Inhibitors targeting ubiquitin-specific protease 7 (USP7)

Abstract

Disclosed herein are inhibitors of the deubiquitinating (DUB) enzyme USP7 (ubiquitin-specific protease 7). Also provided are methods of treating diseases or disorders regulated by USP7.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 223,788, filed July 20, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Deubiquitinating enzymes (DUBs) have attracted significant attention as drug targets over the past 5–10 years. DUB inhibitors effectively promote the degradation of oncogenic proteins, especially those that are difficult to target directly because they are stabilized by DUB family members. Thus, highly optimized and well-characterized DUB inhibitors have become highly sought-after tools. However, most reported DUB inhibitors are combination drugs with weak (micromolar) potency against their primary targets, limiting their utility in target validation and mechanistic studies.

[0003] The DUB enzyme USP7 (ubiquitin-specific protease 7) has been shown to be involved in the regulation of numerous cellular processes including epigenetics, cell cycle, DNA repair, immunity, viral infection and tumor development. USP7, also known as herpesvirus-associated ubiquitin-specific protease (HAUSP), was first discovered as a protein that plays a role in the lytic propagation of viruses. Interest in this enzyme increased when USP7 was implicated in regulating the degradation of the tumor suppressor p53 by stabilizing MDM2, the major E3 ligase for p53.

[0004] Consistent with its regulation of diverse substrates and biological processes, USP7 has emerged as a drug target in a wide range of malignant tumors, including multiple myeloma, breast cancer, neuroblastoma, glioma, and ovarian cancer.However, known USP7 inhibitors have been shown to have modest potency against USP7 and low selectivity against other DUBs.In addition to modest potency and selectivity, the drawbacks of known USP7 inhibitor compounds include low solubility and general toxicity.Therefore, there is a need to develop more potent and selective irreversible USP7 inhibitors. Summary of the Invention

[0005] In some embodiments, the present disclosure provides a compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof, Q is, [ka] and G is CR 10 , N.R. 10 , or N, J is for CR 10 , N.R. 10 , N, or S; L is NR 10 , C.R. 10 , C.R. 11 , or N, K is C or N; [ka] is a single or double bond, where valence permits, provided that the ring containing J, L, and G is aromatic; U is one or more of Hal, -NH2, -CN, -CF3, -OH, oxo, or C 1~3 is a 5-6 membered heterocyclyl optionally substituted with alkyl; V is a 5-6 membered heteroaryl or C 3~6cycloalkyl, 5-6 membered heteroaryl or C 5~6 Cycloalkyl is one or more of Hal, -NH2, -CN, -CF3, -OH, oxo, or C 1~3 is optionally substituted with alkyl; R 1 is H, R 2 is H or -NHC 1~3 Alkylene(C 5~7 heterocyclyl) or or R 1 and R 2 together with the carbon atoms to which they are attached, C 6~10 aryl or 5-6 membered heteroaryl, C 6~10 Aryl or 5-6 membered heteroaryl is Hal, C 1~3 Alkyl, C 1~3 Alkoxy, C 6~10 Aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, -NHC(=O)C 1~3 Alkylene (NR 3 R 4 ), -C(=O)NHC 1~3 Alkylene (NR 3 R 4 ), -NHC 1~3 Alkylene (4-7 membered heterocyclyl), -OC 1~3 Alkylene (4-7 membered heterocyclyl), -OC 1~3 Alkylene-O-(NR 3 R 4 ), -NHC 1~3 Alkylene (NR 3 R 4 ), or -OC 1~3 Alkylene (NR 3 R 4 Optionally substituted with one or more substituents independently selected from C 1~3 Alkyl, C 6~10 The aryl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocyclyl may independently be one or more of Hal, -NH2, -CN, -CF3, C 1~3 Alkyl or -C 0~2optionally substituted with alkyl(5-6 membered heterocyclyl); R 3 is C 1~3 is alkyl, R 4 is C 1~3 Is it an alkyl group? or R 3 and R 4 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclyl or a 5- to 7-membered heteroaryl, the 5- to 7-membered heterocyclyl being selected from one or more C 1~3 is optionally substituted with alkyl; L 1 can be one or more -C 0~2 Alkyl (C6 aryl), -NHC 0~2 Alkyl (C6 aryl), Or -C 0~2 C substituted with alkyl (5-6 membered heteroaryl) 2~4 Alkylene, C 2~4 One or more carbons in an alkylene may be C 1~3 optionally substituted with N which is optionally substituted with alkyl; Or L 1 In either direction, [ka] In either direction [ka] Or in either direction [ka] and -C 0~2 Alkyl (C6 aryl) or -C 0~2 Alkyl (5-6 membered heteroaryl) is independently one or more of Hal, -NH2, -CN, -CF3, or C 1~3 and Z is optionally substituted with C 1~4 is alkylene, [ka] is C 6~10 arylene, 5- to 7-membered heterocyclylene, or 5- to 7-membered heteroarylene; 1~4 Alkylene, 5- to 7-membered heterocyclylene, and 5- to 7-membered heteroarylene are each independently C 0~2 Alkyl (C6 aryl) or C 3~6 Optionally substituted with cycloalkyl; L 2 is -NH-, a bond, or [ka] and [ka] is a 5-membered heteroarylene; L 3 -C(=O)-, -S(=O)2-, C 6~10 arylene, or a bond; L 4 is C 1~3 Alkylene, C 2~4 alkenylene, or a bond; [ka] H, [ka] C 6~10 aryl, or 5- to 7-membered heteroaryl; C 6~10 The aryl or 5- to 7-membered heteroaryl may be one or more of Hal, -CN, C 1~3 Haloalkyl, -NHC(=O)C 1~3 optionally substituted with alkenyl; X is N or CH; Y is N or CR 7 and R 5 Hal, -NH2, -NH2(C 1~3 Alkyl), -OH, C1~3 Alkoxy or C 1~3 is alkyl, R 6 are H, Hal, -NH2, -OH, -C(O)NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 6~10 Aryl, 5-6 membered heteroaryl, or C 3~5 Cycloalkyl, -NH2, -OH, C 1~3 Alkyl, C 6~10 Aryl, 5-6 membered heteroaryl, or C 3~5 Cycloalkyl is one or more of Hal, -NH2, -CN, -CF3, C 1~3 Alkyl, C 1~3 Alkyl (NH2) or C 1~3 optionally substituted with alkyl(CF3); R 7 H, Hal, C 1~3 Alkyl, C 1~3 Haloalkyl, Cyano, C 3~5 Cycloalkyl, -C(O)NH2, -C(O)N(C 1~3 alkyl)2, -C(O)NHC 3~5 Cycloalkyl or -C(=O)NHC 1~3 is alkyl, R 7 -C(O)N(C 1~3 alkyl)2, two C 1~3 the alkyl groups, optionally together with the N atom to which they are attached, form a 3- to 7-membered heterocyclyl; or R 7 and R 6 together with the carbon atoms to which they are attached, C 5~7 Cycloalkyl, C 6~8 Forming a bridged bicyclic cycloalkyl or 5-6 membered heterocyclyl, C 5~7 Cycloalkyl or 5- to 6-membered heterocyclyl may have one or more C 1~3 Alkyl, oxo, or -C(=O)C 1~3 Optionally substituted with alkyl and two C 1~3the alkyls, optionally together with the carbon atoms to which they are attached, form a spiro ring; [ka] is C 6~10 aryl, 5- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl; R 8 is one or more of Hal, -NH2, -CN, -CF3, C 1~3 Alkyl, C 1~3 Alkyl (NH2) or C 1~3 C optionally substituted with alkyl (CF3) 6~10 is aryl, R 9 is a bond, C 2~4 Alkylene, C 6~10 arylene, or [ka] and [ka] is one or more of Hal, -NH2, -CN, -CF3, C 1~3 Alkyl, C 1~3 Alkyl (NH2) or C 1~3 5-6 membered heterocyclyl optionally substituted with alkyl(CF3); R 10 , H, C 1~3 Alkylene(C 5~7 heterocyclyl), or C 6~10 Aryl, C 1~3 Alkylene(C 5~7 Heterocyclyl) or C 6~10 Aryl is one or more of Hal, -NH2, -CN, -CF3, C 1~3 Alkyl, C 1~3 Alkyl (NH2), C 1~3 Alkyl (CF3), or C 1~3 optionally substituted with alkyl(NH2)(CF3); R 11is Hal, -NH2, -CN, -CF3, or C 1~3 is alkyl, provided, however, that the compound is not: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0006] In some embodiments, the disclosure relates to a pharmaceutical composition comprising a compound of Formula (I), such as a compound selected from compounds 4-144, and a pharma- ceutically acceptable carrier.

[0007] In some embodiments, the present disclosure relates to a method of treating a disease or disorder modulated by USP7, comprising administering to a subject in need thereof a compound of formula (I), such as a compound selected from compounds 4-144, or a pharmaceutical composition comprising a compound of formula (I), such as a compound selected from compounds 4-144.

[0008] In some embodiments, the present disclosure relates to a method of inhibiting USP7, comprising administering a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) to a subject in need thereof.

[0009] In some embodiments, the present disclosure relates to a method of treating cancer comprising administering a compound of Formula (I) or a pharmaceutical composition comprising a compound of Formula (I) to a subject in need thereof.

[0010] In some embodiments, the disclosure relates to a method of inhibiting USP7, wherein a compound of formula (I) forms a covalent bond with USP7. In some embodiments, the covalent bond is formed with a cysteine ​​residue of USP7.

[0011] In some embodiments, the present disclosure relates to the use of a compound of formula (I) thereof for the manufacture of a medicament for treating a disease modulated by USP7.

[0012] In some embodiments, the present disclosure relates to compounds of formula (I) thereof for use in the treatment of a disease modulated by USP7. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] USP7 (ubiquitin-specific protease 7) / HAUSP (herpes-associated ubiquitin-specific protease) is a 135 kDa USP family protein. USP7 has been shown to interact with viral proteins such as ICP0 (Vmw110), a herpes simplex virus immediate early gene that stimulates the initiation of the viral lytic cycle, and EBNA1 (Epstein-Barr nuclear antigen-1). The DUB USP7 has been shown to be involved in the regulation of numerous cellular processes including epigenetics, cell cycle, DNA repair, immunity, viral infection, and tumorigenesis. Interest in this enzyme has increased when USP7 was implicated in regulating the degradation of the tumor suppressor p53 by stabilizing MDM2, the major E3 ligase for p53. Consistent with recent reports, USP7 silencing has also been shown to increase steady-state p53 levels by promoting the degradation of Mdm2. Binding of USP7 to p53 has recently been shown to be regulated by TSPYL5, a protein potentially involved in breast carcinogenesis through competition with p53 for binding to the same region of USP7. More recently, both up- and down-regulation of USP7 has been shown to inhibit colon cancer cell proliferation in vitro and tumor growth in vivo by resulting in constitutively high p53 levels.

[0014] In some embodiments, the present disclosure provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, Q is, [ka] and G is CR 10 , N.R. 10 , or N, J is for CR 10 , N.R. 10 , N, or S; L is NR 10 , C.R.10 , C.R. 11 , or N, K is C or N; [ka] is provided that the ring containing J, L, and G is aromatic and the valence, where permitted, is a single or double bond; U is one or more of Hal, -NH2, -CN, -CF3, -OH, oxo, or C 1~3 is a 5-6 membered heterocyclyl optionally substituted with alkyl; V is a 5-6 membered heteroaryl or C 3~6 cycloalkyl, 5-6 membered heteroaryl or C 5~6 Cycloalkyl is one or more of Hal, -NH2, -CN, -CF3, -OH, oxo, or C 1~3 is optionally substituted with alkyl; R 1 is H, R 2 -NHC 1~3 Alkylene(C 5~7 heterocyclyl) or or R 1 and R 2 together with the carbon atoms to which they are attached, C 6~10 aryl or 5-6 membered heteroaryl, C 6~10 Aryl or 5-6 membered heteroaryl is Hal, C 1~3 Alkyl, C 1~3 Alkoxy, C 6~10 Aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, -NHC(=O)C 1~3 Alkylene (NR 3 R 4 ), -C(=O)NHC 1~3 Alkylene (NR 3 R 4 ), -NHC 1~3 Alkylene (4-7 membered heterocyclyl), -OC 1~3 Alkylene (4-7 membered heterocyclyl), -OC 1~3 Alkylene-O-(NR3 R 4 ), or -OC 1~3 Alkylene (NR 3 R 4 Optionally substituted with one or more substituents independently selected from C 1~3 Alkyl, C 6~10 The aryl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocyclyl may independently be one or more of Hal, -NH2, -CN, -CF3, C 1~3 Alkyl or -C 0~2 optionally substituted with alkyl(5-6 membered heterocyclyl); R 3 is C 1~3 is alkyl, R 4 is C 1~3 Is it an alkyl group? or R 3 and R 4 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclyl or a 5- to 7-membered heteroaryl, the 5- to 7-membered heterocyclyl being selected from one or more C 1~3 is optionally substituted with alkyl; L 1 can be one or more -C 0~2 Alkyl (C6 aryl), -NHC 0~2 Alkyl (C6 aryl), Or -C 0~2 C substituted with alkyl (5-6 membered heteroaryl) 2~4 Alkylene, In either direction [ka] In either direction [ka] or in either direction [ka] and -C 0~2Alkyl (C6 aryl) or -C 0~2 Alkyl (5-6 membered heteroaryl) is independently one or more of Hal, -NH2, -CN, -CF3, or C 1~3 and Z is optionally substituted with C 1~4 is alkylene, [ka] is C 6~10 arylene, 5- to 7-membered heterocyclylene, or 5- to 7-membered heteroarylene; 1~4 Alkylene, 5- to 7-membered heterocyclylene, and 5- to 7-membered heteroarylene are each independently C 0~2 Alkyl (C6 aryl) or C 3~6 Optionally substituted with cycloalkyl; L 2 is -NH-, a bond, or [ka] and [ka] is a 5-membered heteroarylene; L 3 -C(=O)-, -S(=O)2-, C 6~10 arylene, or a bond; L 4 is C 1~3 Alkylene, C 2~4 alkenylene, or a bond; [ka] H, [ka] C 6~10 aryl, or 5- to 7-membered heteroaryl; C 6~10 The aryl or 5- to 7-membered heteroaryl may be one or more of Hal, -CN, C 1~3 Haloalkyl, -NHC(=O)C 1~3optionally substituted with alkenyl; X is N or CH; Y is N or CR 7 and R 5 Hal, -NH2, -NH2(C 1~3 Alkyl), -OH, C 1~3 Alkoxy or C 1~3 is alkyl, R 6 are H, Hal, -NH2, -OH, -C(O)NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 6~10 Aryl, 5-6 membered heteroaryl, or C 3~5 Cycloalkyl, -NH2, -OH, C 1~3 Alkyl, C 6~10 Aryl, 5-6 membered heteroaryl, or C 3~5 Cycloalkyl is one or more of Hal, -NH2, -CN, -CF3, C 1~3 Alkyl, C 1~3 Alkyl (NH2) or C 1~3 optionally substituted with alkyl(CF3); R 7 H, Hal, C 1~3 Alkyl, C 1~3 Haloalkyl or -C(=O)NHC 1~3 Is it an alkyl group? or R 7 and R 6 together with the carbon atom to which they are attached, form a C5 cycloalkyl, C 6~8 A bridged bicyclic cycloalkyl or a 5-6 membered heterocyclyl is formed, and the C5 cycloalkyl or the 5-6 membered heterocyclyl is one or more C 1~3 Alkyl, oxo, or -C(=O)C 1~3 is optionally substituted with alkyl; [ka] is C 6~10aryl, 5- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl; R 8 is one or more of Hal, -NH2, -CN, -CF3, C 1~3 Alkyl, C 1~3 Alkyl (NH2) or C 1~3 C optionally substituted with alkyl (CF3) 6~10 is aryl, R 9 is a bond, C 2~4 Alkylene, C 6~10 arylene, or [ka] and [ka] is one or more of Hal, -NH2, -CN, -CF3, C 1~3 Alkyl, C 1~3 Alkyl (NH2) or C 1~3 5-6 membered heterocyclyl optionally substituted with alkyl(CF3); R 10 , H, C 1~3 Alkylene(C 5~7 heterocyclyl), or C 6~10 Aryl, C 1~3 Alkylene(C 5~7 Heterocyclyl) or C 6~10 Aryl is one or more of Hal, -NH2, -CN, -CF3, C 1~3 Alkyl, C 1~3 Alkyl (NH2), C 1~3 Alkyl (CF3), or C 1~3 optionally substituted with alkyl(NH2)(CF3); R 11 is Hal, -NH2, -CN, -CF3, or C 1~3 is alkyl, provided, however, that the compound is not: [ka] [ka] [ka]

[0015] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] It is.

[0016] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] where a is the point of attachment to the carbonyl group and b is the point of attachment to L 2 In some embodiments, L 1 teeth, [ka] where a is the point of attachment to the carbonyl group and b is the point of attachment to L 2 In some embodiments, L 1 teeth, [ka] where a is the point of attachment to the carbonyl group and b is the point of attachment to L 2 It is the attachment point to.

[0017] In some embodiments, R 9 is C 2~4 In some embodiments, R is an alkylene. 9 is C 6~10 It is arylene.

[0018] In some embodiments, L 2 is -NH-.

[0019] In some embodiments, L 3 In some embodiments, L 3 is -C(=O)-.

[0020] In some embodiments, [ka] is H and L 4 is C 1~3 Alkyl or C 3~4 In some embodiments, L is alkenyl. 4 is C 3~4 In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] is a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl. [ka] teeth, [ka] It is.

[0021] In some embodiments, the compound of formula (I) is a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof.

[0022] In some embodiments, L 2 In some embodiments, L 2 teeth, [ka] It is.

[0023] In some embodiments, L 3 is -C(=O)-.

[0024] In some embodiments, the compound of formula (I) is a compound of formula (Ib): [ka] or a pharma- ceutically acceptable salt thereof.

[0025] In some embodiments, R 5 is Hal, for example, R 5 is Cl. In some embodiments, R 5 is -OH. In some embodiments, R 5 is Me.

[0026] In some embodiments, R 7 is H.

[0027] In some embodiments, R 6 is H. In some embodiments, R 6 is F, -NH2, or -OH, and -NH2 or -OH is C 1~3 In some embodiments, R 6 is C 1~3 Alkyl, C 1~3The alkyl is optionally substituted with one or more Hal or -NH. In some embodiments, R 6 is C 6~10 Aryl, C 6~10 Aryl is one or more of Hal, -NH2, -CN, -CF3, C 1~3 Alkyl, C 1~3 Alkyl (NH2) or C 1~3 In some embodiments, R 6 is a 5-6 membered heteroaryl. In some embodiments, R 6 is C 3~5 Cycloalkyl, C 3~5 The cycloalkyl is optionally substituted with one or more Hal.

[0028] In some embodiments, R 7 and R 6 together with the carbon atom to which they are attached form a C5 cycloalkyl or a 5- to 6-membered heterocyclyl, and the C5 cycloalkyl or the 5- to 6-membered heterocyclyl is 1~3 Alkyl, oxo, or -C(=O)C 1~3 In some embodiments, R 7 and R 6 together with the carbon atom to which they are attached form a 5- to 6-membered heterocyclyl, which may be one or more C 1~3 Alkyl, oxo, or -C(=O)C 1~3 In some embodiments, R 7 and R 6 together with the carbon atom to which they are attached form a C5 cycloalkyl.

[0029] In some embodiments, L 1 can be one or more -C 0~2 C substituted with alkyl (C aryl) 2~4 In some embodiments, one or more -C 0~2Alkyl (C6 aryl) is one or more of Hal, -NH2, -CN, -CF3, or C 1~3 In some embodiments, L is substituted with alkyl. 1 is C substituted with -CH2Ph 2~4 In some embodiments, L is alkylene. 1 teeth, [ka] where a is the point of attachment to the carbonyl group and b is the point of attachment to L 2 In some embodiments, L 1 teeth, [ka] where a is the point of attachment to the carbonyl group and b is the point of attachment to L 2 In some embodiments, L 1 teeth, [ka] where a is the point of attachment to the carbonyl group and b is the point of attachment to L 2 In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 In either direction, [ka] In some embodiments, L 1 In either direction, [ka] In some embodiments, L 1 teeth, [ka] where a is the point of attachment to the carbonyl group and b is the point of attachment to L2 In some embodiments, L 1 teeth, [ka] where a is the point of attachment to the carbonyl group and b is the point of attachment to L 2 In some embodiments, L 1 teeth, [ka] where a is the point of attachment to the carbonyl group and b is the point of attachment to L 2 It is the attachment point to.

[0030] In some embodiments, R 9 is C 2~4 In some embodiments, R is an alkylene. 9 is C 6~10 In some embodiments, R is arylene. 9 teeth, [ka] It is.

[0031] In some embodiments, L 2 is a bond. In some embodiments, L 2 In some embodiments, L 2 [ka] .

[0032] In some embodiments, L 3 is -C(=O)-.

[0033] In some embodiments, R 1 is H.

[0034] In some embodiments, R 2 -NHC 1~3 Alkylene(C 5~7In some embodiments, R 1 and R 2 together with the carbon atoms to which they are attached, C 6~10 In some embodiments, C 6~10 Aryl is one or more -NHC(=O)C 1~3 Alkylene (NR 3 R 4 In some embodiments, C 6~10 The aryl is substituted with one or more -NHC(=O)C alkylene (NMe). 6~10 Aryl is one or more -OC 1~3 Alkylene (NR 3 R 4 ) has been substituted.

[0035] In some embodiments, each R 3 and R 4 is independently 1~3 In some embodiments, each R 3 and R 4 is Me. In some embodiments, R 3 and R 4 together with the nitrogen atom to which they are attached form a 5-7 membered heterocyclyl. In some embodiments, the 5-7 membered heterocyclyl is selected from the group consisting of one or more C 1~3 In some embodiments, R 3 and R 4 together with the nitrogen atom to which they are attached form a 5- to 7-membered heteroaryl.

[0036] In some embodiments, R 1 and R 2 together with the carbon atom to which they are attached form a 5-6 membered heteroaryl. In some embodiments, the 5-6 membered heteroaryl is selected from the group consisting of one or more C 6~10 In some embodiments, C is substituted with aryl. 6~10 Aryl is one or more of Hal, -NH2, -CN, -CF3, or C 1~3 It is substituted with alkyl.

[0037] In some embodiments, the compound of formula (I) is a compound of formula (Ic) or a compound of formula (Id): [ka] or a pharma- ceutically acceptable salt thereof.

[0038] In some embodiments, the compound of formula (I) is not: [ka] [ka] [ka]

[0039] In certain embodiments, the compound of formula (I) is selected from the group consisting of: [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16] [Table 3-17] [Table 3-18] [Table 3-19] [Table 3-20] [Table 3-21] [Table 3-22] [Table 3-23] [Table 3-24]

[0040] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0041] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0042] In some embodiments, the disclosure relates to a pharmaceutical composition comprising a compound of Formula (I), such as a compound selected from compounds 4-144, and a pharma- ceutically acceptable carrier.

[0043] In some embodiments, the present disclosure relates to a method of treating a disease or disorder modulated by USP7, comprising administering to a subject in need thereof a compound of formula (I), such as a compound selected from compounds 4-144, or a pharmaceutical composition comprising a compound of formula (I), such as a compound selected from compounds 4-144.

[0044] In some embodiments, the disclosure relates to a method of inhibiting USP7, comprising administering to a subject in need thereof a compound of formula (I), such as a compound selected from compounds 4-144, or a pharmaceutical composition comprising a compound of formula (I), such as a compound selected from compounds 4-144. In some embodiments, the disease or disorder associated with inhibition of USP7 is cancer and metastasis, neurodegenerative diseases, immunological disorders, diabetes, bone and joint diseases, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, viral infectivity and / or latency, and bacterial infections and diseases.

[0045] In some embodiments, the disclosure relates to a method of treating cancer comprising administering to a subject in need thereof a compound of formula (I), such as a compound selected from compounds 4-144, or a pharmaceutical composition comprising a compound of formula (I), such as a compound selected from compounds 4-144. In some embodiments, the cancer is liposarcoma, neuroblastoma, glioblastoma, breast cancer, bladder cancer, glioma, adrenocortical carcinoma, multiple myeloma, colorectal cancer, colon cancer, prostate cancer, non-small cell lung cancer, human papillomavirus-associated cervical cancer, oropharyngeal cancer, penile cancer, ovarian cancer, anal cancer, thyroid cancer, vaginal cancer, Epstein-Barr virus-associated nasopharyngeal cancer, gastric cancer, rectal cancer, thyroid cancer, Hodgkin's lymphoma, diffuse large B-cell lymphoma, and Ewing's sarcoma. In some embodiments, the cancer is neuroblastoma, multiple myeloma, breast cancer, glioma, colon cancer, prostate cancer, or ovarian cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is Ewing's sarcoma.

[0046] In some embodiments, the disclosure relates to a method of inhibiting USP7, wherein a compound of formula (I) thereof, such as a compound selected from compounds 4-144, forms a covalent bond with USP7. In some embodiments, the covalent bond is formed with a cysteine ​​residue of USP7.

[0047] In some embodiments, the present disclosure relates to the use of a compound of formula (I) thereof, such as a compound selected from compounds 4-144, for the manufacture of a medicament for treating a disease modulated by USP7.

[0048] In some embodiments, the disclosure relates to a compound of formula (I) thereof, such as a compound selected from compounds 4-144, for use in the treatment of a disease modulated by USP7.

[0049] How to use Ubiquitin is a 76-residue protein that is dynamically conjugated to proteins via isopeptide bonds. Canonically, the C-terminal glycine of ubiquitin is linked to the side chain of a substrate lysine, and ubiquitin can also be conjugated to substrates via the side chains of cysteine, serine, and threonine, as well as the N-terminal amine. McDowell, GS & Philpott, A. Non-canonical ubiquitylation: Mechanisms and consequences. Int. J. Biochem. Cell Biol. 45, 1833-1842 (2013). Ubiquitin itself has seven lysine side chains, and there are naturally occurring linear or mixed chains of ubiquitin conjugated through these lysine side chains or the N-terminal methionine residue. Ubiquitin conjugation is achieved by the coordinated action of ubiquitin-activating enzymes (E1), conjugating enzymes (E2), and ligases (E3) and can be reversed by deubiquitinating enzymes (DUBs).Monoubiquitin tags or ubiquitin chains of different topologies mediate protein conformational changes and binding to numerous scaffolding and adaptor proteins, and ubiquitination is involved in a number of key mechanisms of protein degradation (Nandi, D., et al., The Ubiquitin-Proteasome System. J Biosci 31, 137-155 (2016)), membrane trafficking (Hurley, JH & Stenmark, H. Molecular Mechanisms of Ubiquitin-Dependent Membrane Traffic. Annu. Rev. Biophys. 40, 119-142 (2011)), chromatin dynamics (Shilatifard, A. Chromatin Modifications by Methylation and Ubiquitination: Implications in the Regulation of Gene Expression. Annu. Rev. Biochem. 75, 243-269 (2006)), and DNA repair (Jackson, S. P. & Ubiquitin and SUMO play important roles in many cellular processes, including ubiquitin-dependent regulation of DNA damage responses (Durocher, D. Review Regulation of DNA Damage Responses by Ubiquitin and SUMO. Mol. Cell 49, 795-807 (2013)).Ubiquitin signaling is also implicated in cancer (Senft, D., Qi, J. & Ronai, ZAU biquitin ligases in oncogenic transformation and cancer therapy. Nat. Rev. Cancer 18, 69-88 (2018); Pinto-Fernandez, A. & Kessler, BMDU giving cancer: Deubiquitylating enzymes involved in epigenetics, DNA damage and the cell cycle as therapeutic targets. Front. Genet. 7, 1-13 (2016)), infection (Isaacson, MK & Ploegh, HL Ubiquitination, Ubiquitin-like Modifiers, and Deubiquitination in Viral Infection. Cell Host Microbe 5, 559-570 (2009)), and neurodegeneration (Ciechanover, A. & Brundin, P. The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg.Neuron 40,427-446 The ubiquitin proteasome system in neurodeg(2003)) is also involved in a number of disease settings.In particular, the ubiquitin-proteasome system (UPS) has become a topic of interest in oncology, as both proteasome inhibitors and bivalent substrate-E3 ligands have been approved as targeted cancer therapies (Manasanch, EE & Orlowski, RZ Proteasome inhibitors in cancer therapy. Nat. Rev. Clin. Oncol. 14, 417-433 (2017); Bartlett, JB, et al. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat. Rev. Cancer 4, 314-322 (2004)). Currently, there are no DUB inhibitors in the clinic, a reality driven in part by the lack of high-quality probe compounds to address both fundamental DUB biology exploration and target validation in preclinical disease models.

[0050] There are approximately 100 human DUBs that belong to seven different families, six of which are cysteine ​​proteases (ubiquitin-specific proteases [USPs], ubiquitin C-terminal hydrolases [UCHs], ovarian tumor proteases [OTUs], Josephin, Mindy, and ZUFSPs), and one of which is a family of zinc metalloproteases (JAB / MPN / MOV34 [JAMM / MPN]). Recently, several high-quality probes targeting USP7 have been developed. These probes share the properties of single- or double-digit nM potency against USP7, co-structural confirmation of USP7 catalytic domain binding, and activity profiling that validates selectivity against over 40 DUBs. Lamberto, I. et al. Structure-Guided Development of a Potent and Selective Non-covalent Active-Site Inhibitor of USP7. Cell Chem. Biol. 24, 1490-1500 (2017), Kategaya, L. et al. USP7 small-molecule inhibitors interfere with ubiquitin binding. Nature 550, 534-538 (2017), Turnbull, AP et al. Molecular basis of USP7 inhibition by selective small-molecule inhibitors. Nature 550, 481-486 (2017), and Gavory, G. et al. Discovery and characterization of highly potent and selective allosteric USP7 inhibitors. 7, (2017). Taken together, this work represents a remarkable shift in thinking about the druggability of USP7 and DUBs more broadly. Prior to 2017, there were no USP:small molecule co-crystal structures published in the Protein Data Bank (PDB), and studies reporting DUB profiling consistently found that previously reported DUB inhibitors typically had weak affinities (above 1 μM) and lacked a high degree of selectivity among DUBs.Ritorto,M.S.et al.Screening of DUB activity and specificity by MALDI-TOF mass spectrometry.Nat.Commun.5,4763(2014)。

[0051] USP7 is one of the most widely studied DUBs and has been linked to multiple substrates, cellular pathways, and pathologies. USP7 was first discovered as an interaction partner and stabilizer of the herpesvirus E3 ligase ICP0. Everett,RD et al.A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein.16,1519-1530(1997). Since then, USP7 has also been linked to MDM2 (Li, M., et al. A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol. Cell 13,879-886 (2004)), UHRF1 (Ma, H. et al. stability.Proc.Natl.Acad.Sci.109,4828-4833(2012)), TRIM27(Zaman,MM-U.et al.Ubiquitination-Deubiquitination by the TRIM27-USP7 Complex Regulates Tumor Necrosis Factor Alpha-Induced Apoptosis.Mol.Cell.Biol.33,4971-4984(2013)), RING1B(de Bie,P.et al.Regulation of the Polycomb protein RING1B ubiquitination by USP7.Biochem.Biophys.Res.Commun.400,389-395(2010)), RAD18(Zlatanou,A.et al.USP7 is essential for maintaining Rad18 stability and DNA damage tolerance.35,965-976(2015)), RNF220(Ma,P.et al.The Ubiquitin Ligase RNF220 Enhances Canonical Wnt Signaling through USP7-Mediated Deubiquitination of -Catenin.Mol.Cell.Biol.34,4355-4366(2014)), MARCH7(Nathan,JAet al.The ubiquitin E3 ligase MARCH7 is differentially regulated by the deubiquitylating enzymes USP7 and USP9X.Traffic 9,1130-1145(2008)), RNF168(Zhu,Q.,Sharma,N.,He,J.,Wani,G.& Wani,AAUSP7 deubiquitinase promotes ubiquitin-dependent DNA damage signaling by stabilizing RNF168.Cell Cycle 14,1413-1425(2015)), and RNF169 (An,L.et al.Dual-utility NLS drives RNF169-dependent DNA damage responses.Proc.Natl.Acad.Sci.114,E2872-E2881(2017)). Furthermore, USP7 has been found in a binary complex with both GMP and UVSSA, and binding of USP7 appears to be essential for the cellular function of these proteins. Van Der Knaap,JAet al.GMP synthetase stimulates histone H2B deubiquitylation by the epigenetic silencer USP7.Mol.Cell 17,695-707(2005), Schwertman,P.et al.UV-sensitive syndrome protein UVSSA recruits USP7 to regulate transcription-coupled repair.Nat.Genet.44,598-602(2012)。.

[0052] Of all these possible substrates, the interaction of USP7 with MDM2 has attracted the most interest from a mechanistic and therapeutic point of view. USP7 has been shown to bind both MDM2 and p53 via its TRAF domain and to have DUB activity for both of these proteins. A new hypothesis has emerged in which USP7 functions as a molecular switch, whereby USP7 deubiquitinates and stabilizes MDM2 during normal cell proliferation, but in the presence of cellular stress signals, its preferred substrate shifts to p53. Brazhnik, P. & Kohn, KW A USP-regulated switch from auto- to p53 ubiquitination by Mdm2 (in silico discovery). Math. Biosci. 210, 60-77 (2007); Kim, RQ & Sixma, TK Regulation of USP7: A high incidence of E3 complexes. J. Mol. Biol. 429, 3395-3408 (2017). Given the important role of p53 in tumor suppression, USP7 has been proposed as a therapeutic target in TP53-WT tumors, with a putative mechanism of action involving increased p53 protein levels, similar to the effects of RG-7388, an MDM2-p53 interaction inhibitor, and ATSP-7041, an MDM2 / MDM4 dual inhibitor (both currently in clinical trials). Ding, Q. et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J. Med. Chem. 56, 5979-5983 (2013); Chang, YSet al. Stapled α-helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc. Natl. Acad. Sci. 110, E3445-E3454 (2013).However, given that USP7 targets multiple substrates, there is much debate about the relative importance of p53 mutation status in predicting response to USP7 inhibition. Several previous studies on nonselective USP7 inhibitors have shown that USP7 inhibitors are effective against both p53 WT and mutant disease. Chauhan, D. et al.Article A Small Molecule Inhibitor of Ubiquitin-Specific Protease-7 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Bortezomib Resistance.Cancer Cell 22, 345-358(2012), Wang, M. et al.The USP7 Inhibitor P5091 Induces Cell Death in Ovarian Cancers with Different P53 Status.Cell.Physiol.Biochem.43, 1755-1766(2018). These results are supported by studies using Genentech's DUB-selective USP7 inhibitor, GNE-6640, which did not produce significantly different responses in TP53-WT or mutant cell lines when screened in a panel of 181 cells. Kategaya, L. et al. USP7 small-molecule inhibitors interfere with ubiquitin binding. Nature 550, 534-538 (2017). On the other hand, for the selective USP7 inhibitor, compound 42, TP53 status has been found to be a significant predictor of response in Ewing's sarcoma and other cancer cell types. Roti, G. et al., J. Exp. Med., 215, 197-216 (2018).

[0053] One of the major missing pieces in previous reports of selective USP7 inhibitors was the spectrum of off-targets outside the DUB family. A well-annotated off-target profile would help clarify whether the p53-independent effects of USP7 inhibitors are due to other USP7 substrates or other compound targets. Based on the structure of compound 42 bound to the catalytic domain of USP7, we designed a rational synthesis of an irreversible, affinity-tagged analogue that would be sufficient for proteome-wide profiling experiments and follow-up studies on USP7 / p53 biology.

[0054] USP7 also alters the levels of p16INK4a tumor suppressor via Bmi1 / Mel18 stabilization. Maertens et al., EmboJ.29,2553-2565(2010). Additional proteins involved in genome integrity / regulation, such as DNMT1 DNA methylase and claspin adaptor, are also stabilized by USP7. Du et al., Science Signaling,3(146):ra80(2010); Faustrup et al., J.Cell Biol.,184(1):13-9(2009). Importantly, the abundance of USP7 and DNMT1, proteins involved in maintaining epigenetic methylation required to repress the expression of genes involved in development and cancer, correlates in human colon cancer (Du et al.,2010). USP7 has also been shown to deubiquitinate PTEN, a well-known tumor suppressor gene, in human cells, which induces its nuclear export and thus its inactivation. Song et al., Nature, 455(7214), 813-7(2008). More importantly, overexpression of USP7 was first reported in prostate cancer, and this overexpression was directly associated with tumor invasiveness (Song et al., 2008).

[0055] Recently, the methyltransferase PHF8 (Wang et al., 2016a), the demethylase DNMT1 (Du et al., 2010; Felle et al., Nucleic Acids Res, 39, 8355-65, 2011; Qin et al., J Cell Biochem, 112, 439-44, 2011), and the acetyltransferase Tip60 (Dar et al., Mol Cell Biol, 33, 3309-20, 2013), as well as H2B itself (van der Knaap et al., Mol Cell, 17, 695-707, 2005), have been identified as direct targets of USP7. Other notable targets of USP7 include FOXP3, a transcription factor that links this DUB enzyme to immune responses in Treg cells (van Loosdregt et al., Immunity, 39, 259-71, 2013), and N-Myc, which is stabilized in neuroblastoma cells (Tavana et al., Nat Med, 22, 1180-1186, 2016). Consistent with its regulation of diverse substrates and biological processes, USP7 has emerged as a drug target in a wide range of malignancies, including multiple myeloma (Chauhan et al., Cancer Cell, 22, 345-58, 2012), breast cancer (Wang et al., 2016a), neuroblastoma (Tavana et al., 2016), glioma (Cheng et al., Oncol Rep, 29, 1730-6, 2013), and ovarian cancer (Zhang et al., Tohoku J Exp Med, 239, 165-75, 2016). USP7 has also been shown to deubiquitinate FOXO4 in human cells, inducing its nuclear export and thus its inactivation, resulting in activation of the oncogenic PI3K / PKB signaling pathway (van der Horst et al., Nat Cell Biol. 2006, 8, 1064-1073).Finally, USP7 plays an important role in the p53-mediated cellular response to various types of stress, such as DNA damage and oxidative stress (Marchenko et al., Embo J. 2007 26, 923-934; Meulmeester et al., Mol Cell 2005, 18, 565-576.; van der Horst et al., Nat Cell Biol. 2006, 8, 1064-1073).

[0056] Multiple myeloma (MM) is an incurable hematological malignancy characterized by the accumulation of abnormal plasma cells in the bone marrow, which interferes with the production of normal blood cells. The average survival rate of MM patients has improved in recent years as a result of the introduction of proteasome inhibitors and immunomodulatory agents into the treatment regimen, but it remains quite low, at only 5 years. The proteasome inhibitor bortezomib validates the validity of the ubiquitin proteasome system as a therapeutic target for MM drug development. USP7 is a therapeutic target in MM due to its role in the degradation of p53. USP7 is highly expressed in tumor cells of MM patients and in MM cell lines compared to normal bone marrow cells. Mutations or deletions in TP53 are late events in MM, suggesting that increasing p53 through pharmacological inhibition of USP7 may be an effective treatment strategy for this malignancy.

[0057] Ewing sarcoma is a rare type of cancer that begins in the bone or the soft tissue surrounding the bone. Ewing sarcoma is more common in adolescents and young adults. The current standard treatment for Ewing sarcoma is chemotherapy, radiation therapy, and surgery.

[0058] Methods for treating and preventing diseases and conditions that benefit from modulation of USP7 are disclosed herein and include administering to a subject in need thereof any one of the compounds disclosed herein or a pharma- ceutically acceptable salt thereof.

[0059] Methods for treating and preventing diseases and conditions that would benefit from the inhibition of USP7 are disclosed herein and include administering to a subject in need thereof any one of the compounds disclosed herein or a pharma- ceutically acceptable salt thereof.

[0060] Methods for inhibiting USP7 are disclosed herein and include administering to a subject in need thereof any one of the compounds disclosed herein or a pharma- ceutically acceptable salt thereof.

[0061] In some embodiments, disclosed herein is a method for treating a disease or disorder modulated by USP7, comprising administering any one of the compounds disclosed herein or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, disclosed herein is a method for preventing a disease or disorder modulated by USP7, comprising administering any one of the compounds disclosed herein or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, the modulation of USP7 involves the inhibition of USP7.

[0062] In some embodiments, the disease or disorder is selected from cancer and metastasis, neurodegenerative diseases, immunological disorders, diabetes, bone and joint diseases, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, viral infectious and / or viral latency, and bacterial infections and diseases.

[0063] Disclosed herein is the use of an inhibitor of USP7 for the preparation of a medicament for treating or preventing a disease or condition modulated by USP7, the medicament comprising any one of the compounds disclosed herein or a pharma- ceutically acceptable salt thereof.

[0064] Disclosed herein is any one of the disclosed compounds, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a disease or condition modulated by USP7.

[0065] A method of treating cancer is disclosed herein, comprising administering to a subject in need thereof any one of the compounds disclosed herein or a pharma- ceutically acceptable salt thereof.

[0066] A method of inhibiting USP7 is disclosed herein, wherein any one of the compounds disclosed herein or a pharma- ceutically acceptable salt thereof forms a covalent bond with USP7. In some embodiments, the covalent bond is formed with a cysteine ​​residue of USP7. In some embodiments, the cysteine ​​residue of USP7 is cysteine ​​223 (C223).

[0067] In some embodiments of the methods and uses disclosed herein, modulating USP7 involves inhibiting USP7. In some embodiments, the inhibition of USP7 is irreversible. In some embodiments, inhibiting USP7 is a novel treatment for a disease or condition.

[0068] In some embodiments, exemplary cancers include, but are not limited to, p53 WT cancers.

[0069] In some embodiments, exemplary cancers include, but are not limited to, solid tumors.

[0070] In some embodiments, exemplary cancers include, but are not limited to, liposarcoma, neuroblastoma, glioblastoma, breast cancer, bladder cancer, glioma, adrenocortical carcinoma, multiple myeloma, colorectal cancer, colon cancer, prostate cancer, non-small cell lung cancer, human papillomavirus-associated cervical cancer, oropharyngeal cancer, penile cancer, ovarian cancer, anal cancer, thyroid cancer, vaginal cancer, Epstein-Barr virus-associated nasopharyngeal cancer, gastric cancer, rectal cancer, thyroid cancer, Hodgkin's lymphoma, diffuse large B-cell lymphoma, and Ewing's sarcoma.

[0071] In some embodiments, the cancer is selected from neuroblastoma, multiple myeloma, breast cancer, glioma, colon cancer, prostate cancer, and ovarian cancer. In some embodiments, the cancer is neuroblastoma, breast cancer, glioma, multiple myeloma, or ovarian cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is Ewing's sarcoma.

[0072] A method of treating a neurodegenerative disease is disclosed herein, comprising administering to a subject in need thereof any one of the compounds disclosed herein or a pharma- ceutically acceptable salt thereof.

[0073] In some embodiments, neurodegenerative diseases include, but are not limited to, Alzheimer's disease, multiple sclerosis, Huntington's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, amyotrophic lateral sclerosis, or encephalitis.

[0074] In certain embodiments, the compounds of the present invention can be administered alone or in combination with another type of therapeutic agent. As used herein, the phrase "conjoint administration" refers to any form of administration of two or more different therapeutic compounds, such that the previously administered therapeutic compound is still effective in the body while the second compound is administered (e.g., the two compounds are effective in the subject at the same time, which may include a synergistic effect of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation, or in separate formulations, either simultaneously or sequentially. In certain embodiments, the different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 1 week of each other. Thus, subjects receiving such treatment can benefit from the combined effect of the different therapeutic compounds.

[0075] In certain embodiments, the combined administration of a compound of the present invention with one or more additional therapeutic agents provides improved efficacy compared to the separate administration of the compound of the present invention (e.g., a compound of formula I or Ia) or one or more additional therapeutic agents. In certain such embodiments, the combined administration provides an additive effect, where the additive effect refers to the sum of the effects of the separate administration of the compound of the present invention with one or more additional therapeutic agents. In some embodiments, the combined administration provides a synergistic effect. In some embodiments, the combination index is less than 0.6.

[0076] In some embodiments, the additional therapeutic agent is a DNA damaging agent. In some embodiments, the additional therapeutic agent is a p53 stabilizer. In some embodiments, the additional therapeutic agent is selected from RG7388, etoposide, GSK2830371, and doxorubicin.

[0077] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art of the present disclosure. The following references provide those skilled in the art with many common definitions of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed.1994), The Cambridge Dictionary of Science and Technology (Walker ed.,1988), The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991), and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless otherwise specified.

[0078] In this disclosure, "comprises," "comprising," "containing," "having," and the like can have the meaning ascribed to them in U.S. Patent Law and can mean "includes," "including," and the like. "Consisting essentially of" or "consists essentially" likewise has the meaning ascribed to them in U.S. Patent Law and the term is open-ended, allowing for the presence of more than what is recited so long as the basic or novel characteristics of what is recited are not changed by the presence of more than what is recited, but excludes prior art embodiments.

[0079] The term "or," as used herein, is understood to be inclusive unless specifically stated otherwise or clear from the context. The terms "a," "an," and "the," as used herein, are understood to be singular or plural unless specifically stated otherwise or clear from the context.

[0080] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise specified.

[0081] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(=O)-, preferably alkylC(=O)-.

[0082] The term "acylamino" is art recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(=O)NH-.

[0083] The term "alkoxy" refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0084] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0085] The term "alkenyl" as used herein refers to an aliphatic group containing at least one double bond, and is intended to include both "unsubstituted alkenyl" and "substituted alkenyl", the latter of which refers to an alkenyl moiety having a substituent replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Furthermore, such substituents include all of the substituents contemplated for alkyl groups, as discussed below, except where stability would be prohibitive. For example, substitution of alkenyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0086] An "alkyl" group or "alkane" is a fully saturated, straight-chain or branched, non-aromatic hydrocarbon. Typically, a straight-chain or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 carbon atoms, unless otherwise defined. Examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. C1-C6 straight-chain or branched alkyl groups are also referred to as "lower alkyl" groups.

[0087] Furthermore, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter of which refers to an alkyl moiety having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, unless otherwise specified, can include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For example, substituents of substituted alkyl may include amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyl and sulfonates), and silyl groups, as well as substituted and unsubstituted forms of ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, and the like. Exemplary substituted alkyls are described below. Cycloalkyls may be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like. Additionally, where valence permits, "alkyl" also refers to diradicals (e.g., "alkylene").

[0088] "C x~y The term "C" when used in combination with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups containing x to y carbons in the chain. For example, "C x~yThe term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups including straight chain alkyl and branched chain alkyl groups containing x to y carbons in the chain, including, for example, haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl indicates a hydrogen if the group is in a terminal position, or a bond if internal. 2~y alkenyl" and "C 2~y The term "alkynyl" refers to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0089] The term "heteroalkyl," as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.

[0090] Furthermore, the term "heteroalkyl" (or "lower heteroalkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted heteroalkyl" and "substituted heteroalkyl", the latter of which refers to a heteroalkyl moiety having substituents replacing hydrogen on one or more carbon or heteroatoms of the backbone. Such substituents, unless otherwise specified, can include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those of skill in the art that the moieties substituted on the heteroalkyl chain can themselves be substituted, where appropriate. For example, substituents of substituted heteroalkyls can include amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyl, and sulfonates), and silyl groups, as well as substituted and unsubstituted forms of ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, and the like.

[0091] The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

[0092] The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0093] The term "alkynyl," as used herein, refers to an aliphatic group containing at least one triple bond, and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl," the latter of which refers to an alkynyl moiety having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Furthermore, such substituents include all of the substituents contemplated for alkyl groups, as discussed above, except where stability would be prohibitive. For example, substitution of alkynyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0094] The term "amide" as used herein means [ka] This refers to the base, In the formula, each R 10 R independently represents a hydrogen or a hydrocarbyl group, or two R 10 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0095] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, and their salts, e.g., [ka] This is the part that can be expressed as In the formula, each R 10 R independently represents a hydrogen or a hydrocarbyl group, or two R 10 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure. The term "aminoalkyl," as used herein, refers to an alkyl group substituted with an amino group.

[0096] The term "aralkyl," as used herein, refers to an alkyl group substituted with an aryl group.

[0097] The term "aryl" as used herein includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings being aromatic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Additionally, where valency permits, "aryl" also refers to diradicals (e.g., "arylene").

[0098] The term "carbamate" is art-recognized and refers to a group. [ka] In the formula, R 9 and R 10 independently represent hydrogen or a hydrocarbyl group such as an alkyl group, or R 9 and R 10 together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0099] The terms "carbocycle" and "carbocyclic" as used herein refer to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings in which all carbon atoms are saturated, and cycloalkene rings that contain at least one double bond.

[0100] The term "carbocycle" includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic molecules in which one, two, or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle, as long as valence permits. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydroacridine, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocycle" may be substituted at any one or more positions that may have a hydrogen atom.

[0101] A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms, unless otherwise defined. The second ring of a bicyclic cycloalkyl can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. Cycloalkyl includes bicyclic molecules in which one, two, or more than two atoms are shared between the two rings. Additionally, where valence permits, "cycloalkyl" also refers to a diradical (e.g., "cycloalkylene"). The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. A "cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds.

[0102] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocycle group.

[0103] The term "carbonate" is art-recognized and refers to the group --OCO.sub.2--R.sub.10, where R.sub.10 represents a hydrocarbyl group.

[0104] The term "carboxy," as used herein, refers to a group represented by the formula -CO2H.

[0105] The term "ester," as used herein, refers to the group --C(O)OR.sup.10, where R.sup.10 represents a hydrocarbyl group.

[0106] The term "ether" as used herein refers to a hydrocarbyl group linked to another hydrocarbyl group via oxygen. Thus, the ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be either symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[0107] The terms "halo", "Hal" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo and iodo.

[0108] The terms "hetaralkyl" and "heteroaralkyl," as used herein, refer to an alkyl group substituted with a hetaryl group.

[0109] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic structures, preferably 5-7 membered rings, more preferably 5-6 membered rings, in which the ring structure contains at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings being heteroaromatic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Additionally, where valency permits, "heteroaryl" also refers to diradicals (e.g., "heteroarylene").

[0110] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0111] The terms "heterocyclyl", "heterocycle", and "heterocyclic" refer to a substituted or unsubstituted non-aromatic ring structure, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring, in which the ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, where at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like. Additionally, where valency permits, "heterocyclyl" also refers to diradicals (e.g., "heterocyclylene").

[0112] The term "heterocycloalkyl," as used herein, refers to an alkyl group substituted with a heterocycle group.

[0113] The term "hydrocarbyl" as used herein refers to a group that does not have =O or =S substituents and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but is bonded through carbon atoms that may optionally contain heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl for purposes of this application, while substituents such as acetyl (which has =O substituents on the connecting carbon) and ethoxy (which is connected through an oxygen rather than a carbon) are not hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

[0114] The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with a hydroxy group.

[0115] The term "lower" when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups in which there are 10 or fewer non-hydrogen atoms present in the substituent, preferably 6 or fewer. "Lower alkyl" refers, for example, to alkyl groups containing 10 or fewer, preferably 6 or fewer carbon atoms. In certain embodiments, an acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituent as defined herein, whether appearing alone or in combination with other substituents such as hydroxyalkyl and aralkyl, is a lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively (where, for example, atoms in an aryl group are not counted when counting the carbon atoms in an alkyl substituent).

[0116] The terms "polycyclyl," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings." Each of the rings of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10 atoms, preferably 5 to 7 atoms, in the ring.

[0117] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbons of the backbone. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution results in a stable compound that does not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, and the like, subject to the permissible valences of the substituted atom and substituent. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. The substituents may include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. Those skilled in the art will appreciate that the substituents themselves may be substituted, where appropriate. Unless specifically described as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, references to an "aryl" group or moiety implicitly include both substituted and unsubstituted variants.

[0118] The term "sulfate" is art recognized and refers to the group -OSO3H, or a pharma- ceutically acceptable salt thereof.

[0119] The term "sulfonamide" is art-recognized and has the general formula [ka] In the formula, R 9 and R 10 independently represents hydrogen or a hydrocarbyl such as alkyl, or R 9 and R 10 together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0120] The term "sulfoxide" is art-recognized and refers to the group -S(O)-R10, where R10 represents a hydrocarbyl.

[0121] The term "sulfonate" is art-recognized and refers to the group SO3H, or a pharma- ceutically acceptable salt thereof.

[0122] The term "sulfone" is art-recognized and refers to the group -S(O)2-R10, where R10 represents a hydrocarbyl.

[0123] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0124] The term "thioester," as used herein, refers to the group --C(O)SR.sup.10 or --SC(O)R.sup.10, where R.sup.10 represents hydrocarbyl.

[0125] The term "thioether," as used herein, is equivalent to an ether where the oxygen is replaced with a sulfur.

[0126] The term "urea" is art-recognized and has the general formula [ka] where R 9 and R 10 independently represents hydrogen or a hydrocarbyl such as alkyl, or R 9Any occurrence of R 10 and together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0127] The term "protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. Typically, a protecting group can be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitroveratryloxycarbonyl ("NVOC"), and the like. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is either acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives, and allyl ethers.

[0128] The term "prodrug" is intended to include compounds that are converted to the therapeutically active agent of the present invention (e.g., a compound of formula I) under physiological conditions. A common method for making a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the subject. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain embodiments, some or all of the compounds of formula I in the formulations depicted above can be replaced with the corresponding suitable prodrugs, for example, hydroxyls in the parent compound are presented as esters, or carbonates or carboxylic acids present in the parent compound are presented as esters.

[0129] The present invention includes all pharma- ceutically acceptable isotopically labeled compounds described herein in which one or more atoms are replaced with an atom having the same atomic number, but an atomic mass or mass number different from that usually found in nature. In certain embodiments, the compounds of the present invention are enriched with such isotopically labeled materials (e.g., compounds in which the isotopic distribution of the compound in the composition differs from the natural or typical distribution of isotopes).

[0130] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, e.g. 2 H and 3 H, isotopes of carbon, e.g. 11 C. 13 C and 14 C, an isotope of chlorine, e.g. 36 Cl, an isotope of fluorine, e.g. 18 F, an isotope of iodine, e.g. 123 I and 125 I, an isotope of nitrogen, e.g. 13 N and 15 N, isotopes of oxygen, e.g. 15 O. 17 O and 18 O, isotopes of phosphorus, e.g. 32 P, as well as sulfur isotopes, e.g.35 Examples include S.

[0131] Certain isotopically labeled compounds disclosed herein, e.g., compounds incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C are useful for this purpose given their ease of incorporation and ready means of detection.

[0132] Deuterium, i.e. 2 Substitution with heavier isotopes, such as H, can offer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances.

[0133] 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0134] The compounds of the present invention may have one or more asymmetric carbon atoms and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereomers, mixtures of diastereomers, racemates of diastereomers, or racemic mixtures of diastereomers. Optically active forms can be obtained, for example, by resolution of racemates, by asymmetric synthesis or asymmetric chromatography (chromatography using chiral adsorbents or eluents). That is, certain of the disclosed compounds may exist in various stereoisomeric forms.

[0135] Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are non-superimposable, most commonly because they contain an asymmetrically substituted carbon atom that serves as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are non-superimposable. "Diastereomers" are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating the enantiomer from a racemate using one or more well-known techniques and methods, such as chiral chromatography and separation methods based thereon. Suitable techniques and / or methods for separating enantiomers of the compounds described herein from racemic mixtures can be readily determined by one of ordinary skill in the art.

[0136] "Geometric isomer" means an isomer that differs in the orientation of substituent atoms in relationship to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. The atoms (other than H) on each side of the carbon-carbon double bond can be in the E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. "R", "S", "S*", "R*", "E", "Z", "cis", and "trans" indicate configurations relative to the core molecule. Some of the disclosed compounds can exist in atropisomeric forms. Atropisomers are stereoisomers that result from hindrance of rotation about a single bond, where the steric strain barrier to rotation is high enough to allow separation of the conformers. The compounds of the present invention can be prepared as individual isomers by isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming salts of the free bases of each isomer of the isomeric pair using optically active acids (followed by fractional crystallization and regeneration of the free bases), forming salts of the acid forms of each isomer of the isomeric pair using optically active amines (followed by fractional crystallization and regeneration of the free acids), forming esters or amides of each isomer of the isomeric pair using optically pure acids, amines or alcohols (followed by chromatographic separation and removal of the chiral auxiliary), or resolving isomeric mixtures of either the starting materials or the final products using a variety of well-known chromatographic methods.

[0137] Diastereomeric purity is the ratio of the weight of one diastereomer or the ratio of the weight of all diastereomers. When the stereochemistry of the disclosed compounds is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% by weight relative to the other stereoisomer. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% optically pure by weight. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by weight. The percentage of optical purity is the ratio of the weights of the enantiomers to the sum of the weight of the enantiomer and the weight of its optical isomer.

[0138] The percent purity by mole fraction is the ratio of moles of an enantiomer (or diastereomer) or the ratio to the sum of the moles of an enantiomer (or diastereomer) and its optical isomer. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction compared to other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction.

[0139] When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has at least one chiral center, the name or structure should be understood to encompass either an enantiomer of the compound without the corresponding optical isomer, a racemic mixture of the compound, or a mixture enriched in one enantiomer compared to the corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has two or more chiral centers, the name or structure should be understood to encompass a diastereomer without the other diastereomer, some diastereomers without other diastereomeric pairs, a mixture of diastereomers, a mixture of diastereomeric pairs, a mixture of diastereomers enriched in one diastereomer compared to the other diastereomer(s), or a mixture of diastereomers enriched in one or more diastereomers compared to the other diastereomers. The present invention encompasses all of these forms.

[0140] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt of a compound of formula (I). For example, any pharmaceutically acceptable salt of a compound described herein includes those that are within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of a compound described herein, or separately by reacting the free base with a suitable organic acid.

[0141] The compounds of the present invention may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts with inorganic or organic acids, or the salts may be prepared from inorganic or organic bases when the compounds of the present invention are in acidic form. In many cases, compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparing suitable salts are known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases.

[0142] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, Representative salts include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0143] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or mammals, including commercially relevant mammals such as other primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, cats, and / or dogs, and / or commercially relevant birds, such as chickens, ducks, geese, quail, and / or turkeys. A preferred subject is a human.

[0144] As used herein, a therapeutic agent that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample compared to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition compared to an untreated control sample.

[0145] In treatment, the objective is to prevent or delay (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical outcome. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms (reducing the extent of the condition, disorder, or disease), stabilization (i.e., not worsening) of the condition, disorder, or disease, delay in onset or slowing down the progression of the condition, disorder, or disease, improvement or remission (whether partial or total) of the condition, disorder, or disease, whether detectable or undetectable, improvement of at least one measurable physical parameter, not necessarily discernible by the patient, or enhancement or amelioration of the condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival in the absence of treatment. EXAMPLES

[0146] Example 1: Preparation of exemplary compounds of the present disclosure Analytical methods, materials, and instrumentation All reagents were commercially obtained in China and used without further purification. 1 H-NMR spectra were recorded in CDCl3, CD3OD, or DMSO-d6 solutions (reported in ppm) on a Bruker instrument (400 MHz or 500 MHz) using tetramethylsilane (TMS) as the reference standard (0.0 ppm).

[0147] Mass spectrometric measurements were performed using an Agilent G6100 series mass spectrometer using an electrospray ionization source.

[0148] Column chromatography was performed on a Biotage system (manufacturer: Biotage Sweden AB) using a silica gel column.

[0149] Synthesis of intermediate A-1 [ka]

[0150] tert-Butyl 4-hydroxy-4-((7-nitro-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate (Intermediate 3) A mixture of 7-nitroquinazolin-4(3H)-one (5.0 g, 26.0 mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (6.9 g, 32.0 mmol) in DMF (60.0 mL) was stirred at 80° C. for 16 h. After cooling to room temperature, the mixture was poured into water (200 mL) and the resulting solid was collected and further purified by column chromatography on silica gel (EA\PE=2\1) to give compound 3 (3.0 g, 28% yield) as a yellow solid. LCMS (m / z): 349.1 [M-56+H] + .

[0151] tert-Butyl 4-((7-amino-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 4) A mixture of intermediate 3 (2700 mg, 6.6 mmol), Fe (1848 mg, 6.6 mmol) and NH4Cl (1848 mg, 6.6 mmol) in EtOH (50.0 mL) and H2O (6.0 mL) was stirred at 80 °C for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (100 mL), washed with saturated NaHCO3 solution (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give compound 4 (2.0 g, yield: 83%) as a white solid. LCMS (m / z): 375.2 [M+H] + .

[0152] tert-Butyl 4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate (Intermediate 6) Oxalyl chloride (1142 mg, 9.0 mmol) was added dropwise to a mixture of intermediate 5 (1032 mg, 6.0 mmol) and DMF (0.2 mL) in DCM (30.0 mL) at 0° C., the mixture was stirred at room temperature for 1 h, and the solvent was removed under vacuum. The residue was dissolved in DCM (20 mL) and added dropwise to a solution of intermediate 4 (748 mg, 2.0 mmol), Et3N (1200 mg, 12.0 mmol) and DMAP (24 mg, 0.2 mmol) in DCM (30.0 mL) at 0° C., the mixture was stirred at 0° C. for 2 h, diluted with saturated NaHCO3 solution (100 mL) and extracted with DCM (100 mL×2). The combined organics were dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel (MeOH / DCM=1 / 20) to give intermediate 6 (1000 mg, yield: 65%) as a yellow solid. LCMS (m / z): 529.3 [M+H] + .

[0153] N-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 7) A mixture of intermediate 6 (1000 mg, 1.9 mmol), HCl-dioxane (4 M, 9.5 mL) in DCM (9.0 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to leave crude intermediate 7 (900 mg, 100% yield) as a white solid. LCMS (m / z): 429.2 [M+H] + .

[0154] tert-Butyl (4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)carbamate (Intermediate 9) A mixture of intermediate 8 (645 mg, 2.1 mmol), HATU (878 mg, 2.3 mmol) and DIPEA (1.8 mL, 10.5 mmol) in DCM (20.0 mL) was stirred at room temperature for 1 h, then the mixture was added dropwise to a mixture of intermediate 7 (900 mg, 2.1 mmol) and DIPEA (1.8 mL, 10.5 mmol) in DCM (20.0 mL), the resulting mixture was stirred at room temperature for 2 h, diluted with water (100 mL) and extracted with DCM (100 mL x 2). The combined organics were dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel (MeOH / DCM = 1 / 10) to give intermediate 9 (1.4 g, 93% yield) as a yellow solid. LCMS (m / z): 718.5 [M+H] +

[0155] N-(3-((1-(5-amino-2-benzylpentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate A-1) To a mixture of intermediate 9 (1400 mg, 1.9 mmol) in DCM (10.0 mL), a solution of HCl in 1,4-dioxane (4 M, 5.0 mL) was added, the mixture was stirred at room temperature for 2 h, and concentrated in vacuo to give intermediate A-1 (1.4 g, 100% yield) as a white solid. LCMS (m / z): 618.3 [M+H] +

[0156] Synthesis of intermediate C [ka]

[0157] tert-Butyl 4-hydroxy-4-((7-nitro-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate (Intermediate 3) A mixture of 7-nitroquinazolin-4(3H)-one (5.0107 g, 26.21 mmol, 1.0 equiv.), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (6.7786 g, 31.78 mmol, 1.2 equiv.) and Cs2CO3 (12.7185 g, 39.04 mmol, 1.5 equiv.) in DMF (60 mL) was stirred at 80° C. for 16 h. The resulting mixture was poured into ice water (200 mL). Ethyl acetate (500 mL) was added to the resulting mixture. The layers were separated and the aqueous phase was extracted with ethyl acetate (150 mL). The organic phase was washed with saturated NaCl solution and dried over Na2SO4. The filtrate was concentrated by rotary evaporation (40° C.) to give the target intermediate 3 (9.88 g, 24.455 mmol, 93.31% yield) as a brown solid. LCMS (m / z): 349.3 [M-55] + .

[0158] tert-Butyl 4-((7-amino-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 4) A mixture of intermediate 3 (9.88 g, 24.445 mmol, 1.0 equiv), Fe (6.8292 g, 122.28 mmol, 5.0 equiv) and NH4Cl (6.5353 g, 122.18 mmol, 5.0 equiv) in ethanol / HO (75 mL / 15 mL) was stirred at 80 °C for 2 h. Under stirring, ethyl acetate (100 mL) was added and the resulting mixture was filtered under vacuum. The filtrate was extracted with ethyl acetate (50 mL x 3) and the combined organic layers were washed with saturated NaCl solution (100 mL). The organics were concentrated and purified by flash column chromatography (DCM / MeOH = 10 / 1) to give the target intermediate 4 (6.48 g, 17.326 mmol, 70.88% yield) as a dark brown solid. LCMS (m / z): 375.3 [M+H] + .

[0159] tert-Butyl 4-((7-(2-chloroacetamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 6) A mixture of intermediate 5 (0.112 g, 1.0 mmol, 2.0 equiv) in anhydrous DCM (10 mL) was added dropwise to a solution of 4 (0.1871 g, 0.5 mmol, 1.0 equiv) and Et3N (0.32 mL, 3.0 equiv) in anhydrous DCM (10 mL) while stirring in an ice-water bath. The ice-water bath was then removed and the resulting mixture was stirred at room temperature for another 4 h. Water (10 mL) and DCM (50 mL) were added to the reaction mixture and the layers were separated. The aqueous was extracted with DCM (50 mL x 3). The combined organic phase was washed with saturated NaCl solution (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated by rotary evaporation (30 °C) to give the target intermediate 6 (0.272 g, 0.604 mmol, 60.44% yield) as a dark gray solid. LCMS(m / z):451.1[M+H] + .

[0160] tert-Butyl 4-((7-(2-(dimethylamino)acetamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 7) In a microwave tube, a mixture of dimethylamine (2M, 3 mL, 6 mmol, 4.0 equiv) and intermediate 6 (0.675 g, 1.5 mmol, 1.0 equiv) in THF (8 mL) was stirred at 25° C. for 16 h. The organic solvent was removed under vacuum. Ethyl acetate (200 mL) was added to the reaction mixture. The mixture was then washed with water (10 mL) and the layers were separated. The aqueous phase was extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with saturated NaCl solution (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated using rotary evaporation (40° C.) to give intermediate 7 (0.645 g, 1.404 mmol, 93.62% yield) as a dark brown solid. LCMS (m / z): 460.3 [M+H] + .

[0161] 2-(Dimethylamino)-N-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)acetamide (Intermediate 8) A mixture of intermediate 7 (0.1191 g, 0.259 mmol, 1.0 equiv.) and HCl solution in 1,4-dioxane (4 M, 2 mL, 20.0 equiv.) in DCM (8 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated using rotary evaporation (50° C.) to give intermediate 8 (0.093 g, 0.259 mmol, 99.86% yield) as a white solid. LC-MS (m / z): 360.2 [M+H] + .

[0162] tert-Butyl 4-benzyl-5-(4-((7-(2-(dimethylamino)acetamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentylcarbamate (Intermediate 10) A mixture of intermediate 8 (0.6636 g, 1.847 mmol, 1.2 eq.) and DIPEA (0.4200 g, 3.250 mmol, 3.0 eq.) in THF (10 mL) was stirred at room temperature, while a mixture of intermediate 9 (0.3312 g, 1.078 mmol, 1.0 eq.), HATU (0.4532 g, 1.192 mmol, 1.2 eq.) and DIPEA (0.2633 g, 2.037 mmol, 2.0 eq.) in THF (15 mL) was stirred at room temperature. After 1 h, the two mixtures were mixed together and the resulting mixture was stirred at room temperature for another 2 h. Water (10 mL) and DCM (100 mL) were added to the reaction mixture and the layers were separated. The aqueous phase was extracted with DCM (100 mL x 3). The combined organic phase was washed with saturated NaCl solution (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified by flash column chromatography (EA / MeOH=9 / 1) to give intermediate 10 (0.453 g, 0.699 mmol, 64.85% yield) as a yellow solid. LC-MS (m / z): 649.4 [M+H] + .

[0163] N-(3-((1-(5-amino-2-benzylpentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-2-(dimethylamino)acetamide (Intermediate C) A mixture of intermediate 10 (0.453 g, 0.7 mmol, 1.0 equiv) and HCl / 1,4-dioxane (4 M, 3.5 mL, 20.0 equiv) in EtOAc (10 mL) was stirred at room temperature for 5 h. The solvent was then removed under vacuum to give the target compound intermediate C (0.3832 g, 0.699 mmol, 100% yield) as a white solid. LC-MS (m / z): 649.4 [M+H] + .

[0164] Synthesis of Compounds 4 and 5 [ka]

[0165] Methyl 4-chloro-2-(4-fluorophenyl)quinoline-7-carboxylate (Intermediate 3) A mixture of 2-amino-4-(methoxycarbonyl)benzoic acid (585 mg, 5.0 mmol) and 1-(4-fluorophenyl)ethanone (1036 mg, 7.5 mmol) in POCl3 (10 mL) was stirred at 100 °C for 3 h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was taken up in ice water (20 mL), adjusted to pH 8-9 with solid NaHCO3, and extracted with DCM (3 x 50 mL). The combined organics were dried over anhydrous Na2SO4, concentrated, and purified by flash chromatography on silica gel (DCM / MeOH = 40 / 1) to give intermediate 3 (174 mg, 11% yield). LCMS: (m / z) 316.0 [M+H] +

[0166] 4-Chloro-2-(4-fluorophenyl)quinoline-7-carboxylic acid (Intermediate 4) To a solution of methyl 4-chloro-2-(4-fluorophenyl)quinoline-7-carboxylate (255 mg, 0.808 mmol) in THF (20 mL) was added a solution of LiOH.H2O (68 mg, 1.616 mmol) in HO (5 mL). The mixture was stirred at room temperature for 16 h and the solvent was removed in vacuo. The residue was taken up in water and acidified to pH 4-5 with 1 M HCl and the resulting mixture was extracted with ethyl acetate (3 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to leave the crude product (233 mg, 95.8% yield) as a thick gum. LCMS: (m / z) 330.2 [M+Na] +

[0167] 2-Benzyl-5-(4-chloro-2-(4-fluorophenyl)quinoline-7-carboxamido)pentanoic acid (Intermediate 6) A mixture of 4-chloro-2-(4-fluorophenyl)quinoline-7-carboxylic acid (203 mg, 0.67 mmol), HATU (255 mg, 0.67 mmol) and DIEA (173 mg, 1.34 mmol) in THF (10 mL) was stirred at room temperature for 30 min, and then added to a mixture of DIEA (134 mg, 1.34 mmol) and 5-amino-2-benzylpentanoic acid hydrochloride (163 mg, 0.67 mmol) in THF (10 mL). The mixture was stirred at room temperature for 16 h, concentrated and purified by flash column chromatography (DCM / CH3OH=20 / 1) to give intermediate 6 (265 mg, 70% yield) as a white solid. LCMS: (m / z) 491.2 [M+H] +

[0168] N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloro-2-(4-fluorophenyl)quinoline-7-carboxamide (Intermediate 7) A mixture of N-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(4-methylpiperazin-1-yl)propanamide hydrochloride (240 mg, 0.49 mmol), 2-benzyl-5-(4-chloro-2-(4-fluorophenyl)quinoline-7-carboxamide)pentanoic acid (210 mg, 0.49 mmol), HATU (205 mg, 0.539 mmol) and DIEA (190 mg, 1.47 mmol) in THF (10 mL) was stirred at room temperature for 16 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (DCM / MeOH=10 / 1) to give the crude product, which was further purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give intermediate 7 (115 mg, 26% yield) as a white solid. LCMS: (m / z) 901.8 [M+H] +

[0169] (S)-N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloro-2-(4-fluorophenyl)quinoline-7-carboxamide (compound 5) (R)-N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloro-2-(4-fluorophenyl)quinoline-7-carboxamide (compound 4) N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloro-2-(4-fluorophenyl)quinoline-7-carboxamide (92 mg, 0.102 mmol) was purified by chiral-HPLC (Instrument: Gilson-281, Column: SA20*250, 10 um, Mobile phase: MEOH (0.2% methanolic ammonia):ACN (0.2% methanolic ammonia)=70:30, Flow rate: 40 ml / min, Run time per injection: 22 min, Injection: 1.5 ml, Sample solution: 100 mg in 45 mL MeOH) to give compound 5 (29.5 mg) and compound 4 (9.0 mg) as solids.

[0170] Compound 5: 1H NMR(500MHz,DMSO-d6) δ(ppm) 10.57(s,1H),9.15(s,1H),8.94-8.86(m,1H),8.65-8.61(m,1H),8.50-8.35(m,3H),8 .28-8.23(m,1H),8.17-7.97(m,4H),7.65-7.57(m,1H),7.44-7.35(m,2H),7.27-7.07 (m,4H),4.88(s,1H),4.17-3.99(m,1H),3.91-3.57(m,3H),3.31-3.10(m,4H),2.89-2 .52(m,9H),2.47-2.20(m,6H),2.13(s,3H),1.72-1.03(m,8H),LCMS:(m / z)901.4[M+H] + ,

[0171] Compound 4: 1 H NMR(400MHz,DMSO-d6) δ(ppm) 8.99-8.88(m,1H),8.66-8.63(m,1H),8.54-8.47(m,1H),8.45-8.36(m,2H),8.3 0-8.21(m,1H),8.20-7.98(m,4H),7.69-7.58(m,1H),7.46-7.35(m,2H),7.27-7. 07(m,4H),4.18-3.97(m,1H),3.94-3.38(m,6H),3.23-3.29(m,4H),2.91-2.54(m ,6H),2.45-2.18(m,6H),2.13(s,3H),1.71-1.00(m,8H),LCMS:(m / z)901.4[M+H] + ,

[0172] Synthesis of compound 6

change

[0173] 5-アミノ-1-(4-フルオロフェニル)-1H-ピラゾール-4-カルボニトリル (Intermediate 3) A mixture of (4-fluorophenyl)hydrazine (1.6 g, 10.0 mmol) and KOAc (0.98 g, 10.0 mmol) in EtOH (80.0 mL) was stirred at 80° C. for 20 min, then 2-(ethoxymethylene)malononitrile (1.2 g, 10.0 mmol) was added, the mixture was stirred at 80° C. for 2 h, concentrated and purified by column chromatography on silica gel (EA / PE=1 / 3) to give intermediate 3 (1.5 g, yield: 75%) as a yellow solid. LCMS (m / z): 203.1 [M+H] + .

[0174] 1-(4-Fluorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Intermediate 4) A mixture of intermediate 3 (808 mg, 4.0 mmol) and HCOOH (8.0 mL) was stirred at 100° C. for 16 h. After cooling to room temperature, the mixture was diluted with ice-cold water (100 mL), filtered and dried in air to give intermediate 4 (600 mg, yield: 65%) as a white solid. LCMS (m / z): 231.1 [M+H] + .

[0175] tert-Butyl 4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 6) A mixture of intermediate 4 (400 mg, 1.45 mmol), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (370 mg, 1.73 mmol) and Cs2CO3 (709 mg, 2.1 mmol) in DMF (15.0 mL) was stirred at 80° C. for 16 h. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL*2), and the combined organics were dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography on silica gel (EA / PE=1 / 2) to give intermediate 6 (500 mg, yield: 77.7%) as a white solid. LCMS (m / z): 344.1 [M-100+H] + .

[0176] 1-(4-Fluorophenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Intermediate 7) A mixture of intermediate 6 (60 mg, 0.13 mmol) and HCl solution in 1,4-dioxane (4 M, 0.6 mL) in DCM (6.0 mL) was stirred at room temperature for 2 h, and the mixture was concentrated to leave crude intermediate 7 (60 mg, 100%) as a white solid. LCMS (m / z): 344.1 [M+H] + .

[0177] N-(4-benzyl-5-(4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (compound 6) A mixture of 2-benzyl-5-(4-chloroquinoline-7-carboxamide)pentanoic acid (intermediate 8) (39.6 mg, 0.1 mmol), compound 7 (34.3 mg, 0.1 mmol), HATU (41.8 mg, 0.11 mmol) and DIPEA (0.1 mL, 0.5 mmol) in DCM (6.0 mL) was stirred at room temperature for 1 h. The mixture was diluted with DCM (30 mL), washed with water (20.0 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give compound 6 (40 mg, 55% yield) as a white solid. 1H NMR(DMSO-d6, 400MHz): δ(ppm) 8.94-8.88(m,2H),8.61-8.59(m,1H),8.39-8.35(m,1H),8.29-8.25(m,2H), 8.20-8.15(m,1H),8.09-8.04(m,2H),7.86(d,J=4.8Hz,1H),7.45-7.40(m,2H ),7.29-7.12(m,5H),4.84(s,1H),4.17-3.83(m,2H),3.72-3.59(m,2H),3.3 2-3.10(m,3H),2.86-2.51(m,3H),1.70-1.05(m,9H).LCMS(m / z):722.2[M+H] +

[0178] Synthesis of compound 7 [ka]

[0179] 1-(4-Nitrophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Intermediate 3) A mixture of ethyl 5-amino-1-(4-nitrophenyl)-1H-pyrazole-4-carboxylate (Intermediate 1) (500 mg, 1.8 mmol) in formamide (10.0 mL) was stirred at 150° C. for 8 h. After cooling to room temperature, the mixture was poured into ice-cold water (100 mL) and the resulting solid was filtered and dried in air to give Intermediate 3 (400 mg, yield: 86%) as a brown solid. LCMS (m / z): 258.1 [M+H] + .

[0180] tert-Butyl 4-hydroxy-4-((1-(4-nitrophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (Intermediate 5) A mixture of intermediate 3 (400 mg, 1.5 mmol), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (490 mg, 2.3 mmol) and Cs2CO3 (758 mg, 2.3 mmol) in DMF (10.0 mL) was stirred at 80° C. for 16 h. After cooling to room temperature, the mixture was diluted with water (100 mL), extracted with EtOAc (100 mL*2), and the combined organics were dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography on silica gel (EA / PE=1 / 2) to give compound intermediate 5 (130 mg, yield: 18%) as a white solid. LCMS (m / z): 371.1 [M-100+H] + .

[0181] 5-((4-Hydroxypiperidin-4-yl)methyl)-1-(4-nitrophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Intermediate 6) A mixture of intermediate 5 (120 mg, 0.25 mmol) and HCl solution in 1,4-dioxane (4M, 1.5 mL) in DCM (6.0 mL) was stirred at room temperature for 2 h, and the mixture was concentrated to leave the crude product, which was further purified by preparative HPLC to give pure intermediate 6 (40 mg, yield: 43%) as a yellow solid. LCMS (m / z): 371.2 [M+H] + .

[0182] N-(4-benzyl-5-(4-hydroxy-4-((1-(4-nitrophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (Intermediate 8) A mixture of intermediate 7 (39.6 mg, 0.1 mmol), intermediate 6 (37 mg, 0.1 mmol), HATU (41.8 mg, 0.11 mmol) and DIPEA (0.1 mL, 0.5 mmol) in DCM (6.0 mL) was stirred at room temperature for 2 h, the suspension was filtered and the cake was dried in air to give intermediate 8 (60 mg, yield: 80%) as a white solid. LCMS (m / z): 749.4 [M+H]+ .

[0183] N-(5-(4-((1-(4-aminophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidin-1-yl)-4-benzyl-5-oxopentyl)-4-chloroquinoline-7-carboxamide (Intermediate 7) A mixture of intermediate 8 (60 mg, 0.08 mmol), Raney Ni (30 mg) and N2H4.H2O (0.9 mL) in EtOH (3.0 mL) and THF (3.0 mL) was stirred at room temperature for 3 h, the mixture was filtered and the filtrate was concentrated and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give intermediate 7 (21 mg, 36% yield) as a white solid. 1 H NMR(DMSO-d6,400MHz):δ(ppm) 8.93-8.88(m,2H),8.61-8.59(m,1H),8.28-8.16(m,4H),7.86(d,J=4.4Hz,1H),7.53-7.51(m,2H),7.26-7.12(m,5H),6.68(d,J=8.0H) z,2H),5.39(s,2H),4.81(s,1H),4.16-3.61(m,4H),3.15-3.13(m,3H),2.86-2.62(m,4H),1.65-1.09(m,8H).LCMS(m / z):719.2[M+H] + ;

[0184] Synthesis of compound 8 [ka]

[0185] 5-Amino-1-(3-nitrophenyl)-1H-pyrazole-4-carbonitrile (Intermediate 2) A mixture of (3-nitrophenyl)hydrazine (1002.8 mg, 5.289 mmol, 1.0 equiv) and KOAc (517.3 mg, 5.271 mmol, 0.8 equiv) in CH3CH2OH (50 mL) was stirred at 80° C. for 30 min in a round-bottom flask. Then, 5-amino-1-(3-nitrophenyl)-1H-pyrazole-4-carbonitrile (537.1 mg, 4.398 mmol, 0.8 equiv) was added to the reaction mixture, and the resulting mixture was stirred at 80° C. for another 2 h. After filtration, the filtrate was concentrated under vacuum to dryness and purified by flash column chromatography (EA / PE=2 / 8) to give intermediate 2 as a brown solid (0.236 g, 19.47% yield). LCMS: (m / z) 230.7 [M+H] +

[0186] 1-(3-Nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (Intermediate 3) In a round bottom flask, 5-amino-1-(3-nitrophenyl)-1H-pyrazole-4-carbonitrile (236 mg, 1.030 mmol, 1.0 q) was dissolved in formic acid (15 mL). The resulting mixture was stirred at 100° C. for 16 h. The reaction mixture was poured into ice water (50 mL) with stirring, and the resulting solid was collected and dried under vacuum to give intermediate 3 as a white solid (93 mg, 35.15% yield). LCMS: (m / z) 257.7 [M+H] +

[0187] tert-Butyl 4-hydroxy-4-((1-(3-nitrophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)piperidine-1-carboxylate (Intermediate 4) A mixture of 1-(3-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (169 mg, 0.657 mmol, 1.0 equiv.), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (308.6 mg, 1.446 mmol, 2.2 equiv.) and Cs2CO3 (535.2 mg, 1.643 mmol, 2.5 equiv.) was stirred at 85° C. for 16 h. Ethyl acetate (100 mL) was added to the reaction mixture and the resulting mixture was washed with water (10 mL×4). The aqueous was extracted with ethyl acetate (50 mL×6). The combined organic phase was washed with saturated NaCl solution (10 mL) and dried over Na2SO4. After filtration, the filtrate was concentrated by rotary evaporation (40° C.). The crude residue was purified by flash column chromatography (EA / PE=1 / 2) to give intermediate 4 as a white solid (231 mg, 0.491 mmol, 74.78% yield). LC-MS: (m / z) 371.1 [M-100+H] +

[0188] 5-((4-Hydroxypiperidin-4-yl)methyl)-1-(3-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (Intermediate 5) To a solution of tert-butyl 4-hydroxy-4-((1-(3-nitrophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)piperidine-1-carboxylate (231 mg, 0.491 mmol, 1.0 equiv.) in dichloromethane (5 mL) was added a solution of HCl in 1,4-dioxane (4 M, 15 mL, 20.0 equiv.), the mixture was stirred at room temperature for 3 h, then concentrated under vacuum to give intermediate 5 as a white solid (181.7 mg, 0.491 mmol, 100% yield). LC-MS: (m / z) 371.1 [M+H] +

[0189] N-(4-benzyl-5-(4-hydroxy-4-((1-(3-nitrophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (Intermediate 6) A mixture of 2-benzyl-5-(4-chloroquinoline-7-carboxamide)pentanoic acid (57.0 mg, 0.144 mmol, 0.8 equiv), HATU (65.5 mg, 0.172 mmol, 1.0 equiv) and DIPEA (93.0 mg, 0.720 mmol, 5.0 equiv) in dichloromethane (2 mL) was stirred for 30 min at 25° C. Then, 5-((4-hydroxypiperidin-4-yl)methyl)-1-(3-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (67.8 mg, 0.183 mmol, 1.0 equiv) was added to the reaction mixture and the resulting mixture was stirred for an additional 3.5 h at 25° C. Dichloromethane (50 mL) and water (10 mL) were added to the reaction mixture and the layers were separated. The aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with saturated NaCl solution (10 mL) and dried over Na2SO4. After filtration, the filtrate was concentrated by rotary evaporation (40 °C). The crude residue was purified by flash column chromatography (DCM / MeOH = 1 / 5) to give intermediate 6 as a white solid (115 mg, 0.153 mmol, 83.61% yield). LCMS (m / z): 749.2 [M+H] +

[0190] N-(5-(4-((1-(3-aminophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-4-benzyl-5-oxopentyl)-4-chloroquinoline-7-carboxamide (compound 8) A mixture of N-(4-benzyl-5-(4-hydroxy-4-((1-(3-nitrophenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (97 mg, 0.1296 mmol, 1.0 equiv.), Raney Ni (100 mg) and N2H4·H2O (6 drops) in ethanol (2 mL) and tetrahydrofuran (2 mL) was stirred at room temperature for 30 min. The reaction mixture was then concentrated by rotary evaporation (40 °C) and further purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give the target compound 8 (10.6 mg, 0.015 mmol, 11.39% yield) as a white solid. 1 H NMR(DMSO-d6,400MHz):δ(ppm) 8.94-8.89(m,2H),8.62-8.58(m,1H),8.32-8.15(m,4H),7.86(d,J=4.4Hz,1H),7.28-7.12(m,8H),6.57(br,1H),5.44( s,2H),4.83(s,1H),4.16-3.58(m,4H),3.31-3.09(m,3H),2.86-2.62(m,4H),1.67-1.07(m,8H).LCMS(m / z):719.3[M+H] +

[0191] Synthesis of compound 9 [ka]

[0192] 1-(4-Bromophenyl)-2,2,2-trifluoroethanamine (Intermediate 2) To a mixture of 1-(4-bromophenyl)-2,2,2-trifluoroethanone (2530 mg, 10.0 mmol) in toluene (60 mL) was added dropwise LiHMDS (11 mL, 11 mmol). After stirring at room temperature for 15 min, borane-THF (10 mL, 20 mmol) was added. The resulting mixture was stirred at room temperature for 20 min, cooled to 0° C., and then 2N NaOH solution (23 mL) was added. After stirring at room temperature for 90 min, the mixture was diluted with EtOAc (100 mL), the organic layer was separated, washed with 2N NaOH solution (100 mL), water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, concentrated and purified by column chromatography (10% EtOAc in hexane) to give intermediate 2 (2.22 g, 87.4 yield) as an oil. LCMS: (m / z) 254.0, 256.0 [M+H] +

[0193] Benzyl 1-(4-bromophenyl)-2,2,2-trifluoroethylcarbamate (Intermediate 3) To a solution of intermediate 2 (1967 mg, 7.74 mmol) in THF (25 mL) was added a solution of K2CO3 (1451 mg, 8.51 mmol) in water (25 mL) at 0° C., followed by dropwise addition of benzyl carbonochloridate (1451 mg, 8.51 mmol). The mixture was stirred at room temperature for 16 h. Brine (20 mL) and EtOAc (50 mL) were added to the mixture and the phases were separated. The aqueous phase was extracted with EtOAc (40 mL×2). The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (PE / EtOAc=10 / 1) to give intermediate 3 (2.05 g, 68.6% yield) as an oil. LCMS: (m / z) 410.0 [M+Na] +

[0194] Benzyl 1-(4-(2-(diphenylmethylene)hydrazinyl)phenyl)-2,2,2-trifluoroethylcarbamate (Intermediate 4) Under an argon atmosphere, a solution of benzyl 1-(4-bromophenyl)-2,2,2-trifluoroethylcarbamate (2.126 g, 5.48 mmol) in toluene (20 mL) was added to a mixture of (diphenylmethylene)hydrazine (1.129 g, 6.58 mmol), sodium-tert-butoxide (790 mg, 8.22 mmol), palladium(II) acetate (123 mg, 0.55 mmol) and X-phos (524 mg, 1.1 mmol) in toluene (30 mL). The reaction mixture was stirred at 90° C. for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (200 mL), washed with brine (200 mL), dried over anhydrous Na2SO4, concentrated and purified by flash column chromatography (DCM / MeOH=30 / 1) to give intermediate 4 (1.575 g, 52.3% yield) as a pale yellow solid. LCMS: (m / z) 504.2 [M+H] +

[0195] Benzyl 2,2,2-trifluoro-1-(4-hydrazinylphenyl)ethylcarbamate hydrochloride (Intermediate 5) To a mixture of benzyl 1-(4-(2-(diphenylmethylene)hydrazinyl)phenyl)-2,2,2-trifluoroethylcarbamate (805 mg, 1.6 mmol) in EtOH (32 mL) was added concentrated HCl solution (8.0 mL, 96.0 mmol). The mixture was stirred at 45° C. for 4 h. After cooling to room temperature, the mixture was diluted with H2O (40 mL) and extracted with DCM (3×50 mL). The combined organics were extracted with H2O (2×25 mL) and the combined aqueous were concentrated and lyophilized to give intermediate 5 (300 mg) as a light brown solid. LCMS: (m / z) 340.1 [M+H] +

[0196] Benzyl 1-(3-(5-amino-4-cyano-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethylcarbamate (Intermediate 6) A mixture of benzyl 2,2,2-trifluoro-1-(4-hydrazinylphenyl)ethylcarbamate hydrochloride (350 mg, 0.93 mmol), 2-(ethoxymethylene)malononitrile (114 mg, 0.93 mmol) and KOAc (91 mg, 0.93 mmol) in EtOH (20 mL) was stirred at 80° C. for 2 h. After cooling to room temperature, the mixture was filtered and washed with EtOH (10 mL). The combined filtrate and washings were concentrated to leave crude intermediate 6 (330 mg, 80% yield) as a pale yellow solid. LCMS: (m / z) 416.1 [M+H] +

[0197] Benzyl 2,2,2-trifluoro-1-(4-(4-oxo-4H-pyrazolo[3,4-d]pyrimidin-1(7H)-yl)phenyl)ethyl carbamate (7) and N-(2,2,2-trifluoro-1-(4-(4-oxo-4H-pyrazolo[3,4-d]pyrimidin-1(7H)-yl)phenyl)ethyl)formamide (Intermediate 8) A mixture of benzyl 1-(3-(5-amino-4-cyano-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethylcarbamate (330 mg, 0.79 mmol) in HCOOH (10 mL) was stirred at 100° C. for 16 h. After allowing the mixture to cool to room temperature, the mixture was poured into ice water (30 mL) and extracted with EtOAc (3×50 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give a mixture of intermediates 7 (26% in LCMS) and 8 (60% in LCMS) (total 270 mg) as a pale yellow solid, which was used directly in the next step. LCMS: 7: (m / z) 441.3 [M+H] + , 8: (m / z) 338.1 [M+H] +

[0198] 1-(4-(1-amino-2,2,2-trifluoroethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(7H)-one (Intermediate 9) A mixture of compounds 7 and 8 (243 mg, 0.72 mmol) in HCl / EtOH (5%, 10 mL) was stirred at 80° C. for 2 h. The mixture was concentrated to give intermediate 9 as a brown solid (260 mg). LCMS: (m / z) 310.1 [M+H] +

[0199] Benzyl 2,2,2-trifluoro-1-(4-(4-oxo-4H-pyrazolo[3,4-d]pyrimidin-1(7H)-yl)phenyl)ethylcarbamate (Intermediate 7) To a stirred mixture of 1-(4-(1-amino-2,2,2-trifluoroethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(7H)-one hydrochloride (260 mg, 0.84 mmol) and NEt3 (255 mg, 2.521 mmol) in DCM (20 mL) was added a solution of CbzCl (172 mg, 1.00 mmol). The mixture was stirred at room temperature for 16 h, diluted with DCM (100 mL), washed with aqueous NaHCO3 (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, concentrated and purified by flash column chromatography (DCM / MeOH=30 / 1) to give intermediate 7 (158 mg, 47% yield) as a brown solid. LCMS: (m / z) 444.1 [M+H] +

[0200] tert-Butyl 4-((1-(4-(1-amino-2,2,2-trifluoroethyl)phenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 10) To a stirred mixture of benzyl 2,2,2-trifluoro-1-(4-(4-oxo-4H-pyrazolo[3,4-d]pyrimidin-1(7H)-yl)phenyl)ethylcarbamate (136 mg, 0.306 mmol) and 1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid, 1,1-dimethylethyl ester (85 mg, 0.398 mmol) in DMF (10 mL) was added CsCO (150 mg, 0.459 mmol). The mixture was stirred at 90° C. for 7 h. After cooling to room temperature, the mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 x 30 mL), and the combined organics were dried over anhydrous Na2SO4, concentrated, and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give intermediate 10 (46.9 mg, 25.2% yield) as a white solid. LCMS: (m / z) 545.3 [M+Na] +

[0201] 1-(4-(1-amino-2,2,2-trifluoroethyl)phenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrochloride (Intermediate 11) To a mixture of tert-butyl 4-((1-(4-(1-amino-2,2,2-trifluoroethyl)phenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate (46.9 mg, 0.09 mmol) in DCM (5 mL) was added a solution of HCl in 1,4-dioxane (4 M, 0.45 mL, 1.8 mmol) at 0° C. The mixture was stirred at room temperature for 4 h and concentrated in vacuo to give intermediate 11 (42 mg, 100% yield) as a white solid. LCMS: (m / z) 423.1 [M+H] + ,

[0202] N-(5-(4-((1-(4-(1-amino-2,2,2-trifluoroethyl)phenyl)-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-4-benzyl-5-oxopentyl)-4-chloroquinoline-7-carboxamide (compound 9) A mixture of 1-(4-(1-amino-2,2,2-trifluoroethyl)phenyl)-5-((4-hydroxypiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrochloride (42 mg, 0.091 mmol), 2-benzyl-5-(4-chloroquinoline-7-carboxamide)pentanoic acid (28 mg, 0.07 mmol), HATU (29 mg, 0.077 mmol) and DIPEA (36 mg, 0.091 mmol) in DMF (5 mL) was stirred at room temperature for 1 h. The mixture was directly purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give compound 9 (18.2 mg, 24.8% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm) 8.96-8.84(m,2H),8.61-8.58(m,1H),8.39-8.35(m,1H),8.31-8.24(m,2H) ,8.20-8.13(m,1H),8.09-8.01(m,2H),7.86(d,4.8Hz),7.70-7.68(m,2H), 7.29-7.09(m,5H),4.84(s,1H),4.65-4.54(m,1H),4.18-3.56(m,4H),3.19 -3.08(m,2H),2.88-2.55(m,6H),1.70-1.04(m,8H).LCMS:(m / z)801.3[M+H] +

[0203] Synthesis of compound 10 [ka]

[0204] 1-(4-Nitrophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Intermediate 3) A mixture of methyl 4-amino-1-methyl-1H-pyrazole-3-carboxylate (500 mg, 3.2 mmol), acetic acid formimidamide (370 mg, 3.5 mmol) and DIPEA (3.0 mL) in n-BuOH (4.0 mL) was stirred at 110° C. for 1 h. After cooling to room temperature, the mixture was filtered to give intermediate 3 (450 mg, 93% yield) as an off-white solid. LCMS (m / z): 151.1 [M+H] + .

[0205] 3-Bromo-2-methyl-2,4-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Intermediate 4) A mixture of intermediate 3 (400 mg, 2.6 mmol) and Br2 (853 mg, 5.2 mmol) in AcOH (15.0 mL) was stirred at 95° C. for 16 h. After cooling to room temperature, the mixture was filtered to give crude compound 4 (800 mg) as a yellow solid. LCMS (m / z): 229.1 [M+H] + .

[0206] 3-(2-Methyl-7-oxo-4,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-3-yl)benzonitrile (Intermediate 6) A mixture of compound 4 (700 mg, 3.0 mmol), (3-cyanophenyl)boronic acid (1100 mg, 7.5 mmol), K3PO4 (1900 mg, 9.0 mmol) and Pd(dppf)Cl2 (220 mg, 0.3 mmol) in 1,4-dioxane (20.0 mL) and H2O (4.0 mL) was heated in a microwave reactor at 150 °C for 40 min, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organics were dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography on silica gel (MeOH / DCM = 1 / 30) to give intermediate 6 (300 mg, 40% yield) as a white solid. LCMS (m / z): 252.2 [M+H] + .

[0207] tert-Butyl 4-((3-(3-cyanophenyl)-2-methyl-7-oxo-2,7-dihydro-6H-pyrazolo[4,3-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 8) A mixture of intermediate 6 (125 mg, 0.5 mmol), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (127 mg, 0.6 mmol) and Cs2CO3 (244 mg, 0.75 mmol) in DMF (10.0 mL) was stirred at 80° C. for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (100 mL), washed with water (20 mL*4), dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography on silica gel (EA / PE=1 / 2) to give intermediate 8 (150 mg, 64% yield) as a yellow solid. LCMS (m / z): 409.2 [M-55+H] + .

[0208] 3-(6-((4-hydroxypiperidin-4-yl)methyl)-2-methyl-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-3-yl)benzonitrile (Intermediate 9) To a mixture of intermediate 8 (92.8 mg, 0.2 mmol) in DCM (4.0 mL) was added a solution of HCl in 1,4-dioxane (4 M, 1.0 mL), the mixture was stirred at room temperature for 2 h and concentrated in vacuo to leave crude intermediate 9 (80 mg) as an oil. LCMS (m / z): 365.2 [M+H] + .

[0209] N-(4-benzyl-5-(4-((3-(3-cyanophenyl)-2-methyl-7-oxo-2,7-dihydro-6H-pyrazolo[4,3-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (compound 10) A mixture of compound A (79.2 mg, 0.2 mmol), HATU (83.6 mg, 0.22 mmol) and DIPEA (0.2 mL, 1.0 mmol) in DCM (10.0 mL) was stirred at room temperature for 30 minutes. The mixture was added to a solution of intermediate 9 (72.8 mg, 0.2 mmol) and DIPEA (0.1 mL, 0.2 mmol) in DCM (10.0 mL), and the resulting mixture was stirred at room temperature for 2 hours, diluted with DCM (20 mL), washed with water (20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography on silica gel (MeOH / DCM=1 / 20) and by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give compound 10 as a white solid (43.3 mg, 29% yield). 1 H NMR(DMSO-d6, 400MHz): δ(ppm) 8.93-8.88(m,2H),8.61-8.58(m,1H),8.30-8.26(m,1H),8.21-8.15(m,2H), 8.09-8.05(m,1H),8.01-7.95(m,2H),7.86(d,J=4.8Hz,1H),7.82-7.78(m,1H ),7.29-7.12(m,5H),4.80(s,1H),4.17-4.15(m,4H),3.95-3.60(m,3H),3.2 8-3.16(m,3H),3.13-2.67(m,4H),1.65-1.09(m,8H).LCMS(m / z):743.3[M+H] +

[0210] Synthesis of Compounds 11, 12, and 13 [ka]

[0211] tert-Butyl 4-((4-chloro-6-oxopyrimidin-1(6H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 2) A mixture of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (5026 mg, 23.6 mmol), 6-chloropyrimidin-4(1H)-one (1536 mg, 11.8 mmol) and DIEA (3 mL) in DMF (50 mL) was stirred at 80° C. overnight. The mixture was diluted with EtOAc (100 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel (EA / PE=1 / 2) to give intermediate 2 (2.7 g, 66% yield) as a white solid. LCMS: (m / z) 366 [M+Na] +

[0212] tert-Butyl 4-hydroxy-4-((6-oxo-4-((2-(pyrrolidin-1-yl)ethyl)amino)pyrimidin-1(6H)-yl)methyl)piperidine-1-carboxylate (Intermediate 3) A mixture of compound 2 (498 mg, 1.45 mmol) and 2-(pyrrolidin-1-yl)ethan-1-amine (550 mg, 4.8 mmol) in 1,4-dioxane (10 mL) was heated in a microwave reactor at 150° C. for 2.5 h. The reaction mixture was concentrated and purified by HPLC to give intermediate 3 (200 mg, 32.6% yield) as a white solid. LCMS: (m / z) 422 [M+H] +

[0213] 3-((4-Hydroxypiperidin-4-yl)methyl)-6-((2-(pyrrolidin-1-yl)ethyl)amino)pyrimidin-4(3H)-one (Intermediate 4) To a mixture of compound 3 (200 mg, 0.47 mmol) in DCM (4 mL) was added HCl-dioxane (2 mL), the mixture was stirred at room temperature for 2 h, and concentrated to leave crude intermediate 4 (250 mg) as a yellow solid. LCMS (m / z): 322 [M+H] +

[0214] N-(4-benzyl-5-(4-hydroxy-4-((6-oxo-4-(2-(pyrrolidin-1-yl)ethylamino)pyrimidin-1(6H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (compounds 11, 12, 13) A mixture of intermediate 4 (180 mg, 0.5 mmol), intermediate 5 (200 mg, 0.5 mmol), DIEA (0.5 mL) and HATU (198 mg, 0.55 mmol) in DMF (4 mL) was stirred at room temperature for 30 min. The reaction mixture was directly purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give 100 mg of compound 11, which was separated by chiral HPLC to give two enantiomers: compound 12 (isomer 1: 29.6 mg) as a white solid and compound 13 (isomer 2: 24 mg) as a white solid.

[0215] Compound 12: 1 H NMR(400MHz,DMSO-d6) δ(ppm) 8.99-8.81(m,2H),8.59(d,J=4.8Hz,1H),8.28(dd,J=8.7,2.0Hz,1H),8.22-8.13(m, 1H),7.90(dd,J=30.3,14.0Hz,2H),7.31-7.07(m,5H),6.96(s,1H),5.08(s,1H),4.11 -3.94(m,1H),3.75-3.65(m,3H),3.31-3.13(m,6H),2.73(ddd,J=26.2,24.9,16.8Hz ,9H),1.78-1.39(m,9H),1.20(ddd,J=53.0,32.7,12.5Hz,4H).LC-MS:(m / z)700[M+H] +

[0216] Compound 13: 1H NMR(400MHz,DMSO-d6) δ(ppm) 8.99-8.81(m,2H),8.59(d,J=4.8Hz,1H),8.28(dd,J=8.7,2.0Hz,1H),8.22-8.13(m ,1H),7.90(dd,J=30.3,14.0Hz,2H),7.31-7.07(m,5H),6.96(s,1H),5.08(s,1H),4 .11-3.94(m,1H),3.75-3.65(m,3H),3.31-3.13(m,6H),2.73(ddd,J=26.2,24.9,16 .8Hz,9H),1.80-1.60(m,5H),1.50(s,3H),1.38-1.00(m,4H).LC-MS:(m / z)700[M+H] +

[0217] Synthesis of compound 14 [ka]

[0218] Methyl 4-chloro-2-(pyridin-3-yl)quinoline-7-carboxylate (Intermediate 2) A mixture of 2-amino-4-(methoxycarbonyl)benzoic acid (506.1 mg, 2.593 mmol) and 1-(pyridin-3-yl)ethanone (322.4 mg, 2.661 mmol) in POCl3 (8 mL) was stirred at 100° C. for 3.5 h. Ice water (50 mL) was poured into the reaction mixture with stirring. To the solution was added saturated Na2CO3 solution and adjusted to pH 8. DCM (50 mL) was added to the solution and the layers were separated. The aqueous phase was extracted with DCM (40 mL×6) and the combined organic phase was washed with saturated NaCl solution (100 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (EA / PE=1 / 4) to give intermediate 2 (0.260 g, 33.63% yield) as a yellow solid. LCMS: (m / z) 299.1 [M+H] +

[0219] 4-Chloro-2-(pyridin-3-yl)quinoline-7-carboxylic acid (Intermediate 3) A mixture of methyl 4-chloro-2-(pyridin-3-yl)quinoline-7-carboxylate (260 mg, 0.872 mmol, 1.0 equiv) and LiOH.H2O (74.9 mg, 1.785 mmol, 2.0 equiv) in tetrahydrofuran (10 mL) and water (3 mL) was stirred at 25° C. for 16 h. The reaction mixture was concentrated under vacuum and the residue was diluted with water (50 mL), adjusted to ph 4 with dilute HCl solution, then lyophilized overnight to give intermediate 3 (180 mg, 72.68% yield) as a yellow solid. LCMS: (m / z) 285.0 [M+H] +

[0220] N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloro-2-(pyridin-3-yl)quinoline-7-carboxamide (compound 14) To a solution of 4-chloro-2-(pyridin-3-yl)quinoline-7-carboxylic acid (0.1857 g, 0.654 mmol, 1.0 equiv) in anhydrous dichloromethane (10 mL) and N,N-dimethylformamide (0.1 mL) was added SOCl2 (76 μL, 0.8 equiv) while stirring in an ice-water bath. The mixture was stirred at 60° C. for 1 h, then concentrated in vacuo, and the residue was dissolved in anhydrous dichloromethane (25 mL) and added dropwise to a solution of N-(3-((1-(5-amino-2-benzylpentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(4-methylpiperazin-1-yl)propanamide (225.2 mg, 0.365 mmol, 0.6 equiv.), Et3N (0.2 mL, 8.0 equiv.) and DMAP (4.5 mg, 0.037 mmol, 0.1 equiv.) in anhydrous dichloromethane (15 mL) with stirring in an ice-water bath. The resulting mixture was stirred at room temperature for 4 h, concentrated, and purified by preparative HPLC to give the target compound 14 (14.9 mg, 2.58% yield) as a white solid. 1H NMR(400MHz,DMSO-d6) δ(ppm) 10.55(d,J=6.9Hz,1H),9.49(s,1H),9.00-8.94(m,1H),8.80-8.60(m,4H),8.32-8.0(m,5H),7.65-7.57(m,2H),7.28-7.10(m,5H),4 .87(s,1H),4.17-4.01(m,1H),3.95-3.49(m,3H),3.45-2.65(m,13H),2.60-2.10(m,9H),1.75-1.02(m,8H).LC-MS:(m / z)884.3[M+H] +

[0221] Synthesis of compound 15 [ka]

[0222] Methyl 4-chloro-2-(3-(trifluoromethyl)phenyl)quinoline-7-carboxylate (Intermediate 2) A mixture of 2-amino-4-(methoxycarbonyl)benzoic acid (344.3 mg, 1.7652 mmol, 1.0 equiv.) and 1-(3-(trifluoromethyl)phenyl)ethanone (504.3 mg, 2.6819 mmol, 1.5 equiv.) in POCl3 (6 mL) was stirred at 100° C. for 3 h. The reaction mixture was concentrated in vacuo, ice water was added with stirring, and the mixture was adjusted to pH 8 with solid sodium bicarbonate and saturated sodium carbonate solutions. Dichloromethane (50 mL) was added and the layers were separated. The aqueous phase was washed with dichloromethane (40 mL×3), and the combined organic phase was washed with saturated NaCl solution (100 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash column chromatography (EA / PE=1 / 5) to give intermediate 2 (250 mg, 0.685 mmol, 38.80% yield) as a white solid. LCMS(m / z):366.0[M+H] +

[0223] 4-Chloro-2-(3-(trifluoromethyl)phenyl)quinoline-7-carboxylic acid (Intermediate 3) A mixture of methyl 4-chloro-2-(3-(trifluoromethyl)phenyl)quinoline-7-carboxylate (250 mg, 0.685 mmol, 1.0 equiv.) and LiOH·HO (56.4 mg, 1.344 mmol, 2.0 equiv.) in tetrahydrofuran (10 mL) and HO (3 mL) was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuo, diluted with water (50 mL) and adjusted to about pH 5 with diluted HCl solution. The mixture was extracted with ethyl acetate (50 mL × 3) and the combined organic phase was washed with saturated NaCl solution (100 mL), dried over anhydrous NaSO, filtered and concentrated in vacuo to leave crude intermediate 3 (173 mg, 0.493 mmol, 71.95% yield) as a white solid. LC-MS (m / z): 352.0 [M+H] +

[0224] N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloro-2-(3-(trifluoromethyl)phenyl)quinoline-7-carboxamide (compound 15) A mixture of 4-chloro-2-(3-(trifluoromethyl)phenyl)quinoline-7-carboxylic acid (32 mg, 0.091 mmol, 1.0 equiv.), DIPEA (75.8 mg, 0.587 mmol, 5.0 equiv.) and HATU (41.6 mg, 0.109 mmol, 1.2 equiv.) in dichloromethane (2 mL) was stirred at 25° C. for 30 min, then N-(3-((1-(5-amino-2-benzylpentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(4-methylpiperazin-1-yl)propanamide (57.1 mg, 0.093 mmol, 1.0 equiv.) was added. The resulting mixture was stirred at 25° C. for 3.5 h and diluted with dichloromethane (10 mL) and water (50 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (50 mL×3). The combined organics were dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative HPLC to give the target compound 15 (27.9 mg, 32.26% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm) 10.52(d,J=7.6Hz,1H),8.95-8.90(m,1H),8.73-8.62(m,4H),8.31-8.27(m,1H),8. 22-8.16(m,1H),8.12-7.98(m,3H),7.93-7.89(m,1H),7.85-7.80(m,1H),7.64-7.56 (m,1H),7.26-7.10(m,5H),4.85-4.84(m,1H),4.16-3.60(m,5H),3.20-3.10(m,2H) ,2.85-2.60(m,7H),2.45-2.20(m,7H),1.75-0.95(m,10H).LC-MS(m / z):951.3[M+H] +

[0225] Synthesis of compound 16 [ka]

[0226] Methyl 4-chloro-2-(3-cyanophenyl)quinoline-7-carboxylate (Intermediate 1) A mixture of 2-amino-4-(methoxycarbonyl)benzoic acid (558 mg, 2.86 mmol) and 3-acetylbenzonitrile (623 mg, 4.29 mmol) in POCl3 (10 mL) was stirred at 100 °C for 3 h. After cooling to room temperature, the mixture was concentrated and the residue was taken up in ice water (20 mL), adjusted to pH 8-9 with solid NaHCO3, and extracted with DCM (50 mL x 3). The combined organics were dried over anhydrous Na2SO4, concentrated, and purified by flash column chromatography (DCM / MeOH = 40 / 1) to give intermediate 1 (245 mg, 11% yield) as a pale yellow solid. LCMS: (m / z) 323.1 [M+H] + ,

[0227] 4-Chloro-2-(3-cyanophenyl)quinoline-7-carboxylic acid (Intermediate 2) To a solution of methyl 4-chloro-2-(3-cyanophenyl)quinoline-7-carboxylate (245 mg, 0.759 mmol) in THF (10 mL) was added a solution of LiOH.H2O (48 mg, 1.138 mmol) in H2O (5 mL). The mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The residue was diluted with water (20 mL), acidified with 1 M HCl solution (pH 4-5) and the resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were dried and concentrated in vacuo to leave crude intermediate 2 (120 mg, 51.3% yield) as a yellow solid. LCMS: (m / z) 309.1 [M+Na] +

[0228] N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloro-2-(3-cyanophenyl)quinoline-7-carboxamide (compound 16) A mixture of intermediate 2 (62 mg, 0.2 mmol), SM-2 (124 mg, 0.2 mmol), HATU (84 mg, 0.22 mmol) and DIEA (78 mg, 0.6 mmol) in THF (5 mL) was stirred at room temperature for 2 h. The mixture was concentrated and purified by flash column chromatography (DCM / MeOH=10 / 1) and by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give compound 16 (24 mg, 13% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6) δ(ppm) 10.52(d,J=9.5Hz,1H),8.98-8.89(m,1H),8.79(d,J=9.0Hz,1H),8.70(d,J=8.5Hz,1H),8.68-8.62 (m,2H),8.31-8.27(m,1H),8.21-8.14(m,1H),8.12-7.97(m,4H),7.82-7.75(m,1H),7.63-7.55(m, 1H),7.26-7.08(m,5H),4.84(d,J=8.0Hz,1H),4.18-3.98(m,1H),3.90-3.58(m,3H),3.32-3.09(m, 4H),2.91-2.52(m,9H),2.47-2.18(m,6H),2.14(s,3H),1.70-1.02(m,8H).LCMS:(m / z)908.3[M+H] +

[0229] Synthesis of compound 17 [ka]

[0230] 2-(3-(aminomethyl)phenyl)-N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (Intermediate 1) To a mixture of compound 16 (239 mg, 0.263 mmol) in EtOH (40 mL) was added Raney Ni (309 mg, 5.26 mmol) and NH3 solution in CH3OH (7M, 5 mL). The mixture was stirred at 50 °C under H2 (1 atm) for 16 h. The mixture was allowed to cool to room temperature, filtered, the cake was washed with EtOH (20 mL) and the combined filtrate and washings were concentrated to leave crude intermediate 1 (254 mg) as a grey solid. LCMS: (m / z) 912.3 [M+H] + ,

[0231] tert-Butyl 3-(7-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentylcarbamoyl)-4-chloroquinolin-2-yl)benzylcarbamate (Intermediate 2) To a mixture of 2-(3-(aminomethyl)phenyl)-N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (254 mg, 0.278 mmol) and TEA (56 mg, 0.556 mmol) in DCM (20 mL) was added (Boc)O (67 mg, 0.306 mmol) at room temperature. The mixture was stirred at room temperature for 16 h, diluted with DCM (100 mL), washed with aqueous NaHCO3 (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give intermediate 2 (48 mg, 17% yield) as a white solid. LCMS: (m / z) 1012.5 [M+Na] +

[0232] 2-(3-(aminomethyl)phenyl)-N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide hydrochloride (Compound 17) To a stirred mixture of tert-butyl 3-(7-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentylcarbamoyl)-4-chloroquinolin-2-yl)benzylcarbamate (40 mg, 0.04 mmol) in DCM (5 mL) was added a solution of HCl in 1,4-dioxane (4 M, 0.5 mL, 2 mmol). The mixture was stirred at room temperature for 3 h, concentrated in vacuo, and the residue was triturated with EtO to give compound 17 (36 mg, 95% yield) as a white solid. 1 H NMR(400MHz,CD3OD) δ(ppm) 9.95(d,J=12.0Hz,1H),8.49-8.46(m,1H),8.25-8.15(m,4H),8.12-7.92(m,3H),7.57-7.47(m,3H),7.21-6.92(m,5H),4.1 0(s,2H),3.98-3.23(m,15H),3.08-2.92(m,3H),2.84(s,3H),2.70-2.58(m,3H),1.72-0.91(m,8H).LCMS:(m / z)912.4[M+H] +

[0233] Synthesis of compound 18 [ka]

[0234] 1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethanone (Intermediate 1) To a mixture of 1-(1H-pyrazol-4-yl)ethanone (500 mg, 4.54 mmol) and 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (1270 mg, 4.99 mmol) in NMP (10 mL) was added Cs2CO3 (2219 mg, 6.81 mmol). The mixture was stirred at 60 °C for 18 h and after cooling to room temperature, the mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 x 40 mL). The combined organics were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (0-50% EtOAc in PE) to give intermediate 1 (720 mg, 82.6% yield) as an oil. LCMS: (m / z) 193.1 [M+H] + ,

[0235] Methyl 4-chloro-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)quinoline-7-carboxylate (Intermediate 2) A mixture of intermediate 1 (720 mg, 3.75 mmol) and 2-amino-4-(methoxycarbonyl)benzoic acid (1098 mg, 5.625 mmol) in POCl3 (10 mL) was stirred at 100 °C for 3 h. After cooling to room temperature, the mixture was concentrated in vacuo, the residue was taken up in ice water (20 mL), adjusted to pH 8-9 with solid NaHCO3, and extracted with DCM (50 mL x 3). The combined organics were dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash column chromatography (DCM / MeOH = 40 / 1) to give intermediate 2 (105 mg, 7.5% yield) as a pale yellow solid. LCMS: (m / z) 370.1 [M+H] +

[0236] 4-Chloro-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)quinoline-7-carboxylic acid (Intermediate 3) To a solution of methyl 4-chloro-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)quinoline-7-carboxylate (105 mg, 0.284 mmol) in THF (50 mL) was added a solution of LiOH.H2O (18 mg, 0.426 mmol) in HO (2 mL). The mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The residue was taken up in water (20 mL) and acidified with 1 M HCl solution (pH 4-5), the resulting mixture was extracted with ethyl acetate (50 mL x 3), the combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to leave crude intermediate 3 (95 mg, 94.2% yield) as a solid. LCMS: (m / z) 356.0 [M+H] +

[0237] N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloro-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)quinoline-7-carboxamide (compound 18) A mixture of 4-chloro-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)quinoline-7-carboxylic acid (95 mg, 0.267 mmol), N-((1-(5-amino-2-benzylpentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-(3-(4-methylpiperazin-1-yl)propanamide)benzamide hydrochloride (178 mg, 0.267 mmol), HATU (112 mg, 0.294 mmol) and DIPEA (103 mg, 0.801 mmol) in THF (10 mL) was stirred at room temperature for 2 h. The mixture was concentrated and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give compound 18 (32.5 mg, 13% yield) as a white solid. 1H NMR(400MHz,CD3OD) δ(ppm) 10.53(d,J=4.8Hz,1H),8.93-8.86(m,1H),8.71(s,1H),8.53(d,J=10.4Hz,1H),8.41(s,1H),8 .30(d,J=3.2Hz,1H),8.23-8.18(m,1H),8.15-8.98(m,4H),7.65-7.57(m,1H),7.28-7.07(m,5H ),5.29(q,J=8.4Hz,2H),4.88(s,1H),4.18-3.98(m,1H),3.97-3.54(m,3H),3.35-3.10(m,4H) ,2.92-2.53(m,9H),2.49-2.20(m,6H),2.14(s,3H),1.71-1.00(m,8H).LCMS:(m / z)955.3[M+H] +

[0238] Synthesis of compound 21 [ka]

[0239] Methyl 4-chloro-2-(1-fluorocyclopropyl)quinoline-7-carboxylate (Intermediate 1) To a mixture of 1-(1-fluorocyclopropyl)ethanone (169 mg, 1.66 mmol) in POCl3 (6 ml) was added 2-amino-4-(methoxycarbonyl)benzoic acid (162 mg, 0.83 mmol) at room temperature. The mixture was heated at 100 °C for 30 min in a microwave reactor. Upon cooling to room temperature, the mixture was concentrated and the residue was taken up in ice water (20 mL), adjusted to pH 8-9 with NaHCO3 solution, and extracted with DCM (50 mL x 3). The combined organics were dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash chromatography (DCM / MeOH = 40 / 1) to give the intermediate (12 mg, 2.76% yield) as a solid. LCMS: (m / z) 280.1 [M+H] +

[0240] 4-Chloro-2-(1-fluorocyclopropyl)quinoline-7-carboxylic acid (Intermediate 2) To a mixture of methyl 4-chloro-2-(1-fluorocyclopropyl)quinoline-7-carboxylate (12 mg, 0.043 mmol) in THF (3 ml) and H2O (1.0 ml) was added LiOH.H2O (2.7 mg, 0.065 mmol). The mixture was stirred at room temperature for 16 h and quenched with a solution of HCl in 1,4-dioxane (4 M, 0.02 mL. 0.08 mmol). The mixture was concentrated to leave crude intermediate 2 (19 mg, 100% yield) as a white solid. LCMS: (m / z) 266.1 [M+H] +

[0241] N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloro-2-(1-fluorocyclopropyl)quinoline-7-carboxamide (compound 21) To a stirred solution of 4-chloro-2-(1-fluorocyclopropyl)quinoline-7-carboxylic acid (19 mg, crude 0.071 mmol), N-((1-(5-amino-2-benzylpentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-(3-(4-methylpiperazin-1-yl)propanamido)benzamide hydrochloride (46 mg, 0.071 mmol) and DIEA (37 mg, 0.284 mmol) in DMF (5 mL) was added HATU (30 mg, 0.078 mmol). The mixture was stirred at room temperature for 1 h, diluted with EtOAc (100 mL), washed with aqueous NaHCO3 (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give compound 21 (12.4 mg, 20% yield) as a white solid. 1H NMR(400MHz,CD3OD) δ(ppm) 10.52(s,1H),8.89-8.82(m,1H),8.48(dd,J=1.2Hz,10.0Hz,1H),8.28-8.23(m,1H),8.1 7-7.95(m,5H),7.65-7.57(m,1H),7.27-7.07(m,5H),(m,5H),4.84(s,1H),4.16-3.97(m ,1H),3.94-3.55(m,3H),3.30-3.08(m,4H),2.90-2.79(m,1H),2.79-2.60(m,5H),2.57- 2.52(m,2H),2.47-2.22(m,7H),2.14(s,3H),1.72-1.02(m,12H).LCMS:(m / z)865.3[M+H] +

[0242] Synthesis of compound 23 [ka]

[0243] Methyl 2'-nitro-[1,1'-biphenyl]-4-carboxylate (Intermediate 3) A mixture of methyl 4-bromobenzoate (1500 mg, 7.0 mmol), (2-nitrophenyl)boronic acid (1520 mg, 9.1 mmol), NaHCO3 (1806 mg, 21.0 mmol) and Pd(PPh3)4 (404 mg, 0.35 mmol) in DMAc (20.0 mL) and H2O (4.0 mL) was heated at 150 °C for 2 h in a microwave reactor. The mixture was diluted with H2O (30 mL), extracted with EtOAc (50 mL), and the organics were dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography on silica gel (EA / PE=1 / 2) to give intermediate 3 (1.2 g, 67% yield) as a white solid. LCMS (m / z): 258.1 [M+H] + .

[0244] 2'-Nitro-[1,1'-biphenyl]-4-carboxylic acid (Intermediate 4) A mixture of compound 3 (1000 mg, 3.8 mmol) and LiOH (186 mg, 7.7 mmol) in THF (15.0 mL) and HO (3.0 mL) was stirred at 40° C. for 16 h. The mixture was concentrated in vacuo, the residue was diluted with water (50 mL), washed with EtOAc (50 mL), the aqueous phase was adjusted to pH 5 with concentrated HCl solution, and the resulting solid was collected and dried under vacuum to give intermediate 4 (800 mg, 86% yield) as a white solid. LCMS (m / z): 244.1 [M+H] + .

[0245] N-(3-((4-hydroxy-1-(2'-nitro-[1,1'-biphenyl]-4-carbonyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 6) A mixture of intermediate 4 (122 mg, 0.5 mmol), HATU (209 mg, 0.55 mmol) and DIPEA (0.6 mL, 2.5 mmol) in DCM (10.0 mL) was stirred at room temperature for 1 h, and then the reaction solution was added dropwise to a mixture of intermediate 5 (214 mg, 0.1 mmol) and DIPEA (0.1 mL, 0.5 mmol) in DCM (5.0 mL). The mixture was stirred at room temperature for 2 h, diluted with DCM (50 mL), washed with water (50 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography on silica gel (MeOH / DCM=1 / 20) to give intermediate 6 (250 mg, 76% yield) as a yellow solid. LCMS (m / z): 654.3 [M+H] + .

[0246] N-(3-((1-(2'-amino-[1,1'-biphenyl]-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 7) A mixture of compound 6 (250 mg, 0.38 mmol) and Pd / C (120 mg) in MeOH (30.0 mL) was stirred under H2 (1 atm) at room temperature for 16 h. The mixture was filtered and the filtrate was concentrated to give intermediate 7 (200 mg, 84% yield) as a yellow solid. LCMS (m / z): 624.3 [M+H] + .

[0247] N-(3-((4-hydroxy-1-(2'-(vinylsulfonamido)-[1,1'-biphenyl]-4-carbonyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(4-methylpiperazin-1-yl)propanamide (compound 23) A solution of ethenesulfonyl chloride (100 mg, 0.8 mmol) in dry DMF (1.0 mL) was added dropwise to a mixture of intermediate 7 (100 mg, 0.16 mmol) and dry pyridine (252 mg, 3.2 mmol) in dry DMF (3.0 mL) at room temperature, the mixture was stirred at room temperature for 16 h, the solvent was purged with N2, and the residue was dissolved in DMF and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give compound 23 (34.3 mg, 30% yield) as a white solid. 1 H NMR(DMSO-d6,400MHz):δ(ppm) 10.52(s,1H),9.26(m,1H),8.22(s,1H),8.09-8.02(m,3H),7.62-7.60(m,1H),7.50-7.43(m,4H),7. 38-7.29(m,4H),6.60(dd,J1=16.4Hz,J2=10.0Hz,1H),5.93(d,J=16.8Hz,1H),5.95(d,J=10.0Hz,1H ),5.04(s,1H),4.25-4.15(m,1H),4.02(br,2H),3.60-3.45(m,1H),3.25-3.10(m,1H),2.66-2.62(m ,3H),2.60-2.54(m,2H),2.42-2.33(m,7H),2.14(s,3H),1.63-1.238(m,5H).LCMS(m / z):714.1[M+H] +

[0248] Synthesis of compound 24 [ka]

[0249] N-(4'-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carbonyl)biphenyl-2-yl)acrylamide (Compound 24) To a mixture of N-(3-((1-(2'-aminobiphenylcarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(4-methylpiperazin-1-yl)propanamide (40 mg, 0.064 mmol) and DIPEA (24 mg, 0.192 mmol) in THF / HO (6 mL / 2 mL) was added acryloyl chloride (17.4 mg, 0.192 mmol) at 0° C. The mixture was stirred at room temperature for 3 h, diluted with EtOAc (50 mL), washed with brine (50 mL), dried over anhydrous NaSO, concentrated, and purified by preparative HPLC (C18 column, CHCN / HO containing 0.05% NHHCO) to give compound 24 (8 mg, 18.5% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm) 10.51(s,1H),9.52(s,1H),8.21(s,1H),8.08(d,J=1.6Hz,1H),8.01(d,J=1.6Hz, 1H),7.63-7.53(m,2H),7.46-7.29(m,7H),6.36-6.27(m,1H),6.16-6.09(m,1H),5 .68-5.61(m,1H),5.02(s,1H),4.26-3.96(m,4H),3.24-3.10(m,1H),2.69-2.54( m,4H),2.46-2.20(m,7H),2.14(s,3H),1.71-1.17(m,5H).LCMS:(m / z)678.3[M+H] +

[0250] Synthesis of compound 25 [ka]

[0251] N-(3-((1-(2'-(ethylsulfonamido)biphenylcarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(4-methylpiperazin-1-yl)propenamide (Compound 25) To a mixture of N-(3-((1-(2'-aminobiphenylcarbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(4-methylpiperazin-1-yl)propanamide (60 mg, 0.096 mmol) and pyridine (38 mg, 0.48 mmol) in THF / H2O (5 mL / 1 mL) was added ethanesulfonyl chloride (123 mg, 0.96 mmol) at 0°C. The mixture was stirred at room temperature for 3 h. The mixture was diluted with EtOAc (50 mL), washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give compound 25 (20.3 mg, 29.6% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm) 10.52(s,1H),8.94(s,1H),8.21(s,1H),,8.08(d,J=8.4Hz,1H),8.01(d,J=1.6Hz,1H),7.61(dd,J=2.0Hz, 8.8Hz,1H),7.50(d,J=8.0Hz,2H),7.45(d,J=8.0Hz,2H),7.42-7.38(m,2H),7.37-7.31(m,2H),5.04(s,1H) ,4.20(bs,1H),4.02(s,2H),3.24-3.11(m,2H),2.80(q,J=7.2Hz,2H),2.64(t,6J=8.0Hz,3H),2.53(t,J=6. 8Hz,2H),2.48-2.23(m,7H),2.15(s,3H),1.73-1.29(m,5H),0.97(t,J=7.2Hz,3H).LCMS:(m / z)716.7[M+H] +

[0252] Synthesis of compound 26 [ka]

[0253] tert-Butyl (3-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carbonyl)benzyl)carbamate (Intermediate 3) A mixture of 3-(((tert-butoxycarbonyl)amino)methyl)benzoic acid (200 mg, 0.8 mmol), HATU (334 mg, 0.88 mmol), DIPEA (0.5 mL, 2.0 mmol) and DCM (20.0 mL) was stirred at room temperature for 1 h, and the reaction mixture was added dropwise to a mixture of compound 2 (340 mg, 0.8 mmol) and DIPEA (0.5 mL, 2.0 mmol) in DCM (20.0 mL). The mixture was stirred at room temperature for 2 h, diluted with DCM (50 mL), washed with water (50 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography on silica gel (MeOH / DCM=1 / 20) to give intermediate 3 (400 mg, 75% yield) as a yellow solid. LCMS (m / z): 662.3 [M+H] + .

[0254] N-(3-((1-(3-(aminomethyl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(4-methylpiperazin-1-yl)propanamide (Intermediate 4) A mixture of compound 3 (400 mg, 0.6 mmol), HCl solution in 1,4-dioxane (3.0 mL) and DCM (5.0 mL) was stirred at room temperature for 2 h, and the mixture was concentrated in vacuo to give the crude product (300 mg) as a solid. LCMS (m / z): 562.3 [M+H] + .

[0255] N-(3-((4-hydroxy-1-(3-(vinylsulfonamidomethyl)benzoyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(4-methylpiperazin-1-yl)propanamide (compound 26) Ethylenesulfonyl chloride (220 mg, 1.75 mmol) was added dropwise to a mixture of compound 4 (200 mg, 0.35 mmol), DIPEA (225 mg, 1.75 mmol) and Py (4.0 mL) with dry DCM (2.0 mL), the mixture was stirred at room temperature for 2 h, quenched with water (0.5 mL), the solvent was blown off with N2, and the residue was dissolved in DMSO (1 mL) and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give compound 26 (15 mg, 6.6% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ(ppm) 10.52(s,1H),8.20(s,1H),8.08-7.89(m,3H),7.62-7.59(m,1H),7.43-7.27(m,4H) ,6.69(dd,J1=16.4Hz,J2=10.0Hz,1H),6.03(d,J=16.4Hz,1H),5.95(d,J=10.0Hz,1 H),5.02(s,1H),4.27-4.00(m,5H),3.20-3.09(m,3H),2.67-2.62(m,2H),2.54-2.5 0(m,2H),2.42-2.17(m,7H),2.13(s,3H),1.59-1.29(m,5H).LCMS(m / z):652.1[M+H] +

[0256] Synthesis of compound 29 [ka]

[0257] 2-(4-Methylpiperazin-1-yl)acetyl chloride (Intermediate 2) To a solution of 2-(4-methylpiperazin-1-yl)acetic acid (474.9 mg, 3.002 mmol, 1.0 equiv.) in anhydrous dichloromethane (30 mL) and N,N-dimethylformamide (0.1 mL) was added oxalyl chloride (0.41 mL, 1.0 equiv.) while stirring in an ice-water bath. The resulting mixture was stirred at room temperature for 2 h and then concentrated in vacuo to leave crude intermediate 2 (525.21 mg, 2.983 mmol, 99% yield) as a brown solid. LCMS (m / z): 173.2 [M-Cl+OCH3] +

[0258] tert-Butyl 4-hydroxy-4-((7-(2-(4-methylpiperazin-1-yl)acetamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate (Intermediate 3) To a mixture of tert-butyl 4-((7-amino-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate (374.3 mg, 1.0 mmol, 0.33 equiv), EtN (1.06 mL, 2.67 equiv) and DMAP (12.3 mg, 0.107 mmol, 0.03 equiv) in anhydrous dichloromethane (20 mL) was added dropwise a solution of 2-(4-methylpiperazin-1-yl)acetyl chloride (525.21 mg, 2.983 mmol, 1.0 equiv) in anhydrous dichloromethane (30 mL) while stirring in an ice-water bath. The resulting mixture was stirred at room temperature for another 16 h, then concentrated and purified by flash column chromatography (DCM / MeOH=9 / 1) to give the target intermediate 3 (286 mg, 0.556 mmol, 55.6% yield) as a brown solid. LC-MS (m / z): 515.3 [M+H] +

[0259] N-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-2-(4-methylpiperazin-1-yl)acetamide (Intermediate 4) To a solution of tert-butyl 4-hydroxy-4-((7-(2-(4-methylpiperazin-1-yl)acetamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate (276 mg, 0.537 mmol, 1.0 equiv.) in dichloromethane (5 mL) was added a solution of HCl in 1,4-dioxane (4 M, 30 mL, 20.0 equiv.). The resulting mixture was stirred at room temperature for an additional 2 h and then concentrated in vacuo to leave crude intermediate 4 (222.3 mg, 0.537 mmol, 100% yield) as a white solid. LC-MS (m / z): 208.2 [M / 2+H] +

[0260] N-(4-benzyl-5-(4-hydroxy-4-((7-(2-(4-methylpiperazin-1-yl)acetamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (compound 29) A mixture of 2-benzyl-5-(4-chloroquinoline-7-carboxamido)pentanoic acid (47.9 mg, 0.121 mmol, 1.0 equiv), HATU (55.1 mg, 0.145 mmol, 1.2 equiv) and DIPEA (31.3 mg, 0.242 mmol, 2.0 equiv) in N,N-dimethylromamide (2 mL) was stirred at 25° C. for 1.5 h, followed by addition of N-(3-((4-hydroxyquinoline-7-carboxamido)-2-phenylpropanediol) in N,N-dimethylromamide (2 mL). To a mixture of (4-methylpiperazin-1-yl)acetamide (0.05 g, 0.121 mmol, 1.0 equiv.) and DIPEA (0.0469 g, 0.363 mmol, 3.0 equiv.), the resulting mixture was stirred at 25° C. for another 3.5 h, concentrated, and purified by preparative HPLC to give the target compound 29 (11.3 mg, 11.79% yield) as a white solid. 1H NMR(400MHz,DMSO-d6):δ(ppm) 10.15(brs,1H),8.98-8.84(m,2H),8.60(d,J=5.2Hz,1H),8.32-8.01(m ,5H),7.86(d,J=4.8Hz,1H),7.74-7.65(m,1H),7.28-7.07(m,5H),4.86 (s,1H),4.17-3.57(m,6H),3.21-3.07(m,5H),2.89-2.64(m,5H),2.45- 2.26(m,3H),2.18(s,3H),1.69-1.03(m,10H).LC-MS(m / z):793.3[M+H] +

[0261] Synthesis of compound 30 [ka]

[0262] 7-Fluoroquinazolin-4(3H)-one (Intermediate 2) A mixture of 2-amino-4-fluorobenzoic acid (1550 mg, 10 mmol) in formamide (6.0 mL) was stirred at 130° C. for 3 h. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and the resulting solid was collected and dried under vacuum to give intermediate 2 (1.3 g, 78% yield) as a brown solid. LCMS (m / z): 165.1 [M+H] + .

[0263] 7-(2-(4-Methylpiperazin-1-yl)ethoxy)quinazolin-4(3H)-one (Intermediate 4) NaH (1100 mg, 27.5 mmol) was added in portions to a mixture of intermediate 3 (1584 mg, 11.0 mmol) in DMF (20.0 mL), the mixture was stirred at room temperature for 1 h, then 2-(4-methylpiperazin-1-yl)ethan-1-ol (900 mg, 5.5 mmol) was added, and the resulting mixture was stirred at 100° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with water (100 mL), washed with DCM (50 mL), the aqueous phase was concentrated in vacuo, and the residue was dissolved in a mixture (DCM / EA=3 / 1 (80 mL)), stirred at room temperature for 3 h, and filtered to give intermediate 4 (1.2 g, 75% yield) as a yellow solid. LCMS (m / z): 289.2 [M+H] + .

[0264] tert-Butyl 4-hydroxy-4-((7-(2-(4-methylpiperazin-1-yl)ethoxy)-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate (Intermediate 6) A mixture of intermediate 4 (800 mg, 2.8 mmol), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (715 mg, 3.3 mmol) and Cs2CO3 (1369 mg, 4.2 mmol) in DMF (12.0 mL) was stirred at 80° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL), washed with water (20 mL*4), dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography on silica gel (MeOH / DCM=1 / 20) to give intermediate 6 (290 mg, 21% yield) as a yellow solid. LCMS (m / z): 502.4 [M+H] + .

[0265] 3-((4-Hydroxypiperidin-4-yl)methyl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4(3H)-one (Intermediate 7) To a mixture of intermediate 6 (90 mg, 0.18 mmol) in DCM (2.0 mL) was added a solution of HCl in 1,4-dioxane (4 M, 1.0 mL), the mixture was stirred at room temperature for 2 h and concentrated in vacuo to leave crude intermediate 7 (80 mg, ) as a solid. LCMS (m / z): 402.1 [M+H] + .

[0266] N-(4-benzyl-5-(4-hydroxy-4-((7-(2-(4-methylpiperazin-1-yl)ethoxy)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (compound 30) A mixture of intermediate 8 (79 mg, 0.2 mmol), HATU (84 mg, 0.22 mmol) and DIPEA (1.0 mL, 0.5 mmol) in DCM (10.0 mL) was stirred at room temperature for 30 min, then the mixture was added dropwise to a solution of intermediate 7 (80 mg, 0.2 mmol) and DIPEA (1.0 mL, 0.5 mmol) in DCM (10.0 mL), the resulting mixture was stirred at room temperature for 2 h, diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organics were dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give compound 30 (38 mg, 24% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ(ppm) 8.94-8.87(m,2H),8.61-8.59(m,1H),8.29-8.26(m,1H),8.20-7.98(m ,3H),7.86(d,J=4.8Hz,1H),7.26-7.07(m,7H),4.84(s,1H),4.23-4.1 9(m,2H),4.15-3.60(m,4H),3.31-3.13(m,4H),2.87-2.65(m,6H),2.5 1-2.40(m,7H),2.15(s,3H),1.64-1.06(m,8H).LCMS(m / z):780.2[M+H] +

[0267] Synthesis of compound 31 [ka]

[0268] Methyl 9-chloro-2-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-6-carboxylate (Intermediate 1) A mixture of 2-amino-4-(methoxycarbonyl)benzoic acid (390 mg, 2.0 mmol) and 1-methylpyrrolidin-3-one (990 mg, 10.0 mmol) in POCl3 (10 mL) was stirred at 100 °C for 30 min under microwave irradiation. The mixture was concentrated in vacuum, the residue was diluted with DCM (100 mL) and adjusted to pH 7-8 with aqueous Na2CO3. The organic layer was separated and the aqueous layer was extracted with DCM (50 mL x 3). The combined organics were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated and purified by flash chromatography (DCM / MeOH = 30 / 1) to give intermediate 1 (62 mg, 10.7% yield) as a brown solid. LCMS: (m / z) 277.1 [M+H] +

[0269] 9-Chloro-2-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-6-carboxylic acid (Intermediate 2) To a mixture of methyl 9-chloro-2-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-6-carboxylate (62 mg, 0.224 mmol) in THF / HO (10 mL / 2 mL) was added LiOH.HO (14 mg, 0.336 mmol). The mixture was stirred at room temperature for 16 h, then a solution of HCl in 1,4-dioxane (4 M, 0.1 mL, 0.4 mmol) was added and the mixture was concentrated and dried under vacuum to leave crude intermediate 2 (70 mg, 100% yield) as a yellow solid. LCMS: (m / z) 263.0 [M+H] +

[0270] N-(4-benzyl-5-(4-((7-(2-(dimethylamino)acetamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-9-chloro-2-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-6-carboxamide (compound 31) To a stirred solution of 9-chloro-2-methyl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoline-6-carboxylic acid (32 mg, crude 0.1 mmol), N-(3-((1-(5-amino-2-benzylpentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-2-(dimethylamino)acetamide hydrochloride (58 mg, 0.1 mmol) and DIEA (52 mg, 0.4 mmol) in DMF (5 mL) was added HATU (421 mg, 0.11 mmol). The mixture was stirred at room temperature for 1 h, then concentrated and the residue was purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give compound 31 (34.5 mg, 43% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm) 10.20(d,4.8Hz,1H),8.85-8.77(m,1H),8.52(dd,J=1.2Hz,11.6Hz,1H),8.22-8.16(m,1 H),8.15-8.00(m,4H),7.79-7.00(m,1H),7.27-7.07(m,5H),4.83(d,J=2.4Hz,1H),4.16- 3.96(m,5H),3.95-3.76(m,2H),3.67-3.56(m,2H),3.30-3.23(m,2H),3.15(s,3H),2.90 -2.60(m,3H),2.59-2.53(m,3H),2.30(s,6H),1.69-0.99(m,8H).LCMS:(m / z)793.3[M+H] +

[0271] Synthesis of compound 32 [ka]

[0272] 10-Chloro-2-methyl-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine-7-carboxylic acid (Intermediate 1) A mixture of 2-aminoterephthalic acid (181 mg, 1.0 mmol) and 1-methylpiperidin-4-one (226 mg, 2.0 mmol) in POCl3 (8 mL) was stirred at 100° C. for 30 min under microwave irradiation. The mixture was concentrated in vacuo and the residue was diluted with H2O (10 mL) and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give intermediate 1 (47.8 mg, 15.7% yield) as a white solid. LCMS: (m / z) 277.1 [M+H] +

[0273] N-(4-benzyl-5-(4-((7-(2-(dimethylamino)acetamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-10-chloro-2-methyl-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine-7-carboxamide (compound 32) To a stirred solution of 10-chloro-2-methyl-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine-7-carboxylic acid (47.8 mg, 0.173 mmol) in dry DCM (10 mL) was added dry DMF (0.05 mL) followed by (COCl)2 (33 mg, 0.26 mmol) at 0° C. The mixture was stirred at room temperature for 3 h, concentrated in vacuo, and the residue was diluted with DCM (10 mL) and added dropwise to a mixture of N-(3-((1-(5-amino-2-benzylpentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-2-(dimethylamino)acetamide hydrochloride (101 mg, 0.173 mmol) and DIEA (89 mg, 0.692 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 2 h, concentrated and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give compound 32 (20.7 mg, 15% yield) as a white solid. 1H NMR(400MHz,DMSO-d6) δ(ppm) 10.20(d,J=5.2Hz,1H),8.84-8.73(m,1H),8.48(d,J=11.2Hz,1H),8.2 3-7.98(m,5H),7.79-7.70(m,1H),7.30-7.05(m,5H),4.83(s,1H),4.17 -3.95(m,1H),3.95-3.54(m,5H),3.29-3.22(m,2H),3.20-2.60(m,11H) ),2.47(s,3H),2.29(s,6H),1.71-0.99(m,8H).LCMS:(m / z)807.3[M+H] +

[0274] Synthesis of compound 33 [ka]

[0275] Methyl 2-acetyl-10-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,6]naphthyridine-7-carboxylate (Intermediate 1) A mixture of 2-amino-4-(methoxycarbonyl)benzoic acid (586 mg, 3.0 mmol) and 1-acetylpiperidin-4-one (847 mg, 6.0 mmol) in diphenyl ether (30 mL) was stirred at 200° C. for 4 h. After cooling to room temperature, PE (200 mL) was added, the mixture was stirred at room temperature for 30 min, filtered, and the cake was purified by flash chromatography (DCM / MeOH=30 / 1) to give intermediate 1 (300 mg, 33% yield) as a brown solid. LCMS: (m / z) 301.1 [M+H] +

[0276] Methyl 2-acetyl-10-chloro-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine-7-carboxylate (Intermediate 2) A mixture of 1-acetylpiperidin-4-one (300 mg, 1.0 mmol) in POCl3 (10 mL) was stirred at 80 °C for 20 min under microwave irradiation. After cooling to room temperature, the mixture was concentrated in vacuo, the residue was diluted with H2O (20 mL), adjusted to pH 5-6, extracted with DCM (3 x 50 mL), and the combined organics were washed with brine (100 ml), dried over anhydrous Na2SO4, concentrated, and purified by flash column chromatography (DCM / MeOH = 30 / 1) to give intermediate 2 (125 mg, 39% yield) as a brown solid. LCMS: (m / z) 319.1 [M+H] +

[0277] 2-Acetyl-10-chloro-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine-7-carboxylic acid (Intermediate 3) To a mixture of methyl 2-acetyl-10-chloro-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine-7-carboxylate (125 mg, 0.393 mmol) in THF / HO (10 mL / 2 mL) was added LiOH.HO (25 mg, 0.59 mmol). The mixture was stirred at room temperature for 16 h, then a solution of HCl in 1,4-dioxane (4 M, 0.2 mL, 0.8 mmol) was added and the mixture was concentrated and dried under vacuum to leave crude intermediate 3 (100 mg, 84% yield) as a yellow solid. LCMS: (m / z) 305.1 [M+H] +

[0278] 2-Acetyl-N-(4-benzyl-5-(4-((7-(2-(dimethylamino)acetamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-10-chloro-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine-7-carboxamide (compound 33) To a stirred mixture of 2-acetyl-10-chloro-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine-7-carboxylic acid (80 mg, 0.263 mmol) and N-(3-((1-(5-amino-2-benzylpentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-2-(dimethylamino)acetamide hydrochloride (154 mg, 0.263 mmol) in DMF (5 mL) was added DIPEA (93 mg, 0.72 mmol) and PyAOP (137 mg, 0.289 mmol). The mixture was stirred at room temperature for 1 h and then purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give compound 33 (24.4 mg, 12.1% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6,60℃) δ(ppm) 10.00(s,1H),8.61(s,1H),8.48(s,1H),8.21(d,J=8.8Hz,1H),8.16-7.97(m,4H),7.73(d,J=7.6Hz,1H),7.27-7.05(m,5H),4.88(s,2H),4 .70(s,1H),4.15-3.54(m,6H),3.37-3.18(m,7H),3.06-2.60(m,5H),2.31(s,6H),2.16(s,2H),1.76-1.06(m,8H).LCMS:(m / z)835.3[M+H] +

[0279] Synthesis of compound 34 [ka]

[0280] (1s,4s)-4-(4-chloroquinoline-7-carboxamide)cyclohexanecarboxylic acid (Intermediate 2) A mixture of 4-chloroquinoline-7-carboxylic acid (0.1235 g, 0.592 mmol, 1.0 equiv), HATU (0.2399 g, 0.631 mmol, 1.05 equiv) and Et3N (0.1236 g, 1.221 mmol, 2.0 equiv) in tetrahydrofuran (15 mL) and N,N-dimethylformamide (0.1 mL) was stirred at 25° C. for 1 h, and then (1s,4s)-4-aminocyclohexanecarboxylic acid (0.1269 g, 0.887 mmol, 1.5 equiv) was added. The resulting mixture was stirred at 25° C. for an additional 5 h. Water (10 mL) was added to the mixture and the layers were separated. The aqueous phase was extracted with ethyl acetate (150 mL×3). The combined organic phases were washed with saturated NaCl solution (100 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative HPLC to give the target intermediate 2 (43 mg, 0.129 mmol, 21.87%) as a white solid. LCMS (m / z): 333.1 [M+H] +

[0281] 4-Chloro-N-((1s,4s)-4-(4-((7-(2-(dimethylamino)acetamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)cyclohexyl)quinoline-7-carboxamide (compound 34) A mixture of intermediate 2 (43 mg, 0.129 mmol, 1.0 equiv) and 2-(dimethylamino)-N-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)acetamide (55.7 mg, 0.155 mmol, 1.2 equiv) in N,N-dimethylformamide (8 mL) was stirred at room temperature for 1 h. Then, PyAOP (73.5 mg, 0.141 mmol, 1.1 equiv) was added. The resulting mixture was stirred at room temperature for another 2 h, diluted with ethyl acetate (50 mL), washed with saturated Na2CO3 solution (100 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative HPLC to give the target compound 34 (22.4 mg, 25.79%) as a white solid. 1H NMR(400MHz,DMSO-d6,60℃) δ(ppm) 10.23(s,1H),8.94(d,J=4.8Hz,1H),8.70-8.62(m,2H),8.28-8.07(m,5H),7.86( d,J=4.8Hz,1H),7.76(dd,J=7.6Hz,1.2Hz,1H),5.009(s,1H),4.07-3.93(m,4H), 3.73-3.68(m,1H),3.168(s,2H),3.02-2.95(m,2H),2.74(br,1H),2.306(s,6H), 1.91-1.65(m,4H),1.65-1.53(m,2H),1.53-1.43(m,6H).LC-MS(m / z):674.3[M+H] +

[0282] Synthesis of compound 35 [ka]

[0283] (1R,4R)-4-(4-chloroquinoline-7-carboxamide)cyclohexanecarboxylic acid (Intermediate 1) To a mixture of 4-chloroquinoline-7-carboxylic acid (104 mg, 0.5 mmol) in dry CH3CN (10 mL) was added oxalyl chloride (70 mg, 0.55 mmol) at room temperature. The mixture was stirred at room temperature for 3 h and then added dropwise to a mixture of trans-4-aminocyclohexanecarboxylic acid (143 mg, 1.0 mmol) and TEA (202 mg, 2.0 mmol) in dry THF (10 mL). The mixture was stirred at room temperature for 4 h, concentrated in vacuo, and the residue was diluted with DCM (100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give intermediate 1 (60 mg, 36% yield) as a white solid. LCMS: (m / z) 333.1 [M+H] + ,

[0284] 4-Chloro-N-((1R,4R)-4-(4-((7-(2-(dimethylamino)acetamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)cyclohexyl)quinoline-7-carboxamide (compound 35) To a stirred mixture of (1R,4R)-4-(4-chloroquinoline-7-carboxamide)cyclohexanecarboxylic acid (80 mg, 0.24 mmol) and 2-(dimethylamino)-N-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)acetamide hydrochloride (95 mg, 0.24 mmol) in DMF (5 mL) was added DIPEA (93 mg, 0.72 mmol) and PyAOP (138 mg, 0.264 mmol). The mixture was stirred at room temperature for 1 h and then purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give the target compound 35 (27.2 mg, 16.6% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm) 10.19(s,1H),8.93(d,J=4.8Hz,1H),8.70(d,J=7.6Hz,1H),8.61(d,J=1.2Hz,1H),8.27(d,J=8.4Hz,1H),8 .22(s,1H),8.17(dd,J=1.6Hz,8.8Hz,1H),8.12-8.05(m,2H),7.86(d,J=4.8Hz,1H),7.76(dd,J=2.0Hz,8. 8Hz,1H),4.98(s,1H),4.13-4.02(m,2H),3.99-3.88(m,1H),3.86-3.68(m,2H),3.14(s,2H),3.02-2.91(m ,1H),2.64-2.53(m,1H),2.29(s,6H),1.94(s,2H),1.73(s,2H),1.61-1.37(m,8H).LCMS:(m / z)674.3[M+H] +

[0285] Synthesis of compound 36 [ka]

[0286] 3-(4-Chloroquinoline-7-carboxamide)cyclohexanecarboxylic acid (Intermediate 1) To a stirred solution of 4-chloroquinoline-7-carboxylic acid (207 mg, 1.0 mmol) in dry DCM (15 mL) was added dry DMF (0.05 mL) followed by (COCl)2 (190 mg, 1.5 mmol) at 0° C. The mixture was stirred at room temperature for 3 h, concentrated in vacuo, and the residue was diluted with dry DCM (15 mL) and added dropwise to a mixture of 3-aminocyclohexanecarboxylic acid (143 mg, 1.0 mmol) and DIEA (517 mg, 4.0 mmol) in dry DCM (15 mL). The resulting mixture was stirred at room temperature for 16 h, quenched with MeOH (5 mL), concentrated, and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give intermediate 1 (90 mg, 27% yield) as a white solid. LCMS: (m / z) 333.1 [M+H] +

[0287] 4-Chloro-N-(3-(4-((7-(2-(dimethylamino)acetamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)cyclohexyl)quinoline-7-carboxamide (compound 36) To a stirred mixture of 3-(4-chloroquinoline-7-carboxamide)cyclohexanecarboxylic acid (90 mg, 0.27 mmol) and 2-(dimethylamino)-N-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)acetamide hydrochloride (107 mg, 0.27 mmol) in DMF (5 mL) was added DIPEA (105 mg, 0.81 mmol) and PyAOP (155 mg, 0.297 mmol). The mixture was stirred at room temperature for 1 h and then directly purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give the target compound 36 (23.9 mg, 13% yield) as a white solid. 1H NMR(400MHz,DMSO-d6) δ(ppm) 10.20(d,J=3.2Hz,1H),8.93(t,J=4.8Hz,1H),8.72(t,J=7.6Hz,1H),8.62(d,J=8.8Hz,1H),8. 27(t,J=8.4Hz,1H),8.23-8.14(m,3H),8.12-8.03(m,2H),7.86(t,J=4.8Hz,1H),7.75(t,J=7. 6Hz,1H),4.98(s,1H),4.13-3.89(m,4H),3.83-3.72(m,1H),3.32-3.27(m,1H),3.14(s,2H),3 .02-2.90(m,1H),2.88-2.77(m,1H),2.29(s,6H),1.94-1.21(m,12H).LCMS:(m / z)674.3[M+H] +

[0288] Synthesis of compound 37 [ka]

[0289] N-Methyl-3-nitropyridin-4-amine (Intermediate 2) A mixture of 4-chloro-3-nitropyridine (2 g, 12.73 mmol, 1.0 equiv.), methylamine (12.7 mL, 2 M in THF, 2.0 equiv.) in DCM (20 mL) was stirred at room temperature for 4 h. Water (50 mL) was added to the reaction mixture, the resulting suspension was filtered, and the cake was dried under vacuum to give the target intermediate 2 (1.74 g, 11.36 mmol, 89.31% yield) as a solid. LCMS (m / z): 154.1

[0290] N4-Methylpyridine-3,4-diamine (Intermediate 3) A mixture of intermediate 2 (1 g, 6.7 mmol, 1.0 equiv) and Pd / C (10%, 0.21 g, 0.03 equiv) in EtOH (10 mL) was stirred under H2 (1 atm) at room temperature for 12 h. The mixture was filtered through Celite and the filtrate was concentrated in vacuo to give the target intermediate 3 (0.72 g, 5.9 mmol, 88.06% yield) as a solid. LCMS (m / z): 124.1

[0291] 1-Methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one (Intermediate 4) A mixture of intermediate 3 (0.4 g, 3.2 mmol, 1.0 equiv) and CDI (0.53 g, 3.36 mmol, 1.05 equiv) in CH3CN (10 mL) was stirred at room temperature for 4 h. The mixture was filtered and the collected solid was washed with CH3CN to give the target intermediate 4 (0.28 g, 1.9 mmol, 59.4% yield) as a white powder. LCMS (m / z): 150.1

[0292] tert-Butyl 4-hydroxy-4-((1-methyl-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)piperidine-1-carboxylate (Intermediate 5) A mixture of intermediate 4 (80 mg, 0.54 mmol, 1.0 equiv), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (170 mg, 0.8 mmol, 1.5 equiv) and Cs2CO3 (300 mg, 0.8 mmol, 1.5 equiv) in DMF (4 mL) was stirred at 95° C. for 16 h. The mixture was concentrated and purified by preparative HPLC to give intermediate 5 (169 mg, 0.468 mmol, 86.69%) as a white solid. LCMS (m / z): 363.2

[0293] 3-((4-Hydroxypiperidin-4-yl)methyl)-1-methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one (Intermediate 6) To a mixture of intermediate 5 (208 mg, 0.574 mmol, 1.0 equiv) in DCM (10 mL) was added a solution of HCl in 1,4-dioxane (4 M, 3.0 mL, 20.0 equiv) and the mixture was stirred at room temperature for 2 h. The solvent was then removed under vacuum to give intermediate 6 (150 mg, 0.573 mmol, 99%) as a pale yellow solid. LC-MS (m / z): 263.2 [M+H] +

[0294] N-(4-benzyl-5-(4-hydroxy-4-((1-methyl-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (compound 37) A mixture of intermediate 6 (54.5 mg, 0.208 mmol, 1.0 equiv), 2-benzyl-5-(4-chloroquinoline-7-carboxamide)pentanoic acid (66.3 mg, 0.167 mmol, 1.2 equiv) and DIPEA (133.7 mg, 1.035 mmol, 5.0 equiv) in DMF (5 mL) was stirred at room temperature. After 10 min, PyAOP (99.4 mg, 0.191 mmol, 1.1 equiv) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 2 h. Ethyl acetate (50 mL) was added to the reaction mixture. Saturated Na2CO3 solution (20 mL) was added to the mixture and the layers were separated. The organic phase was washed with saturated NaCl solution (50 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative HPLC to give the target compound 37 (16.3 mg, 12.24% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm),8.92(d,J=4.8Hz,1H),8.91-8.85(m,1H),8.60(d,J=4.8Hz,1H), 8.45-8.13(m,4H),7.80-7.82(m,1H),7.27-7.01(m,6H),4.76(d,J=5.2H z,1H),4.22-4.01(m,1H),3.77-3.50(m,4H),3.33-3.23(m,4H),3.21-3. 07(m,2H),2.86-2.63(m,3H),1.72-0.99(m,8H).LC-MS(m / z):641.3[M+H] +

[0295] Synthesis of compound 38 [ka]

[0296] 6-Hydroxyquinazolin-4(3H)-one (Intermediate 2) A mixture of 2-amino-5-hydroxybenzoic acid (3000 mg, 19.6 mmol) and formamide (15.0 mL) was stirred at 130° C. for 16 h. After cooling to room temperature, the mixture was poured into water (100 mL) and the cake was collected and washed with MeOH (20 mL) to give intermediate 2 (2.0 g, 62% yield) as a brown solid. LCMS (m / z): 163.1 [M+H] + .

[0297] tert-Butyl 4-hydroxy-4-((6-hydroxy-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate (Intermediate 3) A mixture of intermediate 2 (600 mg, 3.7 mmol), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (606 mg, 2.8 mmol) and K2CO3 (580 mg, 4.2 mmol) in DMF (15.0 mL) was stirred at 60 °C for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL), washed with water (20 mL * 4), dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give intermediate 3 (600 mg, 57% yield) as a white solid. LCMS (m / z): 376.3 [M+H] + .

[0298] tert-Butyl 4-hydroxy-4-((6-(2-(4-methylpiperazin-1-yl)ethoxy)-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate (Intermediate 4) A mixture of intermediate 3 (300 mg, 0.8 mmol), 1-(2-chloroethyl)-4-methylpiperazine (225 mg, 0.96 mmol), Cs2CO3 (521 mg, 1.6 mmol) and NaI (24 mg, 0.16 mmol) in DMAc (6.0 mL) was stirred at 120 °C for 16 h. The mixture was diluted with water (2.0 mL) and directly purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give intermediate 3 (170 mg, 42% yield) as a white solid. LCMS (m / z): 502.2 [M+H] + .

[0299] 3-((4-Hydroxypiperidin-4-yl)methyl)-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4(3H)-one (Intermediate 5) To a mixture of intermediate 4 (170 mg, 0.339 mmol) in DCM (15 mL) was added a solution of HCl in 1,4-dioxane (2.0 mL, 4 M, 8.0 mmol), the mixture was stirred at room temperature for 2.5 h and concentrated in vacuo to give the target intermediate 5 (134 mg, 98% yield) as a white solid. LCMS (m / z): 402.1 [M+H] + .

[0300] N-(4-benzyl-5-(4-hydroxy-4-((6-(2-(4-methylpiperazin-1-yl)ethoxy)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (compound 38) A mixture of 2-benzyl-5-(4-chloroquinoline-7-carboxamide)pentanoic acid (0.0463 g, 0.1167 mmol, 1.0 equiv), HATU (0.0524 g, 0.1378 mmol, 1.2 equiv) and DIPEA (0.0459 g, 0.3552 mmol, 2.0 equiv) in THF (4 mL) was stirred at room temperature for 1 h and then added dropwise to a mixture of intermediate 5 (0.1150 g, 0.2864 mmol, 1.2 equiv), phenol (46.3 mg, 0.4920 mmol, 3.6 equiv) and DIPEA (0.0665 g, 0.5146 mmol, 3.0 equiv) in THF (4 mL) and the mixture was stirred at room temperature for 2 h. Water (100 mL) and DCM (100 mL) were added to the reaction mixture and the layers were separated. The aqueous phase was extracted with DCM (50 mL×3). The combined organic phase was washed with saturated NaCl solution (100 mL), dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give the target compound 38 (14 mg, 15.38% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm) 8.92(d,J=4.4Hz,1H),8.87(t,J=5.6Hz,1H),8.58(d,J=10.8Hz,1H),8.29-8.25(m,1H),8.16(t,J=10 .4Hz,1H),8.09-8.04(m,1H),7.83(d,J=4.4Hz,1H),7.60(d,J=8.8Hz,1H),7.59-7.49(m,1H),7.45-7 .38(m,1H),7.28-7.07(m,5H),4.86(br,1H),4.24-3.80(m,5H),3.68-3.55(m,2H),3.34-3.25(m,2H) ,3.30-3.07(m,2H),2.90-2.60(m,6H),2.45-2.09(m,9H),1.74-1.01(m,8H).LCMS(m / z):780.3[M+H] + .

[0301] Synthesis of compound 39 [ka]

[0302] tert-Butyl 4-((6-(2-(dimethylamino)ethoxy)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate (Intermediate 1) A mixture of tert-butyl 4-hydroxy-4-((6-hydroxy-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate (275 mg, 0.73 mmol), 2-bromo-N,N-dimethylethanamine hydrobromide (172 mg, 0.74 mmol), CsCO (476 mg, 1.46 mmol) and NaI (25 mg, 0.17 mmol) in DMAC (6.0 mL) was stirred at 120° C. for 16 h. The mixture was diluted with water (30 mL), extracted with DCM (20 mL×2) and the combined organics were dried over anhydrous NaSO, concentrated and purified by preparative HPLC (C18 column, CHCN / H0 containing 0.05% NHHCO) to give intermediate 1 (91 mg, 28% yield) as a brown solid. LCMS(m / z):447.3[M+H] + .

[0303] 6-(2-(Dimethylamino)ethoxy)-3-((4-hydroxypiperidin-4-yl)methyl)quinazolin-4(3H)-one hydrochloride (Intermediate 2) To a solution of N-(4-benzyl-5-(4-((6-(2-(dimethylamino)ethoxy)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (91 mg, 0.2 mmol) in DCM (3 mL) was added HCl solution in 1,4-dioxane (4 M, 1 mL, 4 mmol) at room temperature. The mixture was stirred at room temperature for 3 h and concentrated in vacuo to leave crude intermediate 2 (77 mg, 100% yield) as a pale yellow solid. LCMS: (m / z) 347.2 [M+H] +

[0304] N-(4-benzyl-5-(4-((6-(2-(dimethylamino)ethoxy)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (compound 39) To a stirred solution of 2-benzyl-5-(4-chloroquinoline-7-carboxamide)pentanoic acid (38 mg, 0.096 mmol) in dry DCM (10 mL) was added dry DMF (0.05 mL) followed by (COCl)2 (18.3 mg, 0.144 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 h, concentrated in vacuo, and the residue was diluted with dry DCM (10 mL) and added dropwise to a mixture of 6-(2-(dimethylamino)ethoxy)-3-((4-hydroxypiperidin-4-yl)methyl)quinazolin-4(3H)-one hydrochloride (38.5 mg, 0.096 mmol) and DIEA (50 mg, 0.384 mmol) in dry DCM (10 mL). The resulting mixture was stirred at room temperature for 2 h, concentrated and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give the product (18.5 mg, 26.6% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm) 8.93(d,J=4.8Hz,1H),8.88(q,J=5.6Hz,1H),8.60(d,J=10.4Hz,1H),8.30-8. 24(m,1H),8.20-8.13(m,1H),8.11-8.05(m,1H),7.85(d,J=4.8Hz,1H),7.64- 7.49(m,2H),7.45-7.37(m,1H),7.28-7.06(m,5H),4.83(bs,1H),4.30-3.80( m,5H),3.79-3.36(m,10H),3.22-3.06(m,2H),2.91-2.80(m,1H),2.80-2.60(m 4H),2.23(d,J=10.0Hz,6H),1.75-1.01(m,8H).LCMS:(m / z)725.3[M+H] +

[0305] Synthesis of compound 40 [ka]

[0306] 5-Chloro-2-methyl-1,2,3,4-tetrahydrobenzo[b][1,7]naphthyridine-8-carboxylic acid (Intermediate 1) A mixture of 2-aminoterephthalic acid (181 mg, 1.0 mmol) and 1-methylpiperidin-3-one (226 mg, 2.0 mmol) in POCl3 (5 mL) was stirred at 100° C. for 30 min under microwave irradiation. After cooling to room temperature, the mixture was concentrated and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give intermediate 1 (56 mg, 18.4% yield) as a white solid. LCMS (m / z): 277.1 [M+H] + .

[0307] N-(4-benzyl-5-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-5-chloro-2-methyl-1,2,3,4-tetrahydrobenzo[b][1,7]naphthyridine-8-carboxamide (compound 40) To a stirred solution of 5-chloro-2-methyl-1,2,3,4-tetrahydrobenzo[b][1,7]naphthyridine-8-carboxylic acid (30 mg, 0.108 mmol), N-(3-((1-(5-amino-2-benzylpentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(dimethylamino)propanamide hydrochloride (65 mg, 0.108 mmol) and DIPEA (56 mg, 0.432 mmol) in dry DMF (5 mL) was added PyAOP (62 mg, 0.119 mmol). The reaction mixture was stirred at room temperature for 1 h, diluted with EtOAc (100 mL), washed with Na2CO3 solution (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give compound 40 (23 mg, 26% yield) as a white solid. 1H NMR(400MHz,DMSO-d6) δ(ppm) 10.48(d,J=6.0Hz,1H),8.84-8.76(m,1H),8.51-8.44(m,1H),8.20-8.00(m,5H),7. 66-7.58(m,1H),7.28-7.08(m,5H),4.84(d,J=2.8Hz,1H),4.17-3.97(m,1H),3.90- 3.55(m,5H),3.33-3.24(m,2H),3.20-3.09(m,2H),3.06-2.98(m,2H),2.92-2.52(m ,9H),2.41(d,J=9.2Hz,3H),2.18(s,6H),1.72-1.02(m,8H).LCMS:(m / z)821.3[M+H] + .

[0308] Synthesis of compound 44 [ka]

[0309] 5-Chloro-2-methyl-1,2,3,4-tetrahydrobenzo[b][1,7]naphthyridine-8-carboxylic acid (Intermediate 1) To a mixture of ethyl 2-amino-1H-pyrrole-3-carboxylate (846 mg, 6.5 mmol) in HOAc (12 mL) was added 4-methyleneoxetan-2-one (1295 mg, 18.1 mmol). The mixture was stirred at 110° C. (preheated) for 2 h. After cooling to room temperature, the mixture was concentrated and purified by flash chromatography (PE / EA=1 / 1) to give ethyl 2-methyl-4-oxo-1,4-dihydropyrrolo[1,2-a]pyrimidine-8-carboxylate (1-1, 530 mg, 36.9% yield) as a yellow solid and ethyl 4-methyl-2-oxo-1,2-dihydropyrrolo[1,2-a]pyrimidine-8-carboxylate (1-2, 360 mg, 25% yield) as a red solid. LCMS(m / z):1-2,221.1[M+H] + .

[0310] Ethyl 2-chloro-4-methylpyrrolo[1,2-a]pyrimidine-8-carboxylate (Intermediate 2) A mixture of ethyl 4-methyl-2-oxo-1,2-dihydropyrrolo[1,2-a]pyrimidine-8-carboxylate (120 mg, 0.54 mmol) in POCl3 (5 mL) was stirred at 80 °C for 45 min under microwave irradiation. Upon cooling, the mixture was concentrated in vacuo, the residue was diluted with DCM (100 mL) and adjusted to pH 7-8 with NaHCO3 solution, the organic phase was separated, the aqueous was extracted with DCM (50 mL x 2), the combined organics were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to leave crude intermediate 2 (130 mg, 99% yield) as a brown solid. LCMS: (m / z) 239.1 [M+H] + .

[0311] 2-Chloro-4-methylpyrrolo[1,2-a]pyrimidine-8-carboxylic acid (Intermediate 3) A mixture of ethyl 2-chloro-4-methylpyrrolo[1,2-a]pyrimidine-8-carboxylate (82 mg, 0.343 mmol) and (Bu3Sn)2O (818 mg, 1.372 mmol) in dry toluene (3 mL) was heated to reflux for 48 h. Upon cooling, the mixture was concentrated in vacuo and the residue was diluted with EtOAc (50 mL) and extracted with saturated NaHCO3 solution (50 mL x 3). The combined aqueous phase was adjusted to pH 4-5 with 3N HCl solution and extracted with DCM (50 mL x 3). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to leave crude intermediate 3 (31.6 mg, 43.9% yield) as a yellow solid. LCMS: (m / z) 211.0 [M+H] + .

[0312] N-(4-benzyl-5-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-2-chloro-4-methylpyrrolo[1,2-a]pyrimidine-8-carboxamide (compound 44) To a stirred solution of 2-chloro-4-methylpyrrolo[1,2-a]pyrimidine-8-carboxylic acid (31.6 mg, 0.15 mmol), N-(3-((1-(5-amino-2-benzylpentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(dimethylamino)propanamide hydrochloride (90 mg, 0.15 mmol) and DIPEA (78 mg, 0.6 mmol) in DMF (5 mL) was added HATU (63 mg, 0.17 mmol). The mixture was stirred at room temperature for 1 h, diluted with EtOAc (100 mL), washed with aqueous NaHCO (50 mL) and brine (50 mL), dried over anhydrous NaSO, filtered, concentrated and purified by preparative HPLC (C18 column, CHCN / HO containing 0.05% NHHCO) to give compound 44 (24.8 mg, 22% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm) 10.48(d,J=5.2Hz,1H),8.16-7.99(m,3H),7.92-7.86(m,1H),7.65-7.58(m,1H), 7.54-7.50(m,1H),7.38-7.33(m,1H),7.25-7.06(m,5H),7.02(d,J=2.8Hz,1H),4 .82(s,1H),4.15-3.96(m,1H),3.96-3.54(m,4H),3.19-3.06(m,2H),2.89-2.63( m,7H),2.62-2.52(m,4H),2.19(s,6H),1.71-0.98(m,8H).LCMS:(m / z)755.9[M+H] + .

[0313] Synthesis of compound 45 [ka]

[0314] Methyl 5-nitro-1H-pyrrole-3-carboxylate (Intermediate 2) A solution of methyl 1H-pyrrole-3-carboxylate (500 mg, 4.00 mmol) in acetic anhydride (4.8 mL) was added dropwise to a mixture of nitric acid (70%, 1.0 mL) and acetic anhydride (2.4 mL) at 50° C. The mixture was stirred at 60° C. overnight. After cooling to room temperature, the reaction mixture was poured onto crushed ice, and the mixture was extracted with EtOAc (50 mL), dried over anhydrous Na2SO4, concentrated and purified by flash column chromatography (ethyl acetate:petroleum ether=1:1) to give intermediate 2 (130 mg, 19.1% yield) as a yellow solid. LCMS (m / z): 171.7 [M+1] + .

[0315] Methyl 5-amino-1H-pyrrole-3-carboxylate (Intermediate 3) To a solution of methyl 5-nitro-1H-pyrrole-3-carboxylate (130.0 mg, 0.76 mmol) in MeOH (10 mL) was added Pd / C (10%, 13 mg), the mixture was stirred under H2 (1 atm) at room temperature overnight, filtered through Celite, and the filtrate was concentrated in vacuo to give intermediate 3 (80 mg, 74.8% yield) as a grey solid. LCMS (m / z): 141.1 [M+H] + .

[0316] Methyl 2-methyl-4-oxo-1,4-dihydropyrrolo[1,2-a]pyrimidine-7-carboxylate (Intermediate 5) To a solution of methyl 5-amino-1H-pyrrole-3-carboxylate (80.0 mg, 0.57 mmol) in HOAc (10 mL) was added 3-methylenecyclobutan-1-one (134.4 mg, 1.60 mmol) in one portion. The reaction mixture was stirred at 110 °C for 2 h, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (PE / EA: 20 to 10:1) to give intermediate 5 (70 mg, 59.5% yield) as a white solid. LCMS: (m / z) 207.1 [M+H] + .

[0317] Methyl 4-chloro-2-methylpyrrolo[1,2-a]pyrimidine-7-carboxylate (Intermediate 6) A mixture of methyl 2-methyl-4-oxo-1,4-dihydropyrrolo[1,2-a]pyrimidine-7-carboxylate (70.0 mg, 0.34 mmol) in POCl3 (5 mL) was heated at 80°C for 1 h. The reaction mixture was concentrated in vacuo, the residue was adjusted to pH 6-7 with saturated NaHCO3 solution, extracted with ethyl acetate (20 mL*3), the combined organics were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to leave crude intermediate 6 (70 mg, 92.1% yield) as a white solid. LCMS: (m / z) 225.1 [M+H] + .

[0318] 4-Chloro-2-methylpyrrolo[1,2-a]pyrimidine-7-carboxylic acid (Intermediate 7) A solution of LiOH (11.2 mg, 0.312 mmol) in HO (5 mL) was added to a solution of methyl 4-chloro-2-methylpyrrolo[1,2-a]pyrimidine-7-carboxylate (70.0 mg, 0.312 mmol) in THF (5 mL), the mixture was stirred at room temperature overnight, adjusted to pH 1-2 with 1N HCl solution, extracted with ethyl acetate (20 mL x 3), the combined organics were washed with brine (50 mL), dried over anhydrous NaSO, filtered and concentrated to leave intermediate 7 (56 mg, 85.4% yield) as a white solid. LCMS: (m / z) 211.1 [M+H] + .

[0319] N-(4-benzyl-5-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-4-chloro-2-methylpyrrolo[1,2-a]pyrimidine-7-carboxamide (compound 45) To a mixture of 4-chloro-2-methylpyrrolo[1,2-a]pyrimidine-7-carboxylic acid (20.1 mg, 0.10 mmol), N-(3-((1-(5-amino-2-benzylpentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(dimethylamino)propanamide (56.3 mg, 0.10 mmol) and DIPEA (41.5 mg, 0.30 mmol) in DMF (10 mL) was added HATU (41.8 mg, 0.11 mmol). The mixture was stirred at room temperature for 30 min, diluted with EtOAc (80 mL), washed with saturated NaHCO3 solution (5 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give compound 45 (15 mg, 20.0% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm) 10.48(d,J=4.4Hz,1H),8.35(dt,J=11.3,5.8Hz,1H),8.18-7.99(m,3H),7.88(dd,J=15.6,1.5Hz,1H),7.62(td,J=9.0,2.0Hz,1H),7.2 7-7.19(m,2H),7.17-7.08(m,3H),6.91(dd,J=13.0,1.5Hz,1H),6.83(s,1H),4.85(s,1H),4.13(d,J=12.5Hz,1H),4.04-3.76(m,2H),3. 63(d,J=13.6Hz,1H),3.25(d,J=6.0Hz,2H),3.11(d,J=10.5Hz,2H),2.85(t,J=10.7Hz,1H),2.70(ddd,J=17.2,12.9,6.8Hz,3H),2.60( t,J=5.8Hz,5H),2.54(s,1H),2.19(s,6H),1.69-1.56(m,1H),1.45(dd,J=17.0,13.2Hz,4H),1.33-1.05(m,3H).LCMS(m / z):756.3[M+H] + .

[0320] Synthesis of compound 47 [ka]

[0321] tert-Butyl (4-chloropyridin-2-yl)carbamate (Intermediate 2) To a solution of 4-chloropyridin-2-amine (3.0 g, 23.3 mmol) in DCM (100 mL) was added di-tert-butyl dicarbonate (5.6 g, 25.7 mmol), followed by slow addition of DMAP (0.57 g, 4.66 mmol). Vigorous bubbling continued for about 1 h, after which the reaction was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE / EA: 20-10:1) to give intermediate 2 (2.8 g, 52.4% yield) as a white solid. LCMS (m / z): 173.1 [M-55] +

[0322] tert-Butyl (4-chloro-3-formylpyridin-2-yl)carbamate (Intermediate 3) To a solution of tert-butyl (4-chloropyridin-2-yl)carbamate (1.8 g, 7.87 mmol) in THF (30 mL) at -60°C, n-butyllithium solution (2.5 M in hexane, 7.4 mL, 18.50 mmol) was added dropwise. The solution was stirred at -60°C for 1 h, then DMF (2.7 g, 36.99 mmol) was added dropwise. After stirring at -60°C for 1 h, the reaction mixture was quenched by adding saturated ammonium chloride solution (50 mL) dropwise. The mixture was extracted with ethyl acetate (50 mL x 3), and the combined organics were dried over anhydrous MgSO4, filtered, concentrated, and purified by column chromatography (elution with ethyl acetate / PE, 1:10) to give intermediate 3 (1 g, 49.5% yield) as a white solid. LCMS (m / z): 201.0 [M-55] +

[0323] 2-Amino-4-chloronicotinaldehyde (Intermediate 4) To tert-butyl (4-chloro-3-formylpyridin-2-yl)carbamate (1.0 g, 3.90 mmol) was added a solution of HCl in EtOAc (20 mL), the mixture was stirred at room temperature overnight, filtered, and the cake was dried under vacuum to give intermediate 4 (600 mg, 98.5% yield) as a white solid. LCMS: (m / z) 157.1 [M+H] +

[0324] 5-Chloro-1,8-naphthyridine-2-carboxylic acid (Intermediate 6) To a mixture of 2-amino-4-chloronicotinaldehyde (450 mg, 2.87 mmol) and methyl 2-oxopropanoate (322.5 mg, 5.75 mmol) in EtOH (10 mL) and HO (2 mL) was added a solution of NaOH (420.2 mg, 10.5 mmol) in HO (10 mL). The mixture was stirred at room temperature for another 3 h, adjusted to pH 1-2 with 1N HCl solution, concentrated under reduced pressure, the residue was extracted with ethyl acetate (20 mL x 3), the combined organics were washed with brine (50 mL), dried over anhydrous NaSO, filtered and concentrated under vacuum to give intermediate 6 (280 mg, 46.7% yield) as a white solid. LCMS: (m / z) 291.1 [M+Na] + .

[0325] N-(4-benzyl-5-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-5-chloro-1,8-naphthyridine-2-carboxamide (compound 47) To a mixture of 5-chloro-1,8-naphthyridine-2-carboxylic acid (40 mg, 0.192 mmol) in dry DCM (5 mL) was added 1 drop of DMF under N2 at 0°C, then (COCl)2 (36.5 mg, 0.290 mmol) was added and the mixture was stirred at 0°C for 10 min and then warmed to room temperature for another 1 h. The mixture was added dropwise to a mixture of N-(3-((1-(5-amino-2-benzylpentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(dimethylamino)propanamide (70 mg, 0.124 mmol) in dry DCM (5 mL) at 0-5°C and then warmed to room temperature for another 1 h. The reaction mixture was diluted with DCM (80 mL), washed with saturated NaHCO3 solution (5 mL), dried over anhydrous Na2SO4, concentrated and purified by column chromatography (DCM:MeOH 10:1) to give compound 47 (14.1 mg, yield 18.6%) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 10.51(d,J=6.5Hz,1H),9.15(t,J=4.5Hz,2H),8.85(dd,J=8.6,2.8Hz,1H),8.39(dd, J=11.9,8.6Hz,1H),8.19-7.90(m,4H),7.62(dd,J=11.5,9.4Hz,1H),7.32-6.98(m,5H ),4.82(s,1H),4.17-3.74(m,4H),3.64-3.60(m,2H),3.16(s,2H),2.82-2.65(m,6H), 2.57(s,1H),2.30(s,6H),1.75-1.30(m,6H),1.2-1.1(m,2H).LCMS(m / z):753.3[M+H] + .

[0326] Synthesis of compound 48 [ka]

[0327] 4-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2) A solution of LiOH (17.1 mg, 0.71 mmol) in HO (5 mL) was added to a solution of methyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (100.0 mg, 0.47 mmol) in THF (5 mL), the mixture was stirred at room temperature overnight, adjusted to pH 1-2 with 1N HCl solution, and concentrated to leave crude intermediate 2 (110 mg, crude) as a white solid, which was used directly in the next step. LCMS (m / z): 197.1 [M+H] + .

[0328] N-(4-benzyl-5-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (compound 48) N-(3-((1-(5-amino-2-benzylpentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(dimethylamino)propanamide (69.0 mg, 0.12 mmol), 4-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (40.1 mg, 0.20 mmol), DIPEA (41.5 mg, 0.30 mmol) and 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (40.1 mg, 0.20 mmol) in DMF (10 mL). To a mixture of 48 (5.9 mg, 7.96% yield) and phenol (28.2 mg, 0.30 mmol) was added HATU (41.8 mg, 0.11 mmol), the mixture was stirred at room temperature for 30 min, diluted with saturated NaHCO3 solution (30 mL), extracted with ethyl acetate (20 mL × 3), and the combined organics were washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by preparative HPLC to give compound 48 (5.9 mg, 7.96% yield) as a white solid. 1H NMR(400MHz,DMSO-d6) δ(ppm) 12.49(s,1H),10.65(d,J=4.2Hz,1H),9.40(s,1H),8.63(dd,J=12.1,6.1Hz,1H),8.33-7.96(m,4H),7.68-7.57(m,1H),7.26(d,J=5.2Hz,1 H),7.21(dd,J=9.9,4.6Hz,2H),7.15(dd,J=12.3,4.8Hz,2H),7.09(dd,J=13.8,6.6Hz,1H),4.82(s,1H),4.17-3.91(m,2H),3.82(d,J=13. 6Hz,1H),3.63(d,J=13.7Hz,2H),3.41(d,J=5.2Hz,2H),3.25(d,J=5.6Hz,2H),3.15(d,J=11.0Hz,2H),2.91(t,J=6.9Hz,2H),2.83(d,J=4. 3Hz,6H),2.75-2.71(m,1H),2.67(dd,J=12.7,5.1Hz,1H),1.65-1.55(m,1H),1.55-1.35(m,4H),1.33-1.06(m,3H).LCMS(m / z):741.3[M+H] + .

[0329] Synthesis of compounds 49, 50, and 51

change

[0330] 5-クロロ-2-メチル-1,2,3,4-テトラヒドロベンゾ[b][1,7]ナフチリジン-8-カルボン acid (intermediate 1) A mixture of 2-amino-4-(methoxycarbonyl)benzoic acid (605 mg, 3.1 mmol) and acetone (1.8 g, 31 mmol) in POCl3 (10 mL) was stirred at 100 °C for 30 min under microwave irradiation. The mixture was concentrated in vacuum, and the residue was diluted with DCM (100 mL), adjusted to pH 7-8 with Na2CO3 solution, and extracted with DCM (50 mL x 3). The combined organics were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash column chromatography (DCM / MeOH = 30 / 1) to give intermediate 1 (237 mg, 32.2% yield) as a brown solid. LCMS (m / z): 236.1 [M+H] + .

[0331] 4-Chloro-2-methylquinoline-7-carboxylic acid (Intermediate 2) To a mixture of methyl 4-chloro-2-methylquinoline-7-carboxylate (237 mg, 1.0 mmol) in THF / HO (10 mL / 2 mL) was added LiOH.HO (63 mg, 1.5 mmol). The mixture was stirred at room temperature for 16 h, then a solution of HCl in 1,4-dioxane (4 M, 0.4 mL, 1.6 mmol) was added and the mixture was concentrated to leave crude intermediate 2 (280 mg, 100% yield) as a yellow solid. LCMS: (m / z) 222.0 [M+H] + ,

[0332] N-(4-benzyl-5-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-4-chloro-2-methylquinoline-7-carboxamide (compound 49) To a stirred solution of 4-chloro-2-methylquinoline-7-carboxylic acid (28 mg, crude 0.1 mmol), N-(3-((1-(5-amino-2-benzylpentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(dimethylamino)propanamide hydrochloride (60 mg, 0.1 mmol) and DIPEA (52 mg, 0.4 mmol) in DMF (5 mL) was added HATU (42 mg, 0.11 mmol). The mixture was stirred at room temperature for 1 h and then purified directly by preparative HPLC ((C18 column, CH3CN / H2O containing 0.05% TFA) to give compound 49 (33.9 mg, 44% yield) as a solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm) 10.71(d,J=4.4Hz,1H),9.53(s,1H),8.87-8.79(m,1H),8.53-8.47(m,1H),8.23-8.01(m ,5H),7.78(d,J=2.4Hz,1H),7.68-7.59(m,1H),7.27-7.06(m,5H),4.18-3.88(m,4H),3. 67-3.52(m,3H),3.46-3.37(m,2H),3.35-3.24(m,2H),3.21-3.08(m,2H),2.98-2.89(m, 2H),2.84(d,J=4.0Hz,6H),2.79-2.59(m,5H),1.77-0.99(m,7H).LCMS:(m / z)766.3[M+H] + .

[0333] (R)-N-(4-benzyl-5-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-4-chloro-2-methylquinoline-7-carboxamide (compound 50) (S)-N-(4-benzyl-5-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-4-chloro-2-methylquinoline-7-carboxamide (compound 51) N-(4-benzyl-5-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-4-chloro-2-methylquinoline-7-carboxamide (21 mg, 0.1 mmol) was purified by chiral HPLC (Instrument: Gilson-281, Column: IC20*250, 10 um, Mobile phase: MEOH (0.2% methanolic ammonia):CAN (0.2% methanolic ammonia) = 50:50, Flow rate: 50 mL / min, Run time per injection: 26 min, Injection: 1 ml, Sample solution: 20 mg in 3 mL MEOH) to give two enantiomers compound 50 (8.5 mg), LCMS: (m / z) 766.3 [M+H] + , and compound 51 (8.5 mg), LCMS: (m / z)766.3[M+H] + obtained.

[0334] Synthesis of compound 52 [ka]

[0335] (Z)-Ethyl 2-(ethoxymethylene)-3-oxo-4-phenylbutanoate (Intermediate 1) A mixture of ethyl 3-oxo-4-phenylbutanoate (2062 mg, 10 mmol), triethoxymethane (4456 mg, 30 mmol) and Ac2O (1633 mg, 16 mmol) was stirred at 100° C. for 17 h. Upon cooling, the mixture was diluted with EtOAc (100 mL) and H2O (100 mL), the mixture was stirred at room temperature for 10 min, the organic phase was separated, washed with aqueous NaHCO3 (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to leave crude intermediate 1 (2.62 g) as a red oil. LCMS (m / z): 263.1 [M+H] + .

[0336] Ethyl 3-benzyl-1H-pyrazole-4-carboxylate (Intermediate 2) To a stirred solution of (Z)-ethyl 2-(ethoxymethylene)-3-oxo-4-phenylbutanoate (2358 mg, 9.0 mmol) in dry EtOH (30 mL) was added NH2-NH2.H2O (85%, 583 mg, 9.9 mmol) at 0°C. The mixture was stirred at room temperature for 12 h, the mixture was concentrated in vacuo, the residue was diluted with EtOAc (100 mL), washed with H2O (100 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (PE / EA=1 / 1) to give intermediate 2 (1.346 g, 65% yield) as a solid. LCMS: (m / z) 231.1 [M+H] + ,

[0337] Ethyl 3-benzyl-1-(2-(tert-butoxycarbonylamino)ethyl)-1H-pyrazole-4-carboxylate (Intermediate 3-1) Ethyl 5-benzyl-1-(2-(tert-butoxycarbonylamino)ethyl)-1H-pyrazole-4-carboxylate (Intermediate 3-2) To a mixture of ethyl 3-benzyl-1H-pyrazole-4-carboxylate (1.26 g, 5.47 mmol) and CsCO (3.564 g, 10.94 mmol) in CHCN (40 mL) was added tert-butyl 2-bromoethylcarbamate (1.838 g, 8.20 mmol). The mixture was stirred at room temperature for 16 h and filtered. The solid was washed with DCM and the combined filtrate and washings were concentrated and purified by flash column chromatography (DCM / CH3OH=10 / 1) to give ethyl 3-benzyl-1-(2-(tert-butoxycarbonylamino)ethyl)-1H-pyrazole-4-carboxylate (3-1, 920 mg, 38% yield) and ethyl 5-benzyl-1-(2-(tert-butoxycarbonylamino)ethyl)-1H-pyrazole-4-carboxylate (3-2, 430 mg, 17.8% yield). LCMS: 3-1, (m / z) 374.0 [M+H] + ,3-2,(m / z)374.0[M+H] + ,

[0338] 3-Benzyl-1-(2-(tert-butoxycarbonylamino)ethyl)-1H-pyrazole-4-carboxylic acid (Intermediate 4) A mixture of ethyl 3-benzyl-1-(2-(tert-butoxycarbonylamino)ethyl)-1H-pyrazole-4-carboxylate (460 mg, 1.23 mmol) and NaOH (197 mg, 4.92 mmol) in THF / H2O (10 mL / 2 mL) was heated to reflux for 16 h. The mixture was cooled to room temperature, acidified with 1N HCl solution, and extracted with EtOAc (50 mL). The organics were dried over anhydrous Na2SO4, filtered, and concentrated to leave crude intermediate 4 (390 mg, 92% yield) as a white solid. LCMS: (m / z) 346.2 [M+H] + .

[0339] Tert-Butyl 2-(3-benzyl-4-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)-1H-pyrazol-1-yl)ethylcarbamate (Intermediate 5) To a stirred solution of 3-benzyl-1-(2-(tert-butoxycarbonylamino)ethyl)-1H-pyrazole-4-carboxylic acid (138 mg, 0.4 mmol), 3-(dimethylamino)-N-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)propanamide hydrochloride (164 mg, 0.4 mmol) and DIPEA (207 mg, 1.6 mmol) in DMF (6 mL) was added HATU (167 mg, 0.44 mmol). The mixture was stirred at room temperature for 1 h, diluted with EtOAc (100 mL), washed with H2O (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (DCM / MeOH=10 / 1) to give intermediate 5 (216 mg, 77% yield) as a white solid. LCMS: (m / z) 701.4 [M+H] + .

[0340] N-(3-((1-(1-(2-aminoethyl)-3-benzyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(dimethylamino)propanamide hydrochloride (Intermediate 6) To a solution of tert-butyl 2-(3-benzyl-4-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)-1H-pyrazol-1-yl)ethylcarbamate (216 mg, 0.308 mmol) in DCM (10 mL) was added a solution of HCl in 1,4-dioxane (4 M, 1.5 mL, 6.0 mmol). The mixture was stirred at room temperature for 3 h and concentrated to give intermediate 6 (220 mg, 100% yield) as the HCl salt. LCMS: (m / z) 601.3 [M+H] + .

[0341] N-(2-(3-benzyl-4-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)-1H-pyrazol-1-yl)ethyl)-4-chloroquinoline-7-carboxamide (compound 52) To a stirred solution of N-(3-((1-(1-(2-aminoethyl)-3-benzyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(dimethylamino)propanamide hydrochloride (74 mg, 0.116 mmol), 4-chloroquinoline-7-carboxylic acid (24 mg, 0.116 mmol) and DIPEA (60 mg, 0.464 mmol) in DMF (6 mL) was added HATU (48 mg, 0.128 mmol). The mixture was stirred at room temperature for 1 h, diluted with EtOAc (100 mL), washed with H2O (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give compound 52 (18.8 mg, 20.5% yield) as a white solid.1 H NMR(400MHz,DMSO-d6) δ(ppm) 10.47(s,1H),9.00(t,J=5.6Hz,1H),8.88(d,J=4.8Hz,1H),8.54(d,J=1.2Hz,1H),8.23(d, J=8.4Hz,1H),8.15(s,1H),8.11-8.03(m,3H),7.84(s,1H),7.82(d,J=4.8Hz,1H),7.61(dd ,J=2.0Hz,8.8Hz,1H),7.19-7.05(m,5H),4.87(s,1H),3.30(t,J=6.0Hz,2H),3.96-3.69(m ,8H),3.01(bs,2H),2.61-2.52(m,4H),2.18(s,6H),1.22(bs,4H).LCMS:(m / z)790.3[M+H] + .

[0342] Synthesis of compound 53 [ka]

[0343] 5-Benzyl-1-(2-(tert-butoxycarbonylamino)ethyl)-1H-pyrazole-4-carboxylic acid (Intermediate 4) A mixture of ethyl 5-benzyl-1-(2-(tert-butoxycarbonylamino)ethyl)-1H-pyrazole-4-carboxylate (430 mg, 1.15 mmol) and NaOH (184 mg, 4.60 mmol) in THF / H2O (10 / 2 mL) was stirred at reflux for 16 h. The mixture was cooled to room temperature, acidified with 1N HCl solution, extracted with EtOAc (50 mL x 3), and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated to leave crude intermediate 4 (400 mg, 100% yield) as a white solid. LCMS (m / z): 346.1 [M+H] + .

[0344] tert-Butyl 2-(5-benzyl-4-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)-1H-pyrazol-1-yl)ethylcarbamate (Intermediate 5) To a stirred solution of 5-benzyl-1-(2-(tert-butoxycarbonylamino)ethyl)-1H-pyrazole-4-carboxylic acid (138 mg, 0.4 mmol), 3-(dimethylamino)-N-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)propanamide hydrochloride (164 mg, 0.4 mmol) and DIPEA (207 mg, 1.6 mmol) in DMF (6 mL) was added HATU (167 mg, 0.44 mmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (100 mL), washed with H2O (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (DCM / MeOH=10 / 1) to give intermediate 5 (100 mg, 35.7% yield) as a white solid. LCMS: (m / z) 701.4 [M+H] +

[0345] N-(3-((1-(1-(2-aminoethyl)-5-benzyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(dimethylamino)propanamide hydrochloride (Intermediate 6) To a solution of tert-butyl 2-(5-benzyl-4-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)-1H-pyrazol-1-yl)ethylcarbamate (100 mg, 0.143 mmol) in DCM (5 mL) was added a solution of HCl in 1,4-dioxane (4 M, 0.8 mL, 3.2 mmol). The mixture was stirred at room temperature for 3 h and concentrated to leave the crude product (101 mg, 100% yield) as the HCl salt. LCMS: (m / z) 301.0 [M / 2+H] + .

[0346] N-(2-(5-benzyl-4-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)-1H-pyrazol-1-yl)ethyl)-4-chloroquinoline-7-carboxamide (compound 53) To a stirred solution of N-(3-((1-(1-(2-aminoethyl)-5-benzyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(dimethylamino)propanamide hydrochloride (101 mg, 0.158 mmol), 4-chloroquinoline-7-carboxylic acid (32.8 mg, 0.158 mmol) and DIEA (82 mg, 0.632 mmol) in DMF (5 mL) was added HATU (66 mg, 0.174 mmol). The mixture was stirred at room temperature for 1 h, diluted with EtOAc (100 mL), washed with H2O (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give the product (42.2 mg, 34% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm) 10.52(s,1H),9.07(t,J=5.6Hz,1H),8.92(d,J=4.4Hz,1H),8.53(s,1H),8.27(d,J=8.8Hz,1H),8.2 1(s,1H),8.15-8.04(m,3H),7.84(d,J=4.4Hz,1H),7.64(dd,J=1.6Hz,9.2Hz,1H),7.60(s,1H),7.2 9-7.10(m,5H),4.99(s,1H),4.26(t,J=5.6Hz,2H),4.14(s,2H),3.99-3.57(m,6H),3.29-2.98(m,2 H),2.61(t,J=6.4Hz,2H),2.54(t,J=6.4Hz,2H),2.20(s,6H),2.08(bs,4H).LCMS:(m / z)790.3[M+H] + .

[0347] Synthesis of compound 55 [ka]

[0348] Ethyl (Z)-2-benzoyl-3-ethoxyacrylate (Intermediate 3) A mixture of ethyl 3-oxo-3-phenylpropanoate (1.0 g, 5.20 mmol) and triethyl orthoformate (1.6 g, 8.32 mmol) was heated to reflux for 30 min, then acetic anhydride (1.6 g, 15.60 mmol) was added and the resulting mixture was heated to reflux for 12 h. The mixture was cooled to room temperature, diluted with EtOAc (100 mL) and water (50 mL) and the mixture was stirred at room temperature for 10 min to decompose excess triethyl orthoformate. The organic phase was separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to leave crude intermediate 3 (1.5 g, crude) as a yellow solid. LCMS (m / z): 249.1 [M+H] +

[0349] Ethyl 3-phenyl-1H-pyrazole-4-carboxylate (Intermediate 4) A solution of hydrazine monohydrate (1.2 g, 2.21 mmol) in ethanol (1 mL) was added dropwise to a solution of ethyl (Z)-2-benzoyl-3-ethoxyacrylate (0.5 g, 2.01 mmol) in ethanol (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 12 h, then filtered, the cake was washed with water and cold ethanol, and dried under vacuum to give intermediate 4 (0.35 g, 80.4% yield) as a yellow solid. LCMS (m / z): 217.1 [M+H] +

[0350] Ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-phenyl-1H-pyrazole-4-carboxylate (Intermediate 5) A mixture of ethyl 3-phenyl-1H-pyrazole-4-carboxylate (230.0 mg, 1.06 mmol), tert-butyl (2-bromoethyl)carbamate (238.4 mg, 1.06 mmol) and Cs2CO3 (345.4 mg, 1.06 mmol) in MeCN (10 mL) was stirred at 80 °C overnight. The mixture was cooled to room temperature, diluted with H2O (30 mL), extracted with ethyl acetate (20 mL x 3), and the combined organics were washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated and purified by flash column chromatography on silica gel (EA / PE: 5-20: 1) to give intermediate 5 (360 mg, 94.2% yield) as a white solid. LCMS: (m / z) 360.2 [M+H] +

[0351] 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-phenyl-1H-pyrazole-4-carboxylic acid (Intermediate 6) A solution of NaOH (57.9 mg, 40.00 mmol) in HO (5 mL) was added to a solution of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-phenyl-1H-pyrazole-4-carboxylate (260.0 mg, 0.72 mmol) in THF (5 mL) and the mixture was stirred at 70 °C overnight. After cooling to room temperature, the mixture was adjusted to pH 1-2 with 1N HCl solution and extracted with ethyl acetate (20 mL x 3), the combined organics were washed with brine (50 mL), dried over anhydrous NaSO, filtered and concentrated to give 180 mg of crude product, which was purified by HPLC to give intermediate 6 (80 mg, 33% yield) as a white solid. LCMS: (m / z) 332.2 [M+H] + .

[0352] tert-Butyl (2-(4-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)-3-phenyl-1H-pyrazol-1-yl)ethyl)carbamate (Intermediate 8) To a mixture of 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-phenyl-1H-pyrazole-4-carboxylic acid (37.0 mg, 0.112 mmol), 3-(dimethylamino)-N-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)propanamide (41.7 mg, 0.112 mmol) and DIPEA (46.3 mg, 0.336 mmol) in DMF (10 mL) was added HATU (46.8 mg, 0.123 mmol), the mixture was stirred at room temperature for 30 min, diluted with EtOAc (80 mL), washed with saturated NaHCO3 solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to leave crude intermediate 8 (52.1 mg, 67.9% yield), which was used directly in the next step. LCMS: (m / z) 687.4 [M+H] + .

[0353] N-(3-((1-(1-(2-aminoethyl)-3-phenyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(dimethylamino)propanamide (Intermediate 9) To the crude intermediate 8 (52.1 mg, 0.0759 mmol) was added a solution of HCl in EtOAc (1M, 5 mL), the mixture was stirred at room temperature overnight and concentrated under reduced pressure to leave the crude intermediate 9 (45.3 mg, crude) as a white solid. LCMS: (m / z) 587.3 [M+H] + .

[0354] 4-Chloro-N-(2-(4-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)-3-phenyl-1H-pyrazol-1-yl)ethyl)quinoline-7-carboxamide (compound 55) To a mixture of N-(3-((1-(1-(2-aminoethyl)-3-phenyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(dimethylamino)propanamide (45.3 mg, 0.0772 mmol), 4-chloroquinoline-7-carboxylic acid (16.1 mg, 0.0772 mmol) and DIPEA (32.1 mg, 0.2316 mmol) in DMF (10 mL) was added HATU (32.3 mg, 0.0849 mmol), the mixture was stirred at room temperature for 30 min, diluted with EtOAc (80 mL), washed with saturated NaHCO3 solution (50 mL), dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC to give compound 55 (10.2 mg, 17.0% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm) 10.62(s,1H),9.05(s,1H),8.88(d,J=4.7Hz,1H),8.56(s,1H),8.23(d,J=8.7Hz,1H),8.16-8.10(m,2H),8.05( d,J=8.4Hz,2H),7.96(s,1H),7.82(d,J=4.7Hz,1H),7.62(d,J=8.1Hz,1H),7.54(d,J=7.3Hz,2H),7.31(t,J=7. 3Hz,2H),7.25(t,J=7.3Hz,1H),4.83(s,1H),4.40(d,J=5.3Hz,2H),4.18(br,1H),4.0-3.75(m,5H),3.05-1.95 (m,2H),2.81(br,2H),2.66-2.55(m,2H),2.35(s,6H),1.42(br,2H),1.20-0.95(m,2H).LCMS(m / z):775.7[M+H] + .

[0355] Synthesis of compound 56 [ka]

[0356] Ethyl (E)-2-(cyclopropanecarbonyl)-3-ethoxyacrylate (Intermediate 3) A mixture of ethyl 3-cyclopropyl-3-oxopropanoate (1.0 g, 6.40 mmol) and triethyl orthoformate (1.1 g, 7.68 mmol) was heated to reflux for 30 min, then acetic anhydride (1.96 g, 19.2 mmol) was added and the resulting mixture was heated to reflux for 12 h. The mixture was cooled to room temperature, diluted with EtOAc (100 mL) and water (50 mL) and the mixture was stirred at room temperature for 10 min to decompose excess triethyl orthoformate. The organic phase was separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to leave crude intermediate 3 (1 g, 73.6% yield) as a yellow solid. LCMS (m / z): 213.1 [M+H] +

[0357] Ethyl 3-cyclopropyl-1H-pyrazole-4-carboxylate (Intermediate 4) A solution of hydrazine monohydrate (0.25 g, 5.18 mmol) in ethanol (10 mL) was added dropwise to a solution of ethyl (E)-2-(cyclopropanecarbonyl)-3-ethoxyacrylate (1.0 g, 4.71 mmol) in ethanol (10 mL) at 0° C. The reaction mixture was stirred at room temperature for 12 h and the resulting solid was collected, washed with water and cold ethanol, and dried under vacuum to give the crude product, which was further purified by flash column chromatography (PE:EA 20-10:1) to give intermediate 4 (560 mg, 66.0% yield) as a yellow solid. LCMS (m / z): 181.1 [M+H] +

[0358] Ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-cyclopropyl-1H-pyrazole-4-carboxylate (Intermediate 6) A mixture of ethyl 3-cyclopropyl-1H-pyrazole-4-carboxylate (560.0 mg, 3.11 mmol), tert-butyl (2-bromoethyl)carbamate (1044.6 mg, 4.66 mmol) and Cs2CO3 (1013.3 mg, 3.11 mmol) in CH3CN (10 mL) was stirred at 80 °C overnight. The mixture was cooled to room temperature, diluted with H2O (30 mL), extracted with ethyl acetate (20 mL x 3), the combined organics were washed with brine (50 mL), dried over anhydrous Na2SO4 and purified by flash column chromatography on silica gel (PE / EA: 20:1 to 10:1) to give intermediate 6 (250 mg, 25.0% yield) as a white solid. LCMS: (m / z) 324.2 [M+H] +

[0359] 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-cyclopropyl-1H-pyrazole-4-carboxylic acid (Intermediate 7) A solution of NaOH (49.5 mg, 1.24 mmol) in HO (10 mL) was added to a solution of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-cyclopropyl-1H-pyrazole-4-carboxylate (200.0 mg, 0.62 mmol) in EtOH (5 mL) and the mixture was stirred at 90 °C overnight. After cooling to room temperature, the mixture was adjusted to pH 1-2 with 1N HCl solution and extracted with ethyl acetate (20 mL x 3), the combined organics were washed with brine (50 mL), dried over anhydrous NaSO, filtered and concentrated to leave intermediate 7 (138 mg, 75.4% yield) as a white solid. LCMS: (m / z) 296.2 [M+H] + .

[0360] tert-Butyl (2-(3-cyclopropyl-4-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)-1H-pyrazol-1-yl)ethyl)carbamate (Intermediate 9) To a mixture of 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-cyclopropyl-1H-pyrazole-4-carboxylic acid (59.1 mg, 0.20 mmol), 3-(dimethylamino)-N-(3-((4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)propanamide (74.1 mg, 0.20 mmol) and DIPEA (77.6 mg, 0.60 mmol) in DMF (10 mL) was added HATU (83.7 mg, 0.22 mmol). The mixture was stirred at room temperature for 30 min, diluted with EtOAc (80 mL), washed with saturated NaHCO3 solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to leave the crude compound, which was purified by flash column chromatography on silica gel (DCM / MeOH: 10:1) to give intermediate 9 (50 mg, 38.5% yield) as a white solid. LCMS: (m / z) 651.3 [M+H] + .

[0361] N-(3-((1-(1-(2-aminoethyl)-3-cyclopropyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(dimethylamino)propanamide (Intermediate 10) To crude compound 9 (50.0 mg, 0.077 mmol) was added a solution of HCl in EtOAc (1M, 5 mL), the mixture was stirred at room temperature overnight and concentrated under reduced pressure to leave crude intermediate 10 (50 mg, crude) as a white solid. LCMS: (m / z) 551.3 [M+H] + .

[0362] 4-Chloro-N-(2-(3-cyclopropyl-4-(4-((7-(3-(dimethylamino)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidine-1-carbonyl)-1H-pyrazol-1-yl)ethyl)quinoline-7-carboxamide (compound 56) To a mixture of N-(3-((1-(1-(2-aminoethyl)-3-cyclopropyl-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(dimethylamino)propanamide (50.0 mg, 0.10 mmol), 4-chloroquinoline-7-carboxylic acid (20.8 mg, 0.10 mmol) and DIPEA (38.8 mg, 0.30 mmol) in DMF (10 mL) was added HATU (41.8 mg, 0.11 mmol). The mixture was stirred at room temperature for 30 min, diluted with EtOAc (80 mL), washed with saturated NaHCO3 solution (50 mL), dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC to give compound 56 (1.3 mg, 1.93% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm) 10.49(s,1H),8.95(s,1H),8.88(d,J=4.6Hz,1H),8.52(s,1H),8.27-8.16(m,2H),8.08(dd,J=19.2,8.7 Hz,3H),7.86-7.76(m,2H),7.62(d,J=8.7Hz,1H),4.96(s,1H),4.23(t,J=5.7Hz,2H),3.94(s,2H),3.75 -3.6(m,2H),3.25-3.10(m,4H),2.58(d,J=5.9Hz,2H),2.54(s,1H),2.18(s,6H),1.99-1.88(m,2H),1.5 5-1.45(m,2H),1.45-1.30(m,2H),0.78(d,J=8.0Hz,2H),0.72(d,J=2.7Hz,2H).LCMS(m / z):740.3[M+H] + .

[0363] Synthesis of compounds 58 and 59 [ka]

[0364] N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide To a mixture of 4-chloroquinoline-7-carboxylic acid (83 mg, 0.4 mmol) in dry DCM (10 mL) was added DMF (2 drops) followed by (COCl)2 (101 mg, 0.8 mmol). The mixture was stirred at room temperature for 4 h, concentrated in vacuo, and the residue was redissolved in DCM (10 mL) and added dropwise to a mixture of N-(3-((1-(5-amino-2-benzylpentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)-3-(4-methylpiperazin-1-yl)propanamide hydrochloride (209 mg, 0.32 mmol) and DIPEA (155 mg, 1.2 mmol) in DCM (10 mL) at 0° C. The mixture was stirred at room temperature for 1 h, concentrated and purified by preparative HPLC (C18 column, CH3CN / H2O containing 0.05% NH4HCO3) to give N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (75.7 mg, 29% yield) as a white solid. 1H NMR(400MHz,DMSO-d6) δ(ppm) 10.52(d,J=4.0Hz,1H),8.95-8.85(m,2H),8.60(dd,J=1.2Hz,10.8Hz,1H),8.28(dd,J=5.6H z,10.8Hz,1H),8.21-7.98(m,5H),7.85(d,J=4.8Hz,1H),7.65-7.58(m,1H),7.27-7.07(m,5H) ),4.84(s,1H),4.20-3.98(m,1H),3.97-3.56(m,3H),3.34-3.08(m,4H),2.91-2.60(m,6H),2 .58-2.52(m,2H),2.48-2.21(m,7H),2.15(s,3H),1.72-1.02(m,8H).LCMS(m / z):807.4[M+H] + .

[0365] (R)-N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (compound 58) (S)-N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (compound 59) N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (20 mg, 0.025 mmol) was separated by chiral HPLC (instrument: Gilson-281, column: IC, 20*250, 10 um, mobile phase: MEOH (0.2% methanolic ammonia):CAN (0.2% methanolic ammonia) = 50:50, flow rate: 50 mL / min, run time: per injection: 30 min) to give (R)-N-(4 5-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (8.8 mg) as a solid, and (S)-N-(4-benzyl-5-(4-hydroxy-4-((7-(3-(4-methylpiperazin-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (9.1 mg) as a solid. LCMS (m / z): Compound 58, 807.4 [M+H] + ;Compound 59, 807.4[M+H] + .

[0366] Synthesis of compound 60 [ka]

[0367] N-(4-benzyl-5-(4-((7-(3-chloropropanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (Intermediate 3) To a mixture of N-(5-(4-((7-amino-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-4-benzyl-5-oxopentyl)-4-chloroquinoline-7-carboxamide (400.0 mg, 0.6124 mmol) in dry DCM (10 mL) was added dropwise 3-chloropropanoyl chloride (233.2 mg, 1.8372 mmol), the mixture was stirred at room temperature for 1 h, then MTBE (10 mL) was added, the resulting suspension was filtered and the cake was dried under vacuum to give intermediate 3 (350 mg, 76.9% yield) as a white solid. LCMS (m / z): 743.2 [M+H] +

[0368] N-(4-benzyl-5-(4-hydroxy-4-((7-(3-morpholinopropanamido)-4-oxoquinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (compound 60) A mixture of N-(4-benzyl-5-(4-((7-(3-chloropropanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (60.0 mg, 0.0807 mmol), morpholine (21.1 mg, 0.242 mmol), KCO (55.7 mg, 0.403 mmol) and KI (77.0 mg, 0.403 mmol) in MeCN (5 ml) was heated at 120° C. under microwave irradiation for 3 h. The mixture was concentrated in vacuo, the residue was diluted with HO (20 mL) and extracted with ethyl acetate (20 mL*3), and the combined organics were washed with brine (50 mL), dried over anhydrous NaSO, concentrated and purified by prep-HPLC to give compound 60 (19.5 mg, yield 30.5%) as a white solid. 1H NMR(400MHz,DMSO-d6) δ(ppm) 10.66(d,J=4.8Hz,1H),9.78(s,1H),8.98-8.84(m,2H),8.60(d,J=9.7Hz,1H),8.28(dd,J=8.7Hz,5.4Hz,1H),8.19-8.12(m,2 H),8.08-8.03(m,1H),7.86(d,J=4.7Hz,1H),7.70-7.57(m,1H),7.25-7.07(m,5H),4.83(s,1H),4.13(d,J=12.1Hz,1H),3.99( s,2H),3.94-3.87(m,1H),3.82(d,J=13.8Hz,1H),3.68-3.60(m,5H),3.30(s,2H),3.14(s,4H),2.94(t,J=6.8Hz,2H),2.88-2. 81(m,1H),2.80-2.61(m,4H),1.65(s,1H),1.50(s,3H),1.28-1.23(m,2H),4.96(s,1H),1.15-1.0(m,2H).LCMS(m:794.3[M+H] + .

[0369] Synthesis of compound 61 [ka]

[0370] N-(4-benzyl-5-(4-((7-(3-chloropropanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (Intermediate 3) [ka]

[0371] To a mixture of N-(5-(4-((7-amino-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-4-benzyl-5-oxopentyl)-4-chloroquinoline-7-carboxamide (400 mg, 0.612 mmol) in dry DCM (10 mL) was added dropwise 3-chloropropanoyl chloride (233 mg, 1.837 mmol), the mixture was stirred at room temperature for 1 h, then MTBE (10 mL) was added, the resulting suspension was filtered and the cake was dried under vacuum to give intermediate 3 (350 mg, 76.9% yield) as a white solid. LCMS (m / z): 743.2 [M+H] +

[0372] tert-Butyl 4-(3-((3-((1-(2-benzyl-5-(4-chloroquinoline-7-carboxamido)pentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)amino)-3-oxopropyl)piperazine-1-carboxylate (Intermediate 5) A mixture of N-(4-benzyl-5-(4-((7-(3-chloropropanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (60.0 mg, 0.081 mmol), tert-butyl piperazine-1-carboxylate (45.1 mg, 0.242 mmol), KCO (55.7 mg, 0.403 mmol) and KI (66.9 mg, 0.403 mmol) in MeCN (5 ml) was heated at 120° C. under microwave irradiation for 3 h. The mixture was concentrated in vacuo, the residue was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL*3), the combined organics were washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC to give intermediate 5 (30 mg, 41.6% yield) as a white solid. LCMS (m / z): 893.4 [M+H] + .

[0373] N-(4-benzyl-5-(4-hydroxy-4-((4-oxo-7-(3-(piperazin-1-yl)propanamido)quinazolin-3(4H)-yl)methyl)piperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (compound 61) To a mixture of tert-butyl 4-(3-((3-((1-(2-benzyl-5-(4-chloroquinoline-7-carboxamido)pentanoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)amino)-3-oxopropyl)piperazine-1-carboxylate (30 mg, 0.03 mmol) in 1,4-dioxane (5 mL) was added HCl solution in 1,4-dioxane (5 mL), the mixture was stirred at room temperature for 5 h, concentrated and purified by preparative HPLC to give compound 61 (5.2 mg, 19.5% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm) 10.59(d,J=4.8Hz,1H),8.93(dd,J=4.7,1.5Hz,1H),8.89(dt,J=11.2,5.7Hz,1H),8.63-8.55(m,1H),8.28(dd,J=8.7,5.3Hz,1H),8.16(ddd,J =26.6,17.5,5.5Hz,3H),8.01(dd,J=6.6,1.8Hz,1H),7.85(d,J=4.7Hz,1H),7.65-7.58(m,1H),7.17(dtd,J=23.6,15.5,7.4Hz,6H),4.85(s,1 H),4.17-3.97(m,1H),3.94-3.79(m,1H),3.63(d,J=13.7Hz,2H),3.15 (d,J=9.7Hz,2H),2.88-2.82(m,1H),2.79-2.73(m,2H),2.69(s,4H),2. 63-2.58(m,4H),2.56-2.53(m,2H),2.36(s,4H),1.75-1.60(m,1H),1. 50(s,3H),1.40-1.25(m,2H),1.20-1.0(m,2H).LCMS(m / z):793.3[M+H] + .

[0374] Synthesis of compound 63 [ka]

[0375] N-(4-benzyl-5-(4-((7-(3-chloropropanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (Intermediate 3) To a mixture of N-(5-(4-((7-amino-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-4-benzyl-5-oxopentyl)-4-chloroquinoline-7-carboxamide (400 mg, 0.612 mmol) in dry DCM (10 mL) was added dropwise 3-chloropropanoyl chloride (233.2 mg, 1.837 mmol), the mixture was stirred at room temperature for 1 h, then MTBE (10 mL) was added, the resulting suspension was filtered and the cake was dried under vacuum to give intermediate 3 (350 mg, 76.9% yield) as a white solid. LCMS (m / z): 743.2 [M+H] +

[0376] N-(5-(4-((7-(3-(1H-imidazol-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-4-benzyl-5-oxopentyl)-4-chloroquinoline-7-carboxamide (compound 63) A mixture of N-(4-benzyl-5-(4-((7-(3-chloropropanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)-4-chloroquinoline-7-carboxamide (60.0 mg, 0.081 mmol), 1H-imidazole (45.1 mg, 0.242 mmol), KCO (55.7 mg, 0.403 mmol) and KI (66.9 mg, 0.403 mmol) in MeCN (5 mL) was heated at 120 °C under microwave irradiation for 3 h. The mixture was concentrated in vacuo, the residue was diluted with HO (20 mL) and extracted with ethyl acetate (20 mL*3), and the combined organics were washed with brine (50 mL), dried over anhydrous NaSO, concentrated and purified by prep-HPLC to give compound 63 (2.0 mg, yield 4.0%) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ(ppm) 10.60(d,J=4.7Hz,1H),9.06(s,1H),8.97-8.83(m,2H),8.60(d,J=9.7Hz,1H),8.28(dd,J=8.6,4.8Hz,1H),8.20-7.97( m,4H),7.86(d,J=4.7Hz,1H),7.76(s,1H),7.60(d,J=17.3Hz,2H),7.26-7.08(m,5H),4.85(s,1H),4.51(t,J=5.8Hz,2H) ,4.10-4.05(m,1H),3.90-3.75(m,1H),3.63(d,J=13.6Hz,2H),3.14(s,2H),3.07(s,2H),2.84(d,J=10.9Hz,1H),2.75- 2.60(m,2H),2.69-2.52(m,2H),1.65(s,1H),1.50(s,3H),1.35-1.25(m,2H),1.18-1.00(m,2H).LCMS(m / z):775.3[M+H] + .

[0377] Synthesis of compound 64 [ka]

[0378] 3-(1H-Pyrazol-1-yl)propanoyl chloride (Intermediate 3) To an ice-cold solution of 3-(1H-pyrazol-1-yl)propanoic acid (14.0 mg, 0.10 mmol) in THF (5.0 mL) was added oxalyl dichloride (63.5 mg, 0.50 mmol) and the mixture was stirred at 0-5° C. for 10 min and then at room temperature for an additional 1 h. The mixture was concentrated to leave crude intermediate 3 (18 mg, crude) as a red solid. LCMS (m / z): 155.1 [M+H] +

[0379] N-(5-(4-((7-(3-(1H-pyrazol-1-yl)propanamido)-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-4-benzyl-5-oxopentyl)-4-chloroquinoline-7-carboxamide (compound 64) A solution of the above crude 3-(1H-pyrazol-1-yl)propanoyl chloride (18.0 mg, 0.113 mmol) in dry DCM (2 mL) was added dropwise to a solution of N-(5-(4-((7-amino-4-oxoquinazolin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-4-benzyl-5-oxopentyl)-4-chloroquinoline-7-carboxamide (37.1 mg, 0.0567 mmol) in DCM (5 mL) at 0° C. The mixture was stirred at room temperature for 2 h, diluted with HO (10 mL), extracted with DCM (20 mL×3), and the combined organics were washed with brine (50 mL), dried over anhydrous NaSO, concentrated, and purified by preparative HPLC to give compound 64 (3.1 mg, 7.0% yield) as a white solid. 1H NMR(400MHz,DMSO-d6) δ(ppm) 10.46(d,J=4.7Hz,1H),8.93(d,J=4.7Hz,1H),8.88(dt,J=11.0,5.6Hz,1 H),8.60(d,J=10.5Hz,1H),8.28(dd,J=8.7,5.3Hz,1H),8.21-8.04(m,3H) ,8.03-7.99(m,1H),7.85(d,J=4.7Hz,1H),7.71(d,J=2.0Hz,1H),7.64-7 .55(m,1H),7.44(d,J=1.4Hz,1H),7.23(dd,J=15.7,8.2Hz,2H),7.18-7.0 7(m,3H),6.21(t,J=2.0Hz,1H),4.84(s,1H),4.45(t,J=6.7Hz,2H),4.20 -4.0(m,1H),3.94-3.79(m,1H),3.63(d,J=13.6Hz,2H),3.35-3.25(m,2H) ,3.20-3.10(m,2H),2.97(t,J=6.7Hz,2H),2.85(t,J=10.9Hz,1H),2.76- 2.65(m,2H),1.75-1.60(m,1H),1.55-1.0(m,7H).LCMS(m / z):775.3[M+H] + .

[0380] Example 2: In Vitro Assays Using Exemplary Compounds of the Disclosure Enzyme Assays with Exemplary USP7 Irreversible Inhibitors Tables 1 and 2: USP7 activity of exemplary compounds in the USP7 assay. ++++ indicates IC less than about 20 nM 50 +++ indicates IC of about 20 nM to about 100 nM 50 ++ indicates IC of about 100 nM to about 1 μM 50 + indicates IC > 1 μM 50 mouse liver microsomal stability of exemplary compounds; plasma stability of exemplary compounds. ND indicates not disclosed. [Table 1-1] [Table 1-2] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0381] USP7 Assay Protocol 1.Material: USP7, Active Human Recombinant Protein (CP, Lot 20200225001), Ubiquitin-Rhodamine 110 (Rh110) (BostonBiochem, Catalog No. U-555), DMSO (Sigma, Catalog No. N34869), DTT (Sangon Biotech, Catalog No. A620058-0005), 1M Tris pH 8.0 (Sigma, Catalog No. T2694-1L), Tween®-20 (Sigma, Catalog No. P2287-100ML), EDTA (Invitrogen, Catalog No. 15575020, BSA (Sigma, Catalog No. B2064-100G), 384-Well Assay Plates (Corning, Catalog No. 3573), Echo Qualified 384-Well Polypropylene Microplate 2.0, Clear, Flat Bottom (LABCYTE, catalog number 001-14555).

[0382] 2.Device information: [Table 4]

[0383] 3. Experimental Method: Compounds are diluted 400x of the final desired highest inhibitor concentration in the reaction with 100% DMSO. For all compounds, transfer the compound to one well in a 384-well Echo plate and serially dilute the compound in 3-fold dilutions in 100% DMSO in the next wells for a total of 10 concentrations with Precision. To two empty wells in the same 384-well Echo plate, add 30 μL of 100% DMSO for no compound and no enzyme controls. This plate is the source plate.

[0384] For the USP7 assay, 50 nL of each well is transferred from the source plate to a 384-well assay plate (OptiPlate TM-384 F black assay plate) by an Echo550 liquid handler. Prepare 1x Assay Buffer: [Table 5]

[0385] 2x enzyme solution was prepared by adding the appropriate amount of USP7 in 1x assay buffer (USP7 final concentration: 0.05 nM). 2x substrate solution was prepared by adding the appropriate amount of Ubiquitin-Rhodamine 110 in 1x assay buffer (Ubiquitin-Rhodamine 110 final concentration: 190 nM). 10 μL of 2x enzyme solution was added to each reaction well of the 384-well assay plate, except for the control wells without enzyme (as a low control, add 10 μL of 1x assay buffer instead). Centrifuge at 1000 rpm for 1 minute and incubate at room temperature for 15 minutes. The 2x substrate solution was transferred to the assay plate. To start the reaction, 10 μL of 2x substrate solution was added to each well of the 384-well assay plate. Centrifuge at 1000 rpm for 1 minute. The plate is read kinetically for 20 minutes on a SpectraMax paradigm with excitation at 485 nm and emission at 535 nm. The raw data (slope) was copied from the reader and inhibition values ​​were obtained using formula (1) in Excel. Formula (1): Inh% = (Maximum signal) / (Maximum-Min)*100 The maximum signal was obtained from the action of the enzyme and the substrate. The minimum signal was obtained from the substrate alone. IC 50 To obtain the values, formula (2) was used to fit the data with the XLFit Excel add-in, version 5.4.0.8. Formula (2): Y=Bottom+(Top-Bottom) / (1+((IC 50 / X)*HillSlope)) Y is the % inhibition and X is the compound concentration.

[0386] Plasma Assay Protocol 1. Preheat 0.05M sodium phosphate and 0.07M NaCl buffer, pH 7.4. 14.505g / L Na2HPO4·12H2O, 1.483g / L NaH2PO4·2H2O and 4.095g / L NaCl were dissolved in deionized water. The basic solution was then titrated to pH 7.40 with phosphoric acid. Store in refrigerator for up to 7 days. Check pH on the day of experiment and adjust if outside specification of 7.4+ / -0.1.

[0387] 2.Plasma preparation: Frozen plasma was quickly thawed by placing at 37°C. Plasma was centrifuged at 3,000 rpm for 8 min to remove clots, pipetted, and the supernatant was pooled as plasma to be used in the experiments. The pH of plasma was checked and recorded. Only plasma in the range of pH 7.4 to pH 8 was used. If pH was higher than 8, plasma was discarded. By using a 5% CO2 incubator and PBS buffer, a pH of 7.4 was reached after 4 h equilibration dialysis time. Plasma was kept on ice until use.

[0388] 3. Spiking solutions of tested and reference compounds: 0.5 mM test compound spike solution A: To 190 μL of DMSO was added 10 μL of 10 mM test compound stock solution. 0.02 mM spiking solution B: 40 μL of spiking solution A was added to 960 μL of 0.05 mM sodium phosphate buffer containing 0.5% BSA.

[0389] Plasma and spiking solution B were pre-warmed for 5 minutes at 37° C. At all time points (5, 15, 30, 45, 60 minutes), 10 μL of pre-warmed spiking solution B was added to designated wells.

[0390] For 0 min, 400 μL of acetonitrile (ACN) containing internal standard (IS) was added to the wells of the 0 min plate, followed by 90 μL of plasma. 90 μL of pre-warmed plasma was added to the wells designated for the time points (0, 5, 15, 30, 45, 60 min) and timing was started. At 5, 15, 30, 45, 60 min, 400 μL of ACN containing IS was added to the corresponding plate wells, respectively, to stop the reaction. After quenching, the plate was shaken for 10 min (600 rpm / min) on a vibrator (IKA, MTS 2 / 4) and then centrifuged at 5594 g for 15 min (Thermo Multifuge × 3R). 50 μL of supernatant from each well was transferred to a 96-well sample plate containing 50 μL of ultrapure water (Millipore ZMQS50F01) for LC / MS analysis.

[0391] Microsome Assay Protocol 1. Buffer A: 1.0 L of 0.1 M potassium phosphate monobasic buffer containing 1.0 mM EDTA. Buffer B: 1.0 L of 0.1 M potassium phosphate dibasic buffer containing 1.0 mM EDTA. Buffer C: 0.1 M potassium phosphate buffer, 1.0 mM EDTA, pH 7.4 by titrating 700 mL of Buffer B with Buffer A while monitoring with a pH meter.

[0392] 2. Spiking solutions of reference compound (Ketanserin) and test compounds: 500 μM spike solution: To 190 μL of ACN, 10 μL of 10 mM DMSO stock solution was added.

[0393] 1.5 μM spiking solution in microsomes (0.75 mg / mL): To 479.75 μL of Buffer C on ice, 1.5 μL of 500 μM spiking solution and 18.75 μL of 20 mg / mL liver microsomes were added.

[0394] 3. NADPH stock solution (6 mM) was prepared by dissolving NADPH in buffer C. 30 μL of 1.5 μM spike solution containing 0.75 mg / mL microsome solution was dispensed into assay plates on ice designated for different time points (0 min, 5 min, 15 min, 30 min, 45 min). For 0 min, 135 μL of ACN containing IS was added to the wells of the 0 min plate, followed by 15 μL of NADPH stock solution (6 mM). All other plates were pre-incubated at 37° C. for 5 min. 15 μL of NADPH stock solution (6 mM) was added to the plate to start the reaction and timing. At 5 min, 15 min, 30 min, and 45 min, 135 μL of ACN containing IS was added to the wells of the corresponding plate, respectively, to stop the reaction. After quenching, the plate was shaken for 10 min (600 rpm / min) on a vibrator (IKA, MTS 2 / 4) and then centrifuged at 5594 g for 15 min (Thermo Multifuge × 3R). For LC / MS analysis, 50 μL of supernatant from each well was transferred to a 96-well sample plate containing 50 μL of ultrapure water (Millipore, ZMQS50F01).

[0395] Incorporation by Reference All publications and patents mentioned herein are herein incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0396] Equivalent While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those of ordinary skill in the art upon review of this specification and the claims that follow. The full scope of the invention should be determined by reference to the claims, along with the specification, along with their full scope of equivalents, and such variations.

Claims

1. A compound of formula (I): 【Chemical 146】 or a pharmaceutically acceptable salt thereof, wherein Q is 【Chemical 147】 and G is CR １０ , NR １０ , or N, and J is CR １０ , NR １０ , N, or S, and L is NR １０ , CR １０ , CR １１ , or N, and K is C or N, 【Chemical 148】 is a single bond or a double bond when the valence permits, provided that the ring containing J, L, and G is aromatic, U is one or more Hal, -NH ２ , -CN, -CF ３ , -OH, oxo, or C １～３ is a 5- to 6-membered heterocyclyl optionally substituted with alkyl, V is a 5- or 6-membered heteroaryl or C ３～６ cycloalkyl, and the 5- or 6-membered heteroaryl or C ５～６ cycloalkyl is optionally substituted with one or more Hal, -NH ２ , -CN, -CF ３ , -OH, oxo, or C １～３ alkyl R １ and R ２ together with the carbon atom to which they are attached form a C ６～１０ aryl or 5- to 6-membered heteroaryl, and the C ６～１０ aryl or the 5- to 6-membered heteroaryl is independently selected from Hal, C １～３ alkyl, C １～３ alkoxy, C ６～１０ aryl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, -NHC(=O)C １～３ alkylene(NR ３ R ４ ), -C(=O)NHC １～３ alkylene(NR ３ R ４ ), -NHC １～３ alkylene(4- to 7-membered heterocyclyl), -OC １～３ alkylene(4- to 7-membered heterocyclyl), -OC １～３ alkylene -O-(NR ３ R ４ ), -NHC １～３ alkylene(NR ３ R ４ ), or -OC １～３ alkylene(NR ３ R ４ ), and is optionally substituted with one or more substituents independently selected therefrom, and the C １～３ alkyl, the C ６～１０ aryl, the 5- to 6-membered heteroaryl, or the 4- to 7-membered heterocyclyl is independently optionally substituted with one or more of Hal, -NH ２ , -CN, -CF ３ , C １～３ alkyl, or -C ０～２ alkyl(5- to 6-membered heterocyclyl). R ３ is C １～３ alkyl, and R ４ is C １～３ alkyl or or R ３ and R ４ together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclyl or a 5- to 7-membered heteroaryl, and said 5- to 7-membered heterocyclyl is optionally substituted with one or more C １～３ alkyl L １ is one or more -C ０～２ alkyl (C ６ aryl), -NHC ０～２ alkyl (C ６ aryl), or -C ０～２ C substituted with alkyl(5-6 membered heteroaryl) ２～４ is alkylene, said C ２～４ one or more carbons in the alkylene are optionally replaced with N optionally substituted with alkyl １～３ and are optionally replaced with N optionally substituted with alkyl the -C ０～２ alkyl (C ６ aryl) or the -C ０～２ alkyl (5- to 6-membered heteroaryl) is independently optionally substituted with one or more Hal, -NH ２ , -CN, -CF ３ , or C １～３ alkyl and is optionally substituted therewith, L ２ is -NH-, or 【Chemical 153】 and 【Chemical 154】 is a 5-membered heteroarylene, L ３ is -C(=O)-, -S(=O) ２ -, C ６～１０ arylene, or a bond, and L ４ is C １～３ alkylene, C ２～４ alkenylene, or a bond, and 【Chemical 155】 is H, 【Chemical 156】 C ６～１０ is aryl or 5- to 7-membered heteroaryl, and said C ６～１０ aryl or said 5- to 7-membered heteroaryl is optionally substituted with one or more Hal, -CN, C １～３ haloalkyl, -NHC(=O)C １～３ alkenyl, X is N or CH, Y is N or CR ７ wherein R ５ is Hal, -NH ２ , -NH ２ (C １～３ alkyl), -OH, C １～３ alkoxy, or C １～３ alkyl, and R ６ is H, Hal, -NH ２ , -OH, -C(O)NH ２ , C １～３ alkyl, C １～３ alkoxy, C ６～１０ aryl, 5- to 6-membered heteroaryl, or C ３～５ cycloalkyl, and -NH ２ , -OH, said C １～３ alkyl, said C ６～１０ aryl, said 5- to 6-membered heteroaryl, or said C ３～５ cycloalkyl is optionally substituted with one or more Hal, -NH ２ , -CN, -CF ３ , C １～３ alkyl, C １～３ alkyl(NH ２ ), or C １～３ alkyl(CF ３ ), R ７ is H, Hal, C １～３ alkyl, C １～３ haloalkyl, cyano, C ３～５ cycloalkyl, -C(O)NH ２ , -C(O)N(C １～３ alkyl) ２ , -C(O)NHC ３～５ cycloalkyl, or -C(=O)NHC １～３ alkyl, and when R ７ is -C(O)N(C １～３ alkyl) ２ two C １～３ alkyl groups optionally together with the N atom to which they are attached form a 3- to 7-membered heterocyclyl, or R ７ and R ６ are, together with the carbon atom to which they are attached, C ５～７ cycloalkyl, C ６～８ bridged bicyclic cycloalkyl, or 5- to 6-membered heterocyclyl, and said C ５～７ cycloalkyl or said 5- to 6-membered heterocyclyl is one or more C １～３ alkyl, oxo, or -C(=O)C １～３ optionally substituted with alkyl, and two C's on the same carbon １～３ alkyl optionally together with the carbon atom to which they are attached forms a spiro ring, 【Chemical 157】 is C ６～１０ an aryl, 5- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl, R １０ is H, C １～３ alkylene (C ５～７ heterocyclyl), or C ６～１０ aryl, and C １～３ alkylene (C ５～７ heterocyclyl) or C ６～１０ aryl is optionally substituted with one or more Hal, -NH ２ , -CN, -CF ３ , C １～３ alkyl, C １～３ alkyl(NH ２ ), C １～３ alkyl(CF ３ ), or C １～３ alkyl(NH ２ )(CF ３ ). R １１ is Hal, -NH ２ , -CN, -CF ３ , or C １～３ alkyl, and provided that the compound is not 【Chemical 160】 【Chemical 161】 【Chemical 162】 【Chemical 163】 【Chemical 164】 【Chemical 165】 【Chemical 166】 a compound or a pharmaceutically acceptable salt thereof.

2. L ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L is -NH-.

3. L ３ is -S(=O)- ２ - or -C(=O)-, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. 【Fig. 175】 is H and L ４ is C １～３ is alkylene or C ３～４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is alkenylene.

5. L ４ is C ３～４ alkenylene, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. 【Fig. 176】 is 【Chemical 177】 a compound or a pharmaceutically acceptable salt thereof according to claim 1.

7. 【Fig. 178】 is a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, a compound or a pharmaceutically acceptable salt thereof according to claim 6.

8. The compound of formula (I) is a compound of formula (Ia): 【Chemical 181】 a compound or a pharmaceutically acceptable salt thereof according to claim 1.

9. L ２ The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein L is -NH-.

10. L ２ is 【Chemical 182】 is a compound or a pharmaceutically acceptable salt thereof according to claim 8.

11. L ３ The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein L is -C(=O)-.

12. The compound of formula (I) is a compound of formula (Ib): 【Chemical 183】 a compound or a pharmaceutically acceptable salt thereof according to claim 1.

13. R ５ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is Hal, -OH, or Me.

14. R ５ The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R is Cl.

15. R ７ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is H.

16. R ６ is is H; is F, -NH₂, or -OH, wherein the -NH₂ or -OH is optionally substituted with C₁₋₃ alkyl; is C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally substituted with one or more Hal or -NH₂; is C₆₋₁₀ aryl, wherein the C₆₋₁₀ aryl is optionally substituted with one or more Hal, -NH₂, -CN, -CF₃, C₁₋₃ alkyl, C₁₋₃ alkyl(NH₂), or C₁₋₃ alkyl(CF₃); is a 5- to 6-membered heteroaryl; or is C₃₋₅ cycloalkyl, wherein the C₃₋₅ cycloalkyl is optionally substituted with one or more Hal, a compound or a pharmaceutically acceptable salt thereof according to claim 1.

17. R ７ and R ６ together with the carbon atom to which they are attached form a C ５ cycloalkyl or 5- to 6-membered heterocyclyl, said C ５ cycloalkyl or said 5- to 6-membered heterocyclyl being optionally substituted with one or more C １～３ alkyl, oxo, or -C(=O)C １～３ alkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

18. L １ is C alkylene substituted with one or more -C ０～２ alkyl(C ６ aryl), the compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof. ２～４ ​

19. The one or more -C ０～２ alkyl (C ６ aryl) is substituted with one or more Hal, -NH ２ , -CN, -CF ３ , or C １～３ alkyl, the compound according to claim 18 or a pharmaceutically acceptable salt thereof.

20. L １ is -CH ２ substituted C with Ph ２～４ The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein the alkylene is

21. L １ is 【Chemical 184】 wherein a is a bonding point to a carbonyl group and b is a bonding point to L ２ The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein b is a bonding point to L

22. L ２ is 【Chemical 194】 is a compound or a pharmaceutically acceptable salt thereof according to claim 1.

23. R １ and R ２ together with said carbon atom to which they are attached form a C ６～１０ aryl, a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

24. Said C ６～１０ aryl is substituted by one or more -NHC(=O)C １～３ alkylene(NR ３ R ４ ) or -OC1-3 alkylene(NR3R4), the compound according to claim 23 or a pharmaceutically acceptable salt thereof.

25. Said C ６～１０ aryl is substituted with one or more -NHC(=O)C ２ alkylene(NMe ２ ) and the compound according to claim 23 or a pharmaceutically acceptable salt thereof.

26. Each R ３ and R ４ is independently C １～３ alkyl, or The compound or a pharmaceutically acceptable salt thereof according to claim 24, wherein R3 and R4, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl.

27. Each R ３ and R ４ is Me, the compound according to claim 26 or a pharmaceutically acceptable salt thereof.

28. wherein the 5- to 7-membered heterocyclyl is substituted with one or more C １～３ alkyl, the compound according to claim 26, or a pharmaceutically acceptable salt thereof.

29. R ３ and R ４ The compound according to claim 24 or a pharmaceutically acceptable salt thereof, wherein R and R together with the nitrogen atom to which they are attached form a 5- to 7-membered heteroaryl.

30. R １ and R ２ which together with the carbon atom to which they are attached form a 5- or 6-membered heteroaryl, a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

31. The 5- or 6-membered heteroaryl is substituted with one or more C ６～１０ aryl, and the compound according to claim 30 or a pharmaceutically acceptable salt thereof.

32. Said C ６～１０ aryl is substituted with one or more Hal, -NH ２ , -CN, -CF ３ , or C １～３ The compound according to claim 31, or a pharmaceutically acceptable salt thereof, wherein the aryl is substituted with alkyl.

33. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is a compound of formula (Ic) or a compound of formula (Id): 【Chemical 195】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is

34. 【Fig. 199】 【Chemical 200】 【Chemical 201】 【Chemical 202】 【Chemical 203】 【Chemical 204】 【Chemical 205】 【Chemical 206】 【Chemical 207】 【Chemical 208】 【Chemical 209】 【Chemical 210】 【Chemical 211】 【Chemical 212】 【Chemical 213】 【Chemical 214】 【Chemical 215】 【Chemical 216】 【Chemical 217】 【Chemical 218】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the group consisting of

35. The compound is 【Chemical 222】 【Chemical 223】 【Chemical 224】 【Chemical 225】 【Chemical 226】 【Chemical 227】 【Chemical 228】 【Chemical 229】 【Chemical 230】 【Chemical 231】 【Chemical 232】 【Chemical 233】 【Chemical 234】 The compound or a pharmaceutically acceptable salt thereof according to claim 34, which is selected from

36. The compound is 【Chemical 236】 【Chemical 237】 【Chemical 238】 【Chemical 239】 【Chemical 240】 【Chemical 241】 【Chemical 242】 【Chemical 243】 【Chemical 244】 The compound or a pharmaceutically acceptable salt thereof according to claim 34 or 35, which is selected from

37. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

38. A pharmaceutical composition for treating a disease or disorder regulated by USP7, comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8.

39. The composition according to claim 38, wherein the disease or disorder regulated by USP7 is cancer and metastasis, neurodegenerative disease, immunological disorder, diabetes, bone and joint disease, osteoporosis, arthritis inflammatory disorder, cardiovascular disease, ischemic disease, viral infection and viral disease, viral infectivity and / or viral latency, and bacterial infection and bacterial disease.

40. A pharmaceutical composition for treating cancer, comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8.

41. The composition according to claim 40, wherein the cancer is liposarcoma, neuroblastoma, glioblastoma, breast cancer, bladder cancer, glioma, adrenocortical cancer, multiple myeloma, colorectal cancer, colon cancer, prostate cancer, non-small cell lung cancer, human papillomavirus-related cervical cancer, oropharyngeal cancer, penile cancer, ovarian cancer, anal cancer, thyroid cancer, vaginal cancer, Epstein-Barr virus-related nasopharyngeal cancer, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, diffuse large B-cell lymphoma, and Ewing sarcoma.

42. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease regulated by USP7.

43. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer.

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