CN118103372A - Heterocyclic compound capable of inhibiting IL-17A and application thereof - Google Patents

Heterocyclic compound capable of inhibiting IL-17A and application thereof Download PDF

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CN118103372A
CN118103372A CN202280067558.4A CN202280067558A CN118103372A CN 118103372 A CN118103372 A CN 118103372A CN 202280067558 A CN202280067558 A CN 202280067558A CN 118103372 A CN118103372 A CN 118103372A
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alkyl
halogen
alkoxy
cycloalkyl
pharmaceutically acceptable
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李瑶
石宗军
张国彪
王勇利
余彦
张晨
严庞科
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Tibet Haisike Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

There is provided a nitrogen-containing heterocyclic compound represented by formula (I), or a stereoisomer, solvate, pharmaceutically acceptable salt, co-crystal or pharmaceutical composition thereof, and use thereof in preparing a medicament for treating/preventing IL-17A mediated diseases, wherein each group is as defined in the specification.

Description

Heterocyclic compound capable of inhibiting IL-17A and application thereof Technical Field
The present invention relates to an IL-17A inhibitor and its use in the preparation of a medicament for the treatment of psoriasis, arthritis and multiple sclerosis.
Background
Immune function is critical for maintaining homeostasis and for effective response to disease, and aberrant immune responses are well-established contributors to the pathophysiology of autoimmune disease. In certain disease states, some key pathways leading to these aberrant autoimmune responses have been found to be effective methods of therapeutic intervention. A recent example is the development of Interleukin (IL) -17 inhibitors. IL-17A is a well-recognized pro-inflammatory cytokine that plays a key role in chronic inflammation and is a major driver of tissue damage. IL-17A induces normal immune and inflammatory responses to pathogens, but can also contribute to chronic autoimmune diseases including psoriasis, spondyloarthritis, rheumatoid arthritis, and multiple sclerosis.
The IL-17 family consists of six cytokines (IL-17A through IL-17F). IL-17 receptor (IL-17R) refers to heterodimers formed by IL-17RA and IL-17RC subunits. IL-17A is a major pathological cytokine secreted by Th17 cells, which can signal through IL-17R as either homodimers or heterodimers (Isono, F. Et al Inhibiting RORgt/Th17axis for autoimmune disorders, drug Discovery Today (2014) 19 (8) volumes 1205-1211). In the skin and joints, IL-17A acts on cellular targets, including keratinocytes, endothelial cells, fibroblasts, osteoclasts, chondrocytes, and osteoblasts to stimulate the production of various antimicrobial peptides, chemokines, and pro-inflammatory and proliferative cytokines, which in turn promote tissue inflammation and bone remodeling. The critical importance of the IL-23/IL-17A axis for psoriasis pathogenesis has led to a number of novel biotherapeutic approaches targeting these cytokines. These biological agents significantly improve skin and joint symptoms in patients with moderate to severe psoriasis and psoriatic arthritis.
There is currently no effective oral administration treatment for moderate to severe psoriasis. Small molecule IL-17A inhibitors may provide efficacy comparable to anti-IL-17A antibodies for psoriasis and/or other IL-17A dependent diseases, such as psoriatic arthritis. While inhibiting IL-17A may increase susceptibility to opportunistic infections in certain circumstances, orally available small molecule inhibitors with relatively short half-lives may provide improved agents for controlling such risks. Oral agents may enable a patient to stop taking the drug and quickly clear the inhibitor from the body, thereby enabling a faster recovery of the ability to respond to the infection. Furthermore, anti-drug antibodies against anti-IL-17A antibodies may be present in some patients and may decrease the efficacy of antibodies against IL-17A over time. This inactivation pathway does not work with small molecule IL-17A inhibitors.
Thus, there remains a need for small molecule inhibitors of IL-17A to provide improved and/or orally available treatments for IL-17 mediated diseases. The compounds of the present invention are potent modulators of human IL-17 activity and are therefore useful in the treatment and/or prevention of a variety of human diseases, including inflammatory and autoimmune disorders, and in the treatment of psoriasis, rheumatoid arthritis, multiple sclerosis, and the like.
Disclosure of Invention
The invention provides a compound of formula (I), formula (II) or formula (III), and stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, which has the excellent effects of good activity, excellent physicochemical properties, convenience in preparation, high bioavailability and low toxic and side effects.
The compound of formula (I), formula (II) or formula (III), stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof,
Wherein X is O, S or NR, R is hydrogen, C 1-4 alkyl, CN, NO 2; in some embodiments, X is O;
Y is NR', O or S; in some embodiments, Y is NH;
R' is H, C 1-4 alkyl, or C 3-6 cycloalkyl, said alkyl and cycloalkyl being optionally substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl, C 1-4 alkoxy, CN, NH 2, OH; in some embodiments, R' is H;
R 1 is D, H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, NH 2 or CN, said alkyl, alkoxy, alkenyl and alkynyl being optionally further substituted with 1 to 3 groups selected from deuterium, halogen, C 1-4 alkyl, CN, NH 2, OH; in some embodiments, R 1 is D, H, halogen, or C 1-4 alkyl, optionally further substituted with 1-3 groups selected from deuterium, halogen, CN, NH 2, and OH; in some embodiments, R 1 is D, H, halogen, or C 1-4 alkyl, optionally further substituted with 1-3 groups selected from deuterium, F, cl, br, I; in some embodiments, R 1 is D, H, or C 1-2 alkyl, optionally further substituted with 1-3 groups selected from deuterium, F, cl, br, I; the C 1-4 alkyl group comprises methyl, ethyl, propyl, isopropyl, butyl, isobutyl and n-butyl; the C 1-4 alkoxy group comprises methoxy, ethoxy, propoxy and isopropoxy; the C 2-4 alkenyl group comprises ethenyl, propenyl, allyl, 1-butenyl and 2-butenyl; the C 2-4 alkynyl group comprises ethynyl, propynyl, propargyl, 1-butynyl and 2-butynyl;
R 2 is C 7-9 monocycloalkyl, C 6-9 cyclocycloalkyl, C 6-9 bridged cyclocycloalkyl or C 6-9 spirocycloalkyl, said monocycloalkyl, bridged cyclocycloalkyl, and spirocycloalkyl optionally being further substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl, C 1-4 alkoxy, CN, NH 2, OH; in some embodiments, R 2 is C 7-8 monocycloalkyl, C 6- 8 monocycloalkyl, or C 7-8 bridged cycloalkyl, optionally further substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl, C 1-4 alkoxy; in some embodiments, R 2 is Or alternativelyOptionally further substituted with 1 to 3 groups selected from D, F, cl, br, I, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, methoxy, ethoxy; in some embodiments, R 2 is selected from one of the following structures:
R 3 is C 1-4 alkyl, C 3-6 cycloalkyl, or C 4-7 heterocycloalkyl containing 1 to 3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl and heterocycloalkyl optionally being further substituted with 1 to 3 groups selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkyl, deuterated C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 3-6 cycloalkyl, CN, NH 2、-NHC 1-4 alkyl, -N (C 1-4 alkyl) 2, OH; in some embodiments, R 3 is C 1-4 alkyl or C 4-7 heterocycloalkyl containing 1 to 3 heteroatoms selected from N, S, O, said alkyl and heterocycloalkyl optionally being further substituted with 1 to 3 groups selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkyl, deuterated C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 3-6 cycloalkyl and-N (C 1- 4 alkyl) 2; the C 1-4 alkyl group includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, optionally substituted with D, F, cl, br, I, D, CN, methoxy, deuterated methoxy, ethoxy, deuterated ethoxy; the C 3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted with D, F, cl, br, I, D, CN; the C 4-7 heterocycloalkyl group includes an azetidine, oxetane, piperidine ring, piperazine ring, pyrrole ring, and, The C 1-4 alkoxy group includes methoxy, ethoxy, and the like.
R 4 is D, H, halogen, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said alkyl, alkoxy and cycloalkyl optionally being further substituted with 1 to 3 groups selected from halogen, D, C 1-4 alkyl, CN, NH 2, OH; in some embodiments, R 4 is D, H, halo, C 1-4 alkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl, said alkyl, alkoxy, and cycloalkyl optionally being further substituted with 1-3 groups selected from halo, D, C 1-4 alkyl; in some embodiments, R 4 is D, H, halogen, C 1-4 alkyl, halogen C 1-4 alkyl, or C 3-6 cycloalkyl; the C 1-4 alkyl group comprises methyl, ethyl, propyl, isopropyl, butyl, isobutyl and n-butyl; the C 1-4 alkoxy group comprises methoxy, ethoxy, propoxy and isopropoxy;
n is 1,2, or 3; in some embodiments, n is 1 or 2; in some embodiments, n is 1;
ring a is a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, S, O; in some embodiments, ring a is selected from one of the following structures, with any ring atom on the ring as a connecting site, where the valence allows;
in some embodiments of the present invention, in some embodiments, Selected from one of the following structures:
Ring B is a 9-10 membered fused heteroaryl ring containing 1-4 heteroatoms selected from N, S, O, optionally substituted with 1-3 groups selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, CN, NH 2 and OH, with any ring atom on the ring as a connecting site, where the valence of the bond allows; in some embodiments, ring B is In some embodiments, ring B is
As a more specific first embodiment of the present invention, there is provided a compound represented by the formula (I), a stereoisomer, a solvate, a metabolite, a pharmaceutically acceptable salt, a co-crystal or a prodrug thereof,
Wherein X is O, S or NR, R is hydrogen, C 1-4 alkyl, CN, NO 2;
y is NR', O or S;
R' is H, C 1-4 alkyl, or C 3-6 cycloalkyl, said alkyl and cycloalkyl being optionally substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl, C 1-4 alkoxy, CN, NH 2, OH;
R 1 is D, H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, NH 2 or CN, said alkyl, alkoxy, alkenyl and alkynyl being optionally further substituted with 1 to 3 groups selected from deuterium, halogen, C 1-4 alkyl, CN, NH 2, OH;
R 2 is C 7-9 monocycloalkyl, C 6-9 cyclocycloalkyl, C 6-9 bridged cyclocycloalkyl or C 6-9 spirocycloalkyl, said monocycloalkyl, bridged cyclocycloalkyl, and spirocycloalkyl optionally being further substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl, C 1-4 alkoxy, CN, NH 2, OH;
R 3 is H, D, C 1-4 alkyl, C 3-6 cycloalkyl, or C 4-7 heterocycloalkyl containing 1 to 3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl, and heterocycloalkyl optionally being further substituted with 1 to 3 groups selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkyl, deuterated C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 3-6 cycloalkyl, CN, NH 2、-NHC 1-4 alkyl, -N (C 1-4 alkyl) 2, OH;
R 4 is D, H, halogen, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said alkyl, alkoxy and cycloalkyl optionally being further substituted with 1 to 3 groups selected from halogen, D, C 1-4 alkyl, CN, NH 2, OH;
n is 1, 2 or 3;
Ring a is a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, S, O;
Ring B is a 9-10 membered fused-ring heteroaryl ring containing 1-4 heteroatoms selected from N, S, O, ring B optionally being substituted with 1-3 groups selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, CN, NH 2 and OH.
As a more specific second embodiment of the present invention, the compound of formula (I), a stereoisomer, a solvate, a metabolite, a pharmaceutically acceptable salt, a co-crystal or a prodrug thereof, has the structure of formula (II):
As a more specific third embodiment of the present invention, the compound of formula (II), a stereoisomer, a solvate, a metabolite, a pharmaceutically acceptable salt, a co-crystal or a prodrug thereof,
Wherein R 1 is H, halogen or C 1-4 alkyl, said alkyl optionally being further substituted with 1 to 3 groups selected from deuterium, halogen, CN, NH 2 and OH;
R 2 is C 7-8 monocycloalkyl, C 6-8 cyclocycloalkyl, or C 7-8 bridged cycloalkyl, said monocycloalkyl, cyclocycloalkyl, and bridged cycloalkyl optionally further substituted with 1-3 groups selected from D, halogen, C 1-4 alkyl, C 1-4 alkoxy;
R 3 is H, D, C 1-4 alkyl or C 4-7 heterocycloalkyl containing 1 to 3 heteroatoms selected from N, S, O, said alkyl and heterocycloalkyl optionally being further substituted with 1 to 3 groups selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkyl, deuterated C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 3-6 cycloalkyl and-N (C 1-4 alkyl) 2;
R 4 is D, H, halogen, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said alkyl, alkoxy and cycloalkyl optionally being further substituted with 1 to 3 groups selected from halogen, D, C 1-4 alkyl.
As a more specific fourth embodiment of the present invention, a compound of formula (II), a stereoisomer, a solvate, a metabolite, a pharmaceutically acceptable salt, a co-crystal or a prodrug thereof, has the structure of formula III:
r 3 is H, D, or methoxymethyl.
As a more specific fifth embodiment of the present invention, the compound of formula (III), a stereoisomer, a solvate, a metabolite, a pharmaceutically acceptable salt, a co-crystal or a prodrug thereof,
Wherein R 1 is D, H, halogen or C 1-4 alkyl, said alkyl optionally being further substituted with 1-3 groups selected from deuterium, F, cl, br, I;
R 2 is selected from one of the following structures:
as a more specific sixth embodiment of the present invention, the compound of formula (III), a stereoisomer, a solvate, a metabolite, a pharmaceutically acceptable salt, a co-crystal or a prodrug thereof,
Wherein R 1 is D, H, methyl, ethyl, propyl, isopropyl, tert-butyl 、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CHFCH 2F、-CHFCHF 2、-CHFCF 3、-CF 2CH 2F、-CF 2CHF 2、-CF 2CF 3、-CH 2Cl、-CHCl 2、-CCl 3、-CH 2CH 2Cl、-CH 2CHCl 2、-CH 2CCl 3、-CHFCH 2Cl、-CHFCHCl 2、-CHClCCl 3、-CCl 2CH 2Cl、-CCl 2CHCl 2、-CCl 2CCl 3;
R 2 is selected from one of the following structures:
as a more specific seventh embodiment of the present invention, the compound of formula (I), stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, is selected from one of the following structures:
as a more specific eighth embodiment of the present invention, the compound of formula (I), stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, is selected from one of the following structures:
As a more specific ninth aspect of the present invention, there is provided a pharmaceutical composition comprising the compound according to any one of the first to eighth aspects, a stereoisomer, a solvate, a metabolite, a pharmaceutically acceptable salt, a co-crystal or a prodrug thereof, and a pharmaceutically acceptable carrier and/or an adjuvant. Further, the pharmaceutical composition or pharmaceutical formulation comprises 1-1500mg of a compound of any one of the preceding claims, stereoisomers, deuterates, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, or prodrugs thereof, and pharmaceutically acceptable carriers and/or excipients.
As a more specific tenth aspect of the present invention, there is provided a use of the compound according to any one of the first to eighth aspects, a stereoisomer, a solvate, a metabolite, a pharmaceutically acceptable salt, a co-crystal or a prodrug thereof, or the use of the composition according to the ninth aspect in the preparation of a medicament for the treatment/prevention of IL-17A mediated diseases.
Further, IL-17A mediated diseases include, but are not limited to, psoriasis, arthritis or multiple sclerosis.
The present invention also provides a method for treating a disease in a mammal, said method comprising administering to a subject a therapeutically effective amount of a compound according to any one of the preceding claims, stereoisomers, deuterated, solvates, or pharmaceutically acceptable salts or co-crystals thereof, and a pharmaceutically acceptable carrier and/or excipient, preferably a therapeutically effective amount of 1-1500mg, said disease preferably psoriasis, arthritis or multiple sclerosis.
The present invention also provides a method for treating a disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of the invention, or a stereoisomer, deuteride, solvate, pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition. In some embodiments, the mammal of the present invention comprises a human.
By "effective amount" or "therapeutically effective amount" in the present application is meant that a sufficient amount of a compound of the present disclosure is administered that will alleviate one or more symptoms of the disease or condition being treated to some extent. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is that amount of a composition comprising a compound of the present disclosure that is required to provide clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to 1-1500mg、1-1400mg、1-1300mg、1-1200mg、1-1000mg、1-900mg、1-800mg、1-700mg、1-600mg、1-500mg、1-400mg、1-300mg、1-250mg、1-200mg、1-150mg、1-125mg、1-100mg、1-80mg、1-60mg、1-50mg、1-40mg、1-25mg、1-20mg、5-1500mg、5-1000mg、5-900mg、5-800mg、5-700mg、5-600mg、5-500mg、5-400mg、5-300mg、5-250mg、5-200mg、5-150mg、5-125mg、5-100mg、5-90mg、5-70mg、5-80mg、5-60mg、5-50mg、5-40mg、5-30mg、5-25mg、5-20mg、10- 1500mg、10-1000mg、10-900mg、10-800mg、10-700mg、10-600mg、10-500mg、10-450mg、10-400mg、10-300mg、10-250mg、10-200mg、10-150mg、10-125mg、10-100mg、10-90mg、10-80mg、10-70mg、10-60mg、10-50mg、10-40mg、10-30mg、10-20mg;20-1500mg、20-1000mg、20-900mg、20-800mg、20-700mg、20-600mg、20-500mg、20-400mg、20-350mg、20-300mg、20-250mg、20-200mg、20-150mg、20-125mg、20-100mg、20-90mg、20-80mg、20-70mg、20-60mg、20-50mg、20-40mg、20-30mg;50-1500mg、50-1000mg、50-900mg、50-800mg、50-700mg、50-600mg、50-500mg、50-400mg、50-300mg、50-250mg、50-200mg、50-150mg、50-125mg、50-100mg;100-1500mg、100-1000mg、100-900mg、100-800mg、100-700mg、100-600mg、100-500mg、100-400mg、100-300mg、100-250mg、100-200mg.
The present invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of a compound of the invention or a stereoisomer, deuteride, solvate, pharmaceutically acceptable salt or co-crystal thereof and a carrier and/or excipient. The pharmaceutical composition may be in unit dosage form (the amount of the main drug in a unit dosage form is also referred to as "formulation specification"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500mg、5-1000mg、10-800mg、20-600mg、25-500mg、40-200mg、50-100mg、1mg、1.25mg、2.5mg、5mg、10mg、12.5mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg、500mg、525mg、550mg、575mg、600mg、625mg、650mg、675mg、700mg、725mg、750mg、775mg、800mg、850mg、900mg、950mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg a compound of the invention or a stereoisomer, deuterate, solvate, pharmaceutically acceptable salt, or co-crystal thereof.
A method for treating a disease in a mammal comprising administering to a subject a pharmaceutical compound of the invention, a stereoisomer, deuterated, solvate, or pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier and/or excipient, in a daily dose of 1-1500 mg/day, which may be a single dose or a divided dose, in some embodiments, daily dosages include, but are not limited to, 10-1500 mg/day, 20-1500 mg/day, 25-1500 mg/day, 50-1500 mg/day, 75-1500 mg/day, 100-1500 mg/day, 200-1500 mg/day, 10-1000 mg/day, 20-1000 mg/day, 25-1000 mg/day, 50-1000 mg/day, 75-1000 mg/day, 100-1000 mg/day, 200-1000 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day, in some embodiments daily dosages include, but are not limited to, 1 mg/day, 5 mg/day, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 200 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, 1500 mg/day, 1200 mg/day.
The present invention relates to a kit, which may comprise a single or multiple dose form of a composition, which kit comprises a compound of the present invention or a stereoisomer, deuterate, solvate, pharmaceutically acceptable salt or co-crystal thereof, in an amount which is the same as the amount in the above pharmaceutical composition.
The amounts of the compounds of the invention or stereoisomers, deuterates, solvates, pharmaceutically acceptable salts, co-crystals or prodrugs thereof in the present invention are in each case converted in the form of the free base.
"Formulation specification" refers to the weight of the principal drug contained in each individual, tablet or other unit of formulation.
Synthetic route
The compounds of the invention can be prepared by the person skilled in the art in combination with known organic synthesis techniques starting from commercially available chemicals and/or compounds described in the chemical literature. "commercially available chemicals" are obtained from regular commercial sources and include: taitan technology, an Naiji chemistry, shanghai de moer, chengdu Kelong chemical, shaoguan chemical technology, nanjing medical stone, ming Kangde and Budweiser technologies.
The art references and monographs describe in detail the synthesis of reactants useful in the preparation of the compounds described herein or articles describing the preparation process are provided for reference. These references and monographs include ："Synthetic Organic Chemistry",John Wiley&Sons,Inc.,New York;S.R.Sandler et al.,"Organic Functional Group Preparations,"2nd Ed.,Academic Press,New York,1983;H.O.House,"Modern Synthetic Reactions",2nd Ed.,W.A.Benjamin,Inc.Menlo Park,Calif.1972;T.L.Gilchrist,"Heterocyclic Chemistry",2nd Ed.,John Wiley&Sons,New York,1992;J.March,"Advanced Organic Chemistry：Reactions,Mechanisms and Structure",4th Ed.,Wiley-Interscience,New York,1992;Fuhrhop,J.and Penzlin G."Organic Synthesis：Concepts,Methods,Starting Materials",Second,Revised and Enlarged Edition(1994)John Wiley&Sons ISBN：3-527-29074-5;Hoffman,R.V."Organic Chemistry,An Intermediate Text"(1996)Oxford University Press,ISBN 0-19-509618-5;Larock,R.C."Comprehensive Organic Transformations：A Guide to Functional Group Preparations"2nd Edition(1999)Wiley-VCH,ISBN：0-471-19031-4;March,J."Advanced Organic Chemistry：Reactions,Mechanisms,and Structure"4th Edition(1992)John Wiley&Sons,ISBN：0-471-60180-2;Otera,J.(editor)"Modern Carbonyl Chemistry"(2000)Wiley-VCH,ISBN：3-527-29871-1;Patai,S."Patai's 1992Guide to the Chemistry of Functional Groups"(1992)Interscience ISBN：0-471-93022-9;Solomons,T.W.G."Organic Chemistry"7th Edition(2000) John Wiley&Sons,ISBN：0-471-19095-0;Stowell,J.C.,"Intermediate Organic Chemistry"2nd Edition(1993)Wiley-Interscience,ISBN：0-471-57456-2;"Industrial Organic Chemicals：Starting Materials and Intermediates：An Ullmann's Encyclopedia"(1999)John Wiley&Sons,ISBN：3-527-29645-X,in 8volumes;"Organic Reactions"(1942-2000)John Wiley&Sons,in over 55volumes;and"Chemistry of Functional Groups"John Wiley&Sons.in 73volumes.
Specific and similar reactants can be selectively identified by indexes of known chemicals prepared by american chemical abstracts, which are available in most public and university libraries and online. Chemicals known but not commercially available in catalogs are optionally prepared by custom chemical synthesis plants, many of which provide custom synthesis services (e.g., those listed above). References to the preparation and selection of pharmaceutically acceptable salts of the compounds described herein are P.H.Stahl&C.G.Wermuth"Handbook of Pharmaceutical Salts",Verlag Helvetica Chimica Acta,Zurich,2002.
Terminology
Unless otherwise indicated herein, the terms of the present invention have the following meanings:
The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the present invention each include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12C、 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (deuterium, also known as heavy hydrogen), tritium (T, also known as extra heavy hydrogen), the isotopes of oxygen include 16O、 17 O and 18 O, the isotopes of sulfur include 32S、 33S、 34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
"Halogen" herein refers to F, cl, br, I, or isotopes thereof.
"Halo" or "halogen substituted" means substituted with one or more isotopes selected from F, cl, br, I, or their, the upper limit of the number of halogen substituents being equal to the sum of the number of hydrogens that the substituted group may be substituted, the number of halogen substituents being any integer between 1 and this upper limit, when the number of halogen substituents is greater than 1, it may be the same or different halogen to be substituted. Typically include 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, 1 halogen substitution.
"Deuterium" refers to the isotope deuterium of hydrogen (H), synonymous with "D".
"Deuterated" or "deuterated" refers to the case where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, mercapto, heterocycloalkyl, alkenyl, alkynyl, etc., group is substituted with at least one deuterium atom, the upper limit of the number of deuterations being equal to the sum of the numbers of hydrogens that the substituted group may be substituted with, and the number of deuterations is any integer between 1 and this upper limit, such as 1-20 deuterium atom substitutions, 1-10 deuterium atom substitutions, 1-6 deuterium atom substitutions, 1-3 deuterium atom substitutions, 1-2 deuterium atom substitutions, or 1 deuterium atom substitutions, without special limitation.
"C x-y" group refers to a group containing from x to v carbon atoms, such as "C 1-6 alkyl" refers to an alkyl group containing from 1 to 6 carbon atoms.
"Alkyl" refers to a monovalent straight or branched chain saturated aliphatic hydrocarbon group. Typically an alkyl group of 1 to 20 carbon atoms, or an alkyl group of 1 to 8 carbon atoms, or an alkyl group of 1 to 6 carbon atoms, or an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like, the alkyl groups may be further substituted with substituents.
"Alkylene" refers to divalent straight and branched chain saturated alkyl groups. Examples of alkylene include, but are not limited to, methylene, ethylene, and the like.
"Haloalkyl" refers to the case where one or more hydrogens in the alkyl group are replaced with one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine, or isotopes thereof), the upper limit of the number of halogen substituents being equal to the sum of the number of hydrogens in the alkyl group that may be substituted, and the number of halogen substituents being any integer from 1 to this upper limit, without special limitation. Typically alkyl is substituted with 1-5 halogen, or 1-3 halogen, or 1-2 halogen or 1 halogen; when the number of halogen substituents is greater than 1, the same or different halogens are substituted; specific examples include, but are not limited to, -CF 3、-CH 2Cl、-CH 2CF 3、-CCl 2、CF 3, and the like.
"Alkoxy" or "alkyloxy" refers to an-O-alkyl group. For example-O-C 1-8 alkyl, -O-C 1-6 alkyl-O-C 1-4 alkyl or-O-C 1-2 alkyl. Specific non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy groups, and the like; the alkoxy group may be optionally substituted with a substituent.
"Haloalkoxy" refers to an-O-haloalkyl group. Such as-O-halogenated C 1-8 alkyl, -O-halogenated C 1-6 alkyl, -O-halogenated C 1- 4 alkyl or-O-halogenated C 1-2 alkyl; the upper limit of the number of halogen substituents is equal to the sum of the numbers of hydrogens which the substituted group may be substituted, and the number of halogen substituents is any integer from 1 to the upper limit, preferably 1 to 5 halogen substituents, 1 to 3 halogen substituents, 1 to 2 halogen substituents, 1 halogen substituent, without being particularly limited; when the number of halogen substituents is greater than 1, the same or different halogens are substituted; non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.
"Alkenyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond (c=c), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, still further such as 2 to 4 carbon atoms, examples of which include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-pentadienyl, 1, 4-pentadienyl, and the like; the alkenyl group may be optionally further substituted with a substituent.
"Alkenylene" refers to a straight or branched chain divalent unsaturated hydrocarbon radical containing at least one carbon-carbon double bond (c=c), unless otherwise specified, alkynyl groups containing 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, non-limiting examples of which include ethynylene groups, which may be optionally substituted with substituents.
"Alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond (c≡c), typically containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, still further containing 2 to 4 carbon atoms, examples of which include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl and the like; the alkynyl group may be optionally substituted with a substituent.
"Alkynylene" refers to a straight or branched chain, divalent unsaturated hydrocarbon radical containing a carbon-carbon triple bond (C≡C), typically containing 2 to 6 carbon atoms, further containing 2 to 4 carbon atoms, non-limiting examples include ethynylene, propynylene, butynylene, which may be optionally substituted with substituents.
"Cycloalkyl" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group containing no ring heteroatoms. Cycloalkyl groups may be monocyclic, bicyclic or polycyclic may be fused, spiro, bridged or combinations thereof, and may include one or more aromatic rings therein, but the ring system as a whole is not aromatic, and the attachment sites may be on aromatic or non-aromatic rings. Typically cycloalkyl groups contain 3 to 20 carbon atoms, further 3 to 8 carbon atoms, still further 3 to 6 carbon atoms; when monocyclic cycloalkyl, contains 3 to 15 carbon atoms, alternatively 3 to 10 carbon atoms, alternatively 3 to 8 carbon atoms, alternatively 3 to 6 carbon atoms; in the case of a bicyclic or polycyclic cycloalkyl group, from 5 to 12 carbon atoms, alternatively from 5 to 11 carbon atoms, alternatively from 6 to 10 carbon atoms; non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl, Etc., cycloalkyl groups may be optionally substituted with substituents.
"Cycloalkylene" refers to the divalent group of a cycloalkyl group.
"Aryl" refers to a carbocyclic ring having aromaticity and containing no heteroatoms, and includes monocyclic aryl groups and fused ring aryl groups. Typically having 6 to 13 carbon atoms, further having 6 to 9 carbon atoms, further being phenyl, non-limiting examples include phenyl, naphthyl, anthryl, phenanthryl, aryl groups optionally substituted with substituents.
"Carbocycle" or "carbocyclyl" refers to a saturated, partially unsaturated, or aromatic carbocycle, the meaning of which includes aryl and cycloalkyl. Carbocycles may be monocyclic, bicyclic or polycyclic including bridged, fused and spiro rings and combinations thereof. Carbocycles typically have 3 to 12 carbon atoms, alternatively 3 to 10 carbon atoms, alternatively 3 to 6 carbon atoms. In non-limiting embodiments, the monocyclic carbocycle includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, and the like, and the bicyclic bridge ring includesEtc., a double-ring union includes Etc., a bicyclic spiro ring comprising Etc., the carbocycle may be optionally substituted with a substituent.
"Heterocycloalkyl" means a saturated or partially unsaturated, non-aromatic carbocyclic ring containing 1,2, 3, or 4 heteroatoms selected from N, S, O. The heterocycloalkyl group may be a single ring, a double ring or a multiple ring, the double ring or the multiple ring may be a bridged ring, a parallel ring, a spiro ring or a combination thereof, and one or more aromatic rings or heteroaromatic rings may be included in the double ring or the multiple ring, but the whole ring system is not aromatic, and the connection site may be on an aromatic ring or a non-aromatic ring. Typically heterocycloalkyl is a3 to 20 membered ring, typically a3 to 15 membered ring, or a 3-10 membered ring, or a 3-8 membered ring, or a 3-6 membered ring when a monocyclic heterocycloalkyl; when a bicyclic or polycyclic heterocycloalkyl group, it is typically a 5-12 membered ring, or a 5-11 membered ring, or a 6-9 membered ring. Wherein heteroatom N, S includes its oxidation state. Non-limiting examples of heterocycloalkyl groups include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, pyranyl, azacyclopentenyl, azahexenyl, oxapentenyl, oxahexenyl, and the like, which can be optionally substituted with substituents.
"Heteroaryl" or "heteroaryl", when not specifically stated, refers to aromatic rings containing 1 to 4 heteroatoms selected from N, O or S and their oxidation state, and can be monocyclic, bicyclic or polycyclic, which can be bridged, fused, spiro and combinations thereof; when bicyclic or polycyclic, it may be a heteroaryl to aryl fusion or a heteroaryl to heteroaryl fusion, where either heteroaryl or aryl may be the attachment site. Non-limiting examples include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, purinyl, Etc.; the heteroaryl group may be optionally substituted with a substituent.
"Heterocycle" or "heterocyclyl" refers to a saturated or unsaturated, aromatic or non-aromatic ring containing 1 to 4 heteroatoms selected from N, O or S and their oxidation states, the meaning of which includes heteroaryl and heterocycloalkyl. The heterocycle includes monocyclic heterocycle, bicyclic bridged heterocycle, bicyclic heterocycle, and bicyclic spiro heterocycle, or combinations thereof. Typically a 3 to 12 membered heterocycle or a5 to 12 membered heterocycle, or a5 to 7 membered heterocycle. The heterocyclic group may be attached to a heteroatom or carbon atom, non-limiting examples include epoxy ethyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, piperazinyl, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperdinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, dihydrofuranyl, dihydropyranyl, dithianyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, benzodihydropyranyl, azabicyclo [3.2.1] alkyl, azabicyclo [5.2.0] nonyl, oxa [5.3.1.1] oxa-3-pyrrolidinyl, and adamantyl, Etc., the heterocyclic ring may be optionally substituted with a substituent.
"Heterocyclylene" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic, divalent heterocyclic group. Non-limiting embodiments includeEtc.
"Spiro" refers to a polycyclic group having one carbon atom (referred to as a spiro atom) in common between rings, which may contain 0 or more than 1 double or triple bond, and may contain 0 to 5 heteroatoms selected from N, O, S, P, si and their oxidation states. Typically, the spiro ring is a 6 to 14 membered ring, alternatively a 6 to 12 membered ring, alternatively a 6 to 10 membered ring. Typically, the spiro ring is trispiro-trispiro (representing a trispiro-trispiro), trispiro-tetraspiro-penta, trispiro-hexa, tetraspiro-tetra-spiropenta, tetraspiro-hexa, pentaspiropenta, or pentaspirohexa. Non-limiting examples of spirocyclic rings include
The spiro ring may be optionally substituted with substituents.
"Fused ring" means a polycyclic group having two adjacent ring atoms and one chemical bond shared by the ring and the ring, which may contain one or more double or triple bonds, and the ring may contain from 0 to 5 heteroatoms selected from N, S, O, P, si and their oxidation states. Typically, the fused ring is a5 to 20 membered ring, alternatively a5 to 14 membered ring, alternatively a5 to 12 membered ring, alternatively a5 to 10 membered ring. The parallel rings are usually tri-and tetra-rings (meaning the parallel rings formed by the tri-and tetra-rings, it is possible to use the tri-and tetra-rings as basic rings according to the IUPC naming convention and the tetra-ring as basic rings, and the same shall apply hereinafter), tri-and penta-rings, tri-and hexa-rings, tetra-and tetra-rings, tetra-and penta-rings, tetra-and hexa-rings, penta-and penta-rings, and hexa-rings. Non-limiting examples of the fused ring include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene, and the like,
The fused ring may be optionally substituted with substituents.
"Bridged ring" means that two rings share two non-adjacent ring atoms, which may contain 1 or more double or triple bonds. The bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, P, si and their oxidation states. Typically the ring atoms of the bridged ring are from 5 to 20, alternatively from 5 to 14, alternatively from 5 to 12, alternatively from 5 to 10. Non-limiting examples of bridged rings include adamantane,
"Substituted" or "substituent" when not specifically stated means any substitution at a position allowed by chemical theory, and the number of substituents conforms to the chemical bond rule. Exemplary substituents include, but are not limited to: c 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 heteroalkyl, C 5-12 aryl, 5-to 12-membered heteroaryl, hydroxy, C 1-6 alkoxy, C 5-12 aryloxy, thiol, C 1-6 alkylthio, cyano, halogen, C 1-6 alkylthio carbonyl, C 1-6 alkylcarbamoyl, N-carbamoyl, nitro, silyl, Sulfinyl, sulfonyl, sulfoxide, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, amino, phosphonic acid, -CO 2(C 1-6 alkyl), -OC (=o) (C 1-6 alkyl), -OCO 2(C 1-6 alkyl), -C (=o) NH 2,-C(＝O)N(C 1-6 alkyl) 2,-OC(＝O)NH(C 1-6 alkyl, -NHC (=o) (C 1-6 alkyl), -N (C 1-6 alkyl) C (=o) (C 1-6 alkyl), -NHCO 2(C 1-6 alkyl), -NHC (=o) N (C 1-6 alkyl) 2,-HC(＝O)NH(C 1-6 alkyl, -NHC (=o) NH 2,-NHSO 2(C 1-6 alkyl), -SO 2N(C 1-6 alkyl) 2,-SO 2NH(C 1-6 alkyl, -SO 2NH 2,-SO 2C 1-6 alkyl, and the like.
"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. Such as: "alkyl optionally substituted with F" means that the alkyl may be, but is not necessarily, substituted with F, and is intended to include both cases where the alkyl is substituted with F and cases where the alkyl is not substituted with F.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the invention which retain the biological effectiveness and properties of the free acid or free base obtained by reaction with a non-toxic inorganic or organic base.
"Pharmaceutical composition" means a mixture of one or more compounds described herein, or stereoisomers, solvates, pharmaceutically acceptable salts, or co-crystals thereof, with other ingredients, wherein the other ingredients comprise a physiologically/pharmaceutically acceptable carrier and/or excipient.
"Vector" means: non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc., which do not significantly stimulate the organism and do not eliminate the biological activity and properties of the administered compound, and which alter the manner and distribution of the drug into the body, control the release rate of the drug and deliver the drug to the targeted organ.
"Excipient" means: which are not therapeutic agents per se, act as diluents, adjuvants, binders and/or vehicles for addition to pharmaceutical compositions to improve their handling or storage properties or to allow or facilitate the formation of unit dosage forms of the compound or pharmaceutical composition for administration. As known to those skilled in the art, pharmaceutically acceptable excipients may provide various functions and may be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutically acceptable excipients include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and croscarmellose (e.g., sodium croscarmellose); (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) Polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer' ssolution; (19) ethanol; (20) a pH buffer solution; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances for use in pharmaceutical formulations.
"Stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
The compounds of the invention also include tautomers thereof, for example, when the invention sets forth compounds on the left where the pyrimidine ring is substituted with OH, as well as tautomeric compounds on the right.
"Solvate" refers to a substance formed by a chemical or non-chemical solvent to which a compound of the invention or a salt thereof is non-covalently bound to an intermolecular force. When the solvent is water, it is a hydrate.
"Co-crystals" refers to crystals of Active Pharmaceutical Ingredient (API) and co-crystal former (CCF) that are bound by hydrogen bonds or other non-covalent bonds, wherein the pure states of the API and CCF are both solid at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.
Detailed Description
The following will describe the content of the present invention in detail by way of examples. The experimental procedures were carried out under conventional conditions without specifying the specific conditions in the examples. The examples are presented for better illustration of the present invention but are not to be construed as limiting the present invention to only the examples presented. Those skilled in the art will appreciate that various modifications and adaptations of the embodiments described above are possible and can be made without departing from the scope of the invention.
Detection method
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). NMR shift (. Delta.) is given in units of 10-6 (ppm). NMR was performed using a (Bruker AVANCE III and Bruker Avance 300) magnetonuclear instrument with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD) and an internal standard of Tetramethylsilane (TMS);
MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6mm, 3.5. Mu.M);
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 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm;
column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.
Preparation of the Compounds
Example 1.
N- ((6, 6-difluoro-bicyclo [3.1.0] hex-3-yl) (7- (((S) -2-oxo-4- (trifluoromethyl) imidazolin-1-yl) methyl) imidazo [1,2-b ] pyridazin-2-yl) methyl) -4-methyl-1, 2, 5-oxadiazole-3-carboxamide (Compound 1)
N-((6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide
The first step: ethyl 2- (((benzyloxy) carbonyl) amino) -2- (6, 6-difluorobicyclo [3.1.0] hex-3-yl) acetate (1B)
1A (2.2 g,10.04mmol, synthetic reference WO 2012/154777), dichloromethane (30 ml), triethylamine (3.05 g,30.12 mmol) and benzyloxycarbonyl succinimide (3.75 g,15.06 mmol) were added to the flask, and reacted at room temperature for 2 hours. LCMS detected complete reaction of starting material, diluted with dichloromethane, washed with saturated brine, dried, concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:0 to 3:1) to give the target compound 1B (3.4 g, 95.8%).
LC-MS(ESI)：m/z＝354.1[M+H] +.
And a second step of: ((benzyloxy) carbonyl) amino) -2- (6, 6-difluoro-bicyclo [3.1.0] hex-3-yl) acetic acid (1C)
1B (3.4 g,9.62 mmol), lithium hydroxide monohydrate (1.15 g,48.10 mmol), tetrahydrofuran (40 ml), water (20 ml), were added to the flask, the reaction was carried out at room temperature for 2h, LCMS detects the disappearance of the starting material, the solvent was removed by concentration, pH was adjusted to 4 with 4M dilute hydrochloric acid, dichloromethane extraction, washing, drying, concentration, silica gel column chromatography purification (dichloromethane: methanol=1:0 to 10:1) to give 1C as a white solid (3.0 g, 95.9%).
LC-MS(ESI)：m/z＝324.1[M-H] +.
And a third step of: 4- (((benzyloxy) carbonyl) amino) -4- (6, 6-difluoro-bicyclo [3.1.0] hex-3-yl) -3-oxobutanoic acid tert-butyl ester (1D)
1C (1.0 g,3.07 mmol), 10mL tetrahydrofuran, nitrogen blanket, and N, N' -carbonyldiimidazole (0.55 g,3.38 mmol) were added at 0deg.C and reacted for 2h at 0deg.C. The following reaction was then added dropwise. 50mL of tetrahydrofuran was added to the flask, the flask was cooled to-78℃under nitrogen protection, lithium bis (trimethylsilylamide) (15.4 mL,15.35 mmol) was added, and then tert-butyl acetate (1.78 g,15.35 mmol) in tetrahydrofuran (5 mL)) was added dropwise and reacted at-78℃for 1h. The above reaction was then added dropwise to the reaction, and the reaction was continued at-78℃for 2 hours. Saturated aqueous ammonium chloride solution was added, extraction was performed with ethyl acetate, drying was performed with sodium sulfate, filtration and concentration were performed, and silica gel column chromatography was performed for separation and purification (petroleum ether: ethyl acetate=1:0 to 4:1) to obtain the objective compound 1D (0.88 g, 67.7%).
LC-MS(ESI)：m/z＝422.2[M-H] +.
Fourth step: 4- (((benzyloxy) carbonyl) amino) -2-bromo-4- (6, 6-difluorobicyclo [3.1.0] hex-3-yl) -3-oxobutanoic acid tert-butyl ester (1E)
1D (1.0 g,2.36 mmol), 20ml of methanol, 2, 6-lutidine (15 mg,0.14 mmol) and N-bromosuccinimide (0.42 g,2.36 mmol) were added to the flask, and the mixture was reacted at room temperature for 2.5 hours. 100ml of ethyl acetate was added for dissolution, washed three times with 50ml of saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated, and the crude product was used for the next reaction (1.1 g, 92.8%).
LC-MS(ESI)：m/z＝500.1、502.2[M-H] +.
Fifth step: (3-bromo-1- (6, 6-difluoro-bicyclo [3.1.0] hex-3-yl) -2-oxopropyl) carbamic acid benzyl ester (1F)
1E (1.1 g,2.19 mmol), 20ml toluene, and trifluoroacetic acid (1.2 ml,16.10 mmol) were added to the flask and reacted at 80℃for 2.5h. Concentration and purification by column chromatography on silica gel (petroleum ether: ethyl acetate=1:0 to 10:1) gave the title compound 1F (0.78 g, 86.3%).
LC-MS(ESI)：m/z＝402.0、404.2[M-H] +.
Sixth step: benzyl ((1S) - (6-chloro-7- (((S) -2-oxo-4- (trifluoromethyl) imidazolin-1-yl) methyl) imidazo [1,2-b ] pyridazin-2-yl) (6, 6-difluoro-bicyclo [3.1.0] hex-3-yl) methyl) carbamate (1H)
To a 100mL single-necked flask was added reactant 1F (0.57G, 1.94 mmol), 1G (0.78G, 1.94mmol, synthetic reference WO2020146194A 1) and solvent tetrahydrofuran (20 mL), followed by sodium carbonate (0.82G, 7.76 mmol), and heated to 70℃for 16 hours; concentration and purification by column chromatography on silica gel (dichloromethane/methanol=99/1-85/15) afforded the title compound 1H (0.43 g, 37%).
LC-MS(ESI)：m/z＝599.2[M+H] +.
Seventh step: (4S) -1- ((2- ((1S) -amino (6, 6-difluorobicyclo [3.1.0] hex-3-yl) methyl) imidazo [1,2-b ] pyridazin-7-yl) methyl) -4- (trifluoromethyl) imidazolin-2-one (1I)
To a 100mL single-necked flask, 1H (0.43 g,0.72 mmol) and methanol (10 mL) were added, and Pd/C (0.4 g) was further added to conduct a reaction under hydrogen for 2 hours. Filtration and concentration gave the gray title compound 1I (0.26 g, 77.7%).
LC-MS(ESI)：m/z＝531.2[M+H] +.
Eighth step: n- ((6, 6-difluoro-bicyclo [3.1.0] hex-3-yl) (7- (((S) -2-oxo-4- (trifluoromethyl) imidazolin-1-yl) methyl) imidazo [1,2-b ] pyridazin-2-yl) methyl) -4-methyl-1, 2, 5-oxadiazole-3-carboxamide (Compound 1)
N-((6,6-difluorobicyclo[3.1.0]hexan-3-yl)(7-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide
To a 100mL single vial was added reactant 1I (0.26 g,0.60 mmol), 1J (0.09 g,0.72 mmol) and solvent acetonitrile, followed by N-methylimidazole (0.15 g,1.80 mmol) and N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate (0.2 g,0.72 mmol), and then reacted at room temperature for 2 hours; prepared by HPLC after concentration to give target compound 1 (57 mg, 17.6%)
LC-MS(ESI)：m/z＝541.2[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ9.51(dd,1H),8.38(s,1H),8.24(d,1H),7.86(d,1H),7.68(s,1H),5.16-5.06(m,1H),4.38(q,3H),3.65(t,1H),3.41(q,1H),2.54(t,1H),2.47(s,3H),2.33-2.26(m,1H),2.22-2.07(m,2H),2.03-1.94(m,1H),1.88-1.81(m,1H),1.64-1.45(m,1H).
Example 2
4-Methyl-N- ((octahydropenten-2-yl) (7- (((S) -2-oxo-4- (trifluoromethyl) imidazolin-1-yl) methyl) imidazo [1,2-b ] pyridazin-2-yl) methyl) -1,2, 5-oxadiazole-3-carboxamide (Compound 2)
4-methyl-N-((octahydropentalen-2-yl)(7-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide
The first step: 3a ", 4", 6a "-tetrahydro-1" H-dispiro [ fluorene-9, 5'- [1,3] dioxane-2', 2 "-pentene ] -5" (3 "H) -one (2B)
2A (36.0 g,260.60 mmol) was dissolved in toluene (400 mL), 9-fluorenedimethanol (58.9 g,260.60 mmol) was added, and p-toluenesulfonic acid (4, 5g,26.10 mmol) was heated to reflux for 4h. Filtration, concentration, and purification of the residue by column chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =10:1) gave compound 2B as a yellow oil (32.0 g, yield 35.5%).
LCMS m/z＝347.2[M+1]
And a second step of: 3 ", 3 a", 4 ", 5", 6a "-hexahydro-1" H-dispiro [ fluorene-9, 5'- [1,3] dioxan-2', 2 "-pentene ] (2C)
2B (32.0 g,92.37 mmol) was dissolved in diethylene glycol (100 mL), potassium hydroxide (25.9 g,461.85 mmol) was added, and hydrazine hydrate (52 mL) was reacted at 160℃for 1h. Concentrating to remove water, heating to 210 ℃ and reacting for 2h. Cooled to room temperature, water (100 mL) was added, the combined organic phases were extracted with methyl tert-butyl ether (50 ml×3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =80:1 to 60:1) to give compound 2C as a pale yellow liquid (20.1 g, yield 65.5%).
LCMS m/z＝333.2[M+1]
And a third step of: hexahydropenten-2 (1H) -one (2D)
2C (20.1 g,60.46 mmol) was dissolved in methanol (30 mL), 1, 4-dioxane (30 mL), water (15 mL), and p-toluene sulfonic acid (1.0 g,6.05 mmol) was added and the mixture was then allowed to react at 70 ℃. The solvent was removed by concentration, saturated aqueous sodium chloride (50 mL) was added, extraction with ethyl acetate (50 ml×3) was added, the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =10:1) to give compound 2D as a colorless liquid (2.0 g, yield 26.64%).
Fourth step: 2- ((Boc) amino) -2- (hexahydropentene-2 (1H) -linoleic acid) acetic acid methyl ester (2E)
2D (2.0 g,16.11 mmol) was dissolved in tetramethylguanidine (20 mL), and (+ -) -BOC-A-phosphonoglycine trimethyl ester (9.6 g,32.22 mmol) was added and reacted overnight at room temperature after completion of the addition. Water (50 mL) was added, extracted with ethyl acetate (50 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =5:1) to give compound 2E as a white solid (0.8 g, 16.81% yield).
LCMS m/z＝296.2[M+1]
Fifth step: 2- ((Boc) amino) -2- (octahydropent-2-yl) acetic acid methyl ester (2F)
2E (0.8 g,2.71 mmol) was dissolved in methanol (10 mL), palladium on carbon (0.4 g,50% w/w) was added, hydrogen was replaced three times, and the reaction was carried out overnight at room temperature after the addition was completed. Filtering and concentrating to obtain the compound 2F which is directly used for the next reaction.
LCMS m/z＝298.2[M+1]
Sixth step: 2-amino-2- (octahydropenten-2-yl) acetic acid methyl ester (2G)
2F (2.0 g,6.77 mmol) was dissolved in 4M methanol hydrochloride (10 mL) and reacted overnight at room temperature. Saturated aqueous sodium bicarbonate was added to adjust to PH-8, extracted with dichloromethane (20 ml×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (dichloromethane: methanol (v/v) =10:1) to give compound 2G as a white solid (1.28G, yield 95.84%).
LCMS m/z＝198.1[M+1]
Seventh step: methyl 2- (((benzyloxy) carbonyl) amino) -2- (octahydropenten-2-yl) acetate (2H)
2G (1.28G, 6.49 mmol) was dissolved in dichloromethane (20 mL), benzyloxycarbonyl succinimide (3.23G, 12.98 mmol), triethylamine (1.97G, 19.47 mmol) was added and the reaction was completed at room temperature overnight. Concentrated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =5:1) to give compound 2H as a white solid (2.0 g, yield 92.99%).
LCMS m/z＝332.2[M+1]
Eighth step: 2- (((benzyloxy) carbonyl) amino) -2- (octahydropenten-2-yl) acetic acid (2I)
2H (2.0 g,6.03 mmol) was dissolved in methanol (20 mL), water (5 mL), sodium hydroxide (1.2 g,30.15 mmol) was added, and the reaction was completed at room temperature overnight. The methanol was removed by concentration, 4M hydrochloric acid was added to adjust to pH 3, and the mixture was extracted with 2-methyltetrahydrofuran (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (dichloromethane: methanol (v/v) =20:1) to give compound 2I as a white solid (1.90 g, 99.28%).
LCMS m/z＝316.2[M-1]
Ninth step: 4- (((benzyloxy) carbonyl) amino) -4- (octahydropenten-2-yl) -3-oxobutanoic acid tert-butyl ester (2J)
2I (2.0 g,6.30 mmol) was dissolved in tetrahydrofuran (10 mL), and carbonyldiimidazole (1.0 g,6.30 mmol) was added thereto, and the reaction was completed at room temperature for 2 hours. Tert-butyl acetate (3.7 g,31.5 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to-78℃under nitrogen protection, and lithium bis (trimethylsilylamide) (31.5 mL,31.5 mmol) was added dropwise, reacted at-78℃for 1 hour, the above reaction solution was added dropwise, and reacted at-78℃for 1 hour. Saturated aqueous ammonium chloride (50 mL) was added, extracted with ethyl acetate (25 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =5:1) to give compound 2J as a yellow liquid (1.60 g, 61.62%).
LCMS m/z＝416.2[M+1]
Tenth step: 4- (((benzyloxy) carbonyl) amino) -2-bromo-4- (octahydropenten-2-yl) -3-oxobutanoic acid tert-butyl ester (2K)
Compound 2J (1.60 g,3.85 mmol) was dissolved in methanol (10 mL), N-bromosuccinimide (0.69 g,3.85 mmol), 2, 6-lutidine (33 mg,0.31 mmol) was added, and after the addition was completed, the reaction was carried out at room temperature for 2.5h. Ethyl acetate (10 mL) was added, concentrated to dryness, ethyl acetate (50 mL) was added, washed with saturated aqueous sodium chloride (25 mL. Times.3), and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 2K as a yellow solid (1.60 g, 84.05%) which was used directly in the next reaction.
LCMS m/z＝492.2[M-1]
Eleventh step: (3-bromo-1- (octahydropenten-2-yl) -2-oxopropyl) carbamic acid benzyl ester (2L)
Compound 2K (1.60 g,3.24 mmol) was dissolved in toluene (20 mL), trifluoroacetic acid (2 mL,26.84 mmol) was added, and after the addition was completed, the reaction was carried out at 80℃for 2h. Concentrated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =5:1) to give compound 2L as a white solid (0.45 g, 35.22%).
LCMS m/z＝394.1[M+1]
Twelfth step: ((6-chloro-7- (((S) -2-oxo-4- (trifluoromethyl) imidazolin-1-yl) methyl) imidazo [1,2-b ] pyridazin-2-yl) (octahydropenten-2-yl) methyl) carbamic acid benzyl ester (2M)
Compound 2L (0.45G, 1.14 mmol) was dissolved in tetrahydrofuran (10 mL), 1G (0.34G, 1.14 mmol) was added, sodium carbonate (0.48G, 4.56 mmol) was added, and the mixture was heated to 65℃under nitrogen and reacted for 6 hours. Cooled to room temperature, filtered, concentrated to dryness and the residue purified by column chromatography on silica gel (dichloromethane: methanol (v/v) =20:1) to give compound 2M as a yellow solid (0.43 g, 63.82%).
LCMS m/z＝591.2[M+1]
Thirteenth step: ((6-chloro-7- (((S) -2-oxo-4- (trifluoromethyl) imidazolin-1-yl) methyl) imidazo [1,2-b ] pyridazin-2-yl) (octahydropenten-2-yl) methyl) carbamic acid benzyl ester (2N)
Compound 2M (0.43 g,1.14 mmol) was dissolved in methanol (10 mL), 50% palladium on carbon (0.22 g) was added, and after the addition was completed, hydrogen was replaced three times and reacted overnight at room temperature. Filtration, concentration to dryness, and purification of the residue by silica gel column chromatography (dichloromethane: methanol (v/v) =10:1) gave compound 2N as a white solid (0.21 g, 68.10%).
LCMS m/z＝423.2[M+1]
Fourteenth step: 4-methyl-N- ((octahydropenten-2-yl) (7- (((S) -2-oxo-4- (trifluoromethyl) imidazolin-1-yl) methyl) imidazo [1,2-b ] pyridazin-2-yl) methyl) -1,2, 5-oxadiazole-3-carboxamide (Compound 2)
Compound 2N (0.21 g,0.50 mmol) was dissolved in acetonitrile (10 mL), and N-methylimidazole (0.10 g,1.25 mmol), 4-methyl-1, 2, 5-oxadiazole-3-carboxylic acid (0.11 g,0.75 mmol), and N, N, N ', N' -tetramethyl chloroformyl hexafiuorophosphate (0.21 g,0.75 mmol) were added thereto, and after 1 hour at room temperature, the solvent was removed by concentration, concentrated to dryness, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) =10:1) to give compound 2 (40 mg, yield 14.58%).
Compound 2 (40 mg) was subjected to chiral resolution to give 4 isomers, designated as Compound 2-1, compound 2-2 Compound 2-3 and Compound 2-4, respectively, one of which was designated Compound 2-4 (9.1 mg, retention time: 1.749min, chiral HPLC: 100%).
1H NMR(400MHz,CDCl 3)δ8.28(s,1H),7.90(s,1H),7.77(s,1H),7.69(d,1H),5.24(m,2H),4.47(m,2H),4.17(s,1H),3.65(t,1H),3.47(dd,1H),2.59(s,3H),2.44(d,3H),2.26-2.09(m,1H),1.79-1.72(m,2H),1.52(s,3H),1.43-1.22(m,2H),1.07(m,1H),0.92(m,1H)..
The specific splitting method is as follows:
instrument: waters 150MGM
Chromatographic column: DAICEL CHIRALCEL IG (250 mm 30mm 10 μm)
Mobile phase: afor CO2and B for EtOH+CAN
Flow rate: 120 ml/min, backpressure: 100bar, column temperature: 35 ℃, wavelength: 220nm, cycle time: about 10.3min
Sample pretreatment: the compound was dissolved in about 100ml acetonitrile and injected: 2 ml each time.
Post-treatment: after separation, the fractions were dried by rotary evaporator at a bath temperature of 30℃to give the desired isomer
Example 3
N- ((S) -cycloheptyl (7- ((S) -2-methoxy-1- ((S) -2-oxo-4- (trifluoromethyl) imidazolin-1-yl) ethyl) imidazo [1,2-b ] pyridazin-2-yl) methyl) -4-methyl-1, 2, 5-oxadiazole-3-carboxamide (Compound 3)
N-((S)-cycloheptyl(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide
The first step: (S) - (1-cycloheptyl-3- (dimethyl (oxo) -16-sulfinyl) -2-oxopropyl) carbamic acid tert-butyl ester (3B)
To the flask were added 3A (2.00 g,7.37 mmol) and tetrahydrofuran (20 ml), under nitrogen, N' -carbonyldiimidazole (2.39 g,14.74 mmol) was added at 0℃and reacted for 2 hours at 0 ℃. In another flask were added trimethylsulfoxide iodide (4.87 g,22.11 mmol) and tetrahydrofuran (30 ml), followed by potassium tert-butoxide (2.48 g,22.11 mmol) and then reacted at 70℃for 2 hours. Cooled to room temperature. The above reaction solution was then added dropwise to the reaction, and reacted at room temperature for 2 hours. Saturated aqueous ammonium chloride (20 ml) was added, extracted with ethyl acetate (20 ml x 3), washed, dried, filtered and concentrated, and the target compound 3B (2.00 g, yield 78.54%) was obtained by column chromatography separation and purification (ethyl acetate: methanol=20:1).
LCMS m/z＝346.3[M+1] +。
And a second step of: (S) - (3-bromo-1-cycloheptyl-2-oxopropyl) carbamic acid tert-butyl ester (3C)
To a 100mL single-necked flask were added reactant 3B (2.00 g,5.79 mmol) and tetrahydrofuran (20 mL), followed by addition of hydrobromic acid acetic acid solution (1 mL,33% wt) and reaction at 70℃for 16 hours; cooled, 10ml of saturated sodium bicarbonate solution was added, water (20 ml) was added, extraction was performed with ethyl acetate (20 ml x 3), washing, drying, concentration, and column chromatography separation and purification (petroleum ether/ethyl acetate=3:1) gave the objective compound 3C (2.02 g, yield 84.30%).
LCMS m/z＝348.1[M+1] +。
And a third step of: ((S) - (6-chloro-7- ((S) -2-methoxy-1- ((S) -2-oxo-4- (trifluoromethyl) imidazolidin-1-yl) ethyl) imidazo [1,2-b ] pyridazin-2-yl) (cycloheptyl) methyl) carbamic acid tert-butyl ester (3D)
To the flask were added reactant 1G (251 mg,0.74 mmol), 3C (309 mg,0.89 mmol) and dioxane (10 ml), followed by sodium carbonate (240 mg,2.22 mmol) and reacted at 95℃for 16 hours; water, ethyl acetate extraction, washing, drying, concentration, column chromatography purification (petroleum ether/ethyl acetate=1:5) gave the title compound 3D (440 mg, 44.74% yield).
LCMS m/z＝589.3[M+1] +。
Fourth step: ((S) -cycloheptyl (7- ((S) -2-methoxy-1- ((S) -2-oxo-4- (trifluoromethyl) imidazolin-1-yl) ethyl) imidazo [1,2-b ] pyridazin-2-yl) methyl) carbamic acid tert-butyl ester (3E)
To the flask was added 3D (194 mg,0.33 mmol) and methanol (10 ml), and Pd/C (150 mg) was further added and reacted at room temperature under hydrogen for 1 hour; filtration and concentration gave the target compound 3E (180 mg, yield 81.96%).
LCMS m/z＝555.3[M+1] +。
Fifth step: (S) -1- ((S) -1- (2- ((S) -amino (cycloheptyl) methyl) imidazo [1,2-b ] pyridazin-7-yl) -2-methoxyethyl) -4- (trifluoromethyl) imidazolin-2-one (3F)
To the flask was added reactant 3E (150 mg,0.27 mmol) and methanol (3 mL), followed by hydrochloric acid/methanol (6 mL) and reacted at 30℃for 2 hours; concentration gave the title compound 3F (121 mg).
LCMS m/z＝455.2[M+1] +。
Sixth step: n- ((S) -cycloheptyl (7- ((S) -2-methoxy-1- ((S) -2-oxo-4- (trifluoromethyl) imidazolin-1-yl) ethyl) imidazo [1,2-b ] pyridazin-2-yl) methyl) -4-methyl-1, 2, 5-oxadiazole-3-carboxamide (Compound 3)
To the flask was added reactant 3F (132 mg,0.29 mmol), 4-methyl-1, 2, 5-oxadiazole-3-carboxylic acid (111 mg,0.87 mmol) and N, N-dimethylformamide (8 ml), followed by N-methylimidazole (120 mg,1.45 mmol) and N, N, N ', N' -tetramethyl chloroformidine hexafluorophosphate (240 mg,0.87 mmol), followed by reaction at room temperature for 1 hour; water (20 ml) was added, extraction was performed with ethyl acetate (20 ml x 3), drying and HPLC preparation purification after concentration gave the title compound 3 (95 mg, yield: 58.03%).
1H NMR(400MHz,DMSO-d 6)δ9.25(d,1H),8.37(s,1H),8.21(s,1H),7.87(s,1H),7.70(s,1H),5.17-5.09(m,2H),4.47(s,1H),3.94-3.76(m,3H),3.46(q,1H),3.33(s,3H),2.46(s,3H),2.27-2.23(m,2H),1.99-1.79(m,1H),1.61-1.17(m,11H).
LCMS m/z＝565.2[M+1] +。
Biological testing
1. IL-17A binding assay
The purpose of this assay is to assess the ability of a compound to bind IL-17A in vitro. The evaluation was performed using the IL-17A/IL-17RA Binding kit (# 64BDIL17PEG; cisbio). To the wells were added 4. Mu.L of Tag1-IL17A working solution, 2. Mu.L of compound solution (concentration 0.0000256. Mu.M-50. Mu.M), 4. Mu.L of Tag2-IL17RA working solution (negative wells added 4. Mu. L PPI Europium Detection Buffer), 10. Mu.L of anti-Tag HTRF detection solutions. After incubating the well plate at 25 ℃ overnight, signal values were detected. The binding capacity of the compounds was assessed using the following formula and IC 50 was fitted using Graphpad.
The calculation formula is as follows:
Ratio final＝Ratio sampie-Ratio background
the compounds of the invention have an IC 50 < 100nM for IL-17A, and the results of some of the examples are shown in Table 1.
TABLE 1 IL-17A inhibitory Activity
Numbering of compounds IC 50/nM
Compound 1 86
Compounds 2-4 54
Compound 3 19.1
Conclusion: the compounds of the present invention exhibit high inhibitory activity against the IL-17A receptor.
2. Cell level IL-17A stimulation CXCL1 secretion assay
The purpose of this assay is to assess the viability of the compounds at the cellular level. HT-29 cells (#HTB-38; ATCC) were seeded in 96-well plates at 10000 cells/well. IL-17A (# 317-ILB; R & D Systems) at 90ng/mL was added to the wells together with the compound (at a concentration of 4. Mu.M-0.000061. Mu.M). After 48 hours, the wells were assayed for CXCL1 content using an ELISA kit (#SGR00B; R & D Systems). The inhibition of the compounds was assessed using the following formula and IC 50 was fitted using Graphpad.
The calculation formula is as follows:
Inhibition% = { [ CXCL1] IL-17A- [ CXCL1] IL-17A+ Compound }/{ [ CXCL1] IL-17A- [ CXCL1] Medium }. 100
The IC 50 < 100nM of the compounds of the invention against HT-29 cells and the activity of some examples is shown in Table 2.
TABLE 2 HT-29 cell inhibitory Activity
Numbering of compounds IC 50/nM
Compounds 2-4 8.6
Compound 3 1.7
LY3509754 11.9
Note that: LY3509754 has the structure of
Conclusion: the compounds of the invention show high inhibitory activity against IL-17A at cellular level.
3. Rat pharmacokinetic testing
1.1 Test animals: male SD rats, about 220g, 6-8 weeks old, 6/compound. Purchased from Chengdu laboratory animals Inc.
1.2 Test design: on the day of the test, 6 SD rats were randomly grouped by body weight. The water is not forbidden for 12-14 h after 1 day of feeding, and the feed is fed for 4h after the feeding.
TABLE 3 dosing information
Dosing vehicle: 0.5% MC
Before and after administration, 0.1ml of isoflurane was anesthetized and collected via orbit, placed in EDTAK centrifuge tube, centrifuged at 5000rpm at 4℃for 10min, and plasma was collected. Intravenous set blood collection time point: 0,5, 15, 30min,1,2,4,6,8, 24h; time point of blood collection for the lavage group: 0,5, 15, 30min,1,2,4,6,8, 24h. All samples were stored at-80 ℃ prior to analytical testing.
Experimental results show that the compound has good bioavailability and pharmacokinetic characteristics.

Claims (12)

  1. A compound of formula (I), stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof,
    Wherein X is O, S or NR, R is H, C 1-4 alkyl, CN or NO 2;
    Y is NR', O or S;
    R' is H, C 1-4 alkyl or C 3-6 cycloalkyl, said alkyl and cycloalkyl being optionally substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl, C 1-4 alkoxy, CN, NH 2, OH;
    R 1 is D, H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, NH 2 or CN, said alkyl, alkoxy, alkenyl and alkynyl being optionally further substituted with 1 to 3 groups selected from deuterium, halogen, C 1-4 alkyl, CN, NH 2, OH;
    R 2 is C 7-9 monocycloalkyl, C 6-9 cyclocycloalkyl, C 6-9 bridged cyclocycloalkyl or C 6-9 spirocycloalkyl, said monocycloalkyl, bridged cyclocycloalkyl and spirocycloalkyl optionally being further substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl, C 1-4 alkoxy, CN, NH 2, OH;
    R 3 is H, D, C 1-4 alkyl, C 3-6 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, S, O, said alkyl, cycloalkyl and heterocycloalkyl optionally being further substituted with 1 to 3 groups selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkyl, deuterated C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 3-6 cycloalkyl, CN, NH 2、-NHC 1-4 alkyl, -N (C 1-4 alkyl) 2, OH;
    R 4 is D, H, halogen, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said alkyl, alkoxy and cycloalkyl optionally being further substituted with 1 to 3 groups selected from halogen, D, C 1-4 alkyl, CN, NH 2, OH;
    n is 1, 2 or 3;
    Ring a is a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, S, O;
    Ring B is a 9-10 membered fused heteroaryl ring containing 1-4 heteroatoms selected from N, S, O, ring B optionally being substituted with 1-3 groups selected from D, halogen, C 1-4 alkyl, C 1-4 alkoxy, CN, NH 2 and OH.
  2. The compound of claim 1, a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, having the structure of formula (II):
  3. A compound according to claim 2, a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof,
    Wherein R 1 is D, H, halogen or C 1-4 alkyl, said alkyl optionally being further substituted with 1-3 groups selected from deuterium, halogen, CN, NH 2 and OH;
    R 2 is C 7-8 monocycloalkyl, C 6-8 cyclocycloalkyl, or C 7-8 bridged cycloalkyl, said monocycloalkyl, cyclocycloalkyl, and bridged cycloalkyl optionally further substituted with 1-3 groups selected from D, halogen, C 1-4 alkyl, C 1-4 alkoxy;
    R 3 is H, D, C 1-4 alkyl or C 4-7 heterocycloalkyl containing 1 to 3 heteroatoms selected from N, S, O, said alkyl and heterocycloalkyl optionally being further substituted with 1 to 3 groups selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkyl, deuterated C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 3-6 cycloalkyl and-N (C 1-4 alkyl) 2;
    R 4 is D, H, halogen, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said alkyl, alkoxy and cycloalkyl optionally being further substituted with 1 to 3 groups selected from halogen, D, C 1-4 alkyl.
  4. A compound according to claim 3, a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof, said compound having the structure of formula (III):
    r 3 is H, D, or methoxymethyl.
  5. The compound according to claim 4, which is a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof,
    Wherein R 1 is D, H, halogen or C 1-4 alkyl, said alkyl optionally being further substituted with 1-3 groups selected from deuterium, F, cl, br, I;
    R 2 is selected from one of the following structures:
  6. a compound according to claim 1, a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof, selected from one of the following structures:
  7. a compound according to claim 1, a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof, selected from one of the following structures:
  8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof, and a pharmaceutically acceptable carrier and/or adjuvant.
  9. A pharmaceutical composition according to claim 8, comprising a compound according to any one of claims 1 to 7 selected from 1 to 1500mg or a stereoisomer, deuterate, solvate, pharmaceutically acceptable salt or co-crystal thereof and a carrier and/or an adjuvant.
  10. Use of a compound according to any one of claims 1-7, a stereoisomer, a solvate, a metabolite, a pharmaceutically acceptable salt, a co-crystal or a prodrug thereof, or a composition according to claim 8 or 9, for the manufacture of a medicament for the treatment/prophylaxis of IL-17A mediated disorders.
  11. The use of claim 10, wherein the IL-17A mediated disorder is selected from psoriasis, arthritis and multiple sclerosis.
  12. A method for treating a disease in a mammal, said method comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1-7, or a stereoisomer, deuterated, solvate, pharmaceutically acceptable salt or co-crystal thereof, or a composition of claim 8 or 9, preferably 1-1500mg, said disease preferably psoriasis, arthritis and multiple sclerosis.
CN202280067558.4A 2021-11-04 2022-11-03 Heterocyclic compound capable of inhibiting IL-17A and application thereof Pending CN118103372A (en)

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WO2024115662A1 (en) 2022-12-02 2024-06-06 Leo Pharma A/S Small molecule modulators of il-17
WO2024138286A1 (en) * 2022-12-26 2024-07-04 Usynova Pharmaceuticals, Ltd. Il-17a modulators
WO2024163365A1 (en) * 2023-01-30 2024-08-08 Dice Alpha, Inc. Benzimidazole and aza-benzimidazole based il-17a modulators and uses thereof
WO2024201322A1 (en) * 2023-03-28 2024-10-03 Janssen Pharmaceutica Nv Lactam-containing imidazopyridazine il-17 inhibitor compounds

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