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CN117800944A - Pyridine amide derivative, pharmaceutical composition containing same and medical application of pharmaceutical composition - Google Patents

Pyridine amide derivative, pharmaceutical composition containing same and medical application of pharmaceutical composition Download PDF

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Publication number
CN117800944A
CN117800944A CN202311261814.6A CN202311261814A CN117800944A CN 117800944 A CN117800944 A CN 117800944A CN 202311261814 A CN202311261814 A CN 202311261814A CN 117800944 A CN117800944 A CN 117800944A
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compound
mmol
reaction
cancer
nmr
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Inventor
刘治国
吴杰
叶阳亮
王昊
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Suzhou Almai Biotechnology Co ltd
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Suzhou Almai Biotechnology Co ltd
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/4164—1,3-Diazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract

The invention provides a compound (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, and a pharmaceutical composition containing the compound, and also provides the compound as 2 alpha type hypoxia inducible factor (HIF-2 alpha) inhibitorThe application of the preparation, the application in the preparation of the medicine related to the 2 alpha type hypoxia inducible factor and the corresponding medicine composition,

Description

Pyridine amide derivative, pharmaceutical composition containing same and medical application of pharmaceutical composition
Technical Field
The invention belongs to the field of medicines, and particularly relates to a pyridine amide derivative, in particular to a pyridine amide 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 estimated American cancer society, 40.3 tens of thousands of kidney cancers are newly increased worldwide, and 17.5 tens of thousands of kidney cancers die each year; in China, about 6.68 tens of thousands of patients are newly added each year, and 2.34 tens of thousands of patients die. Statistics of cancer spectrum in China show that kidney incidence has increased at an average rate of 6.5% per year over the past 20 years, already exceeding bladder cancer level first in urinary system tumor-related deaths. 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 a picolinamide 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 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 C1-6alkylene-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.
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 、L 1 、R 5 The meaning is the same as that represented by formula (I),
ring A represents a substituted or unsubstituted C3-5 aromatic or heteroaromatic ring, where the substituents are halogen, hydroxy, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, or C3-8 cycloalkoxy;
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, ring A represents the following aromatic ring structure,
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, a so-called "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) 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 monocyclic 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 more (such as 1 to 3) suitable substituents, e.g., 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 groupsEtc. 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" means 5 to 18 membered, two or moreA polycyclic group having a cyclic structure and having single rings sharing one atom with each other, wherein none of the rings has a completely conjugated pi-electron aromatic system, and wherein 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 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 heterocyclyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a common pair of 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 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" may be fused to a heteroaryl, heterocyclyl, or cycloalkyl group, wherein the aryl ring is attached to the parent structure, 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 also contain one or more (e.g., one, twoThree or four) are 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). Radioisotope tritium (i.e 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 (-), solid wedges may be used hereinOr virtual wedge +.>Depicting the chemical bond of the compounds of the present invention. The use of a solid line to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom (e.g., particular enantiomers, racemic mixtures, etc). 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.
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 58, 59, 67, 68, 70, 71, 91, 92, 93, 94, 100, 101 represent two chemical structures in the form of the numbers-P1 and-P2 due to the presence of isomers:
* 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 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.
An important aspect of the present invention is to provide the use of the picolinamide derivatives of the invention described above 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 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 treating cancer using picolinamide derivatives as inhibitors by administering an effective amount of the compounds to a subject suffering from cancer.
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; chromatographic column 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%Awithin 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
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 amide series compounds (compounds 1-88):
acid (2 eq) was dissolved in anhydrous N, N-dimethylacetamide (2V), intermediate amine (1 eq), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (2 eq) and N, N-diisopropylethylamine (3 eq) were added at room temperature, and the reaction was stirred at room temperature for 16 hours, and TLC detected complete reaction of 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
(4-chloropyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 1
White solid, yield 47%.
LC-MS:m/z＝317.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.45(d,J＝5.2Hz,1H),7.87(s,1H),7.37(dd,J＝5.2,2.0Hz,1H),4.35-4.24(m,1H),4.16-4.07(m,1H),3.96-3.91(m,1H),2.59-2.54(m,2H),2.40-2.32(m,1H),2.26-2.20(m,1H),2.13-2.02(m,2H),1.88-1.83(m,1H),1.63-1.54(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-109.53,-120.66.
Synthesis example 4: synthesis of Compound 2
6- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonane-1-carbonyl) pyridine carbonitrile 2
White solid, yield 60%.
LC-MS：m/z＝308.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 ):δ8.29-8.11(m,2H),8.00(dd,J＝7.6,1.2Hz,1H),6.37(d,J＝6.0Hz,1H),4.16-3.87(m,3H),2.47-2.36(m,1H),2.23-2.18(m,1H),2.11-2.00(m,1H),1.99-1.84(m,2H),1.84-1.73(m,1H),1.64-1.46(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-111.24,-119.19.
Synthesis example 5: synthesis of Compound 3
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (5-fluoro-6-methylpyridin-2-yl) methanone 3
White solid, yield 97%.
LC-MS：m/z＝315.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 ):δ7.75(t,J＝9.2Hz,1H),7.62(dd,J＝8.4,4.0Hz,1H),6.34(d,J＝6.0Hz,1H),4.11-3.91(m,3H),2.47(d,J＝2.8Hz,3H),2.44-2.33(m,1H),2.25-2.12(m,1H),2.07-2.00(m,1H),1.98-1.82(m,2H),1.81-1.70(m,1H),1.61-1.44(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-110.83,-119.13,-122.15.
Synthesis example 6: synthesis of Compound 4
(6-chloro-5-methoxypyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 4
White solid, yield 84%.
LC-MS：m/z＝347.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 ):δ7.79(d,J＝8.4Hz,1H),7.69(d,J＝8.4Hz,1H),6.33(d,J＝6.0Hz,1H),4.11-3.98(m,3H),3.95(s,3H),2.42-2.37(m,1H),2.25-2.09(m,1H),2.06-2.00(m,1H),1.95-1.83(m,2H),1.78-1.71(m,1H),1.58-1.46(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-110.84,-119.07.
Synthesis example 7: synthesis of Compound 5
(4, 6-dichloropyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 5
Yellow solid, yield 5.2%.
LC-MS：m/z＝351.1[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ7.95(d,J＝1.6Hz,1H),7.83(d,J＝1.6Hz,1H),6.36(d,J＝6.0Hz,1H),4.06-3.92(m,3H),2.43-2.36(m,1H),2.20-2.14(m,1H),2.05-1.98(m,1H),1.96-1.82(m,2H),1.80-1.74(m,1H),1.59-1.48(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-111.08,-119.12.
Synthesis example 8: synthesis of Compound 6
(6-chloro-5-fluoropyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 6
Pale yellow solid, yield 27%.
LC-MS:m/z＝335.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.06(t,J＝8.4Hz,1H),7.83(dd,J＝8.4,3.6Hz,1H),6.36(d,J＝6.4Hz,1H),4.10-3.94(m,3H),2.45-2.34(m,1H),2.22-2.17(m,1H),2.10-1.97(m,1H),1.98-1.82(m,2H),1.82-1.71(m,1H),1.60-1.45(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-111.04,-117.19,-119.21.
Synthesis example 9: synthesis of Compound 7
2- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonane-1-carbonyl) isonicotinic acid nitrile 7
White solid, yield 80%.
LC-MS:m/z＝308.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.82(d,J＝4.4Hz,1H),8.13(s,1H),7.98(d,J＝4.4Hz,1H),6.36(d,J＝5.6Hz,1H),4.07-3.89(m,3H),2.46-2.36(m,1H),2.25-2.13(m,1H),2.10-2.00(m,1H),1.98-1.83(m,2H),1.82-1.72(m,1H),1.62-1.44(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-111.02,-119.14.
Synthesis example 10: synthesis of Compound 8
2- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonane-1-carbonyl) isonicotinic acid nitrile 8
Yellow solid, yield 47%.
LC-MS:m/z＝351.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.26(d,J＝8.0Hz,1H),7.74(d,J＝8.0Hz,1H),6.36(d,J＝6.4Hz,1H),4.11-3.95(m,3H),2.41-2.36(m,1H),2.24-2.12(m,1H),2.07-1.97(m,1H),1.96-1.82(m,2H),1.82-1.71(m,1H),1.61-1.43(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-111.03,-119.19.
Synthesis example 11: synthesis of Compound 9
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (5- (difluoromethoxy) -6-methylpyridin-2-yl) methanone 9
White solid, yield 72%.
LC-MS:m/z＝363.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.73(d,J＝8.4Hz,1H),7.49(d,J＝8.4Hz,1H),6.58(t,J＝72.4Hz,1H),4.39-4.28(m,1H),4.21-4.12(m,1H),3.96-3.92(m,1H),2.61-2.56(m,1H),2.53(s,3H),2.48-2.47(m,1H),2.39-2.32(m,1H),2.25-2.19(m,1H),2.12-2.01(m,2H),1.88-1.82(m,1H),1.60-1.52(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-81.48,-109.61,-120.56.
Synthesis example 12: synthesis of Compound 10
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (5-methoxy-6-methylpyridin-2-yl) methanone 10
White solid, yield 71%.
LC-MS:m/z＝327.2[M+1] + .
1 H NMR(400MHz,CDCl 3 )δ7.42(d,J＝8.8Hz,1H),7.13(d,J＝8.4Hz,1H),4.41-4.30(m,1H),4.27-4.18(m,1H),3.93(t,J＝7.2Hz,1H),3.87(s,3H),2.63-2.55(m,1H),2.44(s,3H),2.36-2.31(m,1H),2.25-2.17(m,1H),2.06(br,2H),1.85-1.81(m,1H),1.64-1.53(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-109.76,-120.34.
Synthesis example 13: synthesis of Compound 11
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (6- (difluoromethyl) pyridin-2-yl) methanone 11
Yellow solid, yield 50%.
LC-MS:m/z＝333.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.14(t,J＝8.0Hz,1H),7.87(d,J＝7.6Hz,1H),7.80(d,J＝7.6Hz,1H),7.03(t,J＝54.4Hz,1H),6.37(d,J＝6.0Hz,1H),4.06-3.99(m,3H),2.47-2.38(m,1H),2.23-2.18(m,1H),2.11-2.01(m,1H),2.00-1.84(m,2H),1.83-1.73(m,1H),1.61-1.46(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-110.63,-115.97,-119.01.
Synthesis example 14: synthesis of Compound 12
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (6- (trifluoromethyl) pyridin-2-yl) methanone 12
Yellow solid, yield 68%.
LC-MS:m/z＝351.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.25(t,J＝8.0Hz,1H),8.03(dd,J＝7.6,4.4Hz,2H),6.38(d,J＝6.0Hz,1H),4.06-4.00(m,3H),2.48-2.39(m,1H),2.24-2.19(m,1H),2.13-2.02(m,1H),1.99-1.85(m,2H),1.81-1.76(m,1H),1.61-1.48(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-66.48,-110.86,-119.10.
Synthesis example 15: synthesis of Compound 13
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (5-fluoro-4-methylpyridin-2-yl) methanone 13
Yellow solid, yield 9%.
LC-MS:m/z＝315.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.26(s,1H),7.76(d,J＝6.0Hz,1H),4.35-4.24(m,1H),4.18-4.09(m,1H),3.97-3.89(m,1H),2.60-2.53(m,1H),2.48(d,J＝4.0Hz,1H),2.34(s,4H),2.23-2.15(m,1H),2.12-1.98(br,2H),1.90-1.82(m,1H),1.64-1.59(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-109.77,-120.68,-129.12.
Synthesis example 16: synthesis of Compound 14
(4, 6-dichloro-5-fluoropyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 14
White solid, yield 61%.
LC-MS:m/z＝391.0[M+Na] + .
1 H NMR(400MHz,CDCl 3 )δ7.99(t,J＝4.8Hz,1H),4.41-4.30(m,1H),4.19-4.10(m,1H),3.96-3.89(m,1H),2.54-2.47(m,2H),2.33-2.22(m,2H),2.09-2.04(m,2H),1.87-1.82(m,1H),1.66-1.59(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-109.29,-117.74,-120.64.
Synthesis example 17: synthesis of Compound 15
(6-chloropyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 15
White solid, yield 73%.
LC-MS:m/z＝317.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.81-7.75(m,2H),7.41-7.39(m,1H),4.38-4.27(m,1H),4.20-4.11(m,1H),3.97-3.92(m,1H),2.64-2.53(m,1H),2.41-2.31(m,2H),2.27-2.15(m,1H),2.12-2.02(m,2H),1.88-1.83(m,1H),1.68-1.59(m,2H).
Synthesis example 18: synthesis of Compound 16
(6-bromopyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 16
White solid, yield 65%.
LC-MS:m/z＝363.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.84(d,J＝7.6Hz,1H),7.67(t,J＝8.0Hz,1H),7.56(d,J＝7.6Hz,1H),4.39-4.25(m,1H),4.22-4.09(m,1H),3.98-3.90(m,1H),2.62-2.50(m,2H),2.39-2.29(m,1H),2.28-2.18(m,1H),2.12-1.99(m,2H),1.90-1.79(m,1H),1.70 -1.65(m,1H),1.59-1.51(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-109.67,-120.53.
Synthesis example 19: synthesis of Compound 17
(6-bromo-5-fluoropyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 17
White solid, yield 62%.
LC-MS:m/z＝381.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.93(dd,J＝3.6Hz,8.4Hz,1H),7.52(t,J＝8.0Hz,1H),4.43-4.29(m,1H),4.23-4.11(m,1H),3.98-3.90(m,1H),2.59-2.48(m,2H),2.38-2.19(m,2H),2.12-2.01(m,2H),1.90-1.80(m,1H),1.69-1.63(m,1H),1.58-1.52(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-108.31,-109.48,-120.58.
Synthesis example 20: synthesis of Compound 18
(6-chloro-5- (difluoromethoxy) pyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 18
White solid, yield 99%.
LC-MS:m/z＝383.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.90(d,J＝8.4Hz,1H),7.69(d,J＝8.4Hz,1H),6.64(t,J＝71.6Hz,1H),4.42-4.31(m,1H),4.23-4.13(m,1H),3.94(t,J＝6.0Hz,1H),2.58-2.46(m,2H),2.36-2.20(m,2H),2.11-2.01(m,2H),1.90-1.80(m,1H),1.67-1.58(m,2H).
Synthesis example 21: synthesis of Compound 19
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (6- (difluoromethyl) -5-fluoropyridin-2-yl) methanone 19
White solid, yield 14%.
LC-MS:m/z＝351.2[M+1] + .
1 H NMR(400MHz,CDCl 3 )δ8.13(dd,J＝3.6Hz,8.4Hz,1H),7.64(t,J＝9.2Hz,1H),6.79(t,J＝53.6Hz,1H),4.45-4.34(m,1H),4.23-4.15(m,1H),3.96-3.92(m,1H),2.59-2.51(m,1H),2.38-2.21(m,3H),2.13-2.01(m,2H),1.89-1.81(m,1H),1.70-1.59(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-109.43,-117.20,-120.69,-122.54.
Synthesis example 22: synthesis of Compound 20
(5-bromo-6-chloropyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 20
White solid, yield 49%.
LC-MS:m/z＝395.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.06(d,J＝8.0Hz,1H),7.71(d,J＝8.0Hz,1H),4.42-4.28(m,1H),4.22-4.10(m,1H),3.97-3.90(m,1H),2.58-2.47(m,2H),2.38-2.18(m,2H),2.11-2.00(m,2H),1.89-1.80(m,1H),1.69-1.63(m,1H),1.58-1.52(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-109.49,-120.59.
Synthesis example 23: synthesis of Compound 21
(5-chloro-6-methoxypyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 21
White solid, yield 44%.
LC-MS:m/z＝347.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.74(d,J＝8.0Hz,1H),7.48(d,J＝8.0Hz,1H),4.44-4.29(m,1H),4.25-4.13(m,1H),4.02(s,3H),3.97-3.89(m,1H),2.65-2.50(m,2H),2.42-2.31(m,1H),2.28-2.17(m,1H),2.15-2.00(m,2H),1.90-1.79(m,1H),1.69-1.63(m,1H)1.60-1.55(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-109.46,-120.30.
Synthesis example 24: synthesis of Compound 22
(5, 6-dibromopyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 22
White solid, yield 76%.
LC-MS:m/z＝439.0[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.01(d,J＝8.0Hz,1H),7.74(d,J＝8.0Hz,1H),4.42-4.27(m,1H),4.22-4.10(m,1H),3.98-3.89(m,1H),2.58-2.44(m,2H),2.38-2.18(m,2H),2.13-1.99(m,2H),1.90-1.80(m,1H),1.69-1.62(m,1H),1.58-1.51(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-109.47,-120.56.
Synthesis example 25: synthesis of Compound 23
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (6- (difluoromethyl) -4-fluoropyridin-2-yl) methanone 23
White solid, yield 17%.
LC-MS:m/z＝351.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.50(dd,J＝2.0Hz,8.8Hz,1H),7.44(dd,J＝2.4Hz,8.0Hz,1H),6.61(t,J＝55.2Hz,1H),4.41-4.30(m,1H),4.18-4.09(m,1H),3.93(t,J＝6.0Hz,1H),2.60-2.49(m,2H),2.39-2.22(m,2H),2.13-2.01(m,2H),1.91-1.80(m,1H),1.72-1.63(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-96.60,-109.27,-116.36,-120.72.
Synthesis example 26: synthesis of Compound 24
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (5-fluoro-6-iodopyridin-2-yl) methanone 24
White solid, yield 59%.
LC-MS:m/z＝427.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.87-7.71(m,2H),6.38(d,J＝6.0Hz,1H),4.12-3.90(m,3H),2.46-2.34(m,1H),2.25-2.14(m,1H),2.09-1.97(m,1H),1.97-1.82(m,2H),1.82-1.71(m,1H),1.60-1.44(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-101.17,-110.84,-119.10.
Synthesis example 27: synthesis of Compound 25
(6-bromo-5- (difluoromethoxy) pyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 25
White solid, yield 55%.
LC-MS:m/z＝427.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.92(d,J＝8.4Hz,1H),7.64(d,J＝8.4Hz,1H),6.64(t,J＝71.6Hz,1H),4.45-4.30(m,1H),4.25-4.12(m,1H),3.98-3.90(m,1H),2.60-2.49(m,1H),2.48-2.43(m,1H),2.37-2.18(m,2H),2.13-1.99(m,2H),1.90-1.80(m,1H),1.72-1.61(m,1H),1.58-1.50(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-82.30,-109.50,-120.45.
Synthesis example 28: synthesis of Compound 26
(6-bromo-5-chloropyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 26
White solid, yield 56%.
LC-MS:m/z＝395.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.22(d,J＝8.0Hz,1H),7.77(d,J＝8.0Hz,1H),6.38(d,J＝6.0Hz,1H),4.13-3.94(m,3H),2.46-2.34(m,1H),2.24-2.14(m,1H),2.09-1.97(m,1H),1.97-1.82(m,2H),1.82-1.72(m,1H),1.62-1.44(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-110.95,-119.14.
Synthesis example 29: synthesis of Compound 27
(6-chloro-5- (difluoromethyl) pyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 27
White solid, yield 26%.
LC-MS:m/z＝367.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.12(d,J＝8.0Hz,1H),7.94(d,J＝8.0Hz,1H),6.93(t,J＝54.4Hz,1H),4.39-4.28(m,1H),4.17-4.09(m,1H),3.96-3.12(m,1H),2.58-2.51(m,1H),2.46-2.40(m,1H),2.36-2.20(m,2H),2.12-2.01(m,2H),1.91-1.81(m,1H),1.69-1.61(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-109.41,-116.75,-120.62.
Synthesis example 30: synthesis of Compound 28
(6-amino-5-fluoropyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 28
White solid, yield 53%.
LC-MS:m/z＝316.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.42(dd,J＝11.2,8.0Hz,1H),6.82(dd,J＝8.0,2.8Hz,1H),6.46(s,2H),6.32(d,J＝6.0Hz,1H),4.12-3.88(m,3H),2.44-2.31(m,1H),2.20-2.09(m,1H),2.07-1.96(m,1H),1.96-1.80(m,2H),1.78-1.67(m,1H),1.58-1.42(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-110.22,-119.04,-136.48.
Synthesis example 31: synthesis of Compound 29
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (4, 5-difluoro-6-methylpyridin-2-yl) methanone 29
White solid, yield 41%.
LC-MS:m/z＝333.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ7.64-7.60(m,1H),4.40-4.27(m,1H),4.21-4.09(m,1H),3.96-3.89(m,1H),2.58-2.50(m,4H),2.45-2.30(m,2H),2.26-2.19(m,1H),2.12-2.01(m,2H),1.87-1.81(m,1H),1.64-1.59(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-109.45,-120.65,-126.48,-146.91.
Synthesis example 32: synthesis of Compound 30
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (5-fluoro-6- (methylamino) pyridin-2-yl) methanone 30
White solid, yield 14%.
LC-MS:m/z＝330.2[M+H] +
1 H NMR(400MHz,DMSO-d 6 )δ7.40(dd,J＝11.2,8.0Hz,1H),6.96-6.83(m,2H),6.31(s,1H),4.22-4.05(m,2H),4.03-3.91(m,1H),2.83(d,J＝4.8Hz,3H),2.46-2.35(m,1H),2.21-2.10(m,1H),2.08-1.97(m,1H),1.97-1.81(m,2H),1.80-1.68(m,1H),1.59-1.44(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-110.90,-119.30,-137.40.
Synthesis example 33: synthesis of Compound 31
(5-chloro-6- (difluoromethyl) pyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 31
White solid, yield 85%.
LC-MS:m/z＝367.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.04(d,J＝8.4Hz,1H),7.91(d,J＝8.4Hz,1H),6.91(t,J＝13.6Hz,1H),4.47-4.36(m,1H),4.27-4.18(m,1H),3.96-3.92(m,1H),2.60-2.52(m,1H),2.46-2.45(m,1H),2.39-2.31(m,1H),2.30-2.21(m,1H),2.13-2.00(m,2H),1.90-1.81(m,1H),1.69-1.59(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-109.49,118.27,-120.67.
Synthesis example 34: synthesis of Compound 32
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (5- (difluoromethoxy) -6- (difluoromethyl) pyridin-2-yl) methanone 32
White solid, yield 63%.
LC-MS:m/z＝399.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.13(d,J＝8.8Hz,1H),7.77(d,J＝8.8Hz,1H),6.97-6.48(m,2H),4.50-4.35(m,1H),4.29-4.17(m,1H),3.94(dd,J＝11.2,6.0Hz,1H),2.61-2.49(m,2H),2.41-2.20(m,2H),2.15-2.00(m,2H),1.91-1.82(m,1H),1.71-1.65(m,1H),1.62-1.52(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-82.19,-109.50,-117.97,-120.66.
Synthesis example 35: synthesis of Compound 33
(6-chloro-5- (trifluoromethyl) pyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 33
White solid, yield 42%.
LC-MS:m/z＝385.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.15(d,J＝8.0Hz,1H),7.95(d,J＝8.0Hz,1H),4.42-4.28(m,1H),4.20-4.08(m,1H),3.95(dd,J＝10.8,6.0Hz,1H),2.59-2.49(m,1H),2.40-2.37(m,1H),2.35-2.22(m,2H),2.13-2.01(m,2H),1.90-1.84(m,1H),1.70-1.59(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-63.78,-109.03,-120.33.
Synthesis example 36: synthesis of Compounds 34-37, (6-Chloropyridin-2-yl) ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (34);
(6-chloropyridin-2-yl) ((4 r,5 r) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (35);
(6-chloropyridin-2-yl) ((4 s,5 r) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (36);
(6-chloropyridin-2-yl) ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (37)
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=5:95, wavelength: 220/254nm.
Compound 34: white solid, yield 35%; the retention time was 23.303 minutes.
LC-MS:m/z＝353.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.87-7.83(m,2H),7.45(d,J＝8.0Hz,1H),4.56-4.44(m,1H),4.12-4.02(m,2H),3.24-3.11(m,1H),2.87-2.62(m,4H),2.36-2.21(m,1H),2.22-2.07(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-91.70,-98.65,-108.58,-121.92.
Compound 35: white solid, yield 26%; retention time 30.543 min.
LC-MS:m/z＝353.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.87-7.83(m,2H),7.45(d,J＝8.0Hz,1H),4.56-4.44(m,1H),4.12-4.02(m,2H),3.24-3.11(m,1H),2.87-2.62(m,4H),2.36-2.21(m,1H),2.22-2.07(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-91.70,-98.65,-108.58,-121.92.
Compound 36: white solid, yield 51%; retention time 20.087 min.
LC-MS:m/z＝353.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.05-8.01(m,1H),7.79-7.77(m,1H),7.69-7.67(m,1H),6.72(s,1H),4.25-3.96(m,3H),2.81-2.76(m,2H),2.67-2.58(m,2H),2.15-2.04(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-83.27,-83.86,-86.40,-86.99,-108.02,-108.63,-115.30,-115.92.
Compound 37: white solid, yield 9%; retention time 22.560 min.
LC-MS:m/z＝353.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.05-8.01(m,1H),7.79-7.77(m,1H),7.69-7.67(m,1H),6.71(s,1H),4.25-3.96(m,3H),2.81-2.76(m,2H),2.67-2.58(m,2H),2.17-2.05(m,2H).
19 F NMR(377MHz,DMSO-d 6 ) Delta-83.27, -83.86, -86.41, -87.00, -108.02, -108.63, -115.30, -115.92. Synthesis example 37: synthesis of Compound 38-41 (6-chloro-5-fluoropyridin-2-yl) ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [ 4.4)]Nonan-1-yl) methanone (38); (6-chloro-5-fluoropyridin-2-yl) ((4R, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [ 4.4)]Nonan-1-yl) methanone (39); (6-chloro-5-fluoropyridin-2-yl) ((4S, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4]]Nonan-1-yl) methanone (40); (6-chloro-5-fluoropyridin-2-yl) ((4R, 5S) -3,3,7,7-
Tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (41)
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=5:95, wavelength: 220/254nm.
Compound 38: white solid, yield 21%; retention time 18.887 min.
LC-MS:m/z＝371.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.09(t,J＝8.4Hz,1H),7.91(dd,J＝8.4,3.2Hz,1H),6.77(d,J＝6.0Hz,1H),4.19-4.00(m,3H),3.15-3.02(m,1H),2.71-2.53(m,1H),2.47-2.42(m,1H),2.36-2.19(m,2H),2.17-2.03(m,1H).
19 F NMR(377MHz,DMSO-d 6 )δ-88.35,-93.88,-110.01,-116.56,-120.10.
Compound 39: white solid, yield 29%; retention time 22.373 min.
LC-MS:m/z＝371.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.09(t,J＝8.4Hz,1H),7.91(dd,J＝8.4,3.6Hz,1H),6.77(d,J＝6.0Hz,1H),4.18-4.00(m,3H),3.15-3.02(m,1H),2.66-2.53(m,1H),2.47-2.40(m,1H),2.35-2.19(m,2H),2.17-2.02(m,1H).
19 F NMR(377MHz,DMSO-d 6 )δ-88.35,-93.88,-110.01,-116.56,-120.10.
Compound 40: white solid, yield 13%; retention time 25.940 min.
LC-MS:m/z＝371.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.09(t,J＝8.4Hz,1H),7.91(dd,J＝8.4,3.6Hz,1H),6.77(d,J＝6.0Hz,1H),4.24-3.97(m,3H),2.80-2.72(m,2H),2.66-2.55(m,2H),2.16-1.99(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-88.33,-91.46,-113.18,-116.60,-120.45.
Compound 41: white solid, yield 9%; retention time 27.400 min.
LC-MS:m/z＝371.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.09(t,J＝8.8Hz,1H),7.90(dd,J＝8.4,3.6Hz,1H),6.71(d,J＝6.0Hz,1H),4.24-3.97(m,3H),2.82-2.72(m,2H),2.71-2.54(m,2H),2.21-2.01(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-88.33,-91.46,-113.18,-116.60,-120.45.
Synthesis example 38: synthesis of Compound 42-45 (6- (difluoromethyl) pyridin-2-yl) ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (42);
(6- (difluoromethyl) pyridin-2-yl) ((4 r,5 r) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (43);
(6- (difluoromethyl) pyridin-2-yl) ((4 s,5 r) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (44);
(6- (difluoromethyl) pyridin-2-yl) ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (45)
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.
Compound 42: white solid, yield 10%; retention time 10.033 minutes.
LC-MS:m/z＝369.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.17(t,J＝8.0Hz,1H),7.95(d,J＝8.0Hz,1H),7.84(d,J＝8.0Hz,1H),7.05(t,J＝54.8Hz,1H),6.74(d,J＝6.0Hz,1H),4.26-3.99(m,3H),2.87-2.74(m,2H),2.71-2.55(m,2H),2.24-2.02(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-88.30,-91.48,112.59,116.00,120.26.
Compound 43: white solid, yield 9%; retention time 9.630 min.
LC-MS:m/z＝369.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.17(t,J＝8.0Hz,1H),7.95(d,J＝7.6Hz,1H),7.84(d,J＝8.0Hz,1H),7.05(t,J＝54.8Hz,1H),6.74(d,J＝6.0Hz,1H),4.24-3.98(m,3H),3.19-3.03(m,1H),2.70-2.56(m,1H),2.47-2.41(m,1H),2.37-2.24(m,2H),2.18-2.03(m,1H).
19 F NMR(377MHz,DMSO-d 6 )δ-88.42,-93.96,109.54,115.99,119.99.
Compound 44: white solid, yield 9%; retention time 11.740 min.
LC-MS:m/z＝369.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.17(t,J＝8.0Hz,1H),7.95(d,J＝8.0Hz,1H),7.84(d,J＝8.0Hz,1H),7.05(t,J＝54.8Hz,1H),6.74(d,J＝6.0Hz,1H),4.23-3.98(m,3H),3.20-3.03(m,1H),2.71-2.55(m,1H),2.47-2.42(m,1H),2.34-2.24(m,2H),2.17-2.04(m,1H).
19 F NMR(377MHz,DMSO-d 6 )δ-88.42,-93.96,109.54,115.99,119.99.
Compound 45: white solid, yield 7%; retention time 14.783 min.
LC-MS:m/z＝369.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.17(t,J＝8.0Hz,1H),7.95(d,J＝7.6Hz,1H),7.84(d,J＝7.6Hz,1H),7.05(t,J＝54.8Hz,1H),6.74(d,J＝6.0Hz,1H),4.22-4.00(m,3H),2.86-2.73(m,2H),2.68-2.57(m,2H),2.23-2.01(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-88.30,-91.48,112.59,116.00,120.26.
Synthesis example 39: synthesis of (6- (difluoromethyl) -5-fluoropyridin-2-yl) ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (46) from Compound 46-49;
(6- (difluoromethyl) -5-fluoropyridin-2-yl) ((4 r,5 r) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (47); (6- (difluoromethyl) -5-fluoropyridin-2-yl) ((4S, 5R) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (48); (6- (difluoromethyl) -5-fluoropyridin-2-yl) ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (49)
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=10:90, wavelength: 220/254nm.
Compound 46: white solid, yield 17%; retention time 10.693 min.
LC-MS:m/z＝387.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.12(s,1H),8.10(d,J＝1.5Hz,1H),7.23(t,J＝53.2Hz,1H),6.80(d,J＝6.0Hz,1H),4.30-3.98(m,3H),3.21-3.02(m,1H),2.72-2.55(m,1H),2.49-2.41(m,1H),2.37-2.21(m,2H),2.18-2.03(m,1H).
19 F NMR(377MHz,DMSO-d 6 )δ-88.44,-94.00,109.45,117.61,120.02,123.30.
Compound 47: white solid, yield 14%; retention time 11.757 min.
LC-MS:m/z＝387.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.11-8.09(m,2H),7.23(t,J＝52.8Hz,1H),6.80(d,J＝5.6Hz,1H),4.21-4.05(m,3H),2.85-2.73(m,2H),2.68-2.55(m,2H),2.22-2.01(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-88.29,-91.56,112.52,117.62,120.29,123.36.
Compound 48: white solid, yield 17%; retention time 14.130 min.
LC-MS:m/z＝387.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.11(s,1H),8.10(d,J＝1.6Hz,1H),7.23(t,J＝52.8Hz,1H),6.80(d,J＝6.0Hz,1H),4.26-3.99(m,3H),3.18-3.01(m,1H),2.69-2.54(m,1H),2.46-2.41(m,1H),2.36-2.21(m,2H),2.17-2.04(m,1H).
19 F NMR(377MHz,DMSO-d 6 )δ-88.44,-94.00,109.45,117.62,120.02,123.30.
Compound 49: white solid, yield 10%; retention time 17.647 min.
LC-MS:m/z＝387.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.10(m,2H),7.23(t,J＝52.8Hz,1H),6.73(d,J＝6.0Hz,1H),4.19-4.05(m,3H),2.85-2.73(m,2H),2.66-2.57(m,2H),2.21-2.00(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-88.28,-91.56,112.51,117.61,120.29,123.36.
Synthesis example 40: synthesis of Compound 50-53 (6- (difluoromethyl) -4-fluoropyridin-2-yl) ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (50);
(6- (difluoromethyl) -4-fluoropyridin-2-yl) ((4 r,5 r) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (51);
(6- (difluoromethyl) -4-fluoropyridin-2-yl) ((4 s,5 r) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (52);
(6- (difluoromethyl) -4-fluoropyridin-2-yl) ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (53)
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 (+0.1% diethanolamine) =40:60, wavelength: 220/254nm.
Compound 50: white solid, yield 10%; retention time 7.990 min.
LC-MS:m/z＝387.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.81(dd,J＝8.8,2.0Hz,1H),7.47(dd,J＝8.4,2.4Hz,1H),6.61(t,J＝55.2Hz,1H),4.46-4.35(m,1H),4.19-4.09(m,1H),4.08-4.01(m,1H),3.25-3.11(m,1H),2.89-2.62(m,4H),2.24-2.06(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-90.43,-96.43,-97.86,-110.43,-116.44,-122.34.
Compound 51: white solid, yield 25%; retention time 9.950 min.
LC-MS:m/z＝387.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.81(dd,J＝8.8,2.0Hz,1H),7.47(dd,J＝8.0,2.4Hz,1H),6.62(t,J＝55.2Hz,1H),4.55-4.43(m,1H),4.14-4.04(m,2H),3.22-3.08(m,1H),2.87-2.61(m,3H),2.52-2.43(m,1H),2.38-2.28(m,1H),2.22-2.08(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-91.83,-96.45,-98.72,-108.44,-116.44,-122.00.
Compound 52: white solid, yield 30%; retention time 11.430 min.
LC-MS:m/z＝387.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.81(dd,J＝8.8,2.0Hz,1H),7.47(dd,J＝8.0,2.4Hz,1H),6.62(t,J＝55.2Hz,1H),4.55-4.44(m,1H),4.14-4.04(m,2H),3.22-3.08(m,1H),2.87-2.60(m,3H),2.51-2.44(m,1H),2.36-2.28(m,1H),2.22-2.10(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-91.83,-96.45,-98.72,-108.45,-116.44,-122.00.
Compound 53: white solid, yield 10%; retention time 26.800 min.
LC-MS:m/z＝387.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.81(dd,J＝8.4,1.6Hz,1H),7.47(dd,J＝8.0,2.4Hz,1H),6.62(t,J＝54.8Hz,1H),4.46-4.35(m,1H),4.18-4.10(m,1H),4.08-4.01(m,1H),3.25-3.11(m,1H),2.90-2.67(m,4H),2.24-2.05(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-90.44,-96.43,-97.84,-110.43,-116.44,-122.34.
Synthesis example 41: synthesis of Compound 54-57 (6-chloro-5- (difluoromethoxy) pyridin-2-yl) ((4S, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (54); (6-chloro-5- (difluoromethoxy) pyridin-2-yl) ((4 r,5 r) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (55); (6-chloro-5- (difluoromethoxy) pyridin-2-yl) ((4 s,5 r) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (56); (6-chloro-5- (difluoromethoxy) pyridin-2-yl) ((4R, 5S) -3,3,7,7-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (57)
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=10:90, wavelength: 220/254nm.
Compound 54: white solid, yield 14%; retention time 13.333 min.
LC-MS:m/z＝419.1[M+H] + .
1H NMR(400MHz,CDCl 3 )δ7.96(d,J＝8.4Hz,1H),7.71(d,J＝8.4Hz,1H),6.66(t,J＝71.6Hz,1H),4.59-4.47(m,1H),4.16-4.04(m,2H),3.23-3.09(m,1H),2.87-2.53(m,3H),2.50-2.42(m,1H),2.35-2.27(m,1H),2.20-2.09(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-82.46,-91.74,-98.66,-108.49,-121.91.
Compound 55: white solid, yield 6%; retention time 14.397 min.
LC-MS:m/z＝419.1[M+H] + .
1H NMR(400MHz,CDCl 3 )δ7.96(d,J＝8.4Hz,1H),7.71(d,J＝8.4Hz,1H),6.66(t,J＝71.6Hz,1H),4.48-4.36(m,1H),4.22-4.14(m,1H),4.04(t,J＝5.2Hz,1H),3.22-3.09(m,1H),2.88-2.64(m,4H),2.24-2.06(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-82.46,-90.50,-97.81,-110.63,-122.22.
Compound 56: white solid, yield 8%; retention time 15.437 min.
LC-MS:m/z＝419.1[M+H] + .
1H NMR(400MHz,CDCl 3 )δ7.96(d,J＝8.4Hz,1H),7.71(d,J＝8.4Hz,1H),6.66(t,J＝71.6Hz,1H),4.59-4.46(m,1H),4.16-4.08(m,1H),4.04(d,J＝4.0Hz,1H),3.23-3.09(m,1H),2.87-2.57(m,3H),2.49-2.42(m,1H),2.35-2.27(m,1H),2.20-2.09(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-82.45,-91.74,-98.65,-108.49,-121.91.
Compound 57: white solid, yield 5%; retention time 31.707 min.
LC-MS:m/z＝419.1[M+H] + .
1H NMR(400MHz,CDCl 3 )δ7.96(d,J＝8.4Hz,1H),7.71(d,J＝8.4Hz,1H),6.59(t,J＝71.6Hz,1H),4.48-4.36(m,1H),4.22-4.14(m,1H),4.05(t,J＝4.8Hz,1H),3.23-3.09(m,1H),2.88-2.60(m,4H),2.21-2.05(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-82.46,-90.50,-97.84,-110.62,-122.22.
Synthesis example 42: synthesis of (6-chloropyridin-2-yl) ((4S, 5R) -3, 6-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone from Compound 58, 59; (6-chloropyridin-2-yl) ((4 r,5 s) -3, 6-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (58-P1 and 58-P2);
(6-chloropyridin-2-yl) ((4 s,5 s) -3, 6-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone; (6-chloropyridin-2-yl) ((4R, 5R) -3, 6-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (59-P1 and 59-P2)
First step ethyl 2, 2-difluoro-1- (3-methoxy-3-oxopropanamido) cyclopentane-1-carboxylate 58-2
Compound 58-1 (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 58-2 (2.9 g, yield: 60%) as a yellow oily liquid.
Second step 6.6-difluoro-1-azaspiro [4.4] nonane-2.4-dione 58-3
Compound 58-2 (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, and 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 58-3 (1.6 g, yield 97%) as a yellow solid.
Third step 3.3.6.6-tetrafluoro-1-azaspiro [4.4] nonane-2.4-dione 58-4
Compound 58-3 (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 58-4 (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 58-5
Compound 58-4 (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 58-5 (5.1 g, 83% combined in two steps) as a white solid.
Fifth step 3, 6-tetrafluoro-1-azaspiro [4.4] non-4-ol 58-6
Compound 58-5 (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 58-6 (2.9 g, yield 72%) as a white solid.
Sixth step (6-chloropyridin-2-yl) (3, 6-tetrafluoro-4-hydroxy-1-azaspiro [4.4] non-1-yl) methanone 58-7
Compound 58-6 (0.15 g,0.70 mmol) was dissolved in acetonitrile (30 mL), N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate (294.6 mg,1.05 mmol), 6-chloropyridine-2-carboxylic acid (220.6 mg,1.40 mmol) and methylimidazole (172.2 mg,2.10 mmol) were added, the reaction was stirred at room temperature for 16 hours, TLC detected complete reaction starting material, the reaction solution was quenched with water (80 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (EA/PE=1/4) to give the title compound 58-7 as a white solid. The mixture of 58-P1 and 58-P2 and the mixture of 59-P1 and 59-P2 are obtained by chiral column resolution.
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.
58-P1 and 58-P2 in the form of a white solid, 75mg, yield 30%; retention time 5.443 min.
LC-MS:m/z＝353.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.06(d,J＝7.6Hz,1H),7.82(t,J＝8.0Hz,1H),7.53(d,J＝8.0Hz,1H),5.56(d,J＝11.6Hz,1H),3.58-3.47(m,1H),3.41-3.32(m,1H),2.40-1.79(m,7H).
19 F NMR(377MHz,CDCl 3 )δ-99.75,103.53,-110.69,-115.47.
59-P1 and 59-P2 in the form of a white solid, 74mg, yield 30%; retention time 10.823 min.
LC-MS:m/z＝353.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.06(d,J＝7.6Hz,1H),7.82(t,J＝8.0Hz,1H),7.53(d,J＝8.0Hz,1H),5.56(d,J＝11.2Hz,1H),3.54-3.47(m,1H),3.41-3.32(m,1H),2.42-1.65(m,7H).
19 F NMR(377MHz,CDCl 3 )δ-99.75,103.52,-110.70,-115.47.
Synthesis example 43: synthesis of (6-chloropyridin-2-yl) ((4S, 7R, 8S) -3,3,7,8-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone from Compound 60; (6-chloropyridin-2-yl) ((4R, 7R, 8S) -3,3,7,8-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (60)
First step 6-oxabicyclo [3.1.0] hexane-3-carboxylic acid methyl ester 60-2
Compound 60-1 (15.0 g,119 mmol) was dissolved in dichloromethane (300 mL), cooled to 0deg.C with an ice bath, and m-chloroperoxybenzoic acid (41.0 g,237.8 mmol) was added dropwise. After addition, the mixture was slowly warmed to room temperature for 2 hours and 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 sulfite solution to quench, and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated to give the title compound 60-2 (19.0 g, crude product) which was used directly in the next step.
Second step 3-fluoro-4-hydroxycyclopentane-1-carboxylic acid methyl ester 60-3
Compound 60-2 (19.0 g, crude) was dissolved in 1, 2-dichloroethane (100 mL) and triethylamine hydrofluoride (65.0 g,403 mmol) was added at room temperature. After addition, the mixture was reacted at 85 ℃ for 12 hours, TLC (petroleum ether/ethyl acetate=4/1, phosphomolybdic acid color development) showed the disappearance of starting material. The reaction solution was cooled to room temperature, washed with water (200 mL), separated, and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound 60-3 (13.7 g, crude product) as a brown oily liquid, which was used directly in the next step.
Third step (cis) -3, 4-difluorocyclopentane-1-carboxylic acid methyl ester 60-4
Compound 60-3 (12.7 g, crude) was dissolved in dichloromethane (200 mL), cooled to 0deg.C in an ice bath, and diethylaminosulfur trifluoride (31.7 g, 197mmol) was added dropwise. After addition, the mixture was stirred at room temperature overnight, TLC (petroleum ether/ethyl acetate=10/1, phosphomolybdic acid color development) showed the disappearance of starting material and the completion of the reaction. The reaction was slowly poured into a cold saturated sodium carbonate solution to alkalify to ph=8-9, the solution was separated, the organic phase was washed with saturated brine (100 mL), concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound 60-4 (4.7 g, three-step yield 24%) as a brown liquid.
Fourth step 1-benzyl 1-methyl 3, 4-difluorocyclopentane-1, 1-dicarboxylic acid 60-5
Compound 60-4 (4.7 g,28.4 mmol) is dissolved in anhydrous tetrahydrofuran (100 mL), cooled to-60 ℃ under the protection of nitrogen, lithium bis (trimethylsilyl) amide (56.8 mL,56.8 mmol) is added, and the reaction solution is continuously stirred for 1 hour at-60 ℃ after the dropwise addition is completed; benzyl chloroformate (9.7 g,56.8 mmol) was slowly added dropwise to the above reaction solution, kept at-60 ℃ under stirring for 1 hour, TLC showed complete reaction of the starting materials, and after slowly warming up to room temperature, saturated aqueous ammonium chloride solution (200 mL) was added and stirred for 10 minutes, ethyl acetate was added to extract (100 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (EA: PE=1:25) to give the title compound 60-5 (5.6 g, yield: 66%) as a yellow oily liquid.
Fifth step 3, 4-difluoro-1-methoxycarbonylcyclopentane-1-carboxylic acid (cis) 60-6
Compound 60-5 (5.9 g,18.8 mmol) was dissolved in methanol (100 mL), palladium on carbon (0.7 g, 10%) was added, and after 3 times of hydrogen substitution, the mixture was stirred at room temperature under the protection of 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 60-6 (4.0 g, crude) as a yellow solid, which was used directly in the next step.
LC-MS:m/z＝209.2[M+H] +
Sixth step 1- (Boc) amino-3, 4-difluorocyclopentane-1-carboxylic acid methyl ester (cis) 60-7
Compound 60-6 (4.0 g, crude product) was dissolved in dry t-butanol (50 mL), diphenyl azide phosphate (7.9 g,28.8 mmol) and triethylamine (2.9 g,28.8 mmol) were added, and after the addition, the reaction mixture was stirred for 16 hours at 90℃and TLC showed complete reaction of the starting materials. 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 (EA: pe=1:5) to give the title compound 60-7 as a white solid (3.5 g, 67% yield in two steps).
LC-MS:m/z＝280.3[M+H] +
Seventh step 1-amino-3, 4-difluorocyclopentane-1-carboxylic acid methyl ester (cis-difluoro) trifluoroacetate salt 60-8
Compound 60-7 (3.5 g,12.5 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (10 mL) was added, and the reaction was continued to stir 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 60-8 (2.4 g, crude) as a brown oily liquid, which was used directly in the next step.
Eighth step 60-9 methyl 3, 4-difluoro-1- (3-methoxy-3-oxopropanamido) cyclopentane-1-carboxylate (cis-difluoro)
Compound 60-8 (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 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 60-9 (2.4 g, two step yield: 69%) as a yellow oil.
LC-MS:m/z＝280.2[M+H] +
Ninth step 7, 8-difluoro-1-azaspiro [4.4] nonane-2.4-dione 60-10
Compound 60-9 (2.4 g,8.6 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), cooled to 0deg.C under nitrogen protection, potassium tert-butoxide (1.5 g,12.9 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 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, the remainder was added with saturated solution prepared by 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 60-10 (1.8 g, crude product) as a yellow solid, which was directly used in the next step.
Tenth step 3.3.7.8-tetrafluoro-1-azaspiro [4.4] nonane-2.4-dione 60-11
Compound 60-10 (1.8 g, crude product) 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 to stir at room temperature for 12 hours after the addition, and TLC detection of the starting material was complete. 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 60-11 (1.9 g, crude) as a yellow solid, which was used directly in the next step.
LC-MS:m/z＝224.1[M-H] -
Eleventh step 3,3,3,7,8-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-2-one 60-12
Compound 60-11 (1.9 g, crude product) 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 checked the completion of the starting material reaction. The reaction solution was concentrated under reduced pressure to give the title compound 60-12 (2.3 g, crude product) as a white solid, which was used directly in the next step.
Twelfth step 3,3,7,8-tetrafluoro-1-azaspiro [4.4] nonan-4-ol 60-13
Compound 60-12 (2.3 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 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 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 60-13 (0.45 g, 25% combined in three steps) as a white solid.
Thirteenth step (6-Chloropyridin-2-yl) (3,3,7,8-tetrafluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 60
Compound 60-13 (0.1 g,0.47 mmol) was dissolved in N, N-dimethylacetamide (10 mL), benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate (356 mg,0.94 mmol), 6-chloropyridine-2-carboxylic acid (148 mg,0.94 mmol) and N, N-diisopropylethylamine (182 mg,1.41 mmol) were added, the reaction was continued stirring at room temperature for 16 hours after addition, TLC was used to check that the starting material was complete, the reaction solution was quenched with water (80 mL), extracted with ethyl acetate (50 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (EA/PE=1/4) to give compound 60 (78 mg, yield 47%) as a white solid.
LC-MS:m/z＝353.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.03(t,J＝8.0Hz,1H),7.78(d,J＝8.0Hz,1H),7.69(d,J＝8.0Hz,1H),6.83(d,J＝4.0Hz,1H),5.61-5.30(m,2H),4.17-4.00(m,3H),2.71-2.56(m,2H),2.40-2.15(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-110.00,-120.42,-197.32,-198.13.
Synthesis example 44: synthesis of Compound 61
(6-chloropyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-7-en-1-yl) methanone (61)
First step 2-allyl-2-nitropenten-4-enoic acid ethyl ester 61-2
Tetrakis (triphenylphosphine) palladium (850 mg,0.74 mmol) was dissolved in dichloromethane (150 mL), replaced with nitrogen three times, compound 61-1 (20.0 g,150.3 mmol) and allyl acetate (31.6 g,315.6 mmol) were added, sodium hydrogen (13.2 g,330.6 mmol) was added under ice bath, and the reaction solution was stirred at room temperature for 1 hour. TLC (petroleum ether/ethyl acetate=10/1) showed the disappearance of starting material. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL), extracted with dichloromethane (50 mL. Times.2), the organic phases were combined, washed with saturated brine (50 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 61-2 (17.26 g, yield 54%) as a colorless liquid.
1 H NMR(400MHz,DMSO-d 6 )δ5.76-5.63(m,2H),5.28-5.15(m,4H),4.28-4.18(m,2H),2.96-2.82(m,4H),1.20(t,J＝8.0Hz,3H).
Second step 1-nitrocyclopent-3-ene-1-carboxylic acid ethyl ester 61-3
Compound 61-2 (17.26 g,80.95 mmol) was dissolved in dichloromethane (150 mL) and Grubbs was added 2nd The catalyst (687 mg,0.81 mmol) was added and the reaction stirred at room temperature for 5 hours. TLC (petroleum ether/ethyl acetate=10/1) showed the disappearance of starting material. The reaction solution was filtered, and the filtrate was directly concentrated to give the title compound 61-3 (14.6 g, crude) as a black liquid, which was used directly in the next step.
Third step 1-Aminocyclopent-3-ene-1-carboxylic acid ethyl ester 61-4
To a mixed solution of ethanol (50 mL) and water (10 mL) was dissolved compound 61-3 (5.0 g,27.0 mmol), iron powder (7.54 g,135.0 mmol) and ammonium chloride (7.22 g,135.0 mmol) were added, and the reaction mixture was stirred at 60℃for 16 hours. TLC (dichloromethane/methanol=10/1, potassium permanganate color development) showed the disappearance of starting material. The reaction solution was filtered while hot, the filter cake was washed with ethanol (10 mL x 3), the filtrate was concentrated, diluted with water (30 mL), extracted with ethyl acetate (20 mL), the pH was adjusted to 7 in the aqueous phase, extracted with ethyl acetate (20 mL x 2), the organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated to give the title compound 61-4 (1.05 g, crude) as a black liquid, which was used directly in the next step.
LC-MS:m/z＝156.1[M+H] + .
Fourth step 1- (3-methoxy-3-oxopropanamido) cyclopent-3-ene-1-carboxylic acid ethyl ester 61-5
Compound 61-4 (1.05 g,6.77 mmol) was dissolved in dichloromethane (20 mL), and methyl malonate acyl chloride (1.2 g,8.80 mmol) and triethylamine (1.71 g,19.65 mmol) were added under ice-bath, and the reaction solution was stirred at room temperature for 16 hours. TLC (dichloromethane/methanol=10/1, potassium permanganate color development) showed the disappearance of starting material. The reaction mixture was washed with citric acid solution (20 mL), diluted with water (10 mL), extracted with dichloromethane (20 mL. Times.2), combined with organic phases, 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 61-5 (847 mg, three steps yield 12%) as a white solid.
LC-MS:m/z＝256.2[M+H] + .
Fifth step methyl 2, 4-dioxo-1-azaspiro [4.4] nonane-7-ene-3-carboxylate 61-6
Compound 61-5 (1.0 g,3.92 mmol) was dissolved in tetrahydrofuran (20 mL), and potassium tert-butoxide (428 mg,5.88 mmol) was added, followed by reaction at room temperature of 20℃for 2 hours. TLC (petroleum ether/ethyl acetate=1/1, potassium permanganate color development) detected complete reaction of starting material. The reaction solution was directly concentrated to give the title compound 61-6, and the crude product was directly taken to the next step.
Sixth step 1-azaspiro [4.4] nonan-7-ene-2, 4-dione 61-7
Compound 61-6 (crude product of the previous step) was dissolved in tetrahydrofuran (30 mL), 1M diluted hydrochloric acid (10 mL) was added, and after the addition, the reaction mixture was heated to 80℃for 3 hours, and TLC (dichloromethane/methanol=20/1) showed the disappearance of the starting material. The reaction solution was cooled to room temperature and concentrated to remove tetrahydrofuran. Ethyl acetate (20 mL) was added to the solution to extract. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the title compound 61-7 (490 mg, two-step yield 83%) as a pale yellow oil.
LC-MS:m/z＝152.2[M+H] + .
Seventh step 3, 3-difluoro-1-azaspiro [4.4] nonan-7-ene-2, 4-dione 61-8
Compound 61-7 (490 mg,3.24 mmol) was dissolved in acetonitrile (20 mL), selectFluor (2.5 g,7.13 mmol) and water (20 mL) were added, and the reaction mixture was reacted at room temperature for 18 hours after the addition, and TLC (dichloromethane/methanol=20/1) detected complete reaction of the starting material. The reaction mixture was concentrated under reduced pressure to remove acetonitrile, and ethyl acetate (20 mL) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the title compound 61-8 (376 mg, yield 62%) as a pale yellow oil.
LC-MS:m/z＝186.1[M-H] - .
Eighth step 5-ethyl-3, 3-difluoro-4-hydroxy-5-methylpyrrolidin-2-one 61-9
Compound 61-8 (376 mg,2.01 mmol) was dissolved in methanol (6 mL), cooled to 0deg.C, sodium borohydride (114 mg,3.01 mmol) was added, and the reaction was stirred at 0deg.C for 1 hour. TLC (petroleum ether/ethyl acetate=1/1, potassium permanganate color developer) detected complete reaction of the starting material. The reaction was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (PE/ea=1/1 to DCM/meoh=40/1) to give the title compound 61-9 as an off-white solid (198 mg, 53% yield).
LC-MS:m/z＝190.2[M+H] + .
Ninth step 3, 3-difluoro-1-azaspiro [4.4] nonan-7-en-4-ol 61-10
Compound 61-9 (198 mg,1.05 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL), lithium aluminum hydride (79 mg,2.09 mmol) was added, and the reaction mixture was heated to reflux for 2 hours after the addition, and TLC (Petroleum ether/ethyl acetate=1/1, potassium permanganate color development) detected complete reaction of the starting material. The reaction mixture was cooled to 0deg.C, quenched by the addition of water (0.8 mL), sodium hydroxide solution (0.8 mL, 15%) and water (2.4 mL) in this order, stirred at room temperature for 15 min, then added with anhydrous sodium sulfate, stirred for 10 min, filtered with suction, and the filtrate concentrated to give the title compound 61-10 (153 mg, 84% yield) as a pale yellow solid.
LC-MS:m/z＝176.2[M+H] +
Tenth step (6-Chloropyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-7-en-1-yl) methanone 61
6-chloropyridine-2-carboxylic acid (45 mg,0.29 mmol) and compound 61-10 (50 mg,0.29 mmol) were dissolved in N, N-dimethylformamide (3 mL), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (132 mg,0.35 mmol) and triethylamine (75 mg,0.58 mmol) were added in this order, and the reaction mixture was stirred at 20℃for 16 hours, and the completion of the reaction was detected by TLC (Petroleum ether/ethyl acetate=4/1). The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated brine (10 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Perp-TLC (EA/pe=1/2) to give the title compound 61 (44 mg, yield 49%) as a white solid.
LC-MS:m/z＝315.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.88(d,J＝7.6Hz,1H),7.78(d,J＝7.6Hz,1H),7.42(d,J＝8.0Hz,1H),5.79-5.77(m,1H),5.74-5.72(m,1H),4.48-4.37(m,1H),4.26-4.18(m,1H),4.05-4.01(m,1H),3.27-3.22(m,1H),3.04(br,2H),2.57-253(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-110.96,-121.27.
Synthesis example 45: synthesis of Compound 62
(6-chloropyridin-2-yl) (9, 9-difluoro-10-hydroxy-6-azaspiro [4.5] decan-6-yl) methanone (62)
First step 1- ((4-methoxy-4-oxobutyl) amino) cyclopentane-1-carboxylic acid methyl ester 62-2
Compound 62-1 (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 62-2 (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 62-3
Compound 62-2 (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 62-3 (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 62-4
Compound 62-3 (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 62-4 (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 62-5
Compound 62-4 (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 62-5 (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 62-6
Compound 62-5 (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℃under control of temperature, the dry ice bath was reacted for 40 minutes, a solution of N-fluorobis (benzenesulfonamide) (927 mg,2.94 mmol) in tetrahydrofuran (6 mL) was added dropwise at-60-50℃under control of temperature, the dry ice bath was continued to react for 2 hours, 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 62-6 as a pale yellow solid (crude, directly taken to the next step).
LC-MS:m/z＝190.1[M-100+H] + .
Sixth step 62-7-tert-butyl 9, 9-difluoro-10-hydroxy-6-azaspiro [4.5] decane-6-carboxylate
Compound 62-6 (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 62-7 (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 62-8
Compound 62-7 (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 62-8 as a white solid (crude, directly taken to the next step).
LC-MS:m/z＝192.2[M-Cl+H] + .
Eighth step (6-chloropyridin-2-yl) (9, 9-difluoro-10-hydroxy-6-azaspiro [4.5] decan-6-yl) methanone 62
Compound 62-8 (crude) and 6-chloropyridine-2-carboxylic acid (65 mg,0.41 mmol) were dissolved in N, N-dimethylformamide (4 mL), and N, N-diisopropylethylamine (1599 mg,1.23 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (187 mg,0.49 mmol) were added sequentially. After the addition, the reaction was allowed to react at 20℃for 18 hours at room temperature, and TLC (Petroleum ether/ethyl acetate=4/1) 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=2/1) to give the title compound 62 (99 mg, 73% yield) as a pale yellow solid.
LC-MS:m/z＝331.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.90(d,J＝7.6Hz,1H),7.65(d,J＝7.2Hz,1H),7.43(d,J＝7.6Hz,1H),4.50-4.87(m,2H),3.76(t,J＝7.2Hz,1H),3.94(t,J＝6.0Hz,1H),2.38-2.21(m,2H),2.18-2.10(m,1H),2.08-1.91(m,3H),1.86-1.76(m,2H),1.72-1.65(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-100.18.
Synthesis example 46: synthesis of Compound 63
(6-chloropyridin-2-yl) (3, 3-difluoro-4-hydroxy-8-oxa-1-azaspiro [4.5] decan-1-yl) methanone (63)
First step 3, 3-difluoro-8-oxo-1-azaspiro [4.5] decane-2, 4-dione 63-2
Compound 63-1 (2.8 g,16.5 mmol) (DOI: 10.1002/ejoc.20180750) 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, and after the addition, the reaction was continued for 12 hours at room temperature, TLC detected complete reaction of 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, concentrated to give the title compound 63-2 (2.4 g, crude product) as a gray solid, which was directly used in the next step.
LC-MS:m/z＝204.0[M-H] - .
Second step 3, 3-difluoro-4-hydroxy-8-oxa-1-azaspiro [4.5] decan-2-one 63-3
Compound 63-2 (2.4 g,11.7 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 63-3 (11.8 g, crude product) as a white solid, which was used directly in the next step.
Third step 3, 3-difluoro-8-oxo-1-azaspiro [4.5] decan-4-ol 63-4
Compound 63-3 (11.8 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 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 63-4 (0.6 g, 20% combined yield in three steps) as a white solid.
LC-MS:m/z＝194.2[M+H] + .
Fourth step (6-chloropyridin-2-yl) (3, 3-difluoro-4-hydroxy-8-oxa-1-azaspiro [4.5] decan-1-yl) methanone 63
White solid, yield 3.7%.
LC-MS:m/z＝333.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.06(d,J＝7.5Hz,1H),7.83(t,J＝7.8Hz,1H),7.56(d,J＝7.9Hz,1H),5.24(dd,J＝12.9,3.1Hz,1H),3.84-3.71(m,4H),3.41-3.34(m,2H),2.80(s,1H),2.01-1.90(m,2H),1.69 -1.62(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-98.81,-99.45,-109.45,-110.10.
Synthesis example 47: synthesis of Compound 64
(6-chloropyridin-2-yl) (3,3,8,8-tetrafluoro-4-hydroxy-1-azaspiro [4.5] decan-1-yl) methanone (64)
First step 8, 8-difluoro-1, 3-diazaspiro [4.5] decane-2, 4-dione 64-2
4, 4-Difluorocyclohexanone 64-1 (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 64-2 (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 64-3
Compound 64-2 (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 about 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 64-3 (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 64-4
The mixture 64-3 (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 64-4 (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 64-5
Dissolving compound 64-4 (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 liquid, 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 64-5 (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 64-6
Compound 64-5 (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 64-6 (2.0 g, yield 76%) as a yellow solid.
Sixth step 3,3,8,8-tetrafluoro-1-azaspiro [4.5] decane-2, 4-dione 64-7
Compound 64-6 (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 64-7 (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 64-8
Compound 64-7 (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 64-8 (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 64-9
Compound 64-8 (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 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 64-9 (2.0 g, three-step combined yield 90%) as a white solid.
LC-MS:m/z＝228.2[M+H] + .
Ninth step (6-chloropyridin-2-yl) (3,3,8,8-tetrafluoro-4-hydroxy-1-azaspiro [4.5] decan-1-yl) methanone 64
6-chloropyridine-2-carboxylic acid (0.06 g,0.38 mmol) and DIPEA (0.090 g,0.70 mmol) were added to DMF (3 mL), HATU (0.15 g,0.40 mmol) was added under nitrogen at 0deg.C and stirred at room temperature for 30 min. 64-9 (0.079 g,0.35 mmol) was added and stirring was continued for 1.5 hours. TLC showed the reaction ended (PE: ea=2:1, r f =0.6), the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated brine (50 ml×2), and the organic phase was dried over anhydrous sodium sulfate and concentrated. Purification of the crude product by silica gel column chromatography (PE: ea=2:1) afforded the title compound 64 (0.066 g, yield 47.36%) as a white solid.
LC-MS:m/z＝367.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.77(d,J＝4.8Hz,2H),7.41(t,J＝4.4Hz,1H),4.55-4.40(m,1H),4.22(d,J＝8.4Hz,1H),4.02(d,J＝14.4Hz,1H),3.33-3.24(m,1H),3.18-3.09(m,1H),2.48(br,1H),2.28-2.11(m,3H),1.97-1.75(m,3H).
19 F NMR(377MHz,CDCl 3 )δ-93.72,-101.68,-104.56,-121.48.
Synthesis example 48: synthesis of Compound 65
(6-chloropyridin-2-yl) (2, 2-diethyl-4, 4-difluoro-3-hydroxypyrrolidin-1-yl) methanone (65)
First step methyl 2-amino-2-ethylbutyrate hydrochloride 65-2
Compound 65-1 (10.0 g,77.0 mmol) was dissolved in methanol (300 mL), cooled to 0deg.C under nitrogen protection, thionyl chloride (18.3 g,154.0 mmol) was slowly added, and stirring was continued for 30 min at 0deg.C, then warmed to 80deg.C and stirred overnight; after completion of the reaction, cooled to room temperature, the title compound 65-2 (15.8 g, crude product) was concentrated to a white solid.
Second step methyl 2-ethyl-2- (3-methoxy-3-oxopropanamido) butyrate 65-3
Compound 65-2 (15.8 g, crude product) was dissolved in anhydrous dichloromethane (300 mL), cooled to 0 ℃ under nitrogen protection, triethylamine (23.3 g,231 mmol) was added, methyl malonate acyl chloride (15.8 g,116 mmol) was slowly added dropwise 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 (EA: PE=1:3) to give the title compound 65-3 (3.6 g, two steps combined yield: 19%) as a yellow oily liquid.
Third step 5, 5-Diethylpyrrolidine-2, 4-dione 65-4
Compound 65-3 (3.6 g,14.7 mmol) was dissolved in anhydrous tetrahydrofuran (300 mL), cooled to 0deg.C under nitrogen protection, potassium tert-butoxide (2.5 g,22.0 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, the crude product was slurried with petroleum ether (100 mL), filtered with suction, and the filter cake was dried to give the title compound 65-4 (1.8 g, yield 79%) as a yellow solid.
Fourth step 5, 5-diethyl-3, 3-difluoropyrrolidine-2, 4-dione 65-5
Compound 65-4 (1.8 g,11.6 mmol) was dissolved in acetonitrile (50 mL), 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (12.3 g,34.8 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 most of the 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 65-5 (2.2 g, crude) as a gray solid, which was used directly in the next step.
Fifth step 5, 5-diethyl-3, 3-difluoro-4-hydroxypyrrolidin-2-one 65-6
Compound 65-5 (2.2 g, crude product) was dissolved in methanol (50 mL), cooled to 0deg.C, sodium borohydride (0.66 g,17.0 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 solution was concentrated under reduced pressure to give the title compound 65-6 (2.8 g, crude) as a white solid, which was used directly in the next step.
Sixth step 2, 2-diethyl-4, 4-difluoropyrrolidin-3-ol 65-7
Compound 65-6 (2.8 g, crude product) was dissolved in anhydrous tetrahydrofuran (150 mL), lithium aluminum hydride (2.2 g,57.2 mmol) was added at room temperature, 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 (2.2 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 65-7 (1.2 g, 58% combined yield in three steps) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ3.85(dd,J＝10.4,5.2Hz,1H),3.26-3.17(m,2H),1.96(br,2H),1.62-1.40(m,4H),0.94-0.87(m,6H).
19 F NMR(377MHz,CDCl 3 )δ-100.74,-109.81.
Seventh step (6-Chloropyridin-2-yl) (2, 2-diethyl-4, 4-difluoro-3-hydroxypyrrolidin-1-yl) methanone 65
6-chloropyridine-2-carboxylic acid (88 mg,0.56 mmol) was dissolved in anhydrous DMAC (10 mL), and 65-7 (50 mg,0.28 mmol), HATU (236 mg,0.62 mmol) and DIPEA (120 mg,0.93 mmol) were added at room temperature, and the reaction was stirred at room temperature for 16 h and the TLC was complete. The reaction was quenched with water (100 mL), extracted with ethyl acetate (50 mL x 3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (EA/pe=1/3) to give the title compound 65 (52 mg, yield 58%).
LC-MS:m/z＝319.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.78-7.73(m,2H),7.42(dd,J＝8.0,0.8Hz,1H),4.28-4.16(m,3H),2.40-2.38(m,1H),2.28-2.21(m,2H),2.15-2.05(m,2H),1.00-0.95(m,6H).
19 F NMR(377MHz,CDCl 3 )δ-110.06,-115.29.
Synthesis example 49: synthesis of Compound 66
(6-chloropyridin-2-yl) (2, 2-dimethyl-4, 4-difluoro-3-hydroxypyrrolidin-1-yl) methanone (66)
First step methyl 2-amino-2-methylpropionate hydrochloride 66-2
Compound 66-1 (10.0 g,65.0 mmol) was dissolved in anhydrous dichloromethane (300 mL), cooled to 0deg.C under nitrogen protection, triethylamine (13.1 g,130.0 mmol) was added, methyl malonate acyl chloride (10.6 g,78.0 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 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 66-2 (8.3 g, yield: 59%) as a yellow oily liquid.
Second step 5, 5-Dimethylpyrrolidine-2, 4-dione 66-3
Compound 66-2 (8.3 g,38.2 mmol) was dissolved in anhydrous tetrahydrofuran (300 mL), cooled to 0deg.C under nitrogen protection, potassium tert-butoxide (6.4 g,57.3 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, the crude product was slurried with petroleum ether (100 mL), filtered with suction, and the filter cake was dried to give the title compound 66-3 (3.6 g, yield 74%) as a yellow solid.
Third step 3, 3-difluoro-5, 5-dimethylpyrrolidine-2, 4-dione 66-4
Compound 66-3 (3.6 g,28.3 mmol) was dissolved in acetonitrile (50 mL), 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (30.0 g,85.0 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 afford the title compound 66-4 (3.7 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 66-5
Compound 66-4 (3.7 g, crude product) was dissolved in methanol (100 mL), cooled to 0deg.C, sodium borohydride (1.3 g,34.4 mmol) was added, and the reaction was stirred at 0deg.C for 1 hour and TLC detected complete reaction of starting materials. The reaction solution was concentrated under reduced pressure to give the title compound 66-5 (4.7 g, crude) as a white solid, which was used directly in the next step.
Fifth step 4, 4-difluoro-2, 2-dimethylpyrrolidin-3-ol 66-6
Compound 66-5 (4.7 g, crude product) was dissolved in anhydrous tetrahydrofuran (150 mL), lithium aluminum hydride (3.5 mg,92.2 mmol) was added at room temperature, and the reaction mixture was heated to 66℃after the addition was stirred for 2 hours, and TLC detected that the starting material was complete. 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 66-6 (1.9 g, 44% combined yield in three steps) as a white solid.
Sixth step (6-chloropyridin-2-yl) (4, 4-difluoro-3-hydroxy-2, 2-dimethylpyrrolidin-1-yl) methanone 66
6-chloropyridine-2-carboxylic acid (145 mg,0.92 mmol) and N, N-diisopropylethylamine (178 mg,1.38 mmol) were added to N, N-dimethylacetamide (10 mL), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (350 mg,0.92 mmol) and compound 66-6 (70 mg,0.46 mmol) were added, and the reaction mixture was stirred at room temperature overnight, and TLC showed the end of the reaction (PE: EA=2:1, R) f =0.3); the reaction was quenched with water (50 mL), extracted with ethyl acetate (50 mL), washed with saturated brine (50 mL x 2), the combined organic phases dried over anhydrous sodium sulfate, concentrated, and the crude product purified by silica gel column chromatography (PE: ea=2:1) to give the title compound 66 (86 mg, yield 63.8%) as a white solid.
LC-MS:m/z＝291.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.00(t,J＝8.0Hz,1H),7.67(dd,J＝18.4,8.0Hz,2H),6.25(d,J＝6.4Hz,1H),4.17-3.84(m,3H),1.59(s,3H),1.40(s,3H).
19 F NMR(377MHz,DMSO-d 6 )δ-111.45,-116.14.
Synthesis example 50: compounds 67 and 68 were synthesized as (6-chloropyridin-2-yl) ((2 s,3 s) -2-ethyl-4, 4-difluoro-3-hydroxy-2-methylpyrrolidin-1-yl) methanone; (6-chloropyridin-2-yl) ((2 r,3 r) -2-ethyl-4, 4-difluoro-3-hydroxy-2-methylpyrrolidin-1-yl) methanone (67-P1 and 67-P2);
(6-chloropyridin-2-yl) ((2 r,3 s) -2-ethyl-4, 4-difluoro-3-hydroxy-2-methylpyrrolidin-1-yl) methanone; (6-chloropyridin-2-yl) ((2S, 3R) -2-ethyl-4, 4-difluoro-3-hydroxy-2-methylpyrrolidin-1-yl) methanone (68-P1 and 68-P2)
First step methyl 2-amino-2-methylbutanoate hydrochloride 67-2
Compound 67-1 (5.00 g,42.68 mmol) was dispersed in methanol (50 mL) and thionyl chloride (15.2 g,128.0 mmol) was slowly added dropwise at 0deg.C. After the dripping, the reaction solution is heated to 60 ℃ for reaction for 16 hours. TLC (dichloromethane/methanol=20/1, iodine color development) showed the disappearance of starting material. The reaction solution was concentrated under reduced pressure to give the title compound 67-2 (crude product) as a white solid, which was used in the next step.
LC-MS:m/z＝132.2[M-HCl+H] + .
Second step 2- (3-methoxy-3-oxopropanamido) -2-methylbutanoic acid methyl ester 67-3
Compound 67-2 (crude) was dispersed in dichloromethane (50 mL), cooled to 0deg.C under nitrogen protection, triethylamine (10.8 g,106.7 mmol) was added, methyl malonate acyl chloride (7.8 g,55.4 mmol) was slowly added dropwise, and stirring was continued at 0deg.C for 1.5 hours after the addition was completed. TLC (dichloromethane/methanol=20/1, iodine color development) showed the disappearance of the starting material, the reaction was quenched with water (50 mL), stirred for 5 min, and then separated. The organic phase was washed with 10% citric acid (30 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give the title compound 67-3 (8.4 g, two-step yield: 85%) as a pale yellow oily liquid.
LC-MS:m/z＝232.2[M+H] + .
Third step 5-Ethyl-5-methyl-2, 4-dioxopyrrolidine-3-carboxylic acid methyl ester 67-4
Compound 67-3 (4.0 g,17.3 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0deg.C under nitrogen, and potassium tert-butoxide (2.9 g,25.9 mmol) was added in portions and reacted for 2 hours with an ice bath. TLC (petroleum ether/ethyl acetate=2/1, potassium permanganate color development) detected complete reaction of starting material. Dilute hydrochloric acid (26 ml,1 n) was added to the reaction solution to adjust the pH to about 2-3, the reaction solution was warmed to 80 ℃ and reacted for 2 hours, and TLC monitored the disappearance of the intermediate. The reaction was cooled to room temperature, the solution was separated, the aqueous phase was extracted with ethyl acetate (20 ml x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound 67-4 (2.8 g, crude) as a pale yellow oily liquid, which was used directly in the next step.
LC-MS:m/z＝142.2[M+H] + .
Fourth step 5-ethyl-3, 3-difluoro-5-methylpyrrolidine-2, 4-dione 67-5
Compound 67-4 (2.8 g, crude) was dissolved in acetonitrile (50 mL), selectFluor (13.5 g,38.06mmol and water (30 mL) were added, stirring was continued for 12 hours at room temperature 20℃after addition, TLC (Petroleum ether/ethyl acetate=1/1) detected complete reaction of the starting materials, the reaction solution was concentrated to dryness under reduced pressure, ethyl acetate (40 mL) was added and stirred for 1 hour, suction filtration, and the filtrate was concentrated to give the title compound 67-5 (3.1 g, crude) as a colorless oil, which was directly used in the next step.
LC-MS:m/z＝176.1[M-H] - .
Fifth step 5-Ethyl-3, 3-difluoro-4-hydroxy-5-methylpyrrolidin-2-one 67-6
Compound 67-5 (3.1 g, crude) was dissolved in methanol (30 mL), cooled to 0deg.C, sodium borohydride (1.0 g,26.2 mmol) was added, and stirring was continued for 1 hour at 0deg.C. TLC (petroleum ether/ethyl acetate=1/1, aldehyde ketone color reagent) detected complete reaction of starting material. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (30 mL) and water (10 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound 67-6 (2.4 g, crude) as a pale yellow oil, which was used directly in the next step.
LC-MS:m/z＝178.1[M-H] - .
Sixth step 2-ethyl-4, 4-difluoro-2-methylpyrrolidin-3-ol 67-7
Compound 67-6 (2.4 g, crude product) was dissolved in anhydrous tetrahydrofuran (40 mL), lithium aluminum hydride (1.0 g,26.8 mmol) was added at 0deg.C, and after the addition, the reaction was heated to reflux for 2 hours, and TLC (Petroleum ether/ethyl acetate=1/1, potassium permanganate color development) detected the completion of the starting material reaction. The reaction solution was cooled to 0 ℃, quenched by the sequential addition of water (1 mL), sodium hydroxide solution (1 mL, 15%) and water (3 mL), stirred at room temperature for 20 min, filtered off with suction, the filtrate dried over anhydrous sodium sulfate, concentrated, and the crude purified by silica gel column chromatography (PE/ea=2/1) to give the title compound 67-7 (163 mg, 5.7% combined in four steps) as a white solid.
LC-MS:m/z＝166.2[M-H] - .
Seventh step (6-Chloropyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] non-1-yl) methanone 67-8
6-chloropyridine-2-carboxylic acid (48 mg,0.30 mmol) and compound 67-7 (50 mg,0.30 mmol) were dissolved in N, N-dimethylformamide (3 mL), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (137 mg,0.36 mmol) and triethylamine (78 mg,0.60 mmol) were added in this order, and the reaction mixture was stirred at 20℃for 18 hours, and the completion of the reaction was detected by TLC (Petroleum ether/ethyl acetate=4/1). The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated brine (10 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate and concentrated to give compound 67-8.
Compound 67-8 was purified by Perp-TLC (EA/PE=1/3) to give the title compound 67-P1 and 67-P2 as a mixture and 68-P1 and 68-P2 as a white solid.
67-P1 and 67-P2: white solid, yield 60%.
LC-MS:m/z＝305.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.79-7.76(m,2H),7.41-7.39(m,1H),4.48-4.36(m,1H),4.10-4.03(m,1H),4.02-3.96(m,1H),2.51-2.44(m,1H),2.28(br,1H),2.15-2.08(m,1H),1.68(d,J＝1.2Hz,3H),1.01(t,J＝7.2Hz,3H).
19 F NMR(377MHz,CDCl 3 )δ-105.58,-120.15.
68-P1 and 68-P2 as white solid in 19% yield.
LC-MS:m/z＝305.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.79-7.77(m,2H),7.43-7.39(m,1H),4.36-4.18(m,2H),4.15-4.07(m,1H),2.35-2.19(m,2H),2.07-1.98(m,1H),1.56(s,3H),0.95(t,J＝7.2Hz,3H).
19 F NMR(377MHz,CDCl 3 )δ-113.84,-116.56.
Synthesis example 51: synthesis of Compound 69
(6-chloropyridin-2-yl) (2- (3, 3-difluorocyclobutyl) -4, 4-difluoro-3-hydroxypyrrolidin-1-yl) methanone (69)
First step 3, 3-difluorocyclobutal 69-2
Compound 69-1 (25.00 g,166.6 mmol) was dissolved in dichloromethane (750 mL), nitrogen was purged, cooled to-70 ℃, diisobutylaluminum hydride (183 mL,183.0mmol, 1M) was added dropwise, the reaction was continued at-70℃for 2 hours, TLC (Petroleum ether/ethyl acetate=10/1, potassium permanganate) monitored the reaction was complete, the reaction was quenched with saturated aqueous ammonium chloride (700 mL), filtered through celite, the filtrate was separated to give an organic phase, the aqueous phase was extracted with dichloromethane (400 mL), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound 69-2 (16.50 g, crude) as a yellow oil, which was directly used in the next step.
Second step 5- (3, 3-difluorocyclobutyl) imidazolidine-2, 4-dione 69-3
Compound 69-2 (14.00 g, crude product), ammonium carbonate (22.40 g,233.3 mmol) and trimethylcyanosilane (17.36 g,175.0 mmol) were dissolved in a mixed solution of ethanol (140 mL) and water (140 mL), the reaction was warmed to 60℃and reacted for 18 hours, TLC (Petroleum ether/ethyl acetate=10/1, potassium permanganate) monitored the starting material reaction was complete, the reaction solution was concentrated under reduced pressure to remove ethanol, solids precipitated, filtered, and the filter cake was rinsed with water (50 mL) and dried to give the title compound 69-3 (14.02 g, two-step yield: 52.2%) as a white solid.
Third step 2-amino-2- (3, 3-difluorocyclobutyl) acetic acid 69-4
Compound 69-3 (14.02 g,73.8 mmol) was dissolved in aqueous potassium hydroxide (140 mL, 30%) and the reaction was warmed to 100deg.C for 32 hours, and LCMS monitored for starting material and intermediate (209) + The reaction was completed, the reaction solution was cooled to 0 ℃, acidified to ph=6 with dilute sulfuric acid (4N), filtered, the filter cake was rinsed with methanol (50 mL x 2), the filtrate was concentrated under reduced pressure to remove water, the resulting crude product was dissolved with methanol (200 mL), filtered again, the filter cake was rinsed with methanol (50 mL x 2), and the filtrate was concentrated to give the title compound 69-4 (3.01 g, crude product) as a white solid, which was directly used in the next step.
Fourth step methyl 2-amino-2- (3, 3-difluorocyclobutyl) acetate hydrochloride 69-5
Compound 69-4 (3.01 g, crude product) was dissolved in methanol (30 mL), thionyl chloride (2.14 g,18.2 mmol) was added dropwise under ice bath, the reaction was completed after the addition, the reaction was carried out at 26℃for 16 hours, LCMS monitored the completion of the reaction of the starting materials, and the reaction was concentrated directly under reduced pressure to give the title compound 69-5 (3.80 g, crude product) as a yellow oil, which was directly subjected to the next step.
LC-MS:m/z＝216.2[M+H] + .
Fifth step 3- ((1- (3, 3-difluorocyclobutyl) -2-methoxy-2-oxoethyl) amino) -3-oxopropanoic acid methyl ester 69-6
Compound 69-5 (3.80 g, crude) and triethylamine (5.51 g,54.6 mmol) were dissolved in dichloromethane (60 mL), the reaction solution was cooled to 0deg.C under nitrogen protection, methyl malonate acid chloride (2.48 g,18.2 mmol) was slowly added dropwise, after the addition, the reaction solution was stirred continuously at 0deg.C for 3 hours, TLC (Petroleum ether/ethyl acetate=10/1, phosphomolybdic acid) monitored the starting material to be complete, the reaction solution was quenched with water (50 mL), the separated solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to give the title compound 69-6 (700 mg, three step yield: 3.4%) as a yellow oil.
Sixth step 5- (3, 3-difluorocyclobutyl) pyrrolidine-2, 4-dione 69-7
Compound 69-6 (700 mg,2.5 mmol) was dissolved in tetrahydrofuran (10 mL), the reaction solution was cooled to 0 ℃ under nitrogen protection, potassium tert-butoxide (3.65 mg,3.3 mmol) was added, the reaction solution was stirred at 26 ℃ for 3 hours, TLC (petroleum ether/ethyl acetate=10/1, phosphomolybdic acid) monitored the reaction of the starting materials to be complete; acidifying the reaction solution to pH=5 with dilute hydrochloric acid (3N), then heating to 70 ℃ for reaction for 3 hours, and detecting that the raw materials are completely reacted by TLC (petroleum ether/ethyl acetate=1/1, phosphomolybdic acid); the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of tetrahydrofuran, saturated solution was prepared by adding anhydrous sodium sulfate, extracted with ethyl acetate (50 ml x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound 69-7 (550 mg, crude) as a white solid, which was used directly in the next step.
LC-MS:m/z＝190.2[M+H] + .
Seventh step 5- (3, 3-difluorocyclobutyl) -3, 3-difluoropyrrolidine-2, 4-dione 69-8
Compound 69-7 (550 mg, crude product) was dissolved in acetonitrile (6 mL), 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (2.26 g,6.4 mmol) and water (6 mL) were added, and after the addition, the reaction mixture was stirred at 26 ℃ for 16 hours, and TLC (petroleum ether/ethyl acetate=1/1, phosphomolybdic acid) detected that the starting material was completely reacted; the reaction solution was extracted with ethyl acetate (60 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=1/1) to give the title compound 69-8 (330 mg, two-step yield 58.9%) as a white solid.
LC-MS:m/z＝224.1[M-H] - .
Eighth step 5- (3, 3-difluorocyclobutyl) -3, 3-difluoro-4-hydroxypyrrolidin-2-one 69-9
Compound 69-8 (330 mg,1.5 mmol) was dissolved in methanol (4 mL), the reaction solution was cooled to 0 ℃, sodium borohydride (84 mg,2.2 mmol) was added, and after the addition, the reaction solution was stirred continuously at 0 ℃ for 2 hours, TLC (petroleum ether/ethyl acetate=1/1, phosphomolybdic acid) monitored the starting material reaction was complete; the reaction solution was concentrated under reduced pressure to remove methanol to give the title compound 69-9 (401 mg, crude) as a white solid, which was used directly in the next reaction.
Ninth step 2- (3, 3-difluorocyclobutyl) -4, 4-difluoropyrrolidin-3-ol 69-10
Compound 69-9 (401 mg, crude product) was dissolved in anhydrous tetrahydrofuran (12 mL), lithium aluminum hydride (228 mg,6.0 mmol) was added at room temperature, and after the addition, the reaction mixture was stirred at 60 ℃ for 2 hours, and TLC (petroleum ether/ethyl acetate=1/1, phosphomolybdic acid) monitored the starting material reaction was complete; the reaction solution was cooled to 0℃and quenched with water (0.3 mL), aqueous sodium hydroxide (0.3 mL, 15%) and water (0.9 mL) in this order, the reaction solution was stirred at room temperature for 10 minutes, then filtered, the filtrate was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound 69-10 (170 mg, two-step yield 54.3%) as a white solid.
LC-MS:m/z＝214.1[M+H] + .
Tenth step (6-Chloropyridin-2-yl) (2- (3, 3-difluorocyclobutyl) -4, 4-difluoro-3-hydroxypyrrolidin-1-yl) methanone 69
Compound 69-10 (80 mg,0.37 mmol), 6-chloronicotinic acid (70 mg,0.45 mmol) and N, N-diisopropylethylamine (73 mg,0.56 mmol) were dissolved in N, N-dimethylformamide (1 mL), and benzotriazole-N, N' -tetramethylurea hexafluorophosphate (171 mg,0.45 mmol) was added under nitrogen protection, and the reaction mixture was stirred at 20 ℃ for 16 hours after the addition, and TLC (petroleum ether/ethyl acetate=2/1) was monitored for complete reaction of the starting materials; the reaction mixture was quenched with water (5 mL), extracted with ethyl acetate (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give crude product, which was purified by Prep-HPLC to give the title compound 69 (36 mg, yield 27.7%) as a white solid.
LC-MS:m/z＝353.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.09-8.00(m,1H),7.85-7.77(m,1H),7.76-7.67(m,1H),6.26-6.18(m,1H),4.64-4.52(m,1H),4.43-4.25(m,1H),4.25-4.10(m,1H),4.03-3.81(m,1H),2.84-2.52(m,4H),2.48-2.31(m,1H).
19 F NMR(377MHz,DMSO-d 6 )δ-80.13,-97.90,-109.53,-115.60.
Synthesis example 52: compounds 70 and 71 were synthesized as (6-chloropyridin-2-yl) ((2 r,3 s) -2-cyclopentyl-4, 4-difluoro-3-hydroxypyrrolidin-1-yl) methanone; (6-chloropyridin-2-yl) ((2 s,3 r) -2-cyclopentyl-4, 4-difluoro-3-hydroxypyrrolidin-1-yl) methanone (70-P1 and 70-P2);
(6-chloropyridin-2-yl) ((2 s,3 s) -2-cyclopentyl-4, 4-difluoro-3-hydroxypyrrolidin-1-yl) methanone; (6-Chloropyridin-2-yl) ((2R, 3R) -2-cyclopentyl-4, 4-difluoro-3-hydroxypyrrolidin-1-yl) methanone (71-P1 and 71-P2)
First step 2-amino-2-cyclopentylacetic acid methyl ester 70-2
Compound 70-1 (8.0 g,55.8 mmol) was dissolved in methanol (40 mL) and thionyl chloride (13.3 g,111.7 mmol) was added dropwise with stirring at 0deg.C, and the reaction mixture was stirred at room temperature for 12 hours after the addition, and TLC (PE: EA=2:1) showed complete reaction. The reaction solution was concentrated to give the title compound 70-2 (10.8 g, crude) as a yellow oil, which was used directly in the next step.
Second step 3- ((1-cyclopentyl-2-methoxy-2-oxoethyl) amino) -3-oxopropanoic acid methyl ester 70-3
Compound 70-2 (10.8 g, crude product) was dissolved in dichloromethane (200 mL), triethylamine (17.24 g,206.6 mmol) was added dropwise at room temperature, after the addition, methyl malonate acyl chloride (14.1 g,103.3 mmol) was added dropwise at a temperature lower than 0deg.C, after the addition, the reaction was slowly warmed to room temperature and stirred for 2 hours, TLC (PE: EA=2:1) showed complete reaction, the reaction solution was quenched with water (100 mL), dichloromethane (100 mL x 2) was extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, the crude product was purified by silica gel column chromatography to give the title compound 70-3 (11.4 g, 80% yield in two steps) as yellow oil.
Third step 5-cyclopentylpyrrolidine-2, 4-dione 70-4
Compound 70-3 (11.4 g,44.35 mmol) was dissolved in tetrahydrofuran (300 mL), potassium tert-butoxide (7.5 g,66.5 mmol) was added at 0deg.C, the reaction was slowly warmed to room temperature and stirred for 3 hours, TLC (PE: EA=2:1) showed complete reaction, the reaction was acidified with dilute hydrochloric acid to pH=5-6, continued to warm to 85deg.C for 4 hours under reflux, TLC (EA) showed complete reaction, the reaction was cooled to room temperature, tetrahydrofuran was removed by concentration, the residue was diluted with saturated aqueous sodium sulfate (100 mL), ethyl acetate (200 mL x 2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound 70-4 (11.0 g, crude) as a yellow oil, which was used directly in the next step.
Fourth step 5-cyclopentyl-3, 3-difluoropyrrolidine-2, 4-dione 70-5
Compound 70-4 (11.0 g, crude) was dissolved in acetonitrile (300 mL), 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) (58.3 g,164.5 mmol) and water (300 mL) were added at room temperature, the reaction was stirred at room temperature for 12 hours, TLC (PE: EA=2:1) showed complete reaction, the reaction was concentrated directly to remove acetonitrile, the remainder was extracted with ethyl acetate (200 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give title compound 70-5 (10.8 g, crude) as a yellow oil, which was used directly in the next step.
Fifth step 5-cyclopentyl-3, 3-difluoro-4-hydroxypyrrolidin-2-one 70-6
Compound 70-5 (10.8 g, crude) was dissolved in methanol (400 mL), sodium borohydride (3.0 g,79.7 mmol) was added in portions at 0deg.C, slowly warmed to room temperature and stirred for 2 hours after the addition, TLC (PE: EA=2:1) showed complete reaction, and the reaction solution was concentrated to give the title compound 70-6 (14.0 g, crude) as a yellow solid, which was used directly in the next step.
Sixth step 2-cyclopentyl-4, 4-difluoropyrrolidin-3-ol 70-7
Compound 70-6 (14.0 g, crude product) was dissolved in tetrahydrofuran (700 mL), lithium aluminum hydride (8.2 g,215 mmol) was added in portions at room temperature, after the addition, the reaction mixture was warmed to 65℃and stirred for 2 hours, TLC (PE: EA=2:1) showed complete reaction, the reaction mixture was cooled to room temperature, quenched by the sequential addition of water (8.2 mL), 15% aqueous NaOH solution (8.2 mL) and water (24.6 mL), stirred for 0.5 hours, suction filtered, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography to give the title compound 70-7 (819 mg, four steps yield 10%) as a white solid.
Seventh step (6-Chloropyridin-2-yl) (2-cyclopentyl-4, 4-difluoro-3-hydroxypyrrolidin-1-yl) methanone 70-8
Compound 70-7 (0.1 g,0.52 mmol), 6-chloropicolinic acid (163 mg,1.04 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (399mg, 1.04 mmol) were dissolved in N, N-dimethylacetamide (10 mL), N, N-diisopropylethylamine (201 mg,1.56 mmol) was added with stirring at room temperature, and stirring was continued for 12 hours, TLC (PE: EA=2:1) indicated complete reaction. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound 70-8.
70-8 was chiral resolved to give a mixture of the title compounds 70-P1 and 70-P2 and a mixture of 71-P1 and 71-P2 as white solids. 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.
70-P1 and 70-P2: white solid, yield 36%. Retention time 11.31 min.
LC-MS:m/z＝331.2[M+H] + .
1 H NMR(400MHz,DMSO-d6)δ8.01(d,J＝8.0Hz,1H),7.76(d,J＝7.6Hz,1H),7.68(d,J＝8.0Hz,1H),6.10(d,J＝5.6Hz,1H),4.49-4.41(m,1H),4.36-4.23(m,1H),3.97-3.87(m,1H),2.35-2.23(m,1H),1.93-1.81(m,1H),1.66-1.50(m,4H),1.48-1.32(m,4H).
19 F NMR(377MHz,DMSO-d 6 )δ-103.07,-105.51,-107.01,-112.40.
71-P1 and 71-P2: white solid, yield 38%. Retention time 16.79 min.
LC-MS:m/z＝331.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.01(d,J＝7.6Hz,1H),7.76(d,J＝7.6Hz,1H),7.68(d,J＝8.0Hz,1H),6.10(d,J＝5.6Hz,1H),4.50-4.40(m,1H),4.35-4.23(m,1H),3.96-3.87m,1H),2.36-2.23(m,1H),1.91-1.82(m,1H),1.66-1.48(m,4H),1.45-1.31(m,4H).
19 F NMR(377MHz,DMSO-d 6 )δ-103.07,-105.51,-107.03,-112.40.
Synthesis example 53: synthesis of Compound 72
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (2-methylthiazol-4-yl) methanone 72
White solid, yield 85%.
LC-MS:m/z＝303.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.88(s,1H),4.45-4.26(m,2H),3.97-3.88(m,1H),2.86-2.79(m,1H),2.72(s,3H),2.61-2.49(m,1H),2.38-2.14(m,2H),2.12-1.08(m,2H),1.89-1.77(m,1H),1.67-1.50(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-109.44,-120.20.
Synthesis example 54: synthesis of Compound 73
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (4-methylthiazol-2-yl) methanone 73
Yellow solid, yield 66%.
LC-MS:m/z＝303.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.59(s,1H),6.34(d,J＝6.4Hz,1H),4.45(dd,J＝28.4,14.4Hz,2H),4.08-3.98(m,1H),2.43(s,3H),2.39-2.33(m,1H),2.22-2.13(m,1H),2.03-1.71(m,4H),1.59-1.45(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-110.86,-118.55.
Synthesis example 55: synthesis of Compound 74
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (2- (trifluoromethyl) thiazol-5-yl) methanone 74
Yellow solid, yield 63%.
LC-MS:m/z＝357.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.09(s,1H),4.27-4.16(m,1H),4.09-4.01(m,1H),3.94(br,1H),2.64(br,1H),2.52-2.44(m,1H),2.35-2.23(m,2H),2.10-1.98(m,2H),1.91-1.84(m,1H),1.68-1.50(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-61.51,-108.19,-120.31.
Synthesis example 56: synthesis of Compound 75
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (1, 5-dimethyl-1H-pyrazol-3-yl) methanone 75
White solid, yield 85%.
LC-MS:m/z＝300.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ6.39(s,1H),6.25(d,J＝6.0Hz,1H),4.40-4.11(m,2H),
4.05-3.88(m,1H),3.76(s,3H),2.38-2.32(m,1H),2.25(s,3H),2.19-2.06(m,1H),2.06-1.78(m,3H),1.78-1.63(m,1H),1.61-1.40(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-110.86,-118.87.
Synthesis example 57: synthesis of Compound 76
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (2- (trifluoromethyl) thiazol-4-yl) methanone 76
White solid, yield 88%.
LC-MS:m/z＝357.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.35(s,1H),4.53-4.29(m,2H),4.02-3.90(m,1H),2.61-2.46(m,2H),2.41-2.20(m,2H),2.16-1.99(m,2H),1.94-1.82(m,1H),1.74-1.62(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-61.18,-109.01,-120.33.
Synthesis example 58: synthesis of Compound 77
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (2- (difluoromethyl) thiazol-4-yl) methanone 77
White solid, yield 64%.
LC-MS:m/z＝339.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.29(s,1H),6.83(t,J＝54.4Hz,1H),4.49-4.28(m,2H),3.93(dd,J＝10.8,6.4Hz,1H),2.59-2.47(m,2H),2.39-2.18(m,2H),2.14-2.03(m,2H),1.91-1.82(m,1H),1.70-1.62(m,1H),1.59-1.12(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-108.71,-109.02,-120.35.
Synthesis example 59: synthesis of Compound 78
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (2, 2-difluorobenzo [ d ] [1,3] dioxy-5-yl) methanone 78
White solid, yield 95%.
LC-MS:m/z＝362.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.20-7.14(m,2H),7.12-7.07(m,1H),3.97-3.83(m,2H),3.69-3.59(m,1H),2.59-2.48(m,2H),2.39-2.20(m,2H),2.10-1.98(m,2H),1.88-1.78(m,1H),1.67-1.61(m,1H),1.58-1.50(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-49.78,-109.43,-120.54.
Synthesis example 60: synthesis of Compound 79
(6-bromo-3-hydroxypyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 79
White solid, yield 80%.
LC-MS:m/z＝377.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.00(s,1H),7.52(d,J＝8.8Hz,1H),7.30(d,J＝8.8Hz,1H),6.35(d,J＝5.6Hz,1H),4.08-3.96(m,1H),3.87-3.67(m,2H),2.46-2.36(m,1H),2.23-2.13(m,1H),2.05-1.71(m,4H),1.61-1.44(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-110.94,-118.86.
Synthesis example 61: synthesis of Compound 80
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (4- (difluoromethyl) -5-methyl-1H-imidazol-2-yl) methanone 80
White solid, yield 66%.
LC-MS:m/z＝336.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ11.04(s,1H),6.66(t,J＝54.8Hz,1H),4.77-4.67(m,1H),4.61-4.47(m,1H),3.97-3.85(m,1H),2.50-2.45(m,2H),2.39(t,J＝1.6Hz,3H),2.32-2.18(m,2H),2.05-1.96(m,2H),1.90-1.82(m,1H),1.70-1.64(m,1H),1.58-1.52(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-108.62,-109.25,-111.13,-120.16.
Synthesis example 62: synthesis of Compound 81
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (4-methylpyrimidin-2-yl) methanone 81
White solid, yield 75%.
LC-MS:m/z＝298.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.63(d,J＝4.8Hz,1H),7.21(d,J＝5.2Hz,1H),4.11-3.95(m,2H),3.90-3.81(m,1H),2.67-2.61(m,1H),2.59(s,3H),2.46-2.38(m,1H),2.24-2.19(m,1H),2.14-2.04(m,2H),1.90-1.84(m,1H),1.64-1.53(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-109.43,-120.26.
Synthesis example 63: synthesis of Compound 82
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (3 aH-pyrrole [2,3-d ] thiazol-5-yl) methanone 82
White solid, yield 57%.
LC-MS：m/z＝328.1[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.41(s,1H),8.97(s,1H),6.99(s,1H),6.34(d,J＝6.0Hz,1H),4.27-4.20(m,2H),4.03-3.97(m,1H),2.45-2.39(m,1H),2.20-2.13(m,1H),2.07-1.86(m,3H),1.81-1.71(m,1H),1.58-1.48(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-110.49,-118.59.
Synthesis example 64: synthesis of Compound 83
(3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) (6-methylpyrazin-2-yl) methanone 83
Yellow solid, 71% yield.
LC-MS:m/z＝298.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.69(s,1H),8.64(s,1H),6.37(d,J＝6.4Hz,1H),4.12-3.95(m,3H),2.53(s,3H),2.47-2.37(m,1H),2.26-2.13(m,1H),2.13-2.01(m,1H),1.99-1.84(m,2H),1.83-1.71(m,1H),1.64-1.47(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-110.82,-119.02.
Synthesis example 65: synthesis of Compound 84
2- (6-chloropyridin-2-yl) -1- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) ethen-1-one 84
Yellow solid, yield 23%.
LC-MS:m/z＝331.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.80(t,J＝7.6Hz,1H),7.38(d,J＝8.0Hz,1H),7.27(d,J＝7.6Hz,1H),6.25(d,J＝6.0Hz,1H),4.06-3.99(m,2H),3.96-3.86(m,1H),3.83-3.72(m,2H),2.25-2.20(m,1H),2.13-2.03(m,1H),1.90-1.62(m,4H),1.5-1.36(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-110.12,-117.84.
Example 66: synthesis of Compound 85
1- (2- (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) -2-oxoethyl) -3- (difluoromethyl) pyridin-2 (1H) -one 85
First step 3-difluoromethyl-2-methoxypyridine 85-2
Compound 85-1 (2.0 g,14.58 mmol) was dissolved in methylene chloride (30 mL), and diethylaminosulfur trifluoride (DAST) (5.17 g,32.08 mmol) was added to the solution, followed by reaction at room temperature for 16 hours. TLC (petroleum ether/ethyl acetate=10/1) showed the starting material disappeared and the reaction was complete. The reaction was washed with saturated sodium bicarbonate solution (15 mL), extracted with dichloromethane (20 mL x 2), the organic phases were combined, washed with saturated brine (20 mL x 2), 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 85-2 (1.07 g,46% yield) as a yellow oil.
1 H NMR(400MHz,CDCl 3 )δ8.26(d,J＝4.8Hz,1H),7.85(d,J＝7.2Hz,1H),7.00-6.97(m,1H),6.84(t,J＝55.2Hz,1H),4.01(s,3H).
Second step 3- (difluoromethyl) pyridin-2-ol 85-3
Compound 85-2 (500 mg,3.14 mmol) was dissolved in hydrobromic acid in acetic acid (4 mL), and the reaction mixture was stirred at 40℃for 16 hours. TLC (petroleum ether/ethyl acetate=10/1) showed the disappearance of starting material, quench the reaction with water (10 mL), extract with ethyl acetate (15 mL), wash the organic phase with saturated brine (20 mL x 2), dry over anhydrous sodium sulfate, concentrate to give the title compound 85-3 (171 mg, crude) as a yellow solid, which was used directly in the next step.
LC-MS:m/z＝146.1[M+H] + .
Third step 2- (3- (difluoromethyl) -2-oxopyridin-1 (2H) -yl) acetic acid ethyl ester 85-4
Compound 85-3 (171 mg, crude) and ethyl 2- ((methylsulfonyl) oxy) acetate (302 mg,1.66 mmol) were dissolved in acetonitrile (10 mL), potassium carbonate solid (578mg, 4.14 mmol) was added and the reaction was stirred at 80℃for 16 h, TLC (Petroleum ether/ethyl acetate=2/1) showed the starting material disappeared. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (15 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=4/1) to give the title compound 85-4 (197 mg, two-step yield 27.1%) as a yellow oil.
LC-MS:m/z＝232.1[M+H] + .
Fourth step 2- (3-difluoromethyl) -2-oxopyridine-1 (2H) -acetic acid 85-5
To a mixed solution of tetrahydrofuran (4 mL) and water (2 mL) was dissolved compound 85-4 (197mg, 0.85 mmol), lithium hydroxide monohydrate (72 mg,1.70 mmol) was added, the reaction solution was stirred at room temperature for 16 hours after the addition, TLC (petroleum ether/ethyl acetate=2/1) showed the starting material disappeared, and the reaction was completed. The reaction solution was acidified to ph=4, diluted with water (10 mL), extracted with ethyl acetate (15 mL), and the organic phase was washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, and concentrated to give the title compound 85-5 (89 mg, crude) as a pale yellow solid, which was used directly in the next step.
LC-MS:m/z＝204.1[M+H] + .
Fifth step 1- (2- (3, 3-difluoro-4-hydroxy-1-azaspiro) [4.4] nonan-1-yl) -2-oxoethyl) -3-difluoromethylpyridin-2 (1H) one 85
Compound 85-5 (50 mg, crude) and compound 2900-5 (44 mg,0.25 mmol) were dissolved in N, N-dimethylformamide (4 mL), and N, N-diisopropylethylamine (65 mg,0.50 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (114 mg,0.30 mmol) were added sequentially. After the addition, the reaction was allowed to react at room temperature for 16 hours, TLC (petroleum ether/ethyl acetate=2/1, r f =0.5) shows that the reaction is complete. 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=4/1) gave the title compound 85 (33 mg, 19% yield in two steps) as a white solid.
LC-MS:m/z＝363.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.75(d,J＝6.0Hz,1H),7.42(d,J＝6.4Hz,1H),6.79(t,J＝55.2Hz,1H),6.35(t,J＝6.8Hz,1H),4.56(dd,J＝43.2,15.2Hz,2H),4.16-4.00(m,2H),3.89(t,J＝6.0Hz,1H),2.31-2.22(m,1H),2.20-2.13(m,2H),1.99-1.88(m,2H),1.86-1.79(m,1H),1.56-1.44(m,2H),1.25(s,1H).
19 F NMR(377MHz,CDCl 3 )δ-107.15,-118.99,-119.68.
Synthesis example 67: synthesis of Compound 86
(4-amino-3, 3-difluoro-1-azaspiro [4.4] nonan-1-yl) (6-chloropyridin-2-yl) methanone 86
First step benzyl 3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonane-1-carboxylate 86-1
Compound IN-1 (1.0 g,6.1 mmol) was dissolved IN anhydrous dichloromethane (50 mL), sodium bicarbonate (1.0 g,12.2 mmol) and water (50 mL) were added, after the addition, benzyl chloroformate (1.1 g,6.7 mmol) was slowly added dropwise to the reaction mixture after cooling to 0deg.C, and the reaction was stirred at 0deg.C for 3 hours; TLC showed complete reaction of the starting materials, separation, drying of the organic phase over anhydrous sodium sulfate, concentration, purification of the crude product by silica gel column chromatography (EA: pe=1:6) gave the title compound 86-1 (1.8 g, yield: 95%) as a colourless oil.
Second step benzyl 3, 3-difluoro-4- (trifluoromethylsulfonyl) oxy) -1-azaspiro [4.4] nonane-1-carboxylate 86-2
Compound 86-1 (1.2 g,3.9 mmol) was dissolved in anhydrous dichloromethane (50 mL), cooled to 0deg.C under nitrogen, pyridine (1.2 g,15.4 mmol) and triflic anhydride (2.6 g,9.2 mmol) were added and the reaction was kept at 0deg.C for additional stirring for 2 hours; TLC detects complete reaction of starting material. The reaction mixture was quenched with water (50 mL), extracted with dichloromethane (100 mL), dried over anhydrous sodium sulfate, and concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/10) to give the title compound 86-2 (1.6 g, yield 93%) as a pale yellow oily liquid.
Third step 4-aza-3, 3-difluoro-1-azaspiro [4.4] nonane-1-carboxylic acid benzyl ester 86-3
Compound 86-2 (1.3 g,2.9 mmol) was dissolved in N, N-dimethylacetamide (50 mL), sodium azide (5 eq) was added under nitrogen protection, the temperature was raised to 70℃and the reaction was completed by TLC for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with dichloromethane (100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/10) to give the title compound 86-3 (1.1 g, yield 83%) as a pale yellow oily liquid.
Fourth step 4-amino-3, 3-difluoro-1-azaspiro [4.4] nonane-1-carboxylic acid benzyl ester 86-4
To a solution (30 mL) of compound 86-3 (1.1 g,3.3 mmol) in tetrahydrofuran and water was added triphenylphosphine (2 eq) under nitrogen protection, and the reaction was allowed to proceed to 75℃for 48 hours, and TLC showed complete reaction of the starting materials. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate and concentrated to give the crude title compound 86-4 (1.9 g) as a pale yellow oil.
Fifth step 4- (Boc) aminobenzyl-3, 3-difluoro-1-azaspiro [4.4] nonane-1-carboxylate 86-5
Compound 86-4 (1.8 g,5.8 mmol) was dissolved in dioxane (30 mL), di-tert-butyl dicarbonate (3 eq) was added under nitrogen protection, the temperature was raised to 70℃and the reaction was completed by TLC for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/5) to give the title compound 86-5 (0.36 g, yield 15%) as white.
Sixth step tert-butyl (3, 3-difluoro-1-azaspiro [4.4] nonan-4-yl) carbamate 86-6
Compound 86-5 (0.36 g,0.88 mmol) was dissolved in methanol (10 mL), 10% palladium on carbon (0.1 eq) was added, hydrogen was replaced, and the reaction was completed by TLC for 18 hours. Filtration and concentration gave crude, yellow title compound 86-6 (0.22 g, 89% yield).
Seventh step (1- (6-Chloropyridinyl) -3, 3-difluoro-1-azaspiro [4.4] nonan-4-yl) carbamic acid tert-butyl ester 86-7
Compound 86-6 (0.1 g,0.36 mmol), 6-chloropicolinic acid (0.11 g,0.72 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.27 g,0.72 mmol) were dissolved in N, N-dimethylacetamide (10 mL), N, N-diisopropylethylamine (139 mg,1.08 mmol) was added with stirring at room temperature, and stirring was continued at room temperature for 12 hours, TLC showed completion of the reaction. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL x 2), the combined organic phases washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product purified by Prep-TLC (ethyl acetate/petroleum ether=1/2) to give the title compound 86-7 as a yellow solid (144 mg, yield 96.19%).
Eighth step (4-amino-3, 3-difluoro-1-azaspiro [4.4] nonan-1-yl) (6-chloropyridin-2-yl) methanone 86
Compound 86-7 (144 mg,0.35 mmol) was dissolved in 1, 4-dioxane hydrochloride (5 mL) and stirred at room temperature for 3 hours, TLC showed complete reaction, the reaction solution was concentrated to remove most of the solvent, and the crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/2) to give the title compound 86 (91 mg, yield 92%) as a yellow solid.
LC-MS:m/z＝316.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.00(t,J＝8.0Hz,1H),7.69(d,J＝7.6Hz,1H),7.64(d,J＝8.0Hz,1H),4.18-4.02(m,1H),3.96-3.83(m,1H),3.45-3.40(m,1H),2.47-2.37(m,1H),2.04-1.88(m,5H),1.89-1.75(m,2H),1.67-1.47(m,2H).
19 F NMR(377MHz,DMSO-d 6 )δ-113.22,-116.43.
Synthesis example 68: synthesis of Compound 87
(6-chloropyridin-2-yl) (3, 4-trifluoro-1-azaspiro [4.4] nonan-1-yl) methanone 87
First step benzyl 3, 4-trifluoro-1-azaspiro [4.4] nonane-1-carboxylate 87-1
Compound 86-2 (1.3 g,8.0 mmol) was dissolved in N, N-dimethylacetamide (20 mL), cesium fluoride (12.1 g,80.0 mmol) was added, and the reaction was stirred for 2 hours at 120℃under nitrogen protection after the addition, and the completion of the reaction was detected by TLC. The reaction was quenched with water (60 mL), extracted with ethyl acetate (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=5%) to give the title compound 87-1 (0.2 g, crude product) as a gray solid, which was used directly in the next step.
Second step 3, 4-trifluoro-1-azaspiro [4.4] nonane 87-2
Compound 87-1 (0.2 g, crude product) was dissolved in methanol (20 mL), palladium on carbon (0.2 g, 10%) was added, and after 3 changes of hydrogen, the mixture was stirred at room temperature for 1 hour under hydrogen, and TLC showed complete reaction of the starting materials. The reaction solution was filtered through celite, washed with methanol (30 mL), and the combined filtrates were concentrated to give the title compound 87-2 (0.12 g, crude) as a gray solid, which was used directly in the next step.
Third step (6-Chloropyridin-2-yl) (3, 4-trifluoro-1-azaspiro [4.4] nonan-1-yl) methanone 87
Compound 87-2 (0.12 g, crude) was dissolved in N, N-dimethylacetamide (10 mL), benzotriazole-N, N' -tetramethylurea hexafluorophosphate (700 mg,1.9 mmol), 6-chloropyridine-2-carboxylic acid (292 mg,1.9 mmol) and N, N-diisopropylethylamine (970 mg,7.5 mmol) were added, the reaction was continued to be stirred at room temperature for 16 hours after the addition, TLC detection of complete reaction of starting material, quench of the reaction solution with water (80 mL), extraction with ethyl acetate (50 mL x 3), the combined organic phases dried over anhydrous sodium sulfate, concentrated, and the crude product purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/3) to give the title compound 87 as a white solid (52 mg, three step yield 2%).
LC-MS:m/z＝319.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.85-7.81(m,2H),7.43-7.41(m,1H),4.55-4.51(m,2H),4.41-4.12(m,1H),2.59-2.43(m,2H),2.25-2.24(m,3H),1.86-1.80(m,1H),1.73-1.66(m,1H),1.56-1.50(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-108.93,-122.32,-197.21.
Synthesis example 69: synthesis of Compound 88
(6-chloropyridin-2-yl) (4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 88
First step 4-hydroxy-1-azaspiro [4.4] nonan-2-one 88-1
Compound IN-1c (500 mg,3.26 mmol) was dispersed IN methanol (5 mL), sodium borohydride (185.2 mg,4.90 mmol) was added at 0deg.C, and the reaction was stirred at 20deg.C for 2 hours after the addition, and the reaction was complete by TLC. The reaction was quenched with saturated ammonium chloride solution (3 mL), filtered, and concentrated to give the title compound 88-1 (419 mg, crude) as a yellow oil, which was used directly in the next step.
Second step 1-azaspiro [4.4] nonan-4-ol 88-2
Compound 88-1 (419 mg, crude product) was dispersed in tetrahydrofuran (10 mL), lithium aluminum hydride (204.9 mg,5.40 mmol) was added at 0deg.C, and the reaction mixture was stirred for 3 hours at 70deg.C after the addition was completed, and the reaction was detected by TLC. The reaction solution was cooled to room temperature, filtered, concentrated, and the crude product was purified by silica gel column chromatography (methanol/dichloromethane=1/10) to give the title compound 88-2 (173 mg, two-step yield 37.5%) as a pale yellow solid.
LC-MS:m/z＝142.2[M+H] + .
Third step (6-chloropyridin-2-yl) (4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 88
Compound 88-2 (20 mg,0.14 mmol), 6-chloropyridine-2-carboxylic acid (24.5 mg,0.16 mmol) and N, N-diisopropylethylamine (141 mg,1.09 mmol) were dispersed in N, N-dimethylformamide (3 mL), and after stirring for 5 minutes, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (59.2 mg,0.16 mmol) was added, and the reaction solution was reacted at 20℃for 2 hours by TLC to complete the reaction. The reaction was quenched with water (5 mL), extracted with ethyl acetate (10 mL x 2), the combined organic phases dried over anhydrous sodium sulfate, concentrated, and the crude product purified by Prep-TLC (ethyl acetate petroleum ether=1/1) to give the title compound 88 (25.3 mg, yield 63.6%) as a white solid.
LC-MS:m/z＝281.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.02(t,J＝7.6Hz,1H),7.64-7.62(m,2H),5.25(d,J＝4.8Hz,1H),3.83-3.78(m,1H),3.71-3.62(m,1H),3.42-3.34(m,1H),2.34-2.24(m,1H),2.22-2.05(m,2H),2.02-1.87(m,3H),1.80-1.71(m,1H),1.66-1.46(m,3H).
Synthesis example 70: synthesis of Compound 89
3, 3-difluoro-1- (4-isopropylthiazol-2-yl) -1-azaspiro [4.4] nonan-4-ol 89
First step 2-bromo-4-isopropylthiazole 89-2
Compound 89-1 (1 g,7.0 mmol) and copper bromide (1.72 g,7.7 mmol) were dispersed in acetonitrile (15 mL), and tert-butyl nitrite (0.865 g,8.4 mmol) was added at 0 ℃ under nitrogen protection, and the reaction mixture was reacted at 26 ℃ for 2 hours after the addition, and TLC (petroleum ether/ethyl acetate=30/1) detected that the starting material was completely reacted; the reaction was quenched with water (25 mL), extracted with ethyl acetate (25 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give crude product which was purified by silica gel column chromatography (petroleum ether/dichloromethane=5/1 to 1/1) to give the title compound 89-2 (280 mg, yield 19.3%) as a pale yellow oil.
1 H NMR(400MHz,CDCl 3 )δ6.82(s,1H),3.14-3.00(m,1H),1.29(d,J＝7.2Hz,6H).
Second step 3, 3-difluoro-1- (4-isopropylthiazol-2-yl) -1-azaspiro [4.4] nonan-4-ol 89
Compound 89-2 (100 mg,0.48 mmol), compound IN-1 (86 mg,0.48 mmol), xphos (46 mg,0.1 mmol), pd 2 (dba) 3 (44 mg,0.05 mmol) and cesium carbonate (313 mg,0.96 mmol) were dispersed in toluene (3 mL), and the reaction was refluxed under nitrogen for 16 hours, and TLC (petroleum ether/ethyl acetate=5/1) detected that the reaction of a small amount of the starting materials was incomplete; the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound 89 (22 mg, yield 14.6%) as a white solid.
LC-MS:m/z＝303.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ6.35(s,1H),6.29(d,J＝6.4Hz,1H),4.11-4.00(m,1H),3.79-3.59(m,2H),2.85-2.70(m,1H),2.56-2.51(m,1H),2.11-1.92(m,3H),1.90-1.80(m,1H),1.76-1.66(m,1H),1.62-1.45(m,2H),1.17(d,J＝7.2Hz,6H).
19 F NMR(377MHz,DMSO-d 6 )δ-108.44,-115.50.
Synthesis example 71: synthesis of Compound 90
1- (6-chloropyridin-2-yl) methyl) -3, 3-difluoro-1-azaspiro [4.4] nonan-4-ol 90
Intermediate IN-1 (50 mg,0.28 mmol) and compound 90-1 (60 mg,0.42 mmol) were dissolved IN methanol (5 mL), sodium cyanoborohydride (105 mg,1.68 mmol) was added IN portions at room temperature, stirring was continued for 2 hours at room temperature, TLC showed complete reaction, the reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL x 2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC (petroleum ether: ethyl acetate=2:1) to afford compound 90 (15 mg, 11.25%) as a yellow solid.
LC-MS:m/z＝303.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.84(t,J＝7.6Hz,1H),7.41(dd,J＝20.0,7.6Hz,2H),5.86(d,J＝6.4Hz,1H),3.96-3.78(m,2H),3.43(d,J＝14.8Hz,1H),3.12-3.03(m,1H),2.80-2.69(m,1H),1.87-1.70(m,3H),1.67-1.44(m,5H).
19 F NMR(377MHz,DMSO-d 6 )δ-98.71,-106.71.
Synthesis example 72: synthesis of Compounds 91 and 92, (6S, 7R, 9R) -7-fluoro-9- (4-fluoro-3-methylphenyl) spiro [4.5] decan-6-ol; (6 r,7s,9 s) -7-fluoro-9- (4-fluoro-3-methylphenyl) spiro [4.5] decan-6-ol (91-P1 and 91-P2);
(6 s,7r,9 s) -7-fluoro-9- (4-fluoro-3-methylphenyl) spiro [4.5] decan-6-ol; (6R, 7S, 9R) -7-fluoro-9- (4-fluoro-3-methylphenyl) spiro [4.5] decan-6-ol (92-P1 and 92-P2)
First step 1, 4-Dioxospiro [4.4] decan-7-one-8-yl triflate 91-2
Compound 91-1 (5.0 g,32.01 mmol) and 2, 6-di-tert-butyl-4-methylpyridine (13.15 g,64.03 mmol) were dissolved in dichloromethane (150 mL), cooled to 0deg.C in an ice bath, and trifluoromethanesulfonic anhydride (13.6 g,48.02 mmol) was added dropwise and reacted at 20deg.C for 18 hours. TLC showed the starting material disappeared. The reaction mixture was quenched by the addition of water (100 mL). The organic phase was washed with saturated brine (50 ml×2), and concentrated by column chromatography (petroleum ether/ethyl acetate=20/1) to give the title compound 91-2 (4.7 g, yield 51%) as a colorless liquid.
1 HNMR(400MHz,CDCl 3 )δ5.67-5.65(m,1H),4.01-3.97(m,4H),2.56-2.52(m,2H),2.42-2.40(m,2H),1.90(t,J＝6.4Hz,2H).
Second step 8- (4-fluoro-3-methylphenyl) -1, 4-dioxaspiro [4.5] dec-7-ene 91-3
Compound 91-2 (4.7 g,16.31 mmol) and 4-fluoro-3-methylbenzoboric acid (2.5 g,16.31 mmol) were dissolved in 1, 4-dioxane (50 mL)/water (10 mL), and sodium carbonate (3.5 g,32.62 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (661mg, 0.82 mol) were added. The mixture was nitrogen replaced 3 times and reacted at 95℃for 3 hours. TLC showed the starting material disappeared. The reaction was cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (100 mL), and separated. The organic phase was washed with saturated brine (50 ml x 2), dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to column chromatography (petroleum ether/ethyl acetate=15/1) to give the title compound 91-3 (2.5 g, yield 63%) as a white solid.
LC-MS:m/z＝249.1[M+H] + .
1 HNMR(400MHz,CDCl 3 )δ7.21-7.13(m,2H),6.92(t,J＝8.4Hz,1H),5.91-5.89(m,1H),4.02(s,4H),2.64-2.60(m,2H),2.45-2.44(m,2H),2.26(d,J＝2.0Hz,3H),1.90(t,J＝6.4Hz,2H).
Third step 8- (4-fluoro-3-methylphenyl) -1, 4-dioxaspiro [4.5] decane 91-4
Compound 91-3 (2.5 g,10.07 mmol) was dissolved in methanol (25 mL)/ethyl acetate (20 mL), and palladium on carbon (250 mg, 60%) was added and reacted at room temperature under a hydrogen atmosphere for 5 hours. TLC showed complete reaction of starting material. The reaction solution was filtered through celite, and the filtrate was concentrated. The crude product was subjected to column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound 91-4 (2.2 g, yield 88%) as a colorless oil.
LC-MS:m/z＝251.1[M+H] + .
1 HNMR(400MHz,CDCl 3 )δ7.05-6.97(m,2H),6.90(t,J＝8.4Hz,1H),3.98(s,4H),2.56-2.46(m,1H),2.24(d,J＝2.0Hz,3H),1.87-1.83(m,4H),1.76-1.63(m,4H).
Fourth step 4- (4-fluoro-3-methylphenyl) cyclohexane-1-one 91-5
Compound 91-4 (2.2 g,8.79 mmol) was dissolved in tetrahydrofuran (8 mL, 3M hydrochloric acid (12 mL,36.0 mmol) was added and reacted for 3 hours at 50 ℃ C. TLC showed the starting material disappeared, the reaction solution was concentrated, ethyl acetate (20 mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound 91-5 (1.49 g, yield 83%) as a white solid.
1 HNMR(400MHz,CDCl 3 )δ7.05-6.99(m,2H),6.94(t,J＝8.8Hz,1H),3.01-2.93(m,1H),2.52-2.48(m,4H),2.26(d,J＝1.6Hz,3H),2.21-2.17(m,2H),1.95-1.84(m,2H).
Fifth step 9- (4-fluoro-3-methylphenyl) spiro [4.5] decan-6-one 91-6
Compound 91-5 (1.29 g,6.25 mmol) and 1, 4-dibromobutane (1.4 g,6.57 mmol) were dissolved in toluene (30 mL) and potassium tert-butoxide (1.5 mg,13.13 mmol) was added. The mixture was reacted at 100 degrees celsius for 18 hours, TLC showed the starting material disappeared. The reaction mixture was cooled, quenched with water (20 mL), and extracted with ethyl acetate (30 mL). The mixture was washed with saturated brine (30 mL. Times.2), and the organic phase was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to give the title compound 91-6 (1.0 g, yield 61%) as a colorless oil.
1 HNMR(400MHz,CDCl 3 )δ7.04-6.98(m,2H),6.93(t,J＝8.8Hz,1H),3.12-3.04(m,1H),2.75-2.66(m,1H),2.49-2.40(m,2H),2.26(d,J＝1.2Hz,3H),2.16-2.11(m,1H),1.97-1.93(m,1H),1.92-1.81(m,4H),1.68-1.56(m,4H).
Sixth step tert-butyl ((9- (4-fluoro-3-methylphenyl) spiro [4.5] dec-6-en-6-yl) oxy) dimethylsilane 91-7
Compound 91-6 (900 mg,3.46 mmol) and 1, 6-lutidine (741mg, 6.92 mmol) were dissolved in dichloromethane (10 mL), cooled to 0deg.C with ice, and tert-butyldisilyltriflate (1.4 g,5.19 mmol) was added dropwise. The mixture was reacted at 20℃for 18 hours, and TLC showed substantial disappearance of starting material. The solution was quenched with saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (10 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=200/1) to give the title compound 91-7 (1.1 g, yield 85%) as a white solid.
1 HNMR(400MHz,CDCl 3 )δ7.03-6.98(m,2H),6.91(t,J＝8.8Hz,1H),4.76-4.74(m,1H),2.78-2.70(m,1H),2.49-2.40(m,2H),2.26(s,3H),2.18-2.09(m,3H),1.79-1.72(m,2H),1.69-1.60(m,4H),1.26-1.20(m,1H),0.94(s,9H),0.20(s,3H),0.18(s,3H).
Seventh step 7-fluoro-9- (4-fluoro-3-methylphenyl) spiro [4.5] decan-6-one 91-8
Compound 91-7 (1.1 g,2.94 mmol) was dissolved in acetonitrile (20 mL) and the selective fluorine reagent (1.4 g,3.82 mmol) was added. The mixture was reacted at 20℃for 1 hour, and TLC showed the disappearance of starting material. The reaction mixture was concentrated, and water (20 mL) and ethyl acetate (30 mL) were added to dissolve the mixture. The organic phase was washed with saturated brine (30 mL. Times.2) and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound 91-8 (716 mg, yield 88%) as a colorless oil.
Compound 91-8-P1:
1 HNMR(400MHz,CDCl 3 )δ7.05-7.00(m,2H),6.95(t,J＝8.8Hz,1H),4.85(td,J＝49.6Hz,3.6Hz,1H),3.39(tt,1H),2.51-2.35(m,2H),2.27(s,3H),2.16-1.98(m,3H),1.94-1.80(m,2H),1.71-1.59(m,4H),1.22-1.16(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-120.50,-181.40.
compound 91-8-P2:
1 HNMR(400MHz,CDCl 3 )δ7.04-6.98(m,2H),6.95(t,J＝8.8Hz,1H),5.36-5.19(m,1H),3.21-3.14(m,1H),2.62-2.55(m,2H),2.27(s,3H),2.13-2.01(m,1H),1.98-1.94(m,1H),1.91-1.79(m,3H),1.72-1.60(m,4H).
19 F NMR(377MHz,CDCl 3 )δ-120.11,-190.92.
eighth step 7-fluoro-9- (4-fluoro-3-methylphenyl) spiro [4.5] decan-6-ol 91-9
A mixture of 91-8-P1 and 91-8-P2 (200 mg,0.72 mmol) was added to methanol (15 mL) and sodium borohydride (41 mg,1.08 mmol) was added at 0deg.C. After the addition, the reaction was allowed to react at 0℃for 0.5 hours, and TLC showed the disappearance of starting material. The reaction mixture was distilled off to remove most of the methanol, quenched with water (10 mL), and extracted with ethyl acetate (15 mL). Saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated to give crude compound 91-9. Purification of crude compound 91-9 by Prep-TLC (petroleum ether/ethyl acetate=7/1) gave a mixture of the title compounds 91-P1 and 91-P2 and a mixture of 92-P1 and 92-P2.
91-P1 and 91-P2: white solid, yield 41%.
LC-MS:m/z＝281.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.06-6.89(m,3H),4.56-4.34(m,1H),3.61(dd,J＝12,9.6Hz,1H),2.76 -2.56(m,1H),2.29(s,1H),2.26(s,3H),2.13-1.76(m,3H),1.73-1.69(m,2H),1.65-1.46(m,4H),1.44-1.28(m,3H)..
19 F NMR(377MHz,CDCl 3 )δ-120.92,-184.13.
92-P1 and 92-P2: white solid, yield 42%.
LC-MS:m/z＝281.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.06-6.89(m,3H),4.56-4.34(m,1H),3.61(dd,J＝12,9.6Hz,1H),2.76 -2.56(m,1H),2.29(s,1H),2.26(s,3H),2.13-1.76(m,3H),1.73-1.69(m,2H),1.65-1.46(m,4H),1.44-1.28(m,3H)..
19 F NMR(377MHz,CDCl 3 )δ-120.92,-184.13.
Synthesis example 73: synthesis of Compounds 93 and 94 (6S, 9R) -7, 7-difluoro-9- (4-fluoro-3-methylphenyl) spiro [4.5] decan-6-ol; (6 r,9 s) -7, 7-difluoro-9- (4-fluoro-3-methylphenyl) spiro [4.5] decan-6-ol (93-P1 and 93-P2);
(6 s,9 s) -7, 7-difluoro-9- (4-fluoro-3-methylphenyl) spiro [4.5] decan-6-ol; (6R, 9R) -7, 7-difluoro-9- (4-fluoro-3-methylphenyl) spiro [4.5] decan-6-ol (94-P1 and 94-P2)
First step 7, 7-difluoro-9- (4-fluoro-3-methylphenyl) spiro [4.5] decan-6-one 93-1
Compound 91-8 (100 mg,0.36 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), nitrogen was displaced 3 times, the dry ice bath was cooled to-65℃and a solution of zinc chloride in tetrahydrofuran (0.75 mL, 1M) and potassium bis (trimethylsilyl) amide (0.58 mL, 1M) were added dropwise. The mixture was reacted in a dry ice bath for 30 minutes, and tetrahydrofuran (2 mL) of N-fluorobis-benzenesulfonamide (159 mg,0.50 mmol) was added dropwise. The reaction was completed with a dry ice bath for 2 hours and at room temperature for 18 hours. TLC showed the starting material disappeared. The solution was quenched with saturated ammonium chloride (10 mL) and extracted with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 ml×2) and the organic phase was concentrated. The crude product was purified by PreP-TLC (petroleum ether/ethyl acetate=10/1) to give the title compound 93-1 (48 mg, yield 45%) as a colorless oil.
1 HNMR(400MHz,CDCl 3 )δ7.04-6.94(m,3H),3.36-3.29(m,1H),2.66-2.49(m,2H),2.27(d,J＝2.0Hz,3H),2.24-2.04(m,2H),2.02-1.97(m,1H),1.94-1.83(m,2H),1.75-1.60(m,4H).
19 F NMR(377MHz,CDCl 3 )δ-102.52,-119.77.
Second step 7, 7-difluoro-9- (4-fluoro-3-methylphenyl) spiro [4.5] decan-6-ol 93-2
Compound 93-1 (48 mg,0.16 mmol) was dissolved in methanol (4 mL), cooled to 0deg.C in an ice bath, and sodium borohydride (9 mg,0.24 mmol) was added. The mixture was reacted in ice bath for 30 min, TLC showed the disappearance of starting material. The solution 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. Purification of the crude product by PreP-TLC (petroleum ether/ethyl acetate=10/1) gave the title compound 93-2 (40 mg, yield 83%) as a colourless oil. Chiral resolution gave a mixture of 93-P1 and 93-P2 and a mixture of 94-P1 and 94-P2.
Chiral HPLC analysis method: chiralpakAD-H, 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;
93-P1 and 93-P2 as white solid in 35% yield; retention time 5.307 min.
1 HNMR(400MHz,CDCl 3 )δ7.01-6.92(m,3H),3.79-3.70(m,1H),2.94-2.88(m,1H),2.35-2.28(m,1H),2.26(d,J＝1.6Hz,3H),2.05-1.99(m,2H),1.96-1.76(m,3H),1.70-1.57(m,4H),1.48-1.41(m,2H),1.39-1.33(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-108.02,-120.46.
94-P1 and 94-P2 in the form of a white solid in 38% yield; retention time 6.227 min.
1 HNMR(400MHz,CDCl 3 )δ7.01-6.92(m,3H),3.79-3.70(m,1H),2.94-2.88(m,1H),2.35-2.28(m,1H),2.26(d,J＝0.8Hz,3H),2.05-1.99(m,2H),1.96-1.79(m,3H),1.73-1.58(m,3H),1.56-1.51(m,1H),1.47-1.41(m,2H),1.39-1.33(m,1H).
19 F NMR(377MHz,CDCl 3 )δ-108.02,-120.46.
1 HNMR(400MHz,CDCl 3 )δ7.01-6.92(m,3H),3.79-3.70(m,1H),2.94-2.88(m,1H),2.35-2.28(m,1H).
Synthesis example 74: synthesis of Compounds 95 and 96, (6-chloropyridin-2-yl) ((3R, 4S) -3-fluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (95);
(6-chloropyridin-2-yl) ((3S, 4R) -3-fluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone (96)
First step 4-hydroxy-1-azaspiro [4.4] nonane-1-carboxylic acid tert-butyl ester 95-1
Compound 88-2 (2.1 g, crude product) was dissolved in methanol (50 mL), di-tert-butyl dicarbonate (6.5 g,29.8 mmol) was slowly added at room temperature, and the reaction was stirred at room temperature for 16 hours and TLC was used to check that the starting material was complete. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1/3) to give the title compound 95-1 (3.1 g, three steps combined yield 66%) as a white solid.
Second step 4-oxo-1-azaspiro [4.4] nonane-1-carboxylic acid tert-butyl ester 95-2
Compound 95-1 (3.1 g,12.8 mmol) was dissolved in dichloromethane (100 mL), dess-Martin oxidant (10.9 g,25.6 mmol) was slowly added at room temperature, the addition was complete, the reaction was stirred at room temperature for 2 hours, and TLC checked for complete reaction of starting materials. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=8%) to give the title compound 95-2 (3.0 g, yield 98%) as a white solid.
Third step 3-fluoro-4-oxo-1-azaspiro [4.4] nonane-1-carboxylic acid tert-butyl ester 95-3
Compound 95-2 (3.0 g,12.6 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), cooled to-60℃under nitrogen protection, and then lithium bis (trimethylsilylamide) (16.4 g,16.4 mmol) was slowly added dropwise, and the reaction mixture was stirred at-60℃for 1 hour. N-fluorobis-benzenesulfonamide (5.2 g,16.4 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and slowly added dropwise thereto, and stirring was continued for 1 hour after the addition, and TLC detected completion of the starting material reaction. The reaction was quenched by addition of saturated aqueous ammonium chloride (100 mL), extracted with ethyl acetate (100 mL x 3), the combined organic phases dried over anhydrous sodium sulfate, concentrated, and the crude product purified by silica gel column chromatography (ethyl acetate/petroleum ether=8%) to give the title compound 95-3 as a white solid (2.2 g, yield 68%).
Fourth step 3-fluoro-4-hydroxy-1-azaspiro [4.4] nonane-1-carboxylic acid tert-butyl ester 95-4
Compound 95-3 (1.2 g,4.7 mmol) was dissolved in methanol (20 mL), cooled to 0deg.C, sodium borohydride (0.18 g,4.7 mmol) was added in portions, the reaction was slowly warmed to room temperature after the addition, stirring was continued for 30 min, and TLC detected complete reaction of starting materials. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound 95-4 (1.1 g, 91% yield) as a colorless oily liquid.
Fifth step 3-fluoro-1-azaspiro [4.4] nonan-4-ol trifluoroacetate salt 95-5
Compound 95-4 (1.1 g,4.2 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (10 mL) was added, and after the addition, the reaction was continued to stir at room temperature for 60 min, TLC detected complete reaction of starting material and concentrated to give title compound 95-5 (1.3 g, crude product) as a brown oil, which was used directly in the next step.
Sixth step (6-chloropyridin-2-yl) (3-fluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 95-6
Compound 95-5 (0.3 g, crude) was dissolved in N, N-dimethylacetamide (10 mL), benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate (700 mg,1.9 mmol), 6-chloropyridine-2-carboxylic acid (292 mg,1.9 mmol) and N, N-diisopropylethylamine (970 mg,7.5 mmol) were added, the reaction was continued to be stirred at room temperature for 16 hours after the addition, TLC was used to detect complete reaction of starting material, the reaction solution was quenched with water (80 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (EA/PE=1/4) to give the title compound 95-6 (135 mg, two step yield 47%) as a white solid. Chiral resolution gives compound 95 and compound 96.
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.
Compound 95: white solid, yield 17%; retention time 12.497 min.
LC-MS:m/z＝299.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.79-7.74(m,2H),7.40-7.37(m,1H),5.11-4.95(m,1H),4.30-4.19(m,1H),4.10-4.02(m,1H),3.97-3.88(m,1H),2.63-2.56(m,1H),2.40-2.25(m,2H),2.14-2.00(m,3H),1.74-1.61(m,3H).
19 F NMR(377MHz,CDCl 3 )δ-202.44.
Compound 96: white solid, yield 17%; retention time 24.133 min.
LC-MS:m/z＝299.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.79-7.74(m,2H),7.40-7.38(m,1H),5.09-4.96(m,1H),4.30-4.19(m,1H),4.10-4.02(m,1H),3.97-3.88(m,1H),2.63-2.56(m,1H),2.40-2.25(m,2H),2.14-2.00(m,3H),1.74-1.61(m,3H).
19 F NMR(377MHz,CDCl 3 )δ-202.40,-202.42.
Synthesis example 75: synthesis of Compounds 97 and 98 (1R, 4S) -4- ((6-chloropyridin-2-yl) amino) spiro [4.4] nonan-1-ol (97);
(1S, 4R) -4- ((6-chloropyridin-2-yl) amino) spiro [4.4] nonan-1-ol (98)
First step 1, 4-Dioxospiro [4.4] nonane 97-2
Compound 97-1 (10 g,118.88 mmol), ethylene glycol (8.86 g,142.7 mmol) and the ion exchange resin DOWEX 50WX8 (100 mg) were dispersed in toluene (50 mL) and reacted at 120℃under nitrogen for 16 hours; TLC monitored complete reaction of starting material. The reaction was cooled to room temperature, quenched by pouring into an ice sodium hydroxide solution (50 mL, 2M), extracted with ethyl acetate (100 mL. Times.2), the organic phases were combined, washed with saturated brine (100 mL. Times.2), 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 97-2 (2.3 g, yield: 15.09%) as a colorless oil.
Second-step spiro [4.4] nonane-1, 4-dione 97-3
Compound 97-2 (1 g,7.8 mmol) and trimethyl [ (2- [ (trimethylsilyl) oxy ] cyclobut-1-en-1-yl) oxy ] -silane (5.39 g,23.4 mmol) were dissolved in dichloromethane (30 mL), boron trifluoride etherate (5.29 g,78 mmol) was added dropwise under nitrogen protection at-60℃and after incubation for 3 hours, the reaction was continued at room temperature for 18 hours; TLC monitored complete reaction of starting material. The reaction mixture was poured into an ice-saturated sodium bicarbonate solution (50 mL), extracted with ethyl acetate (100 mL. Times.2), and the organic phase was washed with saturated brine (100 mL. Times.2), 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 97-3 (630 mg, yield: 53.07%) as a colorless oil.
Third step 4-hydroxy spiro [4.4] non-1-one 97-4
Compound 97-3 (570 mg,3.75 mmol) was dissolved in methanol (10 mL), sodium borohydride (43 mg,1.13 mmol) was added in portions under nitrogen protection at 0deg.C, and the reaction mixture was allowed to warm to room temperature for 1 hour; TLC monitored complete reaction of starting material. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (50 mL), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound 97-4 (300 mg, yield: 51.88%) as a pale yellow oil.
Fourth step 4-amino-spiro [4.4] nonan-1-ol 97-5
Compound 97-4 (300 mg,1.95 mmol) and benzylamine (310 mg,2.89 mmol) were dissolved in methanol (10 mL), sodium cyanoborohydride (150 mg,2.34 mmol) was added under nitrogen protection, and the reaction solution was warmed to room temperature for 16 hours; TLC monitored complete reaction of starting material. The reaction mixture was quenched with saturated sodium carbonate solution (50 mL), extracted with ethyl acetate (50 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/ethyl acetate=1/1) to give the title compound 97-5 (250 mg, yield: 82.59%) as a colorless oil.
LC-MS:m/z＝246.2[M+1] + .
Fifth step 4-amino-spiro [4.4] nonan-1-ol 97-6
Compound 97-5 (250 mg,1.02 mmol) and palladium on carbon (50 mg,10% wt) were dispersed in ethanol (10 mL) and reacted under hydrogen protection for 16 hours; TLC monitored complete reaction of starting material. The reaction solution was filtered through celite, and the filtrate was concentrated to give the title compound 97-6 (150 mg, yield: 94.73%) as a colorless oil.
LC-MS:m/z＝156.2[M+1] + .
Sixth step (1R, 4S) -4- ((6-chloropyridin-2-yl) amino) spiro [4.4] nonan-1-ol 97& (1S, 4R) -4- ((6-chloropyridin-2-yl) amino) spiro [4.4] nonan-1-ol 98
Compound 97-6 (75 mg,0.48 mmol), potassium carbonate (130 mg,1.2 mmol) and 2-bromo-6-chloropyridine (92 mg,0.48 mmol) were dispersed in N, N-dimethylformamide (10 mL) and reacted under nitrogen at 120℃for 5 hours; TLC (petroleum ether/ethyl acetate=4/1) monitored complete reaction of starting material. The reaction solution was filtered through celite, the filtrate was diluted with ethyl acetate (50 mL), and the saturated brine (100 mL) was washed, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the crude product by Pre-TLC (petroleum ether/ethyl acetate=4/1) gave the title compound 97 and compound 98.
Compound 97: white solid, yield 7.81%.
LC-MS:m/z＝267.1[M+1] + .
1 H NMR(400MHz,CDCl 3 )δ7.28(t,J＝7.6Hz,1H),6.48(d,J＝7.6Hz,1H),6.20(d,J＝8.4Hz,1H),5.57(d,J＝9.6Hz,1H),3.94-3.87(m,2H),2.19-2.13(m,1H),2.08-1.99(m,1H),1.86(d,J＝2.8Hz,1H),1.80-1.76(m,4H),1.69-1.59(m,4H),1.47-1.38(m,1H),1.36-1.29(m,1H).
Compound 98 as white solid in 6.25% yield.
LC-MS:m/z＝267.2[M+1] + .
1 H NMR(400MHz,CDCl 3 ) Delta 7.34 (t, j=8.0 hz, 1H), 6.54 (d, j=7.2 hz, 1H), 6.33 (d, j=8.0 hz, 1H), 4.65 (d, j=9.2 hz, 1H), 4.10-4.03 (m, 1H), 3.89-3.83 (m, 1H), 2.31-2.20 (m, 1H), 2.16-2.05 (m, 1H), 1.91-1.83 (m, 1H), 1.69-1.56 (m, 7H), 1.52-1.44 (m, 1H), 1.39-1.30 (m, 1H), 1.23-1.16 (m, 1H). Synthetic example 76: synthesis of Compound 99 (6-chloro-5- (2, 2-difluoroethyl) pyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [ 4.4)]Nonan-1-yl) methanone (99);
first step 6-chloro-5-formylpyridinium formate 99-2
N, N-dimethylformamide (53.6 g,733.5 mmol) was dissolved in 1, 2-dichloroethane (300 mL), triphosgene (72.5 g,244.5 mmol) was added in portions under nitrogen protection at 0℃and compound 99-1 (5 g,34.9 mmol) was added after the addition, and the reaction mixture was stirred at room temperature for 2 hours; continuously heating to 80 ℃ to react for 5 hours; TLC monitored complete reaction of starting material. The reaction solution was cooled to room temperature, quenched with ice-water (200 mL), extracted with dichloromethane (250 mL x 2), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated, and the crude product purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give the title compound 99-2 (3.3 g, yield 47%) as a yellow solid.
LC-MS:m/z＝200.1[M+H] + .
Second step 6-chloro-5- (2, 2-difluorovinyl) picolinic acid methyl ester 99-3
Compound 99-2 (1.2 g,6.01 mmol) was dissolved in acetonitrile (30 mL) under nitrogen, triphenylphosphine (4.73 g,18.03 mmol), potassium iodide (1.99 g,12.02 mmol) and the reaction mixture were reacted at 70℃for 0.5 hour, methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (2.02 g,10.52 mmol) was slowly added dropwise over one hour, and the reaction was carried out at 70℃for 1 hour. TLC showed the starting material disappeared and the reaction was complete. The reaction was extracted with water (30 mL) ethyl acetate (25 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound 99-3 (114 mg,8% yield) as a white solid.
LC-MS:m/z＝234.1[M+H] + .
Step three, methyl 6-chloro-5- (2, 2-difluoro-2- (1, 3-hexamethyl-2- (trimethylsilyl) trisilan-2-yl) ethane) picolinate 99-4
Compound 99-3 (90 mg,0.39 mmol) was dissolved in benzotrifluoride (4 mL), AIBN (13 mg,0.08 mmol) and tris (trimethylsilyl) silane (194 mg,0.78 mmol) were added and the reaction stirred at 130℃for 3 hours. TLC showed the disappearance of starting material, extraction of the reaction solution with water (10 mL) ethyl acetate (15 mL), washing of the organic phase with saturated brine (20 mL. Times.2), drying over anhydrous sodium sulfate and concentration. Purification of the crude product by Prep-TLC (petroleum ether/ethyl acetate=4/1) gave the title compound 99-4 (80 mg, 43% yield) as a pale yellow solid.
1 H NMR(400MHz,CDCl 3 )δ8.02(d,J＝8.0Hz,1H),7.85(d,J＝8.0Hz,1H),4.00(s,3H),3.52-3.38(m,2H),0.30(s,27H).
Fourth step 6-chloro-5- (2, 2-difluoroethyl) picolinic acid methyl ester 99-5
Compound 99-4 (80 mg,0.17 mmol) was dissolved in tetrahydrofuran (4 mL), cooled to-65℃and TBAF (66 mg,0.25 mmol) was added, and the reaction mixture was stirred at-65℃for 2 hours after the addition, and TLC showed the disappearance of starting material. The reaction mixture was extracted with water (10 mL) and ethyl acetate (15 mL), and the organic phase was washed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated. Purification of the crude product by Prep-TLC (petroleum ether/ethyl acetate=4/1) gave the title compound 99-5 (18 mg, 45% yield) as a white solid.
LC-MS:m/z＝236.1[M+H] + .
Fifth step 6-chloro-5- (2, 2-difluoroethyl) picolinic acid 99-6
Compound 99-5 (18 mg,0.08 mmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL), lithium hydroxide monohydrate (3 mg,0.08 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours, TLC showed the starting material disappeared and the reaction was complete. The reaction solution was adjusted to ph=4 with citric acid, extracted with water (10 mL) and ethyl acetate (15 mL), and the organic phase was washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, and concentrated. The title compound 99-6 (16 mg, crude) was obtained as a white solid.
LC-MS:m/z＝222.1[M+H] + .
Sixth step (6-chloro-5- (2, 2-difluoroethyl) pyridin-2-yl) (3, 3-difluoro-4-hydroxy-1-azaspiro [4.4] nonan-1-yl) methanone 99
Compound 99-6 (16 mg,0.07 mmol) was dissolved IN N, N-dimethylformamide (4 mL), and N, N-diisopropylethylamine (14 mg,0.11 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (33 mg,0.09 mmol) were added sequentially. After the addition, the reaction was allowed to react at room temperature for 16 hours, TLC (petroleum ether/ethyl acetate=4/1, r f =0.5) shows that the reaction is complete. 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=4/1) gave the title compound 99 as a white solid (15 mg, 52% yield in two steps).
LC-MS:m/z＝381.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.81(dd,J＝19.6,8.0Hz,2H),6.22-5.92(m,1H),4.42-4.29(m,1H),4.23-4.13(m,1H),3.95(dd,J＝11.2,6.8Hz,1H),3.36(td,J＝16.4,4.4Hz,2H),2.61-2.51(m,1H),2.38-2.29(m,2H),2.27-2.18(m,1H),2.12-2.02(m,2H),1.90-1.80(m,1H),1.69-1.60(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-109.29,-115.22,-120.27.
Synthesis example 77: synthesis of Compounds 100 and 101 (6S, 9R) -9- (6-chloro-5- (difluoromethoxy) pyridin-2-yl) -7, 7-difluorospiro [4.5] decan-6-ol; (6 r,9 s) -9- (6-chloro-5- (difluoromethoxy) pyridin-2-yl) -7, 7-difluorospiro [4.5] decan-6-ol (100-P1 and 100-P2);
(6 s,9 s) -9- (6-chloro-5- (difluoromethoxy) pyridin-2-yl) -7, 7-difluorospiro [4.5] decan-6-ol; (6R, 9R) -9- (6-chloro-5- (difluoromethoxy) pyridin-2-yl) -7, 7-difluorospiro [4.5] decan-6-ol (101-P1 and 101-P2)
First step 2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane 100-1
Compound 91-2 (9.2 g), pinacol diboronate (10.5 g,41.5 mmol), potassium acetate (9.4 g,95.76 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (260 mg,0.32 mmol) were dissolved in 1, 4-dioxane (100 mL) and reacted for 3 hours at 100℃under nitrogen protection; TLC monitored complete reaction of starting material. The reaction was cooled to room temperature, filtered through celite, the filtrate was diluted with water (300 mL), extracted with ethyl acetate (100 mL x 2), 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=7/1) to give the title compound 100-1 (8.3 g, yield: 97.70%) as a colorless oil.
Second step 2-chloro-3- (difluoromethoxy) -6- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) pyridine 100-2
Compound 100-1 (3.1 mg,11.65 mmol), compound 2-chloro-3- (difluoromethoxy) -6-iodopyridine (3.56 g,11.65 mmol), sodium carbonate (2.47 g,23.3 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (480 mg,0.58 mmol) and water (10 mL) were dispersed in 1, 4-dioxane (50 mL) and reacted at 95 ℃ under nitrogen protection for 16 hours; TLC monitored complete reaction of starting material. The reaction was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (50 mL x 2), 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=3/1) to give the title compound 100-2 (3.03 g, yield: 81.86%) as a colorless oil.
LC-MS:m/z＝318.1[M+H] + .
Third step 2-chloro-3- (difluoromethoxy) -6- (1, 4-dioxaspiro [4.5] decan-8-yl) pyridine 100-3
Compound 100-2 (3 g,9.44 mmol) and platinum dioxide (210 mg,0.94 mmol) were dispersed in ethanol (30 mL) and reacted for 16 hours under hydrogen protection at 50 ℃ temperature; TLC monitored complete reaction of starting material. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated to give the title compound 100-3 (3 g, yield: 99.40%) as a colorless oil.
LC-MS:m/z＝320.1[M+H] + .
Fourth step 4- (6-chloro-5- (difluoromethoxy) pyridin-2-yl) cyclohexan-1-one 100-4
Compound 100-3 (3 g,9.38 mmol) was dissolved in tetrahydrofuran (20 mL), diluted hydrochloric acid (10 mL, 3M) was added, and the mixture was heated to 50℃for 3 hours; TLC monitored complete reaction of starting material. The reaction solution was cooled to room temperature, saturated sodium hydrogencarbonate (70 mL) was added to alkalify to ph=8-9, ethyl acetate (80 ml×2) was extracted, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound 100-4 (2.1 g, yield: 81.21%) as a colorless oil.
Fifth step 9- (6-chloro-5- (difluoromethoxy) pyridin-2-yl) spiro [4.5] decan-6-one 100-5
Compound 100-4 (1.4 g,5.08 mmol), 1, 4-dibromobutane (5.48 g,25.4 mmol) and potassium tert-butoxide (1.25 g,11.18 mmol) were dispersed in toluene (20 mL) and reacted at 130℃for 3 hours with microwaves; the TLC monitoring showed that new spots were generated. The reaction was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (80 mL x 2), 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=4/1) to give the title compound 100-5 (600 mg, yield: 35.82%) as a colorless oil.
Sixth step 9- (6-chloro-5- (difluoromethoxy) pyridin-2-yl) -7, 7-difluorospiro [4.5] decan-6-one 100-6
Compound 100-5 (500 mg,1.52 mmol), optionally fluorogenic reagent (805 mg,1.82 mmol) and concentrated sulfuric acid (0.1 mL) were dispersed in methanol (20 mL) and reacted under nitrogen at 75℃for 4 hours; TLC monitored complete reaction of starting material. Dilute sulfuric acid (20 ml,0.3 m) was added to the reaction mixture, and the reaction was continued for 1 hour at a constant temperature. The reaction was cooled to room temperature, saturated sodium bicarbonate (100 mL) was added to ph=8-9, extracted with ethyl acetate (80 ml×2), 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=3/1) to give the title compound 100-6 (260 mg, yield: 46.77%) as a colorless oil.
LC-MS:m/z＝366.1[M+H] + .
Seventh step 9- (6-chloro-5- (difluoromethoxy) pyridin-2-yl) -7, 7-difluorospiro [4.5] decan-6-ol 100,101
100-6 (230 mg,0.63 mmol) was dissolved in methanol (5 mL), cooled to 0deg.C under nitrogen protection, sodium borohydride (48 mg,1.26 mmol) was added in portions, and the reaction mixture was allowed to warm to room temperature for 1 hour; 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 and purified by Pre-TLC (petroleum ether/ethyl acetate=3/1) to give a mixture of 100 and 101. The title compound is obtained by normal phase resolution.
Chiral HPLC analysis method: chiralpakAD-H, filler particle size (5 μm), inner diameter (4.6 mm), length (250 mm), flow rate: 1.0mL/min, IPA Hexane (+0.1% DEA) =10:90, wavelength: 220/254nm.
100-P1 and 100-P2 in the form of a colorless oil in 23.31% yield; retention time 13.017 min.
LC-MS:m/z＝368.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.54(d,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),6.56(t,J＝72.4Hz,1H),3.79(dt,J＝23.6,5.6Hz,1H),3.10(t,J＝12.4Hz,1H),2.38-1.90(m,6H),1.84-1.80(m,1H),1.77-1.60(m,4H),1.47-1.35(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-82.03,-100.85,-115.68.
A mixture of 101-P1 and 101-P2 as a colorless oil in a yield of 18.99%; retention time 10.503 min.
LC-MS:m/z＝368.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.54(d,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),6.56(t,J＝72.8Hz,1H),3.79(dt,J＝23.2,5.6Hz,1H),3.10(t,J＝12.4Hz,1H),2.39-1.88(m,6H),1.87-1.78(m,1H),1.74-1.59(m,4H),1.46-1.35(m,2H).
19 F NMR(377MHz,CDCl 3 )δ-82.03,-100.85,-115.68.
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: test compound concentration was measured as 50. Mu.M starting, 3-fold dilution, 10 concentration points, and multiplex assay. 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
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)
PT-2977 0.034
18 6.771
35 7.986
48 0.53
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 inoculated into 384 wells, 3000cells/well,30 μl of medium, and 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. According to each ofThe RLU (Record Luminesence) signal values of the wells were used to calculate inhibition (%), and then IC of the corresponding compounds was calculated by Graphpad 9.0 fit 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
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. A picolinamide 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 single 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-、-NR 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 、L 1 、R 5 The meaning is the same as that represented by formula (I),
ring A represents a substituted or unsubstituted C3-5 aromatic or heteroaromatic ring, where the substituents are halogen, hydroxy, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, or C3-8 cycloalkoxy;
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 ring A represents an aromatic ring structure,
4. the 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, 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 injectable formulation comprises a physiologically acceptable sterile aqueous or anhydrous solution, dispersion, suspension or emulsion, and a sterile powder of a compound of any one of claims 1-4 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 1-4, or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof, in the preparation of a 2 alpha hypoxia inducible factor inhibitor.
8. Use 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, in the manufacture of a medicament for treating or preventing a disease associated with 2 alpha hypoxia inducible factor;
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.
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