Isoxazolo[5,4-H]quinazoline compounds as protein kinase inhibitors

A compound of formula (I), or a pharmaceutically acceptable salt, an enantiomer, a diastereomer, and a racemate thereof:

• wherein:
• indicates a single bond or a double bond;
• A1 is selected from CR5 or N;
• A2 is selected from CR6 or N;
• A3 is selected from CR7 or N;
• R1 is selected from H, D, halogen, —CN, —ORa, —SRa, —NRbRc, —C(O)Ra, —C(O)ORa, —C(O)NRbRc, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• wherein the said C3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted by oxo or thioxo;
• R2 is selected from H, D, halogen, —CN, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• wherein the said C3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted by oxo or thioxo;
• R3 is selected from H, D, halogen, —CN, —NO2, —ORa, —SRa, —NRbRc, —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —S(O)mRa, —S(O)mORa, —S(O)mNRbRc, —O—C1-6 alkylene-R8, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 11-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 R8 groups;
• R4 is selected from H, —C(O)Ra, —C(O)ORa, —C(O)NRbRc, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• L is selected from a chemical bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —C1-6 alkylene-, —C2-6 alkenylene- or —C2-6 alkynylene-;
• and wherein,
• R5 is selected from H, D, halogen, —CN, —ORa, —SRa, —NRbRc, —C(O)Ra, —C(O)ORa, C(O)NRbRc, —S(O)mRa, —S(O)mORa, —S(O)mNRbRc, C1-6 alkyl or C1-6 haloalkyl;
• R6 is selected from H, D, halogen, —CN, —ORa, —SRa, —NRbRc, —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —S(O)mRa, —S(O)mORa, —S(O)mNRbRc, C1-6 alkyl or C1-6 haloalkyl;
• R7 is selected from H, D, halogen, —CN, —ORa, —SRa, —NRbRc, —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —S(O)mRa, —S(O)mORa, —S(O)mNRbRc, C1-6 alkyl or C1-6 haloalkyl;
• R8 is selected from H, D, —NH2, —NHC1-6 alkyl, —N(C1-6 alkyl)2, C1-6 alkyl, C1-6 haloalkyl, —C0-6 alkylene-ORa, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• or two R8 on the same atom are taken together to form oxo or thioxo;
• Ra is independently selected from H, —C0-6 alkylene-CN, —C0-6 alkylene-NO2, —C0-6 alkylene-OR′, —C0-6 alkylene-SR′, —C0-6 alkylene-NR″R′″, —C0-6 alkylene-C(O)R′, —C0-6 alkylene-C(O)OR′, —C0-6 alkylene-C(O)NR″R′″, —C0-6 alkylene-S(O)mR′, —C0-6 alkylene-S(O)mOR′, —C0-6 alkylene-S(O)mNR″R′″, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, —C0-6 alkylene-C3-7 cycloalkyl, —C0-6 alkylene-3- to 7-membered heterocyclyl, —C0-6 alkylene-C6-10 aryl or —C0-6 alkylene-5- to 10-membered heteroaryl;
• Rb and Rc are independently selected from H, —C0-6 alkylene-CN, —C0-6 alkylene-NO2, —C0-6 alkylene-OR′, —C0-6 alkylene-SR′, —C0-6 alkylene-NR″R′″, —C0-6 alkylene-C(O)R′, —C0-6 alkylene-C(O)OR′, —C0-6 alkylene-C(O)NR″R′″, —C0-6 alkylene-S(O)mR′, —C0-6 alkylene-S(O)mOR′, —C0-6 alkylene-S(O)mNR″R′″, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, —C0-6 alkylene-C3-7 cycloalkyl, —C0-6 alkylene-3- to 7-membered heterocyclyl, —C0-6 alkylene-C6-10 aryl or —C0-6 alkylene-5- to 10-membered heteroaryl;
• or, Rb, Rc and N atom are taken together to form 3- to 7-membered heterocyclyl;
• R′ is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• R″ and R′″ are independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• or, R″, R′″ and N atom are taken together to form 3- to 7-membered heterocyclyl;
• m represents 0, 1, or 2;
• and,
• R1-R2 and R4-R8 are optionally substituted with 1, 2 or 3 R groups, wherein the R is independently selected from H, —OH, halogen, —NO2, carbonyl, —CN, —ORa, —SRa, —NRbRc, —C(O)Ra, —C(S)Ra, —C(O)ORa, —C(S)ORa, —C(O)—NRbRc, —C(S)—NRbRc, —O—C(O)Ra, —O—C(S)Ra, —N(Rb)—C(O)—Ra, —N(Rb)—C(S)—Ra, —S(O)mRa, —S(O)mORa, —S(O)mNRbRc, —N(Rb)—S(O)m—Ra, —N(Rb)S(O)m—NRbRc, —N(R)C(O)ORa, —N(Rb)—C(S)ORa, —O—C1-6 alkylene-ORa, —C(O)—C1-6 alkylene-NRbRc, —N(Rb)—C(O)—NRbRc, —N(Rb)C(S)—NRbRc, —O—C(O)—NRbRc, —O—C(S)—NRbRc, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• wherein the said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl or 5- to 10-membered heteroaryl is each further optionally substituted by one or more groups consisting of the following:
• —CN, —NO2, carbonyl, —ORa, —SRa, —NRbRc, —C(O)Ra, —C(S)Ra, —C(O)ORa, —C(S)ORa, —C(O)—NRbRc, —C(S)—NRbRc, —O—C(O)Ra, —O—C(S)Ra, —N(Rb)—C(O)—Ra, —N(Rb)—C(S)—Ra, —S(O)mRa, —S(O)mORa, —S(O)mNRbRc, —N(Rb)—S(O)m—Ra, —N(R)S(O)m—RbRc, —N(Rb)—C(O)ORa, —N(Rb)—C(S)ORa, —O—C1-6 alkylene-ORa, —C(O)—C1-6 alkylene-NRbRc, —N(Rb)—C(O)—NRbRc, —N(R)—C(S)—NRbRc, —O—C(O)—NRbRc or —O—C(S)—NRbRc;
• Ra, Rb and Rc are each further optionally substituted by one or more groups consisting of the following:
• C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl or 5- to 10-membered heteroaryl.