Fused tricyclic heterocycle compounds and therapeutic uses thereof

A compound of formula (IA), or a tautomer, or a pharmaceutically acceptable salt thereof:

• wherein:
• Ra is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, wherein the alkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, carboxylic acid, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• or Ra is
• ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;
• G is O;
• Rc is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl and alkynyl;
• R3 and R4 are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R5, R6 and R7 are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• L1 is selected from the group consisting of alkylene, alkenylene, NH, —(CH2)sNH—, —(CH2)sNH(CH2)r—, O, S(O)m, C(O), —C(O)NH—, —NHC(O)— or —HNC(O)NH—, wherein the alkylene or alkenylene is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, oxo, —C(O)OR18, R19, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• two substitutes on the same carbon can form a cycloalkyl or heterocyclyl ring;
• two substitutes on adjacent carbons can form a cycloalkyl, heterocyclyl, aryl and heteroaryl ring;
• or L1 is absent;
• Z is selected from the group consisting of —C(O)O-benzyl, butyloxy carbonyl, hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, —NR9R10, oxo, —C(O)OR18, R19, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• or Z is selected from a formula (Za) or a tautomer:
• wherein, ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R8 each is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R9 and R10 are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, —C(O)O-benzyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R11 each is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, —C(O)NR14R15, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• wherein the alkyl or alkoxy is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, alkenyl, alkynyl, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, —O—P(O)(OH)2, cycloalkyl, heterocyclyl and NR16R17;
• R12 is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl;
• R13 each is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R14 and R15 are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R16 and R17 are identical or different, and each is independently selected from hydrogen or alkyl;
• or, R16 and R17 together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl contains one or two identical or different heteroatoms selected from the group consisting of N, O and S, and the heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy and hydroxyalkyl;
• R18 is hydrogen or alkyl;
• R19 is cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl and cyano;
• n is 0, 1, 2, 3 or 4;
• m is 0, 1 or 2;
• s is integer of 1 to 6;
• r is 1, 2, 3 or 4;
• t is 1;
• p is 0, 1, 2, 3 or 4;
• and
• q is 0, 1, 2, 3 or 4.

A compound of formula (IB), or a tautomer, or a pharmaceutically acceptable salt thereof:

• wherein:
• G is O;
• Rc is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl and alkynyl;
• R1 and R2 are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R3 and R4 are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R5, R6 and R7 are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• L1 is selected from the group consisting of alkylene, alkenylene, NH, —(CH2)sNH—, —(CH2)sNH(CH2)r—, O, S(O)m, C(O), —C(O)NH—, —NHC(O)— or —HNC(O)NH—, wherein the alkylene or alkenylene is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, oxo, —C(O)OR18, R19, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• two substitutes on the same carbon can form a cycloalkyl or heterocyclyl ring;
• two substitutes on adjacent carbons can form a cycloalkyl, heterocyclyl, aryl and heteroaryl ring;
• or L1 is absent;
• Z is selected from the group consisting of —C(O)O-benzyl, butyloxy carbonyl, hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, —NR9R10, oxo, —C(O)OR18, R19, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• or Z is selected from a formula (Za) or a tautomer:
• wherein, ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R9 and R10 are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, —C(O)O-benzyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R11 each is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, —C(O)NR14R15, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• wherein the alkyl or alkoxy is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, alkenyl, alkynyl, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, —O—P(O)(OH)2, cycloalkyl, heterocyclyl and NR16R17;
• R12 is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl;
• R13 each is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R14 and R15 are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R16 and R17 are identical or different, and each is independently selected from hydrogen or alkyl;
• or, R16 and R17 together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl contains one or two identical or different heteroatoms selected from the group consisting of N, O and S, and the heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy and hydroxyalkyl;
• R18 is hydrogen or alkyl;
• R19 is cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl and cyano;
• m is 0, 1 or 2;
• s is integer of 1 to 6;
• r is 1, 2, 3 or 4;
• t is 1;
• p is 0, 1, 2, 3 or 4;
• and
• q is 0, 1, 2, 3 or 4.

A compound of formula (IIIA), or a tautomer, or a pharmaceutically acceptable salt thereof:

• wherein:
• Ra is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, wherein the alkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, carboxylic acid, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• or Ra is
• ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;
• Rc is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl and alkynyl;
• R3 and R4 are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R5, R6 and R7 are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• L1 is selected from the group consisting of alkylene, alkenylene, NH, —(CH2)sNH—, O, S(O)m, C(O), —C(O)NH—, —NHC(O)— or —HNC(O)NH—, wherein the alkylene or alkenylene is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• two substitutes on the same carbon can form a cycloalkyl or heterocyclyl ring;
• two substitutes on adjacent carbons can form a cycloalkyl, heterocyclyl, aryl and heteroaryl ring;
• or L1 is absent;
• Z is selected from the group consisting of —C(O)O-benzyl, butyloxy carbonyl, hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, —NR9R10, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• or Z is selected from a formula (Za) or a tautomer:
• wherein, ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R8 each is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R9 and R10 are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, —C(O)O-benzyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R11 each is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, —C(O)NR14R15, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R12 is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl;
• R13 each is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R14 and R15 are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• n is 0, 1, 2, 3 or 4;
• m is 0, 1 or 2;
• s is integer of 1 to 6;
• p is 0, 1, 2, 3 or 4;
• and
• q is 0, 1, 2, 3 or 4.

A compound of formula (IIIB), or a tautomer, or a pharmaceutically acceptable salt thereof:

• wherein:
• Rc is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl and alkynyl;
• R1 and R2 are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R3 and R4 are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R5, R6 and R7 are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• L1 is selected from the group consisting of alkylene, alkenylene, NH, —(CH2)sNH—, O, S(O)m, C(O), —C(O)NH—, —NHC(O)— or —HNC(O)NH—, wherein the alkylene or alkenylene is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• two substitutes on the same carbon can form a cycloalkyl or heterocyclyl ring;
• two substitutes on adjacent carbons can form a cycloalkyl, heterocyclyl, aryl and heteroaryl ring;
• or L1 is absent;
• Z is selected from the group consisting of —C(O)O-benzyl, butyloxy carbonyl, hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, —NR9R10, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• or Z is selected from a formula (Za) or a tautomer:
• wherein, ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R9 and R10 are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, —C(O)O-benzyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R11 each is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, —C(O)NR14R15, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R12 is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl;
• R13 each is identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• R14 and R15 are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
• m is 0, 1 or 2;
• s is integer of 1 to 6;
• p is 0, 1, 2, 3 or 4;
• and
• q is 0, 1, 2, 3 or 4.