Aromatic heterocyclic compound, intermediate thereof, preparation method therefor, and pharmaceutical composition and use thereof

Abstract

Disclosed are an aromatic heterocyclic compound, an intermediate thereof, a preparation method therefor, and a pharmaceutical composition and use thereof. The aromatic heterocyclic compound of the present invention is a new ALK5 inhibitor, and is used for treating and/or preventing various ALK5-mediated diseases. ##STR00001##

Claims

1. An aromatic heterocyclic compound represented by the general formula I or a pharmaceutically acceptable salt thereof: ##STR00088## wherein, ##STR00089##  is ##STR00090## in ring Q, R.sup.q1, R.sup.q2, R.sup.q3, R.sup.q4, R.sup.q5, R.sup.q6, R.sup.q9, R.sup.q10, and R.sup.q15 are each independently hydrogen, deuterium, halogen, sulfonic acid group, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-8 alkenyl, substituted or unsubstituted C.sub.2-8 alkynyl, substituted or unsubstituted C.sub.3-10 cycloalkyl, substituted or unsubstituted C.sub.2-8 heterocycloalkyl, substituted or unsubstituted C.sub.6-20 aryl, substituted or unsubstituted C.sub.2-10 heteroaryl, cyano, cyano, —OR.sup.61, —SR.sup.62, —NR.sup.a63R.sup.a64, —C(O)R.sup.65, —C(O)OR.sup.66, —OC(O)R.sup.67, —OC(O)OR.sup.68, —C(O)NR.sup.a69R.sup.a610, —N(R.sup.611)C(O)R.sup.612, S(O)R.sup.613, —S(O).sub.2R.sup.614, —S(O).sub.2NR.sup.a615R.sup.a616, —OC(O)NR.sup.a617R.sup.a618, —N(R.sup.619)C(O)OR.sup.620, —N(R.sup.621)C(O)NR.sup.a622R.sup.a623, —N(R.sup.624)S(O).sub.2R.sup.625 or —OP(O)(OR.sup.626).sub.2; R.sup.61, R.sup.62, R.sup.a63, R.sup.a64, R.sup.65, R.sup.66, R.sup.67, R.sup.68, R.sup.a69, R.sup.a610, R.sup.611, R.sup.612, R.sup.613, R.sup.614, R.sup.a615, R.sup.a616, R.sup.a617, R.sup.a618, R.sup.619, R.sup.620, R.sup.621, R.sup.a622, R.sup.a623, R.sup.624, R.sup.625 and R.sup.626 are each independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-8 alkenyl, substituted or unsubstituted C.sub.2-8 alkynyl, substituted or unsubstituted C.sub.3-10 cycloalkyl, substituted or unsubstituted C.sub.2-8 heterocycloalkyl, substituted or unsubstituted C.sub.6-20 aryl, or substituted or unsubstituted C.sub.2-10 heteroaryl; in R.sup.q1, R.sup.q2, R.sup.q3, R.sup.q4, R.sup.q5, R.sup.q6, R.sup.q9, R.sup.q10 and R.sup.q15, substituents in the substituted C.sub.1-6 alkyl, substituted C.sub.2-8 alkenyl, substituted C.sub.2-8 alkynyl, substituted C.sub.3-10 cycloalkyl, substituted C.sub.2-8 heterocycloalkyl, substituted C.sub.6-20, substituted aryl or substituted C.sub.2-10 heteroaryl are each independently one or more of the following groups: deuterium, halogen, C.sub.1-6 alkyl, halogen substituted C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-10 cycloalkyl, C.sub.2-8 heterocycloalkyl, C.sub.6-20 aryl, C.sub.2-10 heteroaryl, cyano, —OR.sup.71, —SR.sup.72, —NR.sup.a73R.sup.a74, —C(O)R.sup.75, —C(O)OR.sup.76, —OC(O)R.sup.77, —OC(O)OR.sup.78, —C(O)NR.sup.a79R.sup.a710, —N(R.sup.711)C(O)R.sup.712, S(O)R.sup.713, —S(O).sub.2R.sup.714, —S(O).sub.2NR.sup.a715R.sup.a716, —OC(O)NR.sup.a717R.sup.a718, —N(R.sup.719)C(O)OR.sup.720, —N(R.sup.721)C(O)NR.sup.a722R.sup.a723, —N(R.sup.724)S(O).sub.2R.sup.725 or —OP(O)(OR.sup.726).sub.2; when there are multiple substituents, the substituents are the same or different; R.sup.71, R.sup.72, R.sup.a73, R.sup.a74, R.sup.75, R.sup.76, R.sup.77, R.sup.78, R.sup.a79, R.sup.a710, R.sup.711, R.sup.712, R.sup.713, R.sup.714, R.sup.a715, R.sup.a716, R.sup.a717, R.sup.a718, R.sup.719, R.sup.720, R.sup.721, R.sup.a722, R.sup.a723, R.sup.724, R.sup.725 and R.sup.726 are each independently C.sub.1-6 alkyl, halogen substituted C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-10 cycloalkyl, C.sub.2-8 heterocycloalkyl, C.sub.6-20 aryl or C.sub.2-10 heteroaryl; in R.sup.61, R.sup.62, R.sup.a63, R.sup.a64, R.sup.65, R.sup.66, R.sup.67, R.sup.68, R.sup.a69, R.sup.a610, R.sup.611, R.sup.612, R.sup.613, R.sup.a614, R.sup.a615, R.sup.a616, R.sup.a617, R.sup.a618, R.sup.619, R.sup.620, R.sup.621, R.sup.a622, R.sup.a623, R.sup.624, R.sup.625 and R.sup.626, substituents in the substituted C.sub.1-6 alkyl, substituted C.sub.2-8 alkenyl, substituted C.sub.2-8 alkynyl, substituted C.sub.3-10 cycloalkyl, substituted C.sub.2-8 heterocycloalkyl, substituted C.sub.6-20 aryl or substituted C.sub.2-10 heteroaryl are each independently one or more of the following groups: deuterium, halogen, cyano, C.sub.1-6 alkyl, halogen substituted C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-10 cycloalkyl, C.sub.2-8 heterocycloalkyl, C.sub.6-20 aryl, C.sub.2-10 heteroaryl, —OR.sup.c—SR.sup.c1, —NR.sup.b1R.sup.b2, —C(O)R.sup.c2, —C(O)OR.sup.c3, —OC(O)R.sup.c4, —OC(O)OR.sup.c5, —C(O)NR.sup.b3R.sup.b4, —N(R.sup.c6)C(O)OR.sup.c7, S(O)R.sup.c8, —S(O).sub.2R.sup.c9, —S(O).sub.2NR.sup.b5R.sup.b6, —N(R.sup.c10)C(O)R.sup.c11, —N(R.sup.c12)C(O)NR.sup.b7R.sup.b8 or —N(R.sup.c13)S(O).sub.2R.sup.c14; R.sup.c, R.sup.c1, R.sup.b1, R.sup.b2, R.sup.c2, R.sup.c3, R.sup.c4, R.sup.c5, R.sup.b3, R.sup.b4, R.sup.c6, R.sup.c7, R.sup.c8, R.sup.c9, R.sup.b5, R.sup.b6, R.sup.c10, R.sup.c11, R.sup.c12, R.sup.b7, R.sup.b8, R.sup.c13 and R.sup.c14 are each independently hydrogen, hydroxyl, C.sub.1-6 alkyl, halogen substituted C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, C.sub.2-8 heterocycloalkyl, C.sub.6-20 aryl or C.sub.2-10 heteroaryl; Q.sup.3 is S; Q.sup.4 is CR.sup.q23; R.sup.q23 and R.sup.q1 have the same definition; or two adjacent R.sup.qx and the atoms to which they are connected form a ring structure; the ring structure is substituted or unsubstituted C.sub.3-10 cycloalkyl, substituted or unsubstituted C.sub.2-8 heterocycloalkyl, substituted or unsubstituted C.sub.6-20 aryl, or substituted or unsubstituted C.sub.2-10 heteroaryl; in the ring structure, substituents in the substituted C.sub.3-10 cycloalkyl, substituted C.sub.2-8 heterocycloalkyl, substituted C.sub.6-20 aryl or substituted C.sub.2-10 heteroaryl are each independently one or more of the following groups: deuterium, halogen, cyano, C.sub.1-6 alkyl, halogen substituted C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, —OR.sup.a15, —SR.sup.a16, —C(O)OR.sup.a17, —COR.sup.a18, —C(O)NH.sub.2, C.sub.3-10 cycloalkyl, C.sub.2-8 heterocycloalkyl, C.sub.6-20 aryl, C.sub.2-10 heteroaryl; R.sup.a15, R.sup.a16, R.sup.a17 and R.sup.a18 are each independently hydrogen or C.sub.1-6 alkyl; when there are multiple substituents, the substituents are the same or different; the two adjacent R.sup.qx refer to R.sup.q1 and R.sup.q2; R.sup.q2 and R.sup.q3; R.sup.q4 and R.sup.q5; R.sup.q5 and R.sup.q6; R.sup.q9 and R.sup.q10; when Q.sup.4 is CR.sup.q23, two adjacent R.sup.qx can also be R.sup.q15 and R.sup.q23; ##STR00091##  is ##STR00092## in ring A, R.sup.3, R.sup.31, R.sup.32 and R.sup.33 are each independently hydrogen, halogen, cyano, nitro, —NR.sup.a3R.sup.a4, —OR.sup.a5, —SR.sup.a6, —C(O)OR.sup.a7, —C(O)NR.sup.a8R.sup.a9, —COR.sup.a10, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-8 alkenyl, substituted or unsubstituted C.sub.2-8 alkynyl, substituted or unsubstituted C.sub.3-10 cycloalkyl, substituted or unsubstituted C.sub.2-8 heterocycloalkyl, substituted or unsubstituted C.sub.4-8 cycloalkenyl, substituted or unsubstituted C.sub.6-20 aryl, or substituted or unsubstituted C.sub.2-10 heteroaryl; R.sup.a4, R.sup.a5, R.sup.a6, R.sup.a7, R.sup.a9 and R.sup.a10 are each independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-10 cycloalkyl, C.sub.2-8 heterocycloalkyl, C.sub.6-20 aryl or C.sub.2-10 heteroaryl; R.sup.a3 and R.sup.a8 are each independently hydrogen, hydroxyl, C.sub.1-6 alkoxy, substituted or unsubstituted C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-10 cycloalkyl, C.sub.2-8 heterocycloalkyl, C.sub.6-20 aryl or C.sub.2-10 heteroaryl; in R.sup.3, R.sup.31, R.sup.32, and R.sup.33, substituents in the substituted C.sub.1-6 alkyl, substituted C.sub.2-8 alkenyl, substituted C.sub.2-8 alkynyl, substituted C.sub.3-10 cycloalkyl, substituted C.sub.2-8 heterocycloalkyl, substituted C.sub.4-8 cycloalkenyl, substituted C.sub.6-20 aryl or substituted C.sub.2-10 heteroaryl, and substituents in the substituted C.sub.1-6 alkyl in R.sup.a3, R.sup.a4, R.sup.a5, R.sup.a6, R.sup.a7, R.sup.a8, R.sup.a9 and R.sup.a10 are each independently one or more of the following groups: deuterium, halogen, cyano, C.sub.1-6 alkyl, halogen substituted C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, —OR.sup.a15, —SR.sup.a16, —C(O)OR.sup.a17, —COR.sup.a18, —C(O)NH.sub.2, C.sub.3-10 cycloalkyl, C.sub.2-8 heterocycloalkyl, C.sub.6-20 aryl or C.sub.2-10 heteroaryl; R.sup.a15, R.sup.a16, R.sup.a17 and R.sup.a18 are each independently hydrogen or C.sub.1-6 alkyl; when there are multiple substituents, the substituents are the same or different; ##STR00093##  is ##STR00094## in ring B, R.sup.5, R.sup.51, R.sup.5a, R.sup.5a1, R.sup.5a2, R.sup.5b, R.sup.5b1, R.sup.5c, R.sup.5c1, and R.sup.5c2 are each independently hydrogen, deuterium or halogen; R.sup.6, R.sup.6a, R.sup.6b, and R.sup.6c are each independently halogen, —C(O)OR.sup.66 or —C(O)NR.sup.a69R.sup.a610; R.sup.66 is hydrogen or C.sub.1-6 alkyl; R.sup.a69 and R.sup.a610 are hydrogen; R.sup.7, R.sup.8, R.sup.9, and R.sup.10 are each independently hydrogen, deuterium or halogen; or in the above groups or substituents, when NR.sup.XR.sup.Y is present, then R.sup.X, R.sup.Y and N to which they are attached form substituted or unsubstituted 3-8 membered heterocyclyl together; heteroatom in the 3-8 membered heterocyclyl is selected from N, N and O, N and S, or N, O and S; the number of heteroatom is 1, 2, 3 or 4; substituents in the substituted 3-8 membered heterocyclyl are one or more of the following groups: deuterium, halogen, cyano, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, —OR.sup.a81, —SR.sup.a82, —C(O)OR.sup.a83, —COR.sup.a84, —C(O)NH.sub.2, C.sub.3-10 cycloalkyl, C.sub.2-8 heterocycloalkyl, C.sub.6-20 aryl or C.sub.2-10 heteroaryl; R.sup.a81, R.sup.a82, R.sup.a83 and R.sup.a84 are each independently hydrogen or C.sub.1-6 alkyl; —NR.sup.xR.sup.Y is —NR.sup.a3R.sup.a4, —NR.sup.a8R.sup.a9, —NR.sup.a63R.sup.a64, —NR.sup.a69R.sup.a610, —NR.sup.a615R.sup.a616, —NR.sup.a617R.sup.a618, —NR.sup.a622R.sup.a623, —NR.sup.a73R.sup.a74, —NR.sup.a79R.sup.a710, —NR.sup.a715R.sup.a716, —NR.sup.a717R.sup.a718, —NR.sup.a722R.sup.a723, —NR.sup.b1R.sup.b2, —NR.sup.b3R.sup.b4, —NR.sup.b5R.sup.b6 or —NR.sup.b7R.sup.b8.

2. The aromatic heterocyclic compound represented by the general formula I or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein the halogen is F, Cl, Br or I; or, the C.sub.1-6 alkyl in the substituted or unsubstituted C.sub.1-6 alkyl and the C.sub.1-6 alkyl are independently C.sub.1-4 alkyl; or, the C.sub.2-8 alkenyl in the substituted or unsubstituted C.sub.2-8 alkenyl and the C.sub.2-8 alkenyl are independently C.sub.2-4 alkenyl; or, the C.sub.2-8 alkynyl in the substituted or unsubstituted C.sub.2-8 alkynyl and the C.sub.2-8 alkynyl are independently C.sub.2-4 alkynyl; or, the C.sub.3-10 cycloalkyl in the substituted or unsubstituted C.sub.3-10 cycloalkyl and the C.sub.3-10 cycloalkyl are independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo [3.1.1] heptyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl or bicyclo [4.2.1] nonyl; or, the C.sub.2-8 heterocycloalkyl in the substituted or unsubstituted C.sub.2-8 heterocycloalkyl and the C.sub.2-8 heterocycloalkyl are independently azetidinyl, azepanyl, aziridine, diazcycloheptyl, 1,3-dioxanyl, 1,3-dioxopenyl, 1,3-dithiopentyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isothiazolyl, isoxazolinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, thiopyranyl, trithianyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indoline-1-yl, indoline-2-yl, indoline-3-yl, 2,3-dihydrobenzothiophene-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl or octahydrobenzofuranyl; or, the C.sub.4-8 cycloalkenyl in the substituted or unsubstituted C.sub.4-8 cycloalkenyl and the C.sub.4-8 cycloalkenyl are independently cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, norbornenyl or bicyclo [2.2.2] octenyl; or, the C.sub.6-20 aryl in the substituted or unsubstituted C.sub.6-20 aryl or the C.sub.6-20 aryl are independently phenyl, naphthyl, anthryl, phenanthryl, azulenyl, indan-1-yl, indan-2-yl, indan-3-yl, indan-4-yl, 2,3-indoline-4-yl, 2,3-indoline-5-yl, 2,3-indoline-6-yl, 2,3-indoline-7-yl, inden-1-yl, inden-2-yl, inden-3-yl, inden-4-yl, dihydronaphthalene-2-yl, dihydronaphthalene-3-yl, dihydronaphthalene-4-yl, dihydronaphthalene-1-yl, 5,6,7,8-tetrahydronaphthalene-1-yl, 5,6,7,8-tetrahydronaphthalene-2-yl, 2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl, 2H-benzofuran-2-one-5-yl, 2H-benzofuran-2-one-6-yl, 2H-benzofuran-2-one-7-yl, 2H-benzofuran-2-one-8-yl, isoindoline-1,3-dione-4-yl, isoindoline-1,3-dione-5-yl, inden-1-one-4-yl, inden-1-one-5-yl, inden-1-one-6-yl, inden-1-one-7-yl, 2,3-dihydrobenzo[b][1,4]dioxane-5-yl, 2,3-dihydrobenzo[b][1,4]dioxane-6-yl, 2H-benzo [b][1,4]oxazine3(4H)-one-5-yl, 2H-benzo [b][1,4] oxazine 3(4H)-one-6-yl, 2H-benzo [b][1,4] oxazine 3(4H)-one-7-yl, 2H-benzo [b][1,4]oxazine3(4H)-one-8-yl, benzo[d]oxazine-2(3H)-one-5-yl, benzo[d]oxazine-2(3H)-one-6-yl, benzo[d]oxazine-2(3H)-one-7-yl, benzo[d]oxazine-2(3H)-one-8-yl, quinazolin-4(3H)-one-5-yl, quinazolin-4(3H)-one-6-yl, quinazolin-4(3H)-one-7-yl, quinazolin-4(3H)-one-8-yl, quinoxalin-2(1H)-one-5-yl, quinoxalin-2(1H)-one-6-yl, quinoxaline-2(1H)-one-7-yl, quinoxaline-2(1H)-one-8-yl, benzo[d]thiazol-2(3H)-one-4-yl, benzo[d]thiazol-2(3H)-one-5-yl, benzo[d]thiazo-2(3H)-one-6-yl or benzo[d]thiazole-2(3H)-one-7-yl; or, the C.sub.2-10 heteroaryl in the substituted or unsubstituted C.sub.2-10 heteroaryl and the C.sub.2-10 heteroaryl are independently furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, triazinyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroquinolin-1-yl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, purinyl, quinolinyl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7, 8-tetrahydroisoquinolin-1-yl, thienopyridyl, 4,5,6,7-tetrahydro[c][1,2,5]oxadiazolyl or 6,7-dihydropyro[c][1,2,5]oxadiazol-4(5H) one.

3. The aromatic heterocyclic compound represented by the general formula I or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein in ring Q, R.sup.q1, R.sup.q2, R.sup.q3, R.sup.q4, R.sup.q5, R.sup.q6, R.sup.q9, R.sup.q10, and R.sup.q15 are each independently hydrogen, deuterium, halogen, sulfonic acid group, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-10 cycloalkyl, C.sub.2-8 heterocycloalkyl, C.sub.6-20 aryl, C.sub.2-10 heteroaryl, cyano, —OR.sup.61, —SR.sup.62, —NR.sup.a63R.sup.a64, —C(O)R.sup.65, —C(O)OR.sup.66, —OC(O)R.sup.67, —OC(O)OR.sup.68, —C(O)NR.sup.a69R.sup.a610, —N(R.sup.611)C(O)R.sup.612, S(O)R.sup.613, —S(O).sub.2R.sup.614, —S(O).sub.2NR.sup.a615R.sup.a616, —OC(O)NR.sup.a617R.sup.a618, —N(R.sup.619)C(O)OR.sup.620, —N(R.sup.621)C(O)NR.sup.a622R.sup.a623, —N(R.sup.624)S(O).sub.2R.sup.625 or —OP(O)(OR.sup.626).sub.2; or, in ring A, R.sup.3, R.sup.31, R.sup.32, and R.sup.33 are independently hydrogen, halogen, cyano, nitro, —NR.sup.a3R.sup.a4, —OR.sup.a5, —SR.sup.a6, —C(O)OR.sup.a7, —C(O)NR.sup.a8R.sup.a9, —COR.sup.a10, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-8 heterocycloalkyl, substituted or unsubstituted C.sub.6-20 aryl, or substituted or unsubstituted C.sub.2-10 heteroaryl.

4. The aromatic heterocyclic compound represented by the general formula I or the pharmaceutically acceptable salt thereof as defined in claim 3, wherein in ring Q, R.sup.q1, R.sup.q2, R.sup.q3, R.sup.q4, R.sup.q5, R.sup.q6, R.sup.q9, R.sup.q10, and R.sup.q15 are each independently hydrogen, deuterium, halogen or C.sub.1-6 alkyl; or, in ring A, R.sup.3, R.sup.31, R.sup.32, and R.sup.33 are each independently hydrogen, halogen, —OR.sup.a5, —SR.sup.a6, —C(O)NR.sup.a8R.sup.a9, or substituted or unsubstituted C.sub.1-6 alkyl.

5. The aromatic heterocyclic compound represented by the general formula I or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein in ring Q, R.sup.q1, R.sup.q2, R.sup.q3, R.sup.q4, R.sup.q5, R.sup.q6, R.sup.q9, R.sup.q10, and R.sup.q15 are each independently hydrogen or C.sub.1-6 alkyl; or, in ring A, R.sup.3, R.sup.31, R.sup.32, and R.sup.33 are each independently hydrogen, halogen, trifluoromethyl, difluoromethyl, deuterated methyl, methyl or methoxy.

6. The aromatic heterocyclic compound represented by the general formula I or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein ##STR00095##  is ##STR00096##

7. The aromatic heterocyclic compound represented by the general formula I or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein ring Q is ##STR00097## or, ##STR00098##  is ##STR00099## or, ##STR00100##  is ##STR00101##

8. The aromatic heterocyclic compound represented by the general formula I or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein the aromatic heterocyclic compound represented by the general formula I is any one of the following compounds: ##STR00102## ##STR00103## ##STR00104## ##STR00105##

9. A method for preparing the aromatic heterocyclic compound represented by general formula I as defined in claim 1, comprising the following steps: coupling compound I-A with compound I-B to obtain the aromatic heterocyclic compound represented by general formula I; ##STR00106## wherein, one of X.sup.a and X.sup.b is H, and the other is halogen; or, one of X.sup.a and X.sup.b is an organotin reagent or an organoboron reagent, and the other is halogen; or one of X.sup.a and X.sup.b is —OPG1, and PG1 is p-toluenesulfonyl or methanesulfonyl; and the other is organotin reagent or organoboron reagent; one of ring C1 and ring C2 is ring A, and the other is ring B; ring A, ring B and ring Q are as defined in claim 1.

10. An intermediate compound for preparing the aromatic heterocyclic compound represented by general formula I as defined in claim 1, which is any of the following compounds: ##STR00107## ##STR00108## ##STR00109##

11. A method for inhibiting ALK5 in a subject in need thereof, comprising: administering an effective amount of the aromatic heterocyclic compound represented by the general formula I or the pharmaceutically acceptable salt thereof as defined in claim 1 to the subject.

12. A pharmaceutical composition comprising one or more of the prophylactically and/or therapeutically effective dose of nitrogen-containing aromatic heterocyclic compound represented by general formula I and the pharmaceutically acceptable salt thereof as defined in claim 1, and a pharmaceutically apreviocceptable carrier.

13. A method for treating ALK5-mediated diseases in a subject in need thereof, comprising: administering an effective amount of the aromatic heterocyclic compound represented by the general formula I or the pharmaceutically acceptable salt thereof as defined in claim 1 to the subject, wherein the ALK5-mediated disease is one or more of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, renal cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, rectal cancer, esophageal cancer, gastric cancer, pancreatic cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.

14. The aromatic heterocyclic compound represented by the general formula I or the pharmaceutically acceptable salt thereof as defined in claim 2, wherein the halogen is F, Cl, Br or I; or, the C.sub.1-6 alkyl in the substituted or unsubstituted C.sub.1-6 alkyl and the C.sub.1-6 alkyl are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; or, the C.sub.2-8 alkenyl in the substituted or unsubstituted C.sub.2-8 alkenyl and the C.sub.2-8 alkenyl are independently vinyl, propenyl, allyl, ##STR00110## or, the C.sub.2-8 alkynyl in the substituted or unsubstituted C.sub.2-8 alkynyl and the C.sub.2-8 alkynyl are independently ethynyl, propynyl, butynyl or 3-methylpropynyl.

15. The aromatic heterocyclic compound represented by the general formula I or the pharmaceutically acceptable salt thereof as defined in claim 4, wherein in ring A, R.sup.3, R.sup.31, R.sup.32, and R.sup.33 are each independently hydrogen, halogen, —OR.sup.a5, or substituted or unsubstituted C.sub.1-6 alkyl; wherein, R.sup.a5 is hydrogen or C.sub.1-6 alkyl, and substituents in the substituted C.sub.1-6 alkyl are one or more of the following substituents: deuterium or halogen.

16. The aromatic heterocyclic compound represented by the general formula I or the pharmaceutically acceptable salt thereof as defined in claim 15, wherein in ring A, R.sup.3, R.sup.31, R.sup.32, and R.sup.33 are each independently hydrogen, C.sub.1-6 alkyl or C.sub.1-6 alkyl substituted with halogen, and the number of the halogen is one or more than one.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

(1) The reagents and raw materials (except intermediates) used in the present invention are all obtained through commercial channels. The room temperature in the present invention refers to the ambient temperature, which is 10° C.−35° C. Overnight means 8-15 hours. Reflux refers to the reflux temperature of the solvent under normal pressure.

(2) The following is a list of abbreviations used in the examples:

(3) DMF N,N-dimethylformamide

(4) DMSO dimethyl sulfoxide

(5) DCM dichloromethane

(6) THF tetrahydrofuran

(7) MeOH methanol

(8) PE petroleum ether

(9) EA ethyl acetate

(10) DME ethylene glycol dimethyl ether

(11) H.sub.2O.sub.2 hydrogen peroxide

(12) Na.sub.2CO.sub.3 sodium carbonate

(13) NB S N-bromosuccinimide

(14) Pd(dppf)Cl.sub.2 [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex

(15) Pd.sub.2(dba).sub.3 tridibenzylideneacetone dipalladium

(16) BINAP (±)-2,2′-bis-(diphenylphosphino)-1,1′-binaphthalene

(17) DMF-DMA N,N-dimethylformamide dimethyl acetal

(18) DIBAL-H diisobutylaluminum hydride

(19) Synthetic Route of Compound 1

(20) ##STR00063##

(21) Synthesis of Compound 1-e

(22) Compound 1-e was synthesized according to the method in WO2015/157093.

(23) Synthesis of Compound 1-d

(24) 1-e (500 mg, 2.07 mmol) was dissolved in dichloromethane (10 mL). Under ice bath, oxalyl chloride (1 mL) and a drop of DMF were slowly added to the solution. The reactants were raised to room temperature and reacted for 60 minutes. The mixture was concentrated under reduced pressure and diluted with dichloromethane (5 mL). Under ice bath, the solution was slowly added dropwise to ammonia water (5 mL), and the reaction mixture reacted at 0° C. for 10 minutes, and then raised to room temperature and stirred overnight. The liquid was separated, and the aqueous layer was extracted with dichloromethane. The combined organic phases were washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 1-d (300 mg, 60%) as a white solid. LC-MS (ESI): m/z=239.9 [M+H].sup.+.

(25) Synthesis of Compound 1-c

(26) 1-d (100 mg, 0.42 mmol) was dissolved in dioxane (10 mL). Under ice bath, pyridine (0.34 mL, 4.2 mmol) was added to the solution. After stirring the solution for 5 minutes, trifluoroacetic anhydride (0.29 mL, 2.08 mmol) was slowly added dropwise. The reactants were raised to room temperature and stirred for 5 hours. After the reaction was completed, the reaction was quenched by the addition of water, and the organic solvent was removed by concentration under reduced pressure. The mixture was dissolved in ethyl acetate, washed successively with water and saturated brine, then dried over anhydrous sodium sulfate, and concentrated to obtain compound 1-c (80 mg, 86%) as a white solid. LC-MS (ESI): m/z=221.9 [M+H].sup.+.

(27) Synthesis of Compound 1-b

(28) 1-Boc-2-pyrrole-boronic acid (1.11 g, 5.27 mmol), 2-bromo-6-methylpyridine (0.5 mL, 4.39 mmol), Pd(dppf)Cl.sub.2 (359 mg, 0.44 mmol), sodium carbonate (1.16 g, 10.99 mmol), 1,4-dioxane (10 mL) and water (2 mL) were added to a reaction flask. The reaction solution was replaced with N.sub.2 and reacted at 85° C. overnight. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, then washed with saturated brine and dried over anhydrous sodium sulfate, then filtered and the filtrate was dried by rotary evaporation. The crude product was separated by silica gel column chromatography (PE:EA=3:1) to obtain compound 1-b (600 mg, 53%) as a white solid. LC-MS (ESI): m/z=259.1 [M+H].sup.+.

(29) Synthesis of Compound 1-a

(30) 1-b (600 mg, 2.36 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (10 mL), and the mixture was stirred at room temperature overnight. After the reaction was completed, the organic solvent was concentrated under reduced pressure, to which saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added, then the liquid was separated. The aqueous layer was extracted with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1-a (300 mg, 81%) as a brown solid. LC-MS (ESI): m/z=159.2 [M+H].sup.+.

(31) Synthesis of Compound 1

(32) Compound 1-a (40 mg, 0.25 mmol), 1-c (56 mg, 0.25 mmol), copper ferrite (6 mg, 0.025 mmol), potassium tert-butoxide (57 mg, 0.51 mmol) and anhydrous DMF (10 mL) were added to a reaction flask. The reaction solution was replaced with N2 and stirred at 150° C. overnight. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, then dried over anhydrous sodium sulfate, then filtered and the filtrate was dried by rotary evaporation. The crude product was purified by prep-HPLC to obtain compound 1 (30 mg, 40%) as a white solid. LC-MS (ESI): m/z=318.1 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.55 (d, J=2.0 Hz, 1H), 8.34 (s, 1H), 7.64 (d, J=10.0 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.36 (dd, J=9.5, 2.0 Hz, 1H), 7.28 (d, J=7.5 Hz, 1H), 7.14 (dd, J=2.0, 1.0 Hz, 1H), 7.01 (d, J=8 Hz, 1H), 6.78 (dd, J=3.5, 1.5 Hz, 1H), 6.43 (dd, J=4, 3 Hz, 1H), 2.21 (s, 3H).

(33) Synthetic Route of Compound 2

(34) ##STR00064##

(35) Synthesis of Compound 2-b

(36) 1-Boc-2-pyrrole-boronic acid (329 mg, 1.56 mmol), SM-1 (350 mg, 1.3 mmol), Pd(dppf)Cl.sub.2 (106 mg, 0.13 mmol), sodium carbonate (345 mg, 3.25 mmol)), 1,4-dioxane (10 mL) and water (2 mL) were added to a reaction flask. The reaction solution was replaced with N.sub.2 and reacted at 85° C. overnight. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was dried by rotary evaporation. The crude product was separated by silica gel column chromatography (PE:EA=5:1) to obtain product 2-b (450 mg, 95%) as a white solid. LC-MS (ESI): m/z=356.0 [M+H].sup.+.

(37) Synthesis of Compound 2-a

(38) 2-b (450 mg, 1.27 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (10 mL), and the mixture was stirred at room temperature overnight. After the reaction was completed, the organic solvent was concentrated under reduced pressure, to which saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added, and the liquid was separated. The aqueous layer was extracted with dichloromethane, and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-a (300 mg, 92%) as a brown solid. LC-MS (ESI): m/z=256.1 [M+H].sup.+.

(39) Synthesis of Compound 2

(40) Compound 2-a (100 mg, 0.39 mmol), 6-bromo-2-methylpyridine (67 mg, 0.39 mmol), tris(dibenzylideneacetone) dipalladium (36 mg, 0.039 mmol), 1,1′-binaphthalene-2,2′-bisdiphenylphosphine (49 mg, 0.078 mmol), sodium tert-butoxide (75 mg, 0.78 mmol) and toluene (10 mL) were added to a reaction flask. The reaction solution was replaced with N2 and stirred at 120° C. overnight. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was dried by rotary evaporation. The crude product was separated by silica gel column chromatography (PE:EA=1:1) to obtain product 2 (20 mg, 15%) as a brown oil. LC-MS (ESI): m/z=347.0 [M+H].sup.+.

(41) Synthetic Route of Compound 3

(42) ##STR00065##

(43) Synthesis of Compound 3

(44) 2 (20 mg, 0.057 mmol) was dissolved in methanol (2 mL) and THF (2 mL), aqueous sodium hydroxide solution (2M, 2 mL) was then added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the organic solvent was concentrated under reduced pressure, water (10 mL) and DCM (10 mL) were added, and the liquid was separated, then the organic layer was discarded. The aqueous layer was cooled to 0° C. and neutralized with 2 M hydrochloric acid to a pH of 5-6. Then the aqueous layer was extracted with dichloromethane, and the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, then filtered and the filtrate was dried by rotary evaporation to obtain 3 (15 mg, 82%). LC-MS (ESI): m/z=319.0 [M+H].sup.+.

(45) Synthetic Route of Compounds 4 and 5

(46) ##STR00066##

(47) Synthesis of Compounds 4 and 5

(48) 3 (15 mg, 0.047 mmol) was dissolved in dichloromethane (10 mL). Under ice bath, oxalyl chloride (1 mL) and a drop of DMF were slowly added to the solution. The reactants were raised to room temperature and reacted for 60 minutes. The mixture was concentrated under reduced pressure and diluted with dichloromethane (5 mL). Under ice bath, the solution was slowly added dropwise to ammonia water (5 mL). The reaction mixture was reacted at 0° C. for 10 minutes, and then raised to room temperature and stirred overnight. The liquid was separated, and the aqueous layer was extracted with dichloromethane. The combined organic phases were washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was subjected to high performance liquid chromatography to obtain 4 as white solid (2 mg, 13%) and 5 (2 mg, 12%).

(49) Compound 4: LC-MS (ESI): LC-MS (ESI): m/z=318.1 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.53 (s, 1H), 8.40 (s, 1H), 7.72 (t, J=7.5 Hz, 1H), 7.63 (s, 1H), 7.39 (s, 1H), 7.34 (dd, J=3, 1.5 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 7.03 (d, J=7.5 Hz, 1H), 6.61 (dd, J=3.5, 1.5 Hz, 1H), 6.44 (t, J=3 Hz, 1H), 2.45 (s, 3H).

(50) Compound 5: LC-MS (ESI): m/z=346.0 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 8.98 (s, 1H), 8.06 (s, 1H), 7.69 (t, J=7.5 Hz, 1H), 7.50 (d, J=9.5 Hz, 1H), 7.33 (dd, J=2.5, 1.5 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 7.14 (dd, J=9.0, 1.5 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 6.56 (dd, J=3.5, 2 Hz, 1H), 6.41 (t, J=3.5 Hz, 1H), 3.27 (s, 6H), 2.47 (s, 3H).

(51) Synthetic Route of Compound 6

(52) ##STR00067##

(53) Synthesis of Compound 6-a

(54) Compound imidazole (531 mg, 7.8 mmol), SM-1 (2 g, 7.43 mmol), cuprous iodide (141 mg, 0.74 mmol), potassium carbonate (2 g, 14.86 mmol), L-proline (171.1 mg, 1.48 mmol) and anhydrous dimethyl sulfoxide (10 mL) were added to a reaction flask. The reaction solution was replaced with N2 and stirred at 120° C. overnight. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, then filtered and the filtrate was dried by rotary evaporation. The crude product was separated by silica gel column chromatography (PE:EA=1:1) to obtain the product 6-a (0.5 g, 26%) as a brown solid. LC-MS (ESI): m/z=257.2 [M+H].sup.+.

(55) Synthesis of Compound 6

(56) Compound 6-a (400 mg, 1.56 mmol), 2-bromo-6-methylpyridine (537 mg, 3.12 mmol), cesium fluoride (474 mg, 3.12 mmol), palladium acetate (35 mg, 0.156 mmol), triphenylarsenic (96 mg, 0.312 mmol) and DMF (10 mL) were added to a reaction flask. The reaction solution was replaced with N.sub.2 and stirred at 140° C. overnight. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, then filtered and the filtrate was dried by rotary evaporation to obtain a crude product. The crude product was subjected to high performance liquid chromatography to obtain compound 6 (30 mg, 5.5%) as a white solid. LC-MS (ESI): m/z=348.1 [M+H].sup.+.

(57) Synthetic Route of Compound 7

(58) ##STR00068##

(59) Synthesis of Compound 7

(60) 6 (30 mg, 0.086 mmol) was added to methanol (2 mL) and THF (2 mL), then aqueous sodium hydroxide solution (2 M, 2 mL) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the organic solvent was concentrated under reduced pressure, water (10 mL) and DCM (30 mL) were added. The liquid was separated, and the organic layer was discarded. The aqueous layer was cooled to 0° C. and neutralized with 2 M hydrochloric acid to a pH of 6-7. The yellowish precipitate was filtered off and dried to obtain compound 7 (20 mg, 72%). LC-MS (ESI): m/z=320.0 [M+H].sup.+.

(61) Synthetic Route of Compound 8

(62) ##STR00069##

(63) Synthesis of Compound 8

(64) 7 (20 mg, 0.063 mmol) was dissolved in dichloromethane (10 mL). Under ice bath, oxalyl chloride (1 mL) and a drop of DMF were slowly added to the solution. The reactants were raised to room temperature and reacted for 60 minutes. The mixture was concentrated under reduced pressure and diluted with dichloromethane (5 mL). Under ice bath, the solution was slowly added dropwise to ammonia water (5 mL), and the reaction mixture reacted at 0° C. for 10 minutes, and then raised to room temperature and stirred overnight. The liquid were separated, and the aqueous layer was extracted with dichloromethane. The combined organic phases were washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was subjected to high performance liquid chromatography to obtain compound 8 (5 mg, 25%) as a white solid. LC-MS (ESI): m/z=319.1 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.65 (s, 1H), 8.38 (s, 1H), 7.72-7.81 (m, 3H), 7.55 (s, 1H), 7.52 (d, J=9.5 Hz, 1H), 7.32 (s, 1H), 7.17 (d, J=7.5 Hz, 1H), 2.12 (s, 3H).

(65) Synthetic Route of Compound 9

(66) ##STR00070##

(67) Synthesis of Compound 9-c

(68) Compound 1-c (1.2 g, 5.4 mmol), benzophenone imine (1.47 g, 8.1 mmol), sodium tert-butoxide (1.04 g, 10.81 mmol), Pd.sub.2(dba).sub.3 (247.4 mg, 0.27 mmol), 1,1′-binaphthalene-2,2′-bisdiphenylphosphine (336 mg, 0.54 mmol) and toluene (40 mL) were added to a reaction flask. The reaction solution was replaced with N.sub.2 and stirred at 100° C. for one hour. After the reaction was completed, it was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, then filtered and the filtrate was dried by rotary evaporation to obtain a black oil. Dilute hydrochloric acid (2M, 10 mL) was added, the reaction solution was stirred for half an hour, neutralized with solid sodium bicarbonate to pH>7, and extracted with dichloromethane. The organic phase was dried, concentrated, and the resulting crude product was subjected to silica gel column chromatography to obtain solid 9-c (0.5 g, 59%). LC-MS (ESI): m/z=159.1 [M+H].sup.+.

(69) Synthesis of Compound 9-b

(70) Compound 6-methyl-2-pyridinecarbaldehyde (200 mg, 1.26 mmol), 9-c (200 mg, 1.26 mmol), methanol (10 mL) and a few drops of formic acid were added to a reaction flask. The reaction solution was stirred at room temperature overnight. After the reaction was completed, it was concentrated, and the resulting solid was washed with ethyl acetate and dried to obtain product 9-b (0.2 g, 61%) which was solid. LC-MS (ESI): m/z=262.1 [M+H].sup.+.

(71) Synthesis of Compound 9

(72) Compound 9-b (50 mg, 0.19 mmol), p-toluenesulfonylmethylisonitrile (56 mg, 0.287 mmol), potassium carbonate (56 mg, 0.4 mmol), DMF (4.6 mL) and ethylene glycol dimethyl ether (3.75 mL) were added to a reaction flask. The reaction solution was replaced with N2 and stirred at 100° C. for 2 hours. After the reaction was completed, it was concentrated and the resulting oil was re-dissolved in dimethyl sulfoxide (2 mL). Under ice bath, 30% hydrogen peroxide (24.9 mg, 0.73 mmol) was added dropwise to the solution. The mixture was heated to room temperature and stirred overnight. After the reaction was completed, it was filtered, and the filtrate was subjected to high performance liquid chromatography to obtain 9 (15 mg, 26%) as a white solid. LC-MS (ESI): m/z=319.0 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOD): δ 9.70 (s, 1H), 8.38 (s, 1H), 8.09 (s, 1H), 7.73 (d, J=9.2, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.46 (dd, J=9.6, 2.0 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.11 (t, J=8.0 Hz, 1H), 2.21 (s, 3H).

(73) Synthetic Route of Compound 10

(74) ##STR00071##

(75) Synthesis of Compound 10-c

(76) At room temperature, concentrated hydrochloric acid (2.0 mL) was added to a solution of 6-trifluoromethylpyridine-2-carboxylic acid (1.91 g, 10.0 mmol) in methanol (20 mL), and the mixture was stirred at 80° C. overnight. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was dissolved in ethyl acetate (100 mL) solution. The solution was washed with saturated sodium bicarbonate solution (50 mL), then washed with sodium chloride (50 mL), and dried over anhydrous sodium sulfate, then filtered and concentrated to obtain 10-c (1.89 g, 92%) as a white solid. LC-MS (ESI): m/z=206.1 [M+H].sup.+.

(77) Synthesis of Compound 10-b

(78) A solution of 10-c (800 mg, 3.9 mmol) in tetrahydrofuran (10 mL) was cooled to −78° C., and after stirring for 10 minutes, DIBAL-H (5.8 mL, 5.8 mmol, 1.0 M in toluene) was added dropwise. After stirring the solution at −78° C. for 1 hour, the reaction was quenched by addition of methanol (2.0 mL). The reaction solution was diluted with sodium bicarbonate solution (30 mL), extracted with ethyl acetate (30 mL*3) and washed with saline (50 mL), and then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain 10-b (142 mg, 21%) as a pale yellow solid. LC-MS (ESI): m/z=176.0 [M+H].sup.+.

(79) Synthesis of Compound 10-a

(80) 10-b (142 mg, 0.81 mmol) and 9-c (128 mg, 0.81 mmol) were dissolved in methanol (8 mL), a drop of formic acid was added, and the mixture reacted for 3 hours at room temperature. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was washed with petroleum ether/ethyl acetate (1/1) to obtain 10-a (174 mg, 68%) as a brown solid. LC-MS (ESI): m/z=316.0 [M+H].sup.+.

(81) Synthesis of Compound 10

(82) Under nitrogen atmosphere, 10-a (174 mg, 0.55 mmol), a solution of p-toluenesulfonylmethylisonitrile (162 mg, 0.83 mmol) and potassium carbonate (160 mg, 1.16 mmol) in DMF/DME (2 mL/1.67 mL) was heated to 100° C. and stirred overnight. After the reaction was completed, one third of the reaction solution was taken for filtration, and the crude product was purified by Prep-HPLC to obtain 10 (15 mg+60 mg crude product, 38%) as a white solid. LC-MS (ESI): m/z=355.0 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ8.92 (t, 1H, J=1.0 Hz), 8.38 (s, 1H), 8.13 (s, 1H), 8.05-8.02 (m, 2H), 7.89 (s, 1H), 7.82 (q, 1H, J=0.5, 9.5 Hz), 7.61-7.55 (m, 2H).

(83) Synthetic Route of Compound 11

(84) ##STR00072##

(85) Synthesis of Compound 11

(86) 30% Hydrogen peroxide (1 mL) was added to 10 (60 mg, 0.17 mmol) the remaining two-thirds of the DMF/DME reaction solution and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered. The crude product was purified by Prep-HPLC to obtain 11 (38 mg, 60%) as a white solid. LC-MS (ESI): m/z=373.0 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ9.55 (s, 1H), 8.42 (s, 1H), 8.17 (s, 1H), 8.06 (s, 3H), 7.92 (s, 1H), 7.74 (d, 1H, J=8.5 Hz), 7.63 (s, 1H), 7.46 (d, 2H, J=9.5 Hz).

(87) Synthetic Route of Compound 13

(88) ##STR00073##

(89) Synthesis of Compound 13-c

(90) Mixture of imidazo[1,2-a]pyridine-6-carboxylic acid (4.86 g, 30.0 mmol) was dissolved in dichloromethane (250 mL). Under ice bath, oxalyl chloride (10 mL) was added to the solution, then DMF (0.5 mL) was slowly added to the reaction solution. The reaction mixture was raised to room temperature and was continued for 4 hours. The reaction solution was concentrated to dryness under reduced pressure, and then diluted with dichloromethane (300 mL). Under ice bath, triethylamine (50 mL) and N,O-dimethylhydroxylamine hydrochloride (6 g, 60.0 mmol) were slowly added to the reaction solution dropwise. The solution was reacted at 0° C. for 10 minutes, and then heated to room temperature and stirred for 2 hours. The dichloromethane was removed through concentration, and then water (100 mL) was added to the aqueous phase to dilute. The solution was stirred vigorously for 1 hour. Finally, the reaction solution was filtered. The filter cake was washed with water and dried to obtain 13-c (4.6 g, 75%) as a white solid. LC-MS (ESI): m/z=206.1 [M+H].sup.+.

(91) Synthesis of Compound 13-b

(92) Mixture of 2,6-dimethylpyridine (8.6 g, 80.0 mmol) was dissolved in tetrahydrofuran (200 mL). Under dry ice bath at −78° C., n-butyllithium (2.5 M, 32 mL, 80.0 mmol) was slowly added dropwise to the solution. The reaction was continued for 2 hours at this temperature. 13-c (4.2 g, 20.0 mmol) was added to the reaction solution. The mixture was reacted at −78° C. for 10 minutes and then raised to room temperature and stirred for 0.5 hour. The organic phase was concentrated and subjected to column chromatography (P/E=3/1) to obtain 13-b as a yellow solid (2.8 g, 56%). LC-MS (ESI): m/z=252.1 [M+H].sup.+.

(93) Synthesis of Compound 13-a

(94) A mixture of compound 13-b (0.5 g, 2.0 mmol) and DMF-DMA (1 mL) was heated to 100° C. After 3 hours of reaction, the mixture was concentrated to obtain the compound 13-a, which was directly used in the next reaction. LC-MS (ESI): m/z=307.3 [M+H].sup.+.

(95) Synthesis of Compound 13

(96) A mixture of compound 13-a (0.62 g, 2.0 mmol), hydroxylamine hydrochloride (0.84 g, 12.0 mmol) and ethanol (10 mL) was heated to 100° C. for 3 hours and concentrated. Saturated sodium bicarbonate (100 mL) was added to the product to alkalize it, and the solution was stirred vigorously for 1 hour. Finally, the reaction solution was filtered. The filter cake was washed with water and dried to obtain solid 13 (0.5 g, 91%). LC-MS (ESI): m/z=277.1 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.36 (s, 1H), 8.88 (s, 1H), 7.98 (s, 1H), 7.77 (t, J=7.5 Hz, 1H), 7.64 (d, J=9.5 Hz, 1H), 7.60 (dd, J=2.0, 9.5 Hz, 2H), 7.46 (d, J=7.5 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 2.59 (s, 3H).

(97) Synthetic Route of Compound 14

(98) ##STR00074##

(99) Synthesis of Compound 14

(100) A mixture of compound 13 (0.14 g, 0.5 mmol), NBS (0.1 g, 0.56 mmol) and dichloromethane (10 mL) was reacted at room temperature for 3 hours and concentrated. Water (10 mL) was added to the product and the solution was stirred vigorously for 1 hour. The solution was filtere and the filter cake was washed with water and dried to obtain solid 14 (0.18 g, 100%). LC-MS (ESI): m/z 355 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOD): δ 9.24 (s, 1H), 8.91 (s, 1H), 7.81 (m, 3H), 7.73 (d, J=6.4 Hz, 1H), 7.51 (d, J=6.0 Hz, 1H), 7.32 (d, J=6.0 Hz, 1H), 2.63 (s, 3H).

(101) Synthetic Route of Compound 15

(102) ##STR00075##

(103) Synthesis of Compound 15

(104) A mixture of the compounds zinc cyanide (0.12 g, 1.0 mmol), 14 (0.15 g, 0.42 mmol), tetratriphenylphosphine palladium (0.115 g, 0.1 mmol) and DMF (10 mL) was heated to 150° C. and reacted for 48-hours in a sealed tube under nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated, and dilute hydrochloric acid (10 mL, 30 mmol) and ethyl acetate (300 mL*3) were added for extraction. The solution was basified to pH to 8 with aqueous solution of sodium bicarbonate and filtered. The filter cake was dried and purified by preparative high-performance liquid chromatography to obtain compound 15 (0.006 g, 3.7%) as a pale yellow solid. LC-MS (ESI): m/z=320.0 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 10.03 (s, 1H), 8.25 (s, 1H), 7.93 (t, J=8.0 Hz, 1H), 7.83 (dd, J=9.0, 1.5 Hz, 1H), 7.64 (d, J=9.5 Hz, 1H), 7.54 (d, J=9.5 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 2.57 (s, 3H).

(105) Synthetic Route of Compound 16

(106) ##STR00076##

(107) Compound 13 (0.276 g, 1.0 mmol), Pd/C (0.1 g) and ethanol (10 mL) were mixed at room temperature. After being replaced with hydrogen, the mixture was stirred and reacted at room temperature for 3 hours, then filtered and concentrated to obtain solid 16-a (0.26 g, 94%). LC-MS (ESI): m/z=279.1 [M+H].sup.+.

(108) Compound 16-a (0.26 g, 0.93 mmol), iodine (0.5 g, 2.0 mmol), P.sub.2S.sub.5 (0.44 g, 2.0 mmol) and dichloromethane (60 mL) were mixed at room temperature, and the reaction was stirred at room temperature for 24 hours. The reaction was quenched with saturated sodium bisulfite (60 mL), extracted with dichloromethane (100*3 mL), and the organic phase was concentrated and subjected to column chromatography (P/E=1/3) to obtain solid 16 (0.05 g, 18%). LC-MS (ESI): m/z=293.0 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 8.84 (s, 1H), 8.76 (s, 1H), 7.93 (s, 1H), 7.70 (t, J=6.0 Hz, 1H), 7.65 (d, J=1.5H, 1H), 7.56 (d, J=9.5 Hz, 1H), 7.27 (s, 1H), 7.26 (s, 1H), 7.15 (d, J=9.5, 1.5 Hz, 1H), 2.53 (s, 3H).

(109) Synthetic Route of Compound 17

(110) ##STR00077##

(111) Synthesis of Compound 17-c

(112) A mixture of compound 1-d (7.2 g, 30.1 mmol), diborate (22.86 g, 90 mmol), potassium acetate (8.82 g, 90 mmol), Pd(dppf)Cl.sub.2 (0.43 g, 0.53 mmol) and dry dioxane (80 mL) was heated to 100° C. and reacted for 3 hours under nitrogen atmosphere. The reaction was cooled to room temperature and concentrated. Water (200 mL) was added and stirred, then filtered and the filter cake was dried. The obtained solid was dissolved in ethyl acetate (200 mL), and a saturated ethyl acetate hydrochloric acid solution (20 mL) was added under stirring, then filtered and the filter cake was dried to obtain compound 17-c (5.96 g, 97%). LC-MS (ESI): m/z=206 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): δ 9.96 (s, 1H), 8.54 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H).

(113) Synthesis of Compound 17-b

(114) 2,3-Dibromothiophene (500 mg, 2.07 mmol), 17-c (424 mg, 2.07 mmol), tetrakis(triphenylphosphine) palladium (120 mg, 0.1 mmol), sodium carbonate (878 mg, 8.28 mmol), 1,4-dioxane (20 mL) and water (5 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 100° C. overnight. After the reaction was completed, the organic solvent was removed through concentration, and the crude product was purified by column chromatography (DCM:MeOH=30:1) to obtain compound 17-b (0.27 g, 41%) as a white solid. LC-MS (ESI): m/z=321.8 [M+H].sup.+.

(115) Synthesis of Compound 17-a

(116) 17-b (0.27 g, 0.84 mmol), bis(pinacolato)diboron (255 mg, 1 mmol), Pd(dppf)Cl.sub.2 (31 mg, 0.042 mmol), potassium acetate (165 mg), 1.68 mmol), 1,4-dioxane (10 mL) and toluene (10 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 90° C. overnight. After the reaction was completed, the organic solvent was removed through concentration, and the crude product was purified by column chromatography (DCM:MeOH=20:1) to obtain compound 17-a (0.22 g, 71%) as a yellow solid. LC-MS (ESI): m/z=370.0 [M+H].sup.+.

(117) Synthesis of Compound 17

(118) 17-a (0.22 g, 0.59 mmol), 2-bromo-6-methylpyridine (123 mg, 0.72 mmol), tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol), sodium carbonate (126 mg, 1.19 mmol), 1,4-dioxane (15 mL) and water (3 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 90° C. overnight. After the reaction was completed, the organic solvent was removed through concentration, and the crude product was purified by Prep-HPLC to obtain compound 17 (45 mg, 23%) as a white solid. LC-MS (ESI): m/z=335.0 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO): δ 9.61 (s, 1H), 8.35 (s, 1H), 7.99 (brs, 1H), 7.71 (d, J=5.0 Hz, 1H), 7.65 (d, J=9.5 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.52 (d, J=5.0 Hz, 1H), 7.41 (brs, 1H), 7.25 (dd, J=9.5, 1.5 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 2.38 (s, 3H).

(119) Synthetic Route of Compound 18

(120) ##STR00078##

(121) Synthesis of Compound 18-c

(122) 4-Bromo-2-methylthiophene (1 g, 5.65 mmol), DMF (5 mL) and NB S (1.1 g, 6.18 mmol) were added to a reaction flask, and the mixture reacted at room temperature overnight. Water (30 mL) was added to the mixture, and then the mixture was extracted with petroleum ether (30 mL). The organic phase was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solution was removed by rotary evaporation, the crude product was purified by column chromatography (using pure petroleum ether as mobile phase) to obtain compound 18-c (1.25 g, 86%) as a yellow liquid. .sup.1H NMR (500 MHz, CDCl.sub.3): δ 6.59 (d, J=1.1 Hz, 1H), 2.41 (d, J=1.0 Hz, 3H).

(123) Synthesis of Compound 18-b

(124) 18-c (1 g, 3.9 mmol), 17-c (801 mg, 3.9 mmol), tetrakis(triphenylphosphine) palladium (225 mg, 0.20 mmol), sodium carbonate (1.65 g, 15.6) mmol), 1,4-dioxane (30 mL) and water (5 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 100° C. overnight. After the reaction was completed, the organic solvent was removed through concentration and the crude product was purified by column chromatography (DCM:MeOH=20:1) to obtain compound 18-b (0.51 g, 39%) as a yellow solid. LC-MS (ESI): m/z=335.9 [M+H].sup.+.

(125) Synthesis of Compound 18-a

(126) 18-b (0.51 g, 1.52 mmol), bis(pinacolato)diboron (0.46 g, 1.82 mmol), Pd(dppf)Cl.sub.2 (56 mg, 0.076 mmol), potassium acetate (298 mg, 3.04 mmol), 1,4-dioxane (30 mL) and toluene (20 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 90° C. overnight. After the reaction was completed, the organic solvent was removed through concentration and the crude product was purified by column chromatography (DCM:MeOH=20:1) to obtain compound 18-a (0.46 g, 79%) as a black solid. LC-MS (ESI): m/z=384.1 [M+H]

(127) Synthesis of Compound 18

(128) 18-a (0.46 g, 1.2 mmol), 2-bromo-6-methylpyridine (0.25 g, 1.44 mmol), tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol), sodium carbonate (254 mg, 2.4 mmol), 1,4-dioxane (15 mL) and water (3 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 90° C. overnight. After the reaction was completed, the organic solvent was removed through concentration and the crude product was purified by Prep-HPLC to obtain compound 18 (70 mg, 17%) as a yellow solid. LC-MS (ESI): m/z=349.0 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 9.56 (s, 1H), 8.34 (s, 1H), 7.96 (brs, 1H), 7.63 (d, J=9.5 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.37 (brs, 1H), 7.23 (d, J=1.0 Hz, 1H), 7.21 (dd, J=9.5, 2.0 Hz, 1H), 7.10 (t, J=7.0 Hz, 2H), 2.52 (s, 3H), 2.37 (s, 3H).

(129) Synthetic Route of Compound 19

(130) ##STR00079##

(131) Synthesis of Compound 19-d

(132) 3-Bromo-2-methoxypyridine (2 g, 10.6 mmol), bis(pinacolato)diboron (2.74 g, 12.8 mmol), Pd(dppf)Cl.sub.2 (388 mg, 0.53 mmol), potassium acetate (2.08 g, 21.2 mmol) and toluene (20 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 90° C. overnight. After the reaction was completed, the mixture was concentrated, and water (20 mL) was added. The solution was extracted with ethyl acetate (30 mL*2), and the organic phase was dried over anhydrous sodium sulfate. After the organic phase was filtered and concentrated, the crude product was purified by column chromatography (PE:EA=4:1) to obtain crude compound 19-d (2.2 g, 88%) as a yellow oil. LC-MS (ESI): m/z=236.1[M+H]

(133) Synthesis of Compound 19-c

(134) 2-bromo-6-methylpyridine (0.9 g, 5.23 mmol), 19-d (1.6 g, 6.8 mmol), Pd(dppf)Cl.sub.2 (191 mg, 0.26 mmol), sodium carbonate (1.11 g, 10.46 mmol), 1,4-dioxane (20 mL) and water (4 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 80° C. overnight. After the reaction was completed, the mixture was concentrated, and water (20 mL) was added. The solution was extracted with ethyl acetate (30 mL*2), and the organic phase was dried over anhydrous sodium sulfate, then filtered and concentrated, the crude product was purified by column chromatography (PE:EA=30:1) to obtain compound 19-c (0.97 g, 92%) as a yellow solid, LC-MS (ESI): m/z=201.1 [M+H].sup.+.

(135) Synthesis of Compound 19-b

(136) 19-c (0.97 g, 4.84 mmol) was dissolved in dichloromethane (15 mL), cooled in dry ice acetone bath, and a solution of boron tribromide in dichloromethane (1.0 M, 14.5 mL, 14.5 mmol) was slowly added. The temperature was slowly raised to room temperature. After reacting overnight, the reaction was quenched by adding saturated sodium bicarbonate aqueous solution. The solution was extracted with dichloromethane (30 mL*2), and the organic phase was dried over anhydrous sodium sulfate. After the organic phase was filtered and concentrated, the crude product was purified by column chromatography (PE:EA=5:1 to DCM:MeOH=30:1) to obtain compound 19-b (0.33 g, 37%) as a yellow solid. LC-MS (ESI): m/z=187.3 [M+H].sup.+.

(137) Synthesis of Compound 19-a

(138) 19-b (0.33 g, 1.77 mmol) and pyridine (0.7 g, 8.85 mmol) were dissolved in dichloromethane (10 mL), cooled in ice water bath, and trifluoromethanesulfonic anhydride (1 g, 3.54 mmol) was slowly added. The mixture was stirred at room temperature overnight. After concentration, the crude product was purified by column chromatography (PE:EA=5:1) to obtain compound 19-a (415 mg, 74%) as a yellow oil. LC-MS (ESI): m/z=319.1[M+H].sup.+.

(139) Synthesis of Compound 19

(140) 19-a (215 mg, 0.68 mmol), 17-c (166 mg, 0.81 mmol), tetrakis(triphenylphosphine) palladium (39 mg, 0.034 mmol), sodium carbonate (144 mg, 1.36 mmol), toluene (6 mL), ethanol (6 mL) and water (3 mL) were added to a reaction flask. The reaction mixture was replaced with N2 and reacted at 90° C. overnight. After the reaction was completed, the organic solvent was removed through concentration. Water (20 mL) was added, and the solution was extracted with ethyl acetate (30 mL). The organic phase was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solution was dried by rotary evaporation. The crude product was purified by Prep-HPLC to obtain compound 19 (88 mg, 40%) as a white solid. LC-MS (ESI): m/z=330.1 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 9.63 (s, 1H), 8.77 (dd, J=4.5, 1.5 Hz, 1H), 8.33 (s, 1H), 8.04 (dd, J=7.5, 1.5 Hz, 1H), 7.93 (brs, 1H), 7.55-7.61 (m, 2H), 7.37 (brs, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.13 (dd, J=9.5, 1.5 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 2.43 (s, 3H).

(141) Synthetic Route of Compound 20

(142) ##STR00080##

(143) Synthesis of Compound 20-a

(144) Compound 20-a was prepared according to the synthetic route of 17-c by using 1-e as the raw material.

(145) Synthesis of Compound 20

(146) 19-a (200 mg, 0.63 mmol), 20-a (208 mg, 0.69 mmol), tetrakis(triphenylphosphine)palladium (36 mg, 0.032 mmol), sodium carbonate (133 mg, 1.26 mmol), toluene (6 mL), ethanol (6 mL) and water (3 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 90° C. overnight. After the reaction was completed, the organic solvent was removed through concentration. Water (30 mL) was added, and the solution was extracted with ethyl acetate (30 mL). The organic phase was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solution was dried by rotary evaporation. The crude product was purified by Prep-HPLC to obtain compound 20 (52 mg, 24%) which was white solid. LC-MS (ESI): m/z=344.1 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 9.65 (s, 1H), 8.76 (dd, J=4.5, 1.5 Hz, 1H), 8.38-8.48 (m, 1H), 8.26 (s, 1H), 8.04 (dd, J=7.5, 1.5 Hz, 1H), 7.61-7.55 (m, 2H), 7.51 (d, J=8.5 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.11-7.05 (m, 2H), 2.80 (d, J=4.5 Hz, 3H), 2.43 (s, 3H).

(147) Synthetic Route of Compound 21

(148) ##STR00081##

(149) Synthesis of Compound 21-c

(150) 3-Bromo-1-methylpyrrole (310 mg, 1.93 mmol), 19-d (543 mg, 2.31 mmol), Pd(dppf)Cl.sub.2 (70 mg, 0.095 mmol), sodium carbonate (403 mg, 3.8 mmol), 1,4-dioxane (20 mL) and water (4 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 90° C. overnight. After the reaction was completed, the mixture was concentrated. Water (20 mL) was added, and the solution was extracted with ethyl acetate (30 mL*2). The organic phase was dried over anhydrous sodium sulfate. After filtration, the solution was concentrated. The crude product was purified by column chromatography (PE:EA=5:1) to obtain compound 21-c (200 mg, 55%) as a yellow solid. LC-MS (ESI): m/z=190.1 [M+H].sup.+.

(151) Synthesis of Compound 21-b

(152) 21-c (200 mg, 1.06 mmol) was dissolved in dichloromethane (10 mL), cooled in dry ice acetone bath, and a solution of boron tribromide in dichloromethane (1.0 M, 2.11 mL, 2.11 mmol) was slowly added. The temperature was slowly raised to room temperature. After reacting overnight, the reaction was quenched by adding saturated sodium bicarbonate aqueous solution. The solution was extracted with dichloromethane (30 mL*2), and the aqueous phase was dried by rotary evaporation. Dichloromethane (20 mL) was added, and the solution was filtered. The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the solution was concentrated. The crude product was purified by column chromatography (DCM:MeOH=20:1) to obtain compound 21-b (139 mg, 74%) as a yellow solid. LC-MS (ESI): m/z=176.1[M+H].sup.+.

(153) Synthesis of Compound 21-a

(154) 21-b (139 mg, 0.79 mmol) and pyridine (312 mg, 3.95 mmol) was dissolved in dichloromethane (10 mL), cooled in ice water bath, and trifluoromethanesulfonic anhydride (448 mg, 0.267 mL, 1.59 mmol) was slowly added, the mixture was stirred at room temperature overnight. After concentration, the crude product was purified by column chromatography (PE:EA=1:1) to obtain compound 21-a (244 mg, 100%) as a yellow oil. LC-MS (ESI): m/z=308.0 [M+H].sup.+.

(155) Synthesis of Compound 21

(156) 21-a (244 mg, 0.79 mmol), 17-c (195 mg, 0.95 mmol), tetrakis(triphenylphosphine) palladium (46 mg, 0.040 mmol), sodium carbonate (167 mg, 1.58 mmol), toluene (8 mL), ethanol (8 mL) and water (4 mL) were added to a reaction flask. The reaction mixture was replaced with N2 and reacted at 90° C. overnight. After the reaction was completed, the organic solvent was removed through concentration. Water (20 mL) was added, and the solution was extracted with ethyl acetate (30 mL*2). The organic phase was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solution was dried by rotary evaporation. The crude product was purified by Prep-HPLC to obtain compound 21 (90 mg, 36%) as a white solid. LC-MS (ESI): m/z=319.1 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 9.68 (s, 1H), 8.67 (dd, J=4.5, 1.5 Hz, 1H), 8.36 (s, 1H), 8.07 (dd, J=8.0, 1.5 Hz, 1H), 7.98 (brs, 1H), 7.64-7.59 (m, 2H), 7.51 (dd, J=8.0, 4.5 Hz, 1H), 7.40 (brs, 1H), 7.28 (dd, J=9.5, 1.5 Hz, 1H), 5.91 (d, J=2.2 Hz, 1H), 3.83 (s, 3H).

(157) Synthetic Route of Compound 22

(158) ##STR00082##

(159) Synthesis of Compound 22-c

(160) Compound 2-bromo-4-methylthiazole (225 mg, 1.26 mmol), 19-d (440 mg, 1.87 mmol), Pd(dppf)Cl.sub.2 (92 mg, 0.12 mmol), Na.sub.2CO.sub.3 (265 mg, 2.5 mmol), dioxane (15 mL) and water (3 mL) were added to a reaction flask. The reaction solution was replaced with N.sub.2 and stirred at 80° C. overnight. The reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (PE:EA=10:1) to obtain product 22-c (225 mg, 86%) as a yellow solid. LC-MS (ESI): m/z=207.1 [M+H].sup.+.

(161) Synthesis of Compound 22-b

(162) Compound 22-c (225 mg, 1.1 mmol) was dissolved in dry dichloromethane (10 mL), cooled to −78° C. in dry ice/acetone bath, and dichloromethane solution of boron tribromide (1.0M, 1.2 mL, 1.2 mmol) was slowly added to a reaction bottle. After the completion of the addition, the temperature of the reaction solution was slowly raised to room temperature and the solution was stirred overnight. The reaction solution was slowly added dropwise with saturated sodium bicarbonate aqueous solution under ice bath to separate the organic phase. The aqueous layer was extracted with dichloromethane (30 mL*2), dried over anhydrous sodium sulfate, and concentrated to obtain compound 22-b as a yellow solid (100 mg, 48%). LC-MS (ESI): m/z=324.9 [M+H].sup.+.

(163) Synthesis of Compound 22-a

(164) 22-b (100 mg, 0.52 mmol) and pyridine (123 mg, 1.56 mmol) were dissolved in dichloromethane (15 mL), cooled in ice water bath, and trifluoromethanesulfonic anhydride (220 mg, 0.78 mmol) was slowly added. After the mixture was stirred at room temperature overnight, the mixture was concentrated. Water (20 mL) was added, and the solution was extracted with dichloromethane (20 mL*2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by Prep-TLC (PE:EA=10:1) to obtain compound 22-a (20 mg, 12%) as a yellow solid. LC-MS (ESI): m/z=324.9 [M+H].sup.+.

(165) Synthesis of Compound 22

(166) 22-a (20 mg, 0.06 mmol), 17-c (13 mg, 0.06 mmol), Pd(dppf)Cl.sub.2 (4 mg, 0.006 mmol), sodium carbonate (13 mg, 0.12 mmol), 1,4-dioxane (10 mL) and water (2 mL) were added to a reaction flask. The reaction mixture was replaced with N2 and reacted at 80° C. overnight. After the reaction was completed, it was concentrated, and the crude product was purified by Prep-HPLC to obtain compound 22 (4 mg, 20%) as a white solid. LC-MS (ESI): m/z=336.0 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOD) δ 9.72 (s, 1H), 8.79 (dd, J=4.8, 1.6 Hz, 1H), 8.38-8.27 (m, 2H), 7.73-7.60 (m, 2H), 7.49 (dd, J=9.3, 1.8 Hz, 1H), 7.21 (s, 1H), 2.41 (s, 3H).

(167) Synthetic Route of Compound 23

(168) ##STR00083##

(169) Synthesis of Compound 23-c

(170) 2-Cyano-3-hydroxypyridine (500 mg, 4.16 mmol), diethyl dithiophosphate (853 mg, 4.58 mmol) and water (6 mL) were added to a 20 mL microwave tube. The microwave tube was sealed, and the reaction solution was stirred at 90° C. overnight. After the reaction was completed, the mixture was filtered, and the filter cake was dried to obtain compound 23-c (535 mg, 83%) as a yellow solid. LC-MS (ESI): m/z=155.1 [M+H]+; .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 12.85 (s, 1H), 10.02-10.39 (m, 2H), 8.18 (dd, J=4.0, 1.5 Hz, 1H), 7.55 (dd, J=8.5, 4.0 Hz, 1H), 7.46 (dd, J=8.5, 1.5 Hz, 1H).

(171) Synthesis of Compound 23-b

(172) Compound 23-c (500 mg, 3.24 mmol), chloroacetone (0.52 mL, 6.49 mmol) and ethanol (20 mL) were added to a reaction flask. The reaction solution was heated to reflux and stirred overnight. After the reaction was completed and concentrated, the crude product was separated by silica gel column chromatography (PE:EA=5:1) to obtain product 23-b (0.55 g, 88%) as a white solid. LC-MS (ESI): m/z=193.0 [M+H].sup.+.

(173) Synthesis of Compound 23-a

(174) Pyridine (93 mg, 1.17 mmol) and 23-b (150 mg, 0.78 mmol) was dissolved in dichloromethane (10 mL), cooled in ice water bath, and trifluoromethanesulfonic anhydride (0.2 mL, 1.17 mmol) was slowly added. The mixture was stirred at room temperature overnight. Water (10 mL) was added, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL*2). The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=5:1) to obtain compound 23-a (150 mg, 59%). LC-MS (ESI): m/z=325.0 [M+H].sup.+.

(175) Synthesis of Compound 23

(176) 23-a (150 mg, 0.46 mmol), 17-c (94.8 mg, 0.46 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (33.8 mg, 0.046 mmol), sodium carbonate (147.1 mg, 1.39 mmol), dioxane (10.0 mL) and water (2.0 mL) were added to a reaction flask. The reaction solution was replaced with N.sub.2 and reacted at 85° C. overnight. After the reaction was completed, the solution was concentrated to obtain a crude product. The crude product was separated by high performance liquid preparative chromatography to obtain product 23 (75 mg, 48%) as a white solid. LC-MS (ESI): m/z=336.0 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 9.47 (s, 1H), 8.72 (dd, J=4.5, 1.5 Hz, 1H), 8.37 (s, 1H), 8.00 (brs, 1H), 7.97 (dd, J=7.5, 2.5 Hz, 1H), 7.65 (d, J=9.0 Hz, 1H), 7.60 (dd, J=8, 4.5 Hz, 1H), 7.40 (brs, 1H), 7.35 (dd, J=9.0, 1.5 Hz, 1H), 7.33 (s, 1H), 2.05 (s, 3H).

(177) Synthetic Route of Compound 24

(178) ##STR00084##

(179) Synthesis of Compound 24-c

(180) A mixture of compound 24-d (2.2 g, 10.0 mmol), benzophenonimine (1.8 g, 10.0 mmol), Pd.sub.2(dba).sub.3 (0.23 g, 0.4 mmol), BINAP (0.25 g, 0.4 mmol), sodium tert-butoxide (2.0 g, 20.0 mmol) and toluene (100 mL) was heated to 100° C. and reacted for 1 hour under nitrogen atmosphere. The reaction was cooled to room temperature and concentrated. Dilute hydrochloric acid (100 mL, 300 mmol) and ethyl acetate (30 mL*3) were added for extraction. The aqueous phase was basified to pH to 8 by aqueous sodium bicarbonate solution, filtered and the filter cake was dried to obtain 24-c (1.28 g, 80%) as a gray solid. LC-MS (ESI): m/z=159.1 [M+H].sup.+.

(181) Synthesis of Compound 24-b

(182) A mixture of compound 24-c (0.16 g, 1.0 mmol), methanol (20 mL), 1-methylpyrrole-3-carbaldehyde (0.14 g, 1.27 mmol) and formic acid (0.20 mL) was stirred at room temperature for 3 hours. The reaction solution was concentrated, and ethyl acetate (5 mL) and petroleum ether (30 mL) were added. The solution was filtered to obtain solid 24-b (0.25 g, 100%). LC-MS (ESI): m/z=251.1 [M+H].sup.+.

(183) Synthesis of Compound 24-a

(184) A mixture of compound p-toluenesulfonylmethylisonitrile (0.38 g, 2.0 mmol), 24-b (0.25 g, 1.0 mmol), potassium carbonate (0.28 g, 2.0 mmol), DME (4 mL) and DMF (10 mL) was heated to 100° C. for 12 hours in a sealed tube under nitrogen atmosphere. The reaction was cooled to room temperature and concentrated, then washed with ethyl acetate (300 mL). After filtration, the solution was concentrated to obtain compound 24-a, which was directly used in the next step. LC-MS (ESI): m/z=290.2 [M+H].sup.+.

(185) Synthesis of Compound 24

(186) 30% H.sub.2O.sub.2 (3 mL) was slowly added dropwise to a mixture of compound 24-a (0.14 g, 0.5 mmol), DMSO (4 mL) and potassium carbonate (0.138 g, 1.0 mmol) at 0° C. After reacting for 3 hours, the solution was concentrated, then diluted with water (10 mL) and filtered. The filter cake was slurried with ethyl acetate (10 mL) to obtain 24 (0.059 g, 38%) as a gray solid. LC-MS (ESI): m/z=308.0 [M+H]+; .sup.1H NMR (500 MHz, MeOD): δ 9.72 (d, J=1.5 Hz, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.75 (d, J=9.5 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.48 (dd, J=9.5, 2.0 Hz, 1H), 7.39 (s, 1H), 6.17 (d, J=2.5 Hz, 1H), 3.81 (s, 3H).

(187) Synthetic Route of Compound 25

(188) ##STR00085##

(189) Synthesis of Compound 25-d

(190) Boc-indole-2-boronic acid (1.4 g, 5.36 mmol), 2-bromo-6-methylpyridine (922 mg, 5.36 mmol), Pd(dppf)Cl.sub.2 (438 mg, 0.54 mmol), sodium carbonate (1.7 g, 16.08 mmol), dioxane (10 mL) and water (2 mL) were added to a reaction flask. The reaction solution was replaced with N.sub.2 and reacted at 85° C. overnight. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate. After filtration, the solution was dried by rotary evaporation. The crude product was separated by silica gel column chromatography (PE:EA=10:1) to obtain the product 25-d (1 g, 60%) as a white solid. LC-MS (ESI): m/z=309.1 [M+H].sup.+.

(191) Synthesis of Compound 25-c

(192) 25-d (1 g, 3.24 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (10 mL), and the mixture was stirred at room temperature overnight. After the reaction was completed, the organic solvent was removed through concentration under reduced pressure, saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added, and the solution was separated. The aqueous layer was extracted with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 25-c (400 mg, 59%) as a white solid. LC-MS (ESI): m/z=209.1 [M+H].sup.+.

(193) Synthesis of Compound 25-a

(194) Compound 25-c (50 mg, 0.24 mmol), 1-c (53.3 mg, 0.24 mmol), cuprous iodide (5 mg, 0.024 mmol), N,N′-dimethyl-1,2-ethanediamine (4.2 mg, 0.048 mmol), potassium phosphate (102 mg, 0.48 mmol) and toluene (2 mL) were added to a reaction flask. The reaction solution was replaced with N.sub.2 and stirred at 110° C. overnight. After the reaction was completed, it was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate. After filtration, the solution was dried by rotary evaporation. The crude product was separated by silica gel column chromatography (PE:EA=1:1) to obtain compound 25-a (50 mg, 60%) as a white solid. LC-MS (ESI): m/z=350.1 [M+H].sup.+.

(195) Synthesis of Compound 25

(196) Under ice bath, hydrogen peroxide (19.5 mg, 0.57 mmol) was added dropwise to a solution of 25-a (50 mg, 0.143 mmol) and potassium carbonate (3 mg, 0.021 mmol) in dimethyl sulfoxide (2 mL). The mixture was raised to room temperature and stirred overnight. After the reaction was completed, water (5 mL) was slowly added to quench the reaction. The solution was stirred for half an hour and white precipitate was precipitated. After filtration, the solid was collected and dried to obtain compound 25 (10 mg, 19%) as a white solid. LC-MS (ESI): m/z=368.0 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.62 (d, J=1.5 Hz, 1H), 8.38 (s, 1H), 7.72-7.77 (m, 2H), 7.66 (t, J=7.5 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.47 (dd, J=9.5, 2.0 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.26 (t, J=7.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.18 (s, 1H), 7.09 (d, J=8.0 Hz, 1H), 2.23 (s, 3H).

(197) Synthetic Route of Comparative Compound 12

(198) ##STR00086##

(199) Synthesis of Compound 12-b

(200) Compound 6-bromo-[1,2,4]triazolo[1,5-a]pyridine (0.7 g, 3.54 mmol), benzophenonimine (961 mg, 5.30 mmol), sodium tert-butoxide (679.5 mg, 7.07 mmol), Pd.sub.2(dba).sub.3 (162 mg, 0.18 mmol), 1,1′-binaphthalene-2,2′-bisdiphenylphosphine (220 mg, 0.35 mmol) and toluene (40 mL) were added to a reaction flask. The reaction solution was replaced with N.sub.2 and stirred at 100° C. for one hour. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation to obtain a black oil. Dilute hydrochloric acid (2 M, 10 mL) was added to the black oil, the solution was stirred for half an hour, then neutralized with solid sodium bicarbonate to pH>7 and extracted with dichloromethane. The organic phase was dried, concentrated, and the resulting crude product was purified by silica gel column chromatography to obtain 12-b (0.3 g, 63%) as a brown solid. LC-MS (ESI): m/z=135.1 [M+H].sup.+.

(201) Synthesis of Compound 12-a

(202) Compound 6-methyl-2-pyridinecarboxaldehyde (45 mg, 0.37 mmol), 12-b (50 mg, 0.37 mmol), methanol (10 mL) and a few drops of formic acid were added to a reaction flask. The reaction solution was stirred at room temperature overnight. After the reaction was completed, the solid was washed with ethyl acetate and dried to obtain product 12-a (50 mg, 56%) as a white solid. LC-MS (ESI): m/z=238.1 [M+H].sup.+.

(203) Synthesis of Comparative Compound 12

(204) Compound 12-a (50 mg, 0.21 mmol), p-toluenesulfonylmethylisonitrile (62 mg, 0.32 mmol), potassium carbonate (61 mg, 0.44 mmol), DMF (4.6 mL) and ethylene glycol dimethyl ether (3.75 mL) were added to a reaction flask. The reaction solution was replaced with N.sub.2 and stirred at 100° C. overnight. After the reaction was completed, the mixture was filtered, and the filtrate was subjected to high performance liquid preparative chromatography to obtain solid 12 (15 mg, 26%). LC-MS (ESI): m/z=277.1 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.16 (s, 1H), 8.54 (s, 1H), 8.10 (s, 1H), 7.82 (d, J=9.5, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.62-7.66 (m, 2H), 7.49 (d, J=8.0 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 2.27 (s, 3H).

Effect Embodiment 1 Evaluation Experiment of ALK5 Enzyme Activity Inhibition IC.SUB.50

(205) 1×kinase buffer preparation: 40 mM Tris (pH 7.5), 20 mM MgCl.sub.2, 0.10% BSA, 1 mM DTT.

(206) Compound preparation: The final detection concentration of the compound was 10 μM, which was configurated to a 100-fold concentration, i.e., 1 mM. In the second well of the 384-well plate, 100 μL of 100-fold compound was added, and 60 μL of 100% DMSO was added to other wells. 30 μL of compound from the second well was taken and added to the third well, and a 3-fold dilution was made in sequence, a total of 10 concentrations were diluted. 50 nL of compound was transferred to the reaction plate with echo.

(207) Kinase reaction: Kinase was added to 1×kinase buffer to form a 2×enzyme solution. The final concentration of kinase solution was ALK5:25 nM. The polypeptide TGFbR1 (purchased from Signal Chem, catalog number T36-58) and ATP were added to 1×kinase buffer to form a 2×substrate solution. The final concentration of the substrate solution was 0.1 mg/mL peptide TGFbR1, 7 μM ATP. 2.5 μL of 2×enzyme solution was added to the 384-well reaction plate (there was already 50 nL of 100% DMSO dissolved compound), and 1×kinase buffer was added to the negative control well. The plate was incubated at room temperature for 10 minutes. 2.5 μL of 2× substrate solution was added to the 384-well reaction plate. The 384-well plate was covered and incubated at 30° C. for 1 hour. ADP-Glo reagent (purchased from Promege, catalog number v9102) was equilibrated to room temperature. 5 μL of ADP-Glo reagent was transferred to the reaction well of the 384-well plate to stop the reaction.

(208) Detection of reaction results: 10 μL of kinase detection reagent was transferred to each reaction well, the plate was shaken for 1 minute and placed at room temperature for 30 minutes. The sample luminescence value was read at Synegy.

(209) Curve fitting: The data of the luminescence reading from the Synegy program were copied. The value of the luminescence reading was converted into the percentage of inhibition by a formula (inhibition percent=(max-sample RLU)/(max-min)*100, wherein “min” was a fluorescence reading of the control sample without enzyme; “max” was the fluorescence reading of sample with DMSO as a control). The data were imported into MS Excel and GraphPad Prism was used for curve fitting. The ICso value was calculated.

(210) TABLE-US-00001 TABLE 1 IC.sub.50 results of some compounds of the present invention on ALK5 activity Compound ALK5 Compound ALK5 No. IC.sub.50 (nM) No. IC.sub.50 (nM) SB431542 108 1 13 4 19 5 105 8 7 9 136 16 165 17 5.2 18 9.4 19 75 20 76 23 21 25 14 Comparative 6111 compounds 12 Comparative >10000 / / compounds 10

(211) Wherein, SB431542 (CAS number: 301836-41-9) is a known ALK5 inhibitor, and its structure is as follows:

(212) ##STR00087##

(213) From the results of the above test, it can be confirmed that the compounds of the present invention have a significant inhibitory effect on ALK5 activity.

(214) Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only illustrative examples, and various changes or modification can be made to these embodiments without departing from the principle and essence of the present invention. Therefore, the protection scope of the present invention is defined by the appended claims.