CN114276351B - Nitrogen-containing heterocyclic derivative, preparation method and medical application thereof - Google Patents
Nitrogen-containing heterocyclic derivative, preparation method and medical application thereof Download PDFInfo
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- CN114276351B CN114276351B CN202111118924.8A CN202111118924A CN114276351B CN 114276351 B CN114276351 B CN 114276351B CN 202111118924 A CN202111118924 A CN 202111118924A CN 114276351 B CN114276351 B CN 114276351B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The present disclosure relates to nitrogen-containing heterocyclic derivatives, methods of preparing the same, and their use in medicine. In particular, the disclosure relates to a nitrogen-containing heterocyclic derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the derivative as a therapeutic agent, particularly application of the derivative as a TLR7/8/9 inhibitor and application of the derivative in preparing medicines for treating and/or preventing inflammatory and autoimmune diseases.
Description
Technical Field
The present disclosure belongs to the field of medicine, and relates to a nitrogenous heterocyclic derivative, a preparation method thereof and application thereof in medicine. In particular, the disclosure relates to nitrogen-containing heterocyclic derivatives represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivatives, and application of the derivatives as TLR7/8/9 inhibitors in treating inflammatory and autoimmune diseases.
Background
Toll-like receptors (Toll like receptors, TLR) are an evolutionarily conserved class of transmembrane innate immune receptors that are involved in the first line of defense in protecting human health and play an important role in the recognition of pathogen-associated molecular patterns (PAMPs) (Kawai, t. Et al, nature immunol.,11,2010,373-384). TLRs are expressed in various immune cells and can be classified into two types according to the site of expression: TLR expressed in cell membrane (TLR 1/2/4/5/6) and TLR expressed in endosomal membrane (TLR 3/7/8/9) recognize different components and molecules in PAMPs, respectively. Wherein TLR7/8/9 is mainly highly expressed in DC cells and B cells, TLR7/8 mainly recognizes ssRNA, and TLR9 mainly recognizes CpG-DNA. TLR7/8/9 binds its ligand and is activated, binds to the adaptor protein MyD88 in the cytoplasm, initiates NF- κb and IRF pathways, activates DC cells, and produces type I interferon and other various inflammatory cytokines. In B cells, TLR7/8/9, in combination with nucleic acids, plays an important role in the production of antinuclear antibodies by B cells, and type I interferons secreted by DC cells also promote further proliferation and activation of such autoimmune B cells, thereby eliciting a series of inflammatory responses.
Systemic Lupus Erythematosus (SLE) belongs to an autoimmune connective tissue disease, and three major classes of clinical first-line drugs for SLE are: hormones, immunosuppressants and antimalarial drugs. In this century, only a new drug belimumab was approved by the FDA, but it had modest and delayed efficacy in only a small proportion of SLE patients (Navarra, s.v. et al, lancet,2011,377,721), with very limited therapeutic options. Thus, there is an urgent need for new therapies that improve a greater proportion of patient populations and that can be used for long periods of time, safely. The phenomenon of significantly up-regulated expression of TLR7/9 and type I interferons was found in PBMC of patients with Systemic Lupus Erythematosus (SLE) (Beverly D.LC et al, mol immunol.,2014, 61:38-43). Mice overexpressing TLR7 have been reported to exacerbate autoimmune diseases and autoinflammation (Santiago-Raber ML, et al, J immunol.,2008, 181:1556-1562), while being functionalInhibition of TLR7/9 can alleviate B6-Fas lpr And pathological manifestations of lupus mice such as BXSB (Dlight H.Kono et al, PNAS,2009,106 (29): 12061-12066). Given the close relationship of TLR7/8/9 to antinuclear antibodies and type I interferons, small molecule inhibitors targeting TLR7/8/9 are likely to have potential for treating SLE.
Published patent applications for inhibitors of TLR7/8/9 include WO 2019233941A 1, WO 2020020800A 1, WO 2018049089A 1, WO 2019238616A 1, WO 2017106607A 1, CN 109923108A and WO 2020048605A 1 and the like.
Disclosure of Invention
The object of the present disclosure is to provide a compound represented by general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein:
ring a is selected from:
wherein each R 1 And R is 2 The same or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, halogen, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
L 1 selected from CR 6a R 6b 、NR 7 And an oxygen atom;
L 2 selected from the group consisting of chemical bonds, C (O) NR 7 And NR 7 ；
Each R is 3 The same or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, oxo, halogen, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R 4 Selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, oxo, halogen, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, cyano, amino, - (CH) 2 ) u NR 11a R 11b One or more substituents selected from the group consisting of nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each R is 5 Identical or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, oxo, halogen, cyano, amino, -NR 7a R 7b 、-COR 8 、-C(O)OR 9 、-OR 10 Nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, cyano, amino, - (CH) 2 ) u NR 11a R 11b One or more substituents selected from the group consisting of nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 6a and R is 6b The same or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R 7 selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R 7a and R is 7b The same or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; or R is 7a And R is 7b Together with the nitrogen atom to which they are attached, form a heterocyclic group, which is optionally substituted with one or more substituents selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
R 8 selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) 2 ) u NR 11a R 11b One or more substituents selected from the group consisting of nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 9 and R is 10 The same or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) 2 ) u NR 11a R 11b One or more substituents selected from the group consisting of nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 11a and R is 11b Identical or identicalDifferent and each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkyl group;
t is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3, 4, 5 or 6;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3; and is also provided with
u is 0, 1, 2, 3, 4, 5 or 6.
In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is 
R 1 、R 2 P and q are as defined in formula (I).
In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein:
ring B, L 1 、L 2 、R 1 To R 5 Q, n and t are as defined in formula (I).
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein:
ring C is a 3 to 12 membered heterocyclic group containing at least one nitrogen atom;
R 0 selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 A hydroxyalkyl group;
n is 1, 2, 3, 4, 5 or 6;
ring B, L 1 、L 2 、R 1 To R 5 Q and t are as defined in formula (I).
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; preferably, ring B is a 5 to 6 membered heteroaryl or a 3 to 12 membered heterocyclyl containing at least one nitrogen atom; more preferably, ring B is pyridinyl or isoindolinyl.
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein:
ring B is a 3 to 12 membered heterocyclic group containing at least one nitrogen atom;
ring C is a 3 to 12 membered heterocyclic group containing at least one nitrogen atom;
R 0 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 A hydroxyalkyl group;
n is 1, 2, 3, 4, 5 or 6;
L 1 、R 1 to R 5 Q and t are as defined in formula (I).
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 Is cyano.
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 A haloalkyl group; preferably, R 3 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 A haloalkyl group; preferably, R 4 Is C 1-6 An alkyl group.
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereofForm, or pharmaceutically acceptable salt thereof, wherein R 5 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and 3 to 12 membered heterocyclyl; preferably, R 5 A 3-to 12-membered heterocyclic group which is a hydrogen atom or contains at least one nitrogen atom; more preferably, R 5 Is a hydrogen atom or a piperazinyl group.
In some preferred embodiments of the present disclosure, the compound of formula (III), formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 Is CH 2 。
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 Is a chemical bond or C (O).
In some preferred embodiments of the present disclosure, the compound of formula (III), formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring C is a 3 to 12 membered heterocyclyl containing at least one nitrogen atom; preferably, ring C is piperazinyl.
In some preferred embodiments of the present disclosure, the compound of formula (III), formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 0 Is a hydrogen atom.
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein q is 0.
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1.
In some preferred embodiments of the present disclosure, the compound of formula (III), formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1.
In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein t is 0.
Table a typical compounds of the present disclosure include, but are not limited to:
another aspect of the present disclosure relates to a compound of formula (IIIa), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein:
R W is an amino protecting group; preferably, R W T-butoxycarbonyl;
ring B, ring C, L 1 、L 2 、R 1 To R 5 Q, n and t are as defined in formula (III).
Another aspect of the present disclosure relates to a compound of formula (IVa), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein:
R W is an amino protecting group; preferably, R W T-butoxycarbonyl;
ring B, ring C, L 1 、R 1 To R 5 Q, n and t are as defined in formula (IV).
Table B typical compounds of the present disclosure include, but are not limited to:
another aspect of the present disclosure relates to a method of preparing a compound of formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
removing protecting group R from a compound of formula (IIIa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof w Obtaining R 0 A compound of the general formula (III) which is a hydrogen atom or a tautomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
R W Is an amino protecting group; preferably, R W T-butoxycarbonyl;
ring B, ring C, L 1 、L 2 、R 1 To R 5 Q, n and t are as defined in formula (III).
Another aspect of the present disclosure relates to a method of preparing a compound of formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
deprotecting a compound of formula (IVa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof w Obtaining R 0 A compound of formula (IV) which is a hydrogen atom or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
R W is an amino protecting group; preferably, R W T-butoxycarbonyl;
ring B, ring C, L 1 、R 1 To R 5 Q, n and t are as defined in formula (IV).
Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, of the present disclosure, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting TLR7, TLR8 or TLR 9; preferably in the manufacture of a medicament for inhibiting TLR7 and TLR8, or in the manufacture of a medicament for inhibiting TLR7 and TLR 9.
The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV), and table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting TLR7, TLR8, and TLR 9.
The present disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of inflammatory or autoimmune diseases. Wherein the inflammatory or autoimmune disease is preferably selected from Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, multiple Sclerosis (MS) and sjogren's syndrome.
The disclosure further relates to a method of inhibiting TLR7, TLR8 or TLR9, preferably a method of inhibiting TLR7 and TLR8, or a method of inhibiting TLR7 and TLR9, comprising administering to a patient in need thereof an effective inhibiting amount of a compound of formula (I), formula (II), formula (III), formula (IV) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
The present disclosure further relates to a method of inhibiting TLR7, TLR8 and TLR9 comprising administering to a patient in need thereof an effective inhibiting amount of a compound of formula (I), formula (II), formula (III), formula (IV) and formula (III) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
The present disclosure further relates to a method of treating and/or preventing an inflammatory or autoimmune disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Wherein the inflammatory or autoimmune disease is preferably selected from Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, multiple Sclerosis (MS) and sjogren's syndrome.
The present disclosure further relates to a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
The present disclosure further relates to a compound of formula (I), formula (II), formula (III), formula (IV) and table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for inhibiting TLR7, TLR8 or TLR9; preferably, TLR7 and TLR8 are inhibited, or TLR7 and TLR9 are inhibited.
The disclosure further relates to a compound of formula (I), formula (II), formula (III), formula (IV), and table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for inhibiting TLR7, TLR8, and TLR9.
The present disclosure further relates to a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of inflammatory or autoimmune diseases. Wherein the inflammatory or autoimmune disease is preferably selected from Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, multiple Sclerosis (MS) and sjogren's syndrome.
In view of their activity as selective inhibitors of TLR7, TLR8 or TLR9, compounds of formula (I), formula (II), formula (III), formula (IV) and table a are useful for the treatment of TLR7, TLR8 or TLR9 family receptor related diseases, respectively, including but not limited to: inflammatory diseases (such as crohn's disease, ulcerative colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease); autoimmune diseases (such as graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis); autoinflammatory diseases (including cyclic syndrome associated with Cryopyrin (CAPS), cyclic syndrome associated with TNF Receptors (TRAPS), familial Mediterranean Fever (FMF), adult stele disease, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis); metabolic diseases (including type 2 diabetes, atherosclerosis, myocardial infarction); destructive bone disorders (such as bone resorption disease, osteoarthritis, osteoporosis, multiple myeloma-related bone disorders); proliferative disorders (such as acute myelogenous leukemia, chronic myelogenous leukemia); angiogenic disorders (such as those including solid tumors, ocular neovascularization, and infantile hemangiomas); infectious diseases (such as sepsis, septic shock, and shigellosis); neurodegenerative diseases (such as Alzheimer's disease, parkinson's disease, cerebral ischemia caused by traumatic injury or neurodegenerative diseases), neoplastic diseases (such as metastatic melanoma, kaposi's sarcoma, multiple myeloma) and viral diseases (such as HIV infection and CMV retinitis, AIDS).
More specifically, specific conditions or diseases that may be treated with the compounds of the present disclosure include, but are not limited to, pancreatitis (acute or chronic), asthma, allergy, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythema, scleroderma, chronic thyroiditis, graves 'disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, crohn's disease, psoriasis, graft versus host disease, endotoxin-induced inflammatory responses, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, reiter's syndrome (Reiter's syndrome), gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory diseases, silicosis, pulmonary sarcoidosis, bone resorption diseases, allograft rejection, fever and myalgia caused by infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, pyresis (pyresis), influenza, osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, kaposi's sarcoma, multiple myeloma, sepsis, septic shock and shigellosis; cerebral ischemia or neurodegenerative diseases caused by Alzheimer's disease, parkinson's disease, traumatic injury; angiogenic disorders including solid tumors, ocular neovascularization, and infantile hemangiomas; viral diseases including acute hepatitis infection (including hepatitis a, hepatitis b and hepatitis c), HIV infection and CMV retinitis, AIDS, ARC or malignancy, and herpes; ischemia in stroke, myocardial ischemia, heart attack, organ hypoxia, vascular proliferation, heart and kidney reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, conditions associated with prostaglandin endoperoxidase synthase-2, and pemphigus vulgaris. In preferred methods of treatment, the condition is Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris. Alternatively preferred methods of treatment are those in which the condition is ischemia reperfusion injury, including cerebral ischemia reperfusion injury caused by stroke and myocardial ischemia reperfusion injury caused by myocardial infarction. In another preferred method of treatment, the condition is multiple myeloma.
The active compounds can be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers by conventional methods to formulate the compositions of the present disclosure. Accordingly, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation. The compounds of the present disclosure may also be formulated in sustained release dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, troches or syrups.
As a general guideline, the active compounds are preferably administered in unit doses, or in a manner whereby the patient can self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation. Suitable unit doses may be in the range 0.1 to 1000mg.
The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of the active compound.
Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or oil vehicle.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.
The oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.
The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which is prepared by injecting a liquid or microemulsion into the blood stream of a patient by topical mass injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.
The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare injections.
The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
The compounds of the present disclosure may be administered by adding water to prepare water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
Description of the terms
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated straight or branched aliphatic hydrocarbon group containing from 1 to 20 carbon atoms, preferably an alkyl group (i.e., C) containing from 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms 1-12 Alkyl groups), more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C 1-6 Alkyl). Non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentylA radical, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. Most preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.
The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably containing from 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 1-12 Alkylene groups), more preferably alkylene groups having 1 to 6 carbon atoms (i.e., C 1-6 An alkylene group). Non-limiting examples of alkylene groups include, but are not limited to: methylene (-CH) 2 (-), 1-ethylene (-CH (CH) 3 ) (-), 1, 2-ethylene (-CH) 2 CH 2 ) -, 1-propylene (-CH (CH) 2 CH 3 ) (-), 1, 2-propylene (-CH) 2 CH(CH 3 ) (-), 1, 3-propylene (-CH) 2 CH 2 CH 2 (-), 1, 4-butylene (-CH) 2 CH 2 CH 2 CH 2 (-), etc. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents preferably being selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
The term "alkenyl" refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups (i.e., C) containing from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred 2-12 Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of hydrogen atoms, alkyl groups, alkoxy groups, halogen, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.
The term "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups (i.e., C) containing from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred 2-12 Alkynyl groups), more preferably alkynyl groups containing 2 to 6 carbon atoms (i.e. C 2-6 Alkynyl). Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., 3 to 12 membered cycloalkyl), preferably comprising 3 to 8 carbon atoms (i.e., 3 to 8 membered cycloalkyl), more preferably comprising 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.
The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between 5-to 20-membered rings, which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spirocycloalkyl groups are classified into single spirocycloalkyl groups or multiple spirocycloalkyl groups (e.g., double spirocycloalkyl groups) according to the number of common spiro atoms between rings, and preferably single spirocycloalkyl groups and double spirocycloalkyl groups. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/4-membered, 6-membered/5-membered or 6-membered/6-membered single spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
The term "fused ring alkyl" refers to an all-carbon polycyclic group having 5 to 20 members with an adjacent pair of carbon atoms shared between the rings, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The polycyclic condensed ring alkyl group may be classified into a bicyclic ring, a tricyclic ring, a tetracyclic ring and the like according to the number of constituent rings, and is preferably a bicyclic or tricyclic ring, and more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicycloalkyl group. Non-limiting examples of fused ring alkyl groups include:
the term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Polycyclic bridged cycloalkyl groups such as bicyclic, tricyclic, tetracyclic and the like can be classified according to the number of constituent rings, and are preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:
The cycloalkyl ring includes cycloalkyl (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples include
Etc.; preferably->
Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, and the like. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of H atom, D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), but excluding the ring portions of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably from 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1,2, 3, and 4) are heteroatoms (i.e., 3 to 12 membered heterocyclyl); more preferably 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1-3 is a heteroatom (e.g., 1,2, and 3) (i.e., 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, 1-3 of which are heteroatoms (i.e., 3 to 6 membered heterocyclyl); most preferably contain 5 or 6 ring atoms, 1-3 of which are heteroatoms (i.e., 5 or 6 membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyl groups include: pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro heterocyclic groups, fused ring heterocyclic groups, and bridged ring heterocyclic groups.
The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having a single ring of 5 to 20 members sharing one atom (referred to as the spiro atom) wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon. Which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spiroheterocyclyl groups are classified into single spiroheterocyclyl groups or multiple spiroheterocyclyl groups (e.g., double spiroheterocyclyl groups) according to the number of common spiro atoms between rings, with single and double spiroheterocyclyl groups being preferred. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl groups include:
The term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group having a ring sharing an adjacent pair of atoms, one or more of which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The number of constituent rings may be classified into a polycyclic fused heterocyclic group such as a bicyclic, tricyclic, tetracyclic and the like, preferably a bicyclic or tricyclic fused heterocyclic group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:
the term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms which are not directly connected, which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Polycyclic bridged heterocyclic groups which can be classified into bicyclic, tricyclic, tetracyclic and the like according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclyl groups include:
The heterocyclyl ring includes heterocyclyl (including monocyclic, spiro, fused and bridged heterocyclic rings) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:
The heterocyclic group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (fused polycyclic being a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. The aryl ring includes aryl rings fused to heteroaryl, heterocyclyl, or cycloalkyl rings as described above, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The term "heteroaryl" refers to heteroaromatic systems containing 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9, or 10 membered), more preferably 5 or 6 membered heteroaryl, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl condensed onto an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents preferably being selected from one or more of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
The cycloalkyl, heterocyclyl, aryl and heteroaryl groups mentioned above include residues derived from the removal of one hydrogen atom from the parent ring atom, or 2 residues derived from the removal of two hydrogen atoms from the same or two different ring atoms of the parent, i.e. "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".
The term "amino protecting group" is intended to mean an amino group that is protected by an easily removable group in order to keep the amino group unchanged when the reaction is carried out at other positions of the molecule. Non-limiting examples include: (trimethylsilyl) ethoxymethyl (SEM), tetrahydropyranyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.
The term "hydroxy protecting group" is a suitable group for hydroxy protection known in the art, see literature ("Protective Groups in Organic Synthesis", 5) Th Ed.T.W.Greene&P.g.m.wuts). As an example, preferably, the hydroxyl protecting group may be (C 1-10 Alkyl or aryl radicals 3 Silyl groups, for example: triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl, and the like; may be C 1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 Alkoxy substituted C 1-6 Alkyl-or phenyl-substituted C 1-6 Alkyl, most preferably C 1-4 Alkoxy substituted C 1-4 Alkyl groups such as: methyl, tert-butyl, benzyl, methoxymethyl (MOM), ethoxyethyl, and the like; may be (C) 1-10 Alkyl or aryl) acyl groups, for example: formyl, acetyl, benzoyl, p-nitrobenzoyl and the like; may be (C) 1-6 Alkyl or C 6-10 Aryl) sulfonyl; may also be (C) 1-6 Alkoxy or C 6-10 Aryloxy) carbonyl; allyl, 2-Tetrahydropyranyl (THP) are also possible.
The term "cycloalkyloxy" refers to a cycloalkyl-O-group, wherein cycloalkyl is as defined above.
The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.
The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.
The term "alkylthio" refers to an alkyl-S-, wherein alkyl is as defined above.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "hydroxy" refers to-OH.
The term "mercapto" refers to-SH.
The term "amino" refers to-NH 2 。
The term "cyano" refers to-CN.
The term "nitro" refers to-NO 2 。
The term "oxo" or "oxo" refers to "=o".
The term "carbonyl" refers to c=o.
The term "aldehyde" refers to-C (O) H;
the term "carboxy" refers to-C (O) OH.
The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl, cycloalkyl are as defined above.
The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopically-enriched derivative" refers to a compound that differs in structure only in the presence of one or more isotopically-enriched atoms. For example, having the structure of the present disclosure, except that "deuterium" or "tritium" is used in place of hydrogen, or 18 F-fluorine labeling [ ] 18 F isotope) instead of fluorine, or with 11 C-、 13 C-or 14 C-enriched carbon 11 C-、 13 C-or 14 C-carbon labeling; 11 C-、 13 c-or 14 C-isotopes) are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as diagnostic imaging tracers in vivo for diseases, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The present disclosure also includes various deuterated forms of the compounds. Each available hydrogen atom attached to a carbon atom may independently be replaced by a deuterogen Sub-replacement. Those skilled in the art are able to refer to the relevant literature for the synthesis of deuterated forms of the compounds. Commercially available deuterated starting materials may be used in preparing the deuterated form of the compound or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, tridentate borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like. Deuterated compounds generally retain activity comparable to non-deuterated compounds and may achieve better metabolic stability when deuterated at certain specific sites, thus achieving certain therapeutic advantages.
In the chemical structure of the compounds of the present disclosure, the bond
Indicating the unspecified configuration, i.e.the bond +.>
Can be +.>
Or->
Or at the same time contain->
And->
Two configurations.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the present disclosure which are safe and effective when used in a mammal, and which possess the desired biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate groups with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic and organic acids.
The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the intended effect. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.
The term "solvate" as used herein refers to a physical combination of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. The physical bond includes a hydrogen bond. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the crystalline solid lattice, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates and isopropanolates. Solvation methods are well known in the art.
"prodrug" means a compound that can be converted in vivo under physiological conditions, for example by hydrolysis in the blood, to yield an active prodrug.
The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and are effective for the intended use.
As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.
When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is shown that the parameter may vary by + -10%, and sometimes more preferably within + -5%. As will be appreciated by those skilled in the art, where parameters are not critical, numerals are generally given for illustration purposes only and are not limiting.
Methods of synthesizing compounds of the present disclosure
In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical scheme:
scheme one
A process for the preparation of a compound of formula (III) of the present disclosure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
(a) Coupling the compound of formula (IIIaa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof with the compound of formula (VI) or a pharmaceutically acceptable salt thereof to obtain a compound of formula (IIIa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;
(b) Removing protecting group R in the presence of an acid from a compound of formula (IIIa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof w Obtaining R 0 A compound of formula (III) which is a hydrogen atom or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;
wherein:
R X is halogen; preferably, R X Is chlorine;
R W is an amino protecting group; preferably, R W T-butoxycarbonyl;
ring B, ring C, L 1 、L 2 、R 1 To R 5 Q, n and t are as defined in formula (III).
Scheme II
A process for the preparation of a compound of formula (IV) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:
(a') a compound of formula (IVaa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is subjected to condensation reaction with a compound of formula (VII) or a pharmaceutically acceptable salt thereof, to obtain a compound of formula (IVa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;
(b) Removing the protecting group R in the presence of an acid from a compound of formula (IVa) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof w Obtaining R 0 A compound of formula (IV) which is a hydrogen atom or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;
wherein:
R Y is hydroxyl;
R W is an amino protecting group; preferably, R W T-butoxycarbonyl;
ring B, ring C, L 1 、R 1 To R 5 Q, n and t are as defined in formula (IV).
The coupling reaction of step (a) above is a coupling reaction well known in the art, including but not limited to Buchwald-Hartwig coupling reaction, negishi coupling reaction, and the like. The conditions of the coupling reaction include, but are not limited to, palladium acetate, preferably (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (RuPhos Pd G3), methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (XPhos Pd G3), chloro (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (RuPhos Pd G2), organozinc reagents, bis (triphenylphosphine) palladium (II) chloride (Pd (PPh) 3 )Cl 2 ) And the like, more preferred is chloro (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II). The metal catalyst may also be used in combination with a ligand including, but not limited to, S- (-) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine (S- (-) -BINAP), R- (-) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine (R- (-) -BINAP), 1' -binaphthyl-2, 2' -Bisdiphenylphosphine (BINAP), 1' -bis (diphenylphosphine) ferrocene (DPPF), 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene (XANTAHOS), 2' -bis (diphenylphosphine) benzophenone (DPBP), 2' -Diallyl Bisphenol A (DBA), and the like. The saidIncluding but not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide, and inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide; sodium tert-butoxide is preferred.
The condensation reaction of step (a ') above is carried out in the presence of a base such as N, N-diisopropylethylamine and a condensing agent such as 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate.
In the deprotection reaction of step (b) above, the acid includes organic acids including but not limited to trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, me 3 SiCl and TMSOTf, preferably trifluoroacetic acid; the inorganic acids include, but are not limited to, hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.
The reaction of the above steps is preferably carried out in solvents including, but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane, and mixtures thereof.
Detailed Description
The present disclosure is further described below in conjunction with the examples, which are not intended to limit the scope of the present disclosure.
Examples
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was performed using Bruker AVANCE NEO M and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard is Tetramethylsilane (TMS).
MS was measured using an Agilent 1200/1290 DAD-6110/6120 Quadrapol MS liquid chromatography-mass spectrometry (manufacturer: agilent, MS model: 6110/6120 Quadrapol MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q actual (manufacturer: THERMO, MS model: THERMO Q Exactive).
High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC1200 DAD, agilent HPLC1200VWD, and Waters HPLC e2695-2489 high performance liquid chromatography.
Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.
High performance liquid chromatography was performed using Waters 2767, waters 2767-SQ detector 2, shimadzu LC-20AP and Gilson-281 preparative chromatographs.
Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.
The CombiFlash flash rapid prep instrument used CombiFlash Rf200 (teldyne ISCO).
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier.
Average inhibition rate of kinase and IC 50 The values were measured using a NovoStar microplate reader (BMG, germany).
Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemicals, and the like.
The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.
An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.
The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.
The pressure hydrogenation reaction uses a Parr 3916 model EKX hydrogenometer and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.
The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.
The microwave reaction used was a CEM Discover-S908860 type microwave reactor.
The examples are not specifically described, and the solution refers to an aqueous solution.
The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: n-hexane/ethyl acetate system, B: the volume ratio of the methylene dichloride to the methanol is adjusted according to the polarity of the compound, and small amounts of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.
Example 1
5- (3-methyl-2- ((6- (piperazin-1-yl) pyridin-3-yl) methyl) pyrrolo [3,4-c ] pyrazol-5 (2H, 4H, 6H) -yl) quinoline-8-carbonitrile 1
First step
3-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazole 1b
3-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) -2, 6-dihydropyrrolo [3,4-c ] pyrazole-5 (4H) -carboxylic acid tert-butyl ester 1a (500 mg,1.41mmol, prepared by the known method "page 19, paragraph 0099-0100, WO2016/127916 A1") was dissolved in methanol (5 mL), and a solution of 1, 4-dioxane (5 mL, 4M) of hydrogen chloride was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title product 1b (409 mg, yield: 99.9%).
MS m/z(ESI):254.2[M+1]。
Second step
5- (3-methyl-2- ((2- (trimethylsilyl) ethoxy) methyl) pyrrolo [3,4-c ] pyrazol-5 (2H, 4H, 6H) -yl) quinoline-8-carbonitrile 1d
5-fluoroquinoline-8-carbonitrile 1c (210 mg,1.22mmol, obtained by the known method "page 16 of the specification in WO2020/020800A1, example 1) and compound 1b (409 mg,1.41 mmol) were dissolved in dimethyl sulfoxide (5 mL), N-diisopropylethylamine (79mg, 6.11 mmol) was added and the reaction heated to 120℃and stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with saturated sodium chloride solution (20 mL. Times.2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product 1d (350 mg, yield: 70.7%).
MS m/z(ESI):406.1[M+1]。
Third step
5- (3-methylpyrrolo [3,4-c ] pyrazol-5 (2H, 4H, 6H) -yl) quinoline-8-carbonitrile 1e
Compound 1d (310 mg,0.76 mmol) was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (3.1 mL,3.1mmol, 1M) was added, and the reaction was heated to 70℃and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with saturated sodium chloride solution (20 mL. Times.2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product 1e (200 mg, yield: 95.0%).
MS m/z(ESI):276.1[M+1]。
Fourth step
5- (2- ((6-chloropyridin-3-yl) methyl) -3-methylpyrrolo [3,4-c ] pyrazol-5 (2H, 4H, 6H) -yl) quinoline-8-carbonitrile 1f
Compound 1e (120 mg,0.44 mmol), 2-chloro-5-chloromethylpyridine (121 mg,0.75mmol, leaching chemical), potassium carbonate (121 mg,0.88 mmol) and sodium iodide (66 mg,0.44 mmol) were dissolved in acetonitrile (20 mL) and the reaction stirred at 85℃for 7 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title product 1f (60 mg, yield: 34.3%). MS m/z (ESI) 401.0[ M+1].
Fifth step
4- (5- ((5- (8-Cyanoquinolin-5-yl) -3-methyl-5, 6-dihydropyrrolo [3,4-c ] pyrazol-2 (4H) -yl) methyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester 1g
Compound 1f (50 mg,0.12 mmol) and 1-t-butoxycarbonyl piperazine (50 mg,0.27 mmol) were dissolved in dioxane (10 mL), sodium t-butoxide (40 mg,0.42 mmol) was added, nitrogen was substituted 3 times, chloro (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (10 mg,0.01mmol, shao-far chemistry) was added, nitrogen was substituted 3 times, and the reaction solution was heated to 80℃and stirred under nitrogen for 4 hours. The reaction solution was cooled, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B (0-10% methanol/dichloromethane) to give the title product 1g (20 mg, yield: 29.1%).
MS m/z(ESI):551.0[M+1]。
Sixth step
5- (3-methyl-2- ((6- (piperazin-1-yl) pyridin-3-yl) methyl) pyrrolo [3,4-c ] pyrazol-5 (2H, 4H, 6H) -yl) quinoline-8-carbonitrile 1
1g (20 mg,0.04 mmol) of the compound was dissolved in methylene chloride (3 mL), and trifluoroacetic acid (3 mL) was added thereto, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution (20 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 1 (10 mg, yield: 61.1%).
MS m/z(ESI):451.1[M+1]。
1 H NMR(500MHz,CDCl 3 )δ9.01-9.00(m,1H),8.59-8.57(m,1H),8.15(s,1H),7.93-7.91(m,1H),7.48-7.46(m,1H),7.39-7.37(m,1H),6.70-6.65(m,2H),5.12(s,2H),4.70(s,2H),4.44(s,2H),3.62-3.58(m,4H),3.05-3.03(m,4H),2.31(s,3H)。
Example 2
5- (3-methyl-2- (2-oxo-2- (5- (piperazin-1-yl) isoindolin-2-yl) ethyl) pyrrolo [3,4-c ] pyrazol-5 (2H, 4H, 6H) -yl) quinoline-8-carbonitrile 2
First step
5-chloroisoindoline-2-carboxylic acid benzyl ester 2b
5-chloroisoindoline hydrochloride 2a (2 g,10.52mmol, after completion of the reaction) was dissolved in methylene chloride (40 mL), and triethylamine (9.3 g,91.61 mmol) and benzyl chloroformate (1.8 g,10.55 mmol) were added in this order, and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with dichloromethane (60 mL), washed with water (40 mL), and the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 2b (2.4 g, yield: 79.3%).
MS m/z(ESI):288.1[M+1]。
Second step
5- (4- (tert-Butoxycarbonyl) piperazin-1-yl) isoindoline-2-carboxylic acid benzyl ester 2c
Compound 2b (800 mg,2.78 mmol) and 1-t-butoxycarbonyl piperazine (1.1 g,5.58 mmol) were dissolved in toluene (30 mL), sodium t-butoxide (803 mg,8.34 mmol) was added, nitrogen substitution was performed 3 times, palladium acetate (63 mg,0.28 mmol) and 2- (di-t-butylphosphine) biphenyl (166 mg,0.57 mmol) were added, nitrogen substitution was performed 3 times, and the reaction solution was heated to 100℃and stirred under nitrogen protection for 3 hours. The reaction solution was cooled, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title product 2c (620 mg, yield: 51.0%).
MS m/z(ESI):438.1[M+1]。
Third step
4- (isoindolin-5-yl) piperazine-1-carboxylic acid tert-butyl ester 2d
Compound 2c (620 mg,1.42 mmol) was dissolved in methanol (20 mL), wet palladium on carbon (151 mg) was added, hydrogen was replaced, and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure to give the title product 2d (350 mg, yield: 81.4%).
MS m/z(ESI):304.2[M+1]。
Fourth step
2- (5- (8-Cyanoquinolin-5-yl) -3-methyl-5, 6-dihydropyrrolo [3,4-c ] pyrazol-2 (4H) -yl) acetic acid tert-butyl ester 2e
Compound 1e (100 mg,0.36 mmol), t-butyl bromoacetate (142 mg,0.73 mmol), cesium carbonate (356 mg,1.09 mmol) and sodium iodide (55 mg,0.37 mmol) were dissolved in acetonitrile (30 mL), and the reaction solution was heated to 65℃and stirred for 4.5 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title product 2e (75 mg, yield: 53.0%).
MS m/z(ESI):390.1[M+1]。
Fifth step
2- (5- (8-cyanoquinolin-5-yl) -3-methyl-5, 6-dihydropyrrolo [3,4-c ] pyrazol-2 (4H) -yl) acetic acid 2f
Compound 2e (75 mg,0.19 mmol) was dissolved in trifluoroacetic acid (3 mL), and the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give the title product 2f (64 mg, yield: 99.7%).
MS m/z(ESI):334.0[M+1]。
Sixth step
2g of tert-butyl 4- (2- (2- (5- (8-cyanoquinolin-5-yl) -3-methyl-5, 6-dihydropyrrolo [3,4-c ] pyrazol-2 (4H) -yl) acetyl) isoindolin-5-yl) piperazine-1-carboxylate
Compound 2f (64 mg,0.19 mmol) and 2d (88 mg,0.29 mmol) were dissolved in N, N-dimethylformamide (5 mL), N, N-diisopropylethylamine (75 mg,0.58 mmol) was added, followed by 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (110 mg,0.29mmol, shaoshao chemical) and the reaction was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with saturated sodium chloride solution (20 mL. Times.2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title product 2g (90 mg, yield: 75.8%). MS m/z (ESI) 619.1[ M+1].
Seventh step
5- (3-methyl-2- (2-oxo-2- (5- (piperazin-1-yl) isoindolin-2-yl) ethyl) pyrrolo [3,4-c ] pyrazol-5 (2H, 4H, 6H) -yl) quinoline-8-carbonitrile 2
2g (90 mg,0.14 mmol) of the compound was dissolved in methylene chloride (3 mL), and trifluoroacetic acid (3 mL) was added thereto, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution (20 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 2 (35 mg, yield: 46.4%).
MS m/z(ESI):519.0[M+1]。
1 H NMR(500MHz,CDCl 3 )δ9.02-9.00(m,1H),8.78-8.74(m,1H),7.97-7.93(m,1H),7.42-7.39(m,1H),7.26-7.17(m,1H),6.93-6.89(m,1H),6.85-6.80(m,2H),4.97-4.94(m,3H),4.91-4.87(m,2H),4.81-4.76(m,5H),3.21-3.19(m,4H),3.12-3.08(m,4H),2.28(s,3H)。
Biological evaluation
The present disclosure is explained in further detail below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.
Test example 1: inhibition of the activation pathway of human TLR7 by compounds of the present disclosure
1. Experimental material and instrument
1.HEK-Blue TM hTLR7 cells (Invivogen)
2. Raximote (R848/Resiquimod, invivogen)
3. Alkaline phosphatase Detection Medium (Quanti-Blue Detection, invivogen)
4. Blasticidin (Blastidin, invivogen)
5. Bleomycin (Zeocin, invivogen)
6. Neomycin (Normocin, invivogen)
DMEM HIGH sugar Medium (DMEM/HIGH Glucose, GE Healthcare)
8. Fetal bovine serum (FBS, gibco)
9. Phosphate buffer (Shanghai Yuan Pe biotechnology Co., ltd.)
10. Sterile pure water (Shanghai Hengrui homemade)
11.15ml centrifuge tube (Corning)
12.96 hole dispensing plate (Corning)
13.96 well flat bottom cell culture plate (Corning)
14. Constant temperature cell incubator (Thermo scientific)
15. Incubator (Shanghai Yiheng scientific instrument limited company)
PHERAstar FS enzyme label instrument (BMG Labtech)
2. Experimental procedure
HEK-Blue purchased from Invivogen TM hTLR7 cells obtained by co-transfection of a human Toll-like receptor 7 (TLR 7) gene and a secreted alkaline phosphatase reporter gene (SEAP) under the control of an IFN-. Beta.minimal promoter comprising 5 NF-kB and AP-1 binding sites into HEK293 cells, wherein upon activation of TLR7 with an agonist, SEAP secretion is induced by downstream NF-kB and AP-1, and upon addition of an antagonistic compound, the pathway is inhibited and SEAP secretion is reduced, and the activity of the compound on the TLR7 pathway is assessed by measuring OD620 via the SEAP substrate.
20mM test compound in 100% DMSO was serially diluted to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256. Mu.M in 100% DMSO, and blank wells were 100% DMSO and 20-fold diluted in DMEM high-glucose medium (complete medium, supra) containing 10% inactivated FBS. R848 was diluted to 10 μm with sterile water. 10. Mu.M 848 diluted with 20. Mu.L/well sterile water was added to 96 well cell culture plates, and the above compound diluted in complete medium and 100% DMSO were added to wells containing R848 at 20. Mu.L per well; negative control wells were added with 20 μl of sterile water and 20 μl of 100% dmso diluted in complete medium.
HEK-Blue TM hTLR7 cells were cultured in DMEM high-glucose medium containing 10% inactivated FBS, 100. Mu.g/mL neomycin, 10. Mu.g/mL blasticidin, and 100. Mu.g/mL bleomycin. Taking the materials which grow well and grow to 70 to 80 percent of fineRemoving cell, removing growth medium, adding 5-10mL of PBS preheated at 37deg.C for washing cell once, adding 2-5mL of PBS preheated, culturing at 37deg.C for 1-2 min, removing cell by pipetting, transferring cell to a 15mL centrifuge tube, counting cell, and regulating cell density to 4.8X10 with complete medium 5 /mL. After 160. Mu.L of the cell suspension was added to the 96-well cell culture plate to adjust the density, the final cell count per well was 76500/well, the final concentration of R848 was 1. Mu.M, and the final concentrations of the test compounds were 10000, 2000, 400, 80, 16, 3.2, 0.64 and 0.128nM, respectively. The cells were placed at 37℃in 5% CO 2 Culturing in incubator for 20 hr, collecting 20 μl of supernatant, adding 180 μl of prepared Quanti-Blue, incubating at 37deg.C in incubator for 120 min under dark condition, and reading OD620 absorbance by enzyme-labeling instrument. The inhibition was calculated using the following formula: inhibition ratio = {1- (OD test compound-OD negative control well)/(OD blank well-OD negative control well) } ×100%, an inhibition curve was drawn by Graphpad Prism software according to each concentration of the compound and the corresponding inhibition ratio, and the concentration of the compound when the inhibition ratio reached 50%, i.e., IC, was calculated 50 The values are shown in Table 1.
Table 1 IC of compounds of the present disclosure as measured by the TLR7 pathway in humans 50 Value of
| Examples numbering | IC 50 (nM) |
| 1 | 42.65 |
| 2 | 17.21 |
Conclusion: the compounds of the present disclosure have inhibitory effects on the TLR7 pathway.
Test example 2: inhibition of the human TLR8 activation pathway by compounds of the present disclosure
1. Experimental material and instrument
1.HEK-Blue TM hTLR8 cells (Invivogen)
2. Raximote (R848/Resiquimod, invivogen)
3. Alkaline phosphatase Detection Medium (Quanti-Blue Detection, invivogen)
4. Blasticidin (Blastidin, invivogen)
5. Bleomycin (Zeocin, invivogen)
6. Neomycin (Normocin, invivogen)
DMEM HIGH sugar Medium (DMEM/HIGH Glucose, GE Healthcare)
8. Fetal bovine serum (FBS, gibco)
9. Phosphate buffer (Shanghai Yuan Pe biotechnology Co., ltd.)
10. Sterile pure water (Shanghai Hengrui homemade)
11.15ml centrifuge tube (Corning)
12.96 hole dispensing plate (Corning)
13.96 well flat bottom cell culture plate (Corning)
14. Constant temperature cell incubator (Thermo scientific)
15. Incubator (Shanghai Yiheng scientific instrument limited company)
PHERAstar FS enzyme label instrument (BMG Labtech)
2. Experimental procedure
HEK-Blue purchased from Invivogen TM hTLR8 cells obtained by co-transfection of a human Toll-like receptor 8 (TLR 8) gene and a secreted alkaline phosphatase reporter gene (SEAP) under the control of an IFN- β minimal promoter comprising 5 NF-kB and AP-1 binding sites into HEK293 cells, wherein upon activation of TLR8 with an agonist, SEAP secretion is induced by downstream NF-kB and AP-1, and upon addition of an antagonistic compound, the pathway is inhibited and SEAP secretion is reduced, and the activity of the compound on the TLR8 pathway is assessed by measuring OD620 via the SEAP substrate.
20mM test compound in 100% DMSO was serially diluted to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256. Mu.M in 100% DMSO, and blank wells were 100% DMSO and 20-fold diluted in DMEM high-glucose medium (complete medium, supra) containing 10% inactivated FBS. R848 was diluted to 60 μm with sterile water. mu.L/well of 60. Mu. M R848 diluted with sterile water was added to 96-well cell culture plates, and the above compound diluted in complete medium and 100% DMSO were added to wells containing R848 at 20. Mu.L/well. Negative control wells were added with 20 μl of sterile water and 20 μl of 100% dmso diluted in complete medium.
HEK-Blue TM hTLR8 cells were cultured in DMEM high-glucose medium containing 10% inactivated FBS, 100. Mu.g/mL neomycin, 10. Mu.g/mL blasticidin, and 100. Mu.g/mL bleomycin. Taking cells which grow well and grow to 70% -80%, discarding the growth medium, adding 5-10mL of PBS preheated at 37 ℃ for washing the cells once, adding 2-5mL of PBS preheated, placing the cells at 37 ℃ for culturing for 1-2 minutes, blowing off the cells by a liquid transfer device, transferring the cells to a 15mL centrifuge tube, counting the cells, and regulating the cell density to 4.8X10 with the complete medium 5 /mL. After 160. Mu.L of the cell suspension was added to the 96-well cell culture plate to adjust the density, the final cell count per well was 76500/well, the final concentration of R848 was 6. Mu.M, and the final concentrations of the test compounds were 10000, 2000, 400, 80, 16, 3.2, 0.64 and 0.128nM, respectively. The cells were placed at 37℃in 5% CO 2 Culturing in incubator for 20 hr, collecting 20 μl of supernatant, adding 180 μl of prepared Quanti-Blue, incubating at 37deg.C in incubator for 120 min under dark condition, and reading OD620 absorbance by ELISA. The inhibition was calculated using the following formula: inhibition ratio = {1- (OD test compound-OD negative control well)/(OD blank well-OD negative control well) } ×100%, an inhibition curve was drawn by Graphpad Prism software according to each concentration of the compound and the corresponding inhibition ratio, and the concentration of the compound when the inhibition ratio reached 50%, i.e., IC, was calculated 50 The values are shown in Table 2.
Table 2 IC of compounds of the present disclosure as measured by the TLR8 pathway in humans 50 Value of
| Examples numbering | IC 50 (nM) |
| 1 | 42.36 |
| 2 | 45.37 |
Conclusion: the compounds of the present disclosure have inhibitory effects on the TLR8 pathway.
Test example 3: inhibition of the activation pathway of human TLR9 by compounds of the present disclosure
1. Experimental material and instrument
1.HEK-Blue TM hTLR9 cells (Invivogen)
2.CpG ODN2006(Invivogen)
3. Alkaline phosphatase Detection Medium (Quanti-Blue Detection, invivogen)
4. Blasticidin (Blastidin, invivogen)
5. Bleomycin (Zeocin, invivogen)
6. Neomycin (Normocin, invivogen)
DMEM HIGH sugar Medium (DMEM/HIGH Glucose, GE Healthcare)
8. Fetal bovine serum (FBS, gibco)
9. Phosphate buffer (Shanghai Yuan Pe biotechnology Co., ltd.)
10. Sterile pure water (Shanghai Hengrui homemade)
11.15ml centrifuge tube (Corning)
12.96 hole dispensing plate (Corning)
13.96 well flat bottom cell culture plate (Corning)
14. Constant temperature cell incubator (Thermo scientific)
15. Incubator (Shanghai Yiheng scientific instrument limited company)
PHERAstar FS enzyme label instrument (BMG Labtech)
2. Experimental procedure
HEK-Blue purchased from Invivogen TM hTLR9 cells obtained by co-transfection of a human Toll-like receptor 9 (TLR 9) gene and a secreted alkaline phosphatase reporter gene (SEAP) under the control of an IFN-. Beta.minimal promoter comprising 5 NF-kB and AP-1 binding sites into HEK293 cells, wherein upon activation of TLR9 with an agonist, SEAP secretion is induced by downstream NF-kB and AP-1, and upon addition of an antagonistic compound, the pathway is inhibited and SEAP secretion is reduced, and the activity of the compound on the TLR9 pathway is assessed by measuring OD620 via the SEAP substrate.
20mM test compound in 100% DMSO was serially diluted to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256. Mu.M in 100% DMSO, and blank wells were 100% DMSO and 20-fold diluted in DMEM high-glucose medium (complete medium, supra) containing 10% inactivated FBS. ODN2006 was diluted to 10 μm with sterile water. To 96-well cell culture plates, 10. Mu.M ODN2006 diluted with 20. Mu.L/well sterile water was added, and the above-described compound diluted in complete medium and 100% DMSO were added to wells containing ODN2006 at 20. Mu.L per well. Negative control wells were added with 20 μl of sterile water and 20 μl of 100% dmso diluted in complete medium.
HEK-Blue TM hTLR9 cells were cultured in DMEM/high-sugar medium containing 10% FBS, 100. Mu.g/mL neomycin, 10. Mu.g/mL blasticidin, and 100. Mu.g/mL bleomycin. Taking cells which grow well and grow to 70% -80%, discarding the growth medium, adding 5-10mL of PBS preheated at 37 ℃ for washing the cells once, adding 2-5mL of PBS preheated, placing the cells at 37 ℃ for culturing for 1-2 minutes, blowing off the cells by a liquid transfer device, transferring the cells to a 15mL centrifuge tube, counting the cells, and regulating the cell density to 4.8X10 with the complete medium 5 /mL. After 160. Mu.L of the cell suspension was added to the 96-well cell culture plate to adjust the density, the final cell number per well was 76500/well, the final ODN2006 concentration was 1. Mu.M, and the final test compound concentrations were 10000, 2000, 400, 80, 16, 3.2, 0.64 and 0.128nM, respectively. The cells were placed at 37℃in 5% CO 2 Culturing in incubator for 20 hr, collecting 20 μl of supernatant, and adding 180 μlAfter incubation of good Quanti-Blue in a 37℃incubator for 15 minutes in the dark, the absorbance of OD620 was read by an microplate reader. The inhibition was calculated using the following formula: inhibition ratio = {1- (OD test compound-OD negative control well)/(OD blank well-OD negative control well) } ×100%, an inhibition curve was drawn by Graphpad Prism software according to each concentration of the compound and the corresponding inhibition ratio, and the concentration of the compound when the inhibition ratio reached 50%, i.e., IC, was calculated 50 The values are shown in Table 3.
Table 3 IC of compounds of the present disclosure as measured by the TLR9 pathway in humans 50 Value of
| Examples numbering | IC 50 (nM) |
| 1 | 486.66 |
| 2 | 552.81 |
Conclusion: the compounds of the present disclosure have inhibitory effects on the TLR9 pathway.
Claims (23)
1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
ring A is
Wherein each R 1 And R is 2 Identical or different and are each independently selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, cyano, amino and hydroxy;
L 1 is CH 2 ；
L 2 Is a bond or C (O);
each R is 3 Identical or different and are each independently selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 A haloalkyl group;
R 4 selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 A haloalkyl group;
Ring B is a 5 to 6 membered heteroaryl or a 3 to 12 membered heterocyclyl containing at least one nitrogen atom;
each R is 5 Identical or different and are each independently selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, halogen, cyano and 3 to 12 membered heterocyclyl; wherein said 3-to 12-membered heterocyclic group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 One or more substituents in the hydroxyalkyl group are substituted;
t is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3, 4, 5 or 6;
p is 0, 1, 2 or 3; and is also provided with
q is 0, 1, 2 or 3.
2. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, which is a compound of formula (II):
wherein:
ring B, L 1 、L 2 、R 1 To R 5 Q, n andt is as defined in claim 1.
3. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, which is a compound of formula (III):
wherein:
ring C is a 3 to 12 membered heterocyclic group containing at least one nitrogen atom;
R 0 selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 A hydroxyalkyl group;
n is 1, 2, 3, 4, 5 or 6;
ring B, L 1 、L 2 、R 1 To R 5 Q and t are as defined in claim 1.
4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2, wherein R 1 Is cyano.
5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2, wherein R 2 Is a hydrogen atom.
6. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein ring B is pyridinyl or isoindolinyl.
7. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2, wherein R 3 Is a hydrogen atom.
8. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2, wherein R 4 Is C 1-6 An alkyl group.
9. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2, wherein R 5 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and 3 to 12 membered heterocyclyl.
10. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2, wherein R 5 Is a hydrogen atom or a 3-to 12-membered heterocyclic group containing at least one nitrogen atom.
11. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2, wherein R 5 Is a hydrogen atom or a piperazinyl group.
12. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the following compounds:
13. a compound of formula (IIIa), or a pharmaceutically acceptable salt thereof:
wherein:
R W is an amino protecting group;
ring B, ring C, L 1 、L 2 、R 1 To R 5 Q, n and t are as defined in claim 3.
14. The compound of formula (IIIa) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R W Is tert-butyloxycarbonyl.
15. The compound of formula (IIIa) according to claim 13 or 14, or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:
16. a process for preparing a compound of formula (III) according to claim 3, or a pharmaceutically acceptable salt thereof, which comprises:
deprotecting a compound of formula (IIIa) or a pharmaceutically acceptable salt thereof w Obtaining R 0 A compound of the general formula (III) which is a hydrogen atom or a pharmaceutically acceptable salt thereof,
wherein:
R W is an amino protecting group;
ring B, ring C, L 1 、L 2 、R 1 To R 5 Q, n and t are as defined in claim 3.
17. The method of claim 16, wherein R W Is tert-butyloxycarbonyl.
18. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
19. Use of a compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the manufacture of a medicament for inhibiting TLR7, TLR8 or TLR 9.
20. Use of a compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the manufacture of a medicament for inhibiting TLR7 and TLR8, or for inhibiting TLR7 and TLR 9.
21. Use of a compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the manufacture of a medicament for inhibiting TLR7, TLR8 and TLR 9.
22. Use of a compound of general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 18 for the manufacture of a medicament for the treatment and/or prophylaxis of inflammatory or autoimmune diseases.
23. The use according to claim 22, wherein the inflammatory or autoimmune disease is selected from Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, multiple Sclerosis (MS) and sjogren's syndrome.
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