Aromatic heterocyclic substituted olefin compound, preparation method for same, pharmaceutical composition of same, and applications thereof

Abstract

Provided in the present application are an aromatic heterocyclic substituted olefin compound, a preparation method for same, a pharmaceutical composition of same, and applications thereof. The aromatic heterocyclic substituted olefin compound of the present invention is a novel ALK5 inhibitor and is for use in treating and/or preventing various ALK5-mediated diseases. ##STR00001##

Claims

1. An aromatic heterocyclic substituted olefin compound represented by general formula I or a pharmaceutically acceptable salt thereof: ##STR00089## wherein ring A and ring B are located on the same side of the double bond; ##STR00090## is ##STR00091## R.sup.3, R.sup.31, R.sup.32, R.sup.33, R.sup.3a, R.sup.3a1, R.sup.3b, R.sup.3b1, R.sup.3c, R.sup.3c1, R.sup.3c2, R.sup.3d, R.sup.3d1, R.sup.3d2, R.sup.3e, R.sup.3e1, R.sup.3f, R.sup.3f1, R.sup.3f2, R.sup.3g and R.sup.3g1 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; wherein 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 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 can also be independently hydroxyl or C.sub.1-6 alkoxy; substituents in the substituted C.sub.1-6 alkyl in R.sup.3, R.sup.31, R.sup.32, R.sup.33, R.sup.3a, R.sup.3a1, R.sup.3b, R.sup.3b1, R.sup.3c, R.sup.3c1, R.sup.3c2, R.sup.3d, R.sup.3d1, R.sup.3d2, R.sup.3e, R.sup.3e1, R.sup.3f, R.sup.3f1, R.sup.3f2, R.sup.3g, R.sup.3g1, 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, and substituents in the 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, and substituted C.sub.2-10 heteroaryl in R.sup.3, R.sup.31, R.sup.32, R.sup.33, R.sup.3a, R.sup.3a1, R.sup.3b, R.sup.3b1, R.sup.3c, R.sup.3c1, R.sup.3c2, R.sup.3d, R.sup.3d1, R.sup.3d2, R.sup.3e, R.sup.3e1, R.sup.3f, R.sup.3f1, R.sup.3f2, R.sup.3g and R.sup.3g1 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; R.sup.4 is hydrogen, cyano, C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, C.sub.2-8 heterocycloalkyl, —C(O)OR.sup.a19 or C.sub.1-6 alkyl substituted with —OR.sup.a20; R.sup.a19 and R.sup.a20 are each independently C.sub.1-6 alkyl; ##STR00092## is ##STR00093## 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, R.sup.5c2, R.sup.5d, R.sup.5d1, R.sup.5d2, R.sup.5e, R.sup.5e1 and R.sup.5e2, are each independently hydrogen, deuterium or halogen; R.sup.6, R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d and R.sup.6e are each independently hydrogen, deuterium, halogen, sulfonyl, 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, —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, —(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)R.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.a64, R.sup.65, R.sup.66, R.sup.67, R.sup.68, 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; R.sup.a63 and R.sup.a69 are each independently hydrogen, hydroxyl, C.sub.1-6 alkoxy, 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.6, R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d and R.sup.6e, 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, and substituted C.sub.2-10 heteroaryl are each independently one or more of the following groups: deuterium, halogen, 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, —NR.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 deuterium, 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.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, 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 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; R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are each independently hydrogen, deuterium or halogen; one of R.sup.1 and R.sup.2 is hydrogen, deuterium, halogen, or substituted or unsubstituted C.sub.1-6 alkyl, and the other is hydrogen, deuterium, halogen, cyano, sulfonyl, substituted or unsubstituted C.sub.1-6 alkyl, —C(O)OR.sup.91, —COR.sup.92, ##STR00094## —S(O)R.sup.95, —S(O).sub.2R.sup.96, —C(O)NR.sup.97R.sup.98, or substituted or unsubstituted C.sub.2-10 heteroaryl; in R.sup.1 and R.sup.2, substituents in the substituted C.sub.1-6 alkyl and the substituted C.sub.2-10 heteroaryl are each independently 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.920, —SR.sup.921, —C(O)OR.sup.922, —COR.sup.923, —C(O)NH.sub.2, —NR.sup.924R.sup.925, C.sub.3-10 cycloalkyl, C.sub.2-8 heterocycloalkyl, C.sub.6-20 aryl or C.sub.2-10 heteroaryl; R.sup.921, R.sup.922, R.sup.923, R.sup.924 and R.sup.925 are each independently hydrogen or C.sub.1-6 alkyl, wherein R.sup.1 is not cyano; R.sup.91, R.sup.92, R.sup.93 and R.sup.94 are independently one or more of the following groups hydrogen, 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.sup.2-10 heteroaryl; R.sup.95 and R.sup.96 are independently hydrogen or C.sub.1-6 alkyl; R.sup.97 and R.sup.98 are independently hydroxyl, 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.97 and R.sup.98, 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, and substituted C.sub.2-10 heteroaryl are each independently 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, C.sub.3-10 cycloalkyl, C.sub.2-8 heterocycloalkyl, C.sub.6-20 aryl, C.sub.2-10 heteroaryl, —OR.sup.101, —SR.sup.102, —NR.sup.b103R.sup.b104, —C(O)R.sup.105, —C(O)OR.sup.106, —OC(O)R.sup.107, —OC(O)OR.sup.108, —C(O)NR.sup.b109R.sup.b1010, —N(R.sup.1011)C(O)OR.sup.1012, S(O)R.sup.1013, —S(O).sub.2R.sup.1014, —S(O).sub.2NR.sup.b1015Rb.sup.1016, —N(R.sup.1017)C(O)OR.sup.1018, —OC(O)NR.sup.b1019R.sup.b1020, —N(R.sup.1021)S(O).sub.2R.sup.1022; when there are multiple substituents, the substituents are the same or different; R.sup.101, R.sup.102, R.sup.b103, R.sup.b104, R.sup.105, R.sup.106, R.sup.107, R.sup.108, R.sup.b109, R.sup.b1010, R.sup.1011, R.sup.1012, R.sup.1013, R.sup.1014, R.sup.b1015, R.sup.b1016, R.sup.1017, R.sup.1018, R.sup.b1019, R.sup.b1020, R.sup.1021 and R.sup.1022 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; or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form substituted or unsubstituted 4-8 membered cycloalkenyl, or a substituted or unsubstituted 4-8 membered heterocycle, and the heteroatoms in the 4-8 membered heterocycle are one or more of O, S and N, and the number of the heteroatoms is 1, 2, 3 or 4; substituents in the substituted 4-8 membered cycloalkenyl and the substituted 4-8 membered heterocycle 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.111, —SR.sup.112, —C(O)OR.sup.113, —COR.sup.114, —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.111, R.sup.112, R.sup.113 and R.sup.114 are each independently hydrogen or C.sub.1-6 alkyl; in each of the above letters and groups, the heteroatoms in the substituted or unsubstituted C.sub.2-8 heterocycloalkyl or the C.sub.2-8 heterocycloalkyl are one or more of N, O and S, and the number of the heteroatoms is 1, 2, 3 or 4; the heteroatoms in the substituted or unsubstituted C.sub.2-10 heteroaryl or the C.sub.2-10 heteroaryl are one or more of N, O and S, and the number of the heteroatoms is 1, 2, 3 or 4; when there are multiple heteroatoms, the heteroatoms are the same or different; or in the above groups or substituents, when NR.sup.XR.sup.Y is present, then R.sup.X and R.sup.Y together with the nitrogen atom to which they are attached form substituted or unsubstituted 3-8 membered heterocyclyl; the heteroatoms in the 3-8 membered heterocyclyl are N, N and O, N and S, or N, O and S; the number of the heteroatoms is 1, 2, 3 or 4; the substituents in the substituted 3-8 membered heterocyclyl are 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.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, —NR.sup.b7R.sup.b8, —NR.sup.93R.sup.94, —NR.sup.97R.sup.98, —NR.sup.924R.sup.925, —NR.sup.b103R.sup.b104, —NR.sup.b109R.sup.b1010, —NR.sup.b1015R.sup.b1016 or —NR.sup.b1019R.sup.b1020.

2. The aromatic heterocyclic substituted olefin compound represented by general formula I or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein 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; and/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; and/or, the C.sub.2-8 alkynyl in the substituted or unsubstituted C.sub.2-8 alkynyl and the C.sub.2-alkynyl are independently C.sub.2-4 alkynyl; and/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; and/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, diazacycloheptyl, 1,3-dioxanyl, 1,3-dioxopenyl, 1,3-dithiopentyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isothiazolyl, isoxazolinyl, morpholinyl, oxadiazolinyl, oxadiazole alkyl, 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, dihydroindole-1-yl, indoline-2-yl, dihydroindole-3-yl, 2,3-dihydrobenzothiophen-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl or octahydrobenzofuranyl; and/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; and/or, the C.sub.6-20 aryl in the substituted or unsubstituted C.sub.6-20 aryl or the C.sub.6-20 aryl is independently phenyl, naphthyl, anthryl, phenanthryl, azulenyl, indan-1-yl, indan-2-yl, indan-3-yl, indan-4-yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl, 2,3-dihydroindol-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]dioxan-5-yl, 2,3-dihydrobenzo[b][1,4]dioxan-6-yl, 2H-benzo[b][1,4]oxazepine 3(4H)-keto-5-yl, 2H-benzo[b][1,4]oxazepine 3(4H)-one-6-yl, 2H-benzo[b][1,4]oxazepine 3(4H)-keto-7-yl, 2H-benzo[b][1,4]oxazepine 3(4H)-one-8-yl, benzo[d]oxazepine-2(3H)-one-5-yl, benzo[d]oxazepine-2(3H)-one-6-yl, benzo[d]oxazepine-2(3H)-one-7-yl, benzo[d]oxazepine-2(3H)-one-8-yl, quinazoline-4(3H)-one-5-yl, quinazoline-4(3H)-one-6-yl, quinazoline-4(3H)-one-7-yl, quinazoline-4(3H)-one-8-yl, quinoxaline-2(1H)-one-5-yl, quinoxaline-2(1H)-one-6-yl, quinoxaline-2(1H)-one-7-yl, quinoxaline-2(1H)-one-8-yl, benzo[d]thiazole-2(3H)-one-4-yl, benzo[d]thiazole-2(3)-one-5-yl, benzo[d]thiazole-2(3H)-one-6-yl or benzo[d]thiazole-2(3H)-one-7-yl; and/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-tetrahydroquinoline-2-yl, 5,6,7,8-tetrahydroquinoline-3-yl, 5,6,7,8-tetrahydroquinoline-4-yl, 5,6,7,8-tetrahydroisoquinoline-1-yl, thienopyridyl, 4,5,6,7-tetrahydro[c][1,2,5]oxadiazolyl or 6,7-dihydropyro [c][1,2,5]oxadiazole-4(5H)keto.

3. The aromatic heterocyclic substituted olefin compound represented by general formula I or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein one of R.sup.1 and R.sup.2 is hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl, and the other is hydrogen, cyano, sulfonyl, substituted or unsubstituted C.sub.1-6 alkyl, —C(O)OR.sup.91, —COR.sup.92, ##STR00095## —S(O)R.sup.95, —S(O).sub.2R.sup.96, —C(O)NR.sup.97R.sup.98, or substituted or unsubstituted C.sub.2-10 heteroaryl; or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form substituted or unsubstituted 4-8 membered cycloalkenyl, or a substituted or unsubstituted 4-8 membered heterocycle; wherein, definitions of R.sup.91, R.sup.92, R.sup.93, R.sup.94, R.sup.95, R.sup.96, R.sup.97 and R.sup.98 are the same as defined in claim 1; definitions of the substitutions in the substituted C.sub.1-6 alkyl, the substituted C.sub.2-10 heteroaryl, the substituted 4-8 membered cycloalkenyl and the substituted 4-8 membered heterocycle are the same as defined in claim 1; and/or, R.sup.3, R.sup.31, R.sup.32, R.sup.33, R.sup.3a, R.sup.3a1, R.sup.3b, R.sup.3b1, R.sup.3c, R.sup.3c1, R.sup.3c2, R.sup.3d, R.sup.3d1, R.sup.3d2, R.sup.3e, R.sup.3e1, R.sup.3f, R.sup.3f1, R.sup.3f2, R.sup.3g and R.sup.3g1 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 heterocycloalkyl, substituted or unsubstituted C.sub.6-20 aryl, or substituted or unsubstituted C.sub.2-10 heteroaryl; wherein, the definitions of 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 the same as defined in claim 1; definitions of the substitutions in the substituted C.sub.1-6 alkyl, substituted C.sub.2-8 heterocycloalkyl, substituted C.sub.6-20 aryl or substituted C.sub.2-10 heteroaryl are the same as defined in claim 1; and/or, R.sup.4 is hydrogen, C.sub.1-6 alkyl or C.sub.3-10 cycloalkyl; and/or, 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, R.sup.5c2, R.sup.5d, R.sup.5d1, R.sup.5d2, R.sup.5e, R.sup.5e1, R.sup.5e2, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are hydrogen; and/or, R.sup.6, R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d and R.sup.6e are each independently hydrogen, halogen, cyano, substituted or unsubstituted C.sub.1-6 alkyl, 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, —OR.sup.61, —SR.sup.62, —C(O)R.sup.65, —C(O)OR.sup.66 or —C(O)NR.sup.a69R.sup.a610, definitions of R.sup.61, R.sup.62, R.sup.65, R.sup.66, R.sup.a69 and R.sup.a610 are the same as defined in claim 1; definitions of the substitutions in the substituted C.sub.1-6 alkyl, substituted C.sub.2-8 heterocycloalkyl, substituted C.sub.6-20 aryl or substituted C.sub.2-10heteroaryl are the same as defined in claim 1.

4. The aromatic heterocyclic substituted olefin compound represented by general formula I or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein one of R.sup.1 and R.sup.2 is hydrogen, and the other is hydrogen, cyano, substituted or unsubstituted C.sub.1-6 alkyl, —C(O)OR.sup.91 or —C(O)NR.sup.97R.sup.98, wherein R.sup.1 is not cyano; or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form substituted or unsubstituted 4-8 membered cycloalkenyl; wherein R.sup.91 is hydrogen or C.sub.1-6 alkyl; R.sup.97 and R.sup.98 are independently hydrogen, or substituted or unsubstituted C.sub.1-6 alkyl; or R.sup.97 and R.sup.98 together with the nitrogen atom to which they are attached form substituted or unsubstituted 3-8 membered heterocyclyl; wherein in R.sup.1 or R.sup.2, definitions of the substitutions in the substituted C.sub.1-6 alkyl, the substituted 4-8 membered cycloalkenyl and the substituted 4-8 membered heterocycle are the same as defined in claim 1; in R.sup.97 or R.sup.98, definitions of the substituents in the substituted C.sub.1-6 alkyl or the substituted 3-8 membered heterocyclyl are the same as defined in claim 1; and/or, R.sup.3, R.sup.31, R.sup.32, R.sup.33, R.sup.3a, R.sup.3a1, R.sup.3b, R.sup.3b1, R.sup.3c, R.sup.3c1, R.sup.3c2, R.sup.3d, R.sup.3d1, R.sup.3d2, R.sup.3e, R.sup.3e1, R.sup.3f, R.sup.3f1, R.sup.3f2, R.sup.3g and R.sup.3g1 are each independently hydrogen, halogen, —OR.sup.a5, or substituted or unsubstituted C.sub.1-6 alkyl; R.sup.a5 is C.sub.1-6 alkyl; the substituents in the substituted C.sub.1-6 alkyl are one or more of the following groups: deuterium or halogen; and/or, R.sub.4 is hydrogen, C.sub.1-6 alkyl or C.sub.3-10 cycloalkyl; and/or, 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, R.sup.5c2, R.sup.5d, R.sup.5d1, R.sup.5d2, R.sup.5e, R.sup.5e1, R.sup.5e2, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are hydrogen; and/or, R.sup.6, R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d and R.sup.6e are each independently cyano, —C(O)OR.sup.66 or —C(O)NR.sup.a69R.sup.a610, wherein R.sup.66 is C.sub.1-6 alkyl; R.sup.a69 and R.sup.a610 are each independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.3-10 cycloalkyl or —OR.sup.627; definitions of the substitutions in the substituted C.sub.1-6 alkyl or the substituted C.sub.3-10 cycloalkyl are the same as defined in claim 1; a definition of R.sup.627 is the same as defined in claim 1.

5. The aromatic heterocyclic substituted olefin compound represented by general formula I or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein one of R.sup.1 and R.sup.2 is hydrogen, and the other is hydrogen, C.sub.1-6 alkyl, —C(O)OR.sup.91 or —C(O)NR.sup.97R.sup.98; or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form 4-8 membered cycloalkenyl; wherein R.sup.91, R.sup.97 and R.sup.98 are independently hydrogen or C.sub.1-6 alkyl; or R.sup.97 and R.sup.98 together with the nitrogen atom to which they are attached form 3-8 membered heterocyclyl; and/or, R.sup.3, R.sup.31, R.sup.32, R.sup.33, R.sup.3a, R.sup.3a1, R.sup.3b, R.sup.3b1, R.sup.3c, R.sup.3c1, R.sup.3c2, R.sup.3d, R.sup.3d1, R.sup.3d2, R.sup.3e, R.sup.3e1, R.sup.3f, R.sup.3f1, R.sup.3f2, R.sup.3g and R.sup.3g1 are each independently hydrogen, halogen, trifluoromethyl, difluoromethyl, methyl, deuterated methyl or methoxy; one or two positions in ring A are not hydrogen; and/or R.sup.4 is hydrogen, C.sub.1-6 alkyl or C.sub.3-10 cycloalkyl; and/or, 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, R.sup.5c2, R.sup.5d, R.sup.5d1, R.sup.5d2, R.sup.5e, R.sup.5e1, R.sup.5e2, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are hydrogen; and/or, R.sup.6, R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d and R.sup.6e are each independently cyano, —C(O)OR.sup.66 or —C(O)NR.sup.a69R.sup.a610, wherein R.sup.66 is C.sub.1-6 alkyl; R.sup.a69 and R.sup.a610 are each independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl or —OR.sup.627; the substituents in the substituted C.sub.1-6 alkyl are C.sub.2-8 heterocycloalkyl; R.sup.627 is C.sub.2-8 heterocycloalkyl.

6. The aromatic heterocyclic substituted olefin compound represented by general formula I or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein R.sup.1 is hydrogen, and R.sup.2 is hydrogen, C.sub.1-6 alkyl, —C(O)OR.sup.91 or —C(O)NR.sup.97R.sup.98; R.sup.91, R.sup.97 and R.sup.98 are independently hydrogen or C.sub.1-6 alkyl; and/or ring A is ##STR00096## wherein R.sup.3 and R.sup.33 are independently hydrogen, halogen, —OR.sup.a5, or substituted or unsubstituted C.sub.1-6 alkyl, but not hydrogen at the same time; R.sup.3b is hydrogen, halogen, —OR.sup.a5, or substituted or unsubstituted C.sub.1-6 alkyl; a definition of R.sup.a5 is the same as defined in claim 1; definitions of the substitutions in the substituted C.sub.1-6 alkyl are the same as defined in claim 1; R.sup.31, R.sup.32 and R.sup.3b1 are hydrogen; and or ##STR00097## is ##STR00098## wherein R.sup.5a, R.sup.5a1, R.sup.5a2, R.sup.5c, R.sup.5c1, R.sup.5c2, R.sup.5d, R.sup.5d1, R.sup.5d2, R.sup.10 and R.sup.11 are hydrogen; R.sup.6a, R.sup.6c and R.sup.6d are each independently cyano, C.sub.2-10 heteroaryl, —C(O)OR.sub.66 or —C(O)NR.sup.a69R.sup.a610, wherein definitions of C.sub.2-10 heteroaryl, R.sup.66, R.sup.a69 and R.sup.a610 are the same as defined in claim 1.

7. The aromatic heterocyclic substituted olefin compound represented by general formula I or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein R.sup.1 and R.sup.2 are both hydrogen; or R.sup.1 is hydrogen, R.sup.2 is ##STR00099## or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form cyclohexene; and/or ##STR00100## is ##STR00101## and/or ##STR00102## is ##STR00103## ##STR00104##

8. The aromatic heterocyclic substituted olefin compound represented by general formula I or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein the aromatic heterocyclic substituted olefin compound represented by general formula I is any one of the following compounds: ##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109##

9. A method for preparing the aromatic heterocyclic substituted olefin compound represented by general formula I as defined in claim 1, comprising any one of the following methods: method I, comprising the following steps of: conducting a coupling reaction of compound II-A with compound II-2 as shown below; ##STR00110## wherein one of X and Y is halogen; the other is an organotin reagent or an organoboron reagent; one of ring C1 and ring C2 is ring A, and the other is ring B; one of R.sup.d and R.sup.c is R.sup.1, and the other is R.sup.2; when ring C1 is ring A, then R.sup.d is R.sup.1 definitions of R.sup.1, R.sup.2, ring A and ring B are the same as defined in claim 1; method II, comprising the following steps of: conducting a reaction of compound III-1 to obtain a compound represented by general formula I, wherein in compound III-1, EWG2 is an electron withdrawing group that can be converted into R1 or R2; ##STR00111## one of ring C1 and ring C2 is ring A, and the other is ring B; one of R.sup.d and R.sup.c is R.sup.1 and the other is R.sup.2; when ring C1 is ring A, then R.sup.d is R.sup.1; definitions of R.sup.1, R.sup.2, ring A and ring B are the same as defined in claim 1; or method III, comprising the following steps of: hydrogenolyzing compound I-1 under the action of a palladium reagent; ##STR00112## wherein R.sup.1 and R.sup.2 are hydrogen, one of ring C1 and ring C2 is ring A, and the other is ring B; wherein definitions of ring A and ring B are the same as defined in claim 1.

10. A method for inhibiting ALK 5 activity, or treating ALK5-mediated diseases comprising administering an effective amount of the aromatic heterocyclic substituted olefin compound represented by general formula I or the pharmaceutically acceptable salt thereof as defined in claim 1 to the subject.

11. The method as defined in claim 10, wherein the ALK5-mediated diseases are one or more of cancer, organ fibrosis, viral infection, chronic nephritis, acute nephritis, diabetic nephropathy, osteoporosis, arthritis, wound healing, ulcers, corneal trauma, heart valve stenosis, congestive heart necrosis, neurological impairment, Alzheimer's syndrome, peritoneal or subcutaneous adhesions, arteriosclerosis, and tumor metastasis and growth.

12. A pharmaceutical composition, comprising one or more of the aromatic heterocyclic substituted olefin compound represented by general formula I and the pharmaceutically acceptable salt thereof as defined in claim 1, and a pharmaceutically acceptable carrier.

13. The method as defined in claim 11, wherein the cancer is one or more of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, colon cancer, esophageal cancer, gastric cancer, pancreatic cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma; and/or the organ fibrosis is one or more of renal fibrosis, liver fibrosis and lung fibrosis.

14. The aromatic heterocyclic substituted olefin compound represented by general formula I or the pharmaceutically acceptable salt thereof as defined in claim 2, wherein 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; the C.sub.1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tent-butyl; and/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 C2-4 alkenyl; the C2-4 alkenyl is vinyl, propenyl, allyl, ##STR00113## and/or, the C.sub.2-8 alkynyl in the substituted or unsubstituted C.sub.2-8 alkynyl and the C.sub.2-8 are independently C.sub.2-4 alkynyl; the C.sub.2-4 alkynyl is ethynyl, propynyl, butynyl or 3-methylpropynyl.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

(1) The reagents and raw materials (except intermediates) used in the present invention are all commercially available. In the present invention, the room temperature refers to the ambient temperature, which is 10° C. to 35° C. Overnight refers to 8 to 15 hours. Reflux is 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) HATU 2-(7-azobenzotriazole)-tetramethylurea hexafluorophosphate

(5) EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

(6) HOBt 1-hydroxybenzotriazole

(7) DIPEA diisopropylethylamine

(8) Pd(PPh.sub.3).sub.4 palladium tetraphenylphosphine

(9) Pd(dppf)Cl.sub.2 [1,1′-bis(diphenylphosphino)ferrocene]palladium di chloride dichloromethane complex

(10) Pd(PPh.sub.3).sub.2Cl.sub.2 dichlorobis(triphenylphosphine)palladium

(11) LiHMDS bis-(trimethylsilyl) lithium amide

(12) TBAF tetrabutylammonium fluoride

(13) TMS trimethyl silyl

(14) In the following examples, the coupling constant of hydrogen on the carbon-carbon double bond in the nuclear magnetic data are used to determine whether the prepared compound is in a cis-configuration (Z) or a trans-configuration (E). In general, the coupling constant between two hydrogen on the double bond of the E configuration compound is significantly greater than the coupling constant between two hydrogen on the double bond of the corresponding Z type compound. In the present invention, for the obtained E type compound, taking comparative compounds 23 and 24 as an example, the coupling constant of two hydrogens on the carbon-carbon double bond is about 16. For the obtained corresponding Z-type compound, i.e., compounds 1 and 3, the coupling constant of two hydrogens on the carbon-carbon double bond is about 12.5.

(15) Synthetic Route of Compound 1

(16) ##STR00058##

(17) Synthesis of Compound 1-f

(18) SM-1 (2 g, 7.4 mmol), trimethylsilylacetylene (0.73 g, 7.4 mmol), bis(triphenylphosphine) palladium dichloride (104 mg, 0.148 mmol), and cuprous iodide (28 mg, 0.148 mmol) and triethylamine (15 mL) were added to a reaction flask.

(19) The reaction mixture was replaced with N.sub.2 and reacted at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was concentrated to remove organic solvents, added with water (30 mL), and extracted with ethyl acetate (30 mL). The organic phase was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation. A crude product was purified by column chromatography (PE:EA=4:1) to obtain compound 1-f (1.34 g, 63%) as a yellow solid. LC-MS (ESI): m/z=287.3 [M+H].sup.+.

(20) Synthesis of Compound 1-e

(21) Potassium carbonate (1.8 g, 13 mmol) was added to a solution of compound 1-f (1.24 g, 4.33 mmol) in methanol (20 mL) and dichloromethane (20 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove organic solvents, added with water (20 mL), and extracted with ethyl acetate (30 mL×2). The organic phase was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation to obtain compound 1-e (435 mg, 50%) as a yellow solid. LC-MS (ESI): m/z=201.3 [M+H].sup.+.

(22) Synthesis of Compound 1-d

(23) 1-e (435 mg, 2.17 mmol), 2-bromo-6-methylpyridine (374 mg, 2.17 mmol), bis(triphenylphosphine) palladium dichloride (152 mg, 0.217 mmol), and cuprous iodide (41 mg, 0.217 mmol) and triethylamine (15 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was concentrated to remove organic solvents, added with water (30 mL), and extracted with ethyl acetate (30 mL×2). The organic phase was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation. A crude product was purified by column chromatography (DCM:MeOH=20:1) to obtain compound 1-d (476 mg, 75%) as a yellow solid. LC-MS (ESI): m/z=292.0 [M+H].sup.+.

(24) Synthesis of Compound 1-c

(25) Compound 1-d (200 mg, 0.69 mmol), tetrahydrofuran (6 mL), methanol (6 mL), water (3 mL), and lithium hydroxide monohydrate (144 mg, 3.43 mmol) were added to a reaction flask. After the mixture was stirred overnight at room temperature, it was added with dilute hydrochloric acid to adjust the pH to 6 to 7, and extracted with ethyl acetate (30 mL×3). The organic phase was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation to obtain a crude compound 1-c (101 mg, 53%). LC-MS (ESI): m/z=278.1 [M+H].sup.+.

(26) Synthesis of Compound 1-b

(27) Oxalyl chloride (3 mL) was slowly added to a solution of compound 1-c (101 mg, 0.36 mmol) in dichloromethane (6 mL) under an ice bath, and then another drop of DMF was added. After the mixture was stirred at room temperature overnight, it was concentrated to obtain a crude compound 1-b (138 mg).

(28) Synthesis of Compound 1-a

(29) A solution of compound 1-b (138 mg, 0.36 mmol) in dichloromethane (6 mL) was slowly added to aqueous ammonia (6 mL) under an ice bath, and the mixture was stirred at room temperature for 10 minutes. The mixture was concentrated. A crude product was purified by Prep-TLC (developing agent DCM:MeOH=10:1) to obtain compound 1-a (45 mg, 45%) as a white solid. LC-MS (ESI): m/z=277.1 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOD): δ 9.85 (s, 1H), 8.35 (s, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.76 (dd, J=9.3, 0.9 Hz, 1H), 7.68 (dd, J=9.3, 1.7 Hz, 1H), 7.53 (d, J=7.7 Hz, 1H), 7.35 (d, J=7.7 Hz, 1H), 2.58 (s, 3H).

(30) Synthesis of Compound 1

(31) Pd—CaCO.sub.3 (10 mg) was added to a solution of compound 1-a (38 mg, 0.14 mmol) in ethyl acetate (8 mL) at room temperature. The reaction solution was evacuated and replaced with H.sub.2 several times, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered and concentrated. A crude was purified by Prep-HPLC to obtain compound 1 (10 mg, 26%) as a white solid. LC-MS (ESI): m/z=279.1 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOD): δ 9.47-9.57 (m, 1H), 8.25 (s, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.52 (dd, J=9.2, 0.8 Hz, 1H), 7.33 (dd, J=8.8, 2.0 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 6.87 (d, J=12.4 Hz, 1H), 6.82 (d, J=12.4 Hz, 1H), 2.50 (s, 3H). Wherein 6.87 (d, J=12.4 Hz, 1H), 6.82 (d, J=12.4 Hz, 1H) is the compound displacement and coupling constant of the hydrogen on the carbon-carbon double bond.

(32) Synthetic Route of Compound 2

(33) ##STR00059##

(34) Synthesis of Compound 2-a

(35) Oxalyl chloride (1 mL) was slowly added to a solution of compound 1-c (100 mg, 0.36 mmol) in dichloromethane (10 mL) under an ice bath, and then another drop of DMF was added. After the mixture was stirred at room temperature for 1 hour, it was concentrated, and added with dichloromethane (10 mL). A solution of SM-2 (93.9 mg, 0.72 mmol) in dichloromethane (10 mL) was slowly added to the solution under an ice bath, and the mixture was stirred overnight at room temperature. The next day, the mixture was concentrated. A crude product was purified by Prep-TLC (DCM:MeOH=10:1) to obtain compound 2-a (60 mg, 43%) as a white solid, LC-MS (ESI): m/z=390.1 [M+H].sup.+.

(36) Synthesis of Compound 2

(37) Quinoline (40 mg, 0.3 mmol) and Pd—CaCO.sub.3 (20 mg) were added to a solution of compound 2-a (60 mg, 0.15 mmol) in ethyl acetate/methanol (v/v=2/1, 5 mL) at room temperature. The reaction solution was evacuated and replaced with H.sub.2 several times, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered and concentrated. A crude was purified by Prep-HPLC to obtain compound 2 (20 mg, 33%) as a white solid. LC-MS (ESI): m/z=392.2 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.52 (s, 1H), 8.19 (s, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.52 (d, J=9.5 Hz, 1H), 7.33 (dd, J=9.5 Hz, 1.5 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 6.85 (d, J=12.5 Hz, 1H), 6.83 (d, J=12.5 Hz, 1H), 3.72-3.74 (m, 4H), 3.54-3.58 (m, 2H), 2.61-2.64 (m, 2H), 2.55-2.60 (m, 4H), 2.51 (s, 3H). Wherein 6.85 (d, J=12.5 Hz, 1H), 6.83 (d, j=12.5 Hz, 1H) is the compound displacement and coupling constant of the hydrogen on the carbon-carbon double bond.

(38) Synthetic Route of Compound 3

(39) ##STR00060##

(40) Synthesis of Compound 3-a

(41) 1-c (100 mg, 0.36 mmol), DMF (8 mL), a methylamine tetrahydrofuran solution (2.0 M, 0.36 mL), HATU (274 mg, 0.72 mmol), and triethylamine (0.25 mL, 1.8 mmol) were added. The mixture was reacted at room temperature for 4 hours. After the reaction was completed, the mixture was added with water (100 mL), and extracted with ethyl acetate (30 mL×3). The organic phase was washed successively with water, a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation. A crude product was purified by column chromatography (DCM:MeOH=20:1) to obtain compound 3-a (70 mg, 67%) a yellow solid. LC-MS (ESI): m/z=291.1 [M+H].sup.+.

(42) Synthesis of Compound 3

(43) Pd—CaCO.sub.3 (30 mg) was added to a solution of compound 3-a (70 mg, 0.24 mmol) in pyridine (10 mL) at room temperature. The reaction solution was evacuated and replaced with H.sub.2 several times, and the mixture was stirred overnight at room temperature. The mixture was filtered and concentrated. A crude was purified by Prep-HPLC to obtain compound 3 (20 mg, 31%) as a white solid. LC-MS (ESI): m/z=293.0 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.51 (s, 1H), 8.14 (s, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.50 (d, J=9.3 Hz, 1H), 7.31 (dd, J=9.3, 1.7 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 6.86 (d, J=12.5 Hz, 1H), 6.82 (d, J=12.5 Hz, 1H), 2.92 (s, 3H), 2.50 (s, 3H). Wherein 6.86 (d, J=12.5 Hz, 1H), 6.82 (d, J=12.5 Hz, 1H) is the compound displacement and coupling constant of the hydrogen on the carbon-carbon double bond.

(44) Synthetic Route of Compound 4

(45) ##STR00061##

(46) Synthesis of Compound 4-d

(47) A solution of compound bromomethyltriphenylphosphonium bromide (2.16 g, 4.95 mmol) in tetrahydrofuran (10 mL) was cooled to −78° C. with a dry ice acetone bath under nitrogen protection, and potassium tert-butoxide (0.56 g, 4.95 mmol) was slowly added. The resulting mixture was reacted at −78° C. for 1 hour, and then 6-methyl-2-pyridinecarboxaldehyde (0.5 g, 4.95 mmol) was added dropwise. After the addition was completed, the mixture was kept at the temperature and stirred for 5 hours. The mixture was slowly heated to room temperature and stirred overnight. The next day, the reaction solution was diluted with petroleum ether, filtered, and concentrated. A crude product was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to obtain compound 4-d (500 mg, 51%). LC-MS (ESI): m/z=197.9 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 7.73-7.75 (m, 2H), 7.26 (d, J=8 Hz, 1H), 7.22 (dd, J=7.5 Hz, 2 Hz, 1H), 6.90 (d, J=8 Hz, 1H), 2.48 (s, 3H).

(48) Synthesis of Compound 4-c

(49) Compound 4-c was synthesized according to the method of WO 2015/157093.

(50) Synthesis of Compound 4-b

(51) Compound 4-c (0.3 g, 1.24 mmol), DCM (3 mL), THF (20 mL), and HATU (943 mg, 2.48 mmol) were added to a reaction flask. After the mixture was stirred at room temperature for half an hour, cyclopropylamine (0.13 mL, 1.88 mmol) and DIPEA (1.08 mL, 6.2 mmol) were added, and the mixture was stirred at room temperature for 4 hours.

(52) The reaction mixture was concentrated, added with water, and extracted with ethyl acetate (30 mL×2). The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation. A crude product was purified by column chromatography (DCM:MeOH=50:1) to obtain crude compound 4-b (350 mg) as yellow oil. LC-MS (ESI): m/z=280.0[M+H].sup.+.

(53) Synthesis of Compound 4-a

(54) 4-b (0.35 g, 1.24 mmol), bis(pinacolato)diboron (381 mg, 1.5 mmol), Pd(dppf)Cl.sub.2 (92 mg, 0.125 mmol), potassium acetate (245 mg, 2.5 mmol), 1,4-dioxane (20 mL) and toluene (4 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted overnight at 90° C. After the reaction was completed, the mixture was concentrated to remove organic solvents. A crude product was purified by column chromatography (DCM:MeOH=20:1) to obtain compound 4-a (0.3 g, 97%) as a black solid. LC-MS (ESI): m/z=246.1 [M+H].sup.+.

(55) Synthesis of Compound 4

(56) 4-a (300 mg, 1.22 mmol), 4-d (241 mg, 1.22 mmol), Pd(dppf)Cl.sub.2 (89 mg, 0.122 mmol), sodium carbonate (259 mg, 2.44 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 overnight at 90° C. After the reaction was completed, the mixture to remove organic solvents. A crude product was purified by column chromatography (DCM:MeOH=20:1) and Prep-HPLC to obtain compound 4 (20 mg, 5%). LC-MS (ESI): m/z=319.0 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.51 (s, 1H), 8.16 (s, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.48 (d, J=9.3 Hz, 1H), 7.29 (dd, J=9.3, 1.6 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.08 (d, J=7.7 Hz, 1H), 6.83 (d, J=12.5 Hz, 1H), 6.79 (d, J=12.5 Hz, 1H), 2.82 (m, 1H), 2.48 (s, 3H), 0.84-0.80 (m, 2H), 0.71-0.59 (m, 2H). Wherein 6.83 (d, J=12.5 Hz, 1H), 6.79 (d, J=12.5 Hz, 1H) is the compound displacement and coupling constant of the hydrogen on the carbon-carbon double bond.

(57) Synthetic Route of Compound 5

(58) ##STR00062##

(59) Synthesis of Compound 5-a

(60) Compound 1-c (0.55 g, 1.98 mmol), DMF (10 mL), THE (20 mL) and HATU (1.5 g, 3.96 mmol) were added to a reaction flask. After the mixture was stirred at room temperature for half an hour, o-(tetrahydro-2hydro-pyran-2-yl)hydroxylamine (0.23 g, 1.98 mmol) and triethylamine (0.6 g, 5.94 mmol) were added. After the mixture was stirred at room temperature overnight, it was concentrated, added with water, and extracted with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation. A crude product was purified by Prep-TLC (DCM:MeOH=20:1) to obtain compound 5-a (200 mg, 27%). LC-MS (ESI): m/z=377.0 [M+H].sup.+.

(61) Synthesis of Compound 5

(62) Pd—CaCO.sub.3 (100 mg) was added to a solution of compound 5-a (38 mg, 0.10 mmol) in pyridine (10 mL) at room temperature. The reaction solution was evacuated and replaced with H.sub.2 several times, and the mixture was stirred overnight at room temperature. The mixture was filtered and concentrated. A crude was purified by Prep-HPLC to obtain compound 5 (5 mg, 13%) as a white solid. LC-MS (ESI): m/z=379.0 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.43 (s, 1H), 8.18 (s, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.55 (d, J=9.4 Hz, 1H), 7.37 (dd, J=9.3, 1.5 Hz, 1H), 7.18 (d, J=7.7 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 6.83 (d, J=12.5 Hz, 1H), 6.79 (d, J=12.5 Hz, 1H), 5.05 (s, 1H), 4.14 (t, J=10.7 Hz, 1H), 3.66 (d, J=11.6 Hz, 1H), 2.87 (s, 1H), 2.50 (s, 3H), 2.01-1.69 (m, 5H). Wherein 6.83 (d, J=12.5 Hz, 1H), 6.79 (d, J=12.5 Hz, 1H) is the compound displacement and coupling constant of the hydrogen on the carbon-carbon double bond.

(63) Synthetic Route of Compound 6

(64) ##STR00063##

(65) Synthesis of Compound 6

(66) Pyridine (180 mg, 2.28 mmol) and trifluoroacetic anhydride (241 mg, 1.15 mmol) were added to a solution of compound 1 (0.16 g, 0.57 mmol) in THF (5 mL) and DCM (5 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, dissolved in ethyl acetate (30 mL), washed with 1 M hydrochloric acid solution and saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation.

(67) A crude product was purified by column chromatography (DCM:MeOH=30:1) and Prep-HPLC to obtain compound 6 (30 mg, 20%) as a white solid. LC-MS (ESI): m/z=261.1[M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 8.86 (s, 1H), 8.26 (s, 1H), 7.70-7.60 (m, 2H), 7.47 (dd, J=9.4, 1.6 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 6.90 (d, J=12.5 Hz, 1H), 6.86 (d, J=12.5 Hz, 1H), 2.54 (s, 3H). Wherein 6.90 (d, J=12.5 Hz, 1H), 6.86 (d, J=12.5 Hz, 1H) is the compound displacement and coupling constant of the hydrogen on the carbon-carbon double bond.

(68) Synthetic Route of Compound 7

(69) ##STR00064##

(70) Synthesis of Compound 7

(71) Compound 6 (28 mg, 0.11 mmol), DMF (6 mL), azidotrimethylsilane (25 mg, 0.22 mmol), and ammonium fluoride (12 mg, 0.33 mmol) were added to a reaction flask. After the mixture was stirred at 70° C. for 4 hours, it was subjected to rotary evaporation and purify by Prep-HPLC to obtain compound 7 (3 mg, 9%) as a white solid. LC-MS (ESI): m/z 304.0[M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.51 (s, 1H), 8.12 (s, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.51 (d, J=9.3 Hz, 1H), 7.26 (dd, J=9.4, 1.6 Hz, 1H), 7.17 (dd, J=7.7, 4.1 Hz, 2H), 6.96 (d, J=12.5 Hz, 1H), 6.85 (d, J=12.5 Hz, 1H), 2.47 (s, 3H). Wherein 6.96 (d, J=12.5 Hz, 1H), 6.85 (d, J=12.5 Hz, 1H) is the compound displacement and coupling constant of the hydrogen on the carbon-carbon double bond.

(72) Synthetic Route of Compound 8

(73) ##STR00065##

(74) Synthesis of Compound 8-c

(75) A mixture of compounds SM-1 (5.4 g, 20 mmol), trimethylsilylacetylene (4 g, 40 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (1.4 g, 2 mmol), cuprous iodide (0.38 g, 2 mmol) and triethylamine (100 mL) was reacted at room temperature for 12 hours under a nitrogen atmosphere. The mixture was subjected to rotary evaporation to remove the organic phase, and purified by column chromatography (EA:PE=1:5) to obtain compound 8-c (2.86 g, 50%) as a yellow solid. LC-MS (ESI): m/z=287.0 [M+H].sup.+.

(76) Synthesis of Compound 8-b

(77) 8-c (2.86 g, 10 mmol) was added to THF (100 mL), and a TBAF solution (1 M, 20 mmol, 20 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to remove organic solvents, and water (1000 mL) and DCM (500 mL) were added. The liquid was separated, subjected to rotary evaporation to remove the organic phase, and purified by column chromatography (EA:PE=1:5 then 1:3) to obtain compound 8-c (1.6 g, 75%) as a yellow solid. LC-MS (ESI): m/z=215.1 [M+H].sup.+.

(78) Synthesis of Compound 8-a

(79) 8-b (1.1 g, 5.1 mmol), and 2-bromo-6-methoxypyridine (1.1 g, 5.85 mmol) were added to triethylamine (20 mL) and cuprous iodide (0.1 g, 0.5 mmol) and PdCl.sub.2(PPh.sub.3).sub.2 (0.35 g, 0.5 mmol) were added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to remove organic solvents, and water (100 mL) and DCM (50 mL) were added. The mixture was purified by column chromatography (PE/EA=5/1) to obtain compound 8-a (0.86 g, 5,2%). LCMS (ESI): m/z=322.0 [M+H].sup.+.

(80) Synthesis of Compound 8

(81) Compound 8-a (0.64 g, 2.0 mmol), Pd/CaCO.sub.3 (0.1 g) and pyridine (10 mL) were mixed at room temperature. After replaced with hydrogen, the mixture was stirred at room temperature for 16 hours, filtered, concentrated, and subjected to column chromatography (PE/EA=5/1) to obtain solid 8 (0.36 g, 56%). LC-MS (ESI): m/z=324.1 [M+H].sup.+; .sup.1H NMR (500 MHz, CDCl.sub.3): δ 9.31 (s, 1H), 8.27 (s, 1H), 7.59 (d, J=9.5 Hz, 1H), 7.56 (s, 1H), 7.43-7.53 (m, 2H), 6.81 (d, J=6.0 Hz, 1H), 6.71 (d, J=12.5 Hz, 1H), 6.68 (d, J=12.5 Hz, 1H), 6.60 (d, J=8.5 Hz, 1H), 4.40 (q, J=7.0 Hz, 2H), 3.53 (s, 3H), 1.40 (t, J=7.0 Hz, 3H). Wherein 6.71 (d, J=12.5 Hz, 1H), 6.68 (d, J=12.5 Hz, 1H) is the compound displacement and coupling constant of the hydrogen on the carbon-carbon double bond.

(82) Synthetic Route of Compound 9

(83) ##STR00066##

(84) Synthesis of Compound 9-a

(85) 8 (0.323 g, 1.0 mmol) was added to methanol (2 mL) and THF (8 mL), and lithium hydroxide monohydrate (0.42 g, 10 mmol) aqueous solution was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to remove organic solvents, water (50 mL) and DCM (10 mL) were added. The liquid was separated, and the organic layer was discarded. The water layer was cooled to 0° C. and neutralized with hydrochloric acid (2 M) to pH 6 to 7. A brown precipitate was filtered off and dried to obtain compound 9-a (0.19 g, 64%). LCMS (ESI): m/z=296.0 [M+H].sup.+.

(86) Synthesis of Compound 9

(87) A mixture of 9-a (0.15 g, 0.5 mmol) was dissolved in dichloromethane (100 mL). Under an ice bath, oxalyl chloride (5 mL) was added to the solution and DMF (0.5 mL) was slowly added to the reaction solution. After the reaction solution was heated to room temperature, the reaction was continued for 6 hours. The reaction solution was concentrated under reduced pressure to dryness, and then diluted with dichloromethane (40 mL). Under an ice bath, the solution was slowly added dropwise to aqueous ammonia (50 mL), reacted at 0° C. for 10 minutes, and then heated to room temperature and stirred for 2 hours. The mixture was concentrate to remove the methylene chloride solution, and then water (60 mL) was added to the aqueous phase to dilute and stir vigorously for 1 hour. The mixture was filtered, washed and dried to obtain compound 9 (0.06 g, 41%) as a white solid. LC-MS (ESI): m/z=295.0 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.56 (s, 1H), 8.27 (s, 1H), 7.50-7.64 (m, 3H), 6.90 (d, J=7.5 Hz, 1H), 6.79 (d, J=12.5 Hz, 1H), 6.74 (d, J=12.5 Hz, 1H), 6.63 (d, J=8.5 Hz, 1H), 3.45 (s, 3H). Wherein 6.79 (d, J=12.5 Hz, 1H), 6.74 (d, J=12.5 Hz, 1H) is the compound displacement and coupling constant of the hydrogen on the carbon-carbon double bond.

(88) Synthetic Route of Compound 10

(89) ##STR00067##

(90) Synthesis of Compound 10-d

(91) 2,6-Dibromopyridine (1 g, 4.22 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to −78° C., and then n-butyllithium (2.5 M, 2.03 mL, 5.07 mmol) was slowly added. The reaction solution was reacted at low temperature for half an hour, added with deuterated methyl iodide (0.32 mL, 5.07 mmol), and heated to normal temperature and stirred for another hour. The reaction solution was quenched with water (10 mL), and extracted with ethyl acetate (10 mL×3). The organic phase was combined, and dried over anhydrous sodium sulfate. The mixture was filtered, and concentrated to obtain compound 10-d (0.5 g, 67%) as a brown liquid. LC-MS (ESI): m/z=175.0 [M+H].sup.+.

(92) Synthesis of Compound 10-c

(93) 1-e (200 mg, 1 mmol), 10-d (192 mg, 1.1 mmol), bis(triphenylphosphine) palladium dichloride (70 mg, 0.1 mmol), cuprous iodide (19 mg, 0.1 mmol) and triethylamine (15 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was concentrated to remove organic solvents, added with water (30 mL), and extracted with ethyl acetate (30 mL×2). The organic phase was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation. A crude product was purified by column chromatography (PE:EA=1:1) to obtain compound 10-c (60 mg, 20%) as a yellow solid. LC-MS (ESI): m/z=295.0 [M+H].sup.+.

(94) Synthesis of Compound 10-b

(95) Compound 10-c (60 mg, 0.2 mmol), tetrahydrofuran (6 mL), methanol (6 mL), water (3 mL), and lithium hydroxide monohydrate (34.2 mg, 0.8 mmol) were added to a reaction flask. After the mixture was stirred at room temperature overnight, it was added with dilute hydrochloric acid to adjust the pH to 6 to 7, and extracted with ethyl acetate (30 mL×3). The organic phase was washed successively with water, saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation to obtain a crude compound 10-b (30 mg, 53%). LC-MS (ESI): m/z=281.1 [M+H].sup.+.

(96) Synthesis of Compound 10-a

(97) Oxalyl chloride (1 mL) was slowly added to a solution of compound 10-b (30 mg, 0.11 mmol) in dichloromethane (10 mL) under an ice bath, and then another drop of DMF was added. The mixture was stirred at room temperature for 1 hour, and concentrated to obtain a crude. The above crude product in dichloromethane (10 mL) was added slowly to aqueous ammonia (5 mL) under an ice bath. The mixture was stirred overnight at room temperature and concentrated. The crude product was purified by Prep-TLC (DCM:MeOH=10:1) to obtain compound 10-a (15 mg, 50%) as a white solid. LC-MS (ESI): m/z=280.2 [M+H].sup.+.

(98) Synthesis of Compound 10

(99) Pd—CaCO.sub.3 (10 mg) was added to a solution of compound 10-a (15 mg, 0.05 mmol) in pyridine (10 mL) at room temperature. The reaction solution was evacuated and replaced with H.sub.2 several times. The mixture was stirred overnight at room temperature, filtered and concentrated. The crude product was purified by Prep-HPLC to obtain compound 10 (5 mg, 33%) as a white solid. LC-MS (ESI): m/z=282.1 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.54 (s, 1H), 8.25 (s, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 7.12 (d, J=7.5 Hz, 1H), 6.88 (d, J=12 Hz, 1H), 6.83 (d, J=12 Hz, 1H). Wherein 6.88 (d, J=12 Hz, 1H), 6.83 (d, J=12 Hz, 1H) is the compound displacement and coupling constant of the hydrogen on the carbon-carbon double bond.

(100) Synthetic Route of Compound 11

(101) ##STR00068##

(102) Synthesis of Compound 11-f

(103) SM-3 (500 mg, 2.07 mmol) was dissolved in dichloromethane (10 mL). Under an ice bath, oxalyl chloride (1 mL) and a drop of DMF were slowly added to the solution. The reactants were heated to room temperature and reacted for 60 minutes. The reactants were concentrated under reduced pressure and diluted with dichloromethane (5 mL). Under an ice bath, aqueous ammonia (5 mL) was slowly added dropwise. The reaction mixture was reacted at 0° C. for 10 minutes, and then heated to room temperature and stirred overnight. The liquid was separated and the aqueous layer was extracted with dichloromethane. The organic phases were combined, washed with water and brine, and dried over anhydrous sodium sulfate. Compound 11-f (300 mg, 60%) was obtained as a white solid by concentration. LC-MS (ESI): m/z=239.9 [M+H].sup.+.

(104) Synthesis of Compound 11-e

(105) 11-f (100 mg, 0.42 mmol) was dissolved in dioxane (10 mL). Under an ice bath, pyridine (0.34 mL, 4.2 mmol) was added to the solution, and after stirring for 5 minutes, trifluoroacetic anhydride (0.29 mL, 2.08 mmol) was slowly added dropwise. The reactants were heated to room temperature and stirred for 5 hours. After the reaction was completed, water was added to quench the reaction, and the organic solvents was removed by concentration under reduced pressure. The mixture was dissolved in ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 11-e (80 mg, 86%) as a white solid. LC-MS (ESI): m/z=221.9 [M+H].sup.+.

(106) Synthesis of Compound 11-d

(107) 11-e (0.5 g, 2.25 mmol), trimethylsilylacetylene (0.24 g, 2.48 mmol), bis(triphenylphosphine) palladium dichloride (31.6 mg, 0.045 mmol), cuprous iodide (8.6 mg, 0.045 mmol) and triethylamine (15 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was concentrated to remove organic solvents, added with water (30 mL), and extracted with ethyl acetate (30 mL). The organic phase was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation. A crude product was purified by column chromatography (PE:EA=4:1) to obtain compound 11-d (0.5 g, 92%) as a yellow solid. LC-MS (ESI): m/z=240.1 [M+H].sup.+.

(108) Synthesis of Compound 11-c

(109) A solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 6.68 mL, 6.68 mmol) was added to a solution of compound 11-d (0.5 g, 2.09 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at room temperature for 2 hours, concentrated to remove organic solvents, added with water (20 mL), and extracted with ethyl acetate (30 mL×2). The organic phase was washed successively with water, saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation. A crude product was purified by silica gel column chromatography (PE:EA=4:1) to obtain compound 11-c (250 mg, 72%) as a yellow solid. LC-MS (ESI): m/z=168.1 [M+H].sup.+.

(110) Synthesis of Compound 11-b

(111) 11-c (250 mg, 1.50 mmol), 2-bromo-6-trifluoromethylpyridine (371.8 mg, 1.65 mmol), bis(triphenylphosphine) palladium dichloride (21 mg, 0.03 mmol), cuprous iodide (5.7 mg, 0.03 mmol) and tri ethyl amine (15 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was concentrated to remove organic solvents, added with water (30 mL), and extracted with ethyl acetate (30 mL×2). The organic phase was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation. A crude product was purified by column chromatography (PE:EA=3:1) to obtain compound 11-b (100 mg, 21%) as a yellow solid. LC-MS (ESI): m/z=313.0 [M+H].sup.+.

(112) Synthesis of Compound 11-a

(113) Compound 11-b (60 mg, 0.19 mmol), potassium carbonate (4 mg, 0.029 mmol), and dimethyl sulfoxide (2 mL) were added to a reaction flask. Under an ice bath, H.sub.2O.sub.2 (26.1 mg, 0.77 mmol) was added dropwise. After the addition was completed, the mixture was stirred overnight at room temperature. The next day, the mixture was filtered, and the filter cake was washed with water and dried to obtain compound 11-a (50 mg, 79%) as a white solid. LC-MS (ESI): m/z=331.0 [M+H].sup.+.

(114) Synthesis of Compound 11

(115) Pd—CaCO.sub.3 (20 mg) was added to a solution of compound 11-a (50 mg, 0.15 mmol) in pyridine (10 mL) at room temperature. The reaction solution was evacuated and replaced with H.sub.2 several times, and the mixture was stirred overnight at room temperature, filtered and concentrated. A crude was purified by Prep-HPLC to obtain compound 11 (20 mg, 40%) as a white solid. LC-MS (ESI): m/z=333.1 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.52 (s, 1H), 8.27 (s, 1H), 7.93 (t, J=8.5 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.50-7.57 (m, 3H), 6.98 (d, J=12.5 Hz, 1H), 6.90 (d, J=12.5 Hz, 1H). Wherein 6.98 (d, J=12.5 Hz, 1H), 6.90 (d, J=12.5 Hz, 1H) is the compound displacement and coupling constant of the hydrogen on the carbon-carbon double bond.

(116) Synthetic Route of Compound 12

(117) ##STR00069##

(118) Synthesis of Compound 12-c

(119) 1-e (400 mg, 2 mmol), 2-bromo-3-fluoro-6-methylpyridine (417 mg, 2.2 mmol), his(triphenylphosphine) palladium dichloride (140 mg, 0.2 mmol), and cuprous iodide (38 mg, 0.2 mmol) and triethylamine (15 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was concentrated to remove organic solvents, added with water (30 mL), and extracted with ethyl acetate (30 mL×2). The organic phase was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation. A crude product was purified by column chromatography (PE:EA=1:1) to obtain compound 12-c (400 mg, 65%) as a yellow solid. LC-MS (ESI): m/z=310.0 [M+H].sup.+.

(120) Synthesis of Compound 12-b

(121) Compound 12-c (400 mg, 1.29 mmol), tetrahydrofuran (6 mL), methanol (6 mL), water (3 mL) and lithium hydroxide monohydrate (217 mg, 5.17 mmol) were added to a reaction flask. After the mixture was stirred overnight at room temperature, it was added with dilute hydrochloric acid to adjust the pH to 6 to 7, and extracted with ethyl acetate (30 mL×3). The organic phase was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation to obtain a crude compound 12-b (300 mg, 78%). LC-MS (ESI): m/z=296.0 [M+H].sup.+.

(122) Synthesis of Compound 12-a

(123) Oxalyl chloride (1 mL) was slowly added to a solution of compound 12-b (100 mg, 0.34 mmol) in dichloromethane (10 mL) under an ice bath, and then another drop of DMF was added. The mixture was stirred at room temperature for 1 hour, and concentrated to obtain a crude. The above crude product in dichloromethane (10 mL) was added slowly to aqueous ammonia (5 mL) under an ice bath. The mixture was stirred overnight at room temperature and concentrated. The crude product was purified by Prep-TLC (DCM:MeOH=10:1) to obtain compound 12-a (50 mg, 50%) as a white solid. LC-MS (ESI): m/z=295.0 [M+H].sup.+.

(124) Synthesis of Compound 12

(125) Pd—CaCO.sub.3 (20 mg) was added to a solution of compound 12-a (50 mg, 0.17 mmol) in pyridine (10 mL) at room temperature. The reaction solution was evacuated and replaced with H.sub.2 several times. The mixture was stirred overnight at room temperature, filtered and concentrated. The crude product was purified by Prep-HPLC to obtain compound 12 (17 mg, 40%) as a white solid. LC-MS (ESI): m/z=297.0 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.58 (s, 1H), 8.25 (s, 1H), 7.53 (d, J=9.5 Hz, 1H), 7.46 (t, J=8.5 Hz, 1H), 7.41 (dd, J=9, 1.5 Hz, 1H), 7.25 (dd, J=8.5, 3.5 Hz, 1H), 6.96 (d, J=12.5 Hz, 1H), 6.82 (dd, j=12.5, 2 Hz, 1H), 2.43 (s, 3H). Wherein 6.96 (d, J=12.5 Hz, 1H), 6.82 (dd, J=12.5, 2 Hz, 1H) is the compound displacement and coupling constant of the hydrogen on the carbon-carbon double bond.

(126) Synthetic Route of Compound 13

(127) ##STR00070##

(128) Synthesis of Compound 13-e

(129) 5-Bromopyrazolo[1,5-A]pyridine-3-carboxylate (2 g, 7.43 mmol), trimethylsilylacetylene (0.8 g, 8.18 mmol), his(triphenylphosphine) palladium dichloride (100 mg, 0.15 mmol), cuprous iodide (30 mg, 0.15 mmol) and triethylamine (15 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was concentrated to remove organic solvents, added with water (30 mL), and extracted with ethyl acetate (30 mL). The organic phase was washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation. A crude product was purified by column chromatography (PE:EA=4:1) to obtain compound 13-e (0.8 g, 38%) as a yellow solid. LC-MS (ESI): m/z=287.0 [M+H].sup.+.

(130) Synthesis of Compound 13-d

(131) A solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 5.6 mL, 5.6 mmol) was added to a solution of compound 13-e (0.8 g, 2.79 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at room temperature for 2 hours, concentrated to remove organic solvents, added with water (20 mL), and extracted with ethyl acetate (30 mL×2). The organic phase was washed successively with water, saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation. A crude product was purified by silica gel column chromatography (PE:EA=4:1) to obtain compound 13-d (500 mg, 83%) as a yellow solid. LC-MS (ESI): m/z=215.3 [M+H].sup.+.

(132) Synthesis of Compound 13-c

(133) 13-d (500 mg, 2.33 mmol), 2-bromo-6-methylpyridine (441.7 mg, 2.57 mmol), bis(triphenylphosphine) palladium dichloride (32.8 mg, 0.047 mmol), cuprous iodide (9 mg, 0.047 mmol) and triethylamine (15 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was concentrated to remove organic solvents, added with water (30 mL), and extracted with ethyl acetate (30 mL×2). The organic phase was washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation. A crude product was purified by column chromatography (PE:EA=3:1) to obtain compound 13-c (400 mg, 56%) as a yellow solid. LC-MS (ESI): m/z=306.0 [M+H].sup.+.

(134) Synthesis of Compound 13-b

(135) Compound 13-c (400 mg, 1.31 mmol), tetrahydrofuran (6 mL), methanol (6 mL), water (3 mL), and lithium hydroxide monohydrate (220 mg, 5.24 mmol) were added to a reaction flask. After the mixture was stirred at room temperature overnight, it was added with dilute hydrochloric acid to adjust the pH to 6 to 7, and extracted with ethyl acetate (30 mL×3). The organic phase was washed successively with water, saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation to obtain a crude compound 13-b (250 mg, 69%). LC-MS (ESI): m/z=278.0 [M+H].sup.+.

(136) Synthesis of Compound 13-a

(137) Oxalyl chloride (1 mL) was slowly added to a solution of compound 13-b (250 mg, 0.9 mmol) in dichloromethane (10 mL) under an ice bath, and then another drop of DMF was added. The mixture was stirred at room temperature for 1 hour, and concentrated to obtain a crude. The above crude product in dichloromethane (10 mL) was added slowly to aqueous ammonia (5 mL) under an ice bath. The mixture was stirred overnight at room temperature and concentrated. The crude product was purified by Prep-TLC (DCM:MeOH=10:1) to obtain compound 13-a (200 mg, 80%) as a white solid. LC-MS (ESI): m/z=277.0 [M+H].sup.+.

(138) Synthesis of Compound 13

(139) Pd—CaCO.sub.3 (20 mg) was added to a solution of compound 13-a (40 mg, 0.15 mmol) in pyridine (10 mL) at room temperature. The reaction solution was evacuated and replaced with H.sub.2 several times. The mixture was stirred overnight at room temperature, filtered and concentrated. A crude product was purified by Prep-HPLC to obtain compound 13 (20 mg, 49%) as a white solid. LC-MS (ESI): m/z=279.0 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 8.4-8.43 (m, 2H), 8.18 (s, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 6.90 (d, J=12.5 Hz, 1H), 6.85 (d, J=12.5 Hz, 1H), 6.81 (dd, J=7, 2 Hz, 1H), 2.51 (s, 3H). Wherein 6.90 (d, j=12.5 Hz, 1H), 6.85 (d, J=12.5 Hz, 1H) is the compound displacement and coupling constant of the hydrogen on the carbon-carbon double bond.

(140) Synthetic Route of Compound 14

(141) ##STR00071##

(142) Synthesis of Compound 14-d

(143) Compounds zinc cyanide (602 mg, 5.13 mmol), 7-bromo-2-chloroquinoxaline (2.5 g, 10.27 mmol), tetratriphenylphosphine palladium (1.2 g, 1.03 mmol) and DMF (10 mL) were added to a reaction flask. The reaction solution was replaced with N.sub.2 and stirred overnight at 80° C. The reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation. A crude product was separated by silica gel column chromatography (PE:EA=5:1) to obtain compound 14-d (2 g, 83%) as a white solid. LC-MS (ESI): m/z=233.9 [M+H].sup.+.

(144) Synthesis of Compound 14-c

(145) 14-d (1 g, 4.27 mmol), trimethylsilylacetylene (0.46 g, 4.7 mmol), bis(triphenylphosphine) palladium dichloride (60 mg, 0.086 mmol), cuprous iodide (16 mg, 0.086 mmol) and triethylamine (15 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was concentrated to remove organic solvents, added with water (30 mL), and extracted with ethyl acetate (30 mL). The organic phase was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation. A crude product was purified by column chromatography (PE:EA=10:1) to obtain compound 14-c (0.7 g, 65%) as a yellow solid. LC-MS (ESI): m/z=252.3 [M+H].sup.+.

(146) Synthesis of Compound 14-b

(147) 14-c (300 mg, 1.19 mmol), 2-bromo-6-trifluoromethylpyridine (226 mg, 1.3 mmol), bis(triphenylphosphine) palladium dichloride (17 mg, 0.024 mmol), cuprous iodide (4.5 mg, 0.024 mmol) and triethylamine (15 mL) were added to a reaction flask. The mixture was replaced with N.sub.2, and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 2.4 mL, 2.4 mmol) was added dropwise. The reaction mixture was reacted at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was concentrated to remove organic solvents, added with water (30 mL), and extracted with ethyl acetate (30 mL×2). The organic phase was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation. A crude product was purified by column chromatography (PE:EA=2:1) to obtain compound 14-b (120 mg, 37%) as a yellow solid. LC-MS (ESI): m/z=271.0 [M+H].sup.+.

(148) Synthesis of Compound 14-a

(149) Compound 14-b (120 mg, 0.44 mmol), potassium carbonate (9 mg, 0.067 mmol), and dimethyl sulfoxide (2 mL) were added to a reaction flask. Under an ice bath, H.sub.2O.sub.2 (60 mg, 1.78 mmol) was added dropwise. After the addition was completed, the mixture was stirred overnight at room temperature. The next day, the mixture was filtered, and the filter cake was washed with water and dried to obtain compound 14-a (100 mg, 78%) as a white solid. LC-MS (ESI): m/z=289.0 [M+H].sup.+.

(150) Synthesis of Compound 14

(151) Pd—CaCO.sub.3 (20 mg) was added to a solution of compound 14-a (50 mg, 0.17 mmol) in pyridine (10 mL) at room temperature. The reaction solution was evacuated and replaced with H.sub.2 several times. The mixture was stirred overnight at room temperature, filtered and concentrated. A crude product was purified by Prep-HPLC to obtain compound 14 (10 mg, 20%) as a white solid. LC-MS (ESI): m/z=291.0 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.45 (s, 1H), 8.09 (s, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.75 (dd, J=8.5 1.5 Hz, 1H), 7.52 (t, J=7.5 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.11 (d, J=12.5 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.91 (d, J=12.5 Hz, 1H), 2.49 (s, 3H). Wherein 7.11 (d, J=12.5 Hz, 1H), 6.91 (d, J=12.5 Hz, 1H) is the compound displacement and coupling constant of the hydrogen on the carbon-carbon double bond.

(152) Synthetic Route of Compound 15

(153) ##STR00072##

(154) Synthesis of Compound 15-c

(155) 1-e (200 mg, 1 mmol), 2-bromo-4-methylthiazole (196 mg, 1.1 mmol), his(triphenylphosphine) palladium dichloride (70 mg, 0.1 mmol), and cuprous iodide (57 mg, 0.3 mmol) and triethylamine (15 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was concentrated to remove organic solvents, added with water (30 mL), and extracted with ethyl acetate (30 mL×2). The organic phase was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation. A crude product was purified by column chromatography (PE:EA=2:1) to obtain compound 15-c (150 mg, 51%) as a yellow solid. LC-MS (ESI): m/z=298.0 [M+H].sup.+.

(156) Synthesis of Compound 15-b

(157) Compound 15-c (150 mg, 0.5 mmol), tetrahydrofuran (6 mL), methanol (6 mL), water (3 mL) and lithium hydroxide monohydrate (84.7 mg, 2 mmol) were added to a reaction flask. After the mixture was stirred overnight at room temperature, it was added with dilute hydrochloric acid to adjust the pH to 6 to 7, and extracted with ethyl acetate (30 mL×3). The organic phase was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation to obtain a crude compound 15-b (100 mg, 70%), LC-MS (ESI): m/z=283.9 [M+H].sup.+.

(158) Synthesis of Compound 15-a

(159) Oxalyl chloride (1 mL) was slowly added to a solution of compound 15-b (100 mg, 0.35 mmol) in dichloromethane (10 mL) under an ice bath, and then another drop of DMF was added. The mixture was stirred at room temperature for 1 hour, and concentrated to obtain a crude. The above crude product in dichloromethane (10 mL) was added slowly to aqueous ammonia (5 mL) under an ice bath. The mixture was stirred overnight at room temperature and concentrated. The crude product was purified by Prep-TLC (DCM:MeOH=10:1) to obtain compound 15-a (35 mg, 35%) as a white solid, LC-MS (ESI): m/z=283.1 [M+H].sup.+.

(160) Synthesis of Compound 15

(161) Pd—CaCO.sub.3 (20 mg) was added to a solution of compound 15-a (35 mg, 0.124 mmol) in pyridine (10 mL) at room temperature. The reaction solution was evacuated and replaced with H.sub.2 several times. The mixture was stirred overnight at room temperature, filtered and concentrated. A crude product was purified by Prep-HPLC to obtain compound 15 (20 mg, 56%) as a white solid. LC-MS (ESI): m/z=285.0 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.83 (s, 1H), 8.29 (s, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.56 (dd, J=9.5, 1.5 Hz, 1H), 7.03 (s, 1H), 6.90-6.98 (m, 2H), 2.40 (s, 3H). Wherein 6.90-6.98 (m, 2H) is the displacement of the hydrogen compound on the carbon-carbon double bond.

(162) Synthetic Route of Compound 16

(163) ##STR00073##

(164) Synthesis of Compound 16-e

(165) A solution of cyclohexanone (5.88 g, 60 mmol) in chloroform (30 mL) was slowly added dr op wise to a solution of phosphorus pentachloride (13.11 g, 63 mmol) in chloroform (30 mL) under an ice bath. The mixture was slowly heated to room temperature, reacted for 2 hours and then reacted under reflux for 2 hours, then poured into 150 g of ice, and slowly neutralized with solid sodium bicarbonate. After the ice was melted, the organic phase was separated, washed with saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, then dissolved in dichloromethane (6 mL), and added dropwise slowly at −5° C. with liquid bromine (6.24 g, 39 mmol). The mixture was stirred at −5° C. for 5 minutes, washed with 10% aqueous sodium thiosulfate solution, and dried over anhydrous sodium sulfate. The mixture was concentrated. A crude was purified by silica gel column chromatography (petroleum ether as eluent) to obtain compound 16-e (10.1 g, 61%) as a white solid.

(166) Synthesis of Compound 16-d

(167) A solution of compound 16-e (10.1 g, 36.5 mmol) in methanol (40 mL) was slowly added to a solution of potassium hydroxide (4.1 g, 73.1 mmol) in methanol (40 mL) under reflux. The mixture was reacted under reflux for 3 hours, then cooled to room temperature, and neutralized with 6 M hydrochloric acid solution. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (40 mL×3). The organic phases were combined, and dried over anhydrous sodium sulfate. The mixture was concentrated. A crude was purified by silica gel column chromatography (petroleum ether as eluent) to obtain compound 16-d (0.68 g, 7.7%) as a white solid. .sup.1H NMR (500 MHz, CDCl.sub.3): δ 2.61-2.51 (m, 4H), 1.80-1.70 (m, 4H).

(168) Synthesis of Compound 16-c

(169) Synthesis of Reference Compound 4-a.

(170) Synthesis of Compound 16-a

(171) 16-d (0.57 g, 2.38 mmol), 16-c (0.44 g, 2.14 mmol), Pd(dppf)Cl.sub.2 (174 mg, 0.238 mmol), sodium carbonate (504 mg, 4.76 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 overnight at 90° C. After the reaction was completed, the mixture was concentrated to remove organic solvents. A crude product was purified by column chromatography (DCM:MeOH=30:1) to obtain compound 16-a (420 mg, 55%) as a yellow solid. LC-MS (ESI): m/z=320.1 [M+H].sup.+.

(172) Synthesis of Compound 16-b

(173) It was prepared according to the method in the literature (Organometallics, 2017, vol. 36, #8, 1541-1549).

(174) Synthesis of Compound 16

(175) 16-a (0.38 g, 1.19 mmol), 16-b (2.27 g, 5.94 mmol), Pd(PPh.sub.3).sub.4 (137 mg, 0.119 mmol) and toluene (20 mL) were added to a reaction flask. The reaction mixture was replaced with N.sub.2 and reacted overnight at 90° C. After the reaction was completed, the mixture was concentrated to remove organic solvents. A crude product was purified by column chromatography (DCM:MeOH=20:1) and Prep-HPLC to obtain compound 16 (40 mg, 10%) as a yellow solid. LC-MS (ESI): m/z=333.3 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.19 (s, 1H), 8.17 (s, 1H), 7.35-7.47 (m, 2H), 7.22 (dd, J=9.5, 2.0 Hz, 1H), 6.99 (d, J=7.5 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 2.58 (m, 4H), 2.48 (s, 3H), 1.94 (m, 4H).

(176) Synthetic Route of Compound 17a

(177) ##STR00074##

(178) Synthesis of Compound 17a-c

(179) Under an ice bath, bromine (12.8 mL, 0.25 mol) was added slowly to a solution of sodium hydroxide (20 g, 0.5 mol) in water (60 mL). The reaction solution was stirred at 0° C. for 25 minutes, and then tert-butyl diethylphosphonoacetate (12.6 mL, 53.65 mmol) was added dropwise. After the dropwise addition, the reaction solution was extracted with dichloromethane (70 mL×2). The organic phase was washed with water (50 mL×1), and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation to obtain product 17a-c (20 g, 91%) as colorless oil. .sup.1H NMR (500 MHz, CDCl.sub.3): δ 4.35-4.41 (m, 4H), 1.54 (s, 9H), 1.39 (t, J=6.5 Hz, 6H).

(180) Synthesis of Compound 17a-b

(181) A solution of stannous chloride dihydrate (5.39 mL, 23.90 mmol) in water (50 mL) was added dropwise slowly to a solution of 17a-c (10 g, 24.39 mmol) in tert-butanol (50 mL) under an ice bath. The white reaction solution was kept at 0° C. and stirred for 15 minutes, and extracted with dichloromethane (50 mL×3). The organic phase was washed with water (50 mL×2), and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation to obtain product 17a-b (7 g, 87%) as yellowish oil. .sup.1H NMR (500 MHz, CDCl.sub.3): δ 4.25-4.30 (m, 5H), 1.50 (s, 9H), 1.38 (t, J=7.5 Hz, 6H).

(182) Synthesis of Compound 17a-a

(183) A solution of 17a-b (4.10 g, 12.38 mmol) in tetrahydrofuran (50 mL) was cooled to −78° C. under nitrogen protection, and LiHMDS (1M in THF, 12.38 mL, 12.38 mmol) was slowly added dropwise over 10 minutes, followed by the addition of 6-methyl-2-pyridinecarboxaldehyde (1 g, 8.25 mmol). After the addition was completed, the reaction solution was stirred at a low temperature for 30 minutes and then heated to room temperature for 1.5 hours. The reaction was quenched with water (20 mL), and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with water (50 mL×1), and dried over anhydrous sodium sulfate. The mixture was filtered and subjected to rotary evaporation. A crude product was purified by silica gel column chromatography (PE:EA=5:1) to obtain 17a-a (2 g, 81%) as colorless oil. LC-MS (ESI): m/z=242.1 [M+H-tBu]+.

(184) Synthesis of Compound 17a

(185) A mixture of compounds 17a-a (2 g, 6.71 mmol), 16-c (10.06 g, 2.06 mmol), Pd(PPh.sub.3).sub.4 (0.78 g, 0.67 mmol), sodium carbonate (1.42 g, 13.4 mmol), toluene (10 mL), ethanol (5 mL) and water (5 mL) was heated to 80° C. and reacted overnight under a nitrogen atmosphere. The reactants were cooled to room temperature and concentrated, and separated with a mixture of water (10 mL) and dichloromethane (30 mL). The aqueous phase was extracted with dichloromethane, and the combined organic layer was washed with water, washed with saturated brine, dried, filtered and concentrated. The mixture was subjected to primary separation by silica gel column chromatography (DCM:MeOH=20:1) to obtain a crude. The crude was added with ethyl acetate (10 mL) and heated to reflux and stirred for 30 minutes. After cooling, it was filtered. A small amount of mother liquor was concentrated and separated by high-performance liquid preparation to obtain 17a as a white solid. LC-MS (ESI): m/z=379.2 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD) δ: 9.79 (s, 1H), 8.32 (s, 1H), 7.84 (dd, J=9.5, 2 Hz, 1H), 7.76 (d, j=9.5 Hz, 1H), 7.73 (t, j=7.5 Hz, 1H), 7.34 (d, j=8 Hz, 1H), 7.22 (d, j=8 Hz, 1H), 7.18 (s, 1H), 2.57 (s, 3H), 1.60 (s, 9H).

(186) Synthetic Route of Compound 17b

(187) ##STR00075##

(188) Synthesis of Compound 17b

(189) Under an ice bath, triethylamine (1.1 mL, 7.93 mmol) and trifluoroacetic anhydride (1.1 mL, 7.93 mmol) were added to a solution of 17a (1.5 g, 3.97 mmol) in tetrahydrofuran (10 mL). After the addition was completed, the mixture was heated to room temperature and stirred for 2 hours. After the reaction was completed, the mixture was added with ice water (10 mL), and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a light yellow solid 17b (1 g, 70%). LC-MS (ESI): m/z=361.3 [M+H].sup.+.

(190) Synthetic Route of Compound 17c

(191) ##STR00076##

(192) Synthesis of Compound 17c

(193) Trifluoroacetic acid (4 mL) was added to a solution of 17b (1 g, 2.77 mmol) in methylene chloride (20 mL). The resulting reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated, carefully neutralized to a pH of about 6 to 7 with a saturated solution of sodium bicarbonate under an ice bath, stirred for half an hour and filtered. The filter cake was washed with water and dried to obtain compound 17c (0.6 g, 71%) as a yellowish solid. LC-MS (ESI): m/z=305.0 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-t/d): δ 13.16 (s, 1H), 9.60 (s, 1H), 8.48 (s, 1H), 7.89 (s, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.59 (t, J=5 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 7.12-7.16 (m, 2H), 2.17 (s, 3H).

(194) Synthetic Route of Compound 18a

(195) ##STR00077##

(196) Synthesis of Compound 18a

(197) EDCI (75.6 mg, 0.39 mmol), HOBt (57.7 mg, 0.43 mmol) and DIPEA (127.4 mg, 0.99 mmol) were added to a solution of 17c (100 mg, 0.33 mmol) and ammonium chloride (1.3 g, 0.66 mmol) in DMF (5 mL). The resulting reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with water and separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated brine and dried over anhydrous Na.sub.2SO.sub.4. The mixture was concentrated. A crude product was purified by Prep-TLC (DCM:MeOH=20:1) to obtain compound 18a (60 mg, 60%) as a white solid. LC-MS (ESI): m/z=304.0 [M+H].sup.+.

(198) Synthetic Route of Compound 18

(199) ##STR00078##

(200) Synthesis of Compound 18

(201) Compound 18a (60 mg, 0.2 mmol), potassium carbonate (4 mg, 0.03 mmol), and dimethyl sulfoxide (2 mL) were added to a reaction flask. Under an ice bath, H.sub.2O.sub.2 (26.9 mg, 0.79 mmol) was added dropwise. After the addition was completed, the mixture was stirred overnight at room temperature. The next day, the mixture was filtered, and the filter cake was washed with water and dried to obtain compound 18 (35 mg, 55%) as a white solid. LC-MS (ESI): m/z=322.0 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.45 (s, 1H), 8.30 (s, 1H), 7.75 (s, 1H), 7.71 (d, J=9 Hz, 1H), 7.50 (t, J=8 Hz, 1H), 7.35 (dd, J=9.0, 1.5 Hz, 1H), 7.11 (d, J=7.5 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 2.37 (s, 3H).

(202) Synthetic Route of Compound 19a

(203) ##STR00079##

(204) Synthesis of Compound 19a

(205) HATU (125 mg, 0.33 mmol) and DIPEA (64 mg, 0.49 mmol) were added to a solution of 17c (50 mg, 0.16 mmol) and methylamine tetrahydrofuran solution (2M, 0.33 mL, 0.66 mmol) in dichloromethane (10 mL). The resulting reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with water and separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated brine and dried over anhydrous Na.sub.2SO.sub.4, and concentrated. A crude product was purified by Prep-TLC (DCM:Methanol=20:1) to obtain the product 19a (30 mg, 58%) as a white solid. LC-MS (ESI): m/z=318.2 [M+H].sup.+.

(206) Synthetic Route of Compound 19

(207) ##STR00080##

(208) Synthesis of Compound 19

(209) Compound 19a (30 mg, 0.095 mmol), potassium carbonate (2 mg, 0.014 mmol), and dimethyl sulfoxide (2 mL) were added to a reaction flask. Under an ice bath, H.sub.2O.sub.2 (12.9 mg, 0.38 mmol) was added dropwise. After the addition was completed, the mixture was stirred overnight at room temperature. The next day, the mixture was filtered, and the filter cake was washed with water and dried to obtain compound 19 (10 mg, 32%) as a white solid. LC-MS (ESI): m/z=336.3 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-tifc): δ 9.31 (s, 1H), 8.35 (s, 1H), 7.95 (bs, 1H), 7.73-7.78 (m, 1H), 7.68 (d, J=9 Hz, 1H), 7.57 (s, 1H), 7.49 (t, J=8.5 Hz, 1H), 7.35 (bs, 1H), 7.18 (dd, J=9.5, 2 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 2.67 (d, J=4 Hz, 3H), 2.22 (s, 3H).

(210) Synthetic Route of Compound 20a

(211) ##STR00081##

(212) Synthesis of Compound 20a

(213) HATU (125 mg, 0.33 mmol) and DIPEA (212 mg, 1.6 mmol) were added to a solution of 17c (50 mg, 0.16 mmol) and dimethylamine hydrochloride (329 mg, 0.66 mmol) in dichloromethane (10 mL). The resulting reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with water and separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous Na.sub.2SO.sub.4, concentrated, and purified by Prep-TLC (DCM:Methanol=20:1) to obtain compound 20a (40 mg, 73%) as a white solid. LC-MS (ESI): m/z=332.2 [M+H].sup.+.

(214) Synthetic Route of Compound 20

(215) ##STR00082##

(216) Synthesis of Compound 20

(217) Compound 20a (40 mg, 0.12 mmol), potassium carbonate (2.5 mg, 0.018 mmol), and dimethyl sulfoxide (2 mL) were added to a reaction flask. Under an ice bath, H.sub.2O.sub.2 (16.4 mg, 0.48 mmol) was added dropwise. After the addition was completed, the mixture was stirred overnight at room temperature. The next day, the mixture was filtered, and the filter cake was washed with water and dried to obtain 20 (25 mg, 59%) as a white solid. LC-MS (ESI): m/z=350.0 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.56 (s, 1H), 8.33 (s, 1H), 7.94 (bs, 1H), 7.62 (dd, J=9.2, 0.8 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H), 7.35 (bs, 1H), 7.26 (dd, J=9.2, 1.6 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 6.98 (d, J=7.6 Hz, 1H), 6.78 (s, 1H), 3.08 (s, 3H), 2.94 (s, 3H), 2.29 (s, 3H).

(218) Synthetic Route of Compound 21a

(219) ##STR00083##

(220) Synthesis of Compound 21a

(221) HATU (125 mg, 0.33 mmol) and DIPEA (64 mg, 0.49 mmol) were added to a solution of 17c (50 mg, 0.16 mmol) and piperidine (56 mg, 0.66 mmol) in methylene chloride (10 mL). The resulting reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with water and separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated brine and dried over anhydrous Na.sub.2SO.sub.4, and concentrated. A crude product was purified by Prep-TLC (DCM:Methanol=20:1) to obtain compound 21a (50 mg, 82%) as a white solid. LC-MS (ESI): m/z=372.1 [M+H].sup.+.

(222) Synthetic Route of Compound 21

(223) ##STR00084##

(224) Synthesis of Compound 21

(225) Compound 21a (50 mg, 0.13 mmol), potassium carbonate (2.8 mg, 0.02 mmol), and dimethyl sulfoxide (2 mL) were added to a reaction flask. Under an ice bath, H.sub.2O.sub.2 (18.3 mg, 0.54 mmol) was added dropwise. After the addition was completed, the mixture was stirred overnight at room temperature. The next day, the mixture was filtered, and the filter cake was washed with water and dried to obtain compound 21 (30 mg, 57%) as a white solid. LC-MS (ESI): m/z=390.2 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.61 (s, 1H), 8.28 (s, 1H), 7.60 (d, J=9.5 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.34 (dd, J=10, 2 Hz, 1H), 7.16 (d, j=8 Hz, 1H), 7.04 (d, j=8 Hz, 1H), 6.89 (s, 1H), 3.70 (m, 4H), 2.46 (s, 3H), 1.55-1.72 (m, 6H).

(226) Synthetic Route of Compound 22

(227) ##STR00085##

(228) Synthesis of Compound 22-a

(229) HATU (949 mg, 1.97 mmol) and DIPEA (637.1 mg, 4.93 mmol) were added to a solution of 17c (300 mg, 0.99 mmol) and methanol (1.97 g, 3.94 mmol) in methylene chloride (10 mL). The resulting reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with water and separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated brine and dried over anhydrous Na.sub.2SO.sub.4, and concentrated. A crude product was purified by Prep-TLC (PE:EA=1:1) to obtain compound 22-a (250 mg, 80%) as a white solid. LC-MS (ESI): m/z=319.0 [M+H].sup.+.

(230) Synthesis of Compound 22

(231) Compound 22-a (80 mg, 0.25 mmol), potassium carbonate (5 mg, 0.038 mmol), and dimethyl sulfoxide (2 mL) were added to a reaction flask. Under an ice bath, H.sub.2O.sub.2 (34.2 mg, 1.0 mmol) was added dropwise. After the addition was completed, the mixture was stirred overnight at room temperature. The next day, the mixture was filtered, and the filter cake was washed with water and dried to obtain a white solid 22 (40 mg, 47%). LC-MS (ESI): m/z=337.2 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ: 9.40 (s, 1H), 8.30 (s, 1H), 8.02 (s, 1H), 7.67 (d, J=9 Hz, 1H), 7.51 (t, J=8 Hz, 1H), 7.37 (dd, J=9, 1.5 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 3.88 (s, 3H), 2.37 (s, 3H).

(232) Synthetic Route of Comparative Compound 23

(233) ##STR00086##

(234) Synthesis of Compound 23-a

(235) Compounds 2-bromo-6-picoline (400 mg, 2.32 mmol), vinylboronic acid pinacol ester (430 mg, 2.79 mmol), Pd(dppf)Cl.sub.2 (85 mg, 0.116 mmol), Na.sub.2CO.sub.3 (49 mg, 4.64 mmol), 1,4-dioxane (15 mL) and water (3 mL) were added to a reaction flask. The reaction solution was replaced with N.sub.2, stirred overnight at 90° C., added with water (30 mL), and extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. A crude product was purified by silica gel column chromatography (PE:EA=10:1) to obtain compound 23-a (160 mg, 58%) as red oil. LC-MS (ESI): m/z=120.2[M+H].sup.+.

(236) Synthesis of Comparative Compound 23

(237) Compounds 23-a (160 mg, 1.3 mmol), 11-f (387 mg, 1.6 mmol), tri(o-tolyl)phosphine (79 mg, 0.26 mmol), palladium acetate (29 mg, 0.13 mmol), tri ethyl amine (0.362 mL, 2.6 mmol) and DMF (10 mL) were added to a reaction flask. The reaction solution was replaced with N.sub.2, stirred overnight at 90° C., added with water (50 mL), and extracted with ethyl acetate (30 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. A crude product was purified by Prep-HPLC to obtain compound 23 (45 mg, 12%) as a white solid. LC-MS (ESI): m/z=279.1 [M+H].sup.+; .sup.1H NMR (500 MHz, CDCl.sub.3): δ 9.63 (s, 1H), 8.05 (s, 1H), 7.75 (dd, 7=9.5, 1.5 Hz, 1H), 7.70 (d, J=9.5 Hz, 1H), 7.64 (d, J=16.5 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.20 (d, J=16.0 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 5.67 (brs, 1H), 2.60 (s, 3H). Wherein 7.64 (d, J=16.5 Hz, 1H), 7.20 (d, J=16.0 Hz, 1H) is the compound displacement and coupling constant of the hydrogen on the carbon-carbon double bond.

(238) Synthetic Route of Comparative Compound 24

(239) ##STR00087##

(240) Synthesis of Compound 24-b

(241) Compounds 23-a (300 mg, 2.52 mmol), SM-1 (677 mg, 2.52 mmol), tri(o-tolyl)phosphine (153 mg, 0.5 mmol), palladium acetate (56 mg, 0.25 mmol), triethylamine (0.7 mL, 5 mmol) and DMF (10 mL) were added to a reaction flask. The reaction solution was replaced with N.sub.2, stirred overnight at 90° C., added with water (50 mL), and extracted with ethyl acetate (30 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. A crude product was purified by silica gel column chromatography to obtain compound 24-b (500 mg, 65%) as a white solid. LC-MS (ESI): m/z=308.0 [M+H].sup.+.

(242) Synthesis of Compound 24-a

(243) 24-b (0.5 g, 1.63 mmol) was added to methanol (10 mL) and THF (10 mL), and a sodium hydroxide aqueous solution (4M, 2 mL) was added. The reaction solution was stirred overnight at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure to remove organic solvents, water (10 mL) and DCM (50 mL) were added. The liquid was separated, and the organic layer was discarded. The water layer was cooled to 0° C. and neutralized with hydrochloric acid (2 M) to pH 6 to 7. A yellowish precipitate was filtered off and dried to obtain compound 24-a (0.4 g, 88%). LC-MS (ESI): m/z=280.3 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOD): δ 9.76 (s, 1H), 8.07 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.71 (t, J=7.6 Hz, 1H), 7.61-7.65 (m, 2H), 7.49 (d, J=8 Hz, 1H), 7.28 (d, 7=16.4 Hz, 1H), 7.17 (d, J=7.6 Hz, 1H), 2.57 (s, 3H).

(244) Synthesis of Comparative Compound 24

(245) 24-a (100 mg, 0.36 mmol) was dissolved in dichloromethane (10 mL). Under an ice bath, oxalyl chloride (1 mL) and a drop of DMF were slowly added to the solution. The reactants were heated to room temperature and reacted for 60 minutes. The reactants were concentrated under reduced pressure and diluted with dichloromethane (5 mL). Under an ice bath, the solution was slowly added dr op wise to a solution of methylamine tetrahydrofuran (2M, 5 mL). The reaction mixture was reacted at 0° C. for 10 minutes, and then heated to room temperature and stirred overnight. The liquid was separated and the aqueous layer was extracted with dichloromethane. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude. The crude was subjected to high performance liquid preparative chromatography to obtain a white solid 24 (10 mg, 10%). LC-MS (ESI): m/z=293.3 [M+H].sup.+; .sup.1H NMR (500 MHz, MeOD): δ 9.43 (s, 1H), 8.06 (s, 1H), 7.75 (dd, 7=9.5, 1.5 Hz, 1H), 7.59 (t, 7=7.5 Hz, 1H), 7.54 (d, 7=9.5 Hz, 1H), 7.44 (d, J=16.0 Hz, 1H), 7.34 (d, J=7.5 Hz, 1H), 7.11 (d, J=16.5 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 4.90 (s, 3H), 2.91 (s, 3H). Wherein 7.44 (d, J=16.0 Hz, 1H), 7.11 (d, J=16.5 Hz, 1H) is the compound displacement and coupling constant of the hydrogen on the carbon-carbon double bond.

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

(246) 1. Preparation of a 1× kinase buffer: 40 mM Tris (pH 7.5), 20 mM MgCl2, 0.10% BSA, 1 mM DTT.

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

(248) 3. Kinase reaction: The kinase was added to a 1× kinase buffer to form a 2× enzyme solution. The final concentration of the kinase solution was ALK5: 25 nM. The polypeptide TGFbR1 (purchased from Signal Chem, catalog number T36-58) and ATP were added to a 1× kinase buffer to form a 2× substrate solution. The final concentration of the substrate solution was peptide TGFbR1 0.1 mg/mL, ATP 7 μM. 2.5 μL of the 2× enzyme solution was added to the 384-well reaction plate (there was already 50 nL of 100% DMSO dissolved compound), and a 1× kinase buffer was added to a negative control well. The reaction solution 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.

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

(250) 5. Curve fitting: The data of the luminescence reading were copied from the Synegy program. The value of the luminescence reading was converted to inhibition percentage by a formula (inhibition percentage=(max−sample RLU)/(max−min)×100, where “min” was a fluorescence reading for a control sample without enzyme; “max” was a fluorescence reading for a sample with DMSO as a control). The data were imported into MS Excel and GraphPad Prism was used for curve fitting. IC.sub.50 value was calculated.

(251) TABLE-US-00001 TABLE 1 IC.sub.50 results of the compounds of the present invention on ALK5 activity ALK5 ALK5 IC.sub.50 IC.sub.50 Compound No. (nM) Compound No. (nM)  1 8  2 44  3 9.2  4 17  5 35  6 25  7 21  8 56  9 15 10 15 11 10 12 8.5 13 5.1 14 78 15 33 16 48 17 616  17a 6.6 18 328 19 207 20 34  21a 4946 21 58 SB431542 108 22 7.4 Comparative compound 23 372 Comparative compound 24 88 / /

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

(253) ##STR00088##

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

(255) Although the specific embodiments of the present invention have been described above, it will be understood by those skilled in the art that these are merely illustrative, and that various alterations or modifications can be made to these embodiments without departing from the principle and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.