Compound for inhibiting irak4 activity and use thereof

A compound represented by formula A, or an enantiomer, a diastereoisomer, a racemate, a tautomer, a stereoisomer, a geometric isomer, a nitrogen oxide, a metabolite or a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isotope-labeled compound (preferably a deuteride), or a prodrug thereof,

• wherein:
• A is selected from 5-6 membered heteroaromatic ring optionally substituted with substituent Rk;
• preferably, A is selected from the group consisting of 5 membered heteroaromatic ring, and 6 membered heteroaromatic ring, the 5 membered heteroaromatic ring containing 2-3 heteroatoms, wherein at least two heteroatoms are N atoms, the 6 membered heteroaromatic ring containing 1-2 heteroatoms, wherein at least one heteroatom is N atom, and, the 5 membered heteroaromatic ring and 6 membered heteroaromatic ring are optionally substituted with substituent Rk;
• further preferably, A is selected from the group consisting of 1,2,3-triazole ring, 1,2,4-triazole ring, pyrazole ring, imidazole ring, 1,3,4-thiadiazole ring, 1,3,4-oxadiazole ring, 2-pyridone, and pyridazine ring, wherein, the 2-pyridone is optionally substituted with substituent Rk;
• further preferably, A is selected from the group consisting of
• wherein, the
• is optionally substituted with substituent Rk, wherein #R1 represents the attachment point to R1, $L1 represents the attachment point to L1;
• further preferably, A is selected from the group consisting of
• wherein #R1 represents the attachment point to R1, $L1 represents the attachment point to L1;
• further preferably, A is selected from the group consisting of
• wherein #R1 represents the attachment point to R1, $L1 represents the attachment point to Ll;
• Rk is selected from the group consisting of C1-C6 alkyl, C3-C7 cycloalkyl, RpRgN—, C1-C6 haloalkyl, C1-C6 heteroalkyl (such as C1-C6 alkoxy), 4-9 membered heterocyclyl (such as 5-6 membered saturated heterocyclyl), 6-10 membered aryl, and 5-10 membered heteroaryl;
• preferably, Rk is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, RpRgN—, C1-C6 haloalkyl, and 4-9 membered saturated heterocyclyl (such as 5-6 membered saturated heterocyclyl);
• further preferably, Rk is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, RpRgN—, C1-C6 haloalkyl, and morpholinyl;
• further preferably, Rk is selected from the group consisting of N isopropyl, cyclopropyl, dimethylamino, difluoromethyl, and
• Rp, Rg are each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl;
• preferably, Rp, Rg are each independently selected from the group consisting of H, and C1-C6 alkyl;
• B is selected from the group consisting of 6-10 membered heteroaryl, and 6-10 membered aryl, and, B is optionally substituted with at least one of substituents Ra, Rb;
• preferably, B is substituted with at least one of substituents Ra, Rb;
• preferably, B is selected from the group consisting of 9 membered heteroaryl, pyridinyl, phenyl, and pyrimidinyl, and, B is substituted with at least one of substituents Ra, Rb;
• preferably, the 9 membered heteroaryl contains 1-4 heteroatoms selected from the group consisting of N, O, and S atoms;
• preferably, B is selected from the group consisting of 9 membered heteroaryl, pyridinyl, and phenyl, and, B is substituted with at least one of substituents Ra, Rb;
• preferably, the 9 membered heteroaryl contains 1-4 heteroatoms selected from the group consisting of N, O, and S atoms;
• further preferably, B is selected from the group consisting of
• pyridinyl, phenyl, and pyrimidinyl, and, B is substituted with at least one of substituents Ra, Rb;
• further preferably, B is selected from the group consisting of
• pyridinyl, and phenyl, and, B is substituted with at least one of substituents Ra, Rb;
• further preferably, B is selected from the group consisting of
• B is substituted with substituents Ra, Rb;
• further preferably, B is selected from the group consisting of
• and, B is substituted with substituents Ra, Rb;
• Ra is selected from the group consisting of H, halogen, cyano, carboxyl,
• C1-C6 alkyl, C1-C6 haloalkyl (such as trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl,
• (wherein Cy1 is 4-9 membered heterocyclyl optionally substituted with Rcy1 and Rcy2), —NRNaRNb (wherein RNa and RNb are each independently selected from the group consisting of H, and C1-C6 alkyl, wherein, the C1-C6 alkyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, and 4-7 membered heterocyclyl), and
• (wherein Rz is H or C1-C6 alkyl, Cy2 is 5-7 membered heterocyclyl, C3-C7 cycloalkyl or C6-C10 aryl, wherein, the 5-7 membered heterocyclyl, C3-C7 cycloalkyl and C6-C10 aryl are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, and hydroxy), wherein, the C4-C9 cycloalkyl, and 4-9 membered saturated heterocyclyl are optionally substituted with 1-3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, —NH2, —NH(C1-C6 alkyl), and —N(C1-C6 alkyl)(C1-C6 alkyl);
• preferably, Cy1 is 5-7 membered heterocyclyl optionally substituted with Rcy1 and Rcy2, further preferably, Cy1 is 6 membered heterocyclyl optionally substituted with Rcy1 and Rcy2, further preferably, Cy1 is morpholinyl, piperazinyl, or thiomorpholinyl, optionally substituted with Rcy1 and Rcy2;
• Rcy1 and Rcy2 are each independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen, hydroxy, nitro, cyano, amino, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)(C1-C6 alkyl), and oxo;
• preferably, Rcy1 and Rcy2 are each independently selected from the group consisting of C1-C6 alkyl, halogen, hydroxy, amino, and oxo, further preferably Rcy1 and Rcy2 are oxo;
• preferably, Cy2 is 5-7 membered heterocyclyl optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, and hydroxy;
• further preferably, Cy2 is selected from the group consisting of azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, and morpholinyl, wherein, the azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, and morpholinyl are optionally substituted with 1-3 substituents selected from the group consisting of halogen, and C1-C6 alkyl;
• further preferably, Cy2 is selected from the group consisting of pyrrolidinyl, imidazolidinyl, and piperidyl, wherein, the pyrrolidinyl, imidazolidinyl, and piperidyl are optionally substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, and methyl;
• further preferably, Cy2 is pyrrolidinyl optionally substituted with 1-3 (such as 1 or 2 or 3) F;
• preferably, Ra is selected from the group consisting of H, halogen, amino, cyano, carboxyl,
• C1-C6 alkyl, C1-C6 haloalkyl (such as trifluoromethyl), C4-C9 cycloalkyl, C4-C9 cycloalkyl-C1-C6 alkyl, 4-9 membered saturated heterocyclyl, 4-9 membered saturated heterocyclyl-C1-C6 alkyl, and —NRNaRNb (wherein RNa and RNb are each independently selected from the group consisting of H, and C1-C6 alkyl, wherein, the C1-C6 alkyl is optionally substituted with 1-3 substituents selected from the group consisting of hydroxy, C3-C6 cycloalkyl, and 4-7 membered heterocyclyl), wherein, the C4-C9 cycloalkyl, and 4-9 membered saturated heterocyclyl are optionally substituted with 1-3 substituents selected from the group consisting of C1-C6 alkyl, halogen, hydroxy, hydroxy-C1-C6 alkyl-, cyano, oxo, —NH2, —NH(C1-C6 alkyl), and —N(C1-C6 alkyl)(C1-C6 alkyl);
• preferably, Ra is selected from the group consisting of H, cyano, carboxyl,
• C1-C6 haloalkyl (such as trifluoromethyl),
• are optionally substituted with 1-3 substituents selected from the group consisting of C1-C6 alkyl, halogen, hydroxy, cyano, —NH2, —NH(C1-C6 alkyl), and —N(C1-C6 alkyl)(C1-C6 alkyl);
• preferably, Ra is selected from the group consisting of H, cyano, carboxyl,
• C1-C6 haloalkyl (such as trifluoromethyl),
• are optionally substituted with 1-3 substituents selected from the group consisting of C1-C6 alkyl, halogen, hydroxy, cyano, —NH2, —NH(C1-C6 alkyl), and —N(C1-C6 alkyl)(C1-C6 alkyl);
• preferably, Ra is selected from the group consisting of H, cyano,
• C1-C6 haloalkyl (such as trifluoromethyl), and
• wherein, the
• is optionally substituted with C1-C6 alkyl (preferably methyl), F, Cl, Br;
• m is selected from the group consisting of 0, 1, 2, and 3;
• preferably, m is selected from the group consisting of 0, and 1;
• n is selected from the group consisting of 0, 1, 2, and 3;
• preferably, n is selected from the group consisting of 0, and 1;
• p is selected from the group consisting of 0, 1, 2, and 3;
• preferably, p is selected from the group consisting of 0, and 1;
• further preferably, m is 0, and n is 0;
• further preferably, Ra is selected from the group consisting of H, cyano, carboxyl,
• further preferably, Ra is selected from the group consisting of H, cyano, carboxyl,
• further preferably, Ra is selected from the group consisting of H, cyano,
• further preferably, Ra is selected from the group consisting of H, cyano,
• Rb is selected from the group consisting of H, halogen, amino, cyano, carboxyl,
• C1-C6 alkyl, C1-C6 haloalkyl (such as trifluoromethyl), and
• preferably, Rb is selected from the group consisting of H, cyano,
• Rl, Rm are each independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl;
• preferably, Rl, Rm are each independently selected from the group consisting of H, and C1-C6 alkyl;
• or, Ra, Rb and the carbon atoms to which they are attached, respectively, together form a substituted or unsubstituted 5-membered heterocycle, wherein, the substituent is selected from C1-C6 alkyl (such as tert-butyl);
• preferably, Ra, Rb and the carbon atoms to which they are attached, respectively, together form
• Rc is selected from the group consisting of H, and C1-C6 alkyl;
• preferably, Rc is selected from C1-C6 alkyl;
• further preferably, B, as a whole, is selected from the group consisting of:
• further preferably, B, as a whole, is selected from the group consisting of
• further preferably, B, as a whole, is selected from the group consisting of
• further preferably, B, as a whole, is selected from the group consisting of
• L1 is selected from the group consisting of a direct bond, C1-C6 alkyl,
• preferably, L1 is selected from the group consisting of a direct bond,
• preferably, Ll is selected from the group consisting of a direct bond, methylene, and
• preferably, L1 is selected from the group consisting of a direct bond, and
• preferably, L1 is a direct bond;
• R1 is selected from the group consisting of
• C is selected from 5-6 membered heteroaryl, and C is optionally substituted with at least one of substituents Rd, Re, and Rf;
• preferably, C is selected from 5-6 membered heteroaryl containing 1-3 heteroatoms, and, C is optionally substituted with at least one of substituents Rd, Re, and Rf;
• further preferably, C is selected from the group consisting of pyrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrrolyl, oxazolyl, furanyl, 1,2,3-triazolyl, and 1,2,4-triazolyl, and, C is optionally substituted with at least one of substituents Rd, Re, and Rf;
• further preferably, C is selected from the group consisting of pyrazolyl, thiazolyl, pyridinyl, pyrrolyl, oxazolyl, furanyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and, C is optionally substituted with at least one of substituents Rd, Re, and Rf;
• Rd, Re, Rf are each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-7 membered saturated heterocyclyl, and
• wherein, the C3-C7 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, and 4-7 membered saturated heterocyclyl are each independently optionally substituted with 1-2 substituents selected from the group consisting of C1-C6 alkyl, halogen, alkoxy (such as C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (such as methylol), amino C1-C6 alkyl, and formyl;
• preferably, Rd, Re, Rf are each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl (such as difluoromethyl), C3-C7 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-7 membered saturated heterocyclyl, and
• wherein, the C3-C7 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, and 4-7 membered saturated heterocyclyl are each independently optionally substituted with 1-2 substituents selected from the group consisting of halogen, alkoxy (such as C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (such as methylol), amino C1-C6 alkyl, and formyl;
• preferably, Rd is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, pyridinyl, morpholinyl, piperazinyl, and piperidyl, wherein, the C3-C6 cycloalkyl, phenyl, pyridinyl, morpholinyl, piperazinyl, and piperidyl are each independently optionally substituted with 1-2 substituents selected from the group consisting of C1-C6 alkyl, halogen, alkoxy (such as C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (such as methylol), amino C1-C6 alkyl, and formyl;
• preferably, Rd is selected from the group consisting of C3-C6 cycloalkyl, phenyl, morpholinyl, and piperidyl, wherein, the C3-C6 cycloalkyl, phenyl, morpholinyl, and piperidyl are each independently optionally substituted with 1-2 substituents selected from the group consisting of halogen, alkoxy (such as C1-C6 alkoxy), hydroxy, amino, hydroxy C1-C6 alkyl (such as methylol), amino C1-C6 alkyl, and formyl;
• further preferably, Rd is selected from the group consisting of C1-C6 alkyl,
• phenyl, morpholinyl, piperazinyl, and piperidyl, wherein, the
• phenyl, morpholinyl, piperazinyl, and piperidyl are optionally substituted with C1-C6 alkyl (preferably methyl);
• further preferably, Rd is selected from the group consisting of
• phenyl, morpholinyl, and piperidyl;
• p is selected from the group consisting of 0, 1, and 2;
• Rg is selected from the group consisting of H, amino, hydroxy, hydroxy C1-C6 alkyl, and formyl;
• further preferably, Rd is selected from the group consisting of methyl, ethyl, isopropyl,
• piperazinyl, piperidyl,
• further preferably, Rd is selected from the group consisting of
• and piperazinyl;
• further preferably, Rd is selected from the group consisting of
• Rh, Ri are each independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl;
• preferably, Rh, Ri are each independently selected from the group consisting of H, methyl, ethyl, isopropyl, and cyclopropyl;
• preferably, Re is selected from the group consisting of H, methyl,
• and —NHCH3;
• preferably, Re is selected from the group consisting of H, methyl,
• or, Re, Rf and the carbon atoms to which they are attached, respectively, together form a substituted or unsubstituted 5-9 membered heterocycle, wherein, the substituent ais selected from the group consisting of C1-C6 alkyl (such as ethyl), alkoxy (such as C1-C6 alkoxy), C3-C6 cycloalkyl, amino, and hydroxy;
• preferably, Re, Rf and the carbon atoms to which they are attached, respectively, together form
• each Rj is independently selected from the group consisting of H, C1-C6 alkyl, alkoxy (such as C1-C6 alkoxy), C3-C6 cycloalkyl, amino, and hydroxy;
• further preferably, Re, Rf and the carbon atoms to which they are attached, respectively, together form
• R2, R3 are each independently selected from the group consisting of H, C1-C6 alkyl, and C3-C6 cycloalkyl;
• or, R2, R3 and the N atom to which they are both attached together form 5-6 membered saturated heterocyclyl, preferably, the 5-6 membered saturated heterocyclyl contains 2-3 heteroatoms selected from the group consisting of N, S, and O atoms;
• preferably, R2, R3 are each independently selected from the group consisting of H, methyl, ethyl, propyl, and
• or preferably, R2, R3 and the N atom to which they are both attached together form
• further preferably, R1, as a whole, is selected from the group consisting of:
• further preferably, R1, as a whole, is selected from the group consisting of:
• further preferably, R1, as a whole, is selected from the group consisting of:
• further preferably, R1, as a whole, is selected from the group consisting of