CN116970029A

CN116970029A - Bridged ring compound, preparation method thereof and application thereof in medicine

Info

Publication number: CN116970029A
Application number: CN202310148764.4A
Authority: CN
Inventors: 李心; 陈阳; 董怀德; 贺峰
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: 2022-02-23
Filing date: 2023-02-22
Publication date: 2023-10-31

Abstract

The disclosure relates to bridged ring compounds, methods for their preparation and their use in medicine. Specifically, the disclosure relates to bridged ring compounds represented by a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compounds, and application of the compounds as 3CL protease inhibitors in treating diseases or conditions related to 3CL protease activity. Wherein each group in the general formula (I) is defined in the specification.

Description

Bridged ring compound, preparation method thereof and application thereof in medicine

Technical Field

The present disclosure belongs to the field of medicine, and relates to bridged ring compounds, a preparation method thereof and application thereof in medicine. In particular, the disclosure relates to bridged ring compounds of formula (I), methods for their preparation, pharmaceutical compositions containing them and their use as 3CL protease inhibitors in the treatment of diseases or conditions associated with 3CL protease activity.

Background

At present, research work on anti-SARS-CoV-2 medicines is actively carried out at home and abroad, and the ideal anti-SARS-CoV-2 medicines can selectively interfere with the replication cycle of SARS-CoV-2 virus, thereby inhibiting the replication process and simultaneously not affecting the normal physiological functions of host cells. Relevant hot targets include: RNA polymerase (RdRp), SARS-CoVS protein (spike protein), ACE2 (angiotensin converting enzyme 2), 3CL hydrolase (3 CL) ^pro ，M ^pro ) Papain-like Protease (PL) ^pro ) Etc.

Wherein the method comprises the steps of，3CL ^pro Also known as 3CL protease or main protease, is a cysteine hydrolase that plays an important role in the viral replication process. The multimeric protein precursors produced by translation of viral RNA into host cells are mainly composed of 3CL protease (3 CL ^pro ) Papain-like Protease (PL) ^pro ) After cleavage, various functional proteins necessary for the virus are formed, and these proteins will further participate in the viral RNA replication process. Thus, 3CL is suppressed ^pro Will prevent viral infection and replication, at the same time 3CL ^pro There is no homologous protein in humans, which allows 3CL ^pro Becomes an ideal target point for researching and developing antiviral drugs. In addition, 3CL ^pro The 3CL protease of SARS-CoV-2 and SARS-CoV is only 12 amino acids worse, the homology is up to 96%, the substrate binding pocket part is more 100% conservative, the drug resistance caused by virus mutation can be avoided, and the screened 3CL protease inhibitor has a certain degree of broad-spectrum anti-coronavirus capability, and can be popularized in other kinds of coronavirus infection. Currently, there are a number of 3CL ^pro Inhibitors that are targets are reported.

The presently published patent applications for 3CL protease inhibitors include WO2021250648A1, WO2021226546A1, WO2021252644A1, WO2021212039A1, WO2021252491A1, WO2022020242A1 and the like.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by general formula (I):

wherein:

ring a is a nitrogen-containing bicyclic bridged heterocyclyl or a nitrogen-containing polycyclic bridged heterocyclyl;

R ¹ selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, cyano, hydroxyalkyl and oxoSubstituted;

R ² selected from alkyl, alkoxy, haloalkyl, haloalkoxy and cyano;

each R is ³ The same or different and are each independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, - (alkylene) _t NR ^a R ^b Hydroxyl, hydroxyalkyl, and cycloalkyl;

R ⁵ 、R ⁶ 、R ⁷ and R is ⁸ The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, and cycloalkyl;

or R is ⁵ 、R ⁶ To a carbon atom, or R ⁷ 、R ⁸ Together with the carbon atom to which they are attached, form a cycloalkyl or heterocyclyl group, each independently of the other optionally being selected from halogen, alkyl, alkoxy, haloalkyl, cyano, - (alkylene) _u NR ^c R ^d One or more substituents selected from the group consisting of hydroxy, hydroxyalkyl and oxo;

R ^a 、R ^b 、R ^c and R is ^d The same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, and a cycloalkyl group;

m is an integer between 0 and 20;

t is 0, 1, 2, 3 or 4; and is also provided with

u is 0, 1, 2, 3 or 4.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I-1):

wherein: ring A, R ¹ 、R ² 、R ³ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ And m is as defined in formula (I).

In some embodiments of the present disclosure, the compounds of formula (I) and (I-1) or pharmaceutically acceptable salts thereof, wherein ring A is a nitrogen-containing 6-to 14-membered bicyclic bridged heterocyclyl; preferably, ring a is a nitrogen-containing 7-or 8-membered bicyclic bridged heterocyclyl.

In some embodiments of the present disclosure, the compounds of formula (I) and (I-1) or pharmaceutically acceptable salts thereof, whereinSelected from->R ³ And m is as defined in formula (I); preferably, the +>Selected from->

In some embodiments of the present disclosure, the compounds of formula (I) and (I-1) or pharmaceutically acceptable salts thereof, whereinSelected from->R ³ And m is as defined in formula (I); preferably, the +>Selected from- >

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

wherein:

p is 0, 1 or 2;

r is 0, 1 or 2;

q is 1, 2 or 3;

s is 1, 2 or 3;

R ¹ 、R ² 、R ³ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ and m is as defined in formula (I).

In some embodiments of the present disclosure, the compounds of formula (I), (I-1) and (II), or pharmaceutically acceptable salts thereof, are compounds of formula (II-1):

wherein: r is R ¹ 、R ² 、R ³ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ M, p, q, r and s are as defined in formula (II).

In some embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, whereinSelected from->R ³ And m is as defined in formula (I); preferably, the +>Selected from->

In some embodiments of the present disclosure, the compound of formula (II-1) or a pharmaceutically acceptable salt thereof, whereinSelected from->R ³ And m is as defined in formula (I); preferablyGround (I)>Selected from->

In some embodiments of the present disclosure, the compounds of formulas (II) and (II-1) or pharmaceutically acceptable salts thereof, wherein p is 0 or 1.

In some embodiments of the present disclosure, the compounds of formula (II) and (II-1) or pharmaceutically acceptable salts thereof, wherein r is 0 or 1; preferably r is 0.

In some embodiments of the present disclosure, the compounds of formulas (II) and (II-1) or pharmaceutically acceptable salts thereof, wherein q is 1 or 2.

In some embodiments of the present disclosure, the compounds of formulas (II) and (II-1) or pharmaceutically acceptable salts thereof, wherein s is 1 or 2.

In some embodiments of the present disclosure, the compounds of formulas (I), (I-1), (II) and (II-1), or pharmaceutically acceptable salts thereof, wherein m is 0, 1, 2, 3, 4, 5 or 6; preferably, m is 0 or 1; more preferably, m is 0.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1), (II) and (II-1), or pharmaceutically acceptable salts thereof, wherein each R ³ Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl and cyano; preferably, each R ³ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1), (II) and (II-1) or pharmaceutically acceptable salts thereof, wherein R ¹ Is a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl, each of said 6 to 10 membered aryl or 5 to 10 membered heteroaryl independently being optionally substituted with a halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, cyano and C _1-6 One or more substituents in the hydroxyalkyl group are substituted.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1), (II) and (II-1) or pharmaceutically acceptable salts thereof, wherein R ¹ Selected from C _1-6 Alkyl, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl, said C _1-6 Alkyl, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl are each independently optionally selected from halogen, C _1-6 Alkyl, C _1-6 One or more substituents in haloalkyl and cyano are substituted; preferably, R ¹ Is C _1-6 Alkyl or 3-to 8-membered cycloalkyl, said C _1-6 Alkyl or 3-to 8-membered cycloalkyl are each independently optionally selected from halogen, C _1-6 Alkyl and C _1-6 One or more substituents in the haloalkyl group; further preferably, R ¹ Is C _1-6 Haloalkyl or halogenated 3-to 6-membered cycloalkyl; more preferably, R ¹ Is trifluoromethyl or 1-fluorocyclopropan-1-yl.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1), (II) and (II-1) or pharmaceutically acceptable salts thereof, wherein R ² Selected from C _1-6 Alkyl, C _1-6 Haloalkyl and cyano; preferably, R ² Is C _1-6 Alkyl or C _1-6 A haloalkyl group; further preferably, R ² Is C _1-6 An alkyl group; more preferably, R ² Is tert-butyl.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1), (II) and (II-1) or pharmaceutically acceptable salts thereof, wherein R ⁵ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ⁵ Is a hydrogen atom.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1), (II) and (II-1) or pharmaceutically acceptable salts thereof, wherein R ⁶ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ⁶ Is a hydrogen atom.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1), (II) and (II-1) or pharmaceutically acceptable salts thereof, wherein R ⁵ Is a hydrogen atom; and/orR ⁶ Is a hydrogen atom.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1), (II) and (II-1) or pharmaceutically acceptable salts thereof, wherein R ⁵ 、R ⁶ Together with the carbon atoms to which they are attached form a 3-to 8-membered cycloalkyl group, said 3-to 8-membered cycloalkyl group optionally being selected from halogen, C _1-6 Alkyl and C _1-6 One or more substituents in the haloalkyl group; preferably, R ⁵ 、R ⁶ Together with the carbon atoms to which they are attached form a cyclopropyl group, which is optionally substituted with a member selected from the group consisting of halogen, C _1-6 Alkyl and C _1-6 One or more substituents in the haloalkyl group.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1), (II) and (II-1) or pharmaceutically acceptable salts thereof, wherein R ⁷ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ⁷ Is a hydrogen atom.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1), (II) and (II-1) or pharmaceutically acceptable salts thereof, wherein R ⁸ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ⁸ Is a hydrogen atom.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1), (II) and (II-1) or pharmaceutically acceptable salts thereof, wherein R ⁷ Is a hydrogen atom; and/or R ⁸ Is a hydrogen atom.

In some embodiments of the present disclosure, the compounds of formula (I), (I-1), (II) and (II-1) or pharmaceutically acceptable salts thereof, wherein R ⁷ 、R ⁸ Together with the carbon atoms to which they are attached form a 3-to 8-membered cycloalkyl group, said 3-to 8-membered cycloalkyl group optionally being selected from halogen, C _1-6 Alkyl and C _1-6 One or more substituents in the haloalkyl group; preferably, R ⁷ 、R ⁸ Together with the carbon atoms to which they are attached form a cyclopropyl group, which is optionally substituted with a member selected from the group consisting of halogen, C _1-6 Alkyl and C _1-6 One or more substituents in the haloalkyl group.

In some embodiments of the present disclosure, the compounds of formula (I) and (I-1) or pharmaceutically acceptable salts thereof, whereinSelected from->Each R is ³ Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl and cyano, m is 0 or 1; r is R ¹ Selected from C _1-6 Alkyl, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl, said C _1-6 Alkyl, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl are each independently optionally selected from halogen, C _1-6 Alkyl, C _1-6 One or more substituents in haloalkyl and cyano are substituted; r is R ² Is C _1-6 Alkyl or C _1-6 A haloalkyl group; r is R ⁵ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; r is R ⁶ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; r is R ⁷ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; and R is ⁸ Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group.

In some embodiments of the present disclosure, the compounds of formulas (II) and (II-1) or pharmaceutically acceptable salts thereof, wherein p is 0 or 1; r is 0; q is 1 or 2; s is 1 or 2; m is 0; r is R ¹ Is C _1-6 Haloalkyl or halogenated 3-to 6-membered cycloalkyl; r is R ² Is C _1-6 An alkyl group; r is R ⁵ Is a hydrogen atom; r is R ⁶ Is a hydrogen atom; r is R ⁷ Is a hydrogen atom; and R is ⁸ Is a hydrogen atom.

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

Another aspect of the present disclosure relates to a compound represented by the general formula (IA):

wherein:

ring A, R ¹ 、R ² 、R ³ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ And m is as defined in formula (I).

Another aspect of the present disclosure relates to a compound represented by the general formula (I-1A):

wherein:

ring A, R ¹ 、R ² 、R ³ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ And m is as defined in formula (I-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIA):

wherein:

R ¹ 、R ² 、R ³ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ m, p, q, r and s are as defined in formula (II). Another aspect of the present disclosure relates to a compound represented by the general formula (II-1A):

wherein:

R ¹ 、R ² 、R ³ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ m, p, q, r and s are as defined in formula (II-1). Table B typical compounds of the present disclosure include, but are not limited to:

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

the compound of the general formula (IA) or the salt thereof is dehydrated to obtain the compound of the general formula (I) or the pharmaceutically acceptable salt thereof,

wherein:

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof, which comprises:

the compound of the general formula (I-1A) or the salt thereof is dehydrated to obtain the compound of the general formula (I-1) or the pharmaceutically acceptable salt thereof,

Wherein:

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

dehydrating the compound of formula (IIA) or a salt thereof to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof,

wherein:

R ¹ 、R ² 、R ³ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ m, p, q, r and s are as defined in formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof, which comprises:

the compound of the general formula (II-1A) or the salt thereof is dehydrated to obtain the compound of the general formula (II-1) or the pharmaceutically acceptable salt thereof,

wherein:

R ¹ 、R ² 、R ³ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ m, p, q, r and s are as defined in formula (II-1).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of general formula (I), (I-1), (II-1) and table a of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure further relates to the use of a compound shown in general formulae (I), (I-1), (II-1) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting a 3CL protease.

The present disclosure further relates to the use of a compound shown in general formulae (I), (I-1), (II-1) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of a disease or disorder mediated by a 3CL protease; preferably, the disease or condition is a viral infection; the virus is preferably Coronavirus (Coronavir), picornavirus (Picornavirus), rhinovirus (Rhinovir), norovirus (Norovirus) and herpes simplex virus type 1 (HSV-1), more preferably Coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.

The present disclosure further relates to the use of a compound shown in general formulae (I), (I-1), (II-1) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of a viral infection; the virus is preferably Coronavirus (Coronavir), picornavirus (Picornavirus), rhinovirus (Rhinovir), norovirus (Norovirus) and herpes simplex virus type 1 (HSV-1), more preferably Coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.

The present disclosure further relates to a method of inhibiting a 3CL protease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formulae (I), (I-1), (II-1) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating and/or preventing a disease or disorder mediated by a 3CL protease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1), (II-1) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the disease or condition is a viral infection; the virus is preferably Coronavirus (Coronavir), picornavirus (Picornavirus), rhinovirus (Rhinovir), norovirus (Norovirus) and herpes simplex virus type 1 (HSV-1), more preferably Coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.

The present disclosure further relates to a method of treating and/or preventing a viral infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1), (II-1) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; the virus is preferably Coronavirus (Coronavir), picornavirus (Picornavirus), rhinovirus (Rhinovir), norovirus (Norovirus) and herpes simplex virus type 1 (HSV-1), more preferably Coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.

The present disclosure further relates to a compound of general formula (I), (I-1), (II-1) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The present disclosure further relates to a compound of formula (I), (I-1), (II-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for inhibiting 3CL protease.

The present disclosure further relates to a compound of general formula (I), (I-1), (II-1) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of a disease or disorder mediated by a 3CL protease; preferably, the disease or condition is a viral infection; the virus is preferably Coronavirus (Coronavir), picornavirus (Picornavirus), rhinovirus (Rhinovir), norovirus (Norovirus) and herpes simplex virus type 1 (HSV-1), more preferably Coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.

The present disclosure further relates to a compound represented by general formula (I), (I-1), (II-1) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of viral infections; the virus is preferably Coronavirus (Coronavir), picornavirus (Picornavirus), rhinovirus (Rhinovir), norovirus (Norovirus) and herpes simplex virus type 1 (HSV-1), more preferably Coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.

The 3CL protease mediated disease or condition described in the present disclosure is preferably selected from the group consisting of viral infection, chronic obstructive pulmonary disease, senile dementia, motor neuron disease, multiple sclerosis, parkinson's disease, mastocytosis, asthma, cognitive disorders, ischemic stroke and tumors; the virus is preferably Coronavirus (Coronavir), picornavirus (Picornavirus), rhinovirus (Rhinovir), norovirus (Norovirus) and herpes simplex virus type 1 (HSV-1), more preferably Coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2; the tumor is preferably gastrointestinal tumor, lymphoma, glioblastoma, pancreatic tumor, prostate cancer, liver cancer, breast cancer, colorectal cancer, lung cancer and head and neck cancer.

Preferably, the lymphomas described in the present disclosure are selected from hodgkin's disease and non-hodgkin's lymphomas (e.g., mantle cell lymphomas, diffuse large B-cell lymphomas, follicular center lymphomas, marginal zone B-cell lymphomas, lymphoplasmacytic lymphomas, and peripheral T-cell lymphomas); the lung cancer is non-small cell lung cancer (NSCLC) (e.g., lung squamous carcinoma and lung adenocarcinoma, wherein lung adenocarcinoma is preferably bronchioloalveolar carcinoma) and Small Cell Lung Cancer (SCLC); the liver cancer is hepatocellular carcinoma (HCC); the pancreatic cancer is pancreatic duct adenocarcinoma; the colorectal cancer is colon cancer and rectal cancer; the prostate cancer is hormone refractory prostate cancer.

As a general guideline, the active compounds of the present disclosure are preferably administered in unit doses, or in a manner that the patient can self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation. Suitable unit doses may be in the range 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 ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of the active compound.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, 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: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing 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 to 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. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

The oil suspensions may be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickener. The above-described sweeteners 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 an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used 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, which injectable solution or microemulsion may be injected into the blood stream of a patient by topical bolus injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.

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 suspension may be formulated according to known techniques 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, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare 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 will therefore melt in the rectum to release the drug.

As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the specific 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, etc.; in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

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

The term "alkyl" refers to a saturated straight or branched 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). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C _1-12 Alkyl groups), more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C _1-6 Alkyl). 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, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. Alkyl groups may be substituted or unsubstituted, when substituted Which may be substituted at any available point of attachment, the substituents are preferably 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 "alkylene" refers to a divalent alkyl group, where 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 An alkylene group). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C _1-12 Alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C _1-6 An alkylene group). 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. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenyl" refers to an alkyl group having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined 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 they may be substituted at any available point of attachment, the substituents preferably being selected from the group consisting of D atoms, alkoxy groups, halogen, haloalkyl groups, haloalkoxy groupsOne or more of a group, 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, where alkyl is as defined 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 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, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, alkoxy groups, halogen, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like. The alkoxy group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, 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, full-carbocyclic (i.e., monocyclic cycloalkyl) or polycyclic (i.e., polycyclic cycloalkyl) system having 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 such monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like.

The polycyclic cycloalkyl group includes: spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl.

The term "spirocycloalkyl" refers to a polycyclic ring system having one or more carbon atoms (referred to as spiro atoms) shared between the 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 a nitroxide; the sulfur may optionally be oxo, i.e., to form a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-S-), provided that at least one full carbocyclic ring is contained and the point of attachment is on the full carbocyclic ring, 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 spirocycloalkyl). The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered spirocycloalkyl group), 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 multi-spirocycloalkyl group (e.g., a double spirocycloalkyl group, etc.), preferably a mono-spirocycloalkyl group or a double spirocycloalkyl 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/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;

etc. />

The term "fused ring alkyl" refers to a polycyclic ring system having two adjacent carbon atoms shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl fused to a heterocyclic, aromatic, ringOne or more of the groups or heteroaryl groups are fused, wherein the point of attachment is on a monocyclic cycloalkyl group, which may contain one or more double bonds within the ring, and 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 fused ring alkyl groups). The condensed ring alkyl group is preferably a condensed ring alkyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered condensed ring alkyl group), more preferably a condensed ring alkyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered condensed ring alkyl group). The condensed ring alkyl group includes a bicyclic condensed ring alkyl group and a polycyclic condensed ring alkyl group (e.g., a tricyclic condensed ring alkyl group, a tetracyclic condensed ring alkyl group, etc.), preferably a bicyclic condensed ring alkyl group or a tricyclic condensed 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/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, or 7-membered/6-membered bicyclic condensed ring alkyl group. Non-limiting examples include:

The connection point can be at any position;

etc.

The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system having two carbon atoms in common between the rings that are not directly attached, which may contain one or more double bonds within the ring, and 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) 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), 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 a bicyclic bridged cycloalkyl group and a polycyclic bridged cycloalkyl group (e.g., a tricyclic bridged cycloalkyl group, a tetracyclic bridged cycloalkyl group, etc.), preferably a bicyclic bridged cycloalkyl group or a tricyclic bridged cycloalkyl group. Non-limiting examples include:

the connection point can be at any position.

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably 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 heterocyclic ring system (i.e., polycyclic heterocyclyl) having at least one (e.g., 1,2,3, or 4) heteroatom (S) selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., forming a nitroxide; the sulfur may optionally be oxo, i.e., forming a sulfoxide or sulfone, but excluding-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 heterocyclyl groups having 3 to 8 ring atoms (i.e., 3 to 8 membered heterocyclyl groups); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3 to 6 membered heterocyclic group), a heterocyclic group having 4 to 6 ring atoms (i.e., a 4 to 6 membered heterocyclic group), or a heterocyclic group having 5 to 7 ring atoms (i.e., a 5 to 7 membered heterocyclic group); most preferred are heterocyclyl groups having 5 or 6 ring atoms (i.e., 5 or 6 membered heterocyclyl groups).

Non-limiting examples of such 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, condensed heterocyclic group and bridged heterocyclic group.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system having one or more double bonds shared between the 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 (S) selected from nitrogen, oxygen and sulfur (which may optionally be oxidized, i.e., form nitrogen oxides; which may optionally be oxo, i.e., form sulfoxides or sulfones, but excluding-O-, -O-S-or-S-) with the proviso that at least one monocyclic heterocyclic ring is contained and the point of attachment is on the monocyclic heterocyclic ring, 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 spiroheterocyclyl group includes a mono-spiroheterocyclyl group and a multi-spiroheterocyclyl group (e.g., a double-spiroheterocyclyl group, etc.), preferably a mono-or double-spiroheterocyclyl group, more preferably a 3/4-, 3/5-, 3/6-, 4/4-, 4/5-, 4/6-, 5/3-, 5/4-, 5/5-, 5/6-, 5/7-, 6/3-, 6/4-, 6/5-, 6/6-, 6/7-, 7/5-or 7-membered mono-spiroheterocyclyl group. Non-limiting examples include:

Etc.

The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system having two adjacent atoms shared between the 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 (S) selected from nitrogen, oxygen and sulfur within the ring (which may optionally be oxidized, i.e., form nitrogen oxides; which may optionally be oxo, i.e., form sulfoxides or sulfones, but excluding-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 cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on a monocyclic heterocyclic group and 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 fused heterocyclic groups). 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 6 to 10 ring atoms (i.e., a 6 to 10-membered fused heterocyclic group), and still more preferably a 6-or 7-membered fused heterocyclic group. The fused heterocyclic group includes a bicyclic and polycyclic fused heterocyclic group (e.g., a tricyclic fused heterocyclic group, a tetracyclic fused heterocyclic group, etc.), preferably a bicyclic fused heterocyclic group or a tricyclic fused heterocyclic 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/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 bicyclic fused heterocyclic group. Non-limiting examples include:

Etc.

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system having two atoms not directly connected between the 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 (S) selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may optionally be oxidized, i.e., form a nitrogen oxide; the sulfur may optionally be oxo, i.e., form a sulfoxide or sulfone, but excluding-O-, -O-S-or-S-), 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 bridged heterocyclyl). 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 6 to 10 ring atoms (i.e., a 6 to 10 membered bridged heterocyclic group), and still more preferably a 6-membered, 7-membered or 8-membered bridged heterocyclic group. The number of constituent rings may be classified into a bicyclic bridged heterocyclic group and a polycyclic bridged heterocyclic group (e.g., a tricyclic bridged heterocyclic group, a tetracyclic bridged heterocyclic group, etc.), with a bicyclic bridged heterocyclic group or a tricyclic bridged heterocyclic group being preferred. Non-limiting examples include:

etc.

The heterocyclic group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of 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 from 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6 to 14 membered aryl) having a conjugated pi electron system. The aryl group is preferably an aryl group having 6 to 10 ring atoms (i.e., a 6 to 10 membered aryl group). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of such polycyclic aryl groups include: naphthyl, anthryl, phenanthryl, and the like. The polycyclic aryl group also includes a phenyl group fused to one or more of a heterocyclic group or a cycloalkyl group, or a naphthyl group fused to one or more of a heterocyclic group or a cycloalkyl group, wherein the point of attachment is on the phenyl or naphthyl group, and in such cases the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:

etc.

Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably 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 having a conjugated pi electron system (i.e., a monocyclic heteroaryl group) or a polycyclic heteroaryl ring system (i.e., a polycyclic heteroaryl group) containing at least one (e.g., 1, 2, 3, or 4) heteroatom (S) selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., form a nitrogen oxide; the sulfur may optionally be oxo, i.e., form a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-) within the ring having 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 group). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10 membered heteroaryl group), more preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6 membered heteroaryl group).

Non-limiting examples of such monocyclic heteroaryl groups include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridones (e.g.)Etc.), pyrazinyl, pyridazinyl, etc.

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

Etc.

Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably 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 an easily removable group introduced on an amino group in order to keep the amino group unchanged when the reaction is performed at other positions of the molecule. Non-limiting examples include: (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (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 "hydroxy protecting group" refers to an easily removable group introduced on a hydroxy group for blocking or protecting the hydroxy group to react on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like.

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

The term "heterocyclyloxy" refers to 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-, 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 "methylene" refers to =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" refers to-NO ₂ 。

The term "oxo" or "oxo" refers to "=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 present disclosure may exist in particular stereoisomeric forms. The term "stereoisomer" refers to an isomer that is identical in structure but differs in the arrangement of 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, conformational isomers and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in compounds of the present disclosure may present additional asymmetric atoms. All such stereoisomers, and 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. An 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 diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is performed by conventional methods well known in the art to give the pure isomer. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.

In the chemical structure of the compounds of the present disclosure, the bondIndicating the unspecified configuration, i.e.the bond +.>Can be +.>Or at the same time contain->And->Two configurations. For all carbon-carbon double bonds, Z and E are included even if only one configuration is named.

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 proportions. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactams, and the like. Examples of the lactam-lactam balance are shown below:

as reference to pyrazolyl, it is understood to include mixtures of either or both tautomers of either of the following structures:

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 wherein 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, iodine, and the like, e.g., 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., deuterium is preferred.

Compared with non-deuterated medicines, deuterated medicines have the advantages of reducing toxic and side effects, increasing medicine stability, enhancing curative effect, prolonging biological half-life of medicines 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, wherein replacement of deuterium may be partial or complete, with partial replacement of deuterium meaning that at least one hydrogen is replaced by at least one deuterium.

When a position of a compound of the present disclosure is specifically designated as "deuterium" or "D", that position is understood to mean that the abundance of deuterium is at least 1000-fold greater than the natural abundance of deuterium (which is 0.015%), i.e., at least 15% deuterium incorporation. In some embodiments, the abundance of deuterium per 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 per 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 per 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 per 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-fold greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per 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 per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium per 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 per 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 per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium incorporation).

"optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that it includes instances where the event or circumstance occurs or does not. For example, "alkyl optionally (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" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated bonds (e.g., alkenes).

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure, which may be selected from inorganic salts or organic salts. Such salts are safe and effective when used in mammals and have desirable biological activity. May be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate groups 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 and 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 will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and the appropriate therapeutically effective amount in an individual case can be determined by one of skill in the art based on routine experimentation.

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

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

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

Methods of synthesizing compounds of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical scheme:

scheme one

A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

the compound of the general formula (IA) or the salt thereof is dehydrated in the presence of a dehydrating agent to obtain the compound of the general formula (I) or the pharmaceutically acceptable salt thereof,

wherein:

Scheme II

A process for the preparation of a compound of formula (I-1) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

the compound of the general formula (I-1A) or the salt thereof is dehydrated in the presence of a dehydrating agent to obtain the compound of the general formula (I-1) or the pharmaceutically acceptable salt thereof,

Wherein:

Scheme III

A process for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

dehydrating the compound of formula (IIA) or a salt thereof in the presence of a dehydrating agent to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof,

wherein:

Scheme IV

A process for the preparation of a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

the compound of the general formula (II-1A) or the salt thereof is dehydrated in the presence of a dehydrating agent to obtain the compound of the general formula (II-1) or the pharmaceutically acceptable salt thereof,

wherein:

The dehydrating agents described in the above synthetic schemes include, but are not limited to, (methoxycarbonylsulfamoyl) triethylammonium hydroxide inner salt (Bogis reagent), trifluoroacetic anhydride (TFAA), methanesulfonyl chloride, POCl ₃ 、P ₂ O ₅ 、SOCl ₂ 、PCl ₅ Etc.; preferably (methoxycarbonylsulfamoyl) triethylammonium hydroxide inner salt (primary gizzard agent).

The reaction of the above steps is preferably carried out in solvents including, but not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane, and mixtures thereof.

Detailed Description

The present disclosure is further described below in conjunction with the examples, which are not intended to 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.) of 10 ^-6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus or Bruker AVANCE NEO M with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS).

MS was determined using an Agilent 1200/1290DAD-6110/6120 Quadrapol MS liquid chromatography-mass spectrometry (manufacturer: agilent, MS model: 6110/6120 Quadrapol MS).

waters ACQuity UPLC-QD/SQD (manufacturers: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)

Thermo Ultimate 3000-Q exact (manufacturer: thermo, MS model: thermo Qexact)

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC 1200DAD, agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high pressure liquid chromatography.

Chiral HPLC analysis was determined using an Agilent 1260DAD high performance liquid chromatograph.

The high performance liquid phase was prepared by using a Waters 2545-2767, waters 2767-SQ Detector 2, shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.

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

The CombiFlash flash rapid prep instrument used CombiFlash Rf200 (teldyne ISCO).

The thin layer chromatography silica gel plate uses a smoke table 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.

The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier.

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

The known starting materials of the present invention may be synthesized using or following methods known in the art, or may be purchased from the companies ABCR GmbH & Co.KG, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemical, and the like.

The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.

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

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

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

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: the volume ratio of the methylene dichloride to the methanol is adjusted according to the polarity of the compound, and small amounts of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

(S) -N- ((S) -1-cyano-2- ((S) -2-oxopyrrolidin-3-yl) ethyl) -2- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl) -2-azabicyclo [2.2.2] octane-3-carboxamide 1

First step

(S) -1-amino-1-oxo-3- ((S) -2-oxopyrrolidin-3-yl) propan-2-yl) carbamic acid tert-butyl ester 1b

Methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- ((S) -2-oxo-pyrrolidin-3-yl) propionate 1a (20.0 g,69.8mmol, shanghai shao) was dissolved in 7M methanolic ammonia solution (250 mL), stirred and reacted for 48 hours, and the reaction solution was concentrated under reduced pressure to give crude title compound 1b (18.8 g) which was used directly in the next reaction without purification.

MS m/z(ESI):272.2[M+1]

Second step

(S) -2-amino-3- ((S) -2-oxopyrrolidin-3-yl) propanamide hydrochloride 1c

The crude compound 1b (18.8 g,69.3 mmol) was dissolved in isopropanol (94 mL), 4M isopropanol hydrochloride solution (87 mL) was added at 0deg.C, the reaction mixture was warmed to 50deg.C and stirred for 4 hours, cooled to room temperature and stirred for 16 hours, the reaction mixture was concentrated under reduced pressure, the residue was slurried with isopropanol (100 mL), filtered, and the filter cake was dried to give the crude title compound 1c (15.4 g), and the product was directly used for the next reaction without purification.

MS m/z(ESI):172.2[M+1]

Third step (S) -3- (((S) -1-amino-1-oxo-3- ((S) -2-oxopyrrolidin-3-yl) propan-2-yl) carboxamide) -2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester 1e

Crude compound 1c (360 mg,1.73 mmol), (S) -2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.2] octane-3-carboxylic acid 1d (400 mg,1.56mmol, shanghai Bifide) was dissolved in N, N-dimethylformamide (10 mL), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (65 mg,1.73 mmol) and N, N-diisopropylethylamine (610 mg,4.7 mmol) were added while ice-bath and the reaction was stirred at room temperature for 14 h with natural recovery, 2mL of water was added and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to give the title compound 1e (639 mg, 99.8% yield).

MS m/z(ESI):409.2[M+1]

Fourth step

(S) -N- ((S) -1-amino-1-oxo-3- ((S) -2-oxopyrrolidin-3-yl) propan-2-yl) -2-azabicyclo [2.2.2] octane-3-carboxamide hydrochloride 1f

Compound 1e (639 mg,1.56 mmol) was dissolved in dichloromethane (4 mL), 4M dioxane hydrochloride solution (4 mL) was added, and the reaction was stirred for 60 min. The reaction solution was concentrated under reduced pressure to give the crude title compound 1f (483 mg), which was used in the next reaction without purification.

MS m/z(ESI):309.2[M+1]

Fifth step

((S) -1- ((S) -3- ((S) -1-amino-1-oxo-3- ((S) -2-oxopyrrolidin-3-yl) propan-2-yl) carboxamide) -2-azabicyclo [2.2.2] oct-2-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamic acid tert-butyl ester 1h

Crude compound 1f (4813 mg,1.4 mmol), ((S) -2- ((tert-butoxycarbonyl) amino) -3, 3-dimethylbutyric acid 1g (356 mg,1.54 mmol) was dissolved in N, N-dimethylformamide (10 mL), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (586 mg,1.54 mmol) and N, N-diisopropylethylamine (725 mg,5.6 mmol) were added while ice-cold and the reaction mixture was stirred at room temperature for 14 hours, after which 2mL of water was added and concentrated under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound 1h (730 mg, yield: 99.9%) as eluent system A.

MS m/z(ESI):522.2[M+1]

Sixth step

(S) -N- ((S) -1-amino-1-oxo-3- ((S) -2-oxopyrrolidin-3-yl) propan-2-yl) -2- ((S) -2-amino-3, 3-dimethylbutyryl) -2-azabicyclo [2.2.2] octane-3-carboxamide hydrochloride 1i

The compound (1 h) (1 g,1.9 mmol) was dissolved in dichloromethane (5 mL), 4M dioxane hydrochloride solution (5 mL) was added, and the reaction was stirred for 60 min. The reaction solution was concentrated under reduced pressure to give the crude title compound 1i (877 mg), which was used in the next reaction without purification.

MS m/z(ESI):422.2[M+1]

Seventh step

(S) -N- ((S) -1-amino-1-oxo-3- ((S) -2-oxopyrrolidin-3-yl) propan-2-yl- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl) -2-azabicyclo [2.2.2] octane-3-carboxamide 1j

Compound 1i (180 mg, 393. Mu. Mol) was dissolved in methanol (4 mL), N-diisopropylethylamine (254 mg,1.96 mmol) was added, ethyl trifluoroacetate (279 mg,1.96mmol, shanghai-tai) was heated to 60℃and reacted for 14 hours with stirring, cooled to room temperature, and the reaction solution was concentrated under reduced pressure to give the crude title compound 1j (203 mg) which was used directly in the next reaction without purification.

MS m/z(ESI):518.2[M+1]

Eighth step

The crude compound 1j (203 mg, 392.2. Mu. Mol) was dissolved in methylene chloride (3 mL), triethylammonium hydroxide inner salt (Bogis reagent) (187 mg, 784.7. Mu. Mol) was added, the reaction was stirred for 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mM; 5. Mu.m; C18 mobile phase 1: water (10 mM ammonium bicarbonate) mobile phase 2: acetonitrile, flow rate: 30mL/min, gradient ratio: acetonitrile 35% -47%) to give the title compound 1 (18 mg, yield: 9.1%).

MS m/z(ESI):500.2[M+1]

¹ H NMR(500MHz,CD ₃ OD):δ5.06(dd,1H),4.26(d,2H),3.32-3.24(m,2H),2.72(tt,1H),2.42-2.26(m,2H),2.18(d,2H),1.81(dddd,9H),1.61(dd,1H),1.08(s,9H)。

Example 2

(1R, 3S, 4S) -N- ((S) -1-cyano-2- ((S) -2-oxopyrrolidin-3-yl) ethyl) -2- ((S) -3, 3-dimethyl

-2- (2, 2-trifluoroacetamido) butanoyl) -2-azabicyclo [2.2.1] heptane-3-carboxamide 2

First step

(1R, 3S, 4S) -3- (((S) -1-amino-1-oxo-3- ((S) -2-oxopyrrolidin-3-yl) propan-2-yl) carboxamide) -2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester 2b

Compound 1c (172 mg, 829. Mu. Mol), ((1R, 3S, 4S) -2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptane-3-carboxylic acid 2a (200 mg, 829. Mu. Mol, prepared by the method disclosed in Example 14 on page 28 of the specification in patent application "WO 2011091532") was dissolved in N, N-dimethylformamide (10 mL), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (345 mg, 909. Mu. Mol) and N, N-diisopropylethylamine (321 mg,2.4 mmol) were added to the reaction mixture under natural recovery at room temperature for 14 hours, and the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography in elution system A to give the title compound 2b (320 mg, yield: 97.8%).

MS m/z(ESI):395.2[M+1]

Second step

(1R, 3S, 4S) -N- ((S) -1-amino-1-oxo-3- ((S) -2-oxopyrrolidin-3-yl) propan-2-yl) -2-azabicyclo [2.2.1] heptane-3-carboxamide hydrochloride 2c

Compound 2b (150 mg, 380. Mu. Mol) was dissolved in methylene chloride (4 mL), and a 4M dioxane solution (4 mL) of hydrochloric acid was added thereto, followed by stirring for 60 minutes. The reaction solution was concentrated under reduced pressure to give the crude title compound 2c (110 mg), which was used in the next reaction without purification.

MS m/z(ESI):295.2[M+1]

Third step

((S) -1- ((1R, 3S, 4S) -3- ((S) -1-amino-1-oxo-3- ((S) -2-oxopyrrolidin-3-yl) propan-2-yl) carboxamide) -2-azabicyclo [2.2.1] hept-2-yl) -3, 3-dimethyl-1-oxobutan-2-yl) carbamic acid tert-butyl ester 2d

Crude compound 2c (87 mg, 263. Mu. Mol), compound 1g (60 mg, 259. Mu. Mol) was dissolved in N, N-dimethylformamide (10 mL), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (99 mg, 260. Mu. Mol) and N, N-diisopropylethylamine (102 mg, 788. Mu. Mol) were added under ice-bath, and the reaction mixture was stirred at room temperature for 14 hours with stirring, and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give the title compound 2d (97 mg, yield: 72.6%).

MS m/z(ESI):508.2[M+1]

Fourth step

(1R, 3S, 4S) -N- ((S) -1-amino-1-oxo-3- ((S) -2-oxopyrrolidin-3-yl) propan-2-yl) -2- ((S) -2-amino-3, 3-dimethylbutyryl) -2-azabicyclo [2.2.1] heptane-3-carboxamide hydrochloride 2e

Compound 2d (97 mg, 191. Mu. Mol) was dissolved in methylene chloride (2 mL), and a 4M dioxane solution (2 mL) of hydrochloric acid was added thereto, followed by stirring for 60 minutes. The reaction solution was concentrated under reduced pressure to give crude title compound 2e (77 mg), which was used in the next reaction without purification.

MS m/z(ESI):408.2[M+1]

Fifth step

(1R, 3S, 4S) -N- ((S) -1-amino-1-oxo-3- ((S) -2-oxopyrrolidin-3-yl) propan-2-yl) -2- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl) -2-azabicyclo [2.2.1] heptane-3-carboxamide 2f

Crude compound 2e (77 mg, 189. Mu. Mol), trifluoroacetic acid (23 mg, 202. Mu. Mol) was dissolved in N, N-dimethylformamide (2 mL), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (80 mg, 210. Mu. Mol) and N, N-diisopropylethylamine (73 mg, 564. Mu. Mol) were added under ice-bath, and the reaction was stirred at room temperature for 14 hours after natural recovery and the residue was purified by silica gel column chromatography with elution system A to give the title compound 2f (5 mg, yield: 5%).

MS m/z(ESI):504.2[M+1]

Sixth step

(1R, 3S, 4S) -N- ((S) -1-cyano-2- ((S) -2-oxopyrrolidin-3-yl) ethyl) -2- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl) -2-azabicyclo [2.2.1] heptane-3-carboxamide 2

Compound 2f (5 mg, 99. Mu. Mol) was dissolved in methylene chloride (0.5 mL), an inner salt of triethylammonium hydroxide (Bogis reagent) (4.7 mg, 19.7. Mu. Mol) was added thereto, the reaction was stirred for 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mM; 5. Mu.m; C18 mobile phase 1: water (10 mM ammonium bicarbonate) mobile phase 2: acetonitrile, flow rate: 30mL/min, gradient ratio: acetonitrile 35% -47%) to give the title compound 2 (2 mg, yield: 41%).

MS m/z(ESI):486.2[M+1]

¹ H NMR(500MHz,CD ₃ OD):δ5.03(dd,1H),3.88(s,1H),3.32-3.23(m,3H),2.73-2.64(m,2H),2.34(tt,2H),2.23(dd,2H),1.95-1.77(m,4H),1.74(d,1H),1.54(t,1H),1.49(d,1H),1.09(s,9H)。

Example 3

(1R, 2S, 5S) -N- ((S) -1-cyano-2- ((S) -2-oxopyrrolidin-3-yl) ethyl) -3- ((S) -3, 3-dimethyl-2- (2, 2-trifluoroacetamido) butanoyl) -3-azabicyclo [3.2.1] octane-2-carboxamide 3 (diastereomer mixture)

Using the synthetic route in example 1, the third starting material 1d was replaced with the compound (1R, 2S, 5S) -3- (tert-butoxycarbonyl) -3-azabicyclo [3.2.1] octane-2-carboxylic acid to give the title compound 3 (diastereomer mixture).

Example 4

(S) -N- ((S) -1-cyano-2- ((S) -2-oxopyrrolidin-3-yl) ethyl) -2- ((S) -2- (1-fluorocyclopropane-1-carboxamide) -3, 3-dimethylbutyryl) -2-azabicyclo [2.2.2] octane-3-carboxamide 4

First step

(S) -N- ((S) -1-amino-1-oxo-3- ((S) -2-oxopyrrolidin-3-yl) propan-2-yl) -2- ((S) -2- (1-fluorocyclopropane-1-carboxamide) -3, 3-dimethylbutyryl) -2-azabicyclo [2.2.2] octane-3-carboxamide 4a

Crude compound 1i (430 mg, 938.8. Mu. Mol), 1-fluorocyclopropane-1-carboxylic acid (100 mg, 960. Mu. Mol, shanghai Bide) was dissolved in N, N-dimethylformamide (6 mL), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (393 mg,1.03 mmol) and N, N-diisopropylethylamine (400 mg,3.1 mmol) were added while ice-cold and the reaction was stirred at room temperature for 14 h and the residue was purified by silica gel column chromatography to give the title compound 4a (476 mg, yield: 99.8%) as eluted with system A.

MS m/z(ESI):508.2[M+1]

Second step

Compound 4a (476 mg, 937.7. Mu. Mol) was dissolved in methylene chloride (10 mL), triethylammonium hydroxide inner salt (Bogis reagent) (447 mg,1.87 mmol) was added, the reaction was stirred for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (instrument model: gilson 281 column: X-Bridge, prep 30X 150mM;5 μm; C18 mobile phase 1: water (10 mM ammonium bicarbonate) mobile phase 2: acetonitrile, flow rate: 30mL/min, gradient ratio: acetonitrile 35% -47%) to give the title compound 4 (80 mg, yield: 17.4%).

MS m/z(ESI):490.2[M+1]

¹ H NMR(500MHz,CD ₃ OD):δ5.06(dd,1H),4.26(t,2H),3.30(d,2H),2.71(dt,1H),2.35(ddt,2H),2.24-2.10(m,2H),1.94-1.63(m,9H),1.60(dd,1H),1.37-1.26(m,4H),1.07(s,9H)。

Biological evaluation

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

Test example 1: determination of inhibitory Activity of Compounds against SARS-CoV-2 3CL protease

Experimental materials:

instrument:

instrument name	Suppliers (suppliers)
		Spark plate reader	TECAN
Incubator at 37 ℃ (ZQTY-70E)	Instrument for knowing Chu

1. Preparation of the reaction reagent

1.1 System reactant preparation

System reagent = 92 μl system buffer +1 μl 3CL protease (stock 1:10 dilution, final concentration 30 nM)

1.2 sample preparation

The test substance was dissolved in DMSO to prepare a 20mM stock solution. In the experiments, the test compounds were tested for inhibition of 3CL activity always at a concentration of 100. Mu.M, semilog diluted, 10 total concentrations (0.003. Mu.M, 0.01. Mu.M, 0.03. Mu.M, 0.1. Mu.M, 0.316. Mu.M, 1. Mu.M, 3.16. Mu.M, 10. Mu.M, 31.6. Mu.M, 100. Mu.M), and were tested in duplicate wells.

The dilution method is shown in the following table.

After DMSO dilution was completed, the dilutions were further 1: and (5) diluting by 10. The diluted samples were labeled as test substances in the table of 1.3.

1.3 preparation of the reaction System

The single well system in the 96-well plate was formulated as follows (the wells were formulated in total volume):

1.4 substrate preparation

Substrate (Dabcyl-KTSAVLQSGFRKME-Edans) stock (20 mM) was diluted 8-fold with DMSO. 2. Mu.L of diluted substrate was added to each well using a row gun.

2. Incubation and fluorescence detection

After incubation at 37℃for 10min (shaking mixing at 250 rpm), incubation was carried out at 25℃for 60min. Fluorescence parameters were measured using a TECAN SPARK multifunctional microplate reader, with excitation and emission wavelengths of 320 (25) nm and 460 (20) nm, respectively, and data were read.

3. Data analysis

Inhibition(％)＝(RFU _100％EA -RFU _sample )/(RFU _100％EA -RFU _BLK )x 100％

The data obtained were processed using the software GraphPad Prism using a nonlinear regression-four parameter model. Ki values were calculated as follows. The experimental results are shown in table 1.

RFU: relative fluorescence value

100% EA:100% enzyme Activity

BLK: blank control

[ S ]: substrate concentration

Km: miq constant

Inhibition of SARS-CoV-2 3CL protease by Compounds of Table 1 ₅₀ Values and Ki values

Compounds of formula (I)	IC ₅₀ (nM)	Ki(nM)
			1	83	34

Conclusion: the compounds of the present disclosure have good inhibitory effect on SARS-CoV-2 3CL protease activity and have high affinity for the enzyme.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

R ¹ selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, cyano, hydroxyalkyl, and oxo;

R ² Selected from alkyl, alkoxy, haloalkyl, haloalkoxy and cyano;

m is an integer between 0 and 20;

t is 0, 1, 2, 3 or 4; and is also provided with

u is 0, 1, 2, 3 or 4.

2. A compound of formula (I) according to claim 1, wherein ring a is a nitrogen-containing 6-to 14-membered bicyclic bridged heterocyclyl group, or a pharmaceutically acceptable salt thereof.

3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

wherein:

p is 0, 1 or 2;

r is 0, 1 or 2;

q is 1, 2 or 3;

s is 1, 2 or 3;

R ¹ 、R ² 、R ³ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ and m is as defined in claim 1.

4. A compound of formula (I) according to claim 3, wherein p is 0 or 1; and/or r is 0; and/or q is 1 or 2; and/or s is 1 or 2; and/or m is 0.

5. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R ¹ Is C _1-6 Alkyl or 3-to 8-membered cycloalkyl, said C _1-6 Alkyl or 3-to 8-membered cycloalkyl are each independently optionally selected from halogen, C _1-6 Alkyl and C _1-6 One or more substituents in the haloalkyl group; and/or R ² Is C _1-6 An alkyl group; and/or R ⁵ Is a hydrogen atom; and/or R ⁶ Is a hydrogen atom; and/or R ⁷ Is a hydrogen atom; and/or R ⁸ Is a hydrogen atom.

6. A compound of general formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

7. a compound of the general formula (IA):

wherein:

ring A, R ¹ 、R ² 、R ³ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ And m is as defined in claim 1;

Preferably selected from the following compounds:

8. a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which comprises:

wherein:

ring A, R ¹ 、R ² 、R ³ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ And m is as defined in claim 1.

9. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

10. Use of a compound of general formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 9 in the manufacture of a medicament for inhibiting a 3CL protease; and/or in the manufacture of a medicament for the treatment and/or prophylaxis of a viral infection; the virus is preferably a coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.