Pyrimidine compounds as Wee-1 inhibitors

Abstract

The present invention discloses pyrimidine compounds as Wee-1 inhibitors.Specifically, the present invention relates to a compound of general formula (1), its preparation method, and the use of the compound of general formula (1) or its isomer, crystal form, pharma-ceutically acceptable salt, hydrate or solvate as Wee-1 inhibitor in preparing an antitumor drug. [Formula 1] TIFF2024508769000261.tif43168

Description

[Technical field]

[0001] This application claims priority to Chinese Patent Application No. 2021101922745, filed on February 19, 2021, Chinese Patent Application No. 2021108156003, filed on July 19, 2021, and Chinese Patent Application No. 2022101294609, filed on February 11, 2022, which are incorporated by reference in their entireties.

[0002] The present invention relates to the field of medicinal chemistry, in particular to novel compounds having inhibitory activity against Wee-1 kinase, their preparation process and the use of said compounds in the preparation of antitumor drugs. [Background technology]

[0003] Wee-1 protein kinase is an important negative control protein in cell cycle checkpoints. Cell cycle checkpoints include the G1 checkpoint, which transitions from the G1 phase (gap 1 phase) to the S phase (DNA synthesis phase), the G2 checkpoint, which transitions from the G2 phase (gap 2 phase) to the M phase (mitosis phase), and the spindle checkpoint, which transitions from mid-phase to late-phase of the M phase. Wee-1 protein kinase plays an important role in the G2 checkpoint. The initiation of the M phase depends on CDK1 kinase activity, and Wee-1 phosphorylates Tyr15 of the CDK1 protein to inhibit CDK1 activity and prevent cells from transitioning to the M phase. On the other hand, when polo kinase phosphorylates Wee-1, the degradation of Wee-1 protein is activated, promoting the initiation of the M phase. Thus, the kinase activity of Wee-1 determines the activity of the G2 checkpoint and regulates the transition of cells from G2 to M [Cell Cycle,2013.12(19):p.3159-3164].

[0004] Cell cycle checkpoints are mainly activated after DNA damage and play an important role in repairing DNA in cells. When cell cycle checkpoints are normally activated, the cell cycle is inhibited and DNA repair is promoted. When the checkpoint function is inhibited, DNA damage cannot be repaired and cells undergo apoptosis. Compared with normal cells, various tumor cells mainly rely on activation of the G2 checkpoint to repair DNA damage and avoid apoptosis due to the reduced function of p53 protein, an important protein of the G1 checkpoint. Therefore, tumor cells can be selectively killed by inhibiting the G2 checkpoint. The important role of Wee-1 kinase activity in the G2 checkpoint suggests that Wee-1 kinase determines the repair or death of tumor cells after DNA damage, and inhibiting Wee-1 activity can promote the initiation of M phase in tumor cells that cannot be repaired after DNA damage, inducing apoptosis [Curr Clin Pharmacol,2010.5(3):p.186-191].

[0005] In addition to its role in the G2 checkpoint, studies have shown that Wee-1 is involved in functions closely related to tumor initiation and progression, such as DNA synthesis, DNA homologous repair, and post-translational modification of chromosomal histones [J Cell Biol,2011.194(4):p.567-579]. Wee-1 expression is highly increased in many tumors, including liver cancer, breast cancer, cervical cancer, melanoma, and lung cancer [PLoS One,2009.4(4):p.e5120.;Hepatology,2003.37(3):p.534-543.;Mol Cancer,2014.13:p.72.]. High expression of Wee-1 is positively correlated with tumor development or poor prognosis, suggesting that Wee-1 kinase may be involved in tumor initiation and progression. Studies using in vitro cell models and in vivo animal models have shown that inhibition of Wee-1 activity while inducing DNA damage can significantly inhibit the growth of various tumors [Cancer Biol Ther,2010.9(7):p.514-522.;Mol Cancer Ther,2009.8(11):p.2992-3000].

[0006] Therefore, the development of specific and highly active small molecule inhibitors of Wee-1 kinase would be of significant clinical value for tumor therapy, especially for targeting tumors with compromised G1 checkpoints, such as p53 deletion. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Cell Cycle,2013.12(19):p.3159-3164 [Non-Patent Document 2] Curr Clin Pharmacol,2010.5(3):p.186-191 [Non-Patent Document 3] J Cell Biol,2011.194(4):p.567-579 [Non-Patent Document 4] PLoS One,2009.4(4):p.e5120. [Non-Patent Document 5] Hepatology,2003.37(3):p.534-543. [Non-Patent Document 6] Mol Cancer, 2014.13:p.72. [Non-Patent Document 7] Cancer Biol Ther,2010.9(7):p.514-522. [Non-Patent Document 8] Mol Cancer Ther,2009.8(11):p.2992-3000 Summary of the Invention

[0008] The present invention provides a compound of general formula (1), or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof: [ka] During the ceremony, X is CH or N; Y is -H, halogen, -CN, -S(O)R 5 , -P(O)(R 6 )2, -C(O)NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkynyl, (C3-C14) cycloalkyl, (C6-C14) aryl, 3- to 11-membered heterocycloalkyl, or 5- to 11-membered heteroaryl, wherein the (C1-C6) alkyl, the (C1-C6) haloalkyl, the (C2-C6) alkynyl, the (C3-C14) cycloalkyl, the (C6-C14) aryl, the 3- to 11-membered heterocycloalkyl, or the 5- to 11-membered heteroaryl are each independently selected from the following groups: -H, halogen, R 8 , -OH, -(CH2)nOR 8 -, -(CH2) n NR 8 R 9 , -OR 8 , -NR8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O)2R 8 , -S(O) p R 8 , and -S(O)NR 8 R 9 may be optionally substituted with one, two, three, or four of Z is a chemical bond, -CH2-, -O-, or -NH-;

[0009] Ring A is (C6-C14)aryl, 5- to 14-membered heteroaryl, or 3- to 14-membered heterocycloalkyl; R 1 and R 2 are each independently a (C1-C6) alkyl, a (C1-C6) haloalkyl, a (C2-C6) alkenyl, or a (C3-C6) cycloalkyl, wherein the (C1-C6) alkyl, the (C1-C6) haloalkyl, the (C2-C6) alkenyl, or the (C3-C6) cycloalkyl are each independently one of the following groups: -H, -D, halogen, R 8 , -OH, -(CH2) n OR 8 , -(CH2) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O)2R 8 , -S(O) p R 8 , and -S(O)NR 8 R 9 or R 1 and R 2can form, together with the S atom to which they are attached, a 4- to 7-membered heterocycloalkyl, wherein said 4- to 7-membered heterocycloalkyl is selected from the following groups: —H, halogen, R 8 , -OR 8 , -NR 8 R 9 and -CN;

[0010] Each R 3 are independently -H, -D, halogen, R 8 , -OH, -(CH2) n OR 8 , -(CH2) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O)2R 8 , -S(O) p R 8 , -S(O)NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C6-C14) aryl, 3- to 11-membered heterocycloalkyl, or 5- to 11-membered heteroaryl, wherein the (C1-C6) alkyl, the (C1-C6) haloalkyl, the (C2-C6) alkenyl, the (C2-C6) alkynyl, the (C3-C9) cycloalkyl, the (C6-C14) aryl, the 3- to 11-membered heterocycloalkyl, or the 5- to 11-membered heteroaryl are each independently selected from the following groups: -H, halogen, R 8 , -OH, -(CH2) n OR 8 , -(CH2) n NR 8 R 9 , -OR 8 , -NR 8 R 9, -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O)2R 8 , -S(O) p R 8 , and -S(O)NR 8 R 9 or two adjacent R 3 may form, together with the atoms to which they are attached, a 5- to 9-membered heterocycloalkyl or a (C5-C9)cycloalkyl, wherein said 5- to 9-membered heterocycloalkyl or said (C5-C9)cycloalkyl is selected from the following groups: -H, halogen, R 8 , -OH, -(CH2) n OR 8 , -(CH2) n NR 8 R 9 , -OR 8 , -NR 8 R 9 , -CN, -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O)2R 8 , -S(O) p R 8 , and -S(O)NR 8 R 9 optionally substituted with one, two, three or four of

[0011] Ring B is (C6-C14)aryl or 5- to 11-membered heteroaryl; Each R 4 are independently -H, halogen, R 8 , -OH, -(CH2) n OR 8 , -OR 8 , -(CH2) n NR 8 R 9 , -NR 8 R 9 , -CN, -O(CH2) mNR 8 R 9 , -N(R 9 )(CH2) m NR 8 R 9 , -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O)2R 8 , -S(O) p R 8 , -S(O)NR 8 R 9 , (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C9)cycloalkyl, (C1-C6)alkoxy, -CH2-3- to 15-membered heterocycloalkyl, 3- to 15-membered heterocycloalkyl, 5- to 9-membered heteroaryl, or (C6-C10)aryl, wherein the (C1-C6)alkyl, the (C1-C6)haloalkyl, the (C2-C6)alkenyl, the (C2-C6)alkynyl, the (C3-C9)cycloalkyl, the (C1-C6)alkoxy, the -CH2-3- to 15-membered heterocycloalkyl, the 3- to 15-membered heterocycloalkyl, the 5- to 9-membered heteroaryl, or the (C6-C10)aryl is selected from the following groups: -H, halogen, R 8 , -OH, -(CH2) n OR 8 , -OR 8 , -(CH2) n NR 8 R 9 , -NR 8 R 9 , -CN, -O(CH2) m NR 8 R 9 , -N(R 9 )(CH2) m NR 8 R 9, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, -CH2-3- to 15-membered heterocycloalkyl, 3- to 15-membered heterocycloalkyl, 5- to 9-membered heteroaryl, (C6-C10) aryl, and -R 7 or two adjacent R 4 may form, together with the atoms to which they are attached, a 5- to 9-membered heterocycloalkyl or a (C5-C9)cycloalkyl, wherein said 5- to 9-membered heterocycloalkyl or said (C5-C9)cycloalkyl is selected from the following groups: -H, halogen, R 8 , -OH, -(CH2) n OR 8 , -OR 8 , -(CH2) n NR 8 R 9 , -NR 8 R 9 , -CN, -O(CH2) m NR 8 R 9 , -N(R 9 )(CH2) m NR 8 R 9 , -C(O)R 8 , -C(O)NR 8 R 9 , -NR 9 C(O)R 8 , -NR 9 S(O)2R 8 , -S(O) p R 8 , -S(O)NR 8 R 9 , [ka] , optionally substituted with one, two, three or four of (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C9)cycloalkyl, (C1-C6)alkoxy, -CH2-4- to 9-membered heterocycloalkyl, 4- to 9-membered heterocycloalkyl, 5- to 9-membered heteroaryl, and (C6-C10)aryl;

[0012] R 5 is (C1-C3) alkyl or (C3-C6) cycloalkyl; R 6 is (C1-C3) alkyl or (C3-C6) cycloalkyl; R 7 is a 3- to 11-membered heterocycloalkyl, wherein said heterocycloalkyl is selected from the following groups: -H, R 8 , -OR 8 , and -NR 8 R 9 may be optionally substituted with one, two, three, or four of R 8 and R 9 are each independently -H, (C1-C6) alkyl or (C3-C14) cycloalkyl, or R 8 and R 9 can form, together with the N atom to which they are attached, a 3- to 11-membered heterocycloalkyl, wherein said 3- to 11-membered heterocycloalkyl is selected from the following groups: —H, halogen, R 10 , and -OR 10 one, two, three, or four of which may be optionally substituted; R 10 is -H, (C1-C3)alkyl, or (C3-C6)cycloalkyl; R 11 and R 12 are each independently -H, (C1-C3) alkyl or (C3-C6) cycloalkyl, or R 11 and R 12may form, together with the N atom to which they are attached, a 4- to 6-membered heterocycloalkyl; and p is an integer of 0, 1, or 2; q is an integer of 1, 2, 3, or 4; r is an integer of 1, 2, or 3; s is an integer of 1, 2, 3, or 4; n is an integer of 0, 1, 2, or 3; and m is an integer of 1, 2, or 3.

[0013] In another preferred embodiment, in the general formula (1), Y is -H, -F, -Cl, -Br, -I, -CN, -S(O)2CH3, -P(O)(CH3)2, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C5)cycloalkyl, (C2-C3)alkynyl, or 5- to 6-membered heteroaryl, wherein the (C1-C3)alkyl, the (C1-C3)haloalkyl, the (C3-C5)cycloalkyl, the (C2-C3)alkynyl, or the 5- to 6-membered heteroaryl may each independently be optionally substituted with 1, 2, 3, or 4 of the following groups: -H, -F, -CN, -CH3, and -OCH3.

[0014] In another preferred embodiment, in the general formula (1), Y is -H, -F, -Cl, -Br, -I, -CN, -S(O)2CH3, -P(O)(CH3), -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3), -CH3, -CF3, [ka] and preferably, Y is -H, -F, -Br, -I, -CN, -S(O)2CH3, -P(O)(CH3), -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3), -CF3, [ka] and more preferably, Y is -CN.

[0015] In another preferred embodiment, in general formula (1), ring A is (C6-C10) aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocycloalkyl.

[0016] In another preferred embodiment, in the general formula (1), ring A is [ka] and preferably, ring A is [ka] and preferably, ring A is [ka] and preferably, ring A is [ka] and preferably, ring A is [ka] and preferably, ring A is [ka] It is.

[0017] In another preferred embodiment, in the general formula (1), R 1 and R 2 are each independently a (C1-C3)alkyl, a (C1-C3)haloalkyl, a (C2-C4)alkenyl, or a (C3-C5)cycloalkyl, wherein said (C1-C3)alkyl, said (C1-C3)haloalkyl, said (C2-C4)alkenyl, or said (C3-C5)cycloalkyl are each independently optionally substituted with one, two, three, or four of the following groups: -H, -D, -F, -Cl, -Br, -I, -CH3, -OH, -CHOCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, and -CN; or R 1 and R2 can form, together with the S atom to which they are bonded, a 4- to 6-membered heterocycloalkyl, which is optionally substituted with one, two, three, or four of the following groups: -H, -F, -Cl, -Br, -I, -CH, -OH, -CHOCH, -CHN(CH), -OCH, -N(CH), and -CN.

[0018] In another preferred embodiment, in the general formula (1), the structural unit: [ka] teeth, [ka] and preferably [ka] and more preferably [ka] and more preferably [ka] It is.

[0019] In another preferred embodiment, in general formula (1), each R 3 are independently -H, -D, -F, -Cl, -Br, -I, -OH, -CHOR 11 , -CHNR 11 R 12 , -OR 11 , -NR 11 R 12 , -CN, -C(O)NR 11 R 12 , -NR 12 C(O)R 11 , -NR 12 S(O)2R 11 , -SR 11 , -S(O)2R 11 , -S(O)NR11 R 12 , (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, phenyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein said (C1-C3)alkyl, said (C1-C3)haloalkyl, said (C2-C4)alkenyl, said (C2-C4)alkynyl, said (C3-C6)cycloalkyl, said phenyl, said 4- to 8-membered heterocycloalkyl, or said 5- to 6-membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -N(CH3)2, and -CN; or two adjacent R 3 can, together with the atoms to which they are bonded, form a 5- to 7-membered heterocycloalkyl or a (C5-C7)cycloalkyl, wherein said 5- to 7-membered heterocycloalkyl or said (C5-C7)cycloalkyl is optionally substituted with one, two, three, or four of the following groups: -H, -F, -Cl, -Br, -I, -CH3, -OH, -CHOCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, and -CN.

[0020] In another preferred embodiment, in general formula (1), each R 3 are independently -H, -D, -F, -Cl, -Br, -I, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, -CN, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, - NHC(O)CH3, -N(CH3)-C(O)CH3, -NHS(O)2CH3, -NCH3S(O)2CH3, -SCH3, -S(O)2CH3, -S(O)2NH2, -S(O)2NH(CH3), -S(O)2N(CH3)2, [ka] and preferably R 3 -H, -D, -F, -Cl, -OCH3, -CN, [ka] and more preferably, R 3 are -H, -F, OCH3, [ka] It is.

[0021] In another preferred embodiment, in the general formula (1), the structural unit: [ka] teeth, [ka] TIFF2024508769000022.tif222168; preferably [ka] TIFF2024508769000024.tif82168; more preferably [ka] and more preferably [ka] It is.

[0022] In another preferred embodiment, in general formula (1), ring B is (C6-C10) aryl or 5- to 10-membered heteroaryl.

[0023] In another preferred embodiment, in the general formula (1), ring B is [ka] It is.

[0024] In another preferred embodiment, in general formula (1), each R 4are independently -H, -F, -Cl, -Br, -I, -OH, -CHOR 11 , -(CH2)2OR 11 , -(CH2)3OR 11 , -OR 11 , -CH2NR 11 R 12 , -(CH2)2NR 11 R 12 , -(CH2)3NR 11 R 12 , -NR 11 R 12 , -CN, -O(CH2)2NR 11 R 12 , -N(R 12 )(CH2)2NR 11 R 12 , -C(O)NR 11 R 12 , -NR 12 C(O)R 11 , -NR 12 S(O)2R 11 , -S(O)2R 11 , -SR 11 , -S(O)NR 11 R 12, (C1-C4) alkyl, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (C1-C4) alkoxy, -CH2-4- to 11-membered heterocycloalkyl, 4- to 11-membered heterocycloalkyl, 5- to 9-membered heteroaryl, or (C6-C10) aryl, wherein the (C1-C4) alkyl, the (C1-C4) haloalkyl, the (C2-C4) alkenyl, the (C2-C4) alkynyl, the (C3-C6) cycloalkyl, the (C1-C4) alkoxy, -CH2-4- to 11-membered heterocycloalkyl, 4- to 11-membered heterocycloalkyl, 5- to 9-membered heteroaryl, or (C6-C10) aryl. the -CH2-4 to 11 membered heterocycloalkyl, the 4 to 11 membered heterocycloalkyl, the 5 to 9 membered heteroaryl, or the (C6 to C10)aryl may be any of the following groups: -H, -F, -Cl, -Br, -I, -OH, -CH2OCH3, -(CH2)2OCH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2, -CN, -O(CH2)2N(CH3)2, -NH-(CH2)2N(CH3)2, -N(CH3)-(CH2)2N(CH3)2, [ka] or two adjacent R on ring B are optionally substituted with one, two, three, or four of 4 may, together with the atom to which they are attached, form a 5- to 7-membered heterocycloalkyl or (C5-C7)cycloalkyl, wherein said heterocycloalkyl and said cycloalkyl are selected from the following groups: -H, -F, -Cl, -Br, -I, -OH, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OH, -OCH3, -OCH2CH3, -OCH(CH3) 2, -CH2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2, -CN, -O(CH2)2N(CH3)2, -NH-(CH2)2N(CH3)2, -N(CH3)- (CH2)2N(CH3)2, -C(O)CH3, -C(O)NH2, -C(O)N(CH3)2, -S(O)2CH3, -SCH3, -S(O)2NH2, -S(O)2N(CH3)2, [ka] may be optionally substituted with 1, 2, 3 or 4 of:

[0025] In another preferred embodiment, in general formula (1), each R 4 are independently -H, -F, -Cl, -Br, -I, -OH, -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH2NH2, -(CH2)2NH2, -(CH2)3NH2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -OCF2H, -CH2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2, -CN, -O(CH2)2N(CH3)2, -NH-(CH2)2N(CH3)2, -N(CH 3)-(CH2)2N(CH3)2, -C(O)NH2, -C(O)N(CH3)2, -S(O)2CH3, -SCH3, -S(O)2NH2, -S(O)2N(CH3)2, [ka] It is.

[0026] In another preferred embodiment, in general formula (1), each R 4 is, independently, [ka] It is.

[0027] In another preferred embodiment, in the general formula (1), R 4 is preferably -H, -F, -Cl, -Br, -I, -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH2NH2, -(CH2)2NH2, -(CH2)3NH2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -OCF2H, -CH2N(CH3)2, -N(CH3)2, -CN, -SCH3, [ka] and more preferably, R 4 is -H, -F, -Cl, -Br, -I, -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -CH2OH, -(CH2)2OH, -(CH2)3OH, - CH2NH2, -(CH2)2NH2, -(CH2)3NH2, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2N(CH3)2, -N(CH3)2, -CN, [ka] It is.

[0028] In another preferred embodiment, in the general formula (1), two adjacent R 4 can form, together with the atom to which they are attached, a 5- to 7-membered heterocycloalkyl, where said heterocycloalkyl is [ka] or two adjacent R on ring B 4 may together with the atom to which they are attached form a (C5-C7)cycloalkyl; wherein said (C5-C7)cycloalkyl is [ka] wherein the 5- to 7-membered heterocycloalkyl and the (C5-C7)cycloalkyl are selected from the following groups: -H, -F, -Cl, -Br, -I, -OH, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2, -CN, -O(CH2)2N(CH3)2, -NH-(CH2)2N(CH3)2, -N(CH3)-(CH2)2N(CH3)2, -C(O)CH3, -C(O)NH2, -C(O)N(CH3)2, -S(O)2CH3, -SCH3, -S(O)2NH2, -S(O)2N(CH3)2, [ka] may be optionally substituted with 1, 2, 3 or 4 of:

[0029] In another preferred embodiment, in the general formula (1), the structural unit: [ka] teeth, [ka] TIFF2024508769000039.tif235168TIFF2024508769000040.tif226168TIFF2024508769000041.tif59168.

[0030] In another preferred embodiment, in the general formula (1), the structural unit: [ka] teeth, [ka] It is.

[0031] In another preferred embodiment, in the general formula (1), the structural unit: [ka] teeth, [ka] It is.

[0032] In another preferred embodiment, in the general formula (1), the structural unit: [ka] is preferably [ka] TIFF2024508769000048.tif230168TIFF2024508769000049.tif118168; more preferably [ka] The file is TIFF2024508769000051.tif83168.

[0033] In some embodiments, the present invention provides a compound of general formula (2), or an isomer, a crystalline form, a pharma- ceutically acceptable salt, hydrate or solvate thereof: [ka] In the formula, A, B, Y, Z, R 1 , R 2 , R 3 , R 4 , q, and s are as defined above and exemplified in the detailed description.

[0034] In some embodiments, the present invention provides a compound of general formula (3a) or general formula (3b), or an isomer, a crystalline form, a pharma- ceutically acceptable salt, a hydrate, or a solvate thereof: [ka] In the formula, A, B, Y, R 1 , R 2 , R 3 , R 4 , q and s are as defined above and exemplified in the detailed description.

[0035] In some embodiments, the present invention provides a compound of general formula (4), or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof: [ka] In the formula, A, Y, Z, R 1 , R 2 , R 3 , R4 , q, and s are as defined above and exemplified in the detailed description.

[0036] In some embodiments, the present invention provides a compound of general formula (5a) or general formula (5b), or an isomer, a crystalline form, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof: [ka] In the formula, A, Y, R 1 , R 2 , R 3 , R 4 , q and s are as defined above and exemplified in the detailed description.

[0037] In some embodiments, the present invention provides a compound of general formula (6), or an isomer, a crystal form, a pharma- ceutically acceptable salt, hydrate or solvate thereof: [ka] In the formula, B, Y, Z, R 1 , R 2 , R 3 , R 4 , q, and s are as defined above and exemplified in the detailed description.

[0038] In some embodiments of the present invention, the present invention provides a compound of general formula (7a), general formula (7b), general formula (7c), general formula (7d), general formula (7e), general formula (7f) or general formula (7g), or an isomer, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [ka] In the formula, B, Y, R 1 , R 2 , R 3 , R 4 , q and s are as defined above and exemplified in the detailed description.

[0039] In some embodiments, the present invention provides a compound of general formula (8a), general formula (8b), general formula (8c), general formula (8d), general formula (8e), general formula (8f) or general formula (8g), or an isomer, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [ka] In the formula, Y, R 1 , R 2 , R 3 , R 4 , q and s are as defined above and exemplified in the detailed description.

[0040] In various different embodiments of the present invention, the compound of general formula (1) has the following structure: [ka] TIFF2024508769000060.tif220168TIFF2024508769000061.tif234168TIFF2024508769000062.tif228168TIFF2024508769000063.tif213168TIFF2024508769000064.tif52168

[0041] The present invention further contemplates providing a pharmaceutical composition comprising a pharma- ceutically acceptable carrier, diluent and / or excipient and a compound of general formula (1) disclosed herein or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof as an active ingredient.

[0042] The present invention further contemplates the use of a compound of general formula (1) disclosed herein, or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or said pharmaceutical composition, in preparing a medicament for treating, modulating or preventing a disease associated with Wee-1 protein kinase.

[0043] The present invention further contemplates providing a method for treating, regulating or preventing a disease associated with Wee-1 protein kinase, comprising administering to a subject a therapeutically effective amount of a compound of general formula (1) disclosed herein, or an isomer, crystalline form, pharma-ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as described above.

[0044] The present inventors, through the synthesis and careful study of various classes of novel compounds having Wee-1 protein kinase inhibitory activity, have found that the compounds of general formula (1) have surprisingly potent Wee-1 protein kinase inhibitory activity.

[0045] It is to be understood that both the foregoing general description and the following detailed description of the invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

[0046] (Synthesis of Compounds)

[0047] Methods for preparing the compounds of general formula (1) disclosed in the present specification are specifically described below, but are not intended to limit the present invention in any way.

[0048] The compounds of formula (1) above can be synthesized using standard synthetic techniques, well-known techniques, in combination with the methods described herein. Additionally, the solvents, temperatures and other reaction conditions described herein may vary. Starting materials for the synthesis of the compounds can be obtained synthetically or commercially. The compounds described herein and other related compounds with various substituents can be synthesized or synthesized using the methods described herein, such as March, ADVANCED ORGANIC CHEMISTRY, 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY, 4th Ed., (Wiley 1992); th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3 rdEd., (Wiley 1999). General methods for preparing compounds can be modified by using appropriate reagents and conditions to introduce various groups into the formulas provided herein.

[0049] In one embodiment, the compounds described herein are prepared according to methods well known in the art. However, the conditions of the methods, such as reactants, solvents, bases, amounts of compounds used, reaction temperature, and reaction time, are not limited to the following description. In addition, the compounds of the present invention can be easily prepared by any combination of various synthetic methods described herein or known in the art, and such combinations can be easily determined by those skilled in the art to which the present invention pertains. In one embodiment, the present invention further provides a method for preparing a compound of general formula (1), wherein the compound of general formula (1) is prepared according to the following general reaction schemes 1, 2, 3, or 4.

[0050] General reaction scheme 1

[0051] [ka]

[0052] Embodiments of compounds of general formula (1) may be prepared according to General Reaction Scheme 1, wherein R 1 , R 2 , R 3 , R 4 , X, Y, Z, s, q, and ring A and ring B are as defined above, H represents hydrogen, N represents nitrogen, Cl represents chlorine, S represents sulfur, and O represents oxygen. As shown in General Reaction Scheme 1, compound 1-1 and compound 1-2 are subjected to a substitution reaction under alkaline conditions to produce compound 1-3, compound 1-3 is reacted with m-CPBA to produce compound 1-4, and compound 1-4 and compound 1-5 are subjected to a substitution reaction to produce target compound 1-6.

[0053] General reaction scheme 2

[0054] [ka]

[0055] Embodiments of compounds of general formula (1) may be prepared according to General Reaction Scheme 2, wherein R 1 , R 2 , R 3 , R 4 , X, Y, s, q, ring A and ring B are as defined above, H represents hydrogen, N represents nitrogen, Cl represents chlorine, S represents sulfur, and O represents oxygen. As shown in General Reaction Scheme 2, compounds 2-1 and 2-2 are subjected to a substitution reaction under alkaline conditions to produce compound 2-3, compound 2-3 is reacted with m-CPBA to produce compound 2-4, and compound 2-4 and compound 2-5 are subjected to a substitution reaction to produce target compound 2-6.

[0056] General reaction scheme 3

[0057] [ka]

[0058] Embodiments of compounds of general formula (1) may be prepared according to General Reaction Scheme 3, wherein R 1 , R 2 , R 3 , R 4 , X, Y, Z, s, q, ring A and ring B are as defined above, H represents hydrogen, N represents nitrogen, Cl represents chlorine, S represents sulfur, O represents oxygen, B represents boronic acid, boronic acid ester or trifluoroborate, L 1 represents bromine or iodine. As shown in General Reaction Scheme 3, compound 3-1 and compound 3-2 are subjected to a substitution reaction under alkaline conditions to produce compound 3-3, compound 3-3 is subjected to a coupling reaction with YB to produce target compound 3-4, compound 3-4 is reacted with m-CPBA to produce compound 3-5, and compound 3-5 and compound 3-6 are subjected to a substitution reaction to produce target compound 3-7.

[0059] General reaction scheme 4

[0060] [ka]

[0061] Embodiments of compounds of general formula (1) may be prepared according to General Reaction Scheme 4, wherein R 1 , R 2 , R 3 , R 4 , X, Y, s, q, ring A and ring B are as defined above, H represents hydrogen, N represents nitrogen, Cl represents chlorine, S represents sulfur, O represents oxygen, L 2 represents bromine or chlorine. As shown in General Reaction Scheme 4, compound 4-1 and compound 4-2 are subjected to a substitution reaction under alkaline conditions to produce compound 4-3, compound 4-3 is reacted with m-CPBA to produce compound 4-4, and compound 4-4 and compound 4-5 are subjected to a substitution reaction to produce the target compound 4-6.

[0062] Further forms of the compound

[0063] As used herein, the term "pharmaceutical acceptable" refers to a relatively non-toxic substance, such as a carrier or diluent, that does not cause the loss of biological activity or properties of a compound. For example, when a substance is administered to an individual, the substance does not cause undesirable biological effects or adverse interactions with any of its components.

[0064] The term "pharmaceutical acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism receiving the compound or does not eliminate the biological activity and properties of the compound.In certain embodiments, the pharmaceutical acceptable salt is obtained by reacting the compound of general formula (1) with an acid, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid and nitric acid, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, acidic amino acids such as aspartic acid and glutamic acid.

[0065] It is to be understood that pharma- ceutically acceptable salts include solvent addition forms or crystal forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization in pharma- ceutical acceptable solvents such as water and ethanol. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is ethanol. Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of general formula (1) are conveniently prepared by recrystallization in a water / organic solvent mixture, and the organic solvents used include, but are not limited to, tetrahydrofuran, acetone, ethanol, or methanol. Furthermore, compounds described herein may exist in either unsolvated or solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0066] In other specific examples, the compound of general formula (1) is prepared in different forms, including but not limited to amorphous, crushed, and nanoparticle forms. In addition, the compound of formula (1) may be a polymorph, including crystalline forms. A polymorph contains different lattice arrangements of the same elements of a compound. Polymorphs generally have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal morphology, optical properties, electrical properties, stability, and solubility. Various factors, such as recrystallization solvent, crystallization rate, and storage temperature, may result in a single predominant crystal system.

[0067] In another embodiment, the compounds of general formula (1) may have chiral centers and / or axial asymmetry and therefore may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, single diastereomers and cis-trans isomers. Each chiral center or axial asymmetry independently produces two optical isomers, and all possible optical isomers, diastereomeric mixtures and pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomers of these compounds.

[0068] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I) and C-14( 14 As another example, deuterium can be used to replace hydrogen atoms to form deuterated compounds. The bond formed by deuterium and carbon is stronger than the bond formed by common hydrogen and carbon, and deuterated drugs generally have the advantages of reduced side effects, improved drug stability, enhanced efficacy, and extended in vivo half-life compared to non-deuterated drugs. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0069] Explanation of terms

[0070] Unless otherwise specified, the terms used in the present specification and claims are defined as follows. Please note that in the present specification and the appended claims, the singular forms "a" and "an" include the plural meaning unless otherwise specified in the context. Conventional methods such as mass spectrometry, nuclear magnetic resonance spectroscopy, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used unless otherwise specified. In the present specification, "or" or "and" means "and / or" unless otherwise specified.

[0071] Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched groups, having 1 to 6 carbon atoms. Lower alkyls having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, or tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyls, particularly those substituted with one or more halogens. Preferred alkyls are CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, i Bu, n Bu and t is selected from Bu.

[0072] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched groups containing 1 to 14 carbon atoms. Lower alkenyl containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl, is preferred.

[0073] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight-chain and branched groups containing 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl, or 1-butynyl, are preferred.

[0074] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic); partially unsaturated cycloalkyls may be referred to as "cycloalkenyls" if the carbocyclic ring contains at least one double bond, or "cycloalkynyls" if the carbocyclic ring contains at least one triple bond. The cycloalkyls may include monocyclic or polycyclic groups, as well as spirocycles (e.g., having 2, 3, or 4 fused rings). In some embodiments, the cycloalkyls are monocyclic. In some embodiments, the cycloalkyls are monocyclic or bicyclic. The ring carbon atoms of the cycloalkyls may be optionally oxidized to form oxo or sulfido groups. The cycloalkyls further include cycloalkylene. In some embodiments, the cycloalkyls include 0, 1, or 2 double bonds. In some embodiments, the cycloalkyls include 1 or 2 double bonds (partially unsaturated cycloalkyls). In some embodiments, the cycloalkyl may be fused with an aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. In some embodiments, the cycloalkyl may be fused with an aryl, cycloalkyl, and heterocycloalkyl. In some embodiments, the cycloalkyl may be fused with an aryl and a heterocycloalkyl. In some embodiments, the cycloalkyl may be fused with an aryl and a cycloalkyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norcamphanyl, norpinanyl, norcarnyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and the like.

[0075] Unless otherwise specified, "alkoxy" refers to an alkyl group attached to the remainder of the molecule via an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, particularly alkoxy substituted with one or more halogens. Preferred alkoxy are OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO and t- BuO.

[0076] Unless otherwise specified, "aryl" refers to an aromatic hydrocarbon group that is monocyclic or polycyclic. For example, a monocyclic aryl ring can be fused with one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl, and phenanthryl.

[0077] Unless otherwise specified, "aryloxy" refers to an aryl group attached to the remainder of the molecule through an ether oxygen atom. Examples of said aryloxy include, but are not limited to, phenoxy and naphthoxy.

[0078] Unless otherwise specified, "arylene" refers to a divalent aryl as defined above. Examples of arylene include, but are not limited to, phenylene, naphthylene, phenanthrylene, and the like.

[0079] Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S, or N), said "heteroaryl" being monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused to one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl include pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridyl, 1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolo[3,2-c]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, [ka] These include, but are not limited to:

[0080] Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl as defined above.

[0081] Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus, which may optionally include one or more alkenylenes as part of the ring structure. A partially unsaturated heterocycloalkyl may be referred to as a "heterocycloalkenyl" when said heterocycloalkyl contains at least one double bond, and may be referred to as a "heterocycloalkynyl" when said heterocycloalkyl contains at least one triple bond. The heterocycloalkyl may include monocyclic, bicyclic, spirocyclic, or polycyclic systems (e.g., having two fused or bridged rings). In some embodiments, the heterocycloalkyl is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring carbon atoms and heteroatoms of the heterocycloalkyl may be optionally oxidized to form oxo or sulfide groups or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O), N-oxide, etc.), or the nitrogen atom may be quaternized. The heterocycloalkyl may be bonded through a ring carbon atom or a ring heteroatom. In some embodiments, the heterocycloalkyl contains 0-3 double bonds. In some embodiments, the heterocycloalkyl contains 0-2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., sharing a bond) to the heterocycloalkyl ring, e.g., benzo derivatives such as piperidine, morpholine, azepine, thienyl, etc. Heterocycloalkyls that contain fused aromatic rings may be bonded through any ring atom, including the ring atoms of the fused aromatic rings.Examples of heterocycloalkyl include azetidinyl, azepinyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-imidazo[ 4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrolactam, valerolactam, imidazolidinonyl, hydantoinyl, dioxolanyl, phthalimidyl, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-oxide, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyronyl, tetrahydrothienyl, 2-azaspiro[3.3]heptanyl, indolinyl,. [ka] These include, but are not limited to:

[0082] Unless otherwise specified, "heterocycloalkylene" refers to a divalent heterocycloalkyl as defined above.

[0083] Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine, or iodine. The term "halo" (or "halogenated") before a radical name indicates that the radical is partially or fully halogenated, i.e., substituted by F, Cl, Br or I, preferably F or Cl, in any combination.

[0084] "Optional" or "optionally" means that the subsequently described event or circumstance may occur, but does not necessarily occur, and the description includes instances in which the event or circumstance occurs and instances in which the event or circumstance does not occur.

[0085] The substituent "-O-CH2-O-" means that the two oxygen atoms in the substituent are attached to two adjacent carbon atoms in a heterocycloalkyl, aryl, or heteroaryl, for example: [ka]

[0086] When the number of a linker group is 0, such as -(CH2)0-, it means that the linker group is a single bond.

[0087] When one of the variables is selected from a chemical bond, it means that the two groups linked by this variable are directly linked, for example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0088] The term "membered ring" includes any cyclic structure. The term "membered" refers to the number of main chain atoms that form the ring. For example, cyclohexyl, pyridyl, pyranyl, and thiopyranyl are 6-membered rings, and cyclopentyl, pyrrolyl, furanyl, and thienyl are 5-membered rings.

[0089] The term "moiety" refers to a specific portion or functional group of a molecule. A chemical moiety is generally considered to refer to a chemical substance contained in or attached to a molecule.

[0090] TIFF2024508769000072.tif35168

[0091] Specific pharmaceutical and medical terms

[0092] The term "acceptable" as used herein means that the formulation or active ingredient does not have unduly deleterious effects on the general health of the subject being treated.

[0093] The terms "treatment", "course of treatment" and "treatment" as used herein include alleviating, inhibiting or ameliorating a disease symptom or condition, inhibiting the occurrence of a complication, improving or preventing the underlying metabolic syndrome, inhibiting the occurrence of a disease or condition (e.g., controlling the progression of a disease or condition), relieving a disease or condition, regressing a disease or condition, and alleviating complications caused by a disease or condition, or preventing or treating symptoms caused by a disease or condition. As used herein, a compound or pharmaceutical composition, when administered, can improve a disease, symptom or condition, and in particular can improve the severity, delay the onset, delay the progression, or shorten the duration of a disease. Fixed or episodic administration, or continuous or intermittent administration, can result from or relate to administration.

[0094] "Active ingredient" refers to compounds of general formula (1) and pharma- ceutically acceptable inorganic or organic salts of compounds of general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial asymmetry) and therefore may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers. The asymmetric centers that may exist depend on the properties of the various substituents on the molecule. Each of these asymmetric centers independently produces two optical isomers, and all possible optical isomers, diastereomeric mixtures, and pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0095] As used herein, terms such as "compound," "composition," "agent," or "medicine or pharmaceutical agent" are used interchangeably and all refer to a compound or composition that, when administered to an individual (human or animal), is capable of eliciting a desired pharmacological and / or physiological response through local and / or systemic action.

[0096] The terms "administered, administering, or administration" as used herein refer to direct administration of a compound or composition, or to administration of a prodrug, derivative, analog, etc. of an active compound.

[0097] Although the numerical ranges and parameters defining the broad scope of the present invention are approximations, the relevant values ​​set forth in certain embodiments are set forth herein as precisely as possible. However, any numerical value inherently contains a standard deviation that necessarily results from certain testing methods. Here, "about" generally means that the actual value is within a particular value or range ±10%, 5%, 1%, or 0.5%. Alternatively, the term "about" indicates that the actual numerical value is within an acceptable standard error of the mean value, as would be understood by one of ordinary skill in the art. Except in experimental examples or unless otherwise indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe amounts of materials, lengths of time, temperatures, operating conditions, proportions of amounts, etc.) are understood to be modified by the term "about". Thus, unless otherwise indicated, all numerical parameters set forth in this specification and the appended claims are approximations that may be varied as desired. At the very least, these numerical parameters should be interpreted as numerical values ​​obtained using the significant digits given or conventional rounding rules.

[0098] Scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art, unless otherwise defined herein. Furthermore, singular nouns used herein include their plurals, unless otherwise contradicted by context, and plural nouns used herein also include their singulars.

[0099] therapeutic use

[0100] The present invention provides the use of a compound of general formula (1) or a pharmaceutical composition of the present invention in the inhibition of Wee1 kinase, and thus in the treatment of one or more disorders associated with Wee1 kinase activity. Thus, in certain embodiments, the present invention provides a method for treating a Wee1 kinase-mediated disorder, comprising administering to a patient in need thereof a compound disclosed herein or a pharma- ceutically acceptable composition thereof.

[0101] In some embodiments, a method for treating cancer is provided, comprising administering to an individual in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of structural general formula (1). In some embodiments, the compound of general formula (1) may be used in combination with an additional anti-cancer agent. In some embodiments, the compound of general formula (1) may be used in combination with gemcitabine. In some embodiments, the cancer is mediated by Wee1 kinase. In other embodiments, the cancer is a hematological cancer and solid tumor, including, but not limited to, hematological malignancies (leukemia, lymphoma, and myeloma, including multiple myeloma, myelodysplastic syndrome, and myeloproliferative family syndrome), and solid tumors (e.g., carcinomas such as prostate, breast, lung, colon, pancreatic, renal, ovarian, and soft tissue cancers, osteosarcoma, and stromal tumors).

[0102] Route of administration

[0103] The compounds disclosed herein and their pharmaceutically acceptable salts can be prepared into various formulations containing a safe and effective amount of the compounds disclosed herein or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers, where "safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious adverse effects.The safe and effective amount of the compound is determined according to the age, condition, course of treatment, and other specific conditions of the subject to be treated.

[0104] "Pharmaceutically acceptable excipient or carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be suitable for human use and have sufficient purity and low toxicity. In this context, "compatible" means that the components of the composition can be mixed with the compounds of the present invention without significantly reducing the pharmaceutical efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose or cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid or magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0105] The compounds of the present invention may be administered orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous) or topically.

[0106] The solid dosage form for oral administration includes capsules, tablets, pills, powders (pulvises) and granules.In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, such as glycerol; (d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retardants, such as paraffin; (f) absorption promoters, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate. (h) an adsorbent such as kaolin; and (i) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol and sodium lauryl sulfate, or a mixture thereof. In the case of capsules, tablets and pills, the dosage form may further comprise a buffering agent.

[0107] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials known in the art.These may contain opacifying agents, and the active compound or compounds in such compositions can be released in a certain part of the digestive tract in a delayed manner.The examples of embedding components that can be used include polymeric materials and wax-based materials.If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0108] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0109] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0110] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate, and agar-agar, or mixtures of these substances.

[0111] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0112] Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier, and any preservatives, buffers, or propellants that may be required as required.

[0113] The compound of the present invention may be administered alone or in combination with other pharma- ceutical acceptable compounds. When the pharmaceutical composition of the present invention is used, a safe and effective amount of the compound of the present invention is administered to the mammal (such as a human) to be treated, and the dose is a pharma- ceutical effective dose. For a 60 kg human, the daily dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. In addition, when determining the specific dose, the route of administration, the health condition of the patient, etc. are also taken into consideration, but these are well known to those skilled in the art.

[0114] The above features described in the present invention or the features described in the embodiments above can be combined in any combination.All features disclosed herein can be used in any composition, and various features disclosed herein can be replaced with any alternative features that provide the same, equivalent or similar purpose.Thus, unless otherwise stated, the features disclosed herein are merely generic examples of equivalent or similar features. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0115] (Detailed Description) Various specific aspects, features and advantages of the above compounds, methods and pharmaceutical compositions will be described in detail as follows, which will make the contents of the present invention very clear. It should be understood that the following detailed description and examples are for reference purposes only and describe specific embodiments. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and such equivalents also fall within the scope of the present invention as defined herein.

[0116] In all examples, 1H-NMR spectra were recorded on a Vian Mercury 400 nuclear magnetic resonance spectrometer, and chemical shifts were expressed in δ (ppm); unless otherwise specified, 200-300 mesh silica gel was used for separation, and the ratio of eluents was by volume.

[0117] In the present invention, the following abbreviations are used: di-tert-butyl dicarbonate ((Boc)2O); deuterated chloroform (CDCl3); 10-camphorsulfonic acid (β) (CSA); ethyl acetate (EtOAc); n-hexane (Hexane); high performance liquid chromatography (HPLC); acetonitrile (MeCN); 1,2-dichloroethane (DCE); dichloromethane (DCM); diisopropylethylamine (DIPEA); 1,4-dioxane (1,4-Dioxane); N,N-dimethylformamide (DMF); 4-(dimethylamino)pyridine (DMAP); dimethylsulfoxide (DMSO); time (h); isopropanol (IPA); minutes (min); potassium carbonate (K2CO3); potassium acetate ammonium (KOAc);potassium phosphate (K3PO4);minutes (min);methanol (MeOH);mass spectrometry (MS);methanesulfonic acid (MsOH);m-chloroperoxybenzoic acid (m-CPBA);n-butyllithium (n-BuLi);nuclear magnetic resonance (NMR);iodosuccinimide (NIS);palladium on carbon (Pd / C);tetrakis(triphenylphosphine)palladium (Pd(PPh3)4);tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3);petroleum ether (PE);(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenylyl)]palladium(II) methanesulfonate (RuPhos Pd G3);2-(Trimethylsilyl)ethoxymethyl chloride (SEMCl);Tetrabutylammonium bromide (TBAB);Tetrabutylammonium fluoride (TBAB);Trifluoroacetic acid (TFA);Trifluoromethanesulfonic acid (TfOH);1-Propylphosphonic anhydride (T3P);4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos);Thin layer chromatography (TLC);2-Dicyclohexylphosphonium-2',4',6'-triisopropylbiphenyl (XPhos);Liquid chromatography-mass spectrometry (LC-MS);Retention time (RT)

[0118] Example 1: Synthesis of Compound 1

[0119] [ka]

[0120] Step 1: Synthesis of compound int_1-2

[0121] [ka]

[0122] int_1-1 (3.46 g, 20 mmol) was dissolved in dichloromethane (100 mL) and DIPEA (5.2 g, 40 mmol), DMAP (1.22 g, 10 mmol), (Boc)2O (4.8 g, 22 mmol) were added. The mixture was incubated overnight at room temperature until LC-MS showed the reaction was complete. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (200 mL), 2N dilute hydrochloric acid (100 mL), aqueous sodium bicarbonate (100 mL), water (100 mL), and finally washed with saturated saline (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give a light brown gel as the crude product (4.0 g, 73% yield). This crude product was used directly in the next reaction.

[0123] ESI-MS m / z: 273 [M+H] +

[0124] Step 2: Synthesis of compounds int_1-4

[0125] [ka]

[0126] int_1-2 (4 g, 14.6 mmol), int_1-3 (1.36 g, 14.6 mmol), cesium carbonate (7.14 g, 161 mmol), Pd2(dba)3 (668 mg, 0.73 mmol), and XantPhos (845 mg, 1.46 mmol) were dissolved in 1,4-dioxane (120 mL), and the mixture was incubated overnight at 85 °C under nitrogen atmosphere until LC-MS showed the reaction was complete. The reaction solution was filtered and distilled under reduced pressure to obtain the crude product, which was subjected to column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to obtain a pale yellow solid product (2.7 g, 65% yield).

[0127] ESI-MS m / z: 286 [M+H] +

[0128] Step 3: Synthesis of compounds int_1-5

[0129] [ka]

[0130] int_1-4 (2.4 g, 8.41 mmol) was dissolved in dichloromethane (30 mL) and trifluoroacetic acid (10 mL) was added. The mixture was incubated overnight at room temperature until LC-MS showed the reaction was complete. The reaction was directly concentrated under reduced pressure to give a pale yellow solid (1.6 g, 100% yield). The crude product was used directly in the next reaction.

[0131] ESI-MS m / z: 186 [M+H] +

[0132] Step 4: Synthesis of compounds int_1-7

[0133] [ka]

[0134] int_1-6 (2 g, 10.8 mmol) and int_1-5 (3.2 g, 10.8 mmol) were dissolved in isopropanol (5 mL) and DIPEA (5.57 g, 43.1 mmol, 7.51 mL) was added. The reaction was heated to 50° C. and incubated overnight until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and a white solid was precipitated and filtered to give the product. The product was dried to give a white solid (1.2 g, 33% yield).

[0135] 1 H NMR: (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.70 (s, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 6.44 (d, J = 7.9 Hz, 1H), 3.41 (s, 6H), 2.49 (s, 3H)

[0136] ESI-MS m / z: 335 [M+H] +

[0137] Step 5: Synthesis of compounds int_1-8

[0138] [ka]

[0139] int_1-7 (334 mg, 1.0 mmol) was dissolved in dichloromethane (40 mL) and m-CPBA (85%, 240 mg, 1.2 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 minutes until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product (335 mg). The crude product was used directly in the next reaction.

[0140] ESI-MS m / z: 351 [M+H] +

[0141] Step 6: Synthesis of compounds int_1-10

[0142] [ka]

[0143] int_1-8 (335 mg, 0.95 mmol) was dissolved in DMF (20 mL) and int_1-9 (298 mg, 1.2 mmol) and trifluoroacetic acid (115 mg, 1 mmol) were added. The reaction was heated to 80 °C and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a white solid (160 mg, 31% yield).

[0144] ESI-MS m / z: 535 [M+H] +

[0145] Step 7: Synthesis of compounds int_1-11

[0146] [ka]

[0147] int_1-10 (800 mg, 1.5 mmol) was dissolved in dichloromethane (80 mL) and trifluoroacetic acid (4.2 g, 37.4 mmol) was added. The mixture was incubated at room temperature for 1 h until LC-MS showed the reaction was complete. The reaction was directly concentrated under reduced pressure to give a yellow solid (800 mg, crude product). This crude product was used directly in the next reaction.

[0148] ESI-MS m / z: 435 [M+H] +

[0149] Step 8: Synthesis of Compound 1

[0150] [ka]

[0151] int_1-11 (800 mg, 1.84 mmol) and DIPEA (4.8 g, 37.4 mmol) were dissolved in dichloromethane (10 mL) and methanol (10 mL), and aqueous formaldehyde (37-40%, 1 mL) and sodium borohydride acetate (3.2 g, 15 mmol) were added. The mixture was incubated at room temperature for 1 h until LC-MS showed the reaction was complete. Water (100 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (100 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was subjected to column chromatography (SiO2, DCM:MeOH = 100:1-20:1) to obtain a pale yellow solid product (500 mg, 60% yield).

[0152] 1 H NMR (400 MHz, Chloroform-d) δ 8.33 (s, 1H), 7.65 (d, J = 9.3 Hz, 2H), 7.45 (s, 2H), 7.25 (d, J = 2.2 Hz, 1H), 7.20-7.13 (m, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 7.9 Hz, 1H), 3.51 (s, 2H), 3.33 (s, 6H), 2.89 (t, J = 6.0 Hz, 2H), 2.67 (t, J = 5.9 Hz, 2H), 2.42 (s, 3H).

[0153] ESI-MS m / z: 449 [M+H] +

[0154] Example 2: Synthesis of Compound 3

[0155] [ka]

[0156] Step 1: Synthesis of compound int_3-2

[0157] [ka]

[0158] int_3-1 (2 g, 8.35 mmol) and int_1-5 (1.55 g, 8.35 mmol) were dissolved in isopropanol (5 mL) and DIPEA (4.32 g, 33.4 mmol, 5.83 mL) was added. The reaction was heated to 80 °C and incubated overnight until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated by rotary evaporation, and purified by column chromatography to give a pale yellow solid (1.5 g, 46.3% yield).

[0159] ESI-MS m / z: 388 [M+H] +

[0160] Step 2: Synthesis of compound int_3-3

[0161] [ka]

[0162] int_3-2 (100 mg, 0.26 mmol), cyclopropylboronic acid (45 mg, 0.52 mmol), and potassium phosphate (166 mg, 0.78 mmol) were dissolved in a mixture of toluene (7.5 mL) and water (0.5 mL). The mixture was purged with argon three times before palladium acetate (7 mg, 0.03 mmol) and tricyclohexylphosphine (17 mg, 0.06 mmol) were added. Under an argon atmosphere, the mixture was heated to 100 °C and stirred for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated by rotary evaporation, and purified by column chromatography to give a pale yellow solid (61 g, 67.1% yield).

[0163] ESI-MS m / z: 350 [M+H] +

[0164] Step 3: Synthesis of compound int_3-4

[0165] [ka]

[0166] Int_3-3 (500 mg, 1.43 mmol) was dissolved in dichloromethane (40 mL) and m-CPBA (85%, 348.6 mg, 1.72 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 minutes until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product (335 mg). The crude product was used directly in the next reaction.

[0167] ESI-MS m / z: 366 [M+H] +

[0168] Step 4: Synthesis of compound 3

[0169] [ka]

[0170] int_3-4 (100 mg, 0.273 mmol) was dissolved in DMF (5 mL) and int_3-5 (45 mg, 0.28 mmol) and trifluoroacetic acid (456 mg, 4.0 mmol) were added. The reaction was heated to 80 °C and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase preparative chromatography to give a white solid (80 mg, 63% yield).

[0171] 1H NMR (400 MHz, Chloroform-d) δ 7.92 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 7.20 (dd, J = 8.1, 2.3 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.89 (s, 1H), 6.51 (d, J = 7.8 Hz, 1H), 3.54 (s, 2H), 3.34 (s, 6H), 2.87 (t, J = 5.9 Hz, 2H), 2.68 (t, J = 5.9 Hz, 2H), 2.43 (s, 3H), 1.57 (td, J = 7.9, 4.0 Hz, 1H), 1.04-0.91 (m, 2H), 0.64-0.54 (m, 2H).

[0172] ESI-MS m / z: 464 [M+H] +

[0173] Example 3: Synthesis of Compound 6

[0174]

change

[0175] ステップ1:Synthesis of compound int_6-3

[0176]

change

[0177] int_6-1 (1.6 g, 6.4 mmol), int_6-2 (1.37 g, 6.4 mmol), cesium carbonate (4.17 g, 12.8 mmol), Pd2(dba)3 (586 mg, 0.64 mmol), and XantPhos (741 mg, 1.28 mmol) were dissolved in 1,4-dioxane (100 mL), and the mixture was incubated at 85 °C overnight until LC-MS showed the reaction was complete. The reaction was filtered and distilled under reduced pressure to obtain the crude product, which was subjected to column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to obtain a pale yellow solid product (1.2 g, 49% yield).

[0178] ESI-MS m / z: 382 [M+H] +

[0179] Step 2: Synthesis of compound int_6-4

[0180] [ka]

[0181] int_6-4 (1.2 g, 3.15 mmol) was dissolved in dichloromethane (80 mL) and m-CPBA (85%, 893.3 mg, 4.4 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 min until LC-MS showed the reaction was complete. The reaction solution was washed with aqueous sodium bicarbonate (100 mL x 2). The aqueous phase was extracted with ethyl acetate (100 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (1.1 g). The crude product was used directly in the next reaction.

[0182] ESI-MS m / z: 398 [M+H] +

[0183] Step 3: Synthesis of compound int_6-5

[0184] [ka]

[0185] int_6-4 (1.3 g, 3.15 mmol) was dissolved in DMF (50 mL) and int_3-5 (767.4 mg, 4.73 mmol) and trifluoroacetic acid (718 mg, 6.3 mmol) were added. The reaction was heated to 80 °C and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a white solid (1.1 g, 70% yield).

[0186] LC-MS: 496 [M+H] +

[0187] Step 4: Synthesis of compound int_6-6

[0188] [ka]

[0189] int_6-5 (580 mg, 1.07 mmol) was dissolved in methanol (50 mL) and lithium hydroxide (675 mg, 16.06 mmol) was added. The mixture was incubated at room temperature for 5 h until LC-MS showed the reaction was complete. The mixture was adjusted to pH 5-6 with dilute hydrochloric acid and concentrated under reduced pressure to remove the solvent to obtain the crude product. The crude product was purified by reverse phase column chromatography to obtain a yellow powder (500 mg, 91% yield).

[0190] ESI-MS m / z: 468 [M+H] +

[0191] Step 5: Synthesis of compound 6

[0192] [ka]

[0193] int_6-6 (93 mg, 0.2 mmol) was dissolved in DMF (10 mL) and ammonium chloride (22 mg, 0.4 mmol), TEA (0.2 mL), and HATU (152 mg, 0.4 mmol) were added. The mixture was stirred and reacted at room temperature overnight until LC-MS showed the reaction was complete. The solvent was removed by concentration under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give an off-white solid (40 mg, 43% yield).

[0194] 1 H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 9.57 (s, 1H), 8.67 (s, 1H), 7.88 (d, J = 72.4 Hz, 2H), 7.41 (dd, J = 8.7, 5.1 Hz, 2H), 7.30 (s, 2H), 6.99 (d, J = 8.3 Hz, 1H), 6.29 (d, J = 7.9 Hz, 1H), 3.40 (s, 2H), 3.34 (s, 6H), 2.73 (t, J = 5.9 Hz, 2H), 2.56 (t, J = 5.9 Hz, 2H), 2.29 (s, 3H).

[0195] ESI-MS m / z: 467 [M+H] +

[0196] Example 4: Synthesis of Compound 7

[0197] [ka]

[0198] Step 1: Synthesis of compound 7

[0199] [ka]

[0200] int_6-6 (80 mg, 0.17 mmol) was dissolved in DMF (10 mL) and methylamine hydrochloride (12 mg, 0.17 mmol), TEA (34 mg, 0.34 mmol) and HATU (129 mg, 0.34 mmol) were added. The mixture was stirred and reacted at room temperature overnight until LC-MS showed the reaction was complete. The solvent was removed by concentration under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give an off-white solid (8 mg, 7% yield).

[0201] 1 H NMR (400 MHz, Chloroform-d) δ 11.06 (s, 1H), 8.27 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.09-7.01 (m, 2H), 6.47 (dd, J = 7.9, 0.8 Hz, 1H), 6.21 (d, J = 5.2 Hz, 1H), 3.52 (s, 2H), 3.39 (s, 6H), 2.98 (d, J = 4.8 Hz, 3H), 2.88 (t, J = 6.0 Hz, 2H), 2.68 (t, J = 6.0 Hz, 2H), 2.43 (s, 3H).

[0202] ESI-MS m / z: 481 [M+H] +

[0203] Example 5: Synthesis of Compound 8

[0204] [ka]

[0205] Step 1: Synthesis of compound 8

[0206] [ka]

[0207] int_6-6 (80 mg, 0.17 mmol) was dissolved in DMF (10 mL) and a solution of dimethylamine in tetrahydrofuran (2.0 M, 0.09 mL, 0.17 mmol), TEA (34 mg, 0.34 mmol) and HATU (129 mg, 0.34 mmol) was added. The mixture was stirred at room temperature overnight and allowed to react until LC-MS showed the reaction was complete. The solvent was removed by concentration under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give an off-white solid (61 mg, 56% yield).

[0208] 1 H NMR (400 MHz, Chloroform-d) δ 9.44 (s, 1H), 8.12 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.23-7.17 (m, 2H), 7.05 (d, J = 8.2 Hz, 1H), 6.47 (d, J = 7.8 Hz, 1H), 3.52 (s, 2H), 3.35 (s, 6H), 3.10 (s, 6H), 2.88 (t, J = 5.9 Hz, 2H), 2.67 (t, J = 5.9 Hz, 2H), 2.42 (s, 3H).

[0209] ESI-MS m / z: 495 [M+H] +

[0210] Example 6: Synthesis of Compound 9

[0211] [ka]

[0212] Step 1: Synthesis of compound int_9-2

[0213] [ka]

[0214] int_9-1 (1.48 g, 5.4 mmol), int_1-5 (1.0 g, 4 mmol), and DIPEA (2.82 mL, 16.2 mmol) were dissolved in isopropanol (15 mL) and the mixture was heated to 60 °C and stirred overnight until LC-MS indicated the reaction was complete. The reaction was concentrated by rotary evaporation and the crude product was purified by reverse phase preparative HPLC to give a pale yellow solid (300 mg, 13% yield).

[0215] ESI-MS m / z: 424 [M+H] +

[0216] Step 2: Synthesis of compound int_9-3

[0217] [ka]

[0218] int_9-2 (84 mg, 0.2 mmol), 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxolane (46 mg, 0.24 mmol), potassium carbonate (56 mg, 0.4 mmol), and Pd(dppf)Cl2 (14 mg, 0.02 mmol) were dissolved in a mixture of 1,4-dioxane (4 mL) and water (0.4 mL). The mixture was heated to 80 °C under argon and stirred for 16 h until LC-MS showed the reaction was complete. The reaction was concentrated by rotary evaporation and the crude product was purified by reverse phase preparative HPLC to give an orange solid (40 mg, 55% yield).

[0219] ESI-MS m / z: 364 [M+H] +

[0220] Step 3: Synthesis of compound 9

[0221] [ka]

[0222] int_9-2 (40 mg, 0.11 mmol) was dissolved in DMF (50 mL) and int_3-5 (18 mg, 0.11 mmol) and CSA (51 mg, 0.22 mmol) were added. The reaction solution was heated to 80 °C and stirred for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give a white solid (50 mg, 93% yield).

[0223] 1 H NMR (400 MHz, Chloroform-d) δ 8.32 (d, J = 21.4 Hz, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 16.8, 8.9 Hz, 2H), 7.36 (s, 1H), 7.05 (d, J = 9.3 Hz, 2H), 6.51 (s, 3H), 3.57 (d, J = 9.5 Hz, 2H), 3.34 (d, J = 6.9 Hz, 6H), 2.91 (t, J = 5.9 Hz, 2H), 2.73 (t, J = 5.8 Hz, 3H), 2.47 (s, 4H).

[0224] ESI-MS m / z: 490 [M+H] +

[0225] Example 7: Synthesis of Compound 11

[0226] [ka]

[0227] Step 1: Synthesis of compound int_11-2

[0228] [ka]

[0229] int_11-1 (1.45 g, 6.4 mmol), int_1-5 (1.3 g, 7 mmol), and DIPEA (2.82 mL, 16.2 mmol) were dissolved in isopropanol (30 mL) and the mixture was heated to 80 °C and stirred overnight until LC-MS indicated the reaction was complete. The reaction was concentrated by rotary evaporation and the crude product was purified by reverse phase preparative HPLC to give a pale yellow solid (1.7 g, 71% yield).

[0230] ESI-MS m / z: 376 [M+H] +

[0231] Step 2: Synthesis of compound 11

[0232] [ka]

[0233] int_11-2 (600 mg, 1.59 mmol) was dissolved in DMF (30 mL) and int_3-5 (258 mg, 1.59 mmol) and CSA (743 mg, 3.2 mmol) were added. The reaction solution was heated to 85 °C and stirred for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give a white solid (510 mg, 64% yield).

[0234] 1H NMR (400 MHz, Chloroform-d) δ 8.15 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.19 (dd, J = 8.1, 2.3 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.93 (s, 1H), 6.53 (d, J = 7.8 Hz, 1H), 3.53 (s, 2H), 3.35 (s, 6H), 2.88 (t, J = 5.9 Hz, 2H), 2.68 (t, J = 5.9 Hz, 2H), 2.43 (s, 3H).

[0235] ESI-MS m / z: 502 [M+H] +

[0236] Example 8: Synthesis of Compound 12

[0237] [ka]

[0238] Step 1: Synthesis of compound int_12-1-2

[0239] [ka]

[0240] Int_12-1-1 hydrochloride (10.0 g, 46.10 mmol) was dissolved in TfOH (50.0 mL) and NIS (15.7 g, 69.88 mmol) was added at 0 °C under nitrogen atmosphere. The reaction was stirred at room temperature for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, poured into ice water, adjusted to pH 8-9 with dilute aqueous NaOH, and filtered to give int_12-1-2 (14 g, 46.0 mmol, crude product) as a black solid. This crude product was used directly in the next reaction.

[0241] ESI-MS m / z: 305 [M+H] +

[0242] Step 2: Synthesis of compound int_12-1-3

[0243] [ka]

[0244] int_12-1-2 (14.0 g, 46.0 mmol) and (Boc)2O (25.1 g, 115 mmol, 26.4 mL) were dissolved in DCM (200 mL) and TEA (14.0 g, 138 mmol, 19.2 mL) was added at room temperature. The reaction solution was stirred at room temperature for 16 h until LC-MS showed the reaction was complete. Water (100 mL) was added to the reaction solution. The aqueous phase was extracted with dichloromethane (150 mL × 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (1.1 mg). The crude product was purified by preparative column chromatography (SiO2, EtOAc / PE = 0 / 1 to 1 / 9) to give a white solid (10 g, yield 53.7%).

[0245] ESI-MS m / z: 349 [M+H] +

[0246] Step 3: Synthesis of compound int_12-1-4

[0247] [ka]

[0248] int_12-1-3 (6.00 g, 14.8 mmol), methylboronic acid (8.90 g, 148.4 mmol), aqueous cesium carbonate (2 M, 14.8 mL), and Pd(dppf)Cl2.CH2Cl2 (1.2 g, 1.5 mmol) were dissolved in a mixture of 1,4-dioxane (100 mL). Under an argon atmosphere, the mixture was heated to 100 °C and stirred for 5 h until LC-MS showed the reaction was complete. The reaction solution was concentrated by rotary evaporation, and the crude product was purified by preparative column chromatography (SiO2, ETOAC / PE=0 / 1 to 1 / 9) to give a white solid (2.5 g, 57.6% yield).

[0249] 1 H NMR: (400 MHz, DMSO-d6) δ 7.92 (br d, J = 8.5 Hz, 2H), 4.61 (br s, 2H), 3.61 (t, J = 5.9 Hz, 2H), 2.75 (t, J = 5.9 Hz, 2H), 2.32 (s, 3H), 1.48-1.37 (m, 9H)

[0250] ESI-MS m / z: 237 [M+H] +

[0251] Step 4: Synthesis of compound int_12-1

[0252] [ka]

[0253] int_12-1-4 (2.30 g, 7.80 mmol) was dissolved in methanol (40.0 mL) and 10% Pd / C (230 mg) was added. The reaction solution was incubated at room temperature under hydrogen atmosphere (15.0 Psi.) for 16 hours until LC-MS showed the reaction was complete. The reaction solution was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain a yellow gel (2.00 g, 96.9% yield).

[0254] 1H NMR (400 MHz, DMSO-d6) δ = 6.28 (d, J = 1.6 Hz, 1H), 6.14 (s, 1H), 5.75 (s, 1H), 4.77 (s, 2H), 4.31 (br s, 2H), 3.51 (t, J = 6.0 Hz, 2H), 2.48-2.44 (m, 2H), 2.04 (s, 3H), 1.41 (s, 9H)

[0255] ESI-MS m / z: 207 [M+H] +

[0256] Step 5: Synthesis of compound int_12-2

[0257] [ka]

[0258] int_1-8 (1.05 g, 3 mmol) was dissolved in DMF (100 mL) and int_12-1 (787 mg, 3 mmol) and trifluoroacetic acid (342 mg, 3 mmol) were added. The reaction was heated to 80 °C and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a yellow solid (1.2 g, 87% yield).

[0259] ESI-MS m / z: 549 [M+H] +

[0260] Step 6: Synthesis of compound int_12-3

[0261] [ka]

[0262] int_12-2 (1.2 g, 2.19 mmol) was dissolved in dichloromethane (100 mL) and trifluoroacetic acid (6.24 g, 54.7 mmol) was added. The mixture was incubated at room temperature for 1 h until LC-MS showed the reaction was complete. The reaction was directly concentrated under reduced pressure to give a yellow solid (1 g, crude product). The crude product was used directly in the next reaction.

[0263] ESI-MS m / z: 449 [M+H] +

[0264] Step 7: Synthesis of compound 12

[0265] [ka]

[0266] int_12-3 (1 g, 2.23 mmol) and DIPEA (6.5 g, 50 mmol) were dissolved in dichloromethane (20 mL) and methanol (20 mL), and aqueous formaldehyde (37-40%, 2 mL) and sodium borohydride acetate (3.4 g, 16 mmol) were added. The mixture was incubated at room temperature for 1 h until LC-MS showed the reaction was complete. Water (100 mL) was added to the reaction. The aqueous phase was extracted with ethyl acetate (100 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was subjected to column chromatography (SiO2, DCM:MeOH = 100:1-20:1) to obtain a pale yellow solid product (700 mg, 92% yield).

[0267] 1H NMR (400 MHz, DMSO-d6) δ 9.96 (brs, 1H), 9.27 (brs, 1H), 8.54 (s, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.28-7.15 (m, 2H), 6.42 (d, J = 8.0 Hz, 1H), 4.13 (s, 2H), 3.35 (s, 9H), 2.83 (d, J = 4.8 Hz, 4H), 2.11 (s, 3H).

[0268] ESI-MS m / z: 463 [M+H] +

[0269] Example 9: Synthesis of Compound 13

[0270] [ka]

[0271] Step 1: Synthesis of compound int_13-1-2

[0272] [ka]

[0273] int_12-1-3 (3.00 g, 7.42 mmol), int_13-1-1 (4.97 g, 37.1 mmol), aqueous cesium carbonate (2.00 M, 7.42 mL), and Pd(dppf)Cl2.CH2Cl2 (606 mg, 742 μmol) were dissolved in 1,4-dioxane (40 mL). Under an argon atmosphere, the mixture was heated to 100 °C and stirred for 5 h until LC-MS showed the reaction was complete. The reaction was concentrated by rotary evaporation, and the crude product was purified by preparative column chromatography (SiO2, EtOAc / PE=0 / 1 to 1 / 9) to give a white solid (1.2 g, 53.1% yield).

[0274] ESI-MS m / z: 249 [M+H] +

[0275] Step 2: Synthesis of compound int_13-1

[0276] [ka]

[0277] int_13-1-2 (1.00 g, 3.29 mmol) was dissolved in methanol (40.0 mL) and 10% Pd / C (100 mg) was added. The reaction solution was incubated at room temperature under hydrogen atmosphere (15.0 Psi.) for 16 hours until LC-MS showed the reaction was complete. The reaction solution was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain a yellow gel (600 mg, 61% yield).

[0278] 1 H NMR (400MHz, DMSO-d6) δ 6.30 (d, J = 2.0 Hz, 1H), 6.15 (br s, 1H), 4.81 (s, 2H), 4.31 (br s, 2H), 3.49 (br t, J = 5.9 Hz, 2H), 2.41 (q, J = 7.5 Hz, 2H), 1.41 (s, 9H), 1.07 (t, J = 7.5 Hz, 3H)

[0279] ESI-MS m / z: 221 [M+H] +

[0280] Step 3: Synthesis of compound int_13-2

[0281] [ka]

[0282] int_1-8 (100 mg, 0.281 mmol) was dissolved in DMF (5 mL) and int_13-1 (79 mg, 0.281 mmol) and trifluoroacetic acid (63.9 mg, 0.56 mmol) were added. The reaction was heated to 80 °C and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a yellow solid (34 mg, 21.5% yield).

[0283] ESI-MS m / z: 563 [M+H] +

[0284] Step 4: Synthesis of compound int_13-3

[0285] [ka]

[0286] int_13-2 (34 mg, 0.06 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was added. The mixture was incubated at room temperature for 2 h until LC-MS showed the reaction was complete. The reaction was directly concentrated under reduced pressure to give a yellow solid (31 mg, crude product). This crude product was used directly in the next reaction.

[0287] ESI-MS m / z: 463 [M+H] +

[0288] Step 5: Synthesis of compound 13

[0289] [ka]

[0290] int_13-3 (500 mg, 1.08 mmol) and DIPEA (3.2 g, 25 mmol) were dissolved in dichloromethane (10 mL) and methanol (10 mL), and aqueous formaldehyde (37-40%, 1 mL) and sodium borohydride acetate (1.7 g, 8 mmol) were added. The mixture was incubated at room temperature for 1 h until LC-MS showed the reaction was complete. Water (100 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (100 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was subjected to column chromatography (SiO2, DCM:MeOH = 100:1-20:1) to obtain a white solid product (129 mg, 25% yield).

[0291] 1 H NMR (400 MHz, Chloroform-d) δ 8.36 (s, 1H), 7.76-7.59 (m, 2H), 7.43 (d, J = 27.0 Hz, 2H), 7.18 (s, 1H), 7.07 (s, 1H), 6.56 (d, J = 7.9 Hz, 1H), 3.55 (s, 2H), 3.36 (s, 6H), 2.83 (d, J = 6.1 Hz, 2H), 2.73 (t, J = 5.8 Hz, 2H), 2.58 (q, J = 7.6 Hz, 2H), 2.45 (s, 3H), 1.18 (t, J = 7.6 Hz, 3H).

[0292] ESI-MS m / z: 477 [M+H] +

[0293] Example 10: Synthesis of Compound 16

[0294] [ka]

[0295] Step 1: Synthesis of compound int_16-1-2

[0296] [ka]

[0297] int_12-1-3 (3.00 g, 7.42 mmol), int_16-1-1 (3.19 g, 37.1 mmol), cesium carbonate (4.84 g, 14.8 mmol), and Pd(dppf)Cl2.CH2Cl2 (606 mg, 742 μmol) were dissolved in 1,4-dioxane (40 mL) and water (4 mL). Under an argon atmosphere, the mixture was heated to 100 °C and stirred for 5 h until LC-MS showed the reaction was complete. The reaction was concentrated by rotary evaporation, and the crude product was purified by preparative column chromatography (SiO2, EtOAc / PE=0 / 1 to 1 / 9) to give a white solid (1.4 g, 59.3% yield).

[0298] 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 4.62 (br s, 2H), 3.63 (br t, J = 5.9 Hz, 2H), 2.98 (t, J = 5.9 Hz, 2H), 2.04-1.94 (m, 1H), 1.47-1.35 (m, 9H), 1.05-0.93 (m, 2H), 0.74-0.62 (m, 2H)

[0299] Step 2: Synthesis of compound int_16-1

[0300] [ka]

[0301] int_16-1-2 (1.20 g, 3.77 mmol) was dissolved in methanol (20.0 mL) and water (20.0 mL) and NH4Cl (2.02 g, 37.7 mmol) and Fe powder (2.10 g, 37.7 mmol) were added. The reaction was heated to 80° C. and incubated for 5 h until LC-MS showed the reaction was complete. The reaction was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain a white solid (470 mg, 43.2% yield).

[0302] 1 H NMR (400 MHz, DMSO-d6) δ 6.18-6.08 (m, 2H), 4.79 (s, 2H), 4.32 (br s, 2H), 3.53 (br t, J = 5.8 Hz, 2H), 2.69 (br t, J = 6.0 Hz, 2H), 1.79-1.71 (m, 1H), 1.42 (s, 10H), 0.86-0.77 (m, 2H), 0.49 - 0.43 (m, 2H)

[0303] ESI-MS m / z: 233 [M+H] +

[0304] Step 3: Synthesis of compound int_16-2

[0305] [ka]

[0306] int_1-8 (100 mg, 0.28 mmol) was dissolved in DMF (5 mL) and int_16-1 (81 mg, 0.28 mmol) and trifluoroacetic acid (63.9 mg, 0.56 mmol) were added. The reaction was heated to 80 °C and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a yellow solid (60 mg, 37% yield).

[0307] ESI-MS m / z: 575 [M+H]+

[0308] Step 4: Synthesis of compound int_16-3

[0309] [ka]

[0310] int_16-2 (60 mg, 0.10 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was added. The mixture was incubated at room temperature for 2 h until LC-MS showed the reaction was complete. The reaction was directly concentrated under reduced pressure to give a yellow solid (55 mg, crude product). This crude product was used directly in the next reaction.

[0311] ESI-MS m / z: 475 [M+H] +

[0312] Step 5: Synthesis of compound 16

[0313] [ka]

[0314] int_16-3 (55 mg, 0.116 mmol) and DIPEA (298 mg, 2.3 mmol) were dissolved in dichloromethane (2 mL) and methanol (2 mL), and aqueous formaldehyde (37-40%, 1 mL) and sodium borohydride acetate (600 mg, 2.83 mmol) were added. The mixture was incubated at room temperature for 1 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product, which was purified by preparative column HPLC to give a white solid product (40 mg, 70% yield).

[0315] 1H NMR (400 MHz, Chloroform-d) δ 8.35 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 35.5 Hz, 3H), 7.16 (s, 1H), 6.88 (s, 1H), 6.56 (d, J = 7.9 Hz, 1H), 3.53 (s, 2H), 3.36 (d, J = 1.7 Hz, 6H), 2.98 (d, J = 6.1 Hz, 2H), 2.75 (t, J = 6.2 Hz, 2H), 2.46 (s, 3H), 1.82 (s, 1H), 0.88 (d, J = 8.0 Hz, 2H), 0.56 (d, J = 5.4 Hz, 2H).

[0316] ESI-MS m / z: 489 [M+H] +

[0317] Example 11: Synthesis of Compound 19

[0318] [ka]

[0319] Step 1: Synthesis of compound int_19-1-2

[0320] [ka]

[0321] int_12-1-3 (5.00 g, 12.4 mmol), int_19-1-1 (2.64 g, 37.1 mmol), cesium carbonate (8.06 g, 24.7 mmol), and RuPhos Pd G3 (606 mg, 742 μmol) were dissolved in 1,4-dioxane (50 mL). Under an argon atmosphere, the mixture was heated to 100 °C and stirred for 5 h until LC-MS showed the reaction was complete. The reaction was concentrated by rotary evaporation, and the crude product was purified by preparative column chromatography (SiO2, EtOAc / PE=0 / 1 to 1 / 9) to give a white solid (1.7 g, 39.6% yield).

[0322] ESI-MS m / z: 348 [M+H] +

[0323] Step 2: Synthesis of compound int_19-1

[0324] [ka]

[0325] int_19-1-2 (0.70 g, 2.01 mmol) was dissolved in methanol (40.0 mL) and 10% Pd / C (100 mg) was added. The reaction solution was incubated at room temperature under hydrogen atmosphere (15.0 Psi.) for 16 hours until LC-MS showed the reaction was complete. The reaction solution was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain a white solid (410 mg, 63.5% yield).

[0326] 1 H NMR (400 MHz, DMSO-d6) δ 6.08 (d, J = 2.0 Hz, 1H), 5.93 (s, 1H), 4.76 (s, 2H), 4.30 (br s, 2H), 3.44-3.37 (m, 2H), 2.99 (br t, J = 6.2 Hz, 4H), 2.42 (br s, 1H), 1.89 - 1.79 (m, 4H), 1.65 (br s, 1H), 1.43 (s, 9H)

[0327] ESI-MS m / z: 318 [M+H] +

[0328] Step 3: Synthesis of compound int_19-2

[0329] [ka]

[0330] int_1-8 (56 mg, 0.158 mmol) was dissolved in DMF (5 mL) and int_19-1 (50 mg, 0.158 mmol) and trifluoroacetic acid (64 mg, 0.631 mmol) were added. The reaction was heated to 80 °C and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give an orange solid (50 mg, 52.6% yield).

[0331] ESI-MS m / z: 604 [M+H] +

[0332] Step 4: Synthesis of compound int_19-3

[0333] [ka]

[0334] int_19-2 (50 mg, 0.083 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was added. The mixture was incubated at room temperature for 2 h until LC-MS showed the reaction was complete. The reaction was directly concentrated under reduced pressure to give a yellow solid (50 mg, crude product). The crude product was used directly in the next reaction.

[0335] ESI-MS m / z: 504 [M+H] +

[0336] Step 5: Synthesis of compound 19

[0337] [ka]

[0338] int_19-3 (30 mg, 0.060 mmol) and DIPEA (298 mg, 2.3 mmol) were dissolved in dichloromethane (2 mL) and methanol (2 mL), and aqueous formaldehyde (37-40%, 1 mL) and sodium borohydride acetate (200 mg, 0.95 mmol) were added. The mixture was incubated at room temperature for 1 h until LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure to give the crude product, which was purified by preparative column HPLC to give a white solid product (5 mg, 16.2% yield).

[0339] 1 H NMR (400 MHz, Chloroform-d) δ 8.30 (s, 2H), 7.56 (d, J = 18.1 Hz, 2H), 7.46 (d, J = 9.7 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.75 (s, 1H), 6.51 (d, J = 7.8 Hz, 1H), 3.93 (s, 2H), 3.30 (s, 6H), 3.06 (d, J = 12.4 Hz, 6H), 2.94 (d, J = 6.0 Hz, 2H), 2.68 (s, 3H), 1.83 (d, J = 6.3 Hz, 4H).

[0340] ESI-MS m / z: 518 [M+H] +

[0341] Example 12: Synthesis of Compound 22

[0342] [ka]

[0343] Step 1: Synthesis of compound int_22-1-1

[0344] [ka]

[0345] int_12-1-3 (500 mg, 1.24 mmol), methanol (39.6 mg, 1.24 mmol), CuI (236 mg, 1.24 mmol), Cs2CO3 (806 mg, 2.47 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (175.96 mg, 1.24 mmol) were dissolved in methanol (8 mL). The mixture was heated to 110 °C in a microwave under nitrogen atmosphere and stirred for 1 h until LC-MS showed the reaction was complete. The reaction was concentrated by rotary evaporation and the crude product was purified by preparative column chromatography (SiO2, EtOAc / PE=1 / 10) to give a white solid (420 mg, 27.5% yield).

[0346] 1 H NMR (400 MHz, Chloroform-d) δ 7.67 (s, 1H), 7.55 (d, J = 1.9 Hz, 1H), 4.64 (s, 2H), 3.94 (s, 3H), 3.68 (t, J = 5.9 Hz, 2H), 2.82 (br t, J = 5.8Hz, 2H), 1.51 (s, 9H)

[0347] Step 2: Synthesis of compound int_22-1

[0348] [ka]

[0349] int_22-1-1 (420 mg, 1.36 mmol) was dissolved in methanol (10.0 mL) and 10% Pd / C (100 mg) was added. The reaction solution was incubated at room temperature under hydrogen atmosphere (15.0 Psi.) for 16 hours until LC-MS showed the reaction was complete. The reaction solution was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain a white gel (370 mg, 97.5% yield).

[0350] 1H NMR (400 MHz, Chloroform-d) δ 6.10 (br d, J = 13.1 Hz, 2H), 4.47 (s, 2H), 3.79 (s, 3H), 3.61 (br s, 4H), 2.65 (br t, J = 5.6 Hz, 2H), 1.50 (s, 9H)

[0351] ESI-MS m / z: 223 [M+H] +

[0352] Step 3: Synthesis of compound int_22-2

[0353] [ka]

[0354] int_1-8 (179 mg, 0.51 mmol) was dissolved in DM (10 mL) and int_22-1 (212 mg, 0.76 mmol) and trifluoroacetic acid (114 mg, 1 mmol) were added. The reaction was heated to 80 °C and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a pale yellow solid (250 mg, 87% yield).

[0355] ESI-MS m / z: 565 [M+H] +

[0356] Step 4: Synthesis of compound int_22-3

[0357] [ka]

[0358] int_22-2 (100 mg, 0.18 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was added. The mixture was incubated at room temperature for 2 h until LC-MS showed the reaction was complete. The reaction was directly concentrated under reduced pressure to give a yellow solid (100 mg, crude product). This crude product was used directly in the next reaction.

[0359] ESI-MS m / z: 465 [M+H] +

[0360] Step 5: Synthesis of compound 22

[0361] [ka]

[0362] int_22-3 (84 mg, 0.18 mmol) and DIPEA (298 mg, 2.3 mmol) were dissolved in dichloromethane (2 mL) and methanol (2 mL), and aqueous formaldehyde (37-40%, 0.5 mL) and sodium borohydride acetate (500 mg, 2.36 mmol) were added. The mixture was incubated at room temperature for 1 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product, which was purified by preparative column HPLC to give a white solid product (45 mg, 52% yield).

[0363] 1 H NMR (400 MHz, Chloroform-d) δ 8.31 (s, 1H), 7.61 (d, J = 18.0 Hz, 2H), 7.39 (s, 2H), 6.75 (s, 2H), 6.49 (d, J = 7.7 Hz, 1H), 3.67 (s, 3H), 3.44 (s, 2H), 3.30 (s, 6H), 2.71 (s, 2H), 2.63 (s, 2H), 2.38(s, 3H).

[0364] ESI-MS m / z: 479 [M+H] +

[0365] Example 13: Synthesis of Compound 29

[0366] [ka]

[0367] Step 1: Synthesis of compound int_29-2

[0368] [ka]

[0369] int_1-8 (105 mg, 0.3 mmol) was dissolved in DMF (5 mL) and int_29-1 (81 mg, 0.3 mmol) and trifluoroacetic acid (34 mg, 0.3 mmol) were added. The reaction was heated to 80 °C and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a pale yellow solid (56 mg, 33.5% yield).

[0370] ESI-MS m / z: 557 [M+H] +

[0371] Step 2: Synthesis of compound int_29-3

[0372] [ka]

[0373] Int_29-2 (190 mg, 0.341 mmol) was dissolved in a mixture of methanol and THF (v / v=1:1, 15 mL) and potassium carbonate (48 mg, 0.341 mmol) was added. The mixture was incubated at room temperature for 2 h until LC-MS showed the reaction was complete. The reaction was directly concentrated under reduced pressure to give a yellow solid (190 mg, crude product). This crude product was used directly in the next reaction.

[0374] ESI-MS m / z: 461 [M+H] +

[0375] Step 3: Synthesis of compound 29

[0376] [ka]

[0377] int_29-3 (190 mg, 0.412 mmol) was dissolved in dichloromethane (5 mL) and methanol (5 mL), and aqueous formaldehyde (37-40%, 1 mL) and sodium borohydride acetate (212 mg, 1 mmol) were added. The mixture was incubated at room temperature for 1 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product, which was purified by preparative column HPLC to give a yellow solid product (106 mg, 55% yield).

[0378] 1 H NMR (400 MHz, Chloroform-d) δ 8.32 (s, 1H), 7.79-7.55 (m, 3H), 7.44 (s, 1H), 7.24 (d, J = 5.8 Hz, 1H), 7.17 (s, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 7.9 Hz, 1H), 3.64 (s, 2H), 3.34 (s, 6H), 2.52 (s, 2H), 2.42 (s, 3H), 0.99 (s, 2H), 0.91 (s, 2H).

[0379] ESI-MS m / z: 475 [M+H] +

[0380] Example 14: Synthesis of Compound 42

[0381] [ka]

[0382] Step 1: Synthesis of compound int_42-1-1

[0383] [ka]

[0384] int_13-1-2 (5.50 g, 18.1 mmol) was dissolved in 1,4-dioxane (50 mL) and HCl / dioxane solution (4 M, 55.0 mL) was added. The reaction was stirred at room temperature for 2 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product (4 g, 91.9% yield). The crude product was used directly in the next reaction.

[0385] ESI-MS m / z: 205 [M+H] +

[0386] Step 2: Synthesis of compound int_42-1-2

[0387] [ka]

[0388] int_42-1-1 (3.80 g, 18.6 mmol) was dissolved in methanol (40 mL) and treated with NaOAc (3.05 g, 37.2 mmol), NaBH3CN (1.75 g, 27.9 mmol) and (HCHO). n (838 mg) was added. The reaction was heated to 50° C. and incubated for 4 hours until LC-MS showed the reaction was complete. Water (50 mL) was added to the reaction. The aqueous phase was extracted with ethyl acetate (50 mL×3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product, which was subjected to column chromatography (ISCO®; 40 g Sepa Flash® Silica Flash Column, eluent gradient of 0-50% ethyl acetate / petroleum ether, 60 mL / min) to give a white solid (3.2 g, 78.8% yield).

[0389] 1 H NMR (400 MHz, Chloroform-d) δ 8.09 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 6.79 (dd, J = 17.3, 11.0 Hz, 1H), 5.72 (d, J = 17.3 Hz, 1H), 5.41 (d, J = 11.0 Hz, 1H), 3.60 (s, 2H), 2.86-2.91 (m, 2H), 2.69-2.73 (m, 2H), 2.43 ppm (s, 3H)

[0390] Step 3: Synthesis of compound int_42-1

[0391] [ka]

[0392] int_42-1-2 (3.00 g, 13.7 mmol) was dissolved in ethanol (30.0 mL) and water (30.0 mL) and added with NH4Cl (4.41 g, 82.5 mmol) and Fe powder (4.61 g, 82.4 mmol) under nitrogen atmosphere. The reaction was heated to 70 °C and incubated for 6 h until LC-MS showed the reaction was complete. The reaction was filtered to obtain a filtrate, which was concentrated to obtain a crude product, which was subjected to column chromatography (ISCO®; 40 g Sepa Flash® Silica Flash Column, eluent gradient of 0-60% ethyl acetate / petroleum ether, 60 mL / min) to obtain a yellow solid (2.43 g, 93.9% yield).

[0393] 1H NMR (400 MHz, DMSO-d6) δ 6.82 (dd, J = 17.3, 10.9 Hz, 1H), 6.72 (d, J = 1.6 Hz, 1H), 6.27 (s, 1H), 5.57 (dd, J = 17.3, 1.3 Hz, 1H), 5.28 (dd, J = 10.9, 1.3 Hz, 1H), 4.13 (s, 2H), 3.34 (br s, 2H), 2.90 (br t, J = 5.9 Hz, 2H), 2.80 ppm (s, 3H)

[0394] ESI-MS m / z: 189 [M+H] +

[0395] Step 4: Synthesis of compound 42

[0396] [ka]

[0397] int_1-8 (100 mg, 0.281 mmol) was dissolved in DMF (30 mL) and int_42-1 (54 mg, 0.281 mmol) and trifluoroacetic acid (113 mg, 1.1 mmol) were added. The reaction was heated to 80° C. and stirred for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give a white solid (3 mg, 2.3% yield).

[0398] ESI-MS m / z: 475 [M+H] +

[0399] Example 15: Synthesis of Compound 43

[0400] [ka]

[0401] Step 1: Synthesis of compound int_43-1-2

[0402] [ka]

[0403] int_12-1-3 (5.00 g, 12.4 mmol), int_43-1-1 (1.64 g, 16.7 mmol, 2.31 mL), CuI (141 mg, 742 μmol), TEA (5.01 g, 49.5 mmol, 6.89 mL), and Pd(PPh3)2Cl2 (434 mg, 618 μmol) were dissolved in 1,4-dioxane (40 mL). Under an argon atmosphere, the mixture was heated to 70 °C and stirred for 1 h until LC-MS showed the reaction was complete. Water (30 mL) was added to the reaction. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was subjected to column chromatography (SiO2, EtOAc / PE = 0 / 1 to 1 / 9) to obtain a yellow solid (3.5 g, 75.6% yield).

[0404] ESI-MS m / z: 319 [M+H] +

[0405] Step 2: Synthesis of compound int_43-1-3

[0406] [ka]

[0407] int_43-1-2 (3.50 g, 9.35 mmol) was dissolved in methanol (50.0 mL) and K2CO3 (645 mg, 4.67 mmol) was added at 10 °C. The reaction was warmed to room temperature and incubated for 5 h until LC-MS showed the reaction was complete. Water (30 mL) was added to the reaction. The aqueous phase was extracted with dichloromethane (50 mL × 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product, which was subjected to column chromatography (SiO2, EtOAc / PE = 0 / 1 to 1 / 9) to give a white solid (2.6 g, 92% yield).

[0408] 1 H NMR (400MHz, Chloroform-d) δ 8.14 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 1.5 Hz, 1H), 4.59 (s, 2H), 3.64 (t, J = 5.9 Hz, 2H), 3.37 (s, 1H), 2.98 (br t, J = 5.8 Hz, 2H), 1.43 (s, 9H)

[0409] ESI-MS m / z: 247 [M+H] +

[0410] Step 3: Synthesis of compound int_43-1

[0411] [ka]

[0412] int_43-1-3 (2.10 g, 6.95 mmol) was dissolved in ethanol (30.0 mL) and water (30.0 mL), and NH4Cl (3.72 g, 69.46 mmol) and Fe powder (3.88 g, 69.5 mmol) were added. The reaction was heated to 70 °C and incubated for 2 h until LC-MS showed the reaction was complete. The reaction was filtered to obtain the filtrate, and the filtrate was concentrated. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was subjected to column chromatography (SiO2, EtOAc / PE = 0 / 1 to 1 / 9) to obtain a white solid (1 g, 52.9% yield).

[0413] 1H NMR (400MHz, DMSO-d6) δ 6.58 (d, J = 2.2 Hz, 1H), 6.38 (s, 1H), 5.07 (s, 2H), 4.33 (s, 2H), 4.22 (s, 1H), 3.51 (br t, J = 5.8 Hz, 2H), 2.66 (t, J = 5.9 Hz, 2H), 1.42 (s, 9H)

[0414] ESI-MS m / z: 217 [M+H] +

[0415] Step 4: Synthesis of compound int_43-2

[0416] [ka]

[0417] int_1-8 (105 mg, 0.3 mmol) was dissolved in DMF (5 mL) and int_43-1 (82 mg, 0.299 mmol) and trifluoroacetic acid (34 mg, 0.3 mmol) were added. The reaction was heated to 80 °C and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a yellow solid (65 mg, 62% yield).

[0418] ESI-MS m / z: 559 [M+H] +

[0419] Step 5: Synthesis of compound int_43-3

[0420] [ka]

[0421] int_43-2 (65 mg, 0.116 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was added. The mixture was incubated at room temperature for 2 h until LC-MS showed the reaction was complete. The reaction was directly concentrated under reduced pressure to give a yellow solid (60 mg, crude product). This crude product was used directly in the next reaction.

[0422] ESI-MS m / z: 459 [M+H] +

[0423] Step 6: Synthesis of compound 43

[0424] [ka]

[0425] int_43-3 (53 mg, 0.116 mmol) and DIPEA (298 mg, 2.3 mmol) were dissolved in dichloromethane (2 mL) and methanol (2 mL), and aqueous formaldehyde (37-40%, 0.5 mL) and sodium borohydride acetate (50 mg, 0.24 mmol) were added. The mixture was incubated at room temperature for 1 h until LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure to give the crude product, which was purified by preparative column HPLC to give a yellow solid product (32 mg, 58.6% yield).

[0426] 1 H NMR (400 MHz, Chloroform-d) δ 8.31 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.57 - 7.44 (m, 3H), 7.25 (s, 1H), 7.12 (s, 1H), 6.51 (dd, J = 7.9, 0.8 Hz, 1H), 3.45 (s, 2H), 3.30 (s, 6H), 3.22 (s, 1H),2.94 (t, J = 6.0 Hz, 2H), 2.66 (t, J = 6.0 Hz, 2H), 2.39 (s, 3H).

[0427] ESI-MS m / z: 473 [M+H] +

[0428] Example 16: Synthesis of Compound 52

[0429] [ka]

[0430] Step 1: Synthesis of compound int_52-1-3

[0431] [ka]

[0432] int_52-1-1 (50 g, 189 mmol, 25.5 mL) and int_52-1-2 (49.5 g, 284 mmol, 40.9 mL) were dissolved in dichloromethane (400 mL) and TBAB (36.6 g, 113 mmol) and NaHCO3 (1 M, 1000 mL) were added. The reaction solution was warmed to 40 °C and incubated for 16 h until LC-MS showed the reaction was complete. Water (300 mL) was added to the reaction. The aqueous phase was extracted with dichloromethane (500 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (52 g, 99% yield) as a brown oil. This crude product was used directly in the next reaction.

[0433] 1 H NMR (400 MHz, Chloroform-d) δ 7.28-7.26 (m, 3H), 7.24 (s, 4H), 4.13 (q, J = 7.3 Hz, 2H), 3.94 (dd, J = 3.4, 8.9 Hz, 2H), 3.87-3.84 (m, 1H), 3.82-3.79 (m, 4H), 3.77- 3.75 (m, 3H), 3.73-3.67 (m, 9H), 3.29-3.21 (m, 3H), 3.20 - 3.10 (m, 4H)

[0434] Step 2: Synthesis of compound int_52-1-4

[0435] [ka]

[0436] int_52-1-3 (52 g, 188 mmol) was dissolved in acetonitrile (50 mL) and H2SO4 (3 M, 240.00 mL) was added. The reaction was heated to 100 °C and incubated for 16 h until LC-MS showed the reaction was complete. Water (50 mL) was added to the reaction. The aqueous phase was extracted with ethyl acetate (300 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (ISCO®; 220 g Sepa Flash® Silica Flash Column, eluent gradient of 0-30% ethyl acetate / petroleum ether, 80 mL / min) to give a white solid (25 g, 82.9% yield).

[0437] 1 H NMR (400 MHz, Chloroform-d) δ 7.20 - 7.09 (m, 4H), 2.89-2.77 (m, 4H), 2.63-2.45 (m, 4H)

[0438] Step 3: Synthesis of compound int_52-1-5

[0439] [ka]

[0440] int_52-1-4 (13 g, 81.1 mmol) was dissolved in H2SO4 (100 mL) and KNO3 (9.02 g, 89.3 mmol) was added at -10 °C. The reaction was incubated at -10 °C for 5 min until LC-MS showed the reaction was complete. The reaction was poured into ice water (500 mL). The aqueous phase was extracted with ethyl acetate (500 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (ISCO®; 120 g Sepa Flash® Silica Flash Column, eluent gradient of 0-30% ethyl acetate / petroleum ether, 60 mL / min) to give a yellow solid (9 g, 54.1% yield).

[0441] 1 H NMR (400 MHz, Chloroform-d) δ 8.19-8.03 (m, 2H), 7.42 (d, J = 8.3 Hz, 1H), 3.10-3.00 (m, 4H), 2.72-2.63 (m, 4H)

[0442] Step 4: Synthesis of compound int_52-1-6

[0443] [ka]

[0444] int_52-1-5 (5 g, 24.4 mmol) and dimethylamine (2 M, 36.5 mL) were dissolved in DCE (50 mL) and HOAc (146 mg, 2.44 mmol, 139.4 μL) and NaBH(OAc)3 (15.5 g, 73.1 mmol) were added at room temperature. The reaction solution was incubated at room temperature for 16 h until LC-MS showed the reaction was complete. Saturated NaHCO3 solution (150 mL) was added to the reaction. The aqueous phase was extracted with ethyl acetate (300 mL × 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (ISCO®; 80 g Sepa Flash® Silica Flash Column, eluent gradient of 0-10% MeOH (10% NH3.H2O) / DCM, 60 mL / min) to give a white solid (3.7 g, 64.8% yield).

[0445] 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 2.5, 8.3 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 3.00 (dt, J = 7.7, 13.4 Hz, 2H), 2.81-2.68 (m, 2H), 2.65-2.55 (m, 1H), 2.17 (s, 6H), 2.04-1.87 (m, 2H), 1.40-1.21 (m, 2H)

[0446] Step 5: Synthesis of compound int_52-1

[0447] [ka]

[0448] int_52-1-6 (3.60 g, 15.4 mmol) was dissolved in methanol (20.0 mL) and 10% Pd / C (3 g, 15.4 mmol) was added. The reaction was incubated at room temperature under hydrogen atmosphere (15.0 Psi.) for 16 hours until LC-MS showed the reaction was complete. The reaction was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain a white solid (2.5 g, 79.6% yield).

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 6.74 (d, J = 8.0 Hz, 1H), 6.34 (d, J = 2.3 Hz, 1H), 6.26 (dd, J = 2.4, 7.9 Hz, 1H), 4.74 (br s, 2H), 2.63-2.52 (m, 3H), 2.48-2.41 (m, 2H), 2.20-2.06 (m, 6H), 2.01-1.77 (m, 2H), 1.33-1.07 (m, 2H)

[0450] ESI-MS m / z: 205 [M+H] +

[0451] Step 6: Synthesis of compound 52

[0452] [ka]

[0453] int_1-8 (200 mg, 0.562 mmol) was dissolved in DMF (10 mL) and int_52-1 (115 mg, 0.562 mmol) and trifluoroacetic acid (226 mg, 2.2 mmol) were added. The reaction was heated to 80° C. and stirred for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give a white solid (71 mg, 15% yield).

[0454] 1 H NMR (400 MHz, Chloroform-d) δ 8.34 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.44 (s, 1H), 7.35 (s, 1H), 7.18 (s, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.54 (d, J = 7.9 Hz, 1H), 3.34 (s, 6H), 2.90-2.55 (m, 5H), 2.26 (s, 6H), 2.12-2.01 (m, 2H), 1.36 (dd, J = 12.4, 7.1 Hz, 2H).

[0455] ESI-MS m / z: 491 [M+H] +

[0456] Example 17: Synthesis of Compound 55

[0457] [ka]

[0458] Step 1: Synthesis of compound int_55-1-2

[0459] [ka]

[0460] int_55-1-1 (40.0 g, 205 mmol) was dissolved in H2SO4 (160 mL) and HNO3 (20.9 g, 216 mmol, 14.9 mL, 65% purity) was added at 0 °C. The reaction was incubated at 0 °C for 4 h until LC-MS showed the reaction was complete. The reaction was poured into ice water (300 mL). The aqueous phase was extracted with ethyl acetate (500 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (32 g, 65% yield) as a yellow solid. This crude product was used directly in the next reaction.

[0461] 1 H NMR (400MHz, DMSO-d6) δ 12.65 (br s, 2H), 8.18 (d, J = 2.5 Hz, 1H), 8.10 (dd, J = 8.3, 2.5 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 3.80 (s, 2H), 3.77 ppm (s, 2H)

[0462] Step 2: Synthesis of compound int_55-1-3

[0463] [ka]

[0464] int_55-1-2 (32.0 g, 133 mmol) was dissolved in THF (500 mL) and BH3-THF solution (1 M, 267 mL) was added at 0 °C. The reaction solution was incubated at 0 °C for 4 h until LC-MS showed the reaction was complete. Water (600 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (500 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (ISCO®; 220 g Sepa Flash® Silica Flash Column, eluent gradient of 0-10% MeOH / DCM, 80 mL / min) to obtain a yellow solid (17 g, 60.1% yield).

[0465] 1H NMR (400MHz, DMSO-d6) δ 8.07 (d, J = 2.5 Hz, 1H), 7.99 (dd, J = 8.5, 2.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 4.82 (br s, 2H), 3.59-3.68 (m, 4H), 2.89 ppm (t, J = 6.8 Hz, 4H)

[0466] Step 3: Synthesis of compound int_55-1-4

[0467] [ka]

[0468] int_55-1-3 (15 g, 71.0 mmol) and TEA (35.9 g, 355 mmol, 49.4 mL) were dissolved in DCM (400 mL) and MsCl (23.6 g, 206 mmol, 16 mL) was added at 0 °C. The reaction solution was incubated at 0 °C for 3 h until TLC showed the reaction was complete. Ice water (200 mL) was added to the reaction solution. The aqueous phase was extracted with dichloromethane (300 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (20 g, 76.7% yield). The crude product was used directly in the next reaction.

[0469] 1 H NMR (400 MHz, Chloroform-d) δ 8.18-8.10 (m, 2H), 7.47 (d, J = 8.3 Hz, 1H), 4.49 (q, J = 6.7 Hz, 4H), 3.25 (t, J = 6.8 Hz, 4H), 3.01 (d, J = 5.5 Hz, 6H)

[0470] Step 4: Synthesis of compound int_55-1-5

[0471] [ka]

[0472] int_55-1-4 (1 g, 2.72 mmol), methylamine (338 mg, 3.27 mmol, 30% purity) and DIPEA (879 mg, 6.80 mmol, 1.19 mL) were dissolved in ethanol (15 mL). The reaction was heated to 50 °C and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (SiO2, DCM / MeOH=10 / 1) to give a red oil (20 g, 76.7% yield).

[0473] 1 H NMR (400MHz, Chloroform-d) δ 8.04-7.98 (m, 2H), 7.28 (s, 1H), 7.26 (s, 1H), 3.13 (br s, 4H), 2.73 (br s, 4H), 2.48 (s, 3H)

[0474] Step 5: Synthesis of compound int_55-1

[0475] [ka]

[0476] int_55-1-5 (1 g, 4.85 mmol) was dissolved in methanol (20.0 mL) and 10% Pd / C (500 mg, 4.85 mmol) was added. The reaction was incubated at room temperature under hydrogen atmosphere (15.0 Psi.) for 16 hours until LC-MS showed the reaction was complete. The reaction was filtered to give a white solid (800 mg, 93.6% yield).

[0477] 1 H NMR (400MHz, Methanol-d4) δ 6.86 (d, J = 7.8 Hz, 1H), 6.58-6.49 (m, 2H), 2.82 (br s, 4H), 2.57 (br s, 4H), 2.36 (s, 3H)

[0478] ESI-MS m / z: 177 [M+H]+

[0479] Step 6: Synthesis of compound 55

[0480] [ka]

[0481] int_1-8 (200 mg, 0.57 mmol) was dissolved in DMF (10 mL) and int_55-1 (99 mg, 0.562 mmol) and trifluoroacetic acid (226 mg, 2.2 mmol) were added. The reaction was heated to 80 °C and stirred for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give a white solid (42 mg, 16.2% yield).

[0482] 1 H NMR (400 MHz, Chloroform-d) δ 8.34 (s, 1H), 7.62 (s, 2H), 7.23 (s, 1H), 7.23 (s, 2H), 7.06 (s, 2H), 6.55 (s, 1H), 3.34 (s, 6H), 3.13 (s, 4H), 2.91 (s, 4H), 2.60 (s, 3H).

[0483] ESI-MS m / z: 463 [M+H] +

[0484] Example 18: Synthesis of Compound 60

[0485] [ka]

[0486] Step 1: Synthesis of compound int_60-1-2

[0487] [ka]

[0488] int_60-1-1 (1.9 g, 10.7 mmol) was dissolved in acetonitrile (8 mL) and a solution of dimethylamine in tetrahydrofuran (2.0 M, 5.9 mL) and triethylamine (3.25 g, 32.1 mmol) were added. After 10 min of reaction, sodium borohydride acetate (6.8 g, 32.1 mmol) was added and the reaction was stirred for 16 h until LC-MS showed the reaction was complete. Water (100 mL) was added to the reaction. The aqueous phase was extracted with ethyl acetate (100 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was subjected to column chromatography (SiO2, DCM:MeOH = 100:1 to 20:1) to obtain a white solid (1.2 g, 55% yield).

[0489] ESI-MS m / z: 207 [M+H] +

[0490] Step 2: Synthesis of compound int_60-1

[0491] [ka]

[0492] Int_60-1-2 (900 mg, 4.36 mmol) was dissolved in methanol (20.0 mL) and 10% Pd / C (150 mg) was added. The reaction was incubated at room temperature under hydrogen atmosphere (15.0 Psi.) for 16 hours until LC-MS showed the reaction was complete. The reaction was filtered to give a white solid (700 mg, 91% yield).

[0493] ESI-MS m / z: 177 [M+H] +

[0494] Step 3: Synthesis of compound 60

[0495] [ka]

[0496] int_1-8 (600 mg, 1.59 mmol) was dissolved in DMF (30 mL) and int_60-1 (258 mg, 1.46 mmol) and trifluoroacetic acid (365 mg, 3.2 mmol) were added. The reaction was heated to 85° C. and stirred for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give a white solid (530 mg, 72% yield).

[0497] 1 H NMR (400 MHz, Chloroform-d) δ 8.35 (s, 1H), 7.68-7.59 (m, 2H), 7.45 (s, 2H), 7.33 (s, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 6.56 (dd, J = 7.9, 0.7 Hz, 1H), 3.35 (s, 6H), 3.35-3.25 (m, 1H), 3.15-2.98 (m, 4H), 2.43 (s, 6H).

[0498] ESI-MS m / z: 463 [M+H] +

[0499] Example 19: Synthesis of Compound 61

[0500] [ka]

[0501] Step 1: Synthesis of compound 61

[0502] [ka]

[0503] int_1-8 (67 mg, 0.2 mmol) was dissolved in DMF (5 mL) and int_61-1 (57 mg, 0.3 mmol) and trifluoroacetic acid (92 mg, 0.8 mmol) were added. The reaction was heated to 85 °C and stirred for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give a white solid (38 mg, 39% yield).

[0504] 1 H NMR (400 MHz, Chloroform-d) δ 8.32 (s, 1H), 7.62 (s, 2H), 7.36 (d, J = 8.6 Hz, 4H), 6.91 (d, J = 9.0 Hz, 2H), 6.53 (d, J = 7.9 Hz, 1H), 3.33 (s, 6H), 3.24-3.16 (m, 4H), 2.58 (t, J = 5.0 Hz, 4H), 2.35 (s, 3H).

[0505] ESI-MS m / z: 478 [M+H] +

[0506] Example 20: Synthesis of Compound 62

[0507] [ka]

[0508] Step 1: Synthesis of compound 62

[0509] [ka]

[0510] int_1-8 (67 mg, 0.2 mmol) was dissolved in DMF (5 mL) and int_62-1 (55 mg, 0.2 mmol) and trifluoroacetic acid (115 mg, 1 mmol) were added. The reaction was heated to 85° C. and stirred for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give a white solid (40 mg, 35% yield).

[0511] 1 H NMR (400 MHz, Chloroform-d) δ 8.31 (s, 1H), 7.66 (s, 2H), 7.33 (d, J = 8.5 Hz, 4H), 6.90 (d, J = 9.0 Hz, 2H), 6.53 (d, J = 7.9 Hz, 1H), 3.70 (d, J = 12.1 Hz, 2H), 3.33 (s, 6H), 2.75-2.66 (m, 2H), 2.63 (s, 4H), 2.45 (s, 4H), 2.40-2.32 (m, 1H), 2.28 (s, 3H), 1.94 (d, J = 12.6 Hz, 2H), 1.66 (qd, J = 12.1, 4.0 Hz, 2H).

[0512] ESI-MS m / z: 561 [M+H] +

[0513] Example 21: Synthesis of Compound 63

[0514] [ka]

[0515] Step 1: Synthesis of compound 63

[0516] [ka]

[0517] int_1-8 (67 mg, 0.2 mmol) was dissolved in DMF (5 mL) and int_63-1 (39 mg, 0.2 mmol) and trifluoroacetic acid (92 mg, 0.8 mmol) were added. The reaction was heated to 85° C. and stirred for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give a white solid (10 mg, 17% yield).

[0518] 1 H NMR (400 MHz, Chloroform-d) δ 8.36 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.46 (t, J = 8.2 Hz, 1H), 7.41 (s, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.13 (s, 1H), 6.97 (d, J = 8.1 Hz, 1H), 6.70 (dd, J = 8.4, 2.4 Hz, 1H), 6.54 (d, J = 7.9 Hz, 1H), 3.34 (s, 6H), 3.27 (t, J = 5.0 Hz, 4H), 2.70 (s, 4H), 2.44 (s, 3H).

[0519] ESI-MS m / z: 478 [M+H] +

[0520] Example 22: Synthesis of Compound 64

[0521] [ka]

[0522] Step 1: Synthesis of compound int_64-3

[0523] [ka]

[0524] int_64-1 (298 mg, 1.2 mmol), int_64-2 (200 mg, 1.2 mmol), cesium carbonate (782 mg, 2.4 mmol), Pd2(dba)3 (110 mg, 0.12 mmol), and XantPhos (138 mg, 0.24 mmol) were dissolved in 1,4-dioxane (20 mL), and the mixture was incubated at 85 °C overnight until LC-MS showed the reaction was complete. The reaction was filtered and distilled under reduced pressure to obtain the crude product, which was subjected to column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to obtain an orange solid product (130 mg, 33% yield).

[0525] ESI-MS m / z: 334 [M+H] +

[0526] Step 2: Synthesis of compound int_64-4

[0527] [ka]

[0528] int_64-3 (130 mg, 0.39 mmol) was dissolved in dichloromethane (15 mL) and m-CPBA (85%, 92 mg, 0.45 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 min until LC-MS showed the reaction was complete. The reaction solution was washed with aqueous sodium bicarbonate (50 mL x 2). The aqueous phase was extracted with ethyl acetate (50 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (120 mg). The crude product was used directly in the next reaction.

[0529] ESI-MS m / z: 350 [M+H] +

[0530] Step 3: Synthesis of compound 64

[0531] [ka]

[0532] int_64-4 (120 mg, 0.34 mmol) was dissolved in DMF (10 mL) and int_3-5 (95 mg, 0.59 mmol) and trifluoroacetic acid (158 mg, 1.56 mmol) were added. The reaction was heated to 80 °C and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give an orange solid (1.1 g, 70% yield).

[0533] 1 H NMR (400 MHz, Chloroform-d) δ 8.27 (s, 1H), 7.49 (s, 1H), 7.23 (s, 2H), 7.07 (s, 2H), 6.98 (s, 1H), 6.94-6.76 (m, 1H), 3.63-3.31 (m, 2H), 3.10 (s, 5H), 2.83 (s, 2H), 2.63 (s, 2H), 2.40 (s, 3H).

[0534] LC-MS: 448 [M+H] +

[0535] Example 23: Synthesis of Compound 77

[0536] [ka]

[0537] Step 1: Synthesis of compound int_77-2

[0538] [ka]

[0539] int_77-1 (350 mg, 1.174 mmol), int_1-3 (110 mg, 1.174 mmol), cesium carbonate (574 mg, 1.761 mmol), Pd2(dba)3 (54 mg, 0.059 mmol), and XantPhos (68 mg, 0.117 mmol) were dissolved in 1,4-dioxane (15 mL) and the reaction solution was incubated at 80 °C overnight until LC-MS showed the reaction was complete. The reaction was filtered and distilled under reduced pressure to obtain the crude product, which was purified by preparative HPLC to obtain a pale yellow solid product (374 mg, 89% yield).

[0540] ESI-MS m / z: 311 [M+H] +

[0541] Step 3: Synthesis of compound int_77-3

[0542] [ka]

[0543] int_77-2 (374 mg, 1.174 mmol) was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (8 mL) was added. The mixture was incubated at room temperature for 1 h until LC-MS showed the reaction was complete. The reaction was directly concentrated under reduced pressure to give a pale yellow solid (252 mg, crude product). This crude product was used directly in the next reaction.

[0544] ESI-MS m / z: 211 [M+H] +

[0545] Step 4: Synthesis of compound int_77-5

[0546] [ka]

[0547] int_77-3 (252 mg, 1.2 mmol) and int_77-4 (209 mg, 1.2 mmol) were dissolved in DMF (12 mL) and DIPEA (3.1 g, 24 mmol) was added. The reaction solution was heated to 50° C. and incubated overnight until LC-MS showed the reaction was complete. The reaction was filtered and distilled under reduced pressure to give the crude product, which was purified by preparative HPLC to give the product (133 mg, 31.9% yield).

[0548] ESI-MS m / z: 348 [M+H] +

[0549] Step 5: Synthesis of compound 77

[0550] [ka]

[0551] int_77-5 (330 mg, 0.95 mmol) was dissolved in DMF (20 mL) and int_3-5 (162 mg, 1 mmol) and trifluoroacetic acid (342 mg, 3 mmol) were added. The reaction was heated to 80° C. and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give a white solid (150 mg, 33% yield).

[0552] 1 H NMR (400 MHz, Chloroform-d) δ 8.37 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 7.22-7.13 (m, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 4.45 (t, J = 8.3 Hz, 2H), 3.52 (s, 2H), 3.16 (m, 8H), 2.90 (t, J = 6.0 Hz, 2H), 2.70 (t, J = 5.9 Hz, 2H), 2.44 (s, 3H).

[0553] ESI-MS m / z: 474 [M+H] +

[0554] Example 24: Synthesis of Compound 78

[0555] [ka]

[0556] Step 1: Synthesis of compound int_78-2

[0557] [ka]

[0558] int_78-1 (2.7 g, 13.77 mmol) was dissolved in DCE (60 mL) and methylmagnesium bromide in THF (3.0 M, 4.6 mL) was added at 0 °C under nitrogen atmosphere. The reaction was stirred for 30 min, then int_1-6 (2.56 g, 13.77 mmol) was added, warmed to room temperature, and stirred overnight until LC-MS showed the reaction was complete. The reaction was poured into ice water, and the solid precipitated and filtered to give the crude product (1.6 g, 34% yield). The crude product was used directly in the next reaction.

[0559] ESI-MS m / z: 345 [M+H] +

[0560] Step 2: Synthesis of compound int_78-3

[0561] [ka]

[0562] int_78-2 (1 g, 2.9 mmol) was dissolved in DMF (50 mL) and NaH (60% in oil, 140 mg, 3.5 mmol) was added at 0 °C under nitrogen atmosphere. The mixture was stirred for 30 min, then SEMCl (584 mg, 3.5 mmol) was added, warmed to room temperature, and stirred overnight until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, DCM:MeOH = 100:1 to 20:1) to give a pale yellow solid (500 mg, 36% yield).

[0563] ESI-MS m / z: 475 [M+H] +

[0564] Step 3: Synthesis of compound int_78-4

[0565] [ka]

[0566] int_78-3 (500 mg, 1.05 mmol), int_1-3 (587 mg, 6.32 mmol), cesium carbonate (855 mg, 2.63 mmol), Pd2(dba)3 (96 mg, 0.105 mmol) and XantPhos (73 mg, 0.126 mmol) were dissolved in DMF (20 mL), and the mixture was incubated overnight at 85 °C under nitrogen atmosphere until LC-MS showed the reaction was complete. The reaction was filtered and distilled under reduced pressure to obtain the crude product, which was subjected to column chromatography (SiO2, DCM:MeOH = 100:1 to 20:1) to obtain a pale yellow solid product (500 mg, 97% yield).

[0567] ESI-MS m / z: 488 [M+H] +

[0568] Step 4: Synthesis of compound int_78-5

[0569] [ka]

[0570] int_78-3 (250 mg, 0.5 mmol) was dissolved in dichloromethane (20 mL) and m-CPBA (85%, 153 mg, 0.75 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 min until LC-MS showed the reaction was complete. Water (100 mL) was added to the reaction. The aqueous phase was extracted with dichloromethane (100 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product (200 mg). The crude product was used directly in the next reaction.

[0571] ESI-MS m / z: 504 [M+H] +

[0572] Step 5: Synthesis of compound int_78-6

[0573] [ka]

[0574] int_78-5 (252 mg, 0.5 mmol) was dissolved in DMF (10 mL) and int_3-5 (81 mg, 0.5 mmol) and trifluoroacetic acid (57 mg, 0.5 mmol) were added. The reaction was heated to 80 °C and stirred for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, DCM:MeOH = 100:1 to 20:1) to give a pale yellow solid (100 mg, 33% yield).

[0575] ESI-MS m / z: 602 [M+H] +

[0576] Step 6: Synthesis of compound 78

[0577] [ka]

[0578] int_78-6 (100 mg, 0.17 mmol) was dissolved in THF (5 mL) and TBAF (536 mg, 1.7 mmol) was added. The reaction was heated to 80 °C and stirred for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give a pale yellow solid (2 mg, 2.5% yield).

[0579] ESI-MS m / z: 472 [M+H] +

[0580] Example 25: Synthesis of Compound 79

[0581] [ka]

[0582] Step 1: Synthesis of compound int_79-1

[0583] [ka]

[0584] int_78-2 (220 mg, 0.637 mmol) was dissolved in DMF (10 mL) and NaH (60% in oil, 40 mg, 1 mmol) was added at 0° C. under nitrogen atmosphere. The mixture was stirred for 10 min, then iodomethane (117 mg, 0.828 mmol) was added, warmed to room temperature, and stirred overnight until LC-MS showed the reaction was complete. The reaction was poured into ice water, and the solid was precipitated and filtered to give the crude product (160 mg, 70% yield). The crude product was used directly in the next reaction.

[0585] ESI-MS m / z: 359 [M+H] +

[0586] Step 2: Synthesis of compound int_79-2

[0587] [ka]

[0588] int_79-1 (160 mg, 0.445 mmol), int_1-3 (84 mg, 0.9 mmol), cesium carbonate (362 mg, 1.11 mmol), Pd2(dba)3 (4 mg, 0.0445 mmol) and XantPhos (3 mg, 0.0534 mmol) were dissolved in DMF (10 mL) and the mixture was incubated at 85 °C under nitrogen overnight until LC-MS showed the reaction was complete. The reaction was poured into ice water, the solid was precipitated and filtered to give the crude product (100 mg, 60% yield). The crude product was used directly in the next reaction.

[0589] ESI-MS m / z: 372 [M+H] +

[0590] Step 3: Synthesis of compound int_79-3

[0591] [ka]

[0592] int_79-2 (100 mg, 0.27 mmol) was dissolved in dichloromethane (10 mL) and DMF (10 mL) and m-CPBA (70 mg, 0.4 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 min until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was used directly in the next reaction.

[0593] ESI-MS m / z: 388 [M+H] +

[0594] Step 5: Synthesis of compound 79

[0595] [ka]

[0596] int_79-3 (100 mg, 0.26 mmol) was dissolved in DMF (10 mL) and int_3-5 (65 mg, 0.4 mmol) and trifluoroacetic acid (62 mg, 0.54 mmol) were added. The reaction was heated to 80° C. and stirred for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give a pale yellow solid (2 mg, 15.8% yield).

[0597] ESI-MS m / z: 486 [M+H] +

[0598] Example 26: Synthesis of Compound 80

[0599] [ka]

[0600] Step 1: Synthesis of compound int_80-2

[0601] [ka]

[0602] int_80-1 (250 mg, 1.269 mmol) was dissolved in dichloromethane (20 mL) and DIPEA (655 mg, 5.075 mmol), DMAP (50 mg, 0.41 mmol), and (Boc)2O (325 mg, 2.538 mmol) were added. The mixture was incubated overnight at room temperature to react until LC-MS showed the reaction was complete. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (200 mL), washed with 2N dilute hydrochloric acid (100 mL), washed with aqueous sodium bicarbonate (100 mL), washed with water (100 mL), and finally washed with saturated saline (100 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product, which was subjected to column chromatography (SiO2, PE:EA = 10:1) to obtain the product (320 mg, 85% yield).

[0603] ESI-MS m / z: 197 [M+H] + .

[0604] Step 2: Synthesis of compound int_80-3

[0605] [ka]

[0606] int_80-2 (1.03 g, 3.468 mmol), int_1-3 (323 mg, 3.468 mmol), cesium carbonate (1.677 g, 5.202 mmol), Pd2(dba)3 (160 mg, 0.173 mmol), and XantPhos (201.6 mg, 0.346 mmol) were dissolved in 1,4-dioxane (50 mL) and the mixture was incubated at 85 °C overnight under nitrogen until LC-MS showed the reaction was complete. The reaction was filtered and distilled under reduced pressure to obtain the crude product, which was subjected to preparative HPLC to obtain the solid product (640 mg, 60% yield).

[0607] ESI-MS m / z: 310 [M+H] +

[0608] Step 3: Synthesis of compound int_80-4

[0609] [ka]

[0610] int_80-3 (640 mg, 2.069 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was added. The mixture was incubated at room temperature for 1 h until LC-MS showed the reaction was complete. The reaction was directly concentrated under reduced pressure to give the crude product (600 mg). The crude product was used directly in the next reaction.

[0611] ESI-MS m / z: 210 [M+H] +

[0612] Step 4: Synthesis of compound int_80-5

[0613] [ka]

[0614] int_80-4 (600 mg, 2.87 mmol) and int_1-6 (630 mg, 3.4 mmol) were dissolved in DMF (10 mL) and DIPEA (661 mg, 5.8 mmol) was added. The reaction solution was heated to 50° C. and incubated overnight until LC-MS showed the reaction was complete. The reaction was filtered and distilled under reduced pressure to obtain the crude product, which was subjected to preparative HPLC to obtain the solid product (320 mg, 53% yield).

[0615] ESI-MS m / z: 359 [M+H] +

[0616] Step 5: Synthesis of compound int_80-6

[0617] [ka]

[0618] int_80-5 (95 mg, 0.265 mmol) was dissolved in dichloromethane (20 mL) and m-CPBA (85%, 70 mg, 0.345 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 minutes until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product (90 mg). The crude product was used directly in the next reaction.

[0619] ESI-MS m / z: 375 [M+H] +

[0620] Step 6: Synthesis of compound 80

[0621] [ka]

[0622] int_80-6 (90 mg, 0.161 mmol) was dissolved in dichloromethane (5 mL) and int_3-5 (298 mg, 1.2 mmol) and trifluoroacetic acid (91 mg, 0.8 mmol) were added. The reaction was heated to 80° C. and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give a white solid (37 mg, 48.7% yield).

[0623] 1 H NMR (400 MHz, Chloroform-d) δ 8.73 (d, J = 26.1 Hz, 2H), 7.81 (s, 1H), 7.61 (s, 1H), 7.37 (s, 1H), 7.14 (dd, J = 22.2, 7.0 Hz, 4H), 3.50 (d, J = 17.6 Hz, 2H), 3.31 (s, 6H), 2.92 (t, J = 6.0 Hz, 2H), 2.70 (t, J = 6.0 Hz, 2H), 2.45 (d, J = 5.1 Hz, 3H).

[0624] ESI-MS m / z: 473 [M+H] +

[0625] Examples 27-160: Synthesis of Compounds 2, 4-5, 10, 14-15, 17-18, 20-21, 23-28, 30-41, 44-51, 53-54, 56-59, 65-76, and 80-160

[0626] The target compounds 2, 4-5, 10, 14-15, 17-18, 20-21, 23-28, 30-41, 44-51, 53-54, 56-59, 65-76 and 80-160 in Table 1 were obtained by using the above synthesis method with different starting materials.

[0627] The LC-MS analysis process is as follows: Equipment: Agilent, LC: 1260 InfinityII+MS: G6125B Column: Welch: Core-shell 2.7 μm, 4.3 × 50 mm Temperature: 30℃ Wavelength: 254nm / 214nm Mobile phase A: HO (0.1% formic acid) Mobile phase B: Acetonitrile (0.1% formic acid) gradient: TIFF2024508769000204.tif49168

[0628] [Table 1] TIFF2024508769000206.tif231168TIFF2024508769000207.tif231168TIFF2024508769000208.tif231168TIFF2024508769000209.tif239168 TIFF2024508769000210.tif231168TIFF2024508769000211.tif237168TIFF2024508769000212.tif231168TIFF2024508769000213.tif231168

[0629] [Table 2] TIFF2024508769000215.tif241168TIFF2024508769000216.tif235168TIFF2024508769000217.tif215168TIFF2024508769000218.tif94168

[0630] Example 161 In vitro assay of the compounds of the present invention for inhibiting the enzymatic activity of recombinant protein Wee-1

[0631] The inhibitory effect of the compounds of the present invention on the enzyme activity of recombinant protein Wee-1 was measured by HTRF. The procedure is as follows: DMSO or serially diluted compounds (up to 200 nM, 1:5 dilution) and recombinant protein were co-incubated in kinase buffer at 37°C for 30 min, then Fluorescein-PolyGAT and ATP were added, and the reaction was started by adding substrate. After 90 min of incubation at room temperature, antibody and detection solution were added, and further incubation at room temperature for 60 min, after which fluorescence values ​​were detected (excitation wavelength: 340 nm, emission wavelength: 495 nm and 520 nm). The 520 nm / 495 nm fluorescence intensity ratio was calculated and compared with the DMSO group to determine the inhibition rate and IC 50 The values ​​were calculated and the results are shown in Table 3 below.

[0632] [Table 3] TIFF2024508769000220.tif157168

[0633] As can be seen from the data in Table 3, the compounds of the present invention have good inhibitory activity against the enzyme activity of the recombinant protein Wee-1.

[0634] Example 162. In vitro antiproliferative activity of compounds of the present invention against MIA PaCa-2 cells

[0635] MIA PaCa-2 cells were seeded in 384-well plates at 3000 cells / well. After overnight adherent culture, DMSO or compounds serially diluted 1:5 starting at 5 μM were added. Viability was assessed 72 h after administration by measuring intracellular ATP content. The inhibition rate of viable cells by compounds was calculated compared to the DMSO group and expressed as IC 50 The values ​​were calculated and the results are shown in Table 4 below.

[0636] [Table 4]

[0637] As can be seen from the data in Table 4, compounds of the present invention have potent antiproliferative activity against MIA PaCa-2 cells.

[0638] Example 163. In vitro antiproliferative activity of compounds of the invention in combination with gemcitabine against MIA PaCa-2 cells

[0639] MIA PaCa-2 cells were seeded at 3000 cells / well in 384-well plates and treated with 20 nM or 200 nM gemcitabine (GMC). After overnight adherent culture, DMSO or compounds serially diluted 1:5 starting at 100 nM were added. Viability was assessed 72 h after treatment by measuring intracellular ATP content. The percentage of inhibition of viable cells by compounds compared to the DMSO group was calculated and expressed as IC 50 The values ​​were calculated and the results are shown in Table 5 below.

[0640] [Table 5] TIFF2024508769000223.tif91168

[0641] As can be seen from the data in Table 5, compounds of the invention in combination with gemcitabine have potent antiproliferative activity against MIA PaCa-2 cells.

[0642] Example 164: In Vivo Efficacy Study - Mouse HT29 Subcutaneous Xenograft Tumor Model

[0643] HT29 is a colon cancer cell line. Each nude mouse was injected with 5 × 10 6 HT29 cells were subcutaneously transplanted. The tumors were 100–200 mm 3 When the tumors grew to 100 mm Hg, the compound was administered orally once a day alone or in combination with gemcitabine 15 mg / kg, which was intraperitoneally injected once a week, and the tumor volume was measured twice a week and at the end of treatment. The tumor growth inhibition rate of the compound was calculated according to the following formula: tumor growth inhibition rate (TGI)=1-(tumor volume of treatment group on day 20-tumor volume of treatment group on day 1) / (tumor volume of vehicle control group on day 20-tumor volume of treatment group on day 1). The results are shown in Tables 6 and 7.

[0644] [Table 6]

[0645] [Table 7]

[0646] Example 165: In Vivo Efficacy Study - Mouse HT29 Subcutaneous Xenograft Tumor Model

[0647] HT29 is a colon cancer cell line. Each nude mouse was injected with 5 × 10 6 HT29 cells were subcutaneously transplanted. The tumors were 100–200 mm 3 When the tumors grew to 100 mm Hg, the compound was administered orally once a day in combination with gemcitabine 30 mg / kg, which was intraperitoneally injected once a week, and the tumor volumes were measured twice a week and at the end of treatment. The tumor growth inhibition rate of the compound was calculated according to the following formula: tumor growth inhibition rate (TGI)=1-(tumor volume of treatment group on day 20-tumor volume of treatment group on day 1) / (tumor volume of vehicle control group on day 20-tumor volume of treatment group on day 1). The results are shown in Table 8.

[0648] [Table 8]

[0649] As can be seen from Tables 6, 7 and 8, when the compounds of the present invention were used alone, they could inhibit the tumor growth of mouse HT29 subcutaneous xenograft tumors, and when the compounds of the present invention were used in combination with gemcitabine, they showed a more significant inhibitory effect on tumor growth.

[0650] Although specific embodiments of the present invention have been described above, those skilled in the art will understand that these embodiments are merely illustrative and that many changes or modifications can be made to these embodiments without departing from the principles and spirit of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of general formula (1), or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula, X is N, Y is -H, -F, -Cl, -Br, -I, or -CN. And; Z is a chemical bond, or -NH-; Ring A is, 【Chemistry 2】 And; Structural units in general formula (1) 【Transformation 3】 teeth, 【Chemistry 4】 And; Each R ３ These are independently -H, -D, halogens, or (C2-C6) alkenyls; Structural units in general formula (1) 【Transformation 5】 teeth, 【Chemistry 6-1】 【Chemistry 6-2】 【Transformation 6-3】 【Chemistry 6-4】 And, q is an integer between 1, 2, 3, or 4.

2. In general formula (1), ring A is, 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. In general formula (1), structural unit 【Transformation 8】 teeth, 【Chemistry 9-1】 【Chemistry 9-2】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. The compound has the following structure: 【Chemistry 10-1】 【Chemistry 10-2】 【Chemistry 10-3】 [Chemistry 10-4] 【Transformation 10-5】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having one of the above.

5. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and the compound described in claim 1, or a pharmaceutically acceptable salt thereof, as an active ingredient.

6. Use of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 5, in preparing a pharmacopoeia for treating related diseases mediated by Wee-1 protein kinase.

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