CN117800895A - Oxalic acid amine derivative, pharmaceutical composition containing oxalic acid amine derivative and medical application of oxalic acid amine derivative - Google Patents

Oxalic acid amine derivative, pharmaceutical composition containing oxalic acid amine derivative and medical application of oxalic acid amine derivative Download PDF

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CN117800895A
CN117800895A CN202311261799.5A CN202311261799A CN117800895A CN 117800895 A CN117800895 A CN 117800895A CN 202311261799 A CN202311261799 A CN 202311261799A CN 117800895 A CN117800895 A CN 117800895A
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cancer
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刘治国
吴杰
叶阳亮
王昊
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Suzhou Almai Biotechnology Co ltd
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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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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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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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    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • 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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    • 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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    • C07D207/02—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
    • 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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    • C07D403/06—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

Abstract

The invention provides the following compounds (I) or pharmaceutically acceptable salts, esters, optical isomers, tautomers, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, chelates, complexes, clathrates or prodrugs thereof, as well as pharmaceutical compositions containing the compounds of the invention, as well as the use of the compounds of the invention as inhibitors of hypoxia inducible factor (HIF-2 alpha) and in the preparation of medicaments for diseases related to hypoxia inducible factor of type 2 alpha, and corresponding pharmaceutical compositions,

Description

Oxalic acid amine derivative, pharmaceutical composition containing oxalic acid amine derivative and medical application of oxalic acid amine derivative
Technical Field
The invention belongs to the field of medicines, and particularly relates to an oxalic acid amine derivative, in particular to an oxalic acid amine derivative serving as a 2 alpha type hypoxia inducible factor (hypoxia inducible factor-2 alpha, HIF-2 alpha) inhibitor and application thereof.
Background
Renal cancer, also known as renal cell carcinoma, is one of the 10 most common cancers worldwide, also one of the most fatal tumors of the urinary system, and histopathology distinguishes renal cancer into three major subtypes: clear cell renal cell carcinoma (ccRCC, 70-75%), papillary renal cell carcinoma (pRCC, 10-16%) and chrophilic renal cell carcinoma (chRCC, 5%), each subtype is associated with a separate genetic syndrome, and thus the treatment method is also different.
Clear cell renal cell carcinoma is the most common kidney malignancy, accounting for about 90% of kidney cancers. According to the American cancer society, 40.3 ten thousand cases of kidney cancer and 17.5 ten thousand cases of death are estimated to be newly increased worldwide each year. Kidney cancer can occur in people of all ages, with high incidence ages mainly between 50 and 70 years. Because the kidney is hidden, and no obvious clinical symptoms exist in the early stage of the kidney cancer, most patients with the kidney cancer already have metastasis during diagnosis, the prognosis of the kidney cancer once the metastasis (late stage) occurs is often poor, and the survival rate of the kidney cancer in 5 years is less than 10 percent. And unlike prostate cancer, bladder cancer, etc., it is insensitive to both radiation and chemotherapy, which also becomes the biggest challenge in the past kidney cancer treatment. Therefore, the discovery of novel and validated drug action targets specific for the treatment of renal cancer is a significant task.
Hypoxia inducible factor, abbreviated as HIF, is critical in sensing changes in oxygen concentration and its family elements include HIF-1α, HIF-1β, HIF-2α, HIF-2β, HIF-3α, and HIF-3β. The abnormality of HIF-2 a activity is a key oncogenic driver of cancers such as clear cell renal cell carcinoma (ccRCC). Under aerobic conditions, prolyl Hydroxylase (PHD) can post-translationally modify HIF-2α to hydroxylate its conserved proline residues, thereby binding to VHL complex (pVHL) and multimerizing HIF-2α, which in turn mediates its degradation, such that intracellular HIF-2α maintains low expression levels. Under hypoxic conditions, HIF-2α cannot be hydroxylated, rendering it unrecognizable to pVHL, and thus accumulates and forms dimers with HIF-1β, which then migrates into the nucleus, where it interacts with the cofactor CBP/p300 and Pol II complex, etc., and binds to HRE (hypoxia responsive element), thereby activating expression of downstream target genes (VEGF-promoting angiogenesis; GLUT1 (glucose transporter-1) -activating glucose transport; LDHA (lactate dehydrogenase) -participating in glycolytic pathway; and Epo-induced erythropoiesis, etc.). Of these, the most obvious is RCC, with 90% of RCC deleted the E3 ligase of VHL (Von Hippel-Lindau), leading to uncontrolled HIF degradation. Thus, the population with an naturally absent portion of VHL function has a higher risk of renal cancer than the normal population, and this type of renal cancer is known as Hippel-Lindau Syndrome (VHL Syndrome). HIF-2 alpha inhibitors may treat/prevent diseases caused by HIF-2 alpha overexpression, such as renal cell carcinoma.
Belzutifan (PT 2977) is a HIF-2 a inhibitor approved by the FDA in 2021 in the united states for the treatment of spell-lindau syndrome adult patients.
Belzutifan is the first and only HIF-2 alpha inhibitor, and the industry still considers that the development of a new HIF-2 alpha inhibitor is very necessary and has social significance.
Disclosure of Invention
The present inventors have found that a compound having a structure represented by the following formula (I) has a good 2 a-type hypoxia inducible factor inhibitory activity in a drug screening model at a cellular level. Specifically disclosed is an amine oxalate compound represented by the following formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof,
in the above, Y 1 Is N or CR 1 ，Y 2 Is CR (CR) 2 R 3 、NR 4 Or is absent;
Y 3 y and Y 4 Each independently selected from CR 2 R 3 、NR 4 、O、SO 2 One of the following; r is R 2 ～R 4 Any two of which may be linked to form a substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl;
R 1 selected from H, halogen, hydroxy, CN, NO 2 、-NR a R b One of C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 hydroxyalkyl, C1-4 alkoxyC 1-4 alkyl, C3-8 cycloalkyl;
Each R is 2 R is R 3 Each independently selected from H, halogen, CN, NO 2 Hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-4 alkoxy C1-4 alkyl, C3-8 cycloalkyl, -S (O) 2 R a 、-CO 2 R a 、-C(O)R a 、-C(O)NR a R b 、-S(O) 2 NR a R b 、-S(O)(＝NR b )R a -NR a R b One of the following; each R is 4 Independently selected from H, halogen, hydroxy, C1-4 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, and-C (O) R a ；
L 1 Is a bond or is selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, saturated or partially unsaturated C3-10 cycloalkylene, -O-, -CO-, -CN (CN) -, -C (=O) O-, -C (=N) N R a -、-N R a C(＝S)-、-N R a CO-、-N R a S(＝O)-、-N R a S(＝O) 2 -、-S-、-S(＝O)-、-S(＝O) 2 -、-S(＝O)O-、-S(＝O) 2 One or more of O-and a divalent group;
e is a bond or is selected from a substituted or unsubstituted saturated or partially unsaturated aliphatic C3-10 cyclic hydrocarbon group, a substituted or unsubstituted saturated or partially unsaturated aliphatic 3-10 membered heterocyclic group, a substituted or unsubstituted C6-12 arylene group, or a substituted or unsubstituted C6-12 heteroarylene group;
R 5 is selected from H, halogen, CN, NO 2 C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxyC1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-4 alkoxyC 1-4 alkyl, C3-8 cycloalkyl, -S (O) 2 R a 、-CO 2 R a 、-C(O)R a 、-C(O)NR a R b 、-S(O) 2 NR a R b 、-S(O)(＝NR b )R a -NR a R b One of the following;
R 9 r is R 10 Independently selected from the group consisting of: H. halogen, CN, NO 2 C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 hydroxyhaloalkyl, C1-4 alkoxyC 1-4 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 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 b C1-6 alkylene-S (O) 2 NR a R b ；
Alternatively, R 9 R is R 10 Are linked together to form a substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocycloalkyl;
alternatively, R 9 Or R is 10 And Y is equal to 4 Are linked together to form a substituted or unsubstituted C3-6 cycloalkyl, a substituted or unsubstituted 3-to 6-membered heterocycloalkyl, a substituted or unsubstituted C6-12 arylene, or a substituted or unsubstituted C6-12 heteroarylene;
each R is a R is R b 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 above-mentioned substituted or unsubstituted means that H in the group is substituted by a member selected from the group consisting of halogen, CN, OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 hydroxyalkyl, C1-4 alkoxyC 1-4 alkyl and-NR a R b One or a group of at least two of the followingSubstituted by the above radicals, or by-CH in the radicals 2 -two H in are replaced with oxo=o.
The present invention also provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof, and a pharmaceutically acceptable carrier, the pharmaceutical composition preferably being a solid formulation, semi-solid formulation, liquid formulation, or gaseous formulation.
In one embodiment of the invention, the pharmaceutical composition is in the form of oral dosage form or injection, and the oral dosage form comprises capsules, tablets, pills, powder and granules. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures; the injectable formulation comprises a physiologically acceptable sterile aqueous or anhydrous solution, dispersion, suspension or emulsion, and sterile powders of a compound of the invention or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof for re-dissolving into a sterile injectable solution or dispersion.
The invention provides the application of the compound and the pharmaceutical composition in treating or preventing cancers, inflammatory diseases and immune related diseases, the diseases are closely related to 2 alpha type hypoxia inducible factors, and the regulation of the 2 alpha type hypoxia inducible factors has the treatment prospect of the diseases.
Specifically, the cancer is the following: prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, stomach cancer, endometrial cancer, uterine cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin (including melanoma and basal carcinoma) cancer, mesothelial cancer, white blood cell cancer, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, intestinal cancer, lung cancer, adrenal cancer, thyroid cancer, kidney or bone; neuroglioblastoma carcinoma, mesothelioma carcinoma, 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 and traumatic infection; the metabolic disease is selected from obesity, dyslipidemia and hyperlipidemia.
The compounds of the invention are particularly suitable for the treatment of renal cell carcinoma, clear cell renal cell carcinoma.
The other elements of the present invention will be described in more detail below.
Definition of the definition
Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.
As used herein, the term "alkylene" means 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.
As used herein, a so-called "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 carbon atoms. For example, as used herein, the term "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 with 1 or more (such as 1 to 3) suitable substituents, such as halogen (this group is referred to as "haloalkyl") (e.g., CH) 2 F、CHF 2 、CF 3 、CCl 3 、C 2 F 5 、C 2 Cl 5 、CH 2 CF 3 、CH 2 Cl or-CH 2 CH 2 CF 3 Etc.). By "C1-4 alkyl" is meant a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).
As used herein, by "alkenyl" is meant a linear or branched monovalent hydrocarbon radical containing one double bond and having 2 to 6 carbon atoms ("C 2-6 Alkenyl "). The alkenyl group is, for example, vinyl, 1-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. When the compounds of the present invention contain alkenyl groups, the compounds may exist in pure E (ipsilateral (entgegen)) form, pure Z (ipsilateral (zusammen)) form or any mixture thereof.
As used herein, the term "alkynyl" refers to a monovalent hydrocarbon radical containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.
As used herein, the term "cycloalkyl" refers to a saturated monocyclic or multicyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo [ 1.1.1:1:]amyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl or bicyclo [5.2.0]Nonyl, decalyl, etc.), optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, so-called "C 3-6 Cycloalkyl "refers to a saturated, mono-or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), optionally substituted with 1 or moreSuch as 1 to 3 suitable substituents, for example methyl substituted cyclopropyl.
As used herein, the terms "cycloalkylene", "cyclic hydrocarbon" and "hydrocarbon ring" refer to a saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double and/or triple bonds within the ring) mono-or polycyclic hydrocarbon ring having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including, but not limited to, cyclopropyl (cyclo), (cyclo) cyclobutyl (cyclo), (cyclopentylene (cyclo), (cyclohexylene), (cycloheptylene (cyclo), (cyclooctylene), (cyclonon) (cyclo), (cyclohexenylene (cyclo), and the like.
As used herein, the terms "heterocyclyl", "heterocyclylene" and "heterocycle" refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) cyclic group having, for example, 3 to 10 (suitably 3 to 8, more suitably 3 to 6) ring atoms, at least one of which is a heteroatom selected from N, O and S, and the remaining ring atoms being C. For example, a "3-10 membered (sub) heterocyclic (group)" is a saturated or partially unsaturated (sub) heterocyclic (group) 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. Examples of heterocyclylene and heterocyclic (groups) include, but are not limited to: ethylene oxide, (subunit) aziridinyl, (subunit) azetidinyl (azetidinyl), (subunit) oxetanyl (oxytanyl), (subunit) tetrahydrofuranyl, (subunit) dioxolyl (dioxanyl), (subunit) pyrrolidinyl, (subunit) pyrrolidinonyl, (subunit) imidazolidinyl, (subunit) pyrazolidinyl, (subunit) pyrrolinyl, (subunit) tetrahydropyranyl, (subunit) piperidinyl, (subunit) morpholinyl, (subunit) dithianyl, (subunit) thiomorpholinyl, (subunit) piperazinyl, or (subunit) trithianyl. The groups also encompass 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, and the like). The heterocyclylene and heterocyclic (groups) may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.
As used herein, the term "(arylene" and "aromatic ring" refer to all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated pi-electron system. For example, as used herein, the so-called "C 6-10 (arylene) and "C 6-10 An aromatic ring "means an aromatic group containing 6 to 10 carbon atoms, such as a phenyl (ene ring) or a naphthyl (ene ring). The aryl (ene) and aryl rings 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.) substitution.
As used herein, the term "(arylene) heteroaryl" and "heteroaryl ring" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, particularly 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 the same or different, such as oxygen, nitrogen or sulfur), and which may additionally be benzo-fused in each case. In particular, "(arylene) heteroaryl" or "heteroaryl ring" is selected from thienyl (ene) furyl (ene) pyrrolyl (ene) oxazolyl (ene) thiazolyl (ene) imidazolyl (ene) pyrazolyl (ene) isoxazolyl (ene) isothiazolyl (ene) oxadiazolyl (ene) triazolyl (ene) thiadiazolyl, and the like, and benzo derivatives thereof; or (sub) pyridyl, (sub) pyridazinyl, (sub) pyrimidinyl, (sub) pyrazinyl, (sub) triazinyl, etc., and their benzo derivatives.
As used herein, the term "aralkyl" preferably means an aryl or heteroaryl substituted alkyl group, wherein the aryl, heteroaryl and alkyl are as defined herein. Typically, the aryl group may have 6 to 14 carbon atoms, the heteroaryl group may have 5 to 14 ring atoms, and the alkyl group may have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
As more specific terms are explained as follows:
"alkyl" refers to a saturated aliphatic hydrocarbon group comprising 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or 1 to 2 carbon atoms, saturated straight or branched chain monovalent hydrocarbon groups, wherein the alkyl groups may be independently optionally substituted with one or more substituents described herein. Examples of alkyl groups further include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be optionally substituted or unsubstituted.
"alkenyl" refers to a straight or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one C-C is sp 2 Double bonds, wherein the alkenyl groups may be independently optionally substituted with 1 or more substituents as described herein, specific examples of which include, but are not limited to, vinyl, allyl, and allyl groups, and the like. Alkenyl groups may be optionally substituted or unsubstituted.
"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms, more preferably comprising 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups may be optionally substituted or unsubstituted.
"spirocycloalkyl" refers to a 5 to 18 membered, two or more cyclic structure, and monocyclic polycyclic groups sharing one carbon atom (called spiro atom) with each other, containing 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro group, a double spiro group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, preferably single spiro group and double spirocycloalkyl group, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to:
"fused ring alkyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of "fused ring alkyl" include, but are not limited to:
"bridged cycloalkyl" means an aromatic system having 5 to 18 members, containing two or more cyclic structures, sharing two all-carbon polycyclic groups with one another that are not directly attached to a carbon atom, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron, preferably 6 to 12 members, more preferably 7 to 10 members. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "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 cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.
"heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein and refer to a saturated or partially unsaturated, monocyclic, bicyclic or tricyclic, non-aromatic heterocyclic group containing 3 to 12 ring atoms, at least one of which is a heteroatom such as oxygen, nitrogen, sulfur, and the like. Preferably having a 5 to 7 membered mono-or 7 to 10 membered bi-or tri-ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulphur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 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 heterocyclyl. The heterocyclyl group may be optionally substituted or unsubstituted.
"spiroheterocyclyl" refers to a 5-to 18-membered, two or more cyclic structure, polycyclic group having single rings sharing one atom with each other, containing 1 or more double bonds within the ring, but no ring having a fully conjugated pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen, sulfur or S (O) m The remaining ring atoms are carbon, m=1 or 2. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to:
"fused heterocyclic group" means an all-ring containing two or more cyclic structures sharing a pair of atoms with each otherCarbon polycyclic groups in which one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen, sulfur or S (O) m The remaining ring atoms are carbon, m=1 or 2. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as 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. Non-limiting examples of "fused heterocyclyl" include, but are not limited to:
"bridged heterocyclyl" means a 5-to 18-membered, polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen, sulfur or S (O) m The remaining ring atoms are carbon, m=1 or 2. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to:
"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferably aryl is C 6 -C 10 Aryl, more preferably aryl is phenyl and naphthyl, most preferably phenyl. Aryl groups may be substituted or unsubstituted. The "aryl" group may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, where the bond to the parent structure is Aryl rings, 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. Examples of "heteroaryl" include, but are 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, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl and benzisoxazolyl. Heteroaryl groups may be optionally substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached 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 (C) 1 -C 6 Is preferably selected. Examples 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 halo substituents, wherein the alkyl group has the meaning as described herein. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1-dichloroethyl, 1, 2-dichloropropyl, and the like.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
"amino" means-NH 2 。
"cyano" refers to-CN.
"nitro" means-NO 2 。
"benzyl" means-CH 2 -phenyl.
"carboxy" means-C (O) OH.
"acetyl" means-C (O) CH 3 Or Ac.
"carboxylate" refers to-C (O) O (alkyl) or (cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
As used herein, a so-called "halo" or "halogen" group is defined to include F, cl, br or I.
As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated mono-or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atom in the ring, which may optionally further comprise one or more (e.g., one, two, three or four) selected from N, O, C = O, S, S =o and S (=o) 2 Is linked to the remainder of the molecule through a nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atoms, the nitrogen-containing heterocycle optionally being benzo-fused and preferably linked to the remainder of the molecule through a nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring.
By "substitution" is meant that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
If a substituent is described as "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent any hydrogens are present) may be replaced with an independently selected optional substituent, alone and/or together. If the nitrogen of a substituent is described as optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogens are present) may each be replaced with an independently selected optional substituent.
If substituents are described as "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.
As used herein, by "one or more" is meant 1 or more than 1, such as 2, 3, 4, 5, or 10, under reasonable conditions.
As used herein, unless indicated, the point of attachment of a substituent may be from any suitable position of the substituent.
When the bond of a substituent is shown as a bond through the ring connecting two atoms, then such substituent may be bonded to any ring-forming atom in the substitutable ring.
The invention also includes all pharmaceutically acceptable isotopically-labelled compounds which are identical to those of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium @ 2 H) The tritium is 3 H) A) is provided; isotopes of carbon (e.g 11 C、 13 C, C is a metal alloy 14 C) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of chlorine (e.g 36 Cl); isotopes of fluorine (e.g 18 F) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of iodine (e.g 123 I, I 125 I) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of nitrogen (e.g 13 N is N 15 N); isotopes of oxygen (e.g 15 O、 17 O and O 18 O); isotopes of phosphorus (e.g 32 P) is as follows; isotopes of sulfur (e.g 35 S). Certain isotopically-labeled compounds of the present invention (e.g., those into which a radioisotope is incorporated) are useful in pharmaceutical and/or substrate tissue distribution studies (e.g., assays). RadioisotopeTritium (i.e. tritium) 3 H) And carbon-14 (i.e., 14C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. Using positron-emitting isotopes (e.g 11 C、 18 F、 15 O and O 13 N) substitution can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labeled compounds of the present invention can be prepared by processes analogous to those described in the accompanying schemes and/or in the examples and preparations by substituting an appropriate isotopically-labeled reagent for the non-labeled reagent previously employed. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g., 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 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"substituted" or "substituted" as used herein, unless otherwise indicated, means that the group may be substituted with one or more groups selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =o, -C (O) R b 、-OC(O)R b 、-NR b R b 、-C(O)NR b R b 、-NR b C(O)R b 、-S(O)NR b R b or-S (O) 2 NR b R b Wherein R is b The definition of (C) is as described in the general formula (I).
As used herein, an "effective amount" of a compound refers to an amount sufficient to down-regulate or agonize the corresponding target.
As used herein, a "therapeutically effective dose" of a compound refers to an amount sufficient to ameliorate or somehow reduce symptoms, stop or reverse progression of a disease, or down-regulate or agonize a corresponding target. Such doses may be administered as a single dose or may be administered according to a regimen so as to be effective.
As used herein, "treating" refers to ameliorating or otherwise altering the condition, disorder, or symptom or pathology of a disease in a patient in any manner.
As used herein, "ameliorating a symptom of a particular disease by use of a particular compound or pharmaceutical composition" refers to any reduction, whether permanent or temporary, persistent or temporary, attributable to or associated with the use of the composition.
The definition and use of stereochemistry in the present invention is generally referred to in the following documents:
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. The compounds of the invention may contain asymmetric or chiral centers and thus exist as different stereoisomers. All stereoisomeric forms of the compounds of the invention, including, but in no way limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Diastereomers can be separated into the individual diastereomers by chromatography, crystallization, distillation, or sublimation, based on their physical-chemical differences. Enantiomers may be converted into diastereomeric mixtures by separation by reaction 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 to the corresponding pure enantiomers. The intermediates and compounds of the invention may also exist in different tautomeric forms and all such forms are encompassed within the scope of the invention. Many organic compounds exist in optically active form, i.e. they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to denote the absolute configuration of the chiral center of the molecule. The prefix d, l or (+), (-) is used to name the sign of the compound plane polarization rotation, where (-) or l means that the compound is left-handed and the prefix (+) or d means that the compound is right-handed. The atoms or groups of atoms of these stereoisomers are connected in the same order but in different steric structures. The particular stereoisomer may be an enantiomer, and the mixture of isomers is commonly referred to as an enantiomeric mixture. 50: mixtures of enantiomers of 50 are referred to as racemic mixtures or racemates, which may result in no stereoselectivity or stereospecificity during chemical reactions. By "racemic mixture" and "racemate" is meant a mixture of two enantiomers in equimolar amounts, lacking optical activity.
"tautomer" or "tautomeric form" refers to isomers of structures of different energies that can be interconverted by a low energy barrier. For example, proton tautomers (i.e., proton-shifted tautomers) include tautomerism by proton shift, such as keto-enol and imine-enamine isomerisation. Valency (valence) tautomers include tautomers that reorganize into bond electrons. Unless otherwise indicated, the structural formulae described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers): for example, R, S configuration containing asymmetric centers, the (Z), (E) isomers of double bonds, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers, or mixtures of geometric isomers thereof, are all within the scope of the invention.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in the human or animal body. Salts of the compounds may be obtained by dissolving the corresponding addition salts in pure solution or in a suitable inert solvent with sufficient amounts of base or acid. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia, magnesium salts, and the like, and pharmaceutically acceptable acid addition salts include inorganic and organic acid salts including 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, fumaric acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, methanesulfonic acid, and the like (see Berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science 66:1-19 (1977)).
Solid lines may be used hereinWedge shaped->Or virtual wedge +.>Depicting the chemical bond of the compounds of the present invention. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom (e.g., particular enantiomers, racemic mixtures, etc.) are included. The use of a solid or virtual wedge to depict a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown. When present in a racemic mixture, real and imaginary wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
Chiral labels for compounds herein indicate uncertainty in the chiral configuration of the position.
The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of any ratio of more than one polymorphs.
It will also be appreciated that certain compounds of the invention may exist in free form for use in therapy or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, chelates, complexes, clathrates or prodrugs which, upon administration to a patient in need thereof, are capable of providing the compounds of the present invention, or metabolites or residues thereof, directly or indirectly. Thus, when reference is made herein to "a compound of the invention" it is also intended to encompass the various derivative forms of the compounds described above.
Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts and base addition salts thereof, including but not limited to salts containing hydrogen or coordination bonds.
Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include acetates, adipates, aspartate, benzoate, benzenesulfonates, bicarbonates, bisulphates/sulfates, borates, camphorsulfonates, citrates, cyclohexanesulphonates, ethanedisulfonates, formates, fumarates, glucoheptonates, gluconates, glucuronates, hexafluorophosphates, maritime salts, hydrochloride/chlorides, hydrobromide/bromides, hydroiodides/iodides, isethionates, lactates, malates, maleates, malonates, methanesulfonates, methylsulfates, naphthaleneates (nathanates), 2-naphthalenesulfonates, nicotinates, nitrates, orotate, oxalates, palmates, pamonates, phosphates/hydrogen phosphates/dihydrogen phosphates, pyroglutamates, glucarates, stearates, succinates, tanninates, tartrates, tosylates, trifluoroacetates, and xinofoates (xinofoate).
Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.
For a review of suitable salts see Stahl, wermpuh, "Handbook of Pharmaceutical Salts: properties, selection, and Use (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.
As used herein, by "ester" is meant an ester derived from the individual compounds of the general formula herein, which includes physiologically hydrolyzable esters (compounds of the present invention that can be hydrolyzed under physiological conditions to release the free acid or alcohol form). The compounds of the invention may themselves be esters.
The compounds of the invention may be present in the form of solvates (preferably hydrates) wherein the compounds of the invention comprise a polar solvent as a structural element of the compound lattice, in particular for example water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.
Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires available lone pairs to oxidize to oxides; those skilled in the art will recognize nitrogen-containing heterocycles 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 and include oxidizing heterocycles and tertiary amines with peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxiranes) such as dimethyl dioxirane. These methods for preparing N-oxides have been widely described and reviewed in the literature, see for example: T.L. Gilchrist, comprehensive Organic Synthesis, vol.7, pp 748-750; katritzky and a.j. Boulton, eds., academic Press; and G.W.H.Cheeseman and E.S.G.Werstiuk, advances in Heterocyclic Chemistry, vol.22, pp 390-392, A.R.Katritzky and A.J.Boulton, eds., academic Press.
Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances that form in vivo upon administration of the compounds of the invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the compound being administered. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by a process of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
The invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity, which, when administered into or onto the body, may be converted into the compounds of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Additional information regarding the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", vol.14, ACS Symposium Series (T.Higuchi and V.stilla). Prodrugs of the invention may be prepared, for example, by replacing the appropriate functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., "Design of Prodrugs", described in h. Bundegaard (Elsevier, 1985) ".
The invention also encompasses compounds of the invention containing a protecting group. During 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 of interest, 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. The protecting group may be removed at a suitable subsequent stage using methods known in the art.
By "about" is meant within 10%, preferably within 5%, more preferably within 2% of the stated value.
In a preferred embodiment of the present invention, the picolinamide-based compound represented by formula (I) has a structure represented by formula (II) or formula (III) below,
in the formula (II) and the formula (III), Y 1 、Y 2 The meaning is the same as that represented by formula (I),
L 1 is selected from C1-6 alkylene, -CO-, -C (=O) O-, -N R a One or more of CO-, and a divalent group formed by combining the two or more of CO-, and CO-, respectively;
e' is selected from a bond or a saturated or partially unsaturated aliphatic C3-10 cyclic hydrocarbon group, a saturated or partially unsaturated aliphatic 3-10 membered heterocyclic group, a C6-12 arylene group, or a C6-12 heteroarylene group,
W 1 、W 2 each independently is a bond, N or CR c R d ，W 3 、W 4 Each independently selected from CR c R d 、NR c 、CO、O、S、SO、SO 2 One of the following;
R 11 independently selected from H, halogen, hydroxy, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C3-8 cycloalkoxy, and-C (O) R c ；R 12 And R is 13 Independently selected from H, halogen, C1-4 alkyl, C3-8 cycloalkyl and-C (O) R c The method comprises the steps of carrying out a first treatment on the surface of the Each R is c R is R d Independently selected from H, halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, and C1-3 hydroxyalkyl.
In a preferred embodiment of the invention, E' represents the structure:
C2-6 alkylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, norbornylene, adamantylene, oxetylene, tetrahydrofuranylene, phenylene, biphenylene, terphenylene, naphthylene, anthrylene, phenanthrylene, indenylene, fluorenylene, fluoranthrylene, triphenylene, pyrenylene, perylene, anda group, a benzocyclobutene group, a benzocyclopentylene group, a benzocyclohexylene group, a benzocycloheptylene group, a benzocyclooctylene group, a thiazolylene group, a furanylene group, a thiophenylene group, a pyrrolylene group, a pyridylene group, a benzofuranylene group, a benzothiophenylene group, an isobenzofuranylene group, an indolylene group, an isoindolylene group, a dibenzofuranylene group, a dibenzothiophene group, a carbazolylene group and derivatives thereof, a quinolinylene group, an isoquinolylene group, an acriylene group, a phenanthreneylene group, a benzoquinolinylene group, a phenothiazine group, a phenazinylene group, a pyrazolylene group, an indazolyene group, an imidazolylene group, a benzimidazolylene group, a naphthylene imidazolylene group, a pyridylimidazolyl group, a pyrazinoimidazolyl group, a quinoxalinmethylimidazolyl group, a thienylene group, a benzothiophenone group, a benzopyrimidinylene group, a pyrrolylene group, a pyrrolizidine group, a benzopyrimidinylene group, a naphthyridine group, a benzopyrimidinylene group, a 5-benzopyrene group, a 1, a 5-naphthyridine group, a 1-5-naphthyridine group, a benzopyrene group, a 1-5-naphthyridine group, 10-tetraazaperylene, pyrazinylene, phenazinylene, phenothiazinylene, naphthyridineylene, azacarbazolylene, benzocarboline, phenanthroline, triazolylene, 1,2, 3-oxadiazolylene, 1,2, 4-oxadiazolylene, 1,2, 5-oxadiazolylene, thiadiazolylene, triazinylene, tetrazolylene, tetrazinylene, purinylene, pteridinylene, indolizinylene, benzothiadiazole, or a combination thereof,
The above radicals being optionally substituted by halogen, C1-3 alkyl, or CH in the above radicals 2 Is oxo-ized by a reaction of c=o,
represents the position of the ligation with the parent nucleus, the expression of the "-" marked loop structure,indicating that the attachment site is at any position on the ring structure that is capable of bonding.
Preferred compounds of the invention
The general formula and preferred ranges of the compounds of the invention have been described. Further preferably, specific examples of the compounds of the present invention may be selected from any one of the following structures, but are not limited to the following compounds, and it is additionally noted that the following compounds 14, 15, 37 to 50, 54 to 57, 62 to 67, 70, 71 represent two chemical structures in the form of the numbers-P1 and-P2 due to the presence of isomers:
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* The configuration and the property of the compound need to be further detected, and the tentative chiral compound is in a graphic configuration.
Pharmaceutical composition, medical use and treatment method
The present invention provides 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, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof, and a pharmaceutically acceptable carrier, preferably in a solid, semi-solid, liquid or gaseous form.
By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting the tissues of humans and/or other animals within the scope of sound medical judgment without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable carriers that may 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, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, in particular for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents, as desired. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
The pharmaceutical compositions of the present invention may act systematically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection (e.g. intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of an ophthalmic formulation or by inhalation.
For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.
Such 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, syrups.
The pharmaceutical composition of the invention can be used for preventing and/or treating pain. In using the pharmaceutical formulations of the present invention, other pain treatment agents, such as fluoxetine, opioid analgesics, non-opioid analgesics, etc., may also be used concurrently.
The pharmaceutical composition of the invention contains a safe and effective amount of the compound of the invention and a pharmaceutically acceptable carrier or excipient. Such vectors include (but are not limited to): saline, buffer solution, glucose, water, glycerol, ethanol, powder, etc. The pharmaceutical formulation should be compatible with the mode of administration.
The pharmaceutical compositions of the invention may be formulated as injectables, e.g. by conventional means using physiological saline or aqueous solutions 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 sterile conditions. The pharmaceutical compositions of the present invention may also be formulated as powders for inhalation by nebulization.
The amount of active ingredient administered is a therapeutically effective amount, for example, from about 1 microgram per kilogram of body weight to about 50 milligrams per kilogram of body weight per day; preferably, from about 5 micrograms/kg body weight to about 10 milligrams/kg body weight; further preferably, from about 10 micrograms/kg body weight to about 5 milligrams/kg body weight. In addition, the compounds of the present invention may also be used with other therapeutic agents.
For the pharmaceutical compositions of the invention, administration to a subject in need thereof (e.g., human and non-human mammals) can be by conventional means. Representative modes of administration include (but are not limited to): oral administration, injection, aerosol inhalation, etc.
When a pharmaceutical composition is used, a safe and effective amount of the drug is administered to the mammal, wherein the safe and effective amount is typically at least about 10 micrograms per kilogram of body weight and in most cases no more than about 50 milligrams per kilogram of body weight, preferably the dose is from about 10 micrograms per kilogram of body weight to about 20 milligrams per kilogram of body weight. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The invention will be further illustrated with reference to specific examples. The procedures, conditions, reagents, experimental methods, etc. for carrying out the present invention are common knowledge and common knowledge in the art, except for those specifically mentioned below, and the present invention is not particularly limited. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
As used herein, an "effective amount" refers to an amount of a compound that, upon administration, will alleviate to some extent one or more symptoms of the condition being treated. Specifically, as used herein, an "effective amount" of a compound refers to an amount sufficient to inhibit 2 alpha hypoxia inducible factor or inhibit cancer. As used herein, a "therapeutically effective dose" of a compound refers to an amount sufficient to ameliorate or somehow reduce symptoms, stop or reverse progression of a disease, or inhibit 2 alpha hypoxia inducible factor. Such doses may be administered as a single dose or may be administered according to a regimen so as to be effective.
The dosing 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 doses may be proportionally reduced or increased as indicated by the urgent need for a therapeutic situation. It is noted that the dosage value 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 particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.
As used herein, "treating" refers to ameliorating or otherwise altering the condition, disorder, or symptom or pathology of a disease in a patient in any manner. As used herein, "ameliorating a symptom of a particular disease by use of a particular compound or pharmaceutical composition" refers to any reduction, whether permanent or temporary, persistent or temporary, attributable to or associated with the use of the composition.
As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
An important aspect of the present invention is to provide the use of the oxalic acid amine derivatives of the present invention for the preparation of a medicament for the treatment of a disease selected from the group consisting of cancer, inflammation, metabolic disease, selected from the group consisting of cancers of head, neck, eye, mouth, throat, esophagus, bronchi, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, breast, ovary, testis or other reproductive organ, skin, thyroid, blood, lymph node, kidney, liver, pancreas, brain, central nervous system, solid tumors and blood-borne 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 invention also provides methods of using oxalic acid amine derivatives as inhibitors for the treatment of cancer by administering an effective amount of the compounds to a subject suffering from cancer.
As used herein, by "effective amount" is meant 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 active ingredient used in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being used, the pharmaceutically acceptable excipient/carrier(s) being used, and similar factors within the knowledge and expertise of the attending physician.
In particular, one effective amount of a compound of formula (I) for use in cancer treatment is an amount sufficient to reduce symptoms of cancer in a human to slow progression of the cancer, or to reduce the risk of worsening symptoms in a patient with cancer. In some embodiments, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.
Detailed Description
The method of the present invention will be described by way of specific examples, so that the technical solution of the present invention can be understood and grasped more easily, but the present invention is not limited thereto. In the following examples 1 The H NMR spectrum was determined with a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation method: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode is ESI.
High performance liquid chromatograph model: agilent 1260, siemens flying U3000; chromatographyColumn model: waters xbridge C18 (4.6. Times.150 mm,3.5 μm); mobile phase: ACN, B Water (0.1% H) 3 PO 4 ) The method comprises the steps of carrying out a first treatment on the surface of the Flow rate: 1.0mL/min; gradient: 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; wavelength: 220nm; column incubator: 35 ℃.
The thin layer chromatography silica gel plate is a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.2mm-0.3mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm.
Column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.
In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, and are used without further purification, and unless otherwise indicated, commercially available manufacturers include, but are not limited to, the national pharmaceutical community, the carbofuran technologies, the tencel (Shanghai) chemical industry development limited, the Shanghai Pico pharmaceutical technologies limited, the Shanghai Michelson chemical technologies limited, and the like.
CD 3 OD: deuterated methanol
CDCl 3 : deuterated chloroform
DMSO-d 6 : deuterated dimethyl sulfoxide
Pd2 (dba) 3: tris (dibenzylideneacetone) dipalladium
Pd (dppf) Cl2: [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride
XantPhos:4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene
XPhos: 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl
HATU:2- (7-Oxybenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate
DCM: dichloromethane (dichloromethane)
PE: petroleum ether
EA: acetic acid ethyl ester
MeOH: methanol
DMF: n, N-dimethylformamide
TLC: thin layer chromatography
HPLC: high performance liquid chromatography
purity: purity of
And (3) the following steps: and
R f : the ratio of the distance from origin to the center of the spot to the distance from origin to the front of the solvent in thin layer chromatography.
The hydrogen atmosphere is defined as the reaction flask being connected to a hydrogen balloon of about 1L volume.
The examples are not particularly described, and the solution in the reaction is an aqueous solution.
The examples are not specifically described, and the reaction temperature is room temperature and is 20℃to 30 ℃.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound or the developing reagent system of thin layer chromatography included: a: petroleum ether and ethyl acetate systems; b: methylene chloride and methanol systems; c: n-hexane: ethyl acetate; the volume ratio of the solvent is different according to the polarity of the compound, and can be adjusted by adding a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine.
Chemical synthesis test:
preparation of intermediates
Synthesis example 1: intermediate 1 Synthesis procedure
3, 3-difluoro-1-azaspiro [4.4] nonan-4-ol IN-1
First step 1- (3-methoxy-3-oxopropanamido) cyclopentane-1-carboxylic acid methyl ester IN-1b
Compound IN-1a (10.0 g,55.7 mmol) was dissolved IN anhydrous dichloromethane (300 mL), cooled to 0deg.C under nitrogen protection, triethylamine (14.2 g,140 mmol) was added, methyl malonate acyl chloride (11.5 g,83.6 mmol) was slowly added dropwise after the addition was completed, and the reaction was stirred at 0deg.C for 3 hours; TLC showed complete reaction of the starting materials, the reaction was slowly warmed to room temperature, water (200 mL) was added and stirred for 10 minutes, then the separated solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/2) to give the title compound IN-1b (12.1 g, yield: 89%) as a yellow oily liquid.
Second step 1-azaspiro [4.4] nonane-2, 4-dione IN-1c
Compound IN-1b (12.1 g,49.7 mmol) was dissolved IN anhydrous tetrahydrofuran (300 mL), cooled to 0deg.C under nitrogen protection, potassium tert-butoxide (8.4 g,74.6 mmol) was added IN portions, after the addition was complete the reaction was warmed to 25deg.C and stirring was continued for 2 hours; TLC detects complete reaction of starting material. Dilute hydrochloric acid (100 ml,1 n) was added to the reaction solution to adjust the PH to about 5, the resulting solution was directly warmed to 85 ℃ without treatment, stirred and refluxed for 4 hours, and TLC detected that the reaction of the starting materials was complete. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of the tetrahydrofuran solution, and after adding anhydrous sodium sulfate to prepare a saturated solution, ethyl acetate (200 mL x 3) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was slurried with petroleum ether (100 mL), suction filtered, and the filter cake was dried to give the title compound IN-1c (6.9 g, yield 91%) as a yellow solid.
Third step 3, 3-difluoro-1-azaspiro [4.4] nonane-2, 4-dione IN-1d
Compound IN-1c (3.5 g,22.8 mmol) was dissolved IN acetonitrile (50 mL), 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (20.4 g,57.5 mmol) and water (50 mL) were added, and the reaction was continued to stir at room temperature for 12 hours after the addition, and TLC was used to detect complete reaction of starting materials. The reaction was concentrated under reduced pressure to remove acetonitrile, the mother liquor was extracted with ethyl acetate (100 ml x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound IN-1d (4.7 g, crude) as a gray solid, which was used directly IN the next step.
Fourth step 3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-2-one IN-1e
Compound IN-1d (2.7 g, crude) was dissolved IN methanol (100 mL), cooled to 0deg.C, sodium borohydride (0.82 g,21.5 mmol) was added, and the reaction was stirred at 0deg.C for 1 hour and TLC detected complete reaction. The reaction solution was concentrated under reduced pressure to give the title compound IN-1e (3.3 g, crude) as a white solid, which was used directly IN the next step.
Fifth step 3, 3-difluoro-1-azaspiro [4.4] nonan-4-ol IN-1
Compound IN-1e (3.3 g, crude product) was dissolved IN anhydrous tetrahydrofuran (150 mL), lithium aluminum hydride (2.2 mg,57.2 mmol) was added at room temperature, and after the addition, the reaction mixture was heated to 66℃and stirred for 2 hours, and TLC checked the completion of the reaction of the starting materials. The reaction solution was cooled to 0℃and quenched with water (2.2 mL), sodium hydroxide solution (2.2 mL, 15%) and water (6.6 mL) IN this order, the reaction was stirred at room temperature for 10 minutes, suction filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to give the title compound IN-1 (2.0 g, 86% combined IN three steps) as a white solid.
Synthesis example 2: intermediate 2 Synthesis procedure
3,3,7,7-tetrafluoro-1-azaspiro [4.4] nonen-4-ol IN-2
First step methyl 3, 3-difluorocyclopentane-1-carboxylate IN-2b
Compound IN-2a (20.0 g,140.7 mmol) was dissolved IN dichloromethane (200 mL), cooled to 0deg.C with an ice bath, and diethylaminosulfur trifluoride (68.0 g,422.09 mmol) was added dropwise. After the addition, the mixture was heated to 30 ℃ and reacted for 40 hours, TLC (petroleum ether/ethyl acetate=4/1, phosphomolybdic acid color development) showed the disappearance of starting material. The reaction solution was slowly poured into a cold saturated sodium carbonate solution to basify to ph=8-9. The mixture was separated, and the organic phase was washed with saturated brine and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=6/1) to give the title compound IN-2b (10.3 g, yield 45%) as a brown liquid.
1 H NMR(400MHz,CDCl 3 )δ3.71(s,3H),3.04-2.96(m,1H),2.44-2.33(m,2H),2.26-2.00(m,4H).
19 F NMR(377MHz,CDCl 3 )δ-90.95,-94.04.
Second step benzyl 1-methyl-3, 3-difluorocyclopentane-1, 1-dicarboxylate IN-2c
Compound IN-2b (4.8 g,29.2 mmol) was dissolved IN anhydrous tetrahydrofuran (500 mL), cooled to-60℃under nitrogen, lithium bis trimethylsilylamide (38.0 mL,38.0 mmol) was added, and after the addition was complete the reaction was stirred at-60℃for a further 1 hour; benzyl chloroformate (6.5 g,38.0 mmol) was slowly added dropwise to the reaction, kept stirring at-60 ℃ for 1 hour, TLC showed complete reaction of the starting material, the reaction solution was slowly warmed to room temperature, saturated aqueous ammonium chloride solution (200 mL) was added, stirred for 10 minutes, extracted with ethyl acetate (100 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/25) to give the title compound IN-2c (5.9 g, yield: 68%) as a yellow oily liquid.
Third step 3, 3-difluoro-1-methoxycarbonylcyclopentane-1-carboxylic acid IN-2d
Compound IN-2c (5.9 g,20.0 mmol) was dissolved IN methanol (100 mL), palladium on carbon (0.7 g, 10%) was added, and after 3 hydrogen substitutions, the mixture was stirred at room temperature under hydrogen for 2 hours; TLC detects complete reaction of starting material. The reaction solution was filtered through celite, and the filtrate was concentrated to give the title compound IN-2d (4.3 g, crude) as a yellow solid, which was used directly IN the next step.
Fourth step 1- (Boc) amino) -3, 3-Difluorocyclopentane-1-carboxylic acid methyl ester IN-2e
Compound IN-2d (4.3 g, crude product) was dissolved IN dry t-butanol (50 mL), diphenyl azide phosphate (8.4 g,30.6 mmol) and triethylamine (3.1 g,30.6 mmol) were added, and after the addition, the reaction mixture was warmed to 90℃and stirred for additional 12 hours, and TLC detection of complete reaction of starting material. The reaction was cooled to room temperature and quenched with water (100 mL), extracted with ethyl acetate (100 mL x 2), the combined organic phases dried over anhydrous sodium sulfate, concentrated, and the crude product purified by silica gel column chromatography (petroleum ether/ethyl acetate=3:1) to give the title compound IN-2e (2.5 g, 45% yield IN two steps) as a white solid.
Fifth step 1-amino-3, 3-difluorocyclopentane-1-carboxylic acid methyl ester trifluoroacetate salt IN-2f
Compound IN-2e (2.5 g,9.0 mmol) was dissolved IN dichloromethane (10 mL), trifluoroacetic acid (10 mL) was added, and the reaction was stirred at room temperature for 1 hour after the addition, and TLC detected complete reaction of starting materials. The reaction solution was concentrated under reduced pressure to give the title compound IN-2f (2.3 g, crude) as a brown oily liquid, which was used directly IN the next step.
Sixth step methyl 2, 2-difluoro-1- (3-methoxy-3-oxopropanamido) cyclopentane-1-carboxylate IN-2g
Compound IN-2f (2.3 g, crude product) was dissolved IN anhydrous dichloromethane (100 mL), cooled to 0 ℃ under nitrogen protection, triethylamine (4.5 g,44.5 mmol) was added, methyl malonate acyl chloride (1.5 g,10.7 mmol) was slowly added dropwise to the reaction solution after the addition was completed, and the reaction was continued to be stirred at 0 ℃ for 3 hours; TLC showed the starting material had reacted completely, the reaction solution was slowly warmed to room temperature, water (200 mL) was added and stirred for 10 minutes, then separated, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2:1) to give the title compound IN-2g (1.7 g, two-step yield: 68%) as a yellow oily liquid.
Seventh step 7.7-difluoro-1-azaspiro [4.4] nonane-2.4-dione IN-2h
Compound IN-2g (1.7 g,6.08 mmol) was dissolved IN anhydrous tetrahydrofuran (100 mL), cooled to 0deg.C under nitrogen protection, potassium tert-butoxide (1.0 g,8.9 mmol) was added IN portions, after addition was complete the reaction was warmed to 25deg.C and stirring was continued for 2 hours; TLC detects complete reaction of starting material. Dilute hydrochloric acid (100 ml,1 n) was added to the reaction solution and acidified to ph=5, the resulting solution was directly warmed to 85 ℃ without treatment, stirred and refluxed for 4 hours, and TLC detected complete reaction of the starting materials. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of the tetrahydrofuran solution, and after adding saturated solution prepared with anhydrous sodium sulfate, extracted with ethyl acetate (200 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, the crude product was slurried with petroleum ether (100 mL), suction filtered, and the filter cake was dried to give the title compound IN-2h (1.3 g, crude product) as a yellow solid, which was directly used IN the next step.
Eighth step 3.3.7.7-tetrafluoro-1-azaspiro [4.4] nonane-2.4-dione IN-2i
Compound IN-2h (1.3 g, crude) was dissolved IN acetonitrile (50 mL), 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (7.3 g,20.7 mmol) and water (50 mL) were added, and the reaction was continued stirring at room temperature for 12 hours after the addition, and TLC was used to detect complete reaction of starting materials. The reaction was concentrated under reduced pressure to remove acetonitrile, the mother liquor was extracted with ethyl acetate (100 ml x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound IN-2i (1.7 g, crude) as a gray solid, which was used directly IN the next step.
Ninth step 3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] non-2-one IN-2j
Compound IN-2i (1.7 g, crude) was dissolved IN methanol (100 mL), cooled to 0deg.C, sodium borohydride (0.42 g,11.1 mmol) was added, and the reaction was stirred at 0deg.C for 1 hour and TLC detected complete reaction. The reaction solution was concentrated under reduced pressure to give the title compound IN-2j (1.9 g, crude) as a white solid, which was used directly IN the next step.
Tenth step 3,3,7,7-tetrafluoro-1-azaspiro [4.4] non-4-ol IN-2
Compound IN-2j (1.9 g, crude product) was dissolved IN anhydrous tetrahydrofuran (100 mL), lithium aluminum hydride (1.3 mg,33.5 mmol) was added at room temperature, and after the addition, the reaction mixture was heated to 66℃and stirred for 2 hours, and TLC checked that the starting material was complete. The reaction mixture was cooled to 0deg.C, quenched with water (1.3 mL), sodium hydroxide solution (1.3 mL, 15%) and water (4.2 mL) IN this order, stirred at room temperature for 10 min, filtered off with suction, the filtrate dried over anhydrous sodium sulfate, and concentrated to give the title compound IN-2 (0.6 g, 31% combined IN three steps) as a white solid.
General synthetic route for oxamide series (Compounds 1-29 and 32-44):
acid (1.5 eq) was dissolved in anhydrous N, N-dimethylformamide (4V), intermediate amine (1 eq), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.5 eq) and N, N-diisopropylethylamine (2 eq) were added at room temperature, and the reaction mixture was stirred at room temperature for 18 hours, and TLC was checked for complete reaction of the starting materials. The reaction mixture was quenched with water (20V), extracted with ethyl acetate (10 v×3), the organic phases combined, washed with saturated brine (10V), dried over anhydrous sodium sulfate, concentrated, and the crude product purified by silica gel column chromatography (petroleum ether/ethyl acetate system or dichloromethane/methanol system) to give the title compound.
Synthesis example 3: synthesis of Compound 1
1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) butane-1, 2-dione 1
White solid, yield 88%.
LC-MS:m/z＝262.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-109.23,-120.95.
Synthesis example 4: synthesis of Compound 2
1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) pentane-1, 2-dione 2
White solid, yield 81%.
LC-MS:m/z＝276.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,DMSO-d 6 )δ-111.29,-119.02.
Synthesis example 5: synthesis of Compound 3
1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -4-methylpentane-1, 2-dione 3
White solid, yield 77%.
LC-MS:m/z＝290.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-109.30,-120.98.
Synthesis example 6: synthesis of Compound 4
1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -3- (3, 3-difluorocyclobutyl) propane-1, 2-dione 4
First step 1, 4-diacetyl-3- ((3, 3-difluorocyclobutyl) methylene) piperazine-2, 5-dione 4-2
Compound 4-1 (500 mg,4.16 mmol) and 1, 4-diacetylpiperazine-2, 5-dione (823mg, 4.16 mmol) were dissolved in methylene chloride (8 mL), 1, 8-diazabicyclo [5.4.0] undec-7-ene (633 mg,4.16 mmol) was added, and the reaction mixture was reacted at room temperature of 20℃for 3 hours. TLC showed little remaining starting material. The reaction mixture was washed with 5% citric acid solution (10 mL) and saturated brine (10 mL. Times.2), and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give the title compound 4-2 (293 mg,27% yield) as a white solid.
LC-MS:m/z＝259.1[M+H] + .
Second step 3- (3, 3-difluorocyclobutyl) -2-oxopropanoic acid 4-3
Compound 4-2 (293 mg,1.13 mmol) was dispersed in dilute hydrochloric acid (4 mL, 6M), and the suspension was heated to 110℃to react for 3 hours, and the starting material was dissolved. TLC (petroleum ether/ethyl acetate=2/1) showed the disappearance of starting material. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, and concentrated to give the title compound 4-3 (168 mg, yield 83%) as a brown feathered form.
LC-MS:m/z＝177.1[M-H] - .
Third step 1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] non-1-yl) -3- (3, 3-trifluorocyclobutyl) propane-1, 2-dione 4
Starting from compound 4-3 (66 mg,0.37 mmol) and compound IN-1 (66 mg,0.37 mmol), the title compound 4 (72 mg, 58% yield) was obtained as a white solid.
LC-MS:m/z＝338.2[M+H] + .
1 HNMR(400MHz,CDCl 3 )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).
19 FNMR(377MHz,CDCl 3 )δ-83.08,-94.68,-108.91,-120.96.
Synthesis example 7: synthesis of Compound 5
1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -5, 5-trifluoropentane-1, 2-dione 5
Colorless oily, yield 51%.
LC-MS:m/z＝330.2[M+H] + .
1 HNMR(400MHz,CDCl 3 )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).
19 FNMR(377MHz,CDCl 3 )δ-66.54,-108.87,-120.96.
Synthesis example 8: synthesis of Compound 6
4-cyclopropyl-1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) butane-1, 2-dione 6
First step (E) -4-cyclopropyl-2-oxo-but-3-enoic acid ethyl ester 6-2
Compound 6-1 (1.0 g,14.3 mmol) was dissolved in toluene (10 mL), ethyl (triphenylphosphine) pyruvate (2.69 g,7.13 mmol) was added, and the reaction mixture was heated to 100deg.C and stirred for 16 hours. TLC showed the reaction was complete. The reaction solution was concentrated under reduced pressure to remove most of the solvent, diluted with water (20 mL), extracted with ethyl acetate (30 mL), and the organic phase was washed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound 6-2 (610 mg, yield 25%) as a yellow liquid.
1 H NMR(400MHz,CDCl 3 )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).
Second step 4-cyclopropyl-2-oxobutanoic acid ethyl ester 6-3
Compound 6-2 (100 mg,0.59 mmol) was dissolved in acetonitrile (5 mL), diethyl 2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate (150 mg,0.59 mmol) was added, the addition was completed, nitrogen was replaced 3 times, a solution of magnesium perchlorate (133 mg,0.59 mmol) in acetonitrile (2 mL) was added, and the reaction mixture was stirred at room temperature for 5 hours. TLC showed the starting material disappeared. The reaction was quenched with water (10 mL), extracted with ethyl acetate (15 mL), washed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated to give the title compound 6-3 (65 mg, crude) as a yellow liquid, which was used directly in the next step.
Third step 4-cyclopropyl-2-oxobutanoic acid 6-4
Compound 6-3 (65 mg,0.38 mmol) was dissolved in a mixed solution of tetrahydrofuran (4 mL) and water (2 mL), sodium hydroxide (30 mg,0.75 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours after the addition. The reaction was quenched with water, acidified to ph=4, extracted with water (10 mL) and ethyl acetate (15 mL), and the organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate and concentrated to give the title compound 6-4 (46 mg, crude) as a yellow liquid, which was used directly in the next step.
Fourth step 4-cyclopropyl-1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) butane-1, 2-dione 6
Compound 6-4 (46 mg,0.32 mmol), compound IN-1 (57 mg,0.32 mmol) was dissolved IN N, N-dimethylformamide (4 mL), and N, N-diisopropylethylamine (83 mg,0.64 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (146 mg,0.38 mmol) were added sequentially. After addition, the reaction was allowed to react at room temperature for 16 hours, and TLC (petroleum ether/ethyl acetate=5/1) showed the disappearance of starting material. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 mL). The mixture was washed with saturated brine (10 mL. Times.3), and the organic phase was concentrated. Purification of the crude product by Prep-TLC (petroleum ether/ethyl acetate=10/1) gave the title compound 6 (12 mg, 7% yield in three steps) as a pale yellow oil.
LC-MS:m/z＝302.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-109.26,-120.97.
Synthesis example 9: synthesis of Compound 7
1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonane) -2- (4.4-difluorocyclohexyl) glyoxal 7
Referring to the synthesis of synthesis example 6, the title compound 7 was synthesized as a white solid in 9% overall yield starting from 4, 4-difluorocyclohexane-1-one.
LC-MS:m/z＝352.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-92.90,-101.51,-109.23,-120.10.
Synthesis example 10: synthesis of Compound 8
1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) hexane-1, 2-dione 8
White solid, yield 74%.
LC-MS:m/z＝290.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-109.27,-120.95.
Synthesis example 11: synthesis of Compound 9
1- (3-chloro-5-fluorophenyl) -2- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonane) glyoxal 9
White solid, yield 64%.
LC-MS:m/z＝362.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-108.21,-109.00,-120.81.
Synthesis example 12: synthesis of Compound 10
1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -3- (2, 2-difluorocyclopropyl) propane-1, 2-dione 10
First step 2, 2-difluoro-N-methoxy-N-methylcyclopropane-1-carboxamide 10-2
Compound 10-1 (2.0 g,16.4 mmol) was dissolved in dichloromethane (50 mL) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (4.7 g,24.6 mmol), N, O-dimethylhydroxylamine hydrochloride (1.9 g,19.7 mmol) and N, N-diisopropylethylamine (6.4 g,49.1 mmol) were added sequentially. After the addition, the mixture was reacted at 15℃for 3 hours at room temperature, and TLC showed the disappearance of starting material. The reaction mixture was quenched by addition of 1M dilute hydrochloric acid (50 mL), stirred for 2 min and then partitioned. The organic phase was washed with saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated to give the title compound 10-2 (1.58 g,58% yield) as a pale yellow solid.
1 H NMR(400MHz,CDCl 3 )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).
Second step 2, 2-difluorocyclopropane-1-carbaldehyde 10-3
Compound 10-2 (600 mg,3.69 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL), nitrogen was replaced 3 times, the dry ice bath was cooled to-65℃and diisobutylaluminum hydride (4.4 mL, 1M) was added dropwise thereto, and the temperature was controlled between-65℃and-60 ℃. After the completion of the dropping, the system was reacted under dry ice bath conditions for 3 hours. The reaction mixture was warmed to room temperature, anhydrous sodium sulfate and sodium sulfate decahydrate (3.0 g,9.31 mmol) were added, and after stirring for 20 minutes, the mixture was filtered through celite, and the filtrate (tetrahydrofuran solution of compound 10-3) was directly added to the next step.
Third step (Z) -2-acetoxy-3- (2, 2-difluorocyclopropyl) acrylic acid ethyl ester 10-4
Compound 10-3 (1.3 g,5.45 mmol) was dissolved in tetrahydrofuran (10 mL), nitrogen was substituted 3 times, lithium chloride (231 mg,5.45 mmol) was added, the mixture was cooled to 0℃in an ice bath, tetramethylguanidine (6278 mg,5.45 mmol) was added, the reaction was continued for 0.5 hours in an ice bath, a tetrahydrofuran solution (crude product of the above step) of mixture 3755-2 was added, and the reaction mixture was warmed to room temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (14 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 ml x 2), concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound 10-4 (205 mg, yield 24%) as a pale yellow liquid.
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-128.05,-139.40.
Fourth step 3- (2, 2-difluorocyclopropyl) -2-oxopropanoic acid 10-5
Compound 10-4 (100 mg,0.43 mmol) was dissolved in 6M hydrochloric acid (6 mL), warmed to 80℃and reacted for 2 hours, TLC showed the disappearance of starting material. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, and concentrated to give the title compound 10-5 (45 mg, yield 64%) as a brown liquid.
LC-MS:m/z＝163.1[M-H] - .
Fifth step 1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] non-1-yl) -3- (2, 2-difluorocyclopropyl) propane-1, 2-dione 10
Compound 10-5 (45 mg,0.27 mmol) and compound IN-1 (48 mg,0.27 mmol) were dissolved IN N, N-dimethylformamide (3 mL), and N, N-diisopropylethylamine (70 mg,0.54 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (123 mg,0.32 mmol) were added sequentially. After the addition, the reaction was allowed to react for 3 hours at 15℃at room temperature, and TLC showed the disappearance of starting material. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL). The mixture was washed with saturated brine (10 mL. Times.2), and the organic phase was concentrated. The crude product was purified by PreP-TLC (petroleum ether/ethyl acetate=3/1) to give the title compound 10 (45 mg, yield 51%) as a white solid.
LC-MS:m/z＝324.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-108.98,-120.94,-129.98,-142.85.
Synthesis example 13: synthesis of Compound 11
1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonane) -2- (3, 3-difluorocyclobutyl) glyoxal 11
First step 2- (3, 3-Difluorocyclobutyl) -2- ((trimethylsilyl) oxy) acetonitrile 11-1
Compound 4-1 (300 mg,2.50 mmol) and zinc iodide (79 mg,0.25 mmol) were dispersed in dichloromethane (10 mL), trimethylcyanosilane (277 mg,3.50 mmol) was added, and the reaction mixture was stirred at 20 ℃ for 2 hours, and TLC monitored complete reaction of the starting materials; the reaction solution was quenched with water (10 mL), extracted with dichloromethane (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/1) to give the title compound 11-1 (232 mg, yield 42.2%) as a colorless oil.
Second step 2- (3, 3-difluorocyclobutyl) -2-hydroxyacetic acid 11-2
Compound 11-1 (120 mg,0.55 mmol) was dissolved in dilute hydrochloric acid (2 mL, 6N), the reaction was allowed to react at 80℃for 4 hours, and TLC monitored for complete reaction of starting material; the reaction solution was concentrated to remove the solvent, and the residue was dissolved in ethyl acetate (10 mL), filtered, and the filtrate was concentrated again to give a crude product, which was slurried with methylene chloride/petroleum ether (3 mL, 1/1) to give the title compound 11-2 (52 mg, yield 57.1%) as a white solid.
LC-MS:m/z＝165.1[M-H] - .
Third step 2- (3, 3-difluorocyclobutyl) -2-oxoacetic acid 11-3
Compound 11-2 (170 mg,1.02 mmol) and 2-iodoxybenzoic acid (284 mg,1.02 mmol) were dissolved in dimethyl sulfoxide (3 mL), and the reaction was stirred at 50deg.C for 3 hours, and TLC monitored the completion of the starting material reaction; the reaction solution was cooled to room temperature, water (10 mL) was added to precipitate a solid, the solid was filtered, the filtrate was extracted with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound 11-3 (120 mg, crude product) as a colorless oil, which was used directly in the next step.
LC-MS:m/z＝163.1[M-H]-.
Fourth step 1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] non-1-yl) -2- (3, 3-trifluorocyclobutyl) ethane-1, 2-dione 11
Compound 11-3 (120 mg, crude product), compound IN-1 (129 mg,0.73 mmol) and N, N-diisopropylethylamine (141 mg,1.09 mmol) were dissolved IN N, N-dimethylformamide (2 mL), the reaction was cooled to 0deg.C under nitrogen protection, benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate (332 mg,0.87 mmol) was added, and after the addition, the reaction was stirred continuously at 26℃for 16 hours, and TLC monitored the reaction was complete; the reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated, and the crude product was purified by Prep-TLC (petroleum ether/ethyl acetate=4/1) to give the title compound 11 (87 mg, two step yield 26.4%) as a white solid.
LC-MS:m/z＝324.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,DMSO-d 6 )δ-82.23,-93.65,-111.22,-118.99.
Synthesis example 14: synthesis of Compounds 12 and 13
(S) -1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -3- (3-fluoro bicyclo [1.1.1] pentan-1-yl) propane-1, 2-dione (12);
(R) -1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -3- (3-fluoro-bicyclo [1.1.1] pentan-1-yl) propane-1, 2-dione (13)
Referring to the synthesis of synthesis example 12, the title compound was synthesized using 3-fluoro bicyclo [1.1.1] pentane-1-carboxylic acid as starting material. The mixture was resolved by chiral resolution to give the title compounds 12 and 13.
Chiral HPLC analysis method: nano-micro AD-5H, filler particle size (5 μm), inner diameter (4.6 mm), length (250 mm), flow rate: 1.0mL/min, ethanol: n-hexane=40:60, wavelength: 220/254nm.
Compound 12: white solid, yield 18%; retention time 6.527 min.
LC-MS:m/z＝332.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-108.69,-109.33,-120.84,-121.48,-144.84.
Compound 13: white solid, yield 15%; retention time 10.890 min.
LC-MS:m/z＝332.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-108.69,-109.33,-120.84,-121.48,-144.84.
Synthesis example 15: synthesis of Compounds 14 and 15
1- ((S) -3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -2- ((S) -3, 3-difluorocyclopentyl) glyoxal &1- ((R) -3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -2- ((R) -3, 3-difluorocyclopentyl) glyoxal (14-P1 and 14-P2);
1- ((S) -3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -2- ((R) -3, 3-difluorocyclopentyl) glyoxal &1- ((R) -3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -2- ((S) -3, 3-difluorocyclopentyl) glyoxal (15-P1 and 15-P2)
Referring to the synthesis of synthesis example 13, the title mixture was synthesized as a colorless oil starting from 3, 3-difluorocyclopentane-1-carbaldehyde. The mixture was resolved by chiral resolution to give a mixture of the title compounds 14-P1 and 14-P2 and a mixture of 15-P1 and 15-P2.
Chiral HPLC analysis method: nano-micro AD-5H, filler particle size (5 μm), inner diameter (4.6 mm), length (250 mm), flow rate: 1.0mL/min, isopropanol: n-hexane=10:90, wavelength: 220/254nm.
14-P1 and 14-P2: colorless oil, yield 1.5%, retention time 9.803 min.
LC-MS:m/z＝338.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )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 and 15-P2: colorless oil, yield 1.5%, retention time 12.027 min.
LC-MS:m/z＝338.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )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).
Synthesis example 16: synthesis of Compound 16
1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -3- (3-fluorocyclobutyl) propane-1, 2-dione (16)
First step benzyl-3-oxetane-1-carboxylic acid ester 16-2
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) were dispersed in acetonitrile (100 mL) and reacted at 50℃for 4 hours; TLC monitored complete reaction of starting material. The reaction solution was cooled to room temperature, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound 16-2 (17.0 g, yield: 94.98%) as a colorless oil.
LC-MS:m/z＝222.2[M+18].
Second step benzyl-3-hydroxycyclobutane-1-carboxylic acid ester 16-3
Compound 16-2 (4.0 g,19.6 mmol) was dissolved in methanol (10 mL), sodium borohydride (1.11 g,29.4 mmol) was added in portions under nitrogen protection at 0deg.C, and the reaction mixture was warmed to room temperature for 1 hour; TLC monitored complete reaction of starting material. The reaction mixture was quenched by the addition of dilute hydrochloric acid (2.0 mL, 2M), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound 16-3 (700 mg, yield: 17.33%) as a colorless oil.
Third step benzyl 3-fluorocyclobutane-1-carboxylate 16-4
Compound 16-3 (651 mg,3.16 mmol) was dissolved in tetrahydrofuran (10 mL), bis (2-methoxyethyl) aminothiotrifluoride (1.0 g,4.74 mmol) was added dropwise under nitrogen protection at-60℃and the reaction mixture was allowed to warm to room temperature for 16 hours; TLC monitored complete reaction of starting material. The reaction was cooled to 0deg.C, quenched by addition of sodium hydroxide solution (2.0 mL, 2M), extracted with ethyl acetate (50 mL. Times.2), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound 16-4 (222 mg, yield: 33.74%) as a colorless oil.
1 H NMR(400MHz,CDCl 3 )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).
Fourth step 3-fluorocyclobutane-1-carbaldehyde 16-5
Compound 16-4 (920 mg,4.42 mmol) was dissolved in dichloromethane (10 mL), diisobutylaluminum hydride (940 mg,6.63mmol, 1M) was added dropwise under nitrogen protection at-65℃and the reaction was continued for 3h; TLC (petroleum ether/ethyl acetate=20/1) monitored complete reaction of starting material. The reaction mixture was quenched by addition of dilute hydrochloric acid (5 mL, 2M), diluted with a solution of potassium sodium half-saturated tartrate (30 mL), the suspension was filtered through celite, the filtrate was separated, the organic phase was dried over anhydrous sodium sulfate, and the next reaction 16-5 (crude) was directly carried out by filtration.
Fifth step (Z) -1-acetyl-3- [ (3-fluorocyclobutyl) methylene ] piperazine-2, 5-dione 16-6
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 above step, and reacted at room temperature for 16 hours; TLC monitored complete reaction of starting material. The reaction was diluted with dilute hydrochloric acid (20 mL, 2M), extracted with dichloromethane (20 mL. Times.4), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound 16-6 (120 mg, yield: 11.35%) as a white solid.
1 H NMR(400MHz,CDCl 3 )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).
Sixth step 3- (3-fluorocyclobutyl) -2-oxopropanoic acid 16-7
Compound 16-6 (120 mg,0.50 mmol) was dispersed in dilute hydrochloric acid (6 mL, 6M), and the reaction mixture was heated to 100deg.C for 3 hours; TLC monitored complete reaction of starting material. The reaction solution was cooled to room temperature, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 16-7 (51 mg, yield: 63.69%) as a pale yellow oil.
LC-MS:m/z＝159.0[M-1] - .
Sixth step 1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] non-1-yl) -3- (3-fluorocyclobutyl) propane-1, 2-dione 16
Compound 16-7 (51 mg,0.32 mmol) and N, N-diisopropylethylamine (120 mg,0.97 mmol) were dissolved IN N, N-dimethylformamide (3 mL), cooled to 0℃under nitrogen protection, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (390 mg,0.39 mmol) was added IN portions, the reaction mixture was allowed to stand for 0.5 hours, IN-1 (57 mg,0.32 mmol) was added, and the reaction mixture was allowed to stand at room temperature for 2 hours; TLC monitored complete reaction of starting material. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give the title compound 16 (10 mg, yield: 9.79%) as a pale yellow solid.
LC-MS:m/z＝320.2[M+1] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-109.05,-121.00,-162.67.
Synthesis example 17: synthesis of Compounds 17-20
3- (3, 3-difluorocyclobutyl) -1- ((4 s,5 s) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) propane-1, 2-dione (17); 3- (3, 3-difluorocyclobutyl) -1- ((4 r,5 r) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) propane-1, 2-dione (18); 3- (3, 3-difluorocyclobutyl) -1- ((4 s,5 r) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) propane-1, 2-dione (19); 3- (3, 3-Difluorocyclobutyl) -1- ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) propane-1, 2-dione (20)
The title compound was synthesized from compound 4-3 and compound IN-2. The mixture was resolved by chiral resolution to give the title compounds 17-20.
Chiral HPLC analysis method: nano-micro AD-5H, filler particle size (5 μm), inner diameter (4.6 mm), length (250 mm), flow rate: 1.0mL/min, isopropanol: n-hexane=20:80, wavelength: 220/254nm.
Compound 17: white solid, yield 6.7%, retention time 5.823 min.
LC-MS:m/z＝372.1[M-H] - .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,DMSO-d 6 )δ-81.10,-88.61,-93.02,-94.12,-110.04,-119.86.
Compound 18: white solid, yield 3.2%, retention time 6.127 min.
LC-MS:m/z＝372.1[M-H] - .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,DMSO-d 6 )δ-81.09,-88.47,-91.52,-93.06,-112.98,-120.14.
Compound 19: white solid, yield 6.4%, retention time 7.216 min.
LC-MS:m/z＝372.1[M-H] - .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,DMSO-d 6 )δ-81.11,-88.61,-93.03,-94.12,-110.04,-119.86.
Compound 20: white solid, yield 4.1% and retention time 9.730 min.
LC-MS:m/z＝372.1[M-H] - .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,DMSO-d 6 )δ-81.09,-88.47,-91.51,-93.06,-112.98,-120.14.
Synthesis example 18: synthesis of Compounds 21-24
3- (3-fluoro-bicyclo [1.1.1] pentan-1-yl) -1- ((4 s,5 s) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) propane-1, 2-dione (21);
3- (3-fluoro-bicyclo [1.1.1] pentan-1-yl) -1- ((4 r,5 r) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) propane-1, 2-dione (22);
3- (3-fluoro-bicyclo [1.1.1] pentan-1-yl) -1- ((4 s,5 r) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) propane-1, 2-dione (23);
3- (3-Fluorobicyclo [1.1.1] pentan-1-yl) -1- ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) propane-1, 2-dione (24)
The title compound was synthesized from 3- (3-fluoro-bicyclo [1.1.1] pentan-1-yl) -2-oxopropionic acid and compound IN-2. The mixture was resolved by chiral resolution to give the title compounds 21-24.
Chiral HPLC analysis method: nano-micro AD-5H, filler particle size (5 μm), inner diameter (4.6 mm), length (250 mm), flow rate: 1.0mL/min, ethanol: n-hexane=20:80, wavelength: 220/254nm.
Compound 21: white solid, yield 7.5%, retention time 9.353 min.
LC-MS:m/z＝366.1[M-H] - .
1 HNMR(400MHz,CDCl 3 )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).
19 FNMR(377MHz,CDCl 3 )δ-92.09,-98,50,-108.37,-122.54,-144.91.
Compound 22: white solid, yield 7.3%, retention time 11.320 min.
LC-MS:m/z＝366.1[M-H] - .
1 HNMR(400MHz,CDCl 3 )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).
19 FNMR(377MHz,CDCl 3 )δ-92.09,-98,50,-108.37,-122.54,-144.91.
Compound 23: white solid, yield 3.2%, retention time 8.353 min.
LC-MS:m/z＝366.1[M-H] - .
1 HNMR(400MHz,CDCl 3 )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).
19 FNMR(377MHz,CDCl 3 )δ-90.17,-96.94,-109.88,-122.70,-144.87.
Compound 24: white solid, yield 3.0%, retention time 25.797 min.
LC-MS:m/z＝366.1[M-H] - .
1 HNMR(400MHz,CDCl 3 )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).
19 FNMR(377MHz,CDCl 3 )δ-90.17,-96.94,-109.88,-122.70,-144.87.
Synthesis example 19: synthesis of Compound 25
3- (3, 3-Difluorocyclobutyl) -1- (3, 6-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) propane-1, 2-dione (25)
First step 2, 2-difluoro-1- (3-methoxy-3-oxopropanamido) cyclopentane-1-carboxylic acid ethyl ester 25-2
Compound 25-1 (3.2 g,16.6 mmol) was dissolved in anhydrous dichloromethane (300 mL), cooled to 0deg.C under nitrogen protection, triethylamine (5.0 g,49.8 mmol) was added, methyl malonate acyl chloride (4.4 g,32.4 mmol) was slowly added dropwise, and the reaction was continued to stir at 0deg.C for 3 hours after the dropwise addition was completed; TLC showed complete reaction of the starting material, the reaction was slowly warmed to room temperature, water (200 mL) was added and stirred for 10 min, then the separated solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (EA: pe=1:2) to give the title compound 25-2 (2.9 g, yield: 60%) as a yellow oily liquid.
Second step 6.6-difluoro-1-azaspiro [4.4] nonane-2.4-dione 25-3
Compound 25-2 (2.9 g,9.9 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), cooled to 0deg.C under nitrogen protection, potassium tert-butoxide (1.7 g,14.5 mmol) was added in portions, after the addition was complete, the reaction was warmed to 25deg.C and stirring was continued for 2 hours; TLC detects complete reaction of starting material. Dilute hydrochloric acid (20 ml,1 n) is added to the reaction solution to acidify to about ph=5, the obtained solution is directly heated to 85 ℃ without treatment, then stirred and refluxed for 4 hours, and TLC detects that the reaction of the raw materials is complete. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of the tetrahydrofuran solution, and after adding anhydrous sodium sulfate to prepare a saturated solution, ethyl acetate (200 mL x 3) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, the crude product was slurried with petroleum ether (100 mL), filtered with suction, and the filter cake was dried to give the title compound 25-3 (1.6 g, yield 97%) as a yellow solid.
Third step 3.3.6.6-tetrafluoro-1-azaspiro [4.4] nonane-2.4-dione 25-4
Compound 25-3 (2.1 g,27.0 mmol) was dissolved in acetonitrile (100 mL), 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (24.0 g,67.5 mmol) and water (100 mL) were added, and the reaction was continued to stir at room temperature for 12 hours after the addition, and TLC was used to detect complete reaction of starting materials. The reaction was concentrated under reduced pressure to remove acetonitrile, the mother liquor was extracted with ethyl acetate (200 ml x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound 25-4 (5.8 g, crude) as a gray solid, which was used directly in the next step.
Fourth step 3, 6-tetrafluoro-4-hydroxy-1-azaspiro [4.4] non-2-one 25-5
Compound 25-4 (5.8 g, crude product) was dissolved in methanol (100 mL), cooled to 0deg.C, sodium borohydride (1.5 g,38.8 mmol) was added, and the reaction was stirred at 0deg.C for 1 hour, and TLC checked the completion of the starting material reaction. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (100 mL), after stirring at room temperature for 10 min, the reaction was concentrated under reduced pressure to remove most of the methanol, the residue was extracted with ethyl acetate (100 mL. Times.4), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound 25-5 (5.1 g, 83% combined in two steps) as a white solid.
Fifth step 3, 6-tetrafluoro-1-azaspiro [4.4] non-4-ol 25-6
Compound 25-5 (4.3 g,18.9 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL), borane dimethyl sulfide solution (47.3 mL,94.5 mmol) was added at room temperature, the reaction was heated to 60℃and stirred for 2 hours, and TLC detected complete reaction of starting materials. After the reaction solution was cooled to 0 ℃, methanol (50 mL) was slowly added dropwise, the reaction was continued to be stirred at 60 ℃ for 60 minutes after the completion of the addition, and after the completion of the reaction, it was cooled to room temperature, concentrated, and the crude product was purified by silica gel column chromatography (EA/pe=30%) to give the title compound 25-6 (2.9 g, yield 72%) as a white solid.
Sixth step 3- (3, 3-difluorocyclobutyl) -1- (3, 6-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) propane-1, 2-dione 25
Compound 4-3 (170 mg,0.95 mmol), compound 25-6 (185 mg,0.87 mmol) and N, N-diisopropylethylamine (168 mg,1.30 mmol) were dissolved in N, N-dimethylformamide (3 mL), the reaction mixture was cooled to 0℃under nitrogen protection, benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate (397 mg,1.04 mmol) was added, and after the addition, the reaction mixture was stirred for 16 hours at 26℃and the reaction was monitored by TLC for completion; the reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give the crude product purified by Prep-TLC (petroleum ether/ethyl acetate=3/1) as a white solid, title compound 25 (20 mg, yield 6.1%).
LC-MS:m/z＝372.1[M-H] - .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,DMSO-d 6 )δ-81.00,-93.36,-97.00,-100.96,-107.45,-116.64.
Synthesis example 20: synthesis of Compound 26
1- (3,3,8,8-tetrafluoro-4-hydroxy-1-azaspiro [4.5] decan-1-yl) butane-1, 2-dione (26)
First step 8, 8-difluoro-1, 3-diazaspiro [4.5] decane-2, 4-dione 26-2
4, 4-Difluorocyclohexanone 26-1 (5.0 g,37.28 mmol) was dissolved in a mixed solution of ethanol (80 mL) and water (60 mL), ammonium carbonate (14.3 g,149.11 mmol) and trimethylcyanosilane (7.4 g,74.56 mmol) were added in this order, the reaction mixture was warmed to 70℃after the addition, and reacted for 18 hours, and TLC (Petroleum ether/ethyl acetate=10/1, phosphomolybdic acid color development) showed the disappearance of the starting material. The reaction was cooled to room temperature, ethanol was concentrated off, ice water (50 mL) was added and stirred under an ice bath for 30 minutes. The reaction solution was suction-filtered, and the cake was dried to give the title compound 26-2 (7.2 g, yield 95%) as a silvery white flaky solid.
1 HNMR(400MHz,DMSO-d 6 )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).
Second step 1-amino-4, 4-difluorocyclohexane-1-carboxylic acid 26-3
Compound 26-2 (7.1 g,34.8 mmol) was dissolved in aqueous potassium hydroxide (150 mL, 30%) and the reaction was warmed to 110℃and stirred for 16 hours, cooled to 65℃and concentrated to remove approximately 75% of the water, cooled again to 0℃and then slowly added dropwise with concentrated hydrochloric acid (80 mL) until pH=2, stirred for 30 minutes at 0℃and cold filtered, the filter cake was rinsed with methanol (100 mL x 2), the mother liquors were combined and concentrated to give the title compound 26-3 as a white solid (crude product) which was used directly in the next step.
Third step 1-amino-4, 4-difluorocyclohexane-1-carboxylic acid methyl ester hydrochloride 26-4
The mixture 26-3 (crude product) was dissolved in methanol (150 mL), thionyl chloride (8.3 g,69.6 mmol) was slowly added dropwise at 0deg.C, and the reaction solution was slowly warmed to 70deg.C under nitrogen protection after the addition, stirred for 16 hours, and concentrated under reduced pressure to give the title compound 26-4 (crude product) as a white solid, which was directly used in the next step.
LC-MS:m/z＝194.1[M+H] + .
Fourth step 4, 4-difluoro-1- (3-methoxy-3-oxopropanamido) cyclohexane-1-carboxylic acid methyl ester 26-5
Dissolving compound 26-4 (crude product) in anhydrous dichloromethane (300 mL), cooling to 0 ℃ under the protection of nitrogen, adding triethylamine (14.0 g,369.2 mmol), slowly dropwise adding methyl malonate acyl chloride (7.1 g,52.2 mmol) after the addition, and continuously stirring the reaction solution at 0 ℃ for 3 hours; TLC detection of the completion of the reaction starting material, slow warming to room temperature, water (200 mL) stirring for 10 minutes followed by separation of the solution, drying of the organic phase over anhydrous sodium sulfate, concentration, purification of the crude product by silica gel column chromatography (ethyl acetate: petroleum ether=1:2) gave the title compound 26-5 (3.8 g, four-step yield: 37%) as a colorless oily liquid.
LC-MS:m/z＝294.2[M+H] + .
Fifth step 8, 8-difluoro-1-azaspiro [4.5] decane-2, 4-dione 26-6
Compound 26-5 (3.8 g,13.0 mmol) was dissolved in anhydrous tetrahydrofuran (300 mL), cooled to 0deg.C under nitrogen protection, potassium tert-butoxide (2.2 g,19.5 mmol) was added in portions, the reaction solution was warmed to 25deg.C and stirred for 2 hours; TLC detects complete reaction of starting material. Dilute hydrochloric acid (25 ml,1 n) was added to the reaction solution to adjust ph=5, and after the reaction solution was continuously warmed to 80 ℃, the reaction solution was stirred and refluxed for 4 hours, and TLC was used to detect that the reaction of the starting materials was complete. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of the tetrahydrofuran solution, saturated solution (100 mL) prepared by anhydrous sodium sulfate was added, extracted with ethyl acetate (200 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was slurried with petroleum ether (100 mL), suction filtered, and the filter cake was dried to give the title compound 26-6 (2.0 g, yield 76%) as a yellow solid.
Sixth step 3,3,8,8-tetrafluoro-1-azaspiro [4.5] decane-2, 4-dione 26-7
Compound 26-6 (2.0 g,9.8 mmol) was dissolved in acetonitrile (50 mL), 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (10.4 g,29.4mmol and water (50 mL) were added at room temperature, the reaction was continued to stir at room temperature for 12 hours after the addition, TLC detected complete reaction starting material was concentrated under reduced pressure to remove acetonitrile, the mother liquor was extracted with ethyl acetate (200 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound 26-7 (3.4 g, crude product) as a gray solid, which was used directly in the next step.
LC-MS:m/z＝238.0[M-H] - .
Seventh step 3,3,8,8-tetrafluoro-4-hydroxy-1-azaspiro [4.5] decan-2-one 26-8
Compound 26-7 (3.4 g,14.2 mmol) was dissolved in methanol (100 mL), cooled to 0deg.C, sodium borohydride (806 m g,21.3 mmol) was added, and the reaction was stirred at 0deg.C for 1 hour and was complete by TLC. The reaction solution was concentrated under reduced pressure to give the title compound 26-8 (4.2 g, crude) as a white solid, which was used directly in the next step.
Eighth step 3,3,8,8-tetrafluoro-1-azaspiro [4.5] decan-4-ol 26-9
Compound 26-8 (4.2 g, crude product) was dissolved in anhydrous tetrahydrofuran (150 mL), lithium aluminum hydride (2.1 g,56.8 mmol) was added in portions at 0deg.C, and the reaction mixture was heated to 66deg.C after the addition was stirred for 2 hours, and TLC detected complete reaction of the starting materials. The reaction solution was cooled to 0℃and quenched with water (2.1 mL), sodium hydroxide solution (2.1 mL, 15%) and water (6.3 mL) in this order, the reaction was stirred at room temperature for 10 minutes, suction filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to give the title compound 26-9 (2.0 g, three-step combined yield 90%) as a white solid.
LC-MS:m/z＝228.2[M+H] + .
Ninth step 1- (3,3,8,8-tetrafluoro-4-hydroxy-1-azaspiro [4.5] decan-1-yl) butane-1, 2-dione 26
2-oxo-butyric acid (50 mg,0.49 mmol) and Compound 26-9 (111 mg,0.49 mmol) were dissolved in N, N-dimethylformamide (4 mL), and N, N-diisopropylethylamine (127 mg,0.98 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (224 mg,0.59 mmol) were added sequentially. After addition, the reaction was allowed to react at room temperature for 18 hours, and TLC showed the disappearance of starting material. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL). The mixture was washed with saturated brine (10 mL. Times.3), and the organic phase was concentrated. Purification of the crude product by Prep-TLC (petroleum ether/ethyl acetate=5/1) gave the title compound 26 (69 mg, 45% yield) as a white solid.
LC-MS:m/z＝312.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-93.99,-101.94,-104.74,-121.96.
Synthesis example 21: synthesis of Compound 27
2- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -N-ethyl-2-oxoacetamide (27)
White solid, yield 88%.
LC-MS:m/z＝299.2[M+Na] + .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,DMSO-d 6 )δ-111.33,-119.15.
Synthesis example 22: synthesis of Compound 28
2- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -N-methyl-2-oxoacetamide (28)
White solid, yield 91%.
LC-MS:m/z＝285.1[M+Na] + .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,DMSO-d 6 )δ-111.33,-119.18.
Synthesis example 23: synthesis of Compound 29
2- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -2-oxoacetic acid ethyl ester (29)
White solid, yield 62%.
LC-MS:m/z＝278.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,DMSO-d 6 )δ-111.57,-119.22.
Synthesis example 24: synthesis of Compound 30
2- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -N-methylacetamide (30)
Compound IN-1 (50 mg,0.28 mmol) was dissolved IN DMF (1 mL), potassium carbonate (87 mg,0.63 mmol) and 2-chloro-N-methylacetamide (45 mg,0.42 mmol) were added, and the reaction was warmed to 50℃and stirred for 2 days. TLC showed that most of the starting material was consumed. The reaction solution was cooled to room temperature, diluted with water (3 mL), extracted with ethyl acetate (5 mL. Times.2), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE/ea=20/1-3/1) to give the title compound 30 (5.95 mg, yield: 5.7%) as a colorless transparent semi-solid.
LC-MS：m/z＝249.2[M+H] + .
1 H NMR(DMSO-d 6 ,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).
19 F NMR(377MHz,DMSO-d 6 )δ-98.64,-106.52.
Synthesis example 25: synthesis of Compound 31
2- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -N- (3, 3-difluorocyclobutyl) acetamide (31)
First step 2-bromo-N- (3, 3-difluorocyclobutyl) acetamide 31-2
Compound 31-1 (300 mg,2.09 mmol) and triethylamine (428 mg,4.17 mmol) were dissolved in dichloromethane (4.5 mL), the reaction solution was cooled to 0deg.C, 2-bromoacetyl chloride (361 mg,2.30 mmol) was added, and after the addition, the reaction solution was stirred continuously at 0deg.C for 1 hour, and TLC monitored the starting material was complete; the reaction solution was quenched with water (10 mL), extracted with dichloromethane (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound 31-2 (100 mg, yield 21.1%) as a white solid.
LC-MS:m/z＝228.0[M+H] + .
Second step 2- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] non-1-yl) -N- (3, 3-trifluorocyclobutyl) acetamide 31
Compound 31-2 (100 mg,0.44 mmol), compound IN-1 (77 mg,0.44 mmol) and potassium carbonate (91 mg,0.66 mmol) were dispersed IN N, N-dimethylformamide (2 mL), the reaction was warmed to 45℃for 24 hours, the TLC monitored the completion of the reaction, the reaction was quenched with water (6 mL), extracted with ethyl acetate (15 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated, and the crude product was purified by Prep-TLC (Petroleum ether/ethyl acetate=2/1) to give the title compound 31 (26 mg, yield 18.6%) as a white solid.
LC-MS:m/z＝325.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-85.26,-97.26,-98.73,-109.97.
Synthesis example 26: synthesis of Compound 32
1- (2- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -2-oxoethyl) pyrrolidin-2-one 32
White solid, yield 14%.
LC-MS:m/z＝303.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,DMSO-d 6 )δ-109.98,-117.86.
Synthesis example 27: synthesis of Compounds 33-36
N- (3-fluoro-bicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (33);
n- (3-fluoro-bicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4 r,5 r) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (34);
n- (3-fluoro-bicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4S, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (35);
N- (3-Fluorobicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (36)
First step tert-butyl N- (3-fluoro-bicyclo [1.1.1] pent-1-yl) carbamate 33-2
Compound 33-1 (0.5 g,3.84 mmol), triethylamine (0.47 g,4.61 mmol) and diphenyl azide phosphate (1.22 g,4.42 mmol) were dissolved in toluene (8 mL), and reacted under nitrogen at 85℃for 3 hours, t-butanol (0.34 g,4.61 mmol) was added, and after the addition, the reaction was continued with continued heat preservation until 16 disappeared; TLC monitored complete reaction of starting material. The reaction solution was cooled to room temperature, diluted with water (40 mL), extracted with ethyl acetate (50 ml×2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give the title compound 33-2 (155 mg, yield: 20.06%) as a colorless oil.
1 H NMR(400MHz,CDCl 3 )δ7.73(s,1H),2.28(d,J＝2.0Hz,6H),1.45(s,9H).
Second step benzyl 3-hydroxycyclobutane-1-carboxylate 33-3
Compound 33-2 (155 mg,0.77 mmol) was dissolved in ethanol solution of hydrogen chloride (10 mL, 2M) and reacted at room temperature for 2h; TLC monitored complete reaction of starting material. The reaction solution was concentrated directly to give the title compound 33-3 (134 mg, yield: 100%) as a white solid.
Third step ethyl [ (3-fluoro-bicyclo [1.1.1] pent-1-yl) carbamoyl ] formate 33-4
Compound 33-3 (134 mg,0.77 mmol) and triethylamine (0.39 g,3.85 mmol) were dissolved in dichloromethane (5 mL), and ethyl 2-chloro-2-oxoacetate (100 mg,0.73 mmol) was added dropwise under nitrogen at 0℃to react at room temperature for 16 hours; TLC monitored complete reaction of starting material. The reaction solution was directly concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give the title compound 33-4 (146 mg, yield: 94.24%) as a pale yellow oil.
LC-MS:m/z＝202.2[M+1] + .
Fourth step [ (3-fluoro-bicyclo [1.1.1] pent-1-yl) carbamoyl ] carboxylic acid 33-5
Compound 33-4 (146 mg,0.73 mmol) was dissolved in tetrahydrofuran (5 mL), and a mixed solution of lithium hydroxide (90 mg,2.19 mmol) and water (1 mL) was added to react at room temperature for 2 hours; TLC monitored complete reaction of starting material. Dilute hydrochloric acid (2 mL,2 m) was added to adjust the acid to ph=2, extracted with ethyl acetate (10 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound 33-5 (118 mg, yield: 94.24%, crude product) as a yellow solid.
LC-MS:m/z＝172.1[M-1] - .
Fifth step N- (3-Fluorobicyclo [1.1.1] pent-1-yl) -2-oxo-2- (3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide 33-6
Compound 33-5 (50 mg,0.29 mmol), intermediate IN-2 (62 mg,0.29 mmol) and N, N-diisopropylethylamine (110 mg,0.87 mmol) were dissolved IN N, N-dimethylformamide (3 mL), cooled to 0℃under nitrogen, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (120 mg,0.32 mmol) was added IN portions, and the reaction mixture was warmed to room temperature for 2 hours; TLC monitored complete reaction of starting material. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (20 mL), the combined organic phases washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated before purification by Pre-TLC (petroleum ether/ethyl acetate=4/1) and chiral resolution to give compounds 33-36.
Chiral HPLC analysis method: nano-micro AD-5H, filler particle size (5 μm), inner diameter (4.6 mm), length (250 mm), flow rate: 1.0mL/min, ethanol: n-hexane=20:80, wavelength: 220/254nm.
Compound 33: white solid, yield 9.3%, retention time 8.800 min.
LC-MS:m/z＝369.1[M+1] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-92.18,-98.69,-108.24,-122.52,-167.47.
Compound 34: white solid, yield 6.5%, retention time 10.687 min.
LC-MS:m/z＝369.1[M+1] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-92.18,-98.69,-108.24,-122.52,-167.47.
Compound 35: white solid, yield 1.9%, retention time 7.617 min.
LC-MS:m/z＝369.1[M+1] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-90.29,-96.86,-109.96,-122.64,-167.47.
Compound 36: white solid, yield 1.8%, retention time 12.373 min.
LC-MS:m/z＝369.1[M+1] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-90.29,-96.86,-109.96,-122.64,-167.47.
Synthesis example 28: synthesis of Compound 37,38
N- (3-chlorobicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (3-chlorobicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4R, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (37-P1 and 37-P2);
n- (3-chlorobicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4S, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (3-chlorobicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (38-P1 and 38-P2)
Referring to the synthesis of synthesis example 27, using 3-chlorobicyclo [1.1.1] pentan-1-amine hydrochloride as a starting material, the title compounds 37 and 38 were synthesized, and further chiral resolution was performed to give compounds 37-P1, 37-P2, 38-P1 and 38-P2.
Chiral HPLC analysis method: nano-micro AD-5H, filler particle size (5 μm), inner diameter (4.6 mm), length (250 mm), flow rate: 1.0mL/min, ethanol: n-hexane=40:60, wavelength: 220nm.
Compound 37-P1: white solid, yield 10.5%, retention time 4.800 min.
LC-MS:m/z＝383.1[M-1] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-90.28,-96.83,-109.97,-122.64.
Compound 37-P2: white solid, yield 14.7%, retention time 6.643 min.
LC-MS:m/z＝383.1[M-1] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-90.28,-96.83,-109.97,-122.64.
Compound 38-P1: white solid, yield 7.1% and retention time 5.090 min.
LC-MS:m/z＝385.1[M+1] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-91.94,-98.68,-108.23,-122.51.
Compound 38-P2: white solid, yield 5.6%, retention time 8.937 min.
LC-MS:m/z＝385.1[M+1] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-92.18,-98.68,-108.23,-122.51.
Synthesis example 29: synthesis of Compound 39,40
N- (1-methyl-3-oxocyclobutyl) -2-oxo-2- ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (1-methyl-3-oxocyclobutyl) -2-oxo-2- ((4R, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (39-P1 and 39-P2);
n- (1-methyl-3-oxocyclobutyl) -2-oxo-2- ((4S, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (1-methyl-3-oxocyclobutyl) -2-oxo-2- ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (40-P1 and 40-P2)
First step ethyl 2-oxo-2- (3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetate 39-1
Compound IN-2 (70 mg,0.33 mmol) was dissolved IN dichloromethane (6 mL) and triethylamine (66 mg,0.66 mmol) and oxalyl chloride monoethyl ester (49 mg,0.36 mmol) were added. The reaction was carried out at room temperature for 1 hour. TLC detects complete reaction of starting material. The reaction was quenched with water (10 mL), extracted with dichloromethane (50 mL x 2), the combined organic layers were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by Pre-TLC (PE/ea=4/1) to give the title compound 39-1 as a white solid (47 mg, yield 45.47%).
Second step 2-oxo-2- (3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetic acid 39-2
To a mixed solution of tetrahydrofuran (3 mL) and water (3 mL) was dissolved compound 39-1 (47 mg,0.15 mmol), and lithium chloride (7.18 mg,0.30 mmol) was added. After the addition, the reaction was carried out at room temperature for 1 hour. TLC detects complete reaction of starting material. The reaction solution was acidified to ph=2 with dilute hydrochloric acid (2 mL,3 n), diluted with water (10 mL), extracted with ethyl acetate (50 mL x 2), the organic layers were combined and washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 39-2 as a white solid (42 mg, yield 98.18%).
Third step N- (3-hydroxy bicyclo [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
Compound 39-2 (42 mg,0.15 mmol) and 1-methyl-3-oxocyclobutane-1-amine hydrochloride (0.15 mmol) are dissolved in DMF (5 mL) and HATU (68 mg,0.18 mmol) and N, N-diisopropylethylamine (58 mg,0.45 mmol) are added. After the addition, the reaction was carried out at room temperature for 1 hour. TLC detects complete reaction of starting material. The reaction was quenched with water (10 mL), extracted with ethyl acetate (50 mL x 2), the combined organic layers were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by Pre-TLC (PE/ea=2/1) to give the title compound 39-P1 and 39-P2 as a mixture of 40-P1 and 40-P2 as a white solid.
39-P1 and 39-P2: white solid, yield 28.9%.
LC-MS:m/z＝367.2[M+1] +
1 H NMR(400MHz,CDCl 3 )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),.
19 F NMR(377MHz,CDCl 3 )δ-92.14,-98.47,-108.17,-122.44.
40-P1 and 40-P2: white solid, yield 6.9%.
LC-MS:m/z＝367.2[M+1] +
1 H NMR(400MHz,CDCl 3 )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),.
19 F NMR(377MHz,CDCl 3 )δ-90.31,-96.49,-109.88 -122.53.
Synthesis example 30: synthesis of Compounds 41,42
N- (3- (difluoromethyl) bicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (3- (difluoromethyl) bicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4R, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (41-P1 and 41-P2);
n- (3- (difluoromethyl) bicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4S, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (3- (difluoromethyl) bicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (42-P1 and 42-P2)
Referring to the synthesis of Synthesis example 27, using 3- (difluoromethyl) bicyclo [1.1.1] pentan-1-amine hydrochloride as a starting material, a mixture of the title compounds 41-P1 and 41-P2 and a mixture of 42-P1 and 42-P2 were synthesized.
41-P1 and 41-P2: white solid, yield 30.9%.
LC-MS:m/z＝401.2[M+1] +
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-92.20,-98.72,-108.26,-121.19,122.52.
42-P1 and 42-P2: white solid, yield 8.2%.
LC-MS:m/z＝401.2[M+1] +
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-90.30,-96.89,-110.02,-121.19,122.65.
Synthesis example 31: synthesis of Compounds 43,44
N- (3- (trifluoromethyl) bicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (3- (trifluoromethyl) bicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4R, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (43-P1 and 43-P2);
n- (3- (trifluoromethyl) bicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4S, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (3- (trifluoromethyl) bicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (44-P1 and 44-P2)
Referring to the synthesis of Synthesis example 27, using 3- (trifluoromethyl) bicyclo [1.1.1] pentan-1-amine hydrochloride as a starting material, a mixture of the title compounds 43-P1 and 43-P2 and a mixture of 44-P1 and 44-P2 were synthesized.
43-P1 and 43-P2: white solid, yield 29.9%.
LC-MS:m/z＝419.2[M+1] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-71.39,-92.20,-98.68,-108.22,-122.36.
44-P1 and 44-P2: white solid, yield 6.8%.
LC-MS:m/z＝419.2[M+1] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-71.39,-90.29,-96.84,-109.93,-122.63.
Synthesis example 32: synthesis of Compounds 45,46
N- (3-methylbicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (3-methylbicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4R, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (45-P1 and 45-P2);
N- (3-Methylbicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4S, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (3-methylbicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (46-P1 and 46-P2)
Referring to the synthesis of synthesis example 27, using 3-methylcyclo [1.1.1] pentan-1-amine hydrochloride as the starting material, a mixture of the title compounds 45-P1 and 45-P2 and a mixture of 46-P1 and 46-P2 were synthesized.
Mixture of 45-P1 and 45-P2: white solid, yield 42.4%.
LC-MS:m/z＝365.1[M+1] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-95.20,-115.12.
46-P1 and 46-P2: white solid, yield 18.0%.
LC-MS:m/z＝365.1[M+1] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-93.35,-116.15.
Synthesis example 33: synthesis of Compounds 47,48
N- (3-cyanobicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (3-cyanobicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4R, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (47-P1 and 47-P2);
n- (3-cyanobicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4S, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (3-cyanobicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (48-P1 and 48-P2)
Referring to the synthesis of Synthesis example 27, using 3-cyanobicyclo [1.1.1] pent-1-amine hydrochloride as a starting material, a mixture of the title compounds 47-P1 and 47-P2 and a mixture of 48-P1 and 48-P2 were synthesized.
47-P1 and 47-P2: white solid, yield 13.3%.
LC-MS:m/z＝376.2[M+1] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-92.22,-98.68,-108.17,-122.50.
48-P1 and 48-P2: white solid, yield 5.1%.
LC-MS:m/z＝374.1[M-1] - .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,CDCl 3 )δ-90.28,-96.79,-109.82,-122.63.
Synthesis example 34: synthesis of Compound 49,50
N- (3, 3-difluorocyclobutyl) -2-oxo-2- ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (3, 3-difluorocyclobutyl) -2-oxo-2- ((4R, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (49-P1 and 49-P2);
n- (3, 3-difluorocyclobutyl) -2-oxo-2- ((4S, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (3, 3-difluorocyclobutyl) -2-oxo-2- ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (50-P1 and 50-P2);
referring to the synthesis of synthesis example 27, using 3, 3-difluorocyclobutane-1-amine hydrochloride as the starting material, a mixture of the title compounds 49-P1 and 49-P2 and a mixture of 50-P1 and 50-P2 were synthesized.
49-P1 and 49-P2: white solid, yield 27%.
LC-MS:m/z＝375.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-84.45,-91.89,-97.29,-98.29,-107.86,-122.12.
50-P1 and 50-P2: white solid, yield 9%.
LC-MS:m/z＝375.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-84.45,-90.03,-96.40,-97.28,-109.57,-122.24.
Synthesis example 35: synthesis of Compound 51
2- (9, 9-difluoro-10-hydroxy-6-azaspiro [4.5] decan-6-yl) -N- (3, 3-difluorocyclobutyl) -2-oxoacetamide (51)
First step 1- ((4-methoxy-4-oxobutyl) amino) cyclopentane-1-carboxylic acid methyl ester 51-2
Compound 51-1 (2.0 g,4.11 mmol) was dissolved in N, N-dimethylformamide (16 mL), and methyl 4-bromobutyrate (2.0 g,11.13 mmol) and potassium carbonate (3.8 g,27.83 mmol) were added. After the addition, the reaction solution was heated to 100℃and reacted for 10 hours. TLC (petroleum ether/ethyl acetate=4/1, iodine color development) showed that there was a small amount of starting material remaining. The reaction mixture was cooled to room temperature, quenched with water (20 mL), and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (50 mL. Times.2) and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=4/1) to give the title compound 51-2 (2.0 g,74% yield) as a colorless liquid.
LC-MS:m/z＝244.2[M+H] + .
Second step 10-oxo-6-azaspiro [4.5] decane-9-carboxylic acid methyl ester 51-3
Compound 51-2 (1.0 g,4.11 mmol) was dissolved in 1, 4-dioxane (10 mL) and sodium methoxide (333 mg,6.17 mmol) was added. After the addition, the reaction mixture was warmed to 100 ℃ and reacted for 4 hours, and TLC (petroleum ether/ethyl acetate=1/1, iodine color development) showed the disappearance of the starting material. The reaction solution was cooled, acidified to ph=1 by dropwise addition of 1M diluted hydrochloric acid, further alkalified to ph=9-10 with saturated sodium carbonate solution, extracted with ethyl acetate (30 mL), and the organic phase was washed with saturated brine (20 ml×2), dried over anhydrous sodium sulfate, and concentrated to give the title compound 51-3 (700 mg, yield 81%) as a yellow liquid.
LC-MS:m/z＝244.2[M+CH 3 OH+H] + .
Third step 6-azaspiro [4.5] decan-10-one hydrochloride 51-4
Compound 51-3 (700 mg,3.31 mmol) was dissolved in concentrated hydrochloric acid (3 mL) and reacted at 95℃for 1.5 hours, TLC (dichloromethane/methanol=20/1) indicated complete reaction of the starting material. The reaction was cooled to room temperature and concentrated to give the title compound 51-4 (crude, directly added next step) as a pale yellow oil.
LC-MS:m/z＝154.2[M-Cl+H] + .
Fourth step 10-oxo-6-azaspiro [4.5] decane-6-carboxylic acid tert-butyl ester 51-5
Compound 51-4 (crude) was dissolved in methanol (10 mL), cooled to 0deg.C in an ice bath, and triethylamine (1.0 g,9.93 mmol) and di-tert-butyl dicarbonate (1.1 g,4.97 mmol) were added. After the addition, the reaction mixture was reacted at room temperature of 20℃for 3 hours, and TLC (Petroleum ether/ethyl acetate=4/1, phosphomolybdic acid color development) showed little polar spot formation. The reaction mixture was concentrated, and ethyl acetate (10 mL) and water (10 mL) were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to give the title compound 51-5 (358 mg, 43% in two steps) as a colorless liquid.
LC-MS:m/z＝154.2[M-100+H] + .
Fifth step 9, 9-difluoro-10-oxo-6-azaspiro [4.5] decane-6-carboxylic acid tert-butyl ester 51-6
Compound 51-5 (358 mg,1.41 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL), nitrogen was replaced 3 times, the dry ice bath was cooled to-60℃and lithium bis (trimethylsilyl) amide (3.5 mL, 1M) was added dropwise, the reaction was completed at-60-55℃for 40 minutes in the dry ice bath, a tetrahydrofuran solution (6 mL) of N-fluorobis (benzenesulfonamide) (927 mg,2.94 mmol) was added dropwise, the reaction was continued at-60-50℃for 2 hours in the dry ice bath, the dry ice bath was removed, and the reaction was slowly warmed to room temperature for 18 hours. TLC (petroleum ether/ethyl acetate=4/1, phosphomolybdic acid color development) showed the disappearance of starting material. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL). The organic phase was washed with 5% citric acid (5 mL) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated to give the title compound 51-6 (crude, directly added to the next step) as a pale yellow solid.
LC-MS:m/z＝190.1[M-100+H] + .
Sixth step 9, 9-difluoro-10-hydroxy-6-azaspiro [4.5] decane-6-carboxylic acid tert-butyl ester 51-7
Compound 51-6 (crude) was dissolved in methanol (6 mL), cooled to 0deg.C in an ice bath, and sodium borohydride (80 mg,2.12 mmol) was added. After the addition, the reaction was ice-bath for 2 hours, and TLC (petroleum ether/ethyl acetate=4/1, phosphomolybdic acid) showed a new spot formation. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (10 mL) and washed with saturated brine (10 mL. Times.2). The organic phase was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give the title compound 51-7 (254 mg, 62% yield in two steps) as a white solid.
LC-MS:m/z＝192.2[M-100+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-100.09.
Seventh step 9, 9-difluoro-6-azaspiro [4.5] decane-10-ol hydrochloride 51-8
Compound 51-7 (120 mg,0.41 mmol) was dissolved in 1, 4-dioxane solution of hydrogen chloride (3 mL, 4M) and reacted at room temperature for 6 hours, TLC (Petroleum ether/ethyl acetate=4/1) showed the starting material disappeared. The reaction was concentrated to give the title compound 51-8 as a white solid (crude, directly taken to the next step).
LC-MS:m/z＝192.2[M-Cl+H] + .
Eighth step 2- (9, 9-difluoro-10-hydroxy-6-azaspiro [4.5] decan-6-yl) -N- (3, 3-difluorocyclobutyl) -2-oxoacetamide 51
Compound 51-8 (1 eq), 2- ((3, 3-difluorocyclobutyl) amino) -2-oxoacetic acid (25 mg,0.14 mmol) was dissolved in N, N-dimethylformamide (4 mL), N, N-diisopropylethylamine (54 mg,0.42 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (64 mg,0.17 mmol) were added sequentially. After addition, the reaction was allowed to react at room temperature for 16 hours, and TLC showed the disappearance of starting material. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL). Saturated brine (10 ml×3), dried over anhydrous sodium sulfate, and concentrated. Purification of the crude product by Prep-TLC (petroleum ether/ethyl acetate=5/1) gave the title compound 51 (7 mg, 14% yield) as a white solid.
LC-MS:m/z＝353.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-85.06,-97.65.
Synthesis example 36: synthesis of Compound 52
N- (3, 3-Difluorocyclobutyl) -2-oxo-2- (3,3,8,8-tetrafluoro-4-hydroxy-1-azaspiro [4.5] decan-1-yl) acetamide (52)
First step 8, 8-difluoro-1, 3-diazaspiro [4.5] decane-2, 4-dione 52-2
4, 4-Difluorocyclohexanone 52-1 (5.0 g,37.28 mmol) was dissolved in a mixed solution of ethanol (80 mL) and water (60 mL), ammonium carbonate (14.3 g,149.11 mmol) and trimethylcyanosilane (7.4 g,74.56 mmol) were added in this order, the reaction mixture was warmed to 70℃after the addition, and reacted for 18 hours, and TLC (Petroleum ether/ethyl acetate=10/1, phosphomolybdic acid color development) showed the disappearance of the starting material. The reaction was cooled to room temperature, ethanol was concentrated off, ice water (50 mL) was added and stirred under an ice bath for 30 minutes. The reaction solution was suction-filtered, and the cake was dried to give the title compound 52-2 (7.2 g, yield 95%) as a silvery white flaky solid.
1 HNMR(400MHz,DMSO-d 6 )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).
Second step 1-amino-4, 4-difluorocyclohexane-1-carboxylic acid 52-3
Compound 52-2 (7.1 g,34.8 mmol) was dissolved in aqueous potassium hydroxide (150 mL, 30%) and the reaction was stirred at 110 ℃ for 16 hours, cooled to 65 ℃ and concentrated to remove approximately 75% of the water, cooled again to 0 ℃ and then slowly added dropwise with concentrated hydrochloric acid (80 mL) until ph=2, stirred for 30 minutes at 0 ℃, cold filtered, the filter cake rinsed with methanol (100 mL x 2), the mother liquor was combined and concentrated to give the title compound 52-3 (crude) as a white solid, which was used directly in the next step.
Third step 1-amino-4, 4-difluorocyclohexane-1-carboxylic acid methyl ester hydrochloride 52-4
The mixture 52-3 (crude product) was dissolved in methanol (150 mL), thionyl chloride (8.3 g,69.6 mmol) was slowly added dropwise at 0deg.C, and the reaction solution was slowly warmed to 70deg.C under nitrogen protection after the addition, stirred for 16 hours, and concentrated under reduced pressure to give the title compound 52-4 (crude product) as a white solid, which was directly used in the next step.
LC-MS:m/z＝194.1[M+H] + .
Fourth step 4, 4-difluoro-1- (3-methoxy-3-oxopropanamido) cyclohexane-1-carboxylic acid methyl ester 52-5
Dissolving compound 52-4 (crude product) in anhydrous dichloromethane (300 mL), cooling to 0 ℃ under the protection of nitrogen, adding triethylamine (14.0 g,369.2 mmol), slowly dropwise adding methyl malonate acyl chloride (7.1 g,52.2 mmol) after the addition, and continuously stirring the reaction solution at 0 ℃ for 3 hours; TLC detection of the completion of the reaction starting material, slow warming to room temperature, water (200 mL) stirring for 10 minutes, separating, drying the organic phase over anhydrous sodium sulfate, concentrating, and purifying the crude product by silica gel column chromatography (ethyl acetate: petroleum ether=1:2) to give the title compound 52-5 (3.8 g, four-step yield: 37%) as a colorless oily liquid.
LC-MS:m/z＝294.2[M+H] + .
Fifth step 8, 8-difluoro-1-azaspiro [4.5] decane-2, 4-dione 52-6
Compound 52-5 (3.8 g,13.0 mmol) was dissolved in anhydrous tetrahydrofuran (300 mL), cooled to 0 ℃ under nitrogen protection, potassium tert-butoxide (2.2 g,19.5 mmol) was added in portions, the reaction solution was warmed to 25 ℃ and stirred for 2 hours; TLC detects complete reaction of starting material. Dilute hydrochloric acid (25 ml,1 n) was added to the reaction solution to adjust ph=5, and after the reaction solution was continuously warmed to 80 ℃, the reaction solution was stirred and refluxed for 4 hours, and TLC was used to detect that the reaction of the starting materials was complete. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of the tetrahydrofuran solution, saturated solution (100 mL) prepared by anhydrous sodium sulfate was added, extracted with ethyl acetate (200 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, the crude product was slurried with petroleum ether (100 mL), suction filtered, and the filter cake was dried to give the title compound 52-6 (2.0 g, yield 76%) as a yellow solid.
Sixth step 3,3,8,8-tetrafluoro-1-azaspiro [4.5] decane-2, 4-dione 52-7
Compound 52-6 (2.0 g,9.8 mmol) was dissolved in acetonitrile (50 mL), 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (10.4 g,29.4mmol and water (50 mL) were added at room temperature, the reaction was continued to stir at room temperature for 12 hours after the addition, TLC detected complete reaction starting material was concentrated under reduced pressure to remove acetonitrile, the mother liquor was extracted with ethyl acetate (200 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound 52-7 (3.4 g, crude product) as a gray solid, which was used directly in the next step.
LC-MS:m/z＝238.0[M-H] - .
Seventh step 3,3,8,8-tetrafluoro-4-hydroxy-1-azaspiro [4.5] decan-2-one 52-8
Compound 52-7 (3.4 g,14.2 mmol) was dissolved in methanol (100 mL), cooled to 0deg.C, sodium borohydride (806 m g,21.3 mmol) was added, and the reaction was stirred at 0deg.C for 1 hour and was complete by TLC. The reaction solution was concentrated under reduced pressure to give the title compound 52-8 (4.2 g, crude) as a white solid, which was used directly in the next step.
Eighth step 3,3,8,8-tetrafluoro-1-azaspiro [4.5] decan-4-ol 52-9
Compound 52-8 (4.2 g, crude product) was dissolved in anhydrous tetrahydrofuran (150 mL), lithium aluminum hydride (2.1 g,56.8 mmol) was added in portions at 0deg.C, and the reaction mixture was heated to 66℃and stirred for 2 hours after the addition, and TLC detected complete reaction of the starting materials. The reaction solution was cooled to 0℃and quenched with water (2.1 mL), sodium hydroxide solution (2.1 mL, 15%) and water (6.3 mL) in this order, the reaction was stirred at room temperature for 10 minutes, suction filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to give the title compound 52-9 (2.0 g, three-step combined yield 90%) as a white solid.
LC-MS:m/z＝228.2[M+H] + .
Ninth step N- (3, 3-difluorocyclobutyl) -2-oxo-2- (3,3,8,8-tetrafluoro-4-hydroxy-1-azaspiro [4.5] decan-1-yl) acetamide 52
Compound 52-9 (50 mg,0.28 mmol), 3,3,8,8-tetrafluoro-1-azaspiro [4.5] decan-4-ol (64 mg,0.28 mmol) was dissolved in N, N-dimethylformamide (4 mL), and N, N-diisopropylethylamine (73 mg,0.56 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (128 mg,0.34 mmol) were added sequentially. After addition, the reaction was allowed to react at room temperature for 16 hours, and TLC showed the disappearance of starting material. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL). The mixture was washed with saturated brine (10 mL. Times.3), and the organic phase was concentrated. Purification of the crude product by Prep-TLC (petroleum ether/ethyl acetate=5/1) gave the title compound 52 (63 mg, 64% yield) as a white solid.
LC-MS:m/z＝389.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-84.97,-94.38,-97.87,-102.60,-104.42,-122.21.
Synthesis example 37: synthesis of Compound 53
9, 9-difluoro-N- (3-chlorobicyclo [1.1.1] pentan-1-yl) -10-hydroxy spiro [4.5] decane-7-carboxamide (53)
First step 9, 9-difluoro-10-oxospiro [4.5] decane-7-carboxylic acid 53-2
Compound 53-1 (88 mg,0.30 mmol) was dissolved in a solution of carbon tetrachloride (2 mL), acetonitrile (2 mL) and water (2 mL), and sodium periodate (640 mg,3.00 mmol) and ruthenium trichloride (31 mg,0.15 mmol) were added sequentially. The reaction was completed at room temperature for 18 hours. TLC showed the starting material disappeared. The reaction mixture was diluted with water (10 mL) and extracted with methylene chloride (10 mL). The organic phase was washed with saturated brine (20 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated to give the title compound 53-2 (58 mg, yield 84%) as a black solid.
LC-MS:m/z＝231.1[M-H] - .
Second step N- (3-chlorobicyclo [1.1.1] pent-1-yl) -9, 9-difluoro-10-oxospiro [4.5] decane-7-carboxamide 53-3
Compound 53-2 (58 mg,0.25 mmol) and 3-chlorobicyclo [1.1.1] pentan-1-amine hydrochloride (39 mg,0.25 mmol) were dispersed in N, N-dimethylformamide (4 mL), N, N-diisopropylethylamine (97 mg,0.75 mmol) was added, and after stirring for 5 minutes, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (114 mg,0.30 mmol) was added, and the reaction was completed by TLC at 20℃for 18 hours. The reaction mixture 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, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound 53-3 as a white solid (36 mg, yield 43%).
LC-MS:m/z＝332.2[M+H] + .
Third step N- (3-chlorobicyclo [1.1.1] pent-1-yl) -9, 9-difluoro-10-hydroxy-spiro [4.5] decane-7-carboxamide 53
Compound 53-3 (36 mg,0.11 mmol) was dissolved in methanol (4 mL), cooled to 0deg.C with an ice bath, and sodium borohydride (6 mg,0.17 mmol) was added. After the addition, the reaction was continued for 30 min in ice bath, and TLC showed the disappearance of starting material. The reaction mixture was quenched with saturated ammonium chloride (10 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (10 ml×2) and the organic phase was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound 53 (29 mg, yield 79%) as a white solid.
LC-MS:m/z＝334.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,CDCl 3 )δ-97.75,-113.15.
Synthesis example 38: synthesis of Compounds 54,55
N- (3, 3-difluoro-1-methylcyclobutyl) -2-oxo-2- ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (3, 3-difluoro-1-methylcyclobutyl) -2-oxo-2- ((4R, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (54-P1 and 54-P2);
n- (3, 3-difluoro-1-methylcyclobutyl) -2-oxo-2- ((4S, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (3, 3-difluoro-1-methylcyclobutyl) -2-oxo-2- ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (55-P1 and 55-P2);
referring to the synthesis of synthesis example 29, the title compounds 54-P1 and 54-P2 and 55-P1 and 55-P2 were synthesized from 3, 3-difluoro-1-methylcyclobutane-1-amine hydrochloride.
54-P1 and 54-P2: white solid, yield 36%.
LC-MS:m/z＝389.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-86.46,-91.91,-93.10,-98.31,-107.84,-122.13.
55-P1 and 55-P2: white solid, yield 14%.
LC-MS:m/z＝389.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-86.47,-90.03,-93.08,-96.36,-109.55,-122.24.
Synthesis example 39: synthesis of Compound 56,57
N- (3-hydroxy bicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (3-hydroxy bicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4R, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (56-P1 and 56-P2);
N- (3-hydroxy bicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4S, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide & N- (3-hydroxy bicyclo [1.1.1] pentan-1-yl) -2-oxo-2- ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (57-P1 and 57-P2);
referring to the synthesis of synthesis example 29, the title compounds 56-P1 and 56-P2 and 57-P1 and 57-P2 were synthesized from 3-hydroxy bicyclo [1.1.1] pentane-1-amine hydrochloride.
56-P1 and 56-P2: white solid, yield 36.43%.
LC-MS:m/z＝367.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-90.31,-96.90,-110.08,-122.67.
57-P1 and 57-P2: white solid, yield 9.11%.
LC-MS:m/z＝452.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
19 F NMR(377MHz,CDCl 3 )δ-92.19,-98.72,-108.29,-122.54.
Synthesis example 40: synthesis of Compound 58-61
N- (3-chlorobicyclo [1.1.1] pent-1-yl) -2- ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (58);
n- (3-chlorobicyclo [1.1.1] pent-1-yl) -2- ((4 r,5 r) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (59);
n- (3-chlorobicyclo [1.1.1] pent-1-yl) -2- ((4S, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (60);
n- (3-chlorobicyclo [1.1.1] pent-1-yl) -2- ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) acetamide (61)
First step 2-bromo-N- (3-chlorobicyclo [1.1.1] pent-1-yl) acetamide 58-2
3-chlorobicyclo [1.1.1] pentane-1-amine hydrochloride 58-1 (500 mg,3.25 mmol) was dispersed in dichloromethane (10 mL), triethylamine (987 mg,9.75 mmol) and bromoacetyl bromide (721 mg,3.57 mmol) were added, and after the addition, the reaction solution was stirred under ice bath for 2 hours and the reaction was complete by TLC. The reaction was quenched with water (10 mL), extracted with dichloromethane (10 mL x 2), the organic phases combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=6/1) to give the title compound 58-2 (306 mg,40% yield) as a pale yellow solid.
LC-MS:m/z＝238.0[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ6.81(br,1H),3.82(s,2H),2.48(s,6H).
Second step N- (3-chlorobicyclo [1.1.1] pent-1-yl) -2-93,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] non-1-yl) acetamide 58,59,60,61
Compound 58-2 (167 mg,0.79 mmol) and compound IN-2 (206 mg,0.86 mmol) were dissolved IN N, N-dimethylformamide (10 mL), and N, N-diisopropylethylamine (204 mg,1.58 mmol) was added. After the addition, the reaction mixture was heated to 80℃and allowed to react for 40 hours, and the reaction was complete by TLC. The reaction mixture was quenched with saturated brine (20 mL), extracted with ethyl acetate (20 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give the title compound 58-61 as a white solid.
Chiral HPLC analysis method: unichiralOD-5H, filler particle size (5 μm), inner diameter (4.6 mm), length (250 mm), flow rate: 1.0mL/min, IPA Hexane=10:90, wavelength: 220/254nm.
Compound 58: white solid, yield 16%, retention time 10.530 min.
LC-MS:m/z＝371.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,DMSO-d 6 )δ-90.90,-93.73,-98.95,-106.57.
Compound 59: white solid, yield 4%, retention time 12.497 min.
LC-MS:m/z＝371.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,DMSO-d 6 )δ-89.00,-93.42,-100.30,-107.11.
Compound 60: white solid, yield 16%, retention time 14.717 min.
LC-MS:m/z＝371.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,DMSO-d 6 )δ-90.90,-93.73,-98.95,-106.57.
Compound 61: white solid, yield 4%, retention time 17.113 min.
LC-MS:m/z＝371.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )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).
19 F NMR(377MHz,DMSO-d 6 )δ-89.00,-93.42,-100.30,-107.11.
Pharmacological test section
Test example 1 Compounds inhibit HIF-2. Alpha. Activity assays (IC 50 )
1. Experimental materials
Reagent name Suppliers of goods Goods number
His-HIF-2α Bioduro Lot20200807-2
GST-HIF-1β Abcam ab268638
Eu-anti-GST Cisbio 61GSTKLA
XL665-anti-His Cisbio 61HISXLA
2. Instrument for measuring and controlling the intensity of light
Centrifuge (manufacturer: eppendorf, model: 5430); enzyme labelling instrument (manufacturer: perkin Elmer, model: enVision); echo 550 (manufacturer: labcyte, model: echo 550)
3. Experimental procedure
Preparing 1X modified TR-FRET assay buffer; preparing a compound concentration gradient: the test compound concentration was measured at 50. Mu.M, starting at 3-fold dilution,and (5) detecting 10 concentration points and multiplexing holes. Dilute to 1000-fold final concentration with DMSO in 384 well plates and then transfer 10 μl of compound to the reaction plate with Echo 550. A2-fold final concentration of GST-HIF-2alpha solution was prepared using 1X modified TR-FRET assay buffer. 5. Mu.L of 2-fold final concentration GST-HIF-2alpha solution was added to each of the compound well and the positive control well; mu.L of 1 XAssay buffer was added to the negative control wells. Centrifuge at 1000rpm for 30 seconds, mix well with shaking and incubate at room temperature for 15 minutes. His-HIF-1beta solution was prepared at 2-fold final concentration using a 1 Xassay buffer. mu.L of His-HIF-1beta solution was added at a final concentration of 2-fold. Centrifuge at 1000rpm for 30 seconds, mix well with shaking and incubate at room temperature for 60 minutes. An Anti mix solution (Eu-Anti-GST at 4 times final concentration and XL665-Anti-His at 4 times final concentration) was prepared at 2 times final concentration with 1 Xassay buffer. mu.L of 2 XAntimix solution (5. Mu.L of Eu-Anti-GST and 5. Mu.L of XL 665-Anti-His) was added. Centrifuge at 1000rpm for 30 seconds, mix well with shaking and incubate at room temperature for 60 minutes. Fluorescence intensities at 665nm and 620nm were read using EnVision and TR-FRET ratios were calculated (665 nm emision/620 nm emision). Calculating inhibition rate, fitting a dose-response curve, taking the log value of concentration as an X axis, taking the percent inhibition rate as a Y axis, and adopting log (inhibitor) vs. response-Variable slope fit of analysis software GraphPad Prism 5 to obtain the IC of each compound on enzyme activity 50 Values.
PT-2977 was used as a positive control for this experiment.
The activity of the compounds of the examples in this disclosure in inhibiting HIF-2 alpha is determined by the above assay, IC 50 The values are shown in Table 1.
Data on HIF-2 alpha inhibition activity by compounds of Table 1
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The compounds of the invention have excellent HIF-2 alpha inhibitory activity.
Test example 2VEGF-ELISA assay (IC 50 )
1. Experimental materials
Items Vendor Cat.
Human VEGF Quantikine ELISA Kit R&D SVE00
Corning 96well clear flat bottom Corning 3599
2. Instrument for measuring and controlling the intensity of light
Instrument Manufacturer Model
Envision PerkinElmer Envision
3. Experimental procedure
Inoculating 786-O cells grown in logarithmic phase into 96-well plate with cell concentration of 4000 cells per ml culture solution and 180 μl per well, placing 96-well plate at 37deg.C and 5% CO 2 Overnight in the incubator of (a).
Preparation of 10-fold Compound the compound concentration was diluted in DMSO to obtain 8 concentration points after an initial 3-fold dilution of 1 mM. The compound was then diluted 100-fold with RPMI 1640 medium to a final 10-fold compound concentration. The concentration of DMSO in the cell culture medium at this time was 1%.
To the cell plate, 20 ul/well of compound solution at 10-fold working concentration was added, and DMSO concentration was 0.1%. Then at 37℃with 5% CO 2 Culturing in an incubator for 72 hours. The supernatant was collected at 150. Mu.L/well, VEGF concentration was measured using ELISA kit, the reaction was terminated finally, the light absorbance of each well was measured using a microplate reader at wavelengths of 450nm and 570nm, and IC was calculated by Graphprism 50 。
PT-2977 was used as a positive control for this experiment.
The activities of the examples in this disclosure were determined by the above assays, measured IC 50 The values are shown in Table 2.
TABLE 2 Activity data for VEGF-ELISA
Compounds of formula (I) IC 50 (μM) Compounds of formula (I) IC 50 (μM)
PT-2977 0.034 23 0.16
4 2.27 33 0.1
17 1.06 34 0.13
18 0.8 36 0.08
20 0.21
Test example 3 luciferase assay (IC 50 )
The cells used in this experiment were 786O-HRE-Luciferase stable cell line (sequence 9. Times. HRE-Luci) and were tested while 786O-HRE-Luci stable cell line was in logarithmic growth phase and cultured using MEDIUM (RPMI 1640 MEDIUM, available from GIBCO). Discarding the culture medium when the cell fullness reaches 80-90%, washing with PBS for three times, adding trypsin (purchased from BI) to digest cells, washing cells with serum-containing culture medium to stop cell digestion, collecting cells, centrifuging, flushing with PBS once to remove phenol red in the culture medium, re-suspending the cells to a proper concentration to detect the cell density and survival rate, and ensuring that the cell survival rate is above 95% for the next experiment.
Cells were seeded into 384 wells, 3000cells/well,30. Mu.L of medium, compounds were added to give final concentrations of 10000, 3333, 1111, 370, 123, 41.1, 13.7, 4.6, 1.5, 0.5nM, respectively. The cells were placed at 37℃with 5% CO 2 Is incubated for 72h in the environment.
ONE-Glo was added after incubation TM Luciferase Assay System (from Promega) to 384 well plates, 30. Mu.L/well, luminescence was detected with a microplate reader. Inhibition (%) was calculated from RLU (Record Luminesence) signal values per well, and then IC of the corresponding compound was calculated by Graphpad 9.0 fitting 50 。
PT-2977 was used as a positive control for this experiment.
The activities of the examples in this disclosure were determined by the above assays, measured IC 50 The values are shown in Table 3.
TABLE 3 Activity data for luciferase assay
Compounds of formula (I) IC 50 (μM) Compounds of formula (I) IC 50 (μM)
PT-2977 0.00397 20 0.0563
4 0.0623 23 0.0283
17 0.042 37-P1 0.017
18 0.018 37-P2 0.016
And the compounds of the present invention have advantages over existing positive compounds in terms of solubility, clearance in vivo and bioavailability.
It is stated that the present invention is illustrated by the above examples to demonstrate the inhibitory activity of the present invention for therapeutic use in the treatment or alleviation of diseases associated with overexpression.
Meanwhile, the compound provided by the invention has very excellent solubility in water, and the in-vivo metabolic stability is suggested, so that the compound has very broad application prospects in industry.
The invention is not limited to the embodiments described above, i.e. it is not meant that the invention has to be carried out in dependence on the embodiments described above. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.

Claims (8)

1. An oxalic acid amine compound represented by formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof,
in the above, Y 1 Is N or CR 1 ，Y 2 Is CR (CR) 2 R 3 、NR 4 Or is absent;
Y 3 y and Y 4 Each independently selected from CR 2 R 3 、NR 4 、O、SO 2 One of the following; r is R 2 ～R 4 Any two of which may be linked to form a substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl;
R 1 Selected from H, halogen, hydroxy, CN, NO 2 、-NR a R b One of C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 hydroxyalkyl, C1-4 alkoxyC 1-4 alkyl, C3-8 cycloalkyl;
each R is 2 R is R 3 Each independently selected from H, halogen, CN, NO 2 Hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-4 alkoxy C1-4 alkyl, C3-8 cycloalkyl, -S (O) 2 R a 、-CO 2 R a 、-C(O)R a 、-C(O)NR a R b 、-S(O) 2 NR a R b 、-S(O)(＝NR b )R a -NR a R b One of the following; each R is 4 Independently selected from H, halogen, hydroxy, C1-4 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, and-C (O) R a ；
L 1 Is a bond or is selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, saturated or partially unsaturated C3-10 cycloalkylene, -O-, -CO-, -CN (CN) -, -C (=O) O-, -C (=N) N R a -、-N R a C(＝S)-、-N R a CO-、-N R a S(＝O)-、-N R a S(＝O) 2 -、-S-、-S(＝O)-、-S(＝O) 2 -、-S(＝O)O-、-S(＝O) 2 One or more of O-and a divalent group;
e is a bond or is selected from a substituted or unsubstituted saturated or partially unsaturated aliphatic C3-10 cyclic hydrocarbon group, a substituted or unsubstituted saturated or partially unsaturated aliphatic 3-10 membered heterocyclic group, a substituted or unsubstituted C6-12 arylene group, or a substituted or unsubstituted C6-12 heteroarylene group;
R 5 is selected from H, halogen, CN, NO 2 C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-4 alkoxy C1-4 alkyl, C3-8 cycloalkyl, -S (O) 2 R a 、-CO 2 R a 、-C(O)R a 、-C(O)NR a R b 、-S(O) 2 NR a R b 、-S(O)(＝NR b )R a -NR a R b One of the following;
R 9 r is R 10 Independently selected from the group consisting of: H. halogen, CN, NO 2 C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 hydroxyhaloalkyl, C1-4 alkoxyC 1-4 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 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 b C1-6 alkylene-S (O) 2 NR a R b ；
Alternatively, R 9 R is R 10 Are linked together to form a substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocycloalkyl;
alternatively, R 9 Or R is 10 And Y is equal to 4 Are linked together to form a substituted or unsubstituted C3-6 cycloalkyl, a substituted or unsubstituted 3-to 6-membered heterocycloalkyl, a substituted or unsubstituted C6-12 arylene, or a substituted or unsubstituted C6-12 heteroarylene;
each R is a R is R b 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 above-mentioned substituted or unsubstituted means that H in the group is substituted by a member selected from the group consisting of halogen, CN, OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 hydroxyalkyl, C1-4 alkoxyC 1-4 alkyl and-NR a R b Substituted by one or a combination of at least two groups, or meaning-CH in the groups 2 -two H in are replaced with oxo=o.
2. The compound according to claim 1, wherein the picolinamide compound represented by formula (I) has a structure represented by formula (II) or (III) below, or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof,
in the formula (II) and the formula (III), Y 1 、Y 2 The meaning is the same as that represented by formula (I),
L 1 is selected from C1-6 alkylene, -CO-, -C (=O) O-, -N R a One or more of CO-, and a divalent group formed by combining the two or more of CO-, and CO-, respectively;
e' is selected from a bond or a saturated or partially unsaturated aliphatic C3-10 cyclic hydrocarbon group, a saturated or partially unsaturated aliphatic 3-10 membered heterocyclic group, a C6-12 arylene group, or a C6-12 heteroarylene group,
W 1 、W 2 each independently is a bond, N or CR c R d ，W 3 、W 4 Each independently selected from CR c R d 、NR c 、CO、O、S、SO、SO 2 One of the following;
R 11 independently selected from H, halogen, hydroxy, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C3-8 cycloalkoxy, and-C (O) R c ；R 12 And R is 13 Independently selected from H, halogen, C1-4 alkyl, C3-8 cycloalkyl and-C (O) R c The method comprises the steps of carrying out a first treatment on the surface of the Each R is c R is R d Independently selected from H, halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, and C1-3 hydroxyalkyl.
3. The compound of claim 2, or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof, wherein E' represents the structure:
c2-6 alkylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, norbornylene, adamantylene, oxetylene, tetrahydrofuranylene, phenylene, biphenylene, terphenylene, naphthylene, anthrylene, phenanthrylene, indenylene, fluorenylene, fluoranthrylene, triphenylene, pyrenylene, perylene, anda group, a benzocyclobutylene group, a benzocyclopentylene group, a benzocyclohexylene group, a benzocycloheptylene group, a benzocyclooctylene group, a thiazolylene group, a furanylene group, a thienyl group, a pyrrolylene group, a pyridyl group, a benzofuranylene, benzothiophenylene, isobenzofuranylene, isobenzothienyl indolylene, isoindolylene, dibenzofuranylene, dibenzothiophenylene, and, Carbazolylene and derivatives thereof, quinolinylene, isoquinolylene, acriylene, phenanthrylene, benzoquinolinylene, phenothiazinylene, phenazinylene, pyrazolylene, indazoylene, imidazolylene, benzimidazolylene, naphthylene-imidazolylene, phenanthreneimidazolylene, pyridoimidazolylene, pyrazinoimidazolyl, quinoxalinoimidazolyl, thienylene, benzoxazolylene, naphthylene oxazolylene, anthracenoxazolylene, phenanthreneoxazolylene, benzothiazolylene, pyridazinylene, benzopyridazinylene, pyrimidinylene, benzopyrimidino, quinoxalinylene, 1, 5-diazaanthrylene, 2, 7-diazapyrenylene, 2, 3-diazapyrenylene, 4,5,9, 10-tetraazaperylene, pyrazinylene, phenazinylene, phenothiazinylene, naphthyridineylene, azacarbazolylene, benzocarboline, phenanthroline, triazolylene, 1,2, 3-oxadiazolylene, 1,2, 4-oxadiazolylene, 1,2, 5-oxadiazolylene, thiadiazolylene, triazinylene, tetrazolylene, tetrazinylene, purinylene, pteridinylene, indolizinylene, benzothiadiazole, or a combination thereof,
The above radicals being optionally substituted by halogen, C1-3 alkyl, or CH in the above radicals 2 Is oxo-ized by a reaction of c=o,
the expression "indicates the position of the ligation to the parent nucleus" and the expression of the "-" marked ring structure indicates the position of the ligation site on the ring structure at any position capable of bonding.
4. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof, that is one of the following specific compounds:
5. a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof, and a pharmaceutically acceptable carrier, the pharmaceutical composition being a solid formulation, semi-solid formulation, liquid formulation, or gaseous formulation.
6. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is in the form of an oral dosage form or an injection, and the oral dosage form comprises a capsule, a tablet, a pill, a powder, and a granule. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures,
The injection comprising a physiologically acceptable sterile aqueous or anhydrous solution, dispersion, suspension or emulsion, and a sterile powder of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof for redissolving into a sterile injectable solution or dispersion.
7. The use of a compound of any one of claims 1-3, or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof, in the preparation of a 2 alpha hypoxia inducible factor inhibitor.
8. Use of a compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof, in the manufacture of a medicament for treating or preventing a disease associated with hypoxia inducible factor type 2;
The diseases related to the 2 alpha type hypoxia-inducible factor are cancers, inflammatory diseases and immune related diseases;
the cancers are the following cancers: prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, stomach cancer, endometrial cancer, uterine cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin (including melanoma and basal carcinoma) cancer, mesothelial cancer, white blood cell cancer, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, intestinal cancer, lung cancer, adrenal cancer, thyroid cancer, kidney or bone; neuroglioblastoma carcinoma, mesothelioma carcinoma, renal cell carcinoma, clear cell renal cell carcinoma \gastric carcinoma, sarcoma, kaposi's sarcoma, choriocarcinoma, basal cell carcinoma of the skin, or testicular seminoma;
the inflammation is selected from pneumonia, enteritis, nephritis, arthritis and traumatic infection;
the metabolic disease is selected from obesity, dyslipidemia and hyperlipidemia;
preferably, the cancer is renal cell carcinoma and clear cell renal cell carcinoma.
CN202311261799.5A 2022-09-30 2023-09-27 Oxalic acid amine derivative, pharmaceutical composition containing oxalic acid amine derivative and medical application of oxalic acid amine derivative Pending CN117800895A (en)

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