CN117980294A

CN117980294A - Ubiquitin-specific protease 1 (USP 1) inhibitors

Info

Publication number: CN117980294A
Application number: CN202280057195.6A
Authority: CN
Inventors: 祝伟; 刘晓武; 邹昊; 汪涛; 陈祥; 祝东星; 孙天文; 李正涛
Original assignee: Hainan Xiansheng Zaiming Pharmaceutical Co ltd
Current assignee: Hainan Xiansheng Zaiming Pharmaceutical Co ltd
Priority date: 2021-09-01
Filing date: 2022-08-30
Publication date: 2024-05-03
Also published as: WO2023030295A1

Abstract

A compound having USP1 inhibitory activity or function, which has the structure of formula (I) and has the substituents and structural features described herein, and pharmaceutically acceptable salts thereof. Also described are pharmaceutical compositions comprising the compounds of formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them and their use as USP1 inhibitors in the prevention or treatment of related diseases.

Description

Ubiquitin-specific protease 1 (USP 1) inhibitors

Cross Reference to Related Applications

The present application claims the benefit and priority of the following chinese patent applications of application, the entire contents of which are hereby incorporated by reference in their entirety:

202111019014.4 submitted to the China national intellectual property office on day 1, 9 of 2021, is named: patent application for ubiquitin-specific protease 1 (USP 1) inhibitors.

Technical Field

The present disclosure pertains to the field of pharmaceutical technology, and relates to USP1 inhibitor compounds or optical isomers, pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and use as USP1 inhibitors in the prevention or treatment of related diseases.

Background

Ubiquitination is a reversible process that involves a series of deubiquitinating enzymes (DUBs) that regulate a variety of cellular processes by deubiquitinating substrates. DUBs are encoded by approximately 100 human genes and are divided into 6 families, the largest of which are ubiquitin-specific proteases (USPs) with more than 50 members. DUBs and their substrate proteins are often deregulated in cancer, a phenomenon that supports the hypothesis that targeting specific DUB enzymes can be mediated by enhancing ubiquitination and degradation of oncogenic substrates and modulating the activity of other key proteins involved in tumor growth, survival, differentiation and maintenance of tumor microenvironment (Hussain,S.,et.al.,"DUBs and cancer:The role of deubiquitinatingenzymes as oncogenes,non-oncogenes and tumor suppressors."Cell Cycle 8,1688-1697(2009)).

USP1 is a cysteine isopeptidase of the USP subfamily in DUBs. Full length human USP1 consists of 785 amino acids, including a catalytic triad (Nijman,S.M.B.,et al."The deubiquitinating enzyme USPl regulates the fanconi anemia pathway.Mal.Cell 17,331-339(2005)).USP1 consisting of Cys90, his593 and Asp751, plays a role in DNA damage repair. USP1 itself is relatively inactive and only binds to the cofactor UAF1 to form the complex required for deubiquitinase activity to obtain complete enzymatic activity. The USP1/UAFl complex de-ubiquitinates mononucleoubiquitinated PCNA (proliferating cell nuclear antigen) and monoubiquitinated FANCD2 (Fanconi anemia group complementary group D2), both proteins play important roles in the translational synthesis (TLS) and Fanconi Anemia (FA) pathways, respectively. Both of these pathways are necessary to repair DNA damage caused by DNA cross-linking agents such as cisplatin and mitomycin C (MMC). The USPl/UAFl complex was also deubiquitinated FANCI (Fanconi anemia complementation group I). The importance of these findings was further confirmed by experiments, i.e. mice lacking USP1 were highly susceptible to DNA damage. Interestingly, USP1 expression was significantly increased in many cancers. Blocking USP1 to inhibit DNA repair can induce apoptosis in multiple myeloma cells, and can also enhance the sensitivity of lung cancer cells to cisplatin. These indicate that USP1 is a promising target for chemotherapy of certain cancers.

In summary, targeted inhibition of USP1 proteins is a potential method of treating cancer and other diseases. Therefore, it is necessary to develop small molecule inhibitors of USP 1.

Disclosure of Invention

In one aspect, the present disclosure relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof,

Wherein,

X ¹ is selected from N or CR ^1a;

X ² is selected from O、NR ^2a、CR ^2aR ^2b、C＝CR ^2aR ^2b、S、S(＝O)R ^2a、C(＝O)、S(＝O) ₂ or C (=nr ^2a);

X ³ is selected from CR ^3aR ^3b、CR ^3a、NR ^3a, N, C (=o), O, or C (=nr ^3a);

X ⁴ is selected from CR ^4aR ^4b、CR ^4a or C (=o);

X ⁵ is selected from CR ^5aR ^5b, C (=o) or S (=o) ₂;

Ring a is selected from aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl or C ₃-C ₁₀ cycloalkyl;

ring B is selected from arylene, 5-10 membered heteroarylene, 4-10 membered heterocyclylene, or C ₃-C ₁₀ membered cycloalkylene;

ring C is selected from aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl;

R ¹、R ² is independently selected from H, halogen, CN, OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl, said OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl being optionally substituted with R ^d;

Or R ¹、R ² together with the atoms to which they are attached form a C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl, said C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl being optionally substituted with R ^d;

R ³ is selected from H, halogen, CN, OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl, 4-8 membered heterocyclyl, alkenyl, alkynyl, said OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl, 4-8 membered heterocyclyl, alkenyl, alkynyl being optionally substituted with R ^d;

R ^1a、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b Independently selected from H, halogen, CN, OH, NH ₂、C ₁-C ₆ alkyl, alkenyl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl, said OH, NH ₂、C ₁-C ₆ alkyl, alkenyl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl being optionally substituted with R ^d;

R ^a、R ^b、R ^c is independently selected from halogen, CN, OH, NH ₂、SH、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl, or 4-8 membered heterocyclyl, said OH, NH ₂、SH、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl, or 4-8 membered heterocyclyl being optionally substituted with R ^d;

Or R ^1a、R ^a taken together with the atom to which it is attached form C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl or C ₃-C ₁₀ cycloalkenyl, said C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl or C ₃-C ₁₀ cycloalkenyl being optionally substituted with R ^d.

Or R ^b、R ^c taken together with the atom to which it is attached form C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl or C ₃-C ₁₀ cycloalkenyl, said C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl or C ₃-C ₁₀ cycloalkenyl being optionally substituted with R ^d;

Or R ^2a、R ^2b taken together with the atoms to which it is attached form a C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocyclyl, said C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocyclyl being optionally substituted with R ^d;

Or R ^2a、R ^3a taken together with the atoms to which it is attached form a 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl, said 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl optionally being substituted with R ^d;

or R ^3a、R ^4a taken together with the atoms to which it is attached form C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl or 5-10 membered heteroaryl, said C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R ^d;

or R ^3a、R ^5a taken together with the atoms to which it is attached form C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl or 5-10 membered heteroaryl, said C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R ^d;

Or R ^4a、R ^4b taken together with the atoms to which it is attached form a C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocyclyl, said C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocyclyl being optionally substituted with R ^d;

or R ^4a、R ^5a taken together with the atoms to which it is attached form a C ₃-C ₁₀ cycloalkyl group or a 4-10 membered heterocyclyl group; the C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R ^d;

or R ^5a、R ^5b taken together with the atoms to which it is attached form a C ₃-C ₁₀ cycloalkyl group or a 4-10 membered heterocyclyl group; the C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R ^d;

or R ^2a、R ^4a taken together with the atoms to which it is attached form a 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl, said 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl optionally being substituted with R ^d;

Or R ^2a、R ^5a taken together with the atoms to which it is attached form a 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl, said 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl optionally being substituted with R ^d;

Or X ² and X ³,X ³ and X ⁴, optionally forming a double bond;

Each R ^d is independently selected from halogen, CN, OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl, or 4-8 membered heterocyclyl, said OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl, or 4-8 membered heterocyclyl being optionally substituted with R ^e;

R ^e is selected from halogen, CN, OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl, said OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl being optionally substituted by R ^f;

R ^f is selected from halogen, CN, OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl;

m, n, p are independently selected from 0, 1, 2,3, 4, 5 or 6.

In some embodiments, X ¹ is selected from N.

In some embodiments, X ¹ is selected from CR ^1a.

In some embodiments, X ² is selected from O, NR ^2a、CR ^2aR ^2b、C＝CR ^2aR ^2b、S、S(＝O)R ^2a, C (=o), or S (=o) ₂.

In some embodiments, X ² is selected from O, NR ^2a、CR ^2aR ^2b or C (=o).

In some embodiments, X ³ is selected from CR ^3aR ^3b、CR ^3a、NR ^3a, N, C (=o), or C (=nr ^3a).

In some embodiments, X ³ is selected from CR ^3aR ^3b、NR ^3a or C (=o).

In some embodiments, X ⁴ is selected from CR ^4aR ^4b or C (=o). In some embodiments, X ⁴ is selected from CR ^4aR ^4b.

In some embodiments, X ⁴ is selected from CR ^4a.

In some embodiments, X ⁵ is selected from CR ^5aR ^5b or C (=o).

In some embodiments, ring a is selected from aryl or 5-10 membered heteroaryl.

In some embodiments, ring a is selected from

In some embodiments, ring B is selected from arylene, 4-8 membered heterocyclylene, or C ₃-C ₆ cycloalkylene.

In some embodiments, ring B is selected from arylene or 4-8 membered heterocyclylene.

In some embodiments, ring B is selected from

In some embodiments, ring C is selected from 5-10 membered heteroaryl.

In some embodiments, ring C is selected from

In some embodiments, R ¹、R ² is independently selected from H, halogen, or C ₁-C ₆ alkyl, said C ₁-C ₆ alkyl optionally substituted with R ^d.

In some embodiments, R ¹、R ² is independently selected from H or C ₁-C ₆ alkyl, which C ₁-C ₆ alkyl is optionally substituted with R ^d. In some embodiments, R ¹、R ² is independently selected from H.

In some embodiments, R ¹、R ² and the atoms to which they are attached together form a C ₃-C ₆ cycloalkyl group, which C ₃-C ₆ cycloalkyl group is optionally substituted with R ^d.

In some embodiments, R ¹、R ² and the atoms to which they are attached together form a cyclopropyl group, optionally substituted with R ^d.

In some embodiments, R ³ is selected from H, halogen, CN, OH, C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl, 4-8 membered heterocyclyl, alkenyl, or alkynyl, said OH, C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl, 4-8 membered heterocyclyl, alkenyl, or alkynyl being optionally substituted with R ^d.

In some embodiments, R ³ is selected from H, halogen, CN, OH, C ₁-C ₆ alkyl, or C ₃-C ₆ cycloalkyl, said OH, C ₁-C ₆ alkyl, or C ₃-C ₆ cycloalkyl being optionally substituted with R ^d.

In some embodiments, R ³ is selected from H, halogen, OH, or C ₁-C ₆ alkyl, which OH or C ₁-C ₆ alkyl is optionally substituted with R ^d.

In some embodiments, R ³ is selected from H.

In some embodiments ,R ^1a、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b is independently selected from H, halogen, CN, OH, NH ₂、C ₁-C ₆ alkyl, alkenyl, C ₃-C ₆ cycloalkyl, or 4-8 membered heterocyclyl, said OH, NH ₂、C ₁-C ₆ alkyl, alkenyl, C ₃-C ₆ cycloalkyl, or 4-8 membered heterocyclyl being optionally substituted with R ^d.

In some embodiments ,R ^1a、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b is independently selected from H, halogen, OH, NH ₂、C ₁-C ₆ alkyl, alkenyl, or C ₃-C ₆ cycloalkyl, said OH, NH ₂、C ₁-C ₆ alkyl, alkenyl, or C ₃-C ₆ cycloalkyl being optionally substituted with R ^d.

In some embodiments, R ^a、R ^b、R ^c is independently selected from halogen, OH, NH ₂、SH、C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl, or 4-8 membered heterocyclyl, said OH, NH ₂、SH、C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl, or 4-8 membered heterocyclyl being optionally substituted with R ^d.

In some embodiments, R ^a is independently selected from OH, C ₁-C ₆ alkyl, or C ₃-C ₆ cycloalkyl, which OH, C ₁-C ₆ alkyl, or C ₃-C ₆ cycloalkyl is optionally substituted with R ^d.

In some embodiments, R ^a is independently selected from-O-CH ₃、-O-CHF ₂, methyl, ethyl, isopropyl, or cyclopropyl.

In some embodiments, R ^a is independently selected from-O-CH ₃, methyl, ethyl, isopropyl, or cyclopropyl.

In some embodiments, R ^a is independently selected from-O-CH ₃、-O-CHF ₂ or cyclopropyl.

In some embodiments, R ^b is independently selected from halogen, OH, or C ₁-C ₆ alkyl, which OH or C ₁-C ₆ alkyl is optionally substituted with R ^d.

In some embodiments, R ^b is independently selected from H.

In some embodiments, R ^c is independently selected from halogen, OH, C ₁-C ₆ alkyl, or C ₃-C ₆ cycloalkyl, which OH, C ₁-C ₆ alkyl, or C ₃-C ₆ cycloalkyl is optionally substituted with R ^d.

In some embodiments, R ^c is independently selected from OH, C ₁-C ₆ alkyl, or C ₃-C ₆ cycloalkyl, which OH, C ₁-C ₆ alkyl, or C ₃-C ₆ cycloalkyl is optionally substituted with R ^d.

In some embodiments, R ^c is independently selected from OH, methyl, ethyl, isopropyl, or cyclopropyl, optionally substituted with R ^d.

In some embodiments, R ^c is independently selected from OCH ₃、CF ₃、CH ₂CF ₃、CH ₃、CH ₂CH ₃, isopropyl, cyclopropyl, or

In some embodiments, R ^c is independently selected from CF ₃ or CH ₃.

In some embodiments, R ^1a、R ^a together with the atoms to which it is attached form a C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocyclyl, which C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R ^d.

In some embodiments, R ^1a、R ^a together with the atoms to which it is attached form a 4-8 membered heterocyclyl, which 4-8 membered heterocyclyl is optionally substituted with R ^d.

In some embodiments, R ^b、R ^c together with the atoms to which it is attached form a C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocyclyl, which C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R ^d.

In some embodiments, R ^b、R ^c together with the atoms to which it is attached form a 4-8 membered heterocyclyl, which 4-8 membered heterocyclyl is optionally substituted with R ^d.

In some embodiments, R ^2a、R ^2b together with the atoms to which it is attached form a C ₃-C ₆ cycloalkyl or 4-7 membered heterocyclyl, which C ₃-C ₆ cycloalkyl or 4-7 membered heterocyclyl is optionally substituted with R ^d.

In some embodiments, R ^2a、R ^2b together with the atoms to which it is attached form a C ₃-C ₁₀ cycloalkyl group, said C ₃-C ₁₀ cycloalkyl group optionally being substituted with R ^d.

In some embodiments, R ^2a、R ^2b together with the atoms to which it is attached form a cyclobutyl, which is optionally substituted with R ^d.

In some embodiments, R ^2a、R ^3a together with the atoms to which it is attached form a 5-10 membered heteroaryl, which 5-10 membered heteroaryl is optionally substituted with R ^d.

In some embodiments, R ^2a、R ^3a together with the atoms to which it is attached formThe saidOptionally substituted with R ^d.

In some embodiments, R ^3a、R ^4a together with the atoms to which it is attached form a C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl, which C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with R ^d.

In some embodiments, R ^3a、R ^4a together with the atoms to which it is attached form cyclopropyl,The cyclopropyl group,Optionally substituted with R ^d.

In some embodiments, R ^3a、R ^5a together with the atoms to which it is attached form a C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl, which C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with R ^d.

In some embodiments, R ^3a、R ^5a together with the atoms to which it is attached formThe said Optionally substituted with R ^d.

In some embodiments, R ^4a、R ^4b together with the atoms to which it is attached form a C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl, which C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with R ^d.

In some embodiments, R ^4a、R ^4b together with the atoms to which it is attached form cyclopropyl, cyclobutyl, orThe cyclopropyl, cyclobutyl orOptionally substituted with R ^d.

In some embodiments, R ^4a、R ^5a together with the atoms to which it is attached form a C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl; the C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with R ^d. In some embodiments, R ^4a、R ^5a together with the atoms to which it is attached form cyclopropyl or cyclobutyl; the cyclopropyl or cyclobutyl is optionally substituted by R ^d.

In some embodiments, R ^5a、R ^5b together with the atoms to which it is attached form a C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl; the C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with R ^d.

In some embodiments, R ^5a、R ^5b together with the atoms to which it is attached form a C ₃-C ₆ cycloalkyl group, said C ₃-C ₆ cycloalkyl group optionally being substituted with R ^d.

In some embodiments, R ^5a、R ^5b together with the atoms to which it is attached form cyclopropyl or cyclobutyl; the cyclopropyl or cyclobutyl is optionally substituted by R ^d.

In some embodiments, R ^2a、R ^4a together with the atoms to which it is attached form a C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl, which C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with R ^d.

In some embodiments, R ^2a、R ^5a together with the atoms to which it is attached form a C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl, which C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with R ^d.

In some embodiments, a double bond is formed between X ² and X ³.

In some embodiments, a double bond is formed between X ³ and X ⁴.

In some embodiments, each R ^d is independently selected from halogen, OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl, or 4-8 membered heterocyclyl, the OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl, or 4-8 membered heterocyclyl being optionally substituted with R ^e.

In some embodiments, each R ^d is independently selected from halogen, OH, NH ₂、C ₁-C ₆ alkyl, or C ₃-C ₁₀ cycloalkyl, which OH, NH ₂、C ₁-C ₆ alkyl, or C ₃-C ₁₀ cycloalkyl is optionally substituted with R ^e.

In some embodiments, R ^e is selected from halogen, OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl, or 4-8 membered heterocyclyl, said OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl, or 4-8 membered heterocyclyl being optionally substituted with R ^f.

In some embodiments, R ^f is selected from halogen, OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl, or 4-8 membered heterocyclyl.

In some embodiments, m is selected from 1,2, 3.

In some embodiments, m is selected from 1 or 2.

In some embodiments, n is selected from 0, 1, 2.

In some embodiments, n is selected from 0 or 1.

In some embodiments, p is selected from 1,2, 3.

In some embodiments, p is selected from 1 or 2.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from the group consisting of a compound of formula (II) or a pharmaceutically acceptable salt thereof,

Wherein,

X ¹ is selected from N or CR ^1a;

X ² is selected from O, NR ^2a、CR ^2aR ^2b、C＝CR ^2aR ^2b、S、C(＝O)、S(＝O) ₂ or C (=nr ^2a);

X ³ is selected from CR ^3aR ^3b、NR ^3a, C (=o), O, or C (=nr ^3a);

x ⁴ is selected from CR ^4aR ^4b or C (=o);

X ⁵ is selected from CR ^5aR ^5b, C (=o) or S (=o) ₂;

Ring a, ring B, ring C、R ¹、R ²、R ³、R ^a、R ^b、R ^c、m、n、p、R ^1a、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a and R ^5b are as defined above.

In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt thereof, X ⁴ is CR ^4aR ^4b.

It is to be understood that in the claims directed to formula (II), when referring to claim x, ring a, ring B, ring C、R ¹、R ²、R ³、R ^a、R ^b、R ^c、m、n、p、R ^1a、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a and R ^5b in formula (II) are as defined in claim x. For example, when claim 27 refers to the preceding claim 1, ring a, ring B, ring C、R ¹、R ²、R ³、R ^a、R ^b、R ^c、m、n、p、R ^1a、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a and R ^5b in said formula (II) are as defined in claim 1; when claim 27 is appended to the preceding claim 7, ring a, ring B, ring C、R ¹、R ²、R ³、R ^a、R ^b、R ^c、m、n、p、R ^1a、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a and R ^5b in formula (II) are as defined in claim 7, and so on.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from the group consisting of a compound of formula (III) or a pharmaceutically acceptable salt thereof,

Wherein,

X ¹ is selected from N or CR ^1a;

X ³ is selected from CR ^3aR ^3b、NR ^3a, C (=o), O, or C (=nr ^3a);

x ⁴ is selected from CR ^4aR ^4b or C (=o);

X ⁵ is selected from CR ^5aR ^5b, C (=o) or S (=o) ₂;

R ¹、R ²、R ³、R ^a、R ^b、R ^c、m、n、p、R ^1a、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a And R ^5b is as defined above.

It is to be understood that in the claims referring to formula (III), R ¹、R ²、R ³、R ^a、R ^b、R ^c、m、n、p、R ^1a、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a and R ^5b in said formula (III) are as defined in claim x when referring to claim x. For example, when claim 28 is appended to claim 1, R ¹、R ²、R ³、R ^a、R ^b、R ^c、m、n、p、R ^1a、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a and R ^5b in said formula (III) are as defined in claim 1; R ¹、R ²、R ³、R ^a、R ^b、R ^c、m、n、p、R ^1a、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a and R ^5b in said formula (III) are as defined in claim 10 when claim 28 refers to the preceding claim 10, and so on.

In the absence of conflict, it should be understood that the above-described embodiments may be combined in any fashion to form a solution that includes the features of the combined embodiments. Such combined solutions are within the scope of the invention.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of,

In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

In another aspect, the present disclosure provides a method of treating a USP1 mediated disease in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In another aspect, the present disclosure provides the use of a compound of formula (i), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of USP1 mediated diseases.

In another aspect, the present disclosure provides the use of a compound of formula (i), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of USP1 mediated diseases.

In another aspect, the present disclosure provides a compound of formula (i), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating USP1 mediated diseases.

In some embodiments, the USP1 mediated disease is a tumor. For example, a solid tumor.

Definition and description of terms

Unless otherwise indicated, the following terms used in the present disclosure have the following meanings, and the groups and term definitions recited in the present disclosure, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and combined with each other. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.

Herein, a method of manufacturing a semiconductor deviceRepresenting the ligation site.

Herein, multiple arrows in the synthetic routeRepresenting a multi-step reaction.

Herein, keys depicted by solid lines and dashed linesIs a single double bond. For example, componentsThe following two are contemplated:

The compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, and thus the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. Particular geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic or other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the definition of compounds of the disclosure. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms may be present in the substituents such as alkyl groups, and all such isomers and mixtures thereof referred to in the substituents are included within the definition of compounds of the present disclosure. The asymmetric atom containing compounds of the present disclosure may be isolated in optically active pure form or in racemic form, which may be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.

The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl can be unsubstituted (CH ₂CH ₃), monosubstituted (CH ₂CH ₂F、CH ₂CH ₂ Cl, etc.), polysubstituted (CHFCH ₂F、CH ₂CHF ₂、CHFCH ₂Cl、CH ₂CHCl ₂, etc.), or fully substituted (CF ₂CF ₃、CF ₂CCl ₃、CCl ₂CCl ₃, etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.

When any variable (e.g., R ^a、R ^b) occurs more than once in the composition or structure of a compound, its definition in each case is independent. For example, if one group is substituted with 2R ^b, then each R ^b has an independent option.

The linking group referred to herein is arbitrary in its linking direction unless the linking direction is indicated. For example when building blocksWhen L ¹ in (a) is selected from "C ₁-C ₃ alkylene-O", L ¹ may be used to connect the rings Q and R ¹ in the same direction as the reading order from left to right to form "ring Q-C ₁-C ₃ alkylene-O-R ¹", or may be used to connect the rings Q and R ¹ in the opposite direction to the reading order from left to right to form "ring Q-O-C ₁-C ₃ alkylene-R ¹".

When the bond of a substituent is cross-linked to two atoms on a ring, the substituent may be bonded to any atom on the ring. For example, structural unitsR ⁵ may be substituted at any position on the benzene ring.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

C _m-C _n herein refers to a group having an integer number of carbon atoms in the m-n range. For example, "C ₁-C ₁₀" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

The term "alkyl" refers to a hydrocarbon group of the formula C _nH _2n+1. The alkyl group may be linear or branched. For example, the term "C ₁-C ₁₀ alkyl" is understood to mean a straight or branched saturated monovalent hydrocarbon radical having 1,2,3,4, 5,6,7,8,9 or 10 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, etc.; the term "C ₁- ₆ alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, and dialkylamino have the same definition as above.

The "C ₁-C ₁₀ alkyl" as described herein may comprise "C ₁-C ₆ alkyl" or "C ₁-C ₃ alkyl", which "C ₁-C ₆ alkyl" may further comprise "C ₁-C ₃ alkyl".

The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, straight or branched chain, and having at least one double bond. The term "C ₂-C ₁₀ alkenyl" is understood to mean a straight-chain or branched unsaturated hydrocarbon radical which contains one or more double bonds and has 2,3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, a "C ₂-C ₁₀ alkenyl" being preferably a "C ₂-C ₆ alkenyl", more preferably a "C ₂-C ₄ alkenyl", even more preferably a C ₂ or C ₃ alkenyl. It is understood that where the alkenyl group comprises more than one double bond, the double bonds may be separated or conjugated to each other. Specific examples of the alkenyl group include, but are not limited to, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, isopropenyl, 2-methylpropan-2-enyl, 1-methylpropan-2-enyl, 2-methylpropan-1-enyl, (E) -1-methylpropan-1-enyl, or (Z) -1-methylpropan-1-enyl, and the like.

The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms having at least one triple bond. The term "C ₂-C ₁₀ alkynyl" is understood to mean a straight or branched unsaturated hydrocarbon radical which contains one or more triple bonds and has 2,3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Examples of "C ₂-C ₁₀ alkynyl" include, but are not limited to, ethynyl (-C.ident.CH), propynyl (-C.ident.CCH _3、-CH ₂ C.ident.CH), but-1-ynyl, but-2-ynyl, or but-3-ynyl. "C ₂-C ₁₀ alkynyl" may include "C ₂-C ₃ alkynyl" examples of "C ₂-C ₃ alkynyl" include ethynyl (-C.ident.CH), prop-1-ynyl (-C.ident.CCH ₃), prop-2-ynyl (-CH ₂ C.ident.CH).

The term "cycloalkyl" refers to a fully saturated carbocycle in the form of a single ring, a parallel ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. The term "C ₃-C ₁₀ cycloalkyl" is understood to mean a saturated monocyclic, fused, spiro or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, spiro [4.5] decyl, and the like. The term "C ₃-C ₁₀ cycloalkyl" may include "C ₃-C ₆ cycloalkyl" and the term "C ₃-C ₆ cycloalkyl" is understood to mean a saturated mono-or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "heterocyclyl" refers to a fully saturated or partially saturated (wholly not aromatic heteroaromatic) monocyclic, bicyclic, spiro, or bridged ring group containing 1-5 heteroatoms or groups of heteroatoms (i.e., groups containing heteroatoms) in the ring atoms, including but not limited to nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S (=o) ₂-、-S(＝O)-、-P(＝O) ₂ -, -P (=o) -, -NH-, -S (=o) (=nh) -, -C (=o) NH-, or-NHC (=o) NH-, or the like. The term "4-10 membered heterocyclic group" means a heterocyclic group having 4,5, 6,7,8, 9 or 10 ring atoms and containing 1 to 5 heteroatoms or groups of heteroatoms independently selected from the above. "4-10 membered heterocyclyl" includes "4-7 membered heterocyclyl", wherein specific examples of 4 membered heterocyclyl include, but are not limited to, azetidinyl or oxetanyl; specific examples of 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4, 5-dihydro-oxazolyl, or 2, 5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclyl groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H- [1,3,4] thiadiazinyl; specific examples of 7-membered heterocyclyl groups include, but are not limited to, diazepinyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5 membered bicyclic groups include, but are not limited to, hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl; specific examples of 5,6 membered bicyclo groups include, but are not limited to, hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl, 5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazinyl, or 5,6,7, 8-tetrahydroimidazo [1,5-a ] pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group of the above 4-7 membered heterocyclic group, specific examples include, but are not limited to, dihydroisoquinolinyl and the like. "4-10 membered heterocyclic group" may include the ranges of "5-10 membered heterocyclic group", "4-7 membered heterocyclic group", "5-6 membered heterocyclic group", "6-8 membered heterocyclic group", "4-10 membered heterocycloalkyl group", "5-10 membered heterocycloalkyl group", "4-7 membered heterocycloalkyl group", "5-6 membered heterocycloalkyl group", "6-8 membered heterocycloalkyl group" and the like, and "4-7 membered heterocyclic group" may further include the ranges of "4-6 membered heterocyclic group", "5-6 membered heterocyclic group", "4-7 membered heterocycloalkyl group", "4-6 membered heterocycloalkyl group", "5-6 membered heterocycloalkyl group" and the like. Although some bicyclic heterocyclic groups in this disclosure contain in part one benzene ring or one heteroaryl ring, the heterocyclic groups as a whole are not aromatic.

The term "aryl" refers to an all-carbon monocyclic or fused-polycyclic aromatic ring radical having a conjugated pi-electron system. The aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms or 6 to 12 carbon atoms. The term "C ₆-C ₂₀ aryl" is understood to mean an aryl group having from 6 to 20 carbon atoms. In particular a ring having 6 carbon atoms ("C ₆ aryl"), such as phenyl; or a ring having 9 carbon atoms ("C ₉ aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C ₁₀ aryl"), such as tetralin, dihydronaphthyl, or naphthyl; or a ring having 13 carbon atoms ("C ₁₃ aryl"), such as fluorenyl; or a ring having 14 carbon atoms ("C ₁₄ aryl"), such as anthracenyl. The term "C ₆-C ₁₀ aryl" is understood to mean an aryl group having 6 to 10 carbon atoms. In particular a ring having 6 carbon atoms ("C ₆ aryl"), such as phenyl; or a ring having 9 carbon atoms ("C ₉ aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C ₁₀ aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.

The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring system containing at least one ring atom selected from N, O, S and the remaining ring atoms being aromatic ring groups of C. The term "5-10 membered heteroaryl" is understood to include such mono-or bicyclic aromatic ring systems: it has 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and their benzo derivatives, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or the like, and their benzo derivatives, such as quinolinyl, quinazolinyl, or isoquinolinyl, or the like; or an axcinyl group, an indolizinyl group, a purinyl group, etc., and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and which contains 1 to 3, preferably 1 to 2 heteroatoms independently selected from N, O and S.

The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and disclosure.

The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable acids or bases, including salts of compounds with inorganic or organic acids, and salts of compounds with inorganic or organic bases.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

Examples of mammals include, but are not limited to, any member of the class mammalia: human, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human.

The words "comprise" or "include" and variations thereof such as "comprises" or "comprising" are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to.

The present disclosure also includes isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the replacement of one or more atoms by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ²H、 ³H、 ¹¹C、 ¹³C、 ¹⁴C、 ¹³N、 ¹⁵N、 ¹⁵O、 ¹⁷O、 ¹⁸O、 ³¹P、 ³²P、 ³⁵S、 ¹⁸F、 ¹²³I、 ¹²⁵I and ³⁶ Cl, respectively, and the like.

Certain isotopically-labeled compounds of the present disclosure (e.g., labeled with ³ H and ¹⁴ C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes such as ¹⁵O、 ¹³N、 ¹¹ C and ¹⁸ F are useful in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the schemes and/or examples below, by substituting an isotopically-labeled reagent for an non-isotopically-labeled reagent.

The pharmaceutical compositions of the present disclosure may be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.

Typical routes of administration of the compounds of the present disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

The pharmaceutical compositions of the present disclosure may be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulating, emulsifying, lyophilizing, and the like.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.

The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, and the like.

The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

Detailed Description

The present disclosure is further described below in conjunction with specific embodiments, and advantages and features of the present disclosure will become apparent as the description proceeds. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

The disclosed embodiments are merely exemplary and do not constitute any limitation on the scope of the present disclosure. It will be understood by those skilled in the art that various changes and substitutions may be made in the details and form of the technical solutions of the present disclosure without departing from the spirit and scope of the present disclosure, but these changes and substitutions fall within the scope of the present disclosure.

Unless otherwise indicated, the ratio of the mixed solvent is a volume mixing ratio.

The compounds being obtained by hand or by handSoftware naming, commercial compounds are referred to by vendor catalog names.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). The NMR shift was in units of 10-6 (ppm). The solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is Tetramethylsilane (TMS); "IC ₅₀" refers to half the inhibitory concentration, and refers to the concentration at which half the maximum inhibitory effect is achieved.

Example 1:2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6,7,8, 9-tetrahydropyrimido [5,4-b ] [1,4] oxazepine (Compound 1)

Step 1:4- (5- (trifluoromethyl) -1H-imidazol-2-yl) benzonitrile (1C)

3, 3-Dibromo-1, 1-trifluoroacetone (9.9 g,37mmol,1.2 eq) and sodium acetate (3.0 g,37mmol,1.2 eq) were added to water at room temperature and the resulting mixture was heated with stirring at 100℃for 1h. The reaction solution was cooled to room temperature, slowly added dropwise to a solution of 4-cyanobenzaldehyde (4.0 g,30mmol,1.0 eq) in methanol (100 mL), then ammonia (35 mL) was added to the reaction solution, and the reaction was stirred at room temperature for 16 hours. After the solvent was distilled off from the resultant mixture under reduced pressure, the resultant residue was added to water (100 mL) and extracted with ethyl acetate (100 ml×3). The organic phases were combined, washed with saturated brine (50 mL), and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column (petroleum ether: ethyl acetate=5:1-1:1) to give the title compound 1C (4.4 g, yield 61%) as a solid. m/z (ESI) 238[ M+H ] ⁺.

Step 2:4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzonitrile (1D)

Compound 1C (3.0 g,13 mmol) was dissolved in tetrahydrofuran (30 mL) and sodium hydride (content 60%,0.67g,17mmol,1.3 eq) was added in portions at 0deg.C. After stirring the reaction solution at 0℃for 0.5 hours, methyl iodide (3.2 g,22mmol,1.7 eq) was added thereto, and the reaction was slowly returned to room temperature for 2 hours. The reaction was added to ice water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then distilled off under reduced pressure to give the title compound 1D (3.0 g, yield 91%) as a solid. LC-MS: m/z (ESI): 252[ M+H ] ⁺.

Step 3:4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzylamine (1E)

Compound 1D (3.0 g,12 mmol) was added to tetrahydrofuran (60 mL) and lithium aluminum hydride (1.4 g,36mmol,3.0 eq) was added in portions at 0deg.C. The resulting mixture was stirred at 0 ℃ for 1 hour and then slowly returned to room temperature for 1 hour. To the reaction solution was added 1.3mL of water, 1.3mL of 15% aqueous NaOH solution and 3.8mL of water in this order at 0 ℃. The resulting mixture was stirred at room temperature for 1 hour, then filtered through celite, the cake was rinsed with dichloromethane, and the resulting filtrates were combined and the solvent was distilled off under reduced pressure to give the title compound 1E (3.0 g, yield 98%) as an oil. m/z (ESI) 256[ M+H ] ⁺.

Step 4: 2-chloro-4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl methylamino) -5-methoxypyrimidine (1G)

2, 4-Dichloro-5-methoxypyrimidine (0.86 g,3.9 mmol) and N, N-diisopropylethylamine (1.0 g,7.8mmol,2.0 eq) were dissolved in tetrahydrofuran (20 mL) at room temperature, cooled to 0℃and 1E (0.93 g,3.7mmol,1.0 eq) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 2 hours and then heated to 50℃for 16 hours. The reaction was then added to ice water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed once with saturated brine (50 mL), and after removing the solvent by distillation under reduced pressure, the residue was purified by silica gel column (petroleum ether: ethyl acetate=5:1 to 3:1) to give solid 1G (0.90G, yield 58%). m/z (ESI): 398[ M+H ] ⁺.

Step 5: 2-chloro-4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl amino) -5-hydroxypyrimidine (1H)

1G (0.90G, 2.3 mmol) was dissolved in dichloromethane (20 mL) and boron tribromide (12 mL,23mmol,10 eq) was added at 0deg.C. The resulting mixture was heated at 40℃for 16 hours. After quenching by adding methanol (20 mL) at 0deg.C, the resultant reaction solution was distilled off under reduced pressure to remove the solvent. The resulting residue was purified by column on silica gel (petroleum ether: ethyl acetate=3:1-1:2) to give the title compound 1H (0.60 g, yield 67%) as a white solid. m/z (ESI) 384[ M+H ] ⁺.

Step 6: 2-chloro-9- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6,7,8, 9-tetrahydropyrimido [5,4-b ] [1,4] oxazepine (1J)

1H (50 mg,0.13 mmol), 1, 3-dibromopropane (52 mg,0.26mmol,2.0 eq), potassium carbonate (36 mg,0.26mmol,2.0 eq) were added to N, N-dimethylformamide (2 mL) at room temperature. The resulting mixture was reacted at 50℃for 3 hours under nitrogen protection, then the system was heated to 100℃for 2 hours, cooled to room temperature, and the reaction mixture was purified by reverse phase column to give 1J (27 mg, yield 49%). m/z (ESI) 424[ M+H ] ⁺.

Step 7:2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6,7,8, 9-tetrahydropyrimido [5,4-b ] [1,4] oxazepine (Compound 1)

1J (27.00 mg,0.064 mmol), 1K (18.62 mg,0.096mmol,1.5 eq), potassium carbonate (17.69 mg,0.128mmol,2.0 eq), pd (dppf) Cl ₂-CH ₂Cl ₂ (0.9 mg, 1.28. Mu. Mol,0.20 eq) were added to a mixed solution of dioxane (2 mL) and water (0.5 mL) at room temperature. The resulting mixture was subjected to microwave reaction at 100℃for 1 hour under nitrogen protection. The reaction solution was cooled, filtered through celite, the filter cake was rinsed with ethyl acetate, the obtained filtrates were combined and the solvent was distilled off under reduced pressure to give the crude compound, which was purified by preparative chromatography (Waters AutoP, xbridge-C18, 19 x 150mm, gradient elution with 20-75% acetonitrile in water, 15 mL/min) to give the title compound 1 as a solid (4 mg, yield) 12％).m/z(ESI):538[M+H] ⁺. ¹H NMR(400MHz,DMSO)δ8.57(s,1H),8.03(s,1H),7.90(s,1H),7.66(d,J＝8.2Hz,2H),7.42(d,J＝8.2Hz,2H),4.85(s,2H),4.26(t,J＝6.6Hz,2H),3.83(s,3H),3.76(s,3H),3.69–3.61(m,2H),2.11(dd,J＝11.8,6.2Hz,2H),1.84–1.72(m,1H),1.02–0.91(m,2H),0.81(dd,J＝8.0,3.2Hz,2H).

Example 2:2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5-methyl-9- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5,7,8, 9-tetrahydro-6H-pyrimido [4,5-b ] [1,4] diazepin-6-one (Compound 2)

Step 1: 2-chloro-N- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5-nitropyrimidin-4-amine (2B)

2, 4-Dichloro-5-nitropyrimidine (708 mg,3.65 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, after which diisopropylethylamine (1.01 g,7.84mmol,2.0 eq) was added and compound 1E (932 mg,3.65mmol,1.0 eq) was added with stirring at 0deg.C. The resulting mixture was slowly returned to room temperature after 0.5 hours of reaction at 0℃and the reaction was continued with stirring for 2 hours. The reaction was added to ice water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column (PE: ea=5:1-3:1) to give compound 2B (900 mg, yield 59.7%). m/z (ESI) 413[ M+H ] ⁺.

Step 2: 2-chloro-N4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrimidine-4, 5-diamine (2C)

Reduced iron powder (676.5 mg,12.11mmol,10 eq) was added to water (5 mL) and ethanol (5 mL) at room temperature, followed by ammonium chloride (640 mg,12.11mmol,10 eq) and compound 2B (500 mg,1.211 mmol) was added after stirring at 100℃for 1 hour. The resulting mixture was stirred at 80℃for a further 1 hour. To the reaction mixture was added 25mL of ethyl acetate, which was then diluted, and the mixture was filtered while it was still hot, and the cake was rinsed with ethyl acetate. The resulting organic phase was washed with saturated brine (20 mL), and the solvent was distilled off under reduced pressure. The resulting residue was purified by a silica gel column (PE: ea=1:1) to give compound 2C (0.35 g, yield 75.5%). m/z (ESI): 383[ M+H ] ⁺.

Step 3: 3-chloro-N- (2-chloro-4- ((4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) amino) pyrimidin-5-yl) propanamide (2E)

2C (500.0 mg,1.3 mmol) and potassium carbonate (361.1 mg,2.6 mmol) were added to N-methylpyrrolidone (5 mL) at room temperature, and 2-chloropropionyl chloride (199.0 mg,1.6mmol, 149.6. Mu.L) was added with stirring at 0 ℃. After stirring the reaction at 0 ℃ for 1 hour, the reaction solution was added to water (20 mL) and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), and the solvent was distilled off under reduced pressure. The residue obtained was purified (PE: ea=2:1-1:1) with a silica gel column to 500mg of crude 2E. m/z (ESI) 473.0[ M+H ] ⁺.

Step 4: 2-chloro-9- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5,7,8, 9-tetrahydro-6H-pyrimido [4,5-b ] [1,4] diazepin-6-one (2F)

2E (500.0 mg, crude, ca. 1.1 mmol) was added to N, N-dimethylformamide (40 mL) at room temperature followed by potassium carbonate (292.0 mg,2.1 mmol). After the resulting mixture was stirred at 60 ℃ for 2 hours, 100mL of water was added to the reaction solution, and extracted three times with ethyl acetate (40 ml×3), and the resultant organic phases were combined, washed with saturated brine (50 mL), and the solvent was distilled off under reduced pressure. The resulting residue was purified by reverse phase C18 silica gel column (acetonitrile: water=1:3-3:1 gradient elution) to give 2F (127 mg, yield 28%). m/z (ESI) 437.1[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d ₆)δ8.19(s,1H),7.92–7.88(m,1H),7.64(d,J＝8.3Hz,2H),7.35(d,J＝8.3Hz,2H),6.24(t,J＝3.1Hz,1H),5.18(s,2H),3.76(s,3H),3.72–3.65(m,2H),2.77–2.70(m,2H).

Step 5:2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5,7,8, 9-tetrahydro-6H-pyrimido [4,5-b ] [1,4] diazepin-6-one (2G)

1K (39.5 mg, 183.1. Mu. Mol), 2F (50.0 mg, 114.5. Mu. Mol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (18.0 mg, 22.9. Mu. Mol), potassium phosphate (72.9 mg, 343.4. Mu. Mol) were added to a mixed solvent of dioxane (1 mL) and water (0.01 mL) at room temperature, and the mixture was stirred under nitrogen at 100℃for 4 hours. The resulting mixture was purified by C18 reverse phase silica gel column (acetonitrile: water=1:3-3:1 gradient elution) to give 2G (29 mg, yield 46%). m/z (ESI): 551.1[ M+H ] ⁺.

Step 6:2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5-methyl-9- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5,7,8, 9-tetrahydro-6H-pyrimido [4,5-b ] [1,4] diazepin-6-one (Compound 2)

2G (8.0 mg, 14.5. Mu. Mol) was added to N, N-dimethylformamide (1 mL), sodium hydride (697.5. Mu.g, 17.4. Mu. Mol, content 60%) was added at 0℃and the reaction was stirred for 10 minutes, and then methyl iodide (2.1 mg, 14.5. Mu. Mol, 7.16. Mu.L) was added thereto, and the reaction was continued for 20 minutes. The resulting mixture was prepared by prep HPLC (Waters AutoP, xbridge-C18, 19X 150mm, gradient elution with 20-75% acetonitrile in water, 15 mL/min) to give Compound 2 (3.0 mg, yield) 37％).m/z(ESI):565.2[M+H] ⁺. ¹H NMR(400MHz,DMSO-d ₆)δ8.63(s,1H),8.61(s,1H),7.90(s,1H),7.60(d,J＝8.3Hz,2H),7.34(d,J＝8.3Hz,2H),5.21(s,2H),3.81(s,3H),3.74(s,3H),3.65(t,J＝6.2Hz,2H),2.94(s,3H),2.69(t,J＝6.2Hz,2H),1.67(m,1H),1.00(m,2H),0.80(m,2H).

Example 3:2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -11- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7,8,9 a-tetrahydro-5H-pyrimido [4,5-e ] pyrrolo [1,2-a ] [1,4] diazepine-5, 10 (11H) -dione (compound 3)

Step 1: 2-chloro-4- ((4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) amino) pyrimidine-5-carboxylic acid ethyl ester (3C)

Compound 3A (500 mg,2.48 mmol) was added to N, N-dimethylformamide (10 mL), naH (119.04 mg,2.98mmol, 60%) was added in portions at 0deg.C, and then compound 3B (791.43 mg,2.48 mmol) was added. The resulting mixture was stirred at room temperature for 2h. To the reaction mixture was added 10mL of saturated ammonium chloride solution to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL. Times.3). The organic phases were combined, washed with saturated brine (20 mL), and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE: ea=5:1 to 1:1) to give compound 3C (400 mg, yield 36.7％).m/z(ESI):440.0[M+H] ⁺. ¹H NMR(400MHz,Chloroform-d)δ8.77(br.s,1H),8.71(s,1H),7.63(d,J＝8.3Hz,2H),7.45(d,J＝8.3Hz,2H),7.32(s,1H),4.81(d,J＝5.8Hz,2H),4.36(q,J＝7.1Hz,2H),3.77(s,3H),1.39(t,J＝7.1Hz,3H).

Step 2:4' -cyclopropyl-6 ' -methoxy-4- ((4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) amino) - [2,5' -bipyrimidine ] -5-carboxylic acid ethyl ester (3D)

1K(135.85mg,700.29μmol),3C(280mg,636.63μmol),K ₃PO ₄(405.40mg,1.91mmol),XPhos Pd G2(100.18mg,127.33μmol) Was added to a mixed solvent of dioxane (4 mL) and H ₂ O (1 mL) at room temperature. The resulting mixture was stirred under nitrogen at 100℃for 4h. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by column chromatography over silica gel (PE: ea=5:1-1:2) to give compound 3D (270 mg, yield 76.6%). m/z (ESI): 554.2[ M+H ] ⁺.

Step 3:4' -cyclopropyl-6 ' -methoxy-4- ((4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) amino) - [2,5' -bipyrimidine ] -5-carboxylic acid (3E)

3D (100 mg, 180.66. Mu. Mol) lithium hydroxide (12.98 mg, 541.97. Mu. Mol) was added to methanol (3 mL) and 0.5mL of water at room temperature. The resulting solution was stirred at 60℃for 2h. The pH of the reaction solution was adjusted to 4 with hydrochloric acid, the solvent was removed by distillation under the reduced pressure, and the resultant mixture was slurried with ethyl acetate and washed with water to give 3E (50 mg, 95.15. Mu. Mol, yield 52.67%) as a white solid. m/z (ESI): 526.1[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d ₆)δ9.13(br.s,1H),8.85(s,1H),8.63(s,1H),7.92(s,1H),7.65(d,J＝8.3Hz,2H),7.44(d,J＝8.3Hz,2H),4.78(d,J＝6.1Hz,2H),3.83(s,3H),3.76(s,3H),1.77–1.67(m,1H),1.03–0.92(m,2H),0.83–0.76(m,2H).

Step 4: (4 ' -cyclopropyl-6 ' -methoxy-4- ((4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) amino) - [2,5' -bipyrimidine ] -5-carbonyl) proline methyl ester (3G)

3E (80.0 mg, 152.2. Mu. Mol), N, N-diisopropylethylamine (78.7 mg, 608.9. Mu. Mol, 106.1. Mu.L), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (68.9 mg, 182.7. Mu. Mol) was added to dichloromethane (2 mL), followed by 3F (30.3 mg, 182.7. Mu. Mol). The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by column chromatography over silica gel (PE: ea=5:1-1:2) to give compound 3G (90 mg, yield 93%). m/z (ESI): 637.2[ M+H ] ⁺.

Step 5: (4 ' -cyclopropyl-6 ' -methoxy-4- ((4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) amino) - [2,5' -bipyrimidine ] -5-carbonyl) proline (3H)

3G (130.0 mg, 204.2. Mu. Mol) lithium hydroxide (13.0 mg, 543. Mu. Mol) was added to methanol (3 mL) and water (0.2 mL). The resulting solution was reacted at room temperature for 2 hours, the pH of the reaction solution was adjusted to 4 with hydrochloric acid, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by a reverse phase C18 silica gel column (acetonitrile: water=1:9-2:1 gradient elution) to give compound 3H (45 mg, yield 35%). m/z (ESI): 623.1[ M+H ] ⁺.

Step 6:2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -11- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7,8,9 a-tetrahydro-5H-pyrimido [4,5-e ] pyrrolo [1,2-a ] [1,4] diazepine-5, 10 (11H) -dione (compound 3)

3H (40.0 mg, 64.3. Mu. Mol), N, N-diisopropylethylamine (33.2 mg, 257.0. Mu. Mol, 44.8. Mu.L), HATU (29.1 mg, 77.1. Mu. Mol) was added to dichloromethane (2 mL). The resulting mixture was distilled under reduced pressure and the residue was prepared by prep HPLC (Waters AutoP, xbridge-C18, 19 x 150mm, gradient elution of 20-75% acetonitrile in water, 15 mL/min) to give compound 3 (15 mg, 39% yield). m/z (ESI) 605.2[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d ₆)δ9.22(s,1H),8.68(s,1H),7.91(s,1H),7.61(d,J＝8.2Hz,2H),7.35(d,J＝8.2Hz,2H),5.39(d,J＝15.7Hz,1H),5.26(d,J＝15.6Hz,1H),4.71(dd,J＝7.7,2.1Hz,1H),3.84(s,3H),3.74(s,3H),3.67(m,1H),3.55(m,1H),2.13–1.86(m,4H),1.80(m,1H),1.07–1.01(m,2H),0.88–0.83(m,2H).

Example 4:2'- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6' -methyl-9 '- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) spiro [ cyclopropane-1, 7' -pyrimido [4,5-e ] [1,4] diazepin ] -5',8' (6 'H,9' H) -dione (compound 4)

By using similar synthetic procedures and operations for compound 3, the compound can be prepared by substituting 3F in step 4 with 4A 4.m/z(ESI):605.2[M+H] ⁺. ¹H NMR(400MHz,DMSO-d ₆)δ9.10(s,1H),8.61(s,1H),7.85(d,J＝1.3Hz,1H),7.56(d,J＝8.3Hz,2H),7.20(d,J＝8.1Hz,2H),5.28–5.13(m,2H),3.78(s,3H),3.68(s,3H),3.02(s,3H),1.66(tt,J＝8.1,4.6Hz,1H),1.44(dt,J＝10.7,6.8Hz,1H),1.32(dt,J＝10.2,6.9Hz,1H),1.19–1.05(m,1H),0.96(s,2H),0.81(dd,J＝7.9,3.4Hz,2H).

Example 5:2' - (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9' - (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5',9' -dihydrospiro [ cyclopropane-1, 7' -pyrimido [4,5-b ] [1,4] diaza] -8 '(6'H) -one (Compound 5)

Step 1: n- (5-amino-2-chloropyrimidin-4-yl) -1- (chloromethyl) -N- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) cyclopropane-1-carboxamide (5B)

Compound 5A (200.0 mg,1.7 mmol) was added to thionyl chloride (2 mL) and reacted for 2h at 80 ℃. After distillation under reduced pressure, the residue was dissolved in methylene chloride (1 mL), and N, N-diisopropylethylamine (445.2 mg,3.4 mmol) and a solution of 2C (659.3 mg,1.7 mmol) in methylene chloride (5 mL) were added dropwise slowly at-20 ℃. The resulting mixture was kept at-20℃for further reaction for 1 hour, the solvent was distilled off under reduced pressure, and the resulting residue was purified by a silica gel column (PE: EA=5:1-1:1) to give 190mg of crude 5B.

Step 2:2' -chloro-9 ' - (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5',9' -dihydrospiro [ cyclopropane-1, 7' -pyrimido [4,5-b ] [1,4] diazoheptyl ] -8' (6'H) -one (5C)

5B (180.0 mg, 360.5. Mu. Mol) and potassium carbonate (99.6 mg, 721.0. Mu. Mol) were added to N, N-dimethylformamide (10 mL) at room temperature, and the reaction mixture was stirred at 50℃for 2 hours. The reaction mixture was added to water (30 mL), and extracted with ethyl acetate (20 mL. Times.3). The resultant organic phases were combined and washed with saturated brine (20 mL), and the solvent was distilled off under reduced pressure to give 180mg of crude 5C. m/z (ESI): 463.0[ M+H ] ⁺.

Step 3:2' - (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9' - (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5',9' -dihydrospiro [ cyclopropane-1, 7' -pyrimido [4,5-b ] [1,4] diazepin ] -8' (6'H) -one (compound 5)

1K (150.9 mg, 777.8. Mu. Mol), 5C (180.0 mg, 388.9. Mu. Mol), XPhos Pd G2 (61.2 mg, 77.8. Mu. Mol), potassium phosphate (247.6 mg,1.2 mmol) were added to a mixed solution of water (0.1 mL) and dioxane (2 mL) at room temperature, and the resultant reaction mixture was reacted at 100℃for 4 hours under nitrogen protection, and purified by a reverse phase C18 silica gel column (acetonitrile: water=1:9-2:1 gradient elution) to give compound 5. (150 mg, yield) 67％).m/z(ESI):577.2[M+H] ⁺. ¹H NMR(400MHz,DMSO-d ₆)δ8.60(s,1H),8.39(s,1H),7.91(s,1H),7.61(d,J＝8.1Hz,2H),7.30(d,J＝8.0Hz,2H),6.42(t,J＝3.2Hz,1H),5.26(s,2H),3.81(s,3H),3.75(s,3H),3.53(d,J＝3.2Hz,2H),1.62(m,1H),0.97(s,4H),0.79(m,4H).

Example 6:2'- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5' -methyl-9 '- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5',9 '-dihydrospiro [ cyclopropane-1, 7' -pyrimido [4,5-b ] [1,4] diaza] -8 '(6'H) -one (Compound 6)

To the reaction flask was added compound 5 (58.0 mg, 100.6. Mu. Mol), 1, 8-diazabicyclo [5.4.0] undec-7-ene (30.6 mg, 201.2. Mu. Mol, 30.0. Mu.L), dissolved in N' N-dimethylformamide (2 mL), and methyl iodide (14.3 mg, 100.6. Mu. Mol, 6.3. Mu. L) was added dropwise. The resulting mixture was reacted at 60℃for 16h. The mixture was directly prepared by prep HPLC (Waters AutoP, xbridge-C18, 19X 150mm, gradient elution with 20-75% acetonitrile in water, 15 mL/min) to give compound 6 (10 mg, yield) 17％).m/z(ESI):591.2[M+H] ⁺. ¹H NMR(400MHz,DMSO-d ₆)δ8.78(s,1H),8.48(s,1H),7.93(s,1H),7.56(d,J＝8.3Hz,2H),7.24(d,J＝8.2Hz,2H),5.33(d,J＝15.5Hz,1H),5.17(d,J＝15.6Hz,1H),3.87(s,3H),3.86(s,3H),3.73(s,3H),3.67–3.52(m,2H),1.73(m,1H),1.04(s,4H),0.86–0.81(m,4H).

Example 7:2'- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5' -methyl-9 '- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -8',9 '-dihydrospiro [ cyclopropane-1, 7' -pyrimido [4,5-b ] [1,4] diaza5' H) -one (Compound 7)

Step 1:1- (((4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) amino) methyl) cyclopropane-1-carboxylic acid ethyl ester (7B)

3B (2.2 g,7.0 mmol), 7A (1.0 g,7.0 mmol) and N' N-diisopropylethylamine (2.7 g,21.0mmol,3.7 mL) were added to dioxane (10 mL). The resulting mixture was reacted at 90℃for 2 hours. The solvent was removed by rotary evaporation under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (PE: ea=3:1-1:2) to give 7B (1.2 g, yield 46%). m/z (ESI): 382.1[ M+H ] ⁺.

Step 2:1- (((2-chloro-5-nitropyrimidin-4-yl) (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) amino) methyl) cyclopropane-1-carboxylic acid ethyl ester (7C)

7B (1.1 g,2.9 mmol), N' N-diisopropylethylamine (1.2 g,8.9mmol,1.6 mL) was dissolved in dioxane (20 mL) and 2A (574.7 mg,2.9 mmol) was added at-20deg.C. The resulting mixture was reacted at this temperature for 2 hours. The solvent was removed by rotary evaporation under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (PE: ea=3:1-1:2) to give 7C (1.4 g, yield 89%). m/z (ESI) 539.1[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d ₆)δ8.94(s,1H),7.94(s 1H),7.68(d,J＝8.3Hz,2H),7.37(d,J＝8.2Hz,2H),4.94(s,2H),3.91(q,J＝7.1Hz,2H),3.77(s,3H),3.65(s,2H),1.13(m,2H),1.00(m,2H),0.93(t,J＝7.1Hz,3H).

Step 3:1- (((4 ' -cyclopropyl-6 ' -methoxy-5-nitro- [2,5' -bipyrimidin ] -4-yl) (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) amino) methyl) cyclopropane-1-carboxylic acid ethyl ester (7D)

7C (600.0 mg,1.1 mmol), 1K (432.0 mg,2.2 mmol), 1,3,5, 7-tetramethyl-8-phenyl-2, 4, 6-trioxa-8-phosphamantane (65.2 mg, 222.7. Mu. Mol), tris (dibenzylideneacetone) dipalladium (203.9 mg, 222.7. Mu. Mol), potassium carbonate (307.7 mg,2.2 mmol) were added to a mixed solvent of water (0.1 mL) and dioxane (2 mL) at room temperature. The resulting mixture was stirred under nitrogen at 70℃for 4h. The solvent was removed by rotary evaporation under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (PE: ea=3:1-0:1) to give 7D (207 mg, yield 57%). m/z (ESI): 653.2[ M+H ] ⁺.

Step 4:2' - (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9' - (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -8',9' -dihydrospiro [ cyclopropane-1, 7' -pyrimido [4,5-b ] [1,4] diazepin ] -6' (5 ' H) -one (7E)

Iron powder (34.2 mg, 612.9. Mu. Mol) was added to acetic acid (3 mL) at room temperature, followed by 7D (80.0 mg, 122.6. Mu. Mol). The resulting mixture was reacted at 90℃for 2 hours. Excess acetic acid was removed by rotary evaporation under reduced pressure, and the pH was adjusted to 5-6 with aqueous sodium hydrogencarbonate, followed by extraction with ethyl acetate (10 mL. Times.3). The organic phases were combined, washed with saturated brine (20 mL), and the solvent was distilled off under reduced pressure. The resulting residue was purified with a reverse phase C18 silica gel column (acetonitrile: water=1:9-2:1 gradient elution) to give compound 7E (70 mg, crude). m/z (ESI): 577.2[ M+H ] ⁺.

Step 5:2'- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5' -methyl-9 '- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -8',9 '-dihydrospiro [ cyclopropane-1, 7' -pyrimido [4,5-b ] [1,4] diaza6 '(5' H) -one (7)

7E (60.0 mg, 104.1. Mu. Mol), sodium hydride (5.0 mg, 124.9. Mu. Mol, 60% content) was added to N' N-dimethylformamide (2 mL) at room temperature, and methyl iodide (14.8 mg, 104.1. Mu. Mol, 6.5. Mu.L) was added. The reaction was continued at room temperature for 1h. The reaction mixture was quenched with saturated aqueous sodium chloride (6 mL), extracted with ethyl acetate (6 mL. Times.3), the organic phases combined and the crude product obtained by rotary evaporation under reduced pressure was prepared by prep HPLC (Waters AutoP, xbridge-C18, 19X 150mm, gradient elution with 20-75% acetonitrile in water, 15 mL/min) to give Compound 7 (18 mg, yield) 29％).m/z(ESI):591.2[M+H] ⁺. ¹H NMR(400MHz,DMSO-d ₆)δ8.61(s,1H),8.36(s,1H),7.93(s,1H),7.67(d,J＝8.3Hz,2H),7.42(d,J＝8.2Hz,2H),4.86(s,2H),3.87(s,3H),3.76(s,3H),3.60(s,2H),3.28(s,3H),1.81(m,1H),1.00(m,4H),0.88(m,2H),0.60–0.53(m,2H).

Example 8:2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7, 7-difluoro-5-methyl-9- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5,7,8, 9-tetrahydro-6H-pyrimidine [4,5-b ] [1,4] diazepin-6-one (Compound 8)

Step 1: ethyl 2, 2-difluoro-3- ((4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) amino) propionate (8C)

8B (352.8 mg,1.9 mmol) and 8A (473.0 mg,1.9 mmol) were dissolved in dichloromethane (20 mL) at room temperature. The resulting solution was added sodium triacetoxyborohydride (1.2 g,5.6 mmol) at 0℃and reacted with stirring at 0℃for 2 hours. The solvent was removed by rotary evaporation under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (PE: ea=3:1-0:1) to give 8C (580 mg, yield 80%). m/z (ESI): 392.1[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d ₆)δ7.95–7.91(m,1H),7.67(d,J＝8.3Hz,2H),7.44(d,J＝8.3Hz,2H),4.30(q,J＝7.1Hz,2H),3.80(s,2H),3.78(s,3H),3.15(t,J＝14.1Hz,2H),1.25(d,J＝7.1Hz,3H).

Compound 8D can be synthesized by a similar method and procedure as in step 2-4 in the synthesis of compound 7. m/z (ESI): 587.2.

Compound 8 can be synthesized by a similar method and procedure as step 5 in the synthesis of compound 7. m/z (ESI): 601.2.

¹H NMR(400MHz,DMSO-d ₆)δ8.64(s,1H),8.62(s,1H),7.95–7.93(m,1H),7.69(d,J＝8.3Hz,2H),7.42(d, J＝8.3Hz,2H),4.97(s,2H),4.23(t,J＝12.9Hz,2H),3.84(s,3H),3.77(s,3H),3.46(s,3H),1.72(m,1H),0.99(m,2H),0.83(m,2H).

Example 9: 5-cyclopropyl-2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7, 7-difluoro-9- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5,7,8, 9-tetrahydro-6H-pyrimidine [4,5-b ] [1,4] diazepin-6-one (Compound 9)

8D (60.0 mg, 102.3. Mu. Mol), cyclopropylboronic acid (17.6 mg, 204.6. Mu. Mol), pyridine (8.1 mg, 102.3. Mu. Mol, 8.2. Mu. L), copper acetate (18.6 mg, 102.3. Mu. Mol), cesium carbonate (16.7 mg, 51.2. Mu. Mol) were mixed in toluene (10.0 mL). The obtained mixed reaction solution was stirred at 80℃under an oxygen atmosphere for 4 hours. The residue was concentrated under reduced pressure and prepared by prep HPLC (Waters AutoP, xbridge-C18, 19 x 150mm, gradient elution with 20-80% acetonitrile in water, 15 mL/min) to give compound 9 (10 mg, yield) 16％).m/z(ESI):627.2[M+H] ⁺. ¹H NMR(400MHz,DMSO-d ₆)δ8.70(s,1H),8.62(s,1H),7.94(s,1H),7.68(d,J＝8.2Hz,2H),7.38(d,J＝8.2Hz,2H),4.94(s,2H),4.20(t,J＝12.6Hz,2H),3.84(s,3H),3.76(s,3H),3.42(m,1H),1.67(m,1H),1.06–0.93(m,4H),0.83(m,2H),0.59–0.51(m,2H).

Example 10:2' - (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9' - (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -8',9' -dihydrospiro [ cyclobutane-1, 5' -pyrimido [4,5-e ] [1,4] diazepine] -7 '(6'H) -one (Compound 10)

Step 1: N-Cyclobutylene-2-methylpropane-2-sulfinamide (10C)

10A (10.0 g,142.0 mmol) and 10B (15.7 g,130 mmol) were dissolved in tetrahydrofuran (100 mL), and tetraethyltitanate (88.8 g,389.0 mmol) was added. The resulting mixture was reacted at 50℃for 5 hours. To the reaction mixture were added ice water (200 mL) and ethyl acetate (200 mL), followed by addition of saturated sodium bicarbonate (40.0 mL), and stirring was continued for 1h. The mixture was filtered, the filter cake was washed with ethyl acetate, the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=10:1-3:1) at 10C (13 g, yield 58%).

Step 2: n- (1- (2-chloro-4- (methylthio) pyrimidin-5-yl) cyclobutyl) -2-methylpropan-2-sulfinamide (10E)

10D (1.5 g,6.4 mmol) was dissolved in toluene (12.0 mL), replaced with nitrogen 3 times, n-butyllithium (1.6M, 4.7 mL) was added dropwise at-78 ℃, -reaction was performed at 78 ℃ for 5min, and then a solution of 10C (1.0 g,5.8 mmol) in toluene (12.0 mL) was slowly added. The resulting reaction solution was stirred at-78℃for 30 minutes. The reaction solution was concentrated directly to dryness, and the obtained crude product was purified by silica gel column (dichloromethane: methanol=100:1-10:1) to give compound 10E (0.9 g, yield 47%). m/z (ESI): 334.1[ M+H ] ⁺.

Step 3:1- (2-chloro-4- (methylthio) pyrimidin-5-yl) cyclobutan-1-amine (10F)

10E (300.0 mg, 898.0. Mu. Mol) was dissolved in hydrochloric acid-ethyl acetate (2.0 mol/L,3.0 mL) and reacted at room temperature for 1h. Ethyl acetate (5.0 mL) was added to the reaction mixture to dilute it, followed by adding water (15.0 mL), and the aqueous phase was separated after stirring. The aqueous phase was adjusted to ph=8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (10.0 ml of x 3). The resulting organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 10F (300 mg, crude).

Step 4: (1- (2-chloro-4- (methylthio) pyrimidin-5-yl) cyclobutyl) carbamic acid tert-butyl ester (10G)

10F (300.0 mg,1.3 mmol) was dissolved in dichloromethane (3.0 mL) and N, N-diisopropylethylamine (422.0 mg, 568.0. Mu.L) and di-tert-butyl dicarbonate (570.0 mg, 600.0. Mu.L) were added. The resulting mixed solution was reacted at room temperature for 2 hours. The reaction solution was concentrated directly, and the obtained crude product was purified by silica gel column (PE: ea=100:1-10:1) to obtain 10G (280 mg, yield 65%). m/z (ESI) 330.1[ M+H ] ⁺.

Step 5: (1- (2-chloro-4- (methylsulfonyl) pyrimidin-5-yl) cyclobutyl) carbamic acid tert-butyl ester (10H)

10G (280.0 mg, 848.0. Mu. Mol) was dissolved in methylene chloride (3.0 mL), and m-chloroperoxybenzoic acid (465.0 mg,2.3 mmol) was added. The resulting mixture was reacted at room temperature for 3 hours. Methylene chloride (10.0 mL) was added to the reaction mixture to dilute it, which was then washed with saturated sodium thiosulfate (10.0 mL). The organic phase was washed with saturated sodium bicarbonate (10.0 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained after concentration was purified by column on silica gel (petroleum ether: ethyl acetate=10:1-3:1) to give 10H (190 mg, yield 62%). M/z (ESI): 362.1[ M+H ] ⁺.

Step 6: (1- (2-chloro-4- ((4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) amino) pyrimidin-5-yl) cyclobutyl) carbamic acid tert-butyl ester (10I)

Intermediate 1E (106.0 mg, 414.0. Mu. Mol) was dissolved in N, N-dimethylformamide (1.0 mL), N-diisopropylethylamine (161.0 mg,1.2 mmol) was added, followed by 10H (150.0 mg, 414.0. Mu. Mol). The resulting mixture was reacted at room temperature for 3 hours. The reaction mixture was diluted with water (10.0 mL), extracted with ethyl acetate (10.0 mL of 3), and the organic phase was washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained after concentration was purified by silica gel column (petroleum ether: ethyl acetate=10:1-2:1) to give 10I (100 mg, yield 45%). m/z (ESI): 537.1[ M+H ] ⁺.

Step 7:5- (1-Aminocyclobutyl) -2-chloro-N- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrimidin-4-amine (10J)

Intermediate 10I (80.0 mg, 149.0. Mu. Mol) was dissolved in hydrochloric acid-dioxane (1.0 mL) and reacted at room temperature for 1h. The reaction solution was directly dried by spin to give 10J (80 mg, crude product). m/z (ESI) 437.1[ M+H ] ⁺.

Step 8: 2-chloro-N- (1- (2-chloro-4- ((4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) amino) pyrimidin-5-yl) cyclobutyl) acetamide (10L)

A solution of chloroacetyl chloride (24.8 mg, 219.9. Mu. Mol) in dichloromethane (0.5 mL) was slowly added to a solution of 10L (100.0 mg, 219.9. Mu. Mol) and N, N-diisopropylethylamine (91.2 mg, 706.9. Mu. Mol) in anhydrous dichloromethane (5 mL) at 0deg.C. After stirring the resulting mixture for 2 hours, the reaction solution was added to a mixed solvent of water and ethyl acetate, and extracted three times with ethyl acetate, the organic phases were combined and dried by spinning, and 10L (100 mg, yield 82%) of the crude product was obtained by column chromatography (dichloromethane: methanol=100:0-98:2). m/z (ESI): 513.0[ M+H ] ⁺.

Step 9: 2-chloro-9 '- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -8',9 '-dihydrospiro [ cyclobutane-1, 5' -pyrimido [4,5-e ] [1,4] diazoheptyl ] -7 '(6'H) -one (10M)

Potassium carbonate (80.8 mg, 584.4. Mu. Mol) was added to a solution of 10L (100.0 mg, 194.8. Mu. Mol) of N' N-dimethylformamide (20 mL) at room temperature. After the mixture was stirred at 50 ℃ for 2 hours, 20mL of water was added to the reaction solution, and extraction was performed with dichloromethane (10.0 mL of 3). The organic phases were combined and dried by spin-drying, and column chromatography (dichloromethane: methanol=100:0-95:5) gave 10M (80 mg, 86% yield). m/z (ESI): 477.1[ M+H ] ⁺ step 10:2' - (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9' - (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -8',9' -dihydrospiro [ cyclobutane-1, 5' -pyrimido [4,5-e ] [1,4] diazepine] -7 '(6'H) -one (Compound 10)

10M (47.0 mg, 98.6. Mu. Mol), 1K (38.2 mg, 197.1. Mu. Mol), XPhos Pd G2 (15.5 mg, 19.7. Mu. Mol), potassium phosphate (62.8 mg, 295.7. Mu. Mol) was added to a mixed solvent of water (0.1 mL) and dioxane (1.0 mL). After the resulting mixture was stirred at 100 ℃ for 2 hours under nitrogen, 10mL of water was added and extracted with dichloromethane (10 mL of 6). The organic phases were combined, dried by spin-drying, and purified by column chromatography (dichloromethane: methanol=100:0-96:4) to give compound 10 (20 mg, yield 34％).m/z(ESI):591.2[M+H] ^+.. ¹H NMR(400MHz,DMSO-d ₆)δ8.61(s,1H),8.60(s,1H),8.58(s,1H),7.95–7.91(m,1H),7.64(d,J＝8.3Hz,2H),7.36(d,J＝8.4Hz,2H),5.01(s,2H),4.10(s,2H),3.81(s,3H),3.76(s,3H),2.80–2.70(m,2H),2.47–2.38(m,2H),1.99–1.89(m,2H),1.76–1.67(m,1H),0.96–0.91(m,2H),0.80–0.72(m,2H).

Example 11:2'- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6' -methyl-9 '- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -8',9 '-dihydrospiro [ cyclobutane-1, 5' -pyrimido [4,5-e ] [1,4] diazepin ] -7 '(6'H) -one (compound 11)

A solution of methyl iodide (21.6 mg, 152.4. Mu. Mol) in N 'N-dimethylformamide (0.5 mL) was added dropwise to a solution of compound 10 (30.0 mg, 50.8. Mu. Mol) and cesium carbonate (49.7 mg, 152.4. Mu. Mol) in N' N-dimethylformamide (1 mL). The mixture was reacted at room temperature for 2h. The mixture was directly prepared by prep HPLC (Waters AutoP, xbridge-C18, 19X 150mm, gradient elution with 20-75% acetonitrile in water, 15 mL/min) to give compound 11 (4 mg, yield) 13％).m/z(ESI):605.2[M+H] ⁺. ¹H NMR(400MHz,DMSO-d ₆)δ8.60(s,1H),8.56(s,1H),7.95(s,1H),7.66(d,J＝8.2Hz,2H),7.35(d,J＝8.1Hz,2H),5.03(s,2H),4.29(s,2H),3.81(s,3H),3.76(s,3H),2.77(s,3H),2.75–2.69(m,2H),2.65–2.60(m,2H),1.81–1.70(m,3H),0.99–0.91(m,2H),0.83–0.75(m,2H).

Example 12:2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5, 5-dimethyl-9- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5,6,8, 9-tetrahydro-7H-pyrimidine [4,5-e ] [1,4] diazepin-7-one (Compound 12)

Referring to the synthetic route and procedure analogous to compound 10, compounds can be made by substituting acetone for cyclobutanone in step 1 12.m/z(ESI):579.2[M+H] ⁺. ¹H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.44(s,1H),7.93(s,1H),7.85(s,1H),7.61-7.54(m,2H),7.34-7.26(m,2H),4.92(s,2H),4.12(s,2H),3.74(s,3H),3.69(s,3H),1.66(s,6H),1.65(m,1H),0.88(m,2H),0.72(m,2H).

Example 13:2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5, 5-dimethyl-9- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6,7,8, 9-tetrahydro-5H-pyrimido [4,5-e ] [1,4] diazepine (Compound 13)

Compound 12 (20.0 mg, 34.6. Mu. Mol) was dissolved in tetrahydrofuran (0.4 mL), and lithium aluminum hydride (1M, 51.8. Mu.L) was added thereto, and the mixture was reacted at 70℃for 1 hour. Quenching the reaction mixture with water, spin-drying, dissolving the crude product in N-methylpyrrolidone, filtering, and preparing the filtrate by prep HPLC (Waters AutoP, xbridge-C18, 19×150mm, gradient elution with 20-75% acetonitrile in water, 15 mL/min) to give compound 13 (12 mg, yield) 62％).m/z(ESI):565.2[M+H] ⁺. ¹H NMR(400MHz,DMSO-d ₆)δ8.58(s,1H),8.40(s,1H),7.92(s,1H),7.73 (d,J＝8.1Hz,2H),7.41(d,J＝8.1Hz,2H),4.87(s,2H),3.82(s,3H),3.76(s,3H),3.34(m,2H),2.94(t,J＝5.7Hz,2H),1.71(m,1H),1.48(s,6H),0.96(m,2H),0.80(m,2H).

Example 14:2- (4-cyclopropyl-6-difluoromethoxy-pyrimidin-5-yl) -5, 5-dimethyl-9- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5,6,8, 9-tetrahydro-7H-pyrimidine [4,5-e ] [1,4] diazepin-7-one (compound 14)

Referring to a similar synthetic route and procedure for compound 10, substitution of acetone for cyclobutanone in step 1 and substitution of compound 14A for 1K in step 10 can produce the compound 14.m/z(ESI):615.2[M+H] ⁺. ¹H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.57(s,1H),8.01(s,1H),7.92(m,1H),7.79(s,1H),7.64(d,J＝8.0Hz,2H),7.37(d,J＝8.0Hz,2H),5.01(s,2H),4.20(s,2H),3.75(s,3H),1.84(m,1H),1.74(s,6H),1.02(m,2H),0.87(m,2H).

Example 15: 6-cyclopropyl 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5, 5-dimethyl-9- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5,6,8, 9-tetrahydro-7H-pyrimidine [4,5-e ] [1,4] diazepin-7-one (Compound 14)

By reference to a similar synthetic method to that of compound 9, the replacement of compound 8D with compound 12 can produce a compound 15.m/z(ESI):619.3[M+H] ⁺. ¹H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.41(s,1H),7.58(s,1H),7.51(d,J＝8.0Hz,2H),7.32(d,J＝8.0Hz,2H),4.97(s,2H),4.30(s,2H),3.81(s,3H),3.68(s,3H),2.40(m,1H),1.95(s,6H),1.67(m,1H),1.20(m,2H),0.98(m,2H),0.82(m,2H),0.77(m,2H).

Other compounds than the compounds synthesized in examples 1 to 15 can be synthesized by the synthetic routes and materials in reference examples 1 to 15.

Test example 1: in vitro activity detection assay for USP1 enzyme

Experimental instrument:

Instrument name	Equipment manufacturer	Model number
Oscillator	Boxun	BSD-YX3400
Board reading instrument	PerkinElmer	Envision
Centrifugal machine	Eppendorf	Eppendorf Mixmate
Compound dilution and sample adding instrument	PerkinElmer	Echo

Experimental materials:

The USP1 enzyme used in the experiment (Recombinant Human His-USP 1/His6-UAF1Complex Protein, CF) was purchased from R & D Systems under the trade designation E-568-050. USP1 with 6 HIS-tags at the N-terminal and UAF1 enzyme complex with 6 HIS-tags at the N-terminal are expressed by a eukaryotic baculovirus expression system. Purifying by nickel column-based affinity chromatography with purity of above 80% and concentration of 1mg/mL, packaging, and preserving at-80deg.C.

The detection kit (Ub-CHOP 2-Reporter Deubiquitination Assay Kit) was purchased from Lifesensors under the trade designation PR1101. And (5) storing at-80 ℃ after sub-packaging. The kit contains a ubiquitinated reporter enzyme, which when de-ubiquitinated by USP1/UAF1, generates an activity, and after catalyzing the substrate, the substrate is excited by 485nm laser to generate 531nm emission light signals.

Other reagents and consumables required for the experiment were as follows:

Reagent(s)	Branding	Goods number
CHAPS	Sangon	A600110-0001
1M Tris-HCl Solution,pH 8.0	Sangon	B548127
Calcium chloride dihydrate	Sangon	A501331
β-mercaptoethanol	sigmaaldrich	M3148-100ml
96-Well plate	Thermofisher	249952
Black 384-well plate	Perkinelmer	6007270

The experimental method comprises the following steps:

Test compounds were dissolved to 10mM with DMSO. Compound dilution and a sample-adding instrument were used to punch compound and pure DMSO onto each well of a 384 well plate, the total volume of compound and DMSO was 50nL, and the instrument was used to obtain gradient diluted sample concentrations by different ratios. The enzyme was diluted with freshly prepared reaction solution (20 mM Tris-HCl (pH 8.0), 2mM CaCl ₂,2mMβ-mercaptoethanol,0.05％CHAPS,ddH ₂ O). 5 mu L of diluted enzyme reaction solution is added into each hole, the enzyme and the compound are mixed by centrifugal shaking, and the mixture is placed on ice after the mixture is centrifuged. The kit reporter system and substrate were diluted with the reaction solution, 5 μl of diluted liquid was added to each well, and mixed by centrifugation. Incubate for 0.5 hours at room temperature. Fluorescence signal the fluorescence signal in each well was measured using an Envision plate reader (PerkinElmer excitation wavelength 485nm, emission wavelength 530 nm). The IC ₅₀ values of the inhibitory activity of the compounds on enzyme activity were calculated using the four parameter Logistic Model method.

In the following formula, x represents the logarithmic form of the concentration of the compound; f (x) represents an effect value (inhibition rate of enzyme activity under the concentration condition): f (x) = (a+ ((B-ase:Sub>A)/(1+ ((C/x)/(D)))). A, B, C and D are four parameters. IC ₅₀ values were further calculated as the concentration of compound required for 50% inhibition of enzyme activity in the best fit curve using Xlfit.

The test results are shown in Table 1.

TABLE 1 UP 1 in vitro enzyme inhibitory Activity

Compounds of formula (I)	IC ₅₀(nM)
Compound 1	14.0
Compound 2	30.5
Compound 3	86.4
Compound 4	52.2
Compound 5	30.4
Compound 7	56.6
Compound 8	57.9
Compound 9	35.0
Compound 10	24.7
Compound 12	10.2
Compound 14	6.7
Compound 15	20.8

Claims

A compound of formula (I) or a pharmaceutically acceptable salt thereof,

Wherein,

X ¹ is selected from N or CR ^1a;

X ² is selected from O、NR ^2a、CR ^2aR ^2b、C＝CR ^2aR ^2b、S、S(＝O)R ^2a、C(＝O)、S(＝O) ₂ or C (=nr ^2a);

X ³ is selected from CR ^3aR ^3b、CR ^3a、NR ^3a, N, C (=o), O, or C (=nr ^3a);

X ⁴ is selected from CR ^4aR ^4b、CR ^4a or C (=o);

X ⁵ is selected from CR ^5aR ^5b, C (=o) or S (=o) ₂;

Ring a is selected from aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl or C ₃-C ₁₀ cycloalkyl;

ring B is selected from arylene, 5-10 membered heteroarylene, 4-10 membered heterocyclylene, or C ₃-C ₁₀ membered cycloalkylene;

ring C is selected from aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl;

R ¹、R ² is independently selected from H, halogen, CN, OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl, said OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl being optionally substituted with R ^d;

Or R ¹、R ² together with the atoms to which they are attached form a C ₃-C ₁₀ cycloalkyl, 4-8 membered heterocyclyl, said C ₃-C ₁₀ cycloalkyl, 4-8 membered heterocyclyl being optionally substituted with R ^d;

R ³ is selected from H, halogen, CN, OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl, 4-8 membered heterocyclyl, alkenyl, alkynyl, said OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl, 4-8 membered heterocyclyl, alkenyl, alkynyl being optionally substituted with R ^d;

R ^1a、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b Independently selected from H, halogen, CN, OH, NH ₂、C ₁-C ₆ alkyl, alkenyl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl, said OH, NH ₂、C ₁-C ₆ alkyl, alkenyl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl being optionally substituted with R ^d;

R ^a、R ^b、R ^c is independently selected from halogen, CN, OH, NH ₂、SH、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl, or 4-8 membered heterocyclyl, said OH, NH ₂、SH、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl, or 4-8 membered heterocyclyl being optionally substituted with R ^d;

Or R ^1a、R ^a taken together with the atom to which it is attached form C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl or C ₃-C ₁₀ cycloalkenyl, said C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl or C ₃-C ₁₀ cycloalkenyl being optionally substituted with R ^d.

Or R ^b、R ^c taken together with the atom to which it is attached form C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl or C ₃-C ₁₀ cycloalkenyl, said C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl or C ₃-C ₁₀ cycloalkenyl being optionally substituted with R ^d;

Or R ^2a、R ^3a taken together with the atoms to which it is attached form a 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl, said 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl optionally being substituted with R ^d;

Or R ^2a、R ^2b taken together with the atoms to which it is attached form a C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocyclyl, said C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocyclyl being optionally substituted with R ^d;

Or R ^3a、R ^4a taken together with the atoms to which it is attached form C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, said C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl optionally substituted with R ^d;

Or R ^3a、R ^5a taken together with the atoms to which it is attached form C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, said C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl optionally substituted with R ^d;

Or R ^4a、R ^4b taken together with the atom to which it is attached form a C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, said C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocyclyl being optionally substituted with R ^d;

Or R ^4a、R ^5a taken together with the atoms to which it is attached form a C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclyl; the C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R ^d;

or R ^5a、R ^5b taken together with the atoms to which it is attached form a C ₃-C ₁₀ cycloalkyl group or a 4-10 membered heterocyclyl group; the C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R ^d;

or R ^2a、R ^4a taken together with the atoms to which it is attached form a 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl, said 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl optionally being substituted with R ^d;

Or R ^2a、R ^5a taken together with the atoms to which it is attached form a 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl, said 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocyclyl optionally being substituted with R ^d;

Or X ² and X ³,X ³ and X ⁴, optionally forming a double bond;

Each R ^d is independently selected from halogen, CN, OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl, or 4-8 membered heterocyclyl, said OH, NH ₂、 C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl, or 4-8 membered heterocyclyl being optionally substituted with R ^e;

R ^e is selected from halogen, CN, OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl, said OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl being optionally substituted by R ^f;

R ^f is selected from halogen, CN, OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl;

m, n, p are independently selected from 0, 1, 2,3, 4, 5 or 6.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ¹ is selected from N.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X ² is selected from O, NR ^2a、CR ^2aR ^2b、C＝CR ^2aR ^2b、S、S(＝O)R ^2a, C (=o) or S (=o) ₂;

Or X ² is selected from O, NR ^2a、CR ^2aR ^2b or C (=o).
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-3 wherein X ³ is selected from CR ^3aR ^3b、CR ^3a、NR ^3a, N, C (=o) or C (=nr ^3a).
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-4 wherein X ⁴ is selected from CR ^4aR ^4b or C (=o); or X ⁴ is selected from CR ^4aR ^4b; or X ⁴ is selected from CR ^4a.
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-5 wherein X ⁵ is selected from CR ^5aR ^5b or C (=o).
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-6 wherein ring a is selected from aryl or 5-10 membered heteroaryl; or ring A is selected from
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7 wherein ring B is selected from arylene, 4-8 membered heterocyclylene or C ₃-C ₆ cycloalkylene; or ring B is selected from arylene or 4-8 membered heterocyclylene; or ring B is selected from
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8 wherein ring C is selected from 5-10 membered heteroaryl; or ring C is selected from
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-9 wherein R ¹、R ² is independently selected from H, halogen or C ₁-C ₆ alkyl, said C ₁-C ₆ alkyl being optionally substituted with R ^d; or R ¹、R ² is independently selected from H or C ₁-C ₆ alkyl, said C ₁-C ₆ alkyl optionally substituted with R ^d; or R ¹、R ² together with the atoms to which they are attached form C ₃-C ₆ cycloalkyl, said C ₃-C ₆ cycloalkyl optionally being substituted by R ^d.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R ³ is selected from H, halogen, CN, OH, C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl, 4-8 membered heterocyclyl, alkenyl or alkynyl, said OH, C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl, 4-8 membered heterocyclyl, alkenyl or alkynyl being optionally substituted by R ^d; or R ³ is selected from H, halogen, CN, OH, C ₁-C ₆ alkyl, or C ₃-C ₆ cycloalkyl, said OH, C ₁-C ₆ alkyl, or C ₃-C ₆ cycloalkyl being optionally substituted with R ^d; or R ³ is selected from H, halogen, OH, or C ₁-C ₆ alkyl, said OH or C ₁-C ₆ alkyl optionally substituted with R ^d; or R ³ is selected from H.
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-11, characterized in that ,R ^1a、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b is independently selected from H, halogen, CN, OH, NH ₂、C ₁-C ₆ alkyl, alkenyl, C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl, said OH, NH ₂、C ₁-C ₆ alkyl, alkenyl, C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl being optionally substituted by R ^d; or R ^1a、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a、R ^5b is independently selected from H, halogen, OH, NH ₂、C ₁-C ₆ alkyl, alkenyl, or C ₃-C ₆ cycloalkyl, said OH, NH ₂、C ₁-C ₆ alkyl, alkenyl, or C ₃-C ₆ cycloalkyl being optionally substituted with R ^d.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R ^a、R ^b、R ^c is independently selected from halogen, OH, NH ₂、SH、C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl, said OH, NH ₂、SH、C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl being optionally substituted by R ^d; or R ^a is independently selected from OH, C ₁-C ₆ alkyl, or C ₃-C ₆ cycloalkyl, said OH, C ₁-C ₆ alkyl, or C ₃-C ₆ cycloalkyl being optionally substituted with R ^d; or R ^a is selected from-O-CH ₃, methyl, ethyl, isopropyl or cyclopropyl; or R ^b is independently selected from halogen, OH or C ₁-C ₆ alkyl, said OH or C ₁-C ₆ alkyl optionally substituted with R ^d; or R ^c is independently selected from halogen, OH, C ₁-C ₆ alkyl, or C ₃-C ₆ cycloalkyl, said OH, C ₁-C ₆ alkyl, or C ₃-C ₆ cycloalkyl being optionally substituted with R ^d; or R ^c is independently selected from OH, C ₁-C ₆ alkyl, or C ₃-C ₆ cycloalkyl, said OH, C ₁-C ₆ alkyl, or C ₃-C ₆ cycloalkyl being optionally substituted with R ^d; or R ^c is independently selected from OH, methyl, ethyl, isopropyl, or cyclopropyl, optionally substituted with R ^d.
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-13 wherein R ^1a、R ^a together with the atoms to which it is attached form a 4-8 membered heterocyclyl, said 4-8 membered heterocyclyl being optionally substituted by R ^d.
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-14 wherein R ^b、R ^c together with the atoms to which it is attached form a 4-8 membered heterocyclyl, said 4-8 membered heterocyclyl being optionally substituted by R ^d.
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-15 wherein R ^2a、R ^2b together with the atoms to which it is attached form a C ₃-C ₆ cycloalkyl or 4-7 membered heterocyclyl, said C ₃-C ₆ cycloalkyl or 4-7 membered heterocyclyl being optionally substituted by R ^d;

Or R ^2a、R ^2b together with the atom to which it is attached form a C ₃-C ₁₀ cycloalkyl group, said C ₃-C ₁₀ cycloalkyl group being optionally substituted with R ^d.
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 16 wherein R ^2a、R ^3a together with the atoms to which it is attached form a 5-10 membered heteroaryl, which 5-10 membered heteroaryl is optionally substituted by R ^d; or R ^2a、R ^3a together with the atoms to which it is attached formThe saidOptionally substituted with R ^d.
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-17 wherein R ^3a、R ^4a together with the atoms to which it is attached form a C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl, which C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl is optionally substituted by R ^d; or R ^3a、R ^4a together with the atoms to which it is attached form cyclopropyl,The cyclopropyl group, Optionally substituted with R ^d.
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-18 wherein R ^3a、R ^5a together with the atoms to which it is attached form a C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl, which C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl is optionally substituted by R ^d; or R ^3a、R ^5a together with the atoms to which it is attached formThe saidOptionally substituted with R ^d.
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-19 wherein R ^4a、R ^4b together with the atoms to which it is attached form a C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl, which C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl is optionally substituted by R ^d; or R ^4a、R ^4b together with the atoms to which it is attached form cyclopropyl, cyclobutyl orThe cyclopropyl, cyclobutyl orOptionally substituted with R ^d.
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 20 wherein R ^4a、R ^5a together with the atoms to which it is attached form a C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl; the C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with R ^d; or R ^4a、R ^5a together with the atoms to which it is attached form cyclopropyl or cyclobutyl; the cyclopropyl or cyclobutyl is optionally substituted by R ^d.
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 21 wherein R ^5a、R ^5b together with the atoms to which it is attached form a C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl; the C ₃-C ₆ cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with R ^d; or R ^5a、R ^5b together with the atoms to which it is attached form a C ₃-C ₆ cycloalkyl group, said C ₃-C ₆ cycloalkyl group optionally substituted with R ^d; or R ^5a、R ^5b together with the atoms to which it is attached form cyclopropyl or cyclobutyl; the cyclopropyl or cyclobutyl is optionally substituted by R ^d.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein each R ^d is independently selected from halogen, OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl, said OH, NH ₂、C ₁-C ₆ alkyl, C ₃-C ₁₀ cycloalkyl or 4-8 membered heterocyclyl being optionally substituted by R ^e; or each R ^d is independently selected from halogen, OH, NH ₂、C ₁-C ₆ alkyl, or C ₃-C ₁₀ cycloalkyl, said OH, NH ₂、C ₁-C ₆ alkyl, or C ₃-C ₁₀ cycloalkyl being optionally substituted with R ^e.
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-23 wherein m is selected from 1, 2, 3; or m is selected from 1 or 2.
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-24 wherein n is selected from 0,1, 2; or n is selected from 0 or 1.
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-25 wherein p is selected from 1, 2, 3; or p is selected from 1 or 2.
The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 7-26, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (II) or a pharmaceutically acceptable salt thereof,

Wherein,

X ¹ is selected from N or CR ^1a;

X ² is selected from O, NR ^2a、CR ^2aR ^2b、C＝CR ^2aR ^2b、S、C(＝O)、S(＝O) ₂ or C (=nr ^2a);

X ³ is selected from CR ^3aR ^3b、NR ^3a, C (=o), O, or C (=nr ^3a);

x ⁴ is selected from CR ^4aR ^4b;

X ⁵ is selected from CR ^5aR ^5b, C (=o) or S (=o) ₂;

Ring a, ring B, ring C、R ¹、R ²、R ³、R ^a、R ^b、R ^c、m、n、p、R ^1a、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a and R ^5b are as defined in any one of claims 1,7 to 26.
The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 10-26, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (III) or a pharmaceutically acceptable salt thereof,

Wherein,

X ¹ is selected from N or CR ^1a;

X ² is selected from O, NR ^2a、CR ^2aR ^2b、C＝CR ^2aR ^2b、S、C(＝O)、S(＝O) ₂ or C (=nr ^2a);

X ³ is selected from CR ^3aR ^3b、NR ^3a, C (=o), O, or C (=nr ^3a);

x ⁴ is selected from CR ^4aR ^4b or C (=o);

X ⁵ is selected from CR ^5aR ^5b, C (=o) or S (=o) ₂;

R ¹、R ²、R ³、R ^a、R ^b、R ^c、m、n、p、R ^1a、R ^2a、R ^2b、R ^3a、R ^3b、R ^4a、R ^4b、R ^5a And R ^5b is as defined in any one of claims 1, 10 to 26.
The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of,
A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1-29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
Use of a compound of formula (i) as defined in any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 30, in the manufacture of a medicament for the prevention or treatment of USP1 mediated diseases.