CN106188027B - Aromatic heterocyclic derivative and application thereof in medicine - Google Patents

Aromatic heterocyclic derivative and application thereof in medicine Download PDF

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CN106188027B
CN106188027B CN201610569848.5A CN201610569848A CN106188027B CN 106188027 B CN106188027 B CN 106188027B CN 201610569848 A CN201610569848 A CN 201610569848A CN 106188027 B CN106188027 B CN 106188027B
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alkylene
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CN106188027A (en
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张英俊
刘兵
余天柱
钟雪
张仕国
雷健华
郑常春
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Guangdong HEC Pharmaceutical
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Sunshine Lake Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

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Abstract

The invention discloses aromatic heterocyclic derivatives and application thereof in medicaments; specifically, the invention provides a class of aromatic heterocyclic compounds or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and a pharmaceutical composition containing the compounds. The invention also discloses the use of a compound of the invention or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of respiratory diseases, particularly Chronic Obstructive Pulmonary Disease (COPD).

Description

Aromatic heterocyclic derivative and application thereof in medicine
Technical Field
The invention belongs to the field of medicines, and particularly relates to an aromatic heterocyclic compound, a pharmaceutical composition containing the compound, and application and a using method of the compound. In particular, the compounds of the invention are PDE4 inhibitors for the treatment of Chronic Obstructive Pulmonary Disease (COPD).
Background
Cyclic nucleotide Phosphodiesterases (PDEs) are an important super enzyme family, which effectively control the intracellular concentrations of cAMP and cGMP by hydrolyzing cAMP and cGMP, thereby regulating the biochemical effects conducted by second messengers in vivo. PDEs are widely distributed in mammalian tissues, and the diversity of PDEs causes different PDE enzymes to have specific distribution at cellular and subcellular levels, can selectively regulate various cellular functions, and is a good drug design and treatment target.
Phosphodiesterase 4(PDE4) has been shown to be a major regulator of cyclic AMP in respiratory smooth muscle and inflammatory cells. Inhibitors of PDE4 are useful in the treatment of a variety of diseases, including allergic and inflammatory diseases, diabetes, central nervous system diseases, and pain.
Cyclic adenosine-3 ', 5' -monophosphate (cAMP) is known to exhibit an important intracellular secondary messenger role (Sutherland and Roll, pharmacol. rev,1960,12: 265). Intracellular hydrolysis of cAMP to adenosine 5 '-monophosphate (AMP) results in a number of inflammatory conditions including, but not limited to, psoriasis, allergic rhinitis, shock, atopic dermatitis, crohn's disease, Adult Respiratory Distress Syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, and ulcerative colitis. Cyclic nucleotide Phosphodiesterases (PDEs) are a highly varied superfamily of biochemical and functional properties of this enzyme, and are important factors for controlling cAMP (and cGMP) levels. There are 11 distinct families of phosphodiesterases with over 25 gene products. While PDE1, PDE2, PDE3, PDE4 and PDE7 all use cAMP as a substrate, only PDE4 and PDE7 types are highly selective for cAMP hydrolysis. Therefore, PDE inhibitors, in particular PDE4 inhibitors (e.g. ciclopirox (rolipram) or Ro-1724) are considered cAMP enhancers. The immune cells contain PDE3 and PDE4, with PDE4 being ubiquitous in human monocytes. Thus, inhibition of phosphodiesterase type iv is a goal of therapeutic intervention that modulates and thereby is useful in a variety of disease processes. Studies have shown that administration of PDE4 inhibitors has a memory loss-restoring effect in animal models, including those of alzheimer's disease (expetopein ther. targets,2005,9(6): 1283-1305; Drug Discovery Today,2005,10(22): 1503-19).
It was initially observed that xanthine derivatives, theophylline and caffeine inhibit cAMP hydrolysis leading to the discovery of the hydrolytic activity required for cyclic nucleotide Phosphodiesterases (PDEs). Recently, various types of PDEs have been identified (Beavo and Reifsnyder, Trends pharmacol. sci.,1990,11:150) whose selective inhibitory action improves the pharmacotherapeutic effect (Nicholus, Challiss and Shahid, Trends pharmacol. sci.,1991,12: 19). Thus, it is recognized that inhibition of PDE4 inhibits the release of inflammatory mediators (Verghese et al, J.mol.cell.Cardiol.,1989,12 (suppl II): S61).
WO 2004046095 discloses certain arylthiourea derivatives and related compounds having antiviral activity. WO 00/35891 discloses the use as human alpha1aCertain morpholinones (morpholinones) and morpholinone derivatives that are selective antagonists of the receptor. WO 200450024 discloses 3-aminopyrrolidine derivatives and their use as modulators of chemokine receptors. WO 2005/21515 relates to isoxazoline derivatives which act as selective inhibitors of Phosphodiesterase (PDE) type iv. WO2005/051931 discloses inhibitors of phosphodiesterase type IV.
Summary of the invention
The present invention relates to novel aromatic heterocyclic derivatives and methods of treating chronic respiratory obstruction. The compound or the pharmaceutical composition containing the compound has better treatment effect on chronic respiratory obstruction as a PDE4 inhibitor.
In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I):
Figure BDA0001052078950000021
wherein:
R1is hydrogen, deuterium, C1-3Alkyl, halo C1-3Alkyl, amino C1-3Alkyl, hydroxy substituted C1-3Alkyl, cyano-substituted C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl radical C1-4Alkyl radical, C2-6Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical C1-4Alkyl or C1-5Heteroaryl C1-4An alkyl group;
R2is hydrogen, deuterium, C1-3Alkyl, halo C1-3Alkyl, amino C1-3Alkyl, hydroxy substituted C1-3Alkyl, cyano-substituted C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl radical, C2-6Heterocyclic group, C6-10Aryl radical, C1-5Heteroaryl group, C3-6Cycloalkyl radical C1-4Alkyl radical, C2-6Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical C1-4Alkyl or C1-5Heteroaryl C1-4An alkyl group;
x is-N (R)8) -, -O-or-S-;
R3is deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxyl, carboxyl, C1-3Alkylamino, NH2-C1-3alkylene-C1-5Heteroarylene group, NH2-C1-3alkylene-C1-5Heteroarylene group-C1-3Alkylene, NH2-C1-3alkylene-C6-10Arylene, NH2-C1-3alkylene-C6-10Arylene radical-C1-3Alkylene radical, C1-3alkyl-C (═ O) -NH-, R9O-C(＝O)-C1-3alkylene-C (═ O) -NH-or C3-6cycloalkyl-C (═ O) -NH-;
each R5And R6Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxyl, carboxyl, C1-5Alkyl, halo C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Alkylamino radical, C1-3Alkoxy, halo C1-3Alkoxy, hydroxy-substituted C1-3Alkyl, carboxy substituted C1-3Alkyl radical, C6-10Aryl radical, C1-5Heteroaryl group, C3-6Cycloalkyl radical, C2-6Heterocyclic group, C6-10Aryl radical C1-3Alkyl radical, C1-5Heteroaryl C1-3Alkyl radical, C3-6Cycloalkyl radical C1-3Alkyl or C2-6Heterocyclyl radical C1-3An alkyl group;
or optionally R3And R5、R3And R6Or R5And R6Together form oxo (═ O);
each R7、R8And R9Independently hydrogen, deuterium or C1-3An alkyl group;
z is a bond, -O-, -CRaRb-, -C (═ O) -, or-S (═ O)2-；
Each RaAnd RbIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, NH2-C(＝S)-、C1-3Alkyl, amino substituted C1-3Alkyl radical, C1-3alkyl-S (═ O)2-NH-、C1-3alkyl-S (═ O)2-NH-C1-3Alkylene radical, C3-6cycloalkyl-S (═ O)2-NH-、C3-6cycloalkyl-S (═ O)2-NH-C1-3Alkylene radical, C1-3alkyl-O-C (═ O) -, C1-3alkyl-S (═ O)2-or C1-3alkyl-S (═ O)2-C1-3An alkylene group;
p is 0,1, 2,3,4, 5,6, 7 or 8;
R4is C3-6Cycloalkyl radical, C3-6Cycloalkenyl or C3-6A heterocyclic group; r4Optionally substituted by 1,2,3,4, 5 or 6R which may be the same or different13Substitution;
each R13Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, R14-C(＝O)-、R14-C(＝O)-C1-4Alkylene radical, R14-C(＝O)-C2-4Alkenylene radical, R15R16N-C(＝O)-、R15R16N-C(＝O)-O-、R15R16N-C(＝O)-C1-4Alkylene radical, R15R16N-C(＝O)-C2-4Alkenylene radical, R14-C(＝O)-N(R15)-、R14-C(＝O)-N(R15)-C1-4Alkylene radical, R14-C(＝O)-N(R15)-C2-4Alkenylene, oxo, C1-4Alkyl, halo C1-4Alkyl, amino C1-4Alkyl, hydroxy substituted C1-4Alkyl, cyano-substituted C1-4Alkyl, carboxy substituted C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Alkylamino radical C1-4Alkylamino radical, C1-4Alkylamino radical C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkylamino radical, C1-4Alkylthio radical, C2-4Alkenyl, carboxyl substituted C2-4Alkenyl or C2-4An alkynyl group;
each R14Independently hydrogen, deuterium, hydroxy, amino, C1-4Alkyl, halo C1-4Alkyl, amino C1-4Alkyl, hydroxy substituted C1-4Alkyl, cyano-substituted C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, hydroxy-substituted C1-4Alkoxy, carboxy substituted C1-4Alkoxy radicalBase, C1-4Alkylamino radical, C3-6Cycloalkyl radical, C2-8Heterocyclic group, C6-10Aryl or C1-6A heteroaryl group;
each R15And R16Independently of one another is hydrogen, deuterium, C1-4Alkyl, halo C1-4Alkyl, hydroxy substituted C1-4Alkyl, carboxy substituted C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-4Alkyl radical, C2-8Heterocyclic group, C2-8Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-6Heteroaryl or C1-6Heteroaryl C1-4An alkyl group; or R15，R16Together with the nitrogen atom to which they are attached form a ring of 3 to 8 atoms;
each R1、R2、R3、R4、R5、R6、R7、R8、R9、Ra、Rb、R13、R14、R15And R16Independently optionally substituted by one or more R17Substitution;
each R17Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, amino, carboxyl, NH2-C(＝O)-、NH2-S(＝O)2-、C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkyl, halo C1-3Alkoxy radical, C1-3alkyl-C (═ O) -or C1-3alkyl-O-C (═ O) -.
In some of these embodiments, R is1Is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-CH2Cl、-CHCl2、-CCl3Cyclopropyl methyl, cyclopropylAn ethyl group, a cyclobutylmethyl group, a cyclobutylethyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a cyclohexylmethyl group or a cyclohexylethyl group.
In some of these embodiments, R is2Is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-CH2Cl、-CHCl2、-CCl3Cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl.
In some of these embodiments, R is3Is fluorine, chlorine, amino or hydroxyl.
In some of these embodiments, each R is5And R6Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
In some of these embodiments, R is4Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, azetidinyl, pyrrolidinyl, piperidinyl, 2, 6-piperidinedionyl, homopiperidinyl, piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1-dioxo-thiomorpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydropyranyl, pyrrolinyl or tetrahydropyridinyl; r4Optionally substituted by 1,2,3,4, 5 or 6R which may be the same or different13Substitution; wherein each R13Have the meaning as described in the present invention.
In some embodiments, the present invention relates to a compound that is a compound of formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (II):
Figure BDA0001052078950000031
wherein:
w is 0,1, 2 or 3;
v is 0,1, 2 or 3;
t is 0,1, 2,3,4, 5 or 6;
y is-N (R)13)-、-CR13R13-, -O-, -S (═ O) -, or-S (═ O)2-；
Wherein each of p and R13Have the meaning as described in the present invention.
Some embodiments of the invention are a compound of formula (I) or formula (II) of the invention, wherein the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, or a combination thereof.
In some of these embodiments, each R is13Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, R14-C(＝O)-、R14-C(＝O)-C1-3Alkylene radical, R14-C(＝O)-C2-4Alkenylene radical, R15R16N-C(＝O)-、R15R16N-C(＝O)-O-、R15R16N-C(＝O)-C1-3Alkylene radical, R15R16N-C(＝O)-C2-4Alkenylene radical, R14-C(＝O)-NH-、R14-C(＝O)-NH-C1-3Alkylene radical, R14-C(＝O)-NH-C2-4Alkenylene, oxo, methyl, ethyl, n-propyl, iso-propylPropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, dimethylamino, ethylamino, or n-propylamino; wherein each R14、R15And R16Have the meaning as described in the present invention.
In some of these embodiments, each R is14Independently hydrogen, deuterium, hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In some of these embodiments, each R is15And R16Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In one aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention.
In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or vehicle.
In some embodiments, the pharmaceutical compositions of the present invention further comprise an additional therapeutic agent.
In still other embodiments, the pharmaceutical composition of the invention, wherein the additional therapeutic agent is: sodium pyruvate, Doxofylline (Doxofylline), Roflumilast (Roflumilast), Apremilast (Apremilast), Tetomilast (Tetomilast), Tipelukast, Theophylline (Theophylline), Formoterol (Formoterol), Salmeterol (Salmeterol), Fluticasone Propionate (Fluticasone Propionate), Salmeterol/Fluticasone Propionate complex (Salmeterol Xinafoate/Fluticasone Propionate), Rolipram (Rolipram), pirlamilast (Piclamist), Cilomilast (Cilomilast), CDP-840, Indacaterol (indataterol), odaterol (olopatrol), QVA149, midecant (midein), Zileuton, salbutamol, carbamazepine, triamcinolone acetonide, isolat, isolatamide, bromucosalbutamol, bromhexulone, tiotropine, isolatone, bromhexulone, isolat-acetate, bromhexuomate, isolat-Bromide, isolatuotasone, bromhexuolate, isolat-acetate, bromelamin, isolat, bromelamin, bromucosalbutamol, naltrexone, isolat, bromamide, isolat, bromate, bromhexuolate, isolat, bromelamin, isolat, bromela, bromate, bromhexuolate, isolat, bromelamin, bromela, isolat, bromelamin, Glycopyrronium bromide, Umeclidinium bromide, vilanterol, Umeclidinium bromide/compound of vilanterol, aclidinium bromide/compound of formoterol fumarate, LAS40464, LAS100977(abediterol), AZD-8999, RPL-554, OCID-2987, CHF-6001, CR-3465, HPP-737, fluticasone furoate/compound of vilanterol, FF/VI, Benralizumab, revatropine or combinations thereof.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for the prevention, treatment or alleviation of a disease or a disorder related to phosphodiesterase type 4(PDE 4).
In some embodiments, the disease associated with phosphodiesterase type 4(PDE4) is a respiratory disease, allergy, inflammation, Central Nervous System (CNS) disease, pulmonary fibrosis or non-insulin dependent diabetes.
In still other embodiments, the respiratory disorder is: chronic respiratory obstruction (COPD), emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, Acute Respiratory Distress Syndrome (ARDS), or respiratory inflammation.
In still other embodiments, the bronchitis comprises acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis, or bronchiolitis obliterans.
In still other embodiments, the inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis, or psoriatic arthritis.
Another aspect of the invention relates to methods for the preparation, isolation and purification of compounds of formula (I) or formula (II).
The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions, as used herein, should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and JerryMarch, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human. The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other. "diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; andEliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemases and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.ofNotreDame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A PracticalApproach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (lowenergy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (prototropic tautomers), also known as proton transfer tautomers (prototropic tautomers), include interconversions by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein said substituent may be, but is not limited to, deuterium, hydroxy, amino, fluorine, chlorine, bromine, iodine, cyano, azido, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo, carboxy, haloalkyl, haloalkoxy, hydroxy-substituted alkyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (═ O) -, alkyl-O-C (═ O) -, alkyl-S (═ O)2-, hydroxy-substituted alkyl-S (═ O)2-, carboxyalkoxy, NH2-C(＝O)-，NH2-S(＝O)2-and so on.
In addition, unless otherwise expressly indicated, the descriptions of "… independently" and "… independently" and "… independently" used in this disclosure are interchangeable and should be understood in a broad sense to mean that the particular items expressed between the same symbols in different groups do not affect each other or that the particular items expressed between the same symbols in the same groups do not affect each otherThe mutual influence is not influenced. With R15For example, the formula "NR15R16-C(＝O)-N(R15) - "and the formula" R14-C(＝O)-N(R15) -alkylene- "between R and R15Are not affected by each other, and are in the same chemical formula "NR15R16-C(＝O)-N(R15) - "in, a plurality of R15Are not affected by each other.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-C6Alkyl "or" C1-6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites, for example, "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein, wherein the substituents are deuterium, hydroxy, amino, fluoro, chloro, bromo, iodo, cyano, azido, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo, carboxy, haloalkyl, hydroxy-substituted alkyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (═ O) -, alkyl-S (═ O)2-, hydroxy-substituted alkyl-S (═ O) -, hydroxy-substituted alkylradical-S (═ O)2Carboxyalkoxy and the like. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl group (Et, -CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl group (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) Tert-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3) N-heptyl, n-octyl, and the like.
The term "alkylene" denotes a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms; in another embodiment, the alkylene group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 3 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 2 carbon atoms. Examples of this include methylene (-CH)2-, ethylene (-CH)2CH2-, propylene (-CH)2CH2CH2-, isopropylidene (-CH (CH)3)CH2-) and the like.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp2A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)2) Allyl (-CH)2CH＝CH2) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-8 carbon atoms; in another embodiment, alkynesThe radical contains 2 to 6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)2C.ident.CH), 1-propynyl (-C.ident.C-CH)3) And so on.
The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", denotes-CO2H or-COOH; the term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl" or "acyloxy", denotes- (C ═ O) -. The terms "cycloalkylcarbonyl," "heterocyclylcarbonyl," "arylcarbonyl," or "heteroarylcarbonyl" refer to a cycloalkyl, heterocyclyl, aryl, or heteroaryl group attached to the remainder of the molecule through a carbonyl group (i.e., (C ═ O)).
The term "deuterium" denotes a single deuterium atom. For example, one such atom replaces one hydrogen atom in a methyl group to form a mono-deuterated methyl (-CDH)2) Two deuterium atoms replace two hydrogen atoms in a methyl group to form a bis-deuterated methyl (-CD)2H) And three deuterium atoms are substituted for three hydrogen atoms in the methyl group to form a tri-deuterated methyl (-CD)3)。
The term "unsaturated" as used herein means that the group contains one or more unsaturations.
The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The terms "hydroxy-substituted alkyl", "hydroxy-substituted alkoxy" or "hydroxy-substituted alkylamino" denote alkyl groups, alkoxy groups or alkylamino groups substituted with one or more hydroxy groups, wherein alkyl groups, alkoxy groups and alkylamino groups have the meaning as described herein. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, hydroxymethoxy, hydroxyethoxy, hydroxymethylamino, hydroxyethylamino, and the like.
The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" denote alkyl, alkenyl or alkoxy groups substituted with one or more halogen atoms, examples of which include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy and the like.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)3) Ethoxy (EtO, -OCH)2CH3) 1-propoxy (n-PrO, n-propoxy, -OCH)2CH2CH3) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)3)2) 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)2CH(CH3)2) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)3)CH2CH3) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)3)3) 1-pentyloxy (n-pentyloxy, -OCH)2CH2CH2CH2CH3) 2-pentyloxy (-OCH (CH)3)CH2CH2CH3) 3-pentyloxy (-OCH (CH))2CH3)2) 2-methyl-2-butoxy (-OC (CH))3)2CH2CH3) 3-methyl-2-butoxy (-OCH (CH)3)CH(CH3)2)，3-methyl-l-butoxy (-OCH)2CH2CH(CH3)2) 2-methyl-l-butoxy (-OCH)2CH(CH3)CH2CH3) And so on.
The term "alkylthio" includes C1-6The linear or branched alkyl group is attached to a divalent sulfur atom. In some of these embodiments, alkylthio is lower C1-4Alkylthio groups, and such examples include, but are not limited to, methylthio (CH)3S-)。
The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is one or two C1-6Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In other embodiments, the alkylamino group is C1-3Lower alkylamino groups of (a). Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.
The term "aminoalkyl" or "amino-substituted alkyl" includes C substituted with one or more amino groups1-10A straight or branched alkyl group. In some of these embodiments, aminoalkyl is C substituted with one or more amino groups1-6Examples of "lower aminoalkyl" radicals include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.
The term "n-atomic" where n is an integer typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, piperidinyl is a heterocycloalkyl group of 6 atoms, and 1,2,3, 4-tetrahydronaphthalene is a carbocyclyl group of 10 atoms.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group contains 3 to 12 carbon atoms; in another embodiment, cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.
The term "cycloalkenyl" denotes mono-, bi-or tricyclic ring systems containing 3 to 12 carbon atoms, mono-or polyvalent, non-aromatic, comprising at least one carbon-carbon double bond. In one embodiment, cycloalkenyl groups contain 3 to 12 carbon atoms; in another embodiment, cycloalkenyl groups contain 3 to 8 carbon atoms; in yet another embodiment, cycloalkenyl groups contain 3 to 6 carbon atoms. The cycloalkenyl groups can be independently unsubstituted or substituted with one or more substituents described herein. Examples include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecenyl, and the like. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for this variable recites "cycloalkenyl," it is understood that "cycloalkenyl" represents a linked cycloalkenylene group.
The term "heterocycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, or oxygen atoms; the nitrogen or sulfur atom of the heterocycloalkyl group can be optionally oxidized to the corresponding N-oxide, S-oxide, or s.s-dioxide. Non-limiting examples of suitable monocyclic heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1-dioxo-thiomorpholinyl, thiazolidinyl, 1, 3-dioxolanyl, and the like.
The term "cycloalkylalkyl" or "cycloalkenylalkyl" denotes an alkyl group substituted with one or more cycloalkyl or cycloalkenyl groups, wherein the alkyl group, cycloalkenyl group, and cycloalkyl groups have the meaning as described herein, examples of which include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, and the like.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, wherein no aromatic ring is included in the monocyclic, bicyclic, or tricyclic ring, and at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1, 1-dioxo-thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaoxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl, 2-oxa-5-azabicyclo [ 2.2.1.1 ]]Hept-5-yl. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl and 3, 5-dioxopiperidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.
In one embodiment, heterocyclyl is a 4-7 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 4-7 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, groups of 4-7 atomsThe heterocyclic group may be carbon-based or nitrogen-based, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 4 to 7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl and 3, 5-dioxopiperidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. Said heterocyclyl group of 4 to 7 atoms may be optionally substituted by one or more substituents as described herein.
In another embodiment, heterocyclyl is a 4-atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 4 ring atoms in which at least one ring atom is substituted by a member selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group consisting of 4 atoms may be carbon-based or nitrogen-based, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 4 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl. The 4-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
In another embodiment, heterocyclyl is a 5-atom heterocyclyl and isRefers to a saturated or partially unsaturated monocyclic ring comprising 5 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, a 5-atom heterocyclic group may be carbon-based or nitrogen-based, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of 5-atom heterocyclic groups include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group. The 5-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
In another embodiment, heterocyclyl is a 6 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 6 atoms may be carbon-based or nitrogen-based, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 6 atoms include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, 1, 1-dioxothiomorpholinyl. The 6-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
In yet another embodiment, heterocyclyl is a 7-12 atom heterocyclyl and refers to a saturated or partially unsaturated spiro-or fused-bicyclic ring containing 7-12 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise specified, a heterocyclic group of 7 to 12 atoms may be carbon-based or nitrogen-based, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 7 to 12 atoms include, but are not limited to: 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. Said heterocyclyl group of 7 to 12 atoms may be optionally substituted by one or more substituents as described herein.
In yet another embodiment, heterocyclyl refers to heterocycloalkyl.
The term "heterocyclylalkyl" refers to a heterocyclyl-substituted alkyl group; wherein heterocyclyl and alkyl groups have the meaning as indicated in the present invention. Examples include, but are not limited to, thiomorpholin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, oxetan-3-ylmethyl, pyrrolidin-2-ylmethyl, morpholin-4-ylmethyl and the like.
The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group may independently be optionally substituted with one or more substituents described herein.
The term "aralkyl" or "arylalkyl" includes aryl-substituted alkyl groups. In some embodiments, an aralkyl group refers to a "lower aralkyl" group, i.e., the aryl group is attached to C1-6On the alkyl group of (a). In still other embodiments, an aralkyl group refers to a group containing C1-4Alkyl of benzeneAlkyl groups ". Specific examples thereof include benzyl, diphenylmethyl, phenethyl. The aryl group on the aralkyl group may be further substituted with halogen, alkyl, alkoxy, haloalkyl and haloalkoxy.
The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring", "aromatic heterocycle" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In some of these embodiments, a 5-10 atom heteroaryl group contains 1,2,3, or 4 heteroatoms independently selected from O, S, and N.
Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), and the like, 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl, pyrimidinonyl, pyridonyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzotetrahydrofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), tetrahydroquinolyl (e.g., 1,2,3, 4-tetrahydroquinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), tetrahydroisoquinolyl (e.g., 1,2,3, 4-tetrahydroisoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridinyl, and the like.
As described herein, the ring system formed by a substituent on a ring that is bonded to the center (as shown in formula e) represents that the substituent may be substituted at any substitutable position on the ring. For example, formula e represents any possible substituted position on the A or B ring, such as formula f1-f7Shown in the figure:
Figure BDA0001052078950000111
the attachment point may be attached to the rest of the molecule at any point on the ring that is attachable, as described in the present invention. For example, formula k represents the point of attachment at any possible attachment position on the A or B ring.
Figure BDA0001052078950000121
The term "heteroarylalkyl" denotes an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl groups have the meaning described herein, and examples include, but are not limited to, imidazol-2-ylmethyl, furan-2-ylethyl, indol-3-ylmethyl, and the like.
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I) or formula (II). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form.Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel delivery systems, Vol.14 of the A.C.S.Sympossium Series, Edward B.Roche, ed., Bioredeployers in Drug designs, American Pharmaceutical Association and PergammonPress, 1987, J.Rautio et al, Prodrugs: Design and Clinical Applications, Nature review Discovery,2008,7, 255-.
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, J.pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, boratesButyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumerate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates and aromatic sulfonates.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butyloxycarbonyl (BOC ), benzyloxycarbonyl (CBZ)Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005。
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, dihydrogenphosphate, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.
Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In e.g. "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., 1985; and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of pharmaceutical salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany,2002) may find some additional lists of suitable salts.
In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms.
Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H，3H，11C，13C，14C，15N，17O，18O，18F，31P，32P，35S，36Cl and125I。
in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present3H，14C and18those compounds of F, or in which a non-radioactive isotope is present, e.g.2H and13C. the isotopically enriched compounds can be used for metabolic studies (use)14C) Reaction kinetics study (using, for example2H or3H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.18F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) or formula (II) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.
In addition, heavier isotopes are, in particular, deuterium (i.e.,2substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is considered as a substituent of the compound of formula (I) or formula (II). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D2O, acetone-d6、DMSO-d6Those solvates of (a).
Description of the Compounds of the invention
The aromatic heterocyclic derivatives, the pharmaceutically acceptable salts and the pharmaceutical preparations thereof can inhibit PDE4 and have potential application in the treatment of chronic respiratory obstruction.
In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I):
Figure BDA0001052078950000141
wherein:
R1is hydrogen, deuterium, alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkylalkyl-C (═ O) -, alkyl-S (═ O)2-, alkyl-C (═ O) -alkylene, cycloalkyl-C (═ O) -alkylene, heterocyclyl-C (═ O) -alkylene, alkyl-S (═ O)2Alkylene, cycloalkyl-S (═ O)2Alkylene, heterocyclyl-S (═ O)2-alkylene, alkenyl, alkynyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl or heteroarylalkyl;
R2are hydrogen, deuterium, alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, alkyl-C (═ O) -, alkyl-S (═ O)2-, alkyl-C (═ O) -alkylene, alkyl-O-C (═ O) -alkylene, alkyl-S (═ O)2-alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, cycloalkyl-C (═ O) -alkylene or heterocyclyl-C (═ O) -alkylene;
x is-N (R)8) -, -O-or-S-;
R3is deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxyl, carboxyl, alkylamino, NH2Alkylene-heteroarylene, NH2Alkylene-heteroarylene-alkylene, NH2Alkylene-arylene, NH2Alkylene-arylene-alkylene, alkyl-C (═ O) -NH-, R9O-C (═ O) -alkylene-C (═ O) -NH-or cycloalkyl-C (═ O) -NH-;
each R5And R6Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxyl, carboxyl, alkyl, haloalkyl, alkenyl, alkynyl, alkylamino, alkoxy, haloalkoxy, hydroxyl-substituted alkyl, carboxyl-substituted alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, aralkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl;
or optionally R3And R5、R3And R6Or R5And R6Together form oxo (═ O);
each R7、R8And R9Independently hydrogen, deuterium, or alkyl;
z is a bond-O-、-CRaRb-, -C (═ O) -, or-S (═ O)2-；
Each RaAnd RbIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, NH2-C (═ S) -, alkyl, amino-substituted alkyl, R10-C(＝O)-NH-、R10-C (═ O) -NH-alkylene, alkyl-S (═ O)2-NH-, alkyl-S (═ O)2-NH-alkylene, cycloalkyl-S (═ O)2-NH-, cycloalkyl-S (═ O)2-NH-alkylene, alkyl-O-C (═ O) -, R11R12N-C(＝O)-、R11R12N-C (═ O) -alkylene, alkyl-S (═ O)2-or alkyl-S (═ O)2-an alkylene group;
p is 0,1, 2,3,4, 5,6, 7 or 8;
each R10Independently hydrogen, deuterium, hydroxy, amino, NH2-C(＝O)-、NH2-C (═ O) -alkylene, alkyl-O-C (═ O) -alkylene, alkyl-C (═ O) -O-alkylene, NH2-S(＝O)2-、NH2-S(＝O)2Alkylene, alkyl-S (═ O)2-, cycloalkyl-S (═ O)2-, alkyl, haloalkyl, amino-substituted alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl or heterocyclylalkyl;
each R11And R12Independently hydrogen, deuterium, hydroxy, amino, NH2-C(＝O)-、NH2-C (═ O) -alkylene, alkyl-O-C (═ O) -alkylene, alkyl-C (═ O) -O-alkylene, NH2-S(＝O)2-、NH2-S(＝O)2Alkylene, alkyl-S (═ O)2-, cycloalkyl-S (═ O)2-, alkyl, haloalkyl, amino-substituted alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl or heterocyclylalkyl;
R4is cycloalkyl, cycloalkenyl or heterocyclyl; r4Optionally substituted by 1,2,3,4, 5 or 6R which may be the same or different13Substitution;
each R13Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, R14-C(＝O)-、R14-C (═ O) -alkylene, R14-C (═ O) -alkenylene, R14-C (═ O) -alkylene-O-C (═ O) -, R14-C (═ O) -alkenylene-O-C (═ O) -, R14-C (═ O) -O-alkylene-O-C (═ O) -, R14-C (═ O) -O-alkenylene-O-C (═ O) -, R15R16N-C(＝O)-、R15R16N-C(＝O)-O-、R15R16N-C (═ O) -alkylene, R15R16N-C (═ O) -alkenylene, R15R16N-C (═ O) -alkylene-O-C (═ O) -, R15R16N-C (═ O) -alkenylene-O-C (═ O) -, R14-C(＝O)-N(R15)-、R14-C(＝O)-N(R15) Alkylene radical, R14-C(＝O)-N(R15) -alkenylene, R14-C (═ O) -alkylene-N (R)15)-、R14-C (═ O) -alkenylene-N (R)15)-、R15R16N-C(＝O)-N(R15)-、R15R16N-C(＝O)-N(R15) Alkylene radical, R15R16N-C(＝O)-N(R15) -alkenylene, R15R16N-C (═ O) -alkylene-N (R)15)-、R15R16N-C (═ O) -alkenylene-N (R)15)-、R14-C(＝O)-N(R15)-C(＝O)-、R14-C(＝O)-N(R15) -C (═ O) -alkylene, R14-C(＝O)-N(R15) -C (═ O) -alkenylene, R14a-O-alkylene, R14a-O-alkenylene, oxo, alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, carboxy-substituted alkyl, alkoxyalkyl, hydroxy-substituted alkoxyalkyl, carboxy-substituted alkoxyalkyl, alkylaminoalkyl, aryloxy-substituted alkyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, alkylaminoalkylamino, alkylaminoalkoxy, alkoxyalkylamino, alkylthio, alkenyl, carboxy-substituted alkenyl, alkynyl, R14-S(＝O)2-、R14-S(＝O)2Alkylene radical, R14-S(＝O)2-alkenylene, R14-S(＝O)2-N(R15)-、R14-S(＝O)2-N(R15) Alkylene radical, R14-S(＝O)2-N(R15) -alkenylene, R15R16N-S(＝O)2-、R15R16N-S(＝O)2Alkylene radical, R15R16N-S(＝O)2-alkenylene, cycloalkyl, cycloalkyloxy, cycloalkylamino, cycloalkylalkyl, cycloalkenyl, cycloalkenyloxy, cycloalkenylamino, cycloalkenylalkyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalkyl, aryl, aryloxy, arylamino, arylalkyl, heteroaryl, heteroaryloxy, heteroarylamino or heteroarylalkyl;
each R14Independently hydrogen, deuterium, hydroxy, amino, alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy-substituted alkoxy, carboxy-substituted alkoxy, alkoxyalkoxy, cycloalkylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, alkylamino, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroaryloxy, or heteroarylalkyl;
each R14aIndependently is H, alkyl, haloalkyl, hydroxy-substituted alkyl, carboxy-substituted alkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
each R15And R16Independently hydrogen, deuterium, alkyl, haloalkyl, hydroxy-substituted alkyl, carboxy-substituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; or R15，R16Together with the nitrogen atom to which they are attached form a ring of 3 to 12 atoms;
each R1、R2、R3、R4、R5、R6、R7、R8、R9、Ra、Rb、R10、R11、R12、R13、R14、R14a、R15And R16Independently optionally substituted by one or more R17Substitution;
each R17Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, amino, carboxyl, NH2-C(＝O)-、NH2-S(＝O)2-、C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radical, C1-6alkyl-C (═ O) -or C1-6alkyl-O-C (═ O) -.
In some of these embodiments, each R is17Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, amino, carboxyl, NH2-C(＝O)-、NH2-S(＝O)2-、C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkyl, halo C1-3Alkoxy radical, C1-3alkyl-C (═ O) -or C1-3alkyl-O-C (═ O) -.
In some of these embodiments, R is1Is hydrogen, deuterium, C1-6Alkyl, halo C1-6Alkyl, amino C1-6Alkyl, hydroxy substituted C1-6Alkyl, cyano-substituted C1-6Alkyl radical, C1-6alkyl-C (═ O) -, C1-6alkyl-S (═ O)2-、C1-6alkyl-C (═ O) -C1-6Alkylene radical, C3-8cycloalkyl-C (═ O) -C1-6Alkylene radical, C2-10heterocyclyl-C (═ O) -C1-6Alkylene radical, C1-6alkyl-S (═ O)2-C1-6Alkylene radical, C3-8cycloalkyl-S (═ O)2-C1-6Alkylene radical, C2-10heterocyclyl-S (═ O)2-C1-6Alkylene radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl or C1-9Heteroaryl C1-6An alkyl group.
Some of which implementScheme is that R2Is hydrogen, deuterium, C1-6Alkyl, halo C1-6Alkyl, amino C1-6Alkyl, hydroxy substituted C1-6Alkyl, cyano-substituted C1-6Alkyl radical, C1-6alkyl-C (═ O) -, C1-6alkyl-S (═ O)2-、C1-6alkyl-C (═ O) -C1-6Alkylene radical, C1-6alkyl-O-C (═ O) -C1-6Alkylene radical, C1-6alkyl-S (═ O)2-C1-6Alkylene radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl group, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C3-8cycloalkyl-C (═ O) -C1-6Alkylene or C2-10heterocyclyl-C (═ O) -C1-6An alkylene group.
In still other embodiments, R is1Is hydrogen, deuterium, C1-3Alkyl, halo C1-3Alkyl, amino C1-3Alkyl, hydroxy substituted C1-3Alkyl, cyano-substituted C1-3Alkyl radical, C1-3alkyl-C (═ O) -, C1-3alkyl-S (═ O)2-、C1-3alkyl-C (═ O) -C1-6Alkylene radical, C3-6cycloalkyl-C (═ O) -C1-6Alkylene radical, C2-6heterocyclyl-C (═ O) -C1-6Alkylene radical, C1-3alkyl-S (═ O)2-C1-6Alkylene radical, C3-6cycloalkyl-S (═ O)2-C1-6Alkylene radical, C2-6heterocyclyl-S (═ O)2-C1-6Alkylene radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl radical C1-4Alkyl radical, C2-6Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical C1-4Alkyl or C1-5Heteroaryl C1-4An alkyl group.
In still other embodiments, R is2Is hydrogen, deuterium, C1-3Alkyl, halo C1-3Alkyl, aminoC1-3Alkyl, hydroxy substituted C1-3Alkyl, cyano-substituted C1-3Alkyl radical, C1-3alkyl-C (═ O) -, C1-3alkyl-S (═ O)2-、C1-3alkyl-C (═ O) -C1-6Alkylene radical, C1-3alkyl-O-C (═ O) -C1-6Alkylene radical, C1-3alkyl-S (═ O)2-C1-6Alkylene radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl radical, C2-6Heterocyclic group, C6-10Aryl radical, C1-5Heteroaryl group, C3-6Cycloalkyl radical C1-4Alkyl radical, C2-6Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical C1-4Alkyl radical, C1-5Heteroaryl C1-4Alkyl radical, C3-6cycloalkyl-C (═ O) -C1-6Alkylene or C2-6heterocyclyl-C (═ O) -C1-6An alkylene group.
In still other embodiments, R is1Is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-CH2Cl、-CHCl2、-CCl3Cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl.
In still other embodiments, R is2Is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-CH2Cl、-CHCl2、-CCl3Cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylEthyl, cyclohexylmethyl or cyclohexylethyl.
In some of these embodiments, R is3Is deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxyl, carboxyl, C1-6Alkylamino, NH2-C1-6alkylene-C1-9Heteroarylene group, NH2-C1-6alkylene-C1-9Heteroarylene group-C1-6Alkylene, NH2-C1-6alkylene-C6-10Arylene, NH2-C1-6alkylene-C6-10Arylene radical-C1-6Alkylene radical, C1-6alkyl-C (═ O) -NH-, R9O-C(＝O)-C1-6alkylene-C (═ O) -NH-or C3-8cycloalkyl-C (═ O) -NH-;
wherein R is9Have the meaning as described in the present invention.
In some of these embodiments, R is5Is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxyl, carboxyl, C1-6Alkyl, halo C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkylamino radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy-substituted C1-6Alkyl, carboxy substituted C1-6Alkyl radical, C6-10Aryl radical, C1-9Heteroaryl group, C3-8Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C3-8Cycloalkyl radical C1-6Alkyl or C2-10Heterocyclyl radical C1-6An alkyl group.
In some of these embodiments, R is6Is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxyl, carboxyl, C1-6Alkyl, halo C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkylamino radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy-substituted C1-6Alkyl, carboxy substituted C1-6Alkyl radical, C6-10Aryl radical, C1-9Heteroaryl group, C3-8Cycloalkyl radical, C2-10A heterocyclic group,C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C3-8Cycloalkyl radical C1-6Alkyl or C2-10Heterocyclyl radical C1-6An alkyl group.
In some of these embodiments, R is3And R5、R3And R6Or R5And R6Together form oxo (═ O).
In still other embodiments, R is3Is deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxyl, carboxyl, C1-3Alkylamino, NH2-C1-3alkylene-C1-5Heteroarylene group, NH2-C1-3alkylene-C1-5Heteroarylene group-C1-3Alkylene, NH2-C1-3alkylene-C6-10Arylene, NH2-C1-3alkylene-C6-10Arylene radical-C1-3Alkylene radical, C1-3alkyl-C (═ O) -NH-, R9O-C(＝O)-C1-3alkylene-C (═ O) -NH-or C3-6cycloalkyl-C (═ O) -NH-;
wherein R is9Have the meaning as described in the present invention.
In still other embodiments, R is3Is fluorine, chlorine, amino or hydroxyl.
In still other embodiments, R is5Is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxyl, carboxyl, C1-5Alkyl, halo C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Alkylamino radical, C1-3Alkoxy, halo C1-3Alkoxy, hydroxy-substituted C1-3Alkyl, carboxy substituted C1-3Alkyl radical, C6-10Aryl radical, C1-5Heteroaryl group, C3-6Cycloalkyl radical, C2-6Heterocyclic group, C6-10Aryl radical C1-3Alkyl radical, C1-5Heteroaryl C1-3Alkyl radical, C3-6Cycloalkyl radical C1-3Alkyl or C2-6Heterocyclyl radical C1-3An alkyl group.
In still other embodiments, R is6Is hydrogen, deuterium, fluorineChlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxyl, C1-5Alkyl, halo C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Alkylamino radical, C1-3Alkoxy, halo C1-3Alkoxy, hydroxy-substituted C1-3Alkyl, carboxy substituted C1-3Alkyl radical, C6-10Aryl radical, C1-5Heteroaryl group, C3-6Cycloalkyl radical, C2-6Heterocyclic group, C6-10Aryl radical C1-3Alkyl radical, C1-5Heteroaryl C1-3Alkyl radical, C3-6Cycloalkyl radical C1-3Alkyl or C2-6Heterocyclyl radical C1-3An alkyl group.
In still other embodiments, R is3And R5、R3And R6Or R5And R6Together form oxo (═ O).
In still other embodiments, R is5Hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
In still other embodiments, R is6Hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
In some of these embodiments, each R isaIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, NH2-C(＝S)-、C1-6Alkyl, amino substituted C1-6Alkyl radical, R10-C(＝O)-NH-、R10-C(＝O)-NH-C1-6Alkylene radical, C1-6alkyl-S (═ O)2-NH-、C1-6alkyl-S (═ O)2-NH-C1-6Alkylene radical, C3-8cycloalkyl-S (═ O)2-NH-、C3-8cycloalkyl-S (═ O)2-NH-C1-6Alkylene radical, C1-6alkyl-O-C (═ O) -, R11R12N-C(＝O)-、R11R12N-C(＝O)-C1-6Alkylene radical, C1-6alkyl-S (═ O)2-or C1-6alkyl-S (═ O)2-C1-6An alkylene group;
wherein each R10、R11And R12Have the meaning as described in the present invention.
In some of these embodiments, each R isbIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, NH2-C(＝S)-、C1-6Alkyl, amino substituted C1-6Alkyl radical, R10-C(＝O)-NH-、R10-C(＝O)-NH-C1-6Alkylene radical, C1-6alkyl-S (═ O)2-NH-、C1-6alkyl-S (═ O)2-NH-C1-6Alkylene radical, C3-8cycloalkyl-S (═ O)2-NH-、C3-8cycloalkyl-S (═ O)2-NH-C1-6Alkylene radical, C1-6alkyl-O-C (═ O) -, R11R12N-C(＝O)-、R11R12N-C(＝O)-C1-6Alkylene radical, C1-6alkyl-S (═ O)2-or C1-6alkyl-S (═ O)2-C1-6An alkylene group;
wherein each R10、R11And R12Have the meaning as described in the present invention.
In some of these embodiments, each R is10Independently hydrogen, deuterium, hydroxy, amino, NH2-C(＝O)-、NH2-C(＝O)-C1-6Alkylene radical, C1-6alkyl-O-C (═ O) -C1-6Alkylene radical, C1-6alkyl-C (═ O) -O-C1-6Alkylene, NH2-S(＝O)2-、NH2-S(＝O)2-C1-6Alkylene radical, C1-6alkyl-S (═ O)2-、C3-8cycloalkyl-S (═ O)2-、C1-6Alkyl, halo C1-6Alkyl, amino substituted C1-6Alkyl radical, C3-8Cycloalkyl radical, C2-10Heterocyclic group, C3-8Cycloalkyl radical C1-6Alkyl or C2-10Heterocyclyl radical C1-6An alkyl group.
In some of these embodiments, each R is11Independent of each otherGround is hydrogen, deuterium, hydroxyl, amino, NH2-C(＝O)-、NH2-C(＝O)-C1-6Alkylene radical, C1-6alkyl-O-C (═ O) -C1-6Alkylene radical, C1-6alkyl-C (═ O) -O-C1-6Alkylene, NH2-S(＝O)2-、NH2-S(＝O)2-C1-6Alkylene radical, C1-6alkyl-S (═ O)2-、C3-8cycloalkyl-S (═ O)2-、C1-6Alkyl, halo C1-6Alkyl, amino substituted C1-6Alkyl radical, C3-8Cycloalkyl radical, C2-10Heterocyclic group, C3-8Cycloalkyl radical C1-6Alkyl or C2-10Heterocyclyl radical C1-6An alkyl group.
In some of these embodiments, each R is12Independently hydrogen, deuterium, hydroxy, amino, NH2-C(＝O)-、NH2-C(＝O)-C1-6Alkylene radical, C1-6alkyl-O-C (═ O) -C1-6Alkylene radical, C1-6alkyl-C (═ O) -O-C1-6Alkylene, NH2-S(＝O)2-、NH2-S(＝O)2-C1-6Alkylene radical, C1-6alkyl-S (═ O)2-、C3-8cycloalkyl-S (═ O)2-、C1-6Alkyl, halo C1-6Alkyl, amino substituted C1-6Alkyl radical, C3-8Cycloalkyl radical, C2-10Heterocyclic group, C3-8Cycloalkyl radical C1-6Alkyl or C2-10Heterocyclyl radical C1-6An alkyl group.
In still other embodiments, each R isaIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, NH2-C(＝S)-、C1-3Alkyl, amino substituted C1-3Alkyl radical, R10-C(＝O)-NH-、R10-C(＝O)-NH-C1-3Alkylene radical, C1-3alkyl-S (═ O)2-NH-、C1-3alkyl-S (═ O)2-NH-C1-3Alkylene radical, C3-6cycloalkyl-S (═ O)2-NH-、C3-6cycloalkyl-S (═ O)2-NH-C1-3Alkylene radical, C1-3alkyl-O-C (═ O)-、R11R12N-C(＝O)-、R11R12N-C(＝O)-C1-3Alkylene radical, C1-3alkyl-S (═ O)2-or C1-3alkyl-S (═ O)2-C1-3An alkylene group;
wherein each R10、R11And R12Have the meaning as described in the present invention.
In still other embodiments, each R isbIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, NH2-C(＝S)-、C1-3Alkyl, amino substituted C1-3Alkyl radical, R10-C(＝O)-NH-、R10-C(＝O)-NH-C1-3Alkylene radical, C1-3alkyl-S (═ O)2-NH-、C1-3alkyl-S (═ O)2-NH-C1-3Alkylene radical, C3-6cycloalkyl-S (═ O)2-NH-、C3-6cycloalkyl-S (═ O)2-NH-C1-3Alkylene radical, C1-3alkyl-O-C (═ O) -, R11R12N-C(＝O)-、R11R12N-C(＝O)-C1-3Alkylene radical, C1-3alkyl-S (═ O)2-or C1-3alkyl-S (═ O)2-C1-3An alkylene group;
wherein each R10、R11And R12Have the meaning as described in the present invention.
In still other embodiments, each R is10Independently hydrogen, deuterium, hydroxy, amino, NH2-C(＝O)-、NH2-C(＝O)-C1-3Alkylene radical, C1-3alkyl-O-C (═ O) -C1-3Alkylene radical, C1-3alkyl-C (═ O) -O-C1-3Alkylene, NH2-S(＝O)2-、NH2-S(＝O)2-C1-3Alkylene radical, C1-3alkyl-S (═ O)2-、C3-6cycloalkyl-S (═ O)2-、C1-3Alkyl, halo C1-3Alkyl, amino substituted C1-3Alkyl radical, C3-6Cycloalkyl radical, C2-6Heterocyclic group, C3-6Cycloalkyl radical C1-3Alkyl or C2-6Heterocyclyl radical C1-3An alkyl group.
In still other embodiments, each R is11Independently hydrogen, deuterium, hydroxy, amino, NH2-C(＝O)-、NH2-C(＝O)-C1-3Alkylene radical, C1-3alkyl-O-C (═ O) -C1-3Alkylene radical, C1-3alkyl-C (═ O) -O-C1-3Alkylene, NH2-S(＝O)2-、NH2-S(＝O)2-C1-3Alkylene radical, C1-3alkyl-S (═ O)2-、C3-6cycloalkyl-S (═ O)2-、C1-3Alkyl, halo C1-3Alkyl, amino substituted C1-3Alkyl radical, C3-6Cycloalkyl radical, C2-6Heterocyclic group, C3-6Cycloalkyl radical C1-3Alkyl or C2-6Heterocyclyl radical C1-3An alkyl group.
In still other embodiments, each R is12Independently hydrogen, deuterium, hydroxy, amino, NH2-C(＝O)-、NH2-C(＝O)-C1-3Alkylene radical, C1-3alkyl-O-C (═ O) -C1-3Alkylene radical, C1-3alkyl-C (═ O) -O-C1-3Alkylene, NH2-S(＝O)2-、NH2-S(＝O)2-C1-3Alkylene radical, C1-3alkyl-S (═ O)2-、C3-6cycloalkyl-S (═ O)2-、C1-3Alkyl, halo C1-3Alkyl, amino substituted C1-3Alkyl radical, C3-6Cycloalkyl radical, C2-6Heterocyclic group, C3-6Cycloalkyl radical C1-3Alkyl or C2-6Heterocyclyl radical C1-3An alkyl group.
In some of these embodiments, R is4Is C3-8Cycloalkyl radical, C3-8Cycloalkenyl or C2-12A heterocyclic group; r4Optionally substituted by 1,2,3,4, 5 or 6R which may be the same or different13Substitution;
wherein each R13Have the meaning as described in the present invention.
In still other embodiments, R is4Is C3-6Cycloalkyl radical, C3-6Cycloalkenyl or C3-6A heterocyclic group; r4Optionally substituted by 1,2,3,4, 5 or 6R which may be the same or different13Substitution;
wherein each R13Have the meaning as described in the present invention.
In still other embodiments, R is4Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, azetidinyl, pyrrolidinyl, piperidinyl, 2, 6-piperidinedionyl, homopiperidinyl, piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1-dioxo-thiomorpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydropyranyl, pyrrolinyl or tetrahydropyridinyl; r4Optionally substituted by 1,2,3,4, 5 or 6R which may be the same or different13Substitution;
wherein each R13Have the meaning as described in the present invention.
In some of these embodiments, R is4Is of the sub-structure:
Figure BDA0001052078950000191
Figure BDA0001052078950000192
R4optionally substituted by 1,2,3,4, 5 or 6R which may be the same or different13Substitution;
wherein:
each Y is1Independently is-N (R)13) -, -O-, -S (═ O) -, or-S (═ O)2-；
J is-N (R)13) -, -O-, -S (═ O) -, or-S (═ O)2-；
Each q and f is independently 0,1, 2,3 or 4;
each r is independently 0,1, 2 or 3;
each s is independently 1,2 or 3;
wherein each of Y and R13Have the meaning as described in the present invention.
In still other embodiments, R is4Is of the sub-structure:
Figure BDA0001052078950000193
Figure BDA0001052078950000201
Figure BDA0001052078950000202
R4optionally substituted by 1,2,3,4, 5 or 6R which may be the same or different13Substitution;
wherein each R13Have the meaning as described in the present invention.
In still other embodiments, R is4Is of the sub-structure:
Figure BDA0001052078950000203
Figure BDA0001052078950000211
wherein each R13Have the meaning as described in the present invention.
In some embodiments, the present invention relates to a compound that is a compound of formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (II):
Figure BDA0001052078950000212
wherein:
w is 0,1, 2 or 3;
v is 0,1, 2 or 3;
t is 0,1, 2,3,4, 5 or 6;
y is-N (R)13)-、-CR13R13-, -O-, -S (═ O) -, or-S (═ O)2-；
Wherein each of p and R13Have the meaning as described in the present invention.
In some embodiments, the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate or a combination thereof.
In some of these embodiments, each R is13Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, R14-C(＝O)-、R14-C(＝O)-C1-6Alkylene radical, R14-C(＝O)-C2-6Alkenylene radical, R14-C(＝O)-C1-6alkylene-O-C (═ O) -, R14-C(＝O)-C2-6alkenylene-O-C (═ O) -, R14-C(＝O)-O-C1-6alkylene-O-C (═ O) -, R14-C(＝O)-O-C2-6alkenylene-O-C (═ O) -, R15R16N-C(＝O)-、R15R16N-C(＝O)-O-、R15R16N-C(＝O)-C1-6Alkylene radical, R15R16N-C(＝O)-C2-6Alkenylene radical, R15R16N-C(＝O)-C1-6alkylene-O-C (═ O) -, R15R16N-C(＝O)-C2-6alkenylene-O-C (═ O) -, R14-C(＝O)-N(R15)-、R14-C(＝O)-N(R15)-C1-6Alkylene radical, R14-C(＝O)-N(R15)-C2-6Alkenylene radical, R14-C(＝O)-C1-6alkylene-N (R)15)-、R14-C(＝O)-C2-6alkenylene-N (R)15)-、R15R16N-C(＝O)-N(R15)-、R15R16N-C(＝O)-N(R15)-C1-6Alkylene oxideRadical, R15R16N-C(＝O)-N(R15)-C2-6Alkenylene radical, R15R16N-C(＝O)-C1-6alkylene-N (R)15)-、R15R16N-C(＝O)-C2-6alkenylene-N (R)15)-、R14-C(＝O)-N(R15)-C(＝O)-、R14-C(＝O)-N(R15)-C(＝O)-C1-6Alkylene radical, R14-C(＝O)-N(R15)-C(＝O)-C2-6Alkenylene radical, R14a-O-C1-6Alkylene radical, R14a-O-C2-6Alkenylene, oxo, C1-6Alkyl, halo C1-6Alkyl, amino C1-6Alkyl, hydroxy substituted C1-6Alkyl, cyano-substituted C1-6Alkyl, carboxy substituted C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, hydroxy substituted C1-6Alkoxy radical C1-6Alkyl, carboxy substituted C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C6-10Aryloxy substituted C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Alkylamino radical C1-6Alkylamino radical, C1-6Alkylamino radical C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkylamino radical, C1-6Alkylthio radical, C2-6Alkenyl, carboxyl substituted C2-6Alkenyl radical, C2-6Alkynyl, R14-S(＝O)2-、R14-S(＝O)2-C1-6Alkylene radical, R14-S(＝O)2-C2-6Alkenylene radical, R14-S(＝O)2-N(R15)-、R14-S(＝O)2-N(R15)-C1-6Alkylene radical, R14-S(＝O)2-N(R15)-C2-6Alkenylene radical, R15R16N-S(＝O)2-、R15R16N-S(＝O)2-C1-6Alkylene radical, R15R16N-S(＝O)2-C2-6Alkenylene radical, C3-8Cycloalkyl radical, C3-8Cycloalkyl oxy, C3-8Cycloalkylamino, C3-8Cycloalkyl radical C1-6Alkyl radical, C3-8Cycloalkenyl radical, C3-8Cycloalkenyloxy, C3-8Cycloalkenyl amino, C3-8Cycloalkenyl radical C1-6Alkyl radical, C2-10Heterocyclic group, C2-10Heterocyclyloxy, C2-10Heterocyclylamino group, C2-10Heterocyclyl radical C1-6Alkyl radical, C6-10Aryl radical, C6-10Aryloxy radical, C6-10Arylamino, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl group, C1-9Heteroaryloxy radical, C1-9Heteroarylamino or C1-9Heteroaryl C1-6An alkyl group;
wherein each R14、R14a、R15And R16Have the meaning as described in the present invention.
In some of these embodiments, each R is14Independently hydrogen, deuterium, hydroxy, amino, C1-6Alkyl, halo C1-6Alkyl, amino C1-6Alkyl, hydroxy substituted C1-6Alkyl, cyano-substituted C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy-substituted C1-6Alkoxy, carboxy substituted C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkoxy radical, C3-8Cycloalkyl radical C1-6Alkoxy radical, C2-10Heterocyclyl radical C1-6Alkoxy radical, C6-10Aryl radical C1-6Alkoxy radical, C1-9Heteroaryl C1-6Alkoxy radical, C1-6Alkylamino radical, C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C3-8Cycloalkyl oxy, C2-10Heterocyclic group, C2-10Heterocyclyl radical C1-6Alkyl radical, C2-10Heterocyclyloxy, C6-10Aryl radical, C6-10Aryl radical C1-6Alkyl radical, C6-10Aryloxy radical, C1-9Heteroaryl group, C1-9Heteroaryloxy or C1-9Heteroaryl C1-6An alkyl group.
In some of these embodiments, each R is14aIndependently H, C1-8Alkyl, halo C1-8Alkyl, hydroxy substituted C1-8Alkyl, carboxy substituted C1-8Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, C3-8Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl or C1-9A heteroaryl group.
In some of these embodiments, each R is15Independently of one another is hydrogen, deuterium, C1-6Alkyl, halo C1-6Alkyl, hydroxy substituted C1-6Alkyl, carboxy substituted C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-10Heterocyclic group, C2-10Heterocyclyl radical C1-6Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl or C1-9Heteroaryl C1-6An alkyl group.
In some of these embodiments, each R is16Independently of one another is hydrogen, deuterium, C1-6Alkyl, halo C1-6Alkyl, hydroxy substituted C1-6Alkyl, carboxy substituted C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-10Heterocyclic group, C2-10Heterocyclyl radical C1-6Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl or C1-9Heteroaryl C1-6An alkyl group.
In some of these embodiments, R is15，R16Together with the nitrogen atom to which they are attached, form a ring of 3 to 12 atoms.
In still other embodiments, each R is13Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, ammoniaRadical, R14-C(＝O)-、R14-C(＝O)-C1-4Alkylene radical, R14-C(＝O)-C2-4Alkenylene radical, R14-C(＝O)-C1-4alkylene-O-C (═ O) -, R14-C(＝O)-C2-4alkenylene-O-C (═ O) -, R14-C(＝O)-O-C1-4alkylene-O-C (═ O) -, R14-C(＝O)-O-C2-4alkenylene-O-C (═ O) -, R15R16N-C(＝O)-、R15R16N-C(＝O)-O-、R15R16N-C(＝O)-C1-4Alkylene radical, R15R16N-C(＝O)-C2-4Alkenylene radical, R15R16N-C(＝O)-C1-4alkylene-O-C (═ O) -, R15R16N-C(＝O)-C2-4alkenylene-O-C (═ O) -, R14-C(＝O)-N(R15)-、R14-C(＝O)-N(R15)-C1-4Alkylene radical, R14-C(＝O)-N(R15)-C2-4Alkenylene radical, R14-C(＝O)-C1-4alkylene-N (R)15)-、R14-C(＝O)-C2-4alkenylene-N (R)15)-、R15R16N-C(＝O)-N(R15)-、R15R16N-C(＝O)-N(R15)-C1-4Alkylene radical, R15R16N-C(＝O)-N(R15)-C2-4Alkenylene radical, R15R16N-C(＝O)-C1-4alkylene-N (R)15)-、R15R16N-C(＝O)-C2-4alkenylene-N (R)15)-、R14-C(＝O)-N(R15)-C(＝O)-、R14-C(＝O)-N(R15)-C(＝O)-C1-4Alkylene radical, R14-C(＝O)-N(R15)-C(＝O)-C2-4Alkenylene radical, R14a-O-C1-4Alkylene radical, R14a-O-C2-4Alkenylene, oxo, C1-4Alkyl, halo C1-4Alkyl, amino C1-4Alkyl, hydroxy substituted C1-4Alkyl, cyano-substituted C1-4Alkyl, carboxy substituted C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl, hydroxy substituted C1-4Alkoxy radicalC1-4Alkyl, carboxy substituted C1-4Alkoxy radical C1-4Alkyl radical, C1-4Alkylamino radical C1-4Alkyl radical, C6-10Aryloxy substituted C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Alkylamino radical C1-4Alkylamino radical, C1-4Alkylamino radical C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkylamino radical, C1-4Alkylthio radical, C2-4Alkenyl, carboxyl substituted C2-4Alkenyl radical, C2-4Alkynyl, R14-S(＝O)2-、R14-S(＝O)2-C1-4Alkylene radical, R14-S(＝O)2-C2-4Alkenylene radical, R14-S(＝O)2-N(R15)-、R14-S(＝O)2-N(R15)-C1-4Alkylene radical, R14-S(＝O)2-N(R15)-C2-4Alkenylene radical, R15R16N-S(＝O)2-、R15R16N-S(＝O)2-C1-4Alkylene radical, R15R16N-S(＝O)2-C2-4Alkenylene radical, C3-6Cycloalkyl radical, C3-6Cycloalkyl oxy, C3-6Cycloalkylamino, C3-6Cycloalkyl radical C1-4Alkyl radical, C3-6Cycloalkenyl radical, C3-6Cycloalkenyloxy, C3-6Cycloalkenyl amino, C3-6Cycloalkenyl radical C1-4Alkyl radical, C2-8Heterocyclic group, C2-8Heterocyclyloxy, C2-8Heterocyclylamino group, C2-8Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryloxy radical, C6-10Arylamino, C6-10Aryl radical C1-4Alkyl radical, C1-6Heteroaryl group, C1-6Heteroaryloxy radical, C1-6Heteroarylamino or C1-6Heteroaryl C1-4An alkyl group;
wherein each R14、R14a、R15And R16Have the meaning as described in the present invention.
In still other embodiments, each R is14Independently hydrogen, deuterium, hydroxy, amino, C1-4Alkyl, halo C1-4Alkyl, amino C1-4Alkyl, hydroxy substituted C1-4Alkyl, cyano-substituted C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, hydroxy-substituted C1-4Alkoxy, carboxy substituted C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkoxy radical, C3-6Cycloalkyl radical C1-4Alkoxy radical, C2-8Heterocyclyl radical C1-4Alkoxy radical, C6-10Aryl radical C1-4Alkoxy radical, C1-6Heteroaryl C1-4Alkoxy radical, C1-4Alkylamino radical, C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-4Alkyl radical, C3-6Cycloalkyl oxy, C2-8Heterocyclic group, C2-8Heterocyclyl radical C1-4Alkyl radical, C2-8Heterocyclyloxy, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C6-10Aryloxy radical, C1-6Heteroaryl group, C1-6Heteroaryloxy or C1-6Heteroaryl C1-4An alkyl group.
In still other embodiments, each R is14aIndependently H, C1-6Alkyl, halo C1-6Alkyl, hydroxy substituted C1-6Alkyl, carboxy substituted C1-6Alkyl radical, C1-3Alkoxy radical C1-4Alkyl radical, C3-6Cycloalkyl radical C1-3Alkyl radical, C2-6Heterocyclyl radical C1-3Alkyl radical, C6-10Aryl radical C1-3Alkyl radical, C1-5Heteroaryl C1-3Alkyl radical, C3-6Cycloalkyl radical, C2-6Heterocyclic group, C6-10Aryl or C1-5A heteroaryl group.
In still other embodiments, each R is15Independently of one another is hydrogen, deuterium, C1-4Alkyl, halo C1-4Alkyl, hydroxy substituted C1-4Alkyl, carboxy substituted C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C3-6CycloalkanesBase, C3-6Cycloalkyl radical C1-4Alkyl radical, C2-8Heterocyclic group, C2-8Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-6Heteroaryl or C1-6Heteroaryl C1-4An alkyl group.
In still other embodiments, each R is16Independently of one another is hydrogen, deuterium, C1-4Alkyl, halo C1-4Alkyl, hydroxy substituted C1-4Alkyl, carboxy substituted C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-4Alkyl radical, C2-8Heterocyclic group, C2-8Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-6Heteroaryl or C1-6Heteroaryl C1-4An alkyl group.
In still other embodiments, R is15，R16Together with the nitrogen atom to which they are attached, form a ring of 3 to 8 atoms.
In still other embodiments, each R is13Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, R14-C(＝O)-、R14-C(＝O)-C1-3Alkylene radical, R14-C(＝O)-C2-4Alkenylene radical, R15R16N-C(＝O)-、R15R16N-C(＝O)-O-、R15R16N-C(＝O)-C1-3Alkylene radical, R15R16N-C(＝O)-C2-4Alkenylene radical, R14-C(＝O)-NH-、R14-C(＝O)-NH-C1-3Alkylene radical, R14-C(＝O)-NH-C2-4Alkenylene, oxo, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, dimethylamino, ethylamino, or n-propylamino;
wherein each R14、R15And R16Have the meaning as described in the present invention.
In still other embodiments, each R is14Independently isHydrogen, deuterium, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In still other embodiments, each R is15Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In still other embodiments, each R is16Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Some of the embodiments are compounds, or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds, having one of the following structures, including, but in no way limited to:
Figure BDA0001052078950000241
Figure BDA0001052078950000251
Figure BDA0001052078950000261
Figure BDA0001052078950000271
the invention also comprises the use of the compounds of the invention and pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical product for the treatment of respiratory disorders (particularly chronic respiratory obstruction), allergy, inflammation, Central Nervous System (CNS) disorders, pulmonary fibrosis or non-insulin dependent diabetes mellitus including those described herein.
The compounds of the invention are likewise useful for the production of a medicament for the alleviation, prevention, control or treatment of PDE 4-mediated disorders, in particular chronic respiratory obstruction.
The present invention encompasses pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) or formula (II) in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent.
Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the present invention.
In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes materials or compositions which must be compatible chemically or toxicologically, with the other components comprising the formulation, and with the mammal being treated.
Salts of the compounds of the present invention also include, but are not necessarily pharmaceutically acceptable salts of intermediates used in the preparation or purification of the compounds of formula (I) or formula (II) or isolated enantiomers of the compounds of formula (I) or formula (II).
Compounds of the invention and pharmaceutical compositions, formulations and administrations thereof
The compounds of the invention may be manufactured and formulated as racemic mixtures, enantiomers, diastereomers, rotamers, N-oxides, polymorphs, solvates and pharmaceutically acceptable salts thereof and as active metabolite forms; pharmaceutical compositions comprising a compound of formula (I) or formula (II) or a metabolite, enantiomer, diastereomer, N-oxide, polymorph, solvate or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier and optionally excipients may also be produced.
The pharmaceutical compositions of the invention may be manufactured and administered in dosage units, each unit containing an amount of at least one compound according to the invention and/or at least one physiologically acceptable addition salt thereof. The dosage can vary over a very wide range, since the compounds are effective even at low dosage levels and are relatively non-toxic. The compounds can be administered in therapeutically effective low micromolar doses, and the dosage can be increased as needed to the maximum dose that the patient can tolerate.
When useful in therapy, a therapeutically effective amount of a compound of formula (I) or formula (II) and pharmaceutically acceptable salts thereof may be administered as the raw chemical or may be provided as the active ingredient of a pharmaceutical composition. Accordingly, the present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
In practice, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions may be presented as discrete units suitable for oral administration, e.g., capsules, cachets or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the composition may be present in the following form: powder, granules, solution, suspension in an aqueous liquid, non-aqueous liquid, oil-in-water emulsion or water-in-oil liquid emulsion. In addition to the usual dosage forms shown above, the compounds, or pharmaceutically acceptable salts thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any method known in the pharmaceutical industry. Generally, such methods include the step of combining the active ingredient with a carrier, which constitutes one or more necessary ingredients. Generally, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently brought into the desired form.
The pharmaceutical carrier employed may be a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Examples of gas carriers include carbon dioxide and nitrogen.
The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to show meaningful patient benefit. When the active ingredient alone is used for separate administration, the term refers only to that ingredient. When used in combination, the term refers to the combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, sequentially or simultaneously. The compound shown in the formula (I) or the formula (II) and pharmaceutically acceptable salts thereof are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to another aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation, which process comprises mixing a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
In general, the compounds of the present invention are administered in therapeutically effective amounts by any conventional means of administration for substances that exert similar effects. Suitable dosage ranges are typically from 1 to 500mg per day, preferably from 1 to 100mg per day, most preferably from 1 to 30mg per day, depending on a variety of factors such as the severity of the disease being treated, the age and relative health of the subject being administered, the potency of the compound used, the route and form of administration, the indication for which administration is being made, and the preferences and experience of the relevant medical practitioner. One of ordinary skill in the art of treating such diseases will be able to determine, without undue experimentation and relying on personal knowledge and the disclosure of this application, a therapeutically effective amount of a compound of the present invention for a given disease.
Administration of the compounds of the present invention may be carried out as desired by the patient, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion), by inhalation, rectally, vaginally, topically, transdermally and ocularly.
Various solid oral dosage forms can be used for administration of the compounds of the present invention, such as solid dosage forms of tablets, soft gelatin capsules, caplets, granules, lozenges and bulk powders. The compounds of the present invention may be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch) and excipients known in the art, including but not limited to suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, colorants, flavoring agents, lubricants, and the like. Timed release capsules, tablets and gels are also advantageous for administration of the compounds of the present invention.
Tablets may be prepared by compression or moulding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.l mg to about 500mg of active ingredient; and each sachet or capsule preferably contains from about 0.1mg to about 500mg of active ingredient. Thus, in the case of one or two tablets, cachets or capsules (once, twice or three times daily), the tablets, cachets or capsules conveniently contain 0.l mg, 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg or 500mg of the active ingredient.
The compounds of the present invention may also be administered in a variety of liquid oral dosage forms, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Such dosage forms may also contain suitable inert diluents known in the art, such as water, and suitable excipients known in the art, such as preservatives, lubricants, sweeteners, flavoring agents. And reagents for emulsifying and/or suspending the compounds of the invention. The compounds of the invention may be administered by injection in the form of an isotonic sterile solution, for example, by intravenous injection. Other preparations are also possible.
Suppositories for rectal administration of the compounds of the invention can be prepared by mixing the compounds with suitable excipients such as cocoa butter, salicylates and polyethylene glycols.
Formulations for vaginal administration may be in the form of creams, gels, pastes, foams or sprays containing in addition to the active ingredient such suitable carriers as are known in the art.
For topical administration, the pharmaceutical compositions may be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays and drops suitable for administration to the skin, eyes, ears or nose. Topical administration may also include transdermal administration by way of, for example, a transdermal patch.
For the treatment of respiratory diseases, the compounds of the invention are preferably administered by inhalation.
Inhalable preparations include inhalable powders, propellant-containing metered aerosol formulations or propellant-free inhalable formulations. For this purpose, they can be administered directly as powders, preferably in micronized form, or via spray solutions or suspensions containing them.
A diluent or carrier, which is generally non-toxic and chemically inert to the compounds of the invention, such as lactose or any other additive suitable for improving the respirable fraction, may be added to the powder compounds of the invention.
Inhalation aerosols comprising a gaseous propellant, for example a hydrofluoroalkane, may comprise the compounds of the invention in solution or in dispersed form. The propellant-driven formulation may also comprise other ingredients, such as co-solvents, stabilizers, and optionally other excipients.
The propellant-free inhalable formulations containing the compounds according to the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic media, and they may be delivered by means of jet nebulizers or ultrasonic nebulizers known from the prior art, orBy means of fine-mist atomizers (soft-mist atomizers), for example
Figure BDA0001052078950000301
And (4) delivering.
The compounds of the invention may be administered as the sole active agent or in combination with other pharmaceutically active ingredients, including those currently used in the treatment of respiratory disorders, e.g., β 2-agonists, such as salbutamol, formoterol, salmeterol and carmoterol (TA 2005); corticosteroids such as budesonide and its epimers, beclomethasone dipropionate, triamcinolone acetonide, fluticasone propionate, flunisolide, mometasone furoate, rofleponide and ciclesonide; and anticholinergics or antimuscarinics, such as ipratropium bromide, oxitropium bromide, tiotropium bromide, glycopyrrolate, revaproxil or the compounds disclosed in WO 03/053966.
Preferably, the compounds of formula (I) or (II) are administered alone or in combination with other active ingredients for the prevention and/or treatment of respiratory diseases characterized by airway obstruction, such as asthma, chronic bronchitis or Chronic Obstructive Pulmonary Disease (COPD).
A method of treatment comprising administering a compound or pharmaceutical composition of the invention, further comprising administering to the patient an additional anti-chronic respiratory obstruction drug (combination therapy), wherein the additional anti-chronic respiratory obstruction drug is sodium pyruvate, Doxofylline (Doxofylline), Roflumilast (Roflumilast), Apremilast (Apremilast), Tetomilast (Tetomilast), Tipelukast, Theophylline (Theophylline), Formoterol (Formoterol), Salmeterol (Salmeterol), Fluticasone Propionate (Fluticasone Propionate), Salmeterol/Fluticasone Propionate (Salmeterol Xinafoate/Fluticasone Propionate), rolipramine (Rolipram), piracetamide (Piclamist), Cilomilast (Ciloast), CDP-840, Indacaterol (stepaloterol), olorate (149), ketoroletamol, ketoroletasone (QVA 149), epimeric acid, and epimeric acid (dexamethasone), triamcinolone acetonide, flunisolide, mometasone furoate, rofleponide, ciclesonide, Ipratropium Bromide (Ipratropium Bromide), Ipratropium Bromide complexed with albuterol, oxitropium Bromide, Tiotropium Bromide (Tiotropium Bromide), glycopyrronium Bromide, Umeclidinium Bromide (Umeclidinium Bromide), vilanterol (vilanterol), Umeclidinium/vilanterol complexed (Umeclidinium/vilanterol), aclidinium Bromide (aclidinium Bromide), aclidinium/formoterol fumarate complexed, LAS40464, LAS100977(abediterol), AZD-8999, RPL-554, OCID-2987, CHF-6001, CR-3465, fluticasone furoate/velutin (flutemazuron Bromide), beryllate/flavonid, bervalazurin/flavonide, or combinations thereof.
The term "combined use" or "combination" is to be understood as meaning: the components may be administered simultaneously or more or less simultaneously, or separately and sequentially. In some of these embodiments, one therapeutic agent/pharmaceutically active ingredient may be administered in the morning and the other at a later time of the day. In other embodiments, one therapeutic agent/pharmaceutically active ingredient may be administered once a day and the other once a week. As will be appreciated, if the components are administered directly in succession, the delay in administration of the second component should not be such as to lose the beneficial effect of the combination.
Simultaneous administration may be by any suitable route, and preferably is such as by administering the therapeutic agents to a subject in need thereof by oral or intravenous route or by intramuscular route or subcutaneous injection, such that the administration form has a fixed ratio of each therapeutic agent.
More or less simultaneous or sequential administration of each therapeutic agent may be by any appropriate route, including but not limited to oral route, intravenous route, intramuscular route, and absorption via mucosal tissue. These therapeutic agents may be administered by the same route or by different routes. For example, both therapeutic agents of the combination may be administered orally.
The compounds of the present invention may be included in pharmaceutical compositions. The pharmaceutical composition comprises a compound described herein or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier; and optionally other therapeutic ingredients or adjuvants (adjuvant). Optional additional therapeutic ingredients include, for example, i) leukotriene receptor antagonists, ii) leukotriene biosynthesis inhibitors, iii) corticosteroids, iv) H1 receptor antagonists, v) β 2 adrenoreceptor agonists, vi) COX-2 selective inhibitors, vii) statins, viii) non-steroidal anti-inflammatory drugs ("NSAIDs"), and ix) M2/M3 antagonists.
The compositions include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in a given case will depend on the particular host and the nature and severity of the condition for which the active ingredient is administered. The pharmaceutical compositions may conveniently be presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
Creams, ointments, jellies, solutions or suspensions containing the compounds can be used for topical application. For the purposes of the present invention, mouth washes and mouthwashes are included within the scope of topical use.
Pharmaceutical compositions suitable for parenteral administration may be prepared as solutions or suspensions of the active ingredient in water. Suitable surfactants, such as hydroxypropyl cellulose, may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof (in oils). In addition, preservatives may be included to prevent the unwanted growth of microorganisms.
Those pharmaceutical compositions suitable for injectable use include sterile aqueous solutions or dispersions. The compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid to enable easy injection.
The pharmaceutical compositions must be stable under the conditions of manufacture and storage; therefore, protection should preferably be against the contaminating action of microorganisms (e.g., bacteria and fungi). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.
The pharmaceutical composition may be in a form suitable for topical use, such as an aerosol, cream, ointment, lotion, dusting powder and the like. In addition, the compositions may be in a form suitable for use in a transdermal device, and these formulations may be prepared by conventional processing methods using the compounds or pharmaceutically acceptable salts thereof. By way of example, creams and ointments are prepared in the following manner: mixing the hydrophilic material and water and about 5 wt% to about 10 wt% of the compound to produce a cream or ointment having a desired consistency.
The present invention provides a method of treating a pulmonary disorder (e.g., COPD, asthma or fibrocystic disorder) in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of at least one compound of formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof, in combination with at least one compound selected from the group consisting of: steroids (e.g., glucocorticoids), 5-lipoxygenase inhibitors, beta-2 adrenoceptor (adrenoreceptor) agonists, alpha-adrenoceptor agonists, muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotriene antagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors, elastase inhibitors, MMP inhibitors, phospholipase A2 inhibitors, phospholipase D inhibitors, histamine H1 antagonists, histamine H3 antagonists, dopamine agonists, adenosine A2 agonists, NK1 and NK2 antagonists, GABA-b agonists, nociceptin agonists, expectorants, mucolytics, decongestants, mast cell stabilizers, antioxidants, anti-IL-8 antibodies, anti-IL-5 antibodies, anti-IgE antibodies, anti-IL-IgE antibodies, and anti-TNF-gamma, and anti-beta-agonists, anti-TNF antibodies, IL-10, adhesion molecule inhibitors, growth hormone and other PDE4 inhibitors.
Non-limiting examples of anti-hindered amine agents useful in combination with the compounds of formula (I) or formula (II) include: astemizole (astemizole), azatadine (azatadine), azelastine (azelastine), acrivastine (acrivastine), brompheniramine (bropheramine), cetirizine (certirizine), chlorpheniramine (chlorpheniramine), clemastine (clemostine), cyclizine (cyclizine), carithamine (carithazine), cyproheptadine (cyproheptadine), carithamine (caroxamine), descarboethoxyloratadine (descarboethoxyloratadine), doxylamine (doxylamine), dimethidine (dimethinide), ebastine (epinastine), epinastine (epinastine), efletirizine (efletirizine), mefenadine (sulfadiazine), pyritinosine (clavine), pyrilamine (clavine), pyrilamine (e), pyrilamine (clavine), pyrilamine (e (clavine), pyrilamine (e), pyrilamine (e), pyrilamine (e), pyrilamine), pyribenoxazimine (e), pyrilamine, Terfenadine (terfenadine), tripelennamine (tripelennamine), temastine (temelastine), alimemazine (trimeprazine) and triprolidine (triprolidine).
Non-limiting examples of histamine H3 receptor antagonists include: thiopronamide (thioperamide), impropridine (impromidine), brimamide (burimamide), clobenpropit, impentamine (impentidine), imifenadine (mifetidine), S-sopromidine (S-sopromidine), R-sopromidine (R-sopromidine), SKF-91486, GR-175737, GT-2016, UCL-1199, and clozapine (clozapine). Other compounds can be evaluated to determine activity at the H3 receptor using known methods, including guinea pig meningeal assays and guinea pig ileal constriction assays, both of which are described in U.S. Pat. No. 5,352,707. Another useful assay utilizes rat meninges and is described by West et al, "Identification of Two Histamine Receptor Subtypes," Molecular Pharmacology,1990, Vol.38, 610-613.
The term "leukotriene inhibitor" includes any agent or compound that inhibits, arrests, delays, or interacts with the action or activity of leukotrienes. Non-limiting examples of leukotriene inhibitors include: montelukast (montelukast) and its sodium salt; 1- (((R) - (3- (2- (6, 7-difluoro-2-quinolinyl) vinyl) phenyl) -3- (2- (2-hydroxy-2-propyl) phenyl) thio) methylcyclopropaneacetic acid and its sodium salt, described in U.S. Pat. No. 5,270,324, 1- (((1(R) -3(3- (2, 3-dichlorothieno [3,2-b ] pyridin-5-yl) - (E) -vinyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) thio) methyl) cyclopropaneacetic acid and its sodium salt, described in U.S. Pat. No. 5,472,964, pranlukast (pranlukast), zalukast (zarlukast), and [2- [ [2 (4-tert-butyl-2-thia ] acetic acid and its sodium salt Azolyl) -5-benzofuranyl ] oxymethyl ] phenyl ] acetic acid, which is described in U.S. Pat. No. 5,296,495.
Non-limiting examples of beta-adrenoceptor agonists include: salbutamol, bitolterol, isoetharine, mataproterenol, perbutyrol, salmeterol, terbutaline, isoproterenol, ephedrine, and epinephrine. Non-limiting examples of alpha-adrenoceptor agonists include arylalkylamines (e.g., phenylpropanolamine and pseudoephedrine), imidazoles (e.g., naphazoline, oxymetazoline, tetrahydrozoline, and xylometazoline), and cycloalkylamines (e.g., hexahydrodeoxyephedrine).
A non-limiting example of a mast cell stabilizer is nedocromil sodium (nedocromil sodium). A non-limiting example of an expectorant is guaifenesin (guaifenesin). Non-limiting examples of decongestants are pseudoephedrine (pseudoephedrine), phenylpropanolamine (phenylpropanolamine), and phenylephrine (phenyleephrine).
Non-limiting examples of NK1, NK2, and NK3 tachykinin receptor antagonists include CP-99, 994, and SR 48968. Non-limiting examples of muscarinic antagonists include ipratropium bromide (ipratropium bromide) and tiaatropium bromide.
GABABNon-limiting examples of agonists include baclofen (baclofen) and 3-aminopropyl-phosphonic acid. Dopamine agonists include quinpirole (quinpirole), ropinirole (ropinairole), pramipexole (pramipexole), pergolide (pergolide) and bromocriptine (bromocriptine).
"5-lipoxygenase inhibitor" includes any agent or compound that inhibits, retards, or interacts with the enzymatic action of 5-lipoxygenase. Non-limiting examples of 5-lipoxygenase inhibitors include zileuton (zileuton), doxobenzone (docbenone), piraprost (piripost), ICI-D2318, and ABT 761.
The dosage of the compounds of the invention will depend upon a variety of factors including the particular disease to be treated, the severity of the symptoms, the route of administration, the frequency of dosage intervals, the particular compound used, the potency of the compound, the toxicological profile and the pharmacokinetic profile.
The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may conveniently contain from about 0.5mg to about 5g of the active agent, in association with a suitable and convenient amount of carrier material which may be from about 5% to about 95% of the total composition. Unit dosage forms will generally contain from about 1mg to about 1000mg of the active ingredient, usually 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000 mg.
Advantageously, they are administered in a dose of 0.01 to 1000 mg/day, preferably 0.1 to 500 mg/day.
When administered by inhalation, the compound of the present invention may be administered at a dose of 0.01 to 10 mg/day, preferably 0.05 to 5 mg/day, more preferably 0.1 to 2 mg/day.
Use of the Compounds and pharmaceutical compositions of the invention
The pharmaceutical composition of the invention is characterized by comprising the compound shown in the formula (I) or the formula (II) or the compounds listed in the invention and pharmaceutically acceptable carriers, auxiliary agents or excipients.
The amount of compound in the compositions of the invention is effective to detectably antagonize PDE4 to treat: pain (e.g., acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain), acute inflammation, chronic inflammation, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative septicemia, toxic shock syndrome, stroke, ischemia reperfusion injury, kidney reperfusion injury, glomerulonephritis, Parkinson's disease, Alzheimer's disease, Mild Cognitive Impairment (MCI), depression, anxiety, graft-to-host reaction (i.e., graft-versus-host disease), allograft rejection (e.g., acute and chronic allograft rejection), acute respiratory distress syndrome, delayed type hypersensitivity reaction, chronic inflammatory bowel disease, and neuropathic pain, Atherosclerosis, cerebral ischemia, osteoarthritis, multiple sclerosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, kaposi's sarcoma-associated virus (i.e. kaposi's sarcoma), meningitis, fibrocysts, premature labor, cough, pruritus, multiple organ dysfunction, psoriatic arthritis, herpes, encephalitis, traumatic brain injury, CNS tumors, interstitial pneumonia, allergy, crystallization-induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, ocular inflammation, corneal neovascularization, polymyositis, acne, esophagitis, glossitis, airflow obstruction, airway allergy (i.e. airway hyperresponsiveness), bronchiectasis, bronchiolitis, obstructive bronchiolitis (i.e. obstructive bronchiolitis syndrome), Chronic bronchitis, cystic fibrosis, dyspnea, emphysema, adult respiratory disease, acute respiratory distress syndrome, respiratory virus, hypercapnia, hyperinflation (hyperinflation), hypoxemia, hyperoxia-induced inflammation, hypoxia, pulmonary fibrosis, pulmonary hypertension, peritonitis associated with continuous emergency peritoneal dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis, small airway (small airway) disease, airway obstruction, disorders of ventilation and blood flow, wheezing, colds, gout, alcoholic liver disease, lupus, periodontitis, cancer, graft reperfusion injury, early graft rejection (e.g., acute allograft rejection), airway hyperreactivity, allergic contact dermatitis, allergic rhinitis, non-allergic rhinitis, alopecia areata, autoimmune ear (including, e.g., meniere's disease), Autoimmune hemolytic syndrome, autoimmune hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune vasculitis, autoimmune thrombocytopenia, chronic inflammatory demyelinating polyneuropathy, cirrhosis, dermatomyositis, diabetes mellitus, drug-induced autoimmunity, endometriosis, fibrotic diseases, gastritis, Goodpasture's syndrome, graves' disease, guillain-Barre disease, hashimoto's thyroiditis, hepatitis-related autoimmunity, HIV-related autoimmune syndrome and blood diseases, hypophyseal hyposecretion (hypophysis), interstitial cystitis, juvenile arthritis, langerhans' cell proliferation, lichen planus, metal-induced autoimmunity, myocarditis (including viral myocarditis), myositis, neuropathy (including, e.g., IgA neuropathy, cell membrane neuropathy and idiopathic neuropathy), Nephritis syndrome, optic neuritis, pancreatitis, post-infection autoimmunity, primary gallbladder cirrhosis, reactive arthritis, ankylosing spondylitis, reiter's syndrome, reperfusion injury, scleritis, scleroderma, a blood disorder secondary to an autoimmune disease (e.g., anemia), a polysiloxane (silicone) implant-associated autoimmune disease, sjogren's syndrome, systemic lupus erythematosus, transverse myelitis, tubulointerstitial nephritis, uveitis, and vitiligo, the method comprising administering to the disease an effective amount of at least one compound of formula (I) or formula (II) or a pharmaceutically acceptable salt or solvate thereof.
An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the invention refers to an amount effective to treat or reduce the severity of one or more of the conditions mentioned herein. The compounds and compositions according to the methods of the present invention can be administered in any amount and by any route effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein.
General synthetic procedure
In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I) or formula (II), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu chemical Co., Ltd., Qingdao Tenglong chemical reagent Co., Ltd., and Qingdao Kaihua factory.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The chromatographic column isSilica gel columns were used. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. The test conditions of the nuclear magnetic resonance hydrogen spectrum are as follows: brookfield (Bruker) nuclear magnetic instrument at 400MHz or 600MHz in CDC1 at room temperature3，d6-DMSO，CD3OD or d6Acetone as solvent (reported in ppm) with TMS (0ppm) or chloroform (7.26ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singlets, singlet), d (doublets ), t (triplets, triplets), q (quatets, quartets), m (multiplets ), br (broadpeded, broad), dd (doubletoflubles, doublets), dt (doublets ). Coupling constants are expressed in hertz (Hz).
The conditions for low resolution Mass Spectrometry (MS) data determination were: agilent 6120Quadrupole HPLC-MS (column model: Zorbax SB-C18,2.1X 30mm,3.5 μm,6min, flow rate 0.6mL/min, mobile phase 5% -95% (CH with 0.1% formic acid)3CN) in (H containing 0.1% formic acid)2Proportion in O)), at 210/254nm with UV detection, using electrospray ionization mode (ESI).
The purity of the compound is characterized in the following way: agilent 1260 preparative high performance liquid chromatography (Pre-HPLC) or Calesep Pump 250 preparative high performance liquid chromatography (Pre-HPLC) (column model: NOVASEP,50/80mm, DAC) with UV detection at 210nm/254 nm.
The following acronyms are used throughout the invention:
g, g; mg; mol; mmol millimole; h hours; min; l liter; mL, mL; r.t, RT room temperature; rt retention time; HPLC high performance liquid chromatography; h2O water; HCl hydrogen chloride; MeOH, CH3OH methanol; CD (compact disc)3OD deuterated methanol; EtOH, ethanol; HCOOH formic acid; HOAc, CH3COOH acetic acid; CH (CH)3CN, MeCN acetonitrile; CDCl3Deuterated chloroform; DCM, CH2Cl2Dichloromethane; CHCl3Chloroform, chloroform; cyclohexane; DMSO dimethyl sulfoxide; THF tetrahydrofuran; EtOAc ethyl acetate; petroleum ether, PE Petroleum ether; HOAT N-hydroxy-7-azabenzotriazole; na (Na)2SO4Sodium carbonate; EDCI 1- (3-dimethylaminopropyl)) -3-ethylcarbodiimide hydrochloride; CDI N, N '-carbonyldiimidazole, N' N-carbonyldiimidazole;
DIPEA N, N-diisopropylethylamine; DBU 1, 8-diazabicyclo [5.4.0]Undec-7-ene; NaHCO 23Sodium bicarbonate; NaOH sodium hydroxide; LiOH lithium hydroxide.
The first synthesis method comprises the following steps:
Figure BDA0001052078950000351
target compound (A)11) Can be prepared by a first synthesis method, wherein R1、R2And R4Have the meaning as described in the present invention. Compound (A) to (B)1) And a compound of (A)2) Condensation to give the compound (A)3) Compound (A) to (B)3) Sulfurization by Lawson's reagent to give compound (A)4) Compound (A) to (B)4) Formation of a thiomethyl group under the conditions of trimethyloxonium tetrafluoroborate to give a compound (A)5) Compound (A) to (B)5) Under basic conditions (e.g., KHMDS, etc.), (6) Reaction to give a compound (7) Compound (A) to (B)7) Under alkaline conditions (e.g. LiOH. H)2O、NH3MeOH, etc.) to yield compound (A)8) Compound (A) to (B)8) And a compound of (A)9) Condensation to give the compound (A)10) Compound (A) to (B)10) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound11)。
And a second synthesis method comprises the following steps:
Figure BDA0001052078950000361
target compound (A)14) Can be prepared by a synthesis method II, wherein R is1、R2、Ra、RbAnd R4Have the meaning as described in the present invention. Compound (A) to (B)8) And a compound of (A)12) Condensation to give the compound (A)13) Compound (A) to (B)13) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound14)。
Examples
Example 1: (S) -4- (5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) piperidine-1-carboxylic acid methyl ester hydrochloride
Figure BDA0001052078950000362
Step 1: synthesis of Compound methyl 2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzamide) acetate
3- (Cyclopropylmethoxy) -4- (difluoromethoxy) benzoic acid (3g,11.63mmol), HOAT (2.37g,17.44mmol) and EDCI (3.33g,17.44mmol) were dissolved in DCM (40mL) and stirred at room temperature for 30min, glycine methyl ester hydrochloride (1.74g,13.95mmol) was added, DIPEA (8.1mL,46.51mmol) was slowly added dropwise under ice bath, stirring was continued at room temperature overnight, water (30mL) was added, and CH was used2Cl2(25 mL. times.3), the organic phases were combined and extracted with anhydrous Na2SO4Drying, removal of solvent, column chromatography of the concentrate (eluent: Petroleum ether/EtOAc (v/v) ═ 2/1) afforded 3.30g of a white solid, yield: 86.1 percent.
1H NMR(400MHz,CDCl3):ppm 7.47(s,1H),7.29(dd,J1＝8.3Hz,J2＝1.9Hz,1H),7.18(d,J＝8.3Hz,1H),6.68(t,JF-H＝75.0Hz,1H),4.22(d,J＝5.0Hz,2H),3.92(d,J＝7.0Hz,2H),3.80(s,3H),1.25-1.32(m,1H),0.62-0.67(m,2H),0.33-0.37(m,2H)；
MS-ESI:m/z 330.2[M+H]+.
Step 2: synthesis of compound methyl 2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenylthiocarboxamide) acetate
The compound methyl 2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzamide) acetate (3.30g,10.02mmol) and lawson's reagent (4.05g,10.02mmol) were dissolved in THF (30mL) and after 2h of reaction at 75 deg.C, THF was removed and saturated NaHCO was added3The solution (30mL) was extracted with ethyl acetate (25 mL. times.3), the organic phases were combined and washed with anhydrous Na2SO4Drying, removing solvent, and separating the concentrated solution by column chromatography (eluent:petroleum ether/EtOAc (v/v) ═ 2/1), yielding 3.32g of a yellow solid, yield: 96 percent.
1H NMR(400MHz,CDCl3):ppm 8.07(s,1H),7.55(d,J＝2.0Hz,1H),7.24(d,J＝2.1Hz,1H),7.16(d,J＝8.3Hz,1H),6.68(t,JF-H＝75.0Hz,1H),4.56(d,J＝4.6Hz,2H),3.94(d,J＝7.0Hz,2H),3.85(s,3H),1.27-1.32(m,1H),0.65-0.67(m,2H),0.36-0.38(m,2H)；
MS-ESI:m/z 346.2[M+H]+.
And step 3: synthesis of compound methyl 2- (((3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) (methylthio) methylene) amino) acetate
The compound methyl 2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenylthiocarboxamide) acetate (3.32g,9.62mmol) in CH was added at-78 deg.C2Cl2(10mL) solution was slowly added dropwise to CH of trimethyloxonium tetrafluoroborate (2.85mg,19.24mmol)2Cl2(10mL) in a solution, the reaction was continued at 0 ℃ for 3h, and then saturated NaHCO was added3The reaction was quenched with solution (25mL), extracted with DCM (25 mL. times.3), and washed with anhydrous Na2SO4Drying and removal of the solvent gave 3.32g of a yellow oily liquid, yield: 96.1 percent.
MS-ESI:m/z 360.1[M+H]+.
And 4, step 4: synthesis of Compound (S) - (1-fluoro-1-oxopropan-2-yl) carbamic acid tert-butyl ester
N-Boc L-alanine (6.5g,34.4mmol) and triethylamine (5.27mL,37.83mmol) were dissolved in dichloromethane (60mL) at-40 deg.C, to this solution was added dropwise melamine fluoride (5.62mL,68.8mmol), reacted at-10 deg.C for 2h, washed with ice water (20 mL. times.5), and the organic phase was washed with anhydrous Na2SO4Drying and removal of the solvent gave 5.84g of a white solid, yield: 89 percent.
And 5: synthesis of the compound (S) -methyl 5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylate
A solution of potassium hexamethyldisilazide (1M,32.39mmol) in THF (32.4mL) was slowly added dropwise to Compound 2- (((3- (cyclo-3-))Propylmethoxy) -4- (difluoromethoxy) phenyl) (methylthio) methylene) amino) acetic acid methyl ester (3.32g,9.25mmol) and the compound tert-butyl (S) - (1-fluoro-1-oxopropan-2-yl) carbamate (2.65g,13.88mmol) in THF (25mL) were reacted for 1h, quenched with water (25mL), extracted with ethyl acetate (25 mL. times.3), the organic phases combined and washed with anhydrous Na2SO4Drying, removal of solvent, column chromatography of the concentrate (eluent: Petroleum ether/EtOAc (v/v) ═ 5/1) afforded 2.39g of a white solid, yield: 53.7 percent.
1H NMR(400MHz,CDCl3):ppm 7.64(s,1H),7.62(d,J＝8.4Hz,1H),7.23(d,J＝8.3Hz,1H),6.70(t,JF-H＝75.0Hz,1H),5.43-5.47(m,1H),3.98(s,3H),3.96(d,J＝7.0Hz,2H),1.54(d,J＝7.0Hz,3H),1.43(s,9H),1.27-1.29(m,1H),0.65-0.68(m,2H),0.36-0.39(m,2H)；
MS-ESI:m/z 483.1[M+H]+.
Step 6: synthesis of the compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid
The compound methyl (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylate (1.75g,3.63mmol) was dissolved in THF (20mL) and H2O (10mL), lithium hydroxide monohydrate (762.4mg,18.15mmol) was added to the mixed solvent, the mixture was reacted at 40 ℃ for 4 hours to remove THF, the pH of the solution was adjusted to about 1 with HCl (1M), extraction was performed with ethyl acetate (25 mL. times.3), the organic phases were combined, and anhydrous Na was added2SO4Drying and removal of the solvent gave 1.45g of a yellow solid, yield: 87.9 percent.
1H NMR(600MHz,CD3OD):ppm 7.80(d,J＝1.8Hz,1H),7.66(dd,J1＝8.3Hz,J2＝1.9Hz,1H),7.29(d,J＝8.3Hz,1H),6.90(t,JF-H＝74.8Hz,1H),5.51(m,1H),4.03(d,J＝7.0Hz,2H),1.54(d,J＝7.1Hz,3H),1.44(s,9H),1.35-1.38(m,1H),0.67-0.70(m,2H),0.42-0.44(m,2H)；
MS-ESI:m/z 467.3[M-H]-.
And 7: synthesis of compound 1-methoxycarbonyl-4-aminopiperidine hydrochloride
To a solution of N' -carbonyldiimidazole (501mg,2.99mmol) and triethylamine (0.63mL,4.49mmol) in anhydrous DMF (12mL) was added 4-Boc-aminopiperidine (500mg,2.50mmol), reacted at 60 ℃ for 30min in a sealed tube, added anhydrous methanol (10mL), reacted at 65 ℃ for 48h, the solvent was removed, washed with saturated sodium chloride solution (10 mL. times.3), extracted with ethyl acetate (15 mL. times.2), the organic phases were combined, and dried over anhydrous Na2SO4Drying, removal of the solvent and column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 4/1) gave 580mg of a white solid: 1-methoxycarbonyl-4-tert-butoxycarbonylaminopiperidine, yield: 89 percent.
1H NMR(400MHz,CDCl3):ppm 4.48(br.s,1H),3.99-4.02(m,2H),3.70(s,3H),3.56-3.61(m,1H),2.91(t,J＝11.9Hz,2H),1.92-1.96(m,2H),1.46(s,9H),1.27-1.35(m,2H)；
MS-ESI:m/z 159.2[M+H-100]+.
To a solution of the compound 1-methoxycarbonyl-4-tert-butoxycarbonylaminopiperidine (0.58g,2.25mmol) in dichloromethane (6mL) was added a solution of HCl in ethyl acetate (4M,6mL), stirred at room temperature for 2h, and the solvent was removed to give 425mg of a white solid: 1-methoxycarbonyl-4-aminopiperidine hydrochloride, yield: 97 percent.
1H NMR(600MHz,CD3OD):ppm 4.08-4.12(m,2H),3.61-3.63(m,3H),3.23-3.26(m,1H),2.80-2.84(m,2H),1.92-1.94(m,2H),1.39-1.45(m,2H)；
MS-ESI:m/z 159.2[M+H-HCl]+.
And 8: synthesis of methyl (S) -4- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) piperidine-1-carboxylate, compound
Compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.25g,0.53mmol), compound 1-methoxycarbonyl-4-aminopiperidine hydrochloride (125mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (154mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in dichloromethane (20mL) at 0 deg.CNext, N-diisopropylethylamine (0.37mL,2.14mmol) was added dropwise to the solution, stirred at room temperature for 18h, washed with water (15mL), and the organic phase was washed with anhydrous Na2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 264mg of a white solid in yield: 81 percent.
1H NMR(400MHz,CDCl3):ppm 7.60(dd,J1＝8.3Hz,J2＝1.9Hz,1H),7.55(d,J＝1.8Hz,1H),7.26(d,J＝8.3Hz,1H),7.12-7.14(m,1H),6.72(t,JF-H＝75.0Hz,1H),5.27-5.32(m,1H),4.11-4.18(m,3H),4.00(d,J＝7.0Hz,2H),3.73(s,3H),2.97-3.03(m,2H),2.05-2.08(m,2H),1.54(d,J＝7.0Hz,3H),1.45(s,9H),1.32-1.37(m,1H),0.69-0.74(m,2H),0.41-0.45(m,2H)；
MS-ESI:m/z 609.4[M+H]+.
And step 9: synthesis of Compound (S) -4- (5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) piperidine-1-carboxylic acid methyl ester hydrochloride
To a solution of the compound (S) -methyl 4- (5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) piperidine-1-carboxylate (0.26g,0.43mmol) in dichloromethane (6mL) was added a solution of HCl in ethyl acetate (4M,6mL), stirred at room temperature for 1h and the solvent was removed to give 235mg of a white solid, yield: 99 percent.
1H NMR(600MHz,CD3OD):ppm 7.80(d,J＝1.9Hz,1H),7.72(dd,J1＝8.3Hz,J2＝1.9Hz,1H),7.33(d,J＝8.3Hz,1H),6.92(t,JF-H＝74.8Hz,1H),5.16-5.19(m,1H),4.13-4.20(m,3H),4.04(d,J＝6.9Hz,2H),3.72(s,3H),2.95-3.01(m,2H),1.94-1.96(m,2H),1.78(d,J＝7.0Hz,3H),1.61-1.68(m,2H),1.35-1.39(m,1H),0.68-0.71(m,2H),0.43-0.45(m,2H)；
MS-ESI:m/z 509.3[M+H-HCl]+.
Example 2: 3- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) piperidine-1-carboxylic acid methyl ester hydrochloride
Figure BDA0001052078950000391
Step 1: synthesis of compound 3-aminopiperidine-1-methyl formate hydrochloride
Triethylamine (380mg,3.75mmol) and N, N' -Carbonyldiimidazole (CDI) (486mg,3.0mmol) were dissolved in anhydrous DMF (2mL), 3-tert-butoxycarbonylaminopiperidine (500mg,2.5mmol) was added, stirring was performed at room temperature for 30min, anhydrous methanol (10mL) was added, the reaction was stopped after 8h at 60 ℃, the solvent was removed, water (5mL) was added, ethyl acetate (10mL × 3) was extracted, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column chromatography (EtOAc: Petroleum ether/eluent (v/v) ═ 3/1) to obtain 480mg of a white solid: methyl 3- ((tert-butoxycarbonyl) amino) piperidine-1-carboxylate, yield: 74 percent.
1H NMR(600MHz,CDCl3):ppm 3.86–4.00(m,1H),3.74–3.82(m,1H),3.70(s,3H),3.40–3.45(m,1H),2.96–3.04(m,1H),2.79–2.94(m,1H),1.89–1.94(m,1H),1.71–1.77(m,1H),1.43–1.54(m,2H),1.46(s,9H)；
MS-ESI:m/z 159.20[M+H-100]+.
The compound methyl 3- ((tert-butoxycarbonyl) amino) piperidine-1-carboxylate (470mg,1.82mmol) was dissolved in dichloromethane (2mL), a solution of HCl in ethyl acetate (4M,4mL) was added, stirred at room temperature for 30min, the solvent was removed to give 350mg of a white solid: 3-aminopiperidine-1-carboxylic acid methyl ester hydrochloride, yield: 99 percent.
1H NMR(600MHz,CD3OD):ppm 3.96–3.98(m,1H),3.73(s,3H),3.65–3.70(m,1H),3.26–3.33(m,3H),2.06–2.12(m,1H),1.77–1.82(m,1H),1.69–1.75(m,1H),1.58–1.63(m,1H)；
MS-ESI:m/z 159.20[M+H-HCl]+.
Step 2: synthesis of compound methyl 3- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) piperidine-1-carboxylate
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (300mg,0.64mmol), 3-aminoPiperidine-1-carboxylic acid methyl ester hydrochloride (150mg,0.77mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (246mg,1.3mmol) and N-hydroxy-7-azabenzotriazole (175mg,1.3mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.45mL,2.56mmol) was added dropwise to the solution at 0 deg.C, stirring was carried out at room temperature for 12 hours, water (10 mL. times.3) was added and the organic phase was washed with anhydrous Na2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: petroleumeher/EtOAc (v/v) ═ 3/1) afforded 300mg of a white solid, yield: 77 percent.
1H NMR(400MHz,CDCl3):ppm 7.61(dd,J1＝8.3Hz,J2＝1.9Hz,1H),7.56(s,1H),7.26(d,J＝8.3Hz,1H),6.73(t,JF-H＝75.0Hz,1H),5.25–5.34(m,1H),4.07–4.16(m,1H),4.01(d,J＝6.9Hz,2H),3.90–4.01(m,1H),3.73(s,3H),3.66–3.75(m,1H),3.19–3.32(m,2H),2.01–2.08(m,1H),1.75–1.85(m,1H),1.61–1.72(m,2H),1.57(dd,J1＝7.0Hz,J2＝2.7Hz,3H),1.46(s,9H),1.31–1.38(m,1H),0.69–0.74(m,2H),0.40–0.45(m,2H)；
MS-ESI:m/z 609.30[M+H]+.
And step 3: synthesis of Compound methyl 3- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) piperidine-1-carboxylate hydrochloride
The compound methyl 3- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) piperidine-1-carboxylate (300mg,0.3mmol) was dissolved in dichloromethane (4mL), a solution of HCl in ethyl acetate (4M,6mL) was added, and the mixture was stirred at room temperature for 30min, and the solvent was removed to give 240mg of a white solid in yield: 97 percent.
1H NMR(600MHz,CD3OD):ppm7.80(s,1H),7.74(d,J＝6.7Hz,1H),7.21(d,J＝8.3Hz,1H),6.93(t,JF-H＝75.0Hz,1H),4.77–4.80(m,1H),4.06–4.11(m,1H),4.05(d,J＝6.9Hz,2H),3.98–4.06(m,1H),3.88–3.98(m,1H),3.72(s,3H),2.97–3.11(m,2H),2.00–2.06(m,1H),1.72–1.86(m,2H),1.78(d,J＝6.8,Hz,3H),1.57–1.64(m,1H),1.34–1.40(m,1H),0.68–0.71(m,2H),0.43–0.46(m,2H)；
MS-ESI:m/z 509.30[M+H-HCl]+.
Example 3: 5- ((S) -1-aminoethyl) -N- (1-carbamoylpiperidin-3-yl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride
Figure BDA0001052078950000401
Step 1: synthesis of compound 3-aminopiperidine-1-formamide hydrochloride
Dissolving the compound 3-tert-butoxycarbonylaminopiperidine (0.5g,2.5mmol) and triethylamine (1.8mL,12.48mmol) in anhydrous tetrahydrofuran (5mL), adding trimethylsilyl isocyanate (1.7mL,12.48mmol) dropwise to the solution at room temperature, stirring at room temperature for 8h, adding ice water (10mL), removing tetrahydrofuran, extracting the aqueous phase with ethyl acetate (10 mL. times.3), and extracting the organic phase with anhydrous Na2SO4Drying, removal of solvent and concentration gave 0.25g of white solid: tert-butyl (1-carbamoylpiperidin-3-yl) carbamate, yield: 41 percent.
1H NMR(400MHz,CDCl3):ppm4.58–4.72(m,3H),3.44–3.61(m,3H),3.16–3.32(m,2H),1.80–1.90(m,1H),1.62–1.75(m,1H),1.49–1.61(m,2H),1.43(s,9H)；
MS-ESI:m/z 188.20[M-55]+.
Compound (1-carbamoylpiperidin-3-yl) carbamic acid tert-butyl ester (0.25g,1.03mmol) is dissolved in dichloromethane (2mL), HCl in ethyl acetate (4M,4mL) is added, stirring is carried out at room temperature for 30min, the solvent is removed, 0.17g of a white solid is obtained: 3-aminopiperidine-1-carboxamide hydrochloride, yield: 97 percent.
1H NMR(600MHz,CD3OD):ppm 3.85(dd,J1＝12.8Hz,J2＝2.9Hz,1H),3.44–3.49(m,1H),3.10–3.15(m,1H),3.02–3.10(m,2H),1.80–1.90(m,1H),1.62–1.69(m,1H),1.42–1.55(m,2H)；
MS-ESI:m/z 144.15[M+H-HCl]+.
Step 2: synthesis of the Compound tert-butyl ((1S) -1- (4- ((1-carbamoylpiperidin-3-yl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate
Compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (400mg,0.85mmol), compound 3-aminopiperidine-1-carboxamide hydrochloride (183mg,1.03mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (327mg,1.71mmol) and N-hydroxy-7-azabenzotriazole (232mg,1.71mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.60mL,3.42mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 5 hours, washed with water (10 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed and the concentrated solution was subjected to column chromatography (eluent: ethyl acetate) to give 320mg of a white solid in yield: and 63 percent.
1H NMR(600MHz,CDCl3):ppm7.57–7.59(m,1H),7.53–7.55(m,1H),7.23(d,J＝8.3Hz,1H),6.70(t,JF-H＝75.0Hz,1H),5.25–5.33(m,1H),4.66–4.72(m,2H),4.02–4.08(m,1H),3.99(d,J＝6.9Hz,2H),3.73–3.79(m,1H),3.59–3.67(m,1H),3.21–3.30(m,2H),2.01–2.06(m,1H),1.78–1.83(m,1H),1.69–1.76(m,1H),1.62–1.69(m,1H),1.52(d,J＝7.0Hz,3H),1.42(s,9H),1.30–1.36(m,1H),0.67–0.71(m,2H),0.40–0.43(m,2H)；
MS-ESI:m/z 594.30[M+H]+.
And step 3: synthesis of the Compound 5- ((S) -1-aminoethyl) -N- (1-carbamoylpiperidin-3-yl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride
To a solution of tert-butyl compound ((1S) -1- (4- ((1-carbamoylpiperidin-3-yl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (320mg,0.54mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 30min, the solvent was removed to give 280mg of a white solid, yield: 98 percent.
1H NMR(600MHz,CD3OD):ppm 7.66(d,J＝1.1Hz,1H),7.59(dd,J1＝8.4Hz,J2＝1.3Hz,1H),7.19(d,J＝8.3Hz,1H),6.78(t,JF-H＝75.0Hz,1H),5.01–5.05(m,1H),3.89–3.95(m,2H),3.90(d,J＝6.9Hz,2H),3.68–3.75(m,1H),2.93–3.02(m,1H),1.91–1.95(m,1H),1.71–1.76(m,1H),1.65–1.68(m,1H),1.64(d,J＝6.9Hz,3H),1.48–1.55(m,1H),1.19–1.25(m,1H),0.53–0.56(m,2H),0.28–0.31(m,2H)；
MS-ESI:m/z 494.30[M+H-HCl]+.
Example 4: (S) -5- (1-aminoethyl) -N- (1-carbamoylpiperidin-4-yl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride
Figure BDA0001052078950000411
Step 1: synthesis of compound 4-aminopiperidine-1-formamide hydrochloride
The compounds piperidin-4-ylcarbamic acid tert-butyl ester (0.5g,2.50mmol) and triethylamine (0.7mL,4.99mmol) were dissolved in anhydrous tetrahydrofuran (5mL), trimethylsilylisocyanate (0.99mL,7.49mmol) was added dropwise to the solution at room temperature, stirred at room temperature for 5h, iced water (10mL) was added, tetrahydrofuran was spun off, the aqueous phase was extracted with ethyl acetate (10 mL. times.3), the organic phase was extracted with anhydrous Na2SO4Drying, solvent removal, and concentration gave 0.36g of a white solid: tert-butyl (1-carbamoylpiperidin-4-yl) carbamate, yield: 59 percent.
1H NMR(600MHz,CDCl3):ppm3.95(d,J＝13.5Hz,2H),3.52–3.55(m,1H),2.92(t,J＝11.8Hz,2H),1.85(d,J＝10.8Hz,2H),1.45(s,9H),1.33–1.40(m,2H)；
MS-ESI:m/z 144.20[M+H-100]+.
Compound (1-carbamoylpiperidin-4-yl) carbamic acid tert-butyl ester (0.19g,0.78mmol) is dissolved in dichloromethane (2mL), HCl in ethyl acetate (4M,2mL) is added, stirring is carried out at room temperature for 30min, the solvent is removed, 0.13g of a white solid is obtained: 4-aminopiperidine-1-carboxamide hydrochloride, yield: 93 percent.
1H NMR(600MHz,CD3OD):ppm 4.16(d,J＝13.2Hz,2H),3.40–3.43(m,1H),3.06(t,J＝12.8Hz,2H),2.09(d,J＝11.8Hz,2H),1.58–1.64(m,2H)；
MS-ESI:m/z 144.30[M+H-HCl]+.
Step 2: synthesis of the Compound (S) - (tert-butyl 1- (4- ((1-carbamoylpiperidin-4-yl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate
Compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (300mg,0.64mmol), compound 4-aminopiperidine-1-carboxamide hydrochloride (137mg,0.77mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (245mg,1.28mmol) and N-hydroxy-7-azabenzotriazole (174mg,1.28mmol) were dissolved in dichloromethane (15mL), to this solution was added dropwise N, N-diisopropylethylamine (0.45mL,2.56mmol) at 0 ℃ and stirred at room temperature for 10 hours, followed by washing with water (10 mL. times.3) and the organic phase with anhydrous Na.2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: ethyl acetate) gave 135mg of a white solid in yield: 36 percent.
1H NMR(600MHz,CDCl3):ppm7.58(dd,J1＝8.3Hz,J2＝1.9Hz,1H),7.53(d,J＝1.8Hz,1H),7.24(d,J＝8.3Hz,1H),6.70(t,JF-H＝75.0Hz,1H),5.25–5.29(m,1H),4.11–4.15(m,1H),3.98(d,J＝6.9Hz,2H),3.97(br.s,2H),3.00–3.05(m,2H),2.07(d,J＝12.3Hz,2H),1.54–1.60(m,2H),1.43(s,9H),1.30–1.35(m,1H),0.67–0.70(m,2H),0.39–0.42(m,2H)；
MS-ESI:m/z 594.20[M+H]+.
And step 3: synthesis of the Compound (S) -5- (1-aminoethyl) -N- (1-carbamoylpiperidin-4-yl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride
Compound (S) -tert-butyl (1- (4- ((1-carbamoylpiperidin-4-yl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (135mg,0.23mmol) was dissolved in dichloromethane (2mL), HCl in ethyl acetate (4M,4mL) was added, stirring was carried out at room temperature for 30min, the solvent was removed to give 120mg of a white solid, yield: 99 percent.
1H NMR(600MHz,CD3OD):ppm7.73(s,1H),7.65(d,J＝9.6Hz,1H),7.26(d,J＝8.3Hz,1H),6.84(t,JF-H＝75.0Hz,1H),5.08–5.11(m,1H),4.11–4.14(m,1H),4.03–4.09(m,2H),3.97(d,J＝6.9Hz,2H),2.98–3.02(m,2H),1.91–1.94(m,2H),1.71(d,J＝5.7Hz,3H),1.61–1.64(m,2H),1.25–1.30(m,1H),0.59–0.63(m,2H),0.33–0.36(m,2H)；
MS-ESI:m/z 494.30[M+H-HCl]+.
Example 5: 3- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) piperidine-1-carboxylic acid methyl ester
Figure BDA0001052078950000421
The compound methyl 3- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) piperidine-1-carboxylate hydrochloride (150mg,0.28mmol) was dissolved in water (10mL), the pH was adjusted to 9 with aqueous NaOH (1.0M), ethyl acetate (10mL × 3) was extracted, and the organic phase was washed with anhydrous Na2SO4Drying and removal of the solvent gave 130mg of a white solid in yield: 93 percent.
1H NMR(600MHz,CD3OD):ppm7.68(s,1H),7.60(d,J＝6.7Hz,1H),7.21(d,J＝8.3Hz,1H),6.81(t,JF-H＝75.0Hz,1H),4.64-4.68(m,1H),3.95(d,J＝6.9Hz,2H),3.87-3.93(m,2H),3.73-3.80(m,1H),3.63(s,3H),2.96-3.07(m,2H),1.91-1.97(m,1H),1.70-1.77(m,1H),1.60-1.68(m,1H),1.48-1.56(m,1H),1.47(d,J＝7.0Hz,3H),1.20-1.30(m,1H),0.59-0.62(m,2H),0.34-0.36(m,2H)；
MS-ESI:m/z 509.30[M+H]+。
Example 6: (S) -5- (1-aminoethyl) -N-cyclopropyl-2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride
Figure BDA0001052078950000431
Step 1: synthesis of Compound (S) - (1- (4- (cyclopropylcarbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), cyclopropylamine (37mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (153mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.37mL,2.14mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 5h, water (10 mL. times.2) was added and the organic phase was washed with anhydrous Na2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 210mg of a white solid in yield: 77 percent.
1H NMR(400MHz,CDCl3):ppm 7.59(dd,J1＝8.3Hz,J2＝1.8Hz,1H),7.55(d,J＝1.7Hz,1H),7.25(d,J＝8.2Hz,1H),6.72(t,JF-H＝75.0Hz,1H),5.30-5.26(m,1H),3.99(d,J＝6.9Hz,2H),2.94-2.89(m,1H),1.55(d,J＝7.0Hz,3H),1.45(s,9H),1.36-1.32(m,1H),0.94-0.89(m,2H),0.72-0.69(m,4H),0.44-0.41(m,2H)；
MS-ESI:m/z 508.8[M+H]+。
Step 2: synthesis of Compound (S) -5- (1-aminoethyl) -N-cyclopropyl-2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride
To a solution of compound (S) - (1- (4- (cyclopropylcarbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester (202mg,0.40mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 1h and the solvent was removed to give 170mg of a white solid, yield: 96 percent.
1H NMR(600MHz,CD3OD):ppm 7.78(d,J＝1.9Hz,1H),7.71(dd,J1＝8.4Hz,J2＝1.9Hz,1H),7.33(d,J＝8.3Hz,1H),6.91(t,JF-H＝74.8Hz,1H),5.19-5.16(m,1H),4.03(d,J＝6.9Hz,2H),2.94-2.91(m,1H),1.78(d,J＝7.0Hz,3H),1.37-1.33(m,1H),0.89-0.86(m,2H),0.75-0.73(m,2H),0.7-0.68(m,2H),0.45-0.42(m,2H)；
MS-ESI:m/z 408.9[M+H-HCl]+。
Example 7: (S) - (3- (5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) cyclobutyl) carbamic acid methyl ester hydrochloride
Figure BDA0001052078950000441
Step 1: synthesis of compound (3-aminocyclobutyl) methyl carbamate hydrochloride
The compound 3-aminocyclobutanone hydrochloride (1.5g,12mmol) and dichloromethane (10mL) were mixed, N-diisopropylethylamine (4.2mL,25mmol) and di-tert-butyl dicarbonate (4.3mL,19mmol) were added dropwise to the solution at 0 deg.C, the reaction was stopped after stirring at room temperature for 10 hours, saturated aqueous sodium bicarbonate solution (10 mL. times.3) was added and the organic phase was washed with anhydrous Na2SO4Drying, removal of solvent, and column chromatography of the concentrate (eluent: Petroleum ether/EtOAc (v/v) ═ 5/1) afforded 1.87g of a white solid: tert-butyl (3-oxocyclobutyl) carbamate, yield: 82 percent.
1H NMR(400MHz,CDCl3):ppm 4.93(s,1H),4.19–4.32(m,1H),3.55–3.42(m,2H),3.00–3.08(m,2H),1.45(s,9H)；
MS-ESI:m/z 130.15[M-55]+.
The compound tert-butyl (3-oxocyclobutyl) carbamate (500mg,2.7mmol), hydroxylamine hydrochloride (568mg,8.1mmol) and dichloromethane (10mL) were mixed, N-diisopropylethylamine (1.9mL,10.8mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 3 hours to stop the reaction, water (10 mL. times.3) was added to wash the organic phase, and the organic phase was washed with anhydrous Na2SO4Drying, removal of solvent, and column chromatography of the concentrate (eluent: Petroleum ether/EtOAc (v/v) ═ 1/1) afforded 370mg of a white solid: tert-butyl (3- (hydroxyimino) cyclobutyl) carbamate, yield: 68 percent.
1H NMR(400MHz,CDCl3):ppm 4.79–4.89(m,1H),4.22(br.s,1H),3.27–3.41(m,2H),2.73–2.83(m,2H),1.45(s,9H)；
MS-ESI:m/z 201.10[M+H]+.
The compound tert-butyl (3- (hydroxyimino) cyclobutyl) carbamate (370mg,1.8mmol), nickel chloride (568mg,8.1mmol) and absolute ethanol (5mL) were mixed, sodium borohydride (4.3mL,19mmol) was added to the solution at 0 ℃, the reaction was stopped after stirring for 1 hour, ice water (5mL) was added, pH was adjusted to 1 with concentrated hydrochloric acid, the reaction system was clarified, pH was adjusted to 10 with aqueous sodium hydroxide (1.0M), ethyl acetate (10mL × 3) was used for extraction, and the organic phase was extracted with anhydrous Na2SO4Dried, the solvent removed and concentrated to give 253mg of a colourless liquid: tert-butyl (3-aminocyclobutyl) carbamate, yield: 73 percent.
1H NMR(400MHz,CD3OD):ppm 4.06–4.13,3.59–3.71(m,0.5H,0.5H),3.51–3.57,3.01–3.11(m,0.5H,0.5H),2.58–2.65(m,1H),2.18–2.25(m,1H),2.08–2.15(m,1H),1.61–1.68(m,1H),1.44(m,9H)；
MS-ESI:m/z 187.25[M+H]+.
Anhydrous THF (5mL) was added to N, N' -Carbonyldiimidazole (CDI) (870mg,5.37mmol), triethylamine (0.73mL,5.37mmol) and anhydrous methanol (193mg,6.04mmol) were added, stirring was performed at room temperature for 15min, tert-butyl (3-aminocyclobutyl) carbamate (250mg,1.34mmol) was added, reaction was stopped at 70 ℃ for 24h, the solvent was removed, water (5mL) was added, ethyl acetate (10mL × 3) was extracted, anhydrous sodium sulfate was dried, the solvent was removed, and the concentrate was subjected to column chromatography (eluent: petroleumer/EtOA c (v/v) ═ 2/1), to obtain 152mg of a white solid: 3-methoxycarbonylaminocyclobutane-1-carbamic acid tert-butyl ester, yield: 46 percent.
1H NMR(400MHz,CDCl3):ppm 4.67–4.88(m,1H),4.08–4.24(m,1H),3.69–3.86(m,1H),3.65(s,3H),2.73–2.80(m,1.5H),2.25–2.28(m,1.5H),1.73–1.86(m,1H),1.43(s,9H)；
MS-ESI:m/z 189.10[M-55]+.
The compound tert-butyl 3-methoxycarbonylaminocyclobutane-1-carbamate (150mg,0.61mmol) was dissolved in dichloromethane (2mL), HCl in ethyl acetate (4M,2mL) was added, the mixture was stirred at room temperature for 30min, and the solvent was removed to give 110mg of a white solid: methyl (3-aminocyclobutyl) carbamate hydrochloride, yield: 99 percent.
1H NMR(400MHz,CD3OD):ppm 4.28–4.35,3.88–3.94(m,0.5H,0.5H),3.81–3.87,3.44–3.53(m,0.5H,0.5H),3.65(s,3H),2.69–2.77(m,1.5H),2.43–2.50(m,1.5H),2.10–2.18(m,1H).
Step 2: synthesis of Compound (S) - (1- (4- ((3- (methoxycarbonylamino) cyclobutyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester
Compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (300mg,0.64mmol), compound (3-aminocycloputyl) carbamic acid methyl ester hydrochloride (115mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (245mg,1.28mmol) and N-hydroxy-7-azabenzotriazole (130mg,0.96mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.45mL,2.56mmol) was added dropwise to the solution at 0 deg.C, stirred at room temperature for 10h, washed with water (10 mL. times.3), and the organic phase was washed with anhydrous Na2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: Petroleum ether/EtOAc (v/v) ═ 2/1) afforded 248mg of a white solid in yield: 65 percent.
1H NMR(400MHz,CDCl3):ppm 7.54–7.60(m,2H),7.24(d,J＝8.2Hz,1H),6.70(t,JF-H＝75.0Hz,1H),5.24–5.29(m,1H),4.54–4.60,3.89–3.96(m,0.5H,0.5H),4.20–4.29(m,1H),3.97–4.02(m,2H),3.68(s,3H),2.86–2.92(m,1.5H),2.38–2.52(m,1.5H),2.02–2.12(m,1H),1.51(d,J＝7.0Hz,3H),1.43(s,9H),1.29–1.35(m,1H),0.67–0.72(m,2H),0.39–0.44(m,2H)；
MS-ESI:m/z 595.80[M+H]+.
And step 3: synthesis of Compound (S) - (3- (5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) cyclobutyl) carbamic acid methyl ester hydrochloride
The compound tert-butyl (S) - (1- (4- ((3- (methoxycarbonylamino) cyclobutyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (240mg,0.41mmol) was dissolved in dichloromethane (4mL), a solution of HCl in ethyl acetate (4M,2mL) was added, stirred at room temperature for 30min, the solvent was removed to give 220mg of a white solid, yield: 94 percent.
1H NMR(600MHz,CD3OD):ppm 7.83–7.85(m,1H),7.75–7.77(m,1H),7.37(d,J＝8.3Hz,1H),6.95(t,JF-H＝75.0Hz,1H),5.16–5.19(m,1H),4.62–4.66,3.87–3.93(m,0.5H,0.5H),4.25–4.31(m,1H),4.07–4.09(m,2H),3.68(s,3H),2.77–2.82(m,1.5H),2.43–2.59(m,1.5H),2.15–2.21(m,1H),1.80(d,J＝7.0Hz,3H),1.37–1.41(m,1H),0.71–0.74(m,2H),0.46–0.48(m,2H)；
MS-ESI:m/z 495.85[M+H-HCl]+.
Example 8: (S) -5- (1-aminoethyl) -N- (3- (cyclopropylcarboxamido) cyclobutyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride
Figure BDA0001052078950000451
Step 1: synthesis of compound N- (3-aminocyclobutyl) cyclopropyl formamide hydrochloride
The compound 3-aminocyclobutanone hydrochloride (1.5g,12mmol) and dichloromethane (10mL) were mixed, N-diisopropylethylamine (4.2mL,25mmol) and di-tert-butyl dicarbonate (4.3mL,19mmol) were added dropwise to the solution at 0 deg.C, the reaction was stopped after stirring at room temperature for 10 hours, saturated aqueous sodium bicarbonate solution (10 mL. times.3) was added and the organic phase was washed with anhydrous Na2SO4Drying, removal of solvent, and column chromatography of the concentrate (eluent: Petroleum ether/EtOAc (v/v) ═ 5/1) afforded 1.87g of a white solid: tert-butyl (3-oxocyclobutyl) carbamate, yield: 82 percent.
1H NMR(400MHz,CDCl3):ppm 4.93(s,1H),4.19–4.32(m,1H),3.55–3.42(m,2H),3.00–3.08(m,2H),1.45(s,9H)；
MS-ESI:m/z 130.15[M-55]+.
The compound tert-butyl (3-oxocyclobutyl) carbamate (500mg,2.7mmol), hydroxylamine hydrochloride (568mg,8.1mmol) and dichloromethane (10mL) were mixed, N-diisopropylethylamine (4.3mL,19mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 3 hours to stop the reaction, water (10 mL. times.3) was added to wash the organic phase, and the organic phase was washed with anhydrous Na2SO4Drying, removal of solvent, and column chromatography of the concentrate (eluent: Petroleum ether/EtOAc (v/v) ═ 1/1) afforded 370mg of a white solid: tert-butyl (3- (hydroxyimino) cyclobutyl) carbamate, yield: 68 percent.
1H NMR(400MHz,CDCl3):ppm 4.79–4.89(m,1H),4.22(br.s,1H),3.27–3.41(m,2H),2.73–2.83(m,2H),1.45(s,9H)；
MS-ESI:m/z 201.10[M+H]+.
The compound tert-butyl (3- (hydroxyimino) cyclobutyl) carbamate (370mg,1.85mmol), nickel chloride (240mg,1.85mmol) and absolute ethanol (5mL) were mixed, sodium borohydride (370mg,9.24mmol) was added to the solution at 0 ℃, the reaction was stopped after stirring for 1 hour, ice water (5mL) was added, pH was adjusted to 1 by adding concentrated hydrochloric acid, the reaction system was clarified, pH was adjusted to 10 by adding an aqueous sodium hydroxide solution (1.0M), extraction was performed with ethyl acetate (10mL × 3), and the organic phase was extracted with anhydrous Na2SO4Dried, the solvent removed and concentrated to give 253mg of a colourless liquid: tert-butyl (3-aminocyclobutyl) carbamate, yield: 73 percent.
1H NMR(400MHz,CD3OD):ppm 4.06–4.13,3.59–3.71(m,0.5H,0.5H),3.51–3.57,3.01–3.11(m,0.5H,0.5H),2.58–2.65(m,1H),2.18–2.25(m,1H),2.08–2.15(m,1H),1.61–1.68(m,1H),1.44(m,9H)；
MS-ESI:m/z 187.25[M+H]+.
Dissolving the compound tert-butyl (3-aminocyclobutyl) carbamate (360mg,1.92mmol), cyclopropylcarboxylic acid (332mg,3.86mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (741mg,3.86mmol) and N-hydroxy-7-azabenzotriazole (394mg,2.89mmol) in dichloromethane (10mL), dropwise adding N, N-diisopropylethylamine (0.99mL,5.8mmol) to the solution at 0 deg.C, stirring at room temperature for 10h, adding water (10 mL. times.3), washing the organic phase with anhydrous Na2SO4Drying, removal of the solvent and column chromatography of the concentrate (eluent: petroleumeher/EtOAc (v/v) ═ 3/2) afforded 195mg of a white solid: tert-butyl (3- (cyclopropylcarboxamido) cyclobutyl) carbamate, yield: 40 percent.
1H NMR(400MHz,CD3OD):ppm 4.25–4.31(m,1H),4.11–4.14(m,1H),2.28(t,J＝6.8Hz,4H),1.58–1.62(m,1H),1.46(s,9H),0.83–0.87(m,2H),0.74–0.78(m,2H)；
MS-ESI:m/z 199.20[M-55]+.
Compound (3- (cyclopropylcarboxamido) cyclobutyl) carbamic acid tert-butyl ester (190mg,0.75mmol) was dissolved in dichloromethane (2mL), a solution of HCl in ethyl acetate (4M,2mL) was added, stirred at room temperature for 30min, the solvent was removed to give 136mg of a white solid: n- (3-aminocyclobutyl) cyclopropylcarboxamide hydrochloride, yield: 95 percent.
1H NMR(400MHz,CD3OD):ppm 4.42–4.49,4.02–4.10(m,0.5H,0.5H),3.82–3.89,3.44–3.52(m,0.5H,0.5H),2.68–2.74(m,1.5H),2.41–2.50(m,1.5H),2.11–2.19(m,1H),1.53–1.59(m,1H),0.72–0.82(m,4H)；
MS-ESI:m/z 155.15[M+H-HCl]+.
Step 2: synthesis of Compound (S) - (1- (4- ((3- (cyclopropylcarboxamido) cyclobutyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester (8-1a)
Synthesis of Compound (S) - (1- (4- ((3- (cyclopropylcarboxamido) cyclobutyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester (8-2a)
Compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (300mg,0.64mmol), compound N- (3-aminocyclobutyl) cyclopropylcarboxamide hydrochloride (121mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (245mg,1.28mmol) and N-hydroxy-7-azabenzotriazole (130mg,0.96mmol) were dissolved in dichloromethane (10mL), and N, N-diisopropylethyl acetate was added dropwise to the solution at 0 deg.CAmine (0.45mL,2.56mmol), stirred at room temperature for 10h, washed with water (10 mL. times.3), and the organic phase over anhydrous Na2SO4Drying, removal of the solvent and column chromatography of the concentrate (eluent: dichloromethane/ethyl acetate (v/v) ═ 4/1) gave 110mg of a white solid: compound 8-1a, yield: 30 percent; 102mg of a white solid are obtained: compound 8-2a, yield: 26 percent.
Compound 8-1 a:1H NMR(400MHz,CDCl3):ppm 7.57–7.60(m,2H),7.45(br.s,1H),7.24(d,J＝8.3Hz,1H),6.84(br.s,1H),6.71(t,JF-H＝75.0Hz,1H),5.97(d,J＝6.7Hz,1H),5.23–5.29(m,1H),4.57–4.64(m,2H),4.00(d,J＝6.9Hz,2H),2.40–2.54(m,4H),1.51(d,J＝7.0Hz,3H),1.42(s,9H),1.30–1.37(m,2H),0.95–0.99(m,2H),0.73–0.78(m,2H),0.66–0.71(m,2H),0.39–0.44(m,2H)；
MS-ESI:m/z 505.30[M+H-100]+.
compound 8-2 a:1H NMR(400MHz,CDCl3):ppm 7.52–7.56(m,2H),7.39(br.s,1H),7.22(d,J＝8.3Hz,1H),6.83(br.s,1H),6.69(t,JF-H＝75.0Hz,1H),6.08–6.14(m,1H),5.23–5.29(m,1H),4.10–4.25(m,2H),3.97(d,J＝6.9Hz,2H),2.84–2.91(m,2H),2.08–2.15(m,2H),1.50(d,J＝6.9Hz,3H),1.41(s,9H),1.28–1.34(m,2H),0.93–0.97(m,2H),0.70–0.75(m,2H),0.66–0.70(m,2H),0.38–0.43(m,2H)；
MS-ESI:m/z 605.30[M+H]+.
and step 3: synthesis of Compound (S) -5- (1-aminoethyl) -N- (3- (cyclopropylcarboxamido) cyclobutyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride (8-1)
Compound (S) - (tert-butyl 1- (4- ((3- (cyclopropylcarboxamido) cyclobutyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (8-1a) (110mg,0.17mmol) was dissolved in dichloromethane (4mL), HCl in ethyl acetate (4M,2mL) was added, stirring was carried out at room temperature for 30min, and the solvent was removed to give 85mg of a white solid: compound 8-1, yield: 96%, time to peak HPLC: 9.07 min.
Compound 8-1:1H NMR(600MHz,CD3OD):ppm 7.85(s,1H),7.75–7.77(m,1H),7.37(d,J＝8.3Hz,1H),6.95(t,JF-H＝75.0Hz,1H),5.16–5.19(m,1H),4.67–4.71(m,1H),4.42–4.47(m,1H),4.08(d,J＝6.9Hz,2H),2.59–2.63(m,2H),2.44–2.49(m,2H),1.80(d,J＝6.9Hz,3H),1.63–1.67(m,1H),1.37–1.42(m,1H),0.88–0.91(m,2H),0.79–0.82(m,2H),0.71–0.74(m,2H),0.46–0.48(m,2H)；
MS-ESI:m/z 505.30[M+H-HCl]+.
and 4, step 4: synthesis of Compound (S) -5- (1-aminoethyl) -N- (3- (cyclopropylcarboxamido) cyclobutyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride (8-2)
Compound (S) - (1- (4- ((3- (cyclopropylcarboxamido) cyclobutyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester (8-2a) (85mg,0.14mmol) was dissolved in dichloromethane (4mL), HCl in ethyl acetate (4M,2mL) was added, stirring was carried out at room temperature for 30min, and the solvent was removed to give 75mg of a white solid: compound 8-2, yield: 99%, time to peak HPLC: 9.18 min.
Compound 8-2:1HNMR(400MHz,CD3OD):ppm 7.82–7.84(m,1H),7.74(dd,J＝8.4,1.8Hz,1H),7.35(d,J＝8.3Hz,1H),6.94(t,JF-H＝75.0Hz,1H),5.13–5.18(m,1H),4.25–4.34(m,1H),4.06–4.13(m,1H),4.07(d,J＝6.9Hz,2H),2.76–2.83(m,2H),2.15–2.23(m,2H),1.78(d,J＝7.0Hz,3H),1.56–1.64(m,1H),1.37–1.41(m,1H),0.86–0.91(m,2H),0.76–0.82(m,2H),0.69–0.73(m,2H),0.43–0.48(m,2H)；
MS-ESI:m/z 505.80[M+H-HCl]+.
example 9: (S) -3- (5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) cyclobutyl cyclopropylcarbamate hydrochloride
Figure BDA0001052078950000481
Step 1: synthesis of compound 3-aminocyclobutyl cyclopropyl carbamate hydrochloride
The compound 3-aminocyclobutanone hydrochloride (1.5g,12mmol) and dichloromethane (10mL) were mixed, N-diisopropylethylamine (4.3mL,19mmol) and di-tert-butyl dicarbonate (4.2mL,25mmol) were added dropwise to the solution at 0 deg.C, the reaction was stopped after stirring at room temperature for 10 hours, saturated aqueous sodium bicarbonate solution (10 mL. times.3) was added and the organic phase was washed with anhydrous Na2SO4Drying, removal of solvent, and column chromatography of the concentrate (eluent: Petroleum ether/EtOAc (v/v) ═ 5/1) afforded 1.87g of a white solid: tert-butyl (3-oxocyclobutyl) carbamate, yield: 82 percent.
1H NMR(400MHz,CDCl3):ppm 4.93(s,1H),4.19–4.32(m,1H),3.55–3.42(m,2H),3.00–3.08(m,2H),1.45(s,9H)；
MS-ESI:m/z 130.15[M-55]+.
The compound tert-butyl (3-oxocyclobutyl) carbamate (670mg,3.6mmol) and anhydrous ethanol (10mL) were mixed, sodium borohydride (270mg,7.2mmol) was slowly added to the solution at 0 deg.C, the reaction was stopped after stirring at room temperature for 1 hour, ice water (10mL) was added, the aqueous phase was extracted with ethyl acetate (10 mL. times.3), and the organic phase was extracted with anhydrous Na2SO4Dried, solvent removed and concentrated to give 672mg of a white solid: tert-butyl (3-hydroxycyclobutyl) carbamate, yield: 99 percent.
1H NMR(400MHz,CDCl3):ppm 4.69(br.s,1H),4.42–4.47,3.97–4.03(m,0.5H,0.5H),4.16–4.23,3.58–3.68(m,0.5H,0.5H),2.71–2.78(m,1H),2.17–2.32(m,2H),1.73–1.81(m,2H),1.43(s,9H)；
MS-ESI:m/z 132.20[M-55]+.
Anhydrous THF (10mL) was added to N, N' -Carbonyldiimidazole (CDI) (311mg,1.92mmol), triethylamine (0.33mL,2.40mmol) and the compound tert-butyl (3-hydroxycyclobutyl) carbamate (300mg,1.60mmol) were added, cyclopropylamine (457mg,8.01mmol) was added after stirring at room temperature for 15min, reaction was stopped at 50 ℃ for 24h, the solvent was removed, water (5mL) was added, ethyl acetate (10mL × 3) was extracted, anhydrous sodium sulfate was dried, the solvent was removed, and the concentrate was subjected to column chromatography (eluent: dichloromethane/ethyl acetate (v/v) ═ 2/1), yielding 333mg of a white solid: 3- ((tert-butoxycarbonyl) amino) cyclobutyl cyclopropylcarbamate, yield: 78 percent.
1H NMR(400MHz,CDCl3):ppm 5.02–5.07,4.79–4.89(m,0.5H,0.5H),4.64–4.71(m,1H),2.78–2.84(m,1H),2.53–2.58(m,1H),2.39–2.48(m,1H),2.21–2.29(m,1H),1.86–1.93(m,1H),1.43(s,9H),0.69–0.73(m,2H),0.48–0.52(m,2H)；
MS-ESI:m/z 171.20[M+H-100]+.
Compound 3- ((tert-butoxycarbonyl) amino) cyclobutyl cyclopropyl carbamate (330mg,1.22mmol) was dissolved in dichloromethane (2mL), a solution of HCl in ethyl acetate (4M,4mL) was added, stirred at room temperature for 30min, the solvent was removed to give 251mg of a white solid: 3-aminocyclobutylcyclopropyl carbamate hydrochloride, yield: 99 percent.
1H NMR(400MHz,CD3OD):ppm 5.13–5.16,4.76–4.81(m,0.5H,0.5H),3.90–3.96,3.46–3.54(m,0.5H,0.5H),2.83–2.90(m,1H),2.51–2.59(m,3.0H),2.20–2.28(m,1H),0.67–0.72(m,2H),0.47–0.51(m,2H)；
MS-ESI:m/z 171.10[M+H-HCl]+.
Step 2: synthesis of the compound (S) -3- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) cyclobutyl cyclopropylcarbamate (9-1a)
Synthesis of the compound (S) -3- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) cyclobutyl cyclopropylcarbamate (9-2a)
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (300mg,0.64mmol), 3-aminocyclopropylcarbamate hydrochloride (135mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (245mg,1.28mmol) and N-hydroxy-7-azabenzotriazole (130mg,0.96mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.45mL,2.56mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 10 hours, water (10 mL. times.3) was added and the organic phase was washed with anhydrous Na2SO4Drying, removal of the solvent and column chromatography of the concentrate (eluent: petroleumeher/EtOAc (v/v) ═ 3/2) gave 52mg of a white solid: compound 9-1a, yield: 13 percent; 110mg of a white solid are obtained: compound 9-2a, yield: 28 percent.
Compound 9-1 a:1H NMR(400MHz,CDCl3):ppm 7.56–7.60(m,2H),7.39(br.s,1H),7.24(d,J＝8.3Hz,1H),6.85(br.s,1H),6.71(t,JF-H＝75.0Hz,1H),5.16–5.22(m,1H),4.85–4.93(m,1H),4.63–4.72(m,1H),4.00(d,J＝6.9Hz,2H),2.53–2.62(m,3H),2.46–2.53(m,2H),1.51(d,J＝7.0Hz,3H),1.42(s,9H),1.30–1.37(m,1H),0.67–0.76(m,4H),0.51–0.55(m,2H),0.40–0.44(m,2H)；
MS-ESI:m/z 521.80[M+H-100]+.
compound 9-2 a:1H NMR(400MHz,CDCl3):ppm 7.54–7.60(m,2H),7.27(br.s,1H),7.24(d,J＝8.3Hz,1H),6.86(br.s,1H),6.70(t,JF-H＝75.0Hz,1H),5.23–5.29(m,1H),4.76–4.87(m,2H),3.99(d,J＝6.9Hz,2H),2.92–2.98(m,2H),2.56–2.60(m,1H),2.10–2.18(m,2H),1.51(d,J＝7.0Hz,3H),1.42(s,9H),1.30–1.36(m,1H),0.67–0.76(m,4H),0.51–0.54(m,2H),0.39–0.43(m,2H)；
MS-ESI:m/z 621.70[M+H]+.
and step 3: synthesis of Compound (S) -3- (5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) cyclobutyl cyclopropylcarbamate hydrochloride (9-1)
Compound (S) -3- (5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) cyclobutyl cyclopropylcarbamate (9-1a) (110mg,0.18mmol) was dissolved in dichloromethane (4mL), HCl in ethyl acetate (4M,4mL) was added, stirring was carried out at room temperature for 30min, and the solvent was removed to give 95mg of a white solid: compound 9-1, yield: 97%, time to peak HPLC: 10.33 min.
Compound 9-1:1H NMR(400MHz,CD3OD):ppm 7.82(s,1H),7.73(d,J＝8.5Hz,1H),7.35(d,J＝8.3Hz,1H),6.93(t,JF-H＝74.8Hz,1H),5.11–5.18(m,2H),4.67–4.75(m,1H),4.05(d,J＝6.9Hz,2H),2.50–2.65(m,5H),1.78(d,J＝6.8Hz,3H),1.35–1.42(m,1H),0.67–0.72(m,4H),0.49–0.53(m,2H),0.43–0.47(m,2H)；
MS-ESI:m/z 521.20[M+H-HCl]+.
and 4, step 4: synthesis of Compound (S) -3- (5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) cyclobutyl cyclopropylcarbamate hydrochloride (9-2)
The compound (S) -3- (5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) cyclobutyl cyclopropylcarbamate (9-2a) (48mg,0.08mmol) was dissolved in dichloromethane (4mL), an ethyl acetate solution of HCl (4M,4mL) was added, and the mixture was stirred at room temperature for 30min, and the solvent was removed to give 41mg of a white solid: compound 9-2, yield: 95%, time to peak HPLC: 10.38 min.
Compound 9-2:1H NMR(600MHz,CD3OD):ppm 7.84(s,1H),7.74–7.76(m,1H),7.36(d,J＝8.3Hz,1H),6.95(t,JF-H＝74.8Hz,1H),5.15–5.18(m,1H),4.75–4.78(m,1H),4.24–4.29(m,1H),4.08(d,J＝6.9Hz,2H),2.85–2.90(m,2H),2.52–2.57(m,1H),2.28–2.34(m,1H),1.80(d,J＝6.9Hz,3H),1.37–1.42(m,1H),0.69–0.74(m,4H),0.50–0.53(m,2H),0.46–0.48(m,2H)；
MS-ESI:m/z 521.25[M+H-HCl]+.
example 10: (S) -4- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylic acid methyl ester hydrochloride
Figure BDA0001052078950000501
Step 1: synthesis of compound 4- (aminomethyl) piperidine-1-carboxylic acid methyl ester hydrochloride
Triethylamine (0.65mL,4.67mmol) was added dropwise to a solution of N' -carbonyldiimidazole (1.17g,7.00mmol) in anhydrous THF (8mL) at room temperature, the mixture was stirred at room temperature, methanol (0.28mL,7.00mmol) was slowly added dropwise, the reaction was carried out at room temperature for 30min, and 4-Bo was added dropwisec-Aminomethylpiperidine (500mg,2.33mmol) in dry THF (8mL) at 75 ℃ for 17h, washing with dilute hydrochloric acid (10 mL. times.3) until the aqueous phase is acidic, extracting with ethyl acetate (15 mL. times.2), washing the organic phase with saturated sodium bicarbonate solution (10 mL. times.2), combining the organic phases, and adding anhydrous Na2SO4Drying, removing solvent, and subjecting the concentrated solution to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1), to give 596mg of colorless liquid: methyl 4- ((tert-butoxycarbonylamino) methyl) piperidine-1-carboxylate, yield: 93 percent.
1H NMR(400MHz,CDCl3):ppm4.64(br.s,1H),4.13–4.08(m,1H),3.67(s,3H),3.01–2.97(m,2H),2.75–2.69(m,2H),1.68–1.65(m,2H),1.62–1.58(m,1H),1.42(s,9H),1.15–1.05(m,2H)；
MS-ESI:m/z 173.2[M+H-100]+.
To a solution of compound 4- ((tert-butoxycarbonylamino) methyl) piperidine-1-carboxylic acid methyl ester (586mg,2.15mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,5mL), stirred at room temperature for 2h, and the solvent was removed to give 449mg of a colorless dope: 4- (aminomethyl) piperidine-1-carboxylic acid methyl ester hydrochloride, yield: 99 percent.
1H NMR(400MHz,CD3OD):ppm 4.18–4.15(m,2H),3.70(s,3H),2.89–2.85(m,4H),1.91–1.87(m,1H),1.81–1.78(m,2H),1.24–1.19(m,2H)；
MS-ESI:m/z 173.1[M+H-HCl]+.
Step 2: synthesis of methyl 4- ((5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate, compound
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), methyl 4- (aminomethyl) piperidine-1-carboxylate hydrochloride (134mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (154mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.37mL,2.14mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 5h, followed by addition of N, N-diisopropylethylamine (0.37mL,2.14mmol)Washed with water (10 mL. times.2) and the organic phase with anhydrous Na2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 214mg of a colorless viscous mass, yield: and 63 percent.
1H NMR(400MHz,CDCl3):ppm 7.58(dd,J1＝8.3Hz,J2＝1.8Hz,1H),7.54(d,J＝1.7Hz,1H),7.24(d,J＝8.4Hz,1H),6.70(t,JF-H＝75.0Hz,1H),5.28–5.24(m,1H),4.20–4.13(m,2H),3.98(d,J＝6.9Hz,2H),3.69(s,3H),3.36–3.35(m,2H),2.81–2.75(m,2H),1.84–1.82(m,1H),1.80–1.77(m,2H),1.52(d,J＝7.0Hz,3H),1.43(s,9H),1.35–1.32(m,1H),0.71–0.67(m,2H),0.43–0.39(m,2H)；
MS-ESI:m/z 523.8[M+H-100]+.
And step 3: synthesis of compound (S) -4- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylic acid methyl ester hydrochloride
To a solution of the compound (S) -4- ((5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylic acid methyl ester (208mg,0.33mmol) in dichloromethane (6mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 1h and the solvent removed to give 168mg of a white solid in yield: 89 percent.
1H NMR(600MHz,CDCl3):ppm 7.57(d,J＝8.2Hz,1H),7.53(s,1H),7.39–7.37(m,1H),7.21(d,J＝8.2Hz,1H),6.70(t,JF-H＝74.9Hz,1H),5.01–5.00(m,1H),4.20–4.13(m,2H),3.96(d,J＝6.8Hz,2H),3.68(s,3H),3.32–3.30(m,2H),2.77–2.72(m,2H),1.86(d,J＝5.3Hz,3H),1.81–1.80(m,1H),1.76–1.74(m,2H),1.32–1.30(m,1H),1.21–1.19(m,2H),0.68–0.65(m,2H),0.40–0.38(m,2H)；
MS-ESI:m/z 523.3[M+H-HCl]+.
Example 11: (S) -5- (1-aminoethyl) -N- (cyclopropylmethoxy) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride
Figure BDA0001052078950000511
Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((cyclopropylmethoxy) carbamoyl) oxazol-5-yl) ethyl) carbamate
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), O-cyclopropylmethylhydroxylamine hydrochloride (79mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (153mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.37mL,2.14mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 17h, water (10 mL. times.2) was added and the organic phase was washed with anhydrous Na2SO4Drying, removal of the solvent, column separation of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 217mg of a colorless viscous mass, yield: 73 percent.
1H NMR(600MHz,CDCl3):ppm 7.56(dd,J1＝8.3Hz,J2＝1.9Hz,1H),7.54(d,J＝1.8Hz,1H),7.23(d,J＝8.3Hz,1H),6.70(t,JF-H＝75.0Hz,1H),5.27-5.24(m,1H),3.96(d,J＝7.0Hz,2H),3.89(d,J＝7.3Hz,2H),1.53(d,J＝7.0Hz,3H),1.42(s,9H),1.34-1.31(m,1H),1.24-1.22(m,1H),0.70-0.68(m,2H),0.66-0.63(m,2H),0.42-0.39(m,2H),0.37-0.35(m,2H)；
MS-ESI:m/z 438.9[M+H-100]+。
Step 2: synthesis of Compound (S) -5- (1-aminoethyl) -N- (cyclopropylmethoxy) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride
To a solution of tert-butyl compound (S) - (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((cyclopropylmethoxy) carbamoyl) oxazol-5-yl) ethyl) carbamate (210mg,0.39mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 1h and the solvent removed to give 160mg of a white solid, yield: 86 percent.
1H NMR(600MHz,CD3OD):ppm 7.79(d,J＝1.7Hz,1H),7.73(dd,J1＝8.3Hz,J2＝1.8Hz,1H),7.33(d,J＝8.3Hz,1H),6.92(t,JF-H＝74.7Hz,1H),5.24-5.20(m,1H),4.04(d,J＝6.9Hz,2H),3.85(d,J＝7.3Hz,2H),1.78(d,J＝7.0Hz,3H),1.37-1.34(m,1H),1.25-1.22(m,1H),0.7-0.68(m,2H),0.65-0.62(m,2H),0.44-0.42(m,2H),0.38-0.35(m,2H)；
MS-ESI:m/z 438.1[M+H-HCl]+。
Example 12: (S) -5- (1-aminoethyl) -N- ((1- (cyclopropylcarbonyl) piperidin-4-yl) methyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride
Figure BDA0001052078950000521
Step 1: synthesis of Compound (4- (aminomethyl) piperidin-1-yl) (cyclopropyl) methanone hydrochloride
4-Boc-aminomethylpiperidine (1.05g,4.88mmol), cyclopropanecarboxylic acid (350mg,4.06mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.17g,6.10mmol) and N-hydroxy-7-azabenzotriazole (1.38g,10.16mmol) were dissolved in dichloromethane (20mL), N-diisopropylethylamine (2.8mL,16.26mmol) was added dropwise to this solution at 0 deg.C, stirring was carried out at room temperature for 17h, water (10 mL. times.2) was added and the organic phase was washed with anhydrous Na2SO4Drying, removal of solvent, column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 1.14g of a colourless oil: tert-butyl ((1- (cyclopropylcarbonyl) piperidin-4-yl) methyl) carbamate, yield: 99 percent.
1H NMR(600MHz,CDCl3):ppm 4.69–4.68(m,1H),4.59–4.57(m,1H),4.22–4.20(m,1H),3.05–2.99(m,4H),2.57–2.54(m,1H),1.78–1.76(m,1H),1.71–1.67(m,2H),1.42(s,9H),1.14–1.10(m,1H),0.94–0.93(m,2H),0.72–0.71(m,2H)；
MS-ESI:m/z 283.3[M+H]+.
To compound tert-butyl ((1- (cyclopropylcarbonyl) piperidin-4-yl) methyl) carbamate (1.30g,4.60mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,9mL), stirred at room temperature for 4h, and the solvent was removed to give 1.0g of a colorless viscous material: (4- (aminomethyl) piperidin-1-yl) (cyclopropyl) methanone hydrochloride, yield: 99 percent.
1H NMR(600MHz,CD3OD):ppm 4.51–4.45(m,2H),2.91–2.90(m,2H),2.07–2.01(m,2H),1.91–1.90(m,2H),1.27–1.21(m,2H),0.88–0.86(m,2H),0.86–0.84(m,2H)；
MS-ESI:m/z 183.1[M+H-HCl]+.
Step 2: synthesis of Compound (S) - (1- (4- (((1- (cyclopropylcarbonyl) piperidin-4-yl) methyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), (4- (aminomethyl) piperidin-1-yl) (cyclopropyl) methanone hydrochloride (140mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (154mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in methylene chloride (20mL), N-diisopropylethylamine (0.37mL,2.14mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 15 hours, washed with water (10 mL. times.2), anhydrous Na for organic phase2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/1.5) afforded 285mg of a white solid, yield: 81 percent.
1H NMR(600MHz,CDCl3):ppm 7.59(dd,J1＝8.3Hz,J2＝1.9Hz,1H),7.54(d,J＝1.9Hz,1H),7.24(d,J＝8.3Hz,1H),6.70(t,JF-H＝75.0Hz,1H),5.30–5.27(m,1H),4.65–4.63(m,1H),4.27–4.25(m,1H),3.98(d,J＝7.0Hz,2H),3.40–3.32(m,2H),3.11–3.08(m,1H),2.61–2.58(m,1H),1.94–1.90(m,1H),1.87–1.82(m,2H),1.76–1.72(m,1H),1.53(d,J＝7.0Hz,3H),1.43(s,9H),1.35–1.32(m,1H),0.97–0.96(m,2H),0.75–0.73(m,2H),0.71–0.68(m,2H),0.42–0.40(m,2H)；
MS-ESI:m/z 633.3[M+H]+.
And step 3: synthesis of compound (S) -5- (1-aminoethyl) -N- ((1- (cyclopropylcarbonyl) piperidin-4-yl) methyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride
To a solution of compound (S) tert-butyl (1- (4- (((1- (cyclopropylcarbonyl) piperidin-4-yl) methyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (279mg,0.44mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 2h, the solvent was removed to give 250mg of a white solid, yield: 99 percent.
1H NMR(600MHz,CDCl3):ppm 7.57(d,J＝8.3Hz,1H),7.54(s,1H),7.42–7.40(m,1H),7.21(d,J＝8.2Hz,1H),6.70(t,JF-H＝74.9Hz,1H),5.01–5.00(m,1H),4.62–4.59(m,1H),4.26–4.23(m,1H),3.96(d,J＝6.8Hz,2H),3.36–3.32(m,2H),3.10–3.06(m,1H),2.60–2.58(m,1H),1.92–1.90(m,1H),1.86(d,J＝6.5Hz,3H),1.85–1.83(m,1H),1.80–1.78(m,1H),1.75–1.72(m,1H),1.29–1.26(m,1H),0.95–0.94(m,2H),0.74–0.73(m,2H),0.68–0.65(m,2H),0.39–0.38(m,2H)；
MS-ESI:m/z 533.3[M+H-HCl]+.
Example 13: 2- ((5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylic acid methyl ester hydrochloride
Figure BDA0001052078950000531
Step 1: synthesis of compound 2- (aminomethyl) piperidine-1-carboxylic acid methyl ester hydrochloride
Adding triethylamine (0.65mL,4.67mmol) dropwise to a solution of N' -N-carbonyldiimidazole (1.17g,7.00mmol) in anhydrous THF (5mL) at room temperature, stirring at room temperature, slowly adding methanol (0.28mL,7.00mmol) dropwise, reacting at room temperature for 30min, adding a solution of 2-Boc-aminomethylpiperidine (500mg,2.33mmol) in anhydrous THF (10mL), reacting at 75 ℃ for 28h, washing with a dilute hydrochloric acid solution (10 mL. times.3) until the aqueous phase is acidic, extracting with ethyl acetate (15 mL. times.2), washing the organic phase with a saturated sodium bicarbonate solution (10 mL. times.2), combining the organic phases, and adding anhydrous Na2SO4The mixture is dried and then is dried,the solvent was removed and the concentrate was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 3/1) to give 150mg of a colorless oil: methyl 2- ((tert-butoxycarbonylamino) methyl) piperidine-1-carboxylate, yield: 23 percent.
1H NMR(600MHz,CDCl3):ppm 4.68–4.65(m,1H),4.32–4.30(m,1H),3.99–3.94(m,1H),3.68(s,3H),3.51–3.46(m,1H),3.12–3.09(m,1H),2.90–2.85(m,1H),1.62–1.58(m,5H),1.55–1.51(m,1H),1.41(s,9H)；
MS-ESI:m/z 173.1[M-100+H]+.
To a solution of compound methyl 2- ((tert-butoxycarbonylamino) methyl) piperidine-1-carboxylate (142mg,0.52mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,6mL), stirred at room temperature for 1h, and the solvent was removed to give 108mg of a pale yellow oil: 2- (aminomethyl) piperidine-1-carboxylic acid methyl ester hydrochloride, yield: 99 percent.
1H NMR(400MHz,CD3OD):ppm4.55–4.52(m,1H),4.11–4.05(m,1H),3.74(s,3H),3.47–3.41(m,1H),3.04–2.95(m,2H),1.76–1.67(m,4H),1.64–1.57(m,1H),1.51–1.43(m,1H)；
MS-ESI:m/z 173.2[M+H-HCl]+.
Step 2: synthesis of the compound methyl 2- ((5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (200mg,0.43mmol), methyl 2- (aminomethyl) piperidine-1-carboxylate hydrochloride (107mg,0.51mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (123mg,0.64mmol) and N-hydroxy-7-azabenzotriazole (145mg,1.06mmol) were dissolved in dichloromethane (16mL), to this solution was added dropwise N, N-diisopropylethylamine (0.30mL,1.71mmol) at 0 deg.C, stirred at room temperature for 7h, washed with water (10 mL. times.2), and the organic phase was washed with anhydrous Na.2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 124mg of a white solid in yield: 46 percent.
1H NMR(400MHz,CDCl3):ppm 7.58–7.56(m,2H),7.23(d,J＝8.0Hz,1H),6.70(t,JF-H＝75.0Hz,1H),5.27–5.23(m,1H),4.52–4.49(m,1H),4.10–4.02(m,1H),3.98(d,J＝6.9Hz,2H),3.83–3.78(m,1H),3.65(s,3H),3.53–3.49(m,1H),3.00–2.93(m,1H),1.70–1.64(m,6H),1.52(d,J＝7.0Hz,3H),1.43(s,9H),1.34–1.31(m,1H),0.71–0.66(m,2H),0.43–0.39(m,2H)；
MS-ESI:m/z 623.3[M+H]+.
And step 3: synthesis of compound methyl 2- ((5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate hydrochloride
To a solution of the compound methyl 2- ((5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate (122mg,0.19mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 1h and the solvent removed to give 109mg of a white solid in yield: 99 percent.
1H NMR(600MHz,CDCl3):ppm 7.57–7.56(m,2H),7.21(d,J＝8.0Hz,1H),6.70(t,JF-H＝74.9Hz,1H),4.98–4.96(m,1H),4.51–4.48(m,1H),4.05–3.99(m,1H),3.96(d,J＝6.2Hz,2H),3.82–3.78(m,1H),3.65–3.62(m,3H),3.45–3.40(m,1H),2.95–2.93(m,1H),1.88–1.86(m,3H),1.70–1.68(m,5H),1.62–1.58(m,1H),1.39–1.35(m,1H),0.67–0.65(m,2H),0.41–0.38(m,2H)；
MS-ESI:m/z 523.8[M+H-HCl]+.
Example 14: (R) -methyl 3- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) pyrrolidine-1-carboxylate hydrochloride
Figure BDA0001052078950000551
Step 1: synthesis of compound (R) -3-aminopyrrolidine-1-carboxylic acid methyl ester
At room temperature, to R-1-Boc-3-aminopyrrolidine (1)00g,5.37mmol) in dichloromethane (15mL) was added dropwise N, N-diisopropylethylamine (2.8mL,16.10mmol), stirred at room temperature, benzyl chloroformate (1.47mL,10.7mmol) was added dropwise, reacted at room temperature for 6h, washed with water (10 mL. times.2), and the organic phase was washed with anhydrous Na2SO4Drying, removing the solvent, and subjecting the concentrated solution to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 3/1), to give 1.72g of a colorless liquid: (R) -3- (benzyloxycarbonylamino) pyrrolidine-1-carboxylic acid tert-butyl ester, yield: 100 percent.
1H NMR(400MHz,CDCl3):ppm 7.37–7.33(m,5H),5.09(s,2H),4.96–4.94(m,1H),4.24–4.22(m,1H),3.61–3.56(m,1H),3.40–3.35(m,2H),3.20–3.17(m,1H),2.13–2.09(m,1H),1.85–1.81(m,1H),1.45(s,9H)；
MS-ESI:m/z 221.1[M-100+H]+.
To a solution of compound (R) -tert-butyl 3- (benzyloxycarbonylamino) pyrrolidine-1-carboxylate (1.72g,5.37mmol) in dichloromethane (6mL) was added a solution of HCl in ethyl acetate (4M,6mL), stirred at room temperature for 2h, and the solvent was removed to give 1.38g of a pale yellow viscous substance: (R) -pyrrolidin-3-yl-carbamic acid benzyl ester hydrochloride, yield: 100 percent.
1H NMR(400MHz,CD3OD):ppm7.37–7.36(m,4H),7.34–7.32(m,1H),5.11(s,2H),4.31–4.29(m,1H),3.51–3.44(m,2H),3.40–3.35(m,1H),3.29–3.27(m,1H),2.35–2.26(m,1H),2.09–2.03(m,1H)；
MS-ESI:m/z 221.1[M+H-HCl]+.
Adding triethylamine (0.86mL,6.13mmol) dropwise to a solution of N' -carbonyldiimidazole (879mg,5.26mmol) in anhydrous THF (5mL) at room temperature, stirring at room temperature, slowly adding methanol (0.21mL,5.26mmol) dropwise, reacting at room temperature for 30min, adding a solution of (R) -pyrrolidine-3-ylcarbamate benzyl hydrochloride (450mg,1.75mmol) in anhydrous THF (10mL), reacting at 75 ℃ for 24h, adding a dilute hydrochloric acid solution (10 mL. times.3) to wash the aqueous phase until the aqueous phase is acidic, extracting with ethyl acetate (15 mL. times.2), washing the organic phase with a saturated sodium bicarbonate solution (10 mL. times.2), combining the organic phases, and adding anhydrous Na2SO4Drying, removing solvent, and separating the concentrated solution by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/1) to obtain 442mg colorless oil: (R) -3- (benzyloxycarbonylamino) pyrrolidine-1-carboxylic acid methyl ester, yield: 90 percent.
1H NMR(400MHz,CDCl3):ppm 7.35–7.30(m,5H),5.09(s,2H),4.96–4.94(m,1H),4.26–4.23(m,1H),3.68(s,3H),3.63–3.61(m,1H),3.47–3.42(m,2H),3.30–3.24(m,1H),2.13–2.10(m,1H),1.84–1.80(m,1H)；
MS-ESI:m/z 279.2[M+H]+.
To a solution of compound (R) -methyl 3- (benzyloxycarbonylamino) pyrrolidine-1-carboxylate (430mg,1.54mmol) in methanol (8mL) was added Pd/C (43mg, 10%), reacted with hydrogen at room temperature for 3.5h, filtered over celite, and the filtrate was spun dry to give 190mg of a colorless liquid: (R) -3-aminopyrrolidine-1-carboxylic acid methyl ester, yield: 85 percent.
1H NMR(400MHz,CD3OD):ppm 3.70(s,3H),3.57–3.50(m,3H),3.43–3.39(m,1H),3.13–3.09(m,1H),2.11–2.09(m,1H),1.77–1.70(m,1H)；
MS-ESI:m/z 145.2[M+H]+.
Step 2: synthesis of methyl compound (R) -3- (5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) pyrrolidine-1-carboxylate
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (350mg,0.75mmol), (R) -3-aminopyrrolidine-1-carboxylic acid methyl ester (129mg,0.90mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (215mg,1.12mmol) and N-hydroxy-7-azabenzotriazole (254mg,1.87mmol) were dissolved in dichloromethane (16mL), n, N-diisopropylethylamine (0.52mL,2.99mmol) was added dropwise to the solution at 0 deg.C, the mixture was stirred at room temperature for 16.5h, water (10 mL. times.2) was added, and the organic phase was washed with anhydrous Na.2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 368mg of a white solid in yield: 82 percent.
1H NMR(400MHz,CDCl3):ppm 7.59(dd,J1＝8.3Hz,J2＝1.8Hz,1H),7.54(d,J＝1.7Hz,1H),7.24(d,J＝8.4Hz,1H),6.71(t,JF-H＝75.0Hz,1H),5.30–5.26(m,1H),4.66–4.63(m,1H),3.99(d,J＝6.9Hz,2H),3.79–3.75(m,1H),3.73(s,3H),3.59–3.54(m,2H),3.48–3.41(m,1H),2.27–2.25(m,1H),2.04–2.00(m,1H),1.52(d,J＝7.0Hz,3H),1.43(s,9H),1.35–1.30(m,1H),0.71–0.66(m,2H),0.43–0.39(m,2H)；
MS-ESI:m/z 495.8[M+H-100]+.
And step 3: synthesis of Compound (R) -methyl 3- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) pyrrolidine-1-carboxylate hydrochloride
To a solution of the compound (R) -methyl 3- (5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) pyrrolidine-1-carboxylate (362mg,0.61mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 1h and the solvent removed to afford 323mg of a white solid, yield: 99 percent.
1H NMR(600MHz,CD3OD):ppm7.79(s,1H),7.71(d,J＝8.2Hz,1H),7.32(d,J＝8.3Hz,1H),6.91(t,JF-H＝74.8Hz,1H),5.17–5.15(m,1H),4.63–4.62(m,1H),4.03(d,J＝6.8Hz,2H),3.76–3.74(m,1H),3.71(s,3H),3.63–3.61(m,1H),3.50–3.48(m,1H),3.43–3.40(m,1H),2.28–2.26(m,1H),2.13–2.10(m,1H),1.77(d,J＝6.8Hz,3H),1.35–1.33(m,1H),0.69–0.67(m,2H),0.43–0.42(m,2H)；
MS-ESI:m/z 495.8[M+H-HCl]+.
Example 15: (R) -methyl 2- ((5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate hydrochloride
Figure BDA0001052078950000561
Step 1: synthesis of Compound (R) -2- (aminoethyl) piperidine-1-carboxylic acid methyl ester hydrochloride
Triethylamine (1.67mL,12.0mmol) was added dropwise to a solution of N' -carbonyldiimidazole (2.67g,16.0mmol) in anhydrous THF (5mL) at room temperature, and the mixture was cooled to room temperatureStirring, slowly adding methanol (0.65mL,16.0mmol) dropwise, reacting at room temperature for 30min, adding (R) -2-Boc-aminomethyl piperidine (1.00g,3.99mmol) and anhydrous THF (10mL), reacting at 75 deg.C for 17h, adding dilute hydrochloric acid solution (10mL × 3) to wash until the aqueous phase is acidic, extracting with ethyl acetate (15mL × 2), washing the organic phase with saturated sodium bicarbonate solution (10mL × 2), combining the organic phases, and adding anhydrous Na2SO4Drying, removal of the solvent and column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 4/1) gave 232mg of a colourless oil: (R) -methyl 2- ((tert-butoxycarbonylamino) methyl) piperidine-1-carboxylate, yield: 21 percent.
1H NMR(400MHz,CDCl3):ppm4.67(br.s,1H),4.33–4.29(m,1H),4.03–3.98(m,1H),3.68(s,3H),3.55–3.50(m,1H),3.13–3.09(m,1H),2.92–2.88(m,1H),1.63–1.58(m,5H),1.55–1.50(m,1H),1.42(s,9H)；
MS-ESI:m/z 173.1[M+H-100]+.
To a solution of compound (R) -methyl 2- ((tert-butoxycarbonylamino) methyl) piperidine-1-carboxylate (230mg,0.84mmol) in dichloromethane (6mL) was added a solution of HCl in ethyl acetate (4M,6mL), stirred at room temperature for 2.5h, and the solvent was removed to give 176mg of a colorless oil: (R) -2- (aminoethyl) piperidine-1-carboxylic acid methyl ester hydrochloride, yield: 99 percent.
1H NMR(600MHz,CD3OD):ppm4.55–4.52(m,1H),4.11–4.05(m,1H),3.74(s,3H),3.46–3.42(m,1H),3.03–3.00(m,1H),3.00–2.95(m,1H),1.75–1.72(m,2H),1.70–1.68(m,2H),1.63–1.58(m,1H),1.50–1.43(m,1H)；
MS-ESI:m/z 173.2[M+H-HCl]+.
Step 2: synthesis of compound (R) -methyl 2- ((5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), (R) -2- (aminoethyl) piperidine-1-carboxylic acid methyl ester hydrochloride (145mg,0.69mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (154 mg)0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) in dichloromethane (16mL), to this solution N, N-diisopropylethylamine (0.37mL,2.14mmol) was added dropwise at 0 deg.C, stirred at room temperature for 5h, washed with water (10 mL. times.2), and the organic phase was washed with anhydrous Na2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 220mg of a white solid in yield: 66 percent.
1H NMR(400MHz,CDCl3):ppm 7.58(d,J＝1.8Hz,1H),7.56(s,1H),7.23(d,J＝8.1Hz,1H),6.70(t,JF-H＝75.0Hz,1H),5.28–5.25(m,1H),4.54–4.49(m,1H),4.10–4.02(m,1H),3.98(d,J＝6.9Hz,2H),3.83–3.76(m,1H),3.64(s,3H),3.53–3.47(m,1H),3.00–2.94(m,1H),1.71–1.65(m,6H),1.52(d,J＝7.0Hz,3H),1.43(s,9H),1.35–1.30(m,1H),0.71–0.66(m,2H),0.43–0.39(m,2H)；
MS-ESI:m/z 623.4[M+H]+.
And step 3: synthesis of compound (R) -methyl 2- ((5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate hydrochloride
To a solution of the compound (R) -methyl 2- ((5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate (215mg,0.34mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 1.5h and the solvent was removed to afford 193mg of a white solid in yield: 100 percent.
1H NMR(600MHz,CD3OD):ppm 7.78(d,J＝1.1Hz,1H),7.72(dd,J1＝8.3Hz,J2＝1.5Hz,1H),7.33(d,J＝8.3Hz,1H),6.92(t,JF-H＝74.7Hz,1H),5.16–5.12(m,1H),4.62–4.55(m,1H),4.03(d,J＝6.9Hz,2H),4.02–3.99(m,2H),3.58(s,3H),3.16–3.11(m,1H),1.77(d,J＝7.0Hz,3H),1.75–1.72(m,3H),1.70–1.69(m,3H),1.36–1.33(m,1H),0.71–0.68(m,2H),0.45–0.42(m,2H)；
MS-ESI:m/z 523.3[M+H-HCl]+.
Example 16: (S) -methyl 2- ((5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate hydrochloride
Figure BDA0001052078950000581
Step 1: synthesis of Compound (S) -2- (aminomethyl) piperidine-1-carboxylic acid methyl ester hydrochloride
Triethylamine (1.8mL,12.8mmol) and N, N' -Carbonyldiimidazole (CDI) (2.1g,12.8mmol) were dissolved in anhydrous THF (5mL), anhydrous methanol (410mg,12.8mmol) was added, stirring was carried out at room temperature for 10min, tert-butyl (S) - (piperidin-2-ylmethyl) carbamate (800mg,3.7mmol) was added, the reaction was stopped after reacting at 75 ℃ for 24h, the solvent was removed, water (15mL) was added, ethyl acetate (10mL × 3) was extracted, anhydrous sodium sulfate was dried, the solvent was removed, and the concentrate was subjected to column chromatography (eluent: peleluentether/EtOAc (v/v) ═ 3/1), to obtain 36mg of a colorless liquid: (S) -methyl 2- (((tert-butoxycarbonyl) amino) methyl) piperidine-1-carboxylate, yield: 4 percent.
1H NMR(400MHz,CDCl3):ppm4.67(br.s,1H),4.28–4.34(m,1H),3.93–4.07(m,1H),3.69(s,3H),3.43–3.58(m,1H),3.07–3.15(m,1H),2.83–2.96(m,1H),1.50–1.65(m,6H),1.42(m,9H)；
MS-ESI:m/z 217.20[M-55]+.
The compound (S) -methyl 2- (((tert-butoxycarbonyl) amino) methyl) piperidine-1-carboxylate (120mg,0.44mmol) was dissolved in dichloromethane (4mL), a solution of HCl in ethyl acetate (4M,2mL) was added, stirred at room temperature for 50min, and the solvent was removed to give 89mg of a white solid: (S) -2- (aminomethyl) piperidine-1-carboxylic acid methyl ester hydrochloride, yield: 98 percent.
1H NMR(400MHz,CD3OD):ppm 4.51–4.58(m,1H),4.04–4.11(m,1H),3.75(s,3H),3.42–3.48(m,1H),2.97–3.05(m,2H),1.68–1.76(m,4H),1.54–1.65(m,1H),1.43–1.53(m,1H)；
MS-ESI:m/z 173.15[M+H-HCl]+.
Step 2: synthesis of compound (S) -methyl 2- ((5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (200mg,0.43mmol), (S) -2- (aminomethyl) piperidine-1-carboxylic acid methyl ester hydrochloride (89mg,0.43mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (163mg,0.86mmol) and N-hydroxy-7-azabenzotriazole (90mg,0.64mmol) were dissolved in dichloromethane (10mL), to this solution was added dropwise N, N-diisopropylethylamine (0.3mL,1.71mmol) at 0 deg.C, stirred at room temperature for 10h, washed with water (10 mL. times.3), and the organic phase was washed with anhydrous Na.2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: Petroleum ether/EtOAc (v/v) ═ 3/1) afforded 204mg of a white solid, yield: 76 percent.
1H NMR(400MHz,CDCl3):ppm 7.58–7.60(m,2H),7.25(d,J＝8.1Hz,1H),6.72(t,JF-H＝75.1Hz,1H),5.24–5.32(m,1H),4.51–4.56(m,1H),4.01–4.09(m,1H),4.00(d,J＝6.9Hz,2H),3.80–3.88(m,1H),3.67(s,3H),3.46–3.55(m,1H),2.95–3.02(m,1H),1.65–1.73(m,6H),1.54(d,J＝6.9Hz,3H),1.45(s,9H),1.32–1.39(m,1H),0.68–0.73(m,2H),0.41–0.45(m,2H)；
MS-ESI:m/z 623.80[M+H]+.
And step 3: synthesis of compound (S) -methyl 2- ((5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate hydrochloride
The compound methyl (S) -2- ((5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate (200mg,0.32mmol) was dissolved in dichloromethane (4mL), a solution of HCl in ethyl acetate (4M,4mL) was added, stirred at room temperature for 2h, the solvent was removed to give 177mg of a white solid, yield: 99 percent.
1H NMR(600MHz,CD3OD):ppm7.77(s,1H),7.71(d,J＝8.3Hz,1H),7.32(d,J＝8.3Hz,1H),6.91(t,JF-H＝74.7Hz,1H),5.11–5.15(m,1H),4.52–4.60(m,1H),4.03(d,J＝6.9Hz,2H),3.97–4.00(m,1H),3.56(s,3H),3.11–3.15(m,1H),1.76(d,J＝6.8Hz,3H),1.68–1.72(m,6H),1.40–1.47(m,2H),1.33–1.37(m,1H),0.67–0.70(m,2H),0.41–0.44(m,2H)；
MS-ESI:m/z 523.80[M+H-HCl]+.
Example 17: 5- ((S) -1-aminoethyl) -N- ((R) -1- (cyclopropylcarbonyl) pyrrolidin-3-yl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride
Figure BDA0001052078950000591
Step 1: synthesis of Compound (R) - (3-Aminopyrrolidin-1-yl) (cyclopropyl) methanone
N, N-diisopropylethylamine (2.8mL,16.10mmol) was added dropwise to a solution of R-1-Boc-3-aminopyrrolidine (1.00g,5.37mmol) in dichloromethane (15mL) at room temperature, the mixture was stirred at room temperature, benzyl chloroformate (1.47mL,10.7mmol) was added dropwise, the mixture was reacted at room temperature for 6 hours, water (10 mL. times.2) was added and the organic phase was washed with anhydrous Na2SO4Drying, removing the solvent, and subjecting the concentrated solution to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 3/1), to give 1.72g of a colorless liquid: (R) -3- (benzyloxycarbonylamino) pyrrolidine-1-carboxylic acid tert-butyl ester, yield: 100 percent.
1H NMR(400MHz,CDCl3):ppm 7.37–7.33(m,5H),5.09(s,2H),4.96–4.94(m,1H),4.24–4.22(m,1H),3.61–3.56(m,1H),3.40–3.35(m,2H),3.20–3.17(m,1H),2.13–2.09(m,1H),1.85–1.81(m,1H),1.45(s,9H)；
MS-ESI:m/z 221.1[M+H-100]+.
To a solution of compound (R) -tert-butyl 3- (benzyloxycarbonylamino) pyrrolidine-1-carboxylate (1.72g,5.37mmol) in dichloromethane (6mL) was added a solution of HCl in ethyl acetate (4M,6mL), stirred at room temperature for 2h, and the solvent was removed to give 1.38g of a pale yellow viscous substance: (R) -pyrrolidin-3-yl-carbamic acid benzyl ester hydrochloride, yield: 100 percent.
1H NMR(400MHz,CD3OD):ppm7.37–7.36(m,4H),7.34–7.32(m,1H),5.11(s,2H),4.31–4.29(m,1H),3.51–3.44(m,2H),3.40–3.35(m,1H),3.29–3.27(m,1H),2.35–2.26(m,1H),2.09–2.03(m,1H)；
MS-ESI:m/z 221.1[M+H-HCl]+.
Dissolving compound (R) -pyrrolidine-3-ylcarbamic acid benzyl ester hydrochloride (600mg,2.34mmol), cyclopropylcarboxylic acid (0.22mL,2.80mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (672mg,3.51mmol) and N-hydroxy-7-azabenzotriazole (795mg,5.84mmol) in dichloromethane (16mL), adding N, N-diisopropylethylamine (1.6mL,9.35mmol) dropwise to the solution at 0 deg.C, stirring at room temperature for 17h, adding water (10 mL. times.3) and washing the organic phase with anhydrous Na2SO4Drying, removal of the solvent and column chromatography of the concentrate (eluent: dichloromethane/methanol (v/v) ═ 50/1) gave 416mg of a white viscous mass: benzyl (R) - (1- (cyclopropylcarbonyl) pyrrolidin-3-yl) carbamate, yield: 61 percent.
1H NMR(400MHz,CDCl3):ppm 7.35–7.30(m,5H),5.10(s,2H),4.35–4.26(m,1H),3.94–3.90,3.72–3.65(m,m,0.5H,1.5H),3.58–3.50,3.42–3.38(m,m,1.5H,0.5H),2.27–2.10(m,1H),2.04–1.99,1.84–1.79(m,m,0.5H,0.5H),1.62–1.53(m,1H),0.99–0.96(m,2H),0.78–0.73(m,2H)；
MS-ESI:m/z 289.3[M+H]+.
To a solution of compound (R) benzyl (1- (cyclopropylcarbonyl) pyrrolidin-3-yl) carbamate (384mg,1.33mmol) in methanol (10mL) was added Pd/C (40mg, 10%), reacted with hydrogen at room temperature for 2h, filtered over celite, and the filtrate was spun dry to give 180mg of a colorless liquid: (R) - (3-aminopyrrolidin-1-yl) (cyclopropyl) methanone, yield: 87 percent.
1H NMR(400MHz,CD3OD):ppm 3.92–3.85(m,1H),3.77–3.71(m,1H),3.65–3.54(m,2H),3.46–3.39(m,1H),3.22–3.18(m,1H),2.23–2.09(m,1H),1.89–1.73(m,2H),0.92–0.87(m,2H),0.86–0.82(m,2H)；
MS-ESI:m/z 155.3[M+H]+.
Step 2: synthesis of Compound tert-butyl ((S) -1- (4- (((R) -1- (cyclopropylcarbonyl) pyrrolidin-3-yl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (300mg,0.64mmol), (R) - (3-aminopyrrolidin-1-yl) (cyclopropyl) methanone (119mg,0.77mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (184mg,0.96mmol) and N-hydroxy-7-azabenzotriazole (218mg,1.60mmol) were dissolved in dichloromethane (16mL), N-diisopropylethylamine (0.45mL,2.56mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 6 hours, washed with water (10 mL. times.2), anhydrous Na for organic phase2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/3) afforded 342mg of a white solid in yield: 87 percent.
1H NMR(400MHz,CDCl3):ppm 7.59–7.57(m,1H),7.55(s,1H),7.24(d,J＝8.4Hz,1H),6.71(t,JF-H＝75.0Hz,1H),5.31–5.27(m,1H),4.76–4.63(m,1H),4.09–4.04,3.85–3.78(m,m,0.5H,1.5H),3.99(d,J＝6.9Hz,2H),3.73–3.57(m,2H),2.41–2.36,2.04–2.00(m,m,0.5H,0.5H),2.30–2.20(m,1H),1.66–1.57(m,1H),1.54–1.52(m,3H),1.43(s,9H),1.37–1.30(m,1H),1.07–1.01(m,2H),0.82–0.77(m,2H),0.71–0.66(m,2H),0.43–0.41(m,2H)；
MS-ESI:m/z 605.4[M+H]+.
And step 3: synthesis of Compound 5- ((S) -1-aminoethyl) -N- ((R) -1- (cyclopropylcarbonyl) pyrrolidin-3-yl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride
To a solution of the compound tert-butyl ((S) -1- (4- (((R) -1- (cyclopropylcarbonyl) pyrrolidin-3-yl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (336mg,0.56mmol) in dichloromethane (6mL) was added a solution of HCl in ethyl acetate (4M,5mL), stirred at room temperature for 1h and the solvent removed to give 300mg of a white solid in yield: 99 percent.
1H NMR(600MHz,CD3OD):ppm7.80(s,1H),7.73(d,J＝8.2Hz,1H),7.33(d,J＝8.3Hz,1H),6.92(t,JF-H＝74.7Hz,1H),5.20–5.15(m,1H),4.77–4.74,4.67–4.65(m,m,0.5H,0.5H),4.13–4.11,3.99–3.95(m,m,0.5H,0.5H),4.04(d,J＝6.9Hz,2H),3.87–3.81(m,1H),3.76–3.66(m,1H),3.57–3.48(m,1H),2.43–2.39,2.16–2.13(m,m,0.5H,0.5H),2.31–2.24(m,1H),1.88–1.84,1.82–1.80(m,m,0.5H,0.5H),1.79–1.77(m,3H),1.37–1.34(m,1H),0.94–0.91(m,2H),0.89–0.86(m,2H),0.71–0.68(m,2H),0.45–0.42(m,2H)；
MS-ESI:m/z 505.9[M+H-HCl]+.
Example 18: (S) -3- ((5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) pyrrolidine-1-carboxylic acid methyl ester hydrochloride
Figure BDA0001052078950000611
Step 1: synthesis of compound (S) -3- (aminomethyl) pyrrolidine-1-carboxylic acid methyl ester hydrochloride
Adding triethylamine (1.18mL,8.45mmol) dropwise into a solution of N' -N-carbonyldiimidazole (2.12g,12.7mmol) in anhydrous THF (5mL) at room temperature, stirring at room temperature, slowly adding methanol (0.51mL,12.7mmol) dropwise, reacting at room temperature for 30min, adding (R) -3-N-Boc-aminomethyl pyrrolidine hydrochloride (1.00g,4.22mmol), reacting at 75 ℃ for 16h, adding a dilute hydrochloric acid solution (10 mL. times.3) to wash until the aqueous phase is acidic, extracting with ethyl acetate (15 mL. times.2), washing the organic phase with a saturated sodium bicarbonate solution (10 mL. times.2), combining the organic phases, and adding anhydrous Na2SO4Drying, removal of the solvent and column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 1.02g of a colourless oil: (S) -3- ((tert-butoxycarbonylamino) methyl) pyrrolidine-1-carboxylic acid methyl ester, yield: 93 percent.
1H NMR(400MHz,CDCl3):ppm 3.68(s,3H),3.54–3.44(m,2H),3.37–3.29(m,1H),3.15–3.02(m,3H),2.42–2.34(m,1H),2.00–1.95(m,1H),1.63–1.59(m,1H),1.43(s,9H)；
MS-ESI:m/z 159.20[M+H-100]+.
To a solution of compound (S) -methyl 3- ((tert-butoxycarbonylamino) methyl) pyrrolidine-1-carboxylate (1.02g,3.95mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,6mL), stirred at room temperature for 2.5h, and the solvent was removed to give 769mg of a white viscous: (S) -3- (aminomethyl) pyrrolidine-1-carboxylic acid methyl ester hydrochloride, yield: 100 percent.
1H NMR(400MHz,CD3OD):ppm 3.71(s,3H),3.68–3.65(m,1H),3.58–3.52(m,1H),3.43–3.36(m,1H),3.16–3.09(m,1H),3.05(d,J＝7.4Hz,2H),2.58–2.50(m,1H),2.20–2.13(m,1H),1.78–1.70(m,1H)；
MS-ESI:m/z 159.3[M+H-HCl]+.
Step 2: synthesis of compound (S) -methyl 3- ((5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) pyrrolidine-1-carboxylate
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), (S) -3- (aminomethyl) pyrrolidine-1-carboxylic acid methyl ester hydrochloride (135mg,0.69mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (154mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in dichloromethane (16mL), N-diisopropylethylamine (0.37mL,2.14mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 17 hours, washed with water (10 mL. times.2), anhydrous Na for organic phase2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/2) afforded 247mg of a white solid in yield: 76 percent.
1H NMR(400MHz,CDCl3):ppm 7.58(d,J＝8.3Hz,1H),7.55(s,1H),7.24(d,J＝8.4Hz,1H),6.71(t,JF-H＝75.0Hz,1H),5.30–5.22(m,1H),3.99(d,J＝6.8Hz,2H),3.70(s,3H),3.59–3.48(m,3H),3.45–3.35(m,2H),3.25–3.14(m,1H),2.61–2.55(m,1H),2.12–2.06(m,1H),1.78–1.70(m,1H),1.53(d,J＝7.0Hz,3H),1.43(s,9H),1.36–1.31(m,1H),0.72–0.67(m,2H),0.42–0.39(m,2H)；
MS-ESI:m/z 509.9[M+H-100]+.
And step 3: synthesis of compound (S) -3- ((5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) pyrrolidine-1-carboxylic acid methyl ester hydrochloride
To a solution of compound (S) -3- ((5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) pyrrolidine-1-carboxylic acid methyl ester (240mg,0.39mmol) in dichloromethane (6mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 1h, and the solvent was removed to give 214mg of a white solid in yield: 99 percent.
1H NMR(600MHz,CD3OD):ppm7.80(s,1H),7.73(d,J＝8.3Hz,1H),7.33(d,J＝8.3Hz,1H),6.92(t,JF-H＝74.8Hz,1H),5.18–5.15(m,1H),4.04(d,J＝6.9Hz,2H),3.70(s,3H),3.56–3.52(m,2H),3.47(d,J＝7.2Hz,2H),3.42–3.38(m,1H),3.23–3.19(m,1H),2.62–2.58(m,1H),2.10–2.05(m,1H),1.78(d,J＝7.0Hz,3H),1.81–1.75(m,1H),1.38–1.33(m,1H),0.71–0.68(m,2H),0.45–0.43(m,2H)；
MS-ESI:m/z 509.3[M+H-HCl]+.
Example 19: 3- ((5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylic acid methyl ester hydrochloride
Figure BDA0001052078950000621
Step 1: synthesis of compound 3- (aminomethyl) piperidine-1-carboxylic acid methyl ester hydrochloride
Adding triethylamine (1.30mL,9.33mmol) dropwise to a solution of N' -N-carbonyldiimidazole (2.34g,14.0mmol) in anhydrous THF (5mL) at room temperature, stirring at room temperature, slowly adding methanol (0.57mL,14.0mmol) dropwise, reacting at room temperature for 30min, adding 3-Boc-aminomethylpiperidine (1.00g,4.67mmol) dropwise, reacting at 75 ℃ for 17h, washing with a dilute hydrochloric acid solution (10 mL. times.3) until the aqueous phase becomes acidic, extracting with ethyl acetate (15 mL. times.2), washing the organic phase with a saturated sodium bicarbonate solution (10 mL. times.2), combining the organic phases, adding anhydrous Na2SO4Drying, removal of the solvent and column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 1.13g of a colourless oil: methyl 3- ((tert-butoxycarbonylamino) methyl) piperidine-1-carboxylate, yield: 88 percent。
1H NMR(400MHz,CDCl3):ppm 4.70–4.60(m,1H),3.92–3.89(m,1H),3.86–3.77(m,1H),3.68(s,3H),3.10–2.90(m,3H),2.75–2.66(m,1H),1.81–1.77(m,1H),1.69–1.63(m,2H),1.43(s,9H),1.21–1.13(m,1H)；
MS-ESI:m/z 173.1[M+H-100]+.
To a solution of compound methyl 3- ((tert-butoxycarbonylamino) methyl) piperidine-1-carboxylate (1.13g,4.15mmol) in dichloromethane (6mL) was added a solution of HCl in ethyl acetate (4M,6mL), stirred at room temperature for 2.5h, and the solvent was removed to give 866mg of a colorless oil: 3- (aminomethyl) piperidine-1-carboxylic acid methyl ester hydrochloride, yield: 100 percent.
1H NMR(400MHz,CD3OD):ppm 4.07–4.04(m,1H),3.98–3.89(m,1H),3.71(s,3H),3.05–2.93(m,1H),2.89–2.85(m,2H),2.81–2.75(m,1H),1.95–1.91(m,1H),1.88–1.81(m,1H),1.78–1.73(m,1H),1.55–1.46(m,1H),1.38–1.31(m,1H)；
MS-ESI:m/z 173.2[M+H-HCl]+.
Step 2: synthesis of methyl 3- ((5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), methyl 3- (aminomethyl) piperidine-1-carboxylate hydrochloride (145mg,0.69mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (154mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in dichloromethane (16mL), to this solution was added dropwise N, N-diisopropylethylamine (0.37mL,2.14mmol) at 0 deg.C, stirred at room temperature for 17h, washed with water (10 mL. times.2), and the organic phase was washed with anhydrous Na.2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: dichloromethane/methanol (v/v) ═ 60/1) afforded 205mg of a pale yellow solid, yield: 61 percent.
1H NMR(400MHz,CDCl3):ppm7.59(dd,J1＝8.3Hz,J2＝1.8Hz,1H),7.55(s,1H),7.24(d,J＝8.3Hz,1H),6.70(t,JF-H＝75.0Hz,1H),5.30–5.22(m,1H),3.98(d,J＝6.9Hz,2H),3.92–3.85(m,1H),3.69(s,3H),3.46–3.26(m,2H),2.99–2.92(m,1H),2.85–2.75(m,1H),1.91–1.84(m,2H),1.73–1.70(m,1H),1.52(d,J＝7.0Hz,3H),1.43(s,9H),1.36–1.31(m,1H),0.71–0.67(m,2H),0.43–0.39(m,2H)；
MS-ESI:m/z 623.4[M+H]+.
And step 3: synthesis of Compound methyl 3- ((5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate hydrochloride
To a solution of the compound methyl 3- ((5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate (200mg,0.32mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 1.5h and the solvent was removed to give 178mg of a white solid in yield: 99 percent.
1H NMR(600MHz,CD3OD):ppm 7.81(d,J＝1.5Hz,1H),7.73(dd,J1＝8.3Hz,J2＝1.4Hz,1H),7.34(d,J＝8.3Hz,1H),6.93(t,JF-H＝74.8Hz,1H),5.18–5.15(m,1H),4.04(d,J＝7.0Hz,2H),4.03–4.01(m,1H),3.94–3.91(m,1H),3.68(s,3H),3.35–3.33(m,2H),3.00–2.90(m,1H),2.79–2.75(m,1H),1.91–1.87(m,2H),1.78(d,J＝7.0Hz,3H),1.76–1.74(m,1H),1.51–1.45(m,1H),1.39–1.35(m,1H),1.33–1.31(m,1H),0.71–0.68(m,2H),0.45–0.42(m,2H)；
MS-ESI:m/z 523.9[M+H-HCl]+.
Example 20: 2- ((5- ((S) -1-amino-2-methylpropyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylic acid methyl ester hydrochloride
Figure BDA0001052078950000631
Step 1: synthesis of methyl 5- (1- ((tert-butoxycarbonyl) amino) -2-methylpropyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylate, a compound
Dissolving N, N' -Carbonyldiimidazole (CDI) (1.20g,7.5mmol) in anhydrous THF (10mL) at room temperature, slowly adding (S) -2- ((tert-butoxycarbonyl) amino) -3-methylbutyric acid (1.4g,6.3mmol), stirring at room temperature for 20min, adding methyl 2- (((3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) (methylthio) methylene) amino) acetate (1.5g,4.2mmol), slowly dropwise adding a THF solution of potassium hexamethyldisilazide (1.0M,13mL,13.0mmol) at-78 deg.C, stopping after 1.5h of reaction, adding water (25mL) to quench the reaction, extracting with ethyl acetate (25 mL. times.3), combining the organic phases, and adding anhydrous Na2SO4Drying, removing the solvent, and subjecting the concentrated solution to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 5/1) to give 1.00g of a white solid, yield: and 47 percent.
1H NMR(400MHz,CDCl3):ppm 7.60–7.64(m,2H),7.23(d,J＝8.3Hz,1H),6.70(t,JF-H＝75.1Hz,1H),5.86–5.89(m,1H),5.07–5.12(m,1H),3.98(s,3H),3.97(d,J＝7.1Hz,2H),2.12–2.19(m,1H),1.44(s,9H),1.29–1.35(m,1H),1.05(d,J＝6.5Hz,3H),0.89(d,J＝6.6Hz,3H),0.65–0.70(m,2H),0.37–0.41(m,2H)；
MS-ESI:m/z 511.30[M+H]+.
Step 2: synthesis of the compound (S) -5- (1- ((tert-butoxycarbonyl) amino) -2-methylpropyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid
The compound methyl (S) -5- (1- ((tert-butoxycarbonyl) amino) -2-methylpropyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylate (1.00g,2.0mmol) was dissolved in a mixed solvent of THF (10mL) and water (5mL), lithium hydroxide monohydrate (410mg,9.8mmol) was added thereto, the reaction was stopped after 1 hour at 45 ℃, concentrated hydrochloric acid was added to adjust the pH of the solution to 1, THF was removed, extraction was performed with ethyl acetate (15 mL. times.3), the organic phases were combined, and then anhydrous Na was added2SO4Drying and removal of the solvent gave 960mg of a light red solid in yield: 99 percent.
1H NMR(400MHz,CD3OD):ppm7.81(s,1H),7.67–7.69(m,1H),7.29(d,J＝8.3Hz,1H),6.90(t,JF-H＝74.9Hz,1H),5.25–5.28(m,1H),4.03(d,J＝6.9Hz,2H),2.13–2.23(m,1H),1.44(s,9H),1.33–1.38(m,H),1.08(d,J＝5.6Hz,3H),0.96(d,J＝6.7Hz,3H),0.66–0.71(m,2H),0.41–0.45(m,2H).
And step 3: synthesis of compound methyl 2- ((5- ((S) -1- (tert-butoxycarbonylamino) -2-methylpropyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) -2-methylpropyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (100mg,0.20mmol), methyl 2- (aminomethyl) piperidine-1-carboxylate hydrochloride (55mg,0.26mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (58mg,0.30mmol) and N-hydroxy-7-azabenzotriazole (69mg,0.50mmol) were dissolved in dichloromethane (16mL), N-diisopropylethylamine (0.14mL,0.81mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 16 hours, washed with water (10 mL. times.3), anhydrous Na for organic phase2SO4Drying, removal of the solvent and column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 3/1) gave 97mg of a colorless viscous substance in yield: 74 percent.
1H NMR(400MHz,CDCl3):ppm 7.58–7.56(m,2H),7.23(d,J＝8.2Hz,1H),6.70(t,JF-H＝75.0Hz,1H),4.89–4.83(m,1H),4.54–4.49(m,1H),3.98(d,J＝6.9Hz,2H),3.83–3.79(m,1H),3.64(s,3H),3.51–3.46(m,1H),3.00–2.91(m,1H),2.16–2.11(m,1H),1.71–1.65(m,5H),1.43(s,9H),1.35–1.32(m,1H),1.01(d,J＝6.5Hz,3H),0.85(d,J＝6.6Hz,3H),0.71–0.67(m,2H),0.43–0.40(m,2H)；
MS-ESI:m/z 651.4[M+H]+.
And 4, step 4: synthesis of compound methyl 2- ((5- ((S) -1-amino-2-methylpropyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate hydrochloride
To a solution of compound methyl 2- ((5- ((S) -1- (tert-butoxycarbonylamino) -2-methylpropyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) piperidine-1-carboxylate (92mg,0.14mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 1h and the solvent was removed to give 83mg of a white solid, yield: 99 percent.
1H NMR(600MHz,CD3OD):ppm7.78(s,1H),7.71(d,J＝7.4Hz,1H),7.34(d,J＝8.3Hz,1H),6.92(t,JF-H＝74.7Hz,1H),4.60–4.54(m,1H),4.04(d,J＝6.9Hz,2H),4.01–3.98(m,1H),3.58(s,3H),3.15–3.11(m,1H),2.45–2.43(m,1H),1.76–1.73(m,2H),1.69(d,J＝5.9Hz,3H),1.48–1.42(m,1H),1.38–1.34(m,1H),1.17(d,J＝5.7Hz,3H),1.00(d,J＝6.7Hz,3H),0.71–0.68(m,2H),0.45–0.43(m,2H)；
MS-ESI:m/z 551.9[M+H-HCl]+.
Example 21: methyl 2- ((5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) pyrrolidine-1-carboxylate hydrochloride
Figure BDA0001052078950000651
Step 1: synthesis of compound 2- (aminomethyl) pyrrolidine-1-carboxylic acid methyl ester hydrochloride
Adding N, N-diisopropylethylamine (2.6mL,14.77mmol) dropwise to a solution of 2-Boc-aminomethyl pyrrolidine (740mg,3.69mmol) in dichloromethane (15mL) at room temperature, stirring at room temperature, slowly adding methyl chloroformate (0.71mL,9.24mmol) dropwise, reacting at room temperature for 15h, adding a dilute hydrochloric acid solution (10 mL. times.3), washing until the aqueous phase is acidic, and using anhydrous Na for the organic phase2SO4Drying, removal of the solvent and column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 3/1) gave 811mg of a colourless oil: methyl 2- ((tert-butoxycarbonylamino) methyl) pyrrolidine-1-carboxylate, yield: 85 percent.
1H NMR(400MHz,CDCl3):ppm 3.93–3.88(m,1H),3.70(s,3H),3.37–3.19(m,4H),1.93–1.75(m,4H),1.43(s,9H)；
MS-ESI:m/z 159.2[M+H-100]+.
To a solution of compound methyl 2- ((tert-butoxycarbonylamino) methyl) pyrrolidine-1-carboxylate (772mg,2.99mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,5mL), stirred at room temperature for 2.5h, and the solvent was removed to give 581mg of a colorless oil: 2- (aminomethyl) pyrrolidine-1-carboxylic acid methyl ester hydrochloride, yield: 99 percent.
1H NMR(400MHz,CD3OD):ppm 4.14–4.09(m,1H),3.74(s,3H),3.55–3.48(m,1H),3.47–3.41(m,1H),3.13–3.03(m,2H),2.18–2.11(m,1H),1.98–1.91(m,2H),1.85–1.77(m,1H)；
MS-ESI:m/z 159.2[M+H-HCl]+.
Step 2: synthesis of methyl 2- ((5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) pyrrolidine-1-carboxylate
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), methyl 2- (aminomethyl) pyrrolidine-1-carboxylate hydrochloride (135mg,0.69mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (154mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in dichloromethane (16mL), to this solution was added dropwise N, N-diisopropylethylamine (0.37mL,2.14mmol) at 0 deg.C, stirred at room temperature for 5h, washed with water (10 mL. times.2), and the organic phase was washed with anhydrous Na.2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 222mg of a white solid in yield: 68 percent.
1H NMR(400MHz,CDCl3):ppm 7.60–7.54(m,2H),7.23(d,J＝8.4Hz,1H),6.70(t,JF-H＝75.0Hz,1H),5.30–5.22(m,1H),4.11–4.07(m,1H),3.98(d,J＝6.7Hz,2H),3.74(s,3H),3.56–3.43(m,4H),2.04–1.95(m,2H),1.90–1.85(m,2H),1.52(d,J＝6.8Hz,3H),1.43(s,9H),1.35–1.31(m,1H),0.71–0.66(m,2H),0.42–0.39(m,2H)；
MS-ESI:m/z 609.8[M+H]+.
And step 3: synthesis of Compound methyl 2- ((5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) pyrrolidine-1-carboxylate hydrochloride
To a solution of compound methyl 2- ((5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) pyrrolidine-1-carboxylate (216mg,0.35mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 1.5h and the solvent was removed to give 190mg of a white solid, yield: 98 percent.
1H NMR(600MHz,CD3OD):ppm 7.80(s,1H),7.73(dd,J1＝8.3Hz,J2＝1.7Hz,1H),7.33(d,J＝8.3Hz,1H),6.92(t,JF-H＝74.7Hz,1H),5.17–5.13(m,1H),4.18–4.14(m,1H),4.04(d,J＝6.9Hz,2H),3.71(s,3H),3.59–3.49(m,2H),3.47–3.42(m,2H),2.05–2.02(m,2H),1.96–1.90(m,2H),1.78(d,J＝7.0Hz,3H),1.37–1.34(m,1H),0.71–0.68(m,2H),0.45–0.42(m,2H)；
MS-ESI:m/z 509.4[M+H-HCl]+.
Example 22: (S) -4- (5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -4-cyanopiperidine-1-carboxylic acid methyl ester hydrochloride
Figure BDA0001052078950000661
Step 1: synthesis of Compound 4-oxopiperidine-1-carboxylic acid methyl ester
Dissolving compound 4-piperidone hydrochloride monohydrate (11.0g,71.6mmol) in N, N-dimethylformamide (40mL), adding N, N-diisopropylethylamine (31mL,178mmol) at room temperature, stirring for reaction for 15min, adding methyl chloroformate (8.2mL,110mmol) in an ice bath, continuing reaction for 2h at room temperature, removing solvent, adding water (50mL) to wash the solid, extracting with ethyl acetate (20mL × 3), and using anhydrous Na as an organic phase2SO4Drying and removal of the solvent gave 8.3g of a light brown liquid, yield: 74 percent.
1H NMR(600MHz,CDCl3):ppm 3.76-3.80(m,4H),3.76(s,3H),2.46-2.48(m,4H)；
MS-ESI:m/z 158.20[M+H]+.
Step 2: synthesis of compound 4-amino-4-cyanopiperidine-1-carboxylic acid methyl ester
Dissolving compound 4-oxopiperidine-1-carboxylic acid methyl ester (2.0g,13mmol) in toluene (15mL), adding trimethylsilyl cyanide (2.4mL,19mmol) and aluminum trichloride (370mg,2.8mmol) at room temperature, reacting at 45 ℃ for 2h, adding methanolic ammonia solution (7.0M,30mL), stopping the reaction for 2h, removing solvent, washing the solid with water (30mL), extracting with ethyl acetate (20 mL. times.3), and extracting the organic phase with anhydrous Na2SO4Drying and removal of the solvent gave 1.9g of a pale yellow solid in yield: 81 percent.
1H NMR(400MHz,DMSO-d6):ppm3.69-3.75(m,2H),3.59(s,3H),3.12-3.17(m,2H),2.66(br.s,2H),1.86-1.91(m,2H),1.50-1.57(m,2H).
And step 3: synthesis of methyl compound (S) -4- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -4-cyanopiperidine-1-carboxylate
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (200mg,0.43mmol), methyl 4-amino-4-cyanopiperidine-1-carboxylate (78mg,0.43mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (336mg,1.75mmol) and N-hydroxy-7-azabenzotriazole (88mg,0.65mmol) were dissolved in dichloromethane (5mL), n, N-diisopropylethylamine (0.4mL,2.0mmol) was added dropwise to the solution at 0 deg.C, stirred at room temperature for 10h, washed with water (10 mL. times.3), and the organic phase was washed with anhydrous Na.2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: Petroleum ether/EtOAc (v/v) ═ 3/1) afforded 137mg of a white solid, yield: 51 percent.
1H NMR(400MHz,CDCl3):ppm 7.60(dd,J1＝8.3Hz,J2＝1.9Hz,1H),7.55(d,J＝1.7Hz,1H),7.40(br.s,1H),7.26(d,J＝8.3Hz,1H),6.73(t,JF-H＝75.0Hz,1H),6.32(br.s,1H),5.24-5.32(m,1H),4.07-4.21(m,2H),4.00(d,J＝6.9Hz,2H),3.75(s,3H),3.36-4.21(m,2H),2.56-2.62(m,2H),1.95-2.00(m,2H),1.57(d,J＝7.0Hz,3H),1.39(s,9H),1.30-1.37(m,1H),0.69-0.74(m,2H),0.41-0.45(m,2H)；
MS-ESI:m/z 656.20[M+Na]+.
And 4, step 4: synthesis of compound (S) -4- (5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -4-cyanopiperidine-1-carboxylic acid methyl ester hydrochloride
The compound methyl (S) -4- (5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -4-cyanopiperidine-1-carboxylate (65mg,0.14mmol) was dissolved in dichloromethane (3mL), an ethyl acetate solution of HCl (4M,2mL) was added, and the mixture was stirred at room temperature for 30min, and the solvent was removed to give 53mg of a pale yellow solid, yield: 90 percent.
1H NMR(600MHz,CD3OD):ppm7.82(s,1H),7.74(d,J＝8.3Hz,1H),7.34(d,J＝8.3Hz,1H),6.73(t,JF-H＝74.7Hz,1H),5.23-5.27(m,1H),4.07-4.09(m,2H),4.05(d,J＝6.9Hz,2H),3.74(s,3H),3.30-3.40(m,2H),2.50-2.55(m,2H),2.04-2.10(m,2H),1.79(d,J＝7.0Hz,3H),1.33-1.39(m,1H),0.68-0.71(m,2H),0.43-0.45(m,2H)；
MS-ESI:m/z 534.20[M+H-HCl]+.
Example 23: (S) -4- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) -4-hydroxypiperidine-1-carboxylic acid methyl ester hydrochloride
Figure BDA0001052078950000671
Step 1: synthesis of Compound 4-hydroxy-4- (nitromethyl) piperidine-1-carboxylic acid methyl ester
Dissolving the compound methyl 4-oxopiperidine-1-carboxylate (500mg,3.18mmol) and nitromethane (0.4mL,7mmol) in methanol (5mL), adding aqueous sodium hydroxide (0.3mL,0.3mmol) while cooling on ice, reacting at room temperature for 4h, removing the solvent, adding water (5mL), extracting with ethyl acetate (10 mL. times.3), and extracting the organic phase with anhydrous Na2SO4Drying and removal of the solvent gave 566mg of a pale yellow solid, yield: 81 percent.
MS-ESI:m/z 219.25[M+H]+.
Step 2: synthesis of Compound 4- (aminomethyl) -4-hydroxypiperidine-1-carboxylic acid methyl ester
The compound methyl 4-hydroxy-4- (nitromethyl) piperidine-1-carboxylate (500mg,3.18mmol) was dissolved in methanol (5mL), Pd/C (10%, 100mg) was added, hydrogen was bubbled through, reaction was carried out at room temperature for 12h, suction filtration, filtrate was concentrated to give 487mg of a colorless liquid, yield: 100 percent.
MS-ESI:m/z 189.20[M+H]+.
And step 3: synthesis of compound (S) -methyl 4- ((5- (1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) -4-hydroxypiperidine-1-carboxylate
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (240mg,0.51mmol), methyl 4- (aminomethyl) -4-hydroxypiperidine-1-carboxylate (106mg,0.56mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (396mg,2.07mmol) and N-hydroxy-7-azabenzotriazole (106mg,0.78mmol) were dissolved in dichloromethane (10mL), n, N-diisopropylethylamine (0.45mL,2.6mmol) was added dropwise to the solution at 0 deg.C, stirred at room temperature for 10h, washed with water (10 mL. times.3), and the organic phase was washed with anhydrous Na.2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: petroleumeher/EtOAc (v/v) ═ 2/1) afforded 238mg of a white solid in yield: 72 percent.
1H NMR(400MHz,CDCl3):ppm 7.59(dd,J1＝8.3Hz,J2＝1.8Hz,1H),7.56(d,J＝1.6Hz,1H),7.26(d,J＝8.3Hz,1H),6.72(t,JF-H＝75.0Hz,1H),5.26-5.35(m,1H),3.99(d,J＝6.9Hz,2H),3.84-3.98(m,2H),3.71(s,3H),3.46-3.55(m,2H),3.26-3.32(m,2H),1.64-1.70(m,2H),1.56-1.62(m,2H),1.54(d,J＝7.0Hz,3H),1.44(s,9H),1.30-1.39(m,1H),0.69-0.73(m,2H),0.41-0.45(m,2H)；
MS-ESI:m/z 661.40[M+Na]+.
And 4, step 4: synthesis of compound (S) -4- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) -4-hydroxypiperidine-1-carboxylic acid methyl ester hydrochloride
The compound (S) -methyl 4- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) -4-hydroxypiperidine-1-carboxylate (72mg,0.11mmol) was dissolved in dichloromethane (3mL), a solution of HCl in isopropanol (25%, 2mL) was added, and stirring was carried out at room temperature for 30min, the solvent was removed to give 59mg of a white solid, yield: 91 percent.
1H NMR(600MHz,CD3OD):ppm7.79(s,1H),7.73(d,J＝8.3Hz,1H),7.34(d,J＝8.2Hz,1H),6.92(t,JF-H＝74.7Hz,1H),5.15-5.18(m,1H),4.04(d,J＝6.9Hz,2H),3.85-3.87(m,2H),3.69(s,3H),3.48(s,2H),3.24-3.33(m,2H),1.77(d,J＝6.9Hz,3H),1.59-1.65(m,4H),1.32-1.40(m,1H),0.67-0.71(m,2H),0.42-0.45(m,2H)；
MS-ESI:m/z 539.40[M+H-HCl]+.
Example 24: (S) -4- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) -4-fluoropiperidine-1-carboxylic acid methyl ester hydrochloride (26)
(S) -4- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid methyl ester hydrochloride (27)
Figure BDA0001052078950000681
Step 1: synthesis of Compound (S) -methyl 4- ((5- (1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) -4-fluoropiperidine-1-carboxylate (26-1) and Compound (S) -methyl 4- ((5- (1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (27-1)
The compound methyl (S) -4- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) -4-hydroxypiperidine-1-carboxylate (780mg,1.22mmol) was dissolved in dichloromethane (8mL), diethylaminosulfur trifluoride (0.3mL,2.0mmol) was added at 0 ℃, reacted at room temperature for 4h, ice water (10mL) was added, dichloromethane was added for extraction (10mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 3/1) to give a mixture of 356mg of a pale yellow solid, yield: and 47 percent.
Compound (26-1): MS-ESI: M/z 663.55[ M + Na ]]+；
Compound (27-1): MS-ESI: M/z 521.40[ M + H-100 ]]+.
Step 2: synthesis of the Compounds (S) -methyl 4- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) -4-fluoropiperidine-1-carboxylate hydrochloride (26) and (S) -methyl 4- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) -5, 6-dihydropyridine-1 (2H) -carboxylate hydrochloride (27)
A mixture (356mg) of methyl compound (S) -4- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) -4-fluoropiperidine-1-carboxylate (26-1) and methyl compound (S) -4- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (27-1) were dissolved in dichloromethane (4mL), HCl in ethyl acetate (4M,4mL) was added, stirred at room temperature for 50min, the solvent was removed, concentrated and preparative separation gave (S) -methyl 4- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) -4-fluoropiperidine-1-carboxylate hydrochloride (26), 136mg of a pale yellow solid; and (S) -4- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid methyl ester hydrochloride (27), 107mg of a pale yellow solid.
Compound (26):1H NMR(600MHz,CD3OD):ppm7.81(s,1H),7.74(d,J＝8.3Hz,1H),7.34(d,J＝8.3Hz,1H),6.92(t,JF-H＝74.8Hz,1H),5.17-5.20(m,1H),4.05(d,J＝6.9Hz,2H),3.98-4.00(m,2H),3.71(s,3H),3.65-3.68(m,2H),3.13-3.23(m,2H),1.86-1.92(m,2H),1.79(d,J＝7.0Hz,3H),1.68-1.77(m,2H),1.33-1.39(m,1H),0.68-0.71(m,2H),0.43-0.45(m,2H)；
MS-ESI:m/z 541.40[M+H-HCl]+.
compound (27):1H NMR(600MHz,CD3OD):ppm7.80(s,1H),7.73(d,J＝8.1Hz,1H),7.33(d,J＝8.3Hz,1H),6.92(t,JF-H＝74.8Hz,1H),5.64-5.69(m,1H),5.14-5.19(m,1H),4.04(d,J＝6.9Hz,2H),3.99-4.02(m,2H),3.94-3.98(m,2H),3.71(s,3H),3.57-3.61(m,2H),2.15-2.19(m,2H),1.78(d,J＝6.7Hz,3H),1.31-1.38(m,1H),0.68-0.71(m,2H),0.42-0.45(m,2H)；
MS-ESI:m/z 521.35[M+H-HCl]+.
example 25: (S) -ethyl 2- (1- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) cyclohexyl) acetate hydrochloride
Figure BDA0001052078950000691
Step 1: synthesis of Compound ethyl 2- (1- (aminomethyl) cyclohexyl) acetate hydrochloride
2- (1- (aminomethyl) cyclohexyl) acetic acid (1.5g,8.8mmol) was dissolved in absolute ethanol (10mL), HCl in ethyl acetate (4M,10mL) was added, the reaction was refluxed at 75 ℃ for 10h, and the solvent was removed to give 2.04g of a white solid, yield: 99 percent.
1H NMR(400MHz,CD3OD):ppm 4.18(q,J＝7.1Hz,2H),3.07(s,2H),2.55(s,2H),1.52–1.57(m,7H),1.39–1.47(m,3H),1.29(t,J＝7.1Hz,3H)；
MS-ESI:m/z 200.30[M+H-HCl]+.
Step 2: synthesis of ethyl (S) -2- (1- ((5- (1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) cyclohexyl) acetate, compound
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (400mg,0.86mmol), ethyl 2- (1- (aminomethyl) cyclohexyl) acetate hydrochloride (221mg,0.94mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (495mg,2.58mmol) and N-hydroxy-7-azabenzocarbodiimide hydrochloride (N-hydroxy-N-methyl-phenyl)Triazole (118mg,0.87mmol) is dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.4mL,2.0mmol) is added dropwise to the solution at 0 deg.C, the solution is stirred at room temperature for 4h, the solution is washed with water (10 mL. times.3), and the organic phase is treated with anhydrous Na2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: petroleumeher/EtOAc (v/v) ═ 3/1) afforded 544mg of a pale yellow solid, yield: 94 percent.
1H NMR(400MHz,CDCl3):ppm7.60(dd,J1＝8.3Hz,J2＝1.6Hz,1H),7.57(s,1H),7.23(d,J＝8.3Hz,1H),6.70(t,JF-H＝75.0Hz,1H),5.21-5.28(m,1H),4.19(q,J＝7.1Hz,2H),3.98(d,J＝6.9Hz,2H),3.47–3.49(m,2H),2.38(s,2H),1.52(d,J＝7.0Hz,3H),1.44–1.49(m,10H),1.42(s,9H),1.30-1.36(m,1H),1.30(t,J＝7.1Hz,3H),0.66-0.71(m,2H),0.38-0.42(m,2H)；
MS-ESI:m/z 650.20[M+H]+.
And step 3: synthesis of ethyl acetate hydrochloride, compound (S) -2- (1- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) cyclohexyl) acetate
The compound ethyl (S) -2- (1- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) cyclohexyl) acetate (66mg,0.1mmol) was dissolved in dichloromethane (2mL), a solution of HCl in ethyl acetate (4M,2mL) was added, stirred at room temperature for 1h, the solvent was removed to give 57mg of a white solid, yield: 96 percent.
1H NMR(600MHz,CD3OD):ppm 7.79(s,1H),7.73(dd,J1＝8.3Hz,J2＝1.7Hz,1H),7.34(d,J＝8.3Hz,1H),6.93(t,JF-H＝74.7Hz,1H),5.14-5.18(m,1H),4.21(q,J＝7.1Hz,2H),4.05(d,J＝6.9Hz,2H),3.53(s,2H),2.44(s,2H),1.78(d,J＝7.0Hz,3H),1.43–1.58(m,10H),1.32–1.38(m,1H),1.31(t,J＝7.1Hz,3H),0.68-0.71(m,2H),0.42-0.45(m,2H)；
MS-ESI:m/z 550.30[M+H-HCl]+.
Example 26: 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 6-dioxopiperidin-3-yl) oxazole-4-carboxamide hydrochloride
Figure BDA0001052078950000701
Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 6-dioxopiperidin-3-yl) carbamoyl) oxazol-5-yl) ethyl) carbamate
The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.54mmol), 3-aminopiperidine-2, 6-dione (91mg,0.71mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (311mg,1.62mmol) and N-hydroxy-7-azabenzotriazole (73mg,0.54mmol) were dissolved in dichloromethane (10mL), to this solution were added dropwise N, N-diisopropylethylamine (0.3mL,2.0mmol) at 0 ℃, the mixture was stirred at room temperature for 10 hours, washed with water (10 mL. times.3), and the organic phase was washed with anhydrous Na2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: Petroleum ether/EtOAc (v/v) ═ 3/1) afforded 271mg of a white solid in yield: 88 percent.
1H NMR(400MHz,CDCl3):ppm8.15(s,1H),7.32(d,J＝7.5Hz,1H),7.58(s,1H),7.62(d,J＝8.4Hz,1H),6.73(t,JF-H＝75.0Hz,1H),5.32-5.37(m,1H),4.80-4.85(m,1H),4.01(d,J＝6.9Hz,2H),2.79-2.92(m,2H),2.64-2.69(m,1H),2.01-2.08(m,1H),1.56(d,J＝7.0Hz,3H),1.45(s,9H),1.32-1.38(m,1H),0.70-0.73(m,2H),0.42-0.47(m,2H)；
MS-ESI:m/z 601.10[M+Na]+.
Step 2: synthesis of the Compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 6-dioxopiperidin-3-yl) oxazole-4-carboxamide hydrochloride
The compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 6-dioxopiperidin-3-yl) carbamoyl) oxazol-5-yl) ethyl) carbamate (264mg,0.46mmol) was dissolved in dichloromethane (4mL), HCl in ethyl acetate (4M,4mL) was added and stirred at room temperature for 1h, the solvent was removed to give 232mg of a white solid in yield: 98 percent.
1H NMR(600MHz,CD3OD):ppm7.81(s,1H),7.74(d,J＝8.3Hz,1H),7.34(d,J＝8.3Hz,1H),6.92(t,JF-H＝74.8Hz,1H),5.17-5.23(m,1H),4.90-4.94(m,1H),4.04(d,J＝6.9Hz,2H),2.83-2.89(m,1H),2.74-2.77(m,1H),2.21-2.34(m,2H),1.79(d,J＝7.0Hz,3H),1.33-1.40(m,1H),0.68-0.71(m,2H),0.42-0.45(m,2H)；
MS-ESI:m/z 479.10[M+H-HCl]+.
Example 27: (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((1- (2- (dimethylamino) -2-oxoethyl) cyclohexyl) methyl) oxazole-4-carboxamide hydrochloride
Figure BDA0001052078950000711
Step 1: synthesis of compound (S) -2- (1- ((5- (1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) cyclohexyl) acetic acid
Ethyl acetate (470mg,0.72mmol) and sodium hydroxide (293mg,7.33mmol) were dissolved in a mixed solvent of tetrahydrofuran (5mL) and water (3mL) to react at 70 ℃ for 24h, pH 1 was adjusted with diluted hydrochloric acid, ethyl acetate was added to extract (10mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate to remove the solvent, and 439mg of a white solid was obtained, yield: 98 percent.
MS-ESI:m/z 622.20[M+H]+.
Step 2: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- (((1- (2- (dimethylamino) -2-oxoethyl) cyclohexyl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate
The compound (S) -2- (1- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) cyclohexyl) acetic acid (170mg,0.27mmol), dimethylamine hydrochloride(221mg,2.7mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (162mg,0.85mmol) and N-hydroxy-7-azabenzotriazole (39mg,0.29mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.4mL,2.0mmol) was added dropwise to the solution at 0 deg.C, stirred at room temperature for 10h, washed with water (10 mL. times.3), and the organic phase was washed with anhydrous Na2SO4Drying, removal of the solvent, and column chromatography of the concentrate (eluent: Petroleum ether/EtOAc (v/v) ═ 2/1) afforded 142mg of a white solid, yield: 77 percent.
MS-ESI:m/z 649.30[M+H]+.
And step 3: synthesis of the Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((1- (2- (dimethylamino) -2-oxoethyl) cyclohexyl) methyl) oxazole-4-carboxamide hydrochloride
The compound tert-butyl (S) - (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- (((1- (2- (dimethylamino) -2-oxoethyl) cyclohexyl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (134mg,0.21mmol) was dissolved in dichloromethane (4mL), HCl in ethyl acetate (4M,4mL) was added and stirred at room temperature for 1h to remove the solvent to give 116mg of a white solid in yield: 96 percent.
1H NMR(600MHz,CD3OD):ppm 7.81(s,1H),7.74(dd,J＝8.3,1.6Hz,1H),7.33(d,J＝8.3Hz,1H),6.92(t,JF-H＝74.8Hz,1H),5.14-5.17(m,1H),4.05(d,J＝6.9Hz,2H),3.55-3.61(m,2H),3.19(s,3H),3.03(s,3H),2.51(s,2H),1.78(d,J＝7.0Hz,3H),1.42–1.67(m,10H),1.31–1.37(m,1H),1.31(t,J＝7.1Hz,3H),0.67-0.70(m,2H),0.42-0.44(m,2H)；
MS-ESI:m/z 549.20[M+H-HCl]+.
The compounds shown in table 1 were prepared by analogous synthetic methods to the examples of the invention, and the synthetic methods described in the present invention, starting with the corresponding starting materials:
table 1 Compounds and characterization data thereof
Figure BDA0001052078950000721
Biological assay
Biological example 1
The compound shown in the formula (I) or the formula (II) is subjected to biological test by adopting the following method: (1) compounds were tested for PDE4B2 enzyme inhibition using the BPS manufacturing kit (BPS, 603343) using fluorescence polarization methods according to the manufacturer's instructions. (2) The concentration of PDE4B2 enzyme was prepared to be 83.33pg/μ L, and the final concentration was 27.78pg/μ L; the concentration of a substrate FAM-Cyclic-3 ', 5' -AMP is prepared to be 300nM, the final reaction concentration is 100nM, and the enzyme and substrate diluent use a self-contained buffer PDEAssay buffer of a kit; the Binding Agent uses the kit to carry the Binding Agent for 100-fold dilution for standby. The reaction system is shown in Table 2.
TABLE 2 Compound on PDE4B2 enzyme IC50Detection system
Figure BDA0001052078950000731
3. The detection is carried out by adopting a 384-well plate, a test sample well, a positive control well, a negative control well and a blank well are arranged in the experiment, each sample utilizes the inhibition effect of double-well detection on the PDE4B2 enzyme concentration under 10 concentrations, a PDE4B2 enzyme and FAM-Cyclic-3 ', 5' -AMP substrate reaction well is used as a positive control, a FAM-Cyclic-3 ', 5' -AMP substrate reaction well is used as a negative control, and a buffer well is used as a blank control. After adding corresponding samples, enzyme, substrate and buffer solution into each well in sequence according to the table 2, incubating for 1h in a constant temperature box at 25 ℃, adding 15 mu L of prepared Binding Agent into each well, shaking for 1h in a constant temperature oscillator at 25 ℃, and detecting at the wavelength of FP485/525 by using a PHERAStar FS multifunctional enzyme-linked immunosorbent assay (BMG). The inhibition of PDE4B2 enzyme at various concentrations of compound was plotted using Graph Padprism 5 software to calculate IC50。
The results of the measurement of the inhibitory effect on PDE4B2 enzyme by the compounds provided in the examples of the present invention according to the above-mentioned method are shown in Table 3, and Table 3 shows the results of the measurement of the inhibitory effect on PDE4B2 enzyme by the examples of the present invention.
TABLE 3 results of the measurement of the inhibitory effect of the compounds of the present invention on PDE4B2 enzyme
Example numbering IC50(nM) Example numbering IC50(nM)
Example 2 8.21 Example 3 6.55
Example 6 11.50 Example 7 6.72
Example 9(9-2) 8.23 Example 10 13.80
Example 12 8.73 Example 13 3.11
Example 14 2.94 Example 15 3.94
Example 16 3.42 Example 17 4.06
Example 18 4.34 Example 19 7.93
Example 21 4.93 Example 26 12.33
Example 27 12.03
The data in table 3 show that the compounds of the present invention generally exhibit high inhibitory activity in vitro screening experiments for PDE4B2 enzyme inhibition.
Biological example 2 PK experiment
The compounds of the invention were administered to male rats intravenously (i.v.) and intragastrically (i.g.), respectively, and blood was collected at time points of 0.083, 0.25, 0.5, 1,2,4, 6, 8, 10, 24 and 36h and centrifuged to prepare plasma. The concentration of the compound of the present invention in plasma at each time point was measured by LC/MS/MS, the major pharmacokinetic parameters thereof were calculated, and the PK parameters of the compound of the present invention in rats and the like were examined.
The LC/MS/MS determination method comprises the following steps: the 4000QTRAP series LC/MS/MS mass spectrometer is provided with an Agilent 1200 binary injection pump, a 1290 automatic sampler and a column incubator; ESI source, positive ion MRM mode detection. A waters xbridge C18 chromatography column was used during the analysis; mobile phase (a) was 2mM ammonium formate + 0.1% aqueous formic acid; mobile phase (B) was 2mM ammonium formate + 0.1% formic acid in methanol; the flow rate is 0.4 mL/min; the column temperature is 40 ℃; the sample size was 3. mu.L.
The results show that the compounds have good pharmacological experiment results and certain medicinal properties.

Claims (7)

1. A compound which is a compound of formula (II) or a pharmaceutically acceptable salt of a compound of formula (II):
Figure FDA0002621405580000011
wherein:
w is 0,1, 2 or 3;
v is 0,1, 2 or 3;
t is 0,1, 2 or 3;
y is-N (R)13) -or-CR13R13-；
p is 0,1 or 2;
each R13Independently of each other is hydrogen, deuterium, R14-C(＝O)-、R15R16N-C(＝O)-、R15R16N-C(＝O)-O-、R15R16N-C(＝O)-C1-4Alkylene radical, R14-C(＝O)-N(R15) -or oxo;
each R14Independently of one another is hydrogen, deuterium, C1-4Alkyl radical, C1-4Alkoxy or C3-6A cycloalkyl group;
each R15And R16Independently of one another is hydrogen, deuterium, C1-4Alkyl or C3-6A cycloalkyl group.
2. The compound of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, or a combination thereof.
3. The compound of claim 1, wherein each R13Independently of each other is hydrogen, deuterium, R14-C(＝O)-、R15R16N-C(＝O)-、R15R16N-C(＝O)-O-、R15R16N-C(＝O)-C1-3Alkylene radical, R14-C (═ O) -NH-, or oxo;
each R14Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
each R15And R16Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
4. The compound of claim 1, which is a compound having one of the following structures or a pharmaceutically acceptable salt of a compound having one of the following structures:
Figure FDA0002621405580000021
Figure FDA0002621405580000031
Figure FDA0002621405580000041
5. a pharmaceutical composition comprising a compound of any one of claims 1-4, further comprising at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or vehicle; or/and
it further comprises an additional therapeutic agent that is: sodium pyruvate, doxofylline, roflumilast, apremilast, tetomilast, tuluelast, theophylline, formoterol, salmeterol, fluticasone propionate, salmeterol/fluticasone propionate combinations, rolipram, pyraramite, cilomilast, CDP-840, indacaterol, odaterol, QVA149, midestan, flukurane, salbutamol, carmoterol, budesonide and its epimers, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, mometasone furoate, rofleponide, ciclesonide, ipratropium bromide in combination with salbutamol, oxitropium bromide, tiotropium bromide, glycopyrronium bromide, umecliam bromide, vilanterol, umeclidinium bromide/vilanterium bromide, aclidinium bromide, aldilium/formoterol fumarate, LAS40464, RPD-897, AZ 1009799, RPD-8999, and RPD-8999, OCID-2987, CHF-6001, CR-3465, HPP-737, fluticasone furoate/vilanterol complex, Benralizumab, Tralogenumab, revatolate, or combinations thereof.
6. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 in the manufacture of a medicament for the prevention, treatment or alleviation of a disease or a disorder related to phosphodiesterase type 4.
7. The use according to claim 6, wherein the diseases associated with phosphodiesterase type 4 are respiratory diseases, allergies, inflammations, central nervous system diseases, pulmonary fibrosis or non-insulin dependent diabetes;
wherein the respiratory disease is: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, pulmonary tuberculosis fibrosis, pulmonary cystic fibrosis, acute respiratory distress syndrome or respiratory inflammation; wherein the bronchitis comprises acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse bronchiolitis or obliterative bronchiolitis;
wherein the inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis, or psoriatic arthritis.
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