WO2024067708A1 - 草酸胺类衍生物、包含其的药物组合物及其医药用途 - Google Patents

草酸胺类衍生物、包含其的药物组合物及其医药用途 Download PDF

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WO2024067708A1
WO2024067708A1 PCT/CN2023/122073 CN2023122073W WO2024067708A1 WO 2024067708 A1 WO2024067708 A1 WO 2024067708A1 CN 2023122073 W CN2023122073 W CN 2023122073W WO 2024067708 A1 WO2024067708 A1 WO 2024067708A1
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compound
cancer
mmol
alkyl
nmr
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刘治国
吴杰
叶阳亮
王昊
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苏州阿尔脉生物科技有限公司
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
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    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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    • 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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to an oxalic acid amine derivative, and specifically relates to an oxalic acid amine derivative as a 2 ⁇ type hypoxia inducible factor (HIF-2 ⁇ ) inhibitor, and uses thereof.
  • HIF-2 ⁇ hypoxia inducible factor
  • Kidney cancer also known as renal cell carcinoma, is one of the 10 most common cancers worldwide and one of the most lethal tumors of the urinary system. Histopathology divides kidney cancer into three main subtypes: clear cell renal cell carcinoma (ccRCC, 70-75%), papillary renal cell carcinoma (pRCC, 10-16%), and pheochromocytic renal cell carcinoma (chRCC, 5%). Each subtype is associated with a separate genetic syndrome, and therefore the treatment is also different.
  • ccRCC clear cell renal cell carcinoma
  • pRCC papillary renal cell carcinoma
  • chRCC pheochromocytic renal cell carcinoma
  • Clear cell renal cell carcinoma is the most common malignant tumor of the kidney, accounting for about 90% of renal cancer. According to the American Cancer Society, there are 403,000 new cases of renal cancer and 175,000 deaths worldwide each year; in China, there are about 66,800 new patients and 23,400 deaths each year. According to statistics from the National Cancer Spectrum of China, the incidence of kidney disease has increased at an average annual rate of 6.5% over the past 20 years, surpassing bladder cancer to rank first in urinary system tumor-related deaths. Kidney cancer can occur in people of all ages, with the high-incidence age mainly between 50 and 70 years old. Due to the relatively hidden location of the kidney and the lack of obvious clinical symptoms in the early stages of renal cancer, most renal cancer patients already have metastasis at the time of diagnosis.
  • renal cancer metastasizes (late stage), the prognosis is often poor, with a 5-year survival rate of less than 10%.
  • prostate cancer, bladder cancer, etc. it is not sensitive to radiotherapy and chemotherapy, which has become the biggest challenge in the treatment of renal cancer in the past. Therefore, it is a significant task to discover novel and confirmed specific drug targets for the treatment of renal cancer.
  • HIF Hypoxia-inducible factor
  • HIF family members include HIF-1 ⁇ , HIF-1 ⁇ , HIF-2 ⁇ , HIF-2 ⁇ , HIF-3 ⁇ , and HIF-3 ⁇ .
  • Abnormal HIF-2 ⁇ activity is a key carcinogenic driver of cancers such as clear cell renal cell carcinoma (ccRCC).
  • ccRCC clear cell renal cell carcinoma
  • PBDs prolyl hydroxylases
  • pVHL VHL complex
  • polyubiquitinate HIF-2 ⁇ mediate its degradation, so that HIF-2 ⁇ in the cell maintains a low expression level.
  • HIF-2 ⁇ Under hypoxic conditions, HIF-2 ⁇ cannot be hydroxylated, which makes it unable to recognize pVHL, so it accumulates and forms dimers with HIF-1 ⁇ , and then transfers to the nucleus, interacts with cofactors such as CBP/p300 and Pol II complex in the nucleus, and binds to HRE (hypoxia response element), thereby activating the expression of downstream target genes (VEGF-promotes angiogenesis; GLUT1 (glucose transporter-1)-activates glucose transport; LDHA (lactate dehydrogenase)-participates in the glycolysis pathway; and Epo-induces erythropoiesis, etc.).
  • VEGF-promotes angiogenesis VEGF-promotes angiogenesis
  • GLUT1 glucose transporter-1
  • LDHA lactate dehydrogenase
  • HIF-2 ⁇ inhibitors can treat/prevent diseases caused by overexpression of HIF-2 ⁇ , such as renal cell carcinoma.
  • Belzutifan (PT2977) is a HIF-2 ⁇ inhibitor approved by the U.S. FDA in 2021 for the treatment of adult patients with Hippel-Lindau syndrome.
  • the present invention provides an oxalic acid amine compound shown in the following formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug thereof,
  • Y 1 is N or CR 1
  • Y 2 is CR 2 R 3 , NR 4 or is absent
  • Y 3 and Y 4 are each independently selected from CR 2 R 3 , NR 4 , O, SO 2 ; any two of R 2 to R 4 can be connected to form a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl;
  • R 1 is selected from one of H, halogen, hydroxyl, CN, NO 2 , -NR a R b , C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 hydroxyalkyl, C1-4 alkoxyC1-4 alkyl, and C3-8 cycloalkyl;
  • E is a chemical bond or is selected from a substituted or unsubstituted saturated or partially unsaturated aliphatic C3-10 cycloalkylene group, a substituted or unsubstituted saturated or partially unsaturated aliphatic 3-10 membered heterocyclylene group, a substituted or unsubstituted C6-12 arylene group, or a substituted or unsubstituted C6-12 heteroarylene group;
  • R9 and R10 are independently selected from the group consisting of H, halogen, CN, NO2 , C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 hydroxyhaloalkyl, C1-4 alkoxyC1-4 alkyl, C3-8 cycloalkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O) 2 NR a R b , -S(O) 2 R a , and C1-6 alkylene-C3-8 cycloalkyl, C1-6 alkylene-S(O) 2 R a , C1-6 alkylene-S(O) 2 R a , C1-6 alkylene-C(O)R a , C1-6 alkylene-C(O)OR a , C1-6 alkylene-C(O)NR a R
  • R9 and R10 are linked together to form a substituted or unsubstituted C3-8 cycloalkyl, or a substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
  • R 9 or R 10 and Y 4 are linked together to form a substituted or unsubstituted C3-6 cycloalkyl, a substituted or unsubstituted 3-membered to 6-membered heterocycloalkyl, a substituted or unsubstituted C6-12 arylene, or a substituted or unsubstituted C6-12 heteroarylene;
  • each of Ra and Rb is independently selected from the group consisting of H, C1-8 alkyl, C1-8 alkoxy, C1-8 haloalkyl, C1-8 haloalkoxy and C1-8 hydroxyalkyl,
  • the present invention also provides a pharmaceutical composition, comprising a preventive or therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
  • the dosage form of the pharmaceutical composition is an oral dosage form or an injection
  • the oral dosage form includes capsules, tablets, pills, powders and granules.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures; the injection comprises a physiologically acceptable sterile aqueous or anhydrous solution, dispersion, suspension or emulsion, and a compound of the present invention or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug sterile powder for re-dissolving into a sterile injectable solution or dispersion.
  • the present invention provides the use of the above-mentioned compounds and pharmaceutical compositions for treating or preventing cancer, inflammatory diseases, and immune-related diseases. These diseases are closely related to type 2 ⁇ hypoxia-inducible factor, and regulating type 2 ⁇ hypoxia-inducible factor has therapeutic prospects for these diseases.
  • the cancer is the following cancer: prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, gastric cancer, endometrial cancer, uterine cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer (including melanoma and basal carcinoma), mesothelial cancer, leukocyte cancer, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, intestinal cancer, lung cancer, adrenal cancer, thyroid cancer, kidney or bone; glioblastoma cancer, mesothelioma cancer, renal cell carcinoma, clear cell renal cell carcinoma, gastric cancer, sarcoma, Kaposi's sarcoma, choriocarcinoma, basal cell carcinoma of the skin or testicular seminoma; the inflammation is selected from pneumonia, enteritis, nephritis, arthritis, traumatic infection; the metabolic disease is selected from obesity, dyslipidemia, hyperlipidemia.
  • the compounds of the present invention are particularly suitable for the treatment of renal cell carcinoma and clear cell renal cell carcinoma.
  • alkylene refers to a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl has 1 to 12, for example 1 to 6 carbon atoms.
  • C1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as halogen (in this case, the group is referred to as " haloalkyl " ) (e.g., CH2F , CHF2 , CF3 , CCl3 , C2F
  • C1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon group containing one double bond and having 2 to 6 carbon atoms (“ C2-6 alkenyl”).
  • the alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compound of the present invention contains an alkenyl group, the compound may exist in the pure E (enthafen) form, the pure Z (zusammen) form or any mixture thereof.
  • alkynyl refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclonon
  • the cycloalkyl has 3 to 15 carbon atoms.
  • the so-called " C3-6 cycloalkyl” refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) of 3 to 6 ring-forming carbon atoms, which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.
  • cycloalkylene refers to saturated (i.e., “cycloalkylene” and “cycloalkyl") or unsaturated (i.e., having one or more double bonds and/or triple bonds in the ring) monocyclic or polycyclic hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including but not limited to (cyclo)propyl (ring), (cyclo)butyl (ring), (cyclo)pentyl (ring), (cyclo)hexyl (ring), (cyclo)heptyl (ring), (cyclo)octyl (ring), (cyclo)nonyl (ring), (cyclo)hexenyl (ring) wait.
  • heterocyclyl As used herein, the so-called “heterocyclyl”, “heterocyclylene” and “heterocycle” refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double bonds and/or triple bonds within the ring) cyclic group having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C.
  • a “3-10 membered (sub)heterocyclyl” is a saturated or partially unsaturated (sub)heterocyclyl having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.
  • heterocyclyl and heterocyclic examples include, but are not limited to: (sub) oxirane, (sub) aziridine, (sub) azetidinyl, (sub) oxetanyl, (sub) tetrahydrofuranyl, (sub) dioxolyl (dioxolinyl), (sub) pyrrolidinyl, (sub) pyrrolidonyl, (sub) imidazolidinyl, (sub) pyrazolidinyl, (sub) pyrrolinyl, (sub) tetrahydropyranyl, (sub) piperidinyl, (sub) morpholinyl, (sub) dithianyl (dithianyl), (sub) thiomorpholinyl, (sub) piperazinyl or (sub) trithianyl (trithianyl).
  • the group also encompasses bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro [4.5] decane, 3,9-diazaspiro [5.5] undecane, 2-azabicyclo [2.2.2] octane, etc.).
  • the heterocyclylene and heterocyclyl groups may be optionally substituted with one or more (eg, 1, 2, 3 or 4) suitable substituents.
  • the so-called “(ylidene)aryl” and “aromatic ring” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ electron system.
  • the so-called “C 6-10 (ylidene)aryl” and “C 6-10 aromatic ring” mean an aromatic group containing 6 to 10 carbon atoms, such as (ylidene)phenyl (benzene ring) or (ylidene)naphthyl (naphthalene ring).
  • the (ylidene)aryl and aromatic ring are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • suitable substituents e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.
  • heteroaryl(ene) and “heteroaromatic ring” refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being, for example, oxygen, nitrogen or sulfur) and, in each case additionally may be benzo-fused.
  • heteroaryl or “heteroaromatic ring” is selected from thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof.
  • aralkyl preferably refers to an alkyl substituted with an aryl or heteroaryl, wherein the aryl, heteroaryl and alkyl are as defined herein.
  • the aryl may have 6-14 carbon atoms
  • the heteroaryl may have 5-14 ring atoms
  • the alkyl may have 1-6 carbon atoms.
  • Exemplary aralkyls include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • Alkyl refers to a saturated aliphatic hydrocarbon group, comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, a saturated straight chain or branched monovalent hydrocarbon group, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.
  • the alkyl group may be optionally substituted or unsubstituted.
  • Alkenyl refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one CC is an sp2 double bond, wherein the alkenyl group may be independently optionally substituted with one or more substituents described herein, wherein specific examples include, but are not limited to, vinyl, allyl, and butylene, etc. Alkenyl may be optionally substituted or unsubstituted.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, more preferably includes 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes cycloalkyl of spiro ring, condensed ring and bridge ring. Cycloalkyl can be optionally substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated ⁇ electron aromatic system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members.
  • the spirocycloalkyl is divided into single spiro, double spiro or multi-spirocycloalkyl, preferably single spiro and double spirocycloalkyl, preferably 4/5 members, 4/6 members, 5/5 members or 5/6 members.
  • spirocycloalkyl include, but are not limited to:
  • “Fused cycloalkyl” refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • Non-limiting examples of "fused cycloalkyl” include, but are not limited to:
  • Bridged cycloalkyl refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include, but are not limited to:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.
  • Heterocyclyl “heterocycle” or “heterocyclic” are used interchangeably in this application and refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic heterocyclic group containing 3-12 ring atoms, wherein at least one ring atom is a heteroatom, such as an oxygen, nitrogen, sulfur atom, etc. Preferably, it has a 5-7 membered monocyclic ring or a 7-10 membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl.
  • the heterocyclyl may be optionally substituted or unsubstituted.
  • spiro heterocyclyl is divided into single spiro heterocyclyl, double spiro heterocyclyl or multi-spiro heterocyclyl, preferably single spiro heterocyclyl and double spiro heterocyclyl. More preferably 4/4, 4/5, 4/6, 5/5 or 5/6 monospiro heterocyclyl.
  • spiro heterocyclyl include, but are not limited to:
  • the number of constituent rings it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic group include, but are not limited to:
  • bridged heterocyclic groups include, but are not limited to:
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected together in a fused manner.
  • the so-called “aryl” includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl.
  • the aryl is a C 6 -C 10 aryl, more preferably, the aryl is phenyl and naphthyl, and most preferably, phenyl.
  • the aryl may be substituted or unsubstituted.
  • the "aryl” may be fused with a heteroaryl, a heterocyclic group, or a cycloalkyl group, wherein the aryl ring is connected to the parent structure, and non-limiting examples include but are not limited to:
  • Heteroaryl refers to an aromatic 5 to 6-membered monocyclic or 9 to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • the embodiment of “heteroaryl” includes, but is not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quino
  • Heteroaryl may be optionally substituted or unsubstituted.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:
  • Alkoxy refers to a group of (alkyl-O-), wherein alkyl is as defined herein.
  • C 1 -C 6 alkoxy is preferred, and examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Haloalkyl refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described herein.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.
  • Hydrophilicity refers to an -OH group.
  • Halogen refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Benzyl refers to -CH2 -phenyl.
  • Carboxy refers to -C(O)OH.
  • Alcohol refers to -C(O) CH3 or Ac.
  • Carboxylate refers to -C(O)O(alkyl) or (cycloalkyl) wherein alkyl and cycloalkyl are as defined above.
  • halo or halogen groups are defined to include F, Cl, Br, or I.
  • substitution is meant that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced by a selection from the indicated group, provided that the normal atomic valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the listed substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and/or together, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the listed substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g., 11C , 13C , and 14C ); isotopes of chlorine (e.g., 36Cl ); isotopes of fluorine (e.g., 18F ); isotopes of iodine (e.g., 123I and 125I ); isotopes of nitrogen (e.g., 13N and 15N ); isotopes of oxygen (e.g., 15O , 17O , and 18O ); isotopes of phosphorus (e.g., 32P ); and isotopes of sulfur (e.g., 35S ).
  • isotopes of hydrogen e.g., deuterium ( 2H ), tritium ( 3H
  • Certain isotopically labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (e.g., assays).
  • the radioisotopes tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because they are easily incorporated and easily detected.
  • Substitution with positron emitting isotopes e.g., 11 C, 18 F, 15 O, and 13 N
  • PET positron emission tomography
  • Isotopically labeled compounds of the invention can be prepared by methods similar to those described in the accompanying routes and/or examples and preparations by using appropriate isotopically labeled reagents in place of the non-labeled reagents previously employed.
  • Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, for example, D 2 O, acetone-d 6 or DMSO-d 6 .
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.
  • an "effective amount" of a compound refers to an amount sufficient to down-regulate or agonize a corresponding target.
  • the "therapeutically effective dose” of a compound refers to an amount sufficient to improve or in some way reduce symptoms, stop or reverse the progression of a disease, or negatively regulate or stimulate a corresponding target. This dose can be used as a single dose or taken according to a regimen to be effective.
  • treating means ameliorating or otherwise altering in any way the symptoms or pathology of a patient's condition, disorder or disease.
  • amelioration of the symptoms of a particular disease by administration of a particular compound or pharmaceutical composition refers to any reduction, whether permanent or temporary, lasting or transient, attributable to or associated with the administration of that composition.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute part of the present invention.
  • Diastereoisomers can be separated into individual diastereomers on the basis of their physical chemical differences by methods such as chromatography, crystallization, distillation or sublimation.
  • Enantiomers can be separated to convert a chiral isomeric mixture into a diastereomeric mixture by reacting with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • the intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention.
  • optically active forms i.e., they have the ability to rotate the plane of plane polarized light.
  • the prefixes D, L or R, S are used to indicate the absolute configuration of the chiral center of the molecule.
  • the prefixes d, l or (+), (-) are used to name the sign of rotation of the plane of polarized light of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed.
  • These stereoisomers have the same order of attachment of atoms or groups of atoms to each other, but their stereostructures are different.
  • Stereoisomers may be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures.
  • a 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions.
  • the so-called “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers that lacks optical activity.
  • Tautomers or “tautomeric forms” refer to structural isomers of different energies that can be interconverted through a low energy barrier.
  • proton tautomers i.e., prototropic tautomers
  • Valence (chemical valence) tautomers include interconversions by reorganization of bonding electrons.
  • the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers are all within the scope of the present invention.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention, which are safe and effective when used in humans or animals. Salts of compounds can be obtained by using a sufficient amount of base or acid in a pure solution or a suitable inert solvent to obtain the corresponding addition salt.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, etc.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts.
  • the inorganic and organic acids include hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, butenedioic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid and methanesulfonic acid, etc. (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)).
  • solid lines can be used Solid wedge Virtual wedge Depicting chemical bonds of the compounds of the invention.
  • the use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.).
  • the use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomer shown is present. When present in a racemic mixture, the solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry.
  • the compounds of the invention are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof.
  • the compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
  • the chiral symbol * in the compounds herein indicates that the chiral configuration at that position is uncertain.
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the invention may be used in free form or, where appropriate, in their pharmaceutically acceptable form.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, chelates, complexes, inclusion compounds or prodrugs, which can directly or indirectly provide the compounds of the present invention or their metabolites or residues after being administered to patients in need thereof. Therefore, when referring to "compounds of the present invention” herein, it is also intended to cover the above-mentioned various derivative forms of the compounds.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, including but not limited to salts containing hydrogen bonds or coordinate bonds.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyaluronate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,
  • Suitable base addition salts are formed with bases which form pharmaceutically acceptable salts.
  • bases include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.
  • esters refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form).
  • physiologically hydrolyzable esters which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form.
  • the compounds of the present invention themselves may also be esters.
  • the compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
  • polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
  • the amount of polar solvents, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
  • nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane.
  • peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA)
  • hydrogen peroxide alkyl hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxirane such as dimethyldioxirane
  • metabolites of the compounds of the present invention i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound.
  • the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compounds of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have less pharmacological activity or no pharmacological activity, which when administered into or onto the body can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties” (e.g., as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).
  • the present invention also encompasses compounds of the present invention containing protecting groups.
  • protecting groups In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference.
  • the protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • the pyridine amide compound represented by formula (I) has a structure as described in the following formula (II) or formula (III):
  • E' is selected from a chemical bond or a saturated or partially unsaturated aliphatic C3-10 cycloalkylene group, a saturated or partially unsaturated aliphatic 3-10 membered heterocyclylene group, a C6-12 arylene group, or a C6-12 heteroarylene group,
  • W 1 and W 2 are each independently a chemical bond, N or CR c R d , and W 3 and W 4 are each independently selected from one of CR c R d , NR c , CO, O, S, SO, and SO 2 ;
  • R 11 is independently selected from H, halogen, hydroxyl, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C3-8 cycloalkyloxy and -C(O)R c ;
  • R 12 and R 13 are independently selected from H, halogen, C1-4 alkyl, C3-8 cycloalkyl and -C(O)R c ;
  • each R c and R d is independently selected from H, halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy and C1-3 hydroxyalkyl.
  • E' represents the following structure:
  • connection site is any position on the ring structure that can form a bond.
  • the general formula and preferred range of the compounds of the present invention have been recorded. Further preferably, the specific examples of the compounds of the present invention can be selected from any one of the following structures, but are not limited to the following compounds.
  • the following compounds 14, 15, 37-50, 54-57, 62-67, 70, 71 have isomers, and two chemical structures are represented by the form of numbering-P1 and numbering-P2: *Indicates that the configuration and properties of the compound need further testing.
  • the chiral compound is tentatively determined to have the configuration shown in the figure.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is preferably a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle that is administered together with a therapeutic agent and is suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic reaction or other problems or complications corresponding to a reasonable benefit/risk ratio within the scope of reasonable medical judgment.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • water is an exemplary carrier.
  • Physiological saline and aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, gluten, glutamine ...
  • compositions may also contain a small amount of wetting agent, emulsifier or pH buffer as needed.
  • Oral formulations may contain standard carriers such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the present invention can act systemically and/or locally.
  • they can be administered by suitable routes, for example by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, local, in the form of ophthalmic preparations or by inhalation.
  • suitable routes for example by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, local, in the form of ophthalmic preparations or by inhalation.
  • the pharmaceutical composition of the present invention can be administered in suitable dosage forms.
  • the dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.
  • the pharmaceutical composition of the present invention can be used to prevent and/or treat pain.
  • other pain treatment agents such as fluoxetine, opioid analgesics, non-opioid analgesics, etc. can also be used simultaneously.
  • the pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutically acceptable carrier or excipient include (but are not limited to): one or more of saline, buffer, glucose, water, glycerol, ethanol, powder, etc.
  • the pharmaceutical preparation should match the administration method.
  • the pharmaceutical composition of the present invention can be prepared in the form of an injection, for example, by conventional methods using physiological saline or an aqueous solution containing glucose and other adjuvants.
  • Pharmaceutical compositions such as tablets and capsules can be prepared by conventional methods.
  • Pharmaceutical compositions such as injections, solutions, tablets and capsules are preferably manufactured under aseptic conditions.
  • the pharmaceutical composition of the present invention can also be prepared in powder form for aerosol inhalation.
  • the dosage of the active ingredient is a therapeutically effective amount, for example, about 1 ⁇ g/kg body weight to about 50 mg/kg body weight per day; preferably, about 5 ⁇ g/kg body weight to about 10 mg/kg body weight; further preferably, about 10 ⁇ g/kg body weight to about 5 mg/kg body weight.
  • the compounds of the present invention can also be used together with other therapeutic agents.
  • composition of the present invention can be administered to a desired subject (such as a human or non-human mammal) in a conventional manner, and representative administration methods include (but are not limited to): oral administration, injection, aerosol inhalation, and the like.
  • a safe and effective amount of the drug is administered to a mammal, wherein the safe and effective amount is usually at least about 10 micrograms/kg body weight, and in most cases does not exceed about 50 milligrams/kg body weight, preferably, the dose is about 10 micrograms/kg body weight to about 20 milligrams/kg body weight.
  • the specific dose should also take into account factors such as the route of administration and the patient's health status, which are all within the skill of a skilled physician.
  • the so-called “effective amount” refers to the amount of the compound that, after being administered, will alleviate one or more symptoms of the treated condition to a certain extent. Specifically, as used herein, the “effective amount” of the compound refers to an amount sufficient to inhibit type 2 ⁇ hypoxia-inducible factor or inhibit cancer. As used herein, the “therapeutically effective dose” of the compound refers to an amount sufficient to improve or reduce symptoms in some way, stop or reverse the progression of the disease, or inhibit type 2 ⁇ hypoxia-inducible factor. This dose can be used as a single dose or taken according to a regimen, so as to be effective.
  • the dosage regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dosage may be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.
  • treat means to ameliorate or otherwise modify in any way the symptoms or pathology of a patient's condition, disorder or disease.
  • “ameliorating the symptoms of a particular disease by the use of a particular compound or pharmaceutical composition” means any reduction, whether permanent or temporary, lasting or temporary, attributable to or associated with the use of the composition.
  • “individual” includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
  • An important aspect of the present invention is to provide the above-mentioned oxalic acid amine derivatives provided by the present invention for preparing a method for treating a patient selected from cancer, inflammation
  • the invention relates to a method for treating a variety of diseases, wherein the cancer is selected from cancers of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, breast, ovary, testis or other reproductive organs, skin, thyroid, blood, lymph node, kidney, liver, pancreas, brain, central nervous system, solid tumors and hematogenous tumors, glioblastoma, renal cell carcinoma (RCC) and clear cell renal cell carcinoma (ccRCC);
  • the inflammation is selected from pneumonia, enteritis, nephritis, arthritis, and traumatic infection
  • the metabolic disease is selected from obesity, dyslipid
  • the present invention also provides a method for treating cancer using the oxalic acid amine derivatives as inhibitors, which is carried out by administering an effective amount of the compound to a subject suffering from cancer.
  • the so-called “effective amount” means an amount of a compound or composition sufficient to significantly and positively alter the symptoms and/or condition to be treated (e.g., provide a positive clinical response).
  • the effective amount of the active ingredient used in a pharmaceutical composition will vary with the specific condition being treated, the severity of the condition, the duration of treatment, the nature of concurrent treatment, the specific active ingredient(s) used, the pharmaceutically acceptable excipient(s)/carrier(s) used, and similar factors within the knowledge and expertise of the attending physician.
  • an effective amount of a compound of formula (I) for use in cancer treatment is an amount sufficient to symptomatically alleviate the symptoms of cancer in humans, to slow the progression of cancer, or to reduce the risk of worsening symptoms in patients with cancer.
  • the pharmaceutical composition of the present invention may also include one or more additional therapeutic or preventive agents.
  • the mass spectrum was obtained by LC/MS using ESI as the ionization method.
  • HPLC model Agilent 1260, Thermo Fisher U3000; chromatographic column model: Waters xbrige C18 (4.6*150 mm, 3.5 ⁇ m); mobile phase: A: ACN, B: Water (0.1% H 3 PO 4 ); flow rate: 1.0 mL/min; gradient: 5% A for 1 min, increase to 20% A within 4 min, increase to 80% A within 8 min, 80% A for 2 min, back to 5% A within 0.1 min; wavelength: 220 nm; column oven: 35°C.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.2mm-0.3mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.
  • Pd2(dba)3 tris(dibenzylideneacetone)dipalladium
  • HATU 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • PE Petroleum ether
  • R f The ratio of the distance from the origin to the center of the spot to the distance from the origin to the solvent front in thin layer chromatography.
  • Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.
  • the solution in the reaction refers to an aqueous solution.
  • reaction temperature is room temperature, 20°C-30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent used in the reaction, the eluent system of column chromatography or the developing solvent system of thin layer chromatography used for purifying the compound includes: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine, can also be added for adjustment.
  • TLC thin layer chromatography
  • reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of the tetrahydrofuran solution, and anhydrous sodium sulfate was added to prepare a saturated solution.
  • Ethyl acetate 200 mL x 3 was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was slurried with petroleum ether (100 mL), filtered, and the filter cake was dried to obtain the yellow solid title compound IN-1c (6.9 g, yield 91%).
  • reaction solution was slowly warmed to room temperature, saturated aqueous ammonium chloride solution (200 mL) was added and stirred for 10 minutes, and then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated.
  • Step 4 1-(tert-Butyloxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylic acid methyl ester IN-2e
  • reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of the tetrahydrofuran solution, and a saturated solution prepared with anhydrous sodium sulfate was added. It was extracted with ethyl acetate (200mL x3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was slurried with petroleum ether (100mL), filtered, and the filter cake was dried to obtain the yellow solid title compound IN-2h (1.3g, crude product), which was directly used in the next step.
  • the acid (1.5 eq) was dissolved in anhydrous N,N-dimethylformamide (4 V), and the intermediate amine (1 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.5 eq) and N,N-diisopropylethylamine (2 eq) were added at room temperature. After the addition was completed, the reaction solution was stirred at room temperature for 18 hours. TLC detected that the reaction of the raw materials was complete. Water (20 V) was added to the reaction solution to quench, and ethyl acetate was extracted (10 V x 3).
  • Step 3 1-(3,3-difluoro-4-hydroxy-1-azaspiro[4.4]nonan-1-yl)-3-(3,3-trifluorocyclobutyl)propane-1,2-dione 4
  • reaction solution was quenched with water (10 mL), extracted with ethyl acetate (15 mL), washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain the yellow liquid title compound 6-3 (65 mg, crude product), which was directly used in the next step.
  • Step 4 4-cyclopropyl-1-(3,3-difluoro-4-hydroxy-1-azaspiro[4.4]nonan-1-yl)butane-1,2-dione 6
  • reaction solution was quenched by adding 1M dilute hydrochloric acid (50 mL), stirred for 2 minutes and then separated.
  • the organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 10-2 (1.58 g, 58% yield) as a light yellow solid.
  • Step 5 1-(3,3-difluoro-4-hydroxy-1-azaspiro[4.4]nonan-1-yl)-3-(2,2-difluorocyclopropyl)propane-1,2-dione 10
  • Step 4 1-(3,3-difluoro-4-hydroxy-1-azaspiro[4.4]nonan-1-yl)-2-(3,3-trifluorocyclobutyl)ethane-1,2-dione 11
  • reaction solution was quenched with water (10 mL), extracted with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Compound 12 white solid, yield 18%; retention time 6.527 minutes.
  • Compound 13 white solid, yield 15%; retention time 10.890 minutes.
  • Synthesis Example 15 Synthesis process of compounds 14 and 15
  • Disperse compound 16-1 (10.0 g, 87.6 mmol), potassium carbonate (24.2 g, 175.3 mmol) and benzyl bromide (22.5 g, 131.5 mmol) in acetonitrile (100 mL) and react at 50°C for 4 hours; TLC monitors the complete reaction of the raw materials.
  • the reaction solution is cooled to room temperature, filtered, and concentrated.
  • 1,4-diacetylpiperazine-2,5-dione (870 mg, 4.42 mmol) and compound 16-5 (670 mg, 4.42 mmol) were added to the dichloromethane mixed solution obtained in the previous step and reacted at room temperature for 16 hours; TLC monitored the complete reaction of the raw materials.
  • the reaction solution was diluted with dilute hydrochloric acid (20 mL, 2M), and extracted with dichloromethane (20 mL x 4). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 6 1-(3,3-difluoro-4-hydroxy-1-azaspiro[4.4]nonan-1-yl)-3-(3-fluorocyclobutyl)propane-1,2-dione 16
  • Compound 18 white solid, yield 3.2%, retention time 6.127 minutes.
  • Compound 20 white solid, yield 4.1%, retention time 9.730 minutes.
  • the title compound was synthesized using 3-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2-oxopropanoic acid and compound IN-2 as raw materials.
  • the title compound 21-24 was obtained by chiral separation of the mixture.
  • Compound 21 white solid, yield 7.5%, retention time 9.353 minutes.
  • Compound 22 white solid, yield 7.3%, retention time 11.320 minutes.
  • Compound 23 white solid, yield 3.2%, retention time 8.353 minutes.
  • Compound 24 white solid, yield 3.0%, retention time 25.797 minutes.
  • reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of the tetrahydrofuran solution, and anhydrous sodium sulfate was added to prepare a saturated solution.
  • Ethyl acetate 200 mL x 3 was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was slurried with petroleum ether (100 mL), filtered, and the filter cake was dried to obtain the yellow solid title compound 25-3 (1.6 g, yield 97%).
  • reaction solution was cooled to room temperature, concentrated to remove ethanol, and ice water (50 mL) was added and stirred in an ice bath for 30 minutes.
  • the reaction solution was filtered and the filter cake was dried to obtain the title compound 26-2 (7.2 g, yield 95%) as a silvery white flaky solid.
  • the mixture 26-3 (crude product) was dissolved in methanol (150 mL), and thionyl chloride (8.3 g, 69.6 mmol) was slowly added dropwise at 0°C. After the addition was completed, the reaction solution was slowly heated to 70°C and stirred for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the title compound 26-4 (crude product) as a white solid, which was directly used in the next step.
  • reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of the tetrahydrofuran solution, and a saturated solution prepared with anhydrous sodium sulfate (100 mL) was added. It was extracted with ethyl acetate (200 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was slurried with petroleum ether (100 mL), filtered, and the filter cake was dried to obtain the yellow solid title compound 26-6 (2.0 g, yield 76%).
  • the reaction solution was cooled to room temperature, diluted with water (40 mL), extracted with ethyl acetate (50 mL x 2), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Compound 33 white solid, yield 9.3%, retention time 8.800 minutes.
  • Compound 34 white solid, yield 6.5%, retention time 10.687 minutes.
  • Compound 35 white solid, yield 1.9%, retention time 7.617 minutes.
  • Compound 36 white solid, yield 1.8%, retention time 12.373 minutes.
  • Synthesis Example 28 Synthesis process of compounds 37 and 38
  • Compound 37-P1 white solid, yield 10.5%, retention time 4.800 minutes.
  • Compound 38-P1 white solid, yield 7.1%, retention time 5.090 minutes.
  • Compound 38-P2 white solid, yield 5.6%, retention time 8.937 minutes.
  • Step 3 N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)-2-oxo-2-(3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro[4.4]nonan-1-yl)acetamide 39, 40
  • Step 8 2-(9,9-difluoro-10-hydroxy-6-azaspiro[4.5]decane-6-yl)-N-(3,3-difluorocyclobutyl)-2-oxoacetamide 51
  • reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (10 mL). The mixture was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated.
  • reaction solution was cooled to room temperature, concentrated to remove ethanol, and ice water (50 mL) was added and stirred in an ice bath for 30 minutes.
  • the reaction solution was filtered and the filter cake was dried to obtain the title compound 52-2 (7.2 g, yield 95%) as a silvery white flaky solid.
  • the mixture 52-3 (crude product) was dissolved in methanol (150 mL), and thionyl chloride (8.3 g, 69.6 mmol) was slowly added dropwise at 0°C. After the addition was completed, the reaction solution was slowly heated to 70°C and stirred for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the title compound 52-4 (crude product) as a white solid, which was directly used in the next step.
  • reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of the tetrahydrofuran solution, and a saturated solution prepared with anhydrous sodium sulfate (100 mL) was added. It was extracted with ethyl acetate (200 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was slurried with petroleum ether (100 mL), filtered, and the filter cake was dried to obtain the yellow solid title compound 52-6 (2.0 g, yield 76%).
  • Step 9 N-(3,3-difluorocyclobutyl)-2-oxo-2-(3,3,8,8-tetrafluoro-4-hydroxy-1-azaspiro[4.5]decan-1-yl)acetamide 52
  • reaction solution was quenched with saturated brine (10 mL), extracted with ethyl acetate (10 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated.
  • Synthesis Example 39 Synthesis process of compounds 56 and 57
  • Synthesis Example 40 Synthesis process of compounds 58-61
  • Step 2 N-(3-chlorobicyclo[1.1.1]pentan-1-yl)-2-93,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro[4.4]nonan-1-yl)acetamide58,59,60,61
  • Compound 60 white solid, yield 16%, retention time 14.717 minutes.
  • Test Example 1 Detection of the activity of compounds inhibiting HIF-2 ⁇ (IC 50 )
  • PT-2977 was used as a positive control in this experiment.
  • the compounds of the present invention have excellent HIF-2 ⁇ inhibitory activity.
  • 786-O cells in logarithmic phase growth were inoculated into 96-well plates at a cell concentration of 4000 cells per ml of culture medium, 180 ⁇ L per well, and the 96-well plates were placed in an incubator at 37°C and 5% CO 2 overnight.
  • PT-2977 was used as a positive control in this experiment.
  • the cells used in this experiment were 786O-HRE-Luciferase stable transfection cell lines (sequence 9*HRE-Luci).
  • the experiment was conducted when the 786O-HRE-Luci stable transfection cell lines were in the logarithmic growth phase and cultured in a culture medium (RPMI1640MEDIUM, purchased from GIBCO). When the cell confluence reached 80-90%, the culture medium was discarded, PBS was was washed three times, trypsin (purchased from BI) was added to digest the cells, and the cells were washed with serum-containing culture medium to terminate cell digestion. After the cells were collected, they were centrifuged and washed once with PBS to remove the phenol red in the culture medium. The cells were resuspended to an appropriate concentration to detect the cell density and viability, and the cell viability was ensured to be above 95% before the next experiment.
  • the cells were seeded into 384-well plates, 3000 cells/well, 30 ⁇ L of culture medium, and the compounds were added to make the final concentrations 10000, 3333, 1111, 370, 123, 41.1, 13.7, 4.6, 1.5, and 0.5 nM, respectively.
  • the cells were placed at 37°C and 5% CO 2 and incubated for 72 h.
  • ONE-Glo TM Luciferase Assay System purchased from Promega was added to a 384-well plate at 30 ⁇ L/well, and the luminescence value was detected by an ELISA instrument.
  • the inhibition rate (%) was calculated based on the RLU (Record Luminesence) signal value of each well, and then the IC 50 of the corresponding compound was calculated by fitting using Graphpad 9.0.
  • PT-2977 was used as a positive control in this experiment.
  • the compound of the present invention has advantages over existing positive compounds in terms of solubility, in vivo clearance rate and bioavailability.
  • the present invention illustrates the inhibitory activity of the present invention through the above examples, thereby proving its therapeutic use in the treatment or alleviation of diseases related to overexpression.
  • the compound of the present invention has excellent solubility in water and indicates metabolic stability in vivo, and has very broad industrial application prospects.
  • the present invention is not limited to the above embodiments, which does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

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Abstract

提供式(I)所示的草酸胺类化合物或者其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，以及含有所述化合物的药物组合物，还提供所述化合物作为2α型缺氧诱导因子(HIF-2α)抑制剂的用途，以及在与2α型缺氧诱导因子相关疾病药物制备中的应用。

Description

草酸胺类衍生物、包含其的药物组合物及其医药用途 技术领域
本发明属于医药领域，具体涉及一种草酸胺类衍生物，具体涉及一种作为2α型缺氧诱导因子(hypoxia inducible factor-2α,HIF-2α)抑制剂的草酸胺类衍生物、及用途。
背景技术
肾癌又称肾细胞癌，是全球范围内最常见的10种癌症之一，也是泌尿系统最致命的肿瘤之一，组织病理学将肾癌区分为三种主要亚型：透明细胞肾细胞癌(ccRCC，70-75％)，乳头状肾细胞癌(pRCC，10-16％)和嗜铬肾细胞癌(chRCC，5％)，每个亚型都与一个单独的遗传综合征相关，因此治疗方法也不同。
透明细胞肾细胞癌是最常见的肾脏恶性肿瘤，约占肾癌的90％。据美国癌症协会估计，全球每年新增肾癌40.3万例，死亡17.5万例；在中国，每年新增患者约6.68万例，死亡2.34万例。据中国国家癌症谱统计显示，肾脏发病率在过去20年间，以平均每年6.5％的速度增长，在泌尿系统肿瘤相关死亡中已经超过膀胱癌位居第一。肾癌可发病于各年龄段人群，高发年龄主要在50-70岁。由于肾脏的位置比较隐蔽，加之肾癌早期无明显临床症状，大多数肾癌患者在诊断时就已经存在转移，肾癌一旦出现转移(晚期)预后往往很差，5年生存率不足10％。而且与前列腺癌、膀胱癌等不同，其对于放疗与化疗都不敏感，这也成为以往肾癌治疗的最大挑战。因此，发现新颖且确证治疗肾癌特异性药物作用靶标是一项意义重大的工作。
缺氧诱导因子简称HIF，是感应氧浓度变化的关键，其家族成元包括HIF-1α、HIF-1β、HIF-2α、HIF-2β、HIF-3α、HIF-3β。HIF-2α活性异常是透明细胞肾细胞癌(ccRCC)等癌症的关键致癌驱动因素。在有氧条件下，脯氨酰羟化酶(PHD)可以对HIF-2α进行翻译后修饰，使其保守脯氨酸残基被羟基化，进而与VHL复合物(pVHL)结合并多聚泛素化HIF-2α，接着介导其降解，使得细胞内的HIF-2α维持低表达水平。在缺氧条件下，HIF-2α无法被羟基化，导致其无法与pVHL识别，因此得以积累并与HIF-1β形成二聚体，随后转移到细胞核内，在核内与辅因子CBP/p300和Pol II复合物等相互作用，并与HRE(缺氧反应元件)结合，由此激活下游靶基因的表达(VEGF-促进血管生成；GLUT1(葡萄糖转运蛋白-1)-激活葡萄糖转运；LDHA(乳酸脱氢酶)-参与糖酵解途径；和Epo-诱导红细胞生成等)。其中最明显的是RCC，有90％的RCC缺失VHL(Von Hippel-Lindau)的E3链接酶、导致HIF降解失控。因此，天生缺失部分VHL功能人群，肾癌风险高于正常人群，这类肾癌称为希佩尔-林道综合征(Von Hippel-Lindau Syndrome，VHL综合征)。HIF-2α抑制剂可以治疗/预防HIF-2α过表达引起的疾病，例如肾细胞癌。
Belzutifan(PT2977)是美国FDA于2021年批准的HIF-2α抑制剂，用于治疗希佩尔-林道综合征成人患者。
Belzutifan是第一款也是唯一一个HIF-2α抑制剂，产业界仍然认为开发一款新的HIF-2α抑制剂非常必要且存在社会意义。
发明内容
本发明的发明人发现，具有以下式(I)所示的结构的化合物在细胞水平的药物筛选模型中具有良好的2α型缺氧诱导因子抑制活性。具体而言，本发明提供以下式(I)所示的草酸胺类化合物或者其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，
上述式中，Y1为N或CR1，Y2为CR2R3、NR4或者不存在；
Y3及Y4各自独立地选自CR2R3、NR4、O、SO2中的一种；R2～R4之间的任意两个可以连接形成取代或未取代的C3-6环烷基、取代或未取代的3元至6元杂环烷基；
R1选自由H、卤素、羟基、CN、NO2、-NRaRb、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4羟烷基、C1-4烷氧基C1-4烷基、C3-8环烷基中的一种；
各R2及R3各自独立地选自H、卤素、CN、NO2、羟基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C1-4烷氧基C1-4烷基、C3-8环烷基、-S(O)2Ra、-CO2Ra、-C(O)Ra、-C(O)NRaRb、-S(O)2NRaRb、-S(O)(＝NRb)Ra及-NRaRb中的一种；各R4独立地选自H、卤素、羟基、C1-4烷基、C3-8环烷基、C1-6烷氧基、及-C(O)Ra；
L1为化学键或者选自C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、饱和或部分不饱和的C3-10亚环烃基、-O-、-CO-、-CN-、-CN(CN)-、-C(＝O)O-、-C(＝N)NRa-、-NRaC(＝S)-、-NRaCO-、-NRaS(＝O)-、-NRaS(＝O)2-、-S-、-S(＝O)-、-S(＝O)2-、-S(＝O)O-、-S(＝O)2O-中的一种或多种组合而成的二价基团；
E为化学键或者选自取代或未取代的饱和或部分不饱和脂肪族C3-10亚环烃基、取代或未取代的饱和或部分不饱和脂肪族3-10元亚杂环基、取代或未取代的C6-12亚芳基、或者取代或未取代的C6-12亚杂芳基；
R5为选自H、卤素、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6卤代羟烷基、C1-6羟烷基、C1-4烷氧基C1-4烷基、C3-8环烷基、-S(O)2Ra、-CO2Ra、-C(O)Ra、-C(O)NRaRb、-S(O)2NRaRb、-S(O)(＝NRb)Ra及-NRaRb中的一种；
R9及R10独立地选自由以下组成的组：H、卤素、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C1-6羟基卤代烷基、C1-4烷氧基C1-4烷基、C3-8环烷基、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-S(O)2NRaRb、-S(O)2Ra及C1-6亚烷基-C3-8环烷基、C1-6亚烷基-S(O)2Ra、C1-6亚烷基-S(O)2Ra、C1-6亚烷基-C(O)Ra、C1-6亚烷基-C(O)ORa、C1-6亚烷基-C(O)NRaRb、C1-6亚烷基-S(O)2NRaRb；
或者，R9及R10连接在一起形成取代或未取代的C3-8环烷基、取代或未取代的3元至8元杂环烷基；
或者，R9或R10与Y4连接在一起形成取代或未取代的C3-6环烷基、取代或未取代的3元至6元杂环烷基、取代或未取代的C6-12亚芳基、或者取代或未取代的C6-12亚杂芳基；
各Ra及Rb独立地选自由以下组成的组：H、C1-8烷基、C1-8烷氧基、C1-8卤代烷基、C1-8卤代烷氧基及C1-8羟烷基，
上述的取代或未取代是指基团中的H被选自卤素、CN、OH、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4羟烷基、C1-4烷氧基C1-4烷基及-NRaRb中的一种或者至少两种的组合以上的基团所取代，或者指基团中的-CH2-中的两个H被替换成氧代＝O。
本发明还提供一种药物组合物，其包含预防或治疗有效量的式(I)所示的化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，以及药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。
本发明的一个实施方式中，所述的药物组合物的剂型为口服剂型或注射剂，所述口服剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂；所述注射剂包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的本发明化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药无菌粉末。
本发明提供上述化合物以及药物组合物作为治疗或者预防癌症、炎症性疾病、免疫相关疾病的用途，这些疾病都与2α型缺氧诱导因子密切相关，调控2α型缺氧诱导因子具有这些疾病的治疗前景。
具体而言，所述癌症为以下的癌症：前列腺癌、结肠癌、直肠癌、胰腺癌、子宫颈癌、胃癌、子宫内膜癌、子宫癌、脑癌、肝癌、膀胱癌、卵巢癌、睪丸癌、头癌、颈癌、皮肤(包括黑素瘤及基底癌)癌、间皮内膜癌、白血球癌、食道癌、乳房癌、肌肉癌、结缔组织癌、肠癌、肺癌、肾上腺癌、甲状腺癌、肾或骨；神经胶母细胞瘤癌、间皮瘤癌、肾细胞癌、透明细胞肾细胞癌、胃癌、肉瘤、卡波西氏肉瘤、绒毛膜癌、皮肤基底细胞癌或睪丸精原细胞瘤；所述的炎症选自肺炎、肠炎、肾炎、关节炎、外伤感染；所述的代谢性疾病选自肥胖症、血脂异常、高脂质血症。
本发明化合物尤其适合肾细胞癌、透明细胞肾细胞癌的治疗。
以下说明本发明其他各要素进行更加详细的说明。
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
所谓的“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
如本文中所使用，所谓的“亚烷基”表示饱和二价烃基，优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基，例如亚甲基、亚乙基、亚丙基或亚丁基。
如本文中所使用，所谓的“烷基”定义为线性或支化饱和脂肪族烃。在一些实施方案中，烷基具有1至12个，例如1至6个碳原子。例如，如本文中所使用，所谓的“C1-6烷基”指1至6个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基)，其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CH2F、CHF2、CF3、CCl3、C2F5、C2Cl5、CH2CF3、CH2Cl或-CH2CH2CF3等)。所谓的“C1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
如本文中所使用，所谓的“烯基”意指线性的或支化的单价烃基，其包含一个双键，且具有2-6个碳原子(“C2-6烯基”)。所述烯基为例如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。
如本文中所使用，所谓的“炔基”表示包含一个或多个三键的单价烃基，其优选具有2、3、4、5或6个碳原子，例如乙炔基或丙炔基。
如本文中所使用，所谓的“环烷基”指饱和的单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等))，其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如，所谓的“C3-6环烷基”指3至6个成环碳原子的饱和的单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。
如本文中所使用，所谓的“亚环烃基”、“环烃基”和“烃环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环碳原子的饱和(即，“亚环烷基”和“环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环烃环，其包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环己烯基(环) 等。
如本文中所使用，所谓的“杂环基”、“亚杂环基”和“杂环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环原子、其中至少一个环原子是选自N、O和S的杂原子且其余环原子是C的饱和(即，杂环烷基)或部分不饱和的(即在环内具有一个或多个双键和/或三键)环状基团。例如，“3-10元(亚)杂环(基)”是具有2-9个(如2、3、4、5、6、7、8或9个)环碳原子和独立地选自N、O和S的一个或多个(例如1个、2个、3个或4个)杂原子的饱和或部分不饱和(亚)杂环(基)。亚杂环基和杂环(基)的实例包括但不限于：(亚)环氧乙烷基、(亚)氮丙啶基、(亚)氮杂环丁基(azetidinyl)、(亚)氧杂环丁基(oxetanyl)、(亚)四氢呋喃基、(亚)二氧杂环戊烯基(dioxolinyl)、(亚)吡咯烷基、(亚)吡咯烷酮基、(亚)咪唑烷基、(亚)吡唑烷基、(亚)吡咯啉基、(亚)四氢吡喃基、(亚)哌啶基、(亚)吗啉基、(亚)二噻烷基(dithianyl)、(亚)硫吗啉基、(亚)哌嗪基或(亚)三噻烷基(trithianyl)。所述基团也涵盖双环系统，包括螺环、稠合或桥连系统(诸如8-氮杂螺[4.5]癸烷、3，9-二氮杂螺[5.5]十一烷、2-氮杂双环[2.2.2]辛烷等)。亚杂环基和杂环(基)可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
如本文中所使用，所谓的“(亚)芳基”和“芳环”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。例如，如本文中所使用，所谓的“C6-10(亚)芳基”和“C6-10芳环”意指含有6至10个碳原子的芳族基团，诸如(亚)苯基(苯环)或(亚)萘基(萘环)。(亚)芳基和芳环任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO2、C1-6烷基等)取代。
如本文中所使用，所谓的“(亚)杂芳基”和“杂芳环”指单环、双环或三环芳族环系，其具有5、6、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)，并且，另外在每一种情况下可为苯并稠合的。特别地，“(亚)杂芳基”或“杂芳环”选自(亚)噻吩基、(亚)呋喃基、(亚)吡咯基、(亚)噁唑基、(亚)噻唑基、(亚)咪唑基、(亚)吡唑基、(亚)异噁唑基、(亚)异噻唑基、(亚)噁二唑基、(亚)三唑基、(亚)噻二唑基等，以及它们的苯并衍生物；或(亚)吡啶基、(亚)哒嗪基、(亚)嘧啶基、(亚)吡嗪基、(亚)三嗪基等，以及它们的苯并衍生物。
如本文中所使用，所谓的“芳烷基”优选表示芳基或杂芳基取代的烷基，其中所述芳基、杂芳基和烷基如本文中所定义。通常，所述芳基可具有6-14个碳原子，所述杂芳基可具有5-14个环原子，并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基。
作为更具体地术语解释如下：
“烷基”指饱和脂肪族烃基团，包括1-20个碳原子，或1-10个碳原子，或1-6个碳原子，或1-4个碳原子，或1-3个碳原子，或1-2个碳原子饱和直链或支链的单价烃基，其中烷基可以独立任选地被一个或多个本发明所描述地取代基所取代。烷基基团更近一步地实例包括，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、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是任选取代或未取代的。
“烯基”指2-12个碳原子，或2-8个碳原子，或2-6个碳原子，或2-4个碳原子直链或支链的一价烃基，其中至少一个C-C为sp2双键，其中烯基的基团可以独立任选地被1个或多个本发明所描述的取代基所取代，其中具体的实例包括，但并不限于乙烯基、烯丙基和烯丁基等等。烯基可以是任选取代或未取代的。
“环烷基”是指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包括3至20个碳原子，优选包括3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实施例包括，但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是任选取代的或未取代的。
“螺环烷基”指5至18元，两个或两个以上环状结构，且单环之间彼此共用一个碳原子(称螺原子)的多环基团，环内含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺、双螺或多螺环烷基，优选为单螺和双螺环烷基，优选为4元/5元、4元/6元、5元/5元或5元/6元。 “螺环烷基”的非限制性实施例包括但不限于：
“稠环烷基”指5至18元，含有两个或两个以上环状结构彼此公用一对碳原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，优选为6至12元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。“稠环烷基”的非限制性实施例包括但不限于：
“桥环烷基”指5至18元，含有两个或两个以上环状结构，彼此共用两个不直接相连接碳原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，优选为6至12元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于：
所述环烷基环可以稠合于芳基、杂芳基或杂环基环上，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。
“杂环基”、“杂环”或“杂环的”在本申请中可交换使用，本申请中可交换使用，都是指包含3-12个环原子的饱和或部分不饱和的单环、双环或三环的非芳香性杂环基，其中至少一个环原子原子是杂原子，如氧、氮、硫原子等。优选具有5至7元单环或7至10元双-或三环，其可以包含1，2或3个选自氮、氧和/或硫中的原子。“杂环基”的实例包括但不限于吗啉基，氧杂环丁烷基，硫代吗啉基，四氢吡喃基，1，1-二氧代-硫代吗啉基，哌啶基，2-氧代-哌啶基，吡咯烷基，2-氧代-吡咯烷基，哌嗪-2-酮，8-氧杂-3-氮杂-双环[3.2.1]辛基和哌嗪基。所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基。杂环基可以是任选取代的或未取代的。
“螺杂环基”指5至18元，两个或两个以上环状结构，且单环之间彼此共用一个原子的多环基团，环内含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧、硫或S(O)m的杂原子，其余环原子为碳，m＝1或2。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。“螺杂环基”的非限制性实施例包括但不限于：
“稠杂环基”指含有两个或两个以上环状结构彼此公用一对原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧、硫或S(O)m的杂原子，其余环原子为碳，m＝1或2。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。“稠杂环基”的非限制性实施例包括但不限于：
“桥杂环基”指5至18元，含有两个或两个以上环状结构，彼此共用两个不直接相连接的原子的多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧、硫或S(O)m的杂原子，其余环原子为碳，m＝1或2。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。“桥杂环基”的非限制性实施例包括但不限于：
“芳基”是指含有一个或者两个环的碳环芳香系统，其中所述环可以以稠合的方式连接在一起。所谓的“芳基”包括比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C6-C10芳基，更优选芳基为苯基和萘基，最优选为苯基。芳基可以是取代或未取代的。所述“芳基”可与杂芳基、杂环基或环烷基稠合，其中与母体结构连接在一起的为芳基环，非限制性实施例包括但不限于：
“杂芳基”是指芳香族5至6元单环或9至10元双环，其可以包含1至4个选自氮、氧和/或硫中的原子。“杂芳基”的实施例包括但不限于呋喃基，吡啶基，2-氧代-1，2-二氢吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异噁唑基、噁唑基、噁二唑基、咪唑基、吡咯基、吡唑基、三唑基、四唑基、噻唑基、异噻唑基、1，2，3-噻二唑基、苯并间二氧杂环戊烯基、苯并咪唑基、吲哚基、异吲哚基、1，3-二氧代-异吲哚基、喹啉基、吲唑基、苯并异噻唑基、苯并噁唑基和苯并异噁唑基。杂芳基可以是任选取代或未取代的。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包括但不限于：
“烷氧基”是指(烷基-O-)的基团。其中，烷基见本文有关定义。C1-C6的烷氧基为优先选择。其实例包括，但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“卤代烷基”指具有一个或者多个卤素取代基的烷基，其中烷基基团具有如本发明所述的含义。卤代烷基的实例包括，但并不限于氟甲基、二氟甲基、三氟甲基、全氟乙基、1,1-二氯乙基、1,2-二氯丙基等。
“羟基”指-OH基团。
“卤素”是指氟、氯、溴和碘，优选氟、氯和溴。
“氨基”指-NH2。
“氰基”指-CN。
“硝基”指-NO2。
“苄基”指-CH2-苯基。
“羧基”指-C(O)OH。
“乙酰基”指-C(O)CH3或Ac。
“羧酸酯基”指-C(O)O(烷基)或(环烷基)，其中烷基、环烷基的定义如上所述。
如本文中所使用，所谓的“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
如本文中所使用，所谓的“含氮杂环”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子，其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C＝O、S、S＝O和S(＝O)2的环成元，其通过所述含氮杂环中的氮原子以及任一其余环原子与分子的其余部分连接，所述含氮杂环任选地为苯并稠合的，并且优选通过所述含氮杂环中的氮原子以及所稠合的苯环中的任一碳原子与分子的其余部分连接。
所谓的“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
如果取代基被描述为“任选地被取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。
如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。
如本文中所使用，所谓的“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘(2H)、氚(3H))；碳的同位素(例如11C、13C及14C)；氯的同位素(例如36Cl)；氟的同位素(例如18F)；碘的同位素(例如123I及125I)；氮的同位素(例如13N及15N)；氧的同位素(例如15O、17O及18O)；磷的同位素(例如32P)；及硫的同位素(例如35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即3H)及碳-14(即14C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如11C、18F、15O及13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D2O、丙酮-d6或DMSO-d6。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1-3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人元能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”，如无特别指出，均是指基团可被一个或多个选自以下的基团取代：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、＝O、-C(O)Rb、-OC(O)Rb、-NRbRb、-C(O)NRbRb、-NRbC(O)Rb、-S(O)NRbRb或-S(O)2NRbRb，其中，Rb的定义如通式(I)中所述。
如本文所用，化合物的“有效量”是指足以负调节或激动相应靶标的量。
如本文所用，化合物的“治疗有效剂量”是指足以改善或以某种方式减少症状、停止或逆转病情进展、或负调节或激动相应靶标的量。这种剂量可以作为单一剂量使用，也可以按照一种方案服用，从而有效。
如此处所用，“治疗”是指以任何方式改善或以其他方式改变患者的病情、紊乱或疾病的症状或病理。
如本文所述，“通过使用某一特定化合物或药物组合物来改善某一特定疾病的症状”是指可归因于或与该组合物的使用有关的任何减少，不论是永久性的还是暂时性的、持久的或暂时性的。
本发明中立体化学的定义和惯例的使用通常参考以下文献：
S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-HillBook Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.本发明的化合物可以包含不对称中心或手性中心，因此存在不同的立体异构体。本发明的化合物所有的立体异构形式，包括但绝不限于，非对映体，对映异构体，阻转异构体，和它们的混合物，如外消旋混合物，组成了本发明的一部分。非对映异构体可以以其物理化学差异为基础，通过层析、结晶、蒸馏或升华等方法被分离为个别非对映异构体。对映异构体可以通过分离，使手性异构混合物转化为非对映异构混合物，其方式是与适当光学活性化合物(例如手性辅助剂，譬如手性醇或Mosher氏酰氯)的反应，分离非对映异构体，且使个别非对映异构体转化为相应的纯对映异构体。本发明的中间体与化合物也可以不同互变异构形式存在，且所有此种形式被包含在本发明的范围内。很多有机化合物都以光学活性形式存在，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀d、l或(+)、(-)用来命名化合物平面偏振光旋转的符号，(-)或l是指化合物是左旋的，前缀(+)或d是指化合物是右旋的。这些立体异构体的原子或原子团互相连接次序相同，但是它们的立体结构不一样。特定的立体异构体可以是对映体，异构体的混合物通常称为对映异构体混合物。50：50的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。所谓的“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。
“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低能垒互相转化。例如质子互变异构体(即质子移变的互变异构体)包括通过质子迁移的互变，如酮式-烯醇式和亚胺-烯胺的同分异构化作用。原子价(化合价)互变异构体包括重组成键电子的互变。除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式(如对映异构，非对映异构，和几何异构)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体的混合物都属于本发明的范围。
“药学上可接受的盐”指本发明化合物的盐，这类盐用于人或动物体内时具有安全性和有效性。化合物的盐可以通过在纯的溶液或合适的惰性溶解中用足量的碱或酸获得相应的加成盐。可药用的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐等，可药用的酸加成盐包括无机酸盐和有机酸盐，所述的无机酸和有机酸包括盐酸、氢溴酸、碳酸、碳酸氢根、磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸一氢根、乙酸、马来酸、丙二酸、琥珀酸、饭丁烯二酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸和甲磺酸等(参见Berge et al.,“Pharmaceutical Salts”,Journal of Pharmaceutical Science 66:1-19(1977))。
本文中可使用实线实楔形或虚楔形描绘本发明的化合物的化学键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。
本文中的化合物的手性标记*表示该位置的手性构型不确定。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接 受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、N-氧化物、代谢物、螯合物、络合物、包合物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐，包括但不限于含有氢键或配位键的盐。
适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、海苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐及昔萘酸盐(xinofoate)。
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钾盐、钠盐、氨丁三醇盐及锌盐。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts：Properties，Selection，and Use”(Wiley-VCH，2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人元已知的。
如本文中所使用，所谓的“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本领域技术人元会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人元会识别能够形成N-氧化物的含氮杂环。本领域技术人元还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人元熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist，Comprehensive Organic Synthesis，vol.7，pp 748-750；A.R.Katritzky和A.J.Boulton，Eds.，Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry，vol.22，pp 390-392，A.R.Katritzky和A.J.Boulton，Eds.，Academic Press。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)。本发明的前药可例如通过用本领域技术人元已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier，1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在T.W.Greene&P.G.M.Wuts，Protective Groups in Organic Synthesis，JohnWiley&Sons，1991中所述的那些保护基，这些参考文献通过援引加入本 文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
所谓的“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
在本发明的优选实施方式中，式(I)所示的吡啶酰胺类化合物具有以下式(II)或式(III)所述的结构，
式(II)和式(III)中，Y1、Y2与式(I)中表示的意义相同，
L1为选自C1-6亚烷基、-CO-、-C(＝O)O-、-NRaCO-、中的一种或多种组合而成的二价基团；
E’选自化学键或者饱和或部分不饱和脂肪族C3-10亚环烃基、饱和或部分不饱和脂肪族3-10元亚杂环基、C6-12亚芳基、或者C6-12亚杂芳基，
W1、W2各自独立地为化学键、N或CRcRd，W3、W4各自独立地选自CRcRd、NRc、CO、O、S、SO、SO2中的一种；
R11独立地选自H、卤素、羟基、C1-4烷基、C3-8环烷基、C1-4烷氧基、C3-8环烷氧基及-C(O)Rc；R12和R13独立地选自H、卤素、C1-4烷基、C3-8环烷基及-C(O)Rc；各Rc及Rd独立地选自H、卤素、C1-3烷基、C1-3烷氧基、C1-3卤代烷基、C1-3卤代烷氧基及C1-3羟烷基。
在本发明的优选实施方式中，E’表示以下结构：
C2～6亚烷基、亚环丙基、亚环丁基、亚环戊基、亚环己基、亚环庚基、亚环辛基、亚降冰片基、亚金刚烷基、亚氧杂环丁基、亚四氢呋喃基、亚苯基、亚联苯基、亚三联苯基、亚萘基、亚蒽基、亚菲基、亚茚基、亚芴基、亚荧蒽基、亚三亚苯基、亚芘基、亚苝基、亚基、亚苯并环丁基、亚苯并环戊基、亚苯并环己基、亚苯并环庚基、亚苯并环辛基、亚噻唑基、亚呋喃基、亚噻吩基、亚吡咯基、亚吡啶基、亚苯并呋喃基、亚苯并噻吩基、亚异苯并呋喃基、亚异苯并噻吩基、亚吲哚基、亚异吲哚基、亚二苯并呋喃基、亚二苯并噻吩基、亚咔唑基及其衍生物、亚喹啉基、亚异喹啉基、亚吖啶基、亚菲啶基、亚苯并喹啉基、、亚吩噻嗪基、亚吩嗪基、亚吡唑基、亚吲唑基、亚咪唑基、亚苯并咪唑基、亚萘并咪唑基、亚菲并咪唑基、亚吡啶并咪唑基、亚吡嗪并咪唑基、亚喹喔啉并咪唑基、亚嗯唑基、亚苯并嗯唑基、亚萘并嗯唑基、亚蒽并嗯唑基、亚菲并嗯唑基、亚苯并噻唑基、亚哒嗪基、亚苯并哒嗪基、亚嘧啶基、亚苯并嘧啶基、亚喹喔啉基、亚1，5-二氮杂蒽基、亚2，7-二氮杂芘基、亚2，3-二氮杂芘基、亚二氮杂芘基、亚4，5，9，10-四氮杂茈基、亚吡嗪基、亚吩嗪基、亚吩噻嗪基、亚萘啶基、亚氮杂咔唑基、亚苯并咔啉基、亚菲咯啉基、亚三唑基、亚1，2，3-噁二唑基、亚1，2，4-嗯二唑基、亚1，2，5_嗯二唑基、亚噻二唑基、亚三嗪基、亚四唑基、亚四嗪基、亚嘌呤基、亚蝶啶基、亚吲嗪基、亚苯并噻二唑或以下基团，或者它们之间的组合，
上述基团可选地被卤素、C1-3的烷基取代，或者上述基团中的CH2被氧代为C＝O，
表示与母核连接的位置，“—”划过的环结构的表达方式，表示连接位点于该环结构上任意能够成键的位置。
本发明的优选化合物
已经记载本发明化合物的通式和优选范围。进一步优选地，本发明化合物的具体例子可以选自如下结构的任意一种，但是并不限于以下化合物，另外需要说明的是下述中化合物14、15、37～50、54-57、62-67、70、71由于存在异构体，用编号-P1和编号-P2的形式表示两个化学结构：









*表示化合物构型及性质需进一步检测，暂定手性化合物为图示构型。
药物组合物、医药用途和治疗方法
本发明提供一种药物组合物，其包含有效量的本发明化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，以及药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。
本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦 芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。
本发明的药物组合物可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射(如静脉内、动脉内、皮下、腹膜内、肌内注射，包括滴注)或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
对于这些给药途径，可以适合的剂型给药本发明的药物组合物。
所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂。
本发明所述的药物组合物可用于预防和/或治疗疼痛症。在使用本发明药物制剂时，还可同时使用其他疼痛症治疗剂，如氟西汀、阿片类镇痛药、非阿片类止痛剂等。
本发明所述药物组合物，含有安全有效量的本发明化合物以及药学上可接受的载体或赋形剂。这类载体包括(但并不限于)：盐水、缓冲液、葡萄糖、水、甘油、乙醇、粉剂等中的一种或几种。药物制剂应与给药方式相匹配。
本发明的药物组合物可以被制成针剂形式，例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。诸如片剂和胶囊之类的药物组合物，可通过常规方法进行制备。药物组合物如针剂、溶液、片剂和胶囊宜在无菌条件下制造。本发明的药物组合物也可以被制成粉剂用于雾化吸入。
活性成分的给药量是治疗有效量，例如每天约1微克/千克体重-约50毫克/千克体重；优选地，为约5微克/千克体重-约10毫克/千克体重；进一步优选地，为约10微克/千克体重-约5毫克/千克体重。此外，本发明化合物还可与其他治疗剂一起使用。
对于本发明的药物组合物，可通过常规的方式施用于所需的对象(如人和非人哺乳动物)。代表性的施用方式包括(但并不限于)：口服、注射、雾化吸入等。
使用药物组合物时，是将安全有效量的药物施用于哺乳动物，其中该安全有效量通常至少约10微克/千克体重，而且在大多数情况下不超过约50毫克/千克体重，较佳地，该剂量是约10微克/千克体重-约20毫克/千克体重。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
下面结合具体实施例，进一步阐述本发明。实施本发明的过程、条件、试剂、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
如本文中所使用的所谓的“有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。具体而言，如本文所用，化合物的“有效量”是指足以抑制2α型缺氧诱导因子或者抑制癌症的量。如本文所用，化合物的“治疗有效剂量”是指足以改善或以某种方式减少症状、停止或逆转病情进展、或抑制2α型缺氧诱导因子的量。这种剂量可以作为单一剂量使用，也可以按照一种方案服用，从而有效。
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人元的专业判断来随时间调整。
如此处所用，“治疗”是指以任何方式改善或以其他方式改变患者的病情、紊乱或疾病的症状或病理。如本文所述，“通过使用某一特定化合物或药物组合物来改善某一特定疾病的症状”是指可归因于或与该组合物的使用有关的任何减少，不论是永久性的还是暂时性的、持久的或暂时性的。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
本发明的一个重要方面是提供本发明上述提供草酸胺类衍生物在制备用于治疗选自癌症、炎 症、代谢性疾病中的用途，所述的癌症选自头、颈、眼、口、咽喉、食道、支气管、喉、咽、胸、骨、肺、结肠、直肠、胃、前列腺、膀胱、子宫、子宫颈、乳腺、卵巢、睾丸或其他生殖器官、皮肤、甲状腺、血液、淋巴结、肾脏、肝脏、胰腺、脑、中枢神经系统的癌症，实体瘤和血源性肿瘤，成胶质细胞瘤，肾细胞癌(RCC)和透明细胞肾细胞癌(ccRCC)；所述的炎症选自肺炎、肠炎、肾炎、关节炎、外伤感染；所述的代谢性疾病选自肥胖症、血脂异常、高脂质血症。
本发明还提供用作抑制剂的草酸胺类衍生物用于治疗癌症的方法，该方法是通过向患有癌症的受试者给予一个有效量的所述的化合物进行的。
如在此所使用的，所谓的“有效量”意指一种化合物或组合物的足以显著和积极改变有待治疗的症状和/或病症(例如，提供积极临床响应)的量。用于一种药物组合物中的活性成分的有效量将随着正在被治疗的具体病症、该病症的严重性，治疗的持续时间、同步治疗的性质，该一种或多种使用的具体的活性成分，一种或多种所使用的药学上可接受的赋形剂/载体、以及主治医生的知识和专业技能内的类似因素而变化。
具体地，用于在癌症治疗中使用的具有化学式(I)的化合物的一个有效量是足以对症减轻在人中癌症的症状的量，以减缓癌症的进展，或减少患有癌症的患者中症状恶化的风险。在一些实施方案中，本发明的药物组合物还可以包含一种或多种另外的治疗剂或预防剂。
具体实施方式
下面通过具体实施例对本发明的方法进行说明，以使本发明技术方案更易于理解、掌握，但本发明并不局限于此。下述实施例中1H NMR图谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。1H NMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，q＝四重峰，m＝多重峰，br＝宽峰，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。
质谱是用LC/MS仪测定得到，离子化方式为ESI。
高效液相色谱仪型号：安捷伦1260、赛默飞U3000；色谱柱型号：Waters xbrige C18(4.6*150mm,3.5μm)；流动相：A:ACN,B:Water(0.1％H3PO4)；流速：1.0mL/min；梯度：5％A for 1min,increase to 20％A within 4min,increase to 80％A within 8min,80％A for 2min,back to 5％A within 0.1min；波长：220nm；柱温箱：35℃。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.2mm-0.3mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
在下列实例中，除非另有指明，所有温度为摄氏温度，除非另有指明，各种起始原料和试剂来自市售或者是根据已知的方法合成，市售原料和试剂均不经进一步纯化直接使用，除非另有指明，市售厂家包括但不限于国药集团，百灵威科技有限公司，梯希爱(上海)化成工业发展有限公司，上海毕得医药科技有限公司和上海迈瑞尔化学科技有限公司等。
CD3OD：氘代甲醇
CDCl3：氘代氯仿
DMSO-d6：氘代二甲基亚砜
Pd2(dba)3：三(二亚苄基丙酮)二钯
Pd(dppf)Cl2：[1,1'-双(二苯基膦基)二茂铁]二氯化钯
XantPhos：4,5-双二苯基膦-9,9-二甲基氧杂蒽
XPhos：2-二环己基磷-2,4,6-三异丙基联苯
HATU：2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
DCM：二氯甲烷
PE：石油醚
EA：乙酸乙酯
MeOH：甲醇
DMF：N,N-二甲基甲酰胺
TLC：薄层色谱法
HPLC：高效液相色谱法
purity：纯度
&：和
Rf：薄层色谱法中原点到斑点中心的距离与原点到溶剂前沿的距离的比值。
氢气氛围是指反应瓶连接一个约1L容积的氢气气球。
实施例中无特殊说明，反应中的溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃-30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系或薄层色谱法的展开剂体系包括：A：石油醚和乙酸乙酯体系；B：二氯甲烷和甲醇体系；C：正己烷：乙酸乙酯；其中溶剂的体积比根据化合物的极性不同而不同，也可以加入少量的酸性或碱性试剂进行调节，如醋酸或三乙胺等。
化学合成试验：
中间体的制备
合成例1：中间体1合成过程
3,3-二氟-1-氮杂螺环[4.4]壬烷-4-醇IN-1
第一步 1-(3-甲氧基-3-氧代丙酰胺基)环戊烷-1-羧酸甲酯IN-1b
将化合物IN-1a(10.0g,55.7mmol)溶于无水二氯甲烷(300mL)中，氮气保护下冷却至0℃，加入三乙胺(14.2g,140mmol)，加毕，缓慢滴加丙二酸甲酯酰氯(11.5g,83.6mmol)，滴加完成后反应在0℃下继续搅拌3小时；TLC显示原料反应完全，反应液缓慢升至室温，加水(200mL)搅拌10分钟后分液，有机相无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯＝1/2)纯化得黄色油状液体标题化合物IN-1b(12.1g,收率：89％)。
第二步 1-氮杂螺环[4.4]壬烷-2,4-二酮IN-1c
将化合物IN-1b(12.1g,49.7mmol)溶于无水四氢呋喃(300mL)中，氮气保护下冷却到0℃，分次加入叔丁醇钾(8.4g,74.6mmol)，加料完成后反应液升温至25℃并继续搅拌2小时；TLC检测原料反应完全。反应液加入稀盐酸(100ml,1N)调节PH至5左右，得到的溶液不处理直接升温至85℃后搅拌回流4小时，TLC检测原料反应完全。反应液冷却至室温，减压浓缩除去大部分四氢呋喃溶液，加入无水硫酸钠配制成饱和溶液后，乙酸乙酯(200mL x3)萃取，合并有机相，无水硫酸钠干燥，浓缩，粗品用石油醚(100mL)打浆，抽滤，滤饼烘干得黄色固体标题化合物IN-1c(6.9g,收率91％)。
第三步 3,3-二氟-1-氮杂螺环[4.4]壬烷-2,4-二酮IN-1d
将化合物IN-1c(3.5g,22.8mmol)溶于乙腈(50mL)中，加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(20.4g,57.5mmol)和水(50mL)，加毕，反应在室温下继续搅拌12小时，TLC检测原料反应完全。反应液减压浓缩除去乙腈，母液用乙酸乙酯(100mL x2)萃取，合并有机相，无水硫酸钠干燥，浓缩得灰色固体标题化合物IN-1d(4.7g,粗品)，直接用于下一步。
第四步 3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-2-酮IN-1e
将化合物IN-1d(2.7g,粗品)溶于甲醇(100mL)中，冷却至0℃，加入硼氢化钠(0.82g,21.5mmol)，加毕，反应在0℃下继续搅拌1小时，TLC检测原料反应完全。反应液减压浓缩得白色固体标题化合物IN-1e(3.3g,粗品)，直接用于下一步。
第五步 3,3-二氟-1-氮杂螺环[4.4]壬烷-4-醇IN-1
将化合物IN-1e(3.3g,粗品)溶于无水四氢呋喃(150mL)中，室温下加入四氢铝锂(2.2mg,57.2mmol)，加毕，反应液加热至66℃搅拌2小时，TLC检测原料反应完全。反应液冷却至0℃后依次加水(2.2mL)，氢氧化钠溶液(2.2mL,15％)和水(6.6mL)淬灭，反应在室温下继续搅拌10分钟，抽滤，滤液用无水硫酸钠干燥，浓缩得白色固体标题化合物IN-1(2.0g,三步合并收率86％)。
合成例2：中间体2合成过程
3,3,7,7-四氟-1-氮杂螺环[4.4]壬烯-4-醇IN-2
第一步 3,3-二氟环戊烷-1-甲酸甲酯IN-2b
将化合物IN-2a(20.0g,140.7mmol)溶于二氯甲烷(200mL)中，冰浴冷却至0℃，滴加二乙胺基三氟化硫(68.0g,422.09mmol)。加毕，混合物升温至30℃反应40小时，TLC(石油醚/乙酸乙酯＝4/1，磷钼酸显色)显示原料消失。反应液缓慢倒入冷的饱和碳酸钠溶液中碱化至PH＝8-9。分液，有机相用饱和食盐水洗涤，浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝6/1)纯化得到棕色液体标题化合物IN-2b(10.3g,收率45％)。
1H NMR(400MHz,CDCl3)δ3.71(s,3H),3.04-2.96(m,1H),2.44-2.33(m,2H),2.26-2.00(m,4H).
19F NMR(377MHz,CDCl3)δ-90.95,-94.04.
第二步 1-甲基-3,3-二氟环戊烷-1,1-二羧酸苄酯IN-2c
将化合物IN-2b(4.8g,29.2mmol)溶于无水四氢呋喃(500mL)中，氮气保护下冷却至-60℃，加入双三甲基硅基胺基锂(38.0mL,38.0mmol)，滴加完成后反应在-60℃下继续搅拌1小时；将氯甲酸苄酯(6.5g,38.0mmol)缓慢滴加到反应中，保持-60℃搅拌1小时，TLC显示原料反应完全，反应液缓慢升至室温，加饱和氯化铵水溶液(200mL)搅拌10分钟后，乙酸乙酯萃取(100mL x3)，合并有机相，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯＝1/25)纯化得黄色油状液体标题化合物IN-2c(5.9g,收率：68％)。
第三步 3,3-二氟-1-甲氧基羰基环戊烷-1-羧酸IN-2d
将将化合物IN-2c(5.9g,20.0mmol)溶于甲醇(100mL)中，加入钯碳(0.7g,10％),氢气置换3次后在氢气保护下室温搅拌2小时；TLC检测原料反应完全。反应液经硅藻土过滤，滤液浓缩得黄色固体标题化合物IN-2d(4.3g,粗品)，直接用于下一步。
第四步 1-(叔丁氧羰基)氨基)-3,3-二氟环戊烷-1-羧酸甲酯IN-2e
将化合物IN-2d(4.3g,粗品)溶于无水叔丁醇(50mL)中，加入叠氮磷酸二苯酯(8.4g,30.6mmol)和三乙胺(3.1g,30.6mmol)，加毕，反应液升温至90℃继续搅拌12小时，TLC检测原料反应完全。反应液冷却至室温后加水(100mL)淬灭，乙酸乙酯(100mL x2)萃取，合并有机相，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯＝3:1)纯化得白色固体标题化合物IN-2e(2.5g,两步收率45％)。
第五步 1-氨基-3,3-二氟环戊烷-1-羧酸甲酯三氟乙酸盐IN-2f
将化合物IN-2e(2.5g,9.0mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(10mL)，加毕，反应在室温下继续搅拌1小时，TLC检测原料反应完全。反应液减压浓缩得棕色油状液体标题化合物IN-2f(2.3g,粗品)，直接用于下一步。
第六步 2,2-二氟-1-(3-甲氧基-3-氧代丙酰胺基)环戊烷-1-甲酸甲酯IN-2g
将化合物IN-2f(2.3g,粗品)溶于无水二氯甲烷(100mL)中，氮气保护下冷却至0℃，加入三乙胺(4.5g,44.5mmol)，加毕，缓慢滴加丙二酸甲酯酰氯(1.5g,10.7mmol)至反应液中，滴加完成后反应在0℃下继续搅拌3小时；TLC显示原料反应完全，反应液缓慢升至室温，加水(200mL)搅拌10分钟后分液，有机相无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯＝2:1)纯化得黄色油状液体标题化合物IN-2g(1.7g,两步收率:68％)。
第七步 7.7-二氟-1-氮杂螺环[4.4]壬烷-2.4-二酮IN-2h
将化合物IN-2g(1.7g,6.08mmol)溶于无水四氢呋喃(100mL)中，氮气保护下冷却到0℃，分次加入叔丁醇钾(1.0g,8.9mmol)，加料完成后反应液升温至25℃并继续搅拌2小时；TLC检测原料 反应完全。反应液加入稀盐酸(100ml,1N)酸化至pH＝5左右，得到的溶液不处理直接升温至85℃后搅拌回流4小时，TLC检测原料反应完全。反应液冷却至室温，减压浓缩除去大部分四氢呋喃溶液，加入无水硫酸钠配制成的饱和溶液后，乙酸乙酯(200mL x3)萃取，合并有机相，无水硫酸钠干燥，浓缩，粗品用石油醚(100mL)打浆，抽滤，滤饼烘干得黄色固体标题化合物IN-2h(1.3g,粗品)，直接用于下一步。
第八步 3.3.7.7-四氟-1-氮杂螺环[4.4]壬烷-2.4-二酮IN-2i
将化合物IN-2h(1.3g,粗品)溶于乙腈(50mL)中，加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(7.3g,20.7mmol)和水(50mL)，加毕，反应在室温下继续搅拌12小时，TLC检测原料反应完全。反应液减压浓缩除去乙腈，母液用乙酸乙酯(100mL x2)萃取，合并有机相，无水硫酸钠干燥，浓缩得灰色固体标题化合物IN-2i(1.7g,粗品)，直接用于下一步。
第九步 3,3,7,7-四氟-4-羟基-1-氮杂螺[4.4]壬-2-酮IN-2j
将化合物IN-2i(1.7g,粗品)溶于甲醇(100mL)中，冷却至0℃，加入硼氢化钠(0.42g,11.1mmol)，加毕，反应在0℃下继续搅拌1小时，TLC检测原料反应完全。反应液减压浓缩得白色固体标题化合物IN-2j(1.9g,粗品)，直接用于下一步。
第十步 3,3,7,7-四氟-1-氮杂螺[4.4]壬-4-醇IN-2
将化合物IN-2j(1.9g,粗品)溶于无水四氢呋喃(100mL)中，室温下加入四氢铝锂(1.3mg,33.5mmol)，加毕，反应液加热至66℃搅拌2小时，TLC检测原料反应完全。反应液冷却至0℃后依次加水(1.3mL)，氢氧化钠溶液(1.3mL,15％)和水(4.2mL)淬灭，反应在室温下继续搅拌10分钟后抽滤，滤液用无水硫酸钠干燥，浓缩得白色固体标题化合物IN-2(0.6g,三步合并收率31％)。
草酰胺系列化合物(化合物1-29和32-44)通用合成路线：
将酸(1.5eq)溶于无水N,N-二甲基甲酰胺(4V)中，室温下加入中间体胺(1eq)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.5eq)和N,N-二异丙基乙胺(2eq)，加毕，反应液在室温下继续搅拌18小时，TLC检测原料反应完全。反应液中加水(20V)淬灭，乙酸乙酯萃取(10V x3)，合并有机相，饱和食盐水洗(10V)，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯体系或二氯甲烷/甲醇体系)纯化得标题化合物。
合成例3：化合物1合成过程
1-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)丁烷-1,2-二酮1
白色固体,收率88％。
LC-MS:m/z＝262.2[M+H]+.
1H NMR(400MHz,CDCl3)δ4.13-3.96(m,2H),3.88-3.84(m,1H),2.95-2.76(m,2H),2.42-2.32(m,2H),2.24-2.15(m,2H),2.06-1.95(m,2H),1.84-1.73(m,1H),1.64-1.57(m,1H),1.55-1.48(m,1H),1.10(t,J＝7.2Hz,3H).
19F NMR(377MHz,CDCl3)δ-109.23,-120.95.
合成例4：化合物2合成过程
1-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)戊烷-1,2-二酮2
白色固体,收率81％。
LC-MS:m/z＝276.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ6.34(d,J＝6.4Hz,1H),4.02-3.83(m,3H),2.73(t,J＝7.2Hz,2H),2.34-2.06(m,2H),1.96-1.64(m,4H),1.59-1.40(m,4H),0.88(t,J＝7.6Hz,3H).
19F NMR(377MHz,DMSO-d6)δ-111.29,-119.02.
合成例5：化合物3合成过程
1-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-4-甲基戊烷-1,2-二酮3
白色固体,收率77％。
LC-MS:m/z＝290.2[M+H]+.
1H NMR(400MHz,CDCl3)δ4.14-3.91(m,2H),3.86(dd,J＝10.4,6.0Hz,1H),2.77-2.64(m,2H),2.44-2.31(m,2H),2.28-2.10(m,3H),2.09-1.94(m,1H),1.86-1.74(m,2H),1.67-1.61(m,1H),1.59-1.57(m,1H),1.01-0.92(m,6H).
19F NMR(377MHz,CDCl3)δ-109.30,-120.98.
合成例6：化合物4合成过程
1-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-3-(3,3-二氟环丁基)丙烷-1,2-二酮4
第一步 1,4-二乙酰-3-((3,3-二氟环丁基)亚甲基)哌嗪-2,5-二酮4-2
将化合物4-1(500mg,4.16mmol)和1,4-二乙酰基哌嗪-2,5-二酮(825mg,4.16mmol)溶于二氯甲烷(8mL)中,加入1,8-二氮杂二环[5.4.0]十一碳-7-烯(633mg,4.16mmol)，加毕，反应液室温20℃反应3小时。TLC显示原料有少量剩余。反应液用5％柠檬酸溶液(10mL)和饱和食盐水洗涤(10mL x2)，浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化得到白色固体标题化合物4-2(293mg,27％收率)。
LC-MS:m/z＝259.1[M+H]+.
第二步 3-(3,3-二氟环丁基)-2-氧代丙酸4-3
将化合物4-2(293mg,1.13mmol)分散于稀盐酸(4mL,6M)中，悬浊液升温至110℃反应3小时，原料溶解。TLC(石油醚/乙酸乙酯＝2/1)显示原料消失。反应液冷却至室温，加水(10mL)稀释，乙酸乙酯(10mL)萃取。有机相用饱和食盐水(10mL x2)洗涤，无水硫酸钠干燥，浓缩得到棕色羽状标题化合物4-3(168mg,收率83％)。
LC-MS:m/z＝177.1[M-H]-.
第三步 1-(3,3-二氟-4-羟基-1-氮杂螺[4.4]壬-1-基)-3-(3,3-三氟环丁基)丙烷-1,2-二酮4
以化合物4-3(66mg,0.37mmol)和化合物IN-1(66mg,0.37mmol)为原料得到白色固体标题化合物4(72mg,收率58％)。
LC-MS:m/z＝338.2[M+H]+.
1HNMR(400MHz,CDCl3)δ4.11-3.95(m,2H),3.85(t,J＝6.0Hz,1H),3.21-2.99(m,2H),2.85-2.73(m,2H),2.55-2.25(m,1H),2.45-2.33(m,2H),2.28-2.13(m,4H),2.07-1.95(m,2H),1.84-1.78(m,1H),1.63-1.60(m,1H),1.57-1.47(m,1H).
19FNMR(377MHz,CDCl3)δ-83.08,-94.68,-108.91,-120.96.
合成例7：化合物5合成过程
1-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-5,5,5-三氟戊烷-1,2-二酮5
无色油状,收率51％。
LC-MS:m/z＝330.2[M+H]+.
1HNMR(400MHz,CDCl3)δ4.17-3.97(m,2H),3.86(t,J＝6.0Hz,1H),3.26-3.07(m,2H),2.49-2.31(m,4H),2.25-2.20(m,2H),2.06-1.94(m,2H),1.88-1.79(m,1H),1.67-1.61(m,2H).
19FNMR(377MHz,CDCl3)δ-66.54,-108.87,-120.96.
合成例8：化合物6合成过程
4-环丙基-1-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)丁烷-1,2-二酮6
第一步 (E)-4-环丙基-2-氧代丁-3-烯酸乙酯6-2
将化合物6-1(1.0g,14.3mmol)溶于甲苯(10mL)中，加入(三苯基膦)丙酮酸乙酯(2.69g,7.13mmol)，加毕，反应液升温至100℃搅拌16小时。TLC显示反应已完成。反应液减压浓缩除去大部分溶剂，加水(20mL)稀释，乙酸乙酯(30mL)萃取，有机相用饱和食盐水洗涤(10mL x2)，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化得到黄色液体标题化合物6-2(610mg,收率25％)。
1H NMR(400MHz,CDCl3)δ6.84-6.73(m,1H),6.71-6.60(m,1H),4.39-4.25(m,2H),1.77-1.65(m,1H),1.41-1.30(m,3H),1.51-1.04(m,2H),0.84-0.75(m,2H).
第二步 4-环丙基-2-氧代丁酸乙酯6-3
将化合物6-2(100mg,0.59mmol)溶于乙腈(5mL)中，加入2,6-二甲基-1,4-二氢吡啶-3,5-二羧酸二乙酯(150mg,0.59mmol)，加毕，氮气置换3次，加入高氯酸镁(133mg,0.59mmol)的乙腈溶液(2mL)，加毕，反应液室温搅拌5小时。TLC显示原料消失。反应液加水(10mL)淬灭，乙酸乙酯(15mL)萃取，饱和食盐水洗涤(10mL x2)，无水硫酸钠干燥，浓缩得到黄色液体标题化合物6-3(65mg,粗品)，直接用于下一步。
第三步 4-环丙基-2-氧代丁酸6-4
将化合物6-3(65mg,0.38mmol)溶于四氢呋喃(4mL)和水(2mL)的混合溶液中，加入氢氧化钠(30mg,0.75mmol)，加毕，反应液室温搅拌16小时。反应液加水淬灭，柠檬酸酸化至pH＝4，加水(10mL)和乙酸乙酯(15mL)萃取，有机相用饱和食盐水洗涤(10mL x2)，无水硫酸钠干燥，浓缩得到黄色液体标题化合物6-4(46mg,粗品)，直接用于下一步。
第四步 4-环丙基-1-(3,3-二氟-4-羟基-1-氮杂螺[4.4]壬烷-1-基)丁烷-1,2-二酮6
将化合物6-4(46mg,0.32mmol)，化合物IN-1(57mg,0.32mmol)溶于N,N-二甲基甲酰胺(4mL) 中，依次加入N,N-二异丙基乙胺(83mg,0.64mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(146mg,0.38mmol)。加毕，反应液室温反应16小时，TLC(石油醚/乙酸乙酯＝5/1)显示原料消失。反应液加水(10mL)淬灭，乙酸乙酯(15mL)萃取。饱和食盐水(10mL x3)洗涤，有机相浓缩。粗品经Prep-TLC(石油醚/乙酸乙酯＝10/1)纯化得到淡黄色油状标题化合物6(12mg,三步收率7％)。
LC-MS:m/z＝302.2[M+H]+.
1H NMR(400MHz,CDCl3)δ4.13-3.95(m,2H),3.90-3.83(m,1H),3.00-2.86(m,2H),2.43-2.33(m,1H),2.31-2.14(m,3H),2.08-1.95(m,2H),1.85-1.76(m,1H),1.67-1.57(m,2H),1.54-1.47(m,2H),0.74-0.64(m,1H),0.47-041(m,2H),0.08-0.02(m,2H).
19F NMR(377MHz,CDCl3)δ-109.26,-120.97.
合成例9：化合物7合成过程
1-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷)-2-(4.4-二氟环己基)乙二醛7
参考合成例6的合成方法，以4,4-二氟环己烷-1-酮为起始物料，合成得到白色固体标题化合物7，总收率为9％。
LC-MS:m/z＝352.2[M+H]+.
1H NMR(400MHz,CDCl3)δ4.09-3.84(m,3H),3.32-3.21(m,1H),2.42-2.31(m,2H),2.26-2.10(m,4H),2.09-1.93(m,4H),1.91-1.60(m,6H),1.57-1.48(m,1H).
19F NMR(377MHz,CDCl3)δ-92.90,-101.51,-109.23,-120.10.
合成例10：化合物8合成过程
1-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)己烷-1,2-二酮8
白色固体,收率74％。
LC-MS:m/z＝290.2[M+H]+.
1H NMR(400MHz,CDCl3)δ4.13-3.91(m,2H),3.86(dd,J＝10.8,6.0Hz,1H),2.90-2.73(m,2H),2.43-2.33(m,2H),2.27-2.14(m,2H),2.09-1.95(m,2H),1.86-1.76(m,1H),1.67-1.59(m,2H),1.58-1.56(m,2H),1.41-1.29(m,2H),0.92(t,J＝7.2Hz,3H).
19F NMR(377MHz,CDCl3)δ-109.27,-120.95.
合成例11：化合物9合成过程
1-(3-氯-5-氟苯基)-2-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷)乙二醛9
白色固体,收率64％。
LC-MS:m/z＝362.1[M+H]+.
1H NMR(400MHz,CDCl3)δ7.78-7.71(m,1H),7.61-7.52(m,1H),7.40-7.36(m,1H),4.00-3.88(m,2H),3.85-3.74(m,1H),2.55-2.42(m,2H),2.42-2.24(m,2H),2.13-2.00(m,2H),1.97-1.88(m,1H),1.75-1.63(m,1H),1.57-1.50(m,1H).
19F NMR(377MHz,CDCl3)δ-108.21,-109.00,-120.81.
合成例12：化合物10合成过程
1-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-3-(2,2-二氟环丙基)丙烷-1,2-二酮10
第一步 2,2-二氟-N-甲氧基-N-甲基环丙烷-1-甲酰胺10-2
将化合物10-1(2.0g,16.4mmol)溶于二氯甲烷(50mL)中，依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(4.7g,24.6mmol),N,O-二甲基羟胺盐酸盐(1.9g,19.7mmol)和N,N-二异丙基乙胺(6.4g,49.1mmol)。加毕，混合物室温15℃反应3小时，TLC显示原料消失。反应液加入1M稀盐酸(50mL)淬灭，搅拌2分钟后分液。有机相用饱和食盐水洗涤(30mL x2)，无水硫酸钠干燥，浓缩得到淡黄色固体标题化合物10-2(1.58g,58％收率)。
1H NMR(400MHz,CDCl3)δ3.76(s,3H),3.25(s,3H),2.98-2.90(m,1H),2.20-2.11(m,1H),1.73-1.64(m,1H).
第二步 2,2-二氟环丙烷-1-甲醛10-3
将化合物10-2(600mg,3.69mmol)溶于无水四氢呋喃(6mL)中，氮气置换3次，干冰浴冷却至-65℃，滴加二异丁基氢化铝(4.4mL,1M)，控温-65～-60℃。滴完，体系在干冰浴条件下反应3小时。反应液升至室温，加入无水硫酸钠和十水硫酸钠(3.0g,9.31mmol)，搅拌20分钟后混合液垫硅藻土抽滤，滤液(化合物10-3的四氢呋喃溶液)直接投下一步。
第三步 (Z)-2-乙酰氧基-3-(2,2-二氟环丙基)丙烯酸乙酯10-4
将化合物10-3(1.3g,5.45mmol)溶于四氢呋喃(10mL)中，氮气置换3次，加入氯化锂(231mg,5.45mmol)，加毕，混合物冰浴冷却至0℃，加入四甲基胍(628mg,5.45mmol)，加毕，冰浴下继续反应0.5小时，加入混合物3755-2的四氢呋喃溶液(上一步粗品)，加毕，反应液升至室温15度反应1小时。反应液加饱和氯化铵溶液(14mL)淬灭，乙酸乙酯(20mL)萃取。有机相用饱和食盐水(20mL x2)洗涤，浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化得到淡黄色液体标题化合物10-4(205mg,收率24％)。
1H NMR(400MHz,CDCl3)δ5.60(td,J＝6.4Hz,2.4Hz,1H),4.27(q,J＝6.4Hz,2H),3.48-3.38(m,1H),2.20(s,3H),1.90-1.83(m,1H),1.30(t,J＝6.4Hz,3H).
19F NMR(377MHz,CDCl3)δ-128.05,-139.40.
第四步 3-(2,2-二氟环丙基)-2-氧代丙酸10-5
将化合物10-4(100mg,0.43mmol)溶于6M盐酸(6mL)中，升温至80℃反应2小时，TLC显示原料消失。反应液冷却至室温，加水(20mL)稀释，乙酸乙酯(20mL)萃取。有机相用饱和食盐水(10mL x2)洗涤，无水硫酸钠干燥，浓缩得到棕色液体标题化合物10-5(45mg,收率64％)。
LC-MS:m/z＝163.1[M-H]-.
第五步 1-(3,3-二氟-4-羟基-1-氮杂螺[4.4]壬-1-基)-3-(2,2-二氟环丙基)丙烷-1,2-二酮10
将化合物10-5(45mg,0.27mmol)和化合物IN-1(48mg,0.27mmol)溶于N,N-二甲基甲酰胺(3mL)中，依次加入N,N-二异丙基乙胺(70mg,0.54mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(123mg,0.32mmol)。加毕，反应液室温15℃反应3小时，TLC显示原料消失。反应液加水(10mL)淬灭，乙酸乙酯(10mL)萃取。饱和食盐水(10mL x2)洗涤，有机相浓缩。粗品经PreP-TLC(石油醚/乙酸乙酯＝3/1)纯化得到白色固体标题化合物10(45mg,收率51％)。
LC-MS:m/z＝324.2[M+H]+.
1H NMR(400MHz,CDCl3)δ4.19-3.96(m,2H),3.96-3.83(m,1H),3.19-3.04(m,1H),3.00-2.87(m,1H),2.39-2.30(m,2H),2.26-2.16(m,2H),2.07-1.95(m,2H),1.88-1.77(m,2H),1.66-1.57(m,2H),1.55-1.49(m,1H),1.07-0.99(m,1H).
19F NMR(377MHz,CDCl3)δ-108.98,-120.94,-129.98,-142.85.
合成例13：化合物11合成过程
1-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷)-2-(3,3-二氟环丁基)乙二醛11
第一步 2-(3,3-二氟环丁基)-2-((三甲基甲硅烷基)氧基)乙腈11-1
将化合物4-1(300mg,2.50mmol)和碘化锌(79mg,0.25mmol)分散于二氯甲烷(10mL)中，加入三甲基氰硅烷(347mg,3.50mmol)，加毕，反应液在20℃下搅拌2小时，TLC监测原料反应完全；反应液加水(10mL)淬灭，二氯甲烷(20mL)萃取，无水硫酸钠干燥，过滤，滤液浓缩得到粗品，粗品经硅胶柱层析(石油醚/乙酸乙酯＝30/1)纯化得到无色油状物标题化合物11-1(232mg,收率42.2％)。
第二步 2-(3,3-二氟环丁基)-2-羟基乙酸11-2
将化合物11-1(120mg,0.55mmol)溶于稀盐酸(2mL,6N)中，反应液在80℃下反应4小时，TLC监测原料反应完全；反应液浓缩除去溶剂，剩余物乙酸乙酯(10mL)溶解，过滤，滤液再浓缩得到粗品，粗品经二氯甲烷/石油醚(3mL,1/1)打浆得到白色固体标题化合物11-2(52mg,收率57.1％)。
LC-MS:m/z＝165.1[M-H]-.
第三步 2-(3,3-二氟环丁基)-2-氧代乙酸11-3
将化合物11-2(170mg,1.02mmol)和2-碘酰基苯甲酸(285mg,1.02mmol)溶于二甲基亚砜(3mL)中，反应液在50℃下搅拌3小时，TLC监测原料反应完全；反应液降至室温，加水(10mL)析出固体，过滤，滤液用乙酸乙酯(20mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩得到无色油状标题化合物11-3(120mg,粗品)，直接用于下一步。
LC-MS:m/z＝163.1[M-H]-.
第四步 1-(3,3-二氟-4-羟基-1-氮杂螺[4.4]壬-1-基)-2-(3,3-三氟环丁基)乙烷-1,2-二酮11
将化合物11-3(120mg,粗品)，化合物IN-1(129mg,0.73mmol)和N,N-二异丙基乙胺(141mg,1.09mmol)溶于N,N-二甲基甲酰胺(2mL)中，氮气保护下，反应液冷却至0℃，加入苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(332mg,0.87mmol)，加毕，反应液升至26℃继续搅拌16小时，TLC监测原料反应完全；反应液加水(10mL)淬灭，乙酸乙酯(20mL)萃取，无水硫酸钠干燥，过滤，滤液浓缩，粗品经Prep-TLC(石油醚/乙酸乙酯＝4/1)纯化得白色固体标题化合物11(87mg,两步收率26.4％)。
LC-MS:m/z＝324.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ6.36(d,J＝6.0Hz,1H),4.14-3.92(m,3H),3.69-3.57(m,1H),2.84-2.66(m,4H),2.30-2.20(m,1H),2.18-2.07(m,1H),1.94-1.76(m,3H),1.76-1.66(m,1H),1.55-1.42(m,2H).
19F NMR(377MHz,DMSO-d6)δ-82.23,-93.65,-111.22,-118.99.
合成例14：化合物12和13合成过程
(S)-1-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-3-(3-氟双环[1.1.1]戊烷-1-基)丙烷-1,2-二酮(12)；
(R)-1-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-3-(3-氟双环[1.1.1]戊烷-1-基)丙烷-1,2-二酮(13)
参考合成例12的合成方法，以3-氟双环[1.1.1]戊烷-1-羧酸为起始物料，合成得到标题混合化合物。混合物通过手性拆分得到标题化合物12和13。
手性HPLC分析方法：纳微AD-5H，填料粒径(5μm)，内径(4.6mm)，长度(250mm)，流速：1.0mL/min，乙醇:正己烷＝40:60，波长：220/254nm。
化合物12：白色固体,收率18％；保留时间6.527分钟。
LC-MS:m/z＝332.2[M+H]+.
1H NMR(400MHz,CDCl3)δ4.13-3.96(m,2H),3.87-3.83(m,1H),3.20(s,2H),2.38-2.31(m,2H),2.25-2.15(m,2H),2.07(d,J＝2.4Hz,6H),2.02-1.94(m,2H),1.85-1.77(m,1H),1.66-1.59(m,1H),1.53-1.49(m,1H).
19F NMR(377MHz,CDCl3)δ-108.69,-109.33,-120.84,-121.48,-144.84.
化合物13：白色固体,收率15％；保留时间10.890分钟。
LC-MS:m/z＝332.2[M+H]+.
1H NMR(400MHz,CDCl3)δ4.14-3.96(m,2H),3.89-3.81(m,1H),3.22(s,2H),2.38-2.31(m,2H),2.25-2.15(m,2H),2.07(d,J＝2.4Hz,6H),2.02-1.94(m,2H),1.85-1.77(m,1H),1.66-1.59(m,1H),1.53-1.49(m,1H).
19F NMR(377MHz,CDCl3)δ-108.69,-109.33,-120.84,-121.48,-144.84.
合成例15：化合物14和15合成过程
1-((S)-3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-2-((S)-3,3-二氟环戊基)乙二醛&1-((R)-3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-2-((R)-3,3-二氟环戊基)乙二醛(14-P1和14-P2)；
1-((S)-3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-2-((R)-3,3-二氟环戊基)乙二醛&1-((R)-3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-2-((S)-3,3-二氟环戊基)乙二醛(15-P1和15-P2)
参考合成例13的合成方法，以3,3-二氟环戊烷-1-甲醛为起始物料，合成得到无色油状标题混合物。混合物通过手性拆分得到标题化合物14-P1和14-P2的混合物以及15-P1和15-P2的混合物。
手性HPLC分析方法：纳微AD-5H，填料粒径(5μm)，内径(4.6mm)，长度(250mm)，流速：1.0mL/min，异丙醇:正己烷＝10:90，波长：220/254nm。
14-P1和14-P2的混合物：无色油状,收率1.5％，保留时间9.803分钟。
LC-MS:m/z＝338.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ6.36(d,J＝6.4Hz,1H),4.10-3.84(m,3H),3.76-3.65(m,1H),2.38-2.22(m,3H),2.18-2.00(m,4H),1.95-1.78(m,4H),1.79-1.67(m,1H),1.59-1.42(m,2H).
15-P1和15-P2的混合物：无色油状,收率1.5％，保留时间12.027分钟。
LC-MS:m/z＝338.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ6.36(d,J＝6.4Hz,1H),4.10-3.84(m,3H),3.76-3.65(m,1H),2.38-2.22(m,3H),2.18-2.00(m,4H),1.95-1.78(m,4H),1.79-1.67(m,1H),1.59-1.42(m,2H).
合成例16：化合物16合成过程
1-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-3-(3-氟环丁基)丙烷-1,2-二酮(16)
第一步 苄基-3-氧环丁烷-1-羧酸酯16-2
将化合物16-1(10.0g,87.6mmol)，碳酸钾(24.2g,175.3mmol)和溴化苄(22.5g,131.5mmol)分散在乙腈(100mL)中，在50℃下反应4小时；TLC监测原料反应完全。反应液冷却至室温，过滤，浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得到无色油状物标题化合物16-2(17.0g,收率:94.98％)。
LC-MS:m/z＝222.2[M+18].
第二步 苄基-3-羟基环丁烷-1-羧酸酯16-3
将化合物16-2(4.0g,19.6mmol)溶解于甲醇(10mL)中，在氮气保护和0℃下，分批加入硼氢化钠(1.11g,29.4mmol)，加毕，反应液升温至室温反应1小时；TLC监测原料反应完全。反应液加入稀盐酸(2.0mL,2M)淬灭，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得到无色油状物标题化合物16-3(700mg,收率:17.33％)。
第三步 苄基3-氟环丁烷-1-羧酸酯16-4
将化合物16-3(651mg,3.16mmol)溶解在四氢呋喃(10mL)中，在氮气保护和-60℃下，滴加双(2-甲氧基乙基)氨基三氟化硫(1.0g,4.74mmol)，滴毕，反应液升温至室温反应16小时；TLC监测原料反应完全。反应液冷却至0℃，加入氢氧化钠溶液(2.0mL,2M)淬灭，乙酸乙酯萃取(50mL x 2)，合并有机相，饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化得到无色油状物标题化合物16-4(222mg,收率:33.74％)。
1H NMR(400MHz,CDCl3)δ7.39-7.31(m,5H),5.33-5.14(m,1H),5.13(s,2H),3.19-3.12(m,1H),2.67-2.43(m,4H).
第四步 3-氟环丁烷-1-甲醛16-5
将化合物16-4(920mg,4.42mmol)溶解在二氯甲烷(10mL)中，在氮气保护和-65℃下滴加二异丁基氢化铝(940mg,6.63mmol,1M)，滴毕，保温反应3h；TLC(石油醚/乙酸乙酯＝20/1)监测原料反应完全。反应液加入稀盐酸(5mL,2M)淬灭，加入半饱和酒石酸钾钠溶液(30mL)稀释，悬浊液经硅藻土过滤，滤液分液，有机相经无水硫酸钠干燥，过滤直接进行下一步反应16-5(粗品)。
第五步 (Z)-1-乙酰基-3-[(3-氟环丁基)亚甲基]哌嗪-2,5-二酮16-6
将1,4-二乙酰哌嗪-2,5-二酮(870mg,4.42mmol)和化合物16-5(670mg,4.42mmol)加到上一步得到的二氯甲烷混合溶液，在室温下反应16小时；TLC监测原料反应完全。反应液加入稀盐酸(20mL,2M)稀释，加入二氯甲烷(20mL x 4)萃取，有机相用无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化得到白色固体标题化合物16-6(120mg,收率:11.35％)。
1H NMR(400MHz,CDCl3)δ7.93(s,1H),6.39(d,J＝9.6Hz,1H),5.32-5.12(m,1H),4.44(s,2H),3.27-3.18(m,1H),2.74-2.63(m,2H),2.61(s,3H),2.41-2.31(m,2H).
第六步 3-(3-氟环丁基)-2-氧丙烷酸16-7
将化合物16-6(120mg,0.50mmol)分散在稀盐酸(6mL,6M)中，反应液加热至100℃反应3小时；TLC监测原料反应完全。反应液冷却至室温，乙酸乙酯(20mL x 3)萃取，合并有机相，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到淡黄色油状物标题化合物16-7(51mg,收率:63.69％)。
LC-MS:m/z＝159.0[M-1]-.
第六步 1-(3,3-二氟-4-羟基-1-氮杂螺[4.4]壬-1-基)-3-(3-氟环丁基)丙烷-1,2-二酮16
将化合物16-7(51mg,0.32mmol)和N,N-二异丙基乙胺(120mg,0.97mmol)溶于N,N-二甲基甲酰胺(3mL)中，氮气保护下，降温至0℃，分批加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(390mg,0.39mmol)，反应液保温反应0.5小时，加入IN-1(57mg,0.32mmol)，反应液升温至室温反应2小时；TLC监测原料反应完全。反应液加水(10mL)淬灭，乙酸乙酯萃取(20mL)，合并有机相，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩后经硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化得到淡黄色固体标题化合物16(10mg,收率:9.79％)。
LC-MS:m/z＝320.2[M+1]+.
1H NMR(400MHz,CDCl3)δ4.99-4.78(m,1H),4.11-3.92(m,2H),3.87-3.83(m,1H),3.09-2.95(m,2H),2.63-2.55(m,2H),2.39-2.29(m,2H),2.24-1.77(m,8H),1.65-1.56(m,2H).
19F NMR(377MHz,CDCl3)δ-109.05,-121.00,-162.67.
合成例17：化合物17-20合成过程
3-(3,3-二氟环丁基)-1-((4S,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)丙烷-1,2-二酮(17)；
3-(3,3-二氟环丁基)-1-((4R,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)丙烷-1,2-二酮(18)；
3-(3,3-二氟环丁基)-1-((4S,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)丙烷-1,2-二酮(19)；
3-(3,3-二氟环丁基)-1-((4R,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)丙烷-1,2-二酮(20)
以化合物4-3和化合物IN-2为物料，合成得到标题混合物。混合物通过手性拆分得到标题化 合物17-20。
手性HPLC分析方法：纳微AD-5H，填料粒径(5μm)，内径(4.6mm)，长度(250mm)，流速：1.0mL/min，异丙醇:正己烷＝20:80，波长：220/254nm。
化合物17：白色固体,收率6.7％，保留时间5.823分钟。
LC-MS:m/z＝372.1[M-H]-.
1H NMR(400MHz,DMSO-d6)δ6.73(d,J＝6.0Hz,1H),4.13-3.90(m,3H),3.19-3.02(m,2H),3.02-2.85(m,1H),2.78-2.63(m,2H),2.62-5.52(m,1H),2.45-2.20(m,5H),2.20-2.00(m,2H).
19F NMR(377MHz,DMSO-d6)δ-81.10,-88.61,-93.02,-94.12,-110.04,-119.86.
化合物18：白色固体,收率3.2％，保留时间6.127分钟。
LC-MS:m/z＝372.1[M-H]-.
1H NMR(400MHz,DMSO-d6)δ6.68(d,J＝6.0Hz,1H),4.18-4.08(m,1H),4.08-3.91(m,2H),3.17-3.03(m,2H),2.80-2.53(m,5H),2.49-2.23(m,4H),2.20-2.06(m,1H),2.06-1.95(m,1H).
19F NMR(377MHz,DMSO-d6)δ-81.09,-88.47,-91.52,-93.06,-112.98,-120.14.
化合物19：白色固体,收率6.4％，保留时间7.216分钟。
LC-MS:m/z＝372.1[M-H]-.
1H NMR(400MHz,DMSO-d6)δ6.73(d,J＝6.0Hz,1H),4.13-3.90(m,3H),3.19-3.02(m,2H),3.01-2.85(m,1H),2.77-2.63(m,2H),2.62-2.52(m,1H),2.45-2.20(m,5H),2.20-2.00(m,2H).
19F NMR(377MHz,DMSO-d6)δ-81.11,-88.61,-93.03,-94.12,-110.04,-119.86.
化合物20：白色固体,收率4.1％，保留时间9.730分钟。
LC-MS:m/z＝372.1[M-H]-.
1H NMR(400MHz,DMSO-d6)δ6.67(d,J＝6.0Hz,1H),4.19-4.08(m,1H),4.08-3.89(m,2H),3.16-3.02(m,2H),2.79-2.52(m,5H),2.48-2.23(m,4H),2.19-2.05(m,1H),2.05-1.94(m,1H).
19F NMR(377MHz,DMSO-d6)δ-81.09,-88.47,-91.51,-93.06,-112.98,-120.14.
合成例18：化合物21-24合成过程
3-(3-氟双环[1.1.1]戊烷-1-基)-1-((4S，5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)丙烷-1,2-二酮(21)；
3-(3-氟双环[1.1.1]戊烷-1-基)-1-((4R，5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)丙烷-1,2-二酮(22)；
3-(3-氟双环[1.1.1]戊烷-1-基)-1-((4S，5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)丙烷-1,2-二酮(23)；
3-(3-氟双环[1.1.1]戊烷-1-基)-1-((4R，5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)丙烷-1,2-二酮(24)
以3-(3-氟双环[1.1.1]戊烷-1-基)-2-氧代丙酸和化合物IN-2为物料，合成得到标题混合物。混合物通过手性拆分得到标题化合物21-24。
手性HPLC分析方法：纳微AD-5H，填料粒径(5μm)，内径(4.6mm)，长度(250mm)，流速：1.0mL/min，乙醇:正己烷＝20:80，波长：220/254nm。
化合物21：白色固体,收率7.5％，保留时间9.353分钟。
LC-MS:m/z＝366.1[M-H]-.
1HNMR(400MHz,CDCl3)δ4.17-3.98(m,3H),3.28-3.17(m,2H),2.96-2.85(m,1H),2.63-2.42(m,3H),2.36-2.24(m,2H),2.16-2.10(m,1H),2.08(s,3H),2.07(s,3H).
19FNMR(377MHz,CDCl3)δ-92.09,-98,50,-108.37,-122.54,-144.91.
化合物22：白色固体,收率7.3％，保留时间11.320分钟。
LC-MS:m/z＝366.1[M-H]-.
1HNMR(400MHz,CDCl3)δ4.17-3.98(m,3H),3.28-3.17(m,2H),2.96-2.85(m,1H),2.63-2.42(m,3H),2.36-2.24(m,2H),2.16-2.10(m,1H),2.08(s,3H),2.07(s,3H).
19FNMR(377MHz,CDCl3)δ-92.09,-98,50,-108.37,-122.54,-144.91.
化合物23：白色固体,收率3.2％，保留时间8.353分钟。
LC-MS:m/z＝366.1[M-H]-.
1HNMR(400MHz,CDCl3)δ4.26-3.97(m,3H),3.22(br,2H),3.14-2.99(m,1H),2.83-2.76(m,1H),2.72-2.49(m,3H),2.18-1.95(m,8H).
19FNMR(377MHz,CDCl3)δ-90.17,-96.94,-109.88,-122.70,-144.87.
化合物24：白色固体,收率3.0％，保留时间25.797分钟。
LC-MS:m/z＝366.1[M-H]-.
1HNMR(400MHz,CDCl3)δ4.26-3.97(m,3H),3.22(br,2H),3.14-2.99(m,1H),2.83-2.76(m,1H),2.72-2.49(m,3H),2.18-1.95(m,8H).
19FNMR(377MHz,CDCl3)δ-90.17,-96.94,-109.88,-122.70,-144.87.
合成例19：化合物25合成过程
3-(3,3-二氟环丁基)-1-(3,3,6,6-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)丙烷-1,2-二酮(25)
第一步 2,2-二氟-1-(3-甲氧基-3-氧代丙酰胺基)环戊烷-1-甲酸乙酯25-2
将化合物25-1(3.2g,16.6mmol)溶于无水二氯甲烷(300mL)中，氮气保护下冷却至0℃，加入三乙胺(5.0g,49.8mmol)，加毕，缓慢滴加丙二酸甲酯酰氯(4.4g,32.4mmol)，滴加完成后反应在0℃下继续搅拌3小时；TLC显示原料反应完全，反应液缓慢升至室温，加水(200mL)搅拌10分钟后分液，有机相无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(EA:PE＝1:2)纯化得黄色油状液体标题化合物25-2(2.9g,收率：60％)。
第二步 6.6-二氟-1-氮杂螺环[4.4]壬烷-2.4-二酮25-3
将化合物25-2(2.9g,9.9mmol)溶于无水四氢呋喃(50mL)中，氮气保护下冷却到0℃，分次加入叔丁醇钾(1.7g,14.5mmol)，加料完成后反应液升温至25℃并继续搅拌2小时；TLC检测原料反应完全。反应液加入稀盐酸(20ml,1N)酸化至pH＝5左右，得到的溶液不处理直接升温至85℃后搅拌回流4小时，TLC检测原料反应完全。反应液冷却至室温，减压浓缩除去大部分四氢呋喃溶液，加入无水硫酸钠配制成饱和溶液后，乙酸乙酯(200mL x3)萃取，合并有机相，无水硫酸钠干燥，浓缩，粗品用石油醚(100mL)打浆，抽滤，滤饼烘干得黄色固体标题化合物25-3(1.6g,收率97％)。
第三步 3.3.6.6-四氟-1-氮杂螺环[4.4]壬烷-2.4-二酮25-4
将化合物25-3(2.1g,27.0mmol)溶于乙腈(100mL)中，加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(24.0g,67.5mmol)和水(100mL)，加毕，反应在室温下继续搅拌12小时，TLC检测原料反应完全。反应液减压浓缩除去乙腈，母液用乙酸乙酯(200mL x2)萃取，合并有机相，无水硫酸钠干燥，浓缩得灰色固体标题化合物25-4(5.8g,粗品)，直接用于下一步。
第四步 3,3,6,6-四氟-4-羟基-1-氮杂螺环[4.4]壬-2-酮25-5
将化合物25-4(5.8g,粗品)溶于甲醇(100mL)中，冷却至0℃，加入硼氢化钠(1.5g,38.8mmol)，加毕，反应在0℃下继续搅拌1小时，TLC检测原料反应完全。反应液加入饱和氯化铵水溶液(100mL)淬灭，反应在室温下搅拌10分钟后，减压浓缩除去大部分甲醇，剩余物加乙酸乙酯萃取(100mL x4)，合并有机相，无水硫酸钠干燥，浓缩得白色固体标题化合物25-5(5.1g,两步合并收率83％)。
第五步 3,3,6,6-四氟-1-氮杂螺[4.4]壬-4-醇25-6
将化合物25-5(4.3g,18.9mmol)溶于无水四氢呋喃(150mL)中，室温下加入硼烷二甲硫醚溶液(47.3mL,94.5mmol)，加毕，反应液加热至60℃搅拌2小时，TLC检测原料反应完全。反应液冷 却至0℃后缓慢滴加甲醇(50mL)，滴加完成后反应在60℃下继续搅拌60分钟，反应完成后，冷却至室温，浓缩，粗品经硅胶柱层析(EA/PE＝30％)纯化得白色固体标题化合物25-6(2.9g,收率72％)。
第六步 3-(3,3-二氟环丁基)-1-(3,3,6,6-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)丙烷-1,2-二酮25
将化合物4-3(170mg,0.95mmol)，化合物25-6(185mg,0.87mmol)和N,N-二异丙基乙胺(168mg,1.30mmol)溶于N,N-二甲基甲酰胺(3mL)中，氮气保护下，反应液冷却至0℃加入苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(397mg,1.04mmol)，加毕，反应液升至26℃继续搅拌16小时，TLC监测原料反应完全；反应液加水(10mL)淬灭，乙酸乙酯(20mL)萃取，无水硫酸钠干燥，过滤，滤液浓缩，粗品经Prep-TLC(石油醚/乙酸乙酯＝3/1)纯化得白色固体标题化合物25(20mg,收率6.1％)。
LC-MS:m/z＝372.1[M-H]-.
1H NMR(400MHz,DMSO-d6)δ6.62(d,J＝6.8Hz,1H),4.31-4.19(m,1H),4.17-3.95(m,2H),3.20-3.09(m,1H),3.07-2.95(m,1H),2.76-2.58(m,3H),2.49-2.21(m,4H),2.13-1.87(m,3H),1.76-1.64(m,1H).
19F NMR(377MHz,DMSO-d6)δ-81.00,-93.36,-97.00,-100.96,-107.45,-116.64.
合成例20：化合物26合成过程
1-(3,3,8,8-四氟-4-羟基-1-氮杂螺环[4.5]癸烷-1-基)丁烷-1,2-二酮(26)
第一步 8,8-二氟-1,3-二氮杂螺环[4.5]癸烷-2,4-二酮26-2
将4,4-二氟环己酮26-1(5.0g,37.28mmol)溶于乙醇(80mL)和水(60mL)的混合溶液中，依次加入碳酸铵(14.3g,149.11mmol)和三甲基氰硅烷(7.4g,74.56mmol)，加毕，反应液升温至70℃反应18小时，TLC(石油醚/乙酸乙酯＝10/1,磷钼酸显色)显示原料消失。反应液冷却至室温，浓缩除掉乙醇，加入冰水(50mL)并在冰浴下搅拌30分钟。反应液抽滤，滤饼干燥得到银白色片状固体标题化合物26-2(7.2g,收率95％)。
1HNMR(400MHz,DMSO-d6)δ10.73(s,1H),8.49(s,1H),2.12-1.96(m,4H),1.90-1.82(m,2H),1.75-1.71(m,2H).
第二步 1-氨基-4,4-二氟环己烷-1-羧酸26-3
将化合物26-2(7.1g,34.8mmol)溶于氢氧化钾水溶液(150mL,30％)中，反应液升温至110℃下搅拌16小时，降温至65℃下浓缩除去大约75％的水，再次冷却到0℃后缓慢滴加浓盐酸(80mL)直至PH＝2，0℃下继续搅拌30分钟，冷过滤，滤饼用甲醇(100mL x2)淋洗，合并母液，浓缩得白色固体标题化合物26-3(粗品)，直接用于下一步。
第三步 1-氨基-4,4-二氟环己烷-1-羧酸甲酯盐酸盐26-4
将混合物26-3(粗品)溶于甲醇(150mL)中，0℃下缓慢滴加氯化亚砜(8.3g,69.6mmol)，加毕，氮气保护下，反应液缓慢升温至70℃搅拌16小时，反应液减压浓缩得白色固体标题化合物26-4(粗品)，直接用于下一步。
LC-MS:m/z＝194.1[M+H]+.
第四步 4,4-二氟-1-(3-甲氧基-3-氧代丙酰胺基)环己烷-1-羧酸甲酯26-5
将化合物26-4(粗品)溶于无水二氯甲烷(300mL)中，氮气保护下冷却至0℃，加入三乙胺(14.0g,369.2mmol)，加毕，缓慢滴加丙二酸甲酯酰氯(7.1g,52.2mmol)，滴毕，反应液在0℃下继续搅拌3小时；TLC检测原料反应完全，反应液缓慢升至室温，加水(200mL)搅拌10分钟后分液，有机 相无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(乙酸乙酯:石油醚＝1:2)纯化得无色油状液体标题化合物26-5(3.8g,四步收率：37％)。
LC-MS:m/z＝294.2[M+H]+.
第五步 8,8-二氟-1-氮杂螺环[4.5]癸烷-2,4-二酮26-6
将化合物26-5(3.8g,13.0mmol)溶于无水四氢呋喃(300mL)中，氮气保护下冷却到0℃，分次加入叔丁醇钾(2.2g,19.5mmol)，加毕，反应液升温至25℃并继续搅拌2小时；TLC检测原料反应完全。反应液加入稀盐酸(25mL,1N)调节PH＝5，继续升温至80℃后搅拌回流4小时，TLC检测原料反应完全。反应液冷却至室温，减压浓缩除去大部分四氢呋喃溶液，加入无水硫酸钠配制成的饱和溶液(100mL)，乙酸乙酯(200mL x3)萃取，合并有机相，无水硫酸钠干燥，浓缩，粗品用石油醚(100mL)打浆，抽滤，滤饼烘干得黄色固体标题化合物26-6(2.0g,收率76％)。
第六步 3,3,8,8-四氟-1-氮杂螺环[4.5]癸烷-2,4-二酮26-7
将化合物26-6(2.0g,9.8mmol)溶于乙腈(50mL)中，室温下加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(10.4g,29.4mmol和水(50mL)，加毕，反应在室温下继续搅拌12小时，TLC检测原料反应完全。反应液减压浓缩除去乙腈，母液用乙酸乙酯(200mL x2)萃取，合并有机相，无水硫酸钠干燥，浓缩得灰色固体标题化合物26-7(3.4g,粗品)，直接用于下一步。
LC-MS:m/z＝238.0[M-H]-.
第七步 3,3,8,8-四氟-4-羟基-1-氮杂螺环[4.5]癸烷-2-酮26-8
将化合物26-7(3.4g,14.2mmol)溶于甲醇(100mL)中，冷却至0℃，加入硼氢化钠(806m g,21.3mmol)，加毕，反应在0℃下继续搅拌1小时，TLC检测原料反应完全。反应液减压浓缩得白色固体标题化合物26-8(4.2g,粗品)，直接用于下一步。
第八步 3,3,8,8-四氟-1-氮杂螺环[4.5]癸烷-4-醇26-9
将化合物26-8(4.2g,粗品)溶于无水四氢呋喃(150mL)中，0℃分次加入四氢铝锂(2.1g,56.8mmol)，加毕，反应液加热至66℃搅拌2小时，TLC检测原料反应完全。反应液冷却至0℃后依次加水(2.1mL)，氢氧化钠溶液(2.1mL,15％)和水(6.3mL)淬灭，反应在室温下继续搅拌10分钟，抽滤，滤液用无水硫酸钠干燥，浓缩得白色固体标题化合物26-9(2.0g,三步合并收率90％)。
LC-MS:m/z＝228.2[M+H]+.
第九步 1-(3,3,8,8-四氟-4-羟基-1-氮杂螺环[4.5]癸烷-1-基)丁烷-1,2-二酮26
将2-氧代丁酸(50mg,0.49mmol)，化合物26-9(111mg,0.49mmol)溶于N,N-二甲基甲酰胺(4mL)中，依次加入N,N-二异丙基乙胺(127mg,0.98mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(224mg,0.59mmol)。加毕，反应液室温反应18小时，TLC显示原料消失。反应液加水(10mL)淬灭，乙酸乙酯(10mL)萃取。饱和食盐水(10mL x3)洗涤，有机相浓缩。粗品经Prep-TLC(石油醚/乙酸乙酯＝5/1)纯化得到白色固体标题化合物26(69mg,收率45％)。
LC-MS:m/z＝312.2[M+H]+.
1H NMR(400MHz,CDCl3)δ4.22-4.03(m,2H),4.00-3.89(m,1H),3.15-2.89(m,3H),2.81-2.68(m,1H),2.55(s,1H),2.26-2.07(m,3H),1.97-1.78(m,2H),1.74-1.66(m,1H),1.10(t,J＝7.2Hz,3H).
19F NMR(377MHz,CDCl3)δ-93.99,-101.94,-104.74,-121.96.
合成例21：化合物27合成过程
2-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-N-乙基-2-氧代乙酰胺(27)
白色固体,收率88％。
LC-MS:m/z＝299.2[M+Na]+.
1H NMR(400MHz,DMSO-d6)δ8.73(t,J＝5.2Hz,1H),6.31(d,J＝6.4Hz,1H),4.10-3.99(m,2H),3.98-3.92(m,1H),3.17-3.07(m,2H),2.32-2.21(m,1H),2.15-2.10(m,1H),1.94-1.78(m,3H),1.75-1.66(m,1H),1.55-1.43(m,2H),1.04(t,J＝7.2Hz,3H).
19F NMR(377MHz,DMSO-d6)δ-111.33,-119.15.
合成例22：化合物28合成过程
2-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-N-甲基-2-氧代乙酰胺(28)
白色固体,收率91％。
LC-MS:m/z＝285.1[M+Na]+.
1H NMR(400MHz,DMSO-d6)δ8.68(d,J＝4.4Hz,1H),6.31(d,J＝6.4Hz,1H),4.06(dd,J＝26.4,13.2Hz,2H),3.98-3.92(m,J＝13.5,6.9Hz,1H),2.63(d,J＝4.8Hz,3H),2.32-2.22(m,1H),2.15-2.10(m,1H),1.91-1.78(m,3H),1.72-1.67(m,1H),1.55-1.43(m,2H).
19F NMR(377MHz,DMSO-d6)δ-111.33,-119.18.
合成例23：化合物29合成过程
2-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-2-氧代乙酸乙酯(29)
白色固体,收率62％。
LC-MS:m/z＝278.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ6.40(d,J＝8.0Hz,1H),4.27-4.22(m,2H),4.06-3.88(m,3H),2.28-2.20(m,1H),2.19-2.08(m,1H),1.92-1.68(m,4H),1.59-1.41(m,2H),1.29-1.24(m,3H).
19F NMR(377MHz,DMSO-d6)δ-111.57,-119.22.
合成例24：化合物30合成过程
2-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-N-甲基乙酰胺(30)
将化合物IN-1(50mg,0.28mmol)溶解在DMF(1mL)中，加入碳酸钾(87mg,0.63mmol)和2-氯-N-甲基乙酰胺(45mg,0.42mmol)，加毕，反应液升温至50℃搅拌2天。TLC显示大部分原料被消耗。反应液冷却至室温，加水(3mL)稀释，乙酸乙酯(5mL x2)萃取，合并有机相，饱和食盐水(5mL)洗，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(PE/EA＝20/1-3/1)纯化得无色透明半固体标题化合物30(5.95mg,收率:5.7％)。
LC-MS：m/z＝249.2[M+H]+.
1H NMR(DMSO-d6,400MHz)δ7.80(d,J＝3.6Hz,1H),5.72(d,J＝7.6Hz,1H),3.88-3.80(m,1H),3.25-3.11(m,2H),2.88-2.76(m,2H),2.60(d,J＝4.8Hz,3H),1.77-1.71(m,1H),1.68-1.61(m,2H),1.56-1.44(m,4H),1.35-1.28(m,1H).
19F NMR(377MHz,DMSO-d6)δ-98.64,-106.52.
合成例25：化合物31合成过程
2-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-N-(3,3-二氟环丁基)乙酰胺(31)
第一步 2-溴-N-(3,3-二氟环丁基)乙酰胺31-2
将化合物31-1(300mg,2.09mmol)和三乙胺(422mg,4.17mmol)溶于二氯甲烷(4.5mL)中，反应液降温至0℃，加入2-溴乙酰氯(361mg,2.30mmol)，加毕，反应液在0℃下继续搅拌1小时，TLC监测原料反应完全；反应液加入水(10mL)淬灭，二氯甲烷(20mL)萃取，无水硫酸钠干燥，过滤，滤液浓缩得到粗品，粗品经硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得到白色固体标题化合物31-2(100mg,收率21.1％)。
LC-MS:m/z＝228.0[M+H]+.
第二步 2-(3,3-二氟-4-羟基-1-氮杂螺[4.4]壬-1-基)-N-(3,3-三氟环丁基)乙酰胺31
将化合物31-2(100mg,0.44mmol)，化合物IN-1(77mg,0.44mmol)和碳酸钾(91mg,0.66mmol)分散于N,N-二甲基甲酰胺(2mL)中，反应液升温至45℃反应24小时，TLC监测原料反应完全，反应液加水(6mL)淬灭，乙酸乙酯(15mL)萃取，无水硫酸钠干燥，过滤，滤液浓缩，粗品经Prep-TLC(石油醚/乙酸乙酯＝2/1)纯化得白色固体标题化合物31(26mg,收率18.6％)。
LC-MS:m/z＝325.2[M+H]+.
1H NMR(400MHz,CDCl3)δ7.28(s,1H),4.37-4.21(m,1H),3.97-3.87(m,1H),3.23-2.93(m,6H),2.67-2.58(m,1H),2.58-2.42(m,2H),2.00-1.90(m,1H),1.86-1.73(m,1H),1.71-1.61(m,5H),1.44-1.34(m,1H).
19F NMR(377MHz,CDCl3)δ-85.26,-97.26,-98.73,-109.97.
合成例26：化合物32合成过程
1-(2-(3,3-二氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)-2-氧乙基)吡咯烷-2-酮32
白色固体,收率14％。
LC-MS:m/z＝303.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ6.26(d,J＝6.0Hz,1H),4.00-3.83(m,5H),3.32-3.30(m,2H),2.30-2.15(m,3H),2.11-2.01(m,1H),2.00-1.89(m,2H),1.88-1.71(m,3H),1.70-1.61(m,1H),1.53-1.37(m,2H).
19F NMR(377MHz,DMSO-d6)δ-109.98,-117.86.
合成例27：化合物33-36合成过程
N-(3-氟双环[1.1.1]戊烷-1-基)-2-氧代-2-((4S,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(33)；
N-(3-氟双环[1.1.1]戊烷-1-基)-2-氧代-2-((4R,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(34)；
N-(3-氟双环[1.1.1]戊烷-1-基)-2-氧代-2-((4S,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(35)；
N-(3-氟双环[1.1.1]戊烷-1-基)-2-氧代-2-((4R,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(36)

第一步 N-(3-氟双环[1.1.1]戊-1-基)氨基甲酸叔丁酯33-2
将化合物33-1(0.5g,3.84mmol)，三乙胺(0.47g,4.61mmol)和叠氮磷酸二苯酯(1.22g,4.42mmol)溶解在甲苯(8mL)中，在氮气保护和85℃下反应3小时，加入叔丁醇(0.34g,4.61mmol)，加毕，继续保温反应16消失；TLC监测原料反应完全。反应液冷却至室温，加入水(40mL)稀释，乙酸乙酯萃取(50mL x 2)，合并有机相，饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化得到无色油状物标题化合物33-2(155mg,收率:20.06％)。
1H NMR(400MHz,CDCl3)δ7.73(s,1H),2.28(d,J＝2.0Hz,6H),1.45(s,9H).
第二步 苄基3-羟基环丁烷-1-羧酸酯33-3
将化合物33-2(155mg,0.77mmol)溶解于氯化氢的乙醇溶液中(10mL,2M)中，在室温下反应2h；TLC监测原料反应完全。反应液直接浓缩得到白色固体标题化合物33-3(134mg,收率:100％)。
第三步 乙基[(3-氟双环[1.1.1]戊-1-基)氨基甲酰基]甲酸酯33-4
将化合物33-3(134mg,0.77mmol)和三乙胺(0.39g,3.85mmol)溶解在二氯甲烷(5mL)中，在氮气保护和0℃下，滴加2-氯-2-氧乙酸乙酯(100mg,0.73mmol)，滴毕，反应液升温至室温反应16小时；TLC监测原料反应完全。反应液直接浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化得到淡黄色油状物标题化合物33-4(146mg,收率:94.24％)。
LC-MS:m/z＝202.2[M+1]+.
第四步 [(3-氟双环[1.1.1]戊-1-基)氨基甲酰]甲酸33-5
将化合物33-4(146mg,0.73mmol)溶在四氢呋喃(5mL)中，加入氢氧化锂(90mg,2.19mmol)和水(1mL)的混合溶液，在室温下反应2小时；TLC监测原料反应完全。加入稀盐酸(2mL,2M)调酸至pH＝2，乙酸乙酯(10mL)萃取，有机相经无水硫酸钠干燥，过滤，滤液浓缩得到黄色固体标题化合物33-5(118mg,收率:94.24％,粗品)。
LC-MS:m/z＝172.1[M-1]-.
第五步 N-(3-氟双环[1.1.1]戊-1-基)-2-氧代-2-(3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺33-6
将化合物33-5(50mg,0.29mmol)，中间体IN-2(62mg,0.29mmol)和N,N-二异丙基乙胺(110mg,0.87mmol)溶于N,N-二甲基甲酰胺(3mL)中，氮气保护下，降温至0℃，分批加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(120mg,0.32mmol)，反应液升温至室温反应2小时；TLC监测原料反应完全。反应液加水(10mL)淬灭，乙酸乙酯萃取(20mL)，合并有机相，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩后经Pre-TLC(石油醚/乙酸乙酯＝4/1)纯化和手性拆分得到化合物33-36。
手性HPLC分析方法：纳微AD-5H，填料粒径(5μm)，内径(4.6mm)，长度(250mm)，流速：1.0mL/min，乙醇:正己烷＝20:80，波长：220/254nm。
化合物33：白色固体,收率9.3％，保留时间8.800分钟。
LC-MS:m/z＝369.1[M+1]+.
1H NMR(400MHz,CDCl3)δ7.91(s,1H),4.54-4.44(m,1H),4.41-4.26(m,1H),3.96(d,J＝5.2Hz,1H),2.97-2.81(m,1H),2.75-2.51(m,3H),2.44(s,6H),2.24-2.16(m,2H),2.16-2.05(m,1H).
19F NMR(377MHz,CDCl3)δ-92.18,-98.69,-108.24,-122.52,-167.47.
化合物34：白色固体,收率6.5％，保留时间10.687分钟。
LC-MS:m/z＝369.1[M+1]+.
1H NMR(400MHz,CDCl3)δ7.91(s,1H),4.54-4.44(m,1H),4.41-4.26(m,1H),3.96(d,J＝5.2Hz,1H),2.97-2.81(m,1H),2.75-2.51(m,3H),2.44(s,6H),2.24-2.16(m,2H),2.16-2.05(m,1H).
19F NMR(377MHz,CDCl3)δ-92.18,-98.69,-108.24,-122.52,-167.47.
化合物35：白色固体,收率1.9％，保留时间7.617分钟。
LC-MS:m/z＝369.1[M+1]+.
1H NMR(400MHz,CDCl3)δ7.84(s,1H),4.49-4.39(m,1H),4.32-4.19(m,1H),3.87(t,J＝5.2Hz,1H),3.02-2.84(m,1H),2.75(t,J＝16.8Hz,1H),2.60-2.45(m,3H),2.45(d,J＝2.0Hz,6H),2.20-1.91(m,3H).
19F NMR(377MHz,CDCl3)δ-90.29,-96.86,-109.96,-122.64,-167.47.
化合物36：白色固体,收率1.8％，保留时间12.373分钟。
LC-MS:m/z＝369.1[M+1]+.
1H NMR(400MHz,CDCl3)δ7.84(s,1H),4.49-4.39(m,1H),4.32-4.19(m,1H),3.87(t,J＝5.2Hz,1H),3.02-2.84(m,1H),2.75(t,J＝16.8Hz,1H),2.60-2.45(m,3H),2.45(d,J＝2.0Hz,6H),2.20-1.91(m,3H).
19F NMR(377MHz,CDCl3)δ-90.29,-96.86,-109.96,-122.64,-167.47.
合成例28：化合物37,38合成过程
N-(3-氯双环[1.1.1]戊烷-1-基)-2-氧代-2-((4S,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺&N-(3-氯双环[1.1.1]戊烷-1-基)-2-氧代-2-((4R,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(37-P1和37-P2)；
N-(3-氯双环[1.1.1]戊烷-1-基)-2-氧代-2-((4S,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺&N-(3-氯双环[1.1.1]戊烷-1-基)-2-氧代-2-((4R,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(38-P1和38-P2)
参考合成例27的合成方法，以3-氯代双环[1.1.1]戊-1-胺盐酸盐为起始物料，合成得到标题化合物37和化合物38，进一步通过手性拆分得到化合物37-P1,化合物37-P2,化合物38-P1和化合物38-P2。
手性HPLC分析方法：纳微AD-5H，填料粒径(5μm)，内径(4.6mm)，长度(250mm)，流速：1.0mL/min，乙醇:正己烷＝40:60，波长：220nm。
化合物37-P1：白色固体,收率10.5％，保留时间4.800分钟。
LC-MS:m/z＝383.1[M-1]+.
1H NMR(400MHz,CDCl3)δ7.92(s,1H),4.55-4.45(m,1H),4.37-4.25(m,1H),3.94(d,J＝5.2Hz,1H),3.08-2.91(m,1H),2.84-2.73(m,1H),2.72-2.40(m,9H),2.15-1.97(m,2H).
19F NMR(377MHz,CDCl3)δ-90.28,-96.83,-109.97,-122.64.
化合物37-P2：白色固体,收率14.7％，保留时间6.643分钟。
LC-MS:m/z＝383.1[M-1]+.
1H NMR(400MHz,CDCl3)δ7.91(s,1H),4.54-4.44(m,1H),4.37-4.23(m,1H),3.94(d,J＝5.2Hz,1H),3.08-2.91(m,1H),2.84-2.73(m,1H),2.70-2.40(m,9H),2.15-1.97(m,2H).
19F NMR(377MHz,CDCl3)δ-90.28,-96.83,-109.97,-122.64.
化合物38-P1：白色固体,收率7.1％，保留时间5.090分钟。
LC-MS:m/z＝385.1[M+1]+.
1H NMR(400MHz,CDCl3)δ7.92(s,1H),4.55-4.44(m,1H),4.37-4.25(m,1H),3.94(d,J＝5.2Hz,1H),2.97-2.81(m,1H),2.74-2.50(m,3H),2.48(s,6H),2.35-2.21(m,2H),2.16-2.05(m,1H).
19F NMR(377MHz,CDCl3)δ-91.94,-98.68,-108.23,-122.51.
化合物38-P2：白色固体,收率5.6％，保留时间8.937分钟。
LC-MS:m/z＝385.1[M+1]+.
1H NMR(400MHz,CDCl3)δ7.92(s,1H),4.55-4.44(m,1H),4.40-4.25(m,1H),3.94(d,J＝5.2Hz,1H),2.97-2.81(m,1H),2.74-2.50(m,3H),2.48(s,6H),2.35-2.21(m,2H),2.16-2.05(m,1H).
19F NMR(377MHz,CDCl3)δ-92.18,-98.68,-108.23,-122.51.
合成例29：化合物39,40合成过程
N-(1-甲基-3-氧代环丁基)-2-氧代-2-((4S,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺&N-(1-甲基-3-氧代环丁基)-2-氧代-2-((4R,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(39-P1和39-P2)；
N-(1-甲基-3-氧代环丁基)-2-氧代-2-((4S,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺&N-(1-甲基-3-氧代环丁基)-2-氧代-2-((4R,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(40-P1和40-P2)
第一步 2-氧代-2-(3,3,7,7-四氟-4-羟基-1-氮杂螺[4.4]壬烷-1-基)乙酸乙酯39-1
将化合物IN-2(70mg,0.33mmol)溶于二氯甲烷(6mL)中，加入三乙胺(66mg,0.66mmol)和草酰氯单乙酯(49mg,0.36mmol)。室温反应1小时。TLC检测原料反应完全。反应液加水(10mL)淬灭，二氯甲烷(50mL x2)萃取，合并有机层并用饱和氯化钠溶液(20mL)洗，无水硫酸钠干燥，过滤并浓缩，粗品经Pre-TLC(PE/EA＝4/1)纯化得白色固体标题化合物39-1(47mg,收率45.47％)。
第二步 2-氧代-2-(3,3,7,7-四氟-4-羟基-1-氮杂螺[4.4]壬烷-1-基)乙酸39-2
将化合物39-1(47mg,0.15mmol)溶于四氢呋喃(3mL)和水(3mL)的混合溶液中，加入氯化锂(7.18mg,0.30mmol)。加毕，室温反应1小时。TLC检测原料反应完全。反应液加入稀盐酸(2mL,3N)酸化至pH＝2，加水(10mL)稀释，乙酸乙酯(50mL x2)萃取，合并有机层并用饱和氯化钠溶液(20mL)洗，无水硫酸钠干燥，过滤并浓缩得白色固体标题化合物39-2(42mg,收率98.18％)。
第三步 N-(3-羟基双环[1.1.1]戊烷-1-基)-2-氧代-2-(3,3,7,7-四氟-4-羟基-1-氮杂螺[4.4]壬烷-1-基)乙酰胺39，40
将化合物39-2(42mg,0.15mmol)和1-甲基-3-氧代环丁烷-1-胺盐酸盐(0.15mmol)溶于DMF(5mL)中，加入HATU(68mg,0.18mmol)和N,N-二异丙基乙胺(58mg,0.45mmol)。加毕，室温反应1小时。TLC检测原料反应完全。反应液加水(10mL)淬灭，乙酸乙酯(50mL x2)萃取，合并有机层并用饱和氯化钠溶液(20mL)洗，无水硫酸钠干燥，过滤并浓缩，粗品经Pre-TLC(PE/EA＝2/1)纯化得白色固体标题化合物39-P1和39-P2的混合物以及40-P1和40-P2的混合物。
39-P1和39-P2的混合物：白色固体,收率28.9％。
LC-MS:m/z＝367.2[M+1]+
1H NMR(400MHz,CDCl3)δ7.89(s,1H),4.54-4.46(m,1H),4.41-4.29(m,1H),3.96(d,J＝5.2Hz,1H),3.56-3.51(m,2H),3.11-3.06(m,2H),2.95-2.85(m,1H),2.67-2.55(m,3H),2.37-2.26(m,2H),2.14-2.09(m,1H),1.67(s,3H),.
19F NMR(377MHz,CDCl3)δ-92.14,-98.47,-108.17,-122.44.
40-P1和40-P2的混合物：白色固体,收率6.9％。
LC-MS:m/z＝367.2[M+1]+
1H NMR(400MHz,CDCl3)δ7.90(s,1H),4.54-4.46(m,1H),4.39-4.27(m,1H),4.00-3.94(m,1H),3.56-3.50(m,2H),3.11-3.06(m,2H),2.95-2.85(m,1H),2.67-2.55(m,3H),2.37-2.26(m,2H),2.14-2.09(m,1H),1.67(s,3H),.
19F NMR(377MHz,CDCl3)δ-90.31,-96.49,-109.88-122.53.
合成例30：化合物41,42合成过程
N-(3-(二氟甲基)双环[1.1.1]戊烷-1-基)-2-氧代-2-((4S,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺&N-(3-(二氟甲基)双环[1.1.1]戊烷-1-基)-2-氧代-2-((4R,5R)-3,3,7,7-四氟-4-羟基-1-氮 杂螺环[4.4]壬烷-1-基)乙酰胺(41-P1和41-P2)；
N-(3-(二氟甲基)双环[1.1.1]戊烷-1-基)-2-氧代-2-((4S,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺&N-(3-(二氟甲基)双环[1.1.1]戊烷-1-基)-2-氧代-2-((4R,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(42-P1和42-P2)
参考合成例27的合成方法，以3-(二氟甲基)双环[1.1.1]戊-1-胺盐酸盐为起始物料，合成得到标题化合物41-P1和41-P2的混合物以及42-P1和42-P2的混合物。
41-P1和41-P2的混合物：白色固体,收率30.9％。
LC-MS:m/z＝401.2[M+1]+
1H NMR(400MHz,CDCl3)δ7.93(s,1H),5.97-5.69(m,1H),4.54-4.46(m,1H),4.40-4.28(m,1H),3.98-3.91(m,1H),2.96-2.83(m,1H),2.73-2.50(m,3H),2.35-2.27(m,2H),2.33(s,6H),2.18-2.03(m,1H).
19F NMR(377MHz,CDCl3)δ-92.20,-98.72,-108.26,-121.19,122.52.
42-P1和42-P2的混合物：白色固体,收率8.2％。
LC-MS:m/z＝401.2[M+1]+
1H NMR(400MHz,CDCl3)δ7.93(s,1H),5.97-5.69(m,1H),4.55-4.47(m,1H),4.38-4.26(m,1H),3.99-3.91(m,1H),3.08-2.95(m,1H),2.83-2.67(m,1H),2.68-2.49(m,3H),2.23(s,6H),2.20-1.98(m,3H).
19F NMR(377MHz,CDCl3)δ-90.30,-96.89,-110.02,-121.19,122.65.
合成例31：化合物43,44合成过程
N-(3-(三氟甲基)双环[1.1.1]戊烷-1-基)-2-氧代-2-((4S,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺&N-(3-(三氟甲基)双环[1.1.1]戊烷-1-基)-2-氧代-2-((4R,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(43-P1和43-P2)；
N-(3-(三氟甲基)双环[1.1.1]戊烷-1-基)-2-氧代-2-((4S,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺&N-(3-(三氟甲基)双环[1.1.1]戊烷-1-基)-2-氧代-2-((4R,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(44-P1和44-P2)
参考合成例27的合成方法，以3-(三氟甲基)双环[1.1.1]戊-1-胺盐酸盐为起始物料，合成得到标题化合物43-P1和43-P2的混合物以及44-P1和44-P2的混合物。
43-P1和43-P2的混合物：白色固体,收率29.9％。
LC-MS:m/z＝419.2[M+1]+.
1H NMR(400MHz,CDCl3)δ7.94(s,1H),4.53-4.45(m,1H),4.39-4.27(m,1H),3.96(d,J＝5.2Hz,1H),2.95-2.81(m,1H),2.75-2.53(m,3H),2.34(s,6H),2.33-2.20(m,2H),2.16-2.04(m,1H).
19F NMR(377MHz,CDCl3)δ-71.39,-92.20,-98.68,-108.22,-122.36.
44-P1和44-P2的混合物：白色固体,收率6.8％。
LC-MS:m/z＝419.2[M+1]+.
1H NMR(400MHz,CDCl3)δ7.88(s,1H),4.49-4.44(m,1H),4.31-4.19(m,1H),3.92-3.85(m,1H),2.77-2.69(m,1H),2.60-2.40(m,3H),2.27(s,6H),2.16-1.90(m,3H).
19F NMR(377MHz,CDCl3)δ-71.39,-90.29,-96.84,-109.93,-122.63.
合成例32：化合物45,46合成过程
N-(3-甲基双环[1.1.1]戊烷-1-基)-2-氧代-2-((4S,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙 酰胺&N-(3-甲基双环[1.1.1]戊烷-1-基)-2-氧代-2-((4R,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(45-P1和45-P2)；
N-(3-甲基双环[1.1.1]戊烷-1-基)-2-氧代-2-((4S,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺&N-(3-甲基双环[1.1.1]戊烷-1-基)-2-氧代-2-((4R,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(46-P1和46-P2)
参考合成例27的合成方法，以3-甲基双环[1.1.1]戊-1-胺盐酸盐为起始物料，合成得到标题化合物45-P1和45-P2的混合物以及46-P1和46-P2的混合物。
45-P1和45-P2的混合物：白色固体,收率42.4％。
LC-MS:m/z＝365.1[M+1]+.
1H NMR(400MHz,CDCl3)δ7.83(s,1H),4.55-4.45(m,1H),4.42-4.28(m,1H),3.94(d,J＝5.2Hz,1H),2.97-2.81(m,1H),2.75-2.49(m,3H),2.35-2.21(m,2H),2.17-2.04(m,1H),1.97(s,6H),1.24(s,3H).
19F NMR(377MHz,CDCl3)δ-95.20,-115.12.
46-P1和46-P2的混合物：白色固体,收率18.0％。
LC-MS:m/z＝365.1[M+1]+.
1H NMR(400MHz,CDCl3)δ7.83(s,1H),4.57-4.46(m,1H),4.40-4.26(m,1H),3.94(t,J＝5.2Hz,1H),3.08-2.92(m,1H),2.83-2.72(m,1H),2.69-2.42(m,3H),2.18-1.95(m,8H),1.24(s,3H).
19F NMR(377MHz,CDCl3)δ-93.35,-116.15.
合成例33：化合物47,48合成过程
N-(3-氰基双环[1.1.1]戊烷-1-基)-2-氧代-2-((4S,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺&N-(3-氰基双环[1.1.1]戊烷-1-基)-2-氧代-2-((4R,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(47-P1和47-P2)；
N-(3-氰基双环[1.1.1]戊烷-1-基)-2-氧代-2-((4S,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺&N-(3-氰基双环[1.1.1]戊烷-1-基)-2-氧代-2-((4R,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(48-P1和48-P2)
参考合成例27的合成方法，以3-氰基双环[1.1.1]戊-1-胺盐酸盐为起始物料，合成得到标题化合物47-P1和47-P2的混合物以及48-P1和48-P2的混合物。
47-P1和47-P2的混合物：白色固体,收率13.3％。
LC-MS:m/z＝376.2[M+1]+.
1H NMR(400MHz,CDCl3)δ7.96(s,1H),4.51-4.32(m,1H),4.38-4.25(m,1H),3.96(d,J＝5.2Hz,1H),2.93-2.80(m,1H),2.74-2.54(m,9H),2.34-2.24(m,2H),2.15-2.05(m,1H).
19F NMR(377MHz,CDCl3)δ-92.22,-98.68,-108.17,-122.50.
48-P1和48-P2的混合物：白色固体,收率5.1％。
LC-MS:m/z＝374.1[M-1]-.
1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),6.66(d,J＝4.8Hz,1H),4.21-4.00(m,3H),2.75-2.55(m,9H),2.14-2.05(m,1H),2.04-1.94(m,2H).
19F NMR(377MHz,CDCl3)δ-90.28,-96.79,-109.82,-122.63.
合成例34：化合物49,50合成过程
N-(3,3-二氟环丁基)-2-氧代-2-((4S,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺& N-(3,3-二氟环丁基)-2-氧代-2-((4R,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(49-P1和49-P2)；
N-(3,3-二氟环丁基)-2-氧代-2-((4S,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺&N-(3,3-二氟环丁基)-2-氧代-2-((4R,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(50-P1和50-P2)；
参考合成例27的合成方法，以3,3-二氟环丁烷-1-胺盐酸盐为起始物料，合成得到标题化合物49-P1和49-P2的混合物以及50-P1和50-P2的混合物。
49-P1和49-P2的混合物：白色固体,收率27％。
LC-MS:m/z＝375.1[M+H]+.
1H NMR(400MHz,CDCl3)δ7.73(d,J＝6.4Hz,1H),4.56-4.17(m,3H),3.97(d,J＝5.2Hz,1H),3.11-2.82(m,3H),2.75-2.50(m,5H),2.39-2.22(m,2H),2.18-2.04(m,1H).
19F NMR(377MHz,CDCl3)δ-84.45,-91.89,-97.29,-98.29,-107.86,-122.12.
50-P1和50-P2的混合物：白色固体,收率9％。
LC-MS:m/z＝375.1[M+H]+.
1H NMR(400MHz,CDCl3)δ7.74(d,J＝6.4Hz,1H),4.55-4.44(m,1H),4.40-4.16(m,2H),3.99-3.91(m,1H),3.11-2.94(m,3H),2.87-2.77(m,1H),2.72-2.48(m,5H),2.19-1.99(m,2H).
19F NMR(377MHz,CDCl3)δ-84.45,-90.03,-96.40,-97.28,-109.57,-122.24.
合成例35：化合物51合成过程
2-(9,9-二氟-10-羟基-6-氮杂螺环[4.5]癸烷-6-基)-N-(3,3-二氟环丁基)-2-氧代乙酰胺(51)
第一步 1-((4-甲氧基-4-氧代丁基)氨基)环戊烷-1-甲酸甲酯51-2
将化合物51-1(2.0g,4.11mmol)溶于N,N-二甲基甲酰胺(16mL)，加入4-溴丁酸甲酯(2.0g,11.13mmol)和碳酸钾(3.8g,27.83mmol)。加毕，反应液加热至100℃反应10小时。TLC(石油醚/乙酸乙酯＝4/1，碘显色)显示原料还有少量剩余。反应液冷却至室温，加水(20mL)淬灭，乙酸乙酯(20mL)萃取。有机相用饱和食盐水洗涤(50mL x2)，浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化得到无色液体标题化合物51-2(2.0g,74％收率)。
LC-MS:m/z＝244.2[M+H]+.
第二步 10-氧代-6-氮杂螺环[4.5]癸烷-9-羧酸甲酯51-3
将化合物51-2(1.0g,4.11mmol)溶于1,4-二氧六环(10mL)中，加入甲醇钠(333mg,6.17mmol)。加毕，反应液升温至100℃反应4小时，TLC(石油醚/乙酸乙酯＝1/1,碘显色)显示原料消失。反应液冷却，滴加1M稀盐酸酸化至pH＝1，再用饱和碳酸钠溶液碱化至pH＝9-10，乙酸乙酯(30mL)萃取，有机相用饱和食盐水(20mL x2)洗涤，无水硫酸钠干燥，浓缩得到黄色液体标题化合物51-3(700mg,收率81％)。
LC-MS:m/z＝244.2[M+CH3OH+H]+.
第三步 6-氮杂螺环[4.5]癸烷-10-酮盐酸盐51-4
将化合物51-3(700mg,3.31mmol)溶于浓盐酸(3mL)中，95℃反应1.5小时，TLC(二氯甲烷/甲醇＝20/1)显示原料反应完全。反应液冷却至室温，浓缩得到淡黄色油状标题化合物51-4(粗品，直接投下一步)。
LC-MS:m/z＝154.2[M-Cl+H]+.
第四步 10-氧代-6-氮杂螺环[4.5]癸烷-6-羧酸叔丁酯51-5
将化合物51-4(粗品)溶于甲醇(10mL)中，冰浴冷却至0℃，加入三乙胺(1.0g,9.93mmol)和二碳酸二叔丁酯(1.1g,4.97mmol)。加毕，反应液室温20℃反应3小时，TLC(石油醚/乙酸乙酯＝4/1，磷钼酸显色)显示有小极性点生成。反应液浓缩，加乙酸乙酯(10mL)和水(10mL)萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝20/1)纯化得到无色液体标题化合物51-5(358mg,两步收率43％)。
LC-MS:m/z＝154.2[M-100+H]+.
第五步 9,9-二氟-10-氧代-6-氮杂螺环[4.5]癸烷-6-羧酸叔丁酯51-6
将化合物51-5(358mg,1.41mmol)溶于无水四氢呋喃(4mL)中，氮气置换3次，干冰浴冷却至-60℃，滴加双三甲基硅基胺基锂(3.5mL,1M)，控温-60～-55℃滴完，干冰浴反应40分钟，滴加N-氟代双苯磺酰胺(927mg,2.94mmol)的四氢呋喃溶液(6mL)，控温-60～-50℃滴完，干冰浴继续反应2小时，撤去干冰浴，缓慢升至室温反应18小时。TLC(石油醚/乙酸乙酯＝4/1，磷钼酸显色)显示原料消失。反应液加水(10mL)淬灭，乙酸乙酯(10mL)萃取。有机相用5％的柠檬酸(5mL)和饱和食盐水(10mL x2)洗涤，无水硫酸钠干燥，浓缩得到淡黄色固体标题化合物51-6(粗品，直接投下一步)。
LC-MS:m/z＝190.1[M-100+H]+.
第六步 9,9-二氟-10-羟基-6-氮杂螺环[4.5]癸烷-6-羧酸叔丁酯51-7
将化合物51-6(粗品)溶于甲醇(6mL)中，冰浴冷却至0℃，加入硼氢化钠(80mg,2.12mmol)。加毕，反应液冰浴反应2小时，TLC(石油醚/乙酸乙酯＝4/1，磷钼酸)显示有新点生成。反应液浓缩，剩余物加乙酸乙酯(10mL)溶解，饱和食盐水(10mL x2)洗涤。有机相浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化得到白色固体标题化合物51-7(254mg,两步收率62％)。
LC-MS:m/z＝192.2[M-100+H]+.
1H NMR(400MHz,CDCl3)δ3.95-3.89(m,1H),3.67-3.63(m,1H),3.31-3.24(m,1H),3.01-2.88(m,1H),2.33-2.30(m,2H),2.21-2.09(m,2H),1.93-1.85(m,2H),184-1.63(m,4H),1.45(s,9H).
19F NMR(377MHz,CDCl3)δ-100.09.
第七步 9,9-二氟-6-氮杂螺环[4.5]癸烷-10-醇盐酸盐51-8
将化合物51-7(120mg,0.41mmol)溶于氯化氢的1,4-二氧六环溶液(3mL,4M)中，室温反应6小时，TLC(石油醚/乙酸乙酯＝4/1)显示原料消失。反应液浓缩得到白色固体标题化合物51-8(粗品，直接投下一步)。
LC-MS:m/z＝192.2[M-Cl+H]+.
第八步 2-(9,9-二氟-10-羟基-6-氮杂螺环[4.5]癸烷-6-基)-N-(3,3-二氟环丁基)-2-氧代乙酰胺51
将化合物51-8(1eq)，2-((3，3-二氟环丁基)氨基)-2-氧代乙酸(25mg,0.14mmol)溶于N,N-二甲基甲酰胺(4mL)中，依次加入N,N-二异丙基乙胺(54mg,0.42mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(64mg,0.17mmol)。加毕，反应液室温反应16小时，TLC显示原料消失。反应液加水(10mL)淬灭，乙酸乙酯(10mL)萃取。饱和食盐水(10mL x3)洗涤，无水硫酸钠干燥，浓缩。粗品经Prep-TLC(石油醚/乙酸乙酯＝5/1)纯化得到白色固体标题化合物51(7mg,收率14％)。
LC-MS:m/z＝353.2[M+H]+.
1H NMR(400MHz,CDCl3)δ4.38-4.17(m,2H),3.71(t,J＝7.2Hz,1H),3.63-3.44(m,1H),3.11-2.95(m,2H),2.65-2.48(m,2H),2.44-1.55(m,11H).
19F NMR(377MHz,CDCl3)δ-85.06,-97.65.
合成例36：化合物52合成过程
N-(3,3-二氟环丁基)-2-氧代-2-(3,3,8,8-四氟-4-羟基-1-氮杂螺环[4.5]癸烷-1-基)乙酰胺(52)
第一步 8,8-二氟-1,3-二氮杂螺环[4.5]癸烷-2,4-二酮52-2
将4,4-二氟环己酮52-1(5.0g,37.28mmol)溶于乙醇(80mL)和水(60mL)的混合溶液中，依次加入碳酸铵(14.3g,149.11mmol)和三甲基氰硅烷(7.4g,74.56mmol)，加毕，反应液升温至70℃反应18小时，TLC(石油醚/乙酸乙酯＝10/1,磷钼酸显色)显示原料消失。反应液冷却至室温，浓缩除掉乙醇，加入冰水(50mL)并在冰浴下搅拌30分钟。反应液抽滤，滤饼干燥得到银白色片状固体标题化合物52-2(7.2g,收率95％)。
1HNMR(400MHz,DMSO-d6)δ10.73(s,1H),8.49(s,1H),2.12-1.96(m,4H),1.90-1.82(m,2H),1.75-1.71(m,2H).
第二步 1-氨基-4,4-二氟环己烷-1-羧酸52-3
将化合物52-2(7.1g,34.8mmol)溶于氢氧化钾水溶液(150mL,30％)中，反应液升温至110℃下搅拌16小时，降温至65℃下浓缩除去大约75％的水，再次冷却到0℃后缓慢滴加浓盐酸(80mL)直至PH＝2，0℃下继续搅拌30分钟，冷过滤，滤饼用甲醇(100mL x2)淋洗，合并母液，浓缩得白色固体标题化合物52-3(粗品)，直接用于下一步。
第三步 1-氨基-4,4-二氟环己烷-1-羧酸甲酯盐酸盐52-4
将混合物52-3(粗品)溶于甲醇(150mL)中，0℃下缓慢滴加氯化亚砜(8.3g,69.6mmol)，加毕，氮气保护下，反应液缓慢升温至70℃搅拌16小时，反应液减压浓缩得白色固体标题化合物52-4(粗品)，直接用于下一步。
LC-MS:m/z＝194.1[M+H]+.
第四步 4,4-二氟-1-(3-甲氧基-3-氧代丙酰胺基)环己烷-1-羧酸甲酯52-5
将化合物52-4(粗品)溶于无水二氯甲烷(300mL)中，氮气保护下冷却至0℃，加入三乙胺(14.0g,369.2mmol)，加毕，缓慢滴加丙二酸甲酯酰氯(7.1g,52.2mmol)，滴毕，反应液在0℃下继续搅拌3小时；TLC检测原料反应完全，反应液缓慢升至室温，加水(200mL)搅拌10分钟后分液，有机相无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(乙酸乙酯:石油醚＝1:2)纯化得无色油状液体标题化合物52-5(3.8g,四步收率：37％)。
LC-MS:m/z＝294.2[M+H]+.
第五步 8,8-二氟-1-氮杂螺环[4.5]癸烷-2,4-二酮52-6
将化合物52-5(3.8g,13.0mmol)溶于无水四氢呋喃(300mL)中，氮气保护下冷却到0℃，分次加入叔丁醇钾(2.2g,19.5mmol)，加毕，反应液升温至25℃并继续搅拌2小时；TLC检测原料反应完全。反应液加入稀盐酸(25mL,1N)调节PH＝5，继续升温至80℃后搅拌回流4小时，TLC检测原料反应完全。反应液冷却至室温，减压浓缩除去大部分四氢呋喃溶液，加入无水硫酸钠配制成的饱和溶液(100mL)，乙酸乙酯(200mL x3)萃取，合并有机相，无水硫酸钠干燥，浓缩，粗品用石油醚(100mL)打浆，抽滤，滤饼烘干得黄色固体标题化合物52-6(2.0g,收率76％)。
第六步 3,3,8,8-四氟-1-氮杂螺环[4.5]癸烷-2,4-二酮52-7
将化合物52-6(2.0g,9.8mmol)溶于乙腈(50mL)中，室温下加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(10.4g,29.4mmol和水(50mL)，加毕，反应在室温下继续搅拌12小时，TLC检测原料反应完全。反应液减压浓缩除去乙腈，母液用乙酸乙酯(200mL x2)萃取，合并有机相，无水硫酸钠干燥，浓缩得灰色固体标题化合物52-7(3.4g,粗品)，直接用于下一步。
LC-MS:m/z＝238.0[M-H]-.
第七步 3,3,8,8-四氟-4-羟基-1-氮杂螺环[4.5]癸烷-2-酮52-8
将化合物52-7(3.4g,14.2mmol)溶于甲醇(100mL)中，冷却至0℃，加入硼氢化钠(806m g,21.3 mmol)，加毕，反应在0℃下继续搅拌1小时，TLC检测原料反应完全。反应液减压浓缩得白色固体标题化合物52-8(4.2g,粗品)，直接用于下一步。
第八步 3,3,8,8-四氟-1-氮杂螺环[4.5]癸烷-4-醇52-9
将化合物52-8(4.2g,粗品)溶于无水四氢呋喃(150mL)中，0℃分次加入四氢铝锂(2.1g,56.8mmol)，加毕，反应液加热至66℃搅拌2小时，TLC检测原料反应完全。反应液冷却至0℃后依次加水(2.1mL)，氢氧化钠溶液(2.1mL,15％)和水(6.3mL)淬灭，反应在室温下继续搅拌10分钟，抽滤，滤液用无水硫酸钠干燥，浓缩得白色固体标题化合物52-9(2.0g,三步合并收率90％)。
LC-MS:m/z＝228.2[M+H]+.
第九步 N-(3,3-二氟环丁基)-2-氧代-2-(3,3,8,8-四氟-4-羟基-1-氮杂螺环[4.5]癸烷-1-基)乙酰胺52
将化合物52-9(50mg,0.28mmol)，3,3,8,8-四氟-1-氮杂螺并[4.5]癸烷-4-醇(64mg,0.28mmol)溶于N,N-二甲基甲酰胺(4mL)中，依次加入N,N-二异丙基乙胺(73mg,0.56mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(128mg,0.34mmol)。加毕，反应液室温反应16小时，TLC显示原料消失。反应液加水(10mL)淬灭，乙酸乙酯(10mL)萃取。饱和食盐水(10mL x3)洗涤，有机相浓缩。粗品经Prep-TLC(石油醚/乙酸乙酯＝5/1)纯化得到白色固体标题化合物52(63mg,收率64％)。
LC-MS:m/z＝389.2[M+H]+.
1H NMR(400MHz,CDCl3)δ7.76(d,J＝6.4Hz,1H),4.63-4.56(m,1H),4.39-4.13(m,3H),3.11-2.94(m,4H),2.65-2.50(m,2H),2.46(s,1H),2.27-2.04(m,3H),1.99-1.76(m,2H),1.74-1.65(m,1H).
19F NMR(377MHz,CDCl3)δ-84.97,-94.38,-97.87,-102.60,-104.42,-122.21.
合成例37：化合物53合成过程
9,9-二氟-N-(3-氯双环[1.1.1]戊烷-1-基)-10-羟基螺环[4.5]癸烷-7-甲酰胺(53)
第一步 9,9-二氟-10-氧螺环[4.5]癸烷-7-羧酸53-2
将化合物53-1(88mg,0.30mmol)溶于四氯化碳(2mL)，乙腈(2mL)和水(2mL)的溶液中，依次加入高碘酸钠(648mg,3.00mmol)和三氯化钌(31mg,0.15mmol)。加完室温反应18小时。TLC显示原料消失。反应液加水(10mL)稀释，二氯甲烷(10mL)萃取。有机相用饱和食盐水洗涤(20mL x2)，无水硫酸钠干燥，浓缩得到黑色固体标题化合物53-2(58mg,收率84％)。
LC-MS:m/z＝231.1[M-H]-.
第二步 N-(3-氯双环[1.1.1]戊-1-基)-9,9-二氟-10-氧螺环[4.5]癸烷-7-甲酰胺53-3
将化合物53-2(58mg,0.25mmol)和3-氯双环[1.1.1]戊-1-胺盐酸盐(39mg,0.25mmol)分散于N,N-二甲基甲酰胺(4mL)中，加入N,N-二异丙基乙胺(97mg,0.75mmol)，搅拌5分钟后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(114mg,0.30mmol)，加毕，在20℃下反应18小时，TLC检测反应完全。反应液加饱和食盐水(10mL)淬灭，乙酸乙酯(10mL x2)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化得白色固体标题化合物53-3(36mg,收率43％)。
LC-MS:m/z＝332.2[M+H]+.
第三步 N-(3-氯双环[1.1.1]戊-1-基)-9,9-二氟-10-羟基螺环[4.5]癸烷-7-甲酰胺53
将化合物53-3(36mg,0.11mmol)溶于甲醇(4mL)中，冰浴冷却至0℃，加入硼氢化钠(6mg,0.17mmol)。加毕，反应液冰浴下继续反应30分钟，TLC显示原料消失。反应液加饱和氯化铵(10mL)淬灭，乙酸乙酯(20mL)萃取。有机相用饱和食盐水(10mL x2)洗涤，有机相浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化得到白色固体标题化合物53(29mg,收率79％)。
LC-MS:m/z＝334.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),5.43(d,J＝6.4Hz,1H),3.55-3.46(m,1H),2.44-2.37(m,1H),2.34(s,6H),2.01-1.72(m,4H),1.62-1.44(m,5H),1.31-1.26(m,1H),1.23-1.16(m,2H).
19F NMR(377MHz,CDCl3)δ-97.75,-113.15.
合成例38：化合物54,55合成过程
N-(3,3-二氟-1-甲基环丁基)-2-氧代-2-((4S,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺[4.4]壬烷-1-基)乙酰胺&N-(3,3-二氟-1-甲基环丁基)-2-氧代-2-((4R,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺[4.4]壬烷-1-基)乙酰胺(54-P1和54-P2)；
N-(3,3-二氟-1-甲基环丁基)-2-氧代-2-((4S,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺[4.4]壬烷-1-基)乙酰胺&N-(3,3-二氟-1-甲基环丁基)-2-氧代-2-((4R,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺[4.4]壬烷-1-基)乙酰胺(55-P1和55-P2)；
参考合成例29的合成方法，以3,3-二氟-1-甲基环丁烷-1-胺盐酸盐为物料，合成得到标题化合物54-P1和54-P2的混合物以及55-P1和55-P2的混合物。
54-P1和54-P2的混合物：白色固体,收率36％。
LC-MS:m/z＝389.1[M+H]+.
1H NMR(400MHz,CDCl3)δ7.72(s,1H),4.57-4.45(m,1H),4.40-4.25(m,1H),3.96(s,1H),3.12-2.90(m,3H),2.74-2.49(m,5H),2.40-2.22(m,2H),2.17-2.06(m,1H),1.57(s,3H).
19F NMR(377MHz,CDCl3)δ-86.46,-91.91,-93.10,-98.31,-107.84,-122.13.
55-P1和55-P2的混合物：白色固体,收率14％。
LC-MS:m/z＝389.1[M+H]+.
1H NMR(400MHz,CDCl3)δ7.73(s,1H),4.56-4.44(m,1H),4.43-4.28(m,1H),3.97(s,1H),3.07-2.83(m,3H),2.87-2.75(m,1H),2.73-2.49(m,5H),2.20-1.99(m,2H),1.57(s,3H).
19F NMR(377MHz,CDCl3)δ-86.47,-90.03,-93.08,-96.36,-109.55,-122.24.
合成例39：化合物56,57合成过程
N-(3-羟基双环[1.1.1]戊烷-1-基)-2-氧代-2-((4S,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺&N-(3-羟基双环[1.1.1]戊烷-1-基)-2-氧代-2-((4R,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(56-P1和56-P2)；
N-(3-羟基双环[1.1.1]戊烷-1-基)-2-氧代-2-((4S,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺&N-(3-羟基双环[1.1.1]戊烷-1-基)-2-氧代-2-((4R,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺环[4.4]壬烷-1-基)乙酰胺(57-P1和57-P2)；
参考合成例29的合成方法，以3-羟基双环[1.1.1]戊烷-1-胺盐酸盐为物料，合成得到标题化合物56-P1和56-P2的混合物以及57-P1和57-P2的混合物。
56-P1和56-P2的混合物：白色固体,收率36.43％。
LC-MS:m/z＝367.1[M+H]+.
1H NMR(400MHz,CDCl3)δ7.88(s,1H),4.62-4.44(m,1H),4.41-4.25(m,1H),4.02-3.86(m,1H),3.13-2.91(m,1H),2.79(t,J＝15.6Hz,1H),2.69-2.45(m,3H),2.29(s,6H),2.19-1.98(m,3H).
19F NMR(377MHz,CDCl3)δ-90.31,-96.90,-110.08,-122.67.
57-P1和57-P2的混合物：白色固体,收率9.11％。
LC-MS:m/z＝452.2[M+H]+.
1H NMR(400MHz,CDCl3)δ7.88(s,1H),4.62-4.44(m,1H),4.42-4.26(m,1H),3.95(d,J＝5.4Hz,1H),3.00-2.81(m,1H),2.77-2.47(m,3H),2.29(s,6H),2.28-2.04(m,4H).
19F NMR(377MHz,CDCl3)δ-92.19,-98.72,-108.29,-122.54.
合成例40：化合物58-61合成过程
N-(3-氯双环[1.1.1]戊-1-基)-2-((4S,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺[4.4]壬烷-1-基)乙酰胺(58)；
N-(3-氯双环[1.1.1]戊-1-基)-2-((4R,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺[4.4]壬烷-1-基)乙酰胺(59)；
N-(3-氯双环[1.1.1]戊-1-基)-2-((4S,5R)-3,3,7,7-四氟-4-羟基-1-氮杂螺[4.4]壬烷-1-基)乙酰胺(60)；
N-(3-氯双环[1.1.1]戊-1-基)-2-((4R,5S)-3,3,7,7-四氟-4-羟基-1-氮杂螺[4.4]壬烷-1-基)乙酰胺(61)
第一步 2-溴-N-(3-氯双环[1.1.1]戊-1-基)乙酰胺58-2
将3-氯双环[1.1.1]戊烷-1-胺盐酸盐58-1(500mg,3.25mmol)分散于二氯甲烷(10mL)中，加入三乙胺(987mg,9.75mmol)和溴乙酰溴(721mg,3.57mmol)，加毕，反应液在冰浴下搅拌2小时，TLC检测反应完全。反应液加水(10mL)淬灭，二氯甲烷(10mL x2)萃取，合并有机相，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝6/1)纯化得淡黄色固体标题化合物58-2(306mg,40％收率)。
LC-MS:m/z＝238.0[M+H]+.
1H NMR(400MHz,CDCl3)δ6.81(br,1H),3.82(s,2H),2.48(s,6H).
第二步 N-(3-氯双环[1.1.1]戊-1-基)-2-93,3,7,7-四氟-4-羟基-1-氮杂螺[4.4]壬-1-基)乙酰胺58,59,60,61
将化合物58-2(167mg,0.79mmol)和化合物IN-2(206mg,0.86mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入N,N-二异丙基乙胺(204mg,1.58mmol)。加毕，反应液升温至80℃下反应40小时，TLC检测反应完全。反应液加饱和食盐水(20mL)淬灭，乙酸乙酯(20mL x2)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化得白色固体标题化合物58-61混合物。
手性HPLC分析方法：UnichiralOD-5H,填料粒径(5μm)，内径(4.6mm)，长度(250mm)，流速：1.0mL/min,IPA:Hexane＝10:90,波长：220/254nm。
化合物58：白色固体,收率16％，保留时间10.530分钟。
LC-MS:m/z＝371.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),6.68(d,J＝7.2Hz,1H),3.96-3.88(m,1H),3.30-3.23(m,1H),3.18(d,J＝16Hz,1H),2.95-2.84(m,2H),2.38(m,6H),2.30-2.23(m,2H),2.09-1.93(m,3H),1.64-1.56(m,1H).
19F NMR(377MHz,DMSO-d6)δ-90.90,-93.73,-98.95,-106.57.
化合物59：白色固体,收率4％，保留时间12.497分钟。
LC-MS:m/z＝371.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),6.22(d,J＝6.4Hz,1H),4.04-3.96(m,1H),3.38-3.29(m,1H),3.20(d,J＝16.0Hz,1H),2.89-2.77(m,2H),2.37(m,6H),2.31-2.24(m,1H),2.09-1.94(m,3H),1.91-1.87(m,2H).
19F NMR(377MHz,DMSO-d6)δ-89.00,-93.42,-100.30,-107.11.
化合物60：白色固体,收率16％，保留时间14.717分钟。
LC-MS:m/z＝371.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),6.68(d,J＝7.2Hz,1H),3.96-3.88(m,1H),3.30-3.23(m,1H),3.18(d,J＝16Hz,1H),2.95-2.84(m,2H),2.38(m,6H),2.30-2.23(m,2H),2.09-1.93(m,3H),1.64-1.56(m,1H).
19F NMR(377MHz,DMSO-d6)δ-90.90,-93.73,-98.95,-106.57.
化合物61：白色固体,收率4％，保留时间17.113分钟。
LC-MS:m/z＝371.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),6.22(d,J＝6.4Hz,1H),4.04-3.96(m,1H),3.38-3.29(m,1H),3.20(d,J＝16.0Hz,1H),2.89-2.77(m,2H),2.37(m,6H),2.31-2.24(m,1H),2.09-1.94(m,3H),1.91-1.87(m,2H).
19F NMR(377MHz,DMSO-d6)δ-89.00,-93.42,-100.30,-107.11.
药理测试部分
测试例1化合物抑制HIF-2α的活性检测(IC50)
1、实验材料
2、仪器
离心机(生产厂家：Eppendorf，型号：5430)；酶标仪(生产厂家：Perkin Elmer，型号：EnVision)；Echo 550(生产厂家：Labcyte，型号：Echo 550)
3、实验步骤
配制1×modified TR-FRET assay buffer；化合物浓度梯度的配制：受试化合物测试浓度为50μM起始，3倍稀释，10个浓度点，复孔检测。在384孔板中用DMSO稀释成1000倍终浓度的溶液，然后用Echo 550转移10μL化合物到反应板中。用1×modified TR-FRET assay buffer配制2倍终浓度的GST-HIF-2 alpha溶液。在化合物孔和阳性对照孔分别加5μL的2倍终浓度的GST-HIF-2alpha溶液；在阴性对照孔中加5μL的1×Assay buffer。1000rpm离心30秒，振荡混匀后室温孵育15分钟。用1×Assay buffer配制2倍终浓度的His-HIF-1beta溶液。加入5μL的2倍终浓度的His-HIF-1beta溶液。1000rpm离心30秒，振荡混匀后室温孵育60分钟。用1×Assay buffer配制2倍终浓度的Anti mix溶液(4倍终浓度的Eu-anti-GST和4倍终浓度的XL665-anti-His)。加入10μL的2×Anti mix溶液(5μL的Eu-anti-GST和5μL的XL665-anti-His)。1000rpm离心30秒，振荡混匀后室温孵育60分钟。使用EnVision读取665nm和620nm的荧光强度，并计算TR-FRET ratio(665nm emission/620nm emission)。计算抑制率，拟合量效曲线，以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC50值。
本实验用PT-2977作为阳性对照。
本公开中实施例化合物抑制HIF-2α的活性通过以上的试验进行测定，测得的IC50值见表1。
表1化合物抑制HIF-2α的活性数据

本发明化合物具有优异的HIF-2α抑制活性。
测试例2 VEGF-ELISA检测(IC50)
1、实验材料
2、仪器
3、实验步骤
取对数期生长的786-O细胞接种于96孔板中，细胞浓度为每毫升培养液4000个细胞，180μL每孔，将96孔板放在37℃、5％CO2的培养箱中过夜。
10倍化合物的制备:化合物浓度在DMSO中稀释，以获得1mM起始3倍稀释后的8个浓度点。然后用RPMI 1640培养基将化合物稀释100倍，为最终的10倍化合物浓度。此时细胞培养基中DMSO的浓度为1％。
在细胞板中加入10倍工作浓度的化合物溶液20ul/孔，DMSO浓度为0.1％。然后在37℃、5％CO2培养箱中培养72小时。收集上清150μL/孔，使用ELISA试剂盒测定VEGF浓度，最后终止反应，使用酶标仪在450nm和570nm波长下测量各孔的光吸收值，通过GraphPrism计算IC50。
本实验用PT-2977作为阳性对照。
本公开中实施例的活性通过以上的试验进行测定，测得的IC50值见表2。
表2 VEGF-ELISA的活性数据
测试例3荧光素酶实验(IC50)
本实验中所用细胞为786O-HRE-Luciferase稳转细胞株(序列为9*HRE-Luci)，在786O-HRE-Luci稳转细胞株处于对数成长期时进行试验，使用培养基(RPMI1640MEDIUM，购自GIBCO)培养。待细胞满度达到80～90％时弃去培养基，PBS清洗三次，加入胰蛋白酶(购自BI)消化细胞，用含血清培养基清洗细胞终止细胞消化，收集细胞后进行离心，用PBS吹洗一次去除培养基中的酚红，将细胞重悬至合适的浓度检测细胞密度和成活率，保证细胞活率在95％以上方可进行下一步实验。
将细胞接种至384孔中，3000cells/well，30μL培养基，加入化合物使终浓度分别为10000、3333、1111、370、123、41.1、13.7、4.6、1.5、0.5nM。将细胞放置于37℃，5％CO2的环境中孵育72h。
孵育结束后加入ONE-GloTM Luciferase Assay System(购自Promega)至384孔板，30μL/well，用酶标仪检测发光值。根据每孔的RLU(Record Luminesence)信号值计算抑制率(％)，然后通过Graphpad 9.0拟合计算相应化合物的IC50。
本实验用PT-2977作为阳性对照。
本公开中实施例的活性通过以上的试验进行测定，测得的IC50值见表3。
表3荧光素酶实验的活性数据
并且本发明化合物在溶解性、体内清除率和生物利用度方面与现有阳性化合物相比存在优势。
需要声明的是，本发明通过上述实施例来说明本发明的抑制活性，以此证明其用于与过表达相关疾病的治疗或者缓解方面的治疗用途。
同时，本发明的化合物在水中的溶解性非常优异，并且提示了体内代谢稳定性，有着非常广阔的产业界应用前景。
本发明并不局限于上述实施例，即不意味着本发明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，对本发明的任何改进，对本发明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，均落在本发明的保护范围和公开范围之内。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。

Claims (8)

  1. 式(I)所示的草酸胺类化合物或者其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，
    上述式中，Y1为N或CR1，Y2为CR2R3、NR4或者不存在；
    Y3及Y4各自独立地选自CR2R3、NR4、O、SO2中的一种；R2～R4之间的任意两个可以连接形成取代或未取代的C3-6环烷基、取代或未取代的3元至6元杂环烷基；
    R1选自由H、卤素、羟基、CN、NO2、-NRaRb、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4羟烷基、C1-4烷氧基C1-4烷基、C3-8环烷基中的一种；
    各R2及R3各自独立地选自H、卤素、CN、NO2、羟基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C1-4烷氧基C1-4烷基、C3-8环烷基、-S(O)2Ra、-CO2Ra、-C(O)Ra、-C(O)NRaRb、-S(O)2NRaRb、-S(O)(＝NRb)Ra及-NRaRb中的一种；各R4独立地选自H、卤素、羟基、C1-4烷基、C3-8环烷基、C1-6烷氧基、及-C(O)Ra；
    L1为化学键或者选自C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、饱和或部分不饱和的C3-10亚环烃基、-O-、-CO-、-CN-、-CN(CN)-、-C(＝O)O-、-C(＝N)N Ra-、-N Ra C(＝S)-、-N Ra CO-、-N Ra S(＝O)-、-N Ra S(＝O)2-、-S-、-S(＝O)-、-S(＝O)2-、-S(＝O)O-、-S(＝O)2O-中的一种或多种组合而成的二价基团；
    E为化学键或者选自取代或未取代的饱和或部分不饱和脂肪族C3-10亚环烃基、取代或未取代的饱和或部分不饱和脂肪族3-10元亚杂环基、取代或未取代的C6-12亚芳基、或者取代或未取代的C6-12亚杂芳基；
    R5为选自H、卤素、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6卤代羟烷基、C1-6羟烷基、C1-4烷氧基C1-4烷基、C3-8环烷基、-S(O)2Ra、-CO2Ra、-C(O)Ra、-C(O)NRaRb、-S(O)2NRaRb、-S(O)(＝NRb)Ra及-NRaRb中的一种；
    R9及R10独立地选自由以下组成的组：H、卤素、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C1-6羟基卤代烷基、C1-4烷氧基C1-4烷基、C3-8环烷基、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-S(O)2NRaRb、-S(O)2Ra及C1-6亚烷基-C3-8环烷基、C1-6亚烷基-S(O)2Ra、C1-6亚烷基-S(O)2Ra、C1-6亚烷基-C(O)Ra、C1-6亚烷基-C(O)ORa、C1-6亚烷基-C(O)NRaRb、C1-6亚烷基-S(O)2NRaRb；
    或者，R9及R10连接在一起形成取代或未取代的C3-8环烷基、取代或未取代的3元至8元杂环烷基；
    或者，R9或R10与Y4连接在一起形成取代或未取代的C3-6环烷基、取代或未取代的3元至6元杂环烷基、取代或未取代的C6-12亚芳基、或者取代或未取代的C6-12亚杂芳基；
    各Ra及Rb独立地选自由以下组成的组：H、C1-8烷基、C1-8烷氧基、C1-8卤代烷基、C1-8卤代烷氧基及C1-8羟烷基，
    上述的取代或未取代是指基团中的H被选自卤素、CN、OH、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4羟烷基、C1-4烷氧基C1-4烷基及-NRaRb中的一种或者至少两种的组合以上的基团所取代，或者指基团中的-CH2-中的两个H被替换成氧代＝O。
  2. 如权利要求1所述的化合物或其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，其中，式(I)所示的吡啶酰胺类化合物具有以下式(II)或式(III)所述的结构，
    式(II)和式(III)中，Y1、Y2与式(I)中表示的意义相同，
    L1为选自C1-6亚烷基、-CO-、-C(＝O)O-、-N Ra CO-、中的一种或多种组合而成的二价基团；
    E’选自化学键或者饱和或部分不饱和脂肪族C3-10亚环烃基、饱和或部分不饱和脂肪族3-10元亚杂环基、C6-12亚芳基、或者C6-12亚杂芳基，
    W1、W2各自独立地为化学键、N或CRcRd，W3、W4各自独立地选自CRcRd、NRc、CO、O、S、SO、SO2中的一种；
    R11独立地选自H、卤素、羟基、C1-4烷基、C3-8环烷基、C1-4烷氧基、C3-8环烷氧基及-C(O)Rc；R12和R13独立地选自H、卤素、C1-4烷基、C3-8环烷基及-C(O)Rc；各Rc及Rd独立地选自H、卤素、C1-3烷基、C1-3烷氧基、C1-3卤代烷基、C1-3卤代烷氧基及C1-3羟烷基。
  3. 如权利要求2所述的化合物或其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，其中，E’表示以下结构：
    C2～6亚烷基、亚环丙基、亚环丁基、亚环戊基、亚环己基、亚环庚基、亚环辛基、亚降冰片基、亚金刚烷基、亚氧杂环丁基、亚四氢呋喃基、亚苯基、亚联苯基、亚三联苯基、亚萘基、亚蒽基、亚菲基、亚茚基、亚芴基、亚荧蒽基、亚三亚苯基、亚芘基、亚苝基、亚基、亚苯并环丁基、亚苯并环戊基、亚苯并环己基、亚苯并环庚基、亚苯并环辛基、亚噻唑基、亚呋喃基、亚噻吩基、亚吡咯基、亚吡啶基、亚苯并呋喃基、亚苯并噻吩基、亚异苯并呋喃基、亚异苯并噻吩基、亚吲哚基、亚异吲哚基、亚二苯并呋喃基、亚二苯并噻吩基、亚咔唑基及其衍生物、亚喹啉基、亚异喹啉基、亚吖啶基、亚菲啶基、亚苯并喹啉基、、亚吩噻嗪基、亚吩嗪基、亚吡唑基、亚吲唑基、亚咪唑基、亚苯并咪唑基、亚萘并咪唑基、亚菲并咪唑基、亚吡啶并咪唑基、亚吡嗪并咪唑基、亚喹喔啉并咪唑基、亚嗯唑基、亚苯并嗯唑基、亚萘并嗯唑基、亚蒽并嗯唑基、亚菲并嗯唑基、亚苯并噻唑基、亚哒嗪基、亚苯并哒嗪基、亚嘧啶基、亚苯并嘧啶基、亚喹喔啉基、亚1，5-二氮杂蒽基、亚2，7-二氮杂芘基、亚2，3-二氮杂芘基、亚二氮杂芘基、亚4，5，9，10-四氮杂茈基、亚吡嗪基、亚吩嗪基、亚吩噻嗪基、亚萘啶基、亚氮杂咔唑基、亚苯并咔啉基、亚菲咯啉基、亚三唑基、亚1，2，3-噁二唑基、亚1，2，4-嗯二唑基、亚1，2，5_嗯二唑基、亚噻二唑基、亚三嗪基、亚四唑基、亚四嗪基、亚嘌呤基、亚蝶啶基、亚吲嗪基、亚苯并噻二唑或以下基团，或者它们之间的组合，
    上述基团可选地被卤素、C1-3的烷基取代，或者上述基团中的CH2被氧代为C＝O，
    表示与母核连接的位置，“—”划过的环结构的表达方式，表示连接位点于该环结构上任意能够成键的位置。
  4. 如权利要求1-2中任一项所述化合物或其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，其为以下具体化合物中的一种：


  5. 一种药物组合物，其包含预防或治疗有效量的权利要求1-4中任一项的化合物或者其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，以及药学上可接受的载体，所述药物组合物为固体制剂、半固体制剂、液体制剂或气态制剂。
  6. 如权利要求4所述的药用组合物，其特征在于，所述的药物组合物的剂型为口服剂型或注射剂，所述口服剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂，
    所述注射剂包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的权利要求1-3中任一项的化合物或者其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药的无菌粉末。
  7. 如权利要求1-3中任一项所述化合物或其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络 合物、包合物或前药在制备2α型缺氧诱导因子抑制剂中的用途。
  8. 如权利要求1-3中任一项所述化合物或其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药在制备用于治疗或预防与2α型缺氧诱导因子相关疾病的药物中的用途；
    所述与2α型缺氧诱导因子相关疾病为癌症、炎症性疾病、免疫相关疾病；
    所述癌症为以下的癌症：前列腺癌、结肠癌、直肠癌、胰腺癌、子宫颈癌、胃癌、子宫内膜癌、子宫癌、脑癌、肝癌、膀胱癌、卵巢癌、睪丸癌、头癌、颈癌、皮肤(包括黑素瘤及基底癌)癌、间皮内膜癌、白血球癌、食道癌、乳房癌、肌肉癌、结缔组织癌、肠癌、肺癌、肾上腺癌、甲状腺癌、肾或骨；神经胶母细胞瘤癌、间皮瘤癌、肾细胞癌、透明细胞肾细胞癌\胃癌、肉瘤、卡波西氏肉瘤、绒毛膜癌、皮肤基底细胞癌或睪丸精原细胞瘤；
    所述的炎症选自肺炎、肠炎、肾炎、关节炎、外伤感染；
    所述的代谢性疾病选自肥胖症、血脂异常、高脂质血症；
    优选地，所述癌症为肾细胞癌和透明细胞肾细胞癌。
PCT/CN2023/122073 2022-09-30 2023-09-27 草酸胺类衍生物、包含其的药物组合物及其医药用途 WO2024067708A1 (zh)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007145835A2 (en) * 2006-06-08 2007-12-21 Amgen Inc. Benzamide derivatives as modulators of 11beta-hsd1 for treating diabetes and obesity
CN101765596A (zh) * 2007-05-18 2010-06-30 拜耳先灵制药股份公司 用于治疗过增生症状和与血管生成有关疾病的缺氧诱导因子(hif)抑制剂
CN103319468A (zh) * 2012-03-21 2013-09-25 广东东阳光药业有限公司 取代的螺双环化合物及其使用方法和用途
CN107072207A (zh) * 2014-09-10 2017-08-18 Epizyme股份有限公司 经取代的哌啶化合物
CN108570048A (zh) * 2017-03-10 2018-09-25 广东东阳光药业有限公司 取代的杂芳基化合物及其组合物和用途
WO2022099144A1 (en) * 2020-11-09 2022-05-12 Eisai R&D Mangement Co., Ltd. ΡΡΑRγ MODULATORS AND METHODS OF USE
CN114901652A (zh) * 2019-09-17 2022-08-12 比亚尔R&D投资股份公司 用于治疗医学病症的经取代的饱和和不饱和n-杂环甲酰胺及相关化合物
CN114948953A (zh) * 2021-06-29 2022-08-30 四川大学华西医院 一种杂原子取代芳香类化合物及其盐的用途

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007145835A2 (en) * 2006-06-08 2007-12-21 Amgen Inc. Benzamide derivatives as modulators of 11beta-hsd1 for treating diabetes and obesity
CN101765596A (zh) * 2007-05-18 2010-06-30 拜耳先灵制药股份公司 用于治疗过增生症状和与血管生成有关疾病的缺氧诱导因子(hif)抑制剂
CN103319468A (zh) * 2012-03-21 2013-09-25 广东东阳光药业有限公司 取代的螺双环化合物及其使用方法和用途
CN107072207A (zh) * 2014-09-10 2017-08-18 Epizyme股份有限公司 经取代的哌啶化合物
CN108570048A (zh) * 2017-03-10 2018-09-25 广东东阳光药业有限公司 取代的杂芳基化合物及其组合物和用途
CN114901652A (zh) * 2019-09-17 2022-08-12 比亚尔R&D投资股份公司 用于治疗医学病症的经取代的饱和和不饱和n-杂环甲酰胺及相关化合物
WO2022099144A1 (en) * 2020-11-09 2022-05-12 Eisai R&D Mangement Co., Ltd. ΡΡΑRγ MODULATORS AND METHODS OF USE
CN114948953A (zh) * 2021-06-29 2022-08-30 四川大学华西医院 一种杂原子取代芳香类化合物及其盐的用途

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