Substituted pyrazolo[4,3-H]quinazolines as protein kinase inhibitors

A method for inhibiting cyclin-dependent kinase (CDK) activity in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I):

• or a pharmaceutically acceptable salt or stereoisomer thereof,
• wherein:
• A1 is N;
• A2 is CR3;
• A3 is CR3;
• R1 is H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, C(O)Ra, C(O)NRbRc, C(O)ORa, NRbRc, ORa, SRa, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• wherein the C3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted by 1 or more substituents independently selected from the group consisting of ═O and ═S;
• and
• wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R″ substituents;
• R2 is H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, C(O)Ra, C(O)NRbRc, C(O)ORa, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• wherein the C3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted by 1 or more substituents independently selected from the group consisting of ═O and ═S;
• and
• wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R″ substituents;
• R3 is H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, L′-C3-7 cycloalkyl, L′-3- to 11-membered heterocyclyl, L′-C6-10 aryl, or L′-5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, L′-C3-7 cycloalkyl, L′-3- to 11-membered heterocyclyl, L′-C6-10 aryl, or L′-5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R6 substituents;
• R4 is 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 C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R′ substituents;
• R5 is H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, C(O)Ra, C(O)NRbRc, C(O)ORa, NRbRc, ORa, SRa, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• wherein the C3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted by 1 or more substituents independently selected from the group consisting of ═O and ═S;
• and
• wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R″ substituents;
• each R6 is independently H, C1-6 alkyl, C1-6 haloalkyl, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted by 1, 2, or 3 independently selected R″ substituents;
• or
• any two geminal R6 substituents, taken together with the carbon atom to which they are attached, independently form ═O or ═S;
• each R′ is independently H, halogen, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C(O)NRbRc, C(O)ORa, NRbRc, ORa, SRa, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• each R″ is independently H, halogen, L-CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, L-C(O)Ra, L-C(O)C1-6 alkylene-NRbRc, L-C(O)NRbRc, L-C(O)ORa, L-C(S)Ra, L-C(S)NRbRc, L-C(S)ORa, L-NRbRc, L-N(Rb)—C(O)Ra, L-N(Rb)—C(O)NRbRc, L-N(Rb)—C(O)ORa, L-N(Rb)—C(S)Ra, L-N(Rb)—C(S)NRbRc, L-N(Rb)—C(S)ORa, L-N(Rb)—S(O)mRa, L-N(Rb)—S(O)mNRbRc, L-ORa, L-OC1-6 alkylene-ORa, L-OC(O)Ra, L-OC(O)NRbRc, L-OC(S)Ra, L-OC(S)NRbRc, ═O, L-S(O)mRa, L-S(O)mNRbRc, L-S(O)mORa, L-C3-7 cycloalkyl, L-3- to 7-membered heterocyclyl, L-C6-10 aryl, or L-5- to 10-membered heteroaryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, L-C3-7 cycloalkyl, L-3- to 7-membered heterocyclyl, L-C6-10 aryl, and L-5- to 10-membered heteroaryl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of L-CN, NO2, L-C(O)Ra, L-C(O)C1-6 alkylene-NRbRc, L-C(O)NRbRc, L-C(O)ORa, L-C(S)Ra, L-C(S)NRbRc, L-C(S)ORa, L-NRbRc, L-N(Rb)—C(O)Ra, L-N(Rb)—C(O)NRbRc, L-N(Rb)—C(O)ORa, L-N(Rb)—C(S)Ra, L-N(Rb)—C(S)NRbRc, L-N(Rb)—C(S)ORa, L-N(Rb)—S(O)mRa, L-N(Rb)—S(O)mNRbRc, L-ORa, L-OC1-6 alkylene-ORa, L-OC(O)Ra, L-OC(O)NRbRc, L-OC(S)Ra, L-OC(S)NRbRc, ═O, L-S(O)mRa, L-S(O)mNRbRc, and L-S(O)mORa;
• each Ra is independently H, 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;
• each Rb is independently H, 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;
• each Rc is independently H, 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;
• or
• each Rb and Rc, taken together with the nitrogen atom to which they are attached, independently forms a 3- to 7-membered heterocyclyl;
• each L is independently a chemical bond, —C1-6 alkylene-, —C2-6 alkenylene-, or —C2-6 alkynylene-;
• L′ is a chemical bond, —C1-6 alkylene-, —C2-6 alkenylene-, —C2-6 alkynylene-, —C(O)—, —C(O)NH—, or —NHC(O)—;
• and
• each m is independently 0, 1, or 2.