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CN119698410A - 3C-like protease inhibitor - Google Patents

3C-like protease inhibitor Download PDF

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CN119698410A
CN119698410A CN202380042986.6A CN202380042986A CN119698410A CN 119698410 A CN119698410 A CN 119698410A CN 202380042986 A CN202380042986 A CN 202380042986A CN 119698410 A CN119698410 A CN 119698410A
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alkyl
haloalkyl
halogen
cycloalkyl
membered heterocyclyl
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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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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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Abstract

本发明提供了一类式(I)所示的3C样蛋白酶抑制剂，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物。本发明还提供了所述化合物的制备方法、包含所述化合物的药物组合物，以及所述化合物在治疗或预防病毒感染导致的疾病中的作用。 The present invention provides a 3C-like protease inhibitor represented by formula (I), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof. The present invention also provides a method for preparing the compound, a pharmaceutical composition comprising the compound, and the effect of the compound in treating or preventing diseases caused by viral infection.

Description

3C-like protease inhibitors
The present application claims priority from chinese application 202210600337.0 filed on month 27 of 2022, and chinese application 202310082317.3 filed on month 19 of 2023, which are incorporated herein by reference in their entireties.
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,
Y is N or CR 7;
R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
r 1s is -C (O) NR 1bR1c or
L 1a is selected from a bond, O, S, or NR 5a;
L 1b is selected from a bond, O, S, or NR 5b;
R 1a 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 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3R 1as;
R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L 1c-ORa、-L1c-SRa、-L1c-NRbRc、C3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
n 1 and n 2 are independently selected from 0, 1,2,3, 4,5 or 6;
R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 1b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
R' 1s is independently selected from H, D, halogen, cyano, -L 1d-ORa、-L1d-SRa、-L1d-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
n 3 is 0, 1,2 or 3;
L 2 is selected from- (CR 4aR4b)m1 -, O, S or NR 4c;
r 4a and R 4b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
m 1 is 0, 1 or 2;
R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2,3, 4, or 5R 2s;
R 2s is independently selected from H, D, halogen, cyano, -L 2a-ORa、-L2a-SRa、-L2a-NRbRc, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl or 3-to 10-membered heterocyclyl;
L 3 is selected from a bond, CR 6aR6b, O, S or NR 6c;
R 6a and R 6b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
R 6c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 3 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2,3, 4, or 5R 3s;
r 3s is independently selected from H, D, halogen, cyano, -L 3a-ORa、-L3a-SRa、-L3a-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
Or two adjacent R 3s and the atoms to which they are attached together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2, or 3R 3ss;
R 3ss is independently selected from H, D, halogen, cyano, -L 3b-ORa、-L3b-SRa、-L3b-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 aryl, or 3-10 membered heteroaryl;
L 1c、L1d、L2a、L3a and L 3b are each independently selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, or C 2-6 alkynylene, optionally substituted with 1,2, or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
R a、Rb and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, or R b、Rc together with the atoms to which they are attached form 3-10 membered heterocyclyl or 5-10 membered heteroaryl;
Wherein each of the above groups are defined as optionally deuterated to fully deuterated;
with the proviso that when ring A is pyridinyl, L 1a is NH, L 1b is a bond, R 1a is not C 1-6 alkyl or C 1-6 haloalkyl, and the compound is not of the structure:
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 1-6 alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, 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 1-6 alkoxy" refers to-O-C 1-6 alkyl. In some embodiments, a C 1-4 alkyl group is preferred. In other embodiments, C 1-3 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 1-6 haloalkyl" refers to the "C 1-6 alkyl" described above, which is substituted with one or more halo groups. In some embodiments, 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 (e.g., OCH 2F、OCHF2 or OCF 3), haloethoxy, and the like.
"C 3-10 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group 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.
"3-10 Membered heterocyclyl" refers to a saturated or unsaturated group of a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 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 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 5-6 membered heterocyclic group is more preferred, which is a 5-6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms. more preferably a 5 membered heterocyclyl which is a 5 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 6-10 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 to 10 ring carbon atoms and zero heteroatoms. 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.
"5-10 Membered heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement), 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, 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 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 "subject" administered includes, but is not limited to, a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle aged adult, or senior adult)) and/or a non-human animal, e.g., a mammal, e.g., primate (e.g., cynomolgus monkey, rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, and/or dog. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.
"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
Herein, "the compound of the present invention" refers to a compound of the following formula (I), formula (II), formula (III-1), formula (III-2), formula (III-3) and the like, 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;
Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
r 1s is -C (O) NR 1bR1c or
L 1a is selected from a bond, O, S, or NR 5a;
L 1b is selected from a bond, O, S, or NR 5b;
R 1a 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 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3R 1as;
R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L 1c-ORa、-L1c-SRa、-L1c-NRbRc、C3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
n 1 and n 2 are independently selected from 0, 1,2,3, 4,5 or 6;
R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 1b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
R' 1s is independently selected from H, D, halogen, cyano, -L 1d-ORa、-L1d-SRa、-L1d-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
n 3 is 0, 1,2 or 3;
L 2 is selected from- (CR 4aR4b)m1 -, O, S or NR 4c;
r 4a and R 4b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
m 1 is 0, 1 or 2;
R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2,3, 4, or 5R 2s;
R 2s is independently selected from H, D, halogen, cyano, -L 2a-ORa、-L2a-SRa、-L2a-NRbRc, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl or 3-to 10-membered heterocyclyl;
L 3 is selected from a bond, CR 6aR6b, O, S or NR 6c;
R 6a and R 6b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
R 6c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 3 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2,3, 4, or 5R 3s;
r 3s is independently selected from H, D, halogen, cyano, -L 3a-ORa、-L3a-SRa、-L3a-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
Or two adjacent R 3s and the atoms to which they are attached together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2, or 3R 3ss;
R 3ss is independently selected from H, D, halogen, cyano, -L 3b-ORa、-L3b-SRa、-L3b-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 aryl, or 3-10 membered heteroaryl;
L 1c、L1d、L2a、L3a and L 3b are each independently selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, or C 2-6 alkynylene, optionally substituted with 1,2, or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
R a、Rb and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, or R b、Rc together with the atoms to which they are attached form 3-10 membered heterocyclyl or 5-10 membered heteroaryl;
Wherein each of the above groups are defined as optionally deuterated to fully deuterated;
with the proviso that when ring A is pyridinyl, L 1a is NH, L 1b is a bond, R 1a is not C 1-6 alkyl or C 1-6 haloalkyl, and the compound is not of the structure:
Y
in one embodiment Y is CR 7, e.g., CH, and in another embodiment Y is N.
R7
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.
Ring A
In one embodiment, ring A is C 3-10 cycloalkyl, in another embodiment, ring A is a 3-10 membered heterocyclyl, in another embodiment, ring A is C 6-10 aryl, such as phenyl, in another embodiment, ring A is a 5-10 membered heteroaryl, such as a 5-6 membered heteroaryl, such as pyridinyl, such as thiazolyl, such asFor example
In one particular embodiment, ring A is C 6-10 aryl or 5-10 membered heteroaryl, in another more particular embodiment, ring A is phenyl or 5-6 membered heteroaryl, in another more particular embodiment, ring A is pyridinyl or thiazolyl, in another more particular embodiment, ring A is pyridinyl, in another more particular embodiment, ring A isIn a more specific embodiment, ring A is
In a specific embodiment, rings A and R 1s compriseIn another specific embodiment, rings A and R 1s constitute
R1s
In one embodiment, R 1s isFor exampleFor exampleMore specifically, for exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleIn another embodiment, R 1s is C (O) NR 1bR1c, such as C (O) NHCH 3, in another embodiment R 1s isFor example
In a more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is not
In a more specific embodiment, R 1s is selected from Preferably isPreferably is
In a more specific embodiment, R 1s is selected from: Preferably selected from: Preferably, the method comprises the steps of, Is thatPreferably, the method comprises the steps of,Is thatPreferably, the method comprises the steps of,Is that
In a more specific embodiment, R 1s is selected from: preferably, it is: Preferably is Preferably, the method comprises the steps of,Is that
In a more specific embodiment, R 1s is selected from: Preferably is Preferably is Preferably is Preferably, the method comprises the steps of,Is that
L1a
In one embodiment, L 1a is O, in another embodiment L 1a is S, in another embodiment L 1a is NR 5a, such as NH, e.g., NMe, and in another embodiment L 1a is a bond.
In one more specific embodiment, L 1a is selected from O, S, NH or NMe, in another more specific embodiment L 1a is selected from O, S or NH, in another more specific embodiment L 1a is O or NH, in another more specific embodiment L 1a is O or S, and in another more specific embodiment L 1a is selected from O, S, NR 5a.
L1b
In one embodiment, L 1b is a bond, in another embodiment L 1b is O, in another embodiment L 1b is S, in another embodiment L 1b is NR 5b, such as NH, for example NMe.
In one more specific embodiment, L 1b is selected from O, S or NR 5b, in another more specific embodiment L 1b is selected from O or NR 5b, in another more specific embodiment L 1b is selected from O, S or NMe, in another more specific embodiment L 1b is selected from O or S, in another more specific embodiment L 1b is selected from O or NMe, and in another more specific embodiment L 1b is selected from O, S or NR 5b.
R1a
In one embodiment, R 1a is C 1-6 alkyl, such as Me, in another embodiment R 1a is C 1-6 haloalkyl, in another embodiment R 1a is C 3-10 cycloalkyl, such as C 3-7 cycloalkyl, such as C 3-5 cycloalkyl, such as cyclopropyl, in another embodiment R 1a is a 3-10 membered heterocyclyl, such as a 3-7 membered heterocyclyl, such as a 3-5 membered heterocyclyl, such as a 4-6 membered heterocyclyl, such as a 4-5 membered heterocyclyl, such as an exampleFor exampleFor exampleFor example 5 membered heterocyclic groups, e.gFor exampleFor exampleIn another embodiment, R 1a is a C 6-10 aryl group, such as phenyl, and in another embodiment R 1a is a 5-to 10-membered heteroaryl group, such as a 5-to 6-membered heteroaryl group, such asFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleIn another embodiment, R 1a is C 1-6 alkoxy, such as OMe, and in another embodiment R 1a is C 1-6 haloalkoxy, such as OCHF 2, such as OCF 3.
In one embodiment, R 1a is unsubstituted, in another embodiment R 1a is substituted with 1R 1as, in another embodiment R 1a is substituted with 2R 1as, and in another embodiment R 1a is substituted with 3R 1as.
In a more particular embodiment, R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, and in another more particular embodiment, R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, in another more particular embodiment R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 cycloalkyl or 3-5 membered heterocyclyl, in another more particular embodiment R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl, in another more particular embodiment R 1a is selected from C 1-6 alkyl or C 1-6 haloalkyl, in another more particular embodiment R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl, in another more particular embodiment R 1a is selected from C 3-7 cycloalkyl or 3-7 membered heterocyclyl.
In a more specific embodiment, R 1a is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, R 1a in another more specific embodiment is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-to 7-membered heterocyclyl or 5-to 6-membered heteroaryl, R 1a in another more specific embodiment is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, in another more particular embodiment, R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-5 cycloalkyl or 3-5 membered heterocyclyl, R 1a in another more specific embodiment is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-5 cycloalkyl, in another more particular embodiment R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl, in another more specific embodiment R 1a is selected from Me, OMe, cyclopropyl orIn another more particular embodiment, R 1a is selected from Me, OMe, or cyclopropyl, in another more particular embodiment R 1a is Me or cyclopropyl, in another more particular embodiment R 1a is selected from C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, in another more particular embodiment R 1a is selected from C 3-7 cycloalkyl, 3-7 membered heterocyclyl, or 5-6 membered heteroaryl, in another more particular embodiment R 1a is selected from 3-7 membered heterocyclyl, or 5-6 membered heteroaryl, in another more particular embodiment R 1a is selected from In another more specific embodiment, R 1a is selected from: In another more specific embodiment, R 1a is selected from C 3-6 cycloalkyl, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl.
In a more specific embodiment of the present invention,Selected from: preferably, it is: Preferably is Preferably, the method comprises the steps of,Is thatIn a more specific embodiment of the present invention,Selected from: Preferably is
In a more specific embodiment of the present invention,Selected from: Preferably is Preferably is Preferably is Preferably, the method comprises the steps of,Is that
R1as
In one embodiment, R 1as is H, in another embodiment R 1as is D, in another embodiment R 1as is halogen, e.g., F, in another embodiment R 1as is cyano, in another embodiment R 1as is C 1-6 alkyl, e.g., me, in another embodiment R 1as is C 1-6 haloalkyl, in another embodiment R 1as is-L 1c-ORa, preferably OR a, in another embodiment R 1as is-L 1c-SRa, preferably SR a, in another embodiment R 1as is-L 1c-NRbRc, preferably NR bRc, e.g., NH 2, e.g., -NHCH 3, e.g., -NH (CH 2), in another embodiment R2 is C 3 cycloalkyl, e.g., C 3 cycloalkyl, in another embodiment R 3 is a 3-10 membered heterocyclyl, e.g., 3-7 membered heterocyclyl, in another embodiment R 3 is C 3 aryl, and in another embodiment R 3 is another embodiment R3935 is heteroaryl.
In a more particular embodiment, R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR a、SRa、NRbRc、C3-10 cycloalkyl, OR 3-10 membered heterocyclyl, and in another more particular embodiment, R 1as is independently selected from H, D. Halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, in another more particular embodiment, R 1as is independently selected from H, D. Halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, in another more particular embodiment, R 1as is independently selected from H, D. In another more specific embodiment, R 1as is independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl.
In a more particular embodiment, R 1as is independently selected from H, D, halogen, cyano, OR a、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, OR 3-7 membered heterocyclyl, and in another more particular embodiment, R 1as is independently selected from H, D. Halogen, NR bRc、C1-6 alkyl or C 1-6 haloalkyl, in another more specific embodiment, R 1as is independently selected from H, D, halogen, CN, C 1-6 alkyl, A C 1-6 haloalkyl, C 3-7 cycloalkyl or a 3-7 membered heterocyclyl; in another more particular embodiment, R 1as is independently selected from H, D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, and in another more particular embodiment, R 1as is independently selected from H, D. Halogen, OR a、NRbRc、C1-6 alkyl, OR C 1-6 haloalkyl, R 1as in another more particular embodiment is independently selected from H, F, me, NH 2、-NHCH3 OR-NH (CH 3)2; in another more particular embodiment R 1as is independently selected from H, F. Me, NH 2 or-NHCH 3, in another more specific embodiment R 1as is independently selected from H, D or NR bRc, preferably from H, NH 2 or-N (CH 3)2; in another more particular embodiment, R 1as is independently selected from H or NH 2; in another more particular embodiment, R 1as is independently selected from H, F. Me, NH 2, or NHCH 3, in another more particular embodiment, R 1as is independently H, F or Me.
N 1 and n 2
In one embodiment, n 1 is 0, in another embodiment, n 1 is 1, in another embodiment, n 1 is 2, in another embodiment, n 1 is 3, in another embodiment, n 1 is 4, in another embodiment, n 1 is 5, and in another embodiment, n 1 is 6.
In one embodiment, n 2 is 0, in another embodiment, n 2 is 1, in another embodiment, n 2 is 2, in another embodiment, n 2 is 3, in another embodiment, n 2 is 4, in another embodiment, n 2 is 5, and in another embodiment, n 2 is 6.
In a more specific embodiment, n 1 is selected from 0, 1,2, or 3, in another more specific embodiment, n 1 is selected from 0, 1, or 2, and in another more specific embodiment, n 1 is selected from 1,2, or 3.
In a more specific embodiment, n 2 is selected from 0, 1,2, or 3, in another more specific embodiment, n 2 is selected from 0 or 1, and in another more specific embodiment, n 2 is 0, 1, or 2.
R 5a and R 5b
In one embodiment, R 5a is H, in another embodiment R 5a is C 1-6 alkyl, such as C 1-3 alkyl, such as Me, and in another embodiment R 5a is C 1-6 haloalkyl, such as C 1-3 haloalkyl.
In one embodiment, R 5b is H, in another embodiment R 5b is C 1-6 alkyl, such as C 1-3 alkyl, such as Me, and in another embodiment R 5b is C 1-6 haloalkyl, such as C 1-3 haloalkyl.
In a more specific embodiment, R 5a is H or Me.
In a more specific embodiment, R 5b is selected from C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-3 alkyl or C 1-3 haloalkyl.
R 1b and R 1c
In one embodiment, R 1b is H, in another embodiment R 1b is C 1-6 alkyl, such as Me, and in another embodiment R 1b is C 1-6 haloalkyl.
In one embodiment, R 1c is H, in another embodiment R 1c is C 1-6 alkyl, such as Me, in another embodiment R 1c is C 1-6 haloalkyl, in another embodiment R 1c is C 3-10 cycloalkyl, in another embodiment R 1c is a 3-10 membered heterocyclyl, in another embodiment R 1c is C 6-10 aryl, and in another embodiment R 1c is a 5-10 membered heteroaryl.
In a more specific embodiment, R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl, in another more specific embodiment, R 1c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, and in another more specific embodiment, R 1c is selected from C 1-6 alkyl or C 1-6 haloalkyl.
R’1s
In one embodiment, R ' 1s is H, in another embodiment R ' 1s is D, in another embodiment R ' 1s is halogen, in another embodiment R ' 1s is cyano, in another embodiment R ' 1s is-L 1d-ORa, preferably OR a, in another embodiment R ' 1s is-L 1d-SRa, preferably SR a, in another embodiment R ' 1s is-L 1d-NRbRc, preferably NR bRc, in another embodiment R ' 1s is C 1-6 alkyl, in another embodiment R ' 1s is C 1-6 haloalkyl, in another embodiment R ' 1s is C 3-10 cycloalkyl, in another embodiment R ' 1s is a 3-10 membered heterocyclyl.
In a more specific embodiment, R '1s is independently selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl, OR C 1-6 haloalkyl, and in another more specific embodiment, R' 1s is independently selected from H, D, halogen, C 1-6 alkyl, OR C 1-6 haloalkyl.
n3
In one embodiment, n 3 is 0, in another embodiment, n 3 is 1, in another embodiment, n 3 is 2, and in another embodiment, n 3 is 3.
In a more specific embodiment, n 3 is 0 or 1, and in another more specific embodiment, n 3 is 0.
L2
In one embodiment, L 2 is- (CR 4aR4b)m1 -such as CR 4aR4b -such as methylene, in another embodiment L 2 is O, in another embodiment L 2 is S, in another embodiment L 2 is NR 4c.
R 4a and R 4b
In one embodiment, R 4a is H, in another embodiment R 4a is D, in another embodiment R 4a is C 1-6 alkyl, in another embodiment R 4a is C 1-6 haloalkyl.
In one embodiment, R 4b is H, in another embodiment R 4b is D, in another embodiment R 4b is C 1-6 alkyl, in another embodiment R 4b is C 1-6 haloalkyl.
m1
In one embodiment, m 1 is 0, in another embodiment, m 1 is 1, and in another embodiment, m 1 is 2.
R4c
In one embodiment, R 4c is H, in another embodiment R 4c is C 1-6 alkyl, and in another embodiment R 4c is C 1-6 haloalkyl.
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, such as phenyl, in another embodiment R 2 is a 5-10 membered heteroaryl, such as a 5-6 membered heteroaryl.
In one embodiment, R 2 is unsubstituted, in another embodiment R 2 is substituted with 1R 2s, in another embodiment R 2 is substituted with 2R 2s, in another embodiment R 2 is substituted with 3R 2s, in another embodiment R 2 is substituted with 4R 2s, in another embodiment R 2 is substituted with 5R 2s, and in another embodiment R 2 isFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor exampleFor example
In one more particular embodiment, R 2 is selected from C 6-10 aryl or 5-to 10-membered heteroaryl, in another more particular embodiment R 2 is phenyl or 5-to 6-membered heteroaryl, in another more particular embodiment R 2 is selected from In another more specific embodiment, R 2 is selected from In another more specific embodiment, R 2 is selected from
In a more specific embodiment, R 2 is optionally substituted with 1,2,3, or 4R 2s, and in another more specific embodiment, R 2 is optionally substituted with 2 or 3R 2s.
R2s
In one embodiment, R 2s is H, in another embodiment R 2s is D, in another embodiment R 2s is halogen, such as F, e.g., cl, in another embodiment R 2s is cyano, in another embodiment R 2s is-L 2a-ORa, preferably OR a, in another embodiment R 2s is-L 2a-SRa, preferably SR a, in another embodiment R 2s is-L 2a-NRbRc, preferably NR bRc, in another embodiment R 2s is C 1-6 alkyl, e.g., me, in another embodiment R 2s is C 1-6 haloalkyl, in another embodiment R 2s is C 3-10 cycloalkyl, in another embodiment R 3-10 is 3-10 membered heterocyclyl, in another embodiment R 3-10 is C2 alkoxy, e.g., OMe, in another embodiment R 3-10 is C2 haloalkoxy, e.g., HF, in another embodiment R 3-10 is HF, e.g., 3-10
In a more specific embodiment, R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl, in another more specific embodiment, R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, or C 1-6 haloalkyl, in another more specific embodiment, R 2s is independently selected from H, D, halogen, cyano, or C 1-6 alkyl, in another more specific embodiment, R 2s is independently selected from H, F, cl, CN, me, CHF 2 or CF 3, and in another more specific embodiment, R 2s is independently selected from H, F, cl, CN or Me.
In a more specific embodiment, R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, orIn another more specific embodiment, R 2s is independently selected from H, D, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy.
In a more specific embodiment, R 2s is independently R 2a、R2b、R2c or R 2d.
In a more particular embodiment, R 2a is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy, and in another more particular embodiment, R 2a is selected from H, D. Halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy, in another more particular embodiment, R 2a is selected from halogen, C 1-4 alkyl or C 1-4 alkoxy, in another more specific embodiment R 2a is selected from H, F, me, CF 3, OMe or OCHF 2, in another more particular embodiment R 2a is selected from F, me or OMe, in another more particular embodiment R 2a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, in another more particular embodiment R 2a is selected from H, D. Halogen, C 1-4 alkyl or C 1-4 haloalkyl, in another more particular embodiment R 2a is selected from H, F, cl or Me, in another more particular embodiment R 2a is selected from H, cl or Me, preferably H, D or halogen, R 2a is selected from H or F in another more particular embodiment, and R 2a is selected from H, F or Me in another more particular embodiment.
In one more specific embodiment, R 2b is selected from H, D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, in another more specific embodiment, R 2b is selected from H, D or halogen, in another more specific embodiment, R 2b is selected from H or F, in another more specific embodiment, R 2b is selected from H, D, halogen, C 1-4 alkyl, or C 1-4 haloalkyl, in another more specific embodiment, R 2b is selected from H, F or Me, in another more specific embodiment, R 2b is selected from H or D, preferably in another more specific embodiment, R 2b is H, in another more specific embodiment, R 2b is selected from H, D, C 1-4 alkyl or C 1-4 haloalkyl, and in another more specific embodiment, R 2b is selected from H or Me.
In one more specific embodiment, R 2c is selected from H, D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, in another more specific embodiment, R 2c is selected from H, D or halogen, in another more specific embodiment, R 2c is selected from H, F or Cl, in another more specific embodiment, R 2c is selected from H or F, in another more specific embodiment, R 2c is selected from H, D, halogen, C 1-4 alkyl, or C 1-4 haloalkyl, in another more specific embodiment, R 2c is selected from H, F or Cl, in another more specific embodiment, R 2c is selected from halogen, C 1-6 alkyl, or C 1-6 haloalkyl, in another more specific embodiment, R 2c is halogen, and in another more specific embodiment, R 2c is F.
In a more specific embodiment, R 2d is selected from H, D, halogen, or cyano, in another more specific embodiment R 2d is halogen or cyano, in another more specific embodiment R 2d is F, cl or CN, in another more specific embodiment R 2d is Cl or CN, and in another more specific embodiment R 2d is F or CN.
L3
In one embodiment, L 3 is a bond, in another embodiment L 3 is CR 6aR6b, in another embodiment L 3 is O, in another embodiment L 3 is S, and in another embodiment L 3 is NR 6c, such as NH.
R 6a and R 6b
In one embodiment, R 6a is H, in another embodiment R 6a is D, in another embodiment R 6a is C 1-6 alkyl, in another embodiment R 6a is C 1-6 haloalkyl.
In one embodiment, R 6b is H, in another embodiment R 6b is D, in another embodiment R 6b is C 1-6 alkyl, in another embodiment R 6b is C 1-6 haloalkyl.
R6c
In one embodiment, R 6c is H, in another embodiment R 6c is C 1-6 alkyl, and in another embodiment R 6c is C 1-6 haloalkyl.
R3
In one embodiment, R 3 is C 3-10 cycloalkyl, in another embodiment R 3 is a 3-10 membered heterocyclyl, in another embodiment R 3 is C 6-10 aryl, such as phenyl, for exampleFor exampleIn another embodiment, R 3 is a 5-10 membered heteroaryl, e.gFor example
In one embodiment, R 3 is unsubstituted, in another embodiment R 3 is substituted with 1R 3s, in another embodiment R 3 is substituted with 2R 3s, in another embodiment R 3 is substituted with 3R 3s, in another embodiment R 3 is substituted with 4R 3s, and in another embodiment R 3 is substituted with 5R 3s.
In a more particular embodiment, R 3 is selected from C 6-10 aryl or 5-10 membered heteroaryl, and in another more particular embodiment, R 3 is selected from
R3s
In one embodiment R 3s is H, in another embodiment R 3s is D, in another embodiment R 3s is halogen, such as Cl, in another embodiment R 3s is cyano, in another embodiment R 3s is-L 3a-ORa, preferably OR a, such as OMe, in another embodiment R 3s is-L 3a-SRa, preferably SR a, in another embodiment R 3s is-L 3a-NRbRc, preferably NR bRc, in another embodiment R 3s is C 1-6 alkyl, in another embodiment R 3s is C 1-6 haloalkyl, in another embodiment R 3s is C 3-10 cycloalkyl, in another embodiment R 3s is a 3-10 membered heterocyclyl, in another embodiment two adjacent R 3s and the atoms to which they are attached together form a C 5-10 cycloalkyl, such as C 5-7, in another embodiment two adjacent R 3s are attached together form a hydrogen, such as a 5-membered heterocyclylFor example, in another embodiment, two adjacent R 3s and the atoms to which they are attached together form a C 6-10 aryl group, such as phenyl, in another embodiment, two adjacent R 3s and the atoms to which they are attached together form a 5-to 10-membered heteroaryl group, such as a 5-to 6-membered heteroaryl group, such as pyrazolyl, such as
In one embodiment, the cyclic group formed by two adjacent R 3s and the atom to which they are attached is unsubstituted, in another embodiment the cyclic group formed by two adjacent R 3s and the atom to which they are attached is substituted with 1R 3ss, in another embodiment the cyclic group formed by two adjacent R 3s and the atom to which they are attached is substituted with 2R 3ss, and in another embodiment the cyclic group formed by two adjacent R 3s and the atom to which they are attached is substituted with 3R 3ss.
In a more specific embodiment, R 3s is selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, OR 3-10 membered heterocyclyl, in another more specific embodiment, R 3s is selected from H, D, halogen, OR a、SRa、NRbRc、C1-6 alkyl, OR C 1-6 haloalkyl, in another more specific embodiment, R 3s is selected from H, D, halogen, OR a、C1-6 alkyl, OR C 1-6 haloalkyl, in another more specific embodiment, R 3s is selected from H, D, cl, OMe OR Me, and in another more specific embodiment, R 3s is Cl OR Me.
In one more particular embodiment, two adjacent R 3s and the atoms to which they are attached together form a C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, in another more particular embodiment, two adjacent R 3s and the atoms to which they are attached together form a 5-7 membered heterocyclyl or 5-6 membered heteroaryl, in another more particular embodiment, two adjacent R 3s and the atoms to which they are attached together form a pyrazolyl or dihydrofuranyl, in another more particular embodiment, two adjacent R 3s and the atoms to which they are attached together form
R3ss
In one embodiment, R 3ss is H, in another embodiment R 3ss is D, in another embodiment R 3ss is halogen, in another embodiment R 3ss is cyano, in another embodiment R 3ss is-L 3b-ORa, preferably OR a, in another embodiment R 3ss is-L 3b-SRa, preferably SR a, in another embodiment R 3ss is-L 3b-NRbRc, preferably NR bRc, in another embodiment R 3ss is C 1-6 alkyl, e.g., me, in another embodiment R 3ss is C 1-6 haloalkyl, in another embodiment R 3ss is C 3-10 cycloalkyl, in another embodiment R 3ss is 3-10 membered heterocyclyl, in another embodiment R 3ss is C 3-10 aryl, in another embodiment R 3ss is 3-10 membered heteroaryl;
In a more specific embodiment, R 3ss is independently selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, OR 3-10 membered heterocyclyl, in another more specific embodiment, R 3ss is independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, OR 3-10 membered heterocyclyl, in another more specific embodiment, R 3ss is independently selected from H, D, halogen, C 1-6 alkyl, OR C 1-6 haloalkyl, and in another more specific embodiment, R 3ss is independently selected from H, D, C 1-6 alkyl, OR C 1-6 haloalkyl.
L 1c、L1d、L2a、L3a and L 3b
In one embodiment, L 1c、L1d、L2a、L3a and L 3b are independently a bond, in another embodiment L 1c、L1d、L2a、L3a and L 3b are independently a C 1-6 alkylene group, such as a C 1-3 alkylene group, in another embodiment L 1c、L1d、L2a、L3a and L 3b are independently a C 2-6 alkenylene group, in another embodiment L 1c、L1d、L2a、L3a and L 3b are independently a C 2-6 alkynylene group, in another embodiment L 1c、L1d、L2a、L3a and L 3b are independently unsubstituted, in another embodiment L 1c、L1d、L2a、L3a and L 3b are independently 1 member selected from the group consisting of H, D. Halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, in another embodiment L 1c、L1d、L2a、L3a and L 3b are independently substituted with 2 groups selected from H, D. Halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, in another embodiment L 1c、L1d、L2a、L3a and L 3b are independently substituted with 3 groups selected from H, D. Halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, in another embodiment L 1c、L1d、L2a、L3a and L 3b are independently substituted with 1 member selected from H, D. Halogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl, in another embodiment, L 1c、L1d、L2a、L3a and L 3b are independently substituted with 2 groups selected from H, D. Halogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl, in another embodiment, L 1c、L1d、L2a、L3a and L 3b are independently substituted with 3 groups selected from H, D. Halogen, C 1-6 alkyl or C 1-6 haloalkyl.
In a more specific embodiment, L 1c、L1d、L2a、L3a and L 3b are each independently selected from a bond or C 1-6 alkylene, optionally substituted with 1,2, or 3 groups selected from H, D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl.
R a、Rb and R c
In one embodiment, R a、Rb and R c are independently H, in another embodiment R a、Rb and R c are independently C 1-6 alkyl, such as Me, in another embodiment R a、Rb and R c are independently C 1-6 haloalkyl, in another embodiment R a、Rb and R c are independently C 3-10 cycloalkyl, such as C 3-7 cycloalkyl, in another embodiment R a、Rb and R c are independently 3-10 membered heterocyclyl, such as 3-7 membered heterocyclyl, in another embodiment R a、Rb and R c are independently C 6-10 aryl, in another embodiment R a、Rb and R c are independently 5-10 membered heteroaryl, in another embodiment R b、Rc together with the atoms to which they are attached form a 3-10 membered heterocyclyl, such as forming a 3-7 membered heterocyclyl.
In a more specific embodiment, R a、Rb and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl, in another more specific embodiment, R a、Rb and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl, in another more specific embodiment, R a、Rb and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, and in another more specific embodiment, R b、Rc and the atoms to which they are attached together form a 3-7 membered heterocyclyl.
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 solutions of ring a or any combination thereof may be combined with any one of the solutions of Y、R7、R1s、L1a、L1b、R1a、R1as、n1、n2、R5a、R5b、R1b、R1c、R'1s、n3、L2、R4a、R4b、m1、R4c、R2、R2s、L3、R6a、R6b、R6c、R3、R3s、R3ss、L1c、L1d、L2a、L3a、L3b、Ra、Rb and R c, 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;
Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
r 1s is -C (O) NR 1bR1c or
L 1a is selected from a bond, O, S, or NR 5a;
L 1b is selected from a bond, O, S, or NR 5b;
R 1a 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 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3R 1as;
R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L 1c-ORa、-L1c-SRa、-L1c-NRbRc、C3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
n 1 and n 2 are independently selected from 0, 1,2,3, 4,5 or 6;
R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 1b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
R' 1s is independently selected from H, D, halogen, cyano, -L 1d-ORa、-L1d-SRa、-L1d-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
n 3 is 0, 1,2 or 3;
L 2 is selected from- (CR 4aR4b)m1 -, O, S or NR 4c;
r 4a and R 4b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
m 1 is 0, 1 or 2;
R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2,3, 4, or 5R 2s;
R 2s is independently selected from H, D, halogen, cyano, -L 2a-ORa、-L2a-SRa、-L2a-NRbRc, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl or 3-to 10-membered heterocyclyl;
L 3 is selected from a bond, CR 6aR6b, O, S or NR 6c;
R 6a and R 6b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
R 6c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 3 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2,3, 4, or 5R 3s;
r 3s is independently selected from H, D, halogen, cyano, -L 3a-ORa、-L3a-SRa、-L3a-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
Or two adjacent R 3s and the atoms to which they are attached together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2, or 3R 3ss;
R 3ss is independently selected from H, D, halogen, cyano, -L 3b-ORa、-L3b-SRa、-L3b-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 aryl, or 3-10 membered heteroaryl;
L 1c、L1d、L2a、L3a and L 3b are each independently selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, or C 2-6 alkynylene, optionally substituted with 1,2, or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
R a、Rb and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, or R b、Rc together with the atoms to which they are attached form 3-10 membered heterocyclyl or 5-10 membered heteroaryl;
Wherein each of the above groups are defined as optionally deuterated to fully deuterated;
with the proviso that when ring A is pyridinyl, L 1a is NH, L 1b is a bond, R 1a is not C 1-6 alkyl or C 1-6 haloalkyl, and the compound is not of the structure:
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;
Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
r 1s is Or-C (O) NR 1bR1c;
L 1a is selected from O, S or NR 5a;
L 1b is selected from a bond, O, S, or NR 5b;
R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2, or 3R 1as;
R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L 1c-ORa、-L1c-SRa、-L1c-NRbRc、C3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
n 1 and n 2 are independently selected from 0, 1,2,3, 4,5 or 6;
R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 1b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
R' 1s is independently selected from H, D, halogen, cyano, -L 1d-ORa、-L1d-SRa、-L1d-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
n 3 is 0, 1,2 or 3;
L 2 is selected from- (CR 4aR4b)m1 -, O, S or NR 4c;
r 4a and R 4b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
m 1 is 0, 1 or 2;
R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2,3, 4, or 5R 2s;
R 2s is independently selected from H, D, halogen, cyano, -L 2a-ORa、-L2a-SRa、-L2a-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
L 3 is selected from a bond, CR 6aR6b, O, S or NR 6c;
R 6a and R 6b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
R 6c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 3 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2,3, 4, or 5R 3s;
r 3s is independently selected from H, D, halogen, cyano, -L 3a-ORa、-L3a-SRa、-L3a-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
Or two adjacent R 3s and the atoms to which they are attached together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2, or 3R 3ss;
R 3ss is independently selected from H, D, halogen, cyano, -L 3b-ORa、-L3b-SRa、-L3b-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 aryl, or 3-10 membered heteroaryl;
L 1c、L1d、L2a、L3a and L 3b are each independently selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, or C 2-6 alkynylene, optionally substituted with 1,2, or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
R a、Rb and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, or R b、Rc together with the atoms to which they are attached form 3-10 membered heterocyclyl or 5-10 membered heteroaryl;
Wherein each of the above groups are defined as optionally deuterated to fully deuterated;
with the proviso that when ring A is pyridinyl, L 1a is NH, L 1b is a bond, R 1a is not C 1-6 alkyl or C 1-6 haloalkyl, and the compound is not of the structure:
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, wherein Y is N.
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, wherein ring A is C 6-10 aryl or 5-10 membered heteroaryl, preferably phenyl or 5-6 membered heteroaryl, preferably pyridinyl or thiazolyl, preferably pyridinylMore preferably
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, wherein R 1s is selected fromPreferably selected from Preferably selected from Preferably selected from More preferably not
In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1a is selected from O, S, NH or NMe, preferably from O, S or NH, preferably O or S, preferably O, preferably S.
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, wherein L 1b is a bond.
Preferably, L 1b is selected from O, S or NR 5b, preferably from O or NR 5b, preferably from O, S or NMe, preferably from O or S, preferably from O or NMe, preferably from O.
In a more specific embodiment, the invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl, preferably selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl, preferably selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 cycloalkyl, or 3-5 membered heterocyclyl, preferably selected from C 1-6 alkyl, C 1-6 haloalkyl, or C 3-5 cycloalkyl, preferably selected from C 1-6 alkyl, or C 1-6 haloalkyl, preferably selected from Me, Preferably selected from Me,Preferably Me.
Preferably, R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl, preferably from C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably 4-5 membered heterocyclyl, preferably from C 3-7 cycloalkyl or 3-7 membered heterocyclyl Preferably is
In a more specific embodiment, the invention provides a compound of formula (I) above, OR a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, OR solvate thereof, wherein R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR a、SRa、NRbRc、C3-10 cycloalkyl, OR 3-10 membered heterocyclyl, preferably selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, OR 3-10 membered heterocyclyl, preferably selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, OR 3-7 membered heterocyclyl, preferably selected from H, D, halogen, C 1-6 alkyl, OR C 1-6 haloalkyl, preferably selected from H, D, C 1-6 alkyl OR C 1-6 haloalkyl, preferably Me.
In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein n 1 is selected from 0, 1,2 or 3, preferably from 0, 1 or 2, preferably from 1,2 or 3, preferably 0, preferably 1, preferably 2.
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, wherein n 2 is selected from 0, 1,2 or 3, preferably from 0 or 1, preferably 0.
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, wherein R 5a is H or Me, preferably H.
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, wherein R 5b is selected from C 1-6 alkyl or C 1-6 haloalkyl, preferably Me.
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, wherein R 1b is H;
Preferably, R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, preferably selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-6 alkyl or C 1-6 haloalkyl, preferably Me.
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, wherein R' 1s is independently selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl, OR C 1-6 haloalkyl, preferably selected from H, D, halogen, C 1-6 alkyl, OR C 1-6 haloalkyl.
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, wherein n 3 is 0 or 1, preferably 0.
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, n 3 is 1,2 or 3, preferably 0 or 1, preferably 0.
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, wherein L 2 is- (CR 4aR4b)m1 -; preferably methylene.
Preferably, m 1 is 1.
Preferably, R 4a and R 4b are H.
In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 2 is selected from C 6-10 aryl or 5-10 membered heteroaryl, preferably phenyl or 5-6 membered heteroaryl, preferably phenyl.
Preferably, R 2 is optionally substituted with 1,2,3 or 4R 2s.
Preferably, R 2 is optionally substituted with 2 or 3R 2s.
Preferably, R 2 is selected from Preferably selected from Preferably selected from
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, wherein R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl, preferably selected from H, D, halogen, cyano, C 1-6 alkyl, or C 1-6 haloalkyl, preferably selected from H, D, halogen, cyano, or C 1-6 alkyl, preferably selected from H, F, cl, CN, me, CHF 2 or CF 3, preferably selected from H, F, cl, CN or Me.
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, wherein L 3 is NR 6c, preferably NH.
Preferably, R 6a and R 6b are H.
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, wherein R 3 is selected from C 6-10 aryl or 5-10 membered heteroaryl, preferably
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, wherein R 3s is selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, OR 3-10 membered heterocyclyl, preferably selected from H, D, halogen, OR a、SRa、NRbRc、C1-6 alkyl, OR C 1-6 haloalkyl, preferably selected from H, D, halogen, OR a、C1-6 alkyl, OR C 1-6 haloalkyl, preferably selected from H, D, cl, OMe OR Me, preferably Cl OR Me.
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, wherein two adjacent R 3s and the atoms to which they are attached together form a C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, preferably a 5-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably a pyrazolyl or dihydrofuranyl, preferablyPreferably form
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, wherein R 3ss is independently selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, OR 3-10 membered heterocyclyl, preferably selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, OR 3-10 membered heterocyclyl, preferably selected from H, D, halogen, C 1-6 alkyl, OR C 1-6 haloalkyl, preferably selected from H, D, C 1-6 alkyl, OR C 1-6 haloalkyl, preferably Me.
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, wherein L 1c、L1d、L2a、L3a and L 3b are each independently selected from a bond or C 1-6 alkylene, optionally substituted with 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, preferably selected from a bond or C 1-3 alkylene.
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, wherein R a、Rb and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl, preferably selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl, preferably selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-6 alkyl, or C 1-6 haloalkyl;
Or R b、Rc together with the atoms to which they are attached form a 3-to 10-membered heterocyclic group, preferably a 3-to 7-membered heterocyclic group.
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, having the formula:
wherein,
M 2 is 1,2,3 or 4;
X 1 is CR 3b or N, and X 2 is CR 3c or N;
Or X 1 is C (O), X 2 is NH;
R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
R 3b is selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, OR 3-10 membered heterocyclyl;
R 3c、R3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
Or R 3b together with R 3c and the atoms to which they are attached form C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2, or 3R 3ss;
R 2a、R2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;
R 2d is selected from H, D, halogen or cyano;
R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
The remaining groups are as defined herein.
In a more specific embodiment, the present invention provides a compound of formula (II) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
Wherein,
Ring a is C 6-10 aryl or 5-10 membered heteroaryl;
r 1s is Or-C (O) NR 1bR1c;
L 1a is selected from O, S or NR 5a;
L 1b is selected from a bond, O, S, or NR 5b;
R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR a、SRa、NRbRc、C3-10 cycloalkyl, OR 3-10 membered heterocyclyl;
n 1 and n 2 are independently selected from 0, 1,2,3, 4,5 or 6;
R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 1b is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-to 10-membered heterocyclyl;
R' 1s is independently selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl, OR C 1-6 haloalkyl;
n 3 is 0, 1,2 or 3;
R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
m 2 is 1,2,3 or 4;
X 1 is CR 3b or N, and X 2 is CR 3c or N;
Or X 1 is C (O), X 2 is NH;
R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
R 3b is selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, OR 3-10 membered heterocyclyl;
R 3c、R3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
Or R 3b together with R 3c and the atoms to which they are attached form C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2, or 3R 3ss;
R 3ss is independently selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, OR 3-10 membered heterocyclyl;
r a、Rb and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, or R b、Rc together with the atoms to which they are attached form 3-10 membered heterocyclyl;
Wherein each of the above groups are defined as optionally deuterated to fully deuterated;
With the proviso that when ring a is pyridinyl, L 1a is NH, L 1b is a bond, R 1a is not C 1-6 alkyl or C 1-6 haloalkyl, and the compound is not of the structure:
in a more specific embodiment, the present invention provides a compound of formula (II) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
Ring A is phenyl or 5-6 membered heteroaryl;
r 1s is Or-C (O) NHR 1c, preferably
L 1a is selected from O, S or NR 5a;
L 1b is selected from a bond, O, S, or NR 5b;
R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
r 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl;
n 1 and n 2 are independently selected from 0, 1,2 or 3;
R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably R 5a is H;
R 1c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R' 1s is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
n 3 is 0 or 1;
R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
m 2 is 1,2,3 or 4;
X 1 is CR 3b,X2 and CR 3c;
Or X 1 is C (O), X 2 is NH;
R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 3b is selected from OR a、SRa OR NR bRc, preferably OR a OR SR a;
R 3c、R3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
Or R 3b together with R 3c and the atoms to which they are attached form C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally substituted with 1,2 or 3R 3ss;
r 3ss is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R a、Rb and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, or R b、Rc together with the atoms to which they are attached form a 3-7 membered heterocyclyl.
In a more specific embodiment, the present invention provides a compound of formula (II) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
Ring a is a 5-6 membered heteroaryl group, preferably pyridinyl or thiazolyl;
r 1s is Or-C (O) NHR 1c, preferably
L 1a is selected from O, S, NR 5a;
L 1b is selected from a bond, O, S, or NR 5b;
R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 cycloalkyl or 3-5 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
n 1 is selected from 0, 1 or 2;
n 2 is selected from 0 or 1;
r 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably R 5a is H, preferably R 5b is C 1-6 alkyl or C 1-6 haloalkyl, preferably Me;
R 1c is selected from C 1-6 alkyl or C 1-6 haloalkyl;
n 3 is 0;
R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl, preferably selected from H, D, halogen, cyano or C 1-6 alkyl;
m 2 is 2 or 3;
X 1 is CR 3b,X2 and CR 3c;
Or X 1 is C (O), X 2 is NH;
R 3a is halogen;
r 3b is OR a;
R 3c、R3d and R 3e are independently H or D;
Or R 3b together with R 3c and the atoms to which they are attached form a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl, preferably pyrazolyl or dihydrofuranyl, optionally substituted with 1,2 or 3R 3ss;
R 3ss is independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-6 alkyl or C 1-6 haloalkyl.
In a more specific embodiment, the present invention provides a compound of formula (II) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
Ring A is
R 1s isOr C (O) NHCH 3, preferably
L 1a is selected from O, S, NH or NMe, preferably from O, S or NH;
L 1b is selected from O, S or NMe;
R 1a is selected from Me,
N 1 is selected from 0, 1 or 2;
n 2 is selected from 0 or 1;
n 3 is 0;
R 2s is independently selected from H, F, cl, CN, me, CHF 2 or CF 3, preferably from H, F, cl, CN or Me;
m 2 is 2 or 3;
X 1 is CR 3b,X2 and CR 3c;
Or X 1 is C (O), X 2 is NH;
r 3a is Cl;
r 3b is OMe;
R 3c、R3d and R 3e are H;
Or R 3b together with R 3c and the atoms to which they are attached form
Preferably, R 1s is selected from
Preferably, ring a and substituents thereon together form:
Preferably, the method comprises the steps of, Selected from the group consisting of
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 (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
Wherein,
L 1a is selected from O, S or NR 5a;
L 1b is selected from O, S or NR 5b;
R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
n 1 is selected from 1,2,3, 4, 5, or 6;
n 2 is selected from 0,1,2, 3,4, 5, or 6;
R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 2a、R2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
R 2d is selected from H, D, halogen or cyano;
R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl;
R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
wherein each of the above groups are optionally deuterated to complete deuteration.
In a more specific embodiment, the present invention provides a compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
L 1a is selected from O or S, preferably O, preferably S;
L 1b is selected from O, S or NR 5b, preferably O or NR 5b;
R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
R 1as is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
n 1 is selected from 1,2 or 3, preferably 2;
n 2 is selected from 0,1, 2 or 3, preferably 0 or 1;
R 5b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-3 alkyl or C 1-3 haloalkyl;
R 2a、R2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 2d is selected from halogen or cyano;
R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
Preferably, the method comprises the steps of,
R 2a is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl;
r 2b is H;
r 2c is selected from H, D or halogen;
R 2d is selected from halogen or cyano;
R 3a is halogen;
R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
In a more specific embodiment, the present invention provides a compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
L 1a is selected from O or S;
l 1b is selected from O or S;
R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl;
n 1 is 2;
n 2 is 0 or 1;
R 2a、R2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 2d is selected from halogen or cyano;
R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
In a more specific embodiment, the present invention provides a compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
L 1a is selected from O or S, preferably O;
L 1b is O;
R 1a is selected from C 1-6 alkyl or C 1-6 haloalkyl;
n 1 is 2;
n 2 is 0;
R 2a、R2c and R 2d are independently halogen;
r 2b is H or D;
R 3a is halogen;
R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
In a more specific embodiment, the present invention provides a compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
L 1a is selected from O or S, preferably O;
L 1b is selected from O or NMe, preferably O;
R 1a is selected from Me, Preferably Me;
n 1 is 2;
n 2 is 0 or 1, preferably 0;
R 2a is selected from F or Me, preferably F;
r 2b is H;
R 2c is selected from H or F, more preferably F;
R 2d is selected from F, cl or CN, preferably F or Cl;
r 3a is Cl;
R 3f is Me.
Preferably, the method comprises the steps of,Selected from: Preferably is
Preferably, the method comprises the steps of,Selected from: Preferably is
In a more specific embodiment, the present invention provides a compound of formula (III-2) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
Wherein,
L 1a is selected from O, S or NR 5a;
R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
n 1 is selected from 1,2,3, 4, 5, or 6;
R 5a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 2a、R2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
R 2d is selected from H, D, halogen or cyano;
R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl;
R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
wherein each of the above groups are optionally deuterated to complete deuteration.
In a more specific embodiment, the present invention provides a compound of formula (III-2) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
L 1a is selected from O or S, preferably O, preferably S;
R 1a is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
n 1 is selected from 1,2 or 3;
R 2a、R2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 2d is selected from halogen or cyano;
R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
In a more specific embodiment, the present invention provides a compound of formula (III-2) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
L 1a is selected from O or S, preferably O;
R 1a is a 3-7 membered heterocyclyl, preferably a 4-5 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
R 1as is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl, preferably Me;
n 1 is 1;
R 2a、R2c and R 2d are independently halogen;
r 2b is H or D;
R 3a is halogen;
R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
In a more specific embodiment, the present invention provides a compound of formula (III-2) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
L 1a is selected from O or S, preferably O;
R 1a is selected from
N 1 is 1;
Is that
R 3a is Cl;
R 3f is Me.
Preferably, the method comprises the steps of,Selected from:
In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
Wherein,
L 1a is selected from O, S or NR 5a;
R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
R 5a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 2a、R2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
R 2d is selected from H, D, halogen or cyano;
R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl;
R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
wherein each of the above groups are optionally deuterated to complete deuteration.
In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
L 1a is selected from O, S or NH, preferably O or NH, preferably S;
R 1a is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably 3-7 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 2a、R2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 2d is selected from halogen or cyano;
R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
L 1a is selected from O, S or NH, preferably O or NH;
R 1a is a 4-6 membered heterocyclyl, preferably a 5 membered heterocyclyl, preferably tetrahydrofuranyl, optionally substituted with 1,2 or 3R 1as;
R 1as is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
r 2a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 2b is selected from H, D or halogen;
R 2c is halogen;
R 2d is selected from halogen or cyano;
R 3a is halogen;
R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein, when the linking atom of R 1a and L 1a is a chiral carbon atom, isIs that
In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
L 1a is selected from O, S or NH, preferably O or NH;
R 1a is selected from Preferably isMore preferably
R 2a is H, F, cl or Me;
R 2b is H or F;
r 2c is F or Cl, preferably F;
R 2d is F, cl or CN;
r 3a is Cl;
R 3f is Me.
Preferably, the method comprises the steps of,Selected from: Preferably not More preferably
Preferably, the method comprises the steps of,Selected from: Preferably selected from
In a more specific embodiment, the present invention provides a compound of formula (II) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
Wherein,
Ring A is phenyl or 5-6 membered heteroaryl;
r 1s is -C (O) NHR 1c or
L 1a is selected from a bond, O, S, or NR 5a;
L 1b is selected from a bond, O, S, or NR 5b;
R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, optionally substituted with 1,2, or 3R 1as;
R 1as is independently selected from H, D, halogen, cyano, OR a、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, OR 3-7 membered heterocyclyl;
n 1 and n 2 are independently selected from 0, 1,2 or 3;
R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably R 5a is H;
R 1c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R' 1s is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
n 3 is 0 or 1;
R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or
M 2 is 1,2,3 or 4;
X 1 is CR 3b,X2 and CR 3c;
Or X 1 is C (O), X 2 is NH;
R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 3b is selected from OR a、SRa OR NR bRc, preferably OR a OR SR a;
R 3c、R3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
Or R 3b together with R 3c and the atoms to which they are attached form C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally substituted with 1,2 or 3R 3ss;
r 3ss is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R a、Rb and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
Wherein each of the above groups are defined as optionally deuterated to fully deuterated;
With the proviso that when ring a is pyridinyl, L 1a is NH, L 1b is a bond, R 1a is not C 1-6 alkyl or C 1-6 haloalkyl, and the compound is not of the structure:
in a more specific embodiment, the present invention provides a compound of formula (II) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
Ring A is a 5-6 membered heteroaryl group, preferably pyridinyl or thiazolyl, preferably pyridinyl, preferably
R 1s isPreferably is
L 1a is selected from O, S, NR 5a;
l 1b is selected from a bond, O, or NR 5b;
R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, or 5-6 membered heteroaryl, optionally substituted with 1,2, or 3R 1as;
r 1as is independently selected from H, D, halogen, NR bRc、C1-6 alkyl or C 1-6 haloalkyl;
n 1 is selected from 0, 1 or 2;
n 2 is selected from 0, 1 or 2;
r 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably R 5a is H, preferably R 5b is C 1-3 alkyl or C 1-3 haloalkyl;
n 3 is 0;
R 2s is independently selected from H, D, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;
m 2 is 2 or 3;
X 1 is CR 3b,X2 and CR 3c;
Or X 1 is C (O), X 2 is NH;
R 3a is halogen;
R 3b is OR a, preferably OMe;
R 3c、R3d and R 3e are independently H or D;
Or R 3b together with R 3c and the atoms to which they are attached form a 5-to 7-membered heterocyclyl or a 5-to 6-membered heteroaryl, optionally substituted with 1,2 or 3R 3ss, preferably forming
R 3ss is independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
R a、Rb and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
In a more specific embodiment of the present invention,Selected from the group consisting of PreferablyPreferably
In more specific embodiments, when L 1b is a bond, R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl.
In a more specific embodiment, the present invention provides a compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
Wherein,
L 1a is selected from O or S;
L 1b is selected from O, S or NR 5b;
R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl, optionally substituted with 1,2, or 3R 1as;
R 1as is independently selected from H, D, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
n 1 is selected from 1,2 or 3;
n 2 is selected from 0, 1,2 or 3;
R 5b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 2a is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;
R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 2d is selected from H, D, halogen or cyano, preferably halogen or cyano;
R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
r 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
wherein each of the above groups are optionally deuterated to complete deuteration.
In a more specific embodiment, the present invention provides a compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
L 1a is selected from O or S;
L 1b is O or NR 5b, preferably O;
R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-5 cycloalkyl or 3-5 membered heterocyclyl, preferably C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-5 cycloalkyl, preferably C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl;
n 1 is 2;
n 2 is 0, 1 or 2;
R 5b is C 1-3 alkyl or C 1-3 haloalkyl, preferably Me;
R 2a is selected from H, D, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy, preferably halogen, C 1-4 alkyl or C 1-4 alkoxy;
r 2b is H, D or halogen;
r 2c is selected from H, D or halogen;
r 2d is halogen or CN;
R 3a is halogen;
R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
In a more specific embodiment, the present invention provides a compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
L 1a is selected from O or S, preferably O;
L 1b is selected from O or NMe, preferably O;
r 1a is selected from Me, OMe, cyclopropyl or Preferably Me, OMe or cyclopropyl; preferably Me or cyclopropyl;
n 1 is 2;
n 2 is 0,1 or 2, preferably 0 or 1;
R 2a is selected from H, F, me, CF 3, OMe or OCHF 2, preferably F, me or OMe;
R 2b is H or F;
R 2c is selected from H, F or Cl, more preferably H or F;
R 2d is selected from F, cl or CN, preferably Cl or CN;
r 3a is Cl;
R 3f is Me.
In a more specific embodiment of the present invention,Selected from: Preferably is Preferably is
In a more specific embodiment of the present invention,Selected from: Preferably is
In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
Wherein,
L 1a is selected from O, S or NR 5a;
R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally substituted with 1,2 or 3R 1as;
R 1as is independently selected from H, D, halogen, OR a、NRbRc、C1-6 alkyl OR C 1-6 haloalkyl;
r 5a is selected from H, C 1-3 alkyl or C 1-3 haloalkyl, preferably R 5a is H;
R 2a、R2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 2d is selected from halogen or cyano;
R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
r 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R a、Rb and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
wherein each of the above groups are optionally deuterated to complete deuteration.
In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
L 1a is selected from O, S or NH;
R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, optionally substituted with 1,2 or 3R 1as;
R 1as is independently selected from H, D, halogen, NR bRc、C1-6 alkyl or C 1-6 haloalkyl, preferably from H, F, me, NH 2、-NHCH3 or-NH (CH 3)2; preferably from H, F, me, NH 2 or-NHCH 3;
R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R 2b is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R 2c is H, D or halogen;
R 2d is halogen or cyano;
R 3a is halogen;
R 3f is C 1-6 alkyl or C 1-6 haloalkyl;
R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein, when the linking atom of R 1a and L 1a is a chiral carbon atom, isIs that
In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
L 1a is selected from O, S or NH;
R 1a is selected from Preferably selected from: Preferably, the method comprises the steps of, Is that
R 2a is H, F, cl or Me;
R 2b is H, F or Me;
R 2c is H, F or Cl;
R 2d is F, cl or CN;
r 3a is Cl;
R 3f is Me.
In a more specific embodiment of the present invention,Selected from: Preferably selected from:
In a more specific embodiment of the present invention, Is that
In a more specific embodiment of the present invention,Is that
In a more specific embodiment of the present invention,Is that
In a more specific embodiment of the present invention,Selected from:
In a more specific embodiment, the present invention provides a compound of formula (IV-1) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
Wherein,
R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally substituted with 1,2 or 3R 1as;
R 1as is independently selected from H, D, halogen, OR a、NRbRc、C1-6 alkyl OR C 1-6 haloalkyl;
R 2a and R 2b are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 2c is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 2d is selected from halogen or cyano;
R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
r 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R a、Rb and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
wherein each of the above groups are optionally deuterated to complete deuteration.
In a more specific embodiment, the present invention provides a compound of formula (IV-1) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably 4-6 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
R 1as is independently selected from H, D, halogen, NR bRc、C1-6 alkyl or C 1-6 haloalkyl, preferably selected from H, D or NR bRc, preferably selected from H, NH 2 or-N (CH 3)2; preferably selected from H or NH 2;
R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R 2b is selected from H, D or halogen;
R 2c is halogen;
R 2d is selected from halogen or cyano;
R 3a is halogen;
R 3f is C 1-6 alkyl or C 1-6 haloalkyl;
R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably H.
In a more specific embodiment, the present invention provides a compound of formula (IV-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein, when the linking atom of R 1a to O is a chiral carbon atom, isIs that
In a more specific embodiment, the present invention provides a compound of formula (IV-1) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
L 1a is selected from O, S or NH, preferably O or NH;
Selected from: preferably, it is: Preferably is Preferably, the method comprises the steps of,Is that
R 2a is H, F, cl or Me, preferably H, cl or Me;
R 2b is H or F, preferably H;
R 2c is F;
R 2d is F, cl or CN, preferably Cl or CN;
r 3a is Cl;
R 3f is Me.
In a more specific embodiment of the present invention,Selected from: Preferably selected from Preferably selected from
In a more specific embodiment, the present invention provides a compound of formula (IV-2) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
Wherein,
R 1a is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably 3-7 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 2a and R 2b are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 2c is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 2d is selected from halogen or cyano;
R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
r 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
wherein each of the above groups are optionally deuterated to complete deuteration.
In a more specific embodiment, the present invention provides a compound of formula (IV-2) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
R 1a is a 4-6 membered heterocyclyl, preferably a 5 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl, preferably from H, D or halogen;
r 2b is selected from H or D;
R 2c is halogen;
R 2d is selected from halogen or cyano;
R 3a is halogen;
R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
In a more specific embodiment, the present invention provides a compound of formula (IV-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein, when the linking atom of R 1a to NH is a chiral carbon atom, isIs that
In a more specific embodiment, the present invention provides a compound of formula (IV-2) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
Selected from: Preferably is
R 2a is H, F, cl or Me, preferably H or F;
r 2b is H;
R 2c is F;
R 2d is F, cl or CN, preferably F or CN;
r 3a is Cl;
R 3f is Me.
In a more specific embodiment of the present invention,Selected from: Preferably selected from Preferably is
In a more specific embodiment, the present invention provides a compound of formula (IV-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
Wherein,
R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally substituted with 1,2 or 3R 1as;
R 1as is independently selected from H, D, halogen, OR a、NRbRc、C1-6 alkyl OR C 1-6 haloalkyl;
R 2a、R2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 2d is selected from halogen or cyano;
R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
r 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R a、Rb and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
wherein each of the above groups are optionally deuterated to complete deuteration.
In a more specific embodiment, the present invention provides a compound of formula (IV-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, optionally substituted with 1,2 or 3R 1as;
R 1as is independently selected from H, D, halogen, NR bRc、C1-6 alkyl or C 1-6 haloalkyl, preferably from H, F, me, NH 2 or NHCH 3, preferably H, F or Me;
R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R 2b is selected from H, D, C 1-4 alkyl or C 1-4 haloalkyl;
r 2c is selected from H, D or halogen;
R 2d is selected from halogen or cyano;
R 3a is halogen;
R 3f is C 1-6 alkyl or C 1-6 haloalkyl;
R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
In a more specific embodiment, the present invention provides a compound of formula (IV-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein, when the linking atom of R 1a and S is a chiral carbon atom, isIs that
In a more specific embodiment, the present invention provides a compound of formula (IV-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
Selected from: Preferably is Preferably is Preferably isPreferably, the method comprises the steps of,Is that
R 2a is H, F or Me;
R 2b is H or Me;
R 2c is H, F or Cl;
r 2d is Cl or CN;
r 3a is Cl;
R 3f is Me.
In a more specific embodiment of the present invention,Selected from: Preferably is Preferably is
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, wherein said compound is selected from the group consisting of:
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, the compounds represented when Y is N and X is NH, and the compounds represented by the formulas (II), (III-1), (III-2), (III-3), (IV-1), (IV-2) and (IV-3) and the like, include 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 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.
Example 1
Synthesis of intermediates 1-3
1- (Bromomethyl) -2,4, 5-trifluorotoluene (8.46 g,37.6 mmol) was added to a mixture of 1-1 (5.73 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) and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=2:1) to give 1-3 (8.3 g, yield: 89%) as a white solid.
LCMS(ESI)m/z:318.0[M+H-56]+。
Synthesis of intermediates 1-4
1-3 (6.7 G,17.9 mmol) was dissolved in dichloromethane and trifluoroacetic acid (30/30 mL) and stirred at room temperature for 6 hours. Concentrating under reduced pressure to obtain white solid 1-4, which is directly used in the next reaction.
LCMS(ESI)m/z:318.0[M+H]+。
Synthesis of intermediates 1-6
To a solution of 1-4 ((250 mg,0.79 mmol)) in N, N-dimethylformamide ((5 mL)) was added triethylamine ((390 mg,3.94 mmol)), 1-5 ((362 mg,2.37 mmol)), copper acetate ((242 mg,1.35 mmol)) and molecular sieve ((300 mg)) at ordinary 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 1-6 ((120 mg, yield: 42.1%) as yellow oily compound).
LCMS(ESI)m/z:425.1[M+H]+。
Synthesis of Compound 1
To a solution of 1-6 ((110 mg,0.26 mmol)) in tetrahydrofuran ((2 mL)) was added 1-7 ((56.7 mg,0.31 mmol)) under an ice bath, and lithium bis (trimethylsilyl) amide (0.65 mL) was added at 0℃under nitrogen and stirred for 2 hours. After the reaction was completed, the mixed solution was quenched with water (10 mL), extracted with ethyl acetate ((10 ml×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. Flowage: ACN- -H 2 O (0.1% FA). Gradient: 35-45)) to give compound 1as a white solid ((49.3 mg, yield: 35.2%).
LCMS(ESI)m/z:544.1[M+H]+。
1H NMR(400MHz,CD3OD)δ8.30(d,J＝2.6Hz,1H),8.18(s,2H),7.75(s,1H),7.66(d,J＝9.6Hz,1H),7.55(s,1H),7.23(s,2H),5.39(s,2H),4.21(s,3H),3.91(s,3H).
The compounds of the following Table A were synthesized in the same manner as described above.
Table A
EXAMPLE 15 Synthesis of Compound 15
Synthesis of intermediate 15-6c
Triphenylphosphine ((11.3 g,43.1 mmol)) was dissolved in tetrahydrofuran ((100 mL)) under ice bath, and diisopropyl azodicarboxylate ((8.71 g,43.1 mmol)) was added, and stirred under ice bath for 15 minutes until a large amount of white solid precipitated. 15-6a ((5.0 g,28.7 mmol)) was then added under ice bath and stirred at this temperature for 15 minutes. 15-6b ((2.53 g,28.7 mmol)) were added and the mixture stirred under nitrogen at 20℃for 16 hours. After completion of the reaction, water ((200 mL)) was added, extraction was performed with ethyl acetate ((200 ml×2)), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography ((silica gel petroleum ether: ethyl acetate=1:2)) to give 15-6c as a yellow oil ((6.46 g, yield: 92.3%)).
LCMS(ESI)m/z:244.0[M+H]+。
Synthesis of intermediate 15-6
Intermediate 15-6C ((6.4 g,26.2 mmol)) was dissolved in a1, 4-dioxane ((100 mL)) solution at ordinary temperature, and pinacol biborate ((9.98 g,39.3 mmol)), potassium acetate ((7.71 g,78.6 mmol)) and 1, 1-bis (diphenylphosphine) iron-palladium dichloride ((1.92 g,2.62 mmol)) were added, and the mixed solution was stirred under nitrogen at 80℃for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, petroleum ether ((500 mL)) was added, the resulting solution was stirred at room temperature for 1 hour, followed by filtration through celite, the cake was washed with petroleum ether, and the resulting filtrate was concentrated to dryness. The crude product obtained was purified by reverse phase column chromatography ((C18, water ((0.1% trifluoroacetic acid)): acetonitrile=5:95-15/85)) to give 15-6 as a yellow solid ((3.8 g, yield: 69.9%).
LCMS(ESI)m/z:210.1[M+H]+。
Synthesis of intermediate 15-2
Intermediate 15-1 ((5.0 g,26.0 mmol)) was dissolved in tetrahydrofuran (50 mL) at room temperature, and a borane solution in tetrahydrofuran (1M, 52mL,52.0 mmol) was added, and the mixed solution was stirred at 60℃for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and then methanol (50 mL) was slowly added dropwise under ice bath, and the resulting mixed solution was stirred at 60 ℃ for 1 hour and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=5:1) to give 2-2 (4.4 g, yield: 94.6%) as a yellow oil.
LCMS(ESI)m/z:161.4[M-18+H]+。
Synthesis of intermediate 15-3
Triphenylphosphine (9.68 g,36.9 mmol) and carbon tetrabromide (8.97 g,27.1 mmol) were added to a solution of 15-2 (4.4 g,24.6 mmol) in dichloromethane (50 mL) under ice-bath, and the mixed solution was stirred at 20℃for 4 hours. Water (50 mL) was added for extraction, dichloromethane (50 mL. Times.2) was extracted twice, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=10:1) to give 15-3 (5.6 g, yield: 94.3%) as a pale yellow oil.
1H NMR(400MHz,CDCl3)δ7.50–7.43(m,1H),6.96–6.90(m,1H),4.42(d,J=0.9Hz,2H).
Synthesis of intermediate 15-4
To a solution of 15-3 (5.6 g,23.2 mmol) in acetonitrile (60 mL) at room temperature was added potassium carbonate (6.41 g,46.4 mmol) and compound 1-1 (3.99 g,17.4 mmol), and the mixed solution was stirred at 80℃for 16 hours. After the reaction is completed, the crude product is obtained by decompression and concentration. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give 15-4 (5.4 g, yield: 79.7%) as a pale yellow solid.
LCMS(ESI)m/z:412.1[M+Na]+。
Synthesis of intermediate 15-5
15-4 (7.2 G,18.5 mmol) was added to a dichloromethane/trifluoroacetic acid=1/1 (30 mL) solution at room temperature, and the mixed solution was stirred at 20 ℃ for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to give 15-5 (6.15 g, crude product) as a pale yellow solid.
LCMS(ESI)m/z:334.0[M+H]+。
Synthesis of intermediate 15-7
To 15-6 (2.0 g,6.0 mmol) of N, N-dimethylformamide (50 mL) was added 15-6 (3.76 g,18.0 mmol) of triethylamine (3.04 g,30.0 mmol), copper acetate (2.18 g,12.0 mmol) and 4A molecular sieve (13.2 g,30.0 mmol) at room temperature, and the mixed solution was stirred under an oxygen atmosphere at 60℃for 16 hours. After completion of the reaction, ethyl acetate (250 mL) and water (250 mL) were added to the reaction solution, a large amount of solids were precipitated, filtration was performed through celite, the cake was washed with ethyl acetate, the obtained filtrate was separated into an organic phase, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane: methanol=10:1) to give 15-7 (2.4 g, yield: 79.7%) as a pale yellow solid.
LCMS(ESI)m/z:497.0[M+H]+。
Synthesis of Compound 15
15-7 (2.5 G,5.0 mmol) and 1-7 (0.95 g,5.25 mmol) were dissolved in tetrahydrofuran (25 mL) at room temperature, cooled to-60℃under nitrogen, and then a tetrahydrofuran solution of potassium t-butoxide (8.3 mL,15.0mmol, 1.8M) was added dropwise to the reaction solution. The resulting solution was stirred at this temperature for 1 hour. After completion of the reaction, saturated brine (50 mL) was added thereto, and the resulting solution was extracted with ethyl acetate (50 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by high performance liquid chromatography to give compound 15 (0.4914 g, yield: 16.0%) as a pale yellow solid.
LCMS(ESI)m/z:615.9[M+H]+。
1H NMR(400MHz,CD3OD)δ8.33(s,1H),8.25(s,1H),8.18(s,1H),7.81(t,J＝7.8Hz,1H),7.71(s,1H),7.69–7.67(m,1H),7.45(br,1H),7.18(t,J＝9.5Hz,1H),5.35(s,2H),5.11(d,J＝1.4Hz,1H),4.18(s,3H),3.95(d,J＝3.1Hz,3H),3.87-3.83(m,1H),2.32-2.23(m,1H),2.16–2.09(m,1H).
The compounds of the following Table B were synthesized in the same manner as described above
Table B
EXAMPLE 27 Synthesis of Compound 27
Synthesis of intermediate 27-2c
To a solution of 27-1a (1.00 g,5.68 mmol) in N-methylpyrrolidone (10 mL) at room temperature was added 27-2b (1.54 g,12.5 mmol), and the mixed solution was stirred in a microwave reactor at 200℃for 4 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=20:1) to give compound 27-2c (1.20 g, yield: 86.9%) as a pale yellow oil.
LCMS(ESI)m/z:241.0[M+H]+。
Synthesis of intermediate 27-2d
To a solution of 27-2c (3.48 g,14.4 mmol) in tetrahydrofuran (35 mL) was added triethylamine (4.37 g,43.2 mmol), di-tert-butyl dicarbonate (7.86 g,36 mmol) and 4-dimethylaminopyridine (0.18 g,1.44 mmol) at ambient temperature. The mixture was stirred at 65 ℃ for 16 hours under nitrogen blanket. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=20:1) to give compound 27-2d (1.41 g, yield: 28.5%) as a pale yellow oil.
LCMS(ESI)m/z:343.1[M+H]+。
Synthesis of intermediate 27-2
To a solution of 27-2d (1.00 g,2.91 mmol) and pinacol borate (2.16 g,11.6 mmol) in tetrahydrofuran (10 mL) at-78℃was added dropwise n-butyllithium (4.8 mL,11.6 mmol). The mixture was stirred at-78 ℃ for 2 hours 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 (dichloromethane: methanol=20:1) to give compound 27-2 (0.76 g, yield: 85.0%) as a pale yellow solid.
LCMS(ESI)m/z:309.1[M+H]+。
Synthesis of intermediate 27-3
To a solution of 27-1 (250 mg,0.75 mmol) in N, N-dimethylformamide (3 mL) was added 27-2 (278 mg,0.90 mmol), copper acetate (272 mg,1.50 mmol) and triethylamine (379 mg,3.75 mmol) at room temperature, and the mixed solution was stirred with oxygen at room temperature for 16 hours. After completion of the reaction, the mixed solution was washed with water (10 mL) and a saturated sodium chloride solution (20 mL) in this order, and the organic phase was dried over anhydrous sodium sulfate. Purification of the crude product by column chromatography (silica gel, dichloromethane: methanol=10:1) gave 27-3 as a yellow oil (179 mg, yield: 40.2%).
LCMS(ESI)m/z:596.0[M+H]+。
Synthesis of intermediate 27-4
To a solution of 27-3- (200 mg,0.36 mmol) in tetrahydrofuran (2 mL) at-40℃was added 1-7 (73.0 mg,0.40 mmol), and the mixed solution was added potassium tert-butoxide solution (1 mL) under nitrogen. Stirring was carried out at-40℃for 2 hours. After completion of the reaction, the mixed solution was extracted with water (10 mL) and ethyl acetate (10 mL) in this order, and the organic phase was dried over anhydrous sodium sulfate. Purification of the crude product by column chromatography (dichloromethane: methanol=10:1) gave 27-4 (96.6 mg, yield: 37.5%) as a yellow oil.
LCMS(ESI)m/z:715.0[M+H]+。
Synthesis of Compound 27
27-4- (100 Mg,0.15 mmol) was added to a dichloromethane/trifluoroacetic acid=1/1 (2 mL) solution at room temperature, and the mixed solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was adjusted to ph=7 with sodium carbonate solution under an ice bath. Dichloromethane (10 mL) was added to the mixed solution to extract, and the organic phase was dried over anhydrous sodium sulfate and 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: 30-50) to give compound 27 (SWD 0309) as a white solid (27.1 mg, yield: 29.4%).
LCMS(ESI)m/z:615.0[M+H]+。
1H NMR(400MHz,CD3OD)δ8.23(s,2H),8.03(d,J＝15.6Hz,2H),7.85(s,1H),7.76(s,1H),7.53(s,1H),7.24(s,1H),5.40(s,2H),4.23(s,3H),4.15(s,1H),3.98-3.94(m,2H),3.90-3.85(m,1H),3.75-3.72(m,1H),2.37-2.28(m,1H),1.94-1.91(m,1H).
The compounds of the following Table C were synthesized in the same manner as described above
Table C
EXAMPLE 32 Synthesis of Compound 32
Synthesis of intermediate 32-2c
Triphenylphosphine (11.3 g,43.1 mmol) was dissolved in tetrahydrofuran (100 mL) under ice bath, and diisopropyl azodicarboxylate (8.71 g,43.1 mmol) was added and stirred under ice bath for 15 min until a large amount of white solid precipitated. 32-2a (5.45 g,28.7 mmol) was then added under ice bath and stirred at this temperature for 15 minutes. 32-2b (2.53 g,28.7 mmol) was added and the mixture stirred under nitrogen at 20℃for 16 hours. After completion of the reaction, water (200 mL) was added, extraction was performed with ethyl acetate (200 ml×2), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=1:2) to give 32-2c (6.9 g, yield: 92.3%) as a yellow oil.
LCMS(ESI)m/z:260.0[M+H]+。
Synthesis of intermediate 32-2
Intermediate 32-1C (6.8 g,26.2 mmol) was dissolved in 1, 4-dioxane (100 mL) at ambient temperature, and pinacol biborate (9.98 g,39.3 mmol), potassium acetate (7.71 g,78.6 mmol) and 1, 1-bis (diphenylphosphine) iron palladium dichloride (1.92 g,2.62 mmol) were added and the mixed solution stirred under nitrogen at 80℃for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, petroleum ether (500 mL) was added, the resulting solution was stirred at room temperature for 1 hour, followed by filtration through celite, the cake was washed with petroleum ether, and the resulting filtrate was concentrated to dryness. The crude product was purified by reverse phase column chromatography (C18, water (0.1% trifluoroacetic acid): acetonitrile=5:95-15/85) to give 32-2 as a yellow solid (4.12 g, yield: 69.9%).
LCMS(ESI)m/z:226.1[M+H]+。
Synthesis of intermediate 32-3
To 32-1 (0.2 g,0.6 mmol) of N, N-dimethylformamide (5 mL) was added 32-2 (0.405 g,1.8 mmol), triethylamine (0.304 g,3.0 mmol), copper acetate (0.218 g,1.2 mmol) and 4A molecular sieve (1.32 g,3.0 mmol) at room temperature, and the mixed solution was stirred under an oxygen atmosphere at 60℃for 16 hours. To the reaction solution were added ethyl acetate (25 mL) and water (25 mL), filtered, the filter cake was washed with ethyl acetate, the obtained filtrate was separated into an organic phase, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane: methanol=10:1) to give 4-32-3 (0.25 g, yield: 80%) as a pale yellow solid.
LCMS(ESI)m/z:513.1[M+H]+。
Synthesis of Compound 32
32-3 (2.5 G,5.0 mmol) and compounds 1-7 (0.95 g,5.25 mmol) were dissolved in tetrahydrofuran (25 mL) at room temperature, cooled to-60℃under nitrogen, and then a tetrahydrofuran solution of potassium t-butoxide (8.3 mL,15.0mmol, 1.8M) was added dropwise to the reaction solution. The resulting solution was stirred at this temperature for 1 hour. Saturated brine (50 mL) was added, extracted with ethyl acetate (50 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by high performance liquid chromatography (column: -Gemini-C18 150x21.2mm,5 μm. Flowage: ACN- -H 2 O (0.1% FA) to give compound 32 (0.474 g, yield: 15.0%) as a pale yellow solid.
LCMS(ESI)m/z:632.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ11.26(s,0.56H),9.73(s,0.44H),8.57(d,J＝16.5Hz,1H),8.47(s,1H),8.33(d,J＝50.2Hz,1H),8.09–7.68(m,3.5H),7.59(dt,J＝40.5,9.5Hz,1H),7.13(s,0.5H),5.25(d,J＝31.6Hz,2H),4.34–3.94(m,5H),3.89–3.70(m,2H),3.59–3.51(m,1H),2.43–2.31(m,1H),1.86–1.73(m,1H).
The compounds of the following Table D were synthesized in the same manner as described above
Table D
EXAMPLE 35 Synthesis of Compound 35
Intermediate 35-2 was synthesized as described in reference to example 32.
LCMS(ESI)m/z:213.1[M+H]+。
Synthesis of intermediate 32-3
To 35-1 (0.2 g,0.6 mmol) of N, N-dimethylformamide (5 mL) was added 35-2 (0.383 g,1.8 mmol), triethylamine (0.304 g,3.0 mmol), copper acetate (0.218 g,1.2 mmol) and 4A molecular sieve (1.32 g,3.0 mmol) at room temperature, and the mixed solution was stirred under an oxygen atmosphere at 60℃for 16 hours. To the reaction solution were added ethyl acetate (25 mL) and water (25 mL), filtered, the filter cake was washed with ethyl acetate, the obtained filtrate was separated into an organic phase, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane: methanol=10:1) to give 35-3 (0.25 g, yield: 82%) as a pale yellow solid.
LCMS(ESI)m/z:513.1[M+H]+。
Synthesis of Compound 35
35-3 (2.5 G,5.0 mmol) and compounds 1-7 (0.95 g,5.25 mmol) were dissolved in tetrahydrofuran (25 mL) at room temperature, cooled to-60℃under nitrogen, and then a tetrahydrofuran solution of potassium t-butoxide (8.3 mL,15.0mmol, 1.8M) was added dropwise to the reaction solution. The resulting solution was stirred at this temperature for 1 hour. Saturated brine (50 mL) was added, extracted with ethyl acetate (50 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by high performance liquid chromatography (column: -Gemini-C18 150x21.2mm,5 μm. Flowage: ACN- -H 2 O (0.1% FA) to give compound 35 (0.434 g, yield: 14.0%) as a pale yellow solid.
LCMS(ESI)m/z:620.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ11.25(s,1H),8.58-8.52(m,1H),8.47-8.42(m,1H),8.26(s,1H),7.97-7.79(m,2H),7.87-7.51(m,3H),5.24-5.21(m,2H),4.16-4.13(m,3H),3.58-3.52(m,2H),3.28–3.17(m,5H).
The compounds of the following Table E were synthesized in the same manner as described above
Table E
Experimental example 1
1. Biochemical IC 50 test method for resisting SARS-Cov-2
Measurement System (120 ul):
Protease (108 ul) (150 nM) WT or P132H
Substrate (10 ul final concentration: 20 uM)
Small molecule (2 ul; 3-fold gradient dilution)
Substrate(s)
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
Detection by enzyme-labeled instrument after incubation for 30min
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 initial reaction rate of the enzyme to the initial reaction rate of the control group enzyme,
IC50 values were then calculated using GRAPHPAD PRISM non-linear 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 V 0 -sample initial speed V 0)/NC initial speed x 100
NC was DMSO-added control and the enzyme activity was set at 100%.
Initial velocity calculation = Slope (RFU within 200 s: time s)
Formula II optimizes the inhibition ratio (%) = (NC initial velocity V 0 - (sample initial velocity V 0 -small molecule control without protein V 0)/NC initial velocity V 0 ×100 to eliminate the problem that V 0 (slope) is negative.
2. Method for testing anti-SARS-Cov-2 cell EC 50
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 are shown in Table 1.
TABLE 1

Claims (74)

  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;
    Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    r 1s is -C (O) NR 1bR1c or
    L 1a is selected from a bond, O, S, or NR 5a;
    L 1b is selected from a bond, O, S, or NR 5b;
    R 1a 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 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3R 1as;
    R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L 1c-ORa、-L1c-SRa、-L1c-NRbRc、C3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    n 1 and n 2 are independently selected from 0, 1,2,3, 4,5 or 6;
    R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R 1b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    R' 1s is independently selected from H, D, halogen, cyano, -L 1d-ORa、-L1d-SRa、-L1d-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
    n 3 is 0, 1,2 or 3;
    L 2 is selected from- (CR 4aR4b)m1 -, O, S or NR 4c;
    r 4a and R 4b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
    m 1 is 0, 1 or 2;
    R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2,3, 4, or 5R 2s;
    R 2s is independently selected from H, D, halogen, cyano, -L 2a-ORa、-L2a-SRa、-L2a-NRbRc, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl or 3-to 10-membered heterocyclyl;
    L 3 is selected from a bond, CR 6aR6b, O, S or NR 6c;
    R 6a and R 6b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
    R 6c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R 3 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2,3, 4, or 5R 3s;
    r 3s is independently selected from H, D, halogen, cyano, -L 3a-ORa、-L3a-SRa、-L3a-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
    Or two adjacent R 3s and the atoms to which they are attached together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2, or 3R 3ss;
    R 3ss is independently selected from H, D, halogen, cyano, -L 3b-ORa、-L3b-SRa、-L3b-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 aryl, or 3-10 membered heteroaryl;
    L 1c、L1d、L2a、L3a and L 3b are each independently selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, or C 2-6 alkynylene, optionally substituted with 1,2, or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
    R a、Rb and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, or R b、Rc together with the atoms to which they are attached form 3-10 membered heterocyclyl or 5-10 membered heteroaryl;
    Wherein each of the above groups are defined as optionally deuterated to fully deuterated;
    with the proviso that when ring A is pyridinyl, L 1a is NH, L 1b is a bond, R 1a is not C 1-6 alkyl or C 1-6 haloalkyl, and the compound is not of the structure:
  2. A compound of formula (I) according to 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;
    Ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    r 1s is Or-C (O) NR 1bR1c;
    L 1a is selected from O, S or NR 5a;
    L 1b is selected from a bond, O, S, or NR 5b;
    R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2, or 3R 1as;
    R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L 1c-ORa、-L1c-SRa、-L1c-NRbRc、C3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    n 1 and n 2 are independently selected from 0, 1,2,3, 4,5 or 6;
    R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R 1b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;
    R' 1s is independently selected from H, D, halogen, cyano, -L 1d-ORa、-L1d-SRa、-L1d-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
    n 3 is 0, 1,2 or 3;
    L 2 is selected from- (CR 4aR4b)m1 -, O, S or NR 4c;
    r 4a and R 4b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
    m 1 is 0, 1 or 2;
    R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2,3, 4, or 5R 2s;
    R 2s is independently selected from H, D, halogen, cyano, -L 2a-ORa、-L2a-SRa、-L2a-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
    L 3 is selected from a bond, CR 6aR6b, O, S or NR 6c;
    R 6a and R 6b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
    R 6c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R 3 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2,3, 4, or 5R 3s;
    r 3s is independently selected from H, D, halogen, cyano, -L 3a-ORa、-L3a-SRa、-L3a-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
    Or two adjacent R 3s and the atoms to which they are attached together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2, or 3R 3ss;
    R 3ss is independently selected from H, D, halogen, cyano, -L 3b-ORa、-L3b-SRa、-L3b-NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 aryl, or 3-10 membered heteroaryl;
    L 1c、L1d、L2a、L3a and L 3b are each independently selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, or C 2-6 alkynylene, optionally substituted with 1,2, or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
    R a、Rb and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, or R b、Rc together with the atoms to which they are attached form 3-10 membered heterocyclyl or 5-10 membered heteroaryl;
    Wherein each of the above groups are defined as optionally deuterated to fully deuterated;
    with the proviso that when ring A is pyridinyl, L 1a is NH, L 1b is a bond, R 1a is not C 1-6 alkyl or C 1-6 haloalkyl, and the compound is not of the structure:
  3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Y is N.
  4. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, as claimed in any one of claims 1 to 3, wherein ring a is C 6-10 aryl or a 5-10 membered heteroaryl, preferably phenyl or a 5-6 membered heteroaryl, preferably pyridinyl or thiazolyl, preferably pyridinyl More preferably
  5. A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1s is selected fromPreferably selected from Preferably selected from Preferably selected from More preferably not
  6. A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1a is selected from O, S, NH or NMe, preferably from O, S or NH, preferably O or S, preferably O, preferably S.
  7. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1b is a bond;
    Preferably, L 1b is selected from O, S or NR 5b, preferably from O or NR 5b, preferably from O, S or NMe, preferably from O or S, preferably from O or NMe, preferably from O.
  8. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, preferably from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably from C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 cycloalkyl or 3-5 membered heterocyclyl, preferably from C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl, preferably from C 1-6 alkyl or C 1-6 haloalkyl, preferably from Me, Preferably selected from Me,Preferably Me;
    Preferably, R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl, preferably from C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably 4-5 membered heterocyclyl, preferably from C 3-7 cycloalkyl or 3-7 membered heterocyclyl Preferably is
  9. A compound of formula (I) according to any one of claims 1 to 8, OR a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate OR solvate thereof, wherein R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR a、SRa、NRbRc、C3-10 cycloalkyl OR 3-10 membered heterocyclyl, preferably from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl OR 3-10 membered heterocyclyl, preferably from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl OR 3-7 membered heterocyclyl, preferably from H, D, halogen, C 1-6 alkyl OR C 1-6 haloalkyl, preferably from H, D, C 1-6 alkyl OR C 1-6 haloalkyl, preferably Me.
  10. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, according to any one of claims 1 to 9, wherein n 1 is selected from 0, 1,2 or 3, preferably from 0, 1 or 2, preferably from 1,2 or 3, preferably 0, preferably 1, preferably 2.
  11. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, according to any one of claims 1 to 10, wherein n 2 is selected from 0, 1,2 or 3, preferably from 0 or 1, preferably 0.
  12. A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 5a is H or Me, preferably H.
  13. A compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 5b is selected from C 1-6 alkyl or C 1-6 haloalkyl, preferably Me.
  14. A compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1b is H;
    Preferably, R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, preferably selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-6 alkyl or C 1-6 haloalkyl, preferably Me.
  15. A compound of formula (I) according to any one of claims 1 to 14, OR a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate OR solvate thereof, wherein R' 1s is independently selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl OR C 1-6 haloalkyl, preferably from H, D, halogen, C 1-6 alkyl OR C 1-6 haloalkyl.
  16. A compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein n 3 is 0 or 1, preferably 0.
  17. A compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, n 3 being 1,2 or 3, preferably 0 or 1, preferably 0.
  18. A compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 2 is- (CR 4aR4b)m1 -;
    Preferably, m 1 is 1;
    Preferably, R 4a and R 4b are H.
  19. A compound of formula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 2 is selected from C 6-10 aryl or 5-10 membered heteroaryl, preferably phenyl or 5-6 membered heteroaryl;
    Preferably, R 2 is optionally substituted with 1,2,3, or 4R 2s;
    Preferably, R 2 is optionally substituted with 2 or 3R 2s;
    Preferably, R 2 is selected from Preferably selected from Preferably selected from
  20. A compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl, preferably from H, D, halogen, cyano, C 1-6 alkyl, or C 1-6 haloalkyl, preferably from H, D, halogen, cyano, or C 1-6 alkyl, preferably from H, F, cl, CN, me, CHF 2 or CF 3, preferably from H, F, cl, CN or Me.
  21. A compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 3 is NR 6c;
    Preferably, R 6a and R 6b are H.
  22. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, as claimed in any one of claims 1 to 21, wherein R 3 is selected from C 6-10 aryl or 5-10 membered heteroaryl, preferably
  23. A compound of formula (I) according to any one of claims 1 to 22, OR a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate OR solvate thereof, wherein R 3s is selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl OR 3-10 membered heterocyclyl, preferably from H, D, halogen, OR a、SRa、NRbRc、C1-6 alkyl OR C 1-6 haloalkyl, preferably from H, D, halogen, OR a、C1-6 alkyl OR C 1-6 haloalkyl, preferably from H, D, cl, OMe OR Me, preferably Cl OR Me.
  24. A compound of formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein two adjacent R 3s and the atoms to which they are attached together form a C 5-7 cycloalkyl, a 5-7 membered heterocyclyl, phenyl or a 5-6 membered heteroaryl, preferably a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl, preferably a pyrazolyl or dihydrofuranyl, preferablyPreferably form
  25. A compound of formula (I) according to any one of claims 1 to 24, OR a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, OR solvate thereof, wherein R 3ss is independently selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, OR 3-10 membered heterocyclyl, preferably from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, OR 3-10 membered heterocyclyl, preferably from H, D, halogen, C 1-6 alkyl, OR C 1-6 haloalkyl, preferably from H, D, C 1-6 alkyl, OR C 1-6 haloalkyl, preferably Me.
  26. A compound of formula (I) according to any one of claims 1 to 25, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1c、L1d、L2a、L3a and L 3b are each independently selected from a bond or C 1-6 alkylene, optionally substituted with 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, preferably from a bond or C 1-3 alkylene.
  27. A compound of formula (I) according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R a、Rb and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, preferably from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-6 alkyl or C 1-6 haloalkyl;
    Or R b、Rc together with the atoms to which they are attached form a 3-to 10-membered heterocyclic group, preferably a 3-to 7-membered heterocyclic group.
  28. A compound of formula (I) according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, having the formula:
    wherein,
    M 2 is 1,2,3 or 4;
    X 1 is CR 3b or N, and X 2 is CR 3c or N;
    Or X 1 is C (O), X 2 is NH;
    R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
    R 3b is selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, OR 3-10 membered heterocyclyl;
    R 3c、R3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    Or R 3b together with R 3c and the atoms to which they are attached form C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2, or 3R 3ss;
    R 2a、R2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;
    R 2d is selected from H, D, halogen or cyano;
    R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
    the remaining groups are as defined in claims 1-27.
  29. The compound of formula (II) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    Wherein,
    Ring a is C 6-10 aryl or 5-10 membered heteroaryl;
    r 1s is Or-C (O) NR 1bR1c;
    L 1a is selected from O, S or NR 5a;
    L 1b is selected from a bond, O, S, or NR 5b;
    R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
    R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR a、SRa、NRbRc、C3-10 cycloalkyl, OR 3-10 membered heterocyclyl;
    n 1 and n 2 are independently selected from 0, 1,2,3, 4,5 or 6;
    R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R 1b is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-to 10-membered heterocyclyl;
    R' 1s is independently selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl, OR C 1-6 haloalkyl;
    n 3 is 0, 1,2 or 3;
    R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
    m 2 is 1,2,3 or 4;
    X 1 is CR 3b or N, and X 2 is CR 3c or N;
    Or X 1 is C (O), X 2 is NH;
    R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
    R 3b is selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, OR 3-10 membered heterocyclyl;
    R 3c、R3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    Or R 3b together with R 3c and the atoms to which they are attached form C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1,2, or 3R 3ss;
    R 3ss is independently selected from H, D, halogen, cyano, OR a、SRa、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, OR 3-10 membered heterocyclyl;
    r a、Rb and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, or R b、Rc together with the atoms to which they are attached form 3-10 membered heterocyclyl;
    Wherein each of the above groups are defined as optionally deuterated to fully deuterated;
    With the proviso that when ring a is pyridinyl, L 1a is NH, L 1b is a bond, R 1a is not C 1-6 alkyl or C 1-6 haloalkyl, and the compound is not of the structure:
  30. The compound of formula (II) of claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    Ring A is phenyl or 5-6 membered heteroaryl;
    r 1s is Or-C (O) NHR 1c, preferably
    L 1a is selected from O, S or NR 5a;
    L 1b is selected from a bond, O, S, or NR 5b;
    R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
    r 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl;
    n 1 and n 2 are independently selected from 0, 1,2 or 3;
    R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably R 5a is H;
    R 1c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R' 1s is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    n 3 is 0 or 1;
    R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
    m 2 is 1,2,3 or 4;
    X 1 is CR 3b,X2 and CR 3c;
    Or X 1 is C (O), X 2 is NH;
    R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 3b is selected from OR a、SRa OR NR bRc, preferably OR a OR SR a;
    R 3c、R3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    Or R 3b together with R 3c and the atoms to which they are attached form C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally substituted with 1,2 or 3R 3ss;
    r 3ss is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R a、Rb and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, or R b、Rc together with the atoms to which they are attached form a 3-7 membered heterocyclyl.
  31. The compound of formula (II) according to claim 29 or 30, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    Ring a is a 5-6 membered heteroaryl group, preferably pyridinyl or thiazolyl;
    r 1s is Or-C (O) NHR 1c, preferably
    L 1a is selected from O, S, NR 5a;
    L 1b is selected from a bond, O, S, or NR 5b;
    R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 cycloalkyl or 3-5 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
    R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    n 1 is selected from 0, 1 or 2;
    n 2 is selected from 0 or 1;
    r 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably R 5a is H, preferably R 5b is C 1-6 alkyl or C 1-6 haloalkyl, preferably Me;
    R 1c is selected from C 1-6 alkyl or C 1-6 haloalkyl;
    n 3 is 0;
    R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl, preferably selected from H, D, halogen, cyano or C 1-6 alkyl;
    m 2 is 2 or 3;
    X 1 is CR 3b,X2 and CR 3c;
    Or X 1 is C (O), X 2 is NH;
    R 3a is halogen;
    r 3b is OR a;
    R 3c、R3d and R 3e are independently H or D;
    Or R 3b together with R 3c and the atoms to which they are attached form a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl, preferably pyrazolyl or dihydrofuranyl, optionally substituted with 1,2 or 3R 3ss;
    R 3ss is independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
    R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-6 alkyl or C 1-6 haloalkyl.
  32. The compound of formula (II) according to any one of claims 29 to 31, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    Ring A is
    R 1s isOr C (O) NHCH 3, preferably
    L 1a is selected from O, S, NH or NMe, preferably from O, S or NH;
    L 1b is selected from O, S or NMe;
    R 1a is selected from Me,
    N 1 is selected from 0, 1 or 2;
    n 2 is selected from 0 or 1;
    n 3 is 0;
    R 2s is independently selected from H, F, cl, CN, me, CHF 2 or CF 3, preferably from H, F, cl, CN or Me;
    m 2 is 2 or 3;
    X 1 is CR 3b,X2 and CR 3c;
    Or X 1 is C (O), X 2 is NH;
    r 3a is Cl;
    r 3b is OMe;
    R 3c、R3d and R 3e are H;
    Or R 3b together with R 3c and the atoms to which they are attached form
    Preferably, R 1s is selected from
    Preferably, ring a and substituents thereon together form:
    Preferably, the method comprises the steps of, Selected from the group consisting of
    Preferably, the method comprises the steps of,Selected from the group consisting of
  33. The compound of formula (III-1) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    Wherein,
    L 1a is selected from O, S or NR 5a;
    L 1b is selected from O, S or NR 5b;
    R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
    R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
    n 1 is selected from 1,2,3, 4, 5, or 6;
    n 2 is selected from 0,1,2, 3,4, 5, or 6;
    R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2a、R2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
    R 2d is selected from H, D, halogen or cyano;
    R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl;
    R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
    wherein each of the above groups are optionally deuterated to complete deuteration.
  34. The compound of formula (III-1) of claim 33, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    L 1a is selected from O or S, preferably O, preferably S;
    L 1b is selected from O, S or NR 5b, preferably O or NR 5b;
    R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
    R 1as is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    n 1 is selected from 1,2 or 3, preferably 2;
    n 2 is selected from 0,1, 2 or 3, preferably 0 or 1;
    R 5b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-3 alkyl or C 1-3 haloalkyl;
    R 2a、R2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2d is selected from halogen or cyano;
    R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    r 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    Preferably, the method comprises the steps of,
    R 2a is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    r 2b is H;
    r 2c is selected from H, D or halogen;
    R 2d is selected from halogen or cyano;
    R 3a is halogen;
    R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  35. The compound of formula (III-1) of claim 33 or 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    L 1a is selected from O or S;
    l 1b is selected from O or S;
    R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl;
    n 1 is 2;
    n 2 is 0 or 1;
    R 2a、R2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2d is selected from halogen or cyano;
    R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  36. The compound of formula (III-1) according to any one of claims 33 to 35, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    L 1a is selected from O or S, preferably O;
    L 1b is O;
    R 1a is selected from C 1-6 alkyl or C 1-6 haloalkyl;
    n 1 is 2;
    n 2 is 0;
    R 2a、R2c and R 2d are independently halogen;
    r 2b is H or D;
    R 3a is halogen;
    R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  37. The compound of formula (III-1) according to any one of claims 33 to 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    L 1a is selected from O or S, preferably O;
    L 1b is selected from O or NMe, preferably O;
    R 1a is selected from Me, Preferably Me;
    n 1 is 2;
    n 2 is 0 or 1, preferably 0;
    R 2a is selected from F or Me, preferably F;
    r 2b is H;
    R 2c is selected from H or F, more preferably F;
    R 2d is selected from F, cl or CN, preferably F or Cl;
    r 3a is Cl;
    r 3f is Me;
    Preferably, the method comprises the steps of, Selected from: Preferably is
    Preferably, the method comprises the steps of,Selected from: Preferably is
  38. The compound of formula (III-2) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    Wherein,
    L 1a is selected from O, S or NR 5a;
    R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
    R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
    n 1 is selected from 1,2,3, 4, 5, or 6;
    R 5a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2a、R2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
    R 2d is selected from H, D, halogen or cyano;
    R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl;
    R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
    wherein each of the above groups are optionally deuterated to complete deuteration.
  39. The compound of formula (III-2) of claim 38, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    L 1a is selected from O or S, preferably O, preferably S;
    R 1a is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
    R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    n 1 is selected from 1,2 or 3;
    R 2a、R2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2d is selected from halogen or cyano;
    R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  40. The compound of formula (III-2) of claim 38 or 39, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    L 1a is selected from O or S, preferably O;
    R 1a is a 3-7 membered heterocyclyl, preferably a 4-5 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
    R 1as is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl, preferably Me;
    n 1 is 1;
    R 2a、R2c and R 2d are independently halogen;
    r 2b is H or D;
    R 3a is halogen;
    R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  41. The compound of formula (III-2) according to any one of claims 38 to 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    L 1a is selected from O or S, preferably O;
    R 1a is selected from
    N 1 is 1;
    Is that
    R 3a is Cl;
    r 3f is Me;
    Preferably, the method comprises the steps of, Selected from:
  42. The compound of formula (III-3) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    Wherein,
    L 1a is selected from O, S or NR 5a;
    R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
    R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;
    R 5a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2a、R2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
    R 2d is selected from H, D, halogen or cyano;
    R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl;
    R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
    wherein each of the above groups are optionally deuterated to complete deuteration.
  43. The compound of formula (III-3) of claim 42, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    L 1a is selected from O, S or NH, preferably O or NH, preferably S;
    R 1a is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably 3-7 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
    R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2a、R2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2d is selected from halogen or cyano;
    R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  44. The compound of formula (III-3) of claim 42 or 43, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    L 1a is selected from O, S or NH, preferably O or NH;
    R 1a is a 4-6 membered heterocyclyl, preferably a 5 membered heterocyclyl, preferably tetrahydrofuranyl, optionally substituted with 1,2 or 3R 1as;
    R 1as is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    r 2a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2b is selected from H, D or halogen;
    R 2c is halogen;
    R 2d is selected from halogen or cyano;
    R 3a is halogen;
    R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  45. The compound of formula (III-3) according to any one of claims 42 to 44, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein, when the linking atom of R 1a and L 1a is a chiral carbon atom, isIs that
  46. The compound of formula (III-3) of any one of claims 44-45, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    L 1a is selected from O, S or NH, preferably O or NH;
    R 1a is selected from Preferably isMore preferably
    R 2a is H, F, cl or Me;
    R 2b is H or F;
    r 2c is F or Cl, preferably F;
    R 2d is F, cl or CN;
    r 3a is Cl;
    r 3f is Me;
    Preferably, the method comprises the steps of, Selected from: Preferably not More preferably
    Preferably, the method comprises the steps of,Selected from: Preferably selected from
  47. The compound of formula (II) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    Wherein,
    Ring A is phenyl or 5-6 membered heteroaryl;
    r 1s is -C (O) NHR 1c or
    L 1a is selected from a bond, O, S, or NR 5a;
    L 1b is selected from a bond, O, S, or NR 5b;
    R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, optionally substituted with 1,2, or 3R 1as;
    R 1as is independently selected from H, D, halogen, cyano, OR a、NRbRc、C1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, OR 3-7 membered heterocyclyl;
    n 1 and n 2 are independently selected from 0, 1,2 or 3;
    R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably R 5a is H;
    R 1c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R' 1s is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    n 3 is 0 or 1;
    R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or
    M 2 is 1,2,3 or 4;
    X 1 is CR 3b,X2 and CR 3c;
    Or X 1 is C (O), X 2 is NH;
    R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 3b is selected from OR a、SRa OR NR bRc, preferably OR a OR SR a;
    R 3c、R3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    Or R 3b together with R 3c and the atoms to which they are attached form C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally substituted with 1,2 or 3R 3ss;
    r 3ss is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R a、Rb and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    Wherein each of the above groups are defined as optionally deuterated to fully deuterated;
    With the proviso that when ring a is pyridinyl, L 1a is NH, L 1b is a bond, R 1a is not C 1-6 alkyl or C 1-6 haloalkyl, and the compound is not of the structure:
  48. the compound of claim 47 of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    Ring A is a 5-6 membered heteroaryl group, preferably pyridinyl or thiazolyl, preferably pyridinyl, preferably
    R 1s isPreferably is
    L 1a is selected from O, S, NR 5a;
    l 1b is selected from a bond, O, or NR 5b;
    R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, or 5-6 membered heteroaryl, optionally substituted with 1,2, or 3R 1as;
    r 1as is independently selected from H, D, halogen, NR bRc、C1-6 alkyl or C 1-6 haloalkyl;
    n 1 is selected from 0, 1 or 2;
    n 2 is selected from 0, 1 or 2;
    r 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably R 5a is H, preferably R 5b is C 1-3 alkyl or C 1-3 haloalkyl;
    n 3 is 0;
    R 2s is independently selected from H, D, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;
    m 2 is 2 or 3;
    X 1 is CR 3b,X2 and CR 3c;
    Or X 1 is C (O), X 2 is NH;
    R 3a is halogen;
    R 3b is OR a, preferably OMe;
    R 3c、R3d and R 3e are independently H or D;
    Or R 3b together with R 3c and the atoms to which they are attached form a 5-to 7-membered heterocyclyl or a 5-to 6-membered heteroaryl, optionally substituted with 1,2 or 3R 3ss, preferably forming
    R 3ss is independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
    R a、Rb and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    Preferably, the method comprises the steps of, Selected from the group consisting ofPreferablyPreferably
    Preferably, when L 1b is a bond, R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl.
  49. The compound of formula (III-1) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    Wherein,
    L 1a is selected from O or S;
    L 1b is selected from O, S or NR 5b;
    R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl, optionally substituted with 1,2, or 3R 1as;
    R 1as is independently selected from H, D, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    n 1 is selected from 1,2 or 3;
    n 2 is selected from 0, 1,2 or 3;
    R 5b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2a is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;
    R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2d is selected from H, D, halogen or cyano, preferably halogen or cyano;
    R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    r 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    wherein each of the above groups are optionally deuterated to complete deuteration.
  50. The compound of formula (III-1) of claim 49, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    L 1a is selected from O or S;
    L 1b is O or NR 5b, preferably O;
    R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-5 cycloalkyl or 3-5 membered heterocyclyl, preferably C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-5 cycloalkyl, preferably C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl;
    n 1 is 2;
    n 2 is 0, 1 or 2;
    R 5b is C 1-3 alkyl or C 1-3 haloalkyl, preferably Me;
    R 2a is selected from H, D, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy, preferably halogen, C 1-4 alkyl or C 1-4 alkoxy;
    r 2b is H, D or halogen;
    r 2c is selected from H, D or halogen;
    r 2d is halogen or CN;
    R 3a is halogen;
    R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  51. The compound of formula (III-1) of claim 49 or 50, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    L 1a is selected from O or S, preferably O;
    L 1b is selected from O or NMe, preferably O;
    r 1a is selected from Me, OMe, cyclopropyl or Preferably Me, OMe or cyclopropyl; preferably Me or cyclopropyl;
    n 1 is 2;
    n 2 is 0,1 or 2, preferably 0 or 1;
    R 2a is selected from H, F, me, CF 3, OMe or OCHF 2, preferably F, me or OMe;
    R 2b is H or F;
    R 2c is selected from H, F or Cl, more preferably H or F;
    R 2d is selected from F, cl or CN, preferably Cl or CN;
    r 3a is Cl;
    r 3f is Me;
    Preferably, the method comprises the steps of, Selected from: Preferably is Preferably is
    Preferably, the method comprises the steps of,Selected from: Preferably is
  52. The compound of formula (III-3) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    Wherein,
    L 1a is selected from O, S or NR 5a;
    R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally substituted with 1,2 or 3R 1as;
    R 1as is independently selected from H, D, halogen, OR a、NRbRc、C1-6 alkyl OR C 1-6 haloalkyl;
    r 5a is selected from H, C 1-3 alkyl or C 1-3 haloalkyl, preferably R 5a is H;
    R 2a、R2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2d is selected from halogen or cyano;
    R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    r 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R a、Rb and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    wherein each of the above groups are optionally deuterated to complete deuteration.
  53. The compound of formula (III-3) of claim 52, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    L 1a is selected from O, S or NH;
    R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, optionally substituted with 1,2 or 3R 1as;
    R 1as is independently selected from H, D, halogen, NR bRc、C1-6 alkyl or C 1-6 haloalkyl, preferably from H, F, me, NH 2、-NHCH3 or-NH (CH 3)2; preferably from H, F, me, NH 2 or-NHCH 3;
    R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R 2b is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R 2c is H, D or halogen;
    R 2d is halogen or cyano;
    R 3a is halogen;
    R 3f is C 1-6 alkyl or C 1-6 haloalkyl;
    R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  54. The compound of claim 52 or 53 of formula (III-3), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein, when the linking atom of R 1a to L 1a is a chiral carbon atom, isIs that
  55. The compound of formula (III-3) of any one of claims 52-54, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    L 1a is selected from O, S or NH;
    R 1a is selected from Preferably selected from: Preferably, the method comprises the steps of, Is that
    R 2a is H, F, cl or Me;
    R 2b is H, F or Me;
    R 2c is H, F or Cl;
    R 2d is F, cl or CN;
    r 3a is Cl;
    r 3f is Me;
    Preferably, the method comprises the steps of, Selected from: Preferably selected from: Preferably, the method comprises the steps of, Is thatPreferably, the method comprises the steps of,Is thatPreferably, the method comprises the steps of,Is that
    Preferably, the method comprises the steps of,Selected from:
  56. The compound of formula (IV-1) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof,
    Wherein,
    R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally substituted with 1,2 or 3R 1as;
    R 1as is independently selected from H, D, halogen, OR a、NRbRc、C1-6 alkyl OR C 1-6 haloalkyl;
    R 2a and R 2b are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2c is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2d is selected from halogen or cyano;
    R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    r 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R a、Rb and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    wherein each of the above groups are optionally deuterated to complete deuteration.
  57. The compound of claim 56 of formula (IV-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably 4-6 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
    R 1as is independently selected from H, D, halogen, NR bRc、C1-6 alkyl or C 1-6 haloalkyl, preferably selected from H, D or NR bRc, preferably selected from H, NH 2 or-N (CH 3)2; preferably selected from H or NH 2;
    R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R 2b is selected from H, D or halogen;
    R 2c is halogen;
    R 2d is selected from halogen or cyano;
    R 3a is halogen;
    R 3f is C 1-6 alkyl or C 1-6 haloalkyl;
    R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably H.
  58. The compound of claim 56 or 57 of formula (IV-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein, when the linking atom of R 1a to O is a chiral carbon atom, isIs that
  59. The compound of formula (IV-1) according to any one of claims 56 to 58, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    L 1a is selected from O, S or NH, preferably O or NH;
    Selected from: preferably, it is: Preferably is Preferably, the method comprises the steps of,Is that
    R 2a is H, F, cl or Me, preferably H, cl or Me;
    R 2b is H or F, preferably H;
    R 2c is F;
    R 2d is F, cl or CN, preferably Cl or CN;
    r 3a is Cl;
    r 3f is Me;
    Preferably, the method comprises the steps of, Selected from: Preferably selected from Preferably selected from
  60. The compound of formula (IV-2) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof,
    Wherein,
    R 1a is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably 3-7 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
    R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2a and R 2b are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2c is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2d is selected from halogen or cyano;
    R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    r 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    wherein each of the above groups are optionally deuterated to complete deuteration.
  61. The compound of formula (IV-2) of claim 60, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    R 1a is a 4-6 membered heterocyclyl, preferably a 5 membered heterocyclyl, optionally substituted with 1,2 or 3R 1as;
    R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl, preferably from H, D or halogen;
    r 2b is selected from H or D;
    R 2c is halogen;
    R 2d is selected from halogen or cyano;
    R 3a is halogen;
    R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  62. The compound of claim 60 or 61 of formula (IV-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein, when the linking atom of R 1a to NH is a chiral carbon atom, isIs that
  63. The compound of formula (IV-2) of any one of claims 60 to 62, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    Selected from: Preferably is
    R 2a is H, F, cl or Me, preferably H or F;
    r 2b is H;
    R 2c is F;
    R 2d is F, cl or CN, preferably F or CN;
    r 3a is Cl;
    r 3f is Me;
    Preferably, the method comprises the steps of, Selected from: Preferably selected from Preferably is
  64. The compound of formula (IV-3) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof,
    Wherein,
    R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally substituted with 1,2 or 3R 1as;
    R 1as is independently selected from H, D, halogen, OR a、NRbRc、C1-6 alkyl OR C 1-6 haloalkyl;
    R 2a、R2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 2d is selected from halogen or cyano;
    R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    r 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R a、Rb and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    wherein each of the above groups are optionally deuterated to complete deuteration.
  65. The compound of formula (IV-3) of claim 64, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, optionally substituted with 1,2 or 3R 1as;
    R 1as is independently selected from H, D, halogen, NR bRc、C1-6 alkyl or C 1-6 haloalkyl, preferably from H, F, me, NH 2 or NHCH 3, preferably H, F or Me;
    R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R 2b is selected from H, D, C 1-4 alkyl or C 1-4 haloalkyl;
    r 2c is selected from H, D or halogen;
    R 2d is selected from halogen or cyano;
    R 3a is halogen;
    R 3f is C 1-6 alkyl or C 1-6 haloalkyl;
    R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  66. The compound of claim 64 or 65 of formula (IV-3), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein, when the linking atom of R 1a and S is a chiral carbon atom, isIs that
  67. The compound of formula (IV-3) of any one of claims 64 to 66, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein,
    Selected from: Preferably is Preferably is Preferably isPreferably, the method comprises the steps of,Is that
    R 2a is H, F or Me;
    R 2b is H or Me;
    R 2c is H, F or Cl;
    r 2d is Cl or CN;
    r 3a is Cl;
    r 3f is Me;
    Preferably, the method comprises the steps of, Selected from: Preferably is Preferably is
  68. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein said compound is selected from the group consisting of:
  69. A pharmaceutical composition comprising a compound of any one of claims 1-68, 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.
  70. Use of a compound of any one of claims 1-68, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutical composition of claim 69, in the manufacture of a medicament for treating or preventing a disease caused by a viral infection.
  71. 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 1-68, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutical composition of claim 69.
  72. A compound of any one of claims 1-68, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutical composition of claim 69, for use in the treatment or prevention of a disease caused by a viral infection.
  73. The use of claim 70 or the method of claim 71 or the use of a compound or pharmaceutical composition of claim 72, 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.
  74. The use of claim 70 or the method of claim 71 or the use of a compound or pharmaceutical composition of claim 72, wherein said viral infection causes a disease selected from the group consisting of fever, nausea, vomiting, headache, dyspnea, debilitation, respiratory tract infections, pneumonia, dysolfaction, dysgeusia and complications thereof, or a combination thereof.
CN202380042986.6A 2022-05-27 2023-05-26 3C-like protease inhibitor Pending CN119698410A (en)

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