CN114621213B - Thiazole-containing compound, intermediate and application thereof - Google Patents

Thiazole-containing compound, intermediate and application thereof Download PDF

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CN114621213B
CN114621213B CN202210304770.XA CN202210304770A CN114621213B CN 114621213 B CN114621213 B CN 114621213B CN 202210304770 A CN202210304770 A CN 202210304770A CN 114621213 B CN114621213 B CN 114621213B
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thiazole
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方进
周继宁
周洁
蒋涛
周明月
徐凯
高阳
王亚农
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Hefei Meinuo Pharmaceutical Co ltd
Suzhou Medinoah Co ltd
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Abstract

The invention discloses a thiazole-containing compound shown as a formula (I) or pharmaceutically acceptable salt thereof, which is suitable for being used as a tyrosine kinase inhibitor, especially an ITK inhibitor, and is therefore suitable for treating inflammatory diseases or cancers or autoimmune diseases mediated by ITK.

Description

Thiazole-containing compound, intermediate and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a thiazole compound and application thereof in inhibiting tyrosine kinase.
Background
The Tec family of protein tyrosine kinases consists mainly of Tec (tyrosine kinase expressed in hepatocellular carcinoma ), BTK (Bruton's tyrosine kinase, bruton's tyrosine kinase), BMX (bone marrow expressed kinase, bone marrow kinase on the X chromosome or ETK), RLK (resting lymphocyte kinase, resting lymphocyte kinase, also called TXK) and ITK (interleukin-2 induced T cell kinase), which can be distinguished by the presence or absence of pleckstrin homology regions, proline being enriched in Tec homology regions, and Src homology SH3, SH2 and SH1 kinase regions located C-terminally from the N-terminus, etc. Tec family kinases are involved in the development of lymphocytes and myeloid cells. Among them, ITK is mainly expressed in T-lymphocytes (EMT), mast cells and natural killer cells. Activation by stimulation of the T Cell Receptor (TCR) in T cells, by activation of high affinity IgE receptors in mast cells, plays an important role in T cell developmental differentiation, downstream signaling, and production of pro-inflammatory cytokines including IL-2, IL-4, IL-5, IL-10, IL-13, and IL-17.
Studies have shown that modulation of ITK activity can treat inflammatory conditions, allergic diseases, autoimmune diseases, and cancers (e.g., T cell lymphomas, etc.). There is also a great deal of clinical or preclinical evidence that ITK inhibition can be used to treat diseases such as allergic asthma, atopic dermatitis, allergic dermatitis and psoriasis.
Patent CN110099684a discloses a series of thiazole derivatives with substituted benzene rings, which have regulatory activity on ITK activity, however, the inhibition of ITK enzyme activity by the derivatives is not enough.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel thiazole-containing compound with higher inhibition activity on tyrosine kinase.
In order to solve the technical problems, the invention adopts the following technical scheme:
thiazole-containing compounds having a structure represented by formula (I) or pharmaceutically acceptable salts thereof,
wherein:
R 1 selected from hydrogen, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 haloalkyl or-SCH 3 ；
R 2 Selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 haloalkyl or-SCH 3 ；
R 3 Selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 haloalkyl or-SCH 3 ；
R 4 Selected from hydrogen, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 haloalkyl or-SCH 3 ；
R 5 Selected from hydrogen, halogen, the following substituted or unsubstituted with a first substituent: c1-8 alkyl, C3-6 cycloalkyl, wherein the first substituent is selected from halogen, C1-6 alkyl, C1-6 alkoxy;
x is F, cl or Br;
L 1 selected from-O-, -S-, -SCH 2 -，-CH 2 -，CH(CH 3 )-，-NH-，-N(CH 3 ) -a group;
L 2 selected from hydrogen or C1-6 alkyl;
L 3 selected from the following groups, substituted or unsubstituted with a second substituent: c1-6 alkylene, 5 membered heterocycloalkylene, 6 membered heterocycloalkylene or C6-9 spiroheterocycloalkylene wherein the second substituent is selected from halogen, C1-6 alkyl, C1-6 alkoxy;
or L 2 、L 3 And together with the nitrogen atom to which they are both attached form an optionally substituted heterocyclic structure which is a 6-membered mono-heterocyclic ring, a 7-membered mono-heterocyclic ring, an 8-membered mono-heterocyclic ring or a C5-9 bridged ring, wherein the heterocyclic structure contains, in addition to L 2 、L 3 The nitrogen to which it is attached also contains another N, said third substituent being selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy;
e is an electron withdrawing group capable of covalently reacting with cysteine.
According to a preferred aspect of the invention: the structure of the thiazole-containing compound is shown as the following formula (I-a):
wherein,
n is 1,2 or 3;
s is an integer between 0 and 6;
R 6 selected from halogen, C1-6 alkyl or C1-6 alkoxy;
R 2 、R 3 、R 4 、R 5 、X、L 1 、L 2 E is as defined above.
According to another preferred aspect of the invention: the structure of the thiazole-containing compound is shown as the following formula (I-b):
wherein R is 7 Selected from halogen, C1-6 alkyl or C1-6 alkoxy;
n、s、R 2 、R 3 、R 4 、R 5 、X、L 1 、L 2 e is as defined above.
According to a specific aspect of the invention, X is F, L 1 is-S-.
In some embodiments, R 5 Is methyl, ethyl, cyclopropyl or cyclobutyl.
In some embodiments, L 2 Is methyl or ethyl.
In some preferred embodiments according to the invention, L 3 Is methylene, -CH 2 CH 2 -、
In some embodiments according to the invention, the third substituent is F, methyl or ethyl.
In some preferred embodiments according to the present invention, the heterocyclic structure is selected from the group consisting of:
in some preferred embodiments according to the invention E isWherein R is 8 、R 9 、R 10 、R 11 Independently selected from hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy.
In some preferred embodiments according to the invention, R 2 Is hydrogen, R 3 Is methoxy.
In some of these embodiments, the compound is selected from:
the present invention encompasses individual E or Z isomers of any of the above compounds and/or pharmaceutically acceptable salts of any of the above compounds.
The invention also provides a method of inhibiting tyrosine kinase in a patient or in a biological sample comprising administering to the patient or contacting the biological sample with an effective inhibiting amount of a compound of the invention.
In another aspect, the invention provides a method of treating any disorder involving tyrosine kinase activity comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the invention.
The invention also provides application of the compound. The specific technical scheme is as follows:
application of the thiazole-containing compound or pharmaceutically acceptable salt thereof in preparing tyrosine kinase inhibitors.
Further, the tyrosine kinase is interleukin-2 induced T cell kinase.
The application of the thiazole-containing compound or the pharmaceutically acceptable salt thereof in preparing medicaments for preventing and treating inflammatory diseases or cancers or autoimmune diseases.
In some embodiments, the inflammatory disease is arthritis or rheumatoid arthritis.
In some embodiments, the cancer is a solid tumor or a hematological tumor.
In some of these embodiments, the hematological tumor is a lymphoma, leukemia, or myeloma.
The invention also relates to a pharmaceutical composition which comprises one or more thiazole-containing compounds or pharmaceutically acceptable salts thereof.
The invention also provides an intermediate for preparing the thiazole compound or the pharmaceutically acceptable salt thereof, which has a structure shown in the following formula (II-a) or formula (II-b):
wherein:
g is an amino protecting group;
n、s、R 6 、R 7 、R 2 、R 3 、R 4 、R 5 、X、L 1 、L 2 e is as defined above.
Further, G is t-butoxycarbonyl (Boc).
Typical intermediates (II-a) or (II-b) are, for example, the compounds synthesized in the examples described below or the compounds which can be directly expected from them.
The invention also provides a preparation method of the quinazoline-containing compound or the pharmaceutically acceptable salt thereof, which comprises the steps of enabling the intermediate with the general formula (II-a) or the general formula (II-b) to be in contact with the compound of acryloyl chlorideA step of reacting to produce the compound (I-a) or (I-b).
Due to the implementation of the technical scheme, compared with the prior art, the invention has the following advantages:
the thiazole-containing compound or the pharmaceutically acceptable salt thereof has higher inhibition activity on tyrosinase, especially ITK, and the compound can be an effective medicament for treating inflammatory symptoms, allergic diseases, autoimmune diseases and cancers through T cell development, differentiation, signal transduction and generation of proinflammatory cytokines (such as IL-2 and the like) and has higher application value.
Detailed Description
Definition of the definition
In the compounds of the invention, when any variable(e.g. R 1 、R 2 Etc.) occur more than once in any component, the definition of each occurrence is independent of the definition of each other occurrence. Also, combinations of substituents and variables are permissible provided that such combinations stabilize the compounds. The lines drawn from the substituents into the ring system indicate that the bond referred to may be attached to any substitutable ring atom. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic carbon and heteroatom substituents of organic compounds. It is to be understood that substituents and substitution patterns of the compounds of this invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that may be readily synthesized from readily available starting materials by techniques in the art and methods set forth below. If the substituent itself is substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, as long as the structure is stabilized.
As used herein, "alkyl" is meant to include both branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, the definition of "C1-6" in "C1-6 alkyl" includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched chain arrangement.
The term "heteroatom" as used herein means an atom of any element other than carbon and hydrogen. Preferred heteroatoms are nitrogen, oxygen, phosphorus and sulfur.
"heteroalkyl" as used herein refers to a straight or branched aliphatic hydrocarbon chain containing from 1 to 3 heteroatoms, where each carbon and heteroatom useful in the heteroalkyl chain may be optionally substituted independently of each other, and the heteroatoms are independently selected from O, N, P, PO, PO 2 S, SO and SO 2 (e.g., dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, 2-diisopropylaminoethyl, bis-2-methoxyethylamino, [2- (dimethylamino-ethyl) -ethyl-amino ]]-methyl, 3- [2- (dimethylamino-ethyl) -ethyl-amino]-propyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxy, ethoxy, propoxy, methoxymethyl, 2-methoxyethyl).
As used herein, "haloalkyl" refers to a hydrocarbon radical in which one or more hydrogen atoms are replaced with halogen atoms. Halogenated hydrocarbon groups including saturated alkyl and unsaturated alkenyl groups and alkynyl groups, e.g. -CF 3 、-CHF 2 、-CH 2 F、-CF 2 CF 3 、-CHFCF 3 、-CH 2 CF 3 、-CF 2 CH 3 、-CHFCH 3 、-CF 2 CF 2 CF 3 、-CF 2 CH 2 CH 3 、-CF＝CF 2 、-CCl＝CH 2 、-CBr＝CH 2 、-CI＝CH 2 、-C≡C-CF 3 、-CHFCH 2 CH 3 -CHFCH 2 CF 3 。
Alkenyl and alkynyl groups include straight, branched or cyclic containing alkenes and alkynes.
"Cyclohydrocarbyl" as used herein refers to a mono-or polycyclic aliphatic hydrocarbon radical having a specified number of carbon atoms, wherein the ring system may be a saturated ring, or may be an unsaturated, non-aromatic or spiro compound, optionally containing double bonds, such as, for example, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, norbornenyl, indanyl, adamantyl, spiroheptyl and spiro [4.2] heptyl. "cycloalkyl" as used herein refers to a mono-or polycyclic aliphatic alkyl group having a specified number of carbon atoms. Cycloalkylalkyl groups include acyclic alkyl groups in which a hydrogen atom bound to a carbon atom is replaced with a cycloalkyl group.
As used herein, "heterocycle" or "heterocyclyl" refers to a saturated or unsaturated, non-aromatic, monocyclic, bicyclic or bridged polycyclic or spiro compound, comprising 3 to 12 carbon atoms, with heteroatoms selected from O, N, P and S in place of one or more carbon atoms. Further examples of "heterocyclyl" include, but are not limited to: imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, 1, 4-dioxanyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S, S-dioxide, tetrahydropyranyl, tetrahydrothienyl, homothiomorpholinyl-S, S-dioxide, oxazolidone, dihydrofuranyl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S, S-dioxide, homothiomorpholin 1-S-oxide, 2-oxa-5-azabicyclo [2.2.1] heptane, 8-oxa-3-aza-bicyclo [3.2.1] octane, 3, 8-diaza-bicyclo [3.2.1] octane, 2, 5-diaza-bicyclo [2.2.1] heptane, 3, 8-diaza-bicyclo [3.2.1] octane, 3, 9-diaza-bicyclo [4.2.1] nonane, and 2, 6-diaza-bicyclo [3.2.2] nonane, and N-oxides thereof. The attachment of the heterocyclic substituent may be through a carbon atom or through a heteroatom. Heterocyclylalkyl refers to an acyclic alkyl group in which a hydrogen atom bound to a carbon atom is replaced with a heterocycloalkyl group.
"heteroaryl" as used herein refers to a mono-or polycyclic ring containing one or more heteroatoms in place of one or more carbon atoms, the heteroatoms being the same or different and being, for example, N, O, S and P. Examples include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl. Examples of bicyclic heteroaryl groups are indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolyl, quinolinyl, quinoxalinyl, cinnolinyl, 2, 3-naphthyridinyl, quinazolinyl and benzotriazinyl, indolizinyl, oxazolopyridinyl, imidazopyridinyl, 1, 5-naphthyridinyl, indolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzothienyl, benzotetrahydrofuranyl, benzothienyl, purinyl, benzodioxolyl, triazinyl benzoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarin, isocoumarinyl, chromanone, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinone, benzodioxan, benzoxazolinone, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, quinolinyl-N-oxide, indolyl-N-oxide, indolinyl-N-oxide, isoquinolinyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, 2, 3-naphthyridinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide, pyrrolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, benzothiopyranyl-S-oxide, and benzothiopyranyl-S, S-dioxide. Heteroarylalkyl includes acyclic alkyl groups in which a hydrogen atom bound to a carbon atom is replaced by a heteroaryl group.
"halogen" as used herein is meant to include chlorine, fluorine, bromine and iodine.
Unless otherwise defined, alkyl, cycloalkyl, aryl, and heterocyclyl substituents may be unsubstituted or substituted. For example, (C1-6) alkyl may be substituted with one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclyl, such as morpholinyl, piperidinyl and the like.
The term "substituted" refers to a moiety having substituents on one or more carbons of the backbone that replace hydrogen. It will be appreciated that "substitution" or "substitution with … …" includes implicit conditions that the substitution is in accordance with the permissible valence of the substituted atom and substituent, and that the substitution results in stable compounds, e.g., transitions such as those resulting from rearrangement, cyclization, elimination, etc., do not occur spontaneously. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents may include, for example, halogen, hydroxy, carbonyl (such as carboxy, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, mercapto, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, C6-16 aromatic hydrocarbon groups, or aromatic or heteroaromatic moieties. It will be appreciated by those skilled in the art that the substituted moiety on the hydrocarbon chain may itself be substituted, if appropriate.
Included herein are the free forms of the compounds of formula I, as well as pharmaceutically acceptable salts thereof. As used herein, "free form" refers to a non-salt form. Pharmaceutically acceptable salts included herein include not only the exemplary salts of the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the compounds of formula I in free form. The free form of the particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous sodium hydroxide, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention such acid and base salts are otherwise pharmaceutically comparable to their respective free forms.
Included herein are pharmaceutically acceptable salts of the present invention which can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess of an inorganic or organic acid in the form of the desired salt in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.
Pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention formed by the reaction of a basic compound of the invention with an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like, and also include those derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethanesulfonic acid, trifluoroacetic acid and the like.
If the compounds of the present invention are acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared with pharmaceutically acceptable non-toxic bases including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, guava, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Obviously, the definition of any substituent or variable at a particular position in a molecule is independent of the other positions in the molecule. It will be readily appreciated that one of ordinary skill in the art can select substituents or substituted forms of the compounds of the invention by prior art means and methods described herein to provide compounds that are chemically stable and readily synthesized.
The compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
The invention includes all stereoisomers of the compounds of formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and isolated specific stereoisomers are also included in the invention. During the synthesis of preparing such compounds, or using racemization or epimerization methods well known to those of ordinary skill in the art, the resulting product may be a mixture of stereoisomers.
When a tautomer is present in a compound of formula I, the present invention includes any of the possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, unless specifically stated otherwise.
In another aspect, the compounds of the invention include compounds defined herein which are labeled with various isotopes, e.g., where a radioisotope, such as 3 H， 14 C and C 18 F, or in which non-radioactive isotopes are present, e.g 2 H and 13 a compound of C.
When the compounds of formula I and pharmaceutically acceptable salts thereof are in the form of solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent forming the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, and the like may be used.
The term "electron withdrawing group" is used in accordance with its usual chemical meaning to refer to a chemical substituent that modifies the electrostatic force acting on a chemical reaction center by attracting a negative charge adjacent to the chemical reaction center. Thus, the electron withdrawing group attracts electrons away from the reaction center. The result is that the reaction center is partially more aggressive than if the electron withdrawing group were not present. In some embodiments the chemical reaction center is one of two carbons forming a carbon-carbon double bond (alkene).
As used herein, "covalent cysteine-modifying moiety" refers to a substituent capable of reacting with a sulfhydryl functional group in a cysteine amino acid (e.g., cysteine Cys442 of an ITK protein) to form a covalent bond.
As used herein, "ITK inhibitor" refers to a compound described herein that reduces the activity of ITK kinase as compared to a control.
The term "tyrosinase-mediated disease" or "tyrosinase-mediated condition" as used herein means any disease or other detrimental condition in which tyrosinase is known to act, as well as those that are alleviated by treatment with a tyrosinase inhibitor, as well as any disease or other detrimental condition or disease in which tyrosinase is known to act.
The compounds of the invention are suitable for use as tyrosinase inhibitors, which, without wishing to be bound by any particular theory, are particularly useful for treating or lessening the severity of a disease, condition or disorder in which tyrosinase activation is involved. When tyrosinase activation is involved in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a "tyrosinase-mediated disease" or disorder.
The disease or condition includes (but is not limited to): inflammatory diseases or cancers or autoimmune diseases.
As used herein, "inflammatory disease" refers to a disease characterized by abnormal inflammation. Examples of inflammatory diseases include, but are not limited to, autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes, type 1 diabetes, guillain-Barre syndrome, hashimoto's encephalitis, hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, huggrega's syndrome (Sjogren's syndrome), vasculitis, glomerulonephritis, autoimmune thyroiditis Behcet's disease, crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, grafos's disease (Graves ophthalmopathy), inflammatory bowel disease, addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemia reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma and atopic dermatitis.
As used herein, "cancer" refers to all types of cancers, neoplasms, or malignant tumors found in a mammal. "lymphoma" as used herein refers to neoplasms of hematopoietic and lymphoid tissues (e.g., blood, bone marrow, lymph, or lymphoid tissues). Non-limiting examples of lymphomas include B acute lymphoblastic lymphomas, non-hodgkin's lymphomas (e.g., burkitt's lymphoma, small cell lymphoma, and large cell lymphoma), or hodgkin's lymphomas.
As used herein, the term "autoimmune disease" refers to a disease in which a healthy population of the immune system has an abnormal immune response. Examples of autoimmune diseases include, but are not limited to, acute disseminated encephalomyelitis, acute necrotizing hemorrhagic leukoencephalitis, addison's disease, agaglobinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM/anti-TBM nephritis, anti-phospholipid syndrome, autoimmune angioedema, autoimmune aplastic anemia, autoimmune autonomic nerve abnormalities, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune deficiency, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura, autoimmune thyroid disease, autoimmune urticaria, axons or neuronal neuropathy, baluosis, bezite's disease, cardiomyopathy, kalman disease, chagas disease, gauss disease chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, chronic Recurrent Multifocal Osteomyelitis (CRMO), che Ge-schttus syndrome, cicatricial pemphigoid/benign mucoid pemphigoid, ke Genshi syndrome, collectinopathy, congenital heart block, coxsackie myocarditis, CREST disease, primary mixed cryoglobulinemia, demyelinating neuropathy, dermatitis herpetiformis, dermatomyositis, neuromyelitis optica, discoid lupus, dresler syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, nodular erythema, experimental allergic encephalomyelitis, evans syndrome, fibromyalgia, fibroalveolar inflammation, giant cell arteritis, giant cell myocarditis, glomerulonephritis, goodpasture's syndrome, granulomatosis with polyangitis, granulomatosis, graves disease, guillain-Barre syndrome, hemolytic anemia, hennochloride, herpes gestation, hypogammaglobulinemia, idiopathic thrombocytopenic purpura, igA nephropathy, igG 4-related sclerosing diseases, immunomodulatory lipoprotein diseases, inclusion body myositis, interstitial cystitis, juvenile myositis, kawasaki syndrome, lanbert-Eton syndrome, leukocyte ruptured vasculitis, lichen planus, lichen sclerosus, lignan conjunctivitis, linear IgA disease, lyme disease, chronic Guan Nier disease, microscopic polyangiitis, mixed connective tissue disease, mu Lunshi stain, muxia-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, somnolence, neutropenia, cicatrizing pemphigoid, optic neuritis, recurrent rheumatism, paraneoplastic cerebroptosis, lymphomas, and the like paroxysmal nocturnal hemoglobinuria, parrisberg syndrome, parsony-Tener syndrome, pars plana ciliary inflammation, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, multiple nodular arteritis, I, II and type III autoimmune polyadenylic syndrome, polymyalgia rheumatica, polymyositis, post myocardial infarction syndrome, pericardial incision post-syndrome, progesterone dermatitis, primary biliary sclerosis, primary sclerosing cholangitis, idiopathic pulmonary fibrosis, pyoderma gangrene, pure red cell aplasia, raynaud's phenomenon, reactive arthritis, reflex inductive dystrophia, leter's syndrome, recurrent multiple chondritis, restless leg syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, midget syndrome, primary biliary sclerosis, primary sclerosing cholangitis, primary pulmonary fibrosis, reactive arthritis, reflex inductive dystrophy, lymphocytic leukemia, and hyperkinetic leg syndrome, scleritis, scleroderma, sperm and testis autoimmune, stiff person syndrome, subacute bacterial endocarditis, susak's syndrome, sympathogenic ophthalmia, gaoan's arteritis, temporal arteritis/giant cell arteritis, toxosa-Hunter syndrome, transverse myelitis, undifferentiated connective tissue disease, uveitis, vasculitis, bullous skin disease, vitiligo or Wegener's granulomatosis.
The compounds of the invention are useful for the prevention, short-term or long-term treatment of the above-mentioned diseases.
In addition to standard methods known in the literature or exemplified in experimental procedures, the compounds of the present invention can be prepared using the following synthetic schemes.
The compounds and methods of synthesis described in this invention can be better understood in conjunction with the synthetic schemes described below. The synthetic schemes describe methods that can be used to prepare the compounds described in this invention, which are described for illustrative purposes only and are not limiting on the scope of the invention.
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
The technical features of the embodiments described below may be combined arbitrarily, and for brevity, all of the possible combinations of the technical features of the embodiments described below are not described, however, they should be considered as the scope of the description provided in this specification as long as there is no contradiction between the combinations of the technical features.
The following examples merely illustrate a few embodiments of the present invention, which are described in greater detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
The following general synthetic methods were used in the following examples to prepare the corresponding compounds:
example 1: a synthetic intermediate a, which has the structure of
The reaction formula is as follows:
to a suspension of 3-fluoro-5-methylphenol (I-1, 5.0g,39.6 mmol) and cesium carbonate (15.5 g,47.6 mmol) in DMF (100 mL) was added methyl iodide (8.4 g,59.5 mmol) at 0deg.C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with water and extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (with 2%Ethyl acetate in hexane) to give the aforementioned intermediate a (3.7 g, yield 67%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6):δ2.28(s,3H),3.74(s,3H),6.58-6.61(m,3H)。
Example 2: a synthetic intermediate b having the structure of
The reaction formula is as follows:
to a solution of intermediate a (2.2 g,14.3 mmol) in THF (30 mL) at-78deg.C was added lithium diisopropylamide (11 mL,21.4mmol, 2M). The mixture was stirred at-78 ℃ for 30 minutes. DMF (2.1 g,28.5 mmol) was then added to the mixture at-78 ℃. The reaction mixture was stirred at-78 ℃ for 1 hour. The mixture was quenched with water at 0 ℃, extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with 100% dichloromethane) to give intermediate b (1.2 g, 45% yield) as a white solid. LC_MS (ES+): m/z 168.9[ M+H ] ]+.tR＝2.587min； 1 H NMR(400MHz,DMSO-d6):δ2.37(s,3H),3.90(s,3H),6.74(d,J＝12.0Hz,1H),6.90(s,1H),10.25(s,1H)。
Example 3: the synthetic intermediate c has the structure of
The reaction formula is as follows:
to a solution of intermediate b (2.8 g,16.6 mmol) and 2-methylbut-2-ene (19.9 g,283 mmol) in THF (50 mL) at 0deg.C was added an aqueous solution of sodium dihydrogen phosphate (14.3 g,91.6 mmol) (25 mL). Then an aqueous sodium chlorite solution (25 mL) was added at 0deg.CInto the mixture. The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with water, extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give intermediate c (2.7 g, yield 88%) as a colorless oil. LC_MS (ES+): m/z 184.8[ M+H ]]+.tR＝2.270min； 1 H NMR(400MHz,DMSO-d6):δ2.32(s,3H),3.79(s,3H),6.69(d,J＝10.0Hz,1H),6.77(s,1H),13.16(s,1H)。
Example 4: a synthetic intermediate d of the structure
The reaction formula is as follows:
to a solution of intermediate c (3.57 g,19.4 mmol) and trifluoroacetic acid (663 mg,5.8 mmol) in acetonitrile (50 mL) was added N-iodosuccinimide (4.36 g,19.4 mmol). The reaction mixture was stirred at 80℃for 4 hours. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (eluting with 2% methanol in dichloromethane) to give intermediate d (4.0 g, 66% yield) as an off-white solid. LC_MS (ES+): m/z 310.7[ M+H ]]+.tR＝2.605min； 1 H NMR(400MHz,DMSO-d6):δ2.44(s,3H),3.81(s,3H),7.04(s,1H),13.42(s,1H)。
Example 5: the synthetic intermediate e has the structure of
The reaction formula is as follows:
To a suspension of intermediate d (4.0 g,12.9 mmol), sulfur (827 mg,25.8 mmol) and cuprous iodide (248 mg,1.3 mmol) in DMF (50 mL) was added potassium carbonate (3.57 g,25.8 mmol). The mixture was stirred at 90℃for 3 hours. Sodium borohydride (1.46 g,38.7 mmol) was then added to the mixture at 0deg.C. The reaction mixture was stirred at 40 ℃ for 4 hours. The mixture was quenched with 5% hydrochloric acid solution at 0 ℃, extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give intermediate e (3.2 g, yield > 100%) as a brown oil. Lc_ms (es+): m/z 216.8[ m+h ] +. Tr=2.400 min.
Example 6: the synthetic intermediate f has the structure of
The reaction formula is as follows:
to a solution of intermediate e (4.0 g,18.5 mmol) and 5-bromothiazol-2-amine hydrobromide (4.8 g,18.5 mmol) in methanol (40 mL) was added sodium methoxide (3.0 g,55.5 mmol) in methanol (10 mL) at 0deg.C. The reaction mixture was stirred at room temperature overnight. The pH of the mixture was adjusted to 2 with a methanol solution of hydrochloric acid (4M) and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with 5% methanol in dichloromethane) to give intermediate f (1.8 g, 31% yield) as a brown solid. LC_MS (ES+): m/z 315.2[ M+H ] ]+.tR＝1.913min； 1 H NMR(400MHz,DMSO-d6):δ2.57(s,3H),3.84(s,3H),7.01(s,1H),7.49(s,1H)。
Example 7: synthetic intermediate g-1:4- (3- (((2-aminothiazol-5-yl) thio) -2-fluoro-6-methoxy-4-methylbenzoyl) piperazine-1-carboxylic acid tert-butyl ester
Intermediate f (480 mg,3.12 mmol), tert-butyl piperazine-1-carboxylate (610 mg,3.27 mmol), N, N-diisopropylethylamine (803 mg,6.22 mmol) and the polypeptide condensing reagent 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (1.2 g,3.72 mmol) were stirred in DMF solution (8 mL) for 1 hour at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by flash column chromatography on silica gel (dichloromethane/methanol=100/3 to 20/1) to give 4- (3- (((2-aminothiazol-5-yl) thio) -2-fluoro-6-methoxy-4-methylbenzoyl) piperazine-1-carboxylic acid tert-butyl ester (500 mg, 33%). Lc_ms (es+): m/z 483.5[ m+h) as a brown solid]+.tR＝2.617min； 1 H NMR(400MHz,DMSO-d6):δ1.40(s,9H),2.56(s,3H),3.10-3.12(m,2H),3.23-3.26(m,2H),3.36-3.42(m,2H),3.54-3.64(m,2H),3.80(s,3H),6.95(s,1H),7.11(s,1H),7.24(s,2H)。
Example 8: synthesis of intermediate II-b-1:4- (3- ((2- (cyclopropanecarboxamido) thiazol-5-yl) thio) -2-fluoro-6-methoxy-4-methylbenzoyl) piperazine-1-carboxylic acid tert-butyl ester
Intermediate g-1 (250 mg,0.52 mmol), N, N-diisopropylethylamine (134 mg,1.04 mmol) was mixed in dichloromethane (5 mL) and cyclopropanecarbonyl chloride (60 mg,0.57 mmol) was added dropwise at room temperature and stirred for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=1/1) to give tert-butyl 4- (3- ((2- (cyclopropanecarboxamido) thiazol-5-yl) thio) -2-fluoro-6-methoxy-4-methylbenzoyl) piperazine-1-carboxylate (220 mg, 77%) as a white solid. LC_MS (ES+): m/z 551.1[ M+H ] ]+.tR＝3.020min； 1 H NMR(400MHz,DMSO-d6):δ0.87-0.90(m,4H),1.40(s,9H),2.58(s,3H),3.08-3.11(m,2H),3.22-3.24(m,2H),3.36-3.41(m,2H),3.58-3.60(m,2H),3.81(s,3H),6.98(s,1H),7.58(s,1H),12.52(s,1H)。
Example 9: synthesis of Compound 1
Intermediate II-b-1 (220 mg,0.40 mmol) and trifluoroacetic acid (0.5 mL) were mixed and stirred in dichloromethane (6 mL) at room temperature for 1 hour. Concentrating the reaction mixture to obtain a crude product, and sequentially adding four componentsTetrahydrofuran (6 mL), saturated potassium carbonate solution (1.4 mL) and acryloyl chloride (44 mg,0.48 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water, extracted with ethyl acetate (30 mL), and washed with brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel column chromatography (dichloromethane/methanol=20/1) gave compound 1 (62 mg, 31%) as a white solid. LC_MS (ES+): m/z 505.4[ M+H ]]+.tR＝2.538min； 1 H NMR(400MHz,CDCl 3 ):δ0.87-0.91(m,4H),1.89-1.92(m,1H),2.58(s,3H),3.10-3.21(m,2H),3.39-3.46(m,2H),3.54-3.63(m,4H),3.81(s,3H),5.70(d,J＝10.0Hz,1H),6.13(d,J＝16.0Hz,1H),6.73-6.81(m,1H),6.99(s,1H),7.59(s,1H),12.53(s,1H)。
Example 10: synthetic intermediate g-2: (R) -4- (3- (((2-aminothiazol-5-yl) thio) -2-fluoro-6-methoxy-4-methylbenzoyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester
Intermediate f (120 mg,0.38 mmol), (R) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (92 mg,0.46 mmol), N, N-diisopropylethylamine (100 mg,0.76 mmol) and polypeptide condensing reagent 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (220 mg,0.57 mmol) were stirred in DMF solution (3 mL) at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by flash column chromatography on silica gel (dichloromethane/methanol=50/1) to give (R) -4- (3- (((2-aminothiazol-5-yl) thio) -2-fluoro-6-methoxy-4-methylbenzoyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (160 mg, 84%). Lc_ms (es+): M/z497.4[ m+h ] +. Tr= 2.703min as a brown solid.
Example 11: synthesis of intermediate II-b-2: (R) 4- (3- ((2- (cyclopropanecarboxamide) thiazol-5-yl) thio) -2-fluoro-6-methoxy-4-methylbenzoyl) piperazine-2-methyl-1-carboxylic acid tert-butyl ester
Intermediate g-2 (160 mg,0.32 mmol), N, N-diisopropylethylamine (83 mg,0.64 mmol) was mixed in dichloromethane (5 mL) and cyclopropanecarbonyl chloride (40 mg,0.38 mmol) was added dropwise at room temperature and stirred for 1 hour. The reaction mixture was diluted with waterRelease and extract with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (dichloromethane/ethyl acetate=1/1) to give (R) -4- (3- ((2- (cyclopropanecarboxamido) thiazol-5-yl) thio) -2-fluoro-6-methoxy-4-methylbenzoyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (130 mg, 71%) as a brown solid. LC_MS (ES+): m/z 565.1[ M+H ]]+.tR＝3.076min. 1 H NMR(400MHz,CDCl 3 ):δ0.98-1.03(m,3H),1.14-1.18(m,2H),1.21-1.24(m,2H),1.44-1.47(m,9H),2.61(s,3H),2.84-2.88(m,1H),2.96-3.02(m,2H),3.05-3.13(m,1H),3.20-3.32(m,1H),3.72-3.77,3.87-3.94(m,1H),3.77-3.83(m,3H),4.09-4.19,4.33-4.40(m,1H),4.47-4.53,4.58-4.64(m,1H),6.61(d,J＝12.8Hz,1H),7.46(d,J＝5.6Hz,1H),11.15(s,1H).
Example 12: synthesis of Compound 2
Intermediate II-b-2 (120 mg,0.21 mmol) and trifluoroacetic acid (1 mL) were mixed in dichloromethane (3 mL) and stirred for 1 h at room temperature. The reaction mixture was concentrated to give a crude product, to which tetrahydrofuran (3 mL), a saturated potassium carbonate solution (2 mL) and acryloyl chloride (30 mg,0.34 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate (30 mL), and washed with brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel column chromatography (dichloromethane/methanol=20/1) gave compound 2 (60 mg, 67%) as a white solid. LC_MS (ES+): m/z 519.4[ M+H ] ]+.tR＝2.578min. 1 H NMR(400MHz,CDCl 3 ):δ0.96-1.10(m,4H),1.11-1.16(m,2H),1.24-1.32(m,3H),1.65-1.71(m,1H),2.55-2.64(m,3H),2.87-3.06(m,2H),3.12-3.40(m,2H),3.78-3.83(m,3H),4.55-4.68(m,1H),5.69-5.72(m,1H),6.25-6.32(m,1H),6.45-6.58(m,1H),6.58-6.63(m,1H),7.40-7.44(m,1H),11.89(br,1H)。
Example 13: synthetic intermediate g-3:4- (3- (((2-aminothiazol-5-yl) thio) -2-fluoro-6-methoxy-4-methylbenzoyl) -1, 4-diaza-1-carboxylic acid tert-butyl ester
Intermediate f (400 mg,1.27 mmol), tert-butyl 1, 4-diaza-1-carboxylate (268 mg,1.34 mmol), N, N-diisopropylethylamine (329 mg,2.54 mmol) and the polypeptide condensing reagent 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (508 mg,1.34 mmol) were stirred in DMF solution (4 mL) for 1 h at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by flash column chromatography on silica gel (dichloromethane/methanol=100/3 to 50/1) to give 4- (3- (((2-aminothiazol-5-yl) thio) -2-fluoro-6-methoxy-4-methylbenzoyl) -1, 4-diaza-1-carboxylic acid tert-butyl ester (440 mg, 70%). Lc_ms (es+): M/z497.5[ m+h ] as a brown solid]+.tR＝2.615min； 1 H NMR(400MHz,DMSO-d6):δ1.35-1.42(s,11H),2.56(s,3H),3.16-3.24(m,4H),3.38-3.60(m,4H),3.79(d,J＝4.4Hz,3H),3.94(d,J＝4.0Hz,1H),7.09-7.10(m,1H),7.24(s,2H).
Example 14: synthesis of intermediate II-b-3:4- (3- ((2- (cyclopropanecarboxamide) thiazol-5-yl) thio) -2-fluoro-6-methoxy-4-methylbenzoyl) -1, 4-diaza-1-carboxylic acid tert-butyl ester
Intermediate g-3 (120 mg,0.24 mmol), N, N-diisopropylethylamine (62 mg,0.48 mmol) was mixed in dichloromethane (3 mL) and cyclopropanecarbonyl chloride (28 mg,0.27 mmol) was added dropwise at room temperature and stirred for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=1/1) to give tert-butyl 4- (3- ((2- (cyclopropanecarboxamido) thiazol-5-yl) thio) -2-fluoro-6-methoxy-4-methylbenzoyl) -1, 4-diaza-1-carboxylate (108 mg, 79%) as a yellow oil. LC_MS (ES+): m/z 565.2[ M+H ] +. TR= 3.013min.
Example 15: synthesis of Compound 3
Intermediate II-b-3 (140 mg,0.24 mmol) and trifluoroacetic acid (2 mL) were mixed in dichloromethane (6 mL) and stirred for 2 hours at room temperature. The reaction mixture was concentrated to give a crude product, to which tetrahydrofuran (3 mL), a saturated potassium carbonate solution (2 mL) and acryloyl chloride (15 mg,0.15 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate (30 mL), and washed with brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel column chromatography (dichloromethane/methanol=20/1) gave compound 3 (22.6 mg, 23%) as a white solid. LC_MS (ES+): m/z 519.1[ M+H ]]+.tR＝2.522min. 1 H NMR(400MHz,DMSO-d6):δ0.86-0.90(m,4H),1.38-1.49(m,1H),1.75-1.81(m,1H),1.90-1.94(m,1H),2.57(s,3H),3.16-3.23(m,2H),3.44-3.66(m,6H),3.76-3.78(m,3H),5.55-5.72(m,1H),6.09-6.19(m,1H),6.53-6.77(m,1H),6.95-6.97(m,1H),7.58-7.59(m,1H)。
Example 16: synthetic intermediate g-4:4- (3- (((2-aminothiazol-5-yl) thio) -2-fluoro-6-methoxy-4-methylbenzoyl) -3, 3-dimethylpiperazine-1-carboxylic acid tert-butyl ester
Intermediate f (60 mg,0.19 mmol), tert-butyl 3, 3-dimethylpiperazine-1-carboxylate (50 mg,0.23 mmol), N, N-diisopropylethylamine (50 mg,0.23 mmol) and the polypeptide condensing reagent 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (110 mg,0.28 mmol) were stirred in DMF solution (3 mL) for 1 h at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by flash column chromatography on silica gel (dichloromethane/methanol=50/1) to give 4- (3- (((2-aminothiazol-5-yl) thio) -2-fluoro-6-methoxy-4-methylbenzoyl) -3, 3-dimethylpiperazine-1-carboxylic acid tert-butyl ester (45 mg, 50%). Lc_ms (es+): m/z 512.1[ m+h ]+.tR＝2.818min. 1 H NMR(400MHz,CDCl3):δ1.48(s,9H),1.58(s,3H),1.61(s,3H),2.57(s,3H),3.35-3.48(m,6H),3.81(s,3H),5.07(br,2H),6.58(s,1H),7.17(s,1H).
Example 17: synthesis of intermediate II-b-4:4- (3- ((2- (cyclopropanecarboxamide) thiazol-5-yl) thio) -2-fluoro-6-methoxy-4-methylbenzoyl) -3, 3-dimethylpiperazine-1-carboxylic acid tert-butyl ester
Intermediate g-4 (45 mg,0.09 mmol), N, N-diisopropylethylamine (22 mg,0.17 mmol) was mixed in dichloromethane (3 mL) and cyclopropanecarbonyl chloride (12 mg,0.1 mmol) was added dropwise at room temperature and stirred for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (dichloromethane/methanol=50/1) to give 4- (3- ((2- (cyclopropanecarboxamido) thiazol-5-yl) thio) -2-fluoro-6-methoxy-4-methylbenzoyl) -3, 3-dimethylpiperazine-1-carboxylic acid tert-butyl ester (30 mg, 60%) as a brown solid. Lc_ms (es+): m/z 579.6[ m+h ] +. Tr=3.198 min.
Example 18: synthesis of Compound 4
Intermediate II-b-4 (30 mg,0.05 mmol) and trifluoroacetic acid (1 mL) were mixed in dichloromethane (3 mL) and stirred for 1 h at room temperature. The reaction mixture was concentrated to give a crude product, to which tetrahydrofuran (3 mL), a saturated potassium carbonate solution (2 mL) and acryloyl chloride (12 mg,0.12 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water, extracted with ethyl acetate (30 mL), and washed with brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel column chromatography (dichloromethane/methanol=20/1) gave compound 4 (7 mg) as a white solid. LC_MS (ES+): m/z 533.9[ M+H ] ]+.tR＝2.673min. 1 H NMR(400MHz,CDCl 3 ):δ0.80-1.45(m,5H),1.53-1.63(m,6H),2.60(d,J＝6.8Hz,3H),3.40-3.70(m,6H),3.81(s,3H),5.70-5.80(m,1H),6.32-6.58(m,3H),7.45(d,J＝6.4Hz,1H),11.71(br,1H)。
Example 19: synthetic intermediate g-5: (R) -3- (3- (((2-aminothiazol-5-yl) thio) -2-fluoro-6-methoxy-N, 4-dimethylbenzamido) pyrrolidine-1-carboxylic acid tert-butyl ester
Intermediate f (200 mg,0.64 mmol), (R) -3- (methylamino) pyrrolidine-1-carboxylic acid tert-butyl ester (166 mg,0.83 mmol), N, N-diisopropylethylamine (181 mg,1.4 mmol) and polypeptide condensing reagent 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (387 mg,1.02 mmol) in DMF (4 mL) were stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by flash column chromatography on silica gel (dichloromethane/methanol=50/1) to give (R) -3- (3- (((2-aminothiazol-5-yl) thio) -2-fluoro-6-methoxy-N, 4-dimethylbenzamido) pyrrolidine-1-carboxylic acid tert-butyl ester (138 mg, 44%). Lc_ms (es+): m/z 497.5[ m+h ] +. Tr=2.622 min as a brown solid.
Example 20: synthesis of intermediate II-b-5: (R) -3- ((2- (cyclopropanecarboxamide) thiazol-5-yl) thio) -2-fluoro-6-methoxy-N, 4-dimethyl-N- (pyrrolidin-3-yl) benzamide
Intermediate g-5 (138 mg,0.28 mmol), N, N-diisopropylethylamine (72 mg,0.55 mmol) was mixed in dichloromethane (5 mL) and cyclopropanecarbonyl chloride (35 mg,0.33 mmol) was added dropwise at room temperature and stirred for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (dichloromethane/methanol=50/1) to give (R) -3- ((2- (cyclopropanecarboxamido) thiazol-5-yl) thio) -2-fluoro-6-methoxy-N, 4-dimethyl-N- (pyrrolidin-3-yl) benzamide (94 mg, 59%) as a brown solid. LC_MS (ES+): m/z 565.4[ M+H ] +. TR=3.006 min.
Example 21: synthesis of Compound 5
Intermediate II-b-5 (94 mg,0.17 mmol) and trifluoroacetic acid (1 mL) were mixed in dichloromethane (3 mL) at room temperatureMix and stir for 2 hours. The reaction mixture was concentrated to give a crude product, to which tetrahydrofuran (3 mL), a saturated potassium carbonate solution (2 mL) and acryloyl chloride (26.5 mg,0.29 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate (30 mL), and washed with brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel column chromatography (dichloromethane/methanol=20/1) gave compound 5 (9 mg) as a white solid. LC_MS (ES+): m/z 519.4[ M+H ] ]+.tR＝2.496min. 1 H NMR(400MHz,CDCl 3 ):δ0.80-1.02(m,2H),1.11-1.25(m,2H),1.53-1.63(m,1H),2.06-2.35(m,2H),2.59-2.62(m,3H),2.74-3.04(m,3H)3.40-3.70(m,4H),3.81-3.84(m,3H),4.06-4.21(m,1H),5.30-5.38(m,1H),5.70-5.80(m,1H),6.32-6.58(m,2H),6.62-6.64(m,1H),7.45(d,J＝4.8Hz,1H),11.71(br,1H)。
Example 22: biological Activity test
ITK enzyme Activity inhibition assay
The inhibitory activity of ITK was determined using Reaction Biology Corporation. Kinase was incubated with substrate, 100. Mu.M ATP and 3-fold serial dilutions of the inhibitor compound starting at 1. Mu.M. DMSO was used as control. Following manufacturer's recommendations, ADP-Glo was used TM Kinase activity was quantified by the kinase assay system (Promega, madison, wisconsin). The following grades were used: for IC 50 In particular, the results are shown in Table 1, wherein E is greater than or equal to 501nM, D is 100-500 nM, C is 36-99 nM, B is 10-35 nM, A is less than or equal to 10 nM.
Table 1: results of inhibition of ITK enzyme Activity
Numbering of compounds ITK
1 A
2 A
3 B
4 B
5 B
Comparative example E
The structural formula of the comparative example is:
it can be seen that the compounds of the present invention have significantly better inhibitory activity against ITK enzymes than the control compounds.
The above description of the embodiments is only for aiding in the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.

Claims (3)

1. A thiazole-containing compound selected from the structures shown below or a pharmaceutically acceptable salt thereof:
2. A pharmaceutical composition characterized by: comprising one or more thiazole-containing compounds according to claim 1 or a pharmaceutically acceptable salt thereof.
3. Use of a thiazole-containing compound or a pharmaceutically acceptable salt thereof according to claim 1 or a pharmaceutical composition according to claim 2 for the preparation of a tyrosine kinase inhibitor; the tyrosine kinase is interleukin-2 induced T cell kinase.
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Citations (2)

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CN110099684A (en) * 2016-11-03 2019-08-06 科尔沃斯制药股份有限公司 For adjusting the Compounds and methods for of proleulzin induced T lymphocyte kinases

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CN110099684A (en) * 2016-11-03 2019-08-06 科尔沃斯制药股份有限公司 For adjusting the Compounds and methods for of proleulzin induced T lymphocyte kinases

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