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WO2024067709A1 - Dérivé de pyridinylamide, composition pharmaceutique le comprenant et utilisation médicale associée - Google Patents

Dérivé de pyridinylamide, composition pharmaceutique le comprenant et utilisation médicale associée Download PDF

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Publication number
WO2024067709A1
WO2024067709A1 PCT/CN2023/122076 CN2023122076W WO2024067709A1 WO 2024067709 A1 WO2024067709 A1 WO 2024067709A1 CN 2023122076 W CN2023122076 W CN 2023122076W WO 2024067709 A1 WO2024067709 A1 WO 2024067709A1
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compound
mmol
cancer
nmr
mhz
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Chinese (zh)
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刘治国
吴杰
叶阳亮
王昊
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Suzhou Alphama Biotechnology Co Ltd
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Suzhou Alphama Biotechnology Co Ltd
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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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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    • A61K31/4164—1,3-Diazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions

  • the present invention belongs to the field of medicine, and specifically relates to a pyridine amide derivative, and specifically relates to a pyridine amide derivative as a 2 ⁇ hypoxia inducible factor (HIF-2 ⁇ ) inhibitor, and its use.
  • 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 a pyridine amide 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 pyridine amide compound represented by formula (I) has a structure as described in the following formula (II) or formula (III):
  • Ring A represents a substituted or unsubstituted C3-5 aromatic ring or heteroaromatic ring, wherein the substituent is halogen, hydroxyl, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, or C3-8 cycloalkoxy;
  • 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.
  • ring A represents the following aromatic ring structure
  • 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 group refers to a saturated (i.e., “cycloalkylene group” and “cycloalkyl group”) or unsaturated (i.e., having one or more double bonds and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring 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) and the like.
  • 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 in 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 (such as 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (such as 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.
  • cyclic and heterocyclic groups include, but are not limited to, oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or 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 group” refers to a polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but none of the rings has completely conjugated ⁇ electrons.
  • 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.
  • ameliorating the symptoms of a particular disease by administering a particular compound or pharmaceutical composition means any reduction, whether permanent or temporary, lasting or temporary, arising from or associated with the use of the 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 present invention may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, chelates, complexes, inclusion compounds or prodrugs, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present invention or a metabolite or residue 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 compound.
  • 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 T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • 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, and the like.
  • 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, and the like.
  • water is an exemplary carrier.
  • Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, particularly for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like.
  • the composition may also contain a small amount of a wetting agent, emulsifier, or pH buffer as desired.
  • Oral preparations may contain standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. 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 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.
  • An important aspect of the present invention is to provide the use of the above-mentioned pyridine amide derivatives provided by the present invention in the preparation of a method for treating a disease selected from cancer, inflammation, and metabolic diseases, wherein the cancer is selected from 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 cancer, 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, dyslipidemia, and hyperlipidemia.
  • the cancer is selected from the head,
  • the present invention also provides a method for treating cancer using the pyridinamide derivatives as inhibitors, which is carried out by administering an effective amount of the compound to a subject suffering from cancer.
  • 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.
  • 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%).
  • the first step is 3,3-difluorocyclopentane-1-carboxylic acid methyl ester IN-2b
  • 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
  • Step 5 1-amino-3,3-difluorocyclopentane-1-carboxylic acid methyl ester trifluoroacetate IN-2f
  • Step 6 2,2-difluoro-1-(3-methoxy-3-oxopropionamido)cyclopentane-1-carboxylic acid methyl ester IN-2g
  • reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of the tetrahydrofuran solution, and a saturated solution prepared by anhydrous sodium sulfate was added.
  • Ethyl acetate 200mL x3 was extracted, 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 (2 eq) was dissolved in anhydrous N,N-dimethylacetamide (2 V), and the intermediate amine (1 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2 eq) and N,N-diisopropylethylamine (3 eq) were added at room temperature. After the addition was completed, the reaction solution was stirred at room temperature for 16 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).
  • Compound 34 white solid, yield 35%, retention time 23.303 minutes.
  • Compound 35 white solid, yield 26%, retention time 30.543 minutes.
  • Compound 36 white solid, yield 51%, retention time 20.087 minutes.
  • Compound 37 white solid, yield 9%, retention time 22.560 minutes.
  • Compound 38 white solid, yield 21%, retention time 18.887 minutes.
  • Compound 39 white solid, yield 29%; retention time 22.373 minutes.
  • Compound 40 white solid, yield 13%; retention time 25.940 minutes.
  • Compound 41 white solid, yield 9%, retention time 27.400 minutes.
  • Compound 42 white solid, yield 10%; retention time 10.033 minutes.
  • Compound 43 white solid, yield 9%; retention time 9.630 minutes.
  • Compound 44 white solid, yield 9%, retention time 11.740 minutes.
  • Compound 45 white solid, yield 7%, retention time 14.783 minutes.
  • Compound 46 white solid, yield 17%; retention time 10.693 minutes.
  • Compound 48 white solid, yield 17%; retention time 14.130 minutes.
  • Compound 49 white solid, yield 10%, retention time 17.647 minutes.
  • Compound 50 white solid, yield 10%; retention time 7.990 minutes.
  • Compound 51 white solid, yield 25%, retention time 9.950 minutes.
  • Compound 52 white solid, yield 30%; retention time 11.430 minutes.
  • Compound 53 white solid, yield 10%; retention time 26.800 minutes.
  • Compound 54 white solid, yield 14%; retention time 13.333 minutes.
  • Synthesis Example 42 Synthesis process of compounds 58 and 59
  • the first step is 2,2-difluoro-1-(3-methoxy-3-oxopropionamido)cyclopentane-1-carboxylic acid ethyl ester 58-2
  • the 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. It was extracted with ethyl acetate (200 mL x3), the organic phases were combined, and anhydrous sodium sulfate was dried The crude product was slurried with petroleum ether (100 mL), filtered with suction, and the filter cake was dried to obtain the title compound 58-3 (1.6 g, yield 97%) as a yellow solid.
  • Step 6 (6-chloropyridin-2-yl)(3,3,6,6-tetrafluoro-4-hydroxy-1-azaspiro[4.4]nonan-1-yl)methanone 58-7
  • the mixture of 58-P1 and 58-P2 and the mixture of 59-P1 and 59-P2 were separated by chiral column.
  • the first step is 6-oxabicyclo[3.1.0]hexane-3-carboxylic acid methyl ester 60-2
  • Step 4 1-Benzyl 1-methyl 3,4-difluorocyclopentane-1,1-dicarboxylate 60-5
  • reaction solution was slowly warmed to room temperature, saturated aqueous ammonium chloride solution (200 mL) was added and stirred for 10 minutes, and then ethyl acetate was added for extraction (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated.
  • Step 6 1-(tert-Butyloxycarbonyl)amino-3,4-difluorocyclopentane-1-carboxylic acid methyl ester (cis) 60-7
  • Step 7 1-amino-3,4-difluorocyclopentane-1-carboxylic acid methyl ester (cis-difluoro) trifluoroacetate 60-8
  • Step 8 3,4-difluoro-1-(3-methoxy-3-oxopropionamido)cyclopentane-1-carboxylic acid methyl ester (cis-difluoro) 60-9
  • reaction solution was cooled to room temperature and concentrated under reduced pressure to remove most of the tetrahydrofuran solution.
  • a saturated solution prepared with anhydrous sodium sulfate was added to the residue, 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 60-10 (1.8 g, crude product), which was directly used in the next step.
  • Step 13 (6-chloropyridin-2-yl)(3,3,7,8-tetrafluoro-4-hydroxy-1-azaspiro[4.4]nonan-1-yl)methanone 60
  • reaction solution was quenched with water (80 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated.
  • the first step is 2-allyl-2-nitropentene-4-enoic acid ethyl ester 61-2
  • reaction solution was quenched with saturated ammonium chloride solution (50mL), extracted with dichloromethane (50mL x2), the organic phases were combined, washed with saturated brine (50mL x2), dried over anhydrous sodium sulfate, and concentrated.
  • the organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 61-4 (1.05 g, crude product) as a black liquid, which was directly used in the next step.
  • Step 4 1-(3-methoxy-3-oxopropionamido)cyclopentene-3-ene-1-carboxylic acid ethyl ester 61-5
  • the reaction solution was washed with citric acid solution (20 mL), the organic phase was diluted with water (10 mL), extracted with dichloromethane (20 mL x 2), the organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated.
  • Step 7 3,3-difluoro-1-azaspiro[4.4]nonane-7-ene-2,4-dione 61-8
  • Step 10 (6-chloropyridin-2-yl)(3,3-difluoro-4-hydroxy-1-azaspiro[4.4]nonane-7-en-1-yl)methanone 61
  • 6-Chloropyridine-2-carboxylic acid 45 mg, 0.29 mmol
  • compound 61-10 50 mg, 0.29 mmol
  • N,N-dimethylformamide 3 mL
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 132 mg, 0.35 mmol
  • triethylamine 75 mg, 0.58 mmol
  • the first step is 1-((4-methoxy-4-oxobutyl)amino)cyclopentane-1-carboxylic acid methyl ester 62-2
  • Step 4 10-oxo-6-azaspiro[4.5]decane-6-carboxylic acid tert-butyl ester 62-5
  • Step 5 9,9-difluoro-10-oxo-6-azaspiro[4.5]decane-6-carboxylic acid tert-butyl ester 62-6
  • Step 6 9,9-difluoro-10-hydroxy-6-azaspiro[4.5]decane-6-carboxylic acid tert-butyl ester 62-7
  • Step 8 (6-chloropyridin-2-yl)(9,9-difluoro-10-hydroxy-6-azaspiro[4.5]decane-6-yl)methanone 62
  • the first step is 3,3-difluoro-8-oxo-1-azaspiro[4.5]decane-2,4-dione 63-2
  • Step 4 (6-chloropyridin-2-yl)(3,3-difluoro-4-hydroxy-8-oxa-1-azaspiro[4.5]decane-1-yl)methanone 63
  • the first step is 8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione 64-2
  • 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 64-2 (7.2 g, yield 95%) as a silvery white flaky solid.
  • the mixture 64-3 (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 64-4 (crude product) as a white solid, which was directly used in the next step.
  • Step 4 4,4-difluoro-1-(3-methoxy-3-oxopropionamido)cyclohexane-1-carboxylic acid methyl ester 64-5
  • 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 64-6 (2.0 g, yield 76%).
  • Step 9 (6-chloropyridin-2-yl)(3,3,8,8-tetrafluoro-4-hydroxy-1-azaspiro[4.5]decane-1-yl)methanone 64
  • the first step is 2-amino-2-ethylbutyric acid methyl ester hydrochloride 65-2
  • 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 65-4 (1.8 g, yield 79%).
  • Step 7 (6-chloropyridin-2-yl)(2,2-diethyl-4,4-difluoro-3-hydroxypyrrolidin-1-yl)methanone 65
  • 6-Chloropyridine-2-carboxylic acid (88 mg, 0.56 mmol) was dissolved in anhydrous DMAC (10 mL), and compound 65-7 (50 mg, 0.28 mmol), HATU (236 mg, 0.62 mmol) and DIPEA (120 mg, 0.93 mmol) were added at room temperature. After addition, the reaction solution was stirred at room temperature for 16 hours. TLC detected that the reaction of the raw materials was complete.
  • the first step is 2-amino-2-methylpropionic acid methyl ester hydrochloride 66-2
  • 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 66-3 (3.6 g, yield 74%).
  • Step 4 3,3-difluoro-4-hydroxy-1-azaspiro[4.4]nonane-2-one 66-5
  • Step 6 (6-chloropyridin-2-yl)(4,4-difluoro-3-hydroxy-2,2-dimethylpyrrolidin-1-yl)methanone 66
  • 6-Chloropyridine-2-carboxylic acid 145 mg, 0.92 mmol
  • N,N-diisopropylethylamine 178 mg, 1.38 mmol
  • 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 350 mg, 0.92 mmol
  • compound 66-6 70 mg, 0.46 mmol
  • Synthesis Example 50 Synthesis process of compounds 67 and 68
  • the first step is 2-amino-2-methylbutyric acid methyl ester hydrochloride 67-2
  • reaction solution was cooled to room temperature, separated, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 67-4 (2.8 g, crude product) as a light yellow oily liquid, which was directly used in the next step.
  • Step 7 (6-chloropyridin-2-yl)(3,3-difluoro-4-hydroxy-1-azaspiro[4.4]nonan-1-yl)methanone 67-8
  • 6-Chloropyridine-2-carboxylic acid 48 mg, 0.30 mmol
  • compound 67-7 50 mg, 0.30 mmol
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 137 mg, 0.36 mmol
  • triethylamine 78 mg, 0.60 mmol
  • the reaction solution was stirred at 20 ° C for 18 hours.
  • the reaction solution was diluted with ethyl acetate (10 mL) and washed with saturated brine (10 mL x 2).
  • the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 67-8.
  • the first step is 3,3-difluorocyclobutanal 69-2
  • Step 4 2-amino-2-(3,3-difluorocyclobutyl)acetic acid methyl ester hydrochloride 69-5
  • Step 5 3-((1-(3,3-difluorocyclobutyl)-2-methoxy-2-oxoethyl)amino)-3-oxopropanoic acid methyl ester 69-6
  • the reaction solution was quenched with water (50 mL), and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove most of the tetrahydrofuran.
  • Anhydrous sodium sulfate was added to prepare a saturated solution, and ethyl acetate (50 mL x 2) was used for extraction.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound 69-7 (550 mg, crude product) as a white solid, which was directly used in the next step.
  • Step 10 (6-chloropyridin-2-yl)(2-(3,3-difluorocyclobutyl)-4,4-difluoro-3-hydroxypyrrolidin-1-yl)methanone 69
  • reaction solution was quenched with water (5 mL), extracted with ethyl acetate (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • the crude product was purified by Prep-HPLC to obtain the title compound 69 (36 mg, yield 27.7%) as a white solid.
  • Synthesis Example 52 Synthesis process of compounds 70 and 71
  • the first step is 2-amino-2-cyclopentyl acetate methyl ester 70-2
  • reaction solution was quenched with water (100 mL), extracted with dichloromethane (100 mL x2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated.
  • the crude product was purified by silica gel column chromatography to obtain the title compound 70-3 (11.4 g, two-step yield 80%) as a yellow oil.
  • Step 4 5-cyclopentyl-3,3-difluoropyrrolidine-2,4-dione 70-5
  • Step 7 (6-chloropyridin-2-yl)(2-cyclopentyl-4,4-difluoro-3-hydroxypyrrolidin-1-yl)methanone 70-8
  • reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL x 2), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 70-8.
  • 70-8 was chirally resolved to obtain a mixture of white solid title compounds 70-P1 and 70-P2 and a mixture of 71-P1 and 71-P2.
  • Synthesis Example 54 Synthesis process of compound 73
  • Synthesis Example 64 Synthesis process of compound 83
  • Synthesis Example 65 Synthesis process of compound 84
  • Step 5 1-(2-(3,3-difluoro-4-hydroxy-1-azaspiro)[4.4]nonan-1-yl)-2-oxoethyl)-3-difluoromethylpyridin-2(1H)one 85
  • the first step is 3,3-difluoro-4-hydroxy-1-azaspiro[4.4]nonane-1-carboxylic acid benzyl ester 86-1
  • Step 4 4-amino-3,3-difluoro-1-azaspiro[4.4]nonane-1-carboxylic acid benzyl ester 86-4
  • Step 5 4-(tert-Butyloxycarbonyl)aminobenzyl-3,3-difluoro-1-azaspiro[4.4]nonane-1-carboxylate 86-5
  • Step 7 Tert-butyl (1-(6-chloropicolinoyl)-3,3-difluoro-1-azaspiro[4.4]nonane-4-yl)carbamate 86-7
  • Step 8 (4-amino-3,3-difluoro-1-azaspiro[4.4]nonane-1-yl)(6-chloropyridin-2-yl)methanone 86
  • the first step is 3,3,4-trifluoro-1-azaspiro[4.4]nonane-1-carboxylic acid benzyl ester 87-1
  • Step 3 (6-chloropyridin-2-yl)(3,3,4-trifluoro-1-azaspiro[4.4]nonan-1-yl)methanone 87
  • reaction solution was quenched with water (80 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated.
  • the first step is 4-hydroxy-1-azaspiro[4.4]nonan-2-one 88-1
  • Step 3 (6-chloropyridin-2-yl)(4-hydroxy-1-azaspiro[4.4]nonan-1-yl)methanone 88
  • Synthesis Example 70 Synthesis process of compound 89
  • reaction solution was quenched with water (25 mL), extracted with ethyl acetate (25 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.

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Abstract

L'invention concerne un composé (I) ou un sel pharmaceutiquement acceptable, un ester, un isomère optique, un tautomère, un stéréoisomère, un polymorphe, un solvate, un N-oxyde, un composé marqué isotopiquement, un métabolite, un chélate, un complexe, un composé d'inclusion ou un promédicament de celui-ci, et une composition pharmaceutique comprenant le composé (I). L'invention concerne en outre l'utilisation du composé en tant qu'inhibiteur du facteur inductible par l'hypoxie de type 2α (HIF-2α) et l'utilisation du composé dans la préparation d'un médicament pour le traitement de maladies associées au facteur inductible par l'hypoxie de type 2α.
PCT/CN2023/122076 2022-09-30 2023-09-27 Dérivé de pyridinylamide, composition pharmaceutique le comprenant et utilisation médicale associée Ceased WO2024067709A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105566321A (zh) * 2014-10-29 2016-05-11 广东东阳光药业有限公司 杂芳化合物及其在药物中的应用
CN111848572A (zh) * 2019-04-30 2020-10-30 四川科伦博泰生物医药股份有限公司 酰胺类化合物及其制备方法和用途
CN112585119A (zh) * 2018-08-14 2021-03-30 Epizyme股份有限公司 经取代的吲哚及其使用方法
CN114760994A (zh) * 2019-12-04 2022-07-15 艾库斯生物科学有限公司 HIF-2α的抑制剂

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Publication number Priority date Publication date Assignee Title
CN105566321A (zh) * 2014-10-29 2016-05-11 广东东阳光药业有限公司 杂芳化合物及其在药物中的应用
CN112585119A (zh) * 2018-08-14 2021-03-30 Epizyme股份有限公司 经取代的吲哚及其使用方法
CN111848572A (zh) * 2019-04-30 2020-10-30 四川科伦博泰生物医药股份有限公司 酰胺类化合物及其制备方法和用途
CN114760994A (zh) * 2019-12-04 2022-07-15 艾库斯生物科学有限公司 HIF-2α的抑制剂

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Title
DATABASE CAS registry; ANONYMOUS : "C21 H24 N2 O3", XP093151858, retrieved from STN *
DATABASE CAS STN; " 1-Azaspiro[4.4]nonane-3-carboxylic acid, 1-[(5-cyano-2-pyridinyl)carbonyl]- (CA INDEX NAME)", XP093151851, retrieved from REGISTRY *
DATABASE REGISTER STN; ANONYMOUS : "Methanone, (4-hydroxy-1-azaspiro[4.4]non-1-yl)(3-hydroxy-2-pyridinyl)- (CA INDEX NAME)", XP093151854, retrieved from CAS *
DATABASE Registry CAS; ANONYMOUS , XP093151868, retrieved from STN *
WITTEKIND RAYMOND R., WEISSMAN CARL, FARBER SHELDON, MELTZER ROBERT I.: "A polyphosphoric acid‐catalyzed spiroamidation. The conversion of N ‐[3‐(1‐cyclohexen‐1‐yl)propyl]‐2‐(3,4‐dimethoxyphenyl)acetamide to 1‐veratrylcarbonyl‐1‐azaspiro[4.5]decane", JOURNAL OF HETEROCYCLIC CHEMISTRY, WILEY-BLACKWELL PUBLISHING, INC., US, vol. 4, no. 1, 1 March 1967 (1967-03-01), US , pages 143 - 145, XP093151307, ISSN: 0022-152X, DOI: 10.1002/jhet.5570040130 *

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