CN117229292A - Preparation and application of RET inhibitor - Google Patents

Preparation and application of RET inhibitor Download PDF

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CN117229292A
CN117229292A CN202211273054.6A CN202211273054A CN117229292A CN 117229292 A CN117229292 A CN 117229292A CN 202211273054 A CN202211273054 A CN 202211273054A CN 117229292 A CN117229292 A CN 117229292A
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alkyl
alkylene
halogen
membered heteroaryl
independently
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梁永宏
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Yaoya Technology Shanghai Co ltd
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Yaoya Technology Shanghai Co ltd
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Abstract

The invention discloses preparation and application of a ret inhibitor, in particular to a compound shown in a formula (I) and pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the compound and/or pharmaceutically acceptable salts thereof, application of the compound or pharmaceutically acceptable salts thereof in medicaments for treating or preventing ret kinase related diseases, especially tumors, which are heterocyclic compounds, and a preparation method of the pharmaceutical composition of the compound or pharmaceutically acceptable salts thereof. Wherein each of the general formula (I)Substituents are as defined in the specification.

Description

Preparation and application of RET inhibitor
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a novel RET inhibitor, and a preparation method and application thereof.
Background
The present invention relates generally to novel compounds, methods for their preparation and use as RET inhibitors (e.g., for the treatment of cancer).
RET genes were found in transformed and cultured mouse NTH3T3 cells by Takahashi et al (Takahashi M, ritz J, cooper GM. Activation of a novel human transforming gene, RET, by DNA rearrangement. Cell,1985,42 (2): 581-588), and were designated RET genes. The RET gene is a protooncogene (10q11.2) located on the long arm of chromosome 10, and the coded RET protein is a tyrosine kinase receptor, and consists of three parts of a cysteine-rich cadherin-like extracellular region, a transmembrane region and an intracellular domain with tyrosine kinase activity, and is 37% identical to the ALK kinase domain in amino acid. RET proteins stimulate receptor dimerization through ligand binding, autophosphorylation of intracellular regions and substrate phosphorylation within cells, thereby activating various downstream pathways such as RAS/RAF/MEK/ERK, PI3K/AKT and STAT pathways, playing an important role in cell proliferation, migration and differentiation (J Clin Oncol,2012,30 (2): 200-202).
With the progressive progress of research, it has been found that the occurrence of various diseases is closely related to RET gene mutation, including papillary thyroid carcinoma, medullary thyroid carcinoma, multiple endocrine adenomatosis type 2, congenital megacolon, lung adenocarcinoma, etc. Only four RET fusion genes of KIF5B-RET, CCDC6-RET, TRIM33-RET, NCOA4-RET are currently reported in non-small cell lung Cancer, while KIF5B-RET is the most common RET fusion gene in non-small cell lung Cancer (Cancer, 2013,119 (8): 1486-1494). KIF5B-RET is a fusion gene formed by chromosome inversion (p 11; q 11) of KIF5B (kinesin family member B) gene and RET gene, which was confirmed in non-smoking korean adenocarcinoma for the first time by whole genome and transcriptome sequencing; the proportion of KIF5B-RET in lung cancer is low, more common in non-smokers and adenocarcinoma patients, and is exclusive to other mutations, such as EGFR, KRAS, BRAF, erbB, EML4-ALK (Genome Res,2012,22 (3): 436-445). The KIF5B-RET fusion protein comprises a motor domain and a coiled-coil domain of KIF5B, and RET tyrosine kinase activity of the fusion protein is abnormally activated by dimerization of the coiled-coil domains, thereby promoting pulmonary tumorigenesis (Cancer, 2011,117 (12): 2709-2718). In Qian et al (Mol Cancer,2014, 13:176), KIF5B-RET fusion kinase was demonstrated to have significant oncogenic activity both in vitro and in vivo, and the signal transduction pathway of STAT3 may be the primary downstream mediator of tumorigenesis. There is evidence that KIF5B-RET can regulate the sustained activation of STAT 3. KIF5B-RET fusion kinase can bind STAT3, directly phosphorylate and activate STAT3-Tyr705; it can also mediate activation of STAT3-Tyr705 via the JAK/STAT 3-dependent pathway and trigger phosphorylation of Ser727 via the RAS/RAF/MEK/ERK1 pathway. Small molecule kinase inhibitors that partially target multiple kinases have RET kinase inhibitory activity, such as Vandetinib (Vandetinib), cabozantinib (Cabozantinib) has been approved by the FDA for the treatment of thyroid cancer, others such as Ponatinib, nintedanib, lenvantinib, etc. have also been developed in clinical studies against tumors in which abnormal activation of RET signals is present, but the above-mentioned multiple kinase inhibitors have different problems in both efficacy and safety due to lack of selectivity against RET proteins, thereby limiting their further study and use in RET abnormal tumors. Thus, there is a great clinical need for small molecule kinase inhibiting compounds that target RET proteins with high selectivity.
Recently, RET selective inhibitors Selpercatinib and Pralsetinib have been marketed in batches for the indications of thyroid cancer and non-small cell lung (Selpercatinib and Pralsetinib drug Specification, FDA). And not all RET rearrangement/mutation patients respond to these drugs, it is necessary to develop inhibitors that are highly active, have little side effects, are highly specific, and are effective against RET mutations and rearrangements
Disclosure of Invention
A compound having the general formula (I), a stereoisomer, a pharmaceutically acceptable salt, a polymorph or an isomer thereof, wherein the compound of the general formula (I) has the structure:
wherein,
each L 1 Independently at each occurrence selected from the group consisting of bond, OC 0-3 Alkyl, NHC 0-6 Alkyl, C 1-3 Alkyl, COC 0-3 Alkyl or SC 0-3 An alkyl group;
each L 2 Independently at each occurrence selected from the group consisting of bond, OC 0-3 Alkyl, NHC 0-6 Alkyl, C 1-3 Alkyl, COC 0-3 Alkyl or SC 0-3 An alkyl group;
each L 3 Independently at each occurrence selected from the group consisting of bond, C 0-3 Alkyl, NHC 0-6 Alkyl, C 1-3 Alkyl, COC 0-3 Alkyl or SC 0-3 An alkyl group;
each L 4 Independently at each occurrence selected from the group consisting of bond, C 0-3 Alkyl, NHC 0-6 Alkyl, C 1-3 Alkyl, COC 0-3 Alkyl or SC 0-3 An alkyl group;
each X is 1 Independently at each occurrence selected from N or CR 9 ；
Each R 1 Independently at each occurrence selected from H, halogen, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -OR 6 、-C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 -C1-6 alkylene-NR 6 R 7 、-C(＝O)R 6 、-C(＝O)OR 6 、-OC(＝O)R 6 、-C(＝O)NR 6 R 7 、-NR 6 C(＝O)R 7 、-S(O) 2 NR 6 R 7 or-C 3-6 Carbocyclyl; each R 1 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OC 1-6 Alkyl, -NC 1-6 Alkyl C 1-6 Alkyl, -CN, -C (=o) C 1-6 Alkyl, -C (=o) OC 1-6 Alkyl, -OC (=o) C 1-6 Alkyl, -C (=o) NC 1-6 Alkyl C 1-6 Alkyl, -NC 1-6 Alkyl C (=O) C 1-6 Alkyl or-S (O) 2 NC 1-6 Alkyl C 1-6 The substituent of the alkyl group is substituted or unsubstituted;
each R 9 Independently at each occurrence selected from H, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, C 3-6 Heterocycloalkyl, C 3-6 Cycloalkyl, -CN, -OR 6 、-C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 -C1-6 alkylene-NR 6 R 7 、-C(＝O)R 6 、-C(＝O)OR 6 、-OC(＝O)R 6 、-C(＝O)NR 6 R 7 、-NR 6 C(＝O)R 7 、-S(O) 2 NR 6 R 7 Or phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl; each R 9 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OC 1-6 Alkyl, -NC 1-6 Alkyl C 1-6 Alkyl, -CN, -C (=o) C 1-6 Alkyl, -C (=o) OC 1-6 Alkyl, -OC (=o) C 1-6 Alkyl, -C (=o) NC 1-6 Alkyl C 1-6 Alkyl, -NC 1-6 Alkyl C (=O) C 1-6 Alkyl or-S (O) 2 NC 1-6 Alkyl C 1-6 The substituent of the alkyl group is substituted or unsubstituted;
each R 2 Independently at each occurrence selected from H, deuterium, -CN, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, C 3-12 Cycloalkyl, C 7-12 Spirocycloalkyl, C 7-12 Heterospirocycloalkyl, C 3-12 Heterocycloalkyl, phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 -C1-6 alkylene-NR 6 R 7 、-C(＝O)R 6 、-C(＝O)OR 6 、-OC(＝O)R 6 、-C(＝O)NR 6 R 7 、-NR 6 C(＝O)R 7 、-S(O) 2 NR 6 R 7 or-C 3-6 Carbocyclyl; each R 2 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OC 1-6 Alkyl, -NC 1-6 Alkyl C 1-6 Alkyl, -CN, -C (=o) C 1-6 Alkyl, -C (=o) OC 1-6 Alkyl, -OC (=o) C 1-6 Alkyl, -C (=o) NC 1-6 Alkyl C 1-6 Alkyl, -NC 1-6 Alkyl C (=O) C 1-6 Alkyl or-S (O) 2 NC 1-6 Alkyl C 1-6 The substituent of the alkyl group is substituted or unsubstituted;
each Ar is provided with 1 Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each R 1 Independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 10 Substituted or unsubstituted;
each Ar is provided with 2 Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each R 1 Independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 10 Substituted or unsubstituted;
each R 10 Independently at each occurrence selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -OR 6 、-C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 -C1-6 alkylene-NR 6 R 7 、-C(＝O)R 6 、-C(＝O)OR 6 、-OC(＝O)R 6 、-C(＝O)NR 6 R 7 、-NR 6 C(＝O)R 7 、-S(O) 2 NR 6 R 7 or-C 3-6 Carbocyclyl; each R 20 Independently optionally 1, 2, 3, 4,5 or 6 are selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(＝O)R 6 、-C(＝O)OR 6 、-OC(＝O)R 6 、-C(＝O)NR 6 R 7 、-NR 6 C(＝O)R 7 or-S (O) 2 NR 6 R 7 Substituted or unsubstituted;
each R 6 And R is 7 Independently at each occurrence selected from hydrogen or-C 1-6 Alkyl, each R 6 And R is 7 Independently optionally substituted with 1, 2, 3, 4, 5 or 6R 8 Substituted or unsubstituted; or R is 7 And R is 7 Together with the N atom to which they are attached, form a 3-10 membered heterocyclic ring, said 3-10 membered heterocyclic ring may further comprise 1, 2, 3 or 4 groups selected from N, O, S, S (=O) or S (=O) 2 And said 3-10 membered heterocyclic ring is independently optionally substituted with 1, 2, 3, 4, 5 or 6R 8 Substituted or unsubstituted;
each R 8 Independently at each occurrence selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -O-C 1-6 Alkylene- (halogen) 1-3 、-SC 1-6 Alkyl, -S-C 1-6 Alkylene- (halogen) 1-3 、-NC 1- 6 C 1-6 、-C 1-6 alkylene-NC 1-6 Alkyl C 1-6 Alkyl, -C (=o) C 1-6 Alkyl, -C (=o) OC 1-6 Alkyl, -OC (=o) C 1-6 Alkyl, -C (=o) NC 1-6 Alkyl C 1-6 Alkyl, -NC 1-6 Alkyl C (=O) C 1-6 Alkyl, -S (O) 2 NC 1-6 Alkyl C 1-6 Alkyl or-C 3-6 Carbocyclyl;
in some embodiments, the compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds, isomers, solvates or precursors thereof, or pharmaceutically acceptable salts thereof:
the invention also provides a medicine
A composition comprising the above compound or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention includes an optional pharmaceutically acceptable carrier means that the composition may or may not contain a pharmaceutically acceptable carrier.
The invention also provides application of the compound or pharmaceutically acceptable salt or pharmaceutical composition thereof in preparing medicines for treating RET-mediated diseases.
The invention also provides application of the compound or pharmaceutically acceptable salt or pharmaceutical composition thereof in preparing medicines for treating RET-mediated diseases. Wherein the RET comprises wild-type RET, mutant RET, RET fusions including, but not limited to, G810R mutant RET, M918T mutant RET, V804L mutant RET, V804M mutant RET, preferably G810R mutant RET, including, but not limited to, KIF5B-RET fusions, CCDC6-RET fusions, preferably KIF5B-RET fusions; the disease includes cancer and irritable bowel syndrome.
The invention also provides application of the compound or pharmaceutically acceptable salt or pharmaceutical composition thereof in preparing medicines for treating diseases mediated by wild RET, mutant RET and RET fusion; wherein the mutant RET includes, but is not limited to, a G810R mutant RET, an M918T mutant RET, a V804L mutant RET, a V804M mutant RET, preferably a G810R mutant RET, the RET fusion includes, but is not limited to, a KIF5B-RET fusion, a CCDC6-RET fusion, preferably a KIF5B-RET fusion; the disease includes cancer and irritable bowel syndrome.
The invention also provides application of the compound or pharmaceutically acceptable salt or pharmaceutical composition thereof in preparing medicines for treating RET-mediated cancers and irritable bowel syndrome. Wherein the RET includes wild-type RET, mutant RET, RET fusions including, but not limited to, G810R mutant RET, M918T mutant RET, V804L mutant RET, V804M mutant RET, preferably G810R mutant RET, including, but not limited to, KIF5B-RET fusions, CCDC6-RET fusions, preferably KIF5B-RET fusions.
The invention also provides application of the compound or pharmaceutically acceptable salt or pharmaceutical composition thereof in preparing medicines for treating cancers and irritable bowel syndrome mediated by wild RET, mutant RET and RET fusion. Wherein the mutant RET includes, but is not limited to, a G810R mutant RET, an M918T mutant RET, a V804L mutant RET, a V804M mutant RET, preferably a G810R mutant RET; the RET fusion includes, but is not limited to, a KIF5B-RET fusion, a CCDC6-RET fusion, preferably a KIF5B-RET fusion.
The invention also provides application of the compound or pharmaceutically acceptable salt or pharmaceutical composition thereof in preparing a medicament for treating cancer.
The invention also provides application of the compound or pharmaceutically acceptable salt or pharmaceutical composition thereof in preparing medicines for treating irritable bowel syndrome.
The present invention also provides a method of treating a disease mediated by RET, comprising administering to a patient in need thereof an effective amount of a compound as described above or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Wherein the RET comprises wild-type RET, mutant RET, RET fusions including but not limited to G810R mutant RET, M918T mutant RET, V804L mutant RET, V804M mutant RET, including but not limited to KIF5B-RET fusions, CCDC6-RET fusions; the disease includes cancer and irritable bowel syndrome.
The present invention also provides a method of treating cancer comprising administering to a patient in need thereof an effective amount of a compound as described above or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
The present invention also provides a method of treating irritable bowel syndrome, the method comprising administering to a patient in need thereof an effective amount of the above compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
Cancers described herein include, but are not limited to, small cell lung cancer, non-small cell lung cancer, papillary thyroid cancer, medullary thyroid cancer, follicular thyroid cancer, undifferentiated thyroid cancer, recurrent thyroid cancer, multiple endocrine neoplasias of type 2A or 2B (MEN 2A or MEN2B, respectively), hepatocellular carcinoma, lung cancer, head and neck cancer, glioma, neuroblastoma, pheochromocytoma, colorectal cancer, testicular cancer, prostate cancer, fallopian tube cancer, ovarian cancer, cervical cancer, breast cancer, and pancreatic cancer.
The irritable bowel syndrome of the present invention includes, but is not limited to, diarrhea predominant, constipation predominant or alternating stool patterns, functional bloating, functional constipation, functional diarrhea, nonspecific functional bowel disease, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain, and inflammatory bowel disease.
Certain chemical terms
Unless stated to the contrary, the following terms used in the specification and claims.
The expression "C" as used herein has the following meaning x-y "means a range of carbon number wherein x and y are integers, e.g. C 3-8 Cycloalkyl denotes cycloalkyl having 3 to 8 carbon atoms, i.e. having 3, 4, 5, 6, 7 or 8 carbon atomsCycloalkyl groups of (a). It is also to be understood that "C 3-8 "also includes any subrange therein, e.g. C 3-7 、C 3-6 、C 4-7 、C 4-6 、C 5-6 Etc.
"alkyl" refers to a straight or branched hydrocarbon group containing 1 to 20 carbon atoms, for example 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, and 2-ethylbutyl. The alkyl group may be substituted or unsubstituted.
"alkenyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond and typically 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1, 4-pentadienyl and 1, 4-butadienyl. The alkenyl group may be substituted or unsubstituted.
"alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond and typically from 2 to 20 carbon atoms, for example from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or from 2 to 4 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl. The alkynyl group may be substituted or unsubstituted.
"cycloalkyl" refers to a saturated cyclic hydrocarbyl substituent containing 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocyclic, typically containing 3 to 7 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may alternatively be bi-or tricyclic fused together, such as decalin, which cycloalkyl groups may be substituted or unsubstituted.
"heterocyclyl", "heterocycloalkyl", "heterocycle" refers to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise indicated, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, spiro or bridged ring systems, a nitrogen, carbon or sulfur atom on a heterocyclyl group may be optionally oxidized, a nitrogen atom may be optionally quaternized, and a heterocyclyl group may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule by a single bond through a carbon atom or heteroatom in the ring. The heterocyclic group containing a condensed ring may contain one or more aromatic or heteroaromatic rings as long as the atom attached to the remainder of the molecule is a non-aromatic ring. For the purposes of the present application, heterocyclyl is preferably a stable 4-11 membered monovalent non-aromatic mono-or bi-ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic mono-ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolyl, dihydrofuranyl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.
"spiroheterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group having one atom in common between the monocyclic rings (referred to as the spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but the electronic system in which none of the rings has complete conjugation is preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, with single spirocycloalkyl groups and double spirocycloalkyl groups being preferred. More preferably 4-membered4-, 6-, 5-, or 5-or 6-membered single spiro-ring radical. Non-limiting examples of spiroheterocyclyl groups include:
"fused heterocyclyl" means a 5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:
"aryl" or "aryl" refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.
"heteroaryl" or "heteroaryl" refers to a 5-16 membered ring system containing 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. Unless otherwise indicated, heteroaryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems, so long as the point of attachment to the rest of the molecule is an aromatic ring atom, the nitrogen, carbon, and sulfur atoms of the heteroaromatic ring may be selectively oxidized, and the nitrogen atom may be selectively quaternized. For the purposes of the present application, heteroaryl groups are preferably stable 4-11 membered monoaromatic rings which contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-8 membered monoaromatic rings which contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxanyl, benzofuranonyl, benzofuranyl, benzonaphtofuranyl, benzopyronyl, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazole, furyl, imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quininyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, and the like. In the present application, the heteroaryl group is preferably a 5-8 membered heteroaryl group comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridyl, pyrimidinyl, thiazolyl. The heteroaryl group may be substituted or unsubstituted.
"halogen" means fluorine, chlorine, bromine or iodine.
"hydroxy" means-OH, "amino" means-NH 2 "amido" means-NHCO-, -cyano "means-CN," nitro "means-CN," Isocyano "means-NC," trifluoromethyl "means-CF 3 。
The term "heteroatom" or "hetero" as used herein alone or as part of other ingredients refers to an atom other than carbon and hydrogen, the heteroatom being independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but is not limited to these atoms, in embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different.
The term "fused" or "fused ring" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.
The term "spiro" or "spiro" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
"optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur, e.g., an "optionally alkyl-substituted heterocyclic group" means that alkyl may but need not be present, and that the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.
"substituted" means that one or more atoms, preferably 5, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. It goes without saying that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort, the substituents being in their possible chemical positions. For example, a carbon atom having a free amine or hydroxyl group bonded to an unsaturated (e.g., olefinic) bond may be unstable. The substituents include, but are not limited to, hydroxy, amino, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl groups, and the like.
"pharmaceutical composition" refers to a composition comprising one or more of the compounds described herein or a pharmaceutically acceptable salt or prodrug thereof, and other components such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and further exert biological activity.
"isomer" refers to a compound having the same molecular formula but differing in the nature or sequence of their atoms bonded or the spatial arrangement of their atoms, and is referred to as an "isomer" and an isomer differing in the spatial arrangement of its atoms is referred to as a "stereoisomer". Stereoisomers include optical isomers, geometric isomers and conformational isomers. The compounds of the present invention may exist in the form of optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are in the "R" or "S" configuration. Optical isomers include enantiomers and diastereomers, and methods for preparing and separating optical isomers are known in the art.
The compounds of the invention may also exist as geometric isomers. The present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configuration, and substituents around cycloalkyl or heterocycle are designated as cis or trans configuration.
The compounds of the invention may also exhibit tautomerism, such as keto-enol tautomerism.
It is to be understood that the present invention includes any tautomeric or stereoisomeric form and mixtures thereof, and is not limited to any one tautomeric or stereoisomeric form used in the naming or chemical formulae of the compounds.
"isotopes" are all isotopes of atoms that are present in compounds of the invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, each such as, but not limited to 2 H、 3 H、 13 C、 14 C、 15 N、 18 O、 31 P、 32 P、 35 S、 18 F and F 36 Cl. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labeled reagent in place of a non-isotopically-labeled reagent. Such compounds have a variety of potential uses, for example as standards and reagents in assaying biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.
By "prodrug" is meant that the compounds of the invention may be administered in the form of a prodrug. Prodrugs refer to derivatives of the biologically active compounds of the present invention which are converted under physiological conditions in vivo, e.g., by oxidation, reduction, hydrolysis, etc. (each of which is performed with or without the aid of an enzyme). Examples of prodrugs are the following compounds: wherein the amine groups in the compounds of the invention are acylated, alkylated or phosphorylated, such as eicosanoylamino, propylamino, pivaloyloxymethylamino, or wherein the hydroxyl groups are acylated, alkylated, phosphorylated or converted to borates, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, propylaminooxy, or wherein the carboxyl groups are esterified or amidated, or wherein the sulfhydryl groups form disulfide bridges with carrier molecules, such as peptides, that selectively deliver the drug to the target and/or cytosol of the cell, these compounds may be prepared from the compounds of the invention according to well known methods.
"pharmaceutically acceptable salts" or "pharmaceutically acceptable" refer to those prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the invention contain one or more acidic or basic groups, the invention also encompasses their corresponding pharmaceutically acceptable salts. Thus, the compounds according to the invention containing acidic groups may be present in salt form and may be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium salts or salts with amines or organic amines, such as primary, secondary, tertiary, cyclic amines, etc., for example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, and caffeine, and particularly preferred organic bases are salts of isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The compounds of the invention containing basic groups may be present in salt form and may be used according to the invention in the form of their addition to inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of the invention contain both acidic and basic groups in the molecule, the invention includes, in addition to the salt forms mentioned, also internal salts or betaines. The individual salts are obtained by conventional methods known to the person skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.
Thus, in the present application, when referring to "a compound", "a compound of the application" or "a compound of the application" all such compound forms, e.g. prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers, meso, racemates, enantiomers, diastereomers and mixtures thereof are included.
Herein, the term "tumor" includes benign tumors and malignant tumors (e.g., cancers).
As used herein, the term "cancer" includes various malignant tumors that the c-ret kinase is involved in, including, but not limited to, non-small cell lung cancer, esophageal cancer, melanoma, striated muscle grenade, cell carcinoma, multiple myeloma, breast cancer ovarian cancer, endometrial cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer, and liver cancer (e.g., hepatocellular carcinoma), more particularly liver cancer, gastric cancer, and bladder cancer.
The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.
The term "polymorph" or "polymorphic form" as used herein means that a compound of the present invention has a plurality of crystalline forms, some compounds of the present invention may have more than one crystalline form, and the present invention encompasses all polymorphic forms or mixtures thereof.
Intermediate compounds of the invention and polymorphs thereof are also within the scope of the present invention.
Crystallization often yields solvates of the compounds of the present invention, and the term "solvate" as used herein refers to a complex composed of one or more molecules of the compounds of the present invention and one or more molecules of a solvent.
The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent is also possible. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, but in other cases the compounds of the invention may simply accidentally retain water or a mixture of water with some other solvent, the compounds of the invention may be reacted in one solvent or precipitated or crystallized in one solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
The term "acceptable" in relation to a formulation, composition or ingredient as used herein means that there is no sustained detrimental effect on the overall health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
"pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizer isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administration for use in humans and domestic animals.
The terms "subject," "patient," "subject," or "individual" as used herein refer to an individual having a disease, disorder, or condition, and the like, including mammals and non-mammals, examples of which include, but are not limited to, any member of the class mammalia: human, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human.
The term "treatment" as used herein refers to the treatment of a disease condition associated with a mammal, particularly a human, including
(i) Preventing the occurrence of a disease or condition in a mammal, particularly a mammal that has been previously exposed to a disease or condition but has not been diagnosed with the disease or condition;
(ii) Inhibiting the disease or disorder, i.e., controlling its progression;
(iii) Alleviating the disease or condition, i.e., slowing the regression of the disease or condition;
(iv) Relieving symptoms caused by diseases or symptoms.
The terms "disease" and "disorder" as used herein may be used interchangeably or differently and, because some specific diseases or disorders have not yet been known to cause a disease (and therefore the cause of the disease is not yet known), they cannot be considered as a disease but rather can be considered as an unwanted condition or syndrome, more or less specific symptoms of which have been confirmed by clinical researchers.
The terms "administering," "administering," and the like as used herein refer to methods that enable delivery of a compound or composition to a desired site for biological action. Including, but not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
Detailed description of the preferred embodiments
The invention also provides a method for preparing the compound. The preparation of the compounds of the general formula (I) according to the invention can be carried out by the following exemplary methods and examples, which, however, should not be regarded as limiting the scope of the invention in any way. The compounds of the present invention may also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of methods known in the art and methods described herein. The product obtained in each step is obtained using separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis can be synthesized conventionally according to the literature (reaxys) or purchased.
Unless otherwise indicated, temperatures are degrees celsius. Reagents were purchased from commercial suppliers such as chemlocks Inc, astatech Inc or michelin and these reagents were used directly without further purification unless otherwise indicated.
Unless otherwise indicated, the following reactions were carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or gas, or using dry tubes; glassware drying and/or heat drying.
Column chromatography purification uses 200-300 mesh silica gel from the Qingdao marine chemical plant unless otherwise indicated; preparation of thin layer chromatography A thin layer chromatography silica gel prefabricated plate (HSGF 254) manufactured by Kagaku chemical industry research institute of tobacco, inc.; MS was determined using a Therno LCD Fleet type (ESI) liquid chromatograph-mass spectrometer.
Nuclear magnetic data (1H NMR) using Bruker Avance-400MHz or Varian Oxford-400Hz nuclear magnetic instruments, the solvent used for the nuclear magnetic data was CDCl 3 、CD 3 OD、D 2 O, DMS-d6, etc., based on tetramethylsilane (0.000 ppm) or on residual solvent (CDCl) 3: 7.26ppm；CD 3 OD:3.31ppm；D 2 O4.79 ppm; d6-DMSO:2.50 ppm) when peak shape diversity is indicated, the following abbreviations indicate the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet), dt (doublet). If the coupling constant is given, it is in Hertz (Hz).
Preparation of intermediates
5-propynyl-2-methylsulfanyl-4, 6-dichloropyrimidine
5-iodo-2-methylthiopyrimidine-4, 6-dione (28.4 g,0.1 mol) was dissolved in DMF (500 mL), followed by addition of tributylpropynyltin (49.35 mL,0.15 mmol) and tetrakis (triphenylphosphine) palladium (23 g,0.02 mmol). The reaction mixture was heated to 120℃with stirring and reacted for 2h with stirring. The reaction mixture was diluted with EtOAc (1000 mL) and saturated NaHCO 3 Aqueous solution (300 mL) and water (300 mL) were washed, then with MgSO 4 Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 50-100% dcm to give 5-propynyl-2-methylthiopyrimidine-4, 6-dione (10.4 g, 53%).
LC/MS(ESI):m/z＝197[M+H] + 。
5-propynyl-2-methylthiopyrimidine-4, 6-dione (9.8 g,0.05 mol) and POCl 3 (50 mL) and the mixture was stirred and heated at reflux for 3 hours, then poured into stirring crushed ice, then extracted with DCM and dissolved under reduced pressure to give 5-propynyl-2-methylsulfanyl-4, 6-dichloropyrimidine as a yellow solid (10.1 g, 87%).
LC/MS(ESI):m/z＝234[M+H] + 。
5-propynyl-2- (1-methyl-1H-pyrazol-3-yl) -4, 6-dichloropyrimidine
Bromine (24 g,0.15 mol)) was added dropwise to a solution of 2- (1-methyl-1H-pyrazol-3-yl) -4, 6-dihydroxypyrimidine (28.8 g,0.15 mol) and sodium hydroxide (7 g,0.175 mol) in 250ml of water, and the mixture was cooled slightly to maintain the temperature below 40 ℃. The mixture was then stirred for a further half hour, cooled and then filtered to give 12g (39.9 g, 98%) of 2- (1-methyl-1H-pyrazol-3-yl) -4, 6-dihydroxy-5-bromopyrimidine.
LC/MS(ESI):m/z＝272[M+H] + 。
2- (1-methyl-1H-pyrazol-3-yl) -4, 6-dihydroxy-5-bromopyrimidine (27.1 g,0.1 mol) was dissolved in DMF (500 m)L) and then tributylpropynyltin (49.35 mL,0.15 mmol) and tetrakis (triphenylphosphine) palladium (23 g,0.02 mmol) were added. The reaction mixture was heated to 120℃with stirring and reacted for 2h with stirring. The reaction mixture was diluted with EtOAc (1000 mL) and saturated NaHCO 3 Aqueous solution (300 mL) and water (300 mL) were washed, then with MgSO 4 Dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 50-100% dcm in cyclohexane to give 5-propynyl-2- (1-methyl-1H-pyrazol-3-yl) pyrimidine-4, 6-dione (11.78 g, 51%).
LC/MS(ESI):m/z＝231[M+H] + 。
5-propynyl-2- (1-methyl-1H-pyrazol-3-yl) pyrimidine-4, 6-dione (11.5 g,0.05 mol) and POCl 3 (50 mL) and the mixture was stirred and heated at reflux for 3H, then poured into stirring crushed ice, then extracted with DCM and dissolved under reduced pressure to give 5-propynyl-2- (1-methyl-1H-pyrazol-3-yl) -4, 6-dichloropyrimidine as a yellow solid (10.95 g, 82%).
LC/MS(ESI):m/z＝268[M+H] + 。
5-cyano-2- (1-methyl-1H-pyrazol-3-yl) -4-chloropyrimidin-6-one
DMF (32 mL) and POCl at 0deg.C 3 The mixture of (100 mL) was stirred for 1H, then the mixture was added to 2- (1-methyl-1H-pyrazol-3-yl) -4, 6-dihydroxypyrimidine (43 g,223 mmol) and stirred at room temperature for 0.5H. The mixture was then stirred at reflux for 3 hours and the compression was reduced. The residue was poured into ice water and extracted six times with DCM. With NaHCO 3 Washing the organic phase with aqueous solution, na 2 SO 4 Dried and reduced in pressure to give 2- (1-methyl-1H-pyrazol-3-yl) -4, 6-dichloropyrimidine-5-carbaldehyde (53.3 g, 93%) as a yellow solid.
LC/MS(ESI):m/z＝258[M+H] + 。
2- (1-methyl-1H-pyrazol-3-yl) -4, 6-dichloropyrimidine-5-carbaldehyde (42.15 g,164 mmol) and hydroxylamine hydrochloride were dissolved in AcOH (200 mL), stirred at reflux For 0.5 hours, then cooled to room temperature. The solvent was removed in vacuo. The yellow solid obtained was taken up in H 2 O and filtering off the product. The solid product was then dried under vacuum overnight to provide the oxime as a yellow solid. A solution of oxime (6.6 g,26.0 mmol) in thionyl chloride (104 mL) was stirred at reflux for 3 h. The reaction was cooled to room temperature and the solvent was removed in vacuo. The resulting yellow-brown solid was dried under vacuum overnight to give 5-cyano-2- (1-methyl-1H-pyrazol-3-yl) -4-chloropyrimidin-6-one (6.14 g, 95%).
LC/MS(ESI):m/z＝236[M+H] + 。
Example 1
2- (2-hydroxy-2-methylpropyloxy) -6- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5- (prop-1-yn-1-yl) pyrimidin-4 (3H) -one (compound 1)
5-propynyl-2-methylsulfanyl-4, 6-dichloropyrimidine 1a (1.92 g,9.8 mmol) and 3- (6-boc-3, 6-diazabicyclo [3.1.1] ne were reacted under nitrogen at room temperature]Heptan-3-yl) pyridine-5-boronic acid pinacol ester (4.13 g,10.3 mmol) was dissolved in 98mL DMF. Then K is added 2 CO 3 Aqueous solution (9.8 mL,1.96 mmol) and then [1,1' -bis (diphenylphosphine) ferrocene was added]Palladium dichloride dichloromethane complex (600 mg,0.735 mmol) and stirred at room temperature for more than 48h. Ethyl acetate and water were then added to the reaction. The layers were separated and the organic layer was washed with water and brine, na 2 SO 4 And (5) drying. Reduced pressure dissolution followed by purification by column chromatography to give 5-propynyl-2-methylsulfanyl-4-chloro-6- (6-boc-3, 6-diazabicyclo [ 3.1.1)]Heptane-3-yl) pyridin-3-yl pyrimidine 1b (2.87 g, 62%).
LC/MS(ESI):m/z＝473[M+H] + 。
5-propynyl-2-methylsulfanyl-4-chloro-6- (6-boc-3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrimidine 1b (1.89 g,4 mmol) was dissolved in 25mL of methanol, then lithium hydroxide (0.2912 mmol) was added, the reaction was stirred at room temperature for 24 hours, and the compression was reduced. The residue was poured into ice water and filtered to give 5-propynyl-2-methylsulfonyl-4 hydroxy-6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrimidine 1c (1.75 g, 97%).
LC/MS(ESI):m/z＝454[M+H] + 。
To a solution of 5-propynyl-2-methylsulfanyl-4 hydroxy-6- (6-boc-3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrimidine 1c (1.58 g,3.5 mmol) in DCM (25 mL) was added m-CPBA (2.4 g 15 mmol) in an ice water bath, stirred overnight at room temperature, diluted with water and extracted with 100mL DCM. The organic phase was washed with sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and the filtrate was reduced in compression. The residue was purified by column chromatography to give the pale yellow target product 5-propynyl-2-methylsulfonyl-4 hydroxy-6- (6-boc-3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrimidine 1d (1.49 g, 88%)
LC/MS(ESI):m/z＝486[M+H] + 。
5-propynyl-2-methylsulfonyl-4 hydroxy-6- (6-boc-3, 6-diazabicyclo [ 3.1.1)]Heptan-3-yl) pyridin-3-yl) pyrimidine 1d (1.455 g,3 mmol), 2-methyl-2- ((tetrahydro-2H-pyran-2-yl) oxy) propan-1-ol (0.522 g,3 mmol) and potassium tert-butoxide (0.5 g,4.5 mmol) were dissolved in DCE, the mixture was then stirred at reflux for 12 hours, the residue was poured into ice water, extracted 2 times with DCM, and taken up in Na 2 SO 4 Drying and decompressing to dissolve, dissolving the residue in methanol, then dripping 1NHCl (5 mL) at 0-5 ℃, then stirring at room temperature for 3h, decompressing to dissolve, dissolving in DCM and then using saturated NaHCO 3 Washing the solution with saturated NaCl, drying with anhydrous sodium sulfate, and concentrating under reduced pressure, and separating with a preparation column to obtain 5-propynyl-2-2- (2-hydroxy-2-methylpropyloxy) -4-hydroxy-6- (3, 6-diazabicyclo [ 3.1.1)]Heptan-3-yl) pyridin-3-yl pyrimidine 1e (0.69 g, 48%)
LC/MS(ESI):m/z＝396[M+H] + 。
5-propynyl-2-2- (2-hydroxy-2-methylpropyloxy) -4 hydroxy-6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrimidine 1e (20 mg,0.05 mmol) was dissolved in DCE, then 6-methoxy-3-pyridinecarbaldehyde (7.59 mg,0.0553 mmol) and sodium triacetoxyborohydride (17.6 mg,0.0830 mmol) were added sequentially, then reacted overnight with stirring at room temperature, and then the resulting 2- (2-hydroxy-2-methylpropyloxy) -6- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-5- (prop-1-yn-1-yl) pyrimidin-4 (3H) -one 1 (25 mg, 97%) was isolated by a preparative column under reduced pressure.
LC/MS(ESI):m/z＝517[M+H] + 。
Example 2
2- (2-hydroxy-2-methylpropyloxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-oxopyrimidine-5-carbonitrile (compound 2)
The compound 6-bromonicotinaldehyde 2a (18.6 g,0.1 mol), 6-boc-3, 6-diazabicyclo [3.1.1] heptane (19.8 g,0.1 mol) and potassium carbonate (20.7 g,0.15 mol) were dissolved in DMSO (280 mL) and reacted overnight with stirring at 90 ℃. After cooling, water was added and extracted with EA. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. And reducing the compression dissolution. Beating with n-hexane and ethyl acetate gives the compound 6- (6-boc-3, 6-diazabicyclo [3.1.1] heptan-3-yl) nicotinaldehyde 2b (23.6 g, 78%).
LC/MS(ESI):m/z＝304[M+H] + 。
S-methyl isothiourea (4.5 g,50 mmol), 6- (6-boc-3, 6-diazabicyclo [ 3.1.1)]To a solution of heptan-3-yl) nicotinaldehyde (15.15 ml,50 mmol) and ethyl cyanoacetate (5.65 g,50 mmol) in ethanol (100 ml) was added K 2 CO 3 (6.9 g,50 mmol) the reaction mixture was heated to 80℃for 5 hours, cooled and filtered. Crystallization of ethanol gives 5-cyano-2-methylsulfanyl-4 hydroxy-6- (6-boc-3, 6-diazabicyclo [ 3.1.1)]Heptane-3-yl) pyridin-3-yl pyrimidine 2c (18.7 g, 85%).
LC/MS(ESI):m/z＝441[M+H] + 。
To a solution of 5-cyano-2-methylsulfanyl-4 hydroxy-6- (6-boc-3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrimidine 2c (1.54 g,3.5 mmol) in DCM (25 mL) was added m-CPBA (2.4 g 15 mmol) in an ice water bath, stirred overnight at room temperature, diluted with water and extracted with 100mL DCM. The organic phase was washed with sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and the filtrate was reduced in compression. The residue was purified by column chromatography to give the pale yellow target product 5-propynyl-2-methylsulfonyl-4 hydroxy-6- (6-boc-3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrimidine 1d (1.47 g, 89%)
LC/MS(ESI):m/z＝473[M+H] + 。
5-cyano-2-methylsulfonyl-4 hydroxy-6- (6-boc-3, 6-diazabicyclo [ 3.1.1)]Heptan-3-yl) pyridin-3-yl) pyrimidine 2d (1.41 g,3 mmol), 2-methyl-2- ((tetrahydro-2H-pyran-2-yl) oxy) propan-1-ol (0.522 g,3 mmol) and potassium tert-butoxide (0.5 g,4.5 mmol) were dissolved in DCE, and the mixture was stirred at reflux for 12 hours, the residue was poured into ice water, extracted 2 times with DCM, taken up in Na 2 SO 4 Drying and decompressing to dissolve, dissolving the residue in methanol, then dripping 1NHCl (5 mL) at 0-5 ℃, then stirring at room temperature for 3h, decompressing to dissolve, dissolving in DCM and then using saturated NaHCO 3 Washing the solution with saturated NaCl, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 5-cyano-2-2- (2-hydroxy-2-methylpropyloxy) -4-hydroxy-6- (3, 6-diazabicyclo [ 3.1.1)]Heptan-3-yl) pyridin-3-yl pyrimidine 2e (0.66 g, 58%)
LC/MS(ESI):m/z＝383[M+H] + 。
5-cyano-2-2- (2-hydroxy-2-methylpropyloxy) -4 hydroxy-6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrimidine 2e (19 mg,0.05 mmol) was dissolved in DCE, then 6-methoxy-3-pyridinecarbaldehyde (7.59 mg,0.0553 mmol) and sodium triacetoxyborohydride (17.6 mg,0.0830 mmol) were added sequentially, then reacted overnight at room temperature with stirring, and then the reduced pressure solution was isolated by preparative column to give 2- (2-hydroxy-2-methylpropyloxy) -6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5 cyano-pyrimidin-4 (3H) -one 2 (24 mg, 96%).
LC/MS(ESI):m/z＝504[M+H] + 。
Example 3
2- ((1-hydroxycyclopropyl) methoxy) -6- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5- (propyl-1-yn-1-yl) pyrimidin-4 (3H) -one (compound 3)
Compound 3 (25 mg, 97% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=515 [ M+H ]] + 。
Example 4
2- ((1-hydroxycyclopropyl) methoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-oxopyrimidine-5-carbonitrile (compound 4)
Compound 4 (23 mg, 91% yield) was obtained by a method similar to example 2. LC/MS (ESI) m/z=502 [ M+H ]] + 。
Example 5
6- (6- (6- ((6-methoxypyridin-3-yl) methyl) -diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -5- (propyl-1-yn-1-yl) pyrimidin-4 (3H) -one (compound 5)
Compound 4 (21 mg, yield 82%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=509 [ M+H ]] + 。
Example 6
6- (6- (6- ((6-methoxypyridin-3-yl) methyl) -diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -5- (propyl-1-yn-1-yl) pyrimidin-4 (3H) -one (compound 6)
Compound 6 (22 mg, 89% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=496 [ M+H ] ] + 。
Example 7
2- ((2-fluoroethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5- (propyl-1-yn-1-yl) pyrimidin-4 (3H) -one (compound 7)
Compound 7 (20 mg, yield 83%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=491 [ M+H ]] + 。
Example 8
2- ((2-fluoroethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-oxopyrimidine-5-carbonitrile (compound 8)
Compound 8 (22 mg, 92% yield) was obtained in a similar manner to example 2. LC/MS (ESI) m/z=478 [ M+H ]] + 。
Example 9
2- ((2-Fluoroethylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5- (propyl-1-yn-1-yl) pyrimidin-4 (3H) -one (compound 9)
Compound 9 (21 mg, yield 87%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=490 [ M+H ]] + 。
Example 10
2- ((2-Fluoroethylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-oxopyrimidine-5-carbonitrile (compound 10)
Compound 10 (22 mg, 92% yield) was obtained in a similar manner to example 2. LC/MS (ESI) m/z=477 [ M+H ] ] + 。
Example 11
2- ((2, 2-trifluoroethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5- (propyl-1-yn-1-yl) pyrimidin-4 (3H) -one (compound 11)
Compound 11 (26 mg, 97% yield) was obtained by a method similar to that of example 1. LC/MS (ESI) m/z=527 [ M+H ]] + 。
Example 12
2- ((2, 2-trifluoroethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-oxopyrimidine-5-carbonitrile (compound 12)
Compound 12 (23 mg, yield 91%) was obtained by a method similar to example 2. LC/MS (ESI) m/z=514 [ M+H ]] + 。
Example 13
2- ((2, 2-trifluoroethylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5- (propyl-1-yn-1-yl) pyrimidin-4 (3H) -one (compound 13)
Compound 13 (25 mg, 94% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=526 [ M+H ]] + 。
Example 14
2- ((2, 2-trifluoroethylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-oxopyrimidine-5-carbonitrile (compound 14)
Compound 14 (24 mg, 48% yield) was obtained by a method similar to example 2. LC/MS (ESI) m/z=513 [ M+H ] ] + 。
Example 15
2- ((3-fluorocyclobutane-1-oxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5- (propyl-1-yn-1-yl) pyrimidin-4 (3H) -one (compound 15)
Compound 15 (23 mg, 89% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=517 [ M+H ]] + 。
Example 16
2- ((3-fluorocyclobutane-1-oxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5-cyanopyrimidin-4 (3H) -one (compound 16)
Compound 16 (22 mg, yield 87%) was obtained by a method similar to example 2. LC/MS (ESI) m/z=504 [ M+H ]] + 。
Example 17
2- ((3-fluorocyclobutane-1-amino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5- (propyl-1-yn-1-yl) pyrimidin-4 (3H) -one (compound 17)
Compound 17 (20 mg, 79% yield) was obtained by a method similar to that of example 1. LC/MS (ESI) m/z=516 [ M+H ]] + 。
Example 18
2- ((3-fluorocyclobutane-1-amino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5-cyanopyrimidin-4 (3H) -one (compound 18)
Compound 18 (22 mg, yield 87%) was obtained by a method similar to example 2. LC/MS (ESI) m/z=503 [ M+H ] ] + 。
Example 19
2- ((3, 3-Difluorocyclobutane-1-oxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5- (propyl-1-yn-1-yl) pyrimidin-4 (3H) -one (compound 19)
Compound 19 (24 mg, 92% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=535 [ M+H ]] + 。
Example 20
2- (3, 3-Difluorocyclobutane-1-oxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5-cyanopyrimidin-4 (3H) -one (compound 20)
Compound 20 (23 mg, 89% yield) was obtained in a similar manner to example 2. LC/MS (ESI) m/z=522 [ M+H ]] + 。
Example 21
2- ((3, 3-Difluorocyclobutane-1-amino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5- (propyl-1-yn-1-yl) pyrimidin-4 (3H) -one (compound 21)
Compound 21 (23 mg, yield 87%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=534 [ M+H ]] + 。
Example 22
2- ((3, 3-Difluorocyclobutane-1-amino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5-cyanopyrimidin-4 (3H) -one (compound 22)
Compound 22 (21 mg, yield 82%) was obtained by a method similar to example 2. LC/MS (ESI) m/z=521 [ M+H ]] + 。
Example 23
2- ((2-fluoroethoxy) -4- (6- (6- ((6-trifluoromethoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5- (propyl-1-yn-1-yl) pyrimidin-4 (3H) -one (compound 23)
Compound 23 (24 mg, yield 88%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=545 [ M+H ]] + 。
Example 24
2- ((2-fluoroethoxy) -4- (6- (6- ((6-trifluoromethylpyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-oxopyrimidine-5-carbonitrile (compound 24)
Compound 24 (24 mg, 90% yield) was obtained in a similar manner to example 2. LC/MS (ESI) m/z=532 [ M+H ]] + 。
Example 25
2- ((2-Fluoroethylamino) -4- (6- (6- ((6-trifluoromethoxy-pyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5- (propyl-1-yn-1-yl) pyrimidin-4 (3H) -one (compound 25)
Compound 25 (25 mg, 92% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=544 [ M+H ]] + 。
Example 26
2- ((2-Fluoroethylamino) -4- (6- (6- ((6-trifluoromethoxy-pyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-oxopyrimidine-5-carbonitrile (compound 26)
Compound 26 (25 mg, 93% yield) was obtained in a similar manner to example 2. LC/MS (ESI) m/z=531 [ M+H ]] + 。
Example 27
2- ((2-fluoroethoxy) -4- (6- (6- ((5-methoxypyrazin-2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5- (propyl-1-yn-1-yl) pyrimidin-4 (3H) -one (compound 27)
Compound 27 (22 mg, 89% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=492 [ M+H ]] + 。
Example 28
2- ((2-fluoroethoxy) -4- (6- (6- ((5-methoxypyrazin-2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-oxopyrimidine-5-carbonitrile (compound 28)
Compound 28 (22 mg, 92% yield) was obtained by a method similar to that of example 2. LC/MS (ESI) m/z=478 [ M+H ]] + 。
Example 29
2- ((2-Fluoroethylamino) -4- (6- (6- ((5-methoxypyrazin-2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5- (propyl-1-yn-1-yl) pyrimidin-4 (3H) -one (compound 29)
Compound 29 (23 mg, yield 95%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=491 [ M+H ]] + 。
Example 30
2- ((2-Fluoroethylamino) -4- (6- (6- ((5-methoxypyrazin-2-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-oxopyrimidine-5-carbonitrile (compound 30)
Compound 30 (23 mg, 96% yield) was obtained in a similar manner to example 2. LC/MS (ESI) m/z=478 [ M+H ]] + 。
The following compounds can be obtained in analogy to the synthetic routes of examples 1-30
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Example 31
2- (2-fluoroethylmercapto) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-oxopyrimidine-5-carbonitrile (compound 59)
To thiourea (3.8 g,50 mmol), 6- (6-boc-3, 6-diazabicyclo [ 3.1.1)]To a solution of heptan-3-yl) nicotinaldehyde (15.15 ml,50 mmol) and ethyl cyanoacetate (5.65 g,50 mmol) in ethanol (100 ml) was added K 2 CO 3 (6.9 g,50 mmol) the reaction mixture was heated to 80℃for 5 hours, cooled and filtered. Crystallization of ethanol gives 5-cyano-2-thio-4 hydroxy-6- (6-boc-3, 6-diazabicyclo [ 3.1.1)]Heptane-3-yl) pyridin-3-yl pyrimidine (16.8 g, 79%).
LC/MS(ESI):m/z＝427[M+H] + 。
5-cyano-2-thio-4 hydroxy-6- (6-boc-3, 6-diazabicyclo [ 3.1.1)]Heptan-3-yl) pyridin-3-yl pyrimidine (1.27 g,3 mmol), 1-fluoro-2-iodoethane (0.57 g,33 mmol) and potassium carbonate (0.5 g,4.5 mmol) were dissolved in DCE, the mixture was then stirred at reflux for 12 hours, the residue was poured into ice water, extracted 2 times with DCM, and taken up in Na 2 SO 4 Drying and concentrating under reduced pressure, dissolving the residue in methanol, then dropwise adding 1N HCl (5 mL) at 0-5deg.C, stirring at room temperature for 3 hr, concentrating under reduced pressure, dissolving in DCM, and concentrating with saturated solution And NaHCO 3 Washing the solution with saturated NaCl, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 5-cyano-2-2- (2-hydroxy-2-methylpropyloxy) -4-hydroxy-6- (3, 6-diazabicyclo [ 3.1.1)]Heptan-3-yl) pyridin-3-yl pyrimidine 2e (0.88 g, 79%)
LC/MS(ESI):m/z＝373[M+H] + 。
5-cyano-2-2- (2-hydroxy-2-methylpropyloxy) -4 hydroxy-6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrimidine 2e (19 mg,0.05 mmol) was dissolved in DCE, then 6-methoxy-3-pyridinecarbaldehyde (7.59 mg,0.0553 mmol) and sodium triacetoxyborohydride (17.6 mg,0.0830 mmol) were added sequentially, then reacted overnight with stirring at room temperature, and then the reduced pressure solution was isolated by preparative column to give 2- (2-hydroxy-2-methylpropyloxy) -6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -5 cyano-pyrimidin-4 (22H) -one 2 (91%).
LC/MS(ESI):m/z＝494[M+H] + 。
Example 32
2- (2, 2-Trifluoroethylmercapto) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-oxopyrimidine-5-carbonitrile (compound 60)
Compound 60 (24.5 mg, 93% yield) was obtained by a method similar to that of example 31. LC/MS (ESI) m/z=530 [ M+H ]] + 。
Example 33
2- (2, 2-Trifluoroethylmercapto) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-oxopyrimidine-5-carbonitrile (compound 61)
Compound 61 (24 mg, yield) was obtained in a similar manner to example 3191％)。LC/MS(ESI):m/z＝532[M+H] + 。
Example 34
2- (2, 2-Trifluoroethylmercapto) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-oxopyrimidine-5-carbonitrile (compound 62)
Compound 62 (23 mg, yield 88%) was obtained by a method similar to example 31. LC/MS (ESI) m/z=531 [ M+H ]] + 。
Example 15 biological Activity test
The invention is further explained below in connection with test examples, but these implementations are not meant to limit the scope of the invention.
Test example 1 measurement of RET enzyme inhibitory Activity of the Compounds of the invention
Test conditions:
enzyme concentration: 2.5nM
ATPKm：16uM
Pre-incubation: 10min
Reaction time: 60min
Compound initial concentration 1 μm, 3-fold dilution, 10 concentrations, multiplex assay.
The test method comprises the following steps:
1. compound preparation compound powder was dissolved in 100% dmso to prepare 10mM stock solution.
2. Kinase reaction process
(1) 1 XKinasebuffer was prepared.
(2) Preparing a compound concentration gradient: the compound test concentration was 1 μm, diluted in 384 plates to 100-fold final concentration of 100% dmso solution, followed by 3-fold dilution of the compound, 10 concentrations. 250nL of 100-fold final concentration of compound was transferred to the destination plate using a dispenser.
(3) A2.5-fold final concentration of kinase solution was prepared using a 1 XKinasebuffer.
(4) Adding 10 mu L of kinase solution with 2.5 times of final concentration to each of the compound well and the positive control well; to the negative control wells, 10. Mu.L of 1 XKinasebuffer was added.
(5) Centrifugation at 1000rpm for 30 seconds, the reaction plate was shaken and mixed well and incubated at room temperature for 10 minutes.
(6) A5/3-fold final concentration of a mixed solution of ATP and Kinase substrate 2 was prepared using a 1 XKinasebuffer.
(7) The reaction was initiated by adding 15. Mu.L of a 5/3-fold final concentration of the mixed solution of ATP and substrate.
(8) The 384-well plate was centrifuged at 1000rpm for 30 seconds, and after shaking and mixing, incubated at room temperature for 60 minutes.
(9) The kinase reaction was stopped by adding 30. Mu.L of stop detection solution, centrifuging at 1000rpm for 30 seconds, and shaking and mixing.
(10) The conversion was read with Caliper EZ Reader.
3. Data analysis
The calculation formula is as follows: % inhibition= (Conversion% _max-Conversion% _sample)/(Conversion% _max-Conversion% _min) ×100%
Wherein: conversion% _sample is a Conversion reading of the sample;
convertion% _min: negative control Kong Junzhi, representing conversion reading without enzyme wells;
convesion% _max: positive control Kong Bizhi mean represents conversion readings for wells without compound inhibition.
Fitting dose-response curve: the log value of the concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and an analytical software GraphPad Prism 5 fit quantitative response curve is adopted to obtain the IC of each compound on the enzyme activity 50 Values. Wherein' ++ + "is indicated by IC 50 Less than or equal to 10nM; "+". ++'s represents 10nM<IC 50 Less than or equal to 500nM; "++" means 500nM<IC 50 Less than or equal to 2000nM; "+" means 2000nM<IC 50 。
The test results are shown in table 1:
TABLE 1 in vitro enzymatic Activity test data
Test example 1 inhibition of Ba/F3KIF5B-RET cell growth by Compounds of the invention
Ba/F3KIF5B-RET, ba/F3KIF5B-RET-V804M, ba/F3 RET-M918T cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was checked by trypan blue exclusion, ensuring that cell viability was above 90%. Cell concentrations were adjusted and 90 μl of cell suspension was added to each 96-well plate. Cells in 96-well plates were incubated overnight at 37 ℃, 5% co2, 95% humidity. A corresponding 10. Mu.L gradient of drug solution (1000 nM maximum) was added to each well of a 96-well plate seeded with cells, three wells were set for each drug concentration, and the final DMSO concentration was 0.1%. Cells in the dosed 96-well plates were incubated at 37℃under 5% CO2 at 95% humidity for a further 72 hours. After completion of the drug action, 100. Mu.L CellTiter-Glo reagent was added to each well, the cells were lysed by shaking on an orbital shaker for 5 minutes, and the cell plates were left at room temperature for 20 minutes to stabilize the luminescence signal, and then the luminescence value was read. Analysis of data using GraphPadPrism 5.0 software, fitting data to derive dose-response curves using nonlinear S-curve regression, and calculating IC therefrom 50 Values, results are shown in table 1. Wherein' ++ + "is indicated by IC 50 Less than or equal to 10nM; "+". ++'s represents 10nM<IC 50 Less than or equal to 500nM; "++" means 500nM<IC 50 Less than or equal to 2000nM; "+" means 2000nM<IC 50 。
Table 1, inhibitory Activity of Compounds against tumor cell proliferation IC 50 (nm)。
Although the invention has been described in detail hereinabove, those skilled in the art will appreciate that various modifications and changes can be made thereto without departing from the spirit and scope of the invention. The scope of the invention is not limited by the detailed description set forth above, but rather is to be attributed to the claims.

Claims (7)

1. A compound having the general formula (I), a stereoisomer, a pharmaceutically acceptable salt, a polymorph or an isomer thereof, wherein the compound of the general formula (I) has the structure:
wherein,
each L 1 Independently at each occurrence selected from the group consisting of bond, OC 0-3 Alkyl, NHC 0-6 Alkyl, C 1-3 Alkyl, COC 0-3 Alkyl or SC 0-3 An alkyl group;
each L 2 Independently at each occurrence selected from the group consisting of bond, OC 0-3 Alkyl, NHC 0-6 Alkyl, C 1-3 Alkyl, COC 0-3 Alkyl or SC 0-3 An alkyl group;
each L 3 Independently at each occurrence selected from the group consisting of bond, C 0-3 Alkyl, NHC 0-6 Alkyl, C 1-3 Alkyl, COC 0-3 Alkyl or SC 0-3 An alkyl group;
each L 4 Independently at each occurrence selected from the group consisting of bond, C 0-3 Alkyl, NHC 0-6 Alkyl, C 1-3 Alkyl, COC 0-3 Alkyl or SC 0-3 An alkyl group;
each X is 1 Independently at each occurrence selected from N or CR 9 ；
Each R 1 Independently at each occurrence selected from H, halogen, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -OR 6 、-C 2-6 Alkenyl radicalsC 2-6 Alkynyl, -C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 -C1-6 alkylene-NR 6 R 7 、-C(＝O)R 6 、-C(＝O)OR 6 、-OC(＝O)R 6 、-C(＝O)NR 6 R 7 、-NR 6 C(＝O)R 7 、-S(O) 2 NR 6 R 7 or-C 3-6 Carbocyclyl; each R 1 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OC 1-6 Alkyl, -NC 1-6 Alkyl C 1-6 Alkyl, -CN, -C (=o) C 1-6 Alkyl, -C (=o) OC 1-6 Alkyl, -OC (=o) C 1-6 Alkyl, -C (=o) NC 1-6 Alkyl C 1-6 Alkyl, -NC 1-6 Alkyl C (=O) C 1-6 Alkyl or-S (O) 2 NC 1-6 Alkyl C 1-6 The substituent of the alkyl group is substituted or unsubstituted;
each R 9 Independently at each occurrence selected from H, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, C 3-6 Heterocycloalkyl, C 3-6 Cycloalkyl, -CN, -OR 6 、-C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 -C1-6 alkylene-NR 6 R 7 、-C(＝O)R 6 、-C(＝O)OR 6 、-OC(＝O)R 6 、-C(＝O)NR 6 R 7 、-NR 6 C(＝O)R 7 、-S(O) 2 NR 6 R 7 Or phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl; each R 9 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl group、-C 1-6 Alkoxy, oxo, -OC 1-6 Alkyl, -NC 1-6 Alkyl C 1-6 Alkyl, -CN, -C (=o) C 1-6 Alkyl, -C (=o) OC 1-6 Alkyl, -OC (=o) C 1-6 Alkyl, -C (=o) NC 1-6 Alkyl C 1-6 Alkyl, -NC 1-6 Alkyl C (=O) C 1-6 Alkyl or-S (O) 2 NC 1-6 Alkyl C 1-6 The substituent of the alkyl group is substituted or unsubstituted;
each R 2 Independently at each occurrence selected from H, deuterium, -CN, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, C 3-12 Cycloalkyl, C 7-12 Spirocycloalkyl, C 7-12 Heterospirocycloalkyl, C 3-12 Heterocycloalkyl, phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 -C1-6 alkylene-NR 6 R 7 、-C(＝O)R 6 、-C(＝O)OR 6 、-OC(＝O)R 6 、-C(＝O)NR 6 R 7 、-NR 6 C(＝O)R 7 、-S(O) 2 NR 6 R 7 or-C 3-6 Carbocyclyl; each R 2 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OC 1-6 Alkyl, -NC 1-6 Alkyl C 1-6 Alkyl, -CN, -C (=o) C 1-6 Alkyl, -C (=o) OC 1-6 Alkyl, -OC (=o) C 1-6 Alkyl, -C (=o) NC 1-6 Alkyl C 1-6 Alkyl, -NC 1-6 Alkyl C (=O) C 1-6 Alkyl or-S (O) 2 NC 1-6 Alkyl C 1-6 The substituent of the alkyl group is substituted or unsubstituted;
each Ar is provided with 1 Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered hetero Aryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each R 1 Independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 10 Substituted or unsubstituted;
each Ar is provided with 2 Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each R 1 Independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 10 Substituted or unsubstituted;
each R 10 Independently at each occurrence selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -OR 6 、-C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 -C1-6 alkylene-NR 6 R 7 、-C(＝O)R 6 、-C(＝O)OR 6 、-OC(＝O)R 6 、-C(＝O)NR 6 R 7 、-NR 6 C(＝O)R 7 、-S(O) 2 NR 6 R 7 or-C 3-6 Carbocyclyl; each R 20 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(＝O)R 6 、-C(＝O)OR 6 、-OC(＝O)R 6 、-C(＝O)NR 6 R 7 、-NR 6 C(＝O)R 7 or-S (O) 2 NR 6 R 7 Substituted or unsubstituted;
each R 6 And R is 7 Independently at each occurrence selected from hydrogen or-C 1-6 Alkyl, each R 6 And R is 7 Independently optionally 1,2. 3, 4, 5 or 6R 8 Substituted or unsubstituted; or R is 7 And R is 7 Together with the N atom to which they are attached, form a 3-10 membered heterocyclic ring, said 3-10 membered heterocyclic ring may further comprise 1, 2, 3 or 4 groups selected from N, O, S, S (=O) or S (=O) 2 And said 3-10 membered heterocyclic ring is independently optionally substituted with 1, 2, 3, 4, 5 or 6R 8 Substituted or unsubstituted;
each R 8 Independently at each occurrence selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -O-C 1-6 Alkylene- (halogen) 1-3 、-SC 1-6 Alkyl, -S-C 1-6 Alkylene- (halogen) 1-3 、-NC 1-6 C 1-6 、-C 1-6 alkylene-NC 1-6 Alkyl C 1-6 Alkyl, -C (=o) C 1-6 Alkyl, -C (=o) OC 1-6 Alkyl, -OC (=o) C 1-6 Alkyl, -C (=o) NC 1-6 Alkyl C 1-6 Alkyl, -NC 1-6 Alkyl C (=O) C 1-6 Alkyl, -S (O) 2 NC 1-6 Alkyl C 1-6 Alkyl or-C 3-6 Carbocyclyl.
2. A compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to claim 1, selected from the group consisting of:
3. a pharmaceutical composition comprising a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
4. Use of a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 3, in the manufacture of a medicament for the treatment of a RET mediated disease.
5. Use according to claim 3, wherein said RET is selected from wild-type RET, mutant RET, RET fusions; the mutant RET is selected from the group consisting of G810R mutant RET, M918T mutant RET, V804L mutant RET, and V804M mutant RET, and the RET fusion is selected from the group consisting of KIF5B-RET fusion and CCDC6-RET fusion.
6. The use according to claim 3, wherein the disease is selected from cancer, irritable bowel syndrome.
7. Use of a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 3, in the manufacture of a medicament for the treatment of cancer.
CN202211273054.6A 2022-10-18 2022-10-18 Preparation and application of RET inhibitor Pending CN117229292A (en)

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