WO2021078021A1 - Petit composé moléculaire - Google Patents

Petit composé moléculaire Download PDF

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WO2021078021A1
WO2021078021A1 PCT/CN2020/120131 CN2020120131W WO2021078021A1 WO 2021078021 A1 WO2021078021 A1 WO 2021078021A1 CN 2020120131 W CN2020120131 W CN 2020120131W WO 2021078021 A1 WO2021078021 A1 WO 2021078021A1
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substituted
compound
methyl
tdm
amino
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PCT/CN2020/120131
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Chinese (zh)
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邢莉
李冠群
王晓磊
蔡雨婷
姜翔
潘翔
朱文浩
汪杨
王增全
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嘉兴特科罗生物科技有限公司
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Publication of WO2021078021A1 publication Critical patent/WO2021078021A1/fr

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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
    • C07D401/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the present invention relates to the field of small molecule compounds, in particular, to a small molecule compound and derivatives that can be used to treat, prevent and alleviate autoimmune diseases and or immune-related inflammatory skin diseases.
  • JAK Janus Kinase-STAT (Signal Transducer and Activator of Transcription proteins) signal transduction pathway is the main pathway of intracellular transmission of signals stimulated by the combination of inflammatory cytokines and receptors.
  • JAKs are a family of intracellular non-receptor tyrosine protein kinases (Tyrosine Kinase), including four members: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). JAKs are mainly expressed in hematopoietic cells, leukocytes and intestinal epithelial cells, and are responsible for mediating the signal transmission of various cytokines involved in inflammation.
  • JAK When the cytokine binds to the cell surface receptor, JAK is activated by autophosphorylation, and the activated JAK is then activated by phosphorylation of the intracellular part of the receptor and recruits members of the STAT protein family. JAK activates STAT through phosphorylation. The activated STAT can form a dimer, break away from the receptor and enter the cell nucleus to regulate gene transcription, thereby affecting the biological function of the cell. JAK-STAT signal transmission, through gene mutation, express or increase the local concentration of cytokine, has been recognized in various inflammatory diseases and various cancers.
  • JAKs have important effects on immune and inflammatory diseases, cancer and many diseases.
  • transgenic mice lacking JAK1 cannot respond to IFN stimulation, suggesting that JAK1 is mainly related to the differentiation of Th1 cells in the immune system.
  • JAK2 The high activity of JAK2 caused by gene fusion is related to leukemia, especially the type of clonal proliferation of eosinophils; the high activity of JAK2 caused by JAK2-V617F and Polycythemia Vera, Essential Thrombocythemia , Myelofirbosis (Myelofirbosis) and other myeloproliferative disorders (Myeloproliferative disorders) are related, because this hyperactive mutation makes hematopoietic stem cells more sensitive to the stimulation of growth factors.
  • JAK3 is mainly expressed in blood system cells, especially T cells and NK cells, as well as epidermal cells.
  • JAK3 In neutrophils, JAK3 is responsible for mediating the chemotaxis of neutrophils induced by IL-8 stimulation.
  • the inactivating mutation of JAK3 leads to autosomal inherited severe combined immunodeficiency (SCID), and its activating mutation (mostly occurring in the JH1 and JH2 regions) can lead to lymphoid and NK cell lineage leukemia or megakaryocyte leukemia.
  • SCID severe combined immunodeficiency
  • JAK3 combines with the villus protein on the cytoskeleton, which plays an important role in the normal differentiation, damage repair and homeostasis maintenance of the intestinal epithelium. In view of the role of JAK3 in the differentiation and development of immune cells, inhibiting JAK3 can achieve immunosuppressive functions.
  • Tyk2 is expressed in a variety of tissues, especially the bone marrow, appendix, lymph nodes and spleen, which are immune-related organs and tissues.
  • Tyk2 knock-out gene (Tyk2-/-) mice have a normal phenotype, but cannot be induced to experimental arthritis; A variety of immune cells isolated from Tyk2-/- mice have decreased response to inflammatory stimuli. In particular, Tyk2-/- macrophages lack production of nitric oxide after being stimulated by LPS.
  • Tyk2-/- and Tyk2-/- and IFN-/- mice lack LPS-induced endotoxin shock response, while STAT1-/- mice are highly sensitive to this response, suggesting that Tyk2 plays an indispensable role in the body's inflammatory response.
  • studies have found that Tyk2 is necessary for the intracellular signal transmission of Type I IFN (IFN ⁇ & IFN ⁇ ), IL-6, IL-10, IL-12, and IL-23. These cells Factors except IL-10 can stimulate inflammation and play an important role in the pathogenesis of autoimmune diseases.
  • Tyk2 loss-of-function gene mutations in humans can cause high IgE syndrome (Hyperimmuoglobulin E syndrome), which is a Th2 cell-driven disease state; this may be because Tyk2-mediated immune responses are mostly achieved by Th1 and Th17 cells. It is an autoimmune response, which inhibits the differentiation of Th2 cells to a certain extent. When Tyk2 is missing, the differentiation of T cells is unbalanced, turning from Th1/Th17 to Th2. It can be seen that inhibition of Tyk2 may be a new direction for immunosuppressive drug development, especially for autoimmune diseases driven by the IL17/IL23 axis.
  • cytokines such as IL21 and IL-23 derived from monocytes and macrophages and DCs play a key role in the differentiation of Th17 cells, and the accumulation of a large number of Th17 cells in the epidermis is psoriasis.
  • One of the characteristics is that blocking the signal transduction induced by inflammatory cytokines in the differentiation process of Th17 cells and the signal transduction induced by inflammatory factors in keratinocytes and other immune cells is expected to obtain efficient and safe autoimmune inhibitors.
  • Tyk2 is extremely important for signaling pathways mediated by Type I interfenons (IFN- ⁇ , IFN- ⁇ ), IL-6, IL-10, IL-12, IL-23 and other cytokines.
  • Tyk2 through different combinations with other members of the JAK family, such as Tyk2/Jak1, Tyk2/Jak2, Tyk2/Jak1/Jak2, directly affects the natural killing of cells, B cells and T cells related to inflammatory diseases and autoimmune diseases. Differentiation and functional changes.
  • many pharmaceutical companies have conducted research and development of new drugs for members of the JAK family, but most of them are focused on inhibiting JAK1 and JAK3. In particular, there are few reports on inhibitors against Tyk2.
  • the present invention aims to develop suitable high-efficiency and specific JAK kinase inhibitors, especially Tyk2 inhibitors, and/or JAK1 inhibitors, Tyk2/Jak2, and/or Jak1/Tyk2 dual inhibitors for the treatment, prevention and relief of self Small molecule compounds and derivatives for immune diseases and or immune-related inflammatory skin diseases, the first indication is psoriasis as an example.
  • the small molecule compound provided by the present invention is characterized in that it is a compound represented by the following structural formula or its stereoisomers, geometric isomers, tautomers, racemates, hydrates, solvates, Metabolites and pharmaceutically acceptable salts or prodrugs:
  • X 1 and X 2 are selected from carbon or nitrogen;
  • the left structure of the small molecule compound can be three types of compounds as shown in the following structures:
  • the above Z is carbon or nitrogen
  • n1 0, 1;
  • Z is preferably N
  • n2 and n3 are the same or different, and are 0 or any natural number;
  • the cyclic group represented by G above is a saturated heterocyclic ring
  • the G ring can be any alkyl heterocycle, such as three-membered, four-membered, five-membered, six-membered, seven-membered aza, oxa, and sulfur heterocycles.
  • alkyl heterocycle such as three-membered, four-membered, five-membered, six-membered, seven-membered aza, oxa, and sulfur heterocycles.
  • the number of aza, oxa, and thia on the ring does not exceed three. It can appear in the following form:
  • each R is the same or different
  • R is selected from hydrogen, halogen, alkyl, substituted alkyl, amino, amino, substituted amine, carboxy, amido -CONH 2 , substituted amido, ester (-C(O)OR z , R z is alkyl, aryl, etc.), substituted carbonyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted The heteroaryl group, substituted sulfone group, substituted sulfoxide group.
  • the above-mentioned alkyl groups are generally branched or branched chain alkyl groups with no more than 6 carbon atoms;
  • the above-mentioned substituted alkyl group means that one or more of the hydrogen atoms on the carbon chain of the alkyl group is substituted by other groups, and the other groups referred to herein may be cycloalkyl groups (in order to be similar to Any hydrogen atom on the cycloalkyl ring can also be substituted by halogen, cyano, alkyl, hydroxyl, carboxyl and other groups), heterocycloalkyl (ie, in the aforementioned cycloalkyl On the basis of, at least one carbon atom on the alkyl ring is replaced by oxygen, sulfur, and nitrogen), halogen (F, Cl, Br, I), carboxyl, cyano (-CN), sulfonic acid (-SO) 4,), a sulfonyl group (-SO 2 R a, R a is hydrogen, an alkyl group, an aryl group, etc.), an alkynyl group (-C ⁇ CH, -C ⁇ CR b, R
  • the above-mentioned substituted alkyl groups can be several types of compounds shown in the following structures:
  • substituted alkyl group can be form
  • n 1, 2, 3...a natural number; preferably within 6.
  • R 1 is an alkyl group, such as a branched or straight chain alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.;
  • One or more hydrogen atoms on the alkyl group can also be cycloalkyl, cyano, halogen, haloalkane (chloromethyl, dichloromethane, trichloromethyl, chloroethyl, chloropropan, Bromomethyl, dibromomethyl, tribromomethyl, bromoethyl, bromopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethane, fluoropropanyl and similar halogenated alkyl groups ) Is substituted, taking the substituted methyl as an example, to form the structure shown in the following molecular formula:
  • R 11 and R 12 are the same or different, and are respectively selected from cyano, halogen, and alkyl halide;
  • R 1 is a cycloalkyl group, such as: cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc.
  • one or more hydrogen atoms on the cycloalkylalkyl ring may be an alkyl group, a cyano group,
  • the specific structure can be a compound shown in the following structural formula:
  • n1 0,1,2,3,4,5;
  • R 13 is that one or more hydrogen atoms on the alkyl ring are substituted or unsubstituted by halogen or cyano;
  • R 1 is a heterocycloalkyl group, such as a four-membered, five-membered, six-membered heterocyclic ring of aza, oxa, or thia.
  • One or more hydrogen atoms on the ring of the heterocycloalkyl group may be an alkyl group , Cyano, halogen, haloalkane, the specific structure can be a compound shown in the following structural formula:
  • B 1 , B 2 , B 3 , B 4 , B 5 , and B 6 are carbon, oxygen, sulfur, and nitrogen;
  • R 14 is that one or more hydrogen atoms on the alkyl ring are substituted or unsubstituted by halogen or cyano.
  • R can also be That is, the methyl group has three substituents, which are substituted by R 2 , R 3 and -C(O)-R 1 ;
  • R 2 and R 3 are the same or different alkyl groups (for example, generally refer to alkyl groups with no more than 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.) ).
  • substituted alkyl group may also be That is, two hydrogens on the methyl group form an alkyl ring through a bridge bond, and the other hydrogen is replaced by -C(O)-R 1;
  • m is 0,1,2,3,4,5, that is, cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc.
  • one or more hydrogens on the cycloalkyl alkyl ring Atoms may be substituted or unsubstituted by R 4 alkyl, cyano, halogen, haloalkane.
  • the above-mentioned substituted amine group means that one or more of the hydrogen atoms on the amine group is substituted by other groups, and the other groups referred to here can be alkyl groups, cycloalkyl groups, carboxyl groups, cyano groups, and sulfonic acid groups. , Amide, ester, etc. groups;
  • the above-mentioned substituted amine groups can be several types of compounds as shown in the following structures:
  • R 1 is hydrogen or an alkyl group (for example, generally refers to an alkyl group with carbon atoms not greater than 6 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.);
  • R 2 is alkyl (same as above), substituted alkyl (same as above), cycloalkyl (cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc.), substituted cycloalkyl (i.e.
  • R 15 is halogen, cyano, alkynyl, etc.
  • heterocycloalkyl at least one carbon atom on the 3- to 7-membered ring is replaced by nitrogen, sulfur or oxygen
  • substituted heterocycle Alkyl one or more of the hydrogen atoms on the heterocycloalkyl ring are substituted by halogen, cyano, or alkynyl
  • sulfone R 16 is an alkyl group, a halogen group, an aryl group, etc.
  • R 17 is alkyl, halogen, aryl, etc.
  • substituted carbonyl R 17 is an alkyl group, a substituted alkyl group, an aryl group, etc.
  • R 3 is hydrogen or alkyl
  • R 4 is the same as R 2 .
  • the above-mentioned substituted amide group can be several types of compounds as shown in the following structures:
  • R 5 is hydrogen or alkyl
  • R 6 is the same as R 2 .
  • the above-mentioned substituted carbonyl group can be several types of compounds as shown in the following structures:
  • R 7 is the same as R 2 .
  • the substituted cycloalkyl mentioned in the present invention means that one or more hydrogen atoms on the ring of the cyclic group are substituted by other groups, and the other groups referred to herein can be alkyl groups, substituted alkyl groups (same as above) , halo (F, Cl, Br, I ), carboxy, cyano (-CN), a sulfonic acid group (-SO 4,), a sulfonyl group (-SO 2 R a, R a is hydrogen, alkyl, aryl, Etc.), alkynyl (-C ⁇ CH, -C ⁇ CR b , R b is alkyl, aryl, etc.), amide group (-C(O)NR x R y , R x R y is alkyl, aryl Groups, etc.), ester groups (-C(O)OR z , R z is alkyl, aryl, etc.), aryl, heteroaryl, etc
  • the substituted heterocycloalkyl mentioned in the present invention refers to the above-mentioned substituted cycloalkyl in which one or more carbon atoms on the ring are replaced by oxygen, sulfur, and nitrogen.
  • the aryl group mentioned in the present invention refers to a six-membered or above aromatic ring such as benzene and naphthalene or a benzo aromatic ring.
  • substituted aryl groups mentioned in the present invention refer to five-membered or above aromatic rings or benzo aromatic rings such as benzene, naphthalene, and fluorene. One or more hydrogen atoms on the ring are replaced by other groups.
  • R a is hydrogen, an alkyl group, an aryl group, etc.), an alkynyl group (-C ⁇ CH, -C ⁇ CR b, R b is an alkyl group, an aryl group, etc.), an amide group (-C (O)NR x R y , R x R y is alkyl, aryl, etc.), ester group (-C(O)OR z , R z is alkyl, aryl, etc.), aryl, heteroaryl, etc. And other groups.
  • heteroaryl mentioned in the present invention refers to thiophene, pyrrole, pyridine, furan, imidazole, benzimidazole, quinoline and other five-membered or above aromatic heterocyclic rings or benzo aromatic heterocyclic rings.
  • the substituted heteroaryl mentioned in the present invention refers to thiophene, pyrrole, pyridine, furan, imidazole, benzimidazole, quinoline and other five-membered or above aromatic heterocycles or benzo aromatic heterocycles, one on the ring Or multiple hydrogen atoms are substituted by other groups.
  • the other groups referred to here can be alkyl, substituted alkyl (same as above), halogen (F, Cl, Br, I), carboxyl, cyano (- the CN), a sulfonic acid group (-SO 4,), a sulfonyl group (-SO 2 R a, R a is hydrogen, an alkyl group, an aryl group, etc.), an alkynyl group (-C ⁇ CH, -C ⁇ CR b, R b is an alkyl group, an aryl group, etc.), an amide group (-C(O)NR x R y , R x R y is an alkyl group, an aryl group, etc.), an ester group (-C(O)OR z , R z is Alkyl, aryl, etc.), aryl, heteroaryl, etc. groups.
  • the sulfone group mentioned in the present invention is in the form shown in the following structure:
  • R 16 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted aryl, etc.;
  • the sulfoxide group mentioned in the present invention is in the form shown in the following structure:
  • R 17 is an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a halogen, an aryl group, a substituted aryl group, and the like.
  • a small molecule compound provided by the present invention also has the characteristics: that is, it is a compound represented by the following structural formula or its stereoisomers, geometric isomers, tautomers, racemates, Hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs:
  • a small molecule compound provided by the present invention also has the characteristics: that is, it is a compound represented by the following structural formula or its stereoisomers, geometric isomers, tautomers, racemates, Hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs:
  • R' is hydrogen, alkyl, substituted alkyl, ester, or substituted carbonyl.
  • a small molecule compound provided by the present invention also has the characteristics: that is, it is a compound represented by the following structural formula or its stereoisomers, geometric isomers, tautomers, racemates, Hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs:
  • At least one of B1 and B2 is nitrogen, sulfur or oxygen.
  • a small molecule compound provided by the present invention also has the characteristics: that is, it is a compound represented by the following structural formula or its stereoisomers, geometric isomers, tautomers, racemates, Hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs:
  • B1 is one of nitrogen or carbon
  • R" is selected from hydrogen, halogen, alkyl, substituted alkyl, amino, amine, substituted amine, carboxy, amide, substituted amide, ester, substituted carbonyl, cycloalkyl, substituted ring Alkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl.
  • a small molecule compound provided by the present invention also has the following characteristics: namely,
  • m is 0 or any natural number
  • R 1 is an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocycloalkyl group, and a substituted heterocycloalkyl group.
  • a small molecule compound provided by the present invention also has the following characteristics: namely,
  • R 2 is an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocycloalkyl group, and a substituted heterocycloalkyl group.
  • a small molecule compound provided by the present invention also has the characteristic that any two hydrogen atoms on the cyclic group represented by G form a bridge bond.
  • G can be represented by the following structure:
  • a small molecule compound provided by the present invention also has the characteristics of being used for the treatment, prevention and alleviation of autoimmune diseases and inflammatory skin diseases related to autoimmunity. It can be oral, external, injection and other dosage forms.
  • a small molecule compound provided by the present invention has the following characteristics: that is, it is a composition; the mass percentage content of the small molecule compound in the composition is 10-6% to 100%.
  • the form can be various types of preparations, such as gels, ointments, tablets and other dosage forms.
  • the present invention is rationally designed.
  • the synthesized compound is first tested for the kinase biochemical activity of JAK, and SAR (structure-activity relationship) is established according to IC50.
  • SAR structure-activity relationship
  • the potent inhibitors below 200nM are then subjected to cytological testing to determine the selectivity of the compound.
  • specific activity experimental data it can be found that the several types of compounds involved in the present invention have good cell activity inhibitory ability.
  • the inhibitors provided by the present invention can also be used for other autoimmune-related skin diseases such as alopecia areata, vitiligo, lupus erythematosus, lichen planus, lichen glaze, atrophic lichen sclerosus, panniculitis, atopic dermatitis. ,and many more.
  • JAK inhibitors, Tyk2 inhibitors, and/or JAK1 inhibitors, and/or JAK1/Tyk2 dual inhibitors obtained in the present invention suitable for oral or intravenous administration can still be used to treat psoriasis and other autoimmunity Sexual diseases such as RA, IBD, MS, etc.
  • Example 1 The reaction equation for the synthesis of compound TDM-180656 is as follows:
  • the solid compound 56 is 4-(1-(ethylsulfonyl)piperidin-4-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (29.3mg, yield Rate 44%).
  • the white solid compound TDM-180657 is N-(1-methyl-1H-pyrazol-4-yl)-4-(1-(propylsulfonyl)piperidin-4-yl)pyrimidin-2-amine (40.3 mg, yield 58%).
  • TDM-180909 yellow solid compound 309 is N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidine-4- Base) ethanesulfonamide (2.2mg, yield: 0.7%)
  • Example 2 The reaction equation for the synthesis of compound TDM-180658 is as follows:
  • TDM-180659 light green oily compound 59 is 1-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-1-yl) Butan-1-one (55.2 mg, yield 43%).
  • TDM-180660 Light yellow solid compound 60 is 3-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-1-yl)-3 -Oxopropionitrile (55.2 mg, 45% yield).
  • TDM-180661 White solid compound 61 is 3,3,3-trifluoro-1-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piper Pyridin-1-yl)propan-1-one (55 mg, yield 38%).
  • TDM-180663 Light gray solid compound 63 is cyclopropyl (4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-1-yl)methyl Ketone (46.7 mg, 37% yield).
  • TDM-180664 Light green oily compound 64 (2,2-difluorocyclopropyl) (4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl ) Piperidin-1-yl) ketone (62.5 mg, yield 44%).
  • the original compound 82a namely 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (674mg, 3.07mmol) and n-butanol (40mL) were added to the single-necked flask, and then Compound 82b, 1-tert-butoxycarbonylpiperazine (735 mg, 6.45 mol) and trifluoroacetic acid (735 mg, 6.45 mol) were added to a single-necked flask. After reacting at 50°C for 16 hours, the reaction solution was concentrated under reduced pressure.
  • the compound 82d (100mg, 0.385mmol), triethylamine (156mg, 1.54mmol) and N,N-dimethylformamide (10mL) were added to a single-neck flask, and after stirring for 5 min, compound 82e was ethyl sulfonate
  • the acid chloride (74 mg, 0.577 mmol) was added to a single-necked flask and stirred at room temperature for 16 h.
  • the reaction solution was washed with water and extracted with ethyl acetate (50mL*3).
  • the organic phases were combined, and then washed with water (50mL*3) and saturated brine (50mL*3) respectively.
  • Example 5 The reaction equation for synthesizing compound TDM-180683 is as follows:
  • White solid compound 84 is 3,3,3-trifluoro-1-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperazine-1 -Yl)-1-acetone (8 mg, yield: 5%).
  • the original compound 82a namely 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (627mg, 3.00mmol) and N,N-dimethylformamide (40mL) Add to a single-neck flask, and then add compound 85b, 4,7-diazaspiro[2-4]octane-4-carboxylic acid tert-butyl ester (636mg, 3.0mmol) and cesium carbonate (1.95g, 6.0mmol) Add it to a single-necked flask and react at 90°C for 16 hours. The reaction solution was washed with water and extracted with ethyl acetate (100mL*3).
  • the compound 85d (100mg, 0.351mmol), triethylamine (143.3mg, 1.40mmol) and N,N-dimethylformamide (10 mL) were added to a single-necked flask, and after stirring for 5 min, compound 85e was ethyl Sulfonyl chloride (67 mg, 0.526 mmol) was added to a single-necked flask and stirred at room temperature for 16 h. The reaction solution was washed with water and extracted with ethyl acetate (50mL*3). The organic phases were combined, and then washed with water (50mL*3) and saturated brine (50mL*3) respectively.
  • the compound 85d (100mg, 0.351mmol), triethylamine (143mg, 1.40mmol) and N,N-dimethylformamide (10mL) were added to the single-neck flask, and after stirring for 5min, the compound 86b was 2, 2-Difluorocyclopropane carboxylic acid (64 mg, 0.526 mmol) and HATU (200 mg, 0.526 mmol) were added to a single-necked flask and stirred at room temperature for 16 hours.
  • the reaction solution was washed with water and extracted with ethyl acetate (50mL*3).
  • the organic phases were combined, and then washed with water (50mL*3) and saturated brine (50mL*3) respectively.
  • TDM-180687 White solid compound 87 is 3-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,7-diazaspiro[ 2.5]oct-4-yl)-3-oxopropionitrile (30 mg, yield: 12%).
  • TDM-180688 White solid compound 88 is 3,3,3-trifluoro-1-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)- 4,7-diazaspiro[2.5]oct-4-yl)propan-1-one (5 mg, yield: 4%).
  • Example 8 The reaction equation for synthesizing compound TDM-180695 is as follows:
  • the original compound 82a namely 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (627mg, 3.00mmol) and N,N-dimethylformamide (20mL)
  • compound 95b (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 600mg, 3.0mol
  • cesium carbonate (1.95g, 6.0mmol
  • the compound 95d (100mg, 0.366mmol), triethylamine (148mg, 1.46mmol) and N,N-dimethylformamide (10mL) were added to the single-necked flask, and after stirring for 5min, the compound 95e was 2, 2-Difluorocyclopropane carboxylic acid (67 mg, 0.549 mmol) and HATU (208 mg, 0.549 mmol) were added to a single-necked flask and stirred at room temperature for 16 h. The reaction solution was washed with water and extracted with ethyl acetate (50mL*3).
  • TDM-180729 white solid compound 129 namely (S)-3,3,3-trifluoro-1-(2-methyl-4-(2-((1-methyl-1H-pyrazole-4- (Yl)amino)pyrimidin-4-yl)piperazin-1-yl)propan-1-one (10mg, yield 8%)
  • TDM-180703 White solid compound 103 is (R)-3-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piper (Azin-1-yl)-3-oxopropionitrile (42.6mg, yield: 34.2%)
  • TDM-180732 White solid compound 132 namely (R)-3,3,3-trifluoro-1-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl) Amino)pyrimidin-4-yl)piperazin-1-yl)propan-1-one (7mg, yield: 10%)
  • Example 10 The reaction equation for synthesizing compound TDM-180701 is as follows:
  • the original compound 82a namely 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (627mg, 3.00mmol) and N,N-dimethylformamide (20mL)
  • compound 701b (S)-2-ethylpiperazine-1-carboxylic acid tert-butyl ester (632mg, 3.0mol) and cesium carbonate (1.95g, 6.0mmol)
  • the reaction solution was washed with water and extracted with ethyl acetate (100mL*3).
  • Compound 701c is (S)-2-ethyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl Ester (670mg, 58% yield).
  • LCMS [M+1] + 388.1.
  • the compound 101d (100mg, 0.348mmol), triethylamine (142mg, 1.39mmol) and N,N-dimethylformamide (10mL) were added to a single-necked flask, and after stirring for 5min, compound 101e was 2, 2-Difluorocyclopropanecarboxylic acid (64mg, 0.522mmol) and HATU (198mg, 0.522mmol) were added to a single-necked flask, and stirred at room temperature for 16h. The reaction solution was washed with water and extracted with ethyl acetate (50mL*3).
  • TDM-180702 white solid compound 102 is (S)-3-(2-ethyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piper Azin-1-yl)-3-oxopropionitrile (21 mg, yield: 17%).
  • TDM-180730 White solid compound 130, namely (S)-1-(2-ethyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl) Piperazin-1-yl)-3,3,3-trifluoropropan-1-one (5mg, yield 7%)
  • Embodiment 11 The reaction equation for synthesizing compound TDM-180690 is as follows:
  • the original compound 82a namely 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (627mg, 3.00mmol) and N,N-dimethylformamide (20mL)
  • compound 90b R-2-ethylpiperazine-1-carboxylic acid tert-butyl ester (632mg, 3.0mmol) and cesium carbonate (1.95g, 6.0mmol) into the single-necked flask , Reaction at 90°C for 16 hours.
  • the reaction solution was washed with water and extracted with ethyl acetate (100mL*3).
  • the compound 90d (100mg, 0.348mmol), triethylamine (142mg, 1.39mmol) and N,N-dimethylformamide (10mL) were added to the single-necked flask, and after stirring for 5min, the compound 90e was 2, 2-Difluorocyclopropane carboxylic acid (64 mg, 0.522 mmol) and HATU (198 mg, 0.522 mmol) were added to a single-necked flask and stirred at room temperature for 16 hours. The reaction solution was washed with water and extracted with ethyl acetate (50mL*3).
  • TDM-180691 white solid compound 91 is (R)-3-(2-ethyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piper Azin-1-yl)-3-oxopropionitrile (15 mg, yield: 6%).
  • TDM-180692 White solid compound 92 is (R)-1-(2-ethyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piper (Azin-1-yl)-3,3,3-trifluoropropan-1-one (15 mg, yield: 11%).
  • Example 12 The reaction equation for synthesizing compound TDM-180733 is as follows:
  • Example 13 The reaction equation for the synthesis of compound TDM-180745 is as follows:
  • Example 14 The reaction equation for synthesizing compound TDM-180708 is as follows:
  • compound 108c (2.2g ⁇ 6.4mmol) into a three-necked flask
  • compound 108d is 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di (1,3,2-dioxaborane) (1.94g, 7.7mmol), PdCl 2 (ddpf) (234mg, 0.32mmol) and potassium acetate (1.25g, 12.8mmol), then add 1,4-two Oxyhexanol (35mL).
  • the system is pumped and replaced with nitrogen three times.
  • the reaction was stirred at 80°C for 2 hours.
  • the reaction solution is directly used in the next step without further post-treatment and purification.
  • compound 108f that is 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (1g, 4.8 mmol), PdCl 2 (dppf) (263 mg, 0.36 mmol), sodium carbonate (1.0 g, 9.6 mmol), 1,4-dioxane (30 mL) and water (8 mL).
  • the system water pump is pumped to replace the nitrogen three times. The reaction was stirred at 100°C for 2.5 hours.
  • TDM-180709 White solid compound 109 is (2,2-difluorocyclopropyl)(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine- 4-yl)piperidin-1-yl)methanone (48.3mg, yield 25%)
  • Embodiment 15 The reaction equation for synthesizing compound TDM-180694 is as follows:
  • Embodiment 16 The reaction equation for synthesizing compound TDM-180723 is as follows:
  • compound 123b (300mg, 1.8mmol), 3-amino-3-methylpyrrolidine-1-carboxylic acid tert-butyl ester and Example 123a (266mg, 1.8mmol), namely 2,4-dichloropyrimidine N,N-diisopropylethylamine (700 mg, 6.86 mmol) was added to the dimethyl sulfoxide (20 mL) solution of dimethyl sulfoxide, and then the mixture was heated to 100°C and stirred at 100°C for 2 hours. After the reaction, the mixture was diluted with water and extracted with ethyl acetate (3 ⁇ 100 mL).
  • TDM-180724 White solid compound 124, namely 3-(3-methyl-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)pyrrole Alk-1-yl)-3-oxopropionitrile (10mg, yield 8%)
  • Embodiment 17 The reaction equation for synthesizing compound TDM-180715 is as follows:
  • TDM-180716 White solid compound 116, namely 3-(4-methyl-4-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)piper (Pyridin-1-yl)-3-oxopropionitrile (6mg, yield 5%)
  • Example 18 The reaction equation for synthesizing compound TDM-180693 is as follows:
  • the compound 93a (1.048 g, 5.0 mmol), compound 93b (1.397 g, 7.5 mmol), Cs 2 CO 3 (2.444 mg, 7.5 mmol) and dimethyl sulfoxide (30 mL) were added to a single-necked flask. After stirring the reaction at 110°C for 16 hours, the mixture was diluted with water and extracted with ethyl acetate (20 mL ⁇ 4). The combined organic layer was washed with water (2 ⁇ 20 mL). The organic layer was separated, dried over Mg 2 SO 4, and concentrated under reduced pressure.
  • Example 19 The reaction equation for synthesizing compound TDM-180706 is as follows:
  • the compound 106a (1.5 g, 7.16 mmol), compound 106b (2.0 g, 10.74 mmol), Cs 2 CO 3 (3.5 g, 10.74 mmol) and dimethyl sulfoxide (40 mL) were added to a single-necked flask. After stirring the reaction at 110°C for 18 hours, the mixture was diluted with water and extracted with ethyl acetate (30 mL ⁇ 4). The combined organic layer was washed with water (2 ⁇ 40 mL). The organic layer was separated, dried over Mg 2 SO 4, and concentrated under reduced pressure.
  • Example 20 The reaction equation for synthesizing compound TDM-180750 is as follows:
  • TDM-180751 white solid compound 151 is N-(cyanomethyl)-4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-4- Base) piperidine-4-carboxamide (12.5mg, yield: 10.9%)
  • TDM-180793 white solid compound 193 that is N-cyclopropyl-4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piper Pyridine-4-carboxamide (25.7 mg, 43.8% yield).
  • Example 21 The reaction equation for synthesizing compound TDM-180809 is as follows:
  • TDM-180811 White solid compound 211 is 3,3,3-trifluoro-N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine- 4-yl)piperidin-4-yl)propionamide (24.6 mg, 37.1% yield).
  • TDM-180812 White solid compound 212 is N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidine-4- Yl)cyclopropane (39.1 mg, yield: 39.3%).
  • TDM-180824 White solid compound 224 is 2-cyano-N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl) Piperidin-4-yl)acetamide (24.6 mg, yield: 20.1%).
  • TDM-180842 White solid compound 242 is 2,2-difluoro-N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-4- Yl)piperidin-4-yl)acetamide (27.2 mg, yield: 26.8%).
  • Example 21 The reaction equation for the synthesis of compound TDM-180825 is as follows:
  • Example 23 The reaction equation for synthesizing compound TDM-180835 is as follows:
  • TDM-180837 White solid compound 237 is N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidine-4- Yl)cyclopropane sulfonamide (18.9 mg, yield: 17.4%).
  • TDM-180838 White solid compound 238 is N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidine-4- Yl)prop-2-ene-1-sulfonamide (17.8 mg, yield: 16.4%).
  • TDM-180839 White solid compound 239 is 3,3,3-trifluoro-N-(4-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine- 4-yl)piperidin-4-yl)propane-1-sulfonamide (30.7 mg, yield: 24.7%).
  • Example 24 The reaction equation for synthesizing compound TDM-180862 is as follows:
  • White solid compound TDM-180864 is 2-cyano-N-(4-(cyanomethyl)-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-4 -Yl)piperidin-4-yl)acetamide (15.5mg, yield: 25.5%)
  • Example 25 The reaction equation for synthesizing compound TDM-180874 is as follows:
  • the white solid compound TDM-180878 is N-(4-ethyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-4-yl )-3,3,3-Trifluoropropionamide (78.2mg, yield: 70.4%).
  • the white solid compound TDM-180879 is N-(4-ethyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piperidin-4-yl )-2,2-Difluorocyclopropanecarboxamide (32.9 mg, yield: 38.6%).
  • the white solid compound TDM-180883 is 2-cyano-N-(4-ethyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)piper (Pyridin-4-yl)acetamide (5.1 mg, yield: 5.2%).
  • the compound 104b (30mg, 0.106mmol), triethylamine (16mg, 0.159mmol), compound 104c (16.3mg, 0.133mmol), HATU is 2-(7-oxybenzotriazole)-N, N ,N',N'-Tetramethylurea hexafluorophosphate (63.4mg, 0.167mmol) and dichloromethane (5mL) were added to a 50mL single-necked flask and stirred at room temperature for 1.5 hours. Then the reaction solution was washed with water (10 mL ⁇ 2), and the organic layer was separated, dried over Mg 2 SO 4 and concentrated under reduced pressure.
  • Embodiment 27 General method for synthesizing compound TDM-180698
  • Embodiment 28 General method for synthesizing compound TDM-180699
  • Compound 99a is 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (824mg, 4.0mmol)
  • compound 99b is 4-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (2.35g, 8.0mmol)
  • Pd(dppf)Cl 2 (292mg, 0.4mol)
  • sodium carbonate (292mg, 0.4mmol
  • the system is pumped to replace nitrogen three times under the condition of water pump.
  • Janus kinases include JAK1, JAK2, JAK3 and Tyk2, which transduce cytokine-mediated signals through the JAK-STAT pathway.
  • the size of the kinase is 120-140kDa, and there are 7 identified homology regions, JH1-JH7.
  • JH1 is an important region of JAK enzyme activity and contains typical tyrosine kinase characteristics. The phosphorylation of tyrosine leads to a change in the conformation of JAK protein, thereby promoting substrate binding.
  • the JAK-STAT system consists of three main parts: receptors that pass through the cell membrane, Janus kinases connected to the receptors, and signal transduction and transcription activators (STAT) that transmit signals to the nucleus and DNA.
  • STAT signal transduction and transcription activators
  • PerkinElmer's EZ Reader can be used to detect the phosphorylation of peptide substrates catalyzed by kinases.
  • the device is based on micro-control fluid separation technology, which can directly detect fluorescently labeled substrates and products.
  • the separation step is controlled by the pressure and electric field strength in the microfluidic chip. achieve.
  • Kinase experiments are generally controlled at a product conversion rate of 20-30%. This biological test method is used to identify the inhibitory effects of compounds on JAK kinase activity.
  • the compound powder was dissolved in DMSO and stored in a refrigerator at -20°C sealed.
  • the internalized substance Ref1 is used as the positive control for JAK1, JAK2 and Tyk2 tests, and Ref2 is used for the positive control for JAK3 tests.
  • Tween 20 Dilute 100% Tween 20 with ultrapure water and store in a refrigerator at 4 degrees.
  • Assay Buffer 20mM HEPES buffer, pH 7.4, 10mM magnesium chloride, 0.01% bovine serum albumin BSA, 0.0005% Tween-20, 1mM dithiothreitol solution.
  • Stop Buffer 180mM HEPES buffer, 20mM ethylenediaminetetraacetic acid, 0.2% Coating Reagent 3.
  • Separation Buffer 100mM HEPES buffer, 10mM ethylenediaminetetraacetic acid, 0.0005% Tween 20, 0.1% Coating Reagent 3,1% dimethyl sulfoxide.
  • the compound was dissolved to 10 mM with dimethyl sulfoxide, a certain volume was diluted to 0.6 mM, and 10 ⁇ l of 0.6 mM dilution was added to a 384 microtiter plate, and then diluted in a 3-fold gradient, with a total of 8 concentration points.
  • the highest final concentration is 10 ⁇ M, 3 times dilution, 8 concentration points, 2 replicates.
  • the final concentrations of JAK1, JAK2, JAK3 and Tyk2 kinases in the reaction system are 20, 1, 1, and 1 nM, respectively
  • the graphing software Xlfit was used to make the concentration curve of the test compound and calculate the IC50 value.
  • TDM-180715 A A A A TDM-180716 A A A A TDM-180723 A A A A TDM-180724 A A A A TDM-180729 C B B A TDM-180730 B B B A TDM-180732 B B B A TDM-180733 A B A A TDM-180745 B B B A TDM-180750 C C B B TDM-180751 C C C TDM-180793 B B To To TDM-180809 C D C B TDM-180811 B B To To TDM-180812 C C B A TDM-180815 B B To To TDM-180816 C C B TDM-180817 B B To To TDM-180824 B B To To TDM-180825 B B B To To TDM-180835 B B B To To TDM-180837 B B B To To TDM-180838 B B B To To TDM-180839 B C B A TDM-180842 B B B A TDM-180862 B B B To To TDM-180863 C C To To TDM-180864 B B

Abstract

La présente invention concerne un petit composé moléculaire, qui est caractérisé en ce qu'il s'agit un composé représenté par la formule structurale suivante ou un stéréoisomère, un isomère géométrique, un tautomère, un racémate, un hydrate, un solvate ou un métabolite de celui-ci et un sel ou promédicament pharmaceutiquement acceptable représenté dans la formule (I) : X1 et X2 sont choisis parmi le carbone ou l'azote ; Z représente carbone ou azote ; n1 vaut 0 ou 1 ; n2 et n3 sont identiques ou différents, et valent 0 ou n'importe quel nombre naturel ; le groupe cyclique représenté par G est un cycle hétérocyclique saturé ; un ou plusieurs atomes d'hydrogène sur le cycle hétérocyclique saturé sont substitués par R ; et R est choisi parmi hydrogène, halogène, alkyle, alkyle substitué, amino, amine, amine substituée, amide, amide substitué, ester, carbonyle substitué, cycloalkyle, cycloalkyle substitué, hétérocycloalkyle, hétérocycloalkyle substitué, aryle, aryle substitué, hétéroaryle, hétéroaryle substitué, sulfone substituée et sulfoxyde substitué. Le petit composé moléculaire selon la présente invention peut être utilisé pour traiter, prévenir et soulager des maladies auto-immunes et/ou des maladies cutanées inflammatoires liées au système immunitaire.
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ANDREW FENSOME, CATHERINE M. AMBLER, ERIC ARNOLD, MARY ELLEN BANKER, MATTHEW F. BROWN, JILL CHRENCIK, JAMES D. CLARK, MARTIN E. DO: "Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of (( S )-2,2-Difluorocyclopropyl)((1 R ,5 S )-3-(2-((1-methyl-1 H -pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841)", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 61, no. 19, 11 October 2018 (2018-10-11), US, pages 8597 - 8612, XP055688622, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.8b00917 *
DATABASE REGISTRY STN; 17 March 2019 (2019-03-17), ANONYMOUS: "Methanone, [(1S)-2,2-dimethylcyclopropyl][3-[2-[(1-methyl-1H-pyrazol-4- yl)amino]-4-pyrimidinyl]-3,8-diazabicyclo[3.2.1]oct-8-yl]- (CA INDEX NAME)", XP055805646, Database accession no. 2287303-49-3 *
DATABASE REGISTRY STN; 30 July 2020 (2020-07-30), ANONYMOUS: "2-Pyrimidinamine, N-(1-methyl-1H-pyrazol-4-yl)-4-(4-piperidinyl)- (CA INDEX NAME)", XP055805643, Database accession no. 2451582-30-0 *
FENSOME ANDREW; AMBLER CATHERINE M.; ARNOLD ERIC; BANKER MARY ELLEN; CLARK JAMES D.; DOWTY MARTIN E.; EFREMOV IVAN V.; FLICK ANDRE: "Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 28, no. 10, 31 March 2020 (2020-03-31), AMSTERDAM, NL, XP086135504, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2020.115481 *

Cited By (2)

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Publication number Priority date Publication date Assignee Title
EP4011865A4 (fr) * 2019-08-09 2022-11-02 The National Institutes of Pharmaceutical R&D Co., Ltd Composé de pyrimidine substitué par hétérocyclyle ponté, son procédé de préparation et son utilisation pharmaceutique
WO2024041397A1 (fr) * 2022-08-22 2024-02-29 Hangzhou Highlightll Pharmaceutical Co., Ltd Inhibiteurs de jak1/jak2/tyk2 pour le traitement topique de maladies dermatologiques

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