WO2023213308A1 - 酰胺取代的杂环化合物及其医药用途 - Google Patents
酰胺取代的杂环化合物及其医药用途 Download PDFInfo
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- WO2023213308A1 WO2023213308A1 PCT/CN2023/092333 CN2023092333W WO2023213308A1 WO 2023213308 A1 WO2023213308 A1 WO 2023213308A1 CN 2023092333 W CN2023092333 W CN 2023092333W WO 2023213308 A1 WO2023213308 A1 WO 2023213308A1
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- Prior art keywords
- amino
- carboxamide
- methyl
- pyridin
- pyridazine
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Classifications
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- 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
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- 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
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- 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]
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- 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
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- 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
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- 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
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- 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
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- 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
- C07D403/14—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 three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
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- 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
- C07D417/02—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 two hetero rings
- C07D417/12—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 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 a class of amide-substituted heterocyclic compounds, isomers, solvates, deuterated derivatives or pharmaceutically acceptable salts of the compounds and drugs using the compounds or their salts as active ingredients. , and its use in preparing diseases related to Tyk2-mediated signal transduction pathways, such as autoimmune diseases and cancer.
- Autoimmune diseases are a group of complex chronic diseases.
- the complex combination of multiple genetic and environmental factors leads to a decrease in the immune system's ability to recognize or regulate responses to one's own tissues, resulting in immune attacks on one's own tissues.
- Early drugs only controlled symptoms, such as painkillers for RA and insulin injections for type 1 diabetes. Because the mechanism of this type of disease is very complex, even now it can only be controlled roughly. However, no matter how complex the mechanism is, there are primary and secondary factors. After all, these immune responses still require specific biomolecules to execute them.
- TNF is the first confirmed cytokine target, and drugs targeting this target are currently the largest family of drugs sold.
- the IL17 and IL23 antibodies that were later launched were also very successful.
- JAK family kinases are key signaling proteins for the expression of immune substances mediated by these cytokines. These cytokines activate JAK after binding to receptors, and JAK re-phosphorylates downstream STAT family proteins to induce gene expression.
- Pfizer was the first to market the JAK1/3 inhibitor Tofacitinib (trade name: Xeljanz), which was the first kinase inhibitor drug other than tumors. It greatly stimulated the development of kinase inhibitors at that time, indicating that the toxicity of kinase inhibitors can be controlled. To the extent that chronically ill patients can tolerate it.
- Incyte launched the JAK2 inhibitor ruxolitinib (trade name Jakafi) for platelet autoimmune diseases.
- Eli Lilly/Incyte also launched the JAK1/JAK2 inhibitor baricitinib (trade name Olumiant).
- Celgene also launched the PDE4 inhibitor Otezla, which inhibits TNF synthesis.
- Another target that made countless manufacturers cry without tears, p38 although very attractive, eventually became one of the most destructive targets in the pharmaceutical industry.
- Janus kinase is a group of protein tyrosine kinases (PTK). This type of protein participates in various cytokine signal transduction through auxiliary cytokine receptors. Four members have been discovered so far, namely JAK1, JAK2, and JAK3. and TYK2. TYK2 is an important member of the JAK family. STAT is its downstream element that transduces cytokine signal activation; JAK/STAT is its classic signal transduction pathway. This pathway in mammalian cells includes four members of the JAK family and seven STATs (STAT1-4, STAT5a, STAT5b and STAT6).
- STAT protein tyrosine kinases
- TYK2 binds to the box functional region of the dimerized receptor, autonomously or transphosphorylates it and makes the receptor chain Phosphorylation, thereby providing anchoring sites for the access of STATs; TYK2 then phosphorylates the recruited STATs to form homo- or heterodimers, which are then transferred into the nucleus to induce the transcription of target genes.
- the heterodimeric cytokines interleukins IL-12 and IL-23 which share the p40 subunit, are produced by activated antigen-presenting cells and are critical in the differentiation and proliferation of Th1 and Th17 cells, which are Two effector T cell lineages that play key roles in autoimmunity.
- IL-23 is composed of the p40 subunit and the unique p19 subunit.
- IL-23 acts through a heterodimeric receptor composed of IL-23R and IL-12R ⁇ 1, which are TH17 cells that produce proinflammatory cytokines such as IL-17A, IL-17F, IL-6, and TNF- ⁇ . Required for survival and expansion.
- cytokines are critical in regulating the pathology of numerous autoimmune diseases including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and lupus.
- IL-12 also contains the p35 subunit and acts through a heterodimeric receptor composed of IL-12R ⁇ 1 and 1L-12R ⁇ 2.
- IL-12 is required for Th1 cell development and IFN ⁇ secretion, a cytokine that plays an important role in immunity by stimulating MHC expression, B cell class switching to IgG subclasses, and activating macrophages.
- mice lacking p40, p19, and IL-23R are protected from autoimmunity in models of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus, and psoriasis Illness troubles.
- Th17 cells have been identified in active lesions in the brains of patients with multiple sclerosis and in the intestinal mucosa of patients with active Crohn's disease.
- the mRNA levels of p19, p40, and p35 were significantly increased in patients with active SLE, and T cells from lupus patients had a dominant Th1 phenotype.
- genes that function in the IL-23 and IL-12 pathways associated with chronic inflammatory and autoimmune diseases include IL23A, IL12A, IL12B, IL12RB2, IL12RB2, IL23R, JAK2, TYK2, STAT3 and STAT4.
- anti-p40 therapies that inhibit both IL-12 and IL-23, as well as IL-23-specific anti-p19 therapies, are effective in treating autoimmune diseases including psoriasis, Crohn's disease, and psoriasis arthritis. disease. Therefore, drugs that inhibit the effects of IL-12 and IL-23 have a promising therapeutic role in human autoimmune disorders.
- Type I interferon (IFN) group which includes members of IFN ⁇ as well as IFN ⁇ , IFN ⁇ , IFN Economics, and IFN ⁇ , acts through the heterodimeric IFN ⁇ / ⁇ receptor (IFNAR).
- IFNAR heterodimeric IFN ⁇ / ⁇ receptor
- Type I IFN has multiple effects on both the innate and adaptive immune systems, including activating both cellular and humoral immune responses and enhancing the expression and release of self-antigens.
- IFN serum interferon
- type I interferon type I interferon
- the expression of IFN-regulated genes is increased, and various studies have shown that serum IFN ⁇ levels are related to both disease activity and severity.
- the use of IFN ⁇ can induce lupus-like syndrome.
- Observation results Demonstrating a direct role for IFN ⁇ in lupus pathology.
- studies have shown that aberrant activation of type I interferon-mediated pathways is also involved in other autoimmune diseases (e.g. syndrome and scleroderma). Therefore, drugs that inhibit the action of type I interferons can be expected to have therapeutic utility in human autoimmune disorders.
- Tyrosine kinase 2 is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases and has been shown to regulate IL-12, IL-23 and type I interferons in both mice and humans. Receptors are critical in regulating downstream signal transduction cascades. Tyk2 is also a member of the JAK family, mediates the signaling of IL23 and IL12, and enhances the function of Th17 immune cells. Tyk2 mediates receptor-induced phosphorylation of STAT family members of transcription factors, an essential signal leading to STAT protein dimerization and transcription of STAT-dependent pro-inflammatory genes. Experimental models of Tyk2-deficient mice resisting colitis, psoriasis, and multiple sclerosis demonstrate the importance of Tyk2-mediated signaling in autoimmunity and related disorders.
- JAK Janus kinase
- novel compounds capable of modulating cytokines and/or interferons such as IL-12, IL-23, and/or IFN ⁇ , and methods of using these compounds patients has important therapeutic value.
- the first object of the present invention is to provide compounds of formula (I), and isomers, solvates, deuterated derivatives or pharmaceutically acceptable salts thereof.
- X 1 and Y 1 are each independently -CR 5 or -N;
- phenyl is phenyl; a 5- to 6-membered monocyclic heteroaryl ring with 1 to 4 independent heteroatoms selected from nitrogen, oxygen, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring with 2 to 4 independent heteroatoms selected from nitrogen, oxygen, and sulfur 7-12 bicyclic heteroaryl;
- R 1 is selected from hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkylamino, and can be optionally substituted by halogen or deuterium;
- R 2 is -NHCy or -NHCOCy, wherein R 2 is substituted by p R 6 ;
- R 4 is hydrogen or halogen, -OR 7 , -N(R 7 ) 2 , -S(O) 2 R 7 , -S(O) 2 N(R 7 ) 2 , -C(O)R 7 , - C(O)OR 7 , -C(O)N(R 7 ) 2 , -C(O)N(R 7 )OR 7 , -OC(O)R 7 , -OC(O)N(R 7 ) 2 , can be replaced by q R 8 ;
- R 4 can also be a 4 to 7-membered heterocyclic ring, and can be substituted by 0-3 R 4a ;
- R 4a is hydrogen, halogen, C1-C6 alkyl, -(CH 2 )rOR 9 , -(CH 2 )rC(O)OR 9 , -(CH 2 )rOC(O)R 9 , -(CH 2 ) rNR 9 C(O)R 10 , -(CH 2 )rNR 9 C(O)OR 10 , -(CH 2 )r-3-14 membered heterocycle;
- R 5 is hydrogen or halogen
- L is a covalent bond, -NH-;
- L 1 is a covalent bond, -N(R 7 )-, -C(O)N(R 7 )-, -S(O) 2 NR 7 -, -C(O)O-, -S(O) 2- ;
- Cy is phenyl, 3-7 membered saturated or unsaturated monocyclic carbocyclic ring or heteroaryl, 6-14 membered bicyclic carbocyclic ring, with 1 to 3 unique A 3-7 membered saturated or unsaturated monocyclic heterocyclic ring independently selected from nitrogen, oxygen and sulfur heteroatoms, a 6-12 membered saturated or unsaturated monocyclic heterocyclic ring with 1-3 independent heteroatoms selected from nitrogen, oxygen and sulfur. Saturated bicyclic heterocycle;
- Cy is selected from but not limited to the following groups:
- R 3 , R 6 , R 7 , and R 8 are each independently hydrogen, halogen, hydroxyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkoxy, -OR 7 , -NR 7 , -( CH 2 ) n N(R 7 )-S(O) 2 NR 7 , -S(O) 2 N(R 7 ) 2 , -C(O)OR 7 , -C(O)N(R 7 ) 2 , -OC(O)R 7 , -OC(O)N(R 7 ) 2 , 3-12 membered saturated or aromatic heterocyclic ring with 1-3 independent heteroatoms selected from nitrogen, oxygen and sulfur;
- R 9 and R 10 are independently selected from hydrogen, halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, and 4-8 membered heterocycle;
- compounds of formula (I) include but are not limited to the following structures:
- the present invention provides a method for preparing triazolopyridine derivatives of formula (I).
- the preparation method is as shown in Synthetic Route 1 or Synthetic Route 2:
- R 1 , R 2 , R 3 , R 4 , A, L, L 1 , X 1 and Y 1 are as defined in claim 1;
- P 2 is halogen, -B(OH) 2 ;
- step 1 of synthetic route 1 the compound of formula (II) and the compound of formula (III) are reacted in an organic solvent at a temperature of -78°C to 200°C, and if necessary, in the presence of an alkali or a palladium catalyst to obtain a compound of formula (IV), organic
- the solvent is a protic solvent or an aprotic solvent.
- the aprotic solvent is selected from but not limited to tetrahydrofuran, dioxychlorocyclohexane, ethyl acetate, dichloromethane, chloroform, ethylene glycol dimethyl ether, and N,N-dimethylformamide.
- Bases include inorganic bases or organic bases, organic bases such as triethylamine, diisopropylamine, lithium diisopropylamide, and lithium bistrimethylsilylamide; inorganic bases are selected from, but are not limited to, sodium hydroxide, potassium hydroxide, and lithium hydroxide. , potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate.
- step 2 the compound of formula (IV) and the compound of R 2 -P 2 are reacted in an organic solvent using suzuki or Buchwald-Hartwig in the presence of a palladium catalyst to obtain the compound of formula (I).
- step 1 of synthetic route 2 the compound of formula (V) and the compound of formula (V-1) are in an organic solvent at a temperature of -78°C-200°C. If necessary, react in the presence of an alkali or a palladium catalyst to obtain the compound of formula (VI).
- the organic solvent is a protic solvent or an aprotic solvent.
- the aprotic solvent is selected from but not limited to tetrahydrofuran, dioxychlorocyclohexane, ethyl acetate, dichloromethane, Chloroform, glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone; protic solvent is selected from but not limited to water, ethanol , n-butanol, isobutanol, isopropyl alcohol, ethylene glycol, ethylene glycol monomethyl ether.
- Bases include inorganic bases or organic bases, organic bases such as triethylamine, diisopropylamine, lithium diisopropylamide, and lithium bistrimethylsilylamide; inorganic bases are selected from, but are not limited to, sodium hydroxide, potassium hydroxide, and lithium hydroxide. , potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate.
- step 2 the compound of formula (VI) is subjected to alkaline hydrolysis to obtain the corresponding acid, which is then subjected to a conventional condensation reaction with R 1 NH 2 to obtain the compound of formula (VII); in step 3, the compound of formula (VII) and R 2 -P 2 The compound is subjected to suzuki or Buchwald-Hartwig reaction in an organic solvent in the presence of a palladium catalyst to obtain the compound of formula (I).
- alkyl refers to a straight-chain or branched alkyl group having 1 to 12 carbon atoms in the chain.
- alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl , butyl, isobutyl, sec-butyl, tert-butyl (t-Bu), pentyl, isopentyl, tert-amyl, hexyl, isohexyl, and according to the teachings provided by those of ordinary skill in the art and the text It is considered to be equivalent to any of the groups in the above examples.
- alkoxy refers to an alkyl group as defined above bonded to an oxygen atom.
- the alkoxy group is attached to the parent structure via an oxygen atom.
- alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, and the like. C2-10 alkenyl is preferred, C2-6 alkenyl is preferred, C2-4 alkenyl is most preferred, and vinyl is the most preferred.
- the alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkoxy, alkylamino, halogen, hydroxyl, cycloalkyl base, heterocycloalkyl, heterocycloalkoxy.
- amino refers to a -NH2 group or a mono- or dialkylamino group.
- cycloalkyl refers to saturated and partially saturated, monocyclic, fused polycyclic, bridged polycyclic, or exploded polycyclic carbocyclic rings having from 3 to 12 ring atoms per carbon atom.
- Illustrative examples of cycloalkyl groups include the following entities in the form of appropriate bonding moieties:
- heteroaryl refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (a ring structure having a carbon atom selected from the group consisting of carbon atoms and up to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur) ring atoms), each heterocycle has 3 to 12 ring atoms.
- suitable bonding moieties include the following entities in the form of appropriate bonding moieties:
- aryl refers to a C5-C20-containing monocyclic, fused bicyclic, or fused polycyclic aromatic ring, which does not contain heteroatoms such as nitrogen, oxygen, sulfur, etc.
- Common aromatic groups include, but Without limitation, residues derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, etc.
- heterocycle refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that includes 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon.
- ring atoms one or more of which are selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon.
- it contains 3 to 12 ring atoms, of which 1 to 4 heteroatoms, more preferred heterocycloalkyl rings contain 3 to 10 ring atoms, more preferred heterocycloalkyl rings contain 5 to 6 ring atoms.
- Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, piperidinyl, morpholinyltetrahydrofuranyl, and the like.
- Polycyclic heterocycloalkyl groups include spiro, fused and bridged heterocycloalkyl groups.
- the heterocycle may be substituted or unsubstituted.
- the substituent is preferably one or more of the following groups, which are independently selected from alkyl, haloalkyl, alkoxy, alkylamino, halogen, hydroxyl , amino, oxo, alkylamino, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, hydroxyalkyl, carboxyl or carboxylate group.
- halogen means chlorine, fluorine, bromine or iodine.
- halo stands for chloro, fluoro, bromo or iodo.
- haloalkyl refers to an alkyl group as defined above, which is substituted by one or more halogen atoms.
- the present invention provides methods for preparing compounds of formula (I), isomers, and deuterated derivatives. See Examples for details.
- the compound of the present invention if it contains a basic group, it can form a salt with an acid, and acyclic nucleoside derivatives and isomers can be prepared using methods well known to those skilled in the art. Salt.
- Common acid salts include organic acid salts, inorganic acid salts, etc.
- organic acid salts include citrate, fumarate, oxalate, malate, lactate, sulfonate (such as camphor sulfonate, p-toluene sulfonate, methanesulfonic acid salt, etc.); inorganic acid salts include hydrohalides, sulfates, phosphates, nitrates, etc.
- lower alkyl sulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid, etc.
- methanesulfonate triflate
- arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid, etc.
- It can form p-toluenesulfonate and benzenesulfonate
- organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid
- it can form corresponding salts with amino acids.
- glutamic acid or aspartic acid can form glutamate or aspartate.
- Corresponding salts can also be formed with inorganic acids, such as hydrohalic acid (such as hydrofluoric acid, hydrobromic acid, hydriodic acid, hydrochloric acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid.
- hydrohalic acid such as hydrofluoric acid, hydrobromic acid, hydriodic acid, hydrochloric acid
- nitric acid carbonic acid, sulfuric acid or phosphoric acid.
- the present invention provides medicines using the compound, isomer, solvate, deuterated derivative of the formula (I) of the present invention or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
- the above-mentioned medicines may also contain one or more pharmaceutically acceptable carriers, including conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, and absorption promoters in the pharmaceutical field.
- Agents, surfactants, adsorption carriers, lubricants, etc., and fragrance can be added if necessary. agents, sweeteners, etc.
- the medicine of the present invention can be made into various forms such as tablets, powders, granules, capsules, oral liquids, and injections.
- the medicines in each of the above dosage forms can be prepared according to conventional methods in the pharmaceutical field.
- the present invention provides compounds of formula (I), isomers, solvates, deuterated derivatives or pharmaceutically acceptable salts thereof, providing regulation by inhibiting Tyk-2-mediated signal transduction.
- a preferred embodiment is a drug for the treatment of inflammatory and autoimmune diseases.
- inflammatory and autoimmune diseases or conditions include systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus, Crohn's disease, ulcerative colitis, type 1 diabetes, psoriasis, etc.
- SLE systemic lupus erythematosus
- lupus nephritis lupus nephritis
- cutaneous lupus cutaneous lupus
- Crohn's disease ulcerative colitis
- type 1 diabetes psoriasis
- psoriasis etc.
- Use of the drug in rheumatoid arthritis, systemic juvenile idiopathic arthritis, ankylosing spondylitis or multiple sclerosis.
- Step 1 Preparation of 6-chloro-5-fluoro-N-methyl-4-((4-(pyrrolidine-1-carbonyl)phenyl)amino)nicotinamide
- Step 2 Preparation of 6-(cyclopropylcarboxamide)-5-fluoro-N-methyl-4-((4-(pyrrolidine-1-acyl)phenyl)amino)nicotinamide
- step 1 Under nitrogen protection, add 0.9g of the product obtained in step 1 into a 10mL three-necked flask of 1,4-dioxane to dissolve, add 0.23g of cyclopropylformamide and 2.0g of cesium carbonate, and depressurize the system to eliminate air charge. Add nitrogen back and forth 3 times, then add 0.32g ( 0.553mmol ) Cool the reaction solution to room temperature, filter the insoluble matter in the system, add an appropriate amount of water to dilute, and then extract three times with ethyl acetate, dry over anhydrous Na 2 SO 4 , filter, and concentrate under reduced pressure, and the residue will be obtained by column chromatography. Material 0.78g.
- Example 36 4-((3-(5-n-butyl-1,2,4-oxadiazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamide )-N-methylnicotinamide
- Example 40 6-(cyclopropanecarboxamido)-4-((3-(5-(ethoxymethyl)-1,2,4-oxadiazol-3-yl)-2-methoxy phenyl)amino)-N-methylnicotinamide
- Example 46 6-(cyclopropanecarboxamide)-4-((3-(5-(ethoxymethyl)-1,2,4-oxadiazol-3-yl)-2-(methoxy Base-d 3 )phenyl)amino)-N-methylnicotinamide
- Example 48 4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-6-((5-(2-hydroxypropan-2-yl)pyridine- 2-yl)amino)-N-(methyl-d 3 )nicotinamide
- Example 50 6-(cyclopropanecarboxamido)-4-((3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine-2 -yl)amino)-N-(methyl-d 3 )nicotinamide
- Example 54 4-((2-methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)amino)-N-methyl-6-( (6-methylpyridin-2-yl)amino)nicotinamide
- Example 60 6-((1R,2R)-2-fluorocyclopropane-1-carboxamide)-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl) Amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
- Example 65 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)amino )-N-methylpyridazine-3-carboxamide
- Example 70 6-(cyclopropanecarboxamido)-4-((2-(methoxy-d 3 )-3-(5-methyl-1,2,4-oxadiazol-3-yl) )phenyl)amino)-N-methylpyridazine-3-carboxamide
- Example 74 4-((3-(5-n-butyl-1,2,4-oxadiazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamide base)-N-(methyl-d 3 )pyridazine-3-carboxamide
- Example 78 6-(cyclopropanecarboxamide)-4-((2-(methoxy-d 3 )-3-(5-(2-methoxyethyl)-1,2,4-oxa) Diazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide
- Example 80 6-(cyclopropanecarboxamide)-4-((3-(5-(2-fluoroethyl)-1,2,4-oxadiazol-3-yl)-2-(methoxy Base-d 3 )phenyl)amino)-N-methylpyridazine-3-carboxamide
- Example 82 4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-(methyl-d 3 )-6-(1-methylcyclo Propane-1-carboxamido)pyridazine-3-carboxamide
- Example 99 4-((3-(1-allyl-1H-1,2,4-triazol-3-yl)-2-(methoxy-d 3 )phenyl)amino)-6 -(cyclopropanecarboxamide)-N-(methyl-d 3 )pyridazine-3-carboxamide
- Example 100 6-(cyclopropanecarboxamido)-4-(5-fluoro-2-(methoxy-d 3 )-3-(1-(prop-2-yn-1-yl)-1H -1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
- Example 103 6-(cyclopropanecarboxamido)-4-(2-(methoxy-d 3 )-3-(1-(oxetan-3-ylmethyl)-1H-1 ,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
- Example 104 6-(cyclopropanecarboxamido)-4-(2-(methoxy-d 3 )-3-(1-(3-methyloxetan-3-yl)-1H -1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
- Example 105 6-(cyclopropanelamido)-4-(3-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-2-(methoxy Base-d 3 )phenyl) amino)-N-(methyl-d 3 ) pyridazine-3-carboxamide
- Example 106 6-(cyclopropaneamide)-4-(2-(methoxy-d3)-5-methyl-3-(1-methyl-1H-1,2,4-triazole- 3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
- Example 110 6-(cyclopropanecarboxamido)-4-((3-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-2- (base)amino)-N-methylpyridazine-3-carboxamide
- Step 1 6-Chloro-N-methoxy-4-((2-methoxy-3-(pyrazin-2-yl)phenyl)amino)-N-methylnicotinamide
- Step 2 1-(6-chloro-4-((2-methoxy-3-(pyrazin-2-yl)phenyl)amino)pyridin-3-yl)ethane-1-one
- Example 1208 6-((4-((3-(5-(2-hydroxyprop-2-yl)pyrazin-2-yl)-2-methoxyphenyl)amino)-5-(propanyl) Acyl-3,3,3-d 3 )pyridin-2-yl)amino)pyridinenitrile
- step 1 Put 6.1g of the intermediate in step 1 into the mixed solution of MeOH (15mL)/THF (10mL), stir to completely dissolve; then add Pa/C (0.5g), and then add 15.8g of ammonium formate dropwise, the reaction is Bubbles were generated and the system gradually turned purple-black. Continue stirring at room temperature for 3 hours (TLC detection). After the reaction is completed, the system is filtered through diatomaceous earth, and the filtrate is concentrated under reduced pressure. The reaction solvent is evaporated, water (150 mL) is added, and the mixture is extracted with dichloromethane (3 ⁇ 50 mL).
- Step 3 Preparation of ethyl 4-(5-(azetidin-1-yl)pyridin-2-yl)-3-thiobutyrate
- step 2 Dissolve 5.1g of the intermediate in step 2 in dichloromethane, put it into a 100mL single-necked flask, then slowly add 4.9g of the raw material ethoxycarbonyl isothiocyanate dropwise, and stir for 3 hours at room temperature (20°C) (TLC detection) . After the reaction is completed, the system is directly concentrated under reduced pressure to obtain a yellow solid. No purification is required and it is directly put into the next step.
- Step 4 6-(1-azetidinyl)-[1,2,4]triazole[1,5- ⁇ ]pyridine-2-amino
- the system was concentrated, spun dry, added water (150 mL), stirred for 30 min, extracted with dichloromethane (3 ⁇ 50 mL), combined the organic phases, and then used saturated sodium chloride aqueous solution (3 ⁇ 50 mL). Wash, dry over anhydrous Na 2 SO 4 , suction filter, and the filtrate is concentrated and spin-dried to obtain a milky white solid.
- Step 5 4-((6-(1-azetidinyl)-[1,2,4]triazole[1,5- ⁇ ]pyridin-2-yl)amino)-6-chloro-N -Deuterated methyl nicotinamide
- Step 6 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-(6-(azetidin-1-ylpyrrolidin-1-yl)-[1,2,4 ]Triazolyl[1,5-a]pyridin-2-yl)amino)nicotinamide
- Example 136 6-((6-cyanopyridin-2-yl)amino)-4-((6-(3-fluoroazetidin-1-yl)-[1,2,4]tri Azolyl[1,5-a]pyridin-2-yl)amino)-N-(methyl-d 3 )nicotinamide
- Example 157 4-((6-(hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl )Amino)-N-methyl-6-((S)-spiro[2.2]pentane-1-carboxamide)pyridazine-3-carboxamide
- Example 162 4-((6-(1-acetylazetidin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino )-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide
- Example 188 4-((6-(2-azaspiro[3.3]heptan-2-yl)-[1,2,4]triazole[1,5-a]pyridin-2-yl]amino )-6-(cyclopropanecarboxamido)-N-(methyl-d 3 )nicotinamide
- Example 190 4-((6-(7-oxa-2-azaspiro[3.5]non-2-yl)-[1,2,4]triazolo[1,5-a]pyridine- 2-yl)amino)-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide
- Example 202 6-(cyclopropanecarboxamido)-4-((8-fluoro-6-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a] Pyridin-2-yl)amino)-(methyl-d 3 )pyridazine-3-carboxamide
- Example 204 4-((6-(5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl) Amino)-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide
- Example 206 4-((6-(5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl) Amino)-6-(cyclopropanecarboxamide)-N-(methyl-d 3 )pyridazine-3-carboxamide
- Example 207 4-((6-(6-azaspiro[3.4]octane-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl) Amino)-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide
- Example 208 4-((6-(2-azaspiro[4.4]nonan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino )-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide
- the compound inhibits kinase (TYK2JH2).
- This experiment uses capillary electrophoresis to detect the phosphorylation conversion rate of the substrate peptide to determine the IC50 value of the test compound for inhibiting a kinase (TYK2JH2).
- This experiment used BMS-986165 as the control compound.
- Compound Dilution Use DMSO to dilute the control compound BMS-986165 and the test compound.
- Use the TECAN EVO2000 system to dilute the compound 3-fold to 11 concentrations, and use the Echo550 to transfer 20nL of the compound to a 384-well plate.
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Abstract
本发明公开了一类酰胺取代的杂环化合物,异构体、溶剂合物、氘代衍生物或该化合物的药学上可接受的盐类,R1、R2、R3、R4、Ⓐ、 L、L1、X、X1、Y1的定义详见说明书。此外,本发明还公开了以该化合物、异构体、溶剂合物、氘代衍生物及其盐类为活性成分的药物,及其在制备与Tyk2介导的信号转导通路有关的疾病如自身免疫性疾病、癌症方面的用途。(I)
Description
本发明涉及一类酰胺取代的杂环化合物、异构体、溶剂合物、氘代衍生物或该化合物的药学上可接受的盐类和以该化合物或其盐类为活性成涉分的药物,及其在制备与Tyk2介导的信号转导通路有关的疾病如自身免疫性疾病、癌症方面的用途。
自身免疫疾病是一组复杂的慢性疾病,因为多种遗传、环境因素的复杂组合导致免疫系统对自身组织的识别能力或应答调控能力下降,造成对自身组织的免疫攻击。早期药物只是控制症状,如RA使用止痛药、一型糖尿病注射胰岛素。因为这类疾病机理非常复杂,所以即使到现在也只能粗线条控制。但机理再复杂也有主次因素,毕竟这些免疫反应还需要具体的生物分子来操刀执行。TNF是最先确证的细胞因子靶点,针对这个靶点的药物是现在销售最大的一个药物家族。后来上市的IL17、IL23抗体也非常成功。但是这些抗体药物需要注射,所以制药界早就开始寻找这些通路上的小分子靶点。JAK家族激酶是这些细胞因子介导免疫物质表达的关键信号传递蛋白,这些细胞因子与受体结合后会激活JAK,JAK再磷酸化下游STAT家族蛋白诱导基因表达。辉瑞最早上市了JAK1/3抑制剂Tofacitinib(商品名Xeljanz),这是第一个肿瘤以外的激酶抑制剂药物,对当时激酶抑制剂开发起了很大的激励作用,说明激酶抑制剂毒性可以控制到慢性病患者可以容忍的程度。后来Incyte上市了用于血小板自身免疫疾病的JAK2抑制剂ruxolitinib(商品名Jakafi),此外礼来/Incyte还上市了JAK1/JAK2抑制剂baricitinib(商品名Olumiant)。新基还上市了PDE4抑制剂Otezla,这个药物抑制TNF合成,去年因为销售不理想诱发新基股票跳水。另一个令无数厂家欲哭无泪的靶点p38虽然非常吸引人,但最后成为制药界最毁人不倦的靶点之一。
两面神激酶是一组酪氨酸蛋白激酶(PTK,protein tyrosine kinase),该类蛋白质通过辅助细胞因子受体参与多种细胞因子信号转导,迄今已发现有四个成员即JAK1、JAK2、JAK3和TYK2。TYK2是JAK家族的重要成员。STAT是其转导细胞因子信号活化的下游元件;JAK/STAT是其经典信号转导路径。哺乳动物细胞中该途径包括JAK家族中的四个成员,七个STATs(STAT1-4,STAT5a,STAT5b及STAT6)。当细胞因子与相应受体胞外区结合,其受体的胞内部分发生二聚体化,TYK2与二聚体化的受体的box功能区结合,自主或转磷酸化并使受体链磷酸化,从而为STATs的接入提供锚定位点;TYK2随后使募集的STATs磷酸化,形成同源或异源二聚体,随后转入细胞核诱导目标基因的转录。
共有p40亚单位的异源二聚体细胞因子白细胞介素IL-12和IL-23是通过活化的抗原呈递细胞产生且在Th1和Th17细胞的分化和增殖中至关重要,Th1和Th17细胞是两个在自体免疫中起关键作用的效应子T细胞谱系。IL-23是有p40亚单位与独特的p19亚单位一起构成。IL-23通过由IL-23R和IL-12Rβ1构成的异源二聚受体起作用,它是产生例如IL-17A、IL-17F、IL-6和TNF-α等促炎细胞因子的TH17细胞的存活和扩增所必需的。这些细胞因子在调节包括类风湿性关节炎、多发性硬化、炎性肠病和狼疮的诸名自体免疫性疾病的病理学中至关重要。IL-12除与1L-23共同含有p40亚单位外,也含有p35亚单位,并通过由IL-12Rβ1和1L-12Rβ2构成的异源二聚受体起作用。IL-12是Th1细胞发育和IFNγ分泌所必需的,IFNγ是通过刺激MHC表达、B细胞类别转换成IgG亚类以及活化巨噬细胞在免疫性中起重要作用的细胞因子。
含p40细胞因子与自身免疫疾病密切相关,在多发性硬化、类风湿性关节炎、炎性肠病、狼疮和牛皮廯等模型中,缺乏p40、p19和IL-23R的小鼠免受自身免疫疾病困扰。
在人类疾病中,检测发现p40和p19在牛皮癬病灶中的高度表达,在多发性硬化患者的脑中的活跃病灶和活跃克罗恩病(Crohn's disease)患者的肠粘膜中鉴别出Th17细胞。与非活跃SLE患者相比,在活跃SLE与患者中p19、p40和p35的mRNA水平明显提高,且来自狼疮患者的T细胞具有优势Th1表型。
此外,全基因组关联研究已鉴别由许多与慢性炎症和自体免疫性疾病相关的、编码在IL-23和IL-12途径中发挥功能的因子的基因座。这些基因包括IL23A、IL12A、IL12B、IL12RB2、IL12RB2、IL23R、JAK2、TYK2、STAT3和STAT4。
实际上,抑制IL-12与IL-23二者的抗p40治疗以及IL-23特异性抗p19疗法,可有效地治疗包括牛皮廯、克罗恩病和牛皮廯性关节炎在内的自身免疫疾病。因此,抑制IL-12和IL-23作用的药物在人类自体免疫性病症中具有可预期治疗作用。
包括IFNα成员以及IFNβ、IFNε、IFNк和IFNω的I型干扰素(IFN)群组通过异源二聚物IFNα/β受体(IFNAR)起作用。I型IFN对先天性和适应性免疫系统二者具有多种效应,包括活化细胞和体液免疫应答二者以及增强自体抗原的表达和释放。
在系统性红斑狼疮(SLE)的患者中,已在大多数患者中表明周边血单核细胞和受影响器官中,血清干扰素(IFN)-α(I型干扰素)的含量增加或I型IFN调控基因的表达增加,且多种研究已显示,血清IFNα含量与疾病活动性和严重程度二者都相关,患有恶性或病毒性疾病的患者,使用IFNα可诱导狼疮样综合征,观察结果证明IFNα在狼疮病理学中的直接作用。除狼疮以外,研究表明,I型干扰素介导途径的异常活化也在其他自体免疫性疾病(例如综合征和硬皮病)的病理学中至关重要。因此,可以预期,抑制I型干扰素作用的药物在人类自身免疫性病症中具有治疗作用。
酪氨酸激酶2(Tyk2)是非受体酪氨酸激酶的Janus激酶的(JAK)家族的成员,且已在小鼠和人类二者中显示在IL-12、IL-23和I型干扰素受体的调控信号转导级联下游中至关重要。Tyk2也是JAK家族一员,介导IL23、IL12的信号传导,增强Th17免疫细胞功能。Tyk2介导转录因子的STAT家族成员的受体诱导的磷酸化,这是导致STAT蛋白二聚和STAT依赖性促炎性基因的转录的基本信号。Tyk2缺失小鼠抵抗结肠炎、牛皮廯和多发性硬化的实验模型证明Tyk2介导的信号传导在自身免疫和相关病症中的重要性。
由于这些疾病可通过调节细胞因子和/或干扰素的治疗而受益,因此能够调节细胞因子和/或干扰素,例如IL-12、IL-23和/或IFNα的新化合物以及使用这些化合物的方法的患者具有重要的治疗价值。
发明内容
本发明的第一个目的是提供式(Ⅰ)化合物,及其异构体、溶剂合物、氘代衍生物或其药学上可接受的盐类。
其中:
X1、Y1各自独立地为-CR5或-N;
为苯基;具有1至4个独立的选自氮、氧及硫之杂原子的5至6元单环杂芳基环;或具有2至4个独立的选自氮、氧及硫杂原子的7-12之双环杂芳基;
R1选自氢、C1-C3烷基、C3-C6环烷基、C1-C3烷基氨基,并可被卤素、氘任意取代;
R2为-NHCy或-NHCOCy,其中R2经p个R6取代;
R4为氢、卤素,-OR7、-N(R7)2、-S(O)2R7、-S(O)2N(R7)2、-C(O)R7、-C(O)OR7、-C(O)N(R7)2、-C(O)N(R7)OR7、-OC(O)R7、-OC(O)N(R7)2,可以被q个R8取代;
R4也可以为4到7元杂环,并可被0-3个R4a取代;
R4a是氢、卤素、C1-C6烷基、-(CH2)rOR9、-(CH2)rC(O)OR9、-(CH2)rOC(O)R9、-(CH2)rNR9C(O)R10、-(CH2)rNR9C(O)OR10、-(CH2)r-3-14元杂环;
R5为氢、卤素;
L为共价键、-NH-;
L1为共价键、-N(R7)-、-C(O)N(R7)-、-S(O)2NR7-、-C(O)O-、-S(O)2-;
Cy为苯基,3-7元饱和或不饱和单环碳环或杂芳基,6-14元双环碳环,具有1至3个独
立地选自氮、氧及硫之杂原子的3-7元饱和或不饱和单环杂环,具有1-3个独立的选自氮、氧及硫之杂原子的6-12元饱和或不饱和双环杂环;
Cy选自但不限于下列基团:
R3、R6、R7、R8各自独立地为氢、卤素、羟基、C1-C6烷氧基、C3-C12环烷氧基、-OR7、-NR7、-(CH2)nN(R7)-S(O)2NR7、-S(O)2N(R7)2、-C(O)OR7、-C(O)N(R7)2、-OC(O)R7、-OC(O)N(R7)2、具有1-3个独立的选自氮、氧及硫之杂原子的3-12元饱和或芳杂环;
R9、R10独立地选自氢、卤素、C1-C3烷基、C3-C6环烷基、4-8元杂环;
p、q、r为0-3;
优选地,式(Ⅰ)结构的化合物中,下式:
选自但不限于下列结构:
更具体地,式(Ⅰ)结构的化合物包括但不限于下列结构:
6-(环丙甲酰胺)-5-氟-N-甲基-4-((4-(吡咯烷-1-酰基)苯基)胺基)烟酰胺;
6-(环丙甲酰胺)-5-氟-N-甲基-4-((4-(哌啶-1-酰基)苯基)胺基)烟酰胺;
6-(环丙甲酰胺)-5-氟-4-((3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)-N-甲基烟酰胺;
6-(环丙烷甲酰氨基)-5-氟-4-((2-甲氧基-3-(1-甲基-1H-吡唑-4-基)苯基)氨基)-N-甲基烟酰胺;
6-(环丙甲酰胺)-5-氟-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)-N-甲基烟酰胺;
6-(环丙烷甲酰氨基)-5-氟-N-甲基-4-((2-(N-甲基甲磺酰氨基)苯基)氨基)烟酰
胺;
6-(环丙甲酰胺)-N-甲基-4-((4-(吡咯烷-1-酰基)苯基)胺基)烟酰胺;
6-(环丙甲酰胺)-N-甲基-4-((4-(哌啶-1-酰基)苯基)胺基)烟酰胺;
6-(环丙烷甲酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-吡唑-4-基)苯基)氨基)-N-甲基烟酰胺;
6-(环丙烷甲酰氨基)-4-((2-甲氧基-3-(5-甲基-1,3,4-噁二唑-2-基)苯基)氨基)-N-甲基烟酰胺;
6-(环丙甲酰胺)-N-甲基-4-((4-(吗啉-4-酰基)苯基)胺基)烟酰胺;
6-(环丙烷甲酰胺)-4-((5-氟-3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺;
6-(环丙烷酰胺基)-4-(3-(5-氟嘧啶-2-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)烟酰胺;
6-(环丙烷酰胺基)-4-(3-(5-氟嘧啶-2-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基烟酰胺;
6-(环丙烷酰胺基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-甲基烟酰胺;
(S)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺;
(R)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺;
6-((6-氰基吡啶-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺;
6-((6-氟吡啶-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺;
6-((5-(2-羟基丙-2-基)吡啶-2-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺;
6-((6-氰基吡啶-2-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺;
6-(3-((2-((6-氰基吡啶-2-基)氨基)-5-((甲基-d3)氨基甲酰基)吡啶-4-基)氨基)-2-甲氧基苯基)-N,N-二甲基吡啶酰胺;
6-((6-氰基吡啶-2-基)氨基)-4-((2-甲氧基-3-(吡啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺;
6-((6-氰基吡啶-2-基)氨基)-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺;
6-((5-(2-羟基丙-2-基)吡啶-2-基)氨基)-4-((2-甲氧基-3-(吡啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺;
6-((5-(2-羟基丙-2-基)吡啶-2-基)氨基)-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-N-(甲基-d3)
烟酰胺;
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-(甲基-d3)烟酰胺;
6-(环丙烷甲酰胺基)-4-((2-(甲氧基-d3)-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基烟酰胺;
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基烟酰胺;
6-((6-氰基吡啶-2-基)氨基)-4-((2-甲氧基-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-(甲基-d3)烟酰胺;
6-(5-(2-羟基丙烷-2-基)吡啶-2-基)氨基)-4-(2-甲氧基-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-(甲基-d3)烟酰胺;
6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺;
6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基烟酰胺;
6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基烟酰胺;
6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺;
4-((3-(5-正丁基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺)-N-甲基烟酰胺;
4-((3-(5-正丁基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺)-N-(甲基-d3)烟酰胺;
6-(环丙烷甲酰胺)-4-((3-(5-(环丙基甲基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺;
6-(环丙烷甲酰胺)-4-((3-(5-(甲氧基乙基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基烟酰胺;
6-(环丙烷甲酰胺基)-4-((3-(5-(乙氧基甲基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基烟酰胺;
6-(环丙烷甲酰胺)-4-((3-(5-(2-氟乙基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基烟酰胺;
6--(环丙烷甲酰胺)-4-((2-甲氧基-3-(5-(2-甲基乙基)-1,2,4-噁二唑-3-基)苯基)
氨基)-N-(甲基-d3)烟酰胺;
6-(环丙烷甲酰胺)-4-((3-(5-(乙氧基甲基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺;
6-(环丙烷甲酰胺)-4-((3-(5-(2-氟乙基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺;
6-(环丙烷甲酰胺)-4-((2-(甲氧基-d3)-3-(5-(2-甲氧基乙基)-1,2,4-恶二唑-3-基)苯基)氨基)-N-甲基烟酰胺;
6-(环丙烷甲酰胺)-4-((3-(5-(乙氧基甲基)-1,2,4-噁二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基烟酰胺;
6-(环丙烷甲酰胺)-4-((3-(5-(2-氟乙基)-1,2,4-噁二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基烟酰胺;
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((5-(2-羟基丙烷-2-基)吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺;
6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-甲基烟酰胺;
6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺;
6-(环丙烷甲酰胺基)-4-((4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺;
6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(嘧啶-2-基)吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺;
6-(环丙烷甲酰胺基)-N-甲基-4-((2-氧代-2H-[1,2’-联吡啶]-3-基)氨基)烟酰胺;
4-((2-甲氧基-3-(5-甲基-1,3,4-噁二唑-2-基)苯基)氨基)-N-甲基-6-((6-甲基吡啶-2-基)胺基)烟酰胺;
6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-甲基烟酰胺;
6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基)氨基)-N-甲基烟酰胺;
6-((6-氟-5-(2-羟基丙烷-2-基)吡啶-2-基)氨基)-4-((4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-酰基)氨基)-N-(甲基-d3)烟酰胺;
6-(((6-氰基吡啶-2-基)氨基)-4-((4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基)氨基)-N-甲基烟酰胺;
6-(((6-氰基吡啶-2-基)氨基)-4-((4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺;
6-((1R,2R)-2-氟环丙烷-1-甲酰胺)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-((2-(甲氧基-d3)-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
(S)-4-((2-甲氧基-3-(5-甲基-1,2,4-恶二唑-3-基)苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((2-甲氧基-3-(5-甲基-1,2,4-恶二唑-3-基)苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-((2-(甲氧基-d3)-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
(R)-4-((3-(5-环丙基-1,2,4-恶二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(S)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-((2-(甲氧基-d3)-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(2-甲基乙基)-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
4-((3-(5-正丁基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-甲基哒嗪-3-甲酰胺;
4-((3-(5-正丁基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-((3-(5-(环丙基甲基)-1,2,4-恶噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-((3-(5-(乙氧基甲基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-((3-(5-(2-氟乙基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N个-甲基哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺)-4-((2-(甲氧基-d3)-3-(5-(2-甲氧基乙基)-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺)-4-((3-(5-(乙氧基甲基)-1,2,4-恶二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺)-4-((3-(5-(2-氟乙基)-1,2,4-噁二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N个-甲基哒嗪-3-甲酰胺;
6-(环丁烷甲酰胺基)-4-(3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(1-甲基环丙烷-1-甲酰胺基)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-(3-(5-氟嘧啶-2-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-(3-(5-氟嘧啶-2-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
(S)-6-(2,2-二氟环丙烷-1-甲酰胺)-4-(3-(5-氟嘧啶-2-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
(S)-6-(2,2-二氟环丙烷-1-甲酰胺)-4-(3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-((1S,2S)-2-氟环丙烷-1-甲酰胺基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-((6-氰基吡啶-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-(环丙烷酰胺基)-4-(3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-(环丙烷酰胺基)-4-(3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-(3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-(环丙烷酰胺基)-4-(3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-(甲氧基-d3)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
6-(环丙烷酰胺基)-4-(2-(甲氧基-d3)-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
6-(环丙甲酰胺基)-4-(5-氟-2-(甲氧基-d3)-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-(2-(甲氧基-d3)-3-(1-(3-甲基氧杂环丁烷-3-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-(2-(甲氧基-d3)-3-(1-(氧杂环丁烷-3-基甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
6-(环丙烷酰胺基)-4-(3-(1-(环丙基甲基)-1H-1,2,4-三唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
6-(环丙烷酰胺基)-4-(2-(甲氧基-d3)-5-甲基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;
4-((3-(1-烯丙基-1H-1,2,4-三唑-3-基)-2-(甲氧基-d3)苯基)氨基)-6-(环丙烷甲酰胺)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-(5-氟-2-(甲氧基-d3)-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
(R)-4-((5-氟-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(S)-4-((5-氟-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-(2-(甲氧基-d3)-3-(1-(氧杂环丁烷-3-基甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-(2-(甲氧基-d3)-3-(1-(3-甲基氧杂环丁烷-3-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-(环丙烷酰胺基)-4-(3-(1-(环丙基甲基)-1H-1,2,4-三唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-(环丙烷酰胺基)-4-(2-(甲氧基-d3)-5-甲基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-((6-氰基吡啶-2-基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)N-(甲基-d3)哒嗪-3-甲酰胺;
4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-甲基-6-(环丙烷甲酰胺基)哒嗪-3-甲酰胺;
4-((2-氧代-2H-[1,2'-联吡啶]-3-基)氨基)N-甲基-6-(环丙烷甲酰胺基)哒嗪-3-羧酰胺;
6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺;
N-(5-乙酰基-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)吡啶-2-基)环丙烷甲酰胺;
N-(4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)环丙烷甲酰胺;
6-((5-乙酰基-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)吡啶-2-基)氨基)吡啶甲腈
6-((4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)氨基)吡啶甲腈;
(1R,2R)-2-氟-N-(4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)环丙烷-1-甲酰胺;
(S)-N-(4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)螺[2.2]戊烷-1-甲酰胺;
(R)-N-(4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)螺[2.2]戊烷-1-甲酰胺;
1-(6-((5-(2-羟基丙烷-2-基)吡啶-2-基)氨基)-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)吡啶-3-基)乙烷-1-酮;
1-(6-((5-(二乙基磷酰基)吡啶-2-基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)吡啶-3-基)丙烷-1-酮;
N-(4-(2-甲氧基-3-(吡啶-2-基)苯基)氨基)-5-丙酰吡啶-2-基)环丙烷甲酰胺;
N-(5-乙酰基-4-((2-甲氧基-3-(吡啶-2-基)苯基)氨基)吡啶-2-基)环丙烷甲酰胺;
6-((4-((3-(5-(2-羟基丙烷-2-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-5-(丙酰基-3,3,3-d3)吡啶-2-基)氨基)吡啶腈;
6-((4-((3-(5-(2-羟基丙烷-2-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-5-丙酰吡啶-2-基)氨基)吡啶腈;
2-(3-((2-((6-氰基吡啶-2-基)氨基)-5-(丙酰3,3,3-d3基-)吡啶-4-基)氨基)-2-甲氧基苯基)-N,N-二甲基嘧啶-5-甲酰胺;
2-(3-((2-((6-氰基吡啶-2-基)氨基)-5-丙酰基吡啶-4-基)氨基)-2-甲氧基苯基)-N,N-二甲基嘧啶-5-甲酰胺;
6-((4-((3-(6-(2-羟基丙烷-2-基)吡啶-2-基)-2-甲氧基苯基)氨基)-5-(丙酰基3,3,3-d3-)吡啶-2-基)氨基]吡啶腈;
6-((4-((3-(5-(2-羟基丙-2-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-5-丙酰基吡啶-2-基)氨基]吡啶腈;
6-((4-((3-(5-(2-羟基丙-2-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-5-(丙酰基-3,3,3-d3)吡啶-2-基)氨基)吡啶腈;
5-(3-((2-((6-氰基吡啶-2-基)氨基)-5-丙酰基吡啶-4-基)氨基)-2-甲氧基苯基)-N,N-二甲基吡嗪-2-羧酰胺;
5-(3-((2-((6-氰基吡啶-2-基)氨基)-5-(丙酰3,3,3-d3基-)吡啶-4-基)氨基)-2-甲氧基苯基)-N,N-二甲基吡嗪-2-甲酰胺;
N-(4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)环丙烷甲酰胺;
N-(4-((3-甲氧基-4-(嘧啶-2-基)吡啶-2-基)氨基)-5-丙酰基吡啶-2-基)环丙烷甲酰胺;
N-(4-((3-甲氧基-4-(嘧啶-2-基)吡啶-2-基)氨基)-5-(丙酰基3,3,3-d3)吡啶-2-基)环丙烷基甲酰胺。
6-(环丙烷甲酰胺)-N-(甲基-d3)-4-(6-(氮杂环丁烷-1-基吡咯烷-1-基)-[1,2,4]三唑基[1,5-a]吡啶-2-基)氨基)烟酰胺;
(R)-4-((6-(氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
6-((6-氰基吡啶-2-基)氨基)-4-((6-(3-氟氮杂环丁烯-1-基)-[1,2,4]三唑基[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺;
(R)-4-((6-(氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(3,3-二氟氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(S)-4-((6-(3,3-二氟氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(3-氟氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(3-氟氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-N-(甲基-d3)-4-((6-((1-甲基氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]
吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-N-(甲基-d3)-4-((6-((1-甲基氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-N-(甲基-d3)-4-((6-((1-(甲基磺酰基)氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-((1-(乙基磺酰基)氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-N-甲基-4-((6-((1-(甲基磺酰基)氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(S)-4-((6-((1-乙酰氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(氮杂环丁烷-3-基氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(3-(二甲基氨基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(S)-4-((6-(3-(二甲基氨基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺;
(R)-4-((6-(3-甲氧基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺;
(R)-4-((6-(3-甲氧基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺;
(R)-4-((6-(3-羟基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(S)-4-((6-(3-羟基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(6-氮杂螺[3.4]辛-6-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(S)-4-((6-(6-氮杂螺[3.4]辛-6-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
4-((6-(六氢环戊[c]吡咯-2(1H)-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-((S)-螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-N-(甲基-d3)-4-((6-(哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-
(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-N-甲基-4-((6-(哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-N-(甲基-d3)-4-((6-(4-(1-甲基氮杂环丁烷-3-基)哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-N-甲基-4-((6-(4-(1-甲基氮杂环丁烷-3-基)哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺;
4-((6-(1-乙酰基氮杂环丁烷-3-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-(甲基-d3)哒嗪-3-甲酰胺;
(R)-4-((6-(1-乙酰基氮杂环丁烷-3-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-N-甲基-4-((6-(1-(甲基磺酰基)氮杂环丁烷-3-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(1-(乙基磺酰基)氮杂环丁烷-3-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(3,3-二甲基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(3,3-二甲基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(S)-4-((6-(3,3-二甲基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(3-(二乙基氨基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(3-(二乙基氨基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(3-氟-3-(甲氧基甲基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(3-氟-3-(甲氧基甲基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(3-(甲氧基甲基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(3-(甲氧基甲基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-
基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(3-(2-甲氧基乙氧基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(3-(2-甲氧基乙氧基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-N-(甲基-d3)-4-((6-(3-(哌啶-1-基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-N-甲基-4-((6-(3-(哌啶-1-基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(2-氮杂螺[3.3]庚烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(2-氮杂螺[3.3]庚烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(2-氮杂螺[3.5]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(7-氧杂-2-氮杂螺[3.5]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(R)-4-((6-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺)-N-甲基-4-((6-(2-氧代吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)烟酰胺;
6-(环丙烷酰胺基)-4-(6-(3-(二氟甲氧基)氮杂环丁烷-1-基)-[1,2,4]三唑基[1,5-a]吡啶-2-基)氨基)-N-甲基烟酰胺;
6-((6-氰基吡啶-2-基)氨基)-4-((6-(3-氟氮杂环丁烯-1-基)-[1,2,4]三唑基[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺;
4-((6-(2-氮杂螺[3.3]庚烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-甲基哒嗪-3-甲酰胺;
4-((6-(2-氮杂螺[3.3]庚烷-2-基)-[1,2,4]三唑[1,5-a]吡啶-2-基]氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)烟酰胺;
4-((6-(2-氮杂螺[3.5]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-甲基哒嗪-3-甲酰胺;
4-((6-(7-氧杂-2-氮杂螺[3.5]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环
丙烷甲酰胺)-N-甲基哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺)-N-甲基-4-((6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)哒嗪-3-甲酰胺;
(R)-N-甲基-4-((6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(S)-N-甲基-4-((6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(S)-N-(甲基-d3)-4-((6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺)-N-(甲基-d3)-4-((6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)哒嗪-3-甲酰胺;
(S)-6-(环丙烷甲酰胺基)-4-((6-(3-氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺;
4-((6-((S)-3-氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-((R)-螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(S)-6-(环丙烷甲酰胺)-4-((6-(3-氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
(S)-6-(环丙烷甲酰胺基)-4-((6-(3-氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺;
(R)-6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((6-(3-甲基吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-((8-氟-6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-4-((8-氟-6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-(甲基-d3)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺基)-N-甲基-4-((8-甲基-6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)哒嗪-3-甲酰胺;
4-((6-(5-氮杂螺[2.4]庚烷-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺基)-N-甲基哒嗪-3-甲酰胺;
(R)-4-((6-(5-氮杂螺[2.4]庚烷-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
4-((6-(5-氮杂螺[2.4]庚烷-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲
酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺;
4-((6-(6-氮杂螺[3.4]辛烷-6-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-甲基哒嗪-3-甲酰胺;
4-((6-(2-氮杂螺[4.4]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-甲基哒嗪-3-甲酰胺;
4-((6-(2-氮杂螺[4.4]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-(甲基-d3)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺)-4-((6-(六氢环戊烷[c]吡咯-2(1H)-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺)-4-((6-(3,3-二氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺;
(R)-4-((6-(3,3-二氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
(S)-4-((6-(3,3-二氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;
6-(环丙烷甲酰胺)-4-((6-(3,3-二氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
(S)-6-(环丙烷甲酰胺)-4-((6-(3-(2-甲氧基乙氧基)吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺;
(S)-6-(环丙烷甲酰胺)-4-((6-(3-(2-甲氧基乙氧基)吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;
(R)-6-(环丙烷甲酰胺)-4-((6-(3-(2-甲氧基乙氧基)吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺或
6-(环丙烷甲酰胺)-N-甲基-4-((6-(2-氧代吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)哒嗪-3-甲酰胺。
第二方面,本发明提供了制备式(Ⅰ)三唑并吡啶衍生物方法,该制备方法如合成路线1或合成路线2所示:
合成路线1
合成路线2
其中:
R1、R2、R3、R4、A、L、L1、X1、Y1的定义如权利要求1所述;
P2为卤素、-B(OH)2;
在合成路线1中步骤1,式(Ⅱ)化合物和式(Ⅲ)化合物在有机溶剂中,温度-78℃-200℃,必要时在碱或钯催化剂存在下反应得到式(Ⅳ)化合物,有机溶剂为质子溶剂或非质子溶剂,非质子溶剂选自但不限于四氢呋喃、二氧氯环、乙酸乙酯、二氯甲烷、氯仿、乙二醇二甲醚、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、N-甲基吡咯烷酮;质子溶剂选自但不限于水、乙醇、正丁醇、异丁醇、异丙醇、乙二醇、乙二醇单甲醚。碱包括无机碱或有机碱,有机碱三乙胺、二异丙胺、二异丙氨基锂、双三甲基硅氨基锂;无机碱选自但不限于氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠。步骤2中,式(IV)化合物和R2-P2化合物在有机溶剂中,利用suzuki或Buchwald-Hartwig反应,钯催化剂存在下,得到式(I)化合物。
在合成路线2中步骤1,式(V)化合物和式(V-1)化合物在有机溶剂中,温度-78℃-200℃,
必要时在碱或钯催化剂存在下反应得到式(VI)化合物,有机溶剂为质子溶剂或非质子溶剂,非质子溶剂选自但不限于四氢呋喃、二氧氯环、乙酸乙酯、二氯甲烷、氯仿、乙二醇二甲醚、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、N-甲基吡咯烷酮;质子溶剂选自但不限于水、乙醇、正丁醇、异丁醇、异丙醇、乙二醇、乙二醇单甲醚。碱包括无机碱或有机碱,有机碱三乙胺、二异丙胺、二异丙氨基锂、双三甲基硅氨基锂;无机碱选自但不限于氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠。步骤2中,式(VI)化合物经碱水解,得到相应的酸,再与R1NH2经常规缩合反应得式(VII)化合物;步骤3中,式(VII)化合物和R2-P2化合物在有机溶剂中,利用suzuki或Buchwald-Hartwig反应,钯催化剂存在下,得到式(I)化合物。
专业术语
术语“烷基”是指链中具有1至12个碳原子的直链或支链的烷基,烷基的实例包括甲基(Me)、乙基(Et)、正丙基、异丙基、丁基、异丁基、仲丁基、叔丁基(t-Bu)、戊基、异戊基、叔戊基、己基、异己基,以及根据本领域普通技术人员和文本所提供的教导认为是相当于上述实例中的任何一种基团。
术语“烷氧基”是指键接氧原子的如上定义的烷基。烷氧基经由氧原子连接到母体结构。
术语“烯基“指由至少两个碳原子和至少一个碳碳双键组成的如上定义的烷基,例如乙烯基、1-丙烯基、2-丙烯基等。优选C2-10烯基,优选C2-6烯基,最优选C2-4烯基,最佳为乙烯基。烯基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烷氧基、烷基氨基、卤素、羟基、环烷基、杂环烷基、杂环烷氧基。
术语“氨基”是指-NH2基团或单或二烷基氨基。
术语环烷基是指饱和和部分饱和的,单环的、稠合多环的、桥连多环的、或爆多环的碳环,每个碳原子具有3至12个环原子数。环烷基的说明性实例包括以下的适当键合部分形式的实体:
术语“杂芳基”是指单环的、稠合双环的、或稠合多环的芳组杂环(环结构具有选自碳原子和至多四个选自氮、氧和硫的杂原子的环原子),每个杂环具有3至12个环原子。杂芳基的说明性实例包括以下的以适当键合部分形式的实体:
术语“芳基”是指含C5-C20的单环的、稠合双环的、或稠合多环的芳组环,不含杂原子氮、氧、硫等,通常的芳香基团包括,但不限于,源自苯的残基、取代的苯、萘、蒽、联苯等。
术语“杂环”是指饱和或部分不饱和单环或多环环状烃取代基,其包括3至20个环原子,其中一个或多个环原子选自氮、氧或S(O)m(其中m是0-2的整数)的杂原子,其余环原子为碳。优选包括3至12个环原子,其中1~4个杂原子,更优选的杂环烷基环包含3至10个环原子,更优选的杂环烷基环包含5至6个环原子。单环杂环烷基的非限制性实例包含吡咯烷基、哌啶基、吗啉基四氢呋喃基等。多环杂环烷基包括螺环、稠环和桥环的杂环烷基。杂环可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、卤代烷基、烷氧基、烷基氨基、卤素、羟基、氨基、氧代基、烷氨基、环烷基、杂环烷基、杂环烷氧基、羟烷基、羧基或羧酸酯基。
术语“卤素”表示氯、氟、溴或碘。术语“卤代”代表氯代,氟代,溴代或碘代。术语“卤代烷基”是指如上所定义的烷基,其被一个或多个卤原子取代。
第三方面,本发明提供了式(Ⅰ)结构化合物、异构体、氘代衍生物的制备方法,具体见实施例。
在本发明所提供的实施方案中,本发明的化合物如含有碱性基团,则可与酸成盐,采用本领域技术人员所熟知的方法可以制备无环核苷衍生物、异构体的盐。
常见酸盐有有机酸盐、无机酸盐等。通常,比较常用的有机酸盐有枸橼酸盐、富马酸盐、草酸盐、苹果酸盐、乳酸盐、磺酸盐(例如樟脑磺酸盐、对甲苯磺酸盐、甲磺酸盐等)等;无机酸盐有氢卤酸盐、硫酸盐、磷酸盐、硝酸盐等。例如,与低级烷基磺酸,如甲磺酸,三氟甲磺酸等可形成甲磺酸盐、三氟甲磺酸盐;与芳基磺酸,如苯磺酸或对甲苯磺酸等可形成对甲苯磺酸盐、苯磺酸盐;与有机羧酸,如乙酸,富马酸,酒石酸,草酸,马来酸,苹果酸,琥珀酸或柠檬酸等可形成相应的盐;与氨基酸,如谷氨酸或天冬氨酸可形成谷氨酸盐或天冬氨酸盐。与无机酸,如氢卤酸(如氢氟酸、氢溴酸、氢碘酸、氢氯酸),硝酸,碳酸,硫酸或磷酸等也可形成相应的盐。
第四方面,本发明提供利用本发明式(I)结构的化合物、异构体、溶剂合物、氘代衍生物或其药学上可接受的盐或溶剂合物为活性成分的药物。在上述药物中还可以含有一种或多种药学上可接受的载体,所述载体包括药学领域的常规稀释剂,赋形剂,填充剂,粘合剂,湿润剂,崩解剂,吸收促进剂,表面活性剂,吸附载体,润滑剂等,必要时还可以加入香味
剂,甜味剂等。本发明药物可以制成片剂,粉剂,粒剂,胶囊,口服液及注射用药等多种形式,上述各剂型的药物均可以按照药学领域的常规方法制备。
第五方面,本发明提供式(I)结构的化合物、异构体、溶剂合物、氘代衍生物或其药学上可接受的盐,提供通过抑制Tyk-2-介导信号转导来调节IL-12、IL-23和/或IFNα的方法,包括向需要此治疗的宿主施用治疗有效量的至少一种本发明化合物。
一种优选的实施方案是治疗炎性和自体免疫性疾病的药物。对于本发明的这一目的,炎性和自体免疫性疾病或病症包括包括系统性红斑狼疮(SLE),狼疮肾炎,皮肤狼疮,克罗恩病,溃疡性结肠炎,1型糖尿病,牛皮癣,类风湿性关节炎,全身发作性幼年特发性关节炎,强直性脊柱炎或多发性硬化等方面的药物的用途。
下面结合具体实施例,对本发明作进一步详细的阐述,下述实施例不用于限制本发明,仅用于说明本发明。以下实施例中所使用的实验方法如无特殊说明,实施例中未注明具体条件的实验方法,通常按照常规条件,下述实施例中所使用的材料、试剂等,如无特殊说明,均可从商业途径得到。
下面通过实施例来说明本发明的可实施性,本领域的技术人员应当理解,根据现有技术的教导,对相应的技术特征进行修改或替换,仍然属于本发明要求保护的范围:
实施例1、6-(环丙甲酰胺)-5-氟-N-甲基-4-((4-(吡咯烷-1-酰基)苯基)胺基)烟酰胺
步骤1:6-氯-5-氟-N-甲基-4-((4-(吡咯烷-1-羰基)苯基)氨基)烟酰胺制备
将(4-氨基苯基)(吡咯烷-1-基)甲酮1.5g(7.88mmol)、4,6-二氯-5-氟-N-甲基烟酰胺1.6g加入100mL茄形瓶中,随后加入四氢呋喃5mL溶解原料,冰浴下搅拌0.5小时,再滴加4mL LiHMDS(1M),反应5~6h,TLC监测反应完全。过滤除去体系中不溶物,滤液加入适量水稀释,再用二氯甲烷萃取3次,无水Na2SO4干燥,过滤,减压浓缩,残留物柱层析得到目的产物6-氯-5-氟-N-甲基-4-((4-(吡咯烷-1-羰基)苯基)氨基)烟酰胺1.30g。
步骤2:6-(环丙甲酰胺)-5-氟-N-甲基-4-((4-(吡咯烷-1-酰基)苯基)胺基)烟酰胺制备
在氮气保护下,将步骤1所得产物0.9g加入到10mL 1,4-二氧六环的三颈瓶中溶解,加入环丙基甲酰胺0.23g、碳酸铯2.0g,体系减压排除空气充入氮气往复3次,再加入
0.32g(0.553mmol)Xantphos、0.25g(0.273mmol)Pd2(dba)3,继续体系减压排除空气充入氮气往复3次,最后将体系升温至110℃,反应6h,TLC监测反应完全。将反应液放冷至室温,抽滤体系中不溶物,加入适量水稀释,再用乙酸乙酯萃取3次,无水Na2SO4干燥,过滤,减压浓缩,残留物柱层析得目的物0.78g。
1H NMR(400MHz,DMSO-D6)δ10.58(s,1H),9.79(s,1H),8.72(d,J=4.6Hz,1H),8.33(s,1H),7.41(d,J=8.6Hz,2H),6.95(dd,J=8.5,3.0Hz,2H),3.57–3.32(m,4H),2.69(d,J=4.5Hz,3H),1.92–1.75(m,4H),1.00–0.62(m,4H).
ESI MS m/z:426.19[M+1]+
实施例2、6-(环丙甲酰胺)-5-氟-N-甲基-4-((4-(哌啶-1-酰基)苯基)胺基)烟酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-D6)δ10.57(s,1H),9.77(s,1H),8.71(d,J=4.6Hz,1H),8.32(s,1H),8.08(s,1H),7.24(d,J=8.5Hz,2H),6.56(s,1H),3.41(s,4H),2.69(d,J=4.6Hz,3H),1.86(dd,J=11.3,6.0Hz,1H),1.51(d,J=41.2Hz,6H),0.81–0.76(m,4H).
ESI MS m/z:440.20[M+1]+
实施例3、6-(环丙甲酰胺)-5-氟-4-((3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)-N-甲基烟酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-D6)δ10.49(s,1H),9.76(s,1H),8.69(d,J=4.5Hz,1H),8.48(s,1H),8.32(s,1H),7.66–7.53(m,2H),7.31(t,J=7.8Hz,1H),6.96(d,J=7.8Hz,1H),3.88(s,3H),2.67(d,J=4.4Hz,3H),1.85(dd,J=10.9,5.9Hz,1H),0.78(dd,J=17.6,9.8Hz,4H).
ESI MS m/z:410.17[M+1]+
实施例4、6-(环丙烷甲酰氨基)-5-氟-4-((2-甲氧基-3-(1-甲基-1H-吡唑-4-基)苯基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-D6)δ9.90(s,1H),8.42(d,J=4.6Hz,1H),8.10(d,J=14.0Hz,2H),7.86(t,J=1.6Hz,1H),7.67(t,J=4.4Hz,1H),7.16(dd,J=7.8,1.4Hz,1H),6.97(t,J=7.9Hz,1H),6.61(t,J=7.7Hz,1H),3.85(d,J=10.9Hz,3H),3.60(d,J=2.2Hz,3H),2.95(s,1H),2.72(dd,J=21.4,4.5Hz,3H),1.20(s,2H),0.84–0.75(m,2H).
实施例5、6-(环丙甲酰胺)-5-氟-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)-N-甲基烟酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-D6)δ10.58(s,1H),10.05(s,1H),8.80(d,J=4.5Hz,1H),8.52(s,1H),8.38(s,1H),7.43(dd,J=7.8,1.3Hz,1H),7.07(t,J=7.9Hz,1H),6.92(t,J=7.2Hz,1H),3.93(d,J=18.5Hz,3H),3.81–3.64(m,3H),2.75(d,J=4.4Hz,3H),1.86(dd,J=11.7,6.1Hz,1H),0.88–0.69(m,4H).
ESI MS m/z:440.18[M+1]+
实施例6、6-(环丙烷甲酰氨基)-5-氟-N-甲基-4-((2-(N-甲基甲磺酰氨基)苯基)氨基)烟酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-D6)δ10.53(s,1H),8.34(s,1H),8.06(s,1H),7.05(d,J=6.4Hz,1H),6.99(d,J=6.4Hz,1H),6.91(d,J=6.4Hz,1H),6.82(d,J=7.1Hz,1H),6.47–6.45(m,1H),3.10(s,3H),2.70(dd,J=18.7,4.5Hz,6H),0.83–0.73(m,5H).
实施例7、6-(环丙甲酰胺)-N-甲基-4-((4-(吡咯烷-1-酰基)苯基)胺基)烟酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-D6)δ10.77(s,1H),10.61(s,1H),8.61(d,J=4.5Hz,1H),8.49(s,1H),8.05(s,1H),7.52(d,J=8.4Hz,2H),7.24(d,J=8.5Hz,2H),3.42(t,J=6.4Hz,4H),2.75(d,J=4.4Hz,3H),1.94(dd,J=11.3,5.2Hz,1H),1.80(dd,J=11.5,6.4Hz,4H),0.80–0.65(m,4H).
ESI MS m/z:408.20[M+1]+
实施例8、6-(环丙甲酰胺)-N-甲基-4-((4-(哌啶-1-酰基)苯基)胺基)烟酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-D6)δ10.76(s,1H),10.58(s,1H),8.61(d,J=4.5Hz,1H),8.49(s,1H),8.02(s,1H),7.36(d,J=8.5Hz,2H),7.25(d,J=8.5Hz,2H),3.36(d,J=29.5Hz,4H),2.75(d,J=4.5Hz,3H),1.98–1.89(m,1H),1.64–1.39(m,6H),0.80–0.67(m,4H).
ESI MS m/z:422.21[M+1]+
实施例9、6-(环丙烷甲酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-吡唑-4-基)苯基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-D6)δ10.74(s,1H),10.63(s,1H),8.60(d,J=4.5Hz,1H),8.48(s,1H),8.13(s,1H),8.02(s,1H),7.88(d,J=0.7Hz,1H),7.32–7.30(m,1H),7.23(dd,J=7.9,1.4Hz,1H),7.10(d,J=7.9Hz,1H),3.86(s,3H),3.55(s,3H),2.76(d,J=4.5Hz,3H),0.77(dd,J=29.8,6.1Hz,5H).
ESI MS m/z:422..21[M+1]+
实施例10、6-(环丙烷甲酰氨基)-4-((2-甲氧基-3-(5-甲基-1,3,4-噁二唑-2-基)苯基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-D6)δ10.81(s,1H),10.75(s,1H),8.64(d,J=4.4Hz,1H),8.51(s,1H),8.02(s,1H),7.63(s,1H),7.55(s,1H),7.31(d,J=8.0Hz,1H),3.73(s,3H),2.76(d,J=4.4Hz,3H),2.57(s,3H),1.95(s,1H),0.81(d,J=6.6Hz,1H),0.75(d,J=6.1Hz,3H).
实施例11、6-(环丙甲酰胺)-N-甲基-4-((4-(吗啉-4-酰基)苯基)胺基)烟酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-D6)δ10.78(s,1H),10.61(s,1H),8.62(d,J=4.4Hz,1H),8.49(s,1H),8.04(s,1H),7.41(d,J=8.4Hz,2H),7.26(d,J=8.4Hz,2H),3.53(d,J=37.9Hz,8H),2.77(dd,J=17.3,4.5Hz,3H),1.98–1.91(m,1H),0.76(t,J=12.0Hz,4H).
ESI MS m/z:424.19[M+1]+
实施例12、6-(环丙烷甲酰胺)-4-((5-氟-3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:458.18[M+1]+
实施例13、6-(环丙烷酰胺基)-4-(3-(5-氟嘧啶-2-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-D6)δ10.78(s,1H),10.66(s,1H),9.04(d,2H),8.59(bs,1H),8.53(s,1H),8.07(s,1H),7.58-7.54(m,1H),7.44-7.41(m,1H),7.29-7.24m,1H),2.01-1.97(m,1H),0.80-0.75(m,4H).
ESI MS m/z:443.20[M+1]+
实施例14、6-(环丙烷酰胺基)-4-(3-(5-氟嘧啶-2-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:440.18[M+1]+
实施例15、6-(环丙烷酰胺基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:437.17[M+1]+
实施例16、(S)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:466.20[M+1]+
实施例17、(R)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(螺
[2.2]戊烷-1-甲酰胺)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:466.20[M+1]+
施例18、6-((6-氰基吡啶-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:474.18[M+1]+
1H NMR(400MHz,DMSO-d6)δ10.87(S,1H),10.24(s,1H),9.03(S,2H),8.55(b,1H)8.52(s,1H),7.98(s,1H),7.83-7.88(m,1H),7.74-7.79(m,2H),7.48-7.51(m,1H),7.35-7.41(m,2H),3.69(S,3H).
实施例19、6-((6-氟吡啶-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:467.18[M+1]+
1H NMR(400MHz,DMSO-d6)δ10.74(S,1H),10.02(s,1H),9.03-9.04(d,2H),8.52(s,1H)
8.51(s,1H),7.73-7.84(m,3H),7.48-7.52(m,1H),7.39-7.43(m,1H),7.24-7.30(m,1H),3.70(S,3H).
实施例20、6-((5-(2-羟基丙-2-基)吡啶-2-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:489.24[M+1]+
1H NMR(400MHz,DMSO-d6)δ10.69(S,1H),9.70(b,1H),8.95-8.96(d,2H),8.49(b,1H),8.48(s,1H),8.25-8.28(m,1H),7.87-7.97(m,1H),7.68-7.75(m,2H),7.40-7.53(m,3H),7.29-7.35(m,1H),5.06(b,1H),3.70(S,3H),1.43(S,6H).
实施例21、6-((6-氰基吡啶-2-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:456.19[M+1]+
1H NMR(400MHz,DMSO-d6)δ10.87(S,1H),10.24(s,1H),8.94-8.95(d,2H),8.55(b,1H),8.52(s,1H),7.98(s,1H),7.83-7.89(m,1H),7.74-7.79(m,2H),7.48-7.52(m,2H),7.36-7.42(m,2H),3.70(S,3H).
实施例22、6-(3-((2-((6-氰基吡啶-2-基)氨基)-5-((甲基-d3)氨基甲酰基)吡啶-4-基)氨基)-2-甲氧基苯基)-N,N-二甲基吡啶酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-d6)δ10.87(S,1H),10.24(s,1H),8.94-8.95(d,2H),8.55(b,1H),8.52(s,1H),7.98(s,1H),7.83-7.89(m,1H),7.74-7.79(m,2H),7.48-7.52(m,2H),7.36-7.42(m,2H),3.70(S,3H).
ESI MS m/z:526.23[M+1]+
实施例23、6-((6-氰基吡啶-2-基)氨基)-4-((2-甲氧基-3-(吡啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-d6)δ10.96(S,1H),10.50(b,1H),8.72-8.73(d,1H),8.66(m,1H),8.53(s,1H),7.86-7.96(m,2H),7.64-7.72(m,2H),7.53-7.58(m,1H),7.34-7.49(m,4H),7.23-7.27(m,1H),3.50(S,3H).
ESI MS m/z:455.19[M+1]+
实施例24、6-((6-氰基吡啶-2-基)氨基)-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-d6)δ10.93(S,1H),10.25(s,1H),9.08-9.09(d,1H),8.77-8.80(m,1H),8.63-8.65(m,1H),8.53(s,1H),7.97(s,1H),7.83-7.88(m,1H),7.48-7.51(m,1H),7.40-7.48(m,2H),3.54(S,3H).
ESI MS m/z:456.19[M+1]+
实施例25、6-((5-(2-羟基丙-2-基)吡啶-2-基)氨基)-4-((2-甲氧基-3-(吡啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-d6)δ10.74(S,1H),9.70(b,1H),8.69-8.73(m,1H),8.49(b,1H),8.48(s,1H),8.25-8.28(m,1H),7.83-7.95(m,3H),7.70-7.76(m,1H),7.62-7.66(m,1H),7.42-7.50(m,2H),7.37-7.41(m,1H),7.28-7.35(m,1H),5.05(S,1H),3.50(S,3H),1.43(S,6H)。
ESI MS m/z:488.24[M+1]+
实施例26、6-((5-(2-羟基丙-2-基)吡啶-2-基)氨基)-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-d6)δ10.77(S,1H),9.67(s,1H),9.09-9.10(d,1H),8.78-8.80(m,1H),8.63-8.65(d,1H),8.49(s,1H),8.47(b,1H),8.24-8.26(d,1H),7.93(s,1H),7.69-7.74(m,1H),7.49-7.52(d,1H),7.45-7.49(m,1H),7.34-7.40(m,1H),5.03(S,1H),3.55(S,3H),1.42(S,6H)。
ESI MS m/z:489.24[M+1]+
实施例27、6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),10.75(s,1H),8.62(s,1H),8.54(s,1H),8.06(s,1H),7.66-7.62(m,1H),7.62-7.58(m,1H),7.35-7.30(t,1H),3.73(s,3H),2.68(s,3H),0.80-0.75(d,4H).
ESI MS m/z:426.19[M+1]+
实施例28、6-(环丙烷甲酰胺基)-4-((2-(甲氧基-d3)-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:426.19[M+1]+
实施例29、6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:423.17[M+1]+
实施例30、6-((6-氰基吡啶-2-基)氨基)-4-((2-甲氧基-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:460.18[M+1]+
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.29(s,1H),8.60(s,1H),8.54(s,1H),8.00(s,1H),7.89–7.83(m,2H),7.75-7.71(d,1H),7.60-7.56(m,1H),7.52-7.49(d,1H),7.46-7.41(t,1H),3.76(s,3H),2.68(s,3H).
实施例31、6-(5-(2-羟基丙烷-2-基)吡啶-2-基)氨基)-4-(2-甲氧基-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:493.23[M+1]+
1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),9.70(s,1H),8.52-8.48(m,2H),8.26-8.24(m,1H),7.97–7.92(m,1H),7.82-7.78(m,1H),7.74–7.69(m,1H),7.61-7.57(m,1H),7.52–7.47(m,1H),7.40-7.35(m,1H),5.05(s,1H),3.76(s,3H),2.69(s,3H),1.42(s,6H).
实施例32、6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:452.20[M+1]+
实施例33、6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:452.20[M+1]+
实施例34、6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:449.19[M+1]+
实施例35、6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:486.20.18[M+1]+
实施例36、4-((3-(5-正丁基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:465.22[M+1]+
实施例37、4-((3-(5-正丁基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:468.24[M+1]+
实施例38、6-(环丙烷甲酰胺)-4-((3-(5-(环丙基甲基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:466.22[M+1]+
实施例39、6-(环丙烷甲酰胺)-4-((3-(5-(甲氧基乙基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:467.20[M+1]+
实施例40、6-(环丙烷甲酰胺基)-4-((3-(5-(乙氧基甲基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:467.20[M+1]+
实施例41、6-(环丙烷甲酰胺)-4-((3-(5-(2-氟乙基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:455.18[M+1]+
实施例42、-(环丙烷甲酰胺)-4-((2-甲氧基-3-(5-(2-甲基乙基)-1,2,4-噁二唑-3-基)苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:470.22[M+1]+
实施例43、6-(环丙烷甲酰胺)-4-((3-(5-(乙氧基甲基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:470.22[M+1]+
实施例44、6-(环丙烷甲酰胺)-4-((3-(5-(2-氟乙基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:458.20[M+1]+
实施例45、6-(环丙烷甲酰胺)-4-((2-(甲氧基-d3)-3-(5-(2-甲氧基乙基)-1,2,4-恶二唑-3-基)苯基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:470.22[M+1]+
实施例46、6-(环丙烷甲酰胺)-4-((3-(5-(乙氧基甲基)-1,2,4-噁二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:470.22[M+1]+
实施例47、6-(环丙烷甲酰胺)-4-((3-(5-(2-氟乙基)-1,2,4-噁二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:458.20[M+1]+
实施例48、4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((5-(2-羟基丙烷-2-基)吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:507.23[M+1]+
1H NMR(400MHz,DMSO-d6)δ10.69(S,1H),9.66(b,1H),9.03-9.04(d,2H),8.48(s,1H),8.46(b,1H),8.245-8.265(m,1H),7.92-7.96(m,1H),7.69-7.74(m,2H),7.47-7.51(m,1H),7.39-7.42(m,1H),7.29-7.34(m,1H),5.03(b,1H),3.70(S,3H),1.42(S,6H).
实施例49、6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:423.18[M+1]+
实施例50、6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:426.20[M+1]+
实施例51、6-(环丙烷甲酰胺基)-4-((4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:441.18[M+1]+
实施例52、6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(嘧啶-2-基)吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:423.19[M+1]+
实施例53、6-(环丙烷甲酰胺基)-N-甲基-4-((2-氧代-2H-[1,2’-联吡啶]-3-基)氨基)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:405.16[M+1]+
实施例54、4-((2-甲氧基-3-(5-甲基-1,3,4-噁二唑-2-基)苯基)氨基)-N-甲基-6-((6-甲基吡啶-2-基)胺基)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:446.19[M+1]+
实施例55、6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:423.18[M+1]+
实施例56、6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:424.17[M+1]+
实施例57、6-((6-氟-5-(2-羟基丙烷-2-基)吡啶-2-基)氨基)-4-((4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-酰基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:526.21[M+1]+
实施例58、6-(((6-氰基吡啶-2-基)氨基)-4-((4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基)氨基)-N-甲基烟酰胺
参考实施例1的方法合成。
ESI MS m/z:472.16[M+1]+
实施例59、6-(((6-氰基吡啶-2-基)氨基)-4-((4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:475.18[M+1]+
实施例60、6-((1R,2R)-2-氟环丙烷-1-甲酰胺)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:459.17[M+1]+
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.96(s,1H),9.19(s,1H),9.05(s,2H),8.09(s,1H),7.59-7.56(m,1H),7.54-7.50(m,1H),7.33-7.28(t,1H),5.00-4.78(m,1H),3.66(s,3H),2.01–1.97(m,1H),0.87-0.82(m,2H).
实施例61、6-(环丙烷甲酰胺基)-4-((2-(甲氧基-d3)-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:427.18[M+1]+
实施例62、(S)-4-((2-甲氧基-3-(5-甲基-1,2,4-恶二唑-3-基)苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:453.20[M+1]+
实施例63、(R)-4-((2-甲氧基-3-(5-甲基-1,2,4-恶二唑-3-基)苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:453.20[M+1]+
实施例64、6-(环丙烷甲酰胺基)-4-((2-(甲氧基-d3)-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:430.20[M+1]+
实施例65、6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:424.17[M+1]+
实施例66、6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:450.18[M+1]+
实施例67、6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:450.18[M+1]+
实施例68、(R)-4-((3-(5-环丙基-1,2,4-恶二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:479.22[M+1]+
实施例69、(S)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:479.22[M+1]+
实施例70、6-(环丙烷甲酰胺基)-4-((2-(甲氧基-d3)-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:453.20[M+1]+
实施例71、6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:456.22[M+1]+
实施例72、6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(2-甲基乙基)-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:468.19[M+1]+
实施例73、4-((3-(5-正丁基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:466.21[M+1]+
实施例74、4-((3-(5-正丁基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:469.23[M+1]+
实施例75、6-(环丙烷甲酰胺基)-4-((3-(5-(环丙基甲基)-1,2,4-恶噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:467.22[M+1]+
实施例76、6-(环丙烷甲酰胺基)-4-((3-(5-(乙氧基甲基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:468.19[M+1]+
实施例77、6-(环丙烷甲酰胺基)-4-((3-(5-(2-氟乙基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N个-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:456.17[M+1]+
实施例78、6-(环丙烷甲酰胺)-4-((2-(甲氧基-d3)-3-(5-(2-甲氧基乙基)-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:471.21[M+1]+
实施例79、6-(环丙烷甲酰胺)-4-((3-(5-(乙氧基甲基)-1,2,4-恶二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:471.21[M+1]+
实施例80、6-(环丙烷甲酰胺)-4-((3-(5-(2-氟乙基)-1,2,4-噁二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N个-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:459.19[M+1]+
实施例81、6-(环丁烷甲酰胺基)-4-(3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:455.20[M+1]+
1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),10.88(s,1H),9.15(s,1H),9.06-9.05(d,2H),8.22(s,1H),7.65-7.62(m,1H),7.56-7.53(m,1H),7.38-7.33(m,1H),3.68(s,3H),3.45–3.39(m,1H),2.23–1.87(m,6H).
实施例82、4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(1-甲基环丙烷-1-甲酰胺基)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:455.48[M+1]+
1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),10.09(s,1H),9.12(s,1H),9.05(s,2H),8.07(s,1H),7.62-7.58(m,1H),7.55-7.51(m,1H),7.35-7.30(t,1H),3.67(s,3H),1.43(s,3H),1.16-1.11(m,2H),0.69-0.65(m,2H).
实施例83、6-(环丙烷甲酰胺基)-4-(3-(5-氟嘧啶-2-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:444.20[M+1]+
实施例84、6-(环丙烷甲酰胺基)-4-(3-(5-氟嘧啶-2-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:441.18[M+1]+
实施例85、(S)-6-(2,2-二氟环丙烷-1-甲酰胺)-4-(3-(5-氟嘧啶-2-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:480.18[M+1]+
实施例86、6-((1S,2S)-2-氟环丙烷-1-甲酰胺基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:459.17[M+1]+
实施例87、6-(3,3-二氟环丁烷-1-甲酰胺)-4-(3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:491.18[M+1]+
1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),10.99(s,1H),9.17(s,1H),9.05(s,2H),8.18(s,1H),7.65-7.61(m,1H),7.57-7.53(m,1H),7.38-7.33(t,1H),3.68(s,3H),3.31–3.27(m,1H),2.82-2.73(m,4H).
实施例88、6-((6-氰基吡啶-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:475.18[M+1]+
1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),10.71(s,1H),9.15(s,1H),9.06-9.04(d,2H),8.29(s,1H),7.95–7.90(m,1H),7.82-7.78(m,1H),7.78-7.75(m,1H),7.60-7.56(m,1H),7.51–7.47(m,1H),7.43-7.38(m,1H),3.70(s,3H).
实施例89、6-(环丙烷酰胺基)-4-(3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-D6)δ11.32(s,1H),10.97(s,1H),9.15-9.12(m,1H),8.69(s,1H),8.14(s,1H),7.67-7.63(m,1H),7.53-7.49(m,1H),7.29-7.24(m,1H),3.90–3.84(m,1H),2.11–2.06(m,1H),1.19–1.15(m,2H),1.10–1.04(m,2H),0.83-0.79(m,4H).
ESI MS m/z:455.23[M+1]+
实施例90、6-(环丙烷酰胺基)-4-(3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
1H NMR(400MHz,DMSO-D6)δ11.31(s,1H),10.97(s,1H),9.18-9.12(m,1H),8.69(s,1H),8.14(s,1H),7.67-7.63(m,1H),7.53-7.49(m,1H),7.29-7.24(m,1H),3.90-3.84(m,1H),2.87(d,3H),2.11–2.06(m,1H),1.20–1.15(m,2H),1.10-1.05(m,2H),0.86–0.79(m,4H).
ESI MS m/z:452.22[M+1]+
实施例91、6-(环丙烷甲酰胺基)-4-(3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:473.23[M+1]+
实施例92、6-(环丙烷酰胺基)-4-(3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-(甲氧基-d3)苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:470.21[M+1]+
实施例93、6-(环丙烷酰胺基)-4-(2-(甲氧基-d3)-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:450.20[M+1]+
实施例94、6-(环丙甲酰胺基)-4-(5-氟-2-(甲氧基-d3)-3-(1-(丙-2-炔-1-基)-1H-1,2,4-
三唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:468.19[M+1]+
实施例95、6-(环丙烷甲酰胺基)-4-(2-(甲氧基-d3)-3-(1-(3-甲基氧杂环丁烷-3-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:482.23[M+1]+
实施例96、6-(环丙烷甲酰胺基)-4-(2-(甲氧基-d3)-3-(1-(氧杂环丁烷-3-基甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:482.23[M+1]+
实施例97、6-(环丙烷酰胺基)-4-(3-(1-(环丙基甲基)-1H-1,2,4-三唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:466.23[M+1]+
实施例98、6-(环丙烷酰胺基)-4-(2-(甲氧基-d3)-5-甲基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:440.22[M+1]+
实施例99、4-((3-(1-烯丙基-1H-1,2,4-三唑-3-基)-2-(甲氧基-d3)苯基)氨基)-6-(环丙烷甲酰胺)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:455.23[M+1]+
实施例100、6-(环丙烷甲酰胺基)-4-(5-氟-2-(甲氧基-d3)-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:471.21[M+1]+
实施例101、(R)-4-((5-氟-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:470.21[M+1]+
实施例102、(S)-4-((5-氟-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:470.21[M+1]+
实施例103、6-(环丙烷甲酰胺基)-4-(2-(甲氧基-d3)-3-(1-(氧杂环丁烷-3-基甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:485.25[M+1]+
实施例104、6-(环丙烷甲酰胺基)-4-(2-(甲氧基-d3)-3-(1-(3-甲基氧杂环丁烷-3-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:485.25[M+1]+
实施例105、6-(环丙烷酰胺基)-4-(3-(1-(环丙基甲基)-1H-1,2,4-三唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:469.25[M+1]+
实施例106、6-(环丙烷酰胺基)-4-(2-(甲氧基-d3)-5-甲基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:443.23[M+1]+
实施例107、6-((6-氰基吡啶-2-基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:460.20[M+1]+
实施例108、4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-甲基-6-
(环丙烷甲酰胺基)哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:424.18[M+1]+
实施例109、4-((2-氧代-2H-[1,2'-联吡啶]-3-基)氨基)N-甲基-6-(环丙烷甲酰胺基)哒嗪-3-羧酰胺
参考实施例1的方法合成。
ESI MS m/z:406.15[M+1]+
实施例110、6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例1的方法合成。
ESI MS m/z:425.16[M+1]+
实施例111、N-(5-乙酰基-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)吡啶-2-基)环丙烷甲酰胺
步骤1:6-氯-N-甲氧基-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-N-甲基烟酰胺
将原料2-甲氧基-3-(吡嗪-2-基)苯胺0.5g与中间体4,6-二氯-N-甲氧基-N-甲基烟酰胺0.6g溶于四氢呋喃,加入50ml三颈烧瓶中,冰浴(<-10℃)条件下,缓慢滴加LiHMDS,搅拌,继续冰浴下反应。反应完毕,加水淬灭,二氯甲烷加水萃取,饱和水溶液洗涤,无水硫酸钠干燥,抽滤,旋干,过柱后得深黄色油状物0.6g。
步骤2:1-(6-氯-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)吡啶-3-基)乙烷-1-酮
将原料步骤1产物0.5g溶于四氢呋喃,加入50ml三颈烧瓶中,冰浴(<-15℃)条件下缓慢滴加甲基溴化镁,搅拌,继续冰浴下反应。反应完毕,加冰水淬灭。乙酸乙酯加水萃取,饱和氯化钠水溶液洗涤,无水硫酸钠干燥,抽滤,旋干。石油醚打浆后得乳白色固体。
步骤3.N-(5-乙酰基-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)吡啶-2-基)环丙烷甲酰胺
将步骤2产物0.2g、环丙酰胺0.1g、碳酸铯0.46g依次加入50ml三颈烧瓶中,加水使碳酸铯完全溶解;抽真空一次,氮气保护,加入Pd2(dba)3,xantphos,搅拌;再次抽真空3次,持续氮气保护,加热,升温至90℃反应。反应完毕,二氯甲烷加水萃取,饱和氯化钠水
溶液洗涤,无水硫酸钠干燥,抽滤,旋干,过柱。
ESI MS m/z:404.16[M+1]+
1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),10.95(s,1H),9.07(s,1H),8.86(s,1H),8.80-8.77(m,1H),8.66-8.63(d,1H),8.04(s,1H),7.62–7.54(m,2H),7.39-7.33(t,1H),3.50(s,3H),2.66(s,3H),2.06–1.98(m,1H),0.83-0.76(d,4H).
实施例112、N-(4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)环丙烷甲酰胺
参考实施例111的方法合成。
ESI MS m/z:418.18[M+1]+
实施例113、6-((5-乙酰基-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)吡啶-2-基)氨基)吡啶甲腈
参考实施例111的方法合成。
ESI MS m/z:438.16[M+1]+
1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),10.48(s,1H),9.10-9.08(d,1H),8.87(s,1H),8.81–8.79(m,1H),8.67-8.65(d,1H),7.99(s,1H),7.92–7.87(m,1H),7.82-7.77(m,2H),7.57-7.52(m,2H),7.50-7.45(t,1H),3.53(s,3H),2.66(s,3H).
实施例114、6-((4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)氨基)吡啶甲腈
参考实施例111的方法合成。
ESI MS m/z:452.18[M+1]+
实施例115、(1R,2R)-2-氟-N-(4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)环丙烷-1-甲酰胺
参考实施例111的方法合成。
ESI MS m/z:436.17[M+1]+
实施例116、(S)-N-(4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)螺[2.2]戊烷-1-甲酰胺
参考实施例111的方法合成。
ESI MS m/z:444.20[M+1]+
实施例117、(R)-N-(4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)螺[2.2]戊烷-1-甲酰胺
参考实施例111的方法合成。
ESI MS m/z:444.20[M+1]+
实施例118、1-(6-((5-(2-羟基丙烷-2-基)吡啶-2-基)氨基)-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)吡啶-3-基)乙烷-1-酮
参考实施例111的方法合成。
ESI MS m/z:471.53[M+1]+
1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),9.95(s,1H),9.10-9.08(d,1H),8.82(s,1H),8.81-8.79(m,1H),8.67-8.65(d,1H),8.27-8.24(d,1H),7.96-7.92(m,1H),7.77-7.72(m,2H),7.57-7.54(m,1H),7.54-7.50(m,1H),7.44-7.39(m,1H),5.06(s,1H),3.53(s,3H),2.62(s,3H),1.42(s,6H).
实施例119、1-(6-((5-(二乙基磷酰基)吡啶-2-基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)吡啶-3-基)丙烷-1-酮
参考实施例111的方法合成。
ESI MS m/z:534.23[M+1]+
实施例120、N-(4-(2-甲氧基-3-(吡啶-2-基)苯基)氨基)-5-丙酰吡啶-2-基)环丙烷甲酰胺
参考实施例111的方法合成。
1H NMR(400MHz,DMSO-D6)δδ11.06(s,1H),10.94(s,1H),8.89(s,1H),8.73-8.70(m,1H),8.09(s,1H),7.93-7.88(m,1H),7.88-7.84(m,1H),7.54-7.50(m,2H),7.42–7.39(m,1H),7.33-7.28(m,1H),3.46(s,3H),3.16–3.10(q,2H),2.04–1.99(m,1H),1.13(t,3H),0.82-0.78(m,4H).
ESI MS m/z:417.18[M+1]+
实施例121、N-(5-乙酰基-4-((2-甲氧基-3-(吡啶-2-基)苯基)氨基)吡啶-2-基)环丙烷甲酰胺
参考实施例111的方法合成。
1H NMR(400MHz,DMSO-D6)δ11.04(s,1H),10.95(s,1H),8.85(s,1H),8.72-8.69(m,1H),8.05(s,1H),7.92–7.86(m,1H),7.86-7.83(m,1H),7.54-7.50(m,2H),7.42–7.38(m,1H),7.32-7.28(m,1H),3.46(s,3H),2.66(s,3H),2.04-1.99(m,1H),0.82-0.78(m,4H).
ESI MS m/z:403.17[M+1]+
实施例122、6-((4-((3-(5-(2-羟基丙烷-2-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-5-(丙酰基-3,3,3-d3)吡啶-2-基)氨基)吡啶腈
参考实施例111的方法合成。
ESI MS m/z:513.24[M+1]+
实施例123、6-((4-((3-(5-(2-羟基丙烷-2-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-5-丙酰吡啶-2-基)氨基)吡啶腈
参考实施例111的方法合成。
ESI MS m/z:510.22[M+1]+
实施例124、2-(3-((2-((6-氰基吡啶-2-基)氨基)-5-(丙酰3,3,3-d3基-)吡啶-4-基)氨基)-2-甲氧基苯基)-N,N-二甲基嘧啶-5-甲酰胺
参考实施例111的方法合成。
ESI MS m/z:526.23[M+1]+
实施例125、2-(3-((2-((6-氰基吡啶-2-基)氨基)-5-丙酰基吡啶-4-基)氨基)-2-甲氧基苯基)-N,N-二甲基嘧啶-5-甲酰胺
参考实施例111的方法合成。
ESI MS m/z:523.21[M+1]+
实施例126、6-((4-((3-(6-(2-羟基丙烷-2-基)吡啶-2-基)-2-甲氧基苯基)氨基)-5-(丙酰基3,3,3-d3-)吡啶-2-基)氨基]吡啶腈
参考实施例111的方法合成。
ESI MS m/z:512.24[M+1]+
实施例127、6-((4-((3-(5-(2-羟基丙-2-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-5-丙酰基吡啶-2-基)氨基]吡啶腈
参考实施例111的方法合成。
ESI MS m/z:510.22[M+1]+
实施例128、6-((4-((3-(5-(2-羟基丙-2-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-5-(丙酰基-3,3,3-d3)吡啶-2-基)氨基)吡啶腈
参考实施例111的方法合成。
ESI MS m/z:513.24[M+1]+
实施例129、5-(3-((2-((6-氰基吡啶-2-基)氨基)-5-丙酰基吡啶-4-基)氨基)-2-甲氧基苯基)-N,N-二甲基吡嗪-2-羧酰胺
参考实施例111的方法合成。
ESI MS m/z:523.21[M+1]+
实施例130、5-(3-((2-((6-氰基吡啶-2-基)氨基)-5-(丙酰3,3,3-d3基-)吡啶-4-基)氨基)-2-甲氧基苯基)-N,N-二甲基吡嗪-2-甲酰胺
参考实施例111的方法合成。
ESI MS m/z:526.23[M+1]+
实施例131、N-(4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)环丙烷甲酰胺
参考实施例111的方法合成。
ESI MS m/z:418.18[M+1]+
实施例132、N-(4-((3-甲氧基-4-(嘧啶-2-基)吡啶-2-基)氨基)-5-丙酰基吡啶-2-基)环丙烷甲酰胺
参考实施例111的方法合成。
ESI MS m/z:419.18[M+1]+
实施例133、N-(4-((3-甲氧基-4-(嘧啶-2-基)吡啶-2-基)氨基)-5-(丙酰基3,3,3-d3)吡啶-2-基)环丙烷基甲酰胺
参考实施例111的方法合成。
ESI MS m/z:422.19[M+1]+
实施例134、6-(环丙烷甲酰胺)-N-(甲基-d3)-4-(6-(氮杂环丁烷-1-基吡咯烷-1-基)-[1,2,4]三唑基[1,5-a]吡啶-2-基)氨基)烟酰胺
步骤1:5-(1-氮杂环丁烷基)-2-硝基吡啶制备
将原料5-氟-2-硝基吡啶5.0g投入至100mL的单口烧瓶中,然后滴加甲醇溶液(20mL),搅拌,再依次加入原料氮杂环丁烷盐酸盐(4.9g,52.8mmol),DIPEA(18.2g,140.8mmol),滴加完毕,加热,升温至70℃回流反应。体系中有大量黄色固体析出。2h后(TLC检测),将体系抽滤,收集滤饼,为黄色固体,得目的物。滤液减压浓缩,蒸除反应溶剂后加水(150mL),用乙酸乙酯(3×50mL)萃取,合并有机相,再用饱和氯化钠水溶液(3×50mL)洗涤,经无水Na2SO4干燥,抽滤,滤液浓缩旋干,得黄色固体(6.1g,96.8%)。1H NMR(400MHz,DMSO-d6)δ:8.04(d,1H),7.75(d,1H),7.34(dd,1H),3.71(t,4H),2.28-2.23(m,2H).
步骤2:5-(1-氮杂环丁烷基)-2-氨基吡啶制备
将步骤1中间体6.1g投入至MeOH(15mL)/THF(10mL)的混合溶液中,搅拌,使其完全溶解;然后加入Pa/C(0.5g),再滴加甲酸铵15.8g,反应有气泡产生,体系逐渐呈紫黑色,继续室温下搅拌3h(TLC检测)。反应完成后,体系用硅藻土抽滤,滤液减压浓缩,蒸除反应溶剂后加水(150mL),用二氯甲烷(3×50mL)萃取,合并有机相,再用饱和氯化钠水溶液(3×50mL)洗涤,经无水Na2SO4干燥,抽滤,滤液浓缩旋干,得棕红色液体,静止一会儿后,有固体析出,得到中间体5-(1-氮杂环丁烷基)-2-氨基吡啶,无需纯化直接投入下一步。
步骤3:4-(5-(氮杂环丁烷-1-基)吡啶-2-基)-3-硫代丁酸乙酯制备
将步骤2中间体5.1g溶于二氯甲烷,投入至100mL的单口烧瓶中,然后缓慢滴加原料乙氧羰基异硫氰酸酯4.9g,室温下(20℃)搅拌反应3h(TLC检测)。反应完成后,直接将体系减压浓缩,得呈黄色固体,无需纯化,直接投入下一步。
步骤4:6-(1-氮杂环丁烷基)-[1,2,4]三唑[1,5-α]吡啶-2-氨基
将上步得到的步骤3产物(7.1g,34.2mmol)投入至100mL的单口烧瓶中,滴加MeOH/EtOH=1:1的混合溶液(20mL),搅拌,然后加入盐酸羟胺(2.4g,34.1mmol)、DIPEA(13.2g,102.2mmol),加毕,加热,升温至70℃回流反应,体系逐渐澄清,呈黄色。反应一段时间后,逐渐有固体析出。3h后,TLC检测,反应完成,将体系浓缩,旋干,加水(150mL)搅拌30min,用二氯甲烷(3×50mL)萃取,合并有机相,再用饱和氯化钠水溶液(3×50mL)洗涤,经无水Na2SO4干燥,抽滤,滤液浓缩旋干,得乳白色固体。得到的固体用二氯甲烷:石油醚=3:1打浆纯化,得中间体6-(1-氮杂环丁烷基)-[1,2,4]三唑[1,5-α]吡啶-2-氨基5.8g。1H
NMR(400MHz,DMSO-d6)δ:7.76(d,1H),7.21(d,1H),6.84(dd,1H),5.69(s,2H),3.76(t,4H),2.56-2.48(m,2H)。
步骤5:4-((6-(1-氮杂环丁烷基)-[1,2,4]三唑[1,5-α]吡啶-2-基)氨基)-6-氯-N-氘甲基烟酰胺
将中间体4,6-二氯吡啶-氘甲基酰胺12.8g投入至100mL的单口烧瓶中,滴加DMF(5mL),搅拌,中间体溶解;然后缓慢加入NaH(12.3g,510.8mmol),继续搅拌。将中间体6-(1-氮杂环丁烷基)-[1,2,4]三唑[1,5-α]吡啶-2-氨基5.8g溶于DMF(10mL)中,缓慢滴加入上述体系中,体系逐渐呈墨绿色,滴加完毕,继续室温下(20℃)搅拌反应4h(TLC检测)。反应完成后,加冰水(150mL)淬灭体系,然后用二氯甲烷(3×50mL)萃取,合并有机相,用水溶液(50mL)洗涤3次,再用饱和氯化钠水溶液(3×50mL)洗涤,经无水硫酸钠干燥,抽滤,滤液浓缩旋干得黄白色固体。固体用二氯甲烷:正己烷=3:1打浆纯化,得白色固体9.8g。1H NMR(400MHz,DMSO-d6)δ:10.64(s,1H),9.01(s,1H),8.52(s,1H),8.41(s,1H),7.63(d,1H),7.45(d,1H),7.01(dd,1H),3.75(t,4H),2.31-2.26(m,2H).
步骤6:6-(环丙烷甲酰胺)-N-(甲基-d3)-4-(6-(氮杂环丁烷-1-基吡咯烷-1-基)-[1,2,4]三唑基[1,5-a]吡啶-2-基)氨基)烟酰胺
将碳酸铯(0.7g,2.1mmol)投入至50mL三口烧瓶中,加水(2mL)搅拌,然后加入中间体16a(0.3g,0.8mmol),环丙甲酰胺(0.2g,2.5mmol),并滴加1,4-二氧六环(4mL),DMF(2mL),搅拌。抽真空,N2置换,加入Pd2(dba)3(0.1g,0.1mmol)和Xantphos(0.1g,0.2mmol),再次抽真空,N2置换3次,加热,升温至110℃反应4.5h(TLC检测)。体系过硅藻土抽滤,滤液减压浓缩,蒸除反应溶剂后加入冰水(150mL),用二氯甲烷(3×50mL)萃取,合并有机相,再用饱和氯化钠水溶液(3×50mL)洗涤,经无水Na2SO4干燥,蒸除溶剂,残余物硅胶柱色谱法[二氯甲烷:甲醇=300:1-150:1为洗脱剂]纯化,得产物17a,为白色固体(0.28g,82.9%),m.p.303-305℃。1H NMR(400MHz,DMSO-d6)δ:11.68(s,1H),10.76(s,1H),9.09(s,1H),8.68(s,1H),8.59(s,1H),
7.82(d,1H),7.51(d,1H),7.06(dd,1H),3.85(t,4H),2.36-2.28(m,2H),2.07-2.00(m,1H),0.92-0.78(m,4H).
实施例135、(R)-4-((6-(氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:434.20[M+1]+
实施例136、6-((6-氰基吡啶-2-基)氨基)-4-((6-(3-氟氮杂环丁烯-1-基)-[1,2,4]三唑基[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺
参考实施例134的方法合成。
1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),10.34(s,1H),9.24(s,1H),8.66-8.63(m,1H),8.60(s,1H),8.17-8.15(m,1H),7.91-7.86(m,1H),7.64–7.55(m,3H),7.18-7.14(m,1H),5.60-5.56(m,0.5H),5.45-5.41(m,0.5H),4.25–4.15(m,2H),3.98-3.88(m,2H).
ESI MS m/z:462.19[M+1]+
实施例137、(R)-4-((6-(氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:437.22[M+1]+
实施例138、(R)-4-((6-(3,3-二氟氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:473.20[M+1]+
实施例139、(S)-4-((6-(3,3-二氟氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:470.18[M+1]+
实施例140、(R)-4-((6-(3-氟氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:455.21[M+1]+
实施例141、(R)-4-((6-(3-氟氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:452.19[M+1]+
实施例142、(R)-N-(甲基-d3)-4-((6-((1-甲基氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:467.23[M+1]+
实施例143、(R)-N-(甲基-d3)-4-((6-((1-甲基氮杂环丁烷-3-基)氧基)-[1,2,4]
三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:464.21[M+1]+
实施例144、(R)-N-(甲基-d3)-4-((6-((1-(甲基磺酰基)氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:531.19[M+1]+
实施例145、(R)-4-((6-((1-(乙基磺酰基)氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:545.20[M+1]+
实施例146、(R)-N-甲基-4-((6-((1-(甲基磺酰基)氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:528.17[M+1]+
实施例147、(S)-4-((6-((1-乙酰氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:492.20[M+1]+
实施例148、(R)-4-((6-(氮杂环丁烷-3-基氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:450.19[M+1]+
实施例149、(R)-4-((6-(3-(二甲基氨基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:480.26[M+1]+
实施例150、(S)-4-((6-(3-(二甲基氨基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺
参考实施例134的方法合成。
ESI MS m/z:477.24[M+1]+
实施例151、(R)-4-((6-(3-甲氧基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺
参考实施例134的方法合成。
ESI MS m/z:467.23[M+1]+
实施例152、(R)-4-((6-(3-甲氧基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺
参考实施例134的方法合成。
ESI MS m/z:464.21[M+1]+
实施例153、(R)-4-((6-(3-羟基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:453.21[M+1]+
实施例154、(S)-4-((6-(3-羟基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:450.19[M+1]+
实施例155、(R)-4-((6-(6-氮杂螺[3.4]辛-6-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:488.24[M+1]+
实施例156、(S)-4-((6-(6-氮杂螺[3.4]辛-6-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:488.24[M+1]+
实施例157、4-((6-(六氢环戊[c]吡咯-2(1H)-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-((S)-螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:488.24[M+1]+
实施例158、(R)-N-(甲基-d3)-4-((6-(哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)
氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:465.25[M+1]+
实施例159、(R)-N-甲基-4-((6-(哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:462.23[M+1]+
实施例160、(R)-N-(甲基-d3)-4-((6-(4-(1-甲基氮杂环丁烷-3-基)哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:534.31M+1]+
实施例161、(R)-N-甲基-4-((6-(4-(1-甲基氮杂环丁烷-3-基)哌啶-1-基)-[1,2,4]
三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺
参考实施例134的方法合成。
ESI MS m/z:530.29[M+1]+
实施例162、4-((6-(1-乙酰基氮杂环丁烷-3-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:453.21[M+1]+
实施例163、(R)-4-((6-(1-乙酰基氮杂环丁烷-3-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:476.21[M+1]+
实施例164、(R)-N-甲基-4-((6-(1-(甲基磺酰基)氮杂环丁烷-3-基)-[1,2,4]三唑
并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:512.18[M+1]+
实施例165、(R)-4-((6-(1-(乙基磺酰基)氮杂环丁烷-3-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:526.19[M+1]+
实施例166、(R)-4-((6-(3,3-二甲基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:465.25[M+1]+
实施例167、(R)-4-((6-(3,3-二甲基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:462.23[M+1]+
实施例168、(S)-4-((6-(3,3-二甲基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:462.23[M+1]+
实施例169、(R)-4-((6-(3-(二乙基氨基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:508.29[M+1]+
实施例170、(R)-4-((6-(3-(二乙基氨基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:505.27[M+1]+
实施例171、(R)-4-((6-(3-氟-3-(甲氧基甲基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:499.23[M+1]+
实施例172、(R)-4-((6-(3-氟-3-(甲氧基甲基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:496.21[M+1]+
实施例173、(R)-4-((6-(3-(甲氧基甲基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:481.24[M+1]+
实施例174、(R)-4-((6-(3-(甲氧基甲基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:478.22[M+1]+
实施例175、(R)-4-((6-(3-(2-甲氧基乙氧基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:511.25[M+1]+
实施例176、(R)-4-((6-(3-(2-甲氧基乙氧基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:508.23[M+1]+
实施例177、(R)-N-(甲基-d3)-4-((6-(3-(哌啶-1-基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:520.29[M+1]+
实施例178、(R)-N-甲基-4-((6-(3-(哌啶-1-基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:517.27[M+1]+
实施例179、(R)-4-((6-(2-氮杂螺[3.3]庚烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:477.25[M+1]+
实施例180、(R)-4-((6-(2-氮杂螺[3.3]庚烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:474.23[M+1]+
实施例181、(R)-4-((6-(2-氮杂螺[3.5]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:502.26[M+1]+
实施例182、(R)-4-((6-(7-氧杂-2-氮杂螺[3.5]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:504.24[M+1]+
实施例183、(R)-4-((6-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:476.21[M+1]+
实施例184、6-(环丙烷甲酰胺)-N-甲基-4-((6-(2-氧代吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)烟酰胺
参考实施例1的方法合成。
ESI MS m/z:435.18[M+1]+
实施例185、6-(环丙烷酰胺基)-4-(6-(3-(二氟甲氧基)氮杂环丁烷-1-基)-[1,2,4]三唑基[1,5-a]吡啶-2-基)氨基)-N-甲基烟酰胺
参考实施例134的方法合成。
ESI MS m/z:473.18[M+1]+
实施例186、6-((6-氰基吡啶-2-基)氨基)-4-((6-(3-氟氮杂环丁烯-1-基)-[1,2,4]三唑基[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺
参考实施例134的方法合成。
1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),10.34(s,1H),9.24(s,1H),8.66-8.63(m,1H),8.60(s,1H),8.17-8.15(m,1H),7.91-7.86(m,1H),7.64–7.55(m,3H),7.18-7.14(m,1H),5.60-5.56(m,0.5H),5.45-5.41(m,0.5H),4.25–4.15(m,2H),3.98-3.88(m,2H).
ESI MS m/z:462.19[M+1]+
实施例187、4-((6-(2-氮杂螺[3.3]庚烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-甲基哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:448.21[M+1]+
实施例188、4-((6-(2-氮杂螺[3.3]庚烷-2-基)-[1,2,4]三唑[1,5-a]吡啶-2-基]氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)烟酰胺
参考实施例134的方法合成。
ESI MS m/z:451.23[M+1]+
实施例189、4-((6-(2-氮杂螺[3.5]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-甲基哒嗪-3-甲酰胺
参考实施例341的方法合成。
ESI MS m/z:476.24[M+1]+
实施例190、4-((6-(7-氧杂-2-氮杂螺[3.5]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-甲基哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:478.22[M+1]+
实施例191、6-(环丙烷甲酰胺)-N-甲基-4-((6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:422.20[M+1]+
实施例192、(R)-N-甲基-4-((6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:448.21[M+1]+
实施例193、(S)-N-甲基-4-((6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:448.21[M+1]+
实施例194、(S)-N-(甲基-d3)-4-((6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:451.23[M+1]+
实施例195、6-(环丙烷甲酰胺)-N-(甲基-d3)-4-((6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:425.22[M+1]+
实施例196、(S)-6-(环丙烷甲酰胺基)-4-((6-(3-氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:440.19[M+1]+
实施例197、4-((6-((S)-3-氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-((R)-螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:466.20[M+1]+
实施例198、(S)-6-(环丙烷甲酰胺)-4-((6-(3-氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:443.21[M+1]+
实施例199、(S)-6-(环丙烷甲酰胺基)-4-((6-(3-氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:436.21[M+1]+
实施例200、(R)-6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((6-(3-甲基吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:439.23[M+1]+
实施例201、6-(环丙烷甲酰胺基)-4-((8-氟-6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:440.19[M+1]+
实施例202、6-(环丙烷甲酰胺基)-4-((8-氟-6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-(甲基-d3)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:443.21[M+1]+
实施例203、6-(环丙烷甲酰胺基)-N-甲基-4-((8-甲基-6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:436.21[M+1]+
实施例204、4-((6-(5-氮杂螺[2.4]庚烷-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺基)-N-甲基哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:448.22[M+1]+
实施例205、(R)-4-((6-(5-氮杂螺[2.4]庚烷-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:474.23[M+1]+
实施例206、4-((6-(5-氮杂螺[2.4]庚烷-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:451.23[M+1]+
实施例207、4-((6-(6-氮杂螺[3.4]辛烷-6-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-甲基哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:462.23[M+1]+
实施例208、4-((6-(2-氮杂螺[4.4]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-甲基哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:476.24[M+1]+
实施例209、4-((6-(2-氮杂螺[4.4]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:479.26[M+1]+
实施例210、6-(环丙烷甲酰胺)-4-((6-(六氢环戊烷[c]吡咯-2(1H)-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:462.23[M+1]+
实施例211、6-(环丙烷甲酰胺)-4-((6-(3,3-二氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:458.18[M+1]+
实施例212、(R)-4-((6-(3,3-二氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:484.19[M+1]+
实施例213、(S)-4-((6-(3,3-二氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:484.19[M+1]+
实施例214、6-(环丙烷甲酰胺)-4-((6-(3,3-二氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:461.20[M+1]+
实施例215、(S)-6-(环丙烷甲酰胺)-4-((6-(3-(2-甲氧基乙氧基)吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:496.23[M+1]+
实施例216、(S)-6-(环丙烷甲酰胺)-4-((6-(3-(2-甲氧基乙氧基)吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:499.25[M+1]+
实施例217、(R)-6-(环丙烷甲酰胺)-4-((6-(3-(2-甲氧基乙氧基)吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:496.23[M+1]+
实施例218、6-(环丙烷甲酰胺)-N-甲基-4-((6-(2-氧代吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]
吡啶-2-基)氨基)哒嗪-3-甲酰胺
参考实施例134的方法合成。
ESI MS m/z:436.18[M+1]+
实施例219、生物活性试验
(1)化合物对激酶(TYK2JH2)抑制。
本实验使用毛细管电泳方法利用检测底物肽段磷酸化转化率,从而测定待测化合物对1种激酶(TYK2JH2)抑制的IC50值。本实验使用BMS-986165为对照化合物。化合物稀释使用DMSO稀释对照化合物BMS-986165和待测化合物。使用TECAN EVO2000系统,3倍梯度稀释化合物至11个浓度,使用Echo550转移20nL化合物至384孔板。
酶反应实验
a)准备1X反应缓冲液:50mM Hepes,0.1%BSA,PH 7.5。
b)加入58μL TYK2protein(终浓度5nM)和2μL稀释好的化合物(DMSO终浓度2.5%)到Isoplate-96板中,1000rpm/min离心1min,震荡5min。
c)加入10μL[3H]BMS-986165(终浓度5nM)和10μL PVT copper His tag SPAbeads(终浓度50μg/well)到Isoplate-96板中,1000rpm/min离心1min,震荡5min。
d)25℃孵育30min,使用Microbeta读数。
数据分析
使用如下公式计算抑制率(Inhibition Ratio):
使用XLfit计算IC50。
注:+表示在0.1μM有抑制作用
注:+表示在0.1μM有抑制作用
**WO2021170046
Claims (9)
- 式(Ⅰ)结构:
异构体、溶剂合物、氘代衍生物及其药学上可接受的盐;其中:X1、Y1各自独立地为-CR5或-N;为苯基;具有1至4个独立的选自氮、氧及硫之杂原子的5至6元单环杂芳基环;或具有2至4个独立的选自氮、氧及硫杂原子的7-12之双环杂芳基;R1选自氢、C1-C3烷基、C3-C6环烷基、C1-C3烷基氨基,并可被卤素、氘任意取代;R2为-NHCy或-NHCOCy,其中R2经p个R6取代;R4为氢、卤素,-OR7、-N(R7)2、-S(O)2R7、-S(O)2N(R7)2、-C(O)R7、-C(O)OR7、-C(O)N(R7)2、-C(O)N(R7)OR7、-OC(O)R7、-OC(O)N(R7)2,可以被q个R8取代;R4也可以为4到7元杂环,并可被0-3个R4a取代;R4a是氢、卤素、C1-C6烷基、-(CH2)rOR9、-(CH2)rC(O)OR9、-(CH2)rOC(O)R9、-(CH2)rNR9C(O)R10、-(CH2)rNR9C(O)OR10、-(CH2)r-3-14元杂环;R5为氢、卤素;L为共价键、-NH-;L1为共价键、-N(R7)-、-C(O)N(R7)-、-S(O)2NR7-、-C(O)O-、-S(O)2-;Cy为苯基,3-7元饱和或不饱和单环碳环或杂芳基,6-14元双环碳环,具有1至3个独立地选自氮、氧及硫之杂原子的3-7元饱和或不饱和单环杂环,具有1-3个独立的选自氮、氧及硫之杂原子的6-12元饱和或不饱和双环杂环;Cy选自但不限于下列基团:
R3、R6、R7、R8各自独立地为氢、卤素、羟基、C1-C6烷氧基、C3-C12环烷氧基、-OR7、-NR7、-(CH2)nN(R7)-S(O)2NR7、-S(O)2N(R7)2、-C(O)OR7、-C(O)N(R7)2、-OC(O)R7、-OC(O)N(R7)2、具有1-3个独立的选自氮、氧及硫之杂原子的3-12元饱和或芳杂环;R9、R10独立地选自氢、卤素、C1-C3烷基、C3-C6环烷基、4-8元杂环;p、q、r为0-3。 - 根据权利要求1所述的化合物,其特征在于所述的式(Ⅰ)结构的化合物中,下式:
选自但不限于下列结构:
- 根据权利要求1所述的化合物,其特征在于所述的化合物包括但不限于下列结构:6-(环丙甲酰胺)-5-氟-N-甲基-4-((4-(吡咯烷-1-酰基)苯基)胺基)烟酰胺;6-(环丙甲酰胺)-5-氟-N-甲基-4-((4-(哌啶-1-酰基)苯基)胺基)烟酰胺;6-(环丙甲酰胺)-5-氟-4-((3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)-N-甲基烟酰胺;6-(环丙烷甲酰氨基)-5-氟-4-((2-甲氧基-3-(1-甲基-1H-吡唑-4-基)苯基)氨基)-N-甲基烟酰胺;6-(环丙甲酰胺)-5-氟-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)-N-甲基烟酰胺;6-(环丙烷甲酰氨基)-5-氟-N-甲基-4-((2-(N-甲基甲磺酰氨基)苯基)氨基)烟酰胺;6-(环丙甲酰胺)-N-甲基-4-((4-(吡咯烷-1-酰基)苯基)胺基)烟酰胺;6-(环丙甲酰胺)-N-甲基-4-((4-(哌啶-1-酰基)苯基)胺基)烟酰胺;6-(环丙烷甲酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-吡唑-4-基)苯基)氨基)-N-甲基烟酰胺;6-(环丙烷甲酰氨基)-4-((2-甲氧基-3-(5-甲基-1,3,4-噁二唑-2-基)苯基)氨基)-N-甲基烟酰胺;6-(环丙甲酰胺)-N-甲基-4-((4-(吗啉-4-酰基)苯基)胺基)烟酰胺;6-(环丙烷甲酰胺)-4-((5-氟-3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3) 烟酰胺;6-(环丙烷酰胺基)-4-(3-(5-氟嘧啶-2-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)烟酰胺;6-(环丙烷酰胺基)-4-(3-(5-氟嘧啶-2-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基烟酰胺;6-(环丙烷酰胺基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-甲基烟酰胺;(S)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺;(R)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺;6-((6-氰基吡啶-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺;6-((6-氟吡啶-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺;6-((5-(2-羟基丙-2-基)吡啶-2-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺;6-((6-氰基吡啶-2-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺;6-(3-((2-((6-氰基吡啶-2-基)氨基)-5-((甲基-d3)氨基甲酰基)吡啶-4-基)氨基)-2-甲氧基苯基)-N,N-二甲基吡啶酰胺;6-((6-氰基吡啶-2-基)氨基)-4-((2-甲氧基-3-(吡啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺;6-((6-氰基吡啶-2-基)氨基)-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺;6-((5-(2-羟基丙-2-基)吡啶-2-基)氨基)-4-((2-甲氧基-3-(吡啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺;6-((5-(2-羟基丙-2-基)吡啶-2-基)氨基)-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺;6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-(甲基-d3)烟酰胺;6-(环丙烷甲酰胺基)-4-((2-(甲氧基-d3)-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基烟酰胺;6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基烟酰胺;6-((6-氰基吡啶-2-基)氨基)-4-((2-甲氧基-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-(甲基-d3)烟酰胺;6-(5-(2-羟基丙烷-2-基)吡啶-2-基)氨基)-4-(2-甲氧基-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-(甲基-d3)烟酰胺;6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺;6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基烟酰胺;6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基烟酰胺;6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺;4-((3-(5-正丁基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺)-N-甲基烟酰胺;4-((3-(5-正丁基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺)-N-(甲基-d3)烟酰胺;6-(环丙烷甲酰胺)-4-((3-(5-(环丙基甲基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺;6-(环丙烷甲酰胺)-4-((3-(5-(甲氧基乙基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基烟酰胺;6-(环丙烷甲酰胺基)-4-((3-(5-(乙氧基甲基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基烟酰胺;6-(环丙烷甲酰胺)-4-((3-(5-(2-氟乙基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基烟酰胺;6--(环丙烷甲酰胺)-4-((2-甲氧基-3-(5-(2-甲基乙基)-1,2,4-噁二唑-3-基)苯基)氨基)-N-(甲基-d3)烟酰胺;6-(环丙烷甲酰胺)-4-((3-(5-(乙氧基甲基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺;6-(环丙烷甲酰胺)-4-((3-(5-(2-氟乙基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺;6-(环丙烷甲酰胺)-4-((2-(甲氧基-d3)-3-(5-(2-甲氧基乙基)-1,2,4-恶二唑-3-基)苯基)氨基)-N-甲基烟酰胺;6-(环丙烷甲酰胺)-4-((3-(5-(乙氧基甲基)-1,2,4-噁二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基烟酰胺;6-(环丙烷甲酰胺)-4-((3-(5-(2-氟乙基)-1,2,4-噁二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基烟酰胺;4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((5-(2-羟基丙烷-2-基)吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺;6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-甲基烟酰胺;6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺;6-(环丙烷甲酰胺基)-4-((4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺;6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(嘧啶-2-基)吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺;6-(环丙烷甲酰胺基)-N-甲基-4-((2-氧代-2H-[1,2’-联吡啶]-3-基)氨基)烟酰胺;4-((2-甲氧基-3-(5-甲基-1,3,4-噁二唑-2-基)苯基)氨基)-N-甲基-6-((6-甲基吡啶-2-基)胺基)烟酰胺;6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-甲基烟酰胺;6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基)氨基)-N-甲基烟酰胺;6-((6-氟-5-(2-羟基丙烷-2-基)吡啶-2-基)氨基)-4-((4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-酰基)氨基)-N-(甲基-d3)烟酰胺;6-(((6-氰基吡啶-2-基)氨基)-4-((4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基)氨基)-N-甲基烟酰胺;6-(((6-氰基吡啶-2-基)氨基)-4-((4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺;6-((1R,2R)-2-氟环丙烷-1-甲酰胺)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-((2-(甲氧基-d3)-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;(S)-4-((2-甲氧基-3-(5-甲基-1,2,4-恶二唑-3-基)苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((2-甲氧基-3-(5-甲基-1,2,4-恶二唑-3-基)苯基)氨基)-N-(甲基-d3)-6- (螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-((2-(甲氧基-d3)-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基哒嗪-3-甲酰胺;6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;(R)-4-((3-(5-环丙基-1,2,4-恶二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(S)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-((2-(甲氧基-d3)-3-(5-甲基-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;6-(环丙烷甲酰胺)-4-((3-(5-环丙基-1,2,4-噁二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(2-甲基乙基)-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;4-((3-(5-正丁基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-甲基哒嗪-3-甲酰胺;4-((3-(5-正丁基-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-((3-(5-(环丙基甲基)-1,2,4-恶噁二唑-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-((3-(5-(乙氧基甲基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N-甲基哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-((3-(5-(2-氟乙基)-1,2,4-噁二唑-3-基)-2-甲氧基苯基)氨基)-N个-甲基哒嗪-3-甲酰胺;6-(环丙烷甲酰胺)-4-((2-(甲氧基-d3)-3-(5-(2-甲氧基乙基)-1,2,4-噁二唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;6-(环丙烷甲酰胺)-4-((3-(5-(乙氧基甲基)-1,2,4-恶二唑-3-基)-2-(甲氧基-d3) 苯基)氨基)-N-甲基哒嗪-3-甲酰胺;6-(环丙烷甲酰胺)-4-((3-(5-(2-氟乙基)-1,2,4-噁二唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N个-甲基哒嗪-3-甲酰胺;6-(环丁烷甲酰胺基)-4-(3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(1-甲基环丙烷-1-甲酰胺基)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-(3-(5-氟嘧啶-2-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-(3-(5-氟嘧啶-2-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;(S)-6-(2,2-二氟环丙烷-1-甲酰胺)-4-(3-(5-氟嘧啶-2-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;(S)-6-(2,2-二氟环丙烷-1-甲酰胺)-4-(3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;6-((1S,2S)-2-氟环丙烷-1-甲酰胺基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;6-((6-氰基吡啶-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;6-(环丙烷酰胺基)-4-(3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;6-(环丙烷酰胺基)-4-(3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-(3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;6-(环丙烷酰胺基)-4-(3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-(甲氧基-d3)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;6-(环丙烷酰胺基)-4-(2-(甲氧基-d3)-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;6-(环丙甲酰胺基)-4-(5-氟-2-(甲氧基-d3)-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-(2-(甲氧基-d3)-3-(1-(3-甲基氧杂环丁烷-3-基)-1H-1,2,4- 三唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-(2-(甲氧基-d3)-3-(1-(氧杂环丁烷-3-基甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;6-(环丙烷酰胺基)-4-(3-(1-(环丙基甲基)-1H-1,2,4-三唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;6-(环丙烷酰胺基)-4-(2-(甲氧基-d3)-5-甲基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基哒嗪-3-甲酰胺;4-((3-(1-烯丙基-1H-1,2,4-三唑-3-基)-2-(甲氧基-d3)苯基)氨基)-6-(环丙烷甲酰胺)-N-(甲基-d3)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-(5-氟-2-(甲氧基-d3)-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;(R)-4-((5-氟-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(S)-4-((5-氟-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-(2-(甲氧基-d3)-3-(1-(氧杂环丁烷-3-基甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-(2-(甲氧基-d3)-3-(1-(3-甲基氧杂环丁烷-3-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;6-(环丙烷酰胺基)-4-(3-(1-(环丙基甲基)-1H-1,2,4-三唑-3-基)-2-(甲氧基-d3)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;6-(环丙烷酰胺基)-4-(2-(甲氧基-d3)-5-甲基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;6-((6-氰基吡啶-2-基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)N-(甲基-d3)哒嗪-3-甲酰胺;4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-甲基-6-(环丙烷甲酰胺基)哒嗪-3-甲酰胺;4-((2-氧代-2H-[1,2'-联吡啶]-3-基)氨基)N-甲基-6-(环丙烷甲酰胺基)哒嗪-3-羧酰胺;6-(环丙烷甲酰胺基)-4-((3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺;N-(5-乙酰基-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)吡啶-2-基)环丙烷甲酰胺;N-(4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)环丙烷甲酰胺;6-((5-乙酰基-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)吡啶-2-基)氨基)吡啶甲腈;6-((4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)氨基)吡啶甲腈;(1R,2R)-2-氟-N-(4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)环丙烷-1-甲酰胺;(S)-N-(4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)螺[2.2]戊烷-1-甲酰胺;(R)-N-(4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)螺[2.2]戊烷-1-甲酰胺;1-(6-((5-(2-羟基丙烷-2-基)吡啶-2-基)氨基)-4-((2-甲氧基-3-(吡嗪-2-基)苯基)氨基)吡啶-3-基)乙烷-1-酮;1-(6-((5-(二乙基磷酰基)吡啶-2-基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)吡啶-3-基)丙烷-1-酮;N-(4-(2-甲氧基-3-(吡啶-2-基)苯基)氨基)-5-丙酰吡啶-2-基)环丙烷甲酰胺;N-(5-乙酰基-4-((2-甲氧基-3-(吡啶-2-基)苯基)氨基)吡啶-2-基)环丙烷甲酰胺;6-((4-((3-(5-(2-羟基丙烷-2-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-5-(丙酰基-3,3,3-d3)吡啶-2-基)氨基)吡啶腈;6-((4-((3-(5-(2-羟基丙烷-2-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-5-丙酰吡啶-2-基)氨基)吡啶腈;2-(3-((2-((6-氰基吡啶-2-基)氨基)-5-(丙酰3,3,3-d3基-)吡啶-4-基)氨基)-2-甲氧基苯基)-N,N-二甲基嘧啶-5-甲酰胺;2-(3-((2-((6-氰基吡啶-2-基)氨基)-5-丙酰基吡啶-4-基)氨基)-2-甲氧基苯基)-N,N-二甲基嘧啶-5-甲酰胺;6-((4-((3-(6-(2-羟基丙烷-2-基)吡啶-2-基)-2-甲氧基苯基)氨基)-5-(丙酰基3,3,3-d3-)吡啶-2-基)氨基]吡啶腈;6-((4-((3-(5-(2-羟基丙-2-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-5-丙酰基吡啶-2-基)氨基]吡啶腈;6-((4-((3-(5-(2-羟基丙-2-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-5-(丙酰基-3,3,3-d3)吡啶-2-基)氨基)吡啶腈;5-(3-((2-((6-氰基吡啶-2-基)氨基)-5-丙酰基吡啶-4-基)氨基)-2-甲氧基苯基)-N,N-二甲基吡嗪-2-羧酰胺;5-(3-((2-((6-氰基吡啶-2-基)氨基)-5-(丙酰3,3,3-d3基-)吡啶-4-基)氨基)-2-甲氧 基苯基)-N,N-二甲基吡嗪-2-甲酰胺;N-(4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-5-丙酰基吡啶-2-基)环丙烷甲酰胺;N-(4-((3-甲氧基-4-(嘧啶-2-基)吡啶-2-基)氨基)-5-丙酰基吡啶-2-基)环丙烷甲酰胺;N-(4-((3-甲氧基-4-(嘧啶-2-基)吡啶-2-基)氨基)-5-(丙酰基3,3,3-d3)吡啶-2-基)环丙烷基甲酰胺;6-(环丙烷甲酰胺)-N-(甲基-d3)-4-(6-(氮杂环丁烷-1-基吡咯烷-1-基)-[1,2,4]三唑基[1,5-a]吡啶-2-基)氨基)烟酰胺;(R)-4-((6-(氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;6-((6-氰基吡啶-2-基)氨基)-4-((6-(3-氟氮杂环丁烯-1-基)-[1,2,4]三唑基[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺;(R)-4-((6-(氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(3,3-二氟氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(S)-4-((6-(3,3-二氟氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(3-氟氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(3-氟氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-N-(甲基-d3)-4-((6-((1-甲基氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-N-(甲基-d3)-4-((6-((1-甲基氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-N-(甲基-d3)-4-((6-((1-(甲基磺酰基)氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-((1-(乙基磺酰基)氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-N-甲基-4-((6-((1-(甲基磺酰基)氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(S)-4-((6-((1-乙酰氮杂环丁烷-3-基)氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(氮杂环丁烷-3-基氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(3-(二甲基氨基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(S)-4-((6-(3-(二甲基氨基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺;(R)-4-((6-(3-甲氧基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺;(R)-4-((6-(3-甲氧基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺;(R)-4-((6-(3-羟基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(S)-4-((6-(3-羟基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(6-氮杂螺[3.4]辛-6-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(S)-4-((6-(6-氮杂螺[3.4]辛-6-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;4-((6-(六氢环戊[c]吡咯-2(1H)-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-((S)-螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-N-(甲基-d3)-4-((6-(哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-N-甲基-4-((6-(哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-N-(甲基-d3)-4-((6-(4-(1-甲基氮杂环丁烷-3-基)哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-N-甲基-4-((6-(4-(1-甲基氮杂环丁烷-3-基)哌啶-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)烟酰胺;4-((6-(1-乙酰基氮杂环丁烷-3-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-(甲基-d3)哒嗪-3-甲酰胺;(R)-4-((6-(1-乙酰基氮杂环丁烷-3-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-N-甲基-4-((6-(1-(甲基磺酰基)氮杂环丁烷-3-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(1-(乙基磺酰基)氮杂环丁烷-3-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(3,3-二甲基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(3,3-二甲基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(S)-4-((6-(3,3-二甲基氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(3-(二乙基氨基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(3-(二乙基氨基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(3-氟-3-(甲氧基甲基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(3-氟-3-(甲氧基甲基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(3-(甲氧基甲基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(3-(甲氧基甲基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(3-(2-甲氧基乙氧基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(3-(2-甲氧基乙氧基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-N-(甲基-d3)-4-((6-(3-(哌啶-1-基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-N-甲基-4-((6-(3-(哌啶-1-基)氮杂环丁烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(2-氮杂螺[3.3]庚烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(2-氮杂螺[3.3]庚烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(2-氮杂螺[3.5]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(7-氧杂-2-氮杂螺[3.5]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(R)-4-((6-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺)-N-甲基-4-((6-(2-氧代吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)烟酰胺;6-(环丙烷酰胺基)-4-(6-(3-(二氟甲氧基)氮杂环丁烷-1-基)-[1,2,4]三唑基[1,5-a]吡啶-2-基)氨基)-N-甲基烟酰胺;6-((6-氰基吡啶-2-基)氨基)-4-((6-(3-氟氮杂环丁烯-1-基)-[1,2,4]三唑基[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺;4-((6-(2-氮杂螺[3.3]庚烷-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-甲基哒嗪-3-甲酰胺;4-((6-(2-氮杂螺[3.3]庚烷-2-基)-[1,2,4]三唑[1,5-a]吡啶-2-基]氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)烟酰胺;4-((6-(2-氮杂螺[3.5]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-甲基哒嗪-3-甲酰胺;4-((6-(7-氧杂-2-氮杂螺[3.5]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-甲基哒嗪-3-甲酰胺;6-(环丙烷甲酰胺)-N-甲基-4-((6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)哒嗪-3-甲酰胺;(R)-N-甲基-4-((6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(S)-N-甲基-4-((6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(S)-N-(甲基-d3)-4-((6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺)-N-(甲基-d3)-4-((6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)哒嗪-3-甲酰胺;(S)-6-(环丙烷甲酰胺基)-4-((6-(3-氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺;4-((6-((S)-3-氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-((R)-螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(S)-6-(环丙烷甲酰胺)-4-((6-(3-氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;(S)-6-(环丙烷甲酰胺基)-4-((6-(3-氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺;(R)-6-(环丙烷甲酰胺基)-N-(甲基-d3)-4-((6-(3-甲基吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-((8-氟-6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-4-((8-氟-6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-(甲基-d3)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺基)-N-甲基-4-((8-甲基-6-(吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)哒嗪-3-甲酰胺;4-((6-(5-氮杂螺[2.4]庚烷-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺基)-N-甲基哒嗪-3-甲酰胺;(R)-4-((6-(5-氮杂螺[2.4]庚烷-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;4-((6-(5-氮杂螺[2.4]庚烷-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺;4-((6-(6-氮杂螺[3.4]辛烷-6-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-甲基哒嗪-3-甲酰胺;4-((6-(2-氮杂螺[4.4]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-甲基哒嗪-3-甲酰胺;4-((6-(2-氮杂螺[4.4]壬-2-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-6-(环丙烷甲酰胺)-N-(甲基-d3)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺)-4-((6-(六氢环戊烷[c]吡咯-2(1H)-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺;6-(环丙烷甲酰胺)-4-((6-(3,3-二氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺;(R)-4-((6-(3,3-二氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;(S)-4-((6-(3,3-二氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基-6-(螺[2.2]戊烷-1-甲酰胺)哒嗪-3-甲酰胺;6-(环丙烷甲酰胺)-4-((6-(3,3-二氟吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;(S)-6-(环丙烷甲酰胺)-4-((6-(3-(2-甲氧基乙氧基)吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺;(S)-6-(环丙烷甲酰胺)-4-((6-(3-(2-甲氧基乙氧基)吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺;(R)-6-(环丙烷甲酰胺)-4-((6-(3-(2-甲氧基乙氧基)吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-N-甲基哒嗪-3-甲酰胺或6-(环丙烷甲酰胺)-N-甲基-4-((6-(2-氧代吡咯烷-1-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)哒嗪-3-甲酰胺;异构体、溶剂合物、氘代衍生物及其药学上可接受的盐。
- 式(Ⅰ)结构化合物的制备方法,其特征在于由合成路线1或合成路线2制备:
其中:R1、R2、R3、R4、A、L1、X1、Y1的定义如权利要求1所述;P2为卤素、-B(OH)2;在合成路线1中步骤1,式(Ⅱ)化合物和式(Ⅲ)化合物在有机溶剂中,温度-78℃-200℃,必要时在碱或钯催化剂存在下反应得到式(Ⅳ)化合物,有机溶剂为质子溶剂或非质子溶剂,非质子溶剂选自但不限于四氢呋喃、二氧氯环、乙酸乙酯、二氯甲烷、氯仿、乙二醇二甲醚、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、N-甲基吡咯烷酮;质子溶剂选自但不限于水、乙醇、正丁醇、异丁醇、异丙醇、乙二醇、乙二醇单甲醚碱包括无机碱或有机碱,有机碱三乙胺、二异丙胺、二异丙氨基锂、双三甲基硅氨基锂;无机碱选自但不限于氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠;步骤2中,式(IV)化合物和R2-P2化合物在有机溶剂中,利用suzuki或Buchwald-Hartwig反应,钯催化剂存在下,得到式(I)化合物;在合成路线2中步骤1,式(V)化合物和式(V-1)化合物在有机溶剂中,温度-78℃-200℃,必要时在碱或钯催化剂存在下反应得到式(VI)化合物,有机溶剂为质子溶剂或非质子溶剂,非质子溶剂选自但不限于四氢呋喃、二氧氯环、乙酸乙酯、二氯甲烷、氯仿、乙二醇二甲醚、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、N-甲基吡咯烷酮;质子溶剂选自但不限于水、乙醇、正丁醇、异丁醇、异丙醇、乙二醇、乙二醇单甲醚;碱包括无机碱或有机碱,有机碱三乙胺、二异丙胺、二异丙氨基锂、双三甲基硅氨基锂;无机碱选自但不限于氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠;步骤2中,式(VI)化合物经碱水解,得到相应的酸,再与R1NH2经常规缩合反应得式(VII)化合物;步骤3中, 式(VII)化合物和R2-P2化合物在有机溶剂中,利用suzuki或Buchwald-Hartwig反应,钯催化剂存在下,得到式(I)化合物。 - 一种药物组合物,其包含权利要求1-3任意所述的化合物、异构体、氘代衍生物或其药学上可接受的盐。
- 权利要求5所述的药物组合物在预防或者治疗与TYK2信号通路有关疾病或制备预防或者治疗与TYK2信号通路有关疾病的药物中的用途。
- 根据权利要求6所述的用途,其中所述疾病为炎性疾病或自身免疫性疾病。
- 根据权利要求7所述的用途,其中所述疾病为系统性红斑狼疮、狼疮肾炎、皮肤狼疮、克罗恩病、溃疡性结肠炎、1型糖尿病、牛皮癣、类风湿性关节炎、全身发作性幼年特发性关节炎、强直性脊柱炎或多发性硬化、特应性皮炎。
- 根据权利要求8所述的用途,其中所述疾病为系统性红斑狼疮、牛皮癣。
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