Benzisothiazole, isothiazolo [3, 4-b] pyridines, quinazolines, phthalazines, pyrido [2, 3-d] pyridazines and pyrido [2, 3-d] pyrimidine derivatives as kras g12c inhibitors for the treatment of lung, pancreatic or colorectal cancer

Abstract

To provide KRASG12C inhibitors for treating lung, pancreatic or colorectal cancer.SOLUTION: Benzisothiazole, isothiazolo [3, 4-b] pyridine, quinazoline, phthalazine, pyrido [2, 3-d] pyridazines and pyrido [2, 3-d] pyrimidine derivatives and associated compounds are provided as KRASG12C inhibitors.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 438,334, filed December 22, 2016, the specification of which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] KRAS gene mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer, and bile duct cancer. KRAS mutations are also observed in approximately 25% of NSCLC patients, and several studies have shown that KRAS mutations are a negative prognostic factor for NSCLC patients. Recently, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations have been found to confer resistance to epidermal growth factor receptor (EGFR)-targeted therapy in colorectal cancer. Therefore, KRAS mutation status can provide important information before prescribing TKI therapy. Overall, there is a need for new medical treatments for patients with pancreatic cancer, lung adenocarcinoma, or colorectal cancer, especially those diagnosed with such cancers characterized by KRAS mutations and those who have progressed after chemotherapy. Summary of the Invention [Means for solving the problem]

[0003] As used herein, a compound having the structure of formula (I): [ka] (In the formula, E 1 and E 2 are each independently N or CR 1 and; R 1 are independently H, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C1~6 Alkoxy, NH-C 1~6 Alkyl, N(C 1~6 alkyl), cyano, or halo; R 2 Ha, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OR', N(R')2, C 2~3 Alkenyl, C 2~3 Alkynyl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene aryl, or C 0~3 alkyleneheteroaryl, and each R' is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~14 Cycloalkyl, C 2~14 Heterocycloalkyl, C 2~3 Alkenyl, C 2~3 is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R 3 is halo, C 1~3 Alkyl, C 1~2 Haloalkyl, C 1~3 Alkoxy, C 3~4 Cycloalkyl, C 2~3 Alkenyl, C 2~3 is alkynyl, aryl, or heteroaryl; R 4 teeth [ka] and; Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C 1~6 Alkylene, -OC 0~5 Alkylene, -SC 0~5 Alkylene, or -NH-C 0~5alkylene, C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 In the case of alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R 4’ is H, C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, cycloalkyl, heterocycloalkyl, C 0~3 Alkylene-C 3~4 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 6~14 aryl, or [ka] Selected from; R 5 and R 6 are independently H, halo, and C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 1~6 Alkyleneamines, C 0~6 Alkylene-amides, C 0~3 Alkylene-C(O)OH, C 0~3 Alkylene-C(O)OC 1~4 Alkyl, C 1~6 Alkylene-O-aryl, C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3Alkylene-C 2~14 Heterocycloalkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 2~14 heteroaryl or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; and R 7 is H or C 1~8 alkyl, or R 7 and R 5 together with the atom to which they are attached form a 4- to 6-membered ring), or a pharmaceutically acceptable salt thereof.

[0004] In another embodiment, the present disclosure provides a compound having the structure of formula (I): [ka] (In the formula, E 1 and E 2 are each independently N or CR 1 and; R 1 are independently H, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, NH-C 1~6 Alkyl, N(C 1~4 alkyl), cyano, or halo; R 2 Ha, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OR', N(R')2, C 2~3 Alkenyl, C 2~3 Alkynyl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 6~14 Aryl, or C 0~3 Alkylene-C2~14 heteroaryl, and each R' is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~14 Cycloalkyl, C 2~3 Alkenyl, C 2~3 is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R 3 is halo, C 1~3 Alkyl, C 1~2 Haloalkyl, C 1~3 Alkoxy, C 3~14 Cycloalkyl, C 2~3 Alkenyl, C 2~3 is alkynyl, aryl, or heteroaryl; R 4 teeth [ka] and; Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C 1~6 Alkylene, -OC 0~5 Alkylene, -SC 0~5 Alkylene, or -NH-C 0~5 alkylene, C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 In the case of alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R 5 and R 6 are independently H, halo, and C 1~8 Alkyl, C 2~8 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 1~6 Alkyleneamines, C 0~6Alkylene-amides, C 0~3 Alkylene-C(O)OH, C 0~3 Alkylene-C(O)OC 1~4 Alkyl, C 1~6 Alkylene-O-aryl, C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 2~14 heteroaryl or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; and R 7 is H or C 1~6 alkyl, or R 7 and R 5 together with the atom to which they are attached form a 4- to 6-membered ring), or a pharmaceutically acceptable salt thereof.

[0005] Additionally, compounds of formula (II), or a pharmaceutically acceptable salt thereof: [ka] (In the formula, E 1 and E 2 are each independently N or CR 1 and J is N, NR 10 or CR 10 and M is N, NR 13 or CR 13 and; [ka] are the single or double bonds necessary to give all atoms their normal valence; R 1 are independently H, hydroxy, C1~6 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, NH-C 1~4 Alkyl, N(C 1~4 alkyl), cyano, or halo; R 2 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OR', N(R')2, C 2~3 Alkenyl, C 2~3 Alkynyl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 6~14 Aryl, or C 0~3 Alkylene-C 2~14 heteroaryl, and each R' is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~14 Cycloalkyl, C 2~14 Heterocycloalkyl, C 2~3 Alkenyl, C 2~3 alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R 3 is halo, C 1~3 Alkyl, C 1~2 Haloalkyl, C 1~3 Alkoxy, C 3~4 Cycloalkyl, C 2~14 Heterocycloalkyl, C 2~3 Alkenyl, C 2~3 is alkynyl, aryl, or heteroaryl; R 4 teeth [ka] wherein ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is a bond, C 1~6 Alkylene, -OC 0~5 Alkylene, -SC0~5 Alkylene or -NH-C 0~5 alkylene, C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 For alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R 4’ is H, C 1~8 Alkyl, C 2~8 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, cycloalkyl, heterocycloalkyl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 6~14 aryl, or [ka] Selected from; R 5 and R 6 are independently H, halo, and C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 1~6 Alkyleneamines, C 0~6 Alkylene-amides, C 0~3 Alkylene-C(O)OH, C 0~3 Alkylene-C(O)OC 1~4 Alkyl, C 1~6 Alkylene-O-aryl, C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 2~14 heteroaryl or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; R 7 is H or C 1~8 alkyl, or R 7 and R 5 form a 4- to 6-membered ring with the atoms to which they are attached; Q is CR 8 R 9 , C=CR 8 R 9 , C=O, C=S, or C=NR 8 and;R 8 and R 9 are independently H, C 1~3 Alkyl, hydroxy, C 1~3 Alkoxy, cyano, nitro or C 3~6 is cycloalkyl, or R 8 and R 9 can form a 3- to 6-membered ring together with the carbon atom to which they are attached; R 10 is C 1~8 Alkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 3~14 Heteroaryl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 1~6 Alkoxy, OC 0~3 Alkylene-C 6~14 Aryl, OC 0~3 Alkylene-C 3~14 Heteroaryl, OC 0~3 Alkylene-C 3~14 Cycloalkyl, OC 0~3 Alkylene-C 2~14Heterocycloalkyl, NH-C 1~8 Alkyl, N(C 1~8 alkyl)2, NH-C 0~3 Alkylene-C 6~14 Aryl, NH-C 0~3 Alkylene-C 2~14 Heteroaryl, NH-C 0~3 Alkylene-C 3~14 Cycloalkyl, NH-C 0~3 Alkylene-C 2~14 Heterocycloalkyl, halo, cyano or C 1~6 an alkylene-amine; and R 13 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkyleneamine, or C 3~14 cycloalkyl), or a pharmaceutically acceptable salt thereof (provided (1) J is NR 10 When M is N or CR 13 and; (2) M is NR 13 When J is N or CR 10 and; (3) J is CR 10 When M is N or NR 13 and (4) M is CR 13 When J is N or NR 10 is) to provide.

[0006] In some embodiments, Q is C=O and E 1 and E 2 are CR 1 If (1) R 10 is C 1~3 Alkylene aryl, C 1~3 Alkylene Heteroaryl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 1~3 Alkylene-C 2~7 heterocycloalkyl, or halo; or (2) R 13 is C 1~3Haloalkyl or C 3~5 In various embodiments, J is either NR 10 and M is CR 13 In some embodiments, J is CR 10 and M is NR 13 In some embodiments, J is N and M is NR 13 In various embodiments, J is NR 10 and M is N.

[0007] Furthermore, a compound having the structure of formula (II) [ka] (In the formula, E 1 and E 2 are each independently N or CR 1 and; J is N, NR 10 or CR 10 and; M is N, NR 13 or CR 13 and; [ka] is the single or double bond necessary to give every atom its normal valence; R 1 are independently H, hydroxy, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, NH-C 1~4 Alkyl, N(C 1~4 alkyl), cyano, or halo; R 2 Ha, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OR', N(R')2, C 2~3 Alkenyl, C 2~3 Alkynyl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 6~14 Aryl, or C 0~3 Alkylene-C 2~14 heteroaryl, and each R' is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~14 Cycloalkyl, C 2~14 Heterocycloalkyl, C 2~3 Alkenyl, C 2~3 is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R 3 is halo, C 1~3 Alkyl, C 1~2 Haloalkyl, C 1~3 Alkoxy, C 3~4 Cycloalkyl, C 2~3 Alkenyl, C 2~3 is alkynyl, aryl, or heteroaryl; R 4 teeth [ka] and; Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C 1~6 Alkylene, -OC 0~5 Alkylene, -SC 0~5 Alkylene, or -NH-C 0~5 alkylene, C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 In the case of alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R 5 and R 6 are independently H, halo, and C 1~6 Alkyl, C 2~6Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 1~6 Alkyleneamines, C 0~6 Alkylene-amides, C 0~3 Alkylene-C(O)OH, C 0~3 Alkylene-C(O)OC 1~4 Alkyl, C 1~6 Alkylene-O-aryl, C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 2~14 heteroaryl or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; R 7 is H or C 1~8 alkyl, or R 7 and R 5 form a 4- to 6-membered ring together with the atoms to which they are attached; Q is CR 8 R 9 , C=CR 8 R 9 , C=O, C=S, or C=NR 8 and; R 8 and R 9 are independently H, C 1~3 Alkyl, hydroxy, C 1~3 Alkoxy, cyano, nitro, or C 3~6 is cycloalkyl, or R 8 and R 9 can form a 3- to 6-membered ring together with the carbon atoms to which they are attached; R 10 is C 1~8 Alkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 3~14 Heteroaryl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 1~6 Alkoxy, OC 0~3 Alkylene-C 6~14 Aryl, OC 0~3 Alkylene-C 3~14 Heteroaryl, OC 0~3 Alkylene-C 3~14 Cycloalkyl, OC 0~3 Alkylene-C 2~14 Heterocycloalkyl, NH-C 1~8 Alkyl, N(C 1~8 alkyl)2, NH-C 0~3 Alkylene-C 6~14 Aryl, NH-C 0~3 Alkylene-C 2~14 Heteroaryl, NH-C 0~3 Alkylene-C 3~14 Cycloalkyl, NH-C 0~3 Alkylene-C 2~14 Heterocycloalkyl, halo, cyano or C 1~6 alkylene-amine; however (1) J is NR 10 When M is N or CR 13 and; (2) M is NR 13 When J is N or CR 10 and; (3) J is CR 10 When M is N or NR 13 and; (4) M is CR 13 When J is N or NR 10 is] to provide.

[0008] In some embodiments, Q is C=O and E 1 and E 2 are CR 1 If (1) R 10 is C 1~3 Alkylene aryl, C 1~3 Alkylene Heteroaryl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 1~3 Alkylene-C 2~7 heterocycloalkyl, or halo; or (2) R 13 is C 1~3 Haloalkyl or C 3~5 In various embodiments, J is either NR 10 and M is CR 13 In some embodiments, J is CR 10 and M is NR 13 In some embodiments, J is N and M is NR 13 In various embodiments, J is NR 10 and M is N.

[0009] Furthermore, the compound represented by formula (III) or (III'): [ka] (In the formula, E 1 and E 2 are each independently N or CR 1 and; R 1 are independently H, hydroxy, C 1~6 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, NH-C 1~4 Alkyl, N(C 1~4 alkyl), cyano, or halo; R 2 Ha, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OR', N(R')2, C 2~3 Alkenyl, C 2~3 Alkynyl, C 0~3Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 6~14 Aryl, or C 0~3 Alkylene-C 2~14 heteroaryl, and each R' is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~14 Cycloalkyl, C 2~14 Heterocycloalkyl, C 2~3 Alkenyl, C 2~3 is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R 3 is halo, C 1~3 Alkyl, C 1~2 Haloalkyl, C 1~3 Alkoxy, C 3~4 Cycloalkyl, C 2~14 Heterocycloalkyl, C 2~3 Alkenyl, C 2~3 is alkynyl, aryl, or heteroaryl; R 4 teeth [ka] and; Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C 1~6 Alkylene, -OC 0~5 Alkylene, -SC 0~5 Alkylene, or -NH-C 0~5 alkylene, C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 In the case of alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R4’ is H, C 1~8 Alkyl, C 2~8 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, cycloalkyl, heterocycloalkyl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 6~14 aryl, or [ka] Selected from; R 5 and R 6 are independently H, halo, and C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 1~6 Alkyleneamines, C 0~6 Alkylene-amides, C 0~3 Alkylene-C(O)OH, C 0~3 Alkylene-C(O)OC 1~4 Alkyl, C 1~6 Alkylene-O-aryl, C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 2~14 heteroaryl or cyano, or R 5 and R 6form a 4- to 6-membered ring together with the atoms to which they are attached; R 7 is H or C 1~8 alkyl, or R 7 and R 5 form a 4- to 6-membered ring together with the atoms to which they are attached; Q is CR 8 R 9 , C=CR 8 R 9 , C=O, C=S, or C=NR 8 and; R 8 and R 9 are independently H, C 1~6 Alkyl, hydroxy, C 1~6 Alkoxy, cyano, nitro, or C 3~14 is cycloalkyl, or R 8 and R 9 can form a 3- to 6-membered ring together with the carbon atoms to which they are attached; R 10 is C 1~8 Alkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 3~14 Heteroaryl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 1~6 Alkoxy, OC 0~3 Alkylene-C 6~14 Aryl, OC 0~3 Alkylene-C 3~14 Heteroaryl, OC 0~3 Alkylene-C 3~14 Cycloalkyl, OC 0~3 Alkylene-C 2~14 Heterocycloalkyl, NH-C 1~8 Alkyl, N(C 1~8 alkyl)2, NH-C 0~3 Alkylene-C 6~14 Aryl, NH-C 0~3 Alkylene-C 2~14Heteroaryl, NH-C 0~3 Alkylene-C 3~14 Cycloalkyl, NH-C 0~3 Alkylene-C 2~14 Heterocycloalkyl, halo, cyano or C 1~6 or a pharmaceutically acceptable salt thereof.

[0010] Furthermore, the compound represented by formula (III) or (III'): [ka] (In the formula, E 1 and E 2 are each independently N or CR 1 and; R 1 are independently H, hydroxy, C 1~6 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, NH-C 1~4 Alkyl, N(C 1~4 alkyl), cyano, or halo; R 2 Ha, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OR', N(R')2, C 2~3 Alkenyl, C 2~3 Alkynyl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 6~14 Aryl, or C 0~3 Alkylene-C 2~14 heteroaryl, and each R' is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~14 Cycloalkyl, C 2~14 Heterocycloalkyl, C 2~3 Alkenyl, C 2~3is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R 3 is halo, C 1~3 Alkyl, C 1~2 Haloalkyl, C 1~3 Alkoxy, C 3~4 Cycloalkyl, C 2~14 Heterocycloalkyl, C 2~3 Alkenyl, C 2~3 is alkynyl, aryl, or heteroaryl; R 4 teeth [ka] and; Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C 1~6 Alkylene, -OC 0~5 Alkylene, -SC 0~5 Alkylene, or -NH-C 0~5 alkylene, C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 In the case of alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R 5 and R 6 are independently H, halo, and C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 1~6 Alkyleneamines, C 0~6 Alkylene-amides, C 0~3 Alkylene-C(O)OH, C 0~3 Alkylene-C(O)OC 1~4 Alkyl, C 1~6Alkylene-O-aryl, C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 2~14 heteroaryl or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; R 7 is H or C 1~8 alkyl, or R 7 and R 5 form a 4- to 6-membered ring together with the atoms to which they are attached; Q is CR 8 R 9 , C=CR 8 R 9 , C=O, C=S, or C=NR 8 and; R 8 and R 9 are independently H, C 1~6 Alkyl, hydroxy, C 1~6 Alkoxy, cyano, nitro, or C 3~14 is cycloalkyl, or R 8 and R 9 can form a 3- to 6-membered ring together with the carbon atoms to which they are attached; R 10 is C 1~8 Alkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 3~14 Heteroaryl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 1~6Alkoxy, OC 0~3 Alkylene-C 6~14 Aryl, OC 0~3 Alkylene-C 3~14 Heteroaryl, OC 0~3 Alkylene-C 3~14 Cycloalkyl, OC 0~3 Alkylene-C 2~14 Heterocycloalkyl, NH-C 1~8 Alkyl, N(C 1~8 alkyl)2, NH-C 0~3 Alkylene-C 6~14 Aryl, NH-C 0~3 Alkylene-C 2~14 Heteroaryl, NH-C 0~3 Alkylene-C 3~14 Cycloalkyl, NH-C 0~3 Alkylene-C 2~14 Heterocycloalkyl, halo, cyano or C 1~6 or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the compound has the structure of Formula (III): In other embodiments, the compound has the structure of Formula (III'):

[0012] Compounds of formula (II) or (III) disclosed herein can have one or more of the following features: In some embodiments, Q is C=O. In some embodiments, Q is C=S. In some embodiments, Q is C=NR 8 In various embodiments, R 8 is C 1~2 In some embodiments, Q is CR 8 R 9 In various embodiments, Q is CR 8 R 9 In some embodiments, R 8 and R 9 together with the carbon atoms to which they are attached form a 3- to 4-membered ring. In some embodiments, R 8 is C 1~2 alkyl, and R9 is H.

[0013] Also, the formula (IV) or (IV'): [ka] (In the formula, E 1 and E 2 are each independently 1 or N; R 1 are independently H, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, NH-C 1~6 Alkyl, N(C 1~6 alkyl), cyano, or halo; R 2 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OR', N(R')2, C 2~3 Alkenyl, C 2~3 Alkynyl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 6~14 Aryl, or C 0~3 Alkylene-C 2~14 heteroaryl, and each R' is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~14 Cycloalkyl, C 2~14 Heterocycloalkyl, C 2~3 Alkenyl, C 2~3 is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R 3 is halo, C 1~2 Haloalkyl, C 1~3 Alkoxy, C 3~4 Cycloalkyl, C 2~3Alkenyl, C 2~3 is alkynyl, aryl, or heteroaryl; R 4 teeth [ka] Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C 1~6 Alkylene, -OC 0~5 Alkylene, -SC 0~5 Alkylene, or -NH-C 0~5 alkylene, C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 In the case of alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R 4’ is H, C 1~8 Alkyl, C 2~8 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, cycloalkyl, heterocycloalkyl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 6~14 aryl, or [ka] Selected from; R 5 and R 6 are independently H, halo, and C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C1~6 Haloalkyl, C 1~6 Alkyleneamines, C 0~6 Alkylene-amides, C 0~3 Alkylene-C(O)OH, C 0~3 Alkylene-C(O)OC 1~4 Alkyl, C 1~6 Alkylene-O-aryl, C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 2~14 heteroaryl or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; R 7 is H or C 1~8 alkyl, or R 7 and R 5 form a 4- to 6-membered ring together with the atoms to which they are attached; R 8 is H, C 1~3 Alkyl, hydroxy, C 1~3 Alkoxy, halo, cyano, nitro, C 3~14 Cycloalkyl, or NR 11 R 12 and; R 11 and R 12 are independently H, C 1~8 Alkyl, or C 3~14 is cycloalkyl; and R 10 is C 1~8 Alkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 2~14 Heteroaryl, C 0~3 Alkylene-C3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 1~6 Alkoxy, OC 0~3 Alkylene-C 6~14 Aryl, OC 0~3 Alkylene-C 2~14 Heteroaryl, OC 0~3 Alkylene-C 3~14 Cycloalkyl, OC 0~3 Alkylene-C 2~14 Heterocycloalkyl, NH-C 1~8 Alkyl, N(C 1~8 alkyl)2, NH-C 0~3 Alkylene-C 6~14 Aryl, NH-C 0~3 Alkylene-C 2~14 Heteroaryl, NC 0~3 Alkylene-C 3~14 Cycloalkyl, NC 0~3 Alkylene-C 2~14 Heterocycloalkyl, halo, cyano or C 1~6 or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the compounds disclosed herein have the structure of formula (IV). In various embodiments, the compounds disclosed herein have the structure of formula (IV'). In some embodiments, E 1 and E 2 are CR 1 and R 8 is hydroxy, halo, nitro, or C 3~6 It is cycloalkyl.

[0015] In some embodiments, R 8 is methyl. Furthermore, compounds having the structure of formula (IV) or (IV') [ka] (In the formula, E 1 and E 2are each independently 1 or N; R 1 are independently H, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, NH-C 1~6 Alkyl, N(C 1~6 alkyl), cyano, or halo; R 2 Ha, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OR', N(R')2, C 2~3 Alkenyl, C 2~3 Alkynyl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 6~14 Aryl, or C 0~3 Alkylene-C 2~14 heteroaryl, and each R' is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~14 Cycloalkyl, C 2~14 Heterocycloalkyl, C 2~3 Alkenyl, C 2~3 is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R 3 is halo, C 1~2 Haloalkyl, C 1~3 Alkoxy, C 3~14 Cycloalkyl, C 2~3 Alkenyl, C 2~3 is alkynyl, aryl, or heteroaryl; R 4 teeth [ka] and; Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C 1~6 Alkylene, -OC 0~5 Alkylene, -SC 0~5 Alkylene, or -NH-C 0~5 alkylene, C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 In the case of alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R 5 and R 6 are independently H, halo, and C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 1~6 Alkyleneamines, C 0~6 Alkylene-amides, C 0~3 Alkylene-C(O)OH, C 0~3 Alkylene-C(O)OC 1~4 Alkyl, C 1~6 Alkylene-O-aryl, C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 2~14 heteroaryl or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; R 7 is H or C 1~8alkyl, or R 7 and R 5 form a 4- to 6-membered ring together with the atoms to which they are attached; R 8 is H, C 1~3 Alkyl, hydroxy, C 1~3 Alkoxy, halo, cyano, nitro, C 3~14 Cycloalkyl, or NR 11 R 12 and; R 11 and R 12 are independently H, C 1~8 Alkyl, or C 3~15 is cycloalkyl; and R 10 is C 1~8 Alkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 3~14 Heteroaryl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 1~6 Alkoxy, OC 0~3 Alkylene-C 6~14 Aryl, OC 0~3 Alkylene-C 3~14 Heteroaryl, OC 0~3 Alkylene-C 3~14 Cycloalkyl, OC 0~3 Alkylene-C 2~14 Heterocycloalkyl, NH-C 1~8 Alkyl, N(C 1~8 alkyl)2, NH-C 0~3 Alkylene-C 6~14 Aryl, NH-C 0~3 Alkylene-C 2~14 Heteroaryl, NH-C 0~3 Alkylene-C 3~14 Cycloalkyl, NH-C 0~3 Alkylene-C 2~14 Heterocycloalkyl, halo, cyano or C 1~6alkylene-amine), or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the compounds disclosed herein have the structure of formula (IV). In various embodiments, the compounds disclosed herein have the structure of formula (IV'). In some embodiments, E 1 and E 2 are CR 1 and R 8 is hydroxy, halo, nitro, or C 3~6 It is cycloalkyl.

[0017] In some embodiments, R 8 is methyl.

[0018] Additionally, compounds having the structure of formula (V), or a pharmaceutically acceptable salt thereof: [ka] (In the formula, E 1 and E 2 are each independently 1 or N; R 1 are independently H, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, NH-C 1~6 Alkyl, N(C 1~6 alkyl), cyano, or halo; R 2 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OR', N(R')2, C 2~3 Alkenyl, C 2~3 Alkynyl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 6~14 Aryl, or C0~3 Alkylene-C 2~14 heteroaryl, and each R' is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~14 Cycloalkyl, C 2~14 Heterocycloalkyl, C 2~3 Alkenyl, C 2~3 is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R 3 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~14 Cycloalkyl, C 2~6 Alkenyl, C 2~6 is alkynyl, aryl, or heteroaryl; R 4 teeth [ka] and; Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C 1~6 Alkylene, -OC 0~5 Alkylene, -SC 0~5 Alkylene, or -NH-C 0~5 alkylene, C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 In the case of alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R 4’ is H, C 1~8 Alkyl, C 2~8 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, cycloalkyl, heterocycloalkyl, C0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 6~14 aryl, or [ka] Selected from; R 5 and R 6 are independently H, halo, and C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 1~6 Alkyleneamines, C 0~6 Alkylene-amides, C 0~3 Alkylene-C(O)OH, C 0~3 Alkylene-C(O)OC 1~4 Alkyl, C 1~6 Alkylene-O-aryl, C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 2~14 heteroaryl or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; R 7 is H or C 1~8 alkyl, or R 7 and R 5 form, together with the atoms to which they are attached, a 4- to 6-membered ring; and R10 is C 1~8 Alkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 3~14 Heteroaryl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 1~6 Alkoxy, OC 0~3 Alkylene-C 6~14 Aryl, OC 0~3 Alkylene-C 3~14 Heteroaryl, OC 0~3 Alkylene-C 3~14 Cycloalkyl, OC 0~3 Alkylene-C 2~14 Heterocycloalkyl, NH-C 1~8 Alkyl, N(C 1~8 alkyl)2, NH-C 0~3 Alkylene-C 6~14 Aryl, NH-C 0~3 Alkylene-C 2~14 Heteroaryl, NH-C 0~3 Alkylene-C 3~14 Cycloalkyl, NH-C 0~3 Alkylene-C 2~14 Heterocycloalkyl, halo, cyano or C 1~6 alkylene-amine), or a pharmaceutically acceptable salt thereof.

[0019] Furthermore, a compound having the structure of formula (V) [ka] (In the formula, E 1 and E 2 are each independently 1 or N; R 1 are independently H, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, NH-C1~6 Alkyl, N(C 1~6 alkyl), cyano, or halo; R 2 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OR', N(R')2, C 2~3 Alkenyl, C 2~3 Alkynyl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 6~14 Aryl, or C 0~3 Alkylene-C 2~14 heteroaryl, and each R' is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~14 Cycloalkyl, C 2~14 Heterocycloalkyl, C 2~3 Alkenyl, C 2~3 is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R 3 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~14 Cycloalkyl, C 2~8 Alkenyl, C 2~8 is alkynyl, aryl, or heteroaryl; R 4 teeth [ka] and; Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C 1~6 Alkylene, -OC 0~5 Alkylene, -SC 0~5 Alkylene, or -NH-C 0~5alkylene, C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 In the case of alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R 5 and R 6 are independently H, halo, and C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 1~6 Alkyleneamines, C 0~6 Alkylene-amides, C 0~3 Alkylene-C(O)OH, C 0~3 Alkylene-C(O)OC 1~4 Alkyl, C 1~6 Alkylene-O-aryl, C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 0~3 Alkylene-C 6~14 Aryl, C 0~3 Alkylene-C 2~14 heteroaryl or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; R 7 is H or C 1~8 alkyl, or R 7 and R 5 form, together with the atoms to which they are attached, a 4- to 6-membered ring; and R 10 is C 1~8 Alkyl, C 0~3 Alkylene-C 6~14 Aryl, C0~3 Alkylene-C 3~14 Heteroaryl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, C 1~6 Alkoxy, OC 0~3 Alkylene-C 6~14 Aryl, OC 0~3 Alkylene-C 3~14 Heteroaryl, OC 0~3 Alkylene-C 3~14 Cycloalkyl, OC 0~3 Alkylene-C 2~14 Heterocycloalkyl, NH-C 1~8 Alkyl, N(C 1~8 alkyl)2, NH-C 0~3 Alkylene-C 6~14 Aryl, NH-C 0~3 Alkylene-C 2~14 Heteroaryl, NH-C 0~3 Alkylene-C 3~14 Cycloalkyl, NH-C 0~3 Alkylene-C 2~14 Heterocycloalkyl, halo, cyano or C 1~6 alkylene-amine), or a pharmaceutically acceptable salt thereof.

[0020] The compounds of formula (I), (II), (III), (III'), (IV), (IV'), or (V) disclosed herein may have one or more of the following features. In some embodiments, E 1 and E 2 Each of the 1 In another embodiment, E 1 is CR 1 and E 2 is N. In some embodiments, E 1 is N and E 2 is CR 1 In various embodiments, E 1 and E 2 Each of these is N.

[0021] The compounds of formula (I), (II), (III), (III'), (IV), (IV'), or (V) disclosed herein may have one or more of the following features. In various embodiments, R 10 is C 1~6 Alkyl, aryl, heteroaryl, C 3~14 Cycloalkyl, C 2~14 Heterocycloalkyl, C 1~6 Alkoxy, OC 0~6 Alkylene-C 6~14 Aryl, OC 0~6 Alkylene-C 2~14 Heteroaryl, OC 0~6 Alkylene-C 3~14 Cycloalkyl, OC 0~6 Alkylene-C 2~14 Heterocycloalkyl, NC 1~8 Alkyl, N(C 1~8 alkyl)2, NH-C 0~6 Alkylene-C 6~14 Aryl, NH-C 0~6 Alkylene-C 2~14 Heteroaryl, NH-C 0~6 Alkylene-C 3~14 Cycloalkyl, or NH-C 0~6 Alkylene-C 2~14 In various embodiments, R is heterocycloalkyl. 10 is C 1~8 In some embodiments, R 10 is C 0~3 Alkylene-C 6~14 In some embodiments, R 10 is C 0~3 Alkylene-C 2~14 In some embodiments, R 10 is C 0~3 Alkylene-C 3~14 In some embodiments, R 10 is C 0~3 Alkylene-C 2~14 In another embodiment, R 10 C 0~6 Alkyleneamines. For example, R10 is i-Pr, t-Bu, phenyl, benzyl, OCH3, Cl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, [ka] [ka] In some embodiments, R 10 includes ortho-substituted aryl, ortho-substituted heteroaryl, or 2-substituted cyclohexyl. For example, R 10 teeth, [ka] It can be said that:

[0022] Compounds of formula (I), (II), (III), (III'), (IV), (IV'), or (V) disclosed herein may have one or more of the following features. In some embodiments, R 1 is H. In some embodiments, R 1 is F. In some embodiments, R 1 is methyl.

[0023] The compounds of formula (I), (II), (III), (III'), (IV), (IV'), or (V) disclosed herein may have one or more of the following features. In various embodiments, R 2 is aryl. In some embodiments, R 2 is heteroaryl. In various embodiments, R 2 is phenyl, naphthyl, pyridyl, indazolyl, indolyl, azaindolyl, indolinyl, benzotriazolyl, benzoxadiazolyl, imidazolyl, cinnolinyl, imidazopyridyl, pyrazolopyridyl, quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, indolinonyl, isoindolinonyl, tetrahydronaphthyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl. 2are Cl, Br, CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidine, pyrrolidine, azetidine, OCH3, OCH2CH3, phenyl, [ka] [ka] [ka] In various embodiments, R 2 is bromine, [ka] It can be said that:

[0024] The compounds of formula (I), (II), (III), (III'), (IV), (IV'), or (V) disclosed herein may have one or more of the following features. In various embodiments, R 3 is halo. In various embodiments, R 3 is Cl. In some embodiments, R 3 is C 1~2 In some embodiments, R 3 is methyl. In some embodiments, R 3 is C 1~2 In various embodiments, R 3 is CF3.

[0025] Compounds of formula (I), (II), (III), (III'), (IV), (IV'), or (V) disclosed herein may have one or more of the following features. In some embodiments, R 4 teeth, [ka] In various embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] [ka] [ka] In various embodiments, R 4’ is H, C 1~8 Alkyl, C 2~8 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 0~3 Alkylene-C 6~14 is aryl, or [ka] In various embodiments, [ka] teeth, [ka] [ka] [ka] [ka] In some embodiments, ring A can be [ka] In some embodiments, Ring A comprises piperidinyl, piperazinyl, pyrrolidinyl, or azetidinyl. In some embodiments, Ring A comprises piperidinyl. In various embodiments, Ring A is [ka] In various embodiments, ring A can be [ka] It can be said that:

[0026] Compounds of Formula (I), (II), (III), (III'), (IV), (IV'), or (V) disclosed herein may have one or more of the following features: In some embodiments, L is a bond. In some embodiments, L is C 1~2 In various embodiments, L is alkylene. In various embodiments, L is O. In some embodiments, L is S. In various embodiments, L is NH. In some embodiments, R 5 is H or halo. In some embodiments, R 5is H, Br, Cl, F, CN, CH3, CF3, CH2Br, CH2OH, CH2CH2OH, CH2OCH2phenyl, cyclopropyl, phenyl, CH2phenyl, CH2OCH3, CH2N(CH3)2, CH2N(CH2CH3)2, CH2CO2H, CH2CO2CH3, CH2NHC(O)CH3, CH2C(O)NHCH3, CH2OC(O)CH3 or [ka] In some embodiments, R 6 is C 1~6 Alkyl, C 1~6 Alkylene-OC 1~6 Alkyl, C 1~6 Alkylene-OH, C 1~3 Haloalkyl, C 1~6 Alkylene-amines, C 0~6 Alkylene-amides, C 0~1 AlkyleneC(O)OC 1~3 Alkyl, C 0~1 Alkylene-C 2~14 Heterocycloalkyl, C 0~1 Alkylene-C 3~14 Cycloalkyl, or C 0~3 Alkylene-C 6~14 In various embodiments, R 6 is C 0~6 Alkyleneamine or C 0~3 It is an alkylene amide, CH2NH2, CH(CH3)NH2, CH(CH3)2NH2, CH2CH2NH2, CH2CH2N(CH3)2, CH2NHCH3, C(O)NHCH3, C(O)N(CH3)2, CH2C(O)NH phenyl, CH2NHC(O)CH3, CH2NHCH2CH2OH, CH2NHCH2CO2H, C H2NH(CH3)CH2CO2CH3, CH2NHCH2CH2OCH3, CH2NH(CH3)CH2CH2OCH3, CH2NH(CH3)CH2C(O)N(CH3)2, CH2NH(CH3)CH2C(O)NHCH3, CH2NMe2, CH2NH(CH3)CH2CH2OH, CH2NH(CH3)CH2CH2F, CH2N +(CH3)3, CH2NHCH2CHF2, CH2NHCH2CH3, [ka] In various embodiments, R 6 are phenyl, cyclopropyl, CH3, CF3, CH2CH3, CH2NH2, CH(CH3)NH2, CH(CH3)2NH2, CH2Cl, CH2Br, CH2OCH3, CH2Ophenyl, CH2OH, CO2H, CO2CH2CH3, CH2CO2H, CH2CH2NH2, CH2CH2OH, CH2CH2N(CH3)2, CH2NHCH3, C(O)NHCH3, C(O)N(CH3)2, CH2C(O)NHphenyl, CH2CHF2, CH2F, CHF2, CH2NHC(O)CH3, CH2NHCH2CH2OH, CH2NHCH2CO2H, CH2NH(CH3)CH2CO2CH3, CH2NHCH2CH2OCH3, CH2NH(CH3)CH2CH2OCH3, CH 2NH(CH3)CH2C(O)N(CH3)2, CH2NH(CH3)CH2C(O)NHCH3, CH2CH2CCH, CH2NMe2, CH2NH(CH3)CH2CH2OH, CH2NH(CH3)CH2CH2F, CH2N + (CH3)3, CH2NHCH2CHF2, CH2NHCH2CH3, [ka] In various embodiments, R 5 and R 6 Both [ka] In some embodiments, R 5 and R 6 Each of is H. In some embodiments, R 7 is H. In some embodiments, R 7 is methyl. In various embodiments, R 7 and R 5 are both -CH2- or -C(O)CH2-.

[0027] The compounds disclosed herein can be in the form of pharmaceutically acceptable salts. The compounds provided can be formulated into pharmaceutical preparations containing the compounds disclosed herein and pharmaceutically acceptable excipients.

[0028] Also provided is a method for inhibiting KRAS G12C in cells, comprising contacting cells with the compound or composition disclosed herein.Further provided is a method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of the compound or composition disclosed herein.In some embodiments, the cancer is lung cancer, pancreatic cancer or colon cancer. DETAILED DESCRIPTION OF THE INVENTION

[0029] definition Abbreviations: The following abbreviations may be used herein:

[0030] [Table 1]

[0031] [Table 2]

[0032] The use of the terms "a," "an," "the," and similar referents in the context of describing the present invention (particularly in the context of the claims) should be construed to encompass both the singular and the plural unless otherwise indicated. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended to better illustrate the invention and is not a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0033] As used herein, the term "alkyl" refers to straight-chain and branched C1-C8 hydrocarbon groups, including, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. m~n The term "alkylene" refers to an alkyl group having m to n carbon atoms. The term "alkylene" refers to an alkyl group having a substituent. The alkyl (e.g., methyl) or alkylene (e.g., -CH2-) group can be any independently selected group, such as halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, -NC, amino, -CO2H, -CO2C1-C8 alkyl, -OCOC1-C8 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocycloalkyl, C5-C 10 Aryl, and C5-C10 Heteroaryl can be substituted with one or more, typically 1 to 3. The term "haloalkyl" specifically refers to an alkyl group in which at least one, e.g., 1 to 6, or all, of the alkyl group's hydrogens have been replaced with a halo atom.

[0034] The terms "alkenyl" and "alkynyl" refer to alkyl groups that further contain double or triple bonds, respectively.

[0035] The term "halo," as used herein, refers to fluoro, chloro, bromo, and iodo. The term "alkoxy" is defined as --OR, where R is alkyl.

[0036] As used herein, the terms "amino" or "amine" refer interchangeably to the group -NR2, where each R is, for example, H or a substituent. In some embodiments, the amino group is further substituted to form an ammonium ion (e.g., NR3 +). Ammonium moieties are specifically included in the definition of "amino" or "amine." Substituents can be, for example, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, amido, or carboxylate. The R group can be further substituted with one or more, e.g., one to four, groups selected from, for example, halo, cyano, alkenyl, alkynyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, urea, carbonyl, carboxylate, amine, and amido. "Amido" or "amido" groups refer interchangeably to groups similar to amine or amino groups, but further include C(O), e.g., —C(O)NR. Some possible amino or amido groups (some optionally alkylene groups, e.g., alkylene-amino or alkylene-amido) include CH2NH2, CH(CH3)NH2, CH(CH3)2NH2, CH2CH2NH2, CH2CH2N(CH3)2, CH2NHCH3, C(O)NHCH3, C(O)N(CH3)2, CH2C(O)NHphenyl, CH2NHC(O)CH3, CH2NH CH2CH2OH, CH2NHCH2CO2H, CH2NH(CH3)CH2CO2CH3, CH2NHCH2CH2OCH3, CH2NH(CH3)CH2CH2OCH3, CH2NH(CH3)CH2C (O)N(CH3)2, CH2NH(CH3)CH2C(O)NHCH3, CH2CH2CCH, CH2NMe2, CH2NH(CH3)CH2CH2OH, CH2NH(CH3)CH2CH2F, CH2N + (CH3)3, CH2NHCH2CHF2, CH2NHCH2CH3, [ka] Includes:

[0037] As used herein, the term "aryl" refers to a C 6~14 monocyclic or polycyclic aromatic groups, preferably C 6~10 monocyclic or bicyclic aromatic groups of C 10~14"Aryl" refers to a polycyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to a C cyclic aromatic ring in which one ring is aromatic and the other ring is saturated, partially unsaturated, or aromatic, such as dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). 10~14 Unless otherwise indicated, aryl groups can be unsubstituted or substituted with any of the following groups: halo, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, -CF3, -OCF3, -NO2, -CN, -NC, -OH, alkoxy, amino, -CO2H, -CO2C1-C8 alkyl, -OCOC1-C8 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocycloaryl, C5-C 10 Aryl and C5-C 10 It may be substituted with one or more, particularly 1 to 4, groups independently selected from heteroaryl.

[0038] As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic carbocyclic ring, wherein the polycyclic rings can be fused, bridged, or spiro. The carbocyclic ring can have 3 to 10 carbon ring atoms. Possible carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl.

[0039] The term "heterocycloalkyl," as used herein, refers to a mono- or polycyclic (e.g., bicyclic), saturated or partially unsaturated ring system containing three or more (e.g., 3 to 12, 4 to 10, 4 to 8, or 5 to 7) total atoms, of which one to five (e.g., one, two, three, four, or five) atoms are independently selected from nitrogen, oxygen, and sulfur. Non-limiting examples of heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dihydropyrrolyl, morpholinyl, thiomorpholinyl, dihydropyridinyl, oxacycloheptyl, dioxacycloheptyl, thiacycloheptyl, and diazacycloheptyl.

[0040] Unless otherwise indicated, a cycloalkyl or heterocycloalkyl group can be unsubstituted or substituted with one or more, especially 1 to 4, groups. Some possible substituents include halo, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, -OCF3, -NO2, -CN, -NC, -OH, alkoxy, amino, -CO2H, -CO2C1-C8 alkyl, -OCOC1-C8 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocycloar, C5-C 10 Aryl, and C5-C 10 Heteroaryl is included.

[0041] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic) ring system containing one to three aromatic rings and one to four (e.g., one, two, three, or four) heteroatoms selected from nitrogen, oxygen, and sulfur in the aromatic rings. In certain embodiments, heteroaryl groups have 5 to 20, 5 to 15, 5 to 10, or 5 to 7 atoms. Heteroaryl also refers to C heteroaryls in which one ring is aromatic and the other ring is saturated, partially unsaturated, or aromatic. 10~14Examples of heteroaryl groups include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, and the like. Heteroaryl groups include, but are not limited to, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indozilinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, thiazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Unless otherwise indicated, heteroaryl groups can be unsubstituted or substituted with one or more, specifically 1 to 4, or 1, or 2, substituents. Possible substituents include halo, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, -OCF3, -NO2, -CN, -NC, -OH, alkoxy, amino, -CO2H, -CO2C1-C8 alkyl, -OCOC1-C8 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocycloar, C5-C 10 Aryl, and C5-C 10 Heteroaryl is included.

[0042] As used herein, the term Boc means [ka] Refers to the structure of

[0043] As used herein, the term Cbz means [ka] Refers to the structure of

[0044] As used herein, the term Bn means [ka] Refers to the structure of

[0045] As used herein, the term trifluoroacetamide refers to [ka] Refers to the structure of

[0046] As used herein, the term trityl refers to [ka] Refers to the structure of

[0047] As used herein, the term tosyl means [ka] Refers to the structure of

[0048] As used herein, the term Troc means: [ka] Refers to the structure of

[0049] As used herein, the term Teoc means: [ka] Refers to the structure of

[0050] As used herein, the term Alloc means: [ka] Refers to the structure of

[0051] As used herein, the term Fmoc refers to: [ka] Refers to the structure of

[0052] Compounds of the Disclosure Provided herein are KRAS inhibitors having the structure of one of Formulas IV, discussed in more detail below.

[0053] The compounds disclosed herein include all pharmaceutically acceptable isotopically labeled compounds in which one or more atoms of the compounds disclosed herein are replaced by an atom having the same atomic number but an atomic mass or mass number different from that usually found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. These radiolabeled compounds may be useful, for example, to aid in determining or measuring the efficacy of a compound by identifying its site or mode of action, or its binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds of the present disclosure, for example, those incorporating a radioisotope, are useful in drug and / or substrate tissue distribution studies. The radioisotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C is particularly effective for this purpose in view of its ease of incorporation and ready means of detection.

[0054] Deuterium, i.e., 2Substitution with heavier isotopes, such as H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some circumstances.

[0055] 11 C. 18 F, 15 O and 13 Substitution with positron-emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of structure (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the preparations and examples below, employing an appropriate isotopically labeled reagent in place of a previously used non-labeled reagent.

[0056] Isotopically labeled compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying Examples and Schemes, substituting an appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0057] Some of the compounds disclosed herein may exist as stereoisomers (i.e., isomers that differ only in the spatial arrangement of atoms), including optical isomers and conformers. The compounds disclosed herein include both pure individual stereoisomer preparations and enriched preparations thereof, as well as racemic mixtures of such stereoisomers, as well as all stereoisomers of the individual diastereomers and enantiomers that can be separated according to methods known to those skilled in the art. Additionally, the compounds disclosed herein include all tautomeric forms of the compounds.

[0058] Some of the compounds disclosed herein may exist as atropisomers, which are conformational stereoisomers that arise when rotation around a single bond in a molecule is hindered or significantly slowed as a result of steric interactions with other parts of the molecule. The compounds disclosed herein include all atropisomers, both as pure individual atropisomer preparations, enriched preparations, or unspecified mixtures. If the barrier to rotation around a single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of isomeric species may be possible.

[0059] The present disclosure provides a compound having the structure of formula (I): [ka] (In the formula, E 1 and E 2 are each independently N or CR 1 and;R 1 are independently H, hydroxy, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, NH-C 1~4 Alkyl, N(C 1~4 alkyl), cyano, or halo; R 2 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OR', N(R')2, C 2~3 Alkenyl, C 2~3 Alkynyl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 0~3 Alkylene aryl or C 0~3 alkyleneheteroaryl, and each R' is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~4 Cycloalkyl, C 2~3 Alkenyl, C 2~3alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R 3 is halo, C 1~3 Alkyl, C 1~2 Haloalkyl, C 1~3 Alkoxy, C 3~4 Cycloalkyl, C 2~3 Alkenyl, C 2~3 alkynyl, aryl, or heteroaryl; R 4 teeth [ka] wherein ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is a bond, C 1~6 Alkylene, -OC 0~5 Alkylene, -SC 0~5 Alkylene or -NH-C 0~5 alkylene, C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 For alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R 4’ is H, C 1~8 Alkyl, C 2~8 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 0~3 alkylene aryl, or [ka] Selected from R 5 and R 6 are independently H, halo, and C 1~8 Alkyl, C 2~8Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 1~6 Alkyleneamines, C 0~6 Alkylene amides, C 0~3 Alkylene-C(O)OH, C 0~3 Alkylene-C(O)OC 1~4 Alkyl, C 1~6 Alkylene-O-aryl, C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 0~3 alkylenearyl, or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; and R 7 is H or C 1~3 Alkyl, or R 7 and R 5 form a 4- to 6-membered ring together with the atom to which they are attached), or a pharmaceutically acceptable salt thereof.

[0060] The compound of formula I can be in the form of formula (IA), (IB), (IC), or (ID): [ka]

[0061] The present disclosure also provides a compound having the structure of formula (II): [ka] (In the formula, E 1 and E 2 are each independently N or CR 1 and J is N, NR 10 or CR 10 and M is N, NR13 or CR 13 and; [ka] are the single or double bonds necessary to give all atoms their normal valence; R 1 are independently H, hydroxy, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, NH-C 1~4 Alkyl, N(C 1~4 alkyl), cyano, or halo; R 2 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OR', N(R')2, C 2~3 Alkenyl, C 2~3 Alkynyl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 0~3 Alkylene aryl, or C 0~3 alkyleneheteroaryl, and each R' is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~4 Cycloalkyl, C 2~3 Alkenyl, C 2~3 alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R 3 is halo, C 1~3 Alkyl, C 1~2 Haloalkyl, C 1~3 Alkoxy, C 3~4 Cycloalkyl, C 2~3 Alkenyl, C 2~3 alkynyl, aryl, or heteroaryl; R 4 teeth, [ka] wherein ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is a bond, C 1~6 Alkylene, -OC 0~5 Alkylene, -SC 0~5 Alkylene or -NH-C 0~5 alkylene, C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 For alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R 4’ is H, C 1~8 Alkyl, C 2~8 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 0~3 alkylene aryl, or [ka] Selected from; R 5 and R 6 are independently H, halo, and C 1~8 Alkyl, C 2~8 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 1~6 Alkyleneamines, C 0~6 Alkylene amides, C 0~3 Alkylene-C(O)OH, C 0~3 Alkylene-C(O)OC 1~4 Alkyl, C 1~6 Alkylene-O-aryl, C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, C 0~3 Alkylene-C3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 0~3 alkylenearyl, or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; R 7 is H or C 1~3 alkyl, or R 7 and R 5 form a 4- to 6-membered ring with the atoms to which they are attached; Q is CR 8 R 9 , C=CR 8 R 9 , C=O, C=S, or C=NR 8 and;R 8 and R 9 are independently H, C 1~3 Alkyl, hydroxy, C 1~3 Alkoxy, cyano, nitro or C 3~6 is cycloalkyl, or R 8 and R 9 can form a 3- to 6-membered ring together with the carbon atom to which they are attached; R 10 is C 1~8 Alkyl, C 0~3 Alkylene aryl, C 0~3 Alkylene Heteroaryl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 1~6 Alkoxy, OC 0~3 Alkylene aryl, OC 0~3 Alkylene heteroaryl, OC 0~3 Alkylene-C 3~8 Cycloalkyl, OC 0~3 Alkylene aryl, OC 0~3 Alkylene-C 2~7 Heterocycloalkyl, NH-C 1~8 Alkyl, N(C 1~8 alkyl)2, NH-C 0~3 Alkylene aryl, NH-C0~3 Alkyleneheteroaryl, NH-C 0~3 Alkylene-C 3~8 Cycloalkyl, NH-C 0~3 Alkylene-C 2~7 Heterocycloalkyl, halo, cyano or C 1~6 alkyleneamine; and R 13 is C 1~4 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkyleneamines, and C 3~5 cycloalkyl], or a pharmaceutically acceptable salt thereof, provided that (1) J is NR 10 When M is N or CR 13 (2) M is NR 13 When J is N or CR 10 (3) J is CR 10 When M is N or NR 13 and (4) M is CR 13 When J is N or NR 10 (which is

[0062] In various embodiments, J is NR 10 and M is CR 13 In some embodiments, J is CR 10 and M is NR 13 In some embodiments, J is CR 10 and M is N. In various embodiments, J is N and M is NR 13 In some embodiments, J is N and M is CR 13 Some specific R 13 In some embodiments, J is NR 10 and M is N. In some embodiments, Q is C=O and E 1 and E 2 Each of these is CR 1 If (1)R 10 is C 1~3 Alkylene aryl, C1~3 Alkylene Heteroaryl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 1~3 Alkylene-C 2~7 heterocycloalkyl, or halo; or (2) R 13 is C 1~3 Haloalkyl or C 3~5 cycloalkyl.

[0063] The compound of formula II can be in the form of formula (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-J), (II-K), (II-L), (II-M), (II-N), (II-O), (II-P) or (II-Q): [ka]

[0064] The present disclosure also provides a compound having the structure of formula (III) or formula (III'): [ka] (In the formula, R 1 are each independently H, hydroxy, or C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, NH-C 1~4 Alkyl, N(C 1~4 alkyl), cyano, or halo; R 2 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OR', N(R')2, C 2~3 Alkenyl, C 2~3 Alkynyl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 0~3 Alkylene aryl or C 0~3alkyleneheteroaryl, and each R' is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~4 Cycloalkyl, C 2~3 Alkenyl, C 2~3 alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R 3 is halo, C 1~3 Alkyl, C 1~2 Haloalkyl, C 1~3 Alkoxy, C 3~4 Cycloalkyl, C 2~3 Alkenyl, C 2~3 alkynyl, aryl, or heteroaryl; R 4 teeth [ka] wherein ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is a bond, C 1~6 Alkylene, -OC 0~5 Alkylene, -SC 0~5 Alkylene or -NH-C 0~5 alkylene, C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 For alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R 4’ is H, C 1~8 Alkyl, C 2~8 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 0~3 alkylene aryl, or [ka] Selected from; R 5 and R 6 are independently H, halo, and C 1~8 Alkyl, C 2~8 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 1~6 Alkyleneamines, C 0~6 Alkylene amides, C 0~3 Alkylene-C(O)OH, C 0~3 Alkylene-C(O)OC 1~4 Alkyl, C 1~6 Alkylene-O-aryl, C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 0~3 alkylenearyl, or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; R 7 is H or C 1~3 alkyl, or R 7 and R 5 form a 4- to 6-membered ring with the atoms to which they are attached; Q is CR 8 R 9 , C=CR 8 R 9 , C=O, C=S, or C=NR 8 and;R 8 and R 9 Each of these is independently H, C 1~3 Alkyl, hydroxy, C 1~3 Alkoxy, cyano, nitro or C 3~6 is cycloalkyl, or R 8 and R 9 can form a 3- to 6-membered ring together with the carbon atom to which they are attached; R 10is C 1~8 Alkyl, C 0~3 Alkylene aryl, C 0~3 Alkylene Heteroaryl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 1~6 Alkoxy, C 1~6 Alkoxy, OC 0~3 Alkylene aryl, OC 0~3 Alkylene heteroaryl, OC 0~3 Alkylene-C 3~8 Cycloalkyl, OC 0~3 Alkylene-C 2~7 Heterocycloalkyl, NH-C 1~8 Alkyl, N(C 1~8 alkyl)2, NH-C 0~3 Alkylene aryl, NH-C 0~3 Alkyleneheteroaryl, NH-C 0~3 Alkylene-C 3~8 Cycloalkyl, NH-C 0~3 Alkylene-C 2~7 Heterocycloalkyl, halo, cyano or C 1~6 alkyleneamine), or a pharmaceutically acceptable salt thereof.

[0065] The compound of formula III can be in the form of formula (III-A), (III-B), (III-C), or (III-D): [ka]

[0066] The compound of formula III' can be in the form of formula (III-A'), (III-B'), (III-C'), or (III-D'): [ka]

[0067] The present disclosure also provides compounds having the structure of formula (IV) or formula (IV'): [ka] (In the formula, E 1 and E 2 are each independently 1 or N;R 1 are independently H, hydroxy, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, NH-C 1~4 Alkyl, N(C 1~4 alkyl), cyano, or halo; R 2 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OR', N(R')2, C 2~3 Alkenyl, C 2~3 Alkynyl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 0~3 Alkylene aryl or C 0~3 alkyleneheteroaryl, and each R' is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~4 Cycloalkyl, C 2~3 Alkenyl, C 2~3 alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R 3 is halo, C 1~2 Haloalkyl, C 1~3 Alkoxy, C 3~4 Cycloalkyl, C 2~3 Alkenyl, C 2~3 alkynyl, aryl, or heteroaryl; R 4 teeth [ka] wherein ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is a bond, C 1~6 Alkylene, -OC 0~5 Alkylene, -SC 0~5 Alkylene or -NH-C 0~5 alkylene, C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 For alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R 4’ is H, C 1~8 Alkyl, C 2~8 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 0~3 alkylene aryl, or [ka] Selected from; R 5 and R 6 are independently H, halo, and C 1~8 Alkyl, C 2~8 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 1~6 Alkyleneamines, C 0~6 Alkylene amides, C 0~3 Alkylene-C(O)OH, C 0~3 Alkylene-C(O)OC 1~4 Alkyl, C 1~6 Alkylene-O-aryl, C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, C 0~3 Alkylene-C3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 0~3 alkylenearyl, or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; R 7 is H or C 1~3 alkyl, or R 7 and R 5 form a 4- to 6-membered ring together with the atoms to which they are attached; R 8 is C 1~3 Alkyl, hydroxy, C 1~3 Alkoxy, halo, cyano, nitro, C 3~6 Cycloalkyl or NR 11 R 12 and;R 11 and R 12 are independently H, C 1~4 Alkyl, or C 3~5 cycloalkyl; and R 10 is C 1~8 Alkyl, C 0~3 Alkylene aryl, C 0~3 Alkylene Heteroaryl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 1~6 Alkoxy, OC 0~3 Alkylene aryl, OC 0~3 Alkylene heteroaryl, OC 0~3 Alkylene-C 3~8 Cycloalkyl, OC 0~3 Alkylene-C 2~7 Heterocycloalkyl, NH-C 1~8 Alkyl, N(C 1~8 alkyl)2, NH-C 0~3 Alkylene aryl, NH-C 0~3 Alkyleneheteroaryl, NH-C 0~3 Alkylene-C 3~8 Cycloalkyl, NH-C 0~3 Alkylene-C2~7 Heterocycloalkyl, halo, cyano, or C 1~6 In some embodiments, E is an alkyleneamine, or a pharmaceutically acceptable salt thereof. 1 and E 2 are CR 1 and R 8 is hydroxy, halo, nitro, or C 3~6 In some embodiments, R 8 is methyl. The compound can have the structure of formula (IV-A), (IV'-A), (IV-B), (IV'-B), (IV-C), (IV'-C), (IV-D) or (IV'-D). [ka]

[0068] Also provided herein are compounds having the structure of formula (V): [ka] (In the formula, E 1 and E 2 are each independently 1 or N;R 1 are independently H, hydroxy, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, NH-C 1~4 Alkyl, N(C 1~4 alkyl), cyano, or halo; R 2 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OR', N(R')2, C 2~3 Alkenyl, C 2~3 Alkynyl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 0~3 Alkylene aryl or C 0~3alkyleneheteroaryl, and each R' is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~4 Cycloalkyl, C 2~3 Alkenyl, C 2~3 alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R 3 is halo, C 1~3 Alkyl, C 1~2 Haloalkyl, C 1~3 Alkoxy, C 3~4 Cycloalkyl, C 2~3 Alkenyl, C 2~3 alkynyl, aryl, or heteroaryl; R 4 teeth [ka] wherein ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is a bond, C 1~6 Alkylene, -OC 0~5 Alkylene, -SC 0~5 Alkylene or -NH-C 0~5 alkylene, C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 For alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R 4’ is H, C 1~8 Alkyl, C 2~8 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 0~3 alkylene aryl, or [ka] Selected from; R 5 and R 6 are independently H, halo, and C 1~8 Alkyl, C 2~8 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, C 1~6 Alkyleneamines, C 0~6 Alkylene amides, C 0~3 Alkylene-C(O)OH, C 0~3 Alkylene-C(O)OC 1~4 Alkyl, C 1~6 Alkylene-O-aryl, C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 0~3 alkylenearyl, or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; R 7 is H or C 1~3 alkyl, or R 7 and R 5 form a 4- to 6-membered ring together with the atoms to which they are attached; R 10 is C 1~8 Alkyl, C 0~3 Alkylene aryl, C 0~3 Alkylene Heteroaryl, C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~3 Alkylene-C 2~7 Heterocycloalkyl, C 1~6 Alkoxy, OC 0~3 Alkylene aryl, OC 0~3 Alkylene heteroaryl, OC 0~3 Alkylene-C 3~8 Cycloalkyl, OC0~3 Alkylene-C 2~7 Heterocycloalkyl, NH-C 1~8 Alkyl, NC 1~8 Alkyl, NH-C 0~3 Alkylene aryl, NH-C 0~3 Alkyleneheteroaryl, NH-C 0~3 Alkylene-C 3~8 Cycloalkyl, NH-C 0~3 Alkylene-C 2~7 Heterocycloalkyl, halo, cyano or C 1~6 alkyleneamine), or a pharmaceutically acceptable salt thereof.

[0069] In compounds of formula (II), (III), and (III'): in some embodiments, Q is C=O. in some embodiments, Q is C=S. in some embodiments, Q is C=NR 8 R 8 is C 1~2 It may be alkyl, for example methyl.

[0070] Q is CR 8 R 9 or C=CR 8 R 9 It can be expressed as R 8 and R 9 can form a 3- or 4-membered ring, e.g., a cyclopropyl ring, together with the carbon atom to which they are attached. In some embodiments, R 8 is C 1~2 alkyl (e.g., methyl), and R 9 is H.

[0071] In compounds of formula (II), (III), (III′), (IV), (IV′), and (V): In various embodiments, R 10 is C 1~4 Alkyl, aryl, heteroaryl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 In various embodiments, R is alkoxy, or aryloxy. 10is C 1~8 Alkyl, C 1~5 Alkyl, or C 1~3 In various embodiments, R 10 is C 0~3 Alkylene aryl, C 0~1 In various embodiments, R is alkylene, aryl, or phenyl. 10 is C 0~3 alkylene heteroaryl, or C 0~1 and alkyleneheteroaryl, where heteroaryl can be, for example, pyridyl. In various embodiments, R 10 is C 0~3 Alkylene-C 3~8 Cycloalkyl, C 0~1 Alkylene-C 3~8 Cycloalkyl, or C 3~8 cycloalkyl, and the cycloalkyl can be, for example, cyclohexyl. In various embodiments, R 10 is C 0~3 Alkylene-C 3~8 Heterocycloalkyl or C 0~1 Alkylene-C 3~8 In various embodiments, R is heterocycloalkyl. 10 is C 0~6 Alkyleneamine or C 0~3 The R is an alkylene amine or amine. 10 These include i-Pr, t-Bu, phenyl, benzyl, OCH3, Cl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, [ka] [ka] Contains R 10 is ortho-substituted aryl, ortho-substituted heteroaryl, or 2-substituted cyclohexyl, e.g., [ka] Includes:

[0072] For all compounds: R 1 can be a fraction, e.g., R 1 is H, C 1~2 Alkyl (e.g., methyl), C 1~2 It can be haloalkyl (e.g., CF), or halo (e.g., F). Some specific contemplated R 1 includes H, F, Me, Cl, and CF3.

[0073] R 2 is C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 0~1 Alkylene-C 3~8 Cycloalkyl, C 3~6 Cycloalkyl, C 0~1 alkylene aryl (e.g., aryl), or C 0~1 It can be alkylene, heteroaryl (e.g., heteroaryl). Some specific contemplated R 2 Groups include phenyl, naphthyl, pyridyl, indazolyl, indolyl, azaindolyl, indolinyl, benzotriazolyl, benzoxadiazolyl, imidazolyl, cinnolinyl, imidazopyridyl, pyrazolopyridyl, quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, indolinonyl, isoindolinonyl, tetrahydronaphthyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl. 2 These include Cl, Br, CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidine, pyrrolidine, azetidine, OCH3, OCH2CH3, phenyl, [ka] [ka] [ka] In some embodiments, R 2 teeth, [ka] is.

[0074] R 3 is halo (e.g., Cl), C 1~2 alkyl (e.g., methyl), or C 1~2 It can be haloalkyl (e.g., CF). Some specific R 3 includes Cl, Me, CF3, OMe, Et, C=CH2 and cyclopropyl.

[0075] L is bond, C 1~6 Alkylene, -OC 0~5 Alkylene, -SC 0~5 Alkylene, or -NH-C 0~5 alkylene, and C 2~6 Alkylene, -OC 2~5 Alkylene, -SC 2~5 Alkylene, and NH-C 2~5 In the case of alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH. For example, L can be -CH-NH when a carbon of the C alkylene group is substituted with NH, or -O-CH-CH-O- when a carbon of the O-C alkylene group is substituted with O. Other options, such as substituting C, C, C, or C alkylene with O, S, or NH, are also specifically contemplated. In some embodiments, L is C 1~2 alkylene, O, S, or NH. In some embodiments, L is a bond.

[0076] Ring A is a monocyclic 4- to 7-membered ring or a bicyclic, bridged, fused, or spiro-6- to 11-membered ring. Some specifically contemplated rings include cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrrolidinyl, piperidinyl, azepanyl, imidazolidinyl, hexahydropyrimidinyl, hexahydropyridazinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, azetidinyl, spiroheptyl, spirooctyl, spirononyl, spirodecyl, diazabicyclodecyl, diazabicyclononyl, diazabicyclooctyl, diazabicycloheptyl, hexahydropyrrolopyridyl, octahydropyrrolopyridyl, and octahydropyrrolopyrimidinyl. In various embodiments, Ring A can include piperidinyl, piperazinyl, pyrrolidinyl, or azetidinyl. In some embodiments, Ring A comprises piperidinyl. Ring A can be further substituted with 1 to 3 substituents. Some non-limiting examples of substitutions on Ring A include 1 to 3 substituents selected from alkyl, alkenyl, alkenyl, hydroxyalkyl, carboxylic acid or ester, haloalkyl, alkylamine, C(O)NH, oxo, halo, cyano, and isocyano.

[0077] R 4 but [ka] In this case, ring A is, for example, [ka] More specifically, R 4 but [ka] In this case, ring A is, for example, [ka] It can be said that:

[0078] R 4 but [ka] More specifically, in the case of [ka] In such embodiments, ring A can be, for example: [ka] It can be said that:

[0079] R 5 and R 6 is a substituent on the acrylamide moiety of the KRAS inhibitors disclosed herein. In some embodiments, R 5 and R 6 are H. Some specific R 5 Substituents include H, Br, Cl, F, CN, CH3, CF3, CH2Br, CH2OH, CH2CH2OH, CH2OCH2phenyl, cyclopropyl, phenyl, CH2phenyl, CH2OCH3, CH2N(CH3)2, CH2N(CH2CH3)2, CH2CO2H, CH2CO2CH3, CH2NHC(O)CH3, CH2C(O)NHCH3, CH2OC(O)CH3, or [ka] Includes:

[0080] Some specific possible R 6Substituents include phenyl, cyclopropyl, CH3, CF3, CH2CH3, CH2NH2, CH(CH3)NH2, CH(CH3)2NH2, CH2Cl, CH2Br, CH2OCH3, CH2Ophenyl, CH2OH, CO2H, CO2CH2CH3, CH2CO2H, CH2CH2NH2, CH2CH2OH, CH2CH2N(CH3)2, CH2NHCH3, C(O)NHCH3, C(O)N(CH3)2, CH2C(O)NHphenyl, CH2CHF2, CH2 F, CHF2, CH2NHC(O)CH3, CH2NHCH2CH2OH, CH2NHCH2CO2H, CH2NH(CH3)CH2CO2CH3, CH2NHCH2CH2OCH3, CH2NH(CH3)CH2CH2OCH3, C H2NH(CH3)CH2C(O)N(CH3)2, CH2NH(CH3)CH2C(O)NHCH3, CH2CH2CCH, CH2NMe2, CH2NH(CH3)CH2CH2OH, CH2NH(CH3)CH2CH2F, CH2N + (CH3)3, CH2NHCH2CHF2, CH2NHCH2CH3, [ka] Includes:

[0081] R 5 and R 6 can, together with the atoms to which they are attached, form a 4- to 6-membered ring, e.g., a 5- or 6-membered ring. Such a ring may include, [ka] R forming 5 and R 6 Includes:

[0082] In most embodiments, R 7 is H. However, in some embodiments, R 7 is methyl. In another embodiment, R 7 and R 5 together form -CH2- or -C(O)CH2-.

[0083] Some specific things to consider: [ka] The options for parts are: [ka] [ka] [ka] [ka] Includes:

[0084] Some specific possible R 4 The substituents include: [ka] [ka] Includes:

[0085] Some specific possible R 4’ The substituents include: [ka] may be included.

[0086] In another embodiment, the present invention provides [ka] Disclosed is a compound having a structure selected from:

[0087] These compounds can be used as intermediates in the processes for making the compounds of the present application.

[0088] These compounds may be in the form of pharmaceutically acceptable salts, or may be in the form of pharmaceutical formulations containing pharmaceutically acceptable excipients.

[0089] The following examples are labeled using a classification system where the first number refers to the method used to synthesize the compound, the second number is an identification number, and the third number, when present, refers to the order of compound elution in a chromatographic separation process. If the third number is absent, the compound is a single compound or a mixture of isomers. Consecutive numbering of the examples is not performed, and specific example numbers have been intentionally omitted for formatting reasons. A "-" indicates that no change was made or that the associated box is not filled in. Specific contemplated compounds include those listed in Table 1:

[0090] [Table 3]

[0091] [Table 4]

[0092] [Table 5]

[0093] [Table 6]

[0094] [Table 7]

[0095] [Table 8]

[0096] Table 9

[0097] Table 10

[0098] Table 11

[0099] Table 12

[0100] Table 13

[0101] Table 14

[0102] Table 15

[0103] Table 16

[0104] Table 17

[0105] Table 18

[0106] Table 19

[0107] Table 20

[0108] Table 21

[0109] Table 22

[0110] Table 23

[0111] Table 24

[0112] Table 25

[0113] Table 26

[0114] Table 27

[0115] Table 28

[0116] Table 29

[0117] [Table 30]

[0118] [Table 31]

[0119] [Table 32]

[0120] [Table 33]

[0121] [Table 34]

[0122] Synthesis of the Disclosed Compounds The compounds disclosed herein can be synthesized through a number of specific methods. The examples outlining specific synthetic routes, and the general schemes below, are intended to provide guidance to a synthetic chemist of ordinary skill, who will readily appreciate that solvents, concentrations, reagents, protecting groups, order of synthetic steps, times, temperatures, and the like, can be varied as necessary, well within the skill and judgment of one of ordinary skill in the art.

[0123] Method 1 [ka] Method 1 Synthesis: Compounds of Formula (I) disclosed herein can be synthesized as outlined in Method 1. In Step 1, an appropriate aromatic or heteroaromatic acid is reacted with a halogenating agent to produce a halogenated aromatic or heteroaromatic acid. In Step 2, this acid is then reacted with an amidating agent to produce an amide intermediate. In Step 3, the amide intermediate is then reacted with a sulfating agent to produce a thioamide intermediate. In Step 4, the thioamide intermediate is then reacted with an oxidizing agent to produce a thiazole ring as shown. In Step 5, the amine of the thiazole is then converted to a leaving group using an activating agent. The leaving group is then converted to R as shown in Step 6. 4 Then in step 7, the appropriate R 2 Cross-coupling of the (protected) reagent with the X halide of the thiazole intermediate affords R 2 Then in step 8, R is introduced under appropriate conditions depending on the protecting group used. 4 The R group is then deprotected to introduce the acrylamide moiety as shown. 4 acylation of the R 2 Suitable protecting groups and deprotecting reagents are known to those skilled in the art, for example, as discussed in Greene's Protective Groups in Organic Synthesis.

[0124] Contemplated halogenating agents include, but are not limited to, chlorine, bromine, N-chlorosuccinimide, and N-bromosuccinimide, optionally in the presence of a catalyst (e.g., iron or aluminum). A synthetic chemist of ordinary skill will readily recognize that other halogenating agents and catalysts can be used.

[0125] Possible amidating agents include, but are not limited to, N,N'-diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, thionyl chloride, isobutyl chloroformate, diethyl cyanophosphonate, carbonyldiimidazole, and polyphosphonic acid anhydride.Synthetic chemists of ordinary skill will readily understand that other amidating agents can be used.

[0126] Contemplated sulfurizing agents include, but are not limited to, sulfur, phosphorus pentasulfide, and Lawesson's reagent. A synthetic chemist of ordinary skill will readily appreciate that other sulfurizing agents can be used.

[0127] Possible oxidizing agents include, but are not limited to, hydrogen peroxide, iodobenzene diacetate, t-butyl hydroperoxide, N-bromosuccinimide, and ammonium peroxodisulfate. A synthetic chemist of ordinary skill will readily recognize that other oxidizing agents can be used.

[0128] Possible activating agents include, but are not limited to, sodium nitrite and t-butyl nitrite. A synthetic chemist of ordinary skill will readily appreciate that other activating agents can be used.

[0129] Possible cross-coupling reactions include, but are not limited to, Suzuki coupling, Negishi coupling, Hiyama coupling, Kumada coupling, and Stille coupling. A chemist of ordinary skill will readily appreciate that the coupling shown in Method 1 can be carried out under a number of conditions.

[0130] Method 2 [ka] Synthesis of Method 2: Method 2 provides an alternative method for producing compounds of formula (I) disclosed herein. After halogenation in step 1, R is converted to R by reaction with an acid in a coupling reaction in step 2. 4 A protecting group is introduced. In step 3, the oxo group is converted to sulfur using a sulfurizing agent. Then, in step 4, the thiazole ring is formed in the presence of an oxidizing agent. The remaining steps 5 to 8 are similar to steps 7 and 8 of Method 1 above.

[0131] Method 3 [ka] Synthesis of Method 3: Method 3 provides an alternative method for producing compounds of formula (I) disclosed herein. 4 The R group is deprotected and acylated in step 1 to introduce the acrylamide moiety. 2 Cross-coupling of the (protected) reagent with the X halide of the thiazole intermediate affords R 2 Finally, in step 3, R 2 The group is deprotected.

[0132] Method 4 [ka] Synthesis of Method 4: Method 4 provides an alternative method for producing compounds of formula (I) disclosed herein. As shown in Step 1, a protected R 4 After substituting the leaving group of the isothiazole intermediate with the R 4 The R intermediate is deprotected and acylated in step 2 to introduce the acrylamide moiety. As in method 1, a cross-coupling reaction in step 3 affords R 2 Introduce the part and in step 4, R 2 The group is deprotected.

[0133] Method 5 [ka] Synthesis of Method 5: Method 5 provides an alternative method for producing compounds of formula (I) disclosed herein. In this alternative method, R is first prepared by cross-coupling of the X halide of the aromatic amide or heteroaromatic amide intermediate shown in Step 1. 2 In step 2, the amide intermediate is then reacted with a sulfating agent to generate a thioamide intermediate. In step 3, this intermediate is oxidized to provide the isothiazole ring. In step 4, the amine group is then converted to a leaving group, followed in step 5 by the addition of a protected R 4 Finally, in step 6, R 4 The R group is deprotected and reacted with an acylating agent. 2 The group is deprotected.

[0134] Method 6 [ka] Synthesis of Method 6: Method 6 provides an alternative method for producing compounds of formula (I) disclosed herein. In this alternative, an isothiazole intermediate is reacted with a metallating agent to activate the X halide. The activated intermediate is then reacted with the appropriate R 2 By reacting with a (protected) reagent, R 2 In the final step, the R 4 The group is deprotected and acylated to introduce the acrylamide moiety.

[0135] Possible metallating agents include, but are not limited to, bis(pinacolato)diboron, magnesium, zinc, hexamethyldistannane, and n-butyllithium. A synthetic chemist of ordinary skill will readily recognize that other metallating agents and catalysts can be used.

[0136] Method 7 [ka] Method 7 Synthesis: Method 7 provides an alternative method for producing compounds of formula (I) disclosed herein. First, R is prepared by cross-coupling of the X halide of the aromatic or heteroaromatic acid intermediate shown in Step 1. 2 Then, in step 2, the acid moiety is converted to the appropriate R 4 The acid derivative is then reacted with a (protected) reagent. Then, in step 3, a sulfurizing agent is used to convert the carbonyl group of the acid derivative to a thiocarbonyl group. The thioacid intermediate is then reacted with an oxidizing agent in step 4 to generate the isothiazole intermediate. Finally, R 4 The R group is deprotected and acylated to introduce the acrylamide moiety. 2 The group is deprotected.

[0137] Method 8 [ka] Method 8 Synthesis: Compounds of formula (II) disclosed herein can be synthesized as outlined in Method 8. In step 1, an appropriate aromatic or heteroaromatic acid is reacted with an amidating agent to form a primary amide intermediate. The amide is then reacted with an isocyanate-generating reagent and R 10 The urea intermediate is then reacted with a substituted amine to form the urea intermediate. Possible isocyanate generating agents include oxalyl chloride, thionyl chloride, and phosphorus oxychloride. In step 3, the urea intermediate is then reacted with a cyclizing agent to form the quinazolinedione ring shown. Possible cyclizing agents include, but are not limited to, bases such as potassium hexamethyldisilazide, potassium tert-butoxide, sodium hydride, and phosphazene bases. Then, in step 4, the appropriate R 2 Cross-coupling of the (protected) reagent with the X halide of the quinazolinedione intermediate affords R 2The oxo group of the quinazolinedione is then converted to a leaving group using an activating agent in step 5. Possible activating agents include, but are not limited to, thionyl chloride, trifluoromethanesulfonic anhydride, phosphorus oxychloride, and phosphorus pentachloride. The leaving group is then converted to R as shown in step 6. 4 The remaining deprotection-acylation-deprotection sequences shown in steps 7-9 are similar to step 8 of Method 1.

[0138] Method 9 [ka] Synthesis of Method 9: Method 9 provides an alternative method for producing compounds of formula (II) disclosed herein. In step 1, the oxo group of the quinazolinedione is converted to a leaving group. In step 2, R 4 Introduction of (protected) groups, R 4 Deprotection of the R group and the freed R 4 In step 3, the appropriate R 2 Cross-coupling of the (protected) reagent with the X halide of the quinazolinedione intermediate affords R 2 Finally, R 2 The group is deprotected.

[0139] Method 10 [ka] Method 10 Synthesis: Compounds of formula (V) disclosed herein can be synthesized as outlined in Method 10. As shown in Step 1, an appropriate anhydride is reacted with hydrazine to generate the phthalazinedione ring. In Step 2, an appropriate R 2 Cross-coupling of the reagent with the X halide of the quinazolinedione intermediate affords R 2 Then in step 3, R 2The phthalazinedione ring is then halogenated twice. Possible halogenating agents include thionyl chloride, phosphorus oxychloride, and oxalyl chloride. One of the halogen groups is then converted to R as shown in Step 5. 4 Then, in steps 6 and 7, R is reacted under appropriate conditions depending on the protecting group used to form a substituted phthalazine ring. 4 The R group is then deprotected and the freed R group is then used to introduce the acrylamide moiety as shown. 4 In step 8, the R 2 Finally, in step 9, the appropriate R 10 Cross-coupling of the reagent with the X halide of the phthalazine intermediate affords R 10 Introduce the part.

[0140] Method 11 [ka] Synthesis of Method 11: Method 11 provides an alternative method for producing compounds of formula (II) disclosed herein. In step 1, the oxo group of the quinazolinedione is converted to a leaving group. In step 2, R 4 In step 3, the appropriate R 2 Cross-coupling of the (protected) reagent with the X halide of the quinazolinedione intermediate affords R 2 Finally, R 4 The groups are deprotected and subsequently acylated in steps 4 and 5.

[0141] Pharmaceutical Compositions, Dosages, and Routes of Administration Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein together with a pharmaceutically acceptable excipient, such as a diluent or carrier. Compounds and pharmaceutical compositions suitable for use in the present invention include those in which the compound can be administered in an amount effective to achieve its intended purpose. Administration of the compounds is described in more detail below.

[0142] Suitable pharmaceutical formulations can be determined by those skilled in the art according to the route of administration and desired dosage.See, for example, Remington's Pharmaceutical Sciences, 1435-712 (18th ed., Mack Publishing Co, Easton, Pennsylvania, 1990).Formulations can affect the physical state, stability, in vivo release rate, and in vivo excretion rate of the administered drug.Depending on the route of administration, suitable dosages can be calculated according to body weight, body surface area, or organ size.Further refinement of calculations required to determine suitable therapeutic dosages can be routinely performed by those skilled in the art without undue experimentation, especially in light of the dosage information and assays disclosed herein and the pharmacokinetic data obtained in animal or human clinical trials.

[0143] The phrases "pharmaceutically acceptable" or "pharmacologically acceptable" refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans. As used herein, "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such excipients for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the therapeutic composition, its use in the therapeutic composition is contemplated. Supplementary active ingredients can also be incorporated into the composition. In an exemplary embodiment, the formulation comprises corn syrup solids, high oleic safflower oil, coconut oil, soybean oil, L-leucine, tricalcium phosphate, L-tyrosine, L-proline, L-lysine acetate, DATEM (emulsifier), L-glutamine, L-valine, dipotassium phosphate, L-isoleucine, L-arginine, L-alanine, glycine, L-asparagine monohydrate, L-serine, potassium citrate, L-threonine, sodium citrate, magnesium chloride, L-histidine, L-methionine, ascorbic acid, calcium carbonate, L-glutamic acid, L-cystine dihydrochloride. May contain: L-tryptophan, L-aspartic acid, choline chloride, taurine, m-inositol, ferrous sulfate, ascorbyl palmitate, zinc sulfate, L-carnitine, alpha-tocopheryl acetate, sodium chloride, niacinamide, mixed tocopherols, calcium pantothenate, copper sulfate, thiamine chloride hydrochloride, vitamin A palmitate, manganese sulfate, riboflavin, pyridoxine hydrochloride, folic acid, beta-carotene, potassium iodide, phylloquinone, biotin, sodium selenate, chromium chloride, sodium molybdate, vitamin D3 and cyanocobalamin.

[0144] The compound may be present in the pharmaceutical composition as a pharmaceutically acceptable salt. As used herein, "pharmaceutically acceptable salt" includes, for example, base addition salts and acid addition salts.

[0145] Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali metals and alkaline earth metals or organic amines. Pharmaceutically acceptable salts of compounds can also be prepared with pharmaceutically acceptable cations. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali, alkaline earth, ammonium, and quaternary ammonium cations. Carbonate or bicarbonate salts are also possible. Examples of metals used as cations include sodium, potassium, magnesium, ammonium, calcium, or iron. Examples of suitable amines include isopropylamine, trimethylamine, histidine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

[0146] Pharmaceutically acceptable acid addition salts include salts of inorganic or organic acids.Examples of suitable acid salts include hydrochloride, formate, acetate, citrate, salicylate, nitrate, and phosphate.Other suitable pharmaceutically acceptable salts are well known to those skilled in the art, and include, for example, formic acid, acetic acid, citric acid, oxalic acid, tartaric acid, mandelic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; organic carboxylic acid, sulfonic acid, sulfoacid, phosphoacid, or N-substituted sulfamic acid, such as acetic acid, trifluoroacetic acid (TFA), propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, pamoic acid, Included are salts with nicotinic acid or isonicotinic acid; with amino acids such as the 20 alpha amino acids involved in natural protein synthesis, for example, glutamic acid or aspartic acid, and also with phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane 1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene 2-sulfonic acid, naphthalene 1,5-disulfonic acid, 2- or 3-phosphoglyceric acid, glucose 6-phosphate, N-cyclohexylsulfamic acid (with the formation of cyclamate), or with other acid organic compounds such as ascorbic acid.

[0147] Pharmaceutical compositions containing the compounds disclosed herein can be manufactured in a conventional manner, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen.

[0148] For oral administration, suitable compositions can be easily formulated by combining the compounds disclosed herein with pharmaceutically acceptable excipients, such as carriers well known in the art. Such excipients and carriers allow the compounds of the present invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding the compounds disclosed herein with solid excipients, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable excipients, if necessary, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If necessary, disintegrants can be added. Pharmaceutically acceptable ingredients are well known for various types of formulations and can be, for example, binders (e.g., natural or synthetic polymers), lubricants, surfactants, sweeteners and flavoring agents, coating materials, preservatives, dyes, thickeners, adjuvants, antimicrobial agents, antioxidants, and carriers for various formulation types.

[0149] When a therapeutically effective amount of a compound disclosed herein is administered orally, the composition is typically in the form of a solid (e.g., a tablet, capsule, pill, powder, or lozenge) or liquid preparation (e.g., an aqueous suspension, solution, elixir, or syrup).

[0150] When administered in tablet form, the composition may further contain a functional solid and / or functional solid carrier such as gelatin or an adjuvant. The tablet, capsule, and powder may contain about 1 to about 95% of the compound, preferably about 15 to about 90% of the compound.

[0151] When administered in liquid or suspension form, a functional liquid and / or functional liquid carrier, such as water, petroleum, or oils of animal or plant origin, can be added. Liquid forms of the composition can further include saline solution, sugar alcohol solution, dextrose or other sugar solution, or glycol. When administered in liquid or suspension form, the composition can contain about 0.5 to about 90% by weight of a compound disclosed herein, preferably about 1 to about 50% by weight of a compound disclosed herein. In one contemplated embodiment, the liquid carrier is non-aqueous or substantially non-aqueous. When administered in liquid form, the composition can be supplied as a rapidly dissolving solid formulation that is dissolved or suspended immediately prior to administration.

[0152] When a therapeutically effective amount of a compound disclosed herein is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, taking into due consideration pH, isotonicity, stability, and the like, is within the skill of the art. Preferred compositions for intravenous, cutaneous, or subcutaneous injection typically contain an isotonic vehicle in addition to the compounds disclosed herein. Such compositions can be prepared for administration as a solution of a free base or pharmacologically acceptable salt in water, suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, as well as in oils. Under ordinary conditions of storage and use, these preparations can optionally contain a preservative to prevent the growth of microorganisms.

[0153] Injectable compositions can include sterile aqueous solutions, suspensions, or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions, suspensions, or dispersions. In all embodiments, the form must be sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms, such as bacteria and fungi, optionally by the inclusion of preservatives. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. In one contemplated embodiment, the carrier is non-aqueous or substantially non-aqueous. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, the maintenance of the required particle size in the case of dispersion embodiments, and the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many embodiments, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0154] Sterile injection solution can be prepared by incorporating the active compound in the required amount in suitable solvent with various other necessary components as listed above, and then sterilize by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains basic dispersion medium and other necessary components from the components listed above.In the embodiment of sterile powder for preparing sterile injection solution, the preferred preparation method is vacuum drying and freeze-drying, which produces powder from the solution of active ingredient and any other necessary components that have been previously sterilized and filtered.

[0155] Slow-release or sustained-release formulations can also be prepared to control the release of active compounds in contact with body fluids in the gastrointestinal tract and provide a substantially constant and effective level of the active compound in plasma. For example, release can be controlled by one or more of dissolution, diffusion, and ion exchange. Furthermore, the slow-release approach can enhance absorption through saturable or limited pathways in the gastrointestinal tract. For example, for this purpose, the compound can be embedded in a polymer matrix of a biodegradable polymer, a water-soluble polymer, or a mixture of both, and optionally a suitable surfactant. In this context, embedding can mean incorporating microparticles into a polymer matrix. Controlled-release formulations can also be obtained by encapsulating dispersed microparticles or emulsified microdroplets using known dispersion or emulsion coating techniques.

[0156] For administration by inhalation, the compound of the present invention is conveniently delivered in the form of aerosol spray dispensed from pressurized pack or nebulizer with suitable propellant.In the pressurized aerosol embodiment, dosage unit can be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, for example, gelatin for use in inhaler or insufflator can be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0157] The compound disclosed herein can be formulated for parenteral administration by injection (for example, by bolus injection or continuous infusion).The preparation for injection can be provided in a unit dosage form (for example, in ampoules or multi-dose containers) with added preservative.The composition can take the form of suspension, solution or emulsion in oily or aqueous vehicle, and can contain formulating agents such as suspending agents, stabilizers and / or dispersing agents.

[0158] Pharmaceutical preparations for parenteral administration include aqueous solutions of the compound in water-soluble form.In addition, suspensions of the compound can be prepared as suitable oily injection suspensions.Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters.Aqueous injection suspensions can contain substances that increase the viscosity of the suspension.Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound and allow the preparation of highly concentrated solutions.Alternatively, the compositions of the present invention can be in powder form, which can be reconstituted with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0159] The compounds disclosed herein can also be formulated into rectal compositions such as suppositories or retention enemas (e.g., containing conventional suppository bases).In addition to the formulations described above, the compounds can also be formulated as depot preparations.Such long-acting preparations can be administered by injection (e.g., subcutaneously or intramuscularly) or by intramuscular injection.Thus, for example, the compounds can be formulated with suitable polymers or hydrophobic materials (e.g., as emulsions in acceptable oils), or ion exchange resins, or can be formulated as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0160] In particular, the compounds disclosed herein can be administered orally, bucally, or sublingually in the form of tablets containing excipients such as starch or lactose, or in capsules or ovoids alone or in a mixture with excipients, or in the form of elixirs or suspensions containing flavorings or colorings.Such liquid preparations can be prepared using pharmaceutically acceptable additives such as suspending agents.The compounds can also be parenterally injected, for example, intravenously, intramuscularly, subcutaneously, or intracoronary.For parenteral administration, the compounds are most often used in the form of sterile aqueous solutions, which can contain other substances, such as salts or sugar alcohols such as mannitol or glucose, to make them isotonic with blood.

[0161] For veterinary use, the compounds disclosed herein are administered in an appropriately acceptable formulation in accordance with normal veterinary practice, and a veterinarian can readily determine the most appropriate dosing regimen and route of administration for a particular animal.

[0162] In some embodiments, in the treatment of KRAS-related disorders, all the components necessary for such treatment can be packaged into a kit, using the compounds disclosed herein alone or in combination with another drug or intervention traditionally used for the treatment of such diseases.Specifically, the present invention provides a kit for use in the treatment of disease, comprising a packaged set containing the compounds disclosed herein and a drug containing buffers and other ingredients for preparing a deliverable form of the drug, and / or a device for delivering such a drug, and / or any drug used in combination therapy with the compounds disclosed herein, and / or instructions for treating the disease packaged with the drug.The instructions can be fixed on any tangible medium, such as printed paper or computer-readable magnetic or optical media, or can refer to a remote computer data source, such as a World Wide Web page accessible via the Internet.

[0163] "Therapeutically effective amount" refers to an amount effective to treat, prevent progression of, or alleviate existing symptoms of the subject being treated. Determining an effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, a "therapeutically effective dose" refers to the amount of a compound that produces a desired effect. For example, in a preferred embodiment, a therapeutically effective amount of a compound disclosed herein reduces KRAS activity by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% compared to a control.

[0164] The amount of compound to be administered can depend on the subject being treated, the subject's age, health, sex and weight, the type of concurrent treatment (if any), the severity of disease, the nature of desired effect, the mode and frequency of treatment, and the judgment of the prescribing physician.The frequency of administration can also depend on the pharmacodynamic effect on arterial oxygen pressure.However, the most suitable dosage can be adjusted to individual subject, as understood and determined by those skilled in the art without undue experimentation.This usually involves adjusting standard dosage (for example, reducing dosage when the patient is underweight).

[0165] Although individual needs vary, determining the optimal range of effective amounts of compounds is within the skill of the art.For example, for administration to humans in the therapeutic or prophylactic treatment of the conditions and disorders specified herein, the typical dosage of the compound of the present invention can be about 0.05mg / kg / day to about 50mg / kg / day, for example, at least 0.05mg / kg, at least 0.08mg / kg, at least 0.1mg / kg, at least 0.2mg / kg, at least 0.3mg / kg, at least 0.4mg / kg, or at least 0.5mg / kg, and preferably not more than 50mg / kg, not more than 40mg / kg, not more than 30mg / kg, not more than 20mg / kg, or not more than 10mg / kg, for example, about 2.5mg / day (0.5mg / kg x 5kg) to about 5000mg / day (50mg / kg x 100kg). For example, the dosage of the compound may be from about 0.1 mg / kg / day to about 50 mg / kg / day, from about 0.05 mg / kg / day to about 10 mg / kg / day, from about 0.05 mg / kg / day to about 5 mg / kg / day, from about 0.05 mg / kg / day to about 3 mg / kg / day, from about 0.07 mg / kg / day to about 3 mg / kg / day, from about 0.09 mg / kg / day to about 3 mg / kg / day, from about 0.05 mg / kg / day to about 0.1 mg / kg / day, The dose can be about 0.1 mg / kg / day to about 1 mg / kg / day, about 1 mg / kg / day to about 10 mg / kg / day, about 1 mg / kg / day to about 5 mg / kg / day, about 1 mg / kg / day to about 3 mg / kg / day, about 3 mg / day to about 500 mg / day, about 5 mg / day to about 250 mg / day, about 10 mg / day to about 100 mg / day, about 3 mg / day to about 10 mg / day, or about 100 mg / day to about 250 mg / day. Such doses can be administered in a single dose or divided into multiple doses.

[0166] How to use KRAS G12C inhibitors The present disclosure provides a method for inhibiting RAS-mediated cell signal transduction, comprising contacting cells with an effective amount of one or more compounds disclosed herein.The inhibition of RAS-mediated cell signal transduction can be evaluated and demonstrated by a wide variety of methods known in the art.Non-limiting examples include: (a) a decrease in the GTPase activity of RAS; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) an increase in the Koff of GTP or a decrease in the Koff of GDP; (d) a decrease in the level of downstream signaling molecules of the RAS pathway, such as a decrease in the level of pMEK, pERK, or pAKT; and / or (e) a decrease in the binding of RAS complex to downstream signaling molecules, including but not limited to Raf.Kits and commercially available assays can be used to determine one or more of the above.

[0167] The present disclosure also provides methods of using the compounds or pharmaceutical compositions of the present disclosure to treat disease conditions, including, but not limited to, conditions caused by G12C KRAS, HRAS, or NRAS mutations (e.g., cancer).

[0168] In some embodiments, a method for treating cancer is provided, the method comprising administering to a subject in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound disclosed herein. In some embodiments, the cancer is mediated by a KRAS, HRAS, or NRAS G12C mutation. In various embodiments, the cancer is pancreatic cancer, colon cancer, or lung cancer. In some embodiments, the cancer is gallbladder cancer, thyroid cancer, or bile duct cancer.

[0169] In some embodiments, the present disclosure provides methods of treating a disorder in a subject in need thereof, the method comprising determining whether the subject has a KRAS, HRAS, or NRAS G12C mutation, and, if the subject is determined to have a KRAS, HRAS, or NRAS G12C mutation, administering to the subject a therapeutically effective amount of at least one compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0170] The disclosed compounds inhibit anchorage-independent cell growth and therefore have the potential to inhibit tumor metastasis. Accordingly, in another embodiment, the present disclosure provides a method of inhibiting tumor metastasis, the method comprising administering an effective amount of a compound disclosed herein.

[0171] KRAS, HRAS, or NRAS G12C mutations have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments relate to the administration (e.g., in the form of a pharmaceutical composition) of the disclosed compounds to patients in need of treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemia and lymphoma. For example, the disclosed compounds can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other embodiments, the compounds are useful for treating lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma. In various embodiments, the compounds are useful in the treatment of plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenstrom's macroglobulinemia.

[0172] Whether a tumor or cancer contains a G12C KRAS, HRAS or NRAS mutation can be determined by evaluating the nucleotide sequence encoding the KRAS, HRAS or NRAS protein, by evaluating the amino acid sequence of the KRAS, HRAS or NRAS protein, or by evaluating the characteristics of a putative KRAS, HRAS or NRAS mutant protein. The sequence of wild-type human KRAS, HRAS or NRAS is known in the art (e.g., accession number NP203524).

[0173] Methods for detecting mutations in KRAS, HRAS or NRAS nucleotide sequences are known to those skilled in the art.These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assay, real-time PCR assay, PCR sequencing, mutant allele-specific PCR amplification (MASA) assay, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation assay, hybridization assay, TaqMan assay, SNP genotyping assay, high-resolution melting assay and microarray analysis.In some embodiments, samples are evaluated for G12C KRAS, HRAS or NRAS mutation by real-time PCR.In real-time PCR, a fluorescent probe specific for KRAS, HRAS or NRAS G12C mutation is used.If a mutation exists, the probe binds and fluorescence is detected. In some embodiments, KRAS, HRAS, or NRAS G12C mutations are identified using direct sequencing of specific regions in the KRAS, HRAS, or NRAS gene (e.g., exon 2 and / or exon 3). This approach identifies all possible mutations in the sequenced region.

[0174] The method of detecting the mutation in KRAS, HRAS or NRAS protein is known to those skilled in the art.These methods include but are not limited to the detection of KRAS, HRAS or NRAS mutants using binding agents (such as antibodies) specific to mutant proteins, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0175] The method for determining whether a tumor or cancer contains a G12C KRAS, HRAS, or NRAS mutation can use a variety of samples. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed, paraffin-embedded sample. In some embodiments, the sample is a circulating tumor cell (CTC) sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA.

[0176] The present disclosure also relates to a method of treating a hyperproliferative disorder in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.In some embodiments, the method is directed to treating acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, Colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), germinoma, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac tumor, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, and lip cancer. and oral cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer of occult primary, midline duct carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, breast cancer For the treatment of subjects with cancer such as craniomatosis, paraganglioma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, childhood anomalies, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.In some embodiments, the methods relate to the treatment of non-cancerous hyperproliferative disorders such as benign hyperplasia of the skin (eg, psoriasis), restenosis, or prostate (eg, benign prostatic hyperplasia (BPH)).

[0177] In some embodiments, the method of treatment relates to treating lung cancer, and the method comprises administering an effective amount of any of the above-mentioned compounds (or pharmaceutical compositions comprising same) to a subject in need thereof. In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In some embodiments, the lung cancer is small cell lung cancer. Other lung cancers treatable by the disclosed compounds include, but are not limited to, ductal tumors, carcinoid tumors, and undifferentiated carcinomas.

[0178] The present disclosure further provides a method for modulating the activity of a G12C mutant KRAS, HRAS, or NRAS protein by contacting the protein with an effective amount of a compound of the present disclosure. Modulation can inhibit or activate the activity of the protein. In some embodiments, the present disclosure provides a method for inhibiting the activity of a protein by contacting a G12C mutant KRAS, HRAS, or NRAS protein with an effective amount of a compound of the present disclosure in solution. In some embodiments, the present disclosure provides a method for inhibiting the activity of a G12C mutant KRAS, HRAS, or NRAS protein by contacting a cell, tissue, or organ expressing the protein of interest. In some embodiments, the present disclosure provides a method for inhibiting the activity of a protein in a subject, including, but not limited to, a rodent and a mammal (e.g., a human), by administering an effective amount of a compound of the present disclosure to the subject. In some embodiments, the percent modulation is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the percent inhibition is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0179] In some embodiments, the present disclosure provides a method for inhibiting the activity of KRAS, HRAS, or NRAS G12C in a cell by contacting the cell with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the cell. In some embodiments, the present disclosure provides a method for inhibiting the activity of KRAS, HRAS, or NRAS G12C in a tissue by contacting the tissue with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the tissue. In some embodiments, the present disclosure provides a method for inhibiting the activity of KRAS, HRAS, or NRAS G12C in an organ by contacting the organ with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the organ. In some embodiments, the present disclosure provides a method for inhibiting the activity of KRAS, HRAS, or NRAS G12C in an animal by contacting the animal with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the animal. In some embodiments, the present disclosure provides a method for inhibiting the activity of KRAS, HRAS, or NRAS G12C in a mammal by contacting the mammal with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the mammal. In some embodiments, the present disclosure provides a method for inhibiting the activity of KRAS, HRAS, or NRAS G12C in a human by contacting the human with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in the human. The present disclosure provides a method for treating a disease mediated by KRAS, HRAS, or NRAS G12C activity in a subject in need of treatment.

[0180] Combination therapy: The present disclosure also provides methods of combination therapy in which agents known to regulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes, are used in combination with the compounds of the present disclosure, or pharmaceutically acceptable salts thereof. In one embodiment, such treatments include, but are not limited to, the combination of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation therapy to provide synergistic or additive therapeutic effects.

[0181] Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds of the present disclosure, hi some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens. Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules (e.g., Gleevec® (imatinib mesylate), Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and adriamycin, as well as a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN™); alkylsulfonates such as busulfan, improsulfan, and piposulfan; benzodopa, carboquone, metholedone, and the like. aziridines such as melamine and uredopa; ethylenimines and methylameramines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Aclacinomycin, actinomycin, ausramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin Antibiotics such as keramicin, rhodrubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites (5-FU) such as methotrexate and 5-fluorouracil; folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, and eno Pyrimidine analogs such as citabine and floxuridine; androgens such as calcitriol, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucide; gallium nitrate; hydrochloride Ciurea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenameth; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2',2''-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa;Taxanes such as paclitaxel and docetaxel; retinoic acid; esperamycin; capecitabine; pharmaceutically acceptable salts, acids, or derivatives of any of the above;

[0182] Also included as suitable chemotherapy cell conditioners are antihormonal agents that act to modulate or inhibit hormone action on tumors, such as antiestrogens including tamoxifen (Nolvadex™), raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY 117018, onapristone, and toremifene (Fareston); and antiandrogens such as flutamide, nilutamide, bicalutamide, luprolide, and goserelin; and chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin. C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); the topoisomerase inhibitor RFS 2000; and difluoromethylornithine (DMFO).

[0183] If desired, the compounds or pharmaceutical compositions of the present disclosure may be used in combination with other agents such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, abagovomab, acridine carboxamide, adecatumab, 17-N-arylamino-17-demethoxygeldanamycin, alfalazine, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, amonafod, anthracenedione, anti-CD22 immunotoxin, antitumor, antitumor herb, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle non-specific antitumor agents, dichloroacetic acid, discodamolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, exisulind, ferruginol, forodesin, fosphestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanton, rutotecan, mafosfamide, mitozolomide, naf It can be used in combination with commonly prescribed anticancer drugs such as oxyzin, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapatitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegaflu-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, or zosuquidar.

[0184] The present disclosure further relates to a method of using the compounds or pharmaceutical compositions provided herein in combination with radiation therapy to inhibit abnormal cell growth or treat hyperproliferative disorders in mammals. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compounds of the present disclosure in this combination therapy can be determined as described herein.

[0185] Radiation therapy can be administered by one of several methods or a combination of methods, including, but not limited to, external beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. The term "brachytherapy," as used herein, refers to radiation therapy delivered by spatially confined radioactive materials inserted into the body at or near the site of a tumor or other proliferative tissue disease. This term is intended to include, but is not limited to, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as cell conditioners of the present disclosure include both solid and liquid sources. By way of non-limiting example, the radiation source can be a radionuclide such as I-125, I-131, Yb-169, Ir-192, I-125 as a solid source, or other radionuclide that emits photons, beta particles, gamma rays, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of the radionuclide, for example, a solution of I-125 or I-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing microparticles of a solid radionuclide, such as Au-198, Y-90, etc. Additionally, the radionuclide can be embodied as a gel or radioactive microspheres.

[0186] The compounds or pharmaceutical compositions of the present disclosure can be used in combination with an amount of one or more substances selected from an anti-angiogenic agent, a signal transduction inhibitor, an anti-proliferative agent, an anti-glycolytic agent, or an autophagy inhibitor.

[0187] Anti-angiogenic agents such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors can be used with the disclosed compounds and pharmaceutical compositions described herein. Anti-angiogenic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors include those described in WO 96 / 33172, WO 96 / 27583, EP 0818442, EP 1004578, WO 98 / 07697, WO 98 / 03516, WO 98 / 34918, WO 98 / 34915, WO 98 / 33768, WO 98 / 30566, EP 606046, EP 931788, and the like. No. 5,861,510, and EP 0 780 386, all of which are incorporated herein by reference in their entireties. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferably, they selectively inhibit MMP-2 and / or MMP-9 relative to other matrix metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP7, MMP8, MMP-10, MMP-11, MMP-12, and MMP-13).Some specific examples of MMP inhibitors useful in the present disclosure are AG-3340, RO32-3555, and RS13-0830.

[0188] The compounds of the present invention also include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestine, ARGLABIN, arsenic trioxide, BAM002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetro Relix, cladribine, clotrimazole, cytarabine ocfosfate, DA3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alfa α, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, efornithine, emiteflu, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fudrabin phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, dimeracil / oteracil / tegafur combination, glycopin, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronate, idarubicin, (imiquimod, interferon alpha, interferon alpha, natural, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-N1, interferon alpha- n3, interferon alfacon-1, interferon alpha, natural, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, natural interferon gamma-1a, natural interferon gamma-1b, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leucocytoalf Interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, mastoprocol, melasoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis-stimulating protein, NSC 631570 Octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronate, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasbriembodiment, rhenium Re 186 etidronate, RII retinamide, rituximab, romurtide, samarium (153Sm) lexidronam, sargramotim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimex bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, barbican, verteporfin, vinorelbine, virulizin, zinostatin stimalamer, or zoledronic acid; abarelix; AE941 (Aeterna), ambamustine, antisense oligonucleotides oligonucleotides, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diaziquone, EL532 (Elan), EM800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin-17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM862 (Cytran), interleukin-2, iproxifen, LDI200 (Milkhaus), religistim, lintuzumab, CA125 MAb (Biomira), cancer MAb (Nihon Yakuhin Kaihatsu Co., Ltd.), HER-2 and Fc MAb (Medarex), idiotypic 105AD7MAb (CRC Technology), idiotypic CEA MAb (Trilex), LYM-1-iodine 131MAb (Techniclone), polymorphic epithelial mucin yttrium 90MAb (Antisoma), marimastat, menogaril, mitumomab, motexafine gadolinium, MX6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RLIt may also be used in co-therapy with other anticancer drugs such as 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma oncolysate vaccine (New York Medical College), viral melanoma lysate vaccine (Royal Newcastle Hospital), or valspodar.

[0189] The compounds of the present invention can also be used with VEGFR inhibitors.Other compounds described in the following patents and patent applications can be used in combination therapy: U.S. Patent No. 6,258,812, U.S. Patent Application Publication No. 2003 / 0105091, WO 01 / 37820, U.S. Patent No. 6,235,764, WO 01 / 32651, U.S. Patent No. 6,630,500, U.S. Patent No. 6,515,004, U.S. Patent No. 6,713,485, U.S. Patent No. 5,521,184, U.S. Patent No. 5,770,599, U.S. Patent No. 5,747,498, WO 02 Nos. 02 / 68406, 02 / 66470, 02 / 55501, 04 / 05279, 04 / 07481, 04 / 07458, 04 / 09784, 02 / 59110, 99 / 45009, 00 / 59509, 99 / 61422, U.S. Patent No. 5,990,141, WO 00 / 12089 and WO 00 / 02871.

[0190] In some embodiments, the combination comprises a composition of the present invention in combination with at least one anti-angiogenic agent. Agents include, but are not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof. Agents can be agonists, antagonists, allosteric modulators, toxins, or more generally, can act to inhibit or stimulate their targets (e.g., activate or inhibit receptors or enzymes), thereby promoting cell death or halting cell proliferation.

[0191] Exemplary anti-angiogenic agents include ERBITUX™ (IMC-C225), KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that specifically bind to kinase domain receptors), anti-VEGF agents (e.g., antibodies or antigen-binding regions that specifically bind to VEGF or soluble VEGF receptors or their ligand-binding regions) such as AVASTIN™ or VEGF-TRAP™, and anti-VEGF receptor drugs (e.g., antibodies or antigen-binding regions that specifically bind thereto), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto) such as Vectibix (panitumumab), IRESSA™ (gefitinib), TARCEVA™ (erlotinib), anti-Ang1 and anti-Ang2 agents (e.g., antibodies that specifically bind thereto or their receptors, such as Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto). The pharmaceutical compositions of the invention can also include one or more agents (e.g., antibodies, antigen-binding regions, or soluble receptors) that specifically bind to and inhibit the activity of a growth factor, such as antagonists and antibodies or antigen-binding regions of hepatocyte growth factor (HGF, also known as scatter factor) that specifically bind to the receptor "c-met."

[0192] Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (Ceretti et al., U.S. Patent Application Publication No. 2003 / 0162712; U.S. Patent No. 6,413,932), anti-TWEAK agents (e.g., specifically binding antibodies or antigen binding regions, or soluble TWEAK receptor antagonists; Wiley, U.S. Patent No. 6,727,225), ADAM disintegrin domains that antagonize the binding of integrins to their ligands (Fanslow et al., U.S. Patent Application Publication No. 2002 / 0042368), and specifically binding anti-eph receptor antagonists. Antibodies and / or anti-ephrin antibodies or antigen-binding regions (see U.S. Patent Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124, and members of those patent families), and anti-PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind), as well as antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto).

[0193] Additional anti-angiogenic / anti-tumor agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EP 770622); pegaptanib octasodium (Gilead Sciences, USA); alphastatin (BioActa, UK); M-PGA (Celgene, USA, U.S. Pat. No. 5,712,291); ilomastat (Arriva, USA, U.S. Pat. No. 5,892,112); emaxanib (Pfizer, USA, U.S. Pat. No. 5,792,783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); alpha-D148 Mab, (Amgen, USA); CEP-7055, (Cephalon, USA); Anti-Vn Mab, (Crucell, Netherlands) DAC: Antiangiogenic, (ConjuChem, Canada); Angiosidin, (InKine Pharmaceutical, USA); KM-2550, (Kyowa Hakko, Japan); SU-0879, (Pfizer, USA); CGP-79787, (Novartis, Switzerland, European Patent No. 970070); ARGENT technology, (Ariad, USA); YIGSR-Stealth, (Johnson & Johnson, USA); Fibrinogen-E fragment, (BioActa, UK); Angiogenesis inhibitor, (Trigen, UK); TBC-1635, (Encysive Pharmaceuticals, USA); SC-236, (Pfizer, USA); ABT-567, (Abbott, USA); metastatin, (EntreMed, USA); angiogenesis inhibitor, (Tripep, Sweden); maspin, (Sosei, Japan); 2-methoxyestradiol, (Oncology Sciences Corporation, USA); ER-68203-00, (IVAX, USA); Benefin, (Lane Labs, USA); Tz-93, (Tsumura Corporation, Japan);TAN-1120, (Takeda Pharmaceutical Co., Ltd., Japan); FR-111142, (Fujisawa Pharmaceutical Co., Ltd., Japan, JP 02233610); Platelet factor 4, (RepliGen, USA, EP 407122); Vascular endothelial growth factor antagonist, (Borean, Denmark); Bevacizumab (pINN), (Genentech, USA); Angiogenesis inhibitor, (SUGEN, USA); XL 784, (Exelixis, USA); XL 647, (Exelixis, USA); MAb, alpha 5 beta 3 integrin, second generation, (Applied Molecular Evolution, USA and MediImmune, USA); Gene therapy, retinopathy, (Oxford BioMedica, UK); Enzastaurin hydrochloride (USAN), (Lilly, USA); CEP 7055, (Cephalon, USA and Sanofi-Synthelabo, France); BC 1, (Genoa Institute of Cancer Research, Italy); angiogenesis inhibitor, (Alchemia, Australia); VEGF antagonist, (Regeneron, USA); rBPI 21 and BPI-derived antiangiogenic agents, (XOMA, USA); PI 88, (Progen, Australia); cilengitide (pINN), (Merck KGaA, German; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); cetuximab (INN), (Aventis, France); AVE 8062, (Ajinomoto Co., Inc., Japan); AS 1404, (Cancer Research Laboratory, New Zealand); SG 292, (Telios, USA); endostatin, (Boston Children's Hospital, USA); ATN 161, (Attenuon, USA); ANGIOSTATIN, (Boston Children's Hospital, USA); 2-methoxyestradiol, (Boston Children's Hospital, USA); ZD 6474, (AstraZeneca, UK);ZD 6126, (Angiogene Pharmaceuticals, UK); PPI 2458, (Praecis, USA); AZD 9935, (AstraZeneca, UK); AZD 2171, (AstraZeneca, UK); vatalanib (pINN), (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitor, (EntreMed, USA); pegaptanib (Pinn), (Gilead Sciences, USA); xanthorrhizole, (Yonsei University, South Korea); vaccine, gene-based, VEGF-2, (Scripps Clinic and Research Foundation, USA); SPV5.2, (Supratek, Canada); SDX 103, (University of California at San Diego, USA); PX 478, (ProlX, USA); METASTATIN, (EntreMed, USA); troponin I, (Harvard University, USA); SU 6668, (SUGEN, USA); OXI 4503, (OXiGENE, USA); o-guanidine, (Dimensional Pharmaceuticals, USA); motuporamine C, (British Columbia University, Canada); CDP 791, (Celltech Group, UK); atiprimod (pINN), (GlaxoSmithKline, UK); E 7820, (Eisai Co., Ltd., Japan); CYC 381, (Harvard University, USA); AE 941, (Aeterna, Canada); vaccine, angiogenesis, (EntreMed, USA); urokinase-type plasminogen activator inhibitor, (Dendreon, USA); oglufanide (pINN), (Melmotte, USA); HIF-1 alpha inhibitor, (Xenova, UK); CEP 5214, (Cephalon, USA); BAY RES 2622, (Bayer, Germany); Angiocidin, (InKine, USA); A6, (Angstrom, USA);KR 31372, (Korea Research Institute of Chemical Technology, South Korea); GW 2286, (GlaxoSmithKline, UK); EHT 0101, (ExonHit, France); CP 868596, (Pfizer, USA); CP 564959, (OSI, USA); CP 547632, (Pfizer, USA); 786034, (GlaxoSmithKline, UK); KRN 633, (Kirin Brewery Co., Ltd., Japan); Drug delivery system, intraocular, 2-methoxyestradiol, (EntreMed, USA); Anginex, (Maastricht University, Netherlands, and University of Minnesota, USA); ABT 510, (Abbott, USA); AAL 993, (Novartis, Switzerland); VEGI, (ProteomTech, USA); tumor necrosis factor alpha inhibitor, (National Institute on Aging, USA); SU 11248, (Pfizer, USA and UGEN USA); ABT 518, (Abbott, USA); YH16, (Yantai Rongchang, China); S-3APG, (Boston Children's Hospital, USA and EntreMed, USA); MAb, KDR, (ImClone Systems, USA); MAb, alpha5 beta1, (Protein Design, USA); KDR kinase inhibitor, (Celltech Group, UK and Johnson & Johnson, USA); GFB 116, (University of South Florida, USA and Yale University, USA); CS 706, (Daiichi Sankyo Co., Ltd., Japan); combretastatin A4 prodrug, (Arizona State University, USA); Chondroitinase AC, (IBEX, Canada); BAY RES 2690, (Bayer, Germany); AGM 1470, (Harvard University, USA, Takeda Pharmaceutical Company Limited, Japan and TAP, USA);AG 13925, (Agouron, USA); tetrathiomolybdate, (University of Michigan, USA); GCS 100, (Wayne State University, USA); CV 247, (Ivy Medical, UK); CKD 732, (Chong Kun Dang, South Korea); MAb, vascular endothelial growth factor, (Xenova, UK); irsogladine (INN), (Nippon Shinyaku Co., Ltd., Japan); RG 13577, (Aventis, France); WX 360, (Wilex, Germany); squalamine (pINN), (Genaera, USA); RPI 4610, (Sirna, USA); cancer treatment, (Marinova, Australia); heparanase inhibitor, (InSight, Israel); KL 3106, (Kolon, South Korea); honokiol, (Emory University, USA); ZK CDK, (Schering AG, Germany); ZK Angio, (Schering AG, Germany); ZK 229561, (Novartis, Switzerland, and Schering AG, Germany); XMP 300, (XOMA, USA); VGA 1102, (Taisho, Japan); VEGF receptor modulator, (Pharmacopeia, USA); VE-cadherin-2 antagonist, (ImClone Systems, USA); vasostatin, (National Institutes of Health, USA); vaccine, Flk-1, (ImClone Systems, USA); TZ 93, (Tsumura & Co., Japan); Tumstatin, (Beth Israel Hospital, USA); truncated soluble FLT 1 (vascular endothelial growth factor receptor 1), (Merck & Co, USA); Tie-2 ligand, (Regeneron, USA); and thrombospondin 1 inhibitor, (Allegheny Health, Education and Research Foundation, USA).

[0194] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Additionally, antisense or siRNA inhibitors that inhibit the expression of proteins, including but not limited to ATG5 (involved in autophagy), can also be used.

[0195] Additional pharmaceutically active compounds / agents that can be used in the treatment of cancer and that can be used in combination with one or more compounds of the present invention include epoetin alfa; darbepoetin alfa; panitumumab; pegfilgrastim; palifermin; filgrastim; denosumab; ancestim; AMG 102; AMG 386; AMG 479; AMG 655; AMG 745; AMG 951; and AMG 706, or a pharmaceutically acceptable salt thereof.

[0196] In certain embodiments, the compositions provided herein are administered in combination with a chemotherapeutic agent. Suitable chemotherapeutic agents include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase, which metabolizes L-asparagine systemically and removes it from cells that do not have the ability to synthesize their own asparagine), antiplatelet agents, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, and analogs, antiproliferative / antimitotic alkylating agents such as melphalan and chlorambucil), ethylenimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkylsulfonates (e.g., busulfan), nitrates, and the like. Antiproliferative / antimitotic antimetabolites such as rosourea (e.g., carmustine (BCNU) and analogs, and streptozocin), trazene-dacarbazine (DTIC), folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoylanilide hydroxamic acid apicidan, vorinostat, LBH589, romidepsin, ACY-1215, and panobinostat), mTor inhibitors (e.g., temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Array 520), DNA binders (e.g., Zalipsis), PI3K delta inhibitors (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitors (e.g., CAL-130), multikinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogen) and hormones such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin). agonists, BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNTO328), telomerase inhibitors (e.g., GRN163L), Aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38)), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17AAG and KOS 953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra™), anti-CD138 (e.g., BT062), Torc1 / 2-specific kinase inhibitors (e.g., INK128), kinase inhibitors (e.g., GS-1101), ER / UPR targeting agents (e.g., MKC-3946), cFMS inhibitors Other chemotherapeutic agents may include anti-cancer agents (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists. Other chemotherapeutic agents may include mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine, sorafenib, or any analog or derived variant of the above.

[0197] The compounds of the present invention may also be used in combination with radiation therapy, hormone therapy, surgery, and immunotherapy, which are well known to those skilled in the art.

[0198] In certain embodiments, the compositions provided herein are administered in combination with a steroid. Suitable steroids include 21-acetoxypregnolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, and flurandreno. The nausea and vomiting medications may include, but are not limited to, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts and / or derivatives thereof. In certain embodiments, the compounds of the present invention may also be used in combination with additional pharmaceutically active agents to treat nausea. Examples of drugs that can be used to treat nausea include dronabinol; granisetron; metoclopramide; ondansetron; and prochlorperazine; or pharmaceutically acceptable salts thereof.

[0199] The compounds or pharmaceutical compositions of the present disclosure may also be used in combination with an amount of one or more agents selected from EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, and anti-immunotherapies (including PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents), GITR agonists, CAR-T cells, and BiTEs.

[0200] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNA. Useful antibody inhibitors of EGFR include cetuximab (Erbitux), panitumab (Vectibix), zalutumumab, nimotuzumab, and matuzumab. Small molecule antagonists of EGFR include gefitinib, erlotinib (Tarceva), and recently lapatinib (TykerB). See, e.g., Yan L, et.al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005;39(4):565-8, and Paez JG, et.al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004;304(5676):1497-500.

[0201] Non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications, and all pharmaceutically acceptable salts and solvates of said EGFR inhibitors: European Patent Application Publication No. 520722, published December 30, 1992; European Patent Application Publication No. 566226, published October 20, 1993; International Patent Application Publication No. WO 96 / 33980, published October 31, 1996; U.S. Patent No. 5,747,498, published May 5, 1998; WO 96 / 30347 published on August 6, 1997; EP 787772 published on August 6, 1997; WO 97 / 30034 published on August 21, 1997; WO 97 / 30044 published on August 21, 1997; WO 97 / 38994 published on October 23, 1997; WO 97 / 49688 published on December 31, 1997; and EP 837063 published on April 22, 1998. WO 98 / 02434, published January 22, 1998; WO 97 / 38983, published October 23, 1997; WO 95 / 19774, published July 27, 1995; WO 95 / 19970, published July 27, 1995; WO 97 / 13771, published April 17, 1997; WO 98 / 02437, published January 22, 1998; WO 98 / 02438, published on September 12, 1997; WO 97 / 32881, published on September 12, 1997; German Patent Application DE 19629652, published on January 29, 1998; WO 98 / 33798, published on August 6, 1998; WO 97 / 32880, published on September 12, 1997; WO 97 / 32880, published on September 12, 1997; European Patent Application 682027, published on November 15, 1995;International Publication No. WO 97 / 02266, published January 23, 1997; International Publication No. WO 97 / 27199, published July 31, 1997; International Publication No. WO 98 / 07726, published February 26, 1998; International Publication No. WO 97 / 34895, published September 25, 1997; International Publication No. WO 96 / 31510, published October 10, 1996; International Publication No. WO 98 / 14449, published April 9, 1998; International Publication No. WO 98 / 14450, published April 9, 1998; International Publication No. WO 98 / 14451, published April 13, 1995 No. 9847; WO 97 / 19065 published May 29, 1997; WO 98 / 17662 published April 30, 1998; U.S. Patent No. 5,789,427 issued August 4, 1998; U.S. Patent No. 5,650,415 issued July 22, 1997; U.S. Patent No. 5,656,643 issued August 12, 1997; WO 99 / 35146 published July 15, 1999; WO 99 / 35132 published July 15, 1999; WO 99 / 07701 published February 18, 1999; and WO 92 / 20642 published November 26, 1992. Further non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler, P., 1998, Exp. Opin. Ther. Patents 8(12):1599-1625.

[0202] Antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand.Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi, H., et al., 1993, Br.J.Cancer 67:247-253; Teramoto, T., et al., 1996, Cancer 77:639-645; Goldstein et al., 1995, Clin.Cancer Res.1:1311-1318; Huang, SM, et al., 1999, Cancer Res.15:59(8):1935-40; and Yang, X., et al., 1999, Cancer Res.59:1236-1243. Thus, the EGFR inhibitor can be the monoclonal antibody Mab E7.6.3 (Yang, 1999, supra), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof.

[0203] MEK inhibitors include, but are not limited to, CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, and PD-325901.

[0204] PI3K inhibitors include wortmannin, a 17-hydroxywortmannin analog described in WO 06 / 044453, 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and described in WO 09 / 036,082 and WO 09 / 055,730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (BEZ 235 or NVP-BEZ 235 and described in WO 06 / 122806), (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO 2008 / 070740), LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one available from Axon Medchem), PI 103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride available from Axon Medchem), PIK 75 (Axon N'-[(1E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-nitrobenzenesulfono-hydrazide hydrochloride), available from Medchem; PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide), available from Axon Medchem; GDC-0941 bismesylate (2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine bismesylate), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione available from Axon Medchem) and TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one available from Axon Medchem), XL-765 and XL-147. Other PI3K inhibitors include demethoxyviridine, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0205] AKT inhibitors include Akt-1-1 (inhibits Akt1) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408); Akt-1-1,2 (inhibits Akt1 and 2) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408); API-59CJ-Ome (e.g., Jin et al. (2004) Br. J. Cancer 91, 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO 05011700); indole-3-carbinol and its derivatives (e.g., U.S. Pat. No. 6,656,963; Sarkar and Li (2004) J. Nutr. 134 (12) Suppl), 3493S-3498S); perifosine (e.g., which interferes with the membrane localization of Akt; Dasmahapatra et al. (2004) Clin. Cancer Res. 10(15), 5242-52, 2004); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13, 787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al. (2004) Cancer Res. 64, 4394-9).

[0206] TOR inhibitors include, but are not limited to, inhibitors of the FKBP12 enhancer, including AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1 / TORC2 inhibitors (including PI-103, PP242, PP30, and Torin 1). Other TOR inhibitors at the FKBP12 enhancer include rapamycin and its derivatives: CCI-779 (temsirolimus), RAD001 (everolimus; WO 9409010), and AP23573; rapalogs, such as those disclosed in WO 98 / 02441 and WO 01 / 14387, e.g., AP23573, AP23464, or AP23841; 40-(2-hydroxybenzoates)-4-hydroxybenzoates; (trimethyloxyethyl)rapamycin, 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779), 40-epi-(tetrazolito)-rapamycin (also known as ABT578), 32-deoxorapamycin, 16-pentynyloxy-32(S)-dihydrorapamycin, and other derivatives disclosed in WO 05005434; U.S. Pat. No. 5,258,389; WO 94 / 044944 No. 090101, WO 92 / 05179, U.S. Pat. No. 5,118,677, U.S. Pat. No. 5,118,678, U.S. Pat. No. 5,100,883, U.S. Pat. No. 5,151,413, U.S. Pat. No. 5,120,842, WO 93 / 111130, WO 94 / 02136, WO 94 / 02485, WO 95 / 14023 derivatives disclosed in WO 94 / 02136, WO 95 / 16691, WO 96 / 41807, WO 96 / 41807 and U.S. Pat. No. 5,256,790; phosphorus-containing rapamycin derivatives (e.g., WO 05016252); 4H-1-benzopyran-4-one derivatives (e.g., U.S. Provisional Patent Application No. 60 / 528,340).

[0207] Immunotherapies include, but are not limited to, anti-PD-1 agents, anti-PDL-1 agents, anti-CTLA-4 agents, anti-LAG1 agents, and anti-OX40 agents. Exemplary anti-PD-1 antibodies and their methods of use are described in Goldberg et al., Blood 110(1):186-192(2007), Thompson et al., Clin. Cancer Res.13(6):1757-1761(2007), and Korman et al., International Application No. PCT / JP2006 / 309606 (International Publication No. WO2006 / 121168A1), each of which is expressly incorporated herein by reference. These include: Yervoy™ (ipilimumab) or tremelimumab (to CTLA-4), galiximab (to B7.1), BMS-936558 (to PD-1), MK-3475 (to PD-1), AMP224 (to B7DC), BMS-936559 (to B7-H1), MPDL3280A (to B7-H1), MEDI-570 (to ICOS), AMG557 (to B7H2), MGA271 (to B7H3), IMP321 (to LAG-3), BMS-663513 (to CD137), PF-05082566 (to CD137), CDX-1127 (to CD27), anti-OX40 (Providence Health) Services), huMAbOX40L (to OX40L), atacicept (to TACI), CP-870893 (to CD40), lucatumumab (to CD40), decatuzumab (to CD40), muromonab-CD3 (to CD3), ipilumumab (to CTLA-4). Immunotherapies also include genetically engineered T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTEs).

[0208] GITR agonists include GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as those described in U.S. Pat. No. 6,111,090box.c, EP 090505B1, U.S. Pat. No. 8,586,023, WO 2010 / 003118 and WO 2011 / 090754, or those described in, for example, U.S. Pat. No. 7,025,962, EP 1947183B1, U.S. Pat. No. 7,812,135, U.S. Pat. No. 8,388,967, U.S. Pat. No. 8,591,886, EP 1866339, WO 2011 / 090754, and the like. Nos. 2011 / 028683, WO 2013 / 039954, WO 2005 / 007190, WO 2007 / 133822, WO 2005 / 055808, WO 99 / 40196, WO 2001 / 03720, WO 99 / 20758, WO 2006 / 083289, WO 2005 / 115451, U.S. Pat. No. 7,618,632, and WO 2011 / 051726.

[0209] The compounds described herein can be used in combination with other suitable agents disclosed herein or other suitable agents, depending on the condition being treated. Thus, in some embodiments, one or more compounds of the present disclosure will be co-administered with the other agent. When used in combination therapy, the compounds described herein are administered simultaneously with the second agent or separately. This combination administration can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the agents described above can be formulated together in the same dosage form and co-administered. Alternatively, the compounds of the present disclosure and any of the agents described above can be administered simultaneously, with both agents being in separate formulations. In another alternative, the compounds of the present disclosure can be administered followed by any of the agents described above, or vice versa. In some embodiments of the separate administration protocol, the compounds of the present disclosure and any of the agents described above can be administered within minutes, hours, or days.

[0210] Since one aspect of the present invention contemplates treating a disease / condition with a combination of pharmaceutically active compounds that can be administered separately, the present invention further relates to combining separate pharmaceutical compositions in the form of a kit. The kit includes two separate pharmaceutical compositions: a compound of the present invention and a second pharmaceutical compound. The kit includes containers for housing the separate compositions, such as divided bottles or divided foil pouches. Other examples of containers include syringes, boxes, and bags. In some embodiments, the kit includes instructions for use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing medical professional. [Example]

[0211] Method 1 Example 1-1: 1-(4-(6-(2-bromo-5-hydroxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one [ka] Step 1: 2-Amino-4-bromo-5-chloro-3-fluorobenzoic acid (Intermediate A). A mixture of 2-amino-4-bromo-3-fluorobenzoic acid (3.91 g, 16.71 mmol, Apollo Scientific Ltd., Stockport, UK) and N-chlorosuccinimide (1.36 mL, 16.7 mmol) in N,N-dimethylformamide (33 mL) was stirred at 70 °C for 20 h. The reaction mixture was then cooled to rt, ice water (40 mL) was added, and the resulting mixture was stirred for 1 h. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid. 1 H NMR(400MHz,DMSO-d6)δ7.69(1H,d,J=2.0Hz),6.48-7.23(2H,brs). 19 F NMR(376MHz,DMSO-d6)δ-119.70(1F,s).m / z(ESI,+ve)270.0(M+H) + .

[0212] Step 2: 2-Amino-4-bromo-5-chloro-3-fluorobenzoic acid (Intermediate B). Ammonium chloride (1.10 g, 20.6 mmol) and diisopropylethylamine (5.13 mL, 29.5 mmol) were added sequentially to a mixture of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (Intermediate A, 3.96 g, 14.7 mmol) and TBTU (4.97 g, 15.5 mmol, Advanced ChemTech, Louisville, KY, USA) in N,N-dimethylformamide (30 mL), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was then added to saturated aqueous sodium bicarbonate and stirred for 15 minutes. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 2-amino-4-bromo-5-chloro-3-fluorobenzamide. 1 H NMR(400MHz,DMSO-d6)δ8.03(1H,brs),7.72(1H,d,J=2.0Hz),7.47(1H,brs),6.86(2H,s). 19 F NMR(376MHz,DMSO-d6)δ-120.79(1F,s).m / z(ESI,+ve)268.9(M+H) + .

[0213] Step 3: 2-Amino-4-bromo-5-chloro-3-fluorobenzothioamide. To 2-amino-4-bromo-5-chloro-3-fluorobenzamide (Intermediate B, 3.10 g, 11.59 mmol) in THF (77 mL) was added Lawesson's reagent (2.81 g, 6.95 mmol), and the resulting mixture was stirred at rt for 1 h. The reaction mixture was then diluted with EtOAc (75 mL) and washed sequentially with 2 M aqueous HCl (50 mL), saturated aqueous sodium bicarbonate (50 mL), and brine (50 mL). The organic extract was then dried over Na2SO4, collected by filtration, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0–3% MeOH in DCM) afforded 2-amino-4-bromo-5-chloro-3-fluorobenzothioamide: 1H NMR(400MHz,DMSO-d6)δ9.93-10.15(1H,m),9.63(1H,brs),7.28(1H,d,J=1.96Hz),6.34(2H,s). 19 F NMR(376MHz,DMSO-d6)δ-119.52(1F,s).m / z(ESI,+ve)284.8(M+H) + .

[0214] Step 4: 6-Bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-amine. Hydrogen peroxide (30 wt% in water, 2.93 mL, 28.7 mmol) was added dropwise to an ice-cold solution of 2-amino-4-bromo-5-chloro-3-fluorobenzothioamide (2.71 g, 9.55 mmol) in pyridine (32 mL), and the resulting mixture was then warmed to RT and stirred for 24 h. Water (50 mL) was added, and the precipitated solid was collected by filtration, washed with water, and dried under vacuum to give 6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-amine: 1 H NMR(400MHz,DMSO-d6)δ8.12-8.26(2H,m),7.95-8.06(1H,m). 19 F NMR(376MHz,DMSO-d6)δ-114.32(1F,s).m / z(ESI,+ve)283.0(M+H) + .

[0215] Step 5: 6-Bromo-3,5-dichloro-7-fluorobenzo[c]isothiazole (Intermediate C). To an ice-cooled mixture of 6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-amine (2.47 g, 8.78 mmol), water (12 mL), and concentrated hydrochloric acid (37 wt%, 12 mL, 395 mmol), an aqueous solution (2.0 mL) of sodium nitrite (0.788 g, 11.4 mmol) was slowly added. The resulting mixture was stirred at 0 °C for 2.5 h, and then a mixture of copper(I) chloride (1.39 g, 14.1 mmol) in concentrated hydrochloric acid (37 wt%, 12 mL, 395 mmol) was added at 0 °C. The reaction mixture was then warmed to RT and stirred for 20 h. The reaction mixture was diluted with water (50 mL), and the precipitated solid was collected by filtration and dried in vacuo. The recovered material was taken up in (3:1) DCM:MeOH (200 mL) and washed sequentially with water (200 mL) and brine (100 mL). The organic layer was then dried over NaSO, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-20% EtOAc in heptane) gave 6-bromo-3,5-dichloro-7-fluorobenzo[c]isothiazole: 1 H NMR(400MHz,DMSO-d6)δ7.99(1H,d,J=1.57Hz). 19 F NMR(376MHz,DMSO-d6)δ-111.48(1F,s).m / z(ESI,+ve)425.0(M+H) + .

[0216] Step 6: tert-Butyl 4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate (Intermediate D). A mixture of 6-bromo-3,5-dichloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate (Intermediate C, 150 mg, 0.497 mmol) and 1-Boc-piperazine (204 mg, 1.09 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at rt for 20 h. The reaction mixture was then adsorbed onto silica gel and chromatographically purified (silica gel, 0–20% EtOAc in heptane) to give tert-butyl 4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate. 1 H NMR(400MHz,chloroform-d)δ7.60(1H,d,J=1.56Hz),3.68-3.79(4H,m),3.40-3.51(4H,m),1.26(9H,s).m / z(ESI,+ve)451.8(M+H) + .

[0217] Step 7: tert-butyl 4-(6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate. To the reaction mixture tert-butyl 4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate (Intermediate D, 111 mg, 0.247 mmol), 2-bromo-5-methoxybenzeneboronic acid (0.114 mL, 0.494 mmol), sodium carbonate (0.041 mL, 0.988 mmol), and tetrakis(triphenylphosphine)palladium (14.3 mL) in 1,4-dioxane (1.6 mL) and water (0.4 mL) was added. mg, 0.012 mmol) was heated at 90 °C for 21 h. The reaction mixture was then concentrated in vacuo, adsorbed onto silica gel, and purified by column chromatography (silica gel, 0-20% (3:1) EtOAc / EtOH in heptane) to give tert-butyl 4-(6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate: m / z (ESI, +ve) 558.1 (M+H). + .

[0218] Step 8: 1-(4-(6-(2-Bromo-5-hydroxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one. Hydrogen chloride (4 M in 1,4-dioxane, 2.0 mL, 8.0 mmol) was added to a mixture of tert-butyl 4-(6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate (107 mg, 0.192 mmol) and methanol (2.0 mL), and the resulting mixture was stirred at rt for 1 h. The reaction mixture was then concentrated in vacuo to give 6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluoro-3-(piperazin-1-yl)benzo[c]isothiazole: m / z (ESI, +ve) 458.0 (M+1) + .

[0219] To this material (88 mg) was added N,N-diisopropylethylamine (0.101 mL, 0.578 mmol) in dichloromethane (2 mL), and the resulting mixture was cooled to 0° C. Acryloyl chloride (0.26 M in DCM, 0.75 mL, 0.19 mmol) was added, and the resulting mixture was stirred at 0° C. for 10 minutes. The reaction mixture was concentrated in vacuo to give 1-(4-(6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one: m / z (ESI, +ve) 512.0 (M+H). + .

[0220] For compounds that did not contain a methyl ether protecting group, the crude material was purified at this stage. For compounds that did have a methyl ether protecting group, the crude material was used in the next transformation without purification:

[0221] The resulting 1-(4-(6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one was taken up in 1,2-dichloroethane (2.0 mL) and cooled to 0 °C. Boron tribromide solution (1.0 M in hexanes, 0.97 mL, 0.97 mmol) was added, and the resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was then added to saturated aqueous sodium bicarbonate solution (2.0 mL) and extracted with (2:1) DCM / MeOH (10 mL). The organic extract was dried over Na SO , filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-3% MeOH in DCM) gave 1-(4-(6-(2-bromo-5-hydroxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one: 1H NMR(400MHz,DMSO-d6)δ9.99(brs,1H),8.04(s,1H),7.55(d,J=8.7Hz,1H),6.81-6.94(m,2H),6.79(d,J=2.9Hz,1 H),6.19(dd,J=16.7,2.2Hz,1H),5.77(dd,J=10.5,2.2Hz,1H),3.87(brd,J=19.5Hz,4H),3.63(brt,J=5.1Hz,4H). 19 F NMR(376MHz,DMSO-d6)δ-124.16(1F,s).m / z(ESI,+ve)498.0(M+H) +

[0222] Table 35

[0223] Table 36

[0224] Table 37

[0225] Table 38

[0226] Table 39

[0227] Table 40

[0228] Table 41

[0229] [Table 42]

[0230] Method 2 Example 2-1: 1-(4-(5-chloro-6-(3-hydroxy-1-naphthalenyl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-1-piperazinyl)-2-propen-1-one [ka] Step 1: 2-amino-6-bromo-5-chloronicotinic acid. N-Chlorosuccinimide (2.78 g, 20.8 mmol) was added to a solution of 2-amino-6-bromonicotinic acid (4.51 g, 20.8 mmol, Ark Pharm Inc. Arlington Heights, IL, USA) in DMF (75 mL), and the resulting mixture was heated at 70° C. for 2.5 h. Heating was then stopped, and stirring was continued for 16 h. The reaction mixture was then poured into ice water. After the ice had melted, the resulting slurry was filtered through a fritted glass funnel. The collected solid was air-dried to give 2-amino-6-bromo-5-chloronicotinic acid: 1 H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.64(br.s,2H).m / z(ESI,+ve)250.9(M+H) + .

[0231] Step 2: tert-Butyl 4-(2-amino-6-bromo-5-chloronicotinoyl)piperazine-1-carboxylate. To a solution of 2-amino-6-bromo-5-chloronicotinic acid (1.12 g, 4.5 mmol) in DMF (14 mL) was added TBTU (1.93 g, 6.0 mmol). After 5 min, the reaction was treated sequentially with 1-Boc-piperazine (912 mg, 4.9 mmol) and DIPEA (2.33 mL, 13.4 mmol). The resulting solution was stirred at rt for 25 h, saturated aqueous NaHCO3 (75 mL) was added, and the resulting mixture was extracted with DCM. The organic layer was separated, washed sequentially with water (2x), dried over anhydrous sodium sulfate, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-7% MeOH in DCM) gave tert-butyl 4-(2-amino-6-bromo-5-chloronicotinoyl)piperazine-1-carboxylate: 1 H NMR(400MHz,DMSO-d6)δ7.58(s,1H),6.66(s,2H),3.33(s,8H),1.40(s,9H).m / z(ESI,+ve)419.0(M+H) + .

[0232] Step 3: tert-butyl 4-(2-amino-6-bromo-5-chloropyridine-3-carbonothioyl)piperazine-1-carboxylate. Lawesson's reagent (353 mg, 0.87 mmol) was added to a solution of tert-butyl 4-(2-amino-6-bromo-5-chloronicotinoyl)piperazine-1-carboxylate (610 mg, 1.45 mmol) in THF (7.5 mL), and the resulting solution was stirred at 50 °C for 2.5 h. The reaction mixture was then cooled to rt and treated sequentially with water (10 mL) and 1 N aqueous HCl (4 mL). The resulting mixture was extracted with EtOAc (2x), and the combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-6% MeOH in DCM) gave tert-butyl 4-(2-amino-6-bromo-5-chloropyridine-3-carbonothioyl)piperazine-1-carboxylate: 1H NMR(400MHz,DMSO-d6)δ7.47(s,1H),6.58(br.s,2H),4.30(ddd,J=13.3,6.3,3.3Hz,1H),4.01-4.13(m ,2H),3.68-3.77(m,1H),3.51-3.59(m,1H),3.40-3.50(m,3H),1.41(s,9H).m / z(ESI,+ve)434.9(M+H) + .

[0233] Step 4: tert-Butyl 4-(5,6-dichloroisothiazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate. NCS (116 mg, 0.87 mmol) was added to a solution of tert-butyl 4-(2-amino-6-bromo-5-chloropyridine-3-carbonothioyl)piperazine-1-carboxylate (343 mg, 0.79 mmol) in THF (8 mL), and the resulting solution was stirred at room temperature for 20 minutes. Water (10 mL) and 1 M aqueous sodium sulfite solution (5 mL) were then added, and the resulting mixture was extracted with EtOAc (2×). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-4% MeOH in DCM) gave tert-butyl 4-(5,6-dichloroisothiazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate: 1 H NMR(400MHz,chloroform-d)δ8.10(s,1H),3.69-3.80(m,4H),3.50-3.57(m,4H),1.51(s,9H).m / z(ESI,+ve)389.0(M+H) + .

[0234] Step 5: tert-Butyl 4-(5-chloro-6-(3-methoxynaphthalen-1-yl)isothiazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate. A mixture of tert-butyl 4-(5,6-dichloroisothiazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate (154 mg, 0.36 mmol), (3-methoxynaphthalen-1-yl)boronic acid (287 mg, 1.42 mmol), and cesium carbonate (463 mg, 1.42 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was purged with argon, followed by the addition of tetrakis(triphenylphosphine)palladium (41 mg, 0.04 mmol). The reaction mixture was again purged with argon and then heated in a sealed tube at 100 °C for 25 h. After cooling to rt, the reaction mixture was diluted with brine (40 mL) and extracted with EtOAc (2x). The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-3.5% MeOH in DCM) gave tert-butyl 4-(5-chloro-6-(3-methoxynaphthalen-1-yl)isothiazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate: m / z (ESI, +ve) 511.1 (M+H)+.

[0235] Step 6: 5-chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)isothiazolo[3,4-b]pyridine. To a solution of tert-butyl 4-(5-chloro-6-(3-methoxynaphthalen-1-yl)isothiazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate (155 mg, 0.30 mmol) in DCM (6 mL) was added trifluoroacetic acid (560 L, 7.6 mmol). The resulting solution was stirred at rt for 2.3 h and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 25% MeOH in DCM) afforded 5-chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)isothiazolo[3,4-b]pyridine as the TFA salt: 1 H NMR (400 MHz, DMSO-d6) δ8.78(s,1H),7.94(d,J=8.2Hz,1H),7.46-7.53(m,2H),7.31(d,J=3.7Hz,2H),7.19(d,J= 2.4Hz,1H),3.95(s,3H),3.76-3.83(m,4H),3.35-3.43(m,4H).m / z(ESI,+ve)411.0(M+H) + .

[0236] Step 7: 1-(4-(5-chloro-6-(3-hydroxy-1-naphthalenyl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-1-piperazinyl)-2-propen-1-one. To an ice-cooled slurry of 5-chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)isothiazolo[3,4-b]pyridine (TFA salt; 100 mg, 0.19 mmol) in DCM (5 mL) was added DIPEA (100 L, 0.57 mmol) and acryloyl chloride (23 L, 0.29 mmol) sequentially. The resulting solution was stirred at 0 °C for 70 min, and saturated aqueous NaHCO (15 mL) was added. The resulting mixture was extracted with DCM (3x), and the combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-7% MeOH in DCM) gave 1-(4-(5-chloro-6-(3-methoxy-1-naphthalenyl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-1-piperazinyl)-2-propen-1-one: 1 H NMR (400 MHz, DMSO-d6) δ 8.73(s,1H),7.93(d,J=8.2Hz,1H),7.45-7.54(m,2H),7.25-7.39(m,2H),7.19(d,J=2.5Hz,1H),6.86(dd,J=16.7,10.3Hz,1H),6.19 (dd,J=16.7,2.3Hz,1H),5.77(dd,J=10.5,2.3Hz,1H),3.94(s,3H),3.81-3.94(m,4H),3.69-3.76(m,4H).m / z(ESI,+ve)465.0(M+H) + .

[0237] Step 8: 1-(4-(5-chloro-6-(3-hydroxy-1-naphthalenyl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-1-piperazinyl)-2-propen-1-one. To an ice-cold solution of 1-(4-(5-chloro-6-(3-methoxynaphthalen-1-yl)isothiazolo[3,4-b]pyridin-3-yl)piperazin-1-yl)prop-2-en-1-one (37.3 mg, 0.08 mmol) in 1,2-dichloroethane (4 mL) was added boron tribromide (1.0 M in hexanes, 400 μL, 0.40 mmol) (dropwise), and the resulting mixture was stirred at 0 °C for 2.3 h. Then, aqueous NaHCO (5 mL) was added and extracted with (4:1) DCM:MeOH (2×). The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-6% MeOH in DCM) gave 1-(4-(5-chloro-6-(3-hydroxy-1-naphthalenyl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-1-piperazinyl)-2-propen-1-one: 1 H NMR (400 MHz, DMSO-d6) δ 9.97(br.s,1H),8.72(s,1H),7.79(d,J=8.6Hz,1H),7.42(t,J=7.1Hz,1H),7.17-7.28(m,3H),7.09(d,J=2.1Hz,1H),6.86(dd,J=1 6.7,10.5Hz,1H),6.19(dd,J=16.7,2.3Hz,1H),5.74-5.79(m,1H),3.81-3.95(m,4H),3.68-3.76(m,4H).m / z(ESI,+ve)451.0(M+H) + .

[0238] [Table 43]

[0239] [Table 44]

[0240] [Table 45]

[0241] [Table 46]

[0242] [Table 47]

[0243] Method 3 Example 3-1: 1-(4-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one [ka] Step 1: 1-(4-(6-Bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one. 0.2 M acryloyl chloride (1.240 mL, 0.248 mmol) in DCM was added to an ice-cold solution of 6-bromo-5-chloro-7-fluoro-3-(piperazin-1-yl)benzo[c]isothiazole (Intermediate D, 87 mg, 0.248 mmol) and N,N-diisopropylethylamine (0.129 mL, 0.744 mmol) in dichloromethane (2.3 mL), and the resulting mixture was stirred at 0 °C for 10 min. The mixture was then concentrated in vacuo, and the residue was sonicated in MeOH (2 mL). The suspended solid was collected by filtration, washed with MeOH, and dried under vacuum to give 1-(4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one: 1 H NMR(400MHz,DMSO-d6)δ8.13(1H,d,J=1.56Hz),6.84(1H,dd,J=10.47,16.73Hz),6.1 7(1H,dd,J=2.35,16.63Hz),5.66-5.82(1H,m),3.73-3.93(4H,m),3.55-3.67(4H,m).19 F NMR(376MHz,DMSO-d6)δ-113.39(s,1F).m / z(ESI,+ve)405.8(M+H) + .

[0244] Step 2: 1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one (Intermediate E). A mixture of 1-(4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one (Intermediate D, 79 mg, 0.20 mmol), (3-methoxynaphthalen-1-yl)boronic acid (47.3 mg, 0.234 mmol), tetrakis(triphenylphosphine)palladium (22.5 mg, 0.020 mmol), and sodium carbonate (83 mg, 0.78 mmol) in water (0.500 mL) and 1,4-dioxane (2.0 mL) was heated at 100 ° C. for 16 h. The reaction mixture was then adsorbed onto silica gel and purified by chromatography (silica gel, 0-3% MeOH in DCM) to give 1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one: m / z (ESI, +ve) 482.0 (M+H). + .

[0245] Step 3: 1-(4-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one. Boron tribromide (1.0 M in hexanes, 0.664 mL, 0.664 mmol) was added to an ice-cold solution of 1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one (64 mg, 0.13 mmol) in 1,2-dichloroethane (2.0 mL), and the resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was then added to saturated aqueous sodium bicarbonate (2.0 mL) and extracted with (2:1) DCM / MeOH (10 mL). The organic extract was dried over NaSO, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-3% MeOH in DCM) gave 1-(4-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one: 1 H NMR(400MHz,DMSO-d6)δ9.90-10.04(1H,m),8.10(1H,s),7.80(1H,d,J=8.41 Hz),7.43(1H,ddd,J=1.96,6.11,8.17Hz),7.16-7.31(3H,m),7.07(1H,d,J= 2.35Hz),6.87(1H,dd,J=10.47,16.73Hz),6.19(1H,dd,J=2.25,16.73Hz),5 .77(1H,dd,J=2.25,10.47Hz),3.88(4H,brd,J=19.56Hz),3.61-3.72(4H,m). 19 F NMR(376MHz,DMSO-d6)δ-123.78(s,1F).m / z(ESI,+ve)468.0(M+H) + .

[0246] Alternative synthesis of intermediate E [ka] 1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one (Intermediate E, Alternative Synthesis). To a solution of 6-bromo-3,5-dichloro-7-fluorobenzo[c]isothiazole (Intermediate C, 715 mg, 2.37 mmol) in N,N-dimethylformamide (5.6 mL) was added a solution of 1-(piperazin-1-yl)prop-2-en-1-one bis(2,2,2-trifluoroacetic acid) (961 mg, 2.61 mmol, eNovation Chemicals LLC, Bridgewater, NJ, USA) in N,N-dimethylformamide (5.6 mL) and N,N-diisopropylethylamine (1.243 mL, 7.12 mmol) sequentially. The resulting mixture was stirred at rt for 1 h and then heated at 50 °C for 22 h. After cooling to rt, the reaction mixture was added to ice water (10 mL) and the resulting precipitate was collected by filtration and washed with water. The collected solid was adsorbed onto silica gel and purified by chromatography (silica gel, 0-3% MeOH in DCM) to give 1-(4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one.

[0247] [Table 48]

[0248] [Table 49]

[0249] [Table 50]

[0250] [Table 51]

[0251] [Table 52]

[0252] [Table 53]

[0253] Method 4 Example 4-1: 1-(6-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one. [ka] Step 1: tert-Butyl 6-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate. A mixture of 6-bromo-3,5-dichloro-7-fluorobenzo[c]isothiazole (Intermediate C, 169 mg, 0.562 mmol) and 2-Boc-2,6-diazaspiro[3.3]heptane (212 mg, 1.07 mmol, AstaTech, Inc., Bristol, PA, USA) in DMF (3.5 mL) was stirred at rt for 5 h. Ice water (5 mL) was added, and the resulting mixture was stirred for 15 min. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give tert-butyl 6-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate: 1 H NMR(400MHz,DMSO-d6)δ7.52-7.74(1H,m),4.55(4H,s),4.09(4H,s),1.38(9H,s). 19 F NMR(376MHz,DMSO-d6)δ-113.55(1F,s).m / z(ESI,+ve)464.0(M+1).

[0254] Step 2: 1-(6-(6-Bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one. A hydrogen chloride solution (4 M in 1,4-dioxane, 5.0 mL, 20 mmol) was added to tert-butyl 6-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (249 mg, 0.538 mmol) in methanol (10 mL), and the resulting mixture was stirred at rt for 2 h. The reaction mixture was then concentrated in vacuo to give 6-bromo-5-chloro-7-fluoro-3-(2,6-diazaspiro[3.3]heptan-2-yl)benzo[c]isothiazole: m / z (ESI, +ve) 363.8 (M+1). + .

[0255] To this material was added N,N-diisopropylethylamine (0.281 mL, 1.61 mmol) in dichloromethane (3.0 mL), and the resulting mixture was cooled to 0 °C. Acryloyl chloride (0.2 M in DCM, 2.69 mL, 0.538 mmol) was added, and the resulting mixture was stirred at 0 °C for 10 minutes. The reaction mixture was then concentrated in vacuo, and the residue was purified by chromatography (silica gel, 0 to 10% (3:1) EtOAc / EtOH in DCM) to give 1-(6-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one: 1 H NMR(400MHz,DMSO-d6)δ7.65(1H,d,J=1.4Hz),6.25-6.36(1H,m),6.10(1H,d d,J=17.0,2.3Hz),5.64-5.72(1H,m),4.58(4H,s),4.47(2H,s),4.18(2H,s). 19 F NMR(376MHz,DMSO-d6)δ-113.54(1F,s).m / z(ESI,+ve)418.0(M+H) + .

[0256] Step 3: 1-(6-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one. A mixture of 1-(6-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one (102 mg, 0.245 mmol), (3-methoxynaphthalen-1-yl)boronic acid (59.3 mg, 0.294 mmol), tetrakis(triphenylphosphine)palladium (28.3 mg, 0.024 mmol), and sodium carbonate (104 mg, 0.979 mmol) in water (0.5 mL) and 1,4-dioxane (2.0 mL) was heated at 100 °C for 1 h. The reaction mixture was then adsorbed onto silica gel and purified by chromatography (silica gel, 0-5% MeOH in DCM). The purified material was sonicated in MeOH and the suspended solid was collected by filtration, washed with MeOH and dried under vacuum to give 1-(6-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one: 1 H NMR(400MHz,DMSO-d6)δ7.93(1H,d,J=8.4Hz),7.67(1H,s),7.45-7.57(2H,m),7.23-7.36(2H,m),7.16(1H,d,J=2.5Hz),6. 27-6.39(1H,m),6.11(1H,dd,J=17.0,2.2Hz),5.65-5.76(1H,m),4.58-4.67(4H,m),4.50(2H,s),4.22(2H,s),3.93(3H,s). 19 F NMR(376MHz,DMSO-d6)δ-123.88(1F,s).m / z(ESI,+ve)494.0(M+H) + .

[0257] Step 4: 1-(6-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one. Boron tribromide (1.0 M in hexanes, 0.638 mL, 0.638 mmol) was added to 1-(6-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one (63 mg, 0.128 mmol) in ice-cold 1,2-dichloroethane (2.0 mL), and the resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was then added to saturated aqueous sodium bicarbonate (2.0 mL), and the resulting mixture was extracted with (2:1) DCM:MeOH (10 mL). The organic extract was dried over NaSO, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0–2% MeOH in DCM (with 2 M ammonia)) gave 1-(6-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one: 1 H NMR(400MHz,DMSO-d6)δ9.82-10.04(1H,m),7.79(1H,d,J=8.2Hz),7.66(1H,s),7.43(1H,dt,J=8.3,4.0Hz),7.26(1H,d,J=2.3Hz),7.22(2H,d,J =3.7Hz),7.05(1H,d,J=2.3Hz),6.26-6.38(1H,m),6.12(1H,dd,J=16.8, 2.2Hz),5.66-5.72(1H,m),4.58-4.67(4H,m),4.50(2H,s),4.22(2H,s). 19 F NMR(376MHz,DMSO-d6)δ-123.98(1F,s).m / z(ESI,+ve)480.0(M+H) + .

[0258] [Table 54]

[0259] [Table 55]

[0260] Method 5 Example 5-1: N-(1-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-azetidinyl)-N-methyl-2-propenamide [ka] Step 1: 2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzamide. A mixture of (3-methoxynaphthalen-1-yl)boronic acid (2.04 g, 10.1 mmol), 2-amino-4-bromo-5-chloro-3-fluorobenzamide (Intermediate B (1.93 g, 7.20 mmol), tetrakis(triphenylphosphine)palladium (0.832 g, 0.720 mmol), sodium carbonate (1.2 mL, 28.8 mmol) and 1,4-dioxane (38.4 mL) in water (9.6 mL) was heated at 90 °C for 2 days. The reaction mixture was then filtered through a pad of Celite and washed with EtOAc. The filtrate was diluted with saturated aqueous NaHCO (50 mL) and EtOAc was added. The residue was suspended in MeOH (5 mL), and the suspended solid was collected by filtration, washed with MeOH, and dried to give 2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzamide. Chromatographic purification of the concentrated filtrate (silica gel, 0% to 100% (3:1) EtOAc-EtOH in heptane) afforded additional 2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzamide. 1H NMR(400MHz,DMSO-d6)δ8.01-8.17(m,1H),7.92(d,J=8.2Hz,1H),7.75(s,1H),7.43-7.55(m,3H ),7.23-7.34(m,2H),7.10(d,J=2.5Hz,1H),6.73(s,2H),3.93(s,3H).m / z(ESI,+ve)345.0(M+H) + .

[0261] Step 2: 2-Amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzothioamide. To a solution of 2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzamide (2.11 g, 6.12 mmol) in tetrahydrofuran (41 mL) was added Lawesson's reagent (1.49 mL, 3.67 mmol), and the resulting mixture was stirred at rt for 1 h. The reaction mixture was then diluted with EtOAc (60 mL) and washed sequentially with 2 M aqueous HCl (60 mL), saturated aqueous NaHCO (60 mL), and brine (60 mL). The organic extract was dried over NaSO, filtered, and concentrated in vacuo. The residue was sonicated in DCM (5 mL), and the resulting precipitate was collected by filtration, washed with DCM, and dried in vacuo to give 2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzothioamide. Chromatographic purification of the filtrate (silica gel, 0% to 100% (3:1) EtOAc-EtOH in heptane) gave additional 2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzothioamide: m / z (ESI, +ve) 361.0 (M+H). + .

[0262] Step 3: 5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-amine. Hydrogen peroxide solution (30% in water, 2.2 mL, 21.3 mmol) was slowly added to an ice-cold solution of 2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzothioamide (1.92 g, 5.33 mmol) in pyridine (18 mL). The resulting mixture was warmed to RT and stirred at RT for 18 h. The reaction mixture was then diluted with water (60 mL), and the resulting precipitate was collected by filtration, washed successively with water and MeOH, and dried under vacuum to give 5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-amine: 1 H NMR(400MHz,DMSO-d6)δ8.14(s,2H),7.99-8.03(m,1H),7.93(d,J=8.3Hz,1H),7.48-7.55 (m,1H),7.47(d,J=2.3Hz,1H),7.31(d,J=3.9Hz,2H),7.16(d,J=2.5Hz,1H),3.94(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-124.71(s,1F).m / z(ESI,+ve)359.0(M+H) + .

[0263] Step 4: 3,5-Dichloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazole. 5-Chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-amine (1.55 g, 4.31 mmol) was added portionwise over 15 minutes to a suspension of copper(II) chloride (0.870 g, 6.47 mmol) and tert-butyl nitrite (0.77 mL, 6.47 mmol) in acetonitrile (43 mL) at 65°C. The resulting mixture was stirred at 65°C for 30 minutes, then cooled to ambient temperature and diluted with ice water (50 mL). The precipitated solid was collected by filtration, washed with water, and dried under vacuum. The residue was sonicated in DCM (10 mL), and the suspended solid was collected by filtration, washed with DCM, and dried under vacuum to recover unreacted 5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-amine. The filtrate was concentrated in vacuo to give 3,5-dichloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazole. 1 H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.96(d,J=8.2Hz,1H),7.49-7.56(m,2H),7.28-7.36(m,2H),7.24-7.28(m,1H),3.95(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-122.17(s,1F).m / z(ESI,+ve)378.0(M+H) + .

[0264] Step 5: tert-Butyl (1-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)azetidin-3-yl)(methyl)carbamate. A mixture of 3,5-dichloroacetic acid-derived 7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazole (100 mg, 0.264 mmol), DIPEA (0.14 mL, 0.793 mmol), and 3-Boc-3-methylaminoazatidine (0.098 mL, 0.529 mmol, Beta Pharma Scientific, Inc.) in DMF (1.3 mL) was stirred at rt for 18 h. Ice water (3 mL) was then added, and the resulting mixture was stirred for 15 min. The precipitated solid was then collected by filtration, washed with water, and dried under vacuum to give tert-butyl (1-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)azetidin-3-yl)(methyl)carbamate: m / z (ESI, +ve) 528.0 (M+H). + .

[0265] Step 6: N-(1-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-azetidinyl)-N-methyl-2-propenamide. The title compound was prepared from tert-butyl (1-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)azetidin-3-yl)(methyl)carbamate (131.1 mg, 0.248 mmol) in three steps according to the procedure reported in Method 1, Step 8: 1H NMR(400MHz,DMSO-d6)δ9.89-10.10(m,1H),7.79(d,J=8.4Hz,1H),7.73(s, 1H),7.43(ddd,J=8.2,5.1,2.9Hz,1H),7.20-7.30(m,3H),7.05(d,J=2.2Hz ,1H),6.81(dd,J=16.7,10.5Hz,1H),6.10-6.23(m,1H),5.69-5.81(m,1H), 5.37-5.59(m,1H),4.63-4.74(m,3H),4.53-4.61(m,1H),3.14-3.23(m,3H). 19 F NMR(376MHz,DMSO-d6)δ-124.10(s,1F).m / z(ESI,+ve)468.0(M+H) + .

[0266] [Table 56]

[0267] [Table 57]

[0268] Method 6 Example 6-1: 1-(4-(6-(6-amino-3-chloro-2-pyridinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one [ka] Step 1: tert-Butyl 4-(5-chloro-7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate. A mixture of tert-butyl 4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate (Intermediate D, 1.10 g, 2.45 mmol), bis(pinacolato)diboron (1.86 g, 7.34 mmol), potassium acetate (0.61 mL, 9.8 mmol), and Pd(dppf)Cl·DCM (0.537 g, 0.734 mmol) in 1,4-dioxane (12 mL) was heated at 100 °C for 40 h. The reaction mixture was then concentrated in vacuo and purified by chromatography (silica gel, 0% to 100% (3:1) EtOAc-EtOH in heptane) to give tert-butyl 4-(5-chloro-7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate: 1 H NMR(400MHz,DMSO-d6)δ7.85(s,1H),3.59(brd,J=4.7Hz,4H),3.44-3.54(m,4H),1.43(s,9H),1.35(s,5H),1.15(s,7H). 19 F NMR(376MHz,DMSO-d6)δ-125.11(s,1F).m / z(ESI,+ve)498.0(M+H) + .

[0269] Step 2: tert-Butyl 4-(6-(6-amino-3-chloropyridin-2-yl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate. A mixture of tert-butyl 4-(5-chloro-7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate (99.5 mg, 0.200 mmol), SPhos Pd G3 (17.3 mg, 0.020 mmol), 6-bromo-5-chloropyridin-2-amine (Combi-blocks Inc., San Diego, CA, USA, 124 mg, 0.6 mmol), sodium carbonate (85 mg, 0.80 mmol) and 1,2-DCE (0.75 mL) in water (0.25 mL) was heated at 50 °C for 2 h. The reaction mixture was concentrated in vacuo and purified by chromatography (silica gel, 0% to 100% (3:1) EtOAc-EtOH in heptane) to give tert-butyl 4-(6-(6-amino-3-chloropyridin-2-yl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate: m / z (ESI, +ve) 498.0 (M+H). + .

[0270] Step 3: 1-(4-(6-(6-amino-3-chloro-2-pyridinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one. The title compound was prepared from tert-butyl 4-(6-(6-amino-3-chloropyridin-2-yl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate (31.6 mg, 0.063 mmol) in two steps following the procedure reported in Method 1, Step 8: 1H NMR(400MHz,DMSO-d6)δ7.97-8.10(m,1H),7.60(d,J=8.9Hz,1H),6.86(dd,J=16.6,10.6Hz,1H),6.57(d,J=8.9Hz,1 H),6.38(s,2H),6.19(dd,J=16.8,2.3Hz,1H),5.71-5.84(m,1H),3.86(brd,J=19.9Hz,4H),3.63(brd,J=1.0Hz,4H). 19 F NMR(376MHz,DMSO-d6)δ-126.04(s,1F).m / z(ESI,+ve)452.0(M+H) + .

[0271] [Table 58]

[0272] Method 7 Example 7-1: 1-((3R)-4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-(difluoromethyl)-1-piperazinyl)-2-propen-1-one | 1-((3S)-4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-(difluoromethyl)-1-piperazinyl)-2-propen-1-one [ka] Step 1: 2-Amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzoic acid. Prepared from intermediate A using a procedure similar to that described in Method 1, step 7: m / z (ESI, +ve) 346.0 (M+H) + .

[0273] Step 2: tert-Butyl 4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzoyl)-3-(difluoromethyl)piperazine-1-carboxylate. A mixture of 2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzoic acid (0.150 g, 0.434 mmol), TBTU (0.188 g, 0.586 mmol), tert-butyl 3-(difluoromethyl)piperazine-1-carboxylate (0.123 g, 0.521 mmol), and DIPEA (0.23 mL, 1.302 mmol) in DMF (4 mL) was stirred at ambient temperature for 3 h. The reaction mixture was then washed with saturated aqueous NaHCO, and the aqueous washes were extracted with EtOAc. The organic layer was then dried over NaSO, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-40% EtOAc / heptane) gave tert-butyl 4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzoyl)-3-(difluoromethyl)piperazine-1-carboxylate: m / z (ESI, +ve) 586 (M+Na). + .

[0274] Step 3: tert-Butyl 4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)phenylcarbonothioyl)-3-(difluoromethyl)piperazine-1-carboxylate. Lawesson's reagent (0.041 mL, 0.10 mmol) was added to a solution of tert-butyl 4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzoyl)-3-(difluoromethyl)piperazine-1-carboxylate (0.095 g, 0.168 mmol) in THF (4 mL), and the resulting mixture was stirred at 50 °C for 18 h. The reaction mixture was then concentrated in vacuo and purified by column chromatography (silica gel, 0-30% EtOAc / heptane) to give tert-butyl 4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)phenylcarbonothioyl)-3-(difluoromethyl)piperazine-1-carboxylate: m / z (ESI, +ve) 602.2 (M+Na). + .

[0275] Step 4: tert-Butyl 4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-3-(difluoromethyl)piperazine-1-carboxylate. NBS (0.022 g, 0.17 mmol) was added to a solution of tert-butyl 4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)phenylcarbonothioyl)-3-(difluoromethyl)piperazine-1-carboxylate in THF (7 mL), and the resulting mixture was stirred at ambient temperature for 15 minutes. The reaction mixture was diluted with water and washed with 10% sodium thiosulfate. The aqueous washes were extracted with EtOAc, then the combined organic layers were concentrated in vacuo to give tert-butyl 4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-3-(difluoromethyl)piperazine-1-carboxylate: m / z (ESI, +ve) 578.2 (M+H). + .

[0276] Step 5: 1-((3R)-4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-(difluoromethyl)-1-piperazinyl)-2-propen-1-one | 1-((3S)-4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-(difluoromethyl)-1-piperazinyl)-2-propen-1-one. Prepared using a procedure similar to that described in Method 1, Step 8: 1 H NMR(400MHz,DMSO-d6)δ10.13(br.s.,1H)8.12(d,J=2.2Hz,1H)7.80(d,J=8.2Hz,1H )7.43(brt,J=7.0Hz,1H)7.20-7.30(m,3H)7.08(dd,J=5.8,2.2Hz,1H)6.78-6.91(m ,1H)6.27-6.70(m,1H)6.20(dd,J=16.6,2.0Hz,1H)5.76-5.84(m,1H)4.73-4.87(m, 1H)4.19-4.72(m,2H)3.55-3.90(m,3H)3.36-3.47(m,1H).m / z(ESI,+ve)518.0(M+H) + .

[0277] [Table 59]

[0278] Method 8 Example 8-1: 6-chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-propenoyl)-1-piperazinyl)-2(1H)-quinazolinone [ka] Step 1: 4-Bromo-5-chloro-2-fluorobenzamide. A mixture of 4-bromo-5-chloro-2-fluorobenzoic acid (23.3 g, 92 mmol) in thionyl chloride (67 mL, 0.92 mol) was stirred at 70 °C for 1 h under a reflux condenser. The reaction mixture was then concentrated in vacuo, and the residue was taken up in 1,4-dioxane (200 mL), treated with ammonium hydroxide (30% aqueous solution, 82 mL, 0.64 mol), and stirred at rt for 15 min. The reaction mixture was concentrated in vacuo to give 4-bromo-5-chloro-2-fluorobenzamide: m / z (ESI, +ve) 251.8 (M+H). + .

[0279] Step 2: 4-Bromo-5-chloro-2-fluoro-N-((2-isopropylphenyl)carbamoyl)benzamide. A mixture of 4-bromo-5-chloro-2-fluorobenzamide (5.90 g, 23.4 mmol) and oxalyl chloride (1 M in DCM; 12.9 mL, 25.7 mmol) in DCE (100 mL) was stirred at 80° C. for 1 h under a reflux condenser. The reaction mixture was then cooled to rt, and 2-isopropylaniline (6.62 mL, 46.7 mmol) was added. The resulting mixture was stirred at rt for 15 min and then cooled to 0° C. The precipitated solid was removed by filtration, and the collected filtrate was concentrated in vacuo to give 4-bromo-5-chloro-2-fluoro-N-((2-isopropylphenyl)carbamoyl)benzamide: 1 H NMR(400MHz,DMSO-d6)δ11.06(br.s.,1H)10.31(s,1H)7.97-8.05(m,2H)7.82(d,J=7.2H z,1H)7.32-7.38(m,1H)7.14-7.25(m,2H)3.11(spt,J=6.8Hz,1H)1.24(d,J=6.8Hz,6H). 19 F NMR(376MHz,DMSO-d6)δ-113.6(s,1F).m / z(ESI,+ve)412.7 and 414.6(M+H) + .

[0280] Step 3: 7-Bromo-6-chloro-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione (Intermediate F). KHMDS (1 M in THF, 8.30 mL, 8.30 mmol) was added to a mixture of 4-bromo-5-chloro-2-fluoro-N-((2-isopropylphenyl)carbamoyl)benzamide (1.56 g, 3.77 mmol) in THF (19 mL) at −20° C., and the resulting mixture was allowed to warm to rt over 1 h. The reaction mixture was then diluted with EtOAc (150 mL) and washed with saturated aqueous ammonium chloride solution (2×100 mL). The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was suspended in DCM (5 mL), sonicated, collected by filtration, and dried under vacuum to give 7-bromo-6-chloro-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione: 1 H NMR(400MHz,CDCl3)δ9.43(br.s.,1H)8.29(s,1H)7.55-7.59(m,2H)7.39-7.44(m,1H)7.16(d,J=7.8Hz,1H )6.75(s,1H)2.59-2.77(m,1H)1.17-1.24(m,3H)1.11(d,J=6.8Hz,3H).m / z(ESI,+ve)392.9 and 395.0(M+H) + .

[0281] Step 4: 6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione. A mixture of 7-bromo-6-chloro-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione (Intermediate F, 1.17 g, 2.96 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (2.02 g, 11.9 mmol), SPhos Pd G3 (0.128 g, 0.148 mmol), and potassium carbonate (2 M aqueous solution, 4.45 mL, 8.90 mmol) in DME (30 mL) was stirred at 85 °C for 16 h. The reaction mixture was then diluted with EtOAc (150 mL) and washed with saturated aqueous NaHCO3 (3 × 100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-50% EtOAc in heptane) gave 6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione: 1 H NMR(400MHz,DMSO-d6)δ11.90(d,J=1.2Hz,1H)8.11(d,J=3.3Hz,1H)7.53-7.5 9(m,1H)7.48(tt,J=7.0,2.2Hz,1H)7.38-7.44(m,1H)7.32-7.37(m,2H)6.93( dd,J=8.4,4.3Hz,1H)6.86(t,J=8.7Hz,1H)6.15(s,1H)3.66(d,J=30Hz,3H)2. 73(dq,J=14.2,7.0Hz,1H)1.11(t,J=7.1Hz,3H)1.03(dd,J=12.7,6.8Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-113.8(s,1F)-115.2(s,1F).m / z(ESI,+ve)439.1(M+H) + .

[0282] Step 5: 4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one. To a solution of 6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2,4(1H,3H)-dione (0.395 g, 0.900 mmol) and EtN (0.753 mL, 5.40 mmol) in acetonitrile (9 mL) was added phosphorus oxychloride (0.503 mL, 5.40 mmol), and the resulting solution was stirred at 80 °C for 1.5 h. The reaction mixture was concentrated in vacuo to give 4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one: m / z (ESI, +ve) 457.1 (M+H). + .

[0283] Alternative procedure for Step 5 (used as indicated in the table below): To a stirred mixture of the product from Step 4 (1.0 equiv.), triethylamine (18.0 equiv.), and 1H-benzo[d][1,2,3]triazole (12 equiv.) in acetonitrile (0.07 M) was added phosphorus oxychloride (6.0 equiv.), and the resulting reaction mixture was stirred at 80° C. for 3.5 h. The reaction mixture was then slowly poured into vigorously stirred water (100 mL) at 10° C. The aqueous suspension was stirred for 15 min and then extracted with EtOAc (100 mL). The organic layer was washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the benzotriazole adduct intermediate, which was used directly in Step 6.

[0284] Step 6: tert-Butyl 4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate. A solution of 4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one (obtained from Method 8, Step 5), tert-butyl piperazine-1-carboxylate (0.335 g, 1.80 mmol), and EtN (0.753 mL, 5.40 mmol) in DCE (9 mL) was stirred at 60° C. for 20 minutes. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO (3×75 mL). The organic layer was dried over NaSO and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 60% (3:1) EtOAc-EtOH in heptane) gave tert-butyl 4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate: m / z (ESI, +ve) 607.3 (M+H). + .

[0285] Note: When (S)-1-(3-methylpiperazin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetic acid was used, the synthesis was as follows:

[0286] (S)-1-(3-Methylpiperazin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetic acid [ka]

[0287] Step 6-a: (S)-tert-Butyl 4-acryloyl-2-methylpiperazine-1-carboxylate. Acryloyl chloride (1.34 mL, 16.5 mmol) was added to a solution of (S)-1-boc-2-methyl-piperazine (3.00 g, 15.0 mmol, Boc Sciences, Shirley, NY) in THF (30.0 mL) at −10° C., and the resulting mixture was stirred at −10° C. for 15 minutes. Triethylamine (6.26 mL, 44.9 mmol) was then added slowly, and the resulting mixture was stirred at −10° C. for 15 minutes, then warmed to rt. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO. The aqueous layer was extracted with EtOAc (3×), and the combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc in heptane) gave (S)-tert-butyl 4-acryloyl-2-methylpiperazine-1-carboxylate: 1 H NMR(400MHz,DMSO-d6)δ6.72-6.85(m,1H)6.10-6.18(m,1H)5.68-5.76(m,1H)4.08-4.32(m,2H)3.68-4.03 (m,2H)2.86-3.14(m,2H)2.66-2.80(m,1H)1.38-1.43(s,9H)0.96-1.04(m,3H).m / z(ESI,+ve)277.3(M+Na) + .

[0288] Step 6-b: (S)-1-(3-methylpiperazin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetic acid A mixture of (S)-tert-butyl 4-acryloyl-2-methylpiperazine-1-carboxylate (3.21 g, 12.62 mmol) and TFA (4.7 mL, 63.1 mmol) in DCM (16 mL) was stirred at rt for 24 h. The reaction mixture was then concentrated in vacuo to give (S)-1-(3-methylpiperazin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetic acid: 1H NMR(400MHz,DMSO-d6)δ8.70-8.99(m,1H)6.74-6.91(m,1H)6.12-6.26(m,1H)5.70-5.84(m,1H)4.25-4.44(m,1H)4 .07-4.25(m,1H)3.49-3.53(m,1H)3.22-3.32(m,2H)2.92-3.08(m,2H)1.14-1.29(m,3H).m / z(ESI,+ve)155.1(M+H) + .

[0289] Step 7: 6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl)quinazolin-2(1H)-one. A solution of tert-butyl 4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate (0.594 g, 0.978 mmol) in TFA (4 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated in vacuo to give 6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl)quinazolin-2(1H)-one: m / z (ESI, +ve) 507.2 (M+H). + .

[0290] Step 8: 4-(4-Acryloylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one. To a solution of 6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl)quinazolin-2(1H)-one and DIPEA (0.85 mL, 4.9 mmol) in DCM (10 mL) was added acryloyl chloride (0.079 mL, 0.98 mmol) at 0° C., and the resulting mixture was stirred at 0° C. for 30 minutes. The reaction mixture was then diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO (3×75 mL). The organic layer was dried over NaSO, decanted, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% (3:1) EtOAc-EtOH in heptane) gave 4-(4-acryloylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one: 1 H NMR(400MHz,CDCl3)δ7.86(d,J=1.2Hz,1H)7.41-7.54(m,2H)7.29-7.37(m,2H)7. 14(dt,J=7.8,1.7Hz,1H)6.70-6.79(m,2H)6.58-6.68(m,1H)6.50(d,J=7.4Hz,1H) 6.39(dd,J=16.8,1.8Hz,1H)5.75-5.84(m,1H)3.79-4.06(m,8H)3.75(s,2H)3.66 (s,1H)2.69(tt,J=13.4,6.8Hz,1H)1.20-1.24(m,3H)1.07(dd,J=6.8,3.9Hz,3H). 19 F NMR(377MHz,CDCl3)δ-113.05(s,1F)-113.55(s,1F).m / z(ESI,+ve)561.2(M+H) + .

[0291] Step 9: 6-Chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-propenoyl)-1-piperazinyl)-2(1H)-quinazolinone. BBr3 (1 M in DCE, 3.3 mL, 3.3 mmol) was added to an ice-cold solution of 4-(4-acryloylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one (0.372 g, 0.663 mmol) in DCE (1.7 mL), and the resulting mixture was stirred at 0 °C for 20 min, then warmed to rt and stirred at rt for 2 h. To the reaction mixture was added saturated aqueous NaHCO3, followed by EtOAc (150 mL). The organic layer was separated and washed with saturated aqueous NaHCO (3 x 100 mL). The organic layer was then dried over NaSO, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% (3:1) EtOAc-EtOH in heptane) gave 6-chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-propenoyl)-1-piperazinyl)-2(1H)-quinazolinone: 1 H NMR(400MHz,DMSO-d6)δ10.06(br.d.,J=15.1Hz,1H)8.03(d,J=1.2Hz,1H)7. 51-7.56(m,1H)7.45(t,J=7.6Hz,1H)7.33(tdd,J=7.5,7.5,3.8,1.4Hz,1H)7. 14-7.25(m,2H)6.84(dd,J=16.8,10.4Hz,1H)6.62-6.74(m,2H)6.14-6.26(m ,2H)5.71-5.78(m,1H)3.71-3.99(m,8H)2.52-2.59(m,1H)1.02-1.12(m,6H). 19 F NMR(377MHz,DMSO-d6)δ-113.6(s,1F)-114.8(s,1F).m / z(ESI,+ve)547.1(M+H) + .

[0292] [Table 60]

[0293] [Table 61]

[0294] Method 9 Example 9-1: 6-chloro-7-(2,3-dichloro-5-hydroxyphenyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)-1-(2-(2-propanyl)phenyl)-2(1H)-quinazolinone [ka] Step 1: 7-Bromo-4,6-dichloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one. To a mixture of 7-bromo-6-chloro-1-(2-isopropylphenyl)quinazolin-2,4(1H,3H)-dione (Intermediate F, 470 mg, 1.194 mmol) and DIPEA (0.623 mL, 3.58 mmol) in acetonitrile (11.4 mL) was added phosphorus oxychloride (0.915 mL, 5.97 mmol). The resulting mixture was heated at 80° C. for 2 h, then cooled to ambient temperature and concentrated in vacuo to give 7-bromo-4,6-dichloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one: m / z (ESI, +ve) 413.0 (M+H). + .

[0295] Step 2: (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-bromo-6-chloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one. A mixture of 7-bromo-4,6-dichloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one (492 mg, 1.19 mmol), (S)-4-N-boc-2-methylpiperazine (478 mg, 2.39 mmol), and DIPEA (0.623 mL, 3.58 mmol) in DMF (2.3 mL) was stirred at rt for 10 min. Ice water (10 mL) was then added, and the resulting mixture was stirred for 15 min. The precipitated solid was collected by filtration, washed with water, and dried under vacuum to give (S)-tert-butyl 4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate: m / z (ESI, +ve) 577.1 (M+H). + .

[0296] TFA (2.0 mL, 26.8 mmol) was added to a solution of (S)-tert-butyl 4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (297 mg, 0.516 mmol) in DCM (2.0 mL), and the resulting mixture was stirred at rt for 15 min. The resulting mixture was concentrated in vacuo to give (S)-7-bromo-6-chloro-1-(2-isopropylphenyl)-4-(2-methylpiperazin-1-yl)quinazolin-2(1H)-one: m / z (ESI, +ve) 477.0 (M+H). + .

[0297] Acryloyl chloride (0.258 M in DCM, 4.0 mL, 1.031 mmol) was added to an ice-cold mixture of (S)-7-bromo-6-chloro-1-(2-isopropylphenyl)-4-(2-methylpiperazin-1-yl)quinazolin-2(1H)-one and DIPEA (0.269 mL, 1.547 mmol) in DCM (2.0 mL), and the resulting mixture was stirred for 20 min at 0° C. Concentration in vacuo followed by chromatographic purification of the residue (silica gel, 0 to 100% (3:1) EtOAc-EtOH in heptane) gave (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-bromo-6-chloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one: 1 H NMR(400MHz,DMSO-d6)δ7.91-8.08(m,1H),7.49-7.67(m,2H),7.41(brd,J=5.8Hz,1H),7.21( brs,1H),6.76-6.98(m,1H),6.52-6.67(m,1H),6.09-6.29(m,1H),5.75(brs,1H),4.61-4.96( m,1H),4.23-4.48(m,1H),3.93-4.21(m,2H),3.50-3.77(m,1H),3.33-3.49(m,1H),3.23-3.28 (m,1H),2.94-3.24(m,1H),1.27(brd,J=9.3Hz,6H),1.09(brs,3H).m / z(ESI,+ve)531.1(M+H) + .

[0298] Step 3: (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-chloro-7-(2,3-dichloro-5-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one. A mixture of (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-bromo-6-chloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one (120 mg, 0.226 mmol), 2-(2,3-dichloro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (82 mg, 0.272 mmol), NaCO (96 mg, 0.906 mmol), and Pd(PPh) (26.2 mg, 0.023 mmol) in 1,4-dioxane (1.6 mL) and water (0.4 mL) was heated at 90 °C for 17 h. The reaction mixture was then concentrated in vacuo and purified by chromatography (silica gel, 0 to 100% (3:1) EtOAc-EtOH in heptane) to give (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-chloro-7-(2,3-dichloro-5-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one: m / z (ESI, +ve) 627.0 (M+H). + .

[0299] Step 4: 6-Chloro-7-(2,3-dichloro-5-hydroxyphenyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)-1-(2-(2-propanyl)phenyl)-2(1H)-quinazolinone. BBr3 (1 M in hexanes, 0.32 mL, 0.320 mmol) was added to an ice-cold mixture of (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-chloro-7-(2,3-dichloro-5-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one (40 mg, 0.064 mmol) and DCE (1.0 mL), and the resulting mixture was stirred at 0 °C for 30 min. Saturated aqueous NaHCO3 (2.0 mL) was added, and the resulting mixture was extracted with (2:1) DCM / MeOH (5 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% MeOH in DCM) gave 6-chloro-7-(2,3-dichloro-5-hydroxyphenyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)-1-(2-(2-propanyl)phenyl)-2(1H)-quinazolinone: 1 H NMR(400MHz,DMSO-d6)δ10.42(brd,J=17.0Hz,1H),7.86-8.11(m,1H),7.50-7.63(m,1H),7.47(brt,J=6 .0Hz,1H),7.36(t,J=7.5Hz,1H),7.15-7.26(m,1H),7.05(d,J=2.3Hz,1H),6.78-6.96(m,1H),6.44-6.5 8(m,1H),6.11-6.29(m,2H),5.71-5.82(m,1H),4.68-4.98(m,1H),3.96-4.52(m,3H),3.52-3.85(m,2H) ,3.34-3.51(m,1H),2.95-3.26(m,1H),1.27-1.41(m,3H),0.95-1.13(m,6H).m / z(ESI,+ve)611.0(M+H) + .

[0300] [Table 62]

[0301] [Table 63]

[0302] [Table 64]

[0303] [Table 65]

[0304] [Table 66]

[0305] [Table 67]

[0306] Method 10 Example 10-1: 1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(2-methylphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one. [ka] Step 1: 6,7-Dichloro-2,3-dihydrophthalazine-1,4-dione (Intermediate G). Hydrazine (0.232 mL, 10.1 mmol) was added to a mixture of 5,6-dichloroisobenzofuran-1,3-dione (2.00 g, 9.22 mmol, TCI America, Portland, OR, USA) and ethanol (30 mL). The resulting mixture was heated at reflux for 2 h and then cooled to rt. The resulting precipitate was collected by filtration and washed with water to give 6,7-dichloro-2,3-dihydrophthalazine-1,4-dione: m / z (ESI, +ve) 231.1 (M+H). + .

[0307] Step 2: 6-chloro-7-(2-fluoro-6-hydroxyphenyl)-2,3-dihydrophthalazine-1,4-dione. A mixture of 6,7-dichloro-2,3-dihydrophthalazine-1,4-dione (Intermediate G, 3.80 g, 16.45 mmol), 2-fluoro-6-hydroxyphenylboronic acid (10.26 g, 65.8 mmol, Combi-blocks Inc., San Diego, CA, USA), SPhos Pd G3 (1.423 g, 1.645 mmol), and 2 M aqueous NaCO3 (32.9 mL, 65.8 mmol) in DME (60 mL) was stirred at 80 °C for 16 h. The reaction mixture was cooled to rt and diluted with water (200 mL) and EtOAc (300 mL). The aqueous layer was separated, acidified with 5 N HCl, and extracted with EtOAc (300 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was suspended in DCM (50 mL) and collected by filtration to give 6-chloro-7-(2-fluoro-6-hydroxyphenyl)-2,3-dihydrophthalazine-1,4-dione: m / z (ESI, +ve) 307.0 (M+H). + .

[0308] Step 3: 6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-2,3-dihydrophthalazine-1,4-dione. tert-Butyl(chloro)diphenylsilane (2.67 mL, 10.25 mmol) was added to an ice-cold mixture of 6-chloro-7-(2-fluoro-6-hydroxyphenyl)-2,3-dihydrophthalazine-1,4-dione (2.62 g, 8.54 mmol) and TEA (4.75 mL, 34.2 mmol) in acetonitrile (40 mL), and the resulting mixture was stirred at 0° C. for 15 min, then warmed to rt and stirred for 1.5 h. Additional tert-butyl(chloro)diphenylsilane (2.67 mL, 10.25 mmol) was added, and the resulting mixture was stirred at rt for 16 h. The reaction mixture was then diluted with water (300 mL), acidified with 5N HCl, and extracted with EtOAc (300 mL). The organic layer was separated and washed successively with brine (250 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was taken up in DCM (200 mL), TFA (20 mL) was added, and the resulting mixture was stirred at rt for 45 min. The reaction mixture was then diluted with saturated aqueous NaHCO3 (200 mL) and extracted with DCM (2 x 250 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give 6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-2,3-dihydrophthalazine-1,4-dione: m / z (ESI, +ve) 545.2 (M+H). + .

[0309] Step 4: 6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-1,4,7-trichlorophthalazine. Pyridine (1.45 mL, 17.1 mmol) was added to a mixture of 6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-2,3-dihydrophthalazine-1,4-dione (4.66 g, 8.55 mmol) and phosphorus oxychloride (6.39 mL, 68.4 mmol), and the resulting mixture was heated at 100° C. for 1.5 h. The reaction mixture was then cooled to rt and slowly poured into stirred water (300 mL), maintaining the internal temperature at <10° C. After stirring for 15 min, the resulting mixture was extracted with EtOAc (400 mL), and the organic extract was successively washed with brine (250 mL), dried over MgSO, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-25% EtOAc in heptane) gave 6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-1,4,7-trichlorophthalazine: m / z (ESI, +ve) 581.1 (M+H). + .

[0310] Step 5: tert-Butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate (Intermediate H). 1-Boc-piperazine (5.00 g, 26.9 mmol) was added to a mixture of 6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-1,4,7-trichlorophthalazine (5.21 g, 8.95 mmol) and triethylamine (3.77 mL, 26.9 mmol) in DCM (35 mL), and the resulting mixture was stirred at rt for 19 h. The reaction mixture was then partitioned between DCM (300 mL) and saturated aqueous NaHCO (200 mL). The organic layer was separated, dried over MgSO, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 50% EtOAc in heptane) gave a mixture of tert-butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate and tert-butyl 4-(7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,6-dichlorophthalazin-1-yl)piperazine-1-carboxylate. The individual regioisomers were isolated by chiral SFC purification (OJ-H column (30 × 250 mm, 5 μm), 15% (20 mM NH in methanol) in supercritical CO to give tert-butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate as the second eluting isomer: 1 H NMR(400MHz,CDCl3)δ8.27(s,1H)8.17(s,1H)7.56-7.61(m,4H)7.40-7.46(m,2H)7.31-7.37(m,4H)6.99-7.07(m,1H)6.77(t ,J=8.61Hz,1H)6.42(d,J=8.22Hz,1H)3.72-3.77(m,4H)3.53-3.59(m,4H)1.51(s,9H)0.66(s,9H).m / z(ESI,+ve)731.2(M+H) + .

[0311] Step 6: 6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichloro-1-(piperazin-1-yl)phthalazine. Trifluoroacetic acid (2 mL, 26.8 mmol) was added to a stirred solution of tert-butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate (Intermediate H, 1.21 g, 1.654 mmol) in DCM (10 mL), and the resulting mixture was stirred at rt for 1.5 h. The reaction mixture was then diluted with saturated aqueous NaHCO (75 mL) and extracted with DCM (2 × 100 mL). The combined organic extracts were dried over MgSO, filtered, and concentrated in vacuo to give 6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichloro-1-(piperazin-1-yl)phthalazine: m / z (ESI, +ve) 631.3 (M+H). + .

[0312] Step 7: 1-(4-(6-(2-(tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one. Acryloyl chloride (0.148 mL, 1.81 mmol) was added to a mixture of 6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichloro-1-(piperazin-1-yl)phthalazine (1.04 g, 1.647 mmol) and triethylamine (0.694 mL, 4.94 mmol) in DCM (10 mL), and the resulting mixture was stirred at rt for 45 min. Saturated aqueous NaHCO3 (75 mL) was added, and the resulting mixture was extracted with DCM (3 × 100 mL). The combined organic extracts were dried over MgSO, filtered, and concentrated in vacuo to give 1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one: m / z (ESI, +ve) 685.1 (M+H).+ .

[0313] Step 8: 1-(4-(4,7-Dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one (Intermediate I). TBAF (1 M in THF, 3.3 mL, 3.30 mmol) was added to a solution of 1-(4-(6-(2-(tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one (1.13 g, 1.648 mmol) in THF (10 mL), and the resulting mixture was stirred at rt for 15 min. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silica gel, 0-100% EtOAc in heptane) to give 1-(4-(4,7-dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one: 1 H NMR(400MHz,DMSO-d6)δ10.26(brs,1H)8.31(s,1H)8.14(s,1H)7.31-7.40(m,1H)6.78-6.92(m,3H)6.17(dd,J=1 6.63,2.35Hz,1H)5.74(dd,J=10.37,2.35Hz,1H)3.79-3.92(m,4H)3.46-3.55(m,4H).m / z(ESI,+ve)447.0(M+H) + .

[0314] Step 9: 1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(o-tolyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one. A mixture of 1,4-(4,7-dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazine-1-prop-2-en-1-one (Intermediate I, 25 mg, 0.056 mmol), 2-tolylboronic acid (30.4 mg, 0.224 mmol, Frontier Scientific Inc., Logan, UT, USA), Pd(PPh) (6.46 mg, 5.59 μmol, Strem Chemicals Inc., NewburyPort, MA, USA), and 2 M aqueous NaCO (0.084 mL, 0.168 mmol) in 1,4-dioxane (0.3 mL) was stirred at 40 °C for 18 h. The reaction mixture was then diluted with EtOAc (20 mL) and washed with water (15 mL). The organic layer was separated, washed with brine (15 mL), dried over MgSO, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% EtOAc in heptane) gave 1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(o-tolyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one: 1H NMR(400MHz,DMSO-d6)δ10.15(brs,1H)8.33(s,1H)7.36-7.45(m,2H)7.24-7.36(m,4H)6.90(dd,J=16.63,10.37Hz,1H)6.70-6.80(m,2H)6.1 8(dd,J=16.73,2.25Hz,1H)5.75(dd,J=10.56,2.15Hz,1H)3.83-3.97(m,4H)3.47-3.62(m,4H)1.98-2.06(m,3H).m / z(ESI,+ve)503.1(M+H)+.

[0315] [Table 68]

[0316] [Table 69]

[0317] [Table 70]

[0318] Method 11 Example 11-1: 6-chloro-7-(5-methyl-1H-indazol-4-yl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-propenoyl)-1-piperazinyl)-2(1H)-quinazolinone [ka] Step 1: 4-(1H-Benzo[d][1,2,3]triazol-1-yl)-7-bromo-6-chloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one. Phosphorus oxychloride (1.204 mL, 7.85 mmol) was added to a stirred mixture of 7-bromo-6-chloro-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione (Intermediate F, 515 mg, 1.308 mmol), triethylamine (3.31 mL, 23.55 mmol), and 1H-benzo[d][1,2,3]triazole (2.01 g, 16.87 mmol) in acetonitrile (15 mL). The reaction mixture was heated to 80 °C and stirred for 1 h. The reaction mixture was cooled to rt and filtered. The filtrate was then slowly poured into rapidly stirred water (150 mL) at approximately 10 °C. The aqueous suspension was stirred for 15 minutes and then extracted twice with EtOAc (150 mL). The organic layers were combined, washed with brine (150 mL), dried over MgSO, filtered, and concentrated in vacuo to give crude 4-(1H-benzo[d][1,2,3]triazol-1-yl)-7-bromo-6-chloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one. m / z (ESI) M+H: 494.0.

[0319] Step 2: tert-Butyl 4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate. tert-Butyl piperazine-1-carboxylate (268 mg, 1.438 mmol) was added to a stirred mixture of crude 4-(1H-benzo[d][1,2,3]triazol-1-yl]-7-bromo-6-chloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one (647 mg, 1.308 mmol) and triethylamine (3.68 mL, 26.2 mmol) in dimethyl sulfoxide (6 mL). The reaction mixture was stirred at 80° C. for 30 minutes. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (75 mL). The organic layer was separated, washed with brine (75 mL), dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% EtOAc in heptane) gave tert-butyl 4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate. 1 H NMR(400MHz,chloroform-d)δ7.79(1H,s)7.49-7.59(2H,m)7.36-7.42(1H,m)7.11(1H,d,J=7.63Hz)6.80(1H,s)3.79-3.92(4H,m)3 .62-3.73(4H,m)2.60(1H,spt,J=6.80Hz)1.49-1.54(9H,m)1.22(3H,d,J=6.85Hz)1.08(3H,d,J=6.85Hz).m / z(ESI)M+H:561.0.

[0320] Step 3: tert-Butyl 4-(6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate. t-Butyl 4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate (115 mg, 0.205 mmol), 4-borono-5-methyl-1h-indazole (0.144 mL, 0.819 mmol, Ark Pharm Inc., Arlington Heights, IL, USA), Sphos Pd G3 (0.016 mL, 0.020 mmol), and sodium carbonate (2 M aqueous solution, 0.409 mL, 0.819 mmol) were mixed in 1,2-dimethoxyethane (1 mL) in a sealed vial under argon atmosphere. The reaction mixture was stirred at 100 °C for 24 h. The reaction mixture was cooled to rt and diluted with EtOAc (50 mL) and water (40 mL). The organic layer was separated, washed with brine (40 mL), dried over MgSO, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-50% (3:1) EtOAc / EtOH in heptane) gave tert-butyl 4-(6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate. m / z (ESI) M+H: 613.2.

[0321] Step 4: 6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)quinazolin-2(1H)-one. Trifluoroacetic acid (0.5 mL, 6.71 mmol) was added to a stirred mixture of tert-butyl 4-(6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate (78 mg, 0.127 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo to give crude 6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)quinazolin-2(1H)-one. m / z (ESI) M+H: 513.2.

[0322] Step 5: 6-chloro-7-(5-methyl-1H-indazol-4-yl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-propenoyl)-1-piperazinyl)-2(1H)-quinazolinone. Acryloyl chloride (10.33 μL, 0.127 mmol) was added to a stirred mixture of 6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)quinazolin-2(1H)-one (65 mg, 0.127 mmol) and triethylamine (0.178 mL, 1.267 mmol) in dichloromethane (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes. Additional acryloyl chloride (5.17 μl, 0.064 mmol) was added, and the reaction mixture was stirred at 0° C. for an additional 20 minutes. The reaction mixture was diluted with DCM (25 mL) and quenched with saturated aqueous sodium bicarbonate (20 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-80% acetone in heptane (3:1 EtOAc / EtOH)) afforded impure product. Further chromatographic purification of the impure product (silica gel, 0-100% acetone in heptane) afforded the separated diastereomers. 6-Chloro-7-(5-methyl-1H-indazol-4-yl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-propenoyl)-1-piperazinyl)-2(1H)-quinazolinone (Example 11-1-1) was the first eluting diastereomer. 1H NMR(400MHz,chloroform-d)δ10.28(1H,brs)7.94(1H,s)7.35-7.49(4H,m)7.25-7.31(2H,m)7.11(1H,d, J=7.67Hz)6.64(1H,dd,J=16.79,10.57Hz)6.54(1H,s)6.41(1H,dd,J=16.79,1.87Hz)5.81(1H,dd,J = 10.57, 1.66 Hz) 3.83-4.07 (8H, m) 2.74 (1H, spt, J = 6.84 Hz) 2.13 (3H, s) 1.23 (3H, d, J = 6.84 Hz) 1.04 (3H, d, J = 6.84 Hz). m / z (ESI) M+H: 567.2. The second eluting diastereomer was further purified by column chromatography (silica gel, 0-80% (3:1 EtOAc / EtOH) in heptane) to give 6-chloro-7-(5-methyl-1H-indazol-4-yl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-propenoyl)-1-piperazinyl)-2(1H)-quinazolinone (Example 11-1-2). 1 H NMR(400MHz,chloroform-d)δ10.37(1H,brs)7.94(1H,s)7.34-7.50(4H,m)7.21-7.31(2H ,m)7.13(1H,d,J=7.67Hz)6.64(1H,dd,J=16.90,10.68Hz)6.55(1H,s)6.41(1H,dd,J =16.79,1.66Hz)5.81(1H,dd,J=10.47,1.55Hz)3.83-4.08(8H,m)2.70(1H,spt,J=6. 84Hz)2.13(3H,s)1.22(3H,d,J=6.84Hz)1.03(3H,d,J=6.84Hz).m / z(ESI)M+H:567.2.

[0323] [Table 71]

[0324] Section 2 - Specific Examples Example 12 1-(4-(7-chloro-4-cyclopropyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one [ka] Step 1: tert-butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropylphthalazin-1-yl)piperazine-1-carboxylate. To a 20 mL vial charged with tert-butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate (Intermediate H, 0.060 g, 0.082 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.033 g, 0.041 mmol) and 2-methyltetrahydrofuran (2.0 mL) were added. The resulting mixture was capped and stirred at rt for 10 min, after which cyclopropylzinc bromide (0.5 M in THF, 0.820 mL, 0.410 mmol; Rieke Metals, Lincoln, NE, USA) was added via syringe. The reaction mixture was heated at 80 °C for 3 h, then cooled to rt and partitioned between EtOAc (30 mL) and water (10 mL). The aqueous layer was extracted again with EtOAc (20 mL). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (silica gel 24 g, 0–30% acetone in heptane) to give tert-butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropylphthalazin-1-yl)piperazine-1-carboxylate. 1H NMR (chloroform-d) δ: 8.31-8.38 (m, 1H), 8.15-8.23 (m, 1H), 7.55-7.64 (m, 4H), 7.39-7.47 (m, 2H), 7.29-7.38 (m, 4H), 6.99-7.09 (m, 1H), 6.74-6.85 (m, 1H), 6.36-6.47 (m, 1H), 3 .68-3.79(m,4H),3.37-3.51(m,4H),2.37-2.48(m,1H),1.48-1.54(m,9H),1.37-1.45 (m,1H),1.30-1.33(m,1H),1.00-1.15(m,2H),0.61-0.71(m,9H).m / z(ESI)M+H:737.4.

[0325] Step 2: 6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropyl-1-(piperazin-1-yl)phthalazine. Trifluoroacetic acid (0.316 mL, 4.10 mmol) was added to a solution of tert-butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropylphthalazin-1-yl)piperazine-1-carboxylate in DCM (0.7 mL). The resulting mixture was capped and stirred at rt for 30 min. The reaction mixture was diluted with DCM (10 mL) and basified with saturated aqueous NaHCO3 (5 mL). The aqueous layer was extracted again with DCM (10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give 6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropyl-1-(piperazin-1-yl)phthalazine. 1H NMR (chloroform-d) δ: 8.30-8.36 (m, 1H), 8.18-8.24 (m, 1H), 7.55-7.64 (m, 4H), 7.40-7.46 (m, 2H), 7.33 (q, J = 7.1 Hz, 4H), 6.97-7.09 (m, 1H), 6.74-6.83 (m, 1H), 6.36-6.4 6(m,1H),3.45-3.55(m,4H),3.16-3.26(m,4H),2.35-2.49(m,1H),1.37-1.46(m,1 H),1.30-1.33(m,1H),1.06-1.12(m,2H),0.61-0.70(m,9H).m / z(ESI)M+H:637.2.

[0326] Step 3: 1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one. To a 20 mL vial charged with 6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropyl-1-(piperazin-1-yl)phthalazine (0.023 g, 0.036 mmol), triethylamine (16 μL, 0.114 mmol) and dichloromethane (1.0 mL) were added. The resulting mixture was capped and stirred at rt for 10 minutes, after which acryloyl chloride (4.0 μL, 0.049 mmol) was added via syringe. The resulting mixture was capped and stirred at rt for 20 minutes. The reaction mixture was quenched with saturated aqueous NaHCO3 (3 mL) and diluted with DCM (10 mL). The aqueous layer was extracted again with DCM (5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give 1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one. 1H NMR (chloroform-d) δ: 8.32-8.38 (m, 1H), 8.16-8.24 (m, 1H), 7.55-7.65 (m, 4H), 7.40-7.48 (m, 2H), 7.31-7.38 (m, 4H), 6.98-7.10 (m, 1H), 6.75-6.84 (m, 1H), 6.60-6.72 (m, 1H), 6.41-6.47 (m, 1H), 6 .31-6.40(m,1H),5.72-5.82(m,1H),3.79-4.08(m,4H),3.44-3.62(m,4H),2.38-2.49(m,1H),1 .40-1.45(m,1H),1.33-1.37(m,1H),1.04-1.13(m,2H),0.62-0.68(m,9H).m / z(ESI)M+H:691.2.

[0327] Step 4: 1-(4-(7-chloro-4-cyclopropyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one. To a 20 mL vial charged with 1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one (0.022 g, 0.032 mmol), tetrahydrofuran (2.0 mL) was added, followed by tetrabutylammonium fluoride (1.0 M solution in THF, 0.070 mL, 0.070 mmol). The vial was capped and stirred at rt for 30 min. The reaction mixture was concentrated in vacuo. The crude product was purified by column chromatography (24 g silica, 0-5% MeOH in DCM) to give 1-(4-(7-chloro-4-cyclopropyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one. 1H NMR (chloroform-d) δ: 8.30-8.37 (m, 1H), 8.11-8.18 (m, 1H), 7.29-7.38 (m, 1H), 6.96-7.18 (m, 1H), 6.88-6.94 (m, 1H), 6.76-6.85 (m, 1H), 6.59-6.72 (m, 1H), 6.31-6.42 (m,1H),5.73-5.84(m,1H),3.73-4.05(m,4H),3.35-3.62(m,4H),2.40-2.52(m,1 H),1.35-1.42(m,1H),1.29-1.34(m,1H),1.03-1.14(m,2H).m / z(ESI)M+H:453.2.

[0328] Example 13 1-(4-(4-anilino-7-chloro-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one [ka] Step 1: tert-Butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phenylamino)phthalazin-1-yl)piperazine-1-carboxylate. To a 20 mL vial charged with tert-butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate (0.060 g, 0.082 mmol), dimethyl sulfoxide (2.0 mL) was added, followed by aniline (0.075 mL, 0.820 mmol). The vial was capped and refluxed at 80° C. for 3 h. The reaction was cooled to rt and partitioned between EtOAc (30 mL) and water (10 mL). The organic layer was separated and washed with water (2×10 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (40 g silica gel, 0-30% EtOAc in heptane) to give tert-butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phenylamino)phthalazin-1-yl)piperazine-1-carboxylate. 1 H NMR(chloroform-d)δ:8.17-8.25(m,1H),7.76-7.81(m,1H),7.60-7.69(m,5H),7 .50-7.55(m,2H),7.40-7.46(m,2H),7.31-7.37(m,5H),7.06-7.11(m,2H),6 .76-6.83(m,1H),6.57-6.66(m,1H),6.39-6.50(m,1H),3.66-3.81(m,4H),3 .32-3.43(m,4H),1.51-1.53(m,9H),0.69-0.75(m,9H).m / z(ESI)M+H:788.2.

[0329] Step 2: 7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-N-phenyl-4-(piperazin-1-yl)phthalazin-1-amine. In the same manner as in Example 12, Step 2, tert-butyl 4-(6-(2-(tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phenylamino)phthalazin-1-yl)piperazine-1-carboxylate was reacted to give 7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-N-phenyl-4-(piperazin-1-yl)phthalazin-1-amine. 1 H NMR (chloroform-d) δ:8.19-8.26(m,1H),7.75-7.80(m,1H),7.60-7.68(m,5H),7.49-7.55(m,2H),7.39-7.46(m,3H),7.32-7.37(m,5H),7.02-7.11 (m,2H),6.75-6.84(m,1H),6.59-6.67(m,1H),6.43-6.53(m,1H),3.35- 3.47(m,4H),3.16-3.27(m,4H),0.70-0.76(m,9H).m / z(ESI)M+H:688.2.

[0330] Step 3: 1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phenylamino)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one. In a manner similar to Example 12, Step 3, 7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-N-phenyl-4-(piperazin-1-yl)phthalazin-1-amine was reacted to give 1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phenylamino)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one. 1H NMR (chloroform-d) δ: 8.16-8.24 (m, 1H), 7.77-7.84 (m, 1H), 7.62-7.67 (m, 4H), 7.52-7.55 (m, 1H), 7.41-7.46 (m, 3H), 7.32-7.38 (m, 6H), 7.02-7.11 (m, 2H), 6.77-6.84 (m,1H),6.65-6.71(m,1H),6.46-6.51(m,1H),6.30-6.39(m,2H),5.73-5.81(m,1 H),3.86-4.05(m,4H),3.37-3.53(m,4H),0.69-0.75(m,9H).m / z(ESI)M+H:742.3.

[0331] Step 4: 1-(4-(4-anilino-7-chloro-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one. In analogy to Example 12, Step 4, reaction of 1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phenylamino)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one gave 1-(4-(4-anilino-7-chloro-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one. 1 H NMR (chloroform-d)δ:7.96-8.09(m,2H),7.46-7.57(m,2H),7.37-7.44(m,1H),7.29-7.33(m,1H),7.20-7.26(m,1H),6.96-7.07(m,1H),6.81-6.87 (m,1H),6.70-6.77(m,1H),6.54-6.67(m,1H),6.29-6.41(m,1H),5.68- 5.82(m,1H),3.74-3.96(m,4H),3.12-3.43(m,4H).m / z(ESI)M+H:504.2.

[0332] Example 14 1-(4-(7-chloro-4-cyclopentyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one [ka] Step 1: tert-butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentylphthalazin-1-yl)piperazine-1-carboxylate. In analogy to Example 12, Step 1, the reaction of tert-butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate (Intermediate H) with cyclopentylzinc bromide (0.5 M in THF, Rieke Metals, Lincoln, NE) gave tert-butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentylphthalazin-1-yl)piperazine-1-carboxylate. 1 H NMR (chloroform-d) δ: 8.18-8.22 (m, 1H), 8.12-8.16 (m, 1H), 7.60-7.66 (m, 2H), 7.50-7.56 (m, 2H), 7.39-7.47 (m, 2H), 7.34-7.38 (m, 2H), 7.28-7.33 (m, 2H), 7.09 (brd, J = 1.2 Hz, 1H), 6.75-6.66. 82(m,1H),6.37-6.44(m,1H),3.72-3.78(m,4H),3.44-3.51(m,4H),2.03-2.23(m,4H),1.87 -1.96(m,2H),1.67-1.79(m,3H),1.51-1.54(m,9H),0.62-0.67(m,9H).m / z(ESI)M+H:765.2.

[0333] Step 2: 6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentyl-1-(piperazin-1-yl)phthalazine. In a manner similar to that of Example 12, Step 2, tert-butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentylphthalazin-1-yl)piperazine-1-carboxylate was reacted to give 6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentyl-1-(piperazin-1-yl)phthalazine. 1 H NMR (chloroform-d) δ: 8.17-8.21 (m, 1H), 8.12-8.16 (m, 1H), 7.61-7.66 (m, 2H), 7.51-7.56 (m, 2H), 7.40-7.46 (m, 2H), 7.34-7.38 (m, 2H), 7.29-7.33 (m, 2H), 6.99-7.08 (m, 1H), 6.74-6.82 (m,1H),6.37-6.45(m,1H),3.58-3.67(m,4H),3.27-3.36(m,4H),2.18-2.22(m,1H),2.08- 2.12(m,2H),1.86-1.91(m,3H),1.69-1.77(m,3H),0.59-0.67(m,9H).m / z(ESI)M+H:665.2.

[0334] Step 3: 1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one. In a manner similar to Example 12, Step 3, 6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentyl-1-(piperazin-1-yl)phthalazine was reacted to give 1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one. 1H NMR (chloroform-d) δ: 8.18-8.25 (m, 1H), 8.13-8.17 (m, 1H), 7.61-7.67 (m, 2H), 7.50-7.57 (m, 2H), 7.39-7.48 (m, 2H), 7.28-7.37 (m, 4H), 6.99-7.10 (m, 1H), 6.75-6.83 (m, 1H), 6.62-6.71 (m,1H),6.33-6.43(m,2H),5.73-5.81(m,1H),3.84-4.07(m,4H),3.71-3.82(m,1H),3.49- 3.65(m,4H),1.80-1.96(m,4H),1.67-1.77(m,4H),0.62-0.67(m,9H).m / z(ESI)M+H:719.2.

[0335] Step 4: 1-(4-(7-chloro-4-cyclopentyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one. In analogy to Example 12, Step 4, reaction of 1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one gave 1-(4-(7-chloro-4-cyclopentyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one. 1 H NMR (chloroform-d) δ:8.10-8.22(m,2H),7.29-7.38(m,1H),6.86-6.93(m,1H),6.77-6.85(m,1H),6.61-6.72(m,1H),6.33-6.44(m,1H),5.74-5.85 (m,1H),3.82-4.05(m,4H),3.75-3.82(m,1H),3.40-3.63(m,4H),2.06- 2.24(m,4H),1.81-1.96(m,2H),1.67-1.79(m,2H).m / z(ESI)M+H:481.2.

[0336] Example 15 1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(1-piperidinyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one [ka] Step 1: tert-butyl 4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(piperidin-1-yl)phthalazin-1-yl)piperazine-1-carboxylate. To a 20 mL vial charged with tert-butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate (Intermediate H, 0.060 g, 0.082 mmol), piperidine (1.0 mL, 10.10 mmol) was added. The vial was capped and heated at 80° C. for 2 h. The reaction was cooled to rt and partitioned between EtOAc (30 mL) and water (10 mL). The organic layer was separated and washed with water (2×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give tert-butyl 4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(piperidin-1-yl)phthalazin-1-yl)piperazine-1-carboxylate. 1 H NMR (chloroform-d) δ:8.09-8.14(m,1H),7.97-8.03(m,1H),7.28-7.35(m,1H),6.75-6.88(m,2H),3.65-3.76 (m,4H),3.30-3.44(m,8H),1.72-1.81(m,4H),1.61-1.71(m,3H),1.48-1.53(m,9H).m / z(ESI)M+H:542.2.

[0337] Step 2: 2-(7-chloro-1-(piperazin-1-yl)-4-(piperidin-1-yl)phthalazin-6-yl)-3-fluorophenol. In a manner similar to Example 12, Step 2, tert-butyl 4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(piperidin-1-yl)phthalazin-1-yl)piperazine-1-carboxylate was reacted to give 2-(7-chloro-1-(piperazin-1-yl)-4-(piperidin-1-yl)phthalazin-6-yl)-3-fluorophenol. 1 H NMR(chloroform-d)δ:8.09-8.13(m,1H),7.95-8.03(m,1H),7.28-7.38(m,1H),6.83-6.89(m,1H),6.75-6.82(m,1H),3 .39-3.48(m,4H),3.31-3.38(m,4H),3.12-3.21(m,4H),1.75-1.80(m,4H),1.64-1.69(m,2H).m / z(ESI)M+H:442.2.

[0338] Step 3: 1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(1-piperidinyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one. In analogy to Example 12, Step 3, reaction of 2-(7-chloro-1-(piperazin-1-yl)-4-(piperidin-1-yl)phthalazin-6-yl)-3-fluorophenol gave 1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(1-piperidinyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one. 1 H NMR (chloroform-d) δ:8.08-8.15(m,1H),7.98-8.05(m,1H),7.29-7.39(m,1H),6.86-6.94(m,1H),6.76-6.85(m,1H),6.59-6.70(m,1H),6.30-6.43 (m,1H),5.72-5.84(m,1H),3.77-4.05(m,4H),3.40-3.56(m,4H),3.32- 3.38(m,4H),1.73-1.85(m,4H),1.64-1.70(m,2H).m / z(ESI)M+H:496.2.

[0339] Example 16 1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxy-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one [ka] Step 1: tert-Butyl 4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxyphthalazin-1-yl)piperazine-1-carboxylate. To 50 mL of dry rbf was added phenol (0.130 g, 1.381 mmol) and tetrahydrofuran (3.0 mL). The mixture was cooled to 0° C., and potassium tert-butoxide (0.153 g, 1.367 mmol) was added. The mixture was stirred at 0° C. for 10 min, then warmed to rt and stirred for 30 min. tert-Butyl 4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate (Intermediate H, 0.100 g, 0.137 mmol) was added, and the resulting mixture was heated at 60° C. for 2 h. The reaction was cooled to rt and quenched with water. The resulting mixture was partitioned between EtOAc (30 mL) and water (15 mL). The aqueous layer was extracted again with EtOAc (20 mL). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (40 g silica gel, 10-50% acetone in acetone) to give tert-butyl 4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxyphthalazin-1-yl)piperazine-1-carboxylate. m / z (ESI) M+H: 551.2.

[0340] Step 2: 2-(7-chloro-4-phenoxy-1-(piperazin-1-yl)phthalazin-6-yl)-3-fluorophenol. In a manner similar to Example 12, Step 2, 4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxyphthalazin-1-yl)piperazine-1-carboxylate was reacted to give 2-(7-chloro-4-phenoxy-1-(piperazin-1-yl)phthalazin-6-yl)-3-fluorophenol. 1 H NMR (chloroform-d) δ:8.37-8.42(m,1H),8.14-8.19(m,1H),7.37-7.45(m,2H),7.29-7.34(m,1H),7.19-7.25 (m,2H),6.89-6.98(m,1H),6.76-6.87(m,4H),3.36-3.45(m,4H),3.13-3.22(m,4H).m / z(ESI)M+H:451.2.

[0341] Step 3: 1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxy-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one. In analogy to Example 12, Step 3, reaction of 2-(7-chloro-4-phenoxy-1-(piperazin-1-yl)phthalazin-6-yl)-3-fluorophenol gave 1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxy-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one. 1 H NMR (chloroform-d)δ:8.41-8.45(m,1H),8.17-8.20(m,1H),7.40-7.45(m,2H),7.28-7.37(m,2H),7.20-7.26(m,1H),6.78-6.87(m,2H),6 .59-6.70(m,1H),6.31-6.41(m,1H),5.97-6.06(m,1H),5.74-5.81(m,1H),3.76-4.03(m,4H),3.38-3.53(m,4H).m / z(ESI)M+H:505.2.

[0342] Examples 17-1 and 17-2 (2E)-1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one (Example 17-1) and (2E)-1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one (Example 17-2) [ka] Step 1: tert-Butyl 4-(5-chloro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate. A slurry of tert-butyl 4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate (Intermediate D, 459 mg, 1.02 mmol), (3-methoxynaphthalen-1-yl)boronic acid (823 mg, 4.07 mmol), and cesium carbonate (1.33 g, 4.07 mmol) in a mixture of 1,4-dioxane (8 mL) and water (2 mL) was degassed with a stream of argon. Tetrakis(triphenylphosphine)palladium (118 mg, 0.10 mmol) was added, and the mixture was again degassed with a stream of argon. The reaction mixture was sealed and heated at 100 °C for 23 h. The reaction was cooled to rt, diluted with brine (60 mL), and extracted twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-2% MeOH in DCM) to give tert-butyl 4-(5-chloro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate. m / z (ESI) M+H: 528.0.

[0343] Step 2: 5-chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)benzo[c]isothiazole. To a solution of tert-butyl 4-(5-chloro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate (327 mg, 0.56 mmol) in DCM (6 mL) was added trifluoroacetic acid (1.04 mL, 13.9 mmol) via syringe. The resulting yellow solution was stirred at rt for 4 h and then concentrated. The residue was purified by silica gel chromatography (eluent: 0-25% MeOH in DCM) to give the mono-TFA salt of 5-chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)benzo[c]isothiazole. m / z (ESI) M+H: 428.0.

[0344] Step 3: (2E)-1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one. To a solution of 5-chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)benzo[c]isothiazole (mono-TFA salt 74 mg, 0.14 mmol) and trans-4-dimethylaminocrotonic acid hydrochloride (38 mg, 0.23 mmol) in DMA (2 mL) was added thionyl chloride (41 L, 0.69 mmol) via syringe. The resulting brown solution was stirred at rt for 2.5 h. The reaction mixture was quenched with water (50 mL) and extracted with 8:1 DCM / MeOH. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-15% MeOH in DCM) to give (2E)-1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one. 1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.94(d,J=8.4Hz,1H),7.46-7.55(m,2H),7.27-7.35(m,2H),7.19(d,J=2.5Hz,1H),6.6 1-6.72(m,2H),3.94(s,3H),3.80-3.93(m,4H),3.62-3.68(m,4H),3.07(d,J=4.3Hz,2H),2.18(s,6H).m / z(ESI)M+H:539.2.

[0345] Step 4: (2E)-1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one. To a solution of (2E)-1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one (23.5 mg, 0.044 mmol) in 1,2-dichloroethane (4 mL) at 0 ° C., boron tribromide (1.0 M in hexane, 218 L, 0.22 mmol) was added dropwise via syringe. The resulting yellow slurry was stirred at 0 °C for 2.75 h and then quenched with saturated aqueous NaHCO3 (4 mL). The mixture was extracted twice with a 4:1 mixture of DCM / MeOH. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0 to 18% MeOH in DCM) to give (2E)-1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one. 1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.10(s,1H),7.80(d,J=8.4Hz,1H),7.40-7.46(m,1H),7.19-7.30(m,3H),7.07(d,J=2. 4Hz,1H),6.62-6.71(m,2H),3.80-3.93(m,4H),3.62-3.69(m,4H),3.07(d,J=4.1Hz,2H),2.17(s,6H).m / z(ESI)M+H:525.0.

[0346] Examples 18-1 to 18-3 1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one (Example 18-1) and 2-(bromomethyl)-1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one (Example 18-2) and 1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one (Example 18-3) [ka] Step 1: 1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one. A solution of 1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one (Intermediate O, 29 mg, 0.06 mmol) in tert-butanol (0.4 mL) and water (0.4 mL) was charged into a vial. Phenol (5.7 mg, 0.06 mmol), DABCO (20.3 mg, 0.18 mmol), and formaldehyde (37% aqueous solution, 24 L, 0.24 mmol) were added sequentially. The resulting mixture was capped and heated at 55 °C for 29 h. The reaction was cooled to rt and partitioned between water (6 mL) and 10:1 DCM / MeOH. The organic layer was separated and the aqueous layer was extracted twice more with 10:1 DCM / MeOH. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0 to 3.5% MeOH in DCM) to give 1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one. 1 H NMR(400MHz,DMSO-d6)δ8.12(s,1H),7.94(d,J=8.2Hz,1H),7.47-7.55(m,2H),7.25-7.34(m,2H),7.19(d,J=2.5Hz,1H),5.43(br.s,1H) ,5.20(br.s,1H),5.14(t,J=5.8Hz,1H),4.12(d,J=5.7Hz,2H),3.94(s,3H),3.78-3.85(m,4H),3.54-3.66(m,4H).m / z(ESI)M+H:512.0.

[0347] Step 2: 2-(bromomethyl)-1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one and 1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one. To a solution of 1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one (17.1 mg, 0.033 mmol) in 1,2-dichloroethane (4 mL) at 0 °C, boron tribromide (1.0 M in hexanes, 167 L, 0.17 mmol) was added dropwise via syringe. The resulting slurry was stirred at 0 °C for 40 min and then quenched with saturated aqueous NaHCO3 (5 mL). The mixture was extracted twice with a 4:1 mixture of DCM / MeOH. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-7% MeOH in DCM) to give two products.

[0348] First eluting peak: 2-(bromomethyl)-1-(4-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one. 1 H NMR(400MHz,DMSO-d6)δ9.96(br.s,1H),8.13(s,1H),7.80(d,J=8.2Hz,1H),7.40-7.47(m,1H),7.19-7.29(m,3H),7. 07(d,J=2.4Hz,1H),5.78(s,1H),5.41(s,1H),4.38(s,2H),3.84-3.93(m,4H),3.62-3.72(m,4H).m / z(ESI)M+H:560.0

[0349] Second eluting peak: 1-(4-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)-2-(hydroxymethyl)prop-2-en-1-one. 1 H NMR(400MHz,DMSO-d6)δ9.98(br.s,1H),8.11(s,1H),7.79(d,J=8.2Hz,1H),7.37-7.48(m,1H),7.17-7.28(m,3H),7.07(d,J=2.4Hz, 1H),5.43(br.s,1H),5.20(br.s,1H),5.07-5.14(m,1H),4.12(br.s,2H),3.78-3.86(m,4H),3.57-3.66(m,4H).m / z(ESI)M+H:498.0

[0350] Examples 19-1 to 19-3 1-(4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one (Example 19-1) and 1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-1-methyl-1H-indazol-7-yl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one (Example 19-2) and 1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-2-methyl-2H-indazol-7-yl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one (Example 19-3) [ka] Step 1: tert-Butyl 4-(5-chloro-7-fluoro-6-(5-methoxy-1H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate. A slurry of Intermediate D (232 mg, 0.51 mmol), 5-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (535 mg, 1.95 mmol, see synthesis below), and cesium carbonate (636 mg, 1.95 mmol) in a mixture of 1,4-dioxane (8 mL) and water (2 mL) was degassed with a stream of argon. Tetrakis(triphenylphosphine)palladium (59 mg, 0.05 mmol) was added, and the mixture was again degassed with a stream of argon. The reaction mixture was sealed and heated at 100 °C for 18 h. The reaction was cooled to rt and partitioned between brine (40 mL) and EtOAc. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-4.5% DCM / MeOH) to give tert-butyl 4-(5-chloro-7-fluoro-6-(5-methoxy-1H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate. LCMS-ESI (POS.) m / z: 518.2 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ12.90(br.s,1H),8.06(s,1H),8.03(s,1H),7.31(d,J=1.4Hz,1H ),6.99(d,J=2.2Hz,1H),3.83(s,3H),3.61-3.69(m,4H),3.54-3.60(m,4H),1.45(s,9H).

[0351] [ka] 5-Methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. A suspension of 7-bromo-5-methoxy-1H-indazole (1.00 g, 4.40 mmol, Ark Pharm Inc., Arlington Heights, IL, USA), potassium acetate (1.30 g, 13.2 mmol), and bis(pinocolato)diboron (1.23 g, 4.84 mmol) in 1,4-dioxane (18 mL) was degassed with a stream of argon. Dichloromethane (108 mg, 0.13 mmol) was added to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex and again degassed with a stream of argon. The reaction mixture was sealed and heated at 80 °C for 2 days. The reaction was cooled to rt and partitioned between water (50 mL) and EtOAc. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 2-65% EtOAc / heptane) to give 5-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. LCMS-ESI (POS.) m / z: 275.1 (M+H). + .

[0352] Step 2: tert-butyl 4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate and tert-butyl 4-(5-chloro-7-fluoro-6-(5-methoxy-2-methyl-2H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(5-chloro-7-fluoro-6-(5-methoxy-1H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate (115 mg, 0.22 mmol) in THF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 44.5 mg, 1.1 mmol). After 10 min, iodomethane (69 L, 1.1 mmol) was added, and the reaction was stirred at rt for an additional 15 min before being partitioned between saturated aqueous ammonium chloride (10 mL) and DCM. The aqueous layer was extracted twice with DCM, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to give a mixture of tert-butyl 4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate and tert-butyl 4-(5-chloro-7-fluoro-6-(5-methoxy-2-methyl-2H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate. The crude mixture was used in the next step without purification. LCMS-ESI (POS.) m / z: 532.0 (M+H). + .

[0353] Step 3: 5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)-3-(piperazin-1-yl)benzo[c]isothiazole (Intermediate J) and 5-chloro-7-fluoro-6-(5-methoxy-2-methyl-2H-indazol-7-yl)-3-(piperazin-1-yl)benzo[c]isothiazole (Intermediate K). To a solution of the crude mixture of tert-butyl 4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate and tert-butyl 4-(5-chloro-7-fluoro-6-(5-methoxy-2-methyl-2H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate (143 mg) in DCM (6 mL) was added trifluoroacetic acid (484 L, 6.5 mmol) via syringe. The resulting yellow solution was stirred at rt for 25 min and then concentrated. The residue was purified by silica gel chromatography (eluent: 0-25% DCM / MeOH).

[0354] First eluting peak: Mono-TFA salt of 5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)-3-(piperazin-1-yl)benzo[c]isothiazole (Intermediate J). LCMS-ESI (POS.) m / z: 432.0 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ8.16(s,1H),8.03(s,1H),7.35(d,J=2.4Hz,1H),6.99(d ,J=2.4Hz,1H),3.84(s,3H),3.67-3.76(m,4H),3.56(s,3H),3.36-3.42(m,4H).

[0355] Second eluting peak: Mono-TFA salt of 5-chloro-7-fluoro-6-(5-methoxy-2-methyl-2H-indazol-7-yl)-3-(piperazin-1-yl)benzo[c]isothiazole (Intermediate K). LCMS-ESI (POS.) m / z: 432.0 (M+H) + .

[0356] Step 4: 1-(4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one. To an ice-cooled slurry of the mono-TFA salt of Intermediate J (108 mg, 0.20 mmol) in DCM (5 mL) was added DIPEA (104 L, 0.60 mmol) followed by acryloyl chloride (24 L, 0.30 mmol) dropwise via syringe. The resulting solution was stirred at 0 °C for 3 h, then quenched with saturated aqueous NaHCO (15 mL) and extracted twice with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-7% DCM / MeOH) to give 1-(4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one. LCMS-ESI (POS.) m / z: 486.0 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ8.13(s,1H),8.02(s,1H),7.33(d,J=2.2Hz,1H),6.99(d,J=2.4Hz,1H),6.85(dd,J=16.6,10.6Hz,1H) ,6.18(dd,J=16.7,2.3Hz,1H),5.76(dd,J=10.5,2.3Hz,1H),3.85-3.95(m,4H),3.84(s,3H),3.62-3.72(m,4H),3.56(s,3H).

[0357] Step 5: 1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-1-methyl-1H-indazol-7-yl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one. To an ice-cold solution of 1-(4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one (72.5 mg, 0.15 mmol) in 1,2-dichloroethane (5 mL) was added dropwise via syringe a boron tribromide solution (1.0 M in hexanes, 746 L, 0.75 mmol). The resulting slurry was stirred at 0 °C for 3.75 h, then quenched with saturated aqueous NaHCO3 (5 mL) and extracted twice with a 4:1 mixture of DCM / MeOH. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-6% DCM / MeOH) to give 1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-1-methyl-1H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one. LCMS-ESI (POS.) m / z: 472.0 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.12(s,1H),7.92(s,1H),7.12(d,J=2.2Hz,1H),6.81-6.91(m,2H),6. 18(dd,J=16.7,2.5Hz,1H),5.76(dd,J=10.4,2.4Hz,1H),3.81-3.94(m,4H),3.62-3.70(m,4H),3.52(s,3H).

[0358] Regarding the synthesis of 1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-2-methyl-2H-indazol-7-yl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one.

[0359] Steps 4 and 5 were carried out as described above using intermediate K from step 3 to give 1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-2-methyl-2H-indazol-7-yl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one. LCMS-ESI (POS.) m / z: 472.0 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.11(s,1H),8.01(s,1H),6.95(d,J=2.0Hz,1H),6.77-6.90(m,2H),6. 18(dd,J=16.7,2.5Hz,1H),5.76(dd,J=10.4,2.2Hz,1H),4.03(s,3H),3.80-3.94(m,4H),3.58-3.66(m,4H).

[0360] Example 20 1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-hydroxy-2-methylidene-1-butanone [ka] Step 1: 4-((tert-butyldiphenylsilyl)oxy)-1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)-2-methylenebutan-1-one. To a solution of 4-((tert-butyldiphenylsilyl)oxy)-2-methylenebutanoic acid (101 mg, 0.29 mmol, prepared according to Pihko, PM, J. Org. Chem., 2006, 71, 2538-2541 and Greaney, MF, Org. Lett., 2007, 9, 1931-1934) in DCM (2 mL) was added a 2 M solution of oxalyl chloride (0.21 mL, 0.43 mmol) at 0° C., followed by the addition of a catalytic amount of DMF (5 L). The reaction mixture was warmed to rt and stirred for 2 h. The reaction mixture was concentrated in vacuo, then diluted with DCM (1 mL) and added to a solution of 5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)benzo[c]isothiazole (Intermediate N, 122 mg, 0.29 mmol), triethylamine (0.20 mL, 1.43 mmol), and DCM (2 mL). The reaction mixture was warmed to rt, and DMAP (2 mg, 0.016 mmol) was added. The reaction mixture was stirred at rt for 15 h, then concentrated in vacuo and purified by silica gel column chromatography (eluent: 0-50% EtOAc:heptane) to give 4-((tert-butyldiphenylsilyl)oxy)-1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)-2-methylenebutan-1-one. 1 H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.94(d,J=8.0Hz,1H),7.63-7.61(m,4H),7.52-7.49(m,2H),7.47-7.40(m,6H),7.33-7.28(m,2H),7 .20-7.19(m,1H),5.37(s,1H),5.24(s,1H),3.94(s,3H),3.83-3.76(m,6H),3.53(brs,2H),3.31(s,4H),1.01(s,9H).m / z(ESI)M+H:764.

[0361] Step 2: 1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-hydroxy-2-methylidene-1-butanone. To a solution of 4-((tert-butyldiphenylsilyl)oxy)-1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)-2-methylenebutan-1-one (85 mg, 0.11 mmol) and DCM (2 mL) was added a 2 M solution of BBr3 (0.28 mL, 0.56 mmol) in DCM at 0 °C. The reaction mixture was quenched with water, concentrated in vacuo, and purified by silica gel column chromatography (eluting with 0–50% heptane / 3:1 EtOAc:EtOH) to give 1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-hydroxy-2-methylidene-1-butanone. 1 H NMR(400MHz,DMSO-d6)δ9.93(brs,1H),8.11(s,1H),7.80(d,J=12Hz,1H),7.43(m,1H),7.26-7.20(m,3H),7.07 (s,1H),5.32(s,1H),5.16(s,1H),3.83(brs,4H),3.63(brs,4H),3.53(t,J=8.0Hz,2H),2.42(t,J=8.0Hz,2H). 19 FNMR(377MHz,DMSO-d6)δ-123.8(s,1F).m / z(ESI)M+H:512.

[0362] Example 21 1-(4-(5-chloro-7-fluoro-6-(7-hydroxy-5-quinolinyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one [ka] 1-(4-(5-chloro-7-fluoro-6-(7-hydroxy-5-quinolinyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one was prepared from Intermediate D by Method 1 using 7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (synthesis below) with the following modifications: S-Phos Pd Using G3, aqueous potassium carbonate, and DME; using TFA / DCM in step 8-1; using DCE as the solvent in step 8-2; and using boron tribromide solution (1.0 M in DCE) in step 8-3, 1-(4-(5-chloro-7-fluoro-6-(7-hydroxy-5-quinolinyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one was obtained. 1 H NMR(400MHz,CDCl3)δ8.81(dd,J=4.2,1.3Hz,1H)7.72-7.78(m,2H)7.64(s,1H)7.28(d,J=2.2Hz,1H)7.16(dd,J=8.4,4.3H z,1H)6.56-6.66(m,1H)6.40(dd,J=16.8,1.6Hz,1H)5.78-5.87(m,1H)4.01(br.s.,2H)3.89(br.s.,2H)3.50-3.60(m,4H). 19 F NMR(376MHz,CDCl3)δ-121.33(s,1F).MS(ESI,+ve)m / z:469.1(M+1) + . [ka]

[0363] 7-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline. A solution of 5-bromo-7-methoxyquinoline (0.407 g, 1.71 mmol, OxChem, Wood Dale, IL, USA), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.912 g, 3.59 mmol), PdCl(dppf) (0.051 g, 0.070 mmol), and potassium acetate (0.503 g, 5.13 mmol) in DMF (9 mL) was stirred at 90 °C for 1 h and then at 100 °C for 45 min. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous sodium bicarbonate (2 × 75 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was adsorbed onto silica and purified by column chromatography (silica gel, 0-80% heptane / EtOAc) to give 7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline. MS (ESI, +ve) m / z: 286.1 (M+1). + .

[0364] Example 22 1-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-4-(2-propenoyl)-2-piperazinecarboxylic acid [ka] To a solution of methyl 4-acryloyl-1-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazine-2-carboxylate (Example 7-3, 0.022 g, 0.042 mmol) in THF / EtOH (1:1; 6 mL) was added NaOH (5 Naq.; 1.0 mL, 5.0 mmol) at 0° C., and the resulting mixture was stirred at 0° C. for 5 minutes. The reaction was acidified with 5N HCl at 0° C., extracted with EtOAc, and purified by HPLC to give 1-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-4-(2-propenoyl)-2-piperazinecarboxylic acid. m / z (ESI, +ve) 512.0 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ3.14-3.28(m,1H)3.52-3.87(m,3H)4.15-5.03(m,2H)5.15-5.23(m,1H)5.77-5.83(m,1H)6.13-6.24(m,1H)6.86 (br.s.,1H)7.06-7.12(m,1H)7.20-7.30(m,3H)7.38-7.49(m,1H)7.76-7.84(m,1H)8.07-8.13(m,1H)9.98(br.s.,1H)13.42(br.s.,1H).

[0365] Example 23 1-(4-(5-chloro-6-(5-cyclopropyl-1H-indazol-4-yl)-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one [ka] Example 23 was made as described in Method 1, using (5-cyclopropyl-1H-indazol-4-yl)boronic acid (see synthesis below) in step 7 and omitting step 8-3. m / z (ESI, +ve) 482.0 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ12.92-13.19(1H,m),8.02-8.21(1H,m),7.47-7.60(2H,m),7.02-7.09(1H,m),6.80-6.93(1H,m),6.15- 6.25(1H,m),5.71-5.82(1H,m),3.80-3.96(4H,m),3.60-3.72(4H,m),1.55-1.74(1H,m),0.72-0.79(2H,m),0.58-0.71(2H,m).

[0366] (5-Cyclopropyl-1H-indazol-4-yl)boronic acid [ka] Step 1: 2-Bromo-1-cyclopropyl-4-fluorobenzene. To a 2 L round-bottom flask at ambient temperature was added 2-bromo-4-fluoro-1-iodobenzene (22 g, 73.1 mmol) and cyclopropylboronic acid (12.6 g, 146 mmol) in cyclopentyl methyl ether (1.1 L). Na2CO3 (2 Maq.; 183 mL) was added, and the reaction was degassed with N2 gas for 20 minutes. Tetrakis(III) (8.45 g, 7.31 mmol) was added, and the reaction was then degassed with N2 gas for 20 minutes. The reaction mixture was then transferred to a 5 L autoclave under a N2 atmosphere and heated to 130 °C for 40 h. The reaction mixture was cooled to ambient temperature, filtered through a Celite pad, and washed with diethyl ether (200 mL). Water (500 mL) was added to the filtrate, and the organic layer was separated. The aqueous layer was extracted with diethyl ether (2 x 300 mL), and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude material was adsorbed onto a plug of silica gel and purified by chromatography (silica gel, 100% petroleum ether) to give 2-bromo-1-cyclopropyl-4-fluorobenzene. GC-MS m / z: 214 / 216 1 H NMR(400MHz,CDCl3)δ7.36-7.23(m,1H),6.95(dt,J=7.0,1.5Hz,2H),2.09(ddd,J=13.8,8.5,5.4Hz,1H),1.12-0.88(m,2H),0.76-0.50(m,2H).

[0367] Step 2: 2-Bromo-3-cyclopropyl-6-fluorobenzaldehyde. To a 500 mL round-bottom flask was added 2-bromo-1-cyclopropyl-4-fluorobenzene (6.5 g, 30.2 mmol) in tetrahydrofuran (130 mL) under a N atmosphere. LDA (18.1 mL, 36.3 mmol, 2 M in THF, 1.2 equiv) was added dropwise at -78 °C (maintaining the internal temperature between -65 °C and -70 °C), and the reaction mixture was stirred for 1 h. Next, DMF (6 mL) was added dropwise to the reaction mixture (maintaining the internal temperature between -65 °C and -70 °C), and the reaction was stirred at -78 °C for an additional 3 h. The reaction was quenched with saturated aqueous ammonium chloride (100 mL) and allowed to warm gradually to ambient temperature. The mixture was diluted with diethyl ether (200 mL), and the organic layer was separated and washed with brine (2 × 50 mL). The combined organic layers were dried over anhydrous NaSO and evaporated under reduced pressure. The crude material was adsorbed onto a plug of silica gel and purified by chromatography (silica gel, 0-2% EtOAc / hexanes) to give 2-bromo-3-cyclopropyl-6-fluorobenzaldehyde. GC-MS m / z: 242 1 H NMR(400MHz,CDCl3)δ10.43(d,J=1.5Hz,1H),7.26-7.12(m,1H),7.06(t,J=9 .3Hz,1H),2.15(td,J=8.4,4.3Hz,1H),1.17-0.94(m,2H),0.78-0.52(m,2H).

[0368] Step 3: 4-Bromo-5-cyclopropyl-1H-indazole. To a 100 mL sealed tube was added 2-bromo-3-cyclopropyl-6-fluorobenzaldehyde (4 g, 16.5 mmol) and hydrazine hydrate (4.0 mL, 82 mmol) in ethylene glycol (40 mL). The reaction was stirred at 90 °C for 2 h and then heated to 150 °C for 16 h. The reaction mixture was cooled to ambient temperature, and ice-cold water (40 mL) and EtOAc (50 mL) were added. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with water (2 × 40 mL) and brine solution (40 mL), dried over anhydrous aqueous sodium sulfate, and concentrated in vacuo. The crude material was adsorbed onto a plug of silica gel and purified by chromatography (silica gel, 0–20% EtOAc / hexanes) to give 4-bromo-5-cyclopropyl-1H-indazole. The compounds were analyzed by reversed-phase preparative liquid chromatography (YMC:C 18 The pure compound was obtained by purification using a column chromatography (150 × 20 mm, 5 μm column; mobile phase: 0.1% TFA in water and acetonitrile; flow rate: 15 mL / min). MS (ESI positive ion) m / z: 237 / 239.0 (M+1). 1 H NMR(400MHz,DMSO-d6)δ13.31(s,1H),7.97(s,1H),7.46(d,J=8.6Hz,1H),6.97(d ,J=8.6Hz,1H),2.21(tt,J=8.5,5.3Hz,1H),1.24-0.87(m,2H),0.93-0.33(m,2H).

[0369] Step 4: 5-Cyclopropyl-1H-indazol-4-yl)boronic acid. To a 100 mL round-bottom flask were added 4-bromo-5-cyclopropyl-1H-indazole (0.62 g, 2.6 mmol) and bis(pinacolato)diboron (0.996 g, 3.92 mmol) in 1,4-dioxane (25 mL). Potassium acetate (0.77 g, 7.84 mmol) was added, and the reaction mixture was degassed with N gas for 10 minutes. PdCl(dppf)DCM adduct (0.213 g, 0.261 mmol) was added to the reaction mixture, and the reaction mixture was again degassed with N gas for 10 minutes and then heated to 100 °C for 16 hours. The reaction mixture was cooled to ambient temperature, filtered through a Celite pad, and washed with EtOAc (50 mL). The filtrate was concentrated in vacuo, and the crude material was adsorbed onto a plug of silica gel and purified by chromatography (silica gel, 0-50% EtOAc / hexanes). The compound was further purified by reverse-phase preparative liquid chromatography (Grace column; 0-70% MeCN / water) to give 5-cyclopropyl-1H-indazol-4-yl)boronic acid. MS (ESI positive ion) m / z: 285.2 (M+1). 1 H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.13(q,J=1.3Hz,1H),7.50(d,J=8.7Hz,1H),6.83(dd,J=8 .8,1.4Hz,1H),2.78-2.60(m,1H),1.38(d,J=1.4Hz,12H),1.07-0.85(m,2H),0.75-0.48(m,2H).

[0370] Example 24 1-(4-(5-chloro-7-fluoro-6-(3-(methylamino)-1-isoquinolinyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one [ka] Step 1: 1-(5-chloro-7-fluoro-3-(piperazin-1-yl)benzo[c]isothiazol-6-yl)-N-methylisoquinolin-3-amine. To a solution of tert-butyl 4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate (Intermediate D, 30 mg, 0.067 mmol) in tetrahydrofuran (0.6 mL) at 0 °C, was added isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran, 0.050 mL, 0.100 mmol). After stirring the mixture for 5 minutes, zinc chloride (1.9 M solution in 2-methyltetrahydrofuran, 0.053 mL, 0.100 mmol) was added, and the reaction mixture was warmed to rt and stirred for 40 minutes. The reaction mixture was then transferred to a vial containing Sphos Pd G3 (5.76 mg, 6.66 μmol) and tert-butyl (1-bromoisoquinolin-3-yl)(methyl)carbamate (24.7 mg, 0.073 mmol, see synthesis below) and heated to 70 °C overnight. The crude reaction was diluted with saturated aqueous NH4Cl (50 mL) and EtOAc (50 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated. Purification by silica gel column chromatography eluting with 6-20% MeOH in DCM gave 1-(5-chloro-7-fluoro-3-(piperazin-1-yl)benzo[c]isothiazol-6-yl)-N-methylisoquinolin-3-amine. m / z (ESI, +ve) 428.1 (M+H). + .

[0371] Synthesis of tert-butyl (1-bromoisoquinolin-3-yl)(methyl)carbamate: To a solution of 1-bromoisoquinolin-3-amine (200 mg, 0.897 mmol, Maybridge Chemical Co., Altrincham, UK) in tetrahydrofuran (5 mL) at rt was added sodium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 1.79 mL, 1.79 mmol). The mixture was stirred for 10 min, and then a solution of Boc-anhydride (0.208 mL, 0.897 mmol) in THF (1 mL) was added. The reaction mixture was stirred for 5 min and then diluted with saturated aqueous NH4Cl (50 mL) and EtOAc (50 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated. Purification by silica gel column chromatography eluting with 0-20% EtOAc in heptane gave tert-butyl (1-bromoisoquinolin-3-yl)carbamate. m / z (ESI, +ve) 345.0 (M+Na). + .

[0372] To a solution of tert-butyl (1-bromoisoquinolin-3-yl)carbamate (140 mg, 0.433 mmol) in tetrahydrofuran (3 mL) at rt was added sodium hydride (60% dispersion in mineral oil, 22.52 mg, 0.563 mmol). The mixture was stirred for 15 min, after which methyl iodide (0.033 mL, 0.520 mmol) was added. After stirring overnight, the reaction was diluted with saturated aqueous NH4Cl (50 mL) and EtOAc (50 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated. Purification by silica gel column chromatography eluting with 0-10% EtOAc in heptane gave tert-butyl (1-bromoisoquinolin-3-yl)(methyl)carbamate. 1 H NMR (400MHz, methanol-d4) δ8.25(d,J=8.61Hz,1H),7.88-7.95(m,2H),7.79(t,J=7.5 Hz,1H),7.70(t,J=7.6Hz,1H),3.42(s,3H),1.54(s,9H).m / z(ESI,+ve)359.1(M+H) + .

[0373] Step 2: 1-(4-(5-chloro-7-fluoro-6-(3-(methylamino)-1-isoquinolinyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one. Procedure similar to Method 1, step 8-2. Purification was carried out by silica gel column chromatography eluting with 0-14% MeOH in DCM over 15 min. 1 H NMR (400MHz, methanol-d4) δ7.90(s,1H),7.63(d,J=8.5Hz,1H),7.43(t,J=7.4Hz,1H),7.24(d,J=8.5Hz,1H),7.05(t,J=7.4Hz,1H),6.72- 6.84(m,1H),6.67(s,1H),6.15-6.28(m,1H),5.68-5.81(m,1H),3.87-3.97(m,4H),3.63(m,4H),2.90(s,3H).m / z(ESI,+ve)482.0(M+H) + .

[0374] Example 25 1-(4-(6-(3-amino-1-isoquinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one [ka] Step 1: tert-Butyl 4-(6-(3-((tert-butoxycarbonyl)amino)isoquinolin-1-yl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate. Procedure as in Example 25, Step 1, using 1.3 M lithium isopropylmagnesium chloride in THF instead of isopropylmagnesium chloride solution, and bis(2-methyl-2-propanyl)(1-bromo-3-isoquinolinyl)-2-imidazocarbamate (synthesis below) instead of tert-butyl(1-bromoisoquinolin-3-yl)(methyl)carbamate. m / z (ESI, +ve) 614.2 (M+H). + .

[0375] Synthesis of bis(2-methyl-2-propanyl)(1-bromo-3-isoquinolinyl)-2-imidodicarbonate: To a solution of 1-bromoisoquinolin-3-amine (1.0 g, 4.48 mmol, Maybridge Chemical Co., Altrincham, UK) in DCM (50 mL) at 0 °C, Boc-anhydride (3.12 mL, 13.45 mmol) and DMAP (0.055 g, 0.448 mmol) were added. The reaction was allowed to warm to rt and stirred overnight. The reaction mixture was diluted with saturated aqueous NH4Cl (100 mL) and DCM (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated. Purification by silica gel column chromatography eluting with 0-10% EtOAc in heptane over 15 min afforded bis(2-methyl-2-propanyl)(1-bromo-3-isoquinolinyl)-2-imidodicarbonate. 1 H NMR(400MHz, methanol-d4)δ8.36(d,J=8.5Hz,1H),8.03(d,J=8.1Hz,1H),7.77-7.92(m,3H),1.44(s,18H).m / z(ESI,+ve)267.0(M+H) + .

[0376] Step 2: 1-(4-(6-(3-amino-1-isoquinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one. Procedure similar to Method 1, Step 8-1 and Step 8-2, using TFA in DCM instead of 4M HCl in dioxane / MeOH in Step 8-1. Purified by silica gel column chromatography eluting with 0-12% MeOH in DCM. This material was then subjected to SFC purification on a diol column (21.2 × 250 mm, 5 μm) using 17% (20 mM NH in MeOH) in supercritical CO (total flow rate of 7 g / min) to give 1-(4-(6-(3-amino-1-isoquinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one. 1H NMR (400MHz, methanol-d4) δ7.85(s,1H),7.53(d,J=8.5Hz,1H),7.39(t,J=7.6Hz,1H),7.23(d,J=8.5Hz,1H),7.03(t,J=7.8Hz,1H),6.82(s,1H),6.71( dd,J=10.8,16.8Hz,1H),6.2(dd,J=1.5,16.8Hz,1H),5.70(dd,J=1.5,10. 8Hz,1H),3.82-3.93(m,4H),3.50-3.66(m,4H).m / z(ESI,+ve)468.0(M+H) + .

[0377] Example 26 1-(4-(6-(2-amino-4-quinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one [ka] Step 1: tert-Butyl 4-(5-chloro-7-fluoro-6-(tributylstannyl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate. A solution of tert-butyl 4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate (Intermediate D, 320 mg, 0.710 mmol), 1,1,1,2,2,2-hexabutyldistannane (824 mg, 1.420 mmol), and tetrakis(triphenylphosphine)palladium(0) (82 mg, 0.071 mmol, Strem Chemicals Inc., NewburyPort, MA, USA) in N,N-dimethylacetamide (5 mL) was placed in a sealed vial and heated at 160 °C in a microwave for 40 min. The reaction mixture was diluted with saturated aqueous NaHCO3 (50 mL), brine (50 mL), and EtOAc (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated. Purification by silica gel column chromatography eluting with 0-30% EtOAc in heptane gave tert-butyl 4-(5-chloro-7-fluoro-6-(tributylstannyl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate. m / z (ESI, +ve) 662.2 (M+H). + .

[0378] Step 2: 2-Methyl-2-propanyl 4-(6-(2-(bis(((2-methyl-2-propanyl)oxy)carbonyl)amino)-4-quinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinecarboxylate. Di-tert-butyl(4-bromoquinolin-2-yl)-2-imidodicarbonate (19.2 mg, 0.045 mmol), prepared in a manner similar to that of bis(2-methyl-2-propanyl)(1-bromo-3-isoquinolinyl)-2-imidodicarbonate in Example 26, was obtained using 4-bromoquinolin-2-amine (Ark Pharm Inc., Arlington Heights, IL, USA) as starting materials, tert-butyl 4-(5-chloro-7-fluoro-6-(tributylstannyl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate (20 mg, 0.030 mmol), and tetrakis(triphenylphosphine)palladium(0) (6.99 mg, 6.05 μmol, Strem Chemicals). A solution of copper(I) iodide (1.153 mg, 6.05 μmol), and cesium fluoride (13.79 mg, 0.091 mmol) in DMF (0.5 mL) was heated at 60 °C in a sealed vial for 30 min. The crude reaction was diluted with saturated aqueous NaHCO (50 mL) and EtOAc (100 mL). The organic layer was separated, dried over NaSO, filtered, and concentrated. Purification by silica gel column chromatography eluting with 0–50% EtOAc in heptane gave 2-methyl-2-propanyl 4-(6-(2-(2-methyl-2-propanyl)oxy)carbonyl)amino-4-quinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinecarboxylate. m / z(ESI,+ve)714.2(M+H) + .

[0379] Step 3: 1-(4-(6-(2-amino-4-quinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one. Procedure similar to Method 1, Step 8-1 and Step 8-2, using TFA in DCM instead of 4M HCl in dioxane / MeOH in Step 8-1. 1 H NMR (400MHz, methanol-d4) δ7.90(s,1H),7.53(d,J=8.2Hz,1H),7.42-7.49(m,1H),7.10(d,J=8.0Hz,1H),7.03-7.08(m,J=7.6Hz,1H),6.67- 6.81(m,2H),6.19(dd,J=1.8,16.6Hz,1H),5.72(dd,J=1.8,10.6Hz,1H),3.87-3.93(m,4H),3.56-3.66(m,4H).m / z(ESI,+ve)468.0(M+H) + .

[0380] Example 27 1-(4-(3-(2-fluoro-6-hydroxyphenyl)-2-methyl-5-(2-(2-propanyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1-piperazinyl)-2-propen-1-one [ka] Step 1: 6,7-Dihydropyrido[2,3-d]pyridazine-5,8-dione. Hydrazine (1.26 mL, 40.2 mmol) was added to a stirred solution of 2,3-pyridinedicarboxylic anhydride (4.00 g, 26.8 mmol) in ethanol (100 mL). The reaction mixture was refluxed for 16 h, then cooled to rt and concentrated in vacuo to give crude 6,7-dihydropyrido[2,3-d]pyridazine-5,8-dione, which was used directly in the next step. m / z (ESI) M+H: 164.1.

[0381] Step 2: 5,8-Dichloropyrido[2,3-d]pyridazine. Pyridine (4.57 mL, 53.7 mmol) was added to a mixture of crude 6,7-dihydropyrido[2,3-d]pyridazine-5,8-dione (4.38 g, 26.8 mmol) in phosphorus oxychloride(v) (20.1 mL, 215 mmol). The reaction mixture was stirred at approximately 100 °C for 2 h. The reaction mixture was cooled and slowly poured into vigorously stirred water (250 mL) at approximately 10 °C. The aqueous suspension was stirred for 15 min and then extracted with EtOAc (250 mL). The organic layer was separated, washed with brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0–100% EtOH in heptane) afforded 5,8-dichloropyrido[2,3-d]pyridazine. 1 H NMR(400MHz,chloroform-d)δ9.41(1H,dd,J=4.30,1.56Hz)8.65(1H,dd,J=8.41,1.56Hz)8.02(1H,dd,J=8.41,4.30Hz).m / z(ESI)M+H:200.0.

[0382] Step 3: 3,5-Dichloropyrido[2,3-d]pyridazin-8(7H)-one and 3,8-dichloropyrido[2,3-d]pyridazin-5(6H)-one. N-Chlorosuccinimide (1268 mg, 9.50 mmol, TCI America, Portland, OR, USA) was added to a stirred solution of 5,8-dichloropyrido[2,3-d]pyridazine (950 mg, 4.75 mmol) in acetic acid (20 mL), and the reaction mixture was heated at 100 °C for 16 h. Additional N-chlorosuccinimide (1268 mg, 9.50 mmol, TCI America, Portland, OR, USA) was added, and the reaction mixture was stirred at 100 °C for an additional 4 h. Additional N-chlorosuccinimide (634 mg, 4.75 mmol, TCI America, Portland, OR, USA) was added, and the reaction mixture was stirred for an additional 4 h. The reaction mixture was then diluted with water (75 mL) and extracted three times with EtOAc (100 mL). The combined organic layers were washed with brine (150 mL), dried over MgSO, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-75% EtOAc in heptane) afforded a regioisomeric mixture of 3,5-dichloropyrido[2,3-d]pyridazin-8(7H)-one and 3,8-dichloropyrido[2,3-d]pyridazin-5(6H)-one. m / z (ESI) M+H: 215.9.

[0383] Step 4: 3,5,8-Trichloropyrido[2,3-d]pyridazine. Pyridine (2.024 mL, 23.79 mmol) was added to a regioisomeric mixture of 3,5-dichloropyrido[2,3-d]pyridazin-8(7H)-one and 3,8-dichloropyrido[2,3-d]pyridazin-5(6H)-one (2.57 g, 11.90 mmol) in phosphorus oxychloride (8.90 mL, 95 mmol). The reaction mixture was stirred at approximately 100°C for 1.5 h. The reaction mixture was cooled and slowly poured into vigorously stirred water (150 mL) at approximately 10°C. The aqueous suspension was stirred for 15 min and then extracted with EtOAc (200 mL). The organic layer was separated, washed with brine (150 mL), dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-50% EtOH in heptane) gave 3,5,8-trichloropyrido[2,3-d]pyridazine. 1 H NMR (400 MHz, chloroform-d) δ 9.27 (1H, d, J = 2.35 Hz) 8.58 (1H, d, J = 2.35 Hz). m / z (ESI) M+H: 233.9.

[0384] Step 5: tert-Butyl 4-(3,5-dichloropyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate. 1-Boc-piperazine (278 mg, 1.494 mmol) was added to a stirred mixture of 3,5,8-trichloropyrido[2,3-d]pyridazine (292 mg, 1.245 mmol) and triethylamine (0.350 mL, 2.491 mmol) in dimethyl sulfoxide (5 mL). The reaction mixture was stirred at rt for 3 h, then diluted with EtOAc (75 mL) and washed with saturated aqueous sodium bicarbonate (75 mL). The organic layer was separated, washed with brine (50 mL), dried over MgSO, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 25% acetone in heptane) afforded t-butyl 4-(3,5-dichloropyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate, the first of two regioisomers to elute. 1H NMR(400MHz,Z-d)δ9.01(1H,d,J=2.54Hz)8.43(1H,d,J=2.54Hz) 4.04-4.15(4H,m)3.64-3.70(4H,m)1.50(9H,s).m / z(ESI)M+H:3

[0385] Step 6: tert-Butyl 4-(3-chloro-5-(2-isopropylphenyl)pyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate. Under an argon atmosphere, tert-butyl 4-(3,5-dichloropyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate (199 mg, 0.518 mmol), 2-isopropylphenylboronic acid (93 mg, 0.570 mmol, Alfa Aesar, Haver Hill, MA, USA), tetrakis(triphenylphosphine)palladium (59.8 mg, 0.052 mmol, Strem Chemicals Inc., NewburyPort, MA, USA), and sodium carbonate (2 M aqueous solution, 1.036 mL, 2.072 mmol) were mixed in 1,4-dioxane (4 mL). The reaction mixture was stirred at 40 °C for 16 h. The reaction mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (40 mL). The organic layer was separated, washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0–50% EtOAc in heptane) afforded a mixture of starting material and the desired product. The mixture was returned to the original reaction conditions using less 2-isopropylphenylboronic acid (56 mg, 0.342 mmol, Alfa Aesar, Haver Hill, MA, USA). The mixture was stirred at 40 °C for 16 h. Additional 2-isopropylphenylboronic acid (28 mg, 0.171 mmol, Alfa Aesar, Haver Hill, MA, USA) was added, and the reaction mixture was stirred for an additional 6 h. The reaction mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (40 mL). The organic layer was separated, washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-50% EtOAc in heptane) afforded tert-butyl 4-(3-chloro-5-(2-isopropylphenyl)pyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate. 1H NMR(400MHz,chloroform-d)δ8.95(1H,d,J=2.35Hz)7.72(1H,d,J=2.54Hz)7.45-7.53(2H,m)7.26-7.33(1H,m)7.16-7.21(1H,m)4.04-4. 23(4H,m)3.66-3.73(4H,m)2.67(1H,spt,J=6.75Hz)1.48(9H,s)1.16(3H,d,J=6.85Hz)1.03(3H,d,J=6.85Hz).m / z(ESI)M+H:468.2.

[0386] Step 7: tert-Butyl 4-(3-chloro-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate. Methyllithium (0.137 mL, 0.219 mmol of a 1.6 M solution in diethyl ether) was added to a stirred solution of tert-butyl 4-(3-chloro-5-(2-isopropylphenyl)pyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate (93 mg, 0.199 mmol) in tetrahydrofuran (1 mL) at −78° C. The reaction mixture was stirred at −78° C. for 5 minutes, then warmed to 0° C. and stirred for 30 minutes. The reaction mixture was cooled back to −78° C., and additional methyllithium (0.068 mL, 0.109 mmol of a 1.6 M solution in diethyl ether) was added. The reaction mixture was stirred at -78 °C for 5 minutes, then warmed to 0 °C and stirred for an additional 15 minutes. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL). The organic layer was separated, washed with brine (20 mL), dried over MgSO4, filtered, and concentrated in vacuo to give crude tert-butyl 4-(3-chloro-5-(2-isopropylphenyl)-2-methyl-1,2-dihydropyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate. m / z (ESI) M+H: 484.3.

[0387] 4,5-Dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile (45.0 mg, 0.198 mmol) was added to a stirred mixture of crude tert-butyl 4-(3-chloro-5-(2-isopropylphenyl)-2-methyl-1,2-dihydropyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate (96 mg, 0.198 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at rt for 10 min. The reaction mixture was diluted with DCM (30 mL) and washed with water (20 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-50% EtOAc in heptane) gave tert-butyl 4-(3-chloro-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate: 1 H NMR(400MHz,chloroform-d)δ7.72(1H,s)7.51-7.55(2H,m)7.32-7.37(1H,m)7.22-7.27(1H,m)4.08-4.25(4H,m)3.71-3.79(4 H,m)2.87(3H,s)2.73(1H,spt,J=6.68Hz)1.54(9H,s)1.21(3H,d,J=6.85Hz)1.07(3H,d,J=6.85Hz).m / z(ESI)M+H:482.1.

[0388] Step 8: tert-Butyl 4-(3-(2-fluoro-6-hydroxyphenyl)-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate. tert-Butyl 4-(3-chloro-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate (78 mg, 0.162 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (101 mg, 0.647 mmol, Combi-Blocks), Sphos Pd G3 (14.00 mg, 0.016 mmol), and sodium carbonate (2 M aqueous solution, 0.324 mL, 0.647 mmol) were mixed in 1,2-dimethoxyethane (1 mL) under an argon atmosphere and then heated at 80 °C for 2.5 h. The reaction mixture was cooled, diluted with EtOAc (30 mL), and washed with water (25 mL). The organic layer was separated, washed with brine (25 mL), dried over MgSO, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-50% EtOAc in heptane) afforded tert-butyl 4-(3-(2-fluoro-6-hydroxyphenyl)-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate (66 mg, 0.118 mmol, 73.1% yield). m / z (ESI) M+H: 558.2.

[0389] Step 9: 3-Fluoro-2-(5-(2-isopropylphenyl)-2-methyl-8-(piperazin-1-yl)pyrido[2,3-d]pyridazin-3-yl)phenol. Trifluoroacetic acid (0.2 mL, 2.68 mmol) was added to a stirred solution of tert-butyl 4-(3-(2-fluoro-6-hydroxyphenyl)-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate (64 mg, 0.115 mmol) in dichloromethane (0.5 mL). The reaction mixture was stirred at rt for 30 min. The reaction mixture was diluted with DCM (30 mL) and quenched with saturated aqueous sodium bicarbonate (20 mL). The organic layer was separated, dried over MgSO, filtered, and concentrated in vacuo to give crude 3-fluoro-2-(5-(2-isopropylphenyl)-2-methyl-8-(piperazin-1-yl)pyrido[2,3-d]pyridazin-3-yl)phenol. m / z (ESI) M+H: 458.1.

[0390] Step 10: 1-(4-(3-(2-Fluoro-6-hydroxyphenyl)-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)piperazin-1-yl)prop-2-en-1-one. Acryloyl chloride (9.45 μL, 0.116 mmol) was added to a stirred mixture of 3-fluoro-2-(5-(2-isopropylphenyl)-2-methyl-8-(piperazin-1-yl)pyrido[2,3-d]pyridazin-3-yl)phenol (53 mg, 0.116 mmol) and triethylamine (0.049 mL, 0.348 mmol) in dichloromethane (1 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes. The reaction mixture was diluted with DCM (25 mL) and quenched with saturated aqueous sodium bicarbonate (20 mL). The organic layer was separated, dried over MgSO, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc in heptane) afforded 1-(4-(3-(2-fluoro-6-hydroxyphenyl)-2-methyl-5-(2-(2-propanyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1-piperazinyl)-2-propen-1-one: 1H NMR(400MHz,chloroform-d)δ9.51(0.6H,brs)8.98(0.4H,brs)7.63(0.4H,s)7.58(0.6H,s)7 .35-7.43(2H,m)7.10-7.26(3H,m)6.78(1H,dd,J=16.63,8.22Hz)6.59-6.71(2H,m)6.36( 1H,dd,J=16.82,1.57Hz)5.78(1H,dd,J=10.56,1.37Hz)4.10-4.38(4H,m)3.80-4.03(4H, m)2.60-2.72(1H,m)2.61(1.2H,s)2.59(1.8H,s)0.91-1.08(6H,m).m / z(ESI)M+H:512.3.

[0391] Example 28 1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-((1R)-1-phenylethyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one and 1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-((1S)-1-phenylethyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one [ka] A mixture of α-methylbenzylzinc bromide (0.5 M in THF, 492 μl, 0.246 mmol), tetrakis(triphenylphosphine)palladium (5.68 mg, 4.92 μmol, Strem Chemicals Inc., NewburyPort, MA, USA), and 1-(4-(4,7-dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one (Intermediate I, 22 mg, 0.049 mmol) was stirred in a sealed vial at 60° C. for 16 h. The reaction mixture was concentrated, and chromatographic purification of the residue (silica gel, 0 to 100% EtOAc in heptane) afforded a mixture of 1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-((1R)-1-phenylethyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one and 1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-((1S)-1-phenylethyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one. 1 H NMR (400 MHz, methanol-d4) δ 8.27 (1H, s), 8.15 (0.33H, s), 8.10 (0.67H, s), 7.19-7.31 (5H, m), 7.10-7.16 (1H, m), 6.86 (1H, dd, J = 16.73, 10.66 Hz), 6.62-6.78 (2H, m), 6.2 7(1H,dd,J=16.82,1.96Hz)5.80(1H,dd,J=10.66,1.86Hz)4.94-5.01(1H,m)3. 93-4.03(4H,m)3.49-3.60(4H,m)1.81(3H,d,J=7.04Hz).m / z(ESI)M+H:517.1.

[0392] Example 29 1-(4-(7-chloro-4-(4-fluorobenzyl)-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one [ka] To a stirred mixture of 1-(4-(4,7-dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one (Intermediate I, 18 mg, 0.040 mmol) and tetrakis(triphenylphosphine)palladium (4.65 mg, 4.02 μmol, Strem Chemicals Inc., NewburyPort, MA, USA) in tetrahydrofuran (0.1 mL) in a sealed vial under an argon atmosphere was added 4-fluorobenzylzinc chloride (0.5 M in THF, 0.089 mL, 0.044 mmol). The reaction mixture was stirred at rt for 2 h and then heated to 40 °C for 3 h. Additional 4-fluorobenzylzinc chloride (0.089 mL, 0.044 mmol) was added, and the reaction mixture was stirred at 40 °C for an additional 16 h. Additional 4-fluorobenzylzinc chloride (0.089 mL, 0.044 mmol) was added, and the reaction mixture was heated to 60 °C and stirred for 6 h. The reaction mixture was concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% EtOAc in heptane) gave 1-(4-(7-chloro-4-(4-fluorobenzyl)-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one. 1 H NMR (400MHz, methanol-d4) δ8.32(1H,s)8.19(1H,s)7.26-7.34(3H,m)6.98(2H,t,J=8.71Hz)6.69-6.91(3H,m)6.28(1H, dd,J=16.92,1.86Hz)5.82(1H,dd,J=10.56,1.76Hz)4.54-4.65(2H,m)3.99(4H,m)3.58(4H,m).m / z(ESI)M+H:521.2.

[0393] Examples 30 and 31 2-(1-(4-acryloyl-1-piperazinyl)-7-chloro-4-phenyl-6-phthalazinyl)-3-fluorophenol (Example 30) and 2-(4-(4-acryloyl-1-piperazinyl)-7-chloro-1-phenyl-6-phthalazinyl)-3-fluorophenol (Example 31) [ka] Step 1: 1,4,6,7-Tetrachlorophthalazine (Intermediate L). To a stirred mixture of 6,7-dichloro-2,3-dihydrophthalazine-1,4-dione (Intermediate G, 610 mg, 2.64 mmol) in phosphorus oxychloride (2.4 mL, 26.4 mmol) was added pyridine (431 μL, 5.28 mmol). The reaction mixture was heated to 100° C. for 2 h, then cooled and poured slowly into vigorously stirred water (75 mL) at approximately 10° C. The resulting suspension was filtered, and the solid was washed with water to give 1,4,6,7-tetrachlorophthalazine. 1 H NMR (400 MHz, chloroform-d) δ 8.43 (2H, s). m / z (ESI) M+H: 266.9.

[0394] Step 2: tert-Butyl 4-(4,6,7-trichlorophthalazin-1-yl)piperazine-1-carboxylate (Intermediate M). To a stirred mixture of 1,4,6,7-tetrachlorophthalazine (Intermediate L, 543 mg, 2.027 mmol) and triethylamine (0.846 mL, 6.08 mmol) in dichloromethane (8 ...

Claims

1. A compound having the structure of formula (I) 【Chemistry 1】 (In the formula, E １ and E ２ are each independently N or CR １ and R １ are independently H, hydroxy, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, NH—C １～６ Alkyl, N(C １～６ alkyl) ２ , cyano, or halo; R ２ Ha, Halo, C １～６ Alkyl, C １～６ Haloalkyl, OR′, N(R′) ２ , C ２～３ Alkenyl, C ２～３ Alkynyl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ heterocycloalkyl, aryl, heteroaryl, and each R' is independently H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１４ Cycloalkyl, C ２～１４ Heterocycloalkyl, C ２～３ Alkenyl, C ２～３ is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R ３ Halo, C １～３ Alkyl, C １～２ Haloalkyl, C １～３ Alkoxy, C ３～４ Cycloalkyl, C ２～３ Alkenyl, C ２～３ alkynyl, aryl, or heteroaryl; R ４ teeth 【Chemistry 2】 and Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C １～６ Alkylene, —O—C ０～５ Alkylene, —S—C ０～５ Alkylene, or —NH—C ０～５ alkylene, and C ２～６ Alkylene, —O—C ２～５ Alkylene, —S—C ２～５ Alkylene, and NH—C ２～５ In the case of alkylene, one carbon atom of said alkylene group can be optionally substituted with O, S or NH; R ４’ is H, C １～６ Alkyl, C ２～６ Alkynyl, C １～６ Alkylene -O-C １～４ Alkyl, C １～６ Alkylene-OH, C １～６ Haloalkyl, cycloalkyl, heterocycloalkyl, C ０～３ Alkylene-C ３～４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ６～１４ aryl, or 【Transformation 3】 Selected from: R ５ and R ６ are each independently H, halo, or C １～６ Alkyl, C ２～６ Alkynyl, C １～６ Alkylene -O-C １～４ Alkyl, C １～６ Alkylene-OH, C １～６ Haloalkyl, C １～６ Alkyleneamines, C ０～６ Alkylene-amides, C ０～３ Alkylene-C(O)OH, C ０～３ Alkylene-C(O)OC １～４ Alkyl, C １～６ Alkylene-O-aryl, C ０～３ Alkylene -C(O)C １～４ Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０－３ Alkylene-C ２～１４ heteroaryl or cyano, or R ５ and R ６ form a 4- to 6-membered ring together with the atoms to which they are attached; and R ７ is H or C １～８ alkyl, or R ７ and R ５ together with the atom to which they are attached form a 4- to 6-membered ring), or a pharmaceutically acceptable salt thereof.

2. A compound having the structure of formula (I) 【Chemistry 4】 (In the formula, E １ and E ２ are each independently N or CR １ and R １ are independently H, hydroxy, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, NH—C １～６ Alkyl, N(C １～４ alkyl) ２ , cyano, or halo; R ２ Ha, Halo, C １～６ Alkyl, C １～６ Haloalkyl, OR′, N(R′) ２ , C ２～３ Alkenyl, C ２～３ Alkynyl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ６～１４ aryl, or C ０～３ Alkylene-C ２～１４ heteroaryl, and each R' is independently H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１４ Cycloalkyl, C ２～３ Alkenyl, C ２～３ is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R ３ Halo, C １～３ Alkyl, C １～２ Haloalkyl, C １～３ Alkoxy, C ３～１４ Cycloalkyl, C ２～３ Alkenyl, C ２～３ alkynyl, aryl, or heteroaryl; R ４ teeth 【Transformation 5】 and Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C １～６ Alkylene, —O—C ０～５ Alkylene, —S—C ０～５ Alkylene, or —NH—C ０～５ alkylene, and C ２～６ Alkylene, —O—C ２～５ Alkylene, —S—C ２～５ Alkylene, and NH—C ２～５ In the case of alkylene, one carbon atom of said alkylene group can be optionally substituted with O, S or NH; R ５ and R ６ are each independently H, halo, or C １～８ Alkyl, C ２～８ Alkynyl, C １～６ Alkylene -O-C １～４ Alkyl, C １～６ Alkylene-OH, C １～６ Haloalkyl, C １～６ Alkyleneamines, C ０～６ Alkylene-amides, C ０～３ Alkylene-C(O)OH, C ０～３ Alkylene-C(O)OC １～４ Alkyl, C １～６ Alkylene-O-aryl, C ０～３ Alkylene -C(O)C １～４ Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ２～１４ heteroaryl or cyano; or R ５ and R ６ form a 4- to 6-membered ring together with the atoms to which they are attached; and R ７ is H or C １～６ alkyl, or R ７ and R ５ together with the atom to which they are attached form a 4- to 6-membered ring), or a pharmaceutically acceptable salt thereof.

3. A compound having the structure of formula (II) 【Transformation 6】 (In the formula, E １ and E ２ are each independently N or CR １ and J is N, NR １０ or CR １０ and M is N, NR １３ or CR １３ and 【Transformation 7】 are the single or double bonds necessary to give all atoms their normal valences; R １ are independently H, hydroxy, C １～６ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, NH—C １～４ Alkyl, N(C １～４ alkyl) ２ , cyano, or halo; R ２ Ha, Halo, C １～６ Alkyl, C １～６ Haloalkyl, OR′, N(R′) ２ , C ２～３ Alkenyl, C ２～３ Alkynyl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ６～１４ aryl, or C ０～３ Alkylene-C ２～１４ heteroaryl, and each R' is independently H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１４ Cycloalkyl, C ２～１４ Heterocycloalkyl, C ２～３ Alkenyl, C ２～３ is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R ３ Halo, C １～３ Alkyl, C １～２ Haloalkyl, C １～３ Alkoxy, C ３～４ Cycloalkyl, C ２～１４ Heterocycloalkyl, C ２～３ Alkenyl, C ２～３ alkynyl, aryl, or heteroaryl; R ４ teeth 【Transformation 8】 and Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C １～６ Alkylene, —O—C ０～５ Alkylene, —S—C ０～５ Alkylene, or —NH—C ０～５ alkylene, and C ２～６ Alkylene, —O—C ２～５ Alkylene, —S—C ２～５ Alkylene, and NH—C ２～５ In the case of alkylene, one carbon atom of said alkylene group can be optionally substituted with O, S or NH; R ４’ is H, C １～８ Alkyl, C ２～８ Alkynyl, C １～６ Alkylene -O-C １～４ Alkyl, C １～６ Alkylene-OH, C １～６ Haloalkyl, cycloalkyl, heterocycloalkyl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ６～１４ aryl, or 【Chemistry 9】 Selected from: R ５ and R ６ are each independently H, halo, or C １～６ Alkyl, C ２～６ Alkynyl, C １～６ Alkylene -O-C １～４ Alkyl, C １～６ Alkylene-OH, C １～６ Haloalkyl, C １～６ Alkyleneamines, C ０～６ Alkylene-amides, C ０～３ Alkylene-C(O)OH, C ０～３ Alkylene-C(O)OC １～４ Alkyl, C １～６ Alkylene-O-aryl, C ０～３ Alkylene -C(O)C １～４ Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ２～１４ heteroaryl or cyano, or R ５ and R ６ form a 4- to 6-membered ring together with the atoms to which they are attached; R ７ is H or C １～８ alkyl, or R ７ and R ５ form, together with the atoms to which they are attached, a 4- to 6-membered ring; Q is CR ８ R ９ , C=CR ８ R ９ , C═O, C═S, or C═NR ８ and R ８ and R ９ are each independently H, C １～３ Alkyl, hydroxy, C １～３ Alkoxy, cyano, nitro, or C ３～６ cycloalkyl, or R ８ and R ９ can form a 3- to 6-membered ring together with the carbon atoms to which they are attached; R １０ is C １～８ Alkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ３～１４ Heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C １～６ Alkoxy, O-C ０～３ Alkylene-C ６～１４ Aryl, O-C ０～３ Alkylene-C ３～１４ Heteroaryl, O-C ０～３ Alkylene-C ３～１４ Cycloalkyl, O-C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, NH—C １～８ Alkyl, N(C １～８ alkyl) ２ , NH-C ０～３ Alkylene-C ６～１４ Aryl, NH—C ０～３ Alkylene-C ２～１４ Heteroaryl, NH—C ０～３ Alkylene-C ３～１４ Cycloalkyl, NH—C ０～３ Alkylene-C ２～１４ heterocycloalkyl, halo, cyano or C １～６ an alkylene-amine, and R １３ is C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkyleneamine, or C ３～１４ cycloalkyl), or a pharmaceutically acceptable salt thereof (however (1) J is NR １０ When M is N or CR １３ and (2) M is NR １３ When J is N or CR １０ and (3) J is CR １０ When M is N or NR １３ and (4) M is CR １３ When J is N or NR １０ (It is).

4. A compound having the structure of formula (II) 【Chemistry 10】 (In the formula, E １ and E ２ are each independently N or CR １ and J is N, NR １０ or CR １０ and M is N, NR １３ or CR １３ and 【Chemistry 11】 are the single or double bonds necessary to give all atoms their normal valences; R １ are independently H, hydroxy, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, NH—C １～４ Alkyl, N(C １～４ alkyl) ２ , cyano, or halo; R ２ Ha, Halo, C １～６ Alkyl, C １～６ Haloalkyl, OR′, N(R′) ２ , C ２～３ Alkenyl, C ２～３ Alkynyl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ６～１４ aryl, or C ０～３ Alkylene-C ２～１４ heteroaryl, and each R' is independently H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１４ Cycloalkyl, C ２～１４ Heterocycloalkyl, C ２～３ Alkenyl, C ２～３ is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R ３ Halo, C １～３ Alkyl, C １～２ Haloalkyl, C １～３ Alkoxy, C ３～４ Cycloalkyl, C ２～３ Alkenyl, C ２～３ alkynyl, aryl, or heteroaryl; R ４ teeth 【Chemistry 12】 and Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C １～６ Alkylene, —O—C ０～５ Alkylene, —S—C ０～５ Alkylene, or —NH—C ０～５ alkylene, and C ２～６ Alkylene, —O—C ２～５ Alkylene, —S—C ２～５ Alkylene, and NH—C ２～５ In the case of alkylene, one carbon atom of said alkylene group can be optionally substituted with O, S or NH; R ５ and R ６ are each independently H, halo, or C １～６ Alkyl, C ２～６ Alkynyl, C １～６ Alkylene -O-C １～４ Alkyl, C １～６ Alkylene-OH, C １～６ Haloalkyl, C １～６ Alkyleneamines, C ０～６ Alkylene-amides, C ０～３ Alkylene-C(O)OH, C ０～３ Alkylene-C(O)OC １～４ Alkyl, C １～６ Alkylene-O-aryl, C ０～３ Alkylene -C(O)C １～４ Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ２～１４ heteroaryl or cyano, or R ５ and R ６ form a 4- to 6-membered ring together with the atoms to which they are attached; R ７ is H or C １～８ alkyl, or R ７ and R ５ form, together with the atoms to which they are attached, a 4- to 6-membered ring; Q is CR ８ R ９ , C=CR ８ R ９ , C═O, C═S, or C═NR ８ and R ８ and R ９ are each independently H, C １～３ Alkyl, hydroxy, C １～３ Alkoxy, cyano, nitro, or C ３～６ cycloalkyl, or R ８ and R ９ can form a 3- to 6-membered ring together with the carbon atoms to which they are attached; R １０ is C １～８ Alkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ３～１４ Heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C １～６ Alkoxy, O-C ０～３ Alkylene-C ６～１４ Aryl, O-C ０～３ Alkylene-C ３～１４ Heteroaryl, O-C ０～３ Alkylene-C ３～１４ Cycloalkyl, O-C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, NH—C １～８ Alkyl, N(C １～８ alkyl) ２ , NH-C ０～３ Alkylene-C ６～１４ Aryl, NH—C ０～３ Alkylene-C ２～１４ Heteroaryl, NH—C ０～３ Alkylene-C ３～１４ Cycloalkyl, NH—C ０～３ Alkylene-C ２～１４ heterocycloalkyl, halo, cyano or C １～６ an alkylene-amine, and R １３ is C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkyleneamine, or C ３～１４ cycloalkyl), or a pharmaceutically acceptable salt thereof (however (1) J is NR １０ When M is N or CR １３ and (2) M is NR １３ When J is N or CR １０ and (3) J is CR １０ When M is N or NR １３ and (4) M is CNR １３ When J is N or NR １０ (It is).

5. Q is C=O, and E １ and E ２ are CR １ When (1) R １０ is C １～３ Alkylene-C ６～１４ Aryl, C １～３ Alkylene-C ３～１４ Heteroaryl, C ０～３ Alkylene-C ３～８ Cycloalkyl, C １～３ Alkylene-C ２～７ heterocycloalkyl or halo, or (2) R １３ is C １～３ Haloalkyl or C ３～５ 5. The compound of claim 3 or 4, which is cycloalkyl.

6. J is NR １０ and M is CR １３ 5. The compound according to claim 3 or 4, wherein

7. J is CR １０ and M is NR １３ 5. The compound according to claim 3 or 4, wherein

8. J is N and M is NR １３ 5. The compound according to claim 3 or 4, wherein

9. J is NR １０ and M is N.

10. A compound having the structure of formula (III) or (III'): 【Chemistry 13】 (In the formula, E １ and E ２ are each independently N or CR １ and R １ are independently H, hydroxy, C １～６ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, NH—C １～４ Alkyl, N(C １～４ alkyl) ２ , cyano, or halo; R ２ Ha, Halo, C １～６ Alkyl, C １～６ Haloalkyl, OR′, N(R′) ２ , C ２～３ Alkenyl, C ２～３ Alkynyl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ６～１４ aryl, or C ０～３ Alkylene-C ２～１４ heteroaryl, and each R' is independently H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１４ Cycloalkyl, C ２～１４ Heterocycloalkyl, C ２～３ Alkenyl, C ２～３ is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R ３ Halo, C １～３ Alkyl, C １～２ Haloalkyl, C １～３ Alkoxy, C ３～４ Cycloalkyl, C ２～１４ Heterocycloalkyl, C ２～３ Alkenyl, C ２～３ alkynyl, aryl, or heteroaryl; R ４ teeth 【Chemistry 14】 and Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C １～６ Alkylene, —O—C ０～５ Alkylene, —S—C ０～５ Alkylene, or —NH—C ０～５ alkylene, and C ２～６ Alkylene, —O—C ２～５ Alkylene, —S—C ２～５ Alkylene, and NH—C ２～５ In the case of alkylene, one carbon atom of said alkylene group can be optionally substituted with O, S or NH; R ４’ is H, C １～８ Alkyl, C ２～８ Alkynyl, C １～６ Alkylene -O-C １～４ Alkyl, C １～６ Alkylene-OH, C １～６ Haloalkyl, cycloalkyl, heterocycloalkyl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ６～１４ aryl, or 【Chemistry 15】 Selected from: R ５ and R ６ are each independently H, halo, or C １～６ Alkyl, C ２～６ Alkynyl, C １～６ Alkylene -O-C １～４ Alkyl, C １～６ Alkylene-OH, C １～６ Haloalkyl, C １～６ Alkyleneamines, C ０～６ Alkylene-amides, C ０～３ Alkylene-C(O)OH, C ０～３ Alkylene-C(O)OC １～４ Alkyl, C １～６ Alkylene-O-aryl, C ０～３ Alkylene -C(O)C １～４ Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ２～１４ heteroaryl or cyano, or R ５ and R ６ form a 4- to 6-membered ring together with the atoms to which they are attached; R ７ is H or C １～８ alkyl, or R ７ and R ５ form, together with the atoms to which they are attached, a 4- to 6-membered ring; Q is CR ８ R ９ , C=CR ８ R ９ , C═O, C═S, or C═NR ８ and R ８ and R ９ are each independently H, C １～６ Alkyl, hydroxy, C １～６ Alkoxy, cyano, nitro, or C ３～１４ cycloalkyl, or R ８ and R ９ can form a 3- to 6-membered ring together with the carbon atoms to which they are attached; R １０ is C １～８ Alkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ３～１４ Heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C １～６ Alkoxy, O-C ０～３ Alkylene-C ６～１４ Aryl, O-C ０～３ Alkylene-C ３～１４ Heteroaryl, O-C ０～３ Alkylene-C ３～１４ Cycloalkyl, O-C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, NH—C １～８ Alkyl, N(C １～８ alkyl) ２ , NH-C ０～３ Alkylene-C ６～１４ Aryl, NH—C ０～３ Alkylene-C ２～１４ Heteroaryl, NH—C ０～３ Alkylene-C ３～１４ Cycloalkyl, NH—C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, halo, cyano or C １～６ alkylene-amine), or a pharmaceutically acceptable salt thereof.

11. A compound having the structure of formula (III) or formula (III') 【Chemistry 16】 (In the formula, E １ and E ２ are each independently N or CR １ and R １ are independently H, hydroxy, C １～６ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, NH—C １～４ Alkyl, N(C １～４ alkyl) ２ , cyano, or halo; R ２ Ha, Halo, C １～６ Alkyl, C １～６ Haloalkyl, OR′, N(R′) ２ , C ２～３ Alkenyl, C ２～３ Alkynyl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ６～１４ aryl, or C ０～３ Alkylene-C ２～１４ heteroaryl, and R' is independently H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１４ Cycloalkyl, C ２～１４ Heterocycloalkyl, C ２～３ Alkenyl, C ２～３ is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R ３ Halo, C １～３ Alkyl, C １～２ Haloalkyl, C １～３ Alkoxy, C ３～４ cycloalkyl, C ２～１４ Heterocycloalkyl, C ２～３ Alkenyl, C ２～３ alkenyl, aryl, or heteroaryl; R ４ teeth 【Chemistry 17】 and Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C １～６ Alkylene, —O—C ０～５ Alkylene, —S—C ０～５ Alkylene, or —NH—C ０～５ alkylene, and C ２～６ Alkylene, —O—C ２～５ Alkylene, —S—C ２～５ Alkylene, and NH—C ２～５ In the case of alkylene, one carbon atom of said alkylene group can be optionally substituted with O, S or NH; R ５ and R ６ are each independently H, halo, or C １～６ Alkyl, C ２～６ Alkynyl, C １～６ Alkylene -O-C １～４ Alkyl, C １～６ Alkylene-OH, C １～６ Haloalkyl, C １～６ Alkyleneamines, C ０～６ Alkylene-amides, C ０～３ Alkylene-C(O)OH, C ０～３ Alkylene-C(O)OC １～４ Alkyl, C １～６ Alkylene-O-aryl, C ０～３ Alkylene -C(O)C １～４ Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ２～１４ heteroaryl or cyano, or R ５ and R ６ form a 4- to 6-membered ring together with the atoms to which they are attached; R ７ is H or C １～８ alkyl, or R ７ and R ５ form, together with the atoms to which they are attached, a 4- to 6-membered ring; Q is CR ８ R ９ , C=CR ８ R ９ , C═O, C═S, or C═NR ８ and R ８ and R ９ are each independently H, C １～６ Alkyl, hydroxy, C １～６ Alkoxy, cyano, nitro, or C ３～１４ cycloalkyl, or R ８ and R ９ can form a 3- to 6-membered ring together with the carbon atoms to which they are attached; R １０ is C １～８ Alkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ３～１４ Heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C １～６ Alkoxy, O-C ０～３ Alkylene-C ６～１４ Aryl, O-C ０～３ Alkylene-C ３～１４ Heteroaryl, O-C ０～３ Alkylene-C ３～１４ Cycloalkyl, O-C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, NH—C １～８ Alkyl, N(C １～８ alkyl) ２ , NH-C ０～３ Alkylene-C ６～１４ Aryl, NH—C ０～３ Alkylene-C ２～１４ Heteroaryl, NH—C ０～３ Alkylene-C ３～１４ Cycloalkyl, NH—C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, halo, cyano or C １～６ alkylene-amine), or a pharmaceutically acceptable salt thereof.

12. 12. The compound of claim 10 or 11 having the structure of formula (III):

13. 12. The compound of claim 10 or 11, having the structure of formula (III'):

14. The compound of any one of claims 3 to 12, wherein Q is C=O.

15. The compound of any one of claims 3 to 12, wherein Q is C=S.

16. Q is C=NR ８ The compound according to any one of claims 3 to 12, wherein

17. R ８ is C １～２ 17. The compound of claim 16, which is alkyl.

18. Q is CR ８ R ９ The compound according to any one of claims 3 to 12, wherein

19. Q is C=CR ８ R ９ The compound according to any one of claims 3 to 12, wherein

20. R ８ and R ９ The compound according to claim 18 or 19, wherein, together with the carbon atoms to which they are attached, form a 3- to 4-membered ring.

21. R ８ is C １～２ alkyl, and R ９ 20. The compound of claim 18 or 19, wherein is H.

22. A compound having the structure of formula (IV) or formula (IV') [Chemistry 18] (In the formula, E １ and E ２ are each independently CR １ or N; R １ are independently H, hydroxy, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, NH—C １～６ Alkyl, N(C １～６ alkyl) ２ , cyano, or halo; R ２ Ha, Halo, C １～６ Alkyl, C １～６ Haloalkyl, OR′, N(R′) ２ , C ２～３ Alkenyl, C ２～３ Alkynyl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ６～１４ aryl, or C ０～３ Alkylene-C ２～１４ heteroaryl, and each R' is independently H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１４ Cycloalkyl, C ２～１４ Heterocycloalkyl, C ２～３ Alkenyl, C ２～３ is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R ３ Halo, C １～２ Haloalkyl, C １～３ Alkoxy, C ３～４ Cycloalkyl, C ２～３ Alkenyl, C ２～３ alkynyl, aryl, or heteroaryl; R ４ teeth 【Chemistry 19】 and Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C １～６ Alkylene, —O—C ０～５ Alkylene, —S—C ０～５ Alkylene, or —NH—C ０～５ alkylene, and C ２～６ Alkylene, —O—C ２～５ Alkylene, —S—C ２～５ Alkylene, and NH—C ２～５ In the case of alkylene, one carbon atom of said alkylene group can be optionally substituted with O, S or NH; R ４’ is H, C １～８ Alkyl, C ２～８ Alkynyl, C １～６ Alkylene -O-C １～４ Alkyl, C １～６ Alkylene-OH, C １～６ Haloalkyl, cycloalkyl, heterocycloalkyl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ６～１４ aryl, or 【Chemistry 20】 Selected from: R ５ and R ６ are each independently H, halo, or C １～６ Alkyl, C ２～６ Alkynyl, C １～６ Alkylene -O-C １～４ Alkyl, C １～６ Alkylene-OH, C １～６ Haloalkyl, C １～６ Alkyleneamines, C ０～６ Alkylene-amides, C ０～３ Alkylene-C(O)OH, C ０～３ Alkylene-C(O)OC １～４ Alkyl, C １～６ Alkylene-O-aryl, C ０～３ Alkylene -C(O)C １～４ Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ２～１４ heteroaryl or cyano, or R ５ and R ６ form a 4- to 6-membered ring together with the atoms to which they are attached; R ７ is H or C １～８ alkyl, or R ７ and R ５ form, together with the atoms to which they are attached, a 4- to 6-membered ring; R ８ is H, C １～３ Alkyl, hydroxy, C １～３ Alkoxy, halo, cyano, nitro, C ３～１４ cycloalkyl, or NR １１ R １２ and R １１ and R １２ are each independently H, C １～８ Alkyl, or C ３～１４ is cycloalkyl; and R １０ is C １～８ Alkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ２～１４ Heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C １～６ Alkoxy, O-C ０～３ Alkylene-C ６～１４ Aryl, O-C ０～３ Alkylene-C ２～１４ Heteroaryl, O-C ０～３ Alkylene-C ３～１４ Cycloalkyl, O-C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, NH—C １～８ Alkyl, N(C １～８ alkyl) ２ , NH-C ０～３ Alkylene-C ６～１４ Aryl, NH—C ０～３ Alkylene-C ２～１４ Heteroaryl, N—C ０～３ Alkylene-C ３～１４ Cycloalkyl, N—C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, halo, cyano or C １～６ alkylene-amine), or a pharmaceutically acceptable salt thereof.

23. A compound having the structure of formula (IV) or formula (IV') 【Chemistry 21】 (In the formula, E １ and E ２ are each independently CR １ or N; R １ are independently H, hydroxy, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, NH—C １～６ Alkyl, N(C １～６ alkyl) ２ , cyano, or halo; R ２ Ha, Halo, C １～６ Alkyl, C １～６ Haloalkyl, OR′, N(R′) ２ , C ２～３ Alkenyl, C ２～３ Alkynyl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ６～１４ aryl, or C ０～３ Alkylene-C ２～１４ heteroaryl, and each R' is independently H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１４ Cycloalkyl, C ２～１４ Heterocycloalkyl, C ２～３ Alkenyl, C ２～３ is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R ３ Halo, C １～２ Haloalkyl, C １～３ Alkoxy, C ３～１４ Cycloalkyl, C ２～３ Alkenyl, C ２～３ alkynyl, aryl, or heteroaryl; R ４ teeth 【Chemistry 22】 and Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C １～６ Alkylene, —O—C ０～５ Alkylene, —S—C ０～５ Alkylene, or —NH—C ０～５ alkylene, and C ２～６ Alkylene, —O—C ２～５ Alkylene, —S—C ２～５ Alkylene, and NH—C ２～５ In the case of alkylene, one carbon atom of said alkylene group can be optionally substituted with O, S or NH; R ５ and R ６ are each independently H, halo, or C １～６ Alkyl, C ２～６ Alkynyl, C １～６ Alkylene -O-C １～４ Alkyl, C １～６ Alkylene-OH, C １～６ Haloalkyl, C １～６ Alkyleneamines, C ０～６ Alkylene-amides, C ０～３ Alkylene-C(O)OH, C ０～３ Alkylene-C(O)OC １～４ Alkyl, C １～６ Alkylene-O-aryl, C ０～３ Alkylene -C(O)C １～４ Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ２～１４ heteroaryl or cyano, or R ５ and R ６ form a 4- to 6-membered ring together with the atoms to which they are attached; R ７ is H or C １～８ alkyl, or R ７ and R ５ form, together with the atoms to which they are attached, a 4- to 6-membered ring; R ８ is H, C １～３ Alkyl, hydroxy, C １～３ Alkoxy, halo, cyano, nitro, C ３～１４ cycloalkyl, or NR １１ R １２ and R １１ and R １２ are each independently H, C １～８ Alkyl, or C ３～１５ is cycloalkyl; and R １０ is C １～８ Alkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ３～１４ Heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C １～６ Alkoxy, O-C ０～３ Alkylene-C ６～１４ Aryl, O-C ０～３ Alkylene-C ３～１４ Heteroaryl, O-C ０～３ Alkylene-C ３～１４ Cycloalkyl, O-C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, NH—C １～８ Alkyl, N(C １～８ alkyl) ２ , NH-C ０～３ Alkylene-C ６～１４ Aryl, NH—C ０～３ Alkylene-C ２～１４ Heteroaryl, NH—C ０～３ Alkylene-C ３～１４ Cycloalkyl, NH—C ０～３ Alkylene-C ２～１４ heterocycloalkyl, halo, cyano or C １～６ alkylene-amine), or a pharmaceutically acceptable salt thereof.

24. 24. The compound of claim 22 or 23, having the structure of formula (IV):

25. 24. The compound of claim 22 or 23, having the structure of formula (IV'):

26. E １ and E ２ are CR １ and R ８ is hydroxy, halo, nitro, or C ３～６ The compound of any one of claims 22 to 25, which is cycloalkyl.

27. R ８ The compound of any one of claims 22 to 25, wherein is methyl.

28. A compound having the structure of formula (V) 【Chemistry 23】 (In the formula, E １ and E ２ are each independently CR １ or N; R １ are independently H, hydroxy, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, NH—C １～６ Alkyl, N(C １～６ alkyl) ２ , cyano, or halo; R ２ Ha, Halo, C １～６ Alkyl, C １～６ Haloalkyl, OR′, N(R′) ２ , C ２～３ Alkenyl, C ２～３ Alkynyl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ６～１４ aryl, or C ０～３ Alkylene-C ２～１４ heteroaryl, and each R' is independently H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１４ Cycloalkyl, C ２～１４ Heterocycloalkyl, C ２～３ Alkenyl, C ２～３ is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R ３ Halo, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C ３～１４ Cycloalkyl, C ２～６ Alkenyl, C ２～６ alkynyl, aryl, or heteroaryl; R ４ teeth 【Chemistry 24】 and Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C １～６ Alkylene, —O—C ０～５ Alkylene, —S—C ０～５ Alkylene, or —NH—C ０～５ alkylene, and C ２～６ Alkylene, —O—C ２～５ Alkylene, —S—C ２～５ Alkylene, and NH—C ２～５ In the case of alkylene, one carbon atom of said alkylene group can be optionally substituted with O, S or NH; R ４’ is H, C １～８ Alkyl, C ２～８ Alkynyl, C １～６ Alkylene -O-C １～４ Alkyl, C １～６ Alkylene-OH, C １～６ Haloalkyl, cycloalkyl, heterocycloalkyl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ６ ~ １４ aryl, or 【Chemistry 25】 Selected from: R ５ and R ６ are each independently H, halo, or C １～６ Alkyl, C ２～６ Alkynyl, C １～６ Alkylene -O-C １～４ Alkyl, C １～６ Alkylene-OH, C １～６ Haloalkyl, C １～６ Alkyleneamines, C ０～６ Alkylene-amides, C ０～３ Alkylene-C(O)OH, C ０～３ Alkylene-C(O)OC １～４ Alkyl, C １～６ Alkylene-O-aryl, C ０～３ Alkylene -C(O)C １～４ Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ２～１４ heteroaryl or cyano, or R ５ and R ６ form a 4- to 6-membered ring together with the atoms to which they are attached; R ７ is H or C １～８ alkyl, or R ７ and R ５ together with the atoms to which they are attached form a 4- to 6-membered ring; and R １０ is C １～８ Alkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ３～１４ Heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C １～６ Alkoxy, O-C ０～３ Alkylene-C ６～１４ Aryl, O-C ０～３ Alkylene-C ３～１４ Heteroaryl, O-C ０～３ Alkylene-C ３～１４ Cycloalkyl, O-C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, NH—C １～８ Alkyl, N(C １～８ alkyl) ２ , NH-C ０～３ Alkylene-C ６～１４ Aryl, NH—C ０～３ Alkylene-C ２～１４ Heteroaryl, NH—C ０～３ Alkylene-C ３～１４ Cycloalkyl, NH—C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, halo, cyano or C １～６ alkylene-amine), or a pharmaceutically acceptable salt thereof.

29. A compound having the structure of formula (V) 【Chemistry 26】 (In the formula, E １ and E ２ are each independently CR １ or N; R １ are independently H, hydroxy, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, NH—C １～６ Alkyl, N(C １～６ alkyl) ２ , cyano, or halo; R ２ Ha, Halo, C １～６ Alkyl, C １～６ Haloalkyl, OR′, N(R′) ２ , C ２～３ Alkenyl, C ２～３ Alkynyl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ６～１４ aryl, or C ０～３ Alkylene-C ２～１４ heteroaryl, and each R' is independently H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１４ Cycloalkyl, C ２～１４ Heterocycloalkyl, C ２～３ Alkenyl, C ２～３ is alkynyl, aryl, or heteroaryl, or two R' substituents together with the nitrogen atom to which they are attached form a 3- to 7-membered ring; R ３ Halo, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C ３～１４ Cycloalkyl, C ２～８ Alkenyl, C ２～８ alkynyl, aryl, or heteroaryl; R ４ teeth 【Chemistry 27】 and Ring A is a monocyclic 4- to 7-membered ring or a bicyclic bridged, fused, or spiro 6- to 11-membered ring; L is bond, C １～６ Alkylene, —O—C ０～５ Alkylene, —S—C ０～５ Alkylene, or —NH—C ０～５ alkylene, and C ２～６ Alkylene, —O—C ２～５ Alkylene, —S—C ２～５ Alkylene, and NH—C ２～５ In the case of alkylene, one carbon atom of said alkylene group can be optionally substituted with O, S or NH; R ５ and R ６ are each independently H, halo, or C １～６ Alkyl, C ２～６ Alkynyl, C １～６ Alkylene -O-C １～４ Alkyl, C １～６ Alkylene-OH, C １～６ Haloalkyl, C １～６ Alkyleneamines, C ０～６ Alkylene-amides, C ０～３ Alkylene-C(O)OH, C ０～３ Alkylene-C(O)OC １～４ Alkyl, C １～６ Alkylene-O-aryl, C ０～３ Alkylene -C(O)C １～４ Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ２～１４ heteroaryl or cyano, or R ５ and R ６ form a 4- to 6-membered ring together with the atoms to which they are attached; R ７ is H or C １～８ alkyl, or R ７ and R ５ together with the atoms to which they are attached form a 4- to 6-membered ring; and R １０ is C １～８ Alkyl, C ０～３ Alkylene-C ６～１４ Aryl, C ０～３ Alkylene-C ３～１４ Heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, C １～６ Alkoxy, O-C ０～３ Alkylene-C ６～１４ Aryl, O-C ０～３ Alkylene-C ３～１４ Heteroaryl, O-C ０～３ Alkylene-C ３～１４ Cycloalkyl, O-C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, NH—C １～８ Alkyl, N(C １～８ alkyl) ２ , NH-C ０～３ Alkylene-C ６～１４ Aryl, NH—C ０～３ Alkylene-C ２～１４ Heteroaryl, NH—C ０～３ Alkylene-C ３～１４ Cycloalkyl, NH—C ０～３ Alkylene-C ２～１４ heterocycloalkyl, halo, cyano or C １～６ alkylene-amine), or a pharmaceutically acceptable salt thereof.

30. E １ and E ２ are CR １ The compound according to any one of claims 1 to 29,

31. E １ is CR １ and E ２ The compound of any one of claims 1, 2, 3, 4 and 6 to 29, wherein is N.

32. E １ is N and E ２ is CR １ 30. The compound according to any one of claims 1, 2, 3, 4 and 6 to 29,

33. E １ and E ２ and each is N.

34. R １０ is C １～６ Alkyl, aryl, heteroaryl, C ３～１４ Cycloalkyl, C ２～１５ Heterocycloalkyl, C １～４ Alkoxy, O-C ０～３ Alkylene-C ６～１４ Aryl, O-C ０～３ Alkylene-C ２～１４ Heteroaryl, O-C ０～３ Alkylene-C ３～１４ Cycloalkyl, O-C ０～３ Alkylene-C ２～１４ Heterocycloalkyl, NH—C １～８ Alkyl, N(C １～８ alkyl) ２ , NH-C ０～３ Alkylene-C ３～１４ Aryl, NH—C ０～３ Alkylene-C ２～１４ Heteroaryl, NH—C ０～３ Alkylene-C ３～１４ Cycloalkyl or NH—C ０～３ Alkylene-C ２～１４ The compound of any one of claims 1, 2, 3, 4 and 6-33, which is heterocycloalkyl.

35. E １ and E ２ are CR １ and R １０ is C １～３ Alkylene-C ６ - １４ Aryl, C １～３ Alkylene-C ２～１４ Heteroaryl, C ０～３ Alkylene-C ３～１４ Cycloalkyl, C １～３ Alkylene-C ２～１４ 30. The compound of claim 28 or 29, which is heterocycloalkyl or halo.

36. R １０ is C １～８ The compound of any one of claims 3 to 33, which is alkyl.

37. R １０ is C ０～３ Alkylene-C ６～１４ The compound of any one of claims 3 to 33, which is aryl.

38. R １０ is C ０～３ Alkylene-C ３～１４ The compound of any one of claims 3 to 34, which is heteroaryl.

39. R １０ is C ０～３ Alkylene-C ３～１４ The compound of any one of claims 3 to 35, which is cycloalkyl.

40. R １０ is C ０～３ Alkylene-C ２～１４ The compound of any one of claims 3 to 24, 26, 27 and 30 to 33, which is a heterocycloalkyl.

41. R １０ is C ０～６ The compound of any one of claims 3 to 33, which is an alkylene-amine.

42. R １０ is i-Pr, t-Bu, phenyl, benzyl, OCH ３ , Cl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 【Chemistry 28】 【Chemistry 29】 The compound according to any one of claims 3 to 33, selected from the group consisting of:

43. R １０ The compound of any one of claims 3 to 33, wherein comprises an ortho-substituted aryl, an ortho-substituted heteroaryl, or a 2-substituted cyclohexyl.

44. R １０ teeth, 【Transformation 30】 44. The compound of claim 43, selected from the group consisting of:

45. R １ The compound of any one of claims 1 to 44, wherein is H.

46. R １ The compound of any one of claims 1 to 44, wherein is F.

47. R １ The compound of any one of claims 1 to 44, wherein is methyl.

48. R ２ The compound of any one of claims 1 to 47, wherein is aryl.

49. R ２ The compound of any one of claims 1 to 47, wherein is heteroaryl.

50. R ２ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidine, pyrrolidine, azetidine, phenyl, naphthyl, pyridyl, indazolyl, indolyl, azaindolyl, indolinyl, benzotriazolyl, benzoxadiazolyl, imidazolyl, cinnolinyl, imidazopyridyl, pyrazolopyridyl, quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, indolinonyl, isoindolinonyl, tetrahydronaphthyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl.

51. R ２ is Cl, Br, CF ３ , OCH ３ , OCH ２ CH ３ , phenyl, 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 48. The compound of any one of claims 1 to 47, selected from the group consisting of:

52. R ２ is bromine, 【Transformation 34】 48. The compound of any one of claims 1 to 47, selected from the group consisting of:

53. R ３ The compound of any one of claims 1 to 52, wherein is halo.

54. R ３ 54. The compound of claim 53, wherein is Cl.

55. R ３ is C １～２ The compound of any one of claims 1 to 52, which is alkyl.

56. R ３ is methyl.

57. R ３ is C １～２ The compound of any one of claims 1 to 52, which is haloalkyl.

58. R ３ is CF ３ 58. The compound of claim 57, wherein:

59. R ４ teeth 【Chemistry 35】 59. The compound of any one of claims 1 to 58, wherein

60. Ring A is 【Transformation 36】 60. The compound of claim 59, wherein:

61. R ４ teeth 【Chemistry 37】 59. The compound of any one of claims 1 to 58, wherein

62. Ring A is 【Transformation 38】 62. The compound of claim 61, selected from the group consisting of:

63. R ４ teeth 【Chemistry 39】 59. The compound of any one of claims 1 to 58, wherein

64. R ４ teeth 【Chemistry 40】 59. The compound of any one of claims 1 to 58, wherein

65. Ring A is 【Chemistry 41】 65. The compound of claim 64, selected from the group consisting of: 【Request Item 66】 【Chemistry 42】 teeth 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 66. The compound of any one of claims 59 to 65, selected from the group consisting of:

67. 67. The compound of any one of claims 59 to 66, wherein L is a bond.

68. L is C １～２ 67. The compound of any one of claims 59 to 66, which is alkylene.

69. 67. The compound of claim 59, 60, 62, 63 or 66, wherein L is O.

70. 67. The compound of claim 59, 60, 62, 63 or 66, wherein L is S.

71. 67. The compound of claim 59, 61, 64, 65 or 66, wherein L is NH.

72. 67. The compound of any one of claims 1 to 59, 61, 63, 64 and 66, wherein Ring A comprises piperidinyl, piperazinyl, pyrrolidinyl or azetidinyl.

73. 73. The compound of claim 72, wherein Ring A comprises piperidinyl.

74. R ５ 66. The compound of any one of claims 1 to 59, 61, 63, 64 and 65, wherein is H or halo.

75. R ５ are H, Br, Cl, F, CN, CH ３ , C.F. ３ , C.H. ２ Br, CH ２ OH, CH ２ CH ２ OH, CH ２ OCH ２ Phenyl, cyclopropyl, phenyl, CH ２ Phenyl, CH ２ OCH ３ , C.H. ２ N (CH ３ ) ２ , C.H. ２ N (CH ２ CH ３ ) ２ , C.H. ２ CO ２ H, CH ２ CO ２ CH ３ , C.H. ２ NHC(O)CH ３ , C.H. ２ C(O)NHCH ３ , C.H. ２ OC(O)CH ３ ,or 【Chemistry 47】 66. The compound according to any one of claims 1 to 59, 61, 63, 64 and 65,

76. R ６ is H, C １～３ Alkyl, C １～３ Alkylene -O-C １～２ Alkyl, C １～３ Alkylene-OH, C １～３ Haloalkyl, C １～３ Alkylene-amines, C ０～３ Alkylene-amides, C ０～１ Alkylene C(O)OC １～３ Alkyl, C ０～１ Alkylene-C ２～７ Heterocycloalkyl, C ０～１ Alkylene-C ３～８ cycloalkyl, or C ０～３ Alkylene-C ６～１４ The compound of any one of claims 1 to 65 and 67 to 75, which is aryl.

77. R ６ is C １～３ Alkylene-amine or C １～３ alkylene amide, CH ２ NH ２ , CH(CH ３ ) NH ２ , CH(CH ３ ) ２ NH ２ , C.H. ２ CH ２ NH ２ , C.H. ２ CH ２ N (CH ３ ) ２ , C.H. ２ NHCH ３ , C(O)NHCH ３ , C(O)N(CH ３ ) ２ , C.H. ２ C(O)NHphenyl, CH ２ NHC(O)CH ３ , C.H. ２ NHCH ２ CH ２ OH, CH ２ NHCH ２ CO ２ H, CH ２ NH (CH ３ ) CH ２ CO ２ CH ３ , C.H. ２ NHCH ２ CH ２ OCH ３ , C.H. ２ NH (CH ３ ) CH ２ CH ２ OCH ３ , C.H. ２ NH (CH ３ ) CH ２ C(O)N(CH ３ ) ２ , C.H. ２ NH (CH ３ ) CH ２ C(O)NHCH ３ , C.H. ２ NMe ２ , C.H. ２ NH (CH ３ ) CH ２ CH ２ OH, CH ２ NH(CH) ３ )CH ２ CH ２ F, CH ２ N ＋ (CH) ３ ) ３ CH ２ NHCH ２ CHF ２ CH ２ NHCH ２ CH ３ 、 【Chemistry 48】 77. The compound of claim 76, selected from the group consisting of:

78. R ６ is phenyl, cyclopropyl, CH ３ , C.F. ３ , C.H. ２ CH ３ , C.H. ２ NH ２ , CH(CH ３ ) NH ２ , CH(CH ３ ) ２ NH ２ , C.H. ２ Cl, CH ２ Br, CH ２ OCH ３ , C.H. ２ Ophenyl, CH ２ OH, CO ２ H, CO ２ CH ２ CH ３ , C.H. ２ CO ２ H, CH ２ CH ２ NH ２ , C.H. ２ CH ２ OH, CH ２ CH ２ N (CH ３ ) ２ , C.H. ２ NHCH ３ , C(O)NHCH ３ , C(O)N(CH ３ ) ２ , C.H. ２ C(O)NHphenyl, CH ２ CHF ２ , C.H. ２ F, CHF ２ , C.H. ２ NHC(O)CH ３ , C.H. ２ NHCH ２ CH ２ OH, CH ２ NHCH ２ CO ２ H, CH ２ NH (CH ３ ) CH ２ CO ２ CH ３ , C.H. ２ NHCH ２ CH ２ OCH ３ CH ２ NH(CH) ３ )CH ２ CH ２ OCH ３ CH ２ NH(CH) ３ )CH ２ C(O)N(CH) ３ ) ２ CH ２ NH(CH) ３ )CH ２ C(O)NHCH ３ CH ２ CH ２ CH, CH ２ NME ２ CH ２ NH(CH) ３ )CH ２ CH ２ OH, CH ２ NH(CH) ３ )CH ２ CH ２ F, CH ２ N ＋ (CH) ３ ) ３ CH ２ NHCH ２ CHF ２ CH ２ NHCH ２ CH ３ 、 【Chemistry 49】 76. The compound according to any one of claims 1 to 65 and 67 to 75,

79. R ５ and R ６ Both [Transformation 50] 74. The compound according to any one of claims 1 to 65 and 67 to 73,

80. R ５ and R ６ The compound according to any one of claims 1 to 65 and 67 to 73, wherein each is H.

81. R ７ The compound of any one of claims 1 to 58 and 63 to 80, wherein

82. R ７ The compound of any one of claims 1 to 58 and 63 to 80, wherein is methyl.

83. R ７ and R ５ are both -CH ２ - or -C(O)CH ２ The compound according to any one of claims 1 to 58, 63 to 65, 67 to 73 and 76 to 78, wherein

84. R ４ teeth 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 59. The compound of any one of claims 1 to 58, selected from the group consisting of:

85. Compounds listed in Table 1.

86. 86. The compound of any one of claims 1 to 85 in the form of a pharmaceutically acceptable salt.

87. 87. A pharmaceutical formulation comprising a compound of any one of claims 1 to 86 and a pharmaceutically acceptable excipient.

88. 88. A method of inhibiting KRAS G12C in a cell, comprising contacting said cell with a compound of any one of claims 1 to 86 or a composition of claim 87.

89. 88. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 86 or a composition of claim 87.

90. 90. The method of claim 89, wherein the cancer is lung cancer, pancreatic cancer, or colon cancer. 【Request Item 91】 【Chemistry 54】 【Transformation 55】 A compound having a structure selected from:

92. 92. The compound of claim 91 in the form of a pharmaceutically acceptable salt.

93. 93. A pharmaceutical formulation comprising a compound of claim 91 or 92 and a pharmaceutically acceptable excipient.

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