CN115894425A

CN115894425A - Fused tricyclic compound, preparation method and application thereof in medicine

Info

Publication number: CN115894425A
Application number: CN202211208925.6A
Authority: CN
Inventors: 李心; 董平; 曹虎; 王浩蔚; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2021-09-30
Filing date: 2022-09-30
Publication date: 2023-04-04

Abstract

The present disclosure relates to fused tricyclic compounds, methods of their preparation, and their use in medicine. Specifically, the disclosure relates to fused tricyclic compounds shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compounds, and application of the compounds as a therapeutic agent, in particular application of the compounds as a complement D factor inhibitor and application of the compounds in preparation of drugs for treating and/or preventing diseases or disorders mediated by complement D factor.

Description

Fused tricyclic compound, preparation method and application thereof in medicine

Technical Field

The disclosure belongs to the field of medicines, and relates to a fused tricyclic compound, a preparation method and application thereof in medicines. Specifically, the disclosure relates to fused tricyclic compounds shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compounds, and application of the compounds as a therapeutic agent, in particular application of the compounds as a complement D factor inhibitor and application of the compounds in preparation of drugs for treating and/or preventing diseases or disorders mediated by complement D factor.

Background

The complement system is an important part of natural immunity and plays an important role in resisting invasion of exogenous microorganisms, eliminating aged and damaged cells and maintaining the homeostasis of the body. Complement can be divided into the classical, lectin and alternative pathways, which converge at the terminal pathway, depending on the activator. The alternative pathway contributes 80% of the activity to the overall complement activation due to the presence of a positive feedback loop. Complement D Factor (Factor D) is an important component in the loop, plays a role in starting and amplifying activation signals, and after being combined with B Factor combined with complement C3B, the complement D Factor generates conformational change, the B Factor is cut into Ba and Bb, the Bb is still combined on the C3B to form C3 convertase to cut C3, new C3B is generated, the C3B is combined with the new B Factor, the process of enzyme cutting by the D Factor is repeated, and the activation signals are continuously amplified.

The complement system is regulated and controlled by the regulatory factor under normal conditions, thereby not only avoiding over-activation and damaging the organism, but also maintaining the immune homeostasis. However, when complement is over-activated, it causes many pathological processes involving multiple organs, either systemic or local. The diseases in which activation of the alternative pathway is a major driving factor include rare diseases such as Paroxysmal Nocturnal Hemoglobinuria (PNH) and C3 Glomerulopathy (compact 3 glorulopathy, C3G), and also include diseases with a large number of patients such as IgA nephropathy (IgA), dry age-related macular degeneration (also referred to as Geographic Atrophy (GA) or atrophic age-related macular degeneration). Therefore, targeting key proteins in the alternative pathway, such as the development of inhibitors of complement factor D, to inhibit the activity of the alternative pathway, can provide an effective therapeutic approach for these diseases.

Diseases in which abnormal complement system activity is involved also include atypical hemolytic uremic syndrome, abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, neuromyelitis optica, myasthenia gravis, fatty liver, nonalcoholic steatohepatitis, hepatitis, cirrhosis, liver failure, dermatomyositis, amyotrophic lateral sclerosis, multiple sclerosis, rheumatoid arthritis, and cytokine release or inflammatory responses associated with biologic therapy.

Related patent applications for complement factor D inhibitors that have been disclosed include WO2021072198A1, WO2021021909A1, WO2021072156A1, WO2019195720A1, WO2020051532A2, WO2020131974A1, WO2021168320A1, WO2017035360A1, WO2017136395A1, WO2012093101A1 and the like.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

G ¹ selected from chemical bonds, - (CR) ^a1 R ^b1 ) _p -、-(CR ^a1 R ^b1 ) _p -O-、-O-(CR ^a1 R ^b1 ) _p -、-NR ^c1 -、-O-、-(CR ^a1 R ^b1 ) _p -NR ^c1 -、-NR ^c1 -(CR ^a1 R ^b1 ) _p -、-C(O)-、-O-C(O)-、-C(O)-O-、-S(O) _q -、-NR ^c1 -C(O)-、-C(O)-NR ^c1 -、-C(O)-NR ^c1 -(CR ^a1 R ^b1 ) _p -、-(CR ^a1 R ^b1 ) _p -NR ^c1 -C (O) -and-NR ^c1 -C(O)-(CR ^a1 R ^b1 ) _p -；

G ² Selected from chemical bonds, - (CR) ^a2 R ^b2 ) _r -、-(CR ^a2 R ^b2 ) _r -O-、-O-(CR ^a2 R ^b2 ) _r -、-NR ^c2 -、-O-、-(CR ^a2 R ^b2 ) _r -NR ^c2 -、-NR ^c2 -(CR ^a2 R ^b2 ) _r -、-C(O)-、-O-C(O)-、-C(O)-O-、-S(O) _q -、-NR ^c2 -C(O)-、-C(O)-NR ^c2 -、-C(O)-NR ^c2 -(CR ^a2 R ^b2 ) _r -、-(CR ^a2 R ^b2 ) _r -NR ^c2 -C (O) -and-NR ^c2 -C(O)-(CR ^a2 R ^b2 ) _r -；

With the proviso that G ¹ And G ² Identical or different and cannot be simultaneously a chemical bond;

ring a is selected from aryl, heteroaryl and heterocyclyl;

ring B is aryl or heteroaryl;

u, V and W are the same or different, and

u is a nitrogen atom or CR ^u ；

V is a nitrogen atom or CR ^v ；

W is a nitrogen atom or CR ^w ；

L ¹ Is selected from- (CR) ^a3 R ^b3 ) _s -、-(CR ^a3 R ^b3 ) _s -O-、-O-(CR ^a3 R ^b3 ) _s -、-NR ^c3 -、-O-、-(CR ^a3 R ^b3 ) _s -NR ^c3 -、-NR ^c3 -(CR ^a3 R ^b3 ) _s -、-(CR ^a3 R ^b3 ) _s -C(O)-、-C(O)-(CR ^a3 R ^b3 ) _s -、-O-C(O)-、-C(O)-O-、-S(O) _q -(CR ^a3 R ^b3 ) _s -、-(CR ^a3 R ^b3 ) _s -S(O) _q -、-NR ^c3 -C(O)-、-C(O)-NR ^c3 -、-C(O)-NR ^c3 -(CR ^a3 R ^b3 ) _s -、-(CR ^a3 R ^b3 ) _s -NR ^c3 -C (O) -and-NR ^c3 -C(O)-(CR ^a3 R ^b3 ) _s -；

L ² Is represented by (A)CR ^a4 R ^b4 ) _t -；

L ³ Selected from chemical bonds, - (CR) ^a5 R ^b5 ) _u -、-C(O)-、-(CR ^a5 R ^b5 ) _u -C(O)-、-(CR ^a5 R ^b5 ) _u -S(O) _q -and- (CR) ^a5 R ^b5 ) _u -NR ^c4 -C(O)-；

Each R is ¹ Identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro, cyano, -NR ³ R ⁴ 、-C(O)NR ³ R ⁴ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-OR ⁵ Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁶ R ⁷ Hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

each R is ² Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, cyano, -NR ³ R ⁴ 、-C(O)NR ³ R ⁴ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-OR ⁵ Cycloalkyl, heterocyclyl, aryl and heteroaryl;

or two of them R ² And the attached carbon atoms together form a cycloalkyl, heterocyclyl, aryl, and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally substituted with a group selected from halogen, oxo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁶ R ⁷ Hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^u 、R ^v and R ^w Are identicalOr are different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro, cyano, -NR ³ R ⁴ 、-C(O)NR ³ R ⁴ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-OR ⁵ Cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ^u And R ^v And the attached carbon atoms together form a cycloalkyl, heterocyclyl, aryl, and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally substituted with a group selected from halogen, oxo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁶ R ⁷ Hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^a1 、R ^b1 、R ^a2 、R ^b2 、R ^a3 、R ^b3 、R ^a4 、R ^b4 、R ^a5 and R ^b5 Identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro, cyano, -NR ³ R ⁴ 、-C(O)NR ³ R ⁴ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-OR ⁵ Cycloalkyl and heterocyclyl;

or R ^a1 And R ^b1 、R ^a2 And R ^b2 、R ^a3 And R ^b3 、R ^a4 And R ^b4 、R ^a5 And R ^b5 Each independently optionally forming a cycloalkyl or heterocyclyl group with the attached carbon atom, wherein the cycloalkyl or heterocyclyl group is each independently optionally substituted with a group selected from halogen, oxo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁶ R ⁷ Hydroxyl and hydroxyalkyl;

R ^c1 、R ^c2 、R ^c3 and R ^c4 Are the same or different and are each independently selectedFrom hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups;

R ³ 、R ⁴ 、R ⁶ and R ⁷ The same or different, and each is independently selected from the group consisting of hydrogen atoms, alkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo groups, alkyl groups, alkoxy groups, haloalkyl groups, and haloalkoxy groups;

or R ³ And R ⁴ Together with the nitrogen atom to which they are attached, form a heterocyclic group, wherein said heterocyclic group formed is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

or R ⁶ And R ⁷ Together with the nitrogen atom to which they are attached, form a heterocyclic group, wherein said heterocyclic group formed is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ⁵ selected from the group consisting of hydrogen atoms, alkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein said alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl groups, alkoxy groups, haloalkyl groups, and haloalkoxy groups;

m is 0, 1,2 or 3;

n is 0, 1,2 or 3;

p is 1,2,3, 4 or 5;

q is 0, 1 or 2;

r is 1,2,3, 4 or 5;

s is 1,2,3, 4 or 5;

t is 1,2,3, 4 or 5; and is

u is 1,2,3, 4 or 5.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: ring B is 6 to 10 membered aryl or 5 to 10 membered heteroaryl; preferably, ring B is a 6 to 10 membered aryl; more preferably, ring B is phenyl.

In some embodiments of the disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: ring B is phenyl or 5 or 6 membered heteroaryl; preferably, it is

Bond with L ³ And (4) connecting.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II):

wherein:

x, Y and Z are the same or different, and

x is a nitrogen atom or CR ^x ；

Y being a nitrogen atom or CR ^y ；

Z is a nitrogen atom or CR ^z ；

R ^x 、R ^y And R ^z Identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro, cyano, -NR ³ R ⁴ 、-C(O)NR ³ R ⁴ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-OR ⁵ Cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ^x And R ^y 、R ^y And R ^z Each independently optionally forming, together with the carbon atom to which it is attached, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected fromHalogen, oxo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁶ R ⁷ Hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

ring A, U, V, W, G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ And m is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein: ring a is selected from 6-to 10-membered aryl, 5-to 10-membered heteroaryl, and 3-to 12-membered heterocyclyl; preferably, ring a is 6 to 10 membered aryl or 5 to 10 membered heteroaryl; further preferably, ring a is a 6 to 10 membered aryl; more preferably, ring a is phenyl.

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein: ring a is phenyl or 5 or 6 membered heteroaryl; preferably, it is

In some preferred embodiments of the present disclosure, the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by formula (III) or a pharmaceutically acceptable salt thereof:

wherein:

x, Y and Z are identical or different, and

x is a nitrogen atom or CR ^x ；

Y being a nitrogen atom or CR ^y ；

Z is a nitrogen atom or CR ^z ；

R ^x 、R ^y And R ^z Are the same or different and are each independentlyIs selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro, cyano, -NR ³ R ⁴ 、-C(O)NR ³ R ⁴ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-OR ⁵ Cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ^x And R ^y 、R ^y And R ^z Each independently optionally forming, together with the attached carbon atoms, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁶ R ⁷ Hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

U、V、W、G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ and m is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein: l is a radical of an alcohol ¹ Is- (CR) ^a3 R ^b3 ) _s -O-、-O-(CR ^a3 R ^b3 ) _s -、-NR ^c3 -、-O-、-NR ^c3 -C(O)-、-C(O)-NR ^c3 -、-C(O)-NR ^c3 -(CR ^a3 R ^b3 ) _s -、-(CR ^a3 R ^b3 ) _s -NR ^c3 -C (O) -and-NR ^c3 -C(O)-(CR ^a3 R ^b3 ) _s -；R ^a3 、R ^b3 、R ^c3 And s is as defined in formula (I); preferably, L ¹ Is- (CR) ^a3 R ^b3 ) _s -O-or-O- (CR) ^a3 R ^b3 ) _s -；R ^a3 、R ^b3 And s is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I),A compound of formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein: l is a radical of an alcohol ¹ Is- (CR) ^a3 R ^b3 ) _s -O-or-O- (CR) ^a3 R ^b3 ) _s -；R ^a3 And R ^b3 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, -OR ⁵ 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; r is ⁵ Is a hydrogen atom or C _1-6 An alkyl group; s is 1 or 2; preferably, L ¹ is-CR ^a3 R ^b3 -O-or-O-CR ^a3 R ^b3 ；R ^a3 And R ^b3 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; more preferably, L ¹ is-CH ₂ -O-or-O-CH ₂ -; most preferably, L ¹ is-CH ₂ -O-。

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein: l is ² Is- (CR) ^a4 R ^b4 ) _t -；R ^a4 And R ^b4 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, -OR ⁵ 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; r ⁵ Is a hydrogen atom or C _1-6 An alkyl group; t is 1 or 2; preferably, L ² is-CR ^a4 R ^b4 -；R ^a4 And R ^b4 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; further preferably, L ² is-CH ₂ -or-C (CH) ₃ ) ₂ -; more preferably, L ² is-CH ₂ -。

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein: l is ³ Selected from chemical bonds, - (CR) ^a5 R ^b5 ) _u -, -C (O) -and- (CR) ^a5 R ^b5 ) _u -C (O) -, preferably- (CR) ^a5 R ^b5 ) _u -；R ^a5 、R ^b5 And u is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein: l is ³ Is- (CR) ^a5 R ^b5 ) _u -；R ^a5 And R ^b5 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, -OR ⁵ 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; r ⁵ Is a hydrogen atom or C _1-6 An alkyl group; u is 1 or 2; preferably, L ³ is-CR ^a5 R ^b5 -；R ^a5 And R ^b5 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; more preferably, L ³ is-CH ₂ -。

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein: r ^a3 、R ^b3 、R ^a4 、R ^b4 、R ^a5 And R ^b5 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkoxy, nitro, cyano, amino, -C (O) R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-OR ⁵ 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl, R ⁵ As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein: r ^a3 Is a hydrogen atom; and/or R ^b3 Is a hydrogen atom; preferably, R ^a3 And R ^b3 Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I) is(II) a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: r ^a4 Is a hydrogen atom; and/or R ^b4 Is a hydrogen atom; preferably, R ^a4 And R ^b4 Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein: r ^a4 Is a hydrogen atom or C _1-6 An alkyl group; and/or R ^b4 Is a hydrogen atom C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein: r ^a5 Is a hydrogen atom; and/or R ^b5 Is a hydrogen atom; preferably, R ^a5 And R ^b5 Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^c3 Is a hydrogen atom or C _1-6 Alkyl groups, preferably hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein s is 1,2 or 3, preferably 1 or 2; more preferably 1.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein t is 1,2 or 3, preferably 1 or 2; more preferably 1.

In some preferred embodiments of the present disclosure, the compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein u is 1,2 or 3, preferably 1 or 2; more preferably 1.

In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, is a compound represented by formula (IV):

wherein:

x, Y and Z are the same or different, and

x is a nitrogen atom or CR ^x ；

Y being a nitrogen atom or CR ^y ；

Z is a nitrogen atom or CR ^z ；

R ^x 、R ^y And R ^z Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro, cyano, -NR ³ R ⁴ 、-C(O)NR ³ R ⁴ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-OR ⁵ Cycloalkyl, heterocyclyl, aryl and heteroaryl;

U、V、W、G ¹ 、G ² 、R ¹ 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ and m is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: u is CR ^u (ii) a V is CR ^v (ii) a W is CR ^w ；R ^u 、R ^v And R ^w As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (II), the general formula (III) or the general formula (IV) or the pharmaceutically acceptable salt thereofA salt for use wherein: u is CR ^u (ii) a V is CR ^v (ii) a W is CR ^w ；R ^u 、R ^v And R ^w Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; preferably, U, V and W are all CH.

In some preferred embodiments of the present disclosure, the compound of formula (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, wherein: x is CR ^x (ii) a Y is CR ^y (ii) a Z is a nitrogen atom or CR ^z ；R ^x 、R ^y And R ^z As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, wherein: x is CR ^x (ii) a Y is CR ^y (ii) a Z is a nitrogen atom or CR ^z ；R ^x 、R ^y And R ^z Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; preferably, X, Y and Z are all CH.

In some preferred embodiments of the present disclosure, the compound of formula (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, wherein: x is CR ^x (ii) a Y is CR ^y (ii) a Z is CR ^z ；R ^x 、R ^y And R ^z Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: r ^u 、R ^v And R ^w Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkoxy, nitro, cyano, -NR ³ R ⁴ 、-C(O)NR ³ R ⁴ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-OR ⁵ 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl anda 5 to 10 membered heteroaryl; r ³ 、R ⁴ And R ⁵ As defined in formula (I); preferably, R ^u 、R ^v And R ^w Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; more preferably, R ^u Is a hydrogen atom; and/or R ^v Is a hydrogen atom; and/or R ^w Is a hydrogen atom; most preferably, R ^u 、R ^v And R ^w Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, wherein: r is ^x 、R ^y And R ^z Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkoxy, nitro, cyano, -NR ³ R ⁴ 、-C(O)NR ³ R ⁴ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-OR ⁵ 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; r is ³ 、R ⁴ And R ⁵ As defined in formula (I); preferably, R ^x 、R ^y And R ^z Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; more preferably, R ^x Is a hydrogen atom; or R ^y Is a hydrogen atom; or R ^z Is a hydrogen atom; most preferably, R ^x 、R ^y And R ^z Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: r ³ And R ⁴ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl and C _1-6 A hydroxyalkyl group, wherein the alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, and alkoxy; preferably, R ³ Is a hydrogen atom; and/or R ⁴ Is a hydrogen atom; more preferably, R ³ And R ⁴ Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: g ¹ Selected from chemical bonds, - (CR) ^a1 R ^b1 ) _p -、-(CR ^a1 R ^b1 ) _p -O-and-O- (CR) ^a1 R ^b1 ) _p -；G ² Is selected from- (CR) ^a2 R ^b2 ) _r -、-(CR ^a2 R ^b2 ) _r -O-and-O- (CR) ^a2 R ^b2 ) _r -；R ^a1 、R ^b1 、R ^a2 、R ^b2 P and r are as defined in formula (I); preferably, G ¹ Is a chemical bond or- (CR) ^a1 R ^b1 ) _p -；G ² Is- (CR) ^a2 R ^b2 ) _r -O-or-O- (CR) ^a2 R ^b2 ) _r -；R ^a1 、R ^b1 、R ^a2 、R ^b2 P and r are as defined in formula (I); more preferably, G ¹ Is a chemical bond; g ² Is- (CR) ^a2 R ^b2 ) _r -O-or-O- (CR) ^a2 R ^b2 ) _r -；R ^a2 、R ^b2 And r is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: g ¹ Is a chemical bond or- (CR) ^a1 R ^b1 ) _p -；G ² Is- (CR) ^a2 R ^b2 ) _r -O-or-O- (CR) ^a2 R ^b2 ) _r -；R ^a1 、R ^b1 、R ^a2 、R ^b2 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy and C _1-6 A haloalkyl group; p is 1 or 2; and/or r is 1 or 2; preferably, G ¹ Is a chemical bond; g ² Is- (CR) ^a2 R ^b2 ) _r -O-or-O- (CR) ^a2 R ^b2 ) _r -；R ^a2 And R ^b2 Are the same or different and are each independentlyIs selected from hydrogen atom, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy and C _1-6 A haloalkyl group; r is 1 or 2; further preferably, G ¹ Is a chemical bond; g ² is-CH ₂ -O-or-O-CH ₂ -; most preferably, G ¹ Is a chemical bond; g ² is-O-CH ₂ -, where O is closer to-NH ₂ 。

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: g ¹ Is a chemical bond or- (CR) ^a1 R ^b1 ) _p -；G ² Is selected from- (CR) ^a2 R ^b2 ) _r -O-、-O-(CR ^a2 R ^b2 ) _r -、-(CR ^a2 R ^b2 ) _r -NR ^c2 -and-NR ^c2 -(CR ^a2 R ^b2 ) _r -；R ^a1 、R ^b1 、R ^a2 And R ^b2 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy and C _1-6 A haloalkyl group; r ^c2 Is a hydrogen atom or C _1-6 An alkyl group; p is 1 or 2; and/or r is 1 or 2; preferably, G ¹ Is a chemical bond; g ² Is selected from- (CR) ^a2 R ^b2 ) _r -O-、-O-(CR ^a2 R ^b2 ) _r -、-(CR ^a2 R ^b2 ) _r -NR ^c2 -and-NR ^c2 -(CR ^a2 R ^b2 ) _r -；R ^a2 And R ^b2 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy and C _1-6 A haloalkyl group; r is ^c2 Is a hydrogen atom or C _1-6 An alkyl group; r is 1 or 2; most preferably, G ¹ Is a chemical bond; g ² Is selected from-CH ₂ -O-、-O-CH ₂ -、-CH ₂ -NH-and-NH-CH ₂ -。

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: p is 1 or 2; and/or r is 1 or 2; preferably, p is 1; and/or r is 1.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: r is ^a1 、R ^b1 、R ^a2 And R ^b2 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Haloalkoxy, nitro, cyano, amino, -C (O) R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-OR ⁵ 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl, R ⁵ As defined in formula (I); preferably, R ^a1 、R ^b1 、R ^a2 And R ^b2 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy and C _1-6 A haloalkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: r is ^a1 Is a hydrogen atom; and/or R ^b1 Is a hydrogen atom; preferably, R ^a1 And R ^b1 Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: r ^a2 Is a hydrogen atom; and/or R ^b2 Is a hydrogen atom; preferably, R ^a2 And R ^b2 Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: r is ^c1 And R ^c2 Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

is selected from->

L ³ U, V, W, X, Y and Z are as defined in formula (I); preferably, is selected>

Is->

L ³ As defined in formula (I); more preferably->

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

selected from the group consisting of>

/>

L ³ U, V, W, X, Y and Z are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, wherein:

is selected from->

U, V, W, X, Y and Z are as defined in formula (II); preferably, it is

In some embodiments of the disclosure, the compound of formula (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, wherein:

selected from the group consisting of>

U, V, W, X, Y and Z are as defined in formula (II).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: each R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy and-C (O) R ⁵ (ii) a Wherein said C _1-6 Alkyl and C _1-6 Alkoxy is independently selected from halogen, oxo, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, nitro, cyano, -NR ⁶ R ⁷ Hydroxy, C _1-6 Hydroxyalkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl; r is ⁵ 、R ⁶ And R ⁷ As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: each R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy, 5-to 10-membered heteroaryl and-C (O) R ⁵ (ii) a Wherein said C _1-6 Alkyl radical, C _1-6 Alkoxy and 5 to 10 membered heteroarylEach independently optionally selected from halogen, oxo, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, nitro, cyano, -NR ⁶ R ⁷ Hydroxy, C _1-6 Hydroxyalkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl; r ⁵ 、R ⁶ And R ⁷ As defined in formula (I); preferably, each R ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy, 5-to 10-membered heteroaryl and-C (O) R ⁵ (ii) a Wherein said C _1-6 Alkyl is optionally selected from C _1-6 Alkoxy, halogen, amino and hydroxyl; r ⁵ Is a hydrogen atom or C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: each R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy and-C (O) R ⁵ (ii) a Wherein said C _1-6 Alkyl is optionally selected from halogen, -NR ⁶ R ⁷ And one or more substituents of hydroxyl; r ⁵ 、R ⁶ And R ⁷ As defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: each R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy, 5-to 10-membered heteroaryl and-C (O) R ⁵ (ii) a Wherein said C _1-6 Alkyl is optionally selected from C _1-6 Alkoxy, halogen, -NR ⁶ R ⁷ And one or more substituents of hydroxyl; r ⁵ 、R ⁶ And R ⁷ As defined in formula (I).

In some embodiments of the disclosure, the composition is administered in the form of a powderA compound represented by the general formula (I), the general formula (II), the general formula (III) or the general formula (IV), or a pharmaceutically acceptable salt thereof, wherein: each R is ¹ Are the same or different and are each independently a hydrogen atom or C _1-6 A hydroxyalkyl group.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: each R is ¹ Are the same or different and are each independently C _1-6 Alkyl or C _1-6 Hydroxyalkyl, wherein said C _1-6 Alkyl optionally substituted with one or more amino groups; preferably, each R ¹ Are the same or different and are each independently C _1-6 A hydroxyalkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: each R is ² Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _2-6 Alkenyl radical, C _2-6 Alkynyl and C _1-6 A haloalkoxy group; preferably, each R ² Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; more preferably, each R ² Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1 or 2; preferably 0.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, wherein: r ⁵ Is a hydrogen atom or C _1-6 An alkyl group; preferably, R ⁵ Is C _1-6 An alkyl group; more preferably methyl.

In some preferred embodiments of the present disclosure, the compound of formula (I) or (I) isI) A compound of formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein: r is ⁶ And R ⁷ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl and C _1-6 Hydroxyalkyl, wherein said C _1-6 Alkyl is optionally selected from halogen, oxo and C _1-6 Substituted with one or more substituents of alkoxy; preferably, R ⁶ Is a hydrogen atom; and/or R ⁷ Is a hydrogen atom; more preferably, R ⁶ And R ⁷ Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: ring a is 6-to 10-membered aryl or 5-to 10-membered heteroaryl; ring B is 6-to 10-membered aryl or 5-to 10-membered heteroaryl; l is a radical of an alcohol ¹ Is- (CR) ^a3 R ^b3 ) _s -O-or-O- (CR) ^a3 R ^b3 ) _s -；L ² Is- (CR) ^a4 R ^b4 ) _t -；L ³ Is- (CR) ^a5 R ^b5 ) _u -；R ^a3 、R ^b3 、R ^a4 、R ^b4 、R ^a5 And R ^b5 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, -OR ⁵ 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; s is 1,2 or 3; t is 1,2 or 3; u is 1,2 or 3; u is CR ^u (ii) a V is CR ^v (ii) a W is CR ^w ；R ^u 、R ^v And R ^w Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; g ¹ Is a chemical bond or- (CR) ^a1 R ^b1 ) _p -；G ² Is- (CR) ^a2 R ^b2 ) _r -O-or-O- (CR) ^a2 R ^b2 ) _r -；R ^a1 、R ^b1 、R ^a2 And R ^b2 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy and C _1-6 A haloalkyl group; p is 1 or 2; r is 1 or 2; each R is ¹ Are the same or different and are each independently selected from a hydrogen atom,Halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy and-C (O) R ⁵ (ii) a Wherein said C _1-6 Alkyl is optionally selected from halogen, -NR ⁶ R ⁷ And one or more substituents of hydroxyl; r ⁵ Is a hydrogen atom or C _1-6 An alkyl group; r ⁶ And R ⁷ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl and C _1-6 Hydroxyalkyl radical, wherein said C _1-6 Alkyl is optionally selected from halogen, oxo and C _1-6 Substituted with one or more substituents of alkoxy; each R is ² Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; m is 0, 1 or 2; and n is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: ring a is 6 to 10 membered aryl or 5 to 10 membered heteroaryl; ring B is 6 to 10 membered aryl or 5 to 10 membered heteroaryl; l is a radical of an alcohol ¹ Is- (CR) ^a3 R ^b3 ) _s -O-or-O- (CR) ^a3 R ^b3 ) _s -；L ² Is- (CR) ^a4 R ^b4 ) _t -；L ³ Is- (CR) ^a5 R ^b5 ) _u -；R ^a3 、R ^b3 、R ^a4 、R ^b4 、R ^a5 And R ^b5 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, -OR ⁵ 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; s is 1,2 or 3; t is 1,2 or 3; u is 1,2 or 3; u is CR ^u (ii) a V is CR ^v (ii) a W is CR ^w ；R ^u 、R ^v And R ^w Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; g ¹ Is a chemical bond or- (CR) ^a1 R ^b1 ) _p -；G ² Is selected from- (CR) ^a2 R ^b2 ) _r -O-、-O-(CR ^a2 R ^b2 ) _r -、-(CR ^a2 R ^b2 ) _r -NR ^c2 -and-NR ^c2 -(CR ^a2 R ^b2 ) _r -；R ^a1 、R ^b1 、R ^a2 And R ^b2 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy and C _1-6 A haloalkyl group; r ^c2 Is a hydrogen atom or C _1-6 An alkyl group; p is 1 or 2; r is 1 or 2; each R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy, 5-to 10-membered heteroaryl and-C (O) R ⁵ (ii) a Wherein said C _1-6 Alkyl is optionally selected from C _1-6 Alkoxy, halogen, amino and hydroxyl; r ⁵ Is a hydrogen atom or C _1-6 An alkyl group; each R is ² Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; m is 0, 1 or 2; and n is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein: ring a is 6 to 10 membered aryl; l is ¹ Is- (CR) ^a3 R ^b3 ) _s -O-or-O- (CR) ^a3 R ^b3 ) _s -；R ^a3 And R ^b3 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, -OR ⁵ 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; s is 1 or 2; l is a radical of an alcohol ² Is- (CR) ^a4 R ^b4 ) _t -；R ^a4 And R ^b4 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, -OR ⁵ 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl; t is 1 or 2; l is a radical of an alcohol ³ Is- (CR) ^a5 R ^b5 ) _u -；R ^a5 And R ^b5 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, -OR ⁵ 3 to 8 memberedCycloalkyl and 3 to 8 membered heterocyclyl; u is 1 or 2; u is CR ^u (ii) a V is CR ^v (ii) a W is CR ^w ；R ^u 、R ^v And R ^w Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; x is CR ^x (ii) a Y is CR ^y (ii) a Z is a nitrogen atom or CR ^z ；R ^x 、R ^y And R ^z Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; g ¹ Is a chemical bond or- (CR) ^a1 R ^b1 ) _p -；G ² Is selected from- (CR) ^a2 R ^b2 ) _r -O-、-O-(CR ^a2 R ^b2 ) _r -、-(CR ^a2 R ^b2 ) _r -NR ^c2 -and-NR ^c2 -(CR ^a2 R ^b2 ) _r -；R ^a1 、R ^b1 、R ^a2 And R ^b2 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy and C _1-6 A haloalkyl group; r ^c2 Is a hydrogen atom or C _1-6 An alkyl group; p is 1 or 2; r is 1 or 2; each R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy, 5-to 10-membered heteroaryl and-C (O) R ⁵ (ii) a Wherein said C _1-6 Alkyl is optionally selected from C _1-6 Alkoxy, halogen, amino and hydroxyl; r ⁵ Is a hydrogen atom or C _1-6 An alkyl group; each R is ² Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; m is 0, 1 or 2; and n is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: l is ¹ is-CR ^a3 R ^b3 -O-or-O-CR ^a3 R ^b3 -；R ^a3 And R ^b3 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; l is a radical of an alcohol ² is-CR ^a4 R ^b4 -；R ^a4 And R ^b4 The same or different, and each independentlyIs selected from hydrogen atom, halogen and C _1-6 An alkyl group; l is ³ is-CR ^a5 R ^b5 -；R ^a5 And R ^b5 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; u is CR ^u (ii) a V is CR ^v (ii) a W is CR ^w ；R ^u 、R ^v And R ^w Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; x is CR ^x (ii) a Y is CR ^y (ii) a Z is a nitrogen atom or CR ^z ；R ^x 、R ^y And R ^z Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; g ¹ Is a chemical bond or- (CR) ^a1 R ^b1 ) _p -；G ² Is selected from- (CR) ^a2 R ^b2 ) _r -O-、-O-(CR ^a2 R ^b2 ) _r -、-(CR ^a2 R ^b2 ) _r -NR ^c2 -and-NR ^c2 -(CR ^a2 R ^b2 ) _r -；R ^a1 、R ^b1 、R ^a2 And R ^b2 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy and C _1-6 A haloalkyl group; r ^c2 Is a hydrogen atom or C _1-6 An alkyl group; p is 1 or 2; r is 1 or 2; each R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy, 5-to 10-membered heteroaryl and-C (O) R ⁵ (ii) a Wherein said C _1-6 Alkyl is optionally selected from C _1-6 Alkoxy, halogen, amino and hydroxyl; r is ⁵ Is a hydrogen atom or C _1-6 An alkyl group; each R is ² Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; m is 0, 1 or 2; and n is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein: u is CR ^u (ii) a V is CR ^v (ii) a W is CR ^w (ii) a X is CR ^x (ii) a Y is CR ^y (ii) a Z is a nitrogen atom or CR ^z ；R ^u 、R ^v 、R ^w 、R ^x 、R ^y And R ^z Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; g ¹ Is a chemical bond or- (CR) ^a1 R ^b1 ) _p -；G ² Is- (CR) ^a2 R ^b2 ) _r -O-or-O- (CR) ^a2 R ^b2 ) _r -；R ^a1 、R ^b1 、R ^a2 And R ^b2 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy and C _1-6 A haloalkyl group; p is 1 or 2; r is 1 or 2; each R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy and-C (O) R ⁵ (ii) a Wherein said C _1-6 Alkyl is optionally selected from halogen, -NR ⁶ R ⁷ And one or more substituents of hydroxyl; r is ⁵ Is a hydrogen atom or C _1-6 An alkyl group; r is ⁶ And R ⁷ Are each a hydrogen atom; m is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein: u is CR ^u (ii) a V is CR ^v (ii) a W is CR ^w (ii) a X is CR ^x (ii) a Y is CR ^y (ii) a Z is a nitrogen atom or CR ^z ；R ^u 、R ^v 、R ^w 、R ^x 、R ^y And R ^z Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; g ¹ Is a chemical bond or- (CR) ^a1 R ^b1 ) _p -；G ² Is selected from- (CR) ^a2 R ^b2 ) _r -O-、-O-(CR ^a2 R ^b2 ) _r -、-(CR ^a2 R ^b2 ) _r -NR ^c2 -and-NR ^c2 -(CR ^a2 R ^b2 ) _p -；R ^a1 、R ^b1 、R ^a2 And R ^b2 Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy and C _1-6 A haloalkyl group; r ^c2 Is a hydrogen atom orC _1-6 An alkyl group; p is 1 or 2; r is 1 or 2; each R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy, 5-to 10-membered heteroaryl and-C (O) R ⁵ (ii) a Wherein said C _1-6 Alkyl is optionally selected from C _1-6 Alkoxy, halogen, amino and hydroxyl; r ⁵ Is a hydrogen atom or C _1-6 An alkyl group; m is 0, 1 or 2.

Table a typical compounds of the present disclosure include, but are not limited to:

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another aspect of the disclosure relates to a compound of formula (IA) or a salt thereof,

wherein:

r is C _1-6 An alkyl group;

ring A, ring B, U, V, W, G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ 、R ² M and n are as defined in formula (I).

Another aspect of the present disclosure relates to a compound represented by formula (IA) or formula (IAa) or a salt thereof,

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wherein:

r is C _1-6 An alkyl group;

r' is an amino protecting group, preferably tert-butoxycarbonyl or tert-butylsulfinyl;

Another aspect of the present disclosure relates to a compound of formula (IB) or a salt thereof,

wherein:

Another aspect of the disclosure relates to a compound of formula (IIA) or a salt thereof,

wherein:

r is C _1-6 An alkyl group;

x, Y and Z are the same or different, and

x is a nitrogen atom or CR ^x ；

Y being a nitrogen atom or CR ^y ；

Z is a nitrogen atom or CR ^z ；

rings A, U, V, W, G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ And m is as defined in formula (I).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIAa) or a salt thereof,

wherein:

r is C _1-6 An alkyl group;

ring A, U, V, W, X, Y, Z, G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ And m is as defined in formula (II).

Another aspect of the present disclosure relates to a compound represented by formula (IIB) or a salt thereof,

wherein:

Another aspect of the present disclosure relates to a compound of formula (IIIA) or a salt thereof,

wherein:

r is C _1-6 An alkyl group;

x, Y and Z are the same or different, and

x is a nitrogen atom or CR ^x ；

Y being a nitrogen atom or CR ^y ；

Z is a nitrogen atom or CR ^z ；

or R ^x And R ^y 、R ^y And R ^z Each independently optionally forming, together with the attached carbon atoms, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with a group selected from halogen, oxo, alkyl, haloalkyl, alkenyl, alkynylRadical, alkoxy, haloalkoxy, nitro, cyano, -NR ⁶ R ⁷ Hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Another aspect of the present disclosure relates to a compound represented by the general formula (IIIAa) or a salt thereof,

wherein:

r is C _1-6 An alkyl group;

U、V、W、X、Y、Z、G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ and m is as defined in formula (III).

Another aspect of the present disclosure relates to a compound of formula (IIIB) or a salt thereof,

wherein:

Another aspect of the present disclosure relates to a compound of formula (IVA) or a salt thereof,

wherein:

r is C _1-6 An alkyl group;

x, Y and Z are the same or different, and

x is a nitrogen atom or CR ^x ；

Y being a nitrogen atom or CR ^y ；

Z is a nitrogen atom or CR ^z ；

or R ^x And R ^y 、R ^y And R ^z Each independently optionally forming, together with the carbon atom to which it is attached, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more groups selected from halogen, oxo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁶ R ⁷ Hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Another aspect of the present disclosure relates to a compound represented by the general formula (IVAa) or a salt thereof,

wherein:

r is C _1-6 An alkyl group;

U、V、W、X、Y、Z、G ¹ 、G ² 、R ¹ and m is as defined in formula (IV).

Another aspect of the present disclosure relates to a compound of formula (IVB) or a salt thereof,

wherein:

Table B typical intermediate compounds of the present disclosure include, but are not limited to:

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another aspect of the present disclosure relates to a method of preparing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, comprising:

carrying out ester hydrolysis reaction on the compound shown in the general formula (IA) or salt thereof to obtain a compound shown in the general formula (I) or pharmaceutically acceptable salt thereof;

wherein:

r is C _1-6 An alkyl group;

Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (IA) or a salt thereof, comprising:

deprotecting a compound represented by general formula (IAa) or a salt thereof to obtain a compound represented by general formula (IA) or a salt thereof;

wherein:

r is C _1-6 An alkyl group;

ring A, ring B, U, V, W, G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ 、R ² M and n are as defined in formula (IA).

Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (IB) or a salt thereof, comprising:

subjecting the compound represented by the general formula (IAa) or a salt thereof to ester hydrolysis reaction to obtain a compound represented by the general formula (IB) or a salt thereof;

wherein:

r is C _1-6 An alkyl group;

ring A, ring B, U, V, W, G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ 、R ² M and n are as defined in formula (IB).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprising:

carrying out deprotection reaction on the compound shown in the general formula (IB) or salt thereof to obtain a compound shown in the general formula (I) or pharmaceutically acceptable salt thereof;

wherein:

Another aspect of the present disclosure relates to a method of preparing a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, comprising:

carrying out ester hydrolysis reaction on the compound shown in the general formula (IIA) or salt thereof to obtain a compound shown in a general formula (II) or pharmaceutically acceptable salt thereof;

wherein:

r is C _1-6 An alkyl group;

x, Y and Z are the same or different, and

x is a nitrogen atom or CR ^x ；

Y being a nitrogen atom or CR ^y ；

Z is a nitrogen atom or CR ^z ；

or R ^x And R ^y 、R ^y And R ^z Each independently optionally forming, together with the attached carbon atoms, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁶ R ⁷ Hydroxy, hydroxyalkyl, cycloalkyl, heterocycleSubstituted with one or more substituents selected from the group consisting of aryl, heteroaryl and heteroaryl;

Another aspect of the present disclosure relates to a method of preparing a compound represented by formula (IIA) or a salt thereof, comprising:

subjecting the compound represented by the general formula (IIAa) or a salt thereof to deprotection reaction to obtain a compound represented by the general formula (IIA) or a salt thereof;

wherein:

r is C _1-6 An alkyl group;

ring A, U, V, W, X, Y, Z, G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ And m is as defined in formula (IIA).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIB) or a salt thereof, comprising:

subjecting the compound represented by the general formula (IIAa) or a salt thereof to ester hydrolysis to obtain a compound represented by the general formula (IIB) or a salt thereof;

wherein:

r is C _1-6 An alkyl group;

rings A, U, V, W, X, Y, Z, G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ And m is as defined in formula (IIB).

carrying out deprotection reaction on the compound shown in the general formula (IIB) or salt thereof to obtain a compound shown in a general formula (II) or pharmaceutically acceptable salt thereof;

wherein:

rings A, U, V, W, X, Y, Z, G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ And m is as defined in formula (II).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (III), or a pharmaceutically acceptable salt thereof, comprising:

carrying out ester hydrolysis reaction on the compound shown in the general formula (IIIA) or salt thereof to obtain a compound shown in a general formula (III) or pharmaceutically acceptable salt thereof;

wherein:

r is C _1-6 An alkyl group;

x, Y and Z are the same or different, and

x is a nitrogen atom or CR ^x ；

Y being a nitrogen atom or CR ^y ；

Z is a nitrogen atom or CR ^z ；

Another aspect of the present disclosure relates to a method of preparing a compound represented by formula (IIIA) or a salt thereof, comprising:

subjecting the compound represented by the general formula (IIIAa) or a salt thereof to deprotection reaction to obtain a compound represented by the general formula (IIIA) or a salt thereof;

wherein:

r is C _1-6 An alkyl group;

U、V、W、X、Y、Z、G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ and m is as defined in formula (IIIA).

Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (IIIB) or a salt thereof, comprising:

subjecting the compound represented by the general formula (IIIAa) or a salt thereof to ester hydrolysis reaction to obtain a compound represented by the general formula (IIIB) or a salt thereof;

wherein:

r is C _1-6 An alkyl group;

U、V、W、X、Y、Z、G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ and m is as defined in formula (IIIB).

Another aspect of the present disclosure relates to a method of preparing a compound represented by the general formula (III), or a pharmaceutically acceptable salt thereof, comprising:

carrying out deprotection reaction on the compound shown in the general formula (IIIB) or salt thereof to obtain a compound shown in a general formula (III) or pharmaceutically acceptable salt thereof;

wherein:

Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, comprising:

carrying out ester hydrolysis reaction on the compound shown in the general formula (IVA) or salt thereof to obtain a compound shown in a general formula (IV) or pharmaceutically acceptable salt thereof;

wherein:

r is C _1-6 An alkyl group;

x, Y and Z are the same or different, and

x is a nitrogen atom or CR ^x ；

Y being a nitrogen atom or CR ^y ；

Z is a nitrogen atom or CR ^z ；

Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (IVA) or a salt thereof, comprising:

subjecting the compound represented by the general formula (IVAa) or a salt thereof to deprotection reaction to obtain a compound represented by the general formula (IVA) or a salt thereof;

wherein:

r is C _1-6 An alkyl group;

U、V、W、X、Y、Z、G ¹ 、G ² 、R ¹ and m is as defined in formula (IVA).

Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (IVB) or a salt thereof, comprising:

subjecting the compound represented by the general formula (IVAa) or a salt thereof to ester hydrolysis reaction to obtain a compound represented by the general formula (IVB) or a salt thereof;

wherein:

r is C _1-6 An alkyl group;

U、V、W、X、Y、Z、G ¹ 、G ² 、R ¹ and m is as defined in formula (IVB).

carrying out deprotection reaction on the compound shown in the general formula (IVB) or salt thereof to obtain a compound shown in a general formula (IV) or pharmaceutically acceptable salt thereof;

wherein:

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure represented by formula (I), formula (II), formula (III), formula (IV), or table a, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of a compound represented by general formula (I), general formula (II), general formula (III), general formula (IV) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting complement factor D.

The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for the treatment and/or prevention of a disease or disorder mediated by complement factor D.

The present disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prevention of Paroxysmal Nocturnal Hemoglobinuria (PNH), reperfusion injury, multiple sclerosis, amyotrophic lateral sclerosis, autoimmune diseases, ophthalmic diseases, inflammatory diseases, respiratory diseases, cardiovascular diseases, liver diseases, kidney diseases, abdominal aortic aneurysms, hemodialysis complications, hemolytic anemia, cancer and diseases or conditions of immune disorders; wherein said kidney disease is preferably selected from the group consisting of lupus nephritis, glomerulopathy and hemolytic uremic syndrome; the ophthalmic disease is preferably dry age-related macular degeneration; the glomerulopathy is preferably C3 glomerulopathy or IgA nephropathy.

The disclosure also relates to a method of inhibiting complement factor D comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV), or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method of treating and/or preventing a disease or disorder mediated by complement factor D comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV), or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a use in a medicament for the treatment and/or prevention of a disease or condition of Paroxysmal Nocturnal Hemoglobinuria (PNH), reperfusion injury, multiple sclerosis, amyotrophic lateral sclerosis, autoimmune diseases, ophthalmic diseases, inflammatory diseases, respiratory diseases, cardiovascular diseases, liver diseases, kidney diseases, abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, cancer and immune disorders; wherein said kidney disease is preferably selected from the group consisting of lupus nephritis, glomerulopathy and hemolytic uremic syndrome; the ophthalmic disease is preferably dry age-related macular degeneration; the glomerulopathy is preferably C3 glomerulopathy or IgA nephropathy.

The disclosure further relates to compounds of formula (I), formula (II), formula (III), formula (IV) or table a or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same for use as a medicament.

The disclosure also relates to compounds of formula (I), formula (II), formula (III), formula (IV), or table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as complement factor D inhibitors.

The disclosure also relates to compounds of formula (I), formula (II), formula (III), formula (IV) or table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as medicaments for the treatment and/or prevention of diseases or disorders mediated by complement factor D.

The present disclosure further relates to a compound of formula (I), formula (II), formula (III), formula (IV) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in a medicament for the treatment and/or prevention of Paroxysmal Nocturnal Hemoglobinuria (PNH), reperfusion injury, multiple sclerosis, amyotrophic lateral sclerosis, autoimmune diseases, ophthalmic diseases, inflammatory diseases, respiratory diseases, cardiovascular diseases, liver diseases, kidney diseases, abdominal aortic aneurysms, hemodialysis complications, hemolytic anemia, cancer and diseases or conditions of immune disorders; wherein said kidney disease is preferably selected from the group consisting of lupus nephritis, glomerulopathy and hemolytic uremic syndrome; the ophthalmic disease is preferably dry age-related macular degeneration; the glomerulopathy is preferably C3 glomerulopathy or IgA nephropathy.

The complement factor D-mediated disease or disorder described in the present disclosure is preferably selected from the group consisting of Paroxysmal Nocturnal Hemoglobinuria (PNH), glomerulopathy, reperfusion injury, multiple sclerosis, amyotrophic lateral sclerosis, autoimmune diseases, ophthalmic diseases, inflammatory diseases, respiratory diseases, cardiovascular diseases, kidney diseases, liver diseases, abdominal aortic aneurysms, hemodialysis complications, hemolytic anemia, cancer, and immune disorders; wherein the kidney disease is preferably selected from lupus nephritis, glomerulopathy or hemolytic uremic syndrome; the ophthalmic disease is preferably dry age-related macular degeneration; the glomerulopathy is preferably C3 glomerulopathy or IgA nephropathy.

The glomerulopathy described in the present disclosure is preferably selected from the group consisting of glomerulonephritis (including membranoproliferative glomerulonephritis (MPGN), immune complex membranoproliferative glomerulonephritis (IC-MPGN), C3 glomerulonephritis (C3 GN)), C3 glomerulopathy, igA nephropathy (IgA nephropathiy, igAN), dense Deposit Disease (DDD), complement Alternative Pathway (AP) related nephropathy, wherein membranoproliferative glomerulonephritis is preferably membranoproliferative glomerulonephritis type II (MPGN II); the hemolytic uremic syndrome is preferably atypical or typical hemolytic uremic syndrome; the inflammatory disease is preferably arthritis or Dermatomyositis (DM), wherein the arthritis is preferably rheumatoid arthritis; the respiratory disease is preferably Chronic Obstructive Pulmonary Disease (COPD); the ophthalmological disease is preferably selected from the group consisting of age-related macular degeneration (AMD), retinal degeneration, autoimmune dry eye and environmental dry eye, wherein age-related macular degeneration is preferably selected from the group consisting of dry age-related macular degeneration, early stage or neovascular age-related macular degeneration; the liver disease is preferably selected from fatty liver, liver inflammation, liver cirrhosis and liver failure, wherein the fatty liver is preferably non-alcoholic steatohepatitis (NASH); the autoimmune disease is preferably selected from neuromyelitis optica, rheumatoid arthritis and Myasthenia Gravis (MG).

As a general guide, the active compound is preferably administered in a unit dose or in a manner such that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be from 0.1 to 1000mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, the injection or microemulsion being injectable into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump of the model Deltec CADD-PLUS. TM. 5400.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, and the like; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 1 to 20 (e.g., 1,2,3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C) _1-20 Alkyl groups). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C) _1-12 Alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C) _1-6 Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, <xnotran> 3- ,4- ,5- ,2,3- ,2,4- ,2,2- ,3,3- ,2- ,3- , ,2,3- ,2,4- ,2,5- ,2,2- ,3,3- ,4,4- ,2- ,3- ,4- ,2- -2- ,2- -3- , ,2- -2- ,2- -3- ,2,2- , ,3,3- ,2,2- , . </xnotran>Chain isomers, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1,2,3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C) _1-20 Alkylene). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C) _1-12 Alkylene), more preferably alkylene having 1 to 6 carbon atoms (i.e., C) _1-6 Alkylene). Non-limiting examples include: -CH ₂ -、-CH(CH ₃ )-、-C(CH ₃ ) ₂ -、-CH ₂ CH ₂ -、-CH(CH ₂ CH ₃ )-、-CH ₂ CH(CH ₃ )-、-CH ₂ C(CH ₃ ) ₂ -、-CH ₂ CH ₂ CH ₂ -、-CH ₂ CH ₂ CH ₂ CH ₂ -and the like. Alkylene groups may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is defined as above, having 2 to 12 (e.g., 2,3, 4,5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C) _2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C) _2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, takingThe substituent is preferably selected from one or more of D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2,3, 4,5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C) _2-12 Alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C) _2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, and butoxy, and the like. Alkoxy groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all carbocycle (i.e., monocyclic cycloalkyl) or multicyclic ring system (i.e., polycyclic cycloalkyl) having from 3 to 20 (e.g., 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl). The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3 to 12-membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3 to 8-membered cycloalkyl group), and most preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3 to 6-membered cycloalkyl group).

Non-limiting examples of said monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl and the like.

Said polycyclic cycloalkyl groups include: spirocycloalkyl, fused ring alkyl, and bridged ring alkyl.

The term "spirocycloalkyl" refers to a polycyclic ring system sharing one carbon atom (referred to as a spiro atom) between rings, which may contain one or more double bonds within the ring, or which may contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur within the ring (the nitrogen may optionally be oxidized, i.e., to form an oxynitride; the sulfur may optionally be oxidized, i.e., to form a sulfoxide or sulfone, but not including-O-, -O-S-, or-S-), provided that at least one all-carbon ring is present and the point of attachment is on the all-carbon ring, which has from 5 to 20 (e.g., 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered spirocycloalkyl). The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6-to 14-membered spirocycloalkyl group), and more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., a 7-to 10-membered spirocycloalkyl group). The spirocycloalkyl group includes a mono-spirocycloalkyl group and a polyspirocycloalkyl group (e.g., a bispirocycloalkyl group, etc.), preferably a mono-spirocycloalkyl group or a bispirocycloalkyl group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered single spirocycloalkyl group. Non-limiting examples include:

the connection point can be at any position;

and the like.

The term "fused cyclic alkyl" refers to a polycyclic ring system in which adjacent two carbon atoms are shared between the rings,which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more of a heterocyclyl, aryl, or heteroaryl, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within its ring, and having 5 to 20 (e.g., 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused ring alkyl). The fused cycloalkyl group is preferably a fused cycloalkyl group having 6 to 14 ring atoms (i.e., a 6-to 14-membered fused cycloalkyl group), and more preferably a fused cycloalkyl group having 7 to 10 ring atoms (i.e., a 7-to 10-membered fused cycloalkyl group). The fused ring alkyl group includes a bicyclic fused ring alkyl group and a polycyclic fused ring alkyl group (e.g., tricyclic fused ring alkyl group, tetracyclic fused ring alkyl group, etc.), preferably a bicyclic fused ring alkyl group or tricyclic fused ring alkyl group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/5-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused ring alkyl group. Non-limiting examples include:

the connection point can be at any position;

and the like.

The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system between rings sharing two carbon atoms not directly connected, which may contain one or more double bonds within the ring, and having 5 to 20 (e.g., 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., a 5 to 20 membered bridged cycloalkyl). The bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e., a 6 to 14-membered bridged cycloalkyl group), and more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e., a 7 to 10-membered bridged cycloalkyl group). The bridged cycloalkyl group includes bicyclic bridged cycloalkyl groups and polycyclic bridged cycloalkyl groups (e.g., tricyclic bridged cycloalkyl groups, tetracyclic bridged cycloalkyl groups, etc.), preferably bicyclic bridged cycloalkyl groups or tricyclic bridged cycloalkyl groups. Non-limiting examples include:

the connection point can be at any position.

Cycloalkyl groups may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclyl) or polycyclic heterocycle system (i.e., polycyclic heterocyclyl) containing at least one heteroatom (e.g., 1,2,3, or 4) selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form an oxynitride; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but does not include-O-, -O-S-, or-S-), and having from 3 to 20 (e.g., 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20 membered heterocyclyl) within the ring. The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3-to 12-membered heterocyclic group); further preferred are heterocyclic groups having 3 to 8 ring atoms (i.e., 3-to 8-membered heterocyclic groups); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3-to 6-membered heterocyclic group); most preferred are heterocyclic groups having 5 or 6 ring atoms (i.e., 5 or 6 membered heterocyclic groups).

Non-limiting examples of said monocyclic heterocyclic groups include: pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

The polycyclic heterocyclic group includes spiro heterocyclic group, fused heterocyclic group and bridged heterocyclic group.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system sharing one atom (referred to as a spiro atom) between rings, which may contain one or more double bonds within the ring and at least one heteroatom (e.g., 1,2,3, or 4) selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form an oxynitride; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but not including-O-, -O-S-, or-S-), provided that at least one monocyclic heterocyclic group is present and the point of attachment is to the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered spiroheterocyclic groups). The spiroheterocyclyl group is preferably a spiroheterocyclyl group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclyl group), more preferably a spiroheterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclyl group). The spiro heterocyclic group includes a mono-spiro heterocyclic group and a poly-spiro heterocyclic group (e.g., a spiro heterocyclic group, etc.), preferably a mono-spiro heterocyclic group or a spiro heterocyclic group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered mono-spiro heterocyclic group. Non-limiting examples include:

and the like.

The term "fused heterocyclic group" refers to a polycyclic heterocyclic ring system which shares adjacent two atoms between rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1,2,3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur within the ring (the nitrogen may be optionally oxidized, i.e., to form an oxynitride; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but does not include-O-, O-S-, or-S-), which is a monocyclic heterocyclic group fused to one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused to one or more of a cycloalkyl, aryl, or heteroaryl group, wherein the point of attachment is on the monocyclic heterocyclic group and has from 5 to 20 (e.g., 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5 to 20 membered fused heterocyclic group). The fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6-to 14-membered fused heterocyclic group), more preferably a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7-to 10-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (e.g., tricyclic fused heterocyclic group, tetracyclic fused heterocyclic group, etc.), preferably bicyclic fused heterocyclic group or tricyclic fused heterocyclic group, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples include:

and the like.

The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system sharing two atoms between the rings that are not directly connected, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1,2,3, or 4) heteroatom (S) selected from nitrogen, oxygen, and sulfur within the ring (which nitrogen may be optionally oxidized, i.e., form a nitrogen oxide; the sulfur may optionally be oxo, i.e., form a sulfoxide or sulfone, but does not include-O-, -O-S-, or-S-), having from 5 to 20 (e.g., 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5-to 20-membered bridged heterocyclic group). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6-to 14-membered bridged heterocyclic group), more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7-to 10-membered bridged heterocyclic group). They may be classified into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (e.g., tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.) depending on the number of constituent rings, and bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups are preferred. Non-limiting examples include:

and the like.

The heterocyclyl group may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of a D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated pi-electron system and having from 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 6-to 14-membered aryl). The aryl group is preferably an aryl group having 6 to 10 ring atoms (i.e., a 6-to 10-membered aryl group). Such monocyclic aryl groups are, for example, phenyl. Non-limiting examples of said polycyclic aromatic groups include: naphthyl, anthryl, phenanthryl, and the like. The polycyclic aryl also includes phenyl fused to one or more of a heterocyclyl or cycloalkyl or naphthyl fused to one or more of a heterocyclyl or cycloalkyl wherein the point of attachment is on the phenyl or naphthyl and in which case the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including:

and the like.

Aryl groups may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated pi-electron system, which contains at least one (e.g., 1,2,3, or 4) heteroatom (S) selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form an oxynitride; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but does not include-O-, -O-S-, or-S-), which has 5 to 14 (e.g., 5,6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5-to 14-membered heteroaryl). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5-to 10-membered heteroaryl group), and more preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5-or 6-membered heteroaryl group).

Non-limiting examples of monocyclic heteroaryls include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidyl, pyridonyl, N-alkylpyridinone (e.g., as in the case of the corresponding compounds)

Etc.), pyrazinyl, pyridazinyl, etc.

Non-limiting examples of said polycyclic heteroaryl include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. The polycyclic heteroaryl also includes monocyclic heteroaryl fused to one or more aryl groups wherein the point of attachment is on the aromatic ring, and in this case the number of ring atoms continues to represent the number of ring atoms in a polycyclic heteroaromatic ring system. The polycyclic heteroaryl also includes monocyclic heteroaryl fused to one or more of cycloalkyl or heterocyclyl, where the point of attachment is on the monocyclic heteroaryl ring, and in this case the number of ring atoms continues to represent the number of ring atoms in a polycyclic heteroaryl ring system. Non-limiting examples include:

and the like.

Heteroaryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "amino protecting group" refers to a group that is easily removed by introduction onto an amino group in order to keep the amino group unchanged during the reaction at other sites of the molecule. Non-limiting examples include: (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butyloxycarbonyl (Boc), t-butylsulfinyl, benzyloxycarbonyl (Cbz), fluorenyl methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2, 4-Dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl and the like.

The term "hydroxyl protecting group" refers to an easily removable group introduced at a hydroxyl group for blocking or protecting the hydroxyl group while performing a reaction on other functional groups of a compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like.

The term "cycloalkyloxy" refers to cycloalkyl-O-wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to the heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "alkylthio" refers to an alkyl-S-group wherein alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.

The term "methylidene" means = CH ₂ 。

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to-NH ₂ 。

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

The term "oxo" or "oxo" means "= O".

The term "carbonyl" refers to C = O.

The term "carboxy" refers to-C (O) OH.

The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl and cycloalkyl are as defined above.

The compounds of the disclosure may exist in specific stereoisomeric forms. The term "stereoisomers" refers to isomers that are structurally identical but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Additional asymmetric atoms may be present in substituents in the compounds of the present disclosure. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers, and (D) -and (L) -isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. One isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or, when a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl) is contained in the molecule, a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then diastereoisomeric resolution is performed by a conventional method known in the art to obtain pure isomers. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

In the chemical structure of the compounds described in the present disclosure, a bond

Denotes an unspecified configuration, i.e. if a chiral isomer is present in the chemical structure, the bond->

Can be based on->

Or both>

Two configurations.

The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, i.e. in the form of a single isomer or in the form of a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, and the like. Examples of lactam-lactam equilibria are shown below:

when referring to pyrazolyl, it is understood to include any one of the following two structures or a mixture of two tautomers:

all tautomeric forms are within the scope of the disclosure, and the naming of the compounds does not exclude any tautomers.

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, and the like, for example, respectively ² H (deuterium, D), ³ H (tritium, T), ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ³² p、 ³³ p、 ³³ S、 ³⁴ S、 ³⁵ S、 ³⁶ S、 ¹⁸ F、 ³⁶ Cl、 ⁸² Br、 ¹²³ I、 ¹²⁴ I、 ¹²⁵ I、 ¹²⁹ I and ¹³¹ i, etc., preferably deuterium.

Compared with the non-deuterated drugs, the deuterated drugs have the advantages of reducing toxic and side effects, increasing the stability of the drugs, enhancing the curative effect, prolonging the biological half-life of the drugs and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, where replacement by deuterium may be partial or complete, partial replacement by deuterium meaning replacement of at least one hydrogen by at least one deuterium.

In the compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D", that position is understood to be an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% of deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% of deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium incorporation).

"optional" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that it includes both instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with halogen or cyano" includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

"substituted" or "substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, independently of each other, being substituted by a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, an amino or hydroxyl group having a free hydrogen may be unstable in combination with a carbon atom (e.g., an alkene) having an unsaturated bond.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or pharmaceutically acceptable salts thereof and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure, which may be selected from inorganic or organic salts. The salt has safety and effectiveness when used in a mammal body, and has due biological activity. Can be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate therapeutically effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The term "pharmaceutically acceptable" as used herein means that the compounds, materials, compositions, and/or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.

As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is meant that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be appreciated by those skilled in the art, when the parameters are not critical, the numbers are generally given for illustrative purposes only and are not limiting.

Synthesis of the Compounds of the disclosure

In order to achieve the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

scheme one

The preparation method of the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof comprises the following steps:

carrying out ester hydrolysis reaction on the compound shown in the general formula (IA) or salt thereof under alkaline conditions to obtain the compound shown in the general formula (I) or pharmaceutically acceptable salt thereof;

wherein:

r is C _1-6 An alkyl group;

Scheme two

The preparation method of the compound shown in the general formula (IA) or the salt thereof comprises the following steps:

deprotecting a compound represented by general formula (IAa) or a salt thereof under acidic conditions to obtain a compound represented by general formula (IA) or a salt thereof;

wherein:

r is C _1-6 An alkyl group;

Scheme three

The preparation method of the compound shown in the general formula (IB) or the salt thereof comprises the following steps:

carrying out ester hydrolysis reaction on the compound shown in the general formula (IAa) or the salt thereof under alkaline conditions to obtain a compound shown in a general formula (IB) or the salt thereof;

wherein:

r is C _1-6 An alkyl group;

Scheme four

carrying out deprotection reaction on the compound shown in the general formula (IB) or salt thereof under high temperature (preferably 140 ℃) to obtain the compound shown in the general formula (I) or pharmaceutically acceptable salt thereof;

wherein:

Scheme five

The preparation method of the compound shown in the general formula (II) or the pharmaceutically acceptable salt thereof comprises the following steps:

carrying out ester hydrolysis reaction on the compound shown in the general formula (IIA) or salt thereof under alkaline conditions to obtain a compound shown in the general formula (II) or pharmaceutically acceptable salt thereof;

wherein:

r is C _1-6 An alkyl group;

x, Y and Z are the same or different, and

x is a nitrogen atom or CR ^x ；

Y being a nitrogen atom or CR ^y ；

Z is a nitrogen atom or CR ^z ；

or R ^x And R ^y 、R ^y And R ^z Each independently optionally together with the carbon atom to which it is attached form cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkylAlkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁶ R ⁷ Hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Scheme six

The preparation method of the compound shown in the general formula (IIA) or the salt thereof comprises the following steps:

deprotecting a compound represented by general formula (IIAa) or a salt thereof under acidic conditions to give a compound represented by general formula (IIA) or a salt thereof;

wherein:

r is C _1-6 An alkyl group;

rings A, U, V, W, X, Y, Z, G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ And m is as defined in formula (IIA).

Scheme seven

The preparation method of the compound shown in the general formula (IIB) or the salt thereof comprises the following steps:

subjecting the compound shown in the general formula (IIAa) or the salt thereof to ester hydrolysis reaction under alkaline conditions to obtain a compound shown in the general formula (IIB) or the salt thereof;

wherein:

r is C _1-6 An alkyl group;

ring A, U, V, W, X, Y, Z, G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ And m is as defined in formula (IIB).

Scheme eight

deprotecting the compound represented by the general formula (IIB) or a salt thereof at a high temperature (preferably 140 ℃) to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

Scheme nine

The preparation method of the compound shown in the general formula (III) or the pharmaceutically acceptable salt thereof comprises the following steps:

performing ester hydrolysis reaction on the compound shown in the general formula (IIIA) or salt thereof under alkaline condition to obtain a compound shown in the general formula (III) or pharmaceutically acceptable salt thereof;

wherein:

r is C _1-6 An alkyl group;

x, Y and Z are identical or different, and

x is a nitrogen atom or CR ^x ；

Y is a nitrogen atom orCR ^y ；

Z is a nitrogen atom or CR ^z ；

Scheme ten

A process for producing a compound represented by the general formula (IIIA) of the present disclosure or a salt thereof, comprising the steps of:

deprotecting a compound represented by general formula (IIIAa) or a salt thereof under acidic conditions to obtain a compound represented by general formula (IIIA) or a salt thereof;

wherein:

r is C _1-6 An alkyl group;

Scheme eleven

A process for producing a compound represented by general formula (IIIB) or a salt thereof of the present disclosure, comprising the steps of:

subjecting the compound represented by the general formula (IIIAa) or a salt thereof to ester hydrolysis reaction under alkaline conditions to obtain a compound represented by the general formula (IIIB) or a salt thereof;

wherein:

r is C _1-6 An alkyl group;

Scheme twelve

carrying out deprotection reaction on the compound shown in the general formula (IIIB) or salt thereof under high temperature (preferably 140 ℃) to obtain the compound shown in the general formula (III) or pharmaceutically acceptable salt thereof;

wherein:

Scheme thirteen

The preparation method of the compound shown in the general formula (IV) or the pharmaceutically acceptable salt thereof comprises the following steps:

carrying out ester hydrolysis reaction on the compound shown in the general formula (IVA) or salt thereof under alkaline conditions to obtain a compound shown in a general formula (IV) or pharmaceutically acceptable salt thereof;

wherein:

r is C _1-6 An alkyl group;

x, Y and Z are the same or different, and

x is a nitrogen atom or CR ^x ；

Y being a nitrogen atom or CR ^y ；

Z is a nitrogen atom or CR ^z ；

U、V、W、G ¹ 、G ² 、R ¹ 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ and m is as followsAs defined in formula (I).

Fourteen scheme

A process for preparing a compound of the general formula (IVA) or a salt thereof, comprising the steps of:

deprotecting a compound represented by general formula (IVAa) or a salt thereof under acidic conditions to give a compound represented by general formula (IVA) or a salt thereof;

wherein:

r is C _1-6 An alkyl group;

Fifteen scheme

A process for producing a compound represented by general formula (IVB) or a salt thereof of the present disclosure, comprising the steps of:

subjecting the compound represented by the general formula (IVAa) or a salt thereof to an ester hydrolysis reaction under a basic condition to obtain a compound represented by the general formula (IVB) or a salt thereof;

wherein:

r is C _1-6 An alkyl group;

Sixteenth scheme

carrying out deprotection reaction on the compound shown in the general formula (IVB) or salt thereof under high temperature (preferably 140 ℃) to obtain a compound shown in a general formula (IV) or pharmaceutically acceptable salt thereof;

wherein:

In the above synthesis scheme, the reagent providing basic conditions comprises organic base and inorganic base, the organic base includes but is not limited to triethylamine, N-diisopropylethylamine, N-butyl lithium, lithium diisopropylamide, potassium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, preferably triethylamine; the inorganic base includes, but is not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide; preferably lithium hydroxide monohydrate or lithium hydroxide.

In the above synthetic schemes, reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, 1, 4-dioxane solution of hydrochloric acid, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, me ₃ SiCl and TMSOTf, preferably selected from the group consisting of a1, 4-dioxane solution of hydrogen chloride, a1, 4-dioxane solution of hydrochloric acid and concentrated sulfuric acid.

The above synthetic schemes are preferably carried out in solvents including, but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, and a mixture thereof.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) at 10 ^-6 The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M in deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS).

MS was measured using Agilent 1200/1290DAD-6110/6120Quadrupole MS LC MS (manufacturer: agilent, MS model: 6110/6120Quadrupole MS), waters ACQuority UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuority Qda Detector/waters SQ Detector) and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC1200 DAD, agilent HPLC1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC analytical determination Agilent 1260DAD HPLC was used.

High Performance liquid preparation preparative chromatographs were prepared using Waters 2545-2767, waters 2767-SQ Detector 2, shimadzu LC-20AP and Gilson GX-281.

Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.

CombiFlash flash rapid preparation instrument uses CombiFlash Rf200 (TELEDYNE ISCO).

The thin-layer chromatography silica gel plate adopts a cigarette platform yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the thin-layer chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin-layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Silica gel column chromatography generally uses 200-300 mesh silica gel of the Litsea crassirhizomes as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were determined with a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a Parr 3916EKX type hydrogenator and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenator.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

A CEM Discover-S908860 type microwave reactor was used for the microwave reaction.

In the examples, the solution means an aqueous solution without specific indication.

In the examples, the reaction temperature is, unless otherwise specified, room temperature and is 20 ℃ to 30 ℃.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: n-hexane/ethyl acetate system, B: dichloromethane/methanol, C: in the petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

2- (2- ((4- (aminomethyl) -6H-benzo (c) chromen-9-yl) methoxy) phenyl) acetic acid 1

First step of

3-bromo-4- (bromomethyl) benzoic acid methyl ester 1b

The compound 3-bromo-4-methyl-benzoic acid methyl ester 1a (2.00g, 8.73mmol, shanghai Bian) was dissolved in carbon tetrachloride (30 mL), N-bromosuccinimide (1.71g, 9.61mmol, shanghai Titan) and benzoyl peroxide (211mg, 0.87mmol, shanghai Titan) were added, and the reaction was stirred at 70 ℃ for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give the title compound 1b (1.20 g, yield: 45%).

MS m/z(ESI):325.8[M+18]。

Second step of

2-Hydroxybenzylcarbamic acid tert-butyl ester 1d

Compound 1C (2.00g, 16.38mmol, shanghaitant) and tert-butyl carbamate (5.76g, 49.13mmol, shanghaitant) were dissolved in acetonitrile (90 mL) and dichloromethane (30 mL), triethylsilane (5.71g, 49.13mmol, shanghaitant) was slowly added, then trifluoroacetic acid (3.74g, 32.76mmol, shanghaitant) was added dropwise, the reaction was stirred for 18 hours, a saturated sodium bicarbonate solution (100 mL) was added to the reaction solution to quench, extraction was performed with dichloromethane (50 mL × 3), the organic phases were combined, washed successively with water, a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to elute system C to give compound 1d (3.60 g, title: 98%).

MS m/z(ESI):222.1[M-1]。

The third step

Methyl 3-bromo-4- ((2- (((tert-butoxycarbonyl) amino) methyl) phenoxy) methyl) benzoate 1e

Compound 1b (138mg, 0.45mmol), compound 1d (100mg, 0.45mmol) and potassium carbonate (185mg, 1.34mmol) were dissolved in N, N-dimethylformamide (2 mL), stirred for reaction for 16 hours, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution System C to give the title compound 1e (130 mg, yield: 64%).

MS m/z(ESI):449.0[M-23]。

The fourth step

4- (((tert-Butoxycarbonyl) amino) methyl) -6H-benzo (c) chromene-9-carboxylic acid methyl ester 1f

Compound 1e (30mg, 67. Mu. Mol), palladium acetate (15mg, 67. Mu. Mol, shanghai Shao Yuan), 2-diphenylphosphine-2' - (N, N-dimethylamino) biphenyl (25mg, 66. Mu. Mol, shanghai Bian) and potassium carbonate (27mg, 196. Mu. Mol) were dissolved in N, N-dimethylformamide (2 mL), replaced with nitrogen, heated to 130 ℃ for reaction for 3 hours, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution System C to give the title compound 1f (15 mg, yield: 61%).

MS m/z(ESI):370.0[M+1]。

The fifth step

((9- (hydroxymethyl) -6H-benzo (c) chromen-4-yl) methyl) carbamic acid tert-butyl ester 1g

Compound 1f (300mg, 0.81mmol) was dissolved in tetrahydrofuran (5 mL), lithium aluminum hydride (36mg, 1.06mmol) was added under ice bath, stirred for 1 hour, the reaction mixture was diluted with ethyl acetate (5 mL), sodium sulfate decahydrate was added, stirred for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to give 1g (200 mg) of the crude title compound, which was used in the next reaction without purification.

MS m/z(ESI):342.1[M+1]。

The sixth step

2- (2- ((4- ((tert-butoxycarbonyl) amino) methyl) -6H-benzo (c) chromen-9-yl) methoxy) phenyl) acetic acid ethyl ester 1i

The crude compound (1 g, 30mg, 0.088mmol), ethyl 2- (2-hydroxyphenyl) acetate (1 h, 32mg,0.178mmol, shanghai Biao) and triphenylphosphine (46mg, 0.176mmol, wako Junyaku) were dissolved in dichloromethane (2 mL), and diisopropyl azodicarboxylate (36mg, 0.178mmol, shanghai Biao) was added and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 1i (30 mg, yield: 68%).

MS m/z(ESI):521.1[M+18]。

Step seven

Ethyl 2- (2- ((4- (aminomethyl) -6H-benzo (c) chromen-9-yl) methoxy) phenyl) acetate 1j

Compound 1i (30mg, 59.6. Mu. Mol) was dissolved in 4M hydrochloric acid in 1, 4-dioxane (2 mL) and stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to give crude title compound 1j (20 mg) which was used in the next reaction without purification.

MS m/z(ESI):404.1[M+1]。

The eighth step

The crude compound 1j (30mg, 74.3. Mu. Mol) was dissolved in methanol (2 mL) and water (0.5 mL), lithium hydroxide (18mg, 0.75mmol) was added, the reaction was stirred for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mm 5 μm; C18 mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 40% -50%, flow rate: 30 mL/min) to give the title compound 1 (46 mg, yield: 55%).

MS m/z(ESI):376.0[M+1]。

¹ H NMR(500MHz,d-DMSO):δ7.93-7.91(m,1H),7.81-7.79(m,1H),7.41-7.38(m,1H),7.34-7.31(m，1H),7.29-7.27(m,1H),7.22-7.19(m，2H),7.05–7.01(m,2H),6.90-6.86(m,1H),5.19-5.13(m,4H),3.74(s,2H),3.56(s,2H)。

Example 2

2- (2- ((4- (aminomethyl) -6H-benzo (c) chromen-9-yl) methoxy) -4-fluorophenyl) acetic acid 2

First step of

2- (4-fluoro-2-hydroxyphenyl) acetic acid methyl ester 2b

Methyl 2- (4-fluorophenyl) acetate 2a (300mg, 1.78mmol, tokyo) was dissolved in 1, 2-dichloroethane (20 mL), isopropylphenylruthenium dichloride (552mg, 0.89mmol, tokyo) and iodobenzene bistrifluoroacetate (1534mg, 3.56mmol, tokyo) were added, replaced with nitrogen, and the mixture was heated to 100 ℃ for 14 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 2b (100 mg, yield: 30%).

MS m/z(ESI):183.0[M-1]。

Second step of

2- (2- ((4- ((tert-butoxycarbonyl) amino) methyl) -6H-benzo (c) chromen-9-yl) methoxy) -4-fluorophenyl) acetic acid methyl ester 2c

Compound 1g (30mg, 0.088mmol), compound 2b (32mg, 0.174mmol, obtained from Shanghai Biao) and triphenylphosphine (46mg, 0.176mmol) were dissolved in dichloromethane (2 mL), and diisopropyl azodicarboxylate (36mg, 0.178mmol) was added thereto, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 2C (40 mg, yield: 90%).

MS m/z(ESI):525.1[M+18]。

The third step

2- (2- ((4- (aminomethyl) -6H-benzo (c) chromen-9-yl) methoxy) -4-fluorophenyl) acetic acid methyl ester 2d

Compound 2c (40mg, 78.8. Mu. Mol) was dissolved in 4M hydrochloric acid in 1, 4-dioxane (2 mL) and reacted with stirring for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude title compound 2d (30 mg) which was used in the next reaction without purification.

MS m/z(ESI):408.1[M+1]。

The fourth step

The crude compound 2d (35mg, 85.9. Mu. Mol) was dissolved in methanol (2 mL) and water (1 mL), lithium hydroxide (10mg, 0.42mmol) was added, the reaction was stirred for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mm, 5 μm; C18 mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 45% -55%, flow rate: 30 mL/min) to give the title compound 2 (14 mg) in 41% yield.

MS m/z(ESI):394.1[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ8.05-8.07(m,1H),7.98-7.96(m,1H),7.50-7.48(m,1H),7.33-7.26(m,2H),7.21-7.14(m,2H),6.80-6.77(m,1H),6.63–6.59(m,1H),5.25(s,2H),5.17(s,2H),4.14-4.13(m,2H),3.55(s,2H)。

Example 3

2- (2- ((4- (aminomethyl) -6H-benzo (c) chromen-9-yl) methoxy) -4-methylphenyl) acetic acid 3

First step of

2- (4-bromo-2-hydroxyphenyl) acetic acid methyl ester 3b

2- (4-bromo-2-hydroxyphenyl) acetic acid 3a (1000mg, 4.33mmol, obtained from Shanghai Biao) was dissolved in methanol (40 mL) and concentrated sulfuric acid (0.4 mL), and heated to 50 ℃ for reaction for 14 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 3b (1 g, yield: 94%). MS m/z (ESI) 242.9[ m-1].

Second step of

Methyl 2- (4-bromo-2- ((4- (((tert-butoxycarbonyl) amino) methyl) -6H-benzo (c) chromen-9-yl) methoxy) phenyl) acetate 3c

Compound 1g (50mg, 0.146mmol), compound 3b (54mg, 0.22mmol) and triphenylphosphine (77mg, 0.29mmol) were dissolved in dichloromethane (2 mL), diisopropyl azodicarboxylate (59mg, 0.29mmol) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 3C (50 mg, yield: 60%).

MS m/z(ESI):468.0[M-100]。

The third step

Methyl 2- (2- ((4- ((tert-butoxycarbonyl) amino) methyl) -6H-benzo (c) chromen-9-yl) methoxy) -4-methylphenyl) acetate 3d

Methylboronic acid (10mg, 0.17mmol, shanghaineao), compound 3c (20mg, 35.2. Mu. Mol), sodium carbonate (15mg, 0.14mmol), tris (dibenzylideneacetone) dipalladium (26mg, 28.4. Mu. Mol, shanghaitant), 2-bicyclohexylphosphine-2 ',6' -diisopropyloxybiphenyl (13mg, 27.8. Mu. Mol, shanghaitant) and toluene (2 mL) were mixed, heated to 100 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 3d (10 mg, yield: 56%).

MS m/z(ESI):521.2[M+18]。

The fourth step

2- (2- ((4- (aminomethyl) -6H-benzo (c) chromen-9-yl) methoxy) -4-methylphenyl) acetic acid methyl ester 3e

Compound 3d (10mg, 19.9. Mu. Mol) was dissolved in a1, 4-dioxane solution (2 mL) of 4M hydrochloric acid, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to give the crude title compound 3e (8 mg), which was used in the next reaction without purification.

MS m/z(ESI):404.1[M+1]。

The fifth step

Crude compound 3e (20mg, 49.6. Mu. Mol) was dissolved in methanol (2 mL) and water (1 mL), lithium hydroxide (12mg, 0.50mmol) was added, the reaction was stirred for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mm 5 μm; C18 mobile phase: water (10 mM ammonium hydrogencarbonate) and acetonitrile, gradient: acetonitrile 40% -55%, flow rate: 30 mL/min) to give the title compound 3 (10 mg, yield: 52%).

MS m/z(ESI):390.1[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ7.99-7.94(m,2H),7.50-7.46(m,1H),7.28–7.22(m,2H),7.14-7.09(m,2H),6.85-6.81(m,1H),6.74-6.70(m,1H),5.19(s,2H),5.15(s,2H),4.04-3.99(m,2H),3.56(s,2H),2.31(s,3H)。

Example 4

2- (4- (aminomethyl) -2- ((4- (aminomethyl) -6H-benzo (c) chromen-9-yl) methoxy) phenyl) acetic acid 4

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First step of

2- (4-cyano-2-hydroxyphenyl) acetic acid methyl ester 4a

Compound 3b (500mg, 2.04mmol) was dissolved in N, N-dimethylformamide (5 mL), tetrakis (triphenylphosphine) palladium (354mg, 0.31mmol) and zinc cyanide (599mg, 5.10mmol, gumbo) were added, and the mixture was heated to 100 ℃ to react for 14 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 4a (150 mg, yield: 38%).

MS m/z(ESI):190.0[M-1]。

Second step of

Methyl 2- (2- ((4- (((tert-butoxycarbonyl) amino) methyl) -6H-benzo (c) chromen-9-yl) methoxy) -4-cyanophenyl) acetate 4b

Compound 1g (50mg, 0.146mmol), compound 4a (56mg, 0.29mmol) and triphenylphosphine (77mg, 0.29mmol) were dissolved in dichloromethane (2 mL), and diisopropyl azodicarboxylate (59mg, 0.29mmol) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 4b (50 mg, yield: 66%).

MS m/z(ESI):515.1[M+1)。

The third step

Methyl 2- (4- (aminomethyl) -2- ((4- (((tert-butoxycarbonyl) amino) methyl) -6H-benzo (c) chromen-9-yl) methoxy) phenyl) acetate 4c

Compound 4b (150mg, 0.29mmol) was dissolved in methanol (5 mL), added with sodium borohydride (55mg, 1.46mmol, shanghaitan) and nickel chloride hexahydrate (19mg, 0.145mmol, shanghaitan) under ice bath, and allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 4C (60 mg, yield: 40%).

MS m/z(ESI):519.1[M+1]。

The fourth step

2- (4- (aminomethyl) -2- ((4- (aminomethyl) -6H-benzo (c) chromen-9-yl) methoxy) phenyl) acetic acid methyl ester 4d

Compound 4c (60mg, 116. Mu. Mol) was dissolved in 4M hydrochloric acid in 1, 4-dioxane (3 mL) and reacted with stirring for 1 hour. The reaction was concentrated to give the crude title compound 4d (48 mg) which was used in the next reaction without purification.

MS m/z(ESI):419.0[M+1]。

The fifth step

The crude compound 4d (48mg, 115. Mu. Mol) was dissolved in methanol (3 mL) and water (1 mL), lithium hydroxide (14mg, 0.57mmol) was added, the reaction was stirred overnight, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mm 5 μm; C18 mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 40% -55%, flow rate: 30 mL/min) to give the title compound 4 (20 mg, yield: 43%).

MS m/z(ESI):405.1[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ7.96-7.93(m,2H),7.48-7.46(m,1H),7.28–7.22(m,3H),7.13-7.08(m,1H),7.04-7.02(m,1H),6.92-6.89(m,1H),5.20-5.17(m,4H),3.97-3.95(m,2H),3.91-3.89(m,2H),3.59(s,2H)。

Example 5

2- (2- ((4- (aminomethyl) -6H-benzo (c) chromen-9-yl) methoxy) -4-cyanophenyl) acetic acid 5

First step of

2- (2- ((4- (aminomethyl) -6H-benzo (c) chromen-9-yl) methoxy) -4-cyanophenyl) acetic acid methyl ester 5a

Compound 4b (20mg, 39. Mu. Mol) was dissolved in a1, 4-dioxane solution (2 mL) of 4M hydrochloric acid, and the reaction was stirred for 1 hour. The reaction was concentrated to give the crude title compound 5a (15 mg) which was used in the next reaction without purification.

MS m/z(ESI):415.0[M+1]。

Second step of

Crude compound 5a (40mg, 96.5. Mu. Mol) was dissolved in methanol (3 mL) and water (1 mL), lithium hydroxide (23mg, 0.96mmol) was added, the reaction was stirred overnight, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mm 5 μm; C18 mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 50% -55%, flow rate: 30 mL/min) to give the title compound 5 (20 mg, yield: 52%).

MS m/z(ESI):401.0[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ8.06-8.04(m,1H),7.99-7.98(m,1H),7.51–7.49(m,1H),7.40-7.38(m,1H),7.32-7.26(m,3H),7.17-7.13(m,2H),5.25-5.22(m,4H),4.11-4.09(m,2H),3.64(s,2H)。

Example 6

2- (2- ((4- (aminomethyl) -6H-benzo (c) chromen-9-yl) methoxy) -4-methoxyphenyl) acetic acid 6

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First step of

2- (2-hydroxy-4-methoxyphenyl) -1-morpholinoethane-1-thione

6b

Mixing 1- (2-hydroxy-4-methoxyphenyl) ethane-1-ketone 6a (2g, 12.04mmol, shanghai Biao, tokyo), sulfur powder (772mg, 24.08mmol, guo Yao) and morpholine (2.097g, 24.07mmol, shanghai Biao), heating to 120 deg.C, and reacting for 14 hr. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 6b (2.6 g, yield: 81%).

MS m/z(ESI):268.0[M+1]。

Second step of

2- (2-hydroxy-4-methoxyphenyl) acetic acid 6c

Compound 6b (500mg, 1.87mmol) was dissolved in ethanol (6 mL) and water (1.4 mL), sodium hydroxide (224mg, 5.60mmol) was added, the mixture was heated to 80 ℃ for reaction for 14 hours, the reaction solution was cooled to room temperature, the pH was adjusted to 2 with 1M aqueous hydrochloric acid, extraction was performed with ethyl acetate (100 mL. Times.2), the organic phases were combined, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give crude title compound 6c (300 mg) which was used in the next reaction without purification.

MS m/z(ESI):181.0[M-1]。

The third step

2- (2-hydroxy-4-methoxyphenyl) acetic acid methyl ester 6d

Crude compound 6c (500mg, 2.74mmol) was dissolved in methanol (10 mL) and concentrated sulfuric acid (0.4 mL) and heated to 50 ℃ for 14 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 6d (200 mg, yield: 37%).

MS m/z(ESI):197.0[M+1]。

The fourth step

Methyl 2- (2- ((4- (((tert-butoxycarbonyl) amino) methyl) -6H-benzo (c) chromen-9-yl) methoxy) -4-methoxyphenyl) acetate 6e

Compound 1g (35mg, 0.103mmol), 6d (30mg, 0.153mmol) and triphenylphosphine (54mg, 0.206mmol) were dissolved in dichloromethane (2 mL), diisopropyl azodicarboxylate (41mg, 0.203mmol) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 6e (50 mg, yield: 94%).

MS m/z(ESI):537.1[M+18]。

The fifth step

2- (2- ((4- (aminomethyl) -6H-benzo (c) chromen-9-yl) methoxy) -4-methoxyphenyl) acetic acid methyl ester 6f

Compound 6e (60mg, 115. Mu. Mol) was dissolved in 4M hydrochloric acid in 1, 4-dioxane (3 mL) and the reaction was stirred for 1 hour. The reaction was concentrated to give crude title compound 6f (48 mg) which was used in the next reaction without purification.

MS m/z(ESI):420.0[M+1]。

The sixth step

The crude compound 6f (48mg, 114. Mu. Mol) was dissolved in methanol (3 mL) and water (1 mL), lithium hydroxide (29mg, 1.21mmol) was added, the reaction was stirred for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mm 5 μm; C18 mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 50% -55%, flow rate: 30 mL/min) to give the title compound 6 (20 mg, yield: 42%).

MS m/z(ESI):406.0[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ8.07-8.05(m,1H),7.99-7.97(m,1H),7.49-7.47(m,1H),7.32-7.30(m,1H),7.28-7.26(m,1H),7.18-7.11(m,2H),6.58-6.56(m,1H),6.49-6.46(m,1H),5.26(s,2H),5.16(s,2H),4.16-4.14(m,2H),3.77(s,3H),3.54(s,2H)。

Example 7

(±) -2- (2- ((4- (aminomethyl) -6H-benzo (c) chromen-9-yl) methoxy) -4- (1-hydroxyethyl) phenyl) acetic acid 7

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First step of

Methyl 2- (4-acetyl-2- ((4- ((tert-butoxycarbonylamino) methyl) -6H-benzo (c) chromen-9-yl) methoxy) phenyl) acetate 7a

Compound 3c (135mg, 237.4. Mu. Mol), tributyl (1-ethoxyvinyl) stannane (102mg, 282.4. Mu. Mol, shanghaitan) and tetrakis (triphenylphosphine) palladium (28mg, 24.2. Mu. Mol, shanghaitan) were dissolved in toluene (5 mL), purged with nitrogen, heated to 110 ℃ and stirred for 14 hours. The reaction solution was cooled to room temperature, quenched by addition of 3M aqueous hydrochloric acid, stirred for 10 minutes, filtered, extracted with ethyl acetate (10 mL × 2), and the organic phases were combined, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 7a (50 mg, yield: 39%). MS m/z (ESI) 532.6[ 2 ] M +1].

Second step methyl (±) -2- (2- ((4- ((tert-butoxycarbonylamino) methyl) -6H-benzo (c) chromen-9-yl) methoxy) -4- (1-hydroxyethyl) phenyl) acetate 7b

Compound 7a (50mg, 94.056. Mu. Mol) was dissolved in tetrahydrofuran (3 mL) and methanol (5 mL), and sodium borohydride (8mg, 211.46. Mu. Mol) was added to stir the reaction for 1 hour, followed by extraction with ethyl acetate (10 mL. Times.2), and the organic phases were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 7b (40 mg, yield: 79%).

MS m/z(ESI):534.6[M+1]。

The third step, methyl (±) -2- (2- ((4- (aminomethyl) -6H-benzo (c) chromen-9-yl) methoxy) -4- (1-hydroxyethyl) phenyl) acetate 7c

Compound 7b (40mg, 56.22. Mu. Mol) was dissolved in 4M hydrochloric acid in 1, 4-dioxane (3 mL) and reacted with stirring for 1 hour. The reaction was concentrated to give the crude title compound 7c (20 mg) which was used in the next reaction without purification.

MS m/z(ESI):434.5[M+1]。

The fourth step

Compound 7C (20mg, 46.13. Mu. Mol) was dissolved in methanol (3 mL), lithium hydroxide monohydrate (35mg, 834.05. Mu. Mol) was added, the reaction was stirred for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (apparatus model: gilson 281 column: X-Bridge, prep 30X 150mm 5. Mu.m; C18 mobile phase: water (10 mM ammonium hydrogencarbonate) and acetonitrile, gradient ratio: acetonitrile 45% -55%, flow rate: 30 mL/min) to obtain the title compound 7 (15 mg, yield: 77%).

MS m/z(ESI):420.5[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ7.929-7.92(m,2H),7.49(d,1H),7.29-7.24(m,2H),7.19(d,1H),7.11(t,1H),7.05(s,1H),6.89(d,1H),5.20(d,4H),4.81-4.77(m,1H),4.00(s,2H),3.58(s,2H),1.40(d,3H)。

Example 8

2- (4-acetyl-2- ((4- (aminomethyl) -6H-benzo (c) chromen-9-yl) methoxy) phenyl) acetic acid 8

First step of

2- (4-acetyl-2- ((4- (aminomethyl) -6H-benzo (c) chromen-9-yl) methoxy) phenyl) acetic acid methyl ester 8a

Compound 7a (30mg, 56.43. Mu. Mol) was dissolved in 4M hydrochloric acid in 1, 4-dioxane (3 mL) and reacted with stirring for 1 hour. The reaction was concentrated to give the crude title compound 8a (20 mg) which was used in the next reaction without purification.

MS m/z(ESI):432.5[M+1]。

Second step of

Compound 8a (20mg, 46.35. Mu. Mol) was dissolved in methanol (3 mL), lithium hydroxide monohydrate (39mg, 927.04. Mu. Mol) was added, the reaction was stirred for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (apparatus model: gilson 281 column: X-Bridge, prep 30X 150mm 5. Mu.m; C18 mobile phase: water (10 mM ammonium hydrogencarbonate) and acetonitrile, gradient ratio: acetonitrile 40% -50%, flow rate: 30 mL/min) to obtain the title compound 8 (13 mg, yield: 67%).

MS m/z(ESI):418.5[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ7.95-7.93(m,2H),7.61(d,2H),7.49(d,1H),7.38(d,1H),7.27-7.24(m,2H),7.10(t,1H),5.25(s,2H),5.18(s,2H),3.93(s,2H),3.66(s,2H),2.58(s,3H)。

Example 9

2- (2- (4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (hydroxymethyl) phenyl) acetic acid 9

First step of

Methyl 2- (2- ((4- ((tert-butoxycarbonylamino) methyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (hydroxymethyl) phenyl) acetate 9a

Compound 3c (100mg, 175.91. Mu. Mol), (tributyltin) methanol (85mg, 264.72. Mu. Mol, yaminkangde) and tetrakis (triphenylphosphine) palladium (21mg, 18.17. Mu. Mol, shanghai Tatan) were added to 1, 4-dioxane (5 mL), replaced with nitrogen, heated to 110 ℃ and stirred for reaction for 14 hours. The reaction solution was cooled to room temperature and then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give the title compound 9a (30 mg, yield: 33%).

MS m/z(ESI):520.2[M+1]。

Second step of

Methyl 2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (hydroxymethyl) phenyl) acetate 9b

Compound 9a (30mg, 57.73. Mu. Mol) was added to a solution of 4M hydrochloric acid in 1, 4-dioxane (2 mL), stirred for reaction for 2 hours, and the reaction solution was concentrated under reduced pressure to give crude title compound 9b (20 mg), which was used in the next reaction without purification.

MS m/z(ESI):420.2[M+1]。

The third step

Compound 9b (20mg, 47.67. Mu. Mol) was dissolved in methanol (3 mL), lithium hydroxide monohydrate (40mg, 953.20. Mu. Mol) was added, the reaction was stirred for 14 hours, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mm, 5 μm; C18 mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 55% -60%, flow rate: 30 mL/min) to give the title compound 9 (10 mg, yield: 51%).

MS m/z(ESI):406.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ7.94-7.91(m,2H),7.49(d,1H),7.27-7.24(m,2H),7.21(d,1H),7.10(t,1H),7.02(s,1H),6.88(d,1H),5.25(s,4H),4.57(s,2H),3.92(s,2H),3.59(s,2H)。

Example 10

2- (2- ((7- (aminomethyl) -6H-benzo [ c ] chromen-2-yl) methoxy) phenyl) acetic acid 10

First step of

3-bromo-4- ((2-bromo-6-formylbenzyl) oxy) benzoic acid methyl ester 10c

3-bromo-2- (bromomethyl) benzaldehyde 10a (180mg, 0.65mmol, prepared by the method disclosed in Organic Letters,2021, 2125-2129) and methyl 3-bromo-4-hydroxybenzoate 10b (150mg, 0.65mmol, shanghai Shao Yuan) were dissolved in acetone (10 mL), followed by addition of potassium carbonate (179mg, 1.3mmol), stirring for 14 hours, concentration of the reaction under reduced pressure, and purification of the residue by silica gel column chromatography eluting with System C gave the title compound 10C (100 mg, 36% yield).

MS m/z(ESI):426.9[M+1]。

Second step of

7-formyl-6H-benzo [ c ] chromene-2-carboxylic acid methyl ester 10d

Compound 10c (1.36g, 3.17mmol) was dissolved in 1, 4-dioxane solution (50 mL), and [1, 1-bis (diphenylphosphino) ferrocene ] dichloropalladium (230mg, 0.314mmol), pinacol ester diborate (1.65g, 6.5 mmol) and potassium carbonate (875mg, 6.34mmol) were added. After the reaction was heated to 90 ℃ for 14 hours under nitrogen substitution and concentrated under reduced pressure, the residue was purified by silica gel column chromatography using elution system C to give the title compound 10d (367 mg, 43% yield).

MS m/z(ESI):269.1[M+1]。

The third step

(Z) -7- (((tert-butylsulfinyl) aminylidene) methyl) -6H-benzo [ c ] chromene-2-carboxylic acid methyl ester 10e

Compound 10d (203mg, 0.76mmol) in tetrahydrofuran (5 mL) was added tert-butylsulfinamide (450mg, 3.71mmol, shanghai Shao Yuan) and tetraethyltitanate (1.04, 4.54mmol). The reaction mixture was heated to 50 ℃ for 2 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system C to give the title compound 10e (250 mg, 89% yield).

MS m/z(ESI):372.2[M+1]。

The fourth step

7- (((tert-butylsulfinyl) amino) methyl) -6H-benzo [ c ] chromene-2-carboxylic acid methyl ester 10f

Compound 10e (250mg, 0.67mmol) was dissolved in methanol solution (10 mL), and sodium borohydride (31mg, 0.81mmol) was added to the solution to react for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system C to give the title compound 10f (200 mg, yield 80%).

MS m/z(ESI):374.1[M+1]。

The fifth step

N- ((2- (hydroxymethyl) -6H-benzo [ c ] chromen-7-yl) methyl) -2-methylpropane-2-sulfinamide 10g

Compound 10f (150mg, 0.4 mmol) was dissolved in tetrahydrofuran solution (5 mL) and 2.5M lithium aluminum hydride in tetrahydrofuran solution (0.4 mmol, 0.16mL) was added dropwise at 0 ℃. After stirring for 2 hours, the mixture was quenched by addition of sodium sulfate decahydrate, the filtrate was concentrated under reduced pressure after filtration, and the residue was purified by silica gel column chromatography with elution A to obtain 10g (76 mg, yield 55%) of the title compound.

MS m/z(ESI):346.0[M+1]。

The sixth step

Methyl 2- (2- ((7- ((tert-butylsulfinyl) amino) methyl) -6H-benzo [ c ] chromen-2-yl) methoxy) phenyl) acetate 10i

Compound 10g (76mg, 0.22mmol) was dissolved in dry dichloromethane (10 mL) and compound 2- (2-hydroxyphenyl) acetic acid methyl ester (40mg, 0.22mmol, shanghai Shao Yuan), triphenylphosphine (115mg, 0.44mmol) and diisopropyl azodicarboxylate (89mg, 0.44mmol) were added for 10 h. The reaction was stirred for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 10i (110 mg, yield 99%).

MS m/z(ESI):494.2[M+1]。

Seventh step

2- (2- ((7- (aminomethyl) -6H-benzo [ c ] chromen-2-yl) methoxy) phenyl) acetic acid methyl ester 10j

Compound 10i (110mg, 0.22mmol) was dissolved in dichloromethane (5 mL), and a 4M solution of hydrochloric acid in 1, 4-dioxane (0.88mL, 0.88mmol) was added. The reaction was stirred for 2 hours and the reaction was concentrated under reduced pressure to give the crude title compound 10j (80 mg) which was used in the next reaction without purification.

MS m/z(ESI):390.2[M+1]。

Eighth step

Crude compound 10j (70mg, 173. Mu. Mol) was dissolved in methanol (3 mL) and water (0.5 mL), lithium hydroxide (21mg, 0.87mmol) was added, the reaction was stirred for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mm 5 μm; C18 mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient: acetonitrile 45% -55%, flow rate: 30 mL/min) to give the title compound 10 (8 mg, yield: 12%).

MS m/z(ESI):376.0[M+1]。

¹ H NMR(500MHz,d-DMSO):δ7.71-7.69(m,1H),7.60-7.58(m,1H),7.42-7.30(m,3H),7.09-7.06(m,1H),6.98-6.94(m,2H),6.88-6.85(m,1H),6.76-6.73(m,1H),5.20(s,2H),3.98(s,2H),3.89-3.87(m,2H),3.49(s,2H)。

Example 11

2- (2- ((8- (aminomethyl) -5, 7-dihydrodibenzo [ c, e ] oxepin-2-yl) methoxy) phenyl) acetic acid 11

First step of

3-bromo-4- (((tert-butyldimethylsilyl) oxy) methyl) benzoic acid methyl ester 11b

Methyl 3-bromo-4- (hydroxymethyl) benzoate 11a (1500mg, 6.12mmol, obtained after Shanghai) was dissolved in methylene chloride (15 mL), and imidazole (625mg, 9.18mmol) and tert-butyldimethylsilyl chloride (1107mg, 7.34mmol) were added thereto, followed by reaction with stirring for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 11b (2.00 g, yield: 91%).

MS m/z(ESI):359.1[M+1]。

Second step of

4- (((tert-butyldimethylsilyloxy) methyl) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoic acid methyl ester 11c

Pinacol diboron (2.16g, 9.02mmol), compound 11b (2.70g, 7.51mmol), potassium acetate (1479 mg, 15.03mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (549mg, 0.75mmol) were dissolved in 1, 4-dioxane (20 mL) and heated to 90 ℃ for 16 hours. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 11C (3.05 g, yield: 65%).

MS m/z(ESI):405.1[M-1]。

The third step

4- (hydroxymethyl) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoic acid methyl ester 11d

Compound 11c (1700mg, 4.18mmol) was dissolved in a1, 4-dioxane solution (20 mL) of 4M hydrochloric acid, and the reaction was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude title compound 11d (900 mg) which was used in the next reaction without purification.

MS m/z(ESI):291.1[M-1]。

The fourth step

Methyl 4- (((2-bromo-6-formylbenzyl) oxy) methyl) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate 11e

Compound 11d (900mg, 3.08mmol) was dissolved in N, N-dimethylformamide (6 mL), sodium hydride (185mg, 4.62mmol) was added under ice bath, and after stirring for 30 minutes while maintaining the temperature, compound 10a (25mg, 66. Mu. Mol, obtained from Shanghai Biao) and potassium carbonate (856 mg, 3.08mmol) were added, the reaction was allowed to react at room temperature for 16 hours, the reaction was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution System C to give the title compound 11e (800 mg, yield: 53%).

MS m/z(ESI):489.0[M+1]。

The fifth step

8-formyl-5, 7-dihydrodibenzo [ c, e ] oxepin-2-carboxylic acid methyl ester 11f

Compound 11e (100mg, 0.20mmol), potassium carbonate (84.6mg, 0.61mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (29.9mg, 40.9. Mu. Mol) were dissolved in water (0.6 mL) and 1, 4-dioxane (43 mL) and reacted with heating to 90 ℃ for 14 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 11f (20 mg, yield: 35%).

MS m/z(ESI):283.1[M+1]。

Sixth step (E) -methyl 8- (((tert-butylsulfinyl) aminylidene) methyl) -5, 7-dihydrodibenzo [ c, E ] oxaheptanol-2-carboxylate 11g

Compound 11f (80mg, 0.28mmol) and tert-butylsulfinamide (137mg, 1.13mmol, shanghai Shao Yuan) were dissolved in tetrahydrofuran (3 mL), tetraethyl titanate (258.6 mg, 1.13mmol) was added, and the mixture was heated to 50 ℃ for 3 hours. The reaction solution was cooled and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give 11g (99 mg, yield: 91%) of the title compound.

MS m/z(ESI):386.0[M+1]。

Seventh step

Methyl 8- (((tert-butylsulfoxy amide) methyl) -5, 7-dihydrodibenzo [ c, e ] oxepin-2-carboxylate 11h

Dissolving 11g (130mg, 0.34mmol) of the compound in methanol (3 mL), adding sodium borohydride (64mg, 1.69mmol) under ice bath, returning to room temperature for 1 hour, adding water to the reaction solution for quenching, extracting with ethyl acetate (5 mL multiplied by 3), combining organic phases, washing with water and saturated sodium chloride solution in turn, drying with anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating the filtrate under reduced pressure to obtain a crude title compound 11h (110 mg) which is directly used in the next reaction without purification.

MS m/z(ESI):388.0[M+1]。

The eighth step

N- ((10- (hydroxymethyl) -5, 7-dihydrodibenzo [ [ c, e ] oxaheptin-4-yl) methyl) -2-methylpropan-2-sulfoxy-lamide 11i

Compound 11h (42mg, 0.108mmol) was dissolved in tetrahydrofuran (2 mL), lithium aluminum hydride (6.6 mg, 0.195mmol) was added under ice bath, the reaction was allowed to react at room temperature for 1 hour, the reaction solution was diluted with ethyl acetate, sodium sulfate decahydrate was added and stirred for one hour, and after filtration and concentration under reduced pressure, crude title compound 11i (35 mg) was obtained and used in the next reaction without purification.

MS m/z(ESI):360.0[M+1]。

The ninth step

Ethyl 2- (2- ((8- (((tert-butylsulfinyl) amino) methyl) -5, 7-dihydrodibenzo [ [ c, e ] oxahept-2-yl) methoxy) phenyl) acetate 11j

Compound 11i (42mg, 0.117mmol), compound 1h (42mg, 0.234mmol) and triphenylphosphine (61mg, 0.234mmol) were dissolved in dichloromethane (3 mL), diisopropyl azodicarboxylate (47mg, 0.234mmol) was added, the reaction was stirred for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to elute system C to give the title compound 11j (45 mg, yield: 74%).

MS m/z(ESI):522.2[M+1]。

The tenth step

Ethyl 2- (2- ((8- (aminomethyl) -5, 7-dihydrodibenzo [ c, e ] oxahept-2-yl) methoxy) phenyl) acetate 11k

Compound 11j (45mg, 86.3. Mu. Mol) was dissolved in 4M hydrochloric acid in 1, 4-dioxane (2 mL), stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to give crude title compound 11k (32 mg) which was used in the next reaction without purification.

MS m/z(ESI):418.1[M+1]。

The eleventh step

Crude compound 11k (32mg, 76.6. Mu. Mol) was dissolved in methanol (2 mL) and water (0.5 mL), lithium hydroxide (18mg, 0.76mmol) was added, the reaction was stirred for 14 hours, the reaction liquid was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mm 5 μm; C18 mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient ratio: acetonitrile 45% -55%, flow rate: 30 mL/min) to obtain title compound 11 (20 mg, yield: 67%).

MS m/z(ESI):390.0[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ7.75-7.73(m,1H),7.67-7.65(m,1H),7.61-7.59(m,1H),7.56-7.53(m,1H),7.49-7.43(m,2H),7.24-7.16(m,2H),7.01-6.98(m,1H),6.92-6.88(m,1H),5.20(s,2H),4.34(s,2H),4.27(s,2H),4.20-4.18(m,2H),.33(s,2H)。

Example 12

2- (2- ((4- (aminomethyl) -5, 6-dihydrophenanthridin-9-yl) methoxy) phenyl) acetic acid 12

First step of

Methyl 3-bromo-4- (((2- (((tert-butoxycarbonyl) amino) methyl) phenyl) amino) methyl) benzoate 12b

Tert-butyl (2-aminobenzyl) carbamate 12a (1g, 4.5mmol, obtained from Shanghai Biao), compound 1b (1386mg, 4.5 mmol) and potassium carbonate (1863mg, 13.5 mmol) were dissolved in acetonitrile (20 mL), reacted at 85 ℃ for 16 hours, the reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution System C to obtain the title compound 12b (1600 mg, yield: 79%).

MS m/z(ESI):450.0[M+1]。

Second step of

4- (((tert-butoxycarbonyl) amino) methyl) -5, 6-dihydrophenanthridine-9-carboxylic acid methyl ester 12c

Compound 12b (700mg, 1.56mmol), palladium acetate (122mg, 543. Mu. Mol, shanghai Yanhou), 2-diphenylphosphino-2' - (N, N-dimethylamino) biphenyl (208mg, 545umol, shanghai Bian) and potassium carbonate (645mg, 4.67mmol) were dissolved in N, N-dimethylformamide (50 mL), replaced with nitrogen, reacted at 130 ℃ for 3 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution System C to give the title compound 12C (230 mg, yield: 40%).

MS m/z(ESI):369.5[M+1]。

The third step

((9- (hydroxymethyl) -5, 6-dihydrophenanthridin-4-yl) methyl) carbamic acid tert-butyl ester 12d

Compound 12c (165mg, 0.447mmol) was dissolved in tetrahydrofuran (5 mL), lithium aluminium hydride (24mg, 0.707mmol) was added under ice bath and stirred for 1 hour, the reaction solution was diluted with ethyl acetate, sodium sulphate decahydrate was added and stirred for 1 hour, filtered and the filtrate was concentrated under reduced pressure to give crude title compound 12d (150 mg) which was used in the next reaction without purification.

MS m/z(ESI):341.2[M+1]。

The fourth step

2- (2- ((4- (((tert-butoxycarbonyl) amino) methyl) -5, 6-dihydrophenanthridin-9-yl) methoxy) phenyl) acetic acid ethyl ester

12e

Crude compound 12d (200mg, 0.588mmol), compound 1h (160mg, 0.888mmol, haichi), and triphenylphosphine (231mg, 0.88mmol) were dissolved in dichloromethane (2 mL), and diisopropyl azodicarboxylate (178mg, 0.88mmol, haichi) was added and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 12e (200 mg, yield: 68%).

MS m/z(ESI):503.3[M+1]。

The fifth step

2- (2- ((4- (aminomethyl) -5, 6-dihydrophenanthridin-9-yl) methoxy) phenyl) acetic acid ethyl ester 12f

Compound 12e (70mg, 139. Mu. Mol) was dissolved in 4M hydrochloric acid in 1, 4-dioxane (4 mL) and the reaction stirred for 1 hour, and the reaction mixture was concentrated under reduced pressure to give the crude title compound 12f (56 mg) which was used in the next reaction without purification.

MS m/z(ESI):403.3[M+1]。

The sixth step

The crude compound 12f (80mg, 199. Mu. Mol) was dissolved in methanol (3 mL) and water (1 mL), lithium hydroxide (48mg, 2mmol) was added, the reaction was stirred overnight, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mm 5 μm; C18 mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile flow rate: 30mL/min, gradient: acetonitrile 35% -45%) to give the title compound 12 (20 mg, yield: 27%).

MS m/z(ESI):375.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ7.62-7.58(m,2H),7.23-7.13(m,2H),7.09-7.06(m,1H),7.02-6.99(m,1H),6.97-6.94(m,1H),6.91-6.88(m,1H),6.76-6.71(m,2H),5.17-5.14(m,2H),4.41-4.35(m,1H),4.12-4.06(m,1H),3.60-3.58(m,2H),3.32-3.30(m,2H)。

Example 13

2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) phenyl) -2-methylpropanoic acid 13

The starting compound 1h from the sixth step was replaced with methyl 2- (2-hydroxyphenyl) -2-methylpropionate (prepared by the method disclosed in example 47 at page 31 of the specification in patent application US20210332009 A1) by the sixth to eighth steps of the synthetic route in example 1 to give the title compound 13 (5 mg, yield: 30%).

MS m/z(ESI):404.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ7.95(s,1H),7.93(d,1H),7.54(d,1H),7.34(d,1H),7.23(d,2H),7.08(t,2H),6.89(t,2H),5.23(s,2H),5.16(s,2H),3.82(s,2H),1.72(s,6H)。

Example 14-P1 or example 14-P2

(S) -2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (1-hydroxyethyl) phenyl) acetic acid 14-P1

Or

(R) -2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (1-hydroxyethyl) phenyl) acetic acid 14-P2

First step of

(S) -methyl 2- (2- ((4- (((tert-butoxycarbonyl) amino) methyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (1-hydroxyethyl) phenyl) acetate 14a-P1

Methyl (R) -2- (2- ((4- (((tert-butoxycarbonyl) amino) methyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (1-hydroxyethyl) phenyl) acetate 14a-P2

Compound 7B (260mg, 0.487mmol) was separated by a preparative manual column (column: CHIRALPAK OD 20 × 250mm,5 μm; mobile phase: A-n-hexane; B-ethanol, 10% by weight, elution at a B ratio, flow rate: 20 mL/min) to give the title compounds (70 mg, yield: 27%) and (60 mg, yield: 23%). MS m/z (ESI) 532.2[ M-1].

Single configuration compound (shorter retention time, 70mg, yield: 27%)

Chiral HPLC analysis: retention time 18.658 min, (instrument: agilent 1260DAD, column: CHIRALPAK OD 150 x 4.6mm,5 μm, flow rate: 1.0mL/min, mobile phase: ethanol: n-hexane = 10%).

MS m/z(ESI):532.2[M-1]。

Single configuration Compound (longer Retention time, 60mg, yield: 23%)

Chiral HPLC analysis: retention time 22.665 min, (instrument: agilent 1260DAD, chromatography column: CHIRALPAK OD 150 x 4.6mm,5 μm, flow rate: 1.0mL/min, mobile phase: ethanol: n-hexane = 10%).

MS m/z(ESI):532.2[M-1]。

Second step of

(S) -methyl 2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (1-hydroxyethyl) phenyl) acetate 14b-P1

Or

(R) -methyl 2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (1-hydroxyethyl) phenyl) acetate 14b-P2

The compound corresponding to the shorter retention time (70mg, 0.13mmol) of the compounds 14a-P1, 14a-P2 was dissolved in a1, 4-dioxane solution (2 mL) of 4M hydrochloric acid, stirred and reacted for 0.5 hour, and the reaction solution was concentrated under reduced pressure to give the crude title compound (56 mg) which was used in the next reaction without purification.

MS m/z(ESI):434.2[M+1]。

The third step

Or

The crude compound 14B-P1 or 14B-P2 (56mg, 0.13mmol) was dissolved in methanol (3 mL) and water (0.5 mL), lithium hydroxide monohydrate (58mg, 1.38mmol) was added, the reaction was stirred for 16 hours, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mm 5 μm; C18 mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, flow rate: 30mL/min column temperature: room temperature) to obtain the title compound 14-P1 or 14-P2 (30 mg, yield: 55%). MS m/z (ESI) 420.0[ m ] +1].

Chiral HPLC analysis: retention time 9.541 min, (instrument: agilent 1260DAD, chromatography column: CHIRALPAK OD 150 x 4.6mm,5 μm, flow rate: 1.0mL/min, mobile phase: ethanol (0.1% diethanolamine +0.1% trifluoroacetic acid): n-hexane = 15%).

¹ H NMR(500MHz,CD ₃ OD):δ7.97-7.86(m,2H),7.49-7.43(m,1H),7.24-7.16(m,3H),7.09-7.02(m,2H),6.91-6.87(m,1H),5.19-5.08(m,4H)，4.82-4.75(m,1H),3.96-3.89(m,2H),3.62-3.55(m,2H),1.44-1.35(m,3H)。

Example 14-P1 or example 14-P2

Or

First step of

Or

The compound corresponding to the longer retention time of the compounds 14a-P1, 14a-P2 (60mg, 0.11mmol) was dissolved in a solution of 4M hydrochloric acid in 1, 4-dioxane (2 mL), stirred for reaction for 0.5 hour, and the reaction solution was concentrated under reduced pressure to give the crude title compound (48 mg) which was used in the next reaction without purification.

MS m/z(ESI):434.2[M+1]。

Second step of

(S) -2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (1-hydroxyethyl) phenyl) acetic acid

14-P1

Or

(R) -2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (1-hydroxyethyl) phenyl) acetic acid

14-P2

The crude compound 14B-P1 or 14B-P2 (48mg, 0.11mmol) was dissolved in methanol (3 mL) and water (0.5 mL), lithium hydroxide monohydrate (48mg, 1.14mmol) was added, the reaction was stirred for 16 hours, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 1505 μm; C18, mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, gradient ratio: acetonitrile 50% -55%, flow rate: 30mL/min, gradient ratio: acetonitrile 35% -45%) to obtain the title compound 14-P1 or 14-P2 (25 mg, yield: 54%).

MS m/z(ESI):420.0[M+1]。

Chiral HPLC analysis: retention time 8.213 minutes (instrument: agilent 1260DAD, column: CHIRALPAK OD 150 x 4.6mm,5 μm; column temperature: 35 ℃, flow rate: 1.0mL/min, mobile phase: ethanol (0.1% diethanolamine +0.1% trifluoroacetic acid): n-hexane = 15%).

Example 15

2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (methoxymethyl) phenyl) acetic acid 15

First step of

Methyl 2- (2- ((4- (((tert-butoxycarbonyl) amino) methyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (methoxymethyl) phenyl) acetate 15a

Compound 9a (200mg, 384.9. Mu. Mol) and boron trifluoride diethyl etherate (82mg, 577.76. Mu. Mol, shanghaitan) were dissolved in methylene chloride (10 mL), trimethylsilylated diazomethane (88mg, 770.43. Mu. Mol, shanghaitan) was added dropwise, the reaction was stirred for 3 hours, the reaction solution was quenched by pouring into water, extracted with methylene chloride (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution System C to give the title compound 15a (60 mg, yield: 29%).

MS m/z(ESI):534.2[M+1]。

Second step of

2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (methoxymethyl) phenyl) acetic acid methyl ester

15b

Compound 15a (60mg, 112.44. Mu. Mol) was dissolved in methanol (3 mL), a 4M solution of hydrochloric acid in 1, 4-dioxane (2 mL) was added, the reaction was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to give crude title compound 15b (40 mg) which was used in the next reaction without purification.

MS m/z(ESI):434.2[M+1]。

The third step

Crude compound 15B (40mg, 92.27. Mu. Mol) was dissolved in methanol (3 mL), lithium hydroxide monohydrate (77 mg, 1.83 mmol) was added, stirring was carried out at room temperature for 14 hours, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mm 5 μm; C18 mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, flow rate: 30mL/min, gradient: acetonitrile 35% -45%) to obtain the title compound 15 (20 mg, yield: 51%).

MS m/z(ESI):420.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ7.94-7.91(m,2H),7.49(d,1H),7.27-7.24(m,2H),7.21(d,1H),7.10(t,1H),7.02(s,1H),6.88(d,1H),5.25(s,4H),4.57(s,2H),3.92(s,2H),3.59(s,2H),3.33(s,3H)。

Example 16

2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (difluoromethyl) phenyl) acetic acid 16

First step of

Methyl 2- (2- ((4- (((tert-butoxycarbonyl) amino) methyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4-formylphenyl) acetate 16a

Compound 9a (100mg, 192.46. Mu. Mol) was dissolved in methylene chloride (10 mL), dess-Martin oxidant (82mg, 193.33. Mu. Mol, shanghaitan) was added, the reaction was stirred for 3 hours, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution System C to give the title compound 16a (80 mg, yield: 80%).

MS m/z(ESI):518.2[M+1]。

Second step of

Methyl 2- (2- ((4- (((tert-butoxycarbonyl) amino) methyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (difluoromethyl) phenyl) acetate 16b

Compound 16a (80mg, 154.56. Mu. Mol) was dissolved in dichloromethane (5 mL), diethylaminosulfur trifluoride (125mg, 775.48. Mu. Mol, shanghaitan) was added dropwise, the reaction was stirred for 14 hours, the reaction liquid was quenched by pouring into water, neutralized with a saturated sodium bicarbonate solution, extracted with dichloromethane (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure after filtration, and the residue was purified by silica gel column chromatography with elution System C to give the title compound 16b (35 mg, yield: 42%).

MS m/z(ESI):540.2[M+1]。

The third step

2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (difluoromethyl) phenyl) acetic acid methyl ester 16c

Compound 16b (35mg, 64.86. Mu. Mol) was dissolved in methanol (3 mL), 4M hydrochloric acid in 1, 4-dioxane (2 mL) was stirred for 2 hours, and the reaction mixture was concentrated under reduced pressure to give crude title compound 16c (20 mg) which was used in the next reaction without purification.

MS m/z(ESI):440.2[M+1]。

The fourth step

Crude compound 16C (20mg, 45.51. Mu. Mol) was dissolved in methanol (3 mL), lithium hydroxide monohydrate (38mg, 905.54. Mu. Mol) was added, the reaction was stirred for 14 hours, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (apparatus model: gilson 281 chromatography column: X-Bridge, prep 30X 150mm, 5. Mu.m; C18 mobile phase: A-water (10 mM ammonium hydrogencarbonate) B-acetonitrile, flow rate: 30mL/min, gradient: acetonitrile 35% -45%) to obtain the title compound 16 (5 mg, yield: 26%).

MS m/z(ESI):426.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ7.95(s,1H),7.82(d,1H),7.49(d,1H),7.27-7.24(m,2H),7.21(d,1H),7.15(t,1H),7.02(s,1H),6.83(d,1H),6.44(t,1H),5.25(s,2H),5.14(s,2H),3.72(s,2H),3.54(s,2H)。

Example 17

2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (1H-pyrazol-4-yl) phenyl) acetic acid 17

First step of

2- (2- ((4- (((tert-butoxycarbonyl) amino) methyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (1H-pyrazole-4-one)

Yl) phenyl) acetic acid methyl ester 17a

4-Pyrazoleboronic acid pinacol ester (51mg, 0.26mmol, shanghai Shaoyuan), compound 3c (100mg, 176umol), potassium carbonate (61mg, 0.44mmol) and 1,1' -bis-diphenylphosphino ferrocene palladium dichloride (26mg, 35.6 umol) were dissolved in a mixed solvent of 1, 4-dioxane (3 mL) and water (0.5 mL) and reacted at 100 ℃ for 16 hours. The reaction solution was cooled and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 17a (90 mg, yield: 92%).

MS m/z(ESI):556.2[M+1]。

Second step of

2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (1H-pyrazol-4-yl) phenyl) acetic acid methyl ester 17b

Compound 17a (100mg, 180. Mu. Mol) was dissolved in 4M hydrochloric acid in 1, 4-dioxane (4 mL) and stirred for 60 minutes, and the reaction solution was concentrated under reduced pressure to give crude title compound 17b (80 mg), which was used in the next reaction without purification.

MS m/z(ESI):456.1[M+1]。

The third step

The crude compound 17B (80mg, 176umol) was dissolved in methanol (2 mL) and water (1 mL), lithium hydroxide (74mg, 1.76mmol) was added, the reaction was stirred for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mm 5 μm; C18 mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, flow rate: 30mL/min, gradient: acetonitrile 35% -45%) to give the title compound 17 (30 mg, yield: 39%).

MS m/z(ESI):442.1[M+1]。

¹ H NMR(500MHz,d ₆ -DMSO):δ8.06-7.95(m,3H),7.84-7.80(m,1H),7.44-7.41(m,1H),7.35-7.26(m,3H),7.17-7.10(m,2H),7.05-7.01(m,1H),5.23(s,2H),5.13(s,2H),3.73-3.71(m,2H),3.51(s,2H)。

Example 18

(±) -2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (1-methoxyethyl) phenyl) acetic acid

18

First step methyl (±) -2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (1-methoxyethyl) phenyl) acetate 18a

Compound 7b (100mg, 0.187mmol) was dissolved in methanol (1.5 mL), concentrated sulfuric acid (15mg, 0.374mmol) was added, the reaction was carried out at 70 ℃ for 24 hours, and the reaction solution was concentrated under reduced pressure to give crude title compound 18a (83 mg), which was used in the next reaction without purification.

MS m/z(ESI):448.3[M+1]。

The second step (±) -2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (1-methoxyethyl) phenyl) acetic acid 18

The crude compound 18a (83mg, 185umol) was dissolved in methanol (2 mL) and water (1 mL), lithium hydroxide (66.6 mg, 2.78mmol) was added, the reaction was stirred for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mm 5 μm; C18 mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, flow rate: 30mL/min, gradient: acetonitrile 35% -45%) to give the title compound 18 (30 mg, yield: 37%).

MS m/z(ESI):434.3[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ8.03-7.97(m,2H),7.50-7.48(m,1H),7.30-7.21(m,3H),7.15-7.11(m,1H),7.96-7.95(m,1H),6.84-6.82(m,1H),5.21-5.18(m,4H),4.32-4.27(m,1H),4.09-4.08(m,2H),3.59(s,2H),3.18(s,3H),1.38-1.35(m,3H)。

Example 19

2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (2-hydroxypropyl-2-yl) phenyl) acetic acid

19

First step of

3- (benzyloxy) -4-bromobenzoic acid methyl ester 19b

Methyl 4-bromo-3-hydroxybenzoate 19a (5 g,21.64mmol, obtained from Shanghai) was dissolved in N, N-dimethylformamide (30 mL), potassium carbonate (5.97g, 43.19mmol) was added, benzyl bromide (4.06g, 23.73mmol, obtained from Shanghai Tantan) was slowly added dropwise, and the reaction was stirred for 2 hours. The reaction solution was quenched with water, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution System C to give the title compound 19b (5.5 g, yield: 79%). MS m/z (ESI) 319.0[ M-1].

Second step of

2- (3- (benzyloxy) -4-bromophenyl) propan-2-ol 19c

Compound 19b (5g, 15.56mmol) was dissolved in tetrahydrofuran (50 mL), and a 3M solution of methylmagnesium bromide in tetrahydrofuran (26mL, 77.82mmol) was slowly added dropwise over an ice bath and stirred for reaction for 18 hours. The reaction solution was quenched by addition of saturated ammonium chloride (100 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution System C to give the title compound 19C (5 g, yield: 89%).

MS m/z(ESI):319.1[M-1]。

The third step

2- (2- (benzyloxy) -4- (2-hydroxypropyl-2-yl) phenyl) acetic acid ethyl ester 19d

Compound 19c (5g, 15.56mmol) was dissolved in mesitylene (30 mL), and monoethyl malonate potassium salt (2.64g, 15.51mmol, shanghaitan), allylpalladium (II) chloride dimer (284mg, 0.77mmol), 2-bicyclohexylphosphine-2 ',6' -diisopropoxybiphenyl (1.08g, 2.31mmol) and 4-dimethylaminopyridine (191mg, 1.55mmol) were added, and the reaction was stirred for 20 minutes, warmed to 150 ℃ and stirred for 20 hours. The reaction solution was cooled to room temperature and then quenched with water, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 19d (1 g, yield: 19%).

MS m/z(ESI):329.1[M+1]。

The fourth step

2- (2-hydroxy-4- (2-hydroxypropyl-2-yl) phenyl) acetic acid ethyl ester 19e

Compound 19d (1.00g, 3.04mmol) was dissolved in methanol (30 mL), 10% palladium on carbon (200 mg) was added, hydrogen gas was substituted three times, and the reaction was stirred for 14 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to give the title compound 19e (500 mg, yield: 69%). MS m/z (ESI) 239.1[ 2 ] M +1].

The fifth step

Ethyl 2- (2- ((4- (((tert-butoxycarbonyl) amino) methyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (2-hydroxypropyl-2-yl) phenyl) acetate 19f

Compound 19e (200mg, 0.84mmol), compound 1h (286mg, 0.84mmol) and triphenylphosphine (46mg, 0.176mmol) were dissolved in dichloromethane (2 mL), bis (4-chlorobenzyl) azodicarboxylate (369mg, 1.00mmol) was added, the reaction was stirred for 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 19f (400 mg, yield: 84%).

MS m/z(ESI):560.1[M-1]。

The sixth step

19g of 2- (2- ((4- ((tert-butoxycarbonyl) amino) methyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (2-hydroxypropyl-2-yl) phenyl) acetic acid

Compound 19f (400mg, 0.71mmol) was dissolved in a mixed solvent of methanol (2 mL), tetrahydrofuran (2 mL) and water (2 mL), and lithium hydroxide (89mg, 2.12mmol) was added to stir the reaction for 14 hours. The reaction solution was concentrated under reduced pressure, the residue was neutralized with saturated ammonium chloride, extracted with dichloromethane (10 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 19g (250 mg, yield: 66%) as an elution system A.

MS m/z(ESI):532.2[M-1]。

Seventh step

2- (2- ((4- (aminomethyl) -6H-benzo [ c ] chromen-9-yl) methoxy) -4- (2-hydroxypropyl-2-yl) phenyl) acetic acid 19

19g (150mg, 0.28mmol) of the compound was dissolved in dimethyl sulfoxide (2 mL), and the reaction was stirred at 140 ℃ for 4 hours. The reaction solution was cooled to room temperature and then filtered, and the filtrate was purified by high performance liquid preparative chromatography (instrument type: gilson 281 column: X-Bridge, prep 30X 150mm, 5 μm; C18 mobile phase: A-water (10 mM ammonium bicarbonate) B-acetonitrile, flow rate: 30mL/min, gradient: acetonitrile 35% -45%) to obtain the title compound 19 (15 mg, yield 12.3%).

MS m/z(ESI):434.1[M+1]。

¹ H NMR(500MHz,d ₆ -DMSO):δ7.94(s,1H),7.81-7.80(m,1H),7.43-7.41(m,1H),7.34-7.32(m,1H),7.29-7.28(m,1H),7.19(s,1H),7.12-7.10(m,1H),7.06-7.05(m,1H),6.98-6.96(m,1H),5.16-5.15(m,4H),3.74(s,2H),3.52(s,2H),1.42(s,6H)。

Biological evaluation

The present disclosure is further described and explained below in connection with test examples, which are not intended to limit the scope of the present disclosure.

Test example 1: biological evaluation of complement alternative pathway hemolysis experiment of compound disclosed by the invention

The following methods were used to determine the inhibitory effect of the compounds of the present disclosure on the hemolytic activity of the alternative complement pathway.

1. The experimental method comprises the following steps:

2mL of 10% rabbit red blood cells (SBJ-RBC-RAB 005, shanghai Dalen Biotech Co., ltd.) were added to 8mL of GVB-EGTA buffer (2.1mM HEPES pH7.4,0.075mM CaCl) ₂ ，70.5mM NaCl，2.25mM MgCl ₂ 0.05% gelatin (Sigma-Aldrich, G7765-1L), 10mM EGTA), gently mixed and centrifuged at 400G for 5 minutes at 4 ℃ to remove the supernatant, which was repeated 2-3 times until the supernatant was clear. The cells were resuspended in 5mL GVB-EGTA buffer and counted until needed. Taking out human serum from-80 deg.C, immediately melting in 37 deg.C water bath, placing on ice after melting, and diluting with GVB-EGTA buffer solution to obtain serum with concentration of 5.45%. In a U-bottom 96-well plate, 88. Mu.L of 5.45% serum was added to each well, and 88. Mu.L of GVB-EGTA buffer was added to the positive control wells. After equilibration for 15 minutes at room temperature, 12. Mu.L of test compound or DMSO was added per well, diluted in a gradient of GVB-EGTA buffer. The well plate was placed in a 37 ℃ incubator and incubated for 15 minutes. Rabbit red blood cells were adjusted to a cell density of 2.5E using GVB-EGTA buffer ⁸ Perml, 20. Mu.L per well was added to all wells of a U-bottom 96-well plate. The red blood cells of the rabbit per hole are 5E ⁶ In each case, the final concentration of the compound was 9 concentration points at which 4-fold gradient dilution was performed from 10. Mu.M,the final DMSO concentration was 1%, and wells containing only 1% DMSO were used as vehicle controls, and wells containing only rabbit erythrocytes were used as positive controls. Duplicate wells were set for each sample and control. The plates were incubated in a 37 ℃ incubator for 30 minutes. The U-bottom 96-well plate was centrifuged at 2500g for 3 minutes, 80. Mu.L of the supernatant was transferred to the flat-bottom 96-well plate, and the OD412 value was read by a microplate reader PHERAStarFS.

The inhibition rate calculation formula is as follows:

inhibition% = [ (OD 412 (vehicle control) -OD412 (compound)]/[ (OD 412 (vehicle control) -OD412 (Positive control)]X 100%. IC of compound was calculated from the log of compound concentration and inhibition using Graphpad Prism software ₅₀ The value is obtained.

2. The experimental results are as follows:

the inhibitory activity of the compounds of the present disclosure on the hemolytic activity of the alternative complement pathway can be determined by the above assay, and the IC measured ₅₀ The values are shown in Table 1.

TABLE 1 IC of inhibition of hemolytic activity of the alternative complement pathway by Compounds of the present disclosure ₅₀ Value of

Example numbering	IC ₅₀ /nM
		1	169
3	335
		4	58
6	119
		7	62
8	273
		9	89
Compounds with longer retention time in 14-P1 and 14-P2	48
		Compounds with shorter retention time in 14-P1 and 14-P2	76
15	124
		18	218
19	69

And (4) conclusion: the compounds disclosed by the invention have good inhibition effect on the hemolytic activity of the alternative complement pathway.

Test example 2 evaluation of inhibition experiment of formation of Membrane Complex (Membrane-attack complex)

The following methods were used to determine the inhibitory effect of the compounds of the present disclosure on the formation of tapping membrane complexes resulting from activation of the alternative complement pathway.

1. The experimental method comprises the following steps:

the first day of the experiment, 100. Mu.L of carbonated solution (0.03M Na2CO) was added to each well of a 96-well plate (Thermo Fisher Scientific, 437111) ₃ ，0.07M NaHCO ₃ ) Plates were coated with zymosan A (Sigma-Aldrich, Z4250-5G) diluted to 1mg/mL overnight at 4 ℃. The following day of the experiment, 2 XGVB-EGTA buffer (4.2 mM HEPES,0.15mM CaCl) ₂ ，141mM NaCl，4.5mM MgCl ₂ 0.1% gelatin, 25mM EGTA, activating the alternative complement pathway) to dilute the test compound. mu.L of 50% human serum diluted in PBS and 16. Mu.L of 2 XGVB-EGTA buffer or 16. Mu.L of 2 XGVB-EDTA buffer (4.2 mM HEPES,0.15mM CaCl2, 141mM NaCl,4.5mM MgCl2,0.1% gelatin, 25mM EDTA, inhibition of the classical, alternative, lectin pathways) were added to each well of a 96-well U-plate (Jite, TCP 002096), and then 4. Mu.L of a compound diluted in 2 XGVB-EGTA solution or DMSO was added to each well at 9 concentration points of 4-fold gradient dilution from 10. Mu.M, at a final DMSO concentration of 1% and at a final serum concentration of 25%. Wells containing only 1% dmso were set as the solvent control, and wells containing 1% dmso and 2 × GVB-EDTA buffer were set as the positive control. The plates were incubated at room temperature for 30 minutes. Zymosan A coated plates were washed three times with TBST (0.05% Tween-20), 25. Mu.L of incubated serum and compound mixture was added per well to initiate the complement reaction, and incubated at 37 ℃ for 40 minutes. After 40 min, the plate was washed three times with TBST, 300. Mu.L of blocking solution (Thermo Fisher Scientific, 37543) was added to each well, incubated at 37 ℃ for 15 min, and the plate was washed three times with TBST. MAC formation was detected by adding 100. Mu.L of Anti-C5b-9des Arg antibody (abcam, ab 66768) diluted 5000-fold with TBST to each well, incubating for 1 hour at 37 ℃ and washing the plate three times with TBST. 100 μ L of Goat Anti-Mouse IgG H diluted 5000-fold with TBST was added to each well&L (HRP) secondary antibody (abcam, ab 205719), incubated at 37 ℃ for 30 minutes, and the plates were washed three times with TBST. Add 100. Mu.L of fluorometric substrate (Thermo Fisher Scientific, 15169) to each well, incubate for 20 min at room temperature, and add 100. Mu.L of stop buffer. Excitation at 320nM wavelength, emission at 460nM wavelength, and fluorescence at 455nM limit (RFUs) were read using a microplate reader (Molecular Devices, flexStation 3).

The inhibition rate calculation formula is as follows: inhibition% = [ (RFUs (vehicle control) -RFUs (compound)]/[ (RFUs (vehicle control) -RFUs (Positive control)]X 100%. IC of compound was calculated from the log of compound concentration and inhibition using Graphpad Prism software ₅₀ The value is obtained.

2. The experimental results are as follows:

the inhibitory activity of the compounds of the present disclosure against the formation of tapping complexes by activation of the alternative complement pathway can be determined by the above assay, the IC measured ₅₀ The values are shown in Table 2.

Table 2 IC50 values for inhibition of tapping membrane complex formation by alternative complement pathway activation by compounds of the present disclosure

And (4) conclusion: the compounds disclosed by the invention have a good inhibition effect on the formation of a tapping membrane complex caused by the activation of the alternative complement pathway.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

ring a is selected from aryl, heteroaryl and heterocyclyl;

ring B is aryl or heteroaryl;

u, V and W are the same or different, and

u is a nitrogen atom or CR ^u ；

V is a nitrogen atom or CR ^v ；

W is a nitrogen atom or CR ^w ；

L ² Is- (CR) ^a4 R ^b4 ) _t -；

Each R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro, cyano, -NR ³ R ⁴ 、-C(O)NR ³ R ⁴ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-OR ⁵ Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁶ R ⁷ Hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

each R is ² Identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro, cyano, -NR ³ R ⁴ 、-C(O)NR ³ R ⁴ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-OR ⁵ Cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^u 、R ^v and R ^w The same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro, cyano、-NR ³ R ⁴ 、-C(O)NR ³ R ⁴ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-OR ⁵ Cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^c1 、R ^c2 、R ^c3 and R ^c4 The same or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

or R ³ And R ⁴ Together with the nitrogen atom to which they are attached form a heterocyclyl group, wherein said heterocyclyl group formed is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ⁶ And R ⁷ Together with the nitrogen atom to which they are attached form a heterocyclyl group, wherein said heterocyclyl group formed is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

m is 0, 1,2 or 3;

n is 0, 1,2 or 3;

p is 1,2,3, 4 or 5;

q is 0, 1 or 2;

r is 1,2,3, 4 or 5;

s is 1,2,3, 4 or 5;

t is 1,2,3, 4 or 5; and is provided with

u is 1,2,3, 4 or 5.

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: ring B is 6-to 10-membered aryl or 5-to 10-membered heteroaryl; preferably, ring B is phenyl or 5 or 6 membered heteroaryl; most preferably, ring B is phenyl.

3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or2, which is a compound represented by the general formula (II):

wherein:

x, Y and Z are identical or different, and

x is a nitrogen atom or CR ^x ；

Y being a nitrogen atom or CR ^y ；

Z is a nitrogen atom or CR ^z ；

ring A, U, V, W, G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ And m is as defined in claim 1.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: ring a is selected from 6-to 10-membered aryl, 5-to 10-membered heteroaryl, and 3-to 12-membered heterocyclyl; preferably, ring a is phenyl or 5 or 6 membered heteroaryl; most preferably, ring a is phenyl.

5. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a compound represented by the general formula (III):

wherein:

x, Y and Z are identical or different, and

x is a nitrogen atom or CR ^x ；

Y being a nitrogen atom or CR ^y ；

Z is a nitrogen atom or CR ^z ；

or R ^x And R ^y 、R ^y And R ^z Each independently optionally forming, together with the carbon atom to which it is attached, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more groups selected from halogen, oxo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, nitro, cyano, -NR ⁶ R ⁷ Hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroarylSubstituted with one or more substituents of the group;

U、V、W、G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ and m is as defined in claim 1.

6. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein: l is ¹ Is- (CR) ^a3 R ^b3 ) _s -O-or-O- (CR) ^a3 R ^b3 ) _s -；R ^a3 、R ^b3 And s is as defined in claim 1; preferably, L ¹ is-CH ₂ -O-or-O-CH ₂ -。

7. A compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein: l is a radical of an alcohol ³ Is (CR) ^a5 R ^b5 ) _u -；R ^a5 、R ^b5 And u is as defined in claim 1; preferably, L ³ is-CH ₂ -。

8. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, which is a compound represented by the general formula (IV):

wherein:

x, Y and Z are identical or different, and

x is a nitrogen atom or CR ^x ；

Y being a nitrogen atom or CR ^y ；

Z is a nitrogen atom or CR ^z ；

R ^x 、R ^y And R ^z Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, an alkeneRadical, alkynyl, haloalkoxy, nitro, cyano, -NR ³ R ⁴ 、-C(O)NR ³ R ⁴ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-OC(O)R ⁵ 、-OR ⁵ Cycloalkyl, heterocyclyl, aryl and heteroaryl;

U、V、W、G ¹ 、G ² 、R ¹ 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ and m is as defined in claim 1.

9. A compound of general formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein: u is CR ^u (ii) a V is CR ^v (ii) a And W is CR ^w ；R ^u 、R ^v And R ^w As defined in claim 1; preferably, U, V and W are all CH.

10. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 9, wherein: x is CR ^x (ii) a Y is CR ^y (ii) a And Z is a nitrogen atom or CR ^z ；R ^x 、R ^y And R ^z As defined in claim 1; preferably, X, Y and Z are all CH.

11. A compound of general formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein: g ¹ And G ² Are the same or different, and G ¹ Selected from chemical bonds, - (CR) ^a1 R ^b1 ) _p -、-(CR ^a1 R ^b1 ) _p -O-and-O- (CR) ^a1 R ^b1 ) _p -；G ² Is selected from- (CR) ^a2 R ^b2 ) _r -、-(CR ^a2 R ^b2 ) _r -O-and-O- (CR) ^a2 R ^b2 ) _r -；R ^a1 、R ^b1 、R ^a2 、R ^b2 P and r are as defined in claim 1; preferably, G ¹ Is a chemical bond or- (CR) ^a1 R ^b1 ) _p -；G ² Is- (CR) ^a2 R ^b2 ) _r -O-or-O- (CR) ^a2 R ^b2 ) _r -；R ^a1 、R ^b1 、R ^a2 、R ^b2 P and r are as defined in claim 1; preferably, G ¹ Is a chemical bond; g ² is-CH ₂ -O-or-O-CH ₂ -。

12. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: p is 1 or 2; and/or r is 1 or 2; preferably, p is 1; and/or r is 1.

13. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein: r ^a1 、R ^b1 、R ^a2 And R ^b2 Are all hydrogen atoms.

14. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 13, wherein:

selected from the group consisting of>

U, V, W, X, Y and Z are as defined in claim 1.

15. A compound of general formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereofWherein: each R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy, 5-to 10-membered heteroaryl and-C (O) R ⁵ (ii) a Wherein said C _1-6 Alkyl radical, C _1-6 Alkoxy and 5-to 10-membered heteroaryl are each independently optionally selected from halogen, oxo, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, nitro, cyano, -NR ⁶ R ⁷ Hydroxy, C _1-6 Hydroxyalkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl; r ⁵ 、R ⁶ And R ⁷ As defined in claim 1; preferably, each R ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy, 5-to 10-membered heteroaryl and-C (O) R ⁵ (ii) a Wherein said C _1-6 Alkyl is optionally selected from C _1-6 Alkoxy, halogen, amino and hydroxyl; r ⁵ Is a hydrogen atom or C _1-6 An alkyl group.

16. A compound of general formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

17. a compound represented by the general formula (IA) or the general formula (IAa) or a salt thereof,

wherein:

r is C _1-6 An alkyl group;

ring A, ring B, U, V, W, G ¹ 、G ² 、L ¹ 、L ² 、L ³ 、R ¹ 、R ² M and n are as defined in claim 1.

18. A compound selected from:

/>

/>

19. a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises:

wherein:

r is C _1-6 An alkyl group;

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

21. Use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, in the manufacture of a medicament for inhibiting complement factor D.

22. Use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, in the manufacture of a medicament for the treatment and/or prevention of a disease or condition mediated by complement factor D;

preferably for the manufacture of a medicament for the treatment and/or prevention of Paroxysmal Nocturnal Hemoglobinuria (PNH), reperfusion injury, multiple sclerosis, amyotrophic lateral sclerosis, autoimmune diseases, ophthalmic diseases, inflammatory diseases, respiratory diseases, cardiovascular diseases, liver diseases, kidney diseases, abdominal aortic aneurysms, hemodialysis complications, hemolytic anemia, cancer and diseases or conditions of immune disorders; wherein said kidney disease is preferably selected from the group consisting of lupus nephritis, glomerulopathy and hemolytic uremic syndrome; the ophthalmic disease is preferably dry age-related macular degeneration; the glomerulopathy is preferably C3 glomerulopathy or IgA nephropathy.