WO2015165342A1 - Isoquinolinesulfonamide derivative, and pharmaceutical composition and pharmaceutical use thereof - Google Patents

Abstract

The present invention discloses a class of isoquinolinesulfonamide derivatives as RHO kinase inhibitors, and pharmaceutical compositions thereof, and relates to pharmaceutically acceptable uses thereof. Specifically, the present invention relates to a compound as represented by formula (I) or (II), or a pharmaceutically acceptable salt thereof.

Description

Isoquinoline sulfonamide derivatives and pharmaceutical compositions thereof and pharmaceutical uses Technical field

The present invention relates to a class of isoquinoline sulfonamide derivatives as RHO kinase inhibitors and pharmaceutical compositions thereof, and to their pharmaceutical use. In particular, the invention relates to a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.

Background technique

Fasudil is a novel drug with a wide range of pharmacological effects. It is a RHO kinase inhibitor that dilates blood vessels by increasing the activity of myosin light chain phosphatase, reduces the tension of endothelial cells, improves brain microcirculation, and does not produce Increase the brain's stealing blood, at the same time can antagonize inflammatory factors, protect nerves against apoptosis, and promote nerve regeneration. The results indicate that fasudil hydrochloride has a certain effect on promoting the recovery of nerve function, alleviating clinical symptoms and reducing the morbidity rate. Therefore, in the primary level due to economic constraints and awareness of the disease, ultra-early thrombolytic therapy can not be achieved, but in order to reduce the further progress of the disease, it is essential to reconstruct the local blood circulation within the treatment time window, while the phlegm hydrochloride It has significant neuroprotective and therapeutic effects on ischemic cerebrovascular disease and is worthy of use in the clinic, especially at the grassroots level, reducing disability and improving quality of life.

WO2004106325 discloses a class of compounds which are prodrugs of fasudil and have the structural formula shown as formula (B-I):

Although the above compounds exist in the prior art as RHO kinase inhibitors, they need to be improved in terms of activity, solubility, pharmacokinetics, drug-forming properties and the like.

Summary of the invention

It is an object of the present invention to provide a compound of the formula (I) or (II) or a pharmaceutically acceptable salt thereof,

Its characteristic is that

R ₁ and R ₂ are each independently selected from the group consisting of R ₃ C(=O)O-, (R ₄ O) ₂ P(=O)O-;

R _{3 is} selected from C _1-6 alkyl, (R ₅ )(R ₆ )N-, R ₇ O-, phenyl, pyridyl, thienyl, furyl;

R ₄ , R ₅ , R ₆ , and R ₇ are each independently selected from an alkyl group selected from H or C _1-3 ;

The C _1-6 alkyl group, C _1-3 alkyl group is optionally substituted by R ₀₁ ;

R _{01 is} selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , and the number of R ₀₁ is 1, 2 or 3.

In one embodiment of the invention, the above R _{3 is} selected from the group consisting of a propyl group, a butyl group, and a dimethylamino group;

In one embodiment of the invention, the above R _{3 is} selected from the group consisting of isopropyl, tert-butyl, and dimethylamino.

In one aspect of the invention, the above R ₁ and R ₂ are each independently selected from the group consisting of

In one embodiment of the invention, the above pharmaceutically acceptable salt is as shown in (III) or (IV):

Wherein X is selected from the group consisting of inorganic acids or organic acids.

In one embodiment of the present invention, the above X is selected from the group consisting of trifluoromethanesulfonic acid, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, Hydroiodic acid, phosphorous acid, etc., acetic acid, propionic acid, isobutyric acid, maleic acid, C Diacid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, amino acid or Portuguese Uronic acid.

In one embodiment of the invention, the above compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of

Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Another object of the present invention is to provide the use of the above compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, for the preparation of a medicament for treating various disorders associated with vasoconstriction, wherein the various disorders involved include the brain Embolism, cerebral ischemia, brain injury, vertebral artery insufficiency, cerebral vasospasm caused by subarachnoid hemorrhage, angina pectoris, glaucoma, hypertension, fibrosis.

The term "pharmaceutically acceptable" as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base. When a relatively acidic functional group is contained in the compound of the present invention, a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When a relatively basic functional group is contained in the compound of the present invention, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine, etc.) And salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain basic and acidic functional groups which can be converted into either A base or an acid addition salt.

Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.

As used herein, a "pharmaceutically acceptable salt" is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturaldehyde, propionic acid, salicylic acid, stearic acid, acrylic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, Tartaric acid and p-toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid. Generally, a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.

In addition to the form of the salt, the compounds provided herein also exist in the form of prodrugs. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention. Furthermore, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.

Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.

Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.

Graphical representations of racemates, ambiscalemic and scalemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. 1985, 62: 114-120. The absolute configuration of a stereocenter is indicated by a wedge key and a dashed key unless otherwise stated. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.

The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.

The optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer. Or, when When a subunit contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, and then subjected to fractional crystallization as is known in the art or Chromatography is carried out for diastereomeric resolution and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, radiolabeled compounds can be used, such as tritium ⁽³ H), iodine -125 ⁽¹²⁵ I) or ^C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.

The term "excipient" generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.

The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect. For oral dosage forms in the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.

The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease or condition.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. . When the substituent is a keto group (ie, =0), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on the aryl group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.

When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Alkyl and heteroalkyl radicals (including what are commonly referred to as alkylene, alkenyl, heteroalkyl, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) Substituents for those groups are generally referred to as "alkyl substituents" which may be selected from, but are not limited to, one or more of the following groups: -R', -OR', =O, =NR' , =N-OR', -NR'R", -SR', halogen, -SiR'R"R"', OC(O)R', -C(O)R', -CO ₂ R', - CONR'R", -OC(O)NR'R", -NR"C(O)R', NR'C(O)NR"R"', -NR"C(O) ₂ R', -NR "-C(NR'R"R'")=NR"", NR""C(NR'R")=NR'", -S(O)R', -S(O) ₂ R' , -S(O) ₂ NR'R", NR"SO ₂ R', -CN, -NO ₂ , -N ₃ , -CH(Ph) ₂ and fluoro(C ₁ -C ₄ )alkyl, substituted The number of radicals is 0 to (2m'+1), where m' is the total number of carbon atoms in such radicals. R', R", R"', R"" and R""' are each independently preferably hydrogen, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group (for example, an aryl group substituted by 1 to 3 halogens), a substituted or unsubstituted alkyl group, an alkoxy group, or a thioalkyl group oxygen a group or an aralkyl group. When a compound of the invention includes more than one R group, for example, each R group is independently selected, as when more than one R', R", R"' Each of these groups, R"" and R""' groups. When R' and R" are attached to the same nitrogen atom, they can form a 5-, 6- or 7-member with the nitrogen atom. ring. For example, -NR'R" is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. In light of the above discussion of substituents, those skilled in the art will appreciate that the term "alkyl" is intended to include carbon. A group bonded to a non-hydrogen group such as a haloalkyl group (e.g., -CF ₃ , -CH ₂ CF ₃ ) and an acyl group (e.g., -C(O)CH ₃ , -C(O)CF ₃ ,- C(O)CH ₂ OCH _{3 ,} etc.).

Similar to the substituents of the alkyl group, the aryl and heteroaryl substituents are generally collectively referred to as "aryl substituents" and are selected, for example, from -R', -OR', -NR'R", -SR', - Halogen, -SiR'R"R"', OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C (O) R', NR'C(O)NR"R"', -NR"C(O)2R', -NR""'-C(NR'R"R'")=NR"", NR ""C(NR'R")=NR'", -S(O)R', -S(O) ₂ R', -S(O) ₂ NR'R", NR"SO ₂ R',- CN, -NO ₂ , -N ₃ , -CH(Ph) ₂ , fluorine (C ₁ -C ₄ ) alkoxy, and fluorine (C ₁ -C ₄ ) alkyl, etc., the number of substituents is 0 to an aromatic ring Between the total number of open valencies; wherein R', R", R"', R"" and R""' are independently preferred from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted a heteroalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group. When the compound of the present invention includes more than one R group, for example, each R group is independently added. Each of these groups is selected as when more than one R', R", R"', R"" and R"" group are present.

Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -TC(O)-(CRR')qU-, wherein T and U are independently selected From -NR-, -O-, CRR'- or a single bond, q is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein A and B are independently selected From -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) ₂ -, -S(O) ₂ NR'- or a single bond, r is 1 to 4 The integer. Optionally, a single bond on the new ring thus formed can be replaced with a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein s and d are each independently An integer selected from 0 to 3, X is -O-, -NR', -S-, -S(O)-, -S(O) ₂ - or -S(O) ₂ NR'-. The substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C ₁ -C ₆ )alkyl.

Unless otherwise specified, the term "halo" or "halogen", by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Further, the term "haloalkyl" is intended to include both monohaloalkyl and polyhaloalkyl. For example, the term "halo(C ₁ -C ₄ )alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.

Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge. The C _1-6 alkoxy group includes a C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy. "Cycloalkyl" includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl. The 3-7 cycloalkyl group includes C ₃ , C ₄ , C ₅ , C ₆ and C ₇ cycloalkyl groups. "Alkenyl" includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.

The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

Unless otherwise specified, the term "hetero" denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O). ), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C (= O) O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, and -C(=O) optionally substituted N(H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- or -S(=O)N(H)-.

Unless otherwise specified, "ring" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring" means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms. Thus, "5- to 7-membered ring" includes, for example, phenylpyridine and piperidinyl; on the other hand, the term "5- to 7-membered heterocycloalkyl ring" includes pyridyl and piperidinyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.

Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites. The nitrogen atom in the heterocycle is optionally quaternized. A preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one. The term "aromatic heterocyclic group" or "heteroaryl" as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one. Bridged rings are also included in the definition of heterocycles. A bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms. Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.

Examples of heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl, indanyl, mesoindolyl, fluorenyl, 3H-indole Sulfhydryl, isatino, isobenzofuranyl, pyran, isodecyl, isoindoline, isodecyl, decyl, isoquinolyl, isothiazolyl, isoxazolyl, Methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, isoxazolyl, oxindole , pyrimidinyl, phenanthryl, phenanthroline, phenazine, phenothiazine, benzoxanthyl, phenolzinyl, pyridazinyl, piperazinyl, piperidinyl, piperidinone, 4 - piperidinone, piperonyl, pteridine, Mercapto, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridylthiazole, pyridyl, pyrimidinyl, pyrrolidine , pyrrolinyl, 2H-pyrrolyl, pyrrolyl, pyrazolyl, quinazolinyl, quinolyl, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquino Alkyl, tetrahydroquinolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thioxyl, thiazolyl, isothiazolylthiophenyl, thienyl, thienooxazolyl, thienothiazolyl, thienoimidazole Base, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and anthracene Tons of base. Also included are fused ring and spiro compounds.

Unless otherwise specified, the term "hydrocarbyl" or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic The hydrocarbon radical or a combination thereof may be fully saturated, unitary or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may include divalent or polyvalent radicals having a specified number of carbon atoms (eg, C1 ₎ -C ₁₀ represents 1 to 10 carbons). "Hydrocarbyl" includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members. An aromatic hydrocarbon group such as benzene, naphthalene or the like. In some embodiments, the term "alkyl" refers to a straight or branched chain of atoms or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl). A homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl. The unsaturated alkyl group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and Structure.

Unless otherwise specified, the term "heterohydrocarbyl" or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl" by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized. The heteroatoms B, O, N and S can be located at any internal position of the heterohydrocarbyl group (including where the hydrocarbyl group is attached to the rest of the molecule). Examples include, but are not limited to, -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S -CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O-CH ₃ ,- CH ₂ -CH=N-OCH ₃ and -CH=CH-N(CH ₃ )-CH ₃ . Up to two heteroatoms may be consecutive, for example, -CH ₂ -NH-OCH _3.

The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are customary expressions and refer to those alkane which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively. Base group.

Unless otherwise specified, the term "cycloalkyl", "heterocycloalkyl" or its subordinate concept (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl) A heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized "hydrocarbyl group" or "heterohydrocarbyl group", respectively. Further, in the case of a heterohydrocarbyl group or a heterocycloalkyl group (such as a heteroalkyl group or a heterocycloalkyl group), a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.

Unless otherwise specified, the term "aryl" denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, It may be monocyclic or polycyclic (preferably 1 to 3 rings) which are fused together or covalently linked. The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl, 1-isoquinolyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolinyl. The substituents of any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

For simplicity, aryl groups, when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen. Those alkyl groups substituted by an atom, such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.

The term "leaving group" refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.

The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing hydroxy side reactions. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.

The present invention employs the following abbreviations: aq for water; HATU for O-7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for carbonyl Diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl and is an amine protecting group; BOC stands for t-butylcarbonyl which is an amine protecting group; HOAc stands for acetic acid; and NaCNBH ₃ stands for sodium cyanoborohydride; Rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc ₂ O stands for di-tert-butyldicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl ₂ stands for thionyl chloride CS ₂ stands for carbon disulfide; TsOH stands for p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione; n-Bu ₄ NF Representative fluorine Tetrabutylammonium; iPrOH represents 2-propanol; mp representative of melting point.

Compound by hand or

Software naming, commercially available compounds using the supplier catalog name.

Unless otherwise specified, the compound is either by hand or

Software naming, commercially available compounds using the supplier catalog name.

Compared with the prior art, the compound of the present invention is highly efficient, low in toxicity, and has achieved remarkable and unexpected progress in activity, half-life, solubility and pharmacokinetics, and is more suitable for pharmaceuticals.

Detailed ways

The invention is described in detail below by the examples, but is not intended to limit the invention. The present invention has been described in detail herein, the embodiments of the present invention are disclosed herein, and various modifications and changes may be made to the embodiments of the present invention without departing from the spirit and scope of the invention. It will be obvious.

Example 1

(5-((1,4-Diazepane-1-yl)sulfonyl)-1-oxoisoquinolin-2(1H)-yl)methyl isobutyl ester

first step

Isoquinoline 1a (47.5 mL, 405 mmol) was slowly added to 22 mL of concentrated sulfuric acid, thoroughly stirred into small pieces, and then added to 200 mL of 20% fuming sulfuric acid, and allowed to stand at room temperature for two days. Then, it was poured into 700 g of ice water and allowed to stand overnight, and the obtained suspension was filtered, and the filter cake was washed twice with water (100 mL×2), and dried to obtain isoquinoline-5-sulfonic acid 1b (50 g, yield: 60%). Used directly in the next step

¹ H NMR (400 MHz, D ₂ O): δ 9.66 (s, 1H), 8.94-8.92 (m, 1H), 8.62-8.60 (m, 2H), 8.58-8.56 (m, 1H), 8.50-8.48 (m, 1H), 7.99-7.95 (m, 1H).

MS-ESI calculated [M+H] ⁺ 210, found 210.

Second step

Isoquinoline-5-sulfonic acid 1b (4.0 g, 0.019 mol) was added to 25 mL of thionyl chloride at room temperature, followed by the addition of 0.1 mL of N,N-dimethylformamide. After the reaction was heated to reflux for two hours, excess thionyl chloride was evaporated under reduced pressure, and the residue was evaporated and washed with cold dichloromethane (10mL?). The title product isoquinoline-5-sulfonyl chloride 1c (3.9 g, yellow solid, yield: 100%) was obtained.

MS-ESI calculated [M+H] ⁺ 227 found 227.

third step

Isoquinoline-5-sulfonyl chloride 1c (3.00 g, 11.3 mmol) was dissolved in 20 mL of dichloromethane, and 1,4-diazepane-1-carboxylic acid tert-butyl was added at 0 ° C under nitrogen. Ester (2.60 g, 13.0 mmol) and N,N-diisopropylethylamine (7.5 mL, 35.0 mmol). The resulting reaction solution was stirred at room temperature for 16 hours until the reaction was completed. Diluted with dichloromethane (100 mL) and water (100 mL), EtOAc (EtOAc (EtOAc) Purification of the title compound 4-(isoquinolin-5-ylsulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 1d (4.5 g, colorless oil, Yield: 100%). MS-ESI calcd for [M ⁺ H] + 392, found 392.

the fourth step

4-(isoquinolin-5-ylsulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 1d (5.38 g, 13.8 mmol) in 200 mL of dichloromethane m-Chloroperoxybenzenecarboxylic acid (4.80 g, 27.6 mmol) was added portionwise, then stirred at room temperature for 2 hours until the end of the reaction. The solvent was evaporated to dryness, and then purified by chromatography on silica gel column (0-100% ethyl acetate / petroleum ether) to give 5-((4-(tert-butoxycarbonyl)-1,4-diazepane-1- Base)sulfonyl)isoquinoline-2-oxide 1e (4.9 g, yellow oily liquid, yield: 86%).

^{1 H NMR (400MHz, DMSO-} d6): δ9.11 (s, 1H), 8.40-8.35 (m, 1H), 8.35-8.30 (m, 1H), 8.20-8.15 (m, 1H), 7.80-7.75 (m, 2H), 3.52-3.42 (m, 8H), 1.85-1.65 (m, 2H), 1.37 (s, 9H).

MS-ESI calcd for [M ⁺ H] + 408, found 408.

the fifth step

Dissolving 5-((4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl)sulfonyl)isoquinoline-2-oxide 1e (5.70 g, 14.0 mmol) It was stirred at 50 ° C for 2 hours in 50 mL of acetic anhydride until the reaction was completed. The reaction mixture was concentrated under reduced pressure to dryness. After removing tetrahydrofuran under reduced pressure, the pH of the reaction mixture was adjusted to 7 with dilute hydrochloric acid, and the obtained suspension was filtered, and the filter cake was washed with water (10 mL×2) and dried to give 4-((1-oxo-1,2-dihydro) Isoquinoline-5-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 1f (3 g, light red solid, yield: 75%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ11.57 (s, 1H), 8.50-8.45 (m, 1H), 8.20-8.15 (m, 1H), 8.08 (s, 1H), 7.85-7.80 (m, 1H), 7.65-7.60 (m, 1H), 3.50-3.30 (m, 8H), 2.05-1.95 (m, 2H), 1.44 (s, 9H).

MS-ESI calcd for [M ⁺ H] + 408, found 408.

Step 6

4-((1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester under nitrogen atmosphere 1f (5.50 g, 13.5 mmol) was dissolved in 110 mL of hexamethylphosphoric triamide, and sodium hydride (0.595 g, 14.9 mmol) was slowly added at 0 ° C and reacted at the same temperature for 15 minutes, then to the reaction droplets. Add chloromethyl isobutyrate (2.24g, 14.9mmol), add to room temperature and react 1 hour. After the completion of the reaction, the reaction mixture was slowly added dropwise to ice water (200 mL), ethyl acetate (100 mL×3), and the organic phase was dried over anhydrous sodium sulfate. (0-100% ethyl acetate / petroleum ether) afforded 4-((2-((isobutyryloxy)methyl)-1-oxo-1,2-dihydroisoquinolin-5-yl) 1 g (sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester (5.8 g, white solid, yield: 85%).

MS-ESI calcd for [M+H] ⁺ 508.

Seventh step

4-((2-((isobutyryloxy)methyl)-1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diazacyclocycle 1 g of heptane-1-carboxylic acid tert-butyl ester (5.80 g, 11.4 mmol) was dissolved in 690 mL of dichloromethane, and trifluoromethanesulfonyltrimethylsilane (5.06 g, was slowly added dropwise at 0 ° C under a nitrogen atmosphere. 22.8 mmol), the control temperature is in the range of 0-5 °C. After reacting the reaction solution for 45 minutes, 2,6-lutidine (3.66 g, 34.2 mmol) was added dropwise thereto, and the reaction was continued at 0 to 5 ° C for 1 hour until the end of the reaction. The reaction mixture was slowly added to ice water (200 mL), EtOAc (EtOAc) ((1,4-Diazepane-1-yl)sulfonyl)-1-oxoisoquinolin-2(1H)-yl)methylisobutyl ester 1 (2.5 g, pale yellow solid, Yield: 54%).

_{^{1 H NMR (400MHz, D 2}} O): δ8.41 (d, J = 8.4Hz, 1H), 8.13 (d, J = 8.0Hz, 1H), 7.58-7.54 (m, 2H), 7.14 (d, J=8.0 Hz, 1H), 5.92 (s, 2H), 3.67-3.64 (m, 2H), 3.50-3.40 (m, 2H), 3.35-3.30 (m, 4H), 2.65-2.55 (m, 1H) , 2.15-2.00 (m, 2H), 1.07 (d, J = 7.2 Hz, 6H).

MS-ESI calcd for [M ⁺ H] + 408, found 408.

Example 2

((5-((1,4-Diazepane-1-yl)sulfonyl)-1-oxoisoquinolin-2(1H)-yl)methyl)phosphonic acid

First step

4-(isoquinolin-5-ylsulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 1d (4.10 g, 11.2 mmol) was dissolved in 30 mL of ethyl acetate. 20 mL of a saturated hydrogen chloride solution of ethyl acetate was added dropwise at 0 ° C, and the reaction solution was reacted at room temperature for 0.5 hour. The obtained suspension was filtered, and the filter cake was washed with ethyl acetate (10 mL×2) and dried to give 5-((1,4-diazepan-1-yl)sulfonyl)isoquinoline 2a (2.6 g , white solid, yield: 87%).

Second step

Add N,N-II to a solution of 5-((1,4-diazepane-1-yl)sulfonyl)isoquinoline 2a (4.00 g, 11.1 mmol) in 80 mL of dichloromethane Methylformamide (5.90 mL, 33.3 mmol) was added dropwise benzyl chloroformate (2.10 g, 12.2 mmol). After the completion of the dropwise addition, the reaction mixture was warmed to room temperature and then reacted for 2 hours. The reaction mixture was diluted with water (50 mL), dichloromethane (30 mL×2), and the organic phase was dried over anhydrous sodium sulfate. Purification (0-100% ethyl acetate / petroleum ether) afforded 4-(isoquinolin-5-ylsulfonyl)-1,4-diaza-1-carboxylic acid benzyl ester 2b (6.4 g, colorless Oily liquid, yield: 100%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.36 (s, 1H), 8.75 - 8.65 (m, 1H), 8.45 - 8.35 (m, 1H), 8.32 - 8.25 (m, 1H), 8.23 - 8.15 ( m, 1H), 7.82-7.62 (m, 1H), 7.40-7.20 (m, 5H), 5.09 (s, 2H), 3.75-3.54 (m, 4H), 3.50-3.32 (m, 4H), 2.11 1.92 (m, 2H).

MS-ESI calcd for [M ⁺ H] + 426, found 426.

third step

4-(isoquinolin-5-ylsulfonyl)-1,4-diaza-1-carboxylic acid benzyl ester 2b (7.4 g, 17.4 mmol) was obtained according to the procedure of Example 1 to give 5-((4- ((Benzyloxy)carbonyl)-1,4-diazepan-1-yl)sulfonyl)isoquinoline-2-oxide 2c (5.0 g, yellow oil, yield: 65%) .

MS-ESI calcd for [M ⁺ H] + 442, found 442.

the fourth step

5-((4-((Benzyloxy)carbonyl)-1,4-diazepan-1-yl)sulfonyl)isoquinoline-2-oxide 2c (5.00 g, 11.3 mmol) Dissolved in 70 mL of acetic anhydride and heated to 130 ° C for 4 hours. After the completion of the reaction, excess acetic anhydride was distilled off under reduced pressure, and the residue was dissolved in 50 mL of THF, and 100% of 30% sodium hydroxide was added. The reaction solution was stirred at room temperature for 0.5 hour, then the tetrahydrofuran was distilled off under reduced pressure and the reaction mixture was adjusted to pH. The obtained suspension was filtered, and the filter cake was dried to give 4-((1-oxo-1,2-dihydroiso) Benzyl-5-yl)sulfonyl)-1,4-diaza-1-carboxylate 2d (4.5 g, brown solid, yield: 90%).

MS-ESI calcd for [M ⁺ H] + 442, found 442.

the fifth step

4-((1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diaza-1-carboxylic acid benzyl ester 2d (1.00 g, 2.27 mmol) and Dibenzyl chloromethyl phosphate (816 mg, 2.5 mmol) was obtained according to the procedure of Example 1 to give 4-((2-((bis(benzyloxy)phosphoryl)methyl)-1-oxo-1,2 Benzyl dihydroisoquinolin-5-yl)sulfonyl)-1,4-diaza-l-carboxylate 2e (140 mg, brown oil, yield: 8.5%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ8.41 (d, J = 8.0Hz, 1H), 8.26 (d, J = 8.0Hz, 1H), 8.20-8.10 (m, 1H), 8.05-8.00 (m , 1H), 7.55-7.50 (m, 1H), 7.40-7.15 (m, 15H), 6.25-6.20 (m 2H), 5.15-5.10 (m, 2H), 5.05 (s, 2H), 5.04 (s, 2H), 3.70-3.50 (m, 4H), 3.45-3.30 (m, 4H), 2.00-1.90 (m, 2H).

MS-ESI calcd for [M+H] ^{+ s} .

Step 6

To 4-((2-((bis(benzyloxy)phosphoryl)methyl)-1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-di To a mixed solvent of benzyl azide-1-carboxylate 2e (100 mg, 0.140 mmol) in 20 mL of tetrahydrofuran and 2.5 mL of water was added wet palladium carbon (70 mg, 10%), and reacted for 4 hours at room temperature under an atmosphere of hydrogen atmosphere. After completion of the reaction, the celite was filtered and concentrated to give ((5-((1,4-diazepan-1-yl)sulfonyl)-1-oxoisoquinolin-2(1H)-yl) )methyl)phosphonic acid 2 (63 mg, white solid, yield: 100%).

¹ H NMR (400 MHz, D ₂ O): δ 8.60 (d, J = 8.0 Hz, 1H), 8.31 - 8.23 (m, 1H), 7.80 - 7.60 (m, 2H), 7.31 (d, J = 7.6 Hz, 1H), 5.64 (s, 2H), 3.60-3.30 (m, 6H), 3.10-3.00 (m, 2H), 1.95-1.70 (m, 2H).

MS-ESI calc. [M+H] ⁺ 402.

Example 3

first step

4-((1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 1f (200 mg, 0.49 Methyl) 4-((2-((Benzoyloxy)methyl)-1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl) was obtained according to the procedure of Example 1. tert-Butyl 1,4-diazepane-1-carboxylate 3a (150 mg, white solid, yield: 56%).

^{1 H NMR (400MHz, DMSO-} 6d): δ8.54 (d, J = 8.0Hz, 1H), 8.23 (d, J = 8.0Hz, 1H), 7.93-7.98 (m, 2H), 7.85 (d, J=8.0 Hz, 1H), 7.51-7.55 (m, 2H), 7.20-7.15 (m, 1H), 6.18 (s, 2H), 4.05-4.02 (m, 1H), 3.41-3.47 (m, 4H) , 3.37-3.41 (m, 2H), 2.69-2.67 (m, 1H), 2.00-1.98 (m, 2H), 1.78-1.75 (m, 2H), 1.36 (s, 9H).

Second step

4-((2-((Benzoyloxy)methyl)-1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diazepine tert-Butyl 3-carboxylic acid tert-butyl ester 3a (150 mg, 0.28 mmol) was obtained according to the procedure of Example 1 (5-(1,4-diazepan-1-yl)sulfonyl)-1-oxo Methyl iodoquinoline-2(1H)-yl)benzoate 3 (50 mg, white solid, yield: 41%).

_{^{1 H NMR (400MHz, D 2}} O): δ8.48 (d, J = 8.0Hz, 1H), 8.11 (d, J = 7.6Hz, 1H), 8.00-7.95 (m, 2H), 7.70 (d, J=8.0 Hz, 1H), 7.60-7.55 (m, 2H), 7.43 (d, J = 7.6 Hz, 2H), 7.16 (d, J = 8.0 Hz, 1H), 6.16 (s, 2H), 3.59- 3.56 (m, 2H), 3.38-3.36 (m, 2H), 3.29-3.23 (m, 4H), 2.02-2.00 (m, 2H).

Example 4

5-((1,4-Diazepane-1-yl)sulfonyl)-1-oxoisoquinolin-2(1H)-yl)oxy)methylpivalate 4,( (5-((1,4-Diazepane-1-yl)sulfonyl)isoquinolin-1-yl)oxy)methyl pivalate 4'

first step

4-((1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 1f (0.50 g, 1.23 mmol) 4-((1-oxo-2-((pivaloyloxy)methyl)-1,2-dihydroisoquinolin-5-yl)sulfonyl was obtained according to the procedure of Example 1. Tert-butyl 1,4-diaza-1-carboxylate 4a1 and 4-((1-((pivaloyloxy)methoxy)isoquinolin-5-yl)sulfonyl)-1 , a mixture of 4-diazepane-1-carboxylic acid tert-butyl ester 4a2 (0.34 g, white solid, yield: 50%).

4a1: ¹ H NMR (400MHz, CDCl ₃ ): δ 8.53 (d, J = 8.4 Hz, 1H), 8.42-8.30 (m, 1H), 8.18 (d, J = 6.4 Hz, 1H), 8.04 (d) , J=6.4 Hz, 1H), 7.65-7.60 (m, 1H), 6.31 (s, 2H), 3.64-3.45 (m, 4H), 3.40-3.30 (m, 4H), 2.05-1.90 (m, 2H) ), 1.43 (s, 9H), 1.21 (s, 9H).

MS-ESI calcd for [M+H] ⁺ 522.

4a2: ¹ H NMR (400MHz, CDCl ₃ ): δ 8.72 (d, J = 8.0 Hz, 1H), 8.25-8.20 (m, 1H), 7.60-7.55 (m, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.30-7.27 (m, 1H), 5.98 (s, 2H), 3.64-3.45 (m, 4H), 3.40-3.30 (m, 4H), 2.05-1.90 (m, 2H), 1.47 (s, 9H), 1.23 (s, 9H).

MS-ESI calcd for [M+H] ⁺ 522.

Second step

4-((1-oxo-2-(p-pentanoyloxy)methyl)-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diaza-1 - tert-butyl carboxylate 4a1 and 4-((1-((pivaloyloxy)methoxy)isoquinolin-5-yl)sulfonyl)-1,4-diazepan-1 - tert-butyl carboxylate 4a2 (100 mg, 0.19 mmol) according to the procedure of Example 1 to give 5-((1,4-diazaheptan-1-yl)sulfonyl)-1-oxoisoquine Porphyrin-2(1H)-yl)oxy)methylpivalate 4 and ((5-((1,4-diazepan-1-yl)sulfonyl)isoquinoline-1- Ethyl)methyl pivalate 4' (50 mg, pale yellow solid, yield: 53%).

^{4: 1 H NMR (400MHz,} CDCl 3): δ8.65 (d, J = 8.0Hz, 1H), 8.19 (d, J = 7.6Hz, 1H), 7.53 (t, J = 6.0Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 5.93 (s, 2H), 3.50-3.30 (m, 4H), 3.05-2.90 (m, 4H), 1.90 -1.75 (m, 2H), 1.18 (s, 9H).

MS-ESI calcd [M+H] ⁺ 422.

4': ¹ H NMR (400MHz, CDCl ₃ ): δ 8.55 (d, J = 8.0 Hz, 1H), 8.31 (m, 1H), 8.19 (d, J = 6.4 Hz, 1H), 8.00 (d, J=6.4 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 6.31 (s, 2H), 3.70-3.60 (m, 2H), 3.58-3.50 (m, 2H), 3.36-3.25 (m) , 4H), 2.20-2.10 (m, 2H), 1.21 (s, 9H).

MS-ESI calcd [M+H] ⁺ 422.

Example 5

Methyl (5-((1,4-diazepane-1-yl)sulfonyl)-1-oxoisoquinolin-2(1H)yl)dimethylaminocarboxylate

first step

4-((1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester under nitrogen atmosphere 1f (200 mg, 0.49 mmol), dimethylamino carboxylic acid chloromethyl ester (149 mg, 0.98 mmol) and potassium carbonate (224 mg, 1.47 mmol) in 20 mL of THF. After the reaction was completed, the reaction solution was cooled to room temperature, and the solvent was removed, and then a thin layer chromatography (50% ethyl acetate / petroleum ether) was used to give 4-((2-((dimethylcarbamoyl)oxy)) 1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 5a (100 mg, white solid , yield: 39%).

MS-ESI calcd [M+H] ⁺ 509, found 509.

Second step

4-((2-(((Dimethylcarbamoyl)oxy)methyl)-1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1 , 4-Diazepane-1-carboxylic acid tert-butyl ester 5a (0.25 g, 0.45 mmol) was added to 4 mL of a saturated solution of hydrogen chloride gas in 1,4-dioxane and stirred at room temperature for 0.5 hour. . After the reaction was completed, the reaction solution was concentrated, and then purified by preparative thin-layer chromatography (ethyl acetate) to give (5-((1,4-diazepan-1-yl)sulfonyl)-1-oxyl Methyl iodoquinoline-2(1H)yl)dimethylaminocarboxylate 5 (150 mg, pale yellow solid, yield: 74%).

^{1 H NMR (400MHz, DMSO-} d6): δ8.92 (brs, 1H), 8.52-8.59 (m, 1H), 8.25 (d, J = 7.6Hz, 1H), 7.69-7.75 (m, 1H), 7.18 (d, J = 7.6 Hz, 1H), 5.93 (s, 2H), 4.85-4.80 (m, 1H), 3.65-3.60 (m, 2H), 3.46 (t, J = 5.73 Hz, 2H), 3.21. (brs, 4H), 2.00 (brs, 2H), 1.38 (d, J = 6.39 Hz, 2H), 1.25-1.20 (m, 3H).

MS-ESI calcd for [M+H] ⁺ 409.

Example 6

(5-((1,4-Diazepane-1-yl)sulfonyl)-1-oxoisoquinolin-2(1H)-yl)methyl isopropyl carbonate

first step

4-((1-oxo-1,2-dihydroisoquinolin-5-yl)sulfonyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester 1f (150 mg, 0.39 Methyl) isopropyl chloromethyl carbonate (77 mg, 0.51 mmol) was obtained by a two-step reaction according to the synthesis method of Example 1 (5-((1,4-diazepan-1-yl)sulfonyl) 1-oxoisoquinoline-2(1H)-yl)methyl isopropyl carbonate 6 (53 mg, white solid, yield: 32%).

^{1 H NMR (400MHz, DMSO-} d6): δ8.92 (brs, 1H), 8.60-8.55 (m, 1H), 8.25 (d, J = 7.6Hz, 1H), 7.73 (t, J = 7.6Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 5.93 (s, 2H), 4.84 - 4.78 (m, 1H), 3.62 (brs, 2H), 3.48-3.45 (m, 2H), 3.21 (brs , 4H), 2.00 (brs, 2H), 1.37 (d, J = 6.4 Hz, 2H), 1.23 (d, J = 6.4 Hz, 4H).

MS-ESI calcd for [M ⁺ H] + 424, found 424.

Experimental Example 1: Rat Dynamics Test

Purpose:

The rate at which the compound produces the active pharmaceutical ingredient in the body and the exposure of the active pharmaceutical ingredient are measured. Experimental Materials:

Male SD rats weighing 200-250 g were purchased from Shanghai Slack Laboratory Animal Co., Ltd.

Experimental operation:

Before the experiment, the animals were subjected to carotid cannulation (for plasma sample collection), and the rats were restored to at least 3 days after surgery, and the experiment was performed after no abnormality was observed. Oral administration dose was 10 mg/kg, and whole blood was collected and plasma samples were prepared at 0, 5 min, 15 min, 30 min, 60 min, 2 h, 4 h, 6 h, 8 h, 24 h after administration. All samples were quantitatively detected in the plasma of the experimental animals by liquid chromatography coupled-mass spectrometry. The measured concentrations were calculated using the WinNonlin non-compartment model and the plasma concentration-time data was used to calculate T _1/2. , C _max , T _max , AUC _(0-t) and AUC _(0-∞) and other parameters, and plot the plasma concentration-time curve.

Experimental results:

Table 1 Rat dynamic blood test results

Note: peak plasma concentration: +> 1000nM; peak plasma time: + <20min; unit exposure: +> 100nM.hr / μmol.

Claims (9)

1. a compound of the formula (I) or (II) or a pharmaceutically acceptable salt thereof,

   

   Its characteristic is that

   R ₁ and R ₂ are each independently selected from the group consisting of R ₃ C(=O)O-, (R ₄ O) ₂ P(=O)O-;

   R _{3 is} selected from C _1-6 alkyl, (R ₅ )(R ₆ )N-, R ₇ O-, phenyl, pyridyl, thienyl, furyl;

   R ₄ , R ₅ , R ₆ , and R ₇ are each independently selected from an alkyl group selected from H or C _1-3 ;

   The C _1-6 alkyl group, C _1-3 alkyl group is optionally substituted by R ₀₁ ;

   R _{01 is} selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , and the number of R ₀₁ is 1, 2 or 3.
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R _{3 is} selected from the group consisting of propyl, butyl, dimethylamino;
3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R _{3 is} selected from the group consisting of isopropyl, tert-butyl and dimethylamino.
4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ₁ and R ₂ are each independently selected from the group consisting of

   
5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is as shown in (III) or (IV):

   

   

   Wherein X is selected from the group consisting of inorganic acids or organic acids.
6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein said X is selected from the group consisting of trifluoromethanesulfonic acid, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, and phosphoric acid. Monohydrogen, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc., acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, amino acids or glucuronic acid.
7. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

   
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
9. The use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for the preparation of a medicament for treating various conditions associated with vasoconstriction, wherein The related various conditions include cerebral embolism, cerebral ischemia, brain damage, vertebral artery insufficiency, cerebral vasospasm caused by subarachnoid hemorrhage, angina pectoris, glaucoma, hypertension, and fibrosis.