Fused Ring Derivatives Useful as KRAS G12D Inhibitors

A compound of formula (I) or formula (IV), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:

• wherein,
• R1 is selected from hydrogen, halogen, —C1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —OH, —SH, —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
• wherein, said —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
• Y1 is selected from NH, O, S, SO, SO2, NHCO, CONH, NHSO2 or SO2NH;
• when Y1 is selected from NH, NHCO, CONH, NHSO2 or SO2NH, each of which is optionally substituted with RS2;
• X1 is selected from CR3 or N;
• n1, n2, n3, n4, n5 and n6 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
• R3 is selected from hydrogen, halogen, —C1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —OH, —SH, —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
• wherein said —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
• X2 is selected from CR21R22, NR23, O, S, SO or SO2;
• R21 and R22 are each independently selected from hydrogen, halogen, —C1-6alkyl, —OH, —OC1-6alkyl, —SH, —SC1-6alkyl, —NH2, —NH(C1-6alkyl) or —N(C1-6alkyl)2;
• R23 is selected from hydrogen or —C1-6alkyl;
• R2 is selected from
• -L-(3-12 membered heterocyclyl), -L-(3-12 membered cycloalkyl), -L-(6-12 member aryl), -L-(5-12 membered heteroaryl) or -L-NR24R25;
• Each L is independently selected from a bond or C1-10alkylene optionally substituted with one or more RS9;
• R24 and R25 are each independently selected from hydrogen or —C1-10alkyl optionally substituted with one or more RS10;
• Said 3-12 membered heterocyclyl in -L-(3-12 membered heterocyclyl) is optionally substituted with one or more RS11;
• Said 3-12 membered cycloalkyl in -L-(3-12 membered cycloalkyl) is optionally substituted with one or more RS12;
• Said 6-12 member aryl in -L-(6-12 member aryl) is optionally substituted with one or more RS13;
• Said 5-12 membered heteroaryl in -L-(5-12 membered heteroaryl) is optionally substituted with one or more RS14;
• Y2 is selected from O, S, SO, SO2, C═O, NH or CH2, when Y2 is selected from NH or CH2, the NH or CH2 is optionally substituted with 1 or 2 RS3;
• m1, m2, m3, m4 or m5 is independently selected from 0, 1, 2, 3, 4, 5 or 6;
• m6 or m7 is independently selected from 0, 1, 2, 3, 4, 5 or 6;
• Y3 and Y4 are each independently selected from O, S, SO, SO2, C═O, NH or CH2, when Y3 and Y4 is selectd from NH or CH2, the NH or CH2 is optionally substituted with 1 or 2 RS4;
• w1 and w2 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
• w3, w4, w5, w6 and w7 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
• provided that w6 and w7 are not 0 at the same time;
• Y5 is selected from O, S, SO, SO2, C═O, NH or CH2, when Y5 is selected from NH or CH2, the NH or CH2 is optionally substituted with 1 or 2 RS5;
• p1 and p2 are each independently selected from 0, 1, 2, 3, 4, 5, or 6, provided that p1 and p2 are not 0 at the same time;
• p3 and p4 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
• Y6 is selected from O, S, NH or CH2, when Y6 is selected from NH or CH2, the NH or CH2 is optionally substituted with 1 or 2 RS6;
• s1 and s2 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
• s3 and s4 are each independently selected from 0, 1, 2, 3, 4, 5, or 6, provided that s3 and s4 are not 0 at the same time;
• r1 and r2 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
• r3 and r4 are each independently selected from 0, 1, 2, 3, 4, 5, or 6;
• v is selected from 0, 1, 2, 3, 4, 5 or 6;
• ring A is selected from a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, said heterocyclic or heteroaryl ring at each occurrence is independently contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
• Ring B and ring C are each independently selected from a 3-10 membered heterocyclic ring which is optionally further contains 1, 2, or 3 heteroatoms selected from N, O or S except the fused N atom;
• RS1, RS2, RS3, RS4, RS5, RS6, RS7, RS8, RS9, RS10, RS11, RS12, RS13 and RS14 are each independently selected from halogen, —C1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NO2, —N3, oxo, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —OH, —O(C1-6alkyl), —SH, —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —OC(═O)O(C1-6alkyl), —NHC(═O)(OC1-6alkyl), —N(C1-6alkyl)C(═O)(OC1-6alkyl), —OC(═O)NH(C1-6alkyl), —OC(═O)N(C1-6alkyl)2, —NHC(═O)NH2, —NHC(═O)NH(C1-6alkyl), —NHC(═O)N(C1-6alkyl)2, —N(C1-6alkyl)C(═O)NH2, —N(C1-6alkyl)C(═O)NH(C1-6alkyl), —N(C1-6alkyl)C(═O)N(C1-6alkyl)2, —S(═O)(OC1-6alkyl), —OS(═O)(C1-6alkyl), —S(═O)NH2, —S(═O)NH(C1-6alkyl), —S(═O)N(C1-6alkyl)2, —NHS(═O)(C1-6alkyl), —N(C1-6alkyl)S(═O)(C1-6alkyl), —S(═O)2(OC1-6alkyl), —OS(═O)2(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), —OS(═O)2O(C1-6alkyl), —NHS(═O)2O(C1-6alkyl), —N(C1-6alkyl)S(═O)2O(C1-6alkyl), —OS(═O)2NH2, —OS(═O)2NH(C1-6alkyl), —OS(═O)2N(C1-6alkyl)2, —NHS(═O)2NH2, —NHS(═O)2NH(C1-6alkyl), —NHS(═O)2N(C1-6alkyl)2, —N(C1-6alkyl)S(═O)2NH2, —N(C1-6alkyl)S(═O)2NH(C1- 6alkyl), —N(C1-6alkyl)S(═O)2N(C1-6alkyl)2, —PH(C1-6alkyl), —P(C1-6alkyl)2, —P(═O)H(C1-6alkyl), —P(═O)(C1-6alkyl)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
• wherein, said —C1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more RSa;
• Each of RSa is independently selected from halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NO2, —N3, oxo, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —OH, —SH, —S(C1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —OC(═O)O(C1-6alkyl), —NHC(═O)(OC1-6alkyl), —N(C1-6alkyl)C(═O)(OC1-6alkyl), —OC(═O)NH(C1-6alkyl), —OC(═O)N(C1-6alkyl)2, —NHC(═O)NH2, —NHC(═O)NH(C1-6alkyl), —NHC(═O)N(C1-6alkyl)2, —N(C1-6alkyl)C(═O)NH2, —N(C1-6alkyl)C(═O)NH(C1-6alkyl), —N(C1-6alkyl)C(═O)N(C1-6alkyl)2, —S(═O)(OC1-6alkyl), —OS(═O)(C1-6alkyl), —S(═O)NH2, —S(═O)NH(C1-6alkyl), —S(═O)N(C1-6alkyl)2, —NHS(═O)(C1-6alkyl), —N(C1-6alkyl)S(═O)(C1-6alkyl), —S(═O)2(OC1-6alkyl), —OS(═O)2(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), —OS(═O)2O(C1-6alkyl), —NHS(═O)2O(C1-6alkyl), —N(C1-6alkyl)S(═O)2O(C1-6alkyl), —OS(═O)2NH2, —OS(═O)2NH(C1-6alkyl), —OS(═O)2N(C1-6alkyl)2, —NHS(═O)2NH2, —NHS(═O)2NH(C1-6alkyl), —NHS(═O)2N(C1-6alkyl)2, —N(C1-6alkyl)S(═O)2NH2, —N(C1-6alkyl)S(═O)2NH(C1-6alkyl), —N(C1-6alkyl)S(═O)2N(C1-6alkyl)2, —PH(C1-6alkyl), —P(C1-6alkyl)2, —P(═O)H(C1-6alkyl), —P(═O)(C1-6alkyl)2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
• wherein said 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is independently optionally substituted with 1, 2, or 3 RSb;
• Each of RSb is independently selected from halogen;
• —C1-6alkyl;
• haloC1-6alkyl;
• —CN;
• —OH;
• —NH2;
• —NH(C1-6alkyl);
• —NH(C1-6alkyl)2;
• —OC1-6alkyl;
• or —C1-6alkyl substituted with 1, 2 or 3 substituents selected form halogen, haloC1-6alkyl, —CN, —OH, —NH2, —NH(C1-6alkyl), —NH(C1-6alkyl)2 or —OC1-6alkyl;
• q1, q2, q3, q4, q5 and q6 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
• R2a, R2b, R2c, R2d and R2e are each independently selected from is selected from halogen, —C1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
• wherein, said —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, —C1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
• t1, t2, t3, t4 and is are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
• R61, R62, R71, R72, R73, R74, R81, R82, R83, R84, R91, R92, R93, R94, R101, R102, R103, R104, R111, R112, R113 and R114 are each independently selected from are independently selected from hydrogen, halogen, —C1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
• wherein, said —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —OH, —O(C1-6alkyl), —SH, —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
• R4 is selected from phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, wherein said R4 is independently optionally substituted with 1, 2, 3, 4, 5, or 6 R4a;
• Each of R4a is independently selected from halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, oxo, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl or R41, wherein said —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2 or 3 R4b;
• Each of R4b is independently selected from halogen;
• —C1-6alkyl;
• haloC1-6alkyl;
• —CN;
• oxo;
• —OH;
• —NH2;
• —NH(C1-6alkyl);
• —NH(C1-6alkyl)2;
• 13 OC1-6alkyl;
• or —C1-6alkyl substituted with 1, 2 or 3 substituents selected form halogen, haloC1-6alkyl, —CN, —OH, —NH2, —NH(C1-6alkyl), —NH(C1-6alkyl)2 or —OC1-6alkyl;
• R41 is selected from
• R4c is selected from hydrogen, —C1-30alkyl, —C2-30alkenyl, —C2-30alkynyl, —C0-6alkylene-(3-20 membered carbocyclyl), —C0-6alkylene-(3-20 membered heterocyclyl), —C0-6alkylene-(6-10 membered aryl) or —C0-6alkylene-(5-10 membered heteroaryl), each of which is independently substituted with one or more R4j;
• R4d and R4e are each selected from hydrogen, —C1-30alkyl, —C2-30alkenyl, —C2-30alkynyl, —C(═O)C1-6alkyl, —C0-6alkylene-(3-20 membered carbocyclyl), —C0-6alkylene-(3-20 membered heterocyclyl), —C0-6alkylene-(6-10 membered aryl) or —C0-6alkylene-(5-10 membered heteroaryl), each of which is independently substituted with one or more R4j;
• R4f and R4g are each selected from hydrogen, —C1-30alkyl, —C2-30alkenyl, —C2-30alkynyl, —C(═O)C1-6alkyl, —C0-6alkylene-(3-20 membered carbocyclyl), —C0-6alkylene-(3-20 membered heterocyclyl), —C0-6alkylene-(6-10 membered aryl) or —C0-6alkylene-(5-10 membered heteroaryl), each of which is independently substituted with one or more R4j;
• R4h, R4i, R4m, R4n and R4p are each selected from hydrogen, halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —OH, —SH, —S(C1-6alkyl), —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
• wherein, said —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, —C1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
• Optionally, R4f and R4g together with the atoms to which they are respectively attached form a 4-10 membered heterocyclyl ring, said 4-10 membered heterocyclyl ring optionally further contains 1 or 2 heteratoms selected from N, O, S, S(═O) or S(═O)2 and optionally substituted with one or more R4j;
• Optionally, R4f and R4h together with the atoms to which they are respectively attached form a 4-10 membered heterocyclyl ring, said 4-10 membered heterocyclyl ring optionally further contains 1 or 2 heteratoms selected from N, O, S, S(═O) or S(═O)2 and optionally substituted with one or more R4j;
• R4j at each occurrence is independently selected from halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, oxo, —NO2, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —OH, —O(C1-6alkyl), —SH, —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein said —C1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2 or 3 substituents selected from halogen;
• —C1-6alkyl;
• haloC1-6alkyl;
• —CN;
• oxo;
• —OH;
• —NH2;
• —NH(C1-6alkyl);
• —NH(C1-6alkyl)2;
• —OC1-6alkyl;
• or —C1-6alkyl substituted with 1, 2 or 3 substituents selected form halogen, haloC1-6alkyl, —CN, —OH, —NH2, —NH(C1-6alkyl), —NH(C1-6alkyl)2 or —OC1-6alkyl;
• R5 is selected from hydrogen or
• R51 and R52 are each independently selected from are independently selected from hydrogen, halogen, —C1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —OH, —SH, —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
• wherein, said —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, —C1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, oxo, —OH, —SH, —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
• R53 is selected from hydrogen, —C1-30alkyl, —C2-30alkenyl, —C2-30alkynyl, —C(═O)C1-6alkyl, —C0-6alkylene-(3-20 membered carbocyclyl), —C0-6alkylene-(3-20 membered heterocyclyl), —C0-6alkylene-(6-10 membered aryl) or —C0-6alkylene-(5-10 membered heteroaryl), each of which is independently substituted with one or more R5a;
• R5a at each occurrence is independently selected from halogen, —C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, —C2-6alkenyl, —C2-6alkynyl, —CN, oxo, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —S(haloC1-6alkyl), —S(═O)(C1-6alkyl), —S(═O)2(C1-6alkyl), —C(═O)(C1-6alkyl), —C(═O)OH, —C(═O)(OC1-6alkyl), —OC(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —S(═O)2NH2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —NHS(═O)2(C1-6alkyl), —N(C1-6alkyl)S(═O)2(C1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
• z1 and z2 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
• Each of (heterocyclyl and heteroaryl) at each occurrence is independently contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(═O) or S(═O)2.