-bromo-3-cyclopropylsulfinyl-phenyl)carbamate (600 mg, 1.67 mmol) and bis(pinacolato)diboron (1.69 g, 6.66 mmol) were dissolved in tetrahydrofuran (15 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (954.97 mg, 1.17 mmol) and potassium acetate (490.35 mg, 5.00 mmol) were added. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 30 mL of dichloromethane (100 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran=3:1) to obtain tert-butyl N-[3-cyclopropylsulfinyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate as a white substance (360 mg).

[0911] MS m/z (ESI): 408.2 [M+H].sup.+;

Step 6: Synthesis of isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-cyclopropylsulfinyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0912] Tert-butyl N-[3-cyclopropylsulfinyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]carbamate (360 mg, 883.80 μmol) and isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (306.92 mg, 883.80 μmol) were dissolved in water (0.5 mL) and dioxane (5 mL). Thereafter, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (72.17 mg, 88.38 μmol) and sodium carbonate (281.02 mg, 2.65 mmol) were added under the condition where nitrogen gas was introduced. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran=3:1) to obtain isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-cyclopropylsulfinyl-phenyl]thiazol-2-yl]cyclohexyl] carbamate as a yellow substance (230 mg).

[0913] MS m/z (ESI): 548.3 [M+H].sup.+;

Step 7: Synthesis of isopropyl trans-N-[4-[5-(4-amino-2-cyclopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate

[0914] Isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-cyclopropylsulfinyl-phenyl] thiazol-2-yl]cyclohexyl]carbamate (230 mg, 419.92 μmol) was dissolved in methanol (2 mL), and hydrochloric acid/dioxane (2.10 mL) was added. The reaction solution was stirred and reacted at 30° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and added with 5 mL of saturated sodium carbonate solution. The reaction solution was added with 9 mL of dichloromethane (3 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain isopropyl trans-N-[4-[5-(4-amino-2-cyclopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate (100 mg).

[0915] MS m/z (ESI): 448.2 [M+H].sup.+;

Step 8: Synthesis of isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate

[0916] Isopropyl trans-N-[4-[5-(4-amino-2-cyclopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (180 mg, 402.13 μmol) was dissolved in acetonitrile (2 mL), and tert-butyl nitrite (124.40 mg, 1.21 mmol) was added at 0° C. The reaction solution was stirred and reacted at 30° C. for 1 hour. The cuprous bromide (144.22 mg, 1.01 mmol) was added into the reaction solution at 0° C. The reaction solution was stirred and reacted at 30° C. for 15 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and added with 50 mL of saturated ammonium chloride solution. The reaction solution was added with 90 mL of dichloromethane (30 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:ethyl acetate=3:2) to obtain isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate as a yellow substance (27 mg).

[0917] MS m/z (ESI): 511.1 [M+H].sup.+;

Step 9: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfinyl]-4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0918] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (17 mg, 33.24 μmol) and 5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-amine (6.63 mg, 36.56 μmol) were dissolved in tetrahydrofuran (4 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (3.01 mg, 3.32 μmol) and potassium acetate (3.26 mg, 33.24 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by thin-layer chromatography (silica, dichloromethane/methanol=15/1) to obtain isopropyl trans-N-[4-[5-[2-cyclopropylsulfinyl]-4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate as the product (10 mg).

[0919] MS m/z (ESI): 612.3 [M+H].sup.+;

Step 10: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfinyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0920] Isopropyl trans-N-[4-[5-[2-cyclopropylsulfinyl]-4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (32 mg, 52.30 μmol) was dissolved in methanol (3 mL), and p-toluenesulfonic acid monohydrate (45.03 mg, 261.52 μmol) was added. The reaction solution was stirred and reacted at 50° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with 9 mL of dichloromethane (3 mL×3) and 5 mL of a saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[5-[2-cyclopropylsulfinyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (2.36 mg).

[0921] MS m/z (ESI): 528.3 [M+H].sup.+;

[0922] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (s, 1H), 8.93 (s, 1H), 7.83 (d, J=2.3 Hz, 1H), 7.68 (s, 1H), 7.54 (dd, J=2.3, 8.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.02 (br d, J=7.5 Hz, 1H), 5.63 (s, 1H), 4.82-4.70 (m, 1H), 3.29-3.26 (m, 1H), 2.98-2.88 (m 1H), 2.52-2.45 (m, 1H), 2.19 (s, 3H), 2.15-2.08 (m, 2H), 1.91 (br d, J=10.4 Hz, 2H), 1.62-1.49 (m, 2H), 1.40-1.26 (m, 2H), 1.16 (d, J=6.3 Hz, 6H), 0.90-0.75 (m, 2H), 0.72-0.60 (m, 1H), 0.57-0.49 (m, 1H).

Example 53: Synthesis of isopropyl trans-N-[4-[5-[4-[(1-methyltriazol-4-yl)amino]-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0923] ##STR00251##

[0924] Isopropyl trans-N-[4-[5-[4-bromo-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl] cyclohexyl]carbamate (35 mg, 66.61 μmol) and 1-methyl-1H-1,2,3-triazol-4-amine (7.19 mg, 73.27 μmol) were dissolved in anhydrous tetrahydrofuran (3 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6.04 mg, 6.66 μmol) and potassium acetate (6.54 mg, 66.61 μmol) were added. The reaction solution appeared as a black suspension, and was stirred and reacted at 100° C. for 1 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with water (10 mL), and extracted with dichloromethane (20 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[5-[4-[(1-methyltriazol-4-yl)amino]-2-(1-oxidophospholan-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (10.49 mg, 19.33 μmol) as a white solid with a yield of 29.02%.

[0925] MS m/z (ESI): 543.3 [M+H].sup.+;

[0926] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.99 (s, 1H), 7.85 (d, J=7.5 Hz, 2H), 7.73-7.66 (m, 1H), 7.37-7.32 (m, 2H), 7.06-6.99 (m, 1H), 4.81-4.69 (m, 1H), 4.03 (s, 3H), 3.33-3.32 (m, 1H), 2.99-2.87 (m, 1H), 2.17-2.08 (m, 2H), 1.96-1.79 (m, 6H), 1.67-1.49 (m, 6H), 1.40-1.28 (m, 2H), 1.17 (d, J=6.0 Hz, 6H).

Example 54: Synthesis of isopropyl trans-N-[4-[5-[2-(cyclopropylsulfonimidoyl)]-4-[(1-methyltriazol-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0927] ##STR00252##

Synthetic Method

[0928] ##STR00253##

Step 1: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfanyl]-4-[(1-methyltriazol-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0929] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfanyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (20 mg, 40.36 μmol) and 1-methyl-1H-1,2,3-triazol-4-amine (4.36 mg, 44.40 μmol) were dissolved in THF (2 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (3.66 mg, 4.04 μmol) and potassium acetate (3.96 mg, 40.36 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by thin-layer chromatography (silica, dichloromethane/methanol=15/1) to obtain isopropyl trans-N-[4-[5-[2-cyclopropylsulfanyl]-4-[(1-methyltriazol-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl] carbamate as the product (20 mg).

[0930] MS m/z (ESI): 513.2 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-N-[4-[5-[2-(cyclopropylsulfonimidoyl)]-4-[(1-methyltriazol-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0931] Isopropyl trans-N-[4-[5-[2-cyclopropylsulfanyl]-4-[(1-methyltriazol-4-yl)amino]phenyl] thiazol-2-yl]cyclohexyl]carbamate (19 mg, 37.06 μmol) was dissolved in a solution of ammonia in methanol (3 mL), and diacetoxyiodobenzene (179.05 mg, 555.89 μmol) was added. The reaction solution was stirred and reacted at 60° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[5-[2-(cyclopropylsulfonimidoyl)]-4-[(1-methyltriazol-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (1.02 mg).

[0932] MS m/z (ESI): 544.2 [M+H].sup.+;

[0933] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (s, 1H), 7.84-7.78 (m, 2H), 7.67 (s, 1H), 7.37-7.32 (m, 1H), 7.29-7.25 (m, 1H), 7.01 (br d, J=7.9 Hz, 1H), 4.80-4.69 (m, 1H), 4.29 (s, 1H), 4.02 (s, 3H), 3.33-3.32 (m, 1H), 2.95-2.84 (m, 1H), 2.31-2.23 (m, 1H), 2.12 (br d, J=12.2 Hz, 2H), 1.90 (br d, J=10.0 Hz, 2H), 1.62-1.48 (m, 2H), 1.39-1.26 (m, 2H), 1.16 (d, J=6.2 Hz, 6H), 0.91-0.76 (m, 4H).

Example 55: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-[(1-methyltriazol-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0934] ##STR00254##

Synthetic Method

[0935] ##STR00255##

Step 1: Synthesis of tert-butyl N-(4-bromo-3-cyclopropylsulfonyl-phenyl)carbamate

[0936] Tert-butyl N-(4-bromo-3-cyclopropylsulfanyl-phenyl)carbamate (5.2 g, 15.10 mmol) was dissolved in dichloromethane (80 mL), and then a solution of m-chloroperoxybenzoic acid (12.27 g, 60.42 mmol) in dichloromethane (85 mL) was slowly added dropwise into the reaction solution. The reaction solution was stirred and reacted at 25° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with saturated sodium carbonate solution (30 mL), and extracted with 90 mL of dichloromethane (30 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=5:1) to obtain tert-butyl N-(4-bromo-3-cyclopropylsulfonyl-phenyl)carbamate as the product (4.4 g).

[0937] MS m/z (ESI): 320.0 [M+H-tert-butyl].sup.+;

[0938] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.79 (s, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.48 (dd, J=2.6, 8.7 Hz, 1H), 2.63-2.58 (m, 1H), 1.48 (s, 9H), 1.02-0.79 (m, 3H), 0.72-0.60 (m, 1H).

Step 2: Synthesis of tert-butyl N-[3-cyclopropylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[0939] Tert-butyl N-(4-bromo-3-cyclopropylsulfonyl-phenyl)carbamate (4.4 g, 11.69 mmol) and bis(pinacolato)diboron (11.88 g, 46.78 mmol) were dissolved in tetrahydrofuran (130 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (954.97 mg, 1.17 mmol) and potassium acetate (3.44 g, 35.08 mmol) were added. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 300 mL of dichloromethane (100 mL×3) and 50 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran=2:1) to obtain tert-butyl N-[3-cyclopropylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate as a white substance (4.4 g).

[0940] MS m/z (ESI): 268.1 [M+H].sup.+;

[0941] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.81 (s, 1H), 8.05 (d, J=1.8 Hz, 1H), 7.67 (dd, J=2.0, 8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 2.98-2.87 (m, 1H), 1.48 (s, 9H), 1.33 (s, 12H), 1.16-1.06 (m, 4H).

Step 3: Synthesis of isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-cyclopropylsulfonyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0942] Tert-butyl N-[3-cyclopropylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]carbamate (1.3 g, 3.07 mmol) and isopropyl trans-N-[4-(5-bromothiazol-2-yl) cyclohexyl]carbamate (969.48 mg, 2.79 mmol) were dissolved in water (3 mL) and dioxane (30 mL). Thereafter, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (227.98 mg, 279.17 μmol) and sodium carbonate (887.67 mg, 8.38 mmol) were added under the condition where nitrogen gas was introduced. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran=3:1) to obtain isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-cyclopropylsulfonyl-phenyl]thiazol-2-yl] cyclohexyl]carbamate as a yellow substance (1.25 g).

[0943] MS m/z (ESI): 564.3 [M+H].sup.+;

Step 4: Synthesis of isopropyl trans-N-[4-[5-(4-amino-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate

[0944] Isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-cyclopropylsulfonyl-phenyl] thiazol-2-yl]cyclohexyl]carbamate (1.25 g, 2.22 mmol) was dissolved in methanol (12 mL), and hydrochloric acid/dioxane (11.09 mL) was added. The reaction solution was stirred and reacted at 30° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and added with 5 mL of saturated sodium carbonate solution. The reaction solution was added with 9 mL of dichloromethane (3 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain isopropyl trans-N-[4-[5-(4-amino-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate (900 mg).

[0945] MS m/z (ESI): 464.2 [M+H].sup.+;

Step 5: Synthesis of isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate

[0946] Isopropyl trans-N-[4-[5-(4-amino-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (900 mg, 1.94 mmol) was dissolved in acetonitrile (30 mL), and tert-butyl nitrite (600.55 mg, 5.82 mmol) was added at 0° C. The reaction solution was stirred and reacted at 30° C. for 1 hour. Cuprous bromide was added into the reaction solution at 0° C. The reaction solution was stirred and reacted at 30° C. for 15 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and added with 50 mL of saturated ammonium chloride solution. The reaction solution was added with 90 mL of dichloromethane (30 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:ethyl acetate=3:2) to obtain isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate as a yellow substance (578 mg).

[0947] MS m/z (ESI): 529.1 [M+H].sup.+;

Step 6: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-[(1-methyltriazol-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0948] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (150 mg, 284.36 μmol) and 1-methyl-1H-1,2,3-triazol-4-amine (30.69 mg, 312.80 μmol) were dissolved in tetrahydrofuran (15 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (25.78 mg, 28.44 μmol) and potassium acetate (27.91 mg, 284.36 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 18 mL of ethyl acetate (6 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-[(1-methyltriazol-4-yl)amino]phenyl]thiazol-2-yl] cyclohexyl]carbamate (44.83 mg).

[0949] MS m/z (ESI): 545.2 [M+H].sup.+;

[0950] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.21 (s, 1H), 7.87-7.78 (m, 2H), 7.65 (s, 1H), 7.48-7.40 (m, 1H), 7.39-7.33 (m, 1H), 7.04 (br d, J=7.7 Hz, 1H), 4.80-4.70 (m, 1H), 4.04 (s, 3H), 3.34-3.30 (m, 1H), 2.98-2.86 (m, 1H), 2.44-2.35 (m, 1H), 2.14 (br d, J=12.0 Hz, 2H), 1.92 (br d, J=10.1 Hz, 2H), 1.65-1.48 (m, 2H), 1.42-1.26 (m, 2H), 1.17 (d, J=6.2 Hz, 6H), 1.01-0.92 (m, 2H), 0.91-0.86 (m, 2H).

Example 56: Synthesis of isopropyl trans-(4-(5-(4-((1H-indazol-3-yl)amino)-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0951] ##STR00256##

Synthetic Method

[0952] ##STR00257##

Step 1: Synthesis of tert-butyl trans-3-((3-(cyclopropylsulfonyl)-4-(2-(4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)amino)-1H-indazole-1-carboxylate

[0953] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (50 mg, 94.79 μmol) and tert-butyl 3-amino-1H-indazole-1-carboxylate (26.53 mg, 113.75 μmol) were dissolved in anhydrous tetrahydrofuran (5 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8.59 mg, 9.48 μmol) and potassium acetate (27.91 mg, 284.36 μmol) were added. The reaction solution was stirred at 100° C. for 1 hour. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and the resultant was subjected to liquid-liquid extraction (extraction with 15 mL of ethyl acetate three times) to obtain tert-butyl trans-3-((3-(cyclopropylsulfonyl)-4-(2-(4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl) amino)-1H-indazole-1-carboxylate as a yellow solid compound (50 mg, crude product).

[0954] MS m/z (ESI): 680.3 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-(4-(5-(4-((1H-indazol-3-yl)amino)-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0955] Tert-butyl trans-3-((3-(cyclopropylsulfonyl)-4-(2-(4-((isopropoxycarbonyl)amino) cyclohexyl)thiazol-5-yl)phenyl)amino)-1H-indazole-1-carboxylate (40 mg, 58.84 μmol) was dissolved in methanol (5 mL), and p-toluenesulfonic acid (50.66 mg, 294.18 μmol) was added. The reaction solution was stirred at 50° C. for 30 minutes. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation. The resultant was added with saturated sodium bicarbonate solution (20 mL), and then the mixture was extracted with dichloromethane (60 mL) three times. The dichloromethane phases were combined, dried over anhydrous sodium sulfate, and subjected to suction filtration. The resultant was purified by preparative high-performance liquid chromatography (Phenomenex Gemini-NX column, 10 μm silica, 30 mm in diameter, 100 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (40% to 60%) as eluents) and lyophilized to obtain isopropyl trans-(4-(5-(4-((lH-indazol-3-yl)amino)-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (10.55 mg).

[0956] MS m/z (ESI): 580.2 [M+H].sup.+;

[0957] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 12.27 (br s, 1H), 9.60 (br s, 1H), 8.38 (br s, 1H), 8.19-7.90 (m, 2H), 7.69 (br s, 1H), 7.51-7.32 (m, 3H), 7.25-6.93 (m, 2H), 4.80-4.65 (m, 1H), 2.94-2.85 (m, 2H), 2.52-2.38 (m, 1H), 2.17-2.05 (m, 2H), 1.98-1.80 (m, 2H), 1.65-1.51 (m, 2H), 1.42-1.28 (m, 2H), 1.16 (d, J=6.3 Hz, 6H), 1.10-0.83 (m, 4H).

Example 57: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-(pyrazolo[1,5-a]pyridin-2-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0958] ##STR00258##

[0959] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (50 mg, 94.79 μmol) and 2-aminopyrazolo[1,5-a]pyridine (13.88 mg, 104.27 μmol) were dissolved in anhydrous tetrahydrofuran (5 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8.59 mg, 9.48 μmol) and potassium acetate (27.91 mg, 284.36 μmol) were added. The reaction solution was stirred at 100° C. for 1 hour. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and the resultant was subjected to liquid-liquid extraction (extraction with 15 mL of ethyl acetate three times) to obtain a yellow solid compound. The compound was purified by preparative high-performance liquid chromatography (Phenomenex Gemini-NX column, 10 μm silica, 30 mm in diameter, 100 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (43% to 63%) as eluents) and lyophilized to obtain isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-(pyrazolo[1,5-a]pyridin-2-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (16.72 mg).

[0960] MS m/z (ESI): 580.2 [M+H].sup.+;

[0961] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.65 (s, 1H), 8.52 (d, J=6.9 Hz, 1H), 8.17 (d, J=2.4 Hz, 1H), 7.93 (dd, J=2.4, 8.5 Hz, 1H), 7.69 (s, 1H), 7.52-7.40 (m, 2H), 7.20-7.14 (m, 1H), 7.02 (br d, J=7.6 Hz, 1H), 6.72 (t, J=6.9 Hz, 1H), 6.12 (s, 1H), 4.80-4.68 (m, 1H), 2.98-2.85 (m, 1H), 2.46-2.41 (m, 1H), 2.14 (br d, J=12.0 Hz, 2H), 1.92 (br d, J=10.3 Hz, 2H), 1.64-1.50 (m, 2H), 1.41-1.27 (m, 2H), 1.16 (d, J=6.1 Hz, 6H), 1.03-0.95 (m, 2H), 0.95-0.88 (m, 2H).

Example 58: Synthesis of isopropyl N-[4-[5-[2-cyclopropylsulfonyl]-4-[(1-methyltriazol-4-yl)amino]phenyl]thiazol-2-yl]-1-bicyclo[2.2.2]octyl]carbamate

[0962] ##STR00259##

Synthetic Method

[0963] ##STR00260## ##STR00261##

Step 1: Synthesis of methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate

[0964] 4-(Tert-butoxycarbonylamino)methylbicyclo[2.2.2]octane-1-carboxylate (1 g, 3.53 mmol) was dissolved in methanol (15 mL), and hydrochloric acid/dioxane (4M, 17.65 mL) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 1 hour. TLC (dichloromethane:methanol=10:1) detection showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, added with a saturated sodium carbonate solution (50 mL), and extracted with dichloromethane (100 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure to obtain methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate as a white solid compound (700 mg, crude product).

Step 2: Synthesis of methyl 4-(isopropoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxyl

[0965] Methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (700 mg, 3.82 mmol) and isopropyl chloroformate (1.40 g, 11.46 mmol, 1.59 mL) were dissolved in anhydrous dichloromethane (5 mL). Under the protection of nitrogen, N,N-diisopropylethylamine (1.48 g, 11.46 mmol, 2.00 mL) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 1 hour. TLC (petroleum ether:ethyl acetate=3:1) detection showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate=3:1) to obtain the compound methyl 4-(isopropoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxyl (900 mg, 3.34 mmol) as a while solid.

[0966] .sup.1H NMR (400 MHz, DMSO-d6) δ=6.72 (br s, 1H), 4.76-4.60 (m, 1H), 3.56 (s, 3H), 1.75 (s, 12H), 1.13 (d, J=6.3 Hz, 6H).

Step 3: Synthesis of 4-(isopropoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid

[0967] Methyl 4-(isopropoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxyl (850 mg, 3.16 mmol) was dissolved in anhydrous methanol (15 mL), and sodium hydroxide (2M, 6.31 mL) was added. The reaction solution appeared as a colorless suspension, and was stirred and reacted at 25° C. for 2 hours. TLC (dichloromethane:methanol=10:1) detection showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure and diluted with dichloromethane (10 mL). The pH of the mixture was adjusted to 3 with 2 mol of hydrochloric acid (10 mL), and then the resultant was extracted with dichloromethane (10 mL) twice. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure to obtain 4-(isopropoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (430 mg, crude product) as a white solid.

Step 4: Synthesis of isopropyl N-(4-carbamoyl-1-bicyclo[2.2.2]octyl)carbamate

[0968] 4-(Isopropoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (400 mg, 1.57 mmol) was dissolved in N,N-dimethylformamide (15 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (893.58 mg, 2.35 mmol), ammonium chloride (251.42 mg, 4.70 mmol) and triethylamine (475.61 mg, 4.70 mmol, 654.21 μL) were added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=10:1) to obtain the compound isopropyl N-(4-carbamoyl-1-bicyclo[2.2.2]octyl)carbamate (350 mg, 1.38 mmol) as a white solid.

[0969] MS m/z (ESI): 255.2 [M+H].sup.+;

Step 5: Synthesis of isopropyl N-(4-carbamothioyl-1-bicyclo[2.2.2]octyl)carbamate

[0970] Isopropyl N-(4-carbamoyl-1-bicyclo[2.2.2]octyl)carbamate (350 mg, 1.38 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL), and Lawesson reagent (278.31 mg, 688.1 μmol) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 80° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=10:1) to obtain the compound isopropyl N-(4-carbamothioyl-1-bicyclo[2.2.2]octyl)carbamate (300 mg, 1.11 mmol) as a yellow solid.

[0971] MS m/z (ESI): 271.2 [M+H].sup.+;

Step 6: Synthesis of isopropyl N-(4-thiazol-2-yl-1-bicyclo[2.2.2]octyl)carbamate

[0972] Isopropyl N-(4-carbamothioyl-1-bicyclo[2.2.2]octyl)carbamate (290 mg, 1.07 mmol) was dissolved in anhydrous ethanol (5 mL), and p-toluenesulfonic acid monohydrate (408.02 mg, 2.15 mmol) and bromoacetaldehyde diethyl acetal (634.09 mg, 3.22 mmol, 484.04 μL) were added. The reaction solution appeared as a light yellow suspension, and was stirred and reacted at 80° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=15:1) to obtain the compound isopropyl N-(4-thiazol-2-yl-1-bicyclo[2.2.2]octyl)carbamate (300 mg) as a light orange solid.

[0973] MS m/z (ESI): 295.1 [M+H].sup.+;

Step 7: Synthesis of isopropyl N-[4-(5-bromothiazol-2-yl)-1-bicyclo[2.2.2]octyl] carbamate

[0974] Isopropyl N-(4-thiazol-2-yl-1-bicyclo[2.2.2]octyl)carbamate (170 mg, 577.42 μmol) was dissolved in N,N-dimethylformamide (3 mL), and N-bromosuccinimide (308.32 mg, 1.73 mmol) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 50° C. for 2 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (petroleum ether:tetrahydrofuran=4:1) to obtain the compound isopropyl N-[4-(5-bromothiazol-2-yl)-1-bicyclo[2.2.2]octyl]carbamate (90 mg, 241.09 μmol) as a white solid.

[0975] MS m/z (ESI): 372.9, 374.9 [M+H].sup.+;

[0976] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.74 (s, 1H), 6.86-6.72 (m, 1H), 4.77-4.65 (m, 1H), 1.88 (br d, J=5.0 Hz, 12H), 1.15 (d, J=6.3 Hz, 6H).

Step 8: Synthesis of isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)-2-cyclopropylsulfonyl-phenyl]thiazol-2-yl]-1-bicyclo[2.2.2]octyl]carbamate

[0977] Isopropyl N-[4-(5-bromothiazol-2-yl)-1-bicyclo[2.2.2]octyl]carbamate (120 mg, 321.45 μmol) and tert-butyl N-[3-cyclopropylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (149.69 mg, 353.60 μmol) were dissolved in anhydrous dioxane (4 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (26.25 mg, 32.15 μmol), sodium carbonate (68.14 mg, 642.90 μmol) and water (400 μL) were added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (dichloromethane:methanol=10:1) to obtain the compound isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)-2-cyclopropylsulfonyl-phenyl]thiazol-2-yl]-1-bicyclo[2.2.2]octyl]carbamate (100 mg, 169.56 μmol) as a white solid.

[0978] MS m/z (ESI): 590.2 [M+H].sup.+;

Step 9: Synthesis of isopropyl N-[4-[5-(4-amino-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]-1-bicyclo[2.2.2]octyl]carbamate

[0979] Isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)-2-cyclopropylsulfonyl-phenyl]thiazol-2-yl]-1-bicyclo[2.2.2]octyl]carbamate (100 mg, 169.56 μmol) was dissolved in anhydrous methanol (2 mL), and hydrochloric acid/dioxane (4M, 847.80 μL) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with a saturated sodium carbonate solution (10 mL), and extracted with dichloromethane (20 mL) twice. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure to obtain crude isopropyl N-[4-[5-(4-amino-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]-1-bicyclo[2.2.2]octyl]carbamate (80 mg) as a white solid.

[0980] MS m/z (ESI): 490.2 [M+H].sup.+;

Step 10: Synthesis of isopropyl N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]-1-bicyclo[2.2.2]octyl]carbamate

[0981] Isopropyl N-[4-[5-(4-amino-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]-1-bicyclo[2.2.2] octyl]carbamate (80 mg, 163.38 μmol) was dissolved in acetonitrile (5 mL). Under the protection of nitrogen, tert-butyl nitrite (50.54 mg, 490.15 μmol, 58.30 μL) was added at −30° C. The reaction solution was stirred and reacted for 1 hour. Under the protection of nitrogen, cuprous bromide (58.59 mg, 408.46 μmol) was added at −30° C. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with saturated ammonium chloride solution (10 mL), and extracted with dichloromethane (20 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (petroleum ether:tetrahydrofuran=3:1) to obtain the compound isopropyl N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]-1-bicyclo[2.2.2]octyl]carbamate (60 mg, 108.40 μmol) as a white solid.

[0982] MS m/z (ESI): 553.2, 555.1 [M+H].sup.+;

Step 11: Synthesis of isopropyl N-[4-[5-[2-cyclopropylsulfonyl-4-[(1-methyltriazol-4-yl)amino]phenyl]thiazol-2-yl]-1-bicyclo[2.2.2]octyl]carbamate

[0983] Isopropyl N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]-1-bicyclo[2.2.2] octyl]carbamate (20 mg, 36.13 μmol) and 1-methyl-1H-1,2,3-triazol-4-amine (3.90 mg, 39.74 μmol) were dissolved in anhydrous tetrahydrofuran (2 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (3.28 mg, 3.61 μmol) and potassium acetate (3.55 mg, 36.13 μmol) were added. The reaction solution appeared as a black suspension, and was stirred and reacted at 100° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl N-[4-[5-[2-cyclopropylsulfonyl-4-[(1-methyltriazol-4-yl)amino]phenyl]thiazol-2-yl]-1-bicyclo[2.2.2]octyl]carbamate (1.39 mg) as a white solid.

[0984] MS m/z (ESI): 571.1 [M+H].sup.+;

[0985] .sup.1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.84 (s, 1H), 7.81 (d, J=2.5 Hz, 1H), 7.64 (s, 1H), 7.42 (d, J=2.5 Hz, 1H), 7.37 (s, 1H), 6.83-6.74 (m, 1H), 4.77-4.67 (m, 1H), 4.04 (s, 3H), 2.41-2.35 (m, 1H), 1.96 (br s, 6H), 1.90 (br d, J=9.0 Hz, 6H), 1.16 (d, J=6.0 Hz, 6H), 0.99-0.92 (m, 2H), 0.89-0.82 (m, 2H).

Example 59: Synthesis of isopropyl N-[4-[5-[2-cyclopropylsulfonyl]-4-[(1-methyltriazol-4-yl)amino]phenyl]thiazol-2-yl]phenyl]carbamate

[0986] ##STR00262##

Synthetic Method

[0987] ##STR00263## ##STR00264##

Step 1: Synthesis of (4-nitrophenyl)thiazole

[0988] 4-Nitrophenylboronic acid (10 g, 59.91 mmol) and 2-bromothiazole (11.10 g, 67.70 mmol) were dissolved in toluene (40 mL), water (16 mL) and dioxane (40 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (2.93 g, 3.59 mmol) and sodium carbonate (15.87 g, 149.77 mmol) were added. The reaction solution was stirred and reacted at 80° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:ethyl acetate=5:1) to obtain (4-nitrophenyl)thiazole as a white solid compound (4.44 g).

[0989] MS m/z (ESI): 206.9 [M+H].sup.+;

[0990] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.39-8.27 (m, 2H), 8.26-8.16 (m, 2H), 8.06 (d, J=3.1 Hz, 1H), 7.99 (d, J=3.1 Hz, 1H).

Step 2: Synthesis of 5-bromo-2-(4-nitrophenyl)thiazole

[0991] (4-Nitrophenyl)thiazole (4.2 g, 20.37 mmol) was dissolved in N,N-dimethylformamide (15 mL), and then a solution of N-bromosuccinimide (10.88 g, 61.12 mmol) in N,N-dimethylformamide (25 mL) was slowly added dropwise into the reaction solution. The reaction solution was stirred and reacted at 80° C. for 15 minutes. The completion of the reaction was detected by LCMS. The reaction solution was added with 1 L of water and then subjected to suction filtration. The filter cake was washed with 50 mL of methanol to obtain 5-bromo-2-(4-nitrophenyl)thiazole as a white solid compound (5.38 g).

[0992] MS m/z (ESI): 285.0, 287.0 [M+H].sup.+;

[0993] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.35-8.27 (m, 2H), 8.17-8.10 (m, 3H).

Step 3: Synthesis of 4-(5-bromothiazol-2-yl)aniline

[0994] 5-Bromo-2-(4-nitrophenyl)thiazole (5.38 g, 18.87 mmol) was dissolved in ethanol (125 mL), tetrahydrofuran (125 mL) and water (62.5 mL), and iron powder (5.27 g, 94.35 mmol) and ammonium chloride (5.05 g, 94.35 mmol) were added. The reaction solution was stirred and reacted at 80° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=5:1) to obtain 4-(5-bromothiazol-2-yl)aniline as a yellow solid compound (2.8 g).

[0995] MS m/z (ESI): 255.0, 257.0 [M+H].sup.+;

[0996] .sup.1H NMR (400 MHz, DMSO-d6) δ 7.86-7.69 (m, 1H), 7.62-7.44 (m, 2H), 6.71-6.53 (m, 2H), 5.77 (s, 2H).

Step 4: Synthesis of isopropyl N-[4-(5-bromothiazol-2-yl)phenyl]carbamate

[0997] 4-(5-Bromothiazol-2-yl)aniline (2.0 g, 7.84 mmol) was dissolved in dichloromethane (300 mL). At 0° C., a solution of isopropyl chloroformate (1.44 g, 11.76 mmol) in dichloromethane (200 mL) was added, and pyridine (3.72 g, 47.03 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=5:1) to obtain isopropyl N-[4-(5-bromothiazol-2-yl)phenyl]carbamate as a white solid compound (2.55 g).

[0998] MS m/z (ESI): 341.0, 343.0 [M+H].sup.+;

[0999] .sup.1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.94-7.90 (m, 1H), 7.84-7.78 (m, 2H), 7.59 (d, J=8.8 Hz, 2H), 4.91 (spt, J=6.2 Hz, 1H), 1.26 (d, J=6.3 Hz, 6H).

Step 5: Synthesis of isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)-2-cyclopropylsulfonyl-phenyl]thiazol-2-yl]phenyl]carbamate

[1000] Isopropyl N-[4-(5-bromothiazol-2-yl)phenyl]carbamate (850 mg, 2.49 mmol) and tert-butyl N-[3-cyclopropylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] carbamate (1.11 g, 2.62 mmol) were dissolved in 1,4-dioxane (30 mL) and water (3 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (203.43 mg, 249.10 μmol) and sodium carbonate (792.07 mg, 7.47 mmol) were added. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:tetrahydrofuran=2:1) to obtain isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)-2-cyclopropylsulfonyl-phenyl]thiazol-2-yl]phenyl]carbamate as a white solid compound (670 mg).

[1001] MS m/z (ESI): 558.2 [M+H].sup.+;

Step 6: Synthesis of isopropyl N-[4-[5-(4-amino-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]phenyl]carbamate

[1002] Isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)-2-cyclopropylsulfonyl-phenyl]thiazol-2-yl]phenyl]carbamate (670 mg, 1.22 mmol) was dissolved in methanol (6 mL), and hydrochloric acid-dioxane (4M, 6.10 mL) was added. The reaction solution was stirred and reacted at 30° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, and the resultant was added with 5 mL of saturated sodium carbonate solution. The reaction solution was extracted with 9 mL of dichloromethane (3 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain isopropyl N-[4-[5-(4-amino-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]phenyl]carbamate as a white solid compound (590 mg).

[1003] MS m/z (ESI): 458.1 [M+H].sup.+;

Step 7: Synthesis of isopropyl N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]phenyl]carbamate

[1004] Isopropyl N-[4-[5-(4-amino-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]phenyl]carbamate (350 mg, 764.92 μmol) was dissolved in acetonitrile (60 mL), and tert-butyl nitrite (236.64 mg, 2.29 mmol) was added at 0° C. The reaction solution was stirred and reacted at 30° C. for 1 hour. Cuprous bromide (274.32 mg, 1.91 mmol) was added into the reaction solution at 0° C. The reaction solution was stirred and reacted at 30° C. for 15 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, and the resultant was added with saturated ammonium chloride solution (50 mL). The reaction solution was extracted with 90 mL of dichloromethane (30 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate=3:2) to obtain isopropyl N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]phenyl]carbamate as a yellow solid compound (100 mg).

[1005] MS m/z (ESI): 521.0, 523.0 [M+H].sup.+;

Step 8: Synthesis of isopropyl N-[4-[5-[2-cyclopropylsulfonyl]-4-[(1-methyltriazol-4-yl)amino]phenyl]thiazol-2-yl]phenyl]carbamate

[1006] Isopropyl N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]phenyl]carbamate (50 mg, 95.89 μmol) and 1-methyl-1H-1,2,3-triazol-4-amine (10.35 mg, 105.48 μmol) were dissolved in tetrahydrofuran (5 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8.69 mg, 9.59 μmol) and potassium acetate (9.41 mg, 95.89 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with water (3 mL) and extracted with ethyl acetate (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (45% to 65%) as eluents) to obtain isopropyl N-[4-[5-[2-cyclopropylsulfonyl]-4-[(1-methyltriazol-4-yl)amino]phenyl]thiazol-2-yl]phenyl]carbamate as a white solid compound (10 mg).

[1007] MS m/z (ESI): 539.0[M+H].sup.+;

[1008] .sup.1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 9.24 (s, 1H), 7.92-7.78 (m, 5H), 7.61 (d, J=8.8 Hz, 2H), 7.51-7.40 (m, 2H), 4.92 (quin, J=6.3 Hz, 1H), 4.04 (s, 3H), 3.32 (br s, 1H), 1.27 (d, J=6.3 Hz, 6H), 1.05-0.88 (m, 4H).

Example 60: Synthesis of isopropyl N-[4-[5-[2-cyclopropylsulfonyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]-1-bicyclo[2.2.2]octylcarbamate

[1009] ##STR00265##

Synthetic Method

[1010] ##STR00266##

Step 1: Synthesis of isopropyl N-[4-[5-[2-cyclopropylsulfonyl]-4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]-1-bicyclo[2.2.2]octyl]carbamate

[1011] Isopropyl N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]-1-bicyclo[2.2.2] octyl]carbamate (40 mg, 72.26 μmol) and 1-methyl-1H-1,2,3-triazol-4-amine (14.41 mg, 79.49 μmol) were dissolved in anhydrous tetrahydrofuran (3 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6.55 mg, 7.23 μmol) and potassium acetate (7.09 mg, 72.26 μmol) were added. The reaction solution appeared as a black suspension, and was stirred and reacted at 100° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (petroleum ether:tetrahydrofuran=2:1) to obtain the compound isopropyl N-[4-[5-[2-cyclopropylsulfonyl]-4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]-1-bicyclo[2.2.2]octyl]carbamate (35 mg, 53.53 μmol) as a white solid.

[1012] MS m/z (ESI): 654.3 [M+H].sup.+;

Step 2: Synthesis of isopropyl N-[4-[5-[2-cyclopropylsulfonyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]-1-bicyclo[2.2.2]octylcarbamate

[1013] Isopropyl N-[4-[5-[2-cyclopropylsulfonyl]-4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]-1-bicyclo[2.2.2]octyl]carbamate (35 mg, 53.53 μmol) was dissolved in anhydrous methanol (2 mL), and p-toluenesulfonic acid monohydrate (46.09 mg, 267.64 μmol) was added. The reaction solution appeared as a black suspension, and was stirred and reacted at 50° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with saturated sodium carbonate solution (10 mL), and extracted with dichloromethane (10 mL) twice. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (YMCCHIRALAmylose-C column, 5 μm silica, 30 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl N-[4-[5-[2-cyclopropylsulfonyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]-1-bicyclo[2.2.2]octylcarbamate (1.24 mg, 2.18 μmol) as a white solid.

[1014] MS m/z (ESI): 570.1 [M+H].sup.+;

[1015] .sup.1H NMR (400 MHz, DMSO-d6) δ12.02-11.74 (m, 1H), 9.04 (s, 1H), 8.12-8.06 (m, 1H), 7.63 (s, 2H), 7.35-7.29 (m, 1H), 6.84-6.73 (m, 1H), 5.64 (s, 1H), 4.77-4.66 (m, 1H), 2.40-2.31 (m, 1H), 2.20 (s, 3H), 1.97 (br d, J=9.3 Hz, 6H), 1.89 (br d, J=8.5 Hz, 6H), 1.15 (d, J=6.3 Hz, 6H), 0.95 (dd, J=2.5, 7.5 Hz, 2H), 0.89-0.81 (m, 2H).

Example 61: Synthesis of isopropyl N-[4-[5-[2-cyclopropylsulfonyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]phenyl]carbamate

[1016] ##STR00267##

Synthetic Method

[1017] ##STR00268##

Step 1: Synthesis of isopropyl N-[4-[5-[2-cyclopropylsulfonyl]-4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]phenyl]carbamate

[1018] Isopropyl N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]phenyl]carbamate (50 mg, 95.89 μmol) and 5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-amine (17.38 mg, 95.89 μmol) were dissolved in tetrahydrofuran (5 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8.69 mg, 9.59 μmol) and potassium acetate (9.41 mg, 95.89 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with water (3 mL) and extracted with ethyl acetate (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by thin-layer chromatography (silica, dichloromethane/methanol=15/1) to obtain isopropyl N-[4-[5-[2-cyclopropylsulfonyl]-4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]phenyl]carbamate as a yellow solid compound (50 mg).

[1019] MS m/z (ESI): 622.2[M+H].sup.+;

Step 2: Synthesis of isopropyl N-[4-[5-[2-cyclopropylsulfonyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]phenyl]carbamate

[1020] Isopropyl N-[4-[5-[2-cyclopropylsulfonyl]-4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]phenyl]carbamate (50 mg, 80.42 μmol) was dissolved in methanol (5 mL), and p-toluenesulfonic acid monohydrate (69.24 mg, 402.08 μmol) was added. The reaction solution was stirred and reacted at 50° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with a saturated sodium bicarbonate solution (5 mL) and extracted with dichloromethane (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Phenomenex Gemini-NX column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (50% to 70%) as eluents) to obtain isopropyl N-[4-[5-[2-cyclopropylsulfonyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]phenyl]carbamate as a yellow solid compound (2.08 mg).

[1021] MS m/z (ESI): 538.0 [M+H].sup.+;

[1022] .sup.1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.88 (s, 1H), 9.09 (s, 1H), 8.13 (d, J=2.3 Hz, 1H), 7.92-7.81 (m, 3H), 7.69-7.57 (m, 3H), 7.42 (d, J=8.5 Hz, 1H), 5.65 (s, 1H), 4.92 (quin, J=6.3 Hz, 1H), 3.31 (s, 1H), 2.20 (s, 3H), 1.27 (d, J=6.3 Hz, 6H), 1.05-0.87 (m, 4H).

Example 62: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-cyclopropylsulfonyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1023] ##STR00269##

Synthetic Method

[1024] ##STR00270##

Step 1: Synthesis of tert-butyl trans-5-cyclopropyl-3-[3-cyclopropylsulfonyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]anilino]pyrazole-1-carboxylate

[1025] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (40 mg, 75.83 μmol) and tert-butyl 3-amino-5-cyclopropyl-pyrazole-1-carboxylate (16.93 mg, 75.83 μmol) were dissolved in tetrahydrofuran (5 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (6.87 mg, 7.58 μmol) and potassium acetate (7.44 mg, 75.83 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, dichloromethane/methanol=15/1) to obtain tert-butyl trans-5-cyclopropyl-3-[3-cyclopropylsulfonyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]anilino] pyrazole-1-carboxylate as the product (40 mg).

[1026] MS m/z (ESI): 670.3 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-cyclopropylsulfonyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1027] Tert-butyl trans-5-cyclopropyl-3-[3-cyclopropylsulfonyl-4-[2-[4-(isopropoxycarbonyl amino)cyclohexyl]thiazol-5-yl]anilino]pyrazole-1-carboxylate (40 mg, 59.71 μmol) was dissolved in methanol (3 mL), and p-toluenesulfonic acid monohydrate (51.41 mg, 298.57 μmol) was added. The reaction solution was stirred and reacted at 50° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with 9 mL of dichloromethane (3 mL×3) and 5 mL of a saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Phenomenex Gemini C18 column: 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[5-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-cyclopropylsulfonyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate (6.01 mg).

[1028] MS m/z (ESI): 570.1 [M+H].sup.+;

[1029] .sup.1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.03 (s, 1H), 8.12 (d, J=2.3 Hz, 1H), 7.66-7.57 (m, 2H), 7.32 (d, J=8.4 Hz, 1H), 7.02 (br d, J=7.8 Hz, 1H), 5.54 (d, J=2.1 Hz, 1H), 4.81-4.70 (m, 1H), 3.35-3.31 (m, 1H), 2.96-2.86 (m, 1H), 2.40-2.34 (m, 1H), 2.13 (br d, J=11.6 Hz, 2H), 1.97-1.81 (m, 3H), 1.63-1.48 (m, 2H), 1.42-1.27 (m, 2H), 1.16 (d, J=6.2 Hz, 6H), 1.01-0.82 (m, 6H), 0.73-0.63 (m, 2H).

Example 63: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-(cyclopropylsulfonimidoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1030] ##STR00271##

Synthetic Method

[1031] ##STR00272##

Step 1: Synthesis of tert-butyl trans-5-cyclopropyl-3-[3-cyclopropylsulfanyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]anilino]pyrazole-1-carboxylate

[1032] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfanyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (20 mg, 40.36 μmol) and tert-butyl 3-amino-5-cyclopropyl-pyrazole-1-carboxylate (9.91 mg, 44.40 μmol) were dissolved in tetrahydrofuran (5 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (3.66 mg, 4.04 μmol) and potassium acetate (3.96 mg, 40.36 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by thin-layer chromatography (silica, dichloromethane/methanol=15/1) to obtain tert-butyl trans-5-cyclopropyl-3-[3-cyclopropylsulfanyl-4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]anilino]pyrazole-1-carboxylate as the product (20 mg).

[1033] MS m/z (ESI): 638.3 [M+H].sup.+;

Step 2: Synthesis of tert-butyl trans-5-cyclopropyl-3-[3-(cyclopropylsulfonimidoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]anilino]pyrazole-1-carboxylate

[1034] Tert-butyl trans-5-cyclopropyl-3-[3-cyclopropylsulfanyl-4-[2-[4-(isopropoxycarbonyl amino)cyclohexyl]thiazol-5-yl]anilino]pyrazole-1-carboxylate (20 mg, 31.36 μmol) was dissolved in a solution of ammonia in methanol (3 mL), and diacetoxyiodobenzene (151.49 mg, 470.33 μmol) was added. The reaction solution was stirred and reacted at 60° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by thin-layer chromatography (silica, dichloromethane/methanol=15/1) to obtain tert-butyl trans-5-cyclopropyl-3-[3-(cyclopropylsulfonimidoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]anilino]pyrazole-1-carboxylate as the product (19 mg).

[1035] MS m/z (ESI): 569.3 [M+H-Boc].sup.+;

Step 3: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-(cyclopropylsulfonimidoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1036] Tert-butyl trans-5-cyclopropyl-3-[3-(cyclopropylsulfonimidoyl)-4-[2-[4-(isopropoxy carbonylamino)cyclohexyl]thiazol-5-yl]anilino]pyrazole-1-carboxylate (15 mg, 22.43 μmol) was dissolved in methanol (2 mL), and p-toluenesulfonic acid monohydrate (19.31 mg, 112.13 μmol) was added. The reaction solution was stirred and reacted at 50° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with 9 mL of dichloromethane (3 mL×3) and 5 mL of a saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Phenomenex Gemini C18 column: 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[5-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-(cyclopropylsulfonimidoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (1.10 mg).

[1037] MS m/z (ESI): 569.4 [M+H].sup.+;

[1038] .sup.1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.91 (s, 1H), 8.05 (s, 1H), 7.70-7.51 (m, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.02 (br d, J=7.5 Hz, 1H), 5.54 (s, 1H), 4.80-4.70 (m, 1H), 4.20 (s, 1H), 4.06 (s, 1H), 2.95-2.83 (m, 1H), 2.32-2.27 (m, 1H), 2.12 (br d, J=13.6 Hz, 2H), 1.95-1.84 (m, 3H), 1.62-1.48 (m, 2H), 1.40-1.27 (m, 2H), 1.16 (d, J=6.2 Hz, 6H), 0.96-0.75 (m, 6H), 0.73-0.62 (m, 2H).

Example 64: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-(isoxazolidin-2-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1039] ##STR00273##

Synthetic Method

[1040] ##STR00274##

Step 1: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylthio)-4-(isoxazolidin-2-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1041] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylthio)phenyl)thiazol-2-yl)cyclohexyl) carbamate (30.0 mg, 60.6 μmol) and isoxazolidine hydrochloride (13.3 mg, 121 μmol) were dissolved in tetrahydrofuran (1 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.3 mg, 11.4 μmol) and potassium acetate (2.74 mg, 3.03 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with water (1 mL) and extracted with ethyl acetate (3 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, dichloromethane:methanol=50:1) to obtain isopropyl trans-(4-(5-(2-(cyclopropylthio)-4-(isoxazolidin-2-yl)phenyl)thiazol-2-yl)cyclohexyl) carbamate as a yellow solid compound (24.0 mg).

[1042] MS m/z (ESI): 488.3 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-(isoxazolidin-2-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1043] Isopropyl trans-(4-(5-(2-(cyclopropylthio)-4-(isoxazolidin-2-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (24.0 mg, 49.2 μmol) was dissolved in a solution of ammonia in methanol (3 mL), and diacetoxyiodobenzene (238 mg, 738 μmol) was added. The reaction solution was stirred and reacted at −20° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by preparative liquid chromatography (Phenomenex Gemini-NX column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.225% aqueous ammonia) and acetonitrile (35% to 55%) as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-(isoxazolidin-2-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (1.01 mg).

[1044] MS m/z (ESI): 519.0 [M+H].sup.+;

[1045] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 8.71-8.31 (m, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.70 (s, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.28 (dd, J=2.4, 8.4 Hz, 1H), 5.19 (s, 1H), 4.75-4.73 (m, 1H), 4.02 (t, J=7.3 Hz, 2H), 3.62 (t, J=7.1 Hz, 2H), 3.43 (br d, J=11.4 Hz, 1H), 3.06-2.94 (m, 1H), 2.44-2.36 (m, 1H), 2.35-2.27 (m, 2H), 2.27-2.17 (m, 2H), 2.12-2.00 (m, 2H), 1.76-1.61 (m, 2H), 1.48-1.34 (m, 2H), 1.31-1.15 (m, 7H), 1.08-0.97 (m, 1H), 0.94-0.81 (m, 2H).

Example 65: Isopropyl trans-(4-(5-(4-(3-benzylureido)-2-(cyclopropanesulfonimidoyl) phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1046] ##STR00275##

Synthetic Method

[1047] ##STR00276##

Step 1: Synthesis of isopropyl trans-N-[3-cyclopropylsulfanyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[1048] Isopropyl trans-N-[4-[5-(4-amino-2-cyclopropylsulfanyl-phenyl)thiazol-2-yl] cyclohexyl]carbamate (500 mg, 1.16 mmol) was dissolved in dichloromethane (50 mL). At 0° C., benzyl isocyanate (463 mg, 3.48 mmol) was added, and N,N-diisopropylethylamine (606 μl, 3.48 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=1:5) to obtain isopropyl trans-N-[3-cyclopropylsulfanyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate as a white solid compound (503 mg).

[1049] MS m/z (ESI): 565.3 [M+H].sup.+;

Step 2: Isopropyl trans-(4-(5-(4-(3-benzylureido)-2-(cyclopropanesulfonimidoyl)phenyl) thiazol-2-yl)cyclohexyl)carbamate

[1050] Isopropyl trans-N-[3-cyclopropylsulfanyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl] thiazol-5-yl]phenyl]carbamate (500 mg, 885 μmol) was dissolved in a solution of ammonia in methanol (7M, 80 mL), and diacetoxyiodobenzene (4.28 g, 13.3 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=70% to 100%) to obtain isopropyl trans-(4-(5-(4-(3-benzylureido)-2-(cyclopropanesulfonimidoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (141.31 mg).

[1051] MS m/z (ESI): 596.2 [M+H].sup.+;

[1052] .sup.1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.11 (d, J=2.3 Hz, 1H), 7.74 (dd, J=2.3, 8.5 Hz, 1H), 7.70 (s, 1H), 7.37-7.20 (m, 6H), 7.01 (br d, J=7.8 Hz, 1H), 6.73 (t, J=6.0 Hz, 1H), 4.77-4.71 (m, 1H), 4.32 (d, J=5.8 Hz, 2H), 3.22 (br s, 1H), 2.97-2.80 (m, 1H), 2.30-2.22 (m, 1H), 2.12 (br d, J=12.0 Hz, 2H), 1.94-1.88 (m, 2H), 1.63-1.46 (m, 2H), 1.41-1.25 (m, 2H), 1.25-1.10 (m, 6H), 0.94-0.74 (m, 4H).

Example 66: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl-4-(2-pyridylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1053] ##STR00277##

[1054] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl] cyclohexyl]carbamate (30 mg, 56.87 μmol) and 2-aminopyridine (5.89 mg, 62.56 μmol) were dissolved in anhydrous tetrahydrofuran (2 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (5.16 mg, 5.69 μmol) and potassium acetate (5.58 mg, 56.87 μmol) were added. The reaction solution appeared as a black suspension, and was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl-4-(2-pyridylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate (13.29 mg, 24.58 μmol) as a white solid.

[1055] MS m/z (ESI): 541.1 [M+H].sup.+;

[1056] .sup.1H NMR (400 MHz, DMSO-d6)=9.68 (s, 1H), 8.36 (d, J=2.3 Hz, 1H), 8.24-8.17 (m, 2H), 7.69 (s, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.02 (br d, J=8.0 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.86 (t, J=6.0 Hz, 1H), 4.78-4.70 (m, 1H), 3.35 (br s, 1H), 3.31-3.27 (m, 1H), 2.97-2.89 (m, 1H), 2.56-2.52 (m, 1H), 2.47-2.39 (m, 1H), 2.17-2.10 (m, 2H), 1.92 (br d, J=10.3 Hz, 2H), 1.63-1.51 (m, 2H), 1.40-1.24 (m, 2H), 1.16 (d, J=6.3 Hz, 6H), 1.01-0.94 (m, 2H), 0.94-0.87 (m, 2H).

Example 67: Synthesis of isopropyl trans-(4-(5-(4-acetylamino-2-(cyclopropanesulfonimidoyl)phenyl]thiazol-2-yl)cyclohexyl)carbamate

[1057] ##STR00278##

Synthetic Method

[1058] ##STR00279##

Step 1: Synthesis of isopropyl trans-(4-(5-(4-acetylamino-2-(cyclopropylthio)phenyl) thiazol-2-yl)cyclohexyl)carbamate

[1059] Isopropyl trans-(4-(5-(4-amino-2-(cyclopropylthio)phenyl)thiazol-2-yl)cyclohexyl) carbamate (50 mg, 115.84 μmol) was dissolved in dichloromethane (2 mL), and chloroacetyl (10.91 mg, 139.01 μmol, 9.92 μL) and triethylamine (35.17 mg, 347.53 μmol, 48.37 μL) were added. The reaction solution was stirred and reacted at 25° C. for 1 hour. The completion of the reaction was detected by LCMS. Thereafter, the resultant was purified by thin-layer chromatography (silica, dichloromethane/methanol=10/1) to obtain isopropyl trans-(4-(5-(4-acetylamino-2-(cyclopropylthio)phenyl)thiazol-2-yl)cyclohexyl)carbamate as the product (20 mg).

[1060] MS m/z (ESI): 474.2 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-(4-(5-(4-acetylamino-2-(cyclopropanesulfonimidoyl)phenyl]thiazol-2-yl)cyclohexyl)carbamate

[1061] Isopropyl trans-(4-(5-(4-acetylamino-2-(cyclopropylthio)phenyl)thiazol-2-yl)cyclohexyl) carbamate (20 mg, 42.23 μmol) was dissolved in a methanol solution (2 mL), and a solution of ammonia in methanol (7M, 30.16 μL) and diacetoxyiodobenzene (34.00 mg, 105.56 μmol) were added. The reaction solution was stirred and reacted at 25° C. for 0.5 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Phenomenex Gemini C18 column: 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (30% to 50%) as eluents) to obtain isopropyl trans-(4-(5-(4-acetylamino-2-(cyclopropanesulfonimidoyl)phenyl]thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (4.5 mg).

[1062] MS m/z (ESI): 505.1 [M+H].sup.+;

[1063] .sup.1H NMR (400 MHz, DMSO-d6) δ=10.39 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 7.93 (dd, J=2.3, 8.3 Hz, 1H), 7.72 (s, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.01 (br d, J=7.8 Hz, 1H), 4.74 (td, J=6.3, 12.4 Hz, 1H), 4.46-4.32 (m, 1H), 3.31 (br s, 1H), 3.00-2.82 (m, 1H), 2.31-2.23 (m, 1H), 2.16-2.09 (m, 2H), 2.08 (s, 3H), 1.91 (br d, J=10.0 Hz, 2H), 1.63-1.48 (m, 2H), 1.40-1.26 (m, 2H), 1.16 (d, J=6.0 Hz, 6H), 0.94-0.75 (m, 4H).

Example 68: Synthesis of isopropyl trans-N-[3-(cyclopropylsulfonimidoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[1064] ##STR00280##

Synthetic Method

[1065] ##STR00281##

Step 1: Synthesis of isopropyl trans-N-[3-cyclopropylsulfanyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[1066] Isopropyl trans-N-[4-[5-(4-amino-2-cyclopropylsulfanyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (2.5 g, 5.79 mmol) was dissolved in dichloromethane (800 mL). At 0° C., isopropyl chloroformate (1.06 g, 8.69 mmol) was added, and pyridine (2.75 g, 34.75 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 3 hours. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether/ethyl acetate=3/1) to obtain isopropyl trans-N-[3-cyclopropylsulfanyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate as a yellow oil (1.32 g).

[1067] MS m/z (ESI): 518.1 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-N-[3-(cyclopropylsulfonimidoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[1068] Isopropyl trans-N-[3-cyclopropylsulfanyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl] thiazol-5-yl]phenyl]carbamate (1.3 g, 2.51 mmol) was dissolved in a solution of ammonia in methanol (150 mL), and diacetoxyiodobenzene (12.13 g, 37.67 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=0:1) to obtain isopropyl trans-N-[3-(cyclopropylsulfonimidoyl)-4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]phenyl]carbamate (527.8 mg) as a white solid compound.

[1069] MS m/z (ESI): 549.1 [M+H].sup.+;

[1070] .sup.1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 7.76-7.58 (m, 2H), 7.38 (d, J=8.3 Hz, 1H), 7.02 (br d, J=7.8 Hz, 1H), 4.91 (quin, J=6.3 Hz, 1H), 4.74 (td, J=6.1, 12.4 Hz, 1H), 4.34 (s, 1H), 3.32-3.31 (m, 1H), 3.02-2.80 (m, 1H), 2.30-2.21 (m, 1H), 2.12 (br d, J=12.0 Hz, 2H), 1.96-1.85 (m, 2H), 1.62-1.48 (m, 2H), 1.40-1.29 (m, 2H), 1.27 (d, J=6.3 Hz, 6H), 1.16 (d, J=6.3 Hz, 6H), 0.95-0.75 (m, 4H).

Example 69: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-((1-methyl-1H-pyrazol-4-yl)amino)phenyl]thiazol-2-yl)cyclohexyl)carbamate

[1071] ##STR00282##

Synthetic Method

[1072] ##STR00283##

Step 1: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylthio)-4-((1-methyl-1H-pyrazol-4-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1073] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylthio)phenyl)thiazol-2-yl)cyclohexyl) carbamate (200 mg, 403 μmol) and 1-methyl-1H-pyrazol-4-amine (78.4 mg, 807 μmol) were dissolved in tetrahydrofuran (10 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (36.6 mg, 40.4 μmol) and potassium acetate (118 mg, 1.21 mmol) were added. The reaction solution was stirred and reacted at 100° C. for 3 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with water (10 mL) and extracted with 21 mL of ethyl acetate (7 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by column chromatography (petroleum ether:ethyl acetate=1:4) to obtain isopropyl trans-(4-(5-(2-(cyclopropylthio)-4-((1-methyl-1H-pyrazol-4-yl)amino)phenyl)thiazol-2-yl)cyclohexyl) carbamate as a brown oily product (175 mg).

[1074] MS m/z (ESI): 512.3 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-((1-methyl-1H-pyrazol-4-yl)amino)phenyl]thiazol-2-yl)cyclohexyl)carbamate

[1075] Isopropyl trans-(4-(5-(2-(cyclopropylthio)-4-((1-methyl-1H-pyrazol-4-yl)amino)phenyl) thiazol-2-yl)cyclohexyl)carbamate (175 mg, 342 μmol) was dissolved in a solution of ammonia in methanol (7M, 5 mL), and diacetoxyiodobenzene (1.65 g, 5.13 mmol) was added. The reaction solution was stirred and reacted at −30° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 7 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.23% formic acid) and acetonitrile as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-((1-methyl-1H-pyrazol-4-yl)amino)phenyl]thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (2.96 mg).

[1076] MS m/z (ESI): 543.1 [M+H].sup.+;

[1077] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.17 (s, 1H), 7.70 (s, 1H), 7.64 (s, 1H), 7.50 (d, J=2.5 Hz, 1H), 7.37 (s, 1H), 7.19 (d, J=8.3 Hz, 1H), 7.02 (br d, J=6.8 Hz, 1H), 6.90 (dd, J=2.5, 8.3 Hz, 1H), 4.77-4.64 (m, 1H), 4.26-4.19 (m, 1H), 3.77 (s, 3H), 3.43-3.33 (m, 1H), 2.89 (br t, J=11.8 Hz, 1H), 2.30-2.24 (m, 1H), 2.12 (br d, J=11.0 Hz, 2H), 1.91 (br d, J=10.5 Hz, 2H), 1.66-1.46 (m, 2H), 1.43-1.26 (m, 2H), 1.17 (d, J=6.4 Hz, 6H), 0.91-0.73 (m, 4H).

Example 70: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-[(1-methylpyrazol-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1078] ##STR00284##

[1079] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (100 mg, 189.58 μmol) and 1-methylpyrazol-4-amine (22.09 mg, 227.49 μmol) were dissolved in tetrahydrofuran (6 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (17.19 mg, 18.96 μmol) and potassium acetate (18.61 mg, 189.58 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with water (3 mL) and extracted with ethyl acetate (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (40% to 60%) as eluents) to obtain isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-[(1-methylpyrazol-4-yl)amino]phenyl] thiazol-2-yl]cyclohexyl]carbamate as a white solid compound (18.57 mg).

[1080] MS m/z (ESI): 544.1 [M+H].sup.+;

[1081] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.72 (s, 1H), 7.65-7.57 (m, 1H), 7.42-7.35 (m, 2H), 7.26 (d, J=8.5 Hz, 1H), 7.06-6.93 (m, 2H), 4.74 (td, J=6.2, 12.4 Hz, 1H), 3.82 (s, 3H), 3.34-3.33 (m, 1H), 2.90 (tt, J=3.5, 11.9 Hz, 1H), 2.40-2.31 (m, 1H), 2.12 (br d, J=11.8 Hz, 2H), 1.90 (br d, J=10.3 Hz, 2H), 1.63-1.47 (m, 2H), 1.41-1.25 (m, 2H), 1.16 (d, J=6.3 Hz, 6H), 0.99-0.78 (m, 4H).

Example 71: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-(1H-pyrazol-4-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1082] ##STR00285##

Synthetic Method

[1083] ##STR00286##

Step 1: Synthesis of tert-butyl trans-4-((3-(cyclopropylsulfonyl)-4-(2-((4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)amino)-1H-pyrazole-1-carboxylate

[1084] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (100 mg, 189.58 μmol) and tert-butyl 4-aminopyrazole-1-carboxylate (41.68 mg, 227.49 μmol) were dissolved in tetrahydrofuran (5 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (17.19 mg, 18.96 μmol) and potassium acetate (18.61 mg, 189.58 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with water (6 mL) and extracted with ethyl acetate (18 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by thin-layer chromatography (silica, dichloromethane:methanol=10:1) to obtain tert-butyl trans-4-((3-(cyclopropylsulfonyl)-4-(2-((4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)amino)-1H-pyrazole-1-carboxylate as a yellow solid compound (90 mg).

[1085] MS m/z (ESI): 630.2 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-(1H-pyrazol-4-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1086] Tert-butyl trans-4-((3-(cyclopropylsulfonyl)-4-(2-((4-((isopropoxycarbonyl)amino) cyclohexyl)thiazol-5-yl)phenyl)amino)-1H-pyrazole-1-carboxylate (90 mg, 142.91 μmol) was dissolved in methanol (5 mL), and then p-toluenesulfonic acid monohydrate (123.04 mg, 714.53 μmol) was added into the reaction solution. The reaction solution was stirred and reacted at 50° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with a saturated aqueous sodium carbonate solution (3 mL) and extracted with ethyl acetate (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (40% to 60%) as eluents) to obtain isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-(1H-pyrazol-4-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate as a white solid compound (24.54 mg).

[1087] MS m/z (ESI): 530.0 [M+H].sup.+;

[1088] .sup.1H NMR (400 MHz, DMSO-d6) δ 12.77 (br s, 1H), 8.23 (s, 1H), 7.75 (br s, 1H), 7.62 (s, 1H), 7.46 (br s, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.08-6.88 (m, 2H), 4.74 (td, J=6.1, 12.4 Hz, 1H), 3.33-3.27 (m, 1H), 2.99-2.82 (m, 1H), 2.42-2.28 (m, 1H), 2.12 (br d, J=11.6 Hz, 2H), 1.90 (br d, J=10.4 Hz, 2H), 1.63-1.46 (m, 2H), 1.42-1.24 (m, 2H), 1.16 (d, J=6.2 Hz, 6H), 1.01-0.74 (m, 4H).

Example 72: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1089] ##STR00287##

Synthetic Method

[1090] ##STR00288##

Step 1: Synthesis of tert-butyl trans-3-((3-(cyclopropylsulfonyl)-4-(2-((4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)amino)-5-(hydroxymethyl)-1H-pyrazole-1-carboxylate

[1091] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (49.5 mg, 93.8 μmol) and tert-butyl 3-amino-5-(hydroxymethyl)-1H-pyrazole-1-carboxylate (20.0 mg, 93.8 μmol) were dissolved in tetrahydrofuran (4 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (85.0 mg, 93.8 μmol) and potassium acetate (9.21 mg, 93.8 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, dichloromethane:methanol=15:1) to obtain the compound tert-butyl trans-3-((3-(cyclopropylsulfonyl)-4-(2-((4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl) amino)-5-(hydroxymethyl)-1H-pyrazole-1-carboxylate as a yellow product (33.0 mg).

[1092] MS m/z (ESI): 660.3[M+H].sup.+;

Step 2: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1093] Tert-butyl trans-3-((3-(cyclopropylsulfonyl)-4-(2-((4-((isopropoxycarbonyl)amino) cyclohexyl)thiazol-5-yl)phenyl)amino)-5-(hydroxymethyl)-1H-pyrazole-1-carboxylate (33.0 mg, 50.0 μmol) was dissolved in methanol (3 mL), and p-toluenesulfonic acid monohydrate (43.1 mg, 250 μmol) was added. The reaction solution was stirred and reacted at 50° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with 9 mL of dichloromethane (3 mL×3) and 5 mL of a saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Phenomenex Gemini C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (33% to 53%) as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (4.66 mg) as a white compound.

[1094] MS m/z (ESI): 560.1 [M+H].sup.+;

[1095] .sup.1H NMR (400 MHz, DMSO-d6) δ 12.33-11.79 (m, 1H), 9.44-8.76 (m, 1H), 8.08 (d, J=2.2 Hz, 1H), 7.58 (s, 1H), 7.72-7.57 (m, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.02 (br d, J=7.7 Hz, 1H), 5.77 (d, J=1.8 Hz, 1H), 5.27 (t, J=5.7 Hz, 1H), 4.74 (quin, J=6.2 Hz, 1H), 4.44 (d, J=5.6 Hz, 2H), 3.31-3.19 (m, 1H), 3.01-2.83 (m, 1H), 2.43-2.33 (m, 1H), 2.13 (br d, J=11.6 Hz, 2H), 1.91 (br d, J=10.3 Hz, 2H), 1.67-1.48 (m, 2H), 1.41-1.25 (m, 2H), 1.12-1.05 (m, 6H), 1.02-0.80 (m, 4H)

Example 73: Synthesis of isopropyl trans-N-[4-[5-(2-cyclopropylsulfonyl-4-isoxazolidin-2-yl-phenyl)thiazol-2-yl]cyclohexyl]carbamate

[1096] ##STR00289##

[1097] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (70 mg, 133 μmol) and isoxazolidine hydrochloride (18.9 mg, 173 μmol) were dissolved in tetrahydrofuran (3 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (12.0 mg, 13.3 μmol) and potassium acetate (13.0 mg, 133 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with water (3 mL) and extracted with ethyl acetate (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (43% to 63%) as eluents) to obtain isopropyl trans-N-[4-[5-(2-cyclopropylsulfonyl-4-isoxazolidin-2-yl-phenyl)thiazol-2-yl] cyclohexyl]carbamate as a white solid compound (2.01 mg).

[1098] MS m/z (ESI): 520.0 [M+H].sup.+;

[1099] .sup.1H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.60 (d, J=2.5 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.29 (dd, J=2.4, 8.4 Hz, 1H), 7.02 (br d, J=8.0 Hz, 1H), 4.74 (td, J=6.1, 12.3 Hz, 1H), 3.94 (t, J=7.3 Hz, 2H), 3.59 (t, J=7.0 Hz, 2H), 3.30-3.27 (m, 1H), 2.99-2.87 (m, 1H), 2.47-2.40 (m, 1H), 2.25 (quin, J=7.2 Hz, 2H), 2.13 (br d, J=11.8 Hz, 2H), 1.91 (br d, J=10.3 Hz, 2H), 1.63-1.49 (m, 2H), 1.41-1.25 (m, 2H), 1.16 (d, J=6.3 Hz, 6H), 1.02-0.84 (m, 4H).

Example 74: Synthesis of isopropyl trans-(4-(5-(4-(cyclopropanecarboxamido)-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1100] ##STR00290##

Synthetic Method

[1101] ##STR00291##

[1102] Isopropyl trans-(4-(5-(4-amino-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (80.0 mg, 173 μmol) and cyclopropylcarboxylic acid (44.6 mg, 518 μmol, 41 μL) were dissolved in anhydrous acetonitrile (3 mL), and tri-n-propylphosphonic anhydride (50% solution in ethyl acetate) (329 mg, 518 μmol, 308 μL) and N,N-diisopropylethylamine (66.9 mg, 518 μmol, 90.2 μL) were added. The reaction solution was stirred and reacted at 80° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 7 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (50% to 75%) as eluents) to obtain isopropyl trans-(4-(5-(4-(cyclopropanecarboxamido)-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (28.34 mg).

[1103] MS m/z (ESI): 532.1 [M+H].sup.+;

[1104] .sup.1H NMR (400 MHz, DMSO-d6) δ=10.72 (s, 1H), 8.33 (d, J=2.3 Hz, 1H), 7.94 (dd, J=2.3, 8.3 Hz, 1H), 7.71 (s, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.02 (br d, J=7.8 Hz, 1H), 4.74 (td, J=6.2, 12.5 Hz, 1H), 3.31-3.27 (m, 1H), 2.94 (tt, J=3.4, 11.8 Hz, 1H), 2.44-2.36 (m, 1H), 2.13 (br d, J=11.8 Hz, 2H), 1.91 (br d, J=10.0 Hz, 2H), 1.80 (quin, J=6.1 Hz, 1H), 1.64-1.49 (m, 2H), 1.40-1.27 (m, 2H), 1.16 (d, J=6.3 Hz, 6H), 1.01-0.93 (m, 2H), 0.90-0.81 (m, 6H).

Example 75: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-[(5-fluoro-2-pyridyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1105] ##STR00292##

Synthetic Method

[1106] ##STR00293##

[1107] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (250 mg, 474 μmol) and 2-amino-5-fluoropyridine (53.1 mg, 474 μmol) were dissolved in tetrahydrofuran (18 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (42.9 mg, 47.4 μmol) and potassium acetate (140 mg, 1.42 mmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. Thereafter, the reaction solution was added with water (3 mL) and extracted with ethyl acetate (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (50% to 70%) as eluents) to obtain isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-[(5-fluoro-2-pyridyl)amino]phenyl] thiazol-2-yl]cyclohexyl]carbamate as a white solid compound (74.96 mg).

[1108] MS m/z (ESI): 559.0 [M+H].sup.+;

[1109] .sup.1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 8.21 (d, J=3.1 Hz, 1H), 8.10 (dd, J=2.3, 8.4 Hz, 1H), 7.71-7.59 (m, 2H), 7.44 (d, J=8.4 Hz, 1H), 7.05-6.90 (m, 2H), 4.74 (td, J=6.1, 12.4 Hz, 1H), 3.29-3.23 (m, 1H), 2.93 (tt, J=3.6, 11.9 Hz, 1H), 2.47-2.37 (m, 1H), 2.13 (br d, J=11.4 Hz, 2H), 1.91 (br d, J=9.9 Hz, 2H), 1.64-1.50 (m, 2H), 1.41-1.26 (m, 2H), 1.16 (d, J=6.2 Hz, 6H), 1.04-0.83 (m, 4H).

Example 76: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl-4-(3-pyridylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1110] ##STR00294##

Synthetic Method

[1111] ##STR00295##

[1112] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (50.0 mg, 94.8 μmol) and 3-aminopyridine (10.7 mg, 114 μmol) were dissolved in tetrahydrofuran (6 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8.59 mg, 9.48 μmol) and potassium acetate (27.9 mg, 284 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. Thereafter, the reaction solution was added with water (3 mL) and extracted with ethyl acetate (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (53% to 73%) as eluents) to obtain isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl-4-(3-pyridylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate as a white solid compound (10.65 mg).

[1113] MS m/z (ESI): 541.1 [M+H].sup.+;

[1114] .sup.1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.44 (d, J=2.6 Hz, 1H), 8.19 (dd, J=1.3, 4.7 Hz, 1H), 7.71-7.56 (m, 3H), 7.45-7.31 (m, 3H), 7.02 (br d, J=7.8 Hz, 1H), 4.77-4.70 (m, 1H), 3.30-3.19 (m, 1H), 3.02-2.82 (m, 1H), 2.46-2.38 (m, 1H), 2.13 (br d, J=11.5 Hz, 2H), 1.91 (br d, J=10.3 Hz, 2H), 1.68-1.47 (m, 2H), 1.42-1.26 (m, 2H), 1.16 (d, J=6.2 Hz, 6H), 1.03-0.80 (m, 4H).

Example 77: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methylpyridin-2-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1115] ##STR00296##

Synthetic Method

[1116] ##STR00297##

Step 1: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methylpyridin-2-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1117] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (50.0 mg, 94.8 μmol) and 2-amino-5-methylpyridine (15.4 mg, 142 μmol) were dissolved in anhydrous tetrahydrofuran (3 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8.59 mg, 9.48 μmol) and potassium acetate (27.9 mg, 284 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was added with 5 mL of water and extracted with ethyl acetate (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (45% to 65%) as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methylpyridin-2-ylamino)phenyl)thiazol-2-yl) cyclohexyl)carbamate as a white solid compound (4.64 mg).

[1118] MS m/z (ESI): 555.0 [M+H].sup.+;

[1119] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.56 (s, 1H), 8.34 (d, J=2.3 Hz, 1H), 8.11 (dd, J=2.3, 8.5 Hz, 1H), 8.06 (s, 1H), 7.68 (s, 1H), 7.49 (dd, J=2.1, 8.4 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.01 (br d, J=7.5 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 4.81-4.69 (m, 1H), 3.30-3.28 (m, 1H), 2.92 (br t, J=11.8 Hz, 1H), 2.44-2.38 (m, 1H), 2.20 (s, 3H), 2.13 (br d, J=12.0 Hz, 2H), 1.91 (br d, J=10.3 Hz, 2H), 1.64-1.48 (m, 2H), 1.41-1.27 (m, 2H), 1.16 (d, J=6.3 Hz, 6H), 1.02-0.85 (m, 4H).

Example 78: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methoxypyridin-2-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1120] ##STR00298##

Synthetic Method

[1121] ##STR00299##

[1122] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (60.0 mg, 114 μmol) and 2-amino-5-methoxypyridine (28.2 mg, 227 μmol) were dissolved in tetrahydrofuran (4 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.3 mg, 11.4 μmol) and potassium acetate (33.4 mg, 341 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered, concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (53% to 73%) as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methoxypyridin-2-yl)amino)phenyl)thiazol-2-yl) cyclohexyl)carbamate as a white solid compound (27.90 mg).

[1123] MS m/z (ESI): 571.1 [M+H].sup.+;

[1124] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.52 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 8.07 (dd, J=2.5, 8.5 Hz, 1H), 7.97 (d, J=3.0 Hz, 1H), 7.68 (s, 1H), 7.44-7.33 (m, 2H), 7.02 (br d, J=7.8 Hz, 1H), 6.90 (d, J=9.0 Hz, 1H), 4.81-4.70 (m, 1H), 3.79 (s, 3H), 3.33-3.32 (m, 1H), 2.93 (s, 1H), 2.46-2.38 (m, 1H), 2.14 (br d, J=12.0 Hz, 2H), 1.92 (br d, J=10.3 Hz, 2H), 1.65-1.50 (m, 2H), 1.42-1.28 (m, 2H), 1.16-1.08 (m, 6H), 1.02-0.88 (m, 4H).

Example 79: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-(pyrimidin-2-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1125] ##STR00300##

Synthetic Method

[1126] ##STR00301##

[1127] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (50.0 mg, 94.8 μmol) and 2-aminopyrimidine (13.5 mg, 142 μmol) were dissolved in anhydrous tetrahydrofuran (3 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8.59 mg, 9.48 μmol) and potassium acetate (27.9 mg, 284 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was added with water (3 mL) and extracted with ethyl acetate (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (48% to 68%) as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-(pyrimidin-2-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid (12.32 mg).

[1128] MS m/z (ESI): 542.1 [M+H].sup.+;

[1129] .sup.1H NMR (400 MHz, DMSO-d6) δ=10.19 (s, 1H), 8.60-8.53 (m, 3H), 8.11 (dd, J=2.5, 8.5 Hz, 1H), 7.70 (s, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.08-6.91 (m, 2H), 4.78-4.71 (m, 1H), 3.31 (s, 1H), 3.01-2.87 (m, 1H), 2.47-2.41 (m, 1H), 2.14 (br d, J=11.5 Hz, 2H), 1.91 (br d, J=10.8 Hz, 2H), 1.65-1.50 (m, 2H), 1.42-1.27 (m, 2H), 1.16 (d, J=6.3 Hz, 6H), 1.04-0.95 (m, 2H), 0.94-0.86 (m, 2H).

Example 80: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-(1,3,5-triazin-2-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1130] ##STR00302##

Synthetic Method

[1131] ##STR00303##

[1132] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (60.0 mg, 114 μmol) and 2-amino-1,3,5-triazine (21.8 mg, 2274 μmol) were dissolved in tetrahydrofuran (4 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.3 mg, 11.4 μmol) and potassium acetate (33.4 mg, 3414 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered, concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (44% to 64%) as eluents) to obtain isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-(1,3,5-triazin-2-ylamino)phenyl]thiazol-2-yl]cyclohexyl] carbamate as a white solid compound (18.7 mg).

[1133] MS m/z (ESI): 543.0 [M+H].sup.+;

[1134] .sup.1H NMR (400 MHz, DMSO-d6) δ=10.78 (s, 1H), 8.78 (s, 2H), 8.47 (s, 1H), 8.04 (br d, J=8.3 Hz, 1H), 7.73 (s, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.03 (br d, J=8.0 Hz, 1H), 4.81-4.67 (m, 1H), 3.29-3.25 (m, 1H), 3.04-2.86 (m, 1H), 2.47-2.40 (m, 1H), 2.15 (br d, J=12.5 Hz, 2H), 1.92 (br d, J=9.8 Hz, 2H), 1.64-1.51 (m, 2H), 1.42-1.28 (m, 2H), 1.17-1.05 (m, 6H), 1.03-0.89 (m, 4H).

Example 81: Synthesis of isopropyl trans-N-[4-[5-[2-(cyclopropylsulfonimidoyl)]-4-[(5-fluoro-2-pyridyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1135] ##STR00304##

Synthetic Method

[1136] ##STR00305##

Step 1: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfanyl]-4-[(5-fluoro-2-pyridyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1137] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfanyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (190 mg, 383 μmol) and 2-amino-5-fluoropyridine (51.6 mg, 460 μmol) were dissolved in tetrahydrofuran (12 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (34.8 mg, 38.4 μmol) and potassium acetate (113 mg, 1.15 mmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with water (3 mL) and extracted with ethyl acetate (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by thin-layer chromatography (silica, dichloromethane:methanol=15:1) to obtain isopropyl trans-N-[4-[5-[2-cyclopropylsulfanyl]-4-[(5-fluoro-2-pyridyl)amino]phenyl]thiazol-2-yl]cyclohexyl] carbamate as a white solid compound (80.0 mg).

[1138] MS m/z (ESI): 527.2 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-N-[4-[5-[2-(cyclopropylsulfonimidoyl)]-4-[(5-fluoro-2-pyridyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1139] Isopropyl trans-N-[4-[5-[2-cyclopropylsulfanyl]-4-[(5-fluoro-2-pyridyl)amino]phenyl] thiazol-2-yl]cyclohexyl]carbamate (80 mg, 152 μmol) was dissolved in a solution of ammonia in methanol (6 mL), and diacetoxyiodobenzene (734 mg, 2.28 mmol) was added. The reaction solution was stirred and reacted at −20° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (48% to 68%) as eluents) to obtain isopropyl trans-N-[4-[5-[2-(cyclopropylsulfonimidoyl)]-4-[(5-fluoro-2-pyridyl)amino]phenyl] thiazol-2-yl]cyclohexyl]carbamate as a white solid compound (20.0 mg).

[1140] MS m/z (ESI): 558.0 [M+H].sup.+;

[1141] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.67 (s, 1H), 8.21 (dd, J=2.7, 18.1 Hz, 2H), 8.11 (dd, J=2.4, 8.5 Hz, 1H), 7.71 (s, 1H), 7.62 (dt, J=3.1, 8.7 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.04-6.90 (m, 2H), 4.78-4.71 (m, 1H), 4.32 (s, 1H), 3.29-3.24 (m, 1H), 2.97-2.84 (m, 1H), 2.31-2.26 (m, 1H), 2.13 (br d, J=10.8 Hz, 2H), 1.91 (br d, J=10.8 Hz, 2H), 1.63-1.49 (m, 2H), 1.41-1.26 (m, 2H), 1.16 (d, J=6.1 Hz, 6H), 0.94-0.76 (m, 4H).

Example 82: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-(cyclopropylsulfonimidoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1142] ##STR00306##

Synthetic Method

[1143] ##STR00307##

Step 1: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylthio)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1144] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylthio)phenyl)thiazol-2-yl)cyclohexyl) carbamate (200 mg, 404 μmol) and 2-amino-6-(trifluoromethyl)pyridine (131 mg, 807 μmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (36.6 mg, 40.4 μmol) and potassium acetate (118.8 mg, 1.21 mmol) were added. The reaction solution was stirred and reacted at 100° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was added with water (3 mL) and extracted with ethyl acetate (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to obtain isopropyl trans-(4-(5-(2-(cyclopropylthio)-4-((5-(trifluoromethyl)pyridin-2-yl)amino) phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (120 mg).

[1145] MS m/z (ESI): 577.1 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-(cyclopropylsulfonimidoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1146] Isopropyl trans-(4-(5-(2-(cyclopropylthio)-4-((5-(trifluoromethyl)pyridin-2-yl)amino) phenyl)thiazol-2-yl)cyclohexyl)carbamate (120 mg, 208 μmol) was dissolved in a solution of ammonia in methanol (7M, 3 mL), and diacetoxyiodobenzene (1.01 g, 3.12 mmol) was added. The reaction solution was stirred and reacted at −25° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (53% to 73%) as eluents) to obtain isopropyl trans-N-[4-[5-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-(cyclopropylsulfonimidoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate as a white solid compound (35.43 mg).

[1147] MS m/z (ESI): 608.0 [M+H].sup.+;

[1148] .sup.1H NMR (400 MHz, DMSO-d6) δ=10.13 (s, 1H), 8.56 (s, 1H), 8.34 (d, J=2.3 Hz, 1H), 8.20 (dd, J=2.4, 8.4 Hz, 1H), 7.95 (dd, J=2.5, 8.9 Hz, 1H), 7.74 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.06-6.98 (m, 2H), 4.78-4.71 (m, 1H), 4.39 (br s, 1H), 2.92 (tt, J=3.5, 11.8 Hz, 1H), 2.38-2.28 (m, 1H), 2.14 (br d, J=11.9 Hz, 2H), 1.92 (br d, J=10.1 Hz, 2H), 1.65-1.50 (m, 2H), 1.42-1.28 (m, 2H), 1.17 (d, J=6.3 Hz, 6H), 0.96-0.79 (m, 4H).

Example 83: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-(pyridin-2-yloxy)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1149] ##STR00308##

Synthetic Method

[1150] ##STR00309##

Step 1: Synthesis of trans-(3-(cyclopropylsulfonyl)-4-(2-((4-((isopropoxycarbonyl) amino)cyclohexyl)thiazol-5-yl)phenyl)boronic acid

[1151] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (200 mg, 379 μmol) and bis(pinacolato)diboron (481 mg, 1.90 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL). Under the protection of nitrogen, dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (II) (31.0 mg, 37.9 μmol) and potassium acetate (112 mg, 1.14 mmol) were added. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, dichloromethane:methanol=15:1) to obtain trans-(3-(cyclopropylsulfonyl)-4-(2-((4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl) phenyl)boronic acid as a yellow solid compound (120 mg).

[1152] MS m/z (ESI): 493.0 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-hydroxyphenyl) thiazol-2-yl)cyclohexyl)carbamate

[1153] Trans-(3-(cyclopropylsulfonyl)-4-(2-((4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)boronic acid (120.0 mg, 244 μmol) was dissolved in a tetrahydrofuran solution (600 μL), and 30% hydrogen peroxide (3.54, 31.2 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 0.5 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of an aqueous sodium sulfite solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain the compound isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-hydroxyphenyl)thiazol-2-yl)cyclohexyl)carbamate (60.0 mg).

[1154] MS m/z (ESI): 465.2 [M+H].sup.+;

Step 3: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-(pyridin-2-yloxy)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1155] Isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-hydroxyphenyl)thiazol-2-yl)cyclohexyl) carbamate (55 mg, 118.38 μmol) and 2-bromopyridine (28.06 mg, 177.57 μmol) were dissolved in dioxane (2.5 mL), and methanesulfonato(2-(di-tert-butylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.11 mg, 11.84 μmol) and cesium carbonate (115.71 mg, 355.15 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by preparative liquid chromatography (Phenomenex Gemini C18 column: 3 μm silica, 40 mm in diameter, 75 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (44% to 84%) as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-(pyridin-2-yloxy)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (14.65 mg).

[1156] MS m/z (ESI): 442.0 [M+H].sup.+;

[1157] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.21 (dd, J=1.3, 5.0 Hz, 1H), 7.98-7.91 (m, 1H), 7.78 (s, 1H), 7.74 (d, J=2.5 Hz, 1H), 7.65-7.59 (m, 1H), 7.58-7.50 (m, 1H), 7.26-7.18 (m, 1H), 7.27-7.17 (m, 1H), 7.03 (br d, J=7.5 Hz, 1H), 4.74 (td, J=6.3, 12.5 Hz, 1H), 3.31 (br s, 1H), 3.31-3.26 (m, 1H), 3.02-2.90 (m, 1H), 2.54 (s, 1H), 2.15 (br d, J=12.3 Hz, 2H), 1.92 (br d, J=10.3 Hz, 2H), 1.65-1.51 (m, 2H), 1.42-1.28 (m, 2H), 1.17-1.11 (m, 6H), 1.03-0.85 (m, 4H).

Example 84: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-[[1-(2-(hydroxyethyl)pyrazol-4-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1158] ##STR00310##

Synthetic Method

[1159] ##STR00311##

[1160] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (60 mg, 114 μmol) and 2-(4-amino-1H-pyrazol-1-yl)ethanol (17.4 mg, 137 μmol) were dissolved in tetrahydrofuran (4 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.3 mg, 11.4 μmol) and potassium acetate (22.3 mg, 227 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with water (3 mL) and extracted with ethyl acetate (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (42% to 62%) as eluents) to obtain isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-[[1-(2-(hydroxyethyl)pyrazol-4-yl]amino] phenyl]thiazol-2-yl]cyclohexyl]carbamate as a white solid compound (30.0 mg).

[1161] MS m/z (ESI): 574.1 [M+H].sup.+;

[1162] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.72 (s, 1H), 7.65-7.60 (m, 1H), 7.62 (s, 1H), 7.45-7.38 (m, 2H), 7.27 (d, J=8.5 Hz, 1H), 7.06-6.93 (m, 2H), 4.90 (t, J=5.3 Hz, 1H), 4.78-4.71 (m, 1H), 4.11 (t, J=5.6 Hz, 2H), 3.73 (q, J=5.8 Hz, 2H), 3.28 (br d, J=2.3 Hz, 1H), 2.98-2.83 (m, 1H), 2.41-2.32 (m, 1H), 2.12 (br d, J=11.8 Hz, 2H), 1.90 (br d, J=10.5 Hz, 2H), 1.65-1.46 (m, 2H), 1.41-1.25 (m, 2H), 1.16 (d, J=6.3 Hz, 6H), 1.00-0.78 (m, 4H).

Example 85: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-[[1-(2-fluoroethyl)pyrazol-4-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1163] ##STR00312##

Synthetic Method

[1164] ##STR00313##

Step 1: Synthesis of tert-butyl trans-4-[3-3-cyclopropylsulfonyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]anilino]pyrazole-1-carboxylate

[1165] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (230 mg, 436 μmol) and tert-butyl 4-aminopyrazole-1-carboxylate (95.9 mg, 523 μmol) were dissolved in tetrahydrofuran (10 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (39.5 mg, 43.6 μmol) and potassium acetate (128.4 mg, 1.31 mmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with water (3 mL) and extracted with ethyl acetate (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by thin-layer chromatography (silica, dichloromethane:methanol=10:1) to obtain tert-butyl trans-4-[3-3-cyclopropylsulfonyl-4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]anilino]pyrazole-1-carboxylate as a yellow solid compound (158 mg).

[1166] MS m/z (ESI): 630.3 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-(1H-pyrazol-4-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1167] Tert-butyl trans-4-[3-3-cyclopropylsulfonyl-4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]anilino]pyrazole-1-carboxylate (158 mg, 251 μmol) was dissolved in methanol (6 mL), and p-toluenesulfonic acid monohydrate (216 mg, 1.25 mmol) was added. The reaction solution was stirred and reacted at 50° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with a saturated aqueous sodium carbonate solution (3 mL) and extracted with ethyl acetate (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-(1H-pyrazol-4-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate as a yellow solid compound (127 mg).

[1168] MS m/z (ESI): 530.2 [M+H].sup.+;

Step 3: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-[[1-(2-fluoroethyl)pyrazol-4-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1169] Isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-(1H-pyrazol-4-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate (98 mg, 185 μmol) and 1-bromo-2-fluoroethane (70.5 mg, 555 μmol) were dissolved in N,N-dimethylformamide (2 mL), and then cesium carbonate (181 mg, 555 μmol) was added. The reaction solution was stirred and reacted at 80° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered, concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 25 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (40% to 60%) as eluents) to obtain the compound isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-[[1-(2-fluoroethyl)pyrazol-4-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (6.35 mg).

[1170] MS m/z (ESI): 576.1 [M+H].sup.+;

[1171] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.80 (s, 1H), 7.62 (s, 1H), 7.47 (s, 1H), 7.41 (d, J=2.5 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.06-6.95 (m, 2H), 4.83 (t, J=4.8 Hz, 1H), 4.78-4.67 (m, 2H), 4.44 (t, J=4.8 Hz, 1H), 4.37 (t, J=4.8 Hz, 1H), 3.28-3.26 (m, 1H), 2.96-2.84 (m, 1H), 2.42-2.32 (m, 1H), 2.12 (br d, J=12.0 Hz, 2H), 1.91 (br d, J=10.0 Hz, 2H), 1.63-1.48 (m, 2H), 1.40-1.26 (m, 2H), 1.16 (d, J=6.3 Hz, 6H), 0.99-0.78 (m, 4H).

Example 86: Synthesis of isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-[[1-(oxetan-3-yl)pyrazol-4-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1172] ##STR00314##

Synthetic Method

[1173] ##STR00315##

[1174] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (60 mg, 114 μmol) and 1-(oxetan-3-yl)-1H-pyrazol-4-amine (19.0 mg, 137 μmol) were dissolved in tetrahydrofuran (4 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.3 mg, 11.4 μmol) and potassium acetate (22.3 mg, 227 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with water (3 mL) and extracted with ethyl acetate (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by thin-layer chromatography (silica, dichloromethane:methanol=15:1)) to obtain isopropyl trans-N-[4-[5-[2-cyclopropylsulfonyl]-4-[[1-(oxetan-3-yl)pyrazol-4-yl]amino] phenyl]thiazol-2-yl]cyclohexyl]carbamate as a yellow solid compound (31.52 mg).

[1175] MS m/z (ESI): 586.1 [M+H].sup.+;

[1176] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.07-7.78 (m, 1H), 7.63 (s, 1H), 7.56 (s, 1H), 7.42 (d, J=2.5 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.02 (dd, J=2.5, 8.5 Hz, 2H), 5.55 (quin, J=7.0 Hz, 1H), 4.91 (d, J=6.8 Hz, 3H), 4.93 (s, 1H), 4.78-4.71 (m, 1H), 3.31 (br s, 1H), 2.98-2.83 (m, 1H), 2.42-2.34 (m, 1H), 2.12 (br d, J=12.0 Hz, 2H), 1.98-1.84 (m, 2H), 1.67-1.45 (m, 2H), 1.42-1.26 (m, 2H), 1.16 (d, J=6.3 Hz, 6H), 1.00-0.76 (m, 4H).

Example 87: Synthesis of isopropyl trans-N-[4-[5-(2-cyclopropylsulfonyl-4-pyrazol-1-yl-phenyl)thiazol-2-yl]cyclohexyl]carbamate

[1177] ##STR00316##

Synthetic Method

[1178] ##STR00317##

[1179] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (150 mg, 284 μmol) and pyrazole (23.2 mg, 341 μmol) were dissolved in dimethyl sulfoxide (800 μL). Under the protection of nitrogen, cuprous iodide (27.1 mg, 142 μmol), N,N-dimethylethylenediamine (25.1 mg, 284 μmol) and cesium carbonate (278 mg, 853 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. Thereafter, the reaction solution was added with a saturated aqueous ammonium chloride solution (5 mL) and extracted with ethyl acetate (15 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (43% to 63%) as eluents) to obtain isopropyl trans-N-[4-[5-(2-cyclopropylsulfonyl-4-pyrazol-1-yl-phenyl)thiazol-2-yl]cyclohexyl]carbamate as a white solid compound (8.55 mg).

[1180] MS m/z (ESI): 515.0 [M+H].sup.+;

[1181] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J=2.5 Hz, 1H), 8.49 (d, J=2.5 Hz, 1H), 8.21 (dd, J=2.4, 8.4 Hz, 1H), 7.86 (d, J=1.5 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.04 (br d, J=8.0 Hz, 1H), 6.67-6.61 (m, 1H), 4.78-4.71 (m, 1H), 3.20 (br s, 1H), 3.02-2.91 (m, 1H), 2.46-2.43 (m, 1H), 2.15 (br d, J=12.5 Hz, 2H), 1.92 (br d, J=10.5 Hz, 2H), 1.66-1.52 (m, 2H), 1.42-1.27 (m, 2H), 1.16 (d, J=6.0 Hz, 6H), 1.05-0.92 (m, 4H).

Example 88: Synthesis of isopropyl trans-(4-(5-(2-(cyclobutylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1182] ##STR00318##

Synthetic Method

[1183] ##STR00319##

Step 1: Synthesis of (2-bromophenyl)(cyclobutyl)sulfane

[1184] o-Bromothiophenol (5 g, 26.4 mmol, 3.1 mL) was dissolved in N,N-dimethylformamide (50 mL), and potassium carbonate (5.48 g, 39.7 mmol) and cyclobutyl bromide (4.64 g, 34.4 mmol, 3.3 mL) were added. The reaction solution was stirred and reacted at 120° C. for 24 hours. TLC (petroleum ether:ethyl acetate=1:0) detection showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=1:0) to obtain (2-bromophenyl)(cyclobutyl)sulfane (4.5 g).

[1185] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.59 (dd, J=1.1, 7.9 Hz, 1H), 7.36 (t, J=7.1 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.08 (t, J=7.3 Hz, 1H), 4.07-3.98 (m, 1H), 2.60-2.53 (m, 2H), 2.09-1.94 (m, 4H).

Step 2: Synthesis of 1-bromo-2-(cyclobutylsulfonyl)benzene

[1186] (2-Bromophenyl)(cyclobutyl)sulfane (2.0 g, 8.22 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperoxybenzoic acid (5.68 g, 32.9 mmol) was added at 0◯° C. The reaction solution was stirred and reacted at 25° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with a saturated sodium carbonate solution (30 mL), and extracted with 90 mL of dichloromethane (30 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate=10:1) to obtain 1-bromo-2-(cyclobutylsulfonyl)benzene as a colorless product (2.0 g, 7.27 mmol).

[1187] MS m/z (ESI): 275.0, 277.0 [M+H].sup.+;

Step 3: Synthesis of 1-bromo-2-(cyclobutylsulfonyl)-4-iodobenzene

[1188] 1-Bromo-2-(cyclobutylsulfonyl)benzene (2.2 g, 8.00 mmol) was dissolved in sulfuric acid (20 mL), and then N-iodosuccinimide (5.40 g, 24.0 mmol) was added at −30° C. The reaction solution was stirred and reacted at 25° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was quenched with water (100 mL), and then extracted with dichloromethane (200 mL) twice. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resultant was slurried with an ethyl acetate solution to obtain 1-bromo-2-(cyclobutylsulfonyl)-4-iodobenzene as a white solid compound (1.5 g, 3.74 mmol).

[1189] MS m/z (ESI): 417.9, 419.9 [M+NH.sub.3].sup.+;

Step 4: Synthesis of N-(4-bromo-3-(cyclobutylsulfonyl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine

[1190] 1-Bromo-2-(cyclobutylsulfonyl)-4-iodobenzene (900 mg, 2.24 mmol) and 5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-amine (447 mg, 2.47 mmol) were dissolved in tetrahydrofuran (5 mL). Under the protection of nitrogen, methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-l,l-diphenyl]palladium (II) dichloromethane adduct (213 mg, 224 μmol) and cesium carbonate (1.46 g, 4.49 mmol) were added. The reaction solution was stirred and reacted at 100° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:ethyl acetate=4:1) to obtain N-(4-bromo-3-(cyclobutylsulfonyl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine as a white solid compound (500 mg, 1.10 mmol).

[1191] MS m/z (ESI): 454.1, 456.1 [M+H].sup.+;

Step 5: Synthesis of N-(3-(cyclobutylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine

[1192] N-(4-bromo-3-(cyclobutylsulfonyl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (300 mg, 660.24 μmol) and bis(pinacolato)diboron (670.64 mg, 2.64 mmol) were dissolved in dioxane (5 mL). Under the protection of nitrogen, dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (II) (46.75 mg, 66.02 μmol) and potassium acetate (129.59 mg, 1.32 mmol) were added. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:ethyl acetate=3:1) to obtain N-(3-(cyclobutylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine as a white substance (150 mg).

[1193] MS m/z (ESI): 502.3 [M+H].sup.+;

Step 6: Synthesis of isopropyl trans-(4-(5-(2-(cyclobutylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1194] N-(3-(cyclobutylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (150 mg, 299 μmol) and isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (94.4 mg, 272 μmol) were dissolved in water (0.4 mL) and dioxane (4 mL). Thereafter, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (22.2 mg, 27.2 μmol) and sodium carbonate (57.7 mg, 544 μmol) were added under the condition where nitrogen gas was introduced. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, petroleum ether:tetrahydrofuran=1:1) to obtain isopropyl trans-(4-(5-(2-(cyclobutylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a yellow substance (70.0 mg, 109 μmol).

[1195] MS m/z (ESI): 642.4 [M+H].sup.+;

Step 7: Synthesis of isopropyl trans-(4-(5-(2-(cyclobutylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1196] Isopropyl trans-(4-(5-(2-(cyclobutylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (70.0 mg, 109 μmol) was dissolved in methanol (3 mL), and p-toluenesulfonic acid monohydrate (93.9 mg, 545 μmol) was added. The reaction solution was stirred and reacted at 50° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with 60 mL of dichloromethane (20 mL×3) and 20 mL of saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclobutylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl) cyclohexyl)carbamate as a white solid compound (23.57 mg).

[1197] MS m/z (ESI): 558.0 [M+H].sup.+;

[1198] .sup.1H NMR (400 MHz, DMSO-d6) δ=11.90-11.87 (m, 1H), 9.06 (s, 1H), 8.13 (d, J=2.5 Hz, 1H), 7.64-7.61 (m, 2H), 7.31 (d, J=8.5 Hz, 1H), 7.03 (br d, J=7.5 Hz, 1H), 5.65-5.63 (m, 1H), 4.78-4.71 (m, 1H), 3.65 (t, J=8.2 Hz, 1H), 3.33-3.30 (m, 1H), 2.96-2.88 (m, 1H), 2.24-2.11 (m, 6H), 2.06-1.97 (m, 2H), 1.95-1.80 (m, 4H), 1.62-1.51 (m, 2H), 1.40-1.29 (m, 2H), 1.17 (d, J=6.3 Hz, 6H).

Examples 89 and 89-1: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiophen-2-yl)cyclohexyl)carbamate and isopropyl cis-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiophen-2-yl) cyclohexyl)carbamate

[1199] ##STR00320##

Synthetic Method

[1200] ##STR00321## ##STR00322##

Step 1: Synthesis of tert-butyl (4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiophen-2-yl)cyclohex-3-en-1-ylcarbamate

[1201] N-(3-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (210 mg, 431 μmol), 2,5-dibromothiophene (130 mg, 538 μmol), and tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohextrien-3-en-1-yl)carbamate (174 mg, 538 μmol) were dissolved in THF (5 mL). Under the protection of nitrogen, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (25 mg, 53 μmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (42 mg, 53 μmol), tris(dibenzylideneacetone)dipalladium (49 mg, 53 μmol) and sodium carbonate (2M, 1.05 mL) were added. The reaction solution was stirred at 100° C. for 3 hours. LCMS showed that the reaction was complete. The reaction system was subjected to liquid-liquid extraction (extraction with 10 mL of ethyl acetate three times) and then evaporated to dryness via rotary evaporation. The resultant was purified by column chromatography (silica, ethyl acetate/petroleum ether=0% to 25%) to obtain tert-butyl (4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiophen-2-yl)cyclohex-3-en-1-ylcarbamate as a yellow solid compound (330 mg).

[1202] MS m/z (ESI): 639.2 [M+H].sup.+;

Step 2: Synthesis of N-(4-(5-(4-(4-aminocyclohex-1-en-1-yl)thiophen-2-yl)-3-(cyclopropylsulfonyl)phenyl)-5-methyl-1H-pyrazol-3-amine

[1203] Tert-butyl (4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiophen-2-yl)cyclohex-3-en-1-ylcarbamate (105 mg, 188 μmol) was dissolved in anhydrous methanol (6 mL), and then hydrochloric acid/dioxane (12 mL) was added. The reaction solution was stirred at 25° C. for 2 hours. LCMS showed that the reaction was complete. The reaction system was evaporated to dryness via rotary evaporation, and then the resultant was purified by column chromatography (silica, dichloromethane/methanol=0% to 10%) to obtain N-(4-(5-(4-(4-aminocyclohex-1-en-1-yl)thiophen-2-yl)-3-(cyclopropylsulfonyl)phenyl)-5-methyl-1H-pyrazol-3-amine as a yellow solid (223 mg).

[1204] MS m/z (ESI): 455.2 [M+H].sup.+;

Step 3: Synthesis of isopropyl (4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiophen-2-yl)cyclohex-3-en-1-yl)carbamate

[1205] N-(4-(5-(4-(4-aminocyclohex-1-en-1-yl)thiophen-2-yl)-3-(cyclopropylsulfonyl)phenyl)-5-methyl-1H-pyrazol-3-amine (200 mg, 352 μmol) and N,N-diisopropylethylamine (136 mg, 1 mmol) were dissolved in dichloromethane (15 mL), and then isopropyl chloroformate (30 mg, 246 μmol) was slowly added dropwise. The reaction solution was stirred and reacted at 25° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, dichloromethane/methanol=10/1) to obtain isopropyl (4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiophen-2-yl)cyclohex-3-en-1-yl)carbamate as a yellow solid product (120 mg).

[1206] MS m/z (ESI): 541.2 [M+H].sup.+;

Step 4: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiophen-2-yl)cyclohexyl)carbamate and isopropyl cis-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiophen-2-yl)cyclohexyl) carbamate

[1207] Compound isopropyl (4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino) phenyl)thiophen-2-yl)cyclohex-3-en-1-yl)carbamate (100 mg, 185 μmol) and wet Pd/C (36 mg, 1.11 mmol) were dissolved in methanol (10 mL). The reaction solution was stirred and reacted at 25° C. for 18 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Boston Prime C18 column, 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (35% to 65%) as eluents) to obtain a pair of enantiomers (retention time on chromatogram: 4.590 minutes, named as Compound of Example 89) and another pair of enantiomers (retention time on chromatogram: 4.189 minutes, named as Compound of Example 89-1).

Example 89

[1208] MS m/z (ESI): 543.2 [M+H].sup.+;

[1209] .sup.1H NMR (400 MHz, DMSO-d6) δ=11.84 (s, 1H), 8.96 (s, 1H), 8.06 (s, 1H), 7.70-7.53 (m, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.04 (d, J=3.5 Hz, 1H), 6.99 (br d, J=7.6 Hz, 1H), 6.84 (d, J=3.5 Hz, 1H), 5.63 (s, 1H), 4.77-4.60 (m, 1H), 3.30-3.22 (m, 1H), 2.75 (br t, J=11.7 Hz, 1H), 2.29-2.22 (m, 1H), 2.20 (s, 3H), 2.03 (br d, J=12.3 Hz, 2H), 1.89 (br d, J=10.6 Hz, 2H), 1.54-1.41 (m, 2H), 1.38-1.29 (m, 2H), 1.21-1.16 (d, J=6.4 Hz, 6H), 0.95-0.84 (m, 4H).

Example 89-1

[1210] MS m/z (ESI): 543.2 [M+H].sup.+;

[1211] .sup.1H NMR (400 MHz, DMSO-d6) δ=11.84 (br s, 1H), 8.96 (s, 1H), 8.07 (br s, 1H), 7.61 (br d, J=8.0 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.13 (br d, J=5.0 Hz, 1H), 7.08-7.03 (m, 1H), 6.89-6.83 (m, 1H), 5.64 (s, 1H), 4.75-4.60 (m, 1H), 3.65-3.55 (m, 1H), 2.95-2.85 (m, 1H), 2.28-2.22 (m, 1H), 2.20 (s, 3H), 1.94-1.81 (m, 2H), 1.80-1.72 (m, 2H), 1.71-1.55 (m, 4H), 1.17 (d, J=6.0 Hz, 6H), 0.94-0.84 (m, 4H).

Example 90: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)-1H-imidazol-2-yl)cyclohexylcarbamate

[1212] ##STR00323##

Synthetic Method

[1213] ##STR00324##

Step 1: Synthesis of tert-butyl trans-(4-(((2,2-dimethoxyethyl)carbamoyl) cyclohexyl)carbamate

[1214] Trans-(4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (4.88 g, 20.1 mmol) was dissolved in N,N-dimethylformamide (50 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (11.4 g, 30.1 mmol), 2,2-dimethoxyethylamine (6.33 g, 60.2 mmol) and triethylamine (8.38 mL, 60.2 mmol) were added. The reaction solution was stirred and reacted at 30° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. Methanol (50 mL) and water (450 mL) were added, and a white solid precipitated. Thereafter, the reaction solution was further stirred at room temperature for 30 minutes. The resultant was filtered and then washed with 150 mL of water (50 mL×3) to obtain tert-butyl trans-(4-(((2,2-dimethoxyethyl)carbamoyl)cyclohexyl)carbamate as a white solid compound (5.1 g).

[1215] MS m/z (ESI): 353.3 [M+H].sup.+;

Step 2: Synthesis of tert-butyl trans-(4-(1H-imidazol-2-yl)cyclohexyl)carbamate

[1216] Tert-butyl trans-(4-(((2,2-dimethoxyethyl)carbamoyl)cyclohexyl)carbamate (2.60 g, 7.87 mmol) was dissolved in glacial acetic acid (40 mL), and ammonium acetate (30.3 g, 393 μmol) was added. The reaction solution was stirred and reacted at 90° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (12% to 52%) as eluents) to obtain tert-butyl trans-((4-(1H-imidazol-2-yl)cyclohexyl)carbamate as a white solid compound (0.37 g).

[1217] MS m/z (ESI): 266.1 [M+H].sup.+;

Step 3: Synthesis of tert-butyl trans-(4-(4,5-dibromo-1H-imidazol-2-yl) cyclohexyl)carbamate

[1218] Tert-butyl trans-(4-(1H-imidazol-2-yl)cyclohexyl)carbamate (266 mg, 501 μmol) was dissolved in anhydrous dichloromethane (10 mL), and liquid bromine (25.8 μl, 501 μmol) was slowly added at −30° C. The reaction solution was stirred and reacted at −30° C. for 10 hours. The completion of the reaction was detected by LCMS. A saturated sodium sulfite solution (10 mL) was added into the reaction solution to quench the reaction. The reaction solution was extracted with DCM (30 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl trans-(4-(4,5-dibromo-1H-imidazol-2-yl)cyclohexyl)carbamate as a white solid compound (150 mg, crude product).

[1219] MS m/z (ESI): 422.0; 424.0; 426.0 [M+H].sup.+;

Step 4: Synthesis of tert-butyl trans-(4-(5-bromo-1H-imidazol-2-yl)cyclohexyl)carbamate

[1220] Tert-butyl trans-(4-(4,5-dibromo-1H-imidazol-2-yl)cyclohexyl)carbamate (100 mg, 118 μmol) was dissolved in anhydrous methanol (5 mL) and water (5 mL), and sodium sulfite (1.49 g, 11.8 mmol) was added. The reaction solution was stirred and reacted at 100° C. for 48 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with water (10 mL), and extracted with DCM (30 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl trans-(4-(5-bromo-1H-imidazol-2-yl)cyclohexyl)carbamate as a white solid compound (50.0 mg, crude product).

[1221] MS m/z (ESI): 344.1; 346.2 [M+H].sup.+;

Step 5: Synthesis of tert-butyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amino)phenyl)-1H-imidazol-2-yl) cyclohexyl)carbamate

[1222] Tert-butyl trans-(4-(5-bromo-1H-imidazol-2-yl)cyclohexyl)carbamate (50.0 mg, 145 μmol) and N-(3-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (70.8 mg, 145 μmol) were dissolved in tetrahydrofuran (5 mL). Thereafter, tris(dibenzylideneacetone)dipalladium (13.3 mg, 14.5 μmol), sodium carbonate (2M, 1 mL), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (11.4 mg, 14.5 μmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (6.92 mg, 14.5 μmol) were added under the condition where nitrogen gas was introduced. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, dichloromethane:methanol=15:1) to obtain tert-butyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amino)phenyl)-1H-imidazol-2-yl)cyclohexyl)carbamate as a yellow solid compound (40.0 mg).

[1223] MS m/z (ESI): 625.3 [M+H].sup.+;

Step 6: Synthesis of N-[4-[2-(4-aminocyclohexyl)-1H-imidazol-5-yl]-3-cyclopropylsulfonyl-phenyl]-5-methyl-1H-pyrazol-3-amine

[1224] Tert-butyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amino)phenyl)-1H-imidazol-2-yl)cyclohexyl)carbamate (40.0 mg, 64.0 μmol) was dissolved in methanol (1 mL), and hydrochloric acid/dioxane (4M, 800 μL) was added. The reaction solution was stirred and reacted at 30° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure to obtain N-[4-[2-(4-aminocyclohexyl)-1H-imidazol-5-yl]-3-cyclopropylsulfonyl-phenyl]-5-methyl-1H-pyrazol-3-amine as a yellow solid (30.0 mg).

[1225] MS m/z (ESI): 441.1 [M+H].sup.+;

Step 7: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)-1H-imidazol-2-yl)cyclohexylcarbamate

[1226] N-[4-[2-(4-aminocyclohexyl)-1H-imidazol-5-yl]-3-cyclopropylsulfonyl-phenyl]-5-methyl-1H-pyrazol-3-amine (24.0 mg, 54.5 μmol) was dissolved in dichloromethane (1 mL), and then a solution of isopropyl chloroformate (4.01 mg, 32.7 μmol) and N,N-diisopropylethylamine (35.2 mg, 272 μmol) in dichloromethane (2 mL) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was filtered and concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (20% to 40%) as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)-1H-imidazol-2-yl)cyclohexylcarbamate as a white solid compound (2.11 mg).

[1227] MS m/z (ESI): 527.0 [M+H].sup.+;

[1228] .sup.1H NMR (400 MHz, DMSO-d6) δ 12.25-11.05 (m, 2H), 8.88-8.65 (m, 1H), 8.76 (br s, 1H), 8.15 (s, 1H), 8.21-8.11 (m, 1H), 7.97 (br s, 1H), 8.02-7.90 (m, 1H), 7.58 (br d, J=7.0 Hz, 1H), 7.46 (br s, 1H), 7.51-7.36 (m, 1H), 7.19 (br s, 1H), 6.97 (br d, J=7.9 Hz, 1H), 5.60 (s, 1H), 4.73 (td, J=6.2, 12.5 Hz, 1H), 3.29-3.28 (m, 1H), 2.99 (br s, 1H), 2.70-2.52 (m, 2H), 2.19 (s, 3H), 2.09-1.80 (m, 4H), 1.61-1.45 (m, 2H), 1.37-1.20 (m, 2H), 1.16-1.05 (m, 6H), 1.04-0.79 (m, 4H).

Examples 91 and 91-1: Synthesis of isopropyl trans-(4-(2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-5-yl)cyclohexyl)carbamate and isopropyl cis-(4-(2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-5-yl) cyclohexyl)carbamate

[1229] ##STR00325##

Synthetic Method

[1230] ##STR00326##

Step 1: Synthesis of N-(4-(5-bromothiazol-2-yl)-3-(cyclopropylsulfonyl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine

[1231] N-[3-cyclopropylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-amine (1.00 g, 2.05 mmol) and 2,5-dibromothiazole (1.25 g, 5.13 mmol) were dissolved in dioxane (30 mL). Thereafter, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (167 mg, 205 μmol) and sodium carbonate (2M, 6 mL) were added under the condition where nitrogen gas was introduced. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran=2:1) to obtain N-(4-(5-bromothiazol-2-yl)-3-(cyclopropylsulfonyl) phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine as a yellow solid compound (220 mg).

[1232] MS m/z (ESI): 523.0; 525.0 [M+H].sup.+;

Step 2: Synthesis of tert-butyl (4-(2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-5-yl)cyclohex-3-en-1-yl)carbamate

[1233] N-(4-(5-bromothiazol-2-yl)-3-(cyclopropylsulfonyl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (150 mg, 286 μmol) and tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate (111 mg, 344 μmol) were dissolved in dioxane (5 mL). Thereafter, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (23.4 mg, 28.7 μmol) and sodium carbonate (2M, 1 mL) were added under the condition where nitrogen gas was introduced. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, petroleum ether:tetrahydrofuran=1:1) to obtain tert-butyl (4-(2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) amino)phenyl)thiazol-5-yl)cyclohex-3-en-1-yl)carbamate as a yellow solid compound (126 mg).

[1234] MS m/z (ESI): 640.5 [M+H].sup.+;

Step 3: Synthesis of tert-butyl (4-(2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-5-yl)cyclohexyl)carbamate

[1235] Tert-butyl (4-(2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-5-yl)cyclohex-3-en-1-yl)carbamate (100 mg, 156 μmol) was dissolved in methanol (4 mL), and then Pd/C (20 mg, 156 μmol) was added into the reaction solution. The reaction solution was purged three times with hydrogen gas. The reaction solution was pressurized by using a hydrogen balloon (15 psi), and was stirred and reacted at 30° C. for 16 hours. The completion of the reaction was detected by LCMS. The resultant was filtered and concentrated to dryness under reduced pressure to obtain tert-butyl (4-(2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) amino)phenyl)thiazol-5-yl)cyclohexyl)carbamate as a yellow solid product (75.0 mg).

[1236] MS m/z (ESI): 642.3 [M+H].sup.+;

Step 4: Synthesis of N-(4-(5-(4-aminocyclohexyl)thiazol-2-yl)-3-(cyclopropylsulfonyl) phenyl)-5-methyl-1H-pyrazol-3-amine

[1237] Tert-butyl (4-(2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-5-yl)cyclohexyl)carbamate (70.0 mg, 109 μmol) was dissolved in methanol (3 mL), and then hydrochloric acid/methanol (4M, 600 μL) was added into the reaction solution. The reaction solution was stirred and reacted at 30° C. for 16 hours. The completion of the reaction was detected by LCMS. The resultant was filtered and concentrated to dryness under reduced pressure to obtain N-(4-(5-(4-aminocyclohexyl)thiazol-2-yl)-3-(cyclopropylsulfonyl)phenyl)-5-methyl-1H-pyrazol-3-amine as a yellow oily product (53.0 mg).

[1238] MS m/z (ESI): 458.1 [M+H].sup.+;

Step 5: Synthesis of isopropyl (4-(2-(2-(2-(cyclopropylsulfonyl))-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-5-yl)cyclohexyl)carbamate

[1239] N-(4-(5-(4-aminocyclohexyl)thiazol-2-yl)-3-(cyclopropylsulfonyl)phenyl)-5-methyl-1H-pyrazol-3-amine (53.0 mg, 116 μmol) was dissolved in dichloromethane (2 mL), and then a solution of isopropyl chloroformate (9.94 mg, 81.1 μmol) and N,N-diisopropylethylamine (74.8 mg, 579 μmol) in dichloromethane (2 mL) was added. The reaction solution was stirred and reacted at 30° C. for 16 hours. The completion of the reaction was detected by LCMS. The resultant was filtered, concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (Phenomenex Gemini C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (40% to 60%) as eluents) to obtain isopropyl (4-(2-(2-(2-(cyclopropylsulfonyl))-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-5-yl) cyclohexyl)carbamate as a white solid compound (23.0 mg).

[1240] MS m/z (ESI): 544.2 [M+H].sup.+;

Step 6: Synthesis of isopropyl trans-(4-(2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-5-yl)cyclohexyl)carbamate and isopropyl cis-(4-(2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-5-yl)cyclohexyl) carbamate

[1241] Isopropyl (4-(2-(2-(2-(cyclopropylsulfonyl))-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl) thiazol-5-yl)cyclohexyl)carbamate (23.0 mg) as a racemic compound was separated by supercritical fluid chromatography (DAICEL CHIRALPAK AS column, 10 μm silica, 30 mm in diameter, 250 mm in length) (using polar mixtures of water (containing 0.1% aqueous ammonia) and ethanol (35% to 35%) as eluents) to obtain a pair of enantiomers (4.52 mg, retention time on chromatogram: 4.396 minutes, named as Compound of Example 91) and another pair of enantiomers (5.17 mg, retention time on chromatogram: 4.092 minutes, named as Compound of Example 91-1).

[1242] MS m/z (ESI): 544.0 [M+H].sup.+;

[1243] .sup.1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.12 (s, 1H), 8.01 (d, J=2.3 Hz, 1H), 7.69 (dd, J=2.3, 8.5 Hz, 1H), 7.62 (s, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.18 (br d, J=6.8 Hz, 1H), 5.65 (s, 1H), 4.77-4.71 (m, 1H), 3.75-3.57 (m, 2H), 3.09-2.94 (m, 1H), 2.20 (s, 3H), 2.05-1.94 (m, 1H), 1.92-1.73 (m, 4H), 1.73-1.55 (m, 4H), 1.17-1.06 (m, 6H), 1.11-0.99 (m, 4H).

[1244] .sup.1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.12 (s, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.71-7.65 (m, 1H), 7.61 (s, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.01 (br d, J=7.8 Hz, 1H), 5.64 (s, 1H), 4.77-4.71 (m, 1H), 3.74-3.62 (m, 1H), 3.26 (s, 1H), 2.86 (br t, J=12.2 Hz, 1H), 2.20 (s, 3H), 2.05 (br d, J=11.3 Hz, 2H), 1.90 (br d, J=10.5 Hz, 2H), 1.60-1.43 (m, 2H), 1.40-1.27 (m, 2H), 1.16-1.05 (m, 6H), 1.11-0.99 (m, 4H).

Example 92: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1245] ##STR00327##

Synthetic Method

[1246] ##STR00328##

Step 1: Synthesis of 3 (oxetan-3 ylsulfanyl)aniline

[1247] 3-Aminothiophenol (1 g, 7.99 mmol) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (1.10 g, 7.99 mmol) and 3-bromooxetane (1.42 g, 10.4 mmol) were added. The reaction solution was stirred and reacted at 120° C. for 24 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=1:1) to obtain 3-(oxetan-3-ylsulfanyl)aniline (400 mg).

[1248] MS m/z (ESI): 182.1 [M+H].sup.+;

Step 2: Synthesis of tert-butyl N-(3-cyclopropylsulfanylphenyl)carbamate

[1249] 3-(Oxetan-3-ylsulfanyl)aniline (400 mg, 2.21 mmol) was dissolved in methanol (5 mL), and di-tert-butyl dicarbonate (4.82 g, 22.1 mmol, 5.07 mL) was added. The reaction solution was stirred and reacted at 25° C. for 16 hours. The completion of the reaction was detected by LCMS. Aqueous ammonia (20 mL) was added into the reaction solution. The reaction solution was stirred and reacted at 0° C. for 2 hours. The reaction solution was extracted with dichloromethane (20 mL) three times. The organic phase was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=20:1) to obtain tert-butyl N-(3-cyclopropylsulfanylphenyl)carbamate (400 mg).

[1250] MS m/z (ESI): 226.0 [M+H-t-Bu].sup.+;

Step 3: Synthesis of tert-butyl N-[4-bromo-3-(oxetan-3-ylsulfanyl)phenyl]carbamate

[1251] Tert-butyl N-(3-cyclopropylsulfanylphenyl)carbamate (350 mg, 1.24 mmol) was dissolved in dichloromethane (5 mL), and then a solution of N-bromosuccinimide (243.54 mg, 1.37 mmol) in dichloromethane (5 mL) was slowly added dropwise into the reaction solution at −30° C. The reaction solution was stirred and reacted at 25° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:ethyl acetate=10:1) to obtain tert-butyl N-[4-bromo-3-(oxetan-3-ylsulfanyl)phenyl]carbamate as a white solid (250 mg).

[1252] MS m/z (ESI): 304.0, 306.0 [M+H-t-Bu].sup.+;

[1253] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.53 (s, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.30 (dd, J=2.3, 8.5 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 5.09 (t, J=6.7 Hz, 2H), 4.57-4.45 (m, 3H), 1.48 (s, 9H).

Step 4: Synthesis of tert-butyl N-[4-bromo-3-(oxetan-3-ylsulfonyl)phenyl]carbamate

[1254] Tert-butyl N-[4-bromo-3-(oxetan-3-ylsulfanyl)phenyl]carbamate (250 mg, 694 μmol) was dissolved in dichloromethane (5 mL), and m-chloroperoxybenzoic acid (479 mg, 2.78 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with saturated sodium carbonate solution (30 mL), and extracted with 90 mL of dichloromethane (30 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate=3:1) to obtain tert-butyl N-[4-bromo-3-(oxetan-3-ylsulfonyl)phenyl]carbamate as the product (150 mg).

[1255] MS m/z (ESI): 336.0, 338.0 [M+H-t-Bu].sup.+;

Step 5: Synthesis of tert-butyl N-[3-(oxetan-3-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[1256] Tert-butyl N-[4-bromo-3-(oxetan-3-ylsulfonyl)phenyl]carbamate (150 mg, 382 μmol) and bis(pinacolato)diboron (388 mg, 1.53 mmol) were dissolved in tetrahydrofuran (2 mL). Under the protection of nitrogen, dichlorobis[di-tert-butyl-(4-dimethylaminophenyl) phosphine]palladium (II) (27.1 mg, 38.2 μmol) and potassium acetate (75.1 mg, 765 μmol) were added. The reaction solution was stirred and reacted at 80° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate=3:1) to obtain tert-butyl N-[3-(oxetan-3-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate as a yellow substance (130 mg).

[1257] MS m/z (ESI): 438.1 [M+H].sup.+;

Step 6: Synthesis of isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1258] Tert-butyl N-[3-(oxetan-3-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]carbamate (127 mg, 288 μmol) and isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (100 mg, 288 μmol) were dissolved in water (0.5 mL) and dioxane (5 mL). Thereafter, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (23.5 mg, 28.8 μmol) and sodium carbonate (61.1 mg, 576 μmol) were added under the condition where nitrogen gas was introduced. The reaction solution was stirred and reacted at 80° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, petroleum ether:tetrahydrofuran=3:1) to obtain isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate as a white substance (80 mg).

[1259] MS m/z (ESI): 580.2 [M+H].sup.+;

Step 7: Synthesis of isopropyl trans-N-[4-[5-[4-amino-2-(oxetan-3-ylsulfonyl)phenyl] thiazol-2-yl]cyclohexyl]carbamate

[1260] Isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(oxetan-3-ylsulfonyl)phenyl] thiazol-2-yl]cyclohexyl]carbamate (80 mg) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (616 mg, 5.40 mmol, 400 μL) was added. The reaction solution was stirred and reacted at 25° C. for 3 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with 5 mL of saturated sodium carbonate solution and 9 mL of dichloromethane (3 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain isopropyl trans-N-[4-[5-[4-amino-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate as a white solid compound (60.0 mg).

[1261] MS m/z (ESI): 480.2 [M+H].sup.+;

Step 8: Synthesis of isopropyl trans-N-[4-[5-[4-bromo-2-(oxetan-3-ylsulfonyl) phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1262] Isopropyl trans-N-[4-[5-[4-amino-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate (50 mg, 104 μmol) was dissolved in acetonitrile (2 mL), and tert-butyl nitrite (32.3 mg, 313 μmol, 37 μL) was added at −30° C. The reaction solution was stirred and reacted at 25° C. for 1 hour. Cuprous bromide (37.39 mg, 260.63 μmol) was added into the reaction solution at −30° C. The reaction solution was stirred and reacted at 25° C. for 15 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with 50 mL of saturated ammonium chloride solution and 90 mL of dichloromethane (30 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, petroleum ether:tetrahydrofuran=2:1) to obtain isopropyl trans-N-[4-[5-[4-bromo-2-(oxetan-3-ylsulfonyl) phenyl]thiazol-2-yl]cyclohexyl]carbamate as a yellow substance (30.0 mg).

[1263] MS m/z (ESI): 543.1, 545.1 [M+H].sup.+;

Step 9: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1264] Isopropyl trans-N-[4-[5-[4-bromo-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate (25.0 mg, 46.0 μmol) and 5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-amine (9.17 mg, 50.6 μmol) were dissolved in tetrahydrofuran (2 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (4.17 mg, 4.60 μmol) and potassium acetate (9.03 mg, 92.0 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by thin-layer chromatography (silica, petroleum ether:tetrahydrofuran=2:1) to obtain isopropyl trans-N-[4-[5-[4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate as a white solid compound (25.0 mg).

[1265] MS m/z (ESI): 644.4 [M+H].sup.+;

Step 10: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1266] Isopropyl trans-N-[4-[5-[4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (25.0 mg, 38.8 μmol) was dissolved in methanol (1 mL), and p-toluenesulfonic acid monohydrate (33.4 mg, 194 μmol) was added. The reaction solution was stirred and reacted at 50° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with 9 mL of dichloromethane (3 mL×3) and 5 mL of a saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, dichloromethane/methanol=15/1) to obtain the compound isopropyl trans-N-[4-[5-[4-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (2.36 mg).

[1267] MS m/z (ESI): 560.0 [M+H].sup.+;

[1268] .sup.1H NMR (400 MHz, DMSO-d6) δ=11.92 (br s, 1H), 9.14 (s, 1H), 8.19 (br s, 1H), 7.63 (d, J=5.4 Hz, 2H), 7.33 (d, J=8.3 Hz, 1H), 7.04 (br d, J=8.0 Hz, 1H), 5.65 (s, 1H), 4.78-4.70 (m, 1H), 4.67-4.60 (m, 2H), 4.55-4.48 (m, 3H), 3.33 (br s, 1H), 2.92 (s, 1H), 2.21 (s, 3H), 2.13 (br d, J=11.8 Hz, 2H), 1.92 (br d, J=10.8 Hz, 2H), 1.56 (br dd, J=2.3, 12.5 Hz, 2H), 1.40-1.28 (m, 2H), 1.17 (d, J=6.3 Hz, 6H).

Example 93: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((6-methoxypyridin-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1269] ##STR00329##

Synthetic Method

[1270] ##STR00330##

[1271] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (30 mg, 56.9 μmol) and 2-methoxy-5-aminopyridine (8.47 mg, 68.3 μmol) were dissolved in tetrahydrofuran (3 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (5.16 mg, 5.69 μmol) and potassium acetate (5.58 mg, 56.9 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by preparative liquid chromatography (Boston Prime column, 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((6-methoxypyridin-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid product (10.95 mg).

[1272] MS m/z (ESI): 571.2 [M+H].sup.+;

[1273] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.66 (s, 1H), 8.07 (d, J=2.6 Hz, 1H), 7.65 (s, 1H), 7.62 (dd, J=2.8, 8.8 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.10 (dd, J=2.6, 8.4 Hz, 1H), 7.05-6.99 (m, 1H), 6.87 (d, J=8.8 Hz, 1H), 4.81-4.68 (m, 1H), 3.85 (s, 3H), 2.97-2.87 (m, 1H), 2.45-2.35 (m, 1H), 2.13 (br d, J=12.8 Hz, 2H), 1.92 (br d, J=10.0 Hz, 2H), 1.63-1.50 (m, 2H), 1.40-1.27 (m, 2H), 1.17 (d, J=6.3 Hz, 6H), 1.00-0.92 (m, 2H), 0.90-0.83 (m, 2H).

Examples 94 and 94-1: Synthesis of isopropyl trans-(4-(5-(2-((S)-cyclopropanesulfonimidoyl))-4-(6-methoxypyridin-3-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate and isopropyl trans-((4-(5-(2-((R)-cyclopropanesulfonimidoyl))-4-(6-methoxypyridin-3-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1274] ##STR00331##

Synthetic Method

[1275] ##STR00332##

Step 1: Synthesis of isopropyl trans-(4-(5-(4-bromo-2-(cyclopropanesulfonimidoyl) phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1276] Isopropyl trans-((4-(5-(4-bromo-2-(cyclopropylthio)phenyl)thiazol-2-yl)cyclohexyl) carbamate (850 mg, 1.72 mmol) was dissolved in a solution of ammonia in methanol (61 mL), and diacetoxyiodobenzene (8.29 g, 25.7 mmol) was added. The reaction solution was stirred and reacted at −20° C. for 0.5 hours, and then slowly warmed to 30° C. at which the reaction solution was stirred and reacted for 0.5 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=0:1) to obtain isopropyl trans-(4-(5-(4-bromo-2-(cyclopropanesulfonimidoyl)phenyl)thiazol-2-yl) cyclohexyl)carbamate as a white solid product (547 mg).

[1277] MS m/z (ESI): 526.2; 528.2 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-((6-methoxypyridin-3-yl)amino)phenyl]thiazol-2-yl)cyclohexyl)carbamate

[1278] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropanesulfonimidoyl)phenyl)thiazol-2-yl) cyclohexyl)carbamate (547 mg, 1.04 mmol) and 6-methoxypyridin-3-amine (194 mg, 1.56 mmol) were dissolved in a tetrahydrofuran solution (20 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (94.2 mg, 104 μmol) and potassium acetate (305 mg, 3.12 mmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by L CMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=0:1) to obtain isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-((6-methoxypyridin-3-yl)amino) phenyl]thiazol-2-yl)cyclohexyl)carbamate as a yellow solid product (450 mg).

[1279] MS m/z (ESI): 569.9 [M+H].sup.+;

Step 3: Synthesis of isopropyl trans-(4-(5-(2-((S)-cyclopropanesulfonimidoyl))-4-(6-methoxypyridin-3-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate and isopropyl trans-((4-(5-(2-((R)-cyclopropanesulfonimidoyl))-4-(6-methoxypyridin-3-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1280] Isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-((6-methoxypyridin-3-yl)amino) phenyl]thiazol-2-yl)cyclohexyl)carbamate (450 mg) as a racemic compound was separated by supercritical fluid chromatography (DAICEL CHIRALCEL OD-H column, 5 μm silica, 30 mm in diameter, 250 mm in length) (using polar mixtures of water (containing 0.1% aqueous ammonia) and ethanol (50% to 50%) as eluents) to obtain a pair of enantiomers (207.40 mg, retention time on chromatogram: 5.708 minutes, named as Compound of Example 94) and another pair of enantiomers (210.80 mg, retention time on chromatogram: 6.506 minutes, named as Compound of Example 94-1).

Example 94

[1281] MS m/z (ESI): 570.1 [M+H].sup.+;

[1282] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.05 (d, J=2.8 Hz, 1H), 7.66 (s, 1H), 7.61-7.56 (m, 2H), 7.24 (d, J=8.3 Hz, 1H), 7.08-6.96 (m, 2H), 6.84 (d, J=8.8 Hz, 1H), 4.74 (td, J=6.2, 12.4 Hz, 1H), 4.29 (br s, 1H), 3.83 (s, 3H), 3.31-3.25 (m, 1H), 2.89 (tt, J=3.5, 11.9 Hz, 1H), 2.31-2.24 (m, 1H), 2.12 (br d, J=11.7 Hz, 2H), 1.96-1.86 (m, 2H), 1.62-1.48 (m, 2H), 1.40-1.26 (m, 2H), 1.16-1.05 (m, 6H), 0.91-0.75 (m, 4H).

Example 94-1

[1283] MS m/z (ESI): 570.1 [M+H].sup.+;

[1284] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.05 (d, J=2.8 Hz, 1H), 7.66 (s, 1H), 7.62-7.55 (m, 2H), 7.24 (d, J=8.3 Hz, 1H), 7.07-6.97 (m, 2H), 6.84 (d, J=8.8 Hz, 1H), 4.74 (td, J=6.2, 12.5 Hz, 1H), 4.28 (br s, 1H), 3.83 (s, 3H), 3.24 (br s, 1H), 2.89 (tt, J=3.4, 11.9 Hz, 1H), 2.30-2.22 (m, 1H), 2.12 (br d, J=11.6 Hz, 2H), 1.98-1.84 (m, 2H), 1.62-1.48 (m, 2H), 1.39-1.26 (m, 2H), 1.16-1.05 (m, 6H), 0.92-0.72 (m, 4H).

Example 95: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-((6-oxo-1,6-dihydropyridin-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1285] ##STR00333##

Synthetic Method

[1286] ##STR00334##

Step 1: Synthesis of isopropyl trans-(4-(5-(4-bromo-2-(cyclopropanesulfonimidoyl) phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1287] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylthio)phenyl)thiazol-2-yl)cyclohexyl) carbamate (200 mg, 403 μmol) was dissolved in a solution of ammonia in methanol (9 mL), and diacetoxyiodobenzene (1.95 g, 6.05 mmol) was added. The reaction solution was stirred and reacted at −30° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=1:1) to obtain isopropyl trans-(4-(5-(4-bromo-2-(cyclopropanesulfonimidoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a yellow solid compound (140 mg).

[1288] MS m/z (ESI): 527.8 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-((6-oxo-1,6-dihydropyridin-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1289] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropanesulfonimidoyl)phenyl)thiazol-2-yl) cyclohexyl)carbamate and 5-amino-2-hydroxypyridine (14.6 mg, 133 μmol) were dissolved in tetrahydrofuran (3 mL), and potassium acetate (39.1 mg, 399 μmol) and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (12.0 mg, 13.3 μmol) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Phenomenex Gemini-NX column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (33% to 53%) as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-((6-oxo-1,6-dihydropyridin-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a yellow solid compound (23.6 mg).

[1290] MS m/z (ESI): 556.0 [M+H].sup.+;

[1291] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.11 (s, 1H), 7.64 (s, 1H), 7.45-7.35 (m, 2H), 7.29 (br s, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.03 (br d, J=7.5 Hz, 1H), 6.81 (dd, J=2.5, 8.3 Hz, 1H), 6.40 (d, J=9.5 Hz, 1H), 4.74 (td, J=6.2, 12.5 Hz, 1H), 4.26 (br s, 1H), 3.31-3.29 (m, 1H), 2.88 (br t, J=12.0 Hz, 1H), 2.28-2.18 (m, 1H), 2.11 (br d, J=11.5 Hz, 2H), 1.90 (br d, J=10.8 Hz, 2H), 1.61-1.47 (m, 2H), 1.40-1.24 (m, 2H), 1.16-1.05 (m, 6H), 0.89-0.73 (m, 4H).

Example 96: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((6-oxo-1,6-dihydropyridin-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1292] ##STR00335##

Synthetic Method

[1293] ##STR00336##

[1294] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (50.0 mg, 94.8 μmol) and 5-amino-2-hydroxypyridine (15.7 mg, 142 μmol) were dissolved in tetrahydrofuran (5 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8.59 mg, 9.48 μmol) and cesium carbonate (92.7 mg, 284 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (33% to 53%) as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((6-oxo-1,6-dihydropyridin-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (2.50 mg).

[1295] MS m/z (ESI): 557.0 [M+H].sup.+;

[1296] .sup.1H NMR (400 MHz, DMSO-d6) δ 11.83-11.16 (m, 1H), 11.83-11.16 (m, 1H), 8.20 (s, 1H), 7.69-7.56 (m, 1H), 7.41 (dd, J=2.9, 9.6 Hz, 1H), 7.35-7.26 (m, 3H), 7.02 (br d, J=7.7 Hz, 1H), 6.90 (dd, J=2.6, 8.4 Hz, 1H), 6.41 (d, J=9.5 Hz, 1H), 4.74 (td, J=6.3, 12.4 Hz, 1H), 3.32 (d, J=1.7 Hz, 1H), 2.91 (tt, J=3.3, 11.8 Hz, 1H), 2.40-2.31 (m, 1H), 2.12 (br d, J=11.6 Hz, 2H), 1.90 (br d, J=10.3 Hz, 2H), 1.63-1.48 (m, 2H), 1.41-1.26 (m, 2H), 1.16-1.05 (m, 6H), 0.99-0.80 (m, 4H).

Example 97: Synthesis of isopropyl trans-(4-(5-(4-((5-methyl-1H-pyrazol-3-yl)amino)-2-(N-methylcyclopropanesulfonimidoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1297] ##STR00337##

Synthetic Method

[1298] ##STR00338##

[1299] Isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-((5-methyl-1H-pyrazol-3-yl) amino)phenyl]thiazol-2-yl)cyclohexyl)carbamate (50.0 mg, 92.2 μmol) was dissolved in anhydrous dioxane (3 mL), and anhydrous copper acetate (1.67 mg, 9.35 μmol) and cesium carbonate (60.1 mg, 184 μmol) were added. The reaction solution was stirred and reacted at 25° C. for 5 minutes. Methylboronic acid (6.6 mg, 111 μmol) was added into the reaction solution. The reaction solution was stirred and reacted at 50° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered, concentrated to dryness, added with a saturated ammonium chloride solution (10 mL), and extracted with ethyl acetate (30 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative high-performance liquid chromatography (YMC-Actus Triart column, 5 μm silica, 30 mm in diameter, 150 mm in length) (using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia and 10 mmol of ammonium bicarbonate) and acetonitrile (40% to 60%) as eluents) and lyophilized to obtain isopropyl trans-(4-(5-(4-((5-methyl-1H-pyrazol-3-yl)amino)-2-(N-methylcyclopropanesulfonimidoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (2.01 mg).

[1300] MS m/z (ESI): 557.0 [M+H].sup.+;

[1301] .sup.1H NMR (400 MHz, DMSO-d6) δ=11.80 (br s, 1H), 8.93 (s, 1H), 7.91 (s, 1H), 7.70-7.48 (m, 2H), 7.24 (d, J=8.6 Hz, 1H), 7.00 (br d, J=7.8 Hz, 1H), 5.58 (s, 1H), 4.70 (td, J=6.3, 12.3 Hz, 1H), 3.30-3.29 (m, 3H), 3.28-3.24 (m, 1H), 2.86 (br t, J=12.0 Hz, 1H), 2.16 (s, 4H), 2.13-2.03 (m, 2H), 1.87 (br d, J=11.0 Hz, 2H), 1.60-1.43 (m, 2H), 1.38-1.22 (m, 2H), 1.13-1.11 (m, 6H), 1.06 (br dd, J=6.5, 10.6 Hz, 1H), 1.00-0.89 (m, 1H), 0.79-0.69 (m, 1H), 0.65-0.51 (m, 1H).

Example 98: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-((1,3-dimethyl-1H-pyrazol-5-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1302] ##STR00339##

Synthetic Method

[1303] ##STR00340##

Step 1: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylthio)-4-((1,3-dimethyl-1H-pyrazol-5-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1304] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylthio)phenyl)thiazol-2-yl)cyclohexyl) carbamate (200 mg, 404 μmol) and 1,3-dimethyl-1H-pyrazol-5-amine (67.3 mg, 605 μmol) were dissolved in tetrahydrofuran (6 mL), and potassium acetate (119 mg, 1.21 mmol) and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (36.6 mg, 40.4 μmol) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:ethyl acetate=1:2) to obtain isopropyl trans-(4-(5-(2-(cyclopropylthio)-4-((1,3-dimethyl-1H-pyrazol-5-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a yellow solid compound (120 mg).

Step 2: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-((1,3-dimethyl-1H-pyrazol-5-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1305] Isopropyl trans-(4-(5-(2-(cyclopropylthio)-4-((1,3-dimethyl-1H-pyrazol-5-yl)amino) phenyl)thiazol-2-yl)cyclohexyl)carbamate (120 mg, 228 μmol) was dissolved in a solution of ammonia in methanol (7M, 6 mL), and diacetoxyiodobenzene (1.10 g, 3.42 mmol) was added. The reaction solution was stirred and reacted at −30° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=1:2) to obtain a yellow solid, which was purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (30% to 50%) as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-((1,3-dimethyl-1H-pyrazol-5-yl)amino)phenyl)thiazol-2-yl) cyclohexyl)carbamate as a yellow solid compound (1.29 mg).

[1306] MS m/z (ESI): 557.0 [M+H].sup.+;

[1307] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.57 (s, 1H), 7.66 (s, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.05-6.94 (m, 2H), 5.88 (s, 1H), 4.82-4.65 (m, 1H), 4.32 (s, 1H), 3.62 (s, 3H), 3.21 (br s, 1H), 2.91-2.86 (m, 1H), 2.28-2.22 (m, 1H), 2.16-2.05 (m, 5H), 1.90 (br d, J=10.1 Hz, 2H), 1.61-1.48 (m, 2H), 1.38-1.28 (m, 2H), 1.16-1.05 (m, 6H), 0.89-0.76 (m, 4H).

Example 99: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-(oxazol-2-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1308] ##STR00341##

Synthetic Method

[1309] ##STR00342##

[1310] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropanesulfonimidoyl)phenyl)thiazol-2-yl) cyclohexyl)carbamate (70.0 mg, 132 μmol) and oxazol-2-amine (12.3 mg, 146 μmol) were dissolved in tetrahydrofuran (3 mL), and potassium acetate (39.1 mg, 398 μmol) and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (12.0 mg, 13.3 μmol) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Phenomenex Gemini-NX column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (33% to 53%) as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclopropanesulfonimidoyl)-4-(oxazol-2-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid (12.8 mg).

[1311] MS m/z (ESI): 530.0 [M+H].sup.+;

[1312] .sup.1H NMR (400 MHz, DMSO-d6) δ=10.62 (s, 1H), 8.34 (d, J=2.3 Hz, 1H), 7.91 (dd, J=2.4, 8.4 Hz, 1H), 7.74-7.69 (m, 2H), 7.41 (d, J=8.5 Hz, 1H), 7.09-6.99 (m, 2H), 4.74 (td, J=6.1, 12.4 Hz, 1H), 4.38 (s, 1H), 3.28 (br s, 1H), 2.96-2.86 (m, 1H), 2.32-2.23 (m, 1H), 2.13 (br d, J=12.3 Hz, 2H), 1.91 (br d, J=9.8 Hz, 2H), 1.81 (d, J=13.6 Hz, 1H), 1.63-1.48 (m, 2H), 1.40-1.26 (m, 2H), 1.16-1.05 (d, J=6.0 Hz, 6H), 0.96-0.75 (m, 4H).

Example 100: Synthesis of isopropyl trans-(4-(5-(4-((1,3,4-oxadiazol-2-yl)amino)-2-(cyclopropanesulfonimidoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1313] ##STR00343##

Synthetic Method

[1314] ##STR00344##

Step 1: Synthesis of isopropyl trans-(4-(5-(4-((1,3,4-oxadiazol-2-yl)amino)-2-(cyclopropylthio)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1315] Isopropyl trans-(4-(5-(4-bromo-2-(cyclopropylthio)phenyl)thiazol-2-yl)cyclohexyl) carbamate (90.0 mg, 182 μmol) and 1,3,4-oxadiazol-2-amine (23.2 mg, 272 μmol) were dissolved in tetrahydrofuran (5 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (16.5 mg, 18.2 μmol) and potassium acetate (53.5 mg, 545 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by thin-layer chromatography (silica, dichloromethane:methanol=15:1) to obtain isopropyl trans-(4-(5-(4-((1,3,4-oxadiazol-2-yl)amino)-2-(cyclopropylthio)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid product (51.0 mg).

[1316] MS m/z (ESI): 537.4 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-(4-(5-(4-((1,3,4-oxadiazol-2-yl)amino)-2-(cyclopropanesulfonimidoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1317] Isopropyl trans-(4-(5-(4-((1,3,4-oxadiazol-2-yl)amino)-2-(cyclopropylthio)phenyl)thiazol-2-yl)cyclohexyl)carbamate (25.0 mg, 50.0 μmol) was dissolved in a solution of ammonia in methanol (1.25 mL), and diacetoxyiodobenzene (242 mg, 751 μmol) was added. The reaction solution was stirred and reacted at −20° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by preparative liquid chromatography (Phenomenex Gemini-NX column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile as eluents) to obtain isopropyl trans-(4-(5-(4-((1,3,4-oxadiazol-2-yl)amino)-2-(cyclopropanesulfonimidoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (2.18 mg).

[1318] MS m/z (ESI): 531.0 [M+H].sup.+;

[1319] .sup.1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.81 (s, 1H), 8.33 (d, J=2.4 Hz, 1H), 7.88 (dd, J=2.4, 8.4 Hz, 1H), 7.73 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.01 (br d, J=7.8 Hz, 1H), 4.74 (td, J=6.2, 12.5 Hz, 1H), 4.43 (br s, 1H), 3.22-3.09 (m, 1H), 2.92 (ddd, J=3.3, 8.4, 11.9 Hz, 1H), 2.34-2.25 (m, 1H), 2.13 (br d, J=11.6 Hz, 2H), 1.91 (br d, J=10.8 Hz, 2H), 1.66-1.47 (m, 2H), 1.43-1.26 (m, 2H), 1.16-1.05 (m, 6H), 0.98-0.71 (m, 4H).

Example 101: Synthesis of isopropyl trans-(4-(5-(2-(cyclobutanesulfonimidoyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl]thiazol-2-yl)cyclohexyl)carbamate

[1320] ##STR00345##

Synthetic Method

[1321] ##STR00346##

Step 1: Synthesis of 3-(cyclobutylthio)aniline

[1322] 3-Aminothiophenol (15.0 g, 119 mmol), triphenylmethanethiol (993 mg, 3.59 mmol) and potassium carbonate (49.6 g, 359 mmol) were dissolved in N,N-dimethylformamide (150 mL), and cyclobutyl bromide (24.2 g, 179 mmol) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 120° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with water (500 mL), and extracted with ethyl acetate (300 mL) three times. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. Thereafter, the resultant was purified by column chromatography (petroleum ether:ethyl acetate=4:1) to obtain the compound 3-(cyclobutylthio)aniline (18.0 g) as a red oily liquid.

[1323] MS m/z (ESI): 180.1 [M+H].sup.+;

Step 2: Synthesis of tert-butyl (3-(cyclobutylthio)phenyl)carbamate

[1324] 3-(Cyclobutylthio)aniline (32.0 g, 178 mmol) was dissolved in anhydrous methanol (500 mL), and BOC anhydride (389 g, 1.78 mol) was added. The reaction solution appeared as a yellow solution, and was stirred and reacted at 30° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was added with dichloromethane (1 L), and the pH of the resulting mixture was adjusted to 10 with aqueous ammonia. The organic layer was washed with saturated saline (1 L), dried over anhydrous magnesium sulfate, and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure to obtain the compound tert-butyl (3-(cyclobutylthio)phenyl)carbamate (120 g, crude product) as a yellow oily liquid.

[1325] MS m/z (ESI): 224.1 [M+H-t-Bu].sup.+;

Step 3: Synthesis of tert-butyl (4-bromo-3-(cyclobutylthio)phenyl)carbamate

[1326] Tert-butyl (3-(cyclobutylthio)phenyl)carbamate (120 g, 171 mmol, 40% purity) was dissolved in anhydrous dichloromethane (1 L), and a suspension of N-bromosuccinimide (389 g, 1.78 mol) in dichloromethane (500 mL) was added at −30° C. The reaction solution appeared as a yellow solution, and was stirred and reacted at 20° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:ethyl acetate=100:1) to obtain the compound tert-butyl (4-bromo-3-(cyclobutylthio) phenyl)carbamate (120 g, crude product) as a white solid.

[1327] MS m/z (ESI): 358.1; 360.1 [M+H].sup.+;

Step 4: Synthesis of tert-butyl N-[3-cyclobutylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[1328] Tert-butyl (4-bromo-3-(cyclobutylthio)phenyl)carbamate (10.0 g, 27.9 mmol) and bis(pinacolato)diboron (28.3 g, 112 mmol) were dissolved in N,N-dimethylformamide (300 mL). Under nitrogen atmosphere, potassium acetate (8.22 g, 83.7 mmol) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium-dichloromethane (2.28 g, 2.79 mmol) were added. The reaction solution was stirred and reacted at 100° C. for 3 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=10:1) to obtain tert-butyl N-[3-cyclobutylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate as a yellow solid product (8.70 g).

[1329] MS m/z (ESI): 406.2 [M+H].sup.+;

[1330] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.52 (s, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.32-7.24 (m, 1H), 7.20-7.15 (m, 1H), 3.85-3.71 (m, 1H), 2.03-1.94 (m, 4H), 1.47 (s, 9H), 1.29 (s, 2H), 1.26 (s, 12H).

Step 5: Synthesis of isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-cyclobutylsulfanyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1331] Tert-butyl N-[3-cyclobutylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]carbamate (8.60 g, 22.0 mmol) and isopropyl trans-(4-(5-bromothiazol-2-yl) cyclohexyl)carbamate (7.63 g, 22.0 mmol) were dissolved in anhydrous dioxane (300 mL), and a saturated sodium carbonate solution (40 mL) was added. Under nitrogen atmosphere, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (1.79 g, 2.20 mmol) was added. The reaction solution was stirred and reacted at 100° C. for 10 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=1:3) to obtain isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-cyclobutylsulfanyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate as a yellow solid product (6.50 g).

[1332] MS m/z (ESI): 546.3[M+H].sup.+;

Step 6: Synthesis of isopropyl trans-N-[4-[5-(4-amino-2-cyclobutylsulfanyl-phenyl) thiazol-2-yl]cyclohexyl]carbamate

[1333] Isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-cyclobutylsulfanyl-phenyl] thiazol-2-yl]cyclohexyl]carbamate (6.50 g, 11.91 mmol) was dissolved in anhydrous methanol (100 mL), and hydrochloric acid/dioxane (4M, 100 mL) was added. The reaction solution was stirred and reacted at 30° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then extracted with dichloromethane (300 mL×3) and a saturated sodium carbonate solution. The organic phases were combined, dried, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain isopropyl trans-N-[4-[5-(4-amino-2-cyclobutylsulfanyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate as a brown oily product (4.00 g).

[1334] MS m/z (ESI): 446.2 [M+H].sup.+;

Step 7: Synthesis of isopropyl trans-N-[4-[5-(4-bromo-2-cyclobutylsulfanyl-phenyl) thiazol-2-yl]cyclohexyl]carbamate

[1335] Isopropyl trans-N-[4-[5-(4-amino-2-cyclobutylsulfanyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (3.90 g, 8.75 mmol) and tert-butyl nitrite (3.91 g, 37.89 mmol) were dissolved in acetonitrile (100 mL). Under nitrogen atmosphere, cuprous bromide (2.54 g, 17.7 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered. The filtrate was concentrated to dryness under reduced pressure and then extracted with ethyl acetate (400 mL×3) and a saturated aqueous ammonium chloride solution (400 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness via rotary evaporation, and then purified by column chromatography (silica, petroleum ether:ethyl acetate=1:1) to obtain isopropyl trans-N-[4-[5-(4-bromo-2-cyclobutylsulfanyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate as a brown solid product (1.00 g).

[1336] MS m/z (ESI): 509.1; 511.1 [M+H].sup.+;

Step 8: Synthesis of isopropyl trans-N-[4-[5-[4-bromo-2-(cyclobutylsulfonimidoyl) phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1337] Isopropyl trans-N-[4-[5-(4-bromo-2-cyclobutylsulfanyl-phenyl)thiazol-2-yl]cyclohexyl] carbamate (950 mg, 1.86 mmol) was dissolved in a solution of ammonia in methanol (7M, 66.6 mL), and diacetoxyiodobenzene (9.01 g, 27.97 mmol) was added. The reaction solution was stirred and reacted at −20° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=1:2) to obtain isopropyl trans-N-[4-[5-[4-bromo-2-(cyclobutylsulfonimidoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate as a brown oily product (1.00 g).

[1338] MS m/z (ESI): 540.0; 542.0 [M+H].sup.+;

Step 9: Synthesis of isopropyl N-[4-[5-[2-(cyclobutylsulfonimidoyl)]-4-((5-methyl-1-tetrahydropyran-2-ylpyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1339] Isopropyl trans-N-[4-[5-[4-bromo-2-(cyclobutylsulfonimidoyl)phenyl]thiazol-2-yl] cyclohexyl]carbamate (100 mg, 555 μmol) was dissolved in anhydrous tetrahydrofuran (6 mL). Under nitrogen atmosphere, potassium acetate (108 mg, 1.11 mmol) and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (33.5 mg, 37.0 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 5 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=1:3) to obtain isopropyl N-[4-[5-[2-(cyclobutylsulfonimidoyl)]-4-((5-methyl-1-tetrahydropyran-2-ylpyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate as a brown solid product (130 mg).

[1340] MS m/z (ESI): 641.1[M+H].sup.+;

Step 10: Synthesis of isopropyl trans-(4-(5-(2-(cyclobutanesulfonimidoyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl]thiazol-2-yl)cyclohexyl)carbamate

[1341] Isopropyl N-[4-[5-[2-(cyclobutylsulfonimidoyl)]-4-((5-methyl-1-tetrahydropyran-2-ylpyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (130 mg, 203 μmol) was dissolved in anhydrous methanol (2 mL), and then hydrochloric acid/dioxane (4M, 2 mL) was added. The reaction solution was stirred and reacted at 30° C. for 5 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (40% to 60%) as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclobutanesulfonimidoyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl]thiazol-2-yl) cyclohexyl)carbamate as a white solid (43.8 mg).

[1342] MS m/z (ESI): 557.1 [M+H].sup.+;

[1343] .sup.1H NMR (400 MHz, DMSO-d6) δ=11.93-11.69 (m, 1H), 8.95 (s, 1H), 8.06 (d, J=2.1 Hz, 1H), 7.70-7.50 (m, 2H), 7.21 (d, J=8.4 Hz, 1H), 7.02 (br d, J=7.8 Hz, 1H), 5.64 (s, 1H), 4.75 (s, 1H), 4.16 (s, 1H), 3.60 (t, J=8.2 Hz, 1H), 3.32-3.26 (m, 1H), 2.90 (tt, J=3.4, 11.8 Hz, 1H), 2.35-2.26 (m, 1H), 2.20 (s, 3H), 2.18-2.09 (m, 3H), 2.01-1.74 (m, 6H), 1.63-1.48 (m, 2H), 1.41-1.27 (m, 2H), 1.17-1.06 (m, 6H).

Example 102: Synthesis of isopropyl trans-N-[4-[5-[2-(cyclobutylsulfonimidoyl)]-4-[[1-(2-fluoroethyl)pyrazol-4-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1344] ##STR00347##

Synthetic Method

[1345] ##STR00348##

[1346] Isopropyl trans-N-[4-[5-[4-bromo-2-(cyclobutylsulfonimidoyl)phenyl]thiazol-2-yl] cyclohexyl]carbamate (100 mg, 185 μmol) and 1-(2-fluoroethyl)pyrazol-4-amine (35.8 mg, 277 μmol) were dissolved in anhydrous tetrahydrofuran (3 mL). Under nitrogen atmosphere, potassium acetate (KOAc) (54.4 mg, 555 μmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (16.7 mg, 18.5 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 3 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (30% to 50%) as eluents) to obtain isopropyl trans-N-[4-[5-[2-(cyclobutylsulfonimidoyl)]-4-[[1-(2-fluoroethyl)pyrazol-4-yl]amino]phenyl]thiazol-2-yl] cyclohexyl]carbamate as a white solid (10.3 mg).

[1347] MS m/z (ESI): 589.1 [M+H].sup.+;

[1348] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.23 (s, 1H), 7.78 (s, 1H), 7.62 (s, 1H), 7.54 (br s, 1H), 7.46 (s, 1H), 7.17 (br d, J=8.3 Hz, 1H), 7.02 (br d, J=7.3 Hz, 1H), 6.90 (br d, J=8.0 Hz, 1H), 4.89-4.66 (m, 3H), 4.48-4.32 (m, 2H), 4.23 (s, 1H), 3.63-3.51 (m, 1H), 3.30-3.24 (m, 1H), 2.89 (br t, J=11.7 Hz, 1H), 2.32-2.07 (m, 4H), 1.99-1.69 (m, 6H), 1.62-1.46 (m, 2H), 1.33 (q, J=11.4 Hz, 2H), 1.16-1.05 (m, 6H).

Example 103: Synthesis of isopropyl trans-(4-(5-(4-((5-methyl-1H-pyrazol-3-yl)amino)-2-(1-oxophosphetan-1-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1349] ##STR00349##

Synthetic Method

[1350] ##STR00350##

Step 1: Synthesis of 1-phenylphosphetane-1-oxide

[1351] Phenylphosphonic dichloride (28.9 g, 148 mmol) was dissolved in diethyl ether (300 mL). Under the protection of nitrogen, bromo-[3-(bromomagnesium)propyl]magnesium (37.2 g, 148 mmol) was added at −30° C. The reaction solution appeared as a gray suspension, and was stirred and reacted at 25° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with a saturated ammonium chloride solution (1 L), and extracted with ethyl acetate (3 L) three times. The organic phase was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=10:1) to obtain the compound 1-phenylphosphetane-1-oxide (3.90 g, crude product) as a yellow oil.

[1352] MS m/z (ESI): 166.8 [M+H].sup.+;

Step 2: Synthesis of 1-(3-nitrophenyl)phosphine-1-oxide

[1353] 1-Phenylphosphetane-1-oxide (3.90 g, 7.04 mmol) was dissolved in concentrated sulfuric acid (30 mL), and concentrated nitric acid (1.33 g, 21.1 mmol) was added at 0° C. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 30° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with water (30 mL), and then extracted with dichloromethane (150 mL). The organic phase was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure to obtain crude 1-(3-nitrophenyl)phosphine-1-oxide (3.00 g) as a yellow oil.

[1354] MS m/z (ESI): 211.9 [M+H].sup.+;

Step 3: Synthesis of 1-(3-aminophenyl)phosphine-1-oxide

[1355] 1-(3-Nitrophenyl)phosphine-1-oxide (3.00 g, 4.26 mmol) was dissolved in anhydrous ethanol (40 mL) and water (8 mL). Under the protection of nitrogen, reduced iron powder (1.43 g, 25.6 mmol) and ammonium chloride (2.28 g, 42.6 mmol) were added. The reaction solution appeared as a black suspension, and was stirred and reacted at 80° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered while it was still hot. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=10:1) to obtain the compound 1-(3-aminophenyl)phosphine-1-oxide (646 mg) as a yellow solid.

[1356] MS m/z (ESI): 181.9 [M+H].sup.+;

Step 4: Synthesis of tert-butyl (3-(1-oxophosphino-1-yl)phenyl)carbamate

[1357] 1-(3-Aminophenyl)phosphine-1-oxide (646 mg, 3.57 mmol) was dissolved in methanol (35 mL), and BOC anhydride (11.7 g, 53.5 mmol) was added at 30° C. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 30° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. Aqueous ammonia (10 mL) was added into the reaction solution. The reaction solution was stirred and reacted at 30° C. for 2 hours, and then extracted with dichloromethane (20 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=10:1) to obtain the compound tert-butyl (3-(1-oxophosphino-1-yl)phenyl)carbamate (1.50 g) as a white solid.

[1358] MS m/z (ESI): 282.1 [M+H].sup.+;

Step 5: Synthesis of tert-butyl 4-bromo-3-(1-oxophosphino-1-yl)phenyl)carbamate

[1359] Tert-butyl (3-(1-oxophosphino-1-yl)phenyl)carbamate (1.40 g, 4.98 mmol) was dissolved in N,N-dimethylformamide (40 mL), and N-bromosuccinimide (1.77 g, 9.95 mmol) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 50° C. for 3 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (dichloromethane:methanol=10:1) to obtain the compound tert-butyl 4-bromo-3-(1-oxophosphino-1-yl)phenyl)carbamate (1.10 g) as a white solid.

[1360] MS m/z (ESI): 360.0 [M+H].sup.+;

Step 6: Synthesis of isopropyl trans-(4-(5-(4-tert-butoxycarbonylamino)-2-(1-oxophosphino-1-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1361] Tert-butyl 4-bromo-3-(1-oxophosphino-1-yl)phenyl)carbamate (482 mg, 1.39 mmol) and bis(pinacolato)diboron (597 mg, 2.35 mmol) were dissolved in anhydrous tetrahydrofuran (18 mL). Under the protection of nitrogen, tris(dibenzylideneacetone)dipalladium (0) (127 mg, 138 μmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (66.2 mg, 139 μmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)] palladium (II) (109 mg, 139 μmol) and potassium acetate (409 mg, 4.16 mmol) were added. The reaction solution appeared as a dark yellow suspension, and was stirred and reacted at 80° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with water (10 mL), and extracted with ethyl acetate (30 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=10:1) to obtain the compound isopropyl trans-(4-(5-(4-tert-butoxycarbonylamino)-2-(1-oxophosphino-1-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (649 mg) as a yellow solid product.

[1362] MS m/z (ESI): 548.4 [M+H].sup.+;

Step 7: Synthesis of isopropyl trans-(4-(5-(4-amino-2-(1-oxophosphino-1-yl)phenyl) thiazol-2-yl)cyclohexyl)carbamate

[1363] Isopropyl trans-(4-(5-(4-tert-butoxycarbonylamino)-2-(1-oxophosphino-1-yl)phenyl) thiazol-2-yl)cyclohexyl)carbamate (600 mg, 1.10 mmol) was dissolved in anhydrous methanol (3 mL), hydrochloric acid/methanol (4M, 8.22 mL) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 30° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with a saturated sodium carbonate solution (30 mL), and extracted with dichloromethane (90 mL) three times. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure to obtain isopropyl trans-(4-(5-(4-amino-2-(1-oxophosphino-1-yl) phenyl)thiazol-2-yl)cyclohexyl)carbamate (410 mg, crude product) as a white solid.

[1364] MS m/z (ESI): 448.1 [M+H].sup.+;

Step 8: Synthesis of isopropyl trans-(4-(5-(4-bromo-2-(1-oxophosphino-1-yl) phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1365] Isopropyl trans-(4-(5-(4-amino-2-(1-oxophosphino-1-yl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (300 mg, 670 μmol) was dissolved in acetonitrile (360 mL). Under the protection of nitrogen, tert-butyl nitrite (1.38 g, 13.4 mmol, 1.59 mL) was added. The reaction solution was stirred and reacted for 1 hour. Under the protection of nitrogen, cuprous bromide (1.92 g, 13.4 mmol) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 15 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with saturated ammonium chloride solution (150 mL), and extracted with dichloromethane (90 mL) three times. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (dichloromethane:methanol=6:1) to obtain the compound isopropyl trans-(4-(5-(4-bromo-2-(1-oxophosphino-1-yl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (245 mg) as a white solid.

[1366] MS m/z (ESI): 512.9 [M+H].sup.+;

Step 9: Synthesis of isopropyl trans-(4-(5-(4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-2-(1-oxophosphetan-1-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1367] Isopropyl trans-(4-(5-(4-bromo-2-(1-oxophosphino-1-yl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (100 mg, 196 μmol) and 5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-amine (70.8 mg, 392 μmol) were dissolved in anhydrous tetrahydrofuran (4 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (17.7 mg, 19.6 μmol) and potassium acetate (57.6 mg, 586 μmol) were added. The reaction solution appeared as a black suspension, and was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with water (5 mL), and extracted with ethyl acetate (9 mL) three times. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (dichloromethane:methanol=8:1) to obtain the compound isopropyl trans-(4-(5-(4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-2-(1-oxophosphetan-1-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (80.0 mg) as a white solid.

[1368] MS m/z (ESI): 612.1 [M+H].sup.+;

Step 10: Synthesis of isopropyl trans-(4-(5-(4-((5-methyl-1H-pyrazol-3-yl)amino)-2-(1-oxophosphetan-1-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1369] Isopropyl trans-(4-(5-(4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) amino)-2-(1-oxophosphetan-1-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (80.0 mg, 131 μmol) was dissolved in anhydrous methanol (2 mL), and p-toluenesulfonic acid monohydrate (113 mg, 654 μmol) was added. The reaction solution appeared as a black suspension, and was stirred and reacted at 50° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with saturated sodium carbonate solution (5 mL), and extracted with dichloromethane (9 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (30% to 50%) as eluents) to obtain the compound isopropyl trans-(4-(5-(4-((5-methyl-1H-pyrazol-3-yl)amino)-2-(1-oxophosphetan-1-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (36.77 mg) as a white solid.

[1370] MS m/z (ESI): 528.1 [M+H].sup.+;

[1371] .sup.1H NMR (400 MHz, DMSO-d6) δ 11.82 (br s, 1H), 8.84 (s, 1H), 8.03 (br d, J=14.6 Hz, 1H), 7.85 (s, 1H), 7.55 (br d, J=8.5 Hz, 1H), 7.36 (dd, J=4.6, 8.4 Hz, 1H), 7.02 (br d, J=7.8 Hz, 1H), 6.84-6.46 (m, 1H), 5.64 (s, 1H), 4.74 (td, J=6.3, 12.5 Hz, 1H), 3.32-3.25 (m, 1H), 2.98-2.84 (m, 1H), 2.46-2.40 (m, 1H), 2.49-2.39 (m, 1H), 2.31-2.22 (m, 2H), 2.20 (s, 3H), 2.11 (br d, J=11.3 Hz, 2H), 2.02-1.77 (m, 3H), 1.64-1.47 (m, 2H), 1.41-1.26 (m, 2H), 1.16-1.05 (m, 6H), 1.23-1.06 (m, 1H).

Example 104: Synthesis of isopropyl trans-(4-(5-(4-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)amino)-2-(1-oxophosphetan-1-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1372] ##STR00351##

Synthetic Method

[1373] ##STR00352##

[1374] Isopropyl trans-(4-(5-(4-bromo-2-(1-oxophosphetan-1-yl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (50 mg, 97.8 μmol) and 1-(2-fluoroethyl)-1H-pyrazol-4-amine (25.3 mg, 195 μmol) were dissolved in tetrahydrofuran (4 mL). Under the protection of nitrogen, methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (8.86 mg, 9.78 μmol) and potassium acetate (28.8 mg, 293 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (38% to 58%) as eluents) to obtain the compound isopropyl trans-(4-(5-(4-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)amino)-2-(1-oxophosphetan-1-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (44.04 mg).

[1375] MS m/z (ESI): 560.0 [M+H].sup.+;

[1376] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.87-7.78 (m, 2H), 7.46 (s, 1H), 7.37-7.21 (m, 2H), 7.08-6.92 (m, 2H), 4.83 (t, J=4.8 Hz, 1H), 4.78-4.69 (m, 2H), 4.48-4.33 (m, 2H), 3.30 (br s, 1H), 2.97-2.83 (m, 1H), 2.45-2.34 (m, 2H), 2.29-2.16 (m, 2H), 2.10 (br d, J=11.6 Hz, 2H), 1.90 (br d, J=10.1 Hz, 1H), 2.01-1.77 (m, 1H), 1.62-1.47 (m, 2H), 1.40-1.25 (m, 2H), 1.16-1.05 (m, 7H)

Example 105: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-methyl-1H-pyrazol-3-yl) amino]-2-(oxetan-3-ylsulfonimidoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1377] ##STR00353##

Synthetic Method

[1378] ##STR00354## ##STR00355##

Step 1: Synthesis of tert-butyl N-[3-(oxetan-3-ylsulfanyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[1379] Tert-butyl N-[4-bromo-3-(oxetan-3-ylsulfanyl)phenyl]carbamate (10.0 g, 27.8 mmol) and bis(pinacolato)diboron (28.2 g, 111 mmol) were dissolved in tetrahydrofuran (200 mL). Under the protection of nitrogen, dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine] palladium (II) (1.97 g, 2.78 mmol) and potassium acetate (5.45 g, 55.5 mmol) were added. The reaction solution was stirred and reacted at 80° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:ethyl acetate=10:1) to obtain tert-butyl N-[3-(oxetan-3-ylsulfanyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate as a yellow substance (130 mg).

[1380] MS m/z (ESI): 430.1 [M+Na].sup.+;

Step 2: Synthesis of isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(oxetan-3-ylsulfanyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1381] Tert-butyl N-[3-(oxetan-3-ylsulfanyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]carbamate (5.50 g, 13.5 mmol) and isopropyl trans-N-[4-(5-bromothiazol-2-yl) cyclohexyl]carbamate (4.26 g, 12.3 mmol) were dissolved in water (10 mL) and dioxane (100 mL). Thereafter, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (1.00 g, 1.23 mmol) and sodium carbonate (2.60 g, 24.6 mmol) were added under the condition where nitrogen gas was introduced. The reaction solution was stirred and reacted at 80° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, dichloromethane:methanol=10:1) to obtain isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(oxetan-3-ylsulfanyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate as a white substance (2.0 g).

[1382] MS m/z (ESI): 548.2 [M+H].sup.+;

Step 3: Synthesis of isopropyl trans-N-[4-[5-[4-amino-2-(oxetan-3-ylsulfanyl)phenyl] thiazol-2-yl]cyclohexyl]carbamate

[1383] Isopropyl trans-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(oxetan-3-ylsulfanyl)phenyl] thiazol-2-yl]cyclohexyl]carbamate (80.0 mg, 138 μmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (15.4 g, 135 mmol, 10 mL) was added. The reaction solution was stirred and reacted at 25° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was added with 30 mL of saturated sodium carbonate solution, and 90 mL of dichloromethane (30 mL×3) was added to the reaction solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain isopropyl trans-N-[4-[5-[4-amino-2-(oxetan-3-ylsulfanyl)phenyl]thiazol-2-yl] cyclohexyl]carbamate as a yellow solid compound (1.80 g, crude product).

[1384] MS m/z (ESI): 448.2 [M+H].sup.+;

Step 4: Synthesis of isopropyl trans-N-[4-[5-[4-bromo-2-(oxetan-3-ylsulfanyl)phenyl] thiazol-2-yl]cyclohexyl]carbamate

[1385] Isopropyl trans-N-[4-[5-[4-amino-2-(oxetan-3-ylsulfanyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate (1.0 g, 2.23 mmol) was dissolved in acetonitrile (20 mL), and tert-butyl nitrite (691 mg, 6.70 mmol, 797 L) was added at −30° C. The reaction solution was stirred and reacted at 25° C. for 1 hour. Cuprous bromide (801.19 mg, 5.59 mmol) was added into the reaction solution at −30° C. The reaction solution was stirred and reacted at 25° C. for 15 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was added with 100 mL of saturated ammonium chloride solution, and 300 mL of dichloromethane (100 mL×3) was added to the reaction solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, dichloromethane:methanol=10:1) to obtain isopropyl trans-N-[4-[5-[4-bromo-2-(oxetan-3-ylsulfanyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate as a white substance (120 mg).

[1386] MS m/z (ESI): 511.1 [M+H].sup.+;

Step 5: Synthesis of isopropyl trans-N-[4-[5-[4-bromo-2-(oxetan-3-ylsulfonimidoyl) phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1387] Isopropyl trans-N-[4-[5-[4-bromo-2-(oxetan-3-ylsulfanyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate (50 mg, 97.8 μmol) was dissolved in a solution of ammonia in methanol (7M, 3 mL), and iodobenzene diacetate (472 mg, 1.47 mmol) was added. The reaction solution was stirred and reacted at −30° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (silica, dichloromethane:methanol=10:1) to obtain isopropyl trans-N-[4-[5-[4-bromo-2-(oxetan-3-ylsulfonimidoyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate as a yellow solid (20.0 mg).

[1388] MS m/z (ESI): 542.1 [M+H].sup.+;

Step 6: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]-2-(oxetan-3-ylsulfonimidoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1389] Isopropyl trans-N-[4-[5-[4-bromo-2-(oxetan-3-ylsulfonimidoyl)phenyl]thiazol-2-yl] cyclohexyl]carbamate (20.0 mg, 36.9 μmol) and 5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-amine (7.35 mg, 40.6 μmol) were dissolved in tetrahydrofuran (2 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (3.34 mg, 3.69 μmol) and potassium acetate (7.24 mg, 73.7 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by thin-layer chromatography (silica, dichloromethane:methanol=10:1) to obtain isopropyl trans-N-[4-[5-[4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]-2-(oxetan-3-ylsulfonimidoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate as a yellow product (20.0 mg).

[1390] MS m/z (ESI): 643.3 [M+H].sup.+;

Step 7: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(oxetan-3-ylsulfonimidoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1391] Isopropyl trans-N-[4-[5-[4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]-2-(oxetan-3-ylsulfonimidoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (20.0 mg, 31.1 μmol) was dissolved in methanol (2 mL), and p-toluenesulfonic acid monohydrate (26.8 mg, 156 μmol) was added. The reaction solution was stirred and reacted at 50° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with 9 mL of dichloromethane (3 mL×3) and 5 mL of a saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (Phenomenex Gemini-NX column, 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia and 10 mM ammonium carbonate) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[5-[4-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(oxetan-3-ylsulfonimidoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (2.53 mg) as a white solid.

[1392] MS m/z (ESI): 559.0 [M+H].sup.+;

[1393] .sup.1H NMR (400 MHz, DMSO-d6) δ=11.85 (s, 1H), 9.00 (s, 1H), 8.09 (d, J=1.8 Hz, 1H), 7.63-7.58 (m, 2H), 7.22 (d, J=8.5 Hz, 1H), 7.02 (br d, J=7.5 Hz, 1H), 5.64 (s, 1H), 4.77-4.71 (m, 1H), 4.69 (s, 1H), 4.64-4.60 (m, 1H), 4.57-4.51 (m, 3H), 4.39-4.32 (m, 1H), 3.31-3.27 (m, 1H), 2.94-2.86 (m, 1H), 2.19 (s, 3H), 2.12 (br d, J=11.5 Hz, 2H), 1.91 (br d, J=10.3 Hz, 2H), 1.61-1.50 (m, 2H), 1.39-1.28 (m, 2H), 1.16 (d, J=6.3 Hz, 6H).

Example 106: Synthesis of isopropyl trans-N-[4-[5-[4-[[1-(2-fluoroethyl)pyrazol-4-yl] amino]-2-(oxetan-3-ylsulfonimidoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1394] ##STR00356##

Synthetic Method

[1395] ##STR00357##

[1396] Isopropyl trans-N-[4-[5-[4-bromo-2-(oxetan-3-ylsulfonimidoyl)phenyl]thiazol-2-yl] cyclohexyl]carbamate (30 mg, 55.3 μmol) and 1-(2-fluoroethyl)pyrazol-4-amine (7.86 mg, 60.8 μmol) was dissolved in tetrahydrofuran (2 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (5.01 mg, 5.53 μmol) and potassium acetate (5.43 mg, 55.3 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was added with 9 mL of ethyl acetate (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain isopropyl trans-N-[4-[5-[4-[[1-(2-fluoroethyl)pyrazol-4-yl]amino]-2-(oxetan-3-ylsulfonimidoyl)phenyl] thiazol-2-yl]cyclohexyl]carbamate as a white solid compound (1.02 mg).

[1397] MS m/z (ESI): 591.0 [M+H].sup.+;

[1398] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.29 (s, 1H), 7.80 (s, 1H), 7.60 (s, 1H), 7.55 (d, J=2.5 Hz, 1H), 7.47 (s, 1H), 7.18 (d, J=8.5 Hz, 1H), 7.03 (br d, J=7.5 Hz, 1H), 6.93 (dd, J=2.6, 8.4 Hz, 1H), 4.84 (t, J=4.6 Hz, 1H), 4.77 (s, 1H), 4.76-4.70 (m, 2H), 4.61-4.56 (m, 1H), 4.53-4.47 (m, 3H), 4.45 (t, J=4.8 Hz, 1H), 4.38 (t, J=4.9 Hz, 1H), 4.35-4.30 (m, 1H), 3.31-3.29 (m, 1H), 2.94-2.86 (m, 1H), 2.18-2.07 (m, 2H), 1.97-1.87 (m, 2H), 1.61-1.50 (m, 2H), 1.40-1.28 (m, 2H), 1.17 (d, J=6.0 Hz, 6H).

Example 107: Synthesis of isopropyl (2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)carbamate

[1399] ##STR00358##

Synthetic Method

[1400] ##STR00359##

Step 1: Synthesis of tert-butyl (2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)carbamate

[1401] N-(3-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (402 mg, 825 μmol) and tert-butyl (2-bromo-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)carbamate (250 mg, 750 μmol) were dissolved in dioxane (6 mL), and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (61.3 mg, 75.0 μmol) and an aqueous sodium carbonate solution (2M, 1 mL) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:tetrahydrofuran=2:1) to obtain the compound tert-butyl (2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)carbamate (420 mg) as a white solid.

[1402] MS m/z (ESI): 614.5 [M+H].sup.+;

Step 2: Synthesis of 2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino) phenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-amine

[1403] Tert-butyl (2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)carbamate (420 mg, 534 μmol) was dissolved in a methanol solution (3 mL), and hydrochloric acid/methanol (4M, 3 mL) was added. The reaction solution was stirred and reacted at 25° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, and aqueous ammonia was added to adjust the pH of the mixture to 7, so as to obtain the compound 2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-amine (250 mg, crude product) as a white solid.

[1404] MS m/z (ESI): 430.1 [M+H].sup.+;

Step 3: Synthesis of isopropyl (2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)carbamate

[1405] 2-(2-(Cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-amine (250 mg, 582 μmol) was dissolved in dichloromethane (3 mL), and isopropyl chloroformate (71.3 mg, 582 μmol, 80.8 μL) and N,N-diisopropylethylamine (226 mg, 1.75 mmol, 304 μL) were added. The reaction solution was stirred and reacted at 25° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, and aqueous ammonia was added to adjust the pH of the mixture to 8. The reaction solution was added with 9 mL of dichloromethane (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (38% to 58%) as eluents) to obtain isopropyl (2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)carbamate as a white solid compound (71.0 mg).

[1406] MS m/z (ESI): 516.0 [M+H].sup.+;

[1407] .sup.1H NMR (400 MHz, DMSO-d6) δ=11.91 (br s, 1H), 9.13 (s, 1H), 8.01 (br s, 1H), 7.66 (br d, J=8.8 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.31 (br d, J=7.0 Hz, 1H), 5.64 (s, 1H), 4.77 (td, J=6.1, 12.4 Hz, 1H), 3.80 (br s, 1H), 3.69-3.59 (m, 1H), 3.09 (br dd, J=4.6, 16.2 Hz, 1H), 2.91-2.81 (m, 1H), 2.80-2.71 (m, 1H), 2.71-2.63 (m, 1H), 2.19 (s, 3H), 2.01 (br d, J=14.3 Hz, 1H), 1.85-1.70 (m, 1H), 1.19-1.08 (m, 6H), 1.11-0.98 (m, 4H).

Example 108: Synthesis of isopropyl 2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)-7,8-dihydro-4H-thiazolo[4,5-d]aza-6(5H)-carboxylate

[1408] ##STR00360##

Synthetic Method

[1409] ##STR00361##

Step 1: Synthesis of tert-butyl 2-bromo-4,5,7,8-tetrahydrothiazolo[4,5-d]aza-6-carboxylate

[1410] Tert-butyl nitrite (191 mg, 1.86 mmol) and cupric bromide (414 mg, 1.86 mmol) were dissolved in anhydrous acetonitrile (6 mL). The reaction solution was stirred at 20° C. for 0.5 hours. Thereafter, tert-butyl 2-amino-4,5,7,8-tetrahydrothiazolo(4,5-d)aza-6-carboxylate (0.25 g, 928 μmol) was added at 60° C. The reaction solution appeared as a blue suspension, and was stirred and reacted at 60° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with water (5 mL), and extracted with ethyl acetate (3 mL) three times. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate=4:1) to obtain the compound tert-butyl 2-bromo-4,5,7,8-tetrahydrothiazolo[4,5-d]aza-6-carboxylate as a yellow oily liquid.

[1411] MS m/z (ESI): 333.0; 335.0 [M+H].sup.+;

Step 2: Synthesis of tert-butyl 2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)-7,8-dihydro-4H-thiazolo[4,5-d]azepine-6(5H)-carboxylate

[1412] Tert-butyl 2-bromo-4,5,7,8-tetrahydrothiazolo[4,5-d]aza-6-carboxylate (0.13 g, 390 μmol), N-(3-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (228 mg, 468 μmol) and sodium carbonate (82.6 mg, 780 μmol) were dissolved in water (0.5 mL) and 1,4-dioxane (2.5 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (31.8 mg, 39.0 μmol) was added. The reaction solution appeared as a brown suspension, and was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered and concentrated to dryness under reduced pressure. The resultant was added with water (10 mL), and the mixture was extracted with dichloromethane (10 mL) three times. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate=4:1) to obtain tert-butyl 2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)-7,8-dihydro-4H-thiazolo [4,5-d]azepine-6(5H)-carboxylate as the product (0.19 g), which was a yellow oily liquid.

[1413] MS m/z (ESI): 614.1 [M+H].sup.+;

Step 3: Synthesis of N-(3-(cyclopropylsulfonyl)-4-(5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]aza-2-yl)phenyl)-5-methyl-1H-pyrazol-3-amine

[1414] Tert-butyl 2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)-7,8-dihydro-4H-thiazolo[4,5-d]azepine-6(5H)-carboxylate (0.18 g, 293 μmol) was dissolved in methanol (1 mL). Hydrochloric acid/methanol (4M, 2 mL) was added at 20° C. The reaction solution appeared as a yellow solution, and was stirred and reacted at 20° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure to obtain N-(3-(cyclopropylsulfonyl)-4-(5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]aza-2-yl)phenyl)-5-methyl-1H-pyrazol-3-amine as the product (0.12 g, crude product), which was a white solid.

[1415] MS m/z (ESI): 430.1 [M+H].sup.+;

Step 4: Synthesis of isopropyl 2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)-7,8-dihydro-4H-thiazolo[4,5-d]aza-6(5H)-carboxylate

[1416] N-(3-(cyclopropylsulfonyl)-4-(5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]aza-2-yl)phenyl)-5-methyl-1H-pyrazol-3-amine (0.12 g, 257 μmol), 4-dimethylaminopyridine (62.9 mg, 515 μmol) and N,N-diisopropylethylamine (332 mg, 2.58 mmol) were dissolved in anhydrous dichloromethane (3 mL). Isopropyl chloroformate (63.1 mg, 515 μmol) was added at −30° C. The reaction solution appeared as a yellow solution, and was stirred and reacted at −30° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was dissolved in methanol (0.1 mL), and then the pH of the mixture was adjusted to 10 with a solution of ammonia in methanol (7M). The resultant was purified by preparative liquid chromatography (Phenomenex Gemini C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl 2-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)-7,8-dihydro-4H-thiazolo[4,5-d]aza-6(5H)-carboxylate (40.00 mg) as a white solid.

[1417] MS m/z (ESI): 516.1 [M+H].sup.+;

[1418] .sup.1H NMR (400 MHz, DMSO-d6) δ=11.92 (br s, 1H), 9.13 (s, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.67 (dd, J=1.8, 8.4 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 5.65 (s, 1H), 4.85 (spt, J=6.2 Hz, 1H), 3.73-3.57 (m, 5H), 3.02 (td, J=4.8, 15.8 Hz, 4H), 2.20 (s, 3H), 1.23-1.13 (m, 6H), 1.12-0.97 (m, 3H), 1.12-0.97 (m, 1H).

Example 109: Synthesis of isopropyl (3-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)-3-azabicyclo[3.1.0]hexanone-6-yl)carbamate

[1419] ##STR00362##

Synthetic Method

[1420] ##STR00363##

Step 1: Synthesis of tert-butyl (3-(thiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate

[1421] Tert-butyl 3-azabicyclo[3.1.0]hex-6-carbamate (220 mg, 1.11 mmol) and 2-bromothiazole (546 mg, 3.33 mmol) were dissolved in n-butanol (4 mL). The reaction solution was stirred and reacted at 140° C. for 5 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (petroleum ether:ethyl acetate=1:3) to obtain tert-butyl (3-(thiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate as a white solid product (120 mg).

[1422] MS m/z (ESI): 282.1 [M+H].sup.+;

Step 2: Synthesis of 3-(thiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-amine

[1423] Tert-butyl (3-(thiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate (78.0 mg, 277 μmol) was dissolved in methanol (3 mL), and then hydrochloric acid/methanol (4M, 2.08 mL) was added into the reaction solution. The reaction solution was stirred and reacted at 40° C. for 16 hours. The completion of the reaction was detected by LCMS. The resultant was filtered and concentrated to dryness under reduced pressure to obtain crude 3-(thiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-amine as a yellow oily product (50.0 mg).

[1424] MS m/z (ESI): 182.0 [M+H].sup.+;

Step 3: Synthesis of isopropyl (3-(thiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate

[1425] 3-(Thiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-amine (50 mg, 276 μmol) was dissolved in dichloromethane (2 mL), and then a solution of isopropyl chloroformate in dichloromethane (2 mL, 50.7 mg, 414 μmol) and N,N-diisopropylethylamine (357 mg, 2.76 mmol) were added. The reaction solution was stirred and reacted at 30° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate=1:1) to obtain isopropyl (3-(thiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate as a white solid substance (50.0 mg).

[1426] MS m/z (ESI): 268.0 [M+H].sup.+;

Step 4: Synthesis of isopropyl (3-(5-bromothiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate

[1427] Isopropyl (3-(thiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate (45.0 mg, 168 μmol) was dissolved in dichloromethane (1 mL), and then a solution of N-bromosuccinimide (29.9 mg, 168 μmol) in dichloromethane (1 mL) was added at −20° C. The reaction solution was stirred and reacted at −20° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate=1:1) to obtain isopropyl (3-(5-bromothiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate as a white solid substance (50.0 mg).

[1428] MS m/z (ESI): 347.9 [M+H].sup.+;

Step 5: Synthesis of isopropyl (3-(5-(2-(cyclopropylsulfonyl))-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)-3-azabicyclo[3.1.0] hex-6-yl)carbamate

[1429] Isopropyl (3-(5-bromothiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate (50.0 mg, 144 μmol) and N-[3-cyclopropylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-amine (84.5 mg, 173 μmol) were dissolved in dioxane (3 mL). Thereafter, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (5.90 mg, 7.22 μmol) and sodium carbonate (2M, 600 L) were added under the condition where nitrogen gas was introduced. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with 9 mL of dichloromethane (3 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate=1:4) to obtain isopropyl (3-(5-(2-(cyclopropylsulfonyl))-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate as a yellow solid substance (60.0 mg).

[1430] MS m/z (ESI): 627.1 [M+H].sup.+;

Step 6: Synthesis of isopropyl (3-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)-3-azabicyclo[3.1.0]hexanone-6-yl)carbamate

[1431] Isopropyl (3-(5-(2-(cyclopropylsulfonyl))-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate (60.0 mg, 76.6 μmol) was dissolved in methanol (1 mL), and then hydrochloric acid/methanol (4M, 1.15 mL) was added into the reaction solution. The reaction solution was stirred and reacted at 30° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (25% to 45%) as eluents) to obtain isopropyl (3-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)-3-azabicyclo[3.1.0]hexanone-6-yl) carbamate as a white solid (4.78 mg).

[1432] MS m/z (ESI): 543.0 [M+H].sup.+;

[1433] .sup.1H NMR (400 MHz, DMSO-d6) δ 11.84 (br s, 1H), 8.97 (s, 1H), 8.04 (br s, 1H), 7.58 (br d, J=7.5 Hz, 1H), 7.36 (br s, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.14 (s, 1H), 5.62 (s, 1H), 4.92-4.75 (m, 1H), 3.61-3.39 (m, 4H), 2.54 (s, 1H), 2.30 (br s, 1H), 2.19 (s, 3H), 1.82 (br s, 2H), 1.17-1.05 (m, 6H), 1.02-0.83 (m, 4H).

Example 110: Synthesis of isopropyl 4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)-1,4-diaza-1-carboxylate

[1434] ##STR00364##

Synthetic Method

[1435] ##STR00365##

Step 1: Synthesis of tert-butyl 4-(thiazol-2-yl)-1,4-diaza-1-carboxylate

[1436] Tert-butyl 1,4-diaza-1-carboxylate (4.09 g, 24.9 mmol) and 2-bromothiazole (5 g, 24.97 mmol) were dissolved in n-butanol (50 mL). The reaction solution was stirred and reacted at 140° C. for 5 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered, concentrated to dryness under reduced pressure, and then purified by column chromatography (petroleum ether:ethyl acetate=1:3) to obtain tert-butyl 4-(thiazol-2-yl)-1,4-diaza-1-carboxylate as a yellow oily product (2.50 g).

[1437] MS m/z (ESI): 284.2 [M+H].sup.+;

Step 2: Synthesis of 2-(1,4-diaza-1-yl)thiazole

[1438] Tert-butyl 4-(thiazol-2-yl)-1,4-diaza-1-carboxylate (438 mg, 1.55 mmol) was dissolved in methanol (6 mL), and then hydrochloric acid/methanol (4M, 11.6 mL) was added into the reaction solution. The reaction solution was stirred and reacted at 40° C. for 2 hours. The completion of the reaction was detected by LCMS. The resultant was filtered and concentrated to dryness under reduced pressure to obtain 2-(1,4-diaza-1-yl)thiazole as a white solid product (283 mg, crude product).

[1439] MS m/z (ESI): 184.1 [M+H].sup.+;

Step 3: Synthesis of isopropyl 4-(thiazol-2-yl)-1,4-diaza-1-carboxylate

[1440] 2-(1,4-Diaza-1-yl)thiazole (283 mg, 1.55 mmol) was dissolved in dichloromethane (4 mL), and then a solution of isopropyl chloroformate (284 mg, 2.32 mmol) and N,N-diisopropylethylamine (2.00 g, 15.5 mmol) in dichloromethane (4 mL) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:ethyl acetate=1:1) to obtain isopropyl 4-(thiazol-2-yl)-1,4-diaza-1-carboxylate as a white solid substance (200 mg).

[1441] MS m/z (ESI): 270.1 [M+H].sup.+;

Step 4: Synthesis of isopropyl 4-(5-bromothiazol-2-yl)-1,4-diaza-1-carboxylate

[1442] Isopropyl 4-(thiazol-2-yl)-1,4-diaza-1-carboxylate (100 mg, 371 μmol) was dissolved in dichloromethane (3 mL), and then a solution of N-bromosuccinimide (66.1 mg, 371 μmol) in dichloromethane (3 mL) was added at −20° C. The reaction solution was stirred and reacted at −20° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate=1:1) to obtain isopropyl 4-(5-bromothiazol-2-yl)-1,4-diaza-1-carboxylate as a yellow solid substance (260 mg).

[1443] MS m/z (ESI): 349.8 [M+H].sup.+;

Step 5: Synthesis of isopropyl 4-(5-(2-(cyclopropylsulfonyl))-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)-1,4-diaza-1-carboxylate

[1444] Isopropyl 4-(5-bromothiazol-2-yl)-1,4-diaza-1-carboxylate (130 mg, 373 μmol) and N-[3-cyclopropylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-amine (218 mg, 448 μmol) were dissolved in dioxane (5 mL). Thereafter, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (15.2 mg, 18.7 μmol) and sodium carbonate (2M, 1 mL) were added under the condition where nitrogen gas was introduced. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The reaction solution was added with 30 mL of dichloromethane (10 mL×3) and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran=1:2) to obtain isopropyl 4-(5-(2-(cyclopropylsulfonyl))-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)-1,4-diaza-1-carboxylate as a yellow solid substance (162 mg).

[1445] MS m/z (ESI): 629.1 [M+H].sup.+;

Step 6: Synthesis of isopropyl 4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)-1,4-diaza-1-carboxylate

[1446] Isopropyl 4-(5-(2-(cyclopropylsulfonyl))-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)-1,4-diaza-1-carboxylate (81.0 mg, 129 μmol) was dissolved in methanol (1 mL), and then hydrochloric acid/methanol (4M, 1.93 mL) was added into the reaction solution. The reaction solution was stirred and reacted at 30° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (30% to 50%) as eluents) to obtain isopropyl 4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)-1,4-diaza-1-carboxylate as a white solid compound (4.65 mg).

[1447] MS m/z (ESI): 545.0 [M+H].sup.+;

[1448] .sup.1H NMR (400 MHz, DMSO-d6) δ 11.82 (br s, 1H), 8.96 (s, 1H), 8.16 (s, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.67-7.45 (m, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.12 (s, 1H), 5.62 (s, 1H), 4.81-4.58 (m, 1H), 3.63 (br s, 5H), 3.30-3.20 (m, 3H), 2.46-2.41 (m, 1H), 2.19 (s, 3H), 1.90-1.74 (m, 2H), 1.16-1.05 (m, 6H), 1.00-0.87 (m, 4H).

Example 111: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-(ethylcarbamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1449] ##STR00366##

Synthetic Method

[1450] ##STR00367##

Step 1: Synthesis of trans-3-(cyclopropylsulfonyl)-4-(2-((4-((isopropoxycarbonyl) amino)cyclohexyl)thiazol-5-yl)benzoic acid

[1451] Ethyl trans-3-(cyclopropylsulfonyl)-4-(2-((4-((isopropoxycarbonyl)amino)cyclohexyl) thiazol-5-yl)benzoate (80.0 mg, 154 μmol) was dissolved in anhydrous methanol (3 mL), and an aqueous sodium hydroxide solution (2M, 230 μL) was added. The reaction solution was stirred and reacted at 50° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with water (5 mL), and extracted with ethyl acetate (9 mL) three times. Thereafter, the aqueous phase was added with dilute hydrochloric acid so that the pH of the mixture was adjusted to 3. The aqueous phase was extracted with ethyl acetate (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain trans-3-(cyclopropylsulfonyl)-4-(2-((4-((isopropoxycarbonyl) amino)cyclohexyl)thiazol-5-yl)benzoic acid as a white solid compound (60.0 mg).

[1452] MS m/z (ESI): 493.0 [M+H].sup.+;

Step 2: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-(ethylcarbamoyl) phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1453] Trans-3-(cyclopropylsulfonyl)-4-(2-((4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)benzoic acid (60.0 mg, 122 μmol) and anhydrous ethylamine (54.9 mg, 1.22 mmol) were dissolved in acetonitrile (2 mL), and tri-n-propylphosphonic anhydride (50% solution in ethyl acetate) (116 mg, 365 μmol, 108 μL) was added. The reaction solution was stirred and reacted at 80° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with a saturated sodium carbonate solution (5 mL), and extracted with dichloromethane (15 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (40% to 60%) as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-(ethylcarbamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (17.5 mg).

[1454] MS m/z (ESI): 520.0 [M+H].sup.+;

[1455] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.85 (t, J=5.5 Hz, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.16 (dd, J=1.8, 8.0 Hz, 1H), 7.81 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.02 (br d, J=7.6 Hz, 1H), 4.74 (td, J=6.3, 12.4 Hz, 1H), 3.43-3.37 (m, 1H), 3.31-3.23 (m, 2H), 3.04-2.91 (m, 1H), 2.48-2.40 (m, 1H), 2.15 (br d, J=12.0 Hz, 2H), 1.92 (br d, J=10.1 Hz, 2H), 1.68-1.49 (m, 2H), 1.45-1.26 (m, 2H), 1.21-1.09 (m, 9H), 1.05-0.85 (m, 4H).

Example 112: Synthesis of isopropyl trans-N-[4-[5-[4-[(5-fluoro-2-pyridyl)amino]-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1456] ##STR00368##

Synthetic Method

[1457] ##STR00369##

[1458] Isopropyl trans-N-[4-[5-[4-bromo-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate (60.0 mg, 110.4 μmol) and 2-amino-5-fluoropyridine (13.6 mg, 121 μmol) were dissolved in tetrahydrofuran (3 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.0 mg, 11.1 μmol) and potassium acetate (21.7 mg, 221 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was added with 30 mL of ethyl acetate (10 mL×3) and 10 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[5-[4-[(5-fluoro-2-pyridyl)amino]-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (8.18 mg) as a white solid.

[1459] MS m/z (ESI): 575.0 [M+H].sup.+;

[1460] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.82 (s, 1H), 8.37 (d, J=2.3 Hz, 1H), 8.24 (d, J=3.0 Hz, 1H), 8.13 (dd, J=2.3, 8.5 Hz, 1H), 7.69-7.63 (m, 2H), 7.45 (d, J=8.5 Hz, 1H), 7.04 (br d, J=7.5 Hz, 1H), 6.96 (dd, J=3.8, 9.3 Hz, 1H), 4.80-4.70 (m, 1H), 4.67-4.60 (m, 2H), 4.59-4.52 (m, 3H), 3.33-3.27 (m, 1H), 2.98-2.90 (m, 1H), 2.14 (br d, J=12.5 Hz, 2H), 1.93 (br d, J=10.0 Hz, 2H), 1.63-1.52 (m, 2H), 1.40-1.29 (m, 2H), 1.17 (d, J=6.3 Hz, 6H).

Example 113: Synthesis of isopropyl trans-N-[4-[5-[4-[(6-methoxy-3-pyridyl)amino]-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1461] ##STR00370##

Synthetic Method

[1462] ##STR00371##

[1463] Isopropyl trans-N-[4-[5-[4-bromo-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate (60.0 mg, 110 μmol) and 6-methoxypyridin-3-amine (15.1 mg, 121 μmol) were dissolved in tetrahydrofuran (3 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.0 mg, 11.1 μmol) and potassium acetate (21.8 mg, 221 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was added with 30 mL of ethyl acetate (10 mL×3) and 10 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[5-[4-[(6-methoxy-3-pyridyl)amino]-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (11.67 mg) as a white solid.

[1464] MS m/z (ESI): 587.0 [M+H].sup.+;

[1465] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.72 (s, 1H), 8.08 (d, J=2.8 Hz, 1H), 7.65-7.59 (m, 2H), 7.53 (d, J=2.5 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.12 (dd, J=2.6, 8.4 Hz, 1H), 7.03 (br d, J=7.8 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 4.79-4.70 (m, 1H), 4.65-4.57 (m, 2H), 4.54-4.44 (m, 3H), 3.85 (s, 3H), 3.31-3.23 (m, 1H), 2.93 (s, 1H), 2.18-2.08 (m, 2H), 1.92 (br d, J=9.8 Hz, 2H), 1.62-1.51 (m, 2H), 1.40-1.27 (m, 2H), 1.17 (d, J=6.3 Hz, 6H).

Example 114: Synthesis of isopropyl trans-(4-(5-(4-((5-methyl-1H-pyrazol-3-yl)amino)-2-((1-methylazetidin-3-yl)sulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1466] ##STR00372##

Synthetic Method

[1467] ##STR00373##

Step 1: Synthesis of tert-butyl 3-((2-bromophenyl)thio)azetidine-1-carboxylate

[1468] o-Bromothiophenol (5.07 g, 26.8 mmol, 3.15 mL) and tert-butyl 3-bromoazetidine-1-carboxylate (9.50 g, 40.2 mmol) were dissolved in N,N-dimethylformamide (100 mL), and potassium carbonate (11.1 g, 80.5 mmol) was added. The reaction solution was stirred and reacted at 100° C. for 24 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered, concentrated to dryness under reduced pressure, and then purified by column chromatography (silica, petroleum ether:ethyl acetate=10:1) to obtain tert-butyl 3-((2-bromophenyl)thio)azetidine-1-carboxylate as a white solid compound (8.74 g).

[1469] MS m/z (ESI): 287.9, 288.0 [M+H].sup.+;

Step 2: Synthesis of tert-butyl 3-((2-bromophenyl)sulfonyl)azetidine-1-carboxylate

[1470] Tert-butyl 3-((2-bromophenyl)thio)azetidine-1-carboxylate (8.70 g, 25.3 mmol) and potassium monopersulfate (109 g, 177 mmol) were dissolved in methanol (100 mL) and water (100 mL). The reaction solution was stirred and reacted at 25° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered, concentrated to dryness under reduced pressure, and extracted with 2.4 L of dichloromethane (800 mL×3) and an aqueous sodium sulfite solution (800 mL). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain the compound tert-butyl 3-((2-bromophenyl)sulfonyl)azetidine-1-carboxylate as a white oily product (6.00 g, crude product).

[1471] MS m/z (ESI): 320.0; 322.0 [M+H-t-Bu].sup.+;

Step 3: Synthesis of 3-((2-bromophenyl)sulfonyl)azetidine

[1472] Tert-butyl 3-((2-bromophenyl)sulfonyl)azetidine-1-carboxylate (5.30 g, 12.0 mmol, purity: 85%) was dissolved in methanol (20 mL), and hydrochloric acid/methanol (4M, 29.9 mL) was added. The reaction solution was stirred and reacted at 25° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered. The filtrate was concentrated to dryness under reduced pressure to obtain 3-((2-bromophenyl)sulfonyl)azetidine as a white solid compound (3.20 g, crude product).

[1473] MS m/z (ESI): 276.0, 278.0 [M+H].sup.+;

Step 4: Synthesis of 3-((2-bromophenyl)sulfonyl)-1-methylazetidine

[1474] 3-((2-Bromophenyl)sulfonyl)azetidine (3.20 g, 11.6 mmol) and 2-methylpyridine borane complex (2.48 g, 23.2 mmol) were dissolved in methanol (60 mL), and formaldehyde (9.40 g, 116 mmol, 8.63 mL, purity: 37%) and glacial acetic acid (39.2 mg, 2.32 mmol, 133 μL) were added. The reaction solution was stirred and reacted at 65° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, dichloromethane:methanol=5:1) to obtain 3-((2-bromophenyl)sulfonyl)-1-methylazetidine as a white solid compound (3.00 g).

[1475] MS m/z (ESI): 290.0 [M+H].sup.+;

Step 5: Synthesis of 3-((2-bromo-5-iodophenyl)sulfonyl)-1-methylazetidine

[1476] 3-((2-Bromophenyl)sulfonyl)-1-methylazetidine (2.00 g, 6.89 mmol) was dissolved in sulfuric acid (30 mL), and N-iodosuccinimide (2.79 g, 12.4 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 16 hours. The completion of the reaction was detected by LCMS. At 0° C., the reaction solution was added with a saturated aqueous sodium hydroxide solution so that the pH of the mixture was adjusted to 7.80 mL of water and 300 mL of dichloromethane (100 mL×3) were added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and the resultant was slurried with ethyl acetate (8 mL) to obtain 3-((2-bromo-5-iodophenyl)sulfonyl)-1-methylazetidine as a white solid compound (800 mg).

[1477] MS m/z (ESI): 415.9, 417.9 [M+H].sup.+.

Step 6: Synthesis of N-(4-bromo-3-((1-methylazetidin-3-yl)sulfonyl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine

[1478] 3-((2-Bromo-5-iodophenyl)sulfonyl)-1-methylazetidine (1.30 g, 3.12 mmol) and 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (566 mg, 3.12 mmol) were dissolved in tetrahydrofuran (40 mL), and cesium carbonate (2.04 g, 6.25 mmol) and methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-l,l-diphenyl] palladium (II)-dichloromethane adduct (148 mg, 156 μmol) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 85° C. for 1.5 hours. The completion of the reaction was detected by LCMS. The reaction solution was filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, dichloromethane:methanol=10:1) to obtain N-(4-bromo-3-((1-methylazetidin-3-yl) sulfonyl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine as a white solid compound (900 mg).

[1479] MS m/z (ESI): 469.1 [M+H].sup.+.

Step 7: Synthesis of 5-methyl-N-(3-(((1-methylazetidin-3-yl)sulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine

[1480] N-(4-bromo-3-((1-methylazetidin-3-yl)sulfonyl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (300 mg, 511 μmol, purity: 80%) and bis(pinacolato)diboron (649 mg, 2.56 mmol) were dissolved in N,N-dimethylformamide (6 mL), and potassium acetate (151 mg, 1.53 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (41.8 mg, 51.1 μmol) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 80° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, dichloromethane:methanol=10:1) to obtain 5-methyl-N-(3-(((1-methylazetidin-3-yl)sulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine as a brown solid compound (230 mg, crude product).

[1481] MS m/z (ESI): 517.3 [M+H].sup.+;

Step 8: Synthesis of isopropyl trans-(4-(5-(4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-2-((1-methylazetidin-3-yl)sulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1482] 5-Methyl-N-(3-(((1-methylazetidin-3-yl)sulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (230 mg, 134 μmol, purity: 30%) and isopropyl trans-(4-(5-bromothiazol-2-yl)cyclohexyl)carbamate (51.0 mg, 147 μmol) were dissolved in dioxane (3 mL), and an aqueous sodium carbonate solution (2M, 0.5 mL) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane (10.9 mg, 13.4 μmol) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 85° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, dichloromethane:methanol=10:1) to obtain isopropyl trans-(4-(5-(4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-2-((1-methylazetidin-3-yl)sulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a brown solid compound (80.0 mg).

[1483] MS m/z (ESI): 657.3 [M+H].sup.+;

Step 9: Synthesis of isopropyl trans-(4-(5-(4-((5-methyl-1H-pyrazol-3-yl)amino)-2-((1-methylazetidin-3-yl)sulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1484] Isopropyl trans-(4-(5-(4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) amino)-2-((1-methylazetidin-3-yl)sulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (80.0 mg, 122 μmol) was dissolved in methanol (3 mL), and p-toluenesulfonic acid monohydrate (105 mg, 609 μmol) was added. The reaction solution was stirred and reacted at 50° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. Aqueous ammonia was added so that the pH of the mixture was adjusted to 8. The resulting mixture was extracted with water (5 mL) and dichloromethane (9 mL) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (40% to 60%) as eluents) to obtain isopropyl trans-(4-(5-(4-((5-methyl-1H-pyrazol-3-yl)amino)-2-((1-methylazetidin-3-yl)sulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (6.39 mg).

[1485] MS m/z (ESI): 572.9 [M+H].sup.+;

[1486] .sup.1H NMR (400 MHz, DMSO-d6) δ=11.90 (br s, 1H), 9.09 (s, 1H), 8.14 (s, 1H), 7.66-7.59 (m, 2H), 7.31 (d, J=8.5 Hz, 1H), 7.03 (br d, J=7.8 Hz, 1H), 5.64 (s, 1H), 4.81-4.64 (m, 1H), 4.04 (s, 1H), 3.91-3.79 (m, 1H), 3.31 (br s, 2H), 3.21-3.09 (m, 2H), 2.98-2.86 (m, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 2.13 (br d, J=14.3 Hz, 2H), 1.91 (br d, J=10.3 Hz, 2H), 1.64-1.49 (m, 2H), 1.40-1.25 (m, 2H), 1.17-1.05 (m, 6H).

Example 115: Synthesis of isopropyl trans-(4-(5-(4-((5-methyl-1H-pyrazol-3-yl) amino)-2-((tetrahydrofuran-3-yl)sulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1487] ##STR00374##

Synthetic Method

[1488] ##STR00375##

Step 1: Synthesis of 3-((2-bromophenyl)thio)tetrahydrofuran

[1489] o-Bromothiophenol (4.20 g, 22.2 mmol) and 3-bromotetrahydrofuran (5.03 g, 33.3 mmol) were dissolved in N,N-dimethylformamide (40 mL), and then potassium carbonate (9.21 g, 66.6 mmol) was added into the reaction solution. The reaction solution was stirred and reacted at 80° C. for 16 hours. TLC detection showed that the reaction was complete. The reaction solution was filtered, concentrated to dryness under reduced pressure, and purified by column chromatography (silica, petroleum ether:ethyl acetate=5:1) to obtain 3-((2-bromophenyl)thio)tetrahydrofuran as a yellow oily substance (5.30 g).

[1490] .sup.1H NMR (400 MHz, DMSO-d6) δ 7.62 (dd, J=1.1, 7.9 Hz, 1H), 7.46-7.34 (m, 2H), 7.23-7.11 (m, 1H), 4.18-3.98 (m, 2H), 3.89-3.71 (m, 2H), 3.56 (dd, J=4.4, 9.1 Hz, 1H), 2.46-2.36 (m, 1H), 1.85-1.75 (m, 1H).

Step 2: Synthesis of 3-((2-bromophenyl)sulfonyl)tetrahydrofuran

[1491] 3-((2-Bromophenyl)thio)tetrahydrofuran (5.30 g, 20.4 mmol) was dissolved in dichloromethane (100 mL), and then m-chloroperoxybenzoic acid (10.7 g, 52.6 mmol) was added into the reaction solution. The reaction solution was stirred and reacted at 30° C. for 16 hours. TLC detection showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure. A saturated sodium carbonate solution (30 mL) and dichloromethane (90 mL, 30 mL×3) were added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=5:1) to obtain 3-((2-bromophenyl)sulfonyl)tetrahydrofuran as a white solid product (4.44 g).

[1492] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.13-8.05 (m, 1H), 7.99-7.93 (m, 1H), 7.74-7.63 (m, 2H), 4.54-4.43 (m, 1H), 4.04-3.94 (m, 1H), 3.92-3.80 (m, 2H), 3.73-3.63 (m, 1H), 2.21-2.04 (m, 2H).

Step 3: Synthesis of 3-((2-bromo-5-iodophenyl)sulfonyl)tetrahydrofuran

[1493] 3-((2-Bromophenyl)sulfonyl)tetrahydrofuran (4.44 g, 15.5 mmol) was dissolved in concentrated sulfuric acid (70 mL), and then N-iodosuccinimide (6.18 g, 27.5 mmol) was added into the reaction solution. The reaction solution was stirred and reacted at 30° C. for 16 hours. TLC detection showed that the reaction was complete. The reaction solution was slowly poured into ice water (100 mL) to quench the reaction. The reaction solution was added with a saturated aqueous sodium sulfite solution (60 mL), and extracted with dichloromethane (600 mL) three times. The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (silica, petroleum ether:ethyl acetate=1:1) to obtain 3-((2-bromo-5-iodophenyl)sulfonyl)tetrahydrofuran as a yellow oily substance (2.80 g).

[1494] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=2.1 Hz, 1H), 8.05-7.95 (m, 1H), 7.71 (d, J=8.3 Hz, 1H), 4.56-4.44 (m, 1H), 4.04-3.99 (m, 1H), 3.93-3.81 (m, 2H), 3.74-3.63 (m, 1H), 2.22-2.06 (m, 2H).

Step 4: Synthesis of N-(4-bromo-3-((tetrahydrofuran-3-yl)sulfonyl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine

[1495] 3-((2-Bromo-5-iodophenyl)sulfonyl)tetrahydrofuran (2.79 g, 6.68 mmol) and 5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-amine (1.45 g, 8.02 mmol) were dissolved in tetrahydrofuran (60 mL). Thereafter, methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-l,l-biphenyl]palladium (II) dichloromethane adduct (317 mg, 335 μmol) and cesium carbonate (6.53 g, 20.1 mmol) were added under the protection of nitrogen. The reaction solution was stirred and reacted at 80° C. for 4 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with water (10 mL), and extracted with ethyl acetate (30 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (silica, petroleum ether:ethyl acetate=1:1) to obtain N-(4-bromo-3-((tetrahydrofuran-3-yl)sulfonyl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine as a yellow solid substance (2.39 g).

[1496] MS m/z (ESI): 470.0, 472.0 [M+H].sup.+;

Step 5: Synthesis of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-N-(3-((tetrahydrofuran-3-yl)sulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-3-amine

[1497] N-(4-Bromo-3-((tetrahydrofuran-3-yl)sulfonyl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (1.00 g, 2.13 mmol) and bis(pinacolato)diboron (1.62 g, 6.38 mmol) were dissolved in dioxane (5 mL). Thereafter, dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (II) (75.3 mg, 106 μmol) and potassium acetate (625 mg, 6.38 mmol) were added under the protection of nitrogen. The reaction solution was stirred and reacted at 100° C. for 16 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with water (5 mL), and extracted with ethyl acetate (18 mL). The organic phase was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (silica, petroleum ether:ethyl acetate=1:1) to obtain 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-N-(3-((tetrahydrofuran-3-yl)sulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-3-amine as a yellow oily substance (150 mg).

[1498] MS m/z (ESI): 540.1 [M+Na].sup.+;

Step 6: Synthesis of isopropyl trans-(4-(5-(2-(2-hydroxy-2-methylpropoxy)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl) carbamate

[1499] 5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-N-(3-((tetrahydrofuran-3-yl)sulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-3-amine (75.0 mg, 145 μmol) and isopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (50.3 mg, 145 μmol) were dissolved in dioxane (3 mL). Thereafter, [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium-dichloromethane (5.92 mg, 7.25 μmol) and sodium carbonate (2M, 750 L) were added under the condition where nitrogen gas was introduced. The reaction solution was stirred and reacted at 100° C. for 16 hours (two parallel reactions of the same scale were carried out and the subsequent treatment was combined). The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with water (5 mL), and extracted with ethyl acetate (9 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (silica, petroleum ether:ethyl acetate=1:1) to obtain isopropyl trans-(4-(5-(2-(2-hydroxy-2-methylpropoxy)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl) thiazol-2-yl)cyclohexyl)carbamate as a yellow solid substance (190 mg, crude product).

[1500] MS m/z (ESI): 658.2 [M+H].sup.+;

Step 7: Synthesis of isopropyl trans-(4-(5-(4-((5-methyl-1H-pyrazol-3-yl)amino)-2-((tetrahydrofuran-3-yl)sulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1501] Isopropyl trans-(4-(5-(2-(2-hydroxy-2-methylpropoxy)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (100 mg, 152 μmol) was dissolved in methanol (1.5 mL), and then hydrochloric acid/methanol (4M, 2.1 mL) was added into the reaction solution. The reaction solution was stirred and reacted at 30° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Agela DuraShell C18 column: 5 μm silica, 25 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (35% to 55%) as eluents) to obtain isopropyl trans-(4-(5-(4-((5-methyl-1H-pyrazol-3-yl)amino)-2-((tetrahydrofuran-3-yl)sulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (40.20 mg).

[1502] MS m/z (ESI): 574.0 [M+H].sup.+;

[1503] .sup.1H NMR (400 MHz, DMSO-d6) δ 11.90 (br s, 1H), 9.11 (s, 1H), 8.17 (s, 1H), 7.77-7.58 (m, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.02 (br d, J=7.6 Hz, 1H), 5.64 (s, 1H), 4.85-4.62 (m, 1H), 3.87-3.80 (m, 1H), 3.80-3.68 (m, 2H), 3.65-3.52 (m, 2H), 3.31 (br s, 1H), 3.01-2.89 (m, 1H), 2.20 (s, 3H), 2.13 (br d, J=11.9 Hz, 2H), 2.11-1.91 (m, 2H), 1.90-1.81 (m, 2H), 1.65-1.48 (m, 2H), 1.41-1.26 (m, 2H), 1.17-1.05 (m, 6H).

Example 116: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((1,3-dimethyl-1H-pyrazol-5-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1504] ##STR00376##

Synthetic Method

[1505] ##STR00377##

Step 1: Synthesis of N-(4-bromo-3-(cyclopropylsulfonyl)phenyl)-1,3-dimethyl-1H-pyrazol-5-amine

[1506] 1-Bromo-2-(cyclopropylsulfonyl)-4-iodobenzene (5.00 g, 12.9 mmol) and 5-amino-1,3-dimethylpyrazole (1.72 g, 15.5 mmol) were dissolved in tetrahydrofuran (150 mL), and cesium carbonate (12.6 g, 38.8 mmol) and methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino) xanthene][2-amino-l,l-diphenyl]palladium (II)-dichloromethane adduct (612 mg, 646 μmol) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 87° C. for 5 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=2:1) to obtain N-(4-bromo-3-(cyclopropylsulfonyl)phenyl)-1,3-dimethyl-1H-pyrazol-5-amine as a yellow solid compound (4.00 g).

[1507] MS m/z (ESI): 371.9 [M+H].sup.+;

Step 2: Synthesis of N-(3-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3-dimethyl-1H-pyrazol-5-amine

[1508] 1-Bromo-2-(cyclopropylsulfonyl)-4-iodobenzene (600 mg, 1.62 mmol) and bis(pinacolato)diboron (2.06 g, 8.10 mmol) were dissolved in N,N-dimethylformamide (10 mL), and potassium acetate (795 mg, 8.10 mmol) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium-dichloromethane (132 mg, 162 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica, petroleum ether:ethyl acetate=1:1) to obtain N-(3-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3-dimethyl-1H-pyrazol-5-amine as a yellow solid compound (400 mg).

[1509] MS m/z (ESI): 418.2 [M+H].sup.+;

Step 3: Synthesis of isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((1,3-dimethyl-1H-pyrazol-5-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1510] N-(3-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3-dimethyl-1H-pyrazol-5-amine (400 mg, 958 μmol) and isopropyl trans-(4-(5-bromothiazol-2-yl)cyclohexyl)carbamate (366 mg, 1.05 mmol) were dissolved in dioxane (10 mL), and an aqueous sodium carbonate solution (2M, 2 mL) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium-dichloromethane (78.2 mg, 95.8 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 2 hours. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, added with water (10 mL), and extracted with dichloromethane (30 mL, 10 mL×3) three times. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC-Actus Triart C18: 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile (44% to 64%) as eluents) to obtain isopropyl trans-(4-(5-(2-(cyclopropylsulfonyl)-4-((1,3-dimethyl-1H-pyrazol-5-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate as a white solid compound (225 mg).

[1511] MS m/z (ESI): 558.1 [M+H].sup.+;

[1512] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.67 (s, 1H), 7.65 (s, 1H), 7.50 (d, J=2.5 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.08-6.99 (m, 2H), 5.90 (s, 1H), 4.81-4.68 (m, 1H), 3.58 (s, 3H), 3.32-3.30 (m, 1H), 2.98-2.87 (m, 1H), 2.41-2.34 (m, 1H), 2.12 (s, 5H), 1.91 (br d, J=10.5 Hz, 2H), 1.62-1.48 (m, 2H), 1.40-1.27 (m, 2H), 1.16 (d, J=6.3 Hz, 6H), 0.99-0.91 (m, 2H), 0.89-0.82 (m, 2H).

Example 117: Synthesis of isopropyl trans-(4-(5-(4-((1,3-dimethyl-1H-pyrazol-5-yl)amino)-2-(oxetan-3-ylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1513] ##STR00378##

Synthetic Method

[1514] ##STR00379##

[1515] Isopropyl trans-N-[4-[5-[4-bromo-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate (60.0 mg, 110 μmol) and 5-amino-1,3-dimethylpyrazole (13.5 mg, 121 μmol) were dissolved in tetrahydrofuran (3 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.0 mg, 11.0 μmol) and potassium acetate (21.7 mg, 220 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was added with 30 mL of ethyl acetate (10 mL×3) and 10 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-(4-(5-(4-((1,3-dimethyl-1H-pyrazol-5-yl)amino)-2-(oxetan-3-ylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (12.20 mg) as a white solid.

[1516] MS m/z (ESI): 573.9 [M+H].sup.+;

[1517] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.74 (s, 1H), 7.63 (s, 1H), 7.56 (d, J=2.5 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.10-7.02 (m, 2H), 5.92 (s, 1H), 4.86-4.72 (m, 1H), 4.64-4.58 (m, 2H), 4.53-4.46 (m, 3H), 3.59 (s, 3H), 3.32-3.27 (m, 1H), 2.97-2.89 (m, 1H), 2.14 (s, 5H), 1.92 (br d, J=9.5 Hz, 2H), 1.62-1.51 (m, 2H), 1.39-1.28 (m, 2H), 1.17-1.05 (m, 6H).

Example 118: Synthesis of isopropyl trans-(4-(5-(4-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)amino)-2-(oxetan-3-ylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1518] ##STR00380##

Synthetic Method

[1519] ##STR00381##

[1520] Isopropyl trans-N-[4-[5-[4-bromo-2-(oxetan-3-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl] carbamate (60.0 mg, 110 μmol) and 1-(2-fluoroethyl)-1H-pyrazol-4-amine (15.7 mg, 121 μmol) were dissolved in tetrahydrofuran (3 mL), and methanesulfonato(2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) (10.0 mg, 11.0 μmol) and potassium acetate (21.7 mg, 220 μmol) were added. The reaction solution was stirred and reacted at 100° C. for 1 hour. The completion of the reaction was detected by LCMS. The reaction solution was added with 30 mL of ethyl acetate (10 mL×3) and 10 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by preparative liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm in diameter, 150 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-(4-(5-(4-((1-(2-fluoroethyl)-1H-pyrazol-4-yl)amino)-2-(oxetan-3-ylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl) carbamate (13.85 mg) as a white solid.

[1521] MS m/z (ESI): 591.9 [M+H].sup.+;

[1522] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.36 (s, 1H), 7.82 (s, 1H), 7.60 (s, 1H), 7.49 (s, 1H), 7.46 (s, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.05-6.99 (m, 2H), 4.86-4.80 (m, 1H), 4.78-4.70 (m, 2H), 4.64-4.58 (m, 2H), 4.52-4.44 (m, 4H), 4.46-4.33 (m, 1H), 3.33-3.25 (m, 1H), 2.96-2.88 (m, 1H), 2.13 (br d, J=11.8 Hz, 2H), 1.95-1.88 (m, 2H), 1.62-1.50 (m, 2H), 1.39-1.28 (m, 2H), 1.19-1.05 (m, 6H).

Example 119: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]-3-(1-phenylethylsulfonyl)phenyl]carbamate

[1523] ##STR00382##

Synthetic Method

[1524] ##STR00383##

Step 1: Synthesis of 2-bromo-5-nitro-benzenethiol

[1525] 2-Bromo-5-nitro-benzenesulfonyl chloride (1.5 g, 4.99 mmol) was dissolved in toluene (20 mL), and triphenylphosphine (3.93 g, 14.97 mmol) was added in two batches. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 110° C. for 1.2 h. TLC (petroleum ether:ethyl acetate=5:1) detection showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to obtain the compound 2-bromo-5-nitro-benzenethiol (200 mg) as a white solid.

[1526] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (d, J=2.26 Hz, 1H) 7.93-7.75 (m, 2H).

Step 2: Synthesis of 1-bromo-4-nitro-2-(1-phenylethylmercapto)benzene

[1527] 2-Bromo-5-nitro-benzenethiol (175 mg, 747.64 μmop and (1-bromoethyl)benzene (207.54 mg, 1.12 mmol) were dissolved in acetonitrile (900 μL). Under the protection of nitrogen, potassium carbonate (309.98 mg, 2.24 mmol) and potassium iodide (124.11 mg, 747.64 μmol) were added. The reaction solution appeared as a red suspension, and was stirred and reacted at 80° C. for 1.5 h. TLC detection showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to obtain 1-bromo-4-nitro-2-(1-phenylethylmercapto)benzene as the product (205 mg), which was a yellow oil.

[1528] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (d, J=2.25 Hz, 1H) 7.93-7.83 (m, 2H) 7.52 (d, J=7.25 Hz, 2H) 7.39-7.32 (m, 2H) 7.29-7.22 (m, 1H) 5.01-4.90 (m, 1H) 1.65 (d, J=7.00 Hz, 3H).

Step 3: Synthesis of 4-bromo-3-(1-phenylethylmercapto)aniline

[1529] 1-Bromo-4-nitro-2-(1-phenylethylmercapto)benzene (240 mg, 709.60 μmol) was dissolved in anhydrous ethanol (2 mL). Under the protection of nitrogen, reduced iron powder (237.77 mg, 4.26 mmol) and ammonium chloride (379.57 mg, 7.10 mmol) were added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 80° C. for 2 h. The completion of the reaction was detected by LCMS. The reaction solution was filtered while it was still hot, added with water (5 mL), and extracted with dichloromethane (10 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure to obtain the crude compound 4-bromo-3-(1-phenylethylmercapto)aniline (175 mg) as a white solid.

[1530] MS m/z (ESI): 308.1, 310.1 [M+H].sup.+;

Step 4: Synthesis of isopropyl N-[4-bromo-3-(1-phenylethylmercapto)phenyl]carbamate

[1531] 4-Bromo-3-(1-phenylethylmercapto)aniline (175 mg, 567.75 μmol) was dissolved in anhydrous dichloromethane (2 mL). Under the protection of nitrogen, pyridine (269.45 mg, 3.41 mmol) and isopropyl chloroformate (208.73 mg, 1.70 mmol, 236.39 μL) were added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 1 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by a thin-layer chromatography plate (petroleum ether:ethyl acetate=3:1) to obtain the compound isopropyl N-[4-bromo-3-(1-phenylethylmercapto)phenyl]carbamate (185 mg) as a white solid.

[1532] MS m/z (ESI): 394.1, 396.1 [M+H].sup.+;

Step 5: Synthesis of isopropyl N-[4-bromo-3-(1-phenylethylsulfonyl)phenyl]carbamate

[1533] Isopropyl N-[4-bromo-3-(1-phenylethylmercapto)phenyl]carbamate (185 mg, 469.16 μmol) was dissolved in anhydrous dichloromethane (3 mL), and m-chloroperoxybenzoic acid (242.88 mg, 1.41 mmol) was added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 25° C. for 1 h. The completion of the reaction was detected by LCMS. The reaction solution was added with saturated ammonium chloride solution (10 mL) and extracted with dichloromethane (20 mL). The organic layer was dried over anhydrous magnesium sulfate and subjected to suction filtration. The filtrate was concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (petroleum ether:ethyl acetate=3:1) to obtain the compound isopropyl N-[4-bromo-3-(1-phenylethylsulfonyl)phenyl]carbamate (200 mg) as a white solid.

[1534] MS m/z (ESI): 443.1, 445.1 [M+H.sub.2O].sup.+;

Step 6: Synthesis of isopropyl N-[3-(1-phenylethylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[1535] Isopropyl N-[4-bromo-3-(1-phenylethylsulfonyl)phenyl]carbamate (200 mg, 469.13 μmol) and bis(pinacolato)diboron (476.52 mg, 1.88 mmol) were dissolved in anhydrous tetrahydrofuran (4 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino) ferrocene]dichloropalladium-dichloromethane complex (38.31 mg, 46.91 μmol) and potassium acetate (138.12 mg, 1.41 mmol) were added. The reaction solution appeared as a black suspension, and was stirred and reacted at 80° C. for 7 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure. The resultant was purified by thin-layer chromatography (petroleum ether:ethyl acetate=3:1) to obtain the compound isopropyl N-[3-(1-phenylethylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (100 mg) as a white solid.

[1536] MS m/z (ESI): 491.2 [M+H.sub.2O].sup.+;

Step 7: Synthesis of isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl] thiazol-5-yl]-3-(1-phenylethylsulfonyl)phenyl]carbamate

[1537] Isopropyl N-[3-(1-phenylethylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]carbamate (50 mg, 105.62 μmol) and isopropyl trans-N-[4-(5-bromothiazol-2-yl) cyclohexyl]carbamate (36.68 mg, 105.62 μmol) were dissolved in 1,4-dioxane (2 mL). Under the protection of nitrogen, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (8.63 mg, 10.56 μmol), sodium carbonate (22.39 mg, 211.24 μmol) and water (0.2 mL) were added. The reaction solution appeared as a yellow suspension, and was stirred and reacted at 80° C. for 7 h. The completion of the reaction was detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure, diluted with water (5 mL), and then extracted with dichloromethane (20 mL). The organic phase was evaporated to dryness via rotary evaporation and purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm in diameter, 250 mm in length; using decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents) to obtain the compound isopropyl trans-N-[4-[2-[4-(isopropoxycarbonylamino) cyclohexyl]thiazol-5-yl]-3-(1-phenylethylsulfonyl)phenyl]carbamate (8.53 mg) as a white solid.

[1538] MS m/z (ESI): 613.0 [M+H].sup.+;

[1539] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 10.11 (s, 1H) 8.21 (d, J=2.26 Hz, 1H) 7.78-7.72 (m, 2H) 7.51 (d, J=8.53 Hz, 1H) 7.34-7.28 (m, 3H) 7.09-7.03 (m, 3H) 4.98-4.87 (m, 1H) 4.81-4.70 (m, 1H) 4.10-4.00 (m, 1H) 3.33-3.28 (m, 1H) 3.06-2.93 (m, 1H) 2.21-2.12 (m, 2H) 1.99-1.89 (m, 2H) 1.68-1.55 (m, 2H) 1.43 (d, J=7.03 Hz, 3H) 1.40-1.30 (m, 2H) 1.27 (d, J=6.27 Hz, 6H) 1.17 (d, J=6.27 Hz, 6H).

TEST EXAMPLES FOR BIOACTIVITIES AND RELATED PROPERTIES

Test Example 1: Experiment on the Inhibition of Human Daudi Lymphoma Cell Proliferation

[1540] Introduction of the experimental principle: After the RAD51 inhibitor to be tested was co-incubated with cancer cells for a period of time, the influence of the test compound on cell proliferation was measured by a method for counting cell proliferation based on the quantitative measurement of intracellular ATP content.

[1541] Materials and Cells: Daudi cells were purchased from ATCC; fetal bovine serum, 1640 medium and penicillin-streptomycin were purchased from Gibco Inc. (U.S.), 96-well plates were purchased from Corning Inc. (U.S.), and Cell-Titer Glo reagent was purchased from Promega Corporation (U.S.).

[1542] Cell culture: Daudi cells were cultured in 1640 culture medium containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37° C. in an atmosphere containing 5% CO.sub.2. Cells in logarithmic growth phase could be used for experiments.

[1543] Assay of cell proliferation and viability: Cell-Titer Glo reagent was used to measure the inhibitory activities of the compounds on the proliferation of Daudi cell strain. The concentration of cells was adjusted, and the cells were seeded in a 96-well plate and cultured at 37° C. in an atmosphere containing 5% CO.sub.2 for 24 hours. The powder of the compound was dissolved in 100% DMSO to form a 10 mM solution. 10 μl of the solution of the compound was aspirated and transferred into a 96-well compound plate containing 20 μl of DMSO solution for 3-fold dilution and was then formulated into 10 serial dilutions. Thereafter, 2 μl of the solution of the compound was aspirated from the corresponding well and added correspondingly into a 96-well intermediate compound dilution plate containing 78 μl of complete culture medium in each well. The resultant was mixed well, and the plate was centrifuged at 1000 rpm for 1 minute. Finally, 10 μl of the solution of the compound was aspirated from the corresponding well of the 96-well intermediate compound dilution plate, and transferred into the corresponding well of the cell culture plate containing 90 μl of complete culture medium. The final concentration of DMSO was 0.25%. After the addition of the compound, the cells were continued to be incubated for 3 days at 37° C. in an atmosphere containing 5% CO.sub.2. Cell-Titer Glo reagent was added to measure cell viability.

[1544] Data Analysis

[1545] % Compound inhibition was calculated and IC.sub.50 of the compound was filled;

% Compound inhibition=1−100%×(Signal−Bottom)/(Top−Bottom)

[1546] Experimental Results:

[1547] The corresponding anti-proliferative activities of the test compounds against Daudi cell were listed in Table 1.

TABLE-US-00002 TABLE 1 Inhibitory activities of the compounds of the present disclosure against the proliferation of Daudi cells Anti-Proliferative Activity Against Daudi cells Compounds IC.sub.50 (μM) Example 1 1.62 Example 2 0.39 Example 3 1.08 Example 4 1.01 Example 5 1.16 Example 6 3.72 Example 7 2.59 Example 8 3.95 Example 9 2.06 Example 10 9.72 Example 11 2.54 Example 12 0.02 Example 13 0.41 Example 14 0.45 Example 15 0.28 Example 16 0.49 Example 17 0.11 Example 18 0.09 Example 19 0.96 Example 20 2.75 Example 21 0.44 Example 22 0.035 Example 23 3.93 Example 24 2.27 Example 25 0.74 Example 26 0.13 Example 27 0.68 Example 28 0.048 Example 29 0.34 Example 30 2.65 Example 32 0.42 Example 33 0.1 Example 34 0.7 Example 35 4.29 Example 36 0.077 Example 37 0.33 Example 38 0.15 Example 39 0.23 Example 40 0.051 Example 41 0.9 Example 42 0.42 Example 43 1.58 Example 44 0.68 Example 45 0.062 Example 46 0.39 Example 47 0.03 Example 48 0.006 Example 49 0.006 Example 50 0.026 Example 51 0.065 Example 52 0.08 Example 53 0.1 Example 54 0.055 Example 56 0.007 Example 57 0.007 Example 58 0.027 Example 59 0.125 Example 60 0.004 Example 61 0.104 Example 62 0.01 Example 63 0.07 Example 64 5.2 Example 65 0.037 Example 66 0.018 Example 67 2.6 Example 68 0.1 Example 69 0.03 Example 70 0.008 Example 71 0.016 Example 72 0.004 Example 73 0.2 Example 74 0.09 Example 75 0.022 Example 76 0.009 Example 77 0.004 Example 78 0.004 Example 79 0.051 Example 80 0.33 Example 81 0.04 Example 82 0.25 Example 83 0.2 Example 84 0.007 Example 85 0.0006 Example 86 0.003 Example 87 0.29 Example 88 0.004 Example 89 0.007 Example 89-1 0.127 Example 90 8.8 Example 91 1.5 Example 91-1 0.06 Example 92 0.004 Example 93 0.01 Example 94 0.02 Example 94-1 0.06 Example 95 0.132 Example 96 0.14 Example 97 0.29 Example 98 0.032 Example 99 0.036 Example 100 0.68 Example 101 0.028 Example 102 0.017 Example 103 0.047 Example 104 0.023 Example 105 0.026 Example 106 0.04 Example 107 0.275 Example 108 0.468 Example 109 0.076 Example 111 0.7 Example 112 0.017 Example 113 0.016 Example 114 0.014 Example 115 0.016 Example 116 0.004 Example 117 0.007

Test Example 2: Experiment on the Inhibition of Human WI-38 Embryonic Lung Cell Proliferation

[1548] Introduction of the experimental principle: After the RAD51 inhibitor to be tested was co-incubated with human embryonic lung cells for a period of time, the influence of the test compound on cell proliferation was measured by a method for counting cell proliferation based on the quantitative measurement of intracellular ATP content.

[1549] Materials and Cells: WI-38 cells were purchased from ATCC; fetal bovine serum, 1640 medium and penicillin-streptomycin were purchased from Gibco Inc. (U.S.), 96-well plates were purchased from Corning Inc. (U.S.), and Cell-Titer Glo reagent was purchased from Promega Corporation (U.S.).

[1550] Cell culture: WI-38 cells were cultured in an EMEM culture medium containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37° C. in an atmosphere containing 5% CO.sub.2. Cells in logarithmic growth phase could be used for experiments.

[1551] Assay of cell proliferation and viability: Cell-Titer Glo reagent was used to measure the inhibitory activities of the compounds on the proliferation of WI-38 cell strain. The concentration of cells was adjusted, and the cells were seeded in a 96-well plate and cultured at 37° C. in an atmosphere containing 5% CO.sub.2 for 24 hours. The powder of the compound was dissolved in 100% DMSO to form a 10 mM solution. 10 μl of the solution of the compound was aspirated and transferred into a 96-well compound plate containing 20 μl of DMSO solution in each well for 3-fold dilution and was then formulated to 10 serial dilutions. Thereafter, 2 μl of the solution of the compound was aspirated from the corresponding well and added correspondingly into a 96-well intermediate compound dilution plate containing 78 μl of complete culture medium in each well. The resultant was mixed well, and the plate was centrifuged at 1000 rpm for 1 minute. Finally, 10 μl of the solution of the compound was aspirated from the corresponding well of the 96-well intermediate compound dilution plate, and transferred into the corresponding well of the cell culture plate containing 90 μl of complete culture medium. The final concentration of DMSO was 0.25%. After the addition of the compound, the cells were continued to be incubated for 3 days at 37° C. in an atmosphere containing 5% CO.sub.2. Cell-Titer Glo reagent was added to measure cell viability.

[1552] Data Analysis:

[1553] % Compound inhibition was calculated and IC.sub.50 of the compound was fitted;

% Compound inhibition=1−100%×(Signal−Bottom)/(Top−Bottom)

[1554] Experimental Results:

[1555] The corresponding anti-proliferative activities of the test compounds against WI-38 cell were listed in Table 2.

TABLE-US-00003 TABLE 2 Inhibitory activities of the compounds of the present disclosure against the proliferation of WI-38 cells Anti-Proliferative Activity Against WI-38 cells Compounds IC.sub.50 (μM) Example 1 >25 Example 2 >25 Example 3 >25 Example 4 7.22 Example 5 >25 Example 6 >25 Example 7 >25 Example 9 >25 Example 12 >25 Example 13 >25 Example 14 >25 Example 15 >25 Example 16 >25 Example 17 >25 Example 18 >25 Example 19 >25 Example 21 >25 Example 22 23.3 Example 25 >25 Example 26 >25 Example 28 15 Example 29 18.4 Example 32 23 Example 33 >25 Example 34 >25 Example 36 24.6 Example 37 >25 Example 39 >25 Example 40 22.9 Example 45 >25 Example 47 >25 Example 48 15.6 Example 49 >25 Example 50 >25 Example 53 >25 Example 54 >25 Example 56 >25 Example 57 >25 Example 62 >25 Example 65 >25 Example 68 >25 Example 69 >25 Example 70 21 Example 72 20 Example 81 14 Example 84 >25 Example 85 17 Example 86 >25 Example 88 >25 Example 92 19.5 Example 98 >25 Example 101 >25 Example 102 >25 Example 103 >25 Example 104 >25 Example 114 >25 Example 115 >25 Example 117 20

[1556] Under the conditions of Test Example 1 and Test Example 2, the test compounds exhibited relatively strong inhibitory activity on the proliferation of Daudi cells and relatively weak inhibitory activity on the proliferation of WI-38 cells, and the compounds also exhibited certain selectivity in terms of the inhibitory activities on the proliferation of Daudi cells and WI-38 cells.

Test Example 3: Metabolic Stability Assay of the Compounds of the Present Disclosure in Liver Microsomes

[1557] I. Test Materials and Instruments

[1558] 1. Source of liver microsomes: human liver microsomes (Corning 452117), CD-1 mouse liver microsomes (XENOTECH M1000)

[1559] 2. Na.sub.2HPO.sub.4 (Tianjin Guangfu Fine Chemical Research Institute, 20180130)

[1560] 3. KH.sub.2PO.sub.4 (Tianjin Guangfu Fine Chemical Research Institute, 20180920)

[1561] 4. MgCl.sub.2 (Tianjin Guangfu Fine Chemical Research Institute, 20191216)

[1562] 5. NADPH (Solarbio 1216C022)

[1563] 6. Verapamil as a positive control compound (Sigma MKBV4993V)

[1564] 7. AB Sciex Triple Quad 4000 liquid chromatography-mass spectrometer

[1565] II. Experimental Steps

[1566] 1. Formulation of 100 mM phosphate buffer solution (PBS): 7.098 g of Na.sub.2HPO.sub.4 was weighed and ultrasonically dissolved in 500 mL of pure water to form Solution A. 3.400 g of KH.sub.2PO.sub.4 was weighed and ultrasonically dissolved in 250 mL of pure water to form Solution B. Solution A was placed in a stirrer and Solution B was slowly added until the pH value reached 7.4, thus formulating 100 mM PBS buffer solution.

[1567] 2. Formulation of the reaction system

[1568] The reaction system was formulated according to Table 3 below.

TABLE-US-00004 TABLE 3 Formulation information of reaction system Conc. of Stock Reagent Solution Volume Final Conc. Liver microsome 20 mg/mL  10 μL 0.5 mg/mL Phosphate buffer 100 mM 346 μL 100 mM solution

[1569] 3. The reaction system was placed in a water bath at 37° C. and pre-incubated for 10 minutes. 40 μL of 10 mM NADPH solution (NADPH was dissolved in 100 mM phosphate buffer solution) was added into the reaction system, and the final concentration of NADPH was 1 mM. 40 μL of Phosphate buffer solution was used instead of the NADPH solution as a negative control. The negative control was used to rule out the influence caused by the chemical stability of the compounds per se.

[1570] 4. The reaction system was added with 4 μL of 100 μM the compound of the present disclosure and Verapamil (the positive control compound) (DMSO as the vehicle), so that the reaction was initiated. The final concentration of the compound was 1 μM.

[1571] 5. At 0.5, 15, 30, 45 and 60 minutes, after being well mixed in a vortex oscillator, 50 μL of the incubated samples were taken out respectively, and the reaction was terminated with ice acetonitrile (4-fold) containing an internal standard. The samples were centrifuged at 3220 g for 45 minutes. After the centrifugation, 90 μL of the supernatants were transferred to a sample plate and mixed well with 90 μL of ultrapure water for LC-MS/MS analysis.

[1572] All data were calculated by Microsoft Excel software. Peak areas were determined from the extracted ion chromatograms. The in-vitro half-life (t.sub.1/2) of the parent drug was determined by the linear fitting of the natural logarithm of the elimination percentage of the parent drug versus time.

[1573] The in-vitro half-life (t.sub.1/2) was calculated from the slope:

In-vitro t.sub.1/2=0.693/k.

[1574] The t.sub.1/2 values calculated by the above formula were as listed in Table 4.

TABLE-US-00005 TABLE 4 Half-life values and intrinsic clearance values of the compounds of the present disclosure in liver microsomes Example No. Species t.sub.1/2 (min) Example 1 Human being >500 CD-1 mouse >500 Example 2 Human being 145 CD-1 mouse 256 Example 3 Human being 477 CD-1 mouse >500 Example 32 Human being 251 CD-1 mouse 162 Example 33 Human being >500 CD-1 mouse 248 Example 47 Human being 303 CD-1 mouse 437 Example 48 Human being >500 CD-1 mouse 432 Example 49 Human being 56 CD-1 mouse 125 Example 50 Human being 475 CD-1 mouse 376 Example 54 Human being >500 CD-1 mouse >500 Example 56 Human being 179 CD-1 mouse 109 Example 57 Human being 56 CD-1 mouse 126 Example 65 Human being 111 CD-1 mouse 80 Example 72 Human being 422 CD-1 mouse 271 Example 68 Human being 187 CD-1 mouse 169 Example 81 Human being 319 CD-1 mouse 210 Example 84 Human being 67 CD-1 mouse 112 Example 85 Human being 82 CD-1 mouse 51 Example 86 Human being 107 CD-1 mouse 84 Example 92 Human being 382 CD-1 mouse 346 Example 94 Human being 231 CD-1 mouse 204 Example 98 Human being 137 CD-1 mouse >500 Example 103 Human being >500 CD-1 mouse >500

Test Example 4: Plasma Protein Binding Rate Assay of the Compounds of the Present Disclosure

[1575] I. Test Materials and Instruments

[1576] 1. CD-1 mouse plasma (BioIVT)

[1577] 2. Na.sub.2HPO.sub.4 (Sigma 55136-500G)

[1578] 3. NaH.sub.2PO.sub.4 (Sigma S3139-500G)

[1579] 4. NaCl (Sigma 55886-IKG)

[1580] 5. 96-well equilibrium dialysis plate (HTDialysis LLC, Gales Ferry, CT, HTD96B), equilibrium dialysis membrane (MWCO 12-14K, #1101)

[1581] 6. Warfarin as a positive control compound

[1582] 7. ABI QTrap 5500 liquid chromatography-mass spectrometer

[1583] II. Experimental Steps

[1584] 1. Formulation of a buffer solution containing 100 mM sodium phosphate and 150 mM NaCl: An alkaline solution containing Na.sub.2HPO.sub.4 (14.2 g/L) and NaCl (8.77 g/L) was formulated with ultrapure water. An acidic solution containing NaH.sub.2PO.sub.4 (12.0 g/L) and NaCl (8.77 g/L) was formulated with ultrapure water. The alkaline solution was titrated with the acidic solution until the pH value was 7.4, thus formulating the buffer solution containing 100 mM sodium phosphate and 150 mM NaCl.

[1585] 2. Preparation of dialysis membrane: The dialysis membrane was immersed in ultrapure water for 60 minutes to separate the membrane into two pieces, then immersed in 20% ethanol for 20 minutes, and finally immersed in a buffer for dialysis for 20 minutes.

[1586] 3. Preparation of plasma: Frozen plasma was thawed rapidly at room temperature. Thereafter, the plasma was centrifuged at 3220 g for 10 minutes at 4° C. to remove clots, and the supernatant was collected into a new centrifuge tube. The pH values of plasma were measured and recorded. The plasma with a pH value of 7 to 8 was used.

[1587] 4. Formulation of compound-containing plasma samples: A 10 mM stock solution of the compound of the present disclosure or the positive control compound was diluted with DMSO to obtain a 200 μM working solution. 3 μl of the 200 μM working solution of the compound was added into 597 μl of mouse plasma to obtain a plasma sample with a final concentration of 1 μM.

[1588] 5. Steps of equilibrium dialysis: The dialysis device was assembled according to the operating instructions. 120 μL of a plasma sample containing 1 μM compound was added on one side of the dialysis membrane, and an equal volume of dialysate (phosphate buffer solution) was added on the other side. Duplicate samples were set in the experiment. The dialysis plate was sealed and placed in an incubation device where the samples were incubated at 37° C. in an atmosphere containing 5% CO.sub.2 for 6 hours with a rotational speed of about 100 rpm. After the incubation was complete, the sealing membrane was removed. 50 μl of samples were respectively aspirated from the buffer solution side and the plasma side of each well and transferred into different wells of a new plate. 50 μl of blank plasma was added into the sample obtained from the phosphate buffer solution side, and an equal volume of blank phosphate buffer solution was added into the plasma sample, followed by the addition of 300 μl of acetonitrile containing the internal standard to precipitate protein. The sample was vortexed for 5 minutes and centrifuged at 3220 g for 30 minutes at 4° C. 100 μl of the supernatant was aspirated and transferred to the sample plate, mixed well with 100 μL of ultrapure water, and used for LC-MS/MS analysis.

[1589] The peak areas of the compounds on the buffer solution side and the plasma side were determined. The formula for calculating the plasma protein binding rate of the compound was as follows:

% Free rate=(the ratio of the peak area of the compound to the peak area of the internal standard on the buffer solution side/the ratio of the peak area of the compound to the peak area of the internal standard on the plasma side)×100

% Binding rate=100−% free rate

[1590] All data were calculated by Microsoft Excel software. The calculated plasma protein binding rates of the compounds of the present disclosure were listed in Table 5.

TABLE-US-00006 TABLE 5 Protein binding rates of the compounds of the present disclosure in CD-1 mouse plasma Example No. % Binding Rate Example 1 94% Example 2 99.4%.sup.  Example 3 97% Example 32 99% Example 33 99% Example 47 99% Example 48 99% Example 49 97% Example 50 96% Example 54 95% Example 56 97% Example 57 99.9%.sup.  Example 65 97% Example 68 97% Example 81 99.7%.sup.  Example 92 98.8%.sup.  Example 94 99.8%.sup.  Example 98 99% Example 103 98%

Test Example 5: Pharmacokinetics Evaluation

[1591] Pharmacokinetic Experiment in Mouse

[1592] Experimental Materials:

[1593] CB17-SCID mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[1594] DMSO, HP-β-CD (hydroxypropyl-β-cyclodextrin), PEG400 (polyethylene glycol 400), and Vitamin E TPGS (D-α-tocopherol polyethylene glycol 1000 succinate) were purchased from Sigma.

[1595] Acetonitrile was purchased from Merck (USA).

[1596] Experimental Method:

[1597] Six female CB17-SCID mice (20 g to 30 g, aged 4 to 6 weeks) were divided randomly into two groups, with 3 mice in each group. In Group 1, the compound in a vehicle of an aqueous solution containing 5% dimethyl sulfoxide and 95% hydroxypropyl-β-cyclodextrin (10%, w/v) was administered by intravenous injection via tail vein. In Group 2, a corresponding dose of the compound in a vehicle of an aqueous solution containing 30% polyethylene glycol 400 and 70% D-α-tocopherol polyethylene glycol 1000 succinate (10%, w/v) was orally administered. The animals were fed normally with food and water before experiment. The mice in each group underwent intravenous blood collection before administration and at 0.083 h (intravenous injection group only), 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The collected whole blood samples were placed in K2EDTA anticoagulation tubes and centrifuged for 5 min (4000 rpm, 4° C.) to collect the plasma for testing.

[1598] 10 μL of the mouse plasma sample was taken, and 150 μL of acetonitrile solvent (containing the internal standard compound) was added to precipitate protein. After the resultant was vortexed for 0.5 min and centrifuged (4700 rpm, 4° C.) for 15 min, the supernatant was subjected to 2-fold dilution with water containing 0.05% (v/v) FA and was then subjected to quantitative measurement in LC-MS/MS system (AB Sciex Triple Quad 6500+). A calibration standard curve was prepared in CB17-SCID mouse plasma along with quality control samples to determine the plasma concentration. As for a 10× diluted sample, 2 μL of sample was taken and 18 μL of blank plasma was added. After being vortexed for 0.5 min, the mixture was added with 300 μL of acetonitrile solvent (containing the internal standard compound) so as to precipitate protein. The rest of the processing steps were the same as those for the undiluted samples.

[1599] PK test results were as shown in Table 6 below.

TABLE-US-00007 TABLE 6 PK of the compounds of the present disclosure in mouse Oral Max. Drug Peak Time Drug Drug Dose Conc. of Drug Elimination Exposure Compound No. mg/kg ng/ml Conc. (h) Half-life (h) ng × h/ml Example 1 80 14640 2.3 3.7 211819 Example 3 80 15438 2.8 32 271377 Example 48 30 17657 2 7.6 203497 Example 50 25 4076 1 4.7 18187 Example 54 25 6698 1 3.1 47683 Example 68 25 14798 1.3 5 156699 Example 70 25 32840 0.75 5 137892 Example 81 25 13563 5 10 223309 Example 92 25 8038 1 3.6 40080 Example 94 25 19257 1.3 3.5 125779

[1600] The embodiments of the present disclosure have been described above, but the present disclosure is not limited to the embodiments described above. Any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present disclosure shall be encompassed in the protection scope of the present disclosure.