WO2023231997A1 - 一种哒嗪类化合物、其制备方法和用途 - Google Patents

一种哒嗪类化合物、其制备方法和用途 Download PDF

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Publication number
WO2023231997A1
WO2023231997A1 PCT/CN2023/096975 CN2023096975W WO2023231997A1 WO 2023231997 A1 WO2023231997 A1 WO 2023231997A1 CN 2023096975 W CN2023096975 W CN 2023096975W WO 2023231997 A1 WO2023231997 A1 WO 2023231997A1
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compound
methyl
alkyl
pharmaceutically acceptable
acceptable salt
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PCT/CN2023/096975
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English (en)
French (fr)
Inventor
许忻
陈嘉
王贯
奚丞昊
刘凤涛
张小娟
李强
李鲜妮
蔡瞻
李敏
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上海华汇拓医药科技有限公司
浙江华海药业股份有限公司
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Publication of WO2023231997A1 publication Critical patent/WO2023231997A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of medicine and relates to a pyridazine compound, its preparation method and use.
  • Psoriasis is an autoimmune system disease. It is a chronic, relapsing, and inflammatory skin disease mediated by immunity. Its pathogenesis is complex and it cannot be completely cured at present.
  • Traditional treatments for psoriasis mainly include topical treatments such as hydrotherapy, phototherapy, traditional Chinese medicine, and salicylates, as well as glucocorticoids, immunosuppressants, and retinoic acid drugs. Due to the remarkable efficacy of biological agents (mainly TNF inhibitors and IL inhibitors) and PDE4 small molecule inhibitors in recent years, they have become the main treatment drugs for psoriasis.
  • Tyrosine Kinase 2 is a non-receptor tyrosine kinase that belongs to the Janus kinase (JAK) family and plays an important role in the pathogenesis of psoriasis.
  • JNK Janus kinase
  • Existing research believes that overactivation of part of the adaptive immune system is the core of the pathogenesis of psoriasis.
  • a variety of immune cells and cytokines jointly lead to the proliferation of downstream keratinocytes, increase angiogenesis, and promote endothelial disease.
  • the expression of adhesion molecules and activated immune cells infiltrate into the diseased skin, eventually forming psoriasis.
  • IL-23 signaling mainly mediates related effects in cells through the TYK2-JAK2 and STAT3 pathways.
  • New tyrosine kinase 2 (Tyrosine Kinase 2, TYK2) inhibitors can block receptor-stimulated activation of TYK2, thereby inhibiting the phosphorylation of STAT1 and STAT3 caused by TYK2, thereby inhibiting the pathogenesis of psoriasis.
  • the present invention provides a class of pyridazine compounds, pharmaceutically acceptable salts and isotope derivatives thereof, their preparation methods, pharmaceutical compositions and their use in medicines for preventing and treating diseases related to the TYK2 signaling pathway.
  • the present invention provides a compound represented by general formula (II) or a pharmaceutically acceptable salt or isotope derivative thereof,
  • R 1 is -C 1-3 deuterated alkyl
  • R 2 is -C 3-6 cycloalkyl, wherein the -C 3-6 cycloalkyl is optionally further selected from the group consisting of hydrogen atoms, -C 1-3 alkyl and halo Substituted by one or more substituents in the element;
  • R 3 is -C 1-3 alkyloxy or -C 3-6 cycloalkyloxy, wherein the -C 1-3 alkyloxy or -C 3-6 cycloalkyloxy is optional Ground is further substituted with one or more substituents selected from hydrogen atoms, deuterium atoms, -C 1-3 alkyl groups and halogens;
  • R 4 is a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally substituted by R a ;
  • R a is -H, -CN, -CF 3 , -C 1-3 alkyl, -C 3-6 cycloalkyl or 4-6 membered heterocyclyl, wherein the -C 1-3 alkyl or -C 3-6 cycloalkyl is optionally further substituted with one or more substituents selected from hydrogen atoms, -C 1-3 alkyl and halogen.
  • R 1 is -CD 3 ;
  • R 2 is substituted or unsubstituted cyclopropyl
  • R 3 is -OCF 3 , -O-CH 2 CF 3 , -OCHF 2 , -O-CH 2 CHF 2 , -OCH(CH 3 ) 2 or
  • R a is -H, -CN, -CHF 2 , methyl, ethyl, trifluoromethyl, -CH(CH 3 ) 2 or cyclopropyl.
  • R 1 is -C 1-3 deuterated alkyl
  • R 2 is -C 3-6 cycloalkyl, wherein the -C 3-6 cycloalkyl is optionally further substituted with one or more selected from hydrogen atoms, -C 1-3 alkyl and halogen substituted by base;
  • R 3 is -C 1-3 alkyloxy or -C 3-6 cycloalkyloxy, wherein the -C 1-3 alkyloxy or -C 3-6 cycloalkyloxy is optional Ground is further substituted with one or more substituents selected from hydrogen atoms, deuterium atoms, -C 1-3 alkyl groups and halogens;
  • R 4 is a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally substituted by R a ;
  • R a is -H, -CN, -CF 3 , -C 1-3 alkyl, -C 3-6 cycloalkyl or 4-6 membered heterocyclyl, wherein the -C 1-3 alkyl or -C 3-6 cycloalkyl is optionally further substituted with one or more substituents selected from hydrogen atoms, -C 1-3 alkyl and halogen.
  • R 1 is -CD 3 ;
  • R 2 is substituted or unsubstituted cyclopropyl
  • R 3 is -OCF 3 , -O-CH 2 CF 3 , -OCHF 2 , -O-CH 2 CHF 2 , -OCH(CH 3 ) 2 or
  • R a is -H, -CN, -CHF 2 , methyl, ethyl, trifluoromethyl, -CH(CH 3 ) 2 or cyclopropyl.
  • R 1 is -C 1-3 deuterated alkyl
  • R 2 is -C 3-6 cycloalkyl
  • R 3 is halogen-substituted C 1-3 alkoxy
  • R 4 is a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally substituted by R a ;
  • R a is -H, -C 1-3 alkyl, -C 1-3 haloalkyl, -C 3-6 cycloalkyl or 4-6 membered heterocyclyl.
  • R 1 is -CD 3 ;
  • R 2 is cyclopropyl
  • R 3 is -OCF 3 or -OCHF 2 .
  • R 4 is a 5-membered heteroaryl group optionally substituted by Ra , the heteroaryl group containing 1, 2, 3 or 4 nitrogen heteroatoms.
  • R 4 is
  • R a is -H, methyl, ethyl, trifluoromethyl or cyclopropyl.
  • R 1 is -C 1-3 deuterated alkyl
  • R 2 is -C 3-6 cycloalkyl
  • R 3 is -C 1-3 alkyloxy or -C 3-6 cycloalkyloxy, wherein the -C 1-3 alkyloxy or -C 3-6 cycloalkyloxy is optional Ground is further substituted with one or more substituents selected from hydrogen atoms, deuterium atoms, -C 1-3 alkyl groups and halogens;
  • R 4 is a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally substituted by R a ;
  • R a is -H, -CN, -CF 3 , -C 1-3 alkyl, -C 3-6 cycloalkyl or 4-6 membered heterocyclyl, wherein the -C 1-3 alkyl or -C 3-6 cycloalkyl is optionally further substituted with one or more substituents selected from hydrogen atoms, -C 1-3 alkyl and halogen.
  • R 1 is -CD 3 ;
  • R 2 is cyclopropyl
  • R 3 is -OCF 3 , -O-CH 2 CF 3 , -OCHF 2 , -O-CH 2 CHF 2 , -OCH(CH 3 ) 2 or
  • R a is -H, -CN, -CHF 2 , methyl, ethyl, trifluoromethyl, -CH(CH 3 ) 2 or cyclopropyl.
  • the compound of the present invention or a pharmaceutically acceptable salt or isotope derivative thereof is selected from the following compounds or a pharmaceutically acceptable salt or isotope derivative thereof:
  • the present invention also provides a preparation method of the compound represented by general formula II, which can be Scheme 1 or Scheme 2,
  • R 1 , R 2 , R 3 and R 4 are as described above.
  • the present invention also provides a pharmaceutical composition, comprising a therapeutically effective amount of a compound represented by formula II and one or more pharmaceutically acceptable carriers and/or diluents.
  • the present invention also provides the use of the compound represented by Formula II or the pharmaceutical composition in the preparation of drugs for preventing and/or treating TYK2-mediated diseases.
  • the TYK2-mediated disease includes an inflammatory disease or an autoimmune disease.
  • the inflammatory and autoimmune diseases are psoriasis, inflammatory bowel disease, or lupus erythematosus.
  • the present invention also provides methods for treating TYK2-mediated diseases, comprising administering a therapeutically effective amount of a compound of Formula II to a patient in need of such treatment.
  • substituted means that any one or more hydrogens on a designated atom or group are replaced by a selected selection of the designated group, provided that the normal valence of the designated atom is not exceeded.
  • 2 hydrogens on the atom are replaced.
  • a stable compound or stable structure is one that is sufficiently stable to withstand isolation from the reaction mixture with useful purity and subsequent formulation into an effective therapeutic agent.
  • “optionally” or “optionally” means that the subsequently described event or situation may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation.
  • “Optionally substituted” refers to a group having 0, 1, 2 or more substituents. It will be understood by those skilled in the art that for any group containing one or more substituents, these groups do not introduce any substitution or substitution pattern that is stereoscopically unrealistic, synthetically unfeasible, and/or inherently unstable. .
  • “optionally substituted aryl” means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.
  • the compounds herein encompass within their scope the compounds, their pharmaceutically acceptable salts and isotopic derivatives thereof, and the compounds of the invention also encompass within their scope their stereoisomers, polymorphs, solvates and prodrug.
  • stereoisomers as used herein encompass within their scope tautomers, meso, racemates, enantiomers, diastereoisomers, and mixtures thereof.
  • isotopic derivative refers to a derivative of a compound in which one or more atoms are replaced by its isotopes (atoms with the same atomic number but an atomic mass or mass number different from the atomic mass or mass number that predominates in nature).
  • isotopes include, but are not limited to, isotopes of hydrogen (e.g. 2 H, 3 H), isotopes of carbon (e.g. 11 C, 13 C and 14 C), isotopes of fluorine (e.g. 18 F), isotopes of nitrogen (e.g. 13 N and 15 N), oxygen isotopes (such as 15 O, 17 O and 18 O).
  • Compounds of the present invention include isotopic derivatives of compounds of the present invention, for example, isotopic derivatives of compound 2
  • alkyl or “alkylene” is meant to include both branched and straight chain saturated aliphatic hydrocarbon radicals having the specified number of carbon atoms.
  • C 1 -C 10 alkyl (or alkylene) is meant to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10 alkyl base.
  • C 1 -C 6 alkyl means an alkyl group having 1 to 6 carbon atoms. An alkyl group may be unsubstituted or substituted such that one or more of its hydrogens are replaced by another chemical group.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl group), pentyl group (for example, n-pentyl group, isopentyl group, neopentyl group), hexyl group (for example, n-hexyl group, isohexyl group), etc.
  • C 1-3 alkyl refers to an alkyl group containing 1 to 3 carbon atoms, specifically methyl, ethyl, n-propyl and isopropyl.
  • deuterated alkyl refers to an alkyl group in which one or more hydrogens are replaced by deuterium.
  • C 1-3 deuterated alkyl refers to a methyl, ethyl, n-propyl and Isopropyl, for example deuterated methyl includes CD 3 , CHD 2 , CH 2 D.
  • halo refers to chlorine, bromine, fluorine and iodine.
  • haloalkyl refers to a substituted alkyl group having one or more halogen substituents.
  • fluoromethyl package Including CF 3 , CHF 2 , CH 2 F.
  • alkyloxy refers to a substituent formed by joining an alkyl group and an oxygen atom as defined herein.
  • C 1-3 alkoxy refers to an alkoxy group containing 1 to 3 carbon atoms, for example, methoxy, ethoxy, propoxy and isopropoxy.
  • haloalkoxy and “halogen-substituted alkoxy” have the same meaning and refer to an alkoxy group having one or more halogen substituents.
  • fluoromethoxy includes OCF3 , OCHF2 , OCH2F .
  • cycloalkyl refers to a cyclized alkyl group, including a monocyclic, bicyclic or polycyclic ring system, wherein the ring of the monocyclic, bicyclic or polycyclic system does not contain an aromatic ring.
  • the cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.
  • C 3-6 cycloalkyl refers to a cycloalkyl group containing 3 to 6 carbon atoms.
  • heterocycle or “heterocyclyl” have the same meaning and refer to any ring structure (saturated, unsaturated, or aromatic) containing at least one ring heteroatom (e.g., nitrogen atom, oxygen atom, or sulfur atom) of).
  • Heterocycles include "aliphatic heterocycles" and "aromatic heterocycles.”
  • the heterocyclyl group is a 4-6 membered heterocyclyl group, examples of which include, but are not limited to, furyl, imidazolidinyl, imidazolinyl, imidazolyl, isoquinolinyl, thiazolyl, Isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, oxazolidinyl, oxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazole 5(4H)-keto, piperazinyl, Piperidinyl, piperidinonyl, 4-piperidinonyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,
  • aliphatic ring or “aliphatic heterocyclyl” have the same meaning and refer to heterocyclic compounds without aromatic characteristics, for example, oxetane, azetidine, pyrrolidinyl, 2H-pyrrolyl , tetrahydrofuranyl.
  • aromatic heterocycle refers to heterocyclic compounds with aromatic characteristics, including single heterocyclic aryl and condensed heterocyclic Ring aromatic group.
  • the monoheterocyclic aryl group can be a 5-6 membered heteroaryl group and can contain 1-4 heteroatoms, such as pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, etc.
  • Typical 5-6 membered heteroaryl groups include, but are not limited to, 2- or 3-thienyl; 2- or 3-furyl; 2- or 3-pyrrolyl; 2-, 4- or 5-imidazolyl; 3 -, 4- or 5-pyrazolyl; 2-, 4- or 5-thiazolyl; 3-, 4- or 5-isothiazolyl; 2-, 4- or 5-azolyl; 3-, 4- or 5-isozolyl; 3-or 5-1,2,4-triazolyl; 4-or 5-1,2,3-triazolyl; tetrazole base; 2-, 3- or 4-pyridyl; 3- or 4-pyridazinyl; 3-, 4- or 5-pyrazinyl; 2-pyrazinyl; 2-, 4- or 5-pyrimidinyl .
  • the fused heterocyclic aryl group can be a tricyclic ring or a bicyclic ring, such as benzoxazole, benzodiazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxybenzene base, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine or indole.
  • aromatic ring of "heteroaryl” may be substituted at one or more ring positions by the substituents mentioned above, such as halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxy Carbonyloxy, aryloxycarbonyloxy, hydroxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl , alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkyl arylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
  • pharmaceutically acceptable salts and “pharmaceutically acceptable salts” and “pharmaceutically acceptable salts” are interchangeable and include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salts” refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include hydrochloride, hydrobromide, etc.; organic acid salts include formate, acetate, etc.
  • the compound molecule of the present invention contains at least one nitrogen atom that can form a salt, it can be converted into the corresponding salt by reacting with the corresponding organic acid or inorganic acid in an organic solvent such as acetonitrile and tetrahydrofuran.
  • organic acids include formic acid and acetic acid
  • typical inorganic acids include hydrochloric acid and hydrobromic acid.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the above compounds and optionally one or more pharmaceutically acceptable carriers and/or diluents.
  • compositions provided by the present invention can be prepared in any form, such as granules, powders, tablets, coated tablets, capsules, pills, syrups, drops, solutions, suspensions and emulsions, or as sustained release of active ingredients.
  • Formulations, where examples of capsules include hard or soft gelatin capsules, granules and powders may be in non-effervescent or effervescent forms.
  • compositions of the present invention may further include one or more pharmaceutically or physiologically acceptable carriers, which will be suitably formulated to facilitate administration.
  • a pharmaceutically or physiologically acceptable carrier may be saline, hot pressurized water, Ringer's solution, buffered saline, glucose, alcohol, honey, mannitol, sorbitol, dextrin, lactose, caramel, gelatin, calcium sulfate , Magnesium stearate, talc, kaolin, glycerin, Tween, agar, calcium carbonate, calcium bicarbonate, surfactants, cyclodextrin and its derivatives, phospholipids, phosphates, starch and its derivatives, One or more of silicon derivatives, cellulose and its derivatives, pyrrolidones, polyethylene glycols, acrylic resins, phthalate esters, acrylic copolymers, and trimellitic acid esters.
  • the pharmaceutical composition of the present invention may also include pharmaceutically or physiologically acceptable additives, such as diluents, lubricants, binders, glidants, disintegrants, sweeteners, flavoring agents, wetting agents, and dispersants. , surfactants, solvents, coating agents, foaming agents, or fragrances.
  • diluents that may be used include, but are not limited to, lactose, sucrose, starch, salt, mannitol, and dicalcium phosphate;
  • examples of lubricants include, but are not limited to, talc, starch, stearates of magnesium or calcium, lycopods, and Stearic acid;
  • examples of binders include, but are not limited to, microcrystalline cellulose, tragacanth, glucose solution, arabic mucilage, gelatin solution, sucrose, and starch paste;
  • examples of glidants include, but are not limited to, colloidal silica ;
  • examples of disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose;Sweetness
  • flavoring agents include, but are not limited to, sucrose, lactose, mannitol
  • Natural flavoring agents such as fruits, and better-tasting compounds, such as, but not limited to, peppermint and methyl salicylate;
  • examples of humectants include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, Diethylene glycol monolaurate and polyoxyethylene lauryl ether.
  • compositions of the present invention can be administered by various routes including oral, intravenous, intraarterial, intraperitoneal, intrathoracic, transdermal, nasal, inhalation, rectal, ocular and subcutaneous administration according to conventional methods.
  • the compounds or pharmaceutical compositions provided by the present invention can treat inflammatory diseases or autoimmune diseases, such as psoriasis, inflammatory bowel disease or lupus erythematosus, through TYK2.
  • inflammatory diseases or autoimmune diseases such as psoriasis, inflammatory bowel disease or lupus erythematosus, through TYK2.
  • the general dosage range of the compounds provided by the present invention is about 0.05 mg/Kg to 1000 mg/kg per day, preferably about 1 mg/kg to 100 mg/kg, and more preferably about 1 to 50 mg/kg.
  • the dosage range of the pharmaceutical composition is Calculated based on the amount of the above compounds it contains.
  • compound 2 can be obtained by replacing 1c with 5-bromo-2-methyl-tetrazole.
  • compound 3 can be obtained by replacing 1c with 3-bromo-1-cyclopropyl-1,2,4-triazole.
  • the first step is the synthesis of 4-(5-methyl-2H-tetrazol-2-yl)-2-(trifluoromethoxy)aniline (4b)
  • compound 5 can be obtained by replacing 1c with 1-methyl-5-bromotetrazole.
  • compound 6 can be obtained by replacing 1c with 3-bromo-2-trifluoromethyl-1,2,4-triazole.
  • compound 7 can be obtained by replacing 1a with 2-(difluoromethoxy)-4-bromophenylamine.
  • compound 8 can be obtained by replacing 1a with 2-(difluoromethoxy)-4-bromophenylamine.
  • compound 9 can be obtained by replacing 1a with 2-(difluoromethoxy)-4-bromophenylamine.
  • compound 10 can be obtained by replacing 1a with 2-(difluoromethoxy)-4-bromophenylamine.
  • compound 11 was obtained by replacing 1a with 2-(difluoromethoxy)-4-bromophenylamine.
  • compound 12 can be obtained by replacing 1a with 2-(difluoromethoxy)-4-bromophenylamine.
  • compound 13 can be obtained by replacing 1c with 5-bromo-2-ethyl-tetrazole.
  • compound 14 can be obtained by replacing 2-methyl-tetrazole with 2-ethyl-tetrazole.
  • compound 15 can be obtained by replacing 1-methyl-5-bromotetrazole with 1-ethyl-5-bromotetrazole.
  • compound 16 can be obtained by replacing 5-methyltetrazole with 5-ethyltetrazole.
  • compound 17 can be obtained by replacing 2-ethyl-5-bromo-tetrazole with 2-ethyl-5-bromo-tetrazole.
  • compound 18 can be obtained by replacing 1a with 2-(difluoromethoxy)-4-bromophenylamine.
  • compound 19 can be obtained by replacing 3-bromo-2-trifluoromethyl-1,2,4-triazole with 2-(trifluoromethyl)-5-bromotetrazole.
  • the third step Synthesis of 2-isopropoxy-4-(1-isopropyl-1H-pyrazol-4-yl)aniline (20g)
  • compound 21 can be obtained by replacing 1-isopropyl-4-bromo-1H-pyrazole with 1-ethyl-4-bromo-1H-pyrazole.
  • compound 22 can be obtained by replacing isopropanol with 2,2,2-trifluoroethanol.
  • compound 23 can be obtained by replacing 1-isopropyl-4-bromo-1H-pyrazole with 1-methyl-4-bromo-1H-pyrazole.
  • compound 24 can be obtained by replacing 1-isopropyl-4-bromo-1H-pyrazole with 1-methyl-4-bromo-1H-1,2,4-triazole.
  • compound 25 can be obtained by replacing 1-isopropyl-4-bromo-1H-pyrazole with 1-cyclopropyl-4-bromo-1H-1,2,4-triazole.
  • compound 26 can be obtained by replacing 1-isopropyl-4-bromo-1H-pyrazole with 2-bromo-5-cyanopyridine.
  • compound 27 can be obtained by replacing isopropanol with cyclopropanol.
  • Step 2 Synthesis of compound 4-[3-(2,2-difluoroethoxy)-4-nitrophenyl]-1-(isopropyl)-1H pyrazole (28d)
  • Step 4 Compound 6-chloro-4-((4-[1-(isopropyl)-1H-pyrazole)-2-(2,2-difluoroethoxy)phenyl]amine)-N -Synthesis of (methyl-d3)pyridazine-3-carboxamide (28f)
  • compound 29 can be obtained by replacing 20b with 28b.
  • compound 30 can be obtained by replacing isopropyl alcohol with 2,2-difluoroethanol.
  • compound 31 can be obtained by replacing isopropyl alcohol with 2,2,2-trifluoroethanol.
  • compound 32 can be obtained by replacing 1-methyl-3-bromo-1H-1,2,4-triazole with 1-difluoromethyl-4-bromo-1H-pyrazole.
  • compound 33 can be obtained by replacing 1-methyl-3-bromo-1H-1,2,4-triazole with 1-cyclopropyl-4-bromo-1H-pyrazole.
  • compound 34 can be obtained by replacing 1-methyl-4-bromo-1H-pyrazole with 1-methyl-3-bromo-1H-1,2,4-triazole.
  • compound 35 can be obtained by replacing 1-methyl-3-bromo-1H-1,2,4-triazole with 1-trifluoromethyl-4-bromo-1H-pyrazole.
  • compound 36 can be obtained by replacing 28c with 1-cyclopropyl-1H-pyrazole-4-boronic acid pinacol ester.
  • compound 37 can be obtained by replacing 1-methyl-3-bromo-1H-1,2,4-triazole with 1-ethyl-4-bromo-1H-pyrazole.
  • compound 38 can be obtained by replacing 28c with 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester.
  • compound 39 can be obtained by replacing propanecarboxamide with (1s,2s)-2-fluorocyclopropanecarboxamide.
  • compound 40 can be obtained by replacing propanecarboxamide with (1s,2s)-2-fluorocyclopropanecarboxamide.
  • compound 41 can be obtained by replacing propanecarboxamide with 2,2-difluorocyclopropanecarboxamide.
  • compound 43 can be obtained by replacing cyclopropylcarboxamide with 2,2-difluorocyclopropane-1-carboxamide.
  • 3-bromo-1-(oxetane-3-methyl)-1H-1,2,4-triazole replaces 3-bromo-1-cyclopropyl-1H- Compound 45 can be obtained from 1,2,4-triazole.
  • compound 47 can be obtained by replacing 1a with 2-(difluoromethoxy)-4-bromophenylamine.
  • compound 48 can be obtained by replacing 3-bromo-1-propyl[1.2.4]triazole with 3-bromo-1-methyl[1.2.4]triazole.
  • compound 49 can be obtained by replacing propanecarboxamide with 3,3-difluorocyclobutanecarboxamide.
  • compound 51 can be obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 3-bromo-1-methoxymethyl[1.2.4]triazole.
  • compound 53 can be obtained by replacing propanecarboxamide with 2,2-difluorocyclopropanecarboxamide.
  • compound 54 can be obtained by replacing 2,2-difluorocyclopropanecarboxamide with cyclopropanecarboxamide.
  • compound 55 can be obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 3-bromo-1-isopropyl[1.2.4]triazole.
  • compound 57 can be obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 1-methyl-3-bromopyrazole.
  • compound 58 can be obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 1-isopropyl-4-bromopyrazole.
  • compound 59 can be obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 1-cyclopropyl-4-bromopyrazole.
  • compound 62 can be obtained by replacing isopropanol with isobutanol.
  • compound 63 can be obtained by replacing isopropoxy group with difluoromethoxy group.
  • compound 64 can be obtained by replacing 5-ethyltetrazole with 5-methyltetrazole.
  • compound 65 can be obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 2-bromo-5-methyl-[1.3.4]oxadiazole.
  • the compound can be obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 4-bromo-1-(2-methoxy-eth-1-yl)pyrazole. 67.
  • compound 68 can be obtained by replacing isopropyl alcohol with trifluoromethanol.
  • compound 69 can be obtained by replacing isopropoxy group with difluoromethoxy group.
  • compound 71 can be obtained by replacing cyclopropyl with fluorocyclopropyl.
  • compound 72 can be obtained by replacing 3-bromo-1-methyltriazole with 4-bromo-1-(3,3,3-trifluoropropyl)pyrazole.
  • compound 73 can be obtained by replacing 3-bromo-1-methyltriazole with 4-bromo-1-cyanomethylpyrazole.
  • compound 79 can be obtained by replacing cyclopropyl with fluorocyclopropyl.
  • compound 80 can be obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 5-fluoro-2-bromopyrimidine.
  • compound 83 can be obtained by replacing 5-methyltetrazole with 4-trifluoromethylpyrazole.
  • compound 83 can be obtained by replacing 5-methyltetrazole with 4-cyanopyrazole.
  • compound 84 can be obtained by replacing 1-ethyl-4-bromopyrazole with 1-(2,2,2-trifluoroethyl)ethyl-4-bromopyrazole.
  • compound 85 can be obtained by replacing 4-bromo-1-ethyl-1H-pyrazole with 4-bromo-1-isopropyl-1H-pyrazole.
  • compound 86 can be obtained from 4-bromo-1-isopropyl-1H-imidazole-5-methyltetrazole.
  • compound 88 can be obtained by replacing 28c with 1-methyl-1H-pyrazole-4-boronic acid pinacol ester.
  • compound 89 can be obtained by replacing 4-bromo-1-(difluoromethyl)-1H-pyrazole with 4-bromo-1-isopropyl-1H-pyrazole.
  • compound 90 can be obtained by replacing 4-bromo-1-methyl-1H-pyrazole with 4-bromo-1-isopropyl-1H-pyrazole.
  • compound 91 can be obtained by replacing 4-bromo-1-isopropylpyrazole with 3-bromo-1-methyl[1.2.4]triazole.
  • compound 92 can be obtained by replacing 4-bromo-1-trifluoroethylpyrazole with 4-bromo-1-isopropylpyrazole.
  • compound 93 can be obtained by replacing cyclopropanecarboxamide with 2,2-difluorocyclopropane-1-carboxamide.
  • compound 94 can be obtained by replacing propanecarboxamide with 2,2-difluorocyclopropanecarboxamide.
  • compound 95 can be obtained by replacing cyclopropanecarboxamide with (2S)-2-fluorocyclopropane-1-carboxamide.
  • compound 96 can be obtained by replacing propanecarboxamide with (1s,2s)-2-fluorocyclopropanecarboxamide.
  • compound 97 can be obtained by replacing cyclopropanamide with 1s,2s-2-fluorocyclopropane-1-carboxamide.
  • compound 97 can be obtained by replacing cyclopropanamide with 1R,2s-2-fluorocyclopropane-1-carboxamide.
  • compound 99 can be obtained by replacing cyclopropanamide with 1s,2s-2-fluorocyclopropane-1-carboxamide.
  • compound 100 can be obtained by replacing 2,2-difluoroethanol with 2-fluoroethanol.
  • compound 101 can be obtained by replacing isopropyl alcohol with ethanol.
  • compound 102 can be obtained by replacing 4-bromo-1-ethylpyrazole with 4-bromo-1-methylpyrazole.
  • compound 103 can be obtained by replacing isopropyl alcohol with methanol.
  • compound 104 can be obtained by replacing 4-bromo-1-isopropylpyrazole with 4-bromo-1-cyclopropylpyrazole.
  • compound 105 can be obtained by replacing 1-ethyl-4-bromopyrazole with 3-bromo-1-aminomethylcarbonylmethyl-1,2,4-triazole.
  • compound 106 can be obtained by replacing 4-bromo-1-methoxypyrazole with 4-bromo-1-ethylpyrazole.
  • the compounds of the present invention have obvious inhibitory activity against TYK2JH2 pseudokinase.
  • liquid chromatography-tandem mass spectrometry (LS/MS/MS) method was used to determine the drug concentration in the plasma of rats at different times after oral administration and intravenous administration of Compound 1 and Compound 7, and to calculate related pharmacokinetic parameters. , to evaluate the pharmacokinetic properties of the compounds of the present invention in rats.
  • Example Compound 1 Example Compound 7.
  • Blood was collected through the orbit before administration and 5 minutes, 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours after administration. Each time, 0.2 milliliters (mL) of blood was collected and placed on the antibiotic. Place in a condenser tube, mix well, and store in a -20°C refrigerator for later use.
  • liquid chromatography-tandem mass spectrometry (LS/MS/MS) method was used to determine the content of compounds in rat whole blood.
  • the pharmacokinetic parameters of the compounds of the present invention after administration are shown in Table 3 below. As shown in Table 3, the compounds of the present invention have good metabolic characteristics and bioavailability.
  • mice Purchase 8-week-old female BALB/c mice with an average weight of 20g.
  • the experiment started after the mice adapted for 3 days.
  • the experiment was divided into five groups: normal control group, model group, example compound group and positive drug group (BMS-986165), with 5-8 mice in each group.
  • the mice in the model group, the example compound group and the positive drug group were anesthetized with intraperitoneal injection of pentobarbital sodium (80 mg/kg). After hair removal on the back, 62.5 mg of 5% imiquimod cream was evenly applied, once a day, normal The control group applied an equal amount of Vaseline.
  • the example compound group (10 mg/kg) was administered intragastrically at 10 mL/kg once a day; the normal control group was intragastrically administered an equal amount of pure water, and the model group was intragastrically administered an equal amount of vehicle for 7 consecutive days.
  • the specific design is shown in Table 4.
  • mice 37 female BALB/c mice, 8 weeks old. Mice were purchased from Beijing Vitong Lihua Experimental Animal Technology Co., Ltd., license number SCXK (Shanghai) 2017-0011, animal certificate number: 20170011003865.
  • Example Compound 1 Example Compound 7.
  • the specific dosage is carried out according to the dosage regimen.
  • mice The skin lesions of the mice were observed every day, and digital photography was used. According to the psoriasis area and severity index (PASI) scoring standards of the mice, erythema, scales and infiltration were given to the skin lesions of the mice. Score the degree (0: none; 1: mild; 2: moderate; 3: severe; 4: extremely severe) and observe the changes in the skin lesions of the mice in each group.
  • PASI psoriasis area and severity index
  • mice Purchase 40 8-week-old C57BL/6 female mice with an average weight of 20g.
  • the animal experiment started after the mice adapted for 7 days.
  • Each mouse was injected with mouse-derived IL-23 subcutaneously in the right ear, once every one day, for a total of 7 times, with a cycle of 14 days.
  • the control and medication groups were orally gavaged twice a day from the first day of modeling. The specific design is shown in Table 5.
  • Example test substance 1 Example test substance 7
  • the efficacy results were analyzed by measuring the skin thickness of the right ear. After the administration, the skin tissue of the right ear was taken for HE staining, and the final efficacy results were confirmed by pathological scoring.
  • Example Compound 1 After administration for 14 days, Example Compound 1, Example Compound 7 and BMS-986165 can all reduce the skin thickness of the right ear of mice, and the final pathological results show that Example Compound 1, Example Compound 7 and BMS-986165 can all improve inflammation. Infiltration, comprehensive pharmacodynamic result analysis shows that Example Compound 1 and Example Compound 7 can achieve the efficacy of high-dose BMS-986165 at low doses. Statistics show that Example Compound 1 and Example Compound 7 have the same efficacy in mice. The medicinal effect is better than BMS-986165.
  • Example compound 1 and example compound 7 groups can significantly reduce the DAI score of mice on the third day of administration, inhibit the weight loss and colon shortening caused by DSS, and significantly reduce the intestinal damage caused by DSS to mice.
  • Pathological examination The compound group of Examples was found to be able to effectively inhibit inflammatory infiltration in the colon.
  • Example Compound 1 Male MRL/lpr mice were selected as the experimental animals of the lupus erythematosus model. The mice were evaluated for lymph node enlargement and skin damage every week, as well as related indicators of urinary albumin and creatinine. The in vivo drug efficacy test found that Example Compound 1, Example Compound 7 can significantly reduce the concentration of autoantibodies (anti-ds DNA, anti-SLE) and urinary protein in Pristane-induced lupus mice, reduce glomerular swelling, and can effectively reduce inflammatory cell infiltration in pathological tissue examination.
  • autoantibodies anti-ds DNA, anti-SLE
  • the purpose of this experiment is to test the acute toxic effects of the example compounds on mice.
  • ICR mice SPF grade, 6-8 weeks old, half male and half male, were purchased from Shanghai Sipur-Bikai Experimental Animal Co., Ltd., license number SCXK (Shanghai) 2018-0006, animal certificate number: 20180006010983.
  • Example Compound 1 Example Compound 7.
  • ICR mice were given different doses of compounds at a single time and were observed continuously for 14 days to record the animal's death, poisoning reaction, weight changes, diet, appearance, behavior, etc. At the end point, animals were dissected, organs were removed, and histopathological examination and related hematological examination were performed.
  • Example Compound 1 and Example Compound 7 were both greater than 1000 milligrams per kilogram (mg/kg). Compared with the mice in the control group, no mice in the administration group showed any signs of toxicity within 14 days from the date of administration. The body weight and behavior were abnormal, and no obvious abnormalities were found in related hematology. Pathological examination showed no toxic effects of the relevant example compounds, indicating that Example Compound 1 and Example Compound 7 of the present invention are safe and can be safely tolerated by animals.
  • the purpose of this experiment is to test the long-term toxic effects of the example compounds on mice.
  • ICR mice SPF grade, 6-8 weeks old, half male and half male, were purchased from Shanghai Sipur-Bikai Experimental Animal Co., Ltd., license number SCXK (Shanghai) 2018-0006, animal certificate number: 20180006010983.
  • Example Compound 1 Example Compound 7.
  • ICR mice were given different doses of compounds and observed continuously for 14 days. Animal death, poisoning reactions, weight changes, diet, appearance, behavior, etc. were recorded. At the end point, animals were dissected, organs were removed, and histopathological examination and related hematological examination were performed.
  • Example Compound 1 and Example Compound 7 were both greater than 500 milligrams per kilogram (mg/kg). Compared with the mice in the control group, the mice in the administration group had no toxicity within 14 days from the date of administration. Abnormalities in body weight and behavior were observed, and no obvious abnormalities were found in related hematology. Pathological examination showed no toxic effects of the relevant example compounds, indicating that Example Compound 1 and Example Compound 7 of the present invention are safe and can be safely tolerated by animals.

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Abstract

本发明提供了式(Ⅱ)所示的哒嗪类化合物、其制备方法和用途。本发明还公开了本发明化合物或其药物组合物在制备用于预防和/或治疗TYK2介导的疾病的药物中的用途。

Description

一种哒嗪类化合物、其制备方法和用途 技术领域
本发明属于医药领域，涉及一种哒嗪类化合物、其制备方法和用途。
背景技术
银屑病属于自身免疫系统疾病，是由免疫介导的慢性、复发性、炎症性皮肤病，其发病机制复杂，目前无法彻底治愈。银屑病的传统疗法主要包括水疗、光疗、中药、水杨酸类等外用治疗方法，以及糖皮质激素、免疫抑制剂和维A酸类药物。由于生物制剂(主要为TNF剂抑制剂和IL抑制剂)和PDE4小分子抑制剂近年来的疗效显著，现已成为银屑病的主要治疗用药。
酪氨酸激酶2(Tyrosine Kinase 2,TYK2)是一种非受体酪氨酸激酶，属于Janus激酶(JAK)家族，在银屑病发病机制上起到重要作用。现有研究认为，部分适应性免疫系统的过度激活是银屑病发病的核心，在银屑病的发病过程中，多种免疫细胞和细胞因子共同导致下游角质细胞增殖，增加血管生成、促进内皮黏附分子的表达，同时激活的免疫细胞浸润到病变皮肤，最终形成银屑病。细胞因子IL-23介导的TH17途径的激活被认为是最主要的途径，而IL-23信号主要通过TYK2-JAK2和STAT3通路在细胞内介导相关效应。新型酪氨酸激酶2(Tyrosine Kinase 2,TYK2)抑制剂可以阻断受体刺激的TYK2的激活，从而抑制TYK2引起的STAT1和STAT3的磷酸化，从而抑制银屑病的发病过程。
本发明提供一类哒嗪化合物、其可药用盐及其同位素衍生物，其制备方法、药物组合物和其在预防和治疗与TYK2信号通路有关疾病药物中的用途。
发明内容
本发明提供一种通式(Ⅱ)所示的化合物或其可药用盐或同位素衍生物，
其中R1为-C1-3氘代烷基；
R2为-C3-6环烷基，其中所述的-C3-6环烷基任选地进一步被选自氢原子、-C1-3烷基和卤 素中的一个或多个取代基所取代；
R3为-C1-3烷基氧基或-C3-6环烷基氧基，其中所述的-C1-3烷基氧基或-C3-6环烷基氧基任选地进一步被选自氢原子、氘原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
R4为5-6元杂芳基，其中所述的5-6元杂芳基任选地被Ra取代；
Ra为-H、-CN、-CF3、-C1-3烷基、-C3-6环烷基或4-6元杂环基，其中所述的-C1-3烷基或-C3-6环烷基任选地进一步被选自氢原子、-C1-3烷基和卤素中的一个或多个取代基所取代。
在本发明的一些实施方式中，
R1为-CD3；
R2为取代或未被取代的环丙烷基；
R3为-OCF3、-O-CH2CF3、-OCHF2、-O-CH2CHF2、-OCH(CH3)2或
在本发明的一些实施方式中，
R4为
Ra为-H、-CN、-CHF2、甲基、乙基、三氟甲基、-CH(CH3)2或环丙烷基。
在本发明的一些实施方式中，R1为-C1-3氘代烷基；
R2为-C3-6环烷基，其中所述的-C3-6环烷基任选地进一步被选自氢原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
R3为-C1-3烷基氧基或-C3-6环烷基氧基，其中所述的-C1-3烷基氧基或-C3-6环烷基氧基任选地进一步被选自氢原子、氘原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
R4为5-6元杂芳基，其中所述的5-6元杂芳基任选地被Ra取代；
Ra为-H、-CN、-CF3、-C1-3烷基、-C3-6环烷基或4-6元杂环基，其中所述的-C1-3烷基或-C3-6环烷基任选地进一步被选自氢原子、-C1-3烷基和卤素中的一个或多个取代基所取代。
在本发明的一些实施方式中，
R1为-CD3；
R2为取代或未被取代的环丙烷基；
R3为-OCF3、-O-CH2CF3、-OCHF2、-O-CH2CHF2、-OCH(CH3)2或
在本发明的一些实施方式中，
R4为
Ra为-H、-CN、-CHF2、甲基、乙基、三氟甲基、-CH(CH3)2或环丙烷基。
在本发明的一些实施方式中，
R1为-C1-3氘代烷基；
R2为-C3-6环烷基；
R3为卤素取代的C1-3烷氧基；
R4为5-6元杂芳基，其中所述的5-6元杂芳基任选地被Ra取代；
Ra为-H、-C1-3烷基、-C1-3卤代烷基、-C3-6环烷基或4-6元杂环基。
在本发明的一些实施方式中，R1为-CD3；
R2为环丙烷基；
R3为-OCF3或-OCHF2。
在本发明的一些实施方式中，
R4为任选被Ra取代5元杂芳基，所述杂芳基包含1、2、3或4个氮杂原子。
在本发明的一些实施方式中，R4为
Ra为-H、甲基、乙基、三氟甲基或环丙烷基。
在本发明的一些实施方式中，R1为-C1-3氘代烷基；
R2为-C3-6环烷基；
R3为-C1-3烷基氧基或-C3-6环烷基氧基，其中所述的-C1-3烷基氧基或-C3-6环烷基氧基任选地进一步被选自氢原子、氘原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
R4为5-6元杂芳基，其中所述的5-6元杂芳基任选地被Ra取代；
Ra为-H、-CN、-CF3、-C1-3烷基、-C3-6环烷基或4-6元杂环基，其中所述的-C1-3烷基或-C3-6环烷基任选地进一步被选自氢原子、-C1-3烷基和卤素中的一个或多个取代基所取代。
在本发明的一些实施方式中，
R1为-CD3；
R2为环丙烷基；
R3为-OCF3、-O-CH2CF3、-OCHF2、-O-CH2CHF2、-OCH(CH3)2或
在本发明的一些实施方式中，
R4为
Ra为-H、-CN、-CHF2、甲基、乙基、三氟甲基、-CH(CH3)2或环丙烷基。
在本发明的一些实施方式中，本发明的化合物或其可药用盐或同位素衍生物，选自如下化合物或其可药用盐或同位素衍生物：



本发明还提供了通式II所示的化合物的制备方法，可以是方案一或方案二，
方案一：
方案二：
化合物IIa硼酸化后和R4X反应得到化合物IId，或化合物IIa和R4H直接反应得到化 合物IId；
化合物IId和化合物IIe反应得到化合物IIf；
化合物IIf和R2C(O)NH2反应得到化合物II；
其中X为Br或I，R1、R2、R3和R4如前所述。
本发明还提供一种药物组合物，包括治疗有效量的式II所示化合物以及一种或多种药学上可接受的载剂和/或稀释剂。
本发明还提供所述的式II所示化合物或者所述的药物组合物在制备用于预防和/或治疗TYK2介导的疾病的药物中的用途。
在本发明的一些实施方式中，所述TYK2介导的疾病包括炎性疾病或自身免疫性疾病。
在本发明的一些实施方式中，所述炎性疾病和自身免疫疾病为银屑病、炎症性肠病或红斑狼疮。
本发明还提供治疗TYK2介导的疾病的方法，包括给需要这种治疗的患者施用治疗有效量的式II所示化合物。
定义和说明
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。
术语“被取代的”是指所指定原子或基团上的任一个或多个氢被指定基团的选择替代，条件为不超过所指定原子的正常价态。当取代基是氧代或酮基(即＝O)时，则所述原子上的2个氢被替代。
取代基和/或变量的组合仅在这些组合产生稳定化合物或可用的合成的中间体时才允许。稳定化合物或稳定结构是指足够稳定以经受自反应混合物以有用的纯度分离出并随后配制成有效治疗药物的化合物。
在本发明中，“任选”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。“任选被取代”是指具有0个、1个、2个或更多个取代基的基团。本领域技术人员应理解，对于含有一或多个取代基的任何基团而言，这些基团不会引入任何立体上不合实际、合成上不可行和/或固有地不稳定的取代或取代模式。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。
术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
除非具体指明，否则本文中化合物在其范围内涵盖化合物、其可药用盐及其同位素衍生物，本发明化合物在其范围内还涵盖其立体异构体、多晶型物、溶剂合物和前药。
除非具体指明，否则本文中立体异构体在其范围内涵盖互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、及其混合物形式。
术语“同位素衍生物”指化合物中一个或多个原子被其同位素(具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子)替代的衍生物。同位素的实例包括但不限于，氢的同位素(例如2H、3H)、碳的同位素(例如11C、13C及14C)、氟的同位素(例如18F)、氮的同位素(例如13N及15N)、氧的同位素(例如15O、17O及18O)。本发明化合物包括本发明化合物的同位素衍生物，例如，化合物2的同位素衍生物
术语“烷基”或”亚烷基”是指包括具有指定碳原子数的支链和直链饱和脂肪族烃基。例如，“C1-C10烷基”(或亚烷基)是指包括C1、C2、C3、C4、C5、C6、C7、C8、C9和C10烷基。另外，例如，“C1-C6烷基”表示具有1至6个碳原子的烷基。烷基可以是未被取代的或被取代的，从而使它的一或多个氢被另一化学基团替代。烷基的实例包括但不限于，甲基(Me)、乙基(Et)、丙基(例如，正丙基和异丙基)、丁基(例如，正丁基、异丁基、叔丁基)、戊基(例如，正戊基、异戊基、新戊基)、己基(例如，正己基、异己基)等。术语“C1-3烷基”是指包含1至3个碳原子的烷基，具体指甲基、乙基、正丙基及异丙基。
术语“氘代烷基”是指烷基中的一或多个氢被氘替代，C1-3氘代烷基指一或多个氢被氘替代的甲基、乙基、正丙基及异丙基，例如氘代甲基包括CD3，CHD2，CH2D。
术语“卤素(halo或halogen)”是指氯、溴、氟和碘。
术语“卤代烷基”是指具有一或多个卤素取代基的被取代的烷基。例如，“氟代甲基”包 括CF3、CHF2、CH2F。
术语“烷氧基”(alkyloxy)是指本文所定义的烷基和氧原子连接形成的取代基。C1-3烷氧基指包含1至3个碳原子的烷氧基，例如，甲氧基、乙氧基、丙氧基和异丙氧基。
术语“卤代烷氧基”和“卤素取代的烷氧基”具有相同含义，是指具有一或多个卤素取代基的烷氧基。例如，“氟代甲氧基”包括OCF3、OCHF2、OCH2F。
术语“环烷基”是指环化的烷基，包括单环、二环或多环体系，其中单环、二环或多环体系的环不包含芳香环。所述环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
C3-6环烷基是指包含3至6个碳原子的环烷基。例如，环丙基、环丁基、环戊基、环己基等。术语“杂环”或“杂环基”具有相同的含义，是指包含至少一个环杂原子(例如，氮原子、氧原子或硫原子)的任何环结构(饱和的、不饱和的或芳族的)。杂环包括“脂杂环”和“芳杂环”。
在本发明的一些实施例中，杂环基为4-6元杂环基，其实例包括但不限于，呋喃基、咪唑烷基、咪唑啉基、咪唑基、异喹啉基、噻唑基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、恶唑烷基、恶唑基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、1,2,4-恶二唑5(4H)-酮基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、四氢呋喃基、四唑基、噻吩基、四氢噻吩、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基、氧杂环丁烷、氮杂环丁烷。术语“脂杂环”或“脂杂环基”具有相同的含义，是指没有芳香特征的杂环化合物，例如，氧杂环丁烷、氮杂环丁烷、吡咯烷基、2H-吡咯基、四氢呋喃基。
术语“芳杂环”、“芳杂环基”、“杂芳环”或“杂芳环基”具有相同的含义，是指有芳香特征的杂环化合物，包括单杂环芳基和稠杂环芳基。所述杂原子独立地选自氮、氧和硫，氮原子可以被取代或不被取代，氮和硫杂原子可任选被氧化(即，N→O和S(O)p，其中p＝1或2)，芳杂环中硫和氧原子的总数不超过1。
在本发明的一些实施方式中，单杂环芳基可以是5-6元杂芳基可以包含1-4个杂原子，例如吡咯、呋喃、噻吩、噻唑、异噻唑、咪唑、三唑、四唑、吡唑、噁唑、异噁唑、吡啶、吡嗪、哒嗪和嘧啶等。
典型的5-6元杂芳基包括但不限于，2-或3-噻吩基；2-或3-呋喃基；2-或3-吡咯基；2-、4-或5-咪唑基；3-、4-或5-吡唑基；2-、4-或5-噻唑基；3-、4-或5-异噻唑基；2-、4- 或5-唑基；3-、4-或5-异唑基；3-或5-1，2，4-三唑基；4-或5-1，2，3-三唑基；四唑基；2-、3-或4-吡啶基；3-或4-哒嗪基；3-、4-或5-吡嗪基；2-吡嗪基；2-、4-或5-嘧啶基。
在本发明的一些实施方式中，稠杂环芳基可以是三环、二环，例如苯并唑、苯并二唑、苯并噻唑、苯并咪唑、苯并噻吩、亚甲二氧基苯基、喹啉、异喹啉、萘啶、吲哚、苯并呋喃、嘌呤、苯并呋喃、脱氮嘌呤或中氮茚。
“杂芳基”的芳环可以在一个或多个环位置上被上文所述的取代基取代，例如卤素、羟基、烷氧基、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、芳基氧基羰基氧基、羟基羰基、烷基羰基、烷基氨基羰基、芳基烷基氨基羰基、烯基氨基羰基、烷基羰基、芳基羰基、芳基烷基羰基、烯基羰基、烷氧基羰基、氨基羰基、烷硫基羰基、磷酸酯、膦酸酯、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、羟基硫代羰基、硫酸酯、烷基亚磺酰基、磺酸酯基、氨磺酰基、磺酰氨基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基，或芳族基团或杂芳族基团，其中芳基基团也可以与非芳族的脂环或杂环稠合或桥连，以形成多环(例如四氢萘)。
术语“药用盐”和“药用可接受的盐”、“药学上可接受的盐”可互换，其包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐例如盐酸盐、氢溴酸盐等；有机酸盐例如甲酸盐、乙酸盐等。
在本发明的化合物分子中包含至少一个可成盐的氮原子时，可以通过在有机溶剂如乙腈、四氢呋喃中与相应的有机酸或无机酸反应，从而转化为相应的盐。典型的有机酸有甲酸、乙酸，典型的无机酸有盐酸、氢溴酸。
本发明还提供了一种药物组合物，其包含上述至少一个化合物以及任选一种或多种药学上可接受的载剂和/或稀释剂。
本发明所提供的药物组合物可以制备为任何形式，例如颗粒、粉末、片剂、包衣片剂、胶囊、药丸、糖浆、滴剂、溶液、混悬剂和乳剂，或者活性成分的缓释制剂，其中胶囊剂的实例包括硬或软明胶胶囊剂，颗粒剂和粉剂可以是非泡腾或泡腾形式。
本发明的药物组合物可进一步包括一种或多种医药或生理上可接受的载体,这些载体将适当配制以便于给药。例如，医药或生理上可接受的载体可以是盐水、热压水、林格氏液、缓冲盐水、葡萄糖、醇、蜂蜜、甘露醇、山梨醇、糊精、乳糖、焦糖、明胶、硫酸钙、 硬脂酸镁、滑石粉、高岭土、甘油、吐温、琼脂、碳酸钙、碳酸氢钙、表面活性剂、环糊精及其衍生物、磷脂类、磷酸盐类、淀粉类及其衍生物、硅衍生物、纤维素类及其衍生物、吡咯烷酮类、聚乙二醇类、丙烯酸树脂类、酞酸酯类、丙烯酸共聚物、苯三酸酯类中的一种或几种。
本发明的药物组合物还可以包括医药或生理上可接受的添加剂，例如稀释剂、润滑剂、粘合剂、助流剂、崩解剂、甜味剂、矫味剂、湿润剂、分散剂、表面活性剂、溶剂、涂层剂、发泡剂、或芳香剂。
可以使用的稀释剂的实例包括但不限于乳糖、蔗糖、淀粉、盐、甘露糖醇和磷酸二钙；润滑剂的实例包括但不限于滑石、淀粉、镁或钙的硬脂酸盐、石松子和硬脂酸；粘合剂的实例包括但不限于微晶纤维素、黄蓍胶、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；助流剂的实例包括但不限于胶体二氧化硅；崩解剂的实例包括但不限于交联羧甲基纤维素钠、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、膨润土、甲基纤维素、琼脂和羧甲基纤维素；甜味剂的实例包括但不限于蔗糖、乳糖、甘露糖醇和人工甜味剂，例如环磺酸钠和糖精，和任意数量的喷雾干燥矫味剂；矫味剂的实例包括但不限于从植物提取的天然矫味剂,例如果实，和味道较好的化合物，例如但不限于薄荷和水杨酸甲酯；湿润剂的实例包括但不限于丙二醇一硬脂酸酯、脱水山梨醇一油酸酯、二甘醇一月桂酸酯和聚氧乙烯月桂基醚。
本发明的药物组合物可以根据传统方法来通过各种途径给药，包括口服、静脉内、动脉内、腹腔内、胸腔内、透皮、鼻腔、吸入、直肠、眼部和皮下导入。
经药理实验验证，本发明所提供的化合物或者药物组合物可通过TYK2治疗炎性疾病或自身免疫性疾病，所述炎性疾病和自身免疫疾病例如银屑病、炎症性肠病或红斑狼疮。
本发明所提供的化合物一般的剂量范围为约每天0.05mg/Kg至1000mg/kg，优选为约1mg/kg至100mg/kg，更优选为约1至50mg/kg，药物组合物的剂量范围为以其含有的上述化合物的量来计算。
具体实施方式
通过以下实施例进一步举例描述本发明，这些方案是说明性的，并不以任何方式限制本发明。对本发明所作的本领域普通技术人员容易实现的任何改动或改变都将落入本发明的范围内。
化合物的制备方法
实施例1
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(1-甲基-1H-1,2,4-三唑-3-基)-2-(三氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(1)的合成
第一步 4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-2-(三氟甲氧基)苯胺(1b)的合成
将4-溴-2-(三氟甲氧基)苯胺(5.00g,19.5mmol)，双联硼(7.44g,29.3mmol)，乙酸钾(4.78g,48.7mmol)和Pd(dppf)Cl2(1.42g,1.95mmol)混合于二氧六环(100mL)中，升温至110℃回流6小时。冷却过滤，滤液浓缩，通过硅胶柱层析纯化(0～20％EA/PE)得到目标产物4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-2-(三氟甲氧基)苯胺(4.2g,产率：71.0％)。
LCMS[M+H]+＝304.2。
第二步 4-(1-甲基-1H-1,2,4-三唑-3-基)-2-(三氟甲氧基)苯胺(1d)的合成
将1b(4.2g,13.9mmol)，1c(2.24g,13.9mmol)碳酸钾(4.80g,34.8mmol)和Pd(dppf)Cl2(1.01g,1.39mmol)混合于二氧六环(100mL)和水(12mL)中,升温至110℃，回流8小时。冷却过滤，滤液加入乙酸乙酯并振荡分层，有机相干燥浓缩，通过硅胶柱层析纯化(0～100％EA/PE，0～12％MeOH/DCM)得到目标产物4-(1-甲基-1H-1,2,4-三唑-3-基)-2-(三氟甲氧基)苯胺(2.3g,产率：64.3％)。
LCMS[M+H]+＝259.2
第三步 6-氯-N-(甲基-d3)-4-((4-(1-甲基-1H-1,2,4-三唑-3-基)-2-(三氟甲氧基)苯基)氨基) 哒嗪-3-甲酰胺(1f)的合成
将1d(500mg,1.94mmol)，1e(524mg,2.52mmol)溶于无水四氢呋喃(30mL)中，冷却至0℃，慢慢滴加LiHMDS(4.85mL,1M in THF,4.85mmol),0℃下搅拌1小时。用饱和氯化铵溶液(20mL)淬灭，然后乙酸乙酯萃取两次。有机相用无水硫酸钠干燥、浓缩，通过硅胶柱层析纯化(0～100％EA/PE，0～12％MeOH/DCM)得到目标产物6-氯-N-(甲基-d3)-4-((4-(1-甲基-1H-1,2,4-三唑-3-基)-2-(三氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(350mg,产率：41.8％)。
LCMS[M+H]+＝431.2。
第四步6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(1-甲基-1H-1,2,4-三唑-3-基)-2-(三氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(1)的合成
将1f(350mg,0.81mmol)，环丙酰胺(208mg,2.44mmol)，碳酸铯(790mg,2.43mmol)，Pd2(dba)3(222mg,0.24mmol)和xantphos(280mg,0.48mmol)混合于无水二氧六环(4mL)中,氮气保护，升温至120℃搅拌16小时。冷却过滤，滤液浓缩，通过硅胶柱层析纯化(0～100％EA/PE，0～12％MeOH/DCM)两次得到目标产物6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(1-甲基-1H-1,2,4-三唑-3-基)-2-(三氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(80mg,产率：20.6％)。
LCMS[M+H]+＝480.2。
1HNMR(400MHz,DMSO-d6)δ11.41(s,1H),11.11(s,1H),9.20(s,1H),8.57(s,1H),8.13(s,1H),8.01(dd,J＝8.4,1.9Hz,1H),7.98-7.95(m,1H),7.73(d,J＝8.4Hz,1H),3.93(s,3H),2.11-2.00(m,1H),0.86-0.74(m,4H).
实施例2
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(2-甲基-四氮唑-5-基)-2-(三氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(2)的合成
参考实施例1的合成方法，以5-溴-2-甲基-四氮唑替代1c可得化合物2。
LCMS[M+H]+＝481.2。
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),11.27(s,1H),9.20(s,1H),8.21(s,1H),8.10(dd,J＝8.5,1.9Hz,1H),8.04(q,J＝1.6Hz,1H),7.83(d,J＝8.4Hz,1H),4.43(s,3H),2.15–1.98(m,1H),0.81(dd,J＝6.1,3.5Hz,4H).
实施例3
6-(环丙烷甲酰胺基)-4-((4-(1-环丙基-1H-1,2,4-三唑-3-基)-2-(三氟甲氧基)苯基)氨基)-N-(甲基-d3)-哒嗪-3-甲酰胺(3)的合成
参考实施例1的合成方法，以3-溴-1-环丙基-1,2,4-三氮唑替代1c可得化合物3。
LCMS[M+H]+＝506.2。
实施例4
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(5-甲基-2H-四唑-2-基)-2-(三氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(4)的合成
第一步 4-(5-甲基-2H-四唑-2-基)-2-(三氟甲氧基)苯胺(4b)的合成
将1a(1.0g,3.90mmol)，4a(656mg,7.80mmol)，碳酸铯(3.17g,9.75mmol)，Pd2(dba)3 (892mg,0.98mmol)和xantphos(1.13g,1.96mmol)混合于无水二氧六环(20mL)中,氮气保护，升温至120℃搅拌16小时。冷却过滤，滤液浓缩，通过硅胶柱层析纯化(0～100％EA/PE，0～10％MeOH/DCM)得到目标产物4b(315mg,产率：31.1％)。
LCMS[M+H]+＝260.2。
第二步 6-氯-N-(甲基-d3)-4-((4-(5-甲基-2H-四唑-2-基)-2-(三氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(4c)的合成
将1e(330mg,1.58mmol)，4b(315mg,1.22mmol)溶于无水四氢呋喃(30mL)中，冷却至0℃，慢慢滴加LiHMDS(3.95mL,1M in THF,3.95mmol),0℃下搅拌1小时。用饱和氯化铵溶液(20mL)淬灭，然后乙酸乙酯萃取两次。有机相用无水硫酸钠干燥、浓缩，通过硅胶柱层析纯化(0～100％EA/PE，0～12％MeOH/DCM)得到目标产物4c(234mg,产率：44.5％)。
[M+H]+＝432.2。
第三步 6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(5-甲基-2H-四唑-2-基)-2-(三氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(4)的合成
将4c(234mg,0.54mmol)，环丙酰胺(138mg,1.63mmol)，碳酸铯(529mg,1.63mmol)，Pd2(dba)3(146mg,0.16mmol)和xantphos(185mg,0.32mmol)混合于无水二氧六环(3mL)中,氮气保护，升温至120℃搅拌16小时。冷却过滤，滤液浓缩，通过硅胶柱层析纯化(0～100％EA/PE，0～15％MeOH/DCM)，然后通过制备HPLC得到目标产物4(32mg,产率：12.3％)。
LCMS[M+H]+＝481.2。
实施例5
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(1-甲基-1H-四唑-5-基)-2-(三氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(5)的合成
参考实施例1的合成方法，以1-甲基-5-溴四氮唑替代1c可得化合物5。
LCMS[M+H]+＝481.2。
1H NMR(400MHz,DMSO-d6)δ11.46(d,J＝7.7Hz,2H),9.24(s,1H),8.30(s,1H),8.01(q,J＝1.6Hz,1H),7.95(dd,J＝8.5,2.0Hz,1H),7.89(d,J＝8.5Hz,1H),4.19(s,3H),2.12–2.03(m,1H),0.83(t,J＝6.0Hz,4H).
实施例6
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(三氟甲氧基)-4-(1-(三氟甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-甲酰胺(6)的合成
参考实施例1的合成方法，以3-溴-2-三氟甲基-1,2,4-三氮唑替代1c可得化合物6。
LCMS[M+H]+＝534.2。
实施例7
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(1-甲基-1H-1,2,4-三唑-3-基)-2-(二氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(7)的合成
参考实施例1的合成方法，以2-(二氟甲氧基)-4-溴苯氨替代1a可得化合物7。
LCMS[M+H]+＝462.2。
1HNMR(400MHz,DMSO-d6)δ11.35(s,1H),10.9(s,1H),9.14(s,1H),8.56(s,1H),8.10(s,1H),7.86-7.89(m,2H),7.61(d,1H),7.33(t,1H),3.92(s,3H),1.97-2.06(m,1H),0.79-1.02(m,4H)。
实施例8
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(5-甲基-2H-四唑-2-基)-2-(二氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(8)的合成
参考实施例4的合成方法，以2-(二氟甲氧基)-4-溴苯氨替代1a可得化合物8。
LCMS[M+H]+＝463.2。
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),11.05(s,1H),9.17(s,1H),8.15(s,1H),7.99(dq,J＝5.0,2.4Hz,2H),7.81(d,J＝9.4Hz,1H),7.43(t,J＝72.9Hz,1H),2.58(s,3H),2.12–2.01(m,1H),0.91–0.71(m,4H).
实施例9
6-(环丙烷甲酰胺基)-4-((4-(1-环丙基-1H-1,2,4-三唑-3-基)-2-(二氟甲氧基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(9)的合成
参考实施例3的合成方法，以2-(二氟甲氧基)-4-溴苯氨替代1a可得化合物9。
LCMS[M+H]+＝488.2。
实施例10
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(2-甲基-2H-四唑-5-基)-2-(二氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(10)的合成
参考实施例2的合成方法，以2-(二氟甲氧基)-4-溴苯氨替代1a可得化合物10。
LCMS[M+H]+＝463.2。
1HNMR(400MHz,DMSO-d6)δ11.38(s,1H),11.05(s,1H),9.15(s,1H),8.18(s,1H), 8.00-7.93(m,2H),7.74(d,1H),7.39(t,1H),4.43(s,3H),2.10-2.00(m,1H),0.82-0.79(m,4H)。
实施例11
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(1-甲基-1H-四唑-5-基)-2-(二氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(11)的合成
参考实施例5的合成方法，以2-(二氟甲氧基)-4-溴苯氨替代1a得化合物11。
LCMS[M+H]+＝463.2。
实施例12
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(二氟甲氧基)-4-(1-(三氟甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-甲酰胺(12)的合成
参考实施例6的合成方法，以2-(二氟甲氧基)-4-溴苯氨替代1a可得化合物12。
LCMS[M+H]+＝516.2。
实施例13
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(2-乙基-四氮唑-5-基)-2-(三氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(13)的合成
参考实施例2的合成方法，以5-溴-2-乙基-四氮唑替代1c可得化合物13。
LCMS[M+H]+＝495.2。
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),11.26(s,1H),9.21(s,1H),8.20(s,1H),8.10(dd,J＝8.4,1.7Hz,1H),8.05(s,1H),7.83(d,J＝8.5Hz,1H),4.76(q,J＝7.3Hz,2H),2.10–2.02(m,1H),1.56(t,J＝7.3Hz,3H),0.85–0.77(m,4H).
实施例14
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(5-乙基-2H-四唑-2-基)-2-(三氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(14)的合成
参考实施例4的合成方法，以2-乙基-四氮唑替代2-甲基-四氮唑可得化合物14。
LCMS[M+H]+＝495.2。
实施例15
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(1-乙基-1H-四唑-5-基)-2-(三氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(15)的合成
参考实施例5的合成方法，以1-乙基-5-溴四氮唑替代1-甲基-5-溴四氮唑可得化合物15。
LCMS[M+H]+＝495.2。
1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),11.45(s,1H),9.25(s,1H),8.29(s,1H),7.96(s,1H),7.88(s,2H),4.51(q,J＝7.2Hz,2H),2.11–2.05(m,1H),1.45(t,J＝7.3Hz,3H),0.89–0.77(m,4H).
实施例16
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(5-乙基-2H-四唑-2-基)-2-(二氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(16)的合成
参考实施例8的合成方法，以5-乙基四氮唑替代5-甲基四氮唑可得化合物16。
LCMS[M+H]+＝477.2。
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),11.05(s,1H),9.17(s,1H),8.15(s,1H),8.00(dq,J＝5.4,2.3Hz,2H),7.81(d,J＝9.4Hz,1H),7.43(t,J＝72.8Hz,1H),2.97(q,J＝7.6Hz,2H),2.15–1.89(m,1H),1.34(t,J＝7.6Hz,3H),0.91–0.67(m,4H).
实施例17
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(2-乙基-2H-四唑-5-基)-2-(二氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(17)的合成
参考实施例10的合成方法，以2-乙基-5-溴-四氮唑替代2-甲基-5-溴-四氮唑可得化合物17。
LCMS[M+H]+＝477.3。
1HNMR(400MHz,DMSO-d6)δ11.41(s,1H),11.07(s,1H),9.18(s,1H),8.21(s,1H),8.00-7.94(m,2H),7.77-7.54(m,1H),7.41(t,1H),4.82(q,2H),2.15-2.08(m,1H),1.59(t,3H),0.82-0.62(m,4H)。
实施例18
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(1-乙基-1H-四唑-5-基)-2-(二氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(18)的合成
参考实施例15的合成方法，以2-(二氟甲氧基)-4-溴苯氨替代1a可得化合物18。
LCMS[M+H]+＝477.3。
1HNMR(400MHz,DMSO-d6)δ11.42(s,1H),11.22(s,1H),9.19(s,1H),8.26(s,1H),7.81-7.74(m,2H),7.54-7.18(t,2H),4.52(q,2H),2.10-2.06(m,1H),1.45(t,3H),0.84-0.80(m,4H).
实施例19
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(二氟甲氧基)-4-(2-(三氟甲基)-四氮唑-5-基)苯基)氨基)哒嗪-3-甲酰胺(19)的合成
参考实施例12的合成方法，以2-(三氟甲基)-5-溴四氮唑替代3-溴-2-三氟甲基-1,2,4-三氮唑可得化合物19。
LCMS[M+H]+＝517.2
实施例20
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-异丙氧基-4-(1-异丙基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(20)的合成
第一步 2-异丙氧基-4-溴硝基苯(20b)的合成
取一个三口瓶，依次加入异丙醇(4.2g,70mmol),THF(180ml),冰水浴下，氮气置换，加入NaH(3.0g,75mmol)，冰水浴下搅拌10min，滴加化合物20a(10.95g，50mmol)的THF(20ml)。反应液于常温反应过夜。反应液饱和NH4Cl，EA萃取。合并有机相，无水Na2SO4干燥，过滤，浓缩。残余物用SiO2柱层析(PE/EA＝2％)得化合物20b(7.2g)。
LCMS[M+H]+＝261.2。
第二步 2-异丙氧基-4-(1-异丙基-1H-吡唑-4-基)硝基苯(20f)的合成
取一个单口瓶，依次加入化合物20b(2.6g，10mmol)，20c(3.04g，12mmol)，Pd(dppf)Cl2(731mg,1mmol)，KOAc(1.56g,20mmol)，1,4-dioxane(100ml)。常温下N2置换3次，反应液于100℃反应2小时。冷却，上述母液中，加入20e(2.07g,11mmol)，K2CO3(3.0g,20mmol),H2O(40mL)。常温下N2换三次，110℃反应2h。反应液加水，EA萃取。合并有机相，无水Na2SO4干燥，过滤，浓缩。残余物用SiO2柱层析(PE/(EA:EtOH＝3:1)＝2-30％)得化合物20f(2.6g)，油状物。
LCMS[M+H]+＝290.2
第三步 2-异丙氧基-4-(1-异丙基-1H-吡唑-4-基)苯胺(20g)的合成
取一个单口瓶，依次加入化合物20f(2.6g，8.99mmol)，Fe(2.5g，45mmol)，饱和氯化铵水溶液(5ml)，EtOH(30mL)。反应液于80℃反应1小时。过滤，浓缩。残余物用SiO2(DCM/MeOH＝2to 5％)纯化得化合物20g(2.2g)褐色油状物
LCMS[M+H]+＝260.2。
第四步 N-(甲基-d3)-4-((2-异丙氧基-4-(1-异丙基-1H-吡唑-4-基)苯基)氨基)-6-氯-哒嗪-3-甲酰胺(20h)的合成
取一个三口瓶，依次加入化合物20g(388mg，1.5mmol)，1e(407mg，1.95mmol)，THF(30mL)，常温下N2置换三次，加入LiHDMS(4.5ml,4.5mmol)。反应液常温反应3h。加水，EA萃取，干燥，过滤，浓缩。残余物用SiO2柱层析(PE/(EA:EtOH＝3:1)＝5-10％)纯化得化合物20h(370mg)。
LCMS[M+H]+＝432.3。
第五步 6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-异丙氧基-4-(1-异丙基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(20)的合成
取一个单口瓶，依次加入化合物20h(200mg，0.46mmol)，环丙酰胺(79mg，0.92mmol)，1,4-dioxane(5mL)，Pd(OAc)2(10mg,0.046mmol),Xantphos(53mg,0.092mmol),Cs2CO3(373g,1.15mmol),常温下N2置换三次，反应液110℃反应3h。加DCM/MeOH＝10:1，用NaSO4过滤，浓缩。残余物用SiO2(PE/(EA:EtOH＝3:1)＝5-40％to DCM/MeOH＝2％)纯化得化合物20(68mg)
LCMS[M+H]+＝481.3。
1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),10.66(s,1H),9.02(s,1H),8.26(d,J＝0.8Hz,1H),8.03(s,1H),7.89(d,J＝0.8Hz,1H),7.37–7.28(m,2H),7.20(dd,J＝8.1,1.8Hz,1H),4.75–4.66(m,1H),4.52–4.41(m,1H),2.11–2.01(m,1H),1.43(d,J＝6.7Hz,6H),1.24(d,J＝6.0Hz,6H),0.87–0.73(m,4H).
实施例21
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-异丙氧基-4-(1-乙基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(21)的合成
参考实施例20的合成方法，以1-乙基-4-溴-1H-吡唑替代1-异丙基-4-溴-1H-吡唑可得化合物21。
LCMS[M+H]+＝467.3。
1H NMR(400MHz,DMSO-d6)δ11.25(s,1H),10.68(s,1H),9.05(s,1H),8.25(s,1H),8.05(s,1H),7.92(s,1H),7.35–7.33(m,2H),7.22–7.19(m,1H),4.75–7.69(m,1H),4.17–4.12(m,2H),2.09–2.04(m,1H),1.41(t,J＝8.0Hz,3H),1.26(d,J＝4.0Hz,6H),0.84–0.78(m,4H).
实施例22
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(2,2,2-三氟乙氧基)-4-(1-异丙基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺
参考实施例20的合成方法，以2,2,2-三氟乙醇替代异丙醇可得化合物22。
MS m/z(ESI):521.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.56(s,1H),9.03(s,1H),8.28(s,1H),7.93(s,1H),7.86(s,1H),7.48(d,J＝1.6Hz,1H),7.35(d,J＝8.2Hz,1H),7.31(dd,J＝8.2,1.6Hz,1H),4.83(q,J＝8.7Hz,2H),4.49(p,J＝6.6Hz,1H),2.04(ddd,J＝12.4,7.7,4.9Hz,1H),1.44(d,J＝6.7Hz,6H),0.82–0.72(m,4H).
实施例23
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-异丙氧基-4-(1-甲基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(23)的合成
参考实施例20的合成方法，以1-甲基-4-溴-1H-吡唑替代1-异丙基-4-溴-1H-吡唑可得化合物23。
LCMS:453.3(M+1)
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.66(s,1H),9.03(s,1H),8.17(s,1H),8.03(s,1H),7.89(d,J＝0.8Hz,1H),7.36–7.25(m,2H),7.18(dd,J＝8.2,1.9Hz,1H),4.69(hept,J＝6.2Hz,1H),3.84(s,3H),2.05(qd,J＝7.4,5.0Hz,1H),1.24(d,J＝6.0Hz,6H),0.87–0.71(m,4H).
实施例24
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-异丙氧基-4-(1-甲基-1H-1,2,4-三氮唑-3-基)苯基)氨基)哒嗪-3-甲酰胺(24)的合成
参考实施例20的合成方法，以1-甲基-4-溴-1H-1,2,4-三氮唑替代1-异丙基-4-溴-1H-吡唑可得化合物24。
LCMS:454.3(M+1)
1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),10.80(s,1H),9.06(s,1H),8.50(s,1H),8.13(s,1H),7.64(d,J＝1.7Hz,1H),7.58(dd,J＝8.3,1.7Hz,1H),7.45(d,J＝8.2Hz,1H),4.65(hept,J＝6.1Hz,1H),3.91(s,3H),2.11–1.99(m,1H),1.28(d,J＝6.0Hz,6H),0.87–0.73(m,4H).
实施例25
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-异丙氧基-4-(1-环丙基-1H-1,2,4-三氮唑-3-基)苯基)氨基)哒嗪-3-甲酰胺(25)的合成
参考实施例20的合成方法，以1-环丙基-4-溴-1H-1,2,4-三氮唑替代1-异丙基-4-溴-1H-吡唑可得化合物25。
LCMS(ESI-MS)m/z:480.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),10.80(s,1H),9.06(s,1H),8.62(s,1H), 8.13(s,1H),7.64(d,J＝1.7Hz,1H),7.58(dd,J＝8.2,1.7Hz,1H),7.45(d,J＝8.2Hz,1H),4.66(p,J＝6.0Hz,1H),3.85–3.75(m,1H),2.10–2.00(m,1H),1.28(d,J＝6.0Hz,6H),1.17–1.11(m,2H),1.07–1.00(m,2H),0.82–0.77(m,4H).
实施例26
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-异丙氧基-4-(5-氰基吡啶-2-基)苯基)氨基)哒嗪-3-甲酰胺(26)的合成
参考实施例20的合成方法，以2-溴-5-氰基吡啶替代1-异丙基-4-溴-1H-吡唑可得化合物26。
LCMS(ESI-MS)m/z:475.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),11.05(s,1H),9.16–8.99(m,2H),8.38–8.21(m,3H),7.93(d,J＝1.9Hz,1H),7.83(dd,J＝8.4,1.9Hz,1H),7.56(d,J＝8.4Hz,1H),4.92–4.56(m,1H),2.07(ddd,J＝7.4,4.2,1.9Hz,1H),1.31(d,J＝6.0Hz,6H),0.91–0.72(m,4H).
实施例27
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-环丙氧基-4-(1-异丙基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(27)的合成
参考实施例20的合成方法，以环丙醇替代异丙醇可得化合物27。
MS m/z(ESI):479.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),10.50(s,1H),9.03(s,1H),8.25(d,J＝0.8Hz,1H),7.90–7.86(m,2H),7.55(d,J＝1.8Hz,1H),7.34–7.20(m,2H),4.49(m,1H),3.98 (tt,J＝6.0,2.9Hz,1H),2.05(ddd,J＝12.4,7.6,4.8Hz,1H),1.44(d,J＝6.6Hz,6H),0.84–0.74(m,6H),0.65–0.58(m,2H).
实施例28
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(2,2-二氟乙氧基)-4-(1-异丙基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(28)的合成
第一步 化合物4-溴-2-(2,2-二氟乙氧基)-1-硝基苯(28b)的合成
将化合物28a(9.0g，41.3mmol)溶于DMF(165mL)中，依次加入Cs2CO3(26.8g,82.6mmol)和1,1-二氟-2-碘代乙烷(9.5g,49.5mmol)，反应液N2保护下于110℃反应7小时。LCMS显示部分原料剩余。反应倒入冰水(300mL)淬灭，析出固体，过滤，滤饼用水洗涤，收集固体干燥得化合物28b(7.2g,收率61.8％)。
LCMS(ESI-MS)m/z:282.0(M+H+).
第二步：化合物4-[3-(2,2-二氟乙氧基)-4-硝基苯基]-1-(异丙基)-1H吡唑(28d)的合成
将化合物28b(1.5g，5.3mmol)溶于1,4-dioxane/H2O(20ml/4ml)中，加入化合物28c(1.51g,6.4mmol)，Pd(dppf)Cl2(387mg,0.53mmol)和Cs2CO3(5.2g,15.9mmol)。反应液于氮气保护下90℃反应4小时。LCMS检测原料反应完全，反应液降至室温，加水(100 mL)，EA(80mL*2)萃取。合并有机相，饱和食盐水(50mL)洗涤，无水Na2SO4干燥，过滤，浓缩。残余物柱层析(EA/PE＝0-35％)得化合物28d(1.4g,收率84.8％)。
LCMS(ESI-MS)m/z:312.2(M+H+).
第三步 化合物2-(2,2-二氟乙氧基)-4-[1-(异丙基)-1H-吡唑-4-基]苯胺(28e)的合成
将化合物28d(1.3g，4.2mmol)溶于THF(20mL)中，加入10％的Pd/C(500mg)。H2保护下室温反应过夜。LCMS显示反应完全。反应液用Celite过滤，THF(20mL)淋洗。滤液减压浓缩，得化合物28e(1.1g,收率98％)，直接用于下一步反应。
LCMS(ESI-MS)m/z:282.2(M+H+).
第四步 化合物6-氯-4-((4-[1-(异丙基)-1H-吡唑)-2-(2,2-二氟乙氧基)苯基]胺基)-N-(甲基-d3)哒嗪-3-甲酰胺(28f)的合成
将化合物28e(0.9g，3.2mmol)和化合物1e(0.67g，3.2mmol)溶于THF(15mL)中，室温下加入LiHMDS(9.6mL,9.6mmol)。室温反应30min。LCMS显示反应完全。反应液倒入冰水(80mL)中，析出固体，固体用水洗涤两次，固体收集，干燥得化合物28f(1.0g,收率69％)。
LCMS(ESI-MS)m/z:454.2(M+H+).
第五步 6-(环丙烷甲酰胺)-4-((4-[1-(异丙基)-1H-吡唑)-2-(2,2-二氟乙氧基)苯基]胺基)-N-(甲基-d3)哒嗪-3-甲酰胺(28)的合成
将化合物28f(400mg，0.88mmol)、环丙酰胺(150mg，1.76mmol)、dppf(98mg，0.176mmol)、K3PO4(560mg，2.64mmol)和1,4-dioxane(10mL)加入反应瓶，抽空换氮后，再加入Pd2(dba)3(81mg，0.088mmol)，再次抽空换氮后，放入90℃油浴，反应5小时。LCMS显示反应完全。，反应液降至室温，加水(80mL)，EA(50mL*2)萃取。合并有机相，饱和食盐水(30mL)洗涤，无水Na2SO4干燥，过滤，浓缩。残余物用Prep-HPLC制备得化合物28(79mg,收率17.8％)。
LCMS(ESI-MS)m/z:503.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.58(s,1H),9.04(s,1H),8.30(s,1H),7.91(d,J＝15.0Hz,2H),7.42(s,1H),7.37–7.22(m,2H),6.28(t,J＝54.8Hz,1H),4.56–4.34(m,3H),2.05(s,1H),1.44(d,J＝6.7Hz,6H),0.86–0.68(m,4H).
实施例29
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(2,2-二氟乙氧基)-4-(5-氰基吡啶-2-基)苯基)氨基)哒嗪-3-甲酰胺(29)的合成
参考实施例26的合成方法，以28b替代20b可得化合物29。
LCMS(ESI-MS)m/z:497.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),10.96(s,1H),9.10(s,1H),9.06(d,J＝2.1Hz,1H),8.38(dd,J＝8.4,2.2Hz,1H),8.29(d,J＝8.4Hz,1H),8.16(s,1H),7.97(d,J＝1.9Hz,1H),7.91(dd,J＝8.4,1.9Hz,1H),7.57(d,J＝8.4Hz,1H),6.35(t,J＝3.6Hz,1H),4.47-4.59(m,2H),2.03-2.09(m,1H),0.78-0.84(m,4H).
实施例30
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(2,2-二氟乙氧基)-4-(1-甲基-1H-1,2,4-三氮唑-3-基)苯基)氨基)哒嗪-3-甲酰胺(30)的合成
参考实施例24的合成方法，以2,2-二氟乙醇替代异丙醇可得化合物30。
LCMS(ESI-MS)m/z:476.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),10.75(s,1H),9.08(s,1H),8.54(s,1H),8.03(s,1H),7.78–7.61(m,2H),7.49(d,J＝8.2Hz,1H),6.78–5.90(m,1H),4.46(td,J＝14.5,3.5Hz,2H),3.93(s,3H),2.14–1.90(m,1H),0.92–0.72(m,4H).
实施例31
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(2,2,2-三氟乙氧基)-4-(1-甲基-1H-1,2,4-三氮唑-3-基)苯基)氨基)哒嗪-3-甲酰胺(31)的合成
参考实施例24的合成方法，以2,2,2-三氟乙醇替代异丙醇可得化合物31。
MS m/z(ESI):494.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),10.72(s,1H),9.06(s,1H),8.54(s,1H),7.99(s,1H),7.76(d,J＝1.7Hz,1H),7.70(dd,J＝8.2,1.7Hz,1H),7.50(d,J＝8.3Hz,1H),4.89(q,J＝8.7Hz,2H),3.92(s,3H),2.05(t,J＝5.5Hz,1H),0.83–0.73(m,4H).
实施例32
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(2,2,2-三氟乙氧基)-4-(1-二氟甲基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(32)的合成
参考实施例31的合成方法，以1-二氟甲基-4-溴-1H-吡唑替代1-甲基-3-溴-1H-1,2,4-三氮唑可得化合物32。
LCMS[M+H]＝529.3
1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.66(s,1H),9.05(s,1H),8.79(s,1H),8.35(s,1H),7.93(s,1H),7.85(t,J＝26.4Hz,1H),7.63(d,J＝1.6Hz,1H),7.48–7.40(m,2H),4.86(q,J＝8.7Hz,2H),2.09–2.01(m,1H),0.84–0.74(m,4H).
实施例33
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(2,2,2-三氟乙氧基)-4-(1-环丙基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(33)的合成
参考实施例31的合成方法，以1-环丙基-4-溴-1H-吡唑替代1-甲基-3-溴-1H-1,2,4-三氮唑可得化合物33。
LCMS(ESI-MS)m/z:519.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.57(s,1H),9.04(s,1H),8.29(s,1H),7.93(s,1H),7.87(s,1H),7.48(d,J＝1.7Hz,1H),7.41–7.28(m,2H),4.83(q,J＝8.8Hz,2H),3.73(tt,J＝7.4,3.9Hz,1H),2.09–2.02(m,1H),1.05(q,J＝3.8,3.0Hz,2H),0.99(dd,J＝7.2,4.5Hz,2H),0.83–0.71(m,4H).
实施例34
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(2,2,2-三氟乙氧基)-4-(1-甲基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(34)的合成
参考实施例31的合成方法，以1-甲基-4-溴-1H-吡唑替1-甲基-3-溴-1H-1,2,4-三氮唑可得化合物34。
LCMS(ESI-MS)m/z:493.20(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.24(s,1H),10.57(s,1H),9.01(s,1H),8.19(s,1H),7.93(s,1H),7.87(s,1H),7.47(s,1H),7.35–7.28(m,2H),4.87–4.80(q,2H),3.86(s,3H),2.06–2.01(m,1H),0.80–0.76(m,4H).
实施例35
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(2,2,2-三氟乙氧基)-4-(1-三氟甲基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(35)的合成
参考实施例31的合成方法，以1-三氟甲基-4-溴-1H-吡唑替代1-甲基-3-溴-1H-1,2,4-三氮唑可得化合物35。
LCMS(ESI-MS)m/z:547.2(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),10.70(s,1H),9.09–9.00(m,2H),8.54(s,1H),7.96(s,1H),7.66(d,J＝1.7Hz,1H),7.53–7.44(m,2H),4.86(q,J＝8.7Hz,2H),2.09–2.01(m,1H),0.84–0.71(m,4H).
实施例36
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(2,2-二氟乙氧基)-4-(1-环丙基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(36)的合成
参考实施例28的合成方法，以1-环丙基-1H-吡唑-4-硼酸频哪醇酯替代28c可得化合物36。
LCMS(ESI-MS)m/z:501.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.25(s,1H),10.60(s,1H),9.06(s,1H),8.32(s,1H),7.95(s,1H),7.91(s,1H),7.44(d,J＝1.7Hz,1H),7.38–7.27(m,2H),6.46-6.13(m,1H),4.5-4.36(m,2H),3.79-3.69(m,1H),2.11–2.02(m,1H),1.12-0.95(m,4H),0.87-0.73(m,4H).
实施例37
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(2,2,2-三氟乙氧基)-4-(1-乙基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(37)的合成
参考实施例31的合成方法，以1-乙基-4-溴-1H-吡唑替代1-甲基-3-溴-1H-1,2,4-三氮唑可得化合物37。
LCMS(ESI-MS)m/z:507.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.56(s,1H),9.04(s,1H),8.25(s,1H),7.94(s,1H),7.87(s,1H),7.48(d,J＝1.7Hz,1H),7.38–7.27(m,2H),4.84(q,J＝8.7Hz,2H),4.14(q,J＝7.3Hz,2H),2.08–2.00(m,1H),1.40(t,J＝7.3Hz,3H),0.89–0.70(m,4H)..
实施例38
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(2,2-二氟乙氧基)-4-(1-乙基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(38)的合成
参考实施例28的合成方法，以1-乙基-1H-吡唑-4-硼酸频哪醇酯替代28c可得化合物38。
LCMS(ESI-MS)m/z:489.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.58(s,1H),9.04(s,1H),8.25(s,1H),7.92(d,J＝16.9Hz,2H),7.42(d,J＝1.8Hz,1H),7.33(d,J＝8.2Hz,1H),7.26(dd,J＝8.2,1.8Hz,1H),6.28(t,J＝3.8Hz,1H),4.42(td,J＝14.2,3.8Hz,2H),4.13(q,J＝7.3Hz,2H),2.05(ddd,J＝10.0,7.6,4.9Hz,1H),1.40(t,J＝7.3Hz,3H),0.83–0.73(m,4H).
实施例39
6-((1s,2s)-2-氟环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(2,2-二氟乙氧基)-4-(1-异丙基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(39)的合成
参考实施例28的合成方法，以(1s,2s)-2-氟环丙烷甲酰胺替代丙烷甲酰胺可得化合物39。
LCMS(ESI-MS)m/z:521.0(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),10.60(s,1H),9.06(s,1H),8.30(s,1H),7.94(s,1H),7.89(s,1H),7.43(d,J＝1.7Hz,1H),7.34(d,J＝8.2Hz,1H),7.29(dd,J＝8.2,1.7Hz,1H),6.27(t,J＝3.8Hz,1H),4.99–4.79(m,1H),4.45(dtd,J＝18.1,14.3,13.8,5.3Hz,3H),2.24(p,J＝6.7Hz,1H),1.63–1.52(m,1H),1.44(d,J＝6.7Hz,6H),1.18-1.10(m,1H)
实施例40
6-((1s,2s)-2-氟环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-异丙氧基-4-(1-乙基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(40)的合成
参考实施例21的合成方法，以(1s,2s)-2-氟环丙烷甲酰胺替代丙烷甲酰胺可得化合物40。
LCMS(ESI-MS)m/z:485.0(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),10.69(s,1H),9.06(s,1H),8.25(s,1H),8.03(s,1H),7.92(s,1H),7.36–7.34(m,2H),7.23–7.21(m,1H),5.02–4.84(m,1H),4.75–4.69(m,1H),4.17–4.12(m,2H),2.29–2.25(m,1H),1.64–1.57(m,1H),1.43–1.39(t,3H),1.27–1.25(d,6H),1.19–1.14(m,1H).
实施例41
6-(2,2-二氟环丙烷-1-甲酰胺基)-N-(甲基-d3)-4-((4-(1-甲基-1H-1,2,4-三唑-3-基)-2-(三氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(41)的合成
参考实施例1的合成方法，以2,2-二氟环丙烷甲酰胺替代丙烷甲酰胺可得化合物41。
LCMS(ESI-MS)m/z:516.2(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),11.13(s,1H),9.22(s,1H),8.57(s,1H),8.06(s,1H),8.03(dd,J＝8.5,1.8Hz,1H),8.00–7.97(m,1H),7.74(d,J＝8.4Hz,1H),3.93(s,3H),3.03(q,J＝11.4,10.6Hz,1H),2.02(t,J＝9.4Hz,2H).
实施例42
6-(2,2-二氟丙烷-1-羧酰胺)-4-((2-(2-(二氟甲氧基))-4-(1-甲基-1H-1,2,4-三氮唑-3-基)苯基)-N-(甲基-D3)吡啶嗪-3-羧酰胺(42)的合成
参考实施例16的合成方法，以3-溴-1-甲基-1H-1,2,4-三唑替代1c，以2,2-二氟环丙烷-1-甲酰胺替代环丙酰胺可得化合物42
LCMS[M+H]+＝498.20
1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.01(s,1H),7.91-7.83(m,2H),7.63(d,J＝8.3Hz,1H),7.45-7.08(m,1H),3.91(s,3H),3.06-2.95(m,1H),2.04-1.93(m,2H).
实施例43
6-(2,2-二氟环丙烷-1-甲酰胺)-4-(2-二氟甲基)氧基-4-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(43)的合成
参考实施例10的合成方法，以2,2-二氟环丙烷-1-甲酰胺替代环丙基甲酰胺可得化合物43。
MS m/z(ESI):499.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),11.08(s,1H),9.20(s,1H),8.12(s,1H),8.00–7.92(m,2H),7.76(d,J＝8.4Hz,1H),7.39(t,J＝73.1Hz,1H),4.43(s,3H),3.10–2.98(m,2H),2.01(q,J＝9.6Hz,3H).
实施例44
4-((4-(1-环丙基-1H-1,2,4-三唑-3-基)-2-(二氟甲氧基)苯基)氨基)-6-(2,2-二氟环丙烷-1-甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺(44)的合成
参考实施例42的合成方法，以3-溴-1-环丙基-1H-1,2,4-三唑替代3-溴-1-甲基-1H-1,2,4-三唑可得化合物44。
LCMS(ESI-MS)m/z:524.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.93(s,1H),9.17(s,1H),8.67(s,1H),8.03(s,1H),7.90-7.86(m,2H),7.63(d,J＝8.4Hz,1H),7.51-7.14(t,J＝73.2Hz,1H),3.84-3.72(m,1H),3.07-2.99(m,1H),2.02-1.96(m,2H),1.21–1.02(m,4H).
实施例45
6-(环丙烷甲酰胺)-4-((2-(二氟甲氧基)-4-(1-(氧杂环丁烷-3-基甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(45)的合成
参考实施例9的合成方法，3-溴-1-(氧杂环丁烷-3-甲基)-1H-1,2,4-三唑替代3-溴-1-环丙基-1H-1,2,4-三唑可得化合物45。
LCMS(ESI-MS)m/z:507.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.75(s,1H),9.11(s,1H),8.32(s,1H),7.95(d,J＝13.8Hz,2H),7.56(dq,J＝3.6,1.9Hz,2H),7.49(d,J＝8.8Hz,1H),7.24(s,1H),4.99(q,J＝5.8Hz,0.5H),4.83(q,J＝5.7,5.3Hz,0.5H),4.49(p,J＝6.6Hz,1H),2.25(t,J＝7.1Hz,1H),1.63–1.54(m,1H),1.44(d,J＝6.7Hz,6H),1.19–1.11(m,1H).
实施例46
6-(环丙基辅助酰基)-4-((2-(二氟甲氧基)-4-(1-乙基-1H-1,2,4-三唑-3-基)苯基)氨基)-n-(甲基-D3)-3-羧酰胺合成
参考实施例7的合成方法，以3-溴-1-乙基-1H-1,2,4-三唑替代3-溴-1-甲基-1H-1,2,4-三唑，可得化合物46。
LCMS[M+H]+＝476.20
1H NMR(400MHz,DMSO-d6)δ11.35(s,1H),10.90(s,1H),9.14(s,1H),8.60(s,1H),8.10(s,1H),7.93-7.82(m,2H),7.62(d,J＝8.3Hz,1H),7.50-7.14(m,1H),4.25(q,J＝7.3Hz,2H),2.08-1.96(m,1H),1.43(t,J＝7.3Hz,3H),0.83-0.79(m,4H).
实施例47
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(5-甲基-1H-四唑-1-基)-2-(二氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(47)的合成
参考实施例4的合成方法，以2-(二氟甲氧基)-4-溴苯氨替代1a可得化合物47。
LCMS[M+H]+＝463.3。
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),11.17(s,1H),9.20(s,1H),8.24(s,1H),7.83(d,J＝8.6Hz,1H),7.76(d,J＝2.3Hz,1H),7.67(dd,J＝8.6,2.4Hz,1H),7.35(t,J＝72.8Hz,1H),2.60(s,3H),2.09(td,J＝7.6,3.8Hz,1H),0.92–0.76(m,4H).
实施例48
6-[(环丙基羰基)氨基]-4-[2-(二氟甲氧基)-4-(1-丙基-1H-1,2,4-三唑-3-基)苯胺基]-N-(三氘代甲基)-哒嗪-3-甲酰胺(48)的合成
参考实施例7的合成方法，以3-溴-1-丙基[1.2.4]三氮唑替代3-溴-1-甲基[1.2.4]三氮唑可得化合物48。
LCMS(ESI-MS)m/z:490.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.35(s,1H),10.91(s,1H),9.14(s,1H),8.62(s,1H),8.11(s,1H),7.91–7.88(m,2H),7.64–7.63(m,1H),7.46–7.22(m,1H),4.21–4.18(m,2H),2.09–2.06(m,1H),1.87–1.84(m,2H),0.88–0.81(m,7H).
实施例49
6-(3,3-二氟环丁烷-1-甲酰胺基)-N-(甲基-d3)-4-((4-(1-环丙基-1H-1,2,4-三唑-3-基)-2-(三氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(49)的合成
参考实施例3的合成方法，以3,3-二氟环丁烷甲酰胺替代丙烷甲酰胺可得化合物49。
LCMS(ESI-MS)m/z:556.3(M+H+).
1H NMR(600MHz,Chloroform-d)δ13.29(s,1H),10.39(s,1H),9.67(s,1H),8.17(s,1H),7.45(dd,J＝8.0,1.7Hz,1H),7.40(td,J＝7.6,1.3Hz,1H),7.35(td,J＝7.8,1.6Hz,1H),7.17(d,J＝8.2Hz,1H),3.68(dd,J＝7.5,3.9Hz,1H),3.26(t,J＝8.4Hz,1H),3.02–2.81(m,4H),1.30(d,J＝3.8Hz,2H),1.19(d,J＝7.2Hz,2H).
实施例50
6-(环丙基辅助酰基)-4-((2-(2-(二氟甲氧基)-4-(1-甲基-1H-吡唑-4-基)苯基)苯基)氨基)-n-(甲基-D3)吡啶嗪-3-吡啶嗪-3-羧酰胺(50)的合成
参考实施例16的合成方法，以1-甲基-4-溴吡唑替代3-溴-1-甲基[1.2.4]三氮唑，可得化合物50
LCMS[M+H]+＝461.30
1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),10.80(s,1H),9.11(s,1H),8.04(s,1H), 7.75(d,J＝2.2Hz,1H),7.70(d,J＝8.6Hz,2H),7.53(d,J＝8.2Hz,1H),7.46-7.10(m,1H),7.28(s,1H),6.76(d,J＝2.3Hz,1H),3.88(s,3H),2.08-1.09(m,1H),0.81-0.77(m,4H).
实施例51
6-(2,2-二氟环丙烷-1-羧酰氨基)-4-((2-(二氟甲氧基)-4-(1-(甲氧基甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(51)的合成
参考实施例42的合成方法，以3-溴-1-甲氧基甲基[1.2.4]三氮唑替代3-溴-1-甲基[1.2.4]三氮唑可得化合物51。
LCMS(ESI-MS)m/z:528.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),10.96(s,1H),9.19(s,1H),8.83(s,1H),8.06(s,1H),7.93(dd,J＝8.3,1.8Hz,1H),7.90(d,J＝1.7Hz,1H),7.67(d,J＝8.3Hz,1H),7.35(t,J＝73.2Hz,1H),5.53(s,2H),3.30(s,3H),3.08–2.98(m,1H),2.06–1.95(m,2H).
实施例52
6-(环丙烷甲酰胺)-4-((2-(二氟甲氧基)-4-(1-(2-(甲基氨基)乙基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(52)的合成
参考实施例7的合成方法，以3-溴-1-(2-氨甲基乙-2-基)-[1.2.4]三氮唑替代3-溴-1- 甲基[1.2.4]三氮唑可得化合物52。
LCMS(ESI-MS)m/z:505.3(M+H+).
1H NMR(400MHz,Methanol-d4)δ8.70(s,1H),8.17–8.12(m,2H),7.76(d,J＝8.9Hz,1H),7.08(s,1H),7.05(t,J＝7.2Hz,1H),4.74–4.67(m,2H),3.63(t,J＝5.7Hz,2H),2.81(s,3H),1.92–1.85(m,1H),1.18–1.05(m,4H).
实施例53
4-((4-(1-环丙基-1H-1,2,4-三唑-3-基)-2-(三氟甲氧基)苯基)氨基)-6-(2,2-二氟环丙烷-1-甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺(53)的合成
参考实施例3的合成方法，以2,2-二氟环丙烷甲酰胺替代丙烷甲酰胺可得化合物53。
LCMS(ESI-MS)m/z:542.2(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),11.65(s,1H),9.24(s,1H),8.71(s,1H),8.11-7.99(m,3H),7.76(d,J＝5.6Hz,1H),3.87-3.83(m,1H),3.08–3.02(m,1H),2.05–2.00(m,2H),1.19–1.06(m,4H).
实施例54
6-(环丙烷甲酰胺)-4-((2-(二氟甲氧基)-4-(1-(甲氧基甲基)-1H-吡唑-4-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(54)的合成
参考实施例51的合成方法，以环丙烷甲酰胺替代2,2-二氟环丙烷甲酰胺可得化合物54。
LCMS(ESI-MS)m/z:491.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),10.75(s,1H),9.10(s,1H),8.44(s,1H),8.07(d,J＝0.80Hz,1H),7.99(s,1H),7.59-7.56(m,2H),7.51-7.49(m,1H),7.25(t,J＝73.6Hz,1H),5.38(s,2H),3.25(s,3H),2.07–2.03(m,1H),0.81–0.77(m,4H).
实施例55
6-[(环丙基羰基)氨基]-4-{2-(二氟甲氧基)-4-[1-异丙基-1H-1,2,4-三唑-3-基]苯胺基}-N-(三氘代甲基)-哒嗪-3-甲酰胺(55)的合成
参考实施例7的合成方法，以3-溴-1-异丙基[1.2.4]三氮唑替代3-溴-1-甲基[1.2.4]三氮唑可得化合物55。
LCMS(ESI-MS)m/z:490.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.36(s,1H),10.91(s,1H),9.15(s,1H),8.65(s,1H),8.11(s,1H),7.92–7.87(m,2H),7.65–7.63(m,1H),7.52–7.15(m,1H),4.70–4.63(m,1H),2.09–2.06(m,1H),1.51–1.50(m,6H),0.85–0.81(m,4H).
实施例56
6-(环丙基辅助酰基)-4-((2-(2-(二氟甲氧基)-4-(1-乙基-1H-吡唑-4-基)苯基)氨基)氨基)-n-(甲基-D3)吡啶嗪-3-吡啶嗪-3-羧酰胺的合成
参考实施例7的合成方法，以1-乙基-4-溴吡唑替代3-溴-1-甲基[1.2.4]三氮唑，可得化合物56
LCMS[M+H]+＝475.30
1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),10.72(s,1H),9.09(s,1H),8.27(d,J＝0.8Hz,1H),7.99–7.90(m,2H),7.57–7.44(m,3H),7.42-7.05(m,1H),4.14(q,J＝7.3Hz,2H),2.04-2.03(m,1H),1.39(t,J＝7.3Hz,3H),0.85–0.74(m,4H).
实施例57
6-(环丙烷甲酰胺)-4-((2-(二氟甲氧基)-4-(1-甲基-1H-吡唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(57)的合成
参考实施例7的合成方法，以1-甲基-3-溴吡唑替代3-溴-1-甲基[1.2.4]三氮唑，可得化合物57。
LCMS(ESI-MS)m/z:461.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),10.80(s,1H),9.11(s,1H),8.03(s,1H),7.75(d,J＝2.2Hz,1H),7.71(d,J＝1.9Hz,1H),7.68(d,J＝1.8Hz,1H),7.53(d,J＝8.1Hz,1H),6.76(d,J＝2.3Hz,1H),3.88(s,3H),2.06(dt,J＝6.1,3.7Hz,1H),0.85–0.66(m,4H).
实施例58
6-(环丙烷甲酰胺)-4-((2-(二氟甲氧基)-4-(1-异丙基-1H-吡唑-4-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(58)的合成
参考实施例7的合成方法，以1-异丙基-4-溴吡唑替代3-溴-1-甲基[1.2.4]三氮唑，可得化合物58。
LCMS(ESI-MS)m/z:489.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),10.72(s,1H),9.09(s,1H),8.31(d,J＝0.8Hz,1H),7.97(s,1H),7.92(d,J＝0.8Hz,1H),7.56–7.51(m,2H),7.47(d,J＝8.9Hz,1H),7.24(s,1H),4.49(p,J＝6.6Hz,1H),2.04(td,J＝7.6,3.9Hz,1H),1.43(d,J＝6.7Hz,6H),0.86–0.73(m,4H).
实施例59
6-(环丙烷甲酰胺)-4-((4-(1-环丙基-1H-吡唑-4-基)-2-(二氟甲氧基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(59)的合成
参考实施例7的合成方法，以1-环丙基-4-溴吡唑替代3-溴-1-甲基[1.2.4]三氮唑，可得化合物59。
LCMS(ESI-MS)m/z:487.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),10.73(s,1H),9.09(s,1H),8.32(d,J＝0.8Hz,1H),7.97(s,1H),7.92(d,J＝0.8Hz,1H),7.56–7.51(m,2H),7.47(d,J＝8.4Hz,1H),3.73(tt,J＝7.4,3.9Hz,1H),2.10–2.01(m,1H),1.09–1.01(m,2H),1.01–0.93(m,2H),0.84–0.73(m,4H).
实施例60
6-[(环丙基羰基)氨基]-4-{2-(二氟甲氧基)-4-[1-(2-氨基-乙-1-基)-1H-1,2,4-三唑-3-基]苯胺基}-N-(三氘代甲基)-哒嗪-3-甲酰胺(60)的合成
参考实施例7的合成方法，以3-溴-1-(2-氨基-乙-1-基)[1.2.4]三氮唑替代3-溴-1-甲基[1.2.4]三氮唑可得化合物60。
MS m/z(ESI):491.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.89(s,1H),9.13(s,1H),8.57(s,1H),8.35(s,2H),8.08(s,1H),7.91–7.84(m,2H),7.62(d,J＝8.3Hz,1H),7.32(t,J＝73.2Hz,1H),4.20(s,2H),2.99(s,2H),2.10–2.01(m,1H),0.80(dd,J＝6.4,3.2Hz,4H).
实施例61
6-(环丙烷甲酰胺)-4-((2-(二氟甲氧基)-4-(1-(2,2,2-三氟乙基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(61)的合成
参考实施例7的合成方法，3-溴-1-(2-氨基-乙-1-基)[1.2.4]三氮唑替代3-溴-1-甲基[1.2.4]三氮唑，可得化合物61。
LCMS(ESI-MS)m/z:530.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),11.16(s,1H),9.18(s,1H),8.24(s,1H),8.21(s,1H),7.78–7.71(m,1H),7.69–7.63(m,2H),7.36(t,J＝7.2Hz,1H),5.31(q,J＝8.8Hz,2H),2.12–2.02(m,1H),0.89–0.76(m,4H).
实施例62
6-((环丙基甲酰胺基)-4-((2-异丁氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3))哒嗪-3-甲酰胺
参考实施例24的合成方法，以异丁醇替代异丙醇可得化合物62。
LCMS:468(M+1)
1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.76(s,1H),9.06(s,1H),8.51(d,J＝0.7Hz,1H),8.05(s,1H),7.64–7.55(m,2H),7.44(d,J＝8.2Hz,1H),3.93–3.88(m,3H),3.85(d,J＝6.3Hz,2H),2.10–1.91(m,2H),0.94(d,J＝6.7Hz,6H),0.85–0.72(m,4H).
实施例63
4-((4-(1-(氰基甲基)-1H-1,2,4-三唑-3-基)-2-(二氟甲氧基)苯基)氨基)-6-(环丙烷甲酰胺)-N-(甲基-d3)哒嗪-3-甲酰胺(63)的合成
参考实施例7的合成方法，以二氟甲氧基替代异丙氧基可得化合物63。
LCMS(ESI-MS)m/z:487.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),8.55(s,1H),7.65(d,J＝1.9Hz,1H),7.36(d,J＝7.7Hz,1H),7.19(s,1H),7.10(s,2H),6.82(d,J＝8.9Hz,1H),5.43(s,2H),2.05–1.96(m,1H),0.83–0.67(m,4H).
实施例64
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(5-乙基-1H-四唑-1-基)-2-(二氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(64)的合成
参考实施例8的合成方法，以5-乙基四氮唑替代5-甲基四氮唑可得化合物64。
LCMS[M+H]+＝477.3。
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),11.15(s,1H),9.18(s,1H),8.22(s,1H),7.80(d,J＝8.6Hz,1H),7.73(d,J＝2.3Hz,1H),7.63(dd,J＝8.6,2.3Hz,1H),7.32(t,J＝72.8Hz,1H),2.90(q,J＝7.5Hz,2H),2.14–1.99(m,1H),1.26(t,J＝7.5Hz,3H),0.82(dd,J＝6.6,4.4Hz,4H).
实施例65
6-(环丙烷甲酰胺基)-N-(三氘代甲基)-4-((4-(5-甲基-[1.3.4]恶二唑-2-基)-2-(二氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(65)的合成
参考实施例7的合成方法，以2-溴-5-甲基-[1.3.4]恶二唑替代3-溴-1-甲基[1.2.4]三氮唑可得化合物65。
MS m/z(ESI):463.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),11.17(s,1H),9.17(s,1H),8.24(s,1H),7.91–7.82(m,2H),7.76(d,J＝8.4Hz,1H),7.49(d,J＝73.0Hz,1H),2.53(d,J＝34.5Hz,3H),2.07(tt,J＝7.3,5.1Hz,1H),0.81(t,J＝2.3Hz,4H).
实施例66
6-(2,2-二氟环丙烷-1-甲酰胺)-4-((2-(二氟甲氧基)-4-(1-异丙基-1H-吡唑-4-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(66)的合成
参考实施例7的合成方法，可得化合物66。
LCMS(ESI-MS)m/z:525.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.78(s,1H),9.15(s,1H),8.34(d,J＝0.8Hz,1H),7.98–7.90(m,2H),7.59–7.48(m,3H),7.26(t,J＝73.6Hz,1H),4.51(p,J＝6.7Hz,1H),3.11–2.99(m,1H),2.06–1.95(m,2H),1.45(d,J＝6.7Hz,6H).
实施例67
6-[(环丙基羰基)氨基]-4-{2-(二氟甲氧基)-4-[1-(2-甲氧基-乙-1-基)-1H-吡唑-4-基]苯胺基}-N-(三氘代甲基)-哒嗪-3-甲酰胺(67)的合成
参考实施例7的合成方法，以4-溴-1-(2-甲氧基-乙-1-基)吡唑替代3-溴-1-甲基[1.2.4]三氮唑可得化合物67。
MS m/z(ESI):505.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),10.73(s,1H),9.09(s,1H),8.23(s,1H),7.96(d,J＝9.2Hz,2H),7.56–7.46(m,3H),7.25(t,J＝73.6Hz,1H),4.26(t,J＝5.2Hz,2H),3.70(t,J＝5.3Hz,2H),3.23(s,3H),2.05(dd,J＝8.5,4.0Hz,1H),0.83–0.75(m,4H).
实施例68
6-(环丙烷甲酰胺)-4-((4-(1-异丙基-1H-吡唑-4-基)-2-(三氟甲氧基)苯基)氨基)-N-(甲基 -d3)哒嗪-3-甲酰胺
参考实施例20的合成方法，以三氟甲醇替代异丙醇可得化合物68。
LCMS:507(M+1)
1H NMR(400MHz,DMSO-d6)δ11.35(s,1H),10.92(s,1H),9.15(s,1H),8.39(d,J＝0.8Hz,1H),8.12–7.94(m,2H),7.79–7.64(m,2H),7.58(d,J＝8.3Hz,1H),4.50(hept,J＝6.6Hz,1H),2.07(tt,J＝7.3,4.9Hz,1H),1.45(d,J＝6.7Hz,6H),0.93–0.58(m,4H).
实施例69
6-(环丙烷甲酰胺)-4-((2-(二氟甲氧基)-4-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-5-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(69)的合成
参考实施例20的合成方法，以二氟甲氧基替代异丙氧基可得化合物69。
LCMS(ESI-MS)m/z:486.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),9.17(s,1H),8.40(s,1H),8.22(s,1H),8.09(s,1H),7.74(d,J＝9.3Hz,3H),7.34(s,1H),5.23(d,J＝2.6Hz,2H),3.56(s,1H),2.07(d,J＝8.4Hz,1H),0.86–0.77(m,4H).
实施例70
6-(环丙烷甲酰胺)-4-((2-(二氟甲氧基)-4-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(70)的合成
参考实施例7的合成方法，4-溴-1-(3,3,3-三氟丙基)吡唑替代3-溴-1-甲基三氮唑，可得化合物70。
LCMS(ESI-MS)m/z:486.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.35(s,1H),10.92(s,1H),9.13(s,1H),8.67(s,1H),8.11(s,1H),7.93–7.85(m,2H),7.64(d,J＝8.3Hz,1H),5.21(d,J＝2.6Hz,2H),3.58(t,J＝2.5Hz,1H),2.05(q,J＝6.1Hz,1H),0.80(d,J＝6.1Hz,4H).
实施例71
-((2-(二氟甲氧基)-4-(1-异丙基-1H-吡唑-4-基)苯基)氨基)-6-(2-氟环丙烷-1-甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺(71)的合成
参考实施例58的合成方法，以氟代环丙基替代环丙基可得化合物71。
LCMS(ESI-MS)m/z:507.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.74(s,1H),9.11(s,1H),8.32(d,J＝0.8Hz,1H),7.96(s,1H),7.93(d,J＝0.8Hz,1H),7.55(dq,J＝3.5,1.9Hz,2H),7.49(d,J＝8.8Hz,1H),5.00(dd,J＝6.3,3.9Hz,1H),4.87–4.80(m,1H),4.49(p,J＝6.7Hz,1H),2.25(p,J＝6.8Hz,1H),1.64–1.51(m,1H),1.44(d,J＝6.7Hz,6H),1.15(ddd,J＝12.6,6.2,2.8Hz,1H).
实施例72
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(1-(3,3,3-三氟丙基)-1H-吡唑-4-基)-2-(二氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(72)的合成
参考实施例7的合成方法，以4-溴-1-(3,3,3-三氟丙基)吡唑替代3-溴-1-甲基三氮唑可得化合物72。
LCMS(ESI-MS)m/z:543.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),10.74(s,1H),9.09(s,1H),8.34(s,1H),7.99(d,J＝8.7Hz,2H),7.59–7.46(m,3H),7.25(t,J＝73.5Hz,1H),4.39(t,J＝6.8Hz,2H),2.90(tdd,J＝11.2,6.9,4.4Hz,2H),2.05(tt,J＝7.2,5.0Hz,1H),0.79(dq,J＝7.5,3.3Hz,4H).。
实施例73
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(1-氰甲基-1H-吡唑-4-基)-2-(二氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(72)的合成
参考实施例7的合成方法，以4-溴-1-氰甲基吡唑替代3-溴-1-甲基三氮唑可得化合物73。
LCMS[M+H]+＝486.3。
1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),10.77(s,1H),9.10(s,1H),8.36(s,1H),8.12(s,1H),8.00(s,1H),7.60–7.48(m,3H),7.26(t,J＝73.5Hz,1H),5.52(s,2H),2.00–1.90(m,1H),0.84–0.78(m,4H).
实施例74
4-((4-(5-氰基吡啶-2-基)-2-(二氟甲氧基)苯基)氨基)-6-(环丙烷甲酰胺)-N- (甲基-d3)哒嗪-3-甲酰胺(74)的合成
参考实施例7的合成方法，2-溴-5-氰基吡啶替代3-溴-1-甲基三氮唑，可得化合物74。
LCMS(ESI-MS)m/z:483.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),11.14(s,1H),9.17(s,1H),9.09(dd,J＝2.2,0.9Hz,1H),8.40(dd,J＝8.4,2.2Hz,1H),8.28(dd,J＝8.4,1.0Hz,1H),8.25(s,1H),8.18–8.11(m,2H),7.71(d,J＝8.4Hz,1H),7.37(t,J＝72Hz,1H),2.10-2.05(m,1H),0.81(h,J＝3.1Hz,4H).
实施例75
4-((2-(二氟甲氧基)-4-(1-异丙基-1H-吡唑-4-基)苯基)氨基)-6-((1R，2S)-2-氟环丙烷-1-甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺(75)的合成
参考实施例66的合成方法，2-氟-环丙酰胺替代2,2-二氟-环丙酰胺，可得化合物75。
LCMS(ESI-MS)m/z:507.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.72(s,1H),9.12(s,1H),8.31(s,1H),7.92(s,1H),7.89(s,1H),7.54(s,1H),7.52–7.43(m,2H),7.23(t,J＝72Hz,1H),4.94–4.89(m,0.5H),4.78–4.74(m,0.5H),4.49(p,J＝6.6Hz,1H),2.64–2.53(m,1H),1.57–1.47(m,1H),1.43(d,J＝6.7Hz,6H),1.21–1.13(m,1H).
实施例76
4-((2-(二氟甲氧基)-4-(1-异丙基-1H-吡唑-4-基)苯基)氨基)-6-((1S，2S)-2-氟环丙烷-1-甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺(76)的合成
参考实施例75的合成方法，可得化合物76。
LCMS(ESI-MS)m/z:507.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.75(s,1H),9.11(s,1H),8.32(s,1H),7.95(d,J＝13.8Hz,2H),7.56(dq,J＝3.6,1.9Hz,2H),7.49(d,J＝8.8Hz,1H),7.06-7.43(s,1H),4.83-4.99(q,J＝5.8Hz,1H),4.49(p,J＝6.6Hz,1H),2.25(t,J＝7.1Hz,1H),1.63–1.54(m,1H),1.44(d,J＝6.7Hz,6H),1.19–1.11(m,1H).
实施例77
4-((2-(2-(二氟甲氧基)-4-(1-异丙基-1H-吡唑-4-基)苯基)苯基)氨基)-6-((1R，2R)-2-氟环丙烷-1-羧酰胺)-n-(甲基-D3)吡啶嗪-3-羧酰胺的合成
参考实施例75的合成方法，可得化合物77。
LCMS[M+H]+＝507.30
1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.75(s,1H),9.11(s,1H),8.32(s,1H),7.96(s,1H),7.93(d,J＝0.7Hz,1H),7.56-7.54(m,2H),7.49-7.47(m,1H),7.42-7.05(m,1H),5.00–4.80(m,1H),4.51-4.45(m,1H),2.26–2.22(m,1H),1.62–1.54(m,1H),1.43(d,J＝6.7Hz,6H),1.17-1.12(m,1H).
实施例78
6-(环丙烷甲酰胺)-4-((2-(二氟甲氧基)-4-(5-(甲基磺酰基)-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例8的合成方法，以5-(甲基磺酰基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑替代5-甲基-2H-四唑可得化合物78。
LCMS:566(M+1)
1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),10.79(s,1H),9.12(s,1H),8.44(s,1H),7.99(d,J＝0.9Hz,1H),7.84–7.72(m,2H),7.63(d,J＝8.7Hz,1H),7.32(d,J＝1.0Hz,1H),4.50(d,J＝12.8Hz,4H),3.03(d,J＝0.9Hz,3H),2.05(td,J＝7.5,3.8Hz,1H),0.87–0.72(m,4H).
实施例79
参考实施例58的合成方法，以氟代环丙基替代环丙基可得化合物79。
LCMS(ESI-MS)m/z:507.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.72(s,1H),9.12(s,1H),8.31(s,1H),7.91(d,J＝13.3Hz,2H),7.56–7.50(m,2H),7.46(d,J＝8.2Hz,1H),7.23(s,1H),4.92(s,1H),4.49(p,J＝6.6Hz,1H),2.61(dt,J＝20.2,8.9Hz,1H),1.52(ddd,J＝18.6,6.5,3.3Hz,1H),1.43(d,J＝6.7Hz,6H),1.20(dt,J＝13.3,6.6Hz,1H).
实施例80
6-[(环丙基羰基)氨基]-4-({2-[(二氟甲基)氧基]-4-(5-氟嘧啶-2-基)苯基}氨基)-N-(三氘基甲基)-1,2-哒嗪-3-甲酰胺(80)的合成
参考实施例7的合成方法，以5-氟-2-溴嘧啶替代3-溴-1-甲基[1.2.4]三氮唑可得化合物80。
LCMS(ESI-MS)m/z:477.2(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),11.07(s,1H),9.16(s,1H),9.00(s,2H),8.40(s,1H),8.26–8.22(m,2H),7.73–7.71(m,1H),7.55–7.18(m,1H),2.10–2.04(m,1H),0.85–0.81(m,4H).
实施例81
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(4-三氟甲基-吡唑-1-基)-2-(二氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(81)的合成
参考实施例8的合成方法，以4-三氟甲基吡唑替代5-甲基四氮唑可得化合物83。
MS m/z(ESI):515.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ11.36(s,1H),10.88(s,1H),9.27(s,1H),9.14(s,1H),8.25(s,1H),8.04(s,1H),7.92–7.82(m,2H),7.70(d,J＝8.8Hz,1H),7.33(t,J＝73.0Hz,1H),2.06(ddd,J＝12.5,7.5,4.7Hz,1H),0.86–0.69(m,4H).
实施例82
6-(环丙烷甲酰胺)-4-((2-(二氟甲氧基)-4-(5-(S-甲基磺酰亚胺基)-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例8的合成方法，以5-(S-甲基磺酰亚胺基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑替代5-甲基-2H-四唑可得化合物82。
LCMS:565(M+1)
1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),10.78(s,1H),9.12(s,1H),8.41(s,1H),7.98(s,1H),7.82–7.72(m,2H),7.62(d,J＝8.7Hz,1H),7.32(s,1H),4.52–4.33(m,5H),2.95(s,3H),2.09–2.00(m,1H),0.88–0.72(m,4H).
实施例83
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((4-(4-氰基-吡唑-1-基)-2-(二氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺(83)的合成
参考实施例8的合成方法，以4-氰基吡唑替代5-甲基四氮唑可得化合物83。
MS m/z(ESI):472.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ11.36(s,1H),10.91(s,1H),9.39(s,1H),9.14(s,1H),8.39(s,1H),8.05(s,1H),7.86(d,J＝2.4Hz,1H),7.84–7.78(m,1H),7.72(d,J＝8.8Hz,1H),7.55–7.10(t,J＝332Hz,1H),2.10–2.02(m,1H),0.87–0.72(m,4H).
实施例84
6-[(环丙基羰基)氨基]-4-{2-(2,2-二氟乙氧基)-4-[1-(2,2,2-三氟乙基)-1H-吡唑-4-基]苯胺基}-N-(三氘基甲基)-哒嗪-3-甲酰胺(84)的合成
参考实施例38的合成方法，以1-(2,2,2-三氟乙基)乙基-4-溴吡唑替代1-乙基-4-溴吡唑可得化合物84。
LCMS(ESI-MS)m/z:543.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.25(s,1H),10.64(s,1H),9.07(s,1H),8.37(s,1H),8.14(s,1H),7.94(s,1H),7.49–7.48(m,1H),7.40–7.32(m,2H),6.45–6.16(m,1H),5.20–5.13(m,2H),4.50–4.42(m,2H),2.08–2.03(m,1H),0.82–0.78(m,4H).
实施例85
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-环丙氧基-4-(1-乙基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(85)的合成
参考实施例27的合成方法，以4-溴-1-乙基-1H-吡唑替代4-溴-1-异丙基-1H-吡唑可得化合物85。
LCMS[M+H]+＝465.3。
1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),10.50(s,1H),9.04(s,1H),8.22(s,1H),7.97–7.77(m,2H),7.54(d,J＝1.8Hz,1H),7.29(d,J＝8.1Hz,1H),7.21(dd,J＝8.1,1.8Hz,1H),4.14(q,J＝7.3Hz,2H),3.97(tt,J＝6.0,2.9Hz,1H),2.04(td,J＝7.4,3.8Hz,1H),1.40(t,J＝7.2Hz,3H),0.88–0.70(m,6H),0.62(dt,J＝4.7,3.1Hz,2H).
实施例86
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-二氟甲氧基)-4-(1-异丙基-1H-咪唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(86)的合成
参考实施例8的合成方法，以4-溴-1-异丙基-1H-咪唑代5-甲基四氮唑可得化合物86
LCMS(ESI-MS)m/z:488.5(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),10.70(s,1H),9.09(s,1H),7.97(s,1H),7.87(d,J＝1.4Hz,1H),7.76(d,J＝1.3Hz,1H),7.71–7.63(m,2H),7.47(d,J＝8.3Hz,1H),7.23(s,1H),4.43(p,J＝6.7Hz,1H),2.04(h,J＝5.9,5.1Hz,1H),1.43(d,J＝6.7Hz,6H),0.79(dt,J＝4.9,2.4Hz,4H).
实施例87
6-(环丙烷甲酰胺)-4-((2-(2,2-二氟乙氧基)-4-(1-(三氟甲基)-1H-吡唑-4-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例28的合成方法，以4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-(三氟甲基)-1H-吡唑替代28c可得化合物87。
LCMS:529(M+1)
1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),10.72(s,1H),9.06(d,J＝9.9Hz,2H),8.55(s,1H),7.98(s,1H),7.61(d,J＝1.6Hz,1H),7.50–7.36(m,2H),6.46–6.19(m,1H),4.45(td,J＝14.1,3.9Hz,2H),2.05(td,J＝7.7,4.0Hz,1H),0.89–0.68(m,4H).
实施例88
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(2,2-二氟乙氧基)-4-(1-甲基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(88)的合成
参考实施例28的合成方法，以1-甲基-1H-吡唑-4-硼酸频哪醇酯替代28c可得化合物88。
LCMS(ESI-MS)m/z:475(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.59(s,1H),9.04(s,1H),8.20(s,1H),7.92(d,J＝14.9Hz,2H),7.41(d,J＝1.8Hz,1H),7.33(d,J＝8.2Hz,1H),7.25(dd,J＝8.2,1.7Hz,1H),6.28(t,J＝3.8Hz,1H),4.42(td,J＝14.2,3.8Hz,2H),3.85(s,3H),2.05(tt,J＝7.4,5.0Hz,1H),0.85–0.72(m,4H).
实施例89
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-环丙氧基-4-(1-二氟甲基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(89)的合成
参考实施例27的合成方法，以4-溴-1-(二氟甲基)-1H-吡唑替代4-溴-1-异丙基-1H-吡唑可得化合物89。
LCMS[M+H]+＝487.3。
1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.60(s,1H),9.05(s,1H),8.78(s,1H),8.32(s,1H),8.06–7.59(m,3H),7.36(s,2H),4.01(dt,J＝6.0,3.1Hz,1H),2.14–1.95(m,1H),0.89–0.71(m,6H),0.69–0.57(m,2H).
实施例90
6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-环丙氧基-4-(1-甲基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(90)的合成
参考实施例27的合成方法，以4-溴-1-甲基-1H-吡唑替代4-溴-1-异丙基-1H-吡唑可得化合物90。
LCMS[M+H]＝451.3
1H NMR(400MHz,DMSO-d6)δ11.24(s,1H),10.52(s,1H),9.05(s,1H),8.53–8.39(m,1H),8.19(s,1H),7.90(d,J＝6.6Hz,2H),7.55(s,1H),7.36–7.18(m,2H),4.04–3.93(m,1H),3.87(s,2H),2.17–1.90(m,2H),0.91–0.71(m,5H),0.70–0.54(m,2H).
实施例91
6-[(环丙基羰基)氨基]-4-{[2-(环丙基氧基)-4-(1-甲基-1,2,4-三氮唑-3-基)苯基]氨基}-N-(三氘基甲基)-1,2-哒嗪-3-甲酰胺(91)的合成
参考实施例27的合成方法，以3-溴-1-甲基[1.2.4]三氮唑替代4-溴-1-异丙基吡唑可得化合物91。
LCMS(ESI-MS)m/z:452.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.64(s,1H),9.06(s,1H),8.52(s,1H),8.01–7.92(m,2H),7.62(dd,J＝8.2,1.8Hz,1H),7.42(d,J＝8.2Hz,1H),3.98(dt,J＝6.0,3.0Hz,1H),3.92(s,3H),2.05(p,J＝6.6Hz,1H),0.86–0.74(m,5H),0.66(d,J＝3.4Hz,2H).
实施例92
6-[(环丙基羰基)氨基]-N-(三氘基甲基)-4-({2-[(2,2,2-三氟乙基)氧基]-4-[1-(2,2,2-三氟乙基)吡唑-4-基]苯基}氨基)-哒嗪-3-甲酰胺(92)的合成
参考实施例22的合成方法，以4-溴-1-三氟乙基吡唑替代4-溴-1-异丙基吡唑可得化合物92。
LCMS[M+H]＝560.9
1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),10.63(s,1H),9.07(s,1H),8.36(s,1H),8.14(s,1H),7.91(s,1H),7.54(s,1H),7.44-7.33(m,2H),5.25-5.11(m,2H),4.94-4.82(m,2H),2.09–2.03(m,1H),0.90–0.68(m,4H).
实施例93
6-{[(2,2-二氟环丙基)羰基]氨基}-4-{[4-(1-乙基吡唑-4-基)-2-(丙-2-基氧基)苯基]氨基}-N-(三氘基甲基)-1,2-二氮杂环己熳-3-甲酰胺(93)的合成
参考实施例21的合成方法，以2,2-二氟环丙烷-1-甲酰胺替代环丙烷甲酰胺可得化合物93。
LCMS(ESI-MS)m/z:503.0(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.69(s,1H),9.07(s,1H),8.24(s,1H),7.95-7.91(m,2H),7.33-7.20(m,3H),4.71(s,1H),4.12(s,2H),3.03(s,1H),1.99(s,2H),1.39(s,3H),1.24–1.21(m,6H).
实施例94
6-(2,2-二氟环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(2,2-二氟乙氧基)-4-(1-异丙基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(94)的合成
参考实施例28的合成方法，以2,2-二氟环丙烷甲酰胺替代丙烷甲酰胺可得化合物94。
LCMS(ESI-MS)m/z:539(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.58(s,1H),9.04(s,1H),8.30(s,1H),7.91(d,J＝15.0Hz,2H),7.42(s,1H),7.37–7.22(m,3H),6.28(t,J＝54.8Hz,2H),4.51–4.37(m,3H),3.06–2.98(m,1H),2.01–1.94(m,2H),1.44(d,J＝6.7Hz,6H).
实施例95
6-({[(2S)-2-氟环丙基]羰基}氨基)-4-{[4-(1-甲基吡唑-4-基)-2-[(2,2,2-三氟乙基)氧基]苯基]氨基}-N-(三氘基甲基)-1,2-二氮杂环己熳-3-甲酰胺(95)的合成
参考实施例34的合成方法，以(2S)-2-氟环丙烷-1-甲酰胺替代环丙烷甲酰胺可得化合物95。
LCMS(ESI-MS)m/z:511.0(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),10.59(s,1H),9.06(s,1H),8.20(s,1H),7.95(s,1H),7.86(s,1H),7.49(s,1H),7.38–7.36(m,1H),7.32–7.30(m,1H),5.01–4.97(m,1H)4.89–4.78(m,2H),3.86(s,3H),2.28–2.21(m,1H),1.60–1.52(m,1H),1.17–1.13(m,1H).
实施例96
6-({[(1R,2S)-2-氟环丙基]羰基}氨基)-4-[2-异丙氧基-4-(1-乙基-1H-吡唑-4-基)苯胺基]-N-(三氘基甲基)-哒嗪-3-甲酰胺(96)的合成
参考实施例21的合成方法，以(1s,2s)-2-氟环丙烷甲酰胺替代丙烷甲酰胺可得化合物96。
LCMS(ESI-MS)m/z:485.0(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.69(s,1H),9.07(s,1H),8.25(s,1H),7.99(s,1H),7.92(s,1H),7.34–7.31(m,2H),7.21–7.18(m,1H),4.96–4.77(m,1H),4.74–4.68(m,1H),4.17–4.12(m,2H),2.66–2.58(m,1H),1.57–1.49(m,1H),1.43–1.39(m,3H),1.27–1.25(m,6H),1.23–1.18(m,1H).
实施例97
6-((1s，2s)-2-氟丙烷-1-羧酰胺)-4-(((2-异丙氧基-4-1-异丙基-1H-吡唑-4-苯基)苯基)-n-(甲基-d3)吡啶嗪-3-羧酰胺的合成
参考实施例20的合成方法，以1s,2s-2-氟环丙烷-1-甲酰胺替代环丙酰胺可得化合物97
LCMS[M+H]+＝499.00
1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),10.68(s,1H),9.05(s,1H),8.27(d,J＝0.8Hz,1H),8.02(s,1H),7.90(d,J＝0.8Hz,1H),7.33(d,J＝8.2Hz,2H),7.22(dd,J＝8.2,1.8Hz,1H),5.01-4.81(m,1H),4.74-4.68(m,1H),4.50-4.44(m,1H),2.27-2.22(m,1H),1.63-1.54(m,1H),1.44(d,J＝6.7Hz,6H),1.24(dd,J＝6.0,3.6Hz,6H),1.18–1.09(m,1H).
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实施例98
6-((1R，2s)-2-氟丙烷-1-羧酰胺)-4-(((2-异丙氧基-4-)(1-异丙基-1H-吡唑-4-苯基)苯基)-n-(甲基-d3)吡啶嗪-3-羧酰胺的合成
参考实施例20的合成方法，以1R,2s-2-氟环丙烷-1-甲酰胺替代环丙酰胺可得化合物97
LCMS[M+H]+＝499.00
1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),10.67(s,1H),9.06(s,1H),8.27(s,1H),7.97(s,1H),7.90(d,J＝0.8Hz,1H),7.37–7.28(m,2H),7.19(dd,J＝8.2,1.8Hz,1H),4.93-4.77(m,1H),4.75-4.58(m,1H),4.48(m,1H),2.66-2.55(m,1H),1.44(d,J＝6.7Hz,6H),1.28–1.16(m,8H).
实施例99
4-((4-(1-环丙基-1H-吡唑-4-基)-2-(2,2,2-三氟乙氧基)苯基)氨基)-6-((1S，2S)-2-氟环丙烷-1-甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺(99)的合成
参考实施例33的合成方法，以1s,2s-2-氟环丙烷-1-甲酰胺替代环丙酰胺可得化合物99。
LCMS(ESI-MS)m/z:537.0(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),10.59(s,1H),9.06(s,1H),8.30(s,1H),7.94(s,1H),7.86(s,1H),7.49(d,J＝1.7Hz,1H),7.41–7.29(m,2H),5.03–4.95(m,1H),4.92–4.75(m,2H),3.78–3.69(m,1H),2.29–2.19(m,1H),1.63–1.50(m,1H),1.18–1.11(m,1H),1.09–0.94(m,4H).
实施例100
6-(环丙烷甲酰胺)-4-((4-(1-乙基-1H-吡唑-4-基)-2-(2-氟乙氧基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(100)的合成
参考实施例38的合成方法，以2-氟乙醇替代2,2-二氟乙醇可得化合物100。
LCMS(ESI-MS)m/z:471.0(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),10.63(s,1H),9.04(s,1H),8.24(d,J＝0.9Hz,1H),7.96(s,1H),7.92(d,J＝0.8Hz,1H),7.36(d,J＝1.8Hz,1H),7.35–7.31(m,1H),7.23(dd,J＝8.2,1.8Hz,1H),4.78–4.70(m,1H),4.66–4.59(m,1H),4.43–4.37(m,1H),4.35–4.29(m,1H),4.13(q,J＝7.3Hz,2H),2.10–2.01(m,1H),1.40(t,J＝7.3Hz,3H),0.84–0.72(m,4H).
实施例101
6-[(环丙基羰基)氨基]-4-[2-乙氧基-4-(1-乙基-1H-吡唑-4-基)苯胺基]-N-(三氘基甲基)-哒嗪-3-甲酰胺(101)的合成
参考实施例21的合成方法，以乙醇替代异丙醇可得化合物101。
LCMS(ESI-MS)m/z:453.0(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.24(s,1H),10.65(s,1H),9.05(s,1H),8.25(s,1H),8.00(s,1H),7.92(s,1H),7.33–7.31(m,2H),7.21–7.19(m,1H),4.18–4.12(m,4H),2.09–2.05(m,1H),1.43–1.39(m,3H),1.31–1.28(m,3H),0.83–0.78(m,4H).
实施例102
6-(环丙烷甲酰胺)-4-((2-乙氧基-4-(1-甲基-1H-吡唑-4-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例101的合成方法，以4-溴-1-甲基吡唑替代4-溴-1-乙基吡唑可得化合物102。
LCMS:439(M+1)
1H NMR(400MHz,DMSO-d6)δ11.24(s,1H),10.64(s,1H),9.05(s,1H),8.18(s,1H),7.98(s,1H),7.90(d,J＝0.9Hz,1H),7.34–7.25(m,2H),7.17(dd,J＝8.1,1.8Hz,1H),4.13(q,J＝6.9Hz,2H),3.84(s,3H),2.05(td,J＝7.4,3.8Hz,1H),1.28(t,J＝6.9Hz,3H),0.79(dq,J＝9.6,3.9,3.4Hz,4H).
实施例103
6-[(环丙基羰基)氨基]-N-(三氘基甲基)-4-({2-甲氧基-4-[1--乙基-吡唑-4-基]苯基}氨基)-哒嗪-3-甲酰胺(103)的合成
参考实施例21的合成方法，以甲醇替代异丙醇可得化合物103。
LCMS[M+H]＝439.0
1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.61(s,1H),9.08(s,1H),8.27(s,1H),7.97(d,J＝19.1Hz,2H),7.40–7.27(m,2H),7.21(d,J＝8.3Hz,1H),4.20-4.05(m,2H),3.87(s,3H),2.13-2.01(m,1H),1.50-1.30(m,3H),0.81(d,J＝7.4Hz,4H).
实施例104
6-((1s,2s)-2-氟环丙烷甲酰胺基)-N-(甲基-d3)-4-((2-(2,2-二氟乙氧基)-4-(1-环丙基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-甲酰胺(104)的合成
参考实施例39的合成方法，以4-溴-1-环丙基吡唑替代4-溴-1-异丙基吡唑可得化合物104。
LCMS[M+H]＝519.0
1H NMR(400MHz,DMSO-d6)δ11.33(d,J＝11.3Hz,1H),10.63(s,1H),9.09(s,1H),8.33(s,1H),7.93(d,J＝19.6Hz,2H),7.43(d,J＝14.7Hz,1H),7.40–7.22(m,2H),6.29(s,1H),5.00(s,1H),4.84(s,1H),4.54-4.32(m,2H),3.79–3.67(m,1H),2.31–2.20(m,1H),1.58(d,J＝24.1Hz,1H),1.22–1.11(m,1H),1.11–0.90(m,4H).
实施例105
6-[(环丙基羰基)氨基]-4-{[2-(异丙基氧基)-4-(1-氨甲基羰基甲基-1,2,4-三氮唑-3-基)苯基]氨基}-N-(三氘基甲基)-1,2-哒嗪-3-甲酰胺(105)的合成
参考实施例21的合成方法，以3-溴-1-氨甲基羰基甲基-1,2,4-三氮唑替代1-乙基-4-溴吡唑可得化合物105。
MS m/z(ESI):511.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),10.82(s,1H),9.07(s,1H),8.53(d,J＝1.0Hz,1H),8.23–8.15(m,1H),8.14(d,J＝1.1Hz,1H),7.64(d,J＝1.7Hz,1H),7.58(dd,J＝8.2,1.7Hz,1H),7.46(d,J＝8.3Hz,1H),4.91(s,2H),4.66(hept,J＝6.0Hz,1H),2.63(d,J＝4.6Hz,3H),2.05(p,J＝6.2Hz,1H),1.28(dd,J＝6.1,0.9Hz,6H),0.80(d,J＝6.1Hz,3H).
实施例106
6-(环丙烷甲酰胺)-4-((2-乙氧基-4-(1-甲氧基-1H-吡唑-4-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(106)的合成
参考实施例101的合成方法，以4-溴-1-甲氧基吡唑替代4-溴-1-乙基吡唑可得化合物106。
LCMS(ESI-MS)m/z:455.0(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.67(s,1H),9.06(s,1H),8.37(d,J＝1.2Hz,1H),8.00(s,1H),7.80(d,J＝1.2Hz,1H),7.35–7.30(m,2H),7.22(dd,J＝8.2,1.7Hz,1H),4.14(q,J＝6.9Hz,2H),4.08(s,3H),2.09–2.01(m,1H),1.28(t,J＝6.9Hz,3H),0.84–0.73(m,4H).
生物活性试验
实验一、本发明TYK2抑制剂小分子化合物的体外活性测定
1.实验目的
本实验通过荧光共振能量转移(TR-FRET)法测试本发明化合物(化合物1-化合物40)对TYK2JH2假激酶的抑制作用，根据半抑制浓度(IC50)评价化合物的体外活性。
2.实验方法
2.1准备1×实验工作液
实验工作液配制
2.2实验流程
(1)用DMSO溶解化合物到10mM的存储浓度。
(2)在化合物稀释板子中配备200倍于终浓度的化合物浓度，按照27倍倍比稀释法，从最高浓度点稀释，共4个浓度点，并转移到Echo板中。
(3)用Echo仪器将化合物从Echo板脉冲到384实验板，使得化合物变成3倍倍比稀释矩阵，11个浓度点。
(4)加5ul 3X TYK2JH2激酶到384实验板中。
(5)加5ul 3X Tb到384实验板中。
(6)加5ul 3X Tracer到384孔实验板中。
(7)离心30秒，室温孵育60分钟。
(8)Envision酶标仪(PerkinElmer)495/520荧光信号值。
(9)使用XL-Fit软件进行数据分析，得出化合物IC50。
2.3实验结果
表1本发明化合物体外活性实验结果





结论：本发明化合物对TYK2JH2假激酶具有明显的抑制活性。
实验二、本发明化合物在大鼠中药物代谢动力学实验
1.实验目的：
以SD大鼠为例，以液相色谱-串联质谱(LS/MS/MS)法测定了大鼠分别灌胃和静脉给予化合物1、化合物7后不同时刻血浆中药物浓度并计算相关药代参数，评价本发明实施例化合物在大鼠体内的药代动力学特性。
2.试验方案
2.1试验药物
实施例化合物1、实施例化合物7。
2.2试验动物
健康成年的SD大鼠，SPF级，雄性，购自上海西普尔-必凯实验动物有限公司，许可证号SCXK(沪)2018-0006，动物合格证编号：20180006006321。
2.3药物配置
称取一定量的化合物，溶于5％乙醇(ethanol)涡旋超声，加入5％水溶性天然维生素E(TPGS，配置前需加热)混匀，加入90％纯水混匀配置成1mg/mL的均一口服溶液。称取一定量的化合物，溶于80％聚乙二醇400(PEG400)涡旋超声，再加入20％纯水配置成0.4mg/mL澄清透明静脉给药溶液。
2.4给药
具体给药按照试验方案进行，详情见表2。
表2大鼠药代动力学试验方案

2.5采血时间及样品处理
给药前及给药后5分钟、15分钟、0.5小时、1小时、2小时、4小时、6小时、8小时及24小时分别通过眼眶采血，每次采血0.2毫升(mL)，置于抗凝管中，混匀，保存于-20℃冰箱中备用。
3.样品测试及数据分析
采用液相色谱-串联质谱(LS/MS/MS)方法测定大鼠全血中化合物的含量。
利用WinNonLin5.3软件的非房室模型计算给药后化合物的药代动力学参数。
4.试验结果
本发明化合物给药后药代动力学参数见以下表3。由表3所示，本发明的化合物具有较好的代谢特征及生物利用度。
表3本发明的化合物的药代动力学参数
实验三、本发明化合物的小鼠体内药效实验
一、银屑病模型
1.造模及给药
购买8周龄雌性BALB/c小鼠，平均体重20g。小鼠适应3天后开始实验，实验分为五组，正常对照组、模型组、实施例化合物组及阳性药组(BMS-986165)，每组5-8只。模型组、实施例化合物组及阳性药组小鼠用戊巴比妥钠腹腔注射麻醉(80mg/kg),背部去毛后均匀涂抹5％咪喹莫特乳膏62.5mg，每日一次，正常对照组涂抹等量凡士林。实施例化合物组(10mg/kg)按10mL/kg灌胃给药，每日一次；正常对照组灌胃等量纯水，模型组灌胃等量溶媒，连续7d。具体设计见表4。
表4化合物体内药效实验方案

NA表示空白项。
2.实验动物
雌性BALB/c小鼠37只，8周龄。小鼠均购自北京维通利华实验动物技术有限公司，许可证号SCXK(沪)2017-0011，动物合格证编号：20170011003865。
3.实验药物
实施例化合物1、实施例化合物7。
4.药物的配置
称取适量化合物，溶于5％乙醇(ethanol)涡旋超声，加入5％水溶性天然维生素E(TPGS，配置前需加热)混匀，加入90％纯水混匀配置成1mg/mL的均一溶液。
5.给药
具体给药按照给药方案进行。
6.检测指标和方法
每天观察小鼠皮损情况，并采用数码照相，依据小鼠银屑病样皮损面积和疾病严重程度(psoriasis area and severity index,PASI)评分标准，给予小鼠皮损处红斑、鳞屑及浸润程度(0:无；1:轻度；2:中度；3:重度；4:极重度)打分，观察各组小鼠皮损的变化情况。
7.实验结果及结论
咪喹莫特外涂与小鼠背部皮肤5d后，模型对照组小鼠背部皮损增厚、浸润显著，大量斑块状鳞屑出现，皮肤变红。实施例化合物1、实施例化合物7组小鼠皮损红斑和鳞屑明显减少，浸润减轻。模型对照组小鼠PASI评分随天数持续增高，实施例化合物1、实施例化合物7组第3天后PASI评分开始明显降低，作用效果优于阳性药组。
二、银屑病模型
1.造模及给药。
购买8周龄C57BL/6雌性小鼠40只，平均体重为20g。小鼠适应7天后开始动物实验，每只小鼠在右耳皮下注射鼠源IL-23，间隔一天注射一次，共7次，周期为14天。对照及给药组从造模第一天每天口服灌胃2次，具体设计见表5。
表5化合物体内药效实验方案

NA表示空白项
2.试验药物
实施例受试物1、实施例受试物7
1.药物配置
称取适量化合物，溶于5％乙醇(ethanol)涡旋超声，加入5％水溶性天然维生素E(TPGS，配置前需加热)混匀，加入90％纯水混匀配置成1.5mg/mL的均一溶液。
2.给药
具体给药以实验方案设计进行
3.检测指标和方法
通过右耳皮肤厚度测量进行药效结果分析，给药结束后取右耳皮肤组织进行HE染色，通过病理评分来确认最后药效结果。
4.实验结果及讨论
通过给药14天，实施例化合物1、实施例化合物7及BMS-986165均能减少小鼠右耳皮肤厚度，最终病理结果显示实施例化合物1、实施例化合物7及BMS-986165均能改善炎症浸润，综合药效结果分析显示实施例化合物1及实施例化合物7在低剂量下便能达到高剂量BMS-986165的药效，统计学显示实施例化合物1及实施例化合物7在小鼠体内的药效作用优于BMS-986165。
三、炎症性肠病模型
口服灌胃2.5％葡聚糖硫酸钠(DSS)诱导小鼠IBD造模后，模型组小鼠出现体重减轻、精神萎靡、嗜睡、血便、腹泻等症状，其疾病活动指数(DAI)明显高于对照组。实施例化合物1、实施例化合物7组在给药第三天能够显著降低小鼠的DAI评分，抑制DSS带来的体重下降和结肠缩短，显著减轻DSS对小鼠的肠道损伤，病理学检查发现实施例化合物组能够有效抑制结肠中的炎症浸润。
四、红斑狼疮模型
选择雌性MRL/lpr小鼠作为红斑狼疮模型的实验动物，每周评估小鼠淋巴结肿大及皮肤损伤，及相关尿白蛋白及肌酐的指标测试，体内药效试验发现实施例化合物1、实施例化合物7能显著降低Pristane诱导的狼疮小鼠自身抗体(anti-ds DNA,anti-SLE)和尿蛋白浓度，降低肾小球肿胀度，病理学组织检查中发现能够有效减少炎症细胞浸润。
实验四、本发明化合物的小鼠急毒实验
1.实验目的
本实验目的是为了测试实施例化合物在小鼠上的急性毒性作用。
2.实验动物
ICR小鼠，SPF级，6-8周龄，雌雄各半，购自上海西普尔-必凯实验动物有限公司，许可证号SCXK(沪)2018-0006，动物合格证编号：20180006010983。
3.试验药物
实施例化合物1、实施例化合物7。
4.实验方法
ICR小鼠单次给予不同剂量的化合物，连续观察14天，记录动物死亡情况，中毒反应，体重变化，饮食，外观，行为等。终点解剖动物，取脏器，进行组织病理学检查及相关血液学检查。
5.实验结果及结论
实施例化合物1、实施例化合物7的无毒性反应剂量(NOAEL)均大于1000毫克每公斤(mg/kg)，与对照组小鼠比较，给药组小鼠自给药日起14天内均未见体重及行为异常，且相关血液学未见明显异常，病理学检查未见相关实施例化合物毒性作用，说明本发明实施例化合物1、实施例化合物7安全性良好，动物能够安全耐受。
实验五、本发明化合物的小鼠长毒实验
1.实验目的
本实验目的是为了测试实施例化合物在小鼠上的长期毒性作用。
2.实验动物
ICR小鼠，SPF级，6-8周龄，雌雄各半，购自上海西普尔-必凯实验动物有限公司，许可证号SCXK(沪)2018-0006，动物合格证编号：20180006010983。
3.试验药物
实施例化合物1、实施例化合物7。
4.实验方法
ICR小鼠给予不同剂量的化合物，连续给药观察14天，记录动物死亡情况，中毒反应，体重变化，饮食，外观，行为等。终点解剖动物，取脏器，进行组织病理学检查及相关血液学检查。
5.实验结果及结论
实施例化合物1、实施例化合物7的无毒性反应剂量(NOAEL)均大于500毫克每公斤(mg/kg)，与对照组小鼠比较，给药组小鼠自给药日起，14天内均未见体重及行为异常，且相关血液学未见明显异常，病理学检查未见相关实施例化合物毒性作用，说明本发明实施例化合物1、实施例化合物7安全性良好，动物能够安全耐受。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，凡是根据本发明精神实质所做的等效变化或修饰，都应涵盖本发明的保护范围之内。

Claims (23)

  1. 一种通式(Ⅱ)所示的化合物或其可药用盐或同位素衍生物，
    其中R1为-C1-3氘代烷基；
    R2为-C3-6环烷基，其中所述的-C3-6环烷基任选地进一步被选自氢原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
    R3为-C1-3烷基氧基或-C3-6环烷基氧基，其中所述的-C1-3烷基氧基或-C3-6环烷基氧基任选地进一步被选自氢原子、氘原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
    R4为5-6元杂芳基或六至十元双环，其中所述的5-6元杂芳基任选地被Ra取代，所述的双环，环与环之间是稠合相连的，且至少有一个环是芳族环，所述的双环任选地被Rb取代；
    Ra为-H、卤素、-CN、-C1-3烷基、-C1-3烷氧基、-C3-6环烷基或4-6元杂环基，其中所述的-C1-3烷基、-C1-3烷氧基或-C3-6环烷基任选地进一步被选自氢原子、-NH2、-CF3、-CN、-C1-3烷基、-C2-3烯基、-C2-3炔基、-C1-3烷氧基、-C1-3烷基氨基、-C(O)NH-C1-3烷基、-C3-6环烷基、4-6元杂环基或卤素中的一个或多个取代基所取代；
    Rb为-S(O)2-C1-3烷基或-S(O)NH-C1-3烷基；
  2. 根据权利要求1所述的化合物或其可药用盐或同位素衍生物，其特征在于，R1为-CD3；
    R2为取代或未被取代的环丙烷基；
    R3为-OCH3、-OCF3、-O-CH2CH3、-O-CH2CF3、-OCHF2、-O-CH2CHF2、-O-CH2CH2F、-O-CH2CH(CH3)2、-OCH(CH3)2或
  3. 根据权利要求1或2所述的化合物或其可药用盐或同位素衍生物，其特征在于，
    R4为
  4. 据权利要求1-3任一项所述的化合物或其可药用盐或同位素衍生物，其特征在于，Ra为-H、-F、-CN、-CHF2、甲基、乙基、丙基、三氟甲基、甲氧基、-CH2-CF3、-CH2-CN、-CH2-CCH、-CH2-OCH3、-CH2CH2-CF3、-CH2CH2-OCH3、-CH2CH2-NH2、-CH2CH2-NH-CH3、-CH(CH3)2、-CH2-C(O)NH-CH3、或环丙烷基；
    Rb为-S(O)2-CH3或-S(O)NH-CH3。
  5. 根据权利要求1～4任一项所述的一种通式(Ⅱ)所示的化合物或其可药用盐或同位素衍生物，其特征在于，
    R1为-C1-3氘代烷基；
    R2为-C3-6环烷基，其中所述的-C3-6环烷基任选地进一步被选自氢原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
    R3为-C1-3烷基氧基或-C3-6环烷基氧基，其中所述的-C1-3烷基氧基或-C3-6环烷基氧基任选地进一步被选自氢原子、氘原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
    R4为5-6元杂芳基，其中所述的5-6元杂芳基任选地被Ra取代；
    Ra为-H、-CN、-CF3、-C1-3烷基、-C3-6环烷基或4-6元杂环基，其中所述的-C1-3烷基或-C3-6环烷基任选地进一步被选自氢原子、-C1-3烷基和卤素中的一个或多个取代基所取代。
  6. 根据权利要求5所述的化合物或其可药用盐或同位素衍生物，其特征在于，R1为-CD3；R2为取代或未被取代的环丙烷基；R3为-OCF3、-O-CH2CF3、-OCHF2、-O-CH2CHF2、-OCH(CH3)2或
  7. 根据权利要求5或6所述的化合物或其可药用盐或同位素衍生物，其特征在于，
    R4为
  8. 根据权利要求5-7任一项所述的化合物或其可药用盐或同位素衍生物，其特征在于，Ra为-H、-CN、-CHF2、甲基、乙基、三氟甲基、-CH(CH3)2或环丙烷基。
  9. 根据权利要求1～4任一项所述的一种通式(Ⅱ)所示的化合物或其可药用盐或同位素衍生物，其特征在于，
    R1为-C1-3氘代烷基；
    R2为-C3-6环烷基；
    R3为卤素取代的C1-3烷氧基；
    R4为5-6元杂芳基，其中所述的5-6元杂芳基任选地被Ra取代；
    Ra为-H、-C1-3烷基、-C1-3卤代烷基、-C3-6环烷基或4-6元杂环基。
  10. 根据权利要求9所述的化合物或其可药用盐或同位素衍生物，其特征在于，R1为-CD3；
    R2为环丙烷基；
    R3为-OCF3或-OCHF2。
  11. 根据权利要求9或10所述的化合物或其可药用盐或同位素衍生物，其特征在于，
    R4为任选被Ra取代5元杂芳基，所述杂芳基包含1、2、3或4个氮杂原子。
  12. 根据权利要求9-11任一项所述的化合物或其可药用盐或同位素衍生物，其特征在于，R4为Ra为-H、甲基、乙基、三氟甲基或环丙烷基。
  13. 根据权利要求1～4任一项所述的一种通式(Ⅱ)所示的化合物或其可药用盐或同位素衍生物，其特征在于，
    R1为-C1-3氘代烷基；
    R2为-C3-6环烷基；
    R3为-C1-3烷基氧基或-C3-6环烷基氧基，其中所述的-C1-3烷基氧基或-C3-6环烷基氧基任选地进一步被选自氢原子、氘原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
    R4为5-6元杂芳基，其中所述的5-6元杂芳基任选地被Ra取代；
    Ra为-H、-CN、-CF3、-C1-3烷基、-C3-6环烷基或4-6元杂环基，其中所述的-C1-3烷基或-C3-6环烷基任选地进一步被选自氢原子、-C1-3烷基和卤素中的一个或多个取代基所取代。
  14. 根据权利要求13所述的化合物或其可药用盐或同位素衍生物，其特征在于，R1为-CD3；
    R2为环丙烷基；
    R3为-OCF3、-O-CH2CF3、-OCHF2、-O-CH2CHF2、-OCH(CH3)2或
  15. 根据权利要求13或14所述的化合物或其可药用盐或同位素衍生物，其特征在于，
    R4为
  16. 据权利要求12-15任一项所述的化合物或其可药用盐或同位素衍生物，其特征在于，Ra为-H、-CN、-CHF2、甲基、乙基、三氟甲基、-CH(CH3)2或环丙烷基。
  17. 根据权利要求1-4任一项所述的化合物或其可药用盐或同位素衍生物，其特征在于，所述化合物选自如下化合物或其可药用盐或同位素衍生物：




  18. 权利要求1-17中任一项所述式II所示化合物的制备方法，其特征在于，包含方案一或方案二的步骤，
    方案一：
    方案二：
    化合物IIa硼酸化后和R4X反应得到化合物IId，或化合物IIa和R4H直接反应得到化合物IId；
    化合物IId和化合物IIe反应得到化合物IIf；
    化合物IIf和R2C(O)NH2反应得到化合物II；
    其中X为Br或I，R1、R2、R3和R4如权利要求1-17中任一项所述。
  19. 一种药物组合物，其特征在于，包括治疗有效量的权利要求1-17中任一项的式II所示化合物或其可药用盐或同位素衍生物，以及任选一种或多种药学上可接受的载剂和/或稀释剂。
  20. 根据权利要求1-17任一项所述的式II所示化合物或其可药用盐或同位素衍生物，或者根据权利要求19所述的药物组合物在制备用于预防和/或治疗TYK2介导的疾病的药 物中的用途。
  21. 根据权利要求20所述的用途，其特征在于，所述TYK2介导的疾病包括炎性疾病或自身免疫性疾病。
  22. 根据权利要求20所述的用途，其特征在于，所述炎性疾病和自身免疫疾病为银屑病、炎症性肠病或红斑狼疮。
  23. 治疗TYK2介导的疾病的方法，包括给需要这种治疗的患者施用治疗有效量的权利要求1-17中任一项所述的式II所示化合物或其可药用盐或同位素衍生物。
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