1H-IMIDAZO[4,5-H]QUINAZOLINE COMPOUND AS PROTEIN KINASE INHIBITOR

Abstract

Provided is a 1H-imidazo[4,5-h]quinazoline compound of formula (I). The compound is a broad spectrum inhibitor having strong activity for cyclin-dependent kinase (CDK) and is applicable in treating cell proliferative disorder

##STR00001##

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof: ##STR00213## wherein: A.sub.1 is selected from CR.sub.3 or N; A.sub.2 is selected from CR.sub.3 or N; A.sub.3 is selected from CR.sub.3 or N; R.sub.1 is selected from H, halogen, —CN, —OR.sub.a, —SR.sub.a, —NR.sub.bR.sub.c, —C(O)R.sub.a, —C(O)OR.sub.a, —C(O)NR.sub.bR.sub.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C.sub.6-10 aryl, or 5- to 10-membered heteroaryl; wherein the said C.sub.3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted with oxo or thioxo; R.sub.2 is selected from H, halogen, —CN, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C.sub.6-10 aryl, or 5- to 10-membered heteroaryl; wherein the said C.sub.3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted with oxo or thioxo; R.sub.3 is selected from H, halogen, —CN, —NO.sub.2, -L-OR.sub.a, -L-SR.sub.a, -L-NR.sub.bR.sub.c, -L-C(O)R.sub.a, -L-C(O)OR.sub.a, -L-C(O)NR.sub.bR.sub.c, -L-S(O).sub.mR.sub.a, -L-S(O).sub.mOR.sub.a, -L-S(O).sub.mNR.sub.bR.sub.c, —O—C.sub.1-6 alkylene-R.sub.6, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, -L′-C.sub.3-7 cycloalkyl, -L′-3- to 11-membered heterocyclyl, -L′-C.sub.6-10 aryl, or -L′-5- to 10-membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4 or 5 R.sub.6 groups; R.sub.4 is selected from —C(O)R.sub.a, —C(O)OR.sub.a, —C(O)NR.sub.bR.sub.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; R.sub.5 is selected from H, halogen, —CN, —OR.sub.a, —SR.sub.a, —NR.sub.bR.sub.c, —C(O)R.sub.a, —C(O)OR.sub.a, —C(O)NR.sub.bR.sub.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C.sub.6-10 aryl, or 5- to 10-membered heteroaryl; wherein the said C.sub.3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted with oxo or thioxo; R.sub.6 is selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, —C.sub.1-6 alkylene-OR.sub.a, -L-C.sub.3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C.sub.6-10 aryl, or -L-5- to 10-membered heteroaryl; or two R.sub.6 groups on the same carbon atom are taken together to form oxo or thioxo; wherein: R.sub.4 is optionally substituted with 1, 2 or 3 R′ groups, wherein R′ is independently selected from H, halogen, —CN, —NO.sub.2, —OR.sub.a, —SR.sub.a, —NR.sub.bR.sub.c, —C(O)OR.sub.a, —C(O)NR.sub.bR.sub.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C.sub.6-10 aryl, or 5- to 10-membered heteroaryl; each of R.sub.3, R.sub.5 and R.sub.6 is optionally substituted with 1, 2 or 3 R″ groups, wherein R″ is independently selected from H, —OH, halogen, —NO.sub.2, carbonyl, -L-CN, -L-OR.sub.a, -L-SR.sub.a, -L-NR.sub.bR.sub.c, -L-C(O)R.sub.a, -L-C(S)R.sub.a, -L-C(O)OR.sub.a, -L-C(S)OR.sub.a, -L-C(O)—NR.sub.bR.sub.c, -L-C(S)—NR.sub.bR.sub.c, -L-O—C(O)R.sub.a, -L-O—C(S)R.sub.a, -L-N(R.sub.b)—C(O)—R.sub.a, -L-N(R.sub.b)—C(S)—R.sub.a, -L-S(O).sub.mR.sub.a, -L-S(O).sub.mOR.sub.a, -L-S(O).sub.mNR.sub.bR.sub.c, -L-N(R.sub.b)—S(O).sub.m—R.sub.a, -L-N(R.sub.b)—S(O).sub.m—NR.sub.bR.sub.c, -L-N(R.sub.b)—C(O)OR.sub.a, -L-N(R.sub.b)—C(S)OR.sub.a, -L-O—C.sub.1-6 alkylene-OR.sub.a, -L-C(O)—C.sub.1-6 alkylene-NR.sub.bR.sub.c, -L-N(R.sub.b)—C(O)—NR.sub.bR.sub.c, -L-N(R.sub.b)—C(S)—NR.sub.bR.sub.c, -L-O—C(O)—NR.sub.bR.sub.c, -L-O—C(S)—NR.sub.bR.sub.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, -L-C.sub.3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C.sub.6-10 aryl, or -L-5- to 10-membered heteroaryl; wherein the said C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, -L-C.sub.3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C.sub.6-10 aryl, or -L-5- to 10-membered heteroaryl is each optionally further substituted with one or more substituents independently selected from the group consisting of -L-CN, —NO.sub.2, carbonyl, -L-OR.sub.a, -L-SR.sub.a, -L-NR.sub.bR.sub.c, -L-C(O)R.sub.a, -L-C(S)R.sub.a, -L-C(O)OR.sub.a, -L-C(S)OR.sub.a, -L-C(O)—NR.sub.bR.sub.c, -L-C(S)—NR.sub.bR.sub.c, -L-O—C(O)R.sub.a, -L-O—C(S)R.sub.a, -L-N(R.sub.b)—C(O)—R.sub.a, -L-N(R.sub.b)—C(S)—R.sub.a, -L-S(O).sub.mR.sub.a, -L-S(O).sub.mOR.sub.a, -L-S(O).sub.mNR.sub.bR.sub.c, -L-N(R.sub.b)—S(O).sub.m—R.sub.a, -L-N(R.sub.b)—S(O).sub.m—R.sub.bR.sub.c, -L-N(R.sub.b)—C(O)OR.sub.a, -L-N(R.sub.b)—C(S)OR.sub.a, -L-O—C.sub.1-6 alkylene-OR.sub.a, -L-C(O)—C.sub.1-6 alkylene-NR.sub.bR.sub.c, -L-N(R.sub.b)—C(O)—NR.sub.bR.sub.c, -L-N(R.sub.b)—C(S)—NR.sub.bR.sub.c, -L-O—C(O)—NR.sub.bR.sub.c, and -L-O—C(S)—NR.sub.bR.sub.c; R.sub.a is independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, -L-C.sub.3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C.sub.6-10 aryl, or -L-5- to 10-membered heteroaryl; R.sub.b and R.sub.c are independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, -L-C.sub.3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C.sub.6-10 aryl, or -L-5- to 10-membered heteroaryl; or, R.sub.b and R.sub.c are taken together with the nitrogen atom to which they are attached to form 3- to 7-membered heterocyclyl; R.sub.a, R.sub.b and R.sub.c are each optionally further substituted with one or more substituents independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, -L-C.sub.3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C.sub.6-10 aryl, and -L-5- to 10-membered heteroaryl; L is selected from a chemical bond, —C.sub.1-6 alkylene-, —C.sub.2-6 alkenylene- or —C.sub.2-6 alkynylene-; L′ is selected from a chemical bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —C.sub.1-6 alkylene-, —C.sub.2-6 alkenylene- or —C.sub.2-6 alkynylene-; and m represents 0, 1 or 2.

2. The compound of formula (I), or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof according to claim 1, wherein, A.sub.1 is N; A.sub.2 is CR.sub.3; A.sub.3 is CR.sub.3; R.sub.1 is selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.1 is H; R.sub.2 is selected from H, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.3 is independently selected from H, halogen, —CN, —NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or 3- to 11-membered heterocyclyl which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; preferably, the said 3- to 11-membered heterocyclyl is selected from ##STR00214## preferably, R.sub.3 is independently selected from H, C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl, or is independently selected from ##STR00215## any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; preferably, R.sub.3 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or 5- to 6-membered heterocyclyl which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; preferably, R.sub.3 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or is independently selected from ##STR00216## any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; R.sub.4 is isopropyl; R.sub.5 is H; R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —C.sub.0-6 alkylene-OR.sub.a; R.sub.a is selected from H or C.sub.1-6 alkyl; or, A.sub.1 is N; A.sub.2 is CR.sub.3; A.sub.3 is CR.sub.3; R.sub.1 is H; R.sub.2 is H; R.sub.3 is independently selected from H, halogen, —CN, —NO.sub.2, C.sub.1-6 alkyl, C.sub.1_haloalkyl, or 5- to 6-membered heterocyclyl which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; preferably, R.sub.3 is independently selected from H, halogen, —CN, —NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or is independently selected from ##STR00217## any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; preferably, R.sub.3 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or is independently selected from ##STR00218## any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; R.sub.4 is selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or C.sub.3-7 cycloalkyl; preferably, R.sub.4 is cyclopentyl; R.sub.5 is H; R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —C.sub.0-6 alkylene-OR.sub.a; R.sub.a is selected from H or C.sub.1-6 alkyl; or, A.sub.1 is CH; A.sub.2 is CR.sub.3; A.sub.3 is CR.sub.3; R.sub.1 is H; R.sub.2 is H; R.sub.3 is independently selected from H, halogen, —CN, —NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or 5- to 6-membered heterocyclyl which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; preferably, R.sub.3 is independently selected from H, halogen, —CN, —NO.sub.2, C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl, or is independently selected from ##STR00219## any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; R.sub.4 is isopropyl; R.sub.5 is H; R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —C.sub.0-6 alkylene-OR.sub.a; R.sub.a is selected from H or C.sub.1-6 alkyl; or, A.sub.1 is CR.sub.3; A.sub.2 is CR.sub.3; A.sub.3 is CR.sub.3; R.sub.1 is H; R.sub.2 is H; R.sub.3 is selected from H, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, —OR.sub.a, —O—C.sub.1-6 alkylene-R.sub.6 or -L′-3- to 7-membered heterocyclyl, each of which is optionally substituted with 1 or 2 R.sub.6 groups; R.sub.4 is isopropyl; R.sub.5 is H; R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.a is selected from H or C.sub.1-6 alkyl; L′ is selected from a chemical bond, —O—, —NH—, —C(O)—, —C(O)NH— or —NHC(O)—.

3. A compound of formula (II-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof: ##STR00220## wherein, R.sub.1 is H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.2 is H, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.3 is selected from 3- to 11-membered heterocyclyl which is optionally substituted with 1, 2 or 3 R.sub.6 groups; preferably, R.sub.3 is selected from ##STR00221## any of which is optionally substituted with 1, 2 or 3 R.sub.6 groups; R.sub.3′ is independently selected from H or C.sub.1-6 alkyl; R.sub.6 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.1 is H or C.sub.1-6 alkyl; R.sub.2 is H, halogen or C.sub.1-6 alkyl; R.sub.3 is selected from ##STR00222## R.sub.3′ is independently selected from H or C.sub.1-6 alkyl; R.sub.6 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.1 is H or methyl; R.sub.2 is H, Br or methyl; R.sub.3 is selected from ##STR00223## R.sub.3′ is independently selected from H or methyl.

4. A compound of formula (II-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof: ##STR00224## wherein, R.sub.2 is selected from H, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.3 is selected from 3- to 11-membered heterocyclyl which is optionally substituted with 1, 2 or 3 R.sub.6 groups; preferably, R.sub.3 is selected from ##STR00225## any of which is optionally substituted with 1, 2 or 3 R.sub.6 groups; R.sub.3′ is independently selected from H, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —C.sub.0-6 alkylene-OR.sub.a; R.sub.a is selected from H or C.sub.1-6 alkyl; preferably, R.sub.2 is selected from H, halogen or C.sub.1-6 alkyl; R.sub.3′ is independently selected from H, halogen or C.sub.1-6 alkyl; R.sub.3 is selected from ##STR00226## R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl or —C.sub.0-6 alkylene-OR.sub.a; preferably, R.sub.2 is selected from H, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.3 is selected from 5- to 6-membered heterocyclyl which is optionally substituted with 1, 2 or 3 R.sub.6 groups; preferably, R.sub.3 is selected from ##STR00227## any of which is optionally substituted with 1, 2 or 3 R.sub.6 groups; R.sub.3′ is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.6 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.2 is selected from H, halogen or C.sub.1-6 alkyl; R.sub.3 is selected from ##STR00228## R.sub.3′ is independently selected from H or C.sub.1-6 alkyl; R.sub.6 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.2 is selected from H, Br or methyl; R.sub.3 is selected from or ##STR00229## R.sub.3′ is independently selected from H or methyl.

5. A compound of formula (II-3), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof: ##STR00230## wherein, R.sub.3 is selected from 3- to 11-membered heterocyclyl which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; preferably, R.sub.3 is selected from ##STR00231## any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; R.sub.3′ is independently selected from H, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —C.sub.0-6 alkylene-OR.sub.a; R.sub.a is selected from H or C.sub.1-6 alkyl; preferably, R.sub.3 is selected from ##STR00232## R.sub.3′ is independently selected from H, halogen or C.sub.1-6 alkyl; R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl or —C.sub.0-6 alkylene-OR.sub.a; R.sub.a is selected from H or C.sub.1-6 alkyl; preferably, R.sub.3 is selected from ##STR00233## R.sub.3′ is independently selected from H, F or methyl; preferably, R.sub.3 is selected from 5- to 6-membered heterocyclyl which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; preferably, R.sub.3 is selected from ##STR00234## any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; R.sub.3′ is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.6 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.3 is selected from ##STR00235## any of which is optionally substituted with 1, 2 or 3 R.sub.6 groups; R.sub.3′ is independently selected from H or C.sub.1-6 alkyl; R.sub.6 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.3 is selected from ##STR00236## R.sub.3′ is independently selected from H or C.sub.1-6 alkyl; R.sub.6 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.3 is selected from ##STR00237## R.sub.3′ is independently selected from H or methyl.

6. A compound of formula (II-4), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof: ##STR00238## wherein, R.sub.3 is selected from 5- to 6-membered heterocyclyl which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; preferably, R.sub.3 is selected from ##STR00239## any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; R.sub.3′ is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.4 is selected from C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl; R.sub.6 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.3 is selected from ##STR00240## R.sub.3′ is independently selected from H or C.sub.1-6 alkyl; R.sub.4 is selected from C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl; R.sub.6 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.3 is selected from ##STR00241## R.sub.3′ is independently selected from H or methyl; R.sub.4 is selected from cyclopropyl, cyclobutyl, cyclopentyl or ethyl.

7. A compound of formula (II-5), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof: ##STR00242## wherein, R.sub.3 is selected from 5- to 6-membered heterocyclyl which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; preferably, R.sub.3 is selected from ##STR00243## any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; R.sub.3′ is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.6 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.3 is selected from ##STR00244## R.sub.3′ is independently selected from H or C.sub.1-6 alkyl; R.sub.6 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.3 is selected from ##STR00245## R.sub.3′ is independently selected from H or methyl.

8. A compound of formula (III), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof: ##STR00246## wherein, R.sub.3 is selected from 5- to 6-membered heterocyclyl which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; preferably, R.sub.3 is selected from ##STR00247## any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; R.sub.3′ is independently selected from H, halogen or C.sub.1-6 alkyl; R.sub.6 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —C.sub.0-6 alkylene-OR.sub.a; R.sub.a is selected from H or C.sub.1-6 alkyl; preferably, R.sub.3 is selected from ##STR00248## R.sub.3′ is independently selected from H or halogen; R.sub.6 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —C.sub.0-6 alkylene-OR.sub.a; R.sub.a is selected from H or C.sub.1-6 alkyl; preferably, R.sub.3 is selected from ##STR00249## R.sub.3′ is independently selected from H or F; or, R.sub.3 is selected from —O—C.sub.1-6 alkylene-R.sub.6 or -L′-3- to 7-membered heterocyclyl, each of which is optionally substituted with 1 or 2 R.sub.6 groups; R.sub.3′ is independently selected from H, halogen, C.sub.1-6 alkyl or —OR.sub.a; R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.a is selected from H or C.sub.1-6 alkyl; L′ is selected from a chemical bond, —O—, —NH—, —C(O)—, —C(O)NH— or —NHC(O)—; preferably, R.sub.3 is selected from ##STR00250## R.sub.3′ is independently selected from H, F, methyl or OMe.

9. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof according to any one of claims 1-8, wherein the said compound is selected from ##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261## ##STR00262## ##STR00263## ##STR00264## ##STR00265## ##STR00266##

10. A pharmaceutical composition, comprising: the compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof according to any one of claims 1-9; and a pharmaceutically acceptable excipient; optionally, the pharmaceutical composition further comprises one or more other therapeutic agents.

11. A kit, comprising: a first container which contains the compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof according to any one of claims 1-9; and optionally, a second container which contains one or more other therapeutic agents; and optionally, a third container which contains a pharmaceutically acceptable excipient for diluting or suspending the said compound and/or other therapeutic agents.

12. Use of the compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof according to any one of claims 1-9 in the manufacture of a medicament for treating and/or preventing a CDK mediated disease.

13. A method of treating and/or preventing a CDK mediated disease in a subject, which comprises administering to the subject the compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof according to any one of claims 1-9, or the pharmaceutical composition according to claim 10.

14. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof according to any one of claims 1-9, or the pharmaceutical composition according to claim 10, for use in treating and/or preventing a CDK mediated disease.

15. The use of claim 12, or the method of claim 13, or the compound or composition for use of claim 14, wherein the said CDK mediated disease includes a cell proliferative disorder, including but not limited to cancers, cardiovascular disorders, infectious diseases, chronic inflammatory diseases, autoimmune disorders, and other cell proliferative disorders; more specifically, the cancers include, but are not limited to, solid tumors and hematological malignancies, such as breast cancer, neuroblastoma, malignant rhabdomyomas, well-differentiated and dedifferentiated liposarcoma, glioma, lung cancer, colorectal cancer, gastric cancer, gastrointestinal stromal tumor (GIST), hepatocellular carcinoma, prostate tumor, sarcoma, ovarian cancer, cervical cancer, pancreatic cancer, melanoma, thyroid cancer, carcinoma of bile duct, endometrial cancer, renal cancer, mesothelioma, lymphoma, leukemia, non-Hodgkin's lymphoma, mantle cell lymphoma, anaplastic large cell lymphoma, acute myeloid leukemia (AML), and multiple myeloma; more specifically, the cardiovascular disorders are for instance restenosis, atherosclerosis, vascular smooth muscle proliferation and intimal hyperplasia secondary to balloon angioplasty, and other vascular disorders caused by abnormal cell proliferation; more specifically, the infectious diseases include infections of fungi, protozoan parasites (such as Plasmodium falciparum), and DNA and RNA virus, such as herpes simplex virus (HSV) infection; more specifically, the chronic inflammatory diseases are for example rheumatoid arthritis; more specifically, the said other cell proliferative disorders include psoriasis (characterized by excessive proliferation of keratinocytes), glomerulonephritis, and lupus.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0082] As used herein, the term “compound disclosed herein” refers to the following compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0083] Compounds are generally described herein using standard nomenclature. For compounds having an asymmetric center, it should be understood, unless otherwise stated, that all optical isomers and mixtures thereof are included. Furthermore, all isomer compounds and carbon-carbon double bonds included in the present disclosure may occur in the form of Z and E unless otherwise specified. Compounds which exist in different tautomeric forms, one of which is not limited to any particular tautomer, but is intended to cover all tautomeric forms. General formula is used for certain compounds, including descriptions and variables. Unless otherwise specified, each variable in such a formula is defined independently of any other variable and multiple variables that independently define any one of the variables in each occurrence.

[0084] In one embodiment, the present disclosure refers to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof:

##STR00005##

[0085] wherein:

[0086] A.sub.1 is selected from CR.sub.3 or N;

[0087] A.sub.2 is selected from CR.sub.3 or N;

[0088] A.sub.3 is selected from CR.sub.3 or N;

[0089] R.sub.1 is selected from H, halogen, —CN, —OR.sub.a, —SR.sub.a, —NR.sub.bR.sub.c, —C(O)R.sub.a, —C(O)OR.sub.a, —C(O)NR.sub.bR.sub.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C.sub.6-10 aryl, or 5- to 10-membered heteroaryl; wherein the said C.sub.3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted with oxo or thioxo;

[0090] R.sub.2 is selected from H, halogen, —CN, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C.sub.6-10 aryl, or 5- to 10-membered heteroaryl; wherein the said C.sub.3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted with oxo or thioxo;

[0091] R.sub.3 is selected from H, halogen, —CN, —NO.sub.2, -L-OR.sub.a, -L-SR.sub.a, -L-NR.sub.bR.sub.c, -L-C(O)R.sub.a, -L-C(O)OR.sub.aa, -L-C(O)NR.sub.bR.sub.c, -L-S(O).sub.mR.sub.a, -L-S(O).sub.mOR.sub.a, -L-S(O).sub.mNR.sub.bR.sub.c, —O—C.sub.1-6 alkylene-R.sub.6, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, -L′-C.sub.3-7 cycloalkyl, -L′-3- to 11-membered heterocyclyl, -L′-C.sub.6-10 aryl, or -L′-5- to 10-membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4 or 5 R.sub.6 groups;

[0092] R.sub.4 is selected from —C(O)R.sub.a, —C(O)OR.sub.aa, —C(O)NR.sub.bR.sub.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, or 3- to 7-membered heterocyclyl;

[0093] R.sub.5 is selected from H, halogen, —CN, —OR.sub.a, —SR.sub.a, —NR.sub.bR.sub.c, —C(O)R.sub.a, —C(O)OR.sub.a, —C(O)NR.sub.bR.sub.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C.sub.6-10 aryl, or 5- to 10-membered heteroaryl; wherein the said C.sub.3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted with oxo or thioxo;

[0094] R.sub.6 is selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, —C.sub.1-6 alkylene-OR.sub.a, -L-C.sub.3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C.sub.6-10 aryl, or -L-5- to 10-membered heteroaryl;

[0095] or two R.sub.6 groups on the same carbon atom are taken together to form oxo or thioxo;

[0096] wherein:

[0097] R.sub.4 is optionally substituted with 1, 2 or 3 R′ groups, wherein R′ is independently selected from H, halogen, —CN, —NO.sub.2, —OR.sub.a, —SR.sub.a, —NR.sub.bR.sub.c, —C(O)OR.sub.a, —C(O)NR.sub.bR.sub.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C.sub.6-10 aryl, or 5- to 10-membered heteroaryl;

[0098] each of R.sub.3, R.sub.5 and R.sub.6 is optionally substituted with 1, 2 or 3 R″ groups, wherein R″ is independently selected from H, —OH, halogen, —NO.sub.2, carbonyl, -L-CN, -L-OR.sub.a, -L-SR.sub.a, -L-NR.sub.bR.sub.c, -L-C(O)R.sub.a, -L-C(S)R.sub.a, -L-C(O)OR.sub.a, -L-C(S)OR.sub.a, -L-C(O)—NR.sub.bR.sub.c, -L-C(S)—NR.sub.bR.sub.c, -L-O—C(O)R.sub.a, -L-O—C(S)R.sub.a, -L-N(R.sub.b)—C(O)—R.sub.a, -L-N(R.sub.b)—C(S)—R.sub.a, -L-S(O).sub.mR.sub.a, -L-S(O).sub.mOR.sub.a, -L-S(O).sub.mNR.sub.bR.sub.c, -L-N(R.sub.b)—S(O).sub.m—R.sub.a, -L-N(R.sub.b)—S(O).sub.m—NR.sub.bR.sub.c, -L-N(R.sub.b)—C(O)OR.sub.a, -L-N(R.sub.b)—C(S)OR.sub.a, -L-O—C.sub.1-6 alkylene-OR.sub.a, -L-C(O)—C.sub.1-6 alkylene-NR.sub.bR.sub.c, -L-N(R.sub.b)—C(O)—NR.sub.bR.sub.c, -L-N(R.sub.b)—C(S)—NR.sub.bR.sub.c, -L-O—C(O)—NR.sub.bR.sub.c, -L-O—C(S)—NR.sub.bR.sub.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, -L-C.sub.3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C.sub.6-10 aryl, or -L-5- to 10-membered heteroaryl; wherein the said C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, -L-C.sub.3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C.sub.6-10 aryl, or -L-5- to 10-membered heteroaryl is each optionally further substituted with one or more substituents independently selected from the group consisting of -L-CN, —NO.sub.2, carbonyl, -L-OR.sub.a, -L-SR.sub.a, -L-NR.sub.bR.sub.c, -L-C(O)R.sub.a, -L-C(S)R.sub.a, -L-C(O)OR.sub.a, -L-C(S)OR.sub.a, -L-C(O)—NR.sub.bR.sub.c, -L-C(S)—NR.sub.bR.sub.c, -L-O—C(O)R.sub.a, -L-O—C(S)R.sub.a, -L-N(R.sub.b)—C(O)—R.sub.a, -L-N(R.sub.b)—C(S)—R.sub.a, -L-S(O).sub.mR.sub.a, -L-S(O).sub.mOR.sub.a, -L-S(O).sub.mNR.sub.bR.sub.c, -L-N(R.sub.b)—S(O).sub.m—R.sub.a, -L-N(R.sub.b)—S(O).sub.m—R.sub.bR.sub.c, -L-N(R.sub.b)—C(O)OR.sub.a, -L-N(R.sub.b)—C(S)OR.sub.a, -L-O—C.sub.1-6 alkylene-OR.sub.a, -L-C(O)—C.sub.1-6 alkylene-NR.sub.bR.sub.c, -L-N(R.sub.b)—C(O)—NR.sub.bR.sub.c, -L-N(R.sub.b)—C(S)—NR.sub.bR.sub.c, -L-O—C(O)—NR.sub.bR.sub.c, and -L-O—C(S)—NR.sub.bR.sub.c;

[0099] R.sub.a is independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, -L-C.sub.3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C.sub.6-10 aryl, or -L-5- to 10-membered heteroaryl;

[0100] R.sub.b and R.sub.c are independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, -L-C.sub.3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C.sub.6-10 aryl, or -L-5- to 10-membered heteroaryl; or, R.sub.b and R.sub.c are taken together with the nitrogen atom to which they are attached to form 3- to 7-membered heterocyclyl;

[0101] R.sub.a, R.sub.b and R.sub.c are each optionally further substituted with one or more substituents independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, -L-C.sub.3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C.sub.6-10 aryl, and -L-5- to 10-membered heteroaryl;

[0102] L is selected from a chemical bond, —C.sub.1-6 alkylene-, —C.sub.2-6 alkenylene- or —C.sub.2-6 alkynylene-;

[0103] L′ is selected from a chemical bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —C.sub.1-6 alkylene-, —C.sub.2-6 alkenylene- or —C.sub.2-6 alkynylene-; and

[0104] m represents 0, 1 or 2.

A.sub.1, A.sub.2 and A.sub.3

[0105] In a specific embodiment, A.sub.1 is CR.sub.3; in another specific embodiment, A.sub.1 is CH; in another specific embodiment, A.sub.1 is N.

[0106] In a specific embodiment, A.sub.2 is CR.sub.3; in another specific embodiment, A.sub.2 is CH; in another specific embodiment, A.sub.2 is N.

[0107] In a specific embodiment, A.sub.3 is CR.sub.3; in another specific embodiment, A.sub.3 is CH; in another specific embodiment, A.sub.3 is N.

[0108] In a specific embodiment, A.sub.1 is N, A.sub.2 is CR.sub.3 and A.sub.3 is CR.sub.3; in another specific embodiment, A.sub.1 is CR.sub.3, A.sub.2 is CR.sub.3 and A.sub.3 is CR.sub.3.

R.SUB.1

[0109] In a specific embodiment, R.sub.1 is H; in another specific embodiment, R.sub.1 is halogen; in another specific embodiment, R.sub.1 is —CN; in another specific embodiment, R.sub.1 is —OR.sub.a; in another specific embodiment, R.sub.1 is —SR.sub.a; in another specific embodiment, R.sub.1 is —NR(R)R; in another specific embodiment, R.sub.1 is —C(O)R.sub.a; in another specific embodiment, R.sub.1 is —C(O)OR.sub.a; in another specific embodiment, R.sub.1 is —C(O)NR.sub.bR.sub.c; in another specific embodiment, R.sub.1 is C.sub.1-6 alkyl; in another specific embodiment, R.sub.1 is C.sub.1-6 haloalkyl; in another specific embodiment, R.sub.1 is C.sub.3-7 cycloalkyl; in another specific embodiment, R.sub.1 is 3- to 7-membered heterocyclyl; in another specific embodiment, R.sub.1 is C.sub.6-10 aryl; in another specific embodiment, R.sub.1 is 5- to 10-membered heteroaryl.

R.SUB.2

[0110] In a specific embodiment, R.sub.2 is H; in another specific embodiment, R.sub.2 is halogen; in another specific embodiment, R.sub.2 is —CN; in another specific embodiment, R.sub.2 is C.sub.1-6 alkyl; in another specific embodiment, R.sub.2 is C.sub.1-6 haloalkyl; in another specific embodiment, R.sub.2 is C.sub.3-7 cycloalkyl; in another specific embodiment, R.sub.2 is 3- to 7-membered heterocyclyl; in another specific embodiment, R.sub.2 is C.sub.6-10 aryl; in another specific embodiment, R.sub.2 is 5- to 10-membered heteroaryl.

[0111] In a specific embodiment, R.sub.2 is H, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; in another specific embodiment, R.sub.2 is H, halogen or C.sub.1-6 alkyl.

R.SUB.3

[0112] In a specific embodiment, R.sub.3 is H; in another specific embodiment, R.sub.3 is halogen; in another specific embodiment, R.sub.3 is —CN; in another specific embodiment, R.sub.3 is —NO.sub.2; in another specific embodiment, R.sub.3 is -L-OR.sub.a; in another specific embodiment, R.sub.3 is -L-SR.sub.a; in another specific embodiment, R.sub.3 is -L-NR.sub.bR.sub.c; in another specific embodiment, R.sub.3 is -L-C(O)R.sub.a; in another specific embodiment, R.sub.3 is -L-C(O)OR.sub.a; in another specific embodiment, R.sub.3 is -L-C(O)NR.sub.bR.sub.c; in another specific embodiment, R.sub.3 is -L-S(O).sub.mR.sub.a; in another specific embodiment, R.sub.3 is -L-S(O).sub.mOR.sub.a; in another specific embodiment, R.sub.3 is -L-S(O).sub.mNR.sub.bR.sub.c; in another specific embodiment, R.sub.3 is —O—C.sub.1-6 alkylene-R.sub.6; in another specific embodiment, R.sub.3 is C.sub.1-6 alkyl; in another specific embodiment, R.sub.3 is C.sub.1-6 haloalkyl; in another specific embodiment, R.sub.3 is -L′-C.sub.3-7 cycloalkyl; in another specific embodiment, R.sub.3 is -L′-3- to 11-membered heterocyclyl; in another specific embodiment, R.sub.3 is -L′-3- to 9-membered heterocyclyl; in another specific embodiment, R.sub.3 is -L′-C.sub.6-10 aryl; in another specific embodiment, R.sub.3 is -L′-5- to 10-membered heteroaryl.

[0113] In the specific embodiments of R.sub.3 as mentioned above, each of the groups is optionally substituted with 1, 2, 3, 4 or 5 R.sub.6 groups. In a specific embodiment, each of the groups is optionally substituted with 1 R.sub.6 group; in another specific embodiment, each of the groups is optionally substituted with 2 R.sub.6 groups; in another specific embodiment, each of the groups is optionally substituted with 3 R.sub.6 groups; in another specific embodiment, each of the groups is optionally substituted with 4 R.sub.6 groups; in another specific embodiment, each of the groups is optionally substituted with 5 R.sub.6 groups.

[0114] In a more specific embodiment, R.sub.3 is selected from -L′-3- to 11-membered heterocyclyl, wherein the said 3- to 11-membered heterocyclyl is selected from:

##STR00006## ##STR00007##

[0115] In another specific embodiment, R.sub.3 is independently selected from H, halogen, —CN, —NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or -L′-3- to 11-membered heterocyclyl (preferably, 3- to 11-membered heterocyclyl) which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; in another specific embodiment, R.sub.3 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or -L′-3- to 11-membered heterocyclyl (preferably, 3- to 11-membered heterocyclyl) which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; in another specific embodiment, R.sub.3 is independently selected from H, halogen, —CN, —NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or -L′-5- to 6-membered heterocyclyl (preferably, 5- to 6-membered heterocyclyl) which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; in another specific embodiment, R.sub.3 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or -L′-5- to 6-membered heterocyclyl (preferably, 5- to 6-membered heterocyclyl) which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups.

[0116] In another specific embodiment, R.sub.3 is independently selected from H, halogen, —CN, —NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or is independently selected from

##STR00008##

any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; in another specific embodiment, R.sub.3 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or is independently selected from

##STR00009##

any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; in another specific embodiment, R.sub.3 is selected from H, halogen, —CN, —NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or is independently selected from

##STR00010##

any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; in another specific embodiment, R.sub.3 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or is independently selected from

##STR00011##

any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups.

[0117] In another specific embodiment, R.sub.3 is independently selected from -L′-3- to 11-membered heterocyclyl (preferably, 3- to 11-membered heterocyclyl) which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; in another specific embodiment, R.sub.3 is independently selected from -L′-5- to 6-membered heterocyclyl (preferably, 5- to 6-membered heterocyclyl) which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups.

[0118] In another specific embodiment, R.sub.3 is independently selected from

##STR00012##

any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; in another specific embodiment, R.sub.3 is selected from

##STR00013##

any of which is optionally substituted with 1, 2 or 3 R.sub.6 groups; in another specific embodiment, R.sub.3 is selected from —O—C.sub.1-6 alkylene-R.sub.6, -L′-3- to 11-membered heterocyclyl or —C(O)NR.sub.bR.sub.c, each of which is optionally substituted with 1 or 2 R.sub.6 groups.

[0119] In a specific embodiment, when A.sub.2 or A.sub.3 is CR.sub.3, then R.sub.3 is R.sub.3′. In another specific embodiment, R.sub.3′ is selected from H, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl, and R.sub.3 is as defined above; in another specific embodiment, R.sub.3′ is selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl, and R.sub.3 is as defined above.

R.SUB.4

[0120] In a specific embodiment, R.sub.4 is —C(O)R.sub.a; in another specific embodiment, R.sub.4 is —C(O)OR.sub.a; in another specific embodiment, R.sub.4 is —C(O)NR.sub.bR.sub.c; in another specific embodiment, R.sub.4 is C.sub.1-6 alkyl; in another specific embodiment, R.sub.4 is C.sub.1-6 haloalkyl; in another specific embodiment, R.sub.4 is C.sub.3-7 cycloalkyl; in another specific embodiment, R.sub.4 is 3- to 7-membered heterocyclyl.

[0121] In another specific embodiment, R.sub.4 is selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; in another specific embodiment, R.sub.4 is selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or C.sub.3-7 cycloalkyl; in another specific embodiment, R.sub.4 is selected from C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl; in another specific embodiment, R.sub.4 is isopropyl; in another specific embodiment, R.sub.4 is cyclopentyl; in another specific embodiment, R.sub.4 is cyclopropyl.

R.SUB.5

[0122] In a specific embodiment, R.sub.5 is H; in another specific embodiment, R.sub.5 is halogen; in another specific embodiment, R.sub.5 is —CN; in another specific embodiment, R.sub.5 is —OR.sub.a; in another specific embodiment, R.sub.5 is —SR.sub.a; in another specific embodiment, R.sub.5 is —NR.sub.bR.sub.c; in another specific embodiment, R.sub.5 is —C(O)R.sub.a; in another specific embodiment, R.sub.5 is —C(O)OR.sub.a; in another specific embodiment, R.sub.5 is —C(O)NR.sub.bR.sub.c; in another specific embodiment, R.sub.5 is C.sub.1-6 alkyl; in another specific embodiment, R.sub.5 is C.sub.1-6 haloalkyl; in another specific embodiment, R.sub.5 is C.sub.3-7 cycloalkyl; in another specific embodiment, R.sub.5 is 3- to 7-membered heterocyclyl; in another specific embodiment, R.sub.5 is C.sub.6-10 aryl; in another specific embodiment, R.sub.5 is 5- to 10-membered heteroaryl.

R.SUB.6

[0123] In a specific embodiment, R.sub.6 is H; in another specific embodiment, R.sub.6 is —NH.sub.2; in another specific embodiment, R.sub.6 is —NHC.sub.1-6 alkyl; in another specific embodiment, R.sub.6 is —N(C.sub.1-6 alkyl).sub.2; in another specific embodiment, R.sub.6 is C.sub.1-6 alkyl; in another specific embodiment, R.sub.6 is C.sub.1-6 haloalkyl; in another specific embodiment, R.sub.6 is —C.sub.1-6 alkylene-OR.sub.a; in another specific embodiment, R.sub.6 is -L-C.sub.3-7 cycloalkyl; in another specific embodiment, R.sub.6 is -L-3- to 7-membered heterocyclyl; in another specific embodiment, R.sub.6 is -L-C.sub.6-10 aryl; in another specific embodiment, R.sub.6 is -L-5- to 10-membered heteroaryl; in another specific embodiment, two R.sub.6 on the same carbon atom are taken together to form oxo. In another specific embodiment, two R.sub.6 on the same carbon atom are taken together to form thioxo.

[0124] In a specific embodiment, R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —C.sub.0-6 alkylene-OR.sub.a; in another specific embodiment, R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl or —C.sub.0-6 alkylene-OR.sub.a; in another specific embodiment, R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; in another specific embodiment, R.sub.6 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —C.sub.0-6 alkylene-OR.sub.a; in another specific embodiment, R.sub.6 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl.

L

[0125] In a specific embodiment, L is a chemical bond; in another specific embodiment, L is —C.sub.1-6 alkylene-; in another specific embodiment, L is —C.sub.2-6 alkenylene-; in another specific embodiment, L is —C.sub.2-6 alkynylene-.

L′

[0126] In a specific embodiment, L′ is a chemical bond; in another specific embodiment, L′ is —O—; in another specific embodiment, L′ is —NH—; in another specific embodiment, L′ is —C(O)—; in another specific embodiment, L′ is —C(O)NH—; in another specific embodiment, L′ is —NHC(O)—; in another specific embodiment, L′ is —C.sub.1-6 alkylene-; in another specific embodiment, L′ is —C.sub.2-6 alkenylene-; in another specific embodiment, L′ is —C.sub.2-6 alkynylene-.

m

[0127] In a specific embodiment, m is 0; in another specific embodiment, m is 1; in another specific embodiment, m is 2.

[0128] Any technical solution in any one of the above specific embodiments, or any combination thereof, may be combined with any technical solution in other specific embodiments or any combination thereof. For example, any technical solution of A.sub.1 or any combination thereof may be combined with any technical solution of A.sub.2, A.sub.3, R.sub.1-R.sub.6, R′, R″, R.sub.a, R.sub.b, R.sub.c, L, L′ and m or any combination thereof. The present disclosure is intended to include all combination of such technical solutions, which are not exhaustively listed here to save space.

[0129] In a specific embodiment, the present disclosure refers to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof:

##STR00014##

[0130] wherein:

[0131] A.sub.1 is selected from CR.sub.3 or N; preferably, A.sub.1 is CR.sub.3; preferably, A.sub.1 is N;

[0132] A.sub.2 is CR.sub.3;

[0133] A.sub.3 is CR.sub.3;

[0134] R.sub.1 is selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.1 is selected from H or C.sub.1-6 alkyl; preferably, R.sub.1 is H;

[0135] R.sub.2 is selected from H, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.2 is selected from H, halogen or C.sub.1-6 alkyl; preferably, R.sub.2 is selected from halogen or C.sub.1-6 alkyl; preferably, R.sub.2 is H; R.sub.3 is independently selected from H, halogen, —CN, —NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or -L′-3- to 11-membered heterocyclyl (preferably, 3- to 11-membered heterocyclyl) which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; preferably, R.sub.3 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or -L′-3- to 11-membered heterocyclyl (preferably, 3- to 11-membered heterocyclyl) which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; preferably, R.sub.3 is independently selected from H, halogen, —CN, —NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or -L′-5- to 6-membered heterocyclyl (preferably, 5- to 6-membered heterocyclyl) which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; preferably, R.sub.3 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or -L′-5- to 6-membered heterocyclyl (preferably, 5- to 6-membered heterocyclyl) which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; preferably, R.sub.3 is independently selected from H, halogen, —CN, —NO.sub.2, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl, or is independently selected from

##STR00015##

any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups;

[0136] preferably, R.sub.3 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or is independently selected from

##STR00016##

any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups;

[0137] preferably, R.sub.3 is independently selected from H, halogen, —CN, —NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or is independently selected from

##STR00017##

any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups;

[0138] preferably, R.sub.3 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or is independently selected from

##STR00018##

any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups;

[0139] or, R.sub.3 is selected from H, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, —OR.sub.a, —O—C.sub.1-6 alkylene-R.sub.6 or -L′-3- to 7-membered heterocyclyl, each of which is optionally substituted with 1 or 2 R.sub.6 groups; preferably, R.sub.3 is selected from —O—C.sub.1-6 alkylene-R.sub.6, -L′-3- to 11-membered heterocyclyl or —C(O)NR.sub.bR.sub.c, each of which is optionally substituted with 1 or 2 R.sub.6 groups;

[0140] R.sub.4 is selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; preferably, R.sub.4 is selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or C.sub.3-7 cycloalkyl; preferably, R.sub.4 is selected from C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl; preferably, R.sub.4 is isopropyl; preferably, R.sub.4 is cyclopentyl; preferably, R.sub.4 is cyclopropyl;

[0141] R.sub.5 is H;

[0142] R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —C.sub.0-6 alkylene-OR.sub.a; preferably, R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl or —C.sub.0-6 alkylene-OR.sub.a; preferably, R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.6 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —C.sub.0-6 alkylene-OR.sub.a; preferably, R.sub.6 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl;

[0143] R.sub.a is selected from H or C.sub.1-6 alkyl;

[0144] R.sub.b and R.sub.c are independently selected from H or 3- to 7-membered heterocyclyl;

[0145] L′ is selected from a chemical bond, —O—, —NH—, —C(O)—, —C(O)NH— or —NHC(O)—.

[0146] In a more specific embodiment, the present disclosure refers to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein the said compound of formula (I) has one of structures of the following general formulae:

##STR00019##

[0147] wherein the groups are as defined above.

[0148] In a specific embodiment, the present disclosure refers to a compound of formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof:

##STR00020##

[0149] wherein:

[0150] R.sub.1 is selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.1 is selected from H or C.sub.1-6 alkyl; preferably, R.sub.1 is selected from H or methyl; preferably, R.sub.1 is H;

[0151] R.sub.2 is selected from H, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.2 is selected from H, halogen or C.sub.1-6 alkyl; preferably, R.sub.2 is selected from H, halogen or methyl; preferably, R.sub.2 is selected from halogen or C.sub.1-6 alkyl; preferably, R.sub.2 is selected from halogen or methyl; preferably, R.sub.2 is H; preferably, wherein the said halogen is Br;

[0152] R.sub.3 is selected from 3- to 11-membered heterocyclyl which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; R.sub.3 is selected from 5- to 6-membered heterocyclyl which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups;

[0153] preferably, R.sub.3 is selected from

##STR00021##

any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups;

[0154] preferably, R.sub.3 is selected from

##STR00022##

any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups;

[0155] preferably, R.sub.3 is selected from

##STR00023##

any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups;

[0156] preferably, R.sub.3 is selected from

##STR00024##

[0157] preferably, R.sub.3 is selected from

##STR00025##

[0158] preferably, R.sub.3 is selected from

##STR00026##

[0159] preferably, R.sub.3 is selected from

##STR00027##

[0160] preferably, R.sub.3 is selected from

##STR00028##

or, R.sub.3 is selected from —O—C.sub.1-6 alkylene-R.sub.6, -L′-3- to 11-membered heterocyclyl or —C(O)NR.sub.bR.sub.c, each of which is optionally substituted with 1 or 2 R.sub.6 groups; preferably, R.sub.3 is selected from

##STR00029##

[0161] R.sub.3′ is independently selected from H, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.3′ is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.3′ is independently selected from H or C.sub.1-6 alkyl; preferably, R.sub.3′ is independently selected from H or methyl; preferably, R.sub.3′ is independently selected from H, halogen, C.sub.1-6 alkyl or —OR.sub.a; preferably, R.sub.3′ is independently —OR.sub.a; preferably, R.sub.3′ is independently —OMe;

[0162] R.sub.4 is selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; preferably, R.sub.4 is selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or C.sub.3-7 cycloalkyl; preferably, R.sub.4 is selected from C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl; preferably, R.sub.4 is selected from cyclopropyl, cyclobutyl, cyclopentyl, ethyl or isopropyl; preferably, R.sub.4 is selected from cyclopropyl, cyclopentyl or isopropyl; preferably, R.sub.4 is selected from cyclopentyl or isopropyl;

[0163] R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —C.sub.0-6 alkylene-OR.sub.a; preferably, R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl or —C.sub.0-6 alkylene-OR.sub.a; preferably, R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.6 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —C.sub.0-6 alkylene-OR.sub.a; preferably, R.sub.6 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.6 is independently selected from H or C.sub.1-6 alkyl;

[0164] R.sub.a is selected from H or C.sub.1-6 alkyl;

[0165] R.sub.b and R.sub.e are independently selected from H or 3- to 7-membered heterocyclyl.

[0166] In a more specific embodiment, the present disclosure refers to a compound of the formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein the said compound of the formula (II) has one of structures of the following general formulae:

##STR00030##

[0167] wherein the said groups are as defined above.

[0168] In a specific embodiment, the present disclosure refers to compound of the formula (III), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof:

##STR00031##

[0169] wherein,

[0170] R.sub.3 is selected from 5- to 6-membered heterocyclyl which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups; preferably, R.sub.3 is selected from

##STR00032##

any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups;

[0171] preferably, R.sub.3 is selected from

##STR00033##

any of which is optionally substituted with 1, 2, 3 or 4 R.sub.6 groups;

[0172] preferably, R.sub.3 is selected from

##STR00034##

[0173] preferably, R.sub.3 is selected from

##STR00035##

[0174] or, R.sub.3 is selected from —O—C.sub.1-6 alkylene-R.sub.6 or -L′-3- to 11-membered heterocyclyl, each of which is optionally substituted with 1 or 2 R.sub.6 groups; preferably, R.sub.3 is selected from

##STR00036##

[0175] R.sub.3′ is independently selected from H, halogen, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.3′ is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.3′ is independently selected from H or C.sub.1-6 alkyl; preferably, R.sub.3′ is independently selected from H or methyl; preferably, R.sub.3′ is independently selected from H, halogen, C.sub.1-6 alkyl or —OR.sub.a; preferably, R.sub.3′ is independently —OR.sub.a; preferably, R.sub.3′ is independently —OMe;

[0176] R.sub.3 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —C.sub.0-6 alkylene-OR.sub.a; preferably, R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl or —C.sub.0-6 alkylene-OR.sub.a; preferably, R.sub.6 is independently selected from H, —NH.sub.2, —NHC.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.6 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or —C.sub.0-6 alkylene-OR.sub.a; preferably, R.sub.6 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; preferably, R.sub.6 is independently selected from H or C.sub.1-6 alkyl;

[0177] R.sub.a is selected from H or C.sub.1-6 alkyl;

[0178] L′ is selected from a chemical bond, —O—, —NH—, —C(O)—, —C(O)NH— or —NHC(O)—.

[0179] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer (such as cis- and trans-isomer), or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.

[0180] The present disclosure also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I), or a therapeutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. All of these forms belong to the present disclosure.

[0181] The preferred compound disclosed herein includes but is not limited to the following compound:

##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052##

Pharmaceutical Compositions, Formulations and Kits

[0182] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (also referred to as the “active ingredient”) and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the compound of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the compound of the present disclosure.

[0183] A pharmaceutically acceptable excipient for use in the present disclosure refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0184] The present disclosure also includes kits (e.g., pharmaceutical packs). Kits provided may include a compound disclosed herein, other therapeutic agent(s), and a first and a second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other suitable container) containing the compound disclosed herein or other therapeutic agent(s). In some embodiments, kits provided can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending the compound disclosed herein and/or other therapeutic agent(s). In some embodiments, the compound disclosed herein provided in the first container and the other therapeutic agent(s) provided in the second container is combined to form a unit dosage form.

Administration

[0185] The pharmaceutical composition provided by the present disclosure can be administered by a variety of routes including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other means of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intracerebroventricular administration, intralesional administration, and intracranial injection or infusion techniques.

[0186] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0187] When used to prevent the disorder disclosed herein, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.

[0188] The pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc, or may be continued indefinitely, for example, for the rest of the subject's life. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.

[0189] The pharmaceutical compostions of the present disclosure may be further delivered using a variety of dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in still yet other embodiments, the pharmaceutical composition may be administered as first as a bolus dose, followed by continuous infusion.

[0190] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.

[0191] With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

[0192] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

[0193] Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.

[0194] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0195] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable excipient and the like.

[0196] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or Formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0197] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0198] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa., which is incorporated herein by reference.

[0199] The compounds of the present disclosure can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0200] The present disclosure also relates to the pharmaceutically acceptable formulations of a compound of the present disclosure. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, e.g., U.S. Pat. No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

Treatment

[0201] The present disclosure provides methods for treating the following disorders or conditions in mammals, including humans: cell proliferative disorders such as cancer, vascular smooth muscle hyperplasia associated with atherosclerosis, postoperative vascular stenosis, restenosis, and endometriosis; infection, including viral infections such as DNA viruses e.g. herpes, and RNA viruses e.g. HIV, and fungal infections; autoimmune diseases such as psoriasis, inflammation, e.g. rheumatoid arthritis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis and glomerulonephritis; organ transplant rejection, including host versus graft disease, the method comprises administering to the mammal a therapeutically effective amount of a compound disclosed herein or a composition thereof.

[0202] The present disclosure further provides compounds disclosed herein useful in the treatment of abnormal cell proliferation, such as cancer. The disclosure further provides a method of treating abnormal cell proliferation, such as cancer selected from the following: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and pharynx (mouth), lips, tongue, mouth, pharynx, small intestine, colorectal, large intestine, rectum, cancer of brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorder, lymphatic disorder, Hodgkin's disease, hairy cell carcinoma and leukemia, comprising administering to the patient in need of such treatment a therapeutically effective amount of a compound disclosed herein or a composition thereof.

[0203] Further, the present disclosure relates to a method of treating a subject having a disease caused by proliferation of vascular smooth muscle cells. The compounds disclosed herein effectively inhibit the proliferation and migration of vascular smooth muscle cells. The method comprises administering to a subject in need of treatment a compound disclosed herein or a composition thereof in an amount sufficient to inhibit vascular smooth muscle proliferation and/or migration.

[0204] The present disclosure further provides a method of treating a subject suffering from gout, comprising administering to the subject in need of treatment a compound disclosed herein or a composition thereof in an amount sufficient to treat the condition.

[0205] The present disclosure further provides a method of treating a subject having a renal disease, such as a polycystic kidney disease, comprising administering to the subject in need of treatment an amount of a compound disclosed herein or a composition thereof in an amount sufficient to treat the condition.

[0206] Due to their inhibitory activity against CDK and other kinases, the compounds disclosed herein are also useful research tools for studying the mechanism of action of these kinases in vitro and in vivo.

[0207] The compounds disclosed herein are useful in the treatment of cancer (e.g., leukemia and cancers of lung, breast, prostate and skin, such as melanoma) and other proliferative diseases including, but not limited to, psoriasis, HSV, HIV, restenosis, and atherosclerosis. To treat cancer with a compound disclosed herein, a therapeutically effective amount of a pharmaceutically acceptable composition comprising at least one compound disclosed herein is administered to a patient in need of such treatment, for example, who has cancer or another proliferative disorder.

[0208] An effective amount of a compound disclosed herein will generally be administered in a single or multiple doses at an average daily dose of from 0.01 mg to 50 mg of compound per kilogram of patient body weight, preferably from 0.1 mg to 25 mg of compound per kilogram of patient body weight. In general, the compounds disclosed herein may be administered to a patient in need of such treatment in a daily dosage range of from about 1 mg to about 3500 mg per patient, preferably from 10 mg to 1000 mg. For example, the daily dose per patient can be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900 or 1000 mg. It can be administered one or more times daily, weekly (or several days apart) or on an intermittent schedule. For example, the compound can be administered one or more times per day on a weekly basis (e.g., every Monday), continually or for several weeks, such as 4-10 weeks. Alternatively, the administration may be continued for several days (e.g., 2-10 days), followed by a few days (e.g., 1-30 days) without administration of the compound, and the cycle may be repeated indefinitely or repeated for a given number of times, such as 4-10. Cycles. For example, the compounds disclosed herein may be administered daily for 5 days, then intermittently for 9 days, then administered daily for 5 days, then intermittent for 9 days, and so on, and the cycle is repeated indefinitely or repeated 4-10 times.

EXAMPLES

[0209] The following examples are provided to provide those skilled in the art with a complete disclosure and description of how to implement, prepare and evaluate the methods and compounds claimed herein, and are intended to be illustrative only and not limiting the scope of the invention.

[0210] The preparation protocol of the compound disclosed herein is shown, for example, in Scheme 1.

##STR00053## ##STR00054##

[0211] The compound of formula I can be prepared according to the general reaction scheme above. First, the substituted 1,3-cyclohexanedione (1) is reacted with titanium tetrachloride to obtain an olefine ketone intermediate (2). The intermediate (2) is then brominated to obtain a brominated olefine ketone intermediate (3). The intermediate (3) is reacted with a substituted formamidine to give 6,7-dihydro-3H-benzoldlimidazol-4(5H)-one (4). The intermediate (4) is then reacted with R.sub.4—I or R.sub.4B(OMe).sub.2 to give 3-substituted 6,7-dihydro-3H-benzoldlimidazol-4(5H)-one (5). Afterwards, (5) is reacted with N,N-dimethylformamide dimethyl acetal to give intermediate (6). Intermediate (6) is reacted with S-methylisothiourea hydrochloride to give 4,5-dihydro-1H-imidazo[4,5-h]quinazoline (7), which is aromatized to give 1H-imidazo[4,5-h]quinazoline (8). The methylthio group of the intermediate (8) is oxidized to obtain a methylsulfinyl intermediate (9). Compound (9) is coupled with an amine (10) to afford a compound of formula (I).

Example 1: Preparation of

[0212] isopropyl-N-(5-(piperazin-1-yl)pyridin-2-yl)-1H-imidazo[4,5-h]quinazolin-8-amine hydrochloride (I-1)

##STR00055## ##STR00056##

1): 3-Methoxycyclohex-2-enone (2a)

[0213] 1,3-cyclohexanedione 1a (90 g, 804 mmol) was dissolved in methanol (800 mL), and to which titanium tetrachloride (2.6 mL, 24.2 mmol, 0.03 equiv.) was slowly added dropwise in an ice-water bath. After the addition, the reaction mixture was stirred for 1 hour at this temperature, and then saturated ammonium chloride aqueous solution (600 mL) was added to quench the reaction. After being concentrated, the reaction mixture was directly purified by flash silica gel column chromatography (petroleum ether/ethyl acetate=2:1) to afford a light yellow oil as the title compound 2a (86 g, 682 mmol, 84.9%). .sup.1H NMR (600 MHz, chloroform-d, ppm) δ 5.37 (s, 1H), 3.68 (s, 3H), 2.39 (t, J=6.3 Hz, 2H), 2.33 (t, J=6.6 Hz, 2H), 1.99-1.94 (m, 2H); LC-MS (ESI), C.sub.7H.sub.11O.sub.2 [M+H].sup.+: m/z=127.1.

2): 2-Bromo-3-methoxycyclohex-2-enone (3a)

[0214] 2a (84 g, 666.6 mmol) was dissolved in dichloromethane/N,N-dimethylformamide (9:1, 1000 mL), and to the reaction mixture N-bromosuccinimide (132.6 g, 700 mmol, 1.05 equiv.) was added at 5-10° C. in five portions. After the addition, the reaction was continued at this temperature for 1 hour. After sucking filtration, the filtrate was concentrated. The resulting residue was diluted with toluene (1000 mL), and immediately washed with ice water (200 mL) twice. After drying, the filtrate was concentrated to around 200 mL, and the residue was moved to an ice-water bath for 5 minutes' stirring. After sucking filtration, the resulting filter residue was dried in vacuo with an oil pump to afford a light yellow powder as the title compound 3a, which was directly used in the next step without further purification (110.2 g, 540 mmol, 81%). LC-MS (ESI), C.sub.7H.sub.10BrO.sub.2 [M+H].sup.+: m/z=205.0, 207.1.

3): 6,7-Dihydro-3H-benzo[d]imidazol-4(5H)-one (4a)

[0215] 3a (101 g, 500 mmol) was dissolved in N,N-dimethylformamide (800 mL), and to which potassium carbonate (206 g, 1.5 mol, 3 equiv.) and formamidine hydrochloride (60.4 g, 750 mmol, 1.5 equiv.) were added in an ice-water bath. The resulting reaction mixture was heated to 80° C., and reacted for 16 hours under the stirring with a mechanical stirrer. The reaction mixture was cooled to room temperature, diluted with dichloromethane (1000 mL) and filtered. The filtrate was concentrated and purified with flash silica gel column chromatography (petroleum ether/ethyl acetate=2:1) to afford a grey solid as the title compound (4a, 24.6 g, 180 mmol, 36%). .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 7.89 (s, 1H), 2.93 (t, J=6.2 Hz, 2H), 2.63-2.50 (m, 2H), 2.27-2.14 (m, 2H); LC-MS (ESI), C.sub.7H.sub.9N.sub.2O [M+H].sup.+: m/z=137.3.

4): 3-Isopropyl-6,7-dihydro-3H-benzo[d]imidazol-4 (5H)-one (5a)

[0216] 4a (24 g, 176.5 mmol), potassium carbonate (73 g, 529.4 mmol, 3.0 equiv.), tetrabutylammonium bromide (5.68 g, 17.65 mmol, 0.1 equiv.) were suspended in acetonitrile (400 mL). The resulting reaction mixture was stirred at room temperature for 30 mins, then 2-iodopropane (43.4 mL, 441.2 mmol, 2.5 equiv.) was added, and then the reaction mixture was heated to 50° C. and stirred for 14 hours. The reaction mixture was cooled to room temperature and filtered, concentrated, and the residue was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate=2:1 to 0:1) to afford a brown oil as the title compound 5a (8.16 g, 45.9 mmol, 26%). .sup.1H NMR (600 MHz, chloroform-d, ppm) δ 7.76 (s, 1H), 5.12 (p, J=6.7 Hz, 1H), 2.87 (t, J=6.2 Hz, 2H), 2.52 (t, J=6.4 Hz, 2H), 2.13 (p, J=6.3 Hz, 2H), 1.48 (d, J=6.7 Hz, 6H); LC-MS (ESI), C.sub.10H.sub.15N.sub.2O [M+H].sup.+: m/z=179.1.

5): (Z)-5-((dimethylamino)methylene)-3-isopropyl-6,7-dihydro-3H-benzo[d]imidazol-4(5H)-one (6a)

[0217] A solution of 5a (8.0 g, 44.94 mmol) and N,N-dimethylformamide dimethyl acetal (59.6 mL, 449.4 mmol, 10 equiv.) in N,N-dimethylformamide (60 mL) was stirred at 130° C. for 13 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure to afford a brown oil as the title compound 6a (8.6 g, 37.0 mmol, 82.3%), which is a crude, and can be directly used in the next step without further purification. LC-MS (ESI), C.sub.13H.sub.20N.sub.3O [M+H].sup.+: m/z=234.2.

6): 1-Isopropyl-8-methylthio-4,5-dihydro-1H-imidazo[4,5-h]quinazoline (7a)

[0218] 6a (8.3 g, 35.6 mmol) and S-methylisothiourea hydrochloride (13.46 g, 106.8 mmol, 3 equiv.) were suspended in N,N-dimethylformamide (100 mL), and heated to 110° C., stirred for 16 hours. After the reaction mixture was cooled to room temperature, it was diluted with about 200 mL ice water, and then extracted with ethyl acetate three times. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated and purified with flash silica gel column chromatography (petroleum ether/ethyl acetate=1:1 to 0:1) to afford a brown solid as the title compound (7a, 4.54 g, 17.44 mmol, 49%). .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 8.31 (s, 1H), 8.24 (s, 1H), 3.08 (t, J=8.2 Hz, 2H), 2.99 (t, J=7.4 Hz, 2H), 2.55 (s, 3H), 1.62 (d, J=6.7 Hz, 6H); LC-MS (ESI), C.sub.13H.sub.17N.sub.4S [M+H].sup.+: m/z=261.2.

7): 1-Isopropyl-8-methylthio-1H-imidazo[4,5-h]quinazoline (8a)

[0219] 7a (4.2 g, 16.16 mmol) was dissolved in acetonitrile (150 mL), to which 2-iodoxybenzoic acid (9.06 g, 32.4 mmol, 2 eqiuv.) was added, and the mixture was heated to 75° C., and stirred for 16 hours. After the reaction mixture was cooled to room temperature, it was filtered, and concentrated. The resulting residue was purified with flash silica gel column chromatography to afford a light yellow solid as the title compound (8a, 3.66 g, 14.22 mmol, 88%). .sup.1H NMR (300 MHz, methanol-d.sub.4, ppm): δ 9.29 (s, 1H), 8.61 (s, 1H), 7.88-7.80 (m, 2H), 6.12-6.03 (m, 1H), 2.73 (s, 3H), 1.76 (d, J=6.6 Hz, 6H); LC-MS (ESI), C.sub.13H.sub.15N.sub.4S [M+H].sup.+: m/z=259.2.

8): 1-Isopropyl-8-methyl sulfinyl-1H-imidazo[4,5-h]quinazoline (9a)

[0220] 8a (1.4 g, 5.43 mmol) was dissolved in chloroform (15 mL), to which 2-phenylsulfonyl-3-phenyloxaziridine (1.7 g, 6.52 mmol, 1.2 equiv.) was added, and the mixture was stirred at room temperature for 18 hours. After concentration, the resulting crude was purified with flash silica gel column chromatography (petroleum ether/acetone=1:1 to 0:1) to afford a white solid as the title compound (9a, 1.34 g, 4.89 mmol, 90%). .sup.1H NMR (400 MHz, chloroform-d, ppm): δ 9.53 (s, 1H), 8.36 (s, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 6.04-5.98 (m, 1H), 3.05 (s, 3H), 1.76 (t, J=7.6 Hz, 6H); LC-MS (ESI), C.sub.13H.sub.15N.sub.4OS [M+H].sup.+: m/z=275.3.

9): Tert-butyl 4-(6-(1-isopropyl-1H-imidazo[4,5-h]quinazolin-8-ylamino)pyridin-3-yl)piperazine-1-carboxylate (I-1a)

[0221] 9a (44.3 mg, 0.16 mmol) and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (10a, 89.9 mg, 0.32 mmol) were suspended in xylene (1.6 mL), which was sealed with rubber stopper and the atmosphere was replaced with argon for 3 times, and the mixture was heated to 150° C. and reacted for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (0.3 mL) was added, and the stirring was continued for about 2 hours. After the precipitated solid was filtered off, the solution was purified with column chromatography to afford yellow powder as the title compound I-1a (17.2 mg, 21.8%). .sup.1H NMR (400 MHz, chloroform-d, ppm): δ 9.19 (s, 1H), 8.40 (s, 1H), 8.32 (d, J=9.2 Hz, 1H), 8.24 (s, 1H), 8.08 (d, J=2.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.35 (dd, J=9.0, 3.0 Hz, 1H), 6.13-6.03 (m, 1H), 3.63 (t, J=5.2 Hz, 4H), 3.13 (t, J=5.0 Hz, 4H), 1.73 (d, J=6.8 Hz, 6H), 1.50 (s, 9H).

10): 1-Isopropyl-N-(5-(piperazin-1-yl)pyridin-2-yl)-1H-imidazo[4,5-h]quinazolin-8-amine hydrochloride (I-1)

[0222] I-1a (14.9 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL), to which HCl in 1,4-dioxane (4 N, 0.76 mL) was added, and the mixture was stirred at room temperature for 2 hours. After sucking filtration, the resulting filter residue was subjected to vacuum drying to a constant weight with an oil pump to give a yellow powder as the title compound I-1 (13 mg, 99%). .sup.1H NMR (400 MHz, water-d.sub.2, ppm): δ 9.55 (s, 1H), 9.39 (s, 1H), 8.12-8.09 (m, 2H), 7.85 (d, J=8.8 Hz, 1H), 7.81 (s, 1H), 7.85 (d, J=9.6 Hz, 1H), 6.00-5.93 (m, 1H), 3.56-3.51 (m, 8H), 1.79 (d, J=6.8 Hz, 6H).

Example 2: Preparation of 1-isopropyl-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-imidazo[4,5-h]quinazolin-8-amine (I-2)

[0223] ##STR00057##

[0224] 9a (30 mg, 0.11 mmol) and 10b (42.2 mg, 0.22 mmol) were suspended in xylene (0.3 mL), and the atmosphere was replaced by argon for 3 times. The mixture was heated to 150° C., and reacted overnight with stirring. After the mixture was cooled to room temperature, ethyl acetate (0.3 mL) was added, and the stirring was continued for about 2 hours. The mixture was filtered, and the filter residue was washed with ethyl acetate to afford a yellow solid as the title compound I-2 (13 mg, 32.5 μmmol, 29.5%). .sup.1H NMR (600 MHz, chloroform-d, ppm) δ 9.17 (s, 1H), 8.32 (brs, 1H), 8.28 (d, J=9.0 Hz, 1H), 8.21 (s, 1H), 8.09 (d, J=3.0 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.33 (dd, J=9.0, 3.0 Hz, 1H), 6.07 (p, J=6.8 Hz, 1H), 3.22 (t, J=5.0 Hz, 4H), 2.63 (t, J=4.9 Hz, 4H), 2.38 (s, 3H), 1.73 (d, J=6.8 Hz, 6H).

TABLE-US-00001 TABLE 1 Examples I-3 to I-41 Side chains Products [00058] 10c [00059] I-3 [00060] 10d [00061] I-4 [00062] 10e [00063] I-5 [00064] 10f [00065] I-6 [00066] 10g [00067] I-7 [00068] 10h [00069] I-8 [00070] 10i [00071] I-9 [00072] 10j [00073] I-10 [00074] 10k [00075] I-11 [00076] 10l [00077] I-12 [00078] 10m [00079] I-13 [00080] 10n [00081] I-14 [00082] 10o [00083] I-15 [00084] 10p [00085] I-16 [00086] 10q [00087] I-17 [00088] 10r [00089] I-18 [00090] 10s [00091] I-19 [00092] 10t [00093] I-20 [00094] 10u [00095] I-21 [00096] 10v [00097] I-22 [00098] 10w [00099] I-23 [00100] 10x [00101] I-24 [00102] 10y [00103] I-25 [00104] 10z [00105] I-26 [00106] 10za [00107] I-27 [00108] 10zb [00109] I-28 [00110] 10zc [00111] I-29 [00112] 10zd [00113] I-30 [00114] 10ze [00115] I-31 [00116] 10zf [00117] I-32 [00118] 10zg [00119] I-33 [00120] 10zh [00121] I-34 [00122] 10zi [00123] I-35 [00124] 10zj [00125] I-36 [00126] 10zk [00127] I-37 [00128] 10zl [00129] I-38 [00130] 10zm [00131] I-39 [00132] 10zn [00133] I-40 [00134] 10zo [00135] I-41

[0225] By referring to the synthetic method of I-2 in Example 2, compounds I-3 (8.7 mg, 20.9 μmmol, 19%), I-4 (10.5 mg, 25.3 μmmol, 23%), I-5 (11.9 mg, 28.6 μmmol, 26%), I-6 (9.9 mg, 23.1 μmmol, 21%), I-7 (8.5 mg, 19.8 μmmol, 18%), I-15 (5.2 mg, 12.1 μmmol, 11%), I-16 (12.3 mg, 31.9 μmmol, 29%), I-17 (5.8 mg, 14.3 μmmol, 13%), I-18 (5.4 mg, 12.1 μmmol, 11%), I-19 (5.2 mg, 12.1 μmmol, 11%), I-20 (5.9 mg, 13.2 μmmol, 12%), I-23 (13.3 mg, 34.1 μmmol, 31%), I-24 (6.6 mg, 16.5 μmmol, 15%), I-25 (xx mg, 27.5 μmmol, 25%), I-26 (12.0 mg, 29.7 μmmol, 27%), I-27 (19.7 mg, 31.9 μmmol, 29%), I-33 (9.0 mg, 11.1 μmmol, 10%), I-34 (3.3 mg, 7.7 μmmol, 7%), I-36 (3.7 mg, 8.8 μmmol, 8%), I-37 (5.4 mg, 12.1 μmmol, 11%), I-38 (5.4 mg, 12.1 μmmol, 11%), I-39 (8.0 mg, 20.9 μmmol, 19%), I-40 (3.6 mg, 7.7 μmmol, 7%), and I-41 (4.3 mg, 9.9 μmmol, 9%) were prepared from 9a (30 mg, 0.11 mmol) and 10 (0.22 mmol, 2 equiv.).

[0226] I-3 LC-MS (ESI), C.sub.24H.sub.29N.sub.8 [M+H].sup.+: m/z=417.1.

[0227] I-4 LC-MS (ESI), C.sub.24H.sub.29N.sub.8 [M+14].sup.+: m/z=417.2.

[0228] I-5 .sup.1H NMR (400 MHz, chloroform-d) δ 9.17 (s, 1H), 8.28 (d, J=9.0 Hz, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 8.09 (d, J=2.9 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.34 (dd, J=9.1, 3.0 Hz, 1H), 6.07 (p, J=6.8 Hz, 1H), 3.24 (t, J=5.0 Hz, 4H), 2.68 (t, J=5.0 Hz, 4H), 2.52 (q, J=7.2 Hz, 2H), 2.51 (s, 3H), 1.73 (d, J=6.8 Hz, 6H), 1.16 (t, J=7.2 Hz, 3H).

[0229] I-6 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.19 (s, 1H), 8.39 (s, 1H), 8.21 (d, J=9.2 Hz, 2H), 8.11 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 6.10 (dt, J=13.4, 6.7 Hz, 1H), 3.08 (t, J=4.4 Hz, 4H), 2.70 (s, 4H), 2.57 (q, J=7.2 Hz, 2H), 2.41 (s, 3H), 1.73 (d, J=6.7 Hz, 6H), 1.18 (t, J=7.2 Hz, 3H).

[0230] I-7 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.21 (s, 1H), 8.35-8.09 (m, 3H), 7.73 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 6.07 (dt, J=13.4, 6.7 Hz, 1H), 2.99 (t, J=4.5 Hz, 4H), 2.67 (s, 4H), 2.59-2.44 (m, 5H), 1.71 (d, J=6.7 Hz, 6H), 1.16 (t, J=7.2 Hz, 3H).

[0231] I-15 LC-MS (ESI), C.sub.23H.sub.29N.sub.8O [M+H].sup.+: m/z=433.1.

[0232] I-16 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.20 (s, 1H), 8.62 (s, 1H), 8.26 (d, J=9.0 Hz, 1H), 8.20 (s, 1H), 8.16-8.05 (m, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.34 (dd, J=9.0, 2.5 Hz, 1H), 6.08 (dt, J=13.5, 6.7 Hz, 1H), 3.37-2.90 (m, 4H), 1.76 (m, 4H), 1.74 (d, J=6.7 Hz, 6H), 1.60 (dt, J=11.2, 5.8 Hz, 2H).

[0233] I-17 LC-MS (ESI), C.sub.22H.sub.26N.sub.7O [M+H].sup.+: m/z=404.2.

[0234] I-18 LC-MS (ESI), C.sub.25H.sub.32N.sub.7O [M+H].sup.+: m/z=446.3.

[0235] I-19 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.23 (s, 1H), 8.51 (s, 1H), 8.05-7.89 (m, 2H), 7.73-7.60 (m, 3H), 5.93 (p, J=6.8 Hz, 1H), 3.83 (d, J=12.5 Hz, 2H), 3.39 (t, J=12.2 Hz, 1H), 2.92 (s, 6H), 2.84 (m, 2H), 2.26 (d, J=12.2 Hz, 2H), 1.89 (qd, J=12.5, 4.2 Hz, 2H), 1.67 (d, J=6.7 Hz, 6H).

[0236] I-20 LC-MS (ESI), C.sub.24H.sub.30FN.sub.8 [M+H].sup.+: m/z=449.3.

[0237] I-23 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.19 (s, 1H), 8.42 (s, 1H), 8.31 (d, J=9.0 Hz, 1H), 8.21 (s, 1H), 8.09 (d, J=2.9 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.32 (dd, J=9.0, 3.0 Hz, 1H), 6.07 (p, J=6.8 Hz, 1H), 3.98-3.81 (m, 4H), 3.19-3.10 (m, 4H), 1.73 (d, J=6.7 Hz, 6H).

[0238] I-24 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.17 (s, 1H), 8.22 (s, 2H), 8.04 (s, 2H), 7.77 (d, J=8.7 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 6.14-6.05 (m, 1H), 3.95-3.78 (m, 4H), 3.05-2.87 (m, 4H), 2.43 (s, 3H), 1.74 (d, J=6.7 Hz, 6H).

[0239] I-25 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.18 (s, 1H), 8.31-8.14 (m, 2H), 8.07 (s, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 6.08 (dt, J=13.3, 6.6 Hz, 1H), 4.01-3.76 (m, 4H), 3.04-2.83 (m, 4H), 2.53 (s, 3H), 1.74 (d, J=6.7 Hz, 6H).

[0240] I-26 LC-MS (ESI), C.sub.22H.sub.26N.sub.7O [M+H].sup.+: m/z=404.2.

[0241] I-27 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.23 (s, 1H), 9.05 (brs, 1H), 8.31 (d, J=9.0 Hz, 1H), 8.22 (s, 1H), 8.11 (d, J=2.9 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.31 (dd, J=9.1, 2.9 Hz, 1H), 6.07 (p, J=6.7 Hz, 1H), 3.85 (dqd, J=12.4, 6.1, 2.2 Hz, 2H), 3.49-3.32 (m, 2H), 2.47 (dd, J=11.6, 10.2 Hz, 2H), 1.73 (d, J=6.7 Hz, 6H), 1.29 (s, 3H). 1.28 (s, 3H).

[0242] I-33 LC-MS (ESI), C.sub.25H.sub.29N.sub.8O [M+H].sup.+: m/z=457.1.

[0243] I-34 LC-MS (ESI), C.sub.24H.sub.30N.sub.7O [M+H].sup.+: m/z=432.2.

[0244] I-36 LC-MS (ESI), C.sub.23H.sub.29N.sub.6O.sub.2[M+H].sup.+: m/z=421.1.

[0245] I-37 LC-MS (ESI), C.sub.25H.sub.31N.sub.6O.sub.2 [M+H].sup.+: m/z=447.3.

[0246] I-38 LC-MS (ESI), C.sub.26H.sub.33N.sub.6O [M+H].sup.+: m/z=445.2.

[0247] I-39 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.13 (s, 1H), 8.22 (s, 1H), 8.07 (d, J=2.1 Hz, 1H), 7.97-7.82 (m, 3H), 7.74 (d, J=8.6 Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.8 Hz, 1H), 6.11 (hept, J=7.1, 6.5 Hz, 1H), 4.09 (s, 3H), 1.69 (d, J=6.7 Hz, 6H).

[0248] I-40 LC-MS (ESI), C.sub.26H.sub.32N.sub.7O.sub.2[M+H].sup.+: m/z=474.3.

[0249] I-41 LC-MS (ESI), C.sub.23H.sub.30N.sub.9 [M+H].sup.+: m/z=432.1.

[0250] By referring to the synthetic method of I-1 in Example 2, compounds I-8 (12.5 mg, 28.6 μmmol, 26%), I-9 (15.9 mg, 36.3 μmmol, 33%), I-10 (10.6 mg, 24.2 μmmol, 22%), I-11 (11.4 mg, 25.3 μmmol, 23%), I-12 (10.4 mg, 23.1 μmmol, 21%), I-13 (7.8 mg, 17.6 μmmol, 16%), I-14 (9.2 mg, 20.9 μmmol, 19%), I-21 (5.3 mg, 12.1 μmmol, 11%), I-22 (6.1 mg, 14.3 μmmol, 13%), I-28 (8.9 mg, 18.7 μmmol, 17%), I-29 (4.5 mg, 9.9 μmmol, 9%), I-30 (6.7 mg, 15.4 μmmol, 14%), I-31 (6.6 mg, 14.3 μmmol, 13%), I-32 (5.6 mg, 12.1 μmmol, 11%), and I-35 (6.3 mg, 14.3 μmmol, 13%) were prepared from 9a (30 mg, 0.11 mmol) and 10 (0.22 mmol, 2 equiv.).

[0251] I-8 .sup.1H NMR (400 MHz, water-d.sub.2, ppm) δ 9.73 (s, 1H), 9.68 (s, 1H), 8.22 (d, J=8.9 Hz, 1H), 8.07 (s, 1H), 7.88 (d, J=8.9 Hz, 1H), 7.52 (s, 1H), 6.21 (p, J=6.7 Hz, 1H), 3.24 (m, 4H), 3.21-3.14 (m, 4H), 2.52 (s, 3H), 1.74 (d, J=6.5 Hz, 6H).

[0252] I-9a .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.19 (s, 1H), 8.21 (s, 1H), 8.18 (d, J=8.7 Hz, 1H), 8.13 (d, J=4.2 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.37 (d, J=8.7 Hz, 1H), 6.07 (p, J=6.7 Hz, 1H), 3.60 (t, J=4.9 Hz, 4H), 2.87 (d, J=5.0 Hz, 4H), 2.52 (s, 3H), 1.73 (d, J=6.7 Hz, 6H), 1.50 (s, 9H).

[0253] I-9 LC-MS (ESI), C.sub.22H.sub.27N.sub.8 [M+H].sup.+: m/z=403.1.

[0254] I-10 LC-MS (ESI), C.sub.22H.sub.27N.sub.8 [M+H].sup.+: m/z=403.2.

[0255] I-11 LC-MS (ESI), C.sub.23H.sub.29N.sub.8 [M+H].sup.+: m/z=417.3.

[0256] I-12 .sup.1H NMR (400 MHz, water-d.sub.2, ppm) δ 9.56 (s, 1H), 9.43 (s, 1H), 8.12 (t, J=9.3 Hz, 2H), 7.89-7.77 (m, 2H), 7.52 (d, J=9.7 Hz, 1H), 6.00 (dt, J=13.2, 6.7 Hz, 1H), 3.89 (d, J=11.5 Hz, 2H), 3.58 (d, J=6.7 Hz, 2H), 2.98-2.84 (m, 2H), 1.77 (d, J=6.7 Hz, 6H), 1.41 (d, J=6.6 Hz, 6H).

[0257] I-13 LC-MS (ESI), C.sub.21H.sub.24FN.sub.8 [M+H].sup.+: m/z=407.1.

[0258] I-14a .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.14 (s, 1H), 8.26-8.13 (m, 2H), 8.01 (s, 1H), 7.90 (s, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.09 (d, J=9.1 Hz, 1H), 6.08 (dt, J=13.3, 6.7 Hz, 1H), 3.60 (d, J=12.5 Hz, 6H), 3.37 (s, 1H), 3.27 (t, J=5.9 Hz, 1H), 2.01 (d, J=5.8 Hz, 2H), 1.72 (d, J=6.8 Hz, 6H), 1.41 (d, J=21.7 Hz, 9H).

[0259] I-14 LC-MS (ESI), C.sub.22H.sub.27N.sub.8 [M+H].sup.+: m/z=403.3.

[0260] I-21 LC-MS (ESI), C.sub.22H.sub.27N.sub.8 [M+H].sup.+: m/z=403.2.

[0261] I-22 LC-MS (ESI), C.sub.21H.sub.25N.sub.8 [M+H].sup.+: m/z=389.2.

[0262] I-28a .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.16 (s, 1H), 8.93 (brs, 1H), 8.29 (d, J=9.1 Hz, 1H), 8.22 (s, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.62 (d, J=2.9 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.02 (dd, J=9.2, 2.8 Hz, 1H), 6.08 (p, J=6.7 Hz, 1H), 3.57-3.34 (m, 8H), 1.94 (t, J=6.9 Hz, 2H), 1.73 (d, J=6.7 Hz, 4H), 1.69-1.53 (m, 6H), 1.47 (s, 9H).

[0263] I-28 LC-MS (ESI), C.sub.25H.sub.31N.sub.8 [M+H].sup.+: m/z=443.2.

[0264] I-29 LC-MS (ESI), C.sub.23H.sub.27N.sub.8 [M+14].sup.+: m/z=415.3.

[0265] I-30a .sup.1H NMR (400 MHz, chloroform-d) δ 9.18 (s, 1H), 8.96 (brs, 1H), 8.41-8.24 (m, 2H), 7.82-7.72 (m, 1H), 7.64-7.50 (m, 2H), 6.95 (d, J=8.7 Hz, 1H), 6.06 (p, J=6.8 Hz, 1H), 4.13 (s, 4H), 4.03 (s, 4H), 1.73 (dd, J=6.8, 1.7 Hz, 6H), 1.45 (s, 9H).

[0266] I-30 LC-MS (ESI), C.sub.22H.sub.25N.sub.8 [M+H].sup.+: m/z=401.1.

[0267] I-31a .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.15 (s, 1H), 8.28 (d, J=9.0 Hz, 1H), 8.21 (s, 1H), 8.04 (d, J=2.8 Hz, 1H), 7.94 (s, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.34 (dd, J=9.1, 2.9 Hz, 1H), 6.07 (p, J=6.8 Hz, 1H), 3.71 (s, 4H), 3.10 (t, J=5.5 Hz, 4H), 1.94 (t, J=5.5 Hz, 4H), 1.73 (d, J=6.7 Hz, 6H), 1.46 (s, 9H).

[0268] I-31 LC-MS (ESI), C.sub.24H.sub.29N.sub.8 [M+14].sup.+: m/z=429.2.

[0269] I-32a .sup.1H NMR (400 MHz, chloroform-d) δ 9.15 (s, 1H), 8.20 (t, J=4.4 Hz, 2H), 8.11 (s, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.66 (d, J=2.9 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 6.86 (dd, J=8.8, 2.9 Hz, 1H), 6.07 (p, J=6.7 Hz, 1H), 3.69 (s, 4H), 3.41 (d, J=5.8 Hz, 4H), 1.82 (t, J=5.7 Hz, 8H), 1.72 (d, J=6.7 Hz, 6H), 1.47 (s, 9H).

[0270] I-32 LC-MS (ESI), C.sub.24H.sub.29N.sub.8 [M+14].sup.+: m/z=429.1.

[0271] I-35a .sup.1H NMR (400 MHz, chloroform-d) δ 9.10 (s, 1H), 8.18 (s, 1H), 8.13 (t, J=9.2 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.19 (s, 1H), 6.74 (m, 2H), 5.97 (p, J=6.7 Hz, 1H), 3.61 (m, 4H), 3.13 (m, 4H), 1.66 (d, J=6.7 Hz, 6H), 1.50 (s, 9H).

[0272] I-35 LC-MS (ESI), C.sub.22H.sub.25FN.sub.7[M+H].sup.+: m/z=406.2.

Preparation of the Key Intermediate 1-ethyl-8-(methylsulfinyl)-1H-imidazo[4,5-h]quinazoline (9b)

[0273] ##STR00136##

[0274] 1): By referring to the synthetic method of 5a in Example 1, 3-ethyl-3,5,6,7-tetrahydrogen-4H-benzo[d]imidazol-4-one (5b, 3.05 g, 18.6 mmol, 23%) was obtained from reaction of the compound 4a (11.0 g, 80.9 mmol). LC-MS (ESI), C.sub.9H.sub.13N.sub.2O [M+H].sup.+: m/z=165.3.

[0275] 2): By referring to the synthetic steps of 5a to 9a in Example 1, the title compound (9b, 523 mg, 2.0 mmol, yield of four steps: 11%) was prepared from 5b (3.0 g, 18.3 mmol) via four reaction steps. .sup.1H NMR (400 MHz, chloroform-d) δ 9.54 (s, 1H), 8.21 (s, 1H), 8.15 (d, J=8.7 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 5.05-4.88 (m, 2H), 3.06 (s, 3H), 1.69 (t, J=7.3 Hz, 3H).

TABLE-US-00002 TABLE 2 Examples I-42 to I-46 Side chains Products [00137] 10a [00138] I-42 [00139] 10b [00140] I-43 [00141] 10za [00142] I-44 [00143] 10w [00144] I-45 [00145] 11z [00146] I-46

[0276] By referring to the synthetic method of I-1 in Example 1, the title compound I-42 (11.1 mg, 27.2 μmmol, 24%) was prepared from 9b (30 mg, 0.115 mmol).

[0277] I-42a .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.17 (s, 1H), 8.36 (d, J=9.0 Hz, 1H), 8.17 (s, 1H), 8.07 (d, J=2.9 Hz, 1H), 8.05 (s, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.36 (dd, J=9.0, 3.0 Hz, 1H), 4.90 (q, J=7.2 Hz, 2H), 3.63 (t, J=5.0 Hz, 4H), 3.12 (t, J=5.1 Hz, 4H), 1.70-1.62 (t, J=7.2 Hz, 3H), 1.50 (s, 9H).

[0278] I-42 LC-MS (ESI), C.sub.20H.sub.23N.sub.8 [M+H].sup.+: m/z=375.2.

[0279] By referring to the synthetic method of I-2 in Example 2, compounds I-43 (13.4 mg, 34.5 μmmol, 30%), I-44 (11.6 mg, 28.7 μmmol, 25%), I-45 (13.0 mg, 34.5 μmmol, 33%), and I-46 (10.3 mg, 26.5 μmmol, 23%) were prepared from 9b (30 mg, 0.115 mmol).

[0280] I-43 .sup.1H NMR (400 MHz, methanol-d.sub.4, ppm) δ 9.03 (s, 1H), 8.19 (d, J=9.0 Hz, 1H), 7.99 (s, 1H), 7.88 (d, J=3.0 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.29 (dd, J=9.1, 3.0 Hz, 1H), 4.79 (q, J=7.2 Hz, 2H), 3.11 (t, J=5.0 Hz, 4H), 2.55 (t, J=5.0 Hz, 4H), 2.27 (s, 3H), 1.53 (t, J=7.2 Hz, 3H).

[0281] I-44 .sup.1H NMR (400 MHz, chloroform-d:methanol-d.sub.4=1:1, ppm) δ 8.34 (d, J=9.1 Hz, 1H), 8.20 (s, 1H), 8.10-8.02 (m, 2H), 7.74 (d, J=8.7 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.33 (dd, J=9.0, 3.0 Hz, 1H), 4.90 (q, J=7.2 Hz, 2H), 3.86 (dtt, J=12.6, 6.4, 4.0 Hz, 2H), 3.44-3.35 (m, 2H), 2.47 (t, J=10.9 Hz, 2H), 1.72-1.60 (t, J=7.2 Hz, 6H), 1.29 (d, J=6.2 Hz, 6H).

[0282] I-45 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.17 (s, 1H), 8.36 (d, J=9.0 Hz, 1H), 8.17 (s, 1H), 8.07 (d, J=2.9 Hz, 1H), 8.05 (s, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.35 (dd, J=9.1, 3.0 Hz, 1H), 4.90 (q, J=7.2 Hz, 2H), 3.95-3.84 (m, 4H), 3.21-3.12 (m, 4H), 1.65 (t, J=7.0 Hz, 3H).

[0283] I-46 LC-MS (ESI), C.sub.21H.sub.24N.sub.7O [M+H].sup.+: m/z=390.1.

Preparation of the Key Intermediate 1-cyclopropyl-8-(methylsulfinyl)-1H-imidazo[4,5-h]quinazoline (9c)

[0284] ##STR00147##

[0285] 1): By referring to the synthetic method of 5a in Example 1, the compound 3-cyclopropyl-3,5,6,7-tetrahydrogen-4H-benzo[d]imidazol-4-one (5c, 2.2 g, 12.6 mmol, 19%) was prepared from compound 4a (9 g, 66.2 mmol). .sup.1H NMR (600 MHz, chloroform-d, ppm) δ 7.48 (s, 1H), 3.53 (dt, J=7.3, 3.5 Hz, 1H), 2.73 (t, J=6.2 Hz, 2H), 2.43 (dd, J=7.2, 5.8 Hz, 2H), 2.07-1.96 (m, 2H), 1.07-0.94 (m, 2H), 0.88-0.77 (m, 2H).

[0286] 2): By referring to the synthetic steps of 5a to 9a in Example 1, 9c (490 mg, 1.8 mmol, 16%) was prepared from 5c (2.0 g, 11.4 mmol) via four reaction steps. .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.54 (d, J=1.1 Hz, 1H), 8.20 (s, 1H), 8.12 (dd, J=8.7, 1.1 Hz, 1H), 7.83 (dd, J=8.8, 1.1 Hz, 1H), 4.16 (tt, J=7.5, 4.0 Hz, 1H), 3.06 (d, J=1.1 Hz, 3H), 1.48-1.36 (m, 2H), 1.20 (qd, J=10.5, 3.9 Hz, 2H).

TABLE-US-00003 TABLE 3 Examples I-47 to I-51 Side chains Products [00148] 10a [00149] I-47 [00150] 10h [00151] I-48 [00152] 10w [00153] I-49 [00154] 10x [00155] I-50 [00156] 10y [00157] I-51

[0287] By referring to the synthetic method of I-1 in Example 1, the title compounds I-47 (9.7 mg, 23.1 μmmol, 21%), and I-48 (11.5 mg, 28.6 μmmol, 26%) were prepared from 9c (30 mg, 0.11 mmol).

[0288] I-47a .sup.1H NMR (600 MHz, methanol-d.sub.4, ppm) δ 9.19 (s, 1H), 8.48 (d, J=9.0 Hz, 1H), 8.26 (d, J=3.4 Hz, 1H), 7.99 (d, J=2.9 Hz, 1H), 7.74 (dt, J=6.9, 2.2 Hz, 1H), 7.68-7.59 (m, 2H), 7.45 (d, J=8.7 Hz, 1H), 4.49 (d, J=5.1 Hz, 1H), 3.60 (m, 4H), 3.13 (t, J=5.1 Hz, 4H), 1.48 (s, 9H), 1.31-1.23 (m, 2H), 1.22 (d, J=4.3 Hz, 2H).

[0289] I-47 LC-MS (ESI), C.sub.21C.sub.23N.sub.8 [M+H].sup.+: m/z=387.1.

[0290] I-48a .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.19 (s, 1H), 8.49 (s, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 8.03 (s, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.58 (d, J=8.6 Hz, 1H), 4.28 (tt, J=7.4, 4.0 Hz, 1H), 3.59 (t, J=4.9 Hz, 4H), 2.92 (t, J=4.9 Hz, 4H), 2.29 (s, 3H), 1.33-1.26 (m, 2H), 1.20 (dt, J=5.1, 2.2 Hz, 2H).

[0291] I-48 LC-MS (ESI), C.sub.22H.sub.25N.sub.8 [M+].sup.+: m/z=401.3.

[0292] By referring to the synthetic method of I-2 in Example 2, compounds I-49 (9.8 mg, 25.3 μmmol, 23%), I-50 (9.3 mg, μmmol, 21%), and I-51 (12.8 mg, 31.9 μmmol, 29%) were prepared from 9c (30 mg, 0.11 mmol).

[0293] I-49 .sup.1H NMR (400 MHz, chloroform-d/methanol-d.sub.4=1:1, ppm) δ 9.11 (d, J=2.3 Hz, 1H), 8.48 (dd, J=9.1, 2.7 Hz, 1H), 8.04 (s, 1H), 7.93 (t, J=3.0 Hz, 1H), 7.62 (dd, J=8.6, 3.4 Hz, 1H), 7.54 (dd, J=8.6, 2.2 Hz, 1H), 7.24 (dt, J=9.1, 2.2 Hz, 1H), 4.17 (dq, J=7.2, 3.4 Hz, 1H), 3.90-3.79 (m, 4H), 3.10 (t, J=3.4 Hz, 4H), 1.36-1.21 (m, 2H), 1.21-1.10 (m, 2H).

[0294] I-50 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.19 (s, 1H), 8.48 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.77-7.67 (m, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.33 (s, 1H), 4.29 (tt, J=7.4, 4.0 Hz, 1H), 3.88 (t, J=4.5 Hz, 4H), 2.98 (t, J=4.5 Hz, 4H), 2.30 (s, 3H), 1.31 (d, J=7.0 Hz, 2H), 1.28-1.17 (m, 2H).

[0295] I-51 .sup.1H NMR (400 MHz, chloroform-d/methanol-d.sub.4=1:1, ppm) δ 9.14 (s, 1H), 8.40 (d, J=8.7 Hz, 1H), 8.05 (s, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 4.22 (dd, J=7.3, 3.9 Hz, 1H), 3.84 (t, J=4.5 Hz, 4H), 2.87 (t, J=4.6 Hz, 4H), 2.49 (s, 3H), 1.30 (d, J=6.9 Hz, 2H), 1.18 (tt, J=7.5, 4.5 Hz, 2H).

Preparation of the Key Intermediate 1-cyclobutyl-8-(methylsulfinyl)-1H-imidazo[4,5-h]quinazoline (9d)

[0296] ##STR00158##

[0297] 1): By referring to the synthetic method of 5a in Example 1, the compound 3-cyclobutyl-3,5,6,7-tetrahydrogen-4H-benzo[d]imidazol-4-one (5d, 1.56 g, 8.23 mmol, 14%) was obtained from reaction of compound 4a (8 g, 58.8 mmol). LC-MS (ESI) for C.sub.11H.sub.15N.sub.2O [M+H].sup.+: m/z=191.3.

[0298] 2): By referring to the synthetic steps of 5a to 9a in Example 1, 9d (429 mg, 1.5 mmol, 19%) was prepared from 5d (1.5 g, 7.89 mmol) via four reaction steps. .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.51 (d, J=1.0 Hz, 1H), 8.38 (s, 1H), 8.14 (d, J=8.7 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 5.88 (p, J=8.5 Hz, 1H), 3.05 (d, J=1.0 Hz, 3H), 2.96-2.85 (m, 2H), 2.55 (pd, J=9.9, 4.1 Hz, 2H), 2.19-1.97 (m, 2H).

TABLE-US-00004 TABLE 4 Examples I-52 to I-56 Side chains Products [00159] 10a [00160] I-52 [00161] 10h [00162] I-53 [00163] 10i [00164] I-54 [00165] 10w [00166] I-55 [00167] 10x [00168] I-56

[0299] By referring to the synthetic method of I-1 in Example 1, compounds I-52 (11.5 mg, 26.3 μmmol, 25%), I-53 (10.9 mg, 24.2 μmmol, 23%), and I-54 (13.7 mg, 30.5 μmmol, 29%) were prepared from 9d (30 mg, 0.105 mmol).

[0300] I-52a .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.16 (s, 1H), 8.39 (d, J=9.0 Hz, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 8.09 (d, J=2.9 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.41 (dd, J=9.0, 2.9 Hz, 1H), 6.16-6.04 (m, 1H), 3.64 (t, J=5.1 Hz, 4H), 3.13 (t, J=5.2 Hz, 4H), 2.74 (tdd, J=9.9, 5.1, 2.5 Hz, 2H), 2.50 (pd, J=9.4, 2.8 Hz, 2H), 2.08-1.90 (m, 2H), 1.50 (s, 9H).

[0301] I-52 LC-MS (ESI), C.sub.22H.sub.25N.sub.8 [M+H].sup.+: m/z=401.2.

[0302] I-53a .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.32 (s, 1H), 8.76 (s, 1H), 8.71 (s, 1H), 8.01-7.94 (m, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.72 (s, 1H), 6.18-5.96 (m, 1H), 3.62 (t, J=4.5 Hz, 4H), 2.90 (t, J=4.5 Hz, 4H), 2.58 (s, 3H), 2.54-2.40 (m, 2H), 2.32 (q, J=9.3 Hz, 1H), 2.03 (q, J=10.0 Hz, 1H), 1.50 (d, J=1.7 Hz, 9H).

[0303] I-53 LC-MS (ESI), C.sub.23H.sub.27N.sub.8 [M+H].sup.+: m/z=415.3.

[0304] I-54a .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.17 (s, 1H), 8.28 (s, 1H), 8.26 (d, J=8.6 Hz, 1H), 8.06 (s, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.43 (d, J=8.7 Hz, 1H), 6.16-6.02 (m, 1H), 3.61 (t, J=4.9 Hz, 4H), 2.87 (t, J=4.9 Hz, 4H), 2.74 (qt, J=7.6, 2.6 Hz, 2H), 2.53 (s, 3H), 2.51-2.44 (m, 2H), 1.98 (ddd, J=18.3, 9.1, 2.7 Hz, 2H), 1.50 (s, 9H).

[0305] I-54 LC-MS (ESI), C.sub.23H.sub.27N.sub.8 [M+H].sup.+: m/z=415.2.

[0306] By referring to the synthetic method of I-2 in Example 2, compounds I-55 (8.9 mg, 22.1 μmmol, 21%), and I-56 (14.4 mg, 34.6 μmmol, 33%) were prepared from 9d (30 mg, 0.105 mmol).

[0307] I-55 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.16 (s, 1H), 8.39 (d, J=9.0 Hz, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 8.08 (d, J=3.0 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.39 (dd, J=9.0, 3.0 Hz, 1H), 6.11 (dq, J=17.1, 8.5, 8.0 Hz, 1H), 3.92 (t, J=4.8 Hz, 4H), 3.18 (t, J=4.8 Hz, 4H), 2.80-2.67 (m, 2H), 2.50 (pd, J=9.6, 2.6 Hz, 2H), 2.07-1.90 (m, 2H).

[0308] I-56 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.18 (s, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 8.06 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 6.08 (p, J=8.5 Hz, 1H), 3.88 (t, J=4.5 Hz, 4H), 3.00 (t, J=4.5 Hz, 4H), 2.85-2.73 (m, 2H), 2.51 (dd, J=9.6, 2.8 Hz, 2H), 2.48 (s, 3H), 1.98 (tt, J=11.0, 8.6 Hz, 2H).

Preparation of the Key Intermediate 1-cyclopentyl-8-(methylsulfinyl)-1H-imidazo[4,5-h]quinazoline (9e)

[0309] ##STR00169##

[0310] 1): By referring to the synthetic method of 5a in Example 1, the title compound 3-cyclopentyl-3,5,6,7-tetrahydrogen-4H-benzoldlimidazol-4-one (5e, 3.6 g, 17.64 mol, 24%) was prepared from the compound 4a (10.0 g, 73.5 mmol). LC-MS (ESI) for C.sub.12H.sub.17N.sub.2O [M+H].sup.+: m/z=205.3.

[0311] 2): By referring to the synthetic steps of 5a to 9a in Example 1, the title compound 9e (594 mg, 1.98 mmol, 13%) was prepared from 5e (3.1 g, 15.2 mmol) via four reaction steps. .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.53 (s, 1H), 8.32 (s, 1H), 8.15 (d, J=8.7 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 6.05 (p, J=6.7 Hz, 1H), 3.05 (d, J=1.1 Hz, 3H), 2.50 (dq, J=13.3, 6.6 Hz, 2H), 2.09 (td, J=13.8, 6.8 Hz, 2H), 1.95 (d, J=8.1 Hz, 4H).

TABLE-US-00005 TABLE 5 Examples I-57 to I-61 Side chains Products [00170] 10a [00171] I-57 [00172] 10h [00173] I-58 [00174] 10i [00175] I-59 [00176] 10x [00177] I-60 [00178] 10x [00179] I-61

[0312] By referring to the synthetic method of I-1 in Example 1, the title compounds I-57 (11.3 mg, 25.0 μmmol, 25%), I-58 (12.1 mg, 26.0 μmmol, 26%), and I-59 (12.5 mg, 27.0 μmmol, 27%) were prepared from 9e (30 mg, 0.10 mmol).

[0313] I-57 .sup.1H NMR (400 MHz, methanol-d.sub.4) δ 9.55 (s, 1H), 9.05 (s, 1H), 8.14 (d, J=9.6 Hz, 1H), 8.06-7.94 (m, 2H), 7.85 (d, J=8.8 Hz, 1H), 7.71 (d, J=9.5 Hz, 1H), 6.23 (p, J=7.1 Hz, 1H), 3.55-3.48 (m, 4H), 3.48-3.39 (m, 4H), 2.51 (dt, J=12.2, 6.0 Hz, 2H), 2.15-2.04 (m, 2H), 1.99-1.86 (m, 4H).

[0314] I-58a .sup.1H NMR (600 MHz, chloroform-d, ppm) δ 9.17 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 8.01 (s, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 6.18 (ddd, J=12.9, 7.3, 5.5 Hz, 1H), 3.59 (t, J=4.8 Hz, 4H), 2.93 (t, J=5.0 Hz, 4H), 2.43 (m, 2H), 2.40 (s, 3H), 2.08 (dd, J=12.7, 6.5 Hz, 2H), 1.94 (m, 2H), 1.86 (m, 2H), 1.50 (s, 9H).

[0315] I -58 LC-MS (ESI), C.sub.24H.sub.29N.sub.8 [M+14].sup.+: m/z=429.1.

[0316] I -59a .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.37 (s, 1H), 8.89 (s, 1H), 8.80 (d, J=9.3 Hz, 1H), 8.07 (d, J=8.9 Hz, 1H), 7.88 (d, J=9.1 Hz, 2H), 6.27-6.11 (m, 1H), 3.62 (d, J=5.0 Hz, 4H), 2.90 (d, J=5.0 Hz, 4H), 2.78 (s, 3H), 2.71-2.64 (m, 2H), 2.07 (d, J=18.9 Hz, 4H), 1.95 (m, 2H). 1.50 (s, 9H).

[0317] I -59 LC-MS (ESI), C.sub.24H.sub.29N.sub.8 [M+14].sup.+: m/z=429.3.

[0318] By referring to the synthetic method of I-2 in Example 2, compounds I-60 (7.9 mg, 19.0 μmmol, 19%), and I-61 (1 mg, 31.0 μmmol, 31%) were prepared from 9e (30 mg, 0.10 mmol).

[0319] I-60 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.17 (s, 1H), 8.29 (d, J=9.0 Hz, 1H), 8.20 (s, 1H), 8.18 (s, 1H), 8.07 (d, J=2.9 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.31 (dd, J=9.1, 3.0 Hz, 1H), 6.15 (p, J=7.0 Hz, 1H), 3.91 (dd, J=5.8, 3.7 Hz, 4H), 3.16 (dd, J=5.9, 3.7 Hz, 4H), 2.45 (dt, J=13.8, 7.3 Hz, 2H), 2.09-1.94 (m, 4H), 1.87 (dq, J=9.9, 3.9 Hz, 2H).

[0320] I-61 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.18 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.76 (d, J=8.7 Hz, 1H), 7.57 (d, J=8.7 Hz, 1H), 6.23-6.13 (m, 1H), 3.92-3.83 (m, 4H), 3.02-2.94 (m, 4H), 2.41 (m, 2H), 2.40 (s, 3H) 2.14-2.05 (m, 2H), 1.97-1.80 (m, 4H).

Preparation of the Key Intermediate 1-isopropyl-5-methyl-8-(methylsulfinyl)-1H-imidazo[4,5-h]quinazoline (9f)

[0321] ##STR00180##

[0322] 1): By referring to the synthetic method of 5a in Example 1, the compound 3-isopropyl-6-methyl-3,5,6,7-tetrahydrogen-4H-benzo[d]imidazol-4-one (5f, 3.82 g, 19.9 mmol, 5%) was prepared from the compound 1b (50 g, 397 mmol) via four reaction steps. .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 7.67 (s, 1H), 5.09 (p, J=6.7 Hz, 1H), 2.92 (dd, J=16.3, 4.4 Hz, 1H), 2.56-2.45 (m, 2H), 2.37 (dtt, J=10.0, 7.0, 3.2 Hz, 1H), 2.27 (dd, J=15.7, 11.5 Hz, 1H), 1.46 (d, J=6.7 Hz, 6H), 1.13 (d, J=6.3 Hz, 3H).

[0323] 2): By referring to the synthetic steps of 5a to 9a in Example 1, the title compound 9f (400 mg, 1.39 mmol, 7%) was prepared from 5f (3.8 g, 19.8 mmol) via four reaction steps.

[0324] .sup.1H NMR (400 MHz, chloroform-d) δ 9.66 (d, J=1.7 Hz, 1H), 8.28 (d, J=1.6 Hz, 1H), 7.91 (d, J=1.2 Hz, 1H), 5.95 (pd, J=6.7, 1.7 Hz, 1H), 3.03 (d, J=1.8 Hz, 3H), 2.86 (d, J=1.1 Hz, 3H), 1.73 (dd, J=8.9, 6.8 Hz, 6H).

TABLE-US-00006 TABLE 6 Examples I-62 to I-66 Side chains Products [00181] 10a [00182] I-62 [00183] 10h [00184] I-63 [00185] 10i [00186] I-64 [00187] 10w [00188] I-65 [00189] 10z [00190] I-66

[0325] By referring to the synthetic method of I-1 in Example 1, the title compounds I-62 (11.0 mg, 25.2 μmmol, 24%), I-63 (8.1 mg, 17.9 μmmol, 17%), and I-64 (10.9 mg, 24.2 μmmol, 23%) were prepared from 9f (30 mg, 0.105 mmol).

[0326] I-62a .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.88 (s, 1H), 9.72 (s, 1H), 8.32 (dd, J=9.6, 3.0 Hz, 1H), 8.05 (d, J=2.9 Hz, 1H), 7.76 (s, 1H), 7.72 (d, J=9.6 Hz, 1H), 6.27 (p, J=6.7 Hz, 1H), 3.58 (dd, J=6.8, 3.8 Hz, 4H), 3.46 (dd, J=6.8, 3.7 Hz, 4H), 2.96 (s, 3H), 1.83 (d, J=6.7 Hz, 6H).

[0327] I-62 LC-MS (ESI), C.sub.22H.sub.27N.sub.8 [M+H].sup.+: m/z=403.1.

[0328] I-63 LC-MS (ESI), C.sub.23H.sub.29N.sub.8 [M+14].sup.+: m/z=417.3.

[0329] I-64 LC-MS (ESI), C.sub.23H.sub.29N.sub.8 [M+14].sup.+: m/z=417.5.

[0330] By referring to the synthetic method of I-2 in Example 2, compounds I-65 (8.0 mg, 20.0 μmmol, 19%), and I-66 (12.6 mg, 30.4 μmmol, 29%) were prepared from 9e (30 mg, 0.105 mmol).

[0331] I-65 LC-MS (ESI), C.sub.22H.sub.26N.sub.7O [M+H].sup.+: m/z=404.3.

[0332] I-66 LC-MS (ESI), C.sub.23H.sub.28N.sub.7O [M+H].sup.+: m/z=418.3.

Preparation of the Key Intermediate 4-bromo-1-isopropyl-8-(methylsulfinyl)-1H-imidazo[4,5-h]quinazoline (12a)

[0333] ##STR00191##

1): 4-Bromo-1-isopropyl-8-(methylthio)-1H-imidazo[4,5-H]quinazoline (12a)

[0334] 8a (1.8 g, 6.98 mmol), N-bromosuccinimide (2.48 g, 13.96 mmol) and azobisisobutyronitrile (344 mg, 2.1 mmol) were suspended in carbon tetrachloride (40 mL), and the atmosphere of the reaction system was replaced with argon for 3 times. The reaction mixture was heated to 80° C., and stirred for 18 hours. After the reaction mixture was concentrated, it was purified with flash silica gel column chromatography (petroleum ether/ethyl acetate=3:1) to afford a light yellow solid as 4-bromo-1-isopropyl-8-(methylthio)-1H-imidazo[4,5-h]quinazoline (11a, 961.0 mg, 2.86 mmol, 41%). LC-MS (ESI) for C.sub.13H.sub.14BrN.sub.4S [M+H].sup.+: m/z=337.3, 339.2.

[0335] 2): By referring to the synthetic steps of 8a to 9a in Example 1, the title compound 12a (401 mg, 1.14 mmol, 83%) was prepared from 11a (460 mg, 1.37 mmol). LC-MS (ESI) for C.sub.13H.sub.14BrN.sub.4OS [M+H].sup.+: m/z=353.1, 355.3.

TABLE-US-00007 TABLE 7 Examples I-67 to I-71 Side chains Products [00192] 10a [00193] I-67 [00194] 10h [00195] I-68 [00196] 10i [00197] I-69 [00198] 10w [00199] I-70 [00200] 10ze [00201] I-71

[0336] By referring to the synthetic method of I-1 in Example 1, the title compounds I-67 (11.5 mg, 23.0 μmmol, 23%), I-68 (7.2 mg, 14.0 μmmol, 14%), I-69 (12.9 mg, 25.0 μmmol, 25%), and I-71 (6.0 mg, 11.0 μmmol, 11%) were prepared from 12a (35 mg, 0.10 mmol).

[0337] I-67a .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.10 (s, 1H), 8.25 (d, J=4.3 Hz, 2H), 8.09-7.98 (m, 2H), 7.80 (s, 1H), 7.34 (dd, J=9.1, 3.0 Hz, 1H), 6.06 (p, J=6.8 Hz, 1H), 3.63 (t, J=5.1 Hz, 4H), 3.13 (t, J=5.1 Hz, 4H), 1.73 (d, J=6.7 Hz, 6H), 1.50 (s, 9H).

[0338] I-67 LC-MS (ESI), C.sub.21H.sub.24BrN.sub.8 [M+H].sup.+: m/z=467.1, 469.2.

[0339] I-68 LC-MS (ESI), C.sub.22H.sub.26BrN.sub.8[M+H].sup.+: m/z=481.1, 483.3.

[0340] I-69 LC-MS (ESI), C.sub.22H.sub.26BrN.sub.8[M+H].sup.+: m/z=481.3, 483.5.

[0341] I-71a .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.10 (s, 1H), 8.31-8.19 (m, 2H), 8.14 (s, 1H), 8.06 (d, J=2.8 Hz, 1H), 7.79 (s, 1H), 7.33 (dd, J=9.0, 2.9 Hz, 1H), 6.06 (dt, J=13.8, 7.0 Hz, 1H), 3.71 (s, 4H), 3.19-3.03 (m, 4H), 2.01-1.86 (m, 4H), 1.73 (d, J=6.8 Hz, 6H), 1.46 (s, 8H).

[0342] I-71 LC-MS (ESI), C.sub.24H.sub.28BrN.sub.8 [M+H].sup.++: m/z=507.3, 509.3.

[0343] By referring to the synthetic method of I-2 in Example 2, the compound I-70 (12.6 mg, 27.0 μmmol, 27%) was prepared from 12a (35 mg, 0.10 mmol). .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.11 (s, 1H), 8.26 (d, J=6.9 Hz, 2H), 8.07 (d, J=17.4 Hz, 2H), 7.80 (s, 1H), 7.32 (d, J=7.5 Hz, 1H), 6.12-5.99 (m, 1H), 4.04-3.81 (m, 4H), 3.30-3.06 (m, 4H), 1.73 (d, J=6.6 Hz, 6H).

Preparation of the Key Intermediate 1-isopropyl-4-methyl-8-(methylsulfinyl)-1H-imidazo[4,5-h]quinazoline (14a)

[0344] ##STR00202##

[0345] 1): 11a (500 mg, 1.49 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (110 mg, 0.15 mmol), potassium carbonate (8.6 g, 62.3 mmol) and trimethylboroxine (3.5 M in THF, 1.7 mL, 6.0 mmol) were suspended in a mixed solvent of N,N-dimethylformamide (8 mL) and water (4 mL). The atmosphere of the reaction system was placed with argon for 3 times, and the mixture was heated to 130° C., and stirred overnight. The reaction mixture was diluted with ethyl acetate (100 mL) and water (30 mL), and the organic layer was washed twice with water (15 mL) and brine (15 mL), respectively, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified with flash silica gel column chromatography (petroleum ether/ethyl acetate=3:1) to afford a light yellow solid as 1-isopropyl-4-methyl-8-(methylthio)-1H-imidazo[4,5-h]quinazoline (13a, 340 mg, 1.25 mmol, 84%). LC-MS (ESI) for C.sub.14H.sub.17N.sub.4S [M+H].sup.+: m/z=273.1.

[0346] 2): By referring to the synthetic steps of 8a to 9a in Example 1, the title compound 14a (317 mg, 1.10 mmol, 91%) was prepared from 13a (330 mg, 1.21 mmol). LC-MS (ESI) for C.sub.14H.sub.17N.sub.4OS [M+H].sup.+: m/z=289.2.

TABLE-US-00008 TABLE 8 Examples I-72 to I-76 Side chains Products [00203] 10a [00204] I-72 [00205] 10h [00206] I-73 [00207] 10i [00208] I-74 [00209] 10w [00210] I-75 [00211] 10x [00212] I-76

[0347] By referring to the synthetic method of I-1 in Example 1, compounds I-72 (9.2 mg, 21 μmmol, 15%), I-73 (10.2 mg, 22.6 μmmol, 13%), and I-74 (20.4 mg, 45.2 μmmol, 26%) were prepared from 14a (50 mg, 0.174 mmol).

[0348] I-72a .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.11 (s, 1H), 8.31 (d, J=9.0 Hz, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 8.06 (d, J=3.0 Hz, 1H), 7.35 (brs, 1H), 7.33 (d, J=3.0 Hz, 1H), 6.07 (p, J=6.7 Hz, 1H), 3.63 (t, J=5.1 Hz, 4H), 3.12 (t, J=5.2 Hz, 4H), 2.75-2.71 (m, 3H), 1.73 (d, J=6.8 Hz, 6H), 1.49 (s, 9H).

[0349] I-73a .sup.1H NMR (400 MHz, chloroform-d) δ 9.12 (s, 1H), 8.22 (d, J=2.7 Hz, 2H), 8.17 (s, 1H), 8.02 (s, 1H), 7.40-7.33 (m, 1H), 6.10 (dt, J=13.4, 6.7 Hz, 1H), 3.69-3.52 (m, 4H), 3.01-2.85 (m, 4H), 2.81-2.69 (m, 3H), 2.42 (s, 3H), 1.74 (d, J=6.7 Hz, 6H), 1.50 (s, 9H).

[0350] I-74a .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.11 (s, 1H), 8.19 (d, J=10.5 Hz, 2H), 8.06 (s, 1H), 7.41-7.32 (m, 2H), 6.07 (dt, J=13.6, 6.8 Hz, 1H), 3.70-3.53 (m, 4H), 2.94-2.80 (m, 4H), 2.77-2.67 (m, 3H), 2.52 (s, 3H), 1.72 (d, J=6.8 Hz, 6H), 1.50 (s, 9H).

[0351] By referring to the synthetic method of I-2 in Example 2, compounds I-75 (16.1 mg, 40.0 μmmol, 23%), and I-76 (18.9 mg, 45.2 μmmol, 26%) were prepared from 14a (50 mg, 0.174 mmol).

[0352] I-75 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.12 (s, 1H), 8.39-8.25 (m, 2H), 8.20 (s, 1H), 8.07 (d, J=2.7 Hz, 1H), 7.42-7.28 (m, 2H), 6.07 (h, J=6.9 Hz, 1H), 4.03-3.81 (m, 4H), 3.28-3.04 (m, 4H), 2.84-2.68 (m, 3H), 1.73 (d, J=6.8 Hz, 6H).

[0353] I-76 .sup.1H NMR (400 MHz, chloroform-d, ppm) δ 9.15 (s, 1H), 8.67 (s, 1H), 8.21 (d, J=3.3 Hz, 2H), 8.12 (s, 1H), 7.35 (s, 1H), 6.09 (dt, J=13.4, 6.6 Hz, 1H), 4.02-3.74 (m, 4H), 3.12-2.91 (m, 4H), 2.73 (s, 3H), 2.42 (s, 3H), 1.73 (d, J=6.7 Hz, 6H).

Example 77

[0354] Potency determination in the biochemical kinase inhibitory assay. Kinase activity assay and IC50 determination.

[0355] First, 10 ng of recombinant CDK4/cyclin D1 (Life Technologies PV4204) was diluted in a kinase buffer (20 mM Tris pH7.5, 10 mM MgCl.sub.2, 0.01% NP-40, 2 mM DTT), and incubated at room temperature for 30 minutes together with indicated concentration of inhibitors. The kinase reaction was initiated by the addition of 1 μg (1.5 μM) of recombinant retinoblastoma protein, 5 μM ATP and 10μ Ci γ-32P-ATP. The reaction was incubated at 30° C. for 20 minutes, and the reaction was stopped by the addition of 2× Laemmli sample buffer, heated at 95° C. for three minutes, and dissolved in 12% acrylamide SDS-PAGE for autoradiography. The corresponding phosphorylated substrate protein bands were quantified using a densitometer (Bio-Rad). The resulting density values were plotted as a function of log drug concentration using Prism 4 Graphpad software, and IC50 values were determined by plotting a non-linear regression curve with a variable slope.

[0356] The compounds disclosed herein were tested in a similar manner for their inhibitory activities against CDK6/cyclin D1, CDK2/cyclin A, CDK5/cyclin P25, CDK9/cyclin T1, CDK7/cyclin H and CDK19/cyclin C.

[0357] The results of the enzyme inhibitory activity of the most representative compounds disclosed herein are shown in the following table. Compounds were tested in a three-fold serial dilution from the starting concentration of 10 μM, over 10-fold of IC50. Control compound, staurosporine, was tested in a four-fold serial dilution from the starting concentration of 20 μM, over 10-fold of IC50. The reaction took place in the presence of 10 μM ATP.

TABLE-US-00009 CDK4/cyclin D1 CDK6/cyclin D1 Compound No. IC50 (nM) IC50 (nM) staurosporine   16   35 I-1   <2  <2 I-2   2-10  2-10 I-3   2-10  2-10 I-4   2-10  2-10 I-5   <2  <2 I-6   2-10  2-10 I-7   2-10  2-10 I-8   <2  <2 I-9   <2  <2 I-10  2-10  2-10 I-11  2-10  2-10 I-12  2-10  2-10 I-13 10-50 10-50 I-14 10-50 10-50 I-15 10-50 10-50 I-16 10-50 10-50 I-17 10-50 10-50 I-18 10-50 10-50 I-19 10-50 10-50 I-20 10-50 10-50 I-21 10-50 10-50 I-22 10-50 10-50 I-23  <2  <2 I-24  2-10  2-10 I-25  2-10  2-10 I-26  2-10  2-10 I-27  2-10  2-10 I-28 10-50 10-50 I-29 10-50 10-50 I-30 10-50 10-50 I-31 10-50 10-50 I-32 10-50 10-50 I-33 10-50 10-50 I-34 10-50 10-50 I-35 10-50 10-50 I-36  50-100  50-100 I-37  50-100  50-100 I-38 10-50 10-50 I-39  50-100  50-100 I-40  50-100  50-100 I-41  50-100  50-100 I-42 10-50 10-50 I-43 10-50 10-50 I-44 10-50 10-50 I-45 10-50 10-50 I-46 10-50 10-50 I-47  2-10  2-10 I-48 10-50 10-50 I-49 10-50 10-50 I-50 10-50 10-50 I-51 10-50 10-50 I-52 10-50 10-50 I-53 10-50 10-50 I-54 10-50 10-50 I-55 10-50 10-50 I-56 10-50 10-50 I-57  <2  <2 I-58  2-10  2-10 I-59  2-10  2-10 I-60  2-10  2-10 I-61  2-10  2-10 I-62  50-100  50-100 I-63  50-100  50-100 I-64  50-100  50-100 I-65  50-100  50-100 I-66  50-100  50-100 I-67  2-10  2-10 I-68  2-10  2-10 I-69  2-10  2-10 I-70  2-10  2-10 I-71 10-50 10-50 I-72  2-10  2-10 I-73  2-10  2-10 I-74  2-10  2-10 I-75  2-10  2-10 I-76 10-50 10-50

[0358] The above is a further detailed description of the present disclosure in connection with the specific preferred embodiments, and the specific embodiments of the present disclosure are not limited to the description. It will be apparent to those skilled in the art that the present disclosure may be practiced by making various simple deduction and replacement, without departing from the spirit and scope of the invention.