CN117659020A - Imidazo [1,2-b ] pyridazine derivative, and preparation method and application thereof - Google Patents

Imidazo [1,2-b ] pyridazine derivative, and preparation method and application thereof Download PDF

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CN117659020A
CN117659020A CN202211090088.1A CN202211090088A CN117659020A CN 117659020 A CN117659020 A CN 117659020A CN 202211090088 A CN202211090088 A CN 202211090088A CN 117659020 A CN117659020 A CN 117659020A
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compound
substituted
imidazo
fluoro
unsubstituted
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邢莉
刘海涛
吴凡
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Suzhou Langrui Biopharmaceutical Co ltd
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Suzhou Langrui Biopharmaceutical Co ltd
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Abstract

The invention discloses imidazo [1,2-b ] shown in formula I]Pyridazine derivatives, or isotopically-labeled compounds thereof, or optical products thereofAn isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutical composition of the derivative. Imidazo [1,2-b ] of formula I]The pyridazine derivatives or pharmaceutical compositions may be used as TRK kinase inhibitors for the treatment or prophylaxis of diseases or conditions mediated by TRK or TRK mutations.

Description

Imidazo [1,2-b ] pyridazine derivative, and preparation method and application thereof
Technical Field
The application belongs to the field of medicines, and in particular relates to an imidazo [1,2-b ] pyridazine derivative, a pharmaceutically acceptable salt thereof, a preparation method thereof, application of the derivative serving as a TRK kinase inhibitor and a pharmaceutical composition containing the derivative.
Background
In 1982, the high molecular weight DNA of two colon cancer patients showed transformation capacity when transfected with NIH-3T3 cells. Subsequently, the same DNA samples were cloned and sequenced in 1986, confirming fusion of non-muscle tropomyosin with a protein kinase not known at the time, later identified as TRKA. This is the first published report identifying members of the Tropomyosin Receptor Kinase (TRK) family that includes TRKA, TRKB and TRKC proteins encoded by the NTRK1, NTRK2 and NTRK3 genes, respectively. Structurally, TRK proteins comprise extracellular and intracellular regions separated by a single transmembrane domain. All three TRK proteins have a high structural homology, including three Leucine Rich Motifs (LRMs) flanked by two cysteine clusters and two immunoglobulin-like C2-type domains located in the extracellular region of the protein.
Although originally found in cancer, under normal physiological conditions, TRK protein acts as a high affinity receptor for Nerve Growth Factor (NGF), a neurotrophic factor. During organogenesis, TRK proteins are expressed in neuronal tissue, playing a key role in the development of the central and peripheral nervous systems. Binding of neurotrophins [ (brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) ] to their cognate receptors causes the formation of TRK homodimers and phosphorylation of their tyrosine residues, which in turn triggers TRK kinase activation, thereby inducing cell proliferation, differentiation, apoptosis and survival of neurons and other types of cells, wherein the signal is likely to be through downstream PI3K activation, RAS/MAPK/ERK and phospholipase C-gamma (PLC-g) signaling pathways, the TRK pathway being involved in pathogenesis of a variety of cancers.
Entrictinib and LOXO-101 (larotinib) are high oral bioavailability tyrosine kinase inhibitors, both of which have low nanomolar potential tyrosine kinase inhibiting catalytic activity. LOXO-101 preferentially locks the ATP binding sites of TRKA, TRKB and TRKC proteins. LOXO-101 is characterized by IC in assays with cells expressing a NTRK family rearrangement 50 Values are in the low nanomolar range. Similarly, emtrictinib also inhibits TRKA, TRKB and TRKC, IC 50 The value is between 0.1 and 1.7 nm. In addition, it also potentially inhibits kinase activity of ROS1 and ALK. Entrictinib and LOXO-101 both exhibit potent clinical activity in patients with metastatic or unresectable solid tumors with NTRK gene fusion. Like other tyrosine kinase inhibitors that are fused to solid tumor oncogenes, TRK inhibitors may not cure. In fact, acquired resistance has emerged, which may present challenges and opportunities for the development of future TRK-directed therapies. For example, some of the newly developed TRK small molecule inhibitors have been disclosed in the documents of chinese patent application CN102264736A, CN104520300a, etc., so that the development of TRK small molecule inhibitors is very significant.
Disclosure of Invention
According to one aspect of the present invention, it is an object of the present invention to provide an imidazo [1,2-b ] pyridazine derivative represented by formula I, or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,
Wherein:
W 1 、W 2 、W 3 、W 4 、W 5 each independently selected from carbon or nitrogen;
R 1 、R 2 、R 3 each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, substituted or unsubstitutedSaturated or unsaturated C of (2) 1 ～C 6 Alkyl, substituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkyl, substituted or unsubstituted saturated or unsaturated 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or substituted or unsubstituted 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, or R 1 And R is 2 Together with the N and C atoms to which they are attached form a substituted or unsubstituted 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, or R 2 And R is 3 Form, together with the C atom to which they are attached, a substituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkyl, substituted or unsubstituted 5 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S; wherein said "substitution" means optionally containing 1 to 4 groups selected from deuterium, hydroxy, halogen, cyano, amino, C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 3 ～C 6 Substituents for cycloalkoxy;
R 4 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 6 Alkyl, saturated or unsaturated C 3 ～C 6 Cycloalkyl;
R 5 selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 6 Alkyl, saturated or unsaturated C 3 ～C 6 Cycloalkyl, or R 5 Absence of;
X 1 selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, substituted or unsubstituted saturated or unsaturated C 1 ～C 6 Alkyl, substituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkyl, substituted or unsubstituted saturated or unsaturated C 1 ～C 6 Alkoxy, substituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkoxy groupWherein the "substitution" means a substitution optionally containing 1 to 4 substituents selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, sulfonyl, amino;
L 1 selected from hydrogen, deuterium, halogen, hydroxy, amino, amido, -NR a R b Substituted or unsubstituted C 1 ～C 6 Alkyl, substituted or unsubstituted C 2 ～C 8 Alkenyl, substituted or unsubstituted C 2 ～C 8 Alkynyl, substituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkyl, substituted or unsubstituted saturated or unsaturated C 1 ～C 6 Alkoxy, substituted or unsubstituted C 6 -C 14 Aryl, substituted or unsubstituted saturated or unsaturated 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or substituted or unsubstituted 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means optionally containing 1 to 4 heteroatoms selected from deuterium, halogen, cyano, hydroxy, carboxyl, carbonyl, sulfinyl, sulfonyl, amino, amido, C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 3 ～C 6 A cycloalkoxy substituent, wherein R a And R is b Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 3 ～C 6 A cycloalkoxy group containing 1 to 4 substituents selected from deuterium, halogen, cyano, hydroxy, amino 1 ～C 4 Alkyl, C containing 1 to 4 substituents selected from deuterium, halogen, cyano, hydroxy, amino 3 ～C 6 Cycloalkyl groups.
Preferably, R 1 、R 2 、R 3 Each independently selected from hydrogen, deuterium, substituted or unsubstituted saturated or unsaturated C 1 ～C 4 Alkyl, substituted or unsubstituted saturated or unsaturated C 4 ～C 6 Cycloalkyl, or R 1 And R is 2 Together with the N and C atoms to which they are attached form a substituted or unsubstituted 5 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, or R 2 And R is 3 Form, together with the C atom to which they are attached, a substituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkyl; wherein said "substitution" means optionally containing 1 to 3 groups selected from deuterium, hydroxy, halogen, C 1 ～C 3 Alkyl, C 5 ～C 6 Substituents of cycloalkyl groups.
More preferably, R 1 、R 2 、R 3 Each independently selected from hydrogen, deuterium, substituted or unsubstituted saturated or unsaturated C 1 ～C 3 Alkyl, or R 1 And R is 2 Together with the N and C atoms to which they are attached form a substituted or unsubstituted 5-to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or R 2 And R is 3 Form, together with the C atom to which they are attached, a substituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkyl; wherein the "substitution" means that 1 to 3 substituents selected from deuterium, hydroxyl, halogen are optionally contained.
Preferably, R 4 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 4 Alkyl, saturated or unsaturated C 5 ～C 6 Cycloalkyl groups.
More preferably, R 4 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 3 An alkyl group.
More preferably, R 4 Selected from hydrogen, deuterium or halogen.
Preferably, R 5 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 4 Alkyl, saturated or unsaturated C 3 ～C 6 Cycloalkyl, or R 5 Is not present.
More preferably, R 5 Selected from hydrogen, deuterium, halogen, and cyanoRadicals, hydroxy, amino, saturated or unsaturated C 1 ～C 3 Alkyl, or R 5 Is not present.
More preferably, when W 5 When C is R 5 Selected from hydrogen, deuterium, halogen; when W is 5 When N is present, R 5 Is not present.
Preferably X 1 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, substituted or unsubstituted saturated or unsaturated C 1 ～C 4 Alkyl, substituted or unsubstituted saturated or unsaturated C 1 ～C 4 Alkoxy, substituted or unsubstituted saturated or unsaturated C 3 ～C 6 A cycloalkoxy group, wherein the "substitution" means that 1 to 4 substituents selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl are optionally contained.
More preferably X 1 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, substituted or unsubstituted saturated or unsaturated C 1 ～C 4 Alkyl, substituted or unsubstituted saturated or unsaturated C 1 ～C 4 Alkoxy, wherein said "substitution" means optionally containing 1 to 3 substituents selected from hydrogen, deuterium, halogen, cyano, hydroxy.
Preferably L 1 Selected from hydrogen, deuterium, halogen, hydroxy, amino, amido, -NR a R b Substituted or unsubstituted C 1 ～C 4 Alkyl, substituted or unsubstituted C 2 ～C 6 Alkenyl, substituted or unsubstituted C 2 ～C 6 Alkynyl, substituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkyl, substituted or unsubstituted saturated or unsaturated C 1 ～C 4 Alkoxy, substituted or unsubstituted C 6 -C 10 A substituted or unsubstituted saturated or unsaturated 4 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a substituted or unsubstituted 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means optionally containing 1 to 4 heteroatoms selected from deuterium, halogen, cyano, hydroxy, carboxyl, carbonyl, vinylidene Sulfonyl, amino, amido, C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 3 ～C 6 A cycloalkoxy substituent, wherein R a And R is b Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C containing 1 to 2 substituents selected from deuterium, halogen, cyano, hydroxy, amino 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl groups.
More preferably L 1 Selected from hydrogen, deuterium, halogen, hydroxy, amino, amido, -NR a R b Substituted or unsubstituted C 1 ～C 3 Alkyl, substituted or unsubstituted C 2 ～C 4 Alkenyl, substituted or unsubstituted C 2 ～C 4 Alkynyl, substituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkyl, substituted or unsubstituted saturated or unsaturated C 1 ～C 3 Alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted saturated or unsaturated 4 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or substituted or unsubstituted 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means optionally containing 1 to 3 heteroatoms selected from deuterium, halogen, cyano, hydroxy, carboxy, carbonyl, sulfinyl, sulfonyl, amino, amido, C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, substituent wherein R a And R is b Each independently selected from hydrogen, deuterium, C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C containing 1 to 2 substituents selected from deuterium, halogen, cyano, hydroxy, amino 3 ～C 6 Cycloalkyl groups.
More preferably L 1 One selected from the following groups
More preferably, the imidazo [1,2-b ] pyridazine derivative according to formula I, or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, is represented by the following formulas 1-1, 1-2, 1-3, 1-4, 1-5 and 1-6:
wherein the substituents W 5 、R 1 、R 2 、R 3 、R 4 、R 5 、X 1 、L 1 Is defined as in formula 1 above.
Preferably, the imidazo [1,2-b ] pyridazine derivative represented by formula I, formula 1-1, formula 1-2, formula 1-3, formula 1-4, formula 1-5 and formula 1-6, or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, is selected from the group consisting of:
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according to a second aspect of the present invention, it is a further object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I according to the present invention or an isotopically-labelled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.
According to a third aspect of the present invention, it is a further object of the present invention to provide the use of a compound of formula I according to the present invention or an isotopically labelled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, for the manufacture of a medicament for use in the treatment or prevention of a disease or condition mediated by TRK or a TRK mutation in a subject in need thereof.
Preferably, the disease or condition mediated by TRK or a TRK mutation is selected from one or more of cancer, neurodegenerative disease, inflammation, pain.
More preferably, the disease or condition mediated by TRK or a TRK mutation is selected from the group consisting of surgical pain, inflammatory pain, neuropathic pain, alzheimer's disease, parkinson's disease, multiple sclerosis, colon cancer, thyroid cancer, lung cancer, prostate cancer, ovarian cancer, breast cancer, salivary gland cancer, pancreatic cancer, melanoma, salivary gland tumor, bile duct cancer, interstitial tumor, brain tumor, and hematological malignancy.
According to a fourth aspect of the present invention, it is a further object of the present invention to provide a kit comprising a compound of formula I according to the present invention or an isotopically labelled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the pharmaceutical composition according to the present invention, together with a container and instructions for use.
According to a fifth aspect of the present invention, it is a further object of the present invention to provide a method of treating a disease or condition mediated by TRK or a TRK mutation, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I according to the present invention or an isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the pharmaceutical composition according to the present invention.
Detailed Description
Hereinafter, the present invention will be described in detail. Before the description, it is to be understood that the terms used in this specification and the appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present invention on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. Accordingly, the description set forth herein is merely a preferred example for the purpose of illustration and is not intended to limit the scope of the invention, so that it should be understood that other equivalents or modifications may be made thereto without departing from the spirit and scope of the invention.
As used herein, the terms "comprising," "including," "having," "containing," or any other similar language, are intended to cover a non-exclusive inclusion, as an open-ended connection (open-ended transitional phrase). For example, a composition or article comprising a plurality of elements is not limited to only those elements listed herein, but may include other elements not explicitly listed but typically inherent to such composition or article. In addition, unless explicitly stated to the contrary, the term "or" refers to an inclusive "or" and not to an exclusive "or". For example, any one of the following conditions satisfies the condition "a or B": a is true (or present) and B is false (or absent), a is false (or absent) and B is true (or present), a and B are both true (or present). Furthermore, the terms "comprising," "including," "having," "containing," and their derivatives, as used herein, are intended to be open ended terms that have been specifically disclosed and encompass both the closed and semi-closed terms, consisting of …, and consisting essentially of ….
All features or conditions defined herein in terms of numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, the description of a numerical range or percentage range should be considered to cover and specifically disclose all possible sub-ranges and individual values within the range, particularly integer values. For example, a range description of "1 to 8" should be taken as having specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly sub-ranges defined by all integer values, and should be taken as having specifically disclosed individual values such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. The foregoing explanation applies to all matters of the invention throughout its entirety unless indicated otherwise, whether or not the scope is broad.
If an amount or other numerical value or parameter is expressed as a range, preferred range, or a series of upper and lower limits, then it is understood that any range, whether or not separately disclosed, from any pair of the upper or preferred value for that range and the lower or preferred value for that range is specifically disclosed herein. Furthermore, where a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range.
In this context, numerical values should be understood to have the accuracy of the numerical significance of the numerical values provided that the objectives of the present invention are achieved. For example, the number 40.0 is understood to cover a range from 39.50 to 40.49.
In this document, where Markush group (Markush group) or option-type language is used to describe features or examples of the present invention, those skilled in the art will appreciate that a sub-group of all elements within a Markush group or option list or any individual element may also be used to describe the present invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it is also meant that the claim of X as X1 and/or X2 have been fully described. Furthermore, where markush groups or option expressions are used to describe features or examples of the present invention, those skilled in the art will appreciate that any combination of sub-groups or individual elements of all elements within a markush group or option list may also be used to describe the present invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3" and Y is described as "selected from the group consisting of Y1, Y2, and Y3," then the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.
Definition of the definition
"alkyl" refers to a group ("C") that is a straight or branched saturated hydrocarbon group having 1 to 8 carbon atoms 1–8 Alkyl "). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 Alkyl "). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 Alkyl "). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 Alkyl "). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 Alkyl "). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 Alkyl "). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 Alkyl "). In some embodiments, the alkyl group has 1 carbon atom ("C 1 Alkyl "). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 Alkyl "). C (C) 1–6 Examples of alkyl groups include methyl (C) 1 ) Ethyl (C) 2 ) Propyl (C) 3 ) (e.g., n-propyl, isopropyl), butyl(C 4 ) (e.g., n-butyl, t-butyl, sec-butyl, isobutyl), pentyl (C) 5 ) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, t-pentyl) and hexyl (C) 6 ) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C 7 ) N-octyl (C) 8 ) Etc. Unless otherwise indicated, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl is unsubstituted C 1-8 Alkyl (e.g. unsubstituted C 1 Alkyl radicals, e.g. -CH 3 ). In certain embodiments, the alkyl is substituted C 1-8 Alkyl (e.g. substituted C 1 Alkyl radicals, e.g. -CF 3 )。
"alkoxy" means a monovalent-O-alkyl group in which the alkyl moiety has the indicated number of carbon atoms. Alkoxy groups in this disclosure typically contain 1-6 carbon atoms ("C1-C6 alkoxy") or 1-4 carbon atoms ("C1-C4 alkoxy"). For example, C1-C4 alkoxy includes methoxy, ethoxy, isopropoxy, tert-butyloxy, and the like. Unless otherwise indicated, each instance of an alkoxy group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkoxy") or substituted (a "substituted alkoxy") with one or more substituents. In certain embodiments, the alkoxy is unsubstituted C1 to C6 alkoxy. In certain embodiments, the alkoxy is a substituted C1 to C6 alkoxy.
"cycloalkyl" means a non-aromatic ring system having 3 to 8 ring carbon atoms ("C 3-8 Cycloalkyl ") and zero heteroatoms. In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 Cycloalkyl "). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 Cycloalkyl "). In some embodiments, cycloalkyl groups have 5 to 8 ring carbon atoms ("C 5-8 Cycloalkyl "). Exemplary C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C) 3 ) Cyclopropenyl (C) 3 ) Cyclobutyl (C) 4 ) Cyclobutenyl (C) 4 ) Ring and ringPentyl (C) 5 ) Cyclopentenyl (C) 5 ) Cyclohexyl (C) 6 ) Cyclohexenyl (C) 6 ) Cyclohexadienyl (C) 6 ) Etc. Exemplary C 3-8 Cycloalkyl groups include, but are not limited to, C described above 3-6 Cycloalkyl group and cycloheptyl (C) 7 ) Cycloheptenyl (C) 7 ) Cycloheptadienyl (C) 7 ) Cycloheptatrienyl (C) 7 ) Cyclooctyl (C) 8 ) Cyclooctenyl (C) 8 ) Etc. Each instance of cycloalkyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents, unless otherwise specified. In certain embodiments, cycloalkyl is unsubstituted C 3-8 Cycloalkyl; in certain embodiments, cycloalkyl is substituted C 3-8 Cycloalkyl groups.
"heterocycloalkyl" refers to a group of a 5-to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-to 14-membered heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as the valence permits. The heterocyclic group may be a single ring ("monocyclic heterocyclic group") or a fused, bridged or spiro ring system, for example a bicyclic ring system ("bicyclic heterocyclic group"), and may be saturated or may be partially unsaturated. "heterocyclic group" also includes ring systems in which a heterocycle as defined above is fused to one or more cycloalkyl groups (where the point of attachment is on the cycloalkyl group or heterocycle), or ring systems in which a heterocycle as defined above is fused to one or more aryl or heteroaryl groups (where the point of attachment is on the heterocycle), and in such cases the number of ring members continues to refer to the number of ring members in the heterocyclic system. Each instance of a heterocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocycloalkyl") or substituted by one or more substituents ("substituted heterocycloalkyl"), unless otherwise specified. In certain embodiments, the heterocycloalkyl is an unsubstituted 5-14 membered heterocycloalkyl. In certain embodiments, heterocycloalkyl substituted 5-14 membered heterocycloalkyl.
"aryl" or "arylAn aromatic ring "or" aromatic ring group "refers to a group (" C ") of a single or multiple ring (e.g., bi-or tri-cyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system 6-14 Aryl "). In some embodiments, aryl groups have 6 ring carbon atoms ("C 6 Aryl "; for example, phenyl). In some embodiments, aryl groups have 10 ring carbon atoms ("C 10 Aryl "; for example, naphthyl groups such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 Aryl "; for example, anthracyl). "aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more cycloalkyl or heterocyclic groups, where the point of attachment is on the aromatic ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Each instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents, unless otherwise indicated. In certain embodiments, aryl is unsubstituted C 6-14 Aryl groups. In certain embodiments, aryl is substituted C 6-14 Aryl groups.
"heteroaryl" is a 5-14 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise indicated, each instance of heteroaryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted by one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl is a substituted 5-14 membered heteroaryl.
"halogen" or "halo" means fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) or iodine (iodine, -I).
"substituted" or "optionally substituted" means that an atom in the group, such as a hydrogen atom, is substituted. In certain embodiments, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are substituted (e.g., "substituted" alkyl, "substituted" cycloalkyl, "substituted" heterocycloalkyl, "substituted" aryl, or "substituted" heteroaryl). Generally, the term "substituted", whether preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., carbon or nitrogen atom) is substituted with an allowable substituent, e.g., a substituent that upon substitution forms a stable compound, e.g., a compound that does not spontaneously undergo conversion (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise indicated, a "substituted" group has substituents at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any substituents described herein which result in the formation of stable compounds. The present disclosure contemplates any and all of these combinations to obtain stable compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein that satisfies the valences of the heteroatoms and results in the formation of a stable moiety. In certain embodiments, the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituent is an oxygen atom substituent. In certain embodiments, the substituent is a sulfur atom substituent.
"unsaturated" or "partially unsaturated" refers to a group that contains at least one double or triple bond. "partially unsaturated" ring systems are also intended to encompass rings having multiple sites of unsaturation, but are not intended to include aromatic groups (e.g., aryl or heteroaryl). Likewise, "saturated" refers to groups that do not contain double or triple bonds, i.e., all contain single bonds.
The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts (i.e., pharmaceutically acceptable salts) may be obtained by contacting neutral forms of such compounds with sufficient amounts of an acid in pure solution or in a suitable inert solvent, examples include inorganic acid salts and organic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; the organic acids include acids such as benzoic acid, 2-hydroxyethanesulfonic acid, sulfamic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid, propionic acid, oxalic acid, sulfanilic acid, p-toluenesulfonic acid, polygalacturonic acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methanesulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, citric acid, malic acid, glucoheptonic acid, gluconic acid, isethionic acid, lactic acid, lactobionic acid, dodecylsulfonic acid, pamoic acid, salicylic acid, suberic acid, folinic acid, edetic acid, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, stearic acid, and the like; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts. The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
As used herein, the modifier term "about" refers to a change in value that may occur, for example, by routine testing and processing; unintentional errors in passing such tests and processing; differences in source or purity by the manufacture of the components used in the present invention; etc. As used herein, a "about" a particular value also includes the particular value, for example, about 10% includes 10%. Whether or not modified by the term "about", the claims include equivalents to the listed amounts. In one embodiment, the term "about" means within 20% of the reported numerical value.
As used herein, the term "treating" refers to eliminating, alleviating or ameliorating a disease or disorder and/or symptoms associated therewith. Although not excluded, treating a disease or condition does not require complete elimination of the disease, condition, or symptom associated therewith. As used herein, the term "treatment" or the like may include "prophylactic treatment" referring to reducing the likelihood of recurrence of a disease or disorder or a previously controlled disease or disorder in a subject that is free of, or at risk of, suffering from, or susceptible to recurrence of the disease or disorder. The term "treatment" and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.
For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For the purposes of the present oral dosage form, an "effective amount" of one active agent in a composition refers to that amount which is required to achieve the desired effect when used in combination with another active agent in the composition. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.
The compounds represented by formula I or isotopically-labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomer mixtures thereof, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof, and pharmaceutical compositions comprising the compounds provided by the present invention may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols and the like, and may be presented in suitable solid or liquid carriers or diluents and in suitable sterilizing devices for injection or instillation.
The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. For example, the unit dose of the formulation comprises from 0.05 to 2000mg of the compound of formula I or a pharmaceutically acceptable salt thereof, preferably the unit dose of the formulation comprises from 0.1mg to 1000mg of the compound of formula I.
The compounds and pharmaceutical compositions of the present invention represented by formula I may be used clinically in mammals, including humans and animals, by oral, nasal, dermal, pulmonary, or gastrointestinal routes of administration. Most preferably orally. The most preferable daily dosage is 0.01-200mg/kg body weight, and can be administered at one time, or 0.01-100mg/kg body weight in divided doses. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment. Typically starting from a small dose, the dose is gradually increased until the most suitable dose is found.
In the present invention, the term "effective amount" may refer to an effective amount of dosage and period of time required to achieve the desired effect. This effective amount may vary depending on factors such as the type of disease or the condition of the disease at the time of treatment, the constitution of the particular target organ to be administered, the individual size of the patient, or the severity of the disease or symptoms. One of ordinary skill in the art will be able to determine empirically the effective amount of a particular compound without undue experimentation.
Typical formulations are prepared by mixing a compound of formula I of the present invention with a carrier, diluent or excipient. Suitable carriers, diluents or excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
The particular carrier, diluent or excipient used will depend upon the manner and purpose of use of the compounds of the present invention. The solvent is generally selected based on the solvent that one of ordinary skill in the art would consider to be safe and effective for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG 300), and the like. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorants, flavoring agents or other known additives to make or use the drug in an acceptable form.
When the compound of formula I according to the present invention is used in combination with at least one other drug, the two or more drugs may be used separately or in combination, preferably in the form of a pharmaceutical composition. The compounds or pharmaceutical compositions of the invention of formula (I) may be administered to a subject separately or together in any known form of oral, intravenous, rectal, vaginal, transdermal, other topical or systemic administration.
These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorants, flavoring agents or other known additives to make the pharmaceutical composition acceptable for manufacture or use.
The medicament of the invention is preferably administered orally. Solid dosage forms for oral administration may include capsules, tablets, powders or granular formulations. In solid dosage forms, the compounds or pharmaceutical compositions of the invention are admixed with at least one inert excipient, diluent or carrier. Suitable excipients, diluents or carriers include substances such as sodium citrate or dicalcium phosphate, or starches, lactose, sucrose, mannitol, silicic acid and the like; binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia, and the like; humectants such as glycerin and the like; disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates, sodium carbonate, and the like; solution retarders such as paraffin and the like; absorption promoters such as quaternary ammonium compounds and the like; adsorbents such as kaolin, bentonite, and the like; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and the like. In the case of capsules and tablets, the dosage form may also include buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using lactose as well as high molecular weight polyethylene glycols and the like as excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compounds of the present invention or pharmaceutical compositions thereof, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizing agents and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide; oils (e.g., cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.); glycerol; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitan; or a mixture of several of these, etc.
In addition to these inert diluents, the compositions can also include excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening, flavoring and perfuming agents.
As for the suspension, in addition to the compound represented by formula I of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, a carrier such as a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, or a mixture of several of these substances, or the like, may be further contained.
The compound represented by formula I of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same may be administered in other topically administrable dosage forms, including ointments, powders, sprays and inhalants. The medicament may be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent or carrier, and with any preservative, buffer or propellant required. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be included within the scope of the present invention.
In addition, kits (e.g., pharmaceutical packaging) are also encompassed by the present disclosure. Kits are provided that can include a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampoule, bottle, syringe, and/or sub-packaging or other suitable container). In some embodiments, the provided kits may optionally further comprise a second container comprising a pharmaceutically acceptable excipient for diluting or suspending the pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical compositions or compounds described herein disposed in the first container and the second container are combined to form one unit dosage form.
In certain embodiments, the kits described herein further comprise instructions contained in the kit for using the compounds or pharmaceutical compositions. The kits described herein may also include information required by regulatory authorities, such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescription information. In certain embodiments, the kits and instructions provide for treating and/or preventing a proliferative disease in a subject in need thereof. The kits described herein may comprise one or more additional pharmaceutical agents as separate compositions.
The invention is described in further detail below in connection with specific examples, but the invention is not limited to the following examples, which are intended to better illustrate certain embodiments of the invention and are not to be construed as limiting the scope of the invention in any way. The conditions not specified in the examples are conventional conditions. Unless otherwise specified, reagents and equipment used in the following examples are commercially available products.
The compounds of formula I of the present application may be synthesized by a variety of methods familiar to those skilled in the art of organic synthesis. Some exemplary methods for synthesizing compounds of formula I are given in the following specific examples, which are well known in the art of synthetic chemistry. Obviously, referring to the exemplary schemes in this patent, one skilled in the art can readily design synthetic routes for other compounds of formula I by appropriate adjustments of reactants, reaction conditions, and protecting groups.
The invention is further illustrated by the following examples; but these examples do not limit the scope of the invention. All reactants used in each example were obtained commercially unless otherwise stated; the instruments and equipment used in the synthesis experiments and the product analysis and detection are all conventional instruments and equipment commonly used in organic synthesis.
In the following examples, the structure of exemplary compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d 6) as solvent, deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
An Agilent 1200 affinity Series mass spectrometer was used for LC-MS measurement. HPLC determination uses agilent 1200DAD high pressure liquid chromatograph. The thin layer chromatography silica gel plate is prepared from tobacco stage yellow sea HSGF254 or Qingdao GF254 silica gel plate. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier. In addition, without specific description, all reactions of the invention are carried out under continuous magnetic stirring in dry nitrogen or argon atmosphere, the solvent is dry solvent, and the reaction temperature is in degrees celsius.
Further, abbreviations used in the examples have the following meanings: imidazole: imidazole; NIS: n-iodosuccinimide; TMS: trimethylsilyl group; PMB: p-methoxybenzyl; TBSCl: t-butylchlorodimethylsilane; bu (Bu) 3 SnCl: tributyl stannane chloride; pdCl 2 (PPh 3 ) 2 : bis (triphenylphosphine) palladium dichloride; pd (PPh) 3 ) 4 : tetrakis (triphenylphosphine) palladium; cuI: cuprous iodide; KF: potassium fluoride; cuSO 4 : copper sulfate; VCNa: sodium ascorbate; pd (dba) 2 : bis (dibenzylideneacetone) palladium; n-BuLi: n-butyllithium; xantphos:4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene; BINAP:1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine; zn: zinc powder; cs (cells) 2 CO 3 : cesium carbonate; na (Na) 2 CO 3 : sodium carbonate; k (K) 2 CO 3 : potassium carbonate; naOAc: sodium acetate; t BuONa: sodium tert-butoxide; KF: potassium fluoride; naBH 4 : sodium borohydride; BBr (BBr) 3 : boron tribromide; LAH: lithium aluminum hydride; naOH: sodium hydroxide; BOC: t-butoxycarbonyl; EA: ethyl acetate; PE: petroleum ether; meOH: methanol; etOH: ethanol; DIEA: n, N-diisopropylethylamine; DMSO: dimethyl sulfoxide; TEA: triethylamine; HCl: hydrochloric acid; h 2 SO 4 : sulfuric acid; DMAP: 4-dimethylaminopyridine; dioxane: a dioxane; DMF: n, N-dimethylformamide; NMP: n-methylpyrrolidone; THF: tetrahydrofuran; DCM: dichloromethane; meCN: acetonitrile; TOL: toluene; TFA: trifluoroacetic acid; TLC: thin layer chromatography; structure: structural formula.
Example 1:3- (4-hydroxymethylpyridin-2-yl) -N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-1)
Step A: 2-bromo-4-tert-butyldimethylsilyloxy methylpyridine (2)
2-bromo-4-pyridinemethanol (Compound 1, 50g,265.93 mmol) and imidazole (23.53 g,345.70 mmol) were placed in dichloromethane (750 mL), t-butyldimethylsilyl chloride (52.11 g,345.70 mmol) was added at 0deg.C, stirred at room temperature for about 16 hours, then quenched with water (1.5L) and extracted 3 times with ethyl acetate (500 mL), the organic phases were combined, washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 2-bromo-4-t-butyldimethylsilyloxy-methylpyridine (64.95 g, 81%).
LCMS:m/z(ESI)，302[M+H]+。
And (B) step (B): 2-tributylstannyl-4-tert-butyldimethylsilyloxy methylpyridine (3)
2-bromo-4-t-Butyldimethylsilanylmethyl pyridine (Compound 2, 30g,99.25 mmol) was placed in tetrahydrofuran (750 mL), n-butyllithium (2.5M, 39.70 mmol) was added dropwise at about-70℃and stirred for half an hour, tributyltin chloride (38.77 g,119.09 mmol) was added, stirring was continued at about-70℃for 2 hours, then quenched with saturated ammonium chloride (1.5L), extracted 3 times with ethyl acetate (500 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 2-tributyltin-4-t-butyldimethylsilanylmethyl pyridine (52 g) by column chromatography.
LCMS:m/z(ESI)，514.3[M+H]+。
Step C:3- (4-tert-Butyldimethylsilanylmethyl pyridin-2-yl) -6-chloroimidazo [1,2-b ] pyridazine (5)
2-tributylstannyl-4-tert-butyldimethylsilyloxy-methylpyridine (50 g,97.57 mmol) was placed in toluene (500 mL) and 3-bromo-6-chloroimidazo [1,2-b ] was added sequentially]Pyridazine (Compound 4, 22.68g,97.57 mmol) and Pd (PPh) 3 ) 4 (11.28 g,9.76 mmol) was stirred at 100℃for about 16 hours, and water was added to the reaction system(1.5L) was diluted and extracted 3 times with ethyl acetate (500 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 3- (4-tert-butyldimethylsilyloxy-methylpyridin-2-yl-6-chloroimidazole [1, 2-b) by column chromatography]Pyridazine (1.94 g, 5.3%).
1 H NMR:(400MHz,DMSO-d6)δ8.48(d,J＝5.0Hz,1H),8.35(d,J＝17.6Hz,2H),8.21(d,J＝9.5Hz,1H),7.34(d,J＝9.5Hz,1H),7.13(br d,J＝4.9Hz,1H),4.71(s,2H),0.80(s,9H),0.00(s,6H).
Step D: 2-p-methoxybenzyloxy-5-fluoroacetophenone (7)
2-hydroxy-5-fluoroacetophenone (Compound 6, 10g,64.88 mmol) was placed in acetonitrile (200 mL), p-methoxybenzyl chloride (12.19 g,77.85 mmol), cesium carbonate (63.41 g,194.63 mmol) was added sequentially, stirred at about 90℃for 12 hours, then diluted with water (300 mL) and extracted 3 times with ethyl acetate (200 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 2-p-methoxybenzyloxy-5-fluoroacetophenone (14.1 g, 79%) by column chromatography.
1 H NMR:(400MHz,CHLOROFORM-d)δ＝7.43-7.34(m,1H),7.29-7.21(m,2H),7.10-7.00(m,1H),6.94-6.78(m,3H),4.97(s,2H),3.74(s,3H),2.48(s,3H).
Step E: 2-Paroxybenzyloxy-5-fluoroacetophenone oxime (8)
P-methoxybenzyloxy-5-fluoro-2-acetophenone (compound 7, 14.1g,51.41 mmol) was placed in ethanol (180 mL), sodium acetate (12.65 g,154.22 mmol), hydroxylamine hydrochloride (4.29 g,61.69 mmol) were added sequentially, stirred at 70℃for 2 hours, then diluted with water (600 mL) and extracted 3 times with ethyl acetate (200 mL), the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate, and column chromatography after concentration afforded 2-p-methoxybenzyloxy-5-fluoro acetophenone oxime (6.5 g, 44%).
1 H NMR:(400MHz,DMSO-d6)δ＝11.15(s,1H),7.37(d,J＝8.5Hz,2H),7.21-7.13(m,2H),7.03(dd,J＝2.4,8.9Hz,1H),6.98-6.91(m,2H),5.04(s,2H),3.81-3.72(m,3H),2.08-2.02(m,3H).
Step F: 2-p-methoxybenzyloxy-5-fluorophenyl-1-ethylamine (9)
2-Parmethoxybenzyloxy-5-fluoroacetophenone oxime (Compound 8,6.50g,22.47 mmol) was taken up in methanol (150 mL), ammonium formate (14.7 g,224.68 mmol) and zinc powder (14.69 g,224.68 mmol) were added in succession, stirred at 40℃for 12 hours, then the filtrate was concentrated by filtration, and 2-p-methoxybenzyloxy-5-fluorophenyl-1-ethylamine (2.8 g, 48.8%) was obtained by column chromatography.
LCMS:m/z(ESI),276.0[M+H] + 。
1 H NMR:(400MHz,DMSO-d6)δ＝7.38(br d,J＝8.6Hz,2H),7.28(dd,J＝3.1,10.0Hz,1H),7.06-7.00(m,1H),6.99-6.93(m,3H),5.05-4.96(m,2H),4.29-4.21(m,1H),3.76(s,3H),1.21-1.17(m,3H).
Step G:3- (4-tert-Butyldimethylsilanylmethyl-pyridin-2-yl) -N- (1- (5-fluoro-2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (10)
3- (4-tert-Butyldimethylsilanylmethyl pyridin-2-yl-6-chloroimidazole [1,2-b ] ]Pyridazine (Compound 5, 100mg,0.267 mmol) was placed in toluene (5 mL) and 2-p-methoxybenzyloxy-5-fluorophenyl-1-ethylamine (73.43 mg,0.27 mol) and Pd (dba) was added sequentially 2 (15.34 mg,0.027 mol), sodium t-butoxide (51.26 mg,0.53 mol) and Xantphos (15.43 mg,0.027 mol) were stirred at 100℃for 16 hours, and after concentration, column chromatography was carried out to obtain 3- (4-t-butyldimethylsilyloxy)Picolin-2-yl) -N- (1- (5-fluoro-2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1,2-b]Pyridazin-6-amine (24 mg, 15%).
LCMS:m/z(ESI),614.5[M+H] + 。
1 H NMR:(400MHz,DMSO-d6)δ＝8.59-8.54(m,1H),8.30(s,1H),8.03(s,1H),7.82(d,J＝9.8Hz,1H),7.30-7.28(m,2H),7.28-7.26(m,2H),7.25-7.24(m,1H),7.20(br d,J＝3.3Hz,2H),6.89-6.80(m,1H),6.68(d,J＝8.6Hz,2H),5.41-5.34(m,1H),5.10-5.03(m,2H),3.65(s,3H),3.17(s,3H),0.86(s,9H),0.03(d,J＝7.1Hz,6H).
Step H:3- (4-hydroxymethylpyridin-2-yl) -N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-1)
3- (4-t-butyldimethylsilyloxy) pyridin-2-yl-N- (1- (5-fluoro-2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (compound 10, 24mg,0.039 mol) was placed in methanol (3 mL), methanol hydrochloride solution (4 m,3 mL) was added, stirred for 2 hours at 25 ℃ and then neutralized to ph=7 with sodium bicarbonate, filtered, and the filtrate was concentrated and separated by column chromatography to give 3- (4-hydroxymethyl) pyridin-2-yl-N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (12 mg, 81%).
LCMS:m/z(ESI),380[M+H] + 。
Example 2:3- (4-hydroxymethyl) pyridin-2-yl-N- (1- (3, 5-difluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-2)
Step A: 2-Paroxybenzyloxy-3, 5-difluoroacetophenone (12)
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2-hydroxy-3, 5-difluoroacetophenone (compound 11, 10g,58.10 mmol) was placed in DMF (200 mL), p-methoxybenzyl chloride (10.01 g,63.91 mmol), potassium carbonate (24.09 g,174.29 mmol) was added sequentially, stirred at 60℃for 12 hours, then diluted with water (300 mL) and extracted 3 times with ethyl acetate (200 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 2-p-methoxybenzyloxy-3, 5-difluoroacetophenone (14.5 g, 85.4%).
1 H NMR:(400MHz,CHLOROFORM-d)δ＝7.33(br d,J＝8.3Hz,2H),7.15(br d,J＝1.1Hz,1H),7.05(br s,1H),6.92(br d,J＝8.4Hz,2H),5.08(s,2H),3.84(s,3H),2.54(s,3H).
And (B) step (B): 2-Paroxybenzyloxy-3, 5-difluoroacetophenone oxime (13)
P-methoxybenzyloxy-3, 5-difluoro-2-acetophenone (compound 12, 13.1g,44.82 mmol) was placed in ethanol (180 mL), sodium acetate (11.03 g,134.46 mmol), hydroxylamine hydrochloride (3.74 g,53.78 mmol) were added sequentially, stirred at 70℃for 2 hours, then diluted with water (600 mL) and extracted 3 times with ethyl acetate (200 mL), the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate, and column chromatography after concentration afforded 2-p-methoxybenzyloxy-3, 5-difluoroacetophenone oxime (6.25 g, 45.4%).
1 H NMR:(400MHz,DMSO-d6)δ＝11.59-11.21(m,1H),7.42-7.34(m,1H),7.30(br d,J＝8.0Hz,2H),7.03-6.97(m,1H),6.93(br d,J＝8.1Hz,2H),4.91(s,2H),3.76(s,3H),2.07(s,3H).
Step C: 2-Paroxybenzyloxy-3, 5-difluorophenyl-1-ethylamine (14)
2-p-methoxybenzyloxy-3, 5-difluoroacetophenone oxime (compound 13,6.20g,20.18 mmol) was taken up in methanol (150 mL), ammonium formate (12.72 g,201.76 mmol) and zinc powder (13.19 g,201.76 mmol) were added in this order, stirred at 40℃for 12 hours, then the filtrate was concentrated by filtration, and column chromatography gave 2-p-methoxybenzyloxy-3, 5-difluorophenyl-1-ethylamine (2.6 g, 43.9%).
LCMS:m/z(ESI),294.2[M+H] + 。
1 H NMR:(400MHz,DMSO-d6)δ＝7.35(d,J＝8.6Hz,2H),7.21-7.10(m,2H),6.95(d,J＝8.6Hz,2H),4.93(s,2H),4.28-4.18(m,1H),3.76(s,3H),1.11(d,J＝6.6Hz,3H).
Step D:3- (4-tert-Butyldimethylsilanylmethyl) pyridin-2-yl-N- (1- (3, 5-difluoro-2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (15)
3- (4-tert-Butyldimethylsilanylmethyl pyridin-2-yl-6-chloroimidazole [1,2-b ]]Pyridazine (Compound 5,100mg,0.267 mmol) was placed in toluene (5 mL) and 2-p-methoxybenzyloxy-3, 5-difluorophenyl-1-ethylamine (Compound 14, 78.23mg,0.27 mol) and Pd (dba) was added sequentially 2 (15.34 mg,0.027 mol), sodium t-butoxide (51.26 mg,0.53 mol) and Xantphos (15.43 mg,0.027 mol) were stirred at 100℃for 16 hours, and after concentration column chromatography was carried out to obtain 3- (4-t-butyldimethylsilyloxy) pyridin-2-yl-N- (1- (3, 5-difluoro-2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1, 2-b)]Pyridazin-6-amine (44 mg, 26%).
LCMS:m/z(ESI),632.2[M+H] + 。
1 H NMR:(400MHz,DMSO-d6)δ＝8.53(d,J＝4.8Hz,1H),8.11(s,1H),7.98(s,1H),7.79(d,J＝9.6Hz,1H),7.44(br d,J＝7.0Hz,1H),7.31(br d,J＝8.4Hz,1H),7.22-7.16(m,4H),7.09(br d,J＝9.3Hz,1H),6.95-6.88(m,1H),6.77(d,J＝9.9Hz,1H),5.29(br d,J＝7.1Hz,1H),4.97-4.84(m,2H),4.70-4.53(m,2H),3.59(s,3H),1.40(br d,J＝6.8Hz,3H),0.84(s,9H),0.00(s,6H).
Step E:3- (4-hydroxymethyl) pyridin-2-yl-N- (1- (3, 5-difluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-2)
3- (4-t-butyldimethylsilyloxy) pyridin-2-yl-N- (1- (3, 5-difluoro-2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (compound 15, 44mg,0.069 mol) was placed in methanol (3 mL), methanol hydrochloride solution (4 m,3 mL) was added, stirred at 25 ℃ for 2 hours, then neutralized to ph=7 with sodium bicarbonate, filtered, and the filtrate was concentrated and separated by column chromatography to give 3- (4-hydroxymethyl) pyridin-2-yl-N- (1- (3, 5-difluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (36 mg).
LCMS:m/z(ESI),398[M+H] + 。
Example 3:3- (4-hydroxymethyl) pyridin-2-yl-N- (1- (2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-3)
Step A: 2-Paroxybenzyloxy acetophenone (17)
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2-hydroxyacetophenone (Compound 16, 10g,73.45 mmol) was placed in acetonitrile (200 mL), p-methoxybenzyl chloride (13.80 g,88.14 mmol), potassium carbonate (30.45 g,220.35 mmol) were added sequentially, stirred at 60℃for 12 hours, then diluted with water (300 mL) and extracted 3 times with ethyl acetate (200 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and column chromatography after concentration gave 2-p-methoxybenzyl acetophenone (18 g, 95.6%).
1 H NMR:(400MHz,DMSO-d6)δ＝7.58(dd,J＝1.8,7.7Hz,1H),7.55-7.50(m,1H),7.44(d,J＝8.6Hz,2H),7.27(d,J＝8.3Hz,1H),7.04-7.00(m,1H),6.99-6.94(m,2H),5.15(s,2H),3.76(s,3H),2.48(s,3H).
And (B) step (B): 2-Paroxybenzyloxy acetophenone oxime (18)
2-Paroxybenzyloxy acetophenone (Compound 17, 18g,70.23 mmol) was placed in ethanol (180 mL), sodium acetate (17.28 g,210.69 mmol) was added sequentially, hydroxylamine hydrochloride (5.86 g,84.28 mmol) was stirred at 70℃for 2 hours, then diluted with water (600 mL) and extracted 3 times with ethyl acetate (200 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 2-p-methoxybenzyloxy acetophenone oxime (10 g, 50.4%) by column chromatography.
1 H N MR:(400MHz,DMSO-d6)δ＝10.96(s,1H),7.38-7.31(m,3H),7.21(dd,J＝
1.6,7.4Hz,1H),7.14(d,J＝8.3Hz,1H),6.97-6.93(m,3H),5.05(s,2H),3.76(s,3H),2.03(s,3H).
Step C: 2-p-methoxybenzyloxyphenyl-1-ethylamine (19)
2-Paroxybenzyloxy acetophenone oxime (Compound 18, 11.0g,40.54 mmol) was placed in methanol (150 mL), ammonium formate (25.57 g,405.44 mmol) and zinc powder (26.67 g,407.94 mmol) were added in this order, stirred at 40℃for 12 hours, then the filtrate was concentrated by filtration, and column chromatography gave 2-p-methoxybenzyloxy-phenyl-1-ethylamine (7.8 g, 74%).
LCMS:m/z(ESI),258.2[M+H] + 。
1 H NMR:(400MHz,DMSO-d6)δ＝7.48-7.34(m,3H),7.18-7.12(m,1H),7.03-6.88(m,4H),5.02(d,J＝1.0Hz,2H),4.27(q,J＝6.6Hz,1H),3.76(s,3H),1.80-1.59(m,2H),1.20(d,J＝6.6Hz,3H).
Step D:3- (4-tert-Butyldimethylsilanylmethyl) pyridin-2-yl-N- (1- (2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (20)
3- (4-tert-Butyldimethylsilanylmethyl pyridin-2-yl-6-chloroimidazole [1,2-b ]]Pyridazine (Compound 19,1.9g,2.53 mmol) was placed in toluene (50 mL) and 2-p-methoxybenzyloxyphenyl-1-ethane was added sequentially Amine (651.08 mg,2.53 mmol), pd (dba) 2 (215.89 mg,0.38 mmol), sodium t-butoxide (487.00 mg,5.07 mmol) and Xantphos (219.91 mg,0.38 mmol) were stirred at 100deg.C for 16 hours, concentrated and then column chromatographed to give 3- (4-t-butyldimethylsilyloxy) pyridin-2-yl-N- (1- (2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1, 2-b)]Pyridazin-6-amine (400 mg, 26.5%).
LCMS:m/z(ESI),596.0[M+H] + 。
1 H NMR:(400MHz,DMSO-d6)δ＝8.57(d,J＝4.9Hz,1H),8.33(s,1H),8.03(s,1H),7.79(d,J＝9.6Hz,1H),7.42(dd,J＝1.3,7.4Hz,1H),7.32(d,J＝7.3Hz,1H),7.27(d,J＝8.6Hz,2H),7.24-7.20(m,2H),7.09(d,J＝7.8Hz,1H),6.93(t,J＝7.4Hz,1H),6.84(d,J＝9.6Hz,1H),6.67(d,J＝8.6Hz,2H),5.41(t,J＝7.0Hz,1H),5.13-5.04(m,2H),4.72-4.55(m,2H),3.65(s,3H),1.55(d,J＝6.8Hz,3H),0.87(s,9H),0.04(d,J＝7.8Hz,6H).
Step E:3- (4-hydroxymethyl) pyridin-2-yl-N- (1- (2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-3)
3- (4-tert-Butyldimethylsilanylmethyl) pyridin-2-yl-N- (1- (2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (compound 20, 300mg,0.53 mol) was placed in methanol (3 mL), methanol hydrochloride solution (4M, 3 mL) was added, stirred at 25℃for 2 hours, then neutralized to pH=7 with sodium bicarbonate, filtered, and the filtrate was concentrated and separated by column chromatography to give 3- (4-hydroxymethyl) pyridin-2-yl-N- (1- (2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (70 mg, 34%).
LCMS:m/z(ESI)，362[M+H] + 。
Example 4:3- (4-hydroxymethyl) pyridin-2-yl-N- (1- (2-hydroxypyridin-3-yl) -ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-4)
Step A: 2-Paroxybenzyloxy-3-acetylpyridine (22)
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2-hydroxy-3-acetylpyridine (Compound 21,10g,72.99 mmol) was placed in acetonitrile (200 mL), p-methoxybenzyl chloride (13.80 g,88.14 mmol), potassium carbonate (30.45 g,220.35 mmol) was added sequentially, stirred at 60℃for 12 hours, then diluted with water (300 mL) and extracted 3 times with ethyl acetate (200 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and column chromatography after concentration gave 2-p-methoxybenzyloxy-3-acetylpyridine (6 g, 32%).
LCMS:m/z(ESI),258.2[M+H] + 。
And (B) step (B): 2-Paroxybenzyloxy pyridine-3-glyoxime (23)
2-Paroxybenzyloxy-3-acetylpyridine (Compound 22,6g,23.26 mmol) was placed in ethanol (60 mL), sodium acetate (5.76 g,70.23 mmol), hydroxylamine hydrochloride (1.96 g,28.08 mmol) was added sequentially, stirred at 70℃for 2 hours, then diluted with water (200 mL) and extracted 3 times with ethyl acetate (100 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 2-p-methoxybenzyloxypyridine-3-ethanone oxime (3 g, 47.4%) by column chromatography.
LCMS:m/z(ESI),273.2[M+H] + 。
Step C:1- (2-p-methoxybenzyloxypyridin-3-yl) -ethylamine (24)
2-Paroxybenzyloxy pyridin-3-glyoxime (Compound 23,3.0g,11.03 mmol) was placed in methanol (50 mL), ammonium formate (25.57 g,405.44 mmol) and zinc powder (26.67 g,407.94 mmol) were added in this order, stirred at 40℃for 12 hours, then the filtrate was concentrated by filtration, and column chromatography gave 1- (2-p-methoxybenzyloxypyridin-3-yl) -ethylamine (2.1 g, 74%).
LCMS:m/z(ESI),259.2[M+H] + 。
Step D:3- (4-tert-Butyldimethylsilanylmethyl) pyridin-2-yl-N- (1- (2- (4-methoxybenzyloxy) -pyridin-3-yl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (25)
3- (4-tert-Butyldimethylsilanylmethyl pyridin-2-yl-6-chloroimidazole [1,2-b ] ]Pyridazine (Compound 5,1.9g,2.53 mmol) was placed in toluene (50 mL) and 1- (2-p-methoxybenzyloxypyridin-3-yl) -ethylamine (Compound 24, 651.08mg,2.53 mmol) and Pd (dba) were added sequentially 2 (215.89 mg,0.38 mmol), sodium t-butoxide (487.00 mg,5.07 mmol) and Xantphos (219.91 mg,0.38 mmol) were stirred at 100deg.C for 16 hours, concentrated and then column chromatographed to give 3- (4-t-butyldimethylsilyloxy) pyridin-2-yl-N- (1- (2- (4-methoxybenzyloxy) -pyridin-3-yl) ethyl) imidazole [1,2-b]Pyridazin-6-amine (300 mg, 20%).
LCMS:m/z(ESI),597.0[M+H] + 。
Step E:3- (4-hydroxymethyl) pyridin-2-yl-N- (1- (2-hydroxypyridin-3-yl) -ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-4)
3- (4-tert-Butyldimethylsilanylmethyl) pyridin-2-yl-N- (1- (2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (compound 25, 300mg,0.52 mol) was placed in methanol (3 mL), methanol hydrochloride solution (4M, 3 mL) was added, stirred at 25℃for 2 hours, then neutralized to pH=7 with sodium bicarbonate, filtered, and the filtrate was concentrated and separated by column chromatography to give 3- (4-hydroxymethyl) pyridin-2-yl-N- (1- (2-hydroxypyridin-3-yl) -ethyl) imidazo [1,2-b ] pyridazin-6-amine (50 mg, 24%).
LCMS:m/z(ESI),363[M+H] + 。
Example 5: 4-fluoro-2- (((3- (4- (hydroxymethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) -amino) -methyl) phenol (I-5)
Step A: 2-aminomethyl-4-fluorophenol (27)
5-fluoro-2-hydroxybenzonitrile (compound 26,2g,14.59 mmol) was placed in tetrahydrofuran (20 mL), lithium aluminum hydride (1.11 g,29.17 mmol) was added at zero degrees and stirred for 1 hour at 0deg.C, then quenched with sodium sulfate decahydrate, diluted with ethyl acetate (50 mL), filtered and the filtrate concentrated to give 2-aminomethyl-4-fluorophenol (2.3 g) by column chromatography.
1 H NMR:(400MHz,CHLOROFORM-d)δ＝6.74-6.48(m,2H),6.29-6.11(m,1H),3.57-3.46(m,2H).
And (B) step (B): 4-fluoro-2- (((3- (4- (hydroxymethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) -amino) -methyl) phenol (I-5)
3- (4-t-Butyldimethylsilanylmethylpyridin-2-yl-6-chloroimidazo [1,2-b ] pyridazine (Compound 27, 100mg,0.267 mmol) was placed in DMSO (3 mL), 2-aminomethyl-4-fluorophenol (188.23 mg,1.33 mol), sodium t-butoxide (51.26 mg,0.53 mol) were added in this order, stirring was carried out at 130℃for 1 hour, and the reaction mixture was filtered and then directly subjected to reverse phase preparation to isolate 4-fluoro-2- (((3- (4- (hydroxymethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) -amino) -methyl) phenol (48 mg, 49%).
LCMS:m/z(ESI),366.2[M+H] + 。
1 H NMR(400MHz,DMSO-d6)δ＝8.59-8.49(m,2H),8.19(s,1H),8.07(s,1H),7.84(d,J＝9.8Hz,1H),7.53-7.47(m,1H),7.25(d,J＝4.5Hz,1H),7.12-7.06(m,1H),6.92-6.85(m,3H),4.54-4.44(m,4H).
Example 6:2- (((3- (4- (hydroxymethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) -amino) -methyl) phenol (I-6)
3- (4-t-Butyldimethylsilanylmethylpyridin-2-yl-6-chloroimidazo [1,2-b ] pyridazine (Compound 5,1g,2.13 mmol) was placed in DMSO (16 mL), 2-aminomethylphenol (Compound 28, 525.53mg,4.27 mmol), sodium t-butoxide (51.26 mg,0.53 mol) were added in this order, stirred at 130℃for 1 hour, and the reaction mixture was filtered and isolated by direct reverse phase preparation to give 2- (((3- (4- (hydroxymethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) -amino) -methyl) phenol (180 mg, 24%).
LCMS:m/z(ESI),348.2[M+H] + 。
1 H NMR(400MHz,DMSO-d6)δ9.73-9.53(m,1H),8.60(s,1H),8.54(d,J＝5.0Hz,1H),8.06(s,1H),7.80(d,J＝9.8Hz,1H),7.39(t,J＝5.1Hz,1H),7.32-7.20(m,2H),7.09(t,J＝7.4Hz,1H),6.93-6.85(m,2H),6.78-6.70(m,1H),5.39(d,J＝6.9Hz,1H),4.50(s,4H).
Example 7:3- (5-hydroxymethyl) pyridin-3-yl-N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-7)
Step A: (5- (6-chloroimidazo [1,2-b ] pyridazin-3-yl) pyridin-3-yl) methanol (30)
5-hydroxymethylpyridine-3-boronic acid (compound 29, 500mg,3.27 mmol), 3-bromo-6-chloroimidazo [1,2-b]Pyridazine (Compound 2, 760mg,3.27 mmol), pd (PPh 3 ) 4 (3831 mg,0.33 mmol) in 1, 4-dioxane (50 mL) and water (5 mL), stirring at 100deg.C for 16 hours, then diluting with water (1.5L) and extracting 3 times with ethyl acetate (500 mL), combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating and column chromatography to give (5- (6-chloroimidazo [1, 2-b)]Pyridazin-3-yl) pyridin-3-yl methanol (150 mg, 17%).
LCMS:m/z(ESI),261[M+H] + 。
And (B) step (B): 3- (5- ((tert-Butyldimethylsilanyloxy) methyl) -pyridin-3-yl) -6-chloroimidazo [1,2-b ] pyridazine (31)
(5- (6-chloroimidazo [1,2-b ] pyridazin-3-yl) pyridin-3-yl) methanol (compound 30, 150mg,0.57 mmol) and imidazole (77.53 mg,1.14 mmol) were placed in dichloromethane (10 mL), tert-butyldimethylsilyl chloride (128.25 mg,0.85 mmol) was added at 0deg.C, stirred at room temperature for 16 hours, then quenched with water (50 mL) and extracted 3 times with ethyl acetate (50 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and column chromatography after concentration afforded 3- (5- ((tert-butyldimethylsilyloxy) methyl) -pyridin-3-yl) -6-chloroimidazo [1,2-b ] pyridazine (70 mg, 32%).
LCMS:m/z(ESI),375[M+H] + 。
Step C:3- (5-tert-Butyldimethylsilanylmethyl) pyridin-3-yl-N- (1- (5-fluoro-2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (32)
33- (5- ((tert-Butyldimethylsilanyloxy) methyl) -pyridin-3-yl) -6-chloroimidazo [1,2-b]Pyridazine (Compound 31,70mg,0.187 mmol) was placed in toluene (5 mL) and 2-p-methoxybenzyloxy-5-fluorophenyl-1-ethylamine (73.43 mg,0.187 mol) and Pd (dba) was added successively 2 (11.74 mg,0.019 mol), sodium t-butoxide (35.93 mg,0.37 mol) and Xantphos (10.03 mg,0.019 mol) were stirred at 100℃for 16 hours, and after concentration column chromatography was carried out to obtain 3- (5-t-butyldimethylsilyloxy) pyridin-3-yl-N- (1- (5-fluoro-2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1, 2-b)]Pyridazin-6-amine (12 mg, 10%).
LCMS:m/z(ESI),614.2[M+H] + 。
Step D:3- (5-hydroxymethyl) pyridin-3-yl-N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-7)
3- (4-t-Butyldimethylsilanylmethyl) pyridin-2-yl-N- (1- (5-fluoro-2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (compound 32,12mg,0.019 mol) was placed in methanol (3 mL), methanol hydrochloride solution (4M, 3 mL) was added, stirred for 2 hours at 25℃and then neutralized to pH=7 with sodium bicarbonate, filtered, and the filtrate was concentrated and separated by column chromatography to give 3- (5-hydroxymethyl) pyridin-3-yl-N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (5 mg).
LCMS:m/z(ESI),380[M+H] + 。
Example 8:2- (((3- (4- (hydroxyethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) -amino) -methyl) phenol (I-8)
Step A: 2-bromo-4-hydroxyethyl pyridine (34)
2-bromopyridine-4-acetic acid ethyl ester (compound 33,1g,4.35 mmol) was taken in tetrahydrofuran (15 mL), lithium aluminum hydride (142.03 mg,6.52 mmol) was added, stirred at 25℃for 1 hour, then extracted with saturated ammonium chloride solution (20 mL) 2 times, and extracted with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 2-bromo-4-hydroxyethylpyridine (870 mg).
LCMS:m/z(ESI),301[M+H] + 。
And (B) step (B): 2-bromo-4-tert-butyldimethylsilyloxy ethyl pyridine (35)
2-bromo-4-hydroxyethyl pyridine (Compound 34,2.57g,12.72 mmol) was placed in dichloromethane (30 mL), tert-butyldimethylsilyl chloride (3.83 g,25.44 mmol) and imidazole (1.73 g,25.44 mmol) were added sequentially at 0deg.C, stirred for 1 hour at 25deg.C, then directly concentrated and column chromatographed to give 2-bromo-4-tert-butyldimethylsilyloxy ethyl pyridine (4 g, 99%) as a colorless liquid.
1 H NMR:(400MHz,CHLOROFORM-d)δ8.24-8.27(m,1H)7.38-7.39(m,1H)7.10-7.13(m,1H)3.83(t,J＝6.19Hz,2H)2.75-2.81(m,2H)0.86(s,9H),0.02(s,6H).
Step C: 2-tributylstannyl-4-tert-butyldimethylsilyloxy ethyl pyridine (36)
2-bromo-4-t-butyldimethylsilyloxy-ethylpyridine (compound 34,4g,12.65 mmol) was placed in tetrahydrofuran (10 mL), n-butyllithium (2.5M, 5.06 mL) was added at-78℃under nitrogen, followed by tributyltin chloride (6.17 g,18.97 mmol), stirred at-78℃for 2 hours, then quenched with saturated ammonium chloride solution (50 mL), then potassium fluoride solution (50 mL) was added and stirred for 1 hour, then extracted 2 times with ethyl acetate (50 mL), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and concentrated to give 2-tributyltin-4-t-butyldimethylsilyloxy-ethylpyridine (5 g, crude) as a yellow liquid.
Step D:3- (4-tert-Butyldimethylsilanylethylpyridin-2-yl-6-chloroimidazo [1,2-b ] pyridazine (37)
3-bromo-6-chloroimidazo [1,2-b ] pyridazine (compound 36,2.21g,9.50 mmol), tetraphenylpalladium phosphate (1.10 g,949.75 umol) was placed in toluene solution (10 mL), 2-tributyltin-4-t-butyldimethylsilyloxy-ethylpyridine (compound 36,5g,9.50 mmol) was added, stirring was performed at 80℃for 12 hours under nitrogen protection, and then the filtrate was concentrated by filtration and column chromatography to obtain 3- (4-t-butyldimethylsilyloxy-ethylpyridin-2-yl-6-chloroimidazo [1,2-b ] pyridazine (270 mg, yield 7.31%) as a yellow solid.
1 H NMR:(400MHz,CHLOROFORM-d)δppm 8.59-8.62(m,1H)8.54-8.57(m,1H)8.39-8.42(m,1H)7.99-8.03(m,1H)7.12-7.18(m,2H)3.94(t,J＝6.63Hz,2H)2.95(t,J＝6.57Hz,2H)0.87(br,9H),0.00-0.02(m,6H).
Step E: 4-fluoro-2- (((3- (4- (hydroxyethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) -amino) -methyl) phenol (I-8)
3- (4-t-Butyldimethylsilanylethylpyridin-2-yl-6-chloroimidazo [1,2-b ] pyridazine (Compound 37, 250mg,0.64 mmol) was placed in DMSO (5 mL), 2-aminomethylphenol (158.31 mg,1.29 mmol) and potassium fluoride (298.74 mg,5.14 mmol) were added, stirred at 130℃under nitrogen protection for 30 minutes, and then directly concentrated followed by reverse phase liquid chromatography to give 2- (((3- (4- (hydroxyethyl) pyridin-2-yl) imidazol [1,2-b ] pyridazin-6-yl) -amino) -methyl) phenol (100 mg, yield 43%) as a white solid.
LCMS:m/z(ESI),362.1[M+H] + 。
1 H NMR:(400MHz,METHANOL-d4)δppm 8.50-8.52(m,1H)8.43(d,J＝5.00Hz,1H)8.06(s,1H)7.67-7.72(m,1H)7.26(d,J＝7.50Hz,1H)7.16-7.21(m,1H)7.06-7.11(m,1H)6.87(d,J＝9.76Hz,1H)6.83(d,J＝8.00Hz,1H)6.77(t,J＝7.50Hz,1H)4.63(s,2H)3.76(t,J＝6.44Hz,2H)2.76(t,J＝6.50Hz,2H).
Example 9:3- (5-hydroxyethyl) pyridin-3-yl-N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-9)
Step A:3- (5-tert-Butyldimethylsilanyloxyethyl) pyridin-3-yl-N- (1- (5-fluoro-2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (38)
3- (4-t-Butyldimethylsilanylethylpyridin-2-yl-6-chloroimidazo [1,2-b ] pyridazine (500 mg,1.28 mmol) and 2-p-methoxybenzyloxy-5-fluorophenyl-1-ethylamine (262.40 mg,1.02 mmol) were placed in 2-methyl-2-butanol (20 mL), sodium t-butoxide (2M, 241.02 uL) and RuPhos Pd G4 (13.44 mg,0.016 mmol) were added, stirred under nitrogen for 2 hours at 100℃and then diluted with water (20 mL) and extracted 3 times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate, and column chromatography was performed after concentration to give 3- (5-t-Butyldimethylsilyloxy ethyl) pyridin-3-yl-N- (1- (5-fluoro-2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (130 mg, 83%).
LCMS:m/z(ESI),610.2[M+H] + 。
And (B) step (B): 3- (5-hydroxyethyl) pyridin-3-yl-N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-9)
3- (4-tert-Butyldimethylsilanylethyl) pyridin-2-yl-N- (1- (5-fluoro-2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (compound 38, 120mg,0.196 mmol) was placed in methanol (10 mL), methanol hydrochloride solution (4M, 3 mL) was added, stirred for 2 hours at 25℃and then neutralized to pH=7 with sodium bicarbonate, filtered, and the filtrate was concentrated and then separated by column chromatography to give 3- (5-hydroxyethyl) pyridin-3-yl-N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (35 mg, 23%).
LCMS:m/z(ESI),376[M+H] + 。
1 H NMR:(400MHz,METHANOL-d4)δ＝8.43-8.39(m,2H)8.05-8.02(m,1H)7.69-7.65(m,1H)7.30-7.26(m,1H)7.21-7.18(m,1H)7.06-7.01(m,1H)6.89(d,J＝9.6Hz,1H)6.82-6.74(m,2H)5.46-5.39(m,1H)3.92-3.76(m,2H)2.94(t,J＝6.6Hz,2H)1.59-1.56(m,3H).
Example 10:3- (6-hydroxymethyl) pyrimidin-4-yl-N- (1- (2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-10)
Step A: 4-chloro-6-tert-butyldimethylsilyloxy methylpyrimidine (40)
Compound 40 was synthesized by the method described with reference to compound 2, starting from compound 39 instead of compound 1.
LCMS:m/z(ESI),259[M+H] + 。
And (B) step (B): 4-tributylstannyl-6-tert-butyldimethylsilyloxy methylpyrimidine (41)
Compound 41 was synthesized by the method described with reference to compound 3, starting from compound 40 instead of compound 2.
LCMS:m/z(ESI),515.0[M+H] + 。
Step C:3- (6-tert-Butyldimethylsilanylmethyl pyridin-4-yl) -6-chloroimidazo [1,2-b ] pyridazine (42)
Compound 42 was synthesized by the method described with reference to compound 5 using compound 41 as a starting material instead of compound 3.
LCMS:m/z(ESI),376.0[M+H] + 。
Step D:3- (6-tert-Butyldimethylsilanylmethyl-pyridin-4-yl) -N- (1- (5-fluoro-2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (43)
Compound 43 was synthesized by the method described with reference to compound 20 starting from compound 42 instead of compound 5.
LCMS:m/z(ESI),597.2[M+H] + 。
Step E:3- (6-hydroxymethylpyrimidin-4-yl) -N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-10)
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Compound I-10 was synthesized by the method described with reference to compound I-1 using compound 43 as a starting material instead of compound 10.
LCMS:m/z(ESI),363[M+H] + 。
Example 11:2- (((3- (6- (hydroxyethyl) pyrimidin-4-yl) imidazo [1,2-b ] pyridazin-6-yl) -amino) -methyl) phenol (I-11)
Step A: 4-chloro-6-hydroxyethyl pyrimidine (45)
Compound 45 was synthesized by the method described with reference to compound 34, starting from compound 44 instead of compound 33.
LCMS:m/z(ESI),159.2[M+H] + 。
And (B) step (B): 4-chloro-6-tert-butyldimethylsilyloxy ethyl pyrimidine (46)
Compound 46 was synthesized by the method described with reference to compound 35 using compound 45 as a starting material instead of compound 34.
LCMS:m/z(ESI),273.0[M+H] + 。
Step C: 4-tributylstannyl-6-tert-butyldimethylsilyloxy ethyl pyrimidine (47)
Compound 47 was synthesized by the method described with reference to compound 36, starting from compound 46 instead of compound 35.
LCMS:m/z(ESI),529.2[M+H] + 。
Step D:3- (6-tert-Butyldimethylsilanylethyl pyrimidin-4-yl-6-chloroimidazo [1,2-b ] pyridazine (48)
Compound 48 was synthesized by the method described with reference to compound 37, starting from compound 47 instead of compound 36.
LCMS:m/z(ESI),390.0[M+H] + 。
Step E:3- (6-tert-Butyldimethylsilanylmethyl pyrimidin-4-yl) -N- (1- (5-fluoro-2- (4-methoxybenzyloxy) -phenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (48-1)
Compound 48-1 was synthesized by the method described with reference to compound 38, starting from compound 48 instead of compound 37.
LCMS:m/z(ESI),611.2[M+H] + 。
Step F:2- (((3- (6- (hydroxyethylpyrimidin) -4-yl) imidazo [1,2-b ] pyridazin-6-yl) -amino) -methyl) phenol (I-11)
Compound 48-1 was used as a starting material in place of compound 37, and compound I-11 was synthesized by referring to compound I-9.
LCMS:m/z(ESI),377.2[M+H] + 。
Example 12:2- (6- ((1- (5-fluoro-2- (hydroxymethyl) pyridin-3-yl) -ethyl) -amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-ol (I-12)
Step A: 2-bromo-4-p-methoxybenzyloxymethylpyridine (50)
2-bromo-4-fluoropyridine (compound 49, 10g,57.47 mmol) and p-methoxybenzyl alcohol (9.52 g,68.96 mmol) were placed in DMF (100 mL), sodium hydride (3.45 g,86.21 mmol) was added at 0deg.C, stirred at room temperature for 16 h, then extracted with water (1L) and 3 times with ethyl acetate (500 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and column chromatography after concentration gave 2-bromo-4-tert-butyldimethylsilyl picoline (14.44 g, 85%).
LCMS:m/z(ESI),294[M+H] + 。
And (B) step (B): 3-tributylstannyl-6-chloroimidazo [1,2-b ] pyridazine (51)
3-chloro-6-chloroimidazo [1,2-b ] pyridazine (compound 4, 10g,43.10 mmol) was placed in tetrahydrofuran (100 mL), butyllithium (2.5M, 17.24 mol) was added dropwise at-70℃and stirred for half an hour, tributyltin-based chloride (18.25 g,43.10 mmol) was added thereto, stirred at-70℃for 2 hours, then extracted with saturated ammonium chloride (1.5L) and extracted 3 times with ethyl acetate (500 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography to give 3-tributyltin-6-chloroimidazo [1,2-b ] pyridazine (2.1 g, 11%).
LCMS:m/z(ESI),444.3[M+H] + 。
Step C:3- (4-Paroxybenzylpyridin-2-yl) -6-chloroimidazo [1,2-b ] pyridazine (52)
3-tributyltin-6-chloroimidazo [1,2-b]Pyridazine (Compound 51,1g,2.25 mmol) was placed in toluene (50 mL), and 2-bromo-4-t-butyldimethylsilyloxymethyl pyridine (Compound 50, 661.3mg,2.25 mmol) and Pd (PPh) were added sequentially 3 ) 4 (58.5 mg,0.225 mmol) was stirred at 100deg.C for 16 hours, then diluted with water (1.5L) and with ethyl acetateThe ester (500 mL) was extracted 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated followed by column chromatography to give 3- (4-p-methoxybenzyloxypyridin-2-yl) -6-chloroimidazo [1,2-b]Pyridazine (517 mg, 62%).
Step D: 3-bromo-5-fluoropyridine-2-carboxylic acid methyl ester (54)
3-bromo-5-fluoropyridine-2-carboxylic acid (compound 53, 10g,45.45 mmol) was taken up in methanol (200 mL), concentrated sulfuric acid (2 mL) was added, stirred at 80℃for 12 hours, then diluted with water (300 mL) and extracted 3 times with ethyl acetate (200 mL), the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate, and column chromatography after concentration afforded methyl 3-bromo-5-fluoropyridine-2-carboxylate (6.3 g, 59%).
LCMS:m/z(ESI),234.0[M+H] + 。
Step E:3- (1-ethoxyvinyl) -5-fluoropyridine-2-carboxylic acid methyl ester (55)
3-bromo-5-fluoropyridine-2-carboxylic acid methyl ester (compound 54,3g,12.82 mmol) was placed in 1, 4-dioxane (100 mL), and Pd (PPh) was added sequentially 3 ) 4 (147.84 mg,0.128 mmol), (1-ethoxyvinyl) tributyltin (6.94 g,19.23 mmol), stirred at 110℃for 16 hours, then diluted with water (600 mL) and extracted 3 times with ethyl acetate (200 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated followed by column chromatography to give methyl 3- (1-ethoxyvinyl) -5-fluoropyridine-2-carboxylate (2.5 g, 86%).
LCMS:m/z(ESI),226.0[M+H] + 。
Step F: (3- (1-ethoxyvinyl) -5-fluoropyridin-2-yl) -methanol (56)
Methyl 3- (1-ethoxyvinyl) -5-fluoropyridine-2-carboxylate (compound 55,1.1g,4.89 mmol) was taken up in tetrahydrofuran (50 mL), diisobutylaluminum hydride (9.77 mL,9.77 mmol) was added, stirred at 0℃for 5 hours, then quenched with water (600 mL), diluted and extracted 3 times with ethyl acetate (200 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated followed by column chromatography to give (3- (1-ethoxyvinyl) -5-fluoropyridin-2-yl) -methanol (803 mg, 83%).
LCMS:m/z(ESI),198.0[M+H] + 。
Step G: (3-acetyl-5-fluoropyridin-2-yl) -methanol (57)
(3- (1-ethoxyvinyl) -5-fluoropyridin-2-yl) -methanol (compound 56, 803mg,4.07 mmol) was placed in methanol (50 mL), a hydrochloric acid methanol solution (1M, 10 mL) was added, stirred at 25℃for 12 hours, then diluted and alkalified with a saturated sodium bicarbonate solution (100 mL) and extracted 3 times with ethyl acetate (200 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography to give (3-acetyl-5-fluoropyridin-2-yl) -methanol (650 mg, 94%).
LCMS:m/z(ESI),170.0[M+H] + 。
Step H:1- ((2-tert-Butyldimethylsilanylmethyl) -5-fluoropyridin-3-yl) -1-ethanone (58)
(3-acetyl-5-fluoropyridin-2-yl) -methanol (compound 57, 650mg,3.84 mmol) was placed in dichloromethane (50 mL), imidazole (537.6 mg,7.68 mmol), tert-butyldimethylsilyl chloride (576 mg,3.84 mmol) was added sequentially, stirred at 25℃for 12 hours, then diluted with water (50 mL) and extracted 3 times with ethyl acetate (50 mL), the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate, and column chromatography after concentration afforded 1- ((2-tert-butyldimethylsilyloxy methyl) -5-fluoropyridin-3-yl) -1-ethanone (463 mg, 32%).
LCMS:m/z(ESI),284.0[M+H] + 。
Step I:1- ((2-tert-Butyldimethylsilanylmethyl) -5-fluoropyridin-3-yl) -1-ethanone oxime (59)
1- ((2-t-Butyldimethylsilanylmethyl) -5-fluoropyridin-3-yl) -1-ethanone (compound 58, 343mg,1.21 mmol) was placed in ethanol (20 mL), sodium acetate (198 mg,2.42 mmol), hydroxylamine hydrochloride (168 mg,2.42 mmol), stirred at 70℃for 2 hours, then diluted with water (60 mL) and extracted 3 times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate, and column chromatography after concentration afforded 1- ((2-t-butyldimethylsilanylmethyl) -5-fluoropyridin-3-yl) -1-ethanone oxime (309 mg, 85.6%).
LCMS:m/z(ESI),299.0[M+H] + 。
Step J:1- ((2-tert-Butyldimethylsilanylmethyl) -5-fluoropyridin-3-yl) -1-ethylamine (60)
1- ((2-t-Butyldimethylsilanylmethyl) -5-fluoropyridin-3-yl) -1-ethanone oxime (compound 59, 309mg,1.07 mmol) was placed in methanol (15 mL), ammonium formate (127 mg,2.14 mmol) and zinc powder (139 mg,2.14 mmol) were added in sequence, stirred at 40℃for 12 hours, then the filtrate was concentrated by filtration, and column chromatography gave 1- ((2-t-butyldimethylsilanylmethyl) -5-fluoropyridin-3-yl) -1-ethylamine (105 mg, 34.5%).
LCMS:m/z(ESI),285.0[M+H] + 。
Step K: n- (1- (2- ((tert-Butyldimethylsilanyloxy) methyl) -5-fluoropyridin-3-yl) ethyl) -3- (4- (4-methoxybenzyloxypyridin) -2-yl) imidazo [1,2-b ] pyridazin-6-amine (61)
3- (4-Paroxybenzylpyridin-2-yl) -6-chloroimidazole [1,2-b]Pyridazine (Compound 52, 100mg,0.272 mmol) was placed in toluene (5 mL) and 1- ((2-tert-butyldimethylsilyloxy-methyl) -5-fluoropyridin-3-yl) -1-ethylamine (93.11 mg,0.328 mol), pd (dba) was added sequentially 2 (15.34 mg,0.027 mol), sodium t-butoxide (51.26 mg,0.53 mol) and Xantphos (15.43 mg,0.027 mol) were stirred at 100℃for 16 hours, and after concentration, column chromatography was carried out to give N- (1- (2- ((t-butyldimethylsilyloxy) methyl) -5-fluoropyridin-3-yl) ethyl) -3- (4- (4-methoxybenzyloxypyridin) -2-yl) imidazo [1, 2-b) ]Pyridazin-6-amine (42 mg, 25%).
LCMS:m/z(ESI),615.2[M+H] + 。
Step L:2- (6- ((1- (5-fluoro-2- (hydroxymethyl) pyridin-3-yl) -ethyl) -amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-ol (I-12)
N- (1- (2- ((tert-butyldimethylsilyloxy) methyl) -5-fluoropyridin-3-yl) ethyl) -3- (4- (4-methoxybenzyloxypyridin) -2-yl) imidazo [1,2-b ] pyridazin-6-amine (compound 61, 42mg,0.068 mol) is placed in methanol (3 mL), a methanolic hydrochloride solution (4M, 3 mL) is added, stirred at 25℃for 2 hours, then neutralized to pH=7 with sodium bicarbonate, filtered, and the filtrate is concentrated and separated by column chromatography to give 2- (6- ((1- (5-fluoro-2- (hydroxymethyl) pyridin-3-yl) -ethyl) -amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-ol (22 mg, 85%).
LCMS:m/z(ESI),381.2[M+H] + 。
Example 13:2- (6- ((1- (5-fluoro-2- (hydroxymethyl) pyridin-3-yl) -ethyl) -amino) imidazo [1,2-b ] pyridazin-3-yl) -4-phenol (I-13)
Step A: 2-bromo-4-fluorobenzoic acid methyl ester (63)
Compound 63 was synthesized by the method described with reference to compound 54 using compound 62 as a starting material instead of compound 53.
LCMS:m/z(ESI),233.0[M+H] + 。
And (B) step (B): 2- (1-ethoxyvinyl) -4-fluorobenzoic acid methyl ester (64)
Compound 64 was synthesized by a method of referring to compound 55 using compound 63 as a starting material instead of compound 54. LCMS: m/z (ESI), 225.0[ M+H ] ] + 。
Step C:2- (1-ethoxyvinyl) -4-fluorobenzyl alcohol (65)
Compound 65 was synthesized by the method described with reference to compound 56, starting from compound 64 instead of compound 55. LCMS: m/z (ESI), 197.0[ M+H ]] + 。
Step D: 2-acetyl-4-fluorobenzyl alcohol (66)
Compound 66 was synthesized by the method described with reference to compound 57 starting from compound 65 instead of compound 56. LCMS: m/z (ESI), 169.0[ M+H ]] + 。
Step E: 2-tert-Butyldimethylsilanylmethyl-5-fluoroacetophenone (67)
Compound 67 was synthesized by the method described with reference to compound 58, starting from compound 66 instead of compound 57. LCMS: m/z (ESI), 283.0[ M+H ]] + 。
Step F: 2-tert-Butyldimethylsilanylmethyl-5-fluoroacetophenone oxime (68)
Compound 68 was synthesized by the method described with reference to compound 59, starting from compound 67 instead of compound 58. LCMS: m/z (ESI), 298.0[ M+H ]] + 。
Step G:1- (2-tert-Butyldimethylsilanylmethyl-5-fluorophenyl) -1-ethylamine (69)
Compound 69 was synthesized by the method described with reference to compound 60 starting from compound 68 instead of compound 59. LCMS: m/z (ESI), 284.0[ M+H ]] + 。
Step H: n- (1- (2-tert-Butyldimethylsilanylmethyl-5-fluorophenyl) ethyl) -3- (4- (4-methoxybenzyloxypyridine) -2-yl) imidazo [1,2-b ] pyridazin-6-amine (70)
Compound 70 was synthesized by the method described with reference to compound 61 using compound 69 as a starting material instead of compound 60. LCMS: m/z (ESI), 614.2[ M+H ] ] + 。
Step L:2- (6- ((1- (5-fluoro-2- (hydroxymethyl) phenyl) -ethyl) -amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-ol (I-13)
Compound I-13 was synthesized by the method of referring to compound I-12 using compound 70 instead of compound 61 as a raw material.
LCMS:m/z(ESI),380.2[M+H] + 。
Examples 14, 15: (R) -3- (4-hydroxymethylpyridin-2-yl) -N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-14), (S) -3- (4-hydroxymethylpyridin-2-yl) -N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-15),
the compound I-14, I-15 is prepared by chiral resolution by taking the compound I-1 as a raw material.
LCMS:m/z(ESI),380.2[M+H] + (I-14),LCMS:m/z(ESI),380.2[M+H] + (I-15).
Examples 16, 17: (R) -3- (4-hydroxymethyl) pyridin-2-yl-N- (1- (3, 5-difluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-16), (S) -3- (4-hydroxymethyl) pyridin-2-yl-N- (1- (3, 5-difluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-17)
The compound I-16, I-17 is prepared by chiral resolution by taking the compound I-2 as a raw material.
LCMS:m/z(ESI),398.2[M+H] + (I-16),LCMS:m/z(ESI),398.0[M+H] + (I-17).
Examples 18, 19: (R) -3- (4-hydroxymethyl) pyridin-2-yl-N- (1- (2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-18), (S) -3- (4-hydroxymethyl) pyridin-2-yl-N- (1- (2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-19)
The compound I-18, I-19 is prepared by chiral resolution by taking the compound I-3 as a raw material.
LCMS:m/z(ESI),362.2[M+H] + (I-18),LCMS:m/z(ESI),362.2[M+H] + (I-19).
Examples 20, 21: (R) -3- (4-hydroxymethyl) pyridin-2-yl-N- (1- (2-hydroxypyridin-3-yl) -ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-20), (S) -3- (4-hydroxymethyl) pyridin-2-yl-N- (1- (2-hydroxypyridin-3-yl) -ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-21)
The compound I-20, I-21 is prepared by chiral resolution by taking the compound I-4 as a raw material.
LCMS:m/z(ESI),363.2[M+H] + (I-20),LCMS:m/z(ESI),363.2[M+H] + (I-21).
Examples 22, 23: (R) -3- (5-hydroxymethyl) pyridin-3-yl-N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-22), (S) -3- (5-hydroxymethyl) pyridin-3-yl-N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-22)
The compound I-22, I-23 is prepared by chiral resolution by taking the compound I-7 as a raw material.
LCMS:m/z(ESI),380.2[M+H] + (I-22),LCMS:m/z(ESI),380.2[M+H] + (I-23).
Examples 24, 25: (R) -2- (6- ((1- (5-fluoro-2- (hydroxymethyl) pyridin-3-yl) -ethyl) -amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-ol (I-24), (S) -2- (6- ((1- (5-fluoro-2- (hydroxymethyl) pyridin-3-yl) -ethyl) -amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-ol (I-25)
The compound I-24, I-25 is prepared by chiral resolution by taking the compound I-12 as a raw material.
LCMS:m/z(ESI),381.2[M+H] + (I-24),LCMS:m/z(ESI),381.2[M+H] + (I-25).
Examples 26, 27: (R) -3- (6-hydroxymethylpyrimidin-4-yl) -N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-26), (S) -3- (6-hydroxymethylpyrimidin-4-yl) -N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-27)
The compound I-26, I-27 is prepared by chiral resolution by taking the compound I-10 as a raw material.
LCMS:m/z(ESI),381.2[M+H] + (I-26),LCMS:m/z(ESI),381.2[M+H] + (I-27).
Examples 28, 29: (R) -3- (5-hydroxyethyl) pyridin-3-yl-N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-28), (S) -3- (5-hydroxyethyl) pyridin-3-yl-N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) imidazo [1,2-b ] pyridazin-6-amine (I-29)
The compound I-28, I-29 is prepared by chiral resolution by taking the compound I-9 as a raw material.
LCMS:m/z(ESI),376.0[M+H] + (I-28),LCMS:m/z(ESI),376.0[M+H] + (I-29).
Examples 30, 31: (R) -2- (6- ((1- (5-fluoro-2- (hydroxymethyl) phenyl) -ethyl) -amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-ol (I-30), (S) -2- (6- ((1- (5-fluoro-2- (hydroxymethyl) phenyl) -ethyl) -amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-ol (I-31)
The compound I-30, I-31 is prepared by chiral resolution by taking the compound I-13 as a raw material.
LCMS:m/z(ESI),380.0[M+H] + (I-30),LCMS:m/z(ESI),380.0[M+H] + (I-31).
Examples 32, 33: (R) -2- (((3- (6- (hydroxyethylpyrimidin) -4-yl) imidazo [1,2-b ] pyridazin-6-yl) -amino) -methyl) phenol (I-32), (S) -2- (((3- (6- (hydroxyethylpyrimidin) -4-yl) imidazo [1,2-b ] pyridazin-6-yl) -amino) -methyl) phenol (I-33)
The compound I-32, I-33 is prepared by chiral resolution by taking the compound I-11 as a raw material.
LCMS:m/z(ESI),377.0[M+H] + (I-32),LCMS:m/z(ESI),377.0[M+H] + (I-33).
Example 34: (S) -1- (2- (6- (((R) -1- (2-methoxy-5-fluorophenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) -4-pyridine) 2-propanol (I-34)
Step A (R) -1- (5-fluoro-2-methoxyphenyl) ethane-1-amine (71)
The synthesis of compound 27 was prepared according to the method of reference Journal of Medicinal Chemistry (1974), 17 (7), 708-15.
LCMS:m/z(ESI),170[M+H] + 。
And (B) step (B): (S) -1- (2-bromopyridin-4-yl) -2-propanol (73)
Reference Tetrahedron Asymmetry, (2006), 17 (2), 268-274.
LCMS:m/z(ESI),216.2[M+H] + 。
Step C: (S) -2-bromo-4- (2-tert-Butyldimethylsilanylpropyl) pyridine (74)
Compound 74 was synthesized by the method described with reference to compound 35, starting from compound 73 instead of compound 34.
LCMS:m/z(ESI),332.2[M+H] + 。
Step D: (S) -2-tributylstannyl-4- (2-t-butyldimethylsilyloxy) propyl) pyridine (75)
Compound 75 was synthesized by the method described with reference to compound 36, starting from compound 74 instead of compound 35.
LCMS:m/z(ESI),542.2[M+H] + 。
Step E:3- (4- (2-t-Butyldimethylsilanylpropyl) pyridin-2-yl) -6-chloroimidazo [1,2-b ] pyridazine (76)
Compound 76 was synthesized by the method described with reference to compound 37 using compound 75 as a starting material instead of compound 36.
LCMS:m/z(ESI),403.2[M+H] + 。
Step F: (S) -1- (2- (6- (((R) -1- (2-methoxy-5-fluorophenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) -4-pyridine) 2-propanol (I-34)
Compound I-34 was synthesized by the method described with reference to compound 38, starting from compound 76 instead of compound 37 and compound 71 instead of compound 19.
LCMS:m/z(ESI),422.1[M+H] + 。
Example 35: (S) -1- (2- (6- (((R) -1- (2-hydroxy-5-fluorophenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) -4-pyridine) 2-propanol (I-35)
Step A: (S) -1- (2- (6- (((R) -1- (2-hydroxy-5-fluorophenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) -4-pyridine) 2-propanol (I-35)
(S) -1- (2- (6- (((R) -1- (2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) -4-pyridine) 2-propanol (compound 77, 74mg, 0.183mol) is placed in dichloromethane (5 mL), boron tribromide (1 m,0.5 mL) is added, stirred at 25 ℃ for 2 hours, then neutralized to ph=7 with sodium bicarbonate, filtered, and the filtrate is concentrated and separated by column chromatography to give (S) -1- (2- (6- (((R) -1- (2-hydroxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) -4-pyridine) 2-propanol (25 mg, 35%).
LCMS:m/z(ESI),408.1[M+H] + 。
Example 36: (S) -1- (2- (6- (((R) -1- (2-methoxy-5-fluorophenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) -4-pyrimidine) 2-propanol (I-36)
Step A: (S) -1- (6-Chloropyrimidin-4-yl) -2-propanol (79)
Reference Tetrahedron Asymmetry, (2006), 17 (2), 268-274.
LCMS:m/z(ESI),173.2[M+H] + 。
And (B) step (B): (S) -6-chloro-4- (2-tert-Butyldimethylsilanylpropyl) pyrimidine (80)
Compound 80 was synthesized by the method described with reference to compound 74, starting from compound 79 instead of compound 73.
LCMS:m/z(ESI),287.0[M+H] + 。
Step C: (S) -6-tributylstannyl-4- (2-t-butyldimethylsilyloxy) propyl) pyrimidine (81)
Compound 81 was synthesized by the method described above with reference to compound 75, using compound 80 as a starting material instead of compound 74.
LCMS:m/z(ESI),543.2[M+H] + 。
Step D:3- (6- (2-t-Butyldimethylsilanylpropyl) pyrimidin-4-yl) -6-chloroimidazo [1,2-b ] pyridazine (82)
Compound 82 was synthesized by the method described with reference to compound 76, starting from compound 81 instead of compound 75.
LCMS:m/z(ESI),404.2[M+H] + 。
Step E: (S) -1- (2- (6- (((R) -1- (2-methoxy-5-fluoro-phenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) -4-pyridine) 2-propanol (I-36)
Compound I-36 was synthesized by the method described with reference to compound I-34 using compound 82 as a starting material instead of compound 76.
LCMS:m/z(ESI),423.1[M+H] + 。
Example 37: (S) -1- (2- (6- (((R) -1- (2-hydroxy-5-fluorophenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) -4-pyrimidine) 2-propanol (I-37)
The compound I-37 is synthesized by taking the compound I-36 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),409.1[M+H] + 。
Example 38: (S) -1- (2- (6- (((R) -1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) -4-pyridine) 2-propanol (I-34)
Compound I-38 was synthesized by the method of referring to compound I-34 using compound (R) -1- (5-fluoro-2-methoxypyridin-3-yl) -1-ethylamine instead of compound 71 as a starting material.
LCMS:m/z(ESI),423.1[M+H] + 。
Example 39: (S) -1- (2- (6- (((R) -1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) -4-pyridine) 2-propanol (I-39)
The compound I-39 is synthesized by taking the compound I-38 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),409.1[M+H] + 。
Example 40: (S) -1- (2- (6- ((R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) -2-propanol (I-40)
Compound I-40 was synthesized by the method of referring to compound I-34 using compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine as a starting material instead of compound 71.
LCMS:m/z(ESI),448.1[M+H] + 。
Example 41: (S) -1- (2- (6- ((R) -2- (5-fluoro-2-hydroxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) -2-propanol (I-41)
The compound I-41 is synthesized by taking I-40 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),434.1[M+H] + 。
Example 42: (S) -1- (2- (6- ((R) -2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) -2-propanol (I-42)
Compound I-40 was synthesized by the method of referring to compound I-34 using compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine as a starting material instead of compound 71.
LCMS:m/z(ESI),449.1[M+H] + 。
Example 43: (S) -1- (2- (6- ((R) -2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) -2-propanol (I-43)
The compound I-43 is synthesized by taking I-42 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),435.1[M+H] + 。
Example 44: (S) -1- (2- (6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) -2-propanol (I-44)
Compound I-44 was synthesized by the method of referring to compound I-34 using compound (2 r,4 s) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidine as a starting material instead of compound 71.
LCMS:m/z(ESI),466.1[M+H] + 。
Example 45: (S) -1- (2- (6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-hydroxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) -2-propanol (I-45)
The compound I-45 is synthesized by taking I-44 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),452.1[M+H] + 。
Example 46: (S) -1- (2- (6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) -2-propanol (46)
Compound I-46 was synthesized by referring to compound I-34 using compound 5-fluoro-3- ((2 r,4 s) -4-fluoropyrrolidin-2-yl) -2-methoxypyridine as a starting material instead of compound 71.
LCMS:m/z(ESI),467.1[M+H] + 。
Example 47: (S) -1- (2- (6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) -2-propanol (I-47)
The compound I-47 is synthesized by taking the compound I-46 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),453.1[M+H] + 。
Example 48: (S) -1- (2- (6- (((R) -1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-pyrrolidinol (I-48)
Step A: (S) -2-bromo-4- (3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) pyridine (83-1)
Compound 83-1 was synthesized by the method of reference to compound 50, starting from compound (S) -3- ((tert-butyldimethylsilyloxy) pyrrolidine instead of p-methoxybenzyl alcohol.
LCMS:m/z(ESI),359.1[M+H] + 。
And (B) step (B): (S) -3- (4- (3-tert-Butyldimethylsilanylpyrrolidin-1-yl) pyridin-2-yl) -6-chloroimidazo [1,2-b ] pyridazine (83)
Compound 83 was synthesized by the method described with reference to compound 52 using compound 83-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),430.1[M+H] + 。
Step C: (S) -1- (2- (6- (((R) -1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-pyrrolidinol (I-48)
Compound I-48 was synthesized by the method described with reference to compound I-34 using compound 83 as a starting material instead of compound 76.
LCMS:m/z(ESI),449.1[M+H] + 。
Example 49: (S) -1- (2- (6- (((R) -1- (5-fluoro-2-hydroxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-pyrrolidinol (I-49)
The compound I-49 is synthesized by taking the compound I-48 as a raw material instead of the compound I-34 and referring to the method of the compound I-35.
LCMS:m/z(ESI),435.1[M+H] + 。
Example 50: (R) -1- (2- (6- (((R) -1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-pyrrolidinol (I-50)
Step A: (R) -2-bromo-4- (3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) pyridine (84-1)
Compound 84-1 was synthesized by the method described with reference to compound 50, starting from compound (R) -3- ((tert-butyldimethylsilyloxy) pyrrolidine instead of p-methoxybenzyl alcohol.
LCMS:m/z(ESI),359.1[M+H] + 。
And (B) step (B): (R) -3- (4- (3-tert-Butyldimethylsilanylpyrrolidin-1-yl) pyridin-2-yl) -6-chloroimidazo [1,2-b ] pyridazine (84)
Compound 84 was synthesized by the method described with reference to compound 52, starting from compound 84-1 instead of compound 50.
LCMS:m/z(ESI),430.1[M+H] + 。
Step C: (R) -1- (2- (6- (((R) -1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-pyrrolidinol (I-50)
Compound I-50 was synthesized by the method described with reference to compound I-34 using compound 84 as a starting material instead of compound 76.
LCMS:m/z(ESI),449.1[M+H]+。
Example 51: (R) -1- (2- (6- (((R) -1- (5-fluoro-2-hydroxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-pyrrolidinol (I-51)
The compound I-51 is synthesized by taking I-50 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),435.1[M+H]+。
Example 52: (R) -1- (2- (6- ((1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-azetidinol (I-52)
Step A: 2-bromo-4- (3- (tert-butyldimethylsilyloxy) azetidin-1-yl) pyridine (85-1)
Compound 85-1 was synthesized by the method of reference to compound 50, starting from compound 3- (tert-butyldimethylsilyloxy) azetidine instead of p-methoxybenzyl alcohol.
LCMS:m/z(ESI),345.1[M+H]+。
And (B) step (B): 3- (4- (3- (tert-Butyldimethylsilanyloxy) azetidin-1-yl) pyridin-2-yl) -6-chloroimidazo [1,2-b ] pyridazine (85)
Compound 85 was synthesized by the method described with reference to compound 52 using compound 85-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),416.1[M+H]+。
Step C: (R) -1- (2- (6- ((1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-azetidinol (I-52)
Compound I-52 was synthesized by the method described with reference to compound I-34 using compound 85 as a starting material instead of compound 76.
LCMS:m/z(ESI),435.1[M+H] + 。
Example 53: (R) -1- (2- (6- ((1- (5-fluoro-2-hydroxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-azetidinol (I-53)
The compound I-53 is synthesized by taking the compound I-52 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),421.1[M+H] + 。
Example 54:2- ((2- (6- (((R) -1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) 1-cyclopropane (I-54)
Step A: 2-bromo-N- (2- (tert-butyldimethylsilyloxy) cyclopropyl) pyridin-4-amine (86-1)
Compound 86-1 was synthesized by the method of reference to compound 50, starting from compound 2- (t-butyldimethylsilyloxy) -1-cyclopropylamine instead of p-methoxybenzyl alcohol.
LCMS:m/z(ESI),345.1[M+H] + 。
And (B) step (B): 2- ((2- (6-chloroimidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) amino) -1-cyclopropanol (86)
Compound 86 was synthesized by the method described with reference to compound 52 using compound 86-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),416.1[M+H] + 。
Step C:2- ((2- (6- (((R) -1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) 1-cyclopropane (I-54)
Compound I-54 was synthesized by the method described with reference to compound I-34 using compound 86 as a starting material instead of compound 76.
LCMS:m/z(ESI),435.1[M+H] + 。
Example 55:2- ((2- (6- (((R) -1- (5-fluoro-2-hydroxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) 1-cyclopropane (I-55)
The compound I-55 is synthesized by taking I-54 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),421.1[M+H] + 。
Example 56: (S) -1- (2- (6- (((R) -1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-piperidinol (I-56)
Step A: (S) -2-bromo-4- (3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) pyridine (87-1)
Compound 87-1 was synthesized by the method of reference to compound 50, starting from compound (S) -3- ((tert-butyldimethylsilyloxy) piperidine instead of p-methoxybenzyl alcohol.
LCMS:m/z(ESI),371.1[M+H] + 。
And (B) step (B): (S) -3- (4- (3- (t-Butyldimethylsilanyloxy) piperidin-1-yl) pyridin-2-yl) -6-chloroimidazo [1,2-b ] pyridazine (87)
Compound 87 was synthesized by the method described with reference to compound 52 using compound 87-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),444.1[M+H] + 。
Step C: (S) -1- (2- (6- (((R) -1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-piperidinol (I-56)
Compound I-56 was synthesized by the method described with reference to compound I-34 using compound 87 as a starting material instead of compound 76.
LCMS:m/z(ESI),463.1[M+H] + 。
Example 57: (S) -1- (2- (6- (((R) -1- (5-fluoro-2-hydroxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-piperidinol (I-57)
The compound I-57 is synthesized by taking I-56 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),449.0[M+H] + 。
Example 58: (R) -1- (2- (6- (((R) -1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-piperidinol (I-58)
Step A: (R) -2-bromo-4- (3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) pyridine (88-1)
Compound 88-1 was synthesized by the method of reference to compound 50, starting from compound (R) -3- ((tert-butyldimethylsilyloxy) piperidine instead of p-methoxybenzyl alcohol.
LCMS:m/z(ESI),371.1[M+H] + 。
And (B) step (B): (R) -3- (4- (3- (t-Butyldimethylsilanyloxy) piperidin-1-yl) pyridin-2-yl) -6-chloroimidazo [1,2-b ] pyridazine (88)
Compound 88 was synthesized by the method described with reference to compound 52 using compound 88-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),444.1[M+H] + 。
Step A: (R) -1- (2- (6- (((R) -1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-piperidinol (I-58)
Compound I-58 was synthesized by the method described with reference to compound I-34 using compound 88 as a starting material instead of compound 76.
LCMS:m/z(ESI),463.1[M+H] + 。
Example 59: (R) -1- (2- (6- (((R) -1- (5-fluoro-2-hydroxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-piperidinol (I-59)
The compound I-59 is synthesized by taking the compound I-58 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),449.1[M+H] + 。
Example 60: (R) -1- (2- (6- ((1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-methyl-3-azetidinol (I-60)
Step A:1- (2-bromopyridin-4-yl) -3-methyl-3-azetidinol (89-1)
Compound 89-1 was synthesized by the method of reference to compound 50, starting from compound 3-hydroxy-3-methylazetidine instead of p-methoxybenzyl alcohol.
LCMS:m/z(ESI),243.1[M+H] + 。
And (B) step (B): 1- (2- (6-chloroimidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) -3-methyl-3-azetidine (89)
Compound 89 was synthesized by the method described with reference to compound 52, starting from compound 89-1 instead of compound 50.
LCMS:m/z(ESI),316.1[M+H] + 。
Step C: (R) -1- (2- (6- ((1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-methyl-3-azetidinol (I-60)
Compound I-60 was synthesized by the method described with reference to compound I-34 using compound 89 as a starting material instead of compound 76.
LCMS:m/z(ESI),449.1[M+H] + 。
Example 61: (R) -1- (2- (6- ((1- (5-fluoro-2-hydroxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -3-methyl-3-azetidinol (I-61)
The compound I-61 is synthesized by taking I-60 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),435.1[M+H] + 。
Example 62: (R) -N- (1- (5-fluoro-2-methoxyphenyl) ethyl) -3- (4-morpholinopyridin-2-yl) imidazo [1,2-b ] pyridazin-6-amine (I-62)
Step A:1- (2-bromopyridin-4-yl) -3-methyl-3-azetidinol (90-1)
Compound 90-1 was synthesized by the method of reference compound 50, using compound morpholine instead of p-methoxybenzyl alcohol as the starting material.
LCMS:m/z(ESI),243.1[M+H] + 。
And (B) step (B): 4- (2- (6-chloroimidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) morpholine (90)
Compound 90 was synthesized by the method described with reference to compound 52 using compound 90-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),316.1[M+H] + 。
Step C: (R) -N- (1- (5-fluoro-2-methoxyphenyl) ethyl) -3- (4-morpholinopyridin-2-yl) imidazo [1,2-b ] pyridazin-6-amine (I-62)
Compound I-62 was synthesized by the method described with reference to compound I-34 using compound 90 as a starting material instead of compound 76.
LCMS:m/z(ESI),449.1[M+H] + 。
Example 63: (R) -N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) -3- (4-morpholinopyridin-2-yl) imidazo [1,2-b ] pyridazin-6-amine (I-63)
The compound I-63 is synthesized by taking I-62 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),435.1[M+H] + 。
Example 64: (R) -1- (2- (6- ((1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -2-methyl-3-butyn-2-ol (I-64)
Step A:4- (2-bromopyridin-4-yl) -2-methyl-3-butyn-2-ol (91-1)
The synthesis of compound 91-1 was prepared by the method of reference Angewandte Chemie-International Edition,2008,47 (9), 1662-1667.
LCMS:m/z(ESI),240.1[M+H] + 。
And (B) step (B): 4- (2- (6-chloroimidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) -2-methyl-3-butyn-2-ol (91)
Compound 91 was synthesized by the method described with reference to compound 52 using compound 91-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),313.1[M+H] + 。
Step C: (R) -1- (2- (6- ((1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -2-methyl-3-butyn-2-ol (I-64)
Compound I-64 was synthesized by the method of referring to compound I-34 using compound 91 as a starting material instead of compound 76.
LCMS:m/z(ESI),446.1[M+H] + 。
Example 65: (R) -1- (2- (6- ((1- (5-fluoro-2-hydroxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -2-methyl-3-butyn-2-ol (I-65)
The compound I-65 is synthesized by taking I-64 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),432.1[M+H] + 。
Example 66: (R) -1- (2- (6- ((1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -2-methyl-2-butanol (I-66)
Step A:4- (2-bromopyridin-4-yl) -2-methyl-2-butanol (92-1)
The synthesis of compound 91-1 was prepared by the method of reference Journal of Medicinal Chemistry,1998,41, (16), 2960-2971.
LCMS:m/z(ESI),244.1[M+H] + 。
And (B) step (B): 4- (2- (6-chloroimidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) -2-methyl-2-butanol (92)
Compound 92 was synthesized by the method described with reference to compound 52 using compound 92-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),317.1[M+H] + 。
Step C: (R) -1- (2- (6- ((1- (5-fluoro-2-methoxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -2-methyl-2-butanol (I-66)
Compound I-66 was synthesized by the method described with reference to compound I-34 using compound 92 as a starting material instead of compound 76.
LCMS:m/z(ESI),450.1[M+H] + 。
Example 67: (R) -1- (2- (6- ((1- (5-fluoro-2-hydroxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -2-methyl-2-butanol (I-67)
The compound I-67 is synthesized by taking I-66 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),436.1[M+H] + 。
Example 68: (R) -N- (1- (5-fluoro-2-methoxyphenyl) ethyl) -3- (4- (2-fluoroethoxy) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-amine (I-68)
Step A:1- (2-bromopyridin-4-yl) -3-methyl-3-azetidinol (93-1)
The compound 93-1 was synthesized by the method of referring to the compound 50 using fluoroethanol as a raw material instead of p-methoxybenzyl alcohol.
LCMS:m/z(ESI),220.1[M+H] + 。
And (B) step (B): 6-chloro-3- (4- (2-fluoroethoxy) pyridin-2-yl) imidazo [1,2-b ] pyridazine (93)
Compound 93 was synthesized by the method described with reference to compound 52 using compound 93-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),293.1[M+H] + 。
Step C: (R) -N- (1- (5-fluoro-2-methoxyphenyl) ethyl) -3- (4- (2-fluoroethoxy) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-amine (I-68)
Compound I-68 was synthesized by the method described with reference to compound I-34 using compound 93 as a starting material instead of compound 76.
LCMS:m/z(ESI),426.1[M+H] + 。
Example 69: (R) -N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) -3- (4- (2-fluoroethoxy) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-amine (I-69)
The compound I-69 is synthesized by taking I-68 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),412.1[M+H] + 。
Example 70: (R) -N- (1- (5-fluoro-2-methoxyphenyl) ethyl) -3- (4- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-amine (I-70)
Step A: 2-bromo-4- (1-methyl-1H-pyrazol-4-yl) pyridine (94-1)
The synthesis of compound 94-1 was prepared by the method of reference Journal of Medicinal Chemistry,2020,63,7,3737-3755.
LCMS:m/z(ESI),238.1[M+H] + 。
And (B) step (B): 6-chloro-3- (4- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) imidazo [1,2-b ] pyridazine (94)
Compound 94 was synthesized by the method described with reference to compound 52 starting from compound 94-1 instead of compound 50.
LCMS:m/z(ESI),311.1[M+H] + 。
Step C: (R) -N- (1- (5-fluoro-2-methoxyphenyl) ethyl) -3- (4- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-amine (I-70)
Compound I-70 was synthesized by the method described with reference to compound I-34 using compound 94 as a starting material instead of compound 76.
LCMS:m/z(ESI),444.1[M+H] + 。
Example 71: (R) -N- (1- (5-fluoro-2-hydroxyphenyl) ethyl) -3- (4- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-amine (I-71)
The compound I-71 is synthesized by taking I-70 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),430.1[M+H] + 。
Example 72: (R) -2- (2- (6- ((1- (5-fluoro-2-hydroxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) acetic acid (I-72)
Step A: 2-bromopyridine-4-acetic acid tert-butyl ester (95-1)
The synthesis of compound 95-1 was prepared by the method of reference Tetrahedron,2009,65, (1), 134-138.
LCMS:m/z(ESI),272.1[M+H] + 。
And (B) step (B): 2- (2- (6-Chloroimidazole [1,2-b ] Pyridazin-3-yl) pyridin-4-yl) acetic acid tert-butyl ester (95)
Compound 95 was synthesized by the method of referring to compound 52 using compound 95-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),345.1[M+H] + 。
Step C: (R) -tert-butyl 2- (2- (6- ((1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) acetate (96)
Compound 96 was synthesized by the method described with reference to compound I-38 using compound 95 as a starting material instead of compound 76.
LCMS:m/z(ESI),479.1[M+H] + 。
Step D: (R) -2- (2- (6- ((1- (5-fluoro-2-hydroxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) acetic acid (I-72)
Compound I-72 was synthesized by the method of referring to compound I-39 using compound 96 as a starting material instead of compound I-38.
LCMS:m/z(ESI),409.1[M+H] + 。
Example 73: (R) -2- (2- (6- ((1- (5-fluoro-2-hydroxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) acetamide (I-73)
Step A: 2-bromopyridine-4-acetyl tert-butylamine (97-1)
The synthesis of compound 97-1 was prepared by the method of reference WO 2018/106636.
LCMS:m/z(ESI),271.1[M+H] + 。
And (B) step (B): 2- (2- (6-Chloroimidazole [1,2-b ] pyridazin-3-yl) pyridin-4-yl) acetyl tert-butylamine (97)
Compound 97 was synthesized by the method described with reference to compound 52, starting from compound 97-1 instead of compound 50.
LCMS:m/z(ESI),344.1[M+H] + 。
Step C: (R) -2- (2- (6- ((1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) acetyl tert-butylamine (98)
Compound 98 was synthesized by the method described with reference to compound I-38 using compound 97 as a starting material instead of compound 76.
LCMS:m/z(ESI),478.1[M+H] + 。
Step D: (R) -2- (2- (6- ((1- (5-fluoro-2-hydroxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) acetamide (I-73)
Compound I-73 was synthesized by the method of referring to compound I-39 using compound 98 as a starting material instead of compound I-38.
LCMS:m/z(ESI),408.1[M+H] + 。
Example 74: (R) -3- (1- ((3- (4- (2-aminoethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) ethyl) -5-fluoropyridin-2 (1H) -one (I-74)
Step A: (2- (2-bromopyridin-4-yl) ethyl) carbamic acid tert-butyl ester (99-1)
The synthesis of compound 99-1 is described in reference Bioorganicand Medicinal Chemistry Letters,1999,9, (9), 1317-1322.
LCMS:m/z(ESI),301.1[M+H] + 。
And (B) step (B): (2- (2- (6-chloroimidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) ethyl) carbamic acid tert-butyl ester (99)
Compound 99 was synthesized by the method described with reference to compound 52 using compound 99-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),374.1[M+H] + 。
Step C: (R) - (2- (2- (6- ((1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) ethyl) carbamic acid tert-butyl ester (100)
Compound 100 was synthesized by the method described with reference to compound I-38 using compound 99 instead of compound 76 as the starting material.
LCMS:m/z(ESI),508.1[M+H] + 。
Step D: (R) -3- (1- ((3- (4- (2-aminoethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) ethyl) -5-fluoropyridin-2 (1H) -one (I-74)
Compound I-74 was synthesized by the method of referring to compound I-39 using compound 100 as a starting material instead of compound I-38.
LCMS:m/z(ESI),394.1[M+H] + 。
Example 75: (R) -3- (1- ((3- (4- (2-aminomethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) ethyl) -5-fluoropyridin-2 (1H) -one (I-75)
Step A:2- (2-bromopyridin-4-yl) -1-cyclohexanone (101-1)
The synthesis of compound 101-1 was prepared by the method of reference Journal of the American Chemical Society,1999,121, (7), 1473-1478.
LCMS:m/z(ESI),254.1[M+H] + 。
And (B) step (B): ((1S, 2R) -2- (2-bromopyridin-4-yl) cyclohexyl) carbamic acid tert-butyl ester (101-2)
The synthesis of compound 101-2 was prepared by the method described in reference Journal of Medicinal Chemistry,2000,43, (9), 1699-1704.
LCMS:m/z(ESI),355.1[M+H] + 。
Step C, ((1S, 2R) -tert-butyl 2- (2- (6-chloroimidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) cyclohexyl) carbamate (101)
Compound 101 was synthesized by a method of referring to compound 52 using compound 101-2 as a starting material instead of compound 50.
LCMS:m/z(ESI),428.1[M+H] + 。
Step D: ((1S, 2R) -2- (2- (6- (((R) -1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) cyclohexyl) carbamic acid tert-butyl ester group) (102)
Compound 102 was synthesized by the method described with reference to compound I-38 using compound 101 as a starting material instead of compound 76.
LCMS:m/z(ESI),561.1[M+H] + 。
Step E: (R) -3- (1- ((3- (4- (2-aminomethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) ethyl) -5-fluoropyridin-2 (1H) -one (I-75)
Compound I-75 was synthesized by the method of referring to compound I-39 using compound 102 as a starting material instead of compound I-38.
LCMS:m/z(ESI),447.1[M+H] + 。
Example 76: (1S, 2R) -2- (2- (6- ((R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -1-cyclopentanol (I-76)
Step A: 2-bromo-4- ((1R, 2S) -2- (tert-butyldimethylsilyloxy) cyclopentyl) pyridine (103-1)
The synthesis of compound 103-1 was prepared by the method of reference Tetrahedron Asymmetry,2004,15, (3), 481-488.
LCMS:m/z(ESI),358.1[M+H] + 。
Step B3- (4- ((1R, 2S) -2- ((tert-Butyldimethylsilanyloxy) cyclopentyl) pyridin-2-yl) -6-chloroimidazo [1,2-B ] pyridazine (103)
Compound 103 was synthesized by the method described with reference to compound 52 using compound 103-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),429.1[M+H] + 。
Step C: (1S, 2R) -2- (2- (6- ((R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -1-cyclopentanol (I-76)
Compound I-76 was synthesized by the method of referring to compound I-40 using compound 103 as a starting material instead of compound 76.
LCMS:m/z(ESI),474.1[M+H] + 。
Example 77: (1S, 2R) -2- (2- (6- ((R) -2- (5-fluoro-2-hydroxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -1-cyclopentanol (I-77)
The compound I-77 was synthesized by the method of substituting the compound I-40 with the compound I-76 as the starting material and referring to the compound I-41.
LCMS:m/z(ESI),460.1[M+H] + 。
Example 78: (1S, 2S) -2- (2- (6- ((R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -1-cyclopentanol (I-78)
Step A: 2-bromo-4- ((1S, 2S) -2- (tert-butyldimethylsilyloxy) cyclopentyl) pyridine (104-1)
The synthesis of compound 104-1 was prepared by the method described in tetrahedronasymmet, 2004,15, (3), 481-488.
LCMS:m/z(ESI),358.1[M+H] + 。
Step B3- (4- ((1S, 2S) -2- ((tert-Butyldimethylsilanyloxy) cyclopentyl) pyridin-2-yl) -6-chloroimidazo [1,2-B ] pyridazine (104)
Compound 104 was synthesized by the method described with reference to compound 52 using compound 104-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),429.1[M+H] + 。
Step C: (1S, 2S) -2- (2- (6- ((R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -1-cyclopentanol (I-78)
Compound I-78 was synthesized by the method described with reference to compound I-40 using compound 104 as a starting material instead of compound 76.
LCMS:m/z(ESI),474.1[M+H] + 。
Example 79: (1S, 2S) -2- (2- (6- ((R) -2- (5-fluoro-2-hydroxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl)) -1-cyclopentanol (I-79)
The compound I-79 is synthesized by taking the compound I-78 as a raw material instead of the compound I-40 and referring to the method of the compound I-41.
LCMS:m/z(ESI),460.1[M+H] + 。
Example 80:6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) -3- (4- ((S) -tetrahydrofuranl-3-yl) pyridin-2-yl) imidazo [1,2-b ] pyridazine (I-80)
Step A: (S) -2-bromo-4- (tetrahydrofuran-3-yl) pyridine (105-1)
The synthesis of compound 105-1 was prepared by the method of reference Journal of the American Chemical Society,2018,140, (36), 11317-11324.
LCMS:m/z(ESI),228.1[M+H] + 。
Step B (S) -6-chloro-3- (4- (tetrahydrofuran-3-yl) pyridin-2-yl) imidazo [1,2-B ] pyridazine (105)
Compound 105 was synthesized by the method described with reference to compound 52 using compound 105-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),301.1[M+H] + 。
Step C:6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) -3- (4- ((S) -tetrahydrofuranl-3-yl) pyridin-2-yl) imidazo [1,2-b ] pyridazine (I-80)
Compound I-80 was synthesized by the method described with reference to compound I-44 using compound 105 instead of compound 76 as the starting material.
LCMS:m/z(ESI),478.1[M+H] + 。
Example 81:6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-hydroxyphenyl) pyrrolidin-1-yl) -3- (4- ((S) -tetrahydrofurane-3-yl) pyridin-2-yl) imidazo [1,2-b ] pyridazine (I-81)
The compound I-81 is synthesized by taking I-80 as a raw material instead of the compound I-44 and referring to a method of the compound I-45.
LCMS:m/z(ESI),464.1[M+H] + 。
Example 82:6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) -3- (4- ((R) -tetrahydrofuranl-3-yl) pyridin-2-yl) imidazo [1,2-b ] pyridazine (I-82)
Step A: (R) -2-bromo-4- (tetrahydrofuran-3-yl) pyridine (106-1)
The synthesis of compound 106-1 was prepared by the method of reference Journal of the American Chemical Society,2018,140, (36), 11317-11324.
LCMS:m/z(ESI),228.1[M+H] + 。
Step B (R) -6-chloro-3- (4- (tetrahydrofuran-3-yl) pyridin-2-yl) imidazo [1,2-B ] pyridazine (106)
Compound 106 was synthesized by the method described with reference to compound 52 using compound 106-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),301.1[M+H] + 。
Step C:6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) -3- (4- ((R) -tetrahydrofuranl-3-yl) pyridin-2-yl) imidazo [1,2-b ] pyridazine (I-82)
Compound I-82 was synthesized by the method described with reference to compound I-44 using compound 106 as a starting material instead of compound 76.
LCMS:m/z(ESI),478.1[M+H] + 。
Example 83:6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-hydroxyphenyl) pyrrolidin-1-yl) -3- (4- ((R) -tetrahydrofurane-3-yl) pyridin-2-yl) imidazo [1,2-b ] pyridazine (I-83)
The compound I-83 is synthesized by taking I-82 as a raw material instead of the compound I-44 and referring to a method of the compound I-45.
LCMS:m/z(ESI),464.2[M+H] + 。
Example 84: (R) -3- (2- (6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) phenol (I-84)
Step A:4- (3- (t-Butyldimethylsilanyloxy) phenyl) pyridin-2-yl-4-methylbenzenesulfonate (107-1)
The synthesis of compound 107-1 was prepared by the method of reference Journal of Organic Chemistry,2020,85, (11), 7399-7412.
LCMS:m/z(ESI),456.1[M+H] + 。
Step B3- (4- (3- ((tert-Butyldimethylsilanyloxy) phenyl) pyridin-2-yl) -6-chloroimidazo [1,2-B ] pyridazine (107)
Compound 107 was synthesized by a method of referring to compound 52 using compound 107-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),437.1[M+H] + 。
Step C: (R) -3- (2- (6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) phenol (I-84)
Compound I-84 was synthesized by the method described with reference to compound I-42 using compound 107 as a starting material instead of compound 76.
LCMS:m/z(ESI),483.2[M+H] + 。
Example 85: (R) -3- (2- (6- (2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) phenol (I-85)
The compound I-85 is synthesized by taking I-84 as a raw material instead of the compound I-42 and referring to a method of the compound I-43.
LCMS:m/z(ESI),469.2[M+H] + 。
Example 86: (R) -2'- (6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) - [4,4' -bipyridin ] -3-ol (I-86)
Step A:4- (3- (tert-Butyldimethylsilanyloxy) phenyl) pyridin-2-yl-4-methylbenzenesulfonate (108-1)
The synthesis of compound 108-1 was prepared by the method of reference Journal of Organic Chemistry,2020,85, (11), 7399-7412.
LCMS:m/z(ESI),457.1[M+H] + 。
Step B3- (3 '- ((tert-Butyldimethylsilyl) oxy) - [4,4' -bipyridyl ] -2-yl) -6-chloroimidazo [1,2-B ] pyridazine (108)
Compound 108 was synthesized by the method described with reference to compound 52 using compound 108-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),438.1[M+H] + 。
Step C: (R) -2'- (6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) - [4,4' -bipyridin ] -3-ol (I-86)
Compound I-86 was synthesized by the method described with reference to compound I-42 using compound 108 as a starting material instead of compound 76.
LCMS:m/z(ESI),484.2[M+H] + 。
Example 87: (R) -2'- (6- (2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) - [4,4' -bipyridin ] -3-ol (I-87)
The compound I-87 is synthesized by taking I-86 as a raw material instead of the compound I-42 and referring to a method of the compound I-43.
LCMS:m/z(ESI),470.0[M+H] + 。
Example 88:6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -3- (4- (2- (methylsulfonyl) ethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazine (I-88)
Step A: 2-bromo-4- (2- (methylsulfonyl) ethyl) pyridine (109-1)
The synthesis of compound 109-1 was prepared by the method of reference Tetrahedron Letters,2009,50, (17), 1928-1933.
LCMS:m/z(ESI),266.0[M+H] + 。
Step B6-chloro-3- (4- (2- (methylsulfonyl) ethyl) pyridin-2-yl) imidazo [1,2-B ] pyridazine (109)
Compound 109 was synthesized by a method of referring to compound 52 using compound 109-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),337.1[M+H] + 。
Step C:6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -3- (4- (2- (methylsulfonyl) ethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazine (I-88)
Compound I-88 was synthesized by the method described with reference to compound I-46 using compound 109 as a starting material instead of compound 76.
LCMS:m/z(ESI),515.2[M+H] + 。
Example 89:6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) -3- (4- (2- (methylsulfonyl) ethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazine (I-89)
The compound I-89 is synthesized by taking I-88 as a raw material instead of the compound I-46 and referring to a method of the compound I-47.
LCMS:m/z(ESI),501.2[M+H] + 。
Example 90:6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -3- (4- (2-cyanoethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazine (I-90)
Step A: 2-bromo-4- (2-cyanoethyl) pyridine (110-1)
The synthesis of compound 110-1 was prepared by the method of Organic Letters,2020,22, (9), 3570-3575.
LCMS:m/z(ESI),211.0[M+H] + 。
Step B6-chloro-3- (4- (2-cyanoethyl) pyridin-2-yl) imidazo [1,2-B ] pyridazine (110)
Compound 110 was synthesized by the method described with reference to compound 52 using compound 110-1 as a starting material instead of compound 50.
LCMS:m/z(ESI),284.1[M+H] + 。
Step C:6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -3- (4- (2-cyanoethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazine (I-90)
Compound I-90 was synthesized by the method described with reference to compound I-46, starting with compound 110 instead of compound 76.
LCMS:m/z(ESI),462.1[M+H] + 。
Example 91:6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) -3- (4- (2-cyanoethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazine (I-91)
The compound I-91 is synthesized by taking I-90 as a raw material instead of the compound I-46 and referring to a method of the compound I-47.
LCMS:m/z(ESI),448.2[M+H] + 。
Example 92: 4-fluoro-2- (1- ((3- (4- (hydroxymethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) amino) cyclopropyl) phenol (I-92)
Step A:1- (5-fluoro-2-methoxy-phenyl) cyclopropylamine (111)
The synthesis of compound 111 was prepared by the method of reference CN 112110938.
LCMS:m/z(ESI),182.0[M+H] + 。
And (B) step (B): 3- (4- (((tert-Butyldimethylsilanyloxy) methyl) pyridin-2-yl) -N- (1- (5-fluoro-2- ((4-methoxybenzyl) oxy) phenyl) cyclopropyl) imidazo [1,2-b ] pyridazin-6-amine (112)
Compound 112 was synthesized by the method described with reference to compound 10, starting from compound 111 instead of compound 9.
LCMS:m/z(ESI),626.2[M+H] + 。
Step C: 4-fluoro-2- (1- ((3- (4- (hydroxymethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) amino) cyclopropyl) phenol (I-92)
Compound I-92 was synthesized by the method described with reference to compound I-1 using compound 112 as a starting material instead of compound 10.
LCMS:m/z(ESI),392[M+H] + 。
Example 93: 4-fluoro-2- (1- ((3- (4- (hydroxymethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) amino) cyclopropyl) phenol (I-93)
Step A:2- (5-fluoro-2-methoxyphenyl) propyl-2-amine (113)
The synthesis of compound 113 was prepared by the method of reference US 2016221948.
LCMS:m/z(ESI),184.0[M+H] + 。
And (B) step (B): 3- (4- (((tert-Butyldimethylsilanyloxy) methyl) pyridin-2-yl) -N- (2- (5-fluoro-2- ((4-methoxybenzyl) oxy) phenyl) -2-propyl) imidazo [1,2-b ] pyridazin-6-amine (114)
Compound 114 was synthesized by the method described with reference to compound 10, starting from compound 113 instead of compound 9.
LCMS:m/z(ESI),628.2[M+H] + 。
Step C: 4-fluoro-2- (1- ((3- (4- (hydroxymethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) amino) -2-propyl) phenol (I-93)
Compound I-93 was synthesized by the method described with reference to compound I-1 using compound 114 as a starting material instead of compound 10.
LCMS:m/z(ESI),394[M+H] + 。
Example 94: (R) -4-fluoro-2- (1- (3- (4- (2-hydroxymethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-94)
Step A: (R) -3- (4- (((tert-Butyldimethylsilanyloxy) methyl) pyridin-2-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine (115)
Compound 115 was synthesized by the method of referring to compound 10, substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 9.
LCMS:m/z(ESI),420.1[M+H] + 。
And (B) step (B): (R) -4-fluoro-2- (1- (3- (4- (2-hydroxymethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-94)
The compound I-94 is synthesized by taking 115 instead of the compound I-34 as a raw material and referring to a method of the compound I-35.
LCMS:m/z(ESI),406.1[M+H] + 。
Example 95: 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (4- (2-hydroxymethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-95)
Step A: (R) -3- (4- (((tert-Butyldimethylsilanyloxy) methyl) pyridin-2-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine (116)
Compound 116 was synthesized by the method described with reference to compound 10, substituting compound (2 r,4 s) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 9.
LCMS:m/z(ESI),438.1[M+H] + 。
And (B) step (B): 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (4- (2-hydroxymethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-95)
116 is used as a raw material to replace the compound I-34, and the compound I-95 is synthesized by referring to a method of the compound I-35.
LCMS:m/z(ESI),424.1[M+H] + 。
Example 96: (R) - (2- (6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) methanol (I-96)
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Compound I-96 was synthesized by the method of referring to compound 10, substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 9.
LCMS:m/z(ESI),421.1[M+H].
Example 97: (2- (6- ((2R, 4S) -4-fluoro-2- (5 fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) methanol (I-97)
Compound I-97 was synthesized by the method of reference to compound 10, substituting compound 5-fluoro-3- ((2 r,4 s) -4-fluoropyrrolidin-2-yl) -2-methoxypyridine for compound 9.
LCMS:m/z(ESI),439.1[M+H]
Example 98: (R) -4-fluoro-2- (1- (3- (4-hydroxyethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-98)
Step A: (R) -3- (4- (hydroxyethyl) pyridin-2-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine (117)
Compound 117 was synthesized by the method of substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 37 and referring to compound 38.
LCMS:m/z(ESI),434.1[M+H] + 。
And (B) step (B): (R) -4-fluoro-2- (1- (3- (4-hydroxyethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-98)
The compound I-98 is synthesized by taking 117 instead of the compound I-34 as a raw material and referring to a method of the compound I-35.
LCMS:m/z(ESI),420.1[M+H] + 。
Example 99: 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (4- (hydroxyethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-99)
Step A: (R) -3- (4- (hydroxyethyl) pyridin-2-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine (118)
Compound 118 was synthesized by the method described with reference to compound 38, substituting compound (2 r,4 s) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 37.
LCMS:m/z(ESI),452.1[M+H] + 。
And (B) step (B): 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (4-hydroxyethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-99)
118 is used as a raw material to replace the compound I-34, and the compound I-99 is synthesized by referring to a method of the compound I-35.
LCMS:m/z(ESI),438.1[M+H] + 。
Example 100: (R) - (2- (6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) ethanol (I-100)
Compound I-100 was synthesized by the method of substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 37, with reference to compound 38.
LCMS:m/z(ESI),435.1[M+H].
Example 101: (2- (6- ((2R, 4S) -4-fluoro-2- (5 fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) ethanol (I-101)
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Compound I-101 was synthesized by the method of substituting compound 5-fluoro-3- ((2 r,4 s) -4-fluoropyrrolidin-2-yl) -2-methoxypyridine for compound 37, reference compound 38.
LCMS:m/z(ESI),453.1[M+H]
Example 102: (R) -4-fluoro-2- (1- (3- (6- (hydroxymethyl) pyrimidin-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-102)
Step A: (R) -3- (6- (((tert-Butyldimethylsilanyloxy) methyl) pyrimidin-4-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine (117)
Compound 117 was synthesized by the method of referring to compound 43, substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19.
LCMS:m/z(ESI),535.1[M+H] + 。
And (B) step (B): (R) -4-fluoro-2- (1- (3- (6- (hydroxymethyl) pyrimidin-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-102)
The compound I-102 is synthesized by taking 117 instead of the compound I-34 as a raw material and referring to a method of the compound I-35.
LCMS:m/z(ESI),407.1[M+H] + 。
Example 103: 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (6- (hydroxymethyl) pyrimidin-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-103)
Step A: (R) -3- (6- (((tert-Butyldimethylsilanyloxy) methyl) pyrimidin-4-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine (118)
Compound 118 was synthesized by the method described with reference to compound 43, substituting compound (2 r,4 s) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19.
LCMS:m/z(ESI),553.1[M+H] + 。
And (B) step (B): 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (6- (hydroxymethyl) pyrimidin-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-103)
118 is used as a raw material to replace the compound I-34, and the compound I-103 is synthesized by referring to a method of the compound I-35.
LCMS:m/z(ESI),425.1[M+H] + 。
Example 104: (R) - (6- (6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) methanol (I-104)
Compound I-104 was synthesized by the method of substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19 and referring to compound 43.
LCMS:m/z(ESI),422.1[M+H].
Example 105: (6- (6- ((2R, 4S) -4-fluoro-2- (5 fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) methanol (I-105)
Compound I-105 was synthesized by the method of substituting compound 5-fluoro-3- ((2 r,4 s) -4-fluoropyrrolidin-2-yl) -2-methoxypyridine for compound 19, reference compound 43.
LCMS:m/z(ESI),440.1[M+H].
Example 106: (R) -4-fluoro-2- (1- (3- (4- (hydroxymethyl) pyrimidin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-106)
Step A:4- (((tert-Butyldimethylsilanyloxy) methyl) -2-chloropyrimidine (119)
The synthesis of compound 113 was prepared by the method of reference WO 2016/196244.
LCMS:m/z(ESI),259.0[M+H] + 。
And (B) step (B): 4- (((tert-Butyldimethylsilanyloxy) methyl) -2-tributyltin pyrimidine (120)
Compound 120 was synthesized by the method described with reference to compound 3, starting from compound 119 instead of compound 2.
LCMS:m/z(ESI),515.0[M+H] + 。
Step C:3- (4- (((tert-Butyldimethylsilanyloxy) methyl) pyrimidin-2-yl) -6-chloroimidazo [1,2-b ] pyridazine (121)
Compound 120 was synthesized by the method described with reference to compound 5, using compound 120 as a starting material instead of compound 3.
LCMS:m/z(ESI),376.0[M+H] + 。
Step D: (R) -3- (4- (((tert-Butyldimethylsilanyloxy) methyl) pyrimidin-2-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine (121)
Compound 121 was synthesized by the method of referring to compound 43, substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19, compound 121 for compound 42.
LCMS:m/z(ESI),535.1[M+H] + 。
Step E: (R) -4-fluoro-2- (1- (3- (4- (hydroxymethyl) pyrimidin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-106)
122 is used as a raw material to replace the compound I-34, and the compound I-106 is synthesized by referring to a method of the compound I-35.
LCMS:m/z(ESI),407.1[M+H] + 。
Example 107: 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (4- (hydroxymethyl) pyrimidin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-107)
Step A: (R) -3- (4- (((tert-Butyldimethylsilanyloxy) methyl) pyrimidin-2-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine (123)
Compound 123 was synthesized by the method of referring to compound 43, substituting compound (2 r,4 s) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19 and compound 121 for compound 42.
LCMS:m/z(ESI),553.1[M+H] + 。
And (B) step (B): 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (4- (hydroxymethyl) pyrimidin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-107)
The compound I-107 is synthesized by taking 123 instead of the compound I-34 as a raw material and referring to a method of the compound I-35.
LCMS:m/z(ESI),425.1[M+H] + 。
Example 108: (R) - (2- (6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) methanol (I-108)
Compound I-108 was synthesized by the method of referring to compound 43, substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19, compound 121 for compound 42.
LCMS:m/z(ESI),422.1[M+H].
Example 109: (2- (6- ((2R, 4S) -4-fluoro-2- (5 fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) methanol (I-109)
Compound I-109 was synthesized by the method of reference to compound 43, substituting compound 5-fluoro-3- ((2 r,4 s) -4-fluoropyrrolidin-2-yl) -2-methoxypyridine for compound 19 and compound 121 for compound 42.
LCMS:m/z(ESI),440.1[M+H].
Example 110: (R) -4-fluoro-2- (1- (3- (4- (hydroxymethyl) pyrimidin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-110)
Step A: 4-hydroxymethyl-6-chloropyridazine (124)
The synthesis of compound 124 was prepared by the method of reference Bioorganic and Medicinal Chemistry Letters,2019, vol.29, # 23.
LCMS:m/z(ESI),145.0[M+H] + 。
And (B) step (B): 4- (((tert-Butyldimethylsilanyloxy) methyl) -6 chloropyridazine (125)
Compound 125 was synthesized by the method described with reference to compound 2, starting from compound 124 instead of compound 1.
LCMS:m/z(ESI),259.0[M+H] + 。
Step C:4- (((tert-Butyldimethylsilanyloxy) methyl) -6 tributyltin pyridazine (126)
Compound 126 was synthesized by the method described with reference to compound 3, starting from compound 125 instead of compound 2.
LCMS:m/z(ESI),515.0[M+H] + 。
Step D:3- (4- (((tert-Butyldimethylsilanyloxy) methyl) pyridazin-6-yl) -6-chloroimidazo [1,2-b ] pyridazine (127)
Compound 127 was synthesized by the method described with reference to compound 5, starting from compound 126 instead of compound 3.
LCMS:m/z(ESI),376.0[M+H] + 。
Step E: (R) -3- (4- (((tert-Butyldimethylsilanyloxy) methyl) pyridazin-6-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin (128)
Compound 128 was synthesized by the method of reference to compound 43, substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19 and compound 127 for compound 42.
LCMS:m/z(ESI),535.1[M+H] + 。
Step F: (R) -4-fluoro-2- (1- (3- (4- (hydroxymethyl) pyridazin-6-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-110)
The compound I-110 is synthesized by taking 128 instead of the compound I-34 as a raw material and referring to a method of the compound I-35.
LCMS:m/z(ESI),407.1[M+H] + 。
Example 111: 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (4- (hydroxymethyl) pyridazin-6-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-111)
Step A: (R) -3- (4- (((tert-Butyldimethylsilanyloxy) methyl) pyridazin-6-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin (129)
Compound 129 was synthesized by the method of referencing compound 43 with compound (2 r,4 s) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidine instead of compound 19 and compound 127 instead of compound 42.
LCMS:m/z(ESI),553.1[M+H] + 。
And (B) step (B): 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (4- (hydroxymethyl) pyridazin-6-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-111)
The compound I-111 was synthesized by using 129 as a starting material instead of the compound I-34 and referring to the method of the compound I-35.
LCMS:m/z(ESI),425.1[M+H] + 。
Example 112: (R) - (6- (6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridazin-4-yl) methanol (I-112)
Compound I-112 was synthesized by the method of referring to compound 43, substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19 and compound 127 for compound 42.
LCMS:m/z(ESI),422.1[M+H].
Example 113: (6- (6- ((2R, 4S) -4-fluoro-2- (5 fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridazin-4-yl) methanol (I-113)
Compound I-113 was synthesized by the method of reference to compound 43, substituting compound 5-fluoro-3- ((2 r,4 s) -4-fluoropyrrolidin-2-yl) -2-methoxypyridine for compound 19 and compound 127 for compound 42.
LCMS:m/z(ESI),440.1[M+H]
Example 114: (R) -4-fluoro-2- (1- (3- (6-hydroxyethyl) pyrimidin-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-114)
Step A: (R) -3- (6- (hydroxyethyl) pyrimidin-4-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine (130)
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Compound 130 was synthesized by the method of substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19 and referring to compound 48-1.
LCMS:m/z(ESI),448.1[M+H] + 。
And (B) step (B): (R) -4-fluoro-2- (1- (3- (6-hydroxyethyl) pyrimidin-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-114)
Compound I-114 was synthesized by the method of referring to compound I-35 using 130 instead of compound I-34 as a raw material.
LCMS:m/z(ESI),434.1[M+H] + 。
Example 115: 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (6- (hydroxyethyl) pyrimidin-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-115)
Step A: (R) -3- (6- (hydroxyethyl) pyrimidin-4-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine (131)
Compound 131 was synthesized by the method of substituting compound (2 r,4 s) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19 and referring to compound 48-1.
LCMS:m/z(ESI),466.1[M+H] + 。
And (B) step (B): 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (6- (hydroxyethyl) pyrimidin-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-115)
The compound I-99 is synthesized by taking 131 instead of the compound I-34 as a raw material and referring to a method of the compound I-35.
LCMS:m/z(ESI),452.1[M+H] + 。
Example 116: (R) - (4- (6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-6-yl) ethanol (I-116)
Compound I-116 was synthesized by the method of substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19 and referring to compound 48-1.
LCMS:m/z(ESI),449.1[M+H].
Example 117: (4- (6- ((2R, 4S) -4-fluoro-2- (5 fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-6-yl) ethanol (I-117)
Compound I-117 was synthesized by the method of substituting compound 5-fluoro-3- ((2 r,4 s) -4-fluoropyrrolidin-2-yl) -2-methoxypyridine for compound 19, reference compound 48-1.
LCMS:m/z(ESI),467.1[M+H]
Example 118: (R) -2- (6- (6- ((1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) -1-ethanol (I-118)
Compound I-118 was synthesized by the method of referring to compound 48-1, substituting compound (R) -1- (5-fluoro-2-methoxypyridin-3-yl) -1-ethylamine for compound 19.
LCMS:m/z(ESI),410.1[M+H]
Example 119: (R) -2- (6- (6- ((1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) -1-ethanol (I-119)
Compound I-119 was synthesized by the method of substituting compound (R) -1- (5-fluoro-2-hydroxyphenyl) -1-ethylamine for compound 19 and referring to compound 48-1.
LCMS:m/z(ESI),395.1[M+H]
Example 120: (R) -4-fluoro-2- (1- ((3- (4- (2-hydroxyethyl) pyridin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) amino) ethyl) phenol (I-120)
Compound I-120 was synthesized by the method of substituting compound (R) -1- (5-fluoro-2-hydroxyphenyl) -1-ethylamine for compound 37 and referring to compound 38.
LCMS:m/z(ESI),394.1[M+H]
Example 121: (R) -2- (2- (6- ((1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridin-4-yl) -1-ethanol (I-121)
Compound I-121 was synthesized by the method of substituting compound (R) -1- (5-fluoro-2-methoxypyridin-3-yl) -1-ethylamine for compound 37 and referring to compound 38.
LCMS:m/z(ESI),409.1[M+H].
Example 122: (R) - (6- (6- ((1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) -1-methanol (I-122)
Compound I-122 was synthesized by the method of reference to compound 43, substituting compound (R) -1- (5-fluoro-2-methoxypyridin-3-yl) -1-ethylamine for compound 19.
LCMS:m/z(ESI),396.1[M+H].
Example 123: (R) - (6- (6- ((1- (5-fluoro-2-hydroxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) -1-methanol (I-123)
Compound I-123 was synthesized by the method of substituting compound (R) -1- (5-fluoro-2-hydroxyphenyl) -1-ethylamine for compound 19 and referring to compound 43.
LCMS:m/z(ESI),381.1[M+H].
Example 124: (R) - (2- (6- ((1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) -1-methanol (I-124)
Compound I-124 was synthesized by the method of reference to compound 43, substituting compound (R) -1- (5-fluoro-2-methoxypyridin-3-yl) -1-ethylamine for compound 19 and compound 121 for compound 42.
LCMS:m/z(ESI),396.1[M+H].
Example 125: (R) - (2- (6- ((1- (5-fluoro-2-hydroxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) -1-methanol (I-125)
Compound I-125 was synthesized by the method of referring to compound 43, substituting compound (R) -1- (5-fluoro-2-hydroxyphenyl) -1-ethylamine for compound 19, compound 121 for compound 42.
LCMS:m/z(ESI),381.1[M+H].
Example 126: (R) - (6- (6- ((1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridazin-4-yl) -1-methanol (I-126)
Compound I-126 was synthesized by the method of reference to compound 43, substituting compound (R) -1- (5-fluoro-2-methoxypyridin-3-yl) -1-ethylamine for compound 19 and compound 127 for compound 42.
LCMS:m/z(ESI),396.1[M+H].
Example 127: (R) - (6- (6- ((1- (5-fluoro-2-hydroxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridazin-4-yl) -1-methanol (I-127)
Compound I-127 was synthesized by the method of referring to compound 43 by substituting compound (R) -1- (5-fluoro-2-hydroxyphenyl) -1-ethylamine for compound 19 and compound 127 for compound 42.
LCMS:m/z(ESI),381.1[M+H].
Example 128: (R) - (2- (6- ((1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) -1-ethanol (I-128)
Step A: 2-chloropyrimidine-4-acetic acid ethyl ester (133)
The synthesis of compound 133 was prepared as described in reference Organic and Biomolecular Chemistry,2017, vol.15, #16, p.3455-3465.
LCMS:m/z(ESI),201.0[M+H] + 。
And (B) step (B): 4-hydroxyethyl-2-chloropyrimidine (134)
Compound 134 was synthesized by the method described with reference to compound 34 using compound 133 as a starting material instead of compound 33.
LCMS:m/z(ESI),159.0[M+H] + 。
Step C:4- (((tert-Butyldimethylsilanyloxy) ethyl) -2-chloropyrimidine (135)
Compound 135 was synthesized by the method described with reference to compound 2, starting from compound 134 instead of compound 1.
LCMS:m/z(ESI),273.0[M+H] + 。
Step D:4- (((tert-Butyldimethylsilanyloxy) ethyl) -2-tributyltin pyrimidine (136)
Compound 136 was synthesized by the method described with reference to compound 3, starting from compound 135 instead of compound 2.
LCMS:m/z(ESI),529.0[M+H] + 。
Step E:3- (4- (((tert-Butyldimethylsilanyloxy) methyl) pyridazin-6-yl) -6-chloroimidazo [1,2-b ] pyridazine (137)
Compound 137 was synthesized by the method described with reference to compound 5, starting from compound 136 instead of compound 3.
LCMS:m/z(ESI),390.0[M+H] + 。
Step F: (R) -2- (2- (6- ((1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) -1-ethanol (I-128)
Compound I-128 was synthesized by the method of reference to compound 43, substituting compound (R) -1- (5-fluoro-2-methoxypyridin-3-yl) -1-ethylamine for compound 19 and compound 137 for compound 42.
LCMS:m/z(ESI),410.1[M+H].
Example 129: (R) -2- (2- (6- ((1- (5-fluoro-2-hydroxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) -1-ethanol (I-129)
Compound I-129 was synthesized by the method of referring to compound 43, substituting compound (R) -1- (5-fluoro-2-hydroxyphenyl) -1-ethylamine for compound 19 and compound 137 for compound 42.
LCMS:m/z(ESI),395.1[M+H].
EXAMPLE 130 (R) -4-fluoro-2- (1- (3- (4- (hydroxyethyl) pyrimidin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-130)
Step A: (R) -3- (4- (((tert-Butyldimethylsilanyloxy) ethyl) pyrimidin-2-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine (138)
Compound 138 was synthesized by the method described with reference to compound 43, substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19 and compound 137 for compound 42.
LCMS:m/z(ESI),435.1[M+H] + 。
And (B) step (B): (R) -4-fluoro-2- (1- (3- (4- (hydroxyethyl) pyrimidin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-130)
138 is used as a raw material to replace the compound I-34, and the compound I-130 is synthesized by referring to a method of the compound I-35.
LCMS:m/z(ESI),421.1[M+H] + 。
Example 131: 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (4- (hydroxyethyl) pyrimidin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-131)
Step A: (R) -3- (4- (((tert-Butyldimethylsilanyloxy) ethyl) pyrimidin-2-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine (139)
Compound 139 was synthesized by the method of referring to compound 43 by substituting compound (2 r,4 s) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19 and compound 137 for compound 42.
LCMS:m/z(ESI),439.1[M+H] + 。
And (B) step (B): 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (4- (hydroxyethyl) pyrimidin-2-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-131)
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139 is used as a raw material instead of the compound I-34, and the compound I-131 is synthesized by referring to a method of the compound I-35.
LCMS:m/z(ESI),439.1[M+H] + 。
Example 132: (R) - (2- (6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) ethanol (I-132)
Compound I-132 was synthesized by the method described with reference to compound 43, substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19 and compound 137 for compound 42.
LCMS:m/z(ESI),436.1[M+H].
Example 133: (2- (6- ((2R, 4S) -4-fluoro-2- (5 fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) ethanol (I-133)
Compound I-133 was synthesized by the procedure of reference to compound 43 substituting compound 5-fluoro-3- ((2 r,4 s) -4-fluoropyrrolidin-2-yl) -2-methoxypyridine for compound 19 and compound 137 for compound 42.
LCMS:m/z(ESI),454.1[M+H].
Example 134: (R) - (2- (6- ((1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) -1-ethanol (I-134)
Step A: 2-chloro-4-hydroxyethyl pyridazine (140)
2-chloro-4-hydroxymethylpyridazine (compound 124, 10g,57.47 mmol) and manganese dioxide (5.99 g,68.96 mmol) were placed in dioxane (100 mL), stirred at room temperature for 16 hours, filtered, the filtrate concentrated and dissolved in tetrahydrofuran (100 mL), methoxymethyl triphenylphosphine (21.01 g,68.96 mmol) was added at room temperature, stirred for 16 hours at 70℃and then extracted 3 times with dilute hydrochloric acid (1L), and ethyl acetate (500 mL), the organic phases were combined, concentrated and dissolved in (100 mL), sodium borohydride (3.19 g,86.21 mmol) was added at 0℃and stirred at room temperature for 16 hours, then extracted with water (1L) and 3 times with ethyl acetate (500 mL), the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate, and column chromatography after concentration gave 2-bromo-4-tert-butyldimethylsilyloxy methylpyridine (2.4 g, 26%).
LCMS:m/z(ESI),159.0[M+H] + 。
And (B) step (B): 4- (((tert-Butyldimethylsilanyloxy) ethyl) -6-chloropyridazine (141)
Compound 141 was synthesized by the method described with reference to compound 2, starting from compound 140 instead of compound 1.
LCMS:m/z(ESI),273.0[M+H] + 。
Step C:4- (((tert-Butyldimethylsilanyloxy) ethyl) -6-tributyltin pyridazine (142)
Compound 142 was synthesized by the method described with reference to compound 3, starting from compound 141 instead of compound 2.
LCMS:m/z(ESI),529.0[M+H] + 。
Step D:3- (4- (((tert-Butyldimethylsilanyloxy) ethyl) pyridazin-6-yl) -6-chloro-imidazo [1,2-b ] pyridazine (143)
Compound 143 was synthesized by the method described with reference to compound 5, starting from compound 142 instead of compound 3.
LCMS:m/z(ESI),390.0[M+H] + 。
Step E: (R) -6- (2- (6- ((1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridazin-4-yl) -1-ethanol (I-134)
Compound I-134 was synthesized by the method of reference to compound 43, substituting compound (R) -1- (5-fluoro-2-methoxypyridin-3-yl) -1-ethylamine for compound 19 and compound 143 for compound 42.
LCMS:m/z(ESI),410.1[M+H].
Example 135: (R) -6- (2- (6- ((1- (5-fluoro-2-hydroxyphenyl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyridazin-4-yl) -1-ethanol (I-135)
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Compound I-135 was synthesized by the method of referring to compound 43, substituting compound (R) -1- (5-fluoro-2-hydroxyphenyl) -1-ethylamine for compound 19 and compound 143 for compound 42.
LCMS:m/z(ESI),395.1[M+H].
Example 136 (R) -4-fluoro-2- (1- (3- (4- (hydroxyethyl) pyridazin-6-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-136)
Step A: (R) -3- (4- (((tert-Butyldimethylsilanyloxy) ethyl) pyridazin-6-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin (144)
Compound 144 was synthesized by the method described with reference to compound 43, substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19, compound 143 for compound 42.
LCMS:m/z(ESI),435.1[M+H] + 。
And (B) step (B): (R) -4-fluoro-2- (1- (3- (4- (hydroxyethyl) pyridazin-6-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-136)
144 is used as a raw material to replace the compound I-34, and the compound I-136 is synthesized by referring to a method of the compound I-35.
LCMS:m/z(ESI),421.1[M+H] + 。
Example 137: 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (4- (hydroxyethyl) pyridazin-6-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-137)
Step A: (R) -3- (4- (((tert-Butyldimethylsilanyloxy) ethyl) pyridazin-6-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin (145)
Compound 145 was synthesized by the method of referring to compound 43, substituting compound (2 r,4 s) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19 and compound 143 for compound 42.
LCMS:m/z(ESI),439.1[M+H] + 。
And (B) step (B): 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (4- (hydroxyethyl) pyridazin-6-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-137)
The compound I-137 is synthesized by taking 145 as a raw material instead of the compound I-34 and referring to a method of the compound I-35.
LCMS:m/z(ESI),439.1[M+H] + 。
Example 138: (R) - (6- (6- (2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridazin-4-yl) ethanol (I-138)
Compound I-138 was synthesized by the method of referring to compound 43, substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19, compound 143 for compound 42.
LCMS:m/z(ESI),436.1[M+H].
Example 133: (6- (6- ((2R, 4S) -4-fluoro-2- (5 fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridazin-4-yl) ethanol (I-139)
Compound I-139 was synthesized by the method of referring to compound 43, substituting compound 5-fluoro-3- ((2 r,4 s) -4-fluoropyrrolidin-2-yl) -2-methoxypyridine for compound 19, compound 143 for compound 42.
LCMS:m/z(ESI),454.1[M+H].
Example 140: (R) - (2- (6- ((1- (5-fluoro-2-methoxypyridin-3-yl) ethyl) amino) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) -1-ethanol (I-140)
Step A: (R) -1- (2-Chloropyrimidin-4-yl) -2-propanol (147)
Compound 147 was synthesized by the method of reference to compound 78, using compound 2-chloro-4-iodopyrimidine as a starting material instead of compound 78.
LCMS:m/z(ESI),173.0[M+H] + 。
And (B) step (B): (R) -4- (2- ((tert-Butyldimethylsilanyloxy) propyl) -2-chloropyrimidine (148)
Compound 148 was synthesized by the method described with reference to compound 2, starting from compound 147 instead of compound 1.
LCMS:m/z(ESI),287.0[M+H] + 。
Step C: (R) -4- (2- ((tert-Butyldimethylsilanyloxy) propyl) -2-tributyltin pyrimidine (149)
Compound 149 was synthesized by the method described with reference to compound 3, starting from compound 148 instead of compound 2.
LCMS:m/z(ESI),543.0[M+H] + 。
Step D: (R) -3- (4- (2- ((tert-Butyldimethylsilanyloxy) propyl) pyrimidin-2-yl) -6-chloroimidazo [1,2-b ] pyridazine (150)
Compound 150 was synthesized by the method described with reference to compound 5, starting from compound 149 instead of compound 3.
LCMS:m/z(ESI),404.0[M+H] + 。
Step E: (R) -1- (2- (6- ((R) -2- (5-fluoro-2-methoxypyridin-3-yl) ethyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) -2-propanol (I-140)
Compound I-140 was synthesized by the method of referring to compound 43, substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 19, compound 150 for compound 42.
LCMS:m/z(ESI),436.1[M+H].
Example 141: (R) -1- (2- (6- ((2R, 4S) -4-fluoro-2- (5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyrimidin-4-yl) -2-propanol (I-141)
Compound I-141 was synthesized by the method of reference to compound 43, substituting compound 5-fluoro-3- ((2 r,4 s) -4-fluoropyrrolidin-2-yl) -2-methoxypyridine for compound 19, compound 150 for compound 42.
LCMS:m/z(ESI),454.1[M+H].
Example 142: (R) -4-fluoro-2- (1- (3- (6- (S) -2-hydroxypropyl) pyrimidin-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-142)
Step A: (R) -3- (6- ((S) -2-hydroxypropyl) pyrimidin-4-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine (151)
Compound 151 was synthesized by the method of referring to compound I-36 by substituting compound (R) -2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 71.
LCMS:m/z(ESI),449.1[M+H] + 。
And (B) step (B): (R) -4-fluoro-2- (1- (3- (6- (S) -2-hydroxypropyl) pyrimidin-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-142)
Compound I-142 was synthesized by the method of substituting compound I-34 with 151 as a raw material and referring to compound I-35.
LCMS:m/z(ESI),434.1[M+H] + 。
Example 143: 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (6- ((S) -2-hydroxypropyl) pyrimidin-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-143)
Step A: (R) -3- (6- ((S) -2-hydroxypropyl) pyrimidin-4-yl) -6- (2- (5-fluoro-2-methoxyphenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazine (152)
Compound 152 was synthesized by the method described with reference to compound I-36, substituting compound (2 r,4 s) -4-fluoro-2- (5-fluoro-2-methoxyphenyl) pyrrolidine for compound 71.
LCMS:m/z(ESI),467.1[M+H] + 。
And (B) step (B): 4-fluoro-2- ((2R, 4S) -4-fluoro-1- (3- (6- ((S) -2-hydroxypropyl) pyrimidin-4-yl) imidazo [1,2-b ] pyridazin-6-yl) pyrrolidin-2-yl) phenol (I-143)
Compound I-143 was synthesized by using compound 152 as a starting material instead of compound I-34 and referring to compound I-35.
LCMS:m/z(ESI),453.1[M+H] + 。
Example 144: biological evaluation
Test one: test for inhibiting the Activity of Compounds against TRKA and TRKA (F589L) kinase, respectively
The experimental method comprises the following steps: compound preparation the compounds of examples 1-143 and Loxo-101 were each pre-dissolved in 100% DMSO to prepare 10mM stock solutions and stored frozen at-20 ℃.
The chemical structure of compound Loxo-101 is as follows and is commercially available and can be prepared with particular reference to WO 2010/48314.
Kinase reaction process: preparing a 1 XKinase buffer; preparing a compound concentration gradient: the test concentrations of the compounds of test examples 1-96 and of the compound Loxo-101 were 1000nM, and 100% DMSO solutions diluted 100-fold to final concentrations in 384 well plates were used to dilute the compounds 3-fold with precision to give 10 concentrations (1000, 333.3, 111.1, 37.0, 12.3, 4.1, 1.4, 0.16, 0.15 and 0.05 nM). The 250nL of 100-fold final concentration of compound was transferred to the destination plate OptiPlate-384F using a dispenser Echo 550; preparing a Kinase solution with a final concentration of 2.5 times by using a 1 XKinase buffer; mu.L of 2.5-fold final concentration Kinase solution was added to each of the compound wells and the positive control wells, and 10. Mu.L of 1 XKinase buffer was added to the negative control wells; centrifuging at 1000rpm for 30 seconds, shaking and uniformly mixing a reaction plate, and incubating at room temperature for 10 minutes; a mixed solution of ATP and Kinase substrate 22 was prepared at 5/3 times the final concentration using a 1 XKinase buffer; adding 15 mu L of a mixed solution of ATP and a substrate with 5/3 times of the final concentration, and initiating a reaction; centrifuging the 384-well plate at 1000rpm for 30 seconds, shaking and uniformly mixing, and incubating at room temperature for corresponding time; adding 30 mu L of stop detection solution to stop kinase reaction, centrifuging at 1000rpm for 30 seconds, and shaking and mixing uniformly; the conversion was read with Caliper EZ Reader.
Data analysis: the calculation formula is as follows:
％Inhibition＝(Conversion％_max-conversion％_sample)÷(Conversion％_max-conversion％_min)x 100
wherein: conversion% _sample is a Conversion reading of the sample; convertion% _min: negative control Kong Junzhi, representing conversion reading without enzyme wells; convesion% _max: positive control Kong Bizhi mean represents conversion readings for wells without compound inhibition. A fitted dose-response curve, using the log of the concentration as X-axis and the percentage inhibition as Y-axis, using log (inhibitor) vs. response-Variable slope fitted dose-response curve of analytical software GraphPad Prism 5 to obtain IC of each compound to enzyme activity 50 Values. The calculation formula is:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))。
where X represents the concentration of the test compound, Y represents the inhibition rate of the test compound at the concentration of X, top represents the maximum response, bottom represents the baseline response, hill Slope represents the Slope of the curve, i.e., the Slope.
IC of the respective Compounds on enzymatic Activity 50 The values are shown in tables 1 to 2 below.
TABLE 1 different compounds vs. kinase TRKA WT In vitro inhibition test IC of (C) 50 Test results (nM)
Experimental results indicate that most of the compounds in the application are expressed in kinase TRKA WT The inhibition ability of the in vitro inhibition experiments of (C) is better than that of the compound Loxo-101.
TABLE 2 different compounds vs. kinase TRKA F589L In vitro inhibition test IC of (C) 50 Test results (nM)
Experimental results indicate that most of the compounds in the application are expressed in kinase TRKA F589L The inhibition ability of the in vitro inhibition experiments of (C) is better than that of the compound Loxo-101.
Experiment II: the compound has the growth inhibition effect on Ba/F3-TPM3-NTRK 1-G667C) cells.
Reagent:
cell line:
compound solution preparation: the compounds of examples 1-96 and Loxo-101 were each pre-dissolved in 100% DMSO in a biosafety cabinet to prepare 10mM stock solution, which was frozen at-20 ℃; the stock solution of the compound is subjected to gradient dilution with DMSO: a clean and sterile 96-well microplate with a V-shaped bottom is placed in a biosafety cabinet, 4 mu L of DMSO is firstly added into a B2 well, 10 mu L of DMSO is added into a B3-B11 well, then 6 mu L of 10mM compound storage solution is added into the B2 well, the mixture is blown up and down for 10 times to uniformly mix, at the moment, the concentration of the compound in the B2 well is 6mM,100% DMSO is obtained, 5 mu L of solution is transferred into the B3 well, blown up and down for 10 times, uniformly mixing is carried out, and the mixture is sequentially diluted until the mixture is diluted to the B10 and B11 wells, and no compound to be tested is added.
Preparation of 6X compound solution (6-fold dilution, X represents dilution factor) (initial final concentration is 10. Mu.M), and placing a clean and sterile 96-well microplate with V-shaped bottom in a biosafety cabinet; adding 99 mu L of cell culture medium into each hole of the B2-G11, adding 1 mu L of the compound solution in each hole prepared in the previous step of compound solution preparation into the corresponding hole by using a 12-channel pipettor, and blowing the solution in each hole up and down for 10 times by using the pipettor to mix uniformly; the highest concentration of the compound at this time was 60. Mu.M;
Compound-treated cells: taking the inoculated cell culture plate out of the incubator; adding 20 mu L of compound solution from each hole into the corresponding cell culture hole, selecting the lowest pipetting speed during sample adding, attaching to the wall and avoiding contacting the bottom of the culture plate; gently shaking the cell culture plate to homogenize the compound solution, and then placing the cell culture plate back into the incubator for continuous culture for 72hr;
the treatment concentration of the compound was at this point at most 10. Mu.M. After 72hr treatment of the cells, cell TiterGlo (CTG) assay was performed. First, the cell culture plate is removed from the CO 2 Taking out the culture plate from the incubator, and placing the culture plate at room temperature for 30 minutes to ensure that the temperature of the culture plate is uniform; taking out a Cell TiterGlo reagent prepared in advance according to the specification, standing at room temperature, and melting; then 60. Mu.L of Cell TiterGlo reagent was added to each Cell-containing well, and the mixture was incubated for 1hr with a horizontal shaker placed at room temperature in the absence of light at 225 rpm; reading the plate according to the method in the specification by using a Tecan Spark enzyme-labelling instrument according to a chemiluminescence method, and performing IC (integrated circuits) on part of compounds for different cell lines 50 Table 3 below:
TABLE 3 in vitro inhibition experiments of different compounds on cells Ba/F3-TPM3-NTRK1-G667C IC 50 Test results (nM)
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Experimental results show that the inhibition capacity of most of the compounds in the application in vitro inhibition experiments of cells Ba/F3-TPM3-NTRK1-G667C is better than that of the compound Loxo-101.
The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily appreciate variations or alternatives within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (10)

1. Imidazo [1,2-b ] pyridazine derivatives of formula I, or isotopically-labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomer mixtures thereof, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof,
wherein:
W 1 、W 2 、W 3 、W 4 、W 5 each independently selected from carbon or nitrogen;
R 1 、R 2 、R 3 each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, substituted or unsubstituted saturated or unsaturated C 1 ～C 6 Alkyl, substituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkyl, substituted or unsubstituted saturated or unsaturated 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or substituted or unsubstituted 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, or R 1 And R is 2 Together with the N and C atoms to which they are attached form a substituted or unsubstituted 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, or R 2 And R is 3 Form, together with the C atom to which they are attached, a substituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkyl, substituted or unsubstituted 5 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S; wherein said "substitution" means optionally containing 1 to 4 groups selected from deuterium, hydroxy, halogen, cyano, amino, C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 3 ～C 6 Substituents for cycloalkoxy;
R 4 selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 6 Alkyl, saturated or unsaturated C 3 ～C 6 Cycloalkyl;
R 5 selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 6 Alkyl, saturated or unsaturated C 3 ～C 6 Cycloalkyl, or R 5 Absence of;
X 1 selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, substituted or unsubstituted saturated or unsaturated C 1 ～C 6 Alkyl, substituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkyl, substituted or unsubstituted saturated or unsaturated C 1 ～C 6 Alkoxy, substituted or unsubstituted saturated or unsaturated C 3 ～C 6 A cycloalkoxy group, wherein the "substitution" refers to a substituent optionally containing 1 to 4 substituents selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, sulfonyl, amino;
L 1 Selected from hydrogen, deuterium, halogen, hydroxy, amino, amido, -NR a R b Substituted or unsubstituted C 1 ～C 6 Alkyl, substituted or unsubstituted C 2 ～C 8 Alkenyl, substituted or unsubstituted C 2 ～C 8 Alkynyl, substituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkyl, substituted or unsubstituted saturated or unsaturated C 1 ～C 6 Alkoxy, substituted or unsubstitutedSubstituted C 6 -C 14 Aryl, substituted or unsubstituted saturated or unsaturated 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or substituted or unsubstituted 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means optionally containing 1 to 4 heteroatoms selected from deuterium, halogen, cyano, hydroxy, carboxyl, carbonyl, sulfinyl, sulfonyl, amino, amido, C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 3 ～C 6 A cycloalkoxy substituent, wherein R a And R is b Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 3 ～C 6 A cycloalkoxy group containing 1 to 4 substituents selected from deuterium, halogen, cyano, hydroxy, amino 1 ～C 4 Alkyl, C containing 1 to 4 substituents selected from deuterium, halogen, cyano, hydroxy, amino 3 ～C 6 Cycloalkyl groups.
2. The imidazo [1,2-b ] pyridazine derivative of formula I according to claim 1, or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,
R 1 、R 2 、R 3 each independently selected from hydrogen, deuterium, substituted or unsubstituted saturated or unsaturated C 1 ～C 4 Alkyl, substituted or unsubstituted saturated or unsaturated C 4 ～C 6 Cycloalkyl, or R 1 And R is 2 Together with the N and C atoms to which they are attached form a substituted or unsubstituted 5 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, or R 2 And R is 3 Together with the C atom to which they are attachedSubstituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkyl; wherein said "substitution" means optionally containing 1 to 3 groups selected from deuterium, hydroxy, halogen, C 1 ～C 3 Alkyl, C 5 ～C 6 Substituents of cycloalkyl;
more preferably, R 1 、R 2 、R 3 Each independently selected from hydrogen, deuterium, substituted or unsubstituted saturated or unsaturated C 1 ～C 3 Alkyl, or R 1 And R is 2 Together with the N and C atoms to which they are attached form a substituted or unsubstituted 5-to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or R 2 And R is 3 Form, together with the C atom to which they are attached, a substituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkyl; wherein said "substitution" means optionally containing 1 to 3 substituents selected from deuterium, hydroxy, halogen;
preferably, R 4 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 4 Alkyl, saturated or unsaturated C 5 ～C 6 Cycloalkyl;
more preferably, R 4 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 3 An alkyl group;
more preferably, R 4 Selected from hydrogen, deuterium or halogen;
preferably, R 5 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 4 Alkyl, saturated or unsaturated C 3 ～C 6 Cycloalkyl, or R 5 Absence of;
more preferably, R 5 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 3 Alkyl, or R 5 Absence of;
more preferably, when W 5 When C is R 5 Selected from hydrogen, deuterium, halogen; when W is 5 When N is present, R 5 Is not present.
3. The imidazo [1,2-b ] pyridazine derivative of formula I according to claim 1, or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,
X 1 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, substituted or unsubstituted saturated or unsaturated C 1 ～C 4 Alkyl, substituted or unsubstituted saturated or unsaturated C 1 ～C 4 Alkoxy, substituted or unsubstituted saturated or unsaturated C 3 ～C 6 A cycloalkoxy group, wherein the "substitution" means optionally containing 1 to 4 substituents selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl;
more preferably X 1 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, substituted or unsubstituted saturated or unsaturated C 1 ～C 4 Alkyl, substituted or unsubstituted saturated or unsaturated C 1 ～C 4 Alkoxy, wherein said "substitution" means optionally containing 1 to 3 substituents selected from hydrogen, deuterium, halogen, cyano, hydroxy.
4. The imidazo [1,2-b ] pyridazine derivative of formula I according to claim 1, or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,
L 1 selected from hydrogen, deuterium, halogen, hydroxy, amino, amido, -NR a R b Substituted or unsubstituted C 1 ～C 4 Alkyl, substituted or unsubstituted C 2 ～C 6 Alkenyl, substituted or unsubstituted C 2 ～C 6 Alkynyl, substituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkyl, substituted or unsubstituted saturated or unsaturated C 1 ～C 4 Alkoxy, substituted or unsubstituted C 6 -C 10 A substituted or unsubstituted saturated or unsaturated 4 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a substituted or unsubstituted 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means optionally containing 1 to 4 heteroatoms selected from deuterium, halogen, cyano, hydroxy, carboxyl, carbonyl, sulfinyl, sulfonyl, amino, amido, C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 3 ～C 6 A cycloalkoxy substituent, wherein R a And R is b Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, amino, C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C containing 1 to 2 substituents selected from deuterium, halogen, cyano, hydroxy, amino 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl;
more preferably L 1 Selected from hydrogen, deuterium, halogen, hydroxy, amino, amido, -NR a R b Substituted or unsubstituted C 1 ～C 3 Alkyl, substituted or unsubstituted C 2 ～C 4 Alkenyl, substituted or unsubstituted C 2 ～C 4 Alkynyl, substituted or unsubstituted saturated or unsaturated C 3 ～C 6 Cycloalkyl, substituted or unsubstituted saturated or unsaturated C 1 ～C 3 Alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted saturated or unsaturated 4 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or substituted or unsubstituted 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means optionally containing 1 to 3 heteroatoms selected from deuterium, halogen, cyano, hydroxy, carboxy, carbonyl, sulfinyl, sulfonyl, amino, amido, C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, substituent wherein R a And R is b Each independently selected from hydrogen, deuterium, C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C containing 1 to 2 substituents selected from deuterium, halogen, cyano, hydroxy, amino 3 ～C 6 Cycloalkyl;
more preferably L 1 One selected from the following groups:
5. imidazo [1,2-b ] pyridazine derivatives of formula i according to claim 1, or isotopically labelled compounds thereof, or optical isomers, geometrical isomers, tautomers or isomer mixtures thereof, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof, characterized in that they are represented by the following formulae 1-1, 1-2, 1-3, 1-4, 1-5 and 1-6:
Wherein the substituent W 5 、R 1 、R 2 、R 3 、R 4 、R 5 、X 1 、L 1 Is as defined in claim 1.
6. Imidazo [1,2-b ] pyridazine derivatives of formula i according to any one of claims 1 to 5, or isotopically labelled compounds thereof, or optical isomers, geometrical isomers, tautomers or mixtures of isomers thereof, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof, characterized in that they are selected from the following compounds:
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7. a pharmaceutical composition comprising a therapeutically effective amount of an imidazo [1,2-b ] pyridazine derivative of formula i according to any one of claims 1-6 or an isotopically labelled compound thereof, or an optical isomer, a geometrical isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, together with a pharmaceutically acceptable carrier.
8. Use of an imidazo [1,2-b ] pyridazine derivative of formula i according to any one of claims 1-6 or an isotopically labelled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, for the manufacture of a medicament for use as a TRK kinase inhibitor for the treatment or prevention of a disease or disorder mediated by a TRK or a TRK mutation in a subject in need thereof;
Preferably, the disease or disorder mediated by TRK or a TRK mutation is selected from one or more of cancer, neurodegenerative disease, inflammation, pain;
more preferably, the disease or condition mediated by TRK or a TRK mutation is selected from the group consisting of surgical pain, inflammatory pain, neuropathic pain, alzheimer's disease, parkinson's disease, multiple sclerosis, colon cancer, thyroid cancer, lung cancer, prostate cancer, ovarian cancer, breast cancer, salivary gland cancer, pancreatic cancer, melanoma, salivary gland tumor, bile duct cancer, interstitial tumor, brain tumor, and hematological malignancy.
9. A kit comprising a compound of formula I according to the invention or an isotopically labelled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the pharmaceutical composition according to the invention, together with a container and instructions for use.
10. A method of treating a disease or condition mediated with TRK or a TRK mutation, the method comprising administering to a subject in need thereof an effective amount of an imidazo [1,2-b ] pyridazine derivative of formula i according to any one of claims 1-6, or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition according to claim 7.
CN202211090088.1A 2022-09-07 2022-09-07 Imidazo [1,2-b ] pyridazine derivative, and preparation method and application thereof Pending CN117659020A (en)

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