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CN119255987A - 3C-like protease inhibitor - Google Patents

3C-like protease inhibitor Download PDF

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Publication number
CN119255987A
CN119255987A CN202380042999.3A CN202380042999A CN119255987A CN 119255987 A CN119255987 A CN 119255987A CN 202380042999 A CN202380042999 A CN 202380042999A CN 119255987 A CN119255987 A CN 119255987A
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alkylene
halogen
alkyl
haloalkyl
compound
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Inventor
张宏波
杨琪
张伟
孙静
石磊
丁康
王虎庭
许庆博
黄博
赵金存
陈新文
彭伟
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Beijing Wangshi Intelligent Technology Co ltd
Guangzhou National Laboratory
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Beijing Wangshi Intelligent Technology Co ltd
Guangzhou National Laboratory
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a 3C-like protease inhibitor shown in a formula (I), or pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorphism, hydrate or solvate thereof. The invention also provides a preparation method of the compound, a pharmaceutical composition containing the compound and an effect of the compound in treating or preventing diseases caused by virus infection.

Description

3C-like protease inhibitors
The present application claims priority from chinese application 202210600337.0, 5, 27, 2022, and chinese application 202310077572.9, 20, 1, 2023, which are incorporated herein by reference in their entirety.
Technical Field
The present invention relates to a novel class of 3C-like protease inhibitors, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof. The invention also relates to a preparation method of the compound, a pharmaceutical composition containing the compound and an effect of the compound in treating or preventing diseases caused by virus infection.
Background
The new coronavirus found in month 12 of 2019 was initially named 2019-nCoV, which was changed by the World Health Organization (WHO) to COVID-19, after which the international committee for classification of viruses formally named the new coronavirus as SARS-CoV-2 according to systemics, taxonomies and conventions. SARS-CoV-2 can cause Severe Acute Respiratory (SARI) symptoms including fever, dyspnea, weakness, pneumonia, etc.
Among all known RNA viruses, coronaviruses have a maximum genome length of between about 26 and 32 kb. In addition to encoding structural proteins, a large portion of the coronavirus genome is transcribed and translated into polypeptides encoding proteins necessary for viral replication and gene expression. A major protease (Mpro) of about 306aa length is a key enzyme for coronavirus replication, and is also encoded by the polypeptide and responsible for processing the polypeptide into a functional protein. Mpro has a similar cleavage site specificity as the picornaviral 3C protease (3 Cpro), and is therefore also referred to as 3C-like protease (3 CLpro). Studies have shown that the 3CLpro of different coronaviruses is highly conserved in both sequence and 3D structure. These features and their functional importance make 3CLpro a target for anti-coronavirus drug design.
The function of 3CLpro is to hydrolyse the expressed peptide chain at the appropriate site in preparation for the peptide chain to form a three-dimensional four-dimensional structure to form the enzyme required for viral proliferation. The enzyme is not changed during the catalysis process, but the activation energy of the hydrolysis reaction is reduced, thereby accelerating the rate of the hydrolysis reaction, wherein the sulfhydryl group on the cysteine plays a critical role in the whole catalytic hydrolysis process, see Thanigaimalai et.al,An Overview of Severe Acute Respiratory Syndrome-Coronavirus(SARS-CoV)3CL Protease Inhibitors:Peptidomimetics and Small Molecule Chemotherapy,Journal of Medicinal Chemistry,59(14):6595-6628.
There are disclosures in the prior art about 3CLpro inhibitors. For example, WO2021/250648A1 discloses a compound currently known as NIRMATRELVIR (PF-07321332) which, as one of the active ingredients of pamphlet Luo Weide (Paxlovid), in combination with ritonavir, is able to reduce the risks of death and hospitalization caused by the novel coronavirus SARS-CoV-2.
Furthermore, WO2021/205290A1 discloses similarly structured compounds which treat SARS-CoV-2 caused disease via a 3C-like protease inhibitor mediated pathway.
However, the compounds of the prior art have disadvantages, such as the inhibition of the CYP3A4 enzyme by Pa Luo Weide, and thus the situation that the metabolism of other medicines by the enzyme is disturbed, the half-life and the clearance rate are changed, the curative effect is reduced or adverse reactions are generated may occur. For example, when the patient takes Pa Luo Weide and terfenadine simultaneously, pa Luo Weide inhibits oxidative metabolism of terfenadine by CYP3A4, so that the concentration of the terfenadine in the patient is abnormally increased, and QT wave prolongation and arrhythmia of the heart are caused. The compounds disclosed in WO2021/205290A1 also face the problem of inefficiency when administered orally. Thus, there is a growing need to develop new 3C-like protease inhibitors.
Disclosure of Invention
The invention takes 3C-like protease as a target point, develops a new class of small molecule inhibitors, and can be used for treating or preventing virus infection.
The compound targets 3C-like protease, has excellent inhibitory activity on the 3C-like protease with P132H mutation, and can remarkably inhibit the proliferation of SARS-CoV-2.
In one aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
Wherein:
Wherein,
Y is N or CR 7;
R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
L 1 is selected from a bond, C 1-6 alkylene, -NH-, -O-, or-S-;
R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl, or 5-20 membered heteroaryl, said R 1 being optionally substituted with 1,2, or 3,4, or 5R 1s, said R 1 preferably being C 6-10 aryl or 5-10 membered heteroaryl;
r 1s is selected from H, deuterium, CN, NO 2、NH2, OH, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, Halogenated C 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3-8 membered heterocyclyl or-O-3-8 membered heteroaryl;
Or two R 1s on the same carbon atom together form oxo or thioxo;
L 2 is selected from a bond or C 1-6 alkylene;
R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, said R 2 being optionally substituted with 1, 2, 3, 4 or 5 independently selected R 2s;
R 2s is selected from H, D, halogen, CN, -L 2a -R' or
L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene- -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene- -C 0-6 alkylene-C (O) NH-C 0-6 alkylene- -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or-C 2-6 alkenylene-, said L 2a optionally being substituted with 1, 2, 3, 4 or 5 independently selected r# substitutions; the L 2a is preferably-O-or-S-, preferably the L 2a is-O-, preferably the L 2a is-S-;
R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-10 alkyl, C 1-10 alkoxy, C 1-10 haloalkyl, C 1- 10 haloalkoxy, C (O) R a、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、Boc、C2-6 alkenyl, OR C 2-6 alkynyl, OR two R on the same carbon atom taken together form c=o OR c=s;
m is selected from 0, 1,2,3,4 or 5;
R' is selected from H, NH 2、CN、C0-6 alkylene-C (O) R a、C0-6 alkylene-C (O) OR a、C1-6 alkylene-OC (O) -R a、C0-6 alkylene-NHC (O) R a、C0-6 alkylene-C (O) NR bRc、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylene-OR a、C2-6 alkenyl, OR C 2- 6 alkynyl;
L 3 is-NR b -or-CR aRb -;
R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, said R 3 being optionally substituted with 1, 2, 3,4 or 5R 3s;
R 3s is selected from H, deuterium, halogen, CN, NO 2、NH2、C1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1- 6 alkyl, halo C 1-6 alkoxy, halo C 2-6 alkenyl, Halogenated C 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3-8 membered heterocyclyl, -O-3-8 membered heteroaryl, or two R 3s on the same carbon atom together form c=o or c=s;
R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
wherein each group definition may be optionally substituted with D until fully deuterated.
In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
Wherein:
Y is N or CR 7;
R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
L 1 is selected from a bond or C 1-6 alkylene, -NH-, -O-, or-S-;
R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl, or 5-20 membered heteroaryl, said R 1 being optionally substituted with 1,2, or 3,4, or 5R 1s, said R 1 preferably being C 6-10 aryl or 5-10 membered heteroaryl;
R 1s is selected from H, deuterium, CN, NO 2、NH2, halogen, C 1-6 alkyl, C 1-6 haloalkyl, halogen, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, Halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8 membered heterocyclyl, 3 to 8 membered heteroaryl, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3-8 membered heterocyclyl or-O-3-8 membered heteroaryl;
L 2 is selected from a bond or C 1-6 alkylene;
R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, said R 2 being optionally substituted with 1, 2, 3, 4 or 5 independently selected R 2s;
R 2s is selected from H, D, halogen, CN, -L 2a -R' or
L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene- -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene- -C 0-6 alkylene-C (O) NH-C 0-6 alkylene- -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or-C 2-6 alkenylene-, said L 2a optionally being substituted with 1, 2, 3, 4 or 5 independently selected r# substitutions; the L 2a is preferably-O-or-S-; preferably, the L 2a is-O-, preferably, the L 2a is-S-;
R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-10 alkyl, C 1-10 alkoxy, C 1-10 haloalkyl, C 1-10 haloalkoxy, C (O) R a、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、Boc、C2-6 alkenyl, OR C 2-6 alkynyl, OR two R on the same carbon atom taken together form c=o OR c=s;
m is selected from 0, 1,2,3,4 or 5;
R' is selected from H, NH 2、CN、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, or C 2-6 alkynyl;
L 3 is-NR b -or-CR aRb -;
R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, said R 3 being optionally substituted with 1, 2, 3,4 or 5R 3s;
R 3s is selected from H, deuterium, halogen, CN, NO 2、NH2、C1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 2-6 alkenyl, haloC 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -O-C 1- 6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3-8 membered heterocyclyl, -O-3-8 membered heteroaryl, or two R 3s on the same carbon atom together form c=o or c=s;
R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
wherein each group definition may be optionally substituted with D until fully deuterated.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant or vehicle.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, which further comprises an additional therapeutic agent, for example selected from the group consisting of rituximab (REMDESIVIR or GS-5734), lopinavir (Lopinavir), mo Nupi (Molnupiravir), ritonavir (Ritonavir), chloroquine (Chloroquine or Sigma-C6628), hydroxychloroquine, and interferon-alpha.
In another aspect, the invention provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment and/or prophylaxis of a disease caused by a viral infection.
In another aspect, the invention provides a method of treating and/or preventing a disease caused by a viral infection in a subject comprising administering to said subject a compound of the invention or a pharmaceutical composition of the invention.
In another aspect, the present invention provides a compound of the invention or a pharmaceutical composition of the invention for use in the treatment and/or prophylaxis of a disease caused by a viral infection.
In particular embodiments, the compounds or pharmaceutical compositions of the invention are useful for inhibiting viral proliferation;
In another specific embodiment, the compounds or pharmaceutical compositions of the invention inhibit the activity of viral 3CL protease.
In another specific embodiment, the 3CL protease has a P132H mutation.
In another specific embodiment, the virus is a coronavirus, preferably an alpha coronavirus and/or a beta coronavirus, more preferably SARS-CoV-2.
In another embodiment, the present invention is used to treat and/or prevent a disease caused by fever, nausea, vomiting, headache, dyspnea, weakness, respiratory tract infection, pneumonia, dyskinesia, dysgeusia and complications thereof, or a combination thereof.
Definition of the definition
Chemical definition
The definition of specific functional groups and chemical terms is described in more detail below.
When numerical ranges are listed, it is intended to include each and every value and subrange within the range. For example, "C 1-6 alkyl" includes C1、C2、C3、C4、C5、C6、C1-6、C1-5、C1-4、C1-3、C1-2、C2-6、C2-5、C2-4、C2-3、C3-6、C3-5、C3-4、C4-6、C4-5 and C 5-6 alkyl.
"C 1-10 alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 10 carbon atoms. In some embodiments, C 1-6 alkyl, C 1-4 alkyl, C 1-3 alkyl, and C 1-2 alkyl are preferred. Examples of C 1-6 alkyl groups include methyl (C 1), ethyl (C 2), n-propyl (C 3), Isopropyl (C 3), n-butyl (C 4), tert-butyl (C 4), sec-butyl (C 4), Isobutyl (C 4), n-pentyl (C 5), 3-pentyl (C 5), pentyl (C 5), Neopentyl (C 5), 3-methyl-2-butyl (C 5), tert-amyl (C 5) and n-hexyl (C 6). The term "C 1-6 alkyl" also includes heteroalkyl groups in which one or more (e.g., 1,2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include ：Me(-CH3)、Et(-CH2CH3)、iPr(-CH(CH3)2)、nPr(-CH2CH2CH3)、n-Bu(-CH2CH2CH2CH3) or i-Bu (-CH 2CH(CH3)2).
"C 2-6 alkenyl" refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 alkenyl is preferred. Examples of C 2-6 alkenyl groups include vinyl (C 2), 1-propenyl (C 3), 2-propenyl (C 3), 1-butenyl (C 4), 2-butenyl (C 4), butadienyl (C 4), pentenyl (C 5), pentadienyl (C 5), hexenyl (C 6), and the like. The term "C 2-6 alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1,2,3, or 4) carbon atoms are replaced with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
"C 2-6 alkynyl" refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 alkynyl is preferred. Examples of C 2-6 alkynyl include, but are not limited to, ethynyl (C 2), 1-propynyl (C 3), 2-propynyl (C 3), 1-butynyl (C 4), 2-butynyl (C 4), pentynyl (C 5), hexynyl (C 6), and the like. The term "C 2- 6 alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1,2,3, or 4) carbon atoms are replaced with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
"C 1-6 alkylene" refers to a divalent group formed by removing another hydrogen of a C 1-6 alkyl group, and may be substituted or unsubstituted. In some embodiments, C 1-4 alkylene, C 2-4 alkylene, and C 1-3 alkylene are preferred. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2CH2 -), propylene (-CH 2CH2CH2 -), butylene (-CH 2CH2CH2CH2 -), pentylene (-CH 2CH2CH2CH2CH2 -), hexylene (-CH 2CH2CH2CH2CH2CH2 -), and the like. Exemplary substituted alkylene groups, for example, alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH (CH 3)-、-C(CH3)2 -), substituted ethylene (-CH(CH3)CH2-、-CH2CH(CH3)-、-C(CH3)2CH2-、-CH2C(CH3)2-)、 substituted propylene (-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH2CH(CH3)-、-C(CH3)2CH2CH2-、-CH2C(CH3)2CH2-、-CH2CH2C(CH3)2-),, and the like.
"C 2-6 alkenylene" refers to a divalent group formed by removal of another hydrogen of a C 2-6 alkenyl group, and may be substituted or unsubstituted. In some embodiments, C 2-4 alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to, vinylidene (-ch=ch-) and propenylene (e.g., -ch=chch 2-、-CH2 -ch=ch-). Exemplary substituted such alkenylene groups, for example, alkenylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylene groups (-C (CH 3)＝CH-、-CH＝C(CH3) -), substituted propenylene groups (-C(CH3)＝CHCH2-、-CH＝C(CH3)CH2-、-CH＝CHCH(CH3)-、-CH＝CHC(CH3)2-、-CH(CH3)-CH＝CH-、-C(CH3)2-CH＝CH-、-CH2-C(CH3)＝CH-、-CH2-CH＝C(CH3)-),, and the like.
"C 2-6 alkynylene" refers to a divalent group formed by removal of another hydrogen of a C 2-6 alkynyl group, and may be substituted or unsubstituted. In some embodiments, C 2-4 alkynylene is particularly preferred. Exemplary such alkynylene groups include, but are not limited to, ethynylene (-C.ident.C-), substituted or unsubstituted propynylene (-C.ident.CCH 2 -), and the like.
"C 0-6 alkylene" refers to a bond and the above-mentioned "C 1-6 alkylene", "C 0-4 alkylene" refers to a bond and the above-mentioned "C 1-4 alkylene", "C 0-3 alkylene" refers to a bond and the above-mentioned "C 1-3 alkylene".
"C 1-10 alkoxy" refers to O-C 1-10 alkyl. In some embodiments, a C 1-6 alkyl group is preferred. In other embodiments, C 1-4 alkoxy is preferred, e.g., methoxy, ethoxy, and the like.
"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
Thus, "C 1-10 haloalkyl" refers to the "C 1-10 alkyl" described above, which is substituted with one or more halo groups. In some embodiments, C 1-6 haloalkyl is preferred, C 1-4 haloalkyl is particularly preferred, more preferably C 1-3 haloalkyl, more preferably C 1-2 haloalkyl. Exemplary such haloalkyl groups include, but are not limited to ：-CF3、-CH2F、-CHF2、-CHFCH2F、-CH2CHF2、-CF2CF3、-CCl3、-CH2Cl、-CHCl2、2,2,2- trifluoro-1, 1-dimethyl-ethyl, and the like. The haloalkyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
"C 1-6 haloalkoxy" refers to O-C 1-6 haloalkyl. In some embodiments, C 1-4 haloalkoxy is preferred, e.g., halomethoxy, haloethoxy, and the like.
"C 3-10 cycloalkyl" and "C 3-10 cycloalkenyl" refer to non-aromatic cyclic hydrocarbon groups having 3 to 10 ring carbon atoms and zero heteroatoms, optionally containing 1,2 or 3 double or triple bonds. In some embodiments, C 5-10 cycloalkyl, C 3-7 cycloalkyl and C 3-6 cycloalkyl are particularly preferred, more preferably C 5-7 cycloalkyl and C 5-6 cycloalkyl. Cycloalkyl also includes ring systems in which the cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to represent the number of carbons in the cycloalkyl system. Cycloalkyl also includes wherein the cycloalkyl rings described above, wherein substituents on any non-adjacent carbon atoms are joined to form a bridged ring, taken together to form a multicyclic alkane sharing two or more carbon atoms. Cycloalkyl also includes the cycloalkyl rings described above, wherein substituents on the same carbon atom are joined to form a ring, together forming a multicycloalkane sharing one carbon atom. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C 3), cyclopropenyl (C 3), cyclobutyl (C 4), cyclobutenyl (C 4), Cyclopentyl (C 5), cyclopentenyl (C 5), cyclohexyl (C 6), cyclohexenyl (C 6), Cyclohexadienyl (C 6), cycloheptyl (C 7), cycloheptenyl (C 7), cycloheptadienyl (C 7), Cycloheptatriene (C 7), and the like. Cycloalkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
"C 3-10 Cycloalkylene" refers to a divalent group formed by removal of another hydrogen of a C 3-10 cycloalkyl group, and may be substituted or unsubstituted. In some embodiments, C 5-10 cycloalkylene, C 5-7 cycloalkylene, C 3-7 cycloalkylene, C 3-6 cycloalkylene, and C 3-4 cycloalkylene are particularly preferred, with cyclopropylene being particularly preferred.
"3-14 Membered heterocyclyl" refers to a saturated or unsaturated group of a 3-14 membered non-aromatic ring system having ring carbon atoms and 1 to 7 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon, optionally containing 1, 2 or 3 double or triple bonds. In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as the valence permits. In some embodiments, a 3-10 membered heterocyclic group is preferred, which is a 3-10 membered non-aromatic ring system having a ring carbon atom and 1 to 5 ring heteroatoms, a 5-10 membered heterocyclic group is preferred, which is a 5-10 membered non-aromatic ring system having a ring carbon atom and 1 to 5 ring heteroatoms, a 3-7 membered heterocyclic group is preferred, which is a 3-7 membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, a 5-7 membered heterocyclic group is preferred, which is a 5-7 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms, a 3-6 membered heterocyclic group is preferred, which is a 3-6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms, a 4-6 membered heterocyclic group is preferred, which is a 4-6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms, and a more preferred, which is a 5-6 membered heterocyclic group, which is a 5-6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms. More preferably a5 membered heterocyclyl which is a5 membered non aromatic ring system heterocyclyl having ring carbon atoms and 1 to 3 ring heteroatoms further comprising a ring system wherein the heterocyclyl ring as described above is fused to one or more cycloalkyl groups, wherein the point of attachment is on the heterocyclyl ring, or a ring system wherein the heterocyclyl ring as described above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such a case the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Heterocyclyl also includes the heterocyclic rings described above in which substituents on any non-adjacent carbon or nitrogen atom are joined to form a bridged ring, taken together to form a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclyl groups also include those wherein the above-mentioned heterocyclyl rings are wherein the substituents on the same carbon atom are joined to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridine, oxetane, thiirane (thiorenyl). Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, 2, 5-dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, pyrazolidinyl, dioxolanyl, oxathiolanyl (oxasulfuranyl), dithiolanyl (disulfuranyl), and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl (thianyl). Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiocyclohexenyl, dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl (triazinanyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepinyl, and thiepanyl. Exemplary 5-membered heterocyclic groups fused to a C 6 aryl ring (also referred to herein as 5, 6-bicyclic heterocyclic groups) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone groups, and the like. Exemplary 6-membered heterocyclyl groups fused to a C 6 aryl ring (also referred to herein as 6, 6-bicyclic heterocyclyl) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Heterocyclyl also includes those wherein the heterocyclyl shares one or two atoms with a cycloalkyl, heterocyclyl, aryl or heteroaryl group to form a bridged or spiro ring, where the shared atoms may be carbon or nitrogen atoms as the valency permits. Heterocyclyl also includes the above heterocyclyl and heterocyclyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
"C 6-20 aryl" refers to a group of a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) having 6-20 ring carbon atoms and zero heteroatoms. In some embodiments, a C 6-10 aryl group is preferred. In some embodiments, aryl groups have six ring carbon atoms ("C 6 aryl"; e.g., phenyl). In some embodiments, aryl groups have ten ring carbon atoms ("C 10 aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the above aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
"3-20 Membered heteroaryl" refers to a group of a 3-20 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) having ring carbon atoms and 1-8 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as the valency permits. The heteroaryl bicyclic ring system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-14 membered heteroaryl groups are particularly preferred, which are 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-6 ring heteroatoms. In some embodiments, 5-10 membered heteroaryl groups are particularly preferred, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-3 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary three heteroatom containing 5 membered heteroaryl groups include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2, 4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl or pyridonyl. Exemplary 6 membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azetidinyl, oxepinyl, and thietaneyl. Exemplary 5, 6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazole, benzopyrazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisotofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indenazinyl, and purinyl. Exemplary 6, 6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Heteroaryl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
The divalent groups formed by removing another hydrogen from the above-defined alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl groups and the like are collectively referred to as "subunits". Cyclic groups such as cycloalkyl, heterocyclyl, aryl, and heteroaryl are collectively referred to as "cyclic groups".
Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like as defined herein are optionally substituted groups.
Exemplary substituents on carbon atoms include, but are not limited to, halo 、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-ORaa、-ON(Rbb)2、-N(Rbb)2、-N(Rbb)3 +X-、-N(ORcc)Rbb、-SH、-SRaa、-SSRcc、-C(＝O)Raa、-CO2H、-CHO、-C(ORcc)2、-CO2Raa、-OC(＝O)Raa、-OCO2Raa、-C(＝O)N(Rbb)2、-OC(＝O)N(Rbb)2、-NRbbC(＝O)Raa、-NRbbCO2Raa、-NRbbC(＝O)N(Rbb)2、-C(＝NRbb)Raa、-C(＝NRbb)ORaa、-OC(＝NRbb)Raa、-OC(＝NRbb)ORaa、-C(＝NRbb)N(Rbb)2、-OC(＝NRbb)N(Rbb)2、-NRbbC(＝NRbb)N(Rbb)2、-C(＝O)NRbbSO2Raa、-NRbbSO2Raa、-SO2N(Rbb)2、-SO2Raa、-SO2ORaa、-OSO2Raa、-S(＝O)Raa、-OS(＝O)Raa、-Si(Raa)3、-OSi(Raa)3、-C(＝S)N(Rbb)2、-C(＝O)SRaa、-C(＝S)SRaa、-SC(＝S)SRaa、-SC(＝O)SRaa、-OC(＝O)SRaa、-SC(＝O)ORaa、-SC(＝O)Raa、-P(＝O)2Raa、-OP(＝O)2Raa、-P(＝O)(Raa)2、-OP(＝O)(Raa)2、-OP(＝O)(ORcc)2、-P(＝O)2N(Rbb)2、-OP(＝O)2N(Rbb)2、-P(＝O)(NRbb)2、-OP(＝O)(NRbb)2、-NRbbP(＝O)(ORcc)2、-NRbbP(＝O)(NRbb)2、-P(Rcc)2、-P(Rcc)3、-OP(Rcc)2、-OP(Rcc)3、-B(Raa)2、-B(ORcc)2、-BRaa(ORcc)、 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd groups;
Or two geminal hydrogens on the carbon atom are substituted with a group ＝O、＝S、＝NN(Rbb)2、＝NNRbbC(＝O)Raa、＝NNRbbC(＝O)ORaa、＝NNRbbS(＝O)2Raa、＝NRbb or = NOR cc;
Each of R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2,3,4, or 5R dd groups;
Each of R bb is independently selected from hydrogen 、-OH、-ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRcc)ORaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)2Raa、-P(＝O)(Raa)2、-P(＝O)2N(Rcc)2、-P(＝O)(NRcc)2、 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R bb groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3,4, or 5R dd groups;
Each of R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2,3,4, or 5R dd groups;
Each of R dd is independently selected from halogen 、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-ORee、-ON(Rff)2、-N(Rff)2,、-N(Rff)3 +X-、-N(ORee)Rff、-SH、-SRee、-SSRee、-C(＝O)Ree、-CO2H、-CO2Ree、-OC(＝O)Ree、-OCO2Ree、-C(＝O)N(Rff)2、-OC(＝O)N(Rff)2、-NRffC(＝O)Ree、-NRffCO2Ree、-NRffC(＝O)N(Rff)2、-C(＝NRff)ORee、-OC(＝NRff)Ree、-OC(＝NRff)ORee、-C(＝NRff)N(Rff)2、-OC(＝NRff)N(Rff)2、-NRffC(＝NRff)N(Rff)2、-NRffSO2Ree、-SO2N(Rff)2、-SO2Ree、-SO2ORee、-OSO2Ree、-S(＝O)Ree、-Si(Ree)3、-OSi(Ree)3、-C(＝S)N(Rff)2、-C(＝O)SRee、-C(＝S)SRee、-SC(＝S)SRee、-P(＝O)2Ree、-P(＝O)(Ree)2、-OP(＝O)(Ree)2、-OP(＝O)(ORee)2、 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3,4, or 5R gg groups, or two geminal R dd substituents may combine to form =o or =s;
Each of R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5R gg groups;
Each of R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ff groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2,3,4, or 5R gg groups;
R gg is each independently halogen, -CN, -NO 2、-N3、-SO2H、-SO3H、-OH、-OC1-6 alkyl, -ON (C 1-6 alkyl) 2、-N(C1-6 alkyl) 2、-N(C1-6 alkyl) 3 +X-、-NH(C1-6 alkyl) 2 +X-、-NH2(C1-6 alkyl) +X-、-NH3 +X-、-N(OC1-6 alkyl) (C 1-6 alkyl), -N (OH) (C 1-6 alkyl), -NH (OH), -SH, -SC 1-6 alkyl, -SS (C 1-6 alkyl), -C (=o) (C 1-6 alkyl), -CO 2H、-CO2(C1-6 alkyl), -OC (=o) (C 1-6 alkyl), -OCO 2(C1-6 alkyl), -C (=o) NH 2、-C(＝O)N(C1-6 alkyl) 2、-OC(＝O)NH(C1-6 alkyl, -NHC (=o) (C 1-6 alkyl), -N (C 1-6 alkyl) C (=o) (C 1-6 alkyl), -NHCO 2(C1-6 alkyl), -NHC (=o) N (C 1-6 alkyl) 2、-NHC(＝O)NH(C1-6 alkyl), -NHC (=o) NH 2、-C(＝NH)O(C1-6 alkyl), -OC (=nh) (C 1- 6 alkyl), -OC (=nh) OC 1-6 alkyl, -C (=nh) N (C 1-6 alkyl) 2、-C(＝NH)NH(C1-6 alkyl), -C (=nh) NH 2、-OC(＝NH)N(C1-6 alkyl) 2、-OC(NH)NH(C1-6 alkyl, -OC (NH) NH 2、-NHC(NH)N(C1-6 alkyl) 2、-NHC(＝NH)NH2、-NHSO2(C1-6 alkyl), -SO 2N(C1-6 alkyl) 2、-SO2NH(C1-6 alkyl, -SO 2NH2、-SO2C1-6 alkyl, -SO 2OC1-6 alkyl, -OSO 2C1-6 alkyl, -SOC 1-6 alkyl, -Si (C 1-6 alkyl) 3、-OSi(C1-6 alkyl) 3、-C(＝S)N(C1-6 alkyl) 2、C(＝S)NH(C1-6 alkyl), C (=s) NH 2、-C(＝O)S(C1-6 alkyl, -C (=s) SC 1-6 alkyl, -SC (=s) SC 1-6 alkyl, -P (=o) 2(C1-6 alkyl), -P (=o) (C 1- 6 alkyl) 2、-OP(＝O)(C1-6 alkyl) 2、-OP(＝O)(OC1-6 alkyl) 2、C1-6 alkyl, C 1-6 haloalkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 3-C7 cycloalkyl, C 6-C10 aryl, C 3-C7 heterocyclyl, C 5-C10 heteroaryl, or two geminal R gg substituents may combine to form =o or =s, wherein X - is a counterion.
Exemplary substituents on the nitrogen atom include, but are not limited to, hydrogen 、-OH、-ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRbb)Raa、-C(＝NRcc)ORaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)2Raa、-P(＝O)(Raa)2、-P(＝O)2N(Rcc)2、-P(＝O)(NRcc)2、 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups attached to a nitrogen atom combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5R dd groups, and wherein R aa、Rbb、Rcc and R dd are as described above.
Other definitions
The term "coronavirus" includes, but is not limited to, HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and/or SARSCoV-2.
In one embodiment, the term "coronavirus" is an alpha coronavirus and/or a beta coronavirus, more preferably a beta coronavirus.
In one embodiment, the alpha coronavirus is selected from the group consisting of HCoV-229E and HCoV-NL63, preferably HCoV-229E.
In one embodiment, the beta coronavirus is selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2, preferably HCoV-OC43 or SARS-CoV-2, more preferably SARS-CoV-2.
The term "treating" as used herein relates to reversing, alleviating, inhibiting the progression or prevention of a disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein relates to the action of a verb treatment, the latter as just defined.
The term "pharmaceutically acceptable salts" as used herein means those carboxylate salts, amino acid addition salts of the compounds of the invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, and effective for their intended use, including (if possible) zwitterionic forms of the compounds of the invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, for example alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
The base addition salts of the acidic compounds may be prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt, in a conventional manner. The free acid can be regenerated by contacting the salt form with the acid in a conventional manner, isolating the free acid. The free acid forms differ somewhat in certain physical properties from their respective salt forms, such as solubility in polar solvents, but for the purposes of the present invention, the salts are also equivalent to their respective free acids.
The salt may be a sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide prepared from an inorganic acid, an acid such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, isethionate, and the like. Salts may also be prepared from organic acids, such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzates, dinitrobenzoates, naphthoates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, methanesulfonates, and the like. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Salts of amino acids, such as arginine salts, gluconate salts, galacturonate salts, and the like are also contemplated (see, e.g., berge s.m. et al, "Pharmaceutical Salts," j.pharm.sci.,1977;66:1-19, incorporated herein by reference).
The term "subject" administered includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle aged adults, or senior adults) and/or animals that are not humans, e.g., mammals, e.g., primates (e.g., cynomolgus, rhesus), cows, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
"Disease," "disorder," and "condition" are used interchangeably herein.
As used herein, unless otherwise indicated, the term "treating" includes an effect that occurs when a subject has a particular disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as an effect that occurs before the subject begins to have the particular disease, disorder, or condition ("prophylactic treatment").
In general, an "effective amount" of a compound refers to an amount sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the present invention may vary depending on such factors as the biological objective, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age health and symptoms of the subject. The effective amount includes a therapeutically effective amount and a prophylactically effective amount.
As used herein, unless otherwise indicated, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to that amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.
As used herein, unless otherwise indicated, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" may include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic effect of other prophylactic agents.
"Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, the compounds of the invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form.
Detailed description of the preferred embodiments
Herein, "the compound of the present invention" refers to a compound of the following formula (I)、(I')、(II)、(II')、(III)、(III')、(IV)、(IV')、(V)、(V')、(VI)、(VI')、(VII)、(VII')、(VIII)、(VIII')、(IX)、(IX')、(X)、(X')、(XI)、(XI')、(XII) or (XII'), etc., a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.
Compounds are named herein using standard nomenclature. Compounds having asymmetric centers, it is to be understood (unless otherwise indicated) that all optical isomers and mixtures thereof are encompassed. Furthermore, unless otherwise specified, all isomeric compounds encompassed by the present invention may occur with carbon-carbon double bonds in the form of Z and E. Compounds that exist in different tautomeric forms, one of the compounds is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.
In one embodiment, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
Wherein,
Y is N or CR 7;
R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
L 1 is selected from a bond, C 1-6 alkylene, -NH-, -O-, or-S-;
R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl, or 5-20 membered heteroaryl, said R 1 being optionally substituted with 1,2, or 3,4, or 5R 1s, said R 1 preferably being C 6-10 aryl or 5-10 membered heteroaryl;
r 1s is selected from H, deuterium, CN, NO 2、NH2, OH, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, Halogenated C 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3-8 membered heterocyclyl or-O-3-8 membered heteroaryl;
Or two R 1s on the same carbon atom together form oxo or thioxo;
L 2 is selected from a bond or C 1-6 alkylene;
R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, said R 2 being optionally substituted with 1, 2, 3, 4 or 5 independently selected R 2s;
R 2s is selected from H, D, halogen, CN, -L 2a -R' or
L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene- -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene- -C 0-6 alkylene-C (O) NH-C 0-6 alkylene- -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or-C 2-6 alkenylene-, said L 2a optionally being substituted with 1, 2, 3, 4 or 5 independently selected r# substitutions; the L 2a is preferably-O-or-S-, preferably the L 2a is-O-, preferably the L 2a is-S-;
R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-10 alkyl, C 1-10 alkoxy, C 1-10 haloalkyl, C 1-10 haloalkoxy, C (O) R a、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、Boc、C2-6 alkenyl, OR C 2-6 alkynyl, OR two R on the same carbon atom taken together form c=o OR c=s;
m is selected from 0, 1,2,3,4 or 5;
R' is selected from H, NH 2、CN、C0-6 alkylene-C (O) R a、C0-6 alkylene-C (O) OR a、C1-6 alkylene-OC (O) -R a、C0-6 alkylene-NHC (O) R a、C0-6 alkylene-C (O) NR bRc、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylene-OR a、C2-6 alkenyl, OR C 2- 6 alkynyl;
L 3 is-NR b -or-CR aRb -;
R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, said R 3 being optionally substituted with 1, 2, 3,4 or 5R 3s;
R 3s is selected from H, deuterium, halogen, CN, NO 2、NH2、C1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1- 6 alkyl, halo C 1-6 alkoxy, halo C 2-6 alkenyl, Halogenated C 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3-8 membered heterocyclyl, -O-3-8 membered heteroaryl, or two R 3s on the same carbon atom together form c=o or c=s;
R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
wherein each group definition may be optionally substituted with D until fully deuterated.
In another embodiment, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
Wherein:
Y is N or CR 7;
R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
L 1 is selected from a bond or C 1-6 alkylene, -NH-, -O-, or-S-;
R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl, or 5-20 membered heteroaryl, said R 1 being optionally substituted with 1,2, or 3,4, or 5R 1s, said R 1 preferably being C 6-10 aryl or 5-10 membered heteroaryl;
R 1s is selected from H, deuterium, CN, NO 2、NH2, halogen, C 1-6 alkyl, C 1-6 haloalkyl, halogen, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, Halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8 membered heterocyclyl, 3 to 8 membered heteroaryl, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3-8 membered heterocyclyl or-O-3-8 membered heteroaryl;
L 2 is selected from a bond or C 1-6 alkylene;
R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, said R 2 being optionally substituted with 1, 2, 3, 4 or 5 independently selected R 2s;
R 2s is selected from H, D, halogen, CN, -L 2a -R' or
L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene- -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene- -C 0-6 alkylene-C (O) NH-C 0-6 alkylene- -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or-C 2-6 alkenylene-, said L 2a optionally being substituted with 1, 2, 3, 4 or 5 independently selected r# substitutions; the L 2a is preferably-O-or-S-; preferably, the L 2a is-O-, preferably, the L 2a is-S-;
R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-10 alkyl, C 1-10 alkoxy, C 1-10 haloalkyl, C 1-10 haloalkoxy, C (O) R a、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、Boc、C2-6 alkenyl, OR C 2-6 alkynyl, OR two R on the same carbon atom taken together form c=o OR c=s;
m is selected from 0, 1,2,3,4 or 5;
R' is selected from H, NH 2、CN、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, or C 2-6 alkynyl;
L 3 is-NR b -or-CR aRb -;
R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, said R 3 being optionally substituted with 1, 2, 3,4 or 5R 3s;
R 3s is selected from H, deuterium, halogen, CN, NO 2、NH2、C1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 2-6 alkenyl, haloC 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -O-C 1- 6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3-8 membered heterocyclyl, -O-3-8 membered heteroaryl, or two R 3s on the same carbon atom together form c=o or c=s;
R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
wherein each group definition may be optionally substituted with D until fully deuterated.
Y
Y is N or CR 7 or CR 7R8;
In one embodiment, Y is CR 7, e.g., CH, in another embodiment Y is CR 7R8, e.g., CH 2, in yet another embodiment Y is N.
The Y may be optionally substituted with D until fully deuterated.
R 7 and R 8
In one embodiment, R 7 is H, in another embodiment R 7 is C 1-6 alkyl, and in another embodiment R 7 is C 1-6 haloalkyl.
In one embodiment, R 8 is H, in another embodiment R 8 is C 1-6 alkyl, and in another embodiment R 8 is C 1-6 haloalkyl.
The R 7 and R 8 may be optionally substituted with D until completely deuterated.
L1
In one embodiment, L 1 is a bond; in another embodiment, L 1 is C 1-6 alkylene; in another embodiment, L 1 is-NH-; in another embodiment, L 1 is-O-, and in another embodiment, L 1 is-S-.
The L 1 may be optionally substituted with D until completely deuterated.
R1
In one embodiment, R 1 is C 1-6 alkyl, in another embodiment R 1 is C 1-6 haloalkyl, in another embodiment R 1 is C 1-6 alkoxy, such as C 1-4 alkoxy, in another embodiment R 1 is C 1-6 haloalkoxy, such as C 1-4 haloalkoxy, in another embodiment R 1 is C 3-10 cycloalkyl, in another embodiment R 1 is a 3-10 membered heterocyclyl, in another embodiment R 1 is C 6-20 aryl, such as C 6-10 aryl, in another embodiment R 1 is a 5-20 membered heteroaryl, such as a 5-10 membered heteroaryl, such as a 5-6 membered heteroaryl.
In one particular embodiment, R 1 is OCH 3, and in another particular embodiment, R 1 isIn another specific embodiment, R 1 isIn another specific embodiment, R 1 isIn another specific embodiment, R 1 isIn another specific embodiment, R 1 isIn another specific embodiment, R 1 isIn another specific embodiment, R 1 isIn another specific embodiment, R 1 isIn another specific embodiment, R 1 isIn another specific embodiment, R 1 isIn another specific embodiment, R 1 isIn another specific embodiment, R 1 isIn another specific embodiment, R 1 is
In one embodiment, R 1 is unsubstituted, and in another embodiment R 1 is optionally substituted with 1, 2, or 3, 4, or 5 independently selected R 1s.
The R 1 may optionally be substituted with D until completely deuterated.
R1s
In one embodiment, R is H, in another embodiment R is deuterium, in another embodiment R is CN, in another embodiment R is NO, in another embodiment R is NH, in another embodiment R is OH, in another embodiment R is halogen such as F, in another embodiment R is C alkyl such as C alkyl, in another embodiment R is C haloalkyl such as CH, in another embodiment R is C alkoxy such as OCH, in another embodiment R is C haloalkoxy such as C haloalkoxy, in another embodiment R is C alkenyl, in another embodiment R is halo C alkenyl, in another embodiment R is C alkynyl, in another embodiment R is halo C alkynyl, in another embodiment R is C aryl, in another embodiment R is C heterocycle, R3 to R is C membered is C heterocycle, in another embodiment R3 to R is C membered is C heteroaryl, in another embodiment R is C-C is C heteroaryl, r 1s is-NH-C 3-8 cycloalkyl; in another embodiment, R 1s is-NH-C 6- 10 aryl; in another embodiment, R 1s is-NH-3-8 membered heterocyclyl; in another embodiment, R 1s is-NH 3-8 membered heteroaryl, in another embodiment R 1s is-O-C 1-6 alkyl, in another embodiment R 1s is-O-C 2-6 alkenyl, in another embodiment R 1s is-O-C 2-6 alkynyl, in another embodiment R 1s is-O-C 3-8 cycloalkyl, in another embodiment R 1s is-O-C 6-10 aryl, in another embodiment R 1s is-O-3-8 membered heterocyclyl, and in another embodiment R 1s is-O-3-8 membered heteroaryl.
In one embodiment, two R 1s on the same carbon atom together form oxo or thioxo.
The R 1s may optionally be substituted with D until completely deuterated.
L2
In one embodiment, L 2 is a bond, and in another embodiment L 2 is C 1-6 alkylene, preferably C 1-4 alkylene, such as-CH 2 -;
The L 2 may be optionally substituted with D until completely deuterated.
R2
In one embodiment, R 2 is C 3-10 cycloalkyl, in another embodiment R 2 is a 3-10 membered heterocyclyl, in another embodiment R 2 is C 6-10 aryl, preferably C 6-10 aryl, more preferably phenyl, and in another embodiment R 2 is a 5-10 membered heteroaryl.
In one embodiment, R 2 is unsubstituted, and in another embodiment, R 2 is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 2s.
The R 2 may optionally be substituted with D until completely deuterated.
R2s
In one embodiment, R 2s is H, in another embodiment R 2s is D, in another embodiment R 2s is halogen, in another embodiment R 2s is CN, in another embodiment R 2s is-L 2a -R', in another embodiment R 2s is
The R 2s may optionally be substituted with D until completely deuterated.
R 2a and R 2b
In one embodiment, R 2a is H, in another embodiment R 2a is D, in another embodiment R 2a isIn another embodiment, R 2a is-L 2a -R'.
In one embodiment, R 2b is H, in another embodiment R 2b is D, in another embodiment R 2b isIn another embodiment, R 2b is-L 2a -R'.
The R 2a and R 2b may be optionally substituted with D until completely deuterated.
L2a
In one embodiment, L 2a is a bond; in another embodiment, L 2a is —c 1-6 alkylene; in another embodiment, L 2a is-C 0-6 alkylene-O-C 0-6 alkylene-; in another embodiment, L 2a is-C 0-6 alkylene-S-C 0-6 alkylene-, in another embodiment L 2a is-C 0-6 alkylene-C (O) -C 0-6 alkylene-, in another embodiment L 2a is-C 0-6 alkylene-C (O) O-C 0-6 alkylene-, in another embodiment L 2a is-C 0-6 alkylene-NH-C 0-6 alkylene-, in another embodiment L 2a is-C 0-6 alkylene-C (O) NH-C 0-6 alkylene-, in another embodiment L 2a is-C 0-6 alkylene-NHC (O) -C 0-6 alkylene-, or-C 2-6 alkenylene-.
In a specific embodiment, L 2a is a bond; in another specific embodiment, L 2a is-O-; in another specific embodiment, L 2a is-S-; in another embodiment, L 2a is-C 1-6 alkylene-, in another embodiment L 2a is-C 1-6 alkylene-O-, in another embodiment L 2a is-O-C 1-6 alkylene-, in another embodiment L 2a is-C (O) -, in another embodiment L 2a is-C (O) O-, in another embodiment L 2a is-NH-, in another embodiment L 2a is-C (O) NH-, in another embodiment L 2a is-NHC (O) -, and in another embodiment L 2a is C 2-6 alkenylene.
In one more embodiment, L 2a is a bond, in another more embodiment, L 2a is-O-, in another more embodiment, L 2a is-S-, in another more embodiment, L 2a is-CH 2 -, in another more embodiment, L 2a is-CH 2 -O-, in another more embodiment, L 2a is-CH 2-CH2 -O-, in another more embodiment, L 2a is-O-CH 2 -, in another more embodiment, L 2a is-C (O) -, in another more embodiment, L 2a is-C (O) O-, in another more embodiment, L 2a is-NH-, in another more embodiment, L 2a is-C (O) NH-, in another more embodiment, L is-ch=35-CH, or is optionally substituted on another more embodiment.
In one embodiment, the L 2a is unsubstituted, and in another embodiment, the L 2a is optionally substituted with 1,2, 3, 4, or 5 independently selected R#.
The L 2a may be optionally substituted with D until completely deuterated.
R#
In one embodiment, R# is H, in another embodiment R# is halogen, in another embodiment R# is C 1- 6 alkyl, e.g., C 1-4 alkyl, in another embodiment R# is C 1-6 haloalkyl, e.g., C 1-4 haloalkyl, in another embodiment R# is C 1-6 alkoxy, e.g., C 1-4 alkoxy, in another embodiment R# is C 1-6 haloalkoxy, e.g., C 1-4 haloalkoxy, in another embodiment R# is C 2-6 alkenyl, in another embodiment R# is C 2-6 alkynyl.
The R# may be optionally substituted with D until completely deuterated.
Loops A, R and m
In one embodiment, ring A is C 3-10 cycloalkyl, in another embodiment, ring A is C 5-10 cycloalkyl, in another embodiment, ring A is C 5-8 cycloalkyl, in another embodiment, ring A is C 3-8 cycloalkyl, in another embodiment, ring A is C 3-6 cycloalkyl, in another embodiment, ring A is C 5-6 cycloalkyl, in another embodiment, ring A is a 3-10 membered heterocyclyl, in another embodiment, ring A is a 4-10 membered heterocyclyl, such as a 3-8 membered heterocyclyl, in another embodiment, such as a 4-7 membered heterocyclyl, ring A is a 5-6 membered heterocyclyl, in another embodiment, ring A is C 6-10 aryl, in another embodiment, ring A is phenyl, in another embodiment, ring A is a 5-10 membered heteroaryl, in another embodiment, ring A is a 5-6 membered heteroaryl, such as a 1-2 membered heteroaryl, such as a 5-6 membered heteroaryl, or a 5-membered heteroaryl, such as a 5-6 membered heteroaryl, such as a 5-membered heteroaryl, or a 5-membered heteroaryl, such as a 5-6-membered heteroaryl, such as a 5-membered heteroaryl, may be selected from the group, and the group may be selected from the group consisting of 5-2-membered heteroaryl, and the examples.
In a specific embodiment, ring A isWherein Q 1 is CH or N.
In a specific embodiment, ring A isWherein Q 2 is selected from S or NH, and Q 3 is selected from CH or N.
In a specific embodiment, ring A isWherein one of Q 4、Q5 and Q 6 is N, and the other two are CH.
In a specific embodiment, ring A isIn another specific embodiment, ring a is a5 membered heteroaryl, for example a heteroaryl containing 1-2 heteroatoms selected from S or N.
In one embodiment, X 2a is CR, and in another embodiment, X 2a is N.
In one embodiment, X 2b is CR, and in another embodiment, X 2b is N.
In one embodiment, R is H, in another embodiment R is halo, in another embodiment R is CN, in another embodiment R is OR a, in another embodiment R is NR bRc, in another embodiment R is C 1- 10 alkyl, in another embodiment R is C 1-6 alkyl, in another embodiment R is C 1-10 alkoxy, in another embodiment R is C 1-6 alkoxy, in another embodiment R is C 1-10 haloalkyl, in another embodiment R is C 1-6 haloalkyl, in another embodiment R is C 1-10 haloalkoxy, in another embodiment R is C 1-6 haloalkoxy, in another embodiment R is C (O) R a, in another embodiment R is C (O) OR a, in another embodiment R is NHC (O) R a, in another embodiment R is C 1-10 haloalkyl, in another embodiment R is C3438 haloalkoxy, in another embodiment R is C3478 haloalkoxy, in another embodiment R is C342, in another embodiment R is C3496, in another embodiment R is C3492, in another embodiment R is C is c=c.
In one embodiment, R is independently selected from H, in another specific embodiment R is halogen, such as F or Cl, in another embodiment R is CN, in another embodiment R is OH, in another embodiment R is NH 2, in another embodiment R is C 1-6 haloalkyl, preferably C 1-4 haloalkyl, such as CF 3, in another embodiment R is C 1-6 alkoxy, in another embodiment R is C 1-6 haloalkoxy, preferably C 1-4 haloalkoxy, such as OCF 3, in another embodiment R is Boc.
In one embodiment, m is 0, in another embodiment, m is 1, in another embodiment, m is 2, in another embodiment, m is 3, in another embodiment, m is 4, and in another embodiment, m is 5.
In one specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is that
In one specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is thatIn a further specific embodiment of the present invention,Is that
In a further specific embodiment of the present invention,Selected from the group consisting of
The rings A, R and m, etc. described above may be optionally substituted with D until completely deuterated.
R’
In one embodiment, R ' is H, in another embodiment, R ' is NH 2, in another embodiment, R ' is CN, in another embodiment, R ' is C (O) R a, in another embodiment, R ' is C (O) OR a, in another embodiment, R ' is NHC (O) R a, preferably NHC (O) -C 1-6 haloalkyl such as NHC (O) -CF 3, in another embodiment, R ' is C (O) NH-R a, preferably C (O) NH-C 1-6 haloalkyl such as C (O) NH-CF 3, in another embodiment, R ' is C 0-6 alkylene-C (O) R a, in another embodiment, R ' is C 0-6 alkylene-C (O) OR a, in another embodiment, R ' is C56 alkylene-OC (O) -R43, in another embodiment, R ' is C43-C 1-6 haloalkyl such as C37C 52, in another embodiment, R ' is C37C 35 alkyl, in another embodiment, R ' is C37C 35, OR in another embodiment, R ' is C37C 35 alkyl such as C37C 35, R ' is C37C 35 alkyl, r ' is C 1-6 haloalkoxy, in another embodiment R ' is C 2-6 alkenyl, in another embodiment R ' is C 2-6 alkynyl.
In one embodiment, R' isIn another embodiment, R' isIn another embodiment, R' isIn another embodiment, R' isIn another embodiment, R' isIn another embodiment, R' isIn another embodiment, R' is
The R' may be optionally substituted with D until completely deuterated.
R 2c and R 2d
In one embodiment, R 2c is halogen, preferably F.
In one embodiment, R 2d is halogen, preferably Cl, and in another embodiment, R 2d is CN.
R”
In one embodiment, R 'is H, in another embodiment R' is halogen, such as F or Cl, in another embodiment R 'is C 1-6 haloalkyl, in another embodiment R' is C 1-6 haloalkoxy, preferably C 1-4 haloalkoxy, such as OCF 3.
The R' may be optionally substituted with D until completely deuterated.
L 3 and L 3'
In one embodiment, L 3 is-NR b -, e.g., -NH-; in another embodiment, L 3 is-CR aRb -such as-CH 2 -.
In one embodiment, L 3 'is-n=, in another embodiment, L 3' is-CR a =, for example-ch=.
The L 3 and L 3' may be optionally substituted with D until completely deuterated.
R3
In one embodiment, R 3 is a C 6-14 aryl, preferably a C 6-10 aryl, in another embodiment R 3 is a 5-14 heteroaryl, such as a 5-10 heteroaryl, in another embodiment R 3 is a C 3-8 cycloalkyl, and in another embodiment R 3 is a 3-14 membered heterocyclyl.
In a specific embodiment, R 3 isIn another specific embodiment, R 3 isIn another specific embodiment, R 3 isIn another specific embodiment, R 3 is
In one embodiment, the R 3 is unsubstituted, and in another embodiment, the R 3 is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 3s.
The R 3 may optionally be substituted with D until completely deuterated.
R3s
In one embodiment, R 3s is H, in another embodiment, R 3s is deuterium, in another embodiment, R 3s is halo, in another embodiment, R 3s is CN, in another embodiment, R 3s is NO 2, in another embodiment, R 3s is NH 2, in another embodiment, R 3s is C 1-6 alkyl, preferably C 1-4 alkyl, in another embodiment, R 3s is C 1-6 alkoxy, preferably C 1-4 alkoxy, in another embodiment, R 3s is C 2-6 alkenyl, in another embodiment, R 3s is C 2-6 alkynyl, in another embodiment, R 3s is halo C 1-6 alkyl, in another embodiment, R 3s is halo C 1-6 alkoxy, in another embodiment, R 1-6 is halo C2 alkenyl, in another embodiment, R 1-6 is halo C2 alkyl, in another embodiment, R 1-6 is C3938 alkenyl, R 1-6 is another embodiment, R 1-6 is C 1-6 alkyl, in another embodiment, R 1-6 is another embodiment is NH 1-6 -another embodiment, R 1-6 is another 3 is C 1-6 alkyl, R 1-6 is another embodiment, R 1-6 is another 3 is cycloalkyl, in another embodiment, R 1-6 is 3 is another 3-C 1-6 is cycloalkyl, r 3s is-NH-3-8 membered heterocyclic group; in another embodiment, R 3s is-NH-3-8 membered heteroaryl; in another embodiment, R 3s is-O-C 1-6 alkyl; in another embodiment, R 3s is-O-C 2-6 alkenyl, in another embodiment R 3s is-O-C 2-6 alkynyl, in another embodiment R 3s is-O-C 3-8 cycloalkyl, in another embodiment R 3s is-O-C 6-10 aryl, in another embodiment R 3s is-O-3-8 membered heterocyclyl, in another embodiment R 3s is-O-3-8 membered heteroaryl, in another embodiment two R 3s on the same carbon atom together form C=O, and in another embodiment two R 3s on the same carbon atom together form C=S.
The R 3s may optionally be substituted with D until completely deuterated.
R 3a and R 3f
In one embodiment, R 3a is halogen, preferably Cl.
In one embodiment, R 3f is C 1-6 alkyl, preferably C 1-4 alkyl, such as CH 3.
The R 3s may optionally be substituted with D until completely deuterated.
R a、Rb and R c
In one embodiment, R a is H, in another embodiment R a is C 1-6 alkyl, in another embodiment R a is C 1-6 haloalkyl, in another embodiment R a is C 2-6 alkenyl, and in another embodiment R a is C 2-6 alkynyl.
In one embodiment, R b is H, in another embodiment R b is C 1-6 alkyl, in another embodiment R b is C 1-6 haloalkyl, in another embodiment R b is C 2-6 alkenyl, and in another embodiment R b is C 2-6 alkynyl.
In one embodiment, R c is H, in another embodiment R c is C 1-6 alkyl, in another embodiment R c is C 1-6 haloalkyl, in another embodiment R c is C 2-6 alkenyl, and in another embodiment R c is C 2-6 alkynyl.
The R a、Rb and R c may be optionally substituted with D until completely deuterated.
Any one of the above embodiments or any combination thereof may be combined with any one of the other embodiments or any combination thereof. For example, any one of the technical schemes of R 1 or any combination thereof may be combined with any one of the technical schemes of Y, L 1、L2、R2、L3, R 3, etc. or any combination thereof. The invention is intended to include all such combinations, limited to the extent that they are not listed.
In a more specific embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
Wherein:
Y is N or CR 7;
R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
L 1 is selected from a bond or C 1-6 alkylene, -NH-, -O-, or-S-;
R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl, or 5-20 membered heteroaryl, said R 1 being optionally substituted with 1,2, or 3,4, or 5R 1s, said R 1 preferably being C 6-10 aryl or 5-10 membered heteroaryl;
R 1s is selected from H, deuterium, CN, NO 2、NH2, halogen, C 1-6 alkyl, C 1-6 haloalkyl, halogen, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, Halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8 membered heterocyclyl, 3 to 8 membered heteroaryl, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3-8 membered heterocyclyl or-O-3-8 membered heteroaryl;
L 2 is selected from a bond or C 1-6 alkylene;
R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, said R 2 being optionally substituted with 1, 2, 3, 4 or 5 independently selected R 2s;
R 2s is selected from H, D, halogen, CN, -L 2a -R' or
L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene- -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene- -C 0-6 alkylene-C (O) NH-C 0-6 alkylene- -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or-C 2-6 alkenylene-, said L 2a optionally being substituted with 1, 2, 3, 4 or 5 independently selected r# substitutions; the L 2a is preferably-O-or-S-; preferably, the L 2a is-O-, preferably, the L 2a is-S-;
R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-10 alkyl, C 1-10 alkoxy, C 1-10 haloalkyl, C 1-10 haloalkoxy, C (O) R a、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、Boc、C2-6 alkenyl, OR C 2-6 alkynyl, OR two R on the same carbon atom taken together form c=o OR c=s;
m is selected from 0, 1,2,3,4 or 5;
R' is selected from H, NH 2、CN、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, or C 2-6 alkynyl;
L 3 is-NR b -or-CR aRb -;
R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, said R 3 being optionally substituted with 1, 2, 3,4 or 5R 3s;
R 3s is selected from H, deuterium, halogen, CN, NO 2、NH2、C1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 2-6 alkenyl, haloC 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -O-C 1- 6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3-8 membered heterocyclyl, -O-3-8 membered heteroaryl, or two R 3s on the same carbon atom together form c=o or c=s;
R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (I'):
Wherein:
Y' is NR 7 or CR 7R8;
R 7 and R 8 are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
L 3' is-n=or-CR a =;
The other groups are as defined above.
In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, of the structure of formula (II), (II '), (III '), (IV '), (V '), (VI '), (VII '), (VIII) or (VIII '):
Wherein,
One of R 2a and R 2b isOr-L 2a -R', the other being H or D;
L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene- -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene- -C 0-6 alkylene-C (O) NH-C 0-6 alkylene- -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or-C 2-6 alkenylene-, said L 2a optionally being substituted with 1, 2, 3, 4 or 5 independently selected r# substitutions; the L 2a is preferably-O-or-S-; preferably, the L 2a is-O-, preferably, the L 2a is-S-;
R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
Ring a is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C (O) R a、C(O)ORa、NHC(O)Ra、C(O)NH-Ra, OR Boc, OR two R on the same carbon atom taken together form c=o OR c=s;
R' is selected from H, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy;
r 2c is halogen, preferably F;
r 2d is halogen or CN, preferably Cl;
m is selected from 0, 1,2,3,4 or 5;
R 3a is halogen, preferably Cl;
R 3f is C 1-6 alkyl, preferably CH 3;
The other groups are as defined above.
In a more specific embodiment, the present invention provides a compound of formula (II) or (II'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:
Wherein:
L 1 is selected from a bond or C 1-6 alkylene;
R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryl, or 5-10 membered heteroaryl, said R 1 being optionally substituted with 1,2, or 3,4, or 5R 1s;
r 1s is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
One of R 2a and R 2b is Or-L 2a -R', the other being H or D;
L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene-, -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C (O) NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or-C 2-6 alkylene-, said L 2a being optionally substituted with 1,2, 3, 4 or 5 independently selected R#;
R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
Ring a is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C (O) R a、C(O)ORa、NHC(O)Ra、C(O)NH-Ra, OR Boc, OR two R on the same carbon atom taken together form c=o OR c=s;
m is selected from 0, 1,2,3,4 or 5;
R' is selected from H, NH 2、CN、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
r 2c is halogen, preferably F;
r 2d is halogen or CN, preferably Cl;
L 3 is-NR b -or-CR aRb -;
L 3' is-n=or-CR a =;
r 3 is selected from C 6-10 aryl or 5-10 heteroaryl, said R 3 optionally substituted with 1,2, 3, 4 or 5R 3s;
R 3s is selected from halogen, C 1-6 alkyl or C 1-6 alkoxy, or two R 3s on the same carbon atom together form c=o or c=s;
R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (II) or (II') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
L 1 is selected from a bond or C 1-6 alkylene;
R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryl, or 5-10 membered heteroaryl, said R 1 being optionally substituted with 1,2, or 3,4, or 5R 1s;
r 1s is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
One of R 2a and R 2b is Or-L 2a -R', the other being H or D;
L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene-, -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C (O) NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or-C 2-6 alkylene-, said L 2a being optionally substituted with 1,2, 3, 4 or 5 independently selected R#;
R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
Ring a is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C (O) R a、C(O)ORa、NHC(O)Ra、C(O)NH-Ra, OR Boc, OR two R on the same carbon atom taken together form c=o OR c=s;
m is selected from 0, 1,2,3,4 or 5;
R' is selected from H, NH 2、CN、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
r 2c is halogen, preferably F;
r 2d is halogen or CN, preferably Cl;
L 3 is-NR b -or-CR aRb -;
L 3' is-n=or-CR a =;
r 3 is selected from C 6-10 aryl or 5-10 heteroaryl, said R 3 optionally substituted with 1,2, 3, 4 or 5R 3s;
R 3s is selected from halogen, C 1-6 alkyl or C 1-6 alkoxy, or two R 3s on the same carbon atom together form c=o or c=s;
R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (III) or (III'):
Wherein:
R 2a is selected from Or-L 2a -R';
L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene- -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene- -C 0-6 alkylene-C (O) NH-C 0-6 alkylene- -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or C 2-6 alkenylene, L 2a is optionally substituted with 1, 2, 3,4, or 5 substituents independently selected from halogen, C 1-6 alkyl, or C 1-6 haloalkyl;
Ring a is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, OH, NH 2、CN、C1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C (O) -C 1-6 haloalkyl, C (O) O-C 1-6 haloalkyl, NHC (O) -C 1-6 haloalkyl, or C (O) NH-C 1-6 haloalkyl, or two R on the same carbon atom together form c=o or c=s;
m is 0, 1,2,3,4 or 5;
R' is selected from NH 2、CN、C1-6 alkyl, C 1-6 haloalkyl, C (O) -C 1-6 haloalkyl, C (O) O-C 1-6 haloalkyl, NHC (O) -C 1-6 haloalkyl or C (O) NH-C 1-6 haloalkyl;
R 2c is selected from halogen;
R 2d is selected from halogen or CN;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (III) or (III') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 2a is selected from Or-L 2a -R';
L 2a is selected from the group consisting of a bond, -O-, -S-, -C 1-6 alkylene-, -C 1-6 alkylene-O-, -O-C 1-6 alkylene-, -C (O) O-, -NH-, -C (O) NH-, -NHC (O) -or C 2-6 alkenylene, L 2a being optionally substituted with 1, 2 or 3 substituents independently selected from halogen or C 1-6 alkyl;
Ring a is selected from C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, OH, NH 2、CN、C1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, or NHC (O) -C 1-6 haloalkyl, or two R on the same carbon atom together form c=o;
m is 0,1, 2,3 or 4;
R' is selected from NH 2、CN、C1-6 haloalkyl, NHC (O) -C 1-6 haloalkyl or C (O) NH-C 1-6 haloalkyl;
R 2c is selected from halogen;
R 2d is selected from halogen or CN;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (III) or (III') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 2a is selected from Or-L 2a -R';
L 2a is selected from the group consisting of bond 、-O-、-S-、-CH2-、-CH2-O-、-CH2-CH2-O-、-O-CH2-、-C(O)-、-C(O)O-、-NH-、-C(O)NH-、-NH-C(O)- or-ch=ch-, said L 2a optionally being substituted with CH 3;
Selected from the group consisting of
R' is selected from CN, NHC (O) -CF 3 or CF 3;
R 2c is selected from F or Cl, preferably F;
R 2d is selected from F, cl or CN, preferably Cl.
In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
Wherein:
L 2a is selected from-O-, -S-or-C 2-6 alkenylene-;
Ring a is selected from C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, CN, OH, NH 2、-C(O)-C1-6 haloalkyl, -C (O) O-C 1-6 haloalkyl, -NHC (O) -C 1-6 haloalkyl, -C (O) NH-C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R on the same carbon atom together form c=o or c=s;
m is selected from 0, 1,2,3,4 or 5;
r 2c is halogen, preferably F;
R 2d is selected from halogen or CN, preferably Cl.
In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
L 2a is selected from-O-or-C 2-6 alkenylene-;
Ring a is selected from C 5-8 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, CN, OH, NH 2、-NHC(O)-C1-6 haloalkyl, -C (O) NH-C 1-6 haloalkoxy, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R on the same carbon atom together form c=o;
m is selected from 0, 1,2,3,4 or 5;
r 2c is halogen, preferably F;
R 2d is selected from halogen or CN, preferably Cl.
In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
l 2a is selected from-O-or-C 2-4 alkenylene-;
Ring a is selected from C 5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, CN, -NHC (O) -C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy, preferably H, F, cl, CN, OCH 3、OCF3 or-NHC (O) -CF 3, or two R on the same carbon atom together form c=o;
m is selected from 0, 1,2 or 3;
r 2c is halogen, preferably F;
R 2d is selected from halogen or CN, preferably Cl.
In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
l 2a is selected from-O-, -ch=ch-;
Selected from the group consisting of
R 2c is selected from F or Cl, preferably F;
R 2d is selected from F, cl or CN, preferably Cl.
In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
Wherein:
l 2a is C 2-6 alkenylene;
Ring a is selected from C 6-10 aryl or 5-10 membered heteroaryl;
R is selected from H, halogen or C 1-6 haloalkyl;
m is selected from 0, 1,2,3,4 or 5;
r 2c is halogen, preferably F;
R 2d is halogen, preferably Cl;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
L 2a is C 2-4 alkenylene, preferably-ch=ch-;
ring a is selected from phenyl or a 5-6 membered heteroaryl, said 5 membered heteroaryl being a heteroaryl containing 1-2 heteroatoms selected from S or N;
R is selected from H or halogen, preferably H or F;
m is selected from 0, 1,2 or 3;
r 2c is halogen, preferably F;
R 2d is halogen, preferably Cl.
In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
L 2a is C 2-4 alkenyl, preferably-ch=ch-;
Selected from the group consisting of
R 2c is F;
R 2d is Cl or F, preferably Cl.
In a more specific embodiment, the present invention provides a compound of formula (V) or (V'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
Wherein:
L 2a is-O-or-S-;
Ring A is selected from Or a5 membered heteroaryl;
x 2a and X 2b are independently selected from CR or N;
Each R is independently selected from H, halogen, CN, OH, NH 2、C1-6 alkoxy or C 1-6 haloalkoxy, preferably H, F, cl, CN, OCF 3;
m is selected from 0, 1,2,3,4 or 5;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
L 2a is-O-;
Ring A is selected from Or a5 membered heteroaryl;
x 2a and X 2b are independently selected from CR or N;
Each R is independently selected from H, halogen, CN or C 1-6 haloalkoxy;
m is selected from 0, 1,2,3,4 or 5;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
L 2a is-O-;
Ring A is selected from Or a 5-membered heteroaryl, said 5-membered heteroaryl being a heteroaryl containing 1-2 heteroatoms selected from S or N;
x 2a and X 2b are independently selected from CR or N;
Each R is independently selected from H, halogen, CN or C 1-4 haloalkoxy, preferably H, F, cl, CN or OCF 3;
m is selected from 0, 1,2 or 3;
Preferably, the method comprises the steps of,
Selected from the group consisting of
In a more specific embodiment, the present invention provides a compound of formula (V) or (V'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
Wherein,
R 2b isOr-L 2a -R';
l 2a is-C 1-6 alkylene-, -C 2-6 alkylene-, -C 0-6 alkylene-O-C 0-6 alkylene-or-C 0-6 alkylene-S-C 0-6 alkylene-;
ring a is C 6-10 aryl or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, NH 2、OH、CN、C1-6 haloalkyl or C 1-6 haloalkoxy;
R' is selected from C (O) -C 1-6 haloalkyl, C (O) O-C 1-6 haloalkyl, NHC (O) -C 1-6 haloalkyl or C (O) NH-C 1-6 haloalkyl;
R 2c is halogen;
R 2d is selected from halogen or CN;
m is 0, 1,2,3,4 or 5;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
r 2b is Or-L 2a -R';
L 2a is selected from the group consisting of-O-, -S-, -C 1-4 alkylene- -C 1-4 alkylene-O- -O-C 1-4 alkylene-, -C 1-4 alkylene-S-or-S-C 1-4 alkylene-;
ring a is phenyl or a 5-6 membered heteroaryl, said 5 membered heteroaryl being a heteroaryl containing 1-2 heteroatoms selected from S or N;
Each R is independently selected from H, halogen, CN, C 1-4 haloalkyl or C 1-4 haloalkoxy, preferably H, F, cl, CN, CF 3 or OCF 3;
R' is selected from NHC (O) -C 1-6 haloalkyl or C (O) NH-C 1-6 haloalkyl, preferably NHC (O) CF 3;
R 2c is halogen;
R 2d is selected from halogen or CN;
m is 0, 1,2 or 3;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
r 2b is Or-L 2a -R';
L 2a is-O-, -S-, -CH 2-、-CH2-O-、-CH2-CH2 -O-or-O-CH 2 -;
Selected from the group consisting of
R' is NHC (O) CF 3;
r 2c is F;
R 2d is selected from F, cl or CN, preferably Cl.
In a more specific embodiment, the present invention provides a compound of formula (VI) or (VI'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
Wherein,
L 2a is-O-or-S-;
ring a is C 6-10 aryl or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy;
m is 0, 1,2,3,4 or 5;
R 2c is halogen;
R 2d is selected from halogen or CN;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (VI) or (VI') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
L 2a is-O-;
Ring A is phenyl;
Each R is independently selected from H, halogen, C 1-4 haloalkyl or C 1-4 haloalkoxy, preferably H, F, cl, CF 3 or OCF 3;
m is 0, 1,2 or 3;
Preferably, the method comprises the steps of, Selected from the group consisting of
R 2c is halogen, preferably F;
r 2d is selected from halogen or CN, preferably F, cl or CN, more preferably Cl;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (VII) or (VII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:
Wherein,
L 2a is O or S;
R is selected from H or halogen;
R' is selected from H, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy.
In a more specific embodiment, the present invention provides a compound of formula (VII) or (VII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
L 2a is selected from-O-;
R is selected from H or halogen, preferably H, F or Cl;
R' is selected from H, halogen or C 1-4 haloalkoxy, preferably H, F, cl or OCF 3.
In a more specific embodiment, the present invention provides a compound of formula (II) or (II'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:
Wherein,
L 1 is selected from a bond or C 1-6 alkylene;
R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryl, or 5-10 membered heteroaryl, said R 1 being optionally substituted with 1, 23, 4, or 5 independently selected R 1s;
r 1s is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
One of R 2a and R 2b is Or-L 2a -R', the other being H or D;
L 2a is selected from the group consisting of a bond, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene-, -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C (O) NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-, or-C 2-6 alkenylene-, said L 2a being optionally substituted with 1,2,3,4, or 5 independently selected R#;
R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
Ring a is selected from C 3-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-6 haloalkyl, C 1-6 haloalkoxy, OR Boc, preferably H, F, cl, CN, CF 3、OCF3 OR Boc;
m is selected from 0, 1,2,3,4 or 5;
R' is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
r 2c is halogen, preferably F;
R 2d is halogen, preferably Cl;
L 3 is-NR b -or-CR aRb -;
R 3 is selected from C 6-10 aryl or 5-10 heteroaryl, said R 3 optionally substituted with 1,2,3,4 or 5 independently selected R 3s;
R 3s is selected from H, halogen, C 1-6 alkyl or C 1-6 alkoxy, or two R 3s on the same carbon atom together form c=o or c=s;
R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (II) or (II') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
L 1 is selected from a bond or C 1-4 alkylene;
R 1 is selected from C 1-4 alkoxy or 5-6 membered heteroaryl, said R 1 optionally substituted with 1,2 or 3 independently selected R 1s;
R 1s is selected from H, halogen, C 1-4 alkyl or C 1-4 alkoxy, preferably F, CH 3 or OCH 3;
One of R 2a and R 2b is Or-L 2a -R', the other being H or D;
L 2a is selected from the group consisting of a bond, -O-, -S-, -C 1-4 alkylene-O-, -O-C 1-4 alkylene-, -C (O) O-, -NH-, -C (O) NH-, -NHC (O) -, -C (O) -or C 2-4 alkenylene, said L 2a being optionally substituted with 1, 2 or 3 independently selected R#;
r# is selected from H, C 1-4 alkyl or C 1-4 haloalkyl;
ring a is selected from C 3-6 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, CN, C 1-4 haloalkyl, C 1-4 haloalkoxy or Boc, preferably H, F, cl, CN, CF 3、OCF3 or Boc;
m is selected from 0, 1,2 or 3;
r' is selected from C 1-4 alkyl or C 1-4 haloalkyl;
r 2c is halogen, preferably F;
R 2d is halogen, preferably Cl;
l 3 is-NH-;
R 3 is selected from C 6-10 aryl or 5-10 heteroaryl, said R 3 optionally substituted with 1,2 or 3 independently selected R 3s;
R 3s is selected from H, halogen, C 1-4 alkyl or C 1-4 alkoxy, or two R 3s on the same carbon atom together form c=o;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (II) or (II') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
L 1 is selected from a bond or-CH 2 -;
R 1 is selected from OCH 3,
One of R 2a and R 2b isOr-L 2a -R', the other being H or D;
l 2a is selected from the group consisting of bond 、-O-、-S-、-CH2-O-、-CH2-CH2-O-、-O-CH2-、-C(O)O-、-NH-、-C(O)NH-、-NHC(O)-、-C(O)- or-ch=ch-, said L 2a optionally being substituted with CH 3;
Selected from the group consisting of
R' is selected from CHF 2 or CF 3;
R 2c is selected from F;
R 2d is selected from F or Cl;
l 3 is-NH-;
R 3 is selected from
L 1 is selected from a bond or-CH 2 -;
R 1 is selected from OCH 3,
One of R 2a and R 2b isOr-L 2a -R', the other being H or D;
l 2a is selected from the group consisting of bond 、-O-、-S-、-CH2-O-、-CH2-CH2-O-、-O-CH2-、-C(O)O-、-NH-、-C(O)NH-、-NHC(O)-、-C(O)- or-ch=ch-, said L 2a optionally being substituted with CH 3;
Selected from the group consisting of
R' is selected from CHF 2 or CF 3;
R 2c is selected from F;
R 2d is selected from F or Cl;
l 3 is-NH-;
R 3 is selected from
In a more specific embodiment, the present invention provides a compound of formula (VIII) or (VIII'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
Wherein:
L 2a is O or S;
R 1s is selected from halogen or C 1-6 haloalkoxy;
R is selected from halogen, CN, C 1-6 haloalkyl or C 1-6 haloalkoxy;
R 3a is halogen, preferably Cl;
R 3f is C 1-6 alkyl, preferably CH 3.
In a more specific embodiment, the present invention provides a compound of formula (VIII) or (VIII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
L 2a is O;
R 1s is selected from halogen or C 1-4 haloalkoxy, preferably F or OCH 3;
R is selected from halogen, CN, C 1-4 haloalkyl or C 1-4 haloalkoxy, preferably F, CN, CF 3 or OCF 3;
R 3a is halogen, preferably Cl;
R 3f is C 1-4 alkyl, preferably CH 3.
In a more specific embodiment, the present invention provides a compound of formula (VIII) or (VIII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:
Wherein:
L 2a is O or S;
R 1s is selected from halogen or C 1-6 haloalkoxy;
R is selected from halogen or CN;
R 3a is halogen, preferably Cl;
R 3f is C 1-6 alkyl, preferably CH 3;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (VIII) or (VIII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
L 2a is O;
R 1s is selected from halogen or C 1-4 haloalkoxy, preferably F or OCH 3;
r is selected from halogen or CN, preferably F or CN;
R 3a is halogen, preferably Cl;
R 3f is C 1-4 alkyl, preferably CH 3.
In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, of the structure of formula (IV), (IV '), (V'), (IX '), (X'), (XI '), (XII) or (XII'):
One of R 2a and R 2b is or-L 2a -R', the other is H or D;
L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene- -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene- -C 0-6 alkylene-C (O) NH-C 0-6 alkylene- -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or-C 2-6 alkenylene-, said L 2a optionally being substituted with 1, 2, 3, 4 or 5 independently selected r# substitutions; the L 2a is preferably-O-or-S-; preferably, the L 2a is-O-, preferably, the L 2a is-S-;
R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
Ring a is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C (O) R a、C(O)ORa、NHC(O)Ra、C(O)NH-Ra, OR Boc, OR two R on the same carbon atom taken together form c=o OR c=s;
r 2c is halogen, preferably F;
r 2d is halogen or CN, preferably Cl;
m is selected from 0, 1,2,3,4 or 5;
R 3a is halogen, preferably Cl;
R 3f is C 1-6 alkyl, preferably CH 3;
The other groups are as defined above.
In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
Wherein,
L 2a is selected from-S-or-O-;
Ring a is selected from C 6-10 aryl or 5-10 membered heteroaryl;
R is selected from H, halogen, CN, OR a、NRbRc、C(O)NRbRc、C1-6 alkyl OR C 1-6 haloalkyl;
m is selected from 0, 1,2,3,4 or 5;
R 2d is selected from halogen;
R 2c is selected from halogen;
R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
l 2a is selected from-S-or-O-;
ring a is selected from phenyl or 5-6 membered heteroaryl;
R is selected from H, halogen, CN, OH, NH 2、C(O)NH2 or C 1-4 haloalkyl, preferably H, F, cl, CN, OH, NH 2、C(O)NH2 or CF 3;
m is selected from 1,2 or 3;
R 2d is selected from halogen, preferably Cl or F;
R 2c is selected from halogen, preferably F.
In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
l 2a is-S-or-O-;
Selected from the group consisting of
R 2d is selected from halogen, preferably Cl or F;
R 2c is selected from halogen, preferably F.
In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
l 2a is selected from-S-or-O-;
Ring a is selected from C 6-10 aryl or 5-10 membered heteroaryl;
r is selected from H, halogen, CN, NH 2、C1-6 alkyl or C 1-6 haloalkyl;
m is selected from 0, 1,2,3,4 or 5;
r 2d is selected from halogen, preferably Cl;
R 2c is selected from halogen, preferably F;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
l 2a is selected from-S-or-O-;
ring a is selected from phenyl or 5-6 membered heteroaryl;
R is selected from H, halogen, CN, NH 2 or C 1-4 haloalkyl, preferably H, F, cl, CN, NH 2 or CF 3;
m is selected from 1,2 or 3;
r 2d is selected from halogen, preferably Cl;
R 2c is selected from halogen, preferably F.
In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
L 2a is-S-or-O-, preferably-S-;
Selected from the group consisting of
R 2d is selected from halogen, preferably Cl;
R 2c is selected from halogen, preferably F.
In a more specific embodiment, the present invention provides a compound of formula (V) or (V'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
Wherein,
R 2b is selected fromOr-L 2a -R';
l 2a is selected from-S-or-O-;
Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 6-10 membered heteroaryl;
R is selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl OR C 2-6 alkynyl;
m is selected from 0, 1,2,3,4 or 5;
R' is selected from C 0-6 alkylene-OC 1-6 alkyl or C 0-6 alkylene-OC 1-6 haloalkyl;
R 2d is selected from halogen;
R 2c is selected from halogen;
R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 2b is selected from Or-L 2a -R';
l 2a is selected from-S-or-O-;
ring a is selected from 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
R is selected from H, halogen, NH 2, CN, OH or C 1-4 haloalkyl, preferably H, F, NH 2, CN, OH or CF 3;
m is selected from 1,2 or 3;
r' is C 1-4 alkylene-OC 1-4 alkyl;
r 2d is selected from halogen, preferably Cl;
R 2c is selected from halogen, preferably F.
In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 2b is selected from Or-L 2a -R';
l 2a is selected from-S-or-O-;
Selected from the group consisting of
R' is
R 2d is selected from halogen, preferably Cl;
R 2c is selected from halogen, preferably F.
In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 2b is selected from Or-L 2a -R';
l 2a is selected from-S-or-O-;
Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 6-10 membered heteroaryl;
R is selected from H, halogen, C 0-6 alkylene-NH 2、C0-6 alkylene-CN or C 0-6 alkylene-OH;
m is selected from 0, 1,2,3,4 or 5;
R' is selected from C 0-6 alkylene-OC 1-6 alkyl or C 0-6 alkylene-OC 1-6 haloalkyl;
R 2d is selected from halogen;
R 2c is selected from halogen;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 2b is selected from Or-L 2a -R';
l 2a is selected from-S-or-O-;
ring a is selected from 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
R is selected from H, halogen, NH 2, CN or OH, preferably H, F, NH 2, CN or OH;
m is selected from 1,2 or 3;
r' is C 1-4 alkylene-OC 1-4 alkyl;
r 2d is selected from halogen, preferably Cl;
R 2c is selected from halogen, preferably F.
In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 2b is selected from Or-L 2a -R';
l 2a is selected from-S-or-O-;
Selected from the group consisting of
R' is
R 2d is selected from halogen, preferably Cl;
R 2c is selected from halogen, preferably F.
In a more specific embodiment, the present invention provides a compound of formula (IX) or (IX'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
Wherein,
R 1S is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
L 2a is-C 0-6 alkylene-O-C 0-6 alkylene-or-C 0-6 alkylene-S-C 0-6 alkylene-;
Ring a is selected from C 6-10 aryl or 5-10 membered heteroaryl;
R is selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy C 2- 6 alkenyl OR C 2-6 alkynyl;
m is selected from 0, 1,2,3,4 or 5;
R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
R 2c is selected from H or halogen, preferably H or F, more preferably F;
R 3a is halogen, preferably Cl;
R 3f is C 1-6 alkyl, preferably CH 3;
R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (IX) or (IX') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 1S is selected from H, halogen, C 1-4 alkyl or C 1-4 alkoxy;
l 2a is-O-C 0-4 alkylene-or-S-C 0-4 alkylene-;
ring a is selected from phenyl or 5-6 membered heteroaryl;
R is selected from H, halogen, CN, NH 2、OH、C1-4 alkyl or C 1-4 haloalkyl, preferably H, F, cl, CN, NH 2、OH、CH3 or CF 3;
m is selected from 1,2 or 3;
R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
R 2c is selected from H or halogen, preferably H or F, more preferably F;
R 3a is halogen, preferably Cl;
R 3f is C 1-4 alkyl, preferably CH 3.
In a more specific embodiment, the present invention provides a compound of formula (IX) or (IX') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 1S is selected from H, F, CH 3 or OCH 3;
L 2a is-S-or-S-CH 2 -;
Selected from the group consisting of
R 2d is selected from Cl or CN;
R 2c is selected from H or F;
R 3a is Cl;
R 3f is CH 3.
In a more specific embodiment, the present invention provides a compound of formula (X) or (X'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
Wherein,
R 1S is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
l 2a is-S-or-O-;
ring a is selected from C 6-10 aryl or 5-10 membered heteroaryl, said 5-10 membered heteroaryl being heteroaryl containing 1-2 heteroatoms selected from O, S or N;
R is selected from H, halogen, CN, NR bRc、ORa、C1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
m is selected from 0, 1,2,3,4 or 5;
R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
R 2c is selected from H or halogen, preferably H or F, more preferably F;
R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (X) or (X') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 1S is selected from C 1-4 alkyl or C 1-4 alkoxy;
l 2a is-S-or-O-;
Ring a is selected from phenyl or a 5-6 membered heteroaryl, said 5-6 membered heteroaryl being a heteroaryl containing 1-2 heteroatoms selected from O, S or N;
R is selected from H, halogen, CN, NH 2、OH、C1-4 alkyl or C 1-4 haloalkyl, preferably H, F, cl, CN, NH 2、OH、CH3 or CF 3;
m is selected from 1,2 or 3;
R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
R 2c is selected from H or halogen, preferably H or F, more preferably F.
In a more specific embodiment, the present invention provides a compound of formula (X) or (X') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 1S is selected from CH 3 or OCH 3;
L 2a is-S-or-O-, preferably-S-;
Selected from the group consisting of
R 2d is selected from Cl or CN;
R 2c is selected from H or F.
In a more specific embodiment, the present invention provides a compound of formula (XI) or (XI'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
Wherein,
R 1S is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
R 2b is selected from Or-L 2a -R';
L 2a is-C 0-6 alkylene-O-C 0-6 alkylene-or-C 0-6 alkylene-S-C 0-6 alkylene-;
Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
R is selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl OR C 2-6 alkynyl;
m is selected from 0, 1,2,3,4 or 5;
R' is selected from C 1-6 alkylene-NHC (O) -R a、C1-6 alkylene-C (O) -R a、C1-6 alkylene-OC (O) -R a、C1-6 alkylene-C (O) O-R a、C1-6 alkylene-C (O) NR bRc OR C 1-6 alkylene-OR a;
R 2d is selected from halogen or CN;
r 2c is selected from H or halogen;
r 3a is halogen;
R 3f is C 1-6 alkyl;
R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (XI) or (XI') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 1S is CH 3;
R 2b is selected from Or-L 2a -R';
l 2a is-S-;
Selected from the group consisting of
R' is selected from
R 2d is selected from F, cl or CN;
R 2c is selected from H or F;
R 3a is Cl;
R 3f is CH 3.
In a more specific embodiment, the present invention provides a compound of formula (XII) or (XII'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:
Wherein,
R 1S is selected from C 1-6 alkyl or C 1-6 alkoxy;
R 2b is selected from Or-L 2a -R';
L 2a is-C 0-6 alkylene-O-C 0-6 alkylene-or-C 0-6 alkylene-S-C 0-6 alkylene-;
Ring A is selected from 3-8 membered heterocyclic group, Or a 5-membered heteroaryl, said 5-membered heteroaryl being a heteroaryl containing 1-2 heteroatoms selected from N, O or S;
Q 1 is CH or N;
R is selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl OR C 2-6 alkynyl;
m is selected from 0, 1,2,3,4 or 5;
R' is selected from C 1-6 alkylene-NHC (O) -R a、C1-6 alkylene-C (O) -R a、C1-6 alkylene-OC (O) -R a、C1-6 alkylene-C (O) O-R a、C1-6 alkylene-C (O) NR bRc OR C 1-6 alkylene-OR a;
r 2d is selected from halogen or CN, preferably F, cl or CN, more preferably Cl;
R 2c is selected from H or halogen, preferably H or F, more preferably F;
R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (XII) or (XII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 1S is selected from C 1-4 alkyl or C 1-4 alkoxy;
R 2b is selected from Or-L 2a -R';
l 2a is-O-C 0-4 alkylene-or-S-C 0-4 alkylene-;
ring A is selected from 3-6 membered heterocyclic group,
Q 1 is CN or N;
Q 2 is selected from S or NH;
Q 3 is selected from CH or N;
One of Q 4、Q5 and Q 6 is N, and the other two are CH;
R is selected from H, halogen, OH, CN, NR bRc、C1-4 alkyl or C 1-4 haloalkyl, preferably H, F, OH, CN, NH 2、NHCH3、CF3 or CH 3;
m is selected from 1,2 or 3;
R' is selected from C 1-6 alkylene-NHC (O) -R a、C1-6 alkylene-C (O) NR bRc OR C 1-6 alkylene-OR a;
r 2d is selected from halogen or CN, preferably F, cl or CN, more preferably Cl;
R 2c is selected from H or halogen, preferably H or F, more preferably F;
R a、Rb and R c are independently selected from H, C 1-4 alkyl or C 1-4 haloalkyl.
In a more specific embodiment, the present invention provides a compound of formula (XII) or (XII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 1S is CH 3;
R 2b is selected from Or-L 2a -R';
l 2a is-S-;
Selected from the group consisting of
R' is selected from
R 2d is selected from F, cl or CN;
R 2c is selected from H or F.
In a more specific embodiment, the present invention provides a compound of formula (XII) or (XII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 1S is selected from C 1-6 alkyl or C 1-6 alkoxy;
R 2b is selected from Or-L 2a -R';
L 2a is-C 0-6 alkylene-O-C 0-6 alkylene-or-C 0-6 alkylene-S-C 0-6 alkylene-;
ring a is selected from phenyl, thienyl, pyrazolyl or thiazolyl;
R is selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl OR C 2-6 alkynyl;
m is selected from 0, 1,2,3,4 or 5;
R' is selected from C 1-6 alkylene-NHC (O) -R a、C1-6 alkylene-C (O) -R a、C1-6 alkylene-OC (O) -R a、C1-6 alkylene-C (O) O-R a、C1-6 alkylene-C (O) NH 2 OR C 1-6 alkylene-OR a;
r 2d is selected from halogen or CN, preferably F, cl or CN, more preferably Cl;
R 2c is selected from H or halogen, preferably H or F, more preferably F;
R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
wherein each group definition may be optionally substituted with D until fully deuterated.
In a more specific embodiment, the present invention provides a compound of formula (XII) or (XII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 1S is selected from C 1-4 alkyl or C 1-4 alkoxy;
R 2b is selected from Or-L 2a -R';
l 2a is-O-C 0-4 alkylene-or-S-C 0-4 alkylene-;
Ring A is selected from phenyl, thienyl,
R is selected from H, halogen, CN, NR bRc、C1-4 alkyl or C 1-4 haloalkyl, preferably H, F, CN, NH 2、NHCH3、CF3 or CH 3;
r b and R c are independently selected from H, C 1-4 alkyl or C 1-4 haloalkyl;
m is selected from 1,2 or 3;
r' is selected from C 1-4 alkylene-NHC (O) -C 1-4 haloalkyl, C 1-4 alkylene-C (O) NH 2 or C 1-4 alkylene-O-C 1-4 alkyl;
r 2d is selected from halogen or CN, preferably F, cl or CN, more preferably Cl;
R 2c is selected from H or halogen, preferably H or F, more preferably F.
In a more specific embodiment, the present invention provides a compound of formula (XII) or (XII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
R 1S is CH 3;
R 2b is selected from Or-L 2a -R';
l 2a is-S-;
Selected from the group consisting of
R' is selected from
R 2d is selected from F, cl or CN;
R 2c is selected from H or F.
In a more specific embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein the compound is selected from the group consisting of:
In a more specific embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein the compound is selected from the group consisting of:
specifically, the invention also relates to the following technical scheme:
1.A compound of formula (P-I) or a physiologically/pharmaceutically acceptable salt or ester thereof, a stereoisomer or tautomer thereof, a racemate, a nitroxide, a solvate, an isotopic label, a prodrug or a metabolite:
Wherein,
Ring A represents a 5-to 20-membered heteroaryl or a C 6-20 -aryl,
R 1 are each independently of the other selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, cyano, nitro, amino, halogenated C 1-6 alkyl, halogenated C 2-6 alkenyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8 membered heterocyclyl, 3 to 8 membered heteroaryl, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3 to 8 membered heterocyclyl, -NH-3 to 8 membered heteroaryl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3 to 8 membered heterocyclyl, -O-3 to 8 membered heteroaryl,
L 1 represents a single bond, -CH 2 -, -NH-, -O-, or-S-,
N is an integer of 0 to 10,
R 2 represents H, C 1-6 alkyl, halogen or deuterated C 1-6 alkyl,
R 3 are each independently of the other selected from H, C 1-6 alkyl, halogen, cyano, nitro or amino,
M is an integer from 0 to 3.
2. A compound of formula (P-I) according to claim 1, having the structure of formula (P-IA) as follows:
Wherein, the rings A, R 1、R2、R3, n, and m are as defined in formula (P-I).
3. A compound of formula (P-I) according to claim 1, having the structure of formula (P-IB) as follows:
Wherein, the rings A, R 1 and n are as defined in formula (P-I).
4. A compound of formula (P-I) according to any one of claims 1 to 3, wherein ring a represents a 5-to 10-membered heteroaryl, preferably a 5-or 6-membered heteroaryl, a 9-or 10-membered fused heteroaryl, such as thiazolyl, pyrazolyl, pyridinyl, isoquinolinyl, pyrazolopyridinyl, pyrrolopyridinyl.
5. A compound of formula (P-I) as claimed in any one of claims 1 to 4, wherein,The following groups are represented:
6. The compound of formula (P-I) according to any one of claims 1 to 6, wherein the compound of formula (P-I) has the structure of formula (P-IC), (P-ID) or (P-IE) as follows:
Wherein R 1、R2、R3, n and m are as defined in formula (P-I).
7. A compound of formula (P-II) or a physiologically/pharmaceutically acceptable salt or ester thereof, a stereoisomer or tautomer thereof, a racemate, a nitroxide, a solvate, an isotopic label, a prodrug or a metabolite:
Wherein,
Ring B represents a 5-to 20-membered heteroaryl or a C 6-20 -aryl,
L 2 represents a single bond, -CH 2 -, -NH-, -O-, or-S-,
R 4 are each independently selected from H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Halogen, cyano, nitro, amino, halogenated C 1- 6 alkyl, halogenated C 2-6 alkenyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3-to 8-membered heterocyclyl, 3-to 8-membered heteroaryl, -NH (C 1-6 alkyl), -N (C 1- 6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3 to 8 membered heterocyclyl, -NH-3 to 8 membered heteroaryl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3 to 8 membered heterocyclyl, -O-3 to 8 membered heteroaryl,
L 3 represents -(CH2)p-O-、-O-(CH2)q-、-(CH2)r-NH-、-NH-(CH2)s-、-(CH2)t-S- or-S- (CH 2)t -,
O, p, q, r, s, t and u are each independently of the other integers from 0 to 3,
E represents a C 1-6 alkylcarbonyl group, a 5 to 20 membered heteroaryl group or a C 6-20 aryl group, which is unsubstituted or optionally substituted by one, two or more R 5 groups,
R 5 each independently of the other represents H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, cyano, nitro, amino, halogenated C 1-6 alkyl, halogenated C 2-6 alkenyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8 membered heterocyclyl, 3 to 8 membered heteroaryl, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3 to 8 membered heterocyclyl, -NH-3 to 8 membered heteroaryl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3 to 8 membered heterocyclyl, -O-3 to 8 membered heteroaryl.
R 6 represents H, C 1-6 alkyl, halogen or deuterated C 1-6 alkyl.
8. A compound of formula (P-II) according to claim 7, having the structure of formula (P-IIA):
Wherein ring B is a 5-or 6-membered heteroaryl, R 4、R6、o、L3 and E are as defined in formula (P-II).
9. A compound of formula (P-II) according to claim 7 or 8, wherein ring B is pyridinyl or triazolyl, more preferably pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-1,2, 4-triazol-3-yl or 1H-1,2, 4-triazol-5-yl.
10. A compound of formula (P-II) according to any one of claims 7 to 9, having the structure of formula (P-IIB) or (P-IIC) below:
11. A compound of formula (P-II) according to any one of claims 7 to 10, wherein L 3 represents- (CH 2)-O-、-O-(CH2)-、-(CH2)-NH-、-NH-(CH2)-、-(CH2) -S-or-S- (CH 2) -.
12. Compounds of formula (P-II) according to any one of claims 7 to 11, wherein E represents a C 1-6 alkylcarbonyl, a5 to 10 membered heteroaryl or a C 6-12 aryl, preferably a C 1-3 alkylcarbonyl, a5 to 10 membered heteroaryl or a phenyl, wherein R 4 each independently of the other represent halogen, cyano, halo C 1-6 alkyl or-N (C 1-6 alkyl) 2, optionally substituted by one, two or more R 4.
13. Compounds of formula (P-II) according to any one of claims 7 to 12, wherein E-L 3 -represents benzyloxy, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 3-cyanobenzyloxy, 2-fluorobenzyloxy, 3-fluorobenzyloxy, 4-fluorobenzyloxy, 3-chloro-4-fluorobenzyloxy, 2-fluoro-3-chlorobenzyloxy, 3-cyanobenzyloxy, thiazol-5-ylmethoxy, 4-trifluoromethylthiazol-5-ylmethoxy, 5-cyanobiazol-2-ylmethoxy, 5-dimethylaminothiazol-2-ylmethoxy, trifluoroacetamidomethyl, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, 1,2, 4-triazolo [1,5-a ] pyridin-7-ylmethoxy, 1H-benzo [ d ] imidazol-6-ylmethoxy, phenoxymethyl or phenoxy.
14. A compound of formula (P-I) or a compound of formula (P-II) according to any one of claims 1 to 13, having the structure:
15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (P-I) according to any one of claims 1 to 14 or a compound of formula (P-II) or a salt or ester thereof, a stereoisomer or tautomer, a racemate, a nitrogen oxide, a solvate, an isotopic label, a prodrug or a metabolite thereof and optionally at least one physiologically/pharmaceutically acceptable auxiliary.
16. The pharmaceutical composition according to claim 15, optionally comprising an additional active ingredient, preferably the additional active ingredient comprises adefovir, lopinavir, mo Nupi-wy, ritonavir, chloroquine, hydroxychloroquine and/or alpha-interferon.
17. Use of a compound of formula (P-I) or a compound of formula (P-II) or a salt or ester thereof according to any one of claims 1-14, a stereoisomer or tautomer, racemate, nitrogen oxide, solvate, isotopic label, prodrug or metabolite thereof in the manufacture of a medicament, preferably an RNA-dependent RNA polymerase inhibitor, 3CLpro protease inhibitor, CYP3A4 inhibitor or an antiviral drug targeting a host, more preferably the medicament optionally comprises an additional active ingredient, wherein the additional active ingredient comprises adefovir, lopinavir, mo Nupi, ritonavir, chloroquine, hydroxychloroquine and/or alpha-interferon, more preferably the medicament is for preventing or treating a disease, disorder, syndrome and/or disorder selected from the group consisting of fever, weakness, nausea, pain, vomiting, headache, and/or any combination thereof caused by a SARS-CoV-2 coronavirus infection.
18. A method for treating or preventing a disease, disorder, syndrome and/or disorder caused by SARS-CoV-2 coronavirus infection, the method comprising administering to a subject in need thereof a compound of formula (P-I) or a compound of formula (P-II) or a salt or ester thereof according to any one of claims 1 to 14, stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotopic labels, prodrugs or metabolites thereof or a pharmaceutical composition according to claim 15 or 16.
The compounds of the invention may include one or more asymmetric centers and thus may exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers may be separated from the mixtures by methods known to those skilled in the art, including chiral High Pressure Liquid Chromatography (HPLC) and formation and crystallization of chiral salts, or the preferred isomers may be prepared by asymmetric synthesis.
The compounds of the present invention may exist in tautomeric forms. Tautomers are functional group isomers generated by rapid movement of an atom in a molecule at two positions, are special functional group isomers, and a pair of tautomers can be mutually converted, but usually take one isomer which is relatively stable as a main existing form. The most prominent examples are enol and keto tautomers.
For example, in the formula (I) of the present invention, a compound represented when Y is N and X is NH, and of the formulae (I '), (II'), (III '), (IV'), (V) Compounds of the formulae (V '), (VI'), (VII '), (VIII) and (VIII'), comprising the following tautomers:
For example, in formula (I) of the present invention, the compounds represented when Y is CH and X is NH, include the following tautomers:
for example, the compound of example 1 of the present invention comprises the following tautomers:
Those skilled in the art will appreciate that the organic compound may form a complex with a solvent in or from which it reacts or from which it precipitates or crystallizes. These complexes are referred to as "solvates". When the solvent is water, the complex is referred to as a "hydrate". The present invention encompasses all solvates of the compounds of the present invention.
The term "solvate" refers to a form of a compound or salt thereof that is bound to a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "solvate" includes both solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates and methanolates.
The term "hydrate" refers to a compound that binds to water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, the hydrates of the compounds may be represented by, for example, the general formula R x H 2 O, where R is the compound and x is a number greater than 0. A given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, e.g., hemihydrate (r.0.5H 2 O) and polyhydrate (x is a number greater than 1, e.g., dihydrate (r.2h 2 O) and hexahydrate (r.6h 2 O)).
The compounds of the present invention may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the present invention. The term "polymorph" refers to a crystalline form (or salt, hydrate or solvate thereof) of a compound of a particular crystal stacking arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can lead to a crystalline form predominating. Various polymorphs of a compound can be prepared by crystallization under different conditions.
The invention also includes isotopically-labelled compounds (isotopically-variant) which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F and 36 Cl, respectively. The compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs thereof, which contain the isotopes described above and/or other isotopes of other atoms, are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes (e.g., 3 H and 14 C) are introduced, are useful in drug and/or substrate tissue distribution assays. Tritium, i.e., 3 H, and carbon-14, i.e., 14 C isotopes are particularly preferred because they are easy to prepare and detect. Further, substitution with heavier isotopes, such as deuterium, i.e., 2 H, may be preferred in some circumstances because greater metabolic stability may afford therapeutic benefits such as increased in vivo half-life or reduced dosage requirements. Isotopically-labeled compounds of formula (I) of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and/or examples and preparations below by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent.
In addition, prodrugs are also included within the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo by hydrolysis, e.g. in blood, into its active form having a medical effect. Pharmaceutically acceptable prodrugs are described in t.higuchi and v.stilla, prodrugs as Novel DELIVERY SYSTEMS, A.C.S.SYMPOSIUM Series Vol.14,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987, and d.fleisher, s.ramon and H.Barbra"Improved oral drug delivery：solubility limitations overcome by the use of prodrugs",Advanced Drug Delivery Reviews(1996)19(2)115-130, each of which are incorporated herein by reference.
Prodrugs are any covalently bonded compounds of the invention which, when administered to a patient, release the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in such a way that the modification may be performed by conventional procedures or cleavage in vivo to yield the parent compound. Prodrugs include, for example, compounds of the invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, may cleave to form the hydroxy, amino, or sulfhydryl group. Representative examples of prodrugs therefore include, but are not limited to, acetate, formate and benzoate/amide derivatives of hydroxy, mercapto and amino functional groups of compounds of formula (I). In addition, in the case of carboxylic acid (-COOH), esters such as methyl ester, ethyl ester, and the like can be used. The esters themselves may be active and/or may be hydrolysed under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups which readily decompose in the human body to release the parent acid or salt thereof.
The invention also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms are within the scope of the invention.
Pharmaceutical compositions and kits
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.
Pharmaceutically acceptable excipients for use in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the co-formulated compounds. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.
Suitable formulations for administration of the compounds of the present invention will be apparent to those of ordinary skill in the art and include, for example, tablets, pills, capsules, suppositories, troches, lozenges, solutions (particularly solutions for injection (subcutaneous, intravenous, intramuscular) and infusion (injectable)), elixirs, syrups, cachets, emulsions, inhalants or dispersible powders. The amount of the one or more pharmaceutically active compounds should be in the range of 0.1 to 90wt%, preferably 0.5 to 50wt% of the composition as a whole, i.e. in an amount sufficient to achieve the dosage ranges specified below. The prescribed dose may be administered several times per day, if necessary.
The invention also includes kits (e.g., pharmaceutical packages). Kits provided can include a compound of the invention, other therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packages or other suitable containers) containing a compound of the invention, other therapeutic agent. In some embodiments, the provided kits may also optionally include a third container containing pharmaceutically acceptable excipients for diluting or suspending the compounds of the invention and/or other therapeutic agents. In some embodiments, the compounds of the invention and other therapeutic agents provided in the first and second containers are combined to form one unit dosage form.
Administration of drugs
The pharmaceutical compositions provided herein may be administered by a number of routes including, but not limited to, oral, parenteral, inhaled, topical, rectal, nasal, buccal, vaginal, by implantation, or other means of administration. For example, the number of the cells to be processed, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, and the like synovial cavity administration, sternal administration, cerebrospinal membrane administration, intralesional administration, and intracranial injection or infusion techniques.
Typically, an effective amount of a compound provided herein is administered. The amount of the compound actually administered may be determined by a physician, according to the circumstances involved, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.
When used to prevent a disorder of the present invention, a subject at risk of developing the disorder is administered a compound provided herein, typically based on physician recommendations and administered under the supervision of a physician, at a dosage level as described above. Subjects at risk for developing a particular disorder generally include subjects having a family history of the disorder, or those subjects determined by genetic testing or screening to be particularly susceptible to developing the disorder.
The pharmaceutical compositions provided herein may also be administered chronically ("chronically"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over a prolonged period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue administration indefinitely, e.g., for the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, e.g., within a therapeutic window.
Various methods of administration may be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus, e.g., in order to increase the concentration of the compound in the blood to an effective level. Bolus doses depend on the targeted systemic level of active ingredient through the body, e.g., intramuscular or subcutaneous bolus doses cause slow release of the active ingredient, whereas bolus injections delivered directly to veins (e.g., by IV intravenous drip) can be delivered more rapidly, causing the concentration of the active ingredient in the blood to rise rapidly to effective levels. In other embodiments, the pharmaceutical composition may be administered in the form of a continuous infusion, for example, by IV intravenous drip, thereby providing a steady state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.
Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. More typically, however, the compositions are provided in unit dosage form in order to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable for producing the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules and the like. In such compositions, the compound is typically a minor component (about 0.1 to about 50 wt.%, or preferably about 1 to about 40 wt.%) with the remainder being various carriers or excipients and processing aids useful for forming the desired administration form.
For oral doses, a typical regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these modes of dosing, each dose provides from about 0.01 to about 20mg/kg of a compound of the invention, with preferred doses each providing from about 0.1 to about 10mg/kg, especially from about 1 to about 5mg/kg.
In order to provide similar blood levels to, or lower than, the use of an injected dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.
From about 1 to about 120 hours, especially 24 to 96 hours, the injection dosage level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. To achieve adequate steady state levels, a preloaded bolus of about 0.1mg/kg to about 10mg/kg or more may also be administered. For human patients of 40 to 80kg, the maximum total dose cannot exceed about 2 g/day.
Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous carriers, buffers, suspending and dispersing agents, colorants, flavors, and the like. Solid forms may include, for example, any of the following components, or compounds having similar properties, a binder, such as microcrystalline cellulose, gum tragacanth or gelatin, an excipient, such as starch or lactose, a disintegrant, such as alginic acid, primogel or corn starch, a lubricant, such as magnesium stearate, a glidant, such as colloidal silicon dioxide, a sweetener, such as sucrose or saccharin, or a flavoring agent, such as peppermint, methyl salicylate or orange flavoring.
Injectable compositions are typically based on sterile saline or phosphate buffered saline for injectable use, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, the remainder being an injectable excipient or the like.
Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as ointments, the active ingredients are typically combined with a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope provided by the present invention.
The compounds of the invention may also be administered via a transdermal device. Transdermal administration may thus be achieved using a reservoir (reservoir) or porous membrane type, or a variety of solid matrix patches.
The above components of the compositions for oral administration, injection or topical administration are merely representative. Other materials and processing techniques, etc. are set forth in Remington's Pharmaceutical Sciences, part 8 of 17th edition,1985,Mack Publishing Company,Easton,Pennsylvania, incorporated herein by reference.
The compounds of the present invention may also be administered in sustained release form, or from a sustained release delivery system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α -, β -and γ -cyclodextrins composed of 6, 7 and 8 α -1, 4-linked glucose units, respectively, optionally including one or more substituents on the linked sugar moiety, including but not limited to methylated, hydroxyalkylated, acylated and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β -cyclodextrin, e.g., sulfobutyl ether β -cyclodextrin, also known as Captisol. See, for example, U.S.5,376,645. In some embodiments, the formulation comprises hexapropyl- β -cyclodextrin (e.g., 10-50% in water).
Indication of disease
For diseases caused by viral infections, the development of 3C-like protease inhibitors may provide therapeutic benefit to a large number of swelling patients. The compounds of the invention exert therapeutic effects by down-regulating the activity of 3C-like proteases within viruses, particularly viruses in which the 3C-like protease has a P132H mutation.
In some embodiments, the 3C-like protease inhibitors of the invention can treat a variety of diseases and complications thereof caused by viral infection.
More specifically, these compounds are useful in the treatment of diseases caused by viral infections such as fever, nausea, vomiting, headache, dyspnea, hypodynamia, respiratory tract infections, pneumonia, dysolfaction, dysgeusia and complications thereof.
More specifically, these compounds are useful for the above-described diseases or conditions caused by SARS-CoV-2 infection.
Combination drug
The 3C-like protease inhibitors of the invention can be used in combination with other drugs to treat cancer, and comprise at least one target drug/viral activity modulator, including rituximab (REMDESIVIR or GS-5734), lopinavir (Lopinavir), mo Nupi (Molnupiravir), ritonavir (Ritonavir), chloroquine (Chloroquine or Sigma-C6628), hydroxychloroquine, alpha-interferon, and the like.
Examples
The compounds and methods of preparation of the present disclosure will be described in further detail below in conjunction with the specific examples. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All technical solutions realized based on the present disclosure are included in the scope of the present disclosure.
Unless otherwise indicated, all experimental procedures used in the examples described below are conventional in the art, and reagents, materials, instruments, equipment, etc. used in the examples described below are all commercially available.
Synthesis of example 1
1. Synthesis of intermediate 1-2
1-1 (1 G,5.32 mmol) was dissolved in acetonitrile (20 mL) at room temperature, and m-chlorobenzyl bromide (1.02 g,5.94 mmol) and potassium carbonate (2.05 g,14.85 mmol) were added and stirred at 70℃for 16 h. After completion of the reaction, water (100 mL) and ethyl acetate (300 mL) were added to extract, and the organic phase was washed with a saturated aqueous sodium chloride solution (3×100 mL) and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=10:1) to give 1-2 (1.1 g, yield: 66.1%) as a pale yellow oil.
LCMS(ESI)m/z:313.1[M+H]+。
2. Synthesis of intermediates 1-3
To a solution of 1-2 (1.1 g,3.53 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.59 g,7.54 mmol) under ice-bath. Stirring was carried out for 2 hours in an ice-water bath, then 15% sodium hydroxide solution was added under an ice-water bath to give solid particles, and the filtrate was filtered and dried by spinning to give white solid 1-3 (0.80 g, yield: 79.9%).
LCMS(ESI)m/z:285.1[M+H]+。
3. Synthesis of intermediates 1-4
Triphenylphosphine (1.26 g,4.80 mmol) and N-bromosuccinimide (0.85 g,4.80 mmol) were added to a solution of 1-3 (0.8 g,2.82 mmol) in dichloromethane (10 mL) under ice. Stirred at 0 ℃ for 30 minutes. After completion of the reaction, water (50 mL) and methylene chloride (100 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=10:1) to give 1-4 (0.8 g, yield: 82.1%) as yellow solid.
LCMS(ESI)m/z:346.9[M+H]+。
4. Synthesis of intermediates 1-6
To a solution of 1-4 (300 mg,0.87 mmol) in acetonitrile (10 mL) at room temperature was added potassium carbonate (379 mg,2.88 mmol) and compound 1-5 (241.8 mg,1.06 mmol), and the mixed solution was stirred at room temperature for 16 hours. Water (10 mL) and methylene chloride (150 mL) were added and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=3:1) to give 1-6 (396 mg, yield: 91.9%) as a pale yellow oil.
LCMS(ESI)m/z:496.1[M+H]+。
5. Synthesis of intermediates 1-7
1-6 (400 Mg,0.81 mmol) was added to a dichloromethane/trifluoroacetic acid=1/1 (6 mL) solution at room temperature, and the mixed solution was stirred at room temperature for 2 hours. The reaction was adjusted to ph=7 with sodium carbonate solution under ice bath. The mixed solution was extracted with dichloromethane (100 mL) and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=1:1) to give 1-7 (301 mg, yield: 84.4%) as a pale yellow oil.
LCMS(ESI)m/z:440.1[M+H]+。
6. Synthesis of intermediates 1-9
To a solution of 1-7 (300 mg,0.68 mmol) in N, N-dimethylformamide (10 mL) was added potassium carbonate (295 mg,2.13 mmol) and 1-8 (139.5 mg,1.07 mmol) at ambient temperature and stirred at 70℃for 2 hours. After completion of the reaction, water (100 mL) and ethyl acetate (300 mL) were added to extract, and the organic phase was washed with a saturated aqueous sodium chloride solution (3×100 mL) and dried over anhydrous sodium sulfate. Purification of the crude product by column chromatography (silica gel, dichloromethane: methanol=10:1) afforded 1-9 as a white solid (250 mg, yield: 68.8%).
LCMS(ESI)m/z:535.1[M+H]+。
7. Synthesis of Compound 1
To a solution of 1-9 (200 mg,0.37 mmol) in tetrahydrofuran (7 mL) was added 1-10 (111 mg,0.62 mmol) under ice-bath, followed by addition of lithium bis (trimethylsilyl) amide (1.2 mL) and stirring at-15℃for 2 hours. Water (50 mL) and ethyl acetate (100 mL) were added and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by high pressure chromatography to give compound 1 (7.2 mg, yield: 2.97%) as a white solid.
LCMS(ESI)m/z:654.1[M+H]+。
1HNMR(400MHz,DMSO-d6)δ8.28(s,1H),8.16(s,1H),7.68–7.60(m,1H),7.45–7.30(m,4H),7.24–7.18(m,2H),5.28(s,2H),5.09(s,2H),5.04(s,2H),4.17(s,3H),3.84(s,3H).
The compounds of the following Table A were synthesized in the same manner as described above.
Table A
EXAMPLE 86 Synthesis of Compound 86
Synthesis of intermediate 86-2
To a solution of 1-1 (2.00 g,10.6 mmol) in dichloromethane (20 mL) was added 4-dimethylaminopyridine (2.60 g,21.3 mmol), 86-1 (4.46 g,31.9 mmol) and copper acetate (3.86 g,21.3 mmol) at room temperature. The mixed solution was stirred at 25 ℃ and oxygen flow for 16 hours. After the reaction was completed, filtration was performed, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, methylene chloride: methanol=30:1) to give 86-2 (401 mg, yield: 15.8%) as a yellow oily compound.
LCMS(ESI)m/z:283.1[M+H]+。
Synthesis of intermediate 86-3
To a solution of 86-2 (626 mg,2.22 mmol) in tetrahydrofuran (7 mL) was added lithium aluminum hydride (210 mg,5.55 mmol) under ice-bath. The mixture was stirred at 0 ℃ for 1 hour under nitrogen blanket. After completion of the reaction, water (0.21 mL), 15% aqueous sodium hydroxide solution (0.21 mL), water (0.63 mL) were sequentially added thereto at 0℃and quenched, and the mixed solution was filtered, and the filtrate was concentrated under reduced pressure to give compound 86-3 (390 mg, yield: 58.8%) as a pale yellow oil.
GCMS(ESI)m/z:254.1[M]+。
Synthesis of intermediate 86-4
Triphenylphosphine (604 mg,2.30 mmol) and carbon tetrabromide (763 mg,2.30 mmol) were added to a solution of 86-3 (390 mg,1.53 mmol) in methylene chloride (4 mL) under ice. The mixture was stirred at 0 ℃ for 1 hour under nitrogen blanket. After completion of the reaction, the mixed solution was extracted with water (40 mL) and dichloromethane (40 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=20:1) to give 86-4 (324 mg, yield: 63.3%) as a pale yellow oily compound.
GCMS(ESI)m/z:316.0[M]+。
Synthesis of intermediate 86-5
To a solution of 86-4 (180 mg,0.785 mmol) in acetonitrile (2 mL) at ordinary temperature were added potassium carbonate (217 mg,1.57 mmol) and 2-5 (324 mg,1.02 mmol), and the mixed solution was stirred at 80℃for 4 hours. After completion of the reaction, ethyl acetate (100 mL) was added to the mixed solution, which was washed with water (40 mL) and saturated sodium chloride solution (40 mL) in this order, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=5:1) to give 86-5 (400 mg, yield: 93.0%) as a pale yellow oily compound.
LCMS(ESI)m/z:466.1[M+H]+。
Synthesis of intermediate 86-6
86-5 (400 Mg,0.860 mmol) was added to a dichloromethane/trifluoroacetic acid=1/1 (8 mL) solution at room temperature, and the mixed solution was stirred at 30 ℃ for 1 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 86-6 (346 mg, yield: 93.4%) as a white solid.
LCMS(ESI)m/z:410.1[M+H]+。
Synthesis of intermediate 86-7
To a solution of 86-6 (346 mg,0.845 mmol) in N, N-dimethylformamide (4 mL) was added 1-8 (170 mg,1.01 mmol) and potassium carbonate (350 mg,2.54 mmol) at ordinary temperature, and the mixed solution was stirred at 80℃for 4 hours. After the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, dichloromethane: methanol=30:1) to give 86-7 (259 mg, yield: 57.9%) as a pale yellow oily compound.
LCMS(ESI)m/z:505.1[M+H]+。
Synthesis of Compound 86
To a solution of 86-7 (260 mg,0.515 mmol) in tetrahydrofuran (2.5 mL) was added 1-10 (112 mg,0.618 mmol) under an ice bath, and lithium bis (trimethylsilyl) amide (1.5 mL) was added under nitrogen. Stirred at 0 ℃ for 2 hours. After the reaction was completed, the mixed solution was quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high pressure chromatography (column: -Gemini-C18:150x21.2mm, 5 μm. Mobile phase: ACN- -H 2 O (0.1% FA). Gradient: 40-60) to give compound 86 (44.8 mg, yield: 13.2%) as a white solid.
LCMS(ESI)m/z:624.1[M+H]+。
1H NMR(400MHz,CD3OD)δ8.40–8.30(m,1H),8.26–8.04(s,1H),7.84–7.66(m,1H),7.62–7.50(m,1H),7.45–7.09(m,2H),7.02–6.72(m,4H),5.30(s,2H),5.05(s,2H),4.20(s,3H),3.90(s,3H).
The compounds of the following Table B were synthesized in the same manner as described above.
Table B
EXAMPLE 115 Synthesis of Compound 115
Synthesis of intermediate 115-3
BINAP (0.99 g,1.59 mol), cesium carbonate (7.8 g,23.9 mol), palladium acetate (0.36 g,1.59 mol) were added to a toluene solution of 115-1 (2.0 g,7.97 mol) and 115-2 (1.13 g,15.9 mol), the reaction mixture was heated to 100℃at room temperature, the reaction was allowed to proceed for 16 hours, cooled to room temperature after completion, and the crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=2:1) to give 115-3 (398 mg, yield: 20.8%) as a pale yellow oil.
LCMS(ESI)m/z:241.9[M+H]+。
Synthesis of intermediate 115-4
To a solution of 115-3 (0.40 g,1.66 mol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.13 g,3.31 mol) under an ice bath. Stirring was carried out in an ice-water bath for 2 hours, then 15% sodium hydroxide solution was added in an ice-water bath to give solid particles, which were filtered and the filtrate was dried by spinning to give 115-4 (303 mg, yield: 84.9%) as a pale yellow oil.
LCMS(ESI)m/z:213.9[M+H]+。
Synthesis of intermediate 115-5
To a solution of 115-4 (270 mg,1.3 mmol) in dichloromethane (6 mL) was added thionyl chloride (452 mg,3.8 mmol) under ice. Stirring at room temperature for 2 hours, and after completion of the reaction, spin-drying gave 115-5 (291 mg, yield: 98.9%) as a pale yellow oil.
Synthesis of intermediate 115-6
To a solution of 1-5 (290 mg,1.25 mmol) in N, N-dimethylformamide (10 mL) was added potassium carbonate (719 mg,1.95 mmol) and compound 115-5 (344 mg,1.5 mmol) at room temperature, and the mixed solution was stirred at room temperature for 16 hours. Water (50 mL) and ethyl acetate (150 mL) were added and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=1:1) to give 115-6 (248 mg, yield: 47.0%) as a pale yellow oil.
LCMS(ESI)m/z:424.8[M+H]+。
Synthesis of intermediate 115-7
115-6 (250 Mg,0.59 mmol) was added to a dichloromethane/trifluoroacetic acid=1/1 (10 mL) solution at room temperature, and the mixed solution was stirred at room temperature for 2 hours. The reaction was adjusted to ph=7 with sodium carbonate solution under ice bath. The mixed solution was extracted with dichloromethane (100 mL) and the organic phase was dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure to give 115-7 (171 mg, crude product) as a pale yellow solid.
LCMS(ESI)m/z:368.8[M+H]+。
Synthesis of intermediate 115-8
To a solution of 115-7 (80 mg,0.21 mmol) in N, N-dimethylformamide (10 mL) was added potassium carbonate (90 mg,0.65 mmol) and 3-9 (42 mg,0.32 mmol) at room temperature, and the mixture was stirred at 60℃for 16 hours. Water (10 mL) and methylene chloride (10 mL) were added and the organic phase was dried over anhydrous sodium sulfate. Purification of the crude product by column chromatography (silica gel, petroleum ether: ethyl acetate=1:1) gave 115-8 (20 mg, yield: 19.8%) as a brown oil.
LCMS(ESI)m/z:464[M+H]+。
Synthesis of Compound 115
To a solution of 115-8 (20 mg,0.04 mmol) in N, N-dimethylformamide (5 mL) was added 1-10 (11 mg,0.06 mmol) under ice-bath, followed by lithium bis (trimethylsilyl) amide (0.1 mL). Stirred at 0 ℃ for 2 hours. Water (10 mL) and ethyl acetate (100 mL) were added and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by high pressure chromatography to give compound 115 (1.1 mg, yield: 4.41%) as a white solid.
LCMS(ESI)m/z:582.7[M+H]+。
1H NMR(400MHz,CD3OD)δ8.28(s,1H),8.16(s,1H),7.64(d,J＝17.0Hz,2H),7.60–7.48(m,1H),7.26(dd,J＝12.2,7.4Hz,1H),5.20(s,2H),5.03(s,2H),4.12(s,3H),3.78(s,3H),3.07(m,4H)1.71(m,4H).
The compounds of the following Table C were synthesized in the same manner as described above.
Table C
EXAMPLE 125 Synthesis of Compound 125
Synthesis of intermediate 125-2
125-1 (3.0 G,0.01 mol) was dissolved in anhydrous toluene (100 mL) at-78 ℃. A solution of diisobutylaluminum hydride in n-hexane (13 mL,0.013 mol) was added thereto and stirred for 30 minutes. After the reaction was completed by stirring the mixture at 25℃for 16 hours, it was quenched by addition of saturated ammonium chloride solution (100 mL), the mixture was extracted with ethyl acetate (500 mL), and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=4:1) to give 125-2 (2.7 g, yield: 98.3%) as a pale yellow oil.
LCMS(ESI)m/z:269.0[M-H]+。
Synthesis of intermediate 125-3
Triphenylphosphine (4.0 g,0.015 mol) and carbon tetrabromide (4.0 g,0.012 mol) were added to a solution of 125-2 (2.7 g,0.01 mol) in methylene chloride (100 mL) under ice. Stirred at 0 ℃ for 30 minutes. After the completion of the reaction, the reaction mixture was concentrated under direct pressure to give a crude product which was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=10:1) to give 125-3 (3.0 g, yield: 89%) as a pale yellow oil.
1H NMR(400MHz,CDCl3)δ7.65(dd,J=9.3,7.7Hz,1H),7.33(dd,J=10.6,7.9Hz,1H),4.51(s,2H).
Synthesis of intermediate 125-4
To a solution of 125-3 (3.0 g,0.009 mol) in acetonitrile (100 mL) at room temperature was added potassium carbonate (3.74 g,0.027 mol) and compound 1-5 (2.1 g,0.009 mol), and the mixed solution was stirred at 80℃for 16 hours. Water (10 mL) and methylene chloride (200 mL) were added and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=1:1) to give 125-4 (3.8 g, yield: 87%) as a pale yellow oily solid.
LCMS(ESI)m/z:504.0[M+Na]+。
Synthesis of intermediate 125-5
To a solution of 125-4 (3.8 g,0.008 mol) in tetrahydrofuran (150 mL) was added compound 1-10 (1.44 g,0.008 mol) under ice-salt bath, followed by lithium bis (trimethylsilyl) amide (16 mL). The mixed solution was stirred under ice-salt bath for 2 hours. After completion of the reaction, a saturated ammonium chloride solution (50 mL) was added to the reaction mixture to quench the reaction mixture, followed by extraction with ethyl acetate (400 mL), and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=1:1) to give 125-5 (4.3 g, yield: 90%) as a white solid.
LCMS(ESI)m/z:601.0[M+H]+。
Synthesis of intermediate 125-7
125-5 (1.0 G,1.66 mmol) was added to a solution of N, N-dimethylformamide (20 mL) at room temperature, and compound 125-6 (867 mg,8.3 mmol), triethylamine (505 mg,5.0 mmol), palladium acetate (37 mg,0.16 mmol) and tris (o-methylphenyl) phosphine (51 mg,0.16 mmol) were added in this order, and after the addition, the mixture was protected with nitrogen. And the mixed solution was stirred at 80 ℃ for 12 hours. Water (60 mL) and ethyl acetate (200 mL) were added and the organic phase was dried over anhydrous sodium sulfate. Purification of the crude product by column chromatography (silica gel, petroleum ether: ethyl acetate=1:1) gave 125-7 as a brown oil (590 mg, yield: 55%).
LCMS(ESI)m/z:577.2[M+H]+。
Synthesis of intermediate 125-8
125-7 (560 Mg,1.0 mmol) was added to a dichloromethane/trifluoroacetic acid=3/1 (6 mL) solution at room temperature, and the mixed solution was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to give 125-8 (241 mg, crude product) as a pale yellow solid.
LCMS(ESI)m/z:521.2[M+H]+。
Synthesis of Compound 125
To a solution of 125-8 (240 mg,0.46 mmol) in N, N-dimethylformamide (10 mL) was added compound 1-8 (116 mg,0.69 mmol) at room temperature, followed by cesium carbonate (450 mg,1.38 mmol) and sodium iodide (138 mg,0.92 mmol). The mixture was stirred at 80 ℃ for 3 hours. Water (10 mL) and ethyl acetate (500 mL) were added and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by high pressure chromatography to give compound 125 (73 mg, yield: 25%) as a white solid.
LCMS(ESI)m/z:616.2[M+Na]+。
1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),8.10(s,1H),7.66(s,1H),7.58–7.35(m,5H),7.33–7.13(m,4H),7.01(d,J＝14.4Hz,1H),5.40(s,2H),5.04(s,2H),4.14(s,3H),3.80(s,3H).
The compounds of the following Table D were synthesized in the same manner as described above.
Table D
EXAMPLE 141 Synthesis of Compound 141
Intermediate 141-1 was synthesized with reference to example 1.
Synthesis of intermediate 141-3
To a solution of 141-1 (150 mg,0.34 mmol) in N, N-dimethylformamide (2 mL) was added triethylamine (173 mg,1.71 mmol), 141-2 (209 mg,1.71 mmol), copper acetate (124 mg,0.682 mmol) and molecular sieve (380 mg) at room temperature. The mixed solution was stirred at 60 ℃ and oxygen flow for 16 hours. After the reaction was completed, filtration was performed, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, dichloromethane: methanol=30:1) to give 141-3 (141 mg, yield: 75.5%) as a yellow oily compound.
LCMS(ESI)m/z:517.1[M+H]+。
Synthesis of Compound 141
To a solution of 141-3 (140 mg, 0.271mmol) in tetrahydrofuran (2 mL) was added 1-10 (59.0 mg,0.325 mmol) under ice-bath, and lithium bis (trimethylsilyl) amide (0.5 mL) was added under nitrogen. Stirred at 0 ℃ for 2 hours. After the reaction was completed, the mixed solution was quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high pressure chromatography (column: -Gemini-C18:150x21.2mm, 5 μm. Mobile phase: ACN- -H 2 O (0.1% FA). Gradient: 40-60) to give compound 141 (36.2 mg, yield: 20.2%) as a white solid.
LCMS(ESI)m/z:636.1[M+H]+。
1H NMR(400MHz,CD3OD)δ8.73–8.65(m,2H),8.20(s,1H),8.18–8.14(m,1H),7.81–7.75(m,1H),7.67(s,1H),7.54–7.46(m,3H),7.35–7.31(m,1H),7.23–7.10(m,3H),5.32(s,2H),5.23(s,2H),4.18(s,3H).
The compounds of the following Table E were synthesized in the same manner as described above.
Table E
EXAMPLE 168 Synthesis of Compound 168
Intermediate 168-1 was synthesized with reference to example 1.
Synthesis of intermediate 168-2
To a solution of 168-1 (20 mg,0.044 mmol) and 1-10 (12 mg,0.066 mmol) in N, N-dimethylformamide (3 mL) was added lithium bis (trimethylsilyl) amide (0.08 mL,0.088 mmol) under salt ice. Stirring was carried out at-20℃for 1 hour. Saturated sodium chloride solution (10 mL) and ethyl acetate (50 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by thin plate chromatography to give 168-2 (28 mg, yield: 100%) as a brown solid.
LCMS(ESI)m/z:574.0[M+H]+。
Synthesis of intermediate 168-3
168-2 (28 Mg,0.048 mmol) was added to a dichloromethane/trifluoroacetic acid=1/1 (4 mL) solution at room temperature, and the mixed solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give 168-3 (30 mg, crude product) as a pale yellow solid.
LCMS(ESI)m/z:518.0[M+H]+。
Synthesis of Compound 168
To a solution of 168-3 (140 mg,0.27 mmol) and 141-2 (49 mg,0.405 mmol) in N, N-dimethylformamide (10 mL) was added copper acetate (97 mg,0.54 mmol), triethylamine (136 mg,1.351 mmol) and 4A molecular sieve (140 mg) at room temperature, and the mixture was stirred at 60℃for 16 hours. Water (20 mL) and ethyl acetate (50 mL) were added and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by high pressure chromatography to give compound 168 (3 mg, yield: 1.8%) as a white solid.
LCMS(ESI)m/z:595.0[M+H]+。
1H NMR(400MHz,CD3OD)δ8.71(d,J＝17.0Hz,2H),8.19-8.16(m,2H),7.78-7.75(m,2H),7.53-7.48(m,2H),6.72(dd,J＝12.6,7.7Hz,1H),5.20(s,2H),4.18(s,3H),3.85–3.75(m,2H),3.41(td,J＝11.6,2.1Hz,3H),1.85(d,J＝11.7Hz,2H),1.42–1.22(m,2H).
The compounds of the following Table F were synthesized in the same manner as described above.
Table F
EXAMPLE 176 Synthesis of Compound 176
Intermediate 176-1 was synthesized with reference to example 1.
Synthesis of intermediate 176-3
To a solution of 176-1 (200 mg,0.47 mmol) in N, N-dimethylformamide (6 mL) was added copper acetate (170 mg,0.94 mmol), 176-2 (319 mg,2.35 mmol), triethylamine (238 mg,2.35 mmol) and 4A molecular sieve (600 mg) at room temperature, and the mixture was stirred at 60℃for 16 hours. Saturated sodium chloride solution (50 mL) and ethyl acetate (200 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. Purification of the crude product by column chromatography (silica gel, dichloromethane: methanol=20:1) gave 176-3 (151 mg, yield: 30.0%) as a brown oil.
LCMS(ESI)m/z:533.0[M+H]+。
Synthesis of Compound 176
To a solution of 176-3 (150 mg,0.28 mmol) in tetrahydrofuran (3 mL) was added 1-10 (71 mg,0.39 mmol) under ice bath, followed by potassium tert-butoxide (0.5 mL). Stirring was carried out at-78℃for 1 hour. Saturated sodium chloride solution (10 mL) and ethyl acetate (100 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. Purification of the crude product by high pressure chromatography gave compound 176 (14.7 mg, yield: 7.9%) as a pale brown solid.
LCMS(ESI)m/z:652.0[M+H]+。
1H NMR(400MHz,CD3OD)δ8.40(s,1H),8.23(d,J＝6.4Hz,2H),7.83–7.72(m,2H),7.68(s,1H),7.53(s,1H),7.15(d,J＝6.2Hz,4H),6.69(d,J＝10.2Hz,1H),5.45(s,2H),4.22(s,3H),3.95(s,3H).
The compounds of the following Table G were synthesized in the same manner as described above.
Table G
EXAMPLE 201 Synthesis of Compound 201
Synthesis of intermediate 201-1 with reference to example 125
Synthesis of Compound 201-3
201-1 (88.0 Mg,0.20 mmol), copper acetate (108.6 mg,0.60 mmol), triethylamine (201.7, 1.99 mmol), DMF (5 mL), 201-2 (98.3 mg,0.70 mmol) were mixed at room temperature and stirred under oxygen for 16 hours at 60 ℃. Water (10 mL) was added, the extracts were extracted with ethyl acetate (10 mL. Times.5), and the organic phases were combined and washed with saturated brine (10 mL. Times.3). The organic phase was separated and the crude product was purified by column chromatography (silica gel, ethyl acetate) to give 201-3 (202 mg, crude product) as a pale yellow oil.
LCMS(ESI)m/z:537.0/539.0[M+H]+。
Synthesis of intermediate 201-4
201-3 (300 Mg,0.56 mmol) and 1-10 (112 mg,0.61 mmol) were added to a tetrahydrofuran (15 mL) solution at room temperature, cooled to-60℃under nitrogen protection, then potassium tert-butoxide (0.16 mL,1.12 mmol) was added, and the mixed solution was stirred at-60℃for 1 hour. Quench with saturated aqueous ammonium chloride (10 mL), extract with ethyl acetate (10 mL x 5), combine the organic phases, wash with saturated brine (10 mL x 3), separate the organic phase, concentrate under reduced pressure and purify the resulting column by chromatography (silica gel, dichloromethane: methanol=20:1) to give 201-4 (229 mg, yellow oil, solid after standing at room temperature, yield: 62.1%).
LCMS(ESI)m/z:656.0/658.0[M+H]+。
Synthesis of intermediate 201-5
201-4 (600 Mg,0.92 mmol) was added to dichloromethane (20 mL) under ice-water bath followed by DIPEA (238 mg,1.84 mmol) and MOMBr (138 mg,1.1 mmol) under nitrogen protection, and after the addition, the reaction was completed at room temperature for 1 hour, and the resultant was purified by column chromatography (dichloromethane: methanol=20:1) to give 201-5 (340 mg, yellow oil, became solid after standing at room temperature, yield: 26.5%).
LCMS(ESI)m/z:696.0/698.0[M+H]+。
Synthesis of Compound 201
A mixed solution of 201-5 (50 mg,0.072 mmol), ethanol/water (3 mL/2 mL), cuI (6.84 mg,0.04 mmol), L-proline (8.27 g,0.07 mmol), K 3PO4 (30.5 mg,0.14 mmol) was stirred at 80℃for 16 hours under nitrogen protection at room temperature. Cool to room temperature, remove the solvent under reduced pressure, and purify the resulting residue by high pressure chromatography to give compound 201 (2 mg, yield: 3.9%) as a pale yellow solid.
LCMS(ESI)m/z:652.1/654.1[M+H]+。
1H NMR(400MHz,MeOD)δ8.61(d,J＝18.7Hz,2H),8.19(d,J＝23.2Hz,4H),7.84(d,J＝8.4Hz,2H),7.73(s,1H),7.68(d,J＝7.3Hz,2H),7.53(s,1H),5.24(s,2H),4.20(s,3H),2.51(s,3H).
The compounds of the following Table H were synthesized in the same manner as described above.
Table H
Example 239 Synthesis of Compound 239
Synthesis of intermediate 239-3
To a solution of 239-1 (750 mg,4.67 mmol) in1, 4-dioxane (8 mL) was added 239-2 (1.19 g,5.14 mmol), N-dimethylglycine (241 mg,2.34 mmol), cuprous iodide (445 mg,2.34 mmol) and cesium carbonate (3.04 g,9.34 mmol) at room temperature. The mixture was stirred at 110 ℃ for 48 hours under nitrogen. Quench with water (100 mL), extract with ethyl acetate (50 mL x 3) and dry the combined organic phases over anhydrous sodium sulfate. Filtering, and concentrating the filtrate under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=50:1) to give compound 239-3 (420 mg, yield: 29.1%) as a yellow oil.
GCMS(ESI)m/z:310.0[M]+。
Synthesis of intermediate 239-4
To a solution of 239-3 (410 mg,1.32 mmol) in carbon tetrachloride (5 mL) was added azobisisobutyronitrile (21.6 mg,0.132 mmol) and N-bromosuccinimide (235 mg,1.32 mmol) under an ice bath. The mixed solution was stirred at 80 ℃ for 16 hours. The mixed solution was extracted with water (40 mL) and dichloromethane (40 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=10:1) to give compound 239-4 (450 mg, yield: 87.7%) as a yellow oil.
LCMS(ESI)m/z:388.9[M+H]+。
Synthesis of intermediate 239-6
To a solution of 239-4 (230 mg,0.591 mmol) in acetonitrile (3 mL) at ordinary temperature were added potassium carbonate (245 mg,1.77 mmol) and 239-5 (120 mg,0.591 mmol), and the mixed solution was stirred at 80℃for 4 hours. The mixed solution was added with ethyl acetate (50 mL), washed successively with water (20 mL) and saturated sodium chloride solution (20 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=10:1) to give compound 239-6 (97.0 mg, yield: 32.0%) as a yellow oil.
LCMS(ESI)m/z:512.0[M+H]+。
Synthesis of Compound 239
To a solution of 239-6 (97.0 mg,0.189 mmol) in tetrahydrofuran (3 mL) was added 1-10 (34.3 mg,0.189 mmol) and the mixture was added potassium tert-butoxide (0.57 mL) under nitrogen. Stirring was carried out for 2 hours at-40 ℃. The mixed solution was quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by high pressure chromatography (column: -Gemini-C18:150x21.2mm, 5 μm. Flowage: ACN- -H 2 O (0.1% FA). Gradient: 40-70) to give compound 240 (14.2 mg, yield: 11.9%) as a white solid.
LCMS(ESI)m/z:631.0[M+H]+。
1H NMR(400MHz,CD3OD)δ8.44(s,1H),8.07(s,1H),7.96(s,1H),7.52(d,J＝8.0Hz,1H),7.42(s,1H),7.21(d,J＝4.0Hz,1H),6.86(d,J＝12.0Hz,1H),4.65(s,1H),4.47(s,1H),4.28(s,3H),3.95(s,3H).
Table H
Biological examples
1. Enzymatic Activity assay
Assay System (120 uL) protease (108 uL) WT or P132H (150 nM)
Substrate (10 uL final concentration: 20 uM)
Small molecule (2 uL 3-fold gradient dilution)
The substrate is fluorogenic substrate MCA-AVLQ ∈ SGFR-Lys (Dnp) -Lys-NH2, main protease universal primer reaction Buffer 50mM Tris pH 7.4,1mM EDTA,0.01%tritonX-100, and enzyme labeling instrument detection after 30min incubation;
The detection of the enzyme label instrument comprises excitation 320nm and emission 405nm;
The inhibition rate of the representative compound on the main protease was determined using the ratio of the different drug concentrations to the enzyme initial reaction rate and the control enzyme initial reaction rate, and IC 50 values were calculated using GRAPHPAD PRISM nonlinear fit curves.
Formula one, inhibition (%) = (RFU 100% enzyme activity control-RFU sample)/(RFU 100% enzyme activity control-RFU blank) ×100%
Formula two, inhibition ratio (%) = (NC initial speed V0-sample initial speed V0)/NC initial speed x 100;
NC is DMSO-added control, and the enzyme activity is set to 100%
Initial velocity calculation = Slope (RFU within 200 s: time s)
Formula II optimizes the inhibition ratio (%) = (NC initial velocity V0- (sample initial velocity V0-small molecule control without protein V0)/NC initial velocity V0X 100 is used to eliminate the problem that V0 (slope) is negative.
2. Anti-SARS-COV-2
Experimental materials
Cell lines Vero E6 (ATCC, CRL-1586), caco-2 (ATCC, HTB-37) and Calu-3 (ATCC, HTB-55).
Viral strain 2019-nCoV-WIV (IVCAS 6.7512)
Dose of infection moi=0.01
(II) Experimental methods
1) 100. Mu.L of cells containing 2X 10 4 were inoculated into 96-well plates and placed in a 37℃constant temperature and humidity incubator for overnight culture;
2) After 20 hours of cell attachment, the culture broth was aspirated and 100. Mu.L of culture broth containing the test compound +CP-100356 at the indicated concentration was added to each well. 8 dilutions were set for each test compound, 3-4 duplicate wells were set for each dilution, and DMSO-treated and normal cell groups were set simultaneously. In addition to the normal cell group, the wells were incubated with a complete culture medium containing 0.01MOI virus in a 37℃constant temperature and humidity incubator for 72 hours.
3) Cytopathic rate, inhibition = (1-disease rate of test compound group) ×100% was recorded using a full field cell scanner 72 hours after infection.
4) And according to the inhibition rate result, performing four-parameter fitting to calculate EC 50.
The test results of representative compounds of the present invention are shown in table 1.
TABLE 1
Example A1
Synthesis of 6- ((6-chloro-2-methyl-2H-indazol-5-yl) amino) -3- (pyridin-3-yl) -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione)
Synthesis of intermediate 1-2
An aqueous solution (10 mL) of sodium nitrite (4.44 g,0.06 mol) was added to a solution of intermediate 1-1 (10 g,0.05 mol) in glacial acetic acid (100 mL) under ice-bath and mixed. The mixed solution was stirred at room temperature for 6 hours, then the reaction mixture was concentrated and diluted with ethyl acetate (200 mL) and washed with saturated sodium bicarbonate solution (100 mL x 2), the organic phase was separated and dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure to give intermediate 1-2 (10 g) as a brown solid, which was used directly in the next reaction.
LCMS(ESI)m/z:198.0[M+H]+。
Synthesis of intermediates 1-3
To a solution of intermediate 1-2 (10 g,0.05 mol) in ethyl acetate (200 mL) was added trimethyloxonium tetrafluoroborate (11.34 g,0.08 mol) at room temperature. The reaction mixture was stirred overnight at room temperature, washed with water (200 mL) and saturated sodium chloride solution (200 mL), the organic phase was separated and dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate=4:1) to give intermediate 1-3 (4.93 g, yield 46.1%) as a yellow solid.
LCMS(ESI)m/z:212.0[M+H]+。
Synthesis of intermediates 1-4
A saturated ammonium chloride solution (100 mL) and reduced iron powder (3.91 g,0.07 mol) were added to a solution of intermediates 1-3 (4.93 g,0.02 mol) in absolute ethanol (100 mL) at room temperature. Stir at 80 ℃ overnight. After cooling, the mixture was filtered, and the filtrate was concentrated under reduced pressure, followed by dilution with ethyl acetate (100 mL). The organic phase was separated and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate=1:1) to give intermediate 1-4 (3.4 g, yield 80.9%) as a brown solid.
LCMS(ESI)m/z:182.2[M+H]+。
Synthesis of intermediates 1-6
To a solution of intermediate 1-5 (10.0 g,0.054 mol) in N, N-dimethylformamide (60 mL) was added 2-isocyanic acid-2-methylpropane (5.62 g,0.057 mol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (10.52 g,0.069 mol) at 0 ℃.1, 8-diazabicyclo [5.4.0] undec-7-ene (10.52 g,0.069 mol) and N, N-carbonyldiimidazole (10.51 g,0.065 mol) were added at 0deg.C for 5 hours at room temperature. Stirring at room temperature for 24 hours. The pH was adjusted to 3-4 with 1N HCl, extracted with ethyl acetate (200 mL x 3), the organic phases combined, washed with saturated sodium chloride solution (100 mL), the organic phase separated and dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, dichloromethane: ethyl acetate=5:1) to give intermediate 1-6 (5.23 g, yield 45.1%) as a white solid.
LCMS(ESI)m/z:252.0[M+Na]+。
Synthesis of intermediates 1-7
1- (Bromomethyl) -2,4, 5-trifluorotoluene (8.46 g,37.6 mmol) was added to a mixture of 1-6 (5.75 g,25.0 mmol), potassium carbonate (6.93 g,50.0 mmol) and acetonitrile (30 mL) and stirred at 85℃for 16 h. Cooled, water (100 mL), ethyl acetate extracted (200 mL x 3) were added, the organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate=2:1) to give intermediate 1-7 (8.6 g, yield: 89%) as a white solid.
LCMS(ESI)m/z:318.0[M+H-56]+。
Synthesis of intermediates 1-8
Intermediate 1-7 (6.7 g,17.9 mmol) was dissolved in dichloromethane and trifluoroacetic acid (30/30 mL) and stirred at room temperature for 6 hours. Concentrated under reduced pressure to give 1-8 (7.8 g) as a white solid which was used directly in the next reaction.
LCMS(ESI)m/z:318.0[M+H]+。
Synthesis of intermediates 1-9
A mixture of intermediate 1-8 (160 mg,0.5 mmol), pyridin-3-ylborane diol (93 mg,0.75 mmol), copper acetate (92 mg,0.5 mmol), 4-dimethylaminopyridine (247 mg,2.0 mmol), pyridine (100 mg,1.2 mmol) and dioxane (10 mL) was stirred under an oxygen balloon at 100℃for 16 hours. Cooled, water (30 mL) was added, extracted with ethyl acetate (3 x 30 mL), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, dichloromethane: methanol=20:1) to give intermediate 1-9 (120 mg, yield: 40%) as a white solid.
LCMS(ESI)m/z:395.0[M+H]+。
Synthesis of Compound 1 (6- ((6-chloro-2-methyl-2H-indazol-5-yl) amino) -3- (pyridin-3-yl) -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione)
To a solution of intermediate 1-9 (120 mg,0.3 mmol) in tetrahydrofuran (20 mL) was added sequentially lithium hexamethyldisilazide (0.6mmol,0.6mL,1.0M in THF) and intermediate 1-4 (67 mg,0.37 mmol) at 0 ℃. Stirring was maintained at 0 ℃ for 2 hours. Saturated ammonium chloride solution (30 mL) was quenched, ethyl acetate (3 x 30 mL) was extracted, the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure, and the crude product was purified by high pressure chromatography (Gemini-C18 150x 21.2mm,5 μm, acetonitrile-water (0.1% formic acid), gradient: 30% -60%) to give white solid 1 (14.5 mg, yield: 9%).
LCMS(ESI)m/z:513.9[M+H]+。
1H NMR(400MHz,DMSO-d6,DCl in D2O)δ9.17(d,J＝2.0Hz,1H),9.05(d,J＝5.5Hz,1H),8.77–8.74(m,1H),8.54(s,1H),8.32-8.27(m,1H),7.88–7.82(m,2H),7.64–7.56(m,2H),5.34(s,2H),4.21(s,3H).
The compounds of the following table A1 were synthesized by reference to the procedure of example A1 above.
Table A1
Example A2
(E) Synthesis of (E) -1- (2- (benzyloxy) -4, 5-difluorobenzyl) -6- ((6-chloro-2-methyl-2H-indazol-5-yl) imino) -3- ((1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) -1,3, 5-triazine-2, 4-dione
Synthesis of intermediate 2-2
To a solution of intermediate 2-1 (10.0 g,0.054 mol) in N, N-dimethylformamide (60 mL) was added 2-isocyanato-2-methylpropane (5.62 g,0.057 mol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (10.52 g,0.069 mol) at 0 ℃.1, 8-diazabicyclo [5.4.0] undec-7-ene (10.52 g,0.069 mol) and N, N-carbonyldiimidazole (10.51 g,0.065 mol) were added at 0deg.C for 5 hours at room temperature. Stirring at room temperature for 24 hours. The pH was adjusted to 3-4 with 1N HCl, extracted with ethyl acetate (200 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, dichloromethane: ethyl acetate=5:1) to give intermediate 2-2 (5.23 g, yield 45.1%) as a white solid.
LCMS(ESI)m/z:252.0[M+Na]+。
Synthesis of intermediate 2-4
Thionyl chloride (15.8 g,0.133 mol) was added dropwise to a solution of intermediate 2-3 (10 g,0.0884 mol) in dichloromethane (100 mL) at 0 ℃. After the dripping, stirring at room temperature for 24 hours. The mixture was concentrated under reduced pressure to give intermediate 2-4 (14 g) as a white solid. Directly used in the next reaction.
LCMS(ESI)m/z:131.9[M+H]+。
Synthesis of intermediate 2-6
Sodium hydroxide (34 g,085 mol) was added to a solution of intermediate 2-5 (30 g,0.17 mol) in 1, 3-dimethyl-2-imidazolidinone (500 mL) under ice-bath. The mixed solution was stirred at 120 ℃ for 16 hours. Cooled to room temperature, the semi-solid was dissolved in water, the pH was adjusted to 2 with hydrochloric acid under ice bath, and the intermediate 2-6 (32 g, yield: 97.0%) was obtained as a white solid by filtration.
LCMS(ESI)m/z:173.1[M-H]-。
Synthesis of intermediate 2-7
To a solution of intermediate 2-6 (32 g,0.18 mol) in methanol (300 mL) was added concentrated sulfuric acid (50 mL) under ice-bath. The mixed solution was refluxed at 70 ℃ for 16 hours, concentrated under reduced pressure, water (100 mL) was added thereto, and filtered. The filter cake was dried to give intermediate 2-7 (18 g, yield: 49.4%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),7.79-7.66(m,1H),7.15-7.03(m,1H),3.89(s,3H)。
Synthesis of intermediate 2-8
To a solution of intermediate 2-7 (2 g,0.01 mol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (4.4 g,0.03 mol) and benzyl bromide (2.18 g,0.013 mol) at ambient temperature. The mixed solution was stirred at 70 ℃ for 16 hours and then cooled to room temperature. The reaction solution was washed with water (20 mL) and saturated sodium chloride solution (20 mL) in this order, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 2-8 (2.4 g) as a white solid, which was directly used in the next reaction.
1H NMR(400MHz,DMSO-d6)δ7.73(dd,J＝10.8,9.4Hz,1H),7.62-7.23(m,6H),5.17(s,2H),3.77(dd,J＝6.4,1.0Hz,3H).
Synthesis of intermediate 2-9
To a solution of intermediate 2-8 (2.4 g,8.6 mmol) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (820 mg,21.5 mmol) under ice-bath. Slowly warmed to room temperature and stirred for 16 hours. The combined solution was quenched with water (30 mL), extracted with ethyl acetate (50 mL x 3), the organic phase separated and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to give intermediate 2-9 (1.8 g) as a white solid, which was used directly in the next reaction.
LCMS(ESI)m/z:273.0[M+Na]+。
Synthesis of intermediate 2-10
Triphenylphosphine (786 mg,3 mmol) and N-bromosuccinimide (534 mg,3 mmol) were added to a solution of intermediate 2-9 (500 mg,2 mmol) in dichloromethane (10 mL) under ice-bath. The mixed solution was stirred at 0 ℃ for 30 minutes. The mixed solution was added with water (10 mL), extracted with dichloromethane (10 mL x 3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, and purification of the crude product by column chromatography (silica, petroleum ether: ethyl acetate=20:1) gave intermediate 2-14 (600 mg, yield: 96.1%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ7.56(dd,J＝10.9,9.4Hz,1H),7.52-7.43(m,2H),7.43-7.21(m,4H),5.17(s,2H),4.60(s,2H).
Synthesis of intermediate 2-11
To a solution of intermediate 2-2 (528 mg,2.31 mmol) in N, N-dimethylformamide (10 mL) was added potassium carbonate (796 mg,5.76 mmol) and intermediate 2-10 (600 mg,1.92 mmol) at room temperature, and the mixed solution was stirred at room temperature for 16 hours. The mixed solution was washed with water (20 mL) and saturated sodium chloride solution (20 mL) in this order, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-11 (700 mg) as a white solid, which was used directly in the next reaction.
LCMS(ESI)m/z:461.8[M+H]+。
Synthesis of intermediate 2-12
Intermediate 2-11 (600 mg,1.3 mmol) was added to dichloromethane/trifluoroacetic acid=1/1 (6 mL) at room temperature, and the mixed solution was stirred at room temperature for 16 hours. The reaction solution was adjusted to pH7 with sodium carbonate solution under ice bath. Dichloromethane (10 ml x 3) was extracted, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give white solid 2-12 (500 mg) which was used directly in the next reaction.
LCMS(ESI)m/z:406.0[M+H]+。
Synthesis of intermediate 2-13
To a solution of intermediate 2-12 (250 mg,0.62 mmol) in N, N-dimethylformamide (5 mL) was added potassium carbonate (426 mg,3.08 mmol) and 2-4 (97 mg,0.74 mmol) at ambient temperature. The mixed solution was stirred at 50 ℃ for 16 hours. Cooled to room temperature, ethyl acetate (50 mL) was added to the mixed solution, washed successively with water (10 mL) and saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate=2:1) to give 2-13 (100 mg, yield: 32.5%) as a white solid.
LCMS(ESI)m/z:501.2[M+H]+。
Synthesis of Compound A21
To a solution of intermediate 2-13 (100 mg,0.2 mmol) and 1-4 (45 mg,0.24 mmol) in tetrahydrofuran (5 mL) was added lithium bis (trimethylsilyl) amide (2 mL) under ice-bath. Stirred at 0 ℃ for 2 hours. The mixture was quenched with water (10 mL), extracted with ethyl acetate (10 mL. Times.3), the combined organic phases dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give compound 21 (19.3 mg, 14.9% yield) as a white solid, which was purified by high pressure liquid preparative chromatography (column: -Gemini-C18. 150. Times.21.2 mm,5 μm. Mobile phase: ACN-H 2 O (0.1% FA). Gradient: 40-55).
LCMS(ESI)m/z:620.0[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.24(s,1H),7.66(s,1H),7.54-7.16(m,8H),5.26-5.11(m,4H),4.88(s,2H),4.13(s,3H),3.78(s,3H).
Example A3
Synthesis of 6- ((6-chloro-2-methyl-2H-indazol-5-yl) amino) -1- (3- ((3-chlorobenzyl) oxy) -4, 5-difluorobenzyl) -3- ((1-methyl-1H-1, 2, 4-triazol-3-yl) methyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione
Synthesis of intermediate 3-2
To a solution of intermediate 3-1 (600 mg,2.97 mmol) in N, N-dimethylformamide (10 mL) was added potassium carbonate (1.2 g,8.91 mol) and 3-chlorobenzyl bromide (727 mg,3.56 mol) at ambient temperature. The mixed solution was stirred at 70 ℃ for 16 hours. Cooled to room temperature, the mixed solution was washed with water (20 mL) and saturated sodium chloride solution (20 mL) in this order, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 3-2 (700 mg) as a white solid, which was used directly in the next reaction.
Synthesis of intermediate 3-3
To a solution of 3-2 (500 mg,1.53 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (174 mg,4.6 mmol) under ice-bath. The mixed solution was slowly warmed to room temperature and stirred for 16 hours. Quench with water (20 mL), extract with ethyl acetate (20 mL x 3), combine the organic phases and dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give intermediate 3-3 (400 mg) as a white solid, which is used directly in the next reaction.
Synthesis of intermediate 3-4
Triphenylphosphine (276 mg,1.05 mmol) and N-bromosuccinimide (188 mg,1.05 mmol) were added to a solution of 3-3 (200 mg,0.7 mmol) in dichloromethane (6 mL) under ice. The mixed solution was stirred at 0 ℃ for 30 minutes. Water (20 mL) was added and dichloromethane (20 mL. Times.3) was extracted, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford intermediate 3-4 (220 mg) as a white solid.
1H NMR(400MHz,DMSO-d6)δ7.56(s,1H),7.55-7.26(m,4H),7.26-7.12(m,1H),5.24(d,J＝12.2Hz,2H),4.66(s,2H).
Synthesis of intermediate 3-5
To a solution of 2-2 (182 mg,0.79 mmol) in N, N-dimethylformamide (10 mL) was added potassium carbonate (263 mg,1.91 mmol) and intermediate 3-4 (220 mg,0.63 mmol) at room temperature, and the mixed solution was stirred at room temperature for 16 hours. The mixed solution was washed with water (20 mL) and saturated sodium chloride solution (20 mL) in this order, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 3-5 (230 mg) as a white solid, which was directly used in the next reaction.
LCMS(ESI)m/z:496.1[M+H]+。
Synthesis of intermediate 3-6
3-5 (230 Mg,0.46 mmol) was added to dichloromethane/trifluoroacetic acid=1/1 (6 mL) at room temperature and stirred at room temperature for 16 hours. The reaction was adjusted to pH7 with sodium carbonate solution in ice bath, extracted with dichloromethane (20 ml x 3), the organic phases combined and dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give intermediate 3-6 (180 mg) as a white solid, which was used directly in the next reaction.
LCMS(ESI)m/z:440.0[M+H]+。
Synthesis of intermediate 3-7
To a solution of 3-6 (180 mg,0.41 mmol) in N, N-dimethylformamide (5 mL) was added potassium carbonate (283 mg,2.05 mmol) and intermediate 2-4 (70 mg,0.54 mmol) under ice-bath, and the mixed solution was stirred at 50℃for 16 hours. To the mixed solution was added ethyl acetate (50 mL), which was washed with water (10 mL) and then with a saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate=2:1) to give intermediate 3-7 (130 mg, yield: 53.4%) as a white solid.
LCMS(ESI)m/z:535.0[M+H]+。
Synthesis of Compound A22
To a solution of intermediate 3-7 (100 mg,0.18 mmol) and intermediate 1-4 (41 mg,0.22 mmol) in tetrahydrofuran (5 mL) was added lithium bis (trimethylsilyl) amide (2 mL) under ice-bath. Stirred at 0 ℃ for 2 hours. Water (10 mL) was added, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by high pressure liquid chromatography (column: -Gemini-C18 150x21.2mm, 5 μm. Mobile phase: ACN-H 2 O (0.1% FA). Gradient: 55-65) to give compound 22 (16 mg, yield: 13%) as a white solid.
LCMS(ESI)m/z:653.9[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.33–8.19(m,3H),7.70(s,1H),7.41(s,1H),7.17(d,J＝6.8Hz,1H),7.11–7.06(m,1H),5.21(s,4H),4.91(s,2H),4.14(s,3H),3.78(s,3H).
The compounds of table B below were synthesized by reference to the methods of examples A2 and A3 above.
Table A2
Example A4 Synthesis of Compound 61 ((E) -1- (2- (benzyloxy) -4, 5-difluorobenzyl) -6- ((6-chloro-2-methyl-2H-indazol-5-yl) imino) -3- (pyridin-2-yl) -1,3, 5-triazine-2, 4-dione)
Synthesis of intermediate 4-1
A mixture of intermediate 2-12 (380 mg,0.93 mmol), pyridin-3-ylborane diol (230 mg,1.87 mmol), copper acetate (560 mg,2.8 mmol), 4-dimethylaminopyridine (11.4 mg,0.09 mmol), pyridine (370 mg,4.68 mmol), molecular sieves (380 mg) and dioxane (10 mL) was stirred under oxygen at 100℃for 16 hours. Cooled, water (30 mL) was added, extracted with ethyl acetate (3 x 30 mL), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate=1:1) to give intermediate 4-1 (200 mg, yield: 44.2%) as a white solid.
LCMS(ESI)m/z:483.1[M+H]+。
Synthesis of Compound A61
To a solution of intermediate 4-1 (200 mg,0.36 mmol) and intermediate 1-4 (90 mg,0.49 mmol) in tetrahydrofuran (5 mL) was added lithium bis (trimethylsilyl) amide (2 mL) under ice-bath. Stirred at 0 ℃ for 2 hours. Water (10 mL) was added, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by high pressure liquid chromatography (column: -Gemini-C18 150x 21.2mm,5 μm. Mobile phase: ACN-H 2 O (0.1% FA). Gradient: 40-55) to give compound 61 (38.8 mg, yield: 14.9%) as a pink solid.
LCMS(ESI)m/z:602.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.59(s,2H),8.32(s,1H),7.90(d,J＝8.0Hz,1H),7.61–7.54(m,4H),7.43(d,J＝7.2Hz,2H),7.35–7.23(m,4H),5.15(s,4H),4.12(s,3H).
Biological example A
Safety assessment of hERG Potassium ion channel
HEK293 cell lines stably expressing hERG ion channels were purchased from Invitrogen. The cell line was digested in culture and inoculated onto a slide for subsequent manual patch clamp experiments.
Test compounds were dissolved in DMSO and formulated into stock solutions at a final concentration of 10 mM. Stock solutions were diluted in DMSO as solvent in a 1:3 ratio gradient to three other intermediate concentration solutions at concentrations (mM): 3.33,1.11 and 0.37, respectively. Before the experiment, the gradient intermediate solution of the compound to be tested is diluted again with extracellular fluid in the ratio of 1:1000 to form working solutions with a series of concentrations, wherein the final concentrations are respectively (M): 10,3.33,1.11 and 0.37, and the 30M working solution is diluted 333.33 times by 10mM stock solution. The DMSO content in the working solution is 0.1-0.3% (volume ratio). 5 different concentration gradients 30,10,3.33,1.11 and 0.37M working solution were used to determine potential inhibition of hERG channel by compounds and to fit the dose-response curve and calculate IC 50.
The slide with HEK293 cells in the petri dish was placed in a perfusion channel of a micromanipulation station. The appropriate cells were centered in the field of view under an Olympus IX51, IX71 or IX73 inverted microscope, and the tip of the glass electrode was found using a x 10 objective lens and centered in the field of view. The electrode is then moved down using the micromanipulator while the coarse focusing helix is adjusted so that the electrode approaches the cell slowly. When approaching the cells quickly, the objective lens is changed into a multiplied by 40 to observe, and the micromanipulator is used for fine tuning, so that the electrodes gradually approach the surfaces of the cells. Negative pressure is given to form a seal with a resistance higher than 1G between the electrode tip and the cell membrane. The instantaneous capacitance current Cfast is compensated in the voltage clamp mode. And then repeatedly giving short negative pressure to rupture membranes to finally form a whole-cell recording mode. The slow capacitance current Cslow, cell membrane capacitance (Cm) and input membrane resistance (Ra) were compensated for under membrane potential clamping at-60 mV. After the cells were stabilized, the clamping voltage was changed to-90 mV, the sampling frequency was set to 20kHz, and the filtration frequency was 10kHz. The detection condition of the leakage current is that the clamp voltage is changed to-80 mV, and the time period is 500ms.
The hERG current test method is as follows, applying a 4.8 second depolarization command voltage depolarizes the membrane potential from-80 mV to +30mV, then momentarily applying a 5.2 second repolarization voltage to drop the membrane potential to-50 mV to remove channel deactivation, thus yielding the observed hERG tail current. The peak of the tail current is the magnitude of hERG current.
The hERG currents used to detect test compounds were recorded for 120 seconds prior to dosing to assess the stability of the test cells to produce hERG currents. Only stable cells within the acceptance range of the evaluation criteria can enter subsequent compound detection.
Test of hERG Current inhibition by test Compounds first, the hERG current measured in extracellular fluid containing 0.1% DMSO was used as the baseline for detection. Solutions containing the test compound were perfused around the cells sequentially from low to high concentration after hERG current remained stable for at least 5 minutes. Wait about 5 minutes after each perfusion end to allow the compound to act adequately on the cells and record hERG current simultaneously. The last 5 hERG current values were recorded after the current to be recorded tended to stabilize and their average value was taken as the current value at the specific concentration at which it was finally obtained. After testing the compounds, 150nM of dofetid was added to the same cells and their currents were completely inhibited as positive controls for the cells. Meanwhile, the positive compound, i.e. the Duofeide, is synchronously detected by the same patch clamp system before and after the end of the test drug experiment so as to ensure the reliability and the sensitivity of the whole detection system.
After filling a blank solvent or a compound gradient solution, 5 continuous current values are obtained stably, and an average value is obtained and used as a tail current size Blank space and a tail current size Compounds of formula (I) respectively.
The percent current suppression is calculated by the following formula.
The dose response curves were fitted by GRAPHPAD PRISM 8.0.0 software and IC 50 values calculated.
Table A3
Pharmacokinetic experiments in Male CD1 mice after oral administration
Male CD1 mice were fasted overnight prior to dosing, were free to drink water, and were given feed 4 hours after dosing. The dosage of administration is 10mg/kg, and the volume is 10mL/kg, and oral administration is adopted. Samples were formulated at 5% DMSO/95% "10% HP-beta-CD IN WATER".
Blood was taken using the dorsum of the foot vein at time points 0.25, 0.5, 1, 2, 4, 8 and 24 hours. 30 mu L of blood is taken each time, placed in an anticoagulation tube containing EDTA-K2 and inverted for a plurality of times and fully mixed. Whole blood samples were centrifuged at 4 ℃ and 4000g for 5 minutes to separate plasma. The plasma samples were aliquoted into clean polyethylene microcentrifuge tubes and then stored in a-75.+ -. 15 ℃ freezer until analysis.
The pharmacokinetic parameters were calculated using the LC-MS/MS assay for plasma assay results using WinNonlin 8.3 (phoenix tm) or other similar software.
Table A4 oral (10 mg/kg) pharmacokinetic parameters of representative compounds of the present disclosure

Claims (68)

  1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
    Wherein,
    Y is N or CR 7;
    R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    L 1 is selected from a bond, C 1-6 alkylene, -NH-, -O-, or-S-;
    R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl, or 5-20 membered heteroaryl, said R 1 being optionally substituted with 1,2, or 3,4, or 5R 1s, said R 1 preferably being C 6-10 aryl or 5-10 membered heteroaryl;
    r 1s is selected from H, deuterium, CN, NO 2、NH2, OH, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, Halogenated C 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3-8 membered heterocyclyl or-O-3-8 membered heteroaryl;
    Or two R 1s on the same carbon atom together form oxo or thioxo;
    L 2 is selected from a bond or C 1-6 alkylene;
    R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, said R 2 being optionally substituted with 1, 2, 3, 4 or 5 independently selected R 2s;
    R 2s is selected from H, D, halogen, CN, -L 2a -R' or
    L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene- -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene- -C 0-6 alkylene-C (O) NH-C 0-6 alkylene- -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or-C 2-6 alkenylene-, said L 2a optionally being substituted with 1, 2, 3, 4 or 5 independently selected r# substitutions; the L 2a is preferably-O-or-S-, preferably the L 2a is-O-, preferably the L 2a is-S-;
    R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
    Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-10 alkyl, C 1-10 alkoxy, C 1-10 haloalkyl, C 1- 10 haloalkoxy, C (O) R a、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、Boc、C2-6 alkenyl, OR C 2-6 alkynyl, OR two R on the same carbon atom taken together form c=o OR c=s;
    m is selected from 0, 1,2,3,4 or 5;
    R' is selected from H, NH 2、CN、C0-6 alkylene-C (O) R a、C0-6 alkylene-C (O) OR a、C1-6 alkylene-OC (O) -R a、C0-6 alkylene-NHC (O) R a、C0-6 alkylene-C (O) NR bRc、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylene-OR a、C2-6 alkenyl, OR C 2-6 alkynyl;
    L 3 is-NR b -or-CR aRb -;
    r 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3-to 14-membered heterocyclyl, said R 3 being optionally substituted with 1,2
    A substitution of one, 3, 4 or 5R 3s;
    R 3s is selected from H, deuterium, halogen, CN, NO 2、NH2、C1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1- 6 alkyl, halo C 1-6 alkoxy, halo C 2-6 alkenyl, Halogenated C 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3-8 membered heterocyclyl, -O-3-8 membered heteroaryl, or two R 3s on the same carbon atom together form c=o or c=s;
    R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof:
    Wherein:
    Y is N or CR 7;
    R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    L 1 is selected from a bond, C 1-6 alkylene, -NH-, -O-, or-S-;
    R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl, or 5-20 membered heteroaryl, said R 1 being optionally substituted with 1,2, or 3,4, or 5R 1s, said R 1 preferably being C 6-10 aryl or 5-10 membered heteroaryl;
    R 1s is selected from H, deuterium, CN, NO 2、NH2, halogen, C 1-6 alkyl, C 1-6 haloalkyl, halogen, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, Halogenated C 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, -NH (C 1- 6 alkyl), -N (C 1-6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -O-C 1-6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3-8 membered heterocyclyl or-O-3-8 membered heteroaryl;
    L 2 is selected from a bond or C 1-6 alkylene;
    R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, said R 2 being optionally substituted with 1, 2, 3, 4 or 5 independently selected R 2s;
    R 2s is selected from H, D, halogen, CN, -L 2a -R' or
    L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene- -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene- -C 0-6 alkylene-C (O) NH-C 0-6 alkylene- -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or-C 2-6 alkenylene-, said L 2a optionally being substituted with 1, 2, 3, 4 or 5 independently selected r# substitutions; the L 2a is preferably-O-or-S-, preferably the L 2a is-O-, preferably the L 2a is-S-;
    R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
    Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-10 alkyl, C 1-10 alkoxy, C 1-10 haloalkyl, C 1-10 haloalkoxy, C (O) R a、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、Boc、C2-6 alkenyl, OR C 2-6 alkynyl, OR two R on the same carbon atom taken together form c=o OR c=s;
    m is selected from 0, 1,2,3,4 or 5;
    R' is selected from H, NH 2、CN、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, or C 2-6 alkynyl;
    L 3 is-NR b -or-CR aRb -;
    R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, said R 3 being optionally substituted with 1, 2, 3,4 or 5R 3s;
    R 3s is selected from H, deuterium, halogen, CN, NO 2、NH2、C1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 2-6 alkenyl, haloC 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2、-NH-C3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -O-C 1- 6 alkyl, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -O-C 3-8 cycloalkyl, -O-C 6-10 aryl, -O-3-8 membered heterocyclyl, -O-3-8 membered heteroaryl, or two R 3s on the same carbon atom together form c=o or c=s;
    R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (I'):
    Wherein:
    Y' is NR 7 or CR 7R8;
    R 7 and R 8 are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    L 3' is-n=or-CR a =;
    The other groups are as defined in claim 1.
  4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, of formula (II), (II '), (III '), (IV '), (V '), (VI '), (VII '), (VIII) or (VIII '):
    Wherein,
    One of R 2a and R 2b isOr-L 2a -R', the other being H or D;
    L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene- -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene- -C 0-6 alkylene-C (O) NH-C 0-6 alkylene- -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or-C 2-6 alkenylene-, said L 2a optionally being substituted with 1, 2, 3, 4 or 5 independently selected r# substitutions; the L 2a is preferably-O-or-S-; preferably, the L 2a is-O-, preferably, the L 2a is-S-;
    R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    Ring a is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C (O) R a、C(O)ORa、NHC(O)Ra、C(O)NH-Ra, OR Boc, OR two R on the same carbon atom taken together form c=o OR c=s;
    R' is selected from H, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy;
    r 2c is halogen, preferably F;
    r 2d is halogen or CN, preferably Cl;
    m is selected from 0, 1,2,3,4 or 5;
    R 3a is halogen, preferably Cl;
    R 3f is C 1-6 alkyl, preferably CH 3;
    The other groups are as defined in any one of claims 1 to 3.
  5. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (II) or (II'):
    Wherein:
    L 1 is selected from a bond or C 1-6 alkylene;
    R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryl, or 5-10 membered heteroaryl, said R 1 being optionally substituted with 1,2, or 3,4, or 5R 1s;
    r 1s is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    One of R 2a and R 2b is Or-L 2a -R', the other being H or D;
    L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene-, -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C (O) NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or-C 2-6 alkylene-, said L 2a being optionally substituted with 1,2, 3, 4 or 5 independently selected R#;
    R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    Ring a is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C (O) R a、C(O)ORa、NHC(O)Ra、C(O)NH-Ra, OR Boc, OR two R on the same carbon atom taken together form c=o OR c=s;
    m is selected from 0, 1,2,3,4 or 5;
    R' is selected from H, NH 2、CN、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    r 2c is halogen, preferably F;
    r 2d is halogen or CN, preferably Cl;
    L 3 is-NR b -or-CR aRb -;
    L 3' is-n=or-CR a =;
    r 3 is selected from C 6-10 aryl or 5-10 heteroaryl, said R 3 optionally substituted with 1,2, 3, 4 or 5R 3s;
    R 3s is selected from halogen, C 1-6 alkyl or C 1-6 alkoxy, or two R 3s on the same carbon atom together form c=o or c=s;
    R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  6. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    L 1 is selected from a bond or C 1-6 alkylene;
    R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryl, or 5-10 membered heteroaryl, said R 1 being optionally substituted with 1,2, or 3,4, or 5R 1s;
    r 1s is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    One of R 2a and R 2b is Or-L 2a -R', the other being H or D;
    L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene-, -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C (O) NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or-C 2-6 alkylene-, said L 2a being optionally substituted with 1,2, 3, 4 or 5 independently selected R#;
    R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    Ring a is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C (O) R a、C(O)ORa、NHC(O)Ra、C(O)NH-Ra, OR Boc, OR two R on the same carbon atom taken together form c=o OR c=s;
    m is selected from 0, 1,2,3,4 or 5;
    R' is selected from H, NH 2、CN、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    r 2c is halogen, preferably F;
    r 2d is halogen or CN, preferably Cl;
    L 3 is-NR b -or-CR aRb -;
    L 3' is-n=or-CR a =;
    r 3 is selected from C 6-10 aryl or 5-10 heteroaryl, said R 3 optionally substituted with 1,2, 3, 4 or 5R 3s;
    R 3s is selected from halogen, C 1-6 alkyl or C 1-6 alkoxy, or two R 3s on the same carbon atom together form c=o or c=s;
    R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  7. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (III) or (III'):
    Wherein:
    R 2a is selected from Or-L 2a -R';
    L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene- -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene- -C 0-6 alkylene-C (O) NH-C 0-6 alkylene- -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or C 2-6 alkenylene, L 2a is optionally substituted with 1, 2, 3,4, or 5 substituents independently selected from halogen, C 1-6 alkyl, or C 1-6 haloalkyl;
    Ring a is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    Each R is independently selected from H, halogen, OH, NH 2、CN、C1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C (O) -C 1-6 haloalkyl, C (O) O-C 1-6 haloalkyl, NHC (O) -C 1-6 haloalkyl, or C (O) NH-C 1-6 haloalkyl, or two R on the same carbon atom together form c=o or c=s;
    m is 0, 1,2,3,4 or 5;
    R' is selected from NH 2、CN、C1-6 alkyl, C 1-6 haloalkyl, C (O) -C 1-6 haloalkyl, C (O) O-C 1-6 haloalkyl, NHC (O) -C 1-6 haloalkyl or C (O) NH-C 1-6 haloalkyl;
    R 2c is selected from halogen;
    R 2d is selected from halogen or CN;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  8. The compound of claim 7, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 2a is selected from Or-L 2a -R';
    L 2a is selected from the group consisting of a bond, -O-, -S-, -C 1-6 alkylene-, -C 1-6 alkylene-O-, -O-C 1-6 alkylene-, -C (O) O-, -NH-, -C (O) NH-, -NHC (O) -or C 2-6 alkenylene, L 2a being optionally substituted with 1, 2 or 3 substituents independently selected from halogen or C 1-6 alkyl;
    Ring a is selected from C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    Each R is independently selected from H, halogen, OH, NH 2、CN、C1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, or NHC (O) -C 1-6 haloalkyl, or two R on the same carbon atom together form c=o;
    m is 0,1, 2,3 or 4;
    R' is selected from NH 2、CN、C1-6 haloalkyl, NHC (O) -C 1-6 haloalkyl or C (O) NH-C 1-6 haloalkyl;
    R 2c is selected from halogen;
    R 2d is selected from halogen or CN;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  9. The compound of claim 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 2a is selected from Or-L 2a -R';
    L 2a is selected from the group consisting of bond 、-O-、-S-、-CH2-、-CH2-O-、-CH2-CH2-O-、-O-CH2-、-C(O)-、-C(O)O-、-NH-、-C(O)NH-、-NH-C(O)- or-ch=ch-, said L 2a optionally being substituted with CH 3;
    Selected from the group consisting of
    R' is selected from CN, NHC (O) -CF 3 or CF 3;
    R 2c is selected from F or Cl, preferably F;
    R 2d is selected from F, cl or CN, preferably Cl.
  10. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (IV) or (IV'):
    Wherein:
    L 2a is selected from-O-, -S-or-C 2-6 alkenylene-;
    Ring a is selected from C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    Each R is independently selected from H, halogen, CN, OH, NH 2、-C(O)-C1-6 haloalkyl, -C (O) O-C 1-6 haloalkyl, -NHC (O) -C 1-6 haloalkyl, -C (O) NH-C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, or two R on the same carbon atom together form c=o or c=s;
    m is selected from 0, 1,2,3,4 or 5;
    r 2c is halogen, preferably F;
    R 2d is selected from halogen or CN, preferably Cl.
  11. The compound of claim 10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    L 2a is selected from-O-or-C 2-6 alkenylene-;
    Ring a is selected from C 5-8 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    Each R is independently selected from H, halogen, CN, OH, NH 2、-NHC(O)-C1-6 haloalkyl, -C (O) NH-C 1-6 haloalkoxy, C 1-6 alkoxy or C 1-6 haloalkoxy, or two R on the same carbon atom together form c=o;
    m is selected from 0, 1,2,3,4 or 5;
    r 2c is halogen, preferably F;
    R 2d is selected from halogen or CN, preferably Cl.
  12. The compound of claim 11, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    l 2a is selected from-O-or-C 2-4 alkenylene-;
    Ring a is selected from C 5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-10 membered heteroaryl;
    Each R is independently selected from H, halogen, CN, -NHC (O) -C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy, preferably H, F, cl, CN, OCH 3、OCF3 or-NHC (O) -CF 3, or two R on the same carbon atom together form c=o;
    m is selected from 0, 1,2 or 3;
    r 2c is halogen, preferably F;
    R 2d is selected from halogen or CN, preferably Cl.
  13. The compound of claim 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    l 2a is selected from-O-, -ch=ch-;
    Selected from the group consisting of
    R 2c is selected from F or Cl, preferably F;
    R 2d is selected from F, cl or CN, preferably Cl.
  14. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (IV) or (IV'):
    Wherein:
    l 2a is C 2-6 alkenylene;
    Ring a is selected from C 6-10 aryl or 5-10 membered heteroaryl;
    R is selected from H, halogen or C 1-6 haloalkyl;
    m is selected from 0, 1,2,3,4 or 5;
    r 2c is halogen, preferably F;
    R 2d is halogen, preferably Cl;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  15. The compound of claim 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    L 2a is C 2-4 alkenylene, preferably-ch=ch-;
    ring a is selected from phenyl or a 5-6 membered heteroaryl, said 5 membered heteroaryl being a heteroaryl containing 1-2 heteroatoms selected from S or N;
    R is selected from H or halogen, preferably H or F;
    m is selected from 0, 1,2 or 3;
    r 2c is halogen, preferably F;
    R 2d is halogen, preferably Cl.
  16. The compound of claim 15, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    L 2a is C 2-4 alkenyl, preferably-ch=ch-;
    Selected from the group consisting of Preferably, the method comprises the steps of,Selected from the group consisting of
    R 2c is F;
    R 2d is Cl or F, preferably Cl.
  17. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (V) or (V'):
    Wherein:
    L 2a is-O-or-S-;
    Ring A is selected from Or a5 membered heteroaryl;
    x 2a and X 2b are independently selected from CR or N;
    Each R is independently selected from H, halogen, CN, OH, NH 2、C1-6 alkoxy, or C 1-6 haloalkoxy, preferably H, halogen, CN, OH, or NH 2, more preferably H, F, cl or CN;
    m is selected from 0, 1,2,3,4 or 5;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  18. The compound of claim 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    L 2a is-O-;
    Ring A is selected from Or a5 membered heteroaryl;
    x 2a and X 2b are independently selected from CR or N;
    Each R is independently selected from H, halogen, CN or C 1-6 haloalkoxy, preferably H, halogen or CN;
    m is selected from 0, 1,2,3,4 or 5;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  19. The compound of claim 18, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    L 2a is-O-;
    Ring A is selected from Or a 5-membered heteroaryl, said 5-membered heteroaryl being a heteroaryl containing 1-2 heteroatoms selected from S or N;
    x 2a and X 2b are independently selected from CR or N;
    Each R is independently selected from H, halogen, CN or C 1-4 haloalkoxy, preferably H, halogen or CN, more preferably H, F, cl or CN;
    m is selected from 0, 1,2 or 3;
    Preferably, the method comprises the steps of,
    Selected from the group consisting of Preferably is
  20. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (V) or (V'):
    Wherein,
    R 2b isOr-L 2a -R';
    l 2a is-C 1-6 alkylene-, -C 2-6 alkylene-, -C 0-6 alkylene-O-C 0-6 alkylene-or-C 0-6 alkylene-S-C 0-6 alkylene-;
    ring a is C 6-10 aryl or 5-10 membered heteroaryl;
    Each R is independently selected from H, halogen, NH 2、OH、CN、C1-6 haloalkyl or C 1-6 haloalkoxy;
    R' is selected from C (O) -C 1-6 haloalkyl, C (O) O-C 1-6 haloalkyl, NHC (O) -C 1-6 haloalkyl or C (O) NH-C 1-6 haloalkyl;
    R 2c is halogen;
    R 2d is selected from halogen or CN;
    m is 0, 1,2,3,4 or 5;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  21. The compound of claim 20, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    r 2b is Or-L 2a -R';
    L 2a is selected from the group consisting of-O-, -S-, -C 1-4 alkylene- -C 1-4 alkylene-O- -O-C 1-4 alkylene-, -C 1-4 alkylene-S-or-S-C 1-4 alkylene-;
    ring a is phenyl or a 5-6 membered heteroaryl, said 5 membered heteroaryl being a heteroaryl containing 1-2 heteroatoms selected from S or N;
    Each R is independently selected from H, halogen, CN, C 1-4 haloalkyl or C 1-4 haloalkoxy, preferably H, F, cl, CN, CF 3 or OCF 3;
    R' is selected from NHC (O) -C 1-6 haloalkyl or C (O) NH-C 1-6 haloalkyl, preferably NHC (O) CF 3;
    R 2c is halogen;
    R 2d is selected from halogen or CN;
    m is 0, 1,2 or 3;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  22. The compound of claim 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    r 2b is Or-L 2a -R';
    L 2a is-O-, -S-, -CH 2-、-CH2-O-、-CH2-CH2 -O-or-O-CH 2 -;
    Selected from the group consisting of
    R' is NHC (O) CF 3;
    r 2c is F;
    R 2d is selected from F, cl or CN, preferably Cl.
  23. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (VI) or (VI'):
    Wherein,
    L 2a is-O-or-S-;
    ring a is C 6-10 aryl or 5-10 membered heteroaryl;
    Each R is independently selected from H, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy;
    m is 0, 1,2,3,4 or 5;
    R 2c is halogen;
    R 2d is selected from halogen or CN;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  24. The compound of claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    L 2a is-O-;
    Ring A is phenyl;
    Each R is independently selected from H, halogen, C 1-4 haloalkyl or C 1-4 haloalkoxy, preferably H, F, cl, CF 3 or OCF 3;
    m is 0, 1,2 or 3;
    Preferably, the method comprises the steps of, Selected from the group consisting of
    R 2c is halogen, preferably F;
    r 2d is selected from halogen or CN, preferably F, cl or CN, more preferably Cl;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  25. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (VII) or (VII'):
    Wherein,
    L 2a is O or S;
    R is selected from H or halogen;
    R' is selected from H, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy.
  26. The compound of claim 25, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    L 2a is selected from-O-;
    R is selected from H or halogen, preferably H, F or Cl;
    R' is selected from H, halogen or C 1-4 haloalkoxy, preferably H, F, cl or OCF 3.
  27. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (II) or (II'):
    Wherein,
    L 1 is selected from a bond or C 1-6 alkylene;
    R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryl, or 5-10 membered heteroaryl, said R 1 being optionally substituted with 1, 23, 4, or 5 independently selected R 1s;
    r 1s is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    One of R 2a and R 2b is Or-L 2a -R', the other being H or D;
    L 2a is selected from the group consisting of a bond, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0- 6 alkylene-, -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C (O) NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-, or-C 2-6 alkenylene-, said L 2a being optionally substituted with 1,2,3,4, or 5 independently selected R#;
    R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    Ring a is selected from C 3-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-6 haloalkyl, C 1-6 haloalkoxy, OR Boc, preferably H, F, cl, CN, CF 3、OCF3 OR Boc;
    m is selected from 0, 1,2,3,4 or 5;
    R' is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    r 2c is halogen, preferably F;
    R 2d is halogen, preferably Cl;
    L 3 is-NR b -or-CR aRb -;
    R 3 is selected from C 6-10 aryl or 5-10 heteroaryl, said R 3 optionally substituted with 1,2,3,4 or 5 independently selected R 3s;
    R 3s is selected from H, halogen, C 1-6 alkyl or C 1-6 alkoxy, or two R 3s on the same carbon atom together form c=o or c=s;
    R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  28. The compound of claim 27, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    L 1 is selected from a bond or C 1-4 alkylene;
    R 1 is selected from C 1-4 alkoxy or 5-6 membered heteroaryl, said R 1 optionally substituted with 1,2 or 3 independently selected R 1s;
    R 1s is selected from H, halogen, C 1-4 alkyl or C 1-4 alkoxy, preferably F, CH 3 or OCH 3;
    One of R 2a and R 2b is Or-L 2a -R', the other being H or D;
    L 2a is selected from the group consisting of a bond, -O-, -S-, -C 1-4 alkylene-O-, -O-C 1-4 alkylene-, -C (O) O-, -NH-, -C (O) NH-, -NHC (O) -, -C (O) -or C 2-4 alkenylene, said L 2a being optionally substituted with 1, 2 or 3 independently selected R#;
    r# is selected from H, C 1-4 alkyl or C 1-4 haloalkyl;
    ring a is selected from C 3-6 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    Each R is independently selected from H, halogen, CN, C 1-4 haloalkyl, C 1-4 haloalkoxy or Boc, preferably H, F, cl, CN, CF 3、OCF3 or Boc;
    m is selected from 0, 1,2 or 3;
    r' is selected from C 1-4 alkyl or C 1-4 haloalkyl;
    r 2c is halogen, preferably F;
    R 2d is halogen, preferably Cl;
    l 3 is-NH-;
    R 3 is selected from C 6-10 aryl or 5-10 heteroaryl, said R 3 optionally substituted with 1,2 or 3 independently selected R 3s;
    R 3s is selected from H, halogen, C 1-4 alkyl or C 1-4 alkoxy, or two R 3s on the same carbon atom together form c=o;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  29. The compound of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    L 1 is selected from a bond or-CH 2 -;
    R 1 is selected from OCH 3,
    One of R 2a and R 2b isOr-L 2a -R', the other being H or D;
    l 2a is selected from the group consisting of bond 、-O-、-S-、-CH2-O-、-CH2-CH2-O-、-O-CH2-、-C(O)O-、-NH-、-C(O)NH-、-NHC(O)-、-C(O)- or-ch=ch-, said L 2a optionally being substituted with CH 3;
    Selected from the group consisting of
    R' is selected from CHF 2 or CF 3;
    R 2c is selected from F;
    R 2d is selected from F or Cl;
    l 3 is-NH-;
    R 3 is selected from
    L 1 is selected from a bond or-CH 2 -;
    R 1 is selected from OCH 3,
    One of R 2a and R 2b isOr-L 2a -R', the other being H or D;
    l 2a is selected from the group consisting of bond 、-O-、-S-、-CH2-O-、-CH2-CH2-O-、-O-CH2-、-C(O)O-、-NH-、-C(O)NH-、-NHC(O)-、-C(O)- or-ch=ch-, said L 2a optionally being substituted with CH 3;
    Selected from the group consisting of
    R' is selected from CHF 2 or CF 3;
    R 2c is selected from F;
    R 2d is selected from F or Cl;
    l 3 is-NH-;
    R 3 is selected from
  30. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (VIII) or (VIII'):
    Wherein:
    L 2a is O or S;
    R 1s is selected from halogen or C 1-6 haloalkoxy;
    R is selected from halogen, CN, C 1-6 haloalkyl or C 1-6 haloalkoxy;
    R 3a is halogen, preferably Cl;
    R 3f is C 1-6 alkyl, preferably CH 3.
  31. The compound of claim 30, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    L 2a is O;
    R 1s is selected from halogen or C 1-4 haloalkoxy, preferably F or OCH 3;
    R is selected from halogen, CN, C 1-4 haloalkyl or C 1-4 haloalkoxy, preferably F, CN, CF 3 or OCF 3;
    R 3a is halogen, preferably Cl;
    R 3f is C 1-4 alkyl, preferably CH 3.
  32. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (VIII) or (VIII'):
    Wherein:
    L 2a is O or S;
    R 1s is selected from halogen or C 1-6 haloalkoxy;
    R is selected from halogen or CN;
    R 3a is halogen, preferably Cl;
    R 3f is C 1-6 alkyl, preferably CH 3;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  33. The compound of claim 32, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    L 2a is O;
    R 1s is selected from halogen or C 1-4 haloalkoxy, preferably F or OCH 3;
    r is selected from halogen or CN, preferably F or CN;
    R 3a is halogen, preferably Cl;
    R 3f is C 1-4 alkyl, preferably CH 3.
  34. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, of formula (IV), (IV '), (V'), (IX '), (X'), (XI '), (XII) or (XII'):
    One of R 2a and R 2b is Or-L 2a -R', the other being H or D;
    L 2a is selected from the group consisting of a bond, -C 1-6 alkylene, -C 0-6 alkylene-O-C 0-6 alkylene-, -C 0-6 alkylene-S-C 0-6 alkylene-, -C 0-6 alkylene-C (O) -C 0-6 alkylene- -C 0-6 alkylene-C (O) O-C 0-6 alkylene-, -C 0-6 alkylene-NH-C 0-6 alkylene- -C 0-6 alkylene-C (O) NH-C 0-6 alkylene- -C 0-6 alkylene-NHC (O) -C 0-6 alkylene-or-C 2-6 alkenylene-, said L 2a optionally being substituted with 1, 2, 3, 4 or 5 independently selected r# substitutions; the L 2a is preferably-O-or-S-; preferably, the L 2a is-O-, preferably, the L 2a is-S-;
    R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    Ring a is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    Each R is independently selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C (O) R a、C(O)ORa、NHC(O)Ra、C(O)NH-Ra, OR Boc, OR two R on the same carbon atom taken together form c=o OR c=s;
    r 2c is halogen, preferably F;
    r 2d is halogen or CN, preferably Cl;
    m is selected from 0, 1,2,3,4 or 5;
    R 3a is halogen, preferably Cl;
    R 3f is C 1-6 alkyl, preferably CH 3;
    The other groups are as defined in any one of claims 1 to 3.
  35. The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (IV) or (IV'):
    Wherein,
    L 2a is selected from-S-or-O-;
    Ring a is selected from C 6-10 aryl or 5-10 membered heteroaryl;
    R is selected from H, halogen, CN, OR a、NRbRc、C(O)NRbRc、C1-6 alkyl OR C 1-6 haloalkyl;
    m is selected from 0, 1,2,3,4 or 5;
    R 2d is selected from halogen;
    R 2c is selected from halogen;
    R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  36. The compound of claim 35, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    l 2a is selected from-S-or-O-;
    ring a is selected from phenyl or 5-6 membered heteroaryl;
    R is selected from H, halogen, CN, OH, NH 2、C(O)NH2 or C 1-4 haloalkyl, preferably H, F, cl, CN, OH, NH 2、C(O)NH2 or CF 3;
    m is selected from 1,2 or 3;
    R 2d is selected from halogen, preferably Cl or F;
    R 2c is selected from halogen, preferably F.
  37. The compound of claim 35 or 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    l 2a is-S-or-O-;
    Selected from the group consisting of
    R 2d is selected from halogen, preferably Cl or F;
    R 2c is selected from halogen, preferably F.
  38. The compound of claim 35, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    l 2a is selected from-S-or-O-;
    Ring a is selected from C 6-10 aryl or 5-10 membered heteroaryl;
    r is selected from H, halogen, CN, NH 2、C1-6 alkyl or C 1-6 haloalkyl;
    m is selected from 0, 1,2,3,4 or 5;
    r 2d is selected from halogen, preferably Cl;
    R 2c is selected from halogen, preferably F;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  39. The compound of claim 38, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    l 2a is selected from-S-or-O-;
    ring a is selected from phenyl or 5-6 membered heteroaryl;
    R is selected from H, halogen, CN, NH 2 or C 1-4 haloalkyl, preferably H, F, cl, CN, NH 2 or CF 3;
    m is selected from 1,2 or 3;
    r 2d is selected from halogen, preferably Cl;
    R 2c is selected from halogen, preferably F.
  40. The compound of claim 38 or 39, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    L 2a is-S-or-O-, preferably-S-;
    Selected from the group consisting of
    R 2d is selected from halogen, preferably Cl;
    R 2c is selected from halogen, preferably F.
  41. The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (V) or (V'):
    Wherein,
    R 2b is selected fromOr-L 2a -R';
    l 2a is selected from-S-or-O-;
    Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 6-10 membered heteroaryl;
    R is selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl OR C 2-6 alkynyl;
    m is selected from 0, 1,2,3,4 or 5;
    R' is selected from C 0-6 alkylene-OC 1-6 alkyl or C 0-6 alkylene-OC 1-6 haloalkyl;
    R 2d is selected from halogen;
    R 2c is selected from halogen;
    R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  42. The compound of claim 41, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 2b is selected from Or-L 2a -R';
    l 2a is selected from-S-or-O-;
    ring a is selected from 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
    R is selected from H, halogen, NH 2, CN, OH or C 1-4 haloalkyl, preferably H, F, NH 2, CN, OH or CF 3;
    m is selected from 1,2 or 3;
    r' is C 1-4 alkylene-OC 1-4 alkyl;
    r 2d is selected from halogen, preferably Cl;
    R 2c is selected from halogen, preferably F.
  43. The compound of claim 41 or 42, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 2b is selected from Or-L 2a -R';
    l 2a is selected from-S-or-O-;
    Selected from the group consisting of
    R' is
    R 2d is selected from halogen, preferably Cl;
    R 2c is selected from halogen, preferably F.
  44. The compound of claim 41, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 2b is selected from Or-L 2a -R';
    l 2a is selected from-S-or-O-;
    Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 6-10 membered heteroaryl;
    R is selected from H, halogen, C 0-6 alkylene-NH 2、C0-6 alkylene-CN or C 0-6 alkylene-OH;
    m is selected from 0, 1,2,3,4 or 5;
    R' is selected from C 0-6 alkylene-OC 1-6 alkyl or C 0-6 alkylene-OC 1-6 haloalkyl;
    R 2d is selected from halogen;
    R 2c is selected from halogen;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  45. The compound of claim 46, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 2b is selected from Or-L 2a -R';
    l 2a is selected from-S-or-O-;
    ring a is selected from 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
    R is selected from H, halogen, NH 2, CN or OH, preferably H, F, NH 2, CN or OH;
    m is selected from 1,2 or 3;
    r' is C 1-4 alkylene-OC 1-4 alkyl;
    r 2d is selected from halogen, preferably Cl;
    R 2c is selected from halogen, preferably F.
  46. The compound of claim 44 or 45, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 2b is selected from Or-L 2a -R';
    l 2a is selected from-S-or-O-;
    Selected from the group consisting of
    R' is
    R 2d is selected from halogen, preferably Cl;
    R 2c is selected from halogen, preferably F.
  47. The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (IX) or (IX'):
    Wherein,
    R 1S is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    L 2a is-C 0-6 alkylene-O-C 0-6 alkylene-or-C 0-6 alkylene-S-C 0-6 alkylene-;
    Ring a is selected from C 6-10 aryl or 5-10 membered heteroaryl;
    R is selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy C 2- 6 alkenyl OR C 2-6 alkynyl;
    m is selected from 0, 1,2,3,4 or 5;
    R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
    R 2c is selected from H or halogen, preferably H or F, more preferably F;
    R 3a is halogen, preferably Cl;
    R 3f is C 1-6 alkyl, preferably CH 3;
    R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  48. The compound of claim 47, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 1S is selected from H, halogen, C 1-4 alkyl or C 1-4 alkoxy;
    l 2a is-O-C 0-4 alkylene-or-S-C 0-4 alkylene-;
    ring a is selected from phenyl or 5-6 membered heteroaryl;
    R is selected from H, halogen, CN, NH 2、OH、C1-4 alkyl or C 1-4 haloalkyl, preferably H, F, cl, CN, NH 2、OH、CH3 or CF 3;
    m is selected from 1,2 or 3;
    R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
    R 2c is selected from H or halogen, preferably H or F, more preferably F;
    R 3a is halogen, preferably Cl;
    R 3f is C 1-4 alkyl, preferably CH 3.
  49. The compound of claim 48, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 1S is selected from H, F, CH 3 or OCH 3;
    L 2a is-S-or-S-CH 2 -;
    Selected from the group consisting of
    R 2d is selected from Cl or CN;
    R 2c is selected from H or F;
    R 3a is Cl;
    R 3f is CH 3.
  50. The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (X) or (X'):
    Wherein,
    R 1S is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    l 2a is-S-or-O-;
    ring a is selected from C 6-10 aryl or 5-10 membered heteroaryl, said 5-10 membered heteroaryl being heteroaryl containing 1-2 heteroatoms selected from O, S or N;
    R is selected from H, halogen, CN, NR bRc、ORa、C1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    m is selected from 0, 1,2,3,4 or 5;
    R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
    R 2c is selected from H or halogen, preferably H or F, more preferably F;
    R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  51. The compound of claim 50, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 1S is selected from C 1-4 alkyl or C 1-4 alkoxy;
    l 2a is-S-or-O-;
    Ring a is selected from phenyl or a 5-6 membered heteroaryl, said 5-6 membered heteroaryl being a heteroaryl containing 1-2 heteroatoms selected from O, S or N;
    R is selected from H, halogen, CN, NH 2、OH、C1-4 alkyl or C 1-4 haloalkyl, preferably H, F, cl, CN, NH 2、OH、CH3 or CF 3;
    m is selected from 1,2 or 3;
    R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
    R 2c is selected from H or halogen, preferably H or F, more preferably F.
  52. The compound of claim 50 or 51, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 1S is selected from CH 3 or OCH 3;
    L 2a is-S-or-O-, preferably-S-;
    Selected from the group consisting of
    R 2d is selected from Cl or CN;
    R 2c is selected from H or F.
  53. The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (XI) or (XI'):
    Wherein,
    R 1S is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    R 2b is selected from Or-L 2a -R';
    L 2a is-C 0-6 alkylene-O-C 0-6 alkylene-or-C 0-6 alkylene-S-C 0-6 alkylene-;
    Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    R is selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl OR C 2-6 alkynyl;
    m is selected from 0, 1,2,3,4 or 5;
    R' is selected from C 1-6 alkylene-NHC (O) -R a、C1-6 alkylene-C (O) -R a、C1-6 alkylene-OC (O) -R a、C1-6 alkylene-C (O) O-R a、C1-6 alkylene-C (O) NR bRc OR C 1-6 alkylene-OR a;
    R 2d is selected from halogen or CN;
    r 2c is selected from H or halogen;
    r 3a is halogen;
    R 3f is C 1-6 alkyl;
    R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  54. The compound of claim 53, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 1S is CH 3;
    R 2b is selected from Or-L 2a -R';
    l 2a is-S-;
    Selected from the group consisting of
    R' is selected from
    R 2d is selected from F, cl or CN;
    R 2c is selected from H or F;
    R 3a is Cl;
    R 3f is CH 3.
  55. The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which is a structure of formula (XII) or (XII'):
    Wherein,
    R 1S is selected from C 1-6 alkyl or C 1-6 alkoxy;
    R 2b is selected from Or-L 2a -R';
    L 2a is-C 0-6 alkylene-O-C 0-6 alkylene-or-C 0-6 alkylene-S-C 0-6 alkylene-;
    Ring A is selected from 3-8 membered heterocyclic group, Or a 5-membered heteroaryl, said 5-membered heteroaryl being a heteroaryl containing 1-2 heteroatoms selected from N, O or S;
    Q 1 is CH or N;
    R is selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl OR C 2-6 alkynyl;
    m is selected from 0, 1,2,3,4 or 5;
    R' is selected from C 1-6 alkylene-NHC (O) -R a、C1-6 alkylene-C (O) -R a、C1-6 alkylene-OC (O) -R a、C1-6 alkylene-C (O) O-R a、C1-6 alkylene-C (O) NR bRc OR C 1-6 alkylene-OR a;
    r 2d is selected from halogen or CN, preferably F, cl or CN, more preferably Cl;
    R 2c is selected from H or halogen, preferably H or F, more preferably F;
    R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  56. The compound of claim 55, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 1S is selected from C 1-4 alkyl or C 1-4 alkoxy;
    R 2b is selected from Or-L 2a -R';
    l 2a is-O-C 0-4 alkylene-or-S-C 0-4 alkylene-;
    ring A is selected from 3-6 membered heterocyclic group,
    Q 1 is CH or N;
    Q 2 is selected from S or NH;
    Q 3 is selected from CH or N;
    One of Q 4、Q5 and Q 6 is N, and the other two are CH;
    R is selected from H, halogen, OH, CN, NR bRc、C1-4 alkyl or C 1-4 haloalkyl, preferably H, F, OH, CN, NH 2、NHCH3、CF3 or CH 3;
    m is selected from 1,2 or 3;
    R' is selected from C 1-6 alkylene-NHC (O) -R a、C1-6 alkylene-C (O) NR bRc OR C 1-6 alkylene-OR a;
    r 2d is selected from halogen or CN, preferably F, cl or CN, more preferably Cl;
    R 2c is selected from H or halogen, preferably H or F, more preferably F;
    R a、Rb and R c are independently selected from H, C 1-4 alkyl or C 1-4 haloalkyl.
  57. The compound of claim 55 or 56, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 1S is CH 3;
    R 2b is selected from Or-L 2a -R';
    l 2a is-S-;
    Selected from the group consisting of
    R' is selected from
    R 2d is selected from F, cl or CN;
    R 2c is selected from H or F.
  58. The compound of claim 55, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 1S is selected from C 1-6 alkyl or C 1-6 alkoxy;
    R 2b is selected from Or-L 2a -R';
    L 2a is-C 0-6 alkylene-O-C 0-6 alkylene-or-C 0-6 alkylene-S-C 0-6 alkylene-;
    ring a is selected from phenyl, thienyl, pyrazolyl or thiazolyl;
    R is selected from H, halogen, CN, OR a、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl OR C 2-6 alkynyl;
    m is selected from 0, 1,2,3,4 or 5;
    R' is selected from C 1-6 alkylene-NHC (O) -R a、C1-6 alkylene-C (O) -R a、C1-6 alkylene-OC (O) -R a、C1-6 alkylene-C (O) O-R a、C1-6 alkylene-C (O) NH 2 OR C 1-6 alkylene-OR a;
    r 2d is selected from halogen or CN, preferably F, cl or CN, more preferably Cl;
    R 2c is selected from H or halogen, preferably H or F, more preferably F;
    R a、Rb and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    wherein each group definition may be optionally substituted with D until fully deuterated.
  59. The compound of claim 58, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 1S is selected from C 1-4 alkyl or C 1-4 alkoxy;
    R 2b is selected from Or-L 2a -R';
    l 2a is-O-C 0-4 alkylene-or-S-C 0-4 alkylene-;
    Ring A is selected from phenyl, thienyl,
    R is selected from H, halogen, CN, NR bRc、C1-4 alkyl or C 1-4 haloalkyl, preferably H, F, CN, NH 2、NHCH3、CF3 or CH 3;
    r b and R c are independently selected from H, C 1-4 alkyl or C 1-4 haloalkyl;
    m is selected from 1,2 or 3;
    r' is selected from C 1-4 alkylene-NHC (O) -C 1-4 haloalkyl, C 1-4 alkylene-C (O) NH 2 or C 1-4 alkylene-O-C 1-4 alkyl;
    r 2d is selected from halogen or CN, preferably F, cl or CN, more preferably Cl;
    R 2c is selected from H or halogen, preferably H or F, more preferably F.
  60. The compound of claim 58 or 59, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein:
    R 1S is CH 3;
    R 2b is selected from Or-L 2a -R';
    l 2a is-S-;
    Selected from the group consisting of
    R' is selected from
    R 2d is selected from F, cl or CN;
    R 2c is selected from H or F.
  61. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein the compound is selected from the group consisting of:
  62. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein the compound is selected from the group consisting of:
  63. a pharmaceutical composition comprising a compound of any one of claims 1-62, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, optionally other therapeutic agents;
    Preferably, the additional therapeutic agent is selected from the group consisting of Ritonavir (REMDESIVIR or GS-5734), lopinavir (Lopinavir), mo Nupi (Molnupiravir), ritonavir (Ritonavir), chloroquine (Chloroquine or Sigma-C6628), hydroxychloroquine, or interferon-alpha.
  64. Use of a compound of any one of claims 1-62, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutical composition of claim 63, in the manufacture of a medicament for treating or preventing a disease caused by a viral infection.
  65. A method of treating or preventing a disease caused by a viral infection in a subject comprising administering to the subject a compound of any one of claims 1-62, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutical composition of claim 63.
  66. A compound of any one of claims 1-62, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutical composition of claim 63, for use in the treatment or prevention of a disease caused by a viral infection.
  67. The use of claim 64 or the method of claim 65 or the use of a compound or pharmaceutical composition of claim 66, wherein said compound or pharmaceutical composition inhibits viral proliferation;
    preferably, the compound or pharmaceutical composition inhibits the activity of viral 3CL protease;
    preferably, the 3CL protease has a P132H mutation;
    Preferably, the virus is a coronavirus, preferably an alpha coronavirus and/or a beta coronavirus, more preferably SARS-CoV-2.
  68. The method of claim 64 or the method of claim 65 or the compound of claim 66 or the pharmaceutical composition of claim 66, wherein said viral infection causes a disease selected from the group consisting of fever, nausea, vomiting, headache, dyspnea, weakness, respiratory tract infection, pneumonia, dysolfaction, dysgeusia and complications thereof, or a combination thereof.
CN202380042999.3A 2022-05-27 2023-05-26 3C-like protease inhibitor Pending CN119255987A (en)

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