WO2023236947A1 - 取代的哒嗪-3-甲酰胺化合物作为tyk2抑制剂 - Google Patents

取代的哒嗪-3-甲酰胺化合物作为tyk2抑制剂 Download PDF

Info

Publication number
WO2023236947A1
WO2023236947A1 PCT/CN2023/098585 CN2023098585W WO2023236947A1 WO 2023236947 A1 WO2023236947 A1 WO 2023236947A1 CN 2023098585 W CN2023098585 W CN 2023098585W WO 2023236947 A1 WO2023236947 A1 WO 2023236947A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkylene
group
alkyl
haloalkyl
optionally substituted
Prior art date
Application number
PCT/CN2023/098585
Other languages
English (en)
French (fr)
Inventor
邓代国
钟文和
卢杰联
雷曾荣
Original Assignee
广州费米子科技有限责任公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广州费米子科技有限责任公司 filed Critical 广州费米子科技有限责任公司
Publication of WO2023236947A1 publication Critical patent/WO2023236947A1/zh

Links

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to substituted pyridazine-3-carboxamide compounds, compositions containing them, their preparation methods and their use as TYK2 inhibitors.
  • the Janus kinase family is an intracellular non-receptor tyrosine kinase that mediates the signaling and activation of various cytokines. JAK gain-of-function expression or mutations are associated with many autoimmune diseases, inflammation, and cancer. This family includes JAK1, JAK2, JAK3 and TYK2. Among them, JAK1, JAK2 and TYK2 are widely found in various tissues and cells of the human body. JAK3 mainly exists in bone marrow cells, thymocytes, NK cells and activated B cells and T cells. .
  • the JAK-mediated signaling pathway includes three key parts: cytokine receptors on the cell surface, JAKs, and downstream proteins.
  • Cytokines such as various interferons (IFN) and interleukins (IL) bind to cytokine receptors on the cell surface, bringing the JAKs that bind to the intracellular domain of the receptors close to each other.
  • the tyrosine residues of JAK are then phosphorylated, increasing the activity of the kinase domain.
  • the activated JAK phosphorylates the receptor's tyrosine residues, creating a binding site for proteins with SH2 domains.
  • STAT signal transducer and activator of transcription
  • other proteins with SH2 domains can also bind to activated JAK, thereby cross-linking with other signaling pathways, such as PI3K/AKT, MAPK/ERK, etc.
  • TYK2 is a non-receptor tyrosine kinase that mediates immune signaling. It mainly regulates signaling pathways driven by IL-23, IL-12 and type I interferon (IFN ⁇ ). It is used as a molecule by inhibiting TYK2-mediated signal transduction. IL-12, IL-23 and/or IFNa modulators. TYK2 plays an important role in transmitting inflammatory and immune response signals and is involved in the pathophysiological processes of a variety of immune-related diseases, such as psoriasis (PS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). , inflammatory bowel disease (IBD), etc.
  • PS psoriasis
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • IBD inflammatory bowel disease
  • TYK2 does not mediate cytokine responses driven by other kinases (such as IL-6, hematopoietic growth factor, IL-2), so TYK2 inhibitors can avoid the adverse effects of currently marketed JAK inhibitors by not acting on other isoforms. .
  • JAK inhibitors are active site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain (JH1) of the JAK protein. Due to the high homology of the ATP sites of JAK family kinases and the similarity of the ATP-binding regions of the human kinome, there is a common problem of low selectivity.
  • ATP adenosine triphosphate
  • JH2 pseudokinase domain
  • the present invention provides a substituted pyridazine-3-carboxamide compound, which has excellent selective inhibition of TYK2 activity and can treat a variety of TYK2-mediated diseases.
  • the present invention provides compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, and pro-forms thereof.
  • the invention provides a pharmaceutical composition containing a compound as defined in the invention, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, Solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, and pharmaceutically acceptable excipients; preferably, they also contain other therapeutic agents.
  • the invention provides a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, Diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, as well as mixtures thereof, pharmaceutical compositions containing the same for the preparation of therapeutic and/or prophylactic Use in drugs for TYK2-mediated diseases.
  • the invention provides a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Polymorphs, prodrugs or isotopic variants, as well as mixtures thereof, or pharmaceutical compositions containing said compounds, for the treatment and/or prevention of TYK2 kinase-mediated diseases.
  • the invention provides a method for treating and/or preventing a TYK2 kinase-mediated disease in a subject with a compound as defined herein, comprising administering to the subject the compound or a pharmaceutical thereof.
  • the TYK2 kinase-mediated diseases according to the present invention are selected from autoimmune diseases, skin diseases, allergic diseases, organ rejection, cancer, dry eye disease, myelofibrosis, and polycythemia.
  • the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease or autoimmune thyroid disease; the skin disease It is psoriasis, rash or atopic dermatitis;
  • the allergic disease is asthma or rhinitis;
  • the organ transplant rejection is allogeneic suppression rejection or graft-versus-host disease;
  • the cancer is kidney cancer, liver cancer, pancreatic cancer, Stomach, breast, prostate, head and neck, thyroid, lung, glioblastoma, melanoma, lymphoma, or leukemia.
  • the method involves the TYK2 kinase-mediated disease being selected from the group consisting of rheumatoid arthritis, psoriasis, ulcerative colitis and Crohn's disease.
  • alkyl refers to a saturated hydrocarbon containing primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or combinations thereof.
  • Alkyl groups are preferably, for example, C 1 -C 6 alkyl, C 1 -C 5 alkyl, C 1 -C 4 alkyl and C 1 -C 3 alkyl.
  • C 1 -C 3 alkyl as an example, which refers to an alkyl group containing 1 to 3 carbon atoms. Each time it appears, it can be independently C 1 alkyl, C 2 alkyl, or C 3 alkyl. base.
  • Suitable examples include, but are not limited to: methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ).
  • Alkylene refers to a divalent group formed by removing the other hydrogen of an alkyl group, and may be substituted or unsubstituted. In some embodiments, C 1-6 alkylene, C 1-4 alkylene, C 2-4 alkylene, and C 1-3 alkylene are preferred.
  • the unsubstituted alkylene group includes, but is not limited to: methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), ethylene Base (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -) ,etc.
  • alkylene groups substituted by one or more alkyl (methyl) include, but are not limited to: substituted methylene (-CH(CH 3 )- , -C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2- ), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 ) -, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -), etc.
  • alkenyl is an alkyl group as defined herein that contains at least one carbon-carbon double bond.
  • the alkenyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, further preferably 2 to 8 carbon atoms, even more preferably 2 to 6 carbon atoms.
  • alkenyl groups include substituted or unsubstituted vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl or 4-decenel, etc.
  • Alkynyl as defined herein is an alkyl group containing at least one carbon-carbon triple bond.
  • the alkynyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, further preferably 2 to 8 carbon atoms, even more preferably 2 to 6 carbon atoms.
  • Carbocyclyl or “cycloalkyl” refers to a saturated or partially unsaturated cyclic carbon-containing group, such as a 5-6 membered saturated carbocyclic ring and a 5-6 membered partially unsaturated carbocyclic ring.
  • the carbocyclyl group is a 3- to 4-membered monocyclic ring, a 3- to 5-membered monocyclic ring, a 3- to 5-membered monocyclic ring, or a 3- to 5-membered monocyclic ring.
  • Carbon rings include bridged rings or spiro rings.
  • Non-limiting examples of carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, Benzocyclopentyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, tricyclo[5.3.1.1]dodecyl, adamantyl or spiro[3.3]heptane Key et al. Carbocyclyl groups may be optionally substituted.
  • halogen refers to -F, -Cl, -Br or -I.
  • haloalkyl refers to an alkyl group substituted by a halogen group, wherein the alkyl group is as defined above, preferably C 1-6 haloalkyl, C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl and C 1-2 haloalkyl.
  • aryl refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing one hydrogen atom. It can be a single-ring aryl group, a condensed-ring aryl group, or a polycyclic aryl group, preferably a 6-10-membered aryl group. base. For polycyclic ring species, at least one is an aromatic ring system. Phrases including this term, for example, "5-6 membered aryl" mean that the aromatic ring system contains 5-6 ring atoms. Preferably, the aryl group is phenyl.
  • heteroaryl refers to an aryl group containing heteroatoms, which may be monocyclic or fused rings, and the heteroatoms are independently selected from N, O and S, preferably 5-12 membered heteroaryl, 5 -10-membered heteroaryl group, preferably 5-8-membered heteroaryl group, more preferably 5-6-membered heteroaryl group, more preferably 5-membered heteroaryl group.
  • Heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, Isoquinolyl, triazolyl, tetrahydropyrrolyl and thiadiazolyl.
  • a 5-6 membered monocyclic heteroaryl group typically contains 1 or more, preferably 1-3 heteroatoms independently selected from N, O and S.
  • 5-membered heteroaryl is an exemplary 5-membered heteroaryl group containing one heteroatom including, but not limited to, pyrrolyl, furyl, and thienyl; exemplary 5-membered heteroaryl groups containing two heteroatoms 5-membered heteroaryl groups include, but are not limited to, imidazolyl, pyrazolyl, oxazolinyl, isoxazolinyl, thiazolyl, and isothiazolyl; exemplary 5-membered heteroaryl groups include three heteroatoms.
  • Aryl groups include, but are not limited to, thiazolyl, oxadiazolyl, and thiadiazolyl; exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or partially unsaturated cyclic group containing heteroatoms selected from N, O and S. Furthermore, the term “heterocyclyl” refers to a group of a stable 3-10 membered saturated heterocyclic system in which one or more atoms constituting the ring are heteroatoms and the remainder are carbon. The heteroatoms include, but are not limited to, nitrogen atoms, oxygen atoms, sulfur atoms, etc.
  • the heterocyclic group may be a 3- to 7-membered monocyclic ring, a 5- to 8-membered monocyclic ring, a 5- to 6-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, preferably 3 to 10-membered Heterocyclyl, and contains at least 1, preferably 1 to 4 heteroatoms selected from N, O or S.
  • a heterocycloalkyl group may be monocyclic ("monocyclic heterocycloalkyl"), or a bicyclic, tricyclic or higher ring system, which may include and cyclic (fused), bridged (bridged) or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocycloalkyl").
  • a bicyclic heterocycloalkyl ring system can be in one or include one or more heteroatoms in both rings; and are saturated.
  • Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridyl, oxiranyl, and thiiranyl , or a stereoisomer thereof;
  • exemplary 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, propylene oxide, thietanyl, or isomers thereof and Stereoisomers;
  • exemplary 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidine base, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathialanyl, dithiolanyl, or isomers and stereoisomers thereof.
  • Exemplary 6-membered Heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, thiacyclyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, Triazinealkyl, or isomers and stereoisomers thereof;
  • exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxeptanyl, thiocyclyl Heptyl, and diazacycloheptyl, or isomers and stereoisomers thereof.
  • a typical heterocyclyl group contains 1 or more, preferably 1-4 , more preferably a 5-6 membered monocyclic heterocyclyl group with 1-3 heteroatoms independently selected from N, O and S.
  • heterocycloalkyl is a 4-6 membered heterocycloalkyl group , where the heteroatoms are selected from one or more types of N, O and S, and the number of heteroatoms is 1, 2 or 3.
  • linking substituents are described.
  • the Markush variables listed for that group should be understood as referring to the linking group.
  • the alkyl group represents a linked alkylene group, for example, the group "-C 1 -C 3 haloalkyl”
  • the alkyl group in should be understood as an alkylene group.
  • salts means a compound that can be converted by conventional means into a corresponding salt that is chemically or physically compatible with the other ingredients constituting a pharmaceutical dosage form and is physiologically compatible with the receptor .
  • the salts may be acidic and/or basic salts of the compound with inorganic and/or organic acids and/or with inorganic and/or organic bases, also including zwitterion salts (inner salts), and also including quaternary ammonium salts, for example Alkylammonium salt. These salts can be obtained directly from the final isolation and purification of the compounds. It can also be obtained by appropriately mixing the compound of the present invention or its stereoisomer or solvate with a certain amount of acid or base.
  • the salt is preferably a water-soluble pharmaceutically acceptable non-toxic acid addition salt.
  • examples are amino and inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfur acid and perchloric acid) or salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods conventional in the art (e.g. Salt formed by ion exchange method).
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethane sulfonate, formate, fumarate, glucoheptonic acid Salt, glycerophosphate, gluconate, hemisulfate, enanthate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurate Sulfate, malate, maleate, malonate, methane sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, bis Hydroxylate, pectate
  • additional pharmaceutically acceptable salts may also include salts derived from appropriate bases, including alkali metal salts, alkaline earth metal salts, and ammonium salts.
  • Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like.
  • Additional pharmaceutically acceptable salts include the use of counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates with nontoxic ammonium, when appropriate. , quaternary ammonium and amine cations form salts.
  • solvate can also be called “solvent compound” or “solvate”, which refers to a compound containing solvent molecules, where the solvent molecules can include coordination bonds, covalent bonds, van der Waals forces, ionic bonds, hydrogen Combined with compound molecules through bonds and other means.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, etc.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates.
  • the solvate will be able to isolate, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates, and methoxides.
  • hydrate refers to a compound combined with water. Typically, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined.
  • a hydrate of a compound may be represented, for example, by the general formula R.xH2O , where R is the compound and x is a number greater than zero.
  • a given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1), for example, hemihydrate (R ⁇ 0.5H 2 O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)).
  • monohydrate x is 1
  • lower hydrate x is a number greater than 0 and less than 1
  • hemihydrate R ⁇ 0.5H 2 O
  • polyhydrates x is a number greater than 1, for example, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)
  • prodrug refers to any compound that when administered to an organism produces a drug, ie, an active ingredient, as a result of a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, a photolytic and/or a metabolic chemical reaction.
  • Prodrugs are thus covalently modified analogs or potential forms of therapeutically active compounds. Suitable examples include, but are not limited to: carboxylic acid esters, carbonic acid esters, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides , ether, acetal and other forms.
  • the present invention also includes isotopically labeled compounds (isotopic variants) which are equivalent to those of general formula or specific compounds described herein, but with one or more atoms having an atomic mass or mass number different from that commonly seen in nature. Replaced by number of atoms.
  • isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 respectively. O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl, preferably 2 H (ie deuterium, D).
  • isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when performing the processes disclosed in the following schemes and/or examples and preparation examples.
  • the compounds of the present invention contain one or more asymmetric centers and thus may exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, Includes racemic mixtures and mixtures enriched in one or more stereoisomers.
  • the isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers may be separated by Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • aryl optionally substituted by alkyl means that alkyl may but need not be present, and the term includes both cases where aryl is substituted with alkyl and cases where aryl is not substituted by alkyl.
  • “Pharmaceutically acceptable excipient” refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • pharmaceutically acceptable excipient includes buffers compatible with pharmaceutical administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents and other Such. Each excipient must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
  • Suitable examples include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch and substituted or unsubstituted ⁇ -cyclodextrin; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) Powdered tragacanth; (5) Malt; (6) Gelatin; (7) Talc; (8) Fu excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols Alcohols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Esters, such as ethyl oleate and ethyl laurate; (13) Agar; (14) Bu
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms often have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the present invention uses traditional methods such as mass spectrometry and nuclear magnetism to identify compounds.
  • Each step and condition can refer to the conventional operating steps and conditions in the art.
  • this invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.
  • the present invention relates to the following technical solutions
  • the present invention relates to compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates thereof , polymorphs, prodrugs or isotopic variants, and mixtures thereof:
  • R 1 is selected from H, C 1-6 haloalkyl, C 1-6 alkylene-OR a , C 1-6 alkylene-SR a , C 1-6 alkylene-NR b R c , C 1 -6 alkylene-C(O)R a , C 1-6 alkylene -C(O)OR a , C 1-6 alkylene -C(O)NR b R c , C 1-6 alkylene Alkyl-OC(O)R a , C 1-6 alkylene -NR b C(O)R a , C 1-6 alkylene -S(O) m R a , C 1-6 alkylene -S(O) m NR b R c or C 1-6 alkylene group -NR b S(O) m R a , said group optionally substituted by one or more deuteriums until completely deuterated;
  • R 2 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6 -10 aryl or 5-10 membered heteroaryl, which group is optionally substituted by one or more deuteriums until completely deuterated;
  • R 3 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, which group is optionally substituted by one or more deuteriums until completely deuterated;
  • R 1 , R 2 and R 3 are optionally substituted by 1, 2, 3 or 4 R;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl , 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R is selected from H, D, halogen, CN, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof substances, polymorphs, prodrugs or isotopic variants, and mixtures thereof, which
  • R 1 is selected from H, C 1-6 haloalkyl, C 1-6 alkylene-OR a , C 1-6 alkylene-SR a , C 1-6 alkylene-NR b R c , C 1-6 alkylene-C(O)R a , C 1-6 alkylene-C(O)OR a , C 1-6 alkylene-C(O)NR b R c , C 1- 6 alkylene-OC(O)R a or C 1-6 alkylene -NR b C(O)R a , the group is optionally substituted by one or more deuteriums until completely deuterated; preferably Ground, R 1 is selected from H, C 1-6 haloalkyl
  • the present invention provides the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof Materials, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 2 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, the group is optionally substituted by one or more deuteriums until completely deuterated; preferably, R 2 is selected from C 1-6 alkyl group, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, the group is optionally substituted by one or more deuterium until completely deuterated; preferably, R 2 Selected from C 1-6 alkyl or C 3-7 cycloalkyl, said group optionally substituted by
  • the present invention provides the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof substances, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 3 is selected from C 1-6 alkyl or C 1-6 haloalkyl, which group is optionally replaced by one or more Deuterium-substituted until fully deuterated; preferably, R3 is methyl, which is optionally substituted with one or more deuteriums until fully deuterated.
  • the present invention provides the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof substances, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein:
  • R 1 is selected from H, C 1-6 haloalkyl, C 1-6 alkylene-OR a , C 1-6 alkylene-SR a or C 1-6 alkylene-C(O)OR a , The group is optionally substituted with one or more deuteriums, until fully deuterated;
  • R 2 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, which group is optionally substituted by one or more deuterium, until Completely deuterated;
  • R 3 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, which group is optionally substituted by one or more deuteriums until completely deuterated;
  • R 1 , R 2 and R 3 are optionally substituted by 1, 2, 3 or 4 R;
  • R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R is selected from H, D, halogen, CN, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof substances, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein:
  • R 1 is selected from H, C 1-4 haloalkyl, C 1-4 alkylene-OR a or C 1-4 alkylene-C(O)OH, which group is optionally replaced by one or more Deuterium substitution, until complete deuterium substitution;
  • R 2 is selected from C 1-4 alkyl, C 1-4 haloalkyl or C 3-7 cycloalkyl, which group is optionally substituted by one or more deuteriums until completely deuterated;
  • R 3 is selected from C 1-4 alkyl or C 1-4 haloalkyl, which group is optionally substituted by one or more deuteriums until completely deuterated;
  • R a is selected from H, C 1-4 alkyl or C 1-4 haloalkyl.
  • the present invention provides the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof substances, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein:
  • R 1 is C 1-4 alkylene-OR a , which is optionally substituted with one or more deuteriums until fully deuterated;
  • R 2 is selected from C 1-4 alkyl, C 1-4 haloalkyl or C 3-7 cycloalkyl, which group is optionally substituted by one or more deuteriums until completely deuterated; preferably C 1- 4 alkyl, which is optionally substituted by one or more deuteriums until completely deuterated;
  • R 3 is selected from C 1-4 alkyl or C 1-4 haloalkyl, which group is optionally substituted by one or more deuteriums until completely deuterated;
  • R a is selected from C 1-4 alkyl or C 1-4 haloalkyl.
  • the present invention provides the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof substances, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein:
  • R 1 is selected from H, C 1-4 haloalkyl, C 1-4 alkylene-OH or C 1-4 alkylene-C(O)OH, which group is optionally replaced by one or more deuterium Substitution, until complete deuteration;
  • R 2 is selected from C 1-4 alkyl, C 1-4 haloalkyl or C 3-7 cycloalkyl, which group is optionally substituted by one or more deuterium, until completely deuterated Generation; preferably C 1-4 alkyl, which is optionally substituted by one or more deuteriums until completely deuterated;
  • R 3 is selected from C 1-4 alkyl or C 1-4 haloalkyl, which group is optionally substituted with one or more deuteriums until fully deuterated.
  • the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein:
  • R 1 is selected from H, C 1-6 alkylene-OR a and C 1-6 alkylene-SR a , said group optionally substituted with one or more deuteriums until fully deuterated;
  • R 2 is selected from C 1-6 alkyl and C 1-6 haloalkyl, which group is optionally substituted by one or more deuteriums until completely deuterated;
  • R 3 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, which group is optionally substituted by one or more deuteriums until completely deuterated;
  • R 1 , R 2 and R 3 are optionally substituted by 1, 2, 3 or 4 R;
  • R a is selected from H, C 1-6 alkyl and C 1-6 haloalkyl
  • R is selected from H, D, halogen, CN, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein:
  • R 1 is selected from H and C 1-6 alkylene-OR a , said group optionally substituted with one or more deuteriums until fully deuterated;
  • R 2 is selected from C 1-6 alkyl and C 1-6 haloalkyl
  • R 3 is C 1-6 alkyl, which group is optionally substituted by one or more deuteriums until completely deuterated;
  • R a is selected from H and C 1-6 alkyl.
  • the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein:
  • R 1 is selected from H and C 1-4 alkylene-OR a , said group optionally substituted with one or more deuteriums until fully deuterated;
  • R 2 is C 1-4 alkyl, which group is optionally substituted by one or more deuteriums until completely deuterated;
  • R 3 is C 1-4 alkyl, which group is optionally substituted with one or more deuteriums until fully deuterated,
  • R a is C 1-4 alkyl.
  • the present invention provides the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof compounds, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein said compound is selected from the following:
  • the invention provides a pharmaceutical composition containing a compound as defined in the invention, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, Solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, and pharmaceutically acceptable excipients; preferably, they also contain other therapeutic agents.
  • the invention provides a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Use of polymorphs, prodrugs or isotopic variants, as well as mixtures thereof, and pharmaceutical compositions containing the same for the preparation of medicaments for the treatment and/or prevention of TYK2 kinase-mediated diseases.
  • the invention provides a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Polymorphs, prodrugs or isotopic variants, as well as mixtures thereof, or pharmaceutical compositions containing said compounds, for the treatment and/or prevention of TYK2 kinase-mediated diseases.
  • the invention provides a method for treating and/or preventing a TYK2 kinase-mediated disease in a subject with a compound as defined herein, comprising administering to the subject the compound or a pharmaceutical thereof.
  • the TYK2 kinase-mediated diseases according to the present invention are selected from autoimmune diseases, skin diseases, allergic diseases, organ rejection, cancer, dry eye disease, myelofibrosis, and polycythemia.
  • the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease or autoimmune thyroid disease; the skin disease It is psoriasis, rash or atopic dermatitis;
  • the allergic disease is asthma or rhinitis;
  • the organ transplant rejection is allogeneic suppression rejection or graft-versus-host disease;
  • the cancer is kidney cancer, liver cancer, pancreatic cancer, Stomach, breast, prostate, head and neck, thyroid, lung, glioblastoma, melanoma, lymphoma, or leukemia.
  • the method involves the TYK2 kinase-mediated disease being selected from the group consisting of rheumatoid arthritis, psoriasis, ulcerative colitis and Crohn's disease.
  • Compounds (I) of the present invention may be administered by any means appropriate to the disease state to be treated, which means may depend on the need for site-specific treatment or the amount of drug to be delivered. Although other modes of delivery are contemplated, topical administration is generally preferred for skin-related diseases, and systemic treatment is preferred for cancerous or precancerous disease states.
  • the compounds may be delivered: orally, for example in the form of tablets, capsules, granules, powders or liquid preparations (including syrups); topically, for example as solutions, suspensions, gels or Form of ointment; sublingual; buccal; parenteral, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); via Nasally, for example by inhalation spray; topically, for example in the form of a cream or ointment; rectal, for example in the form of a suppository; or liposomal.
  • parenteral such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); via Nasally, for example by inhalation spray; topically, for example in the form of
  • Unit dose formulations may be administered containing nontoxic pharmaceutically acceptable carriers or diluents.
  • the compounds may be administered in a form suitable for immediate release or extended release. Immediate or prolonged release may be achieved using suitable pharmaceutical compositions or, especially in the case of extended release, using, for example, subcutaneous implants or osmotic pump devices.
  • compositions for topical administration include a topical carrier.
  • compositions for oral administration include suspensions, which may contain, for example, microcrystalline cellulose to impart volume, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosifier, and sweetening agents or flavorings, such as those known in the art; and immediate release tablets, which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients , binders, extenders, disintegrants, diluents and lubricants, such as those known in the art.
  • the compounds of the invention may also be delivered bucally by sublingual and/or buccal administration, for example, using molded, compressed or freeze-dried tablets.
  • compositions may include fast dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrin. These formulations may also include high molecular weight excipients such as cellulose (AV1CEL ) or polyethylene glycol (PEG); excipients used to aid mucoadhesion, such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (SCMC) ) and/or maleic anhydride copolymers (e.g., ); and agents for controlled release, such as polyacrylic copolymers (e.g., CARBOPOL ). Lubricants, glidants, flavoring agents, colorants and stabilizers may also be added to facilitate preparation and use.
  • AV1CEL high molecular weight excipients
  • PEG polyethylene glycol
  • excipients used to aid mucoadhesion such as hydroxypropylcellulose (HPC), hydroxyprop
  • compositions for nasal aerosol or inhalation administration include solutions, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers and/or other solubilizers to enhance absorption and/or bioavailability, or Dispersing agents, such as those known in the art.
  • compositions for parenteral administration include injectable solutions or suspensions, which may contain, for example, a suitable nontoxic parenterally acceptable diluent or solvent, such as mannitol, 1,3-butanediol, water, linol, etc.
  • a suitable nontoxic parenterally acceptable diluent or solvent such as mannitol, 1,3-butanediol, water, linol, etc.
  • Grignard solution, isotonic sodium chloride solution, or other suitable dispersing or wetting agents and suspending agents including synthetic mono- or diglycerides and fatty acids, including oleic acid.
  • compositions for rectal administration include suppositories, which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glycerides, or polyethylene glycols, which are solid at ordinary temperatures but dissolve in the rectal lumen. Liquefies and/or dissolves to release the drug.
  • suitable non-irritating excipients such as cocoa butter, synthetic glycerides, or polyethylene glycols, which are solid at ordinary temperatures but dissolve in the rectal lumen. Liquefies and/or dissolves to release the drug.
  • the therapeutically effective amount of a compound of the present invention can be determined by one skilled in the art, and for mammals includes about 0.05-1000 mg/kg, 1-1000 mg/kg, 1-50 mg/kg, 5-250 mg/kg, 250-1000 mg per day Exemplary doses of active compound per kg body weight, which may be administered as a single dose or in individual divided doses (eg 1 to 4 times per day). It is understood that the specific dosage levels and frequency of administration for any particular individual may vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, the species, age of the individual , body weight, general health, sex and diet, mode and timing of administration, excretion rate, drug combination and severity of the specific disease state.
  • Preferred subjects for treatment include animals, most preferably mammalian species, such as humans, and domestic animals, such as dogs, cats, horses, and the like. Accordingly, when the term "patient” is used herein, this term is meant to include all individuals, most preferably mammalian species suffering from a TYK2 kinase-mediated disease.
  • 2-Methoxy-3-nitrobenzamide (5.2g, 26.53mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (67.6 mL), react at 95°C for 1 hour, spin off the solvent in vacuum, and dissolve it in ethanol (13 mL) to obtain the crude product; stir ethanol (110 mL) and acetic acid (26 mL) at 0° C. for 5 minutes, and then add Hydrazine hydrate (13.18 mL), stir and react for fifteen minutes, add the above crude solution, raise to room temperature, stir and react for one hour.
  • Step 4 3-(2-methoxy-3-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole
  • Step 6 ((6-chloro-4-((2-methoxy-3-(1-(tetrahydro-2H-pyran-2-yl))-1H-1,2,4-triazole- 3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5)
  • Step 7 ((6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahydro-2H-pyran-2-yl))-1H-1,2 ,4-triazol-3-yl)phenyl)amino))pyridazine-3-carbonyl)oxy)zinc (0.5)
  • Step 8 6-(cyclopropanecarboxamido)-N-ethoxy-4-((2-methoxy-3-(1-(tetrahydro-2H-pyran-2-yl))-1H -1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide
  • Step 9 6-(cyclopropanecarboxamido)-N-ethoxy-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl) )amino)pyridazine-3-carboxamide (compound 1)
  • Step 1 3-(2-methoxy-3-nitrophenyl)-1-(2-methoxyethyl)-1H-1,2,4-triazole
  • Step 3 ((6-chloro-4-((2-methoxy-3-(1-(2-methoxyethyl))-1H-1,2,4-triazol-3-yl)benzene base)amino)pyridazine-3-carbonyl)oxy)zinc (0.5)
  • Step 4 ((6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(2-methoxyethyl))-1H-1,2,4-tri Azol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5)
  • Step 5 6-(cyclopropylcarboxamido)-N-ethoxy-4-((2-methoxy-3-(1-(2-methoxyethyl))-1H-1,2 ,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (compound 2)
  • Step 4 6-(cyclopropylcarboxamido)-N-cyclopropoxy-4-((2-methoxy-3-(1-(2-methoxyethyl))-1H-1, 2,4-Triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (compound 3)
  • Step 1 1-(2-fluoroethyl)-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole
  • Step 3 ((6-chloro-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl) )amino)pyridazine-3-carbonyl) Oxygen) zinc
  • Step 4 ((6-(cyclopropanecarboxamido)-4-((3-(1-(2-fluoroethyl))-1H-1,2,4-triazol-3-yl)-2 -Methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5)
  • Step 5 6-(cyclopropylcarboxamido)-N-ethoxy-4-((3-(1-(2-fluoroethyl))-1H-1,2,4-triazole-3- (base)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (compound 4)
  • Step 1 1-(2,2-difluoroethyl)-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole
  • Step 3 ((6-chloro-4-((3-(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxy Phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5)
  • Step 4 ((6-(cyclopropanecarboxamido)-4-((3-(1-(2,2-difluoroethyl))-1H-1,2,4-triazol-3-yl )-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5)
  • Step 5 6-(cyclopropanecarboxamido)-4-((3-(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)- 2-methoxyphenyl)amino)-N-ethoxypyridazine-3-carboxamide (compound 5)
  • Step 1 2-(3-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)acetate tert-butyl
  • Step 2 2-(3-(3-Amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)acetate tert-butyl ester
  • Step 3 ((4-((3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-2 -Methoxyphenyl)amino)-6-chloropyridazine-3-carbonyl)oxy)zinc (0.5)
  • Step 4 ((4-((3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-2 -Methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3-carbonyl)oxy)zinc (0.5)
  • Step 5 2-(3-(3-((6-(cyclopropylcarboxamido)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzene tert-butyl)-1H-1,2,4-triazole-1-acetate
  • Step 6 2-(3-(3-((6-(cyclopropylcarbamoyl)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzene (Hydroxy)-1H-1,2,4-triazol-1-yl)acetic acid (Compound 7)
  • Step 1 tert-butyl 3-(3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)propionate
  • Step 2 tert-butyl 3-(3-(3-amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)propionate
  • Step 3 ((4-((3-(1-(3-(tert-butoxy)-3-oxopropyl)-1H-1,2,4-triazol-3-yl)-2 -Methoxyphenyl)amino)-6-chloropyridazine-3-carbonyl)oxy)zinc (0.5)
  • Step 4 ((4-((3-(1-(3-(tert-butoxy)-3-oxopropyl)-1H-1,2,4-triazol-3-yl)-2- Methoxyphenyl)amino)-6-(cyclopropylcarboxamido)pyridazine-3-carbonyl)oxy)zinc (0.5)
  • Step 5 3-(3-(6-(cyclopropylcarboxamide)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H- 1,2,4-Triazol-1-yl)tert-butylpropionate
  • Step 6 3-(3-(3-((6-(cyclopropylcarbamoyl)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzene (Hydroxy)-1H-1,2,4-triazol-1-yl)propionic acid (compound 8)
  • Step 1 tert-butyl 4-(3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)butyrate
  • Step 2 tert-butyl 4-(3-(3-amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)butyrate
  • Step 3 ((4-((3-(1-(4-(tert-butoxy)-4-oxobutyl)-1H-1,2,4-triazol-3-yl)-2 -Methoxyphenyl)amino)-6-chloropyridazine-3-carbonyl)oxy)zinc (0.5)
  • Step 4 ((4-((3-(1-(4-(tert-butoxy)-4-oxobutyl)-1H-1,2,4-triazol-3-yl)-2 -Methoxyphenyl)amino)-6-(cyclopropylcarboxamido)pyridazine-3-carbonyl)oxy)zinc (0.5)
  • Step 5 4-(3-((6-(cyclopropylcarboxamide)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H -1,2,4-Triazol-1-yl)butyric acid tert-butyl ester
  • Step 6 4-(3-(3-((6-(cyclopropylcarbamoyl)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzene (Hydroxy)-1H-1,2,4-triazol-1-yl)butyric acid (Compound 9)
  • Step 1 1-(2-(benzyloxy)ethyl)-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole
  • Step 3 ((4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl) Amino)-6-chloropyridazine-3-carbonyl)oxy)zinc (0.5)
  • Step 4 ((4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl) Amino)-6-(cyclopropylcarboxamido)pyridazine-3-carbonyl)oxy)zinc (0.5)
  • Step 5 4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino )-6-(cyclopropanecarboxamido)-N-ethoxypyridazine-3-carboxamide
  • Step 6 6-(cyclopropylcarboxamide)-N-ethoxy-4-((3-(1-(2-hydroxyethyl))-1H-1,2,4-triazol-3-yl )-2-methoxyphenyl)amino)pyridazine-3-carboxamide (compound 10)
  • Step 1 4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino )-6-(cyclopropanecarboxamide)-N-(2-fluoroethoxy)pyridazine-3-carboxamide
  • N-methylpyrrolidone (9mL) and acetonitrile (9mL) were stirred at room temperature for ten minutes, and ((4-((3-(1-(2-(benzyloxy)ethyl))-1H-1,2 ,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamido)pyridazine-3-carbonyl)oxy)zinc (0.5) (300mg, 0.64mmol ), O-(2-fluoroethyl)hydroxylamine hydrochloride (110.91mg, 0.96mmol) and N-methylimidazole (158.45mg, 1.93mmol), after nitrogen replacement, react in an oil bath at 65°C for 15 minutes, Finally, 1-hydroxybenzotriazole (172.95mg, 1.28mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2
  • Step 2 6-(cyclopropanecarboxamide)-N-(2-fluoroethoxy)-4-((3-(1-(2-hydroxyethyl))-1H-1,2,4- Triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (compound 11)
  • Step 1 4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino )-6-(cyclopropylcarboxamide)-N-(2,2-difluoroethoxy)pyridazine-3-carboxamide
  • Step 2 6-(cyclopropanecarboxamide)-N-(2,2-difluoroethoxy)-4-((3-(1-(2-hydroxyethyl))-1H-1,2 ,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (compound 12)
  • Test Example A In vitro enzyme binding experiment of the compound TYK2 JH2 of the present invention
  • TR-FRET fluorescence resonance energy transfer
  • Test Example B Determination of STAT5 phosphorylation test (JAK1/3) of CD3+ cell subsets in IL-2-induced human PBMC by compounds of the present invention
  • the purpose of this test example is to use protein phosphorylation flow cytometry analysis technology to detect the inhibitory effect of compounds on IL-2-induced STAT5 phosphorylation.
  • Pre-incubate human PBMC cells with compounds induce STAT5 phosphorylation under appropriate stimulation conditions, and stain corresponding cell subpopulations and targets.
  • the compound of the present invention has lower inhibitory activity on the JAK1/3 signaling pathway and has better selectivity.
  • Test Example C Determination of the inhibitory effect of the compounds of the present invention on JAK1 JH1/JAK2 JH1/JAK3 JH1/TYK2 JH1 kinase
  • the purpose of this test example is to use homogeneous time-resolved fluorescence resonance energy transfer technology (HTRF) to detect the inhibitory effect of compounds on JAK1 JH1/JAK2 JH1/JAK3 JH1/TYK2 JH1 kinase activity.
  • HTRF time-resolved fluorescence resonance energy transfer technology
  • the compound of the present invention has lower inhibitory activity against JAK1 JH1/JAK2 JH1/JAK3 JH1 and has better selectivity.

Abstract

本发明提供了通式(I)的哒嗪-3-甲酰胺化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体。本发明还提供了包含所述化合物的药物组合物，其制备方法及其在治疗或预防TYK2激酶介导的疾病中的用途。

Description

取代的哒嗪-3-甲酰胺化合物作为TYK2抑制剂 发明领域
本发明涉及药物化学领域，具体涉及取代的哒嗪-3-甲酰胺化合物、包含其的组合物、其制备方法及其作为TYK2抑制剂的用途。
背景技术
Janus激酶家族(JAK)是胞内非受体酪氨酸激酶，介导各种细胞因子的信号传导和激活。JAK功能获得性表达或突变与诸多自体免疫疾病、炎症和癌症相关。该家族包括JAK1、JAK2、JAK3和TYK2，其中，JAK1、JAK2和TYK2广泛存在于人体各种组织和细胞中，JAK3主要存在于骨髓细胞、胸腺细胞、NK细胞及活化的B细胞、T细胞中。
JAK介导的信号通路包括3个关键部分：细胞表面的细胞因子受体、JAK和下游蛋白。细胞因子如多种干扰素(IFN)和白介素(IL)与细胞表面的细胞因子受体结合，使与受体胞内结构域结合的JAK靠近。然后，JAK的酪氨酸残基被磷酸化，增加了激酶域的活性。接着，激活的JAK磷酸化受体的酪氨酸残基，为具有SH2域的蛋白创造了结合位点。STAT(信号转导和转录激活因子)通过其SH2域与受体上的磷酸化酪氨酸结合，被JAK磷酸化，产生磷酸化的STAT二聚体，然后二聚体转位到细胞核诱导靶基因的转录。此外，其他具有SH2域的蛋白质也可以与激活的JAK结合，从而与其他信号通路交联，如PI3K/AKT、MAPK/ERK等。
TYK2是一种介导免疫信号的非受体酪氨酸激酶，主要调控IL-23、IL-12和I型干扰素(IFNα)驱动的信号通路，通过抑制TYK2介导的信号转导用作IL-12、IL-23和/或IFNa调节剂。TYK2在传递炎症和免疫应答信号方面具有重要的作用，参与多种免疫相关疾病的的病理生理过程，如银屑病(PS)、类风湿性关节炎(RA)、系统性红斑狼疮(SLE)、炎性肠病(IBD)等。TYK2不介导其他激酶(如IL-6、造血生长因子、IL-2)驱动的细胞因子应答，因此TYK2抑制剂通过不作用于其他亚型，可以避开现有上市JAK抑制剂的不良反应。
通常的小分子JAK抑制剂为活性位点导向的抑制剂，其结合于JAK蛋白的催化结构域(JH1)的腺苷三磷酸(ATP)位点。由于JAK家族激酶ATP位点的高度同源性和人激酶组ATP结合区的相似性，因此普遍存在选择性不高的问题。
经研究，JAK家族中具有明显催化活性的假激酶结构域(JH2)，其可以为发现TYK2选择性抑制剂提供一个理想的变构位点。化合物BMS-986165是目前已知的一种可以选择性地结合到TYK2的JH2的化合物，通过变构效应抑制TYK2激酶功能。
目前需要活性更优的通过结合JH2而选择性抑制TYK2的药物，从而在疾病的治疗中提供治疗益处。
发明内容
基于此，本发明提供了一种取代的哒嗪-3-甲酰胺化合物，其具有优异的选择性抑制TYK2的活性，治疗多种TYK2介导的疾病。
本发明提供通式(I)的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：
其中，各取代基如本发明中所定义。
在一个实施方案中，本发明提供药物组合物，其含有如本发明所定义的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，和药学上可接受的赋形剂；优选地，其还含有其它治疗剂。
在一个实施方案中，本发明提供如本发明所定义的化合物或其药学上可接受的盐、对映异构体、 非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，包含其的药物组合物在制备用于治疗和/或预防TYK2介导的疾病的药物中的用途。
在一个实施方案中，本发明提供如本发明所定义的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，或包含所述化合物的药物组合物，其用于治疗和/或预防TYK2激酶介导的疾病。
在一个实施方案中，本发明提供如本发明所定义的化合物在受试者中治疗和/或预防TYK2激酶介导的疾病的方法，包括向所述受试者给药所述化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，或包含其的的药物组合物。
如本发明所述的TYK2激酶介导的疾病选自自身免疫性疾病、皮肤病、变应性疾病、器官排斥、癌症、干眼病、骨髓纤维化、红细胞增多症。进一步，所述自身免疫性疾病为狼疮、多发性硬化、类风湿性关节炎、青少年关节炎、银屑病、溃疡性结肠炎、克罗恩氏病或自体免疫性甲状腺疾病；所述皮肤病为牛皮癣、皮疹或特应性皮炎；所述变应性病症为哮喘或鼻炎病；所述器官移植排斥为异体抑制排斥或移植物抗宿主疾病；所述癌症为肾癌、肝癌、胰腺癌、胃癌、乳腺癌、前列腺癌、头颈部癌、甲状腺癌、肺癌、胶质母细胞瘤、黑素瘤、淋巴瘤或白血病。
在一些实施方案中，本方法涉及所述TYK2激酶介导的疾病选自类风湿性关节炎、银肩病、溃疡性结肠炎和克罗恩病。
具体实施方式
定义
以下结合具体实施例对本发明的化合物、其制备方法及其用途作进一步详细的说明。本发明可以以许多不同的形式来实现，并不限于本文所描述的实施方式。相反地，提供这些实施方式的目的是使对本发明公开内容理解更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文在说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。文所使用的术语“和/或”意指一个或多个相关的所列项目中的任意一种和所有项目的组合。
术语“烷基”是指包含伯(正)碳原子、或仲碳原子、或叔碳原子、或季碳原子、或其组合的饱和烃。烷基优选为例如C1-C6烷基、C1-C5烷基、C1-C4烷基和C1-C3烷基。以“C1-C3烷基”为例，其是指包含1～3个碳原子的烷基，每次出现时，可以互相独立地为C1烷基、C2烷基、C3烷基。合适的实例包括但不限于：甲基(Me、-CH3)、乙基(Et、-CH2CH3)、1-丙基(n-Pr、n-丙基、-CH2CH2CH3)、2-丙基(i-Pr、i-丙基、-CH(CH3)2)。
“亚烷基”是指除去烷基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C1-6亚烷基、C1-4亚烷基、C2-4亚烷基和C1-3亚烷基是优选的。未取代的所述亚烷基包括但不限于：亚甲基(-CH2-)、亚乙基(-CH2CH2-)、亚丙基(-CH2CH2CH2-)、亚丁基(-CH2CH2CH2CH2-)、亚戊基(-CH2CH2CH2CH2CH2-)、亚己基(-CH2CH2CH2CH2CH2CH2-)，等等。示例性的取代的所述亚烷基，例如，被一个或多个烷基(甲基)取代的所述亚烷基，包括但不限于：取代的亚甲基(-CH(CH3)-、-C(CH3)2-)、取代的亚乙基(-CH(CH3)CH2-、-CH2CH(CH3)-、-C(CH3)2CH2-、-CH2C(CH3)2-)、取代的亚丙基(-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH2CH(CH3)-、-C(CH3)2CH2CH2-、-CH2C(CH3)2CH2-、-CH2CH2C(CH3)2-)，等等。
“烯基”是本发明定义的烷基中包含至少一个碳-碳双键。在其中一个实例中，所述烯基含有2至20个碳原子，优选2至12个碳原子，进一步优选2至8个碳原子，更进一步优选为2至6个碳原子。烯基的非限定实例包括取代或未取代的乙烯基、2-丙烯基、3-丁烯基、2-丁烯基、4-戊烯基、3-戊烯基、2-己烯基、3-己烯基、2-庚烯基、3-庚烯基、4-庚烯基、3-辛烯基、3-壬烯基或4-癸烯基等。当被取代时，取代基优选为1至5个，并且取代基独立地选自F、Cl、Br、I、＝O、烷基、烯基、炔基、烷氧基、羟基、硝基、氰基和氨基。
“炔基”是本发明定义的烷基中包含至少一个碳-碳叁键。在其中一个实例中，所述炔基含有2至20个碳原子，优选2至12个碳原子，进一步优选2至8个碳原子,更进一步优选2至6个碳原子。炔基的非限定实例包括取代或未取代的乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、4-戊炔基、3-戊炔基、2-己炔基、3-己炔基、3-丁炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基或4-癸炔基等，当被取代时，取代基优选为1至5个，并且取代基独立地选自F、Cl、Br、I、＝O、烷基、烯基、炔基、烷氧基、羟基、硝基、氰基和氨基。
“碳环基”或“环烷基”是指饱和或者部分不饱和的环状含碳基团，例如5-6元的饱和碳环和5-6元的部分不饱和碳环。在其中一个实施方案中，碳环基是3至4元的单环、3至5元的单环、3 至6元的单环、3至7元的单环、3至8元的单环、3至10元的单环、5至8元的单环、5至6元的单环、4至12元双环或者10至15元三环系统。碳环包括桥环或者螺环。碳环基的非限制性实例包括环丙基、环丁基、环戊基、环己基、环己烯基、环庚基、环戊烯基、环己二烯基、环庚三烯基、苯并环戊基、二环[3.2.1]辛烷基、二环[5.2.0]壬烷基、三环[5.3.1.1]十二烷基、金刚烷基或螺[3.3]庚烷基等。碳环基可以任选被取代。当被取代时，取代基优选为1至5个，并且所述取代基独立地选自F、Cl、Br、I、＝O、烷基、烯基、炔基、烷氧基、羟基、硝基、氰基和氨基。
术语“卤素”是指-F、-Cl、-Br或-I。进一步，术语“卤代烷基”是指经卤素基团取代的烷基，其中烷基如上文所定义，优选为C1-6卤代烷基、C1-5卤代烷基、C1-4卤代烷基、C1-3卤代烷基和C1-2卤代烷基。
术语“芳基”是指在芳香环化合物的基础上除去一个氢原子衍生的芳族烃基，可以为单环芳基、或稠环芳基、或多环芳基，优选为6-10元芳基。对于多环的环种，至少一个是芳族环系。包含该术语的短语，例如，“5-6元芳基”是指芳香环系包含5-6个环原子。优选地，芳基为苯基。
术语“杂芳基”是指含有杂原子的芳基，其可为单环或稠合环，所述杂原子独立地选自N、O和S，优选为5-12元杂芳基，5-10元杂芳基，优选为5-8元杂芳基，更优选为5-6元杂芳基，更优选为5元杂芳基。杂芳基包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、喹啉基、异喹啉基、三唑基、四氢吡咯基和噻二唑基。在某一方案中，典型地含1个或多个，优选1-3个独立选自N、O和S的杂原子的5-6元单环杂芳基。除非另外说明，“5-元杂芳基”为包含一个杂原子的示例性5-元杂芳基基团包括但不限于，吡咯基、呋喃基以及噻吩基；包含两个杂原子的示例性5-元杂芳基基团包括但不限于，咪唑基、吡唑基、噁唑啉基、异噁唑啉基、噻唑基以及异噻唑基；包含三个杂原子的示例性5-元杂芳基基团包括但不限于，噻唑基、噁二唑基以及噻二唑基；包含四个杂原子的示例性5-元杂芳基基团包括但不限于，四唑基。
“杂环基”或“杂环”是指取代的或未取代的饱和或者部分不饱和的含杂原子的环状基团，所述杂原子选自N、O和S。进一步，术语“杂环基”指的是非芳香环的一个或多个构成环的原子是杂原子、其余为碳的稳定的3-10元饱和杂环系统的基团。所述的杂原子包括而不限于氮原子、氧原子和硫原子等。所述杂环基可以是3至7元的单环、5至8元的单环、5至6元的单环、4至12元双环或者10至15元三环系统，优选3至10元杂环基，且包含至少1个，优选1至4个选自N、O或S的杂原子。除非本说明书中另外特别指明，否则杂环烷基基团可以是单环的(“单环的杂环烷基”)，或者是双环、三环或更多环的环体系，其可包括并环的(稠合的)、桥联的(桥环的)或螺的环系统(例如二环系统(“二环的杂环烷基”)。二环杂环烷基的环系统可以在一个或两个环中包括一个或多个杂原子；并且是饱和的。示例性3-元杂环基基团包括但不限于，氮杂环丙基、环氧乙烷基以及硫杂环丙烷基，或者其立体异构体；示例性4-元杂环基基团包括但不限于，氮杂环丁烷基，环氧丙烷基，硫杂环丁烷基，或者其同分异构体和立体异构体；示例性5-元杂环基基团包括但不限于，四氢呋喃基，四氢噻吩基，吡咯烷基，噻唑烷基，异噻唑烷基，噁唑烷基，异噁唑烷基，咪唑烷基，吡唑烷基，二氧戊环基，氧杂硫杂环戊基，二硫杂环戊基，或者其同分异构体和立体异构体。示例性6-元杂环基基团包括但不限于，哌啶基，四氢吡喃基，硫杂环己烷基，吗啉基，硫吗啉基，二噻烷基，二噁烷基，哌嗪基，三嗪烷基，或者其同分异构体和立体异构体；示例性7-元杂环基基团包括但不限于，氮杂环庚烷基，氧杂环庚烷基，硫杂环庚烷基，以及二氮杂环庚烷基，或者其同分异构体和立体异构体。在某一方案中，典型的杂环基为含1个或多个，优选1-4个，更优选1-3个独立选自N、O和S的杂原子的5-6元单环杂环基。在一个实施方案中，“杂环烷基”为4-6元杂环烷基，其中杂原子选自N、O和S中的一种或多种，杂原子数为1、2或3个。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。在一些具体的结构中，当烷基基团清楚地表示为连接基团时，则该烷基基团代表连接的亚烷基基团，例如，基团“-C1-C3卤代烷基”中的烷基应当理解为亚烷基。
术语“药学上可接受的盐”是指化合物可以通过传统的方法转化为相应的盐，其在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。该盐可以为化合物与无机和/或有机酸和/或与无机和/或有机碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将本发明的化合物或其立体异构体或溶剂合物，与一定数量的酸或碱适当混合而得到的。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷却干燥制得。具体地，盐优选为水溶性的药学上可接受的无毒酸加成盐，实例为氨基与无机酸(如盐酸、氢溴酸、磷酸、硫 酸以及高氯酸)或与有机酸(如乙酸、草酸、顺丁烯二酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐，或通过使用本领域中传统的其他方法(例如离子交换法)形成的盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘化物、2-羟基-乙烷磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对-甲苯磺酸盐、十一烷酸盐、戊酸盐等。适当时，另外的药学上可接受的盐还可以包括衍生自适当碱的盐，包括碱金属盐、碱土金属盐以及铵盐。代表性碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐等。适当时，另外的药学上可接受的盐包括使用如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根以及芳基磺酸根等平衡离子与无毒铵、季铵以及胺阳离子形成的盐。
术语“溶剂合物”也可以称为“溶剂化合物”、“溶剂化物”，指的是含有溶剂分子的化合物，其中溶剂分子可以以包括配位键、共价键、范德华力、离子键、氢键等方式与化合物分子相结合。常规溶剂包括包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂化物包括药学上可接受的溶剂化物且进一步包括化学计量的溶剂化物和非化学计量的溶剂化物。在一些情况下，所述溶剂化物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂化物”包括溶液状态的溶剂化物和可分离的溶剂化物。代表性的溶剂化物包括水合物、乙醇合物和甲醇合物。
术语“水合物”是指与水相结合的化合物。通常，包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此，化合物的水合物可用例如通式R·x H2O代表，其中R是该化合物，和x是大于0的数。给定化合物可形成超过一种水合物类型，包括，例如，单水合物(x为1)、低级水合物(x是大于0且小于1的数，例如，半水合物(R·0.5H2O))和多水合物(x为大于1的数，例如，二水合物(R·2H2O)和六水合物(R·6H2O))。
术语“前药”是指当被施用至生物体时由于自发化学反应、酶催化的化学反应、光解和/或代谢化学反应而产生药物，即活性成分的任何化合物。前药因此是治疗活性化合物的共价改性的类似物或潜在形式。合适的实例包括但不限于：化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
本发明还包括同位素标记的化合物(同位素变体)，它们等同于本申请所述的那些通式或具体化合物，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl，优选为2H(即氘，D)。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如3H和14C)的那些可用于药物和/或底物组织分布测定。氚、即3H和碳-14、即14C同位素是特别优选的，因为它们容易制备和检测。另外，被较重的同位素例如氘(即2H)取代，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下是优选的。同位素标记的本发明化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。
本发明化合物包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋体混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
"任选的"或"任选地"意味着随后所描述的事件或环境可以但不必发生，包括该事件或环境发生或不发生的场合。例如，“芳基任选被烷基取代”意味着烷基可以但不必须存在，该术语包括芳基被烷基取代的情形和芳基不被烷基取代的情形。
“药学上可接受的赋形剂”指药学上可接受的材料、组合物或媒剂，例如液体或固体填充剂、稀释剂、赋形剂、溶剂或囊封材料。如本文所用，术语“药学上可接受的赋形剂”包括与药物施用相容的缓冲剂、注射用无菌水、溶剂、分散介质、包衣、抗细菌剂及抗真菌剂、等渗剂及吸收延迟剂及诸 如此类。在与配制物中其他成分兼容且对患者无害的意义上，每种赋形剂必须为“药学上可接受的”。合适的实例包括但不限于：(1)糖，例如乳糖、葡萄糖及蔗糖；(2)淀粉，例如玉米淀粉、马铃薯淀粉及经取代或未经取代的β-环糊精；(3)纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素及乙酸纤维素；(4)粉状黄蓍胶；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，例如可可脂及栓剂蜡；(9)油类，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油；(10)二醇，例如丙二醇；(11)多元醇，例如甘油、山梨醇、甘露醇及聚乙二醇；(12)酯类，例如油酸乙酯及月桂酸乙酯；(13)琼脂；(14)缓冲剂，例如氢氧化镁及氢氧化铝；(15)海藻酸；(16)无热原水；(17)等渗盐水；(18)林格氏溶液；(19)乙醇；(20)磷酸盐缓冲液；及(21)药物配制物中所采用的其他无毒兼容物质。
术语“多晶型”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂化物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。
除非另有规定，本文使用的所有技术术语和科学术语具有要求保护主题所属领域的标准含义。倘若对于某术语存在多个定义，则以本文定义为准。应该理解，在本发明中使用的单数形式，如“一种”，包括复数指代，除非另有规定。
此外，术语“包括”、“包含”是开放性限定并非封闭式，即包括本发明所指明的内容，但并不排除其他方面的内容。
除非另有说明，本发明采用质谱、核磁等传统方法鉴定化合物，各步骤和条件可参照本领域常规的操作步骤和条件。
除非另有指明，本发明采用分析化学、有机合成化学和光学的标准命名及标准实验室步骤和技术。在某些情况下，标准技术被用于化学合成、化学分析、发光器件性能检测。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“…分别独立地”应做广义理解，是指所描述的各个个体之间是相互独立的，可以独立地为相同或不同的具体基团。更详细地，描述方式“…分别独立地”既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响；也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
具体地，本发明涉及如下技术方案
在一个实施方案中，本发明涉及通式(I)的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：
其中：
R1选自H、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-SRa、C1-6亚烷基-NRbRc、C1-6亚烷基-C(O)Ra、C1-6亚烷基-C(O)ORa、C1-6亚烷基-C(O)NRbRc、C1-6亚烷基-OC(O)Ra、C1-6亚烷基-NRbC(O)Ra、C1-6亚烷基-S(O)mRa、C1-6亚烷基-S(O)mNRbRc或C1-6亚烷基-NRbS(O)mRa，所述基团任选地被一个或多个氘取代，直至完全氘代；
R2选自C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基，所述基团任选地被一个或多个氘取代，直至完全氘代；
R3选自H、C1-6烷基或C1-6卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
R1、R2和R3中的各基团任选地被1、2、3或4个R取代；
其中Ra、Rb和Rc独立地选自H、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基；
m＝1或2；
R选自H、D、卤素、CN、C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述式(I)化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其 中，R1选自H、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-SRa、C1-6亚烷基-NRbRc、C1-6亚烷基-C(O)Ra、C1-6亚烷基-C(O)ORa、C1-6亚烷基-C(O)NRbRc、C1-6亚烷基-OC(O)Ra或C1-6亚烷基-NRbC(O)Ra，所述基团任选地被一个或多个氘取代，直至完全氘代；优选地，R1选自H、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-SRa、C1-6亚烷基-NRbRc、C1-6亚烷基-C(O)ORa或C1-6亚烷基-C(O)NRbRc，所述基团任选地被一个或多个氘取代，直至完全氘代；优选地，R1选自H、C1-6卤代烷基、C1-6亚烷基-OH、C1-6亚烷基-SH、C1-6亚烷基-NH2、C1-6亚烷基-C(O)OH或C1-6亚烷基-C(O)NH2，所述基团任选地被一个或多个氘取代，直至完全氘代；优选地，R1选自H或C1-6卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；优选地，R1为C1-6亚烷基-ORa，其中Ra选自C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述式(I)化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，R2选自C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基或3-7元杂环基，所述基团任选地被一个或多个氘取代，直至完全氘代；优选地，R2选自C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基，所述基团任选地被一个或多个氘取代，直至完全氘代；优选地，R2选自C1-6烷基或C3-7环烷基，所述基团任选地被一个或多个氘取代，直至完全氘代。
在更具体的实施方案中，本发明提供了上述式(I)化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，R3选自C1-6烷基或C1-6卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；优选地，R3为甲基，其任选地被一个或多个氘取代，直至完全氘代。
在更具体的实施方案中，本发明提供了上述式(I)化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中：
R1选自H、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-SRa或C1-6亚烷基-C(O)ORa，所述基团任选地被一个或多个氘取代，直至完全氘代；
R2选自C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基，所述基团任选地被一个或多个氘取代，直至完全氘代；
R3选自H、C1-6烷基或C1-6卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
R1、R2和R3中的各基团任选地被1、2、3或4个R取代；
其中Ra选自H、C1-6烷基或C1-6卤代烷基；
R选自H、D、卤素、CN、C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述式(I)化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中：
R1选自H、C1-4卤代烷基、C1-4亚烷基-ORa或C1-4亚烷基-C(O)OH，所述基团任选地被一个或多个氘取代，直至完全氘代；
R2选自C1-4烷基、C1-4卤代烷基或C3-7环烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
R3选自C1-4烷基或C1-4卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
其中Ra选自H、C1-4烷基或C1-4卤代烷基。
在更具体的实施方案中，本发明提供了上述式(I)化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中：
R1为C1-4亚烷基-ORa，其任选地被一个或多个氘取代，直至完全氘代；
R2选自C1-4烷基、C1-4卤代烷基或C3-7环烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；优选C1-4烷基，其任选地被一个或多个氘取代，直至完全氘代；
R3选自C1-4烷基或C1-4卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
其中Ra选自C1-4烷基或C1-4卤代烷基。
在更具体的实施方案中，本发明提供了上述式(I)化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中：
R1选自H、C1-4卤代烷基、C1-4亚烷基-OH或C1-4亚烷基-C(O)OH，所述基团任选地被一个或多个氘取代，直至完全氘代；
R2选自C1-4烷基、C1-4卤代烷基或C3-7环烷基，所述基团任选地被一个或多个氘取代，直至完全氘 代；优选C1-4烷基，其任选地被一个或多个氘取代，直至完全氘代；
R3选自C1-4烷基或C1-4卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代。
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中：
R1选自H、C1-6亚烷基-ORa和C1-6亚烷基-SRa，所述基团任选地被一个或多个氘取代，直至完全氘代；
R2选自C1-6烷基和C1-6卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
R3选自H、C1-6烷基或C1-6卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
R1、R2和R3中的各基团任选地被1、2、3或4个R取代；
其中Ra选自H、C1-6烷基和C1-6卤代烷基；
R选自H、D、卤素、CN、C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中：
R1选自H和C1-6亚烷基-ORa，所述基团任选地被一个或多个氘取代，直至完全氘代；
R2选自C1-6烷基和C1-6卤代烷基；
R3为C1-6烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
其中Ra选自H和C1-6烷基。
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中：
R1选自H和C1-4亚烷基-ORa，所述基团任选地被一个或多个氘取代，直至完全氘代；
R2为C1-4烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
R3为C1-4烷基，所述基团任选地被一个或多个氘取代，直至完全氘代，
其中Ra为C1-4烷基。在更具体的实施方案中，本发明提供了上述式(I)化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中所述化合物选自以下：

在一个实施方案中，本发明提供药物组合物，其含有如本发明所定义的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，和药学上可接受的赋形剂；优选地，其还含有其它治疗剂。
在一个实施方案中，本发明提供如本发明所定义的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，包含其的药物组合物在制备用于治疗和/或预防TYK2激酶介导的疾病的药物中的用途。
在一个实施方案中，本发明提供如本发明所定义的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，或包含所述化合物的药物组合物，其用于治疗和/或预防TYK2激酶介导的疾病。
在一个实施方案中，本发明提供如本发明所定义的化合物在受试者中治疗和/或预防TYK2激酶介导的疾病的方法，包括向所述受试者给药所述化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，或包含其的的药物组合物。
如本发明所述的TYK2激酶介导的疾病选自自身免疫性疾病、皮肤病、变应性疾病、器官排斥、癌症、干眼病、骨髓纤维化、红细胞增多症。进一步，所述自身免疫性疾病为狼疮、多发性硬化、类风湿性关节炎、青少年关节炎、银屑病、溃疡性结肠炎、克罗恩氏病或自体免疫性甲状腺疾病；所述皮肤病为牛皮癣、皮疹或特应性皮炎；所述变应性病症为哮喘或鼻炎病；所述器官移植排斥为异体抑制排斥或移植物抗宿主疾病；所述癌症为肾癌、肝癌、胰腺癌、胃癌、乳腺癌、前列腺癌、头颈部癌、甲状腺癌、肺癌、胶质母细胞瘤、黑素瘤、淋巴瘤或白血病。
在一些实施方案中，本方法涉及所述TYK2激酶介导的疾病选自类风湿性关节炎、银肩病、溃疡性结肠炎和克罗恩病。
本领域技术人员可以理解，在不违背本领域常识的基础上，上述各优选条件可任意组合，即得本 发明各较佳实例。
给药
本发明的(I)化合物可通过适于所要治疗疾病状态的任何手段施用，该手段可取决于对位点特异性治疗的需要或所要递送药物的量。虽然涵盖其它递送模式，但是局部施用通常对于皮肤相关疾病是优选的，且全身治疗对于癌性或癌前疾病状态是优选的。例如，所述化合物可以下列方式递送：口服，例如以片剂、胶囊剂、颗粒剂、粉末剂或液体制剂(包括糖浆剂)的形式；局部，例如以溶液剂、悬浮剂、凝胶剂或软膏剂的形式；舌下；经颊；肠胃外，例如通过皮下、静脉内、肌内或胸骨内注射或输注技术(例如，以无菌可注射水溶液或非水溶液或悬浮液形式)；经鼻，例如通过吸入喷雾；局部，例如以乳霜或软膏形式；直肠，例如以栓剂形式；或脂质体。可施用含有无毒可药用载体或稀释剂的单位剂量制剂。所述化合物可以适于立即释放或延长释放的形式施用。立即释放或延长释放可利用适宜药物组合物或尤其在延长释放的情况下利用例如皮下植入体或渗透性泵装置来达到。
用于局部施用的示例性组合物包括局部载体。
用于口服施用的示例性组合物包括悬浮液，其可含有例如用于赋予体积的微晶纤维素、作为悬浮剂的海藻酸或海藻酸钠、作为增粘剂的甲基纤维素和甜味剂或矫味剂，例如本领域已知的那些；和速释片剂，其可含有例如微晶纤维素、磷酸二钙、淀粉、硬脂酸镁和/或乳糖和/或其它赋形剂、粘合剂、增量剂、崩解剂、稀释剂和润滑剂，例如本领域已知的那些。本发明化合物也可通过舌下和/或经颊施用口腔递送，例如，利用模制的、压缩的或冷冻干燥的片剂。示例性组合物可包括快速溶解稀释剂，例如甘露醇、乳糖、蔗糖和/或环糊精。这些制剂也可包括高分子量赋形剂，例如纤维素(AV1CEL)或聚乙二醇(PEG)；用以帮助粘膜粘附的赋形剂，例如羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羧甲基纤维素钠(SCMC)和/或马来酸酐共聚物(例如，)；和用于控制释放的试剂，例如聚丙烯酸系共聚物(例如，CARBOPOL)。也可添加润滑剂、助流剂、矫味剂、着色剂和稳定剂以便于制备和使用。
用于经鼻气溶胶或吸入施用的示例性组合物包括溶液，其可含有例如苯甲醇或其它适宜防腐剂、用以增强吸收和/或生物利用度的吸收促进剂和/或其它增溶剂或分散剂，例如本领域已知的那些。
用于肠胃外施用的示例性组合物包括可注射溶液或悬浮液，其可含有例如肠胃外可接受的适宜无毒稀释剂或溶剂，例如甘露醇、1,3-丁二醇、水、林格氏溶液、等渗氯化钠溶液，或其它适宜分散剂或湿润剂和悬浮剂，包括合成的单-或二甘油酯和脂肪酸，包括油酸。
用于直肠施用的示例性组合物包括栓剂，其可含有例如适宜的非刺激性赋形剂，例如可可油、合成甘油酯或聚乙二醇，这些赋形剂在常温为固体但在直肠腔内液化和/或溶解以释放药物。
本发明化合物的治疗有效量可由本领域技术人员测定，且对于哺乳动物而言包括每天约0.05-1000mg/kg、l-1000mg/kg、l-50mg/kg、5-250mg/kg、250-1000mg/kg体重的活性化合物的示例性剂量，其可以单剂或以个别分次剂量的形式(例如每天1至4次)施用。应理解，任一特定个体的具体剂量水平和给药频率可能有所不同且应取决于各种因素，包括所用具体化合物的活性、该化合物的代谢稳定性和作用时长、该个体的物种、年龄、体重、总体健康状况、性别和饮食、施用模式和时间、排泄速率、药物组合和特定疾病状态的严重程度。用于治疗的优选的个体包括动物，最优选为哺乳动物物种，例如人类和家畜，例如狗、猫、马等。因此，当在本文中使用术语“患者”时，此术语是指包括所有个体，最优选为患有TYK2激酶介导的疾病的哺乳动物物种。
实施例
本文所用的材料或试剂为可购买到的或由本领域通常已知的合成方法制备。
实施例1
6-(环丙甲酰胺基)-N-乙氧基-4-((2-甲氧基-3-(1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-甲酰胺(化合物1)
第一步：2-甲氧基-3-硝基苯甲酸甲酯
将3-硝基水杨酸(15g,81.91mmol)和碳酸铯(106.756g,327.65mmol)溶解在N-N二甲基甲酰胺(300mL)中，反应体系加入碘甲烷(58.54g,409.57mmol)，反应液在室温下搅拌反应16小时。停止反应，向反应液中加水(1.5L)进行淬灭，过滤后，干燥滤饼得到标题化合物(12.886g，收率：74.5％，白色固体)。
MS(ESI):m/z 212.1[M+H]+；
第二步：2-甲氧基-3-硝基苯甲酰胺
将2-甲氧基-3-硝基苯甲酸甲酯(6.66g，31.54mmol)溶解在甲醇(36.63mL)中，加入氨水(27.3mL)，室温中反应16小时。停止反应，反应液减压浓缩后柱层析(硅胶，二氯甲烷：甲醇＝95:5)分离纯化得到标题化合物(5.2g，收率：84％，黄色固体)。
MS(ESI):m/z 197.0[M+H]+；
第三步：3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑
将2-甲氧基-3-硝基苯甲酰胺(5.2g，26.53mmol)溶解在N,N-二甲基甲酰胺二甲基缩醛(67.6 mL)中，在95℃下反应1h，将反应液真空旋除溶剂，用乙醇(13mL)溶解得粗品；将乙醇(110mL)和醋酸(26mL)于0℃下搅拌5分钟，再向其中加入水合肼(13.18mL),搅拌反应十五分钟之后加入上述粗品液，升至室温，搅拌反应一小时。停止反应，将反应液减压浓缩之后，加入乙酸乙酯(451mL)萃取，后用饱和碳酸氢钠溶液(451mL)洗涤两次，用饱和食盐水洗涤，无水硫酸钠干燥后减压浓缩，粗品通过柱层析(硅胶，二氯甲烷：甲醇＝9:1)分离纯化得到标题化合物(3.71g，收率：63.5％，黄色固体)。
MS(ESI):m/z 221.1[M+H]+；
第四步：3-(2-甲氧基-3-硝基苯基)-1-(四氢-2H-吡喃-2-基)-1H-1,2,4-三唑
将3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(1.3g,5.9mmol)、3,4-二氢-2H-吡喃(2.5g,29.52mmol)和4-甲基苯磺酸(224.61mg,1.18mmol)溶解在四氢呋喃(52mL)中，反应液在80℃下搅拌16小时。停止反应，向反应液中加水(50m L)进行淬灭，后用乙酸乙酯(100mL)萃取三次，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、减压浓缩后柱层析(硅胶，石油醚：乙酸乙酯＝1:1)分离纯化得到标题化合物(1.8g，收率：100％，黄色油状物)。
MS(ESI):m/z 305.1[M+H]+；
第五步：2-甲氧基-3-(1-(四氢-2H-吡喃-2-基)-1H-1,2,4-三唑-3-基)苯胺
将3-(2-甲氧基-3-硝基苯基)-1-(四氢-2H-吡喃-2-基)-1H-1,2,4-三唑(1.8g，5.92mmol)溶解在甲醇(50mL)中，加入氨水(0.85mL)，再分批加入钯/炭(251.8mg,2.4mmol)；氢气置换后，室温中反应16小时。停止反应，将反应液过滤，滤液减压浓缩后柱层析(硅胶，二氯甲烷：甲醇＝100:1)分离纯化得到标题化合物(1.572g，收率：97％，黄色油状物)。
MS(ESI):m/z 275.1[M+H]+；
第六步：((6-氯-4-((2-甲氧基-3-(1-(四氢-2H-吡喃-2-基)-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-羰基)氧基)锌(0.5)
将2-甲氧基-3-(1-(四氢-2H-吡喃-2-基)-1H-1,2,4-三唑-3-基)苯胺(400mg，1.46mmol)和4,6-二氯哒嗪-3-羧酸锂(348.21mg,1.75mmol)和醋酸锌(321.08mg,1.75mmol)溶解在水：异丙醇＝7：1的10mL溶剂中；氮气置换后，65℃下反应16小时。停止反应，反应液加入15mL水，搅拌一小时后抽滤，并用四氢呋喃(0.5mL)洗涤，干燥滤饼后得到标题化合物(365mg，收率：54％，白色固体)。
MS(ESI):m/z 431.1[M+H]+；
第七步：((6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(1-(四氢-2H-吡喃-2-基)-1H-1,2,4-三唑-3-基)苯基)氨基))哒嗪-3-羰基)氧基)锌(0.5)
将((6-氯-4-((2-甲氧基-3-(1-(四氢-2H-吡喃-2-基)-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-羰基)氧基)锌(0.5)(335mg，0.724mmol)，环丙甲酰胺(308.18mg,3.62mmol)，(2R)-1-[(1R)-1-[双(1,1-二叔丁基)膦]乙基]-2-(二环己基膦)二茂铁(120.49mg,0.217mmol)，三[二亚苄基丙酮]二钯(132.64mg,0.145mmol)和碳酸铯(471.97mg,1.45mmol)溶于N,N-二甲基乙酰胺(5mL)中，氮气置换后，140℃下反应1小时。停止反应，反应液过滤后，滤液经反相柱层析(C18，水/0.1％TFA：乙腈＝70:30)分离纯化得到标题化合物(216mg，产率：58％，黄色固体)。
MS(ESI):m/z 480.4[M+H]+；
第八步：6-(环丙甲酰胺基)-N-乙氧基-4-((2-甲氧基-3-(1-(四氢-2H-吡喃-2-基)-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-甲酰胺
将N-甲基吡咯烷酮(3mL)和乙腈(3mL)加入到反应瓶中，再加入((6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(1-(四氢-2H-吡喃-2-基)-1H-1,2,4-三唑-3-基)苯基)氨基))哒嗪-3-羰基)氧基)锌(0.5)(100mg,0.196mmol)，O-乙基羟胺盐酸盐(28.62mg,0.293mmol),N-甲基咪唑(48.18mg,0.587mmol)，氮气置换后，油浴65℃中反应15分钟后，最后加入1-羟基苯并三唑(52.87mg,0.39mmol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(75mg,0.39mmol)，氮气置换后，油浴65℃中反应16小时。停止反应，向反应液中加水(10m L)进行淬灭，后用乙酸乙酯(10mL×3)萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤滤液真空旋除溶剂得到标题化合物(124mg，褐色油状物)。
MS(ESI):m/z 523.2[M+H]+；
第九步：6-(环丙甲酰胺基)-N-乙氧基-4-((2-甲氧基-3-(1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-甲酰胺(化合物1)
将6-(环丙烷甲酰胺基)-N-乙氧基-4-((2-甲氧基-3-(1-(四氢-2H-吡喃-2-基)-1H-1,2,4-三唑-3-基)苯基))氨基)哒嗪-3-甲酰胺(114mg)溶于甲醇(2mL)中，向其中加入氯化氢二氧六环溶液(2mL)，于室温下反应1小时。停止反应，将反应液真空旋除溶剂得到粗品，粗品经反相制备色谱(甲酸体系)分离纯化得到标题化合物(12.71mg，收率：13.38％，白色固体)。
MS(ESI):m/z 439.1[M+H]+；
1H NMR(400MHz,DMSO-d6)δ12.29(s,1H),11.34(s,1H),10.57(s,1H),8.35(s,1H),8.14(s,1H),7.77(d,J＝7.6Hz,1H),7.56(d,J＝6.6Hz,1H),7.33(t,J＝7.9Hz,1H), 3.99(q,J＝7.0Hz,2H),3.70(s,3H),2.08(t,J＝5.8Hz,1H),1.23(t,J＝7.0Hz,3H),0.83-0.81(m,4H).
实施例2
6-(环丙甲酰胺基)-N-乙氧基-4-((2-甲氧基-3-(1-(2-甲氧基乙基)-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-甲酰胺(化合物2)
第一步：3-(2-甲氧基-3-硝基苯基)-1-(2-甲氧基乙基)-1H-1,2,4-三唑
将3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(1.0g,4.542mmol)溶解在超干N,N-二甲基甲酰胺(10mL)中，加入碳酸铯(4439mg,13.626mmol)，氮气置换后，缓慢滴加1-溴-2-甲氧基乙烷(947mg,6.813mmol)，在室温下反应2小时。停止反应，将反应液过滤后倒入水(30mL)中，水相用乙酸乙酯(15mL×3)萃取，合并的有机相经饱和食盐水(20mL×2)洗涤、无水硫酸钠干燥、过滤，滤液真空旋除溶剂得到标题化合物(1.33g，淡黄色油状物)
MS(ESI):m/z 279.0[M+H]+；
第二步：2-甲氧基-3-(1-(2-甲氧基乙基)-1H-1,2,4-三唑-3-基)苯胺
将3-(2-甲氧基-3-硝基苯基)-1-(2-甲氧基乙基)-1H-1,2,4-三唑(1.3g,4.672mmol)溶于甲醇(30mL)中，加入钯/炭(198mg,1.869mmol)，置换氢气三次，室温下反应16小时。停止反应，将反应液过滤后旋干，粗品经硅胶柱层析(石油醚：乙酸乙酯＝1:3)分离纯化得到标题化合物(830mg，收率：71.6％，无色油状物)。
MS(ESI):m/z 249.1[M+H]+；
第三步：((6-氯-4-((2-甲氧基-3-(1-(2-甲氧乙基)-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-羰基)氧基)锌(0.5)
将2-甲氧基-3-(1-(2-甲氧基乙基)-1H-1,2,4-三唑-3-基)苯胺(750mg,3.021mmol)溶于水(21mL)和异丙醇(3mL)中，加入4,6-二氯哒嗪-3-羧酸锂(722mg,3.625mmol)、醋酸锌(665mg,3.625mmol)，氮气置换三次后，油浴65℃中反应16小时。停止反应，反应液中加水(21mL)，室温下搅拌1小时，然后抽滤，滤饼用水(6mL×2)、四氢呋喃(1mL)淋洗，滤饼干燥得到标题化合物(730mg，收率：55.3％，淡黄色固体)。
MS(ESI):m/z 404.9[M+H]+；
第四步：((6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(2-甲氧基乙基)-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-羰基)氧基)锌(0.5)
将((6-氯-4-((2-甲氧基-3-(1-(2-甲氧乙基)-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-羰基)氧基)锌(0.5)(730mg，1.672mmol)溶于甲苯(8mL)和乙腈(4mL)中，加入环丙甲酰胺(356mg,4.180mmol)、(R)-(-)-1-[(S)-2-(二环己基膦)二茂铁]乙基二叔丁基膦(185mg,0.334mmol)、1,8-二氮杂二环十一碳-7-烯(254mg,1.672mmol)、碳酸钾(462mg,3.344mmol)、醋酸钯(75mg,0.334mmol)，氮气置换后，油浴75℃中反应16小时。停止反应，反应液冷却至室温，加入水(15mL)、醋酸(7.5mL)，混合体系用石油醚(30mL×2)洗涤，水相用二氯甲烷(15mL×3)萃取，合并的二氯甲烷有机相经无水硫酸钠干燥、过滤，滤液真空旋除溶剂得到标题化合物(1410mg，褐色固体)，直接投下一步。
MS(ESI):m/z 454.6[M+H]+；
第五步：6-(环丙甲酰胺基)-N-乙氧基-4-((2-甲氧基-3-(1-(2-甲氧基乙基)-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-甲酰胺(化合物2)
取一50mL反应瓶，瓶中加入N-甲基吡咯烷酮(3mL)和乙腈(3mL)，混合溶剂在室温下搅拌10分钟，然后加入((6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(2-甲氧基乙基)-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-羰基)氧基)锌(0.5)(400mg,0.825mmol)、O-乙基羟胺盐酸盐(121mg,1.238mmol)、N-甲基咪唑(202mg,2.475mmol)，反应液在油浴65℃中搅拌15分钟，然后加入1-羟基苯并三唑(223mg,1.650mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(316mg,1.650mmol)，反应液在油浴65℃中继续搅拌反应16小时。停止反应，将反应液过滤，滤液粗品经高效液相色谱制备(洗脱体系：甲酸，水，乙腈)分离纯化得到标题化合物(79.51mg，收率：19.4％，白色固体)。
MS(ESI):m/z 497.3[M+H]+；
1H NMR(400MHz,DMSO-d6)δ12.25(s,1H),11.31(s,1H),10.55(s,1H),8.57(s,1H),8.15(s,1H),7.66(dd,J＝7.8,1.5Hz,1H),7.50(dd,J＝7.9,1.4Hz,1H),7.27(t,J＝7.9Hz,1H),4.40(t,J＝5.2Hz,2H),3.98(q,J＝7.0Hz,2H),3.78–3.69(m,5H),3.25(s,3H),2.13–2.02(m,1H),1.22(t,J＝7.0Hz,3H),0.81(d,J＝5.4Hz,4H).
实施例3
6-(环丙甲酰胺基)-N-环丙氧基-4-((2-甲氧基-3-(1-(2-甲氧基乙基)-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-甲酰胺(化合物3)
第一步：2-(乙烯基)异吲哚啉-1,3-二酮
将2-羟基异吲哚啉-1,3-二酮(900mg,5.517mmol)溶解在超干四氢呋喃(20mL)中，加入乙烯硼酐吡啶络合物(876mg,3.641mmol)、二乙基脲(256mg，2.207mmol)、二(((三氟甲基)磺酰基)氧基)铜(798mg，2.207mmol)和三乙胺(1114mg，11.034mmol)，氧气置换后，在50℃下反应16小时。停止反应，将反应液过滤后收集滤液旋干，粗品经硅胶柱层析(石油醚：乙酸乙酯＝4：1)分离纯化得到标题化合物(950mg，收率：91.1％，白色固体)。
1H NMR(400MHz,DMSO-d6)δ7.92–7.86(m,4H),6.92(dd,J＝13.6,6.4Hz,1H),4.73(dd,J＝13.6,3.5Hz,1H),4.40(dd,J＝6.4,3.5Hz,1H).
第二步：2-环丙氧基异吲哚啉-1,3-二酮
将二乙基锌(19mL，19.0mmol,1.0M solution in Hexanes)在0℃下滴入超干二氯甲烷中(16mL)，置换氮气，保持0℃；将三氟乙酸(2.172g，19.048mmol)溶于超干二氯甲烷(8mL)后缓慢滴入上述溶液，搅拌20分钟。将二碘甲烷(5.101g，19.048mmol)溶于超干二氯甲烷(8mL)后缓慢滴入，继续搅拌20分钟。将2-(乙烯基)异吲哚啉-1,3-二酮(900mg,4.762mmol)溶于超干二氯甲烷溶液(5.5mL)后缓慢滴入，置换氮气，在室温下反应16小时。停止反应，往反应液中加入稀盐酸(0.1N，16mL)，分液，将有机相收集后依次用饱和碳酸氢钠溶液(17mL)、饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，旋干得到粗品。粗品经硅胶柱层析(石油醚：乙酸乙酯＝5：1)分离纯化得到标题化合物(850mg，收率：87.9％，白色固体)。
第三步：O-环丙基羟胺盐酸盐
将2-环丙氧基异吲哚啉-1,3-二酮(450mg,2.217mmol)溶于二氯甲烷(20mL)，加入水合肼(222mg,4.434mmol)，氮气置换后，室温下反应16小时。停止反应，将反应液过滤，滤液用水(20mL×2)洗涤。收集水相，用氯仿/异丙醇混合溶液(3:1，15mL×6)萃取。将有机相合并后 干燥，加入氯化氢1,4二氧六环溶液(1mL)，搅拌1h后旋干得到标题化合物(130mg，收率：53.5％，白色固体)。
第四步：6-(环丙甲酰胺基)-N-环丙氧基-4-((2-甲氧基-3-(1-(2-甲氧基乙基)-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-甲酰胺(化合物3)
将N-甲基吡咯烷酮(3mL)和乙腈(3mL)加入到反应瓶中，加入((6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(2-甲氧基乙基)-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-羰基)氧基)锌(0.5)(400mg,0.825mmol)、O-环丙基羟胺盐酸盐(136mg,1.238mmol)、N-甲基咪唑(202mg,2.475mmol)，反应液在油浴65℃中搅拌15分钟，然后加入1-羟基苯并三唑(223mg,1.650mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(316mg,1.650mmol)，反应液在油浴65℃中搅拌反应16小时。停止反应，将反应液过滤，滤液粗品经高效液相色谱制备(洗脱体系：甲酸，水，乙腈)分离纯化得到标题化合物(57mg，收率：13.6％，白色固体)。
MS(ESI):m/z 509.2[M+H]+；
1H NMR(400MHz,DMSO-d6)δ12.46(s,1H),11.33(s,1H),10.56(s,1H),8.58(s,1H),8.17(s,1H),7.68(dd,J＝7.8,1.5Hz,1H),7.52(dd,J＝8.0,1.5Hz,1H),7.30–7.26(m,1H),4.42(t,J＝5.2Hz,2H),4.13–4.06(m,1H),3.78–3.71(m,5H),3.26(s,3H),2.14–2.05(m,1H),0.90(brs,2H),0.82(d,J＝5.4Hz,4H),0.62–0.55(m,2H).
实施例4
6-(环丙甲酰胺基)-N-乙氧基-4-((3-(1-(2-氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)哒嗪-3-甲酰胺(化合物4)
第一步：1-(2-氟乙基)-3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑
将3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(1g,4.54mmol)、1-氟-2-碘乙烷(1.2g,6.81mmol)和碳酸铯(4.44g,13.62mmol)溶解在N-N二甲基甲酰胺(10mL)中，反应液在室温下搅拌反应2小时。停止反应，向反应液中加水(10m L)进行淬灭，后用乙酸乙酯(20mL×3)萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥，过滤后滤液减压浓缩后柱层析(硅胶，二氯甲烷：甲醇＝97:3)分离纯化得到标题化合物(1.16g，收率：91.37％，黄色固体)。
MS(ESI):m/z 267.0[M+H]+；
第二步：3-(1-(2-氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯胺
将1-(2-氟乙基)-3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(1.11g，4.17mmol)溶解在四氢呋喃(12mL)中，加入甲醇(20mL)和氨水(0.6mL)，再分批加入钯/炭(177.48mg,1.67mmol)，氢气置换后，室温中反应16小时。停止反应，将反应液过滤，减压浓缩后柱层析(硅胶，二氯甲烷：甲醇＝98:2)分离纯化得到标题化合物(728mg，收率：70.75％，白色固体)。
MS(ESI):m/z 237.1[M+H]+；
第三步：((6-氯-4-((3-(1-(2-氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)哒嗪-3-羰基) 氧基)锌
将3-(1-(2-氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯胺(300mg，1.27mmol)、4，6-二氯哒嗪-3-羧酸锂(303.24mg,1.52mmol)和醋酸锌(279.62mg,1.52mmol)溶解在水：甲苯＝7：1的9mL溶剂中，氮气置换后，65℃下反应16小时。停止反应，反应液加入12mL水，搅拌一小时后抽滤，并用四氢呋喃(0.5mL)洗涤，干燥滤饼后得到标题化合物(360mg，收率：66.8％，白色固体)。
MS(ESI):m/z 393.0[M+H]+；
第四步：((6-(环丙甲酰胺基)-4-((3-(1-(2-氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)哒嗪-3-羰基)氧基)锌(0.5)
将((6-氯-4-((3-(1-(2-氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)哒嗪-3-羰基)氧基)锌(0.5)(360mg，0.848mmol)，环丙甲酰胺(216.53mg,2.544mmol)，(2R)-1-[(1R)-1-[双(1,1-二叔丁基)膦]乙基]-2-(二环己基膦)二茂铁(94.07mg,0.17mmol)，1,8-二氮杂双环[5.4.0]十一碳-7-烯(129.12mg,0.848mmol)，碳酸钾(351.66mg,2.544mmol)和醋酸钯(38.08mg,0.17mmol)溶于甲苯：乙腈＝2:1的6mL溶剂中，氮气置换后，75℃下反应16小时。停止反应，反应液加入水：醋酸＝2:1的12mL溶液，用石油醚(20mL)洗涤，水相用二氯甲烷(20mL×3)萃取，合并的二氯甲烷有机相经饱和食盐水洗涤、无水硫酸钠干燥，过滤后滤液真空旋除溶剂得到标题化合物(382mg，产率：95.2％，褐色固体)。
MS(ESI):m/z 442.2[M+H]+；
第五步：6-(环丙甲酰胺基)-N-乙氧基-4-((3-(1-(2-氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)哒嗪-3-甲酰胺(化合物4)
将N-甲基吡咯烷酮(11.4mL)和乙腈(11.4mL)加入到反应瓶中，加入二((6-(环丙烷甲酰胺基)-4-((3-(1-(2-氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)哒嗪-3-羰基)氧基)锌(380mg,0.803mmol)，O-乙基羟胺盐酸盐(117.52mg,1.205mmol)和N-甲基咪唑(197.83mg,2.41mmol)，氮气置换后，油浴65℃中反应15分钟后，最后加入1-羟基苯并三唑(217.06mg,1.61mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(307.95mg,1.61mmol)，氮气置换后，油浴65℃中继续反应16小时。停止反应，向反应液中加水(20m L)进行淬灭，然后用乙酸乙酯(25mL×3)萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥，过滤后滤液真空旋除溶剂得到粗 品。粗品经反相制备色谱(洗脱体系：甲酸，水，乙腈)分离纯化得到标题化合物(29.6mg，收率：7.6％，白色固体)。
MS(ESI):m/z 485.2[M+H]+；
1H NMR(400MHz,DMSO)δ12.22(s,1H),11.33(s,1H),10.57(s,1H),8.66(s,1H),8.16(s,1H),7.69(d,J＝7.7Hz,1H),7.53(d,J＝7.8Hz,1H),7.29(t,J＝7.9Hz,1H),4.91(t,J＝4.6Hz,1H),4.79(t,J＝4.6Hz,1H),4.64(t,J＝4.6Hz,1H),4.57(t,J＝4.6Hz,1H),3.99(q,J＝7.0Hz,2H),3.73(s,3H),2.15–2.01(m,1H),1.23(t,J＝7.0Hz,3H),0.82(d,J＝5.4Hz,4H).
实施例5
6-(环丙甲酰胺基)-4-((3-(1-(2,2-二氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-N-乙氧基哒嗪-3-甲酰胺(化合物5)
第一步：1-(2,2-二氟乙基)-3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑
将3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(900mg,4.087mmol)溶解在N,N-二甲基甲酰胺(8mL)中，加入碳酸铯(3.995g，12.261mmol)，然后在0℃下加入1,1-二氟-2-碘乙烷(1.177g,6.131mmol)，氮气置换后，在65℃下反应5小时。停止反应，将反应液过滤后加入水(20mL)，用乙酸乙酯萃取(10mL×3)；将有机相合并后用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤后滤液旋干得到标题化合物(1.05g，收率：90.3％，浅黄色油状物)。
MS(ESI):m/z 285.2[M+H]+；
第二步：3-(1-(2,2-二氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯胺
将1-(2,2-二氟乙基)-3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(950mg,3.339mmol)溶于MeOH(20mL)中，加入钯/炭(146mg,1.336mmol)，氢气置换后，室温下反应2小时。停止反应，将反应液过滤后旋干，粗品经硅胶柱层析(石油醚：乙酸乙酯＝1：1)分离纯化得到标题化合物(910mg，收率：83.6％，浅黄色油状物)。
MS(ESI):m/z 255.0[M+H]+；
第三步：((6-氯-4-((3-(1-(2,2-二氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)哒嗪-3-羰基)氧基)锌(0.5)
将3-(1-(2,2-二氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯胺(830mg,3.264mmol)溶于水(21mL)和异丙醇(3mL)中，加入4,6-二氯哒嗪-3-羧酸锂(779mg,3.917mmol)、醋酸锌(719mg,3.917mmol)，氮气置换三次后，油浴65℃中反应16小时。停止反应，往反应液中加水(25mL)，室温下搅拌1小时，然后抽滤，滤饼用水(5mL×2)、四氢呋喃(1mL)淋洗，滤饼干燥得到标题化合物(940mg，收率：65.1％，白色固体)。
MS(ESI):m/z 411.0[M+H]+；
第四步：((6-(环丙甲酰胺基)-4-((3-(1-(2,2-二氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)哒嗪-3-羰基)氧基)锌(0.5)
将((6-氯-4-((3-(1-(2,2-二氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)哒嗪-3-羰基)氧基)锌(0.5)(420mg，0.949mmol)溶于甲苯(4mL)和乙腈(2mL)，然后加入环丙甲酰胺(202mg，2.373mmol)、碳酸钾(262mg，1.898mmol)、1,8-二氮杂环[5.4.0]十一碳-7-烯(144mg，0.949mmol)、(R)-(-)-1-[(S)-2-(二环己基膦)二茂铁]乙基二叔丁基膦(105mg，0.190mmol)和醋酸钯(43mg，0.190mmol)，置换氮气，在75℃下反应16小时。停止反应，向反应液中加入水(15mL)和乙酸(7.5mL)，用石油醚(30mL×2)洗涤，水相再用二氯甲烷萃取(10mL×3)；将二氯甲烷合并后用无水硫酸钠干燥，滤液过滤后旋干得到粗品标题化合物(520mg，褐色油状物)，直接投下一步。
MS(ESI):m/z 460.0[M+H]+；
第五步：6-(环丙甲酰胺基)-4-((3-(1-(2,2-二氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-N-乙氧基哒嗪-3-甲酰胺(化合物5)
将N-甲基吡咯烷酮(3mL)和乙腈(3mL)加入到反应瓶中，然后加入((6-(环丙甲酰胺基)-4-((3-(1-(2,2-二氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)哒嗪-3-羰基)氧基)锌(0.5)(470mg,0.957mmol)、O-乙基羟胺盐酸盐(140mg,1.436mmol)、N-甲基咪唑(235mg,2.871mmol)，反应液在油浴65℃中搅拌15分钟，然后加入1-羟基苯并三唑(259mg,1.914mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(367mg,1.914mmol)，反应液在油浴65℃中搅拌反 应5小时。停止反应，将反应液过滤，滤液粗品经高效液相色谱制备(洗脱体系：三氟乙酸，水，乙腈)分离纯化得到标题化合物(13.54mg，收率：2.8％，白色固体)。
MS(ESI):m/z 503.0[M+H]+；
1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),11.33(s,1H),10.57(s,1H),8.69(s,1H),8.16(s,1H),7.68(dd,J＝7.8,1.3Hz,1H),7.54(d,J＝6.7Hz,1H),7.29(t,J＝7.9Hz,1H),6.64–6.32(m,1H),4.83(td,J＝15.2,3.4Hz,2H),3.99(q,J＝7.0Hz,2H),3.72(s,3H),2.12–2.04(m,1H),1.23(t,J＝7.0Hz,3H),0.82(d,J＝4.6Hz,4H).
实施例6
6-(环丙甲酰胺基)-N-环丙氧基-4-((3-(1-(2-氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)哒嗪-3-甲酰胺(化合物6)
将N-甲基吡咯烷酮(4mL)和乙腈(4mL)加入到反应瓶中，加入((6-(环丙甲酰胺基)-4-((3-(1-(2-氟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)哒嗪-3-羰基)氧基)锌(830mg,1.754mmol)、O-环丙基羟胺盐酸盐(288mg,2.631mmol)和N-甲基咪唑(430mg,5.262mmol)，反应液在油浴65℃中搅拌15分钟，然后加入1-羟基苯并三唑(474mg,3.508mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(672mg,3.508mmol)，反应液在油浴65℃中搅拌反应16小时。停止反应，将反应液过滤，滤液粗品经高效液相色谱制备(洗脱体系：甲酸，水，乙腈)分离纯化得到标题化合物(82.74mg，收率：63.3％，灰色固体)。
MS(ESI):m/z 497.3[M+H]+；
1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),11.32(s,1H),10.55(s,1H),8.65(s,1H),8.16(s,1H),7.68(dd,J＝7.8,1.4Hz,1H),7.52(dd,J＝7.9,1.3Hz,1H),7.28(t,J＝7.9Hz,1H),4.90(t,J＝4.6Hz,1H),4.78(t,J＝4.6Hz,1H),4.63(t,J＝4.6Hz,1H),4.56(t,J＝4.6Hz,1H),4.09(brs,1H),3.72(s,3H),2.10–2.05(m,1H),0.89(brs,2H),0.81(d,J＝5.3Hz,4H),0.61–0.54(m,2H).
实施例7
2-(3-(3-((6-(环丙甲酰胺基)-3-(乙氧基氨基甲酰基)哒嗪-4-基)氨基)-2-甲氧基苯基)-1H-1,2,4-三唑-1-基)乙酸(化合物7)
第一步：2-(3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑-1-基)乙酸叔丁酯
将3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(550mg,2.50mmol)、2-溴乙酸叔丁酯(730.8mg,3.75mmol)和碳酸铯(1.63g,5.00mmol)溶解在N-N二甲基甲酰胺(5.5mL)中，反应液在50℃下搅拌反应1小时。停止反应，向反应液中加水(5m L)进行淬灭，后用乙酸乙酯(10mL×3)萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥，过滤后滤液减压浓缩后柱层析(硅胶，石油醚：乙酸乙酯＝4:1)分离纯化得到得到标题化合物(554mg，收率：66.34％，白色固体)。
MS(ESI):m/z 335.0[M+H]+；
第二步：2-(3-(3-氨基-2-甲氧基苯基)-1H-1,2,4-三唑-1-基)乙酸叔丁酯
将2-(3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑-1-基)乙酸叔丁酯(554mg，1.66mmol)溶解 在甲醇(20mL)中，加入氢氧化铵(0.3mL)，再分批加入钯/炭(70.54mg,0.66mmol)，氢气置换后，室温中反应16小时。停止反应，将反应液过滤，滤液减压浓缩后柱层析(硅胶，石油醚：乙酸乙酯＝3:7)分离纯化得到标题化合物(300mg，收率：59.49％，黄色固体)。
MS(ESI):m/z 305.1[M+H]+；
第三步：((4-((3-(1-(2-(叔丁氧基)-2-氧代乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-6-氯哒嗪-3-羰基)氧基)锌(0.5)
将2-(3-(3-氨基-2-甲氧基苯基)-1H-1,2,4-三唑-1-基)乙酸叔丁酯(200mg，0.657mmol)和4，6-二氯哒嗪-3-羧酸锂(156.93mg,0.789mmol)和醋酸锌(144.7mg,0.789mmol)溶解在水：甲苯＝7：1的6mL溶剂中，氮气置换后，油浴65℃下反应16小时。停止反应，反应液加入8mL水，搅拌一小时后抽滤，并用四氢呋喃(0.5mL)洗涤，干燥滤饼后得到标题化合物(185mg，收率：57.4％，白色固体)。
MS(ESI):m/z 461.1[M+H]+；
第四步：((4-((3-(1-(2-(叔丁氧基)-2-氧代乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰氨基)哒嗪-3-羰基)氧基)锌(0.5)
将((4-((3-(1-(2-(叔丁氧基)-2-氧代乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-6-氯哒嗪-3-羰基)氧基)锌(0.5)(140mg，0.285mmol)，环丙甲酰胺(72.86mg,0.856mmol)，(2R)-1-[(1R)-1-[双(1,1-二叔丁基)膦]乙基]-2-(二环己基膦)二茂铁(31.65mg,0.0571mmol)，1,8-二氮杂双环[5.4.0]十一碳-7-烯(43.45mg,0.285mmol)，碳酸钾(118.33mg,0.856mmol)和醋酸钯(12.81mg,0.0571mmol)溶于甲苯：乙腈＝2:1的2mL溶剂中，氮气置换后，75℃下反应16小时。停止反应，反应液加入水：醋酸＝2:1的4.5mL溶液，用石油醚(8mL)洗涤，然后二氯甲烷(16mL×3)萃取，合并的二氯甲烷有机相经饱和食盐水洗涤、无水硫酸钠干燥，过滤后滤液真空旋除溶剂得到标题化合物(104mg，产率：67.3％，褐色油状)。
MS(ESI):m/z 510.1[M+H]+；
第五步：2-(3-(3-((6-(环丙甲酰胺基)-3-(乙氧基氨基甲酰基)哒嗪-4-基)氨基)-2-甲氧基苯基)-1H-1,2,4-三唑-1-乙酸叔丁酯
将N-甲基吡咯烷酮(2mL)和乙腈(2mL)加入到反应瓶中，加入((4-((3-(1-(2-(叔丁氧基)-2- 氧代乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰氨基)哒嗪-3-羰基)氧基)锌(0.5)(84mg,0.155mmol)，O-乙基羟胺盐酸盐(22.91mg,0.233mmol),N-甲基咪唑(38.23mg,0.466mmol)氮气置换后，油浴65℃中反应15分钟后，最后加入1-羟基苯并三唑(41.94mg,0.31mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(59.51mg,0.31mmol)，氮气置换后，油浴65℃中反应16小时。停止反应，将反应液用乙酸乙酯(8mL×3)萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥，过滤后滤液真空旋除溶剂得到标题化合物(305mg，纯度：73.73％，褐色油状)。
MS(ESI):m/z 553.1[M+H]+；
第六步：2-(3-(3-((6-(环丙甲酰胺基)-3-(乙氧基氨基甲酰基)哒嗪-4-基)氨基)-2-甲氧基苯基)-1H-1,2,4-三唑-1-基)乙酸(化合物7)
将2-(3-(3-((6-(环丙甲酰胺基)-3-(乙氧基氨基甲酰基)哒嗪-4-基)氨基)-2-甲氧基苯基)-1H-1,2,4-三唑-1-乙酸叔丁酯(300mg)溶于三氟乙酸：1,2-二氯乙烷＝1:1的10mL溶剂中，室温下反应5小时。停止反应，反应液经真空旋除溶剂得到粗品，粗品经反相制备色谱分离纯化得到标题化合物(5mg，收率：1.8％，白色固体)。
MS(ESI):m/z 497.1[M+H]+；
1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),10.55(s,1H),8.49(s,1H),8.16(s,1H),7.67(d,J＝7.7Hz,1H),7.49(d,J＝7.6Hz,1H),7.26(t,J＝7.9Hz,1H),4.71(s,2H),3.99(q,J＝7.0Hz,2H),3.71(s,3H),2.14–2.01(m,1H),1.23(t,J＝7.0Hz,3H),0.82(d,J＝5.5Hz,4H).
实施例8
3-(3-(3-((6-(环丙甲酰胺基)-3-(乙氧基氨甲酰基)哒嗪-4-基)氨基)-2-甲氧基苯基)-1H-1,2,4-三唑-1-基)丙酸(化合物8)
第一步：3-(3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑-1-基)丙酸叔丁酯
将3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(400mg,1.818mmol)溶解在超干N,N-二甲基甲酰胺(5mL)中，加入碳酸铯(1.78g,5.454mmol)，氮气置换后，冰浴0℃下缓慢滴加3-溴丙酸叔丁酯(570mg,2.727mmol)，然后在50℃下反应16小时。停止反应，将反应液倒入水(20mL)中，水相用乙酸乙酯(10mL×3)萃取，合并的有机相经饱和食盐水(15mL×3)洗涤、无水硫酸钠干燥，过滤后滤液真空旋除溶剂得到粗品，粗品经硅胶柱层析(二氯甲烷：甲醇＝20：1)分离纯化得到标题化合物(490mg，收率：77.5％，淡黄色油状物)。
MS(ESI):m/z 349.0[M+H]+；
第二步：3-(3-(3-氨基-2-甲氧基苯基)-1H-1,2,4-三唑-1-基)丙酸叔丁酯
将3-(3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑-1-基)丙酸叔丁酯(490mg,1.408mmol)溶于甲醇(20mL)中，加入钯/炭催化剂(37mg,0.352mmol)，氢气置换三次后，室温下反应2小时。停止反应，过滤掉钯/炭，滤液真空旋除溶剂得到粗品，粗品经硅胶柱层析(二氯甲烷：甲醇＝10:1)分离纯化得到标题化合物(420mg，收率：93.8％，淡黄色油状物)。
MS(ESI):m/z 319.4[M+H]+；
第三步：((4-((3-(1-(3-(叔丁氧基)-3-氧代丙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-6-氯哒嗪-3-羰基)氧基)锌(0.5)
将3-(3-(3-氨基-2-甲氧基苯基)-1H-1,2,4-三唑-1-基)丙酸叔丁酯(420mg,1.321mmol)溶于水(7mL)和异丙醇(1mL)中，加入4,6-二氯哒嗪-3-羧酸锂(304mg,1.585mmol)、醋酸锌(291mg,1.585mmol)，氮气置换三次后，油浴65℃中反应16小时。停止反应，反应液中加水(10mL)，室温下搅拌1小时，然后抽滤，滤饼用水(6mL×2)、四氢呋喃(1mL)淋洗，滤饼干燥得到标题化合物(320mg，收率：47.9％，棕色固体)。
MS(ESI):m/z 475.1[M+H]+；
第四步：((4-((3-(1-(3-(叔丁氧)-3-氧代丙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙甲酰胺基)哒嗪-3-羰基)氧基)锌(0.5)
将((4-((3-(1-(3-(叔丁氧基)-3-氧代丙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-6-氯哒嗪-3-羰基)氧基)锌(0.5)(320mg,0.632mmol)溶于甲苯(4mL)和乙腈(2mL)中，加入环丙甲酰胺(134mg,1.580mmol)、(R)-(-)-1-[(S)-2-(二环己基膦)二茂铁]乙基二叔丁基膦(70mg,0.126mmol)、1,8-二氮杂二环十一碳-7-烯(96mg,0.632mmol)、碳酸钾(174mg,1.264mmol)和醋酸钯(28mg,0.126mmol)，氮气置换后，油浴100℃中反应16小时。停止反应，反应液冷却至室温，加入水(8mL)、醋酸(4mL)，混合体系用石油醚(15mL×2)洗涤，水相用二氯甲烷(20mL×3)萃取，合并的二氯甲烷有机相经饱和食盐水(10mL×2)洗涤、无水硫酸钠干燥，过滤后滤液真空旋除溶剂得到标题化合物(275mg，收率：78.4％，褐色固体)。
MS(ESI):m/z 524.2[M+H]+；
第五步：3-(3-(6-(环丙甲酰胺)-3-(乙氧基氨甲酰)哒嗪-4-基)氨基)-2-甲氧基苯基)-1H-1,2,4-三唑-1-基)丙酸叔丁酯
将N-甲基吡咯烷酮(2mL)和乙腈(2mL)加入到反应瓶中，加入((4-((3-(1-(3-(叔丁氧)-3-氧代丙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙甲酰胺基)哒嗪-3-羰基)氧基)锌(0.5)(275mg,0.495mmol)、O-乙基羟胺盐酸盐(72mg,0.743mmol)、N-甲基咪唑(121mg,1.485mmol)，反应液在油浴65℃中搅拌15分钟，然后加入1-羟基苯并三唑(134mg,0.990mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(190mg,0.990mmol)，反应液在油浴65℃中搅拌16小时。停止反应，向反应液中加水(10mL)进行淬灭，水相乙酸乙酯(10mL×3)萃取，合并的有机相经饱和食盐水(10mL×2)洗涤、无水硫酸钠干燥，过滤后滤液真空旋除溶剂得到标题化合物(300mg，收率：8.02％，黄色固体)。
MS(ESI):m/z 567.1[M+H]+；
第六步：3-(3-(3-((6-(环丙甲酰胺基)-3-(乙氧基氨甲酰基)哒嗪-4-基)氨基)-2-甲氧基苯基)-1H-1,2,4-三唑-1-基)丙酸(化合物8)
将3-(3-(6-(环丙烷甲酰胺)-3-(乙氧基氨甲酰)哒嗪-4-基)氨基)-2-甲氧基苯基)-1H-1,2,4-三唑-1-基)丙酸叔丁酯10(300mg，0.531mmol)溶于二氯甲烷(1mL)，加入三氟乙酸(1mL)， 室温下搅拌1小时。停止反应，将反应液旋干，粗品经高效液相色谱制备(洗脱体系：甲酸，水，乙腈)分离纯化得到标题化合物(37.98mg，收率：14.0％，淡黄色固体)。
MS(ESI):m/z 511.2[M+H]+；
1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),11.32(s,1H),10.57(s,1H),8.59(s,1H),8.16(s,1H),7.67(d,J＝7.8Hz,1H),7.51(d,J＝7.9Hz,1H),7.27(t,J＝7.9Hz,1H),4.45(t,J＝6.5Hz,2H),3.99(q,J＝7.0Hz,2H),3.71(s,3H),2.89(t,J＝6.5Hz,2H),2.12–2.04(m,1H),1.23(t,J＝7.0Hz,3H),0.82(d,J＝5.5Hz,4H).
实施例9
4-(3-(3-((6-(环丙甲酰胺基)-3-(乙氧基氨甲酰)哒嗪-4-基)氨基)-2-甲氧基苯基)-1H-1,2,4-三唑-1-基)丁酸(化合物9)
第一步：4-(3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑-1-基)丁酸叔丁酯
将3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑1(500mg,2.27mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入4-溴代丁酸叔丁酯(760mg,3.41mmol)和碳酸铯(1.48g,4.54mmol)，氮气置换三次后，反应液在油浴50℃中搅拌2小时。停止反应，将反应液倒入水(40mL)中，水相用乙酸乙酯(40mL×3)萃取，合并的有机相经饱和食盐水(40mL×3)洗涤、无水硫酸钠干燥，过滤后滤液真空旋除溶剂得到粗品，粗品经硅胶柱层析(石油醚：乙酸乙酯＝1:1)分离纯化得到标题化合物(720mg，收率：87.4％，黄色油状物)。
MS(ESI):m/z 363.1[M+H]+；
第二步：4-(3-(3-氨基-2-甲氧基苯基)-1H-1,2,4-三唑-1-基)丁酸叔丁酯
将4-(3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑-1-基)丁酸叔丁酯(720mg,1.987mmol)溶于甲醇(12mL)中，加入钯/炭催化剂(72mg)，氢气置换三次后，室温下反应16小时。停止反应，抽滤掉钯/炭，滤液真空旋除溶剂得到粗品，粗品经硅胶柱层析(二氯甲烷：甲醇＝15:1)分离纯化得到标题化合物(500mg，收率：75.8％，无色透明油状物)。
MS(ESI):m/z 333.2[M+H]+；
第三步：((4-((3-(1-(4-(叔丁氧基)-4-氧代丁基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-氯哒嗪-3-羰基)氧基)锌(0.5)
将4-(3-(3-氨基-2-甲氧基苯基)-1H-1,2,4-三唑-1-基)丁酸叔丁酯(500mg,1.504mmol)溶于异丙醇(3mL)和水(21mL)中，加入4,6-二氯哒嗪-3-羧酸锂(357.4mg,1.805mmol)、醋酸锌(331.2mg,1.805mmol)，氮气置换三次后，油浴65℃中反应16小时。停止反应，反应液中加水(10mL)，室温下搅拌1小时，然后抽滤，滤饼用水(10mL×2)、四氢呋喃(2mL)淋洗，滤饼干燥后得到标题化合物(620mg，收率：79.2％，白色固体)。
MS(ESI):m/z 489.1[M+H]+；
第四步：((4-((3-(1-(4-(叔丁氧基)-4-氧代丁基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺基)哒嗪-3-羰基)氧基)锌(0.5)
将((4-((3-(1-(4-(叔丁氧基)-4-氧代丁基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-氯哒嗪-3-羰基)氧基)锌(0.5)(620mg,1.191mmol)溶于甲苯(6mL)和乙腈(3mL)中，加入环丙甲酰胺(253.4mg,2.978mmol)、(R)-(-)-1-[(S)-2-(二环己基膦)二茂铁]乙基二叔丁基膦(132.1mg,0.238mmol)、1,8-二氮杂二环十一碳-7-烯(181.3mg,1.191mmol)、碳酸钾(329.2mg,2.382mmol)和醋酸钯(53.5mg,0.238mmol)，氮气置换后，油浴75℃中反应16小时。停止反应，反应液冷却至室温，加入水(20mL)、醋酸(10mL)，混合体系用石油醚(30mL×3)洗涤，水相用二氯甲烷(40mL×3)萃取，合并的二氯甲烷有机相经饱和食盐水(40mL×3)洗涤、无水硫酸钠干燥，过滤后滤液真空旋除溶剂得到标题化合物(650mg，收率：95.9％，褐色固体)。
MS(ESI):m/z 538.1[M+H]+；
第五步：4-(3-((6-(环丙甲酰胺)-3-(乙氧基氨甲酰)哒嗪-4-基)氨基)-2-甲氧基苯基)-1H-1,2,4-三唑-1-基)丁酸叔丁基酯
将N-甲基吡咯烷酮(6mL)和乙腈(6mL)加入到反应瓶中，加入((4-((3-(1-(4-(叔丁氧基)-4-氧代丁基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺基)哒嗪-3-羰基)氧基)锌(0.5)(650mg,1.142mmol)、O-乙基羟胺盐酸盐(334.2mg,3.426mmol)、N-甲基咪唑(281.3mg,3.426mmol)，反应液在油浴65℃中搅拌15分钟，然后加入1-羟基苯并三唑(308.6mg,2.284mmol)、 1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(437.8mg,2.284mmol)，反应液在油浴65℃中搅拌反应16小时。停止反应，将反应液倒入水(40mL)中，水相乙酸乙酯(40mL×3)萃取，合并的有机相经饱和食盐水(40mL×3)洗涤、无水硫酸钠干燥，过滤后滤液真空旋除溶剂得到粗品标题化合物(1g，黄色油状物)，直接投下一步。
MS(ESI):m/z 581.1[M+H]+；
第六步：4-(3-(3-((6-(环丙甲酰胺基)-3-(乙氧基氨甲酰)哒嗪-4-基)氨基)-2-甲氧基苯基)-1H-1,2,4-三唑-1-基)丁酸(化合物9)
将4-(3-((6-(环丙甲酰胺)-3-(乙氧基氨甲酰)哒嗪-4-基)氨基)-2-甲氧基苯基)-1H-1,2,4-三唑-1-基)丁酸叔丁酯(1g,1.722mmol)溶于二氯甲烷(8mL)中，加入三氟乙酸(2mL)，氮气置换三次后，室温下反应8小时。停止反应，反应液真空旋除溶剂得到粗品，粗品经高效液相色谱制备(洗脱体系：甲酸，水，乙腈)分离纯化得到标题化合物(85.41mg，收率：9.46％，黄色固体)。
MS(ESI):m/z 525.0[M+H]+；
1H NMR(400MHz,DMSO-d6)δ12.25(s,1H),11.31(s,1H),10.56(s,1H),8.61(s,1H),8.16(s,1H),7.68(dd,J＝7.7,1.0Hz,1H),7.51(d,J＝8.0Hz,1H),7.28(t,J＝7.9Hz,1H),4.28(t,J＝6.8Hz,2H),4.02–3.97(m,2H),3.72(s,3H),2.29(t,J＝7.3Hz,2H),2.10–2.04(m,3H),1.23(t,J＝7.0Hz,3H),0.82(d,J＝6.0Hz,4H).
实施例10
6-(环丙甲酰胺)-N-乙氧基-4-((3-(1-(2-羟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)哒嗪-3-甲酰胺(化合物10)
第一步：1-(2-(苄氧基)乙基)-3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑
将3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(1000mg,4.542mmol)溶解在超干N,N-二甲基甲酰胺(10mL)中，加入碳酸铯(4440mg,13.626mmol)与((2-溴乙氧基)甲基)苯(1465mg,6.813mmol)，在50℃下反应1小时。停止反应，将反应液过滤后倒入水(20mL)中，水相用乙酸乙酯(10mL×3)萃取，合并的有机相经饱和食盐水(10mL×3)洗涤、无水硫酸钠干燥，滤液过滤 后真空旋除溶剂得到粗品，粗品经硅胶柱层析(石油醚：乙酸乙酯＝3:1)分离纯化得到标题化合物(1.5g，收率：93.3％，淡黄色油状物)
MS(ESI):m/z 355.5[M+H]+；
第二步：3-(1-(2-(苄氧基)乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯胺
将1-(2-(苄氧基)乙基)-3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(1.5g,4.233mmol)溶于异丙醇(10mL)与水(0.8mL)中，加入铁粉(233mg,21.165mmol)，氯化铵(1132mg，21.165)，置换氮气三次，70℃下反应1小时。停止反应，将反应液过滤后旋干，粗品经硅胶柱层析(石油醚：乙酸乙酯＝1:5)分离纯化得到标题化合物(1.32g，收率：96.1％，无色油状物)。
MS(ESI):m/z 325.0[M+H]+；
第三步：((4-((3-(1-(2-(苄氧基)乙基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-氯哒嗪-3-羰基)氧基)锌(0.5)
将3-(1-(2-(苄氧基)乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯胺(1.2g,3.699mmol)溶于水(35mL)和异丙醇(5mL)中，加入4,6-二氯哒嗪-3-羧酸锂(879mg,4.439mmol)、醋酸锌(815mg,4.439mmol),氮气置换三次后，油浴65℃中反应16小时。停止反应，反应液中加水(40mL)，室温下搅拌1小时，然后抽滤，滤饼用水(10mL×2)、四氢呋喃(1mL)淋洗，滤饼干燥后得到标题化合物(1.2g，收率：63.3％，灰色固体)。
MS(ESI):m/z 481.1[M+H]+；
第四步：((4-((3-(1-(2-(苄氧基)乙基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺基)哒嗪-3-羰基)氧基)锌(0.5)
将((4-((3-(1-(2-(苄氧基)乙基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-氯哒嗪-3-羰基)氧基)锌(0.5)(1.2g，2.138mmol)溶于甲苯(24mL)和乙腈(12mL)中，加入环丙甲酰胺(454mg,5.345mmol)、(R)-(-)-1-[(S)-2-(二环己基膦)二茂铁]乙基二叔丁基膦(237mg,0.428mmol)、1,8-二氮杂二环十一碳-7-烯(325mg,2.138mmol)、碳酸钾(590mg,4.276mmol)、醋酸钯(96mg,0.428mmol)，氮气置换后，油浴75℃中反应16小时。停止反应，反应液冷却至室温，加入水(30mL)、醋酸(15mL)，混合体系用石油醚(50mL×2)洗涤，水相用二氯甲烷(10mL×3)萃取，合并的二氯甲烷有机相经饱和食盐水(10mL×3)洗涤、无水硫酸钠干燥，过滤后滤液真空旋除溶剂得到标题化合物(1.8g，褐色油状物)，直接投下一步反应。
MS(ESI):m/z 530.0[M+H]+；
第五步：4-((3-(1-(2-(苄氧基)乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙甲酰胺基)-N-乙氧基哒嗪-3-甲酰胺
取一25mL反应瓶，瓶中加入N-甲基吡咯烷酮(2mL)和乙腈(2mL)，加入((4-((3-(1-(2-(苄氧基)乙基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺基)哒嗪-3-羰基)氧基)锌(0.5)(400mg,0.713mmol)、O-乙基羟胺盐酸盐(104mg,1.070mmol)、N-甲基咪唑(175mg,2.139mmol)，反应液在油浴65℃中搅拌15分钟，然后加入1-羟基苯并三唑(193mg,1.426mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(273mg,1.426mmol)，反应液在油浴65℃中搅拌16小时。停止反应，向反应液中加入水(20mL)，用乙酸乙酯萃取(10mL×3)。将有机相合并后用饱和食盐水洗涤(10mL×3)，无水硫酸钠干燥，过滤后滤液旋干得到标题化合物(510mg，褐色油状物)，直接投下一步反应。
MS(ESI):m/z 573.1[M+H]+；
第六步：6-(环丙甲酰胺)-N-乙氧基-4-((3-(1-(2-羟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)哒嗪-3-甲酰胺(化合物10)
将4-((3-(1-(2-(苄氧基)乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-乙氧基哒嗪-3-甲酰胺(510mg，0.891mmol)溶于甲醇(20mL)，加入钯炭(38mg，0.356mmol)，置换氢气后在室温下反应16小时。停止反应，将反应液过滤后旋干，粗品经高效液相色谱制备(洗脱体系：氨水，乙腈，水)分离纯化得到标题化合物(20.4mg，收率：4.7％，白色固体)。
MS(ESI):m/z 483.0[M+H]+；
1H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.10(s,1H),7.63(d,J＝7.7Hz,1H),7.47(d,J＝8.0Hz,1H),7.24(t,J＝8.0Hz,1H),5.00(s,1H),4.26(d,J＝4.9Hz,2H),3.94(d,J＝6.4Hz,2H),3.78(brs,2H),3.72(s,3H),2.05(brs,1H),1.20(t,J＝6.7Hz,3H),0.80(d,J＝5.7Hz,4H).
实施例11
6-(环丙甲酰胺基)-N-(2-氟乙氧基)-4-((3-(1-(2-羟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)哒嗪-3-甲酰胺(化合物11)
第一步：4-((3-(1-(2-(苄氧基)乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙甲酰胺基)-N-(2-氟乙氧基)哒嗪-3-甲酰胺
将N-甲基吡咯烷酮(9mL)和乙腈(9mL)于室温下搅拌十分钟，加入((4-((3-(1-(2-(苄氧基)乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙甲酰胺基)哒嗪-3-羰基)氧基)锌(0.5)(300mg,0.64mmol)，O-(2-氟乙基)羟胺盐酸盐(110.91mg,0.96mmol)和N-甲基咪唑(158.45mg,1.93mmol)，氮气置换后，油浴65℃中反应15分钟后，最后加入1-羟基苯并三唑(172.95mg,1.28mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(245.38mg,1.28mmol)，氮气置换后，油浴65℃中反应16小时。停止反应，向反应液中加水(20m L)进行淬灭，后用乙酸乙酯(30mL×3)萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥，过滤后滤液真空旋除溶剂得到标题化合物(300mg，产率：95.1％，褐色固体)。
MS(ESI):m/z 591.3[M+H]+；
第二步：6-(环丙甲酰胺基)-N-(2-氟乙氧基)-4-((3-(1-(2-羟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)哒嗪-3-甲酰胺(化合物11)
将4-((3-(1-(2-(苄氧基)乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙甲酰胺基)-N-(2-氟乙氧基)哒嗪-3-甲酰胺(158mg,0.268mmol)溶于乙腈(3mL)，后加入三甲基碘硅烷(267.64mg,1.338mmol)，室温下反应4小时。停止反应，真空旋除溶剂得到粗品，粗品经反相制备色谱(洗脱体系：甲酸，乙腈，水)分离纯化得到标题化合物(27.91mg，收率：20.85％，白色固体)。
MS(ESI):m/z 501.1[M+H]+；
1H NMR(400MHz,DMSO-d6)δ12.46(s,1H),11.34(s,1H),10.51(s,1H),8.56(s,1H),8.15(s,1H),7.70(dd,J＝7.8,1.3Hz,1H),7.51(d,J＝6.7Hz,1H),7.28(t,J＝7.9Hz,1H),4.77–4.73(m,1H),4.65–4.59(m,1H),4.29(t,J＝5.3Hz,2H),4.26–4.23(m,1H),4.19–4.14(m,1H),3.80(t,J＝5.4Hz,2H),3.73(s,3H),2.12–2.05(m,1H),0.85–0.80(m,4H).
实施例12
6-(环丙甲酰胺基)-N-(2,2-二氟乙氧基)-4-((3-(1-(2-羟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)哒嗪-3-甲酰胺(化合物12)
第一步：4-((3-(1-(2-(苄氧基)乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙甲酰胺)-N-(2,2-二氟乙氧基)哒嗪-3-甲酰胺
将N-甲基吡咯烷酮(2mL)和乙腈(2mL)加入到反应瓶中，加入((4-((3-(1-(2-(苄氧基)乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙甲酰胺基)哒嗪-3-羰基)氧基)锌(0.5)(400mg,0.713mmol)、O-(2,2-二氟乙基)羟胺盐酸盐(143mg,1.070mmol)、N-甲基咪唑(175mg,2.139mmol)，反应液在油浴65℃中搅拌15分钟，然后加入1-羟基苯并三唑(193mg,1.426mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(273mg,1.426mmol)，反应液在油浴65℃中搅拌反应16小时。停止反应，向反应液中加入水(20mL),用乙酸乙酯萃取(10mL×3)；将有机相合并，用饱和食盐水洗涤(10mL×3)，无水硫酸钠干燥，过滤后滤液旋干得到标题化合物(290mg，收率：66.8％，褐色油状物)。
MS(ESI):m/z 609.0[M+H]+；
第二步：6-(环丙甲酰胺基)-N-(2,2-二氟乙氧基)-4-((3-(1-(2-羟乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)哒嗪-3-甲酰胺(化合物12)
取一50mL反应瓶，将4-((3-(1-(2-(苄氧基)乙基)-1H-1,2,4-三唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙甲酰胺)-N-(2,2-二氟乙氧基)哒嗪-3-甲酰胺(260mg，0.427mmol)溶于甲醇(20mL)，加入钯/炭(18mg，0.171mmol)，置换氢气后在室温下搅拌反应40小时。停止反应，将反应液过滤后滤液旋干，粗品经高效液相色谱制备(洗脱体系：甲酸，乙腈，水)分离纯化得到标题化合物(7.65mg，收率：3.5％，白色固体)。
MS(ESI):m/z 519.1[M+H]+；
1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),10.48(s,1H),8.54(s,1H),8.13(s,1H),7.68(d,J＝7.5Hz,1H),7.50(d,J＝8.0Hz,1H),7.27(t,J＝7.9Hz,1H),6.34(t,J＝54.5Hz,1H),5.00(s,1H),4.29–4.21(m,4H),3.82–3.70(m,5H),2.13–2.01(m,1H),0.81(d,J＝5.2Hz,4H).
生物学测试评价
测试例A、本发明化合物TYK2 JH2体外酶结合实验
实验目的：该测试例的目的是采用荧光共振能量转移(TR-FRET)的方法测试化合物对TYK2 JH2假激酶的结合作用，进而评价化合物对TYK2 JH2的亲和力。
实验方法：
DMSO溶解化合物配制为10mM母液，然后在化合物稀释板子中配备200X化合物不同梯度浓度，并转移至Echo板中。通过Echo仪器将化合物从Echo板转移75nL至384实验板，分别加入5μL 3X TYK2JH2假激酶(Bioduro)、5μL 3X Tb antibody(Cisbio)、5μL 3X TRACER(Bioduro)至384孔实验板中，离心30秒，室温孵育60分钟。Envision酶标仪(PerkinElmer)读取495nm/520nm荧光信号比值，使用XL-Fit软件进行数据分析，并计算出化合物IC50。
实验结果：

从实验数据结果可以看出，本发明化合物对TYK2 JH2假激酶具有良好的结合作用。
测试例B、本发明化合物对IL-2诱导的人PBMC中CD3+细胞亚群STAT5磷酸化试验(JAK1/3)的测定
实验目的：该测试例的目的是采用蛋白磷酸化流式细胞分析技术检测化合物对IL-2诱导的STAT5磷酸化的抑制作用。
实验方法：
用化合物对人PBMC细胞进行预孵育，在适当刺激条件下诱导STAT5进行磷酸化，并对相应细胞亚群和靶标进行染色，使用流式细胞仪读取细胞数据并分析不同化合物浓度条件下磷酸化抗体信号的强弱。将PBMC重悬并分配到96孔板，62.5μL/孔；加入3.5μL 20X化合物工作液，37℃孵育30分钟；加入5μL PE小鼠抗人CD3(BD)，37℃避光孵育30分钟；每孔加入4μL 20X IL-2(R&D)，37℃避光孵育20分钟；将96孔板中所有细胞转移到深孔板，每孔加入400μL固定工作液(Biolegend)，室温避光孵育20分钟。PBS清洗两遍，加入400μL Perm Buffer III(BD)，4℃避光孵育40分钟；PBS清洗细胞两遍，加入100μL STAT5 pY694抗体工作液(BD)，室温孵育40分钟；PBS清洗一遍，加入200μL染色缓冲液重悬细胞，转移至上样板，使用FlowJo软件分析抗体荧光强度，通过XL-Fit软件计算化合物IC50。
实验结论：
从实验数据结果可以看出，本发明化合物对JAK1/3信号通路抑制活性更低，具有更优的选择性。
测试例C、本发明化合物对JAK1 JH1/JAK2 JH1/JAK3 JH1/TYK2 JH1激酶抑制作用的测定
实验目的：该测试例的目的是采用均相时间分辨荧光共振能量转移技术(HTRF)检测化合物对JAK1 JH1/JAK2 JH1/JAK3 JH1/TYK2 JH1激酶活性的抑制作用。
实验方法：
用自动化微量移液系统将化合物工作液以100nL每孔转移到384孔实验板，每孔加入5μL 2X JAK1 JH1/JAK2 JH1/JAK3 JH1/TYK2 JH1激酶溶液或反应缓冲液，离心混匀，25℃室温孵育15分钟。孵育完成后每孔加入5μL 2X TK-SUB-biotin底物和ATP混合溶液，离心混匀，25℃孵育45分钟(JAK1/JAK2)或60分钟(JAK3/TYK2)。孵育完成后每孔加入10μL检测混合液(TK Antibody-EU和Streptavidin-XL混合液)，离心混匀，25℃孵育60分钟(JAK1/JAK2)或120分钟(JAK3/TYK2)。孵育结束转入4℃冰箱过夜孵育，在Envision 2104 Multilabel Reader上读取荧光值，通过XL-Fit软件计算化合物IC50。
实验结论：
从实验数据结果可以看出，本发明化合物对JAK1 JH1/JAK2 JH1/JAK3 JH1抑制活性更低，具有更优的选择性。

Claims (18)

  1. 通式(I)的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：
    其中：
    R1选自H、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-SRa、C1-6亚烷基-NRbRc、C1-6亚烷基-C(O)Ra、C1-6亚烷基-C(O)ORa、C1-6亚烷基-C(O)NRbRc、C1-6亚烷基-OC(O)Ra、C1-6亚烷基-NRbC(O)Ra、C1-6亚烷基-S(O)mRa、C1-6亚烷基-S(O)mNRbRc或C1-6亚烷基-NRbS(O)mRa，所述基团任选地被一个或多个氘取代，直至完全氘代；
    R2选自C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基，所述基团任选地被一个或多个氘取代，直至完全氘代；
    R3选自H、C1-6烷基或C1-6卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
    R1、R2和R3中的各基团任选地被1、2、3或4个R取代；
    其中Ra、Rb和Rc独立地选自H、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-10元杂芳基；
    m＝1或2；
    R选自H、D、卤素、CN、C1-6烷基或C1-6卤代烷基。
  2. 权利要求1的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，R1选自H、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-SRa、C1-6亚烷基-NRbRc、C1-6亚烷基-C(O)Ra、C1-6亚烷基-C(O)ORa、C1-6亚烷基-C(O)NRbRc、C1-6亚烷基-OC(O)Ra或C1-6亚烷基-NRbC(O)Ra，所述基团任选地被一个或多个氘取代，直至完全氘代；优选地，R1选自H、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-SRa、C1-6亚烷基-NRbRc、C1-6亚烷基-C(O)ORa或C1-6亚烷基-C(O)NRbRc，所述基团任选地被一个或多个氘取代，直至完全氘代；优选地，R1选自H、C1-6卤代烷基、C1-6亚烷基-OH、C1-6亚烷基-SH、C1-6亚烷基-NH2、C1-6亚烷基-C(O)OH或C1-6亚烷基-C(O)NH2，所述基团任选地被一个或多个氘取代，直至完全氘代；优选地，R1选自H或C1-6卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；优选地，R1为C1-6亚烷基-ORa，其中Ra选自C1-6烷基或C1-6卤代烷基。
  3. 权利要求1或2的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，R2选自C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基或3-7元杂环基，所述基团任选地被一个或多个氘取代，直至完全氘代；优选地，R2选自C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基，所述基团任选地被一个或多个氘取代，直至完全氘代；优选地，R2选自C1-6烷基或C3-7环烷基，所述基团任选地被一个或多个氘取代，直至完全氘代。
  4. 权利要求1-3中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，R3选自C1-6烷基或C1-6卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；优选地，R3为甲基，其任选地被一个或多个氘取代，直至完全氘代。
  5. 权利要求1的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中：
    R1选自H、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-SRa或C1-6亚烷基-C(O)ORa，所述基团任选地被一个或多个氘取代，直至完全氘代；
    R2选自C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基，所述基团任选地被一个或多个氘取代，直至完全氘代；
    R3选自H、C1-6烷基或C1-6卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
    R1、R2和R3中的各基团任选地被1、2、3或4个R取代；
    其中Ra选自H、C1-6烷基或C1-6卤代烷基；
    R选自H、D、卤素、CN、C1-6烷基或C1-6卤代烷基。
  6. 权利要求1的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中：
    R1选自H、C1-4卤代烷基、C1-4亚烷基-ORa或C1-4亚烷基-C(O)OH，所述基团任选地被一个或多个氘取代，直至完全氘代；
    R2选自C1-4烷基、C1-4卤代烷基或C3-7环烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
    R3选自C1-4烷基或C1-4卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
    其中Ra选自H、C1-4烷基或C1-4卤代烷基。
  7. 权利要求1的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中：
    R1为C1-4亚烷基-ORa，其任选地被一个或多个氘取代，直至完全氘代；
    R2选自C1-4烷基、C1-4卤代烷基或C3-7环烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；优选C1-4烷基，其任选地被一个或多个氘取代，直至完全氘代；
    R3选自C1-4烷基或C1-4卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
    其中Ra选自C1-4烷基或C1-4卤代烷基。
  8. 权利要求1的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中：
    R1选自H、C1-4卤代烷基、C1-4亚烷基-OH或C1-4亚烷基-C(O)OH，所述基团任选地被一个或多个氘取代，直至完全氘代；
    R2选自C1-4烷基、C1-4卤代烷基或C3-7环烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；优选C1-4烷基，其任选地被一个或多个氘取代，直至完全氘代；
    R3选自C1-4烷基或C1-4卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代。
  9. 权利要求1的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中：
    R1选自H、C1-6亚烷基-ORa和C1-6亚烷基-SRa，所述基团任选地被一个或多个氘取代，直至完全氘代；
    R2选自C1-6烷基和C1-6卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
    R3选自H、C1-6烷基或C1-6卤代烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
    R1、R2和R3中的各基团任选地被1、2、3或4个R取代；
    其中Ra选自H、C1-6烷基和C1-6卤代烷基；
    R选自H、D、卤素、CN、C1-6烷基或C1-6卤代烷基。
  10. 权利要求1的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中：
    R1选自H和C1-6亚烷基-ORa，所述基团任选地被一个或多个氘取代，直至完全氘代；
    R2选自C1-6烷基和C1-6卤代烷基；
    R3为C1-6烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
    其中Ra选自H和C1-6烷基。
  11. 权利要求1的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中：
    R1选自H和C1-4亚烷基-ORa，所述基团任选地被一个或多个氘取代，直至完全氘代；
    R2为C1-4烷基，所述基团任选地被一个或多个氘取代，直至完全氘代；
    R3为C1-4烷基，所述基团任选地被一个或多个氘取代，直至完全氘代，
    其中Ra为C1-4烷基。
  12. 权利要求1的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中所述化合物选自以下：

  13. 药物组合物，其含有权利要求1-12中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，和药学上可接受的赋形剂；优选地，其还含有其它治疗剂。
  14. 权利要求1-12中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物在制备用于治疗和/或预防TYK2激酶介导的疾病的药物中的用途。
  15. 权利要求1-12中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，或权利要求13的药物组合物，其用于治疗和/或预防TYK2激酶介导的疾病。
  16. 一种在受试者中治疗和/或预防TYK2激酶介导的疾病的方法，包括向所述受试者给药权利要求1-12中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，或权利要求13的药物组合物。
  17. 权利要求14的用途或者权利要求15的化合物或药物组合物的用途或者权利要求16的方法，其中所述TYK2激酶介导的疾病选自自身免疫性疾病、皮肤病、变应性疾病、器官排斥、癌症、干眼病、骨髓纤维化、红细胞增多症；优选地，所述自身免疫性疾病为狼疮、多发性硬化、类风湿性关节炎、青少年关节炎、银屑病、溃疡性结肠炎、克罗恩氏病或自体免疫性甲状腺疾病；所述皮肤病为牛皮癣、皮疹或特应性皮炎；所述变应性病症为哮喘或鼻炎病；所述器官移植排斥为异体抑制排斥或移植物抗宿主疾病；所述癌症为肾癌、肝癌、胰腺癌、胃癌、乳腺癌、前列腺癌、头颈部癌、甲状腺癌、肺癌、胶质母细胞瘤、黑素瘤、淋巴瘤或白血病。
  18. 权利要求14的用途或者权利要求15的化合物或药物组合物的用途或者权利要求16的方法，所述TYK2激酶介导的疾病选自类风湿性关节炎、银肩病、溃疡性结肠炎和克罗恩病。
PCT/CN2023/098585 2022-06-07 2023-06-06 取代的哒嗪-3-甲酰胺化合物作为tyk2抑制剂 WO2023236947A1 (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202210638601 2022-06-07
CN202210638601.X 2022-06-07
CN202310398880 2023-04-13
CN202310398880.1 2023-04-13

Publications (1)

Publication Number Publication Date
WO2023236947A1 true WO2023236947A1 (zh) 2023-12-14

Family

ID=89000460

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/098585 WO2023236947A1 (zh) 2022-06-07 2023-06-06 取代的哒嗪-3-甲酰胺化合物作为tyk2抑制剂

Country Status (3)

Country Link
CN (1) CN117186075A (zh)
TW (1) TW202348227A (zh)
WO (1) WO2023236947A1 (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020156311A1 (zh) * 2019-01-28 2020-08-06 江苏豪森药业集团有限公司 一种哒嗪类衍生物抑制剂、其制备方法和应用
CN113563309A (zh) * 2020-04-28 2021-10-29 浙江海正药业股份有限公司 吡啶类衍生物及其制备方法和用途
WO2022117016A1 (zh) * 2020-12-02 2022-06-09 深圳微芯生物科技股份有限公司 羟肟酸酯化合物、其制备方法及其应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020156311A1 (zh) * 2019-01-28 2020-08-06 江苏豪森药业集团有限公司 一种哒嗪类衍生物抑制剂、其制备方法和应用
CN113563309A (zh) * 2020-04-28 2021-10-29 浙江海正药业股份有限公司 吡啶类衍生物及其制备方法和用途
WO2022117016A1 (zh) * 2020-12-02 2022-06-09 深圳微芯生物科技股份有限公司 羟肟酸酯化合物、其制备方法及其应用

Also Published As

Publication number Publication date
TW202348227A (zh) 2023-12-16
CN117186075A (zh) 2023-12-08

Similar Documents

Publication Publication Date Title
KR102223227B1 (ko) Glp-1 수용체 아고니스트 작용을 갖는 피라졸로피리딘 유도체
CN110312719B (zh) 作为jak家族激酶抑制剂的咪唑并吡咯并吡啶
CN109803962B (zh) 囊性纤维化跨膜传导调控蛋白的调节剂、以及药物组合物
CN104910161B (zh) 作为jak抑制剂的吡唑并嘧啶化合物和方法
CN105916856B (zh) 作为酪蛋白激酶1d/e抑制剂的取代的4,5,6,7-四氢吡唑并[1,5-a]吡嗪衍生物
WO2020135771A1 (zh) 杂环类化合物、中间体、其制备方法及应用
EP3766882B1 (en) Phthalazine isoxazole alkoxy derivatives, preparation method thereof, pharmaceutical composition and use thereof
CN110337294A (zh) 作为cftr增效剂的吡咯并嘧啶
JP2017518276A (ja) ブルトン型チロシンキナーゼ（ｂｔｋ）インヒビターとしての多フルオロ置換化合物
CN107207472B (zh) Akt激酶的抑制剂
CN110167933A (zh) 作为αV整联蛋白抑制剂的唑酰胺和胺
CN107567450B (zh) 用作tnf抑制剂的杂环化合物
CN114423753A (zh) 作为cd38抑制剂的杂双环酰胺
WO2020042995A1 (zh) 一种高活性sting蛋白激动剂化合物
WO2021164746A1 (zh) 取代芳基类化合物
WO2023246656A1 (zh) Sos1蛋白降解靶向嵌合体及其组合物、制剂和用途
JP2019516804A (ja) ナトリウム−グルコース共輸送体阻害薬の新規な結晶形及びその製造方法並びに用途
WO2023041055A1 (zh) Kif18a抑制剂
WO2019085996A1 (zh) 作为mTORC1/2双激酶抑制剂的吡啶并嘧啶类化合物
WO2023236947A1 (zh) 取代的哒嗪-3-甲酰胺化合物作为tyk2抑制剂
WO2019024809A1 (zh) 作为RORγ抑制剂的双环化合物
WO2022222911A1 (zh) 嘧啶酮化合物及其用途
WO2021228217A1 (zh) 可用作RORγ调节剂的苯胺类化合物
WO2021228216A1 (zh) 可用作RORγ调节剂的联芳基类化合物
CN113896669A (zh) 雌激素受体调节剂及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23819112

Country of ref document: EP

Kind code of ref document: A1