CN117813090A - Methods and compositions for targeting PD-L1 - Google Patents

Methods and compositions for targeting PD-L1 Download PDF

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Publication number
CN117813090A
CN117813090A CN202280052023.XA CN202280052023A CN117813090A CN 117813090 A CN117813090 A CN 117813090A CN 202280052023 A CN202280052023 A CN 202280052023A CN 117813090 A CN117813090 A CN 117813090A
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compound
group
alkyl
hydrogen
haloalkyl
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Inventor
吴同飞
皮埃尔·让马里·伯纳德·拉博森
弗朗索瓦·冈萨尔维斯
安蒂萨·迪米特洛娃·斯托伊切娃
刘程
杰罗姆·德瓦尔
大卫·麦高万
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Anligo Pharmaceutical Co ltd
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Anligo Pharmaceutical Co ltd
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Priority claimed from PCT/US2022/033653 external-priority patent/WO2022266236A1/en
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Abstract

The present disclosure relates to compounds useful as inhibitors of PD-1, PD-Ll, or PD-1/PD-Ll interactions. Also disclosed herein are pharmaceutical compositions that may comprise a compound of formula (I), or a pharmaceutically acceptable salt thereof, and uses or methods of using a compound of formula (I), or a pharmaceutically acceptable salt thereof, for treating PD-L1 related disorders, including but not limited to liver disease, cancer, hepatocellular carcinoma, viral disease, or hepatitis b.

Description

Methods and compositions for targeting PD-L1
Incorporation by reference of any priority application
Any and all applications for which foreign or domestic priority claims are identified, for example, in an application data sheet or request filed with the present application, are hereby incorporated by reference under 37cfr 1.57 and rules 4.18 and 20.6, including U.S. provisional application No. 63/212,388 filed on 18, 2021, U.S. provisional application No. 63/263,427, and U.S. provisional application No. 63/363,777 filed on 28, 2022, and 11, respectively.
Technical Field
The present application relates to the fields of chemistry, biochemistry, molecular biology and medicine. The present disclosure relates to compounds useful as inhibitors of PD-1, PD-Ll, or PD-1/PD-Ll interactions. Also disclosed herein are pharmaceutical compositions of the compounds described herein and uses or methods of using the compounds to treat PD-L1 related diseases, including but not limited to liver disease, cancer, hepatocellular carcinoma, viral disease, or hepatitis b.
Background
In activated CD4 + And CD8 + Programmed cell death 1 (PD-1) immune checkpoints expressed on the surface of T cells control the inhibitory mechanisms that prevent autoimmunity. PD-1 and in a variety of cellsEngagement of programmed death ligand 1 (PD-L1) expressed on types including macrophages, dendritic cells, mast cells, and cancer cells induces T cell depletion, resulting in a reduction or loss of effector cytokine production (e.g., IL-2, TNF- α, IFN- γ) and up-regulation of other inhibitory receptors and immune checkpoints (e.g., CTLA-4, LAG-3, and BTLA) or T cell apoptosis. Many types of cancer exhibit high expression of PD-L1 to evade tumor immune surveillance and are associated with poor prognosis. PD-1 mediated immunosuppression is also associated with some viral infections (such as hepatitis b). There is a continuing need for improved PD-1/PD-L1 therapies and their use in the treatment of disease.
Disclosure of Invention
Some embodiments disclosed herein relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Some embodiments disclosed herein relate to pharmaceutical compositions that may contain an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Some embodiments described herein relate to methods of treating HBV and/or HDV infection, which methods may comprise administering an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, to a subject identified as having HBV and/or HDV infection. Other embodiments described herein relate to the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, for treating HBV and/or HDV infection.
Some embodiments disclosed herein relate to methods of inhibiting replication of HBV and/or HDV, which methods may comprise contacting a cell infected with HBV and/or HDV with an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, for inhibiting HBV and/or HDV replication.
These are other embodiments described in more detail below.
Drawings
FIGS. 1A and 1B show the absolute configuration and ORTEP crystal structure of formate salt of intermediate 5-1B.
Detailed Description
Hepatocellular carcinoma (HCC) is the most common form of liver cancer. HCC can be caused by a variety of conditions such as alcohol consumption, cirrhosis, and viral infections that cause hepatitis, such as hepatitis b virus, hepatitis c virus, and hepatitis delta virus. Inflammation, fibrosis, and cirrhosis associated with these conditions can induce malignancy in the affected hepatocytes. HCC has a relatively poor prognosis with five-year survival of about 30% depending on whether complete surgical resection of the tumor is possible.
For early stage disease, surgical excision is used. However, most HCC is identified later due to diagnostic difficulties. At advanced diagnosis, the tumor is unresectable and most patients are given systemic treatment. Current standards of care for the front line are multi-kinase inhibitors including, for example, sorafenib (sorafenib) and/or lenvatinib (lenvatinib). Most patients are refractory or relapsed from these treatments and undergo two-line therapy with anti-angiogenic agents, including, for example, regorafinib, cabozantinib (Cabozantinib) and/or ramucirumab (ramiirumab), or immune checkpoint inhibitors, including, for example, nivolumab (nivolumab) and/or pambrizumab (pembrolizumab). However, most patients do not respond to the first and second therapies and have poor clinical benefit, with overall survival not exceeding one year. Furthermore, biomarker-driven therapies are lacking. Thus, there is a need to develop more tolerable and effective therapies for the treatment of HCC and related liver diseases.
HBV is a partially double-stranded circular DNA of about 3.2 kilobase (kb) pair and is classified into eight genotypes, a through H. The HBV replication pathway has been studied in more detail. Some replication involves the formation of covalently closed circular DNA (cccDNA) forms. The presence of cccDNA poses the risk of the virus reappearance over the life of the host organism. HBV carriers can spread the disease for many years. It is estimated that 3 hundred million people have hepatitis b virus infection, and it is estimated that over 750,000 people die annually worldwide from hepatitis b. Furthermore, immunosuppressed individuals or individuals undergoing chemotherapy are at risk of reactivation of HBV infection, among others. HBV may be acute and/or chronic. Acute HBV infection may be asymptomatic or symptomatic acute hepatitis.
HBV may be transmitted by blood, semen and/or another body fluid. This may occur by: direct blood-blood contact, unprotected intercourse, shared needle, and from the infected mother to her infant during the course of delivery. HBV surface antigen (HBsAg) is most commonly used to screen for the presence of such infection. Currently available drugs cannot cure HBV and/or HDV infection. In contrast, drugs inhibit viral replication.
Hepatitis Delta Virus (HDV) is also a DNA virus in hepadnaviridae. HDV can only reproduce in the presence of HBV. The transmission pathways of HDV are similar to those of HBV. Transmission of HDV can occur via simultaneous infection with HBV (co-infection) or in addition to chronic hepatitis b or hepatitis b carrier status (superinfection). Both the superinfection and co-infection of HDV lead to more serious complications than HBV infection alone. These complications include a greater likelihood of experiencing liver failure and rapid progression of cirrhosis in acute infections, where the risk of developing liver cancer is increased in chronic infections. In combination with hepatitis b, hepatitis d has the highest mortality rate of 20% among all hepatitis infections. There is currently no treatment or vaccine for hepatitis d.
Programmed cell death 1 or programmed death 1 (PD-1) is a 268 amino acid long type I transmembrane protein found as a surface marker on T cells and other immune cells. As an immune checkpoint, PD-1 is used to down-regulate immune responses to prevent autoimmune disorders. The PD-1 protein (NCBI accession No. NP-005009.2) is expressed from cluster of differentiation 279 (CD 279) gene (NCBI accession No. NG-012110.1) or mRNA transcript (NCBI accession No. NM-005018.3). In some preferred embodiments, PD-1 is a human PD-1 protein and CD279 is a human CD279 transcript or gene on chromosome 2. It should be understood that when considering nucleic acids (DNA or RNA) or corresponding translated proteins or sequences thereof, one of ordinary skill in the art will recognize that the terms PD-1 and CD279 are generally nominally interchangeable.
Programmed cell death-ligand 1 or programmed death-ligand 1 (PD-L1), also known as B7 homolog 1 (B7-H1), is a 272 amino acid long type I transmembrane protein found as a surface marker on many different cell types. PD-L1 is the primary ligand for PD-1 and results in inhibition of T cell cytotoxicity and cytokine production. Cancer cells such as HCC cells utilize this immune checkpoint by up-regulating PD-L1 expression, resulting in dysfunctional anti-tumor immunity of proximal T cells. Viruses have also been observed to modulate the PD-1/PD-L1 pathway to suppress host immune responses. Hepatitis b virus has been shown to up-regulate PD-L1 in infected hepatocytes and PD-1 in related T cells. The PD-L1 protein (NCBI accession No. NP-054862.1) is expressed by cluster of differentiation 274 (CD 274) transcript (NCBI accession No. NM-014143.4). In some preferred embodiments, PD-L1 is a human PD-L1 protein and CD274 is a human CD274 transcript or gene on chromosome 9. It should be understood that when considering nucleic acids (DNA or RNA) or corresponding translated proteins or sequences thereof, one of ordinary skill in the art will recognize that the terms PD-L1 and CD274 are generally nominally interchangeable.
Definition of the definition
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications, and other publications cited herein are incorporated by reference in their entirety unless otherwise indicated. In the event that publications and patents or patent applications incorporated by reference conflict with the disclosures contained in this specification, this specification intends to replace and/or take precedence over any such conflicting material. Where there are multiple definitions for terms herein, the definitions in this section control unless otherwise indicated.
Whenever a group is described as "optionally substituted," the group may be unsubstituted or substituted with one or more of the indicated substituents. Also, when a group is described as "unsubstituted or substituted," if substituted, the one or more substituents may be selected from one or more of the indicated substituents. If no substituent is indicated, it is intended that the indicated "optionally substituted" or "substituted" group may be substituted with one or more groups (such as 1, 2 or 3 groups) independently and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl), (heterocyclyl) alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanate, isothiocyanate, nitro, azido, silyl, sulfinyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amine and di-substituted amine.
As used herein, "C" wherein "a" and "b" are integers a To C b "refers to the number of carbon atoms of an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms of a ring in a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group. That is, an alkyl, alkenyl, alkynyl, cycloalkyl ring, cycloalkenyl ring, aryl ring, heteroaryl ring, or heterocyclyl ring may contain "a" to "b" (inclusive). Thus, for example, "C 1 To C 4 Alkyl "groups refer to all alkyl groups having 1 to 4 carbons, i.e., CH 3 -、CH 3 CH 2 -、CH 3 CH 2 CH 2 -、(CH 3 ) 2 CH-、CH 3 CH 2 CH 2 CH 2 -、CH 3 CH 2 CH(CH 3 ) -and (CH) 3 ) 3 C-. If "a" and "b" are not specified with respect to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl groups, it should be assumed that what is depicted in these definitionsThe broadest range as described.
As used herein, "alkyl" refers to a straight or branched hydrocarbon chain containing a fully saturated (no double or triple bonds) hydrocarbon group. An alkyl group may have from 1 to 20 carbon atoms (whenever it occurs herein, a numerical range such as "1 to 20" means each integer within the given range; e.g., "1 to 20 carbon atoms" means an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the definition of the invention also covers the term "alkyl" which occurs without a numerical range specified). The alkyl group may also be a medium size alkyl group having 1 to 10 carbon atoms. The alkyl group may also be a lower alkyl group having 1 to 6 carbon atoms. The alkyl group of the compound may be designated as "C 1 -C 4 Alkyl "or similar designations. By way of example only, "C 1 -C 4 Alkyl "indicates the presence of one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and hexyl. The alkyl group may be substituted or unsubstituted.
As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. The length of the alkenyl group may vary. For example, alkenyl can be C 2-4 Alkenyl, C 2-6 Alkenyl or C 2-8 Alkenyl groups. Examples of alkenyl groups include allenyl, vinylmethyl, and vinyl. The alkenyl group may be unsubstituted or substituted.
As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight or branched hydrocarbon chain. The length of the alkynyl group can vary. For example, alkynyl groups may be C 2-4 Alkynyl, C 2-6 Alkynyl or C 2-8 Alkynyl groups. Examples of alkynyl groups include ethynyl and propynyl. Alkynyl groups may be unsubstituted or substituted.
As used herein, "cycloalkyl" refers to a fully saturated (no double or triple bonds) mono-or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused form. Cycloalkyl groups may contain 3 to 10 atoms in the ring. Containing 3 to 8 atoms in the ring or 3 to 6 atoms in the ring. Cycloalkyl groups may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
As used herein, "cycloalkenyl" refers to a mono-or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if more than one double bond is present, the double bond cannot form a fully delocalized pi-electron system throughout all rings (otherwise the group would be an "aryl" as defined herein). When composed of two or more rings, the rings may be joined together in a fused form. Cycloalkenyl groups may contain 3 to 10 atoms in the ring or 3 to 8 atoms in the ring. Cycloalkenyl groups may be unsubstituted or substituted.
As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system having a completely delocalized pi electron system throughout all rings (including fused ring systems in which two carbocycles share a chemical bond). The number of carbon atoms in the aryl group can vary. For example, the aryl group may be C 6 To C 14 Aryl group, C 6 To C 10 Aryl groups or C 6 An aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. The aryl group may be substituted or unsubstituted.
As used herein, "heteroaryl" refers to mono-, bi-and tricyclic aromatic ring systems (ring systems having a fully delocalized pi-electron system) containing one or more heteroatoms (e.g., 1 to 5 heteroatoms) that are elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. The number of atoms in the ring of the heteroaryl group can vary. For example, a heteroaryl group may contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings, such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, thiazole, 1,2, 3-thiadiazole, 1,2, 4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups may be substituted or unsubstituted.
As used herein, "heterocyclyl" refers to mono-, bi-and tricyclic ring systems wherein the carbon atoms together with 1 to 5 heteroatoms constitute the ring system. The heterocyclic ring may optionally contain one or more unsaturated bonds positioned in such a way that a fully delocalized pi-electron system does not occur throughout all rings. The number of atoms in the ring of the heterocyclyl group may vary. For example, a heterocyclyl group may contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur, and nitrogen. The heterocyclic ring may also contain one or more carbonyl or thiocarbonyl functional groups, so that this definition includes oxo-and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused form. In addition, any nitrogen in the heterocyclyl may be quaternized. The heterocyclyl group may be unsubstituted or substituted. Examples of such "heterocyclyl" groups include, but are not limited to, 1, 3-dioxin, 1, 3-dioxane, 1, 4-dioxane, 1, 2-dioxolane, 1, 3-dioxolane, 1, 4-dioxolane, 1, 3-oxathiolane, 1, 4-oxathiolane, 1, 3-dithiolane, 1, 4-oxathiolane, tetrahydro-1, 4-thiazine, 2H-1, 2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, barbituric acid, thiobarbituric acid, and the like dihydro uracil, trioxane, hexahydro-1, 3, 5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidinedione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxo-pyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiomorpholine sulfoxide, thiomorpholine sulfone, and benzo-fused analogues thereof (e.g., benzoimidazolone, tetrahydroquinoline and 3, 4-methylenedioxyphenyl).
As used herein, "aryl (alkyl)" refers to an aryl group attached as a substituent via a lower alkylene group. The lower alkylene of aryl (alkyl) and aryl groups may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenyl (alkyl), 3-phenyl (alkyl), and naphthyl (alkyl).
As used herein, "heteroaryl (alkyl)" refers to a heteroaryl group attached as a substituent via a lower alkylene group. Lower alkylene and heteroaryl groups of heteroaryl (alkyl) groups may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienyl (alkyl), 3-thienyl (alkyl), furyl (alkyl), thienyl (alkyl), pyrrolyl (alkyl), pyridyl (alkyl), isoxazolyl (alkyl), imidazolyl (alkyl), and benzofused analogs thereof.
"heterocyclyl (alkyl)" refers to a heterocyclic group attached as a substituent via a lower alkylene group. Lower alkylene of heterocyclyl (alkyl) and heterocyclyl may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl (methyl), piperidin-4-yl (ethyl), piperidin-4-yl (propyl), tetrahydro-2H-thiopyran-4-yl (methyl) and 1, 3-thiazinan-4-yl (methyl).
"lower alkylene group" is a straight chain-CH that forms a bond to connect a molecular fragment via its terminal carbon atom 2 -a tether group. In some embodiments, the lower alkylene may include 1, 2, 3, 4, 5, or 6 carbons. Examples include, but are not limited to, methylene (-CH) 2 (-), ethylene (-CH) 2 CH 2 (-), propylene (-CH) 2 CH 2 CH 2 (-) and butylene (-CH) 2 CH 2 CH 2 CH 2 -). The lower alkylene group may be substituted by replacing one or more hydrogens of the lower alkylene group with one or more substituents listed according to the definition of "substituted".
As used herein, "alkoxy" refers to the formula-OR, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl), OR heterocyclyl (alkyl) as defined herein. A non-limiting list of alkoxy groups are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, phenoxy and benzoyloxy. In some cases, the alkoxy group may be-OR, where R is unsubstituted C 1-4 An alkyl group. Alkoxy groups may be substituted or unsubstituted.
As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl), or heterocyclyl (alkyl) attached as a substituent via a carbonyl group. Examples include formyl, acetyl, propionyl, benzoyl and acryloyl. Acyl groups may be substituted or unsubstituted.
As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced with hydroxyl groups. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2, 2-dihydroxyethyl. Hydroxyalkyl groups may be substituted or unsubstituted.
As used herein, "haloalkyl" refers to an alkyl group (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl) in which one or more of the hydrogen atoms are replaced with a halogen. Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl. Haloalkyl groups may be substituted or unsubstituted.
As used herein, "haloalkoxy" refers to a compound in which one or more of the hydrogen atomsA plurality of halogen-substituted O-alkyl groups (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. In some cases, haloalkoxy may be-OR, wherein R is C substituted with 1, 2, OR 3 halogens 1-4 An alkyl group. Haloalkoxy groups may be substituted or unsubstituted.
"oxysulfide" group refers to an "-SR" group wherein R may be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl), or heterocyclyl (alkyl). The oxysulfide group can be substituted or unsubstituted.
"sulfinyl" group refers to an "-S (=o) -R" group in which R may be the same as defined with respect to the sulfinyl group. Sulfinyl groups may be substituted or unsubstituted.
"sulfonyl" group refers to an "SO" group in which R may be the same as defined with respect to the sulfinyl group 2 An R' group. Sulfonyl groups may be substituted or unsubstituted.
"O-carboxy" group refers to a "RC (=o) O-group where R may be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl), or heterocyclyl (alkyl) as defined herein. The O-carboxy group may be substituted or unsubstituted.
The terms "ester" and "C-carboxyl" refer to the same "-C (=o) OR" group in which R may be as defined with respect to O-carboxyl. The esters and C-carboxyl groups may be substituted or unsubstituted.
"thiocarbonyl" group refers to a "-C (=s) R" group wherein R may be the same as defined with respect to the O-carboxyl group. Thiocarbonyl groups may be substituted or unsubstituted.
"Trihalomethylsulfonyl" group means an "X" wherein each X is halogen 3 CSO 2 - "group.
The term "trihalomethylsulfonylamino" refers to a radical wherein each X is halogen and R A "X" is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl) 3 CS(O) 2 N(R A ) - "group.
The term "amino" as used herein refers to-NH 2 A group.
As used herein, the term "hydroxy" refers to an-OH group.
"cyano" group refers to the "-CN" group.
The term "azido" as used herein refers to-N 3 A group.
"isocyanate" group refers to an "-NCO" group.
"thiocyanate" group refers to an "-SCN" group.
"Isothiocyanate" group refers to the "-NCS" group.
"mercapto" group refers to an "-SH" group.
"carbonyl" group refers to a-C (=o) -group.
"S-sulfonylamino" group means where R A And R is B -SO that can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl), or heterocyclyl (alkyl) 2 N(R A R B ) "group". The S-sulfonylamino group may be substituted or unsubstituted.
"N-sulfonylamino" group means where R and R A "RSO" which may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl), or heterocyclyl (alkyl) 2 N(R A ) - "group. The N-sulfonylamino group may be substituted or unsubstituted.
"O-carbamoyl" group means where R A And R is B -OC (=o) N (R) which may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl) A R B ) "baseA bolus. O-carbamoyl may be substituted or unsubstituted.
"N-carbamoyl" groups refer to those wherein R and R A "ROC (=o) N (R) which may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl), or heterocyclyl (alkyl) A ) - "group. The N-carbamoyl group may be substituted or unsubstituted.
"O-thiocarbamoyl" group refers to a group wherein R A And R is B -OC (=s) -N (R) which may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl) A R B ) "group". The O-thiocarbamoyl group may be substituted or unsubstituted.
"N-thiocarbamoyl" group refers to a group wherein R and R A "ROC (=s) N (R) which may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl), or heterocyclyl (alkyl) A ) - "group. The N-thiocarbamoyl group may be substituted or unsubstituted.
"C-amido" group refers to where R A And R is B -C (=o) N (R) which may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl) A R B ) "group". The C-amido group may be substituted or unsubstituted.
"N-acylamino" group means where R and R A "RC (=O) N (R) which may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl), or heterocyclyl (alkyl) A ) - "group. The N-amido group may be substituted or unsubstituted.
"Mono-substituted amine" means "-NHR A ", wherein R is A Can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). The mono-substituted amine may be substituted or unsubstituted. In some cases, the mono-substituted amine may be-NHR A Wherein R is A May be unsubstituted C 1-6 Alkyl or unsubstituted or substituted benzyl.
"di-substituted amine" means "-NR A R B ", wherein R is A And R is B Can independently be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl), or heterocyclyl (alkyl). The mono-substituted amine may be substituted or unsubstituted. In some cases, the mono-substituted amine may be-NR A R B Wherein R is A And R is B Can independently be unsubstituted C 1-6 Alkyl or unsubstituted or substituted benzyl.
As used herein, the term "halogen atom" or "halogen" means any of the radioactively stable atoms in column 7 of the periodic table of elements, such as fluorine, chlorine, bromine and iodine.
Where the number of substituents (e.g., haloalkyl) is not specified, one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C 1 To C 3 Alkoxyphenyl "may include one or more of the same or different alkoxy groups containing one, two or three atoms.
As used herein, unless otherwise indicated, the abbreviations for any protecting group, amino acid, and other compound conform to their common usage, accepted abbreviations, or IUPAC-IUB biochemical nomenclature committee (see biochem.11:942-944 (1972)).
The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is applied and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of a compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts may also be obtained by reacting a compound with an organic acid such as an aliphatic or aromatic carboxylic or sulfonic acid (e.g., formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid). Pharmaceutical salts may also be obtained by reacting a compound with a base to form a salt, such as an ammonium salt (e.g., an ammonium salt or a triethylammonium salt), an alkali metal salt (such as a lithium, sodium, or potassium salt), an alkaline earth metal salt (such as a calcium or magnesium salt), an organic base (such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, C 1 -C 7 Salts of alkylamines, cyclohexylamines, triethanolamine, ethylenediamine) and salts formed by reaction with amino acids such as arginine and lysine.
Terms and phrases used in this application, and particularly in the appended claims, and variations thereof, should be construed to be open ended, and not limiting, unless otherwise specifically noted. For the foregoing examples, the term "including" should be construed as "including but not limited to", etc.; as used herein, the term "comprising" is synonymous with "comprising," "containing," or "characterized as" and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term "having" is to be construed as "having at least"; the term "comprising" should be interpreted as "including but not limited to"; the term "example" is used to provide an illustrative example of the item in question, rather than an exhaustive or limiting list thereof. Furthermore, the term "comprising" should be interpreted as synonymous with the phrase "having at least" or "comprising at least". The term "comprising" when used in the context of a compound or composition means that the compound or composition includes at least the recited feature or component, but may also include additional features or components.
For substantially any plural and/or singular terms used herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. For clarity, various singular/plural permutations may be explicitly stated herein. The indefinite article "a" or "an" does not exclude a plurality.
It will be appreciated that in any of the compounds described herein having one or more chiral centers, each center may independently be in the (R) configuration or the (S) configuration, or mixtures thereof, if absolute stereochemistry is not explicitly indicated. Thus, the compounds provided herein can be enantiomerically pure enantiomerically enriched racemic mixtures or diastereomerically pure diastereomerically enriched stereoisomeric mixtures. Furthermore, it should be understood that in any of the compounds described herein having one or more double bonds that produce a geometric isomer that may be defined as E or Z, each double bond may independently be E or Z or a mixture thereof. Also, it should be understood that in any of the compounds described, all tautomeric forms are also intended to be included.
It is to be understood that where the compounds disclosed herein have an valency less than full, they are filled with hydrogen or isotopes thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).
It is understood that the compounds described herein may be isotopically labeled. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements, for example. Each chemical element as represented in the structure of the compound may comprise any isotope of the element. For example, in the structure of a compound, the presence of a hydrogen atom in the compound may be explicitly disclosed or understood. At any position of the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, unless the context clearly indicates otherwise, reference to a compound herein encompasses all possible isotopic forms.
For the range values provided, it is understood that each intervening value, between the upper and lower limit of that range, is encompassed within the embodiments.
Compounds of formula (I)
Examples of embodiments of the present application include the following:
embodiment 1
A compound of formula (I), or a pharmaceutically acceptable salt thereof, having the structure:
wherein: a is that 1 May beB 1 May beEach X is 1 May be selected from CH and N (nitrogen); x is X 2 May be O (oxygen); x is X 3 May be selected from CH, C-halo, and N; y is Y 1 May be selected from N (nitrogen) and CH; y is Y 2 May be selected from N (nitrogen) and CH; y is Y 3 May be selected from N (nitrogen) and CH; y is Y 4 May be selected from N (nitrogen) and CH; y is Y 5 Can be selected from N (nitrogen), CH and C-OCH 3 ；Y 6 Can be selected from N and CR 5c ；Y 7 Can be CR 5e ；Y 8 Can be CR 5f The method comprises the steps of carrying out a first treatment on the surface of the Each R 1a Can be selected from-C 1-4 Alkyl, -C 1-4 Haloalkyl, -CH 2 (C 3-6 Monocyclic cycloalkyl) -C 2-4 Alkyl (C) 1-4 Alkoxy), -C 2-4 Alkyl (C) 1-4 Haloalkoxy) -CH 2 (4-to 6-membered monocyclic heterocyclyl) and-CH 2 (5-to 6-membered monocyclic heteroaryl); each R 1b Can be selected from-N (R) m1 )R n1 and-R x1 ；R 1c Can be selected from-N (R) m1 )R n1 and-R x1 ；R 1d Can be selected from hydrogen, -CH 3 、-CH 2 CH 3 、-OH、-OCH 3 and-F; r is R 1e Can be selected from hydrogen, -CH 3 、-CH 2 CH 3 and-F; r is R 1f Can be selected from hydrogen, -CH 3 、-CH 2 CH 3 、-OH、-OCH 3 and-F; r is R 1g Can be selected from hydrogen, -CH 3 、-CH 2 CH 3 and-F; r is R 2a 、R 2b 、R 2c 、R 2e 、R 2g 、R 2h May be independently selected from hydrogen and halogen; r is R 2d And R is 2f Can be independently selected from hydrogen, halogen, cyano, -CH 3 、-CH 2 CH 3 、-CH 2 OH、-OCH 3 and-SCH 3 ；R 3a Can be selected from H (hydrogen), -CH 3 、-CF 3 and-CHF 2 ；R 4a Is selected from H (hydrogen), halogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -CH 2 R 4b and-C (CH) 3 )R 4b ；R 4b Can be selected from-N (R) m2 )R n2 and-R y1 ；R 5a Can be selected from hydrogen, -CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group; r is R 5b Can be selected from hydrogen, -CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group; r is R 5c Can be selected from hydrogen, -CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group; r is R 5b Can be selected from hydrogen, -CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group; r is R 5e Can be selected from hydrogen, halogen and-CH 3 ；R 5f Can be selected from hydrogen, halogen, -OH, -CN and-CH 3 ；R m1 Can be selected from hydrogen and C 1-4 Alkyl, C 3-6 Monocyclic cycloalkyl, C 5-12 Bicyclic cycloalkyl, 5-or 6-membered monocyclic heteroaryl, 4-to 7-membered monocyclic heterocyclyl, 8-to 11-membered fused heteroaryl, 8-to 11-membered fused heterocyclyl and-R x2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the monocyclic heteroaryl, the bicyclic heteroaryl, the monocyclic heterocyclyl, and the bicyclic heterocyclyl may contain at least one atom or group of atoms independently selected from the group consisting of: o (oxygen), S (sulfur), C (=o), S (=o) 2 And N (nitrogen); wherein said-C 1-4 The alkyl group may be optionally substituted with one or two or three substituents independently selected from: halogen, cyano, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR Z1 、-C(＝O)NHS(＝O) 2 R Z3 、-C(＝O)N(R Z1 )R Z2 、-S(＝O) 2 R Z3 、-S(＝O) 2 N(R Z1 )R Z2 、-N(R Z1 )C(＝O)R Z3 、-N(R Z1 )S(＝O)R Z3 、-N(R Z1 )C(＝O)N(R Z2 )R Z3 and-N (R) Z1 )S(＝O)N(R Z2 )R Z3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C 3-6 Monocyclic cycloalkyl, the C 5-12 Bicyclic cycloalkyl, the 5-or 6-membered monocyclic heteroaryl, the 4-to 7-membered monocyclic heterocyclyl, the 8-to 11-membered fused heteroaryl, and the 8-to 11-membered fused heterocyclyl may be optionally substituted with one, two, three, or four substituents independently selected from: halogen, cyano, -C 1-4 Alkyl, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR Z1 、-C(＝O)OR Z1 、-C(＝O)NHS(＝O) 2 R Z3 、-C(＝O)N(R Z1 )R Z2 、-S(＝O) 2 R Z3 、-S(＝O) 2 N(R Z1 )R Z2 、-N(R Z1 )C(＝O)R Z3 、-N(R Z1 )S(＝O)R Z3 、-N(R z1 )C(＝O)N(R Z2 )R Z3 and-N (R) Z1 )S(＝O)N(R Z2 )R Z3 The method comprises the steps of carrying out a first treatment on the surface of the And R is n1 Can be hydrogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, C 3-6 Monocyclic Cycloalkyl (CH) 2 ) -OR-C (=o) OR Z4 ；R m2 Can be selected from-CH 3 、-C 2-4 Alkyl, -C 1-4 Haloalkyl and-R y2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said-C 2-4 Alkyl is optionally substituted with hydroxy; r is R n2 Can be selected from H (hydrogen), -C 1-4 Alkyl and-C 1-4 A haloalkyl group; r is R x1 Can be selected from:
/>wherein R is x1 Optionally substituted with one or two substituents independently selected from: halogen, cyano, -C 1-4 Alkyl, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR Z1 、-C(＝O)NHS(＝O) 2 R Z3 、-C(＝O)N(R Z1 )R Z2 、-S(＝O) 2 R Z3 、-S(＝O) 2 N(R Z1 )R Z2 、-N(R Z1 )C(＝O)R Z3 、-N(R Z1 )S(＝O)R Z3 、-N(R Z1 )C(＝O)N(R Z1 )R Z3 and-N (R) Z1 )S(＝O) 2 N(R Z2 )R Z3 ；R x2 Can be selected from: /> R y1 Can be selected from: /> /> Wherein R is y1 Optionally substituted with one or two substituents independently selected from: halogen, cyano, -C 1-4 Alkyl, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR W1 、-C(＝O)NHS(＝O) 2 R W3 、-C(＝O)N(R W1 )R W2 、-S(＝O) 2 R W3 、-S(＝O)N(R W1 )R W2 、-N(R W1 )C(＝O)R W3 、-N(R W1 )S(＝O)R W3 、-N(R W1 )C(＝O)N(R W2 )R W3 and-N (R) W1 )S(＝O)N(R W2 )R W3 ；R y2 Can be selected from: m 1 、m 2 、m 3 、n 1 、n 2 and n 3 May independently be 1 or 2; m is m 4 And n 4 May independently be 0, 1 or 2; m is m 5 And n 5 May independently be 1, 2, 3 or 4; each R X3 Can be independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C (=o) R Z3 、-C(＝O)OR Z1 、-S(＝O) 2 R Z1 、-C(＝O)N(R Z1 )R Z2 and-S (=o) N (R Z1 )R Z2 The method comprises the steps of carrying out a first treatment on the surface of the Each R Y3 Can be independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C (=o) R W3 、-C(＝O)OR W3 、-S(＝O) 2 R W3 、-C(＝O)N(R W1 )R W2 and-S (=o) N (R W1 )R W2 ；R Z1 And R is Z2 Can be independently selected from hydrogen, -C 1-4 Alkyl and-C 1-4 A haloalkyl group; or R is Z1 And R is Z2 May together form a monocyclic heterocyclic group when attached to the same nitrogen; r is R W1 And R is W2 Can be independently selected from hydrogen, -C 1-4 Alkyl and-C 1-4 A haloalkyl group; r is R Z3 And R is W3 Can be independently selected from hydrogen, -C 1-4 Alkyl and-C 1-4 A haloalkyl group; and R is Z4 Can be selected from hydrogen and C 1-4 Alkyl and optionally-C 1-4 Alkyl-substituted 5-to 6-membered monocyclic heterocyclyl (CH 2 ) -. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be wherein a 1 May beB 1 Can be +.> X 1 May be selected from CH and N (nitrogen); x is X 2 Can be selected from O (oxygen) and CH 2 ；Y 1 May be selected from N (nitrogen) and CH; y is Y 2 May be selected from N (nitrogen) and CH; y is Y 3 May be selected from N (nitrogen) and CH; y is Y 4 May be selected from N (nitrogen) and CH; y is Y 5 Can be selected from N (nitrogen), CH and C-OCH 3 ；R 1a Can be selected from-C 1-4 Alkyl, -C 1-4 Haloalkyl, -CH 2 (C 3-6 Monocyclic cycloalkyl) and-CH 2 (4-to 6-membered monocyclic heterocyclyl) and-CH 2 (5-to 6-membered monocyclic heteroaryl); r is R 1b Can be selected from-N (R) m1 )R n1 and-R x1 ；R 1c Can be selected from-N (R) m1 )R n1 and-R x1 ；R 2a 、R 2b 、R 2c 、R 2e 、R 2g 、R 2h May be independently selected from hydrogen and halogen; r is R 2d And R is 2f Can be independently selected from hydrogen, halogen, cyano, -CH 3 、-CH 2 CH 3 、-CH 2 OH、-OCH 3 and-SCH 3 ；R 3a Can be selected from H (hydrogen), -CH 3 、-CF 3 and-CHF 2 ；R 4a Is selected from H (hydrogen), halogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -CH 2 R 4b and-C (CH) 3 )R 4b ；R 4b Can be selected from-N (R) m2 )R n2 and-R y1 ；R 5a Can be selected from-CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group; r is R 5b Can be selected from-CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group; r is R m1 Can be selected from hydrogen and C 1-4 Alkyl, C 3-6 Monocyclic cycloalkyl, C 5-12 Bicyclic cycloalkyl, 5-or 6-membered monocyclic heteroaryl, 4-to 7-membered monocyclic heterocyclyl, 8-to 11-membered fused heteroaryl, 8-to 11-membered fused heterocyclyl and-R x2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the monocyclic heteroaryl, the bicyclic heteroarylThe cycloheteroaryl, the monocyclic heterocyclyl, and the bicyclic heterocyclyl may contain at least one atom or group of atoms independently selected from the group consisting of: o (oxygen), S (sulfur), C (=o), S (=o) 2 And N (nitrogen); wherein said-C 1-4 The alkyl group may be optionally substituted with one or two or three substituents independently selected from: halogen, cyano, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR Z1 、-C(＝O)NHS(＝O) 2 R Z3 、-C(＝O)N(R Z1 )R Z2 、-S(＝O) 2 R Z3 、-S(＝O) 2 N(R Z1 )R Z2 、-N(R Z1 )C(＝O)R Z3 、-N(R Z1 )S(＝O)R Z3 、-N(R Z1 )C(＝O)N(R Z2 )R Z3 and-N (R) Z1 )S(＝O)N(R Z2 )R Z3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C 3-6 Monocyclic cycloalkyl, the C 5-12 Bicyclic cycloalkyl, the 5-or 6-membered monocyclic heteroaryl, the 4-to 7-membered monocyclic heterocyclyl, the 8-to 11-membered fused heteroaryl, and the 8-to 11-membered fused heterocyclyl may be optionally substituted with one or two or three substituents independently selected from: halogen, cyano, -C 1-4 Alkyl, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR Z1 、-C(＝O)NHS(＝O) 2 R Z3 、-C(＝O)N(R Z1 )R Z2 、-S(＝O) 2 R Z3 、-S(＝O) 2 N(R Z1 )R Z2 、-N(R Z1 )C(＝O)R Z3 、-N(R Z1 )S(＝O)R Z3 、-N(R z1 )C(＝O)N(R Z2 )R Z3 and-N (R) Z1 )S(＝O)N(R Z2 )R Z3 The method comprises the steps of carrying out a first treatment on the surface of the And R is n1 Can be hydrogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl or C 3-6 Monocyclic Cycloalkyl (CH) 2 )；R m2 Can be selected from-CH 3 、-C 2-4 Alkyl, -C 1-4 Haloalkyl and-R y2 Wherein said-C 2-4 Alkyl radicalOptionally substituted with hydroxy; r is R n2 Can be selected from H (hydrogen), -C 1-4 Alkyl and-C 1-4 A haloalkyl group; r is R x1 Can be selected from: /> Wherein R is x1 Optionally substituted with one or two substituents independently selected from: halogen, cyano, -C 1-4 Alkyl, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR Z1 、-C(＝O)NHS(＝O) 2 R Z3 、-C(＝O)N(R Z1 )R Z2 、-S(＝O) 2 R Z3 、-S(＝O) 2 N(R Z1 )R Z2 、-N(R Z1 )C(＝O)R Z3 、-N(R Z1 )S(＝O)R Z3 、-N(R Z1 )C(＝O)N(R Z1 )R Z3 and-N (R) Z1 )S(＝O) 2 N(R Z2 )R Z3 ；R x2 Can be selected from: /> />R y1 Can be selected from: wherein R is y1 Optionally substituted with one or two substituents independently selected from: halogen, cyano, -C 1-4 Alkyl, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR W1 、-C(＝O)NHS(＝O) 2 R W3 、-C(＝O)N(R W1 )R W2 、-S(＝O) 2 R W3 、-S(＝O)N(R W1 )R W2 、-N(R W1 )C(＝O)R W3 、-N(R W1 )S(＝O)R W3 、-N(R W1 )C(＝O)N(R W2 )R W3 and-N (R) W1 )S(＝O)N(R W2 )R W3 ；R y2 Can be selected from: /> />m 1 、m 2 、m 3 、n 1 、n 2 And n 3 May independently be 1 or 2; m is m 4 And n 4 May independently be 0, 1 or 2; m is m 5 And n 5 May independently be 1, 2, 3 or 4; each R X3 Can be independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C (=o) R Z3 、-C(＝O)OR Z1 、-S(＝O) 2 R Z1 、-C(＝O)N(R Z1 )R Z2 and-S (=o) N (R Z1 )R Z2 The method comprises the steps of carrying out a first treatment on the surface of the Each R Y3 Can be independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C (=o) R W3 、-C(＝O)OR W3 、-S(＝O) 2 R W3 、-C(＝O)N(R W1 )R W2 and-S (=o) N (R W1 )R W2 ；R Z1 、R Z2 、R W1 And R is W2 Can be independently selected from hydrogen, -C 1-4 Alkyl and-C 1-4 A haloalkyl group; and R is Z3 And R is W3 Can be independently selected from hydrogen, -C 1-4 Alkyl and-C 1-4 A haloalkyl group. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be wherein a 1 Can be +.> B 1 Can be +.> X 1 May be selected from CH and N (nitrogen); x is X 2 Can be selected from O (oxygen) and CH 2 ；Y 1 May be selected from N (nitrogen) and CH; y is Y 2 May be selected from N (nitrogen) and CH; y is Y 3 May be selected from N (nitrogen) and CH; y is Y 4 May be selected from N (nitrogen) and CH; y is Y 5 Can be selected from N (nitrogen), CH and C-OCH 3 ；Y 6 Can be selected from N and CR 5c ；Y 7 Can be CR 5e ；Y 8 Can be CR 5f ；R 1a Can be selected from-C 1-4 Alkyl, -C 1-4 Haloalkyl, -CH 2 (C 3-6 Monocyclic cycloalkyl) -CH 2 (4-to 6-membered monocyclic heterocyclyl) and-CH 2 (5-to 6-membered monocyclic heteroaryl); r is R 1b Can be selected from-N (R) m1 )R n1 and-R x1 ；R 1c Can be selected from-N (R) m1 )R n1 and-R x1 ；R 2a 、R 2b 、R 2c 、R 2e 、R 2g 、R 2h May be independently selected from hydrogen and halogen; r is R 2d And R is 2f Can be independently selected from hydrogen, halogen, cyano, -CH 3 、-CH 2 CH 3 、-CH 2 OH、-OCH 3 and-SCH 3 ；R 3a Can be selected from H (hydrogen), -CH 3 、-CF 3 and-CHF 2 ；R 4a Is selected from H (hydrogen), halogen, -C 1-4 Alkyl, -C 1-4 HaloalkanesRadical, -CH 2 R 4b and-C (CH) 3 )R 4b ；R 4b Can be selected from-N (R) m2 )R n2 and-R y1 ；R 5a Can be selected from hydrogen, -CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group; r is R 5b Can be selected from hydrogen, -CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group; r is R 5b Can be selected from hydrogen, -CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group; r is R 5b Can be selected from hydrogen, -CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group; r is R 5e Can be selected from hydrogen, halogen and-CH 3 ；R 5f Can be selected from hydrogen, halogen, -OH, -CN and-CH 3 ；R m1 Can be selected from hydrogen and C 1-4 Alkyl, C 3-6 Monocyclic cycloalkyl, C 5-12 Bicyclic cycloalkyl, 5-or 6-membered monocyclic heteroaryl, 4-to 7-membered monocyclic heterocyclyl, 8-to 11-membered fused heteroaryl, 8-to 11-membered fused heterocyclyl and-R x2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the monocyclic heteroaryl, the bicyclic heteroaryl, the monocyclic heterocyclyl, and the bicyclic heterocyclyl may contain at least one atom or group of atoms independently selected from the group consisting of: o (oxygen), S (sulfur), C (=o), S (=o) 2 And N (nitrogen); wherein said-C 1-4 The alkyl group may be optionally substituted with one or two or three substituents independently selected from: halogen, cyano, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR Z1 、-C(＝O)NHS(＝O) 2 R Z3 、-C(＝O)N(R Z1 )R Z2 、-S(＝O) 2 R Z3 、-S(＝O) 2 N(R Z1 )R Z2 、-N(R Z1 )C(＝O)R Z3 、-N(R Z1 )S(＝O)R Z3 、-N(R Z1 )C(＝O)N(R Z2 )R Z3 and-N (R) Z1 )S(＝O)N(R Z2 )R Z3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C 3-6 Monocyclic cycloalkyl, the C 5-12 Bicyclic cycloalkyl, the 5-or 6-membered monocyclic heteroaryl, the 4-to 7-membered monocyclic heterocyclyl, the 8-to 11-membered fused heteroarylAryl and the 8-to 11-membered fused heterocyclic group may be optionally substituted with one or two or three substituents independently selected from: halogen, cyano, -C 1-4 Alkyl, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR Z1 、-C(＝O)NHS(＝O) 2 R Z3 、-C(＝O)N(R Z1 )R Z2 、-S(＝O) 2 R Z3 、-S(＝O) 2 N(R Z1 )R Z2 、-N(R Z1 )C(＝O)R Z3 、-N(R Z1 )S(＝O)R Z3 、-N(R z1 )C(＝O)N(R Z2 )R Z3 and-N (R) Z1 )S(＝O)N(R Z2 )R Z3 The method comprises the steps of carrying out a first treatment on the surface of the And R is n1 Can be hydrogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, C 3-6 Monocyclic Cycloalkyl (CH) 2 ) -OR-C (=o) OR Z4 ；R m2 Can be selected from-CH 3 、-C 2-4 Alkyl, -C 1-4 Haloalkyl and-R y2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said-C 2-4 Alkyl is optionally substituted with hydroxy; r is R n2 Can be selected from H (hydrogen), -C 1-4 Alkyl and-C 1-4 A haloalkyl group; r is R x1 Can be selected from: /> Wherein R is x1 Optionally substituted with one or two substituents independently selected from: halogen, cyano, -C 1-4 Alkyl, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR Z1 、-C(＝O)NHS(＝O) 2 R Z3 、-C(＝O)N(R Z1 )R Z2 、-S(＝O) 2 R Z3 、-S(＝O) 2 N(R Z1 )R Z2 、-N(R Z1 )C(＝O)R Z3 、-N(R Z1 )S(＝O)R Z3 、-N(R Z1 )C(＝O)N(R Z1 )R Z3 and-N (R) Z1 )S(＝O) 2 N(R Z2 )R Z3 ；R x2 Can be selected from: R y1 can be selected from: wherein R is y1 Optionally substituted with one or two substituents independently selected from: halogen, cyano, -C 1-4 Alkyl, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR W1 、-C(＝O)NHS(＝O) 2 R W3 、-C(＝O)N(R W1 )R W2 、-S(＝O) 2 R W3 、-S(＝O)N(R W1 )R W2 、-N(R W1 )C(＝O)R W3 、-N(R W1 )S(＝O)R W3 、-N(R W1 )C(＝O)N(R W2 )R W3 and-N (R) W1 )S(＝O)N(R W2 )R W3 ；R y2 Can be selected from: />
m 1 、m 2 、m 3 、n 1 、n 2 And n 3 May independently be 1 or 2; m is m 4 And n 4 May independently be 0, 1 or 2; m is m 5 And n 5 May independently be 1, 2, 3 or 4; each R X3 Can be independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C (=o) R Z3 、-C(＝O)OR Z1 、-S(＝O) 2 R Z1 、-C(＝O)N(R Z1 )R Z2 and-S (=o) N (R Z1 )R Z2 The method comprises the steps of carrying out a first treatment on the surface of the Each R Y3 Can be independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C (=o) R W3 、-C(＝O)OR W3 、-S(＝O) 2 R W3 、-C(＝O)N(R W1 )R W2 and-S (=o) N (R W1 )R W2 ；R Z1 And R is Z2 Can be independently selected from hydrogen, -C 1-4 Alkyl and-C 1-4 A haloalkyl group; or R is Z1 And R is Z2 May together form a monocyclic heterocyclic group when attached to the same nitrogen; r is R W1 And R is W2 Can be independently selected from hydrogen, -C 1-4 Alkyl and-C 1-4 A haloalkyl group; r is R Z3 And R is W3 Can be independently selected from hydrogen, -C 1-4 Alkyl and-C 1-4 A haloalkyl group; and R is Z4 Can be selected from hydrogen and C 1-4 Alkyl and optionally-C 1-4 Alkyl-substituted 5-to 6-membered monocyclic heterocyclyl (CH 2 ) -. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be wherein a 1 May be B 1 Can be +.> Each X is 1 May be selected from CH and N (nitrogen); x is X 2 May be O (oxygen); x is X 3 May be selected from CH, C-halo, and N; y is Y 1 May be selected from N (nitrogen) and CH; y is Y 2 May be selected from N (nitrogen) and CH; y is Y 3 May be selected from N (nitrogen) and CH; y is Y 4 May be selected from N (nitrogen) and CH; y is Y 5 Can be selected from N (nitrogen), CH and C-OCH 3 ；Y 6 Can be selected from N and CR 5c ；Y 7 Can be CR 5e ；Y 8 Can be CR 5f The method comprises the steps of carrying out a first treatment on the surface of the Each R 1a Can be selected from-C 1-4 Alkyl, -C 1-4 Haloalkyl, -CH 2 (C 3-6 Monocyclic cycloalkyl) -C 2-4 Alkyl (C) 1-4 Alkoxy), -C 2-4 Alkyl (C) 1-4 Haloalkoxy) -CH 2 (4-to 6-membered monocyclic heterocyclyl) and-CH 2 (5-to 6-membered monocyclic heteroaryl); each R 1b Can be selected from-N (R) m1 )R n1 and-R x1 ；R 1c Can be selected from-N (R) m1 )R n1 and-R x1 ；R 1d Can be selected from hydrogen, -CH 3 、-CH 2 CH 3 、-OH、-OCH 3 and-F; r is R 1e Can be selected from hydrogen, -CH 3 、-CH 2 CH 3 and-F; r is R 1f Can be selected from hydrogen, -CH 3 、-CH 2 CH 3 、-OH、-OCH 3 and-F; r is R 1g Can be selected from hydrogen, -CH 3 、-CH 2 CH 3 and-F; r is R 2a 、R 2b 、R 2c 、R 2e 、R 2g 、R 2h May be independently selected from hydrogen and halogen; r is R 2d And R is 2f Can be independently selected from hydrogen, halogen, cyano, -CH 3 、-CH 2 CH 3 、-CH 2 OH、-OCH 3 and-SCH 3 ；R 3a Can be selected from H (hydrogen), -CH 3 、-CF 3 and-CHF 2 ；R 4a Is selected from H (hydrogen), halogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -CH 2 R 4b and-C (CH) 3 )R 4b ；R 4b Can be selected from-N (R) m2 )R n2 and-R y1 ；R 5a Can be selected from hydrogen, -CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group; r is R 5b Can be selected from hydrogen, -CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group; r is R 5b Can be selected from hydrogen, -CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group; r is R 5d Can be selected from hydrogen, -CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group; r is R 5e Can be selected from hydrogen, halogen and-CH 3 ；R 5f Can be selected from hydrogen, halogen, -OH, -CN and-CH 3 ；R m1 Can be selected from hydrogen and C 1-4 Alkyl, C 3-6 Monocyclic cycloalkyl, C 5-12 Bicyclic cycloalkyl, 5-or 6-membered monocyclic heteroaryl, 4-to 7-membered monocyclic heterocyclyl, 8-to 11-membered fused heteroaryl, 8-to 11-membered fused heterocyclyl and-R x2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the monocyclic heteroaryl, the bicyclic heteroaryl, the monocyclic heterocyclyl, and the bicyclic heterocyclyl may contain at least one atom or group of atoms independently selected from the group consisting of: o (oxygen), S (sulfur), C (=o), S (=o) 2 And N (nitrogen); wherein said-C 1-4 The alkyl group may be optionally substituted with one or two or three substituents independently selected from: halogen, cyano, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR Z1 、-C(＝O)NHS(＝O) 2 R Z3 、-C(＝O)N(R Z1 )R Z2 、-S(＝O) 2 R Z3 、-S(＝O) 2 N(R Z1 )R Z2 、-N(R Z1 )C(＝O)R Z3 、-N(R Z1 )S(＝O)R Z3 、-N(R Z1 )C(＝O)N(R Z2 )R Z3 and-N (R) Z1 )S(＝O)N(R Z2 )R Z3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C 3-6 Monocyclic cycloalkyl, the C 5-12 Bicyclic cycloalkyl, the 5-or 6-membered monocyclic heteroaryl, the 4-to 7-membered monocyclic heterocyclyl, the 8-to 11-membered fused heteroaryl, and the 8-to 11-membered fused heterocyclyl may be optionally substituted with one or two or three substituents independently selected from: halogen, cyano, -C 1-4 Alkyl, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR Z1 、-C(＝O)NHS(＝O) 2 R Z3 、-C(＝O)N(R Z1 )R Z2 、-S(＝O) 2 R Z3 、-S(＝O) 2 N(R Z1 )R Z2 、-N(R Z1 )C(＝O)R Z3 、-N(R Z1 )S(＝O)R Z3 、-N(R z1 )C(＝O)N(R Z2 )R Z3 and-N (R) Z1 )S(＝O)N(R Z2 )R Z3 The method comprises the steps of carrying out a first treatment on the surface of the And R is n1 Can be hydrogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, C 3-6 Monocyclic Cycloalkyl (CH) 2 ) -OR-C (=o) OR Z4 ；R m2 Can be selected from-CH 3 、-C 2-4 Alkyl, -C 1-4 Haloalkyl and-R y2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said-C 2-4 Alkyl is optionally substituted with hydroxy; r is R n2 Can be selected from H (hydrogen), -C 1-4 Alkyl and-C 1-4 A haloalkyl group; r is R x1 Can be selected from: />/> Wherein R is x1 Optionally substituted with one or two substituents independently selected from: halogen, cyano, -C 1-4 Alkyl, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR Z1 、-C(＝O)NHS(＝O) 2 R Z3 、-C(＝O)N(R Z1 )R Z2 、-S(＝O) 2 R Z3 、-S(＝O) 2 N(R Z1 )R Z2 、-N(R Z1 )C(＝O)R Z3 、-N(R Z1 )S(＝O)R Z3 、-N(R Z1 )C(＝O)N(R Z1 )R Z3 and-N (R) Z1 )S(＝O) 2 N(R Z2 )R Z3 ；R x2 Can be selected from: /> R y1 Can be selected from: /> />Wherein R is y1 Optionally substituted with one or two substituents independently selected from: halogen, cyano, -C 1-4 Alkyl, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR W1 、-C(＝O)NHS(＝O) 2 R W3 、-C(＝O)N(R W1 )R W2 、-S(＝O) 2 R W3 、-S(＝O)N(R W1 )R W2 、-N(R W1 )C(＝O)R W3 、-N(R W1 )S(＝O)R W3 、-N(R W1 )C(＝O)N(R W2 )R W3 and-N (R) W1 )S(＝O)N(R W2 )R W3 ；R y2 Can be selected from: m 1 、m 2 、m 3 、n 1 、n 2 and n 3 May independently be 1 or 2; m is m 4 And n 4 May independently be 0, 1 or 2; m is m 5 And n 5 May independently be 1, 2, 3 or 4; each R X3 Can be independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C (=o) R Z3 、-C(＝O)OR Z1 、-S(＝O) 2 R Z1 、-C(＝O)N(R Z1 )R Z2 and-S (=o) N (R Z1 )R Z2 The method comprises the steps of carrying out a first treatment on the surface of the Each R Y3 Can be independently selected from hydrogen, halogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C (=o) R W3 、-C(＝O)OR W3 、-S(＝O) 2 R W3 、-C(＝O)N(R W1 )R W2 and-S (=o) N (R W1 )R W2 ；R Z1 And R is Z2 Can be independently selected from hydrogen, -C 1-4 Alkyl and-C 1-4 A haloalkyl group; or R is Z1 And R is Z2 May together form a monocyclic heterocyclic group when attached to the same nitrogen; r is R W1 And R is W2 Can be independently selected from hydrogen, -C 1-4 Alkyl and-C 1-4 A haloalkyl group; r is R Z3 And R is W3 Can be independently selected from hydrogen, -C 1-4 Alkyl and-C 1-4 A haloalkyl group; and R is Z4 Can be selected from hydrogen and C 1-4 Alkyl and optionally-C 1-4 Alkyl-substituted 5-to 6-membered monocyclic heterocyclyl (CH 2 )-。
Embodiment 2
The compound of embodiment 1 wherein A 1 May be
Embodiment 3
The compound of embodiment 2, wherein X 1 May be CH.
Embodiment 4
The compound of embodiment 2, wherein X 1 May be N (nitrogen).
Embodiment 5
The compound according to any one of embodiments 2 to 4, wherein R 1a Can be-C 1-4 An alkyl group. C (C) 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
Embodiment 6
According to embodiments 2 to 4The compound of any one of claims, wherein R 1a Can be-C 1-4 Haloalkyl groups, such as-CF 3 、-CHF 2 、-CH 2 F、-CCl 3 、-CHCl 2 、-CH 2 Cl、-CH 2 CF 3 and-CH 2 CHF 2 。
Embodiment 7
The compound according to any one of embodiments 2 to 4, wherein R 1a Can be-C 2-4 Alkyl (C) 1-4 Alkoxy) or-C 2-4 Alkyl (C) 1-4 Haloalkoxy).
Embodiment 8
The compound according to any one of embodiments 2 to 4, wherein R 1a Can be selected from-CH 2 (C 3-6 Monocyclic cycloalkyl) -CH 2 (4-to 6-membered monocyclic heterocyclyl) and-CH 2 (5-to 6-membered monocyclic heteroaryl). Exemplary monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, the-CH 2 4-to 6-membered monocyclic heterocyclic group (4-to 6-membered monocyclic heterocyclic group) and/or the-CH 2 The 5-to 6-membered monocyclic heteroaryl (5-to 6-membered monocyclic heteroaryl) may include one or more ring atoms (such as 1, 2 or 3) selected from N (nitrogen), O (oxygen) and S (sulfur).
Embodiment 9
The compound according to any one of embodiments 2 to 8, wherein R 1b Can be-N (R) m1 )R n1 。
Embodiment 10
The compound of embodiment 9, wherein R n1 May be hydrogen, such that R 1b Can be-NH (R) m1 )。
Embodiment 11
The compound according to any one of embodiments 2 to 8, wherein R n1 Can be-C (=O) OR Z4 . In some embodiments, R Z4 May be C 1-4 An alkyl group. In other embodiments, R Z4 Can be optionally-C 1-4 Alkyl-substituted 5-to 6-membered monocyclic heterocyclyl (CH 2 )-。
Embodiment 12
The compound according to any one of embodiments 9 to 11, wherein R m1 Can be optionally-C (=o) OR Z1 substituted-C 1-4 Alkyl or 4-to 7-membered monocyclic heterocyclyl optionally substituted with hydroxy. C (C) 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. In some embodiments, the 4-to 7-membered monocyclic heterocyclyl optionally substituted with hydroxy may include one or more ring atoms (such as 1, 2, or 3) selected from N (nitrogen), O (oxygen), and S (sulfur).
Embodiment 13
The compound of embodiment 12 wherein R m1 May be
Embodiment 14
The compound of embodiment 12 wherein R m1 May be tetrahydrofuran or tetrahydro-2H-pyran, each of which is optionally substituted with hydroxy.
Embodiment 15
The compound of embodiment 14 wherein R m1 May be/> In some embodiments, R m1 Can be +.>In other embodiments, R m1 Can be +.>
Embodiment 16
The compound according to any one of embodiments 9 to 11, wherein R m1 Can be-R x2 。
Embodiment 17
The compound of embodiment 16, wherein-R x2 May beIn some embodiments, -R x2 Can be +.>
Embodiment 18
The compound according to any one of embodiments 2 to 8, wherein R 1b Can be-R x1 。
Embodiment 19
The compound of embodiment 18, wherein-R x1 Can be selected from:
embodiment 20
The compound of embodiment 19, wherein-R x1 Can be selected from:/> in some embodiments, -R x1 Can be selected from:
embodiment 21
The compound of embodiment 1 wherein A 1 May be
Embodiment 22
The compound of embodiment 21 wherein X 1 May be CH.
Embodiment 23
The compound of embodiment 21 wherein X 1 May be N (nitrogen).
Embodiment 24
The compound according to any one of embodiments 21 to 23, wherein R 1a Can be-C 1-4 Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
Embodiment 25
The compound according to any one of embodiments 21 to 23, wherein R 1a Can be-C 1-4 A haloalkyl group. Suitable C 1-4 Examples of haloalkyl groups include, but are not limited to, -CF 3 、-CHF 2 、-CH 2 F、-CCl 3 、-CHCl 2 、-CH 2 Cl、-CH 2 CF 3 and-CH 2 CHF 2 。
Embodiment 26
According to embodiments 21 to 23The compound of any one of claims, wherein R 1a Can be selected from-CH 2 (C 3-6 Monocyclic cycloalkyl) -CH 2 (4-to 6-membered monocyclic heterocyclyl) and-CH 2 (5-to 6-membered monocyclic heteroaryl). Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, the-CH 2 4-to 6-membered monocyclic heterocyclic group (4-to 6-membered monocyclic heterocyclic group) and/or the-CH 2 The 5-to 6-membered monocyclic heteroaryl (5-to 6-membered monocyclic heteroaryl) may include one or more ring atoms (such as 1, 2 or 3) selected from N (nitrogen), O (oxygen) and S (sulfur).
Embodiment 27
The compound of any one of embodiments 21 to 26, wherein R 1c Can be-N (R) m1 )R n1 。
Embodiment 28
The compound of embodiment 27, wherein R n1 May be hydrogen.
Embodiment 29
The compound of embodiment 27, wherein R n1 Can be-C (=O) OR Z4 . In some embodiments, R Z4 May be C 1-4 An alkyl group. In other embodiments, R Z4 Can be optionally-C 1-4 Alkyl-substituted 5-to 6-membered monocyclic heterocyclyl (CH 2 )-。
Embodiment 30
The compound of any one of embodiments 27 to 29, wherein R m1 May be C 3-6 Monocyclic cycloalkyl, optionally by-C (=o) OR Z1 substituted-C 1-4 Alkyl or 4-to 7-membered monocyclic heterocyclyl optionally substituted with hydroxy. Exemplary C 1-4 Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. In some embodiments, the 4-to 7-membered monocyclic heterocyclyl optionally substituted with hydroxy may include one or more ring atoms selected from N (nitrogen), O (oxygen) and S (sulfur) (such as1, 2 or 3).
Embodiment 31
The compound of embodiment 30, wherein R m1 May be
Embodiment 32
The compound of embodiment 30, wherein R m1 May be oxetane (oxetane), tetrahydrofuran or tetrahydro-2H-pyran, each optionally substituted with hydroxy.
Embodiment 33
The compound of embodiment 32, wherein R m1 May be In some embodiments, R m1 Can be +. >In other embodiments, R m1 Can be +.>
Embodiment 34
The compound of any one of embodiments 27 to 29, wherein R m1 Can be-R x2 。
Embodiment 35
The compound of embodiment 34 wherein-R x2 May beIn some embodiments, -R x2 Can be +.>
Embodiment 36
The compound of any one of embodiments 21 to 26, wherein R 1c Can be-R x1 。
Embodiment 37
The compound of embodiment 36, wherein-R x1 Can be selected from:
embodiment 38
The compound of embodiment 37, wherein-R x1 Can be selected from: in some embodiments, -R x1 Can be selected from: />
Embodiment 39
The compound of embodiment 1 wherein A 1 Is that
Embodiment 40
The compound of embodiment 39 wherein X 1 CH.
Embodiment 41
The compound of embodiment 39 wherein X 1 Is N.
Embodiment 42
The compound of any one of embodiments 39 to 41, wherein X 3 CH.
Embodiment 43
The compound of any one of embodiments 39 to 41, wherein X 3 Is a C-halo group.
Embodiment 44
The compound of any one of embodiments 39 to 41, wherein X 3 Is N.
Embodiment 45
The compound of any of embodiments 39 through 44 wherein R 1a is-C 1-4 An alkyl group. By way of example, X 1a Can be-CH 3 。
Embodiment 46
The compound of any of embodiments 39 through 44 wherein R 1a is-C 1-4 A haloalkyl group.
Embodiment 47
The compound of any of embodiments 39 through 44 wherein R 1a Selected from the group consisting of: -CH 2 (C 3-6 Monocyclic cycloalkyl) -CH 2 (4-to 6-membered monocyclic heterocyclyl) and-CH 2 (5-to 6-membered monocyclic heteroaryl).
Embodiment 48
The compound of any one of embodiments 39 to 47, wherein R 1b is-N (R) m1 )R n1 。
Embodiment 49
The compound of any one of embodiments 39 to 47, wherein R n1 Is hydrogen.
Embodiment 50
The compound of any one of embodiments 39 to 47, wherein R n1 is-C (=O) OR Z4 。
Embodiment 51
The compound of any one of embodiments 39 to 50, wherein R m1 Is hydrogen.
Embodiment 52
The compound of any one of embodiments 39 to 50, wherein R m1 Is optionally-C (=o) OR Z1 substituted-C 1-4 Alkyl or 4-to 7-membered monocyclic heterocyclyl optionally substituted with hydroxy.
Embodiment 53
The compound of any one of embodiments 39 to 50, wherein R m1 Is C 5 Monocyclic cycloalkyl or C 6 A monocyclic cycloalkyl group.
Embodiment 54
The compound of embodiment 52, wherein R m1 Is that
Embodiment 55
The compound of embodiment 52, wherein R m1 Tetrahydrofuran or tetrahydro-2H-pyran each optionally substituted by hydroxy, or optionally substituted by-C (=O) R Z1 Substituted piperidines.
Embodiment 56
The compound of embodiment 55, wherein R m1 Is R is m1 May be In some embodiments, R m1 Can be +.>In other embodiments, R m1 Can be +.>
Embodiment 57
The compound of any one of embodiments 39 to 50, wherein R m1 is-R x2 。
Embodiment 58
The compound of embodiment 57 wherein-R x2 Is thatIn some embodiments, -R x2 Is->
Embodiment 59
The compound of embodiment 57 wherein-R x2 Is thatOr->
Embodiment 60
The compound of any one of embodiments 39 to 47, wherein R 1b is-R x1 。
Embodiment 61
The compound of embodiment 60, wherein-R x1 Selected from the group consisting of: in some embodiments, R X1 Can be +.>For example, R x1 May beOne of R X3 May be hydrogen; and another R X3 Can be-C (=O) OR Z1 Wherein R is Z1 Can be-C 1-4 An alkyl group.
Embodiment 62
The compound of embodiment 61, wherein-R x1 Selected from the group consisting of:
in some embodiments, -R x1 Can be selected from:
embodiment 63
The compound according to any one of embodiments 39 to 62, wherein R 1d Is hydrogen.
Embodiment 64
The compound according to any one of embodiments 39 to 62, wherein R 1d is-OH.
Embodiment 65
The compound according to any one of embodiments 39 to 62, wherein R 1d is-CH 3 。
Embodiment 66
The compound according to any one of embodiments 39 to 62, wherein R 1d is-F.
Embodiment 67
The compound of any of embodiments 63 to 66, wherein R 1e Is hydrogen.
Embodiment 68
The compound of any of embodiments 63 to 66, wherein R 1e is-CH 3 。
Embodiment 69
The compound of any of embodiments 63 to 68, wherein R 1f Is hydrogen.
Embodiment 70
The compound of any of embodiments 63 to 68, wherein R 1f is-CH 3 。
Embodiment 71
The compound of any of embodiments 63 to 70, wherein R 1g Is hydrogen.
Embodiment 72
According to an embodiment1 to 71, wherein B 1 May be
Embodiment 73
The compound of embodiment 72 wherein Y 1 May be N (nitrogen).
Embodiment 74
The compound of embodiment 72 wherein Y 1 May be CH.
Embodiment 75
The compound of any of embodiments 72 to 74, wherein Y 2 May be N (nitrogen).
Embodiment 76
The compound of any of embodiments 72 to 74, wherein Y 2 CH.
Embodiment 77
The compound of any of embodiments 72 to 76, wherein R 3a May be H (hydrogen).
Embodiment 78
The compound of any of embodiments 72 to 76, wherein R 3a Can be-CH 3 。
Embodiment 79
The compound of any of embodiments 72 to 76, wherein R 3a May be-CF 3 。
Embodiment 80
The compound of any of embodiments 72 to 76, wherein R 3a Can be-CHF 2 。
Embodiment 81
The compound of any one of embodiments 1 to 71, wherein B 1 May be/>
Embodiment 82
The compound of embodiment 81 wherein Y 3 May be N (nitrogen).
Embodiment 83
The compound of embodiment 81 wherein Y 3 May be CH.
Embodiment 84
The compound of any one of embodiments 81 to 83 wherein Y 4 May be N (nitrogen).
Embodiment 84
The compound of any one of embodiments 81 to 83 wherein Y 4 May be CH.
Embodiment 86
The compound of any one of embodiments 81 to 85 wherein Y 5 May be N (nitrogen).
Embodiment 87
The compound of any one of embodiments 81 to 85 wherein Y 5 May be CH.
Embodiment 88
The compound of any one of embodiments 81 to 85 wherein Y 5 Can be C-OCH 3 。
Embodiment 89
The compound of any one of embodiments 81 to 88, wherein R 4a May be H (hydrogen).
Embodiment 90
The compound of any one of embodiments 81 to 88, wherein R 4a May be halogen. In some embodiments, R 4a May be fluorine. In other embodiments, R 4a May be chlorine.
Embodiment 91
The compound of any one of embodiments 81 to 88, wherein R 4a Can be-C 1-4 Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
Embodiment 92
The compound of any one of embodiments 81 to 88, wherein R 4a Can be-C 1-4 A haloalkyl group. For example, R 4a Can be selected from-CF 3 、-CHF 2 、-CH 2 F、-CCl 3 、-CHCl 2 、-CH 2 Cl、-CH 2 CF 3 or-CH 2 CHF 2 。
Embodiment 93
The compound of any one of embodiments 81 to 88, wherein R 4a Can be-CH 2 R 4b 。
Embodiment 94
The compound of any one of embodiments 81 to 88, wherein R 4a Can be-C (CH) 3 )R 4b 。
Embodiment 95
The compound of embodiment 93 or 94 wherein R 4b Can be-N (R) m2 )R n2 。
Embodiment 96
The compound of embodiment 95 wherein R m2 Can be-CH 3 。
Embodiment 97
The compound of embodiment 95 wherein R m2 Can be-C 2-4 Alkyl groups such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
Embodiment 98
The compound of embodiment 95 wherein R m2 Can be-C 1-4 A haloalkyl group. In some embodiments, R m2 Can be selected from-CF 3 、-CHF 2 、-CH 2 F、-CCl 3 、-CHCl 2 、-CH 2 Cl、-CH 2 CF 3 and-CH 2 CHF 2 。
Embodiment 99
The compound of embodiment 95 wherein R m2 Can be-C substituted by hydroxy 2-4 An alkyl group. Suitable C 2-4 Examples of alkyl groups include ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
Embodiment 100
The compound of any one of embodiments 95 to 99, wherein R n2 May be H (hydrogen).
Embodiment 101
The compound of any one of embodiments 95 to 99, wherein R n2 Can be-C 1-4 An alkyl group. For example, R n2 Can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
Embodiment 102
The compound of any one of embodiments 95 to 99, wherein R n2 Can be-C 1-4 A haloalkyl group. For example, R n2 May be-CF 3 、-CHF 2 、-CH 2 F、-CCl 3 、-CHCl 2 、-CH 2 Cl、-CH 2 CF 3 or-CH 2 CHF 2 。
Embodiment 103
The compound of embodiment 93 or 94 wherein R 4b Can be-R y1 。
Embodiment 104
The compound of any one of embodiments 1 to 71, wherein B 1 May be
Embodiment 105
The compound of embodiment 104, R 5a May be hydrogen.
Embodiment 106
The compound of embodiment 104 wherein R 5a Can be-CH 3 。
Embodiment 107
The compound of embodiment 104 wherein R 5a Can be-C 2-4 An alkyl group. Exemplary C 2-4 Alkyl groups include ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
Embodiment 108
The compound of embodiment 104 wherein R 5a Can be-C 2-4 A haloalkyl group. Suitable C 2-4 Haloalkyl includes, but is not limited to, -CH 2 CF 3 、-CH 2 CHF 2 、-CH 2 CH 2 CF 3 、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CH 2 CF 3 and-CH 2 CH 2 CH 2 CHF 2 。
Embodiment 109
The compound of any one of embodiments 104 to 108, wherein R 5b Is hydrogen.
Embodiment 110
The compound of any one of embodiments 104 to 108, wherein R 5b Can be-CH 3 。
Embodiment 111
The compound of any one of embodiments 104 to 108, wherein R 5b Can be-C 2-4 Alkyl groups such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
Embodiment 112
The compound of any one of embodiments 104 to 108, wherein R 5b Can be-C 2-4 A haloalkyl group. Exemplary C 2-4 Haloalkyl includes, but is not limited to, -CH 2 CF 3 、-CH 2 CHF 2 、-CH 2 CH 2 CF 3 、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CH 2 CF 3 and-CH 2 CH 2 CH 2 CHF 2 。
Embodiment 113
The compound of any of embodiments 104 to 112, wherein Y 6 May be N (nitrogen).
Embodiment 114
The compound of any of embodiments 104 to 112, wherein Y 6 Can be CR 5c 。
Embodiment 115
The compound of embodiment 114, wherein R 5c May be hydrogen.
Embodiment 116
The compound of embodiment 114, wherein R 5c Can be-CH 3 。
Embodiment 117
The compound of embodiment 114, wherein R 5c Can be-C 2-4 Alkyl groups such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
Embodiment 118
The compound of embodiment 114, wherein R 5c Can be-C 2-4 A haloalkyl group. C (C) 2-4 A non-limiting list of haloalkyl groups includes, but is not limited to, -CH 2 CF 3 、-CH 2 CHF 2 、-CH 2 CH 2 CF 3 、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CH 2 CF 3 and-CH 2 CH 2 CH 2 CHF 2 。
Embodiment 119
The compound of any one of embodiments 1 to 71, wherein B 1 May be
Embodiment 120
The compound of embodiment 119, wherein R 5d May be hydrogen.
Embodiment 121
The compound of embodiment 119, wherein R 5d Can be-CH 3 。
Embodiment 122
The compound of embodiment 119, wherein R 5d Can be-C 2-4 An alkyl group.
Embodiment 123
The compound of embodiment 119, wherein R 5d Can be-C 2-4 A haloalkyl group.
Embodiment 124
The compound according to any one of embodiments 119 to 123, wherein Y 7 Can be CR 5e Wherein R is 5e Is hydrogen.
Embodiment 125
According to any one of embodiments 119 to 123Said compound wherein Y 7 Can be CR 5e Wherein R is 5e Halogen, such as fluorine or chlorine.
Embodiment 126
The compound according to any one of embodiments 119 to 123, wherein Y 7 Can be CR 5e Wherein R is 5e is-CH 3 。
Embodiment 127
The compound of any of embodiments 119 to 126, wherein Y 8 Can be CR 5f Wherein R is 5f May be hydrogen.
Embodiment 128
The compound of any of embodiments 119 to 126, wherein Y 8 Can be CR 5f Wherein R is 5f May be halogen such as F, cl or Br.
Embodiment 129
The compound of any of embodiments 119 to 126, wherein Y 8 Can be CR 5f Wherein R is 5f Can be-OH.
Embodiment 130
The compound of any of embodiments 119 to 126, wherein Y 8 Can be CR 5f Wherein R is 5f May be CN.
Embodiment 131
The compound of any of embodiments 119 to 126, wherein Y 8 Can be CR 5f Wherein R is 5f Can be-CH 3 。
Embodiment 132
The compound of any one of embodiments 1 to 131, wherein R 2a 、R 2b 、R 2c 、R 2e 、R 2g And R is 2g Each may be hydrogen.
Implementation of the embodimentsScheme 133
The compound of any one of embodiments 1 to 131, wherein R 2a 、R 2c 、R 2e 、R 2g And R is 2h Each hydrogen; and R is 2b Is halogen.
Embodiment 134
The compound of any one of embodiments 1 to 131, wherein R 2b 、R 2c 、R 2e 、R 2g And R is 2h Each hydrogen; and R is 2a Is halogen.
Embodiment 135
The compound of any one of embodiments 1 to 134, wherein R 2d And R is 2f Each may be hydrogen. In some embodiments, R 2d And R is 2f Each may be fluorine. In other embodiments, R 2d And R is 2f Each may be chlorine.
Embodiment 136
The compound of any one of embodiments 1 to 134, wherein R 2d And R is 2f Can each be-CH 3 。
Embodiment 137
The compound of any one of embodiments 1 to 134, wherein R 2d May be halogen; and R is 2f Can be-CH 3 。
Embodiment 138
The compound of any one of embodiments 1 to 134, wherein R 2d is-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the And R is 2f Is halogen.
Embodiment 139
The compound of any one of embodiments 1 to 134, wherein R 2d Is cyano; and R is 2f Is halogen.
Embodiment 140
The compound of any one of embodiments 1 to 134, wherein R 2d is-OCH 3 The method comprises the steps of carrying out a first treatment on the surface of the And R is 2f Is halogen.
Embodiment 141
The compound of any of embodiments 133 through 135 or 137 through 140 wherein the halogen can be chloro or fluoro.
Embodiment 142
A compound according to embodiment 1 selected from:
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or a pharmaceutically acceptable salt of any of the foregoing.
Embodiment 143
A compound according to embodiment 1 selected from:
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or a pharmaceutically acceptable salt of any of the foregoing.
Embodiment 144
A compound according to embodiment 1 selected from:
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or a pharmaceutically acceptable salt of any of the foregoing.
Embodiment 145
A compound according to embodiment 1 selected from:
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or a pharmaceutically acceptable salt of any of the foregoing.
Embodiment 146
A compound according to embodiment 1 selected from:
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or a pharmaceutically acceptable salt of any of the foregoing.
Embodiment 147
A compound according to embodiment 1 selected from:
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or a pharmaceutically acceptable salt of any of the foregoing compounds.
Embodiment 148
A compound according to embodiment 1 selected from: a-1 to A-139, B-1, B-2, B-3, B-4, C-1, D-2, D-3, D-4, D-5, D-6, D-7, D-8a, D-8B, D-10, D-11, D-12, D-13, D-14, D-15, D-16, D-17, D-18, D-19, E-1, E-2, E-3, F-1, G-1, H-1, I-1, J-2, J-3, J-4, K-1a, K-1B, L-1a, L-1B, M-1a, M-1B, M-2a, M-2B, M-3a and M-3B, or a pharmaceutically acceptable salt of any of the foregoing.
Embodiment 149
A pharmaceutical composition, which may comprise an effective amount of a compound according to any one of embodiments 1 to 148, or a pharmaceutically acceptable salt thereof, and an excipient.
Embodiment 150
A method for treating hepatitis b in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof.
Embodiment 151
A method for treating hepatocellular carcinoma (HCC) in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof.
Embodiment 152
The method according to any one of embodiments 150 to 151, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.
Embodiment 153
A compound according to any one of embodiments 1 to 148, or a pharmaceutically acceptable salt thereof, for use in the treatment of hepatitis b.
Embodiment 154
A compound according to any one of embodiments 1 to 148, or a pharmaceutically acceptable salt thereof, for use in the treatment of hepatocellular carcinoma (HCC).
Embodiment 155
The compound of any one of embodiments 153-154, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.
Embodiment 156
Use of a compound according to any one of embodiments 1 to 148, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of hepatitis b.
Embodiment 157
Use of a compound according to any one of embodiments 1 to 148, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of hepatocellular carcinoma (HCC).
Embodiment 158
The use according to any one of embodiments 156 to 157, which may further comprise administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy or antiviral therapy.
Preparation method
In this section, as in all other sections, references to formula (I) and pharmaceutically acceptable salts thereof include all other subgroups and examples thereof as provided herein, unless the context indicates otherwise. The general preparation of some representative examples of compounds of formula (I) is described herein, and they are generally prepared from starting materials that are commercially available or prepared by standard synthetic procedures used by those skilled in the art.
In this section, as in all other sections, references to formula (I), formula (II), formula (III) and formula (IV) and pharmaceutically acceptable salts thereof include all other subgroups and examples thereof as provided herein, unless the context indicates otherwise. General preparation of some representative examples of compounds of formula (I), formula (II), formula (III) and formula (IV) are described herein, and they are generally prepared from starting materials that are commercially available or prepared by standard synthetic procedures used by those skilled in the art.
The following schemes represent exemplary preparations of compounds of formula (I), formula (II), formula (III) and formula (IV), and pharmaceutically acceptable salts thereof. The compounds of formula (I), formula (II), formula (III) and formula (IV), and pharmaceutically acceptable salts thereof, may also be prepared by a combination of similar reaction schemes as described in the following general schemes with standard synthetic procedures used by those skilled in the art.
Unless otherwise indicated or apparent from the context, all variables shown in a scheme are defined as referred to herein.
General scheme 1
Generally, compounds of formula (I) can be prepared according to scheme 1. In scheme 1, LG is defined as Br or Cl. All other variables in scheme 1 are defined according to the description provided herein. In scheme 1, the following reaction conditions apply: (1) The presence of a suitable catalyst (e.g., bis (triphenylphosphine) palladium (II) dichloride), in a suitable solvent such as 1, 4-dioxane, with a suitable base (e.g., KOAc), at a suitable temperature (e.g., 90 ℃); (2) In the presence of a suitable catalyst, for example bis (triphenylphosphine) palladium (II) dichloride, in a suitable solvent, such as 1, 4-dioxane, there is a suitable base, such as K 2 CO 3 At a suitable temperature (e.g., 90 ℃).
General scheme 2
Generally, compounds of formula (II) and formula (III) can be prepared according to scheme 2. In scheme 2, the following reaction conditions apply: (1) In the presence of a suitable catalyst, for example bis (triphenylphosphine) palladium (II) dichloride, in a suitable solvent, such as 1, 4-dioxane, there is a suitable base, for example K 2 CO 3 ) At a suitable temperature (e.g., 90 ℃); (2) A suitable reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, is present in a suitable solvent (e.g., DCM or MeOH) at a suitable temperature, such as about 20 ℃.
General scheme 3
Generally, intermediates used in the preparation of compounds of formulas (I), (II) and (III) can be prepared according to scheme 3 using suitable protecting groups. In scheme 3, the following reaction conditions apply: (1) In the presence of a suitable catalyst (e.g., bis (triphenylphosphine) palladium (II) dichloride), in a suitable solvent such as 1, 4-dioxane, there is a suitable base (e.g., K 2 CO 3 ) At a suitable temperature (e.g., 90 ℃); (2) The presence of a suitable acid (e.g., HCL in 1, 4-dioxane) in a suitable solvent (e.g., t-BuOH) at a suitable temperature (e.g., 100 ℃); (3) The presence of a suitable base (e.g., potassium t-butoxide) in a suitable solvent such as THF at a suitable temperature (e.g., 20 ℃); (4) Suitable coupling reagents (e.g., N' -tetramethyl chloroformyl amine hexafluorophosphate and N-methylimidazole) are present in a suitable solvent (e.g., acetonitrile) at a suitable temperature (e.g., 50 ℃).
General scheme 4
Generally, compounds of formula (IV) are also prepared according to scheme 4. In scheme 4, the following reaction conditions apply: (1) The presence of a suitable base (e.g., potassium t-butoxide) in a suitable solvent such as THF at a suitable temperature (e.g., 20 ℃); (2) In the presence of a suitable catalyst (e.g., bis (triphenylphosphine) palladium (II) dichloride), in a suitable solvent such as 1, 4-dioxane, there is a suitable base (e.g., K 2 CO 3 ) At a suitable temperature (e.g., 90 ℃); (3) In the presence of a suitable catalyst (e.g., bis (triphenylphosphine) palladium (II) dichloride), in a suitable solvent such as 1, 4-dioxane, there is a suitable base (e.g., K 2 CO 3 ) In a proper position(e.g., 90 ℃ C.). (4) In the presence of a suitable acid such as concentrated hydrochloric acid in a suitable solvent (e.g., H 2 A mixture of O and THF) at a suitable temperature (e.g., about 20 ℃); (5) In the presence of a suitable reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, in a suitable solvent (e.g., DCM or MeOH) at a suitable temperature (such as about 20deg.C).
Pharmaceutical composition
Some embodiments described herein relate to a pharmaceutical composition comprising, consisting essentially of, or consisting of: an effective amount of a compound described herein, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof. The pharmaceutical compositions described herein are suitable for human and/or veterinary use.
As used herein, the terms "function" and "functional" refer to biological, enzymatic, or therapeutic functions.
The term "effective amount" or "effective dose" is used to indicate the amount of active compound or agent that elicits the biological or medicinal response being indicated. For example, an effective amount of a compound may be an amount required to alleviate or ameliorate symptoms of a disease or to extend the survival of a subject being treated. The response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the ability of those skilled in the art, given the disclosure provided herein. The effective amount of a compound disclosed herein required as a dose will depend on the route of administration, the type of animal (including humans) being treated, and the physical characteristics of the particular animal being considered. The dose may be modulated to achieve the desired effect, but will depend on the following factors: such as weight, diet, concurrent medication, and other factors as will be appreciated by those skilled in the medical arts.
The term "pharmaceutically acceptable salts" includes relatively non-toxic inorganic and organic acid or base addition salts of the compositions, including but not limited to analgesics, therapeutic agents, other substances, and the like. Examples of pharmaceutically acceptable salts include those derived from inorganic acids such as hydrochloric acid and sulfuric acid, and those derived from organic acids such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Examples of suitable inorganic bases for salt formation include hydroxides, carbonates and bicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc, and the like. Salts may also be formed from suitable organic bases, including those that are non-toxic and strong enough to form such salts. For example, classes of such organic bases may include, but are not limited to, mono-, di-and tri-alkylamines, including methylamine, dimethylamine and triethylamine; mono-, di-or tri-hydroxyalkylamines, including monoethanolamine, diethanolamine and triethanolamine; amino acids including glycine, arginine, and lysine; guanidine; n-methyl glucamine; n-methyl glucamine; l-glutamine; n-methylpiperazine; morpholine; ethylenediamine; n-benzyl phenethylamine; trimethylolethane.
"formulation," "pharmaceutical composition," and "composition" as used interchangeably herein refer to equivalent terms of a composition of matter for administration to a subject.
The term "pharmaceutically acceptable" means compatible with the treatment of a subject, particularly a human.
The term "agent" refers to an active agent that is biologically active and useful in therapy. In addition, an "agent" may be synonymous with "at least one agent", "compound" or "at least one compound" and may refer to any form of agent, such as a derivative, analog, salt or prodrug thereof. The agents can exist in various forms, components of molecular complexes, and pharmaceutically acceptable salts (e.g., hydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate, tartrate, and salicylate). The term "agent" may also refer to any drug molecule or compound, therapeutic molecule or compound, matrix forming molecule or compound, polymers, synthetic molecules and compounds, natural molecules and compounds, and any combination thereof.
As used herein, the term "subject" has its ordinary meaning as understood in accordance with the present specification, and refers to an animal that is the subject of treatment, inhibition or amelioration, observation or experiment. "animal" has its ordinary meaning as understood in the present specification and includes cold and warm-blooded vertebrates and/or invertebrates such as fish, shellfish or reptiles, and in particular mammals. "mammal" has its ordinary meaning as understood in the present specification and includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cattle, horses, primates such as humans, monkeys, chimpanzees, or apes. In some embodiments, the subject is a human.
The correct formulation depends on the route of administration selected. Techniques for formulating and administering the compounds described herein are known to those skilled in the art. There are a variety of techniques in the art for administering a compound including, but not limited to, enteral, oral, rectal, topical, sublingual, buccal, intra-aural, epidural, epidermal, aerosol, parenteral delivery (including intramuscular, subcutaneous, intra-arterial, intravenous injection, portal intravenous, intra-articular, intradermal, intraperitoneal, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injection). The pharmaceutical compositions will generally be formulated according to the particular intended route of administration. The pharmaceutical composition may also be administered to isolated cells from a patient or individual, such as T cells, natural killer cells, B cells, macrophages, lymphocytes, stem cells, bone marrow cells, or hematopoietic stem cells.
The pharmaceutical compounds may also be administered in a local manner rather than a systemic manner, for example, via direct injection of the compounds into an organ, tissue, cancer, tumor or infected area, typically in the form of a depot or sustained release formulation. Furthermore, the compounds may be administered in targeted drug delivery systems, for example, in liposomes coated with tissue specific antibodies. Liposomes can be targeted to and selectively taken up by organs, tissues, cancers, tumors, or infected areas.
The pharmaceutical compositions disclosed herein may be manufactured in a manner known per se, for example by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes. As described herein, the compounds used in the pharmaceutical compositions may be provided as salts with pharmaceutically compatible counterions.
As used herein, "carrier" refers to a compound, particle, solid, semi-solid, liquid, or diluent that facilitates the passage, delivery, and/or binding of the compound to a cell, tissue, and/or body organ. For example, but not limited thereto, lipid Nanoparticles (LNPs) are one type of carrier that can encapsulate a compound as described herein or a pharmaceutically acceptable salt thereof, thereby protecting the compound as described herein or a pharmaceutically acceptable salt thereof from degradation during passage through the blood stream and/or facilitating delivery to a desired organ, such as the liver.
As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that is not pharmaceutically active but may be pharmaceutically necessary or desirable. For example, diluents may be used to increase the volume of a powerful drug product that is too small in mass to be manufactured and/or administered. It may also be a dissolved liquid for a pharmaceutical product to be administered by injection, ingestion or inhalation. A common form of diluent in the art is an aqueous buffer solution such as, but not limited to, phosphate buffered saline that mimics the composition of human blood.
The term "excipient" has its ordinary meaning as understood in the present specification and refers to an inert substance, compound, or material that is added to a pharmaceutical composition to provide the composition with, but is not limited to, volume, consistency, stability, cohesiveness, lubricity, disintegrating ability, and the like. Excipients having the desired properties include, but are not limited to, preservatives, adjuvants, stabilizers, solvents, buffers, diluents, solubilizers, detergents, surfactants, chelating agents, antioxidants, alcohols, ketones, aldehydes, ethylenediamine tetraacetic acid (EDTA), citric acid, salts, sodium chloride, sodium bicarbonate, sodium phosphate, sodium borate, sodium citrate, potassium chloride, potassium phosphate, magnesium sulfate, sugars, dextrose, fructose, mannose, lactose, galactose, sucrose, sorbitol, cellulose, serum, amino acids, polysorbate 20, polysorbate 80, sodium deoxycholate, taurodeoxycholate, magnesium stearate, octylphenol ethoxylate, benzethonium chloride, thimerosal, gelatin, esters, ethers, 2-phenoxyethanol, urea, or vitamins, or any combination thereof. The amount of excipient may be present in the pharmaceutical composition in a percentage of 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 100% w/w or any weight percentage within the range defined by any two of the foregoing numbers.
As used herein, the term "adjuvant" refers to a substance, compound or material that stimulates an immune response and increases the efficacy of protective immunity and is administered in conjunction with an immunogenic antigen, epitope or composition. Adjuvants are used to improve immune responses by being able to sustained release of antigens, up-regulate cytokines and chemokines, recruit cells at the site of administration, increase antigen uptake and presentation in antigen presenting cells, or activate antigen presenting cells and inflammasomes. Common adjuvants include, but are not limited to: alum, aluminum salt, aluminum sulfate, aluminum hydroxide, aluminum phosphate, calcium hydroxide, aluminum potassium sulfate, oil, mineral oil, paraffin oil, oil-in-water emulsion, detergent,Squalene, AS03, alpha-tocopherol, polysorbate 80, AS04, monophosphoryl lipid A, polysorbate, virions, nucleic acids, polyinosine, polycytidylic acid, saponin, QS-21, proteins, flagellin, cytokines, chemokines, IL-1, IL-2, IL-12, IL-15, IL-21, imidazoquinolines, cpG oligonucleotides, lipids, phospholipids, dioleoyl phosphatidylcholine (DOPC), trehalose dimycolate, peptidoglycans, bacterial extracts, lipopolysaccharides or Freund's adjuvant, or any combination thereof.
The term "purity" of any given substance, compound or material as used herein refers to the actual abundance of the substance, compound or material relative to the expected abundance. For example, a substance, compound, or material may be at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% pure, including all decimal places therebetween. Purity may be affected by unwanted impurities including, but not limited to, byproducts, isomers, enantiomers, degradation products, solvents, carriers, vehicles, or contaminants, or any combination thereof. Techniques by which purity can be measured include, but are not limited to, chromatography, liquid chromatography, gas chromatography, spectroscopy, UV-visible spectroscopy, infrared spectroscopy, mass spectrometry, nuclear magnetic resonance, gravimetric or titration methods, or any combination thereof.
Application method
Some embodiments disclosed herein relate to selecting a subject or patient in need thereof. In some embodiments, a patient is selected in need of treatment, inhibition, amelioration, prevention, or alleviation of a disease or condition associated with a PD-L1 disorder. In some embodiments, such diseases or conditions associated with PD-L1 dysregulation may include, for example, cancer, HCC, viral infection, or HBV. In some embodiments, a subject may be selected that has previously been treated for a disease or disorder described herein. In some embodiments, a subject that has been previously treated to be at risk of a disease or disorder described herein may be selected. In some embodiments, a subject who has developed a recurrence of a disease or disorder described herein may be selected. In some embodiments, a subject may be selected that has developed resistance to therapy for a disease or disorder described herein. In some embodiments, a subject may be selected that may have any combination of the foregoing selection criteria.
Known methods can be used to evaluate the efficacy and toxicity of the compounds disclosed herein and pharmaceutically acceptable salts thereof. A non-limiting list of potential advantages of the compounds described herein, or pharmaceutically acceptable salts thereof, include improved stability, increased safety profile, increased efficacy, increased binding to a target, increased specificity for a target (e.g., cancer cells or virus-infected cells).
As used herein, the terms "treatment", "therapeutic" or "therapy" have their ordinary meanings as understood in the present specification and do not necessarily mean to completely cure or eliminate a disease or disorder. As used herein, the term "treatment" or "treatment" (and as is well understood in the art) also means a method of achieving a beneficial or desired result (including clinical results) in a subject's condition. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread or spread of disease, delaying or slowing of disease progression, amelioration or palliation of the disease state, diminishment of recurrence and remission of the disease, whether partial or total, and whether detectable or undetectable. As used herein, "treatment" and "treatment" also include prophylactic treatment. The method of treatment comprises administering to the subject a therapeutically effective amount of an active agent. The administering step may consist of a single administration, or may comprise a series of administrations. The composition is administered to the subject in an amount and for a duration sufficient to treat the subject. The length of the treatment period depends on a variety of factors such as the severity of the condition, the age and genetic characteristics of the subject, the concentration of the active agent, the activity of the composition used in the treatment, or a combination thereof. It will also be appreciated that the effective dose of the agent for treatment or prevention may be increased or decreased during a particular treatment or prevention regimen. The variation in dosage may be produced and become apparent by standard diagnostic assays known in the art. In some cases, long-term administration may be required.
Some embodiments described herein relate to methods of treating, inhibiting, ameliorating, preventing, or slowing the diseases or conditions described herein. In some embodiments, the methods comprise administering to a subject identified as having a disease or disorder described herein an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating, inhibiting, ameliorating, preventing, or slowing a disease or disorder described herein. Still other embodiments described herein relate to the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, for treating, inhibiting, ameliorating, preventing, or slowing the diseases or conditions described herein.
Some embodiments described herein relate to methods for inhibiting replication of a cancer cell or virus, which methods may include contacting the cell or virus with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject identified as having cancer or a viral infection. Other embodiments described herein relate to the use of an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting cancer cell or viral replication. Still other embodiments described herein relate to an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, for inhibiting cancer cell or viral replication. In some embodiments, the cancer cell is an HCC cell. In some embodiments, the virus is hepatitis b.
Some embodiments described herein relate to methods for inhibiting cell proliferation, such as inhibiting cancer cells or cells infected with a virus, which methods may include administering to a subject identified as having a disease in which inhibition of cell proliferation is desired an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting cell proliferation, such as inhibiting cell proliferation of cancer cells or cells infected with a virus. Still other embodiments described herein relate to a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell proliferation, such as inhibiting cell proliferation of cancer cells or cells infected with a virus. In some embodiments, the cancer cell is an HCC cell. In some embodiments, the virus-infected cells are infected with hepatitis b virus.
Some embodiments described herein relate to methods of inducing apoptosis in a cell (e.g., a cancer cell or a virus-infected cell), which may include contacting the cell with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to the use of an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inducing apoptosis in a cell, such as a cancer cell or a cell infected with a virus. Still other embodiments described herein relate to the use of an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, for inducing apoptosis in a cell, such as a cancer cell or a virus-infected cell. In some embodiments, the cancer cell is an HCC cell. In some embodiments, the virus-infected cells are infected with hepatitis b virus.
Some embodiments described herein relate to methods of reducing the viability of a cell (e.g., a cancer cell or a virus-infected cell), which may include contacting the cell with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing the viability of a cell, such as a cancer cell or a cell infected with a virus. Still other embodiments described herein relate to the use of an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, for reducing the viability of a cell, such as a cancer cell or a virus-infected cell. In some embodiments, the cancer cell is an HCC cell. In some embodiments, the virus-infected cells are infected with hepatitis b virus.
The effective therapeutic daily amount can be determined from the test results by those skilled in the art of treatment of such diseases. An effective therapeutic daily amount will be about 0.005mg/kg to 50mg/kg, particularly 0.01mg/kg to 50mg/kg body weight, more particularly 0.01mg/kg to 25mg/kg body weight, preferably about 0.01mg/kg to about 15mg/kg, more preferably about 0.01mg/kg to about 10mg/kg, even more preferably about 0.01mg/kg to about 1mg/kg, most preferably about 0.05mg/kg to about 1mg/kg body weight.
In some embodiments, an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is administered more than once. In some embodiments, the compound described herein, or a pharmaceutically acceptable salt thereof, is administered every 1, 2, 3, 4, 5, 6, 7 days or 1, 2, 3, 4 weeks or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or 1, 2, 3, 4, 5 years or any period of time within the range defined by any two of the foregoing times, or a combination thereof. In some embodiments, at least one loading dose and at least one maintenance dose are administered to the subject, wherein the at least one loading dose is a higher dose of a compound described herein or a pharmaceutically acceptable salt thereof than the at least one maintenance dose.
As used herein, the term "combination therapy" is intended to define a therapy that includes the use of a combination of two or more pharmaceutical compounds/agents or therapies. Thus, references in this application to "combination therapy," "combination," and the use of a compound/agent "combination" may refer to a compound/agent administered as part of the same overall treatment regimen. Thus, the dose or timing of each of the two or more compounds/agents may be different: each may be administered simultaneously or at different times. Thus, the combined compounds/agents may be administered sequentially (e.g., before or after) or simultaneously in the same pharmaceutical formulation (i.e., together) or in different pharmaceutical formulations (i.e., separately). Each of the two or more compounds/agents in the combination therapy may also be different relative to the route of administration.
As used herein, the term "inhibitor" refers to an enzyme inhibitor or receptor inhibitor, which is a molecule that binds to an enzyme or receptor and reduces and/or blocks its activity. The term may relate to reversible or irreversible inhibitors.
The cancer may be treated with surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, or hormonal therapy. Any of these mentioned therapies may be used as a combination therapy in combination with another therapy. Chemotherapeutic compounds include, but are not limited to, alemtuzumab, altretamine, azacytidine (azacitidine), bendamustine (bendamustine), bleomycin (bleomycin), bortezomib (bortezomib), busulfan, cabazitaxel (cabazitaxel), capecitabine (capecitabine), carboplatin (carboplatin) carmofur (carmofur), carmustine (carmustine), chlorambucil (chlorrambucil), mechlorethamine (chlorrethane), cisplatin (cispetin), cladribine (cladribine), clofarabine (clofaberine), cyclophosphamide, cytarabine, dacarbazine (dacarbazine), dacarbazine (dactinomycin), daunorubicin (daunorubicin) Decitabine (Decistabine), denobizumab (Demostabine), docetaxel (docetaxel), doxorubicin (doxorubicin), epirubicin (epirubicin), estramustine (estramustine), etoposide (etoposide), everolimus (everolimus), fluorouridine, fludarabine (fludarabine), fluorouracil, fotemustine, gemcitabine (gemcitabine), gemtuzumab (gemtuzumab), hydroxyurea, temozolomab (ibritumab), idarubicin (idarubicin), ifosfamide, irinotecan (irinotecan), ixabepilone (ixabepilone), lomustine (spheroplatine), melphalan (mevalan), mercaptopurine, methotrexate (methotrexate), mitomycin (mitomycin), mitoxantrone (mitoxantrone), nedaplatin (nedaplatin), nelarabine (nilaparine), ofatumumab (olsalazine), oxaliplatin (oxaipine), paclitaxel, pemetrexed (pemetrexed), penstatin (pentastatin), pertuzumab (pertuzumab), procarbazine (procarbazine), raltitrexed (raltitrexed), streptozotocin (streptozotocin), tegafur (tegafur), temozolomide (temozolomide), temsirolimus (temsirolimus), teniposide (teniposide), thioguanine, topotecan (tometecan), tositumomab (tositumab), valrubicin (valbicin), base (vincristine), vincristine (vincristine), vinblastine (vinblastine), or any combination thereof (vinorelbine).
As used herein, the term "protein kinase inhibitor" refers to an inhibitor of a protein kinase, serine/threonine kinase, tyrosine kinase, or bispecific kinase for use in the treatment of cancer or other diseases. In some embodiments, the protein kinase inhibitor is a small molecule, a compound, a polysaccharide, a lipid, a peptide, a polypeptide, a protein, an antibody, a nucleoside analog, a nucleotide analog, a nucleic acid, or an oligonucleotide. In some embodiments of the present invention, in some embodiments, protein kinase inhibitors include, but are not limited to, alemtinib (acalabrutinib), adavitertib (adavitertib), afatinib (afatinib), aletinib (alcitinib), axitinib (axitinib), bimetinib (binimeinib), bosutinib (bosutinib), buganinib (briatinib), ceritinib (ceritinib), cetuximab (cetuximab), cobratinib (cobimab), crizotinib (crizotinib), carbotinib, dacatinib (dacomitinib), dasatinib (dasatinib), emtrictinib (entrectinib), erdasatinib), erlotinib (erlotinib), fostinib (mattinib), fostinib (fostanib) gefitinib, ibrutinib, imatinib, lapatinib, lenatinib, lortatinib, macatinib, molatinib, mubrinib, and lenatinib nilotinib (nilotinib), nildanib (nintedanib), omutinib (olmutinib), octtinib (osiertinib), pactinib (pacritinib), panitumumab (panitumab), pezopanib (pazopanib), pipratanib (pegaptanib), ponatinib (ponatinib), radotinib (radotinib), regorafenib (regorafenib), nostinib (rociletinib), ruxotinib (ruxolitinib), semantenib (selumetinib), semaxanib (semaxanib), sorafenib, sunitinib (sunitinib), SU6656, tivozanib (tivozanib), toreminib (toceranib), trametinib (trametinib), trastuzumab (trastuzumab), vandetanib (vanretanib) or vemurafenib (vemurafenib), or any combination thereof.
As used herein, the term "checkpoint inhibitor" refers to an immunotherapy that targets an immune checkpoint to stimulate immune function. In some embodiments, the checkpoint inhibitor is a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside analog, nucleotide analog, nucleic acid, or oligonucleotide. In some embodiments, the immune checkpoint is a PD-1/PD-L1 checkpoint. In some embodiments, the PD-1 checkpoint includes, but is not limited to, nivolumab, pamezizumab, swabbizumab (spartalizumab), cemipramiab Li Shan antibody (cemiplimab), karilizumab (camrelizumab), sildi Li Shan antibody (sintilimab), tirelizumab (tisrelizumab), terlipp Li Shan antibody (toripalimab), AMP-224, or AMP-514, or any combination thereof. In some embodiments, the PD-L1 checkpoint inhibitor includes, but is not limited to, atezolizumab (atezolizumab), avistuzumab (avelumab), durvauumab (KN 035), AUNP12, CA-170, or BMS-986189, or any combination thereof. In some embodiments, the immune checkpoint is a CTLA-4 checkpoint. In some embodiments, CTLA-4 checkpoint inhibitors include, but are not limited to, ipilimumab (ipilimumab) or tremelimumab (tremelimumab), or any combination thereof.
As used herein, the term "VEGF inhibitor" refers to an inhibitor of Vascular Endothelial Growth Factor (VEGF) or VEGF receptor (VEGFR). In some embodiments, the VEGF inhibitor is a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside analog, nucleotide analog, nucleic acid, or oligonucleotide. In some embodiments, the VEGF inhibitor includes, but is not limited to, aflibercept, axitinib, bevacizumab, brivaranib, cabotinib, ceridinib, lenvatinib, li Nifa, nipanib, pezopanib, pluratinib, ramucirumab (ramucirumab), regorafenib, simaxanib, sorafenib, sunitinib, tivozanib, torseminib, or vandetanib, or any combination thereof.
As used herein, the term "antiviral drug" refers to a pharmaceutical composition administered to treat a viral infection. In some embodiments, the viral infection is caused by adenovirus, ebola virus, coronavirus, epstein Barr Virus (EBV), friedel virus, hantavirus, hepatitis B Virus (HBV), hepatitis C Virus (HCV), herpes simplex virus, human Immunodeficiency Virus (HIV), human metapneumovirus, human Papilloma Virus (HPV), influenza virus, japanese encephalitis virus, kaposi's sarcoma-associated herpesvirus, lymphocytic choriomeningitis virus, parainfluenza virus, rabies virus, respiratory syncytial virus, rhinovirus, varicella zoster virus.
In some embodiments, the antiviral drug is a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside analog, nucleotide analog, nucleic acid, or oligonucleotide. In some embodiments, the antiviral drug is an interferon, a capsid assembly modulator, a sequence specific oligonucleotide, an entry inhibitor, or a small molecule immunomodulator. In some embodiments, the antiviral drug includes, but is not limited to, AB-423, AB-506, ABI-H2158, vebicor (ABI-HO 731), acyclovir (acyclovir), adaplamine (adaplamine), adefovir (adefovir), adefovir dipivoxil (adefovir dipivoxil), alafenamide (alafenamide), amantadine (amantadine), atazanavir (asunape vir), baalo Sha Weima Boschia (baloxavir marboxil), bei Kela, baciclovir (beclomethavir), boplaprevir (boceprevir), brivudine (brivudine), cidofovir (cidofovir), ci Lu Puwei (ciluprevir), clevidin (clevidin), cytaravidine (cyracavine), dacarbazole Lei Weier (daiplamid), dabaspride (asupir), valvir (valvidin), valvidin (valvidarabine), valproamide (valvidae), valaciclovir (valvidin) and valproate (valvidin) and valvidin (valvidin) are included in the form of one or more than one or two or more of the other drugs, JNJ-6379 (JNJ-56136379), lamivudine (lamivudine), zanavir (lanamivir), ledipasvir (ledipasvir), meracil (mericitabine), methimazone (methimazole), MK-608, moroxydine (moroxydine), ritonavir (naraprevir), NITD008, NZ-4, ondarnavir (odalasvir), obetavir (ombetasvir), oseltamivir (oseltamivir), paritaprevir, pegylated interferon alpha-2 a (peginterferon alfa-2 a), penciclovir, peramivir (peramivir), pibutovir (pimentavir), pimozir (pimozvir), prandi (pli), placinal (plecril), podophylloxin (podophylloxin) Pravatovir, radalbuvir, radassvir, remdeivir, REP 2139, REP 2165, resiquimod, R07049389 (RG 7907), ribavirin, rifampicin, rimantadine, lu Zasi, ruzasvir, samamasvir, plug Luo Buwei (setrobuvir), staveprevir, sofosbuvir, solifudine, tebuvir, telbivudine, tebuvir, tenofovir, norfovir, and norfovir Wei Anji, tenofovir alfenamide, and pharmaceutical compositions containing the same, ribavirin, fluorouracil, qu Jingang amine, zanamivir, clavulanine, ANA-380/LB80380, thymalfasin, zadoxine, ATI-2173, VIR-2218, RG6346, JN-73763989, JNJ-3989, AB-729, BB-103, hederamcicle, previously Myrcludex B), hzVSF, morpholinium (morphodin), JNJ-56136379, EDP-514, QL-007, ABI-H3733, ZM-H1505R, B-836, VNSX-9945, GLP-26, ABI-4334, IONIS-HBVRx (GSK 3228836), EBT107, NASVAC, GS-4774, heptcell, VBI-2601 (BRII-179), VVX001, VTP-300, CVI-HBV-002, AIC-649, HB-110, JNJ-64300535, CARG-201, PRGN-2013, SA104, VRON-0200, sel Gan Tuoli mod (gantimmod), RG7854, SBT-8230, HBV-002, blue Wei Weima (lenvimab), vir-3434, IMC-I V, LTCR-H2-002, APG-7, YPS 42, EYP-001, and so on, EDP-721, ENOB-HB-01, GV1001, CP101, DF-006, ALG-000184, ALG-010133, ALG-125097, ALG-020572, ALG-125755, or any combination thereof.
As used herein, the term "% w/w" or "% wt/wt" has its ordinary meaning as understood in accordance with the present specification and refers to the percentage expressed as the weight of the ingredient or agent relative to the total weight of the composition multiplied by 100. As used herein, the term "% v/v" or "% vol/vol" has its ordinary meaning as understood in the present specification and refers to the percentage expressed as the liquid volume of a compound, substance, ingredient or agent relative to the total liquid volume of the composition multiplied by 100.
Examples
Some aspects of the embodiments discussed above are disclosed in more detail in the examples below, which are not intended to limit the scope of the disclosure in any way. Those skilled in the art will appreciate that many other embodiments are also within the scope of the present disclosure, as described above and in the claims.
Hereinafter, the terms "RT," "r.t." or "RT" mean room temperature; "h" means hours; "Me" means methyl; "MeOH" meansMethanol; "Et" means ethyl; "EtOH" means ethanol; "NaH" means sodium hydride; "NaBH (AcO) 3 OR NaBH (OAc) 3 "means sodium triacetoxyborohydride; "EtOAc" means ethyl acetate; "TEA" or "Et 3 N "means triethylamine; "DCM" means dichloromethane; "MeCN" or "ACN" means acetonitrile; "DMF" means-dimethylformamide; "DMA" means dimethylacetamide; "Pd (dppf) Cl 2 "means [1.1' -bis (diphenylphosphine) ferrocene]-palladium (II) dichloride; "THF" means tetrahydrofuran; "i-PrOH" or "iPrOH" means 2-propanol; "LC" means liquid chromatography; "LCMS" means liquid chromatography/mass spectrometry; "HPLC" means high performance liquid chromatography; "preparative HPLC" means preparative high performance liquid chromatography; "TFA" means trifluoroacetic acid; "RP" means reverse phase; "min" means minutes; "h" means hours; "PE" means petroleum ether; "v/v" means the volume ratio;meaning diatomaceous earth; "DMSO" means dimethylsulfoxide; "SFC" means supercritical fluid chromatography; "DIPE" means diisopropyl ether; "DIPEA" or "DIEA" means N, N-diisopropylethylamine; "Pd 2 (dba) 3 "means tris (dibenzylideneacetone) -dipalladium; "Pd (OAc) 2 "means palladium (II) acetate; "AcOH" means acetic acid; "DMAP" means 4- (dimethylamino) pyridine; "t-BuOK", "BuO" or "KOtBu" means potassium tert-butoxide; "TLC" means thin layer chromatography; "prep-TLC" means preparative TLC; "KOAc" means potassium acetate.
For intermediates used in the next reaction step, either in crude form or in partially purified form, the estimated molar amount (indicated by-in some cases) or alternatively the theoretical molar amount is indicated in the reaction scheme below.
The meaning of abbreviations in nuclear magnetic resonance spectroscopy is provided below: s=singlet, d=doublet, dd=doublet, dt=doublet of doublet, sept=heptadoublet, t=triplet, br=broad, brs=broad singlet, q=quartet.
Preparation of intermediates
Example A1
Preparation of intermediate 1
TEA (23.3 mL,167.41 mmol) was added dropwise to HCOOH (16.5 mL, 319 mmol) at 0deg.C. The mixture was stirred at 0 ℃ for 30 minutes. To the mixture was added dropwise a solution of 3-bromo-5-methoxybenzaldehyde (30 g,140 mmol) and isopropylidene malonate (20.1 g,140 mmol) in DMF (180 mL) at 25 ℃. The mixture was stirred at 100℃for 50 hours. Once the mixture was cooled to 0 ℃, the reaction was quenched with concentrated hydrochloric acid (120 mL) and diluted with water (800 mL). The mixture was extracted with DCM (2X 400 mL). The combined organic layers were washed with NaOH (1N, 2X 800 mL). The combined aqueous phases were acidified to pH 2 with concentrated HCl and then extracted with EtOAc (2X 300 mL). The combined organic layers were washed with brine (2X 300 mL), and dried over Na 2 SO 4 Dried, filtered and concentrated to give intermediate 1-1 (70 g) as a pink solid which was used in the next step without further purification. 1 H NMR(400MHz,CDCl 3 )δ6.96(s,1H),6.91(t,J＝1.9Hz,1H),6.69(s,1H),3.78(s,3H),2.95-2.88(m,2H),2.70-2.62(m,2H)。
A solution of intermediate 1-1 (70 g,270 mmol) in TfOH (150 mL) was stirred at 25℃for 2 hours. The reaction was quenched by addition of 0 ℃ ice water (1500 mL) and extracted with DCM (3×600 mL). The combined organic layers were treated with NaHCO 3 (2X 800 mL) washing over anhydrous Na 2 SO 4 Dried and concentrated to give a residue, which was purified by flash chromatography on silica gel to give intermediate 1 (12.6 g) as a yellow solid. 1 H NMR(400MHz,CDCl 3 )δ7.19(d,J＝0.9Hz,1H),6.93(s,1H),3.94(s,3H),3.11-2.97(m,2H),2.73-2.59(m,2H)。
Example A2
Preparation of intermediate 2
To a solution of compound intermediate 1 (3.7 g,15.4 mmol) in THF (120 mL) at-10deg.C was added BH 3 -Me 2 S (10M, 2.61 mL). The mixture was stirred at 25℃for 2 hours. The reaction was quenched by addition of 0 ℃ ice water (200 mL) and then extracted with EtOAc (3×200 mL). The combined organic layers were treated with NaHCO 3 (2X 150 mL) washing, washing with anhydrous Na 2 SO 4 Drying and concentrating to obtain residue, and subjecting the residue to flash silica gel chromatography20g/>Silica flash column, 0-10% EtOAc: PE) to afford intermediate 2-1 (3.68 g) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.02(s,1H),6.85(s,1H),5.41(dd,J＝4.4,7.1Hz,1H),3.86(s,3H),3.17-2.98(m,1H),2.93-2.72(m,1H),2.56-2.35(m,2H),2.15-1.93(m,1H)。
To a solution of intermediate 2-1 (3.68 g,15.1 mmol) in THF (350 mL) at 25deg.C was added TsOH (782 mg,4.54 mmol). The mixture was stirred at 60℃for 16 hours. The mixture was treated with H 2 O (200 mL) was diluted and then extracted with EtOAc (3X 150 mL). The combined organic layers were washed with brine (200 mL), and dried over Na 2 SO 4 Drying, filtering and concentrating to obtain residue, and subjecting the residue to flash silica gel chromatography40g/>Silica gel flash column, 0-5% EtOAc: PE) purification to afford intermediate 2-2 (3.16 g) as whiteColor solids. 1 H NMR(400MHz,CDCl 3 )δ7.26(s,1H),7.01-6.90(m,2H),6.45(td,J＝1.9,5.6Hz,1H),3.88(s,3H),3.40(s,2H)；
BH was added to a solution of intermediate 2-2 (3.16 g,14.0 mmol) in THF (60 mL) at 0deg.C 3 THF (1M, 42.12 mL). The mixture was stirred at 25℃for 2 hours. The reaction was quenched by the addition of ice water (100 mL) at 0deg.C and extracted with EtOAc (3X 100 mL). The combined organic layers were treated with NaHCO 3 (2X 80 mL) washing over anhydrous Na 2 SO 4 Drying and concentrating to obtain residue, and subjecting the residue to flash silica gel chromatography40g/>Silica gel flash column, 0-10% EtOAc: PE) to afford intermediate 2-3 (2.86 g) as a yellow oil.
To a solution of intermediate 2-3 (2.86 g) in DCM (40 mL) was added Dess-Martin periodate (7.48 g,17.7 mmol) at 25deg.C. The mixture was stirred at 25℃for 1 hour. The mixture was treated with Na 2 SO 3 (100 mL) was diluted and extracted with DCM (3X 80 mL). The combined organic layers were washed with brine (100 mL), and dried over Na 2 SO 4 Drying, filtering and concentrating to obtain residue, and subjecting the residue to flash silica gel chromatography 12g/>Silica flash column, 0-10% etoac: pe) to afford intermediate 2 (1.4 g) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.08(s,1H),6.93(s,1H),3.85(s,3H),3.53(s,2H),3.40(s,2H)。
Example A3
Preparation of intermediate 3
To a solution of 3- (5-bromo-2-chloro-4-pyridinyl) -N-methoxy-N-methyl-propionamide (27.5 g,89.4 mmol) in DCM (400 mL) was added m-CPBA (46.3 g,268 mmol) at 0 ℃. The mixture was stirred at 35℃for 16h. Saturated Na for the reaction 2 S 2 O 4 The aqueous solution (300 mL) was quenched and then extracted with DCM (2X 100 mL). The combined organic layers were concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give intermediate 3-1 as a yellow solid. 1 H NMR(400MHz,CDCl 3 )δ8.50(s,1H),7.48(s,1H),3.67(s,3H),3.18(s,3H),3.06-2.99(m,2H),2.81-2.75(m,2H)
TEA (41.9 g,414 mmol) was added dropwise to a solution of intermediate 3-1 (26.8 g,82.8 mmol) and methyl chloroformate (26.9 g, 284 mmol) in MeOH (150 mL) at 0deg.C, and the mixture was stirred at 0deg.C for 1.5 hr. Additional methyl chloroformate (26.9 g, 284 mmol) was added at 0deg.C followed by TEA (41.9 g,414 mmol) dropwise. The mixture was stirred at 30 ℃ for 15 hours and then concentrated under reduced pressure. The mixture was diluted with 1M aqueous NaOH (300 mL) and extracted with EtOAc (2X 300 mL). The combined organic layers were washed with brine (2X 100 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel to give intermediate 3-2 as a white solid (17 g,61% yield). 1 H NMR(400MHz,CDCl 3 )δ6.87(s,1H),4.00(s,3H),3.66(s,3H),3.19(s,3H),3.06-3.01(m,2H),2.74(br t,2H)。
To intermediate 3-2 (3.4 g,10.1 mmol) in THF (40 mL) at-70℃was added n-BuLi (2.5M, 6.04 mL). The mixture was stirred at-70℃for 0.5h. Pouring the mixture into saturated NH 4 Aqueous Cl (80 mL) and then extracted with EtOAc (2X 100 mL). The combined organic layers were washed with brine (2X 80 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel to give intermediate 3 as a white solid (1.45 g,73% yield). 1 H NMR(400MHz,CDCl 3 )δ7.03(s,1H),4.11(s,3H),3.20-2.97(m,2H),2.79-2.52(m,2H)。
Example A4
Preparation of intermediate 4
5-bromo-2-chloro-pyridin-4-ol (3 g,14.4 mmol), 2-bromo-N-methoxy-N-methyl-acetamide (3.93 g,21.6 mmol) and K were reacted at 60 ℃ 2 CO 3 A mixture of (5.97 g,43.2 mmol) in DMF (30 mL) was stirred for 16 h. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give intermediate 4-1 (3.5 g) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ8.38(s,1H),6.73(s,1H),4.99(s,2H),3.80(s,3H),3.26(s,3H)。
A mixture of intermediate 4-1 (2 g,6.46 mmol), m-CPBA (6.69 g,38.8 mmol) in DCM (50 mL) was stirred at 55deg.C for 16 h. The crude mixture was poured into saturated Na 2 S 2 O 3 Aqueous solution (100 mL) and then extracted with DCM (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give intermediate 4-2 (1 g,48% yield). 1 H NMR(400MHz,CDCl 3 )δ8.50(s,1H),6.93(s,1H),4.99(s,2H),3.80(s,3H),3.25(s,3H)。
TEA (1.59 g,15.7mmol,2.18 mL) was added dropwise to a solution of intermediate 4-2 (1.7 g,5.22 mmol) and methyl chloroformate (1.21 mL,15.67 mmol) in MeOH (20 mL) at 0deg.C. After the addition, the mixture was stirred at 20 ℃ for 1 hour. Additional methyl chloroformate (1.21 mL,15.67 mmol) was added at 20deg.C, and then TEA (2.18 mL,15.67 mmol) was added dropwise at 0deg.C. The mixture was stirred at 20 ℃ for 3 hours and then concentrated under reduced pressure. The residue is taken up in H 2 O (40 mL) was diluted and then extracted with EtOAc (2X 50 mL). Will be combined withThe organic layer was washed with brine (30 mL. Times.2), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give intermediate 4-3 (1.3 g,73% yield) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ6.44(s,1H),4.96(s,2H),4.01(s,3H),3.79(s,3H),3.25(s,3H)。
At-70 ℃ and N 2 Next, n-BuLi (2.5M, 2.30 mL) was added to a solution of intermediate 4-3 (1.3 g,3.83 mmol) in THF (15 mL). The mixture was stirred at-70℃for 1 hour. The reaction is carried out by adding saturated NH at 0 DEG C 4 Aqueous Cl (10 mL) was quenched and then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give intermediate 4 (534 mg,70% yield) as a yellow solid. 1 H NMR(400MHz,CDCl 3 )δ6.75(s,1H),4.72(s,2H),4.12(s,3H)。
Example A4a
Preparation of intermediate 4a
To a mixture of intermediate 3 (500 mg,2.53 mmol) and NaI (1.14 g,7.59 mmol) in MeCN (20 mL) was added dropwise chloro-trimethyl-silane (963. Mu.L, 7.59 mmol) at 0deg.C. The mixture was stirred at 85 ℃ for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give intermediate 4a-1 (460 mg) as a yellow solid. C (C) 8 H 7 ClNO 2 The calculated value of ES M/z is [ M+H ]] + 184.0, found 184.2.
To a solution of intermediate 4a-1 (460 mg,2.51 mmol) and 1-bromo-2-methoxyethane (471. Mu.L, 5.01 mmol) in DMF (15 mL) was added K 2 CO 3 (693 mg,5.01 mmol). The mixture was stirred at 50℃for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was passed throughPurification by preparative HPLC gave intermediate 4a (150 mg) as a brown oil. C (C) 11 H 13 ClNO 3 The calculated value of ES M/z is [ M+H ]] + 242.1, found 242.0; 1 H NMR(400MHz,Chloroform-d)δ＝7.02(s,1H),4.71-4.55(m,2H),3.87-3.73(m,2H),3.46(s,3H),3.17-3.03(m,2H),2.80-2.64(m,2H)。
example A4b
Preparation of intermediates 4B, 4B-A and 4B-B
A solution of intermediate 3 (250 mg,1.27 mmol) and KOH (781 mg,13.9 mmol) in MeOH (10 mL) was stirred at 0deg.C for 30 min. To the reaction mixture was added [ acetoxy (phenyl) -lambda ] 3 Iodine group]Acetate (488.97 mg,1.52mmol,1.2 eq.). The resulting solution was stirred at 0℃for 1 hour, followed by stirring at 25℃for 16 hours. The reaction mixture was concentrated under reduced pressure to give crude intermediate 4b-1 (1.3 g) as a black solid. C (C) 11 H 14 ClNO 4 The calculated value of ES M/z is [ M+H ]] + 260.1, found 260.0.
To a solution of crude intermediate 4b-1 (1.3 g) in THF (10 mL) and H 2 Hydrochloric acid (12M H) was added to an O (8 mL) solution 2 O aqueous solution, 417. Mu.L). The mixture was stirred at 20℃for 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL). The organic layer was treated with NaHCO 3 Aqueous (20 mL. Times.3) and brine (20 mL) were washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give intermediate 4b (350 mg) as a brown oil. C (C) 9 H 9 ClNO 3 The calculated value of ES M/z is [ M+H ]] + 214.0, found 213.9; 1 H NMR(400MHz,CHLOROFORM-d)δ＝7.04(s,1H),4.49(dd,J＝4.9,7.8Hz,1H),4.12(s,3H),3.49(dd,J＝7.8,17.6Hz,1H),2.96(ddd,J＝0.7,5.0,17.6Hz,1H)
intermediate 4b (350 mg) was purified by SFC (column: apparatus: SFC-80; column: DAICEL CHIRALCEL OX (250 mm. Times.30 mm,10 um); conditions are as follows: 0.1% NH 3 H 2 O ETOH; start B:25, a step of selecting a specific type of material; end B:25, a step of selecting a specific type of material; flow rate (ml/min): 70; and (3) sample injection: 60 Isolation to give intermediate 4b-A (130 mg,99.6% ee), C 9 H 9 ClNO 3 The calculated value of ES M/z is [ M+H ]] + 214.0 found 213.9 and intermediate 4B-B (145 mg,98.9% ee) as a brown solid. C (C) 9 H 9 ClNO 3 The calculated value of ES M/z is [ M+H ]] + 214.0, found 213.9.
Example A4c
Preparation of intermediate 4c
A mixture of intermediate 4b (100 mg, 468. Mu. Mol), 0-benzylhydroxylamine hydrochloride (112 mg, 702. Mu. Mol) and NaOAc (115 mg,1.40 mmol) in EtOH (3 mL) was stirred at 45℃for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give intermediate 4c-1 (100 mg) as a yellow liquid.
Borane (828. Mu.L of 1M in THF) was added to a solution of intermediate 4c-1 (88 mg) in THF (2 mL) at 10deg.C. The reaction mixture was then stirred at 50 ℃ for 16 hours. The reaction mixture was quenched with additional 1N NaOH and then extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO 4 Dried, filtered and concentrated under reduced pressure to give intermediate 4c (32 mg) as a brown solid. C (C) 9 H 12 ClN 2 O 2 The calculated value of ES M/z is [ M+H ]] + 215.1, found 214.9.
Example A4d
Preparation of intermediate 4d
To a solution of intermediate 3 (300 mg,1.52 mmol) in MeOH (3 mL) was added 1- (chloromethyl) -4-fluoro-1, 4-diazoniabicyclo [2.2.2]Octane bistetrafluoroborate (1.61 g,4.55 mmol). The reaction mixture was stirred at 85 ℃ for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give crude intermediate 4d (310 mg) as a yellow solid. C (C) 9 H 8 ClFNO 2 The calculated value of ES M/z is [ M+H ]] + 216.1, found 216.0.
Examples A4e
Preparation of intermediate 4e
To a solution of intermediate 3 (2 g,10.12 mmol) and MeI (7.18 g,50.60mmol,3.15mL,5 eq.) in THF (20 mL) at-20deg.C was slowly added LiHMDS (1M, 20.24mL,2 eq.). The mixture was stirred at-15 ℃ for 1 hour, then the reaction was warmed to 15 ℃ and stirred for 2 hours. By addition of saturated NH at 0 DEG C 4 Cl (20 mL) to quench the reaction mixture, followed by H 2 O (50 mL) was diluted and extracted with EtOAc (3X 60 mL). The combined organic layers were washed with brine (1X 100 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give intermediate 4e-1 (70 mg) as a yellow oil, C 10 H 11 ClNO 2 The calculated value of ES M/z is [ M+H ]] + 212.0, found 211.9; intermediate 4e-2 (300 mg) as a yellow oil, C 10 H 11 ClNO 2 The calculated value of ES M/z is [ M+H ]] + 212.0, found 211.9; and intermediate 4e-3 (1.05 g) as a yellow oil, C 11 H 13 ClNO 2 The calculated value of ES M/z is [ M+H ]] + 226.1, found 226.0.
Example A5
Preparation of intermediates 5-1a and 5-1b
A mixture of intermediate 3 (1.45 g,7.34 mmol) and (5S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (2.21 g,14.7 mmol) in EtOH (20 mL) was stirred at 20-45℃for 1 hour. NaBH was added to the mixture at 20 ℃ 3 CN (1.38 g,22 mmol). The mixture was stirred at 20-45 ℃ for 15 hours, filtered and concentrated under reduced pressure to give a residue. The residue is taken up in H 2 O (80 mL) was diluted and extracted with EtOAc (2X 100 mL). The combined organic layers were washed with brine (2X 80 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel to give intermediate 5-1 (2.2 g,92% purity) as a yellow oil.
Intermediate 5-1 was further passed through SFC (column: DAICEL CHIRALPAK IC (250 mm. Times.50 mm,10 um), mobile phase: A: CO 2 ；B：IPA(0.1％ NH 3 ·H 2 O); gradient: 55% B; flow rate (mL/min): 140; and (3) sample injection: 300min (3 mL for each sample injection, circulation time is about 6.8 min); column temperature: 40 ℃) to give pure enantiomer intermediate 5-1a and intermediate 5-1b. The absolute chiral center of the intermediate is attributed to the single crystal structure of intermediate 5-1b.
Intermediate 5-1a (800 mg) was obtained as a yellow oil using SFC. Rt=3.44 minutes (SFC analyzer: CAS-QD-ANA-SFC-SD (Agilent 1260 equipped with DAD detector), method: column: chrialpak IC-3X 4.6mm inner diameter, 3 μm, mobile phase: CO 2 40% IPA (0.05%); flow rate: column temperature 2.8 mL/min: 40 ℃ C.). 1 H NMR(400MHz,CD 3 OD)δ6.96(s,1H),4.51(dd,J＝3.9,7.7Hz,1H),3.98(s,3H),3.91-3.80(m,1H),3.61(q,J＝7.1Hz,1H),3.18-3.02(m,1H),2.95-2.74(m,3H),2.52-2.40(m,1H),2.39-2.25(m,3H),2.08(tdd,J＝4.4,8.9,13.4Hz,1H),1.92-1.76(m,1H)。
Intermediate 5-1b (1.14 g) was obtained using SFC) It is a yellow solid. Rt=4.74 min (SFC analyzer: CAS-QD-ANA-SFC-SD (Agilent 1260 equipped with DAD detector) method: column: chrialpak IC-3X 4.6mm inner diameter, 3 μm mobile phase: CO) 2 40% IPA (0.05%); flow rate: column temperature 2.8 mL/min: 40 ℃ C.). 1 H NMR(400MHz,CD 3 OD)δ6.91(s,1H),4.37(dd,J＝4.8,7.5Hz,1H),3.96(s,3H),3.86-3.74(m,1H),3.05(ddd,J＝5.9,8.8,17.1Hz,1H),2.89-2.68(m,2H),2.59(dd,J＝7.1,11.9Hz,1H),2.46-2.19(m,4H),1.97(tdd,J＝5.3,8.4,13.5Hz,1H),1.89-1.72(m,1H)。
A single crystal of formate of intermediate 5-1b was obtained. The crystals were colorless needles with the following dimensions: 0.30X0.04 X0.04 mm 3 . Symmetry of the crystal structure is attributed to monoclinic space group P2 with the following parameters 1 ：α＝90°，β＝102.238(3)°，γ＝90°，/>Z=8, dc=1.359 g/cm3, F (000) = 1440.0, μ (cukα) =2.236 mm-1, and t= 149.99 (10) K. FIGS. 1A and 1B show the absolute configuration and ORTEP crystal structure of formate salt of intermediate 5-1B.
The intermediates in Table A-1 were prepared using a similar procedure as described for the preparation of intermediate 5-1a and intermediate 5-1 b.
Table A-1
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SFC method E: column: uniChiral ND 100X 4.6mm inside diameter, 5 μm; mobile phase: a: CO 2 The method comprises the steps of carrying out a first treatment on the surface of the B: isopropyl alcohol (0.05% DEA); gradient: b reaches 40% from 5% in 4.5 minutes and holds 40% for 0.5 minutes, then holds 5% B for 1 minute; flow rate: 2.8mL/min; column temperature: 40 ℃.
SFC method F: column: chiralpak AD-3X 4.6mm inside diameter, 3 μm; mobile phase: a: CO 2 And B: ethanol (0.05% DEA); gradient: b reaches 40% from 5% in 4.5 minutes and holds 40% for 2.5 minutes, then holds 5% B for 1 minute; flow rate: 2.8mL/min; column temperature: 40 ℃.
SFC method G: column: chiralpak AD-3.50X4.6 mm inside diameter, 3 μm; mobile phase: a: CO 2 And B: ethanol (0.05% DEA); gradient: b reaches 40% from 5% in 2.5min and holds 40% for 0.5min, then holds 5% B for 1min; flow rate: 4mL/min; column temperature: 35 ℃.
SFC squareMethod H: column: lux cellulose-2X 4.6mm inside diameter, 3 μm; mobile phase: a: CO 2 The method comprises the steps of carrying out a first treatment on the surface of the B: IPA (0.05% DEA); gradient: b reaches 40% from 5% in 4.5 minutes and holds 40% for 2.5 minutes, then holds 5% B for 1 minute; flow rate: 2.5mL/min; column temperature: 40 ℃.
SFC method I: column: chiralpak AY-3.50X4.6 mm inside diameter, 3 μm; mobile phase: a: CO 2 The method comprises the steps of carrying out a first treatment on the surface of the B: IPA (0.05% DEA); gradient: b reaches 40% from 5% in 2.5min and holds 40% for 0.5min, then holds 5% B for 1min; flow rate: 4mL/min; column temperature: 35 ℃.
SFC method J: column: chiralpak AY-3.50X4.6 mm inside diameter, 3 μm; mobile phase: a: CO 2 The method comprises the steps of carrying out a first treatment on the surface of the B: ethanol (0.05% DEA); gradient: b reaches 40% from 5% in 2.5 minutes and holds 40% for 0.5 minutes, then holds 5% B for 1 minute; flow rate: 4mL/min; column temperature: 35 ℃.
SFC method K: column: (S, S) -Whelk-0-1.8X14.6 mm inside diameter, 1.8 μm; mobile phase: a: CO 2 The method comprises the steps of carrying out a first treatment on the surface of the B: methanol (0.05% DEA); gradient: b reaches 40% from 5% in 2 minutes and holds 40% for 1 minute, then holds 5% B for 1 minute; flow rate: 2.8mL/min; column temperature: 35 ℃.
SFC method H: column: lux cellulose-2X 4.6mm inside diameter, 3 μm; mobile phase: a: CO 2 The method comprises the steps of carrying out a first treatment on the surface of the B: IPA (0.05% DEA); gradient: b reaches 40% from 5% in 4.5 minutes, then holds 5% B for 2.5 minutes, then holds 5% B for 1 minute; flow rate: 2.5mL/min; column temperature: 40 ℃.
SFC method M: column: MChiral NS-3X 4.6mm inside diameter, 3 μm; mobile phase: a: CO2, B: IPA (0.05% dea); gradient: b reaches 40% from 5% in 2 minutes and holds 40% for 1 minute, then holds 5% B for 1 minute; flow rate: 2.8mL/min; column temperature: 35 ℃;
SFC method N: column: chiralcel OJ-3X 4.6mm inside diameter, 3 μm; mobile phase: a: CO2, B: ethanol (0.05% dea); gradient: b reaches 40% from 5% in 2 minutes and holds 40% for 1 minute, then holds 5% B for 1 minute; flow rate: 2.8mL/min; column temperature: 35 ℃;
SFC method O: column: chiralpak AS-3 50X 4.6mm inner diameter, 3 μm; mobile phase: a: CO 2 The method comprises the steps of carrying out a first treatment on the surface of the B: ethanol (0.05% DEA); gradient: b reaches 40% from 5% in 2.5 minutes, then 40% B is kept for 0.5 minutes, then 5% B is kept for 1 minute; flow rate: 4mL/min; column temperature: 35 ℃.
SFC method P: column: chiralpak IG 50×4.6mm inside diameter, 3 μm; mobile phase: a: CO 2 The method comprises the steps of carrying out a first treatment on the surface of the B: ethanol (0.05% DEA); gradient: b reaches 40% from 5% in 2.5 minutes, then 40% B is kept for 0.5 minutes, then 5% B is kept for 1 minute; flow rate: 4mL/min; column temperature: 35 ℃.
SFC method Q: column: chiralpak IC-3.50X4.6 mm inside diameter, 3 μm; mobile phase: a: CO 2 The method comprises the steps of carrying out a first treatment on the surface of the B: methanol (0.05% DEA); gradient: b reaches 40% from 20% in 2.5 minutes and holds 40% for 0.5 minutes, then holds 20% B for 1 minute; flow rate: mL/min; column temperature: 35 ℃;
example A6
Preparation of intermediate 7-1
To a solution of intermediate 3 (500 mg,2.53 mmol) in EtOH (6 mL) was added 3-hydroxyazetidine hydrochloride (416 mg,3.80 mmol). The mixture was stirred at 50℃for 1 hour. NaBH was added to the mixture at 25 DEG C 3 After CN (477 mg,7.59 mmol), the resulting mixture was stirred at 50℃for 15 hours to give a yellow mixture. H for the reaction 2 O (30 mL) was quenched and then extracted with EtOAc (3X 30 mL). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give intermediate 7-1 (280 mg,39% yield, 90% purity) as a yellow solid. C (C) 12 H 16 ClN 2 O 2 The calculated value of ES M/z is [ M+H ]] + 255.1, found 255.0.
The intermediates shown in table a-2 were prepared by a similar reaction scheme as used for the preparation of intermediate 7-1 using the appropriate starting materials.
Table A-2
Example 7
Preparation of intermediate 8-1
2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (2.1 g,8.28 mmol), 1, 3-dibromo-2-chlorobenzene (4.48 g,16.6 mmol), pd (dppf) Cl 2 (602 mg, 828. Mu. Mol) and K 2 CO 3 (3.43 g,24.9 mmol) in dioxane (25 mL) and H 2 The mixture in O (2.5 mL) was degassed and N 2 Purge (3×). At N 2 After stirring the mixture at 100℃for 2 hours under an atmosphere, H was used for the reaction 2 O (30 mL) was quenched and then extracted with EtOAc (3X 30 mL). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give intermediate 8-1 (1.4 g) as a yellow solid. C (C) 12 H 9 BrCl 2 MS of N ES M/z calculated as [ M+H ]] + 315.9, found 316.0.
The intermediates shown in table a-3 were prepared by a similar reaction scheme as used for the preparation of intermediate 8-1 using the appropriate starting materials.
Table A-3
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Example A8
Preparation of intermediate 10-1
To a solution of compound intermediate 8-1 (300 mg, 946. Mu. Mol) and 1, 3-dimethyl-2, 4-dioxopyrimidine-5-carboxylic acid (145 mg, 789. Mu. Mol) in MeCN (4 mL) was added N, N, N ', N' -tetramethyl chloroformyl amine hexafluorophosphate (TCFH, 447 mg,1.58 mmol) and N-methylimidazole (NMI, 157.16. Mu.L, 1.97 mmol). The mixture was stirred at 50℃for 16 hours. H for the reaction 2 O (20 mL) was quenched and then extracted with EtOAc (3X 20 mL). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give intermediate 9-1 (420 mg, crude product) as a yellow solid. C (C) 19 H 14 BrCl 2 N 3 O 3 MS of Na the calculated ES M/z value was [ M+Na ]] + 504.0, found 504.0.
Crude intermediate 9-1 (420 mg), bis (pinacolato) diboron (132 mg, 521. Mu. Mol), KOAc (128 mg,1.30 mmol) and Pd (dppf) Cl 2 (31.8 mg, 43.5. Mu. Mol) in dioxane (3 mL) was degassed and N 2 Purge (3×). At N 2 The mixture was stirred at 100 ℃ for 16 hours under an atmosphere, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel4g/>Silica gel flash column, 0-50% EtOAc: PE) to afford intermediate 10-1 (330 mg) as a yellow solid. C (C) 25 H 27 BCl 2 N 3 O 5 The calculated value of ES M/z is [ M+H ]] + 530.1, found 530.1.
Example A8a
Preparation of intermediate 9-2
To a solution of intermediate 8-2 (850 mg,2.87 mmol) and 1, 3-dimethyl-2, 4-dioxopyrimidine-5-carboxylic acid (580 mg,3.15 mmol) in MeCN (8 mL) was added N, N, N ', N' -tetramethyl chloroformyl amine hexafluorophosphate (TCFH) (1.61 g,5.73 mmol) and N-methylimidazole (NMI) (571. Mu.L 7.16 mmol). The reaction mixture was stirred at 50 ℃ for 16 hours. The reaction mixture was filtered and the crude product was triturated with EtOAc (30 mL) at 25 ℃ for 10 min. The solid residue was filtered and dried to give intermediate 9-2 (1 g) as a white solid.
The intermediates shown in table a-4 were prepared by a similar reaction scheme as for the preparation of intermediate 9-2 using the appropriate starting materials.
Table A-4
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Example A8b
Preparation of intermediate 10-2
Intermediate 9-2 (1.0 g), bis (pinacolato) diboron (823 mg,3.24 mmol), KOAc (636 mg,6.48 mmol) and Pd (dppf) Cl 2 (158 mg, 216. Mu. Mol) in dioxane (10 mL) was degassed and N 2 Purge (3×). At N 2 The mixture was stirred at 100℃for 16 hours under an atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel column to give intermediate 10-2 (780 mg) as a white solid. C (C) 26 H 30 BClN 3 O 5 The calculated value of ES M/z is [ M+H ]] + 510.2, found 510.0.
The intermediates shown in table a-5 were prepared by a similar reaction scheme as used for the preparation of intermediate 10-2 using the appropriate starting materials.
Table A-5
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Example A9
Preparation of intermediate 12-1
Intermediate 8-1 (200 mg, 631. Mu. Mol), 4-chloro-2-methylpyrido [3,2-d]A mixture of pyrimidine (113 mg, 631. Mu. Mol) and HCl/dioxane (4M, 156. Mu.L) in t-BuOH (3.5 mL) was stirred at 100deg.C for 16 hours. The mixture was concentrated under reduced pressure to give a residue, which was triturated with EtOAc (20 mL) to give intermediate 11-1 (211 mg, crude product) as an off-white solid. C (C) 20 H 14 BrCl 2 N 4 The calculated value of ES M/z is [ M+H ]] + 459.0, found 458.9.
Intermediate 11-1 (100 mg, 217. Mu. Mol), bis (pinacolato) diboron (166 mg, 652. Mu. Mol), KOAc (597 mg,6.08 mmol) and Pd (dppf) Cl 2 (15.9 mg, 21.7. Mu. Mol) in dioxane (2.5 mL) and under N 2 Stirring is carried out for 16 hours at 100℃under an atmosphere. After DMF (1 mL) was added to the mixture, the resulting mixture was taken up in N 2 Stirring is carried out for 3 hours at 110℃under an atmosphere. The mixture was partitioned between EtOAc (50 mL) and H 2 O (50 mL) between partitions. The organic layer was separated, washed with brine (50 mL), and dried over Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give intermediate 12-1 (244 mg, crude product) as a brown solid. C (C) 26 H 26 BCl 2 N 4 O 2 The calculated value of ES M/z is [ M+H ]] + 507.1, found 507.1.
The intermediates shown in table a-6 were prepared by a similar reaction scheme as used for the preparation of intermediate 12-1 using the appropriate starting materials.
Table A-6
Example A10
Preparation of intermediate 13-1
To a solution of ethyl 5- (1, 3-dioxolan-2-yl) pyridine-2-carboxylate (800 mg,3.82 mmol) and 3-bromo-2-chloroaniline (780 mg,3.82 mmol) in THF (6 mL) was added t-BuOK (640 mg,5.74 mmol). The mixture was stirred at 20 ℃ for 16 hours to give a yellow solution. In use of NH 4 After the pH of the mixture was adjusted to about 7 with aqueous Cl solution, the mixture was treated with H 2 O (20 mL) was diluted and extracted with EtOAc (3X 20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give intermediate 13-1 (950 mg) as a yellow solid. C (C) 15 H 13 BrClN 2 O 3 The calculated value of ES M/z is [ M+H ]] + 383.0, found 382.9.
Example A11
Preparation of intermediate 14-1
At 25℃and N 2 KOAc (90.76 g,924.73mmol,5 eq.) and Pd (dppf) Cl were added to a mixture of 1, 3-dibromo-2-chloro-benzene (50 g,185 mmol) and 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (93.9 g,370 mmol) in dioxane (400 mL) 2 (13.53 g,18.49mmol,0.1 eq.). The mixture was stirred at 110℃for 12 hours. The mixture was evaporated and diluted with water (500 mL). The mixture was treated with MTBE (2X 500 m)L) extraction. The combined organic layers were evaporated to give the crude product. The crude product was triturated with MeOH (150 mL) to give intermediate 14-1 (41.3 g,61% yield) as a white solid. 1 H NMR：(400MHz,CDCl 3 )δ7.59(d,J＝7.2Hz,2H),7.13(t,J＝7.2Hz,1H),1.29(s,24H)。
Example A12
Preparation of intermediate 15-1
Intermediate 13-1 (950 mg,2.35 mmol), intermediate 14-1 (2.57 g,7.05 mmol) and Pd-118 (153 mg, 235. Mu. Mol), K 2 PO 4 (1.50 g,7.05 mmol) in dioxane (10 mL) and N 2 Purge (3×). At N 2 The mixture was stirred at 100 ℃ for 16 hours under an atmosphere to give a black mixture. LC-MS showed that intermediate 13-1 was not completely consumed. Additional intermediate 14-1 (2.57 g,7.05 mmol), pd-118 (153 mg, 235. Mu. Mol), K were added to the mixture 3 PO 4 (1.50 g,7.05 mmol) and dioxane (10 mL). The mixture was degassed and used with N 2 Purge (3×), and then place the mixture under N 2 Stirring was carried out at 110℃for 4 hours. H for the reaction 2 O (30 mL) was quenched and then extracted with EtOAc (3X 30 mL). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give intermediate 15-1 (550 mg) as a yellow solid. C (C) 27 H 28 BCl 2 N 2 O 5 The calculated value of ES M/z is [ M+H ]] + 541.1, found 541.1.
Example A13
Preparation of intermediate 17-1
Intermediate 15-1 (127 mg, 236. Mu. Mol), intermediate 7-1 (50 mg, 196. Mu. Mol), pd-118 (12.8 mg, 19.6. Mu. Mol) and K 3 PO 4 (125 mg, 589. Mu. Mol) in dioxane (3 mL) and H 2 The mixture in O (0.3 mL) was degassed and N 2 Purge (3×). At N 2 The mixture was stirred at 110 ℃ for 2 hours under an atmosphere to give a black mixture. H for the reaction 2 O (30 mL) was quenched and then extracted with EtOAc (3X 30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give intermediate 16-1 (35 mg) as a yellow solid. C (C) 33 H 31 Cl 2 N 4 O 5 The calculated value of ES M/z is [ M+H ]] + 633.2, found 633.1.
To a mixture of intermediate 16-1 (20 mg) in THF (0.7 mL) was added H 2 O (0.6 mL) and aqueous HCl (12M, 0.2 mL), and then the mixture was stirred at 20deg.C for 2 hours to give a yellow solution. The mixture was diluted with THF (30 mL) and then concentrated to give intermediate 17-1 (15 mg, crude product) as a yellow solid. C (C) 31 H 27 Cl 2 N 4 O 4 The calculated value of ES M/z is [ M+H ]] + 589.1, found 589.1.
Example A14
Preparation of intermediate 18-1
To dioxane (3 mL) and H 2 A solvent mixture of O (0.3 mL) was added intermediate 10-1 (150 mg, 283. Mu. Mol), intermediate 3 (56 mg, 283. Mu. Mol), K 3 PO 4 (180 mg, 849. Mu. Mol) and Pd (dppf) Cl 2 (21 mg, 29. Mu. Mol). The reaction mixture was degassed and used with N 2 Purging 3 times. Then at N 2 The reaction mixture was stirred at 110℃for 2 hours under an atmosphere. Will beThe reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give intermediate 18-1 (27 mg) as a white solid. C (C) 28 H 23 Cl 2 N 4 O 5 The calculated value of ES M/z is [ M+H ]] + 565.1, found 565.3; 1 H NMR(400MHz,CHLOROFORM-d)δ＝11.50(s,1H),8.58(d,J＝8.3Hz,1H),8.53(s,1H),7.68(dd,J＝1.3,7.6Hz,1H),7.46(t,J＝7.6Hz,1H),7.42 -7.32(m,3H),7.12-7.06(m,1H),4.16(s,3H),3.59(s,3H),3.46(s,3H),3.20-3.12(m,2H),2.79-2.70(m,2H)。
the intermediates shown in table a-7 were prepared by a similar reaction scheme as used for the preparation of intermediate 18-1 using the appropriate starting materials.
Table A-7
Preparation of the Compounds
Example 1
Preparation of Compound A-1
Intermediate 10-1 (60 mg), intermediate 5-1b (26 mg,87.1 mol), K 3 PO 4 (50.4 mg, 238. Mu. Mol) and Pd-118 (5.2 mg, 7.9. Mu. Mol) in dioxane (2 mL) and H 2 The mixture in O (0.2 mL) was degassed and N 2 Purge (3×). At N 2 The mixture was stirred at 100 ℃ for 16 hours under an atmosphere to give a black mixture. H for the reaction 2 O (20 mL) was quenched and then extracted with EtOAc (3X 20 mL). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound a-1 (15.7 mg,98% purity) as a white solid.
Example 1a
Preparation of Compound A-2
Intermediate 10-2 (240 mg), intermediate 5-1b (107 mg, 363. Mu. Mol), di-tert-butyl (cyclopentyl) phosphane, palladium dichloride; iron (Pd-118, 22mg, 33. Mu. Mol) and K 2 PO 4 (210 mg, 989. Mu. Mol) in dioxane (2.5 mL) and H 2 The mixture in O (0.25 mL) was degassed and N 2 Purge (3×). At N 2 The mixture was stirred at 100℃for 2 hours under an atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound a-2 (56 mg) as an off-white solid.
The compounds shown in table 1 below were prepared by a similar reaction scheme as used for the preparation of compound a-2 using the appropriate starting materials.
TABLE 1
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Example 2
Preparation of Compound B-1
Intermediate 12-1 (64 mg, 126. Mu. Mol), intermediate 5-1b (18 mg, 63. Mu. Mol), pd (dppf) Cl 2 (4.62 mg, 6.31. Mu. Mol) and K 3 PO 4 (40 mg, 189. Mu. Mol) in dioxane (1 mL) and H 2 The mixture in O (0.1 mL) was degassed and N 2 Purge (3×). After the mixture is put in N 2 After stirring at 110 ℃ for 4.5 hours under an atmosphere, the mixture was filtered and concentrated to give a residue, which was purified by preparative HPLC to give compound B-1 (8.8 mg) as a yellow solid.
The compounds shown in table 2 below were prepared by a similar reaction scheme as used for the preparation of compound B-1 using the appropriate starting materials.
TABLE 2
Example 3
Preparation of Compound C-1
A mixture of intermediate 17-1 (37 mg, 62.8. Mu. Mol) and 2-aminoethan-1-ol (5.7. Mu.L, 94.2. Mu. Mol) in MeOH (2 mL) was stirred at 20℃for 0.5 h. Adding NaBH to the mixture 3 After CN (11.8 mg, 188. Mu. Mol), the reaction mixture was stirred at 40℃for 16 hours. The reaction mixture was concentrated under reduced pressure, using H 2 O (20 mL) was diluted and extracted with EtOAc (20 mL. Times.3). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound C-1 (11 mg) as a yellow solid.
Example 3a
Preparation of Compound D-1
Intermediate 18-1 (100 mg, 177. Mu. Mol), 3-methoxyazetidine hydrochloride (44 mg, 354. Mu. Mol) and NaBH were added at 50℃ 3 A mixture of CN (33 mg, 531. Mu. Mol) in EtOH (2 mL) was stirred for 16 hours. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound D-1 (23 mg) as an off-white solid.
The compounds shown in table 3 below were prepared by a similar reaction scheme as used for the preparation of compound D-1 using the appropriate starting materials.
TABLE 3 Table 3
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Example 3b
Preparation of Compound E-1
To a solution of Compound A-2 (120 mg) in THF (3 mL) was added K 2 CO 3 (46 mg, 336. Mu. Mol) and ethyl chloroformate (40. Mu.L, 420. Mu. Mol). The mixture was stirred at 25℃for 2 hours. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound E-1 (17 mg,99% purity) as a yellow solid.
The compounds shown in table 4 below were prepared by a similar reaction scheme as used for the preparation of compound E-1 using the appropriate starting materials.
TABLE 4 Table 4
Example 3c
Preparation of Compound F-1
To a solution of compound A-2 (75 mg, 117. Mu. Mol) and (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl 4-nitrophenylcarbonate (69 mg, 233. Mu. Mol) in DMF (1 mL) was added TEA (49. Mu.L, 350. Mu. Mol). The mixture was stirred at 60℃for 48 hours. The mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound F-1 (3.0 mg,96% purity) as a white solid.
Example 3d
Preparation of Compound G-1
To a solution of compound D-16 (80 mg, 105. Mu. Mol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at 20 ℃ for 0.5 hours to give a colorless solution. The mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound G-1 (6.27 mg,97% purity) as a white solid.
Example 3e
Preparation of Compound H-1
To a solution of compound G-1 (40 mg, 61. Mu. Mol) in DCM (2 mL) was added KOH (10 mg, 181. Mu. Mol) and acetic anhydride (6.0. Mu.L, 60. Mu. Mol). The mixture was stirred at 20 ℃ for 2 hours to give a yellow solution. The mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound H-1 (9.48 mg) as a white solid.
Example 3f
Preparation of Compound I-1
A mixture of intermediate 5-1b (50 mg, 169. Mu. Mol) and paraformaldehyde (15 mg, 507. Mu. Mol) in EtOH (1 mL) was stirred at 50℃for 15 hours. After adding NaBH 3 After CN (53 mg, 845. Mu. Mol), the mixture was stirred at 50℃for 1 hour. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative TLC to give intermediate I-1-1 (30 mg) as a liquid. C (C) 15 H 21 ClN 3 O 2 The calculated value of ES M/z is [ M+H ]] + 310.1, found 310.1.
Intermediate I-1-1 (30 mg), intermediate 10-2 (54 mg, 107. Mu. Mol), [1,1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) dichloride (6.3 mg, 9.68. Mu. Mol), K 2 CO 3 (40 mg, 291. Mu. Mol) in dioxane (2 mL) and H 2 The mixture in O (0.2 mL) was degassed and then N was used 2 Purge (3×). At N 2 The mixture was stirred at 100℃for 16 hours under an atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound I-1 (2.4 mg) as an off-white solid.
EXAMPLE 3g
Preparation of Compound J-1
Compound A-87 (90 mg, 139. Mu. Mol) was reacted with hydrochloric acid (12M H) at 20 ℃ 2 The mixture of O solution, 1 mL) and AcOH (1 mL) was stirred for 16 h. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound J-1 (12 mg) as an off-white solid.
The compounds shown in table 5 below were prepared by a similar reaction scheme as used for the preparation of compound J-1 using the appropriate starting materials.
TABLE 5
Example 3h
Preparation of Compound K-1a and Compound K-1b
To a solution of intermediate 18-4 (50 mg, 88.81. Mu. Mol) in MeOH (1 mL) was added (5S) -5- (aminomethyl) pyrrolidin-2-one hydrochloride (20 mg, 133. Mu. Mol). The mixture was stirred at 50℃for 13 hours. NaBH was added to the mixture at 20 DEG C 3 CN (17 mg, 266. Mu. Mol). The mixture was stirred at 50℃for 3 hours. The mixture was filtered to give a filtrate, which was purified by preparative HPLC to give compound K-1a (3.3 mg) as a white solid and compound K-1b (3.81 mg) as a white solid.
Example 3i
Preparation of Compound L-1a and Compound L-1b
3-bromo-4-fluoro-2-methylaniline (390 mg,1.91 mmol), bis (pinacolato) diboron (1.21 g,4.78 mmol), pd (dppf) Cl 2 A mixture of (140 mg, 191. Mu. Mol) and AcOK (563 mg,5.73 mmol) in dioxane (10 mL) was degassed and N 2 Purge (3×). At N 2 The mixture was stirred at 100℃for 16 hours under an atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give intermediate L-1-4 (390 mg). C (C) 13 H 20 BFNO 2 The calculated value of ES M/z is [ M+H ]] + 252.1, found 252.3.
Intermediate L-1-4 (390 mg), 1, 3-dibromo-2-chlorobenzene (840 mg,3.11 mmol), pd (PPh) 3 ) 4 (180 mg, 155. Mu. Mol) and CsF (706 mg,4.66 mmol) in dioxane (5 mL) and H 2 The mixture in O (0.5 mL) was degassed and N 2 Purge (3×). At N 2 The mixture was stirred at 100℃for 16 hours under an atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give intermediate L-1-3 (190 mg) as a yellow liquid. C (C) 13 H 11 BrClFN 2 The calculated value of ES M/z is [ M+H ]] + 314.0, found 314.0.
To a solution of intermediate L-1-3 (190 mg) and 1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydro-5-pyrimidinecarboxylic acid (167 mg, 906. Mu. Mol) in MeCN (3 mL) was added chloro-N, N, N ', N' -tetramethylformamidine hexafluorophosphate (TCFH, 399 mg,1.21 mmol) and N-methylimidazole (NMI, 124mg,1.51 mmol). The mixture was stirred at 50 ℃ for 16 hours to give a yellow mixture. The mixture was filtered and concentrated under reduced pressure to give a residue, which was triturated with ethyl acetate at 25 ℃ for 1 hour to give intermediate L-1-2 (130 mg) as a white solid. C (C) 20 H 17 BrClFN 3 O 3 The calculated value of ES M/z is [ M+H ] ] + 480.0, found 480.0.
Intermediate L-1-2 (130 mg, 270. Mu. Mol), bis (pinacolato) diboron (172 mg, 676. Mu. Mol), pd (dppf) Cl 2 A mixture of (20 mg, 27. Mu. Mol) and KOAc (80 mg, 811. Mu. Mol) in dioxane (5 mL) was degassed and N 2 Purge (3×). At N 2 The mixture was stirred at 100℃for 16 hours under an atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give intermediate L-1-1 (230 mg) as a yellow liquid. C (C) 26 H 29 BClFN 3 O 5 The calculated value of ES M/z is [ M+H ]] + 528.2, found 528.3.
Intermediate L-1-1 (76 mg, 144. Mu. Mol), intermediate 5-2a (37 mg, 120. Mu. Mol), K 2 CO 3 (50 mg, 360. Mu. Mol) and Pd-118 (7.8 mg, 12. Mu. Mol) in dioxane (1.5 mL) and H 2 The mixture in O (0.15 mL) was degassed and N 2 Purge (3×). At N 2 The mixture was stirred at 100℃for 3 hours under an atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound L-1 (34 mg,99% purity) as a yellow solid. C (C) 35 H 34 ClFN 6 O 5 The calculated value of ES M/z is [ M+H ]] + 673.23, found 673.6.
Compound L-1 (10 mg) was subjected to SFC (instrument: SFC-80; column: DAICEL CHIRALPAK AS (250 mm. Times.30 mm,10 um); condition: A: CO) 2 ；B：0.1％NH 3 H 2 O ETOH; start B:60; end B:60; flow rate (mL/min): 80; and (3) sample injection: 90 Isolation to give compound L-1a (2.46 mg,98% purity, 96% ee) and compound L-1b (2.95 mg,98% purity, 100% ee) as white solids.
Example 3j-1
Preparation of Compounds M-1a and M-1b
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To a solution of 2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (3.80 g,16.3 mmol) and 1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydro-5-pyrimidinecarboxylic acid (3 g,16.29 mmol) in MeCN (30 mL) was added chloro-N, N' -tetramethylformamidine hexafluorophosphate (TCFH, 9.14g,32.6 mmol) and N-methylimidazole (NMI, 3.34g,40.73mmol,3.25 mL). The mixture was stirred at 60℃for 16 hours. The mixture was filtered and concentrated under reduced pressure to give a residue which was triturated with EtOAc (30 mL) at 25 ℃ for 10 min to give intermediate M-1-4 (4.5 g) as a white solid.
Intermediate M-1-4 (3.5 g,8.77 mmol), 3-bromo-2-chloro-4-fluoroaniline (1.97 g,8.77 mmol), K 2 CO 3 (3.63 g,26.3 mmol) and Pd (dppf) Cl 2 (641 mg, 877. Mu. Mol) in dioxane (35 mL) and H 2 The mixture in O (3.5 mL) was degassed and N 2 Purge (3×). At N 2 The mixture was stirred at 100℃for 16 hours under an atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give intermediate M-1-3 (2.2 g) as a yellow solid. C (C) 20 H 19 ClFN 4 O 3 The calculated value of ES M/z is [ M+H ]] + 417.0, found 417.1.
To a solution of intermediate M-1-3 (1.7 g,4.08 mmol) in MeCN (15 mL) was added CuBr (878 mg,6.12 mmol) and isoamyl nitrite (956 mg,8.16 mmol). The mixture was stirred at 40℃for 16 hours. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel to give intermediate M-1-2 (1.2 g) as a yellow solid.
Intermediate M-1-2 (1.49 g,3.10 mmol), bis (pinacolato) diboron (866 mg,3.41 mmol), KOAc (913 mg,9.30 mmol) and Pd (dppf) Cl 2 (227 mg, 310. Mu. Mol,0.1 eq.) in dioxane (15 mL) was degassed and N 2 Purge (3×). At N 2 The mixture was stirred at 100℃for 16 hours under an atmosphere. The mixture was filtered and concentrated to give a residue which was purified by flash silica gel chromatography12g/>Silica gel column, gradient elution with 0% to 50% ethyl acetate/petroleum ether at 60 mL/min) to afford intermediate M-1-1 (1.1 g,43.99% yield, 70% purity) as a yellow solid. C (C) 26 H 29 BClFN 3 O 5 The calculated value of ES M/z is [ M+H ]] + 528.2, found 528.1.
Intermediate M-1-1 (211 mg), intermediate 5-2a (80 mg, 260. Mu. Mol), K 2 CO 3 (108 mg, 780. Mu. Mol) and Pd-118 (16.9 mg, 26. Mu. Mol) in dioxane (2 mL) and H 2 The mixture in O (0.2 mL) was degassed and N 2 Purge (3×). At N 2 The mixture was stirred at 100℃for 16 hours under an atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound M-1 (45 mg) as a white solid. C (C) 35 H 35 ClFN 6 O 5 The calculated value of ES M/z is [ M+H ]] + 673.2, found 673.5.
Compound M-1 (45 mg) was subjected to SFC (instrument: SFC-80; column: DAICEL CHIRALPAK AS (250 mm. Times.30 mm,10 um); condition: A: CO) 2 ；B：0.1％NH 3 H 2 O EtOH; start B:60; end B:60; flow rate (mL/min): 80; and (3) sample injection: 90 Is separated. The separated peaks were purified by preparative HPLC, column: xtime C18 x 30mm x 10um; conditions are as follows: water (0.225% FA) -ACN; start B:25, a step of selecting a specific type of material; end B:55; gradient time (minutes): 10;100% b hold time (minutes): 2; and (3) sample injection: 1) To give compound M-1a (4.77 mg,100% ee,>99% pure) and compound M-1b (5.01 mg,99% ee,>99% purity) as a white solid.
Example 3j-2
Preparation of Compounds M-2a and M-2b
Intermediate M-1-1 (150 mg, 284. Mu. Mol), intermediate 5-5b (60 mg, 237. Mu. Mol), K 2 CO 3 (98 mg, 711. Mu. Mol) and Pd-118 (15 mg, 24. Mu. Mol) dioxane (2 mL) and H 2 O (0.2 mL) solution was degassed and N was used 2 Purge (3×). At N 2 The mixture was stirred at 100℃for 3 hours under an atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound M-2 (32 mg) as an off-white solid. C (C) 32 H 31 ClFN 5 O 5 The calculated value of ES M/z is [ M+H ]] + 621.2, found 620.5.
Compound M-2 (32 mg) was subjected to SFC (instrument: SFC-80; column: DAICEL CHIRALPAK AS (250 mm. Times.30 mm,10 um); condition: A: CO) 2 ；B：0.1％NH 3 H 2 O EtOH; start B:30; end B:30; flow rate (mL/min): 70; and (3) sample injection: 90 Isolation to give compound M-2a (7.5 mg,94.5% ee,96% purity) as a white solid and compound M-2b (6.6 mg,97.3% ee,96% purity) as a white solid.
Example 3j-3
Preparation of Compounds M-3a and M-3b
Intermediate M-1-1 (151 mg), intermediate 5-1b (55 mg, 186. Mu. Mol), K 2 CO 3 (77 mg, 558. Mu. Mol) and Pd-118 (12 mg, 18.6. Mu. Mol) in dioxane (2 mL) and H 2 The mixture in O (0.2 mL) was degassed and N 2 Purge (3×). At N 2 The mixture was stirred at 100℃for 16 hours under an atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound M-3 (80 mg) as a brown solid. C (C) 34 H 35 ClFN 6 O 5 The calculated value of ES M/z is [ M+H ]] + 661.2, found 661.2.
Compound M-3 (80 mg) was purified by SFC (instrument:SFC-80; column: DAICEL CHIRALPAK AS (250 mm. Times.30 mm,10 um); conditions are as follows: a: CO 2 ；B：0.1％NH 3 H 2 O MeOH; start B:60; end B:60; flow rate (mL/min): 80; and (3) sample injection: 150 Is separated. The two separate peaks were repurified by preparative HPLC to give compound M-3a (16.5 mg,96.38% ee,99.76% purity) and compound M-3b (6.5 mg,96.98% ee,99.71% purity) as white solids.
Example 4
Additional compounds
Other compounds, including those provided in embodiments 145-147 and below, can be prepared using methods similar to those described herein.
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(including pharmaceutically acceptable salts thereof).
Example A
LCMS (liquid chromatography/Mass Spectrometry)
High Performance Liquid Chromatography (HPLC) measurements were performed using LC pumps, diode Arrays (DADs) or UV detectors and columns as specified in the corresponding methods. Additional detectors are included if necessary (see table for methods below). The liquid flow from the column is brought to a position where it is largely disposedMass Spectrometer (MS) of a gas pressure ion source. Tuning parameters (e.g., scan range, residence time) are set so as to obtain ions that allow the identification of the nominal monoisotopic Molecular Weight (MW) of the compound, which is within the knowledge of the skilled artisan. The data acquisition is performed with appropriate software. The compounds are described by their experimental retention time (Rt) and ion. If there is no different specification in the data table, the reported molecular ion corresponds to [ M+H ] ] + (protonated molecule) and/or [ M-H] - (deprotonated molecules). In the case where the compound is not directly ionizable, the type of adduct is specified (i.e., [ M+NH ] 4 ] + 、[M+Na] + 、[M+HCOO] - Etc.). For molecules with multiple isotopic modes (Br, CI), the reported values are the values obtained for the lowest isotopic mass. All results were obtained with experimental uncertainties generally associated with the methods used. Hereinafter, "SQD" means single quadrupole detector, "MSD" means mass selective detector, "RT" means room temperature, "BEH" means bridged ethyl siloxane/silica hybrid, "DAD" means diode array detector, "HSS" means high intensity silica, "Q-Tof" means quadrupole time-of-flight mass spectrometer, "CLND" means nitrogen chemiluminescence detector, "ELSD" means evaporative light scattering detector.
Table a: LCMS method code
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Flow rate is expressed in mL/min; column temperature (T) is expressed in degrees Celsius; run time is expressed in minutes.
Table B: LCMS (liquid Crystal Module)
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Retention time (R) t ) Expressed in minutes; LC/MS: in the unspecified case, the mass corresponds to [ M+H ]] +
Example B
Nuclear magnetic resonance spectroscopy
For many compounds, recordings were made on a Bruker DPX-360 operating at 360MHz, on a Bruker Avance 600 operating at 600Z, on a Bruker Avance 400 operating at 400MHz or on a Varian 400MR spectrometer operating at 400MHz 1 H NMR spectrum. The solvent used was chloroform-d 3 (deuterated chloroform, CDC 1) 3 ) And/or DMSO-d 6 (deuterated DMSO, dimethyl-d) 6 Sulfoxide). Chemical shifts (d) are reported in parts per million (ppm) relative to Tetramethylsilane (TMS) used as an internal standard.
Compound a-1: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝11.48(s,1H),8.57(dd,J＝1.4,8.3Hz,1H),8.53(s,1H),7.63(d,J＝7.9Hz,1H),7.39(td,J＝7.8,15.4Hz,2H),7.29(br d,J＝1.6Hz,1H),7.21(br s,1H),7.09(dd,J＝1.3,7.6Hz,1H),4.62-4.31(m,1H),4.05(s,3H),3.90(br dd,J＝3.6,6.8Hz,1H),3.59(s,3H),3.46(s,3H),3.31-3.12(m,1H),3.07-2.96(m,1H),2.94-2.83(m,1H),2.77-2.60(m,1H),2.38(br t,J＝8.1Hz,3H),2.33-2.25(m,1H),2.15-2.01(m,1H),1.85-1.73(m,2H)。
compound a-2: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝10.92(br d,J＝4.6Hz,1H),8.61-8.51(m,1H),8.22(br d,J＝8.0Hz,1H),7.59(ddd,J＝1.5,4.4,7.5Hz,1H),7.40(br t,J＝7.3Hz,1H),7.36-7.27(m,2H),7.21(d,J＝7.6Hz,1H),7.03(d,J＝7.5Hz,1H),6.98-6.64(m,1H),5.33-4.38(m,1H),4.13-3.93(m,4H),3.64-3.58(m,3H),3.45(s,3H),3.28-3.19(m,1H),3.03(br d,J＝12.8Hz,1H),2.94-2.86(m,1H),2.76-2.66(m,1H),2.44(br d,J＝6.6Hz,1H),2.39-2.34(m,2H),2.30(br dd,J＝6.4,13.8Hz,2H),2.22-2.17(m,4H),1.78-1.73(m,1H)。
compound a-71: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝11.43(s,1H),8.66(d,J＝8.3Hz,1H),8.00(s,1H),7.63(br d,J＝8.1Hz,1H),7.49-7.39(m,2H),7.37-7.29(m,2H),7.14(d,J＝7.5Hz,1H),4.72-4.48(m,2H),4.40-4.03(m,9H),3.94-3.62(m,5H),3.49(s,3H),3.02-2.92(m,1H),2.63-2.29(m,2H),1.92-1.85(m,3H)。
compound a-87: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝12.24(s,1H),8.64(dd,J＝1.4,8.3Hz,1H),8.33(d,J＝4.1Hz,1H),8.06(d,J＝4.3Hz,1H),7.63(ddd,J＝1.7,6.1,7.7Hz,1H),7.43-7.40(m,1H),7.39-7.37(m,1H),7.31-7.28(m,1H),7.19(d,J＝5.1Hz,1H),7.14-7.10(m,1H),4.18(dq,J＝0.8,7.1Hz,2H),4.05(br d,J＝6.0Hz,1H),4.01(d,J＝1.4Hz,3H),3.97(s,3H),3.68(br dd,J＝7.3,14.9Hz,2H),3.58(br t,J＝6.9Hz,1H),3.46(br t,J＝7.2Hz,1H),3.34-3.27(m,1H),3.17-3.09(m,1H),2.84-2.76(m,1H),2.14-2.06(m,1H),2.02-1.95(m,1H),1.29(dt,J＝0.9,7.1Hz,3H)。
compound a-126: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝10.91(s,1H),8.54(s,1H),8.22(d,J＝8.0Hz,1H),7.56(br d,J＝7.4Hz,1H),7.39(t,J＝7.6Hz,1H),7.34-7.28(m,2H),7.19(s,1H),7.03(br d,J＝7.5Hz,1H),6.34(br s,1H),4.49-4.42(m,1H),4.25(br d,J＝3.9Hz,1H),4.06(s,3H),3.94(br d,J＝4.0Hz,1H),3.59(s,3H),3.45(s,3H),3.09-3.03(m,3H),2.75(br dd,J＝7.9,12.2Hz,1H),2.44-2.39(m,2H),2.37-2.30(m,2H),2.19(s,3H),1.91-1.85(m,1H)。
compound a-129: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝11.48(s,1H),8.59-8.52(m,2H),8.26(s,1H),7.67-7.61(m,1H),7.45-7.35(m,2H),7.32-7.28(m,1H),7.22(s,1H),7.11-7.06(m,1H),5.87(br s,1H),4.25(br d,J＝7.0Hz,1H),4.02(d,J＝1.4Hz,3H),3.88(br t,J＝7.8Hz,1H),3.81-3.75(m,1H),3.67-3.58(m,7H),3.45(s,3H),3.19(br d,J＝8.5Hz,1H),2.86-2.79(m,1H),2.55(d,J＝2.6Hz,2H),2.28-2.18(m,1H),2.11(br d,J＝7.4Hz,1H)。
compound a-130: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝11.48(s,1H),8.60-8.47(m,2H),8.26(s,1H),7.63(ddd,J＝1.6,3.3,7.7Hz,1H),7.40(td,J＝7.9,17.0Hz,2H),7.30(d,J＝1.5Hz,1H),7.22(s,1H),7.09(ddd,J＝1.4,3.0,7.5Hz,1H),5.72(br s,1H),4.20(br d,J＝6.9Hz,1H),4.02(d,J＝1.3Hz,3H),3.81(br t,J＝6.4Hz,1H),3.77-3.71(m,1H),3.66-3.53(m,6H),3.46(s,3H),3.26-3.15(m,1H),2.86-2.78(m,1H),2.55(d,J＝1.5Hz,2H),2.20-2.17(m,1H),2.10-2.05(m,1H)。
compound a-131: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝10.91(s,1H),8.54(s,1H),8.22(d,J＝8.0Hz,1H),7.59(td,J＝2.0,7.6Hz,1H),7.40(t,J＝7.6Hz,1H),7.34-7.28(m,2H),7.21(d,J＝3.8Hz,1H),7.03(br d,J＝7.6Hz,1H),5.72(s,1H),4.27(br d,J＝5.6Hz,1H),4.03(s,3H),3.91(br d,J＝6.6Hz,1H),3.85-3.77(m,1H),3.71-3.56(m,7H),3.45(s,3H),3.29-3.18(m,1H),2.97(s,1H),2.89(s,1H),2.88-2.81(m,1H),2.56(s,2H),2.23-2.18(m,4H)。
compound a-132: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝10.91(s,1H),8.55(s,1H),8.22(d,J＝8.0Hz,1H),7.59(td,J＝1.9,7.6Hz,1H),7.43-7.36(m,1H),7.34-7.29(m,1H),7.26-7.24(m,1H),7.21(d,J＝3.4Hz,1H),7.05-7.00(m,1H),5.88(s,1H),4.24(br d,J＝7.0Hz,1H),4.02(s,3H),3.87(br t,J＝6.8Hz,1H),3.78(br dd,J＝4.6,8.3Hz,1H),3.67-3.57(m,7H),3.45(s,3H),3.23-3.17(m,1H),2.86-2.78(m,1H),2.55(s,2H),2.19(d,J＝3.1Hz,4H),2.14-2.05(m,1H)。
compound a-135: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝11.49(s,1H),8.61-8.49(m,2H),7.63(br d,J＝7.6Hz,1H),7.44-7.34(m,2H),7.32-7.29(m,1H),7.24(br s,1H),7.08(br d,J＝7.5Hz,1H),6.03(br s,1H),4.65(br d,J＝2.3Hz,1H),4.08-3.99(m,3H),3.71-3.63(m,1H),3.59(s,3H),3.45(s,3H),3.36-3.25(m,2H),3.03-2.88(m,4H),2.62-2.47(m,3H),2.19-2.13(m,2H)。
compound a-136: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝11.49(s,1H),8.81-8.38(m,2H),7.63(br d,J＝7.5Hz,1H),7.40(td,J＝7.8,19.1Hz,2H),7.31(br s,1H),7.24(br s,1H),7.09(br d,J＝7.6Hz,1H),6.06(br s,1H),4.74(br d,J＝3.8Hz,1H),4.11-3.99(m,3H),3.71-3.57(m,4H),3.46(s,3H),3.42-3.28(m,2H),3.11-2.99(m,2H),2.99-2.88(m,2H),2.65-2.47(m,3H),2.24-2.18(m,2H)。
compound a-137: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝10.91(s,1H),8.55(s,1H),8.22(br d,J＝8.1Hz,1H),7.59(br d,J＝6.9Hz,1H),7.40(t,J＝7.6Hz,1H),7.34-7.30(m,1H),7.26-7.24(m,1H),7.22(s,1H),7.06-7.00(m,1H),5.96(br s,1H),4.63(br d,J＝1.1Hz,1H),4.10-3.98(m,3H),3.70-3.56(m,4H),3.45(s,3H),3.35-3.20(m,2H),3.02-2.83(m,4H),2.67-2.43(m,3H),2.19(br d,J＝1.9Hz,5H)。
compound a-138: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝10.91(s,1H),8.55(s,1H),8.22(br d,J＝8.1Hz,1H),7.59(br d,J＝7.1Hz,1H),7.40(br t,J＝7.3Hz,1H),7.34-7.29(m,2H),7.24(br s,1H),7.06-7.00(m,1H),6.03(br s,1H),4.70(br d,J＝2.3Hz,1H),4.11-3.98(m,3H),3.71-3.55(m,4H),3.45(s,3H),3.40-3.25(m,2H),3.08-2.85(m,4H),2.65-2.45(m,3H),2.19(br d,J＝2.8Hz,5H)。
compound 139: 1 H-NMR(400MHz,DMSO-d 6 )δ＝11.06(d,J＝2.9Hz,1H),8.75(s,1H),8.25(d,J＝8.3Hz,1H),8.13(s,1H),8.10(s,1H),7.62-7.57(m,1H),7.51(t,J＝7.6Hz,1H),7.37-7.29(m,2H),7.19(s,1H),6.98(dd,J＝3.4,7.3Hz,1H),3.90(s,4H),3.50(s,4H),3.27(s,3H),3.25(br s,2H),3.19-3.16(m,1H),3.03-2.96(m,1H),2.77(br dd,J＝7.8,17.2Hz,1H),2.19-2.11(m,4H),2.09(d,J＝6.4Hz,3H),2.02(br dd,J＝7.8,13.9Hz,1H),1.91-1.85(m,1H)。
compound J-1: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝12.23(d,J＝4.0Hz,1H),8.64(dd,J＝1.4,8.3Hz,1H),8.33(d,J＝4.3Hz,1H),8.06(d,J＝4.1Hz,1H),7.65(dd,J＝1.7,7.7Hz,1H),7.44-7.37(m,2H),7.35-7.27(m,2H),7.25(d,J＝2.4Hz,1H),7.11(td,J＝1.3,7.6Hz,1H),4.57(br d,J＝7.5Hz,2H),4.28(br s,1H),4.25-4.19(m,1H),4.11(br t,J＝9.4Hz,1H),4.02(d,J＝3.4Hz,3H),3.97(s,3H),3.48(br dd,J＝8.7,16.1Hz,1H),3.17(br s,1H),2.93-2.85(m,1H),2.62-2.51(m,1H),2.37-2.27(m,1H)。
compound H-1: 1 H-NMR(400MHz,DMSO-d 6 )δ＝11.62(d,J＝2.9Hz,1H),8.79(s,1H),8.57(dd,J＝1.3,8.3Hz,1H),8.17(s,1H),7.64(d,J＝7.6Hz,1H),7.55-7.45(m,2H),7.40(dd,J＝1.5,7.5Hz,1H),7.19(s,1H),7.14(ddd,J＝1.4,3.4,7.6Hz,1H),3.95-3.87(m,4H),3.50(br s,1H),3.51(s,4H),3.34-3.32(m,2H),3.27(s,3H),3.25-3.23(m,1H),3.18-3.06(m,3H),3.02-2.95(m,1H),2.76(br dd,J＝8.6,16.8Hz,1H),2.05-1.95(m,2H),1.93-1.86(m,5H)。
compound L-1a: 1 H-NMR(400MHz,DMSO-d 6 )δ＝10.99(s,1H),8.75(s,1H),8.20(dd,J＝5.4,9.0Hz,1H),8.11(s,1H),7.66(br d,J＝7.5Hz,1H),7.55(t,J＝7.6Hz,1H),7.39(br d,J＝7.4Hz,1H),7.25-7.18(m,2H),3.90(s,3H),3.87(br d,J＝6.5Hz,1H),3.50(s,3H),3.27(br s,4H),3.21-3.20(m,1H),3.14(br d,J＝6.8Hz,1H),3.09-2.94(m,2H),2.77(br dd,J＝8.1,16.8Hz,1H),2.15(br dd,J＝5.4,10.9Hz,4H),2.04(s,3H),1.99(br s,1H),1.91-1.85(m,1H)。
compound L-1b: 1 H-NMR(400MHz,DMSO-d 6 )δ＝11.00(s,1H),8.75(s,1H),8.20(dd,J＝5.6,8.8Hz,1H),8.11(s,1H),7.65(br d,J＝7.3Hz,1H),7.55(t,J＝7.6Hz,1H),7.42-7.35(m,1H),7.24-7.19(m,2H),3.90(s,3H),3.86(br d,J＝6.5Hz,1H),3.50(s,3H),3.27(br s,4H),3.21(br s,1H),3.14(br d,J＝6.9Hz,1H),2.98(br d,J＝8.8Hz,2H),2.77(br dd,J＝8.9,16.2Hz,1H),2.19-2.11(m,4H),2.06(s,3H),1.99(br d,J＝6.4Hz,1H),1.89(br d,J＝7.3Hz,1H)。
compound M-2a: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝10.94(s,1H),8.54(s,1H),8.29(br d,J＝8.1Hz,1H),7.62(dd,J＝6.1,8.5Hz,1H),7.38-7.37(m,1H),7.38-7.33(m,1H),7.22-7.17(m,2H),7.04(br d,J＝7.5Hz,1H),4.42(br s,1H),4.27(br s,1H),4.30-4.21(m,1H),4.08-3.97(m,4H),3.91-3.79(m,1H),3.71-3.63(m,1H),3.59(s,3H),3.45(s,4H),3.33-3.25(m,1H),2.85(br dd,J＝8.5,16.9Hz,1H),2.28-2.21(m,1H),2.19(s,3H),2.14-2.04(m,2H)。
compound M-2b: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝10.94(s,1H),8.54(s,1H),8.30(d,J＝7.9Hz,1H),7.62(dd,J＝6.1,8.6Hz,1H),7.35(br t,J＝8.0Hz,2H),7.21(br s,1H),7.05-7.00(m,1H),4.76-4.54(m,2H),4.53-4.40(m,1H),4.29-4.15(m,2H),4.13-3.99(m,4H),3.98-3.87(m,1H),3.59(s,3H),3.46(s,3H),2.94(br dd,J＝8.3,17.0Hz,1H),2.48-2.24(m,3H),2.19(s,3H)。
compound M-3a: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝10.95(s,1H),8.63-8.51(m,1H),8.29(br d,J＝7.6Hz,1H),7.61(dd,J＝6.1,8.5Hz,1H),7.36(t,J＝7.8Hz,1H),7.21-7.14(m,2H),7.07-7.00(m,1H),6.69(br s,1H),4.47(br dd,J＝4.1,7.3Hz,1H),4.03(s,3H),3.95(br d,J＝6.9Hz,1H),3.60(s,3H),3.45(s,3H),3.17(td,J＝7.8,15.8Hz,1H),2.99(br dd,J＝3.1,12.1Hz,1H),2.94-2.82(m,1H),2.65(br dd,J＝9.3,11.9Hz,1H),2.46-2.25(m,6H),2.19(s,3H),1.82-1.72(m,1H)。
compound M-3b: 1 H-NMR(400MHz,CHLOROFORM-d 3 )δ＝10.94(s,1H),9.84-9.55(m,1H),8.55(s,1H),8.29(br d,J＝8.1Hz,1H),8.14-7.95(m,1H),7.77-7.57(m,1H),7.34(t,J＝7.9Hz,1H),7.26-7.11(m,2H),7.07-6.99(m,1H),4.96-4.74(m,1H),4.46-3.88(m,4H),3.59(s,4H),3.45(d,J＝3.6Hz,3H),3.30-2.89(m,3H),2.78-2.12(m,7H),2.10-1.80(m,1H)。
example C
PDL1/PD1 binding assay
The compounds to be tested were serially diluted in DMSO and further diluted in assay buffer (25mM Hepes pH 7.4, 150mM NaCl,0.005% Tween 20, bsa 0.01%). Diluted compounds were added to the wells with a final DMSO concentration of 1%. PDL1-6XHis protein was added to the wells and mixed well with the compound. Plates were incubated for 30min at room temperature. PD 1-Fc-Avi-biotin protein was added to the wells. The final concentrations of PDL1 and PD1 proteins were 0.3nM and 2.5nM, respectively. After a binding time of 30min at room temperature, anti-6 xHis receptor beads (final concentration 20 ug/ml) were added to the wells and incubation was continued for 1h. Adding streptavidin under reduced light Avidin donor beads (final concentration 20 ug/mL). Plates were sealed with foil and incubated in the dark for an additional 1h or overnight before reading on an Envision microplate reader. Determination of IC by fitting a curve using four parameter equations in Graphpad Prism 8 50 Values.
Example D
PD-1/PD-L1 NFAT reporter assay
The cell activity of the compounds was assessed using a co-culture reporter assay in which TCR-mediated NFAT activity of Jurkat T cells was constitutively inhibited by CHO cells expressing PD-L1 engaging PD-1. Blocking the PD-1/PD-L1 interaction will release the inhibitory signal and cause TCR signaling and NFAT-mediated luciferase activity.
CHO cells expressing surface-bound anti-CD 3 antibodies and PD-L1 were first seeded overnight and treated with the compound. Jurkat cells overexpressing the PD-1 and luciferase constructs under the NFAT promoter were then immediately seeded on monolayer CHO cells. The co-culture was then incubated at 37℃for 6 hours. Luciferase activity was assessed by addition of ONE-Glo reagent and luminescence measured with an enzyme-labeled instrument. Determination of EC from fitting of dose response curves 50 Values.
The compounds described herein as exemplified in the examples show EC within the following ranges 50 Or IC (integrated circuit) 50 Value: a: IC (integrated circuit) 50 Or EC (EC) 50 ≤10nM；B：10nM<IC 50 Or EC (EC) 50 ≤100nM；C：100nM<IC 50 Or EC (EC) 50 ≤1000nM；D：1000nM<IC 50 Or EC (EC) 50 ≤10000nM；E：IC 50 Or EC (EC) 50 >10000nM；F：IC 50 Or EC (EC) 50 >5000nM; n.d. =undetermined; n.r. =ec 50 A test concentration range starting from 1nM to 10000nM is not reached.
Table C：
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Furthermore, although the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be understood by those skilled in the art that many and various modifications may be made without departing from the spirit of the disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to cover all modifications and alternatives falling within the true scope and spirit of the present disclosure.

Claims (158)

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, having the structure:
wherein:
A 1 is that
B 1 Is thatEach X is 1 Selected from the group consisting of: CH and N;
X 2 is O;
X 3 selected from the group consisting of: CH. C-halo and N;
Y 1 selected from the group consisting of: n and CH;
Y 2 selected from the group consisting of: n and CH;
Y 3 selected from the group consisting of: n and CH;
Y 4 selected from the group consisting of: n and CH;
Y 5 selected from the group consisting of: n, CH and C-OCH 3 ；
Y 6 Selected from the group consisting of: n and CR 5c ；
Y 7 Is CR (CR) 5e ；
Y 8 Is CR (CR) 5f ；
Each R 1a Selected from the group consisting of: -C 1-4 Alkyl, -C 1-4 Haloalkyl, -CH 2 (C 3-6 Monocyclic cycloalkyl) -C 2-4 Alkyl (C) 1-4 Alkoxy), -C 2-4 Alkyl (C) 1-4 Haloalkoxy) -CH 2 (4-to 6-membered monocyclic heterocyclyl) and-CH 2 (5-to 6-membered monocyclic heteroaryl);
each R 1b Selected from the group consisting of: -N (R) m1 )R n1 and-R x1 ；
R 1d Selected from the group consisting of: hydrogen, -CH 3 、-CH 2 CH 3 、-OH、-OCH 3 and-F;
R 1e selected from the group consisting of: hydrogen, -CH 3 、-CH 2 CH 3 and-F;
R 1f selected from the group consisting of: hydrogen, -CH 3 、-CH 2 CH 3 、-OH、-OCH 3 and-F;
R 1g selected from the group consisting of: hydrogen, -CH 3 、-CH 2 CH 3 and-F;
R 1c selected from the group consisting of: -N (R) m1 )R n1 and-R x1 ；
R 2a 、R 2b 、R 2c 、R 2e 、R 2g 、R 2h Independently selected from the group consisting of: hydrogen and halogen;
R 2d and R is 2f Independently selectA group consisting of: hydrogen, halogen, cyano, -CH 3 、-CH 2 CH 3 、-CH 2 OH、-OCH 3 and-SCH 3 ；
R 3a Selected from the group consisting of: H. -CH 3 、-CF 3 and-CHF 2 ；
R 4a Selected from the group consisting of: H. halogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -CH 2 R 4b and-C (CH) 3 )R 4b ；
R 4b Selected from the group consisting of: -N (R) m2 )R n2 and-R y1 ；
R 5a Selected from the group consisting of: hydrogen, -CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group;
R 5b selected from the group consisting of: hydrogen, -CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group;
R 5c Selected from the group consisting of: hydrogen, -CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group;
R 5d selected from the group consisting of: hydrogen, -CH 3 、-C 2-4 Alkyl and-C 2-4 A haloalkyl group;
R 5e selected from the group consisting of: hydrogen, halogen and-CH 3 ；
R 5f Selected from the group consisting of: hydrogen, halogen, -OH, -CN and-CH 3 ；
R m1 Selected from the group consisting of: hydrogen, -C 1-4 Alkyl, C 3-6 Monocyclic cycloalkyl, C 5-12 Bicyclic cycloalkyl, 5-or 6-membered monocyclic heteroaryl, 4-to 7-membered monocyclic heterocyclyl, 8-to 11-membered fused heteroaryl, 8-to 11-membered fused heterocyclyl and-R x2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heterocyclyl and bicyclic heterocyclyl contain at least one atom or group of atoms independently selected from the group consisting ofIs set of (3): o (oxygen), S (sulfur), C (=o), S (=o) 2 And N (nitrogen); wherein said-C 1-4 The alkyl group is optionally substituted with one or two or three substituents independently selected from: halogen, cyano, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR Z1 、-C(＝O)NHS(＝O) 2 R Z3 、-C(＝O)N(R Z1 )R Z2 、-S(＝O) 2 R Z3 、-S(＝O) 2 N(R Z1 )R Z2 、-N(R Z1 )C(＝O)R Z3 、-N(R Z1 )S(＝O)R Z3 、-N(R Z1 )C(＝O)N(R Z2 )R Z3 and-N (R) Z1 )S(＝O)N(R Z2 )R Z3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said C 3-6 Monocyclic cycloalkyl, the C 5-12 Bicyclic cycloalkyl, the 5-or 6-membered monocyclic heteroaryl, the 4-to 7-membered monocyclic heterocyclyl, the 8-to 11-membered fused heteroaryl, and the 8-to 11-membered fused heterocyclyl are optionally substituted with one, two, three, or four substituents independently selected from: halogen, cyano, -C 1-4 Alkyl, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) R Z1 、-C(＝O)OR Z1 、-C(＝O)NHS(＝O) 2 R Z3 、-C(＝O)N(R Z1 )R Z2 、-S(＝O) 2 R Z3 、-S(＝O) 2 N(R Z1 )R Z2 、-N(R Z1 )C(＝O)R Z3 、-N(R Z1 )S(＝O)R Z3 、-N(R z1 )C(＝O)N(R Z2 )R Z3 and-N (R) Z1 )S(＝O)N(R Z2 )R Z3 The method comprises the steps of carrying out a first treatment on the surface of the And R is n1 Is hydrogen, -C 1-4 Alkyl, -C 1-4 Haloalkyl, C 3-6 Monocyclic Cycloalkyl (CH) 2 ) -OR-C (=o) OR Z4 ；
R m2 Selected from the group consisting of: -CH 3 、-C 2-4 Alkyl, -C 1-4 Haloalkyl and-R y2 Wherein said-C 2-4 Alkyl is optionally substituted with hydroxy;
R n2 selected from the group consisting of: H. -C 1-4 Alkyl and-C 1-4 A haloalkyl group;
R x1 selected from the group consisting of:
wherein R is x1 Optionally substituted with one or two substituents independently selected from: halogen, cyano, -C 1-4 Alkyl, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR Z1 、-C(＝O)NHS(＝O) 2 R Z3 、-C(＝O)N(R Z1 )R Z2 、-S(＝O) 2 R Z3 、-S(＝O) 2 N(R Z1 )R Z2 、-N(R Z1 )C(＝O)R Z3 、-N(R Z1 )S(＝O)R Z3 、-N(R Z1 )C(＝O)N(R Z1 )R Z3 and-N (R) Z1 )S(＝O) 2 N(R Z2 )R Z3 ；
R x2 Selected from the group consisting of:
R y1 selected from the group consisting of:
wherein R is y1 Optionally substituted with one or two substituents independently selected from: halogen, cyano, -C 1-4 Alkyl, hydroxy, -C 1-4 Alkoxy, -C 1-4 Haloalkyl, -C 1-4 Haloalkoxy, -C (=o) OR W1 、-C(＝O)NHS(＝O) 2 R W3 、-C(＝O)N(R W1 )R W2 、-S(＝O) 2 R W3 、-S(＝O)N(R W1 )R W2 、-N(R W1 )C(＝O)R W3 、-N(R W1 )S(＝O)R W3 、-N(R W1 )C(＝O)N(R W2 )R W3 and-N (R) W1 )S(＝O)N(R W2 )R W3 ；
R y2 Selected from the group consisting of:
m 1 、m 2 、m 3 、n 1 、n 2 and n 3 Independently 1 or 2;
m 4 and n 4 Independently 0, 1 or 2;
m 5 and n 5 Independently 1, 2, 3 or 4;
each R X3 Independently selected from the group consisting of: hydrogen, halogen, -C 1-4 Alkyl group,
-C 1-4 Haloalkyl, -C (=o) R Z3 、-C(＝O)OR Z1 、-S(＝O) 2 R Z1 、-
C(＝O)N(R Z1 )R Z2 and-S (=o) N (R Z1 )R Z2 ；
Each R Y3 Independently selected from the group consisting of: hydrogen, halogen, -C 1-4 Alkyl group,
-C 1-4 Haloalkyl, -C(＝O)R W3 、-C(＝O)OR W3 、-S(＝O) 2 R W3 、-
C(＝O)N(R W1 )R W2 and-S (=o) N (R W1 )R W2 ；
R Z1 And R is Z2 Independently selected from the group consisting of: hydrogen, -C 1-4 Alkyl and-C 1-4 A haloalkyl group; or alternatively
R Z1 And R is Z2 Together form a monocyclic heterocyclyl when attached to the same nitrogen;
R W1 and R is W2 Independently selected from the group consisting of: hydrogen, -C 1-4 Alkyl and-C 1-4 A haloalkyl group;
R Z3 and R is W3 Independently selected from the group consisting of: hydrogen, -C 1-4 Alkyl and-C 1-4 A haloalkyl group; and is also provided with
R Z4 Selected from the group consisting of: hydrogen, -C 1-4 Alkyl and optionally-C 1-4 Alkyl substituted 5-to 6-membered monocyclic heterocyclyl (CH 2 )-。
2. The compound of claim 1, wherein a 1 Is that
3. The compound according to claim 2, wherein X 1 CH.
4. The compound according to claim 2, wherein X 1 Is N.
5. The compound according to any one of claims 2 to 4, wherein R 1a is-C 1-4 An alkyl group.
6. The compound according to any one of claims 2 to 4, wherein R 1a is-C 1-4 A haloalkyl group.
7. The compound according to any one of claims 2 to 4, wherein R 1a is-C 2-4 Alkyl (C) 1-4 Alkoxy) or-C 2-4 Alkyl (C) 1-4 Haloalkoxy).
8. The compound according to any one of claims 2 to 4, wherein R 1a Selected from the group consisting of: -CH 2 (C 3-6 Monocyclic cycloalkyl) -CH 2 (4-to 6-membered monocyclic heterocyclyl) and-CH 2 (5-to 6-membered monocyclic heteroaryl).
9. The compound according to any one of claims 2 to 8, wherein R 1b is-N (R) m1 )R n1 。
10. The compound of claim 9, wherein R n1 Is hydrogen.
11. The compound of claim 9, wherein R n1 is-C (=O) OR Z4 。
12. The compound according to any one of claims 9 to 11, wherein R m1 Is optionally-C (=o) OR Z1 substituted-C 1-4 Alkyl or 4-to 7-membered monocyclic heterocyclyl optionally substituted with hydroxy.
13. The compound of claim 12, wherein R m1 Is that
14. The compound of claim 12, wherein R m1 Is tetrahydrofuran or tetrahydro-2H-pyran, each of which is optionally substituted with hydroxy or C 1-4 Alkyl substitution.
15. The compound of claim 14, wherein R m1 Is that
16. The compound according to any one of claims 9 to 11, wherein R m1 is-R x2 。
17. The compound of claim 16, wherein-R x2 Is that
18. The compound according to any one of claims 2 to 8, wherein R 1b is-R x1 。
19. The compound of claim 18, wherein-R x1 Selected from the group consisting of:
20. the compound of claim 19, wherein-R x1 Selected from the group consisting of:
21. the compound of claim 1, wherein a 1 Is that
22. The compound of claim 21, wherein X 1 CH.
23. The compound of claim 21, wherein X 1 Is N.
24. The compound according to any one of claims 21 to 23, wherein R 1a is-C 1-4 An alkyl group.
25. The compound according to any one of claims 21 to 23, wherein R 1a is-C 1-4 A haloalkyl group.
26. The compound according to any one of claims 21 to 23, wherein R 1a Selected from the group consisting of: -CH 2 (C 3-6 Monocyclic cycloalkyl) -CH 2 (4-to 6-membered monocyclic heterocyclyl) and-CH 2 (5-to 6-membered monocyclic heteroaryl).
27. The compound according to any one of claims 21 to 26, wherein R 1c is-N (R) m1 )R n1 。
28. The compound of claim 27, wherein R n1 Is hydrogen.
29. The compound of claim 27, wherein R n1 is-C (=O) OR Z4 。
30. A compound according to any one of claims 27 to 29, wherein R m1 Is C 3-6 Monocyclic cycloalkyl, optionally by-C (=o) OR Z1 substituted-C 1-4 Alkyl or 4-to 7-membered monocyclic heterocyclyl optionally substituted with hydroxy.
31. The compound of claim 30, wherein R m1 Is that
32. The compound of claim 30, wherein R m1 Is tetrahydrofuran or tetrahydro-2H-pyran, each of which is optionally substituted with hydroxy.
33. The compound of claim 32, wherein R m1 Is that
34. The compound according to any one of claims 27 to 29, wherein R m1 is-R x2 。
35. The compound of claim 34, wherein-R x2 Is that
36. The compound according to any one of claims 21 to 26, wherein R 1c is-R x1 。
37. Root of Chinese characterThe compound of claim 36, wherein-R x1 Selected from the group consisting of:
38. the compound of claim 37, wherein-R x1 Selected from the group consisting of:
39. the compound of claim 1, wherein a 1 Is that
40. The compound of claim 39, wherein X 1 CH.
41. The compound of claim 39, wherein X 1 Is N.
42. The compound of any one of claims 39 to 41, wherein X 3 CH.
43. The compound of any one of claims 39 to 41, wherein X 3 Is a C-halo group.
44. The compound of any one of claims 39 to 41, wherein X 3 Is N.
45. The compound of any one of claims 39 to 44, wherein R 1a is-C 1-4 An alkyl group.
46. The compound of any one of claims 39 to 44, wherein R 1a is-C 1-4 A haloalkyl group.
47. The compound of any one of claims 39 to 44, wherein R 1a Selected from the group consisting of: -CH 2 (C 3-6 Monocyclic cycloalkyl) -CH 2 (4-to 6-membered monocyclic heterocyclyl) and-CH 2 (5-to 6-membered monocyclic heteroaryl).
48. The compound of any one of claims 39 to 47, wherein R 1b is-N (R) m1 )R n1 。
49. The compound of any one of claims 39 to 47, wherein R n1 Is hydrogen.
50. The compound of any one of claims 39 to 47, wherein R n1 Is-
C(＝O)OR Z4 。
51. The compound of any one of claims 39 to 50, wherein R m1 Is hydrogen.
52. The compound of any one of claims 39 to 50, wherein R m1 Is optionally-C (=o) OR Z1 substituted-C 1-4 Alkyl or 4-to 7-membered monocyclic heterocyclyl optionally substituted with hydroxy.
53. The compound of any one of claims 39 to 50, wherein R m1 Is C 5 Monocyclic cycloalkyl or C 6 A monocyclic cycloalkyl group.
54. The compound of claim 52, wherein R is m1 Is that
55. The compound of claim 52, wherein R is m1 Tetrahydrofuran or tetrahydro-2H-pyran each optionally substituted by hydroxy, or optionally substituted by-C (=O) R Z1 Substituted piperidines.
56. The compound of claim 55, wherein R is m1 Is that
57. The compound of any one of claims 39 to 50, wherein R m1 is-R x2 。
58. The compound of claim 57, wherein-R x2 Is that
59. The compound of claim 57, wherein-R x2 Is that
60. The compound of any one of claims 39 to 47, wherein R 1b is-R x1 。
61. The method according to claim 60A compound, wherein-R x1 Selected from the group consisting of:
62. the compound of claim 61, wherein-R x1 Selected from the group consisting of:
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63. the compound of any one of claims 39 to 62, wherein R 1d Is hydrogen.
64. The compound of any one of claims 39 to 62, wherein R 1d is-OH.
65. The compound of any one of claims 39 to 62, wherein R 1d is-CH 3 。
66. The compound of any one of claims 39 to 62, wherein R 1d is-F.
67. The compound of any one of claims 63 to 66, wherein R 1e Is hydrogen.
68. The compound of any one of claims 63 to 66, wherein R 1e is-CH 3 。
69. According toThe compound of any one of claims 63 to 68, wherein R 1f Is hydrogen.
70. The compound of any one of claims 63 to 68, wherein R 1f is-CH 3 。
71. The compound of any one of claims 63 to 70, wherein R 1g Is hydrogen.
72. A compound according to any one of claims 1 to 71, wherein B 1 Is that
73. The compound of claim 72, wherein Y 1 Is N.
74. The compound of claim 72, wherein Y 1 CH.
75. The compound of any one of claims 72 to 74, wherein Y 2 Is N.
76. The compound of any one of claims 72 to 74, wherein Y 2 CH.
77. The compound of any one of claims 72 to 76, wherein R 3a H.
78. The compound of any one of claims 72 to 76, wherein R 3a is-CH 3 。
79. The compound of any one of claims 72 to 76, wherein R 3a is-CF 3 。
80. The compound of any one of claims 72 to 76, wherein R 3a is-CHF 2 。
81. A compound according to any one of claims 1 to 71, wherein B 1 Is that
82. The compound of claim 81, wherein Y 3 Is N.
83. The compound of claim 81, wherein Y 3 CH.
84. The compound of any one of claims 81 to 83, wherein Y 4 Is N.
85. The compound of any one of claims 81 to 83, wherein Y 4 CH.
86. The compound of any one of claims 81 to 85 wherein Y 5 Is N.
87. The compound of any one of claims 81 to 85 wherein Y 5 CH.
88. The compound of any one of claims 81 to 85 wherein Y 5 Is C-OCH 3 。
89. The compound of any one of claims 81 to 88, wherein R 4a H.
90. The compound of any one of claims 81 to 88, wherein R 4a Is halogen.
91. The compound of any one of claims 81 to 88, wherein R 4a is-C 1-4 An alkyl group.
92. The compound of any one of claims 81 to 88, wherein R 4a is-C 1-4 A haloalkyl group.
93. The compound of any one of claims 81 to 88, wherein R 4a is-CH 2 R 4b 。
94. The compound of any one of claims 81 to 88, wherein R 4a is-C (CH) 3 )R 4b 。
95. The compound of claim 93 or 94, wherein R 4b is-N (R) m2 )R n2 。
96. The compound of claim 95, wherein R m2 is-CH 3 。
97. The compound of claim 95, wherein R m2 is-C 2-4 An alkyl group.
98. The compound of claim 95, wherein R m2 is-C 1-4 A haloalkyl group.
99. The compound of claim 95, wherein R m2 is-C substituted by hydroxy 2-4 An alkyl group.
100. The compound of any one of claims 95 to 99, wherein R n2 H.
101. The compound according to any one of claims 95 to 99 whichR in (B) n2 is-C 1-4 An alkyl group.
102. The compound of any one of claims 95 to 99, wherein R n2 is-C 1-4 A haloalkyl group.
103. The compound of claim 93 or 94, wherein R 4b is-R y1 。
104. A compound according to any one of claims 1 to 71, wherein B 1 Is that
105. The compound of claim 104, wherein R 5a Is hydrogen.
106. The compound of claim 104, wherein R 5a is-CH 3 。
107. The compound of claim 104, wherein R 5a is-C 2-4 An alkyl group.
108. The compound of claim 104, wherein R 5a is-C 2-4 A haloalkyl group.
109. The compound of any one of claims 104 to 108, wherein R 5b Is hydrogen.
110. The compound of any one of claims 104 to 108, wherein R 5b is-CH 3 。
111. The compound of any one of claims 104 to 108, wherein R 5b is-C 2-4 An alkyl group.
112. The compound of any one of claims 104 to 108, wherein R 5b is-C 2-4 A haloalkyl group.
113. The compound of any one of claims 104 to 112, wherein Y 6 Is N.
114. The compound of any one of claims 104 to 112, wherein Y 6 Is CR (CR) 5c 。
115. The compound of claim 114, wherein R 5c Is hydrogen.
116. The compound of claim 114, wherein R 5c is-CH 3 。
117. The compound of claim 114, wherein R 5c is-C 2-4 An alkyl group.
118. The compound of claim 114, wherein R 5c is-C 2-4 A haloalkyl group.
119. A compound according to any one of claims 1 to 71, wherein B 1 Is that
120. The compound of claim 119, wherein R 5d Is hydrogen.
121. The compound of claim 119, wherein R 5d is-CH 3 。
122. The compound of claim 119, wherein R 5d is-C 2-4 An alkyl group.
123. The compound of claim 119, wherein R 5d is-C 2-4 A haloalkyl group.
124. The compound of any one of claims 119 to 123, wherein Y 7 Is CR (CR) 5e Wherein R is 5e Is hydrogen.
125. The compound of any one of claims 119 to 123, wherein Y 7 Is CR (CR) 5e Wherein R is 5e Is halogen.
126. The compound of any one of claims 119 to 123, wherein Y 7 Is CR (CR) 5e Wherein R is 5e is-CH 3 。
127. The compound of any one of claims 119 to 126, wherein Y 8 Is CR (CR) 5f Wherein R is 5f Is hydrogen.
128. The compound of any one of claims 119 to 126, wherein Y 8 Is CR (CR) 5f Wherein R is 5f Is halogen.
129. The compound of any one of claims 119 to 126, wherein Y 8 Is CR (CR) 5f Wherein R is 5f is-OH.
130. The compound of any one of claims 119 to 126, wherein Y 8 Is CR (CR) 5f Wherein R is 5f Is CN.
131. The compound of any one of claims 119 to 126, wherein Y 8 Is CR (CR) 5f Wherein R is 5f is-CH 3 。
132. A compound according to any of claims 1 to 131, wherein R 2a 、R 2b 、R 2c 、R 2e 、R 2g And R is 2h Each hydrogen.
133. A compound according to any of claims 1 to 131, wherein R 2a 、R 2c 、R 2e 、R 2g And R is 2h Each hydrogen; and R is 2b Is halogen.
134. A compound according to any of claims 1 to 131, wherein R 2b 、R 2c 、R 2e 、R 2g And R is 2h Each hydrogen; and R is 2a Is halogen.
135. The compound of any one of claims 1 to 134, wherein R 2d And R is 2f Each hydrogen.
136. The compound of any one of claims 1 to 134, wherein R 2d And R is 2f Each is-CH 3 。
137. The compound of any one of claims 1 to 134, wherein R 2d Is halogen; and R is 2f is-CH 3 。
138. The compound of any one of claims 1 to 134, wherein R 2d is-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the And R is 2f Is halogen.
139. The compound of any one of claims 1 to 134, wherein R 2d Is cyano; and R is 2f Is halogen.
140. Root of Chinese characterThe compound of any one of claims 1 to 134, wherein R 2d is-OCH 3 The method comprises the steps of carrying out a first treatment on the surface of the And R is 2f Is halogen.
141. The compound of any of claims 133-135 or 137-140 wherein the halogen is chloro or fluoro.
142. The compound of claim 1, selected from the group consisting of:
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or a pharmaceutically acceptable salt of any of the foregoing.
143. The compound of claim 1, selected from the group consisting of:
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/>
/>
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Or a pharmaceutically acceptable salt of any of the foregoing.
144. The compound of claim 1, selected from the group consisting of:
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or a pharmaceutically acceptable salt of any of the foregoing.
145. The compound of claim 1, selected from the group consisting of:
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or a pharmaceutically acceptable salt of any of the foregoing.
146. The compound of claim 1, selected from the group consisting of:
/>
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or a pharmaceutically acceptable salt of any of the foregoing.
147. The compound of claim 1, selected from the group consisting of:
/>
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/>
/>
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or a pharmaceutically acceptable salt of any of the foregoing.
148. The compound of claim 1, selected from the group consisting of: a-1 to A-139, B-1, B-2, B-3, B-4, C-1, D-2, D-3, D-4, D-5, D-6, D-7, D-8a, D-8B, D-10, D-11, D-12, D-13, D-14, D-15, D-16, D-17, D-18, D-19, E-1, E-2, E-3, F-1, G-1, H-1, I-1, J-2, J-3, J-4, K-1a, K-1B, L-1a, L-1B, M-1a, M-1B, M-2a, M-2B, M-3a and M-3B, or a pharmaceutically acceptable salt of any of the foregoing.
149. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 148, or a pharmaceutically acceptable salt thereof, and an excipient.
150. A method for treating hepatitis b in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-148, or a pharmaceutically acceptable salt thereof.
151. A method for treating hepatocellular carcinoma (HCC) in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-148, or a pharmaceutically acceptable salt thereof.
152. The method of any one of claims 150 to 151, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.
153. A compound according to any one of claims 1 to 148, or a pharmaceutically acceptable salt thereof, for use in the treatment of hepatitis b.
154. A compound according to any one of claims 1 to 148, or a pharmaceutically acceptable salt thereof, for use in the treatment of hepatocellular carcinoma (HCC).
155. The compound of any one of claims 153 to 154, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.
156. Use of a compound according to any one of claims 1 to 148, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of hepatitis b.
157. Use of a compound according to any one of claims 1 to 148, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of hepatocellular carcinoma (HCC).
158. The use of any one of claims 156-157, further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.
CN202280052023.XA 2021-06-18 2022-06-15 Methods and compositions for targeting PD-L1 Pending CN117813090A (en)

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US63/212,388 2021-06-18
US63/263,427 2021-11-02
US202263363777P 2022-04-28 2022-04-28
US63/363,777 2022-04-28
PCT/US2022/033653 WO2022266236A1 (en) 2021-06-18 2022-06-15 Methods and compositions for targeting pd-l1

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