CN114072412B - Tricyclic compound, pharmaceutical composition and application thereof - Google Patents

Tricyclic compound, pharmaceutical composition and application thereof Download PDF

Info

Publication number
CN114072412B
CN114072412B CN202180004265.7A CN202180004265A CN114072412B CN 114072412 B CN114072412 B CN 114072412B CN 202180004265 A CN202180004265 A CN 202180004265A CN 114072412 B CN114072412 B CN 114072412B
Authority
CN
China
Prior art keywords
cancer
pyrrole
pyridin
amino
tricyclic compound
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.)
Active
Application number
CN202180004265.7A
Other languages
Chinese (zh)
Other versions
CN114072412A (en
Inventor
黄立晔
李华
刘华斌
王志远
李涛
欧阳飞燕
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Bolijian Pharmaceutical Co ltd
Original Assignee
Shenzhen Bolijian Pharmaceutical Co ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Shenzhen Bolijian Pharmaceutical Co ltd filed Critical Shenzhen Bolijian Pharmaceutical Co ltd
Publication of CN114072412A publication Critical patent/CN114072412A/en
Application granted granted Critical
Publication of CN114072412B publication Critical patent/CN114072412B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The application provides a tricyclic compound, an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical composition and an application thereof, wherein the tricyclic compound has a structure shown as a formula I, has a remarkable effect of inhibiting the activity of RET kinase, can effectively inhibit the proliferation of cancer cells, can be used as an RET kinase inhibitor, can be used for preparing a medicament for treating diseases mediated by RET kinase, has a good treatment effect on the diseases mediated by RET kinase, such as cancers, and the like, and has a wide application prospect.

Description

Tricyclic compound, pharmaceutical composition and application thereof
Technical Field
The application belongs to the technical field of pharmaceutical chemistry, and particularly relates to tricyclic compounds, pharmaceutical compositions containing the compounds and application of the compounds or the pharmaceutical compositions in preparation of drugs.
Background
RET is a receptor tyrosine kinase. In normal tissues, RET plays a key role in fetal kidney development and neurogenesis. However, mutation of RET promotes ligand-independent, sustained activation of RET kinase, driving tumorigenesis (literature 1). RET kinases can be oncogenically activated by gene rearrangements or point mutations. RET gene rearrangement produces a fusion protein dimer that is continuously activated. The most common RET fusion proteins are KIF5B-RET, CCDC6-RET, NCOA4-RET and TRIM33-RET (reference 2). RET fusions are present in 10-20% of Papillary Thyroid Carcinomas (PTC), 1-2% of non-small cell lung carcinomas (NSCLC) (references 3-4), and other cancers (reference 5). RET mutations can occur at extracellular cysteine residues (e.g., C620R, C R or C634W), causing aberrant receptor dimerization, or in the intracellular kinase region (e.g., V804L, V M or M918T), facilitating ligand-independent kinase activation. RET mutations are predominantly present in Medullary Thyroid Carcinoma (MTC).
RET inhibitors have been clinically proven effective for the treatment of MTC with RET mutation and lung cancer positive for RET fusion (references 6 to 10). For example, vandetanib and cabozantinib have been approved for the treatment of metastatic or locally advanced MTC. However, these drugs have limited disease control because these multi-kinase inhibitors were originally designed to inhibit other kinases and have less activity than other kinases, thereby creating off-target side effects and limiting the dose that patients can tolerate.
Therefore, the development of a novel RET kinase inhibitor to inhibit RET kinase activity and RET fusion and mutant cellular activity, to effectively inhibit RET fusion and RET mutant tumors in animals, and to achieve RET driven cancer therapy is a major research point in the art.
Citations
1.Jhiang,SM.The RET proto-oncogene in human cancers.Oncogene 2000,19:5590-5597.
2.Kato,S.et al.RET aberrations in diverse cancers:next-generation sequencing of 4871 patients.Clin.Cancer Res.2017,23(8):1988–1997.
3.Giuseppe B.et al.Targeting RET-rearranged non-small-cell lung cancer:future prospects.Lung Cancer:Targets and Therapy 2019,10:27-36.
4.Christoph,J.et al.Targeted therapy for RET-rearranged non-small cell lung cancer:Clinical development and future directions.OncoTargets and Therapy 2019,12:7857-7864.
5.Le Rolle,AF.et al.Identification and characterization of RET fusions in advanced colorectal cancer.Oncotarget 2015,6:28929-28937.
6.Kurzrock,R.et al.Activity of XL184(Cabozantinib),an oral tyrosine kinase inhibitor,in patients with medullary thyroid cancer.J.Clin.Oncol.2011,29(19):2660-2666.
7.Elisei,R.et al.Cabozantinib in progressive medullary thyroid cancer.J.Clin.Oncol.2013,31(29):3639-3646.
8.Wells,SA Jr.et al.Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer:a randomized,double-blind phase III trial.J.Clin.Oncol.2012,30(2):134-141.
9.Drilon,A.et al.Cabozantinib in patients with advanced RET-rearranged non-smallcell lung cancer:an open-label,single-centre,phase 2,single-arm trial.Lancet Oncol.2016,17:1653-1560.
10.Lee,S.H.et al.Vandetanib in pretreated patients with advanced non-small cell lung cancer harboring RET rearrangement:a phase II clinical trial.Ann.Oncol.2017,28:292-297.
Disclosure of Invention
The application provides a tricyclic compound, a pharmaceutical composition and application thereof.
In a first aspect, the present application provides a tricyclic compound having a structure as shown in formula I:
Figure BDA0003442482540000021
wherein
R 1 Selected from H, halogen, C1-C10 straight chain or branched chain alkyl, C3-C10 naphthenic base, C2-C10 heterocyclic alkyl, C6-C20 aryl or C3-C20 heteroaryl;
R 2 、R 3 each independently selected from H, C-C10 straight chain or branched chain alkyl, C3-C10 cycloalkyl; the R is 2 、R 3 Not linked or linked by chemical bonds to form a ring;
R 4 selected from H, C straight chain or branched chain alkyl, C3-C10 naphthenic base, C2-C10 heterocyclic alkyl, C6-C20 aryl, C3-C20 heteroaryl and COR a 、CONR b R c 、CO 2 R d 、SO 2 R a Or SO 2 NR b R c (ii) a Said straight or branched alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl being unsubstituted or substituted by 1 to 3 (e.g. 1,2 or 3) R 4a Substitution;
R 4a selected from D, halogen, cyano, OR a1 、SR a1 、NR b1 R c1 、COR a1 、CONR b1 R c1 、CO 2 R d1 、SO 2 R a1 、SO 2 NR b1 R c1 C1-C10 straight chain or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 naphthenic base, C2-C10 heterocyclic alkyl, C6-C20 aryl or C3-C20 heteroaryl; said straight or branched alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl being unsubstituted or substituted by 1 to 3 (e.g. 1,2 or 3) R 4b Substitution;
R a 、R b 、R c 、R d 、R a1 、R b1 、R c1 、R d1 each independently selected from H, C-C10 straight chain or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; said straight or branched alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl being unsubstituted or substituted by 1 to 4 (e.g. 1,2, 3 or 4) R 5 Substitution;
R 4b 、R 5 each independently selected from D, halogen, cyano, hydroxy, unsubstituted OR halogenated C1-C10 linear OR branched alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl, C3-C20 heteroaryl, OR a2 、SR a2 、NR b2 R c2 、COR a2 、CONR b2 R c2 、CO 2 R d2 、SO 2 R a2 、SO 2 NR b2 R c2 、NR b2 COR d2 、NR a2 CONR b2 R c2 、NR b2 SO 2 R d2 、NR b2 SO 2 NR b2 R c2 Or SOR a2 (ii) a And is
R a2 、R b2 、R c2 、R d2 Each independently selected from H, C1-C10 straight or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl, or C3-C20 heteroaryl.
In the above groups, 2 substituents R attached to the same N b And R c 、R b1 And R c1 、R b2 And R c2 Are not linked to each other or are linked by a chemical bond to form a heterocycloalkyl group; said heterocycloalkyl being unsubstituted or substituted by 1 to 3 (e.g. 1,2 or 3) substituents selected from the group consisting of 5 The same is true.
In the present application, all of C1 to C10 may be C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10.
The C3-C10 can be C3, C4, C5, C6, C7, C8, C9 or C10.
The C2-C10 can be C2, C3, C4, C5, C6, C7, C8, C9 or C10.
The C6-C20 can be C6, C10, C12, C13, C14, C16, C18, C19 or C20, etc.
The C3 to C20 may be C3, C4, C5, C6, C10, C12, C13, C14, C16, C18, C19 or C20, etc.
Preferably, the azatricyclic compound has the structure shown in formula IA:
Figure BDA0003442482540000031
in formula IA, R 1 、R 4 Each independently having the same limitations as in formula I.
In formula IA, R 1 Selected from H, halogen, C1-C10 straight chain or branched chain alkyl, C3-C10 naphthenic base, C2-C10 heterocyclic alkyl, C6-C20 aryl or C3-C20 heteroaryl;
R 4 selected from H, C straight chain or branched chain alkyl, C3-C10 naphthenic base, C2-C10 heterocyclic alkyl, C6-C20 aryl, C3-C20 heteroaryl and COR a 、CONR b R c 、CO 2 R d 、SO 2 R a Or SO 2 NR b R c (ii) a The straight chain or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are unsubstituted or substituted by 1 to 3R 4a Substitution;
R 4a selected from D, halogen, cyano, OR a1 、SR a1 、NR b1 R c1 、COR a1 、CONR b1 R c1 、CO 2 R d1 、SO 2 R a1 、SO 2 NR b1 R c1 C1-C10 straight chain or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 naphthenic base, C2-C10 heterocyclic alkyl, C6-C20 aryl or C3-C20 heteroaryl; the straight chain or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are unsubstituted or substituted by 1 to 3R 4b Substitution;
R a 、R b 、R c 、R d 、R a1 、R b1 、R c1 、R d1 each independently selected from H, C-C10 straight chain or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl, or C3-C20 heteroaryl; the straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted by 1 to 4R 5 Substitution;
R 4b 、R 5 each independently selected from D, halogen, cyano, hydroxy, unsubstituted OR halogenated C1-C10 linear OR branched alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl, C3-C20 heteroaryl, OR a2 、SR a2 、NR b2 R c2 、COR a2 、CONR b2 R c2 、CO 2 R d2 、SO 2 R a2 、SO 2 NR b2 R c2 、NR b2 COR d2 、NR a2 CONR b2 R c2 、NR b2 SO 2 R d2 、NR b2 SO 2 NR b2 R c2 Or SOR a2 (ii) a And is
R a2 、R b2 、R c2 、R d2 Each independently selected from H, C1-C10 straight or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl, or C3-C20 heteroaryl.
Preferably, said R is 1 Selected from H or halogen.
Preferably, the azatricyclic compound has the structure shown in formula IB:
Figure BDA0003442482540000041
in the formula IB, R 1 、R 4 Each independently having the same limitations as in formula I.
In the formula IB, R 1 Selected from H, halogen, C1-C10 straight chain or branched chain alkyl, C3-C10 naphthenic base, C2-C10 heterocyclic alkyl, C6-C20 aryl or C3-C20 heteroaryl;
R 4 selected from H, C straight chain or branched chain alkyl, C3-C10 naphthenic base, C2-C10 heterocyclic alkyl, C6-C20 aryl, C3-C20 heteroaryl and COR a 、CONR b R c 、CO 2 R d 、SO 2 R a Or SO 2 NR b R c (ii) a The straight chain or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are unsubstituted or substituted by 1 to 3R 4a Substitution;
R 4a selected from D, halogen, cyano, OR a1 、SR a1 、NR b1 R c1 、COR a1 、CONR b1 R c1 、CO 2 R d1 、SO 2 R a1 、SO 2 NR b1 R c1 C1-C10 straight chain or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 naphthenic base, C2-C10 heterocyclic alkyl, C6-C20 aryl or C3-C20 heteroaryl; the straight chain or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are unsubstituted or substituted by 1 to 3R 4b Substitution;
R a 、R b 、R c 、R d 、R a1 、R b1 、R c1 、R d1 each independently selected from H, C-C10 straight chain or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; the straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted by 1 to 4R 5 Substitution;
R 4b 、R 5 each independently selected from D, halogen, cyano, hydroxy, unsubstituted OR halogenated C1-C10 linear OR branched alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl, C3-C20 heteroaryl, OR a2 、SR a2 、NR b2 R c2 、COR a2 、CONR b2 R c2 、CO 2 R d2 、SO 2 R a2 、SO 2 NR b2 R c2 、NR b2 COR d2 、NR a2 CONR b2 R c2 、NR b2 SO 2 R d2 、NR b2 SO 2 NR b2 R c2 Or SOR a2 (ii) a And is
R a2 、R b2 、R c2 、R d2 Each independently selected from H, C1-C10 straight or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl, or C3-C20 heteroaryl.
Preferably, said R is 1 Selected from H or halogen.
Preferably, said R is 4 Selected from C1-C10 (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10) straight or branched chain alkyl, C3-C10 (e.g., C3, C4, C5, C6, C7, C8, C9 or C10) cycloalkyl, C2-C10 (e.g., C2, C3, C4, C5, C6, C7, C8, C9 or C10) heterocycloalkyl, COR a Or CONR b R c (ii) a Said straight or branched alkyl, cycloalkyl, heterocycloalkyl being unsubstituted or substituted by 1 to 3 (e.g. 1,2 or 3) R 4a And (4) substitution.
Preferably, said R is 4a Selected from D, halogen, cyano, OR a1 A C1-C10 (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10) straight or branched chain alkyl group, a C3-C10 (e.g., C3, C4, C5, C6, C7, C8, C9, or C10) cycloalkyl group, a C2-C10 (e.g., C2, C3, C4, C5, C6, C7, C8, C9, or C10) heterocycloalkyl group, a C6-C20 (e.g., C6, C10, C12, C13, C14, C16, C18, C19, or C20, etc.) aryl group, or a C3-C20 (e.g., C3, C4, C5, C6, C10, C12, C13, C14, C16, C18, C19, or C20, etc.) heteroaryl group; said straight or branched alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl being unsubstituted or substituted by 1 to 3 (e.g. 1,2 or 3) R 4b And (4) substitution.
Preferably, said R is a 、R b 、R c 、R d 、R a1 、R b1 、R c1 、R d1 Each independently selected from H, C (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10) straight or branched chain alkyl, C3 to C10 (e.g., C3, C4, C5, C6, C7, C8, C9, or C10) cycloalkyl, C2 to C10 (e.g., C2, C3, C4, C5, C6, C10, C3, C10, C9, or C10) cycloalkyl,C7, C8, C9, or C10) heterocycloalkyl, C6 to C20 (e.g., C6, C10, C12, C13, C14, C16, C18, C19, or C20, etc.) aryl, or C3 to C20 (e.g., C3, C4, C5, C6, C10, C12, C13, C14, C16, C18, C19, or C20, etc.) heteroaryl; said straight or branched alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl being unsubstituted or substituted by 1 to 4 (e.g. 1,2, 3 or 4) R 5 And (4) substitution.
Preferably, said R is 4b 、R 5 Each independently selected from D, halogen, cyano, hydroxy, unsubstituted or halogenated C1 to C10 (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10) straight or branched alkyl, C3 to C10 (e.g., C3, C4, C5, C6, C7, C8, C9, or C10) cycloalkyl, or C2 to C10 (e.g., C2, C3, C4, C5, C6, C7, C8, C9, or C10) heterocycloalkyl.
Preferably, the tricyclic compound comprises any one of the following compounds:
Figure BDA0003442482540000051
Figure BDA0003442482540000061
Figure BDA0003442482540000071
Figure BDA0003442482540000081
in another aspect, the present application provides a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof of the tricyclic compound described above.
In another aspect, the present application provides a pharmaceutical composition comprising an active ingredient comprising a tricyclic compound as described above, and/or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof, as described above, and at least one pharmaceutically acceptable carrier or excipient.
In another aspect, the present application provides a tricyclic compound as described above, a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition as described above, for use in the manufacture of a medicament for inhibiting RET kinase.
Preferably, the RET kinase includes RET mutant kinase and RET fusion protein kinase.
In another aspect, the present application provides a tricyclic compound as described above, a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof as described above, or a pharmaceutical composition as described above for use in the preparation of a medicament for the treatment of a disease mediated by RET kinase.
Preferably, the disease is cancer.
Preferably, the cancer comprises breast cancer, small cell lung cancer, non-small cell lung cancer, bronchoalveolar carcinoma, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, cancer of gastrointestinal tissue, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, vaginal cancer, leukemia, multiple myeloma, or lymphoma.
Compared with the prior art, the method has the following beneficial effects:
the application provides a tricyclic compound with a novel chemical structure, which has a remarkable effect of inhibiting the activity of RET kinase and has half inhibitory concentration IC (total inhibitory concentration) on the RET kinase 50 The molecular weight is as low as 0.53-2.1 nM, can effectively inhibit cancer cell proliferation, can be used as an RET kinase inhibitor, can be used for preparing a medicament for treating RET kinase mediated diseases, has good treatment effect on RET kinase mediated cancers and other diseases, and has wide application prospect.
Detailed Description
The technical solution of the present application is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present application and should not be construed as a specific limitation of the present application.
The term "halo" or "halogen" in this application includes fluorine, chlorine, bromine, and iodine.
The term "linear or branched alkyl" refers to a linear or branched saturated hydrocarbon group. Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl (e.g., n-hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 3-ethylpentyl-1, etc.), heptyl (e.g., n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl-1, etc.), octyl (e.g., 1-octyl, 2-ethylhexyl, etc.), nonyl (e.g., 1-nonyl), decyl (e.g., n-decyl, etc.), and the like. More preferably, the alkyl group is a linear or branched alkyl group having 1,2, 3, 4, 5 or 6 carbon atoms. Unless defined to the contrary, all radical definitions in this application are as defined herein.
The term "haloalkyl" refers to an alkyl group having one or more halo substituents. Wherein the alkyl group and halo or halogen are as defined above. Examples of haloalkyl groups include CH 2 F、CHF 2 、CF 3 、C 2 F 5 、CCl 3 And the like.
The term "alkenyl" refers to a hydrocarbyl group having one or more C = C double bonds. Examples of alkenyl groups include ethenyl, propenyl, allyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 1,3-pentadienyl, 1-hexenyl, 2-hexenyl, and the like.
The term "alkynyl" refers to a hydrocarbyl group having one or more C ≡ C triple bonds. Examples of alkynyl groups include ethynyl, propynyl, propargyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, and the like.
The term "cycloalkyl" refers to a non-aromatic carbocyclic ring, including cyclized alkyl, cyclized alkenyl, and cyclized alkynyl groups. Cycloalkyl groups can be monocyclic or polycyclic (e.g., having 2,3, or 4 fused rings) ring systems, including spirocyclic rings. In certain embodiments, cycloalkyl groups may have 3, 4, 5, 6,7,8,9, 10 carbon atoms. The cycloalkyl group may further have 0, 1,2 or 3C = C double bonds and/or 0, 1 or 2C ≡ C triple bonds. Also included in the definition of cycloalkyl are those moieties having one or more aromatic rings fused to the cycloalkyl ring (e.g., having a common bond), such as benzo derivatives of pentane, pentene, hexane, hexene, and the like. Cycloalkyl groups having one or more fused aromatic rings can be linked through aromatic or non-aromatic moieties. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, adamantyl, indanyl, tetrahydronaphthyl, and the like.
The term "heterocycloalkyl" refers to a non-aromatic heterocyclic ring in which one or more of the ring-forming atoms is a heteroatom such as O, N, P or S. Heterocyclyl groups may include monocyclic or polycyclic (e.g. having 2,3 or 4 fused rings) ring systems as well as spirocyclic rings. Examples of preferred "heterocycloalkyl" groups include, but are not limited to: aziridinyl, azetidinyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, and the like. Also included in the definition of heterocycloalkyl are those moieties having one or more aromatic rings (e.g., having a shared bond) fused to a non-aromatic heterocycloalkyl ring, such as 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, benzo-1,4-dioxacyclohexyl, phthalimido, naphthalimide, and the like. Heterocycloalkyl groups having one or more fused aromatic rings can be attached through an aromatic or non-aromatic moiety.
The term "aryl" refers to a monocyclic or polycyclic (e.g., having 2,3, or 4 fused rings) aromatic hydrocarbon such as phenyl, naphthyl, anthryl, phenanthryl, indenyl, and the like.
The term "heteroaryl" refers to an aromatic heterocyclic ring having at least one heteroatom ring member such as O, N or S. Heteroaryl groups include monocyclic or polycyclic (e.g., having 2,3, or 4 fused rings) ring systems. Any ring-forming N atom in the heterocyclic group may also be oxidized to form an N-oxide. Examples of preferred "heteroaryl" groups include, but are not limited to: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, thienyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, benzofuranyl, benzothienyl, benzothiazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzimidazolyl, pyrrolopyridyl, pyrrolopyrimidyl, pyrazolopyridyl, pyrazolopyrimidinyl, and the like.
The term "tricyclic compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, isotopes.
The tricyclic compounds of the present application can be asymmetric, e.g., having one or more stereocenters. Unless otherwise defined, all stereoisomers, both enantiomers and diastereomers, may be present. Compounds of the present application containing asymmetrically substituted carbon atoms may be isolated in optically pure or racemic forms. Optically pure forms can be prepared by resolution of the racemate or by using chiral synthons (synthons) or chiral reagents.
The tricyclic compounds of the present application may also include tautomeric forms. The novel forms of tautomers result from the exchange of a single bond and an adjacent double bond together with the migration of a proton.
The tricyclic compounds of the present application may also include all isotopic forms of the atoms present in the intermediate or final compound. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.
The present application also includes pharmaceutically acceptable salts of the tricyclic compounds. "pharmaceutically acceptable salt" refers to a derivative of a compound in which the parent compound is modified by conversion of an existing base moiety to its salt form, or a derivative of a compound in which the parent compound is modified by conversion of an existing acid moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to: salts of inorganic or organic acids of basic groups, such as ammonia, or salts of inorganic or organic bases of acidic groups, such as carboxylic acids. The pharmaceutically acceptable salts of the present application can be synthesized from the parent compounds of formula I, formula IA and formula IB by reacting the free base forms of these compounds with 1 to 4 equivalents of the appropriate acid in a solvent system. Suitable salts are listed in Remington's Pharmaceutical Sciences,17th ed., mack Publishing Company, easton, pa.,1985,1418 and Journal of Pharmaceutical Science,66,2,1977.
The tricyclic compounds of the present application, and pharmaceutically acceptable salts thereof, also include solvate forms or hydrate forms. In general, the solvate form or hydrate form is equivalent to the non-solvate form or non-hydrate form and is included within the scope of the present application. Some of the compounds of the present application may exist in various crystalline forms or amorphous forms. In general, all physical forms of the compounds are included within the scope of the present application.
Prodrugs of the tricyclic compounds are also included. A prodrug is a pharmacological substance (i.e., drug) that is derived from the parent drug. Once administered, the prodrug is metabolized in vivo to the parent drug. Prodrugs can be prepared by substituting one or more functional groups present in the compound. Preparation and use of prodrugs can be found in T.Higuchi and V.Stella, "Pro-drugs as Novel Delivery Systems", vol.14 of the A.C.S.Symphosis Series and Bioreversible Carriers in Drug Delivery, ed.Edward B.Roche, american Pharmaceutical Association and Pergamon Press, 1987.
In one embodiment, the tricyclic compound includes the following compounds:
(4-amino-9,9-dimethyl-5- (1H-pyrrole [2,3-b ] pyridin-2-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (tetrahydro-2H-pyran-4-yl) methanone
(4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (tetrahydro-2H-pyran-4-yl) methanone
5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-7- ((tetrahydro-2H-pyran-4-yl) methyl) -6,7,8,9-tetrahydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-4-amine
(4 '-amino-5' - (1H-pyrrole [2,3-b ] pyridin-2-yl) -6'H-spiro [ cyclopropane-1,9' -pyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine ] -7 '(8'H) -yl) (tetrahydro-2H-pyran-4-yl) methanone
(4 '-amino-5' - (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -6'H-spiro [ cyclopropane-1,9' -pyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine ] -7 '(8'H) -yl) (tetrahydro-2H-pyran-4-yl) methanone
5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -7- (2-methoxyethyl) -9,9-dimethyl-6,7,8,9-tetrahydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-4-amine
(4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-N- (tetrahydro-2H-pyran-4-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine-7 (6H) carboxamide
(4-amino-9,9-dimethyl-5- (1H-pyrrole [2,3-b ] pyridin-2-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (2- (trifluoromethyl) pyridin-4-yl) methanone
(4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (2- (trifluoromethyl) pyridin-4-yl) methanone
5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-7- ((2- (trifluoromethyl) pyridin-4-yl) methyl) -6,7,8,9-tetrahydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-4-amine
(S) -1- (4-amino-9,9-dimethyl-5- (1H-pyrrole [2,3-b ] pyridin-2-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) -2-hydroxypropan-1-one
(S) -1- (4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) -2-hydroxypropan-1-one
(S) -1- (4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) propan-2-ol
(R) -1- (4-amino-9,9-dimethyl-5- (1H-pyrrole [2,3-b ] pyridin-2-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) -2-hydroxypropan-1-one
(R) -1- (4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) -2-hydroxypropan-1-one
(R) -1- (4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) propan-2-ol
(R) - (4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (tetrahydrofuran-2-yl) methanone
(R) -5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-7- ((tetrahydrofuran-2-yl) methyl) -6,7,8,9-tetrahydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-4-amine
(S) - (4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (tetrahydrofuran-2-yl) methanone
(S) -5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-7- ((tetrahydrofuran-2-yl) methyl) -6,7,8,9-tetrahydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-4-amine
1- (4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) -2-hydroxyethan-1-one
2- (4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) ethan-1-ol
1- (4-amino-9,9-dimethyl-5- (1H-pyrrole [2,3-b ] pyridin-2-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) ethan-1-one
1- (4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) -2-ethan-1-one
1- (4-amino-5- (3-bromo-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) -2-ethan-1-one
(4-amino-9,9-dimethyl-5- (1H-pyrrole [2,3-b ] pyridin-2-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (2-methylpyridin-4-yl) methanone
(4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (2-methylpyridin-4-yl) methanone
(S) -1- (4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) -2-morpholinopropan-1-one
(R) -1- (4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) -2-morpholinopropan-1-one
1- (4 '-amino-5' - (1H-pyrrole [2,3-b ] pyridin-2-yl) -6'H-spiro [ cyclopropane-1,9' -pyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine ] -7 '(8'H) -yl) ethan-1-one
1- (4 '-amino-5' - (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -6'H-spiro [ cyclopropane-1,9' -pyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine ] -7 '(8'H) -yl) ethan-1-one
1- (4 '-amino-5' - (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -6'H-spiro [ cyclopropane-1,9' -pyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine ] -7 '(8'H) -yl) -2-methylpropan-1-one
(S) -1- (4 '-amino-5' - (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -6'H-spiro [ cyclopropane-1,9' -pyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine ] -7 '(8'H) -yl) -2-hydroxypropan-1-one
(R) -1- (4 '-amino-5' - (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -6'H-spiro [ cyclopropane-1,9' -pyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine ] -7 '(8'H) -yl) -2-hydroxypropan-1-one
(4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-N- (2,2,2-trifluoroethyl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine-7 (6H) carboxamide
4 '-amino-5' - (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -N- (2,2,2-trifluoroethyl) -6'H-spiro [ cyclopropane-1,9' -pyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine ] -7 '(8'H) carboxamide
4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-N- (1-methyl-1H-pyrazol-4-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine-7 (6H) carboxamide
4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -N-cyclopropyl-9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine-7 (6H) carboxamide
4 '-amino-5' - (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -N-cyclopropyl-6'H-spiro [ cyclopropane-1,9' -pyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine ] -7 '(8'H) carboxamide
4 '-amino-5' - (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -N- (1-methyl-1H-pyrazol-4-yl) -6'H-spiro [ cyclopropane-1,9' -pyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine ] -7 '(8'H) carboxamide
1- (4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) -2-morpholinoethane-1-one
5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-7- (2-morpholinoethyl) -6,7,8,9-tetrahydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-4-amine
4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-N- (2-morpholinoethyl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine-7 (6H) carboxamide
(4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (cyclopropyl) methanone
(4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (1-methylpiperidin-4-yl) methanone
(4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (1-methyl-1H-pyrazol-4-yl) methanone
1- (4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) -2-methylpropan-1-one
(R) - (4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (1-methylpyrrolidin-3-yl) methanone
(S) - (4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (1-methylpyrrolidin-3-yl) methanone
4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-N- (1-methylpiperidin-4-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine-7 (6H) carboxamide
(S) -4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-N- (1-methylpyrrolidin-3-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine-7 (6H) carboxamide
(R) -4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-N- (1-methylpyrrolidin-3-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine-7 (6H) carboxamide
The application provides a pharmaceutical composition consisting of the tricyclic compound or an N-oxide derivative, an individual isomer, or a mixture of isomers thereof, and a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient. The pharmaceutical compositions of the present application may be administered orally, parenterally (by injection), by inhalation spray, topically, rectally, nasally, vaginally, intraperitoneally, or via an implanted reservoir.
In another aspect of the present application, the tricyclic compounds and pharmaceutically acceptable salts can be used in combination with one or more other drugs. When used in combination, the tricyclic compounds of the present application may act additively or synergistically with the drugs used in combination. The drugs used in combination can be small molecule drugs, monomer clone drugs, fusion protein drugs and anti-influenza DNA drugs.
In one embodiment, the tricyclic compound is obtainable by the following preparative route:
Figure BDA0003442482540000151
in the above preparation route, R 1 、R 2 、R 3 、R 4 Each independently having the same selection ranges as in formula I; cbz and SEM represent amino protecting groups; x represents a reactive group capable of undergoing a coupling reaction with-NH-, such as hydroxyl, halogen, etc.; y represents a reactive group capable of undergoing a substitution reaction, illustratively R 1 Y includes NCS or NBS, etc.; DIEA is N, N-diisopropylethylamine.
Example 1
(4-amino-9,9-dimethyl-5- (1H-pyrrole [2,3-b ] pyridin-2-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (tetrahydro-2H-pyran-4-yl) methanone
Step 1. Synthesis of tert-butyl (2-cyanopropan-2-yl) carbamate
Figure BDA0003442482540000152
In a 1L round-bottom flask, 2-amino-2-methylpropanenitrile hydrochloride (25.0 g,208.3 mmol) was dissolved in tetrahydrofuran (THF, 350 mL) and placed in an ice-water bath to cool. Adding K to the above system 2 CO 3 (57.5g, 416.6mmol) and H was added slowly 2 O to K 2 CO 3 After complete dissolution, boc anhydride (45.8 g,210.0 mmol) was added and heated to 50 ℃ for 16h. After completion of the reaction, the layers were separated and the aqueous layer was extracted with ethyl acetate (EtOAc). Combining the ester phase and the THF phase over anhydrous Na 2 SO 4 Drying, filtering and concentrating. To the residue was added petroleum ether (200 mL), stirred in an ice-water bath for 30min, filtered and dried to give 30g of product as a white solid in 73% yield. LCMS (ESI): m/z =185 (M + H) + 。
Step 2. Synthesis of tert-butyl (1-amino-2-methylpropan-2-yl) carbamate
Figure BDA0003442482540000161
In a 1L round-bottom flask, tert-butyl (2-cyanopropan-2-yl) carbamate (30.0 g,163.0 mmol) was dissolved in THF (500 mL) and placed in an ice-water bath to cool. Slowly adding LiAlH into the system 4 (6.2g, 163.0 mmol), and the reaction was allowed to naturally warm to room temperature for 16 hours. After the reaction, the reaction system was cooled in an ice-water bath, and ice water (50 mL) was slowly added dropwise thereto, followed by stirring for 30min. Filter and wash the filter residue with THF/MeOH (tetrahydrofuran/methanol = 20/1). The filtrate was concentrated to give 25g of oil, which was used directly in the next reaction. LCMS (ESI): m/z =189 (M + H) + 。
Step 3. Synthesis of benzyl (2-tert-butoxycarbonylamino-2-methylpropanyl) carbamate
Figure BDA0003442482540000162
In a 1-L round-bottomed flask, tert-butyl (1-amino-2-methylpropan-2-yl) carbamate (25.0 g,133.0 mmol) was dissolved in CH 2 Cl 2 (400 mL), triethylamine (Et) was added in that order 3 N,40.3g, 399.0mmol) and N-benzyloxycarbonyloxysuccinimide (49.7g, 199.5 mmol) were reacted at room temperature for 1 hour. After the reaction was complete, water was added and the organic phase was washed with water and anhydrous Na 2 SO 4 After drying, filtration and concentration 38g of solid was obtained and used directly in the next reaction. LCMS (ESI): m/z =323 (M + H) + 。
Step 4. Synthesis of benzyl (2-amino-2-methylpropanyl) carbamate
Figure BDA0003442482540000163
Concentrated hydrochloric acid (50 mL) was dissolved in methanol (150 mL) in an ice-water bath, and benzyl (2-tert-butoxycarbonylamino-2-methyl) was addedPropyl) carbamate (38.0 g,118.0 mmol), and reacted at room temperature for 1 hour. After completion of the reaction, water was added for dilution, methanol was removed on a rotary evaporator and the aqueous phase was extracted with EtOAc. Removing the ester phase and the aqueous phase with Na 2 CO 3 Made basic and extracted with EtOAc. The ester phase was washed with saturated aqueous NaCl solution, anhydrous Na 2 SO 4 Dried, filtered and concentrated to give 18g of oil which was used directly in the next reaction. LCMS (ESI): m/z =223 (M + H) + 。
Step 5 Synthesis of benzyl (2- ((6-chloropyrimidin-4-yl) amino) -2-methylpropanyl) carbamate
Figure BDA0003442482540000164
In a 250mL round bottom flask, 4,6-dichloropyrimidine (10.0g, 67.6 mmol), benzyl (2-amino-2-methylpropanyl) carbamate (18.0g, 81.1 mmol), KF (3.9g, 67.6 mmol), N, N-diisopropylethylamine (DIEA, 17.4g, 135.2mmol) and dimethyl sulfoxide (DMSO, 100 mL) were charged, and heated to 90 ℃ to react for 1 hour. After completion of the reaction, it was diluted with water and extracted with EtOAc. The ester phase was washed with saturated aqueous NaCl solution and anhydrous Na 2 SO 4 Drying, filtering and concentrating. The residue was purified by column chromatography on silica gel (volume ratio of petroleum ether PE to EtOAc 4:1) to give 12.5g of product in 55% yield. LCMS (ESI): m/z =335 (M + H) + 。
Step 6 Synthesis of benzyl (2- ((6-chloro-5-iodopyrimidin-4-yl) amino) -2-methylpropanyl) carbamate
Figure BDA0003442482540000171
In a 250mL round bottom flask, benzyl (2- ((6-chloropyrimidin-4-yl) amino) -2-methylpropanyl) carbamate (12.5g, 37.4 mmol) was dissolved in glacial acetic acid (100 mL) and placed in an ice-water bath to cool. N-iodosuccinimide (NIS, 25.2g,112.2 mmol) was added to the above system and reacted at room temperature for 16h. After completion of the reaction, the reaction solution was poured into ice water and extracted with EtOAc. The ester phase is successively saturated with Na 2 SO 3 Aqueous solution, na 2 CO 3 Washing with aqueous solution and NaCl aqueous solution, anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain solid 15.8g which is the product and is directly used for the next reaction. LCMS (ESI): m/z =461 (M + H) + 。
Step 7 Synthesis of benzyl (2- ((6-chloro-5- (3,3-diethoxyprop-1-yn-1-yl) pyrimidin-4-yl) amino) -2-methylpropanyl) carbamate
Figure BDA0003442482540000172
In a nitrogen blanketed 250mL round bottom flask, benzyl (2- ((6-chloro-5-iodopyrimidin-4-yl) amino) -2-methylpropanyl) carbamate (15.8g, 34.3mmol) and 3,3-diethoxyprop-1-yne (13.2g, 103.0mmol) were dissolved in THF (60 mL)/acetonitrile (MeCN, 60 mL). CuI (190mg, 1.0 mmol) and Et were added to the above system 3 N (10.4g, 103.0mmol), stirred until CuI was dissolved, and then 1,1' -bis (diphenylphosphino) ferrocenyl palladium chloride Pd (dppf) Cl was added 2 (1.2g, 1.7mmol), heated to 60 ℃ and reacted for 16h. After completion of the reaction, water was added and extracted with EtOAc. The ester phase was washed with saturated aqueous NaCl solution, anhydrous Na 2 SO 4 Drying, filtering and concentrating. The residue was purified by column chromatography on silica gel (PE: etOAc/vol: 4: 1) to give 13.2g, 84% yield. LCMS (ESI): m/z =461 (M + H) + 。
Step 8 Synthesis of benzyl (2- (4-chloro-6- (diethoxymethyl) -7H-pyrrole [2,3-d ] pyrimidin-7-yl) -2-methylpropanyl) carbamate
Figure BDA0003442482540000173
In a 150mL round bottom flask was added benzyl (2- ((6-chloro-5- (3,3-diethoxyprop-1-yn-1-yl) pyrimidin-4-yl) amino) -2-methylpropanyl) carbamate (13.2g, 28.7 mmol), cs 2 CO 3 (23.4g, 71.8mmol) and MeCN (70 mL) were heated at 90 ℃ for 2 hours under reflux. After completion of the reaction, it was filtered and the filter residue was washed with EtOAc. The filtrate was diluted with EtOAcWashed with saturated aqueous NaCl solution, anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain solid 11.5g which is the product and is directly used for the next reaction. LCMS (ESI): m/z =461 (M + H) + 。
Step 9 Synthesis of benzyl (2- (5-bromo-4-chloro-6- (diethoxymethyl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-methylpropanyl) carbamate
Figure BDA0003442482540000181
In a 250mL round bottom flask, benzyl (2- (4-chloro-6- (diethoxymethyl) -7H-pyrrole [2,3-d)]Pyrimidin-7-yl) -2-methylpropanyl) carbamate (11.5g, 25.0mmol) was dissolved in CH 2 Cl 2 (100 mL). N-bromosuccinimide (NBS, 4.5g,25.0 mmol) and glacial acetic acid (0.5 mL) were added to the above system, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into ice water and extracted with EtOAc. The ester phase is successively saturated with Na 2 SO 3 Aqueous solution, na 2 CO 3 Washing with aqueous solution and NaCl aqueous solution, anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain solid 12.3g which is the product and is directly used for the next reaction. LCMS (ESI): m/z =539, 541 (M + H) + 。
Step 10 Synthesis of benzyl (2- (4-amino-5-bromo-6- (diethoxymethyl) -7H-pyrrole [2,3-d ] pyrimidin-7-yl) -2-methylpropanyl) carbamate
Figure BDA0003442482540000182
In a 500mL sealed jar, benzyl (2- (5-bromo-4-chloro-6- (diethoxymethyl) -7H-pyrrole [2,3-d) was added]Pyrimidin-7-yl) -2-methylpropanyl) carbamate (12.3g, 22.8mmol), dioxane (Dioxane, 50 mL) and aqueous ammonia (25%, 300 mL) were heated to 120 ℃ and reacted for 16h. After completion of the reaction, water was added and extracted with EtOAc. The ester phase was washed with saturated aqueous NaCl solution, anhydrous Na 2 SO 4 Drying, filtering and concentrating. The residue was purified by silica gel column Chromatography (CH) 2 Cl 2 MeOH volume ratio 40: 1) to yield 8.6g, 72% yield. LCMS (ESI): m/z =520, 522 (M + H) + 。
Step 11, synthesizing 5-bromo-9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine-4-amine
Figure BDA0003442482540000183
Benzyl (2- (4-amino-5-bromo-6- (diethoxymethyl) -7H-pyrrole [2,3-d)]Pyrimidin-7-yl) -2-methylpropanyl) carbamate (8.6 g,16.5 mmol) was dispersed in HBr (25% solution, 50 mL) and reacted at room temperature for 16h. After the reaction is completed, diluting with water, and adding CH 2 Cl 2 Extracting, discarding organic phase, and adding Na to water phase 2 CO 3 Adjusting pH of the aqueous solution to alkaline, and adding CH 2 Cl 2 Extraction, CH 2 Cl 2 The phases were washed with aqueous NaCl, anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain solid 4.2g which is the product and is directly used for the next reaction. LCMS (ESI): m/z =294, 296 (M + H) + 。
Step 12 Synthesis of 1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine
Figure BDA0003442482540000191
1H-pyrrole [2,3-b ] in a 250mL round bottom flask]Pyridine (11.8g, 100.0mmol) was dissolved in THF (100 mL), and K was added 2 CO 3 (27.6g, 200.0 mmol) and stirred for 30min. 2- (trimethylsilyl) ethoxymethyl chloride (SEM-Cl, 20.0g,120.0 mmol) was added dropwise to the above system, and the reaction was carried out at room temperature for 16 hours. After completion of the reaction, it was diluted with water and extracted with EtOAc. The ester phase was washed with saturated aqueous NaCl solution, anhydrous Na 2 SO 4 Drying, filtering and concentrating. The residue was purified by column chromatography on silica gel (PE: etOAc/volume ratio 20: 1) to give 19.2g, 77% yield. LCMS (ESI): m/z =249 (M + H) + 。
Step 13 Synthesis of (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridin-2-yl) boronic acid
Figure BDA0003442482540000192
1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] in a 500mL three-necked round bottom flask with thermometer under nitrogen protection]Pyridine (19.2g, 77.4 mmol) was dissolved in THF (200 mL) and cooled to-65 ℃ in a dry ice/acetone bath. Then, n-butyllithium (n-BuLi, 1.6M,58mL,92.8 mmol) was slowly added dropwise to the reaction mixture, followed by reaction for 30min, and a THF solution (50 mL) of triisopropyl borate (17.5g, 92.8 mmol) was added dropwise thereto, followed by reaction for 1h while maintaining the temperature. After the reaction was complete, caution was taken to saturate the NH 4 The reaction was quenched with aqueous Cl, diluted with water and extracted with EtOAc. The ester phase was washed with saturated aqueous NaCl solution, anhydrous Na 2 SO 4 Drying, filtering and concentrating. Dispersing the obtained residue in petroleum ether, stirring for 30min, filtering, and concentrating the filtrate to obtain solid 12.7g, which is the product and is directly used for the next reaction. LCMS (ESI): m/z =293 (M + H) + 。
Step 14 Synthesis of 9,9-dimethyl-5- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridin-2-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-4-amine
Figure BDA0003442482540000193
5-bromo-9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] was added to a 50mL round bottom flask under nitrogen protection]Pyrrole [2,3-d]Pyrimidin-4-amine (1.2g, 4.1mmol), (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b]Pyridin-2-yl) boronic acid (1.8g, 6.2mmol), pd (dppf) Cl 2 (150mg, 0.2mmol), tetra-n-butylammonium fluoride (n-Bu) 4 NF，104mg，0.4mmol)，Na 2 CO 3 (869mg, 8.2mmol), DMSO (15 mL) and H 2 O (5 mL), and the reaction was carried out at 80 ℃ for 3 hours. After completion of the reaction, the reaction was poured into water and extracted with EtOAc. The ester phase was washed with saturated NaCl solution, anhydrous Na 2 SO 4 Drying, filtering and concentrating. The obtained residue was subjected to silica gel column chromatographyPurification (CH) 2 Cl 2 MeOH volume ratio 60: 1) to yield 1.6g of product, 85% yield. LCMS (ESI): m/z =462 (M + H) + 。
Step 15 Synthesis of 9,9-dimethyl-5- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridin-2-yl) -6,7,8,9-tetrahydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-4-amine
Figure BDA0003442482540000201
In a 50mL round bottom flask, 9,9-dimethyl-5- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b]Pyridin-2-yl) -8,9-dihydropyrazine [1',2':1,5]Pyrrole [2,3-d]Pyrimidin-4-amine (1.6g, 3.5mmol) in CH 2 Cl 2 (20 mL)/MeOH (10 mL), CNBH was added 3 Na (661mg, 10.5 mmol) was reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was poured into ice water, stirred for 30min, and then added with CH 2 Cl 2 And (4) extracting. The organic phase was washed with saturated NaCl solution and anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain solid 1.1g, namely the product which is directly used for the next reaction. LCMS (ESI): m/z =464 (M + H) + 。
Step 16 Synthesis of (4-amino-9,9-dimethyl-5- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridin-2-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (tetrahydro-2H-pyran-4-yl) methanone
Figure BDA0003442482540000202
9,9-dimethyl-5- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b]Pyridin-2-yl) -6,7,8,9-tetrahydropyrazine [1',2':1,5]Pyrrole [2,3-d]Pyrimidin-4-amine (150mg, 0.32mmol) in CH 2 Cl 2 (5 mL), 4-dimethylaminopyridine (DMAP, 78mg, 0.64mmol), tetrahydropyran-4-carboxylic acid (50mg, 0.38mmol) and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI, 123mg, 0.64mmol) were added and reacted at room temperature for 0.5h. After the reaction is completed, water is added to the reaction mixture to obtain CH 2 Cl 2 And (4) extracting. The organic phase was washed with saturated NaCl solution and anhydrous Na 2 SO 4 Drying, filtering and concentrating. The residue was purified by silica gel column Chromatography (CH) 2 Cl 2 MeOH volume ratio 40: 1) to yield 150mg, 82% yield. LCMS (ESI): m/z =576 (M + H) + 。
Step 17 Synthesis of (4-amino-9,9-dimethyl-5- (1H-pyrrole [2,3-b ] pyridin-2-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (tetrahydro-2H-pyran-4-yl) methanone
Figure BDA0003442482540000203
In a 50mL round bottom flask, (4-amino-9,9-dimethyl-5- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b]Pyridin-2-yl) -8,9-dihydropyrazine [1',2':1,5]Pyrrole [2,3-d]Pyrimidin-7 (6H) -yl) (tetrahydro-2H-pyran-4-yl) methanone (150mg, 0.26mmol) in CH 2 Cl 2 (5 mL), trifluoroacetic acid (2 mL) was added and the reaction was carried out at room temperature for 1h, followed by concentration under reduced pressure to remove the solvent and trifluoroacetic acid. The residue was dissolved in methanol (5 mL), and ammonia (25%, 5 mL) was added to the solution to react at room temperature for 8 hours. After the reaction is completed, water is added to the reaction mixture to obtain CH 2 Cl 2 And (4) extracting. The organic phase was washed with saturated NaCl solution and anhydrous Na 2 SO 4 Drying, filtering and concentrating. The residue was purified by silica gel column Chromatography (CH) 2 Cl 2 MeOH volume ratio of 20: 1) to yield 85mg of product in 73% yield. LCMS (ESI): m/z =446 (M + H) + 。
1 H-NMR(400MHz，CDCl 3 )：δ11.82(s,1H),8.15(s,1H),8.06(d,J＝4.8Hz,1H),7.94(d,J＝7.7Hz,1H),7.13(dd,J＝8.0,4.8Hz,1H),6.53(s,1H),5.37(s,2H),4.85-4.53(m,3H),3.97-3.71(m,4H),3.45-3.30(m,2H),2.05-1.58(m,10H)。
Example 2
(4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-7 (6H) -yl) (tetrahydro-2H-pyran-4-yl) methanone
Figure BDA0003442482540000211
In a 50mL round bottom flask, (4-amino-9,9-dimethyl-5- (1H-pyrrole [2,3-b)]Pyridin-2-yl) -8,9-dihydropyrazine [1',2':1,5]Pyrrole [2,3-d]Pyrimidin-7 (6H) -yl) (tetrahydro-2H-pyran-4-yl) methanone (100mg, 0.22mmol) was dissolved in CH 2 Cl 2 (5 mL), N-chlorosuccinimide (NCS, 27mg, 0.20mmol) was added thereto, and the mixture was reacted at room temperature for 10min. After the reaction is completed, water is added to the reaction mixture to obtain CH 2 Cl 2 And (4) extracting. The organic phase was washed with saturated NaCl solution and anhydrous Na 2 SO 4 Drying, filtering and concentrating. The residue was purified by silica gel column Chromatography (CH) 2 Cl 2 MeOH volume ratio of 20: 1) to yield 90mg of product in 85% yield. LCMS (ESI): m/z =480 (M + H) + 。
1 H-NMR(400MHz，CDCl 3 )：δ11.82(s,1H),8.15(s,1H),8.06(d,J＝4.8Hz,1H),7.94(d,J＝7.7Hz,1H),7.13(dd,J＝8.0,4.8Hz,1H),5.37(s,2H),4.85-4.53(m,3H),3.97-3.71(m,4H),3.45-3.30(m,2H),2.05-1.58(m,10H)。
Example 3
5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-7- ((tetrahydro-2H-pyran-4-yl) methyl) -6,7,8,9-tetrahydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-4-amine
Figure BDA0003442482540000212
In a 50mL round-bottom flask, (4-amino-5- (3-chloro-1H-pyrrole [2,3-b)]Pyridin-2-yl) -9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5]Pyrrole [2,3-d]Pyrimidin-7 (6H) -yl) (tetrahydro-2H-pyran-4-yl) methanone (50mg, 0.11mmol) was dissolved in THF (10 mL), boron trifluoride diethyl ether (312mg, 2.2mmol) and sodium borohydride (83.6 mg, 2.2mmol) were added, and the mixture was heated to 70 ℃ for reaction for 2H. The reaction system is cooled to room temperature, 5mL of 5% hydrochloric acid aqueous solution is carefully added dropwise to quench the reaction, 10mL of methanol is added, and the reaction is heated to 70 ℃ for 2h. After the reaction is completed, water is added to add CH 2 Cl 2 And (4) extracting. The organic phase was washed with saturated NaCl solution and anhydrous Na 2 SO 4 Drying, filtering and concentrating. The residue was purified by silica gel column Chromatography (CH) 2 Cl 2 MeOH volume ratio of 20: 1) to yield 30mg of product in 59% yield. LCMS (ESI): m/z =466 (M + H) + 。
1 H-NMR(400MHz，CDCl 3 )：δ11.82(s,1H),8.15(s,1H),8.06(d,J＝4.8Hz,1H),7.94(d,J＝7.7Hz,1H),7.13(dd,J＝8.0,4.8Hz,1H),5.37(s,2H),4.85-4.53(m,3H),3.97-3.71(m,4H),3.45-3.30(m,2H),2.96-2.61(m,2H),2.05-1.58(m,10H)。
Example 4
(4 '-amino-5' - (1H-pyrrole [2,3-b ] pyridin-2-yl) -6'H-spiro [ cyclopropane-1,9' -pyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine ] -7 '(8'H) -yl) (tetrahydro-2H-pyran-4-yl) methanone
Step 1 Synthesis of benzyl ((1-aminocyclopropyl) methyl) carbamate
Figure BDA0003442482540000221
The above-mentioned target compound was synthesized by the method in steps 1 to 4 of example 1 using 1-amino-1-cyclopropyl cyanamide hydrochloride as a starting material. LCMS (ESI): m/z =221 (M + H) + 。
Step 2, synthesizing 4,6-dichloro-5-iodopyrimidine
Figure BDA0003442482540000222
To a 500mL round bottom three-necked flask with a thermometer under nitrogen, 2,2,6,6-tetramethylpiperidine (8.5g, 60.0mmol) and dry THF (80 mL) were charged and cooled to-78 ℃ in a dry ice/acetone bath. n-BuLi (1.6M, 60mL) was added dropwise to the system, and after the addition was completed, the temperature was slowly raised to-20 ℃ for reaction for 1 hour. Then, znCl was dropped in while maintaining the temperature at-20 deg.C 2 A solution (14.0g, 102.7mmol) in THF (100 mL) was allowed to spontaneously warm to room temperature after dropping for 1 hour. After the reaction is completed, the solvent is distilled off under reduced pressure, and the remainder is dissolved in freshTHF (80 mL) was used to prepare solution A.
To the resulting solution A, a solution of 4,6-dichloropyrimidine (6.0 g,40.5 mmol) in THF (80 mL) was added dropwise, and the mixture was reacted at room temperature for 1 hour. Then the reaction system is placed in an ice water bath for cooling, and I is dripped 2 A solution of (14.0 g,55.1 mmol) in THF (60 mL) was warmed to room temperature and reacted for 16h. After the reaction is finished, the reaction system is placed in an ice-water bath for cooling, water is added for diluting, and 5 percent of Na is dripped 2 SO 3 The solution faded in color and was extracted with EtOAc. The ester phase was washed with saturated NaCl solution, anhydrous Na 2 SO 4 Drying, filtering and concentrating. The residue was purified by column chromatography on silica gel (PE: etOAc 40: 1 by volume) to give 5.6g of the product in 51% yield.
Step 3 Synthesis of benzyl ((1- ((6-chloro-5-iodopyrimidin-4-yl) amino) cyclopropylmethyl) aminocarbonate
Figure BDA0003442482540000231
A250 mL round bottom flask was charged with 4,6-dichloro-5-iodopyrimidine (10.0g, 36.6 mmol), benzyl ((1-aminocyclopropyl) methyl) carbamate (9.6 g, 43.9mmol), KF (2.1g, 36.6 mmol), DIEA (9.4g, 73.2 mmol) and DMSO (100 mL), and heated to 90 ℃ for 1h. After completion of the reaction, it was diluted with water and extracted with EtOAc. The ester phase was washed with saturated aqueous NaCl solution, anhydrous Na 2 SO 4 Drying, filtering and concentrating. The residue was purified by column chromatography on silica gel (PE: etOAc/vol: 4: 1) to give 13.2g of the product in 79% yield. LCMS (ESI): m/z =459 (M + H) + 。
Step 4, synthesizing 5 '-bromo-8'H-spiro [ cyclopropane-1,9 '-pyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine ] -4' -ammonia
Figure BDA0003442482540000232
The above-mentioned objective compound was synthesized in the same manner as in steps 7 to 11 of example 1, using a benzyl ((1-aminocyclopropyl) methyl) carbamate as a starting material. LCMS (ESI): m/z =292, 294 (M + H) + 。
Step 5 Synthesis of (4 '-amino-5' - (1H-pyrrole [2,3-b ] pyridin-2-yl) -6'H-spiro [ cyclopropane-1,9' -pyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine ] -7 '(8'H) -yl) (tetrahydro-2H-pyran-4-yl) methanone
Figure BDA0003442482540000233
5' -bromo-8'H-spiro [ cyclopropane-1,9 ' -pyrazine [1',2':1,5]Pyrrole [2,3-d]Pyrimidines]The target compound was synthesized from (E) -4' -ammonia by the method in steps 14 to 17 of example 1. LCMS (ESI): m/z =430 (M + H) + 。
1 H-NMR(400MHz，CDCl 3 )：δ11.82(s,1H),8.15(s,1H),8.06(d,J＝4.8Hz,1H),7.94(d,J＝7.7Hz,1H),7.13(dd,J＝8.0,4.8Hz,1H),6.53(s,1H),5.37(s,2H),4.85-4.53(m,3H),3.97-3.71(m,4H),3.45-3.30(m,2H),2.46-1.58(m,8H)。
Example 5
(4 '-amino-5' - (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -6'H-spiro [ cyclopropane-1,9' -pyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine ] -7 '(8'H) -yl) (tetrahydro-2H-pyran-4-yl) methanone
Figure BDA0003442482540000234
With (4 '-amino-5' - (1H-pyrrole [2,3-b)]Pyridin-2-yl) -6'H-spiro [ cyclopropane-1,9' -pyrazine [1',2':1,5]Pyrrole [2,3-d]Pyrimidines]-7 '(8'H) -yl) (tetrahydro-2H-pyran-4-yl) methanone as a starting material, the above target compound was synthesized according to the method in example 2. LCMS (ESI): m/z =464 (M + H) + 。
1 H-NMR(400MHz，CDCl 3 )：δ11.82(s,1H),8.15(s,1H),8.06(d,J＝4.8Hz,1H),7.94(d,J＝7.7Hz,1H),7.13(dd,J＝8.0,4.8Hz,1H),5.37(s,2H),4.85-4.53(m,3H),3.97-3.71(m,4H),3.45-3.30(m,2H),2.46-1.58(m,8H)。
Example 6
5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -7- (2-methoxyethyl) -9,9-dimethyl-6,7,8,9-tetrahydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-4-amine
Step 1 Synthesis of 7- (2-methoxyethyl) -9,9-dimethyl-5- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridin-2-yl) -6,7,8,9-tetrahydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-4-amine
Figure BDA0003442482540000241
9,9-dimethyl-5- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b]Pyridin-2-yl) -6,7,8,9-tetrahydropyrazine [1',2':1,5]Pyrrole [2,3-d]Pyrimidin-4-amine (300mg, 0.64mmol) was dissolved in DMSO (5 mL) and K was added 2 CO 3 (177mg, 1.28mmol), reacted at room temperature for 0.5h, then added with 2-bromoethyl methyl ether (133mg, 0.96mmol), heated to 70 ℃ and reacted for 2h. After the reaction is completed, water is added to the reaction mixture to obtain CH 2 Cl 2 And (4) extracting. The organic phase was washed with saturated NaCl solution and anhydrous Na 2 SO 4 Drying, filtering and concentrating. The residue was purified by silica gel column Chromatography (CH) 2 Cl 2 MeOH volume ratio 40: 1) to yield 270mg, 81% yield. LCMS (ESI): m/z =522 (M + H) + 。
Step 2 Synthesis of 5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -7- (2-methoxyethyl) -9,9-dimethyl-6,7,8,9-tetrahydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidin-4-amine
Figure BDA0003442482540000242
With 7- (2-methoxyethyl) -9,9-dimethyl-5- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b]Pyridin-2-yl) -6,7,8,9-tetrahydropyrazine [1',2':1,5]Pyrrole [2,3-d]The above target compound was synthesized from pyrimidin-4-amine as a starting material by the method of example 1, step 17 and example 2 in this order. LCMS (ESI): m/z =426 (M + H) + 。
1 H-NMR(400MHz，CDCl 3 )：δ11.86(s,1H),8.22(s,1H),8.01(d,J＝4.8Hz,1H),7.94(dd,J＝7.9,1.5Hz,1H),7.12(dd,J＝7.9,4.8Hz,1H),5.37(s,2H),3.75(s,2H),3.52(t,J＝5.5Hz,2H),3.30(s,3H),2.96-2.61(m,4H),1.86(s,6H)。
Example 7
(4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-N- (tetrahydro-2H-pyran-4-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine-7 (6H) carboxamide
Step 1 Synthesis of 4-amino-9,9-dimethyl-N- (tetrahydro-2H-pyran-4-yl) -5- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridin-2-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine-7 (6H) carboxamide
Figure BDA0003442482540000251
In a 50mL round-bottom flask, 4-aminotetrahydropyran (174mg, 1.7 mmol) was dissolved in dimethylformamide (DMF, 10 mL). To the above system were added N', N-carbonyldiimidazole (CDI, 275mg,1.7 mmol) and Et 3 N (343mg, 3.4mmol), reacted at room temperature for 2H, followed by addition of 9,9-dimethyl-5- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b]Pyridin-2-yl) -6,7,8,9-tetrahydropyrazine [1',2':1,5]Pyrrole [2,3-d]Pyrimidine-4-amine (200mg, 0.43mmol) in CH 2 Cl 2 (10 mL) and reacted at room temperature for 8h. After the reaction is completed, water is added to the reaction mixture to obtain CH 2 Cl 2 And (4) extracting. The organic phase was washed with saturated NaCl solution and anhydrous Na 2 SO 4 Drying, filtering and concentrating. The residue was purified by silica gel column Chromatography (CH) 2 Cl 2 MeOH volume ratio 40: 1) to obtain 160mg of product with a yield of 63%. LCMS (ESI): m/z =591 (M + H) + 。
Step 2 Synthesis of (4-amino-5- (3-chloro-1H-pyrrole [2,3-b ] pyridin-2-yl) -9,9-dimethyl-N- (tetrahydro-2H-pyran-4-yl) -8,9-dihydropyrazine [1',2':1,5] pyrrole [2,3-d ] pyrimidine-7 (6H) carboxamide
Figure BDA0003442482540000252
With 4-amino-9,9-dimethyl-N- (tetrahydro-2H-pyran-4-yl) -5- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b]Pyridin-2-yl) -8,9-dihydropyrazine [1',2':1,5]Pyrrole [2,3-d]The above-mentioned objective compound was synthesized from pyrimidine-7 (6H) carboxamide as a starting material by the method of step 17 of example 1 and the method of example 2 in that order. LCMS (ESI): m/z =495 (M + H) + 。
1 H-NMR(400MHz，CDCl 3 )：δ11.82(s,1H),8.15(s,1H),8.06(d,J＝4.8Hz,1H),7.94(d,J＝7.7Hz,1H),7.13(dd,J＝8.0,4.8Hz,1H),5.37(s,2H),4.85-4.53(m,3H),3.97-3.71(m,4H),3.57(s,1H),3.45-3.30(m,2H),2.05-1.58(m,10H).
Examples 8 to 52 shown in the following Table 1 were prepared according to the methods in examples 1 to 7.
TABLE 1
Figure BDA0003442482540000261
Figure BDA0003442482540000271
Figure BDA0003442482540000281
Figure BDA0003442482540000291
Figure BDA0003442482540000301
Figure BDA0003442482540000311
Figure BDA0003442482540000321
Figure BDA0003442482540000331
Figure BDA0003442482540000341
Figure BDA0003442482540000351
Figure BDA0003442482540000361
Figure BDA0003442482540000371
Figure BDA0003442482540000381
Test example 1
Tricyclic compounds were tested for RET kinase inhibitory activity as follows:
measuring the inhibitory activity (IC) of said tricyclic compound on the kinase RET at Km ATP using a Mobility Shift Assay (MSA) 50 ). RET Kinase was purchased from Carna (cat # 08-159, batch # 13 CBS-0134F) and Kinase Substrate 2 was purchased from GL Biochem (cat # 112394, batch # P191104-TL 112394).
Test compounds were prepared in DMSO at 100-fold final reaction concentration, and 10 concentrations were sequentially diluted at 3-fold dilution ratio starting from 1 μ M. Then 0.25. Mu.L was transferred to a 384-well reaction plate using Echo 550. Using 1-fold kinase buffer (50mM HEPES, pH =7.5,0.0015%, brij-35, 10mM MgCl 2 2mM DTT) 2.5 fold final concentrationAnd adding 10 mu L of kinase solution with 2.5 times of final concentration into each compound hole, shaking and uniformly mixing, and then incubating at room temperature for 10min. A mixed solution of ATP and Substrate Kinase Substrate 2 with 25/15 times of final concentration is prepared by using 1 time of Kinase buffer solution, 15 mu L of the mixed solution of ATP and Substrate with 25/15 times of final concentration is added into each well (the final concentration of RET Kinase is 1nM, the final concentration of Substrate is 3 mu M, and the final concentration of ATP is 16 mu M), and reaction is carried out for 60min at room temperature after shaking and uniform mixing. Finally, 30. Mu.L of stop solution (100mM HEPES, pH =7.5,0.0015%, brij-35,0.2% cooling reagent #3, 50mM EDTA) was added to terminate the reaction. And reading the conversion rate data by using a drug screening platform CaliperEZ Reader II, and converting the conversion rate into inhibition rate data. Calculating IC of half inhibitory concentration by using Logit method according to inhibition rate data of each concentration 50 The results are shown in Table 2.
TABLE 2
Figure BDA0003442482540000391
Test example 2
Tricyclic compounds were tested for inhibition of cancer cell proliferation by the following method:
inhibition of cell proliferation by the tricyclic compounds described herein was tested using human thyroid cancer cells TT (RET C634W mutant).
A culture solution of 100. Mu. L F-12K containing 10% fetal bovine serum (Invitrogen, catalog No. 21127-022) containing 5000 TT cells (ATCC, catalog No. TCTU-78) was added to each well of a 96-well plate (Corning # 3903), and placed in a carbon dioxide incubator for overnight culture. The following day 0.5 μ L of test compound (configured as 8 consecutive concentration gradients in DMSO at an initial concentration of 1 μ M, 3-fold dilution) was added to each well, in duplicate, and cell-free wells (blank) and DMSO wells (solvent control) were set up. After the addition of the drug, the cells were cultured for 7 days at 37 ℃ under 5% carbon dioxide. Finally, 100. Mu.L of CellTiter-Glo reagent (Promega, catalog number: G7571) was added to each well, luminescence signal was detected by Flex Station3 (Molecular Devices), and compound-to-fine was calculated by XLFit softwareIC for inhibition of cell proliferation 50 The results are shown in Table 3.
TABLE 3
Examples IC 50 (nM) Examples IC 50 (nM) Examples IC 50 (nM)
1 3.5 19 11 37 5.7
2 4.4 20 8.5 38 1.5
3 16 21 19 39 4.8
4 11 22 12 40 12
5 22 23 9.8 41 19
6 23 24 7.9 42 12
7 3.5 25 13 43 11
8 9.3 26 6.4 44 2.5
9 10 27 7.5 45 11
10 8.5 28 11 46 5.5
11 12 29 70 47 2.0
12 8.5 30 12 48 8.5
13 9.2 31 15 49 9.5
14 16 32 18 50 7.0
15 15 33 22 51 11
16 5.5 34 15 52 4.0
17 12 35 0.5 cabozantinib 256
18 10 36 1.5
It can be seen from the data in tables 2 and 3 that the tricyclic compounds provided herein are effective in inhibiting the activity of RET kinase and have half the inhibitory concentration IC on RET kinase 50 As low as 0.53-2.1 nM, can also effectively inhibit cancer cell proliferation, and has IC effect on human thyroid cancer cell TT 50 The value is as low as 0.5-23 nM, and the activity is obvious compared with the existing medicine cabozantinibAnd (5) lifting.
The applicant states that the tricyclic compound, the pharmaceutical composition and the application thereof are illustrated by the above examples, but the application is not limited to the above examples, i.e., the application does not depend on the above examples to be implemented. It should be understood by those skilled in the art that any modification, equivalent substitution of each raw material, addition of auxiliary components, selection of specific modes and the like, of the product of the present application falls within the scope and disclosure of the present application.

Claims (8)

1. A tricyclic compound, comprising any one of the following compounds:
Figure FDA0003914185800000011
Figure FDA0003914185800000021
Figure FDA0003914185800000031
Figure FDA0003914185800000041
2. a pharmaceutically acceptable salt of the tricyclic compound of claim 1.
3. A pharmaceutical composition comprising an active ingredient comprising the tricyclic compound of claim 1, and/or a pharmaceutically acceptable salt of the tricyclic compound of claim 2, and at least one pharmaceutically acceptable carrier or excipient.
4. Use of the tricyclic compound of claim 1, a pharmaceutically acceptable salt of the tricyclic compound of claim 2, or a pharmaceutical composition of claim 3 in the manufacture of a medicament for inhibiting RET kinase.
5. Use of the tricyclic compound of claim 1, a pharmaceutically acceptable salt of the tricyclic compound of claim 2, or a pharmaceutical composition of claim 3 in the manufacture of a medicament for treating a RET kinase mediated disease.
6. The use according to claim 5, wherein the RET kinases comprise RET mutant kinases and RET fusion protein kinases.
7. The use of claim 5, wherein the disease is cancer.
8. The use of claim 7, wherein the cancer comprises breast cancer, small cell lung cancer, non-small cell lung cancer, bronchoalveolar carcinoma, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, cancer of gastrointestinal tissue, cancer of esophagus, ovary cancer, pancreas cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, vaginal cancer, leukemia, multiple myeloma, or lymphoma.
CN202180004265.7A 2020-06-10 2021-06-07 Tricyclic compound, pharmaceutical composition and application thereof Active CN114072412B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN2020105223247 2020-06-10
CN202010522324 2020-06-10
PCT/CN2021/098519 WO2021249319A1 (en) 2020-06-10 2021-06-07 Tricyclic compound, pharmaceutical composition, and use thereof

Publications (2)

Publication Number Publication Date
CN114072412A CN114072412A (en) 2022-02-18
CN114072412B true CN114072412B (en) 2023-01-10

Family

ID=77082831

Family Applications (2)

Application Number Title Priority Date Filing Date
CN202110613431.5A Withdrawn CN113214294A (en) 2020-06-10 2021-06-02 Tricyclic compound, pharmaceutical composition and application thereof
CN202180004265.7A Active CN114072412B (en) 2020-06-10 2021-06-07 Tricyclic compound, pharmaceutical composition and application thereof

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN202110613431.5A Withdrawn CN113214294A (en) 2020-06-10 2021-06-02 Tricyclic compound, pharmaceutical composition and application thereof

Country Status (2)

Country Link
CN (2) CN113214294A (en)
WO (1) WO2021249319A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113214294A (en) * 2020-06-10 2021-08-06 深圳铂立健医药有限公司 Tricyclic compound, pharmaceutical composition and application thereof
CN117964643B (en) * 2024-04-01 2024-07-02 苏州朗睿生物医药有限公司 Pyrrole [2,3-b ] pyridine derivative and preparation method and application thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104447765A (en) * 2014-12-31 2015-03-25 深圳铂立健医药有限公司 Tricyclic compound and pharmaceutical compositions thereof and application thereof
CN105431436A (en) * 2013-05-14 2016-03-23 内尔维阿诺医学科学有限公司 Pyrrolo[2,3-D]pyrimidine derivatives, processes for their preparation and their use as kinase inhibitors
CN107108631A (en) * 2014-11-14 2017-08-29 内尔维阿诺医学科学有限公司 It is used as the deazapurine derivatives of 6 amino, 7 two ring 7 of kinases inhibitor
CN109195972A (en) * 2016-04-15 2019-01-11 癌症研究科技有限公司 Heterocyclic compound as RET kinase inhibitor
CN110506043A (en) * 2017-04-13 2019-11-26 癌症研究科技有限公司 Compounds suitable as RET inhibitors
CN110662536A (en) * 2017-03-29 2020-01-07 普渡研究基金会 Kinase network inhibitors and uses thereof
CN113214294A (en) * 2020-06-10 2021-08-06 深圳铂立健医药有限公司 Tricyclic compound, pharmaceutical composition and application thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105431436A (en) * 2013-05-14 2016-03-23 内尔维阿诺医学科学有限公司 Pyrrolo[2,3-D]pyrimidine derivatives, processes for their preparation and their use as kinase inhibitors
CN107108631A (en) * 2014-11-14 2017-08-29 内尔维阿诺医学科学有限公司 It is used as the deazapurine derivatives of 6 amino, 7 two ring 7 of kinases inhibitor
CN104447765A (en) * 2014-12-31 2015-03-25 深圳铂立健医药有限公司 Tricyclic compound and pharmaceutical compositions thereof and application thereof
CN109195972A (en) * 2016-04-15 2019-01-11 癌症研究科技有限公司 Heterocyclic compound as RET kinase inhibitor
CN110662536A (en) * 2017-03-29 2020-01-07 普渡研究基金会 Kinase network inhibitors and uses thereof
CN110506043A (en) * 2017-04-13 2019-11-26 癌症研究科技有限公司 Compounds suitable as RET inhibitors
CN113214294A (en) * 2020-06-10 2021-08-06 深圳铂立健医药有限公司 Tricyclic compound, pharmaceutical composition and application thereof

Also Published As

Publication number Publication date
CN114072412A (en) 2022-02-18
WO2021249319A1 (en) 2021-12-16
CN113214294A (en) 2021-08-06

Similar Documents

Publication Publication Date Title
EP3524603B1 (en) Fgfr4 inhibitor, preparation method therefor and pharmaceutical use thereof
CN110167941B (en) Substituted fused heteroaryl compounds as kinase inhibitors and uses thereof
EP3677583A1 (en) Nitrogenous heterocyclic compound, preparation method, intermediate, composition, and application
EP3967695A1 (en) Quinazoline compound and pharmaceutical application thereof
WO2016007185A1 (en) Aminopyridazinone compounds as protein kinase inhibitors
TW200829589A (en) Compound for inhibiting mitotic progression
EP3345906A1 (en) 2-arylamino pyridine, pyridine or triazine derivative, preparation method and use thereof
CN104987324A (en) Pyrimidine derivative used as anaplastic lymphoma kinase (ALK) inhibitor
CN114072412B (en) Tricyclic compound, pharmaceutical composition and application thereof
CN113825757B (en) Substituted fused bicyclic derivatives, preparation method thereof and application thereof in medicine
CN110627812A (en) Heterocyclic compounds as TRK inhibitors
CN115073469B (en) Preparation and application of pyrrolopyrimidine compound as kinase inhibitor
KR20140139023A (en) 6-(4-(1-amino-3-hydroxycyclobutyl)phenyl)-5-phenyl(furo, thieno or pyrrolo)[2,3-d]pyrimidin-4-one derivatives for the treatment of cancer
CN104447765A (en) Tricyclic compound and pharmaceutical compositions thereof and application thereof
CN112939982A (en) Alkyne heterocyclic BTK inhibitor and preparation method and application thereof
CN111875620A (en) Pyrazolopyrimidine macrocyclic derivative and application thereof
CN104557871B (en) Arylmorpholine compounds with spiro substituents as well as preparation method and use thereof
EP2373657B1 (en) 5,7-dihydro-6h-pyrimido[5,4-d][1]benzazepin-6-thiones as plk inhibitors
CN115362155A (en) Arylamine derivatives, and preparation method and medical application thereof
CN104557913B (en) Pyridopyrimidine compounds as well as preparation method and application thereof
CN110312717A (en) The condensed heteroaryl tricyclic compound replaced is as kinase inhibitor and its application
CN114805359B (en) Preparation method and application of acetylenic heterocyclic compound FGFR inhibitor
CN102452989B (en) Aniline substituted quinazoline derivative
CN115028633B (en) Preparation and application of pyrrolopyrimidine compound
CN114853752B (en) Preparation and application of BTK inhibitor pyrido heterocyclic compound

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant