CN116891437A - Amino acid derivative, pharmaceutical composition, preparation method and application thereof - Google Patents

Amino acid derivative, pharmaceutical composition, preparation method and application thereof Download PDF

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Publication number
CN116891437A
CN116891437A CN202310353536.0A CN202310353536A CN116891437A CN 116891437 A CN116891437 A CN 116891437A CN 202310353536 A CN202310353536 A CN 202310353536A CN 116891437 A CN116891437 A CN 116891437A
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alkyl
amino
group
cycloalkyl
trifluoromethyl
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Inventor
黄悦
俞立挺
骆庆和
傅啸云
范景荣
傅东林
梁妍琦
张智全
杨方龙
王思勤
金磊
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Changchun Genescience Pharmaceutical Co Ltd
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Changchun Genescience Pharmaceutical Co Ltd
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Abstract

The application relates to an amino acid derivative, a pharmaceutical composition, a preparation method and application thereof, and in particular provides a compound shown in a formula I, which has good LRRK2 inhibition effect, can be used for treating or preventing diseases and diseases related to LRRK2, and can be used for preparing medicines for treating the diseases and the diseases.

Description

Amino acid derivative, pharmaceutical composition, preparation method and application thereof
The present application claims priority from a prior application filed on 4/6 2022 to the intellectual property office of China, having patent application number 202210360017.2, entitled "amino acid derivatives, pharmaceutical compositions, methods for their preparation and uses". The entirety of this prior application is incorporated by reference into the present application.
Technical Field
The application belongs to the field of medicine synthesis, and in particular relates to an amino acid derivative, a medicine composition, a preparation method and application thereof.
Background
Parkinson's Disease (PD) is the second most neurodegenerative disease next to alzheimer's disease, whose major pathology is manifested by loss of degeneration of nigral dopaminergic neurons and formation of Lewy bodies. The parkinsonism is clinically manifested as motor symptoms such as resting tremor, bradykinesia, muscle rigidity and disturbance of posture balance, and is often accompanied by non-motor symptoms such as sleep disturbance, autonomic nerve disturbance, mental symptoms and cognitive function impairment. The pathogenesis of the Parkinson disease is not completely elucidated, and is currently widely considered as a result of the combined action of a plurality of factors, and the occurrence of the Parkinson disease is finally caused under the combined action of environmental factors and genetic factors. The complexity and concealment of the disease often results in a clinically unequivocal diagnosis at the early stages of the disease, with symptoms that are difficult to control at the end stage. The role of parkinsonism disease and genetic genes is gradually paid attention to, and as the technology of gene sequencing is mature, gene detection means are widely applied to the parkinsonism diagnosis field, and more than 20 pathogenic genes including Leucine-rich repeat kinase 2 (Leucine-Rich Repeat Kinase 2, LRRK2) have been discovered to date. LRRK2, also known as PARK8, is located on chromosome 12q12 and is approximately 144kb long, contains 51 exons, encodes 2527 amino acids, and is composed of protein domains such as LRR, ras protein complex (ROC), C-terminal repeat (COR) of Ras protein complex, kinase active region (MAPKKK), WD40, and the like. ROC and COR have the role of protein kinase, WD40 is a repeat sequence consisting of every 40 tryptophan and aspartic acids, which region is capable of participating in the interaction of LRRK2 with other proteins, and also capable of reversibly binding to proteins, participating in their signaling and transport. LRRK2 protein, in combination with GTP and protein kinase, can be widely expressed in various tissues and is involved in central nervous system functions such as the striatum and caudate nucleus. Mutation of the LRRK2 gene is a common cause of autosomal dominant inherited parkinson's disease, and is also associated with sporadic parkinson's disease. Several missense mutations have been identified at present, which are distributed over the entire LRRK2 gene segment and affect all predicted functional domains. Preclinical studies have found that there is loss of substantia nigra neurons in parkinsonism caused by mutations in LRRK2, and other pathological manifestations also include the formation of lewy bodies, presumably the LRRK2 protein and the alpha-synuclein may be in a common pathway leading to parkinsonism. Further studies have found that an abnormally increased LRRK2 kinase activity can lead to a 3-4 fold increase in kinase activity, resulting in dopaminergic neuronal damage, greatly increasing the risk of Parkinson's disease. Clinical studies have also found that parkinsonism patients carrying LRRK2 variant genes may develop more rapidly in terms of motor severity. Today, scientists have found that inhibitors of LRRK2 kinase can protect neurons from neurodegeneration induced by overactivation of LRRK2, block increased aggregation of α -synuclein in neurons, inhibit inclusion body formation, and slow down disease progression. LRRK2 is therefore considered a new very potential target for the treatment of parkinson's disease. Clinical trials targeting LRRK2 specific therapies for LRRK2 mutation carriers have begun, highlighting the rapid progress made in this field over the past decade. Advances in established clinical studies have also demonstrated that inhibitors of LRRK2 are promising as potential disease modifying therapies for improving LRRK 2-parkinson's disease. The kinase activity of LRRK2 is important for pathogenesis, and the LRRK2 kinase domain can regulate overall LRRK2 function. Despite advances in the field of central research, there remains a need for inhibitors of LRRK2 receptors that are useful in the treatment of various neurodegenerative diseases such as parkinson's disease, alzheimer's disease, and amyotrophic lateral sclerosis. The application provides an amino acid derivative with a novel structure, and a compound with the structure is found to have good activity.
Disclosure of Invention
To solve the above technical problem, the present invention provides, in a first aspect, a compound represented by formula I, a racemate, a stereoisomer, a tautomer, an isotopic label, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug thereof:
wherein R is 1 Selected from unsubstituted or optionally substituted with 1, 2 or more R 11 Substituted with the following groups: NH (NH) 2 、C 6-20 Aryl, 5-20 membered heteroaryl; each R 11 Identical or different, independently of one another, from C 1-40 Alkyl, halogenated C 1-40 Alkyl, C 3-20 Cycloalkyl, di C 1-40 alkyl-phosphoryl-C 6-20 An aryl group;
R 2 selected from C 1-40 Alkyl, C 1-40 Alkoxy, halo C 1-40 Alkyl, halogen;
R 3 selected from H, C 1-40 Alkyl, C 1-40 An alkoxy group;
alternatively, R 1 、R 2 Together with the atoms to which they are attached form a group of 1, 2 or more R 21 Substituted with the following groups: c (C) 3-20 Cycloalkyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl; each R 21 The same or different, independently of one another, are selected from halogen, CN, oxo (= O), C 1-40 Alkyl, C 3-20 Cycloalkyl;
alternatively, R 2 、R 3 Together with the atoms to which they are attached form a group of 1, 2 or more R 22 Substituted with the following groups: c (C) 3-20 Cycloalkyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl; each R 22 The same or different, independently of one another, are selected from halogen, CN, oxo (= O), C 1-40 Alkyl, C 3-20 Cycloalkyl;
x is selected from N or CH;
R 4 selected from H, halogen, CN, OH, unsubstituted or optionally substituted with 1, 2 or more R 41 Substituted with the following groups: c (C) 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-20 Cycloalkyl, C 1-40 Alkoxy, C 3-20 Cycloalkyl oxy; each R 41 Identical or different, independently of one another, from deuterium, halogen, C 1-40 Alkyl, halogenated C 1-40 Alkyl, C 3-20 Cycloalkyl;
and/or X and one of R 4 Together with the ring atoms to which they are attached and the imino group (NH) form a 5-6 membered heterocyclic group;
m is selected from integers from 0 to 6; for example 1, 2, 3, 4, 5;
ring A is selected from C 6-20 Aryl, 5-20 membered heteroaryl;
e is selected from chemical bonds orR E1 Selected from C 1-40 Alkyl, C 1-40 Alkoxy, halo C 1-40 Alkyl, halogen; g is selected from chemical bond, C 6-20 Aryl or 5-20 membered heteroaryl; n is selected from 0, 1, 2, 3 or 4;
R 5 、R 6 、R 7 、R 8 identical or different, independently of one another, from H, C 1-40 Alkyl, C 1-40 Alkoxy, NH 2 、NH 2 -C 1-40 Alkyl groups being either bound to each other in a ring, or to one of R 4 To form C condensed with ring A 3-20 Cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, or R 5 、R 6 To which the atoms are attached to form C 3-20 Cycloalkyl, 3-20 membered heterocyclyl; and R is 5 、R 6 、R 7 、R 8 At least one of which is NH 2 Or NH 2 -C 1-40 An alkyl group;
y is selected from OR a 、N(R b )(R c )；R a Selected from H, C 1-40 Alkyl orR b 、R c Identical or different, independently of one another, from H, C 1-40 An alkyl group.
According to an embodiment of the invention, R 1 Selected from unsubstituted or optionally substituted with 1, 2 or more R 11 Substituted with the following groups: NH (NH) 2 、C 6-14 An aryl group; each R 11 Identical or different, independently of one another, from C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 3-12 Cycloalkyl, di C 1-12 alkyl-phosphoryl-C 6-14 An aryl group;
R 2 can be selected from C 1-12 Alkyl, C 1-12 Alkoxy, halo C 1-12 Alkyl, halogen;
R 3 can be selected from H, C 1-12 Alkyl, C 1-12 An alkoxy group;
alternatively, R 1 、R 2 And they are connected withThe atoms joined together form a group consisting of 1, 2 or more R 21 Substituted with the following groups: c (C) 3-12 Cycloalkyl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl; each R 21 The same or different, independently of one another, are selected from halogen, CN, oxo (= O), C 1-12 Alkyl, C 3-12 Cycloalkyl;
alternatively, R 2 、R 3 Together with the atoms to which they are attached form a group of 1, 2 or more R 22 Substituted with the following groups: c (C) 3-12 Cycloalkyl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl; each R 22 The same or different, independently of one another, are selected from halogen, CN, oxo (= O), C 1-12 Alkyl, C 3-12 Cycloalkyl groups.
According to an embodiment of the invention, R 1 Selected from unsubstituted or optionally substituted with 1, 2 or more R 11 Substituted with the following groups: NH (NH) 2 Phenyl; each R 11 Identical or different, independently of one another, from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, di C 1-6 Alkyl-phosphoryl-phenyl;
R 2 can be selected from halogenated C 1-6 Alkyl, halogen;
R 3 may be H;
alternatively, R 1 、R 2 Together with the atoms to which they are attached form a group of 1, 2 or more R 21 Substituted 3-8 membered heterocyclyl, 5-8 membered heteroaryl; each R 21 The same or different, independently of one another, from the group halogen, oxo (=o), C 1-6 Alkyl, C 3-6 Cycloalkyl;
alternatively, R 2 、R 3 Together with the atoms to which they are attached form a group of 1, 2 or more R 22 Substituted 3-8 membered heterocyclyl, 5-8 membered heteroaryl; each R 22 The same or different, independently of one another, are selected from halogen, CN, oxo (= O), C 1-6 Alkyl, C 3-6 Cycloalkyl groups.
According to an embodiment of the invention, R 1 Selected from methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino and cyclobutaneAlkylamino, difluoroethylamino, trifluoroethylamino, tolyl, dimethyl-phosphoryl-phenylamino;
R 2 may be selected from trifluoromethyl, F, cl, br;
alternatively, R 1 、R 2 Together with the atoms to which they are attached form a group of 1, 2 or more R 21 Substituted tetrahydropyrrolyl; each R 21 The same or different, independently of one another, from F, oxo (=o), cyclopropyl; for example
Alternatively, R 2 、R 3 Together with the atoms to which they are attached form a group of 1, 2 or more R 22 Substituted with the following groups: tetrahydropyrrolyl, 1H-pyrrolyl; each R 22 The same or different, independently of one another, selected from F, CN, oxo (=o), cyclopropyl; for example
According to an embodiment of the invention, R 4 Selected from H, halogen, CN, unsubstituted or optionally substituted with 1, 2 or more R 41 Substituted with the following groups: c (C) 1-12 Alkyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl oxy; each R 41 Identical or different, independently of one another, from deuterium, halogen, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 3-12 Cycloalkyl;
and/or X and one of R 4 Together with the ring atoms to which they are attached and the imino group (NH) form a 5-6 membered heterocyclic group;
and/or R 5 And one of R 4 To form C condensed with ring A 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl.
According to an embodiment of the invention, R 4 Selected from H, halogen, CN, C 1-12 Alkyl, C 2-12 Alkynyl, C 3-12 NaphtheneRadical, C 1-12 Alkoxy, C 3-12 Cycloalkyloxy, halogenated C 1-12 Alkoxy, deuterated C 1-12 An alkoxy group;
and/or X and one of R 4 Together with the ring atoms to which they are attached and the imino group (NH) form a 5-6 membered heterocyclic group;
And/or R 4 And R is 5 And linked to form a 5-6 membered heterocyclic group fused to ring A.
According to an embodiment of the invention, R 4 Selected from H, F, cl, br, I, CN, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 An alkoxy group;
and/or X and one of R 4 Together with the ring atoms to which they are attached and the imino group (NH) form a 6 membered heterocyclic group;
and/or R 5 And one of R 4 To form a 5 membered heterocyclyl or 5 membered heteroaryl group fused to ring a.
According to an embodiment of the invention, R 4 Selected from H, F, cl, CN, methyl, methoxy, ethoxy, cyclopropyl, cyclopropyloxy, difluoromethoxy, trifluoromethoxy, tridecylmethoxy, ethynyl;
and/or X and one of R 4 Together with the ring atoms to which they are attached and the imino group (NH) form morpholino;
and/or R 4 And R is 5 To form a ring A-condensed ring
According to an embodiment of the invention, ring A is selected from C 6-14 Aryl, 5-14 membered heteroaryl; for example from C 6-8 Aryl, 5-8 membered heteroaryl; such as phenyl, pyridyl, thienyl, pyrazolyl.
According to an embodiment of the invention, E is selected from the group consisting of a bond orR E1 Selected from fluorine, chlorine, bromine, iodine; g is selected from a bond or C 6-14 An aryl group; n is selected from 1 or 2; preferably, when n is 1, R E1 Is in R configuration;
e is selected from, for example, chemical bonds,Preferably, the +>Selected from the group consisting of
According to an embodiment of the invention, R 5 、R 6 、R 7 、R 8 Identical or different, independently of one another, from H, C 1-12 Alkyl, NH 2 Or NH 2 -C 1-12 An alkyl group; and R is 5 、R 6 、R 7 、R 8 At least one of which is NH 2 Or NH 2 -C 1-12 An alkyl group;
alternatively, R 5 、R 6 To which the atoms are attached to form C 3-12 Cycloalkyl, 3-12 membered heterocyclyl.
According to an embodiment of the invention, R 5 、R 6 、R 7 、R 8 Identical or different, independently of one another, from H, C 1-6 Alkyl, NH 2 Or NH 2 -C 1-6 Alkyl radicals, e.g. H, methyl, NH 2 、NH 2 -methyl; and R is 5 、R 6 、R 7 、R 8 At least one of which is NH 2 Or NH 2 Methyl radicals, e.g. when R 5 、R 6 、R 7 When both are H, R 8 Is NH 2 The method comprises the steps of carrying out a first treatment on the surface of the When R is 5 、R 7 、R 8 When both are H, R 6 Is NH 2 Or NH 2 -methyl; when R is 5 、R 6 When both are H, R 7 Is methyl, R 8 Is NH 2 The method comprises the steps of carrying out a first treatment on the surface of the When R is 5 、R 7 When both are H, R 6 Is methyl orEthyl, R 8 Is NH 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, when R 8 Is NH 2 When the structure is S-shaped;
alternatively, R 5 、R 6 To which the atoms are attached to form C 3-6 Cycloalkyl groups such as cyclopropyl.
According to an embodiment of the invention, Y is selected from OR a 、N(R b )(R c )；R a Selected from H, C 1-12 Alkyl orR b 、R c Identical or different, independently of one another, from C 1-12 An alkyl group.
According to an embodiment of the invention, Y is selected from OR a 、N(R b )(R c )；R a Selected from H, C 1-6 Alkyl orR b 、R c Identical or different, independently of one another, from C 1-6 An alkyl group; y is selected from OH, methylamino, dimethylamino, isopropoxy, tert-butyloxy, heptyloxy or +.>
According to an embodiment of the present invention, the compound of formula I may be selected from structures of formula II or formula III:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 E, Y and m independently have the definition set out above.
According to an embodiment of the present invention, the compound of formula I may be selected from the structures of formula I-1, I-2, I-3 or I-4:
wherein R is 1 、R 4 、R 5 、R 6 G and Y independently have the definitions described above.
According to a preferred embodiment of the present invention, the representative compounds of formula I according to the present invention have a structure selected from the group consisting of:
the invention also provides a preparation method of the compound of the formula I, which at least comprises the following scheme one or scheme two:
scheme one: deprotection of compound I-1 to give compounds of formula I;
scheme II: deprotection of compound I-2 to give compounds of formula I;
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 M, A, E, X, Y independently have the definition set out above, PG is selected from amino protecting groups, for example t-butoxycarbonyl, benzyloxycarbonyl;
according to an embodiment of the present invention, the deprotection reaction in scheme one or scheme two may be carried out in the presence of an acid, preferably selected from HCl solution, trifluoroacetic acid, or in the presence of a catalyst; the catalyst is preferably selected from palladium on carbon, palladium dioxide.
The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of a compound of formula I, racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof.
According to an embodiment of the invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
According to embodiments of the present invention, the pharmaceutical composition may further comprise one or more additional therapeutic agents.
In a third aspect, the invention provides the use of a compound of formula I, a racemate, a stereoisomer, a tautomer, an isotopic label, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug thereof, for the preparation of a medicament, for example, for the preparation of an LRRK2 inhibitor.
According to an embodiment of the invention, the medicament or pharmaceutical composition is for the prevention or treatment of a disease or condition mediated with LRRK 2.
According to an embodiment of the invention, the LRRK2 mediated related disease or symptom is selected from parkinson's disease, leprosy, IBD, alzheimer's disease, L-dopa induced dyskinesia, dementia, amyotrophic lateral sclerosis, renal cancer, breast cancer, prostate cancer, blood cancer, papillary carcinoma, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis or ankylosing spondylitis.
According to the present invention, the compounds of formula I, racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts or prodrugs thereof, may be prepared in a form suitable for administration by any suitable route, formulated by conventional means using one or more pharmaceutically acceptable carriers. Thus, the compounds of formula I, racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts or prodrugs thereof, may be formulated into various dosage forms for oral administration, injection (e.g. intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation; sustained release dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups may also be formulated.
The present invention also provides a method for treating or preventing a disease associated with LRRK2 mediated diseases, comprising administering to a patient a prophylactically or therapeutically effective amount of at least one of a compound of formula I, racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound thereof, or a pharmaceutical composition described above.
In some embodiments, the patient mammal, preferably a human.
The invention also provides application of at least one of the compounds shown in the formula I, racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof or a pharmaceutical composition thereof in treating or preventing diseases related to LRRK2 mediation.
According to an embodiment of the invention, the LRRK2 mediated related disease or symptom is selected from parkinson's disease, leprosy, IBD, alzheimer's disease, L-dopa induced dyskinesia, dementia, amyotrophic lateral sclerosis, renal cancer, breast cancer, prostate cancer, blood cancer, papillary carcinoma, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis or ankylosing spondylitis.
Advantageous effects
The compound provided by the invention has good LRRK2 inhibition effect, can be used for treating or preventing diseases and diseases related to LRRK2, and can be used for preparing medicines for treating the diseases and the diseases.
Definition and description of terms
Unless otherwise indicated, the radical and term definitions recited in the specification and claims of the present application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combinations of radical definitions and structures should be understood to be within the scope of the present description and/or claims.
The numerical ranges recited in the specification and claims are equivalent to at least each specific integer number recited therein unless otherwise stated. For example, the numerical range "1 to 40" corresponds to each of the integer numbers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 in the numerical range "1 to 10", and each of the integer numbers 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 in the numerical range "11 to 40". Furthermore, when certain numerical ranges are defined as "numbers," it is to be understood that both endpoints of the range, each integer within the range, and each fraction within the range are delineated. For example, a "number of 0 to 10" should be understood to describe not only each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least the sum of each integer with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.
It should be understood that in the description of 1,2 or more herein, "more" shall mean an integer greater than 2, such as greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.
The term "halogen" means fluorine, chlorine, bromine and iodine.
The term "C 1-40 Alkyl "is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having from 1 to 40 carbon atoms. For example, "C 1-10 Alkyl "means straight having 1,2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atomsChain and branched alkyl, "C 1-8 Alkyl "means straight and branched alkyl having 1,2, 3, 4, 5, 6, 7, or 8 carbon atoms," C 1-6 Alkyl "means straight and branched alkyl groups having 1,2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, or the like, or an isomer thereof.
The term "C 2-40 Alkenyl "is understood to mean a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has from 2 to 40 carbon atoms, preferably" C 2-10 Alkenyl groups). "C 2-10 Alkenyl "is understood to mean preferably a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably" C 2-8 Alkenyl groups). "C 2-10 Alkenyl "is understood to mean preferably a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7 or 8 carbon atoms, for example 2, 3, 4, 5 or 6 carbon atoms (i.e.C 2-6 Alkenyl) having 2 or 3 carbon atoms (i.e., C 2-3 Alkenyl). It will be appreciated that where the alkenyl group comprises more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex-4-enyl, (Z) -hex-4-enyl, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -hex-2-enyl, (Z) -hex-2-enyl, (E) -hex-1-enyl, (Z) -hex-1-enyl, isopropenyl 2-methylpropan-2-enyl, 1-methylpropan-2-enyl, 2-methylpropan-1-enyl, (E) -1-methylpropan-1-enyl, (Z) -1-methylpropan-1-enyl, 3-methylbutan-3-enyl, 2-methylbutan-3-enyl, 1-methylbutan-3-enyl, 3-methylbutan-2-enyl, (E) -2-methylbutan-2-enyl, (Z) -2-methylbutan-2-enyl, (E) -1-methylbutan-2-enyl, (Z) -1-methylbutan-2-enyl, (E) -3-methylbutan-1-enyl, (Z) -3-methylbutan-1-enyl, (E) -2-methylbutan-1-enyl, (Z) -1-methylbutan-1-enyl, 1-dimethylpan-2-enyl, 1-ethylpan-1-enyl, 1-propylvinyl, 1-isopropylvinyl.
The term "C 2-40 Alkynyl "is understood to mean a monovalent hydrocarbon radical, directly or branched, containing one or more triple bonds and having from 2 to 40 carbon atoms, preferably" C 2-10 Alkynyl groups. The term "C 2-10 Alkynyl "is understood to mean preferably a straight-or branched-chain monovalent hydrocarbon radical which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e." C 2-8 Alkynyl ") having 2, 3, 4, 5, or 6 carbon atoms (i.e.," C 2-6 Alkynyl ") having 2 or 3 carbon atoms (" C 2-3 Alkynyl "). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylpropan-2-ynyl, 2-methylbutan-3-ynyl, 1-methylbutan-2-ynyl, 3-methylbutan-1-ynyl, 1-ethylpropan-2-ynyl 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2-dimethylbbut-3-ynyl, 1, 1-dimethylbut-3-ynyl, 1-dimethylbut-2-ynyl or 3, 3-dimethylbut-1-ynyl. In particular, the alkynyl isEthynyl, prop-1-ynyl or prop-2-ynyl.
The term "C 3-40 Cycloalkyl "is understood to mean a saturated monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) hydrocarbon ring or tricyclic hydrocarbon ring having 3 to 40 carbon atoms, preferably" C 3-10 Cycloalkyl ", more preferably" C 3-8 Cycloalkyl groups). The term "C 3-10 Cycloalkyl "is understood to mean a saturated monovalent monocyclic, bicyclic (e.g. bridged, spiro) hydrocarbon ring or tricycloalkane having 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms. The C is 3-10 Cycloalkyl can be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as campholyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo [2.1.1 ]]Hexyl, bicyclo [2.2.1]Heptyl, bicyclo [2.2.1]Heptenyl, 6-dimethylbicyclo [3.1.1]Heptyl, 2, 6-trimethylbicyclo [3.1.1]Heptyl, bicyclo [2.2.2]Octyl, 2, 7-diazaspiro [3,5 ]]Nonylalkyl, 2, 6-diazaspiro [3,4 ]]Octyl, or tricyclic hydrocarbon groups such as adamantyl.
The term "3-20 membered heterocyclyl" refers to a saturated or unsaturated, non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic (e.g., fused, bridged, spiro) or 10-, 11-, 12-, 13-, 14-, or 15-membered tricyclic ring system, and contains at least one, e.g., 1, 2, 3,4, 5, or more heteroatoms selected from O, S and N, wherein N and S may also optionally be oxidized to various oxidation states to form nitrogen oxides, -S (O) -or-S (O) 2 -a state of the device. Preferably, the heterocyclic group may be selected from "3-10 membered heterocyclic groups". The term "3-10 membered heterocyclyl" means a saturated or unsaturated, non-aromatic ring or ring system and contains at least one heteroatom selected from O, S and N. The heterocyclic group may be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present. The heterocyclic group may include fused or bridged rings as well as spiro rings. In particular, the heterocyclic groups may include, but are not limited to: 4-membered rings, e.g. azetidinyl, oxetaneAn alkyl group; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6 membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5 membered ring, such as hexahydrocyclopenta [ c ]]Pyrrol-2 (1H) -yl ring, or 5,6 membered bicyclic ring, e.g. hexahydropyrrolo [1,2-a ]]Pyrazin-2 (1H) -yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4 ]Thiadiazinyl, 1,2,3, 5-tetrahydrooxazolyl or 4H- [1,4]Thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. When the 3-20 membered heterocyclic group is linked to other groups to form the compound of the present invention, the carbon atom on the 3-20 membered heterocyclic group may be linked to other groups, or the heterocyclic atom on the 3-20 membered heterocyclic ring may be linked to other groups. For example, when the 3-20 membered heterocyclic group is selected from piperazinyl, it may be that the nitrogen atom on the piperazinyl group is attached to other groups. Or when the 3-20 membered heterocyclic group is selected from piperidyl, it may be that the nitrogen atom on the piperidyl ring and the carbon atom at the para position thereof are attached to other groups.
The term "C 6-20 Aryl "is understood to mean preferably a mono-, bi-, e.g. fused-, bridged-, spiro-or tricyclic hydrocarbon ring of monovalent aromatic or partly aromatic character having 6 to 20 carbon atoms, which may be a monoaromatic ring or a polyaromatic ring fused together, preferably" C 6-14 Aryl group). The term "C 6-14 Aryl "is understood to mean preferably a mono-, bi-or tricyclic hydrocarbon ring (" C ") having a monovalent aromatic or partially aromatic character of 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms 6-14 Aryl), in particular a ring having 6 carbon atoms ("C) 6 Aryl "), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C 9 Aryl "), e.g. indanyl or indenyl, or a ring having 10 carbon atoms (" C 10 Aryl "),for example tetralin, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 Aryl "), e.g. fluorenyl, or a ring having 14 carbon atoms (" C) 14 Aryl "), such as anthracenyl. When said C 6-20 When aryl is substituted, it may be mono-substituted or poly-substituted. The substitution site is not limited, and may be, for example, ortho, para or meta substitution.
The term "5-20 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic aromatic ring systems: having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, such as "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: it has 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and it contains 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S and, in addition, can be benzo-fused in each case. Examples of monocyclic "heteroaryl" groups include, for example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, and the like. "heteroaryl" also refers to groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, wherein the point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl (phtalazinyl), 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-naphthyridinyl, 2-, 4-, 6-, 7-, or 7-, 1-, 3-, 4-, 3-, 5-, 6-, 1-and 2-amino 4-, 5-, 6-, 7-or 8-carbazolylcarbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-or 9-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 5-, 8-, 9-or 10-phenanthrolinyl 2-, 3-, 4-, 6-, 7-, 8-or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-or 10-phenazinyl, 2-, 3-, 4-, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10-benzisoquinolinyl, 2-, 3-, 4-or thieno [2,3-b ] furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-or 11-7H-pyrazino [2,3-c ] carbazolyl, 2-, 3-, 5-, 6-or 7-2H-furo [3,2-b ] -pyranyl, 2-, 3-, 4-, 5-, 7-or 8-5H-pyrido [2,3-d ] -o-oxazinyl, 1-, 3-or 5-1H-pyrazolo [4,3-d ] -oxazolyl, 2-, 4-or 54H-imidazo [4,5-d ] thiazolyl, 3-, 5-or 8-pyrazino [2,3-d ] pyridazinyl, 2-, 3-, 5-or 6-imidazo [2,1-b ] thiazolyl 1-, 3-, 6-, 7-, 8-or 9-furo [3,4-c ] cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10-or 11-4H-pyrido [2,3-c ] carbazolyl, 2-, 3-, 6-or 7-imidazo [1,2-b ] [1,2,4] triazinyl, 7-benzo [ b ] thienyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 2-, 4-, 5-, 6-or 7-benzimidazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-or 9-benzoxepin (benzoxapinyl), 2-, 4-, 5-, 6-, 7-or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-or 11-4H-pyrrolo [1,2-b ] [2] benzazapinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 2-, 3-, 4-, 5-, 6-or 7-benzo [ b ] thienyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 2-, 4-, 5-, 6-or 7-benzimidazolyl, and 2-, 4-, 5-, 6-or 7-benzothiazolyl. When the 5-20 membered heteroaryl is attached to other groups to form the compounds of the invention, the carbon atom on the 5-20 membered heteroaryl ring may be attached to other groups, or the heteroatom on the 5-20 membered heteroaryl ring may be attached to other groups. When the 5-20 membered heteroaryl is substituted, it may be mono-substituted or poly-substituted. And, the substitution site thereof is not limited, and for example, hydrogen attached to a carbon atom on a heteroaryl ring may be substituted, or hydrogen attached to a heteroatom on a heteroaryl ring may be substituted.
The term "spiro" refers to a ring system in which two rings share 1 ring-forming atom.
The term "fused ring" refers to a ring system in which two rings share 2 ring atoms.
The term "bridged ring" refers to a ring system in which two rings share more than 3 ring members.
Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylene include all possible isomeric forms thereof, e.g. positional isomers thereof. Thus, for some illustrative non-limiting examples, forms that may include substitution at 1, 2, or more of its 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) or bonding to other groups include pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thienyl or thienylene include thiophen-2-yl, thienylene-2-yl, thiophen-3-yl and thienylene-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.
The term "oxo" refers to the substitution of a carbon atom, nitrogen atom or sulfur atom in a substituent with an oxo group (=o) formed after oxidation.
The term "alkylamino" refers to-NH- (alkyl) or-N- (alkyl) 2 Wherein alkyl is as defined above. Non-limiting examples of alkylamino groups include: methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, and the like.
The term "alkyloxy" refers to the radical-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy or heterocycloalkyloxy.
The terms "alkyleneoxy" and "oxyalkylene" refer to-alkylene-O-or-O-alkylene-, wherein alkylene represents a straight or branched saturated divalent hydrocarbon radical. The definition of the number of carbon atoms for "alkylene" applies to the definition of "alkyl" above. It will be appreciated by those skilled in the art that an alkyleneoxy or oxyalkylene group may be attached to the remainder of the molecule containing it in any orientation, i.e., the two may be used interchangeably.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
In the present invention, reference to a compound also includes isotopically-labeled compounds, which are identical to those shown in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually naturally occurring. Examples of isotopes that can be incorporated into compounds of the invention include H, C, N, O, S, F and Cl isotopes, respectively, such as 2 H、 3 H、 13 C、 11 C、 14 C、 15 N、 18 O、 17 O、 32 P、 35 S、 18 F, F is a single crystal 36 Cl. The compounds of the invention, prodrugs thereof, or pharmaceutically acceptable salts of the compounds or prodrugs, which contain the isotopes described above and/or other isotopes of other atoms, are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example, are incorporated into radioisotopes (such as 3 H and 14 c) The compounds of (2) are useful in drug and/or substrate tissue distribution assays. Tritium (i.e. tritium) 3 H) And carbon 14 (i.e 14 C) Isotopes are particularly preferred for ease of preparation and detectability. Furthermore, with heavier isotopes (such as deuterium, i.e 2 H or D) substitution may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) resulting from higher metabolic stability, and thus may be preferred in certain circumstances. As claimed in claimThe protected compounds of the invention may be specifically limited to substitution with deuterium or tritium. Furthermore, the presence of hydrogen in a substituent is not listed solely by the term deuterium or tritium and is not meant to exclude deuterium or tritium, but may equally well comprise deuterium or tritium.
Those skilled in the art will appreciate that the compounds of formula I may exist in various pharmaceutically acceptable salt forms. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; these compounds may also form internal salts if they contain both acidic (e.g., carboxyl) and basic (e.g., amino) centers.
The compounds of the invention may exist in the form of solvates (e.g. hydrates) wherein the compounds of the invention comprise a polar solvent as a structural element of the compound lattice, in particular, for example, water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.
Depending on its molecular structure, the compound of the invention may be chiral and thus various enantiomeric forms may exist. These compounds may thus be present in racemic or optically active form. The compounds of the present invention encompass isomers or mixtures, racemates thereof wherein each chiral carbon is in the R or S configuration. The compounds of the invention or intermediates thereof may be isolated as enantiomer compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g.N-benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulfonic acids in R and S form. The chromatographic resolution can also advantageously be carried out with the aid of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers, immobilized on silica. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile.
The corresponding stable isomer may be isolated according to known methods, for example by extraction, filtration or column chromatography.
The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.
The term "therapeutically effective amount" refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought by a researcher, veterinarian, medical doctor or other clinician in a tissue, system, animal, individual or human, which includes one or more of the following: (1) prevention of disease: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not experienced or developed a pathology or symptomatology of the disease. (2) inhibition of disease: for example, inhibiting a disease, disorder or condition (i.e., preventing further development of pathology and/or symptoms) in an individual experiencing or presenting with the pathology or symptoms of the disease, disorder or condition. (3) alleviation of disease: for example, alleviating a disease, disorder or condition (i.e., reversing the pathology and/or symptoms) in an individual experiencing or presenting with the pathology or symptoms of the disease, disorder or condition.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
And (3) preparing part of raw materials:
1. synthesis of 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine
2, 4-dichloro-5-trifluoromethylpyrimidine (20 g,0.089 mol) and methanol (45 mL) were added to the reaction flask, the system was stirred at-10℃for 10 minutes, then triethylamine (12.5 mL,0.089 mol) and a methanol solution of methylamine (2M, 45 mL) were added, the system was stirred for 1 hour, and then warmed naturally, and stirred at room temperature overnight. Concentrating, adding water into the reaction system, extracting with ethyl acetate three times, mixing the organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying the residue by column chromatography to obtain 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (8.5 g, 45%)
MS m/z(ESI):212[M+1] + .
2. Synthesis of 2-chloro-N-ethyl-5- (trifluoromethyl) pyrimidin-4-amine
Synthesis is seen in 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine
MS m/z(ESI):226[M+1] + .
3. Synthesis of 2-chloro-N-cyclopropyl-5- (trifluoromethyl) pyrimidin-4-amine
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Synthesis is seen in 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine
MS m/z(ESI):238[M+1] + .
4. Synthesis of 2-chloro-N- (2, 2-difluoroethyl) -5- (trifluoromethyl) pyrimidin-4-amine
Synthesis is seen in 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine
MS m/z(ESI):262[M+1] + .
5. Synthesis of 2-chloro-N- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrimidin-4-amine
Synthesis is seen in 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine
MS m/z(ESI):280[M+1] + .
Example 1
(S) -2-amino-3- (3-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoic acid
First step
Preparation of benzyl (R) -2- ((benzyloxycarbonyl) amino) -3-iodopropionate
Triphenylphosphine (1.2 g,4.5 mmol) and imidazole (0.3 g,4.5 mmol) were added to an eggplant-shaped bottle, nitrogen was replaced three times, and then dichloromethane (10 mL) and iodine (1.1 g,4.5 mmol) were added. The reaction solution was stirred at room temperature for 10 minutes and then cooled to 0℃and then a methylene chloride solution of (N-benzyloxycarbonyl) -L-serine benzyl ester Cpd-01A (1.0 g,3.0 mmol) was slowly added dropwise. The reaction solution was stirred at 0℃for 2 hours. After the reaction was completed, the solid in the reaction solution was removed by filtration, the filtrate was dried by spin-drying, and separated and purified by a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain benzyl (R) -2- ((benzyloxycarbonyl) amino) -3-iodopropionate Cpd-01B (1.2 g, white solid), yield: 83%.
MS m/z(ESI):462[M+23] + .
Second step
Preparation of zinc (R) - (3- (benzyloxy) -2- (benzyloxycarbonyl) amino) -3-oxopropyl) iodide
Activated zinc powder (0.75 g,11.5 mmol) and iodine (0.15 g,0.6 mmol) were added to a three-necked flask, the nitrogen was replaced three times, the iodine was blown to sublimation with a blower, and then a solution of benzyl (R) -2- ((benzyloxycarbonyl) amino) -3-iodopropionate Cpd-01B (1.0 g,2.3 mmol) in N, N-dimethylformamide (10 mL) was added to the three-necked flask in one portion, maintaining the temperature in the flask and stirring for 10 minutes. The reaction solution was withdrawn by syringe and directly used for the next reaction without any treatment.
Third step
Preparation of benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (3-methoxy-4-nitrophenyl) propionate
4-bromo-2-methoxy-1-nitrobenzene (0.27 g,1.2 mmol), bis triphenylphosphine palladium dichloride (0.08 g,0.1 mmol), cuprous iodide (0.05 g,0.3 mmol) and N, N-dimethylformamide were added to a three-necked flask, the nitrogen was replaced three times, and then the flask was placed in an oil bath at 80℃for 10 minutes, followed by slowly dropping a solution of (R) - (3- (benzyloxy) -2- (benzyloxycarbonyl) amino) -3-oxypropyl) zinc iodide Cpd-01C in N, N-dimethylformamide using a syringe. The reaction solution was stirred at 80℃for 0.5 hours. After the completion of the reaction, the reaction solution was filtered through celite, then poured into water (200 mL), extracted with ethyl acetate (50 ml×3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The crude product obtained was isolated and purified on a silica gel column (petroleum ether/ethyl acetate=3/1) to give benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (3-methoxy-4-nitrophenyl) propionate Cpd-01D (0.45 g, brown oil), yield: 70%.
MS m/z(ESI):487[M+23] + .
Fourth step
Preparation of benzyl (S) -3- (4-amino-3-methoxyphenyl) -2- ((benzyloxycarbonyl) amino) propionate
Benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (3-methoxy-4-nitrophenyl) propionate Cpd-01D (400 mg,0.86 mmol), iron powder (385 mg,6.89 mmol) and ethanol (5 mL) were added to the reaction flask followed by saturated ammonium chloride solution (5 mL). The reaction solution was stirred at 90℃for 1 hour. After the reaction was completed, the reaction solution was filtered with celite, diluted with water, extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated, and the obtained crude product was isolated and purified with a preparative plate (petroleum ether/ethyl acetate=3/1) to give benzyl (S) -3- (4-amino-3-methoxyphenyl) -2- ((benzyloxycarbonyl) amino) propionate Cpd-01E (340 mg, light brown oil), yield: 73%
MS m/z(ESI):435[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.78(d,J＝7.9Hz,1H),7.50-7.09(m,10H),6.70(s,1H),6.52(s,2H),5.09(s,2H),4.99(s,2H),4.57(s,2H),4.33-4.16(m,1H),3.68(s,3H),2.96-2.67(m,2H).
Fifth step
Preparation of benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (3-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propionate
Benzyl (S) -3- (4-amino-3-methoxyphenyl) -2- ((benzyloxycarbonyl) amino) propionate Cpd-01E (226 mg,0.52 mmol), 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (111 mg,0.52 mmol) was added to t-butanol (5 mL), and then trifluoroacetic acid (5 mg,0.052 mmol) was added thereto and nitrogen was replaced three times. The reaction mixture was reacted at 110℃for 1 hour. After the reaction was completed, the solvent was removed by rotary evaporation, the residue was dispersed in ethyl acetate (5 mL), suction filtration, and the solid was washed 2 times with ethyl acetate (2 mL), and after drying in vacuo, benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (3-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propionate Cpd-01F (260 mg, white solid), yield: 74%.
MS m/z(ESI):610[M+1] + .
Sixth step
Preparation of (S) -2-amino-3- (3-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoic acid
Benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (3-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propionate Cpd-01F (250 mg,0.41 mmol), palladium on carbon (10 mg) was added to methanol (5 mL). The reaction solution was stirred at room temperature for 1 hour under a hydrogen atmosphere. After the reaction was completed, palladium carbon was removed by suction filtration through celite, and the filtrate was dried, and the resulting crude product was purified by reverse phase chromatography to give (S) -2-amino-3- (3-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoic acid Cpd-01 (40 mg) in 25% yield.
MS m/z(ESI):386[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ8.26-8.18(m,1H),8.14(s,1H),8.10(d,J＝8.1Hz,1H),7.95(s,1H),7.15(d,J＝4.2Hz,1H),6.98(s,1H),6.82(d,J＝8.2Hz,1H),3.85(s,3H),3.50(s,1H),3.22-3.06(m,1H),2.90(d,J＝4.4Hz,3H),2.87-2.77(m,1H).
Example 2
(S) -2-amino-3- (4- ((4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propanoic acid
The procedure of reference example 1 was followed, except that 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine was replaced with 2-chloro-N-ethyl-5- (trifluoromethyl) pyrimidin-4-amine, to obtain compound (S) -2-amino-3- (4- ((4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionic acid Cpd-02 (180 mg) in 62% yield. MS m/z (ESI) 400[ M+1 ]] + .
1 H NMR(400MHz,DMSO-d6)δ8.14(s,1H),8.05(d,J＝8.2Hz,1H),7.94(s,1H),7.38(s,2H),7.15(s,1H),6.97(s,1H),6.81(d,J＝8.3Hz,1H),3.84(d,J＝7.9Hz,3H),3.46(m,2H),3.38(m,1H),3.14(dd,J＝14.3,3.9Hz,1H),2.79(dd,J＝14.4,8.8Hz,1H),1.15(t,J＝7.1Hz,3H).
Example 3
(S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propanoic acid
The procedure of reference example 1 was followed, except for replacing 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine with 2-chloro-N-cyclopropyl-5- (trifluoromethyl) pyrimidin-4-amine, to give (S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionic acid Cpd-03 (45 mg), yield: 30%. MS m/z (ESI) 412[ M+1 ]] + .
1 H NMR(400MHz,DMSO-d6)δ8.34(s,1H),8.17(s,1H),7.95(s,1H),7.29(d,J＝73.0Hz,3H),6.98(s,1H),6.82(d,J＝8.3Hz,1H),3.86(s,3H),3.45-3.24(m,1H),3.14(dd,J＝14.4,3.6Hz,1H),2.79(dd,J＝14.4,8.8Hz,2H),0.78(d,J＝5.4Hz,2H),0.67(d,J＝2.8Hz,2H).
Example 4
(S) -2-amino-3- (4- ((4- ((2, 2-difluoroethyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propanoic acid
The procedure of reference example 1 was followed, except for replacing 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine with 2-chloro-N- (2, 2-difluoroethyl) -5- (trifluoromethyl) pyrimidin-4-amine, to obtain compound (S) -2-amino-3- (4- ((4- ((2, 2-difluoroethyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionic acid Cpd-04 (50 mg), yield: 33%.
MS m/z(ESI):436[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.21(s,1H),7.82(d,J＝8.1Hz,1H),7.37(s,3H),6.99(s,1H),6.80(d,J＝8.1Hz,1H),6.20(t,J＝56.6Hz,1H),3.83(s,3H),3.76(t,J＝12.6Hz,2H),3.36(ddt,J＝36.7,26.0,5.2Hz,1H),3.14(dd,J＝14.3,3.7Hz,1H),2.79(dd,J＝14.2,8.6Hz,1H).
Example 5
Preparation of (S) -2-amino-3- (3-methoxy-4- ((4- ((2, 2-trifluoroethyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoic acid
The procedure of reference example 1 was followed, except for replacing 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine with 2-chloro-N- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrimidin-4-amine, to give compound (S) -2-amino-3- (3-methoxy-4- ((4- ((2, 2-trifluoroethyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propionic acid Cpd-05 (100 mg), yield: 57%.
MS m/z(ESI):454[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.26(s,1H),7.82(d,J＝8.1Hz,1H),7.54(br,3H),6.99(d,J＝1.2Hz,1H),6.87–6.73(m,1H),4.23(d,J＝9.3Hz,2H),3.82(s,3H),3.38(dd,J＝8.6,4.1Hz,1H),3.14(dd,J＝14.6,4.2Hz,1H),2.80(dd,J＝14.3,8.7Hz,1H).
Example 6
(S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) -N-methylpropanamide
The first to fourth steps were carried out with reference to the second to fifth steps in example 1 in this order, except that (R) -2- ((benzyloxycarbonyl) amino) -3-iodopropionic acid benzyl ester Cpd-01B was replaced with compound Cpd-07A as a starting compound and 2-chloro-N-cyclopropyl-5- (trifluoromethyl) pyrimidin-4-amine was replaced with 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine to obtain compound (S) -2- ((t-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionic acid methyl ester Cpd-07E (1.8 g, white solid), yield: 35%.
MS m/z(ESI):526[M+1] + Fifth step
Preparation of (S) -2- ((tert-Butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propanoic acid
Methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propanoate Cpd-07E (1.8 g,3.4 mmol) was dissolved in tetrahydrofuran (10 mL), and an aqueous solution (10 mL) of lithium hydroxide (0.4 g,10.2 mmol) was dropped to react at room temperature for 1 hour. After the reaction was completed, ph=4 was adjusted with HCl of 1mol/L, and the precipitated solid was collected by filtration and washed with methanol and ethyl acetate, and dried in vacuo to give (S) -2- ((t-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionic acid Cpd-07F (1.2 g, white solid), yield: 65%.
MS m/z(ESI):512[M+1] + .
Sixth step
Preparation of tert-butyl (S) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) -1- (methylamino) -1-oxopropan-2-yl) carbamate
Cpd-07F (100 mg,19.5 mmol) of (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionic acid, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (148 mg,39.0 mmol) and N, N-diisopropylethylamine (126 mg,97.5 mmol) were added to N, N-dimethylformamide (10 mL), and after a reaction at room temperature for 30 minutes methylamine hydrochloride (20 mg,29.2 mmol) was added, and the reaction was continued for 2 hours. After completion of the reaction, water (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed 3 times with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was isolated and purified on a silica gel column (petroleum ether/ethyl acetate=3/1) to give tert-butyl (S) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) -1- (methylamino) -1-oxypropane-2-yl) carbamate Cpd-07G (100 mg, white solid), yield: 92%.
MS m/z(ESI):525[M+1] + .
Seventh step
Preparation of (S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) -N-methylpropylamine
Tert-butyl (S) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) -1- (methylamino) -1-oxopropan-2-yl) carbamate Cpd-07G (100 mg,19.0 mmol) was dissolved in HCl in dioxane (10 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated and dried in vacuo to give (S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) -N-methylpropanamide Cpd-07 (70 mg) hydrochloride, yield: 82%.
MS m/z(ESI):425[M+1] + .
1 H NMR(400MHz,MeOD)δ8.26(s,2H),7.05(s,1H),6.92(d,J＝8.0Hz,1H),4.13–4.00(m,1H),3.98(s,3H),3.20(dd,J＝13.8,6.9Hz,1H),3.08(dd,J＝13.6,7.6Hz,1H),2.96(s,1H),2.74(s,3H),1.04–0.86(m,2H),0.86–0.71(m,2H).
Example 7
(S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) -N, N-dimethylpropionamide
The first step: compound Cpd-07F was obtained by referring to the synthetic procedure of example 6, and then methylamine hydrochloride therein was replaced with dimethylamine hydrochloride by referring to the sixth step of example 6.
And a second step of: reference example 6 seventh step the hydrochloride salt of the compound (S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) -N, N-dimethylpropionamide Cpd-08 (70 mg, white solid), yield: 90%.
MS m/z(ESI):439[M+1] + .
1 H NMR(400MHz,MeOD)δ8.29(s,2H),7.05(s,1H),6.95(d,J＝8.2Hz,1H),4.69(t,J＝7.3Hz,1H),3.98(s,3H),3.14(d,J＝7.3Hz,2H),3.03–2.94(m,1H),2.93(s,3H),2.82(s,3H),0.99–0.90(m,2H),0.86–0.75(m,2H).
Example 8
(S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propanoic acid isopropyl ester
First step
Preparation of isopropyl (S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionate
Isopropanol (40.3 mg,67.1 mmol) was cooled to 0 ℃, followed by slow dropwise addition of acetyl chloride (5.8 mg,10.9 mmol), stirring at 0 ℃ for 1 hour, followed by addition of (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionic acid Cpd-07F (80.0 mg,15.6 mmol), and heating to 70 ℃ for reaction overnight. After the reaction was completed, the reaction solution was concentrated, and dried in vacuo to give isopropyl (S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionate Cpd-09 (50 mg) hydrochloride, yield: 66%.
MS m/z(ESI):454[M+1] + .
1 H NMR(400MHz,MeOD)δ8.36(s,1H),8.24(s,1H),7.04(s,1H),6.93(d,J＝8.3Hz,1H),5.15–4.99(m,1H),4.31(t,J＝7.0Hz,1H),3.97(s,3H),3.28–3.13(m,2H),3.00–2.86(m,1H),1.29(d,J＝6.2Hz,3H),1.23(d,J＝6.2Hz,3H),0.97–0.88(m,2H),0.81–0.72(m,2H).
Example 9
(S) -2-amino-3- (2-fluoro-5-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoic acid
With reference to the synthetic procedure of example 1, compound Cpd-01C was first prepared, then 4-bromo-2-methoxy-1-nitrobenzene in the third step was replaced with 1-bromo-2-fluoro-5-methoxy-4-nitrobenzene to continue the reaction, and compound Cpd-10 (180 mg) was finally obtained in 72% yield as (S) -2-amino-3- (2-fluoro-5-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoic acid. MS m/z (ESI) 404[ M+1 ] ] + .
1 H NMR(400MHz,DMSO-d6)δ8.39(br,2H),8.25-8.16(m,2H),8.03(s,1H),7.32(d,J＝4.3Hz,1H),7.06(d,J＝7.0Hz,1H),4.08(t,J＝6.6Hz,1H),3.87(s,3H),3.12(ddd,J＝35.9,14.3,6.7Hz,2H),2.93(d,J＝4.3Hz,3H).
Example 10
(S) -2-amino-3- (2-fluoro-5-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoic acid isopropyl ester
The procedure of reference example 8 was followed, starting from compound Cpd-10, to give isopropyl (S) -2-amino-3- (2-fluoro-5-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propionate Cpd-11 (27 mg) hydrochloride in 75% yield. MS m/z (ESI) 446[ M+1 ]] + .
1 H NMR(400MHz,MeOD)δ8.32(s,1H),8.05(s,1H),7.10(d,J＝6.7Hz,1H),5.06(dt,J＝12.5,6.3Hz,1H),4.28(t,J＝7.2Hz,1H),3.97(s,3H),3.14(s,3H),1.23(dd,J＝23.6,6.3Hz,6H).
Example 11
4-amino-3- (2-fluoro-5-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) butanoic acid
First step
Preparation of (4-bromo-5-fluoro-2-methoxyphenyl) carbamic acid tert-butyl ester
4-bromo-5-fluoro-2-methoxyaniline Cpd-12A (2.0 g,9.2 mmol), di-tert-butyl dicarbonate (3.0 g,6.5 mmol) and cesium carbonate (9.9 g,45.8 mmol) were dissolved in methanol (60 mL) and stirred overnight at 70 ℃. After the reaction was completed, the crude product was distilled off by hand, and purified by column (petroleum ether/ethyl acetate=20/1) to give tert-butyl (4-bromo-5-fluoro-2-methoxyphenyl) carbamate Cpd-12B (2.25 g, pale yellow oil), yield: 77%.
MS m/z(ESI):320[M+1] + .
Second step
(E) Preparation of ethyl-3- (4- ((tert-butoxycarbonyl) amino) -2-fluoro-5-methoxyphenyl) acrylate
Tert-butyl (4-bromo-5-fluoro-2-methoxyphenyl) carbamate Cpd-12B (500 mg,1.57 mmol), (E) -2- (ethoxycarbonyl) vinylboronic acid pinacol ester (530 mg,2.35 mmol), bis (triphenylphosphine) palladium dichloride (110 mg,0.16 mmol) and sodium carbonate (248 mg,2.35 mmol) were dissolved in 1, 4-dioxane (10 mL) and water (1 mL) and reacted at 100℃for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the reaction mixture was filtered through celite, quenched with water (5 mL), extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and distilled off to obtain a crude product. Purification of the crude product by column (petroleum ether/ethyl acetate=9/1) gave ethyl (E) -3- (4- ((tert-butoxycarbonyl) amino) -2-fluoro-5-methoxyphenyl) acrylate Cpd-12C (450 mg, white oil), yield: 84.5%.
MS m/z(ESI):340[M+1] + .
Third step
Preparation of ethyl 3- (4- ((tert-butoxycarbonyl) amino) -2-fluoro-5-methoxyphenyl) -4-nitrobutanoate
Nitromethane (0.8 g,13.2 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (1.0 g,6.6 mmol) were dissolved in acetonitrile (7.5 mL) and stirred at 0deg.C for 10 min, ethyl (E) -3- (4- ((tert-butoxycarbonyl) amino) -2-fluoro-5-methoxyphenyl) acrylate Cpd-12C (450 mg,1.3 mmol) was slowly added to the reaction solution and reacted at 0deg.C for 12 h. After the reaction was completed, the reaction solution was poured into a large amount of water, the pH was adjusted to 2 with 10% hcl, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the crude product was obtained by rotary evaporation, and 3- (4- ((tert-butoxycarbonyl) amino) -2-fluoro-5-methoxyphenyl) -4-nitrobutanoic acid ethyl ester Cpd-12D (0.39 g, white oil) was obtained by column purification (petroleum ether/ethyl acetate=5/1), yield: 73.8%.
MS m/z(ESI):401[M+1] + .
1 H NMR(400MHz,CDCl 3 )δ7.93(d,J＝12.6Hz,1H),7.74(d,J＝16.1Hz,1H),7.22(s,1H),6.88(d,J＝6.4Hz,1H),6.36(d,J＝16.1Hz,1H),4.23(q,J＝7.1Hz,2H),3.86(s,3H),1.51(s,9H),1.31(t,J＝7.1Hz,3H),0.85(dt,J＝8.3,3.0Hz,2H).
Fourth step
Preparation of ethyl 3- (4-amino-2-fluoro-5-methoxyphenyl) -4-nitrobutanoate
Ethyl 3- (4- ((tert-butoxycarbonyl) amino) -2-fluoro-5-methoxyphenyl) -4-nitrobutanoate Cpd-12D (0.39 g,0.98 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2.2 g,19.5 mmol) was added and stirred at 25℃for 1 hour. After the reaction was completed, ethyl 3- (4-amino-2-fluoro-5-methoxyphenyl) -4-nitrobutanoate Cpd-12E (0.4 g, white solid) was obtained by rotary evaporation, yield: 99%.
MS m/z(ESI):301[M+1] + .
Fifth step
Preparation of ethyl 3- (2-fluoro-5-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) -4-nitrobutanoate
Ethyl 3- (4-amino-2-fluoro-5-methoxyphenyl) -4-nitrobutyrate Cpd-12E (0.4 g,0.96 mmol), 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (0.2 g,0.98 mmol) was dissolved in N-butanol (10 mL), trifluoroacetic acid (0.12 g,0.98 mmol) was added and reacted at 90℃for 1 hour. After the reaction was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to give crude product, which was purified by column (dichloromethane/methanol=30/1) to give ethyl 3- (2-fluoro-5-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) -4-nitrobutyrate Cpd-12F (0.21 g, white solid), yield: 46.8%.
MS m/z(ESI):476[M+1] + .
Sixth step
Preparation of 3- (2-fluoro-5-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) -4-nitrobutanoic acid
Ethyl 3- (2-fluoro-5-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) -4-nitrobutanoate Cpd-12F (0.12 g,0.25 mmol) was dissolved in tetrahydrofuran (5 mL), and a saturated aqueous lithium hydroxide solution (0.5 mL) was added to react at room temperature for 1 hour. After the reaction was completed, the pH was adjusted to 4 with dilute hydrochloric acid, extracted with a mixed solvent (dichloromethanol/methanol=10/1), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to obtain crude product, which was purified by column to obtain 3- (2-fluoro-5-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) -4-nitrobutyric acid Cpd-12G (0.1G, white solid), yield: 89%.
MS m/z(ESI):448[M+1] + .
Seventh step
Preparation of 4-amino-3- (2-fluoro-5-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) butanoic acid
3- (2-fluoro-5-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) -4-nitrobutanoic acid Cpd-12G (0.1G, 0.22 mmol) was dissolved in methanol (5 mL), raney nickel (0.5 mL) was added and reacted at room temperature under hydrogen atmosphere for 2 hours. After the reaction was completed, it was filtered through celite, and rotary evaporation gave 4-amino-3- (2-fluoro-5-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) butanoic acid Cpd-12 (0.02 g), yield: 21.8%.
MS m/z(ESI):418[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ8.19(s,1H),8.09(d,J＝12.3Hz,1H),7.96(s,1H),7.25(s,1H),6.92(d,J＝6.6Hz,1H),3.84(s,3H),3.30(s,9H),2.92(d,J＝3.7Hz,3H),2.80(s,1H),2.25(d,J＝11.7Hz,1H),1.23(s,2H).
Example 12
4-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) butanoic acid
The procedure of reference example 11 was followed, except that 4-bromo-2-methoxyaniline Cpd-13A was used in place of 4-bromo-5-fluoro-2-methoxyaniline Cpd-12A in the first step of example 11 and 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine was used in place of 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine in the fifth step, to obtain compound 4-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) butanoic acid Cpd-13 (68 mg), yield: 29%. MS m/z (ESI): 426[ M+1 ] ] + .
1 H NMR(400MHz,DMSO-d6)δ8.34(s,1H),8.17(s,1H),7.97(s,1H),7.19(s,1H),6.93(s,1H),6.80(d,J＝8.3Hz,1H),3.87(s,3H),3.06(dd,J＝10.2,5.7Hz,1H),2.99(d,J＝8.9Hz,1H),2.90(dd,J＝11.7,3.4Hz,1H),2.82(d,J＝3.1Hz,1H),2.71(dd,J＝16.1,9.0Hz,1H),2.42(d,J＝13.0Hz,1H),0.84–0.70(m,2H),0.70–0.50(m,2H).
Example 13
(S) -2-amino-3- (2-chloro-4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -5-methoxyphenyl) propionic acid
First step
Preparation of 1-bromo-2-chloro-5-methoxy-4-nitrobenzene
1-bromo-2-chloro-5-fluoro-4-nitrobenzene Cpd-16A (2.0 g,7.9 mmol) was dissolved in methanol (20 mL), stirred at 0deg.C and sodium methoxide (1.4 g,7.9 mmol) was added and the mixture reacted at 0deg.C for 1.5 hours. After completion of the reaction, water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated in vacuo to give crude product, which was purified by column (petroleum ether/ethyl acetate=9/1) to give 1-bromo-2-chloro-5-methoxy-4-nitrobenzene Cpd-16B (2.1 g, yellow solid), yield: 95%.
1 H NMR(400MHz,CDCl 3 )δ7.99(s,1H),7.36(s,1H),3.97(s,3H).
Second step
Preparation of methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (2-chloro-5-methoxy-4-nitrophenyl) propanoate
Zinc powder (0.98 g,18.8 mmol) and iodine (0.19 g,0.91 mmol) were added to a three-necked flask to displace nitrogen and heated until the iodine sublimated. 1-bromo-2-chloro-5-methoxy-4-nitrobenzene Cpd-16B (1.0 g,3.70 mmol) was dissolved in N, N-dimethylformamide (10 mL) and the solution was rapidly poured into a three-necked flask and stirred. Meanwhile, in another three-necked flask, cuprous iodide (0.07 g,0.40 mmol), bis triphenylphosphine palladium dichloride (0.11 g,0.20 mmol), methyl (R) -2- ((t-butoxycarbonyl) amino) -3-iodopropionate (0.40 g,1.80 mmol) and N, N-dimethylformamide (10 mL) were added, and nitrogen was replaced, and preheated to 80 ℃. The mixed solution with zinc powder was sucked out by a syringe and slowly dropped into a three-necked flask for reaction at 80℃to continue the reaction for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature and was filtered with celite, quenched with water (20 mL), extracted with ethyl acetate (20 ml×3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated by rotary evaporation to give crude product, which was purified by column (petroleum ether/ethyl acetate=3/1) to give methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (2-chloro-5-methoxy-4-nitrophenyl) propionate Cpd-16C (400 mg, yellow oil), yield: 28%.
MS m/z(ESI):389[M+1] + .
Third step
Preparation of methyl (S) -3- (4-amino-2-chloro-5-methoxyphenyl) -2- ((tert-butoxycarbonyl) amino) propanoate
Methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (2-chloro-5-methoxy-4-nitrophenyl) propanoate Cpd-16C (400 mg,1.03 mmol), iron powder (287 mg,5.15 mmol) and saturated aqueous ammonium chloride (275 mg,5.15 mmol) were dissolved in ethanol (5 mL) and reacted at reflux for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and was filtered with celite, quenched with water (5 mL), extracted with ethyl acetate (10 ml×3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated in vacuo to give crude product, which was purified by column (petroleum ether/ethyl acetate=2/1) to give methyl (S) -3- (4-amino-2-chloro-5-methoxyphenyl) -2- ((tert-butoxycarbonyl) amino) propionate Cpd-16D (200 mg, yellow oil), yield: 54%.
MS m/z(ESI):359[M+1] + .
Fourth step
Preparation of methyl (S) -2- ((tert-Butoxycarbonyl) amino) -3- (2-chloro-4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -5-methoxyphenyl) propanoate
Methyl (S) -3- (4-amino-2-chloro-5-methoxyphenyl) -2- ((tert-butoxycarbonyl) amino) propanoate Cpd-16D (200 mg,0.56 mol), 2-chloro-N-cyclopropyl-5- (trifluoromethyl) pyrimidin-4-amine (160 mg,0.67 mmol) and trifluoroacetic acid (32 mg,0.28 mmol) were dissolved in N-butanol (10 mL) and reacted at 90℃for 1 hour. After the reaction was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated in vacuo to give crude product, which was purified by column (petroleum ether/ethyl acetate=3/1) to give methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (2-chloro-4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -5-methoxyphenyl) propanoate Cpd-16E (100 mg, white solid), yield: 32%.
MS m/z(ESI):560[M+1] + .
Fifth step
Preparation of (S) -2- ((tert-Butoxycarbonyl) amino) -3- (2-chloro-4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -5-methoxyphenyl) propanoic acid
Methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (2-chloro-4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -5-methoxyphenyl) propanoate Cpd-16E (100 mg,0.18 mmol) was dissolved in tetrahydrofuran (5 mL), and an aqueous lithium hydroxide solution (0.5 mL) was added and reacted at room temperature for 1 hour. After the reaction was completed, the pH was adjusted to 4 with dilute hydrochloric acid, extracted with a mixed solvent (dichloromethanol/methanol=10/1), and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to give (S) -2- ((tert-butoxycarbonyl) amino) -3- (2-chloro-4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -5-methoxyphenyl) propionic acid Cpd-16F (70 mg, white solid), yield: 87%.
MS m/z(ESI):546[M+1] + .
Sixth step
Preparation of (S) -2-amino-3- (2-chloro-4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -5-methoxyphenyl) propionic acid
Cpd-16F (70 mg,0.13 mmol) of (S) -2- ((tert-butoxycarbonyl) amino) -3- (2-chloro-4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -5-methoxyphenyl) propanoic acid was added to a solution of hydrogen chloride in methanol (4 mL,4 mol/L). The reaction mixture was reacted at 25℃for 4 hours. After the completion of the reaction, the reaction solution was concentrated to give (S) -2-amino-3- (2-chloro-4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -5-methoxyphenyl) propionic acid Cpd-16 (30 mg) hydrochloride in yield: 51%.
MS m/z(ESI):446[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.23(s,1H),8.02(s,1H),7.39(s,1H),7.10(s,1H),3.88(s,3H),3.61(s,1H),3.37(d,J＝5.1Hz,1H),2.91-2.70(m,2H),0.93-0.85(m,2H),0.74-0.66(m,2H).
Example 14
(S) -2-amino-3- (5- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -4-methoxypyridin-2-yl) propionic acid
The procedure of reference example 13 was followed, except that compound Cpd-16A was replaced with compound 2, 4-dibromo-5-nitropyridin Cpd-17A, to obtain compound (S) -2-amino-3- (5- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -4-methoxypyridin-2-yl) propionic acid Cpd-17.
MS m/z(ESI):413[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.88(s,1H),8.27(s,1H),7.47(d,J＝18.4Hz,2H),4.47(t,J＝6.7Hz,1H),4.04(s,3H),3.44(dd,J＝15.3,6.3Hz,1H),3.33(dd,J＝15.3,7.2Hz,1H),2.97–2.72(m,1H),0.79(dd,J＝6.9,4.6Hz,2H),0.71–0.60(m,2H).
Example 15
(S) -2-amino-3- (2-cyano-4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -5-methoxyphenyl) propionic acid
First step
Preparation of 2-bromo-4-fluoro-5-nitrobenzonitrile
2-bromo-4-fluorobenzonitrile Cpd-18A (3.0 g,15 mmol) and concentrated sulfuric acid (5 mL) were added to the reaction flask, potassium nitrate (1.6 g,16 mmol) was added at 0deg.C, and the reaction was carried out at room temperature for 1.5 hours. After the reaction was completed, it was then poured into ice water (20 mL), extracted with ethyl acetate (20 ml×3), and the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and concentrated to give 2-bromo-4-fluoro-5-nitrobenzonitrile Cpd-18B (3.4 g, pale yellow solid), yield: 83%.
1 H NMR(400MHz,DMSO-d6)δ8.89(d,J＝7.6Hz,1H),8.38(d,J＝10.7Hz,1H).
The procedure of the synthesis of example 13 was referred to, except that compound Cpd-16A was replaced with compound Cpd-18B in the first step of example 13, to obtain (S) -2-amino-3- (2-cyano-4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -5-methoxyphenyl) propionic acid Cpd-18.
MS m/z(ESI):437[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ13.90(s,1H),9.32(s,1H),8.86(s,1H),8.66(s,3H),8.48(s,1H),8.19(s,1H),7.45(s,1H),4.25(d,J＝4.8Hz,1H),3.98(s,3H),3.47–3.22(m,2H),2.84(dt,J＝6.9,3.1Hz,1H),1.02–0.67(m,4H).
Example 16
(S) -2-amino-3- (4-methoxy-3- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoic acid
First step
Preparation of benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (4-hydroxy-3-nitrophenyl) propionate
(benzyloxycarbonyl) -L-tyrosine benzyl ester Cpd-21A (1.0 g,2.5 mmol) was dissolved in dichloromethane (10 mL) and 20% dilute nitric acid (240 mg,3.7 mmol) was slowly added thereto. The reaction solution was reacted at room temperature for 8 hours. After completion of the reaction, methylene chloride (20 mL) was added thereto for dilution and then washed with water (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (4-hydroxy-3-nitrophenyl) propionate Cpd-21B (730 mg, yellow solid), yield: 60%.
1 H NMR(400MHz,DMSO-d6)δ10.83(s,1H),7.90(d,J＝8.2Hz,1H),7.80(d,J＝1.8Hz,1H),7.43(dd,J＝8.5,2.1Hz,1H),7.30(tt,J＝7.6,6.6Hz,10H),7.02(d,J＝8.5Hz,1H),5.12(s,2H),4.99(s,2H),4.34(td,J＝9.9,5.3Hz,1H),3.05(dd,J＝13.9,5.2Hz,1H),2.87(dd,J＝13.8,10.3Hz,1H).
Second step
Preparation of benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (4-methoxy-3-nitrophenyl) propionate
Benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (4-hydroxy-3-nitrophenyl) propionate Cpd-21B (470 mg,1.0 mmol) was dissolved in N, N-dimethylformamide (8 mL), to which was added sodium bicarbonate (132 mg,1.5 mmol) and methyl iodide (4474 mg,3.0 mmol). The reaction mixture was reacted at 25℃for 8 hours. After completion of the reaction, water (10 mL) was added thereto, followed by extraction with ethyl acetate (20 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (4-methoxy-3-nitrophenyl) propionate Cpd-21C (510 mg, yellow oil), yield: 81%.
MS m/z(ESI):487[M+23] + .
The procedure of reference example 1 was followed, except that compound Cpd-01D was replaced with compound Cpd-21C, to obtain compound (S) -2-amino-3- (4-methoxy-3- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propionic acid Cpd-21 (230 mg), yield: 88%.
MS m/z(ESI):386[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ13.83(s,1H),8.21(s,1H),8.17(s,1H),8.00(s,1H),7.21(d,J＝4.4Hz,1H),7.01(d,J＝8.4Hz,1H),6.92(dd,J＝8.4,1.8Hz,1H),4.04(s,1H),3.85(s,3H),3.04(d,J＝6.3Hz,2H),2.93(d,J＝4.3Hz,3H).
Example 17
(S) -2-amino-3- (3-methoxy-4- ((4-m-tolyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoic acid
First step
Preparation of 2-chloro-4-m-tolyl-5- (trifluoromethyl) pyrimidine
2, 4-dichloro-5- (trifluoromethyl) pyrimidine Cpd-27A (3.24 g,14.8 mmol), m-methylphenylboronic acid pinacol ester (3.24 g,14.8 mmol), bis triphenylphosphine palladium dichloride (1.04 g,1.48 mmol) and sodium carbonate (2.36 g,22.2 mmol) were dissolved in ethylene glycol (52 mL) and water (13 mL) and nitrogen was replaced and reacted at 40℃for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and then, the reaction mixture was filtered through celite, water (50 mL) was added thereto, and the mixture was extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated in vacuo to give crude product, which was purified by column (petroleum ether/ethyl acetate=2/1) to give 2-chloro-4-m-tolyl-5- (trifluoromethyl) pyrimidine Cpd-27B (600 mg, white oil). Yield: 15%.
MS m/z(ESI):273[M+1] + .
1 H NMR(400MHz,CDCl 3 )δ8.93(s,1H),7.39(dd,J＝16.0,9.5Hz,4H),2.43(s,3H).
The fourth to sixth steps of reference example 13, compound Cpd-07D was reacted with compound Cpd-27B to obtain compound (S) -2-amino-3- (3-methoxy-4- ((4-m-tolyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoic acid Cpd-27.
MS m/z(ESI):447[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.77(s,1H),8.42(d,J＝3.5Hz,3H),7.72(d,J＝8.1Hz,1H),7.42-7.27(m,4H),7.06(d,J＝1.5Hz,1H),6.83(dd,J＝8.1,1.3Hz,1H),4.26-4.10(m,1H),3.83(s,3H),3.13(qd,J＝14.3,6.2Hz,2H),2.37(s,3H).
Example 18
(S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-ethoxyphenyl) propionic acid
First step
Preparation of 4-bromo-2-ethoxy-1-nitrobenzene
5-bromo-2-nitrophenol Cpd-28A (1.0 g,4.6 mmol), ethyl iodide (1.0 g,6.9 mmol) and cesium carbonate (3.0 g,9.2 mmol) were added to acetone (10 mL) and reacted at 65℃for 3 hours. After completion of the reaction, water (20 mL) was added, extraction was performed with ethyl acetate (20 ml×3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated to give 4-bromo-2-ethoxy-1-nitrobenzene Cpd-28B (1.1 g, yellow solid), yield: 91%.
1 H NMR(400MHz,DMSO-d6)δ7.85(d,J＝8.6Hz,1H),7.61(d,J＝1.9Hz,1H),7.34(dd,J＝8.6,1.9Hz,1H),4.27(q,J＝7.0Hz,2H),1.35(t,J＝7.0Hz,3H).
The second to sixth steps of reference example 13 were different in that compound Cpd-16B was replaced with compound Cpd-28B to obtain compound (S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-ethoxyphenyl) propionic acid Cpd-28.
MS m/z(ESI):426[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ13.84(s,1H),8.78(s,1H),8.38(s,5H),7.89(s,1H),7.05(s,1H),6.86(d,J＝8.2Hz,1H),4.27–4.00(m,2H),3.11(s,2H),2.88(s,1H),1.49–1.23(m,4H),0.94–0.58(m,4H).
Example 19
(S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-ethynylphenyl) propanoic acid
First step
Preparation of methyl (S) -3- (4-amino-3-iodophenyl) -2- ((tert-butoxycarbonyl) amino) propanoate
Methyl (S) -3- (4-aminophenyl) -2- ((tert-butoxycarbonyl) amino) propanoate Cpd-32A (1.8 g,6.1 mmol) was dissolved in N, N-dimethylformamide (30 mL), N-iodosuccinimide (1.5 g,6.7 mmol) was added, and the reaction was stirred at 70℃for 16 hours. Ethyl acetate (100 mL) was added to the reaction solution, washed once with water (100 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column (dichloromethane/methanol=10/1) to give methyl (S) -3- (4-amino-3-iodophenyl) -2- ((tert-butoxycarbonyl) amino) propionate Cpd-32B (1.8 g, yellow oil), yield: 67%.
MS m/z(ESI):443[M+23] + .
Second step
Preparation of methyl (S) -2- ((tert-Butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-iodophenyl) propanoate
Methyl (S) -3- (4-amino-3-iodophenyl) -2- ((tert-butoxycarbonyl) amino) propanoate Cpd-32B (1.3 g,3.1 mmol) was dissolved in N-butanol (20 mL), 2-chloro-N-cyclopropyl-5- (trifluoromethyl) pyrimidin-4-amine (0.74 g,3.1 mmol) and trifluoroacetic acid (0.18 g,1.6 mmol) were added and stirred at 80℃for 16 hours. To the reaction solution was added ethyl acetate (150 mL), the organic phase was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and distilled to give a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-iodophenyl) propanoate Cpd-32C (0.75 g, pale yellow oil), yield: 35%.
MS m/z(ESI):622[M+1] + .
Third step
Preparation of methyl (S) -2- ((tert-Butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- ((trimethylsilyl) ethynyl) phenyl) propanoate
Methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-iodophenyl) propanoate Cpd-32C (200 mg,0.32 mmol) was dissolved in acetonitrile (5 mL), ethynyl trimethylsilane (35 mg,0.35 mmol), triethylenediamine (180 mg,1.6 mmol), chloroallylpalladium (II) dimer (47 mg,0.13 mmol), and tri-tert-butylphosphine (13 mg,0.06 mmol) were added. Stirring is carried out at 40 ℃ for 4 hours under the protection of nitrogen. The reaction solution was filtered, concentrated under reduced pressure to give crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- ((trimethylsilyl) ethynyl) phenyl) propanoate Cpd-32D (60 mg, white solid), yield: 47%.
MS m/z(ESI):592[M+1] + .
Fourth step
Preparation of (S) -2- ((tert-Butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-ethynylphenyl) propanoic acid
Methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- ((trimethylsilyl) ethynyl) phenyl) propanoate Cpd-32D (80 mg,0.13 mmol) was dissolved in a mixed solvent of tetrahydrofuran/water=1/4 (2 mL), lithium hydroxide monohydrate (11 mg,0.27 mmol) was added thereto and stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate (20 ml×2), the aqueous phase was adjusted to pH 3 to 4 with 20% hydrochloric acid, ethyl acetate (50 ml×2) was extracted, saturated brine (50 ml×2) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-ethynylphenyl) propionic acid Cpd-32E (60 mg, yellow oil), yield: 87%.
MS m/z(ESI):506[M+1] + .
Fifth step
Preparation of (S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-ethynylphenyl) propionic acid
(S) -2- ((tert-Butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-ethynylphenyl) propanoic acid Cpd-32E (50 mg,0.10 mmol) was added to a solution of hydrochloric acid/dioxane (4N, 2 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was lyophilized with water to give (S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-ethynylphenyl) propanoic acid Cpd-32 (40 mg), 99%
MS m/z(ESI):406[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.37(d,J＝27.3Hz,5H),7.85(s,1H),7.44(s,1H),7.35(d,J＝8.6Hz,1H),4.70(s,1H),4.20(d,J＝5.5Hz,1H),3.15-3.06(m,2H),2.85-2.83(m,1H),0.81-0.69(m,4H).
Example 20
(S) -2-amino-3- (4- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) propanoic acid
The fourth to sixth steps of reference example 13, compound Cpd-07D was reacted with the compound 2-chloro-N- (2- (dimethylphosphoryl) phenyl) -5-chloropyrimidin-4-amine to finally obtain the compound (S) -2-amino-3- (4- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionic acid Cpd-34.
Cpd-34：
MS m/z(ESI):490[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ11.20(s,1H),8.50(dd,J＝8.3,4.2Hz,1H),8.15(s,1H),8.06(s,1H),7.79(d,J＝8.1Hz,1H),7.54(m,3H),7.16(t,J＝7.2Hz,1H),6.98(s,1H),6.79(d,J＝8.1Hz,1H),3.82(s,3H),3.56(s,1H),3.16(dd,J＝14.2,4.2Hz,1H),2.85(dd,J＝14.3,8.3Hz,1H),1.78(d,J＝13.5Hz,6H).
Example 21
(S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- (deutero-methoxy) phenyl) propanoic acid:
first step
Preparation of 4-bromo-2- (deuterated methoxy) -1-nitrobenzene
5-bromo-2-nitrophenol Cpd-35A (1.0 g,4.6 mmol), deuterated iodomethane (1.0 g,6.9 mmol) and cesium carbonate (3.0 g,9.2 mmol) were added to acetone (10 mL) and reacted at 65℃for 3 hours. After the reaction was completed, water (20 mL) was added, extraction was performed with ethyl acetate (20 ml×3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated to give 4-bromo-2- (deuteromethoxy) -1-nitrobenzene Cpd-35B (1.0 g, yellow solid), yield: 87%.
1 H NMR(400MHz,DMSO-d6)δ7.85(d,J＝8.6Hz,1H),7.61(d,J＝1.9Hz,1H),7.34(dd,J＝8.6,1.9Hz,1H).
The procedure of reference example 13 was followed, except that compound Cpd-16B was replaced with compound Cpd-35B, to obtain compound (S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- (deutero-methoxy) phenyl) propanoic acid Cpd-35.
MS m/z(ESI):415[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ13.85(s,1H),8.80(s,1H),8.40(d,J＝36.3Hz,5H),7.87(s,1H),7.05(d,J＝1.3Hz,1H),6.86(dd,J＝8.3,1.5Hz,1H),4.19(s,1H),3.11(qd,J＝14.3,6.4Hz,2H),2.87(s,1H),1.25(s,1H),0.86–0.68(m,4H).
Example 22
(S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propanoic acid tert-butyl ester
First step
Preparation of tert-butyl (S) -2- ((tert-Butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propanoate
(S) -2- ((tert-Butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propanoic acid Cpd-07F (120 mg,0.23 mmol) was dissolved in dichloromethane (5 mL), tert-butanol (173 mg,2.30 mmol) and 4-dimethylaminopyridine (3 mg,0.02 mmol) were added at 0deg.C and reacted for 10 min, and N, N' -dicyclohexylcarbodiimide (97 mg,0.46 mmol) was added at 0deg.C. The reaction solution was warmed from 0 ℃ to room temperature and continued to react overnight. After the reaction was completed, the reaction solution was filtered with celite, and the crude product was distilled off by spin to obtain tert-butyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propanoate Cpd-36B (140 mg, white solid), yield: 95%.
MS m/z(ESI):568[M+1] + .
Second step
Preparation of tert-butyl (S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionate
To tert-butyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propanoate Cpd-36B (100 g,0.24 mmol) was added a solution of hydrogen chloride in dioxane (5 mL,4 mol/L). The reaction mixture was reacted at 25℃for 2 hours. After the completion of the reaction, the reaction solution was concentrated to give tert-butyl (S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propanoate Cpd-36 (15 mg) hydrochloride, yield: 14%.
MS m/z(ESI):468[M+1] + .
1 H NMR(400MHz,CD 3 OD)δ8.31(s,2H),7.12(s,1H),6.98(d,J＝8.1Hz,1H),4.27(t,J＝6.9Hz,1H),3.99(s,3H),3.23(d,J＝5.1Hz,2H),2.99(s,1H),1.46(s,9H),0.96(d,J＝5.6Hz,2H),0.86-0.75(m,2H).
Example 23
(S) - ((2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionyl) oxy) pivalate methyl ester
First step
Preparation of methyl (S) - ((2- ((tert-Butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionyl) oxy) pivalate
Cpd-07F (250 mg,0.48 mmol) of (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propanoic acid, iodomethyl pivalate (142 mg,0.58 mmol) and potassium carbonate (134 mg,0.97 mmol) were added to N, N-dimethylformamide (5 mL). The reaction was carried out at room temperature for 8 hours. After completion of the reaction, the reaction mixture was added to water (10 mL), extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. To give methyl (S) - ((2- ((tert-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionyl) oxy) pivalate Cpd-37B (320 mg, white oil), yield: 99%.
MS m/z(ESI):626[M+1] + .
Second step
Preparation of methyl (S) - ((2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionyl) oxy) pivalate
Methyl (S) - ((2- ((tert-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionyl) oxy) pivalate Cpd-37B (320 mg,0.51 mmol) was dissolved in hydrochloric acid/dioxane (4M, 10 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated and dried in vacuo to give methyl (S) - ((2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propionyl) oxy) pivalate Cpd-37 (250 mg) hydrochloride, yield: 88%.
MS m/z(ESI):526[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ8.61(s,3H),8.36(s,2H),7.08(s,1H),6.84(d,J＝8.2Hz,1H),5.84(d,J＝5.9Hz,1H),5.78(d,J＝5.9Hz,1H),4.46(s,2H),3.90(s,3H),3.11(s,2H),2.88(s,1H),1.15(s,9H),0.89–0.65(m,4H).
Example 24
(S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propanoic acid heptyl ester
The procedure of reference example 22 was followed, except that tert-butanol was replaced with heptanol, to obtain the compound (S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) propanoic acid heptyl ester Cpd-38.
MS m/z(ESI):510[M+1] + .
1 H NMR(400MHz,CD 3 OD)δ8.29(s,2H),7.07(s,1H),6.94(d,J＝8.2Hz,1H),4.37(t,J＝7.1Hz,1H),4.19(t,J＝6.6Hz,2H),3.98(s,3H),3.24(dd,J＝6.2,4.4Hz,2H),3.05-2.89(m,1H),1.66-1.54(m,2H),1.27(s,8H),0.95(dd,J＝7.1,5.4Hz,2H),0.87(t,J＝6.9Hz,3H),0.83-0.73(m,2H).
Example 25
(S) -2-amino-3- (3-methyl-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propionic acid
First step
Preparation of benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (3-methyl-4-nitro-1H-pyrazol-1-yl) propionate
Benzyl 3-methyl-4-nitro-1H-pyrazole Cpd-39A (0.8 g,6.5 mmol), (R) -2- ((benzyloxycarbonyl) amino) -3-iodopropionate (3.0 g,6.5 mmol) and cesium carbonate (2.7 g,7.8 mmol) were dissolved in N, N-dimethylformamide (20 mL) and stirred overnight at room temperature. After completion of the reaction, water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated in vacuo to give crude product, which was purified by column (petroleum ether/ethyl acetate=2/1) to give benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (3-methyl-4-nitro-1H-pyrazol-1-yl) propionate Cpd-39B (2.2 g, white oil), yield: 70%.
MS m/z(ESI):439[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ8.72(s,1H),7.96(dd,J＝11.9,8.5Hz,1H),7.37-7.30(m,10H),5.15(s,2H),5.02(d,J＝3.7Hz,2H),4.68(dt,J＝8.3,4.2Hz,1H),4.03(q,J＝7.1Hz,2H),1.17(t,J＝7.1Hz,3H).
Second step
Preparation of benzyl (S) -3- (4-amino-3-methyl-1H-pyrazol-1-yl) -2- ((benzyloxycarbonyl) amino) propionate
Benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (3-methyl-4-nitro-1H-pyrazol-1-yl) propionate Cpd-39B (1.0 g,2.3 mmol), iron powder (0.96 g,17 mmol) and saturated aqueous ammonium chloride (0.18 g,3.5 mmol) were dissolved in ethanol (10 mL) and refluxed for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and was filtered with celite, water (5 mL) was added, ethyl acetate (10 ml×3) was extracted, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and distilled off to give a crude product, which was purified by column (petroleum ether/ethyl acetate=1/2) to give benzyl (S) -3- (4-amino-3-methyl-1H-pyrazol-1-yl) -2- ((benzyloxycarbonyl) amino) propionate Cpd-39C (0.4 g, brown oil), yield: 42%.
MS m/z(ESI):409[M+1] + .
Third step
Preparation of benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (3-methyl-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propionate
Benzyl (S) -3- (4-amino-3-methyl-1H-pyrazol-1-yl) -2- ((benzyloxycarbonyl) amino) propionate Cpd-39C (0.4 g,0.98 mmol), 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (0.2 g,0.98 mmol) was dissolved in N-butanol (10 mL), and trifluoroacetic acid (0.12 g,0.98 mmol) was added and reacted at 90℃for 1 hour. After the reaction was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (10 ml×3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the crude product was purified by column (petroleum ether/ethyl acetate=1/1) to give benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (3-methyl-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propionate Cpd-39D (0.29 g,0.5 mmol), yield: 51%.
MS m/z(ESI):584[M+1] + .
Fourth step
Preparation of (S) -2-amino-3- (3-methyl-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propionic acid
Benzyl (S) -2- ((benzyloxycarbonyl) amino) -3- (3-methyl-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propionate Cpd-39D (0.2 g,0.34 mmol), palladium on carbon (0.04 g) was added to methanol (10 mL), and replaced with hydrogen, and reacted at room temperature for 1 hour. After the reaction, the reaction mixture was filtered with celite, and the filtrate was dried to give a crude product, which was isolated and purified by reverse preparation (acetonitrile/water (1 millof trifluoroacetic acid)) to give (S) -2-amino-3- (3-methyl-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propionic acid Cpd-39 (0.08 g,0.22 mmol), yield: 67%
MS m/z(ESI):360[M+1] + .
1 H NMR(400MHz,MeOD)δ7.98-7.72(m,2H),4.61(s,2H),4.36(s,1H),3.05(s,3H),2.20(s,3H).
Example 26
(S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) propionic acid
First step
Preparation of methyl (S) -2- ((tert-Butoxycarbonyl) amino) -3- (3-methyl-4-nitro-1H-pyrazol-1-yl) propanoate
Methyl 3-methyl-4-nitro-1H-pyrazole Cpd-40A (1.9 g,15.2 mmol), (R) -2- ((tert-butoxycarbonyl) amino) -3-iodopropionate (5.0 g,15.2 mmol) and cesium carbonate (6.0 g,18.2 mmol) were dissolved in N, N-dimethylformamide (40 mL) and stirred overnight at room temperature. After completion of the reaction, water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated in vacuo to give crude product, which was purified by column (petroleum ether/ethyl acetate=2/1) to give methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (3-methyl-4-nitro-1H-pyrazol-1-yl) propanoate Cpd-40B (3.5 g, white oil), yield: 70%.
MS m/z(ESI):329[M+1] + .
Second step
Preparation of methyl (S) -3- (4-amino-3-methyl-1H-pyrazol-1-yl) -2- ((tert-butoxycarbonyl) amino) propanoate
Methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (3-methyl-4-nitro-1H-pyrazol-1-yl) propanoate Cpd-40B (0.5 g,1.5 mmol) and palladium on carbon (0.05 g) were added to methanol (10 mL), and replaced with hydrogen, and reacted at room temperature for 1 hour. After the reaction, the reaction mixture was filtered through celite, and the filtrate was dried to give crude (S) -methyl 3- (4-amino-3-methyl-1H-pyrazol-1-yl) -2- ((t-butoxycarbonyl) amino) propanoate Cpd-40C (0.4 g, pink oil), yield: 88%.
MS m/z(ESI):299[M+1] + .
Third step
Preparation of methyl (S) -2- ((tert-Butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) propanoate
Methyl (S) -3- (4-amino-3-methyl-1H-pyrazol-1-yl) -2- ((tert-butoxycarbonyl) amino) propanoate Cpd-40C (0.40 g,1.3 mmol), 2-chloro-N-cyclopropyl-5- (trifluoromethyl) pyrimidin-4-amine (0.32 g,1.3 mmol) was dissolved in N-butanol (8 mL), and trifluoroacetic acid (0.15 g,1.3 mmol) was added and reacted at 90℃for 1 hour. After the reaction was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (10 ml×3), and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and distilled to give crude product, which was purified by column (petroleum ether/ethyl acetate=1/1) to give methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) propanoate Cpd-40D (0.2 g,0.4 mmol), yield: 30%.
MS m/z(ESI):500[M+1] + .
Fourth step
Preparation of (S) -2- ((tert-Butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) propionic acid
Methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) propanoate Cpd-40D (0.2 g,0.4 mmol) was dissolved in tetrahydrofuran (5 mL), and a saturated aqueous lithium hydroxide solution (0.5 mL) was added to the solution, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, the pH was adjusted to 4 with dilute hydrochloric acid, extracted with a mixed solvent (dichloromethanol/methanol=10/1), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to obtain crude product, which was purified by column to obtain Cpd-40E (0.15 g, white solid) of (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) propionic acid, yield: 77%.
MS m/z(ESI):486[M+1] + .
Fifth step
Preparation of (S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) propionic acid
(S) -2- ((tert-Butoxycarbonyl) amino) -3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) propanoic acid Cpd-40E (0.15 g,0.31 mmol) was dissolved in HCl/1, 4-dioxane (15 mL) and stirred at 25℃for 1 hour. After the reaction, the filtrate was dried to give a crude product, and (S) -2-amino-3- (4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) propionic acid Cpd-40 (46 mg) was isolated and purified by reverse preparation (acetonitrile/water (1% of formic acid)), yield: 39%.
MS m/z(ESI):386[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.22(s,1H),8.12(s,1H),7.61(s,3H),7.02(s,1H),4.39(s,1H),4.20(dd,J＝14.4,8.0Hz,1H),3.55(d,J＝4.8Hz,1H),2.92(s,1H),2.19(s,3H),0.81(s,2H),0.64(s,2H).
Example 27
(S) -2-amino-3- (3-cyclopropyl-4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propionic acid
The procedure of reference example 26 was followed, except that 3-methyl-4-nitro-1H-pyrazole Cpd-40A was replaced with the compound 3-cyclopropyl-4-nitro-1H-pyrazole Cpd-41A as starting compound, to give the compound (S) -2-amino-3- (3-cyclopropyl-4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propionic acid Cpd-41.
MS m/z(ESI):412[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.29–8.09(m,3H),7.02(s,1H),4.36(d,J＝13.2Hz,1H),4.15(dd,J＝14.4,7.8Hz,1H),3.49(d,J＝4.8Hz,2H),2.93(s,1H),2.18(s,1H),0.80–0.61(m,8H).
Example 28
(S) -2-amino-3- (4- ((3S, 4S) -4- (5-chloro-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) phenyl) propanoic acid
First step
Preparation of (3S, 4S) -3-fluoro-4- (4-nitro-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester
(3S, 4R) -3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester Cpd-42A (2.0 g,91 mmol), 4-nitro-1H-pyrazole (1.1 g,10 mmol), triphenylphosphine (3.6 g,14 mmol) was dissolved in tetrahydrofuran (100 mL) and diisopropyl azodicarboxylate (2.8 g,14 mmol) was added dropwise at 0deg.C under nitrogen. After the completion of the dropwise addition, the mixture was stirred at 35℃overnight. After the reaction was completed, the mixture was concentrated under reduced pressure, methylene chloride (100 mL) was added to the residue, the residue was washed once with water, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. Purification of the crude product by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) gave the compound (3 s,4 s) -3-fluoro-4- (4-nitro-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester Cpd-42B (2.6 g, pale yellow oil), yield: 86%.
1 H NMR(400MHz,CDCl 3 )δ8.27(s,1H),8.13(s,1H),4.83-4.69(m,2H),4.28(dt,J＝10.5,6.3Hz,2H),2.87(s,2H),2.28-2.14(m,2H),1.49(s,9H).
Second step
Preparation of (3S, 4S) -4- (5-chloro-4-nitro-1H-pyrazol-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester
(3S, 4S) -3-fluoro-4- (4-nitro-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester Cpd-42B (2.6 g,8.2 mmol) was dissolved in tetrahydrofuran (50 mL) and nitrogen blanketed, and a solution of lithium bistrimethylsilylamino in tetrahydrofuran (16.4 mL,1mol/L,16.4 mmol) was added dropwise at-78deg.C. After the addition was completed, stirring was continued for 40 minutes at-78 ℃. A solution of hexachloroethane (3.9 g,16.4 mmol) in tetrahydrofuran was then added dropwise at-78 ℃. After the completion of the dropwise addition, stirring was continued for 30 minutes at-78 ℃. After the reaction was completed, saturated ammonium chloride (50 mL) was added to the reaction mixture to quench the reaction mixture. Ethyl acetate extraction (100 ml×2), drying of the organic layer over anhydrous sodium sulfate and concentration under reduced pressure gave crude product. Purification of the crude product by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) gave (3 s,4 s) -4- (5-chloro-4-nitro-1H-pyrazol-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester Cpd-42C (2.5 g, pale yellow oil), yield: 83%.
1 H NMR(400MHz,CDCl 3 )δ8.24(s,1H),4.97-4.78(m,1H),4.57-4.51(m,2H),4.27(s,1H),2.90(d,J＝10.8Hz,2H),2.26-2.18(m,1H),2.00-1.98(m,1H),1.49(s,9H).
Third step
Preparation of (3S, 4S) -4- (4-amino-5-chloro-1H-pyrazol-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester
(3S, 4S) -4- (5-chloro-4-nitro-1H-pyrazol-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester Cpd-42C (2.4 g,6.9 mmol) was dissolved in the mixed solvent (60 mL, ethanol/water=5/1), reduced iron powder (2.9 g,51 mmol) and ammonium chloride (1.1 g,21 mmol) were added, and stirred at 75℃for 2 hours. After completion of the reaction, the reaction mixture was filtered through celite while it was still hot, concentrated under reduced pressure, ethyl acetate (200 mL) was added to the residue to extract it, washed once with water, and the organic layer was dried over anhydrous sodium sulfate and concentrated. Purification of the crude product by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) gave (3 s,4 s) -4- (4-amino-5-chloro-1H-pyrazol-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester Cpd-42D (1.7 g, yellow oil), yield: 74%.
MS m/z(ESI):319[M+1] + .
Fourth step
Preparation of (3S, 4S) -4- (5-chloro-4- ((4-methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester
(3S, 4S) -4- (4-amino-5-chloro-1H-pyrazol-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester Cpd-42D (1.6 g,5.0 mmol) was dissolved in ethylene glycol monomethyl ether (30 mL), 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (2.1 g,10 mmol) and trifluoroacetic acid (0.57 g,5.0 mmol) were added and stirred at room temperature for 16 hours. To the reaction solution was added ethyl acetate (500 mL), the organic phase was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and distilled to give crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give (3 s,4 s) -4- (5-chloro-4- ((4-methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester Cpd-42E (1.9 g, pale yellow oil), yield: 72%.
MS m/z(ESI):494[M+1] + .
Fifth step
N 2 - (5-chloro-1- ((3 s,4 s) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -N 4 Preparation of (E) -methyl-5-) trifluoromethyl pyrimidine-2, 4-diamine
To (3 s,4 s) -4- (5-chloro-4- ((4-methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester Cpd-42E (1.9 g,3.8 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL) and stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was adjusted to pH 8-9 with saturated sodium carbonate solution, extracted with ethyl acetate (200 mL. Times.2), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give N 2 - (5-chloro-1- ((3 s,4 s) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -N 4 -methyl-5-) trifluoromethyl pyrimidine-2, 4-diamine Cpd-42F (1.6 g, pale yellow solid), yield: 95%.
MS m/z(ESI):394[M+1] + .
Sixth step
Preparation of methyl (S) -2- ((tert-Butoxycarbonyl) amino) -3- (4- ((3S, 4S) -4- (5-chloro-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) phenyl) propanoate
Will N 2 - (5-chloro-1- ((3 s,4 s) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -N 4 Methyl-5-) trifluoromethyl pyrimidine-2, 4-diamine Cpd-42F (500 mg,1.3 mmol) was dissolved in dioxane (10 mL), to which methyl N- (t-butoxycarbonyl) -L-4-bromophenylalaninate (1.4G, 3.8 mmol), cesium carbonate (495mg, 1.5 mmol) and XPhos Pd G3 (214 mg,0.25 mmol) were added and reacted at 105℃for 16 hours under nitrogen. The reaction solution was passed through celite Filtration over earth, addition of ethyl acetate (50 mL), washing once with water, drying of the organic phase over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified on a silica gel column (petroleum ether/ethyl acetate=4/1) to give (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- ((3S, 4S) -4- (5-chloro-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) phenyl) propanoic acid methyl ester Cpd-42G (100 mg, pale yellow oil), yield: 11%.
MS m/z(ESI):671[M+1] + .
Seventh step
Preparation of methyl (S) -2-amino-3- (4- ((3S, 4S) -4- (5-chloro-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) phenyl) propanoate
Methyl (S) -2- ((tert-Butoxycarbonyl) amino) -3- (4- ((3S, 4S) -4- (5-chloro-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) phenyl) propanoate Cpd-42G (90 mg,0.13 mmol) was dissolved in dioxane (0.1 mL), HCl/dioxane (2 mL, 4M) was added thereto and stirred at room temperature for 1 hour. The reaction solution was concentrated to give methyl (S) -2-amino-3- (4- ((3S, 4S) -4- (5-chloro-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) phenyl) propanoate Cpd-42H (70 mg, pale yellow solid), yield: 87%.
MS m/z(ESI):571[M+1] + .
Eighth step
Preparation of (S) -2-amino-3- (4- ((3S, 4S) -4- (5-chloro-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) phenyl) propanoic acid
Preparation of methyl (S) -2-amino-3- (4- ((3S, 4S) -4- (5-chloro-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) phenyl) propanoate Cpd-42H (70 mg,0.12 mmol) was dissolved in a mixed solvent (1 mL, methanol/water=10/1), to which was added lithium hydroxide (6 mg,0.25 mmol) and stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 3 to 4 with 20% hydrochloric acid, and the resulting solution was directly purified by reverse phase preparation (ACN/H 2 O (0.1% TFA)), to give (S) -2-amino-3- (4- ((3S, 4S) -4- (5-chloro-4-)(4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) phenyl) propionic acid Cpd-42 (10 mg), yield: 14%.
MS m/z(ESI):557[M+1] + .
H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.09(s,1H),7.90(s,1H),7.14(d,J＝8.2Hz,2H),7.03(s,1H),6.97(d,J＝8.3Hz,2H),5.05-4.86(m,1H),4.68-4.59(m,1H),4.13(d,J＝11.8Hz,1H),3.77(s,1H),3.32(s,1H),3.03-2.97(m,4H),2.82(s,3H),2.21-2.13(m,1H),2.11-2.00(m,1H).
Example 29
(S) -2-amino-3- (3- ((3S, 4S) -4- (5-chloro-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) phenyl) propanoic acid
The synthetic procedure of reference example 28 was followed, first, to give compound Cpd-42F, in which methyl (S) -3- (4-bromophenyl) -2- (tert-butoxycarbonyl) amino) propionate was used in the sixth step in place of methyl N- (tert-butoxycarbonyl) -L-3-bromophenylalaninate to give compound Cpd-43 (35 mg) as (S) -2-amino-3- (3- ((3S, 4S) -4- (5-chloro-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) phenyl) propanoic acid, yield: 49%.
MS m/z(ESI):557[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.45(d,J＝38.1Hz,4H),8.09(d,J＝41.9Hz,2H),7.20(t,J＝7.8Hz,1H),7.02-6.97(m,2H),6.73(d,J＝7.4Hz,1H),4.96(d,J＝52.1Hz,1H),4.76-4.71(m,,1H),4.19(s,2H),3.85-3.82(m,1H),3.15-3.03(m,4H),2.92(s,3H),2.22-2.10(m,2H).
Example 30
(S) -2-amino-3- ((3S, 4S) -4- (5-chloro-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) propanoic acid
First step
Preparation of (S) -2- ((tert-Butoxycarbonyl) amino) -3- ((3S, 4S) -4- (5-chloro-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) propionic acid
Will N 2 - (5-chloro-1- ((3 s,4 s) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -N 4 Methyl-5-) trifluoromethyl pyrimidine-2, 4-diamine Cpd-42F (200 mg,0.51 mmol) was dissolved in dichloromethane (10 mL), to which was added Compound F-1 (142 mg,0.76 mmol) and reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified on a silica gel column (petroleum ether/ethyl acetate=5/1) to give (S) -2- ((tert-butoxycarbonyl) amino) -3- ((3S, 4S) -4- (5-chloro-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) propionic acid Cpd-44B (60 mg, pale yellow oil), yield: 19%.
MS m/z(ESI):581[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.63(s,1H),8.99(s,1H),8.09(s,1H),7.87(s,1H),7.00(d,J＝11.3Hz,2H),4.88-4.70(m,1H),4.40-4.35(m,1H),4.16-4.04(m,4H),2.88-2.75(m,6H),2.34 -2.29(m,2H),2.02-1.89(m,1H),1.40(s,9H).
Second step
(S) -2-amino-3- ((3S, 4S) -4- (5-chloro-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) propanoic acid
(S) -2- ((tert-Butoxycarbonyl) amino) -3- ((3S, 4S) -4- (5-chloro-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) propanoic acid Cpd-44B (50 mg,0.09 mmol) was dissolved in dioxane (0.5 mL), HCl/dioxane (2 mL, 4M) was added thereto and stirred at room temperature for 1 hour. The reaction solution was concentrated and dried in vacuo to give (S) -2-amino-3- ((3S, 4S) -4- (5-chloro-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) propionic acid Cpd-44 (27 mg) as the hydrochloride salt, yield: 50%.
MS m/z(ESI):481[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.44(s,4H),8.02(s,1H),5.09(d,J＝48.5Hz,1H),4.51-4.30(m,2H),3.77-3.49(m,1H),3.05-2.91(m,6H),2.67(s,1H),2.19(dd,J＝17.8,10.2Hz,1H),2.01(s,1H).
Example 31
(S) -2-amino-3- ((3S, 4S) -4- (5-chloro-4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) propionic acid
First step
Preparation of (3S, 4S) -4- (5-chloro-4- ((4-cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester
(3S, 4S) -4- (4-amino-5-chloro-1H-pyrazol-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester Cpd-42D (500 mg,1.6 mmol) was dissolved in ethylene glycol monomethyl ether (10 mL), 2-chloro-N-cyclopropyl-5- (trifluoromethyl) pyrimidin-4-amine (447 mg,1.9 mmol) and trifluoroacetic acid (178 mg,1.6 mmol) were added, and stirred at room temperature for 16 hours. To the reaction solution was added ethyl acetate (150 mL), the organic phase was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and distilled to give crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give (3 s,4 s) -4- (5-chloro-4- ((4-cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester Cpd-45B (580 mg, pale yellow oil), yield: 70%.
MS m/z(ESI):520[M+1] + .
And a second step of: reference example 28 fifth step, boc deprotection of Compound Cpd-45B to give Compound N 2 - (5-chloro-1- ((3 s,4 s) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -N 4 -cyclopropyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine Cpd-45C (180 mg, pale yellow solid), yield: 98%.
MS m/z(ESI):420[M+1] + .
Third and fourth steps referring to the first and second steps of example 30, the hydrochloride salt of the compound (S) -2-amino-3- ((3S, 4S) -4- (5-chloro-4- ((4- (cyclopropylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) propionic acid Cpd-45 (30 mg) was obtained in the yield: 50%.
MS m/z(ESI):507[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.51(s,1H),8.49(d,J＝22.2Hz,4H),8.17(s,1H),5.15(d,J＝48.9Hz,1H),4.61-4.56(m,1H),4.42(s,1H),3.83-3.73(m,1H),3.30-3.11(m,3H),2.90(s,3H),2.30(m,1H),2.09(s,1H),0.74(d,J＝3.9Hz,4H).
Example 32
(S) -2-amino-3- (5-chloro-2-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoic acid
First step
Preparation of 1-bromo-5-chloro-2-methoxy-4-nitrobenzene
2-bromo-4-chloro-5-nitrophenol Cpd-54A (1.0 g,3.9 mmol), methyl iodide (1.0 g,5.9 mmol) and cesium carbonate (3.0 g,7.9 mmol) were added to acetone (20 mL) and reacted at 65℃for 5 hours. After completion of the reaction, water (20 mL) was added thereto, extraction was performed with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product obtained was isolated and purified by silica gel column (petroleum ether/ethyl acetate=5/1) to give 1-bromo-5-chloro-2-methoxy-4-nitrobenzene Cpd-54B (1.0 g, yellow solid), yield: 97%.
1 H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.82(s,1H),3.95(s,3H).
Second step
Preparation of methyl (S) -2- ((tert-Butoxycarbonyl) amino) -3- (5-chloro-2-methoxy-4-nitrobenzene) propanoate
1-bromo-5-chloro-2-methoxy-4-nitrobenzene Cpd-54B (1.0 g,3.8 mmol), bis (triphenylphosphine) palladium dichloride (0.27 g,0.38 mmol), cuprous iodide (0.17 g,0.92 mmol) and N, N-dimethylformamide (20 mL) were added to a three-necked flask, the mixture was placed in an oil bath at 80℃for 10 minutes after replacing nitrogen three times, and then a solution of methyl (R) -2- (t-butoxycarbonyl) amino) -3-iodopropionate in zinc iodide in N, N-dimethylformamide was slowly dropped by syringe. The reaction solution was stirred at 80℃for 0.5 hours. After the completion of the reaction, the reaction mixture was filtered through celite, then poured into water (30 mL), extracted with ethyl acetate (50 ml×3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The crude product obtained was isolated and purified by silica gel column (petroleum ether/ethyl acetate=3/1) to give (S) -2- ((tert-butoxycarbonyl) amino) -3- (5-chloro-2-methoxy-4-nitrobenzene) propionic acid methyl ester Cpd-54C (700 mg, yellow solid), yield: 47%.
MS m/z(ESI):411[M+23] + .
Third step
Preparation of methyl (S) -3- (4-amino-5-chloro-2-methoxyphenyl) -2- ((tert-butoxycarbonyl) amino) propanoate
Methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (5-chloro-2-methoxy-4-nitrobenzene) propanoate Cpd-54C (700 mg,1.8 mmol), ammonium chloride (144 mg,2.7 mmol) and iron powder (753 mg,13 mmol) were added to a mixed solvent (ethanol/water=5/1, 18 mL) and reacted under nitrogen atmosphere at 75 ℃ for 1 hour. After the reaction was completed, the reaction solution was filtered through celite, the filtrate was concentrated and poured into water (30 mL), extracted with ethyl acetate (50 ml×3), dried over anhydrous sodium sulfate and concentrated, and the obtained crude product was purified by separation on a silica gel column (petroleum ether/ethyl acetate=5/1) to give (S) -methyl 3- (4-amino-5-chloro-2-methoxyphenyl) -2- ((t-butoxycarbonyl) amino) propionate Cpd-54D (500 mg, orange-red solid), yield: 78%.
MS m/z(ESI):381[M+23] + .
Fourth step
Preparation of methyl (S) -2- ((tert-Butoxycarbonyl) amino) -3- (5-chloro-2-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoate
Methyl (S) -3- (4-amino-5-chloro-2-methoxyphenyl) -2- ((tert-butoxycarbonyl) amino) propanoate Cpd-54D (500 mg,1.4 mmol), 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (317 mg,1.7 mmol) were added to tert-butanol (10 mL), followed by the addition of trifluoroacetic acid (80 mg,0.70 mmol), dichloromethane (10 mL) and nitrogen substitution three times. The reaction mixture was reacted at 80℃for 1 hour. After the reaction was completed, the reaction solution was concentrated, followed by addition of ethyl acetate, filtration after stirring, and washing of the filter cake with ethyl acetate to give methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (5-chloro-2-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoate Cpd-54E (360 mg, white solid), yield: 48%.
MS m/z(ESI):534[M+1] + .
Fifth step
Preparation of (S) -2- ((tert-Butoxycarbonyl) amino) -3- (5-chloro-2-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoic acid
Methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (5-chloro-2-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoate Cpd-54E (360 mg,0.67 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of lithium hydroxide (49 mg,2.0 mmol) in water (5 mL) was added dropwise and reacted at room temperature for 1 hour. After the reaction was completed, poured into water (20 mL), the aqueous phase was adjusted to pH 4 with dilute hydrochloric acid (1 mol/L), ethyl acetate (20 ml×3) was extracted, and the organic phases were combined and concentrated to give (S) -2- ((t-butoxycarbonyl) amino) -3- (5-chloro-2-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propionic acid Cpd-54F (190 mg, white solid), yield: 54%.
MS m/z(ESI):520[M+1] + .
Sixth step
Preparation of (S) -2-amino-3- (5-chloro-2-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoic acid
(S) -2- ((tert-Butoxycarbonyl) amino) -3- (5-chloro-2-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoic acid Cpd-54F (190 mg,0.37 mmol) was dissolved in a dioxane solution of hydrogen chloride (10 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated and dried in vacuo to give (S) -2-amino-3- (5-chloro-2-methoxy-4- ((4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) propanoic acid Cpd-54 (168 mg), yield: 95%.
MS m/z(ESI):420[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ13.73(s,1H),9.54(s,1H),8.35(s,4H),8.00(s,1H),7.67(s,1H),7.35(s,1H),4.06(d,J＝5.5Hz,1H),3.78(s,3H),3.19–2.96(m,2H),2.91(d,J＝4.4Hz,3H).
Example 33
2-amino-3- (2, 5-dimethoxy-4- (4-methylamino) -5-trifluoromethylpyrimidin-2-ylamino) phenyl) propionic acid
First step
Preparation of 2, 5-dimethoxy-4-nitro bromobenzene
2-bromo-1, 4-dimethoxybenzene Cpd-55A (1.0 g,4.6 mmol) was dissolved in acetonitrile (2 mL), stirred at room temperature and concentrated nitric acid (0.4 mL) was slowly added and the mixture reacted at room temperature for 15 min. After the reaction was completed, water (10 mL) was added to the reaction solution, the reaction solution was filtered to obtain a solid, and the crude product was distilled off in a rotary manner to obtain 2, 5-dimethoxy-4-nitrobromobenzene Cpd-55B (1.1 g, yellow solid), yield: 92%.
1 H NMR(400MHz,DMSO-d6)δ7.68(d,J＝1.9Hz,1H),7.64(s,1H),3.91(s,3H),3.87(s,3H).
Second step
Preparation of methyl 2- (tert-butoxycarbonyl) amino-3- (2, 5-dimethoxy-4-nitrophenyl) propionate
Zinc powder (0.98 g,15 mmol) and iodine (0.19 g,0.75 mmol) were replaced with nitrogen in a three-necked flask and heated to sublimate the iodine. 2, 5-dimethoxy-4-nitrobromobenzene Cpd-55B (0.4 g,1.5 mmol) was dissolved in N, N-dimethylformamide (10 mL), and the solution was rapidly poured into a three-necked flask and stirred. Meanwhile, cuprous iodide (0.07 g,0.36 mmol), ditriphenylphosphine palladium dichloride (0.11 g,0.15 mmol), methyl (R) -2- ((t-butoxycarbonyl) amino) -3-iodopropionate (1.0 g,3 mmol), was added to another three-necked flask, dissolved in N, N-dimethylformamide (10 mL) and replaced with nitrogen, and reacted at 80℃for 30 minutes. The mixed solution with zinc powder was sucked out by a syringe and rapidly injected into a three-necked flask for reaction at 80℃and the reaction was continued for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature and was filtered with celite, quenched with water (20 mL), extracted with ethyl acetate (20 ml×3), and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and distilled off to give a crude product, which was purified by column (petroleum ether/ethyl acetate=3/1) to give methyl 2- (tert-butoxycarbonyl) amino-3- (2, 5-dimethoxy-4-nitrophenyl) propionate Cpd-55C (400 mg, yellow oil). Yield: 35%.
MS m/z(ESI):385[M+1] + .
Third step
Preparation of methyl 3- (4-amino-2, 5-dimethoxyphenyl) -2- (t-butoxycarbonyl) amino) propionate
Methyl 2- (tert-butoxycarbonyl) amino-3- (2, 5-dimethoxy-4-nitrophenyl) propionate Cpd-55C (400 mg,1 mmol) was dissolved in methanol (10 mL), palladium on carbon (109 mg,0.1 mmol) was added, the reaction was allowed to react at room temperature under hydrogen for 1 hour, after the completion of the reaction, the reaction solution was filtered through celite, rinsed with methanol, and the crude methyl 3- (4-amino-2, 5-dimethoxyphenyl) -2- (tert-butoxycarbonyl) amino) propionate Cpd-55D (200 mg, yellow oil) was obtained by rotary evaporation. Yield: 55%.
MS m/z(ESI):355[M+1] + .
Fourth step
Preparation of methyl 2-tert-butoxycarbonylamino-3- (2, 5-dimethoxy-4- (4-methylamino) -5-trifluoromethyl pyrimidin-2-ylamino) phenyl) propanoate
Methyl 3- (4-amino-2, 5-dimethoxyphenyl) -2- (t-butoxycarbonyl) amino) propionate Cpd-55D (200 mg,0.56 mol), 2-chloro-N-cyclopropyl-5- (trifluoromethyl) pyrimidin-4-amine (159.61 mg,0.67 mmol) and trifluoroacetic acid (32 mg,0.28 mmol) were dissolved in N-butanol (10 mL) and reacted at 90℃for 1 hour. After the reaction was completed, cooled to room temperature, the crude product was distilled off by rotary evaporation, and methyl 2-t-butoxycarbonylamino-3- (2, 5-dimethoxy-4- (4-methylamino) -5-trifluoromethylpyrimidin-2-ylamino) phenyl) propanoate Cpd-55E (100 mg, white solid) was obtained by column purification (petroleum ether/ethyl acetate=3/1). Yield: 34%.
MS m/z(ESI):530[M+1] + .
Fifth step
Preparation of 2-Boc-amino-3- (2, 5-dimethoxy-4- (4-methylamino) -5-trifluoromethyl-pyrimidin-2-ylamino) phenyl) propionic acid
Methyl 2-t-Butoxycarbonylamino-3- (2, 5-dimethoxy-4- (4-methylamino) -5-trifluoromethyl-pyrimidin-2-ylamino) phenyl) propanoate Cpd-55E (100 mg,0.18 mmol) was dissolved in tetrahydrofuran (5 mL), and an aqueous lithium hydroxide solution (0.5 mL) was added and reacted at room temperature for 1 hour. After the reaction was completed, the pH was adjusted to neutrality with dilute hydrochloric acid, extracted with dichloromethanol/methanol (10/1), and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary distilled to obtain 2-t-butoxycarbonylamino-3- (2, 5-dimethoxy-4- (4-methylamino) -5-trifluoromethylpyrimidin-2-ylamino) phenyl) propionic acid Cpd-55F (70 mg, white solid), yield: 76%.
MS m/z(ESI):516[M+1] + .
Sixth step
Preparation of 2-amino-3- (2, 5-dimethoxy-4- (4-methylamino) -5-trifluoromethylpyrimidin-2-ylamino) phenyl) propionic acid
Cpd-55F (70 mg,0.13 mmol) of 2-t-butoxycarbonylamino-3- (2, 5-dimethoxy-4- (4-methylamino) -5-trifluoromethylpyrimidin-2-ylamino) phenyl) propionic acid was added to a solution of hydrogen chloride dioxane (4 mL,4 mol/L). The reaction solution was reacted at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was concentrated and purified by reverse direction to give Cpd-55 (30 mg) 2-amino-3- (2, 5-dimethoxy-4- (4-methylamino) -5-trifluoromethylpyrimidin-2-ylamino) phenyl) propanoic acid. Yield: 56%.
MS m/z(ESI):416[M+1] + .
1 H NMR(400MHz,CD 3 OD)δ8.29(s,1H),8.16(s,1H),8.10(s,1H),6.92(s,1H),3.90(s,3H),3.87(s,3H),3.87–3.80(m,2H),3.37(dd,J＝14.3,4.1Hz,1H),3.09(s,3H),2.95(dd,J＝14.3,8.8Hz,1H).
Biological evaluation
Test example 1 determination of inhibitory Activity of Compounds of the invention against recombinant human LRRK2 protein
Biochemical assay of (one) Compounds
Experimental purposes:
the transfer of the energy signal (520 nM/485nM fluorescence signal ratio) resulting from the binding of the phosphate group of phosphorylated Fluorescein-ERM (LRRKtide) peptide to the LanthaScreen. Tb-pERM (pLRRKtide) anti Antibody was detected by homogeneous time-resolved fluorescence. The LRRK2 kinase inhibition IC50 values of the test compounds were calculated.
Experimental materials:
1. the reaction solution:
LRRK2:Invitrogen-PR8604B
Fluorescein-ERM(LRRKtide)peptide:Invitrogen-PV4901
ATP:Sigma-A7699
Tb-anti-pLRRKtide antibody:Invitrogen-PV4900
lrrk2 final concentration
LRRK2:2nM
Fluorescein-ERM(LRRKtide)peptide:400nM
ATP:38μM
Tb-anti-pLRRKtide antibody:0.25nM
Experimental procedure:
1. compound dilution is carried out by using Echo, and the final concentration is 10 mu M-0.17 nM;
2. mu.L of protease and peptide mixture was added to the wells of the assay plate (containing compound);
3.1000 rpm, centrifuging for about 15 seconds, and incubating at 23 ℃ for 15 minutes;
4. the reaction was started by adding 5. Mu.L/well ATP solution;
5. the plates were inspected at 1000 rpm for about 15 seconds and closed with a sealing film;
incubating at 6.23 ℃ for 120min;
7. adding 10 mu L/hole antibody detection solution to stop the reaction;
8.1000 revolutions per minute of the heart test plate for about 15 seconds, and incubating at 23 ℃ for 60 minutes;
9. the assay plate was read at Envision.
10. Relative enzyme activity inhibition was calculated by signal ratio versus DMSO blank and IC50 values were calculated using software XLfit5 fitted curve.
Experimental results:
TABLE 1LRRK2 kinase inhibition Activity test results
The experiment shows that the compounds have better LRRK2 enzyme inhibition activity.
(II) pharmacokinetic assay
Experimental purposes:
study of the pharmacokinetics of Compounds in C57BL/6 mice: brain tissue and plasma drug concentration ratio (B/P ratio)
Experimental materials:
c57BL/6 mouse (Male, 8 weeks old, weight 25g-30 g)
Experimental procedure:
1. candidate compounds were formulated as a 0.6mg/mL solution and the mice were given in a single intravenous injection. The vehicle was 5% dimethyl sulfoxide/10% solutol/85% physiological saline. Male C57BL/6 mice were used for the experiment, and were administered by single intravenous injection at a dose of 3mg/kg and a volume of 5mL/kg. Blood and whole brain tissue samples were collected 0.25,1,4 and 24 hours after dosing.
2. Brain tissue was homogenized with 3x 0.9% NaCl, and the homogenate was stored at-80 ℃ for subsequent LC-MS/MS analysis.
3. Blood samples were collected for half an hour, and the supernatant was centrifuged at 4000rpm for 15 minutes to obtain plasma. Plasma samples were stored in polypropylene tubes.
Before LC-MS/MS detection, adding the brain homogenate and plasma into acetonitrile solution containing an internal standard to precipitate protein, fully mixing, centrifuging to obtain supernatant, taking samples, quantitatively analyzing cerebral medicine and blood medicine concentration by an LC-MS/MS analysis method, and calculating medicine generation parameters such as peak reaching concentration (Cmax), half-life (T1/2), peak reaching time (Tmax), medicine concentration of different tissues in medicine (AUC 0-last), and medicine concentration proportion (B/P) of brain tissue and plasma. Since Cpd-11 is a prodrug of Cpd-10, the pharmacokinetics of Cpd-11 was assessed by detecting the concentration of Cpd-10 in mice.
Experimental results:
table 2: in vivo pharmacokinetic assay results
The experiment shows that the compound has better brain distribution characteristics in mice.
The embodiments of the technical solution of the present application have been described above by way of example. It should be understood that the protection scope of the present application is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principles of the present application should be included in the scope of the present application as defined in the appended claims.

Claims (10)

1. A compound of formula I, racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts or prodrugs thereof:
wherein R is 1 Selected from unsubstituted or optionally substituted with 1, 2 or more R 11 Substituted with the following groups: NH (NH) 2 、C 6-20 Aryl, 5-20 membered heteroaryl; each R 11 Identical or different, independently of one another, from C 1-40 Alkyl, halogenated C 1-40 Alkyl, C 3-20 Cycloalkyl, di C 1-40 alkyl-phosphoryl-C 6-20 An aryl group;
R 2 selected from C 1-40 Alkyl, C 1-40 Alkoxy, halo C 1-40 Alkyl, halogen;
R 3 selected from H, C 1-40 Alkyl, C 1-40 An alkoxy group;
alternatively, R 1 、R 2 Together with the atoms to which they are attached form a quilt of 1, 2 or More R 21 Substituted with the following groups: c (C) 3-20 Cycloalkyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl; each R 21 The same or different, independently of one another, are selected from halogen, CN, oxo (= O), C 1-40 Alkyl, C 3-20 Cycloalkyl;
alternatively, R 2 、R 3 Together with the atoms to which they are attached form a group of 1, 2 or more R 22 Substituted with the following groups: c (C) 3-20 Cycloalkyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl; each R 22 The same or different, independently of one another, are selected from halogen, CN, oxo (= O), C 1-40 Alkyl, C 3-20 Cycloalkyl;
x is selected from N or CH;
R 4 selected from H, halogen, CN, OH, unsubstituted or optionally substituted with 1, 2 or more R 41 Substituted with the following groups: OH, C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-20 Cycloalkyl, C 1-40 Alkoxy, C 3-20 Cycloalkyl oxy; each R 41 Identical or different, independently of one another, from deuterium, halogen, C 1-40 Alkyl, halogenated C 1-40 Alkyl, C 3-20 Cycloalkyl;
and/or X and one of R 4 Together with the ring atoms to which they are attached and the imino group (NH) form a 5-6 membered heterocyclic group;
m is selected from integers from 0 to 6; for example 1, 2, 3, 4, 5;
ring A is selected from C 6-20 Aryl, 5-20 membered heteroaryl;
e is selected from chemical bonds orR E1 Selected from C 1-40 Alkyl, C 1-40 Alkoxy, halo C 1-40 Alkyl, halogen; g is selected from chemical bond, C 6-20 Aryl or 5-20 membered heteroaryl; n is selected from 0, 1, 2, 3 or 4;
R 5 、R 6 、R 7 、R 8 identical or different, independently of one another, from H, C 1-40 Alkyl group,C 1-40 Alkoxy, NH 2 Or NH 2 -C 1-40 Alkyl groups being either bound to each other in a ring, or to one of R 4 To form C condensed with ring A 3-20 Cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, or R 5 、R 6 To which the atoms are attached to form C 3-20 Cycloalkyl, 3-20 membered heterocyclyl; and R is 5 、R 6 、R 7 、R 8 At least one of which is NH 2 Or NH 2 -C 1-40 An alkyl group;
y is selected from OR a 、N(R b )(R c )；R a Selected from H, C 1-40 Alkyl orR b 、R c Identical or different, independently of one another, from H, C 1-40 An alkyl group.
2. A compound according to claim 1, wherein R 1 Selected from unsubstituted or optionally substituted with 1, 2 or more R 11 Substituted with the following groups: NH (NH) 2 、C 6-14 An aryl group; each R 11 Identical or different, independently of one another, from C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 3-12 Cycloalkyl, di C 1-12 alkyl-phosphoryl-C 6-14 An aryl group;
R 2 can be selected from C 1-12 Alkyl, C 1-12 Alkoxy, halo C 1-12 Alkyl, halogen;
R 3 can be selected from H, C 1-12 Alkyl, C 1-12 An alkoxy group;
alternatively, R 1 、R 2 Together with the atoms to which they are attached form a group of 1, 2 or more R 21 Substituted with the following groups: c (C) 3-12 Cycloalkyl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl; each R 21 The same or different, independently of one another, are selected from halogen, CN, oxo (= O), C 1-12 Alkyl, C 3-12 Cycloalkyl;
alternatively, R 2 、R 3 Together with the atoms to which they are attached form a group of 1, 2 or more R 22 Substituted with the following groups: c (C) 3-12 Cycloalkyl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl; each R 22 The same or different, independently of one another, are selected from halogen, CN, oxo (= O), C 1-12 Alkyl, C 3-12 Cycloalkyl;
preferably, R 1 Selected from unsubstituted or optionally substituted with 1, 2 or more R 11 Substituted with the following groups: NH (NH) 2 Phenyl; each R 11 Identical or different, independently of one another, from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, di C 1-6 Alkyl-phosphoryl-phenyl;
R 2 can be selected from halogenated C 1-6 Alkyl, halogen;
R 3 may be H;
alternatively, R 1 、R 2 Together with the atoms to which they are attached form a group of 1, 2 or more R 21 Substituted 3-8 membered heterocyclyl, 5-8 membered heteroaryl; each R 21 The same or different, independently of one another, from the group halogen, oxo (=o), C 1-6 Alkyl, C 3-6 Cycloalkyl;
alternatively, R 2 、R 3 Together with the atoms to which they are attached form a group of 1, 2 or more R 22 Substituted 3-8 membered heterocyclyl, 5-8 membered heteroaryl; each R 22 The same or different, independently of one another, are selected from halogen, CN, oxo (= O), C 1-6 Alkyl, C 3-6 Cycloalkyl;
preferably, R 1 Selected from methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, cyclobutylamino, difluoroethylamino, trifluoroethylamino, tolyl, dimethyl-phosphoryl-phenylamino;
R 2 may be selected from trifluoromethyl, F, cl, br;
alternatively, R 1 、R 2 Together with the atoms to which they are attached form a group of 1, 2 or more R 21 Substituted tetrasA hydrogen pyrrolyl group; each R 21 The same or different, independently of one another, from F, oxo (=o), cyclopropyl; for example
Alternatively, R 2 、R 3 Together with the atoms to which they are attached form a group of 1, 2 or more R 22 Substituted with the following groups: tetrahydropyrrolyl, 1H-pyrrolyl; each R 22 The same or different, independently of one another, selected from F, CN, oxo (=o), cyclopropyl; for example
3. A compound according to claim 1 or 2, wherein R 4 Selected from H, halogen, CN, unsubstituted or optionally substituted with 1, 2 or more R 41 Substituted with the following groups: c (C) 1-12 Alkyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl oxy; each R 41 Identical or different, independently of one another, from deuterium, halogen, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 3-12 Cycloalkyl;
and/or X and one of R 4 Together with the ring atoms to which they are attached and the imino group (NH) form a 5-6 membered heterocyclic group;
and/or R 5 And one of R 4 To form C condensed with ring A 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, or 3-12 membered heterocyclyl or 5-12 membered heteroaryl;
preferably, R 4 Selected from H, halogen, CN, C 1-12 Alkyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyloxy, halogenated C 1-12 Alkoxy, deuterated C 1-12 An alkoxy group;
and/or X and one of R 4 Together with the ring atoms to which they are attached and the imino groups (NH) formA 5-6 membered heterocyclyl;
and/or R 4 And R is 5 To form a 5-6 membered heterocyclyl group fused to ring A;
preferably, R 4 Selected from H, F, cl, br, I, CN, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 An alkoxy group;
and/or X and one of R 4 Together with the ring atoms to which they are attached and the imino group (NH) form a 6 membered heterocyclic group;
and/or R 5 And one of R 4 To form a 5 membered heterocyclyl or 5 membered heteroaryl group fused to ring a;
preferably, R 4 Selected from H, F, cl, CN, methyl, methoxy, ethoxy, cyclopropyl, cyclopropyloxy, difluoromethoxy, trifluoromethoxy, tridecylmethoxy, ethynyl;
And/or X and one of R 4 Together with the ring atoms to which they are attached and the imino group (NH) form morpholino;
and/or R 4 And R is 5 To form a ring A-condensed ring
4. A compound according to any one of claims 1 to 3, wherein R 5 、R 6 、R 7 、R 8 Identical or different, independently of one another, from H, C 1-12 Alkyl, NH 2 Or NH 2 -C 1-12 An alkyl group; and R is 5 、R 6 、R 7 、R 8 At least one of which is NH 2 Or NH 2 -C 1-12 An alkyl group;
alternatively, R 5 、R 6 To which the atoms are attached to form C 3-12 Cycloalkyl, 3-12 membered heterocyclyl;
preferably, R 5 、R 6 、R 7 、R 8 Identical or different, independently of one another, from H, C 1-6 Alkyl, NH 2 Or NH 2 -C 1-6 Alkyl radicals, e.g. H, methyl, NH 2 、NH 2 -methyl; and R is 5 、R 6 、R 7 、R 8 At least one of which is NH 2 Or NH 2 Methyl radicals, e.g. when R 5 、R 6 、R 7 When both are H, R 8 Is NH 2 The method comprises the steps of carrying out a first treatment on the surface of the When R is 5 、R 7 、R 8 When both are H, R 6 Is NH 2 Or NH 2 -methyl; when R is 5 、R 6 When both are H, R 7 Is methyl, R 8 Is NH 2 The method comprises the steps of carrying out a first treatment on the surface of the When R is 5 、R 7 When both are H, R 6 Is methyl or ethyl, R 8 Is NH 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, when R 8 Is NH 2 When the structure is S-shaped;
alternatively, R 5 、R 6 To which the atoms are attached to form C 3-6 Cycloalkyl groups such as cyclopropyl.
5. A compound according to any one of claims 1 to 4 wherein ring a is selected from C 6-14 Aryl, 5-14 membered heteroaryl; for example from C 6-8 Aryl, 5-8 membered heteroaryl; such as selected from phenyl, pyridyl, thienyl, pyrazolyl;
Preferably E is selected from chemical bonds orR E1 Selected from fluorine, chlorine, bromine, iodine; g is selected from chemical bond, C 6-14 An aryl group; n is selected from 1 or 2; preferably, when n is 1, R E1 Is in R configuration; e is selected from, for example, chemical bonds, (-) -> Selected from->
Preferably Y is selected from OR a 、N(R b )(R c )；R a Selected from H, C 1-12 Alkyl orR b 、R c Identical or different, independently of one another, from C 1-12 An alkyl group;
preferably Y is selected from OR a 、N(R b )(R c )；R a Selected from H, C 1-6 Alkyl orR b 、R c Identical or different, independently of one another, from C 1-6 An alkyl group; y is selected from OH, methylamino, dimethylamino, isopropoxy, tert-butyloxy, heptyloxy or heptyloxy
6. The compound of any one of claims 1-5, wherein the compound of formula I is selected from the group consisting of structures of formula II or formula III:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 E, Y and m independently have the definition of any one of claims 1 to 5;
preferably, the compound of formula I is selected from the structures of formula I-1, I-2, I-3 or I-4:
wherein R is 1 、R 4 、R 5 、R 6 G and Y independently have the definition as defined in any one of claims 1 to 5.
7. A compound according to any one of claims 1 to 6, wherein the compound of formula I has a structure selected from the group consisting of:
8. a process for the preparation of a compound according to any one of claims 1 to 7, comprising the following scheme one or scheme two:
Scheme one: deprotection of compound I-1 to give compounds of formula I;
scheme II: deprotection of compound I-2 to give compounds of formula I;
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 M, A, E, X, Y independently have the definition of any one of claims 1 to 7, PG being selected from amino protecting groups, such as t-butoxycarbonyl, benzyloxycarbonyl.
9. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound of any one of claims 1-7, racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof.
10. Use of a compound according to any one of claims 1-7, a racemate, a stereoisomer, a tautomer, an isotopic label, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug thereof, for the preparation of a medicament, for example for the preparation of an LRRK2 inhibitor;
preferably, the medicament or pharmaceutical composition is for preventing or treating a disease or condition mediated by LRRK 2;
preferably, the disease or condition mediated with LRRK2 is selected from parkinson's disease, leprosy, IBD, alzheimer's disease, L-dopa induced dyskinesia, dementia, amyotrophic lateral sclerosis, renal cancer, breast cancer, prostate cancer, blood cancer, papillary carcinoma, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
CN202310353536.0A 2022-04-06 2023-04-04 Amino acid derivative, pharmaceutical composition, preparation method and application thereof Pending CN116891437A (en)

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