Compounds and their uses

Abstract

This disclosure features compounds useful for the treatment of EP300-related disorders.

Description

[Background technology]

[0001] EP300 is a histone acetyltransferase that regulates gene transcription through chromatin rearrangement. EP300 is involved in regulating cell proliferation and division. This invention relates to useful compositions and methods for the treatment of EP300-related disorders such as cancer and infectious diseases. [Overview of the project]

[0002] EP300 is an intracellular protein that regulates cell proliferation and division. EP300 is overexpressed in several cancer cell lines. Therefore, agents that reduce the levels and / or activity of EP300 may offer novel methods for treating diseases and disorders such as cancer and infections. We have found that depletion of EP300 leads to downregulation / depletion of MYC in those cells. Therefore, agents (e.g., compounds) that degrade EP300 are useful for treating disorders related to EP300 and / or MYC (e.g., cancer or infections).

[0003] This disclosure features compounds and methods useful for treating EP300-related disorders (e.g., cancer or infection). 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 EP300 bonding portion, B is the decomposition part, L has the structure of formula II, A 1 -C-(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 0 or 1, Each C is, independently, absent, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, E is absent, O, S, NR N , optionally substituted C 1~10 alkylene, optionally substituted C 2~10 alkenylene, optionally substituted C 2~10 alkynylene, optionally substituted C2-C 10 polyethylene glycol, optionally substituted C 1~10 heteroalkylene, optionally substituted C 2~10 carbocyclylene, or optionally substituted C 2~10 heterocyclylene, each R N is, independently, H, optionally substituted C 1~4 alkyl, optionally substituted C 2~4 alkenyl, optionally substituted C 2~4 alkynyl, optionally substituted C 2~6 heterocyclylene, optionally substituted C 6~12 aryl, or optionally substituted C 1~7 heteroalkyl, F is optionally substituted C3-C 10 carbocyclylene, optionally substituted C 2~12 heterocyclylene, optionally substituted C6-C 10 arylene, or optionally substituted C2-C9 heteroarylene, a compound, or a pharmaceutically acceptable salt thereof.

[0004] In some embodiments, m is 0 or 1. In some embodiments, C is absent, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl.

[0005] In some embodiments, E is absent, O, S, NR N , optionally substituted C 1~10 alkylene, optionally substituted C 2~10Alkenylene, optionally replaced with C 2~10 Alkynylene, optionally substituted C2-C 10 Polyethylene glycol, or optionally substituted C 1~10 It is a heteroalkylene.

[0006] Several embodiments, each R N These are H and C, which are substituted independently and of any 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.

[0007] In some embodiments, F is optionally replaced by C 3~10 Carbocyclylene, optionally substituted with C 2~10 Heterocyclylene, optionally substituted with C 6~10 Arrine, or C as optionally replaced. 2~9 Heterorialene, or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the EP300 coupling portion has the following structure:

[0009] [ka]

[0010] It has, in the formula, R 1 However, C 1~12 Alkyl, C 2~12 Alkenil, C 2~12 Alkynyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R 1 Each C 1~12 Alkyl, C 2~12 Alkenil, C 2~12Alkynnyls, 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, 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 Heteroaryls), and -(C1~C 20 Heteroaryl)-(C1~C 20 (heteroaryl) is A 1 , independently, and / or independently, R c , 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)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)-Ra , -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, optionally substituted with one or more substituents selected from R 3 is C 1~12 alkyl, C 2~12 alkenyl, C 2~12 alkynyl, a 3- to 12-member carbocyclic ring, or a 3- to 12-member heterocyclic ring, and each C 3 alkyl, C 1~12 alkenyl, C 2~12 alkynyl, a 3- to 12-member carbocyclic ring, and a 3- to 12-member heterocyclic ring are optionally substituted with A 2~12 and / or one or more groups R 1 , or e R of formula (I) and R 2 together with the nitrogen to which they are attached form a 3- to 12-member heterocyclic ring optionally substituted with A 3 and / or one or more groups R 1 , e R is C 4 alkyl, C 1~4 alkenyl, C 2~4 alkynyl, a 3- to 5-member carbocyclic ring, a 3- to 5-member heterocyclic ring, -C(O)-N(R 2~4 )2, -S(O)-N(R h )2, -S(O)2-N(R h )2, -C(O)-R h , -C(O)-O-R h , -S(O)-R h , or -S(O)2-R h , and any C h alkyl, C 1~4 alkenyl, C 2~4 alkynyl, a 3- to 5-member carbocyclic ring, and a 3- to 5-member heterocyclic ring are A 2~4 , and / or independently, -F, -Cl, -Br, -I, a 3- to 5-member carbocyclic ring, -C(O)-N(R 1 ), and / or h)2, -S(O)-N(R h )2, -S(O)2-N(R h )2, -OR h , -SR h -OC(O)-R h -OC(O)-OR h , -C(O)-R h , -C(O)-OR h ,-S(O)-R h -S(O)2-R h -OC(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 )-S(O)-R h , -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 ) Optionally substituted with one or more substituents selected from 2, Each R a However, independently, hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~12 Carbocyclyl, and C 3~12 It is a heterocycline, and each C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, carbocyclyl, and heterocyclyl can be independently classified as oxo, halo, amino, hydroxyl, or C. 1~6 Alkoxy, carbocykrill, heterocyclyl, or A 1 Furthermore, and / 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 aHowever, together with the nitrogen to which they are bound, C is independently substituted with oxo, halo, and optionally substituted with 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 b However, independently, oxo, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, Carbocyclyl, C 3~12 Heterocyclyl, C 2~9 Ariel, C 2~10 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)2-N(R c )2, -OR c , -SR c -OC(O)-OR c -OC(O)-OR c , -C(O)-R c , -C(O)-OR c ,-S(O)-R c -S(O)2-R c -OC(O)-N(R c )2, -N(R c )-C(O)-OR c , -N(R c )-C(O)-N(R c )2, -N(R c )-C(O)-R c , -N(R c )-S(O)-R c , -N(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 1~6 Alkyl, C 2~6 Alkenil, C 2~6Alkinyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are A 1 , and / or independently, oxo, halo, -NO2, -N(R) c )2, -CN, -C(O)-N(R c )2, -S(O)-N(R c )2, -S(O)2-N(R c )2, -OR c , -SR c -OC(O)-R c , -C(O)-R c ,-S(O)-R c -S(O)2-R c -C(O)-N(R c )2, -N(R c )-C(O)-R c , -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 1~6 It is optionally substituted with one or more groups selected from alkyl groups. Each R c However, independently, hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, carbocyclyl, or heterocyclyl, any C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~12 Carbocyclyl, and C 3~12 Heterocyclines, A 1 , and / or independently, oxo, carbocyclyl, heterocyclyl, halo, -NO2, -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)-ORd ,-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 1~6 It is optionally substituted with one or more groups selected from alkyl groups, and its carbocyclyl and C 1~6 Alkyl groups can independently be oxo, halo, and C. 1~6 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 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 3~12 Carbocyclyl, or C 3~12 It is a heterocycline, and each C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, carbocykrill, and heterocyclyl are A 1 , and / or independently, oxo, halo, amino, hydroxyl, C 1~6 Optionally substituted with one or more groups selected from alkoxy, carbocyryl, heterocyclyl, and C1-C6 alkyl groups independently selected from oxo and halo, or two R groups d However, together with the nitrogen to which they are bound, C is independently substituted with oxo, halo, and optionally substituted with one or more groups independently selected from oxo and halo. 1~3Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R e However, independently, oxo, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~12 Carbocyclyl, C 3~12 Heterocyclyl, C 2~9 Ariel, C 2~10 Heteroaryl, -F, -Cl, -Br, -I, -NO2, -N(R) f )2, -CN, -C(O)-N(R f )2, -S(O)-N(R f )2, -S(O)2-N(R f )2, -OR f , -SR f -OC(O)-R f -OC(O)-OR f , -C(O)-R f , -C(O)-OR f ,-S(O)-R f -S(O)2-R f -OC(O)-N(R f )2, -N(R f )-C(O)-OR f , -N(R f )-C(O)-N(R f )2, -N(R f )-C(O)-R f , -N(R f )-S(O)-R f , -N(R f )-S(O)2-R f , -N(R f )-S(O)-N(R f )2, or -N(R f )-S(O)2-N(R f )2, and any C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are A 1 , and / or independently, oxo, halo, -NO2, -N(R) f )2, -CN, -C(O)-N(Rf )2, -S(O)-N(R f )2, -S(O)2-N(R f )2, -OR f , -SR f -OC(O)-R f , -C(O)-R f , -C(O)-OR f ,-S(O)-R f -S(O)2-R f -C(O)-N(R f )2, -N(R f )-C(O)-R f , -N(R f )-S(O)-R f , -N(R f )-S(O)2-R f , 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 f However, independently, hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, carbocyclyl, or heterocyclyl, any C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~12 Carbocyclyl, and C 3~12 Heterocyclyl can be independently oxo, carbocyclyl, heterocyclyl, halo, -NO2, -N(R) g )2, -CN, -C(O)-N(R g )2, -S(O)-N(R g )2, -S(O)2-N(R g )2, -OR g , -SR g -OC(O)-R g , -C(O)-R g , -C(O)-OR g ,-S(O)-R g -S(O)2-R g -C(O)-N(R g )2, -N(R g )-C(O)-Rg , -N(R g )-S(O)-R g , N(R g )-S(O)2-R g , and C 1~6 It is optionally substituted with one or more groups selected from alkyl groups, and its carbocyclyl and C 1~6 Alkyl is A 1 , and / or independently, oxo, halo, C 1~6 Alkyl, cyano, -N(R) g )2, -OR g , 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 g However, independently, hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 3~12 Carbocyclyl, or C 3~12 It is a heterocycline, and each C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, carbocykrill, and heterocyclyl are A 1 , and / or independently, oxo, halo, amino, hydroxyl, C 1~6 Optionally substituted with one or more groups selected from alkoxy, carbocyryl, heterocyclyl, and C1-C6 alkyl groups independently selected from oxo and halo, or two R groups g However, together with the nitrogen to which they are bound, C is independently substituted with oxo, halo, and optionally substituted with 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 h However, independently, hydrogen, C 1~4 Alkyl, C 2~4Alkenil, C 2~4 Alkinyl, or C 2~5 It is a cycloalkyl, and each C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl and C 2~5 Cycloalkyl groups are independently oxo, halo, amino, hydroxyl, and C. 1~3 Alkoxy, and A 1 and / or optionally substituted with one or more groups selected from C1-C3 alkyl groups, which are independently substituted with one or more groups selected from halos. R 1 , R 2 , R 3 , or R 4 Only one of them is A 1 Includes.

[0011] In some embodiments, R 1 C 1~12 Alkyl, C 2~12 Alkenil, C 2~12 Alkynyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R 1 Each C 1~12 Alkyl, C 2~12 Alkenil, C 2~12 Alkynnyls, 3-12 membered carbon rings, and 3-12 membered heterorings are A 1 and / or one or more base R b It is being replaced by an optional choice.

[0012] In some embodiments, R 2 C6~C 20 Aryl, C1~C 20 Heteroaryl, -(C6~C 20 Ariel)-(C1~C 20 Heteroaryl), -(C1~C 20 Heteroaryl)-(C6~C 20 (aryl), or -(C1~C 20 Heteroaryl)-(C1~C 20 (Heteroaryl) and each C6~C 20 Aryl, C1~C 20Heteroaryl, -(C6~C 20 Ariel)-(C1~C 20 Heteroaryls), and -(C1~C 20 Heteroaryl)-(C1~C 20 Heteroaryls are, independently, A 1 , and / or independently, R c , 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)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 ) It is optionally replaced with one or more substituents selected from 2.

[0013] In some embodiments, R 3 C 1~12 Alkyl, C 2~12 Alkenil, C 2~12 Alkynyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R 3 Each C 1~12 Alkyl, C2~12 Alkenil, C 2~12 Alkynnyls, 3-12 membered carbon rings, and 3-12 membered heterorings are A 1 and / or one or more base R e It is being replaced by an optional choice.

[0014] In some embodiments, R 2 and R 3 Together with the nitrogen to which they are bound, they form one or more R groups e This forms a 3- to 12-membered complex ring with arbitrary substitutions. In some embodiments, R 4 C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkynyl, 3-5 membered carbon ring, 3-5 membered hetero ring, -C(O)-N(R h )2, -S(O)-N(R h )2, -S(O)2-N(R h )2, -C(O)-R h , -C(O)-OR h ,-S(O)-R h , or -S(O)2-R h And any C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkynnyls, 3- to 5-membered carbon rings, and 3- to 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, -S(O)2-N(R h )2, -OR h , -SR h -OC(O)-R h -OC(O)-OR h , -C(O)-R h , -C(O)-OR h ,-S(O)-R h -S(O)2-R h -OC(O)-N(R h )2, -N(R h )-C(O)-OR h , -N(Rh )-C(O)-N(R h )2, -N(R h )-C(O)-R a , -N(R h )-S(O)-R h , -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 ) It is optionally replaced with one or more substituents selected from 2.

[0015] Several embodiments, each R a These are, independently, hydrogen and C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, carbocyclyl, or heterocyclyl, each C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~12 Carbocyclyl, and C 3~12 Heterocyclines are A 1 , and / or independently, oxo, halo, amino, hydroxyl, C 1~6 Optionally substituted with one or more groups selected from alkoxy, carbocyryl, heterocyclyl, and C1-C6 alkyl groups independently selected from oxo and halo, or two R groups a These, together with the nitrogen to which they are bound, are C, independently, oxo, halo, and optionally substituted with one or more groups independently selected from oxo and halo. 1~3 They form heterocyclines that are optionally substituted with one or more groups selected from alkyl groups.

[0016] Several embodiments, each R b These are independently oxo and C. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, Carbocyclyl, C 3~12Heterocyclyl, C 2~9 Ariel, C 2~10 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)2-N(R c )2, -OR c , -SR c -OC(O)-R c -OC(O)-OR c , -C(O)-R c , -C(O)-OR c ,-S(O)-R c -S(O)2-R c -OC(O)-N(R c )2, -N(R c )-C(O)-OR c , -N(R c )-C(O)-N(R c )2, -N(R c )-C(O)-R c , -N(R c )-S(O)-R c , -N(R c )-S(O)2-R c , -N(R c )-S(O)-N(R c )2, or -N(R)-S(O)2-N(R c )2, and any C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are A 1 , and / or independently, oxo, halo, -NO2, -N(R) c )2, -CN, -C(O)-N(R c )2, -S(O)-N(R c )2, -S(O)2-N(R c )2, -OR c , -SR c -OC(O)-R c , -C(O)-R c , -C(O)-OR c ,-S(O)-Rc -S(O)2-R c -C(O)-N(R c )2, -N(R c )-C(O)-R c , -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 1~6 It is optionally substituted with one or more groups selected from alkyl groups.

[0017] Several embodiments, each R c These are, independently, hydrogen and C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~12 Carbocyclyl, or C 3~12 It is a heterocycline and any C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, carbocyclyl, and heterocyclyl are A 1 , and / or independently, oxo, carbocyclyl, heterocyclyl, halo, -NO2, -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 1~6It is optionally substituted with one or more groups selected from alkyl groups, and its carbocyclyl and C 1~6 Alkyl groups are independently oxo, halo, and C. 1~6 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 then optionally substituted with one or more groups selected from carbocyrillic molecules.

[0018] Several embodiments, each R d These are, independently, hydrogen and C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 3~12 Carbocyclyl, or C 3~12 It is a heterocycline, and each C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, carbocykrill, and heterocyclyl are A 1 , and / or independently, oxo, halo, amino, hydroxyl, C 1~6 C is optionally substituted with one or more groups independently selected from alkoxy, carbocykryl, heterocyclyl, and oxo and halo. 1~ It is optionally substituted with one or more groups selected from C6 alkyl groups, or two R groups. d These, together with the nitrogen to which they are bound, are C, independently, oxo, halo, and optionally substituted with one or more groups independently selected from oxo and halo. 1~3 They form heterocyclines that are optionally substituted with one or more groups selected from alkyl groups.

[0019] Several embodiments, each R e These are independently oxo and C. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~12Carbocyclyl, C 3~12 Heterocyclyl, aryl, heteroaryl, -F, -Cl, -Br, -I, -NO2, -N(R f )2, -CN, -C(O)-N(R f )2, -S(O)-N(R f )2, -S(O)2-N(R f )2, -OR f , -SR f -OC(O)-R f -OC(O)-OR f , -C(O)-R f , -C(O)-OR f ,-S(O)-R f -S(O)2-R f -OC(O)-N(R f )2, -N(R f )-C(O)-OR f , -N(R f )-C(O)-N(R f )2, -N(R f )-C(O)-R f , -N(R f )-S(O)-R f , -N(R f )-S(O)2-R f , -N(R f )-S(O)-N(R f )2, or -N(R f )-S(O)2-N(R f )2, and any C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are A 1 , and / or independently, oxo, halo, -NO2, -N(R) f )2, -CN, -C(O)-N(R f )2, -S(O)-N(R f )2, -S(O)2-N(R f )2, -OR f , -SR f -OC(O)-R f , -C(O)-R f , -C(O)-OR f ,-S(O)-Rf -S(O)2-R f -C(O)-N(R f )2, -N(R f )-C(O)-R f , -N(R f )-S(O)-R f , -N(R f )-S(O)2-R f , 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.

[0020] Several embodiments, each R f These are, independently, hydrogen and C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~12 Carbocyclyl, or C 3~12 It is a heterocycline and any C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, carbocyclyl, and heterocyclyl are A 1 , and / or independently, oxo, carbocyclyl, heterocyclyl, halo, -NO2, -N(R) g )2, -CN, -C(O)-N(R g )2, -S(O)-N(R g )2, -S(O)2-N(R g )2, -OR g , -SR g -OC(O)-R g , -C(O)-R g , -C(O)-OR g ,-S(O)-R g -S(O)2-R g -C(O)-N(R g )2, -N(R g )-C(O)-R g , -N(R g )-S(O)-R g , N(R g )-S(O)2-R g , and C 1~6It is optionally substituted with one or more groups selected from alkyl groups, and its carbocyclyl and C 1~6 Alkyl groups are independently oxo, halo, and C. 1~6 Alkyl, cyano, -N(R) g )2, -OR g , heterocyclyl, and independently halo and C 1~6 It is optionally substituted with one or more groups selected from alkyl groups, and then optionally substituted with one or more groups selected from carbocyrillic molecules.

[0021] Several embodiments, each R g These are, independently, hydrogen and C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, C 3~12 Carbocyclyl, or C 3~12 It is a heterocycline, and each C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, carbocykrill, and heterocyclyl are A 1 , and / or independently, oxo, halo, amino, hydroxyl, C 1~6 Optionally substituted with one or more groups selected from alkoxy, carbocyryl, heterocyclyl, and C1-C6 alkyl groups independently selected from oxo and halo, or two R groups g These, together with the nitrogen to which they are bound, are C, independently, oxo, halo, and optionally substituted with one or more groups independently selected from oxo and halo. 1~3 They form heterocyclines that are optionally substituted with one or more groups selected from alkyl groups.

[0022] Several embodiments, several embodiments, each R h These are, independently, hydrogen and C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, or C2~5 It is a cycloalkyl, and each C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl and C 2~5 Cycloalkyl, A 1 , and / or independently, oxo, halo, amino, hydroxyl, C 1~3 Alkoxy, and A 1 And / or optionally substituted with one or more groups selected from C1-C3 alkyl groups, which are optionally substituted with one or more groups independently selected from the halo.

[0023] In some embodiments, R 1 These are methyl, oxetanyl, tetrahydrofuranil, tetrahydropyranil, dioxothiolanil, piperidyl, or pyrrolidinil, and R 1 Each of the following compounds contains one or more R groups: methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl. b It is being replaced by an optional choice.

[0024] In some embodiments, R 1 teeth,

[0025] [ka]

[0026] That is the case. In some embodiments, R 4 These are acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole, or isoxazole.

[0027] In some embodiments, R 4 Structure:

[0028] [ka]

[0029] It has. In some embodiments, R 2 and R 3 Together with the nitrogen to which they are bound, A 1 and / or one or more base R e The optionally substituted 9 or 10-membered biring complex rings are formed.

[0030] In some embodiments, R 2 and R 3 Together with the nitrogen to which they are bound, A 1 and / or one or more base R 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.

[0031] In some embodiments, NR 2 R 3 Together, the structure:

[0032] [ka]

[0033] It has. In some embodiments, the EP300 coupling portion has the following structure:

[0034] [ka]

[0035] [ka]

[0036] It has. In some embodiments, R 2 is, A 1 and / or independently R cC6~C 20 It is Ariel.

[0037] In some embodiments, R 3 C 1~12 It is alkyl. In some embodiments, the EP300 coupling portion has the following structure:

[0038] [ka]

[0039] It has. In some embodiments, the decomposition portion is the ubiquitin ligase binding portion. In some embodiments, the ubiquitin ligase binding moiety includes cereblon ligand, IAP (inhibitor of apoptosis) ligand, mouse double micro2 homolog (MDM2), or von Hippel-Lindau (VHL) ligand, or derivatives or analogs thereof.

[0040] In some embodiments, the decomposed part (B) has the structure of formula IVa,

[0041] [ka]

[0042] During the ceremony, R B1 However, H, A 2 -C(O)-A 2 , C replaced by arbitrary selection 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 Aryl, or C(O)R K And alkyl, heteroalkyl, carbocycryl, or aryl is A 2 and / or halogen or C 1~4It is optionally substituted with alkyl, R B3 However, A 2 -C(O)-A 2 , C replaced by arbitrary selection 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 It is an aryl, and is alkyl, heteroalkyl, carbocykryl, or aryl. 2 and / or halogen or C 1~4 It is optionally substituted with alkyl, R B4 However, H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 It is Ariel, R B5 However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. 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 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, H, optionally substituted C1-C6 alkyl, or A 2 And, Each R K However, independently, C is replaced by arbitrary choice. 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C3-C10 Carbocyclyl, optionally replaced with C6-C 10 It is an aryl, and is alkyl, heteroalkyl, carbocykryl, or aryl. 2 , and / or halogen, CN, or C 1~4 It is optionally substituted with alkyl, R B1 , R B3 , or R B9 Only one of them is A 2 or -C(O)-A 2 Structure, including or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the structure of formula IVa is,

[0044] [ka]

[0045] That is the case. In some embodiments, R B9 H is H. In some embodiments, R B9 These are C1-C6 alkyl groups that have been optionally substituted.

[0046] In some embodiments, R B9 It is methyl. In some embodiments, R B4 H is H. In some embodiments, R B5 H is H.

[0047] In some embodiments, R B1 is, A 2 That is the case. In some embodiments, R B1 is -C(O)-A 2 That is the case. In some embodiments, R B3 These are C1-C6 alkyl groups that have been optionally substituted.

[0048] In some embodiments, R B3 teeth,

[0049] [ka]

[0050] That is the case. In some embodiments, R B6 These are C2-C9 heteroaryls that have been optionally substituted.

[0051] In some embodiments, R B6 teeth,

[0052] [ka]

[0053] That is the case. In some embodiments, the structure of formula IVa is,

[0054] [ka]

[0055] or its derivatives or analogues. In some embodiments, the structure of formula IVa is,

[0056] [ka]

[0057] or its derivatives or analogues. In some embodiments, the structure of formula IVa is,

[0058] [ka]

[0059] or its derivatives or analogues. In some embodiments, the structure of formula IVa is,

[0060] [ka]

[0061] or its derivatives or analogues. In some embodiments, the structure of formula IVa is,

[0062] [ka]

[0063] or its derivatives or analogues. In some embodiments, the structure of formula IVa is,

[0064] [ka]

[0065] or its derivatives or analogues. In some embodiments, the structure of formula IVa is,

[0066] [ka]

[0067] or its derivatives or analogues. In some embodiments, the structure of formula IVa is,

[0068] [ka]

[0069] or its derivatives or analogues. In some embodiments, R B6These are halogens or optionally substituted C2-C6 alkynyl compounds.

[0070] In some embodiments, R B6 These are C1-C6 heteroalkyls that have been optionally substituted. In some embodiments, the optionally substituted C1-C6 heteroalkyl group is methoxy.

[0071] In some embodiments, the structure of formula IVa is,

[0072] [ka]

[0073] or its derivatives or analogues. In some embodiments, the structure of formula IVa is,

[0074] [ka]

[0075] or its derivatives or analogues. In some embodiments, the structure of formula IVa is,

[0076] [ka]

[0077] or its derivatives or analogues. In some embodiments, the decomposed part has the structure of formula IVaa,

[0078] [ka]

[0079] During the ceremony, R B11 However, A 2, C3~C replaced by optional selection 10 Carbocyclyl, C2-C9 heterocyclyls substituted with optional substitution, C6-C9 heterocyclyls substituted with optional substitution 10 An aryl, or optionally substituted C2-C9 heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is A 2 , and / or halogen or C 1~4 It is optionally substituted with alkyl, R B3 However, A 2 -C(O)-A 2 , C replaced by arbitrary selection 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 It is an aryl, and is alkyl, heteroalkyl, carbocykryl, or aryl. 2 and / or halogen or C 1~4 It is optionally substituted with alkyl, R B4 However, H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 It is Ariel, R B5 However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. 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 10These 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, H, optionally substituted C1-C6 alkyl, or A 2 And, R B9 , R B11 , and R B3 Only one of them is A 2 or -C(O)-A 2 Structure, including or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the structure of formula IVaa is,

[0081] [ka]

[0082] That is the case. In some embodiments, R B11 These are C2-C9 heteroaryls that have been optionally substituted.

[0083] In some embodiments, the optionally substituted C2-C9 heteroaryls are

[0084] [ka]

[0085] That is the case. In some embodiments, R B6 These are C2-C9 heteroaryls that have been optionally substituted.

[0086] In some embodiments, R B6 teeth,

[0087] [ka]

[0088] That is the case. In some embodiments, the structure of formula IVaa is,

[0089] [ka]

[0090] or its derivatives or analogues. In some embodiments, the structure of formula IVaa is,

[0091] [ka]

[0092] or its derivatives or analogues. In some embodiments, the structure of formula IVaa is,

[0093] [ka]

[0094] or its derivatives or analogues. In some embodiments, the structure of formula IVaa is,

[0095] [ka]

[0096] or its derivatives or analogues. In some embodiments, the structure of formula IVaa is,

[0097] [ka]

[0098] or its derivatives or analogues. In some embodiments, the structure of formula IVaa is,

[0099] [ka]

[0100] or its derivatives or analogues. In some embodiments, R B6 It is a halogen. In some embodiments, the structure of formula IVaa is,

[0101] [ka]

[0102] or its derivatives or analogues. In some embodiments, the structure of formula IVaa is,

[0103] [ka]

[0104] or its derivatives or analogues. In some embodiments, the structure of formula IVaa is,

[0105] [ka]

[0106] or its derivatives or analogues. In some embodiments, R 9 is, A 2 That is the case. In some embodiments, the structure of formula IVaa is,

[0107] [ka]

[0108] or its derivatives or analogues. In some embodiments, the structure of formula IVaa is,

[0109] [ka]

[0110] or its derivatives or analogues. In some embodiments, the structure of formula IVaa is,

[0111] [ka]

[0112] or its derivatives or analogues. In some embodiments, the structure of formula IVaa is,

[0113] [ka]

[0114] or its derivatives or analogues. In some embodiments, the disassembled part has the structure of formula IV,

[0115] [ka]

[0116] During the ceremony, R B1 However, H, A 2 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, C(O)-A 2 , C3~C replaced by optional selection 10 Carbocyclyl, optionally replaced with C6-C 10 Aryl, C(O)RK And alkyl, heteroalkyl, carbocycryl, or aryl is A 2 and / or halogen or C 1~4 It is optionally substituted with alkyl, R B2 However, H is optionally substituted with a C1-C6 alkyl group, or optionally substituted with a C1-C6 heteroalkyl group. R B3 However, A 2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 It is an aryl, and is alkyl, heteroalkyl, carbocykryl, or aryl. 2 and / or halogen or C 1~4 It is optionally substituted with alkyl, R B4 However, H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 It is Ariel, R B5 However, H is replaced by C by arbitrary choice. 1~6 Alkyl or optionally substituted C 1~6 It is heteroalkyl, v2 is 0, 1, 2, 3, or 4, Each R B6 However, independently, halogen, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 3~10 Carbocyclyl, optionally replaced with C 2~9 Heterocyclines, C substituted by choice 6~10 Arial, C replaced by any choice 2~9 Heteroaryl, optionally substituted C 2~6 Alkenil, C replaced by any choice 2~6Heteroalkenyl, 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. 1~6 Alkyl or optionally substituted C 6~10 It is Ariel, R B9 and R B10 However, independently, H and C are substituted by choice. 1~6 Alkyl, or A 2 And, Each R K However, independently, C is replaced by arbitrary choice. 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C3-C 10 Carbocyclyl, optionally replaced with C6-C 10 It is an aryl, and is alkyl, heteroalkyl, carbocykryl, or aryl. 2 , and / or halogen, CN, or C 1~4 It is optionally substituted with alkyl, R B1 R B3 , R B9 , or R B10 Only one of them is A 2 Structure, including or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the structure of formula IV is

[0118] [ka]

[0119] That is the case. In some embodiments, R B1 H is H. In some embodiments, R B1 is, A 2 That is the case.

[0120] In some embodiments, R B2 is H. In some embodiments, R B3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl, and any C 1~6 alkyl and C1-C6 heteroalkyl are independently oxo, halo, -NO2, -N(R f )2, -CN, -C(O)-N(R f )2, -S(O)-N(R f )2, -S(O)2-N(R f )2, -O-R f -S-R f -O-C(O)-R f -C(O)-R f -C(O)-O-R f -S(O)-R f -S(O)2-R f -C(O)-N(R f )2, -N(R f )-C(O)-R f -N(R f )-S(O)-R f -N(R f )-S(O)2-R, a carbocyclic ring, and one or more groups selected from C 1~6 alkyl optionally substituted with one or more groups selected from oxo and halo.

[0121] In some embodiments, R B3 is

[0122]

Chemical formula

[0123] as follows. In some embodiments, R B3 is

[0124]

Chemical formula

[0125] That is the case. In some embodiments, R B3 It is methyl. In some embodiments, R B4 H is H.

[0126] In some embodiments, R B5 H is H. In some embodiments, R B6 H is H. In some embodiments, R B7 is a C1-C6 alkyl group that is substituted with H or optionally.

[0127] In some embodiments, R B7 It is either H or methyl. In some embodiments, R B8 It is either H or methyl. In some embodiments, the structure of formula IV is

[0128] [ka]

[0129] or its derivatives or analogues. In some embodiments, the structure of formula IV is

[0130] [ka]

[0131] or its derivatives or analogues. In some embodiments, R B9 is a C1-C6 alkyl group that is substituted with H or optionally.

[0132] In some embodiments, R B9 H is H. In some embodiments, R B9 It is methyl. In some embodiments, R B10 is a C1-C6 alkyl group that is substituted with H or optionally.

[0133] In some embodiments, R B10 H is H. In some embodiments, R B10 It is methyl. In some embodiments, the structure of formula IV is

[0134] [ka]

[0135] or its derivatives or analogues. In some embodiments, the structure of formula IV is

[0136] [ka]

[0137] or its derivatives or analogues. In some embodiments, the structure of formula IV is

[0138] [ka]

[0139] or its derivatives or analogues. In some embodiments, the structure of formula IV is

[0140] [ka]

[0141] or its derivatives or analogues. In some embodiments, the structure of formula IV is

[0142] [ka]

[0143] or its derivatives or analogues. In some embodiments, the structure of formula IV is

[0144] [ka]

[0145] or its derivatives or analogues. In some embodiments, the structure of formula IV is

[0146] [ka]

[0147] or its derivatives or analogues. In some embodiments, the structure of formula IV is

[0148] [ka]

[0149] or its derivatives or analogues. In some embodiments, the structure of formula IV is

[0150] [ka]

[0151] or its derivatives or analogues. In some embodiments, the structure of formula IV is

[0152] [ka]

[0153] or its derivatives or analogues. In some embodiments, the disassembled part has the structure of formula V,

[0154] [ka]

[0155] R C1 However, these are C1-C6 alkyl groups that have been optionally substituted. R C2 However, A 2 , or C replaced by any choice 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 3~10 Carbocyclyl, optionally replaced with C 6~10 Arial, C replaced by any choice 2~9 It is a heteroaryl, C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~10 Carbocyclyl, C 6~10 Ariel, C 2~9 Heteroaryls are A 2 and / or one or more base R J It is replaced by an optional selection, R C3 However, H is replaced by C by arbitrary choice. 1~6 Alkyl, optionally substituted C 3~10 Carbocyclyl, optionally replaced with C 6~10 It is Ariel, R C4 However, H is replaced by C by arbitrary choice. 1~6 Alkyl or optionally substituted C 1~6 It is heteroalkyl, v2 is 0, 1, 2, 3, or 4, R C5 and R C6 Each of these is independently replaced by H and C by any choice. 1~6 Alkyl, or A 2 And, Each RC7 is, independently, halogen, optionally substituted C 1~6 alkyl, optionally substituted C 1~6 heteroalkyl, optionally substituted C 3~10 carbocyclic, optionally substituted C2-C9 heterocyclic, optionally substituted C6-C 10 aryl, optionally substituted C 2~9 heteroaryl, optionally substituted C 2~6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino, and R C8 and R C9 each is, independently, H, halogen, optionally substituted C 1~6 alkyl, or optionally substituted C 6~10 aryl, and each R J is, independently, hydrogen, C 1~6 alkyl, carbocyclic, and heterocyclic, and each C 1~6 alkyl, carbocyclic, and heterocyclic is, independently, amino, hydroxyl, C 1~6 alkoxy, carbocyclic, heterocyclic, or A 2 and / or independently optionally substituted with one or more groups selected from oxo and halo and C 1~6 alkyl optionally substituted with one or more groups selected therefrom, and R C2 , R C5 , R C6 or R J only one of which contains A 1 a structure, or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the structure of Formula V is

[0157]

Chemical Structure

[0158] That is the case. In some embodiments, R C1 teeth,

[0159] [ka]

[0160] That is the case. In some embodiments, R C2 is, A 2 These are C2-C9 heteroaryls that have been optionally substituted.

[0161] In some embodiments, R C3 H is H. In some embodiments, R C4 H is H. In some embodiments, v2 is 0.

[0162] In some embodiments, R C5 and R C6 Each of them is independently either H or methyl. In some embodiments, R C8 and R C9 Each of them is independently either H or methyl.

[0163] In some embodiments, the structure of formula V is

[0164] [ka]

[0165] or its derivatives or analogues. In some embodiments, the structure of formula V is

[0166] [ka]

[0167] or its derivatives or analogues. In some embodiments, the structure of formula V is

[0168] [ka]

[0169] or its derivatives or analogues. In some embodiments, the structure of formula V is

[0170] [ka]

[0171] or its derivatives or analogues. In some embodiments, the structure of formula V is

[0172] [ka]

[0173] or its derivatives or analogues. In some embodiments, the disassembled part has the structure of formula IVb,

[0174] [ka]

[0175] During the ceremony, R B1 However, H, A 2 -C(O)-A 2 ,-C(O)-J 2 , C replaced by arbitrary selection 1~6 Alkyl or optionally substituted C 1~6 It is heteroalkyl, R B3 However, A 2 -C(O)-A 2 , C replaced by arbitrary selection 1~6Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 3~10 Carbocyclyl, optionally replaced with C 6~10 It is an aryl, and is alkyl, heteroalkyl, carbocykryl, or aryl. 2 and / or one or more base R J2 It is replaced by an optional selection, R B4 However, H is replaced by C by arbitrary choice. 1~6 Alkyl, optionally substituted C 3~10 Carbocyclyl, optionally replaced with C 6~10 It is Ariel, R B5 However, A 2 H, C replaced by any choice 1~6 Alkyl or optionally substituted C 1~6 It is heteroalkyl, Each R J2 However, independently, hydrogen, C 1~6 These are alkyl, carbocykryl, and heterocyclyl compounds, and each C 1~6 Alkyl, carbocyryl, and heterocyclyl compounds can be independently classified as halo, amino, hydroxyl, or C. 1~6 Alkoxy, carbocykrill, heterocyclyl, or A 2 and / or 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. R B1 , R B3 , R B5 , or R J2 Only one of them is A 1 Structure, including or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, R B4 H is H. In some embodiments, R B5 H is H. In some embodiments, R B1 is, A2 That is the case.

[0177] In some embodiments, R B1 is -C(O)-A 2 That is the case. In some embodiments, R B3 These are C1-C6 alkyl groups that have been optionally substituted.

[0178] In some embodiments, R B3 teeth,

[0179] [ka]

[0180] That is the case. In some embodiments, the structure of formula IVb is,

[0181] [ka]

[0182] That is the case. In some embodiments, the structure of formula IVb is,

[0183] [ka]

[0184] or its derivatives or analogues. In some embodiments, the structure of formula IVb is,

[0185] [ka]

[0186] or its derivatives or analogues. In some embodiments, the decomposed part has the structure of formula IVc,

[0187] [ka]

[0188] During the ceremony, R E2 However, H, A 2 -C(O)-A 2 ,-C(O)-J 3 , C replaced by arbitrary selection 1~6 Alkyl or optionally substituted C 1~6 It is heteroalkyl, R E3 However, A 2 -C(O)-A 2 , C replaced by arbitrary selection 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 3~10 Carbocyclyl, optionally replaced with C 6~10 C replaced by an aryl or optional character. 2~10 It is a heteroaryl compound, and the alkyl, heteroalkyl, carbocykyl, aryl, or heteroaryl compound has one or more R groups. J3 It is replaced by an optional selection, R E4 However, H is replaced by C by arbitrary choice. 1~6 Alkyl, optionally substituted C 3~10 Carbocyclyl, optionally replaced with C 6~10 It is Ariel, R E5 However, A 2 H, C replaced by any choice 1~6 Alkyl or optionally substituted C 1~6 It is heteroalkyl, R E2 , R E3 , and R E5 One of them is A 2 or -C(O)-A 2 And, Each R J3 However, independently, hydrogen, C 1~6 These are alkyl, carbocykryl, and heterocyclyl compounds, and each C 1~6Alkyl, carbocyryl, and heterocyclyl compounds can be independently classified as halo, amino, hydroxyl, or C. 1~6 Alkoxy, carbocykrill, heterocyclyl, or A 2 and / or C optionally substituted with one or more groups independently selected from oxo and halo 1~6 It is optionally replaced by one or more elements selected from the alky, R E2 , R E3 , R E5 , or R J3 Only one of them is A 1 Structure, including or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments, the structure of formula IVc is,

[0190] [ka]

[0191] That is the case. In some embodiments, the structure of formula IVc is,

[0192] [ka]

[0193] or its derivatives or analogues. In some embodiments, the structure of formula IVc is,

[0194] [ka]

[0195] or its derivatives or analogues. In some embodiments, L has the structure of formula II, A 1 -C1-(F)-(E) m -C2-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 bond between B and the linker, m is 0 or 1, C1 and C2 are independently absent, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl. E is NR N , C replaced by arbitrary selection 1~10 Alkylene, optionally replaced with C 2~12 Heteroalkylenes, optionally substituted with C 2~12 Carbocyclylene, or optionally substituted C 2~12 It is a heterocycline, 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 Heterocyclylene, optionally substituted with C 6~12 C replaced by an aryl or optional character. 1~7 It is heteroalkyl, F is replaced by C by any choice. 2~12 These are heterocyclylenes or C2-C9 heteroarylenes that have been optionally substituted.

[0196] In some embodiments, C1 is a carbonyl group. In some embodiments, C1 is absent. In some embodiments, F is optionally replaced by C 2~12 It is a heterocycline.

[0197] In some embodiments, F is

[0198] [ka]

[0199] That is the case. In some embodiments, F is bridging or spirocyclic. In some embodiments, F is

[0200] [ka]

[0201] That is the case. In some embodiments, F is an optionally substituted C2-C9 heteroarylene.

[0202] In some embodiments, F is

[0203] [ka]

[0204] That is the case. In some embodiments, F is

[0205] [ka]

[0206] That is the case. In some embodiments, F is

[0207] [ka]

[0208] That is the case. In some embodiments, F is

[0209] [ka]

[0210] That is the case. In some embodiments, F is

[0211] [ka]

[0212] That is the case. In some embodiments, F is

[0213] [ka]

[0214] That is the case. In some embodiments, m is 0. In some embodiments, m is 1.

[0215] In some embodiments, E is methylene or ethylene. In some embodiments, E is NR N That is the case. In some embodiments, E is NH.

[0216] In some embodiments, E is optionally replaced by C 2~12 Carbocyclylene, or optionally substituted C 2~12 It is a heterocycline. In some embodiments, E is

[0217] [ka]

[0218] That is the case. In some embodiments, E is optionally replaced by C 1~10 It is alkylene. In some embodiments, E is

[0219] [ka]

[0220] That is the case. In some embodiments, E is optionally replaced by C 2~12 It is a heteroalkylene.

[0221] In some embodiments, E is

[0222] [ka]

[0223] That is the case. In some embodiments, (F)-(E) m teeth,

[0224] [ka]

[0225] [ka]

[0226] [ka]

[0227] [ka]

[0228] That is the case. In some embodiments, C2 is a carbonyl group. In some embodiments, C2 is absent.

[0229] In some embodiments, the compound is one of the compounds 1 to 87 in Table 1A. In some embodiments, the compound is one of the compounds 88-197 in Table 1B.

[0230] Table 1-1

[0231] Table 1-2

[0232] Table 1-3

[0233] Table 1-4

[0234] Table 1-5

[0235] Table 1-6

[0236] Table 1-7

[0237] Table 1-8

[0238] Table 1-9

[0239] Table 1-10

[0240] Table 1-11

[0241] Table 1-12

[0242] Table 1-13

[0243] Table 1-14

[0244] Table 1-15

[0245] Table 1-16

[0246] Table 1-17

[0247] Table 1-18

[0248] Table 1-19

[0249] Table 1-20

[0250] Table 1-21

[0251] Table 1-22

[0252] Table 1-23

[0253] Table 1-24

[0254] Table 2-1

[0255] Table 2-2

[0256] Table 2-3

[0257] Table 2-4

[0258] Table 2-5

[0259] Table 2-6

[0260] Table 2-7

[0261] Table 2-8

[0262] Table 2-9

[0263] Table 2-10

[0264] Table 2-11

[0265] Table 2-12

[0266] Table 2-13

[0267] Table 2-14

[0268] Table 2-15

[0269] Table 2-16

[0270] Table 2-17

[0271] Table 2-18

[0272] Table 2-19

[0273] Table 2-20

[0274] Table 2-21

[0275] Table 2-22

[0276] Table 2-23

[0277] Table 2-24

[0278] Table 2-25

[0279] Table 2-26

[0280] Table 2-27

[0281] [Table 2-28]

[0282] 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. In another embodiment, the present invention is characterized by a method for reducing the level and / or activity of EP300 in cells, comprising contacting cells with an effective amount of any of the aforementioned compounds or a pharmaceutically acceptable composition thereof.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] In some embodiments, the cells are cancer cells. In another embodiment, the present invention relates to a method for treating an EP300-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.

[0287] In some embodiments, the EP300-related disorder is cancer. In a further embodiment, the present invention relates to a method for inhibiting EP300, 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.

[0288] In one embodiment, the present disclosure is characterized by a method for inhibiting intracellular levels and / or activity of EP300, comprising contacting cells with an effective amount of any of the aforementioned compounds, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0289] 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.

[0290] 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).

[0291] 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.

[0292] 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.

[0293] 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, urinary tract 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, myeloma, skin, endometrial, esophageal, cervical, gastric, 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. In some embodiments, the cancer is carcinoma.

[0294] In some embodiments, cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, myeloma, skin, endometrial, cervical, stomach, prostate cancer, acute leukemia, ovarian cancer, neuroblastoma, lymphoma, leukemia, esophageal, gastric, or lung cancer.

[0295] In some embodiments, cancer is metastatic. In some embodiments, the subject or cancer has a CBP loss-of-function mutation. In some embodiments, the method further includes administering anti-cancer therapy to the subject.

[0296] In some embodiments, anticancer therapy includes chemotherapy agents or cytotoxic agents, immunotherapy, surgery, radiotherapy, hyperthermia, or photocoagulation, or a combination thereof. 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.

[0297] In some embodiments, breast cancer is found to be ER-positive, meaning that cancer cells contain estrogen receptors. In some embodiments, breast cancer is found to be ER-negative, meaning that the cancer cells do not contain estrogen receptors.

[0298] In some embodiments, prostate cancer is found to be AR-positive, meaning that cancer cells contain androgen receptors. In some embodiments, the prostate cancer is CRPC, or castration-resistant prostate cancer.

[0299] In some embodiments, prostate cancer is castration-sensitive prostate cancer. In some embodiments, the cancer is lymphoma. In some embodiments, the lymphoma is diffuse large B-cell lymphoma (DLBCL).

[0300] In one embodiment, the present disclosure provides a method for treating an EP300-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 EP300-related disorder is cancer. In some embodiments, the EP300-related disorder is an infection.

[0301] 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.

[0302] 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).

[0303] 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 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.

[0304] 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.

[0305] In some embodiments of the methods described above, the cancer has or is determined to have an EP300 mutation. In some embodiments of the methods described above, the EP300 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.

[0306] In another aspect, the disclosure provides a method for treating a disorder associated with EP300 (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.

[0307] 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).

[0308] 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, myeloma, skin, endometrium, esophagus, cervix, stomach, 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.

[0309] In another embodiment, the present invention relates to a method for treating a subject in need of treatment for melanoma, myeloma, skin, endometrium, esophagus, cervix, stomach, 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.

[0310] In another embodiment, the present invention provides a method for inhibiting the metastatic progression of melanoma, myeloma, skin, endometrium, esophagus, cervix, stomach, 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.

[0311] In another embodiment, the present invention provides a method for suppressing metastatic colony formation of melanoma, myeloma, skin, endometrium, esophagus, cervix, stomach, 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.

[0312] In another embodiment, the present invention is a method for reducing the levels and / or activity of EP300 and / or CBP in melanoma, myeloma, skin, endometrium, esophagus, cervix, stomach, 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.

[0313] In some of the embodiments described above, melanoma, prostate cancer, breast cancer, bone cancer, myeloma, skin, endometrium, esophagus, cervix, stomach, renal cell carcinoma, osteosarcoma, neuroblastoma, esophagus, stomach, or blood cells are included in the subject.

[0314] 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%).

[0315] In some embodiments of the above-described aspects, an effective amount of the compound reduces the level 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 reduction rate of the level of CBP. In some embodiments, the effective amount of the compound reduces the level of EP300 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 CBP. In some embodiments, the compound is an effective amount that reduces the level of EP300 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 CBP.

[0316] 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).

[0317] 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%).

[0318] 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).

[0319] In some embodiments, the subject has cancer. In some embodiments, the cancer expresses EP300 and / or CBP proteins, and / or the cells or subject are identified as expressing EP300 and / or CBP. In some embodiments, the cancer expresses EP300 protein, and / or the cells or subject are identified as expressing EP300. In some embodiments, the cancer expresses CBP protein, and / or the cells or subject are identified as expressing CBP. 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 EP300 and / or CBP is an effective amount to inhibit the formation of metastatic cancer colonies in the liver.

[0320] 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.

[0321] 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. 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). chemical terms The terms used herein are intended to describe specific embodiments and are not intended to be limiting.

[0322] 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.

[0323] 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.

[0324] 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.

[0325] 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.

[0326] As used herein, the term "amino" means -N(RN) 1 ) represents 2, and in the formula, each RN 1 These are independently H, OH, NO2, N(RN2)2, SO2ORN 2 SO2RN 2 SORN 2 , N protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others as described herein), and these listed RN 1 Each of the elements can be replaced by any choice, or two R N1 These combine to form alkylenes or heteroalkylenes, and each RN 2 The amino group is independently H, alkyl, or aryl. The amino group of the compounds described herein is either an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(RN)). 1 )2) This could be the case.

[0327] 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.

[0328] 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.

[0329] As used herein, the term "halo" means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical. 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. 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 alkenyl groups. An example of a heteroalkenyl group is “alkenoxy,” which, as used herein, refers to alkenyl-O-. A heteroalkenylene is a divalent heteroalkenyl group. 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.

[0330] 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.

[0331] As used herein, the term “heterocyclyl” refers to a monocyclic or polycyclic radical having 3 to 12 atoms and at least one ring containing 1, 2, 3, or 4 ring atoms selected from N, O, or S, none of which rings are aromatic. The heterocyclyl ring may be spirocyclic or bridged. Examples of heterocyclyls include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperadinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl. “Heterocyclylene” is a divalent heterocyclyl group.

[0332] As used herein, the term "hydroxyl" refers to the -OH group. As used herein, the term "thiol" refers to the -SH group. As used herein, the term "carbonyl" refers to a -C(O)- group.

[0333] As used herein, the term "thiocarbonyl" refers to the -C(S)- group. As used herein, the term "sulfonyl" refers to the -S(O)2- group.

[0334] As used herein, the term "phosphoryl" refers to the P(O) group. 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. When substituted, there are generally 1 to 4 substituents unless otherwise specified. Examples of substituents include alkyl (e.g., unsubstituted and substituted, substituents include any group described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocykyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH2 or mono or dialkylamino), azide, cyano, nitro, or thiol. The aryl, carbocykryl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl groups (unsubstituted and substituted groups such as arylalkyls (e.g., substituted and unsubstituted benzyl)).

[0335] 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.

[0336] 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.

[0337] 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.

[0338] A.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.

[0339] 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.

[0340] 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.

[0341] As used herein, the term "EP300" refers to the EP300 protein in human cells. As used herein, the term "CBP" refers to CREB-binding protein in human cells.

[0342] As used herein, the term “EP300-related disorder” refers to a disorder caused by or affected by the level of CBP activity. As used herein, the term “EP300 loss of function mutation” refers to a mutation in EP300 that results in a protein with reduced activity (e.g., a reduction of at least 1% in EP300 activity, or a reduction of 2%, 5%, 10%, 25%, 50%, or 100% in CBP activity). Examples of EP300 loss of function mutations include, but are not limited to, homozygous EP300 mutations and chromosomal translocations.

[0343] As used herein, the term “EP300 loss of function disorder” refers to a disorder (e.g., cancer) that presents with reduced EP300 activity (e.g., a reduction of at least 1% of EP300 activity, e.g., a reduction of 2%, 5%, 10%, 25%, 50%, or 100% of EP300 activity).

[0344] The term "cancer" refers to a condition caused by the proliferation of malignant new cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas. 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.

[0345] "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.

[0346] Where used herein, the terms “effective dose,” “therapeutic effective dose,” and “sufficient dose” of an agent that reduces the level and / or activity of EP300 (e.g., in cells or subjects) as described herein 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 an agent that reduces the level and / or activity of EP300 sufficient to achieve a therapeutic response compared to a response obtained without administration of the agent that reduces the level and / or activity of EP300. The amount of a given agent that reduces the level and / or activity of EP300 as 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 an agent that reduces the level and / or activity of EP300 in this disclosure is the amount that produces a beneficial or desirable result in the subject compared to a control. As defined herein, the therapeutic dose of an agent that reduces the level and / or activity of EP300 in this disclosure 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.

[0347] As used herein, the term “inhibitor” refers to any agent that reduces the level and / or activity of a protein (e.g., EP300). Non-exclusive examples of inhibitors include small molecule inhibitors, degradation agents, antibodies, enzymes, or polynucleotides (e.g., siRNA).

[0348] "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.

[0349] "Reducing the activity of EP300" means reducing the level of activity associated with EP300, or any associated downstream effects. The activity level of EP300 can be measured using any method known in the art, for example, using the HiBit assay.

[0350] 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.

[0351] 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.

[0352] 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.

[0353] 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.

[0354] "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.

[0355] 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.

[0356] 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.

[0357] 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.

[0358] 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. As used herein, the term “degradant” refers to a small molecule compound containing a degradation moiety, the compound interacting with a protein (e.g., EP300) 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.

[0359] As used herein, the term “degradation moiety” refers to a portion of a protein whose binding results in the degradation of a protein, such as EP300. For example, such a moiety binds to a protein, such as a protease or ubiquitin ligase that metabolizes EP300. [Brief explanation of the drawing]

[0360] [Figure 1] This graph illustrates the effect of the EP300 selective degrading agent on the CBPmut and EP300-dependent cell lines described in Example 46. [Figure 2] This graph illustrates the dose-response effect of the EP300 selective degrading agent on the survival rate of AR+ prostate cancer cells, as described in Example 47. [Figure 3A] This graph illustrates the effect of an EP300-selective degrading agent on EP300 and CBP in the U2OS cell line described in Example 48. [Figure 3B] This graph illustrates the effect of an EP300-selective degrading agent on EP300 and CBP in the U2OS cell line described in Example 48. [Figure 4] This graph illustrates the effect of subcutaneous administration of compound 1 on CBP and EP protein levels in MM1S xenografts in the mouse model described in Example 50. [Figure 5]This graph illustrates the effects of Compound 1 on plasma concentration after subcutaneous administration in the mouse model described in Example 51, as well as on CBP and EP protein levels in VCAP xenografts. [Figure 6A] This graph demonstrates the effect of compound 1 treatment on AR-driven transcription in VCAP xenograft tumors described in Example 52. [Figure 6B] This graph demonstrates the effects of compound 1 and enzalutamide on the upregulation of AR targets in VCAP cells after DHT stimulation, as described in Example 52. [Figure 7A] This graph illustrates the effects of subcutaneous administration of compound 1 and oral administration of enzalutamide on tumor volume in the VCAP xenograft mouse model described in Example 53. [Figure 7B] This graph illustrates the effects of subcutaneous administration of compound 1 and oral administration of enzalutamide on body weight in the VCAP xenograft mouse model described in Example 53. [Figure 7C] This graph illustrates the effects of subcutaneous administration of compound 1 and oral administration of enzalutamide on CBP and EP protein levels in the VCAP xenograft mouse model described in Example 53. [Figure 8] This graph illustrates the effect of the EP300 selective degrading agent on protein levels in the U2OS cell line described in Example 54. [Figure 9A] This graph illustrates the effects of subcutaneous administration of compound 1 and oral administration of GNE-781 on the number of platelets in the mouse model described in Example 55. [Figure 9B] This graph illustrates the effects of subcutaneous administration of compound 1 and oral administration of GNE-781 on platelet count in the mouse model described in Example 55, with additional concentrations of GNE-781 shown. [Figure 10] (A) Describe in vitro megakaryocyte differentiation, and (B) Plateletogenesis assay demonstrates that treatment with compounds 1 and 12 results in less platelet reduction than inhibition by GNE-781. [Figure 11] This graph illustrates the dose-response effect of the EP300 selective degrading agent on prostate cancer cell survival rates as described in Example 57. Figure 11A depicts AR- and AR+ cell lines, while Figure 11B depicts castration-sensitive and castration-resistant cell lines. [Figure 12] This graph illustrates the dose-response effect of the EP300 selective degrading agent on DLBCL cell viability, as described in Example 58. [Figure 13] A) Volume of KARPAS422 tumor xenograft up to 42 days post-transplant. Mice were treated with either a vehicle control (BID) or compound 1 (10, 20, or 50 mg / kg, BID). B) Body weight change in tumor-bearing mice treated with either a vehicle or compound 1 up to 42 days post-transplant. [Modes for carrying out the invention]

[0361] This disclosure features compositions and methods useful for treating EP300-related disorders (e.g., cancer and infections). This disclosure further features compositions and methods useful for inhibiting the level and / or activity of EP300 in a subject requiring treatment, for example, for the treatment of disorders such as cancer (e.g., sarcoma) and infections (e.g., viral infections).

[0362] compound The compounds described herein reduce the level of activity or associated downstream effects related to EP300, or reduce the level of EP300 in cells or subjects. Exemplary compounds described herein have a structure according to formula I, ALB Equation I During the ceremony, A is the EP300 bonding portion, B is the decomposition part, L has the structure of formula II, A 1 -C-(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 0 or 1, Each C is independently either absent, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl. E is nonexistent, 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, optionally substituted C 1~10 Heteroalkylenes, optionally substituted with C 2~10 Carbocyclylene, or optionally substituted C 2~10 It is a heterocycline, 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 Heterocyclylene, optionally substituted with C 6~12 C replaced by an aryl or optional character. 1~7 It is heteroalkyl, F is replaced by C3~C 10 Carbocyclylene, optionally substituted with C 2~12 Heterocyclylene, optionally substituted C6~C 10 Arylene, or C2-C9 heteroarylene with optional substitution, structure, or a pharmaceutically acceptable salt thereof.

[0363] 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 through their ability to modulate the level, state, and / or activity of EP300, for example, by inhibiting the activity or level of EP300 in cells within mammals.

[0364] One aspect of the present invention relates to a method for treating EP300-related disorders such as cancer in subjects 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.

[0365] 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.

[0366] 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).

[0367] 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).

[0368] Treating cancer can result in an increase in the mean survival time of a population treated according to the present invention compared to an untreated population of subjects. For example, the mean survival time increases by more than 30 days (more than 60, 90, or 120 days). The increase in the mean survival time of a population can be measured by any reproducible means. The increase in the mean survival time of a population can be measured, for example, by calculating the length of the mean survival time for a population after the initiation of treatment with the compounds described herein. The increase in the mean survival time of a population can also be measured, for example, by calculating the length of the mean survival time for a population after completion of the first treatment with a pharmaceutically acceptable salt of the compounds described herein.

[0369] Treating cancer 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 average 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 average 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.

[0370] 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 or related symptoms, or in combination with other types of therapies for treating cancer. 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.

[0371] 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)); dynemicin including dynemicin 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, chromoma Icinis, 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, puromycin Antimetabolites such as isine, 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, dideoxyuridine, dox Pyrimidine analogs such as cyfluridine, 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; eriptinium acetate; epotilon; etogluside; gallium nitrate; hydroxyurea; lentinan; ronidynin; mytansinoids such as mytansin and anthamitosin; mitogwazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; fenamet; pirarubicin; rosoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK (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).

[0372] 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 (trademark) (tositumomab-I-131), RAPTIVA (trademark) (efalizumab), ERBITUX (registered trademark) (cetuximab), AVASTIN (registered trademark) (bevacizumab), TYSABRI (registered trademark) (natalizumab), ACTEMR (registered trademark) (tosirimuzumab) Mab), VECTIBIX(registered trademark) (panitumumab), LUCENTIS(registered trademark) (ranivizumab), 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.

[0373] 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. 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).

[0374] 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.

[0375] 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.

[0376] 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.

[0377] 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.

[0378] 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 conventional suppository bases 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.

[0379] 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.

[0380] 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).

[0381] 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).

[0382] kit The present invention also features a kit comprising (a) a pharmaceutical composition comprising an agent that reduces the level and / or activity of EP300 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 EP300 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]

[0383] The following schemes and definitions used elsewhere in this specification are as follows:

[0384] [Table 3-1]

[0385] [Table 3-2]

[0386] 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.

[0387] Preparation of intermediates Intermediate 11-(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

[0388] [ka]

[0389] 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. 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 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. 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 Palladacycle 3G (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. 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. 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. 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.

[0390] 1 H NMR(300 MHz,DMSO-d6)δ=7.32(s,1H),7.12-6.59(m,2H),4.37-4.24(m,1H),4.18(s,2H),4.01-3.91(m,2H),3.74(t,J=5.8 Hz,2H),3.62-3.55(m,2H),3.49(td,J=11.7,2.3 Hz,2H),2.92-2.70(m,4H),2.08(s,2H),2.03-1.89(m,5H),1.81(dt,J=9.4,4.1 Hz,2H)ppm.LCMS(ESI)m / z[M+H]+=509.1. Intermediate 21-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid

[0391] [ka]

[0392] Step 1. Methyl 1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate To a 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 (500 mg, 0.982 mmol) in MeOH (10 mL), Pd(Dppf)Cl2 and Et3N (297.98 mg, 2.95 mmol) were added in a pressure tank. The mixture was purged with nitrogen for 30 minutes and then pressurized to 20 atmospheres with carbon monoxide at 100°C for 48 hours. The reaction mixture was cooled to room temperature and filtered to remove the solid. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (10:1) to obtain the title compound (431 mg) as a yellowish-brown solid. LCMS(ESI)m / z[M+H]+=488.5. Step 2.1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid A stirred solution of methyl 1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (420 mg, 0.86 mmol) in THF (7 mL), MeOH (7 mL), and H2O (7 mL) is mixed with LiOH. .H2O (180.1 mg, 4.295 mmol) was added gradually at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was acidified to pH=5 with 1N HCl (aqueous solution). The resulting mixture was extracted with ELISA (200 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 reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% TFA), gradient from 0% to 100% over 20 minutes, detector, UV 254 nm. The title compound (316 mg) was obtained as a brown solid. LC-MS(ESI) m / z[M+H] + =474.5. Intermediate 3: 1-(5-acetyl-1-(1-acetylpiperidine-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid

[0393] [ka]

[0394] Step 1: 6-Bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline To a stirred solution of 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (1.5 g, 8.188 mmol) in MeCN (30 mL), NBS (1.46 g, 8.188 mmol) was added dropwise at 0°C under an air atmosphere. 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 eluted with PE / EA (8:1) to obtain the title compound (2.1 g) as a white solid.

[0395] Step 2. (Methyl 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate) To a solution of 6-bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (1 g, 3.82 mmol) and Et3N (1.16 g, 11.4 mmol) in 15 mL of MeOH, Pd(dppf)Cl2-CH2Cl2 (1.55 g, 1.91 mmol) was added in a pressure tank. The mixture was purged with nitrogen for 30 minutes and then pressurized to 20 atmospheres with carbon monoxide at 100°C for 2 days. The reaction mixture was cooled to room temperature and filtered to remove the solid. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (10:1) to obtain the title compound (431 mg) as an off-white solid. LCMS(ESI)m / z[M+H] + =241.1. Step 3. Methyl 1-(1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (Methyl 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (200 mg, 0.829 mmol), tert-butyl 4-{3-bromopyrazolo[4,3-c]pyridine-1-yl}piperidine-1-carboxylate (316.10 mg, 0.829 mmol), RuPhos Pd in ​​toluene (2 mL) RuPhos (58.03 mg, 0.124 mmol) was added to a stirred solution of G3 (104.01 mg, 0.124 mmol) and Cs2CO3 (540.24 mg, 1.658 mmol). The resulting mixture was stirred overnight at 80°C. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL). The resulting mixture was extracted with ₹ (50 mL × 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 / EA (1:1) to obtain the title compound (205 mg) as a brown solid. LCMS(ESI)m / z[M+H] + =541.6. Step 4. Methyl 1-(1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate To a solution of methyl 1-(1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (280 mg, 0.517 mmol) in 5 mL of MeOH, PtO2 (39.92 mg, 0.176 mmol) was added in a pressure tank. The mixture was purged with nitrogen for 30 minutes and then pressurized to 10 atm with H2 for 3.5 hours at room temperature. The reaction mixture was cooled to room temperature and filtered to remove the solid. The resulting mixture was filtered and the filter cake was washed with MeOH (10 mL × 3). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (10:1) to obtain the title compound (278 mg) as a white solid. LCMS(ESI)m / z[M+H] + =545.6. Step 5. Methyl 1-(5-acetyl-1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate To a stirred solution of methyl 1-(1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (290 mg, 0.531 mmol) and acetic anhydride (59.69 mg, 0.584 mmol) in DCM (5 mL), Et3N (161.35 mg, 1.593 mmol) was gradually added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL). The resulting mixture was extracted with Â(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 to obtain the title compound (278 mg) as a white solid. The crude product was used directly in the next step without further purification. LC-MS(ESI)m / z[M+H] + =587.7. Step 6. Methyl 1-(5-acetyl-1-(piperidine-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate Trifluoroacetic acid (0.3 mL) was added to a stirred solution of methyl 1-(5-acetyl-1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (200 mg, 0.340 mmol) in DCM (0.9 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 reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% TFA), gradient from 0% to 100% over 20 minutes, detector, UV 254 nm. This yielded the title compound (100 mg) as a colorless oil. LCMS(ESI) m / z[M+H]+ =487.6. Step 7. Methyl 1-[5-acetyl-1-(1-acetylpiperidine-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylate To a stirred solution of methyl 1-(5-acetyl-1-(piperidine-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (70 mg, 0.144 mmol) and Et3N (43.59 mg, 0.432 mmol) in DCM, Ac2O (11.73 mg, 0.115 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using a column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, and UV 254 nm, to obtain the title compound (60 mg) as an off-white solid. LCMS(ESI)m / z[M+H] + =530.2. Step 8.1-[5-acetyl-1-(1-acetylpiperidine-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylic acid LiOH.H2O (13.57 mg, 0.565 mmol) was added to a stirred solution of methyl 1-[5-acetyl-1-(1-acetylpiperidine-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylate (60 mg, 0.123 mmol) in MeOH (1.6 mL) and H2O (0.4 mL). The mixture was stirred at room temperature for 2 hours. The residue was acidified to pH=5 with (1 M) aqueous HCl. The resulting mixture was extracted with ELISA (30 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 residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm, to obtain the title compound (52 mg) as a white solid. LC-MS(ESI) m / z[M+H] + = 516.5. Intermediate 4: (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride

[0396] [ka]

[0397] Step 1. tert-butyl(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-carboxylate EEDQ (9.7g, 39.25mmol) was added to a stirred solution of (1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethaneamine hydrochloride (10g, 39.25mmol) and (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (9.08g, 39.25mmol) in DCM (100mL). The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The mixture was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes, detector, UV 254nm, to obtain the title compound (13.9g) as a white solid. LCMS(ESI)m / z[M+H] += 432.1. Step 2. (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide A solution of tert-butyl(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-carboxylate (11.7 g, 27.11 mmol) in 4N HCl in 1,4-dioxane (70 mL) and DCM (70 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The mixture was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.05% TFA), gradient from 0% to 100% over 15 minutes, detector, UV 254 nm, to obtain the title compound (5.4 g) as a brown solid. LCMS(ESI) m / z[M+H] += 332.3. 1H NMR(300 MHz,DMSO-d6)δ=9.01(s,1H),8.22-8.06(m,1H),7.48(d,J=8.3 Hz,2H),7.40(d,J=8.3 Hz,2H),5.10-4.93(m,1H),4.47-4.25(m,3H),3.11(s,1H),2.46(s,3H),2.36(dd,J=13.2,7.2 Hz,3H),1.92-1.75(m,1H),1.43(d,J=7.0 Hz,3H).LCMS(ESI)m / z[M+H] + =332.2. Intermediate 5: (2S,4R)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide

[0398] [ka]

[0399] Step 1. tert-butyl tert-butyl(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}carbamoyl)pyrrolidine-1-carboxylate HATU (4.93 g, 12.97 mmol) was added to a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2 g, 8.65 mmol), 1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]methanamine hydrochloride (2.50 g, 10.38 mmol), and DIEA (5.59 g, 43.24 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 2 hours. Without any further work, the resulting mixture was purified by reverse-phase flash chromatography using a column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes, detector, and UV 254 nm to obtain the title compound (3.0 g) as a yellowish-brown oil. LCMS(ESI)m / z[M+H] += 418.1. Step 2. (2S,4R)-4-hydroxy-N-{[4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide A solution of tert-butyl(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazole-5-yl)phenyl]methyl}carbamoyl)pyrrolidine-1-carboxylate (300 mg, 0.719 mmol) in TFA (1 mL) and DCM (3 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to obtain the title compound (395 mg, crude) as a yellowish-brown oil. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] += 318.3. Intermediate 6: Methyl 3-methyl-2-(3-(((perfluorobutyl)sulfonyl)oxy)isoxazole-5-yl)butanoate

[0400] [ka]

[0401] Step 1. Methyl 3-methyl-2-{3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazole-5-yl}butanoate To a stirred solution of methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (1 g, 5.02 mmol) and K2CO3 (2.08 g, 15.06 mmol) in MeCN (10 mL), perfluorobutanesulfonyl fluoride (3.03 g, 10.04 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 3 hours. 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 (300 mL) 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, MeCN in water (0.1% FA), gradient from 60% to 100% over 10 minutes, detector, UV 254 nm. This yielded the title compound (4.28 g) as a white solid. LC-MS(ESI)m / z[M+H] + =482.3. Intermediate 7: 6-(difluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

[0402] [ka]

[0403] Step 1: 1-(2-chloroethoxy)-4-(difluoromethyl)-2-nitrobenzene

[0404] [ka]

[0405] A solution of 2-chloroethanol 11 (5.09 g, 63.36 mmol, 1.2 equivalents) in THF (110 mL) was cooled to 0°C in an ice bath, and 2 M LDA (39.5 mL, 79.1 mmol, 1.5 equivalents) in THF was added dropwise. The reaction mixture was heated to room temperature and stirred for 15 minutes. A solution of 4-(difluoromethyl)-1-fluoro-2-nitrobenzene (10.12 g, 52.8 mmol, 1 equivalent) 10 in THF (10 mL) was added to the reaction mixture at room temperature. After the starting material was completely consumed at room temperature for 2 hours, water (150 mL) was added and extracted with EA (300 mL × 2). The organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, and removed under reduced pressure. The crude product was dry-packed into a 120 g silica column and eluted with 0-30% EA in heptane. The fractions containing the desired product were combined, and the solvent was removed to obtain intermediate 12 (13.05 g, 51.8 mmol, 98%) as an off-white solid. LC-MS(ESI)m / z[M+H] + =252.1. Step 2: 2-(2-chloroethoxy)-5-(difluoromethyl)aniline

[0406] [ka]

[0407] To a stirred solution of 1-(2-chloroethoxy)-4-(difluoromethyl)-2-nitrobenzene 12 (13.05 g, 51.8 mmol, 1.0 equivalent) in AcOH (60 mL), Fe (17.3 g, 310.8 mmol, 6 equivalents) was added at room temperature. After completely consuming the starting material at room temperature for 4 hours, water (150 mL) was added and extracted with EA (300 mL × 2). The organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, and removed under reduced pressure. The crude product was dry-packed onto a 120 g silica column and eluted with 0-25% EA in heptane. The fractions containing the desired product were combined, and the solvent was removed to obtain intermediate 13 (8.9 g, 40.4 mmol, 78%) as an off-white solid. LC-MS(ESI) m / z[M+H] + =222.1. Step 3: 6-(difluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

[0408] [ka]

[0409] To a stirred solution of 2-(2-chloroethoxy)-5-(difluoromethyl)aniline 13 (6.95 g, 31.3 mmol, 1.0 equivalent) in DMAc (35 mL), KI (10.3 g, 62.6 mmol, 2 equivalents) and K2CO3 (12.9 g, 93.9 mmol, 3 equivalents) were added at room temperature. The reaction mixture was heated at 90 °C for 7 hours. After complete consumption of the starting materials, the reaction mixture was cooled to room temperature, water (150 mL) was added, and extraction was performed 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 crude product was dry-packed into a 120 g silica column and eluted with 0-25% EA in heptane. The fractions containing the desired product were combined, and the solvent was removed to obtain intermediate 7 (5.79 g, 28.8 mmol, 98%) as an off-white solid. LC-MS(ESI)m / z[M+H] + =186.1. Synthesis of benzomorpholine building blocks

[0410] [ka]

[0411] Step 1: tert-butyl3-amino-1H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0412] [ka]

[0413] To a solution of tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate (100 g, 0.45 mol) in EtOH (600 mL), hydrazine hydrate (50-60% in water) (105 mL, 1.35 mol, 3 equivalents) was added at room temperature. The resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The reaction was monitored by TLC (iodine, 10% DCM in MeOH). The resulting mixture was concentrated under reduced pressure, 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 crude product 2 (106.6 g, 445 mmol, 95%) as a white solid. LCMS(ESI)m / z[M+H] + =239.1. Step 2: tert-butyl3-bromo-1H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0414] [ka]

[0415] 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), CuBr2 (108 g, 484 mmol, 1.1 equivalents) and 3-methylbutyl nitrite (64.4 mL, 484 mmol, 1.1 equivalents) were added at 0°C. The resulting mixture was stirred at 60°C for 2 hours. After complete consumption of the starting materials, the reaction mixture was 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 3 (68 g, 224 mmol, 51%) as an off-white crystalline solid. LCMS(ESI)m / z[M+H] + =304.0. Step 3: tert-butyl3-bromo-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0416] [ka]

[0417] To a stirred solution of tert-butyl 3-bromo-1H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate 3 (20.5 g, 67.8 mmol) and oxan-4-ylmethanesulfonate (18.3 g, 101.7 mmol, 1.5 equivalents) in DMAc (130 mL), Cs2CO3 (63.3 g, 203 mmol, 3 equivalents) was added. The resulting mixture was stirred at 80°C for 3.5 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (300 mL) and extracted with ₹ (400 mL and 100 mL). The organic layers were combined and washed with brine (100 mL). Organic matter was dried over anhydrous Na2SO4 and removed under reduced pressure. The residue was divided into two fractions, dry-packed into two 220g silica columns, and eluted with 0-45% EA in heptane 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 intermediate 4 (13.1g, 34.02 mmol, 50%) as a white solid. LC-MS(ESI) m / z[M+H] + =386.2. Step 4: 3-Bromo-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

[0418] [ka]

[0419] To a solution of tert-butyl 3-bromo-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate 4 (21.6 g, 55.6 mmol) in DCM (60 mL), TFA (15 mL) was added and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solvent was concentrated under reduced pressure, and the TFA was co-evaporated with toluene (20 mL x 2) to obtain crude intermediate 5 (approximately 24 g) as a yellow, sticky mass. The crude product was used in the next step without further purification. LC-MS (ESI) m / z [M+H] + =288.1. 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

[0420] [ka]

[0421] To a solution of 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine 5 (15.84 g, 55.4 mmol) in DCM (150 mL), TEA (19.3 mL, 138 mmol, 2.5 equivalents) was added and the mixture was stirred at room temperature for 15 minutes. The mixture was cooled to 0°C in an ice bath, and acetic anhydride (5.75 mL, 60.9 mmol, 1.1 equivalents) was added in two portions. After the reaction was complete in 2 hours, water (150 mL) was added to quench the reaction. The crude product was extracted with DCM (300 mL x 3), washed with brine (100 mL), dried with anhydrous Na2SO4, and removed under reduced pressure. The crude product was dry-packed into a 220 g silica column eluted by 0-5% MeOH in DCM. The fractions containing the desired product were combined, and the solvent was removed to obtain intermediate 6 (15.75 g, 47.6 mmol, 86%) as an off-white solid. LC-MS(ESI)m / z[M+H] + =328.1. 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

[0422] [ka]

[0423] To a stirred solution of 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline 7 (3.94 g, 21.2 mmol, 1 equivalent) 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 6 (8.99 g, 27.4 mmol, 1.3 equivalents) in degassed 1,4-dioxane (100 mL), Cs2CO3 (20.7 g, 63.6 mmol, 3 equivalents) and XPhos Pd Gen.3 (2.15 g, 2.5 mmol, 0.12 equivalents) were added. The resulting mixture was stirred at 120°C for 18 hours under a nitrogen atmosphere. After completely consuming the starting materials, the reaction mixture was cooled to room temperature and water (300 mL) was added. The crude product was extracted with EA (300 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, and removed under reduced pressure. The crude product was dry-packed onto a 220 g silica column and eluted with 0-5% MeOH in DCM. The fractions containing the desired product were combined, and the solvent was removed to obtain intermediate 8 (9.07 g, 21.0 mmol, 99%) as an off-white solid. LC-MS(ESI) m / z[M+H] + =433.1. 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

[0424] [ka]

[0425] 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 8 (9.07 g, 21.0 mmol) in ACN (100 mL), NBS (3.73 g, 21.0 mmol) was added in three portions at 30 minutes each at 0°C. After stirring at room temperature for a total of 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 crude product was dry-packed into a 220 g silica column and eluted with 0-4.5% MeOH in DCM. The fractions containing the desired product were combined, and the solvent was removed to obtain intermediate 9 (10.6 g, 20.7 mmol, 98%) as an off-white solid. LC-MS(ESI)m / z[M+H] + =511.1. This disclosure is not intended to be seen as limiting the scope or spirit of this disclosure to the specific procedures described herein, and is further illustrated by the following examples and synthesis schemes. It should be understood that the examples are provided to illustrate a particular embodiment and are not intended to imply any limitation on the scope of this disclosure. It should also be understood that various other embodiments, modifications, and equivalents may be taken, which themselves may be suggested to those skilled in the art, without departing from the spirit of this disclosure and / or the appended claims.

[0426] Example 1: Preparation of (2S,4R)-1-[(2R)-2-[3-(1-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carbonyl}piperidine-4-yl)-1,2-oxazole-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Compound 1)

[0427] [ka]

[0428] Step 1. tert-butyl 4-[(1E)-(hydroxyimino)methyl]piperidine-1-carboxylate To a stirred solution of tert-butyl 4-formylpiperidine-1-carboxylate (10 g, 46.89 mmol) and hydroxylamine hydrochloride (6.52 g, 93.77 mmol) in MeOH (50 mL) and H2O (50 mL), Na2CO3 (14.91 g, 140.66 mmol) was added. The resulting mixture was stirred overnight at room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with RINKAN (100 mL x 3). The combined organic layer was washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (13.9 g, crude) as a white solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] + =229.1. Step 2. tert-butyl 4-[(1Z)-chloro(hydroxyimino)methyl]piperidine-1-carboxylate To a stirred solution of tert-butyl 4-[(1E)-(hydroxyimino)methyl]piperidine-1-carboxylate (13.9 g, 60.89 mmol) in DMF (140 mL), NCS (12.20 g, 91.33 mmol) was added. The mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with ELISA (200 mL x 3). The combined organic layer was washed with brine (600 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (20.0 g, crude) as a white solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] + =263.2. Step 3. tert-butyl 4-[5-(2-methoxy-2-oxoethyl)-1,2-oxazol-3-yl]piperidine-1-carboxylate To a stirred solution of tert-butyl 4-[(1Z)-chloro(hydroxyimino)methyl]piperidine-1-carboxylate (20 g, 76.12 mmol) and NaHCO3 (19.18 g, 228.37 mmol) in toluene (200 mL), methylbuto-3-inoate (7.47 g, 76.12 mmol) was added dropwise at 0°C. The resulting mixture was stirred overnight at room temperature. The mixture was diluted with toluene (300 mL) and washed with water (500 mL x 2) and saturated brine (400 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 flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 0% to 60% over 30 minutes, detector, UV 254 nm, to obtain the title compound (8.9 g) as a pale yellow oil. LC-MS(ESI) m / z[M+H] += 324.3. Step 4. tert-butyl 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazol-3-yl]piperidine-1-carboxylate 2-iodopropane (7.55 g, 44.39 mmol) was added to a stirred solution of Cs2CO3 (14.46 g, 44.39 mmol), MgSO4 (6.31 g, 44.39 mmol), and tert-butyl 4-[5-(2-methoxy-2-oxoethyl)-1,2-oxazole-3-yl]piperidine-1-carboxylate (7.2 g, 22.20 mmol) in THF (80 mL). The resulting mixture was stirred overnight at 60°C. The resulting mixture was concentrated under reduced pressure. The mixture was diluted with siRNA (500 mL) and washed with water (300 mL) and saturated brine (400 mL x 2). 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 flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 20% to 80% over 30 minutes, and a UV 254 nm detector to obtain the title compound (3.5 g) as a yellowish-brown oil. LC-MS(ESI) m / z[M+H] += 366.4. Step 5. tert-butyl 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazol-3-yl]piperidine-1-carboxylate A stirred solution of tert-butyl 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazole-3-yl]piperidine-1-carboxylate (3.5 g, 9.55 mmol) in MeOH (32 mL) and H2O (8 mL) is mixed with LiOH. . H2O (2.00 g, 47.76 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with 1N HCl to pH=4-5. The resulting mixture was extracted with RINKAN (300 mL x 3). The combined organic layer was washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded the title compound (3.3 g) as a white solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] += 353.1. Step 6. tert-butyl 4-(5-{1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1,2-oxazole-3-yl)piperidine-1-carboxylate PyBOP (7.31 g, 14.05 mmol) was added to a stirred solution of tert-butyl 4-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazole-3-yl]piperidine-1-carboxylate (3.3 g, 9.36 mmol), (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (3.10 g, 9.36 mmol), and DIEA (3.63 g, 28.09 mmol) in DMF (30 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ELISA (300 mL) and washed with water (500 mL x 2) and saturated brine (400 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 reverse-phase flash chromatography using a column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes, detector, and UV 254 nm, to obtain a chiral mixture of the title compound (5.9 g) as a white solid. The title compound (5.7g) was purified using a preparative SFC column: CHIRAL ART Amylose-SA 5*25cm, 5μm, mobile phase A: CO2, mobile phase B: MeOH, flow rate: 150mL / min, gradient: isocratic 35%B, column temperature (°C): 35, back pressure (bar): 100, wavelength: 290 / 268nm, RT1 (min): 3.88, RT2 (min): 5.45, sample solvent: MeOH:DCM=1:1, injection volume: 2mL, number of runs: 6. The desired stereoisomer of the title compound (2.7g) was obtained as a white solid. LCMS(ESI)m / z[M+H] += 666.4. Step 7. (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(piperidine-4-yl)-1,2-oxazole-5-yl]butanoyl]pyrrolidine-2-carboxamide A solution of tert-butyl 4-(5-{1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1,2-oxazole-3-yl)piperidine-1-carboxylate (500 mg, 0.751 mmol) in TFA (2 mL) and DCM (6 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The mixture was purified by reverse-phase flash chromatography using a column, C18 silica gel, mobile phase, MeCN in water (0.05% TFA), gradient from 0% to 100% over 15 minutes, detector, and UV 254 nm under the following conditions to obtain the title compound (412 mg) as a white solid. LCMS(ESI)m / z[M+H] += 566.3. Step 8. (2S,4R)-1-[(2R)-2-[3-(1-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carbonyl}piperidine-4-yl)-1,2-oxazole-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(piperidine-4-yl)-1,2-oxazole-5-yl]butanoyl]pyrrolidine-2-carboxamide (150 mg, 0.265 mmol), 1-[5-acetate] in MeCN (2 mL) NMI (43.54 mg, 0.530 mmol) was added to a stirred solution of 125.81 mg, 0.265 mmol of thiol-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylic acid and 111.59 mg, 0.398 mmol of TCFH. The mixture was stirred at 60°C for 2 hours. The reaction mixture was diluted with water (25 mL). The resulting mixture was extracted with RINKAN (20 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 (211 mg) was purified by preparative HPLC under the following conditions (column: XSelect CSH Prep C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30%B to 50%B over 8 minutes; wavelength: 220 nm; RT1 (min): 7.1) to obtain the title compound (95.6 mg) as a white solid.

[0429] 1H NMR(300 MHz,DMSO-d6)δ=8.96(s,1H),8.18(d,J=7.8 Hz,1H),7.52-7.32(m,4H),7.11-6.92(m,1H),6.85-6.16(m,3H),5.08-4.59(m,1H),4.43(t,J=7.6 Hz,1H),4.31(d,J=4.7 Hz,2H),4.19(s,2H),3.97(d,J=11.3 Hz,3H),3.83-3.69(m,4H),3.68-3.57(m,6H),3.17-2.94(m,3H),2.87(s ,4H),2.47(s,4H),2.38-2.15(m,1H),2.14-1.76(m,13H),1.59(d,J=12.1 Hz,2H),1.44(dd,J=14.6,7.0 Hz,3H),1.00(d,J=6.5 Hz,3H),0.82(d,J=6.9 Hz,3H).LCMS(ESI)m / z[M+H]+=1022.4. The following compounds in Tables 2 and 2A were prepared using standard chemical operations and procedures similar to those used for the preparation of compound 1.

[0430] [Table 4-1]

[0431] [Table 4-2]

[0432] [Table 4-3]

[0433] [Table 4-4]

[0434] [Table 4-5]

[0435] Table 4-6

[0436] Table 4-7

[0437] Table 4-8

[0438] Table 4-9

[0439] Table 4-10

[0440] Table 4-11

[0441] Table 4-12

[0442] Table 4-13

[0443] Table 4-14

[0444] Table 4-15

[0445] Table 5-1

[0446] Table 5-2

[0447] Table 5-3

[0448] Table 5-4

[0449] Table 5-5

[0450] Table 5-6

[0451] Table 5-7

[0452] Table 5-8

[0453] Table 5-9

[0454] Table 5-10

[0455] Table 5-11

[0456] [Table 5-12]

[0457] [Table 5-13]

[0458] [Table 5-14]

[0459] [Table 5-15]

[0460] [Table 5-16]

[0461] [Table 5-17]

[0462] [Table 5-18]

[0463] Example 2: Preparation of (2S,4R)-1-((R)-2-(3-((1-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carbonyl)piperidine-4-yl)oxy)isoxazole-5-yl)3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 17)

[0464] [ka]

[0465] Step 1. tert-butyl 4-{[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazole-3-yl]oxy}piperidine-1-carboxylate A stirred solution of methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (200 mg, 1.00 mmol) and tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (420.70 mg, 1.51 mmol) in DMF (1 mL) was mixed with K2CO3 (346.89 mg, 2.51 mmol). The resulting mixture was stirred at 60°C for 2 hours. The mixture was diluted with EA (50 mL) and washed with water (30 mL x 2) and saturated brine (20 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 flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm, to obtain the title compound (230 mg) as a yellow oil. LC-MS(ESI) m / z[M+H] + =383.2. Step 2.2-(3-{[1-(tert-butoxycarbonyl)piperidine-4-yl]oxy}-1,2-oxazole-5-yl)-3-methylbutanoic acid A stirred solution of tert-butyl 4-{[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazole-3-yl]oxy}piperidine-1-carboxylate (200 mg, 0.523 mmol) in MeOH (1 mL) and H2O (1 mL) is mixed with LiOH .H2O (87.77 mg, 2.09 mmol) was added. The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm, to obtain the title compound (225 mg, crude) as a yellow solid. LC-MS(ESI) m / z[M+H] + =369.2. Step 3. tert-butyl4-[(5-{1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1,2-oxazole-3-yl)oxy]piperidine-1-carboxylate PyBOP (621.49 mg, 1.19 mmol) was added to a stirred solution of 2-(3-{[1-(tert-butoxycarbonyl)piperidine-4-yl]oxy}-1,2-oxazole-5-yl)-3-methylbutanoic acid (220 mg, 0.597 mmol), (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (237.49 mg, 0.716 mmol), and DIEA (308.71 mg, 2.39 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with H2O (10 mL) and extracted with ELISA (3 × 20 mL). 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-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm, to obtain a chiral mixture of the title compound (249 mg) as a yellow solid. A mixture of stereoisomers (249 mg) was purified by preparative chiral HPLC using a column: (R,R)-WHELK-01-Kromasil, 5*25 cm, 5 μm; mobile phase A: MtBE (0.5% 2M NH3-MeOH), mobile phase B: MeOH; flow rate: 40 mL / min; gradient: 16.5 mins to 5%B~5%B; wavelength: 222 / 272 nm; RT1 (min): 8.5; RT2 (min): 12.5; sample solvent: MeOH:DCM = 1:1; injection volume: 0.5 mL; number of runs: 6. The fraction containing the desired isomer was evaporated to dryness to obtain the title compound (74 mg) as a yellow solid. LC-MS(ESI) m / z[M+H] + =682.3. Step 4. (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(piperidine-4-yloxy)-1,2-oxazole-5-yl]butanoyl]pyrrolidine-2-carboxamide A solution of tert-butyl 4-[(5-{1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1,2-oxazole-3-yl)oxy]piperidine-1-carboxylate (25 mg, 0.037 mmol) in TFA (0.5 mL) and DCM (0.5 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to obtain the title compound (28 mg, crude) as a yellow oil. The crude product was used directly in the next step without further purification.

[0466] Step 5. (2S,4R)-1-[(2R)-2-{3-[(1-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carbonyl}piperidine-4-yl)oxy]-1,2-oxazole-5-yl}-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-(piperidine-4-yloxy)-1,2-oxazole-5-yl]butanoyl]pyrrolidine-2-carboxamide (20 mg, 0.034 mmol), 1-[5- 16.31 mg, 0.034 mmol of acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylic acid (16.31 mg, 0.034 mmol) and HATU (15.69 mg, 0.041 mmol) were stirred together, to which DIEA (8.89 mg, 0.068 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EA (20 mL). The resulting mixture was washed with water (10 mL) and saturated brine (10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product (20 mg) was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3); mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 31%B~51%B, 51%B at 11.5 mins; wavelength: 254 / 220 nm; RT1 (min): 10.03; number of runs: 0) to obtain the title compound (9.6 mg) as a white solid.

[0467] 1H NMR(300 MHz,DMSO-d6)δ=8.95(s,1H),8.19(d,J=7.7 Hz,1H),7.50-7.33(m,4H),7.04(s,1H),7.01-6.60(m,2H),6.13-5.89(m,1H),5.03-4.65(m,3H),4.43(t,J=7.7 Hz,1H),4.38-4.24(m,2H),4.19(s,2H),3.97(d,J=11.3 Hz,2H),3.84-3.57(m,7H),3.55-3.39(m,4H),3.33(s,2H),2.95-2.69(m,4H),2.47(s,3H),2.34-2.18(m,1H),2.14-1.92(m,10H) ),1.91-1.80(m,3H),1.76-1.58(m,2H),1.50-1.37(m,3H),1.04-0.95(m,3H),0.90-0.80(m,3H).LCMS(ESI)m / z[M+H]+=1038.4. The compounds listed in Table 3 were prepared using standard chemical operations and procedures similar to those used for the preparation of compound 17.

[0468] [Table 6-1]

[0469] [Table 6-2]

[0470] [Table 6-3]

[0471] [Table 6-4]

[0472] [Table 6-5]

[0473] [Table 6-6]

[0474] [Table 6-7]

[0475] [Table 6-8]

[0476] Example 3: Preparation of (2S,4R)-1-((R)-2-(3-((1-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carbonyl)piperidine-4-yl)oxy)isoxazole-5-yl)3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 18)

[0477] [ka]

[0478] Step 1. tert-butyl6-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazol-3-yl]-2,6-diazaspiro[3.3]heptan-2-carboxylate DIEA (453.41 mg, 3.51 mmol) was added to a stirred solution of 3-methyl-2-{3-[(1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl)oxy]-1,2-oxazole-5-yl}butanoate (562.8 mg, 1.17 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (231.84 mg, 1.17 mmol) in DMSO (5 mL). The resulting mixture was stirred at 100 °C for 2 hours. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with RINKAN (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 10% to 70% over 10 minutes, detector, UV 254 nm, to obtain the title compound (230.5 mg) as a yellow oil. LC-MS(ESI) m / z[M+H] + =380.2. Step 2.2-{3-[6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl]-1,2-oxazole-5-yl}-3-methylbutanoic acid A solution of tert-butyl 6-[5-(1-methoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazole-3-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (1300 mg, 3.26 mmol) and LiOH (43.08 mg, 1.80 mmol) in THF (3 mL) and H2O (3 mL) was stirred at room temperature under an air atmosphere for 1 hour. The residue was acidified to pH=5 with (0.5 M) aqueous HCl. The resulting mixture was extracted with  (60 mL × 3). The combined organic layers were washed with water (60 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (205.5 mg) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] + =366.1 Step 3. tert-butyl6-(5-{1-[(2S,4R)-4-hydroxy--2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1,2-oxazole-3-yl)-2,6-diazaspiro[3.3]heptan-2-carboxylate HATU (309.34 mg, 0.813 mmol) was added to a stirred solution of 2-{3-[6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl]-1,2-oxazole-5-yl}-3-methylbutanoic acid (198.2 mg, 0.542 mmol), (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (179.76 mg, 0.542 mmol), and DIEA (140.20 mg, 1.084 mmol) in DMF (2 mL). The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. The resulting mixture was diluted with ELISA (50 mL). The combined organic layers were washed with water (50 mL x 3) and brine (50 mL) 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, MeCN in water (0.1% TFA), gradient from 10% to 50% over 10 minutes, detector, UV254 nm, to obtain a chiral mixture of the title compound (113.3 mg) as a pale yellow oil. The stereoisomer (113.3 mg) was purified by preparative chiral HPLC using a column (CHIRAL ART Cellulose-SB 2*25 cm, 5 μm, mobile phase A: MtBE (0.5% 2M NH3-MeOH), mobile phase B: MEOH (0.1% 2M NH3-MEOH), flow rate: 20 mL / min, gradient: isocratic 10, wavelength: 218 / 270 nm, RT1 (min): 10, RT2 (min): 12, sample solvent: MeOH:DCM = 1:1, injection volume: 0.5 mL, number of runs: 7). The fraction containing the desired stereoisomer was evaporated to dryness to obtain the title compound (15.3 mg) as a pale yellow oil. LC-MS (ESI) m / z [M+H] + =679.4 Step 4. (2S,4R)-1-[(2R)-2-(3-{2,6-diazaspiro[3,3]heptan-2-yl}-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide A solution of tert-butyl 6-(5-{1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1,2-oxazole-3-yl)-2,6-diazaspiro[3.3]heptan-2-carboxylate (10 mg, 0.015 mmol) in TFA (0.3 mL) and DCM (2 mL) was stirred at room temperature under an air atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain the title compound (19.6 mg) as a pale yellow oil. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] + =579.4. Step 5. (2S,4R)-1-[(2R)-2-[3-(6-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carbonyl}-2,6-diazaspiro[3,3]heptan-2-yl)-1,2-oxazole-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (2S,4R)-1-[(2R)-2-(3-{2,6-diazaspiro[3.3]heptan-2-yl}-1,2-oxazole-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (16.1 mg, 0.028 mmol) in DMF (1 mL) DIEA (7.19 mg, 0.056 mmol) was added to a stirred solution of 1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylic acid (13.20 mg, 0.028 mmol) and HATU (15.87 mg, 0.042 mmol). The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. Without any additional work, the reaction mixture was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 23%B~37%B, 37%B over 10 minutes; wavelength: 254 / 220 nm; RT1 (min): 8) to obtain the title compound (4.8 mg) as a white solid.

[0479] 1H NMR(300 MHz,DMSO-d6)δ=8.94(s,1H),8.13(d,J=7.9 Hz,1H),7.58-7.03(m,6H),6.85(s,1H),5.80(d,J=26.7 Hz,1H),4.94(d,J=7.3 Hz,1H),4.42(t,J=7.6 Hz,1H),4.36-4.27(m,2H),4.24(s,4H),4.20(s,2H),4.04(s,4H),4.03-3.91(m,2H),3.81-3.66(m,3H),3.62(t,J=6.7 Hz,3H),3.56-3.31(m,4H),2.87(s,4H),2.47(s,3H),2.26(d,J=9.3 Hz,1H),2.13-1.93(m,8H),1.88(s,3H),1.42(d,J=7.0 Hz,3H),0.97(d,J=6.6 Hz,3H),0.83(d,J=6.7 Hz,3H).LCMS(ESI)m / z[M+H] + =1035.5. The compounds listed in Tables 4 and 4A were prepared using standard chemical operations and procedures similar to those used for the preparation of compound 18.

[0480] [Table 7-1]

[0481] [Table 7-2]

[0482] [Table 7-3]

[0483] [Table 8-1]

[0484] [Table 8-2]

[0485] Table 8-3

[0486] Table 8-4

[0487] Table 8-5

[0488] Table 8-6

[0489] Table 8-7

[0490] Table 8-8

[0491] Table 8-9

[0492] Table 8-10

[0493] Table 8-11

[0494] Table 8-12

[0495] Example 4: Preparation of (2S,4R)-1-((S)-2-(4-(1-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carbonyl)piperidine-4-yl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 31)

[0496] [ka]

[0497] Step 1. Preparation of tert-butyl 4-{1-[(2S)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl]-1,2,3-triazole-4-yl}piperidine-1-carboxylate A stirred solution of tert-butyl 4-ethinylpiperidine-1-carboxylate (250 mg, 1.19 mmol), tert-butyl(2S)-2-azido-3-methylbutanoate (476.03 mg, 2.39 mmol), and sodium ascorbate (118.92 mg, 0.598 mmol) in MeOH (6 mL) and H2O (3 mL) is prepared by adding CuSO4. . 5H2O (149.12 mg, 0.598 mmol) was added at room temperature. The resulting mixture was stirred overnight. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 30 mL). 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, MeCN in water (10 mmol / L NH4HCO3), gradient from 20% to 100% over 30 minutes, detector, UV 254 nm. This yielded the title compound (436 mg) as a yellow oil. LCMS(ESI) m / z:[M+H] + =409. Step 2. Preparation of tert-butyl(2S)-3-methyl-2-[4-(piperidine-4-yl)-1,2,3-triazole-1-yl]butanoate To a stirred solution of tert-butyl 4-{1-[(2S)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl]-1,2,3-triazole-4-yl}piperidine-1-carboxylate (200 mg, 0.490 mmol) in DCM (0.8 mL), TFA (0.4 mL) was added at 0°C. The solution was stirred at 0°C for 3 hours. The mixture was neutralized to pH=9 with Et3N. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 30 minutes, detector, UV254 nm. This yielded the title compound (80 mg) as a yellow solid. LCMS(ESI) m / z:[M+H] + =309. Step 3. Preparation of tert-butyl(2S)-2-[4-(1-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carbonyl}piperidine-4-yl)-1,2,3-triazole-1-yl]-3-methylbutanoate HATU (96.16 mg, 0.254 mmol) was gradually added at room temperature to a stirred solution of tert-butyl(2S)-3-methyl-2-[4-(piperidine-4-yl)-1,2,3-triazole-1-yl]butanoate (52.00 mg, 0.169 mmol), 1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylic acid (80 mg, 0.169 mmol), and DIEA (65.37 mg, 0.507 mmol) in DMF (2 mL). The resulting mixture was stirred for 1 hour. The mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 100% over 25 minutes, detector, UV 254 nm. This yielded the title compound (98 mg) as a white solid. LCMS(ESI) m / z:[M+H] + =765. Step 4. Preparation of (2S)-2-[4-(1-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carbonyl}piperidine-4-yl)-1,2,3-triazole-1-yl]-3-methylbutanoic acid A stirred solution of tert-butyl(2S)-2-[4-(1-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carbonyl}piperidine-4-yl)-1,2,3-triazole-1-yl]-3-methylbutanoate (98 mg, 0.128 mmol) in TFA (1 mL) was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% HCl), gradient from 10% to 100% over 25 minutes, detector, and UV 254 nm. This yielded the title compound (89 mg) as a white solid. LCMS(ESI)m / z:[M+H] + =709. Step 5. Preparation of (2S,4R)-1-[(2S)-2-[4-(1-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carbonyl}piperidine-4-yl)-1,2,3-triazole-1-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (2S)-2-[4-(1-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carbonyl}piperidine-4-yl)-1,2,3-triazole-1-yl]-3-methylbutanoic acid (89 mg, 0.12) in DMF (2 mL) HATU (71.61 mg, 0.189 mmol) was gradually added at room temperature to a stirred solution of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (6 mmol), DIEA (48.69 mg, 0.378 mmol), and HATU (71.61 mg, 0.189 mmol). The resulting mixture was stirred for 1 hour. The mixed solution was purified by preparative HPLC under the following conditions (column: XSelect CSH Prep C18 OBD column, 30*150 mm, 5 m; mobile phase A: water (0.1% FA); mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 29%B to 45%B over 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 9.23) to obtain the title compound (52.4 mg) as a white solid. LCMS(ESI)m / z:[M+H] + =1022.30. 1 H NMR(300 MHz,DMSO-d6)δ=8.93(s,1H),8.62-8.09(m,1H),7.91(s,1H),7.53-7.38(m,4H),7.03(s,1H),6.99-6.54(m,2H),5.23(d,J=9.8 Hz,1H),5.06-4.78(m,1H),4.46(t,J=7.8 Hz,1H),4.39-4.25(m,2H),4.20(s,2H),4.10-3.91(m,4H),3.88-3.69(m,3H),3.66-3.57(m,3H),3.55-3.43(m ,3H),3.14-2.95(m,4H),2.93-2.77(m,4H),2.47(s,3H),2.14-1.81(m,13H),1.71-1.52(m,2H),1.44(d,J=7.0 Hz,3H),1.05(d,J=6.6 Hz,3H),0.71(d,J=6.7 Hz,3H). Example 5: Preparation of (2S,4R)-1-[(2R)-2-[5-(1-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carbonyl}piperidine-4-yl)-1,2-oxazole-3-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 32)

[0498] [ka]

[0499] Step 1. Preparation of ethyl 2-[(1E)-(hydroxyimino)methyl]-3-methylbutanoate A stirred solution of ethyl 2-formyl-3-methylbutanoate (4g, 25.285 mmol) and Na2CO3 (13.40g, 126.42 mmol) in THF (40 mL) and H2O (20 mL) is mixed with NH2OH. . HCl (8.79 g, 126.42 mmol) was added gradually at room temperature. The resulting mixture was stirred overnight. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with toluene (3 × 50 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded the title compound (3.42 g) as a yellow oil. The crude product was used directly in the next step without further purification. LC-MS(ESI) m / z:[M+H] + =174. Step 2. Preparation of ethyl 2-[(Z)-hydroxy-C-hydroxycarbonimidoyl]-3-methylbutanoate To a stirred solution of ethyl 2-[(1E)-(hydroxyimino)methyl]-3-methylbutanoate (3.4 g, 19.63 mmol) in DMF (40 mL), NCS (2.62 g, 19.63 mmol) was gradually added at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with water (120 mL). The resulting mixture was extracted with ELISA (2 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This yielded the title compound (4.29 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] + =208. Step 3. Preparation of tert-butyl 4-[3-(1-ethoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazole-5-yl]piperidine-1-carboxylate To a stirred solution of ethyl 2-[(Z)-hydroxy-C-hydroxycarbonimidoyl]-3-methylbutanoate (4.2 g, 20.23 mmol) and tert-butyl 4-ethynylpiperidine-1-carboxylate (4.23 g, 20.23 mmol) in RINKAN (50 mL), NaHCO3 (5.10 g, 60.68 mmol) was added at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was washed with 2 × 30 mL of water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / THF (30:1) to obtain the title compound (3.68 g) as a yellow solid. LCMS(ESI)m / z:[M+H] + =381. Step 4.2 - Preparation of {5-[1-(tert-butoxycarbonyl)piperidine-4-yl]-1,2-oxazole-3-yl}-3-methylbutanoic acid To a stirred solution of tert-butyl 4-[3-(1-ethoxy-3-methyl-1-oxobutan-2-yl)-1,2-oxazole-5-yl]piperidine-1-carboxylate (1 g, 2.63 mmol) in MeOH (10 mL) and H2O (10 mL), add LiOH . H2O (1.10 g, 26.28 mmol) was added at room temperature. The resulting mixture was stirred at 30°C for 2 hours. The mixture was acidified to pH=2 with aqueous HCl (0.5 M). The resulting mixture was extracted with toluene (3 × 30 mL). The combined organic layer was dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded the title compound (856 mg) as a white solid. The crude product was used directly in the next step without further purification. LC-MS(ESI) m / z:[M+H] + =353. Step 5. Preparation of tert-butyl 4-(3-{1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1,2-oxazole-5-yl)piperidine-1-carboxylate DIEA (330.06 mg, 2.55 mmol) and HATU (388.40 mg, 1.02 mmol) were added to a stirred solution of 2-{5-[1-(tert-butoxycarbonyl)piperidine-4-yl]-1,2-oxazole-3-yl}-3-methylbutanoic acid (300 mg, 0.851 mmol) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (282.12 mg, 0.851 mmol) in DMF (2 mL). The resulting mixture was stirred overnight at room temperature. The mixture was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 60% over 20 minutes, detector, and UV 254 nm. This yielded a chiral mixture of the title compound (287 mg) as a white solid. A chiral mixture (287 mg) was purified by preparative SFC under the following conditions (column: CHIRAL ART Cellulose-SZ 3*25 cm, 5 μm; mobile phase A: CO2; mobile phase B: MeOH (0.1% 2M NH3-MeOH); flow rate: 90 mL / min; gradient: isocratic 45% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 270 / 210 nm; RT1 (min): 3.65; RT2 (min): 4.55; sample solvent: MEOH; injection volume: 0.5 mL) to obtain the title compound (160 mg) as a white solid. LCMS(ESI)m / z:[M+H] + =666. Step 6. Preparation of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[5-(piperidine-4-yl)-1,2-oxazole-3-yl]butanoyl]pyrrolidine-2-carboxamide To a stirred solution of tert-butyl 4-(3-{1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1,2-oxazole-5-yl)piperidine-1-carboxylate (70 mg, 0.105 mmol) in DCM (1 mL), TFA (0.5 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. This yielded the title compound (55 mg) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + = 566. Step 7. Preparation of (2S,4R)-1-[(2R)-2-[5-(1-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carbonyl}piperidine-4-yl)-1,2-oxazole-3-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[5-(piperidine-4-yl)-1,2-oxazole-3-yl]butanoyl]pyrrolidine-2-carboxamide (55 mg, 0.097 mmol) and 1-[5-acetyl]ethyl in DMF (1 mL). To a stirred solution of ru-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylic acid (46.13 mg, 0.097 mmol), TCFH (54.56 mg, 0.194 mmol) and NMI (15.96 mg, 0.194 mmol) were added at room temperature. The resulting mixture was stirred at 60°C for 4 hours. The mixture was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA); mobile phase B: 20 ​​mm NaOH + 10% MeCN; flow rate: 60 mL / min; gradient: 33%B to 49%B over 10 minutes; wavelength: 254 nm / 220 nm; RT1 (min): 8.7) to obtain the title compound (56.3 mg) as a white solid.

[0500] 1 HNMR(300 MHz,DMSO-d6)δ=8.93(s,1H),8.52-7.92(m,1H),7.51-7.33(m,4H),7.21-6.56(m,3H),6.22( s,1H),5.06-4.86(m,1H),4.81-4.37(m,1H),4.37-4.25(m,2H),4.20(s,2H),3.98(d,J=11.7 Hz,4H),3.83-3.69(m,3H),3.65-3.56(m,3H),3.54-3.41(m,3H),3.18-3.01(m,3H),2.92-2.79(m,4H), 2.47(s,3H),2.37-2.13(m,1H),2.12-1.72(m,13H),1.67-1.53(m,2H),1.51-1.36(m,3H),1.01(d,J=6.5 Hz,3H),0.78(d,J=6.7 Hz,3H).LCMS(ESI)m / z:[M+H] +=1022.35. Example 6: Preparation of (2S,4R)-1-((S)-2-(2-(3-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-yl)-1H-pyrrolo[3,2-c]pyridine-1-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl))pyrrolidine-2-carboxamide (compound 33)

[0501] [ka]

[0502] Step 1. Ethyl 2-{3-bromopyrrolo[3,2-c]pyridine-1-yl}acetate To a stirred solution of 3-bromo-1H-pyrrolo[3,2-c]pyridine (1 g, 5.08 mmol) in DMF (12 mL), NaH (0.21 g, 8.63 mmol) was gradually added at 0°C. The resulting mixture was stirred at 0°C for 1.5 hours. To the above mixture, ethyl bromo (0.68 g, 4.06 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for a further 1.5 hours. The reaction product was quenched with water at 0°C. The resulting mixture was extracted with Âx (150 mL x 3). The combined organic layer was washed with brine (500 mL x 3) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH₂Cl₂ / MeOH 20:1) to obtain title compound 2 (477 mg) as a white solid. LC-MS (ESI) m / z [M+H] + =283.1. Step 2. Ethyl 2-(3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}pyrrolo[3,2-c]pyridine-1-yl) acetate PdCl2 (dtbpf) (34.53 mg, 0.053 mmol) was added to a stirred solution of dioxane (0.8 mL), ethyl 2-{3-bromopyrrolo[3,2-c]pyridine-1-yl}acetate (50 mg, 0.177 mmol), 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 (147.41 mg, 0.265 mmol), and K3PO4 (74.97 mg, 0.354 mmol). The resulting mixture was stirred at 70°C for 4 hours. The resulting mixture was diluted with water (20 mL) and extracted with siRNA (20 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 reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm. This yielded the title compound (74 mg) as a red solid. LC-MS(ESI) m / z[M+H] + =633.2. Step 3. tert-butyl(3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}pyrrolo[3,2-c]pyridine-1-yl)acetic acid A stirred solution of ethyl 2-(3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}pyrrolo[3,2-c]pyridine-1-yl) acetate (74 mg, 0.117 mmol) in MeOH (0.3 mL), THF (0.3 mL), and H2O (0.3 mL) is mixed with LiOH. .H2O (24.54 mg, 0.585 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The residue was acidified to pH=4 with 1N HCl. The resulting mixture was extracted with RINKAN (20 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 reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% TFA), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm. This yielded the title compound (67 mg) as a white solid. LCMS(ESI)m / z[M+H] + =605.2. Step 4. (2S,4R)-1-[(2S)-2-[2-(3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}pyrrolo[3,2-c]pyridine-1-yl)acetamide]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide DMF (1 mL) contains tert-butyl(3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl)pyrrolo[3,2-c]pyridine-1-yl)acetic acid (30 mg, 0.050 mmol), (2S,4R)-1-[(2S)-2 HATU (28.30 mg, 0.075 mmol) was added to a stirred solution of -amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (22.06 mg, 0.050 mmol) and DIEA (12.83 mg, 0.100 mmol). The resulting mixture was stirred at room temperature for 1 hour. The crude product was purified by preparative HPLC under the following conditions (column: Sunfire C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA); mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 38%B to 54%B over 10 minutes; wavelength: 254 nm / 220 nm; RT1 (min): 9.14) to obtain the title compound (20.0 mg) as a white solid.

[0503] 1 H NMR(300 MHz,DMSO-d6)δ=8.94(d,J=3.7 Hz,1H),8.74(d,J=3.3 Hz,1H),8.28(d,J=5.8 Hz,1H),8.21-8.04(m,2H),7.55-7.30(m,6H),7.28-7.09(m,1H),6.95(s,1 H),6.88-6.37(m,1H),5.25-4.82(m,3H),4.60-4.43(m,2H),4.31(d,J=5.0 Hz,2H),4.24(s,2H),4.04-3.91(m,2H),3.75(s,2H),3.64(q,J=4.7 Hz,3H),3.59-3.40(m,4H),3.00-2.68(m,4H),2.47(s,3H),2.19-1.95(m,8 H),1.96-1.77(m,3H),1.49-1.16(m,3H),0.96(s,9H).LCMS(ESI)m / z[M+H] + =1031.45. The compounds listed in Tables 5 and 5A were prepared using standard chemical operations and procedures similar to those used for the preparation of compound 33.

[0504] [Table 9-1]

[0505] [Table 9-2]

[0506] [Table 9-3]

[0507] [Table 9-4]

[0508] [Table 9-5]

[0509] [Table 10-1]

[0510] [Table 10-2]

[0511] [Table 10-3]

[0512] [Table 10-4]

[0513] Table 10-5

[0514] Table 10-6

[0515] Table 10-7

[0516] Table 10-8

[0517] Table 10-9

[0518] Table 10-10

[0519] Table 10-11

[0520] Table 10-12

[0521] Table 10-13

[0522] Table 10-14

[0523] Table 10-15

[0524] Table 10-16

[0525] Table 10-17

[0526] Table 10-18

[0527] Table 10-19

[0528] Table 10-20

[0529] Table 10-21

[0530] Table 10-22

[0531] Table 10-23

[0532] Table 10-24

[0533] Table 10-25

[0534] Table 10-26

[0535] Table 10-27

[0536] Table 10-28

[0537] Table 10-29

[0538] Table 10-30

[0539] Table 10-31

[0540] Table 10-32

[0541] Table 10-33

[0542] Table 10-34

[0543] Table 10-35

[0544] Table 10-36

[0545] Table 10-37

[0546] Table 10-38

[0547] Table 10-39

[0548] Table 10-40

[0549] Table 10-41

[0550] Table 10-42

[0551] Table 10-43

[0552] Table 10-44

[0553] Table 10-45

[0554] [Table 10-46]

[0555] [Table 10-47]

[0556] [Table 10-48]

[0557] [Table 10-49]

[0558] [Table 10-50]

[0559] [Table 10-51]

[0560] Example 7. Preparation of (2S,4R)-1-[(2S)-2-[2-(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyrididine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}-4-(azetidine-1-yl)pyrrolo[3,2-c]pyridazin-5-yl)acetamide]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 39)

[0561] [ka]

[0562] Step 1: Preparation of 5-chloro-3-[(E)-2-ethoxyethenyl]pyridazine-4-amine (intermediate 2)

[0563] [ka]

[0564] To a solution of 3,5-dichloropyridazine-4-amine (1 g, 6.098 mmol, 1 equivalent) and 2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.33 g, 6.708 mmol, 1.1 equivalent) in 1,4-dioxane (15 mL) and H2O (3 mL), Pd(dppf)Cl2.CH2Cl2 (0.50 g, 0.610 mmol, 0.1 equivalent) and Na2CO3 (1.62 g, 15.245 mmol, 2.5 equivalents) were added. After stirring at 100°C for 2 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / SiO(1:1.5) to obtain intermediate 2 (850 mg, 69.82%) as a yellow solid. LCMS(ESI)m / z[M+H] + =200. Step 2: Preparation of 4-chloro-5H-pyrrolo[3,2-c]pyridazine (intermediate 3)

[0565] [ka]

[0566] To a stirred solution of intermediate 2 (846 mg, 4.238 mmol, 1 equivalent) in MeOH (10 mL), HCl (6 M) (2 mL) was added at room temperature. The resulting mixture was stirred at 60 °C for 4 hours. The resulting mixture was concentrated under reduced pressure. This yielded intermediate 3 (877 mg, 134.76%, crude) as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS (ESI) m / z [M+H] + =154. Step 3: Preparation of 7-bromo-4-chloro-5H-pyrrolo[3,2-c]pyridazine (intermediate 4)

[0567] [ka]

[0568] To a stirred solution of intermediate 3 (300 mg, 1.954 mmol, 1.35 equivalents) in DMF (5 mL), NBS (257.55 mg, 1.447 mmol, 1 equivalent) was added at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (10 mL). The precipitated solid was collected by filtration and washed with water (3 × 10 mL). This yielded intermediate 4 (136 mg, 40.43%) as a white solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] + =232. Step 4: Preparation of tert-butyl 2-{7-bromo-4-chloropyrrolo[3,2-c]pyridazine-5-yl}acetate (intermediate 5)

[0569] [ka]

[0570] Intermediate 4 (153 mg, 0.658 mmol, 1 equivalent) and Cs2CO3 (428.88 mg, 1.316 mmol, 2 equivalents) were stirred in DMF (2 mL) to which tert-butyl 2-bromoacetate (205.40 mg, 1.053 mmol, 1.6 equivalents) was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 0% to 70% over 30 minutes, detector, UV 230 nm. This yielded intermediate 5 (155 mg, 67.95%) as a yellow solid. LCMS(ESI)m / z[M+H] + =346. Step 5: Preparation of (tert-butyl2-(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}-4-chloropyrrolo[3,2-c]pyridazine-5-yl) acetate (intermediate 6)

[0571] [ka]

[0572] Intermediate 5 (145 mg, 0.418 mmol, 1 equivalent) in 1,4-dioxane (3 mL) and H2O (0.6 mL), and 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 (279.35 mg, 0.502 mmol, 1.2 equivalents) were added to a solution of these, along with Pd(dppf)Cl2 (30.61 mg, 0.042 mmol, 0.1 equivalent) and Cs2CO3 (408.91 mg, 1.254 mmol, 3 equivalents). The mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (30:1) to obtain intermediate 6 (214 mg, 73.48%) as a yellow solid. LCMS(ESI)m / z[M+H] + =696. Step 6: Preparation of tert-butyl 2-(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyrididine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}-4-(azetidine-1-yl)pyrrolo[3,2-c]pyridazine-5-yl) acetate (intermediate 7)

[0573] [ka]

[0574] To a stirred solution of intermediate 6 (189 mg, 0.271 mmol, 1 equivalent) and azetidine (23.25 mg, 0.407 mmol, 1.5 equivalents) in 1,4-dioxane (2 mL), Cs2CO3 (265.35 mg, 0.813 mmol, 3 equivalents) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (11.42 mg, 0.014 mmol, 0.05 equivalents) were added at room temperature. The resulting mixture was stirred at 100°C for 4 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (40:1) to obtain intermediate 7 (167 mg, 85.82%) as a yellow solid. LCMS(ESI)m / z[M+H] + =717. Step 7: Preparation of (7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyrididine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}-4-(azetidine-1-yl)pyrrolo[3,2-c]pyridazine-5-yl)acetic acid (intermediate 8)

[0575] [ka]

[0576] To a stirred solution of intermediate 7 (42 mg, 0.059 mmol, 1 equivalent) in THF (1 mL) and H2O (0.5 mL), LiOH.H2O (12.29 mg, 0.295 mmol, 5 equivalents) was added at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under vacuum. This yielded intermediate 8 (66 mg, 170.49%, crude) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] + =661. Step 8: Preparation of (2S,4R)-1-[(2S)-2-[2-(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyrididine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}-4-(azetidine-1-yl)pyrrolo[3,2-c]pyridazin-5-yl)acetamide]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (9))

[0577] [ka]

[0578] To a stirred solution of intermediate 8 in DMF (1 mL), TFA (68.34 mg, 0.600 mmol, 6 equivalents) was added at room temperature. The resulting mixture was stirred at room temperature for 2 minutes. The mixture was basicized to pH 9 with NMI (123.02 mg, 1.500 mmol, 15 equivalents). To the above mixture, (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (44.41 mg, 0.100 mmol, 1 equivalent) and TCFH (42.04 mg, 0.150 mmol, 1.5 equivalents) were added at room temperature. The resulting mixture was stirred at room temperature for a further 1 hour. The mixture was purified to compound 9 (28.6 mg, 24.41%) as an off-white solid by preparative HPLC using the following conditions (column: YMC-Actus Triart C18 EXRS, 30*150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 28%B to 47%B over 8 mins, wavelength: 254 nm / 220 nm, RT1 (min): 9.95). 1H NMR(300 MHz,DMSO-d6)δ 8.98-8.68(m,1H),8.32(s,1H),8.20-7.82(m,2H),7.53(s,1H),7.47-7.39(m,4H),7.37-7.32(m ,1H),7.19-6.75(m,2H),5.20-4.99(m,2H),4.98-4.90(m,2H),4.83-4.53(m,1H),4.47(t,J=7.8 Hz,1H),4.33-4.28(m,2H),4.25-4.10(m,6H),4.03-3.94(m,2H),3.75 (s,2H),3.67-3.61(m,3H),3.57-3.48(m,2H),3.46-3.43(m,1H),2.95- 2.86(m,4H),2.47(s,3H),2.42-2.32(m,2H),2.10-2.00(m,8H),1.93- 1.82(m,3H),1.44-1.19(m,3H),1.01-0.94(m,9H).LCMS(ESI)m / z[M+H] + =1087.60. The compounds listed in Table 6 were prepared using standard chemical operations and procedures similar to those used for the preparation of compound 39.

[0579] [Table 11-1]

[0580] [Table 11-2]

[0581] [Table 11-3]

[0582] [Table 11-4]

[0583] [Table 11-5]

[0584] Table 11-6

[0585] Table 11-7

[0586] Table 11-8

[0587] Table 11-9

[0588] Table 11-10

[0589] Table 11-11

[0590] Table 11-12

[0591] Table 11-13

[0592] Table 11-14

[0593] Table 11-15

[0594] [Table 11-16]

[0595] [Table 11-17]

[0596] Example 8: Preparation of (2S,4R)-1-((S)-2-(4-((3-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-yl)-1H-pyrrolo[3,2-c]pyridine-1-yl)methyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound 40)

[0597] [ka]

[0598] Step 1: Preparation of 3-bromo-1-(prop-2-in-1-yl)-1H-pyrrolo[3,2-c]pyridine (intermediate 2)

[0599] [ka]

[0600] To a stirred solution of 3-bromo-1H-pyrrolo[3,2-c]pyridine (300 mg, 1.523 mmol, 1 equivalent) and 3-bromoprop-1-yin (181.13 mg, 1.523 mmol, 1 equivalent) in DMF (3 mL), Cs2CO3 (1488.25 mg, 4.569 mmol, 3 equivalents) was gradually added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The desired product was detected by LC-MS. The mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 0% to 50% over 30 minutes, detector, UV 254 nm. This yielded intermediate 2 (194 mg, 54.20%) as a yellow solid. LC-MS (ESI) m / z: [M+H] + = 235 / 237. Step 2: Preparation of tert-butyl2-(4-((3-bromo-1H-pyrrolo[3,2-c]pyridine-1-yl)methyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoate (intermediate 3)

[0601] [ka]

[0602] To a stirred solution of 3-bromo-1-(prop-2-in-1-yl)pyrrolo[3,2-c]pyridine (181 mg, 0.770 mmol, 1 equivalent) and tert-butyl(2S)-2-azido-3-methylbutanoate (16.95 mg, 0.086 mmol, 2 equivalents) in MeOH (1.0 mL) and H2O (0.5 mL), CuSO4.5H2O (19.22 mg, 0.077 mmol, 0.1 equivalent) and sodium(5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2,5-dihydrofuran-2-one (4.23 mg, 0.021 mmol, 0.5 equivalent) was gradually added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The desired product could be detected by LC-MS. The mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 0% to 100% over 30 minutes, detector, and UV 254 nm. This yielded intermediate 3 (250 mg, 74.76%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 434 / 436. Step 3: Preparation of tert-butyl2-(4-((3-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-yl)-1H-pyrrolo[3,2-c]pyridine-1-yl)methyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoate (intermediate 4)

[0603] [ka]

[0604] Dioxane (0.5 mL), H2O (0.1 mL) containing tert-butyl 2-[4-({3-bromopyrrolo[3,2-c]pyridine-1-yl}methyl)-1,2,3-triazole-1-yl]-3-methylbutanoate (110 mg, 0.253 mmol, 1 equivalent) and 1-{3-[7-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroxymethyl To a stirred solution of dro-2H-quinoline-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (281.86 mg, 0.506 mmol, 2 equivalents), Cs2CO3 (247.55 mg, 0.759 mmol, 3 equivalents) and Pd(DtBPF)Cl2 (33.01 mg, 0.051 mmol, 0.2 equivalents) were gradually added at room temperature under an argon atmosphere. The resulting mixture was stirred at 80°C for 2 hours under an argon atmosphere. The desired product was detected by LC-MS. The resulting mixture was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (10:1) to obtain intermediate 4 (100 mg, 50.37%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =784. Step 4: Preparation of 2-(4-((3-(1-(5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-yl)-1H-pyrrolo[3,2-c]pyridine-1-yl)methyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoic acid (intermediate 5)

[0605] [ka]

[0606] A solution of tert-butyl 2-{4-[(3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}pyrrolo[3,2-c]pyridine-1-yl)methyl]-1,2,3-triazole-1-yl}-3-methylbutanoate (110 mg, 0.140 mmol, 1 equivalent) and LiOH (16.80 mg, 0.700 mmol, 5 equivalents) in MeOH (0.5 mL) and H2O (0.1 mL) was stirred at room temperature for 1 hour. The desired product was detected by LC-MS. The mixture was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% TFA), gradient from 0% to 100% over 30 minutes, detector, and UV 254 nm. This yielded intermediate 5 (90 mg, 88.13%) as a yellow solid. LCMS(ESI) m / z:[M+H] + =728. Step 5: Preparation of (2S,4R)-1-(2-(4-((3-(1-(5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-yl)-1H-pyrrolo[3,2-c]pyridine-1-yl)methyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (intermediate 6)

[0607] [ka]

[0608] 2-{4-[(3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}pyrrolo[3,2-c]pyridine-1-yl)methyl]-1,2,3-triazole-1-yl}-3-methylbutanoic acid (90 mg, 0.124 mmol, 1 gram) in DMF (1 mL) To a stirred solution of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (45.08 mg, 0.136 mmol, 1.1 equivalents), HATU (70.53 mg, 0.186 mmol, 1.5 equivalents) and DIEA (31.96 mg, 0.248 mmol, 2 equivalents) were gradually added at room temperature. The resulting mixture was stirred at room temperature for 0.5 hours. The desired product could be detected by LC-MS. The mixture was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3); mobile phase B: MeOH; flow rate: 60 mL / min; gradient: 57%B~64%B over 10 mins; wavelength: 254 nm / 220 nm; RT1 (min): 9.1) to obtain intermediate 6 (45 mg, 34.95%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =1041. Step 6: Preparation of (2S,4R)-1-((S)-2-(4-(3-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-yl)-1H-pyrrolo[3,2-c]pyridine-1-yl)methyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (7)

[0609] [ka]

[0610] Intermediate 6 (45 mg) was purified by preparative HPLC under the following conditions (column: CHIRAL ART Amylose-C NEO, 2*25 cm, 5 μm; mobile phase A: Hex (0.1% DEA) -- HPLC; mobile phase B: EtOH -- HPLC; flow rate: 20 mL / min; gradient: isocratic 50; wavelength: 210 / 282 nm; RT1 (min): 5.46; RT2 (min): 10.027; sample solvent: MEOH; injection volume: 0.3 mL; number of runs: 6) to obtain 7 (15.8 mg, 32.06%) as a white solid. 1 H NMR(300 MHz,DMSO-d6)δ 8.95(s,1H),8.74(s,1H),8.32-8.13(m,3H),7.65(d,J=5.8 Hz,1H),7.49-7.33(m,5H),7.23(s,1H),6.94(s,1H),6.66(t,J=55.4 Hz,1H),5.56(s,2H),5.29(d,J=9.7 Hz,1H),5.10-4.77(m,3H),4.41(t,J=7.8 Hz,1H),4.35-4.30(m,2H),4.23(s,2H),3.98(d,J=11.4 Hz,2H),3.82-3.72(m,3H),3.71-3.58(m,3H),3.49(t,3H),2.98-2.85(m,3H),2. 81-2.66(m,1H),2.46(s,3H),2.13-1.95(m,8H),1.91-1.77(m,3H),1.40(d,J=7.0 Hz,3H),1.02(d,J=6.6,4.3 Hz,3H),0.66(d,J=6.6,2.0 Hz,3H).LCMS(ESI)m / z:[M+H] + =1041.24. The compounds listed in Table 7 were prepared using standard chemical operations and procedures similar to those used for the preparation of compound 40.

[0611] [Table 12-1]

[0612] Table 12-2

[0613] Table 12-3

[0614] Table 12-4

[0615] Table 12-5

[0616] Table 12-6

[0617] Table 12-7

[0618] Table 12-8

[0619] Table 12-9

[0620] Table 12-10

[0621] Example 9: Preparation of (2S,4R)-1-[(2S)-2-[2-(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}imidazo[1,2-a]pyridine-6-yl)acetamide]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 41)

[0622] [ka]

[0623] Step 1: Preparation of 6-bromo-7-chloroimidazo[1,2-a]pyridine (intermediate 2)

[0624] [ka]

[0625] A solution of 5-bromo-4-chloropyridine-2-amine (2.0 g, 9.640 mmol, 1.00 equivalent) and chloroacetaldehyde (3.78 g, 48.200 mmol, 5.00 equivalent) in iPrOH (15 mL) was stirred at 80°C for 2 hours. The desired product was detected by LC-MS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% NH3, H2O), gradient from 40% to 70% over 10 minutes, detector, UV 254 nm. This yielded intermediate 2 (1.26 g, 29.98%) as a brown solid. LC-MS (ESI) m / z: [M+H] + =230. Step 2: Preparation of 4-{7-chloroimidazo[1,2-a]pyridine-6-yl}-1,2-oxazole (intermediate 3)

[0626] [ka]

[0627] To a stirred mixture of dioxane (15 mL) and intermediate 2 (1.25 g, 5.400 mmol, 1.00 equivalent) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (2.11 g, 10.800 mmol, 2.00 equivalent) in H2O (3 mL), K3PO4 (3.44 g, 16.200 mmol, 3.00 equivalent) and Pd(dtbpf)Cl2 (351.95 mg, 0.540 mmol, 0.100 equivalent) were gradually added at room temperature. The resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The desired product was detected by LC-MS. The resulting mixture was extracted with SiO2 (3 × 100 mL). The combined organic layers were washed with brine (3 × 30 mL) 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, MeCN in water (0.1% FA), gradient from 40% to 70% over 10 minutes, detector, and UV 254 nm. This yielded intermediate 3 (512 mg, 43.17%) as an off-white solid. LCMS(ESI) m / z:[M+H] + =219. Step 3: Preparation of 2-{7-chloroimidazo[1,2-a]pyridine-6-yl}acetonitrile (intermediate 4)

[0628] [ka]

[0629] Intermediate 3 (500.0 mg, 2.277 mmol, 1.00 equivalent) and KF (661.3 mg, 11.385 mmol, 5.00 equivalent) in MeOH (3 mL) and H2O (3 mL) were stirred at 120°C for 1 hour. The desired product was detected by LC-MS. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 50% to 70% over 15 minutes, detector, UV 254 nm. This yielded intermediate 4 (224 mg, 51.35%) as a white solid. LC-MS (ESI) m / z: [M + H] + =191. Step 4: Preparation of ethyl 2-{7-chloroimidazo[1,2-a]pyridine-6-yl}acetate (intermediate 5)

[0630] [ka]

[0631] Intermediate 4 (219.0 mg, 1.143 mmol, 1.00 equivalent) was stirred in H2SO4 (0.8 mL) and H2O (0.8 mL) at 0°C for 5 minutes, to which EtOH (1.6 mL) was gradually added at 0°C. The resulting mixture was stirred at 100°C for 2 hours. The desired product was detected by LC-MS. The reaction was quenched by adding water (10 mL) at 0°C. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% NH4HCO3), gradient from 10% to 50% over 10 minutes, detector, UV 254 nm. This yielded intermediate 5 (92 mg, 6.75%) as a white solid. LC-MS (ESI) m / z: [M + H] + =238. Step 5: Preparation of ethyl 2-(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}imidazo[1,2-a]pyridine-6-yl) acetate (intermediate 6)

[0632] [ka]

[0633] To a stirred mixture of dioxane (1 mL) and intermediate 5 (87.0 mg, 0.365 mmol, 1.00 equivalent) in H2O (0.2 mL), and 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 (304.3 mg, 0.547 mmol, 1.50 equivalent), XPhos Pd G3 (30.9 mg, 0.036 mmol, 0.1 equivalent) and Cs2CO3 (356.3 mg, 1.095 mmol, 3.00 equivalent) were gradually added at room temperature. The resulting mixture was stirred at 80°C for 2 hours under an N2 atmosphere. The desired product was detected by LC-MS. The resulting mixture was extracted with RINKAN (3 × 50 mL). The combined organic layer was washed with brine (3 × 20 mL) 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, MeCN in water (0.1% FA), gradient from 60% to 80% over 10 minutes, detector, and UV 254 nm. This yielded intermediate 6 (68 mg, 29.48%) as a yellow solid. LC-MS (ESI) m / z: [M + H] + =632. Step 6: Preparation of (7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}imidazo[1,2-a]pyridine-6-yl)acetic acid (intermediate 7)

[0634] [ka]

[0635] At room temperature, intermediate 6 (63 mg, 0.100 mmol, 1.00 equivalent) and LiOH (7.2 mg, 0.300 mmol, 3.00 equivalent) were gradually added to a stirred mixture of THF (3 mL) and H2O (1 mL). The resulting mixture was stirred at room temperature for 2 hours. The desired product was detected by LC-MS. The residue was acidified to pH 6 with 1 M HCl. The mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% TFA), gradient from 60% to 75% over 10 minutes, detector, UV 254 nm. This yielded intermediate 7 (54 mg, 89.69%) as a yellow solid. LC-MS (ESI) m / z: [M + H] + =604. Step 7: Preparation of (2S,4R)-1-[(2S)-2-[2-(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}imidazo[1,2-a]pyridine-6-yl)acetamide]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (8)

[0636] [ka]

[0637] To a stirred mixture of intermediate 7 (48.0 mg, 0.079 mmol, 2.00 equivalents) and NMI (26.1 mg, 0.316 mmol, 4.00 equivalents) in DMF (2 mL), (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (35.3 mg, 0.079 mmol, 1.00 equivalent) and TCFH (44.6 mg, 0.158 mmol, 2.00 equivalents) were gradually added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The desired product could be detected by LC-MS. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Shield RP C18 column 30*150 mm, 5 μm; mobile phase A: water (0.1% FA); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 16%B~33%B over 10 mins; wavelength: 254 nm / 220 nm; RT1 (min): 10.40) to obtain 8 (8.9 mg, 11.26%) as a pale white solid. LCMS(ESI)m / z:[M+H] + =1030.47. 1 H NMR(300 MHz,DMSO-d6)δ 8.95(s,1H),8.44(s,1H),8.13(s,1H),7.91(s,1H),7.76-7.51(m,2H),7.49-7.34(m,4H),7.21(d,J=9.0 Hz,1H),7.07-6.85(m,2H),6.76-6.19(m,1H),5.01-4.66(m,2H),4.52 -4.42(m,1H),4.42-4.14(m,5H),4.03-3.91(m,2H),3.79-3.69(m,1H), 3.67-3.57(m,4H),3.54-3.41(m,3H),3.41-3.31(m,2H),2.94-2.77(m ,4H),2.47(s,3H),2.14-1.94(m,8H),1.92-1.80(m,3H),1.40(d,J=6.9 Hz,3H),0.97-0.82(m,9H).). The compounds listed in Table 8 were prepared using standard chemical operations and procedures similar to those used for the preparation of compound 41.

[0638] Table 13-1

[0639] Table 13-2

[0640] Table 13-3

[0641] Table 13-4

[0642] Table 13-5

[0643] Table 13-6

[0644] Table 13-7

[0645] Table 13-8

[0646] Table 13-9

[0647] Table 13-10

[0648] [Table 13-11]

[0649] [Table 13-12]

[0650] [Table 13-13]

[0651] [Table 13-14]

[0652] Example 10: Preparation of (2S,4R)-1-[(2R)-2-[3-(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}imidazo[1,2-a]pyridine-3-yl)-1,2-oxazole-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 42)

[0653] [ka]

[0654] Step 1: Preparation of (E)-N-({7-bromoimidazo[1,2-a]pyridine-3-yl}methylidene)hydroxylamine (intermediate 2)

[0655] [ka]

[0656] To a stirred solution of 7-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (1.5 g, 6.665 mmol, 1 equivalent) in THF (10 mL) and H2O (10 mL), NH2OH.HCl (0.93 g, 13.330 mmol, 2 equivalents) and Na2CO3 (2.12 g, 19.995 mmol, 3 equivalents) were added at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with ELISA (3 × 50 mL). The combined organic layer was washed with brine (3 × 30 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded intermediate 2 (1.2 g, 75.00%) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + =240. Step 2: Preparation of (Z)-7-bromo-N-hydroxyimidazo[1,2-a]pyridine-3-carbonimidoyl chloride (intermediate 3)

[0657] [ka]

[0658] To a stirred solution of intermediate 2 (1.00 g, 4.166 mmol, 1 equivalent) and potassium chloride (0.31 g, 4.166 mmol, 1 equivalent) in H2O (20 mL) and MeOH (2 mL), potassium peroxymonosulfate (5.12 g, 8.332 mmol, 2 equivalents) was gradually added at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with SiO2 (3 × 50 mL). The combined organic layer was washed with brine (3 × 30 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded intermediate 3 (620 mg, 54.22%) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + =274. Step 3: Preparation of methyl 2-(3-{7-bromoimidazo[1,2-a]pyridine-3-yl}-1,2-oxazole-5-yl) acetate (intermediate 4)

[0659] [ka]

[0660] To a stirred solution of intermediate 3 (600.0 mg, 2.186 mmol, 1 equivalent) and methylbuto-3-inoate (857.7 mg, 8.744 mmol, 4 equivalents) in SiO2 (30 mL), NaHCO3 (918.1 mg, 10.930 mmol, 5 equivalents) was added at 0°C. The resulting mixture was stirred at room temperature for 6 hours. The resulting mixture was filtered, and the filter cake was washed with SiO2 (30 mL). The filtrate was concentrated under reduced pressure. The mixture was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), 55% gradient over 5 minutes, detector, UV254 nm. This yielded intermediate 4 (210 mg, 28.58%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =336. Step 4: Preparation of methyl 2-(3-{7-bromoimidazo[1,2-a]pyridine-3-yl}-1,2-oxazole-5-yl)-3-methylbutanoate (intermediate 5)

[0661] [ka]

[0662] To a stirred solution of intermediate 4 (200.0 mg, 0.595 mmol, 1 equivalent) and 2-iodopropane (1011.4 mg, 5.950 mmol, 10 equivalents) in THF (5 mL), Cs2CO3 (969.3 mg, 2.975 mmol, 5 equivalents) and MgSO4 (968.9 mg, 8.050 mmol, 13.53 equivalents) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80°C under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with  (3 × 50 mL). 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, MeCN in water (0.1% FA), gradient of 45% to 50% over 10 minutes, detector, UV 220 nm. This yielded intermediate 5 (97 mg, 40.88%) as a yellow oil. LCMS(ESI)m / z:[M+H] + =378. Step 5: Preparation of methyl 2-[3-(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}imidazo[1,2-a]pyridine-3-yl)-1,2-oxazole-5-yl]-3-methylbutanoate (intermediate 6)

[0663] [ka]

[0664] Pd(dppf)Cl2 (20.9 mg, 0.026 mmol, 0.1 equivalent) and Cs2CO3 (250.7 mg, 0.768 mmol, 3 equivalents) were added to a stirred solution of methyl intermediate 5 (97.0 mg, 0.256 mmol, 1 equivalent) in 1,4-dioxane (3 mL) and H2O (0.6 mL) and 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 (142.7 mg, 0.256 mmol, 1 equivalent) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. The resulting mixture was extracted with dimethylethanol (3 × 50 mL). The combined organic layer was washed with brine (3 × 20 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The mixture was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), 50% gradient over 5 minutes, detector, and UV 254 nm. This yielded intermediate 6 (112 mg, 60.00%) as a yellow solid. LCMS(ESI) m / z:[M+H] + =728. Step 6: Preparation of 2-[3-(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}imidazo[1,2-a]pyridine-3-yl)-1,2-oxazole-5-yl]-3-methylbutanoic acid (intermediate 7)

[0665] [ka]

[0666] A solution of intermediate 6 (104.0 mg, 0.143 mmol, 1 equivalent) and LiOH (29.9 mg, 0.715 mmol, 5 equivalents) in MeOH (3 mL) and H2O (1 mL) was stirred at 60°C for 1 hour. The mixture was neutralized to pH 7 with 1 M HCl. The resulting mixture was extracted with SiO2 (3 × 30 mL). The combined organic layer was washed with brine (3 × 30 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded intermediate 7 (95 mg, crude) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS(ESI)m / z:[M+H] + =714. Step 7: Preparation of (2S,4R)-1-{2-[3-(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}imidazo[1,2-a]pyridine-3-yl)-1,2-oxazole-5-yl]-3-methylbutanoyl}-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (intermediate 8)

[0667] [ka]

[0668] To a stirred solution of intermediate 7 (95 mg, 0.133 mmol, 1 equivalent) and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (44.1 mg, 0.133 mmol, 1 equivalent) in DMF (1 mL), TCFH (74.7 mg, 0.266 mmol, 2 equivalents) and NMI (32.8 mg, 0.399 mmol, 3 equivalents) were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The crude product was purified by preparative HPLC under the following conditions (column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5 m, mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 30%B to 50%B over 10 mins, wavelength: 254 nm / 220 nm, RT1 (min): 8.29) to obtain intermediate 8 (25 mg, 18.29%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =704. Step 8: Preparation of (2S,4R)-1-[(2R)-2-[3-(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}imidazo[1,2-a]pyridine-3-yl)-1,2-oxazole-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (9)

[0669] [ka]

[0670] Intermediate 8 was separated by preparative chiral chromatography under the following conditions (column: CHIRAL ART Cellulose-SB, 3*25cm, 5μm; mobile phase A: MtBE (10mM NH3-MeOH); mobile phase B: MEOH; flow rate: 40mL / min; gradient: isocratic 15; wavelength: 216 / 254nm; RT1 (min): 9.87; RT2 (min): 16.12; sample solvent: MEOH; injection volume: 2.0mL; number of runs: 2) to obtain the compound (11.6mg, 45.58%) as a white solid. LCMS[M+H] + =1027.30. 1 H NMR(300 MHz,DMSO-d6)δ 9.18(d,J=7.0 Hz,1H),8.93(s,1H),8.35(s,1H),8.22(d,J=7.8 Hz,1H),7.61(s,1H),7.50-7.33(m,4H),7.23-7.14(m,2H),7.02(s,1H),6.92(s,1H),6.73(t,J=54.7 Hz,1H),5.03-4.86(m,2H),4.47(t,J=7.7 Hz,1H),4.37-4.31(m,2H),4.23(s,2H),4.03-3.89(m,3H),3.88-3.72(m,3H),3.70-3.60(m,2H),3.57-3.42( m,3H),3.19-3.19(m,1H),2.95-2.73(m,4H),2.45(s,3H),2.14-1.96(m,8H),1.92-1.82(m,3H),1.48(d,J=7.0 Hz,3H),1.07(d,J=6.5 Hz,3H),0.93(d,J=6.4 Hz,3H). The compounds listed in Table 9 were prepared using standard chemical operations and procedures similar to those used for the preparation of compound 42.

[0671] [Table 14-1]

[0672] [Table 14-2]

[0673] Example 11: Preparation of (2S,4R)-1-[(2R)-2-{3-[(3R)-3-[3-(4-{[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl](methyl)amino}-2-(difluoromethyl)phenyl)pyrrolo[3,2-c]pyridine-1-yl]pyrrolidine-1-yl]-1,2-oxazole-5-yl}-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 43)

[0674] [ka]

[0675] Step 1: Preparation of 1-bromo-2-(difluoromethyl)-4-nitrobenzene (intermediate 2)

[0676] [ka]

[0677] To a stirred solution of 2-bromo-5-nitrobenzaldehyde (4 g, 17.390 mmol, 1 equivalent) in DCM (50 mL), DAST (14.02 g, 86.950 mmol, 5 equivalents) was added under a nitrogen atmosphere at 0°C. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction product was quenched with 10% NaHCO3 (200 mL) at 0°C. The resulting mixture was extracted with CH2Cl2 (3 × 300 mL). The combined organic layers were washed with brine (1 × 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 eluted with PE / Â(10:1) to obtain intermediate 2 (3.55 g, 81.00%) as a yellow liquid. GCMS(ESI) m / z = 253. Step 2: Preparation of 4-bromo-3-(difluoromethyl)aniline (intermediate 3)

[0678] [ka]

[0679] To a stirred solution of intermediate 2 (3.6 g, 14.285 mmol, 1 equivalent) and NH4Cl (3.82 g, 71.425 mmol, 5 equivalents) in MeOH (15 mL) and H2O (30 mL), iron dust (3.99 g, 71.425 mmol, 5 equivalents) was added at room temperature. The resulting mixture was stirred at 80°C for 3 hours. The resulting mixture was filtered, and the filter cake was washed with CH2Cl2 (3 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (1:1) to obtain intermediate 3 (2.85 g, 89.86%) as a yellow solid. LCMS(ESI)m / z[M+H] + = 222 / 224. Step 3: Preparation of N-[4-bromo-3-(difluoromethyl)phenyl]-1-(oxan-4-yl)pyrazolo[4,3-c]pyridine-3-amine (intermediate 4)

[0680] [ka]

[0681] To a stirred solution of intermediate 3 (500 mg, 2.252 mmol, 1 equivalent) and 3-bromo-1-(oxan-4-yl)pyrazolo[4,3-c]pyridine (635.36 mg, 2.252 mmol, 1 equivalent) in toluene (9 mL), Cs2CO3 (2201.15 mg, 6.756 mmol, 3 equivalents), XantPhos (130.30 mg, 0.225 mmol, 0.1 equivalent), and XantPhos Pd G4 (216.72 mg, 0.225 mmol, 0.1 equivalent) were added at room temperature. The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (10:1) to obtain intermediate 4 (855 mg, 89.70%) as a yellowish-brown solid. LCMS(ESI)m / z[M+H] + = 423 / 425. Step 4: Preparation of N-[4-bromo-3-(difluoromethyl)phenyl]-1-(oxan-4-yl)-4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-3-amine (intermediate 5)

[0682] [ka]

[0683] To a solution of intermediate 4 (850 mg, 2.008 mmol, 1 equivalent) in 15 mL of siRNA, PtO2 (4%, 340 mg) was added in a 100 mL round-bottom flask under a nitrogen atmosphere. The mixture was hydrogenated overnight at room temperature under a hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad, and concentrated under reduced pressure. This yielded intermediate 5 (770 mg, 89.73%) as a yellowish-brown solid. The crude product mixture was used directly in the next step without further purification. LCMS(ESI)m / z[M+H] + = 427 / 429. Step 5: Preparation of 1-(3-{[4-bromo-3-(difluoromethyl)phenyl]amino}-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-yl)ethanone (intermediate 6)

[0684] [ka]

[0685] To a stirred solution of intermediate 5 (760 mg, 1.779 mmol, 1 equivalent) and TEA (1799.85 mg, 17.790 mmol, 10 equivalents) in CH2Cl2 (9 mL), Ac2O (363.16 mg, 3.558 mmol, 2 equivalents) was added at 0°C. 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 eluted with CH2Cl2 / MeOH (10:1) to obtain intermediate 6 (710 mg, 85.05%) as a yellowish-brown solid. LCMS(ESI)m / z[M+H] + = 469 / 471. Step 6: Preparation of 1-(3-{[4-bromo-3-(difluoromethyl)phenyl](methyl)amino}-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-yl)ethanone (intermediate 7)

[0686] [ka]

[0687] To a stirred solution of intermediate 6 (350 mg, 0.746 mmol, 1 equivalent) and Cs2CO3 (728.93 mg, 2.238 mmol, 3 equivalents) in DMF (5 mL), CH3I (211.70 mg, 1.492 mmol, 2 equivalents) was added at room temperature. The resulting mixture was stirred at 60 °C for 2 hours. The mixture was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 0% to 100% over 30 minutes, detector, UV 254 nm. This yielded intermediate 7 (300 mg, 83.23%) as a yellow oil. LCMS(ESI)m / z[M+H] + = 483 / 485. Step 7: Preparation of 4-{[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl](methyl)amino}-2-(difluoromethyl)phenylboronic acid (intermediate 8)

[0688] [ka]

[0689] To a stirred solution of intermediate 7 (300 mg, 0.621 mmol, 1 equivalent) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (140.20 mg, 0.621 mmol, 1 equivalent) in 1,4-dioxane (5 mL), XPhos Pd G3 (52.54 mg, 0.062 mmol, 0.1 equivalent), KOAc (182.74 mg, 1.863 mmol, 3 equivalents), and XPhos (29.59 mg, 0.062 mmol, 0.1 equivalent) were added at room temperature. The resulting mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH2Cl2 / MeOH (10:1) elution to obtain intermediate 8 (270 mg, 97.04%) as a yellowish-brown oil. LCMS(ESI)m / z[M+H] + =449. Step 8: Preparation of methyl 2-{3-[(3R)-3-[3-(4-{[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl](methyl)amino}-2-(difluoromethyl)phenyl)pyrrolo[3,2-c]pyridine-1-yl]pyrroridine-1-yl]-1,2-oxazole-5-yl}-3-methylbutanoate (intermediate 9)

[0690] [ka]

[0691] To a stirred solution of 1,4-dioxane (2 mL) and intermediate 8 (150 mg, 0.335 mmol, 1 equivalent) in H2O (0.4 mL), and methyl 2-{3-[(3R)-3-{3-bromopyrrolo[3,2-c]pyridine-1-yl}pyrrolidine-1-yl]-1,2-oxazole-5-yl}-3-methylbutanoate (149.68 mg, 0.335 mmol, 1 equivalent), Cs2CO3 (327.07 mg, 1.005 mmol, 3 equivalents) and Pd(dtbpf)Cl2 (21.81 mg, 0.034 mmol, 0.1 equivalent) were added at room temperature. The resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 0% to 100% over 30 minutes, detector, UV 254 nm. This yielded intermediate 9 (166 mg, 64.35%) as a yellowish-brown oil. LCMS(ESI)m / z[M+H] + =771. Step 9: Preparation of 2-{3-[(3R)-3-[3-(4-{[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl](methyl)amino}-2-(difluoromethyl)phenyl)pyrrolo[3,2-c]pyridine-1-yl]pyrroridine-1-yl]-1,2-oxazole-5-yl}-3-methylbutanoic acid (intermediate 10)

[0692] [ka]

[0693] To a stirred solution of intermediate 9 (156 mg, 0.202 mmol, 1 equivalent) in THF (0.5 mL), MeOH (0.5 mL), and H2O (0.5 mL), LiOH (48.47 mg, 2.020 mmol, 10 equivalents) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified to pH 4 with concentrated HCl. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% HCl), gradient from 0% to 100% over 30 minutes, detector, UV 254 nm. This yielded intermediate 10 (120 mg, 78.35%) as a yellow oil. LCMS(ESI)m / z[M+H] + =757. Step 10: Preparation of (2S,4R)-1-(2-{3-[(3R)-3-[3-(4-{[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl](methyl)amino}-2-(difluoromethyl)phenyl)pyrrolo[3,2-c]pyridine-1-yl]pyrrolidine-1-yl]-1,2-oxazole-5-yl}-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (intermediate 11)

[0694] [ka]

[0695] To a stirred solution of intermediate 10 (110 mg, 0.145 mmol, 1 equivalent) in DMF (2 mL), (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (48.17 mg, 0.145 mmol, 1 equivalent), and DIEA (93.92 mg, 0.725 mmol, 5 equivalents), HATU (82.89 mg, 0.217 mmol, 1.5 equivalents) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 0% to 100% over 30 minutes, detector, UV 254 nm. This yielded intermediate 11 (95 mg, 61.07%) as a white solid. LC-MS(ESI)m / z[M+H] + =1070. Step 11: Preparation of (2S,4R)-1-[(2R)-2-{3-[(3R)-3-[3-(4-{[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl](methyl)amino}-2-(difluoromethyl)phenyl)pyrrolo[3,2-c]pyridine-1-yl]pyrrolidine-1-yl]-1,2-oxazole-5-yl}-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (12)

[0696] [ka]

[0697] Intermediate 11 (93 mg, 0.087 mmol, 1 equivalent) was purified by preparative chiralization under the following conditions (column: CHIRALPAK ID, 2*25 cm, 5 μm; mobile phase A: MtBE (10 mM NH3-MeOH); mobile phase B: MEOH; flow rate: 20 mL / min; gradient: isocratic 30; wavelength: 220 / 254 nm; RT1 (min): 8.0; RT2 (min): 15.0; sample solvent: MeOH:DCM = 1:2; injection volume: 0.3 mL; number of runs: 3) to obtain 12 (14.8 mg, 15.48%) as a white solid. 1 H NMR(300 MHz,DMSO-d6)δ 8.95(s,1H),8.70(s,1H),8.33-8.10(m,2H),7.66(d,J=5.8 Hz,1H),7.50-7.35(m,6H),7.16(d,J=2.6 Hz,1H),7.09-6.95(m,1H),6.99-6.58(m,1H),6.02(s,1H),5.46-5.36(m,1H),4.99-4.83(m,2H),4.42(t,J=7.5 Hz,1H),4.35-4.27(m,2H),4.15(s,2H),4.02-3.94(m,2H),3.87-3.79(m,1H),3.7 8-3.71(m,2H),3.66-3.56(m,3H),3.53-3.48(m,2H),3.47-3.39(m,2H),3.35(s,3 H),2.92-2.70(m,2H),2.65-2.56(m,2H),2.47(s,3H),2.46-2.41(m,1H),2.32-2. 15(m,1H),2.11-1.97(m,6H),1.92-1.82(m,3H),1.51-1.37(m,3H),0.98(d,J=6.5 Hz,3H),0.84(d,J=6.8 Hz,3H).LCMS(ESI)m / z[M+H] + =1070.50. The compounds listed in Table 10 were prepared using standard chemical operations and procedures similar to those used for the preparation of compound 43.

[0698] [Table 15-1]

[0699] Table 15-2

[0700] Table 15-3

[0701] Table 15-4

[0702] Table 15-5

[0703] Table 15-6

[0704] Table 15-7

[0705] Table 15-8

[0706] Table 15-9

[0707] Table 15-10

[0708] Table 15-11

[0709] Table 15-12

[0710] Table 15-13

[0711] Table 15-14

[0712] Table 15-15

[0713] Table 15-16

[0714] Table 15-17

[0715] Table 15-18

[0716] Table 15-19

[0717] Table 15-20

[0718] Table 15-21

[0719] Example 12: Preparation of 7-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)imidazo[1,2-a]pyrimidine-3-carboxamide (compound 44)

[0720] [ka]

[0721] Step 1: Preparation of (E)-N'-(4-methoxypyrimidine-2-yl)-N,N-dimethylformimidoamide (Intermediate 2)

[0722] [ka]

[0723] A solution of 4-methoxypyrimidine-2-amine (1.00 g, 7.992 mmol, 1 equivalent) and DMF-DMA (1.90 g, 15.984 mmol, 2 equivalents) in DMF (10 mL) was stirred at 60°C for 2 hours. The desired product was detected by LC-MS. The resulting crude mixture was used directly in the next step without further purification. LC-MS(ESI)m / z:[M+H] + =181. Step 2: Preparation of ethyl 7-methoxyimidazo[1,2-a]pyrimidine-3-carboxylate (intermediate 3)

[0724] [ka]

[0725] To a stirred solution of intermediate 2 and ethyl bromoacetate (1.11 g, 6.659 mmol, 1.2 equivalents) in DMF (10 mL), NaHCO3 (1.40 g, 16.647 mmol, 3 equivalents) and KI (0.18 g, 1.110 mmol, 0.2 equivalents) were gradually added at room temperature. The resulting mixture was stirred at 80°C for 2 hours. The desired product was detected by LC-MS. The resulting mixture was extracted with SiO2 (3 × 50 mL). The combined organic layer was washed with brine (3 × 20 mL) 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, MeCN in water (0.1% FA), gradient from 10% to 50% over 10 minutes, detector, UV254 nm. This yielded intermediate 3 (497 mg, 40.49%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =222. Step 3: Preparation of ethyl 7-chloroimidazo[1,2-a]pyrimidine-3-carboxylate (intermediate 4)

[0726] [ka]

[0727] To a stirred solution of intermediate 3 (200.0 mg, 0.904 mmol, 1 equivalent) and POCl3 (1.38 g, 9.040 mmol, 10 equivalents) in toluene (10 mL), DIEA (233.7 mg, 1.808 mmol, 2 equivalents) was gradually added at room temperature. The resulting mixture was stirred at 100 °C for 72 hours. The desired product was detected by LC-MS. The mixture was acidified to pH 7.0 with DIEA. The resulting mixture was extracted with siRNA (3 × 50 mL). The combined organic layer was washed with brine (3 × 20 mL) 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, MeCN in water (0.1% FA), gradient from 0% to 100% over 15 minutes, detector, UV 254 nm. This yielded intermediate 4 (65 mg, 31.92%) as a brown solid. LC-MS(ESI)m / z:[M+H] + =226. Step 4: Preparation of 7-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-yl)imidazo[1,2-a]pyrimidine-3-carboxylate (intermediate 5)

[0728] [ka]

[0729] To a stirred solution of dioxane (5 mL) and intermediate 4 (60.0 mg, 0.266 mmol, 1 equivalent) in H2O (1 mL) and 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 (177.6 mg, 0.319 mmol, 1.2 equivalents), Pd(dppf)Cl2 (19.5 mg, 0.027 mmol, 0.1 equivalent) and Cs2CO3 (259.9 mg, 0.798 mmol, 3 equivalents) were gradually added at room temperature. The resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The desired product was detected by LC-MS. The resulting mixture was extracted with ₹ (3 × 50 mL). The combined organic layer was washed with brine (3 × 20 mL) 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, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes, detector, and UV 254 nm. This yielded intermediate 5 (56 mg, 33.98%) as a yellow solid. LC-MS(ESI) m / z:[M+H] + =620. Step 5: Preparation of 7-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-yl)imidazo[1,2-a]pyrimidine-3-carboxylic acid (intermediate 6)

[0730] [ka]

[0731] A solution of intermediate 5 (56.0 mg, 0.090 mmol, 1 equivalent) and LiOH (10.8 mg, 0.450 mmol, 5 equivalents) in THF (3 mL) and H2O (1 mL) was stirred at room temperature for 2 hours. The desired product was detected by LC-MS. The mixture was acidified to pH 5.0 with 1 M HCl. The mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% TFA), gradient from 0% to 100% over 15 minutes, detector, UV 254 nm. This yielded intermediate 6 (22 mg, 41.21%) as a white solid. LC-MS (ESI) m / z: [M + H] + = 592. Step 6: Preparation of 7-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)imidazo[1,2-a]pyrimidine-3-carboxamide (7)

[0732] [ka]

[0733] To a stirred solution of intermediate 6 (19.0 mg, 0.032 mmol, 1 equivalent) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-N-benzyl-4-hydroxypyrrolidine-2-carboxamide (11.8 mg, 0.035 mmol, 1.1 equivalents) in DMF (1 mL), TCFH (13.5 mg, 0.048 mmol, 1.5 equivalents) and NMI (6.6 mg, 0.080 mmol, 2.5 equivalents) were gradually added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The desired product could be detected by LC-MS. The crude product was purified by preparative HPLC under the following conditions (column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5 m, mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 31%B to 51%B over 10 min, wavelength: 254 nm / 220 nm, RT1 (min): 8.02) to obtain 7 (10.1 mg, 30.16%) as a pale yellow solid. LCMS(ESI)m / z:[M+H] + =1004.30. 1 H NMR(300 MHz,DMSO-d6)δ 9.68(d,J=7.4 Hz,1H),8.96(s,1H),8.82(s,1H),8.38(m,1H),8.25-8.10(m,1H),7.78-7.51(m,3H),7.41(m,4H),7.00(s,1H),4.88(d,J=9.2 Hz,1H),4.58-4.28(m,5H),4.23(s,2H),4.03-3.92(m,2H),3.83-3.72(m,3H),3.71-3.64(m,2H),3. 63-3.36(m,4H),3.02-2.76(m,4H),2.47(s,3H),2.17-1.95(m,9H),1.93-1.82(m,2H),1.08(s,9H). Example 13: Preparation of (2S,4R)-N-((S)-3-(4-(7-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-yl)imidazo[1,2-a]pyridine-3-yl)piperazine-1-yl)--1-(4-(4-methylthiazole-5-yl)phenyl)-3-oxopropyl)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazole-5-yl)butanoyl)pyrrolidine-2-carboxamide (compound 195)

[0734] [ka]

[0735] Step 1: Di-tert-butyl 4,4'-(1,2-bis(1H-benzo[d][1,2,3]triazole-1-yl)ethane-1,2-diyl)bis(piperazine-1-carboxylate) (Intermediate 2)

[0736] [ka]

[0737] A mixture of 1H-benzo[d][1,2,3]triazole (300.0 mg, 2.521 mmol, 1.00 equivalent), tert-butylpiperazine-1-carboxylate (937.8 mg, 4.502 mmol, 2.00 equivalent), and glyoxal (261.1 mg, 4.502 mmol, 2.00 equivalent) in EtOH (5 mL) was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was used directly in the next step without further purification.

[0738] Step 2: tert-butyl 4-(7-bromoimidazo[1,2-a]pyridine-3-yl)piperazine-1-carboxylate (intermediate 3)

[0739] [ka]

[0740] A mixture of intermediate 2 (331.0 mg, 0.523 mmol, 1.00 equivalent) and 4-bromopyridine-2-amine (71.9 mg, 0.418 mmol, 0.8 equivalent) in DCE (3 mL) was stirred at 100°C for 2 hours. Then, powdered KOH (87.9 mg, 1.569 mmol, 3.00 equivalent) was added, and the mixture was stirred at room temperature for 12 hours. The desired product was detected by LC-MS. The resulting mixture was diluted with water (30 mL) and extracted with RINKAN (3 × 50 mL). The combined organic layer was washed with brine (3 × 30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions (column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes, detector, UV 254 nm) to obtain intermediate 3 (141 mg, 70.94%) as a colorless oil. LCMS(ESI)m / z[M+H] + =381. Step 3: tert-butyl4-(7-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-yl)imidazo[1,2-a]pyridine-3-yl)piperazine-1-carboxylate (intermediate 4)

[0741] [ka]

[0742] Intermediate 3 (120.0 mg, 0.315 mmol, 1.00 equivalent) in 1,4-dioxane (5 mL) and H2O (1 mL) and 1-(3-(7-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-yl)-1-(tetrahydro-2H-pyran-4- A mixture of (149.2 mg, 0.315 mmol, 1.00 equivalent) and Cs2CO3 (204.7 mg, 0.630 mmol, 2.00 equivalent) and Pd(dppf)Cl2 (25.7 mg, 0.031 mmol, 0.10 equivalent) was added. The mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The desired product was detected by LC-MS. The resulting mixture was extracted with siRNA (3 × 30 mL). The combined organic layer was washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions (column, C18 silica gel, mobile gel, mobile phase, MeCN in water (0.1% TFA), gradient from 0% to 80% over 25 minutes, detector, UV 254 nm) to obtain intermediate 4 (128 mg, 55.66%) as a pale yellow solid. LCMS(ESI)m / z[M+H] + =731. Step 4: 1-(3-(7-(difluoromethyl)-6-(3-(piperazin-1-yl)imidazo[1,2-a]pyridine-7-yl)-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 (intermediate 5)

[0743] [ka]

[0744] A mixture of intermediate 4 (120.0 mg, 0.164 mmol, 1.00 equivalent) in TFA (1 mL) and DCM (3 mL) was stirred at room temperature for 1 hour. The desired product was detected by LC-MS. The crude product was purified by reverse-phase flash chromatography under the following conditions (column, C18 silica gel, mobile phase, MeCN in water (0.1% TFA), gradient from 0% to 80% over 25 minutes, detector, UV 254 nm) to obtain intermediate 5 (96 mg, 92.91%) as a pale yellow solid. LC-MS (ESI) m / z [M+H] + =631. Step 5: (2S,4R)-N-((S)-3-(4-(7-(1-(5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-yl)imidazo[1,2-a]pyridine-3-yl)piperazine-1-yl)-1-(4-(4-methylthiazole-5-yl)phenyl)-3-oxopropyl)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazole-5-yl)butanoyl)pyrrolidine-2-carboxamide (compound 195)

[0745] [ka]

[0746] A mixture of intermediate 5 (90.0 mg, 0.142 mmol, 1.00 equivalent), (S)-3-((2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazole-5-yl)butanoyl)pyrrolidine-2-carboxamide)-3-(4-(4-methylthiazole-5-yl)phenyl)propanoic acid (76.6 mg, 0.142 mmol, 1.00 equivalent), TCFH (79.5 mg, 0.284 mmol, 2.00 equivalent), and NMI (34.9 mg, 0.426 mmol, 3.00 equivalent) in DMF (2 mL) was stirred at room temperature for 2 hours. The desired product was detected by LC-MS. The crude product was purified by preparative HPLC under the following conditions (column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5 m, mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 15%B to 35%B in 10 mins, wavelength: 254 nm / 220 nm, RT1 (min): 10.1) to obtain compound 195 (26.1 mg, 15.95%) as a white solid. 1 H NMR(300 MHz,DMSO-d6)δ 8.96(s,1H),8.69(d,J=7.0 Hz,1H),8.27(d,J=8.1 Hz,1H),7.85(s,1H),7.73(s,1H),7.46(s,5H),7.20(s,1H),6.94(s,1H),6.72(t,J=54.6 Hz,1H),6.20(s,1H),5.37-5.23(m,1H),4.45-4.19(m,5H),4.03-3.93(m,2H),3.86-3.62(m,12H),3.12-2.98( m,5H),2.97-2.85(m,5H),2.46(s,3H),2.37-2.16(m,5H),2.13-1.96(m,9H),1.91-1.83(m,3H),0.99(d,J=6.5 Hz,3H),0.82(d,J=6.7 Hz,3H).LCMS(ESI)m / z[M+H] + =1153.45. The compounds listed in Table 11 were prepared using standard chemical operations and procedures similar to those used for the preparation of compound 195.

[0747] Table 16-1

[0748] Table 16-2

[0749] Table 16-3

[0750] Table 16-4

[0751] Table 16-5

[0752] Table 16-6

[0753] Table 16-7

[0754] Table 16-8

[0755] Table 16-9

[0756] Table 16-10

[0757] Table 16-11

[0758] Example 14: Preparation of (2S,4R)-N-((S)-3-(4-(7-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-fluoro-4-methyl-1,2,3,4-tetrahydroquinoxaline-6-yl)imidazo[1,2-a]pyridine-3-yl)piperazine-1-yl)-1-(4-(4-methylthiazole-5-yl)phenyl)-3-oxopropyl)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazole-5-yl)butanoyl)pyrrolidine-2-carboxamide (compound 143) 1-{3-[7-fluoro-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydroquinoxaline-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-yl}ethenone (intermediate A)

[0759] [ka]

[0760] Step 1: 2-[(5-chloro-4-fluoro-2-nitrophenyl)(methyl)amino]ethanol (intermediate 2)

[0761] [ka]

[0762] To a stirred mixture of 1-chloro-2,5-difluoro-4-nitrobenzene (2 g, 10.334 mmol, 1 equivalent) and methylethanolamine (830.18 uL, 10.334 mmol, 1.00 equivalent) in THF (70 mL), TEA (5.75 mL, 41.336 mmol, 4 equivalents) was gradually added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% TFA), gradient from 10% to 100% over 30 minutes, detector, UV 254 nm) to obtain intermediate 2 (2.05 g, 79.78%) as a red oil. LCMS(ESI) m / z:[M+H] + =249. Step 2: 2-[(5-chloro-4-fluoro-2-nitrophenyl)(methyl)amino]ethylmethanesulfonate (intermediate 3)

[0763] [ka]

[0764] To a stirred mixture of intermediate 2 (2.04 g, 8.205 mmol, 1 equivalent) and MsCl (952.46 uL, 12.308 mmol, 1.50 equivalents) in DCM (12 mL), TEA (3.42 mL, 24.615 mmol, 3 equivalents) and DMAP (100.24 mg, 0.821 mmol, 0.1 equivalent) were added. 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 eluted with PE / SiO(1:1) to obtain intermediate 3 (2.56 g, 95.50%) as a red oil. LCMS(ESI)m / z:[M+H] + =327 Step 3: 7-Chloro-6-fluoro-1-methyl-3,4-dihydro-2H-quinoxaline (Intermediate 4)

[0765] [ka]

[0766] Intermediate 3 (2.5 g, 7.652 mmol, 1 equivalent) and Fe (3419 mg, 76.10 mmol, 10 equivalents) in H2O (5 mL) and EtOH (36 mL) were stirred, and 2N HCl (20 mL) was added. The resulting mixture was stirred at 90°C for 2 hours under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3 × 30 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with H2O (100 mL). The resulting mixture was extracted with siRNA (3 × 60 mL). The combined organic layer was washed with brine (3 × 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 PE / siRNA (5:1) to obtain intermediate 4 (650 mg, 42.34%) as a black solid. LCMS(ESI)m / z:[M+H] + =201. Step 4: 1-[3-(6-chloro-7-fluoro-4-methyl-2,3-dihydroquinoxaline-1-yl)-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-yl]etanone (intermediate 5)

[0767] [ka]

[0768] To a stirred solution of intermediate 4 (165.06 mg, 0.823 mmol, 1.00 equivalent) and 1-[3-bromo-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-yl]ethanone (270 mg, 0.823 mmol, 1.00 equivalent) in toluene (5 mL), t-BuONa (237.18 mg, 2.469 mmol, 3 equivalents) and XPhos Pd G3 (69.63 mg, 0.082 mmol, 0.1 equivalent) were gradually added at 20°C under an argon atmosphere. The resulting mixture was stirred at 100°C for 1 hour under an argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (40:1) to obtain intermediate 5 (365 mg, 99.05%) as a yellow solid. LCMS(ESI)m / z:[M+H] + = 448. Step 5: 1-{3-[7-fluoro-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydroquinoxaline-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-yl}ethanone (intermediate 6)

[0769] [ka]

[0770] To a stirred solution of intermediate 5 (500 mg, 1.116 mmol, 1 equivalent) and bis(pinacolate)diborone (566.91 mg, 2.232 mmol, 2.00 equivalent) in 1,4-dioxane (4 mL), KOAc (328.64 mg, 3.348 mmol, 3.00 equivalent) and XPhos Pd G3 (0.94 mg, 0.001 mmol, 0.1 equivalent) were gradually added under an argon atmosphere at 20°C. The resulting mixture was stirred under an argon atmosphere at 80°C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (20:1) to obtain intermediate 6 (750 mg) as a yellowish-brown solid. LCMS(ESI)m / z:[M+H] + =540.

[0771] [ka]

[0772] Step 1: tert-butyl4-(7-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-fluoro-4-methyl-1,2,3,4-tetrahydroquinoxaline-6-yl)imidazo[1,2-a]pyridine-3-yl)piperazine-1-carboxylate (intermediate 2)

[0773] [ka]

[0774] A stirred solution of 1-(3-(7-fluoro-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoxaline-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 (141.49 mg, 0.262 mmol, 2 equivalents) and tert-butyl4-(7-bromoimidazo[1,2-a]pyridine-3-yl)piperazine-1-carboxylate (50 mg, 0.131 mmol, 1.00 equivalent) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was prepared by adding XPhos Pd G3 (11.10 mg, 0.013 mmol, 0.1 equivalent) and Cs2CO3 (128 mg, 0.393 mmol, 3 equivalents) were added gradually at room temperature under an argon atmosphere. The resulting mixture was stirred at 80°C for 2 hours under an argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (12:1) to obtain intermediate 2 (45 mg, 43.26%) as a yellow solid. LCMS(ESI)m / z:[M+H] + =714. Step 2: 1-(3-(7-fluoro-4-methyl-6-(3-(piperazin-1-yl)imidazo[1,2-a]pyridine-7-yl)-3,4-dihydroquinoxaline-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 (intermediate 3)

[0775] [ka]

[0776] A solution of intermediate 2 (45 mg, 0.063 mmol, 1 equivalent) and hydrogen chloride (4.0 M in 1,4-dioxane) (1 mL) in DCM (1 mL) was stirred at room temperature under an atmospheric atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. This yielded intermediate 3 (43 mg, 80% purity) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS(ESI) m / z:[M+H] + =614. Step 3: (2S,4R)-N-((S)-3-(4-(7-(1-(5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)-7-fluoro-4-methyl-1,2,3,4-tetradloquinoxaline-6-yl)imidazo[1,2-a]pyridine-3-yl)piperazine-1-yl)-1-(4-(4-methylthiazole-5-yl)phenyl)-3-oxopropyl)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazole-5-yl)butanoyl]pyrrolidine-2-carboxamide (compound 143)

[0777] [ka]

[0778] To a stirred solution of intermediate 3 (27.25 mg, 0.044 mmol, 1.2 equivalents) and (S)-3-((2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazole-5-yl)butanoyl)pyrrolidine-2-carboxamide)-3-(4-(4-methylthiazole-5-yl)phenyl)propanoic acid (20 mg, 0.037 mmol, 1.00 equivalent) in DMF (1 mL), NMI (9.11 mg, 0.111 mmol, 3 equivalents) and TCFH (20.76 mg, 0.074 mmol, 2 equivalents) were gradually added at room temperature under an air atmosphere. The resulting mixture was stirred at room temperature under an air atmosphere for 2 hours. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 10% to 100% over 30 minutes, detector, and UV 254 nm. This yielded compound 143 (13 mg, 30.74%) as a yellow solid. 1 H NMR(300 MHz,DMSO-d6)δ 8.96(s,1H),8.63-8.11(m,2H),7.59(s,1H),7.46(s,4H),7.23(s,1H),7.12(d,J=7.1 Hz,1H),6.72(d,J=7.7 Hz,1H),6.34-6.23(m,1H),6.23-6.14(m,1H),5.34-5.26(m,1H),4.98-4.82(m,1H) ,4.79-4.38(m,1H),4.37-4.26(m,2H),4.23(s,2H),4.03-3.94(m,2H),3.84-3.62(m ,10H),3.56-3.37(m,3H),3.36-3.28(m,2H),3.07-2.70(m,11H),2.46(s,3H),2.35- 2.24(m,1H),2.23-2.16(m,3H),2.11-1.98(m,6H),1.91-1.81(m,3H),0.99(d,J=6.5 Hz,3H),0.88-0.77(m,3H).LCMS(ESI)m / z:[M+H] + =1136.65. Example 15: Preparation of (2S,4R)-1-[(2R)-2-[3-(1'-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}-2'H-spiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine]-1-yl)-1,2-oxazole-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 91)

[0779] [ka]

[0780] Step 1: tert-butyl 3-(3-bromopyridine-4-yl)-3-cyanoazetidine-1-carboxylate (intermediate 2)

[0781] [ka]

[0782] A solution of 3-bromo-4-fluoropyridine (1 g, 5.682 mmol, 1 equivalent) and tert-butyl 3-cyanoazetidine-1-carboxylate (2.07 g, 11.364 mmol, 2 equivalents) in THF (15 mL) was stirred at -78°C for 30 minutes under a nitrogen atmosphere. LDA (in 2 M THF) (1.22 g, 11.364 mmol, 2 equivalents) was gradually added to the mixture over 10 minutes at -78°C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / SiO(1:1) to obtain intermediate 2 (1.2 g, 62.44%) as a yellow oil. LCMS(ESI)m / z[M+H] + =338 / 340. Step 2: tert-butyl 3-(aminomethyl)-3-(3-bromopyridine-4-yl)azetidine-1-carboxylate (intermediate 3)

[0783] [ka]

[0784] A solution of intermediate 2 (6 g, 17.74 mmol, 1 equivalent) and lithium aluminum hydride (2.0 M in THF) (17.8 mL, 35.48 mmol, 2 equivalents) in THF (10 mL) was stirred at -10°C for 1 hour under a nitrogen atmosphere. The reaction mixture was quenched with water / ice at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using a column, C18 silica gel, mobile phase, MeCN (10 mmol / L NH4HCO3) in water, a 10% to 100% gradient over 20 minutes, a detector, and UV 254 nm, to obtain intermediate 3 (400 mg, 6.59% yield, 95% purity) as a white solid. LCMS(ESI)m / z[M+H] + = 342 / 344. Step 3: tert-butyl1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine]-1-carboxylate (intermediate 4)

[0785] [ka]

[0786] Intermediate 3 (120 mg, 0.351 mmol, 1 equivalent) and 3-chloropyridine;{1,3-bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazole-2-yl}dichloropalladium (68.29 mg, 0.070 mmol, 0.2 equivalents) were stirred in 4 mL of 1,4-dioxane. Dicethium carbonate (1+) (342.73 mg, 1.053 mmol, 3 equivalents) was gradually added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN (10 mmol / L NH4HCO3) in water, gradient from 10% to 100% over 20 minutes, detector, and UV 254 nm, to obtain intermediate 4 (52 mg) as a white solid. LCMS(ESI)m / z[M+H] + =262. Step 4: tert-butyl1'-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-yl}-2'H-spiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine]-1-carboxylate (intermediate 5)

[0787] [ka]

[0788] Intermediate 4 (50 mg, 0.191 mmol, 1 equivalent) and 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 (97.46 mg, 0.191 mmol, 1 equivalent) were stirred in 1,4-dioxane (1 mL). XPhos Pd G3 (3.24 mg, 0.004 mmol, 0.2 equivalents) and Cs2CO3 (187.02 mg, 0.573 ...

Claims

1. A compound having the structure of formula I, A-L-B Equation I During the ceremony, A is the EP300 bonding portion, B is the decomposition part, L has the structure of formula II, A １ -C-(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, Each C is independently either absent, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl. E is non-existence, O, S, NR Ｎ , optionally substituted C １～１０ alkylene, optionally substituted C ２～１０ alkenylene, optionally substituted C ２～１０ alkynylene, optionally substituted C ２ ~C １０ polyethylene glycol, optionally substituted C １～１０ heteroalkylene, optionally substituted C ２～１０ carbocyclylene, or optionally substituted C ２～１０ heterocyclylene, and Each R Ｎ However, independently, H and C are substituted by choice. １～４ Alkyl, optionally substituted C ２～４ Alkenyl, C substituted by choice ２～４ Alkinyl, optionally replaced with C ２～６ Heterocyclylene, C by optional substitution ６～１２ A C replaced by an aryl or of any choice. １～７ It is heteroalkyl, F is replaced by C by arbitrary choice. ３ ~C １０ Carbocyclylene, optionally substituted with C ２～１２ 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 EP300 connecting portion has the following structure: 【Chemistry 1】 It has, in the formula, R １ However, C １～１２ Alkyl, C ２～１２ Alkenil, C ２～１２ Alkynyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R １ Each C １～１２ Alkyl, C ２～１２ Alkenil, C ２～１２ Alkynnyl, 3-12 membered carbon rings, and 3-12 membered hetero rings are A １ and / or one or more base R ｂ It is replaced by an optional selection, R ２ However, 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 , -O-R ａ , -S-R ａ , -O-C(O)-R ａ , -O-C(O)-OR ａ , -C(O)-R ａ , -C(O)-OR ａ , -S(O)-R ａ , -S(O) ２ -R ａ , -O-C(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 is optionally substituted with one or more substituents selected from R ３ However, C １～１２ Alkyl, C ２～１２ Alkenil, C ２～１２ Alkynyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R ３ Each C １～１２ Alkyl, C ２～１２ Alkenil, C ２～１２ 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, C １～４ Alkyl, C ２～４ Alkenil, C ２～４ Alkynyl, 3-5 membered carbon ring, 3-5 membered hetero ring, -C(O)-N(R ｈ ) ２ , -S(O)-N(R ｈ ) ２ , -S(O) ２ -N(R) ｈ ) ２ , -C(O)-R ｈ , -C(O)-OR ｈ , -S(O)-R ｈ , or -S(O) ２ -R ｈ And any C １～４ Alkyl, C ２～４ Alkenil, C ２～４ Alkynnyls, 3- to 5-membered carbon rings, and 3- to 5-membered heterorings are A １ , and / or independently, -F, -Cl, -Br, -I, 3- to 5-membered carbon rings, -C(O)-N(R ｈ ) ２ , -S(O)-N(R ｈ ) ２ , -S(O) ２ -N(R) ｈ ) ２ , -O-R ｈ , -S-R ｈ , -O-C(O)-R ｈ , -O-C(O)-OR ｈ , -C(O)-R ｈ , -C(O)-OR ｈ , -S(O)-R ｈ , -S(O) ２ -R ｈ , -O-C(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 )-S(O)-R ｈ , -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 １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, and C ３～１２ It is a heterocycline, and each C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, carbocyclyl, and heterocyclyl can be independently classified as oxo, halo, amino, hydroxyl, or C. １～６ 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. 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. １～３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｂ However, independently, oxo, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, Carbocyclyl, C ３～１２ Heterocyclyl, C ２～９ Ariel, C ２～１０ 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 , -O-R ｃ , -S-R ｃ , -O-C(O)-OR ｃ , -O-C(O)-OR ｃ , -C(O)-R ｃ , -C(O)-OR ｃ , -S(O)-R ｃ , -S(O) ２ -R ｃ , -O-C(O)-N(R ｃ ) ２ , -N(R ｃ )-C(O)-OR ｃ , -N(R ｃ )-C(O)-N(R ｃ ) ２ , -N(R ｃ )-C(O)-R ｃ , -N(R ｃ )-S(O)-R ｃ , -N(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 １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are A １ , and / or independently, oxo, halo, -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 , -O-R ｃ , -S-R ｃ , -O-C(O)-R ｃ , -C(O)-R ｃ , -S(O)-R ｃ , -S(O) ２ -R ｃ , -C(O)-N(R ｃ ) ２ , -N(R ｃ )-C(O)-R ｃ , -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 １～６ It is optionally substituted with one or more groups selected from alkyl groups. Each R ｃ However, independently, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, carbocykrill, or heterocyclyl, any C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, and C ３～１２ 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 , -O-C(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 １～６ 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. １～６ Alkyl, cyano, -N(R) ｄ ) ２ , -O-R 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 １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxy, C ３～１２ Carbocyclyl, or C ３～１２ It is a heterocycline, and each C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxy, carbocykrill, and heterocyclyl are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １～６ 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. １～３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｅ However, independently, oxo, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, C ３～１２ Heterocyclyl, C ２～９ Ariel, C ２～１０ Heteroaryl, -F, -Cl, -Br, -I, -NO ２ , -N(R ｆ ) ２ , -CN, -C(O)-N(R ｆ ) ２ , -S(O)-N(R ｆ ) ２ , -S(O) ２ -N(R) ｆ ) ２ , -O-R ｆ , -S-R ｆ , -O-C(O)-R ｆ , -O-C(O)-OR ｆ , -C(O)-R ｆ , -C(O)-OR ｆ , -S(O)-R ｆ , -S(O) ２ -R ｆ , -O-C(O)-N(R ｆ ) ２ , -N(R ｆ )-C(O)-OR ｆ , -N(R ｆ )-C(O)-N(R ｆ ) ２ , -N(R ｆ )-C(O)-R ｆ , -N(R ｆ )-S(O)-R ｆ , -N(R ｆ )-S(O) ２ -R ｆ , -N(R ｆ )-S(O)-N(R ｆ ) ２ , or -N(R ｆ )-S(O) ２ -N(R) ｆ ) ２ And any C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are A １ , and / or independently, oxo, halo, -NO ２ , -N(R ｆ ) ２ , -CN, -C(O)-N(R ｆ ) ２ , -S(O)-N(R ｆ ) ２ , -S(O) ２ -N(R) ｆ ) ２ , -O-R ｆ , -S-R ｆ , -O-C(O)-R ｆ , -C(O)-R ｆ , -C(O)-OR ｆ , -S(O)-R ｆ , -S(O) ２ -R ｆ , -C(O)-N(R ｆ ) ２ , -N(R ｆ )-C(O)-R ｆ , -N(R ｆ )-S(O)-R ｆ , -N(R ｆ )-S(O) ２ -R ｆ , 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 ｆ However, independently, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, carbocykrill, or heterocyclyl, any C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, and C ３～１２ Heterocyclyl can be independently classified as oxo, carbocyclyl, heterocyclyl, halo, -NO ２ , -N(R ｇ ) ２ , -CN, -C(O)-N(R ｇ ) ２ , -S(O)-N(R ｇ ) ２ , -S(O) ２ -N(R) ｇ ) ２ , -O-R ｇ , -S-R ｇ , -O-C(O)-R ｇ , -C(O)-R ｇ , -C(O)-OR ｇ , -S(O)-R ｇ , -S(O) ２ -R ｇ , -C(O)-N(R ｇ ) ２ , -N(R ｇ )-C(O)-R ｇ , -N(R ｇ )-S(O)-R ｇ , N(R ｇ )-S(O) ２ -R ｇ , and C １～６ 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 １～６ Alkyl, cyano, -N(R) ｇ ) ２ , -O-R ｇ , 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 ｇ However, independently, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxy, C ３～１２ Carbocyclyl, or C ３～１２ It is a heterocycline, and each C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxy, carbocykrill, and heterocyclyl are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １～６ 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. ｇ 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 ｈ However, independently, hydrogen, C １～４ Alkyl, C ２～４ Alkenil, C ２～４ Alkinyl, or C ２～５ It is a cycloalkyl, and each C １～４ Alkyl, C ２～４ Alkenil, C ２～４ Alkinyl and C ２～５ Cycloalkyl groups are independently oxo, halo, amino, hydroxyl, and C. １～３ 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 1, comprising:

3. R １ However, C １～１２ Alkyl, C ２～１２ Alkenil, C ２～１２ Alkynyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R １ Each C １～１２ Alkyl, C ２～１２ Alkenil, C ２～１２ Alkynnyl, 3-12 membered carbon rings, and 3-12 membered hetero rings are A １ and / or one or more base R ｂ It is replaced by an optional selection, R ２ However, 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 , -O-R ａ , -S-R ａ , -O-C(O)-R ａ , -O-C(O)-OR ａ , -C(O)-R ａ , -C(O)-OR ａ , -S(O)-R ａ , -S(O) ２ -R ａ , -O-C(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, C １～１２ Alkyl, C ２～１２ Alkenil, C ２～１２ Alkynyl, 3-12 membered carbon ring, or 3-12 membered heterocycle, R ３ Each C １～１２ Alkyl, C ２～１２ Alkenil, C ２～１２ 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 ２ and R ３ However, together with the nitrogen to which they are bound, A1 and / or one or more R groups ｅ This forms a 3- to 12-membered heterocycle with arbitrary substitutions. R ４ However, C １～４ Alkyl, C ２～４ Alkenil, C ２～４ Alkynyl, 3-5 membered carbon ring, 3-5 membered hetero ring, -C(O)-N(R ｈ ) ２ , -S(O)-N(R ｈ ) ２ , -S(O) ２ -N(R) ｈ ) ２ , -C(O)-R ｈ , -C(O)-OR ｈ , -S(O)-R ｈ , or -S(O) ２ -R ｈ And any C １～４ Alkyl, C ２～４ Alkenil, C ２～４ Alkynnyls, 3- to 5-membered carbon rings, and 3- to 5-membered heterorings are A １ , and / or independently, -F, -Cl, -Br, -I, 3- to 5-membered carbon rings, -C(O)-N(R ｈ ) ２ , -S(O)-N(R ｈ ) ２ , -S(O) ２ -N(R) ｈ ) ２ , -O-R ｈ , -S-R ｈ , -O-C(O)-R ｈ , -O-C(O)-OR ｈ , -C(O)-R ｈ , -C(O)-OR ｈ , -S(O)-R ｈ , -S(O) ２ -R ｈ , -O-C(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 )-S(O)-R ｈ , -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 １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, carbocyclyl, or heterocyclyl, each C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, and C ３～１２ Heterocyclines are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １～６ 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. １～３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｂ However, independently, oxo, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, Carbocyclyl, C ３～１２ Heterocyclyl, C ２～９ Ariel, C ２～１０ 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 , -O-R ｃ , -S-R ｃ , -O-C(O)-R ｃ , -O-C(O)-OR ｃ , -C(O)-R ｃ , -C(O)-OR ｃ , -S(O)-R ｃ , -S(O) ２ -R ｃ , -O-C(O)-N(R ｃ ) ２ , -N(R ｃ )-C(O)-OR ｃ , -N(R ｃ )-C(O)-N(R ｃ ) ２ , -N(R ｃ )-C(O)-R ｃ , -N(R ｃ )-S(O)-R ｃ , -N(R ｃ )-S(O) ２ -R ｃ , -N(R ｃ )-S(O)-N(R ｃ ) ２ , or -N(R)-S(O) ２ -N(R) ｃ ) ２ And any C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are A １ , and / or independently, oxo, halo, -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 , -O-R ｃ , -S-R ｃ , -O-C(O)-R ｃ , -C(O)-R ｃ , -C(O)-OR ｃ , -S(O)-R ｃ , -S(O) ２ -R ｃ , -C(O)-N(R ｃ ) ２ , -N(R ｃ )-C(O)-R ｃ , -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 １～６ It is optionally substituted with one or more groups selected from alkyl groups. Each R ｃ However, independently, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, or C ３～１２ It is a heterocycline and any C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, carbocyclyl, and heterocyclyl 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 , -O-C(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 １～６ 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. １～６ Alkyl, cyano, -N(R) ｄ ) ２ , -O-R 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 １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxy, C ３～１２ Carbocyclyl, or C ３～１２ It is a heterocycline, and each C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxy, carbocykrill, and heterocyclyl are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １～６ 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. １～３ Forming heterocyclines that are optionally substituted with one or more groups selected from alkyl groups, Each R ｅ However, independently, oxo, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, C ３～１２ Heterocyclyl, aryl, heteroaryl, -F, -Cl, -Br, -I, -NO ２ , -N(R ｆ ) ２ , -CN, -C(O)-N(R ｆ ) ２ , -S(O)-N(R ｆ ) ２ , -S(O) ２ -N(R) ｆ ) ２ , -O-R ｆ , -S-R ｆ , -O-C(O)-R ｆ , -O-C(O)-OR ｆ , -C(O)-R ｆ , -C(O)-OR ｆ , -S(O)-R ｆ , -S(O) ２ -R ｆ , -O-C(O)-N(R ｆ ) ２ , -N(R ｆ )-C(O)-OR ｆ , -N(R ｆ )-C(O)-N(R ｆ ) ２ , -N(R ｆ )-C(O)-R ｆ , -N(R ｆ )-S(O)-R ｆ , -N(R ｆ )-S(O) ２ -R ｆ , -N(R ｆ )-S(O)-N(R ｆ ) ２ , or -N(R ｆ )-S(O) ２ -N(R) ｆ ) ２ And any C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are A １ , and / or independently, oxo, halo, -NO ２ , -N(R ｆ ) ２ , -CN, -C(O)-N(R ｆ ) ２ , -S(O)-N(R ｆ ) ２ , -S(O) ２ -N(R) ｆ ) ２ , -O-R ｆ , -S-R ｆ , -O-C(O)-R ｆ , -C(O)-R ｆ , -C(O)-OR ｆ , -S(O)-R ｆ , -S(O) ２ -R ｆ , -C(O)-N(R ｆ ) ２ , -N(R ｆ )-C(O)-R ｆ , -N(R ｆ )-S(O)-R ｆ , -N(R ｆ )-S(O) ２ -R ｆ , 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 ｆ is independently hydrogen, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～１２ carbocyclic, or C ３～１２ heterocyclic, and any C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, carbocyclic, and heterocyclic are A １ and / or independently oxo, carbocyclic, heterocyclic, halo, -NO ２ , -N(R ｇ ) ２ , -CN, -C(O)-N(R ｇ ) ２ , -S(O)-N(R ｇ ) ２ , -S(O) ２ -N(R ｇ ) ２ , -O-R ｇ , -S-R ｇ , -O-C(O)-R ｇ , -C(O)-R ｇ , -C(O)-O-R ｇ , -S(O)-R ｇ , -S(O) ２ -R ｇ , -C(O)-N(R ｇ ) ２ , -N(R ｇ )-C(O)-R ｇ , -N(R ｇ )-S(O)-R ｇ , N(R ｇ )-S(O) ２ -R ｇ , and C １～６ alkyl is optionally substituted with one or more groups selected from, and the carbocyclic and the C １～６ alkyl are independently oxo, halo, C １～６ alkyl, cyano, -N(R ｇ ) ２ , -O-R ｇ , heterocyclic, 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 ｇ However, independently, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxy, C ３～１２ Carbocyclyl, or C ３～１２ It is a heterocycline, and each C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxy, carbocykrill, and heterocyclyl are A １ , and / or independently, oxo, halo, amino, hydroxyl, C １～６ 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. ｇ However, together with the nitrogen to which they are bound, C is independently substituted with oxo, halo, and optionally substituted with 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 ｈ However, independently, hydrogen, C １～４ Alkyl, C ２～４ Alkenil, C ２～４ Alkinyl, or C ２～５ It is a cycloalkyl, and each C １～４ Alkyl, C ２～４ Alkenil, C ２～４ Alkinyl and C ２～５ Cycloalkyl, A １ , and / or independently, oxo, halo, amino, hydroxyl, C １～３ 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 2, wherein it is optionally substituted with one or more groups selected from alkyl groups.

4. 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 2 or 3, which is optionally substituted with [the specified compound].

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

6. R ４ The compound according to any one of claims 2 to 5, wherein the compound is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole, or isoxazole.

7. R ４ However, the structure: 【Transformation 3】 A compound according to any one of claims 2 to 6, having the following characteristics.

8. 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 2 to 7, wherein a 9 or 10-membered bicyclic heterocycle is formed by an optional substitution.

9. 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 2 to 8, 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.

10. NR ２ R ３ Together, the structure: 【Chemistry 4】 A compound according to any one of claims 2 to 9, having the following characteristics.

11. The EP300 connecting portion has the following structure: 【Chemistry 5-1】 【Chemistry 5-2】 A compound according to any one of claims 2 to 10, having the following characteristics.

12. R ２ is A １ and / or independently R ｃ optionally substituted with one or more substituents selected from ６ C ２０ to C aryl, the compound according to any one of claims 2 to 7

13. R ３ However, C １～１２ The compound according to any one of claims 2 to 7 or 12, wherein it is alkyl.

14. The EP300 connecting portion has the following structure: 【Transformation 6】 A compound according to any one of claims 2 to 7 or 12 to 13, having the properties of:

15. The compound according to any one of claims 1 to 14, wherein the decomposition portion is a ubiquitin ligase binding portion.

16. The compound according to claim 15, 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.

17. The aforementioned disassembled portion includes the structure of formula IVa, 【Transformation 7】 During the ceremony, R Ｂ１ However, H, A ２ , -C(O)-A ２ , C replaced by arbitrary selection １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aryl, or C(O)R Ｋ The alkyl, heteroalkyl, carbocykyl, or aryl is A ２ and / or halogen or C １～４ It is optionally substituted with alkyl, R Ｂ３ However, A ２ , -C(O)-A ２ , C replaced by arbitrary selection １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ The alkyl, the heteroalkyl, the carbocykyl, or the aryl is A ２ and / or halogen or C １～４ It is optionally substituted with alkyl, R Ｂ４ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ It is Ariel, R Ｂ５ However, H is replaced by C by arbitrary 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, C by optional substitution ２ ~C ６ It is an alkynyl, hydroxy, thiol. R Ｂ９ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, or A ２ And, Each R Ｋ However, C is replaced independently and by choice. １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ The alkyl, the heteroalkyl, the carbocykyl, or the aryl is A ２ , and / or halogen, CN, or C １～４ It is optionally substituted with alkyl, R Ｂ１ , R Ｂ３ , or R Ｂ９ Only one of them is A ２ or -C(O)-A ２ A compound according to any one of claims 1 to 16, including or a pharmaceutically acceptable salt thereof.

18. R Ｂ６ However, C was replaced by an arbitrary choice. ２ ~C ９ The compound according to claim 17, which is a heteroaryl compound.

19. R Ｂ６ but, 【Transformation 8】 The compound according to claim 17 or 18.

20. The structure of the above formula IVa is, 【Chemistry 9】 The compound according to any one of claims 17 to 19, which is a derivative or analog thereof.

21. The structure of the above formula IVa is, 【Chemistry 10】 The compound according to any one of claims 17 to 19, which is a derivative or analog thereof.

22. The structure of the above formula IVa is, 【Chemistry 11】 The compound according to any one of claims 17 to 19, which is a derivative or analog thereof.

23. The structure of the above formula IVa is, 【Chemistry 12】 The compound according to any one of claims 17 to 19, which is a derivative or analog thereof.

24. The structure of the above formula IVa is, 【Chemistry 13】 The compound according to any one of claims 17 to 19, which is a derivative or analog thereof.

25. The structure of the above formula IVa is, 【Chemistry 14】 The compound according to any one of claims 17 to 19, which is a derivative or analog thereof.

26. R Ｂ６ However, C is replaced by halogen or of any choice. ２ ~C ６ The compound according to claim 17, wherein it is an alkynyl.

27. R Ｂ６ However, C was replaced by an arbitrary choice. １ ~C ６ The compound according to claim 17, which is a heteroalkyl compound.

28. C replaced by arbitrary choice １ ~C ６ The compound according to claim 27, wherein the heteroalkyl group is methoxy.

29. The structure of the above formula IVa is, 【Chemistry 15】 The compound according to any one of claims 17-19 or 26-28, which is a derivative or analog thereof.

30. The structure of the above formula IVa is, 【Chemistry 16】 The compound according to any one of claims 17-19 or 26-28, which is a derivative or analog thereof.

31. The aforementioned disassembled portion includes the structure of formula IVaa, 【Chemistry 17】 During the ceremony, R Ｂ１１ However, A ２ , C replaced by arbitrary selection ３ ~C １０ Carbocyclyl, optionally replaced with C ２ ~C ９ Heterocycline, C by optional substitution ６ ~C １０ A C replaced by an aryl or of any choice. ２ ~C ９ A heteroaryl, wherein the carbocyclyl, the heterocyclyl, the aryl, or the heteroaryl is A ２ , and / or halogen or C １～４ It is optionally substituted with alkyl, R Ｂ３ However, A ２ , -C(O)-A ２ , C replaced by arbitrary selection １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ The alkyl, the heteroalkyl, the carbocykyl, or the aryl is A ２ and / or halogen or C １～４ It is optionally substituted with alkyl, R Ｂ４ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ It is Ariel, R Ｂ５ However, H is replaced by C by arbitrary 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, C by optional substitution ２ ~C ６ It is an alkynyl, hydroxy, thiol. R Ｂ９ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, or A ２ And, R Ｂ９ , R Ｂ１１ , and R Ｂ３ Only one of them is A ２ or -C(O)-A ２ A compound according to any one of claims 1 to 16, including or a pharmaceutically acceptable salt thereof.

32. R Ｂ１１ However, C was replaced by an arbitrary choice. ２ ~C ９ The compound according to claim 31, which is a heteroaryl compound.

33. C replaced by arbitrary choice ２ ~C ９ Heteroaryls [Chemistry 18] The compound according to claim 32.

34. R Ｂ６ However, C was replaced by an arbitrary choice. ２ ~C ９ The compound according to claim 31, which is a heteroaryl compound.

35. R Ｂ６ but, 【Chemistry 19】 The compound according to any one of claims 31 to 34.

36. The structure of the above formula IVaa is, 【Chemistry 20】 The compound according to any one of claims 31 to 35, which is a derivative or analog thereof.

37. The structure of the above formula IVaa is, 【Chemistry 21】 The compound according to any one of claims 31 to 35, which is a derivative or analog thereof.

38. The structure of the above formula IVaa is, 【Chemistry 22】 The compound according to any one of claims 31 to 35, which is a derivative or analog thereof.

39. The structure of the above formula IVaa is, 【Chemistry 23】 The compound according to any one of claims 31 to 35, which is a derivative or analog thereof.

40. R Ｂ６ The compound according to claim 31, wherein the compound is a halogen.

41. The structure of the above formula IVaa is, 【Chemistry 24】 The compound according to any one of claims 31 to 35 or 40, which is a derivative or analog thereof.

42. The structure of the above formula IVaa is, 【Chemistry 25】 The compound according to any one of claims 31 to 35 or 40, which is a derivative or analog thereof.

43. R ９ However, A ２ The compound according to claim 31.

44. The structure of the above formula IVaa is, 【Chemistry 26】 The compound according to any one of claims 31 to 35 or 43, which is a derivative or analog thereof.

45. The structure of the above formula IVaa is, 【Chemistry 27】 The compound according to any one of claims 31 to 35 or 43, which is a derivative or analog thereof.

46. The aforementioned disassembled portion includes the structure of formula IV, 【Chemistry 28】 During the ceremony, R Ｂ１ However, H, A ２ , C replaced by arbitrary selection １ ~C ６ Alkyl or optionally substituted C １ ~C ６ Heteroalkyl, C(O)-A ２ , C replaced by arbitrary selection ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ Aryl, C(O)R Ｋ The alkyl, heteroalkyl, carbocykyl, or aryl is A ２ and / or halogen or C １～４ It is optionally substituted with alkyl, R Ｂ２ However, H is replaced by C by arbitrary 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, optionally replaced with C ６ ~C １０ The alkyl, the heteroalkyl, the carbocykyl, or the aryl is A ２ and / or halogen or C １～４ It is optionally substituted with alkyl, R Ｂ４ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ It is Ariel, R Ｂ５ However, H is replaced by C by arbitrary choice. １～６ Alkyl or optionally substituted C １～６ It is heteroalkyl, v2 is 0, 1, 2, 3, or 4, Each R Ｂ６ However, independently, halogen, and optionally substituted C １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ３～１０ Carbocyclyl, optionally replaced with C ２～９ Heterocycline, C by optional substitution ６～１０ Aaryl, replaced by C of any choice ２～９ Heteroaryl, optionally substituted C ２～６ Alkenyl, C substituted by choice ２～６ 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. １～６ Alkyl or optionally substituted C ６～１０ It is Ariel, R Ｂ９ and R Ｂ１０ However, independently, H and C are substituted by choice. １～６ Alkyl, or A ２ And, Each R Ｋ However, C is replaced independently and by choice. １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ３ ~C １０ Carbocyclyl, optionally replaced with C ６ ~C １０ The alkyl, the heteroalkyl, the carbocykyl, or the aryl is A ２ , and / or halogen, CN, or C １～４ It is optionally substituted with alkyl, R Ｂ１ R Ｂ３ , R Ｂ９ , or R Ｂ１０ Only one of them is A ２ A compound according to any one of claims 1 to 16, including or a pharmaceutically acceptable salt thereof.

47. The structure of the above formula IV is, 【Chemistry 29】 The compound according to claim 46, which is a derivative or analog thereof.

48. The structure of the above formula IV is, 【Transformation 30】 The compound according to claim 46, which is a derivative or analog thereof.

49. The structure of the above formula IV is, 【Chemistry 31】 The compound according to claim 46, which is a derivative or analog thereof.

50. The structure of the above formula IV is, 【Chemistry 32】 The compound according to claim 46, which is a derivative or analog thereof.

51. The structure of the above formula IV is, 【Transformation 33】 The compound according to claim 46, which is a derivative or analog thereof.

52. The structure of the above formula IV is, 【Transformation 34】 The compound according to claim 46, which is a derivative or analog thereof.

53. The structure of the above formula IV is, 【Chemistry 35】 The compound according to claim 46, which is a derivative or analog thereof.

54. The structure of the above formula IV is, 【Transformation 36】 The compound according to claim 46, which is a derivative or analog thereof.

55. The aforementioned decomposition part includes the structure of formula V, 【Chemistry 37】 R Ｃ１ However, C was replaced by an arbitrary choice. １ ~C ６ It is alkyl, R Ｃ２ However, A ２ , or C replaced by any choice １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ３～１０ Carbocyclyl, optionally replaced with C ６～１０ Aaryl, replaced by C of any choice ２～９ It is a heteroaryl, and the C １～６ alkyl, the C １～６ Heteroalkyl, the C ３～１０ Carbocyclyl, the above C ６～１０ Aryl, the aforementioned C ２～９ Heteroaryl is A ２ and / or one or more base R Ｊ It is replaced by an optional selection, R Ｃ３ However, H is replaced by C by arbitrary choice. １～６ Alkyl, optionally substituted C ３～１０ Carbocyclyl, optionally replaced with C ６～１０ It is Ariel, R Ｃ４ However, H is replaced by C by arbitrary choice. １～６ Alkyl or optionally substituted C １～６ It is heteroalkyl, v2 is 0, 1, 2, 3, or 4, R Ｃ５ and R Ｃ６ Each of these is independently replaced by H and C by any choice. １～６ Alkyl, or A ２ And, Each R Ｃ７ However, independently, halogen, and optionally substituted C １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ３～１０ 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 ２～６ 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. １～６ Alkyl or optionally substituted C ６～１０ It is Ariel, Each R Ｊ However, independently, hydrogen, C １～６ These are alkyl, carbocykryl, and heterocyclyl compounds, and each C １～６ Alkyl, carbocyryl, and heterocyclyl compounds can be independently amino, hydroxyl, or C. １～６ Alkoxy, carbocyryl, heterocyclyl, or A ２ , and / or 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. R Ｃ２ , R Ｃ５ , R Ｃ６ , or R Ｊ Only one of them is A １ A compound according to any one of claims 1 to 16, including or a pharmaceutically acceptable salt thereof.

56. The structure of the above formula V is, 【Transformation 38】 The compound according to claim 55, which is a derivative or analog thereof.

57. The structure of the above formula V is, 【Chemistry 39】 The compound according to claim 55, which is a derivative or analog thereof.

58. The structure of the above formula V is, 【Chemistry 40】 The compound according to claim 55, which is a derivative or analog thereof.

59. The structure of the above formula V is, 【Chemistry 41】 The compound according to claim 55, which is a derivative or analog thereof.

60. The aforementioned decomposed portion includes the structure of formula IVb, 【Chemistry 42】 During the ceremony, R Ｂ１ However, H, A ２ , -C(O)-A ２ , -C(O)-J ２ , C replaced by arbitrary selection １～６ Alkyl or optionally substituted C １～６ It is heteroalkyl, R Ｂ３ However, A ２ , -C(O)-A ２ , C replaced by arbitrary selection １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ３～１０ Carbocyclyl, optionally replaced with C ６～１０ It is an aryl, and is alkyl, heteroalkyl, carbocykryl, or aryl, A ２ and / or one or more base R Ｊ２ It is replaced by an optional selection, R Ｂ４ However, H is replaced by C by arbitrary choice. １～６ Alkyl, optionally substituted C ３～１０ Carbocyclyl, optionally replaced with C ６～１０ It is Ariel, R Ｂ５ However, A ２ , H, C replaced by any choice １～６ Alkyl or optionally substituted C １～６ It is heteroalkyl, R Ｂ１ , R Ｂ３ , and R Ｂ３ One of them is A ２ or -C(O)-A ２ And, Each R Ｊ２ However, independently, hydrogen, C １～６ These are alkyl, carbocykryl, and heterocyclyl compounds, and each C １～６ Alkyl, carbocyryl, and heterocyclyl compounds can be independently classified as halo, amino, hydroxyl, or C. １～６ Alkoxy, carbocyryl, heterocyclyl, or A ２ and / or 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. R Ｂ１ , R Ｂ３ , R Ｂ５ , or R Ｊ Only one of them is A １ A compound according to any one of claims 1 to 16, including or a pharmaceutically acceptable salt thereof.

61. The structure of formula IVb is, 【Chemistry 43】 The compound according to claim 60, or a derivative or analog thereof.

62. The aforementioned decomposed portion includes the structure of formula IVc, 【Chemistry 44】 During the ceremony, R Ｅ２ However, H, A ２ , -C(O)-A ２ , -C(O)-J ３ , C replaced by arbitrary selection １～６ Alkyl or optionally substituted C １～６ It is heteroalkyl, R Ｅ３ However, A ２ , -C(O)-A ２ , C replaced by arbitrary selection １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ３～１０ Carbocyclyl, optionally replaced with C ６～１０ A C replaced by an aryl or of any choice. ２～１０ It is a heteroaryl compound, and the alkyl, heteroalkyl, carbocycryl, aryl, or heteroaryl compound has one or more R groups. Ｊ３ It is replaced by an optional selection, R Ｅ４ However, H is replaced by C by arbitrary choice. １～６ Alkyl, optionally substituted C ３～１０ Carbocyclyl, optionally replaced with C ６～１０ It is Ariel, R Ｅ５ However, A ２ , H, C replaced by any choice １～６ Alkyl or optionally substituted C １～６ It is heteroalkyl, R Ｅ２ , R Ｅ３ , and R Ｅ５ One of them is A ２ or -C(O)-A ２ And, Each R Ｊ２ However, independently, hydrogen, C １～６ These are alkyl, carbocykryl, and heterocyclyl compounds, and each C １～６ Alkyl, carbocyryl, and heterocyclyl compounds can be independently classified as halo, amino, hydroxyl, or C. １～６ Alkoxy, carbocyryl, heterocyclyl, or A ２ and / or 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. R Ｅ２ , R Ｅ３ , R Ｅ５ , or R Ｊ３ Only one of them is A １ A compound according to any one of claims 1 to 16, including or a pharmaceutically acceptable salt thereof.

63. The structure of the above formula IVC is, 【Chemistry 45】 The compound according to claim 62, which is a derivative or analog thereof.

64. L has the structure of formula II, A １ -C １ -(F)-(E) ｍ -C ２ -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 １ and C ２ However, independently, they are absent, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl. E is NR Ｎ , C replaced by arbitrary selection １～１０ Alkylene, optionally replaced with C ２～１２ Heteroalkylene, C by optional substitution ２～１２ Carbocyclylene, or optionally substituted C ２～１２ It is a heterocycline, Each R Ｎ However, independently, H and C are substituted by choice. １～４ Alkyl, optionally substituted C ２～４ Alkenyl, C substituted by choice ２～４ Alkinyl, optionally replaced with C ２～６ Heterocyclylene, C by optional substitution ６～１２ A C replaced by an aryl or of any choice. １～７ It is heteroalkyl, F is replaced by C by arbitrary choice. ２～１２ Heterocyclylene or C substituted by choice ２ ~C ９ A compound according to any one of claims 1 to 63, which is a heteroarylene.

65. C １ The compound according to any one of claims 1 to 64, wherein the compound is a carbonyl group.

66. C １ However, the compound according to any one of claims 1 to 64 does not exist.

67. F is replaced by C by arbitrary choice. ２～１２ A compound according to any one of claims 1 to 66, wherein the compound is a heterocyclylene.

68. F is, 【Chemistry 46】 The compound according to claim 67.

69. The compound according to claim 67, wherein F is crosslinked or has a spirocyclic structure.

70. F is, 【Chemistry 47】 The compound according to claim 69.

71. F is replaced by C by arbitrary choice. ２ ~C ９ A compound according to any one of claims 1 to 66, which is a heteroarylene.

72. F is, 【Chemistry 48】 The compound according to claim 71.

73. F is, 【Chemistry 49】 The compound according to claim 71.

74. F is, [Transformation 50] The compound according to claim 71.

75. F is, 【Chemistry 51】 The compound according to claim 71.

76. F is, 【Chemistry 52】 The compound according to claim 71.

77. F is, 【Chemistry 53】 The compound according to claim 71.

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

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

80. The compound according to any one of claims 1 to 77 or 79, wherein E is methylene or ethylene.

81. E is NR Ｎ The compound according to any one of claims 1 to 77 or 79.

82. The compound according to claim 81, wherein E is NH.

83. E is replaced by C by arbitrary choice. ２～１２ Carbocyclylene, or optionally substituted C ２～１２ A compound according to any one of claims 1 to 77 or 79, wherein the compound is a heterocyclylene.

84. E is, 【Chemistry 54】 The compound according to claim 83.

85. E is replaced by C by arbitrary choice. １～１０ The compound according to any one of claims 1 to 77 or 79, which is an alkylene.

86. E is, 【Transformation 55】 The compound according to claim 85.

87. E is replaced by C by arbitrary choice. ２～１２ A compound according to any one of claims 1 to 77 or 79, which is a heteroalkylene.

88. E is, 【Transformation 56】 The compound according to claim 87.

89. (F) - (E) ｍ but, 【Chemistry 57-1】 【Chemistry 57-2】 【Chemistry 57-3】 【Chemistry 57-4】 The compound according to any one of claims 1 to 77 or 79 to 88.

90. C ２ The compound according to any one of claims 1 to 89, wherein the compound is a carbonyl compound.

91. C ２ However, the compound according to any one of claims 1 to 89 does not exist.

92. The compound according to any one of claims 1 to 91, wherein the compound is any one of compounds 1 to 197 or a pharmaceutically acceptable salt thereof.

93. A pharmaceutical composition comprising a compound according to any one of claims 1 to 92 and a pharmaceutically acceptable excipient.

94. 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 92, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 93.

95. The method according to claim 94, wherein the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemia, ovarian cancer, neuroblastoma, myeloma, skin, endometrium, esophagus, cervix, stomach, lymphoma, leukemia, esophagus, stomach, lung cancer, or non-small cell lung cancer.

96. The method according to claim 94 or 95, wherein the cancer is metastatic.

97. The method according to any one of claims 94 to 96, wherein the subject or cancer has a CBP loss-of-function mutation.

98. The method according to any one of claims 94 to 97, wherein the cancer is prostate cancer.

99. The method according to claim 98, wherein the cancer is castration-resistant prostate cancer (CRPC).

100. The method according to claim 98, wherein the cancer is castration-sensitive prostate cancer.

101. The method according to claim 98, wherein the cancer is AR+ prostate cancer.

102. The method according to any one of claims 94 to 97, wherein the cancer is lymphoma.

103. The method according to claim 102, wherein the lymphoma is diffuse large B-cell lymphoma (DLBCL).

104. The method according to any one of claims 94 to 103, further comprising administering anticancer therapy to the subject.

105. The method according to claim 104, wherein the anti-cancer therapy is a chemotherapeutic agent or cytotoxic agent, immunotherapy, surgery, radiotherapy, hyperthermia, or photocoagulation, or a combination thereof.

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