CN114478519A - Pyrazolopyridine compound or salt thereof, and preparation method and application thereof - Google Patents
Pyrazolopyridine compound or salt thereof, and preparation method and application thereof Download PDFInfo
- Publication number
- CN114478519A CN114478519A CN202111231819.5A CN202111231819A CN114478519A CN 114478519 A CN114478519 A CN 114478519A CN 202111231819 A CN202111231819 A CN 202111231819A CN 114478519 A CN114478519 A CN 114478519A
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- CN
- China
- Prior art keywords
- compound
- formula
- pharmaceutically acceptable
- membered
- pyrazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- -1 Pyrazolopyridine compound Chemical class 0.000 title claims abstract description 264
- 150000003839 salts Chemical class 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 150000001875 compounds Chemical class 0.000 claims abstract description 291
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 46
- 201000010099 disease Diseases 0.000 claims abstract description 43
- 239000012453 solvate Substances 0.000 claims abstract description 36
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 35
- 230000000155 isotopic effect Effects 0.000 claims abstract description 31
- 239000003814 drug Substances 0.000 claims abstract description 22
- 238000011282 treatment Methods 0.000 claims abstract description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 43
- 229910052717 sulfur Inorganic materials 0.000 claims description 43
- 125000005842 heteroatom Chemical group 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
- 125000004414 alkyl thio group Chemical group 0.000 claims description 24
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 125000002883 imidazolyl group Chemical group 0.000 claims description 14
- 125000000335 thiazolyl group Chemical group 0.000 claims description 14
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 11
- 125000002541 furyl group Chemical group 0.000 claims description 11
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 11
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 11
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- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 125000001544 thienyl group Chemical group 0.000 claims description 11
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000005549 heteroarylene group Chemical group 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
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- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 claims description 7
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- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 7
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 7
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 7
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical group C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 claims description 6
- 206010033701 Papillary thyroid cancer Diseases 0.000 claims description 6
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
- 239000013543 active substance Substances 0.000 claims description 6
- 125000003838 furazanyl group Chemical group 0.000 claims description 6
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 claims description 6
- 201000002510 thyroid cancer Diseases 0.000 claims description 6
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 claims description 6
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- 206010008342 Cervix carcinoma Diseases 0.000 claims description 5
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- 201000006778 chronic monocytic leukemia Diseases 0.000 claims description 4
- 201000010902 chronic myelomonocytic leukemia Diseases 0.000 claims description 4
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
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- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 230000000306 recurrent effect Effects 0.000 claims description 4
- 125000004977 cycloheptylene group Chemical group 0.000 claims description 3
- 125000004979 cyclopentylene group Chemical group 0.000 claims description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
- 125000005565 oxadiazolylene group Chemical group 0.000 claims description 3
- 125000005564 oxazolylene group Chemical group 0.000 claims description 3
- 125000005550 pyrazinylene group Chemical group 0.000 claims description 3
- 125000005551 pyridylene group Chemical group 0.000 claims description 3
- 201000003804 salivary gland carcinoma Diseases 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 125000005730 thiophenylene group Chemical group 0.000 claims description 3
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- 125000005558 triazinylene group Chemical group 0.000 claims description 3
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- 125000004976 cyclobutylene group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 36
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- 239000007787 solid Substances 0.000 description 72
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 68
- 238000003786 synthesis reaction Methods 0.000 description 68
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- 239000012043 crude product Substances 0.000 description 49
- 238000000746 purification Methods 0.000 description 49
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 44
- 239000000706 filtrate Substances 0.000 description 44
- 239000012074 organic phase Substances 0.000 description 44
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 43
- 238000005160 1H NMR spectroscopy Methods 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 41
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 40
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 36
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 36
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
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- 150000003254 radicals Chemical class 0.000 description 26
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- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 24
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 23
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- 239000000460 chlorine Substances 0.000 description 21
- 238000002953 preparative HPLC Methods 0.000 description 20
- WIRTYVGMQVIVDM-UHFFFAOYSA-N pyridine-3-carbonitrile Chemical compound N#CC1=C=NC=C[CH]1 WIRTYVGMQVIVDM-UHFFFAOYSA-N 0.000 description 20
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 19
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 18
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
-
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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Abstract
The invention relates to a pyrazolopyridine compound or salt thereof, a preparation method and application thereof, in particular to a compound in which R is1、R2、R3、R4、R5Ring A, B, m and n are as defined in the specification, or a stereoisomer, tautomer, stable isotopic derivative, pharmaceutically acceptable salt or solvate thereof, a process for their preparation and pharmaceutical compositions containing them, and said compoundsUse of a compound in the manufacture of a medicament for the treatment or prevention of a disease associated with RET.
Description
Technical Field
The invention belongs to the technical field of chemical medicines, and particularly relates to a pyrazolopyridine compound with RET inhibitory activity, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the pyrazolopyridine compound in preparation of a medicine for preventing or treating diseases related to RET.
Background
The RET (secreted transformation) protein is a Receptor Tyrosine Kinase (RTK) and also a transmembrane glycoprotein, expressed by the protooncogene RET located on chromosome 10, plays an important role in the development of the renal and enteric nervous systems at the embryonic stage, and is also critical in various tissues, such as neurons, neuroendocrine, hematopoietic tissues, and male germ cells. Unlike other receptor tyrosine kinases, RET does not bind directly to the ligand molecule: such as neurotropic hormone (artemin), glial cell line-derived neurotrophic factor (GDNF), Nerve Growth Factor (NGF), which are ligands belonging to the GNDF Family (GFLs). These ligands typically bind to GDNF family receptor alpha (GFR α), and the resulting GFLs-GFR α complex mediates the auto-dimerization of RET proteins, leading to trans autophosphorylation of tyrosine on the intracellular domain, recruitment of related adaptor proteins, activation of signaling cascades such as cell proliferation, leading to cell hyperproliferation and cancer generation, and related signaling pathways including MAPK, PI3K, JAK-STAT, PKA, PKC, and the like.
There are two major oncogenic activation mechanisms of RET: one is a new fusion protein resulting from chromosomal rearrangements, usually a fusion of the kinase domain of RET and a protein comprising a self-dimerization domain; secondly, RET mutations activate RET kinase activity either directly or indirectly. These somatic or germ cells change horizontally and are involved in the pathogenesis of a variety of cancers. RET chromosomal rearrangements are present in 10-20% of Papillary Thyroid Cancer (PTC) patients; 60% of the myeloid thyroid medullary carcinoma (MTC) has RET point mutation; of all non-small cell lung cancer (NSCLC) patients, there is probably 1-2% with RET fusion proteins, with KIF5B being the most common.
Multiple kinase inhibitors with RET inhibitory activity are currently mainly used to treat cancer patients with RET fusions. However, under these conditions, the dose of drug is insufficient to achieve a level sufficient to inhibit the expression of RET due to off-target effects and drug toxicity. In addition, cancer cells develop resistance through mutation during the course of cancer treatment. Once resistance develops, patient treatment options become very limited. Therefore, selective inhibition of aberrant RET expression, drugs for RET fusion and mutation are highly desirable.
The medicament which is currently marketed or clinically researched and is selectively designed aiming at the RET target shows good curative effect and safety on clinical experiments of non-small cell lung cancer and thyroid cancer.
Currently, there is still a great need to discover and develop new RET inhibitor compounds for the prevention and/or treatment of RET related diseases. In addition to satisfactory RET inhibitory activity, such compounds are expected to have good or even improved druggability based on structural optimization, so as to provide more medication options and better therapeutic effects for patients with related diseases.
Brief description of the invention
The present invention relates to compounds useful for preventing or treating diseases associated with RET. In particular, it has been identified that the compounds of the invention show satisfactory RET inhibitory activity. Therefore, the compound of the present invention can not only achieve the object for preventing or treating diseases associated with RET, but also the prepared drug is expected to have improved absorption, enhanced therapeutic effect at the same dose, or provide the same therapeutic effect at a lower dose and/or reduce possible side effects. Thus, the present invention also provides the use of the compounds of the present invention for the preparation of a medicament for the prevention or treatment of a disease associated with RET, a pharmaceutical composition comprising said compounds and a method for the prevention and/or treatment of a disease associated with RET by administering said compounds.
Accordingly, in one aspect of the present invention, there is provided a compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof:
wherein:
R1selected from hydrogen, halogen, cyano, nitro and C optionally substituted by halogen or cyano1-C6An alkyl group;
R2selected from hydrogen, C6-C10Aryl, 5-9 membered heteroaryl, C3-C8Cycloalkyl radical, C3-C8Cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6Alkylthio, wherein the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkyl, alkoxy, and alkylthio are optionally substituted with 1,2, or 3 groups independently selected from: halogen, cyano, nitro, hydroxy, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6An alkylthio group;
R3selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6An alkylthio group;
R4selected from hydrogen, C6-C10Aryl, 5-9 membered heteroaryl, C3-C8Cycloalkyl radical, C3-C8Cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, -SO2-C1-C6Alkyl, -SO-C1-C6Alkyl radical, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6Alkylthio, wherein the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkyl, alkoxy, and alkylthio are optionally substituted with 1,2, or 3 groups independently selected from: halogen, cyano, nitro, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6An alkylthio group;
R5selected from halogen, cyano, nitro, hydroxy, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6An alkylthio group;
ring A is selected from C6-C10Arylene, 5-9 membered heteroarylene, C3-C8Cycloalkylene radical, C3-C8Cycloalkenylene, 3-8 membered heterocycloalkylene and 3-8 membered heterocycloalkenylene rings;
ring B is selected from C6-C10Aryl, 5-9 membered heteroaryl, C3-C8Cycloalkyl radical, C3-C8Cycloalkenyl, 3-8 membered heterocycloalkyl, and 3-8 membered heterocycloalkenyl rings;
m is 0, 1,2 or 3; and is
n is 0, 1,2 or 3.
In another aspect of the present invention, there is provided a compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, having RET inhibitory activity for use as a medicament, in particular as a RET inhibitor.
In another aspect of the invention, there is provided a compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, for use in the treatment or prophylaxis, particularly in the treatment of a disease associated with RET.
In another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient. In a particular aspect, the pharmaceutical composition of the present invention is provided for the prevention or treatment of diseases associated with RET. In a particular aspect, the pharmaceutical composition may additionally comprise additional therapeutically active ingredients suitable for use in combination with the compounds of the present invention.
In another aspect of the present invention, there is provided a pharmaceutical combination (or pharmaceutical combination product) comprising a compound of the present invention and an additional active agent.
In another aspect of the present invention, there is provided a method for the prevention or treatment of a disease associated with RET in an individual, e.g. a mammal, particularly a human, comprising administering an effective amount of a compound of the invention as described herein or a pharmaceutical composition comprising the same.
In another aspect of the present invention, there is provided a use of the above-mentioned compound or pharmaceutical composition of the present invention for preventing or treating a disease associated with RET.
In another aspect of the present invention, there is provided a use of the above-described compound or pharmaceutical composition of the present invention for the preparation of a medicament for the prevention or treatment of a disease associated with RET.
Preferably, the RET-associated disease according to the present invention is selected from the group consisting of tumors including, but not limited to, non-small cell lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine tumors 2A or 2B, pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal ganglioma, pancreatic duct adenocarcinoma, multiple endocrine tumors, testicular cancer, chronic monocytic leukemia, salivary gland carcinoma, ovarian cancer, cervical cancer, etc., or Irritable Bowel Syndrome (IBS).
In further aspects, methods are provided for the synthesis of compounds of the invention, wherein representative synthetic schemes and routes are described below.
Other objects and advantages of the present invention will become apparent to those skilled in the art from a reading of the following detailed description.
For the above-mentioned compounds of the invention for use as a medicament, the prophylactic or therapeutic methods, pharmaceutical compositions, pharmaceutical combinations or uses of the invention, the various preferred embodiments of the compounds of formula (I) as defined herein are preferred, more preferred are the specific compounds listed herein.
Definition of
Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Reference to the techniques used herein is intended to refer to techniques commonly understood in the art, including those variations of or alternatives to those techniques that would be apparent to one of ordinary skill in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
The term "halo" or "halogen" as used herein means fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). Preferred halo is fluoro or chloro. The term "halogen-substituted" group as used herein is intended to include monohalo or polyhalo groups in which one or more (e.g., 2,3, 4,5 or 6) of the same or different halogen substituents are hydrogen.
The term "cyano" as used herein means the group-CN.
The term "nitro" as used herein means the group-NO2。
The term "hydroxy" as used herein refers to-OH.
The term "alkyl" as used herein refers to a straight or branched chain saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms. Specifically, the alkyl group has 1-10, e.g., 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, as used herein, the term "C1-C6Alkyl "refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof are methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl and the like. Particular alkyl groups have 1 to 3 carbon atoms.
The term "alkoxy" as used herein means the group-O-alkyl, wherein alkyl has the meaning described herein. Specifically, the term includes the group-O-C1-6Alkyl, more particularly-O-C1-3An alkyl group. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy, isopropoxy), butoxy (including n-butoxy, isobutoxy, t-butoxy), pentoxy (including n-pentoxy, isopentoxy, neopentoxy), hexoxy (including n-hexoxy, isohexoxy), and the like. Particular alkoxy groups have 1 to 3 carbon atoms.
The term "alkylthio" as used herein refers to-S-alkyl, wherein the alkyl is as defined above for "alkyl". Specifically, the term includes the group-S-C1-6Alkyl, more particularly-S-C1-3An alkyl group. Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio, isopropylthio), butylthio (including n-butylthio, isobutylthio, tert-butylthio), pentylthio (including n-pentylthio, isopentylthio, neopentylthio), hexylthio (including n-hexylthio, isohexylthio), and the like. Particular alkylthio groups have 1 to 3 carbon atoms. The term "halogen-substituted C" as used herein1-C6Alkyl "means C as defined above1-C6Alkyl, wherein one or more (e.g. 1,2, 3, 4 or 5) hydrogen atoms are replaced by halogen. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. "halogen-substituted C1-C6Examples of alkyl radicals "are, for example, -CH2F、-CHF2、-CF3、-CCl3、-C2F5、-C2Cl5、-CH2CF3、-CH2Cl、-CH2CH2CF3or-CF (CF)3)2And the like.
The term "halogen-substituted C" as used herein1-C6Alkoxy "means C as defined above1-C6Alkoxy, wherein one or more (e.g. 1,2, 3, 4 or 5) hydrogen atoms are replaced by halogen. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. "halogen-substituted C1-C6Examples of alkoxy "are e.g. -OCH2F、-OCHF2、-OCF3、-OCCl3、-OC2F5、-OC2Cl5、-OCH2CF3、-OCH2Cl or-OCH2CH2CF3And the like.
The term "cycloalkyl" as used herein refers to a monocyclic, fused polycyclic, bridged polycyclic, or spiro non-aromatic saturated monovalent hydrocarbon ring structure having the indicated number of ring atoms. The cycloalkyl group may have 3 to 12 carbon atoms (i.e., C)3-C12Cycloalkyl), for example 3 to 10, 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms. Examples of suitable cycloalkyl groups include, but are not limited to, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; or polycyclic (e.g. bicyclic) structures, including spiro, fused or bridged systems, such as bicyclo [1.1.1]Pentyl, bicyclo [2.2.1]Heptyl, spiro [3.4 ]]Octyl, bicyclo [3.1.1]Hexane radical, bicyclo [3.1.1]Heptyl or bicyclo [3.2.1]Octyl, etc.).
The term "cycloalkylene" as used herein refers to a cycloalkyl group as defined above, but which is a divalent group, the two valencies not being on the same ring atom. The cycloalkylene group may have 3 to 12 carbon atoms (i.e., C)3-C12Cycloalkylene), for example 3 to 10, 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms. Examples of suitable cycloalkylene groups include, but are not limited to, monocyclic structures such as cyclopropylene, cyclobutylene, cyclopentylene (e.g., cyclopent-1, 2-diyl, cyclopent-1, 3-diyl), cyclohexylene (e.g., cyclohex-1, 2-diyl, cyclohex-1, 3-diyl, cyclohex-1, 4-diyl), cycloheptylene, or cyclooctylene; or polycyclic (e.g. bicyclic) structures, including spiro, fused or bridged systems, such as bicyclo [1.1.1]Pentylene, bicyclo [2.2.1]Heptylene, spiro [3.4 ]]Octylidene, bicyclo [3.1.1]Hexanylidene, bicyclo [3.1.1]Heptylene or bicyclo [3.2.1]Octylidene, etc.).
The term "cycloalkenyl" as used herein means a monocyclic, fused polycyclic, bridged polycyclic, or spiro non-aromatic unsaturated hydrocarbon ring structure having the indicated number of ring atoms, containing at least one (e.g., 1,2, or 3) carbon-carbon double bond. Cycloalkenyl groups can have 3 to 12 carbon atoms (i.e., C)3-C12Cycloalkenyl) such as 3 to 10, 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms. Examples of suitable cycloalkenyl groups include, but are not limited to, monocyclic structures such as cyclopropenyl, cyclobutenyl, and,Cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, or cyclooctenyl.
The term "cycloalkenylene" as used herein refers to a cycloalkenyl group as defined above, but which is a divalent group, the two valencies not being on the same ring atom. Cycloalkenylene groups may have 3 to 12 carbon atoms (i.e., C)3-C12Cycloalkenylene), for example 3 to 10, 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms. Examples of suitable cycloalkenylene groups include, but are not limited to, monocyclic structures such as cyclopropenylene, cyclobutenyl, cyclopentenylene, cyclopentadienylene, cyclohexenylene, cyclohexadienylene, cycloheptenylene, cycloheptatrienylene, or cyclooctenylene.
The term "heterocycloalkyl" as used herein is intended to include one or more (e.g., 1,2, 3, or 4) heteroatoms independently selected from O, N and S, and a monocyclic, fused polycyclic, spiro, or bridged polycyclic non-aromatic saturated ring structure of the indicated ring atom number, or an N-oxide thereof, or an S-oxide or S-dioxide thereof. The heterocycloalkyl group can have 3 to 12 ring members (can be referred to as a 3-12 membered heterocycloalkyl group), for example 3 to 10 ring members, 3 to 8 ring members, 3 to 7 ring members, 4 to 7 ring members, 5 to 6 ring members. Heterocycloalkyl typically contains up to 4 (e.g., 1,2, 3, or 4) heteroatoms. Examples of suitable heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl), tetrahydrothienyl (e.g., 1-tetrahydrothienyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl), piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g., 4-tetrahydrothiopyranyl), morpholinyl (e.g., morpholino), thiomorpholinyl, dioxanyl, piperazinyl, or azepanyl, azacycloheptyl, and mixtures thereof, Diazepanyl radicals are, for example, 1, 4-diazepanyl, 3, 6-diaza-bicyclo [3.1.1] heptyl or 3-aza-bicyclo [3.2.1] octyl.
The term "heterocycloalkylene" as used herein means a heterocycloalkyl group as defined above, but which is a divalent radical, the two valencies not being on the same ring atom. Heterocycloalkylene can have 3 to 12 ring members (can be referred to as 3-12 membered heterocycloalkylene), for example 3 to 10 ring members, 3 to 8 ring members, 3 to 7 ring members, 4 to 7 ring members, 5 to 6 ring members. Heterocycloalkylene groups typically contain up to 4 (e.g., 1,2, 3, or 4) heteroatoms. Examples of suitable heterocycloalkylene groups include, but are not limited to, azetidinylene, oxetanylene, thienylene, pyrrolidinylene (e.g., pyrrolidin-1, 2-diyl, pyrrolidin-1, 3-diyl, pyrrolidin-2, 3-diyl), tetrahydrofurylene (e.g., tetrahydrofuran-2, 4-diyl, tetrahydrofuran-2, 3-diyl, and tetrahydrofuran-2, 5-diyl), piperidinylene (e.g., piperidin-1, 2-diyl, piperidin-1, 3-diyl, piperidin-1, 4-diyl, piperidin-2, 4-diyl), tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinylene, thiomorpholinylene, dioxanyl, piperazinyl, or azepanyl, Diazacyclocycloheptylene radicals, for example 1, 4-diazacyclocycloheptyl, 3, 6-diaza-bicyclo [3.1.1] heptylene or 3-aza-bicyclo [3.2.1] octylene, preferably
It is understood that structures having asymmetric centers encompass racemic and/or single enantiomeric forms thereof, e.g.Can representAnd/or
The term "heterocycloalkenyl" as used herein means a "heterocycloalkyl" as defined herein, which contains at least one (e.g., 1,2, or 3) double bond. Examples of suitable heterocycloalkenyl groups include, but are not limited to:
wherein each W is selected from CH2NH, O and S; each Y is selected from NH, O, C (═ O), SO2And S; and each Z is selected from N and CH, provided that at least one atom selected from N, O or S is included in each ring; for example, pyrrolinyl (e.g., 1-pyrrolinyl, 2-pyrrolidinyl, 3-pyrrolinyl, 4-pyrrolinyl, or 5-pyrrolinyl), dihydrofuranyl (e.g., 1-dihydrofuranyl, 2-dihydrofuranyl, 3-dihydrofuranyl, 4-dihydrofuranyl, or 5-dihydrofuranyl), dihydrothienyl (e.g., 1-dihydrothienyl, 2-dihydrothienyl, 3-dihydrothienyl, or 4-dihydrothienyl), tetrahydropyranyl (e.g., 1-, 2-, 3-, 4-, 5-, or 6-tetrahydropyranyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), or tetrahydrothiopyranyl (e.g., 4-tetrahydrothiopyranyl).
The term "heterocycloalkenylene" as used herein means a heterocycloalkenyl group as defined above, but which is a divalent group, the two valencies not being on the same ring atom. Examples of suitable heterocycloalkenylene groups include, but are not limited to:
wherein each W is selected from CH2NH, O and S; each Y is selected from NH, O, C (═ O), SO2And S; and each Z is selected from N and CH, provided that each ring contains at least one atom selected from N, O or S; for example pyrrolinylidene, dihydrofuranylidene, dihydrothienyl, tetrahydropyridinylidene, tetrahydropyranylidene or tetrahydrothiopyranyl, preferablyMore preferably
The term "aryl" as used herein means a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom in an aromatic ring system. Specifically, aryl refers to a monocyclic or fused polycyclic aromatic ring structure having the specified number of ring atoms. In particular, the term includes groups comprising 6 to 14, such as 6 to 10, preferably 6 ring members. Specific aryl groups include phenyl and naphthyl, with the most specific aryl group being phenyl.
The term "arylene" as used herein means an aryl group as defined above, but which is a divalent group, the two valencies not being on the same ring atom. Specific arylene groups include phenylene groups, such as benzene-1, 2-diyl, benzene-1, 3-diyl, or benzene-1, 4-diyl.
The term "heteroaryl" as used herein is intended to include one or more (e.g., 1,2, 3 or 4) heteroatoms independently selected from O, N and S, and monocyclic or fused polycyclic aromatic ring structures of the indicated number of ring atoms, or N-oxides thereof, or S-oxides or S-dioxides thereof. Specifically, the aromatic ring structure may have 5 to 9 ring members. Heteroaryl groups can be, for example, a 5-6 membered monocyclic ring, or a fused bicyclic ring structure formed by two fused 5-membered rings or fused 5-and 4-membered rings. Heteroaryl rings will typically contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2, for example a single heteroatom independently selected from O, N and S, where N and S may be in oxidation states such as N-oxide, S ═ O or S (O)2. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom, at least one ring sulfur atom, or at least one epoxy atom. For example, the heteroaryl group can be a 5-6 membered heteroaryl group comprising 1 or 2 heteroatoms independently selected from N, O or S. Examples of suitable 5-membered monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl; examples of suitable 6-membered monocyclic heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
The term "heteroarylene" as used herein means a heteroaryl group as defined above, but which is a divalent radical, the two valencies not being on the same ring atom. The heteroarylene group may be a 5-6 membered heteroarylene group comprising 1 or 2 heteroatoms independently selected from N, O or S. Examples of suitable 5-membered monocyclic heteroarylenes include, but are not limited to, pyrrolylene, furanylene, thiophenylene, imidazolyl, furazanyl, oxazolylene, oxadiazolylene, oxatriazolylene, isoxazolylene, thiazolyl, isothiazolylene, pyrazolyl, triazolylene, and tetrazolylene; examples of suitable 6-membered monocyclic heteroaryls include, but are not limited to, pyridinylene, pyrazinylene, pyridazinylene, pyrimidinyl and triazinylene, with preference given to
The description of a substituent as "optionally substituted" means that the group may be unsubstituted or substituted with one or more substituents (e.g., 0, 1,2, 3, 4, or 5 or more, or any range derivable therein) as set forth for that group, where the substituents may be the same or different. In one embodiment, the optionally substituted group is substituted with 1 substituent. In another embodiment, the optionally substituted group is substituted with 2 substituents. In another embodiment, the optionally substituted group is substituted with 3 substituents. In another embodiment, the optionally substituted group is substituted with 4 substituents.
It will be understood by those of ordinary skill in the art of organic synthesis that stable, chemically feasible heterocycles, whether aromatic or non-aromatic, have a maximum number of heteroatoms or type of heteroatoms included that is determined by the ring size, degree of unsaturation, and the valency of the heteroatom. In general, a heterocycle may have from 1 to 4 heteroatoms, provided that the heterocycle or heteroaromatic ring is chemically feasible and stable.
The term "compound of the invention" as used herein is intended to encompass a compound of general formula (I) or any preferred or specific embodiment thereof (including compounds of formula (Ia) and formula (Ib)), stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates, and prodrugs thereof, as defined herein. Similarly, references herein to "intermediates", whether or not they are themselves claimed, are intended to cover the free forms thereof as well as the various derivatives described above, if the context permits.
The term "pharmaceutically acceptable" as used herein means molecular entities and compositions that are approved by or can be approved by the corresponding authorities in the various countries or listed in the generally recognized pharmacopoeias for animals, and more particularly humans, or that do not produce adverse, allergic, or other untoward reactions when administered in moderate amounts to animals, such as humans.
The term "pharmaceutically acceptable salt" as used herein means a salt of a compound of the present invention which is pharmaceutically acceptable and which possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic acid addition salts or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or an acid addition salt formed with an organic acid such as acetic acid, propionic acid, hexanoic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) a salt formed when an acidic proton present in the parent compound is replaced with a metal ion such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, or the like. One skilled in the art will know the general principles and techniques for preparing pharmaceutically acceptable salts, such as those described in Berge et al, Pharm ScL, 66, 1-19, (1977).
The term "prodrug" as used herein means a compound having a cleavable group and which is cleaved by a solvent or under physiological conditionsCompounds that become compounds of the present invention having pharmaceutical activity in vivo include derivatives of the compounds of the present invention. Prodrugs include acid derivatives well known in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, or anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from the pendant acid groups of the compounds of the present invention are particularly useful prodrugs. Particular such prodrugs are C of the compounds of the present invention1-8Alkyl radical, C2-8Alkenyl, optionally substituted C6-10Aryl and (C)6-10Aryl group) - (C1-4Alkyl) esters.
The invention also includes all pharmaceutically acceptable isotopic compounds, which are identical to those of the present invention, except that one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. 2H, 3H); isotopes of carbon (e.g., 11C, 13C, and 14C); isotopes of chlorine (e.g., 36 Cl); isotopes of fluorine (e.g., 18F); isotopes of iodine (e.g., 123I and 125I); isotopes of nitrogen (e.g., 13N and 15N); isotopes of oxygen (e.g., 15O, 17O, and 18O); isotopes of phosphorus (e.g., 32P); and isotopes of sulfur (e.g., 35S).
The term "stereoisomer" as used herein denotes an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., 1,2, 3, or 4) asymmetric centers, they can result in racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as a mixture of two or more different structural forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, a nitroso-oxime may exist in solution in equilibrium in the following tautomeric form:
it is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).
Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerization and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
The term "solvate" as used herein refers to a form of solvent addition comprising a stoichiometric or non-stoichiometric amount of solvent, including for example solvates with water, such as hydrates, or with organic solvents, such as methanol, ethanol or acetonitrile, i.e. as methanolate, ethanolate or acetonitrilate, respectively; or in the form of any polymorph. It will be understood that such solvates of the compounds of the invention also include solvates of pharmaceutically acceptable salts of the compounds of the invention.
The term "prevention" as used herein means the administration of one or more compounds of the invention to an individual, e.g. a mammal, e.g. a human, suspected to suffer from or to be susceptible to a disease associated with RET, especially an inflammatory or autoimmune disease, as defined herein, such that the risk of suffering from the defined disease is reduced. The term "prevention" encompasses the use of a compound of the invention prior to diagnosis or determination of any clinical and/or pathological condition.
The term "treating" as used herein refers to administering one or more compounds of the invention described herein to a subject, e.g., a mammal, e.g., a human, suffering from, or having symptoms of, the disease, for the purpose of curing, alleviating, or otherwise affecting the disease or symptoms of the disease. In a particular embodiment of the invention, the disease is a RET-associated disease, in particular an inflammatory or autoimmune disease, as defined herein.
The term "diseases associated with RET" as used herein means diseases in which RET contributes to the development and progression of the disease, or in which inhibition of RET reduces the incidence of disease, reduces or eliminates disease symptoms. For the purposes of the present invention, a "RET-associated disease" is selected from the group consisting of tumors including, but not limited to, non-small cell lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine tumors 2A or 2B, pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal gangliomas, pancreatic duct adenocarcinoma, multiple endocrine tumors, testicular cancer, chronic monocytic leukemia, salivary gland carcinoma, ovarian cancer, cervical cancer, and the like, or Irritable Bowel Syndrome (IBS).
The term "cancer" or "tumor" as used herein refers to neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous cells and cancer cells and tissues. For the compounds, methods, pharmaceutical compositions, pharmaceutical combinations and uses of the present invention, the cancer or tumor includes, but is not limited to, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterine cancer, pemphigus cancer, liver cancer, acoustic neuroma, oligodendroglioma, meningioma of brain (spinal) membrane, neuroblastoma, eye cancer.
The term "therapeutically effective amount" as used herein means an amount sufficient to alleviate or completely alleviate the symptoms or other deleterious effects of a disorder when administered to an individual to treat a disease; reversing, completely stopping, or slowing the progression of the disorder; or an amount that reduces the risk of worsening the condition, "effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, etc. of the individual to be treated.
The term "individual" as used herein includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) with a disease (e.g., a disease described herein) or normal individuals. "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
"pharmaceutical composition" as used herein, refers to a composition comprising one or more compounds of formula (I) or a stereoisomer, tautomer, stable isotopic derivative, pharmaceutically acceptable salt or solvate thereof, and a carrier for the delivery of the biologically active compound to an organism (e.g., human) as is commonly accepted in the art.
The term "pharmaceutical combination" as used herein means that the compounds of the present invention can be used in combination with other active agents for the purpose of the present invention. The additional active agent may be one or more additional compounds of the invention, or may be a second or additional (e.g., third) compound that is compatible with, i.e., does not adversely affect, each other, or has complementary activity. Such active agents are suitably present in combination in an effective amount to achieve the intended purpose. The additional active agents may be co-administered with the compounds of the present invention in a single pharmaceutical composition, or separately administered in separate discrete units from the compounds of the present invention, either simultaneously or sequentially when administered separately. The sequential administration may be close in time or remote in time.
The term "pharmaceutically acceptable excipient or carrier" as used herein refers to one or more compatible solid or liquid filler or gel substances which are pharmacologically inactive, compatible with the other ingredients of the composition, and which are intended to be acceptable for administration to a warm-blooded animal such as man, and which serve as a carrier or vehicle for the compounds of the present invention in the form in which they are to be administered, examples of which include, but are not limited to, cellulose and its derivatives (e.g., sodium carboxymethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., magnesium stearate), calcium sulfate, vegetable oils, polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g., tweens), wetting agents (e.g., sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, and the like.
It is to be understood that the dosages referred to when describing the compounds of the present invention, pharmaceutical compositions, pharmaceutical combinations comprising the same, and related uses and methods, are by weight of the free form, and not by any salt, hydrate, solvate or the like thereof, unless otherwise defined in the specification.
Compounds of the invention
The terms "inventive compound" and the like, as used throughout this application, unless otherwise indicated, encompass compounds of formula (I), as defined in the various embodiments herein and in the specific or preferred embodiments thereof, stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates thereof, and prodrugs. The stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates, and prodrugs are described in the definitions section above. Preferably, the compounds of the invention are free forms of the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof; most preferred is the free form of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
Certain compounds of the present invention may exist in polymorphic or amorphous forms, which also fall within the scope of the present invention. When in a solid crystalline form, the compound of formula (I) may be in the form of a co-crystal with another chemical entity, and the specification includes all such co-crystals.
Where chiral centers are present, the compounds of the present invention may exist as individual enantiomers or as mixtures of enantiomers. According to one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a single enantiomer with enantiomeric excess (% ee) > 95, > 98% or > 99%. Preferably, the single enantiomer is present in an enantiomeric excess (% ee) of > 99%.
In particular, in one aspect, the present invention provides compounds of formula (I), stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts, or solvates thereof:
wherein:
R1selected from hydrogen, halogen, cyano, nitro and C optionally substituted by halogen or cyano1-C6An alkyl group;
R2selected from hydrogen, C6-C10Aryl, 5-9 membered heteroaryl, C3-C8Cycloalkyl radical, C3-C8Cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6Alkylthio, wherein the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkyl, alkoxy, and alkylthio are optionally substituted with 1,2, or 3 groups independently selected from: halogen, cyano, nitro, hydroxy, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6An alkylthio group;
R3selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6An alkylthio group;
R4selected from hydrogen, C6-C10Aryl, 5-9 membered heteroaryl, C3-C8Cycloalkyl radical, C3-C8Cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, -SO2-C1-C6Alkyl, -SO-C1-C6Alkyl radical, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6Alkylthio, wherein the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkyl, alkoxy, and alkylthio are optionally independently selected from1,2 or 3 of the following groups: halogen, cyano, nitro, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6An alkylthio group;
R5selected from halogen, cyano, nitro, hydroxy, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6An alkylthio group;
ring A is selected from C6-C10Arylene, 5-9 membered heteroarylene, C3-C8Cycloalkylene radical, C3-C8Cycloalkenylene, 3-8 membered heterocycloalkylene, and 3-8 membered heterocycloalkenylene rings;
ring B is selected from C6-C10Aryl, 5-9 membered heteroaryl, C3-C8Cycloalkyl radical, C3-C8Cycloalkenyl, 3-8 membered heterocycloalkyl and 3-8 membered heterocycloalkenyl rings;
m is 0, 1,2 or 3; and is
n is 0, 1,2 or 3.
In one embodiment of the compounds of formula (I), R1Is halogen, cyano or nitro.
In one embodiment of the compounds of formula (I), R1Is cyano.
In one embodiment of the compounds of formula (I), R2Selected from 5-6 membered heteroaryl comprising 1,2 or 3 heteroatoms independently selected from N, O or S, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6Alkylthio optionally substituted with 1,2 or 3 groups independently selected from: halogen, hydroxy and C1-C6An alkyl group;
in one embodiment of the compounds of formula (I), R2Selected from 5 membered heteroaryl comprising 1,2 or 3 heteroatoms independently selected from N, O or S, C1-C6Alkoxy and C1-C6Alkylthio optionally substituted with 1 group independently selected from: hydroxy and C1-C6An alkyl group;
in one embodiment of the compounds of formula (I), R2Is selected fromOptionally is covered with C1-C6Alkyl-substituted 5-membered heteroaryl comprising 1,2 or 3 heteroatoms independently selected from N, O or S, and C optionally substituted with hydroxy1-C6An alkoxy group;
in one embodiment of the compounds of formula (I), R2The 5-6 membered heteroaryl of (a) is selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl;
preferably, R2The 5-membered heteroaryl group in (a) is selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or pyrazolyl.
In one embodiment of the compounds of formula (I), R2Is methyl-substituted pyrazolyl or hydroxy-substituted C1-C6An alkoxy group;
In one embodiment of the compounds of formula (I), R3Selected from hydrogen and C1-C6An alkyl group.
In one embodiment of the compounds of formula (I), R3Selected from hydrogen and C1-C3An alkyl group.
In one embodiment of the compounds of formula (I), R3Is hydrogen or methyl.
In one embodiment of the compounds of formula (I), R3Is hydrogen.
In one embodiment of the compounds of formula (I), R4Selected from phenyl, 5-6 membered heteroaryl comprising 1,2 or 3 heteroatoms independently selected from N, O or S, -SO2-C1-C6Alkyl, -SO-C1-C6Alkyl radical, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6Alkylthio optionally substituted with 1,2 or 3 halogen groups; preferably, the 5-6 membered heteroaryl group isFrom pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl;
in one embodiment of the compounds of formula (I), R4Selected from 5-membered heteroaryl comprising 1,2 or 3 heteroatoms independently selected from N, O or S, -SO2-C1-C6Alkyl radical, C1-C6Alkyl and C1-C6Alkoxy, optionally substituted with 1,2 or 3 halo groups; preferably, the 5-membered heteroaryl is selected from the group consisting of pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and pyrazolyl.
In one embodiment of the compounds of formula (I), R4Selected from pyrazolyl optionally substituted by halogen, -SO2-C1-C6Alkyl radical, C1-C6Alkyl and C1-C6An alkoxy group.
In one embodiment of the compounds of formula (I), R5Selected from halogen, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6An alkylthio group;
in one embodiment of the compounds of formula (I), R5Is selected from C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6An alkylthio group.
In one embodiment of the compounds of formula (I), R5Is selected from C1-C3An alkyl group;
in one embodiment of the compounds of formula (I), R5Is methyl;
in one embodiment of the compounds of formula (I), m is 0 or 1.
In one embodiment of the compounds of formula (I), n is 0 or 1.
In one embodiment of the compounds of formula (I), m is 1.
In one embodiment of the compounds of formula (I), n is 0.
In one embodiment of the compound of formula (I), ring A is selected from phenylene, 5-6 membered heteroarylene comprising 1,2, or 3 heteroatoms independently selected from N, O or S, C3-C8Cycloalkylene radical, C3-C8Cycloalkenylene, 3-8 membered heterocycloalkylene comprising 1,2, or 3 heteroatoms independently selected from N, O or S, and 3-8 membered heterocycloalkenylene comprising 1,2, or 3 heteroatoms independently selected from N, O or S;
in one embodiment of the compounds of formula (I), ring a is selected from phenylene, 5-membered heteroarylene comprising 1,2, or 3 heteroatoms independently selected from N, O or S, C3-C6Cycloalkylene radical, C3-C6Cycloalkenylene, 3-6 membered heterocycloalkylene comprising 1,2, or 3 heteroatoms independently selected from N, O or S, and 3-6 membered heterocycloalkenylene comprising 1,2, or 3 heteroatoms independently selected from N, O or S;
in one embodiment of the compound of formula (I), ring a is selected from phenylene, pyrrolylene, furanylene, thiophenylene, imidazolyl, furazanyl, oxazolylene, oxadiazolylene, oxatriazolylene, isoxazolylene, thiazolyl, isothiazolylene, pyrazolyl, thiadiazolylene, triazolylene, tetrazolylene, pyridinylene, pyrazinylene, pyridazinylene, pyrimidinyl, triazinylene, azetidinylene, pyrrolidinylene, pyrrolinylene, cyclobutyl, cyclopentylene, cyclohexylene, cycloheptylene, piperazinyl, piperidylene, and azepanylene.
In one embodiment of the compounds of formula (I), ring a is selected from the group consisting of pyrazolylene, azetidinylene, pyrrolidinylene, cyclohexylene, piperidylene and azepanylene.
In one embodiment of the compounds of formula (I), ring A is selected from
In one embodiment of the compound of formula (I), ring B is selected from phenyl, 5-9 membered heteroaryl containing 1,2 or 3 heteroatoms independently selected from N, O or S, C3-C8Cycloalkyl radical, C3-C8Cycloalkenyl, a 3-8 membered heterocycloalkyl comprising 1,2 or 3 heteroatoms independently selected from N, O or S, and a 3-8 membered heterocycloalkenyl ring comprising 1,2 or 3 heteroatoms independently selected from N, O or S;
in one embodiment of the compound of formula (I), ring B is selected from phenyl and 5-6 membered heteroaryl comprising 1,2 or 3 heteroatoms independently selected from N, O or S;
in one embodiment of the compound of formula (I), ring B is selected from phenyl, and 6 membered heteroaryl comprising 1,2 or 3 heteroatoms independently selected from N, O or S;
in one embodiment of the compounds of formula (I), ring B is selected from phenyl, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl rings.
In one embodiment of the compounds of formula (I), ring B is a phenyl or pyridyl ring.
It is to be understood that the compounds of formula (I) of the present invention encompass each of the above independent embodiments or each specific embodiment, and also encompass embodiments comprised of any combination or subcombination of the above-described embodiments or specific embodiments, as well as embodiments comprised of any combination of any of the above preferences or exemplifications.
It will be appreciated that the combination and/or substitution of groups in compounds of formula (la) should be premised on compliance with the valency rules.
Preferably, the compounds of formula (I) of the present invention have the structure of formula (Ia),
wherein X is N or CH; r1、R2、R3、R4、R5M, n and A each have the meanings as defined above for the general or specific embodiments of the compounds of formula (I).
More preferably, the compounds of formula (I) of the present invention have the structure of formula (Ib),
wherein X is N or CH; r1、R2、R3、R4、R5N and A each have the meanings as defined above for the general or specific embodiments of the compounds of formula (I).
More preferably, the compounds of formula (I) of the present invention have the structure of formula (Ic),
wherein X is N or CH; r2、R3、R4、R5N and A each have the meanings as defined above for the general or specific embodiments of the compounds of formula (I).
Most preferably, the compound of formula (I) according to the present invention is selected from the following specific compounds or stereoisomers, tautomers, stable isotopic variations, pharmaceutically acceptable salts or solvates thereof:
advantageous effects of the invention
The invention provides a pyrazolopyridine compound with structural characteristics of a general formula (I), and researches show that the compound can effectively inhibit RET kinase, RET fusion and mutation activity and is used as a therapeutic drug for related diseases with abnormal RET expression.
The compound of the invention has the following beneficial effects:
high RET kinase inhibitory activity; the kinase RET inhibition assay shows IC50 in the range of 0.1nM to 1 μ M, preferably in the range of 0.1nM to 0.1 μ M; and/or
High RET fusion and mutation activity; and/or
Having good pharmacokinetic properties, e.g. having a longer t1/2Thus, for example, the dosing interval can be increased, the half-life is longer, and the patient has better compliance; and/or
The compound has improved AUC0-t data, better druggability and higher bioavailability; and/or
Good safety, excellent properties like membrane permeability, P450 (reduced risk of drug interaction), solubility, etc.
Based on the above beneficial effects of the compounds of the present invention, the present invention also provides the following technical solutions.
Compounds of the invention for use in therapy or as medicaments
In one aspect, the present invention provides compounds of the invention for use as medicaments, in particular as RET inhibitors.
In another aspect, the present invention provides a compound of the invention for use in the treatment, especially for use in the treatment and/or prevention of diseases associated with RET.
In particular embodiments, the invention provides compounds of the invention for use in the treatment and/or prevention of diseases in which RET contributes to the onset and progression of the disease or inhibits RET so as to reduce the incidence of the disease or eliminate the disease condition, such as tumors or Irritable Bowel Syndrome (IBS), including, but not limited to, non-small cell lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, polyendocrine tumor 2A or 2B, pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal gangliomas, pancreatic duct adenocarcinoma, multiple endocrine tumors, testicular cancer, chronic monocytic leukemia, salivary gland cancer, ovarian cancer, cervical cancer, and the like.
Pharmaceutical compositions and their administration
In another aspect, for use of the compounds of the present specification for therapeutic or prophylactic purposes, the compounds of the present invention may be formulated as pharmaceutical compositions in accordance with standard pharmaceutical practice. Meanwhile, based on good pharmacokinetic property, improved AUC0-last and good drug forming property of the compound, the compound can be used for preparing a drug with better pharmacokinetic property and higher bioavailability.
Accordingly, the present invention provides a pharmaceutical composition comprising a compound of the invention as described above and a pharmaceutically acceptable excipient.
In a particular embodiment, the pharmaceutical composition of the invention is provided for use in the prevention or treatment of a disease associated with RET, for example in a mammalian, e.g. human, subject.
In a particular embodiment, the pharmaceutical composition of the invention may additionally comprise additional therapeutically active ingredients suitable for use in combination with the compounds of the invention.
The Pharmaceutical compositions of the present invention may be formulated by techniques known to those skilled in the art, such as those disclosed in Remington's Pharmaceutical Sciences, 20 th edition. For example, the pharmaceutical compositions of the present invention described above may be prepared by mixing a compound of the present invention with one or more pharmaceutically acceptable excipients. The preparation may further comprise the step of mixing one or more other active ingredients with the compound of the present invention and one or more pharmaceutically acceptable excipients.
The choice of excipients to include in a particular composition will depend on a variety of factors, such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Ansel, Howard C., et al, Ansel's Pharmaceutical Delivery Forms and Drug Delivery systems Philadelphia, Lippincott, Williams & Wilkins,2004, including, for example, adjuvants, diluents (e.g., glucose, lactose or mannitol), carriers, pH adjusting agents, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, flavorants, flavoring agents, other known additives.
The pharmaceutical compositions of the present invention may be administered in a standard manner. For example, suitable modes of administration include oral, intravenous, rectal, parenteral, topical, transdermal, ocular, nasal, buccal or pulmonary (inhalation) administration, with parenteral infusion including intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. For these purposes, the compounds of the present invention may be formulated by methods known in the art into the form of, for example, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops, aerosols, dry powder formulations and sterile injectable aqueous or oily solutions or suspensions.
The size of a prophylactic or therapeutic dose of a compound of the invention will vary depending upon a number of factors, including the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the judgment of the prescribing physician. Generally, an effective dose is in the range of about 0.0001 to about 5000mg per kg body weight per day, e.g., about 0.01 to about 1000 mg/kg/day (single or divided administration). For a 70kg human, this may amount to about 0.007 mg/day to about 7000 mg/day, for example about 0.7 mg/day to about 1500 mg/day. Depending on the mode of administration, the amount or amount of a compound of the invention in a pharmaceutical composition may be from about 0.01mg to about 1000mg, suitably 0.1-500mg, preferably 0.5-300mg, more preferably 1-150mg, especially preferably 1-50mg, e.g. 1.5mg, 2mg, 4mg, 10mg, 25mg etc.; accordingly, the pharmaceutical composition of the invention will comprise 0.05 to 99% w/w (weight percentages), such as 0.05 to 80% w/w, such as 0.10 to 70% w/w, such as 0.10 to 50% w/w of the compound of the invention, all weight percentages being based on the total composition. It will be appreciated that it may be necessary in some cases to use dosages outside these limits.
In a specific embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, the composition being formulated for oral administration. The composition may be provided in unit dosage form, for example in the form of a tablet, capsule or oral liquid formulation. Such unit dosage forms may contain, as active ingredient, from 0.1mg to 1g, for example from 5mg to 250mg, of a compound of the invention.
In a specific embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, the composition being formulated for topical administration. Topical administration may be in the form of, for example, a cream, lotion, ointment, or transdermal patch.
In a specific embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, the composition being formulated for administration by inhalation. Inhalation administration can be by oral inhalation, or by intranasal administration. When administered by oral inhalation, the compounds of the invention may be effectively used in the present invention in a daily dose, for example up to 500. mu.g, such as 0.1 to 50. mu.g, 0.1 to 40. mu.g, 0.1 to 30. mu.g, 0.1 to 20. mu.g or 0.1 to 10. mu.g of a compound of the invention. The pharmaceutical compositions of the present invention for oral inhalation may be formulated as a dry powder, a suspension (in a liquid or gas) or a solution (in a liquid), and may be administered in any suitable form and using any suitable inhaler device known in the art, including for example Metered Dose Inhalers (MDIs), Dry Powder Inhalers (DPIs), nebulizers and soft mist inhalers. The multi-compartment device may be used to deliver a compound of the present specification and one or more other active ingredients (when present).
Methods of treatment and uses
Based on the beneficial effects described above with respect to the compounds of the present invention, the compounds of the present invention are useful in methods of treating various conditions in animals, particularly mammals such as humans.
Thus, in another aspect, the invention provides a method of modulating, particularly inhibiting, the activity of RET in a cell, said method comprising contacting the cell with a compound of the invention as described above to modulate, particularly inhibit, the activity of RET in the cell.
In another aspect, the present invention provides a method of preventing or treating a disease associated with RET (e.g. a disease treatable or preventable by RET inhibition), the method comprising administering to a subject in need thereof an effective amount of a compound of the invention as described hereinbefore or a pharmaceutical composition of the invention comprising the same.
In another aspect, the invention provides the use of a compound of the invention or a pharmaceutical composition comprising the same as described above, for inhibiting RET activity, or for the treatment and/or prevention of diseases associated with RET, e.g. diseases treatable or preventable by RET inhibition.
In another aspect, the present invention also provides the use of a compound of the invention or a pharmaceutical composition comprising the same as described above for the manufacture of a medicament, in particular a medicament having RET receptor inhibitor activity.
In another aspect, the invention provides the use of a compound of the invention, or a pharmaceutical composition comprising the same, as described hereinbefore, optionally in combination with one or more chemotherapeutics or immunotherapeutics, in the manufacture of a medicament for the treatment or prevention of a disease associated with RET, for example a disease treatable or preventable by RET inhibition.
Synthesis of Compounds of the invention
The present invention also provides a process for the preparation of compounds of formula (I), the general synthetic scheme for the synthesis of the compounds of the invention being illustrated below. Suitable reaction conditions for each reaction step are known to those skilled in the art or can be routinely determined. The starting materials and reagents used in the preparation of these compounds are generally commercially available or can be prepared by the methods hereinafter, by methods similar to those given hereinafter, or by methods known in the art, if not otherwise specified. If desired, the starting materials and intermediates in the synthetic reaction schemes can be isolated and purified using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. The materials may be characterized using conventional methods including physical constants and spectroscopic data.
Synthesis scheme 1
In one aspect, the present invention relates to a method of synthesizing a compound of formula (I), comprising the steps of:
reacting a compound of formula I-1 with a compound of formula I-2 to give a compound of formula (I), wherein R1、R2、R3、R4、R5M, n, A and B are each as defined above for compounds of formula (I);
wherein the reaction may be carried out in the presence of a condensing agent, which is well known in the art for coupling carboxylic acids to amines, including but not limited to 1-propylphosphoric anhydride (T3P), EDC, DCC, HATU, EDCI, and the like; the reaction is preferably carried out in a suitable organic solvent, which may be selected from the group consisting of dichloromethane, tetrahydrofuran, ethers (e.g., diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, N-Dimethylformamide (DMF), N-dimethylacetamide, 1, 4-dioxane, dimethyl sulfoxide, and any combination thereof; the reaction is preferably carried out in the presence of a suitable base including, but not limited to, sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, HOBt or pyridine, preferably the base is N, N-diisopropylethylamine; the reaction is preferably carried out at a suitable temperature, for example from 0 to 200 ℃, from 10 to 100 ℃, from 20 to 50 ℃ or at room temperature (20 to 25 ℃).
When the A ring of the compound of formula I-1 is linked to the pyrazolo [1,5-a ] pyridine ring through the N atom (i.e., the compound of formula I-1'), it can be synthesized as shown in FIG. 2.
Synthesis scheme 2
Wherein R is1、R2、R5N and A are each as defined above for compounds of formula (I);
the present invention provides a method of synthesizing a compound of formula I-1', comprising the steps of:
a, obtaining a product of a formula I-5 by nucleophilic substitution reaction of a formula I-3 and a formula I-4; preferably, the reaction is carried out in the presence of a base;
step b-reaction of formula I-5 with an appropriate boronic acid or boronic ester (e.g.boronic acid)) Obtaining a product of a formula I-6 through Suzuki coupling reaction under the action of a catalyst; preferably, the reaction is carried out in the presence of a base; preferably, the catalyst comprises a palladium catalyst, such as Pd (dppf) Cl2DCM or Pd (dppf) Cl2(ii) a And
deprotection of formula I-6 in the presence of an acid to give a product of formula I-1', preferably the acid is selected from hydrochloric acid, sulphuric acid, nitric acid, trifluoroacetic acid and acetic acid.
Bases described in steps a) and b) include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, N-diisopropylethylamine, triethylamine, HOBt, or pyridine;
the reactions of steps a) -c) are preferably carried out in a suitable organic solvent which may be selected from the group consisting of alcohols (e.g. methanol, ethanol), dichloromethane, tetrahydrofuran, ethers (e.g. diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, N-Dimethylformamide (DMF), N-dimethylacetamide, 1, 4-dioxane, dimethyl sulfoxide and any combination thereof; the reaction is preferably carried out at a suitable temperature, for example-70-200 ℃, 0-200 ℃, 10-100 ℃, 100-150 ℃, 70-100 ℃, 20-50 ℃, room temperature (20-25 ℃) or-70-0 ℃.
The above synthetic schemes are only illustrative of some of the methods of preparation of the compounds of the present invention. The compounds of the present invention or stereoisomers, tautomers, stable isotopic derivatives, pharmaceutically acceptable salts or solvates thereof can be prepared by a variety of methods, including those set forth above, in the examples, or by analogous methods thereto, by one of ordinary skill in the art based on the synthetic schemes described above, in conjunction with routine techniques in the art.
Detailed Description
The technical solutions of the present invention are further described below with reference to specific examples, but the scope of the present invention is not limited to these examples. All changes, modifications and equivalents that do not depart from the spirit of the invention are intended to be included within the scope thereof.
Experimental procedures without specific conditions noted in the following examples are generally carried out according to conventional conditions for such reactions, or according to conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight. Unless otherwise specified, the ratio of liquids is by volume.
The experimental materials and reagents used in the following examples are commercially available, prepared according to methods of the prior art or prepared according to methods similar to those disclosed herein, unless otherwise specified.
Abbreviations used herein have the meaning commonly understood in the art unless clearly defined otherwise in the specification. The meanings of the abbreviations used in the specification are listed below:
boc: tert-butyloxycarbonyl radical
Pd(dppf)Cl2: [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
Pd(dppf)Cl2DCM [1,1' -bis (diphenylphosphino) ferrocene ]]Palladium dichloride dichloromethane complex
HATU: 2- (7-azobenzotriazol) -N, N, N ', N', -tetramethyluronium hexafluorophosphate
DIEA: n, N-diisopropylethylamine
DCM dichloromethane
EA ethyl acetate
PE petroleum ether
DMF: n, N-dimethylformamide
LC-MS: liquid chromatography-mass spectrometry
ESI electrospray ionization
m/z: mass to charge ratio
EDCI: 1-Ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride
HOBt: 1-hydroxybenzotriazoles
TLC thin layer chromatography
HPLC, high performance liquid chromatography
Synthetic examples
In the preparation method of the target compound, the column chromatography adopts silica gel (300-400 meshes) produced by Ningsan Sun drying agent GmbH; thin layer chromatography using GF254(0.25 mm); nuclear magnetic resonance chromatography (NMR) was measured using a Varian-400 nuclear magnetic resonance spectrometer; LC/MS an Agilent technology ESI 6120 LC/MS instrument was used.
In addition, all operations involving easily oxidizable or hydrolyzable raw materials were carried out under nitrogen protection. Unless otherwise indicated, all starting materials used in the present invention are commercially available, can be used without further purification, and are used in the present invention at temperatures in degrees Celsius.
When the structure of the compound of the present invention is inconsistent with the name of the compound, the structural formula is generally subject to the standard unless the name of the compound can be determined to be correct by context.
Example 1:n- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) piperazines Pyridin-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide (Compound 1) and its hydrochloride salt (Compound 1- 1) Synthesis of (2)
Step 1 Synthesis of tert-butyl (1- (5-bromopyridin-3-yl) piperidin-4-yl) carbamate
To a solution of 3, 5-dibromopyridine (1.00g,4.22mmol) in N-methylpyrrolidinone (1.00mL) was added tert-butyl piperidine-4-carbamate (1.69g,8.44mmol) and DIEA (0.500mL,3.02 mmol). Sealing the tube and reacting the solutionThe reaction was heated to 140 ℃ and stirred for 48 hours. The reaction mixture was cooled to room temperature, poured carefully into water (50.0mL) to give a suspension, filtered, and the filter cake was washed with water (100mL) to give the crude product. Purification by column chromatography (PE: EA ═ 5:1-3:1) gave the title compound (480mg, yield 32.0%, white solid). LC-MS (ESI) M/z 356.0, 358.0[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.27(d,J=2.6Hz,1H),7.99(d,J=1.8Hz,1H),7.52–7.49(m,1H),6.85(d,J=7.5Hz,1H),3.82–3.70(m,2H),3.51–3.38(m,1H),2.93–2.77(m,2H),1.84–1.71(m,2H),1.48–1.40(m,2H),1.39(s,9H)。
Step 2: synthesis of 1-amino-3-bromo-5- (4- ((tert-butoxycarbonyl) amino) piperidin-1-yl) pyridin-1-ium 2,4, 6-trimethylbenzenesulfonate
A solution of (1- (5-bromopyridin-3-yl) piperidin-4-yl) amino tert-butyl ester (480mg,1.35mmol) and o- (trimesoyl) hydroxylamine (870mg,4.04mmol) in DCM (15.0mL) was stirred at 0 ℃ for 16 h, then warmed to room temperature and stirred for 16 h. The reaction was concentrated under reduced pressure to give the product (700mg, crude, yellow solid). LC-MS (ESI) M/z 371.1[ M ]]+. Step 3 (1- (6-bromo-3-cyanopyrazolo [1, 5-a)]Synthesis of pyridin-4-yl) piperidin-4-yl) carbamic acid tert-butyl ester
To a solution of 1-amino-3-bromo-5- (4- ((tert-butoxycarbonyl) amino) piperidin-1-yl) pyridin-1-amine 2,4, 6-trimethylbenzenesulfonate (700mg,1.22mmol) in 1, 4-dioxane (15.0mL) was added acrylonitrile (149mg,2.82mmol) and DIEA (206mg,1.59mmol) at room temperature. After the reaction mixture was stirred at room temperature for 2 hours, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (584mg,2.57mmol) was added thereto. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (50.0mL) and extracted with EA (250 mL). The organic phase was washed with saturated brine (40.0 mL. times.3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the crude product. Purification by column chromatography (PE: EA ═ 10:1-5:1) gave the title compound (260mg, 45.9% yield in two steps, yellow solid). LC-MS (ESI) M/z 442.0, 444.0[ M + Na [ ]]+。1H NMR(400MHz,MeOH-d4)δ8.65(d,J=1.4Hz,1H),8.36(s,1H),7.13(d,J=1.4Hz,1H),6.80(d,J=7.3Hz,1H),3.62–3.53(m,1H),3.53–3.44(m,2H),2.89(t,J=10.7Hz,2H),2.09–2.03(m,1H),2.02–1.97(m,1H),1.93–1.82(m,2H),1.47(s,9H)。
Step 4 Synthesis of tert-butyl (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) piperidin-4-yl) carbamate
To (1- (6-bromo-3-cyanopyrazolo [1,5-a ]]Pyridin-4-yl) piperidin-4-yl) carbamic acid tert-butyl ester (200mg,0.476mmol) and 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (119mg,0.571mmol) in a mixture of water (2.00mL) and 1, 4-dioxane (10.0mL) was added sodium carbonate (101mg,0.952mmol) and Pd (dppf) Cl2(15.5mg,0.024 mmol). After the argon gas was replaced with the reaction mixture three times, the reaction mixture was stirred at 80 ℃ for 16 hours. The reaction mixture was cooled to room temperature, poured into water (50.0mL), and extracted with EA (250 mL). The organic phase was washed with saturated brine (40.0 mL. times.3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the crude product. Purification by column chromatography (PE: EA ═ 3:1-1:1) gave the title compound (200mg, yield 90.5%, off-white solid). LC-MS (ESI) M/z 422.1[ M + H ]]+。1H NMR(400MHz,MeOH-d4)δ8.64(d,J=1.2Hz,1H),8.34(s,1H),8.13(s,1H),7.95(d,J=0.5Hz,1H),7.23(d,J=1.1Hz,1H),6.81(d,J=6.9Hz,1H),3.97(s,3H),3.63–3.56(m,1H),3.56–3.48(m,2H),2.93(t,J=10.9Hz,2H),2.09–2.01(m,2H),1.95–1.83(m,2H),1.48(s,9H)。
Step 5 Synthesis of 4- (4-aminopiperidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrochloride
(1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) piperidin-4-yl) carbamic acid tert-butyl ester (200mg,0.474mmol) in 1, 4-dioxane hydrochloric acid (10.0mL,40.0mmol,4.0M) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried to obtain the objective compound (160mg, yield 86.0%, yellow solid). LC-MS (ESI) M/z 322.2[ M + H ]]+。
Step 6 Synthesis of N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) piperidin-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide and hydrochloride thereof
To 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetic acid (44.4mg,0.201mmol) and 4- (4-aminopiperidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a) at room temperature]Pyridine-3-carbonitrile hydrochloride (60.0mg,0.152mmol) in DMF (3.00mL) was added EDCI (48.3mg,0.252mmol), HOBt (33.9mg,0.252mmol) and DIEA (65.1mg,0.504mmol), the reaction mixture was stirred at room temperature for 16 h, then the reaction was heated to 50 ℃ and stirring was continued for 16 h. The reaction mixture was poured slowly into water (50.0mL) and extracted with EA (150 mL). The organic phase was washed with saturated brine (40.0 mL. times.3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product (compound 1). Purification by preparative HPLC (acetonitrile/water containing 0.05% hydrochloric acid) gave the target compound (compound 1-1) as the hydrochloride salt (28.2mg, yield 33.2%, white solid). LC-MS (ESI) M/z 525.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.67(d,J=4.3Hz,1H),8.56(s,1H),8.34(s,2H),8.31(d,J=7.3Hz,1H),8.05(s,1H),7.93–7.85(m,3H),7.25(s,1H),3.88(s,3H),3.83–3.70(m,1H),3.53(s,2H),3.44(d,J=12.1Hz,2H),2.87(t,J=11.2Hz,2H),1.96–1.90(m,2H),1.86-1.78(m,2H)。
Example 2:n- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) piperazines Pyridin-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) propanamide (Compound 2) and its hydrochloride salt (Compound 2- 1) Synthesis of (2)
Step 1 Synthesis of N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) piperidin-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) propionamide and hydrochloride thereof
4- (4-aminopiperidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] at room temperature]Pyridine-3-carbonitrile hydrochloride (80mg,0.203mmol), 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) propionic acid (47.4mg,0.203mmol), HATU (116mg,0.305mmol), and DIEA (78.7mg,0.609mmol) were added to DMF (1.50 mL). The reaction mixture was at room temperatureThe reaction was stirred for 1 hour. Water (10.0mL) was added to the reaction mixture, and extraction was performed with EA (15.0 mL. times.3). The combined organic phases were dried over water (10.0mL), saturated brine (10.0 mL. times.1), anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude product (compound 2). Purification by preparative HPLC (acetonitrile/water containing 0.05% hydrochloric acid) gave the title compound (compound 2-1) as the hydrochloride salt (26.2mg, yield 22.5%, off-white solid). LC-MS (ESI) M/z 539.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.89(d,J=0.7Hz,1H),8.68(d,J=4.5Hz,1H),8.56(s,1H),8.40(d,J=1.9Hz,1H),8.35(s,1H),8.29(d,J=7.6Hz,1H),8.06(s,1H),7.99–7.94(m,1H),7.93–7.86(m,2H),7.24(s,1H),3.88(s,3H),3.80–3.70(m,2H),3.50–3.36(m,2H),2.93–2.79(m,2H),2.00–1.91(m,1H),1.88–1.66(m,3H),1.40(d,J=7.0Hz,3H)。
Example 3:n- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) piperazines Synthesis of pyridin-4-yl) -2- (4-methoxyphenyl) acetamide (Compound 3)
Step 1 Synthesis of tert-butyl (1- (6-bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl) piperidin-4-yl) carbamate
To 6-bromo-4-fluoropyrazolo [1,5-a ]]Pyridine-3-carbonitrile (500mg,2.08mmol) and tert-butyl piperidin-4-ylcarbamate (500mg,2.50mmol) in N-methylpyrrolidinone (2.00mL) was added potassium carbonate (576mg,4.17 mmol). The tube was sealed and the reaction mixture was stirred at 100 ℃ for 16 hours. The reaction mixture was cooled to room temperature, poured into water (20.0mL), and extracted with EA (100 mL). The organic phase was washed with saturated brine (20.0mL), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (PE: EA ═ 10:1-5:1) gave the title compound (400mg, yield 45.7%, grey solid). LC-MS (ESI) M/z 419.9, 421.9[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.38(d,J=1.4Hz,1H),8.18(s,1H),6.88(d,J=1.3Hz,1H),4.64–4.48(m,1H),3.73–3.62(m,1H),3.51–3.42(m,2H),2.89–2.78(m,2H),2.19–2.09(m,2H),1.91–1.80(m,2H),1.46(s,9H)。
Step 2 Synthesis of tert-butyl 1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) piperidin-4-yl) carbamate
To (1- (6-bromo-3-cyanopyrazolo [1,5-a ]]Pyridin-4-yl) piperidin-4-yl) carbamic acid tert-butyl ester (400mg,0.952mmol) and 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (238mg,1.14mmol) in water (1.00mL) and 1, 4-dioxane (5.00mL) sodium carbonate (202mg,1.90mmol) and Pd (dppf) Cl were added to a solution of sodium carbonate (202mg,1.90mmol) and Pd (dppf) Cl2DCM (39.0mg,0.047 mmol). The reaction mixture was stirred at 80 ℃ for 16 hours under nitrogen. The reaction mixture was cooled to room temperature and poured into EA (20.0mL) to give a black solution. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. Purification by column chromatography (PE: EA ═ 10:1-5:1) gave the title compound (300mg, yield 74.8%, grey solid). LC-MS (ESI) M/z 422.5[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.39–8.34(m,1H),8.20(s,1H),7.78(s,1H),7.68(s,1H),7.03–6.85(m,1H),4.66–4.51(m,1H),4.02(s,3H),3.77–3.64(m,1H),3.58–3.45(m,2H),3.00–2.82(m,2H),2.20–2.12(m,2H),1.96–1.85(m,2H),1.46(s,9H)。
Step 3 Synthesis of 4- (4-aminopiperidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrochloride
To (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]To a solution of tert-butyl pyridin-4-yl) piperidin-4-yl) carbamate (100mg,0.237mmol) in methanol (2.00mL) was added a solution of hydrogen chloride in methanol (3.0M,4.00 mL). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (100mg, theoretical yield 100%, grey solid). LC-MS (ESI) M/z 322.0[ M + H ]]+。
Step 4 Synthesis of N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) piperidin-4-yl) -2- (4-methoxyphenyl) acetamide
To 4- (4-aminopiperidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrilesTo a solution of the hydrochloride salt (80.0mg,0.224mmol) and 2- (4-methoxyphenyl) acetic acid (40.0mg,0.241mmol) in DMF (2.00mL) were added DIEA (60.0mg,0.464mmol), EDCI (68.0mg,0.355mmol) and HOBt (48.0mg,0.355mmol) in that order. The reaction mixture was stirred at room temperature for 12 hours. Water (10.0mL) was added to the reaction mixture, and extraction was performed with EA (30.0 mL. times.2). The combined organic phases were washed with saturated brine (30.0 mL. times.2), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Preparative HPLC (acetonitrile/water with 0.05% formic acid) gave the title compound (21.4mg, yield 20.4%, white solid). LC-MS (ESI) M/z 470.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.56(s,1H),8.35(s,1H),8.17(d,J=7.4Hz,1H),8.06(s,1H),7.25(s,1H),7.19(d,J=8.5Hz,2H),6.86(d,J=8.5Hz,2H),3.88(s,3H),3.79–3.74(m,1H),3.73(s,3H),3.48–3.40(m,2H),3.34(s,2H),2.86(t,J=10.6Hz,2H),1.93–1.85(m,2H),1.85–1.72(m,2H)。
Example 4:n- (1- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1, 5-a)]Pyridin-4-yl) piperazines Synthesis of pyridin-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide (Compound 4)
Step 1 Synthesis of tert-butyl 1- (3-cyano-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] pyridin-4-yl) piperidin-4-yl) carbamate
To (1- (6-bromo-3-cyanopyrazolo [1,5-a ]]Pyridin-4-yl) piperidin-4-yl) carbamic acid tert-butyl ester (2.21g,5.26mmol) and pinacol diboron (6.68g,26.3mmol) in dry 1, 4-dioxane (40.0mL) was added potassium acetate (1.03g,10.5mmol) and Pd (dppf) Cl2(227mg,0.263 mmol). The reaction mixture was stirred at 70 ℃ for 3 hours under argon. The reaction solution was cooled to room temperature, filtered, the residue was washed with EA (30.0mL), and the filtrate was concentrated under reduced pressure to give a crude product. Purification by column chromatography (PE: EA ═ 10: 1-4: 1) gave the title compound (1.80g, 73.2% yield, light yellow oil). LC-MS (ESI) M/z 468.3[ M +H]+。1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.55(s,1H),7.96(s,1H),7.02(s,1H),3.97–3.94(m,2H),3.66–3.64(m,1H),2.83–2.75(m,2H),1.91–1.84(m,2H),1.80–1.69(m,2H),1.40(s,9H),1.33(s,12H)。
Step 2 Synthesis of tert-butyl (1- (3-cyano-6-hydroxypyrazolo [1,5-a ] pyridin-4-yl) piperidin-4-yl) carbamate
To (1- (3-cyano-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] at 0 DEG C]Pyridin-4-yl) piperidin-4-yl) carbamic acid tert-butyl ester (1.20g,2.57mmol) in tetrahydrofuran (50.0mL) was added sodium hydroxide solid (514mg,12.8mmol) and 30% aqueous hydrogen peroxide (1.80mL,20.5 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then the reaction was stopped. To the reaction mixture was added a saturated aqueous solution of ammonium chloride (30.0mL), followed by stirring at room temperature for 30 minutes. Standing for layering, and separating out an organic phase. The aqueous phase was extracted with EA (60.0 mL). The combined organic phases are dried by anhydrous sodium sulfate, filtered, and the filtrate is decompressed and concentrated to obtain a crude product. Purification by column chromatography (PE: EA ═ 4:1-2:1) gave the title compound (295mg, yield 32.1%, yellow solid). LC-MS (ESI) M/z 358.1[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.42(s,1H),7.97(d,J=1.6Hz,1H),6.98(d,J=7.5Hz,1H),6.73(d,J=1.6Hz,1H),3.47–3.41(m,1H),3.38–3.33(m,2H),2.78–2.70(m,2H),1.90–1.83(m,2H),1.79–1.68(m,2H),1.40(s,9H)。
Step 3 Synthesis of tert-butyl (1- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a ] pyridin-4-yl) piperidin-4-yl) carbamate
To (1- (3-cyano-6-hydroxypyrazolo [1,5-a ]]Pyridin-4-yl) piperidin-4-yl) carbamic acid tert-butyl ester (290mg,0.811mmol) in tetrahydrofuran (3.50mL) was added 2.0N aqueous sodium hydroxide (0.81mL,1.62 mmol). The reaction mixture was stirred at room temperature for 15 minutes and 2, 2-dimethyloxirane (293mg,4.06mmol) was added. The tube was sealed, and the reaction mixture was stirred at 60 ℃ for 16 hours, and then 2, 2-dimethyloxirane (293mg,4.06mmol) was added. The mixture was stirred at 60 ℃ for 16 hours. The reaction mixture was poured into water (15.0mL) and washed with EA (25.0 mL. times.2) was extracted. The combined organic phases are dried by anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a crude product. Purification by reverse phase separation (acetonitrile/water with 0.05% formic acid) gave the title compound (240mg, yield 68.9%, yellow solid). LC-MS (ESI) M/z430.3[ M + H ]]+。
Step 4 Synthesis of 4- (4-aminopiperidin-1-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrochloride
Reacting (1- (3-cyano-6- (2-hydroxy-2-methylpropyloxy) pyrazolo [1, 5-a)]Pyridin-4-yl) piperidin-4-yl) carbamic acid tert-butyl ester (240mg,0.559mmol) was added to a solution of hydrogen chloride in methanol (3.0M,15.0mL,45.0 mmol). The reaction mixture was stirred at room temperature for 16 hours. Concentration under reduced pressure gave the title compound (180mg, yield 88.2%, yellow solid). LC-MS (ESI) M/z 330.2[ M + H ]]+。
Step 5 Synthesis of N- (1- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a ] pyridin-4-yl) piperidin-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide formate
To 4- (4-aminopiperidin-1-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a at room temperature]Pyridine-3-carbonitrile hydrochloride (90.0mg,0.246mmol) and 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetic acid (54.4mg,0.246mmol) in DMF (2.00mL) were added EDCI (70.7mg,0.369mmol), HOBt (49.9mg,0.369mmol) and DIEA (63.6mg,0.492 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (10.0mL) and extracted with EA (30.0 mL). The organic phase was washed with saturated brine (10.0 mL. times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. Purification by preparative (acetonitrile/water containing 0.05% formic acid) gave the title compound (42.9mg, yield 30.1%, white solid). LC-MS (ESI) M/z 533.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.69–8.66(m,1H),8.49(s,1H),8.35–8.29(m,3H),7.91(d,J=3.9Hz,1H),7.89–7.85(m,2H),6.81(d,J=1.6Hz,1H),4.68(s,1H),3.78(s,2H),3.77-3.73(m,1H),3.52(s,2H),3.41–3.37(m,2H),2.84–2.77(m,2H),1.93–1.86(m,2H),1.83–1.73(m,2H),1.21(s,6H)。
Example 5:n- (1- (3-cyano)6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a]Pyridin-4-yl) - 4-methylpiperidin-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide (compound 5) and hydrochloride thereof Synthesis of (Compound 5-1)
Step 1 Synthesis of 1-amino-3-bromo-5-fluoropyridin-1-ium 2,4, 6-trimethylbenzenesulfonate
3-bromo-5-fluoropyridine (10.0g,56.8mmol) and O-2,4, 6-trimethylbenzenesulfonylhydroxylamine (14.7g,68.2mmol) were added to DCM (150 mL). The reaction mixture was stirred at 0 ℃ for 1 hour. PE (150mL) was slowly added to the reaction mixture at 0 ℃ and stirred for 15 minutes to obtain a white suspension. After filtration, the product (15.5g, white solid) and the crude product (5.50g, white solid) were obtained. LC-MS (ESI) M/z 191.1,193.1[ M ]]+。
Step 2 Synthesis of 6-bromo-4-fluoropyrazolo [1,5-a ] pyridine-3-carbonitrile
To a solution of 1-amino-3-bromo-5-fluoropyridin-1-ium 2,4, 6-trimethylbenzenesulfonate (20.0g,51.1mmol) in 1, 4-dioxane (200mL) was added acrylonitrile (7.74mL,118mmol) and DIEA (11.0mL,66.4mmol) at 0 ℃. After the reaction mixture was stirred at 0 ℃ for 2 hours, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (23.2g,102mmol) was added thereto. The reaction mixture was stirred at 0 ℃ for 1 hour, and then warmed to room temperature for further reaction for 16 hours. The reaction mixture was poured into ice water (300mL) to give a brown suspension. The suspension was stirred at room temperature for 20 minutes and then filtered, and the filter cake was washed with ice water (100mL) to give a crude solid. Purification by column chromatography (PE: EA 100:1-10:1) gave the title compound (5.70g, 41.9% yield in two steps, yellow solid).
Step 3 Synthesis of tert-butyl (1- (6-bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl) -4-methylpiperidin-4-yl) carbamate
To 6-bromo-4-fluoropyrazolo [1,5-a ]]Pyridine-3-carbonitrile (300mg,1.25mmol) and tert-butyl (4-methylpiperidin-4-yl) carbamate (295mg,1.37mmol) in N-methylpyrrolidone (2.00mL) was added potassium carbonate (346mg,250 mmol). The reaction mixture was stirred at 100 ℃ for 16 hours. The reaction mixture was cooled to room temperature and poured into water (15.0 mL). Extract with EA (50.0 mL). The organic phase was washed with saturated brine (15.0 mL. times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. Purification by column chromatography (PE: EA: 10:1) gave the title compound (400mg, yield 63.2%, off-white solid). LC-MS (ESI) M/z 434.0,436.0[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.95(s,1H),8.62(s,1H),7.13(s,1H),6.55(s,1H),3.20–3.07(m,2H),3.04–2.92(m,2H),2.26–2.14(m,2H),1.82–1.68(m,2H),1.41(s,9H),1.31(s,3H)。
Step 4 Synthesis of tert-butyl 1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) -4-methylpiperidin-4-yl) carbamate
To (1- (6-bromo-3-cyanopyrazolo [1,5-a ]]Pyridin-4-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester (400mg,0.921mmol) and a solution of 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (230mg,1.11mmol) in water (0.80mL) and 1, 4-dioxane (4.00mL) was added sodium carbonate (195mg,1.84mmol) and Pd (dppf) Cl2DCM (39.7mg,0.046 mmol). The argon was replaced three times. The reaction mixture was stirred at 80 ℃ for 16 hours. The reaction mixture was cooled to room temperature, poured into water (20.0mL), and extracted with EA (60 mL. times.2). The combined organic phases are dried by anhydrous sodium sulfate, filtered, and the filtrate is decompressed and concentrated to obtain a crude product. Purification by column chromatography (PE: EA ═ 3:1-1:1) gave the title compound (360mg, yield 89.6%, light yellow solid). LC-MS (ESI) M/z 436.1[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.88(d,J=1.0Hz,1H),8.56(s,1H),8.39(s,1H),8.08(s,1H),7.24(s,1H),6.53(s,1H),3.88(s,3H),3.21–3.11(m,2H),3.08–2.95(m,2H),2.31–2.17(m,2H),1.85–1.72(m,2H),1.42(s,9H),1.32(s,3H)。
Step 5 Synthesis of 4- (4-amino-4-methylpiperidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrochloride
(1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]pyridin-4-Yl) -4-Methylpiperidin-4-Yl) carbamic acid Tert-butylA solution of butyl ester (180mg,0.413mmol) in methanolic hydrogen chloride (3.0M,5.00mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give the objective compound (150mg, yield 98.0%, yellow solid). LC-MS (ESI) M/z336.1[ M + H ]]+。
Step 6 Synthesis of N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) -4-methylpiperidin-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide
To a solution of 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetic acid (65.5mg,0.296mmol) in DMF (2.00mL) at room temperature were added EDCI (77.3mg,0.403mmol), HOBt (54.5mg,0.403mmol), DIEA (69.5mg,0.538mmol), and 4- (4-amino-4-methylpiperidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a-]Pyridine-3-carbonitrile hydrochloride (100mg,0.269 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (15.0mL) and extracted with EA (60.0 mL). The organic phase was washed with saturated brine (10.0 mL. times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product (Compound 5). Purification by preparative HPLC (acetonitrile/water containing 0.05% hydrochloric acid) gave the title compound (compound 5-1) as a hydrochloride salt (35.5mg, yield 22.9%, light yellow solid). LC-MS (ESI) M/z 539.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.64(d,J=4.3Hz,1H),8.56(s,1H),8.37-8.33(m,2H),8.05(s,1H),7.94–7.87(m,3H),7.85(s,1H),7.19(s,1H),3.87(s,3H),3.56(s,2H),3.22–3.15(m,2H),3.06–2.98(m,2H),2.32–2.25(m,2H),1.89–1.80(m,2H),1.36(s,3H)。
Example 6:n- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) - 4-methylpiperidin-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) propanamide (compound 6) and hydrochloride salt thereof Synthesis of (Compound 6-1)
To a solution of 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) propionic acid (48.7mg,0.207mmol) in DMF (2.00mL) at room temperatureHATU (107mg,0.282mmol) was added. After the reaction mixture was stirred at room temperature for 15 minutes, DIEA (72.9mg,0.564mmol) and 4- (4-amino-4-methylpiperidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] were added]Pyridine-3-carbonitrile hydrochloride (70.0mg,0.188 mmol). The reaction mixture was stirred at room temperature for a further 16.5 hours. The reaction mixture was poured into water (20.0mL) and extracted with EA (60.0 mL). The organic phase was washed with saturated brine (15.0 mL. times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product (Compound 6). Purification by preparative HPLC (acetonitrile/water containing 0.05% hydrochloric acid) gave the title compound (compound 6-1) as a hydrochloride salt (26.1mg, yield 23.6%, light yellow solid). LC-MS (ESI) M/z 553.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.59(d,J=4.4Hz,1H),8.55(s,1H),8.41(d,J=2.0Hz,1H),8.31(s,1H),8.02(s,1H),7.98–7.95(m,1H),7.89–7.86(m,2H),7.74(s,1H),7.12(s,1H),3.88(s,3H),3.85–3.83(m,1H),3.20–3.13(m,2H),3.01–2.95(m,1H),2.86–2.80(m,1H),2.33–2.29(m,1H),2.25–2.20(m,1H),1.87–1.78(m,2H),1.39(d,J=7.0Hz,3H),1.32(s,3H)。
Example 7:n- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) nitrogen Synthesis of heterocycloheptan-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide (Compound 7)
Step 1 Synthesis of tert-butyl (1- (6-bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl) azepan-4-yl) carbamate
To 6-bromo-4-fluoropyrazolo [1,5-a ]]Pyridine-3-carbonitrile (540mg,2.25mmol) and tert-butyl azepan-4-ylcarbamate (579mg,2.70mmol) in N-methylpyrrolidinone (4.00mL) were added DIEA (582mg,4.50 mmol). The tube was sealed and the reaction mixture was stirred at 100 ℃ for 16 hours. The reaction mixture was cooled to room temperature and slowly poured into water (15.0 mL). Extraction was carried out with EA (20.0 mL. times.2). The combined organic phases were washed with water (10.0 mL. times.2) and saturated brine (10.0 mL. times.2), anhydrous sulfuric acidDrying with sodium, and filtering. The filtrate was concentrated under reduced pressure to give the title compound (300mg, crude, grey solid) which was used directly in the next step. LC-MS (ESI) M/z 434.0,436.0[ M + H ]]+。
Step 2 Synthesis of tert-butyl 1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) azepan-4-yl) carbamate
1- (6-bromo-3-cyanopyrazolo [1,5-a ]]Pyridin-4-yl) azepan-4-yl) carbamic acid tert-butyl ester (300mg,0.691mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (216mg,1.04mmol), potassium carbonate (191mg,1.38mmol) and Pd (dppf) Cl2DCM (28.2mg,0.034mmol) was added to a mixed solvent of 1, 4-dioxane (2.00mL) and water (0.500 mL). The tube was sealed and replaced with argon 3 times. The reaction mixture was stirred at 100 ℃ for 2 hours. After cooling the reaction mixture to room temperature, the organic phase was separated off. Concentrating under reduced pressure to obtain crude product. Purification by column chromatography (PE: EA ═ 1:1) followed by reverse phase purification (acetonitrile/water with 0.05% formic acid) gave the title compound (120mg, 12.2% yield in two steps, yellow solid). LC-MS (ESI) M/z 436.0[ M + H ]]+。
Step 3 Synthesis of 4- (4-Aminoazepan-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrochloride
1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a]Pyridin-4-yl) azepan-4-yl) carbamic acid tert-butyl ester (120mg,0.276mmol) was added to a solution of 1, 4-dioxane hydrochloride (4.0M,2.00 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the objective compound (90.0mg, yield 87.4%, grey solid). LC-MS (ESI) M/z 336.5[ M + H ]]+。
Step 4 Synthesis of N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) azepan-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide
Reacting 4- (4-amino azepan-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile hydrochloride (90.0mg,0.242mmol), 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetic acid (53.5mg,0.242 m)mol), HOBt (49.0mg,0.363mmol), EDCI (92.8mg,0.484mmol) and DIEA (93.8mg,0.726mmol) were added sequentially to DMF (2.00 mL). The reaction mixture was stirred at room temperature for 16 hours. Water (10.0mL) was added, and the mixture was extracted with EA (15.0 mL. times.2). The combined organic phases were washed with water (10.0 mL. times.2) and saturated brine (10.0 mL. times.2), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by preparative plate separation (PE: EA ═ 1:4) afforded the title compound (19.5mg, yield 14.9%, yellow solid). LC-MS (ESI) M/z 539.2[ M + H ]]+。1H NMR(400MHz,MeOH-d4)δ8.60(d,J=1.2Hz,1H),8.49-8.46(m,1H),8.35-8.33(m,1H),8.32(s,1H),8.10(s,1H),7.93(s,1H),7.91–7.84(m,2H),7.69-7.65(m,1H),7.28(d,J=1.2Hz,1H),4.14–4.04(m,1H),3.94(s,3H),3.57(s,2H),3.54–3.46(m,2H),3.45–3.33(m,2H),2.17–2.07(m,2H),2.05–1.97(m,2H),1.92–1.80(m,2H)。
Example 8:n- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) pyridine Synthesis of pyrrolidin-3-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide (Compound 8)
Step 1 Synthesis of tert-butyl (1- (6-bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl) pyrrolidin-3-yl) carbamate
To 6-bromo-4-fluoropyrazolo [1,5-a ]]Pyridine-3-carbonitrile (300mg,1.25mmol) and t-butyl pyrrolidin-3-ylcarbamate (244mg,1.31mmol) in N-methylpyrrolidone (2.00mL) was added potassium carbonate (345mg,2.50 mmol). The tube was sealed and the reaction mixture was stirred at 100 ℃ for 16 hours. The reaction mixture was cooled to room temperature, poured into water (15.0mL), and extracted with EA (60.0 mL). The organic phase was washed with saturated brine (15.0mL), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (PE: EA ═ 3:1-1:1) gave the title compound (290mg, yield 57.2%, grey solid). LC-MS (ESI) M/z 350.0,351.9[ M-56+ H ]]+。1H NMR(400MHz,CDCl3)δ8.31(d,J=1.3Hz,1H),8.18(s,1H),6.71–6.69(m,1H),5.02–4.91(m,1H),4.47–4.34(m,1H),3.82–3.69(m,1H),3.60–3.48(m,1H),3.46–3.36(m,1H),3.34–3.22(m,1H),2.47–2.36(m,1H),2.03–1.93(m,1H),1.46(s,9H)。
Step 2 Synthesis of tert-butyl 1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyrrolidin-3-yl) carbamate
To (1- (6-bromo-3-cyanopyrazolo [1,5-a ]]Pyridin-4-yl) pyrrolidin-3-yl) carbamic acid tert-butyl ester (160mg,0.394mmol) and 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (99.0mg,0.473mmol) in water (1.00mL) and 1, 4-dioxane (5.00mL) sodium carbonate (84.0mg,0.788mmol) and Pd (dppf) Cl were added to a solution of sodium carbonate (84.0mg,0.788mmol) and Pd (dppf) Cl2DCM (17.0mg,0.020 mmol). The reaction mixture was stirred at 80 ℃ for 16 hours under nitrogen. The reaction mixture was cooled to room temperature and poured into EA (20.0mL) to give a black solution. The solution is dried by anhydrous sodium sulfate, filtered, and the filtrate is decompressed and concentrated to obtain a crude product. Purification by column chromatography (PE: EA ═ 9:1-5:1) gave the title compound (110mg, yield 68.8%, grey solid). LC-MS (ESI) M/z 408.0[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.30(d,J=1.1Hz,1H),8.19(s,1H),7.75–7.73(m,1H),7.64(s,1H),6.76(s,1H),5.12–5.02(m,1H),4.47–4.36(m,1H),3.98(s,3H),3.85–3.74(m,1H),3.53–3.37(m,2H),3.26–3.15(m,1H),2.50–2.40(m,1H),2.03–1.93(m,1H),1.46(s,9H)。
Step 3 Synthesis of 4- (3-Aminopyrrolidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrochloride
To (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) pyrrolidin-3-yl) carbamic acid tert-butyl ester (110mg,0.270mmol) in methanol (2.00mL) was added hydrogen chloride in methanol (3.0M,2.00 mL). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to give the objective compound (90.0mg, yield 96.8%, grey solid). LC-MS (ESI) M/z 308.0[ M + H ]]+。
Step 4 Synthesis of N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyrrolidin-3-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide
To 4- (3-aminopyrrolidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile hydrochloride (60.0mg,0.174mmol), 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetic acid (39.0mg,0.176mmol), and DIEA (45.0mg,0.348mmol) in DMF (2.00mL) were added EDCI (51.0mg,0.266mmol) and HOBt (36.0mg,0.266 mmol). The reaction mixture was stirred at room temperature for 4 hours. Water (10.0mL) was added to the reaction mixture, and extraction was performed with EA (30.0 mL. times.3). The combined organic phases were washed with saturated brine (30.0 mL. times.2), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Preparative HPLC (acetonitrile/water with 0.05% formic acid) gave the title compound (32.0mg, yield 36.0%, white solid). LC-MS (ESI) M/z 511.0[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.81–8.78(m,1H),8.69–8.64(m,1H),8.58(s,1H),8.54(d,J=6.6Hz,1H),8.37(s,1H),8.32(s,1H),8.07(s,1H),7.92(d,J=4.3Hz,1H),7.89–7.83(m,2H),7.04(s,1H),4.43–4.36(m,1H),3.87(s,3H),3.71–3.65(m,1H),3.63–3.57(m,1H),3.53(s,2H),3.45–3.41(m,1H),3.31–3.28(m,1H),2.31–2.24(m,1H),1.98–1.91(m,1H)。
Example 9:(R) -N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridine-4- Synthesis of yl) pyrrolidin-3-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide (Compound 9)
Step 1 Synthesis of tert-butyl (R) - (1- (6-bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl) pyrrolidin-3-yl) carbamate
To 6-bromo-4-fluoropyrazolo [1,5-a ]]Pyridine-3-carbonitrile (300mg,1.25mmol) and tert-butyl (R) -pyrrolidin-3-ylcarbamate (256mg,1.37mmol) in N-methylpyrrolidinone (3.00mL) was added potassium carbonate (346mg,2.50 mmol). The reaction mixture was stirred at 100 ℃ for 6 hours. The reaction mixture was cooled to room temperature, poured into water (20.0mL), and extracted with EA (100 mL). The organic phase was washed with saturated brine (15.0 mL. times.3)Drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain crude product. Purification by column chromatography (PE: EA 100:1-10:1) gave the title compound (240mg, yield 46.2%, grey solid). LC-MS (ESI) M/z 406.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.75(d,J=1.4Hz,1H),8.60(s,1H),7.20(d,J=6.2Hz,1H),6.80(d,J=1.3Hz,1H),4.20–4.10(m,1H),3.80–3.71(m,1H),3.55–3.43(m,2H),3.30–3.26(m,1H),2.20–2.12(m,1H),1.95–1.87(m,1H),1.39(s,9H)。
Step 2 Synthesis of tert-butyl (R) - (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyrrolidin-3-yl) carbamate
To (R) - (1- (6-bromo-3-cyanopyrazolo [1, 5-a)]Pyridin-4-yl) pyrrolidin-3-yl) carbamic acid tert-butyl ester (240mg,0.591mmol) and 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (148mg,0.709mmol) in water (0.800mL) and 1, 4-dioxane (4.00mL) sodium carbonate (125mg,1.18mmol) and Pd (dppf) Cl were added2DCM (25.5mg,0.030 mmol). The reaction mixture was stirred at 100 ℃ for 8 hours under argon. The reaction mixture was cooled to room temperature and poured into EA (40.0mL) to give a black solution. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. Purification by column chromatography (PE: EA ═ 10:1-1:1) gave the title compound (190mg, yield 79.2%, light green solid). LC-MS (ESI) M/z 408.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.77–8.75(m,1H),8.55(s,1H),8.36(s,1H),8.05(s,1H),7.23–7.17(m,1H),6.99(s,1H),4.21–4.11(m,1H),3.87(s,3H),3.77–3.69(m,1H),3.52–3.45(m,2H),3.25–3.19(m,1H),2.24–2.15(m,1H),1.95–1.86(m,1H),1.39(s,9H)。
Step 3 Synthesis of (R) -4- (3-aminopyrrolidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrochloride
Reacting (R) - (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) pyrrolidin-3-yl) carbamic acid tert-butyl ester (190mg,0.466mmol) was added to a solution of hydrogen chloride in methanol (3.0M,10.0 mL). The reaction mixture was stirred at room temperature for 16 hours. Mixing the reactionThe mixture was concentrated under reduced pressure to give the title compound (160mg, yield 99.9%, yellow solid). LC-MS (ESI) M/z 308.2[ M + H ]]+。
Step 4 Synthesis of (R) -N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyrrolidin-3-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide
To (R) -4- (3-aminopyrrolidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] at room temperature]Pyridine-3-carbonitrile hydrochloride (90.0mg,0.262mmol) and 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetic acid (69.5mg,0.314mmol) in DMF (2.00mL) were added EDCI (75.3mg,0.393mmol), HOBt (53.1mg,0.393mmol) and DIEA (67.7mg,0.524 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (15.0mL) and extracted with EA (80.0 mL). The organic phase was washed with saturated brine (15.0 mL. times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) gave the title compound (55.0mg, yield 41.4%, white solid). LC-MS (ESI) M/z 511.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.79–8.78(m,1H),8.67–8.65(m,1H),8.57(s,1H),8.52(d,J=6.7Hz,1H),8.36(s,1H),8.33–8.31(m,1H),8.06(s,1H),7.92–7.90(m,1H),7.89–7.83(m,2H),7.03(s,1H),4.43–4.36(m,1H),3.87(s,3H),3.71–3.65(m,1H),3.64–3.57(m,1H),3.53(s,2H),3.46–3.39(m,1H),3.31–3.28(m,1H),2.34–2.24(m,1H),1.98–1.90(m,1H)。
Example 10:(R) -N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridine-4- Synthesis of Yl) pyrrolidin-3-yl) -2- (4-methoxyphenyl) acetamide (Compound 10)
To (R) -4- (3-aminopyrrolidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] at room temperature]Pyridine-3-carbonitrile hydrochloride (90.0mg,0.262mmol) and 2- (4-methoxyphenyl) acetic acid (52.2mg,0.314mmol) in DMF (2.00mL) were added EDCI (75.3mg,0.393mmol) with,HOBt (53.1mg,0.393mmol) and DIEA (67.7mg,0.524 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (15.0mL) and extracted with EA (80.0 mL). The organic phase was washed with saturated brine (15.0 mL. times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. Purification by preparative HPLC (acetonitrile/water containing 0.05% formic acid) gave the title compound (68.3mg, yield 57.1%, white solid). LC-MS (ESI) M/z 456.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.79–8.77(m,1H),8.57(s,1H),8.37–8.33(m,2H),8.06(s,1H),7.15(d,J=8.6Hz,2H),7.02(s,1H),6.83(d,J=8.6Hz,2H),4.40–4.32(m,1H),3.87(s,3H),3.73–3.67(m,1H),3.71(s,3H),3.64–3.57(m,1H),3.47–3.39(m,1H),3.34(s,2H),3.28–3.24(m,1H),2.31–2.20(m,1H),1.97–1.87(m,1H)。
Example 11:(R) -N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridine-4- Process for producing yl) pyrrolidin-3-yl) -2- (6-methoxypyridin-3-yl) acetamide (Compound 11) and its hydrochloride (Compound 11-1) Synthesis of
Step 1 preparation of (R) -N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyrrolidin-3-yl) -2- (6-methoxypyridin-3-yl) acetamide hydrochloride
To (R) -4- (3-aminopyrrolidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile hydrochloride (120mg,0.349mmol) and 2- (6-methoxypyridin-3-yl) acetic acid (58.3mg,0.349mmol) in DMF (2.00mL) were added EDCI (100mg,0.524mmol), HOBt (70.7mg,0.524mmol) and DIEA (67.6mg,0.524 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (15.0mL) and extracted with EA (100 mL). The organic phase was washed with saturated brine (15.0 mL. times.3), dried over anhydrous sodium sulfate, and filtered. Concentration under reduced pressure gave the crude product (compound 11). Purification by preparative HPLC (acetonitrile/water containing 0.05% hydrochloric acid) gave the title compound (Compound 11-1) as a hydrochloride salt (77.3mg, yield 44.9%, yellow solid)。LC-MS(ESI)m/z 457.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.79(s,1H),8.57(s,1H),8.49(d,J=6.6Hz,1H),8.37(s,1H),8.06(s,1H),8.05–8.01(m,1H),7.67–7.63(m,1H),7.03(s,1H),6.80(d,J=8.5Hz,1H),4.41–4.34(m,1H),3.88(s,3H),3.84(s,3H),3.71–3.66(m,1H),3.63–3.56(m,1H),3.47–3.42(m,1H),3.40(s,2H),3.30–3.25(m,1H),2.31–2.22(m,1H),1.97–1.88(m,1H)。
Example 12:(R) -N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridine-4- Synthesis of yl) pyrrolidin-3-yl) -2- (4- (methylsulfonyl) phenyl) acetamide (Compound 12)
Step 1 preparation of (R) -N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyrrolidin-3-yl) -2- (4- (methylsulfonyl) phenyl) acetamide
To (R) -4- (3-aminopyrrolidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] at room temperature]Pyridine-3-carbonitrile hydrochloride (80.0mg,0.237mmol) and 2- (4- (methylsulfonyl) phenyl) acetic acid (64.8mg,0.302mmol) in DMF (2.00mL) were added EDCI (66.7mg,0.349mmol), HOBt (47.2mg,0.349mmol) and DIEA (60.1mg,0.465 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (15.0mL) and extracted with EA (50.0 mL. times.2). The combined organic phases were washed with saturated brine (15.0 mL. times.3), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% ammonia) gave the title compound (26.1mg, yield 22.3%, off-white solid). LC-MS (ESI) M/z 504.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.80–8.78(m,1H),8.57(s,1H),8.53(d,J=6.5Hz,1H),8.36(s,1H),8.06(s,1H),7.87–7.82(m,2H),7.54–7.50(m,2H),7.03(s,1H),4.40–4.35(m,1H),3.87(s,3H),3.72–3.66(m,1H),3.63–3.59(m,1H),3.59-3.55(m,2H),3.44–3.40(m,1H),3.29–3.26(m,1H),3.19(s,3H),2.31–2.25(m,1H),1.96–1.90(m,1H)。
Example 13:(S) -N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridine-4- Synthesis of yl) pyrrolidin-3-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide (Compound 13)
Step 1 preparation of tert-butyl (S) - (1- (6-bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl) pyrrolidin-3-yl) carbamate
To 6-bromo-4-fluoropyrazolo [1,5-a ]]Pyridine-3-carbonitrile (300mg,1.25mmol) and tert-butyl (S) -pyrrolidin-3-ylcarbamate (256mg,1.37mmol) in N-methylpyrrolidinone (2.50mL) was added potassium carbonate (346mg,2.50 mmol). The reaction mixture was stirred at 100 ℃ for 6 hours. The reaction mixture was cooled to room temperature, poured into water (15.0mL), and extracted with EA (60.0 mL). The organic phase was separated, washed with saturated brine (15.0 mL. times.3), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (PE: EA 50:1-10:1) gave the title compound (255mg, yield 50.2%, white solid). LC-MS (ESI) M/z 406.1, 408.1[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.75(d,J=1.3Hz,1H),8.60(s,1H),7.20(d,J=6.4Hz,1H),6.81(d,J=1.2Hz,1H),4.18–4.09(m,1H),3.79–3.72(m,1H),3.53–3.43(m,2H),3.30–3.25(m,1H),2.20–2.11(m,1H),1.95–1.86(m,1H),1.39(s,9H)。
Step 2 preparation of tert-butyl (S) - (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyrrolidin-3-yl) carbamate
To (S) - (1- (6-bromo-3-cyanopyrazolo [1, 5-a)]Pyridin-4-yl) pyrrolidin-3-yl) carbamic acid tert-butyl ester (255mg,0.628mmol) and 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (144mg,0.690mmol) in water (0.800mL) and 1, 4-dioxane (4.00mL) sodium carbonate (133mg,1.26mmol) and Pd (dppf) Cl were added to a solution of sodium carbonate (133mg,1.26mmol) and Pd (dppf) Cl2DCM (27.0mg,0.031 mmol). The reaction mixture was stirred at 100 ℃ for 8 hours under nitrogen. After cooling the reaction mixture to room temperaturePour into EA (60.0mL) to give a black solution. The solution was dried over anhydrous sodium sulfate and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (PE: EA ═ 3:1-1:1) gave the title compound (190mg, yield 74.2%, light green solid). LC-MS (ESI) M/z 408.3[ M + H ]]+。
Step 3 preparation of (S) -4- (3-aminopyrrolidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrochloride
(S) - (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) pyrrolidin-3-yl) carbamic acid tert-butyl ester (190mg,0.466mmol) in methanolic hydrogen chloride (3.0M,10.0mL) was stirred for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure to give the objective compound (150mg, yield 93.6%, yellow solid). LC-MS (ESI) M/z 308.3[ M + H ]]+。
Step 4 preparation of (S) -N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyrrolidin-3-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide
To (S) -4- (3-aminopyrrolidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] at room temperature]Pyridine-3-carbonitrile hydrochloride (60.0mg,0.175mmol) and 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetic acid (46.3mg,0.209mmol) in DMF (1.50mL) were added EDCI (50.2mg,0.262mmol), HOBt (35.4mg,0.262mmol) and DIEA (45.1mg,0.349 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (10.0mL) and extracted with EA (20.0 mL. times.3). The combined organic phases were washed with saturated brine (10.0 mL. times.2), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by preparative (acetonitrile/water containing 0.05% formic acid) gave the title compound (20.9mg, yield 21.6%, white solid). LC-MS (ESI) M/z 511.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),8.66(d,J=4.5Hz,1H),8.57(s,1H),8.53(d,J=6.6Hz,1H),8.36(s,1H),8.34-8.31(m,1H),8.06(s,1H),7.91(d,J=4.2Hz,1H),7.88–7.83(m,2H),7.03(s,1H),4.43–4.37(m,1H),3.87(s,3H),3.71–3.65(m,1H),3.63–3.57(m,1H),3.53(s,2H),3.44–3.40(m,1H),2.34–2.24(m,2H),1.97–1.91(m,1H)。
Example 14:(S) -N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridine-4- Synthesis of Yl) pyrrolidin-3-yl) -2- (4-methoxyphenyl) acetamide (Compound 14)
Step 1 preparation of (S) -N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyrrolidin-3-yl) -2- (4-methoxyphenyl) acetamide
To (S) -4- (3-aminopyrrolidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] at room temperature]Pyridine-3-carbonitrile hydrochloride (60mg,0.175mmol) and 2- (4-methoxyphenyl) acetic acid (34.8mg,0.209mmol) in DMF (1.50mL) were added EDCI (50.2mg,0.262mmol), HOBt (35.4mg,0.262mmol) and DIEA (45.1mg,0.349 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (10.0mL) and extracted with EA (10.0 mL. times.3). The combined organic phases were washed with saturated brine (10.0 mL. times.2), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) gave the title compound (37.29mg, yield 46.9%, white solid). LC-MS (ESI) M/z 456.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),8.57(s,1H),8.38–8.33(m,2H),8.06(s,1H),7.15(d,J=8.5Hz,2H),7.02(s,1H),6.83(d,J=8.5Hz,2H),4.41–4.32(m,1H),3.87(s,3H),3.73–3.67(m,1H),3.71(s,3H),3.64–3.56(m,1H),3.46–3.40(m,1H),3.34(s,2H),3.28–3.24(m,1H),2.30–2.21(m,1H),1.97–1.87(m,1H)。
Example 15:n- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) Synthesis of azetidin-3-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide (Compound 15)
Step 1 Synthesis of tert-butyl (1- (6-bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl) azetidin-3-yl) carbamate
To 6-bromo-4-fluoropyrazolo [1,5-a ]]Pyridine-3-carbonitrile (1.20g,5.00mmol) and t-butyl azetidin-3-ylcarbamate (1.03g,6.00mmol) in N-methylpyrrolidinone (6.00mL) were added DIEA (2.48mL,15.0 mmol). The tube is sealed, and the reaction mixture is stirred and reacted for 36 hours at the temperature of 100 ℃. The reaction mixture was cooled to room temperature and slowly poured into ice water (10.0mL) to gradually precipitate a gray solid. Filtration was carried out, and the filter cake was washed with water (2.00 mL. times.2) and PE (2.00 mL. times.2) in this order, and dried under reduced pressure to give the objective compound (1.70g, crude product, gray solid). LC-MS (ESI) M/z 392.1,394.1[ M + H ]]+. Step 2 (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Synthesis of pyridin-4-yl) azetidin-3-yl) carbamic acid tert-butyl ester
To (1- (6-bromo-3-cyanopyrazolo [1,5-a ]]Pyridin-4-yl) azetidin-3-yl) carbamic acid tert-butyl ester (1.70g,4.33mmol) and 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.35g,6.50mmol) in water (2.00mL) and 1, 4-dioxane (8.00mL) was added potassium carbonate (1.20g,8.66mmol) and Pd (dppf) Cl2DCM (354mg,0.433 mmol). The tube was sealed and argon was replaced 3 times. The reaction mixture was stirred at 100 ℃ for 2 hours. And cooling the reaction liquid to room temperature, separating an organic phase, and concentrating under reduced pressure to obtain a crude product. Column chromatography (100% EA) separation and purification gave the title compound (1.35g, 68.6% yield in two steps, yellow solid). LC-MS (ESI) M/z 394.0[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.76–8.73(m,1H),8.56(s,1H),8.36(s,1H),8.06(s,1H),7.63–7.58(m,1H),6.75(s,1H),4.48–4.40(m,3H),3.99–3.93(m,2H),3.88(s,3H),1.40(s,9H)。
Step 3 Synthesis of 4- (3-Aminoazetidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Reacting (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) azetidin-3-yl) carbamic acid tert-butyl ester (200mg,0.508mmol) was added to trifluoroacetic acid (1.00 mL). The reaction mixture was stirred at room temperature for 1 hour. Subjecting the reaction mixture to an ice-water bathAfter cooling, the pH was adjusted to 9 with a saturated aqueous sodium bicarbonate solution, and dimethyl sulfoxide (5.00mL) was added. Filtration and liquid phase preparation of the filtrate (acetonitrile/water with 0.05% formic acid) gave the title compound (58.0mg, yield 38.9%, light yellow solid). LC-MS (ESI) M/z 294.4[ M + H ]]+。1H NMR(400MHz,DMSO)δ8.73(d,J=0.9Hz,1H),8.55(s,1H),8.36(s,1H),8.27(s,2H),8.06(s,1H),6.73(s,1H),4.42(t,J=7.4Hz,2H),3.94–3.89(m,1H),3.88(s,3H),3.84–3.78(m,2H)。
Step 4 Synthesis of N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) azetidin-3-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide
Reacting 4- (3-amino azetidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (58.0mg,0.198mmol), 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetic acid (43.7mg,0.198mmol), HOBt (40.1mg,0.297mmol), EDCI (75.9mg,0.396mmol), and DIEA (76.7mg,0.594mmol) were sequentially added to DMF (2.00 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (10.0mL) and extracted with EA (15.0 mL. times.2). The combined organic phases were washed with water (10.0mL) and saturated brine (10.0mL), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) gave the title compound (18.1mg, yield 18.4%, off-white solid). LC-MS (ESI) M/z 497.1[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.90(d,J=6.7Hz,1H),8.76(d,J=0.8Hz,1H),8.67(d,J=4.1Hz,1H),8.57(s,1H),8.36(s,1H),8.35–8.34(m,1H),8.07(s,1H),7.93–7.90(m,1H),7.90–7.85(m,2H),6.79(s,1H),4.67–4.58(m,1H),4.50(t,J=7.9Hz,2H),4.06–3.99(m,2H),3.87(s,3H),3.57(s,2H)。
Example 16:n- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) Synthesis of azetidin-3-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) propanamide (Compound 16)
Step 1 preparation of N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) azetidin-3-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) propionamide
4- (3-Aminoazetidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] at room temperature]Pyridine-3-carbonitrile formate (45.0mg,0.133mmol) and 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) propionic acid (37.4mg,0.159mmol) in DMF (2.00mL) were added EDCI (38.1mg,0.199mmol), HOBt (26.9mg,0.199mmol) and DIEA (34.2mg,0.265 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (15.0mL) and extracted with EA (80.0 mL). The organic phase was washed with saturated brine (15.0 mL. times.3), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) gave the title compound (15.2mg, yield 22.5%, off-white solid). LC-MS (ESI) M/z 511.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.84(d,J=6.5Hz,1H),8.75(s,1H),8.66(d,J=4.2Hz,1H),8.56(s,1H),8.41–8.37(m,1H),8.35(s,1H),8.06(s,1H),7.96–7.86(m,3H),6.77(s,1H),4.65–4.58(m,1H),4.54–4.48(m,1H),4.46–4.41(m,1H),4.05–4.00(m,1H),3.96–3.90(m,1H),3.87(s,3H),3.78–3.71(m,1H),1.41(d,J=6.9Hz,3H)。
Example 17:n- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) Synthesis of azetidin-3-yl) -2- (4-methoxyphenyl) acetamide (Compound 17)
Step 1 preparation of N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) azetidin-3-yl) -2- (4-methoxyphenyl) acetamide
To 4- (3-aminoazetidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] at room temperature]Pyridine-3-carbonitrile formate (45.0mg,0.133mmol) and 2- (4-methoxyphenyl) acetic acid (26.4mg,0.15 mmol)9mmol) in DMF (2.00mL) was added EDCI (38.1mg,0.199mmol), HOBt (26.9mg,0.199mmol) and DIEA (34.2mg,0.266 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (15.0mL) and extracted with EA (80.0 mL). The organic phase was washed with saturated brine (15.0 mL. times.3), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) gave the title compound (16.6mg, yield 28.3%, white solid). LC-MS (ESI) M/z 442.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.76–8.72(m,2H),8.56(s,1H),8.36(s,1H),8.07(s,1H),7.18(d,J=8.8Hz,2H),6.86(d,J=8.8Hz,2H),6.78(s,1H),4.64–4.57(m,1H),4.51–4.45(m,2H),4.02–3.97(m,2H),3.87(s,3H),3.72(s,3H),3.37(s,2H)。
Example 18:n- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) Synthesis of azetidin-3-yl) -2- (6-methoxypyridin-3-yl) acetamide (Compound 18)
Step 1: preparation of N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) azetidin-3-yl) -2- (6-methoxypyridin-3-yl) acetamide
To 4- (3-aminoazetidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] at room temperature]Pyridine-3-carbonitrile formate (84mg,0.248mmol) and 2- (6-methoxypyridin-3-yl) acetic acid (62.1mg,0.371mmol) in DMF (3.0mL) were added HATU (141.2mg,0.371mmol) and DIEA (0.18mL,0.990 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was directly purified by preparative HPLC (acetonitrile/water containing 0.05% formic acid) to give the title compound (50.0mg, yield 45.7%, white solid). LC-MS (ESI) M/z 443.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.81(d,J=6.7Hz,1H),8.75(d,J=0.9Hz,1H),8.56(s,1H),8.36(s,1H),8.07(s,1H),8.02(d,J=2.1Hz,1H),7.60(dd,J=8.5,2.4Hz,1H),6.79–6.74(m,2H),4.60(m,1H),4.48(t,J=7.8Hz,2H),4.00(m,2H),3.87(s,3H),3.82(s,3H),3.40(s,2H)。
Example 19:n- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) Synthesis of azetidin-3-yl) -2- (6-methoxypyridin-3-yl) propanamide (Compound 19)
Step 1: preparation of dimethyl 2- (6-methoxypyridin-3-yl) malonate
To a solution of 5-bromo-2-methoxypyridine (2.13mL,16.5mmol), dimethyl malonate (3.76mL,32.9mmol), and cuprous bromide (4.72g,32.9mmol) in 1, 4-dioxane (20.0mL) was slowly added sodium hydride (1.45g,36.2mmol) at room temperature. The reaction mixture was stirred at 100 ℃ overnight under nitrogen. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give a brown oil. Purification by column chromatography (PE: EA ═ 10:1-2:1) gave the title compound (490mg, yield 12.8%, light yellow solid). LC-MS (ESI) M/z 240.3[ M + H ]]+。
Step 2: preparation of dimethyl 2- (6-methoxypyridin-3-yl) -2-methylmalonate
To a solution of dimethyl 2- (6-methoxypyridin-3-yl) malonate (450mg,1.88mmol) in DMF (5.00mL) under ice bath was slowly added sodium hydride (150mg,3.76 mmol). After the reaction mixture was stirred at 0 ℃ for 30 minutes, methyl iodide (401mg,2.83mmol) was added. The reaction mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was quenched with ice water (5.00mL) and extracted with EA (10.0 mL. times.2). The combined organic phases were washed with saturated brine (5.00 mL. times.3), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (PE: EA ═ 10:1-3:1) gave the title compound (300mg, yield 63.0%, yellow oil). LC-MS (ESI) M/z 254.3[ M + H ]]+。
And step 3: preparation of 2- (6-methoxypyridin-3-yl) propionic acid
To dimethyl 2- (6-methoxypyridin-3-yl) -2-methylmalonate (250mg,0.987mmol) in tetrahydroTo a solution of furan (4.00mL) was added aqueous sodium hydroxide (1M,3.95mL,3.95 mmol). The reaction mixture was stirred at 50 ℃ for 8 hours. After the reaction solution was cooled to room temperature, the pH was adjusted to 6 with dilute hydrochloric acid (1M,4.50 mL). Extraction was carried out with EA (10.0 mL. times.2). The combined organic phases were washed with saturated brine (5.00 mL. times.2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the objective compound (90.0mg, yield 50.3%, white solid). LC-MS (ESI) M/z 182.1[ M + H ]]+。
And 4, step 4: preparation of N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) azetidin-3-yl) -2- (6-methoxypyridin-3-yl) propionamide formate salt
To 4- (3-aminoazetidin-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile formate (100mg,0.296mmol) in DMF (3.00mL) was added DIEA (84.2mg,0.652 mmol). After the reaction mixture was stirred at room temperature for 10 minutes, 2- (6-methoxypyridin-3-yl) propionic acid (53.6mg,0.296mmol), EDCI (93.6mg,0.488mmol) and HOBt (66.0mg,0.488mmol) were added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water (10.0mL) and extracted with EA (15.0 mL. times.3). The combined organic phases were washed with saturated brine (10.0 mL. times.2), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) gave the title compound (18.2mg, yield 12.2%, white solid). LC-MS (ESI) M/z 457.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ8.76–8.71(m,2H),8.56(s,1H),8.36(s,1H),8.08–8.04(m,2H),7.67–7.62(m,1H),6.79–6.74(m,2H),4.62–4.57(m,1H),4.53–4.47(m,1H),4.45–4.40(m,1H),4.04–3.99(m,1H),3.94–3.89(m,1H),3.87(s,3H),3.81(s,3H),3.63–3.56(m,1H),1.33(d,J=7.1Hz,3H)。
Example 20:n- (1- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1, 5-a)]Pyridin-4-yl) - Synthesis of 1H-pyrazol-4-yl) -2- (6-methoxypyridin-3-yl) acetamide (Compound 20)
Step 1 preparation of tert-butyl (1H-pyrazol-4-yl) carbamate
To a solution of 1H-pyrazol-4-amine (1.58g,19.0mmol) and sodium bicarbonate (3.19g,38.0mmol) in water (2.00mL) and tetrahydrofuran (20.0mL) was added di-tert-butyl dicarbonate (4.57g,20.9 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (50.0mL) and extracted with EA (100 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (PE: EA ═ 3:1-1: 2) gave the title compound (3.20g, yield 91.8%, off-white solid). LC-MS (ESI) M/z 184.1[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),9.06(s,1H),7.58(s,1H),7.34(s,1H),1.44(s,9H)。
Step 2 preparation of tert-butyl (1- (6-bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl) -1H-pyrazol-4-yl) carbamate
To 6-bromo-4-fluoropyrazolo [1,5-a ]]Pyridine-3-carbonitrile (1.50g,6.25mmol) and tert-butyl (1H-pyrazol-4-yl) carbamate (1.26g,6.87mmol) in N-methylpyrrolidinone (10.0mL) was added potassium carbonate (1.73g,12.5 mmol). The reaction mixture was stirred at 100 ℃ for 16 hours. The reaction mixture was cooled to room temperature and poured into water (30.0 mL). Extract with EA (200 mL). The organic phase was washed with saturated brine (20.0 mL. times.3), dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (PE: EA ═ 5:1-3:1) gave the title compound (1.40g, yield 55.6%, light yellow solid). LC-MS (ESI) M/z 403.0,405.0[ M + H ]]+。1H NMR(400MHz,DMSO-d6) δ 9.55(s,1H), 9.41-9.36 (m,1H),8.74(s,1H),8.30(s,1H),8.02(s,1H),7.72(s,1H),1.48(s, 9H). Step 3 (1- (3-cyano-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1, 5-a)]Preparation of pyridin-4-yl) -1H-pyrazol-4-yl) carbamic acid tert-butyl ester
To (1- (6-bromo-3-cyanopyrazolo [1,5-a ]]Pyridin-4-yl) -1H-pyrazol-4-yl) carbamic acid tert-butyl ester (1.40g,3.47mmol) and pinacol diboron (4.41g,17.4mmol) in dry 1, 4-dioxane (25.0mL) was added potassium acetate (681mg,6.94mmol) andPd(dppf)Cl2DCM (150mg,0.174 mmol). The reaction mixture was stirred at 90 ℃ for 16 hours under argon. The reaction mixture was cooled to room temperature and poured into EA (50.0 mL). Filtration and washing of the filter cake with EA (20.0 mL). The filtrate was concentrated under reduced pressure to give the title compound (7.00g, crude, black solid). LC-MS (ESI) M/z 369.1[ M-82+ H]+。
Step 4 preparation of tert-butyl (1- (3-cyano-6-hydroxypyrazolo [1,5-a ] pyridin-4-yl) -1H-pyrazol-4-yl) carbamate
To (1- (3-cyano-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] at 0 DEG C]To a solution of tert-butyl pyridin-4-yl) -1H-pyrazol-4-yl) carbamate (7.00g,15.5mmol) in tetrahydrofuran (200mL) was added sodium hydroxide (2.49g,62.2 mmol). Then 30% aqueous hydrogen peroxide (12.7mL,124mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added a saturated ammonium chloride (100mL) solution, followed by stirring at room temperature for 30 minutes. The organic phase was separated off and the aqueous phase was extracted with EA (100 mL. times.2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a crude product. Purification by column chromatography (PE: EA ═ 3:1-1:1) gave the title compound (400mg, 33.8% yield in two steps, yellow solid). LC-MS (ESI) M/z 341.2[ M + H ]]+。
Step 5 preparation of tert-butyl (1- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a ] pyridin-4-yl) -1H-pyrazol-4-yl) carbamate
To (1- (3-cyano-6-hydroxypyrazolo [1,5-a ]]To a solution of tert-butyl pyridin-4-yl) -1H-pyrazol-4-yl) carbamate (400mg,1.18mmol) in tetrahydrofuran (6.00mL) was added sodium hydroxide (2.0N,1.18mL,2.35 mmol). The reaction mixture was stirred at room temperature for 15 minutes and 2, 2-dimethyloxirane (1.05mL,11.8mmol) was added. The reaction mixture was stirred at 80 ℃ for 16 hours under sealed conditions. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a crude product. Purification by column chromatography (PE: EA ═ 2:1-1:5) gave the title compound (200mg, yield 41.2%, yellow solid). LC-MS (ESI) M/z 413.3[ M + H ]]+。
Step 6 preparation of 4- (4-amino-1H-pyrazol-1-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrochloride
(1- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1, 5-a)]Pyridin-4-yl) -1H-pyrazol-4-yl) carbamic acid tert-butyl ester (200mg,0.485mmol) in methanol hydrogen chloride (3.0M,10.0mL) was reacted with stirring at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give the objective compound (160mg, yield 94.5%, yellow solid). LC-MS (ESI) M/z 313.2[ M + H ]]+。
Step 7 preparation of N- (1- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a ] pyridin-4-yl) -1H-pyrazol-4-yl) -2- (6-methoxypyridin-3-yl) acetamide
To 4- (4-amino-1H-pyrazol-1-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a]Pyridine-3-carbonitrile hydrochloride (80.0mg,0.229mmol) and 2- (6-methoxypyridin-3-yl) acetic acid (42.2mg,0.252mmol) in DMF (2.00mL) were added EDCI (65.9mg,0.344mmol), HOBt (46.5mg,0.344mmol) and DIEA (59.3mg,0.459 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (15.0mL) and extracted with EA (100 mL). The organic phase was washed with saturated brine (15.0 mL. times.3), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by preparative (acetonitrile/water with 0.05% formic acid) gave the title compound (18.6mg, yield 17.6%, off-white solid). LC-MS (ESI) M/z 462.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.74(d,J=1.9Hz,1H),8.62(s,1H),8.48(s,1H),8.09(d,J=2.1Hz,1H),7.86(s,1H),7.68–7.64(m,1H),7.62(d,J=1.9Hz,1H),6.79(d,J=8.5Hz,1H),4.70(s,1H),3.89(s,2H),3.83(s,3H),3.61(s,2H),1.22(s,6H)。
Example 21:n- (1- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1, 5-a)]Pyridin-4-yl) - 1H-pyrazol-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide (compound 21) and hydrochloride thereof (compound formula) Synthesis of Compound 21-1)
Step 1 preparation of N- (1- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a ] pyridin-4-yl) -1H-pyrazol-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide hydrochloride
To 4- (4-amino-1H-pyrazol-1-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a]Pyridine-3-carbonitrile hydrochloride (80.0mg,0.229mmol) and 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetic acid (60.9mg,0.275mmol) in DMF (2.00mL) were added EDCI (65.9mg,0.344mmol), HOBt (46.5mg,0.344mmol) and DIEA (59.3mg,0.459 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (15.0mL) and extracted with EA (100 mL). The organic phase was washed with saturated brine (15.0 mL. times.3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude product (compound 21). Purification by preparative HPLC (acetonitrile/water containing 0.05% hydrochloric acid) gave the target compound (compound 21-1) as a hydrochloride salt (20.8mg, yield 16.4%, yellow solid). LC-MS (ESI) M/z 516.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.75(d,J=1.9Hz,1H),8.70–8.68(m,1H),8.62(s,1H),8.50(s,1H),8.41(d,J=1.7Hz,1H),7.98–7.94(m,1H),7.93–7.88(m,2H),7.88(s,1H),7.63(d,J=1.9Hz,1H),3.89(s,2H),3.78(s,2H),1.22(s,6H)。
Example 22:n- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) - Synthesis of 1H-pyrazol-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide (Compound 22)
Step 1 preparation of tert-butyl (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) -1H-pyrazol-4-yl) carbamate
To (1- (6-bromo-3-cyanopyrazolo [1,5-a ]]Pyridin-4-yl) -1H-pyrazol-4-yl) carbamic acid tert-butyl ester (190mg,0.470mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (118mg,0.570mmol), potassium carbonate (130mg,0.940mmol) in water (1.00mL) and 1, 4-dioxane (5.00mL)Adding Pd (dppf) Cl into the solution2DCM (38.4mg,0.047 mmol). The reaction mixture was stirred at 90 ℃ for 16 hours under nitrogen. The reaction mixture was cooled to room temperature, poured into EA (40.0mL), washed with saturated brine (10.0mL), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by column chromatography (PE: EA ═ 10:1-1:1) gave the title compound (130mg, yield 68.4%, yellow solid). LC-MS (ESI) M/z 405.2[ M + H ]]+。
Step 2 preparation of 4- (4-amino-1H-pyrazol-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrochloride
(1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) -1H-pyrazol-4-yl) carbamic acid tert-butyl ester (101mg,0.250mmol) in HCl/EA (3.0M,8.00mL) was stirred at room temperature for reaction for 13 hours. The reaction mixture was concentrated under reduced pressure to give the objective compound (84.0mg, yield 98.8%, white solid). LC-MS (ESI) M/z 305.2[ M + H ]]+。
Step 3 preparation of N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) -1H-pyrazol-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetamide
To 4- (4-amino-1H-pyrazol-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile hydrochloride (100mg,0.293mmol), 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetic acid (77.9mg,0.352mmol), EDCI (84.4mg,0.440mmol) and HOBt (59.5mg,0.440mmol) in DMF (5.00mL) was added DIEA (189mg,1.46 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (15.0mL) and extracted with EA (30.0X 2 mL). The combined organic phases were washed with saturated brine (15.0mL), dried over anhydrous sodium sulfate, and filtered. And concentrating the filtrate under reduced pressure to obtain a crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) gave the title compound (35.0mg, yield 21.6%, white solid). LC-MS (ESI) M/z 508.3[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),9.30(s,1H),8.73–8.65(m,2H),8.57(s,1H),8.45–8.40(m,2H),8.16(s,1H),8.04(s,1H),7.99–7.95(m,1H),7.94–7.86(m,3H),3.88(s,3H),3.79(s,2H)。
Example 23:n- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) - Synthesis of 1H-pyrazol-4-yl) -2- (6-methoxypyridin-3-yl) acetamide (Compound 23)
Step 1 preparation of N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) -1H-pyrazol-4-yl) -2- (6-methoxypyridin-3-yl) acetamide
To 4- (4-amino-1H-pyrazol-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile hydrochloride (65.0mg,0.191mmol) and 2- (6-methoxypyridin-3-yl) acetic acid (38.3mg,0.229mmol) in DMF (2.00mL) were added EDCI (54.8mg,0.286mmol), HOBt (38.6mg,0.286mmol) and DIEA (49.3mg,0.381 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (15.0mL) and extracted with EA (80.0 mL). The organic phase was washed with saturated brine (15.0 mL. times.3), dried over anhydrous sodium sulfate, and filtered. Concentrating the filtrate under reduced pressure to obtain a crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) gave the title compound (26.5mg, yield 30.6%, white solid). LC-MS (ESI) M/z 454.1[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.30(d,J=1.2Hz,1H),8.69(s,1H),8.55(s,1H),8.43(s,1H),8.16(s,1H),8.12–8.09(m,1H),8.05–8.02(m,1H),7.86(s,1H),7.67(dd,J=8.5Hz,2.4Hz,1H),6.80(d,J=8.5Hz,1H),3.88(s,3H),3.83(s,3H),3.62(s,2H)。
Example 24:n- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1, 5-a)]Pyridin-4-yl) - 1H-pyrazol-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) propanamide (Compound 24) and hydrochloride salt thereof Synthesis of Compound 24-1)
Step 1 preparation of N- (1- (3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) -1H-pyrazol-4-yl) -2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) propionamide hydrochloride
To 4- (4-amino-1H-pyrazol-1-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile hydrochloride (65.0mg,0.191mmol) and 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) propionic acid (53.8mg,0.229mmol) in DMF (2.00mL) were added EDCI (54.8mg,0.286mmol), HOBt (38.6mg,0.286mmol) and DIEA (49.3mg,0.381 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (20.0mL) and extracted with EA (100 mL). The organic phase was washed with saturated brine (15.0 mL. times.3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude product (compound 24). Purification by preparative HPLC (acetonitrile/water containing 0.05% hydrochloric acid) gave the title compound (compound 24-1) as the hydrochloride salt (60.1mg, yield 56.5%, yellow solid). LC-MS (ESI) M/z 522.2[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),9.30(d,J=1.2Hz,1H),8.70–8.66(m,2H),8.58(s,1H),8.48(d,J=2.1Hz,1H),8.43(s,1H),8.16(s,1H),8.05(d,J=1.2Hz,1H),8.03–7.99(m,1H),7.94–7.89(m,2H),7.86(s,1H),3.98(q,J=7.0Hz,1H),3.88(s,3H),1.51(d,J=7.0Hz,3H)。
Active examples
Unless otherwise indicated, the experimental materials, reagents, procedures and methods used in the following active examples are all commercially available or readily known or prepared based on the prior art.
Active example 1: kinase RET inhibition assay
Kinase RET inhibition assays were performed using methods similar to those described in the literature (Vivek. sub. J.F.G., Precision Targeted Therapy with BLU-667for RET-drive cancer. cancer Discov,2018.8(7): 836-849). The inhibition effect of the compound on the kinase RET is detected by using a Caliper Mobility Shift Assay method, the test final concentration of the compound is started from 1000nM, the compound is serially diluted by 3 times, the total concentration is 10, and the compound is detected by multiple wells.
Test compounds were dissolved in 100% DMSO (Sigma, D8418-1L, SHBG3288V) to prepare 10mM stock solutions, which were stored under nitrogen in the dark. Prepare 1 × Kinase buffer, and prepare compound concentration gradient as follows: the test compound was initially diluted to 1000nM in a 384-well plate (Corning,3573,12619003) with 3-fold serial dilutions of DMSO at 10 concentrations, and the test was repeated at final concentrations of 1000, 333, 111, 37, 12.3, 4.12, 1.37, 0.457, 0.152, 0.0508nM, then 250nl was transferred to 384 reaction plates with Echo550(Labcyte, model: Echo 550) for use, and 250nl of 100% DMSO was added to each of the negative control wells and the positive control wells. A Kinase solution of RET (Carna, cat # 08-159, lot # 13CBS-0134E) was prepared at 2.5 fold final concentration (1 nM) using 1 XKinase buffer. 10 μ L of 2.5 fold final concentration kinase solution was added to each of the compound wells and the positive control wells; add 10. mu.L of 1 XKinase buffer to the negative control wells.
The reaction plate was centrifuged at 1000rpm (Eppendorf, type 5430) for 30 seconds, shaken well and incubated at room temperature for 10 minutes. A mixed solution of 25-fold final concentration (final concentration of 16. mu.M) of ATP and 15-fold final concentration (final concentration of 3. mu.M) of Kinase substrate 2(GL, cat. No. 112394, run No. P171207-MJ112394) was prepared using 1 XKinase buffer, and 15. mu.L of this mixed solution was added to each well to start the reaction. The 384 well plates were centrifuged at 1000rpm for 30 seconds, shaken well and incubated for 60 minutes at room temperature. Add 30. mu.L of EDTA-containing termination detection solution to stop the kinase reaction, centrifuge at 1000rpm for 30 seconds, shake and mix. The conversion was read with a microplate Reader (Perkin Elmer, model: Caliper EZ Reader II).
The following formula is used for calculation:
% inhibition [ (% conversion. max. -% conversion. sample)/(% conversion. sample. -% conversion. min.). 100 [% ]
Wherein: "percent conversion _ sample" is the conversion reading for the sample; "percent conversion _ min" is the negative control well mean, representing the conversion reading for wells without enzyme activity; "percent conversion _ max" is the mean of the positive control wells and represents the conversion reading for wells without compound inhibition.
The log value of the concentration is taken as an X axis, the percentage inhibition rate is taken as a Y axis, a dose-effect curve is fitted by using the log (inhibitor) vs. the response-Variable slope of the analytic software GraphPad Prism 5,
calculating the formula: y ═ Bottom + (Top-Bottom)/(1+10^ ((Logic50-X) > HillSlope))
Thus, the IC of each compound for the enzyme activity was obtained50The value is obtained.
TABLE 1RET kinase assay results
Active example 2: cell proliferation assay
The cell proliferation inhibition effect of the compound of the invention was tested by using CellTiter-GloTM live cell assay kit. The kit adopts luciferase as a detection object, the luciferase needs the participation of ATP in the luminescence process, CellTiter-GloTM reagent is added into a cell culture medium, the luminescence value is measured, the light signal is in direct proportion to the ATP amount in the system, and the ATP is in positive correlation with the number of living cells, so that the proliferation activity of the cells is determined.
Cell culture and inoculation: cells in logarithmic growth phase (Ba/F3 KIF5B-RET from Congyuan Bow-Chuang, RPMI1640(Hyclone, SH30027.01) + 10% FBS (GBICO, 10099-141)) were harvested and counted using a platelet counter. Cell viability was checked by trypan blue exclusion to ensure cell viability above 90%. Add 90. mu.L of each cell suspension to a 96-well clear flat-bottomed black-panel (Thermo,165305) and adjust the cell concentration to 3000/well/90 ul. Cells in 96-well plates were incubated at 37 ℃ with 5% CO2And incubated overnight at 95% humidity (Thermo, Model 3100 Series).
Firstly, DMSO is used as a solvent to prepare 10000 mu M of a compound mother solution to be detected, then PBS is used for diluting 100 times to prepare a solution with 10 times of final concentration, the highest concentration is 100 mu M,10 mu L of the compound solution to be detected is added into each hole of a 96-hole plate inoculated with cells, and the solution is diluted 10 times, and the concentration reaches 10 mu M of the final concentration. The final concentration of test compound was serially diluted 3-fold starting at 10. mu.M for a total of 9 concentrations in 3 duplicate wells. Will be added to be testedThe 96-well plate of the composition and cells was placed at 37 ℃ in 5% CO2After incubation for a further 72 hours under 95% humidity conditions, CellTiter-Glo analysis was carried out.
Thawing CellTiter-Glo reagent: (Luminescent Cell Viability Assay, Promega, G7572) and equilibrate the Cell plates to room temperature for 30 minutes. An equal volume of CellTiter-Glo solution was added to each well and the cells were lysed by shaking on an orbital shaker for 5 minutes. The plates were left at room temperature for 20 minutes to stabilize the luminescence signal and the luminescence values were read using a SpectraMax multi-label microplate detector (MD, M3).
Cell survival rate (%) ═ (Lum)Drug to be tested-LumCulture fluid control)/(LumCell controls-LumCulture fluid control)×100%
Data were analyzed using GraphPad Prism 7.0 software, fitted to the data using non-linear sigmoidal regression to derive a dose-effect curve, and IC was calculated therefrom50The value is obtained.
TABLE 2 results of cell proliferation experiments
Active example 3: human and mouse liver microsome metabolic stability assay
Liver Microsomal metabolic Stability assays with the compounds of the present invention are similarly performed according to standard Methods of in vitro metabolic Stability studies that are conventional in the art, e.g., (Kerns, Edward H.and Di Li (2008); Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization. san Diego: Academic Press; Di, Li et al, Optimization of a high thread Throughput micro particulate Stable Screening Assay for Profiling Drug Discovery drugs, J.biomol. Screen.2003, 8), (4), 453).
Liver microsomes (protein concentration 0.56mg/mL) were added to 1 μ M compound working solution (diluted to 100 μ M from 10mM DMSO stock solution with 100% acetonitrile, organic phase content: 99% ACN, 1% DMSO), and after preincubation at 37 ℃ for 10min, the reaction was initiated by addition of cofactor (NADPH) (prepared from magnesium chloride solution). After incubation for an appropriate time (e.g., 5, 10, 20, 30, and 60 minutes), samples are taken and the reaction is stopped by adding an appropriate stop solution (glacial acetonitrile (i.e., acetonitrile at 4 ℃) containing 200ng/mL tolbutamide and 200ng/mL labetalol).
Sample treatment (n ═ 1): adding appropriate samples, vortexing, centrifuging at high speed, taking supernatant, and detecting the substrate by HPLC-MS/MS. The peak area at the time point of 0min was taken as 100%. The peak areas at other time points are converted into residual percentages, the natural logarithm of the residual percentages at each time point is plotted against the incubation time, the slope (-k) is calculated, and then according to the intrinsic clearance (Clint) ═ k × volume of incubation solution)/mass of liver microsomes, Clint (uL/min/mg) and the half-life of the compound (T1/2, min) are calculated. The results are shown in Table 3.
TABLE 3 results of the stability of liver microsome metabolism in human and mouse
Those skilled in the art will appreciate that the foregoing description is exemplary and illustrative in nature and is intended to illustrate the present invention and its preferred embodiments. Obvious modifications and variations will be apparent to those skilled in the art without departing from the spirit of the invention. All such modifications within the scope of the appended claims are intended to be included therein. Accordingly, it is intended that the invention not be limited by the foregoing description, but be defined by the scope of the following claims and their equivalents.
All publications cited in this specification are herein incorporated by reference.
Claims (18)
1. A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof:
wherein:
R1selected from hydrogen, halogen, cyano, nitro and C optionally substituted by halogen or cyano1-C6An alkyl group;
R2selected from hydrogen, C6-C10Aryl, 5-9 membered heteroaryl, C3-C8Cycloalkyl radical, C3-C8Cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6Alkylthio, wherein the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkyl, alkoxy, and alkylthio are optionally substituted with 1,2, or 3 groups independently selected from: halogen, cyano, nitro, hydroxy, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6An alkylthio group;
R3selected from hydrogen, halogen, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6An alkylthio group;
R4selected from hydrogen, C6-C10Aryl, 5-9 membered heteroaryl, C3-C8Cycloalkyl radical, C3-C8Cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, -SO2-C1-C6Alkyl, -SO-C1-C6Alkyl radical, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6Alkylthio, wherein the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkyl, alkoxy, and alkylthio are optionally substituted with 1,2, or 3 groups independently selected from: halogen, cyano, nitro, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6An alkylthio group;
R5selected from halogen, cyano, nitro, hydroxy, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6An alkylthio group;
ring A is selected from C6-C10Arylene, 5-9 membered heteroarylene, C3-C8Cycloalkylene radical, C3-C8Cycloalkenylene, 3-8 membered heterocycloalkylene, and 3-8 membered heterocycloalkenylene rings;
ring B is selected from C6-C10Aryl, 5-9 membered heteroaryl, C3-C8Cycloalkyl radical, C3-C8Cycloalkenyl, 3-8 membered heterocycloalkyl, and 3-8 membered heterocycloalkenyl rings;
m is 0, 1,2 or 3; and is
n is 0, 1,2 or 3.
2. A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof according to claim 1, wherein R1Is halogen, cyano or nitro; preferably, R1Is cyano.
3. A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof according to any one of claims 1-2, wherein R2Selected from 5-6 membered heteroaryl comprising 1,2 or 3 heteroatoms independently selected from N, O or S, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6Alkylthio optionally substituted with 1,2 or 3 groups independently selected from: halogen, hydroxy and C1-C6An alkyl group; wherein preferably said 5-6 membered heteroaryl is selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl;
preferably, R2Selected from the group consisting of1-C6Alkyl substituted containing 1,2 or 3 independently selected fromN, O or S and C optionally substituted by hydroxy1-C6An alkoxy group; wherein preferably the 5-membered heteroaryl is selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or pyrazolyl.
5. A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof, according to any one of claims 1 to 4, wherein R3Selected from hydrogen and C1-C6An alkyl group;
preferably, R3Selected from hydrogen and C1-C3An alkyl group;
more preferably, R3Is hydrogen or methyl;
most preferably, R3Is hydrogen.
6. A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof, according to any one of claims 1 to 5, wherein R4Selected from phenyl, 5-6 membered heteroaryl comprising 1,2 or 3 heteroatoms independently selected from N, O or S, -SO2-C1-C6Alkyl, -SO-C1-C6Alkyl radical, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6Alkylthio optionally substituted with 1,2 or 3 halogen groups; preferably, the 5-6 membered heteroaryl is selected fromPyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl;
preferably, R4Selected from 5-membered heteroaryl comprising 1,2 or 3 heteroatoms independently selected from N, O or S, -SO2-C1-C6Alkyl radical, C1-C6Alkyl and C1-C6Alkoxy, optionally substituted with 1,2 or 3 halo groups; preferably, the 5-membered heteroaryl is selected from the group consisting of pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and pyrazolyl.
7. A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof according to claim 6, wherein R4Selected from pyrazolyl optionally substituted by halogen, -SO2-C1-C6Alkyl radical, C1-C6Alkyl and C1-C6An alkoxy group;
8. A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof according to any one of claims 1 to 7, wherein R5Selected from halogen, C1-C6Alkyl radical, C1-C6Alkoxy and C1-C6An alkylthio group; preferably, R5Is selected from C1-C3An alkyl group; more preferably methyl.
9. A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof according to any one of claims 1 to 8, wherein m is 0 or 1; preferably m is 1; and/or
Wherein n is 0 or 1; preferably, n is 0.
10. A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof according to any one of claims 1 to 9, wherein ring a is selected from phenylene, a 5-6 membered heteroarylene comprising 1,2, or 3 heteroatoms independently selected from N, O or S, C3-C8Cycloalkylene radical, C3-C8Cycloalkenylene, 3-8 membered heterocycloalkylene comprising 1,2, or 3 heteroatoms independently selected from N, O or S, and 3-8 membered heterocycloalkenylene comprising 1,2, or 3 heteroatoms independently selected from N, O or S;
preferably, ring a is selected from phenylene, 5-membered heteroarylene comprising 1,2 or 3 heteroatoms independently selected from N, O or S, C3-C6Cycloalkylene radical, C3-C6Cycloalkenylene, 3-6 membered heterocycloalkylene comprising 1,2, or 3 heteroatoms independently selected from N, O or S, and 3-6 membered heterocycloalkylene comprising 1,2, or 3 heteroatoms independently selected from N, O or S.
11. A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt or a solvate thereof according to claim 10, wherein ring a is selected from the group consisting of phenylene, pyrrolylene, furanylene, thiophenylene, imidazolyl, furazanyl, oxazolylene, oxadiazolylene, oxatriazolylene, isoxazolylene, thiazolyl, isothiazolylene, pyrazolyl, thiadiazolylene, triazolylene, tetrazolylene, pyridinylene, pyrazinylene, pyridazinylene, pyrimidinyl, triazinylene, azetidinylene, pyrrolidinylene, pyrrolinylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, piperazinyl, piperidylene and azepanylene;
preferably, ring a is selected from the group consisting of pyrazolylene, azetidinylene, pyrrolidinylene, cyclohexylene, piperidylene and azepanylene;
more preferably, ring A is selected from
12. A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof, according to any one of claims 1 to 11, wherein ring B is selected from phenyl, a 5-9 membered heteroaryl comprising 1,2, or 3 heteroatoms independently selected from N, O or S, C3-C8Cycloalkyl radical, C3-C8Cycloalkenyl, a 3-8 membered heterocycloalkyl comprising 1,2 or 3 heteroatoms independently selected from N, O or S, and a 3-8 membered heterocycloalkenyl ring comprising 1,2 or 3 heteroatoms independently selected from N, O or S;
preferably, ring B is selected from phenyl, and 6-membered heteroaryl comprising 1,2 or 3 heteroatoms independently selected from N, O or S;
more preferably, ring B is selected from phenyl, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl rings;
most preferably, ring B is a phenyl or pyridyl ring.
14. A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variation, a pharmaceutically acceptable salt, or a solvate thereof according to any one of claims 1-13, wherein said compound of formula (I) has the structure of formula (Ia),
wherein X is N or CH; r1、R2、R3、R4、R5M, n and a each have the meaning as defined in claims 1 to 13;
more preferably, the compound of formula (I) has the structure of formula (Ib),
wherein X is N or CH; r1、R2、R3、R4、R5N and A each have the meaning as defined in claims 1 to 13;
more preferably, the compound of formula (I) has the structure of formula (Ic),
wherein X is N or CH; r is2、R3、R4、R5N and a each have the meaning as defined in claims 1 to 13.
16. a pharmaceutical composition comprising a compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, according to any one of claims 1-15, and a pharmaceutically acceptable excipient; the pharmaceutical composition optionally further comprises a further therapeutically active ingredient suitable for use in combination with a compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, according to any one of claims 1 to 15.
17. A pharmaceutical combination comprising a compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof according to any one of claims 1 to 15 and an additional active agent.
18. Use of a compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 15, or a pharmaceutical composition according to claim 16, for the preparation of a medicament for the prophylaxis or treatment of a RET-associated disease;
preferably, the RET-associated disease is selected from the group consisting of tumors including, but not limited to, non-small cell lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine tumors 2A or 2B, pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal gangliomas, pancreatic duct adenocarcinoma, multiple endocrine tumors, testicular cancer, chronic monocytic leukemia, salivary gland carcinoma, ovarian cancer, cervical cancer, and the like, or Irritable Bowel Syndrome (IBS).
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CN111961034A (en) * | 2019-05-20 | 2020-11-20 | 浙江同源康医药股份有限公司 | Compounds useful as RET kinase inhibitors and uses thereof |
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