Compounds and their uses

Abstract

This disclosure features compounds useful for the treatment of CBP-related disorders.

Description

[Technical Field]

[0001] Regarding compounds and their uses. [Background technology]

[0002] CREB-binding proteins (CBPs) are transcriptional coactivators that maintain gene expression programs through lysine acetylation and act as protein scaffolds that help mobilize and construct complexes necessary for transcription or chromatin remodeling. CBPs are involved in cell differentiation, apoptosis, and the cell cycle. This invention relates to useful compositions and methods for the treatment of CBP-related disorders such as cancer and infectious diseases. [Overview of the project]

[0003] CREB-binding proteins are intracellular proteins that are important for regulating gene expression and establishing and activating enhancer-mediated transcription. CBP is overexpressed in several cancer cell lines. Therefore, agents that reduce CBP levels and / or activity may offer novel methods for treating diseases and disorders such as cancer and infections. We have found that CBP depletion leads to downregulation / depletion of MYC in those cells. Therefore, agents (e.g., compounds) that degrade CBP are useful for treating CBP and / or MYC-related disorders (e.g., cancer or infections).

[0004] This disclosure features compounds and methods useful for treating CBP-related disorders (e.g., cancer or infection).

[0005] In one embodiment, the present disclosure relates to a compound having the structure of formula I, ALB Equation I During the ceremony, A is the CBP binding site, B is the decomposition part, L has the structure of formula II, A 1 -(F)-(E) m-C-A 2 Formula II wherein A 1 is the bond between the linker and A, A 2 is the bond between B and the linker, m is independently 0 or 1, C is independently absent, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, E is independently absent, O, S, NR N , optionally substituted C1-C 10 alkylene, optionally substituted C2-C 10 alkenylene, optionally substituted C2-C 10 alkynylene, optionally substituted C2-C 10 polyethylene glycol, or optionally substituted C1-C 10 heteroalkylene, and any C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C2-C 10 polyethylene glycol, or C1-C 10 heteroalkylene is independently oxo, halo, NO2, N(R f )2, CN, C(O)N(R f )2, S(O)N(R f )2, S(O)2N(R f )2, OR f , SR f , C(O)R f , S(O)2R f , C(O)N(R f )2, N(R f )2, N(R f )S(O)R f , N(R f )S(O)2R f , a carbocyclic ring, and is optionally substituted with one or more groups selected from one or more groups selected from C1-C6 alkyl optionally substituted with one or more groups independently selected from oxo and halo, each R NHowever, independently, H, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C6 heterocyclyl, optionally substituted C6-C 12 It is an aryl or optionally substituted C1-C7 heteroalkyl, and any C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C6 heterocyclyl, C6-C 12 Aryl or C1-C7 heteroalkyl groups can independently be oxo, halo, NO2, or N(R) f )2, CN, C(O)N(R f )2, S(O)N(R f )2, S(O)2N(R f )2, OR f , SR f , C(O)R f S(O)2R f , C(O)N(R f )2, N(R f )2, N(R f )S(O)R f , N(R f )S(O)2R f , a carbocyclic ring, and optionally substituted with one or more groups selected from C1-C6 alkyl groups, independently selected from oxo and halo groups, F is independently and arbitrarily replaced by C3~C 10 Carbocyclylene, optionally substituted with C2-C 10 Heterocyclylene, optionally substituted C6~C 10 Arylene, or C2-C9 heteroarylene with optional substitution, and any C3-C 10 Carbocyclylene, C2~C 10 Heterocyclylene, C6~C 10 Arylene, or C2-C9 heteroarylene, oxo, halo, NO2, N(R) f )2, CN, C(O)N(R f )2, S(O)N(R f )2, S(O)2N(R f )2, OR f , SR f, C(O)R f S(O)2R f , C(O)OR f , N(R f )S(O)R f , N(R f )S(O)2R f , a carbocyclic ring, and optionally substituted with one or more groups selected from C1-C6 alkyl groups, independently selected from oxo and halo groups, Each R f However, independently, they are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, or heterocyclyl, and any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, and heterocyclyl are independently oxo, carbocykrill, heterocyclyl, NO2, N(R) g )2, CN, C(O)N(R g )2, S(O)N(R g )2, S(O)2N(R g )2, OR g , SR g , C(O)R g S(O)2R g , C(O)N(R g )2, N(R g )2, N(R g )S(O)R g , N(R g )S(O)2R g , and optionally substituted with one or more groups selected from C1-C6 alkyl groups, wherein the carbocyclyl and C1-C6 alkyl groups are independently oxo, halo, C1-C6 alkyl, cyano, N(R) g )2, OR g , and also optionally substituted with one or more groups selected from carbocyclyls that are independently substituted with one or more groups selected from halos and C1-C6 alkyls, Each R gis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyclic, or heterocyclic, and each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyclic, and heterocyclic is independently optionally substituted with one or more groups selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, carbocyclic, heterocyclic, and C1-C6 alkyl optionally substituted with one or more groups independently selected from oxo and halo, or two Rs g together with the nitrogen to which they are attached, independently form a heterocyclic optionally substituted with one or more groups selected from oxo, halo, and C1-C3 alkyl optionally substituted with one or more groups independently selected from oxo and halo, a compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the linker has the structure of Formula II. A 1 -(F)-(E) m -C-A 2 Formula II

[0006] In some embodiments, A 1 is the bond between the linker and A. In some embodiments, A 2 is the bond between B and the linker.

[0007] In some embodiments, m is 0.

[0008] In some embodiments, E is absent.

[0009] In some embodiments, m is 1.

[0010] In some embodiments, E is optionally substituted C 1~10 alkylene.

[0011] In some embodiments, E is methylene or ethylene.

[0012] In some embodiments, E is [ka] That is the case.

[0013] In some embodiments, F is an optionally substituted C2-C9 heteroarylene.

[0014] In some embodiments, F is structure: [ka] It has, In the formula, X7 and X8 are independently either C or N. R 15 and R 16 However, when they combine with the atoms to which they are bonded, they form optionally substituted 3- to 12-membered heteroaryls, and the heteroaryl is A 1 and / or one or more of the following groups: optionally substituted with halogens or C1-C6 alkyl groups.

[0015] In some embodiments, F is [ka] That is the case.

[0016] In some embodiments, F is [ka] That is the case.

[0017] In some embodiments, F is [ka] is as follows.

[0018] In some embodiments, F is an optionally substituted C2-C 10 heterocyclylene.

[0019] In some embodiments, F is

Chemical formula

[0020] In some embodiments, C is absent.

[0021] In some embodiments, C is a carbonyl.

[0022] In some embodiments, the CBP binding moiety has the structure of formula III,

Chemical formula

[0023] In some embodiments, the CBP binding portion of formula III has the following structure: [ka] It has.

[0024] In some embodiments, the CBP binding portion of formula III has the following structure: [ka] It has.

[0025] In some embodiments, the CBP binding portion of formula III has the following structure: [ka] It has.

[0026] In some embodiments, the CBP binding portion of formula III has the following structure: [ka] It has.

[0027] In some embodiments, the CBP binding portion of formula III has the following structure: [ka] It has.

[0028] In some embodiments, R 1d teeth, [ka] That is the case.

[0029] In some embodiments, the CBP binding portion of formula III has the following structure: [ka] [ka] It has.

[0030] In some embodiments, the CBP binding portion of formula (III) has the structure: [ka] [ka] [ka] It has.

[0031] In some embodiments, R 1c NR 2a R 3a teeth, [ka] That is the case.

[0032] In some embodiments, R 1c NR 2a R 3a teeth, [ka] That is the case.

[0033] In some embodiments, R 1c teeth, [ka] That is the case.

[0034] In some embodiments, R 1d teeth, [ka] That is the case.

[0035] In some embodiments, the CBP binding portion of formula (III) has the structure: [ka] It has.

[0036] In some embodiments, the CBP binding portion of formula (III) has the structure: [ka] It has.

[0037] In some embodiments, the CBP binding portion of formula (III) has the structure: [ka] It has.

[0038] In some embodiments, the CBP binding portion of formula (III) has the structure of formula (III-A), [ka] In the formula, R 8 However, independently, C1~C 12 Alkyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R 8 Each C 1~12 Alkyl, 3-12 membered carbon rings, and 3-12 membered heterocycles are one or more groups R O It is replaced by an optional selection, R 9 However, independently, C1-C4 alkyl, C2-C6 heteroaryl, C2-C9 heterocyclic, and C(O)N(R) compounds exist. h2 )2, S(O)N(R h2 )2, S(O)2, C(O)Rh2 , C(O)OR h2 , S(O)R h2 , or S(O)2R h2 And any C1-C4 alkyl, C2-C6 heteroaryl, or C2-C9 heterocycle can independently be F, Cl, Br, I, a 3-5 membered carbon ring, or C(O)N(R h2 )2, S(O)N(R h2 )2, N(R h2 )C(O)OR h2 , N(R h2 )C(O)N(R h2 )2, N(R h2 )C(O)R h2 , N(R h2 )2, N(R h2 )S(O)2R h2 , N(R h2 )S(O)N(R h2 )2, and N(R h2 )S(O)2N(R h2 ) One or more substituents that are optionally substituted from 2, R 10 However, independently, C6~C 20 Aryl, C1~C 20 Heteroaryl, (C6~C 20 Ariel) (C1~C 20 (heteroaryl), (C1~C 20 (Heteroaryl) (C6~C 20 (aryl), and (C1~C 20 (Heteroaryl) (C1~C 20 (Heteroaryl) and each C6~C 20 Aryl, C1~C 20 Heteroaryl, (C6~C 20 Ariel) (C1~C 20 (heteroaryl), and (C1~C 20 (Heteroaryl) (C1~C 20 Heteroaryls) independently, A 1 , and / or independently, R PP , oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(R a2 )2, CN, C(O)N(R a2)2, S(O)N(R a2 )2, S(O)2N(R a2 )2, N(R a2 )C(O)OR a2 )C(O)N(R a2 )C(O)N(R a2 )S(O)2R a2 , N(R a2 )S(O)N(R a2 )2, and N(R a2 )S(O)2N(R a2 ) Optionally substituted with one or more substituents selected from 2, Each R a2 However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, and heterocyclyl, and each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, and heterocyclyl is independently oxo, halo, amino, hydroxyl, C1-C6 alkoxy, carbocykrill, heterocyclyl, or A 1 Furthermore / or optionally substituted with one or more groups selected from C1-C6 alkyl groups, which are independently substituted with one or more groups selected from oxo and halo groups, or two R groups a2 However, together with the nitrogen to which they are bound, they independently form oxo, halo, and heterocyclines optionally substituted with one or more C1-C3 alkyl groups optionally substituted with one or more groups optionally substituted with one or more groups optionally substituted with oxo and halo groups. Each R O However, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(R) P )2, CN, C(O)N(R P )2, S(O)N(R P )2, S(O)2N(R c )2, C(O)OR P ,OCOC(O)R P , C(O)OR P , S(O)R P S(O)2R P OCRP (O)2, N(R) P )2, N(R P )R P C(O)R P N(R P )2, R P N(R P )2, N(R P S(O)R P , N(R P S(O)R PP N(R P R P R P )2, or N(R P )S(O)2N(R P )2, and any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl can independently be oxo, halo, NO2, N(R) P )2, CN, C(O)N(R P )2, S(O)R P , S(O)2N(R P )S(O)R P , N(R P )S(O)2R P , and optionally substituted with one or more groups selected from C1-C6 alkyl groups, which are independently substituted with one or more groups selected from oxo and halo groups. Each R P R P These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, or heterocyclyl, and any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, and heterocyclyl are independently oxo, carbocykrill, heterocyclyl, halo, NO2, N(R) d2 )2, CN, C(O)N(R d2 )2, S(O)N(R d2 )2, S(O)2N(R d2 )2, OR d2 , SR d2 , C(O)R d2 , S(O)R d2 , C(O)N(R d2 )2, N(R d2 )C(O)Rd2 , N(R d2 )S(O)R d2 , N(R d2 )S(O)2R d2 , and are optionally substituted with one or more groups selected from C1-C6 alkyl groups, wherein the carbocyclyl and C1-C6 alkyl groups are independently oxo, halo, C1-C6 alkyl, cyano, N(R) d2 )2, OR d2 , and also optionally substituted with one or more groups selected from carbocyclyls that are independently substituted with one or more groups selected from halos and C1-C6 alkyls, Each R d2 However, independently, they are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyryl, or heterocyclyl, and each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyryl, and heterocyclyl is independently optionally substituted with one or more groups selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, carbocyryl, heterocyclyl, and C1-C6 alkyl which are optionally substituted with one or more groups independently selected from oxo and halo, or two R d2 However, together with the nitrogen to which they are bound, they independently form oxo, halo, and heterocyclines optionally substituted with one or more C1-C3 alkyl groups optionally substituted with one or more groups optionally substituted with one or more groups optionally substituted with oxo and halo groups. Each R h2 However, independently, these are hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, and each of the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is independently oxo, halo, amino, hydroxyl, C 1~3 It is substituted with one or more groups selected from C1-C3 alkyl groups, which are optionally substituted with one or more groups independently selected from alkoxys and halos. R 10 However, A1 Includes.

[0039] In some embodiments, R 8 These are methyl, oxetanyl, tetrahydrofuranil, tetrahydropyranil, dioxothiolanil, piperidyl, or pyrrolidinil, and R 8 Each of the following compounds contains one or more R groups: methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl. b2 It is being replaced by an optional choice.

[0040] In some embodiments, R 8 teeth, [ka] That is the case.

[0041] In some embodiments, R 9 These are acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole, or isoxazole.

[0042] In some embodiments, R 9 Structure: [ka] It has.

[0043] In some embodiments, the CBP binding portion has the following structure: [ka] It has.

[0044] In some embodiments, the CBP binding portion has the following structure: [ka] It has.

[0045] In some embodiments, R 10 Structure: [ka] It has, During the ceremony, X3, NR N2 It is CH2 or O, X4 is N, CH, X5 is N, CH, X6 is NR N2 It is CH2 or O, R 14 However, it is CHF2, CHCl2, CH3, Cl, F, or H. Each R N2 However, it is a C1-C3 alkyl group or H.

[0046] In some embodiments, R 10 teeth, [ka] That is the case.

[0047] In some embodiments, R 10 teeth, [ka] That is the case.

[0048] In some embodiments, X3 is CH2 and X4 is CH.

[0049] In some embodiments, R 10 Structure: [ka] It has.

[0050] In some embodiments, the CBP binding portion has the following structure: [ka] It has.

[0051] In some embodiments, the CBP binding portion of formula (III) has the structure of formula (III-B), [ka] In the formula, R 1 However, independently, C1~C 12 Alkyl, C2~C 12 Alkenyl, C2~C 12 Alkynnyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R 1 Each C1~C 12 Alkyl, C2~C 12 Alkenyl, C2~C 12 Alkynnyls, 3-12 membered carbon rings, and 3-12 membered heterorings are A 1 and / or one or more base R b It is replaced by an optional selection, R 2 However, independently, C6~C 20 Aryl, C1~C 20 Heteroaryl, (C 6~20 Ariel) (C1~C 20 (heteroaryl), (C1~C 20 (Heteroaryl) (C6~C 20 (aryl), and (C1~C 20 (Heteroaryl) (C1~C 20 (Heteroaryl) and each C6~C 20 Aryl, C1~C 20 Heteroaryl, (C6~C 20 Ariel) (C1~C 20 (heteroaryl), and (C1~C 20 (Heteroaryl) (C1~C 20 Heteroaryls) independently, A 1 , and / or independently, Rc , oxo, F, Cl, Br, I, NO2, N(R) a )2, CN, C(O)N(R a )2, S(O)N(R a )2, S(O)2N(R a )2, N(R a )C(O)OR a )C(O)N(R a )2, N(R a )2, N(R a )S(O)R a , N(R a )S(O)2R a , N(R a )S(O)N(R a )2, and N(R a )S(O)2N(R a )Optionally substituted with one or more substituents selected from 2, R 3 However, independently, C1~C 12 Alkyl, C2~C 12 Alkenyl, C2~C 12 Alkynnyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R 3 Each C 1~ C 12 Alkyl, C 2~ C 12 Alkenil, C 2~ C 12 Alkynnyls, 3-12 membered carbon rings, and 3-12 membered heterorings are A 1 and / or one or more base R e It is either optionally replaced, or R in equation (I) 2 and R 3 However, together with the nitrogen to which they are bound, A 1 and / or one or more base R e This forms a 3- to 12-membered complex ring with arbitrary substitutions. R 4 However, independently, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 3-5 membered carbon ring, 3-5 membered heterocycle, C(O)N(R) h )2, S(O)N(R h )2, S(O)2, C(O)R h, C(O)OR h , S(O)R h , or S(O)2R h And any C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkynnyls, 3-5 membered carbon rings, and 3-5 membered heterorings are A 1 , and / or independently, F, Cl, Br, I, 3-5 membered carbon rings, C(O)N(R h )2, S(O)N(R h )2, N(R h )C(O)OR h , N(R h )C(O)N(R h )2, N(R h )C(O)N(R h )2, N(R h )S(O)2R h , N(R h )S(ON(R h )2, and N(R h )S(O)N(R h ) Optionally substituted with one or more substituents selected from 2, Each R a However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, and heterocyclyl, and each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, and heterocyclyl is A 1 , and / or independently, oxo, halo, amino, hydroxyl, C1-C6 alkoxy, carbocykrill, heterocyclyl, or A 1 and / or optionally substituted with one or more groups selected from C1-C6 alkyl groups, which are independently and optionally substituted with one or more groups selected from oxo and halo groups, or two R groups a However, together with the nitrogen to which they are bound, A 1 , and / or independently, oxo, halo, and A 1 and / or independently form a heterocycline optionally substituted with one or more groups selected from C1-C3 alkyl groups, which are optionally substituted with one or more groups selected from oxo and halo groups. Each R b However, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(R) c )2, CN, C(O)N(R c )2, S(O)N(R c )2, S(O)2N(R c )2, N(R c )C(O)R c )C(O)N(R c , S(O)R c S(O)2R c , N(R c )S(O)N(R c )2, or N(R c )S(O)2N(R c )2, and any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl are A 1 , and / or independently, oxo, halo, NO2, N(R) c )2, CN, C(O)N(R c )2, N(R c )C(O)2N(R c )S(O)R c , N(R c )S(O)2R c , and C optionally substituted with one or more groups independently selected from oxo and halo 1~6 It is optionally substituted with one or more groups selected from alkyl groups. Each R c However, independently, they are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyryl, or heterocyclyl, and any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyryl, and heterocyclyl are independently oxo, carbocyryl, heterocyclyl, halo, NO2, N(R) d )2, CN, C(O)N(R d )2, S(O)N(R d )2, S(O)2N(R d )2, OR d, SR d , C(O)R d S(O)2R d , C(O)N(R d )2, N(R d )2, N(R d )S(O))R d , N(R d )S(O)2R d , and are optionally substituted with one or more groups selected from C1-C6 alkyl groups, wherein the carbocyclyl and C1-C6 alkyl groups are A 1 , and / or independently, oxo, halo, C1-C6 alkyl, cyano, N(R) d )2, OR d , and are optionally substituted with one or more groups selected from heterocyclyls and carbocyclyls that are optionally substituted with one or more groups independently selected from halo and C1-C6 alkyl groups, Each R d However, independently, they are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyryl, or heterocyclyl, and each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyryl, and heterocyclyl is A 1 , and / or independently, optionally substituted with one or more groups selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, carbocykryl, heterocyclyl, and C1-C6 alkyl groups optionally substituted with one or more groups independently selected from oxo and halo, or two R d However, together with the nitrogen to which they are bound, they independently form oxo, halo, and heterocyclines optionally substituted with one or more C1-C3 alkyl groups optionally substituted with one or more groups optionally substituted with one or more groups optionally substituted with oxo and halo groups. Each R e However, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(R) f1 )2, CN, C(O)N(Rf1 )2, S(O)N(R f1 )2, S(O)2N(R f1 )2, OR f1 , OC(OC(O)R f1 , C(O)OR f1 , S(O)R f1 S(O)2R f1 OCR f1 (O)2, R f1 N(R f1 )2, N(R f1 )R f1 C(O)R f1 N(R f11 )2, N(R f1 )S(O)R f1 , N(R f1 )R f1 S(O)2R f1 , N(R f1 )R f1 S(O)R f1 N(R f1 )2, or N(R f1 )R f1 S(O)2N(R f1 )2, and any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl are A 1 , and / or independently, oxo, halo, NO2, N(R) f1 R f1 )2, CN, C(O)N(R f1 )2, S(O)N(R f1 )2, S(O)R f1 , SR f1 ,OC(O)R f1 , N(R f1 )R f1 S(O)R f1 , N(R f1 S(O)2R f1 , carbon rings, and C optionally substituted with one or more groups independently selected from oxo and halo. 1~6 It is optionally substituted with one or more groups selected from alkyl groups. Each R f1 R f1However, independently, they are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyryl, or heterocyclyl, and any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyryl, and heterocyclyl are independently oxo, carbocyryl, heterocyclyl, halo, NO2, N(R) g1 )2, CN, C(O)N(R g1 )2, S(O)N(R g1 )2, S(O)2N(R g1 )2, O)R g1 , C(R g1 O)R g1 , R g1 C(O)R g1 , C(O)N(R g1 )2, N(R g1 )R g1 C(O)R g1 , N(R g1 )S(O)R g1 , N(R g1 )R g1 S(O)2R g1 , and are optionally substituted with one or more groups selected from C1-C6 alkyl groups, wherein the carbocyclyl and C1-C6 alkyl groups are A 1 , and / or independently, oxo, halo, C1-C6 alkyl, cyano, N(R) g1 R g1 )2, OR g1 R g1 , and are optionally substituted with one or more groups selected from heterocyclyls and carbocyclyls that are optionally substituted with one or more groups independently selected from halo and C1-C6 alkyl groups, Each R g1 However, independently, they are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyryl, or heterocyclyl, and each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyryl, and heterocyclyl is A 1, and / or independently, optionally substituted with one or more groups selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, carbocykryl, heterocyclyl, and C1-C6 alkyl groups optionally substituted with one or more groups independently selected from oxo and halo, or two R g1 However, together with the nitrogen to which they are bound, they independently form oxo, halo, and heterocyclines optionally substituted with one or more C1-C3 alkyl groups optionally substituted with one or more groups optionally substituted with one or more groups optionally substituted with oxo and halo groups. Each R h However, independently, they are hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, and each of the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is A 1 , and / or independently, substituted with one or more groups selected from C1-C3 alkyl groups that are optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and halo. R 1 , R 2 , R 3 , or R 4 Only one of them is A 1 Includes.

[0052] In some embodiments, R 1 C1~C 12 It is an alkyl group or a 3- to 12-membered heterocycle.

[0053] In some embodiments, R 1 It is methyl.

[0054] In some embodiments, R 1 This refers to 3- to 12-membered complex rings, for example, [ka] That is the case.

[0055] In some embodiments, R b H is H.

[0056] In some embodiments, R 2 R is independent c C6~C 20 It is Ariel.

[0057] In some embodiments, R 2 is, A 1 Includes.

[0058] In some embodiments, R 2 teeth, [ka] That is the case.

[0059] In some embodiments, R 2 teeth, [ka] That is the case.

[0060] In some embodiments, R c This is a C1-C6 alkyl group that is optionally substituted with one or more groups independently selected from the halo.

[0061] In some embodiments, R c It is CHF2.

[0062] In some embodiments, R 3 is one or more base R e C1~C which were replaced by arbitrary selection. 12 It is an alkyl group or a 3- to 12-membered heterocycle.

[0063] In some embodiments, R in formula (III-B) 2 and R 3Together with the nitrogen to which they are bound, they form one or more R groups e The optionally substituted 9 or 10-membered biring complex rings are formed.

[0064] In some embodiments, R in formula (III-B) 2 and R 3 Together with the nitrogen to which they are bound, they form one or more R groups e The 9- or 10-membered bicyclic heterocycle is optionally substituted, and the 9- or 10-membered bicyclic heterocycle includes at least one aromatic ring.

[0065] In some embodiments, R in formula (III-B) 2 and R 3 Together with the nitrogen to which they are bound, [ka] That is the case.

[0066] In some embodiments, [ka] That is the case.

[0067] In some embodiments, [ka] That is the case.

[0068] In some embodiments, R e H is H.

[0069] In some embodiments, R 4 C(O)R h That is the case.

[0070] In some embodiments, R 4 acetyl, for example, [ka] That is the case.

[0071] In some embodiments, R h It is methyl.

[0072] In some embodiments, the CBP binding portion has the following structure: [ka] It has.

[0073] In some embodiments, the CBP binding portion of formula (III) has the structure of formula (III-C), [ka] During the ceremony, X1 is either C or N, X2 is either C or N, R 5 However, independently, C1~C 12 Alkyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R 5 Each C1~C 12 Alkyl, 3-12 membered carbon rings, and 3-12 membered heterocycles are one or more groups R k1k It is replaced by an optional selection, R 6 However, independently, C 1~4 Alkyl, C6~C 20 Aryl, C1~C 20 Heteroaryl, (C6~C 20 Ariel) (C1~C 20 (heteroaryl), (C1~C 20 Heteroaryl)-(C6~C 20 (aryl), and (C1~C 20 Heteroaryl)-(C1~C 20 Heteroaryl), C(O)N(R h1 )2, S(O)N(R h1 )2, S(O)2, C(O)R h1, C(O)OR h1 , S(O)R h1 , or S(O)2R h1 It consists of C1-C4 alkyl and C6-C 20 Aryl, C1~C 20 Heteroaryl, (C6~C 20 Ariel)-(C1~C 20 (heteroaryl), and (C1~C 20 Heteroaryl)-(C1~C 20 Heteroaryls) independently, A 1 , and / or independently, F, Cl, Br, I, 3-5 membered carbon rings, C(O)N(R h1 )2, S(O)2N(R h1 )2, OR h1 S(O)2R h1 , OC(OR h1 , C(O)OR h1 , N(R h1 )2, N(R h1 )2, N(R h1 )C(O)N(R h1 )2, N(R h1 S(O)2R h1 , N(R h1 )S(O)N(R h1 )2, and N(R h1 )S(O)2N(R h1 ) Optionally substituted with one or more substituents selected from 2, R 7 However, independently, C6~C 20 Aryl, C1~C 20 Heteroaryl, (C6~C 20 Ariel) (C1~C 20 (heteroaryl), (C1~C 20 Heteroaryl)-(C6~C 20 (aryl), and (C1~C 20 (Heteroaryl) (C1~C 20 (Heteroaryl) and each C6~C 20 Aryl, C1~C 20 Heteroaryl, (C6~C 20 Ariel) (C1~C 20 (heteroaryl), and (C1~C 20 (Heteroaryl) (C1~C20 Heteroaryls) independently, A 1 , and / or independently, R L1 R L1 , oxo, F, Cl, Br, I, NO2, N(R) a1 )2, CN, C(O)N(R a1 )2, S(O)N(R a1 )2, S(O)2N(R a1 )2, N(R a1 )C(O)R a1 )C(O)OR a1 , S(O)R a1 , N(R a1 )S(O)2R a1 , N(R a1 )S(O)N(R a1 )2, and N(R a1 )S(O)2N(R a1 ) Optionally substituted with one or more substituents selected from 2, Each R a1 However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, and heterocyclyl, and each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, and heterocyclyl is independently oxo, halo, amino, hydroxyl, C1-C6 alkoxy, carbocykrill, heterocyclyl, or A 1 Furthermore / or optionally substituted with one or more groups selected from C1-C6 alkyl groups, which are independently substituted with one or more groups selected from oxo and halo groups, or two R groups a1 However, together with the nitrogen to which they are bound, they independently form oxo, halo, and heterocyclines optionally substituted with one or more C1-C3 alkyl groups optionally substituted with one or more groups optionally substituted with one or more groups optionally substituted with oxo and halo groups. Each R k1 However, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(R) L1 )2, CN, C(O)N(R L1)2, S(O)N(R L1 )2, S(O)2N(R L1 )2, OR L1 , OC(R L1 OC(O)R L1 , R L1 C(O)OR L1 , C(O)OR L1 , N(R L1 )R L1 C(O)R L1 N(R L1 )2, R L1 N(R L1 )2, N(R L1 )S(O)R L1 , N(R L1 )R L1 S(O)R L1 , R L1 N(R L1 )R L1 S(O)R L1 N(R L1 )2, or N(R L1 )R L1 S(O)2N(R L1 )2, and any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl can independently be oxo, halo, NO2, N(R) L1 R L1 )2, CN, C(O)N(R L1 R L1 )2, S(O)N(R L1 )2, S(O)2N(R L1 )R L1 , S(O)R L1 S(O)2R L1 , and optionally substituted with one or more groups selected from C1-C6 alkyl groups, which are independently substituted with one or more groups selected from oxo and halo groups. Each R L1 However, independently, hydrogen, C1-C6 alkyl, C 2~6 Alkenil, C 2~6 Alkynyl, carbocyrill, or heterocyclyl, any C1-C6 alkyl, C 2~6 Alkenil, C 2~6Alkinyl, carbocyclyl, and heterocyclyl are independently oxo, carbocyclyl, heterocyclyl, halo, NO2, N(R) d1 )2, CN, C(O)N(R d1 )2, S(O)N(R d1 )2, S(O)2N(R d1 )2, OR d1 , SR d1 , C(O)R d1 , S(O)R d1 , C(O)N(R d1 )2, N(R d1 )C(O)R d1 , N(R d1 )S(O)R d1 , N(R d1 )S(O)2R d1 , and optionally substituted with one or more groups selected from C1-C6 alkyl groups, wherein the carbocyclyl and C1-C6 alkyl groups are independently oxo, halo, C1-C6 alkyl, cyano, N(R) d1 )2, OR d1 , and are optionally substituted with one or more groups selected from heterocyclyls and carbocyclyls that are optionally substituted with one or more groups independently selected from halo and C1-C6 alkyl groups, Each R d1 However, independently, they are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyryl, or heterocyclyl, and each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyryl, and heterocyclyl is independently optionally substituted with one or more groups selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, carbocyryl, heterocyclyl, and C1-C6 alkyl which are optionally substituted with one or more groups independently selected from oxo and halo, or two R d1 However, together with the nitrogen to which they are bound, they independently form oxo, halo, and heterocyclines optionally substituted with one or more C1-C6 alkyl groups optionally substituted with one or more groups optionally substituted with one or more groups optionally substituted with oxo and halo groups. Each R h1 is independently hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C 2~5 cycloalkyl, and each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is independently optionally substituted with one or more groups selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and independently halo-substituted C1-C 44 alkyl selected from alkyl, R 7 is A 1 including.

[0074] In some embodiments, the CBP binding moiety has the structure of Formula IV,

Chemical formula

[0075] In some embodiments, R 12 teeth, [ka] That is the case.

[0076] In some embodiments, the CBP binding portion of formula IV has the structure: [ka] It has.

[0077] In some embodiments, R 11 teeth, [ka] That is the case.

[0078] In some embodiments, R 13 C1~C 20 Heteroaryls, for example, [ka] That is the case.

[0079] In some embodiments, R 13 , NR 2 R 3 ,for example, [ka] That is the case.

[0080] In some embodiments, R 13 C1~C 20 Heteroaryls, for example, [ka] That is the case.

[0081] In some embodiments, the CBP binding portion of formula IV has the structure: [ka] It has.

[0082] In some embodiments, the decomposition portion (B) is a ubiquitin ligase binding portion.

[0083] In some embodiments, the degraded portion (B) includes cereblon ligand, IAP (inhibitor of apoptosis) ligand, mouse dual micro2 homolog (MDM2), or von Hippel-Lindau (VHL) ligand, or derivatives or analogs thereof.

[0084] In some embodiments, the disassembled part (B) includes the structure of formula V, [ka] During the ceremony, R B1a However, independently, H, A 2 , C(O)A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2a However, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B3a However, A 2 , C(O)A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, or optionally replaced with C6-C 10 It is Ariel, R B4a However, independently, H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 10 Carbocyclyl, or optionally replaced with C6-C10 It is Ariel, R B5a However, independently, H and C are substituted by choice. 1~6 Alkyl or optionally substituted C 1~6 It is heteroalkyl, R B6a However, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl or arylalkyl, R B1a and R B3a Only one of them is A 2 or C(O)A 2 That is the case.

[0085] In some embodiments, the decomposition part (B) of formula (V) includes the structure of formula (VA), [ka] During the ceremony, R B1a However, independently, H, A 2 , C(O)A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2a However, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B3a However, A 2 , C(O)A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, or optionally replaced with C6-C 10 It is Ariel, R B4a However, independently, H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 10 Carbocyclyl, or optionally replaced with C6-C 10 It is Ariel, R B5a However, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B6a However, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl or arylalkyl, R B1a and R B3a Only one of them is A 2 or C(O)A 2 That is the case.

[0086] In some embodiments, the decomposition part (B) of equation (V) includes the structure of equation (VB), [ka] During the ceremony, R B1a However, independently, H, A 2 , C(O)A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2a However, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B3a However, A 2 , C(O)A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, or optionally replaced with C6-C 10 It is Ariel, R B4a However, independently, H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 10 Carbocyclyl, or optionally replaced with C6-C 10 It is Ariel, R B5a However, independently, H and C are substituted by choice. 1~6Alkyl or optionally substituted C 1~6 It is heteroalkyl, R B6a However, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl or arylalkyl, R B1a and R B3a Only one of them is A 2 or C(O)A 2 That is the case.

[0087] In some embodiments, R B6a teeth, [ka] And, In the formula, each R B6 However, independently, halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, and optionally substituted C3-C6 alkyls 10 Carbocyclyl, C2-C9 heterocyclyls substituted with optional substitution, C6-C9 heterocyclyls substituted with optional substitution 10 These include aryls, optionally substituted C2-C9 heteroaryls, optionally substituted C2-C6 alkenyls, optionally substituted C2-C6 heteroalkenyls, optionally substituted C2-C6 alkynyls, hydroxyls, and thiols. R B9 However, independently, they are H, or optionally substituted C1-C6 alkyl groups. R B10 However, independently, they are H, or optionally substituted C1-C6 alkyl groups. v2 is 0, 1, 2, 3, or 4.

[0088] In some embodiments, R B6a teeth, [ka] That is the case.

[0089] In some embodiments, R B6a teeth, [ka] That is the case.

[0090] In some embodiments, R B6 teeth, [ka] That is the case.

[0091] In some embodiments, R B6 teeth, [ka] That is the case.

[0092] In some embodiments, R B6a teeth, [ka] And, During the ceremony, Each R B6 However, independently, halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, and optionally substituted C3-C6 alkyls 10 Carbocyclyl, C2-C9 heterocyclyls substituted with optional substitution, C6-C9 heterocyclyls substituted with optional substitution 10 These include aryls, optionally substituted C2-C9 heteroaryls, optionally substituted C2-C6 alkenyls, optionally substituted C2-C6 heteroalkenyls, optionally substituted C2-C6 alkynyls, hydroxyls, and thiols. R B11 However, C3~C were replaced by arbitrary selection. 10 Carbocyclyl, C2-C9 heterocyclyls substituted with optional substitution, C6-C9 heterocyclyls substituted with optional substitution 10These are aryls, and C2-C9 heteroaryls that have been optionally substituted. R B9 However, independently, they are H, or optionally substituted C1-C6 alkyl groups. R B10 However, independently, they are H, or optionally substituted C1-C6 alkyl groups. v2 is 0, 1, 2, 3, or 4.

[0093] In some embodiments, R B11 teeth, [ka] That is the case.

[0094] In some embodiments, R B11 teeth, [ka] That is the case.

[0095] In some embodiments, R B6a teeth, [ka] That is the case.

[0096] In some embodiments, R B6a teeth, [ka] That is the case.

[0097] In some embodiments, R B6a teeth, [ka] That is the case.

[0098] In some embodiments, RB6a teeth, [ka] That is the case.

[0099] In some embodiments, R B6a teeth, [ka] And, In the formula, v2 is 0, 1, 2, 3, or 4. Each R B6 However, independently, halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, and optionally substituted C3-C6 alkyls 10 Carbocyclyl, C2-C9 heterocyclyls substituted with optional substitution, C6-C9 heterocyclyls substituted with optional substitution 10 The aryl group is an aryl group, an optionally substituted C2-C9 heteroaryl group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C2-C6 heteroalkenyl group, a hydroxyl group, a thiol group, or an optionally substituted amino group. R B7 and R B8 Each of these can independently be H, a halogen, an optionally substituted C1-C6 alkyl, or an optionally substituted C6-C 10 It is Ariel, R B9 and R B10 However, these are independently H or C1-C6 alkyl groups that are optionally substituted.

[0100] In some embodiments, R B6a teeth, [ka] And, In the formula, v2 is 0, 1, 2, 3, or 4. Each R B6However, independently, halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, and optionally substituted C3-C6 alkyls 10 Carbocyclyl, C2-C9 heterocyclyls substituted with optional substitution, C6-C9 heterocyclyls substituted with optional substitution 10 The aryl group is an aryl group, an optionally substituted C2-C9 heteroaryl group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C2-C6 heteroalkenyl group, a hydroxyl group, a thiol group, or an optionally substituted amino group. R B7 and R B8 Each of these can independently be H, a halogen, an optionally substituted C1-C6 alkyl, or an optionally substituted C6-C 10 It is Ariel, R B9 and R B10 However, these are independently H or C1-C6 alkyl groups that are optionally substituted.

[0101] In some embodiments, R B6a That is.

[0102] In some embodiments, R B6a teeth, [ka] That is the case.

[0103] In some embodiments, R B6a teeth, [ka] That is the case.

[0104] In some embodiments, the decomposition part of formula V is structure: [ka] [ka] It has derivatives or analogues thereof.

[0105] In some embodiments, the decomposition part (B) of equation (V) is the structure of equation (VC), [ka] During the ceremony, R B1 However, independently, H, A 2 , C(O)A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B3 However, A 2 , C(O)A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 Aryl, optionally substituted C1-C6 alkyl, C3-C 10 Carbocyclyl, or optionally substituted C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 10 Carbocyclyl, C6~C 10 Aryl, C1-C6 alkyl, C3-C 10 Carbocyclyl, or C6~C 10 A 2 and / or R J2 It is replaced by one of the more numerous groups, R B4 However, independently, H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 Aryl, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C1-C6 alkyl, or optionally substituted C6-C 10 It is Ariel, R B5 However, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, v2 is independently 0, 1, 2, 3, or 4. Each R B6 However, independently, halogens, optionally substituted C1-C6 alkyls, and optionally substituted C 1~6 Heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, C2-C9 heterocyclyls substituted with optional substitution, C6-C9 heterocyclyls substituted with optional substitution 10 These include aryls, optionally substituted C2-C9 heteroaryls, optionally substituted C2-C6 alkenyls, optionally substituted C2-C6 heteroalkenyls, optionally substituted C2-C6 alkynyls, hydroxyls, and thiols. R B9 However, independently, they are H, or optionally substituted C1-C6 alkyl groups. Each R J2 However, independently, hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 12 Carbocyclyl and optionally substituted C3-C 12 It is a heterocycline, with each C1-C6 alkyl and C3-C 12 Carbocyclyl, and C3~C 12 Heterocyclines can independently be amino, hydroxyl, thio, C1-C6 alkoxy, and C3-C6. 12 Carbocyclyl, C3~C 12 Heterocycline, or A 2 Furthermore / or optionally substituted with one or more groups selected from C1-C6 alkyl groups, which are independently substituted with one or more groups selected from oxo and halo groups. R B1 and R B3 One of them is A 2 or C(O)A 2 The structure, or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, R B9 H is H.

[0107] In some embodiments, R B9 These are C1-C6 alkyl groups that have been optionally substituted.

[0108] In some embodiments, R B9 It is methyl.

[0109] In some embodiments, R B4 H is H.

[0110] In some embodiments, R B5 H is H.

[0111] In some embodiments, R B1 is, A 2 That is the case.

[0112] In some embodiments, R B1 C(O)A 2 That is the case.

[0113] In some embodiments, R B3 These are C1-C6 alkyl groups that have been optionally substituted.

[0114] In some embodiments, R B3 teeth, [ka] That is the case.

[0115] In some embodiments, R B6 These are C2-C9 heteroaryls that have been optionally substituted.

[0116] In some embodiments, R B6 teeth, [ka] That is the case.

[0117] In some embodiments, the structure of formula V-CC is, [ka] [ka] or its derivatives or analogues.

[0118] In some embodiments, R B6 These are halogens or optionally substituted C2-C6 alkynyl compounds.

[0119] In some embodiments, R B6 These are C1-C6 heteroalkyls that have been optionally substituted.

[0120] In some embodiments, the optionally substituted C1-C6 heteroalkyl group is methoxy.

[0121] In some embodiments, the structure of the expression VC is, [ka] , or its derivatives or analogs.

[0122] In some embodiments, the decomposition part of formula (V) has the structure of formula VD, [ka] During the ceremony, R B1 However, independently, H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B2However, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B3 However, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, or optionally replaced with C6-C 10 It is Ariel, R B4 However, independently, H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 10 Carbocyclyl, or optionally replaced with C6-C 10 It is Ariel, R B5 However, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, v2 is independently 0, 1, 2, 3, or 4. Each R B6 However, independently, halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, and optionally substituted C3-C6 alkyls 10 Carbocyclyl, C2-C9 heterocyclyls substituted with optional substitution, C6-C9 heterocyclyls substituted with optional substitution 10 The aryl group is an aryl group, an optionally substituted C2-C9 heteroaryl group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C2-C6 heteroalkenyl group, a hydroxyl group, a thiol group, or an optionally substituted amino group. R B7 and R B8 Each of these can independently be H, a halogen, an optionally substituted C1-C6 alkyl, or an optionally substituted C6-C 10 It is Ariel, R B9 and R B10 However, independently, they are H or optionally substituted C1-C6 alkyl groups. R B1 and R B3 One of them is A2 The structure, or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, R B1 H is H.

[0124] In some embodiments, R B1 is, A 2 That is the case.

[0125] In some embodiments, R B2 H is H.

[0126] In some embodiments, R B3 is an optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl, and any C1-C6 alkyl and C1-C6 heteroalkyl can independently be oxo, halo, NO2, N(R) f3 )2, CN, C(O)N(R f3 )2, S(O)N(R f3 )2, S(O)2N(R f3 )2, O)R f3 , C(R f3 O)R f3 , R f3 C(O)R f3 , C(O)N(R f3 )2, N(R f3 )R f3 C(O)R f3 , R f3 N(R f3 )S(O)R f3 , N(R f3 )R f3 S(O)2R f3 The carbon ring is optionally substituted with one or more groups selected from C1-C6 alkyl groups, which are optionally substituted with one or more groups independently selected from oxo and halo groups.

[0127] In some embodiments, R B3 teeth, [ka] That is the case.

[0128] In some embodiments, R B3 teeth, [ka] That is the case.

[0129] In some embodiments, R B4 H is H.

[0130] In some embodiments, R B5 H is H.

[0131] In some embodiments, R B6 H is H.

[0132] In some embodiments, R B7 C is replaced by H or of any choice. 1~6 It is alkyl.

[0133] In some embodiments, R B7 It is methyl.

[0134] In some embodiments, R B8 H is H.

[0135] In some embodiments, R B9 is replaced by H or C of any choice. 1~6 It is alkyl.

[0136] In some embodiments, R B9 H is H.

[0137] In some embodiments, R B9 It is methyl.

[0138] In some embodiments, R B10 is replaced by H or C of any choice. 1~6 It is alkyl.

[0139] In some embodiments, R B10 H is H.

[0140] In some embodiments, R B10 It is methyl.

[0141] In some embodiments, the structure of formula V-DD is, [ka] or its derivatives or analogues.

[0142] In some embodiments, the disassembled part is structured as follows: [ka] It has.

[0143] In some embodiments, the disassembled part is structured as follows: [ka] It has.

[0144] In some embodiments, the decomposed part has the structure of formula VE, [ka] R C1 However, they are independently and optionally substituted C1-C6 alkyl groups. R C2 However, A 2 , or A 2 and / or one or more base R J substituted by choice, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 alkyl 10 Carbocyclyl, optionally replaced with C6-C 10It is an aryl or C2-C9 heteroaryl, R C3 However, independently, H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 10 Carbocyclyl, or optionally replaced with C6-C 10 It is Ariel, R C4 However, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, v2 is independently 0, 1, 2, 3, or 4. R C5 and R C6 Each of these is independently a C1-C6 alkyl group substituted with H or optionally. Each R C7 However, independently, halogens, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, and optionally substituted C3-C6 alkyls 10 Carbocyclyl, C2-C9 heterocyclyls substituted with optional substitution, C6-C9 heterocyclyls substituted with optional substitution 10 The aryl group is an aryl group, an optionally substituted C2-C9 heteroaryl group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C2-C6 heteroalkenyl group, a hydroxyl group, a thiol group, or an optionally substituted amino group. R C8 and R C9 Each of these can independently be H, a halogen, an optionally substituted C1-C6 alkyl, or an optionally substituted C6-C 10 It is Ariel, Each R J However, independently, these are hydrogen, C1-C6 alkyl, carbocykrill, and heterocyclyl, and each C1-C6 alkyl, carbocykrill, and heterocyclyl is independently amino, hydroxyl, C1-C6 alkoxy, carbocykrill, heterocyclyl, or A 2 , and / or optionally substituted with one or more groups selected from C1-C6 alkyl groups, independently selected from oxo and halo groups, or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, R C1 teeth, [ka] That is the case.

[0146] In some embodiments, R C2 is, A 2 These are C2-C9 heteroaryls that have been optionally substituted.

[0147] In some embodiments, R C3 H is H.

[0148] In some embodiments, R C4 H is H.

[0149] In some embodiments, v2 is 0.

[0150] In some embodiments, R C5 and R C6 Each of them is independently either H or methyl.

[0151] In some embodiments, R C8 and R C9 Each of them is independently either H or methyl.

[0152] In some embodiments, the disassembled part is structured as follows: [ka] It has derivatives or analogues thereof.

[0153] In some embodiments, the decomposition portion of equation (V) has the structure of equation V-FF, [ka] During the ceremony, R B1 However, independently, H, A 2 , C(O)A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, R B3 However, A 2 , C(O)A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, or optionally replaced with C6-C 10 It is Ariel, R B4 However, independently, H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 10 Carbocyclyl, or optionally replaced with C6-C 10 It is Ariel, R B5 However, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl or arylalkyl, R B1 and R B3 One of them is A 2 or C(O)A 2 The structure, or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, R B4 H is H.

[0155] In some embodiments, R B5 H is H.

[0156] In some embodiments, R B1 is, A 2 That is the case.

[0157] In some embodiments, R B1 C(O)A 2 That is the case.

[0158] In some embodiments, R B3 These are C1-C6 alkyl groups that have been optionally substituted.

[0159] In some embodiments, R B3 teeth, [ka] That is the case.

[0160] In some embodiments, the decomposition part has the structure of formula VG: [ka] It has derivatives or analogues thereof.

[0161] In some embodiments, the compound is one of the compounds listed in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 [Table 1-64] [Table 1-65] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0162] In another embodiment, the present disclosure features a pharmaceutical composition comprising any of the aforementioned compounds or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0163] In another embodiment, the present invention is characterized by a method for reducing intracellular CBP levels and / or activity, comprising contacting cells with an effective amount of any of the aforementioned compounds or a pharmaceutically acceptable composition thereof.

[0164] In another embodiment, the present invention is characterized by a method for reducing the level or activity of MYC in cells, comprising contacting cells with an effective amount of any of the aforementioned compounds or a pharmaceutically acceptable composition thereof.

[0165] In another embodiment, the present invention is characterized by a method for reducing intracellular AR, i.e., androgen receptor levels or activity, comprising contacting the cells with an effective amount of any of the aforementioned compounds or a pharmaceutically acceptable composition thereof.

[0166] In some embodiments, the cells are cancer cells.

[0167] In another embodiment, the present invention relates to a method for treating a CBP-related disorder in a subject requiring treatment, the method comprising administering to the subject an effective amount of any of the aforementioned compounds or a pharmaceutically acceptable composition thereof.

[0168] In some embodiments, the CBP-related disorder is cancer.

[0169] In further embodiments, the present invention relates to a method for inhibiting CBP, comprising contacting cells with an effective amount of any of the aforementioned compounds or a pharmaceutically acceptable composition thereof. In some embodiments, the cells are cancer cells.

[0170] In one embodiment, the present disclosure is characterized by a method for inhibiting intracellular CBP levels and / or activity, comprising contacting cells with an effective amount of any of the aforementioned compounds, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0171] In another embodiment, the present invention relates to a method for treating a disorder associated with the EP300 loss of function mutation in a subject, the method comprising administering to the subject an effective amount of any of the aforementioned compounds or a pharmaceutically acceptable composition thereof.

[0172] In some embodiments, the disorder associated with EP300 loss-of-function mutations is cancer. In other embodiments, the subject is determined to have an EP300 loss-of-function disorder, for example, to have EP300 loss-of-function cancer (for example, the cancer is determined to include cancer cells with loss of EP300 function).

[0173] In another embodiment, the present invention is characterized by a method for inducing apoptosis in cells, comprising contacting the cells with an effective amount of any of the aforementioned compounds or a pharmaceutically acceptable composition thereof. In some embodiments, the cells are cancer cells.

[0174] In a further embodiment, the present invention relates to a method for treating cancer in a subject requiring treatment, the method comprising administering to the subject an effective amount of any of the aforementioned compounds or a pharmaceutically acceptable composition thereof.

[0175] In some embodiments, cancer is malignant rhabdoid tumor, CD8+ T-cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, head and neck cancer, gastric cancer, renal cell carcinoma, melanoma, colorectal cancer, sarcoma (e.g., soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, fibroplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi's sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymal tumor, malignant peripheral nerve sheath tumor, myxoid fibrosarcoma, low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T-cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, neuroblastoma, or colorectal cancer. In some embodiments, the cancer is sarcoma (e.g., synovial sarcoma or Ewing's sarcoma), non-small cell lung cancer (e.g., squamous cell or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is sarcoma (e.g., synovial sarcoma or Ewing's sarcoma). In some embodiments, the sarcoma is synovial sarcoma.

[0176] In some embodiments of the methods described above, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, head and neck cancer, prostate cancer, acute leukemia, gastric cancer, or breast cancer.

[0177] In some embodiments, the cancer is gastric cancer.

[0178] In some embodiments, breast cancer is found to be ER-positive, meaning that cancer cells contain estrogen receptors.

[0179] In some embodiments, breast cancer is found to be ER-negative, meaning that the cancer cells do not contain estrogen receptors.

[0180] In some embodiments, prostate cancer is found to be AR-positive, meaning that cancer cells contain androgen receptors.

[0181] In some embodiments, the prostate cancer is CRPC, or castration-resistant prostate cancer.

[0182] In some embodiments, the prostate cancer is CRPC, or castration-sensitive prostate cancer.

[0183] In one embodiment, the present disclosure provides a method for treating a CBP-related disorder in a subject requiring treatment, the method comprising administering to the subject an effective amount of any of the aforementioned compounds, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof. In some embodiments, the CBP-related disorder is cancer. In some embodiments, the CBP-related disorder is an infection.

[0184] In some embodiments, cancers include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancers of the bladder, intestines, breasts, cervix, colon, esophagus, head, kidneys, liver, lungs, neck, ovaries, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, and peripheral neuroepithelioma. These include synovial sarcoma, glioma, astrocytoma, oligodendronoma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, and sarcomas including Schwannoma, as well as intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma, carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratoma. Additional cancers that may be treated using the compounds disclosed according to the present invention include, for example, acute granulocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenocortical carcinoma, anal carcinoma, anaplastic astrocytoma, angiosarcoma, appendiceal carcinoma, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, bladder carcinoma, bone carcinoma, bone marrow carcinoma, intestinal carcinoma, brain carcinoma, brainstem glioma, breast carcinoma, triple (estrogen, progesterone, and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone, and HER-2 are negative), and single negative (estrogen, progesterone, and H Breast cancer (one of ER-2 is negative), estrogen receptor positive, HER2 negative, estrogen receptor negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2 negative breast cancer, HER2 positive or negative breast cancer, progesterone receptor negative breast cancer, progesterone receptor positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, extrahepatic cholangiocarcinoma, eye cancercancer), fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumor (GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer Cancer, hemangioendothelioma, Hodgkin's lymphoma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal cancer, intrahepatic cholangiocarcinoma, invasive / invasive breast cancer, islet cell carcinoma, jaw cancer, Kaposi Sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous cell carcinoma of the neck, mixed glioma, monodermal teratoma, oral cancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), ophthalmic cell carcinoma, ocular cancer Cancer, intraocular melanoma, oligodendroglioma, oral cancer, oral cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, primary peritoneal cancer of the ovary, ovarian cord-stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal gland tumor, pineoblastoma, pituitary cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma sarcoma), sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spine cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), testicular cancer, throat cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube carcinoma, tubular carcinoma carcinoma), undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-BALL, Pre-B lymphoma, Large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, Juvenile myelomonocytic leukemia (JMML), Acute promyelocytic leukemia (AML subtype), Large granular lymphocytic leukemia, Adult T-cell chronic leukemia, Diffuse large B-cell lymphoma, Follicular lymphoma, Mucosa-associated lymphoid tissue lymphoma (MALT), Small cell lymphocytic lymphoma, Mediastinal large B-cell lymphoma, Nodal marginal zone B-cell lymphoma (NMZL), Splenic marginal zone lymphoma (SMZL), Intravascular large B-cell lymphoma, Primary exudative lymphoma, or lymphomatoid granulomatosis, B-cell prelymphocytic leukemia, Unclassified splenic lymphoma / leukemia, Diffuse red pulp small B-cell lymphoma, Lymphoid Examples include plasmacytic lymphoma, heavy chain disease (e.g., α-heavy chain disease, γ-heavy chain disease, μ-heavy chain disease), plasmacytic myeloma, solitary plasmacytoma of bone, extraskeletal plasmacytoma, primary cutaneous follicular lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, DLBCL associated with chronic inflammation, Epstein-Barr virus (EBV) + DLBCL in the elderly, primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL lower extremity type, ALK + large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma occurring in HHV8-associated multicentric Castleman disease, unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, or unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0185] In some embodiments of the methods described above, the cancer is either drug-resistant or has not responded to previous therapies (e.g., vemurafenib, dacarbazine, CTLA4 inhibitors, PD1 inhibitors, interferon therapy, BRAF inhibitors, MEK inhibitors, radiotherapy, temozolomide, irinotecan, CAR-T therapy, platinum agents such as Herceptin, Perjeta, tamoxifen, Xeloda, docetaxol, and carboplatin, taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inhibitors, Alimta, Abraxane, Adriamycin®, gemcitabine, Avastin, Halaven, neratinib, PARP inhibitors, ARN810, mTOR inhibitors, topotecan, gemzar, VEGFR2 inhibitors, folate receptor antagonists, demcizumab, fosbletabrin, or PDL1 inhibitors).

[0186] In some embodiments, cancers include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancers of the bladder, intestines, breasts, cervix, colon, esophagus, head, kidneys, liver, lungs, neck, ovaries, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, and peripheral neuroepithelioma. These include synovial sarcoma, glioma, astrocytoma, oligodendronoma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, and sarcomas including Schwannoma, as well as intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma, carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratoma. Additional cancers that may be treated using the compounds disclosed according to the present invention include, for example, acute granulocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenocortical carcinoma, anal carcinoma, anaplastic astrocytoma, angiosarcoma, appendiceal carcinoma, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, bladder carcinoma, bone carcinoma, bone marrow carcinoma, intestinal carcinoma, brain carcinoma, brainstem glioma, breast carcinoma, triple (estrogen, progesterone, and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone, and HER-2 are negative), and single negative (estrogen, progesterone, and H Breast cancer (one of ER-2 is negative), estrogen receptor positive, HER2 negative, estrogen receptor negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2 negative breast cancer, HER2 positive or negative breast cancer, progesterone receptor negative breast cancer, progesterone receptor positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, extrahepatic cholangiocarcinoma, eye cancercancer), fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumor (GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer Cancer, hemangioendothelioma, Hodgkin's lymphoma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal cancer, intrahepatic cholangiocarcinoma, invasive / invasive breast cancer, islet cell carcinoma, jaw cancer, Kaposi Sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous cell carcinoma of the neck, mixed glioma, monodermal teratoma, oral cancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), ophthalmic cell carcinoma, ocular cancer Cancer, intraocular melanoma, oligodendroglioma, oral cancer, oral cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, primary peritoneal cancer of the ovary, ovarian cord-stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal gland tumor, pineoblastoma, pituitary cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma sarcoma), sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spine cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma / thymic cancer, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, fallopian tube cancer, tubular cancer carcinoma), undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-BALL, Pre-B lymphoma, Large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, Juvenile myelomonocytic leukemia (JMML), Acute promyelocytic leukemia (AML subtype), Large granular lymphocytic leukemia, Adult T-cell chronic leukemia, Diffuse large B-cell lymphoma, Follicular lymphoma, Mucosa-associated lymphoma Medial lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma (NMZL), diffuse large B-cell lymphoma (DLBCL), splenic marginal zone lymphoma (SMZL), intravascular large B-cell lymphoma, primary exudative lymphoma, or lymphomatous granulomatosis, B-cell prelymphocytic leukemia, unclassifiable splenic lymphoma / leukemia, diffuse red pulp small B-cell lymphoma Examples include cellular lymphomas, lymphoplasmacytic lymphomas, heavy chain diseases such as α-heavy chain disease, γ-heavy chain disease, μ-heavy chain disease, plasmacytogenic myeloma, solitary plasmacytoma of bone, extraskeletal plasmacytoma, primary cutaneous follicular lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, DLBCL associated with chronic inflammation, Epstein-Barr virus (EBV) + DLBCL in the elderly, primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL lower extremity type, ALK + large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease, unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, or unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0187] In some embodiments, cancer is malignant rhabdoid tumor, CD8+ T-cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, sarcoma (e.g., soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, fibroplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi's sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymal tumor, malignant peripheral nerve sheath tumor, myxoid fibrosarcoma, low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T-cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colorectal cancer. In some embodiments, the cancer is sarcoma (e.g., synovial sarcoma or Ewing's sarcoma), non-small cell lung cancer (e.g., squamous cell or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is sarcoma (e.g., synovial sarcoma or Ewing's sarcoma). In some embodiments, the sarcoma is synovial sarcoma.

[0188] In some embodiments of the methods described above, the cancer has or is determined to have a CBP mutation. In some embodiments of the methods described above, the CBP mutation is homozygous. In some embodiments of the methods described above, the cancer does not have or is determined to have an epidermal growth factor receptor (EGFR) mutation. In some embodiments of the methods described above, the cancer does not have or is determined to have an EP300 mutation. In some embodiments of the methods described above, the cancer does not have or is determined to have an EP300 mutation. In some embodiments of the methods described above, the cancer does not have or is determined to have an anaplastic lymphoma kinase (ALK) driver mutation. In some embodiments of the methods described above, the cancer has or is determined to have a KRAS mutation. In some embodiments of the methods described above, the CBP mutation is a chromosomal translocation.

[0189] In another aspect, the disclosure provides a method for treating a CBP-related disorder (e.g., cancer or viral infection) in a subject requiring treatment. The method involves contacting cells with an effective amount of any of the aforementioned compounds or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, the impairment is caused by retroviridae such as lentiviruses (e.g., human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T-cell leukemia virus type 1 (HTLV-I), human T-cell leukemia virus type 2 (HTLV-II)), hepadnaviridae (e.g., hepatitis B virus (HBV)), flaviviridae (e.g., hepatitis C virus (HCV)), adenoviridae (e.g., human adenovirus), herpesviridae (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), human herpesvirus type 6 (HHV-6), herpesvirus K*, CMV, varicella-zoster virus), and papillomaviridae (e.g., human papillomavirus (HPV, HPV)). E1)) is a viral infection, which is an infection caused by viruses of the parvoviridae family (e.g., parvovirus B19), polyomaviridae family (e.g., JC virus and BK virus), paramyxoviridae family (e.g., measles virus), or togaviridae family (e.g., rubella virus). In some embodiments, the disorder is coffin sillis, neurofibromatosis (e.g., NF-1, NF-2, or schwannomatosis), or multiple meningiomas.

[0190] In another embodiment, the present disclosure provides a method for treating gastric cancer in a subject requiring treatment, the method comprising administering to the subject an effective amount of the compound of the present disclosure or a pharmaceutically acceptable composition thereof.

[0191] In another aspect, the Disclosure provides a method for treating an inflammatory and / or autoimmune disorder in a subject requiring treatment, comprising administering an effective amount of the compound or a pharmaceutically acceptable composition of the compound or subject.

[0192] In some embodiments, inflammatory and / or autoimmune disorders include rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, scarring alopecia, Crohn's disease, graft-versus-host disease, systemic lupus erythematosus, Ecardi-Goutier syndrome, Sjögren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or psoriasis vulgaris.

[0193] In some embodiments, inflammatory and / or autoimmune disorders include moderate to severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiological axial spondyloarthritis, moderate to severe active ulcerative colitis, Crohn's disease, refractory moderate to severe atopic dermatitis, moderate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, moderate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 10⁹ / L, polycythemia vera, steroid-refractory graft-host disease, chronic graft-versus-host disease, or juvenile idiopathic arthritis of a particular course.

[0194] In some embodiments, inflammatory and / or autoimmune disorders include noninfectious non-anterior uveitis, dermatomyositis, scarring alopecia, alopecia areata, rheumatoid arthritis, non-segmental vitiligo, pyoderma gangrenosum, onychopsoriasis, lichen planus pilaris, inflammatory hereditary dermatopathy, palmoplantar pustulosis, moderate to severe psoriasis vulgaris, alopecia areata, Sjögren's syndrome, or systemic lupus erythematosus.

[0195] In some embodiments, inflammatory and / or autoimmune disorders include rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, scarring alopecia, Crohn's disease, graft-versus-host disease, systemic lupus erythematosus, Ecardi-Goutier syndrome, Sjögren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and psoriasis vulgaris.

[0196] In some embodiments, the method further includes administering a JAK inhibitor to the subject.

[0197] In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.

[0198] In another aspect, the Disclosure provides a method for treating a disease, disorder, or condition mediated by components of the JAK-STAT pathway, comprising administering an effective amount of a compound of the Disclosure to a subject.

[0199] In some embodiments, the component of the JAK-STAT pathway is Janus kinase (JAK).

[0200] In some embodiments, the components of the JAK-STAT pathway are signaling and transcriptional activators (STATs).

[0201] In some embodiments, the mediated diseases, disorders, or conditions by components of the JAK-STAT pathway include rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, scarring alopecia, Crohn's disease, graft-versus-host disease, systemic lupus erythematosus, Ecardi-Goutier syndrome, Sjögren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, psoriasis vulgaris, or myelofibrosis.

[0202] In some embodiments, the diseases, disorders, or conditions mediated by components of the JAK-STAT pathway include moderate to severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiological axial spondyloarthritis, moderate to severe active ulcerative colitis, Crohn's disease, refractory moderate to severe atopic dermatitis, moderate or high-risk primary or secondary (post-polycythemia or post-essential thrombocythemia) myelofibrosis, moderate or high-risk primary or secondary (post-polycythemia or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 10⁹ / L, polycythemia, steroid-refractory graft-host disease, chronic graft-versus-host disease, or juvenile idiopathic arthritis of a specific course.

[0203] In some embodiments, the diseases, disorders, or conditions mediated by components of the JAK-STAT pathway include noninfectious non-anterior uveitis, dermatomyositis, scarring alopecia, alopecia areata, rheumatoid arthritis, non-segmental vitiligo, pyoderma gangrenosum, onychopsoriasis, lichen planus pilaris, inflammatory hereditary dermatopathy, palmoplantar pustulosis, moderate to severe psoriasis vulgaris, alopecia areata, Sjögren's syndrome, or systemic lupus erythematosus.

[0204] In some embodiments, the diseases, disorders, or conditions mediated by components of the JAK-STAT pathway include rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, scarring alopecia, Crohn's disease, graft-versus-host disease, systemic lupus erythematosus, Ecardi-Goutier syndrome, Sjögren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and psoriasis vulgaris.

[0205] In another aspect, the Disclosure provides a method for inducing immune tolerance in a subject requiring it, comprising administering an effective amount of the compound or a pharmaceutically acceptable composition of the compound or subject.

[0206] In another aspect, the Disclosure provides a method for inhibiting an inflammatory or autoimmune response in a subject requiring inhibition, comprising administering an effective amount of the compound or a pharmaceutically acceptable composition of the compound or subject.

[0207] In another aspect, the disclosure relates to the storage of CD8 in subjects that have or are at risk of developing an inflammatory response. + The present invention provides a method for suppressing a T cell response, comprising administering an effective amount of the compound or a pharmaceutically acceptable composition thereof to a subject.

[0208] Aspects of the present invention relate to methods for treating CBP-related disorders such as inflammation and / or autoimmune disorders in subjects requiring treatment. In some embodiments, the compound (a) T cells (e.g., CD8) + It is administered in an effective dose and for a duration effective to produce one (or more, e.g., two or more, three or more, four or more) of the following: (b) reduced memory T cell activity, (c) reduced inflammation, (d) reduced thrombus formation, (e) reduced B cell proliferation, (e) increased survival rate of the subject, and (f) increased progression-free survival of the subject.

[0209] In some embodiments, treating inflammatory disorders and / or autoimmune disorders involves T cells (e.g., CD8) + This can lead to a reduction in memory T cell activity. In some embodiments, for example, after treatment, T cells (e.g., CD8) may be reduced. + Memory T cell activity is reduced by more than 5% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) compared to its size before treatment.

[0210] In some embodiments, treating inflammatory disorders and / or autoimmune disorders can result in a reduction of inflammation. In some embodiments, for example, after treatment, inflammation is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) compared to its size before treatment.

[0211] In some embodiments, treating inflammatory and / or autoimmune disorders can typically result in altered cytokine signaling when phosphorylation within the JAK-STAT pathway is modified (e.g., by downstream effects such as JAK inhibition or CBP degradation). In some embodiments, inhibiting JAK2 can affect the phosphorylation of EPO, TPO, GM-CSF, IL-3, IL-5, IL-12, IL-23, INF-γ, IL-6, IL-11, IL-13, IL-25, IL-27, and / or IL-31, which can then affect the immune system response. Other cytokines that interact with JAK1, JAK3, and / or TYK2 include IL-10, IL-22, type 1 IFN(α / β), IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.

[0212] In another embodiment, the Disclosure provides a method for treating a viral infection in a subject requiring treatment. This method comprises administering to the subject an effective amount of any of the aforementioned compounds or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, viral infections include retroviridae such as lentiviruses (e.g., human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T-cell leukemia virus type 1 (HTLV-I), human T-cell leukemia virus type 2 (HTLV-II))), hepadnaviridae (e.g., hepatitis B virus (HBV)), flaviviridae (e.g., hepatitis C virus (HCV)), adenoviridae (e.g., human adenovirus), herpesviridae (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), human herpesvirus type 6 (HHV-6), herpesvirus K*, CMV, varicella-zoster virus), and papillomaviridae (e.g., human papillomavirus (HPV)). E1)) Infections caused by viruses belonging to the Parvoviridae family (e.g., parvovirus B19), Polyomaviridae family (e.g., JC virus and BK virus), Paramyxoviridae family (e.g., measles virus), or Togaviridae family (e.g., rubella virus).

[0213] In another embodiment, the present invention relates to a method for treating a subject in need of treatment for melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer, comprising administering to the subject an effective amount of any of the aforementioned compounds or their pharmaceutically acceptable compositions.

[0214] In another embodiment, the present invention is a method for reducing tumor growth in subjects requiring reduction of tumor growth of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer, comprising administering to a subject an effective amount of any of the aforementioned compounds or their pharmaceutically acceptable compositions.

[0215] In another embodiment, the present invention is a method for suppressing the metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject, comprising administering an effective amount of any of the aforementioned compounds or their pharmaceutically acceptable compositions.

[0216] In another embodiment, the present invention is a method for suppressing metastatic colony formation of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject, comprising administering an effective amount of any of the aforementioned compounds or their pharmaceutically acceptable compositions.

[0217] In another embodiment, the present invention is a method for reducing the levels and / or activity of CBP and / or EP300 in melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, osteosarcoma, neuroblastoma, esophageal, gastric, or hematological cancer cells, comprising contacting cells with an effective amount of any of the aforementioned compounds or their pharmaceutically acceptable compositions.

[0218] In some of the embodiments described above, melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, osteosarcoma, neuroblastoma, esophageal cancer, gastric cancer, or hematopoietic cancer are included.

[0219] In some embodiments of the above-described models, an effective amount of the compound reduces the level and / or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference. In some embodiments, the effective amount of the compound reduces the level and / or activity of CBP by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference. In some embodiments, the effective amount of the compound reduces the level and / or activity of CBP by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0220] In some embodiments of the above-described aspects, an effective amount of the compound reduces the level of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to the reduction rate of the level of EP300. In some embodiments, the effective amount of the compound reduces the level of CBP by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to the reduction rate of the level of EP300. In some embodiments, the compound is an effective amount that reduces the level of CBP by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) compared to the reduction rate of the level of EP300.

[0221] In some embodiments, an effective amount of the compound reduces the level and / or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 22%, 24%, 30%, 36%, 48%, 72 hours, or more) compared to a reference for at least 12 hours (e.g., 14, 16, 18, 20, 22, 24, 30, 36, 48, 72 hours, or more). In some embodiments, the compound is an effective amount that reduces the level and / or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference for at least 4 days (e.g., 5, 6, 7, 14, 28 days, or longer).

[0222] In some embodiments of the above-described aspects, an effective amount of the compound reduces the level and / or activity of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to the reference. In some embodiments, the effective amount of the compound reduces the level and / or activity of EP300 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to the reference. In some embodiments, the compound is an effective amount that reduces the level and / or activity of EP300 by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0223] In some embodiments, an effective amount of the compound reduces the level and / or activity of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 22%, 24%, 30%, 36%, 48%, 72 hours, or more) compared to the reference for at least 12 hours (e.g., 14, 16, 18, 20, 22, 24, 30, 36, 48, 72 hours, or more). In some embodiments, the compound is an effective amount that reduces the level and / or activity of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to the reference for at least 4 days (e.g., 5, 6, 7, 14, 28 days, or longer).

[0224] In some embodiments, the subject has cancer. In some embodiments, the cancer expresses CBP and / or EP300 protein, and / or the cell or subject is identified as expressing CBP and / or EP300. In some embodiments, the cancer expresses CBP protein, and / or the cell or subject is identified as expressing CBP. In some embodiments, the cancer expresses EP300 protein, and / or the cell or subject is identified as expressing EP300. In some embodiments, the cancer is melanoma (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a hematological cancer, e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin Aλ myeloma, diffuse mixed histiocytic lymphoma and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia (e.g., T-cell acute lymphoblastic leukemia or B-cell acute lymphoblastic leukemia), diffuse large cell lymphoma, or non-Hodgkin lymphoma. In some embodiments, the cancer is breast cancer (e.g., ER-positive breast cancer, ER-negative breast cancer, triple-positive breast cancer, or triple-negative breast cancer). In some embodiments, the cancer is bone cancer (e.g., Ewing's sarcoma). In some embodiments, the cancer is renal cell carcinoma (e.g., microphthalmia transcription factor (MITF) family translocation renal cell carcinoma (tRCC)). In some embodiments, the cancer is metastatic (e.g., the cancer has spread to the liver). Metastatic cancer may include cells exhibiting migratory cell migration and / or infiltration, and / or cells exhibiting endothelial mobilization and / or angiogenesis. In other embodiments, migratory cancer is cell-migrating cancer. In yet another embodiment, cell-migrating cancer is non-metastatic cell-migrating cancer. Metastatic cancer may spread by dissemination to the surface of the peritoneum, pleura, pericardium, or subarachnoid space. Alternatively, metastatic cancer may be cancer that has spread via the lymphatic system or by bloodstream.In some embodiments, an effective amount of a drug that reduces the levels and / or activity of CBP and / or EP300 is an effective amount to inhibit the formation of metastatic cancer colonies in the liver.

[0225] In some embodiments, the method further includes administering to or bringing into contact with cells an anticancer therapy, such as a chemotherapeutic agent or cytotoxic agent, immunotherapy, surgery, radiotherapy, hyperthermia, or photocoagulation. In some embodiments, the anticancer therapy is a chemotherapeutic agent or cytotoxic agent, such as antimetabolites, mitotic inhibitors, antitumor antibiotics, asparagine-specific enzymes, bisphosphonates, antineoplastic agents, alkylating agents, DNA repair enzyme inhibitors, histone deacetylase inhibitors, corticosteroids, demethylating agents, immunomodulators, Janus-related kinase inhibitors, phosphinocitide 3-kinase inhibitors, proteasome inhibitors, or tyrosine kinase inhibitors. Examples of chemotherapeutic agents and cytotoxic agents include, but are not limited to, alkylating agents, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposides, and other agents (e.g., paclitaxel, taxol, docetaxel, taxotere, cis-platinum). A list of additional compounds with anticancer activity can be found in L. Brunton, B. Chabner, and B. Knollman (eds). Goodman and Gilman's *The Pharmacological Basis of Therapeutics*, Twelfth Edition, 2011, McGraw Hill Companies, New York, NY.

[0226] In some embodiments, the anticancer therapy and the compound of the present invention are administered within 28 days of each other, in amounts effective to treat the target together.

[0227] In some embodiments, the cancer exhibits resistance to one or more chemotherapeutic agents or cytotoxic agents (for example, the cancer is determined to be resistant to chemotherapeutic agents or cytotoxic agents by genetic markers, etc., or is likely to be resistant to chemotherapeutic agents or cytotoxic agents, such as cancer that could not respond to chemotherapeutic agents or cytotoxic agents). In some embodiments, the cancer could not respond to one or more chemotherapeutic agents or cytotoxic agents. In some embodiments, cancer was resistant to or unable to respond to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, CTLA-4 inhibitors (e.g., ipilimumab), PD-1 inhibitors (e.g., nivolumab or pembrolizumab), PD-L1 inhibitors (e.g., atezolizumab, avelumab, or durvalumab), mitogen-activated protein kinase (MEK) inhibitors (e.g., selumetinib, binimetinib, or trametinib), and / or protein kinase C (PKC) inhibitors (e.g., sotrastaurin or IDE196).

[0228] chemical terms The terms used herein are intended to describe specific embodiments and are not intended to be limiting.

[0229] For any of the following chemical definitions, the number following the atomic symbol indicates the total number of atoms of that element present in the particular chemical part. As to be understood, other atoms, such as hydrogen atoms, or substituents as described herein, may be present to satisfy the valence of the atoms, as necessary. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. When used with the groups defined herein, references to the number of carbon atoms include the divalent carbons in acetal and ketal groups, but do not include the carbonyl carbons in acyl, ester, carbonate, or carbamate groups. References to the number of oxygen, nitrogen, or sulfur atoms in heteroaryl groups include only the atoms that form part of the heterocycle.

[0230] As used herein, the term "alkyl" refers to a branched or linear monovalent saturated aliphatic hydrocarbon radical having 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms). Alkylenes are divalent alkyl groups.

[0231] As used herein, the term “alkenyl” refers to a linear or branched hydrocarbon residue having a carbon-carbon double bond and containing 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms), either alone or in combination with other groups.

[0232] As used herein, the term "alkynyl" refers to a linear or branched hydrocarbon residue having a carbon-carbon triple bond and containing 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms), either alone or in combination with other groups.

[0233] As used herein, the term “amino” represents -N(RN1)2, where each RN1 is independently H, OH, NO2, N(RN2)2, SO2ORN2, SO2RN2, SORN2, an N protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, or acyl (e.g., acetyl, trifluoroacetyl, or others as described herein), and each of these enumerated RN1 groups may be optionally substituted, or two RN1s may combine to form an alkylene or heteroalkylene, and each RN2 is independently H, alkyl, or aryl. The amino groups of the compounds described herein may be unsubstituted aminos (i.e., -NH2) or substituted aminos (i.e., -N(RN1)2).

[0234] As used herein, the term “aryl” refers to a 6- to 12-carbon aromatic monocyclic or polycyclic radical having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.

[0235] As used herein, the term “arylalkyl” refers to an alkyl group substituted with an aryl group. Unsubstituted arylalkyl groups contain 7 to 30 carbon atoms (e.g., 7 to 16 or 7 to 20 carbon atoms, such as benzyl and phenethyl, C1-C6 alkylC6-C10 aryl, C1-C10 alkylC6-C10 aryl, or C1-C20 alkylC6-C10 aryl). In some embodiments, alkyl and aryl groups are further substituted with 1, 2, 3, or 4 substituents, as defined herein for each group, if the valence is permissible.

[0236] As used herein, the term "carbocyclyl" refers to a non-aromatic C3-C12 monocyclic, bicyclic, or tricyclic structure in which the ring is formed by carbon atoms. Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals. Carbocyclylene is a divalent carbocyclyl group.

[0237] As used herein, the term “cycloalkyl” refers to a saturated, non-aromatic, and monovalent monocyclic, bicyclic, or tricyclic radical having 3 to 10, preferably 3 to 6, carbon atoms. A cycloalkyl group may be fully saturated or contain one or more double or triple bonds, provided the ring is non-aromatic. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. As used herein, the term “cycloalkoxy” refers to a cycloalkyl-O-group (e.g., cyclopropoxy and cyclobutoxy).

[0238] As used herein, the term "halo" means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0239] As used herein, the term “heteroalkyl” refers to an alkyl group as defined herein, in which one or more of its constituent carbon atoms are replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group may be further substituted with one, two, three, or four substituents, as described herein for alkyl groups. An example of a heteroalkyl group is “alkoxy,” which, as used herein, refers to alkyl-O- (e.g., methoxy and ethoxy). A heteroalkylene is a divalent heteroalkyl group.

[0240] As used herein, the term “heteroalkenyl” refers to an alkenyl group as defined herein, in which one or more of its constituent carbon atoms are replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group may be further substituted with one, two, three, or four substituents, as described herein for an alkenyl group. An example of a heteroalkenyl group is “alkenoxy,” which, as used herein, refers to alkenyl-O-. A heteroalkenylene is a divalent heteroalkenyl group.

[0241] As used herein, the term “heteroalkynyl” refers to an alkynyl group as defined herein, in which one or more of its constituent carbon atoms are replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group may be further substituted with one, two, three, or four substituents, as described herein for an alkynyl group. An example of a heteroalkynyl group is “alkynoxy,” which, as used herein, refers to alkynyl-O-. Heteroalkynylene is a divalent heteroalkynyl group.

[0242] As used herein, the term “heteroaryl” refers to a 5-12 atom aromatic monocyclic or polycyclic radical having at least one aromatic ring containing one, two, or three ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced by carbonyl groups. Examples of heteroaryl groups include pyridyl, pyrazoyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.

[0243] As used herein, the term “heteroarylalkyl” refers to an alkyl group substituted with a heteroaryl group. Unsubstituted heteroarylalkyl groups contain 7 to 30 carbon atoms (e.g., 7 to 16 or 7 to 20 carbon atoms, such as C1-C6 alkylC2-C9 heteroaryl, C1-C10 alkylC2-C9 heteroaryl, or C1-C20 alkylC2-C9 heteroaryl). In some embodiments, the alkyl and heteroaryl groups are further substituted with 1, 2, 3, or 4 substituents, as defined herein for each group, if the valence is permissible.

[0244] As used herein, the term “heterocyclyl” refers to a monocyclic or polycyclic radical having 3 to 12 atoms, with at least one ring containing 1, 2, 3, or 4 ring atoms selected from N, O, or S, none of which rings are aromatic. Examples of heterocyclyls include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl. “Heterocyclylene” is a divalent heterocyclyl group.

[0245] As used herein, the term "hydroxyl" refers to the -OH group.

[0246] As used herein, the term "thiol" refers to the -SH group.

[0247] As used herein, the term "carbonyl" refers to a -C(O)- group.

[0248] As used herein, the term "thiocarbonyl" refers to the -C(S)- group.

[0249] As used herein, the term "sulfonyl" refers to the -S(O)2- group.

[0250] Alkyl groups, alkenyl groups, alkynyl groups, heteroalkyl groups, heteroalkenyl groups, heteroalkynyl groups, carbocykyl (e.g., cycloalkyl) groups, aryl groups, heteroaryl groups, and heterocyclyl groups may be substituted or unsubstituted. If substituted, there are generally 1 to 4 substituents unless otherwise specified. Substituents include, for example, alkyl (e.g., unsubstituted and substituted, the substituents include any group described herein, e.g., aryl, halo, hydroxyl), aryl (e.g., substituted and unsubstituted phenyl), carbocyryl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl (e.g., substituted and unsubstituted thiazole, substituted and unsubstituted pyridine, substituted and unsubstituted benzothiazole, substituted and unsubstituted furan, substituted and unsubstituted pyrazole, etc.), heterocyclyl, amino (e.g., NH2 or mono or dialkylamino), azide, cyano, nitro, or thiol. The aryl, carbocyryl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted, such as arylalkyl (e.g., substituted and unsubstituted benzyl)).

[0251] The compounds described herein may have one or more chiral carbon atoms and may exist in the form of optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereomers, mixtures of diastereomers, diastereomer racemates, or mixtures of diastereomer racemates. The optically active form may be obtained, for example, by resolution of racemates, asymmetric synthesis, or asymmetric chromatography (chromatography using chiral adsorbents or eluents). That is, a particular disclosed compound may exist in various stereoisomerized forms. Stereoisomers are compounds that differ only in their spatial arrangement.

[0252] Enantiomers are, most commonly, pairs of stereoisomers whose mirror images cannot be superimposed because they contain an asymmetrically substituted carbon atom that functions as a chiral center. An enantiomer means one of a pair of molecules that are mirror images of each other and cannot be superimposed. Diastereomers are, most commonly, stereoisomers that are not related as mirror images because they contain two or more asymmetrically substituted carbon atoms and represent the stereoconfiguration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating the enantiomer from a racemic mixture using one or more well-known techniques and methods, such as chiral chromatography and separation methods thereafter. Suitable techniques and / or methods for separating enantiomers of compounds described herein from racemic mixtures can be readily determined by those skilled in the art. “Racemic mixture” means a compound containing two enantiomers such that such a mixture is not optically active, i.e., they do not rotate the plane of polarization. "Geometric isomers" refer to isomers in which the orientation of substituent atoms differs in relation to a carbon-carbon double bond, cycloalkyl ring, or bridging bicyclic system. The atoms (other than H) on each side of the carbon-carbon double bond are in either an E (substituent is on the opposite side of the carbon-carbon double bond) or Z (substituent is oriented on the same side). "R", "S", "S*", "R*", "E", "Z", "cis", and "trans" indicate the stereoconfiguration relative to the core molecule. Certain disclosed compounds may exist in atropisomer form. Atropisomers are stereoisomers resulting from the hindrance of rotation around a single bond, and their conformational isomers can be isolated due to a sufficiently high steric strain barrier against rotation. The compounds described herein may be prepared as individual isomers by isomer-specific synthesis or by separation from an isomer mixture.Conventional resolution methods include forming salts of the free bases of each isomer of an isomer pair using an optically active acid (followed by fractional crystallization and regeneration of the free bases), forming salts of the acidic forms of each isomer of an isomer pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming esters or amides 35 of each isomer of an isomer pair using an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliaries), or resolving isomer mixtures of either the starting material or the final product using various well-known chromatographic methods. Where the stereochemistry of a disclosed compound is named or described by structure, the named or described stereoisomer is at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight, or 99.9% by weight relative to other stereoisomers. When a single enantiomer is named or described by structure, the described or named enantiomer is optically pure to at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight, or 99.9% by weight. When a single diastereomer is named or described by structure, the described or named diastereomer is pure to at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight, or 99.9% by weight. Optical purity percentage is the weight of the enantiomer, or the ratio of the weight of the enantiomer to the weight of its optical isomers. Diastereomer purity by weight is the ratio of the weight of one diastereomer to the weight of all diastereomers combined. If the stereochemistry of a disclosed compound is named or described by its structure, the named or described stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure in mole fraction relative to other stereoisomers. If a single enantiomer is named or described by its structure, the described or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure in mole fraction. If a single diastereomer is named or described by its structure, the described or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure in mole fraction.The purity percentage by mole fraction is the mole of the enantiomer, or the ratio of the mole of the enantiomer to the mole of its optical isomer. Similarly, the purity percentage by mole fraction is the mole of the diastereomer, or the ratio of the mole of the diastereomer to the mole of its isomer. If a disclosed compound is named or described by structure without showing its 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 a corresponding optical isomer, a racemic mixture of the compound, a mixture of the compound, or a mixture in which one enantiomer is concentrated relative to its corresponding optical isomer. If a disclosed compound is named or described by structure without showing stereochemistry and has two or more chiral centers, the name or structure should be understood to encompass diastereomers that do not contain other diastereomers, several diastereomers that do not contain other diastereomer pairs, mixtures of diastereomers, mixtures of diastereomer pairs, mixtures of diastereomers in which one diastereomer is concentrated relative to the other diastereomers, or mixtures of diastereomers in which one or more diastereomers are concentrated relative to the other diastereomers. The present invention encompasses all of these forms.

[0253] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. Methods and materials for use in this disclosure are described herein. Other suitable methods and materials known in the art may also be used. Materials, methods, and examples are illustrative and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references referenced herein are incorporated by reference in their entirety. In case of any conflict, this specification, including definitions, shall prevail.

[0254] definition In this application, unless otherwise clearly indicated by the context, (i) the term "a" may be understood to mean "at least one", (ii) the term "or" may be understood to mean "and / or", and (iii) the terms "including" and "including" may be understood to encompass the itemized component or step, whether expressed alone or together with one or more additional components or steps.

[0255] As used herein, the terms “about” and “approximately” refer to values ​​within 10% above or below the described value. For example, the term “about 5 nM” refers to a range of 4.5 to 5.5 nM.

[0256] As used herein, the term “administration” means the administration of a composition (e.g., a compound or a preparation containing a compound described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any suitable route. For example, in some embodiments, administration may be by the bronchus (including by bronchial infusion), buccal, enteral, intradermal, intra-arterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intramedullary, intratumoral, intravenous, intraventricular, mucosa, nasal, oral, rectal, subcutaneous, sublingual, topical, trachea (including by intratracheal infusion), percutaneous, vaginal, and vitreous humor.

[0257] As used herein, the term "CBP" refers to Creb-binding protein in human cells.

[0258] As used herein, the term "CBP-related disorder" refers to a disorder caused by or affected by levels of CBP activity.

[0259] As used herein, the term “CBP loss-of-function mutation” refers to a mutation in CBP that results in a protein with reduced activity (e.g., a reduction of at least 1% of CBP activity, e.g., a reduction of 2%, 5%, 10%, 25%, 50%, or 100% of CBP activity). Examples of CBP loss-of-function mutations include, but are not limited to, homozygous CBP mutations and chromosomal translocations.

[0260] As used herein, the term “CBP loss of function disorder” refers to a disorder (e.g., cancer) that presents with reduced CBP activity (e.g., a reduction of at least 1% of CBP activity, e.g., a reduction of 2%, 5%, 10%, 25%, 50%, or 100% of CBP activity).

[0261] The term "cancer" refers to a condition caused by the proliferation of malignant new cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

[0262] As used herein, “combination therapy” or “administered in combination” means that two (or more) different drugs or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the dose and periodicity of administration of each drug so that the effects of the distinct drugs on the subject overlap. In some embodiments, the delivery of two or more drugs may be simultaneous or parallel, and the drugs may be co-formulated. In some embodiments, the two or more drugs are not co-formulated and are administered sequentially as part of a prescribed regimen. In some embodiments, the administration of two or more combined drugs or treatments results in a greater reduction of symptoms or other parameters related to the disorder than that observed with a single drug or treatment delivered alone or in the absence of one of them. The effects of the two treatments may be partially additive, fully additive, or more than additive (e.g., synergistic). The sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or by different routes. For example, the first therapeutic agent of a combination may be administered by intravenous injection, while the second therapeutic agent of a combination may be administered orally.

[0263] "Determining the level" of a protein or RNA means the detection of the protein or RNA by methods known in the art, either directly or indirectly. "Direct determination" means performing a process to obtain a physical entity or value (e.g., performing an assay or test on a sample, or "analyzing a sample" as the term is defined herein). "Indirect determination" means receiving a physical entity or value from another entity or source (e.g., a third-party laboratory that directly obtained the physical entity or value). Methods for measuring protein levels generally include, but are not limited to, Western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescence polarization, phosphorescence, immunohistochemistry, matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometry, microscopy, fluorescence-activated cell classification (FACS), and flow cytometry, as well as assays based on the properties of the protein, including but not limited to enzyme activity or interactions with other protein partners. Methods for measuring RNA levels are well known in the art.

[0264] Where used herein, the terms “effective dose,” “therapeutic effective dose,” and “sufficient dose” of a CBP-reducing agent described herein (e.g., in cells or subjects) refer to an amount sufficient to produce a beneficial or desirable outcome, including clinical outcomes, when administered to a subject, including humans. Therefore, “effective dose” or its synonyms depend on the context in which it is applied. For example, in the context of treating cancer, it is the amount of a CBP-reducing agent sufficient to achieve a therapeutic response compared to a response obtained without administration of the CBP-reducing agent. The amount of a given CBP-reducing agent described herein that would correspond to such an amount will vary depending on a variety of factors, such as a given agent, pharmaceutical formulation, route of administration, type of disease or disorder, identity of the subject (e.g., age, sex, and / or weight), or host being treated, but can nevertheless be routinely determined by those skilled in the art. Furthermore, as used herein, the “therapeutic dose” of a CBP-reducing agent is the amount that produces a beneficial or desirable result in a subject compared to a control. As defined herein, the therapeutic dose of a CBP-reducing agent can be readily determined by a person skilled in the art by routine methods known in the art. The drug regimen can be adjusted to provide an optimal therapeutic response.

[0265] As used herein, the term “inhibitor” refers to any agent that reduces the level and / or activity of a protein (e.g., CBP). Non-exclusive examples of inhibitors include small molecule inhibitors, degradation agents, antibodies, enzymes, or polynucleotides (e.g., siRNA).

[0266] "Level" means the level of a protein or protein-coding mRNA compared to a reference. The reference may be any useful reference as defined herein. A "decreased level" or "increased level" of a protein or RNA means a decrease or increase in the level of the protein or RNA compared to a reference (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more than a decrease or increase of about 1% compared to the reference. This means a decrease or increase of 0%, approximately 15%, approximately 20%, approximately 50%, approximately 75%, approximately 100%, or more than approximately 200%, a decrease or increase of less than approximately 0.01 times, approximately 0.02 times, approximately 0.1 times, approximately 0.3 times, approximately 0.5 times, approximately 0.8 times, or less, or a decrease or increase of approximately 1.2 times, approximately 1.4 times, approximately 1.5 times, approximately 1.8 times, approximately 2.0 times, approximately 3.0 times, approximately 3.5 times, approximately 4.5 times, approximately 5.0 times, approximately 10 times, approximately 15 times, approximately 20 times, approximately 30 times, approximately 40 times, approximately 50 times, approximately 100 times, approximately 1000 times, or more. Protein levels may be expressed as mass / volume (e.g., g / dL, mg / mL, μg / mL, ng / mL) or as a percentage of the total protein in the sample.

[0267] "Reducing CBP activity" means reducing the level of activity associated with CBP, or any associated downstream effects. The activity level of CBP can be measured using any method known in the art, for example, the HiBit assay.

[0268] As used herein, the term “pharmaceutical composition” refers to a composition containing the compounds described herein, formulated with pharmaceutically acceptable excipients, and suitable for administration to a mammal, e.g., a human. Typically, pharmaceutical compositions are manufactured or marketed with the approval of a government regulatory body as part of a therapeutic regimen for the treatment of diseases in mammals. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage forms (e.g., tablets, capsules, caplets, gel caps, or syrups), for topical administration (e.g., as creams, gels, lotions, or ointments), for intravenous administration (e.g., as sterile solutions free of particulate embolic materials and in solvent systems suitable for intravenous use), or in any other pharmaceutically acceptable formulation.

[0269] As used herein, “pharmaceutically acceptable excipients” means any component other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving the active compound) that is substantially non-toxic and non-inflammatory to the patient. Examples of excipients include antifouling agents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film-forming agents or coatings, flavoring agents, fragrances, lubricants (flow enhancers), preservatives, printing inks, adsorbents, suspending agents or dispersants, sweeteners, and water for hydration. Examples of excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, dibasic calcium phosphate, calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0270] As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of a compound, e.g., any compound of formula I. Any pharmaceutically acceptable salt of any of the compounds described herein may be suitable for use in contact with human and animal tissues without excessive toxicity, irritation, or allergic reactions, within the bounds of sound medical judgment, and may include salts that are balanced by a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well 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. PHStahl and CGWermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free basic group with a suitable organic acid.

[0271] 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 in the acidic form of the compounds of the present invention. Frequently, the 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, as well as methods for preparing suitable salts, are well known in the art. The salts may be prepared from pharmaceutically acceptable, non-toxic acids and bases, including inorganic and organic acids and bases. Typical acid addition salts include acetate, adipine, 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, and 2-hydroxyethanesulfonic acid. Examples of alkali or alkaline earth metal salts include salts, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, toluenesulfons, undecanoates, and valersates. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as amine cations, including but not limited to non-toxic ammonium, quaternary ammonium, and ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0272] "Reference" means any useful reference used to compare protein or RNA levels. A reference may be any sample, standard, standard curve, or level used for comparison purposes. A reference may be a typical reference sample or reference standard or level. A "reference sample" may be, for example, a control, a predetermined negative control value such as "normal control," or a previous sample taken from the same subject, a sample from a normal healthy subject such as normal cells or normal tissue, a sample from a subject without disease (e.g., cells or tissue), a sample from a subject diagnosed with a disease but not yet treated with the compound of the present invention, a sample from a subject being treated with the compound of the present invention, or a sample of purified protein or RNA (e.g., any as described herein) at a known normal concentration. "Reference standard or level" means a value or number derived from a reference sample. "Normal control value" is a predetermined value indicating a non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range ("X~Y"), a high threshold ("less than or equal to X"), or a low threshold ("greater than or equal to X"). A subject having a measurement of a particular biomarker within the normal control range is typically referred to as being "within the normal range" for that biomarker. The normal reference standard or level may be a value or figure derived from a healthy subject without disease or disorder (e.g., cancer) or a subject being treated with the compound of the present invention. In a preferred embodiment, the reference sample, standard, or level is matched to the sample subject by at least one of the following criteria: age, weight, sex, disease stage, and overall health. A standard curve of levels of purified protein or RNA within the normal reference range, e.g., any of those described herein, can also be used as a reference.

[0273] As used herein, the term “subject” refers to any organism to which a composition according to the present invention may be administered, for example, for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may be a human or animal that seeks or needs treatment, requests treatment, is receiving treatment, will receive treatment in the future, or is receiving treatment from a specialist trained for a particular disease or condition.

[0274] As used herein, the terms “to treat,” “to be treated,” or “to treat” mean a therapeutic action or any action whose purpose is to slow (reduce) 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, relief of symptoms, reduction of the severity of a condition, disorder, or disease, stabilization (i.e., non-worsening) of a condition, disorder, or disease, delay or slowing of the onset of progression of a condition, disorder, or disease, improvement or remission (partial or complete) of a condition, disorder, or disease, improvement of at least one measurable physical parameter not necessarily identifiable by the patient, or enhancement or improvement of a condition, disorder, or disease. Treatment includes inducing a clinically significant response without excessive levels of side effects. Treatment also includes extending survival compared to the predicted survival without treatment. The compounds of the present invention may also be used, for example, to “preventively treat” or “prevent” a disorder in subjects at high risk of developing the disorder.

[0275] As used herein, the terms “variant” and “derivative” are used synonymously and refer to naturally occurring, synthetic, and semi-synthetic analogs of the compounds, peptides, proteins, or other substances described herein. Variants or derivatives of the compounds, peptides, proteins, or other substances described herein may retain or improve the biological activity of the original material.

[0276] Details of one or more embodiments of the present invention are described below. Other features, purposes, and advantages of the present invention will become apparent from the description and the claims.

[0277] As used herein, the term “degradant” refers to a small molecule compound containing a degradation moiety, the compound interacting with a protein (e.g., CBP) in such a way that the compound’s binding results in, for example, a reduction of at least 5% in the protein’s level in a cell or subject, thereby causing the degradation of the protein.

[0278] As used herein, the term “degradation moiety” refers to a moiety whose binding results in the degradation of a protein, such as CBP. For example, such a moiety binds to a protein, such as a protease or ubiquitin ligase that metabolizes CBP. [Brief explanation of the drawing]

[0279] [Figure 1] This is a series of graphs illustrating dose-dependent depletion of CBP and EP300 levels in osteosarcoma cell lines in the presence of the CBP-selective degrading agent described in Example 536. [Figure 2] This is a series of graphs illustrating dose-dependent depletion of CBP and EP300 levels in osteosarcoma cell lines in the presence of the CBP-selective degrading agent described in Example 536. [Figure 3] This graph illustrates the effect of the CBP-degrading agent described in Example 537 on the cell proliferation of four bladder cancer cell lines (UM-UC-3, ScaBER, 647V, and 639V). [Figure 4] This graph illustrates the effect of the two gastric cancer cell lines (IM95 and AGS) described in Example 538 on cell proliferation. [Figure 5] This graph illustrates the effect on cell proliferation of the two colorectal cancer cell lines (HT29 and RKO) described in Example 539. [Figure 6]This is a series of graphs illustrating the results of WB assessments of percentage residual CBP and EP300 protein levels (normalized to the vehicle) after treatment with the CBP selective degrading agent of the present invention at 20 mg / kg and 50 mg / kg at 2, 6, and 24 hours after the final dose described in Example 540. [Figure 7] This is a volcano plot illustrating all proteins identified in the proteome database for the treated and untreated groups (with compound 6) collected 6 hours after treatment. Purple dots represent all bromodomain proteins identified in this analysis. The results show that a statistically significant and selective downregulation of CBP relative to EP300 is observed using a CBP-selective degrading agent, as described in Example 541. [Figure 8] Platelet count on day 14: This graph illustrates the dose-response decrease in platelets induced by GNE-781 and the absence of thrombocytopenia induced by exemplary compound 132, as described in Example 542. [Figure 9A] This graph illustrates tumor volume in response to the administration of FHT-76118 (compound 142) and FHT-77559 over time. [Figure 9B] This graph illustrates the time course of body weight in response to the administration of FHT-76118 (compound 142) and FHT-77559. [Figure 9C] This graph illustrates the PK / PD effects of FHT-77559 on CBP at concentrations of 3 mg / kg, 1 mg / kg, 0.3 mg / kg, and 0.1 mg / kg. [Figure 9D] This graph illustrates the PK / PD effects of FHT-77559 on c-MYC at concentrations of 3 mg / kg, 1 mg / kg, 0.3 mg / kg, and 0.1 mg / kg. [Figure 10A] This graph illustrates the time course of tumor volume in response to administration of FHT-76118 (compound 142) and FHT-77559. [Figure 10B] This graph illustrates the time-dependent changes in body weight in response to the administration of FHT-76118 (compound 142) and FHT-77559. [Figure 10C] This graph illustrates the PK / PD effects of FHT-76118 (compound 142) and FHT-77559 on CBP. [Figure 10D] This graph illustrates the PK / PD effects of FHT-76118 (compound 142) and FHT-77559 on c-MYC. [Figure 11A] This graph illustrates the time course of tumor volume in response to administration of FHT-76118 (compound 142) and FHT-77559. [Figure 11B] This graph illustrates the time-dependent changes in body weight in response to the administration of FHT-76118 (compound 142) and FHT-77559. [Figure 11C] This graph illustrates the PK / PD effects of FHT-76118 (compound 142) and FHT-77559 on CBP. [Figure 11D] This graph illustrates the PK / PD effects of FHT-76118 (compound 142) and FHT-77559 on c-MYC. [Modes for carrying out the invention]

[0280] This disclosure features compositions and methods useful for the treatment of CBP-related disorders (e.g., cancer and infections). This disclosure further features compositions and methods useful for inhibiting CBP levels and / or activity in subjects requiring treatment, for example, for the treatment of disorders such as cancer (e.g., sarcoma) and infections (e.g., viral infections).

[0281] compound The compounds described herein reduce the level of activity or associated downstream effects related to CBP, or reduce the level of CBP in cells or subjects. Exemplary compounds described herein have a structure according to formula I, ALB Equation I During the ceremony, A is the CBP binding site, B is the decomposition part, L has the structure of formula II, A 1 -(F)-(E) m -CA 2 Formula II During the ceremony, A 1 However, this is a bond between the linker and A, A 2 However, this is a bond between B and the linker, m is independently either 0 or 1. C is independently either absent, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl. E is independent, non-existent, O, S, NR N , C replaced by arbitrary selection 1~10 Alkylene, optionally replaced with C 2~10 Alkenylene, optionally replaced with C 2~10 Alkynylene, optionally substituted C2-C 10 Polyethylene glycol, or optionally substituted C 1~10 It is a heteroalkylene, Each R N However, independently, H and C are substituted by choice. 1~4 Alkyl, optionally substituted C 2~4 Alkenil, C replaced by any choice 2~4 Alkinyl, optionally replaced with C 2~6 Heterocyclines, C substituted by choice 6~12 C replaced by an aryl or optional character. 1~7 It is heteroalkyl, F is independently and arbitrarily replaced by C3~C 10 Carbocyclylene, optionally substituted with C 2~10 Heterocyclylene, optionally substituted C6~C 10 Arylene, or C2-C9 heteroarylene with optional substitution, structure, or a pharmaceutically acceptable salt thereof.

[0282] CBP and Janus kinase (JAK) pathways Protein kinases (PKs) regulate a diverse range of biological processes, including, among others, cell proliferation, survival, differentiation, organogenesis, morphogenesis, neovascularization, tissue repair, and regeneration. Protein kinases also play specific roles in many human diseases, including cancer. Cytokines, small polypeptides, or glycoproteins regulate many pathways involved in the host's inflammatory response to sepsis. Cytokines can influence cell differentiation, proliferation, and activation, and can regulate both pro-inflammatory and anti-inflammatory responses to enable the host to respond appropriately to pathogens. The broad spectrum of cytokine signaling involves the Janus kinase family (JAKs) of protein tyrosine kinases and signaling and transcriptional activators (STATs). There are four known mammalian JAKs: JAK1 (Janus kinase-1), JAK2, JAK3 (Janus kinase leukocyte, also known as JAKL and L-JAK), and TYK2 (protein tyrosine kinase 2). There are seven identified mammalian STAT family members: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6.

[0283] In memory CD8+ T cells, Janus kinase 2 (JAK2) hyperactivation is coupled with CBP phosphorylation, and phosphorylated CBP is observed to be important for the CD8+ memory T cell recall response (J Biol Chem. 2019 Feb 15;294(7):2397-2406). JAK2-catalyzed phosphorylation has been suggested to enable CBP to bind with higher affinity to acetylated histone peptides such as H3, increasing the number of acetylated histone markers recognized by CBP. This may indicate a mechanism that contributes to the initiation of the transcriptional program in memory CD8+ T cells. Furthermore, CBP has been observed to be essential for conventional effector and memory CD8+ T cell formation. Therefore, treatment with JAK inhibitors (e.g., JAK2 inhibitors) may also inhibit CBP via non-phosphorylation.

[0284] The JAK-STAT pathway plays a role in the transduction of cytokine and growth factor signaling in inflammatory and autoimmune diseases. Globally approved JAK inhibitors include abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, and upadacitinib. Other JAK inhibitors include AG-490, brepocitinib, celduratinib, desernotinib, duklavacitinib, gandotinib, gusacitinib, itacitinib, momerotinib, nezurcitinib, and ritrecitinib.

[0285] In one embodiment, the present disclosure provides a method for treating an inflammatory and / or autoimmune disorder, comprising administering to a subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0286] In some embodiments, the method further includes administering a JAK inhibitor to the subject. In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib. In some embodiments, the JAK inhibitor is AG-490, brepocitinib, celduratinib, desernotinib, duklavacitinib, gandotinib, gusacitinib, itacitinib, momerotinib, nezurcitinib, or ritrecitinib. In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, AG-490, brepocitinib, celduratinib, desernotinib, duklavacitinib, gandotinib, gusacitinib, itacitinib, momerotinib, nezurcitinib, or ritrecitinib.

[0287] Filgotinib, oclacitinib, and upadacitinib are JAK1 inhibitors. Filgotinib (e.g., Jyseleca, Europe) is approved for use in moderate to severe rheumatoid arthritis. Upadacitinib (e.g., Rinvoq) is approved for use in moderate to severe rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiological axial spondyloarthritis, moderate to severe active ulcerative colitis, Crohn's disease, and refractory moderate to severe atopic dermatitis. Filgotinib has shown promising responses in Crohn's disease and ulcerative colitis and has also been tested in psoriatic arthritis. Oclacitinib is approved for the treatment of pruritus associated with atopic dermatitis and allergic dermatitis in dogs. In some embodiments, JAK inhibitors are JAK1 inhibitors. In some embodiments, the JAK inhibitor is filgotinib, oclacitinib, or upadacitinib. In some embodiments, the JAK inhibitor is filgotinib or upadacitinib. In some embodiments, the inflammatory and / or autoimmune disorder is moderate to severe rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiological axial spondyloarthritis, moderate to severe active ulcerative colitis, Crohn's disease, and refractory moderate to severe atopic dermatitis.

[0288] Fedratinib and pacritinib are JAK2 inhibitors. Fedratinib (e.g., Inrebic) is approved for use in moderate to high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis. Pacritinib (e.g., Vonjo) is 50 × 10 9It is approved for use in moderate to high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 10⁻¹⁰ / L. Pacritinib acts as both a JAK2 and FLT3 inhibitor and can be used to overcome resistance in existing acute myeloid leukemia (AML) treatments. Pacritinib has been tested in combination with temozolomide in glioblastoma multiforme. In some embodiments, the JAK inhibitor is a JAK2 inhibitor. In some embodiments, the JAK2 inhibitor is fedratinib or pacritinib. In some embodiments, the impairment is moderate to high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, or 50 × 10⁻¹⁰ / L. 9 This is a moderate to high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below / L.

[0289] Abrocitinib, baricitinib, and ruxolitinib are JAK1 / 2 inhibitors. Abrocitinib (e.g., Cibinqo) is approved for use in refractory moderate to severe atopic dermatitis. Baricitinib (e.g., Olumiant) is approved for use in moderate to severe rheumatoid arthritis. Ruxolitinib (e.g., Jakafi) is approved for use in moderate or high-risk myelofibrosis (including primary myelofibrosis, post-polycythemia myelofibrosis, and post-essential thrombocythemia myelofibrosis), polycythemia vera, steroid-refractory acute graft-versus-host disease, and chronic graft-versus-host disease. Baricitinib was approved for emergency use in combination with remdesivir for the treatment of COVID-19. Baricitinib, when used with topical corticosteroids, has been shown to improve symptoms of systemic lupus erythematosus and reduce inflammation / pruritus in atopic dermatitis. Baricitinib has been studied in Ecardi-Goutier syndrome and primary Sjögren's syndrome. The combination of ruxolitinib and an ERBB1 / 2 / 4 inhibitor has also shown synergistic anticancer activity against lung, breast, and ovarian cancer cells. In some embodiments, the JAK inhibitor is a JAK1 / 2 inhibitor. In some embodiments, the JAK1 / 2 inhibitor is abrocitinib, baricitinib, or ruxolitinib. In some embodiments, the inflammatory and / or autoimmune disorder is refractory moderate to severe atopic dermatitis, moderate to severe rheumatoid arthritis, moderate or high-risk myelofibrosis (including primary myelofibrosis, post-polycythemia myelofibrosis, and post-essential thrombocythemia myelofibrosis), polycythemia vera, steroid-refractory acute graft-versus-host disease, or chronic graft-versus-host disease. In some embodiments, the inflammatory and / or autoimmune disorder is a consequence of COVID-19 infection in the lungs. In some embodiments, the inflammatory and / or autoimmune disorder is systemic lupus erythematosus, inflammatory / pruritic conditions in atopic dermatitis, Ecardi-Goutier syndrome, or primary Sjögren's syndrome.

[0290] Tofacitinib is a JAK1 / 2 / 3 inhibitor. Tofacitinib (e.g., Xeljanz) is approved for use in active psoriatic arthritis, moderate to severe rheumatoid arthritis, moderate to severe active ulcerative colitis, juvenile idiopathic arthritis of a specific course, and active ankylosing spondylitis. Trials are underway to study tofacitinib in COVID-19-related lung problems. Tofacitinib is being studied in combination with abrocitinib for the treatment of toxic epidermal necrolysis. In some embodiments, the JAK inhibitor is a JAK1 / 2 / 3 inhibitor. In some embodiments, the JAK1 / 2 / 3 inhibitor is tofacitinib. In some embodiments, the inflammatory and / or autoimmune disorder is active psoriatic arthritis, moderate to severe rheumatoid arthritis, moderate to severe active ulcerative colitis, juvenile idiopathic arthritis of a specific course, and active ankylosing spondylitis. In some embodiments, the inflammatory and / or autoimmune disorder is a result of COVID-19 infection in the lungs. In some embodiments, the inflammatory and / or autoimmune disorder is toxic epidermal necrolysis.

[0291] Delgocitinib is a non-selective JAK inhibitor approved in Japan for use in atopic dermatitis. Delgocitinib has been tested and shown improvement in psoriasis and chronic hand eczema. In some embodiments, the JAK inhibitor is delgocitinib. In some embodiments, the inflammatory and / or autoimmune disorder is atopic dermatitis. In some embodiments, the inflammatory and / or autoimmune disorder is psoriasis or chronic hand eczema.

[0292] Peficitinib is a pan-JAK inhibitor approved in Japan for use in rheumatoid arthritis. In some embodiments, the pan-JAK inhibitor is peficitinib. In some embodiments, the inflammatory and / or autoimmune disorder is rheumatoid arthritis.

[0293] Brepocitinib has been evaluated for active non-infectious non-anterior uveitis, dermatomyositis, and scarring alopecia.

[0294] Celduratinib has been evaluated for relapsed / refractory peripheral T-cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell non-Hodgkin lymphoma, follicular lymphoma, T-cell lymphoma, and vitiligo.

[0295] Desernotinib is a JAK3 inhibitor that has been evaluated for the treatment of rheumatoid arthritis.

[0296] Duke lavacitinib has been evaluated particularly for pyoderma gangrenosum, onychopsoriasis, lichen planus pilaris, inflammatory hereditary dermatosis, palmoplantar pustulosis, Crohn's disease, ulcerative colitis, moderate to severe psoriasis vulgaris, alopecia areata, Sjögren's syndrome, and systemic lupus erythematosus.

[0297] Gandotinib is a JAK2 inhibitor that has been evaluated for myeloproliferative disorders, including myelofibrosis, graft-versus-host disease, and rheumatoid arthritis.

[0298] Itacitinib is a JAK1 inhibitor that has been evaluated for acute graft-versus-host disease.

[0299] Momerotinib has been evaluated particularly for primary myelofibrosis, polycythemia vera myelofibrosis, essential post-thrombocytopenia myelofibrosis, and non-small cell lung cancer.

[0300] Nezurcitinib is being evaluated for COVID-19-related lung problems.

[0301] Ritrecitinib is a JAK3 inhibitor that has been evaluated for non-segmental vitiligo, cutaneous T-cell lymphoma, scarring alopecia, and alopecia areata.

[0302] In some embodiments, the JAK inhibitor is brepocitinib, celduratinib, desernotinib, duklavacitinib, gandotinib, ikacitinib, momerotinib, nezurcitinib, or ritrecitinib.

[0303] In one embodiment, the present disclosure provides a method for treating an inflammatory and / or autoimmune disorder, comprising administering to a subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0304] In some embodiments, the compounds described herein are administered as replacement therapy for the treatment of diseases associated with JAK activity. In some embodiments, the diseases associated with JAK activity are inflammatory and / or autoimmune disorders.

[0305] In some embodiments, inflammatory and / or autoimmune disorders include moderate to severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiological axial spondyloarthritis, moderate to severe active ulcerative colitis, Crohn's disease, refractory moderate to severe atopic dermatitis, moderate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, moderate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 10⁹ / L, polycythemia vera, steroid-refractory graft-host disease, chronic graft-versus-host disease, or juvenile idiopathic arthritis of a particular course.

[0306] In some embodiments, the inflammatory and / or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis, ulcerative colitis, Crohn's disease, atopic dermatitis, polycythemia vera, graft-versus-host disease, or juvenile idiopathic arthritis.

[0307] In some embodiments, inflammatory and / or autoimmune disorders include noninfectious non-anterior uveitis, dermatomyositis, scarring alopecia, alopecia areata, rheumatoid arthritis, non-segmental vitiligo, pyoderma gangrenosum, onychopsoriasis, lichen planus pilaris, inflammatory hereditary dermatopathy, palmoplantar pustulosis, moderate to severe psoriasis vulgaris, alopecia areata, Sjögren's syndrome, or systemic lupus erythematosus.

[0308] In some embodiments, inflammatory and / or autoimmune disorders include rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, scarring alopecia, Crohn's disease, graft-versus-host disease, systemic lupus erythematosus, Ecardi-Goutier syndrome, Sjögren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and psoriasis vulgaris.

[0309] In one embodiment, the present disclosure provides a method for treating rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis, ulcerative colitis, Crohn's disease, atopic dermatitis, polycythemia vera, graft-versus-host disease, or juvenile idiopathic arthritis, comprising administering to a subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0310] In another embodiment, the present disclosure provides a method for treating an inflammatory and / or autoimmune disorder in a subject requiring treatment, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the inflammatory and / or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, scarring alopecia, Crohn's disease, graft-versus-host disease, systemic lupus erythematosus, Ecardi-Goutier syndrome, Sjögren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or psoriasis vulgaris. In some embodiments, the method further comprises administering a JAK inhibitor to the subject. In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.

[0311] In another embodiment, the present disclosure provides a method for treating a disease, disorder, or condition mediated by JAK activity, comprising administering to a subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the diseases, disorders, or conditions mediated by JAK activity are rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, scarring alopecia, Crohn's disease, graft-versus-host disease, systemic lupus erythematosus, Ecardi-Goutier syndrome, Sjögren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, psoriasis vulgaris, or myelofibrosis.

[0312] In another embodiment, the present disclosure provides a method for treating a disease, disorder, or condition mediated by components of the JAK-STAT pathway, comprising administering to a subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the components of the JAK-STAT pathway are Janus kinases (JAKs). In some embodiments, the components of the JAK-STAT pathway are signaling and transcriptional activators (STATs). In some embodiments, the treatment of a disease, disorder, or condition mediated by components of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, scarring alopecia, Crohn's disease, graft-versus-host disease, systemic lupus erythematosus, Ecardi-Goutier syndrome, Sjögren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, psoriasis vulgaris, or myelofibrosis.

[0313] In another aspect, the present disclosure provides a method for inducing immune tolerance in a subject requiring it, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0314] In another aspect, the Disclosure provides a method for inhibiting inflammation or an autoimmune response in a subject requiring inhibition, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0315] In another aspect, the Disclosure provides a method for suppressing a memory CD8+ T cell response in a subject having or at risk of developing an inflammatory response, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0316] In another embodiment, the Disclosure provides a method for treating a patient in need of treatment for an autoimmune disease, cancer, myeloproliferative disorder, inflammatory disease, bone resorption disorder, or organ transplant refusal, comprising administering to a subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, type 1 diabetes, lupus, inflammatory bowel disease, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, myocarditis, or autoimmune thyroid disorder. In some embodiments, the autoimmune disease is rheumatoid arthritis. In some embodiments, the autoimmune disease is a skin disorder. In some embodiments, the skin disorder is atopic dermatitis, psoriasis, skin sensitization, dermatitis, skin rash, contact dermatitis, or allergic contact sensitization. In some embodiments, cancer is a solid tumor. In some embodiments, the cancer is prostate cancer, kidney cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, Castleman disease, or pancreatic cancer. In some embodiments, the cancer is lymphoma, leukemia, or multiple myeloma. In some embodiments, the myeloproliferative disorder is polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), eosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD). In some embodiments, the myeloproliferative disorder is myelofibrosis. In some embodiments, the myeloproliferative disorder is primary myelofibrosis (PMF). In some embodiments, the myeloproliferative disorder is post-polycythemia myelofibrosis (post-PV MF). In some embodiments, the myeloproliferative disorder is post-essential thrombocythemia myelofibrosis (post-ET MF).

[0317] Pharmaceutical uses The compounds described herein are useful in the methods of the present invention and are not bound by theory, but are thought to exert their desired effects, for example, through their ability to modulate the level, state, and / or activity of CBP by inhibiting the activity or level of CBP in cells within mammals.

[0318] One aspect of the present invention relates to a method for treating a CBP-related disorder, such as cancer, in a subject requiring treatment. In some embodiments, the compound is administered in an effective amount and time to produce one (or more, e.g., two or more, three or more, four or more) of the following: (a) reduction in tumor size, (b) reduction in tumor growth rate, (c) increase in tumor cell death, (d) reduction in tumor progression, (e) reduction in the number of metastases, (f) reduction in the rate of metastasis, (g) reduction in tumor recurrence, (h) increase in the subject's survival rate, and (i) increase in the subject's progression-free survival.

[0319] Treating cancer can result in a reduction in tumor size or volume. For example, after treatment, tumor size may be reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) compared to its size before treatment. Tumor size can be measured by any reproducible means of measurement. For example, tumor size can be measured as the diameter of the tumor.

[0320] Treating cancer can lead to a further reduction in the number of tumors. For example, after treatment, the number of tumors may be reduced by more than 5% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) compared to the number before treatment. The number of tumors can be measured by any reproducible means; for example, the number of tumors can be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).

[0321] Treating cancer can result in a reduction in the number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules may be reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) compared to the pre-treatment number. The number of metastatic nodules can be measured by any reproducible measurement method. For example, the number of metastatic nodules can be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, 10x, or 50x).

[0322] Aspects of the present invention relate to methods for treating CBP-related disorders such as inflammation and / or autoimmune disorders in subjects requiring treatment. In some embodiments, the compound (a) T cells (e.g., CD8) + It is administered in an effective dose and for a duration effective to produce one (or more, e.g., two or more, three or more, four or more) of the following: (b) reduced memory T cell activity, (c) reduced inflammation, (d) reduced thrombus formation, (e) reduced B cell proliferation, (e) increased survival rate of the subject, and (f) increased progression-free survival of the subject.

[0323] Treating inflammatory disorders and / or autoimmune disorders involves T cells (e.g., CD8 + This can lead to a reduction in memory T cell activity. For example, after treatment, T cells (e.g., CD8 + Memory T cell activity is reduced by more than 5% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) compared to its size before treatment. T cell activity can be measured by any reproducible measurement method.

[0324] Treating inflammatory disorders and / or autoimmune disorders can lead to a reduction in inflammation. For example, after treatment, inflammation is reduced by more than 5% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) compared to its pre-treatment level. T cell activity can be measured by any reproducible measurement method.

[0325] Treating inflammatory and / or autoimmune disorders can typically lead to alterations in cytokine signaling when phosphorylation within the JAK-STAT pathway is modified (e.g., by JAK inhibition or downstream effects such as CBP degradation). Specifically, each cytokine receptor is paired with a JAK pair. When a JAK pair is cross-linked by its cytokine, the JAKs phosphorylate each other and also phosphorylate the cytokine receptor, creating a STAT binding site for which STAT is then phosphorylated. In some embodiments, inhibiting JAK2 can affect the phosphorylation of EPO, TPO, GM-CSF, IL-3, IL-5, IL-12, IL-23, INF-γ, IL-6, IL-11, IL-13, IL-25, IL-27, and / or IL-31, which can then affect the immune system response. Other cytokines that interact with JAK1, JAK3, and / or TYK2 include IL-10, IL-22, type 1 IFN(α / β), IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Treating cancer, inflammatory disorders, and / or autoimmune disorders can result in an increase in the mean survival time of a population of subjects treated according to the present invention compared to an untreated population of subjects. For example, mean survival time increases by more than 30 days (more than 60, 90, or 120 days). The increase in mean survival time of a population can be measured by any reproducible means. The increase in mean survival time of a population can be measured, for example, by calculating the length of mean survival time for a population after the initiation of treatment with the compounds described herein. The increase in mean survival time of a population can also be measured, for example, by calculating the length of mean survival time for a population after completion of initial treatment with a pharmaceutically acceptable salt of the compounds described herein.

[0326] Treating cancer, inflammatory disorders, and / or autoimmune disorders can also result in a reduction in mortality in the treated population compared to the untreated population. For example, mortality may be reduced by more than 2% (e.g., more than 5%, 10%, or 25%). The reduction in mortality in the treated population can be measured by any reproducible means, for example, by calculating the mean number of disease-related deaths per unit time after the start of treatment with a pharmaceutically acceptable salt of the compound described herein for the population. The reduction in mortality in the population can also be measured, for example, by calculating the mean number of disease-related deaths per unit time after the completion of the first treatment with a pharmaceutically acceptable salt of the compound described herein for the population.

[0327] Combination therapy The method of the present invention can be used alone or in combination with additional therapeutic agents, such as other agents that treat cancer, inflammatory disorders, and / or immune disorders, or related conditions, or in combination with other types of therapies for treating cancer, inflammatory disorders, and / or immune disorders. In combination therapy, the dosage of one or more of the therapeutic compounds may be reduced from the standard dosage when administered alone. For example, the dosage may be determined empirically from the combination and permutation of drugs, or estimated by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)). In this case, the dosage of the compound when combined should provide a therapeutic effect.

[0328] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical useful for treating cancer). These include alkylating agents, antimetabolites, folate analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracendione-substituted ureas, methylhydrazine derivatives, adrenocortican inhibitors, corticosteroids, progestins, estrogens, antiestrogens, androgens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-exclusive examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carbocone, metsuredopa, and uredopa; ethyleneimines and methylamelamines, including altretamine; triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bratacin and bratacinone); camptothecin (including its synthetic analog topotecan); briostatin; calistatin; CC-1065 (including its synthetic analogs adzeresin, karzeresin, and baizeresin); Cryptophycin (specifically cryptophycin 1 and cryptophycin 8); dorastatin; duocalmycin (including synthetic analogs KW-2189 and CB1-TM1); eryuterobin; pancratistatin; sarcodictiin; spongistatin; chlorambucil, chlornafadin, colophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobenbitin, fenesterine, prednimustine, trophosphamide, uracil mustard and other nitrogen mustards; nitrosoureas such as camulstine, chlorozotosine, fotemustine, lomustine, nimustine, and ranimustine;Antibiotics such as engine antibiotics (e.g., calicheamicin, especially calicheamicin gamma II and calicheamicin omega II (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemycin including dynemycin A, bisphosphonates such as chlordronate; esperamicin; and neocardinostatin chromophore and related pigment protein engine antibiotic chromophores), acrasinomycin, actinomycin, autramycin, azaserin, bleomycin, kakutinomycin, carabicin, caminomycin, cardinophilin, chromo Mycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin, doxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potophyllomycin Antimetabolites such as puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, zolubicin, methotrexate and 5-fluorouracil (5-FU); folate analogs such as denopterin, methotrexate, pteropterin and trimethrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine and thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxy Pyrimidine analogs such as uridine, doxifluridine, enocitabine, and phloxuridine; androgens such as carsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; anti-adrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid infusions such as phloric acid; acegraton; aldofamide glycoside; aminolevulinic acid; enyluracil; amsacrin; bestrabusil; bisantren; edatrexate; defofamine;Demecolsin; Diadiquan; Elfomithine; Erliptinium acetate; Epotilon; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Ronidynin; Mytansinoids such as Mytansin and Ansamitosin; Mitoguazone; Mitoxantrone; Mopidanmol; Nitraeline; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK (Registered Trademark) Polysaccharide Complex (JHS Natural) Products (Eugene, OR), razoxane; rhizoxin; schizophyllan; spirogermanium; tenuazonic acid; triadicone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veraculin A, loridine A, and anguidin); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitractol; pipobromane; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE®, albumin-modified nanoparticle formulations of paclitaxel without chromophores (American Pharmaceuticals) Partners, Schaumberg, IL), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum-coordinated complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine;Furthermore, examples include any pharmaceutically acceptable salt, acid, or derivative of any of the above. Two or more chemotherapeutic agents may be used in a cocktail administered in combination with the first therapeutic agent described herein. Suitable drug regimens for combination chemotherapy are known in the art and are described, for example, in Saltz et al., Proc.Am.Soc.Clin.Oncol.18:233a (1999) and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0329] In some embodiments, the second therapeutic agent is a biological agent such as a cytokine used in cancer treatment (e.g., interferon or interleukin (e.g., IL-2)). In some embodiments, the biological agent is an anti-VEGF agent, such as an anti-angiogenic agent such as bevacizumab (AVASTIN®). In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that acts on a target to stimulate an anti-cancer response or antagonizes an antigen important to cancer.Such drugs include RITUXAN® (rituximab), ZENAPAX® (daclizumab), SIMULECT® (basiliximab), SYNAGIS® (palivizumab), REMICADE® (infliximab), HERCEPTIN® (trastuzumab), MYLOTARG® (gemtuzumab ozogamicin), CAMPATH® (alemtuzumab), ZEVALIN (registered trademark) (ibritumomab tiuxetan), HUMIRA (registered trademark) (adalimumab), XOLAIR (registered trademark) (omalizumab), BEXXAR (registered trademark) (tositumomab-I-131), RAPTIVA (registered trademark) (efalizumab), ERBITUX (registered trademark) (cetuximab), AVASTIN (registered trademark) (bevacizumab), TYSABRI (registered trademark) (natalizumab), ACTEMA (registered trademark) (tosi Lizumab), VECTIBIX (registered trademark) (panitumumab), LUCENTIS (registered trademark) (ranibizumab), SOLIRIS (registered trademark) (eculizumab), CIMZIA (registered trademark) (certolizumab pegol), SIMPONI (registered trademark) (golimumab), ILARIS (registered trademark) (canakinumab), STELARA (registered trademark) (ustekinumab), ARZERRA (registered trademark) (ofatumumab), PROLIA (registered trademark) (denos This includes mab), NUMAX® (motavizumab), ABTHRAX® (laxibakumab), BENLYSTA® (belimumab), YERVOY® (ipilimumab), ADCETRIS® (brentuximab vedotin), PERJETA® (pertuzumab), KADCYLA® (ado-trastuzumab emtansine), and GAZYVA® (obinutuzumab). Antibody drug conjugates are also included.

[0330] The second treatment may be a non-pharmacological therapeutic agent. For example, the second therapeutic agent may be radiotherapy, cryotherapy, hyperthermia, and / or surgical excision of tumor tissue.

[0331] The second drug may be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is a drug, such as an antibody, that interacts with the checkpoint protein. In some embodiments, the checkpoint inhibitor is a drug, such as an antibody, that interacts with the ligand of the checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor of CTLA-4 (e.g., an anti-CTLA4 antibody or fusion protein such as ipilimumab / YERVOY® or tremelimumab) (e.g., an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor of PD-1 (e.g., nivolumab / OPDIVO®, pembrolizumab / KEYTRUDA®, pidilizumab / CT-011) (e.g., an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor of PDL1 (e.g., MPDL3280A / RG7446, MEDI4736, MSB0010718C, BMS 936559) (e.g., an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor of PDL2 (e.g., a PDL2 / Ig fusion protein such as AMP 224) (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof (e.g., an inhibitory antibody or small molecule inhibitor).

[0332] In some embodiments, the anticancer therapy is T cell adoptive transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells can be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding a CAR into T cells. Prior to T cell proliferation and genetic modification, a T cell source is obtained from the subject. T cells can be obtained from several sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymic tissue, tissue from infection sites, ascites, pleural fluid, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art can be used. In some embodiments, the T cells are autologous T cells. Whether before or after gene modification of T cells to express a desired protein (e.g., CAR), T cells are generally, for example, U.S. Patent Nos. 6,352,694, 6,534,055, 6,905,680, 6,692,964, 5,858,358, 6,887,466, 6,905,681, and 7,144. It can be activated and propagated using the methods described in U.S. Patent Publication No. 575, No. 7,067,318, No. 7,172,869, No. 7,232,566, No. 7,175,843, No. 5,883,223, No. 6,905,874, No. 6,797,514, No. 6,867,041, and U.S. Patent Publication No. 20060121005.

[0333] The second agent may be a Janus kinase (JAK) inhibitor. In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, AG-490, brepocitinib, celduratinib, desernotinib, duklavacitinib, gandotinib, gusacitinib, itacitinib, momerotinib, nezurcitinib, or ritrecitinib.

[0334] In any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously, sequentially, or in any order. The first therapeutic agent may be administered immediately, before or after the second therapeutic agent, for up to 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or up to 1-7 days, 1-14 days, 1-21 days, or 1-30 days.

[0335] Pharmaceutical composition The pharmaceutical compositions described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biocompatible form suitable for in vivo administration.

[0336] The compounds described herein may be used in the form of free bases, salts, solvates, and as prodrugs. All forms are within the scope of the methods described herein. As will be understood by those skilled in the art, according to the methods of the present invention, the compounds described, or their salts, solvates, or prodrugs, may be administered to a patient in various forms depending on the selected route of administration. The compounds described herein may be administered, for example, orally, parenterally, orally, sublingually, nasally, rectally, by patch, pump, intratumorally, or transdermally, and pharmaceutical compositions may be formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, subarachnoid, rectal, and topical administration methods. Parenteral administration may be by continuous infusion over a selected period of time.

[0337] The compounds described herein may be administered orally, for example, with an inert diluent or an assimilated edible carrier, or encapsulated in hard or soft shell gelatin capsules, or compressed into tablets, or directly incorporated with food in a meal. For oral therapeutic administration, the compounds described herein may be incorporated with excipients and used in the form of digestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, and wafers. The compounds described herein may also be administered parenterally. Solutions of the compounds described herein can be prepared in water suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, as well as in oil. Under normal storage and use conditions, these preparations may contain preservatives to prevent microbial growth. Conventional procedures and components for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2012, 22nd ed.) and in The United States Pharmacopeia: The National Formulary (USP 41 NF36), published in 2018. Suitable pharmaceutical forms for injectable applications include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of injectable sterile solutions or dispersions. In all cases, the form must be sterile and fluid enough to be readily administered via syringe. Compositions for nasal administration can be conveniently formulated as aerosols, drops, gels, and powders. Aerosol formulations typically contain a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are supplied in a sterile form in single or multiple doses in a sealed container that can take the form of a cartridge or refill for use with a spray device. Alternatively, the sealed container may be a single-dose dispensing device, such as a nasal inhaler or aerosol dispenser fitted with a metering valve, intended for disposal after use.If the dosage form includes an aerosol dispenser, it includes a propellant which may be a compressed gas such as compressed air or an organic propellant such as a fluorochloro hydrocarbon. The aerosol dosage form may also take the form of a pump sprayer. Compositions suitable for oral or sublingual administration include tablets, lozenges, and troches in which the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, gelatin, and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter. The compounds described herein may be administered intratumorally, for example, as an intratumor injection. Intratumor injection is a direct injection into the tumor vascular system and is particularly intended for individual solid, accessible tumors. Topical, regional, or systemic administration may also be appropriate. The compounds described herein may be advantageously contacted by administering one or more injections to the tumor, for example, at intervals of approximately 1 cm. In the case of surgical intervention, the present invention may be used preoperatively, such as to induce resection of an inoperable tumor. Continuous administration can also be applied, where appropriate, for example, by implanting a catheter into the tumor or tumor vascular system.

[0338] The compounds described herein may be administered to animals, such as humans, alone or in combination with pharmaceutically acceptable carriers, as described herein, in proportion to the solubility and chemical properties of the compounds, the selected route of administration, and standard pharmacopoeias.

[0339] Dosage The dosage of the compounds described herein, and / or compositions containing the compounds described herein, may vary depending on many factors, including the pharmacodynamic properties of the compounds, the mode of administration, the age, health, and weight of the recipient, the nature and severity of the symptoms, the frequency of treatment, and, if present, the type of concomitant therapy, as well as the clearance rate of the compounds in the treated animal. Those skilled in the art can determine an appropriate dosage based on the above factors. The compounds described herein may be initially administered at a suitable dosage that may be adjusted as needed depending on the clinical response. Generally, satisfactory results can be obtained when the compounds described herein are administered to humans at a daily dose of, for example, 0.01 mg to 3000 mg (measured in solid form). The dose range includes, for example, 10 to 1000 mg (e.g., 50 to 800 mg).

[0340] Alternatively, the dosage can be calculated using the patient's weight. For example, the dose of a compound or its pharmaceutical composition administered to a patient may range from 0.1 to 50 mg / kg (e.g., 0.25 to 25 mg / kg).

[0341] kit The present invention also features a kit comprising (a) a pharmaceutical composition comprising an agent that reduces the level and / or activity of CBP in cells or subjects described herein, and (b) a package insert comprising instructions for carrying out any of the methods described herein. In some embodiments, the kit comprises (a) a pharmaceutical composition comprising an agent that reduces the level and / or activity of CBP in cells or subjects described herein, (b) an additional therapeutic agent (e.g., an anticancer agent), and (c) a package insert comprising instructions for carrying out any of the methods described herein. [Examples]

[0342] [Table 3-1] [Table 3-2] material Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. All reactions involving air or moisture-sensitive reagents were carried out under a nitrogen atmosphere.

[0343] Preparation of intermediates Preparation of intermediate 1: 1-{3-[7-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-quinoline-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-yl}ethanone [ka] Step 1. tert-butyl3-amino-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate A solution of tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate (20 g, 89 mmol) in EtOH (200 mL) was treated with hydrazine hydrate (80%) (6.7 g, 130 mmol) at 0°C. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with water (1.5 L), and extracted with dimethyl phosphate (1 L x 3). The combined organic layers were washed with brine (1 L x 2) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was purified by FCC (eluent: CH2Cl2 / MeOH (20:1)) to obtain the title compound (16 g, 67 mmol) as a white solid. LC-MS (ESI) m / z [M+H] + =239.1.

[0344] Step 2. tert-butyl3-bromo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate CuBr2 (15.5 g, 69 mmol) was added to a stirred solution of tert-butyl 3-amino-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (15 g, 63 mmol) in ACN (100 mL). Then, 3-methylbutyl nitrite (11.1 mL, 63 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 60°C for a further 3 hours. The mixture was cooled to room temperature. The mixture was diluted with ELISA (500 mL), washed with saturated NH4Cl (aqueous solution) (500 mL x 7) and brine (500 mL x 2), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was purified by FCC (eluent: PE / THF (3:1)) to obtain a semi-pure product, which was then purified by grinding with PE / siRNA (5:1) to obtain the title compound (10.2 g, 34 mmol) as a white solid. LC-MS (ESI) m / z [M+H]+=302.0

[0345] Step 3. tert-butyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate Cs2CO3 (32.4 g, 99.3 mmol) was added to a stirred solution of tert-butyl 3-bromo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (10 g, 33.1 mmol) and tetrahydro-2H-pyran-4-ylmethanesulfonate (8.95 g, 49.6 mmol) in DMF (100 mL). The reaction mixture was stirred at 80°C for 3.5 hours. The resulting mixture was then diluted with water (700 mL) and extracted with ELISA (700 mL x 2). The organic layers were combined, washed with brine (1 L x 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by FCC (eluent:PE / (THF:MTBE=1:1)(1.5:1)) to obtain two isomers. The second eluted isomer was collected and concentrated under reduced pressure. The residue was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), 10% to 50% gradient over 10 minutes, detector, UV 254 nm) to obtain the title compound (6.7 g, 17 mmol) as a white solid. LC-MS (ESI) m / z[M+H]+=386.1.

[0346] Step 4. tert-butyl3-(7-(difluoromethyl)-3,4-dihydroquinoline-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate t-BuONa (2.31 g, 24.1 mmol) and RuPhos Pd G3 (671 mg, 0.80 mmol) were added to a stirred solution of tert-butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (3.1 g, 8.0 mmol) and 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (1.5 g, 8.0 mmol) in 1,4-dioxane (30 mL). The reaction mixture was stirred at 85°C for 8 hours. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by FCC (eluent: PE / siRNA (1:1)) to obtain the title compound (3.1 g, 6.3 mmol) as a yellow solid. LCMS(ESI)m / z[M+H] + =489.2.

[0347] Step 5. tert-butyl3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinoline-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate NBS (1.0 g, 5.6 mmol) was gradually added to a stirred solution of tert-butyl 3-(7-(difluoromethyl)-3,4-dihydroquinoline-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (3.1 g, 6.3 mmol) in ACN (30.0 mL) at 0°C. After stirring at room temperature for 2 hours, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by FCC (eluent: PE / siRNA (1:1)) to obtain the title compound (3.5 g, 6.2 mmol) as a yellow solid. LC-MS (ESI) m / z [M+H] + =567.2.

[0348] Step 6. 6-Bromo-7-(difluoromethyl)-1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-1,2,3,4-tetrahydroquinoline A mixture of tert-butyl 3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinoline-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (3.5 g, 6.1 mmol) in DCM (28 mL) and TFA (7 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (700 mL) and extracted with ethyl acetate (700 mL x 3). The organic layers were combined, washed with brine (600 mL x 2), dried over anhydrous sodium 2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate 7 (2.5 g, 5.3 mmol) as a yellow oil. LC-MS (ESI) m / z [M+H]+ = 467.1.

[0349] Step 7.1-(3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinoline-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl)ethane-1-one Ac2O (596 mg, 5.8 mmol) was gradually added at 0°C to a stirred mixture of 6-bromo-7-(difluoromethyl)-1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-1,2,3,4-tetrahydroquinoline (2.5 g, 5.3 mmol) and TEA (1.6 g, 15.9 mmol) in DCM (25.0 mL). After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (600 mL) and extracted with CH2Cl2 (600 mL x 3). The organic layers were combined, washed with brine (500 mL x 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by FCC (eluent: CH2Cl2 / MeOH (20:1)) to obtain the title compound (2.1 g, 4.1 mmol) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ=7.32(s,1H),7.12-6.59(m,2H),4.37-4.24(m,1 H),4.18(s,2H),4.01-3.91(m,2H),3.74(t,J=5.8Hz,2H),3.62-3.55(m,2 H),3.49(td,J=11.7,2.3Hz,2H),2.92-2.70(m,4H),2.08(s,2H),2.03-1 .89(m,5H),1.81(dt,J=9.4,4.1Hz,2H)ppm.LCMS(ESI)m / z[M+H]+=509.1.

[0350] Step 8.1-{3-[7-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-quinoline-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-yl}ethanone KOAc (0.58 g, 5.89 mmol) and Pd(dppf)Cl2CH2Cl2 (0.24 g, 0.294 mmol) were added to a stirred solution of 1-{3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-yl}ethanone (1 g, 1.96 mmol) and bis(pinacolate)diborone (1.25 g, 4.91 mmol) in dioxane (20 mL). The resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with siRNA (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by FCC (eluent: Â1 / PE (0-100%)) to obtain the title compound (1.59 g, crude) as a brown solid, which was used directly without further purification. LC-MS(ESI) m / z[M+H] + =557.0.

[0351] Intermediate 2: 1-(3-(6-bromo-3,4-dihydroquinoline-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl)ethane-1-one [ka] Step 1. tert-butyl3-(3,4-dihydroquinoline-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate RuPhos Pd G3 (108 mg, 0.13 mmol) and t-BuONa (498 mg, 5.2 mmol) were added to a stirred solution of tert-butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (500 mg, 1.3 mmol) and tetrahydroquinoline (172 mg, 1.3 mmol) in dioxane (7 mL). The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was then diluted with toluene (100 mL) and washed with water (50 mL x 2) and brine (50 mL x 1). The organic layer was dried over Na2SO4, filtered, and evaporated to obtain the crude product. The residue was purified by FCC (eluent: CH2Cl2 / MeOH (10:1)) to obtain the title compound (451 mg, 1.0 mmol) as a yellow solid. LC-MS (ESI) m / z[M+H]+=439.2.

[0352] Step 2. tert-butyl3-(6-bromo-3,4-dihydroquinoline-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate NBS (74.7 mg, 0.42 mmol) was gradually added to a stirred solution of tert-butyl 3-(3,4-dihydroquinoline-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (230 mg, 0.52 mmol) in ACN (3 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ELISA (30 mL), washed with water (30 mL x 2) and brine (30 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative HPLC (column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 63%B~80%B, 80%B over 9 min, wavelength: 254 / 220 nm, RT1 (min): 7.68) to obtain the title compound (112 mg, 0.21 mmol) as a white solid. LC-MS (ESI) m / z[M+H]+=517.4.

[0353] Step 3.6-Bromo-1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-1,2,3,4-tetrahydroquinoline A solution of tert-butyl 3-(6-bromo-3,4-dihydroquinoline-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (112 mg, 0.22 mmol) in DCM (0.9 mL) and TFA (0.3 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain intermediate 4 (138 mg, crude) as a yellow oil. The crude product was used directly in the next step without further purification. LC-MS (ESI) m / z[M+H]+=417.35.

[0354] Step 4.1-(3-(6-bromo-3,4-dihydroquinoline-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl)ethane-1-one Acetic anhydride (37.1 mg, 0.36 mmol) was added dropwise to a stirred solution of 6-bromo-1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-1,2,3,4-tetrahydroquinoline (138 mg, 0.33 mmol) and TEA (100 mg, 0.99 mmol) in DCM (2 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase FCC (column, C18 silica gel, mobile phase, ACN in water (0.1% FA), gradient from 0% to 100% over 20 minutes, detector, UV 254 nm) to obtain the title compound (84 mg, 0.18 mmol) as an off-white solid. LCMS(ESI)m / z[M+H]+=453.3.

[0355] Intermediate 3: 1-(3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinoline-1(2H)-yl)-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl)ethane-1-one [ka] Step 1. tert-butyl3-bromo-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate A solution of tert-butyl 3-bromo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (500 mg, 1.66 mmol) in DMF (10 mL) was treated with NaH (119 mg, 5.0 mmol) at 0°C. After stirring at 0°C for 30 minutes, MeI (352 mg, 2.48 mmol) was added. The reaction mixture was stirred at room temperature for a further 2 hours. The reaction product was quenched by adding saturated NH4Cl (aqueous solution) (30 mL) at 0°C and extracted with ₹ (30 mL × 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (eluent: PE / THF (8:1)) to obtain a semi-pure product. Next, the product was purified by reverse-phase FCC (column, C18 silica gel, mobile phase, MeOH in water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain the title compound (450 mg, 1.4 mmol) as a white solid. LC-MS (ESI) m / z[M+H]+=315.9.

[0356] Step 2. tert-butyl3-(7-(difluoromethyl)-3,4-dihydroquinoline-1(2H)-yl)-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate RuPhos Pd G3 (106 mg, 0.13 mmol) and t-BuONa (365 mg, 3.8 mmol) were added to a stirred solution of tert-butyl 3-bromo-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (400 mg, 1.26 mmol) and 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (232 mg, 1.26 mmol) in dioxane (12 mL). The reaction mixture was stirred at 100 °C for 1 hour. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase FCC (column, C18 silica gel, mobile phase, ACN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain the title compound (80 mg, 0.19 mmol) as a yellow solid. LC-MS (ESI) m / z[M+H]+=419.2.

[0357] Step 3. tert-butyl3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinoline-1(2H)-yl)-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate NBS (29.7 mg, 0.17 mmol) was added at 0°C to a stirred solution of tert-butyl 3-(7-(difluoromethyl)-3,4-dihydroquinoline-1(2H)-yl)-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 3 (70 mg, 0.17 mmol) in ACN (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ELISA (50 mL) and washed with water (30 mL x 2) and brine (30 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by FCC (eluent: PE / EA 1:1) to obtain the title compound (107 mg, crude) as a white solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z[M+H]+=497.2.

[0358] Step 4.6-Bromo-7-(difluoromethyl)--1-(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-1,2,3,4-tetrahydroquinoline A solution of tert-butyl 3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinoline-1(2H)-yl)-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (100 mg, 0.20 mmol) and TFA (1 mL) in DCM (3 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain the title compound (165 mg, crude) as a black oil. The crude product was used directly in the next step without further purification. LC-MS(ESI) m / z[M+H]+=397.0.

[0359] Step 5.1-(3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinoline-1(2H)-yl)-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl)ethane-1-one Acetic anhydride (61.6 mg, 0.60 mmol) was added at 0°C to a stirred solution of 6-bromo-7-(difluoromethyl)-1-(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-1,2,3,4-tetrahydroquinoline (160 mg, 0.40 mmol) and TEA (122 mg, 1.21 mmol) in DCM (4 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (50 mL) and washed with water (30 mL x 2) and brine (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by FCC (eluent: CH2Cl2 / MeOH (20:1)) to obtain the title compound (69 mg, 0.16 mmol) as a white solid. LCMS(ESI)m / z[M+H]+=439.1.

[0360] Intermediate 4: 1-(3-(7-bromo-6-(difluoromethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl)ethane-1-one [ka] Step 1. 1-(2-chloroethoxy)-4-(difluoromethyl)-2-nitrobenzene LDA (2M in THF, 39.5 ml, 79.1 mmol) was added dropwise to a solution of 2-chloroethanol (5.09 g, 63.4 mmol) in THF (110 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 15 minutes. A solution of 4-(difluoromethyl)-1-fluoro-2-nitrobenzene (10.1 g, 52.8 mmol) in THF (10 mL) was added to the reaction mixture at room temperature. After stirring for 2 hours, water (150 mL) was added and extracted with EA (300 mL x 2). The organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, and removed under reduced pressure. The residue was purified by FCC (eluent: heptane, 0-30% EA) to obtain the title compound (13.0 g, 51.8 mmol) as an off-white solid. LCMS(ESI)m / z[M+H] + =252.1.

[0361] Step 2. 2-(2-chloroethoxy)-5-(difluoromethyl)aniline Iron powder (17.3 g, 310.8 mmol, 6 equivalents) was added to a stirred solution of 1-(2-chloroethoxy)-4-(difluoromethyl)-2-nitrobenzene (13.0 g, 51.8 mmol) in AcOH (60 mL). After stirring for 4 hours, the reaction mixture was quenched with water (150 mL) and extracted with EA (300 mL x 2). The organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by FCC (eluent: heptane with 0-25% EA) to obtain the title compound (8.90 g, 40.4 mmol) as an off-white solid. LC-MS (ESI) m / z [M+H] + =222.1.

[0362] Step 3. 6-(difluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine KI (10.3 g, 62.6 mmol) and K2CO3 (12.9 g, 93.9 mmol) were added to a stirred solution of 2-(2-chloroethoxy)-5-(difluoromethyl)aniline (6.95 g, 31.3 mmol) in DMAc (35 mL). The reaction mixture was heated at 90 °C for 7 hours. The reaction mixture was then cooled to room temperature and quenched with water (150 mL). The reaction mixture was then extracted with EA (300 mL x 2). The organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, and removed under reduced pressure. The residue was purified by FCC (eluent: heptane with 0-25% EA) to obtain the title compound (5.79 g, 28.8 mmol) as an off-white solid. LC-MS (ESI) m / z [M+H] + =186.1.

[0363] Intermediate 5: 1-(3-(7-bromo-6-(difluoromethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl)ethane-1-one [ka] Step 1: tert-butyl3-amino-1H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate Hydrazine hydrate (50-60% in water) (105 mL, 1.35 mol) was added to a solution of tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate (10 g, 0.45 mol) in EtOH (600 mL). The resulting mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude substance was diluted with water (1.5 L) and extracted with DCM (1 L x 3). The combined organic layers were washed with brine (1 L x 2) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (107 g, 445 mmol) as a white solid. LCMS(ESI)m / z[M+H] + =239.1.

[0364] Step 2: tert-butyl3-bromo-1H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate CuBr2 (108 g, 484 mmol) and 3-methylbutyl nitrite (64.4 mL, 484 mmol) were added at 0°C to a stirred solution of tert-butyl 3-amino-1H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate 2 (106.6 g, 445 mmol) in anhydrous MeCN (170 mL). The resulting mixture was stirred at 60°C for 2 hours. The reaction mixture was then diluted with SiO2 (1 L) and washed with saturated NH4Cl (aqueous solution) (600 mL x 4), 1 M HCl (600 mL x 3), and brine (600 mL x 2). The organic phases were combined and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The crude product was dried overnight under high vacuum to obtain a reddish solid. Methyl tert-butyl ether (MTBE) was gradually added to the crude product and stirred to prepare a slurry. The solid was filtered off and washed with a minimum amount of MTBE and heptane to obtain the title compound (68 g, 224 mmol) as an off-white crystalline solid. LC-MS(ESI) m / z[M+H] + =304.0.

[0365] Step 3: tert-butyl3-bromo-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate Cs2CO3 (63.3 g, 203 mmol) was added to a stirred solution of tert-butyl 3-bromo-1H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate (20.5 g, 67.8 mmol) and oxan-4-ylmethanesulfonate (18.3 g, 101.7 mmol) in DMAc (130 mL). The resulting mixture was stirred at 80°C for 3.5 hours. The resulting mixture was diluted with water (300 mL) and extracted with RINKAN (400 mL x 2). The organic layers were combined and washed with brine (100 mL). The organic layers were then dried over anhydrous Na2SO4 and removed under reduced pressure. The residue was purified by FCC (eluent: heptane 0-45% EA) to obtain two isomers. The retention time of the desired isomer was longer than that of the undesired isomer. The fractions containing the desired isomer were combined, and the solvent was removed to obtain the title compound (13.1 g, 34.0 mmol) as a white solid. LC-MS(ESI) m / z[M+H] + =386.2.

[0366] Step 4. 3-Bromo-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine TFA (15 mL) was added to a solution of tert-butyl 3-bromo-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate (21.6 g, 55.6 mmol) in DCM (60 mL). The reaction mixture was stirred for 4 hours. The reaction mixture was then concentrated under reduced pressure, and the TFA was co-evaporated with toluene (20 mL x 2) to obtain the title compound (approximately 24 g, crude) as a yellow viscous substance. The crude product was used in the next step without further purification. LC-MS (ESI) m / z [M+H] + =288.1.

[0367] Step 5.1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl)ethane-1-one TEA (19.3 mL, 138 mmol) was added to a solution of 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (15.8 g, 55.4 mmol) in DCM (150 mL). The reaction mixture was stirred for 15 minutes. The mixture was cooled to 0°C, and acetic anhydride (5.75 mL, 60.9 mmol) was added in two batches. After 2 hours, water (150 mL) was added to quench the reaction product. The crude product was extracted with DCM (300 mL x 3), washed with brine (100 mL), dried over anhydrous Na2SO4, and removed under reduced pressure. The residue was purified by FCC (eluent: 0-5% MeOH in DCM) to obtain the title compound (15.8 g, 47.6 mmol) as an off-white solid. LCMS(ESI)m / z[M+H] + =328.1.

[0368] Step 6.1-(3-(6-(difluoromethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl)ethane-1-one Cs2CO3 (20.7 g, 63.6 mmol) and XPhos Pd G3 (2.15 g, 2.5 mmol) were added to a stirred solution of 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline 7 (3.94 g, 21.2 mmol) and 1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl)ethane-1-one (8.99 g, 27.4 mmol) in nitrogen-degassed 1,4-dioxane (100 mL). The resulting mixture was stirred at 120 °C for 18 hours. The reaction mixture was then cooled to room temperature and quenched with water (300 mL). The crude product was extracted with EA (300 mL x 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na₂SO₄, and removed under reduced pressure. The residue was purified by FCC (eluent: 0-5% MeOH in DCM) to obtain the title compound (9.07 g, 21.0 mmol) as an off-white solid. LC-MS(ESI) m / z[M+H] + =433.1.

[0369] Step 7.1-{3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-yl}ethanone NBS (3.73 g, 21.0 mmol) was added in three portions to a stirred solution of 1-(3-(6-(difluoromethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl)ethane-1-one (9.07 g, 21.0 mmol) in MeCN (100 mL) at 0 °C. After stirring for 2 hours, the resulting mixture was diluted with water (100 mL) and extracted with EA (400 mL x 2). The organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, and removed under reduced pressure. The residue was purified by FCC (eluent: 0-5% MeOH in DCM) to obtain the title compound (10.6 g, 20.7 mmol) as an off-white solid. LC-MS (ESI) m / z [M+H] + =511.1.

[0370] Intermediate 6: (2S,4R)-1-(L-valyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] Step 1. tert-butyl(2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate Ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (2.7 g, 11 mmol) was added to a stirred solution of (1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethaneamine (2 g, 9.2 mmol) and (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.1 g, 9.2 mmol) in DCM (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM (100 mL) and washed with water (50 mL x 2) and brine (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain the title compound (1.06 g, 2.5 mmol) as a white solid. LC-MS (ESI) m / z[M+H]+=432.2.

[0371] Step 2. (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TFA (2 mL) was added to a stirred solution of tert-butyl(2S,4R)-4-hydroxy-2-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (1 g, 2.3 mmol) in DCM (8 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by reverse-phase FCC (column, C18 silica gel, mobile phase, ACN in water (0.1% TFA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain the title compound (682 mg, 2.1 mmol) as a yellow solid. LC-MS (ESI) m / z[M+H]+=332.1.

[0372] Step 3. tert-butyl((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate HATU (936 mg, 2.5 mmol) was added to a stirred solution of (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (680 mg, 2.0 mmol), (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (446 mg, 2.0 mmol), and DIEA (796 mg, 6.2 mmol) in DMF (7 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ELISA (100 mL) and washed with water (70 mL x 2) and brine (70 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reverse-phase FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain the title compound (578 mg, 1.1 mmol) as a yellow solid. LC-MS (ESI) m / z[M+H]+=531.3.

[0373] Step 4. (2S,4R)-1-(L-valyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a stirred solution of tert-butyl((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (80 mg, 0.15 mmol) in DCM (1 mL), TFA (0.3 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (71 mg, crude) as a white solid. LC-MS(ESI) m / z[M+H]+=431.2.

[0374] Intermediate 7: tert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate [ka] Step 1. tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylate LiHMDS (792 mg, 4.73 mmol) was added dropwise to a stirred solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 2.36 mmol) in THF (5 mL) at -78°C. The mixture was stirred for 0.5 hours, and then 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (1.69 g, 4.73 mmol) was added to the mixture. The reaction mixture was heated and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase FCC to obtain the title compound (220 mg, 0.64 mmol) as a yellow solid. LC-MS(ESI) m / z: [M+H]+=329.

[0375] Step 2. tert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate KOAc (252 mg, 2.56 mmol) and Pd(dppf)Cl2 (46.9 mg, 0.064 mmol) were added at room temperature to a stirred solution of tert-butyl 6-(trifluoromethanesulfonyloxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (220 mg, 0.64 mmol) and bis(pinacolate)diborone (325 mg, 1.28 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by FCC (eluent: PE / siRNA(12:1)) to obtain the title compound (100 mg, 0.31 mmol) as a black solid. LCMS(ESI) m / z:[M+H]+=322.

[0376] Intermediate 8: tert-butyl9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azaspiro[5.5]undec-8-ene-3-carboxylate [ka] Step 1. tert-butyl 9-(((trifluoromethyl)sulfonyl)oxy)-3-azaspiro[5.5]undec-8-ene-3-carboxylate Lithium bis(trimethylsilyl)amide (0.06 mL, 0.56 mmol) was added dropwise to a stirred solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (100 mg, 0.37 mmol) in THF (3 mL) at -78°C. After stirring at -78°C for 1 hour, a solution of 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (200 mg, 0.56 mmol) in THF (5 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was quenched with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with  (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (eluent: PE / SiO(5:1)) to obtain the title compound (1.3 g, 3.3 mmol) as a yellow oil. LC-MS(ESI) m / z[M+H]+=399.4.

[0377] Step 2. tert-butyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azaspiro[5.5]undec-8-ene-3-carboxylate Pd(dppf)Cl2 (238 mg, 0.33 mmol) was added to a solution of tert-butyl 9-(((trifluoromethyl)sulfonyl)oxy)-3-azaspiro[5.5]undec-8-ene-3-carboxylate (1.3 g, 3.3 mmol), bis(pinacolate)diborone (1.65 g, 6.5 mmol), and KOAc (958 mg, 9.8 mmol) in dioxane (20 mL). The solution was stirred at 80°C for 3 hours. The precipitated solid was collected by filtration and washed with Â(50 mL × 2). The crude product was purified by reversed-phase FCC (column, C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain the title compound (1.03 g, 2.7 mmol) as a white solid. LC-MS (ESI) m / z[M+H]+=377.3

[0378] Intermediate 9: 7-bromopyrido[3,2-d]pyrimidine-2-carboxylic acid [ka] Step 1. Ethyl [(5-bromo-2-formylpyridine-3-yl)carbamoyl]formate Ethyl chloroglyoxylate (441 mg, 3.23 mmol) was gradually added at 0°C to a stirred solution of 3-amino-5-bromopyridine-2-carbaldehyde (500 mg, 2.49 mmol) and pyridine (590 mg, 7.46 mmol) in DCM (6 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was diluted with DCM (60 mL), washed with water (60 mL x 2) and saturated brine (60 mL x 3), and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (755 mg, crude) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] + =301.1.

[0379] Step 2. Ethyl 7-bromopiride[3,2-d]pyrimidine-2-carboxylate CH3COONH4 (1.93 g, 25.1 mmol) was added gradually at room temperature to a stirred solution of ethyl [(5-bromo-2-formpyridine-3-yl)carbamoyl]formate (755 mg, 2.51 mmol) in HOAc (25 mL). The resulting mixture was stirred at 115 °C for 1 hour. The reaction mixture was diluted with water (75 mL), and the resulting mixture was neutralized to pH 7 with 1 N NaOH (aqueous solution) and extracted with ₹ (100 mL × 3). The combined organic layer was washed with saturated brine (300 mL × 1), dried over Na₂SO₄, filtered, and evaporated. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to obtain the title compound (480 mg, 1.70 mmol) as a reddish-brown solid. 1H NMR(300MHz,DMSO-d6)δ=9.85(s,1H),9.36(d,J=2.2Hz,1H),9.06(dd,J=2.2,0.9H z,1H),4.46(q,J=7.1Hz,2H),1.39(t,J=7.1Hz,3H).LCMS(ESI)m / z[M+H]+=282.1.

[0380] Step 3. 7-Bromopyride[3,2-d]pyrimidine-2-carboxylic acid LiOH . H2O (134 mg, 3.19 mmol) was added to a stirred solution of ethyl 7-bromopiride[3,2-d]pyrimidine-2-carboxylate (300 mg, 1.06 mmol) in MeOH (4 mL) and H2O (1 mL). The resulting mixture was stirred at 15°C for 1 hour. The mixture was neutralized to pH 5-6 with 1 N HCl (aqueous solution). The resulting mixture was concentrated under reduced pressure. This yielded the title compound (351 mg, 1.38 mmol) as a yellowish-brown solid. LC-MS(ESI) m / z[M+H] + =254.0

[0381] Intermediate 10: 7-bromoquinazoline-2-carboxylic acid [ka] Step 1. Ethyl [(5-bromo-2-formylphenyl)carbamoyl]formate Ethyl chloroglyoxylate (512 mg, 3.75 mmol) was added dropwise to a stirred mixture of 2-amino-4-bromobenzaldehyde (500 mg, 2.50 mmol) and pyridine (593 mg, 7.50 mmol) in DCM (5 mL) at 0°C. The resulting mixture was stirred further at room temperature for 1 hour. The reaction was quenched with water (100 mL). The mixture was extracted with DCM (3 × 80 mL). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na₂SO₄. The resulting mixture was concentrated under reduced pressure to obtain the title compound (1.2 g, crude) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] + =299.9.

[0382] Step 2. Ethyl 7-bromoquinazoline-2-carboxylate CH3COONH4 (3.08 g, 40.0 mmol) was gradually added to a stirred mixture of ethyl [(5-bromo-2-formylphenyl)carbamoyl]formate (1.20 g, 4.00 mmol) in AcOH (36 mL) at room temperature. The resulting mixture was stirred further at 115°C for 1 hour. The resulting mixture was neutralized to pH 7 with 1N NaOH (aqueous solution) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (150 mL x 2) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (0%~100%) to obtain the title compound (420 mg, 1.50 mmol) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=9.80(d,J=0.9Hz,1H),8.46(d,J=0.8Hz,1H),8.25(d,J=8.7Hz,1H), 8.08(dd,J=8.7,1.9Hz,1H),4.45(q,J=7.1Hz,2H),1.38(t,J=7.1Hz,3H).LCMS(ESI)m / z[M+H] + =281.0

[0383] Step 3. 7-Bromoquinazoline-2-carboxylic acid LiOH . H2O (179 mg, 4.27 mmol) was added to a stirred solution of ethyl 7-bromoquinazoline-2-carboxylate (300 mg, 1.07 mmol) in MeOH (4 mL) and H2O (1 mL). The resulting mixture was stirred at 15°C for 1 hour. The mixture was acidified to pH 5 with 1 N HCl (aqueous solution). The resulting mixture was extracted with siRNA (100 mL x 3). The combined organic layer was washed with brine (100 mL x 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeOH in water (0.1% TFA), gradient from 0% to 100% over 30 minutes, detector, UV 254 nm, to obtain the title compound (200 mg, 0.79 mmol) as a white solid. LCMS(ESI)m / z[M+H] + =252.0

[0384] Intermediate 11: 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazine [ka] Step 1. 1-Chloro-2-(difluoromethyl)-5-fluoro-4-nitrobenzene DAST (19.8 g, 122.8 mmol) was added at 0°C to a stirred solution of 2-chloro-4-fluoro-5-nitrobenzaldehyde (5.0 g, 24.6 mmol) in DCM (50 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched by adding saturated NH4HCO3 (aqueous solution) (100 mL) at 0°C. The resulting mixture was extracted with Âx (100 mL x 3). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (20:1) to obtain the title compound (4.9 g) as a yellow oil. LCMS(ESI)m / z[M+H] + =226.0.

[0385] Step 2. Methyl 2-[5-chloro-4-(difluoromethyl)-2-nitrophenoxy]acetate K2CO3 (2.5 g, 17.7 mmol) was added to a stirred solution of 1-chloro-2-(difluoromethyl)-5-fluoro-4-nitrobenzene (2.0 g, 8.9 mmol) and 2-hydroxymethyl acetate (1.6 g, 17.7 mmol) in DMF (20 mL). The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was diluted with water (50 mL) and extracted with SiO2 (50 mL x 3). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel, mobile phase, ACN in water (0.1% FA), gradient from 0% to 100% over 15 minutes, detector, UV254 nm) to obtain the title compound (2.05 g) as a gray solid. LCMS(ESI) m / z[M+H] + =296.0.

[0386] Step 3. 7-Chloro-6-(difluoromethyl)-2,4-dihydro-1,4-benzoxazine-3-one AcOH (4 mL) and Fe (2.1 g, 37.2 mmol) were added to a stirred solution of methyl 2-[5-chloro-4-(difluoromethyl)-2-nitrophenoxy]acetate (2.0 g, 7.4 mmol) and H2O (10 mL) in EtOH (10 mL). The resulting mixture was stirred at 80°C for a further 1 hour. The resulting mixture was neutralized to pH=8 with saturated Na2CO3 (aqueous solution) and extracted with SiO2 (50 mL x 3). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / SiO2 (10:1) to obtain the title compound (1.1 g) as a yellow solid. LCMS(ESI)m / z[M+H] + =234.0.

[0387] Step 4. 7-Chloro-6-(difluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine A solution of 7-chloro-6-(difluoromethyl)-2,4-dihydro-1,4-benzoxazine-3-one (700 mg, 3.0 mmol) and BH3-THF (5 mL, 48.0 mmol) in THF (10 mL) was stirred at 60°C for 1 hour. The reaction mixture was quenched with MeOH at 0°C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (10:1) to obtain the title compound (624 mg) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.15-6.78(m,3H),6.26(t,J=2.4Hz,1H),4.19-4.11(m,2H),3.33-3.25(m,2H).LCMS(ESI)m / z[M+H] + =220.0.

[0388] Intermediate 12: 6-Chloro-7-(difluoromethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine [ka] Step 1: 5-Bromo-2-chloro-3-(difluoromethyl)pyridine DAST (43.9 g, 272.2 mmol) was added dropwise to a stirred mixture of 5-bromo-2-chloropyridine-3-carbaldehyde (20.0 g, 90.7 mmol) in DCM (100 mL) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at room temperature for a further 2 hours. The reaction mixture was quenched with saturated NaHCO3 (aqueous solution) at 0°C. The mixture was extracted with DCM (500 mL x 2). The combined organic layers were washed with brine (300 mL x 2) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (20:1) to obtain the title compound (18.8 g) as a yellow oil. 1 H NMR(300MHz,DMSO-d6)δ 8.78(s,1H),8.41(s,1H),7.51-6.92(m,1H).

[0389] Step 2. N-(6-chloro-5-(difluoromethyl)pyridine-3-yl)-1,1-diphenylmethanymine t-BuONa (9.3 g, 96.5 mmol), XantPhos (8.6 g, 14.8 mmol), and Pd2(dba)3 (6.8 g, 7.4 mmol) were added to a stirred mixture of 5-bromo-2-chloro-3-(difluoromethyl)pyridine (18.0 g, 74.2 mmol) and diphenylmethanimine (13.5 g, 74.2 mmol) in toluene (200 mL) under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (300 mL) and then extracted with siRNA (500 mL x 2). The combined organic layer was washed with brine (300 mL x 2) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (34.2 g, crude) as a brown oil. The crude product was used directly in the next step without further purification. LC-MS(ESI)m / z[M+H] + =342.95.

[0390] Step 3. 6-Chloro-5-(difluoromethyl)pyridine-3-amine 1M HCl (200 mL, 200 mmol) was added dropwise to a stirred solution of N-(6-chloro-5-(difluoromethyl)pyridine-3-yl)-1,1-diphenylmethaneimine (34.2 g, 99.8 mmol) in THF (200 mL) at room temperature. The resulting mixture was stirred at room temperature for 6 hours. The mixture was basicized to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was diluted with water (200 mL) and then extracted with ethyl phosphate (500 mL x 2). The combined organic layer was washed with brine (300 mL x 2) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / ethyl phosphate (5:1) to obtain the title compound (9.4 g) as a pale yellow oil. LCMS(ESI)m / z[M+H] + =179.10. 1 H NMR(300MHz,DMSO-d6)δ 7.85(s,1H),7.26(d,J=2.9Hz,1H),7.05(t,J=54.3Hz,1H),5.85(s,2H).

[0391] Step 4. 2-Bromo-6-chloro-5-(difluoromethyl)pyridine-3-amine NBS (9.37 g, 52.6 mmol) in ACN (50 mL) was added dropwise to a stirred solution of 6-chloro-5-(difluoromethyl)pyridine-3-amine (9.4 g, 52.6 mmol) in ACN (100 mL) at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was quenched with saturated Na₂S₂O₃ (aqueous solution). The resulting mixture was extracted with RINKAN (300 mL x 2). The combined organic layers were washed with brine (100 mL x 2) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / RINKAN (10:1) to obtain the title compound (11.8 g) as a yellow solid. LC-MS (ESI) m / z[M+H]+=256.8 & 258.8. 1H NMR(300MHz,DMSO-d6)δ 7.40(s,1H),7.08(t,J=54.0Hz,1H),6.06(s,2H).

[0392] Step 5. Ethyl(E)-3-(3-amino-6-chloro-5-(difluoromethyl)pyridine-2-yl)acrylate K2CO3 (19.0 g, 137.5 mmol) and Pd(dppf)Cl2 (3.4 g, 4.6 mmol) were added under a nitrogen atmosphere to a stirred mixture of dioxane (100 mL), 2-bromo-6-chloro-5-(difluoromethyl)pyridine-3-amine (11.8 g, 45.8 mmol), and ethyl(2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (8.8 mg, 0.039 mmol) in H2O (20 mL). The resulting mixture was stirred at 60°C for 4 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (200 mL) and then extracted with ethyl(300 mL x 2). The combined organic layer was washed with brine (100 mL x 2) and dried over anhydrous sodium(2 SO4). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / SiO(10:1) to obtain the title compound (9.1g) as a yellow solid. LC-MS(ESI) m / z[M+H]+=276.80.

[0393] Step 6. Ethyl 3-(3-amino-6-chloro-5-(difluoromethyl)pyridine-2-yl)propanoate Rh(PPh3)3Cl (1.5 g, 1.6 mmol) was added to a stirred solution of ethyl(E)-3-(3-amino-6-chloro-5-(difluoromethyl)pyridine-2-yl)acrylate (9.1 g, 32.9 mmol) in MeOH (150 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The solvent was removed under reduced pressure. The mixture was filtered, and the filter cake was washed with ELISA (200 mL x 2). The filtrate was concentrated under reduced pressure to obtain the title compound (9.2 g, crude). The crude product was used directly in the next step without further purification. LCMS(ESI) m / z[M+H]+=279.00

[0394] Step 7. 6-Chloro-7-(difluoromethyl)-3,4-dihydro-1,5-naphthyridine-2(1H)-one AcOH (5.7 mL, 99.0 mmol) was added dropwise to a stirred solution of ethyl 3-(3-amino-6-chloro-5-(difluoromethyl)pyridine-2-yl)propanoate (9.2 g, 33.0 mmol) in EtOH (90 mL) at room temperature. The resulting mixture was stirred at 80°C for 3 hours. The solvent was removed under reduced pressure. The mixture was neutralized to pH 8 with saturated NaHCO3 (aqueous solution). The mixture was extracted with ELISA (300 mL x 2). The combined organic layer was washed with brine (100 mL x 2) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / ELISA (1:1) to obtain the title compound (5.5 g) as a white solid. LCMS(ESI) m / z[M+H]+=233.2. 1 H NMR(300MHz,DMSO-d6)δ 10.39(s,1H),7.47(s,1H),7.16(t,J=54.1Hz,1H),3.14-2.98(m,2H),2.73-2.57(m,2H).

[0395] Step 8. 6-Chloro-7-(difluoromethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine BH3-THF (70.93 mL, 70.94 mmol) was added dropwise to a stirred solution of 6-chloro-7-(difluoromethyl)-3,4-dihydro-1,5-naphthyridine-2(1H)-one (5.5 g, 23.6 mmol) in THF (50 mL) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was quenched by adding MeOH (100 mL) at 0°C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (10:1) to obtain the title compound (4.53 g) as a white solid. LC-MS (ESI) m / z[M+H]+=219.00. 1 H NMR(400MHz,DMSO-d6)δ 7.19-6.83(m,2H),6.36(s,1H),3.26-3.11(m,2H),2.77(t,J=6.5Hz,2H),1.95-1.77(m,2H).

[0396] Intermediate 13: 3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-1-yl]-N-methyl-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxamide [ka] Step 1. Methyl 3-bromo-1H-pyrazolo[4,3-b]pyridine-5-carboxylate NBS (1.00 g, 5.645 mmol) was gradually added to a stirred mixture of methyl 1H-pyrazolo[4,3-b]pyridine-5-carboxylate (1 g, 5.64 mmol) in ACN (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated Na₂S₂O₅ (aqueous solution) (20 mL) at room temperature. The resulting mixture was extracted with ELISA (50 mL x 3). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), 10% to 50% gradient over 10 mins, detector, UV 254 nm) to obtain the title compound (903 mg) as a yellow solid. LC-MS (ESI) m / z [M+H] + =256.1

[0397] Step 2. Methyl 3-bromo-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate Cs2CO3 (2.04 g, 6.25 mmol) was added to a stirred mixture of methyl 3-bromo-1H-pyrazolo[4,3-b]pyridine-5-carboxylate (800 mg, 3.12 mmol) and oxan-4-ylmethanesulfonate (563 mg, 3.12 mmol) in DMF (8 mL). The resulting mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with ELISA (100 mL x 3). The combined organic layer was washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), 10% to 50% gradient over 10 minutes, detector, UV 254 nm) to obtain the title compound (420 mg) as a yellow solid. LC-MS (ESI) m / z [M+H] + =340.1

[0398] Step 3. Methyl 3-[7-(difluoromethyl)-3,4-dihydro-2H-quinoline-1-yl]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate XPhos Pd G3 (1.24 mg, 0.002 mmol) and Cs2CO3 (766 mg, 2.35 mmol) were added to a stirred mixture of methyl 3-bromo-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate (400 mg, 1.18 mmol) and 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (215 mg, 1.18 mmol) in dioxane (4 mL). The resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (100 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), 10% to 50% gradient over 10 minutes, detector, UV 254 nm) to obtain the title compound (320 mg) as a yellow solid. LC-MS (ESI) m / z [M+H] + =442.5

[0399] Step 4. Methyl 3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-1-yl]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate NBS (156.48 mg, 0.879 mmol) was gradually added to a stirred solution of methyl 3-[7-(difluoromethyl)-3,4-dihydro-2H-quinoline-1-yl]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate (389 mg, 0.879 mmol) in ACN (5 mL) at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain the title compound (180 mg) as a yellow oil. LC-MS (ESI) m / z [M+H] + = 521.4

[0400] Step 5.3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-1-yl]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylic acid LiOH . H2O (39.8 mg, 0.948 mmol) was gradually added at room temperature to a stirred mixture of methyl 3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-1-yl]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate (165 mg, 0.316 mmol) in MeOH (2 mL) and H2O (2 mL). Without any further steps, the crude product was purified by reverse FCC (column, C18 silica gel, mobile phase, ACN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain the title compound (134 mg) as a yellow solid. LC-MS (ESI) m / z [M+H] + = 507.3

[0401] Step 6.3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-1-yl]-N-methyl-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxamide HATU (146.15 mg, 0.384 mmol) was added to a stirred mixture of 3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-1-yl]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylic acid (130 mg, 0.256 mmol) in DMF (2 mL), 2M methylamine in THF (0.128 mL, 0.256 mmol), and DIEA (66.2 mg, 0.512 mmol). The resulting mixture was stirred at room temperature for 1 hour. No further steps were taken. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain the title compound (80 mg) as a yellow solid. LCMS(ESI)m / z[M+H] + = 520.4

[0402] Intermediate 14: 3-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyridine-1-yl]-N-methyl-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxamide [ka] Step 1. Methyl 3-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyridine-1-yl]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate Xantphos Pd G4 (81.3 mg, 0.085 mmol) was added to a stirred solution of methyl 3-bromo-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate (287.4 mg, 0.845 mmol), K3PO4 (538 mg, 2.54 mmol), XantPhos (97.7 mg, 0.169 mmol), and 2-chloro-3-(difluoromethyl)-5,6,7,8-tetrahydro-1,5-naphthiridine (185 mg, 0.845 mmol) in dioxane (4 mL). The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was acidified to pH 6 with HCl (aqueous solution). The resulting mixture was extracted with Âr (20 mL x 3). The combined organic layers were washed with brine (20 mL x 1) and dried over anhydrous Na₂SO₄. The resulting mixture was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), 10% to 50% gradient over 10 minutes, detector, UV 254 nm) to obtain the title compound (231.3 mg) as a brown oil. LC-MS (ESI) m / z[M+H]+=478.1.

[0403] Step 2.3-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyrizin-1-yl]-N-methyl-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxamide TCFH (108 mg, 0.384 mmol) was added to a stirred solution of methyl 3-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyrizin-1-yl]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate (88.9 mg, 0.192 mmol), NMI (47.21 mg, 0.576 mmol), and methylamine (5.95 mg, 0.192 mmol) in ACN (1.5 mL). The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. Without any additional work, the crude product was purified by reverse FCC (column, C18 silica gel, mobile phase, ACN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain the title compound (72.3 mg) as a yellow oil. LC-MS (ESI) m / z[M+H]+=477.1.

[0404] Intermediate 15: tert-butyl 3-[(4-chlorophenyl)(methyl)amino]-N-methyl-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxamide. [ka] Step 1. Methyl 3-[(4-chlorophenyl)(methyl)amino]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate XPhos Pd G3 (28.03 mg, 0.059 mmol) was added to a stirred solution of methyl 3-bromo-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate (200 mg, 0.588 mmol), 4-chloro-N-methylaniline (83.2 mg, 0.588 mmol), and Cs2CO3 (383 mg, 1.18 mmol) in dioxane (5 mL). The resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with  (50 mL x 3). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), 10% to 50% gradient over 15 minutes, detector, UV 254 nm) to obtain the title compound (152 mg) as a yellowish-green oil. LC-MS (ESI) m / z [M+H] + =401.5

[0405] Step 2.3 - [(4-chlorophenyl)(methyl)amino]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylic acid LiOH . H2O (75.9 mg, 1.81 mmol) was added to a stirred solution of methyl 3-[(4-chlorophenyl)(methyl)amino]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate (145 mg, 0.362 mmol) in THF (4 mL) and H2O (2 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was acidified to pH 5 with HCl (aqueous solution) and extracted with RINKAN (50 mL x 3). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), 20% to 60% gradient over 15 minutes, detector, UV 254 nm) to obtain the title compound (122 mg) as a yellowish-green oil. LCMS(ESI)m / z[M+H] + =387.1.

[0406] Step 3. tert-butyl3-[(4-chlorophenyl)(methyl)amino]-N-methyl-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxamide HATU (170 mg, 0.446 mmol) was added to a stirred solution of 3-[(4-chlorophenyl)(methyl)amino]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylic acid (115 mg, 0.297 mmol), methanamine hydrochloride (20.1 mg, 0.297 mmol), and DIEA (154 mg, 1.19 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 2 hours. Without any further steps, the crude product was purified by reverse FCC (column, C18 silica gel, mobile phase, ACN in water (0.1% FA), gradient from 20% to 60% over 15 minutes, detector, UV 254 nm) to obtain the title compound (88 mg) as a yellow-green solid. LC-MS (ESI) m / z [M+H] + =400.2.

[0407] Intermediate 16: 3-[(6-chloropyridine-3-yl)(methyl)amino]-N-methyl-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxamide. [ka] Step 1. Methyl 3-[(6-chloropyridine-3-yl)(methyl)amino]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate XPhos Pd G3 (37.3 mg, 0.044 mmol) was added to a stirred mixture of 3-bromo-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate (150 mg, 0.441 mmol), 6-chloro-N-methylpyridine-3-amine (62.87 mg, 0.441 mmol), and Cs2CO3 (287.34 mg, 0.882 mmol) in toluene (5 mL). The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with ethylethanol (50 mL x 3). The combined organic layers were washed with brine (30 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), 10% to 50% gradient over 10 minutes, detector, UV 254 nm) to obtain the title compound (78 mg) as a yellow solid. LC-MS (ESI) m / z [M+H] + =402.1.

[0408] Step 2.3 - [(6-chloropyridine-3-yl)(methyl)amino]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylic acid LiOH (19.4 mg, 0.810 mmol) was added to a stirred solution of methyl 3-[(6-chloropyridine-3-yl)(methyl)amino]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate (65 mg, 0.162 mmol) in THF (2 mL) and H2O (2 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was acidified to pH 5 with a 1 M solution of HCl (aqueous solution) and extracted with ₹ (50 mL × 3). The combined organic layer was washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (58 mg) as a yellow solid, which was used directly without further purification. LCMS(ESI)m / z[M+H] + =388.1.

[0409] Step 3.3-[(6-chloropyridine-3-yl)(methyl)amino]-N-methyl-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxamide HATU (66.2 mg, 0.174 mmol) was added to a stirred mixture of 3-[(6-chloropyridine-3-yl)(methyl)amino]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylic acid (45 mg, 0.116 mmol), methanamine hydrochloride (9.40 mg, 0.139 mmol), and DIEA (30 mg, 0.232 mmol) in DMF (2 mL). The resulting mixture was stirred at room temperature for 1 hour. Without any further steps, the crude product was purified by reverse FCC (column, C18 silica gel, mobile phase, ACN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain the title compound (46 mg) as a yellow solid. LC-MS (ESI) m / z [M+H] + =401.1.

[0410] Intermediate 17: 1-{1-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-1-yl]-3-(oxolan-3-yl)-5H,6H,8H-imidazo[1,5-a]pyrazine-7-yl}ethenone. [ka] Step 1. N-(pyrazine-2-ylmethyl)oxolane-3-carboxamide Oxolane-3-carbonyl chloride (5 g, 37.16 mmol) was added dropwise to a stirred solution of 1-(pyrazine-2-yl)methaneamine (4.06 g, 37.16 mmol) and TEA (7.52 g, 74.32 mmol) in DCM (60 mL) at 0°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was concentrated under vacuum. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% NH4HCO3), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain the title compound (4.6 g) as a yellow oil. LC-MS (ESI) m / z [M+H] + =208.1.

[0411] Step 2.3-(oxolan-3-yl)imidazo[1,5-a]pyrazine POCl3 (3.40 g, 22.20 mmol) was added dropwise to a stirred solution of N-(pyrazine-2-ylmethyl)oxolane-3-carboxamide (4.6 g, 22.20 mmol) and DMF (1.62 g, 22.20 mmol) in MeCN (60 mL) at 0°C. The resulting mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. The reaction was quenched by adding saturated NH4HCO3 (aqueous solution) (350 mL) at room temperature. The mixture was extracted with (CH2Cl2 / MeOH=10:1) (450 mL × 2) and washed with saturated brine (300 mL × 1). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using CH2Cl2 / MeOH (18:1) elution to obtain the title compound (2.5 g) as a yellow oil. LCMS(ESI)m / z[M+H] + =190.1.

[0412] Step 3.1-Bromo-3-(oxolan-3-yl)imidazo[1,5-a]pyrazine NBS (2.35 g, 13.21 mmol) was added to a stirred solution of 3-(oxolan-3-yl)imidazo[1,5-a]pyrazine (2.5 g, 13.21 mmol) in ACN (25 mL). The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), 10% to 50% gradient over 10 minutes, detector, UV 254 nm) to obtain the title compound (2.1 g) as an orange solid. LC-MS (ESI) m / z [M+H] + =268.0.

[0413] Step 4.7-(difluoromethyl)-1-[3-(oxolan-3-yl)imidazo[1,5-a]pyrazine-1-yl]-3,4-dihydro-2H-quinoline XPhos Pd G3 (994 mg, 1.18 mmol) was added to a stirred solution of 1-bromo-3-(oxolan-3-yl)imidazo[1,5-a]pyrazine (2.1 g, 7.83 mmol), 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (1.43 g, 7.83 mmol), and t-BuONa (22.19 g, 23.50 mmol) in 1,4-dioxane (25 mL). The mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with toluene (10 mL x 3). The filtrate was concentrated under reduced pressure. The mixture was diluted with toluene (200 mL) and washed with saturated brine (200 mL x 1). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using CH2Cl2 / MeOH (16:1) elution to obtain the title compound (2.08 g) as an orange solid. LCMS(ESI)m / z[M+H] + =371.1.

[0414] Step 5.6-Bromo-7-(difluoromethyl)-1-[3-(oxolan-3-yl)imidazo[1,5-a]pyrazine-1-yl]-3,4-dihydro-2H-quinoline A solution of NBS (1.10 g, 6.18 mmol) in HFIP (10 mL) was added dropwise to a stirred solution of 7-(difluoromethyl)-1-[3-(oxolan-3-yl)imidazo[1,5-a]pyrazine-1-yl]-3,4-dihydro-2H-quinoline (2.08 g, 5.62 mmol) in HFIP (20 mL) at -10°C. The mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% NH4HCO3), gradient from 10% to 50% over 10 minutes, detector, UV254 nm) to obtain the title compound (801 mg) as a brown solid. LCMS(ESI) m / z[M+H] + =449.1.

[0415] Step 6. 6-Bromo-7-(difluoromethyl)-1-[3-(oxolan-3-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-1-yl]-3,4-dihydro-2H-quinoline PtO2 (40.4 mg, 0.178 mmol) was added to a stirred solution of 6-bromo-7-(difluoromethyl)-1-[3-(oxolan-3-yl)imidazo[1,5-a]pyrazine-1-yl]-3,4-dihydro-2H-quinoline (400 mg, 0.890 mmol) in MeOH (8 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The resulting mixture was filtered, and the filter cake was washed with MeOH (20 mL x 2). The filtrate was concentrated under reduced pressure to obtain the title compound (426 mg) as a yellow solid. LC-MS(ESI) m / z[M+H]+=453.2.

[0416] Step 7.1-{1-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-1-yl]-3-(oxolan-3-yl)-5H,6H,8H-imidazo[1,5-a]pyrazine-7-yl}ethenone Ac2O (115.12 mg, 1.128 mmol) was added dropwise to a stirred solution of 6-bromo-7-(difluoromethyl)-1-[3-(oxolan-3-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-1-yl]-3,4-dihydro-2H-quinoline (426 mg, 0.940 mmol) and TEA (285 mg, 2.82 mmol) in DCM (6 mL) at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain the title compound (184 mg) as a yellow solid. LCMS(ESI)m / z[M+H]+=495.2.

[0417] Intermediate 18: 1-{1-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-1-yl]-3-isopropyl-5H,6H,8H-imidazo[1,5-a]pyrazine-7-yl}ethenone. [ka] Step 1. 2-Methyl-N-(pyrazine-2-ylmethyl)propanamide 2-methyl propanoyl chloride (2.93 g, 27.49 mmol) was added dropwise to a stirred solution of 1-(pyrazine-2-yl)methaneamine (3 g, 27.49 mmol) and TEA (5.56 g, 54.98 mmol) in DCM (30 mL) at 0°C. The resulting mixture was stirred further at 0°C for 1 hour. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH2Cl2 (300 mL x 3). The combined organic layer was washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (5.26 g, crude) as a brown oil, which was used directly without further purification. LCMS(ESI)m / z[M+H] + =180.1.

[0418] Step 2.3-Isopropylimidazo[1,5-a]pyrazine POCl3 (2.08 mL, 22.32 mmol) was added dropwise to a stirred solution of 2-methyl-N-(pyrazine-2-ylmethyl)propanamide (4 g, 22.32 mmol) and DMF (1.73 mL, 22.32 mmol) in ACN (40 mL) at 0°C. The resulting mixture was stirred at 80°C for 1 hour. The reaction was quenched with water / ice at 0°C. The resulting mixture was basicized to pH 8 with saturated Na2CO3 (aqueous solution) and extracted with CH2Cl2 (300 mL x 3). The combined organic layer was washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and elution gradient of 0-10% MeOH in DCM. The pure fraction was evaporated to dryness to obtain the title compound (2.36 g) as a red oil. LCMS(ESI)m / z[M+H] + =162.1.

[0419] Step 3. 1-Bromo-3-isopropylimidazo[1,5-a]pyrazine NBS (552.04 mg, 3.102 mmol) was gradually added to a stirred solution of 3-isopropylimidazo[1,5-a]pyrazine (500 mg, 3.10 mmol) in ACN (5 mL) at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The reaction product was diluted with water (50 mL) and extracted with  (50 mL x 3). The combined organic layer was washed with brine (30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and elution gradient of 0-10% MeOH in DCM. The pure fraction was evaporated to dryness to obtain the title compound (518 mg) as a red oil. LCMS(ESI)m / z[M+H] + =240.0.

[0420] Step 4.7-(difluoromethyl)-1-{3-isopropylimidazo[1,5-a]pyrazine-1-yl}-3,4-dihydro-2H-quinoline XPhos Pd G3 (141 mg, 0.167 mmol) and t-BuONa (472 mg, 4.998 mmol) were added to a stirred solution of 1-bromo-3-isopropylimidazo[1,5-a]pyrazine (400 mg, 1.67 mmol) and 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (305 mg, 1.67 mmol) in dioxane (5 mL). The resulting mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (50 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), gradient from 0% to 100% over 15 minutes, detector, UV 254 nm) to obtain the title compound (461 mg) as a yellow solid. LC-MS (ESI) m / z [M+H] + =343.2.

[0421] Step 5.6-Bromo-7-(difluoromethyl)-1-{3-isopropylimidazo[1,5-a]pyrazine-1-yl}-3,4-dihydro-2H-quinoline NBS (207.9 mg, 1.168 mmol) was gradually added to a stirred solution of 7-(difluoromethyl)-1-{3-isopropylimidazo[1,5-a]pyrazine-1-yl}-3,4-dihydro-2H-quinoline (400 mg, 1.168 mmol) in HFIP (5 mL) at -15°C. The resulting mixture was stirred at -15°C for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient from 0% to 100% over 15 minutes, detector, UV 254 nm) to obtain the title compound (357 mg) as a white solid. LCMS(ESI) m / z[M+H] + =421.1.

[0422] Step 6. 6-Bromo-7-(difluoromethyl)-1-{3-isopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-1-yl}3,4-dihydro-2H-quinoline PtO2 (16.2 mg, 0.071 mmol) was added to a stirred solution of 6-bromo-7-(difluoromethyl)-1-{3-isopropylimidazo[1,5-a]pyrazine-1-yl}-3,4-dihydro-2H-quinoline (150 mg, 0.356 mmol) in MeOH (3 mL). The resulting mixture was stirred at room temperature for 30 minutes under a hydrogen atmosphere of 10 atm. The resulting mixture was filtered, and the filter cake was washed with MeOH (10 mL x 3). The filtrate was concentrated under reduced pressure to obtain the title compound (158 mg, crude) as a yellow solid, which was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] + =425.1.

[0423] Step 7.1-{1-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-1-yl]-3-isopropyl-5H,6H,8H-imidazo[1,5-a]pyrazine-7-yl}ethenone TEA (112.24 mg, 1.110 mmol) was added dropwise to a stirred solution of 6-bromo-7-(difluoromethyl)-1-{3-isopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-1-yl}-3,4-dihydro-2H-quinoline (158 mg, 0.370 mmol) and acetic anhydride (37.8 mg, 0.370 mmol) in DCM (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient from 0% to 100% over 10 minutes, detector, UV 254 nm) to obtain the title compound (87 mg) as a yellow solid. 1H NMR(300MHz,DMSO-d6)δ=7.29(s,1H),7.10-6.64(m,1H),6.57(d,J=7.8Hz,1H),4.39(d,J=23.2Hz,2H),4.08(s,1H),3.95(d,J=5.6Hz,1H),3 .82(t,J=5.5Hz,2H),3.53-3.42(m,2H),3.13-2.93(m,1H),2.81(s,2H),2.16-1.86(m,5H),1.19(dd,J=6.8,3.5Hz,6H).LCMS(ESI)m / z[M+H] + =467.1.

[0424] Intermediate 19: 1-{1-[7-chloro-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazine-4-yl]-3-isopropyl-5H,6H,8H-imidazo[1,5-a]pyrazine-7-yl}ethenone. [ka] Step 1. 7-Chloro-6-(difluoromethyl)-4-{3-isopropylimidazo[1,5-a]pyrazine-1-yl}-2,3-dihydro-1,4-benzoxazine XPhos Pd G3 (94.6 mg, 0.112 mmol) was added to a stirred solution of 1-bromo-3-isopropylimidazo[1,5-a]pyrazine (268 mg, 1.118 mmol), K3PO4 (712 mg, 3.35 mmol), and 7-chloro-6-(difluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine (245.5 mg, 1.118 mmol) in dioxane (3.5 mL). The resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The resulting mixture was extracted with ELISA (20 mL x 3). The combined organic layer was washed with brine (20 mL x 1) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% TFA), 10% to 50% gradient over 10 minutes, detector, UV 254 nm) to obtain the title compound (256.2 mg) as a red oil. LC-MS (ESI) m / z[M+H]+=379.1.

[0425] Step 2. 7-Chloro-6-(difluoromethyl)-4-{3-isopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-1-yl}-2,3-dihydro-1,4-benzoxazine [RhCl2CP]2 (22.7 mg, 0.037 mmol) was added to a stirred solution of 7-chloro-6-(difluoromethyl)-4-{3-isopropylimidazo[1,5-a]pyrazine-1-yl}-2,3-dihydro-1,4-benzoxazine (139 mg, 0.367 mmol) and KI (121.8 mg, 0.734 mmol) in TEA (0.58 mL) and formic acid (0.42 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was basicized to pH 8 with NaHCO3 (aqueous solution). The resulting mixture was extracted with ELISA (20 mL x 3). The combined organic layer was washed with brine (20 mL x 1) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (154.6 mg) as a reddish-brown oil. LCMS(ESI)m / z[M+H]+=383.1.

[0426] Step 3.1-{1-[7-chloro-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazine-4-yl]-3-isopropyl-5H,6H,8H-imidazo[1,5-a]pyrazine-7-yl}ethanone Ac2O (40.0 mg, 0.392 mmol) was added to a solution of 7-chloro-6-(difluoromethyl)-4-{3-isopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-1-yl}-2,3-dihydro-1,4-benzoxazine (150 mg, 0.392 mmol) and TEA (119 mg, 1.176 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), 10% to 50% gradient over 10 minutes, detector, UV 254 nm) to obtain the title compound (85.4 mg) as a yellow oil. LC-MS (ESI) m / z[M+H]+=425.2.

[0427] Intermediate 20: 1-{1-[(4-chlorophenyl)(methyl)amino]-3-isopropyl-5H,6H,8H-imidazo[1,5-a]pyrazine-7-yl}ethenone. [ka] Step 1. N-(4-chlorophenyl)-3-isopropyl-N-methylimidazo[1,5-a]pyrazine-1-amine Cs2CO3 (2.24 g, 6.87 mmol) and XPhos Pd G3 (193.90 mg, 0.229 mmol) were added to a stirred solution of 1-bromo-3-isopropylimidazo[1,5-a]pyrazine (550 mg, 2.29 mmol) and 4-chloro-N-methylaniline (324 mg, 2.29 mmol) in dioxane (10 mL). The resulting mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. The resulting mixture was diluted with water (150 mL) and extracted with  (150 mL x 3). The combined organic layer was washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), 10% to 60% gradient over 15 minutes, detector, UV 254 nm) to obtain the title compound (469 mg) as a red oil. LC-MS (ESI) m / z [M+H] + =301.2.

[0428] Step 2. N-(4-chlorophenyl)-3-isopropyl-N-methyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-1-amine (Cp*RhCl2)2 (116 mg, 0.146 mmol) was added to a stirred solution of N-(4-chlorophenyl)-3-isopropyl-N-methylimidazo[1,5-a]pyrazine-1-amine (440 mg, 1.46 mmol) in HCOOH (5 mL) and TEA (7 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting mixture was diluted with water (50 mL). The resulting mixture was basicized to pH 8 with saturated Na2CO3 (aqueous solution) and extracted with ethyl acetate (150 mL x 3). The combined organic layer was washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and elution gradient of 0-100% ethyl acetate in PE. The pure fraction was evaporated to dryness to obtain the title compound (365 mg) as a brown oil. LCMS(ESI)m / z[M+H] + =305.2.

[0429] Step 3.1-{1-[(4-chlorophenyl)(methyl)amino]-3-isopropyl-5H,6H,8H-imidazo[1,5-a]pyrazine-7-yl}ethanone Ac2O (176 mg, 1.72 mmol) was added to a stirred solution of N-(4-chlorophenyl)-3-isopropyl-N-methyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-1-amine (350 mg, 1.148 mmol) and TEA (349 mg, 3.44 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, using an elution gradient of 0-100% ethyl phosphate in PE. The pure fraction was evaporated to dryness to obtain the title compound (267 mg) as a yellow oil. LCMS(ESI)m / z[M+H] + =347.2.

[0430] Intermediate 21: 1-(1-(6-chloro-7-(difluoromethyl)-3,4-dihydroquinoline-1(2H)-yl)-3-morpholino-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl)ethane-1-one. [ka] Step 1. N-(pyrazine-2-ylmethyl)morpholine-4-carboxamide Morpholine-4-carbonyl chloride (2.50 g, 13.37 mmol) was added dropwise to a stirred solution of 1-(pyrazine-2-yl)methaneamine (1.82 g, 16.72 mmol) in 40 mL of DCM at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and elution gradient of 0-10% MeOH in DCM. The pure fraction was evaporated to dryness to obtain the title compound (3.6 g) as a white solid. LC-MS(ESI) m / z[M+H] + =223.0.

[0431] Step 2.4 - (Imidazou[1,5-a]pyrazine-3-yl)morpholine POCl3 (7.13 mL, 76.49 mmol) was added to a stirred solution of N-(pyrazine-2-ylmethyl)morpholine-4-carboxamide (3.4 g, 15.30 mmol) and pyridine (12.37 mL, 152.98 mmol) and DMF (0.24 mL, 3.06 mmol) in ACN (50 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding water / ice (100 mL) at 0°C and basicized to pH 8 with saturated Na2CO3 (aqueous solution). The resulting mixture was extracted with CH2Cl2 (100 mL x 3). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and elution gradient of 0-10% MeOH in DCM. The pure fraction was evaporated to dryness to obtain the title compound (1.1 g) as a red solid. LC-MS(ESI) m / z[M+H] + =205.0.

[0432] Step 3.4 - (1-bromoimidazo[1,5-a]pyrazine-3-yl)morpholine NBS (436 mg, 2.45 mmol) was added to a stirred solution of 4-(imidazo[1,5-a]pyrazine-3-yl)morpholine (500 mg, 2.45 mmol) in ACN (1 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), 10% to 50% gradient over 10 minutes, detector, UV 254 nm) to obtain the title compound (408 mg) as a dark red solid. LC-MS (ESI) m / z [M+H] + =282.8.

[0433] Step 4.4-(1-(6-chloro-7-(difluoromethyl)-3,4-dihydroquinoline-1(2H)-yl)imidazo[1,5-a]pyrazine-3-yl)morpholine Cs2CO3 (1.04 g, 3.18 mmol) and XPhos Pd G3 (89.7 mg, 0.106 mmol) were added to a stirred mixture of 4-{1-bromoimidazo[1,5-a]pyrazine-3-yl}morpholine (300 mg, 1.06 mmol) and 2-chloro-3-(difluoromethyl)-5,6,7,8-tetrahydro-1,5-naphthiridine (196 mg, 0.901 mmol) in dioxane (10 mL). The resulting mixture was stirred at 80°C for 6 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain the title compound (108 mg) as a yellow solid. LCMS(ESI)m / z[M+H] + =420.1.

[0434] Step 5.4-(1-(6-chloro-7-(difluoromethyl)-3,4-dihydroquinoline-1(2H)-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-yl)morpholine [Rh(Cp*)Cl2]2 (15.4 mg, 0.025 mmol) was added to a stirred mixture of 4-(1-(6-chloro-7-(difluoromethyl)-3,4-dihydroquinoline-1(2H)-yl)imidazo[1,5-a]pyrazine-3-yl)morpholine (100 mg, 0.25 mmol) in HCOOH (0.5 mL, 13.25 mmol) and TEA (0.7 mL, 5.036 mmol). The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was basicized to pH 8 with saturated NaHCO3 (aqueous solution) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (97 mg, crude) as a brown solid, which was used directly without further purification. LCMS(ESI)m / z[M+H] + =424.0.

[0435] (1-(6-Chloro-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-3-morpholino-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)ethan-1-one Ac2O (35.7 μL, 0.378 mmol) was added to a stirred solution of 4-(1-(6-chloro-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)morpholine (80 mg, 0.189 mmol) and TEA (78.7 μL, 0.567 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient 10% - 50% in 10 min, detector, UV254 nm) to afford the title compound (43 mg) as a yellow solid. LCMS (ESI) m / z + = 466.1.

[0436] Intermediate 22: 1-{1-[6-Bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-3-cyclopropyl-5H,6H,8H-imidazo[1,5-a]pyrazin-7-yl}ethenone. [Chemical Structure Diagram] Step 1. N-(Pyrazin-2-ylmethyl)cyclopropanecarboxamide Cyclopropane carbonyl chloride (9.58 g, 91.63 mmol) was added dropwise to a stirred solution of 1-(pyrazine-2-yl)methaneamine (10 g, 91.63 mmol) and TEA (25.47 mL, 183.3 mmol) in DCM (100 mL) at 0°C. The resulting mixture was stirred at room temperature for a further 1 hour. The resulting mixture was diluted with water (100 mL) and extracted with CH2Cl2 (100 mL x 3). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (17.6 g, crude) as a yellow solid, which was used directly without further purification. LCMS(ESI)m / z[M+H] + =178.1.

[0437] Step 2.3-Cyclopropylimidazo[1,5-a]pyrazine POCl3 (6.31 mL, 67.72 mmol) was added dropwise to a stirred solution of N-(pyrazine-2-ylmethyl)cyclopropanecarboxamide (12 g, 67.72 mmol) and DMF (5.24 mL, 67.72 mmol) in ACN (100 mL) at 0°C. The resulting mixture was stirred further at 80°C for 1 hour. The reaction was quenched by adding water / ice (100 mL) at 0°C and basicized to pH 8 with saturated Na2CO3 (aqueous solution). The resulting mixture was extracted with CH2Cl2 (100 mL x 3). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and elution gradient of 0-10% MeOH in DCM. The pure fraction was evaporated to dryness to obtain the title compound (5.6 g) as a red oil. LC-MS(ESI)m / z[M+H] + =160.1.

[0438] Step 3. 1-Bromo-3-cyclopropylimidazo[1,5-a]pyrazine NBS (2.80 g, 15.70 mmol) was added dropwise to a stirred solution of N-(pyrazine-2-ylmethyl)cyclopropanecarboxamide (2.5 g, 15.70 mmol) in ACN (25 mL) at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding saturated sodium hypochlorite (aqueous solution) (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and elution gradient of 0-10% MeOH in DCM. The pure fraction was evaporated to dryness to obtain the title compound (3 g) as a yellow solid. LCMS(ESI)m / z[M+H] + =238.0.

[0439] Step 4.1-{3--cyclopropylimidazo[1,5-a]pyrazine-1-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazine XPhos Pd G3 (284 mg, 0.336 mmol) was added to a stirred mixture of 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazine (800 mg, 3.360 mmol), 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (616 mg, 3.360 mmol), and t-BuONa (969 mg, 10.08 mmol) in toluene (8 mL). The resulting mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (100 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), 10% to 50% gradient over 10 minutes, detector, UV 254 nm) to obtain the title compound (728 mg) as a brick-colored solid. LC-MS (ESI) m / z [M+H] + =341.1.

[0440] Step 5.6-Bromo-1-{3-cyclopropylimidazo[1,5-a]pyrazine-1-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline NBS (345 mg, 0.162 mmol) was gradually added to a stirred mixture of 1-{3-cyclopropylimidazo[1,5-a]pyrazine-1-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazine (600 mg, 0.147 mmol) in HFIP (6 mL) at -15°C. The resulting mixture was stirred at 0°C for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm) to obtain the title compound (192 mg) as a yellow solid. LC-MS (ESI) m / z [M+H] + =419.0.

[0441] Step 6. 6-Bromo-1-{3-cyclopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-1-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline PtO2 (20.6 mg, 0.091 mmol) was added to a stirred mixture of 6-bromo-1-{3-cyclopropylimidazo[1,5-a]pyrazine-1-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline (190 mg, 0.453 mmol) in MeOH (5 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered, and the filter cake was washed with MeOH (10 mL x 2). The filtrate was concentrated under reduced pressure to obtain the title compound (170 mg, crude) as a yellow solid, which was used directly without further purification.

[0442] Step 7.1-{1-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-1-yl]-3-cyclopropyl-5H,6H,8H-imidazo[1,5-a]pyrazine-7-yl}ethanone Ac2O (114 μL, 1.21 mmol) and TEA (112 μL, 0.80 mmol) were added to a stirred mixture of 6-bromo-1-{3-cyclopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-1-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline (170 mg, 0.402 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to obtain a residue. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), 10% to 50% gradient over 10 minutes, detector, UV 254 nm) to obtain the title compound (109 mg) as a yellow solid. LC-MS (ESI) m / z [M+H] + =465.1.

[0443] Intermediate 23: 1-{1-[7-chloro-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazine-4-yl]-3-cyclopropyl-5H,6H,8H-imidazo[1,5-a]pyrazine-7-yl}ethanone. [ka] Step 1. 7-Chloro-4-{3-cyclopropylimidazo[1,5-a]pyrazine-1-yl}-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazine t-BuONa (350.1 mg, 3.64 mmol) and XPhos Pd G3 (154.2 mg, 0.182 mmol) were added to a stirred solution of 7-chloro-6-(difluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine (400 mg, 1.82 mmol) and 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazine (520.4 mg, 2.18 mmol) in dioxane (4 mL). The resulting mixture was stirred further at 80°C for 1 hour. The reaction was quenched with water at room temperature. The resulting mixture was extracted with RINKAN (30 mL x 3). The combined organic layer was washed with brine (30 mL x 1) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by inverse FCC (C18 silica gel, mobile phase, ACN in water (0.1% FA), gradient from 0% to 100% over 10 minutes, detector, UV 254 nm) to obtain the title compound (619 mg) as a yellow solid. LC-MS (ESI) m / z [M+H] + =377.1.

[0444] Step 2. 7-Chloro-4-{3-cyclopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-1-yl}-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazine A solution of 7-chloro-4-{3-cyclopropylimidazo[1,5-a]pyrazine-1-yl}-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazine (600 mg, 1.59 mmol) and PtO2 (72.3 mg, 0.318 mmol) in MeOH (10 mL) was stirred at room temperature under a hydrogen atmosphere for 3 hours. The precipitated solid was collected by filtration and washed with MeOH (5 mL x 3). The filtration was concentrated under vacuum to obtain the title compound (509 mg, crude) as a yellow oil. LCMS(ESI)m / z[M+H] + =381.1.

[0445] Step 3.1-{1-[7-chloro-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazine-4-yl]-3-cyclopropyl-5H,6H,8H-imidazo[1,5-a]pyrazine-7-yl}ethenone TEA (239.2 mg, 2.36 mmol) was added to a stirred solution of 7-chloro-4-{3-cyclopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-1-yl}-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazine (300 mg, 0.788 mmol) and Ac2O (160.8 mg, 1.576 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for a further 1 hour. The resulting mix...

Claims

1. A compound having the structure of formula I, A-L-B Equation I During the ceremony, A is the CBP binding site, B is the decomposition part, L has the structure of formula II, A １ -(F)-(E) ｍ -C-A ２ Formula II During the ceremony, A １ However, this is a bond between the linker and A, A ２ However, this is a connection between B and the linker, m is 0 or 1, C is independently either absent, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl. E is, independently, non-existent, O, S, NR Ｎ , optionally substituted C １ ~C １０ alkylene, optionally substituted C ２ ~C １０ alkenylene, optionally substituted C ２ ~C １０ alkynylene, optionally substituted C ２ ~C １０ polyethylene glycol, or optionally substituted C １ ~C １０ heteroalkylene, and Each R Ｎ However, independently, H and C are substituted by choice. １ ~C ４ Alkyl, optionally substituted C ２ ~C ４ Alkenyl, C substituted by choice ２ ~C ４ Alkinyl, optionally replaced with C ２ ~C ６ Heterocycline, C by optional substitution ６ ~C １２ A C replaced by an aryl or of any choice. １ ~C ７ It is heteroalkyl, F is independently and arbitrarily replaced by C. ３ ~C １０ Carbocyclylene, optionally substituted with C ２ ~C １０ Heterocyclylene, C by optional substitution ６ ~C １０ Arrine, or optionally replaced with C ２ ~C ９ The compound is a heteroarylene, or a pharmaceutically acceptable salt thereof.

2. The CBP binding portion has the structure of formula III, 【Chemistry 1】 During the ceremony, X １ａ However, independently, it is C or N, R １ａ and R １ｂ However, independently, they combine with the atoms to which they are bonded, and are optionally substituted C ３ ~C １０ Carbon ring, optionally substituted C ５ ~C １０ Aaryl, replaced by C of any choice ３ ~C ９ Heteroaryl or optionally substituted C ３ ~C ９ A heterocycle is formed, and the carbon ring, the aryl, the heteroaryl, or the heterocycle is A １ , and / or one or more of the following groups: halogen, C １ ~C ６ Alkyl, C ５ ~C １０ Ariel, C ２ ~C ９ Heteroaryl, C ２ ~C ９ Heterogeneous algebras, C ３ ~C １０ Carbocycle, C(O)N(R １ｅ ) ２ , S(O)N(R １ｅ ) ２ , S(O) ２ N(R) １ｅ ) ２ , OR １ｅ , C(O)R １ｅ , C(O)OR １ｅ S(O)R １ｅ , S(O) ２ R １ｅ , SR １ｅ OC(O)R １ｅ , OC(O)OR １ｅ ,OC(O)N(R １ｅ ) ２ , N(R １ｅ ) C(O)N(R １ｅ ) ２ , N(R １ｅ ) C(O)OR １ｅ , N(R １ｅ ) C(O)R １ｅ , N(R １ｅ ) S(O)R １ｅ , N(R １ｅ ) S(O) ２ R １ｅ , N(R １ｅ ),SON(R １ｅ ), ２ ), or N(R １ｅ ),SON(R １ｅ ), ２ is optionally replaced with any C １ -C ６ alkyl, C ５ -C １０ aryl, C ２ -C ９ heteroaryl, C ２ -C ９ heterocyclic ring, C ３ -C １０ carbocyclic ring is optionally substituted A １ , and / or independently, halogen, C １ -C ６ alkyl, C ２ -C ９ heteroaryl, C ３ -C １２ carbocyclic ring, C ２ -C ９ heterocyclic ring, C(O)N(R １ｅ ), ２ , S(O)N(R １ｅ ), ２ , S(O) ２ N(R １ｅ ), ２ , C(O)R １ｅ , C(O)OR １ｅ , S(O)R １ｅ , or S(O) ２ R １ｅ is one or more substituents selected from, R １ｃ However, A １ , NR ２ａ R ３ａ , C ６ ~C ２０ Ariel, C ２ ~C ９ Heterosyl, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), (C １ ~C ２０ (heteroaryl)-(C ６ ~C ２０ (Aryl), and (C １ ~C ２０ (Heteroaryl) (C １ ~C ２０ (heteroaryl) and each C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), and (C １ ~C ２０ (heteroaryl)-(C １ ~C ２０ A heteroaryl is independent of A １ , and / or independently, R １ｈ Oxo, F, Cl, Br, I, C １ ~C ９ Alkyl, C １ ~C ９ Heteroalkyl, CHF ２ CF ３ NO ２ , N(R １ｆ ) ２ ,CN,C(O)N(R １ｆ ) ２ , S(O)N(R １ｆ ) ２ , S(O) ２ N(R) １ｆ ) ２ , OR １ｆ , SR １ｆ OC(O)R １ｆ , OC(O)OR １ｆ , C(O)R １ｆ , C(O)OR １ｆ S(O)R １ｆ , S(O) ２ R １ｆ ,OC(O)N(R １ｆ ) ２ , N(R １ｆ ) C(O)OR １ｆ , N(R １ｆ ) C(O)N(R １ｆ ) ２ , N(R １ａ１ ) C(O)R １ｆ , N(R １ｆ ) S(O)R １ｆ , N(R １ｆ ) S(O) ２ R １ｆ , N(R １ｆ ) S(O)N(R １ｆ ) ２ , and N(R １ｆ ) S(O) ２ N(R) １ｆ ) ２ It is optionally substituted with one or more substituents selected from the following: R １ｄ However, independently, C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R １ｄ Each C １ ~C １２ Alkyl, 3-12 membered carbon rings, and 3-12 membered heterocycles are one or more groups R １ｇ It is replaced by an optional selection, Each R １ｅ However, independently, hydrogen, C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, or C ２ ~C ５ It is a cycloalkyl, and each C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl and C ２ ~C ５ Cycloalkyl groups are independently oxo, halo, amino, hydroxyl, and C. １ ~C ３ C is optionally substituted with one or more groups independently selected from alkoxys and halos. １ ~C ３ It is optionally substituted with one or more groups selected from alkyl groups. R ２ａ However, independently, H and C １ ~C １２ Alkyl, C ５ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), (C １ ~C ２０ (Heteroaryl) (C ６ ~C ２０ (Aryl), and (C １ ~C ２０ (Heteroaryl) (C １ ~C ２０ (heteroaryl) and each C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), and (C １ ~C ２０ (Heteroaryl) (C １ ~C ２０ A heteroaryl is independent of A １ , and / or independently, R １ｋ Oxo, F, Cl, Br, I, NO ２ , N(R １ｊ ) ２ ,CN,C(O)N(R １ｊ ) ２ , S(O)N(R １ｊ ) ２ , S(O) ２ N(R) １ｊ ) ２ , OR １ｊ , SR １ｊ OC(O)R １ｊ , OC(O)OR １ｊ , C(O)R １ｊ , C(O)OR １ｊ S(O)R １ｊ , S(O) ２ R １ｊ ,OC(O)N(R １ｊ ) ２ , N(R １ｊ ) C(O)OR １ｊ , N(R １ｊ ) C(O)N(R １ｊ ) ２ , N(R １ｊ ) C(O)R １ｊ , N(R １ｊ ) S(O)R １ｊ , N(R １ｊ ) S(O) ２ R １ｊ , N(R １ｊ ) S(O)N(R １ｊ ) ２ , and N(R ａ ) S(O) ２ N(R) １ｊ ) ２ It is optionally substituted with one or more substituents selected from the following: R ３ａ However, independently, C １ ~C １２ Alkyl, C ２ ~C １２ Alkenil, C ２ ~C １２ Alkynyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R ３ａ Each C １ ~C １２ Alkyl, C ２ ~C １２ Alkenil, C ２ ~C １２ Alkynnyl, 3-12 membered carbon rings, and 3-12 membered hetero rings are A １ and / or one or more base R １ｋ It is either optionally replaced by R in formula (I). ２ａ and R ３ａ However, together with the nitrogen to which they are bound, A １ and / or one or more base R １ｋ This forms a 3- to 12-membered heterocycle with arbitrary substitutions. Each R １ｆ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ９ Carbocyclyl, and C ２ ~C ９ It is a heterocycline, and each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, and heterocyclyl can be independently classified as oxo, halo, amino, hydroxyl, or C. １ ~C ６ Alkoxy, carbocyryl, heterocyclyl, or A １ and / or C optionally substituted with one or more groups independently selected from oxo and halo １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or with two R groups. １ｆ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R １ｇ However, independently, oxo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ９ Carbocyclyl, C ２ ~C ９ Heterocyclyl, C ５ ~C ９ Ariel, C １ ~C ２０ Heteroaryl, F, Cl, Br, I, NO ２ , N(R １Ｌ ) ２ ,CN,C(O)N(R １Ｌ ) ２ , S(O)N(R １Ｌ ) ２ , S(O) ２ N(R) ｃ ) ２ , OR １Ｌ , SR １Ｌ , OC(O)OR １Ｌ , OC(O)OR １Ｌ , C(O)R １Ｌ , C(O)OR １Ｌ S(O)R １Ｌ , S(O) ２ R １Ｌ ,OC(O)N(R １Ｌ ) ２ , N(R １Ｌ ) C(O)OR １Ｌ , N(R １Ｌ ) C(O)N(R １Ｌ ) ２ , N(R １Ｌ ) C(O)R １Ｌ , N(R １Ｌ S(O)R １Ｌ , N(R １Ｌ ) S(O) ２ R １Ｌ , N(R １Ｌ ) S(O)N(R １Ｌ ) ２ , or N(R １Ｌ ) S(O) ２ N(R) １Ｌ ) ２ And any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently oxo, halo, and NO ２ , N(R １Ｌ ) ２ ,CN,C(O)N(R １Ｌ ) ２ , S(O)N(R １Ｌ ) ２ , S(O) ２ N(R) １Ｌ ) ２ , OR １Ｌ , SR １Ｌ OC(O)R １Ｌ , C(O)R １Ｌ S(O)R １Ｌ , S(O) ２ R １Ｌ , C(O)N(R １Ｌ ) ２ , N(R １Ｌ ) C(O)R １Ｌ , N(R １Ｌ ) S(O)R １Ｌ , N(R １Ｌ ) S(O) ２ R １Ｌ , as well as C, which is optionally substituted with one or more groups independently selected from oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups. Each R １ｈ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocykrill, or heterocyclyl, any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, and heterocyclyl are independently oxo, carbocyclyl, heterocyclyl, halo, NO ２ , N(R １Ｍ ) ２ ,CN,C(O)N(R １Ｍ ) ２ , S(O)N(R １Ｍ ) ２ , S(O) ２ N(R) １Ｍ ) ２ , OR １Ｍ , SR １Ｍ OC(O)R １Ｍ , C(O)R １Ｍ , C(O)OR １Ｍ S(O)R １Ｍ S(O)R １Ｍ , C(O)N(R １Ｍ ) ２ , N(R １Ｍ ) C(O)R １Ｍ , N(R １Ｍ ) S(O)R １Ｍ , N(R １Ｍ ) S(O) ２ R １Ｍ , and C １ ~C ６ The carbocyryl and the C are optionally substituted with one or more groups selected from alkyl groups. １ ~C ６ Alkyl groups can independently be oxo, halo, and C. １ ~C ６ Alkyl, cyano, N(R) １Ｍ ) ２ , OR １Ｍ , heterocyclyl, and independently halo and C １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, and is optionally substituted with one or more groups selected from carbocyclyl groups. Each R １ｊ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocykrill, and heterocyclyl, each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, and heterocyclyl are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １ ~C ６ Alkoxy, carbocyryl, heterocyclyl, or A １ and / or C is optionally substituted with one or more groups independently selected from oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or with two R groups. １ｊ However, together with the nitrogen to which they are bound, A １ , and / or independently, oxo, halo, and A １ and / or C is optionally substituted with one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R １ｋ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocykrill, or heterocyclyl, any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, and heterocyclyl are independently oxo, carbocyclyl, heterocyclyl, halo, NO ２ , N(R １Ｎ ) ２ , CN, CHF ２ CF ３ , C(O)N(R １Ｎ ) ２ , S(O)N(R １Ｎ ) ２ , S(O) ２ N(R) １Ｎ ) ２ , OR １Ｎ , SR １Ｎ OC(O)R １Ｎ , C(O)R １Ｎ , C(O)OR １Ｎ S(O)R １Ｎ , S(O) ２ R １Ｎｄ , C(O)N(R １Ｎ ) ２ , N(R １Ｎ ) C(O)R １Ｎ , N(R １Ｎ ) S(O)R １Ｎ , N(R １Ｎ ) S(O) ２ R １Ｎ , and C １ ~C ６ The carbocyryl and the C are optionally substituted with one or more groups selected from alkyl groups. １～６ Alkyl is A １ , and / or independently, oxo, halo, C １ ~C ６ Alkyl, cyano, N(R) １Ｎ ) ２ , OR １Ｎ , heterocyclyl, and independently halo and C １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, and is optionally substituted with one or more groups selected from carbocyclyl groups. Each R １Ｍ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ It is an alkoxy, carbocykryl, or heterocyclyl, and each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, carbocyryl, and heterocyclyl can be independently classified as oxo, halo, amino, hydroxyl, or C. １ ~C ６ C is optionally substituted with one or more groups independently selected from alkoxy, carbocykryl, heterocyclyl, and oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or two R groups. ｄ２ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R １Ｎ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ It is an alkoxy, carbocykryl, or heterocyclyl, and each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, carbocykrill, and heterocyclyl are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １ ~C ６ C is optionally substituted with one or more groups independently selected from alkoxy, carbocyryl, heterocyclyl, and oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or two R groups. １Ｎ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, R １ａ , R １ｂ , R １ｃ , or R １ｄ Only one of them is A １ The compound according to claim 1, comprising:

3. The CBP binding portion of the above formula III has the following structure: 【Chemistry 2】 The compound according to claim 2, having the following characteristics.

4. The CBP binding portion of the above formula III has the following structure: 【Transformation 3】 The compound according to claim 2 or 3, having the following characteristics.

5. R １ｄ but, 【Chemistry 4】 The compound according to any one of claims 2 to 4.

6. R １ｃ NR ２ａ R ３ａ but, 【Transformation 5】 The compound according to any one of claims 2 to 4.

7. R １ｃ but, 【Transformation 6】 The compound according to any one of claims 2 to 4.

8. The CBP binding portion of the above formula III has the following structure: 【Chemistry 7-1】 【Chemistry 7-2】 The compound according to claim 2, having the following characteristics.

9. The CBP binding portion of the above formula III has the following structure: 【Chemistry 8-1】 【Chemistry 8-2】 The compound according to claim 2, having the following characteristics.

10. The CBP binding portion of the above formula III has the following structure: 【Chemistry 9】 It has, in the formula, R ８ However, independently, C １ ~C １２ Alkyl, C ３ ~C １２ A carbon ring, or C ３ ~C １２ It is a complex algebra, and each C １ ~C １２ Alkyl, C ３ ~C １２ Carbon rings, and C ３ ~C １２ A hetero ring is formed by one or more bases R ｏ It is replaced by an optional selection, R ９ However, independently, C １ ~C ４ Alkyl, C(O)N(R) ｈ２ ) ２ , S(O)N(R ｈ２ ) ２ , S(O) ２ , C(O)R ｈ２ , C(O)OR ｈ２ , S(O) ２ R ｈ２ , C ２ ~C ６ Heteroaryl, or C ２ ~C ９ It is a complex algebra, and any C １ ~C ４ Alkyl, C ２ ~C ６ Heteroaryl, or C ２ ~C ９ The complex rings are independently F, Cl, Br, I, and C. ３ ~C ５ Carbocycle, C(O)N(R ｈ２ ) ２ , S(O) ２ N(R) ｈ２ ) ２ , OR ｈ２ , S(O) ２ R ｈ２ OC(O)R ｈ２ , C(O)OR ｈ２ , N(R ｈ２ ) ２ , N(R ｈ２ ) ２ , N(R ｈ２ ) C(O)N(R ｈ２ ) ２ , N(R ｈ２ ) S(O) ２ R ｈ２ , N(R ｈ２ ) S(O)N(R ｈ２ ) ２ , and N(R ｈ２ ) S(O) ２ N(R) ｈ２ ) ２ One or more substituents are substituted by any choice selected from the following: R １０ However, independently, C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), (C １ ~C ２０ (Heteroaryl) (C ６ ~C ２０ (Aryl), and (C １～２０ (Heteroaryl) (C １～２０ (heteroaryl) and each C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), and (C １ ~C ２０ (Heteroaryl) (C １ ~C ２０ A heteroaryl is independent of A １ , and / or independently, R ｐ Oxo, F, Cl, Br, I, C １ ~C ９ Alkyl, C １ ~C ９ Heteroalkyl, CHF ２ CF ３ NO ２ , N(R ａ２ ) ２ ,CN,C(O)N(R ａ２ ) ２ , S(O)N(R ａ２ ) ２ , S(O) ２ N(R) ａ２ ) ２ , N(R ａ２ ) C(O)OR ａ２ ) C(O)N(R ａ２ ), C(O)N(R ａ２ ), S(O) ２ R ａ２ , N(R ａ２ ) S(O)N(R ａ２ ) ２ , and N(R ａ２ ) S(O) ２ N(R) ａ２ ) ２ It is optionally substituted with one or more substituents selected from the following: Each R ａ２ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, and C ２ ~C １２ It is a heterocycline, and each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, and C ２ ~C １２ Heterocyclines can independently be oxo, halo, amino, hydroxyl, and C. １ ~C ６ Alkoxy, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocyclyl, or A １ and / or C optionally substituted with one or more groups independently selected from oxo and halo １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or with two R groups. ａ２ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R Ｏ However, independently, oxo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocyclyl, C ６ ~C １０ Ariel, C ２ ~C ９ Heteroaryl, F, Cl, Br, I, NO ２ , N(R Ｐ ) ２ ,CN,C(O)N(R Ｐ ) ２ , S(O)N(R Ｐ ) ２ , S(O) ２ N(R) Ｐ ) ２ , OR Ｐ , SR Ｐ , OC(O)OR Ｐ , OC(O)OR Ｐ , C(O)R Ｐ , C(O)OR Ｐ S(O)R Ｐ , S(O) ２ R Ｐ ,OC(O)N(R Ｐ ) ２ , N(R Ｐ ) C(O)OR Ｐ , N(R Ｐ ) C(O)N(R Ｐ ) ２ , N(R Ｐ ) C(O)R Ｐ , N(R Ｐ ) S(O)R Ｐ , N(R Ｐ ) S(O) ２ R Ｐ , N(R Ｐ ) S(O)N(R Ｐ ) ２ , or N(R Ｐ ) S(O) ２ N(R) Ｐ ) ２ And any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocyclyl, C ６ ~C １０ Aryl, and C ２ ~C ９ Heteroaryls independently become oxo, halo, and NO ２ , N(R Ｐ ) ２ ,CN,C(O)N(R Ｐ ) ２ , S(O)N(R Ｐ ) ２ , S(O) ２ N(R) Ｐ ) ２ , OR Ｐ , SR Ｐ OC(O)R Ｐ , C(O)R Ｐ S(O)R Ｐ , S(O) ２ R Ｐ , C(O)N(R Ｐ ) ２ , N(R Ｐ ) C(O)R Ｐ , N(R Ｐ ) S(O)R Ｐ , N(R ｃ２ ) S(O) ２ R ｃ２ , as well as C, which is optionally substituted with one or more groups independently selected from oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups. Each R Ｐ is, independently, hydrogen, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C １２ carbocyclic, or C ３ -C １２ heterocyclic, and any C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C １２ carbocyclic, and C ３ -C １２ heterocyclic are, independently, oxo, carbocyclic, heterocyclic, halo, NO ２ , N(R ｄ２ ), ２ , CN, C(O)N(R ｄ２ ), ２ , S(O)N(R ｄ２ ), ２ , S(O) ２ N(R ｄ２ ), ２ , OR ｄ２ , SR ｄ２ , C(O)R ｄ２ , S(O) ２ , R ｄ２ , C(O)N(R ｄ２ ), ２ , N(R ｄ２ ), ２ , N(R ｄ２ ), S(O)R ｄ２ , N(R ｄ２ ), S(O) ２ , R ｄ２ , and C １ -C ６ alkyl, and are optionally substituted with one or more groups selected therefrom, and said C ３ -C １２ carbocyclic and said C １ -C ６ alkyl are, independently, oxo, halo, C １ -C ６ Alkyl, cyano, N(R) ｄ２ ) ２ , OR ｄ２ , C ３ ~C １２ Heterocyclyl, and independently halos and C １～６ C is optionally substituted with one or more groups selected from alkyl groups. ３ ~C １２ It is optionally substituted with one or more groups selected from carbocyclyl, Each R ｄ２ is independently hydrogen, C １ to C ６ alkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C １ C ～６ alkoxy, carbocyclic, or heterocyclic, and each C １ to C ６ alkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C １ to C ６ alkoxy, C ３ to C １２ carbocyclic, and C ３ to C １２ heterocyclic are independently oxo, halo, amino, hydroxyl, C １ C ～６ alkoxy, C ３ to C １２ carbocyclic, C ３ to C １２ heterocyclic, and are optionally substituted with one or more groups selected from oxo and halo and independently optionally substituted with one or more groups selected from C １ to C ６ alkyl, or two Rs ｄ２ together with the nitrogen to which they are attached are independently oxo, halo, and C １ to C ３ alkyl optionally substituted with one or more groups selected from oxo and halo and independently optionally substituted with one or more groups selected from C ３ to C １２ heterocyclic to form Each R ｈ２ However, independently, hydrogen, C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, or C ２ ~C ５ It is a cycloalkyl, and each C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl and C ２ ~C ５ Cycloalkyl groups are independently oxo, halo, amino, hydroxyl, and C. １ ~C ３ C is optionally substituted with one or more groups independently selected from alkoxys and halos. １ ~C ３ It is optionally substituted with one or more groups selected from alkyl groups. R １０ However, A １ The compound according to claim 2, comprising:

11. R ８ However, these are methyl, oxetanyl, tetrahydrofuranil, tetrahydropyranil, dioxothiolanil, piperidyl, or pyrrolidinil, and R ８ Each of the following is a methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, with one or more groups R Ｏ The compound according to claim 10, which is optionally substituted with [the specified compound].

12. R ８ but, 【Chemistry 10】 The compound according to claim 10 or 11.

13. R ８ but, 【Chemistry 11】 The compound according to claim 12.

14. R ９ The compound according to any one of claims 10 to 13, wherein the compound is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole, or isoxazole.

15. R ９ However, the structure: 【Chemistry 12】 A compound according to any one of claims 10 to 14, having the following characteristics.

16. The CBP binding portion has the following structure: 【Chemistry 13】 A compound according to any one of claims 10 to 15, having the following characteristics.

17. R １０ However, the structure: 【Chemistry 14】 It has, During the ceremony, X ３ However, NR Ｎ２ ,CH ２ , or O, X ４ However, N and CH are X ５ However, N and CH are X ６ However, NR Ｎ２ ,CH ２ , or O, R １４ However, CHF ２ , CHCl ２ ,CH ３ , Cl, F, or H, Each R Ｎ２ However, independently, C １ ~C ３ The compound according to any one of claims 10 to 16, wherein the compound is alkyl or H.

18. X ３ However, CH ２ X ４ The compound according to claim 17, wherein the compound is CH.

19. R １０ However, the structure: 【Chemistry 15】 A compound according to any one of claims 10 to 18, having the following characteristics.

20. R １０ However, the structure: 【Chemistry 16】 The compound according to claim 19, having the following characteristics.

21. The CBP binding portion has the following structure: 【Chemistry 17-1】 【Chemistry 17-2】 A compound according to any one of claims 10 to 20, having the following characteristics.

22. The CBP binding portion of the above formula III has the following structure: [Chemistry 18] It has, in the formula, R １ However, independently, C １ ~C １２ Alkyl, C ２ ~C １２ Alkenil, C ２ ~C １２ Alkinyl, C ３ ~C １２ A carbon ring, or C ２ ~C １２ It is a complex algebra, R １ Each C １ ~C １２ Alkyl, C ２ ~C １２ Alkenil, C ２ ~C １２ Alkinyl, C ３ ~C １２ Carbon rings, and C ２ ~C １２ A complex algebra is A １ and / or one or more base R ｂ It is replaced by an optional selection, R ２ However, independently, C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), (C １ ~C ２０ (Heteroaryl) (C ６ ~C ２０ (Aryl), and (C １ ~C ２０ (Heteroaryl) (C １ ~C ２０ (heteroaryl) and each C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), and (C １ ~C ２０ (heteroaryl)-(C １ ~C ２０ A heteroaryl is independent of A １ , and / or independently, R ｃ Oxo, F, Cl, -Br, I, NO ２ , N(R ａ ) ２ ,CN,C(O)N(R ａ ) ２ , S(O)N(R ａ ) ２ , S(O) ２ -N(R) ａ ) ２ , N(R ａ ) C(O)-O-R ａ ) C(O)N(R ａ )-C(O)-N(R ａ ) S(O) ２ R ａ , N(R ａ ) S(O)N(R ａ ) ２ , and N(R ａ ) S(O) ２ N(R) ａ ) ２ It is optionally substituted with one or more substituents selected from, R ３ However, independently, C １ ~C １２ Alkyl, C ２ ~C １２ Alkenil, C ２ ~C １２ Alkynyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R ３ Each C １ ~C １２ Alkyl, C ２ ~C １２ Alkenil, C ２ ~C １２ Alkynnyl, 3-12 membered carbon rings, and 3-12 membered hetero rings are A １ and / or one or more base R ｅ It is either optionally replaced, or R in equation (I) ２ and R ３ However, together with the nitrogen to which they are bound, A １ and / or one or more base R ｅ This forms a 3- to 12-membered heterocycle with arbitrary substitutions. R ４ However, independently, C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, C ３ ~C ５ Carbon ring, 3- to 5-membered heterocycle, C(O)N(R) ｈ ) ２ , S(O)N(R ｈ ) ２ , S(O) ２ , C(O)R ｈ , C(O)-O)R ｈ , or S(O) ２ R ｈ And any C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, C ３ ~C ５ Carbon rings, and C ２ ~C ５ A complex algebra is A １ , and / or independently, F, Cl, Br, I, C ３ ~C ５ Carbocycle, C(O)-N(R ｈ ) ２ , S(O) ２ N(R) ｈ ) ２ , -O) OR ｈ ,C(OC(O)-R ｈ , -O-C(O)-OR ｈ , -C(O)OR ｈ , N(R ｈ ) ２ , -N(R ｈ ) ２ , N(R ｈ )C(O)-N(R ｈ ) S(O)R ｈ , -N(R ｈ )-S(O)-R ｈ , -N(R ｈ ) S(O)N(R ｈ ) ２ , and N(R ｈ ) S(O) ２ N(R) ｈ ) ２ It is optionally substituted with one or more substituents selected from the following: Each R ａ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, and C ３ ~C １２ It is a heterocycline, and each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, and C ３ ~C １２ Heterocyclines can independently be oxo, halo, amino, hydroxyl, and C. １ ~C ６ Alkoxy, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocyclyl, or A １ and / or C optionally substituted with one or more groups independently selected from oxo and halo １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or with two R groups. ａ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｂ However, independently, oxo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocyclyl, C ６ ~C １０ Ariel, C ２ ~C １２ Heteroaryl, F, Cl, Br, I, NO ２ , N(R ｃ ) ２ ,CN,C(O)N(R ｃ ) ２ , S(O)N(R ｃ ) ２ , S(O) ２ -N(R) ｃ ) ２ , N(R ｃ ) C(O)-R ｃ ) C(O)N(R ｃ , -S(O)R ｃ , -S(O) ２ R ｃ , N(R ｃ ) S(O)N(R ｃ ) ２ , or N(R ｃ ) S(O) ２ N(R) ｃ ) ２ And any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocyclyl, C ６ ~C １０ Aryl, and C ２ ~C １２ Heteroaryl is A １ , and / or independently, oxo, halo, NO ２ , N(R ｃ ) ２ , CN, -C(O)-N(R ｃ ) ２ , N(R ｃ ) C(O) ２ -N(R) ｃ ) S(O)R ｃ , N(R ｃ ) S(O) ２ R ｃ , and C optionally substituted with one or more groups independently selected from oxo and halo １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups. Each R ｃ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, or C ３ ~C １２ It is a heterocycline and any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, and C ３ ~C １２ Heterocyclines are A １ , and / or independently, oxo, carbocyclyl, heterocyclyl, halo, NO ２ , -N(R ｄ ) ２ ,CN,C(O)N(R ｄ ) ２ , S(O)N(R ｄ ) ２ , S(O) ２ -N(R) ｄ ) ２ , -O-R ｄ , -S-R ｄ , C(O)-R ｄ , S(O) ２ R ｄ , C(O)N(R ｄ ) ２ , N(R ｄ ) ２ , -N(R ｄ ) S(O)R ｄ , N(R ｄ ) S(O) ２ R ｄ , and C １ ~C ６ The C is optionally substituted with one or more groups selected from alkyl groups. ３ ~C １２ Carbocyclyl and the aforementioned C １ ~C ６ Alkyl groups can independently be oxo, halo, and C. １ ~C ６ Alkyl, cyano, N(R) ｄ ) ２ , OR ｄ , C ３ ~C １２ Heterocyclyl, and independently halos and C １ ~C ６ C is optionally substituted with one or more groups selected from alkyl groups. ３ ~C １２ It is optionally substituted with one or more groups selected from carbocyclyl, Each R ｄ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, C ３ ~C １２ Carbocyclyl, or C ３ ~C １２ It is a heterocycline, and each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, C ３ ~C １２ Carbocyclyl, and C ３ ~C １２ Heterocyclines are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １ ~C ６ Alkoxy, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocyclyl and C, optionally substituted with one or more groups independently selected from oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or two R groups. ｄ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｅ However, independently, oxo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocyclyl, C ２ ~C ９ Ariel, C ２ ~C １２ Heteroaryl, F, Cl, Br, I, NO ２ , N(R ｆ１ ) ２ ,CN,C(O)N(R ｆ１ ) ２ , S(O)N(R ｆ１ ) ２ , S(O) ２ N(R) ｆ１ ) ２ , OR ｆ１ , SR ｆ１ OC(O)R ｆ１ , OC(O)OR ｆ１ , C(O)R ｆ１ , C(O)OR ｆ１ S(O)R ｆ１ , S(O) ２ R ｆ１ ,OC(O)N(R ｆ１ ) ２ , N(R ｆ１ ) C(O)OR ｆ１ , N(R ｆ１ ) C(O)N(R ｆ１ ) ２ , N(R ｆ１ ) C(O)R ｆ１ , N(R ｆ１ ) S(O)R ｆ１ , N(R ｆ１ ) S(O) ２ R ｆ１ , N(R ｆ１ ) S(O)N(R ｆ１ ) ２ , or N(R ｆ１ ) S(O) ２ N(R) ｆ１ ) ２ And any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocyclyl, C ２ ~C ９ Aryl, and C ２ ~C １０ Heteroaryl is A １ , and / or independently, oxo, halo, NO ２ , N(R ｆ１ ) ２ ,CN,C(O)N(R ｆ１ ) ２ , S(O)N(R ｆ１ ) ２ , S(O) ２ N(R) ｆ１ ) ２ , OR ｆ１ , SR ｆ１ OC(O)R ｆ１ , C(O)R ｆ１ , C(O)OR ｆ１ S(O)R ｆ１ , S(O) ２ R ｆ１ , C(O)N(R ｆ１ ) ２ , N(R ｆ１ ) C(O)R ｆ１ , N(R ｆ１ ) S(O)R ｆ１ , N(R ｆ１ ) S(O) ２ R ｆ１ , carbon rings, and C optionally substituted with one or more groups independently selected from oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups. Each R ｆ１ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocykrill, or heterocyclyl, any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, and C ３ ~C １２ Heterocyclyl can be independently identified as oxo, carbocyclyl, heterocyclyl, halo, NO ２ , N(R ｇ１ ) ２ ,CN,C(O)N(R ｇ１ ) ２ , S(O)N(R ｇ１ ) ２ , S(O) ２ N(R) ｇ１ ) ２ , OR ｇ１ , SR ｇ１ OC(O)R ｇ１ , C(O)R ｇ１ , C(O)OR ｇ１ S(O)R ｇ１ , S(O) ２ R ｇ１ , C(O)N(R ｇ１ ) ２ , N(R ｇ１ ) C(O)R ｇ１ , N(R ｇ１ ) S(O)R ｇ１ , N(R ｇ１ ) S(O) ２ R ｇ１ , and C １ ~C ６ The C is optionally substituted with one or more groups selected from alkyl groups. ３ ~C １２ Carbocyclyl and the aforementioned C １ ~C ６ Alkyl is A １ , and / or independently, oxo, halo, C １ ~C ６ Alkyl, cyano, N(R) ｇ１ ) ２ , OR ｇ１ , heterocyclyl, and independently halo and C １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, and is optionally substituted with one or more groups selected from carbocyclyl groups. Each R ｇ１ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, C ３ ~C １２ Carbocyclyl, or C ３ ~C １２ It is a heterocycline, and each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, C ３ ~C １２ Carbocyclyl, and C ３ ~C １２ Heterocyclines are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １ ~C ６ Alkoxy, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocyclyl and C, optionally substituted with one or more groups independently selected from oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or two R groups. ｇ１ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｈ However, independently, hydrogen, C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, or C ２ ~C ５ It is a cycloalkyl, and each C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl and C ２ ~C ５ Cycloalkyl groups are independently oxo, halo, amino, hydroxyl, and C. １ ~C ３ Alkoxy, and A １ C is optionally replaced with one or more groups independently selected from the halo. １ ~C ３ It is optionally substituted with one or more groups selected from alkyl groups. R １ , R ２ , R ３ , or R ４ Only one of them is A １ The compound according to claim 2, comprising:

23. R １ However, independently, C １ ~C １２ Alkyl, C ２ ~C １２ Alkenil, C ２ ~C １２ Alkinyl, C ３ ~C １２ A carbon ring, or C ３ ~C １２ It is a complex algebra, and each C １ ~C １２ Alkyl, C ２ ~C １２ Alkenil, C ２ ~C １２ Alkinyl, C ３ ~C １２ Carbon rings, and C ３ ~C １２ A complex algebra is A １ and / or one or more base R ｂ It is replaced by an optional selection, R ２ However, independently, C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), (C １ ~C ２０ (Heteroaryl) (C ６ ~C ２０ (Aryl), or (C １ ~C ２０ (Heteroaryl) (C １ ~C ２０ (heteroaryl) and each C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), and (C １ ~C ２０ (Heteroaryl) (C １ ~C ２０ A heteroaryl is independent of A １ , and / or independently, R ｃ Oxo, F, Cl, -Br, I, NO ２ , N(R ａ ) ２ ,CN,C(O)N(R ａ ) ２ , S(O)N(R ａ ) ２ , S(O) ２ N(R) ａ ) ２ , N(R ａ ) C(O)OR ａ ) C(O)N(R ａ ) C(O)N(R ａ ) S(O) ２ R ａ , N(R ａ ) S(O)N(R ａ ) ２ , and N(R ａ ) S(O) ２ N(R) ａ ) ２ It is optionally substituted with one or more substituents selected from, R ３ However, independently, C １ ~C １２ Alkyl, C ２ ~C １２ Alkenil, C ２ ~C １２ Alkinyl, C ３ ~C １２ A carbon ring, or C ３ ~C １２ It is a complex algebra, R ３ Each C １ ~C １２ Alkyl, C ２ ~C １２ Alkenil, C ２ ~C １２ Alkinyl, C ３ ~C １２ Carbon rings, and C ３ ~C １２ A complex algebra is A １ and / or one or more base R ｅ It is either optionally replaced, or R ２ and R ３ However, together with the nitrogen to which they are bound, one or more R groups ｅ This forms a 3- to 12-membered heterocycle with arbitrary substitutions. R ４ However, independently, C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, C ３ ~C ５ carbocycle, C ３ ~C ５ Heterogeneous ring, C(O)N(R) ｈ ) ２ , S(O)N(R ｈ ) ２ , S(O) ２ , C(O)R ｈ , C(O)-O)R ｈ , or S(O) ２ R ｈ And any C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, C ３ ~C ５ Carbon rings, and C ３ ~C ５ A complex algebra is A １ , and / or independently, F, Cl, Br, I, 3-5 membered carbon rings, C(O)-N(R ｈ ) ２ , -S(O)-N(R ｈ ) ２ , N(R ｈ ) C(O)OR ｈ , N(R ｈ ) C(O)N(R ｈ ) ２ , N(R ｈ ) C(O)R ａ , N(R ｈ ) ２ , -N(R ｈ ) S(O) ２ R ｈ , N(R ｈ ) S(O)N(R ｈ ) ２ , and N(R ｈ ) S(O) ２ N(R) ｈ ) ２ It is optionally substituted with one or more substituents selected from the following: Each R ａ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, or C ３ ~C １２ It is a heterocycline, and each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, and C ３ ~C １２ Heterocyclines are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １ ~C ６ C is optionally substituted with one or more groups independently selected from alkoxy, carbocyryl, heterocyclyl, and oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or two R groups. ａ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｂ However, independently, oxo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocyclyl, C ２ ~C ９ Ariel, C ２ ~C １０ Heteroaryl, F, Cl, Br, I, NO ２ , N(R ｃ ) ２ ,CN,C(O)N(R ｃ ) ２ , S(O)N(R ｃ ) ２ , S(O) ２ -N(R) ｃ ) ２ , N(R ｃ )C(O)-O)N(R ｃ ) ２ IR ｃ ) C(O)R ｃ , N(R ｃ ) S(O)R ｃ , N(R ｃ ) S(O)-N(R ｃ ) S(O)N(R ｃ ) ２ , or N(R)S(O) ２ N(R) ｃ ) ２ And any C １ C ～６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocyclyl, C ２ ~C ９ Aryl, and C ２ ~C １０ Heteroaryl is A １ , and / or independently, oxo, halo, NO ２ , -N(R ｃ ) ２ , N(R ｃ )C(O)-N(R ｃ ) S(O) ２ -N(R) ｃ ) S(O) ２ R ｃ , and C optionally substituted with one or more groups independently selected from oxo and halo １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups. Each R ｃ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, or C ３ ~C １２ It is a heterocycline and any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, and C ３ ~C １２ Heterocyclines are A １ , and / or independently, oxo, carbocyclyl, heterocyclyl, halo, NO ２ , N(R ｄ ) ２ ,CN,C(O)N(R ｄ ) ２ , S(O)N(R ｄ ) ２ , S(O) ２ -N(R) ｄ ) ２ , -O-R ｄ , -S-R ｄ , C(O)-R ｄ , S(O) ２ R ｄ , C(O)N(R ｄ ) ２ , N(R ｄ ) ２ , -N(R ｄ ) S(O)R ｄ , N(R ｄ ) S(O) ２ R ｄ , and C １ ~C ６ The carbocyryl and the C are optionally substituted with one or more groups selected from alkyl groups. １～６ Alkyl groups can independently be oxo, halo, and C. １ ~C ６ Alkyl, cyano, N(R) ｄ ) ２ , OR ｄ , heterocyclyl, and independently halo and C １～６ It is optionally substituted with one or more groups selected from alkyl groups, and is optionally substituted with one or more groups selected from carbocyclyl groups. Each R ｄ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, C ３ ~C １２ Carbocyclyl, or C ３ ~C １２ It is a heterocycline, and each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, C ３ ~C １２ Carbocyclyl, and C ３ ~C １２ Heterocyclines are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １ ~C ６ Alkoxy, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocyclyl and C, optionally substituted with one or more groups independently selected from oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or two R groups. ｄ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｅ However, independently, oxo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocyclyl, C ２ ~C ９ Ariel, C ２ ~C １０ Heteroaryl, F, Cl, Br, I, NO ２ , N(R ｆ１ ) ２ ,CN,C(O)N(R ｆ１ ) ２ , S(O)N(R ｆ１ ) ２ , S(O) ２ N(R) ｆ１ ) ２ , OR ｆ１ , SR ｆ１ OC(O)R ｆ１ , OC(O)OR ｆ１ , -C(O)-R ｆ１ , C(O)OR ｆ１ S(O)R ｆ１ , S(O) ２ -R ｆ１ ,OC(O)N(R ｆ１ ) ２ , N(R ｆ１ ) C(O)OR ｆ１ , N(R ｆ１ ) C(O)N(R ｆ１ ) ２ , N(R ｆ１ ) C(O)R ｆ１ , N(R ｆ１ ) S(O)R ｆ１ , N(R ｆ１ ) S(O) ２ R ｆ１ , N(R ｆ１ ) S(O)N(R ｆ１ ) ２ , or N(R ｆ１ ) S(O) ２ N(R) ｆ１ ) ２ And any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocyclyl, C ２～９ Aryl, and C ２～１０ Heteroaryl is A １ , and / or independently, oxo, halo, NO ２ , N(R ｆ１ ) ２ ,CN,C(O)N(R ｆ１ ) ２ , S(O)N(R ｆ１ ) ２ , S(O) ２ N(R) ｆ１ ) ２ , OR ｆ１ , SR ｆ１ OC(O)-R ｆ１ , C(O)R ｆ１ , C(O)OR ｆ１ S(O)R ｆ１ , S(O) ２ R ｆ１ , C(O)N(R ｆ１ ) ２ , N(R ｆ１ ) C(O)R ｆ１ , N(R ｆ１ ) S(O)R ｆ１ , N(R ｆ１ ) S(O) ２ R ｆ１ , carbon rings, and C optionally substituted with one or more groups independently selected from oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups. Each R ｆ１ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, or C ３ ~C １２ It is a heterocycline and any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Carbocyclyl, and C ３ C ～１２ Heterocyclines are A １ , and / or independently, oxo, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocycline, halo, NO ２ , N(R ｇ１ ) ２ ,CN,C(O)-N(R ｇ１ ) ２ , S(O)N(R ｇ１ ) ２ , S(O) ２ N(R) ｇ１ ) ２ , OR ｇ１ , SR ｇ１ OC(O)R ｇ１ , C(O)R ｇ１ , C(O)OR ｇ１ , -S(O)R ｇ１ , S(O) ２ R ｇ１ , C(O)N(R ｇ１ ) ２ , N(R ｇ１ ) C(O)R ｇ１ , N(R ｇ１ ) S(O)R ｇ１ , N(R ｇ１ ) S(O) ２ R ｇ１ , and C １ ~C ６ The carbocyryl and the C are optionally substituted with one or more groups selected from alkyl groups. １～６ Alkyl groups can independently be oxo, halo, and C. １ ~C ６ Alkyl, cyano, N(R) ｇ１ ) ２ , OR ｇ１ , heterocyclyl, and independently halo and C １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, and is optionally substituted with one or more groups selected from carbocyclyl groups. Each R ｇ１ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, C ３ ~C １２ Carbocyclyl, or C ３ ~C １２ It is a heterocycline, and each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, C ３ ~C １２ Carbocyclyl, and C ３ ~C １２ Heterocyclines are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １ ~C ６ C is optionally substituted with one or more groups independently selected from alkoxy, carbocyryl, heterocyclyl, and oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or two R groups. ｇ１ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｈ However, independently, hydrogen, C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, or C ２ ~C ５ It is a cycloalkyl, and each C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl and C ２ ~C ５ Cycloalkyl, A １ , and / or independently, oxo, halo, amino, hydroxyl, C １ ~C ３ Alkoxy, and A １ C is optionally replaced with one or more groups independently selected from the halo. １ ~C ３ The compound according to claim 22, which is optionally substituted with one or more groups selected from alkyl groups.

24. R １ However, these are methyl, oxetanyl, tetrahydrofuranil, tetrahydropyranil, dioxothiolanil, piperidyl, or pyrrolidinil, and R １ Each of the following is a methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, with one or more groups R ｂ The compound according to claim 22 or 23, which is optionally substituted with [the specified compound].

25. R １ but, 【Chemistry 19】 The compound according to any one of claims 22 to 24.

26. R １ but, 【Chemistry 20】 The compound according to any one of claims 22 to 24.

27. R ２ and R ３ However, together with the nitrogen to which they are bound, A １ and / or one or more base R ｅ The compound according to any one of claims 22 to 26, wherein a 9 or 10-membered bicyclic heterocycle is formed by an optional substitution.

28. R ２ and R ３ However, together with the nitrogen to which they are bound, A １ and / or one or more base R ｅ The compound according to any one of claims 22 to 27, wherein a 9 or 10-membered bicyclic heterocycle is formed by an optional substitution, and the 9 or 10-membered bicyclic heterocycle comprises at least one aromatic ring.

29. NR ２ R ３ Together, the structure: 【Chemistry 21】 A compound according to any one of claims 22 to 28, having the following characteristics.

30. R ４ The compound according to any one of claims 22 to 29, wherein the compound is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole, or isoxazole.

31. R ４ However, the structure: 【Chemistry 22】 A compound according to any one of claims 22 to 30, having the following characteristics.

32. The CBP binding portion has the following structure: 【Chemistry 23-1】 【Chemistry 23-2】 【Chemistry 23-3】 [Chemistry 23-4] A compound according to any one of claims 22 to 31, having the following characteristics.

33. The CBP binding portion has the following structure: 【Chemistry 24】 It has, in the formula, X １ However, it is C or N, X ２ However, it is C or N, R ５ However, independently, C １ ~C １２ Alkyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R ５ Each C １ ~C １２ Alkyl, 3-12 membered carbon rings, and 3-12 membered heterocycles are one or more groups R ｋ１ｋ It is replaced by an optional selection, R ６ However, independently, C １～４ Alkyl, C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), (C １ ~C ２０ (heteroaryl)-(C ６ ~C ２０ (Aryl), and (C １ ~C ２０ (Heteroaryl) (C １ ~C ２０ Heteroaryl), C(O)N(R ｈ１ ) ２ , S(O)N(R ｈ１ ) ２ , S(O) ２ N(R) ｈ１ ) ２ , C(O)R ｈ１ , C(O)OR ｈ１ S(O)R ｈ１ , or S(O) ２ R ｈ１ C １ ~C ４ Alkyl, C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) - (C １ ~C ２０ (heteroaryl), and (C １ ~C ２０ (heteroaryl)-(C １ ~C ２０ A heteroaryl is independent of A １ , and / or independently, F, Cl, Br, I, 3-5 membered carbon rings, C(O)N(R ｈ１ ) ２ , S(O)N(R ｈ１ ) ２ , S(O) ２ N(R) ｈ１ ) ２ , OR ｈ１ , SR ｈ１ OC(O)R ｈ１ , OC(O)OR ｈ１ , C(O)R ｈ１ , C(O)OR ｈ１ S(O)R ｈ１ , S(O) ２ R ｈ１ ,OC(O)N(R ｈ１ ) ２ , N(R ｈ１ ) C(O)OR ｈ１ , N(R ｈ１ ) C(O)N(R ｈ１ ) ２ , N(R ｈ１ ) C(O)R ｈ１ , N(R ｈ１ ) S(O)R ｈ１ , N(R ｈ１ S(O) ２ R ｈ１ , N(R ｈ１ ) S(O)N(R ｈ１ ) ２ , and N(R ｈ１ ) S(O) ２ N(R) ｈ１ ) ２ It is optionally substituted with one or more substituents selected from the following: R ７ However, it became independent, NR ２ R ３ , C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), (C １ ~C ２０ (heteroaryl)-(C ６ ~C ２０ (Aryl), and (C １ ~C ２０ (Heteroaryl) (C １ ~C ２０ (heteroaryl) and each C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), and (C １ ~C ２０ (Heteroaryl) (C １ ~C ２０ A heteroaryl is independent of A １ , and / or independently, R Ｌ１ Oxo, F, Cl, Br, I, NO ２ , N(R ａ１ ) ２ ,CN,C(O)N(R ａ１ ) ２ , S(O)N(R ａ１ ) ２ , S(O) ２ N(R) ａ１ ) ２ , OR ａ１ , SR ａ１ OC(O)R ａ１ , OC(O)OR ａ１ , C(O)R ａ１ , C(O)OR ａ１ S(O)R ａ１ S(O)R ａ１ ,OC(O)N(R ａ１ ) ２ , N(R ａ１ )C(OOR ａ１ , N(R ａ１ ) C(O)N(R ａ１ ) ２ , N(R ａ１ ) C(O)R ａ１ , N(R ａ１ ) S(O)R ａ１ , N(R ａ１ ) S(O) ２ R ａ１ , N(R ａ１ ) S(O)N(R ａ１ ) ２ , and N(R ａ１ ) S(O) ２ N(R) ａ１ ) ２ It is optionally substituted with one or more substituents selected from the following: R ２ However, independently, C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６～２０ Ariel) (C １ ~C ２０ (heteroaryl), (C １ ~C ２０ (Heteroaryl) (C ６ ~C ２０ (Aryl), and (C １ ~C ２０ (Heteroaryl) (C １ ~C ２０ (heteroaryl) and each C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), and (C １ ~C ２０ (Heteroaryl) (C １ ~C ２０ A heteroaryl is independent of A １ , and / or independently, R ｃ Oxo, F, Cl, Br, I, NO ２ , N(R ａ ) ２ ,CN,C(O)N(R ａ ) ２ , S(O)N(R ａ ) ２ , S(O) ２ N(R) ａ ) ２ , OR ａ , SR ａ OC(O)R ａ , OC(O)OR ａ , C(O)R ａ , C(O)OR ａ S(O)R ａ , S(O) ２ R ａ ,OC(O)N(R ａ ) ２ , N(R ａ ) C(O)OR ａ , N(R ａ ) C(O)N(R ａ ) ２ , N(R ａ ) C(O)R ａ , N(R ａ ) S(O)R ａ , N(R ａ ) S(O) ２ R ａ , N(R ａ ) S(O)N(R ａ ) ２ , and N(R ａ ) S(O) ２ N(R) ａ ) ２ It is optionally substituted with one or more substituents selected from, R ３ However, independently, C １ ~C １２ Alkyl, C ２ ~C １２ Alkenil, C ２ ~C １２ Alkynyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R ３ Each C １ ~C １２ Alkyl, C ２ ~C １２ Alkenil, C ２ ~C １２ Alkynnyl, 3-12 membered carbon rings, and 3-12 membered hetero rings are A １ and / or one or more base R ｅ It is either optionally replaced, or R in equation (I) ２ and R ３ However, together with the nitrogen to which they are bound, A １ and / or one or more base R ｅ This forms a 3- to 12-membered heterocycle with arbitrary substitutions. Each R ａ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocykrill, and heterocyclyl, each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, and heterocyclyl are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １ ~C ６ Alkoxy, carbocyryl, heterocyclyl, or A １ and / or C is optionally substituted with one or more groups independently selected from oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or with two R groups. ａ However, together with the nitrogen to which they are bound, A １ , and / or independently, oxo, halo, and A １ and / or C is optionally substituted with one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｃ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocykrill, or heterocyclyl, any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, and heterocyclyl are independently oxo, carbocyclyl, heterocyclyl, halo, NO ２ , N(R ｄ ) ２ ,CN,C(O)N(R ｄ ) ２ , S(O)N(R ｄ ) ２ , S(O) ２ N(R) ｄ ) ２ , OR ｄ , SR ｄ OC(O)R ｄ , C(O)R ｄ , C(O)OR ｄ S(O)R ｄ , S(O) ２ R ｄ , C(O)N(R ｄ ) ２ , N(R ｄ ) C(O)R ｄ , N(R ｄ ) S(O)R ｄ , N(R ｄ ) S(O) ２ R ｄ , and C １ ~C ６ The carbocyryl and the C are optionally substituted with one or more groups selected from alkyl groups. １ ~C ６ Alkyl is A １ , and / or independently, oxo, halo, C １ ~C ６ Alkyl, cyano, N(R) ｄ ) ２ , OR ｄ , heterocyclyl, and independently halo and C １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, and is optionally substituted with one or more groups selected from carbocyclyl groups. Each R ｄ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ It is an alkoxy, carbocykryl, or heterocyclyl, and each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, carbocykrill, and heterocyclyl are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １ ~C ６ C is optionally substituted with one or more groups independently selected from alkoxy, carbocyryl, heterocyclyl, and oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or two R groups. ｄ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｅ However, independently, oxo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, Carbocyclyl, Heterocyclyl, Aryl, Heteroaryl, F, Cl, Br, I, NO ２ , N(R ｆ１ ) ２ ,CN,C(O)N(R ｆ１ ) ２ , S(O)N(R ｆ１ ) ２ , S(O) ２ N(R) ｆ１ ) ２ , OR ｆ１ , SR ｆ１ OC(O)R ｆ１ , OC(O)OR ｆ１ , C(O)R ｆ１ , C(O)OR ｆ１ S(O)R ｆ１ , S(O) ２ R ｆ１ ,OC(O)N(R ｆ１ ) ２ , N(R ｆ１ ) C(O)OR ｆ１ , N(R ｆ１ ) C(O)N(R ｆ１ ) ２ , N(R ｆ１ ) C(O)R ｆ１ , N(R ｆ１ ) S(O)R ｆ１ , N(R ｆ１ ) S(O) ２ R ｆ１ , N(R ｆ１ ) S(O)N(R ｆ１ ) ２ , or N(R ｆ１ ) S(O) ２ N(R) ｆ１ ) ２ And any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are A １ , and / or independently, oxo, halo, NO ２ , N(R ｆ１ ) ２ ,CN,C(O)-N(R ｆ１ ) ２ , S(O)N(R ｆ１ ) ２ , S(O) ２ N(R) ｆ１ ) ２ , OR ｆ１ , SR ｆ１ OC(O)R ｆ１ , C(O)R ｆ１ , C(O)OR ｆ１ S(O)R ｆ１ , S(O) ２ R ｆ１ , C(O)N(R ｆ１ ) ２ , N(R ｆ１ ) C(O)R ｆ１ , N(R ｆ１ ) S(O)R ｆ１ , N(R ｆ１ S(O) ２ R ｆ１ , carbon rings, and C optionally substituted with one or more groups independently selected from oxo and halo. １～６ It is optionally substituted with one or more groups selected from alkyl groups. Each R ｆ１ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocykrill, or heterocyclyl, any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, and heterocyclyl are independently oxo, carbocyclyl, heterocyclyl, halo, NO ２ , N(R ｇ１ ) ２ ,CN,C(O)N(R ｇ１ ) ２ , S(O)N(R ｇ１ ) ２ , S(O) ２ N(R) ｇ１ ) ２ , OR ｇ１ , R ｇ１ OC(O)R ｇ１ , C(O)R ｇ１ , C(O)OR ｇ１ S(O)R ｇ１ , S(O) ２ R ｇ１ , C(O)N(R ｇ１ ) ２ , N(R ｇ１ ) C(O)R ｇ１ , N(R ｇ１ ) S(O)R ｇ１ , N(R ｇ１ ) S(O) ２ R ｇ１ , and C １ ~C ６ The carbocyryl and the C are optionally substituted with one or more groups selected from alkyl groups. １ ~C ６ Alkyl is A １ , and / or independently, oxo, halo, C １ ~C ６ Alkyl, cyano, N(R) ｇ１ ) ２ , OR ｇ１ , heterocyclyl, and independently halo and C １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, and is optionally substituted with one or more groups selected from carbocyclyl groups. Each R ｇ１ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ It is an alkoxy, carbocykryl, or heterocyclyl, and each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, carbocykrill, and heterocyclyl are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １ ~C ６ C is optionally substituted with one or more groups independently selected from alkoxy, carbocyryl, heterocyclyl, and oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or two R groups. ｇ１ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ａ１ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocykrill, and heterocyclyl, each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, and heterocyclyl can be independently classified as oxo, halo, amino, hydroxyl, or C. １ ~C ６ Alkoxy, carbocyryl, heterocyclyl, or A １ and / or C optionally substituted with one or more groups independently selected from oxo and halo １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or two R groups. ａ１ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｋ１ However, independently, oxo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, Carbocyclyl, Heterocyclyl, Aryl, Heteroaryl, F, Cl, Br, I, NO ２ , N(R Ｌ１ ) ２ ,CN,C(O)N(R Ｌ１ ) ２ , S(O)N(R Ｌ１ ) ２ , S(O) ２ N(R) Ｌ１ ) ２ , OR Ｌ１ , SR Ｌ１ , OC(O)OR Ｌ１ , OC(O)OR Ｌ１ , C(O)R Ｌ１ , C(O)OR Ｌ１ S(O)R Ｌ１ , S(O) ２ R Ｌ１ ,OC(O)N(R Ｌ１ ) ２ , N(R Ｌ１ ) C(O)OR Ｌ１ , N(R Ｌ１ ) C(O)N(R Ｌ１ ) ２ , N(R Ｌ１ ) C(O)R Ｌ１ , N(R Ｌ１ ) S(O)R Ｌ１ , N(R Ｌ１ ) S(O)R Ｌ１ , N(R Ｌ１ ) S(O)N(R Ｌ１ ) ２ , or N(R Ｌ１ ) S(O) ２ N(R) Ｌ１ ) ２ And any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently oxo, halo, and NO ２ , N(R Ｌ１ ) ２ ,CN,C(O)N(R Ｌ１ ) ２ , S(O)N(R Ｌ１ ) ２ , S(O) ２ N(R) Ｌ１ ) ２ , OR Ｌ１ , SR Ｌ１ OC(O)R Ｌ１ , C(O)R Ｌ１ S(O)R Ｌ１ , S(O) ２ R Ｌ１ , C(O)N(R Ｌ１ ) ２ , N(R Ｌ１ ) C(O)R Ｌ１ , N(R Ｌ１ ) S(O)R Ｌ１ , N(R Ｌ１ ) S(O) ２ R Ｌ１ , as well as C, which is optionally substituted with one or more groups independently selected from oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups. Each R Ｌ１ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, carbocykrill, or heterocyclyl, any C １ ~C ６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, carbocyclyl, and heterocyclyl are independently oxo, carbocyclyl, heterocyclyl, halo, NO ２ , N(R ｄ１ ) ２ ,CN,C(O)N(R ｄ１ ) ２ , S(O)N(R ｄ１ ) ２ , S(O) ２ N(R) ｄ１ ) ２ , OR ｄ１ , SR ｄ１ OC(O)R ｄ１ , C(O)R ｄ１ , C(O)R ｄ１ S(O)R ｄ１ , S(O) ２ R ｄ１ , C(O)N(R ｄ１ ) ２ , N(R ｄ１ ) C(O)R ｄ１ , N(R ｄ１ ) S(O)R ｄ１ , N(R ｄ１ ) S(O) ２ R ｄ１ , and C １ ~C ６ The carbocyryl and the C are optionally substituted with one or more groups selected from alkyl groups. １ ~C ６ Alkyl groups can independently be oxo, halo, and C. １ ~C ６ Alkyl, cyano, N(R) ｄ１ ) ２ , OR ｄ１ , heterocyclyl, and independently halo and C １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, and is optionally substituted with one or more groups selected from carbocyclyl groups. Each R ｄ１ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ It is an alkoxy, carbocykryl, or heterocyclyl, and each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, carbocyryl, and heterocyclyl can be independently classified as oxo, halo, amino, hydroxyl, or C. １ ~C ６ C is optionally substituted with one or more groups independently selected from alkoxy, carbocykryl, heterocyclyl, and oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or two R groups. ｄ１ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ６ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｈ１ However, independently, hydrogen, C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, or C ２ ~C ５ It is a cycloalkyl, and each C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl and C ２ ~C ５ Cycloalkyl groups are independently oxo, halo, amino, hydroxyl, and C. １ ~C ３ C is optionally substituted with one or more groups independently selected from alkoxys and halos. １ ~C ４ It is optionally substituted with one or more groups selected from alkyl groups. R ７ However, A １ The compound according to claim 2, comprising:

34. R ５ but, 【Chemistry 25】 The compound according to claim 33.

35. R ７ but, 【Chemistry 26】 The compound according to claim 33 or 34.

36. The CBP binding portion has the following structure: 【Chemistry 27】 It has, in the formula, R １１ However, independently, C １ ~C １２ Alkyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R １１ Each C １ ~C １２ Alkyl, 3-12 membered carbon rings, and 3-12 membered heterocycles are one or more groups R Ｍ It is replaced by an optional selection, R １２ However, independently, C １ ~C ４ Alkyl, C(O)N(R) ｈ３ ) ２ , S(O)N(R ｈ３ ) ２ , S(O)N(R ｈ３ ) ２ , C(O)R ｈ３ , C(O)OR ｈ３ S(O)R ｈ３ , or S(OR) ｈ３ And any C １ ~C ４ Alkyl groups are independently F, Cl, Br, I, 3-5 membered carbon rings, C(O)N(R) ｈ３ ) ２ , S(O)N(R ｈ３ ) ２ , S(O) ２ N(R) ｈ３ ) ２ , OR ｈ３ , SR ｈ３ OC(O)R ｈ３ , OC(O)OR ｈ３ , C(O)R ｈ３ , C(O)OR ｈ３ S(O)R ｈ３ , S(O) ２ R ｈ３ ,OC(O)N(R ｈ３ ) ２ , N(R ｈ３ ) C(O)OR ｈ３ , N(R ｈ３ ) C(O)N(R ｈ３ ) ２ , N(R ｈ３ ) C(O)R ｈ３ , N(R ｈ３ ) S(O)R ｈ３ , N(R ｈ３ ) S(O) ２ R ｈ３ , N(R ｈ３ ) S(O)N(R ｈ３ ) ２ , and N(R ｈ３ ) S(O) ２ N(R) ｈ３ ) ２ One or more substituents are substituted by any choice selected from the following: R １３ However, it became independent, NR ２ R ３ , C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), (C １ ~C ２０ (Heteroaryl) (C ６ ~C ２０ (Aryl), and (C １ ~C ２０ (Heteroaryl) (C １ ~C ２０ (heteroaryl) and each C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), and (C １ ~C ２０ (Heteroaryl) (C １ ~C ２０ A heteroaryl is independent of A １ , and / or independently, R Ｎ１ Oxo, F, Cl, Br, I, NO ２ , N(R ａ３ ) ２ ,CN,C(O)N(R ａ３ ) ２ , S(O)N(R ａ３ ) ２ , S(O) ２ N(R) ａ３ ) ２ , OR ａ３ , SR ａ３ OC(O)R ａ３ , OC(O)OR ａ３ , C(O)R ａ３ , C(O)OR ａ３ S(O)R ａ３ , S(O) ２ R ａ３ ,OC(O)N(R ａ３ ) ２ , N(R ａ３ ) C(O)OR ａ３ , N(R ａ３ )C(ON(R ａ３ ) ２ , N(R ａ３ ) C(O)R ａ３ , N(R ａ３ ) S(O)R ａ３ , N(R ａ３ ) S(O) ２ R ａ３ , N(R ａ３ ) S(O)N(R ａ３ ) ２ , and N(R ａ３ ) S(O) ２ N(R) ａ３ ) ２ It is optionally substituted with one or more substituents selected from the following: R ２ However, independently, C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６～２０ Ariel) (C １ ~C ２０ (heteroaryl), (C １ ~C ２０ (Heteroaryl) (C ６ ~C ２０ (Aryl), and (C １ ~C ２０ (Heteroaryl) (C １ ~C ２０ (heteroaryl) and each C ６ ~C ２０ Ariel, C １ ~C ２０ Heteroaryl, (C ６ ~C ２０ Ariel) (C １ ~C ２０ (heteroaryl), and (C １ ~C ２０ (Heteroaryl) (C １ ~C ２０ A heteroaryl is independent of A １ , and / or independently, R ｃ Oxo, F, Cl, Br, I, NO ２ , N(R ａ ) ２ ,CN,C(O)N(R ａ ) ２ , S(O)N(R ａ ) ２ , S(O) ２ N(R) ａ ) ２ , OR ａ , SR ａ OC(O)R ａ , OC(O)OR ａ , C(O)R ａ , C(O)OR ａ S(O)R ａ , S(O) ２ R ａ ,OC(O)N(R ａ ) ２ , N(R ａ ) C(O)OR ａ , N(R ａ ) C(O)N(R ａ ) ２ , N(R ａ ) C(O)R ａ , N(R ａ ) S(O)R ａ , N(R ａ ) S(O) ２ R ａ , N(R ａ ) S(O)N(R ａ ) ２ , and N(R ａ ) S(O) ２ N(R) ａ ) ２ It is optionally substituted with one or more substituents selected from, R ３ However, independently, C １ ~C １２ Alkyl, C ２ ~C １２ Alkenil, C ２ ~C １２ Alkynyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R ３ Each C １ ~C １２ Alkyl, C ２ ~C １２ Alkenil, C ２ ~C １２ Alkynnyl, 3-12 membered carbon rings, and 3-12 membered hetero rings are A １ and / or one or more base R ｅ It is either optionally replaced, or R in equation (I) ２ and R ３ However, together with the nitrogen to which they are bound, A １ and / or one or more base R ｅ This forms a 3- to 12-membered heterocycle with arbitrary substitutions. Each R ａ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocykrill, and heterocyclyl, each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, and heterocyclyl are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １ ~C ６ Alkoxy, carbocyryl, heterocyclyl, or A １ and / or C is optionally substituted with one or more groups independently selected from oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or with two R groups. ａ However, together with the nitrogen to which they are bound, A １ , and / or independently, oxo, halo, and A １ and / or C is optionally substituted with one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｃ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocykrill, or heterocyclyl, any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, and heterocyclyl are independently oxo, carbocyclyl, heterocyclyl, halo, NO ２ , N(R ｄ ) ２ ,CN,C(O)N(R ｄ ) ２ , S(O)N(R ｄ ) ２ , S(O) ２ N(R) ｄ ) ２ , OR ｄ , SR ｄ OC(O)R ｄ , C(O)R ｄ , C(O)OR ｄ S(O)R ｄ , S(O) ２ R ｄ , C(O)N(R ｄ ) ２ , N(R ｄ ) C(O)R ｄ , N(R ｄ ) S(O)R ｄ , N(R ｄ ) S(O) ２ R ｄ , and C １ ~C ６ The carbocyryl and the C are optionally substituted with one or more groups selected from alkyl groups. １ ~C ６ Alkyl is A １ , and / or independently, oxo, halo, C １ ~C ６ Alkyl, cyano, N(R) ｄ ) ２ , OR ｄ , heterocyclyl, and independently halo and C １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, and is optionally substituted with one or more groups selected from carbocyclyl groups. Each R ｄ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ It is an alkoxy, carbocykryl, or heterocyclyl, and each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, carbocykrill, and heterocyclyl are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １ ~C ６ C is optionally substituted with one or more groups independently selected from alkoxy, carbocyryl, heterocyclyl, and oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or two R groups. ｄ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｅ However, independently, oxo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, Carbocyclyl, Heterocyclyl, Aryl, Heteroaryl, F, Cl, Br, I, NO ２ , N(R ｆ１ ) ２ ,CN,C(O)N(R ｆ１ ) ２ , S(O)N(R ｆ１ ) ２ , S(O) ２ N(R) ｆ１ ) ２ , OR ｆ１ , SR ｆ１ OC(O)R ｆ１ , OC(O)OR ｆ１ , C(O)R ｆ１ , C(O)OR ｆ１ S(O)R ｆ１ , S(O) ２ R ｆ１ ,OC(O)N(R ｆ１ ) ２ , N(R ｆ１ ) C(O)OR ｆ１ , N(R ｆ１ ) C(O)N(R ｆ１ ) ２ , N(R ｆ１ ) C(O)R ｆ１ , N(R ｆ１ ) S(O)R ｆ１ , N(R ｆ１ ) S(O) ２ R ｆ１ , N(R ｆ１ ) S(O)N(R ｆ１ ) ２ , or N(R ｆ１ ) S(O) ２ N(R) ｆ１ ) ２ And any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are A １ , and / or independently, oxo, halo, NO ２ , N(R ｆ１ ) ２ ,CN,C(O)-N(R ｆ１ ) ２ , S(O)N(R ｆ１ ) ２ , S(O) ２ N(R) ｆ１ ) ２ , OR ｆ１ , SR ｆ１ OC(O)R ｆ１ , C(O)R ｆ１ , C(O)OR ｆ１ S(O)R ｆ１ , S(O) ２ R ｆ１ , C(O)N(R ｆ１ ) ２ , N(R ｆ１ ) C(O)R ｆ１ , N(R ｆ１ ) S(O)R ｆ１ , N(R ｆ１ S(O) ２ R ｆ１ , carbon rings, and C optionally substituted with one or more groups independently selected from oxo and halo. １～６ It is optionally substituted with one or more groups selected from alkyl groups. Each R ｆ１ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocykrill, or heterocyclyl, any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, and heterocyclyl are independently oxo, carbocyclyl, heterocyclyl, halo, NO ２ , N(R ｇ１ ) ２ ,CN,C(O)N(R ｇ１ ) ２ , S(O)N(R ｇ１ ) ２ , S(O) ２ N(R) ｇ１ ) ２ , OR ｇ１ , R ｇ１ OC(O)R ｇ１ , C(O)R ｇ１ , C(O)OR ｇ１ S(O)R ｇ１ , S(O) ２ R ｇ１ , C(O)N(R ｇ１ ) ２ , N(R ｇ１ ) C(O)R ｇ１ , N(R ｇ１ ) S(O)R ｇ１ , N(R ｇ１ ) S(O) ２ R ｇ１ , and C １ ~C ６ The carbocyryl and the C are optionally substituted with one or more groups selected from alkyl groups. １ ~C ６ Alkyl is A １ , and / or independently, oxo, halo, C １ ~C ６ Alkyl, cyano, N(R) ｇ１ ) ２ , OR ｇ１ , heterocyclyl, and independently halo and C １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, and is optionally substituted with one or more groups selected from carbocyclyl groups. Each R ｇ１ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ It is an alkoxy, carbocykryl, or heterocyclyl, and each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, carbocykrill, and heterocyclyl are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １ ~C ６ C is optionally substituted with one or more groups independently selected from alkoxy, carbocyryl, heterocyclyl, and oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or two R groups. ｇ１ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ａ３ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocykrill, and heterocyclyl, each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, and heterocyclyl can be independently classified as oxo, halo, amino, hydroxyl, or C. １ ~C ６ Alkoxy, carbocyryl, heterocyclyl, or A １ and / or C optionally substituted with one or more groups independently selected from oxo and halo １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or two R groups. ａ３ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １ ~C ３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R Ｍ However, independently, oxo, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, Carbocyclyl, Heterocyclyl, Aryl, Heteroaryl, F, Cl, Br, I, NO ２ , N(R Ｎ１ ) ２ ,CN,C()N(R Ｎ１ ) ２ , S(O)N(R Ｎ１ ) ２ , S(O) ２ N(R) ｃ ) ２ , OR Ｎ１ , SR Ｎ１ , OC(O)OR Ｎ１ , OC(O)OR Ｎ１ , C(O)R Ｎ１ , C(O)OR Ｎ１ S(O)R Ｎ１ , S(O) ２ R Ｎ１ ,OC(O)N(R Ｎ１ ) ２ , N(R Ｎ１ ) C(O)OR Ｎ１ , N(R Ｎ１ ) C(O)N(R Ｎ１ ) ２ , N(R Ｎ１ ) C(O)R Ｎ１ , N(R Ｎ１ ) S(O)R Ｎ１ , N(R Ｎ１ ) S(O) ２ R Ｎ１ , N(R Ｎ１ ) S(O)N(R Ｎ１ ) ２ , or N(R Ｎ１ ) S(O) ２ N(R) Ｎ１ ) ２ And any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently oxo, halo, and NO ２ , N(R Ｎ１ ) ２ ,CN,C(O)N(R Ｎ１ ) ２ , S(O)N(R Ｎ１ ) ２ , S(O) ２ N(R) Ｎ１ ) ２ , OR Ｎ１ , SR Ｎ１ OC(O)R Ｎ１ , C(O)R Ｎ１ S(O)R Ｎ１ , S(O) ２ R Ｎ１ , C(O)N(R Ｎ１ ) ２ , N(R Ｎ１ ) C(O)R Ｎ１ , N(R Ｎ１ ) S(O)R Ｎ１ , N(R Ｎ１ ) S(O) ２ R Ｎ１ , as well as C, which is optionally substituted with one or more groups independently selected from oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups. Each R Ｎ１ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocykrill, or heterocyclyl, any C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, carbocyclyl, and heterocyclyl are independently oxo, carbocyclyl, heterocyclyl, halo, NO ２ , N(R ｄ３ ) ２ ,CN,C(O)N(R ｄ３ ) ２ , S(O)N(R ｄ３ ) ２ , S(O) ２ N(R) ｄ３ ) ２ , OR ｄ３ , SR ｄ３ OC(O)R ｄ３ , C(O)R ｄ３ , C(O)OR ｄ３ S(O)R ｄ３ , S(O) ２ R ｄ３ , C(O)N(R ｄ３ ) ２ , N(R ｄ３ ) C(O)R ｄ３ , N(R ｄ３ ) S(O)R ｄ３ , N(R ｄ３ ) S(O) ２ R ｄ３ , and C １～６ The carbocyryl and the C are optionally substituted with one or more groups selected from alkyl groups. １ ~C ６ Alkyl groups can independently be oxo, halo, and C. １ ~C ６ Alkyl, cyano, N(R) ｄ３ ) ２ , OR ｄ３ , heterocyclyl, and independently halo and C １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, and is optionally substituted with one or more groups selected from carbocyclyl groups. Each R ｄ３ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ It is an alkoxy, carbocykryl, or heterocyclyl, and each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, carbocyryl, and heterocyclyl can be independently classified as oxo, halo, amino, hydroxyl, or C. １ ~C ６ C is optionally substituted with one or more groups independently selected from alkoxy, carbocykryl, heterocyclyl, and oxo and halo. １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups, or two R groups. ｄ３ However, together with the nitrogen to which they are bound, C is optionally substituted independently with oxo, halo, and one or more groups independently selected from oxo and halo. １～３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｈ３ However, independently, hydrogen, C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, or C ２ ~C ５ It is a cycloalkyl, and each C １ ~C ４ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl and C ２ ~C ５ Cycloalkyl groups are independently oxo, halo, amino, hydroxyl, and C. １ ~C ３ C is optionally substituted with one or more groups independently selected from alkoxys and halos. １ ~C ３ It is optionally substituted with one or more groups selected from alkyl groups. R １３ However, A １ The compound according to claim 1, comprising:

37. R １２ but, 【Chemistry 28】 The compound according to claim 36.

38. The CBP binding portion of the above formula IV has the following structure: 【Chemistry 29】 The compound according to claim 37, having the following characteristics.

39. R １１ but, 【Transformation 30】 The compound according to any one of claims 36 to 38.

40. R １３ However, C １ ~C ２０ A compound according to any one of claims 36 to 39, wherein the compound is a heteroaryl compound.

41. R １３ but, 【Chemistry 31】 The compound according to any one of claims 36 to 40.

42. R １３ but, 【Chemistry 32】 The compound according to any one of claims 36 to 40.

43. R １３ but, 【Transformation 33】 The compound according to any one of claims 36 to 40.

44. The CBP binding portion of the above formula IV has the following structure: 【Transformation 34】 The compound according to claim 36, having the following characteristics.

45. The compound according to any one of claims 1 to 44, wherein the decomposition portion is a ubiquitin ligase binding portion.

46. The compound according to claim 45, wherein the ubiquitin ligase binding portion comprises a cereblon ligand, an IAP (inhibitor of apoptosis) ligand, a mouse double micro2 homolog (MDM2), or a von Hippel-Lindou (VHL) ligand, or a derivative or analog thereof.

47. The aforementioned decomposition part includes the structure of formula V, 【Chemistry 35】 During the ceremony, R Ｂ１ａ However, independently, H, A ２ CA(O)A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ２ａ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ３ａ However, A ２ CA(O)A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ４ａ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ５ａ However, independently, H and C are substituted by choice. １～６ Alkyl or optionally substituted C １～６ It is heteroalkyl, R Ｂ６ａ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is a heteroalkyl or arylalkyl, R Ｂ１ａ and R Ｂ３ａ Only one of them is A ２ or C(O)A ２ The compound according to any one of claims 1 to 46.

48. The decomposition part (B) of the above formula (V) includes the structure of formula (V-A), 【Transformation 36】 During the ceremony, R Ｂ１ａ However, independently, H, A ２ CA(O)A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ２ａ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ３ａ However, A ２ CA(O)A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ４ａ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ５ａ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ６ａ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is a heteroalkyl or arylalkyl, R Ｂ１ａ and R Ｂ３ａ Only one of them is A ２ or C(O)A ２ The compound according to claim 47.

49. The decomposition part (B) of the above formula (V) includes the structure of formula (V-B), 【Chemistry 37】 During the ceremony, R Ｂ１ａ However, independently, H, A ２ CA(O)A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ２ａ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ３ａ However, A ２ CA(O)A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ４ａ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ５ａ However, independently, H and C are substituted by choice. １～６ Alkyl or optionally substituted C １～６ It is heteroalkyl, R Ｂ６ａ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is a heteroalkyl or arylalkyl, R Ｂ１ａ and R Ｂ３ａ Only one of them is A ２ or C(O)A ２ The compound according to claim 47.

50. R Ｂ６ａ but, 【Transformation 38】 And, In the formula, each R Ｂ６ However, independently, halogen, and optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ２ ~C ９ Heterocycline, C by optional substitution ６ ~C １０ Aaryl, replaced by C of any choice ２ ~C ９ Heteroaryl, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Heteroalkenyl, C by optional substitution ２ ~C ６ It is an alkynyl, hydroxy, thiol. R Ｂ９ However, independently, H, or C which is optionally replaced. １ ~C ６ It is alkyl, R Ｂ１０ However, independently, H, or C which is optionally replaced. １ ~C ６ It is alkyl, The compound according to any one of claims 47 to 49, wherein v2 is 0, 1, 2, 3, or 4.

51. R Ｂ６ａ but, 【Chemistry 39】 The compound according to any one of claims 47 to 50.

52. R Ｂ６ａ but, 【Chemistry 40】 The compound according to any one of claims 47 to 50.

53. R Ｂ６ but, 【Chemistry 41】 The compound according to any one of claims 47 to 50.

54. R Ｂ６ but, 【Chemistry 42】 The compound according to any one of claims 47 to 50.

55. R Ｂ６ａ but, 【Chemistry 43】 And, During the ceremony, Each R Ｂ６ However, independently, halogen, and optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ２ ~C ９ Heterocycline, C by optional substitution ６ ~C １０ Aaryl, replaced by C of any choice ２ ~C ９ Heteroaryl, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Heteroalkenyl, C by optional substitution ２ ~C ６ It is an alkynyl, hydroxy, thiol. R Ｂ１１ However, C is replaced independently and by choice. ３ ~C １０ Carbocyclyl, optionally replaced with C ２ ~C ９ Heterocycline, C by optional substitution ６ ~C １０ Aaryl, replaced by C of any choice ２ ~C ９ It is a heteroaryl, R Ｂ９ However, independently, H, or C which is optionally replaced. １ ~C ６ It is alkyl, R Ｂ１０ However, independently, H, or C which is optionally replaced. １ ~C ６ It is alkyl, The compound according to any one of claims 47 to 50, wherein v2 is 0, 1, 2, 3, or 4.

56. R Ｂ１１ but, 【Chemistry 44】 The compound according to any one of claims 47 to 55.

57. R Ｂ１１ but, 【Chemistry 45】 The compound according to any one of claims 47 to 55.

58. R Ｂ６ａ but, 【Chemistry 46】 And, v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ However, independently, halogen, and optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ２ ~C ９ Heterocycline, C by optional substitution ６ ~C １０ Aaryl, replaced by C of any choice ２ ~C ９ Heteroaryl, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Heteroalkenyl, hydroxyl, thiol, or optionally substituted amino acids, R Ｂ７ and R Ｂ８ Each of these can be independently replaced by H, halogen, or C of any choice. １ ~C ６ Alkyl or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ９ and R Ｂ１０ However, independently, C is replaced by H or of any choice. １ ~C ６ The compound according to any one of claims 47 to 55, wherein it is alkyl.

59. R Ｂ６ａ but, 【Chemistry 47】 The compound according to any one of claims 47 to 58.

60. The decomposition portion (B) of the above formula (V) includes the structure of formula V-C, 【Chemistry 48】 R Ｂ１ However, independently, H, A ２ CA(O)A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ３ However, A ２ CA(O)A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice １ ~C ６ Alkyl, C ３ ~C １０ Carbocyclyl, or optionally substituted C １ ~C ６ Alkyl, and the C １ ~C ６ alkyl, the C １ ~C ６ Heteroalkyl, the C ３ ~C １０ Carbocyclyl, the above C ６ ~C １０ Aryl, the aforementioned C １ ~C ６ alkyl, the C ３ ~C １０ Carbocyclyl, or the aforementioned C ６ ~C １０ A ２ and / or R Ｊ２ It is substituted with one of the more numerous groups, R Ｂ４ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C １ ~C ６ Alkyl or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ５ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ However, independently, halogen, and optionally substituted C １ ~C ６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ２ ~C ９ Heterocycline, C by optional substitution ６ ~C １０ Aaryl, replaced by C of any choice ２ ~C ９ Heteroaryl, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Heteroalkenyl, C by optional substitution ２ ~C ６ It is an alkynyl, hydroxy, thiol. R Ｂ９ However, independently, H, or C which is optionally replaced. １ ~C ６ It is alkyl, Each R Ｊ２ However, independently, hydrogen, and optionally substituted C １ ~C ６ Alkyl, optionally substituted C ３ ~C １２ Carbocyclyl and optionally substituted C ３ ~C １２ It is a heterocycline, and each C １ ~C ６ Alkyl, C ３ ~C １２ Carbocyclyl, and C ３ ~C １２ Heterocyclines can independently be amino, hydroxyl, thio, and C. １ ~C ６ Alkoxy, C ３ ~C １２ Carbocyclyl, C ３ ~C １２ Heterocyclyl, or A ２ and / or C optionally substituted with one or more groups independently selected from oxo and halo １ ~C ６ It is optionally substituted with one or more groups selected from alkyl groups. R Ｂ１ and R Ｂ３ Only one of them is A ２ or C(O)A ２ The compound according to claim 47, or a pharmaceutically acceptable salt thereof.

61. R Ｂ６ However, C was replaced by an arbitrary choice. ２ ~C ９ The compound according to claim 60, which is a heteroaryl compound.

62. R Ｂ６ but, 【Chemistry 49】 The compound according to claim 60 or 61.

63. The structure of the above formula V-C is, [Transformation 50] The compound according to any one of claims 60 to 62, which is a derivative or analog thereof.

64. R Ｂ６ However, C is replaced by halogen or of any choice. ２ ~C ６ The compound according to claim 60, which is an alkynyl.

65. R Ｂ６ However, C was replaced by an arbitrary choice. １ ~C ６ The compound according to claim 60, which is a heteroalkyl compound.

66. The C that was replaced by the aforementioned optional selection １ ~C ６ The compound according to claim 65, wherein the heteroalkyl group is methoxy.

67. The structure of the above formula V-C is, 【Chemistry 51】 The compound according to claim 65 or 66, which is a derivative or analog thereof.

68. The decomposition portion (B) of the above formula (V) includes the structure of formula V-D, 【Chemistry 52】 During the ceremony, R Ｂ１ However, independently, H, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ２ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ３ However, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ４ However, independently, H and C are substituted by choice. １～６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ５ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ However, independently, halogen, and optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ２ ~C ９ Heterocycline, C by optional substitution ６ ~C １０ Aaryl, replaced by C of any choice ２ ~C ９ Heteroaryl, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Heteroalkenyl, hydroxyl, thiol, or optionally substituted amino acids, R Ｂ７ and R Ｂ８ Each of these can be independently replaced by H, halogen, or C of any choice. １ ~C ６ Alkyl or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ９ and R Ｂ１０ However, independently, C is replaced by H or of any choice. １ ~C ６ It is alkyl, R Ｂ１ and R Ｂ３ Only one of them is A ２ The compound according to claim 48, or a pharmaceutically acceptable salt thereof.

69. The structure of the above formula V-D is, 【Chemistry 53】 The compound according to claim 68, which is a derivative or analog thereof.

70. The aforementioned disassembled part has the following structure: 【Chemistry 54】 The compound according to claim 69, having the following characteristics.

71. The aforementioned disassembled part has the following structure: 【Transformation 55】 The compound according to claim 69, having the following characteristics.

72. The decomposition part (B) of the above formula (V) includes the structure of formula V-E, 【Transformation 56】 R Ｃ１ However, C is replaced independently and by choice. １ ~C ６ It is alkyl, R Ｃ２ However, A ２ , or C replaced by any choice １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aaryl, replaced by C of any choice ２ ~C ９ It is a heteroaryl, and each C １ ~C ６ Alkyl, C ３～１０ Carbocyclyl, C １ ~C ６ Heteroalkyl, C ６ ~C １０ Ariel, C ２ ~C ９ Heteroaryl is A ２ and / or one or more base R Ｊ It is replaced by an optional selection, R Ｃ３ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, or optionally substituted C ６ ~C １０ It is Ariel, R Ｃ４ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, v2 is 0, 1, 2, 3, or 4, R Ｃ５ and R Ｃ６ Each of these is independently replaced by H or C of any choice. １ ~C ６ It is alkyl, Each R Ｃ７ However, independently, halogen, and optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ２ ~C ９ Heterocycline, C by optional substitution ６ ~C １０ Aaryl, replaced by C of any choice ２～９ Heteroaryl, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Heteroalkenyl, hydroxyl, thiol, or optionally substituted amino acids, R Ｃ８ and R Ｃ９ Each of these can be independently replaced by H, halogen, or C of any choice. １ ~C ６ Alkyl or optionally substituted C ６ ~C １０ It is Ariel, Each R Ｊ However, independently, hydrogen, C １ ~C ６ Alkyl, C ３ ~C ６ Carbocyclyl, and C ２ ~C ６ It is a heterocycline, and each C １ ~C ６ Alkyl, C ３ ~C ６ Carbocyclyl, and C ２ ~C ６ Heterocyclines can independently be amino, hydroxyl, and C. １ ~C ６ Alkoxy, C ３ ~C ６ Carbocyclyl, C ２ ~C ６ Heterocyclyl, or A ２ and / or C optionally substituted with one or more groups independently selected from oxo and halo １ ~C ６ The compound according to claim 48, which is optionally substituted with one or more groups selected from alkyl groups, or a pharmaceutically acceptable salt thereof.

73. The linker disassembly section has the following structure: 【Chemistry 57】 The compound according to claim 72, having the following characteristics.

74. The decomposition part (B) of the above formula (V) includes the structure of formula V-F, 【Chemistry 58】 During the ceremony, R Ｂ１ However, independently, H, A ２ CA(O)A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl, R Ｂ３ However, A ２ CA(O)A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ４ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, or optionally substituted C ６ ~C １０ It is Ariel, R Ｂ５ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is a heteroalkyl or arylalkyl, R Ｂ１ and R Ｂ３ Only one of them is A ２ or C(O)A ２ The compound according to claim 48, or a pharmaceutically acceptable salt thereof.

75. The aforementioned disassembled part has the structure of formula V-F, which is, 【Chemistry 59】 The compound according to claim 74, which is a derivative or analog thereof.

76. L has the structure of formula II, A １ -(F)-(E) ｍ -C-A ２ Formula II During the ceremony, A １ However, this is a bond between the linker and A, A ２ However, this is a connection between B and the linker, m is 0 or 1, C is independently either absent, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl. E is replaced by C independently, in nonexistence, and of arbitrary choice. １ ~C １０ It is alkylene, F is independently and arbitrarily replaced by C. ２ ~C １０ Heterocyclylene, or C as optionally substituted. ２ ~C ９ A compound according to any one of claims 1 to 75, which is a heteroarylene.

77. The compound according to any one of claims 1 to 76, wherein m is 0.

78. The compound according to any one of claims 1 to 76, wherein m is 1.

79. E stands for methylene, ethylene, 【Transformation 60】 The compound according to any one of claims 1 to 77 or 79.

80. The compound according to any one of claims 1 to 79, wherein C is a carbonyl group.

81. A compound according to any one of claims 1 to 79, wherein C is absent.

82. F is replaced by C by arbitrary choice. ２ ~C １０ A compound according to any one of claims 1 to 81, wherein the compound is a heterocyclylene.

83. F is, 【Chemistry 61】 The compound according to claim 82.

84. F is replaced by C by arbitrary choice. ２ ~C ９ A compound according to any one of claims 1 to 81, which is a heteroarylene.

85. F is structure: 【Transformation 62】 And, In the formula, X ７ and X ８ However, each is independently either C or N, R １７ However, independently, H and C are substituted by choice. １ ~C ６ Alkyl, or A １ And, R １５ and R １６ However, when combined with the atoms to which they are bonded, they result in the optional substitution of C ３ ~C １２ Form a heteroaryl, and the C ３ ~C １２ The heteroaryl group is A1 and / or one or more of the following groups: halogen or C １ ~C ６ The compound according to claim 84, which is optionally substituted with an alkyl group.

86. F is, 【Transformation 63】 The compound according to claim 84.

87. The compound according to any one of claims 1 to 86, wherein the compound is any one of the compounds 1 to 536 in Table 1 or a pharmaceutically acceptable salt thereof.

88. The compound according to any one of claims 1 to 86, wherein the compound is one of the compounds 1A to 28A in Table 2 or a pharmaceutically acceptable salt thereof.

89. A pharmaceutical composition comprising a compound according to any one of claims 1 to 88 and a pharmaceutically acceptable excipient.

90. A method for treating cancer in a subject requiring treatment, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 89.

91. The method according to claim 90, wherein the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemia, ovarian cancer, neuroblastoma, myelofibrosis, lymphoma, leukemia, esophageal, gastric, or lung cancer.

92. The method according to claim 91, wherein the cancer is gastric cancer.

93. A method for treating gastric cancer in a subject requiring treatment, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 89.

94. The method according to any one of claims 90 to 93, wherein the cancer is metastatic.

95. The method according to any one of claims 90 to 94, wherein the subject or cancer has an EP300 loss-of-function mutation.

96. The method according to any one of claims 90 to 95, wherein the method further comprises administering anticancer therapy to the subject.

97. The method according to claim 96, wherein the anti-cancer therapy is a chemotherapeutic agent or cytotoxic agent, immunotherapy, surgery, radiotherapy, hyperthermia, or photocoagulation, or a combination thereof.

98. A method for treating a subject in need of treatment for an inflammatory and / or autoimmune disorder, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 89.

99. The method according to claim 98, wherein the inflammatory and / or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, scarring alopecia, Crohn's disease, graft-versus-host disease, systemic lupus erythematosus, Ecardi-Goutier syndrome, Sjögren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or psoriasis vulgaris.

100. The method according to claim 98 or 99, further comprising administering a JAK inhibitor to the subject.

101. The method according to claim 100, wherein the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.

102. A method for treating a disease, disorder, or condition mediated by components of the JAK-STAT pathway, comprising administering to a subject an effective amount of a compound according to any one of claims 1 to 88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 89.

103. The method according to claim 102, wherein the component of the JAK-STAT pathway is Janus kinase (JAK).

104. The method according to claim 102, wherein the component of the JAK-STAT pathway is a signal transduction and transcription activator (STAT).

105. The method according to claim 102, wherein the disease, disorder, or condition mediated by the components of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, scarring alopecia, Crohn's disease, graft-versus-host disease, systemic lupus erythematosus, Ecardi-Goutier syndrome, Sjögren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, psoriasis vulgaris, or myelofibrosis.

106. A method for inducing immune tolerance in a subject requiring such tolerance, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 89.

107. A method for inhibiting an inflammatory or autoimmune response in a subject requiring inhibition, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 89.

108. In subjects with an inflammatory response or at risk of developing an inflammatory response, memory CD8 ＋ A method for suppressing a T cell response, comprising administering to a subject an effective amount of a compound according to any one of claims 1 to 88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 89.

109. A method for treating an infectious disease in a subject requiring treatment, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 95, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 96.

110. The method according to claim 109, wherein the infectious disease is herpesvirus K*.

111. A method for treating Rubinstein-Taybe syndrome in a subject requiring treatment, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 89.

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