WO2022111499A1 - 一种酰胺化合物、药物组合物及其应用 - Google Patents

一种酰胺化合物、药物组合物及其应用 Download PDF

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WO2022111499A1
WO2022111499A1 PCT/CN2021/132652 CN2021132652W WO2022111499A1 WO 2022111499 A1 WO2022111499 A1 WO 2022111499A1 CN 2021132652 W CN2021132652 W CN 2021132652W WO 2022111499 A1 WO2022111499 A1 WO 2022111499A1
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cancer
cycloalkyl
heterocycloalkyl
amide compound
chain alkyl
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PCT/CN2021/132652
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English (en)
French (fr)
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黄立晔
李华
刘华斌
王志远
李涛
欧阳飞燕
张新苗
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深圳铂立健医药有限公司
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Priority to EP21897000.2A priority Critical patent/EP4253375A1/en
Priority to US18/254,089 priority patent/US20230416237A1/en
Priority to JP2023532714A priority patent/JP2023551313A/ja
Priority to CN202180004138.7A priority patent/CN114269736B/zh
Publication of WO2022111499A1 publication Critical patent/WO2022111499A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • 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
    • 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
    • C07D405/14—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 three or more hetero rings

Definitions

  • the application belongs to the technical field of medicinal chemistry, and specifically relates to an amide compound, a pharmaceutical composition containing the amide compound, and the application of the amide compound or the pharmaceutical composition in the preparation of medicines.
  • JAKs are non-receptor tyrosine kinases that include four family members: JAK1, JAK2, JAK3 and TYK2. JAKs play key roles in the signaling of many cytokines and growth factors. When a cytokine binds to its receptor, JAKs coupled to that receptor are phosphorylated and activated. Activated JAKs in turn phosphorylate cytokine receptors and signal transducers and activators of transcription (STAT) proteins. Activated STAT proteins form dimers, translocate into the nucleus, and regulate gene expression ("The regulation of JAKs in cytokine signaling and its breakdown in disease", Hammaren H.M. et al., Cytokine, 2019, 118, 48-63).
  • JAK/STAT signaling pathway mediates the signaling of many cytokines
  • dysregulation of the JAK/STAT signaling pathway causes many inflammatory and autoimmune diseases and cancers
  • JAK-STAT Pathway: Impact on Human Disease and Therapeutic Intervention O'Shea J.J. et al., Annual Review of Medicine, 2015, 66, 311-328.
  • JAK kinases Therapeutic targeting of JAKs: from hematology to rheumatology and from the first to the second generation of JAK inhibitors", Bertsias G., Mediterranean Journal of Rheumatology, 2020, p. 31, Supp 1, 105-111).
  • JAK inhibitors have been approved for the treatment of inflammatory and autoimmune diseases (such as tofacitinib and baricitinib) and primary myelofibrosis (such as ruxolitinib), but these drugs are dose-limiting Toxicity, such as side effects of anemia and thrombocytopenia (“Clinical efficacy of launched JAK inhibitors in rheumatoid arthritis”, Taylor P.C., Rheumatoid arthritis, 2019, 58, i17-i26; “Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have an inadequate response to methotrexate”, Keystone E.C.
  • JAK1 is the most widely involved kinase in cytokine signaling, and is the only member capable of pairing with the other three JAKs to modulate signaling. Due to this feature of JAK1, selective inhibition of JAK1 without the need to inhibit other JAKs, especially JAK2, is sufficient to block the JAK/STAT signaling pathway (“Selective JAKinibs: Prospects in Infammatory and Autoimmune Diseases”, Virtanen A.T. et al. , BioDrugs, 2019, 33, 15-32). Therefore, selective JAK1 inhibitors may be sufficient for the treatment of inflammatory and autoimmune diseases and cancers associated with dysregulation of the JAK/STAT signaling pathway.
  • the present application provides an amide compound, a pharmaceutical composition and an application thereof, wherein the amide compound has the effect of inhibiting the kinase activity of JAK1 and has good JAK2 selectivity.
  • the application provides an amide compound, the amide compound has a structure as shown in formula I:
  • R 1 is selected from H, halogen, C1-C6 straight-chain or branched-chain alkyl, C3-C6 cycloalkyl or OR a ; the straight-chain or branched-chain alkyl, cycloalkyl is unsubstituted or is 1 to 3 (eg 1, 2 or 3) R 1a substitutions.
  • R 1a is selected from D or halogen.
  • R 2 is selected from H, C1-C6 linear or branched alkyl, C3-C10 cycloalkyl or C2-C10 heterocycloalkyl; the linear or branched alkyl, cycloalkyl, Heterocycloalkyl is unsubstituted or substituted with 1 to 3 (eg 1, 2 or 3) R 2a .
  • R 2a is selected from D, halogen, cyano, unsubstituted or halogenated C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, OR a1 , SR a1 , NR b1 R c1 , COR a1 , CONR b1 R c1 , COOR a1 , SO 2 R a1 , SO 2 NR b1 R c1 , NR b1 COR a1 , NR d1 CONR b1 R c1 , NR b1 SO 2 R a1 , NR d1 SO 2 NR b1 R c1 or SOR a1 .
  • R 3 is selected from H, halogen, cyano, unsubstituted or halogenated C1-C6 straight or branched chain alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl .
  • R 4 is selected from SO 2 R a2 , COR a2 , COOR a2 , C3-C10 cycloalkyl or C2-C10 heterocycloalkyl; the cycloalkyl and heterocycloalkyl are unsubstituted or replaced by 1- 5 (eg 1, 2, 3, 4 or 5) R 4a substitutions.
  • R 4a is selected from D, halogen, cyano, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, OR a3 , SR a3 , NR b3 R c3 , COR a3 , CONR b3 R c3 , COOR a3 , SO 2 R a3 or SO 2 NR b3 R c3 ; the straight-chain or branched-chain alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or replaced by 1 to 5 (for example, 1 , 2, 3, 4 or 5) R 4b substitutions.
  • R 4b is selected from D, halogen, cyano, OR a4 or NR b4 R c4 .
  • R 5 is selected from F, cyano group, C1-C6 straight or branched chain alkyl, OR a5 .
  • R a , R a1 , R b1 , R c1 , R d1 , R a2 , R a3 , R b3 , R c3 , R a4 , R b4 , R c4 , R a5 are each independently selected from H, C1-C10 linear chains or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl or C2-C10 heterocycloalkyl; the straight or branched chain alkyl, alkenyl, alkynyl, ring Alkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 (eg 1, 2, 3 or 4) R 6 .
  • 1 to 4 eg 1, 2, 3 or 4
  • R 6 is selected from D, halogen, cyano, hydroxyl, unsubstituted or halogenated C1-C6 straight or branched chain alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2 ⁇ C6 heterocycloalkyl, OR a6 , SR a6 , NR b6 R c6 , COR a6 , CONR b6 R c6 , COOR d6 , SO 2 R a6 , SO 2 NR b6 R c6 , NR b6 COR a6 , NR d6 CONR b6 R c6 , NR b6 SO 2 R a6 , NR d6 SO 2 NR b6 R c6 or SOR a6 .
  • R a6 , R b6 , R c6 , and R d6 are each independently selected from H, C1-C10 straight or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl or C2- C10 heterocycloalkyl.
  • n is selected from an integer from 0 to 3, such as 0, 1, 2 or 3.
  • R 5 is not connected or connected by chemical bonds to form a 3- to 6-membered carbocyclic or carboheterocycle, that is, two substituents R 5 connected to the same C atom, connected to adjacent two
  • the 2 substituents R on each carbon atom are not connected to each other, or are connected by chemical bonds to form a ring, which is a 3- to 6-membered (eg, 3-, 4-, 5- or 6-membered) carbocyclic or carboheterocycle .
  • the two substituents R b1 and R c1 , R b3 and R c3 , R b4 and R c4 , R b6 and R c6 connected to the same N atom are not connected to each other, or are connected to form a heterocycle through chemical bonds base (N-containing heterocycle).
  • the heterocyclic group is unsubstituted or substituted by 1 to 3 (for example, 1, 2 or 3) substituents, and the selection range of the substituents is the same as that of R 6 .
  • the halogen includes F, Cl, Br or I; the same description is referred to below, and all have the same meaning.
  • the C1-C10 straight-chain or branched-chain alkyl groups can each independently be C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 straight-chain or branched-chain alkyl groups, for example Properties include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, or neopentyl, and the like.
  • the C3-C10 cycloalkyl groups can each independently be C3, C4, C5, C6, C7, C8, C9 or C10 cycloalkyl groups, exemplarily including but not limited to: cyclopropyl, cyclobutyl, cyclo pentyl or cyclohexyl, etc.
  • the C2-C10 heterocycloalkyl groups can each independently be C2, C3, C4, C5, C6, C7, C8, C9 or C10 heterocycloalkyl groups, wherein the heteroatoms include O, N, S, P or Si, etc., illustratively include, but are not limited to, a tetrahydrofuran ring, a tetrahydropyrrole ring (pyrrolidine ring), a piperidine ring, and the like.
  • the C1-C6 linear or branched alkyl groups can each independently be C1, C2, C3, C4, C5 or C6 linear or branched alkyl groups, exemplarily including but not limited to: methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or neopentyl, etc.
  • the C3-C6 cycloalkyl groups can each independently be C3, C4, C5 or C6 cycloalkyl groups, exemplarily including but not limited to: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.
  • the C2-C6 heterocycloalkyl groups can each independently be C2, C3, C4, C5 or C6 heterocycloalkyl groups, wherein the heteroatoms include O, N, S or P, etc., exemplarily including but not limited to : tetrahydrofuran ring, tetrahydropyrrole ring (pyrrolidine ring), piperidine ring, etc.
  • the C2-C6 alkenyl groups can each independently be C2, C3, C4, C5 or C6 alkenyl groups, exemplarily including but not limited to: vinyl, propenyl, allyl or 1-butenyl and the like.
  • the C2-C6 alkynyl groups can each independently be C2, C3, C4, C5 or C6 alkynyl groups, exemplarily including but not limited to: ethynyl, propynyl, propargyl, 1-butynyl or 2-butynyl, etc.
  • the C2-C10 alkenyl groups may each independently be C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkenyl groups.
  • the C2-C10 alkynyl groups can each independently be a C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkynyl group.
  • the amide compound has a structure as shown in formula IA:
  • R 3 and R 4 each independently have the same limited range as in formula I.
  • R 5a and R 5b are each independently selected from H, F, cyano, C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl or OR a5 ; R 5a and R 5b are not connected or A 3- to 6-membered carbocyclic or heterocarbocyclic ring is formed by chemical bonding.
  • the R 3 is selected from H, halogen, C1-C6 straight or branched chain alkyl.
  • the R 4 is selected from SO 2 R a2 ( The dashed line represents the attachment site of the group), unsubstituted or R 4a substituted C2-C10 heterocycloalkyl.
  • C2-C10 heterocycloalkyl exemplarily includes but is not limited to: etc.; the dotted line represents the attachment site of the group.
  • the R a2 is selected from C1-C6 linear or branched alkyl groups.
  • the R a5 is selected from C1-C6 straight or branched chain alkyl, more preferably methyl or ethyl.
  • the amide compound has a structure as shown in formula IB:
  • R 3 , R 5a , and R 5b each independently have the same defined ranges as in formula IA.
  • Y is NR 7 or O.
  • R 7 is selected from H, C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, C2-6 heterocycloalkyl; the linear or branched chain alkyl, cycloalkyl, heterocycloalkyl Unsubstituted or substituted with 1 to 5 (eg 1, 2, 3, 4 or 5) R 7a .
  • R 7a is selected from D, halogen, cyano, C1-C6 (eg C1, C2, C3, C4, C5 or C6) straight or branched chain alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl , hydroxyl, C1-C6 linear or branched alkoxy; the linear or branched alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or replaced by 1 to 5 (for example, 1, 2, 3 , 4 or 5) R 7b substitutions.
  • C1-C6 eg C1, C2, C3, C4, C5 or C6 straight or branched chain alkyl
  • C3-C6 cycloalkyl C2-C6 heterocycloalkyl
  • hydroxyl C1-C6 linear or branched alkoxy
  • the linear or branched alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or replaced by
  • R 7b is selected from D, halogen, cyano, hydroxyl, C1-C6 linear or branched alkoxy.
  • n 1 or 2
  • p is selected from the integer of 1-3, for example, it may be 1, 2 or 3.
  • the R 3 is selected from H, halogen, methyl.
  • the R 5a and R 5b are each independently selected from H, F, methoxy or ethoxy.
  • the R 7 is H or methyl.
  • the p is 2.
  • the amide compound includes any one or a combination of at least two of the following compounds:
  • the present application provides a stereoisomer, geometric isomer, tautomer of the amide compound described in the first aspect, or a pharmaceutically acceptable salt thereof.
  • the application provides a pharmaceutical composition, the pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable carrier or excipient; the active ingredient comprises the amide compound described in the first aspect, the Any one or a combination of at least two of the stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof described in the second aspect.
  • the present application provides an amide compound as described in the first aspect, a stereoisomer, geometric isomer, tautomer or a pharmaceutically acceptable salt thereof as described in the second aspect, Use of the pharmaceutical composition according to the third aspect in the preparation of a medicament for inhibiting JAK kinase.
  • the JAK kinase is JAK1 kinase.
  • the present application provides an amide compound as described in the first aspect, a stereoisomer, geometric isomer, tautomer or a pharmaceutically acceptable salt thereof as described in the second aspect, Use of the pharmaceutical composition according to the third aspect in the preparation of a medicament for treating JAK kinase-mediated diseases.
  • the diseases include autoimmune diseases, inflammatory diseases, pain diseases, respiratory diseases, airway diseases, lung diseases, pneumonia and injuries, pulmonary hypertension, gastrointestinal diseases, allergic diseases, infectious diseases, trauma and tissue damage diseases , fibrotic disease, eye disease, joint disease, muscle disease, bone disease, skin disease, kidney disease, hematopoietic system disease, liver disease, oral disease, metabolic disease, heart disease, vascular disease, neuroinflammatory disease, neurodegenerative disease , sepsis, genetic disease or cancer.
  • the disease includes inflammation, autoimmune disease or cancer.
  • the inflammatory, autoimmune diseases include systemic lupus erythematosus, lupus nephritis, arthritis, psoriasis, Crohn's disease, ulcerative colitis, atopic dermatitis, gout, alopecia areata, vitiligo, suppurative Hidradenitis, type 1 diabetes, chronic kidney disease, acute kidney injury, chronic obstructive pulmonary disease, asthma, bronchitis, or graft-versus-host disease.
  • the cancer includes breast cancer, lung cancer, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer , testicular cancer, thyroid cancer, uterine cancer, cervical cancer, vaginal cancer, leukemia, myelofibrosis, multiple myeloma or lymphoma.
  • the present application provides an amide compound with a new chemical structure, which has a significant inhibitory activity against JAK kinase, especially the activity of inhibiting JAK1 kinase, and its inhibitory activity on JAK1 kinase is higher than that on JAK2 kinase, and can be used as a highly selective sexual JAK1 kinase inhibitor.
  • the amide compounds of the present application can be used to prepare medicines for the treatment of diseases mediated by JAK1 kinase, and will exert a good therapeutic effect in diseases such as inflammation, autoimmune diseases or cancer mediated by JAK1 kinase, and have broad application prospects.
  • straight or branched chain alkyl refers to a straight or branched chain saturated hydrocarbon group.
  • alkyl groups include methyl (Me), ethyl (Et), propyl (eg n-propyl, isopropyl), butyl (eg n-butyl, isobutyl, tert-butyl), pentyl (eg e.g. n-pentyl, isopentyl, neopentyl), hexyl (e.g.
  • heptyl such as n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 2-methylhexyl, 3-methylhexyl, 2, 2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl-1, etc.
  • octyl eg 1-octyl, 2-octyl, 2-ethylhexyl, etc.
  • nonyl such as 1-nonyl
  • decyl such as n-decyl, etc.
  • similar groups are further preferred linear or branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. Unless defined to the contrary, all groups in this application are defined as defined here
  • haloalkyl refers to an alkyl group having one or more halogen substituents. wherein the alkyl group and the halo or halogen are as defined above. Examples of haloalkyl groups include CH2F , CHF2 , CF3 , C2F5 , CCl3 , and the like.
  • alkenyl groups include vinyl, propenyl, allyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 1, 3-pentadienyl, 1-hexenyl, 2-hexenyl, etc., and the like.
  • alkynyl refers to a hydrocarbyl group having one or more C ⁇ C triple bonds.
  • alkynyl groups include ethynyl, propynyl, propargyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl base, etc., and similar groups.
  • cycloalkyl refers to a non-aromatic carbocyclic ring, including cyclized alkyl, cyclized alkenyl, cyclized alkynyl.
  • Cycloalkyl groups can be monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) ring systems, including spiro rings. In certain embodiments, a cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10 carbon atoms. Cycloalkyl groups may further have 0, 1, 2 or 3 C ⁇ C double bonds, and/or 0, 1 or 2 C ⁇ C triple bonds.
  • cycloalkyl also included in the definition of cycloalkyl are those moieties having one or more aromatic rings fused to the cycloalkyl ring (eg with a shared bond), eg pentane, pentene, hexane, hexane Benzo derivatives of alkenes, etc., and similar compounds. Cycloalkyl groups having one or more fused aromatic rings can be attached through an aromatic moiety or a non-aromatic moiety.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene group, adamantyl, indenyl, tetrahydronaphthyl and similar groups.
  • heterocycloalkyl refers to a non-aromatic heterocycle wherein one or more of the atoms forming the ring is a heteroatom such as O, N, P or S.
  • Heterocyclyl groups can include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) ring systems as well as spiro rings.
  • heterocycloalkyl examples include, but are not limited to: aziridine, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, oxazolidinyl , thiazolidinyl, imidazolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, and the like.
  • heterocycloalkyl those moieties having one or more aromatic rings fused to a non-aromatic heterocycloalkyl ring (eg with a shared bond), eg 2,3-dihydrobenzene furanyl, 1,3-benzodioxolyl, benzo-1,4-dioxanyl, phthalimido, naphthalimide, and the like group.
  • Heterocycloalkyl groups with one or more fused aromatic rings can be attached through an aromatic moiety or a non-aromatic moiety.
  • amide compound as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, isotopes.
  • the amide compounds described herein may be asymmetric, eg, having one or more stereocenters. Unless otherwise limited, all stereoisomers may be enantiomers and diastereomers.
  • the amide compounds of the present application containing asymmetrically substituted carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be prepared by resolution of racemates, or by using chiral synthons or chiral reagents.
  • the amide compounds described herein may also include tautomeric forms. New forms of tautomers result from the exchange of single bonds and adjacent double bonds together with the migration of protons.
  • the amide compounds described herein may also include all isotopic forms of atoms present in intermediates or final compounds.
  • Isotopes include atoms with the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • the present application also includes pharmaceutically acceptable salts of the amide compounds.
  • “Pharmaceutically acceptable salt” refers to a derivative of a compound wherein the parent compound is modified by conversion of the base moiety present to its salt form, or wherein the parent compound is converted to its salt by the presence of an acid moiety Derivatives of compounds modified in form.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, salts of inorganic or organic acids with basic groups such as ammonia, or salts of inorganic or organic bases with acidic groups such as carboxylic acids.
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compounds of formula I, formula IA and formula IB by reacting the free base forms of these compounds with 1 to 4 equivalents of the appropriate acid in a solvent system. Suitable salts are listed in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton Pa., 1985, 1418 and Journal of Pharmaceutical Science, 66, 2, 1977.
  • amide compounds described herein, and pharmaceutically acceptable salts thereof also include solvated or hydrated forms.
  • solvated or hydrated forms are equivalent to unsolvated or non-hydrated forms and are included within the scope of this application.
  • Some of the amide compounds of the present application may exist in various crystalline or amorphous forms. In general, all physical forms of the compounds are included within the scope of this application.
  • the present application also includes prodrugs of the amide compounds.
  • a prodrug is a pharmacological substance (ie, drug) derived from the parent drug. Once administered, the prodrug is metabolized in vivo to the parent drug.
  • Prodrugs can be prepared by substituting one or more functional groups present in a compound. Information on the preparation and use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", T. Higuchi and V. Stella, Vol. 14 of the A.C.S. Symposium Series and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Found in Pharmaceutical Association and Pergamon Press, 1987.
  • the amide compound includes the following compounds:
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the amide compound or its N-oxide derivative, individual isomers, or a mixture of isomers thereof, and a pharmaceutically acceptable salt and a pharmaceutically acceptable of carriers or excipients.
  • the pharmaceutical compositions of the present application may be administered orally, parenterally (by injection), by nebulization, topically, rectally, nasally, vaginally, intraperitoneally or via Implanted depot dosing.
  • the amide compounds and pharmaceutically acceptable salts can be used in combination with one or more other drugs.
  • the amide compounds described in the present application and the drugs used in combination may have a superimposed effect or a synergistic effect.
  • the drugs used in combination can be small molecule drugs, monoclonal drugs, fusion protein drugs or anti-sense DNA drugs.
  • the amide compound can be obtained by the following preparation route 1 or preparation route 2:
  • NH 2 -pyrazole represents R 1 , R 2 , R 3 , R 4 , R 5 , and n each independently have the same limited range as in formula I; Ts, Boc, and SEM are amino protecting groups; Bzl represents benzyl, which is carboxylic acid protecting groups; Y is a leaving group such as Cl.
  • Ts, Boc, and SEM are amino protecting groups;
  • Bzl represents benzyl, which is carboxylic acid protecting groups;
  • Y is a leaving group such as Cl.
  • N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-5-methyl-4-(7-nitro-1-((2-(trimethyl) silyl)ethoxy)methyl)-1H-indol-3-yl)pyrimidin- 2 -amine (2.3 g, 4.5 mmol) was dissolved in CH2Cl2 (15 mL), trifluoroacetic acid (TFA) was added, 15 mL), and the reaction was naturally raised to room temperature for 1 h.
  • intermediate 6 (1.2 g, 3.4 mmol) and (2R,4S)-N-Boc-4-fluoroproline (792 mg, 3.4 mmol) were dissolved in pyridine (10 mL), then added Propylphosphoric acid tricyclic anhydride (50%, the solvent is EtOAc, 10.8 g, 17.0 mmol), and reacted at room temperature for 18 h. After the reaction was complete, it was diluted with EtOAc and neutralized with 4M hydrochloric acid. The organic phase was washed with water, dried over anhydrous Na 2 SO 4 , filtered and concentrated.
  • Examples 2-4 shown in Table 4 below were prepared according to the method in Example 1.
  • the aqueous phase was basified with saturated Na2CO3 solution and extracted with CH2Cl2 .
  • the organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated, and the obtained residue was separated and purified by silica gel column chromatography (the mobile phase was CH 2 Cl 2 and MeOH with a volume ratio of 10:1, 0.1% Et 3 N) to obtain Product 64 mg. Yield 60%.
  • LCMS (ESI): m/z 534 (M+H) + .
  • Examples 6-17 shown in Table 5 below were prepared according to the method in Example 5.
  • Examples 22-39 shown in Table 6 below were prepared according to the methods in Examples 18 and 19, and Examples 20 and 21.
  • amide compounds provided in the above examples were tested for the inhibitory activity of JAK1 and JAK2 kinases, and the methods were as follows:
  • the inhibitory activity (IC 50 ) of the amide compounds against the kinases JAK1 and JAK2 at 1 mM ATP was detected by the Mobility Shift Assay method.
  • JAK1 kinase was purchased from Carna (Cat. No. 08-144, Lot: 11CBS-0144V) and JAK2 kinase was purchased from Carna (Cat. No. 08-045, Lot: 10CBS-0289R).
  • JAK1Peptide was purchased from GL Corporation (catalog number: 758318, lot number: P191104-TL758318), and Kinase substrate22 was purchased from GL company (catalog number: 112393, lot number: P200403-CL112393).
  • the positive control compound used was baricitinib. Specific steps are as follows:
  • the initial concentration of the test compound is 10000nM (JAK1) or 30000nM (JAK2), diluted to 100 times the final concentration of 100% DMSO solution in 384-well plate, 3 times diluted compound, 10 concentrations .
  • the amide compounds provided in this application can effectively inhibit JAK1 kinase at a concentration of 1 mM ATP. Moreover, the amide compounds described in the present application are more active in inhibiting JAK1 kinase than JAK2 kinase, and have high JAK1 selectivity. Compared with the two JAK1 inhibitors, abrocitinib and AZD4205, most of the compounds in this application are more selective for inhibiting JAK1 kinase than for inhibiting JAK2 kinase.
  • the cytokine IFN ⁇ can induce STAT3 phosphorylation (pSTAT3) through the JAK1/TYK2 signaling pathway.
  • the present application uses mouse whole blood experiments to test the inhibition of INF ⁇ -induced pSTAT3 by the compounds provided in Example 30 and Example 32 of the present application, and simultaneously tests two selective JAK1 inhibitors abrocitinib and AZD4205 for comparison.
  • the IFN ⁇ used was Recombinant mouse IFN ⁇ (Miltenyi #130-093-131), the pSTAT3 antibody used was Alexa Fluor 488 anti-STAT3 Phospho (Tyr705) Antibody (Biolegend #651106), and the CD3 antibody used was Brilliant Violet 421 anti-mouse CD3 Antibody (Biolegend #100228).
  • Cytokine dilution buffer was: PBS + 0.1% BSA, filtered and stored at -4°C.
  • the FACS buffer was: PBS+0.2%BSA+1mM EDTA. Specific steps are as follows:
  • Example 30 and Example 32 for inhibiting the expression of pSTAT3 induced by IFN ⁇ are respectively 127nM and 121nM, and higher inhibitory activity than two JAK1-selective inhibitors, abrocitinib and AZD4205.
  • the present application illustrates the amide compounds, pharmaceutical compositions and applications of the present application through the above-mentioned examples, but the present application is not limited to the above-mentioned examples, that is, it does not mean that the present application must rely on the above-mentioned examples for implementation.
  • Those skilled in the art should understand that any improvement to the application, the equivalent replacement of each raw material of the product of the application, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the application.

Abstract

本申请提供一种酰胺化合物、其异构体、药学上可接受的盐、药物组合物及其应用，所述酰胺化合物具有式I所示结构。本申请的酰胺化合物具有显著的JAK激酶抑制活性、尤其是JAK1激酶抑制活性，对JAK1激酶的抑制活性比对JAK2激酶的抑制活性高，能够作为高选择性的JAK1激酶抑制剂。因此本申请的酰胺化合物可用于制备治疗JAK1激酶介导的疾病的药物。

Description

一种酰胺化合物、药物组合物及其应用
相关申请
本申请要求申请号为202011348554.2专利申请的优选权(在先申请的申请日为2020年11月26日，发明名称为“一种酰胺化合物、药物组合物及其应用”)，其全部内容通过引用结合在本申请中。
技术领域
本申请属于药物化学技术领域，具体涉及一种酰胺化合物、含有所述酰胺化合物的药物组合物以及所述酰胺化合物或药物组合物在制备药物中的应用。
背景技术
JAKs(Janus-associated kinases)是一种非受体酪氨酸激酶，其中包括四个家族成员：JAK1、JAK2、JAK3和TYK2。JAKs在许多细胞因子和生长因子的信号传导中起关键的作用。当一个细胞因子与其受体结合时，与该受体偶联的JAK发生磷酸化和激活。激活的JAK依次磷酸化细胞因子受体和信号转导子与转录激活子(STAT)蛋白。激活的STAT蛋白形成二聚体，转移至细胞核内，调节基因的表达(“The regulation of JAKs in cytokine signaling and its breakdown in disease”，Hammaren H.M.等，Cytokine，2019，118，48-63)。
由于JAK/STAT信号通路介导了许多细胞因子的信号传递，JAK/STAT信号通路的失调引起了许多炎症和自身免疫性疾病以及癌症(“The JAK-STAT Pathway:Impact on Human Disease and Therapeutic Intervention”，O'Shea J.J.等，Annual Review of Medicine，2015，66，311-328)。这些疾病已经在临床上被证实可以通过抑制JAK激酶来治疗(“Therapeutic targeting of JAKs:from hematology to rheumatology and from the first to the second generation of JAK inhibitors”，Bertsias G.，Mediterranean Journal of Rheumatology，2020，31，Supp 1，105-111)。目前，已经有多个非选择性的JAK抑制剂被批准用于治疗炎症和自身免疫性疾病(例如tofacitinib和baricitinib)以及原发性骨髓纤维化(例如ruxolitinib)，但这些药物都有剂量限制性毒性，例如贫血和血小板降低的副作用(“Clinical efficacy of launched JAK inhibitors in rheumatoid arthritis”，Taylor P.C.，Rheumatology，2019，58，i17-i26；“Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have an inadequate response to methotrexate”，Keystone E.C.等，Annals of the Rheumatic Diseases，2015，74，333-340)，其原因是这些抑制剂都抑制了JAK2激酶，从而干扰了***(EPO)和血小板生成素(TPO)的信号(“Selective JAKinibs:Prospects in Infammatory and Autoimmune Diseases”，Virtanen A.T.等，BioDrugs，2019，33，15-32)。
在JAK家族的四个成员中，JAK1是参与细胞因子信号最广的激酶，而且是唯一能够与其它三个JAKs形成配对来调节信号的成员。由于JAK1的这一特点，有选择性地抑制JAK1而不需要抑制其它的JAKs，尤其是JAK2就足以阻断JAK/STAT的信号通路(“Selective JAKinibs：Prospects in Infammatory and Autoimmune Diseases”，Virtanen A.T.等，BioDrugs，2019，33，15-32)。因此，有选择性的JAK1抑制剂有可能足以用于治疗与JAK/STAT信号通 路失调相关的炎症和自身免疫性疾病以及癌症。目前，已经公开的有选择性的JAK1抑制剂(例如upadacitinib、filgotinib)被批准用于治疗RA，但这些抑制剂对JAK2的选择性都不高，在激酶测试中都小于3倍(“In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib(ABT-494)”，Parmentier J.M.等，BMC Rheumatology，2018，2，23；“Preclinical Characterization of GLPG0634，a selective inhibitor of JAK1，for the treatment of inflammatory diseases”，Van Rompaey L.等，Journal of Immunology，2013，191，3568-3577；“Triazolopyridines as Selective JAK1Inhibitors:From Hit Identification to GLPG0634”，Menet C.J.等，Journal of Medicinal Chemistry，2014，57，9323-9342)。
因此，开发一种对JAK2选择性更高、对JAK1抑制作用更显著的化合物，是本领域亟待解决的问题。
发明内容
本申请提供一种酰胺化合物、药物组合物及其应用，其中，所述酰胺化合物具有抑制JAK1激酶活性的作用，以及良好的JAK2选择性。
第一方面，本申请提供一种酰胺化合物，所述酰胺化合物具有如式I所示结构：
Figure PCTCN2021132652-appb-000001
式I中，R 1选自H、卤素、C1～C6直链或支链烷基，C3～C6环烷基或OR a；所述直链或支链烷基、环烷基无取代或被1～3个(例如1个、2个或3个)R 1a取代。
R 1a选自D或卤素。
式I中，R 2选自H、C1～C6直链或支链烷基、C3～C10环烷基或C2～C10杂环烷基；所述直链或支链烷基、环烷基、杂环烷基无取代或被1～3个(例如1个、2个或3个)R 2a取代。
R 2a选自D、卤素、氰基、未取代或卤代的C1～C6直链或支链烷基、C3～C6环烷基、C2～C6杂环烷基、OR a1、SR a1、NR b1R c1、COR a1、CONR b1R c1、COOR a1、SO 2R a1、SO 2NR b1R c1、NR b1COR a1、NR d1CONR b1R c1、NR b1SO 2R a1、NR d1SO 2NR b1R c1或SOR a1。
式I中，R 3选自H、卤素、氰基、未取代或卤代的C1～C6直链或支链烷基、C2～C6烯基、C2～C6炔基或C3～C6环烷基。
式I中，R 4选自SO 2R a2、COR a2、COOR a2、C3～C10环烷基或C2～C10杂环烷基；所述环烷基、杂环烷基无取代或被1～5个(例如1个、2个、3个、4个或5个)R 4a取代。
R 4a选自D、卤素、氰基、C1～C6直链或支链烷基、C3～C6环烷基、C2～C6杂环烷基、OR a3、SR a3、NR b3R c3、COR a3、CONR b3R c3、COOR a3、SO 2R a3或SO 2NR b3R c3；所述直链或支链烷基、环烷基、杂环烷基无取代或被1～5个(例如1个、2个、3个、4个或5个)R 4b取 代。
R 4b选自D、卤素、氰基、OR a4或NR b4R c4。
式I中，R 5选自F、氰基、C1～C6直链或支链烷基、OR a5。
R a、R a1、R b1、R c1、R d1、R a2、R a3、R b3、R c3、R a4、R b4、R c4、R a5各自独立地选自H、C1～C10直链或支链烷基、C2～C10烯基、C2～C10炔基、C3～C10环烷基或C2～C10杂环烷基；所述直链或支链烷基、烯基、炔基、环烷基、杂环烷基无取代或被1～4个(例如1个、2个、3个或4个)R 6取代。
R 6选自D、卤素、氰基、羟基、未取代或卤代的C1～C6直链或支链烷基、C2～C6烯基、C2～C6炔基、C3～C6环烷基、C2～C6杂环烷基、OR a6、SR a6、NR b6R c6、COR a6、CONR b6R c6、COOR d6、SO 2R a6、SO 2NR b6R c6、NR b6COR a6、NR d6CONR b6R c6、NR b6SO 2R a6、NR d6SO 2NR b6R c6或SOR a6。
R a6、R b6、R c6、R d6各自独立地选自H、C1～C10直链或支链烷基、C2～C10烯基、C2～C10炔基、C3～C10环烷基或C2～C10杂环烷基。
式I中，n选自0～3的整数，例如0、1、2或3。
当n≥2时，R 5之间不连接或通过化学键连接形成3至6元的碳环或碳杂环，即连接在同一个C原子上的2个取代基R 5、连接在相邻两个碳原子上的2个取代基R 5彼此不连接，或通过化学键连接成环，该环为3至6元(例如3元、4元、5元或6元)的碳环或碳杂环。
本申请中，连接于同一个N原子上的2个取代基R b1和R c1、R b3和R c3、R b4和R c4、R b6和R c6彼此不连接，或通过化学键连接成杂环基(含N杂环)。所述杂环基无取代或被1～3个(例如1个、2个或3个)取代基取代，所述取代基的选择范围与R 6相同。
本申请中，所述卤素包括F、Cl、Br或I；下文涉及到相同描述，均具有相同的含义。
本申请中，所述C1～C10直链或支链烷基各自独立地可以为C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的直链或支链烷基，示例性地包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基或新戊基等。
所述C3～C10环烷基各自独立地可以为C3、C4、C5、C6、C7、C8、C9或C10的环烷基，示例性地包括但不限于：环丙基、环丁基、环戊基或环己基等。
所述C2～C10杂环烷基各自独立地可以为C2、C3、C4、C5、C6、C7、C8、C9或C10的杂环烷基，其中的杂原子包括O、N、S、P或Si等，示例性地包括但不限于：四氢呋喃环、四氢吡咯环(吡咯啶环)、哌啶环等。
所述C1～C6直链或支链烷基各自独立地可以为C1、C2、C3、C4、C5或C6的直链或支链烷基，示例性地包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基或新戊基等。
所述C3～C6环烷基各自独立地可以为C3、C4、C5或C6的环烷基，示例性地包括但不限于：环丙基、环丁基、环戊基或环己基等。
所述C2～C6杂环烷基各自独立地可以为C2、C3、C4、C5或C6的杂环烷基，其中的杂原子包括O、N、S或P等，示例性地包括但不限于：四氢呋喃环、四氢吡咯环(吡咯啶环)、哌啶环等。
所述C2～C6烯基各自独立地可以为C2、C3、C4、C5或C6的烯烃基，示例性地包括但 不限于：乙烯基、丙烯基、烯丙基或1-丁烯基等。
所述C2～C6炔基各自独立地可以为C2、C3、C4、C5或C6的炔烃基，示例性地包括但不限于：乙炔基、丙炔基、炔丙基、1-丁炔基或2-丁炔基等。
所述C2～C10烯基各自独立地可以为C2、C3、C4、C5、C6、C7、C8、C9或C10的烯烃基。
所述C2～C10炔基各自独立地可以为C2、C3、C4、C5、C6、C7、C8、C9或C10的炔烃基。
优选地，所述酰胺化合物具有如式IA所示结构：
Figure PCTCN2021132652-appb-000002
式IA中，R 3、R 4各自独立地具有与式I中相同的限定范围。
式IA中，R 5a、R 5b各自独立地选自H、F、氰基、C1～C6直链或支链烷基、C3～C6环烷基或OR a5；R 5a与R 5b不连接或通过化学键连接形成3至6元的碳环或杂碳环。
优选地，所述R 3选自H、卤素、C1～C6直链或支链烷基。
优选地，所述R 4选自SO 2R a2(
Figure PCTCN2021132652-appb-000003
虚线代表基团的连接位点)、无取代或R 4a取代的C2～C10杂环烷基。
上述基团中，C2～C10杂环烷基示例性地包括但不限于：
Figure PCTCN2021132652-appb-000004
Figure PCTCN2021132652-appb-000005
等；虚线代表基团的连接位点。
优选地，所述R a2选自C1～C6直链或支链烷基。
优选地，所述R a5选自C1～C6直链或支链烷基，进一步优选为甲基或乙基。
优选地，所述酰胺化合物具有如式IB所示结构：
Figure PCTCN2021132652-appb-000006
式IB中，R 3、R 5a、R 5b各自独立地具有与式IA中相同的限定范围。
式IB中，Y为NR 7或O。
R 7选自H、C1～C6直链或支链烷基、C3～C6环烷基、C2～6杂环烷基；所述直链或支链烷基、环烷基、杂环烷基无取代或被1～5个(例如1个、2个、3个、4个或5个)R 7a取代。
R 7a选自D、卤素、氰基、C1～C6(例如C1、C2、C3、C4、C5或C6)直链或支链烷基、C3～C6环烷基、C2～C6杂环烷基、羟基、C1～C6直链或支链烷氧基；所述直链或支链烷基、环烷基、杂环烷基无取代或被1～5个(例如1个、2个、3个、4个或5个)R 7b取代。
R 7b选自D、卤素、氰基、羟基、C1～C6直链或支链烷氧基。
m为1或2，p选自1～3的整数，例如可以为1、2或3。
优选地，所述R 3选自H、卤素、甲基。
优选地，所述R 5a、R 5b各自独立地选自H、F、甲氧基或乙氧基。
优选地，所述R 7为H或甲基。
优选地，所述p为2。
优选地，所述酰胺化合物包括如下化合物中的任意一种或至少两种的组合：
Figure PCTCN2021132652-appb-000007
Figure PCTCN2021132652-appb-000008
Figure PCTCN2021132652-appb-000009
第二方面，本申请提供一种如第一方面所述的酰胺化合物的立体异构体、几何异构体、互变异构体或其药学上可接受的盐。
第三方面，本申请提供一种药物组合物，所述药物组合物包括活性成分与至少一种药用载体或赋形剂；所述活性成分包括如第一方面所述的酰胺化合物、如第二方面所述的立体异构体、几何异构体、互变异构体或其药学上可接受的盐中的任意一种或至少两种的组合。
第四方面，本申请提供一种如第一方面所述的酰胺化合物、如第二方面所述的立体异构体、几何异构体、互变异构体或其药学上可接受的盐、如第三方面所述的药物组合物在制备用于抑制JAK激酶的药物中的应用。
优选地，所述JAK激酶为JAK1激酶。
第五方面，本申请提供一种如第一方面所述的酰胺化合物、如第二方面所述的立体异构体、几何异构体、互变异构体或其药学上可接受的盐、如第三方面所述的药物组合物在制备用于治疗JAK激酶介导的疾病的药物中的应用。
所述疾病包括自身免疫性疾病、炎症疾病、疼痛病、呼吸道疾病、气道疾病、肺疾病、肺炎症和损伤、肺动脉高压、胃肠道疾病、过敏性疾病、感染疾病、创伤和组织损伤疾病、纤维化疾病、眼疾病、关节疾病、肌肉疾病、骨疾病、皮肤疾病、肾脏疾病、造血***疾病、肝脏疾病、口腔疾病、代谢疾病、心脏疾病、血管疾病、神经炎性疾病、神经变性疾病、脓毒症、基因疾病或癌症。
优选地，所述疾病包括炎症、自身免疫性疾病或癌症。
优选地，所述炎症、自身免疫性疾病包括***性红斑狼疮、狼疮性肾炎、关节炎、牛皮癣、克罗恩病、溃疡性结肠炎、特应性皮炎、痛风、脱发秃头症、白癜风、化脓性汗腺炎、I型糖尿病、慢性肾脏病、急性肾脏损伤、慢性阻塞性肺疾病、哮喘、支气管炎或移植物抗宿主病。
优选地，所述癌症包括乳腺癌、肺癌、***癌、胆小管癌、骨癌、膀胱癌、头颈癌、肾癌、肝癌、胃肠组织癌、食道癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌、甲状腺癌、子宫癌、子***、***癌、白血病、骨髓纤维化、多发性骨髓瘤或淋巴瘤。
相对于现有技术，本申请具有以下有益效果：
本申请提供一种具有新化学结构的酰胺化合物，其具有显著的抑制JAK激酶的活性、尤其是抑制JAK1激酶的活性，对JAK1激酶的抑制活性比对JAK2激酶的抑制活性高，能够作为高选择性的JAK1激酶抑制剂。本申请酰胺化合物可用于制备治疗JAK1激酶介导的疾病的药物，在JAK1激酶介导的炎症、自身免疫性疾病或癌症等病症中将发挥良好的治疗效果，具有广阔的应用前景。
具体实施方式
下面通过具体实施方式来进一步说明本申请的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本申请，不应视为对本申请的具体限制。
本申请的术语“卤基”或“卤素”包括氟、氯、溴、和碘。
术语“直链或支链烷基”是指直链或支链的饱和烃基团。烷基的实例包括甲基(Me)、乙基(Et)、丙基(例如正丙基、异丙基)、丁基(例如正丁基、异丁基、特丁基)、戊基(例如正戊基、异戊基、新戊基)、己基(例如正己基、2-己基、3-己基、2-甲基戊基、3-甲基戊基、2,2-二甲基丁基、3-乙基戊基-1等)、庚基(例如正庚基、2-庚基、3-庚基、4-庚基、2-甲基己基、3-甲基己基、2,2-二甲基戊基、3,3-二甲基戊基、3-乙基戊基-1等)、辛基(例如1-辛基、2-辛基、2-乙基己基等)、壬基(如1-壬基)、癸基(如正癸基等)，以及类似基团。进一步优选的碳原子数为1、2、3、4、5、6的直链或支链的烷基。除非有相反定义，本申请 中的所有基团定义如在本文中所定义。
术语“卤代烷基”是指具有一个或多个卤素取代基的烷基基团。其中烷基基团和卤基或卤素的定义如上。卤代烷基基团的实例包括CH 2F、CHF 2、CF 3、C 2F 5、CCl 3，以及类似基团。
术语“烯基”是指具有一个或多个C＝C双键的烃基基团。烯基的实例包括乙烯基、丙烯基、烯丙基、1-丁烯基、2-丁烯基、1,3-丁二烯基、1-戊烯基、2-戊烯基、1,3-戊二烯基、1-己烯基、2-己烯基等，以及类似基团。
术语“炔基”是指具有一个或多个C≡C三键的烃基基团。炔基的实例包括乙炔基、丙炔基、炔丙基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、1-己炔基、2-己炔基等，以及类似基团。
术语“环烷基”是指非芳香碳环，包括环化的烷基、环化的烯基、环化的炔基。环烷基可以为单环或多环(例如具有2、3或4个的稠合环)的环***，包括螺环。在某些实施方式中，环烷基可具有3、4、5、6、7、8、9、10个碳原子。环烷基可进一步具有0、1、2或3个C＝C双键，和/或，0、1或2个C≡C三键。同时被包括在环烷基的定义中的还有那些具有一个或多个稠合于环烷基环的芳香环(例如具有共用的键)的部分，例如戊烷、戊烯、己烷、己烯的苯并衍生物等，以及类似化合物。具有一个或多个稠合芳环的环烷基可以通过芳香部分或非芳香部分连接。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环己二烯基、环庚烯基、环庚二烯基、金刚烷基、二氢茚基、四氢萘基以及类似基团。
术语“杂环烷基”是指其中一个或多个形成环的原子是如O、N，P或S等杂原子的非芳香杂环。杂环基可包括单环或多环(如具有2、3或4个稠合环)的环***以及螺环。优选的“杂环烷基”的实例包括但不限于：氮杂环丙烷基、氮杂环丁烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、吡咯烷基、噁唑烷基、噻唑烷基、咪唑烷基、异噁唑烷基、异噻唑烷基、吡唑烷基、吗啉基、硫代吗啉基、哌嗪基、哌啶基，以及类似基团。同时被包括在杂环烷基的定义中还有那些具有一个或多个稠合于非芳香杂环烷基环的芳香环(例如具有共用的键)的部分，例如2,3-二氢苯并呋喃基、1,3-苯并二氧杂环戊烯基、苯并-1,4-二氧杂环己基、邻苯二甲酰亚胺基、萘二甲酰亚胺基，以及类似基团。具有一个或多个稠合芳环的杂环烷基基团可以通过芳香部分或非芳香部分连接。
术语“酰胺化合物”，如在本文中所使用，是指包括所有的立体异构体、几何异构体、互变异构体、同位素。
本申请所述酰胺化合物可以是非对称的，例如具有一个或多个立体中心。除非有另外的限定，所有的立体异构体，可以是对映异构体和非对映异构体。含有非对称取代的碳原子的本申请的酰胺化合物可以被分离成光学纯或外消旋形式。光学纯形式可以通过外消旋体的拆分来制备，或者通过使用手性合成子(synthon)或手性试剂来制备。
本申请所述酰胺化合物也可以包括互变异构体形式。互变异构体新形式由单键和相邻的双键一起伴随质子的迁移而互换所产生的。
本申请所述酰胺化合物也可以包括存在于中间体或最终化合物中的原子的所有同位素形式。同位素包括具有相同的原子序数但不同的质量数的原子。例如，氢的同位素包括氘和氚。
本申请还包括所述酰胺化合物的药学上可接受的盐。“药学上可接受的盐”是指其中母 体化合物通过所存在的碱部分转化成它的盐形式而进行改性的化合物的衍生物，或者其中母体化合物通过所存在的酸部分转化成它的盐形式而进行改性的化合物的衍生物。药学上可接受的盐的实例包括但不限于：碱性基团(如氨)的无机或有机酸的盐，或者酸性基团(如羧酸)的无机或有机碱的盐。本申请的药学上可接受的盐可以由式I、式IA和式IB的母体化合物通过在溶剂体系中使这些化合物的游离碱形式与1～4当量适当的酸反应而合成。合适的盐在Remington's Pharmaceutical Sciences，17th ed.，Mack Publishing Company，Easton Pa.，1985，1418和Journal of Pharmaceutical Science，66，2，1977中列出。
本申请所述酰胺化合物、及其药学上可接受的盐还包括溶剂化物形式或水合物形式。一般而言，溶剂化物形式或水合物形式与非溶剂化物形式或非水合物形式是等同的，均包括在本申请的范围内。本申请的一些酰胺化合物可以多种晶型形式或非晶型形式存在。总体而言，化合物的所有的物理形式都包括在本申请的范围内。
本申请还包括所述酰胺化合物的前药。前药是一种由母体药物衍生的药理学物质(即药物)。一旦给药之后，前药在体内被代谢成为母体药物。前药可以通过取代在化合物中存在的一个或多个官能团来制备。关于前药的制备和使用可以在“Pro-drugs as Novel Delivery Systems”，T.Higuchi and V.Stella，Vol.14 of the A.C.S.Symposium Series和Bioreversible Carriers in Drug Design，ed.Edward B.Roche，American Pharmaceutical Association and Pergamon Press，1987中找到。
在一个具体实施方式中，所述酰胺化合物包括如下化合物：
(S)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(甲磺酰基)吡咯啶-2-甲酰胺(S)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(乙磺酰基)吡咯啶-2-甲酰胺；
(S)-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1-(甲磺酰基)吡咯啶-2-甲酰胺；
(S)-N-(3-(5-氯-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(甲磺酰基)吡咯啶-2-甲酰胺；
(R)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(哌啶-4-基)吡咯啶-2-甲酰胺；
(2R,4S)-4-氟-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(哌啶-4-基)吡咯啶-2-甲酰胺；
(2R,4R)-4-氟-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(哌啶-4-基)吡咯啶-2-甲酰胺；
(2R,4R)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-4-甲氧基)-1-(哌啶-4-基)吡咯啶-2-甲酰胺；
(2R,4S)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-4-甲氧基-1-(哌啶-4-基)吡咯啶-2-甲酰胺；
(R)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺；
(R)-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1-(1- 甲基哌啶-4-基)吡咯啶-2-甲酰胺；
(2R,4S)-4-乙氧基-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺；
(2R,4S)-4-甲氧基-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺；
(2R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺；
(R)-N-(3-(5-氯-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺；
(R)-4,4-二氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺；
(R)-4,4-二氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺；
(2R,3'R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'S,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'R,4S)-4-氟-N-(3(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'S,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'R)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'S)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'R)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'S)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'R)-4,4-二氟-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'S)-4,4-二氟-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'R)-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'S)-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲 哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'S,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'R)-4,4-二氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'S)-4,4-二氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺；
(R)-4,4-二氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1-((R)-四氢呋喃-3-基)吡咯啶-2-甲酰胺；
(R)-4,4-二氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1-((S)-四氢呋喃-3-基)吡咯啶-2-甲酰胺；
(2R,3'R)-4,4-二氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'S)-4,4-二氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'R,4S)-4-氟-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺；
(2R,3'S,4S)-4-氟-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺；和
(2R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺。
本申请提供了一种药物组合物，由所述酰胺化合物或其N-氧化物衍生物、单独的异构体、或其异构体的混合物，以及药学上可接受的盐与药学上可接受的载体或赋形剂组成。本申请的药物组合物可以通过口服给药、胃肠外给药(注射给药)、喷雾吸入、局部给药、经直肠给药、经鼻腔给药、***给药、腹膜内给药或经由植入的储库给药。
本申请的另一方面，所述酰胺化合物和药学上可接受的盐可与一个或多个其它药物联合使用。联合用药时，本申请所述酰胺化合物与联合使用的药物可能起到叠加的作用或协同的作用。联合使用的药物可以是小分子药物、单体克隆药物、融合蛋白药物或抗感DNA药物。
在一个具体实施方式中，所述酰胺化合物可通过如下制备路线1或制备路线2获得：
制备路线1
Figure PCTCN2021132652-appb-000010
Figure PCTCN2021132652-appb-000011
制备路线2
Figure PCTCN2021132652-appb-000012
上述制备路线中，NH 2-pyrazole代表
Figure PCTCN2021132652-appb-000013
R 1、R 2、R 3、R 4、R 5、n各自独立地具有与式I中相同的限定范围；Ts、Boc、SEM为氨基保护基；Bzl代表苄基，为羧酸保护基；Y为离去基团，例如Cl。具体合成方法在实施例中进行详细描述。
制备例1
制备中间体1：3-甲氧基-1-甲基-4-氨基-1H-吡唑，具体步骤如下：
(1)合成3-甲氧基-1H-吡唑-4-甲酸甲酯
Figure PCTCN2021132652-appb-000014
于一1L圆底烧瓶中，加入2-(甲氧基亚甲基)马来酸二甲酯(25.0g，143.7mmol)、盐酸肼(20.0g，292.0mmol)和乙醇(EtOH，500mL)，然后加热回流反应16h。反应完成后，减压浓缩除掉乙醇，余物分散于乙酸乙酯(EtOAc，500mL)，搅拌30min后过滤，滤渣以EtOAc洗涤。滤液浓缩除去溶剂得10.0g产物。产率45％。LCMS(ESI)：m/z＝157(M+H) +。
(2)合成3-甲氧基-1H-吡唑
Figure PCTCN2021132652-appb-000015
于一100mL圆底烧瓶中，3-甲氧基-1H-吡唑-4-甲酸甲酯(10.0g，64.1mmol)溶于盐酸(6M，30mL)，然后加热到90℃反应16h。反应完成后，加水稀释，以NaHCO 3固体中和。所得水相以EtOAc萃取，酯相以无水Na 2SO 4干燥，过滤后浓缩得6.0g产物。产率95％。LCMS(ESI)：m/z＝99(M+H) +。
(3)合成3-甲氧基-4-硝基-1H-吡唑
Figure PCTCN2021132652-appb-000016
冰水浴下，3-甲氧基-1H-吡唑(6.0g，61.2mmol)溶于浓硫酸(36mL)，向溶液中分批加入硝酸钾固体(6.2g，61.2mmol)，维持温度反应30min。反应完成后，将反应液倒入冰水中，以NaHCO 3固体中和。水相以EtOAc萃取，酯相以无水Na 2SO 4干燥，过滤后浓缩得4.2g产物。产率48％。LCMS(ESI)：m/z＝144(M+H) +。
(4)合成3-甲氧基-1-甲基-4-硝基-1H-吡唑
Figure PCTCN2021132652-appb-000017
于一100mL圆底烧瓶中，3-甲氧基-4-硝基-1H-吡唑(4.2g，29.4mmol)溶于二甲基甲酰胺(DMF，40mL)，向溶液中加入K 2CO 3(6.1g，44.1mmol)，室温反应30min后加入碘甲烷(12.5g，88.2mmol)，室温反应16h。反应完成后，加水稀释，以EtOAc萃取，酯相以无水Na 2SO 4干燥，过滤后浓缩得3.8g产物。产率82％。LCMS(ESI)：m/z＝158(M+H) +。
(5)合成3-甲氧基-1-甲基-4-氨基-1H-吡唑
Figure PCTCN2021132652-appb-000018
往3-甲氧基-1-甲基-4-硝基-1H-吡唑(3.8g，24.2mmol)的EtOAc/EtOH(40mL/10mL)溶液中，加入钯炭(10％Pd/C，55％水，1.0g)和水合肼(8mL)，室温反应16h。反应完成后，过滤，滤渣以EtOAc洗涤。合并滤液，减压浓缩，所得余物溶于EtOAc，快速搅拌下滴入HCl/EtOAc至沉淀析出完全。过滤，滤渣以EtOAc和乙腈(MeCN)洗涤，得到产物的盐酸盐3.5g。产率89％。LCMS(ESI)：m/z＝128(M+H) +。
制备例2
制备中间体2：7-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1-(4-甲基苯磺酰基)-1H-吲哚，具体步骤如下：
(1)合成7-硝基-1-(4-甲基苯磺酰基)-1H-吲哚
Figure PCTCN2021132652-appb-000019
于一1000mL圆底烧瓶中，7-硝基-1H-吲哚(16.2g，100.0mmol)和四丁基溴化铵(3.2g，10.0mmol)溶于CH 2Cl 2(300mL)，置于冰水浴冷却。向上述溶液滴入NaOH水溶液(10M，40mL)，维持温度反应30min，然后加入4-甲基苯磺酰氯(28.5g，150.0mmol)。反应体系可自然升室温反应16h。反应完成后，加CH 2Cl 2稀释，有机相依次以水、10％K 2CO 3水溶液、水、1M稀盐酸、饱和NaCl水溶液洗涤，无水Na 2SO 4干燥，过滤后浓缩得产物30.0g。产率95％。LCMS(ESI)：m/z＝317(M+H) +。
(2)合成3-溴-7-硝基-1-(4-甲基苯磺酰基)-1H-吲哚
Figure PCTCN2021132652-appb-000020
冰水浴下，7-硝基-1-(4-甲基苯磺酰基)-1H-吲哚(31.6g，100.0mmol)溶于CH 2Cl 2/CCl 4(250mL/250mL)，然后缓慢滴入Br 2(24.0g，150.0mmol)的CCl 4溶液(100mL)，滴完后自然升室温反应16h。反应完成后，减压浓缩除去溶剂，加入EtOAc(500mL)，加热回流1h，然后冷至室温，过滤，滤渣以EtOAc洗涤，干燥得到淡黄色固体25g。产率63％。
(3)合成7-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1-(4-甲基苯磺酰基)-1H-吲哚
Figure PCTCN2021132652-appb-000021
N 2保护下，于一500mL圆底烧瓶中，加入3-溴-7-硝基-1-(4-甲基苯磺酰基)-1H-吲哚(10.0g，31.6mmol)，联硼酸频哪醇酯(16.0g，63.2mmol)，钯催化剂Pd(dppf)Cl 2(2.3g，3.2mmol)，乙酸钾(AcOK，9.3g，94.8mmol)和二氧六环(300mL)，加热到100℃反应16h。反应完成后，将反应液倒入水中，以EtOAc萃取。酯相以无水Na 2SO 4干燥，过滤后浓缩至50mL，然后加入石油醚300mL，快速搅拌1min后迅速过滤。滤液置于冰水浴中冷却析出固体，过 滤。滤渣以石油醚，冷乙醇洗涤得淡黄色固体7.5g。产率54％。LCMS(ESI)：m/z＝443(M+H) +。
制备例3
制备中间体3：3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-胺，具体步骤如下：
(1)合成3-(2-氯嘧啶-4-基)-7-硝基-1-(4-甲基苯磺酰基)-1H-吲哚
Figure PCTCN2021132652-appb-000022
N 2保护下，于一100mL圆底烧瓶中，加入中间体2(2.0g，4.5mmol)，2,4-二氯嘧啶(666mg，4.5mmol)，Pd(dppf)Cl 2(366mg，0.5mmol)，四丁基氟化铵(131mg，0.5mmol)，Na 2CO 3(1.4g，13.5mmol)和DMSO(30mL)，置于预加热到120℃的油浴锅中反应2h。反应完成后，将反应液倒入水中，以EtOAc萃取。酯相以无水Na 2SO 4干燥，过滤后浓缩，所得余物以硅胶柱层析分离纯化(流动相为CH 2Cl 2与甲醇MeOH体积比为20:1的混合液)，得产物1.5g。产率78％。LCMS(ESI)：m/z＝429(M+H) +。
(2)合成N-(3-甲氧基-1-甲基-1H-吡唑-4-基)-4-(7-硝基-1H-吲哚-3-基)嘧啶-2-胺
Figure PCTCN2021132652-appb-000023
N 2保护下，于一100mL圆底烧瓶中，加入3-(2-氯嘧啶-4-基)-7-硝基-1-(4-甲基苯磺酰基)-1H-吲哚(1.5g，3.5mmol)，3-甲氧基-1-甲基-1H-吡唑-4-胺盐酸盐(570mg，3.5mmol)，钯催化剂Pd(dba) 2(230mg，0.4mmol)，联萘二苯磷(BINAP，249mg，0.4mmol)，Cs 2CO 3(4.5g，14.0mmol)和二氧六环(30mL)，加热到110℃反应2h。反应体系冷至室温，加入NaOH水溶液(3M，10mL)，室温反应1h。反应完成后，将反应液倒入水中，以EtOAc萃取。酯相以无水Na 2SO 4干燥，过滤后浓缩，所得余物以硅胶柱层析分离纯化(流动相为CH 2Cl 2与MeOH体积比为10:1的混合液)，得产物1.0g。产率78％。LCMS(ESI)：m/z＝366(M+H) +。
(3)合成3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-胺
Figure PCTCN2021132652-appb-000024
冰水浴下，N-(3-甲氧基-1-甲基-1H-吡唑-4-基)-4-(7-硝基-1H-吲哚-3-基)嘧啶-2-胺(1.0g，2.7mmol)溶于EtOH(20mL)，然后加入乙酸(AcOH，1.6g，27mmol)和锌粉(864mg，13.5mmol)，自然升室温反应1h。反应完成后，将反应液倒入水中，以EtOAc萃取。酯相以 无水Na 2SO 4干燥，过滤后浓缩得产物850mg。产率94％。LCMS(ESI)：m/z＝336(M+H) +。
按照制备例3中的中间体3的合成路线合成中间体4-5，具体结构及产物质谱信息如表1所示。
表1
Figure PCTCN2021132652-appb-000025
制备例4
制备中间体6：3-(2((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-胺，具体步骤如下：
(1)合成3-(2-氯-5-甲基嘧啶-4-基)-7-硝基-1H-吲哚
Figure PCTCN2021132652-appb-000026
N 2保护下，于一100mL圆底烧瓶中，中间体2(2.0g，4.5mmol)，2,4-二氯-5-甲基嘧啶(734mg，4.5mmol)，Pd(dppf)Cl 2(366mg，0.5mmol)，四丁基氟化铵(131mg，0.5mmol)，Na 2CO 3(1.4g，13.5mmol)和DMSO(30mL)，置于预加热到120℃的油浴锅中反应2h。反应体系冷至室温，加入NaOH水溶液(3M，10mL)，室温反应1h。反应完成后，将反应液倒入水中，以EtOAc萃取。酯相以无水Na 2SO 4干燥，过滤后浓缩，所得余物以硅胶柱层析分离纯化(流动相为CH 2Cl 2与MeOH体积比为10:1的混合液)得产物1.0g。产率77％。LCMS(ESI)：m/z＝289(M+H) +。
(2)合成3-(2-氯-5-甲基嘧啶-4-基)-7-硝基-1-((2-(三甲硅基)乙氧基)甲基)-1H-吲哚
Figure PCTCN2021132652-appb-000027
冰水浴下，3-(2-氯-5-甲基嘧啶-4-基)-7-硝基-1H-吲哚(2.0g，6.9mmol)分散于四氢呋喃 (THF，30mL)。向上述混合物加入NaH(556mg，60％，13.9mmol)，维持温度反应30min。然后滴入2-(三甲基硅烷基)乙氧甲基氯(SEMCl，1.7g，10.4mmol)，反应1h。反应完成后，将反应液小心倒入冰水中，以EtOAc萃取。酯相以无水Na 2SO 4干燥，过滤后浓缩，所得余物以硅胶柱层析分离纯化(流动相为PE与EtOAc体积比为5:1的混合液)得产物2.6g。产率90％。LCMS(ESI)：m/z＝419(M+H) +。
(3)合成N-(3-甲氧基-1-甲基-1H-吡唑-4-基)-5-甲基-4-(7-硝基-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吲哚-3-基)嘧啶-2-胺
Figure PCTCN2021132652-appb-000028
N 2保护下，于一100mL圆底烧瓶中，加入3-(2-氯-5-甲基嘧啶-4-基)-7-硝基-1-((2-(三甲硅基)乙氧基)甲基)-1H-吲哚(2.6g，6.2mmol)，3-甲氧基-1-甲基-1H-吡唑-4-胺盐酸盐(1.0g，6.2mmol)，Pd(dba) 2(345mg，0.6mmol)，BINAP(373mg，0.6mmol)，Cs 2CO 3(6.0g，18.6mmol)和二氧六环(50mL)，加热到110℃反应2h。反应完成后，将反应液倒入水中，以EtOAc萃取。酯相以无水Na 2SO 4干燥，过滤后浓缩，所得余物以硅胶柱层析分离纯化(流动相为PE与EtOAc体积比为3:1的混合液)，得产物2.3g。产率73％。LCMS(ESI)：m/z＝510(M+H) +。
(4)合成N-(3-甲氧基-1-甲基-1H-吡唑-4-基)-5-甲基-4-(7-硝基-1H-吲哚-3-基)嘧啶-2-胺
Figure PCTCN2021132652-appb-000029
冰水浴下，N-(3-甲氧基-1-甲基-1H-吡唑-4-基)-5-甲基-4-(7-硝基-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吲哚-3-基)嘧啶-2-胺(2.3g，4.5mmol)溶于CH 2Cl 2(15mL)，加入三氟乙酸(TFA，15mL)，自然升室温反应1h。减压浓缩除去TFA，余物溶于MeOH(15mL)，冰水浴冷却，加入氨水(25％，15mL)，升室温反应6h。反应完成后，将反应液倒入水中，以EtOAc萃取。酯相以无水Na 2SO 4干燥，过滤后浓缩，所得余物以硅胶柱层析分离纯化(流动相CH 2Cl 2与MeOH体积比为20:1)，得产物1.4g。产率为82％。LCMS(ESI)：m/z＝380(M+H) +。
(5)合成3-(2((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-胺
Figure PCTCN2021132652-appb-000030
冰水浴下，N-(3-甲氧基-1-甲基-1H-吡唑-4-基)-5-甲基-4-(7-硝基-1H-吲哚-3-基)嘧啶-2-胺(1.4g，3.7mmol)溶于EtOH(20mL)，然后加入AcOH(2.2g，37mmol)和锌粉(1.2g，18.5mmol)，升室温反应1h。反应完成后，将反应液倒入水中，以EtOAc萃取。酯相以无水Na 2SO 4干燥，过滤后浓缩得产物1.2g。产率93％。LCMS(ESI)：m/z＝350(M+H) +。
制备例5
制备中间体7：(S)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)吡咯啶-2-甲酰胺
Figure PCTCN2021132652-appb-000031
于一100mL圆底烧瓶中，加入中间体4(1.2g，3.4mmol)和N-Boc-L-脯氨酸(731mg，3.4mmol)溶于CH 2Cl 2(30mL)，然后加入N,N-二异丙基乙胺(DIEA，877mg，6.8mmol)和缩合试剂HATU(1.9g，5.1mmol)，室温反应8h。反应完成后，加CH 2Cl 2稀释。有机相以水洗，无水Na 2SO 4干燥，过滤后浓缩。上所得余物溶于CH 2Cl 2(10mL)，加入TFA(10mL)，室温反应1h。反应完成后，加水，水相以EtOAc萃取，分液去掉有机相。水相以饱和Na 2CO 3溶液调碱，以CH 2Cl 2萃取。有机相以无水Na 2SO 4干燥，过滤后浓缩，得产物1.0g。产率65％。LCMS(ESI)：m/z＝451(M+H) +。
按照制备例5中间体7的合成路线依次合成中间体8-12，具体结构及产物质谱信息如表2所示。
表2
Figure PCTCN2021132652-appb-000032
Figure PCTCN2021132652-appb-000033
制备例6
制备中间体13：(2R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)吡咯啶-2-甲酰胺，具体步骤如下：
(1)合成叔丁基(2R,4S)-4-氟-2-((3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)胺甲酰基)吡咯啶-1-甲酸酯
Figure PCTCN2021132652-appb-000034
于一100mL圆底烧瓶中，中间体6(1.2g，3.4mmol)和(2R,4S)-N-Boc-4-氟脯氨酸(792mg，3.4mmol)溶于吡啶(10mL)，然后加入丙基磷酸三环酸酐(50％，溶剂为EtOAc，10.8g，17.0mmol)，室温反应18h。反应完成后，加EtOAc稀释，以4M盐酸中和。有机相水 洗，无水Na 2SO 4干燥，过滤后浓缩。所得余物以硅胶柱层析分离纯化(流动相为CH 2Cl 2与MeOH体积比20:1混合液)得产物650mg。产率34％。LCMS(ESI)：m/z＝565(M+H) +。
(2)合成(2R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)吡咯啶-2-甲酰胺
Figure PCTCN2021132652-appb-000035
叔丁基(2R,4S)-4-氟-2-((3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)胺甲酰基)吡咯啶-1-甲酸酯(650mg，1.2mmol)溶于CH 2Cl 2(10mL)，加入TFA(10mL)，室温反应1h。反应完成后，加水，水相以EtOAc萃取，分液去掉有机相。水相以饱和Na 2CO 3溶液调碱，以CH 2Cl 2萃取。有机相无水Na 2SO 4干燥，过滤后浓缩，得产物460mg。产率83％。LCMS(ESI)：m/z＝465(M+H) +。
按照制备例6中间体13的合成路线分别合成中间体14-19，具体结构及产物质谱信息如表3所示。
表3
Figure PCTCN2021132652-appb-000036
Figure PCTCN2021132652-appb-000037
实施例1
(S)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(甲磺酰基)吡咯啶-2-甲酰胺
Figure PCTCN2021132652-appb-000038
冰水浴下，于一25mL圆底烧瓶中，中间体7(45mg，0.1mmol)和三乙胺(Et 3N，30mg，0.3mmol)溶于CH 2Cl 2(2mL)，然后加入甲烷磺酰氯(14mg，0.12mmol)，反应10min。反应完成后，减压浓缩，所得余物以硅胶柱层析分离纯化(流动相为CH 2Cl 2与MeOH体积比10:1的混合液)，得产物36mg。产率68％。LCMS(ESI)：m/z＝529(M+H) +。
1H-NMR(400MHz，CDCl 3)：δ11.61(s,1H),10.05(s,1H),8.50(d,J＝8.1Hz,1H),8.18(d,J＝3.7Hz,1H),8.07(t,J＝2.8Hz,1H),7.75(s,1H),7.15(t,J＝7.8Hz,1H),6.82(d,J＝7.5Hz,1H),6.56(s,1H),4.38(dd,J＝8.6,3.5Hz,1H),3.97(s,3H),3.80-3.62(m,4H),3.53-3.36(m,1H),2.98(s,3H),2.62-2.46(m,1H),2.28-2.17(m,1H),2.15-2.00(m,2H)。
以下表4所示的实施例2-4根据实施例1中的方法制备得到。
表4
Figure PCTCN2021132652-appb-000039
Figure PCTCN2021132652-appb-000040
实施例5
(R)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(哌啶-4-基)吡咯啶-2-甲酰胺
Figure PCTCN2021132652-appb-000041
冰水浴下，于一25mL圆底烧瓶中，加入中间体8(90mg，0.2mmol)，N-叔丁氧羰基-4-哌啶酮(80mg，0.4mmol)，CH 2Cl 2(3mL)和MeOH(2mL)。往上反应液加入氰基硼氢化钠(19mg，0.3mmol)，反应30min。然后，小心加入TFA(5mL)，室温反应1h。反应完成后，加水，水相以EtOAc萃取，分液去掉有机相。水相以饱和Na 2CO 3溶液调碱，以CH 2Cl 2萃取。有机相以无水Na 2SO 4干燥，过滤后浓缩，所得余物以硅胶柱层析分离纯化(流动相为CH 2Cl 2与MeOH体积比为10:1，0.1％Et 3N)，得产物64mg。产率60％。LCMS(ESI)：m/z＝534(M+H) +。
1H-NMR(400MHz，CDCl 3)：δ11.61(s,1H),10.05(s,1H),8.50(d,J＝8.1Hz,1H),8.18(d,J＝3.7Hz,1H),8.07(t,J＝2.8Hz,1H),7.75(s,1H),7.15(t,J＝7.8Hz,1H),6.82(d,J＝7.5Hz,1H),6.56(s,1H),3.98(s,3H),3.76(s,3H),3.56-3.46(m,1H),3.29(t,J＝7.3Hz,1H),3.22-3.05(m,2H),2.71-2.52(m,4H),2.31-2.05(m,2H),2.02-1.72(m,4H),1.64-1.45(m,2H)。
以下表5所示的实施例6-17根据实施例5中的方法制备得到。
表5
Figure PCTCN2021132652-appb-000042
Figure PCTCN2021132652-appb-000043
Figure PCTCN2021132652-appb-000044
Figure PCTCN2021132652-appb-000045
Figure PCTCN2021132652-appb-000046
实施例18和实施例19
(2R,3'R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺(实施例18)和(2R,3'S,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺(实施例19)
(1)合成2-苄基1-(叔丁基)(2R,4S)-4-氟吡咯啶-1,2-二甲酸酯
Figure PCTCN2021132652-appb-000047
于一250mL圆底烧瓶中，加入(2R,4S)-1-(叔丁氧羰基)-4-氟吡咯啶-2-羧酸(7.0g，30.0mmol)、碳酸铯(14.6g，45.0mmol)和MeCN(100mL)，室温搅拌反应1h。向上述反应体系加入苄溴(7.7g，45.0mmol)，然后加热至60℃反应2h。反应完成后，过滤，滤渣以EtOAc洗涤。滤液浓缩除去溶剂，得8.5g产物，产率88％。LCMS(ESI)：m/z＝324(M+H) +。
(2)合成苄基(2R,4S)-4-氟吡咯啶-2-甲酸酯
Figure PCTCN2021132652-appb-000048
2-苄基1-(叔丁基)(2R,4S)-4-氟吡咯啶-1,2-二甲酸酯(8.5g，26.3mmol)溶于MeOH(40mL)，置于冰水浴冷却，然后加入浓盐酸(12M，20mL)，自然升室温反应1h。反应完成后，减压浓缩除去甲醇，余物溶于水，水相以EtOAc萃取，分液去掉有机相。水相以饱和Na 2CO 3溶液调碱，以CH 2Cl 2萃取。有机相以无水Na 2SO 4干燥，过滤后浓缩，得产物5.2g。产率89％。LCMS(ESI)：m/z＝224(M+H) +。
(3)合成2-苄基1'-(叔丁基)(2R,4S)-4-氟-[1,3'-联吡咯啶]-1',2-二甲酸酯
Figure PCTCN2021132652-appb-000049
冰水浴下，于一100mL圆底烧瓶中，加入苄基(2R,4S)-4-氟吡咯啶-2-甲酸酯(5.2g，23.3mmol)，N-Boc-3-吡咯烷酮(6.6g，35.6mmol)和MeOH(50mL)。向上述反应液加入氰基硼氢化钠(2.2g，35.6mmol)，反应20h。反应完成后，加水，减压浓缩除去甲醇，水相以EtOAc萃取。有机相以无水Na 2SO 4干燥，过滤后浓缩，所得余物以硅胶柱层析分离纯化(流动相为PE与EtOAc体积比为10:1的混合液)，得产物7.6g。产率83％。LCMS(ESI)：m/z＝393(M+H) +。
(4)合成(2R,4S)-1'-(叔丁氧羰基)-4-氟-[1,3'-联吡咯啶]-2-甲酸
Figure PCTCN2021132652-appb-000050
于一250mL装有氢气球的三口圆底烧瓶中，2-苄基1'-(叔丁基)(2R,4S)-4-氟-[1,3'-联吡咯啶]-1',2-二甲酸酯(7.6g，19.4mmol)溶于MeOH(40mL)，然后加入Pd/C(2.0g，10％，55wt％水)，室温反应20h。反应完成后，过滤，滤渣以甲醇洗涤。滤液减压浓缩得产物4.9g。产率85％。LCMS(ESI)：m/z＝303(M+H) +。
(5)合成叔丁基(2R,4S)-4-氟-2-((3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)氨甲酰基)-[1,3'-联吡咯啶]-1'-甲酸酯
Figure PCTCN2021132652-appb-000051
于一50mL圆底烧瓶中，中间体3(191mg，0.57mmol)和(2R,4S)-1'-(叔丁氧羰基)-4-氟-[1,3'-联吡咯啶]-2-甲酸(172mg，0.57mmol)溶于DMF(5mL)，然后加入DIEA(219mg，1.7mmol)、HATU(260mg，0.68mmol)，室温反应1h。反应完成后，加CH 2Cl 2稀释。有机相以水洗，无水Na 2SO 4干燥，过滤后浓缩，所得余物以硅胶柱层析分离纯化(流动相为CH 2Cl 2与MeOH体积比为30:1的混合液)，得产物254mg。产率72％。LCMS(ESI)：m/z＝620(M+H) +。
(6)合成(2R,3'R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺和(2R,3'S,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺
Figure PCTCN2021132652-appb-000052
于一50mL圆底烧瓶中，叔丁基(2R,4S)-4-氟-2-((3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)氨甲酰基)-[1,3'-联吡咯啶]-1'-甲酸酯(127mg，0.21mmol)溶于CH 2Cl 2(5mL)，置于冰水浴冷却。然后往上溶液加入TFA(2.0mL)，室温反应1h。反应完成后，减压浓缩除去TFA和溶剂。余物以手性色谱柱(chiral ND(2)SU 250×21.1mm；流动相为乙醇、异丙醇、甲醇和正己烷，体积比为35:30:10:15的混合液(含0.3％三乙胺)；流速12mL/min)分离。第一个洗脱出来的组分42mg，为实施例18，产率38％。LCMS(ESI)：m/z＝520(M+H) +。 1H-NMR(400MHz，CDCl 3)：δ12.05(s,1H),10.05(s,1H),8.30(d,J＝5.3Hz,1H),8.23(d,J＝8.0Hz,1H),7.85(s,1H),7.82(s,1H),7.32–7.25(m,1H),7.19(t,J＝7.8Hz,1H),6.97(d,J＝5.3Hz,1H),6.62(s,1H),5.21(d,J＝53.1Hz,1H),3.98(s,3H),3.85–3.70(m,5H),3.60–3.51(m,1H),3.49–3.32(m,1H),3.29–3.19(m,2H),3.18–3.07(m,2H),3.06–2.97(m,1H),2.86–2.69(m,1H),2.29–2.07(m,1H),2.06–1.98(m,2H)；第二个洗脱出来的组分36mg，为实施例19，产率33％。LCMS(ESI)：m/z＝520(M+H) +。 1H-NMR(400MHz，CDCl 3)： δ12.35(s,1H),9.68(s,1H),8.30(d,J＝5.3Hz,1H),8.23(d,J＝8.0Hz,1H),7.83(s,1H),7.81(s,1H),7.32–7.25(m,1H),7.19(t,J＝7.8Hz,1H),6.97(d,J＝5.3Hz,1H),6.62(s,1H),5.21(d,J＝53.1Hz,1H),3.96(s,3H),3.85–3.70(m,5H),3.60–3.51(m,1H),3.49–3.32(m,1H),3.29–3.19(m,2H),3.18–3.07(m,2H),3.06–2.97(m,1H),2.86–2.69(m,1H),2.29–2.07(m,1H),2.06–1.98(m,2H).
实施例20和实施例21
(2R,3'R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺(实施例20)和(2R,3'S,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺(实施例21)
Figure PCTCN2021132652-appb-000053
冰水浴下，于一50mL圆底烧瓶中，加入(2R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺(127mg，0.21mmol)，40％甲醛水溶液(47mg，0.63mmol)和MeOH(10mL)。向上述反应液加入氰基硼氢化钠(2.2g，35.6mmol)，反应1h。反应完成后，加水，减压浓缩除去甲醇，水相以EtOAc萃取。有机相以无水Na 2SO 4干燥，过滤后浓缩，余物以手性色谱柱(chiral ND(2)SU 250×21.1mm；流动相为乙醇、异丙醇、甲醇和正己烷，体积比为35:30:10:15的混合液(含0.3％三乙胺)；流速12mL/min)分离。第一个洗脱出来的组分37mg，为实施例20，产率33％。LCMS(ESI)：m/z＝534(M+H) +。 1H-NMR(400MHz，CDCl 3)：δ11.50(s,1H),9.96(s,1H),8.31(d,J＝5.3Hz,1H),8.22(d,J＝8.0Hz,1H),7.86(s,1H),7.83(s,1H),7.31–7.24(m,1H),7.20(t,J＝7.8Hz,1H),6.99(d,J＝5.3Hz,1H),6.62(s,1H),5.20(d,J＝53.0Hz,1H),3.98(s,3H),3.84–3.72(m,4H),3.63–3.53(m,1H),3.50–3.31(m,1H),3.25–3.08(m,2H),3.03–2.92(m,1H),2.87–2.70(m,4H),2.42–2.27(m,2H),2.26–2.15(m,1H),2.11–1.93(m,2H)。第二个洗脱出来的组分30mg，为实施例21，产率27％。LCMS(ESI)：m/z＝534(M+H) +。 1H-NMR(400MHz，CDCl 3)：δ11.30(s,1H),9.86(s,1H),8.31(d,J＝5.3Hz,1H),8.21(d,J＝8.0Hz,1H),7.86(s,1H),7.84(s,1H),7.31–7.24(m,1H),7.20(t,J＝7.8Hz,1H),6.99(d,J＝5.3Hz,1H),6.62(s,1H),5.20(d,J＝53.0Hz,1H),3.97(s,3H),3.84–3.72(m,4H),3.63–3.53(m,1H),3.50–3.31(m,1H),3.25–3.08(m,2H),3.03–2.92(m,1H),2.87–2.70(m,4H),2.42–2.27(m,2H),2.26–2.15(m,1H),2.11–1.93(m,2H)。
以下表6所示的实施例22-39根据实施例18和19、实施例20和21中的方法制备得到。
表6
Figure PCTCN2021132652-appb-000054
Figure PCTCN2021132652-appb-000055
Figure PCTCN2021132652-appb-000056
Figure PCTCN2021132652-appb-000057
Figure PCTCN2021132652-appb-000058
Figure PCTCN2021132652-appb-000059
Figure PCTCN2021132652-appb-000060
实施例40
(2R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺
(1)合成甲基(2R,4S)-4-氟-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酸酯
Figure PCTCN2021132652-appb-000061
冰水浴下，于一100mL圆底烧瓶中，1-(叔丁基)2-甲基(2R,4S)-4-氟吡咯啶-1,2-二羧酸酯(1.0g，4.0mmol)溶于CH 2Cl 2(50mL)。往上溶液加入TFA(10mL)，室温反应2h。反应完成后减压浓缩除去TFA和溶剂。余物溶于MeOH(50mL)，置于冰水浴中冷却，然后加入N-甲基-哌啶-4-酮(678mg，6.0mmol)和氰基硼氢化钠(378mg，6.0mmol)，反应20h。反应完成后，以硅藻土过滤，甲醇洗涤，收集滤液，减压浓缩除去甲醇，所得余物直接用于下一步反应。得产物1.2g。LCMS(ESI)：m/z＝245(M+H) +。
(2)合成(2R,4S)-4-氟-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酸盐酸盐
Figure PCTCN2021132652-appb-000062
于一100mL圆底烧瓶中，加入甲基(2R,4S)-4-氟-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酸酯(1.2g，4.9mmol)和6M盐酸(50mL)，加热回流6h。反应完成后，减压浓缩除去溶剂。余物加到异丙醇(150mL)中，搅拌加热至100℃至完全溶解，再反应30min，逐渐析出固体，继续反应2h。然后自然冷至室温，搅拌10h。过滤，滤渣以异丙醇洗涤，干燥得目标产物850mg，两步总产率70％。LCMS(ESI)：m/z＝231(M+H) +。
(3)合成(2R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺
Figure PCTCN2021132652-appb-000063
于一50mL圆底烧瓶中，中间体3(191mg，0.57mmol)和(2R,4S)-4-氟-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酸盐酸盐(172mg，0.57mmol)溶于DMF(5mL)，然后加入DIEA(294mg，2.3mmol)、HATU(260mg，0.68mmol)，室温反应1h。反应完成后，加CH 2Cl 2稀释。有机相以水洗，无水Na 2SO 4干燥，过滤后浓缩，所得余物以硅胶柱层析分离纯化(流动相为CH 2Cl 2与MeOH体积比为10:1的混合液)，得产物245mg。产率78％。LCMS(ESI)：m/z＝548(M+H) +。 1H-NMR(400MHz，CDCl 3)：δ11.30(s,1H),9.74(s,1H),8.34–8.26(m,2H),7.88(d,J＝2.8Hz,1H),7.83(s,1H),7.14(t,J＝7.8Hz,1H),6.98(d,J＝5.4Hz,1H),6.77(d,J＝7.5Hz,1H),6.63(s,1H),5.20(d,J＝53.6Hz,1H),3.99(s,3H),3.94–3.84(m,1H),3.76(s,3H),3.53–3.35(m,1H),3.32–3.16(m,1H),2.98–2.85(m,2H),2.80(s,1H),2.77–2.55(m,2H),2.26(s,3H),2.17–2.01(m,1H),2.01–1.87(m,3H),1.76–1.60(m,2H)。
测试例1
对以上实施例提供的酰胺化合物进行JAK1和JAK2激酶抑制活性的测试，方法如下：
用Mobility Shift Assay方法检测所述酰胺化合物对激酶JAK1和JAK2在1mM ATP下的抑制活性(IC 50)。JAK1激酶购自Carna公司(目录号：08-144，批号：11CBS-0144V)，JAK2激酶购自Carna公司(目录号：08-045，批号：10CBS-0289R)。JAK1Peptide购自GL公司(目录号：758318，批号：P191104-TL758318)，Kinase substrate22购自GL公司(目录号:112393，批号：P200403-CL112393)。使用的阳性对照化合物是baricitinib。具体步骤如下：
1、配制1×Kinase buffer。
2、化合物浓度梯度的配制：受试化合物起始浓度为10000nM(JAK1)或30000nM(JAK2)，在384孔板中稀释成100倍终浓度的100％DMSO溶液，3倍稀释化合物，10个浓度。使用分液器Echo 550向目的板转移250nL 100倍终浓度的化合物。
3、用1×Kinase buffer配制2.5倍终浓度的激酶溶液。
4、在化合物孔和阳性对照孔分别加10μL的2.5倍终浓度的激酶溶液；在阴性对照孔中加10μL的1×Kinase buffer。
5、1000rpm离心30秒，反应板振荡混匀后室温孵育10分钟。
6、用1×Kinase buffer配制5/3倍终浓度的ATP(ATP终浓度＝1mM)和Kinase substrate的混合溶液。
7、加入15μL的5/3倍终浓度的ATP和底物的混合溶液，起始反应。
8、将384孔板1000rpm离心30秒，振荡混匀后室温分别孵育相应的时间。
9、加入30μL终止检测液停止激酶反应，1000rpm离心30秒，振荡混匀。
10、用Caliper EZ Reader读取转化率，计算半数抑制浓度的IC 50，数据如表7所示。
表7
Figure PCTCN2021132652-appb-000064
根据表7的测试数据可知，本申请提供的酰胺化合物在1mM ATP浓度下，能够有效地抑制JAK1激酶。而且，本申请所述酰胺化合物对抑制JAK1激酶的活性比对抑制JAK2激酶的活性都高，具有高的JAK1选择性。跟两个JAK1抑制剂abrocitinib和AZD4205相比，本申请大多数化合物对抑制JAK1激酶比对抑制JAK2激酶的选择性更高。
测试例2
细胞因子IFNα可以通过JAK1/TYK2信号通路诱导STAT3磷酸化(pSTAT3)。本申请用小鼠全血实验来测试本申请实施例30和实施例32提供的化合物对INFα诱导的pSTAT3的抑制，同时测试两个选择性的JAK1抑制剂abrocitinib和AZD4205作为比较。使用的IFNα是Recombinant mouse IFNα(Miltenyi#130-093-131)，使用的pSTAT3抗体是Alexa Fluor 488 anti-STAT3 Phospho(Tyr705)Antibody(Biolegend#651106)，使用的CD3抗体是Brilliant Violet 421 anti-mouse CD3Antibody(Biolegend#100228)。细胞因子稀释缓冲液为：PBS+0.1％BSA，过滤并在-4℃储存。FACS缓冲液为：PBS+0.2％BSA+1mM EDTA。具体步骤如下：
1、将C57BL/6J小鼠血液以每孔90μL加入96孔板。
2、每孔加入5μL的化合物(19X)并混匀，培养箱中37℃60min。
3、每孔加入5μL 20X的IFNα(工作浓度为20000IU/mL)刺激因子并混匀，37℃30min。
4、将血液转移到96深孔板，每孔加入1mL Lyse fix buffer(1X)并混匀，37℃10min。
5、600g 5min离心，弃上清。每孔加入1mL PBS，600g 5min离心，弃上清，重复两遍。每孔加入100μL anti-mCD3antibody(用细胞因子稀释缓冲液80倍稀释)并混匀，4℃30min。
6、每孔加入1mL PBS，600g 5min离心，弃上清，重复两遍。每孔加入1000μL Perm III，混匀，4℃30min。
7、600g 5min离心，弃上清。每孔加入1mL PBS，600g 5min离心，弃上清，重复两遍。
8、每孔加入100μL anti-pSTAT3antibody(用FACS缓冲液50倍稀释)并混匀，25℃40min。
9、每孔加入1mL FACS缓冲液，600g 5min离心，弃上清。每孔加入200μL FACS缓冲液并重悬，将所有样品转移到96孔尖底板中并上机。
10、收集数据并分析。其50％抑制率(IC 50)列于表8。
表8
Figure PCTCN2021132652-appb-000065
从表8的测试结果可以看出，本申请化合物在小鼠全血实验中能有效地抑制JAK1/TYK2的信号通路，实施例30和实施例32对抑制IFNα诱导的pSTAT3表达的IC 50分别为127nM和121nM，而且比两个JAK1选择性的抑制剂abrocitinib和AZD4205的抑制活性还高。
申请人声明，本申请通过上述实施例来说明本申请的酰胺化合物、药物组合物及其应用，但本申请并不局限于上述实施例，即不意味着本申请必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本申请的任何改进，对本申请产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本申请的保护范围和公开范围之内。

Claims (12)

  1. 一种酰胺化合物，其具有如式I所示结构：
    Figure PCTCN2021132652-appb-100001
    其中，R 1选自H、卤素、C1～C6直链或支链烷基、C3～C6环烷基或OR a；所述直链或支链烷基、环烷基无取代或被1～3个R 1a取代；
    R 1a选自D或卤素；
    R 2选自H、C1～C6直链或支链烷基、C3～C10环烷基或C2～C10杂环烷基；所述直链或支链烷基、环烷基、杂环烷基无取代或被1～3个R 2a取代；
    R 2a选自D、卤素、氰基、未取代或卤代的C1～C6直链或支链烷基、C3～C6环烷基、C2～C6杂环烷基、OR a1、SR a1、NR b1R c1、COR a1、CONR b1R c1、COOR a1、SO 2R a1、SO 2NR b1R c1、NR b1COR a1、NR d1CONR b1R c1、NR b1SO 2R a1、NR d1SO 2NR b1R c1或SOR a1；
    R 3选自H、卤素、氰基、未取代或卤代的C1～C6直链或支链烷基、C2～C6烯基、C2～C6炔基或C3～C6环烷基；
    R 4选自SO 2R a2、COR a2、COOR a2、C3～C10环烷基或C2～C10杂环烷基；所述环烷基、杂环烷基无取代或被1～5个R 4a取代；
    R 4a选自D、卤素、氰基、C1～C6直链或支链烷基、C3～C6环烷基、C2～C6杂环烷基、OR a3、SR a3、NR b3R c3、COR a3、CONR b3R c3、COOR a3、SO 2R a3或SO 2NR b3R c3；所述直链或支链烷基、环烷基、杂环烷基无取代或被1～5个R 4b取代；
    R 4b选自D、卤素、氰基、OR a4或NR b4R c4；
    R 5选自F、氰基、C1～C6直链或支链烷基、C3～C6环烷基或OR a5；
    R a、R a1、R b1、R c1、R d1、R a2、R a3、R b3、R c3、R a4、R b4、R c4、R a5各自独立地选自H、C1～C10直链或支链烷基、C2～C10烯基、C2～C10炔基、C3～C10环烷基或C2～C10杂环烷基；所述直链或支链烷基、烯基、炔基、环烷基、杂环烷基无取代或被1～4个R 6取代；
    R 6选自D、卤素、氰基、羟基、未取代或卤代的C1～C6直链或支链烷基、C2～C6烯基、C2～C6炔基、C3～C6环烷基、C2～C6杂环烷基、OR a6、SR a6、NR b6R c6、COR a6、CONR b6R c6、COOR d6、SO 2R a6、SO 2NR b6R c6、NR b6COR a6、NR d6CONR b6R c6、NR b6SO 2R a6、NR d6SO 2NR b6R c6或SOR a6；
    R a6、R b6、R c6、R d6各自独立地选自H、C1～C10直链或支链烷基、C2～C10烯基、C2～C10炔基、C3～C10环烷基或C2～C10杂环烷基；以及
    n选自0～3的整数，当n≥2时，R 5之间不连接或通过化学键连接形成3至6元的碳环或 碳杂环。
  2. 根据权利要求1所述的酰胺化合物，其中，所述酰胺化合物具有如式IA所示结构：
    Figure PCTCN2021132652-appb-100002
    其中，R 3、R 4各自独立地具有与式I中相同的限定范围；
    R 5a、R 5b各自独立地选自H、F、氰基、C1～C6直链或支链烷基、C3～C6环烷基或OR a5；R 5a与R 5b不连接或通过化学键连接形成3至6元的碳环或杂碳环。
  3. 根据权利要求2所述的酰胺化合物，其中，所述R 3选自H、卤素、C1～C6直链或支链烷基。
  4. 根据权利要求2所述的酰胺化合物，其中，所述R 4选自SO 2R a2、无取代或R 4a取代的C2～C10杂环烷基；
    任选地，所述R a2选自C1～C6直链或支链烷基；
    任选地，所述R 4a选自C1～C6直链或支链烷基；
    任选地，所述R a5选自C1～C6直链或支链烷基。
  5. 根据权利要求2-4任一项所述的酰胺化合物，其中，所述酰胺化合物具有如式IB所示结构：
    Figure PCTCN2021132652-appb-100003
    其中，R 3、R 5a、R 5b各自独立地具有与式IA中相同的限定范围；
    Y为NR 7或O；
    R 7选自H、C1～C6直链或支链烷基、C3～C6环烷基、C2～C6杂环烷基；所述直链或支链烷基、环烷基、杂环烷基无取代或被1～5个R 7a取代；
    R 7a选自D、卤素、氰基、C1～C6直链或支链烷基、C3～C6环烷基、C2～C6杂环烷基、羟基、C1～C6直链或支链烷氧基；所述直链或支链烷基、环烷基、杂环烷基无取代或被1～5个R 7b取代；
    R 7b选自D、卤素、氰基、羟基、C1～C6直链或支链烷氧基；以及
    m为1或2，p选自1～3的整数。
  6. 根据权利要求5所述的酰胺化合物，其中，所述R 3选自H、卤素或甲基；
    任选地，所述R 5a、R 5b各自独立地选自H、F、甲氧基或乙氧基。
  7. 根据权利要求5所述的酰胺化合物，其中，所述R 7为H或甲基；
    任选地，所述p为2。
  8. 根据权利要求1-7任一项所述的酰胺化合物，其中，所述酰胺化合物包括如下化合物中的任意一种或至少两种的组合：
    Figure PCTCN2021132652-appb-100004
    Figure PCTCN2021132652-appb-100005
    Figure PCTCN2021132652-appb-100006
  9. 一种如权利要求1-8任一项所述的酰胺化合物的立体异构体、几何异构体、互变异构体或其药学上可接受的盐。
  10. 一种药物组合物，其包括活性成分与至少一种药用载体或赋形剂；所述活性成分包括如权利要求1-8任一项所述的酰胺化合物、如权利要求9所述的立体异构体、几何异构体、互变异构体或其药学上可接受的盐中的任意一种或至少两种的组合。
  11. 一种如权利要求1-8任一项所述的酰胺化合物、如权利要求9所述的立体异构体、几何异构体、互变异构体或其药学上可接受的盐、如权利要求10所述的药物组合物在制备用于抑制JAK激酶的药物中的应用；
    任选地，所述JAK激酶为JAK1激酶。
  12. 一种如权利要求1-8任一项所述的酰胺化合物、如权利要求9所述的立体异构体、几何异构体、互变异构体或其药学上可接受的盐、如权利要求10所述的药物组合物在制备用于治疗JAK激酶介导的疾病的药物中的应用；
    任选地，所述疾病包括炎症、自身免疫性疾病或癌症；
    任选地，所述炎症、自身免疫性疾病包括***性红斑狼疮、狼疮性肾炎、关节炎、牛皮癣、克罗恩病、溃疡性结肠炎、特应性皮炎、痛风、脱发秃头症、白癜风、化脓性汗腺炎、I型糖尿病、慢性肾脏病、急性肾脏损伤、慢性阻塞性肺疾病、哮喘、支气管炎或移植物抗宿主病；
    任选地，所述癌症包括乳腺癌、肺癌、***癌、胆小管癌、骨癌、膀胱癌、头颈癌、肾癌、肝癌、胃肠组织癌、食道癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌、甲状腺癌、子宫癌、子***、***癌、白血病、骨髓纤维化、多发性骨髓瘤或淋巴瘤。
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