Cyclic compounds used as multi-target kinase inhibitors and preparation method therefor

A compound as shown in general formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof:

• wherein:
• is selected from the following ring structures:
• is selected from the following ring structures:
• R1 is selected from hydrogen, halo, cyano, SF5, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, C(O)R4, C(O)OR4, —NR4R5, C(O)NR4R5, SO2R4, and SO2NR4R5, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R1 is unsubstituted or independently substituted with one or more groups selected from halogen, hydroxy, amino, cyano, C1-6 alkoxy, and oxo (═O);
• R2 is selected from hydrogen, halogen, cyano, C1-12 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-6 cycloalkyl, C(O)R4, C(O)OR4, —NR4R5, C(O)NR4R5, SO2R4, and SO2NR4R5, wherein each alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl of R2 is unsubstituted or independently substituted with one or more groups selected from halo, hydroxy, amino, and cyano;
• R3a is selected from hydrogen, halo, cyano, C1-12 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-6 cycloalkyl, C(O)R4, C(O)OR4, —NR4R5, C(O)NR4R5, SO2R4, and SO2NR4R5, wherein each alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl of R3a is unsubstituted or independently substituted with one or more groups selected from halo, hydroxy, amino, and cyano;
• R3 is independently selected from hydrogen, halo, cyano, SF5, C1-12 alkyl, C1-12 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-6 alkoxy, —NR4R5, —C(O)R4, SO2R4, SO2NR4R5, —C(O)OR4, and —C(O)NR4R5, wherein the alkyl of R3 is unsubstituted or substituted with one or more halo or C1-3 alkoxy;
• or R3 and R3a, together with the carbon atoms they are attached to, form a 5-membered heterocyclic or heteroaromatic ring containing N, NR6, NC1-6 alkyl, O, or S;
• or two R3, together with the carbon atom they are attached to, form ═O;
• R4 and R5 are each independently selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R4 or R5 is unsubstituted or independently substituted with one or more groups selected from halo, hydroxy, amino, nitro, cyano, (C1-6) alkoxy, and oxo (═O);
• or R4 and R5 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl;
• Y is a carbon atom or nitrogen atom, provided that the requirements for the necessary covalent bonds are satisfied;
• Z and W are independently CH, CH2, (CR32)t, (CR3)t, NH, O, S, or N;
• or Z and W together with the substituents to which they are attached form a 3-7 membered ring, comprising a cycloalkane ring, cycloalkene ring, heterocyclic or heteroaryl ring containing 1-3 heteroatoms selected from N, O, or S;
• or when Z or W is (CR32)t, any two R3 join to the carbon atom to form ═O or a 3-6 membered ring, and the ring comprises a cycloalkane or cycloalkene ring;
• represents a single bond or double bond;
• t is 1, 2, or 3;
• L1 is selected from a chemical bond, —(CRaRb)nNR6(CRaRb)m—, —O(CRaRb)nNR6(CRaRb)m—, —(CRaRb)nNR6C(O)—, —O(CRaRb)nNR6C(O)—, —NR6(CRaRb)nNR6C(O)—C3-6 cycloalkyl, —(CRaRb)nNR6C(O)—(CRaRb)m, —(CRaRb)NC(O)NR6a-, —O(CRaRb)nC(O)NR6—, —(CRaRb)nNR6(CRaRb)mNR6—, —(CRaRb)nO(CRaRb)m—, —NR6(CRaRb)nO(CRaRb)m—, —(CRaRb)nO(CRaRb)mNR6—, —(CRaRb)nO(CRaRb)mO—, —(CRaRb)nS(CRaRb)m—, —(CRaRb)nS(CRaRb)mNR6—, —(CRaRb)m—, —NR6(CRaRb)m—, —(CRaRb)mNR6—, —O(CRaRb)m—, —(CRaRb)mO—, —O(CRaRb)mO—, —(CRaRb)nNR6C3-6 cycloalkyl-, —(CRaRb)nNR6C3-6 cycloalkyl-NR6—, —O(CRaRb)qCH═CH(CRaRb)r—, —(CRaRb)qCH═CH(CRaRb)r—, —O(CRaRb)qCH═CH(CRaRb)rNR6—, —O(CRaRb)qCH═CH(CRaRb)rNR6C(O)—, —O(CRaRb)qCH═CH(CRaRb)rC(O)NR6—, —(CRaRb)qCH═CH(CRaRb)rNR6—, —(CRaRb)qCH═CH(CRaRb)rNR6CO—, —(CRaRb)qCH═CH(CRaRb)rC(O)NR6—, —O(CRaRb)nCH═CH(CRaRb)mO—, —NR6(CRaRb)nCH═CH(CRaRb)m—, —NR6(CRaRb)nCH═CH(CRaRb)mO—, —NR6(CRaRb)nCH═CH(CRaRb)mS—, —NR6(CRaRb)nCH═CH(CRaRb)mNR6—, —S(CRaRb)nCH═CH(CRaRb)m—, S(CRaRb)nCH═CH(CRaRb)mNR6—, —NR6(CRaRb)nCH═CH(CRaRb)mS—, —(RaRb)nCH═CH(CRaRb)mS—, —O(CRaRb)nCH═CH(CRaRb)mS—, —S(CRaRb)nCH═CH(CRaRb)mO—, -phenyl-, -heterocyclyl-, -heteroaryl-, and NR6(CRaRb)nC—C(CRaRb)m—;
• n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• L2 is selected from —CRaRb—, —CRaa—CRbb—, —C(O)—, —C(O)C(O)—, —C(S)—, —S(O)2—, —C3-6 cycloalkyl-, -phenyl-, -5- or 6-membered heterocyclyl-, and -5- or 6-membered heteroaryl-;
• L3 is selected from a chemical bond, —(CRaRb)q—, —(CRaRb)q—NR6—, —NR6(CRaRb)q—, —O(CRaRb)q—NR6—, —NR6(CRaRb)qO—, —O(CRaRb)q—, —(CRaRb)qO—, —(CRaRb)q—C3-6 cycloalkyl-, -5- or 6-membered heterocyclyl, —(CRaRb)q—CRaa—CRbb—, —C3-6 cycloalkyl-NR6—, —(CRaRb)qNR6—, —(CRaRb)qNR6C(O)—, —(CRaRb)NR6C(O)O—, —(CRaRb)q C(O)NR6—, and (CRaRb)q OC(O)NR6—;
• q is selected from 0, 1, 2, 3, 4, 5, and 6;
• r is 1, 2, 3, or 4;
• each R6 is each independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-6 cycloalkyl, —C(O)C1-6 alkyl, —C(O)C1-6 aryl, —C(O)C1-6 heteroaryl, —C(O)C3-6 cycloalkyl, —S(O)2C1-6 alkyl, —S(O)2C1-6 aryl, —S(O)2C1-6 heteroaryl, —S(O)2C3-6 cycloalkyl, —C(O)NR7C1-6 aryl, —C(O)NR7C1-6 heteroaryl, —C(O)NR7C3-6 cycloalkyl, —SO2NR7C1-6 alkyl, —S(O)2NR7C1-6 aryl, —S(O)2NR7C1-6 heteroaryl, —S(O)2NR7C3-6 cycloalkyl, —C(O)C(O)NR7C1-6 aryl, —C(O)C(O)NR7C1-6 heteroaryl, and —C(O)C(O)NR7C3-6 cycloalkyl;
• wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R6 is unsubstituted or independently substituted with one or more groups selected from halogen, hydroxy, amino, cyano, (C1-6)alkoxy, and oxo (═O);
• R7 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R7 is unsubstituted or independently substituted with one or more groups selected from halo, hydroxy, amino, cyano, (C1-6)alkoxy, and oxo (═O);
• Ra and Rb are independently selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 cycloalkyl, C1-6 halocycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, hydroxy, C(O)NH2, C(O)NHC1-6 alkyl, C(O)N(C1-6 alkyl)2, C1-6 alkylsulfonyl, S(O)2NH2, S(O)2NHC1-6 alkyl, NHC(O)NH2, NHC(O)NHC1-6 alkyl, NHC(O)OC1-6 alkyl, C(O)—C1-6 alkyl, C1-6 heteroalkyl, heterocyclyl, and heterocyclylalkyl;
• or Ra and Rb together with the carbon atom to which they are attached form a 3- to 6-membered carbocycle or heterocycle, wherein the heteroatom in the heterocycle is selected from NR6, O, and S;
• Raa and Rbb are independently selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 cycloalkyl, and C1-6 halocycloalkyl;
• or Raa and Rbb together with the carbon atom to which they are attached form a 3- to 6-membered carbocycle or heterocycle, wherein the heteroatom in the heterocycle is selected from NR, O, and S;
• Unless otherwise specially indicated, each cycloalkyl or cycloalkane ring is C3-6 cycloalkyl, each cycloalkenyl or cycloalkene ring is C3-6 cycloalkenyl, each heterocyclyl is a 3- to 10-membered heterocyclyl, each aryl is C6-10 aryl, and each heteroaryl is a 5- to 10-membered heteroaryl.