HK1238249B - 6-amino-7-bicyclo-7-deaza-purine derivatives as protein kinase inhibitors - Google Patents

Description

6-Amino-7-bicyclo-7-deaza-purine derivatives as protein kinase inhibitors

The present invention relates to certain 6-amino-7-bicyclo-7-deaza(deaza)-purine derivatives that modulate the activity of protein kinases. Thus, the compounds of the present invention are useful in treating diseases caused by dysregulated protein kinase activity. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods for treating diseases using pharmaceutical compositions comprising these compounds.

RET is a single-pass transmembrane receptor belonging to the tyrosine kinase superfamily (reviewed in Arighi et al., Cytokine Growth Factor Rev, 2005, 16, 441-67). The extracellular portion of the RET protein contains four calcium-dependent cadherin-like repeat units that are involved in ligand binding, as well as a membrane-proximal cysteine-rich region required for the correct folding of the RET extracellular domain, while the cytoplasmic portion of the receptor includes two tyrosine kinase subdomains. RET is the signaling component of a multiprotein complex: RET binds to glial-derived neurotrophic factor (GDNF) family ligands (GDNF, artemin, neurotrophin, and persephin) via ligand-specific GDNF-family receptor α co-receptors (GFRα1-4), inducing the formation of active RET dimers and autophosphorylation of specific tyrosine residues in the cytoplasmic domain. These phosphorylated tyrosines serve as docking sites for effector/adapter proteins such as PLC-γ, PI3K, Shc, Grb2, Src, Enigma, STAT3, which in turn activate downstream signal transduction pathways, including Ras/Raf/ERK, PI3K/Akt/mTOR and PLC-γ/PKC. During embryogenesis, RET signal transduction is key to the development of the enteric nervous system and renal organogenesis (Schuchardt et al., Nature, 1994, 367, 380-3). In adults, RET is expressed in neural crest-derived cell types such as neuroendocrine cells (thyroid parafollicular cells and adrenal medullary cells), peripheral ganglia, urogenital tract cells, and spermatogonia.

Abnormal RET expression and/or activity has been demonstrated in different human cancers. The carcinogenic effect of RET was first described in papillary thyroid carcinoma (PTC) (Grieco et al., Cell, 1990, 60, 557-63), which is derived from follicular thyroid cells and is the most common thyroid malignancy. About 20-30% of PTCs have somatic chromosomal rearrangements (translocations or inversions) that connect the promoter and 5′ portion of constitutively expressed unrelated genes to the RET tyrosine kinase domain (reviewed in Greco et al., Q.J.Nucl.Med.Mol.Imaging, 2009, 53, 440-54), thereby driving its ectopic expression in thyroid cells. To date, 12 different fusion partners have been identified, all of which provide protein/protein interaction domains that induce ligand-independent RET dimerization and constitutive kinase activity. The role of RET-PTC rearrangement in the pathogenesis of PTC has been confirmed in transgenic mice (Santoro et al., Oncogene, 1996, 12, 1821-6). Recently, a 10.6Mb pericentric inversion in chromosome 10 (where the ret gene maps) has been identified in approximately 2% of lung adenocarcinoma patients, resulting in different variants of the chimeric gene KIF5B-RET (Ju et al., Genome Res., 2012, 22, 436-45; Kohno et al., 2012, Nature Med., 18, 375-7; Takeuchi et al., Nature Med., 2012, 18, 378-81; Lipson et al., 2012, Nature Med., 18, 382-4). The fusion transcripts are highly expressed and all resulting chimeric proteins contain the N-terminal portion of the KIF5B coiled-coil region that mediates homodimerization and the complete RET kinase domain. None of the RET-positive patients had other known oncogenic alterations (e.g., EGFR or K-Ras mutations, ALK translocations), supporting the possibility that KIF5B-RET fusions may be driver mutations in lung adenocarcinoma. The oncogenic potential of KIF5B-RET has been confirmed by transfection of the fusion gene into cultured cell lines: similar to what was observed with the RET-PTC fusion protein, KIF5B-RET was constitutively phosphorylated and induced IL-3-independent growth of NIH-3T3 transformation and BA-F3 cells. However, other RET fusion proteins have been identified in patients with lung adenocarcinoma, such as the CCDC6-RET protein, which has been found to play a key role in the proliferation of the human lung adenocarcinoma cell line LC-2/ad (Journal of Thoracic Oncology, 2012, 7(12):1872-1876).

In addition to RET sequence rearrangements, the acquisition of functional point mutations in the RET proto-oncogene also drives oncogenic events, as shown in medullary thyroid carcinoma (MTC), which arises from parafollicular calcitonin-producing cells (reviewed in de Groot et al., Endocrine Rev., 2006, 27, 535-60; Wells and Santoro, Clin. Cancer Res., 2009, 15, 7119-7122). Approximately 25% of MTCs are associated with multiple endocrine neoplasia type 2 (MEN2), a group of hereditary cancer syndromes affecting neuroendocrine organs caused by germline activating point mutations in RET. Among the MEN2 subtypes (MEN2A, MEN2B, and familial MTC/FMTC), RET gene mutations have a strong phenotype-genotype correlation that determines the different MTC aggressiveness and clinical manifestations of the disease. In MEN2A syndrome, mutations involve one of the six cysteine residues (primarily C634) located in the cysteine-rich extracellular region, leading to ligand-independent homodimerization and constitutive RET activation. Patients develop MTC at a young age (onset between 5 and 25 years of age) and also develop pheochromocytoma (50%) and hyperparathyroidism. MEN2B is mainly caused by the M918T mutation located in the kinase domain. This mutation constitutively activates RET in its monomeric state and alters substrate recognition by the kinase. The MEN2B syndrome is characterized by early onset (<1 year of age) and a very aggressive form of MTC, pheochromocytoma (50% of patients) and ganglioneuroma. In FMTC, the only disease manifestation is MTC, which usually occurs in adult age. Many different mutations across the entire RET gene have been detected. The remaining 75% of MTC cases are sporadic, and of these, approximately 50% have somatic mutations in RET: the most frequent mutation is M918T, as in MEN2B, which is associated with the most aggressive phenotype. Somatic point mutations in RET have also been described in other tumors such as colorectal cancer (Wood et al., Science, 2007, 318, 1108-13) and small cell lung cancer (Jpn. J. Cancer Res., 1995, 86, 1127-30).

RET signaling components have been found to be expressed in primary breast tumors and functionally interact with the estrogen receptor-α pathway in breast tumor cell lines (Boulay et al., Cancer Res. 2008, 68, 3743-51; Plaza-Menacho et al., Oncogene, 2010, 29, 4648-57), and RET expression and activation of GDNF family ligands may play an important role in peripheral nerve invasion of different types of cancer cells (Ito et al., Surgery, 2005, 138, 788-94; Gil et al., J Natl Cancer Inst., 2010, 102, 107-18; Iwahashi et al., Cancer, 2002, 94, 167-74).

Recently, RET rearrangements have been reported in a subset of PDXs established from colorectal cancer (patient-derived xenografts). Although the frequency of such events in colorectal cancer patients remains to be defined, these data suggest a role for RET as a target in this indication (Gozgit et al, AACR Annual Meeting 2014).

Considering the relevant role of RET in human cancer, RET tyrosine kinase inhibitors may have high therapeutic value. The applicant, Institute of Organic Chemistry and Biochemistry ASCR, V.V.I., has disclosed in WO2010/121576 novel 7-substituted-7-deazaadenosines for the treatment of cancer.

The applicant, Glaxo Group Limited, has disclosed pyrrolo[2,3-d]pyrimidine derivatives as CGRP receptor antagonists in WO2009/080682.

The applicant Glaxo Smithkline, LLC has disclosed in WO 2011/119663 indoline derivatives as PERK inhibitors.

The applicant Basf Aktiengesellschaft has already disclosed 4-aminopyrrolopyrimidines as kinase inhibitors (WO 00/17202).

The applicant, Pfizer Products Inc., has disclosed pyrrolopyrimidine derivatives in WO2004/056830 for use in treating hyperproliferative diseases, such as cancer.

The applicant, Pfizer Inc, has disclosed novel 4-(substituted amino)-7H-pyrrolo[2,3-d]pyrimidines as LRRK2 inhibitors in US 2014/0005183.

Applicant OSI Pharmaceuticals, LLC has disclosed in US Pat. No. 8,586,546 the combination of an EGFR kinase inhibitor and an agent that sensitizes tumor cells to the effects of the EGFR kinase inhibitor.

A series of naphthamides as VEGFR kinase inhibitors have been disclosed in Med. Chem. Lett. 2014, 5, 592-597. Despite these advances, there remains a need for effective agents for treating diseases such as cancer.

The present inventors have now found that compounds of formula (I) as described below are kinase inhibitors and are therefore useful in therapy as anti-tumour agents.

Therefore, the first object of the present invention is to provide a substituted 6-amino-7-bicyclo-7-deaza-purine compound represented by formula (I):

in

R1 and R2 are independently hydrogen or an optionally substituted group selected from linear or branched (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl and COR′, wherein R′ is an optionally substituted group selected from linear or branched (C ₁ -C ₆ )alkyl and (C ₃ -C ₆ )cycloalkyl;

R3 is hydrogen or an optionally substituted group selected from the group consisting of linear or branched (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, (C ₃ -C ₆ )cycloalkyl, aryl, heteroaryl and 3- to 7-membered heterocyclyl rings;

R4 is hydrogen or an optionally substituted group selected from the following: linear or branched (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, aryl, heteroaryl or heterocyclic group;

A is a 5- or 6-membered heteroaryl ring or a phenyl ring;

B is a 5- or 6-membered ring selected from: heteroaryl, (C ₅ -C ₆ )cycloalkyl and heterocyclyl rings or phenyl rings;

wherein Ring A and Ring B are fused together to form a bicyclic ring system comprising a 6-membered aromatic or 5- to 6-membered heteroaromatic ring fused to a 6-membered aromatic or 5- to 6-membered heteroaromatic, (C ₅ -C ₆ )cycloalkyl or heterocyclic ring;

Y is carbon or nitrogen;

X is hydrogen, halogen, hydroxy, cyano or an optionally substituted group selected from linear or branched (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )alkoxy;

R5 and R6 are independently hydrogen or an optionally substituted group selected from the group consisting of linear or branched (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, heterocyclyl, aryl and heteroaryl;

or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for preparing a substituted 6-amino-7-bicyclic-7-deaza-purine compound represented by formula (I), which is prepared by a method consisting of standard synthetic transformations. The present invention also provides a method for treating diseases caused by and/or associated with dysregulated protein kinase activity, particularly RET, RAF family, different isoforms of protein kinase C, Abl, Aurora A, Aurora B, Aurora C, EphA, EphB, FLT3, KIT, LCK, LYN, EGF-R, PDGF-R, FGF-R, PAK-4, P38α, TRKA, TRKB, VEGFR, more particularly RET family kinases, the method comprising administering to a mammal in need thereof, more particularly a human, an effective amount of a substituted 6-amino-7-bicyclic-7-deaza-purine compound represented by formula (I) as defined above.

A preferred method of the present invention is to treat a disease caused by and/or associated with dysregulated protein kinase activity selected from the group consisting of cancer, cell proliferative disorders, viral infections, immune-related disorders, and neurodegenerative disorders.

Another preferred method of the present invention is to treat certain types of cancer, including but not limited to: carcinomas, including bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, including small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer, including squamous cell carcinoma; hematopoietic tumors of the lymphoid lineage, including leukemias, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma , hairy cell lymphoma, and Burkitt's lymphoma; hematopoietic neoplasms of the myeloid lineage, including acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous systems, including astrocytomas, neuroblastomas, gliomas, and schwannomas; other tumors, including melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid cancers such as papillary thyroid carcinoma and medullary thyroid carcinoma, and Kaposi's sarcoma.

Another preferred method of the invention is the treatment of specific cell proliferative disorders such as, for example, benign prostatic hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis, and post-operative stenosis and restenosis.

Another preferred method of the present invention is the treatment of viral infections, including the prevention of AIDS development in HIV-infected individuals.

Another preferred method of the present invention is the treatment of immune-related disorders, including but not limited to: transplant rejection, skin disorders such as psoriasis, allergies, asthma and autoimmune-mediated diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Crohn's disease and amyotrophic lateral sclerosis.

Another preferred method of the present invention is the treatment of neurodegenerative disorders, including, but not limited to, Alzheimer's disease, degenerative neurological diseases, encephalitis, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), Huntington's disease, and Pick's disease.

Additionally, the methods of the present invention provide for inhibition of tumor angiogenesis and metastasis, as well as treatment of organ transplant rejection and host-versus-graft disease.

Moreover, the methods of the present invention further comprise administering to a mammal in need thereof a radiation therapy or chemotherapy regimen in combination with at least one cytostatic or cytotoxic agent.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, carrier and/or diluent.

The present invention further provides pharmaceutical compositions of compounds of formula (I) further comprising one or more chemotherapeutic agents - e.g., cytostatic or cytotoxic agents, antibiotic agents, alkylating agents, antimetabolites, hormonal agents, immunological agents, interferon agents, cyclooxygenase inhibitors (e.g., COX-2 inhibitors), matrix metalloproteinase inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenic agents (e.g., angiogenesis inhibitors), farnesyltransferase inhibitors, ras-raf signaling pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin adhesives, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like.

Furthermore, the present invention provides an in vitro method for inhibiting the activity of a RET family protein, which comprises contacting said protein with an effective amount of a compound of formula (I) as defined above.

Additionally, the present invention provides a product comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.

In yet another aspect, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as a medicament.

Furthermore, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer.

Finally, the present invention provides the use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof in the preparation of a medicament having anticancer activity.

Unless otherwise indicated, when referring to a compound of formula (I) per se and any pharmaceutical composition or any therapeutic treatment containing the same, the invention includes all hydrates, solvates, complexes, metabolites, prodrugs, carriers, N-oxides and pharmaceutically acceptable salts of the compounds of the invention.

The metabolite of a compound of formula (I) is any compound that is converted into the same compound of formula (I) in vivo, for example, when administered to a mammal in need thereof. Generally, but not limiting examples, when administering a compound of formula (I), the same derivative may be converted into various compounds, for example, including more soluble derivatives such as hydroxylated derivatives, which are easily excreted. Therefore, any of these hydroxylated derivatives may be considered as a metabolite of a compound of formula (I), depending on the metabolic pathways thus occurring.

Prodrugs are any covalently bonded compounds which release the active parent drug according to formula (I) in vivo.

If there is a chiral center or another form of asymmetric center in the compounds of the present invention, such isomers are contemplated herein, including all forms of enantiomers and diastereomers. Compounds containing chiral centers can be used in the form of racemic mixtures, enantiomerically enriched mixtures, or racemic mixtures can be separated using well-known techniques and individual enantiomers can be used separately. In the case where the compound has an unsaturated carbon-carbon double bond, both cis (Z) and trans (E) isomers are within the scope of the present invention.

In cases where compounds can exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is intended to be included within the scope of the invention, whether in equilibrium or predominantly in one form.

Pharmaceutically acceptable salts of the compounds of formula (I) include salts formed with inorganic or organic acids, such as nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, oxalic acid, fumaric acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, isethionic acid and salicylic acid.

Pharmaceutically acceptable salts of the compounds of formula (I) also include salts formed with inorganic or organic bases, such as hydroxides, carbonates or bicarbonates of alkali metals or alkaline earth metals, in particular sodium, potassium, calcium, ammonium or magnesium, acyclic or cyclic amines.

The term "straight or branched (C ₁ -C ₆ )alkyl" refers to any radical such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, and the like.

Unless otherwise specified, the term "(C ₃ -C ₆ )cycloalkyl" refers to a 3- to 6-membered all-carbon monocyclic ring that may contain one or more double bonds but does not have a completely conjugated π-electron system. Examples of cycloalkyl groups are, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, and cyclohexadiene. The (C ₃ -C ₆ )cycloalkyl ring may optionally be further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings.

The term "heterocyclyl" refers to a 3- to 7-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulphur. The limiting examples of heterocyclyl groups are, for example, pyrans, tetrahydropyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine, morpholine, etc. The heterocyclic ring can optionally be further fused or connected to aromatic and non-aromatic carbocyclic rings and heterocycles.

The term "C ₂ -C ₆ alkenyl" refers to an aliphatic (C ₂ -C ₆ ) hydrocarbon chain containing at least one carbon-carbon double bond, and which may be linear or branched. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and the like.

The term "C ₂ -C ₆ alkynyl" refers to an aliphatic (C ₂ -C ₆ ) hydrocarbon chain containing at least one carbon-carbon triple bond, and which may be linear or branched. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the like.

The term "aryl" refers to a monocyclic, bicyclic, or polycyclic hydrocarbon having from one to four ring systems, which are optionally further fused or linked to each other by single bonds, wherein at least one of the carbocyclic rings is "aromatic," wherein the term "aromatic" refers to a fully conjugated π-electron bond system. Non-limiting examples of such aryl groups are phenyl, α-naphthyl or β-naphthyl, α-tetrahydronaphthyl or β-tetrahydronaphthyl, biphenyl, and indanyl groups. The aryl rings may optionally be further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings.

The term "heteroaryl" refers to an aromatic heterocyclic ring, typically a 5- to 7-membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur; the heteroaryl ring may optionally be further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings. Non-limiting examples of such heteroaryl groups are, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, pyrrolyl, phenyl-pyrrolyl, furanyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, thiadiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, indazolyl, cinnolinyl, benzo[1,3]dioxolyl, benzo[ 1,4-dioxalyl, benzothiazolyl, benzothiophenyl, isoindolinyl, benzimidazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl, 1-phenyl-1,2,3-triazolyl, 2,3-dihydroindolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothiophenyl, benzopyranyl, 2,3-dihydrobenzoxazinyl, 2,3-dihydroquinoxalinyl, and the like.

According to the present invention and unless otherwise specified, any of the above R1, R2, R3, R4, R5, R6 can be optionally substituted at any of their free positions by one or more groups, for example 1 to 6 groups, independently selected from: halogen, nitro, oxo (=O), cyano, (C ₁ -C ₆ ) alkyl, polyfluorinated alkyl, polyfluorinated alkoxy, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ )alkynyl, hydroxyalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, alkylheterocyclylalkyl, (C3-C6)cycloalkyl, hydroxy, polyhydroxyalkyl, alkoxy, aryloxy, heterocyclyloxy, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, heterocyclylcarbonyloxy, alkyleneaminooxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, amino, heterocyclylalkoxycarbonylamino, urea, alkylamino, aminoalkyl, dialkylamino, arylamino, diarylamino, heterocyclyl The substituents include amino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino, hydroxyaminocarbonylalkoxyimino, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclylaminosulfonyl, arylthio, alkylthio, phosphonate and alkylphosphonate. Therefore, each of the above substituents may be further substituted by one or more of the aforementioned groups, if appropriate.

The term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.

The term "polyfluorinated alkyl" or "polyfluorinated alkoxy" refers to any of the above linear or branched (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy groups, which is substituted with more than one fluorine atom, such as trifluoromethyl, trifluoroethyl, 1,1,1,3,3,3-hexafluoropropyl, trifluoromethoxy, etc.

The term "hydroxyalkyl" refers to any of the above-mentioned ( _C1 - _C6 )alkyl groups having a hydroxy group, such as, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like.

From all the above it will be apparent to the skilled person that any group whose name is a composite name, such as for example "arylamino" must be expected to be conventionally interpreted as meaning the moiety derived therefrom, such as amino further substituted with aryl, wherein aryl is as defined above.

Likewise, any of the terms such as, for example, alkylthio, alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, cycloalkoxycarbonyl and the like, include radicals in which the alkyl, alkoxy, aryl, (C ₃ -C ₆ )cycloalkyl and heterocyclyl portions are as defined above.

A preferred class of compounds of formula (I) are those wherein:

R1 is hydrogen;

R2 is hydrogen, methyl, cyclopropyl or COR', wherein R' is methyl;

R3 is hydrogen or an optionally substituted group selected from the group consisting of linear or branched ( _C1 - _C6 )alkyl, ( _C3 - _C6 )cycloalkyl, aryl, heteroaryl, and 3- to 7-membered heterocyclyl rings; and

R4 is hydrogen or an optionally substituted linear or branched (C ₁ -C ₆ ) alkyl group.

A more preferred class of compounds of formula (I) are compounds wherein:

R1, R2 and R4 are hydrogen;

R3 is hydrogen or an optionally substituted group selected from the group consisting of linear or branched (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, aryl, heteroaryl, and 3- to 7-membered heterocyclyl rings;

B is a 5- or 6-membered heteroaryl, heterocyclyl ring or phenyl ring;

X is hydrogen, halogen, cyano or optionally substituted linear or branched (C ₁ -C ₃ )alkyl; and

R5 is hydrogen.

Preferred specific compounds of formula (I) or pharmaceutically acceptable salts thereof are the following compounds:

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropaneamide (Compound 1),

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-2-carboxylic acid cyclopropaneamide (Compound 2)

6-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropaneamide (Compound 3),

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxamide (Compound 4),

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid isopropylamide (Compound 5),

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid methylamide (Compound 6),

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid (2,2,2-trifluoroethyl)-amide (Compound 7),

6-[4-amino-7-(tetrahydropyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-naphthalene-1-carboxylic acid cyclopropylamide (Compound 8),

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopentylamide (Compound 9),

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid [4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide (Compound 10),

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclobutylamide (Compound 11),

6-(4-amino-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (Compound 12),

6-(4-amino-7-cyclopropylmethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (Compound 13),

6-(4-amino-7-cyclobutylmethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (Compound 14),

6-[4-amino-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-naphthalene-1-carboxylic acid cyclopropylamide (Compound 15),

5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclopropylamide (Compound 16),

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclopropylamide (Compound 17),

5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclopropylmethyl-amide (Compound 18),

5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclobutylamide (Compound 19),

5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclohexylamide (Compound 20),

5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclohexylmethyl-amide (Compound 21),

5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclopentylamide (Compound 22),

5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid (tetrahydropyran-4-yl)-amide (Compound 23),

5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (Compound 24),

5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid isopropylamide (Compound 25),

5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid (1-methyl-piperidin-4-yl)-amide (Compound 26),

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,4-dihydro-2H-quinoline-1-carboxylic acid cyclopropylamide (Compound 27),

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-isoquinoline-1-carboxylic acid cyclopropylamide (Compound 28),

6-(4-amino-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (Compound 29),

6-[4-amino-7-(4,4-difluoro-cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-naphthalene-1-carboxylic acid cyclopropylamide (Compound 30),

6-[4-amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-naphthalene-1-carboxylic acid cyclopropylamide (Compound 31),

6-[4-amino-7-(1-cyclopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-naphthalene-1-carboxylic acid cyclopropylamide (Compound 32),

6-{4-amino-7-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-naphthalene-1-carboxylic acid cyclopropylamide (Compound 33),

6-[7-(1-Acetyl-piperidin-4-yl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-naphthalene-1-carboxylic acid cyclopropylamide (Compound 34),

6-[4-amino-7-(2,2,6,6-tetramethyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-naphthalene-1-carboxylic acid cyclopropylamide (Compound 35),

6-[4-amino-7-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-naphthalene-1-carboxylic acid cyclopropylamide (Compound 36),

6-[4-amino-7-(1-methyl-piperidin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-naphthalene-1-carboxylic acid cyclopropylamide (Compound 37),

6-[4-amino-7-(1-methyl-azetidin-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-naphthalene-1-carboxylic acid cyclopropylamide (Compound 38),

6-[4-amino-7-(1-cyclopropyl-azetidin-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-naphthalene-1-carboxylic acid cyclopropylamide (Compound 39),

6-[7-(1-Acetyl-azetidin-3-ylmethyl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-naphthalene-1-carboxylic acid cyclopropylamide (Compound 40),

6-{4-amino-7-[1-(2-hydroxy-ethyl)-azetidin-3-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-naphthalene-1-carboxylic acid cyclopropylamide (Compound 41),

2-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-indole-5-carboxylic acid cyclopropylamide (Compound 42),

2-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-indole-6-carboxylic acid cyclopropylamide (Compound 43),

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-imidazo[1,2-a]pyridine-2-carboxylic acid cyclopropylamide (Compound 44),

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-indole-3-carboxylic acid cyclopropylamide (Compound 45),

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-benzo[b]thiophene-3-carboxylic acid cyclopropylamide (Compound 46),

6-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-indazole-3-carboxylic acid cyclopropylamide (Compound 47).

The present invention also provides methods for preparing compounds of formula (I) as defined above by using the reaction routes and synthesis schemes described below, using techniques available in the art and readily available starting materials. The preparation of some embodiments of the present invention is described in the following examples, but those of ordinary skill in the art will recognize that the preparations described can be easily adjusted to prepare other embodiments of the present invention. For example, the synthesis of non-exemplary compounds according to the present invention can be carried out by modifications that are obvious to those skilled in the art, such as by suitably protecting interfering groups, by changing other suitable reagents known in the art, or by performing conventional modifications of reaction conditions. Alternatively, other reactions mentioned herein or known in the art will be considered to be suitable for preparing other compounds of the present invention.

The following general method and process can be used to prepare the compounds of the present invention from readily available starting materials. Unless otherwise indicated, starting materials are known compounds or can be prepared by known compounds according to well-known methods. It should be understood that when general or preferred preparation conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure) are given, other process conditions may also be used unless otherwise described. Optimum reaction conditions can vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art according to conventional optimization processes. In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to protect some functional groups to prevent them from undergoing undesirable reactions. Suitable protecting groups for different functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, a large number of protecting groups are described in T.W.Greenec P.G.M.Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991 and the references cited therein.

The compounds of each general formula can be further converted into other compounds of the same general formula according to methods well known in the literature, as reported in the experimental section. In the following schemes, the general preparation of compounds of formula (I) is shown, wherein A, B, R1, R2, R3, R4, R5, R6, X and Y are as defined above.

The general preparation of compounds of formula (I) and salts thereof, for purposes of the present invention, is shown in Scheme 1 below, wherein A, B, R1, R2, R3, R4, R5, R6, X and Y are as defined above.

Solution 1

According to the above scheme 1, the method of the present invention comprises the following steps:

Step a): reacting an intermediate of formula (II), wherein Y is carbon, and A, B, R1, R2, R3, R4 and X are as defined above, with an intermediate of formula (VI), wherein R5 and R6 are as defined above, to obtain a compound of formula (I), wherein Y is carbon, A, B, R1, R2, R3, R4, R5, R6 and X are as defined above;

Optionally,

Step b): reacting an intermediate of formula (III), wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, and A, R1, R2, R3, R4 and X are as defined above, with an intermediate of formula (VI), wherein R5 and R6 are as defined above, to obtain a compound of formula (I), wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, and A, R1, R2, R3, R4, R5, R6 and X are as defined above;

or

Step b'): reacting an intermediate of formula (III) wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, and A, R1, R2, R3, R4 and X are as defined above with an intermediate of formula (VII) wherein R6 is as defined above to obtain a compound of formula (I) wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, R5 is hydrogen, and A, R1, R2, R3, R4, R6 and X are as defined above;

Optionally

Step c): cross-coupling the intermediate of formula (IV), wherein R1, R2, R3, R4 are as defined above, and Hal is iodine or bromine, preferably iodine, with the intermediate of formula (V), wherein R7 is boronic acid or boronic ester, and A, B, R5, R6, X and Y are as defined above, to obtain a compound of formula (I), wherein A, B, R1, R2, R3, R4, R5, R6, X and Y are as defined above;

Optionally, a compound of formula (I) is converted into another compound of formula (I) and, if desired, into a pharmaceutically acceptable salt thereof, or into the free compound (I).

According to step a) of the present invention, at a temperature ranging from about -10°C to reflux, in a suitable solvent such as, for example, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, 1,4-dioxane, acetonitrile, toluene or N,N-dimethylformamide, N,N-dimethylacetamide, in the presence of a coupling agent such as, for example, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 1,3-dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), N-cyclohexylcarbodiimide-N'-propoxymethylpolystyrene or N-cyclohexylcarbodiimide-N'-methylpolystyrene, reacting the intermediate of formula (II) with the intermediate of formula (VI) for a suitable time, for example, from about 30 minutes to about 96 hours, to obtain the compound of formula (I). Optionally, the reaction is carried out in the presence of a suitable catalyst such as 4-dimethylaminopyridine (DMAP), or in the presence of other coupling agents such as N-hydroxybenzotriazole (HOBT), or in the presence of a suitable base such as triethylamine (TEA) or N,N-diisopropyl-N-ethylamine (DIPEA).

According to step b) of the present invention, the compound of formula (I) can be prepared by reacting the intermediate of formula (VI) with triphosgene (bis(trichloromethyl)carbonate, O═C(OCCl ₃ ) ₂ ) or phosgene, followed by the addition of the intermediate of formula (III). The reaction can be carried out in a solvent such as dichloromethane or chloroform, at a temperature ranging from about −10° C. to reflux, in the presence of a base such as diisopropylethylamine (DIPEA), triethylamine (TEA), or Na ₂ CO ₃ , for a time period ranging from about 30 minutes to about 96 hours.

Alternatively, according to step b') of the present invention, the compound of formula (I) can be prepared by reacting the intermediate of formula (III) with a suitable isocyanate of formula (VII). Such reaction is carried out in a suitable solvent such as dichloromethane or tetrahydrofuran, typically at a temperature ranging from about -10°C to reflux, for a time ranging from about 30 minutes to about 96 hours.

According to step c) of the present invention, the reaction of the intermediate of formula (IV) with the intermediate of formula (V) can be carried out under standard conditions, such as for Suzuki coupling, in a suitable organic solvent such as 1,4-dioxane, 1,2-dimethoxyethane, water/1,4-dioxane mixture, water/1,2-dimethoxyethane mixture, water/acetonitrile mixture, N,N-dimethylformamide, toluene, etc., in the presence of a ligand such as but not limited to triphenylphosphine, 3,3′,3″-phosphanetriyltris(benzenesulfonic acid) trisodium salt (TPPTS), diphenylphosphinoferrocene (dppf), using a Pd-based catalyst (PdCl ₂ dppf, PdCl ₂ (PPh ₃ ) ₂ , Pd(PPh ₃ ) ₄ , Pd(OAc) ₂ ) and a suitable base such as sodium carbonate (Na ₂ CO ₃ ), cesium carbonate (Cs ₂ CO ₃ ), potassium phosphate (K ₃ PO ₄ ), and react at room temperature to reflux for 1 to 48 hours (see Med. Chem. Lett. 2014, 5, 592-597; J. Med. Chem. 2011, 54, 5498-5507; ChemMedChem 2013, 8, 832-846).

The preparation of intermediates of formula (II) can be carried out as described in Scheme 2 below, wherein Y is carbon, and A, B, R1, R2, R3, R4 and X are as defined above.

Option 2

According to the above scheme 2, the method of the present invention comprises the following steps:

Step c): cross-coupling the intermediate of formula (IV), wherein R1, R2, R3, R4 are as defined above, and Hal is iodine or bromine, preferably iodine, with the intermediate of formula (VIII), wherein Y is carbon, R7 is boronic acid or boronic ester, R10 is a linear or branched (C ₁ -C ₄ ) alkyl group, and A, B and X are as defined above, to obtain the intermediate of formula (IX), wherein Y is carbon, R10 is a linear or branched (C ₁ -C ₄ ) alkyl group, and A, B, R1, R2, R3, R4 and X are as defined above.

Step d): Hydrolyze the obtained intermediate of formula (IX) to obtain the intermediate of formula (II), wherein Y is carbon, and A, B, R1, R2, R3, R4 and X are as defined above.

According to step c) of scheme 2, the reaction is carried out as described in step c) of scheme 1.

According to step d) of the present invention, the hydrolysis of the intermediate of formula (IX) can be carried out at a temperature ranging from room temperature to reflux in a suitable solvent such as methanol, ethanol, tetrahydrofuran, dichloromethane, tetrahydrofuran/water mixture, etc., in the presence of a base such as LiOH, NaOH, KOH or an acid such as HCl, TFA, for a period of 1 hour to 48 hours.

Alternatively, intermediates of formula (II), i.e., intermediates of formula (IIa), wherein Y is carbon, R4 is ( _C2 - _C6 )alkenyl, aryl, heteroaryl or heterocyclyl, and A, B, R1, R2, R3 and X are as defined above, can be prepared as described in Scheme 2a below.

Option 2a

According to the above scheme 2a, the method of the present invention comprises the following steps:

Step e): Halogenating the intermediate of formula (IX), wherein R4 is hydrogen, Y is carbon, R10 is a linear or branched (C ₁ -C ₄ ) alkyl group, and A, B, R1, R2, R3 and X are as defined above, i.e., the intermediate of formula (IXa), to obtain the intermediate of formula (X), wherein Hal is iodine or bromine, Y is carbon, R10 is a linear or branched (C ₁ -C ₄ ) alkyl group, and A, B, R1, R2, R3 and X are as defined above;

Step f): The intermediate of formula (X) obtained is reacted with an intermediate of formula R4-Q (XI), wherein Q is boronic acid or boronic ester or stannane, and R4 is (C ₂ -C ₆ ) alkenyl, aryl, heteroaryl or heterocyclic group, or when R4 is (C ₂ -C ₆ ) alkenyl, Q is hydrogen to obtain an intermediate of formula (IXb), wherein Y is carbon, R4 is (C ₂ -C ₆ ) alkenyl, aryl, heteroaryl or heterocyclic group, R10 is linear or branched (C ₁ -C ₄ ) alkyl, and A, B, R1, R2, R3 and X are as defined above;

Step d'): The intermediate of formula (IXb) obtained is hydrolyzed to obtain an intermediate of formula (IIa), wherein Y is carbon, R4 is ( _C2 - _C6 ) alkenyl, aryl, heteroaryl or heterocyclyl, and A, B, R1, R2, R3 and X are as defined above. According to step e) of the present invention, the halogenation of the intermediate of formula (IXa) can be carried out at room temperature in a suitable solvent such as dichloromethane, N,N-dimethylformamide or N,N-dimethylacetamide in the presence of N-iodosuccinimide or N-bromosuccinimide for a period of 1 hour to 48 hours to obtain an intermediate of formula (X), wherein Hal is iodine or bromine (see Bioorg. Med. Chem. Lett. 2000, 2171-2174; Chem. Commun. 1997, 695-696).

According to step f) of the present invention, when Q is a boronic acid or a boronic ester, the reaction can be carried out under typical thermal conditions or in a microwave apparatus at a temperature range of 70°C to 160°C in a suitable solvent such as 1,4-dioxane, 1,2-dimethoxyethane, a water/1,4-dioxane mixture, a water/1,2-dimethoxyethane mixture, N,N-dimethylformamide, toluene, etc., in the presence or absence of lithium chloride, over a Pd-based catalyst ( _PdCl2dppf , _{PdCl2 ( PPh3} ) ₂ , Pd( _PPh3 ) ₄ , Pd(OAc) ₂ ), in the presence of a base such as sodium carbonate ( _Na2CO3 ), potassium carbonate ( _K2CO3 ), potassium _acetate (KOAc), by using a suitable aryl, heteroaryl or heterocyclic boronic acid derivative.

Alternatively, when Q is stannane, the reaction can be carried out by using a suitable (C 2 -C 6 )alkenylstannane derivative in a suitable solvent such as N,N-dimethylformamide, ethanol, toluene, in the presence of tetrabutylammonium chloride or tetrabutylammonium bromide or lithium chloride and in the presence of a Pd-based catalyst (PdCl ₂ dppf, PdCl ₂ (PPh ₃ ) ₂ , Pd(PPh ₃ ) ₄ , Pd(OAc) ₂ ) at a temperature ranging from room temperature to reflux for a period of 1 hour to 48 hours (Ref. _Bioorg . Med. Chem. Lett. 2000, 2171-2174; Chem. Commun. _{1997, 695-696} ).

Alternatively, when Q is hydrogen and R4 is ( _C2 - _C6 )alkenyl, the reaction can be carried out at a temperature ranging from room temperature to reflux in a suitable solvent such as N,N-dimethylformamide or acetonitrile, in the presence of potassium acetate, sodium carbonate, triethylamine, tetrabutylammonium bromide or tetrabutylammonium chloride, in the presence or absence of a phosphine such as triphenylphosphine or tri(o-tolyl)phosphine, and in the presence of a catalyst such as Pd(OAc) ₂ , _Pd2 (dba) ₃ , for a period of 1 hour to 48 hours.

According to step d') of scheme 2a, the reaction is carried out as in step d) of scheme 2.

The preparation of intermediates of formula (III) wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, and A, R1, R2, R3, R4 and X are as defined above can be carried out as described in Scheme 3 below.

Option 3

According to the above scheme 3, the method of the present invention comprises the following steps:

Step c): an intermediate of formula (IV), wherein Hal is iodine or bromine, preferably iodine, and R1, R2, R3 and R4 are as defined above, optionally:

Cross-coupling reaction with an intermediate of formula (XIIa), wherein Y is nitrogen, B is a 5- or 6-membered heteroaryl ring, R7 is boronic acid or boronic ester, and A and X are as defined above, to obtain a compound of formula (XIIIa), wherein Y is nitrogen, B is a 5- or 6-membered heteroaryl ring, and A, R1, R2, R3, R4 and X are as defined above;

or

reacting with an intermediate of formula (XIIb), wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, R7 is boronic acid or boronic ester, R8 is a suitable protecting group COR10 or COOR10, wherein R10 is a linear or branched (C ₁ -C ₄ ) alkyl group, and A and X are as defined above, to obtain a compound of formula (XIIIb), wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, R8 is a suitable protecting group COR10 or COOR10, wherein R10 is a linear or branched (C ₁ -C ₄ ) alkyl group, and A, R1, R2, R3, R4 and X are as defined above;

Then

Step g): reducing the obtained intermediate of formula (XIIIa) to obtain an intermediate of formula (III), wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, and A, R1, R2, R3, R4 and X are as defined above;

or

Step h): Deprotecting the obtained intermediate of formula (XIIIb) to obtain the intermediate of formula (III) as defined above.

Alternatively, intermediates of formula (XIIIa) and (XIIIb) can be prepared according to the following steps:

Step c'): reacting an intermediate of formula (XIV) wherein R4 is hydrogen or an optionally substituted linear or branched (C ₁ -C ₆ ) alkyl, Hal is iodine or bromine, preferably iodine, and R3 is as defined above with an intermediate of formula (XIIa) as defined above or an intermediate of formula (XIIb) as defined above, respectively, to give an intermediate of formula (XVa) wherein Y is nitrogen, B is a 5- or 6-membered heteroaryl ring, R4 is hydrogen or an optionally substituted linear or branched (C ₁ -C ₆ ) alkyl, and R3, A and X are as defined above, or to give an intermediate of formula (XVb) wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, R4 is hydrogen or an optionally substituted linear or branched (C ₁ -C ₆ ) alkyl, and R8 is a suitable protecting group COR10 or COOR10, wherein R10 is a linear or branched (C ₁ -C ₄ ) alkyl, and R3, A and X are as defined above;

Then

Step i): The obtained intermediate of formula (XVa) or (XVb) as defined above is reacted with an intermediate of formula (XVI) wherein R1 and R2 are as defined above to obtain an intermediate of formula (XIIIa) or (XIIIb) as defined above, respectively. According to steps c) and c') of scheme 3, the intermediate of formula (IV) or (XIV) is reacted with intermediates of formula (XIIa) and (XIIb) to obtain intermediates of formula (XIIIa) and (XIIIb), respectively, or (XVa) and (XVb) can be carried out as described in step c) of scheme 1.

According to step g) of the present invention, the reduction of the intermediate of general formula (XIIIa) to obtain the intermediate _of formula (III) can be carried out at a temperature ranging from room temperature to reflux, in a solvent such as methanol, ethanol, dichloromethane, etc., in the presence of a reducing agent such as _NaBH4 , _NBu4BH4 , _NaCNBH3 , _Et3SiH , _BH3 · _NMe3 , and by adding an acid such as acetic acid or TFA (trifluoroacetic acid) for a period of 1 hour to 48 hours.

According to step h) of the present invention, the reaction of the intermediate of formula (XIIIb) to obtain the intermediate of formula (III) can be carried out at a temperature ranging from room temperature to reflux in a suitable solvent such as methanol, ethanol, tetrahydrofuran, dioxane, dichloromethane, water, etc., in the presence of a base such as LiOH, NaOH, KOH or an acid such as HCl, TFA for a period of 1 hour to 48 hours.

According to step i) of the present invention, the reaction of the intermediate of formula (XVa) or (XVb) with the intermediate of formula (XVI) to obtain the intermediate of formula (XIIIa) or (XIIIb) can be carried out under typical thermal conditions or in a microwave apparatus, in a temperature range of 60° C. to 150° C., in the absence of a solvent or in a solvent such as 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide for a period of 1 hour to 24 hours.

Alternatively, step i) can be carried out under typical thermal conditions under reflux or in a microwave apparatus at a temperature range of 50°C to 100°C in a suitable solvent such _as tetrahydrofuran or 1,4-dioxane, in the presence of a base such as _sodium carbonate ( _Na2CO3 ), cesium carbonate ( _Cs2CO3 ), potassium phosphate ( _K3CO4 ) and _a Pd-based catalyst (Pd(OAc) ₂ , _Pd2dba3 ), and in the presence _of a ligand such as Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), P(o-Tol) ₃ , for 1 to 24 hours.

The preparation of intermediates of formula (III), i.e., intermediates of formula (IIIb), wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, R4 is ( _C2 - _C6 )alkenyl, aryl, heteroaryl or heterocyclyl, and A, R1, R2, R3 and X are as defined above, can be carried out as described in Scheme 3a below.

Option 3a

Step e) halogenating an intermediate of formula (III), i.e., an intermediate of formula (IIIa), wherein R4 is hydrogen, Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, A, R1, R2, R3, and X are as defined above, to obtain an intermediate of formula (XVII), wherein Hal is iodine or bromine, Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, and A, R1, R2, R3, and X are as defined above;

Step f): The obtained intermediate of formula (XVII) is reacted with an intermediate of formula R4-Q (XI), wherein Q is boronic acid or boronic ester or stannane, and R4 is (C ₂ -C ₆ )alkenyl, aryl, heteroaryl or heterocyclyl, or when R4 is (C ₂ -C ₆ )alkenyl, Q is hydrogen, to obtain the intermediate of formula (III), i.e., the intermediate of formula (IIIb), wherein R4 is (C ₂ -C ₆ )alkenyl, aryl, heteroaryl or heterocyclyl, Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, and A, R1, R2, R3 and X are as defined above.

According to step e) of scheme 3a, the halogenation of the intermediate of formula (IIIa) wherein R4 is hydrogen can be carried out as described for step e) of scheme 2a (cf. Bioorg. Med. Chem. Lett. 2000, 2171-2174; Chem. Commun. 1997, 695-696).

According to step f) of scheme 3a, the reaction is carried out as described in step f) of scheme 2a.

The preparation of intermediates of formula (IV), i.e., intermediates of formula (IVa), wherein R4 is hydrogen or optionally substituted linear or branched ( _C1 - _C6 ) alkyl, Hal is iodine or bromine, and R1, R2, and R3 are as defined above, can be carried out as described in Scheme 4a below.

Option 4a

According to Scheme 4a, the intermediate of formula (IVa) can be prepared by the following reaction:

Step j): Halogenating the intermediate of formula (XVIII), wherein R4 is hydrogen or an optionally substituted linear or branched (C ₁ -C ₆ ) alkyl, to obtain the intermediate of formula (XIX), wherein Hal is iodine or bromine, and R4 is hydrogen or an optionally substituted linear or branched (C ₁ -C ₆ ) alkyl;

Step k): The intermediate of formula (XIX) obtained is reacted with an intermediate of formula (XX), wherein Z is iodine, bromine, mesylate, tosylate, triflate, hydroxyl, boronic acid or boronate, and R3 is as defined above, to obtain an intermediate of formula (XIV), wherein Hal is iodine or bromine, R4 is hydrogen or an optionally substituted linear or branched (C ₁ -C ₆ ) alkyl group, and R3 is as defined above.

Optionally

Step k') an intermediate of formula (XVIII), wherein R4 is hydrogen or an optionally substituted linear or branched (C ₁ -C ₆ ) alkyl, reacted with an intermediate of formula (XX), wherein Z is iodine, bromine, mesylate, tosylate, triflate, hydroxyl, boronic acid or borate, and R3 is as defined above, to obtain an intermediate of formula (XXI), wherein R4 is hydrogen or an optionally substituted linear or branched (C ₁ -C ₆ ) alkyl, and R3 is as defined above;

Step j') halogenating the obtained intermediate of formula (XXI) to obtain the intermediate of formula (XIV), wherein Hal is iodine or bromine, R4 is hydrogen or an optionally substituted linear or branched (C ₁ -C ₆ ) alkyl group, and R3 is as defined above;

Then

The intermediate of formula (XIV) obtained in step i), wherein Hal is iodine or bromine, R4 is hydrogen or an optionally substituted linear or branched (C ₁ -C ₆ ) alkyl group, and R3 is as defined above, is reacted with the intermediate of formula (XVI) wherein R1 and R2 are as defined above to obtain the intermediate of formula (IVa), wherein Hal is iodine or bromine, R4 is hydrogen or an optionally substituted linear or branched (C ₁ -C ₆ ) alkyl group, and R1, R2 and R3 are as defined above.

According to steps j and j') of the present invention, intermediates (XVIII) and (XXI) are subjected to halogenation with N-iodosuccinimide to obtain intermediates of formula (XIX) and (XIV), wherein Hal is iodine, or halogenation with N-bromosuccinimide or pyridine hydrobromide perbromide to obtain intermediates of formula (XIX) and (XIV), wherein Hal is bromine. The reaction can be carried out in a suitable solvent such as acetonitrile, N,N-dimethylformamide, chloroform or tetrahydrofuran, under typical thermal conditions or in a microwave apparatus operating at a temperature range of room temperature to 70°C. Alternatively, the reaction to obtain compounds of formula (XIX) and (XIV), wherein Hal is iodine, can be carried out using molecular iodine in a suitable solvent such as N,N-dimethylformamide or a water-methanol mixture in the presence or absence of potassium hydroxide at room temperature, or in a suitable solvent such as N,N′-dimethylformamide or dichloromethane in the presence of silver acetate or silver trifluoroacetate at a temperature ranging from room temperature to 80° C. The reaction can also be carried out using iodine monochloride in a suitable solvent such as 1,4-dioxane or dichloromethane in the presence or absence of sodium carbonate or potassium carbonate at a temperature ranging from room temperature to reflux.

According to steps k) and k′) of the present invention, when Z is iodine, bromine, chlorine, mesylate, tosylate or triflate, the reaction can be carried out under typical thermal conditions or in a microwave apparatus at a temperature range of room temperature to 100° C. in a suitable solvent such as 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, in the presence of a suitable base such as cesium carbonate (Cs ₂ CO ₃ ), sodium carbonate (Na ₂ CO ₃ ) or potassium carbonate (K ₂ CO ₃ ). Alternatively, when Z is hydroxy, the reaction can be carried out under Mitsunobu conditions at a temperature range of 0° C. to 70° C. in a suitable solvent such as tetrahydrofuran or dichloromethane, in the presence of diethyl azodicarboxylate or diisopropyl azodicarboxylate and triphenylphosphine.

In a further alternative, when Z is boronic acid or a boronic ester, the reaction can be carried out in N,N-dimethylacetamide in the presence of cupric acetate, 2,2′-bipyridyl and sodium carbonate at a temperature range of 70° C. to 120° C., or in methanol with cuprous oxide at reflux.

The alkyl iodide, bromide, chloride, mesylate, tosylate, triflate, hydroxy and aryl, heteroaryl or heterocyclic boronic acid derivatives used as reactants in the above steps k) and k') are commercially available compounds or can be prepared according to methods described in the literature.

According to step i) of scheme 4a, the reaction can be carried out as described in step i) of scheme 3.

The intermediate of formula (XVIII) wherein R4 is an optionally substituted linear or branched (C ₁ -C ₆ )alkyl group is commercially available or can be prepared according to the method described in patent WO99065609.

Preparation of intermediates of formula (IV), i.e., intermediates of formula (IVb), wherein R4 is an optionally substituted linear or branched ( _C2 - _C6 )alkenyl, aryl, heteroaryl or heterocyclyl, and R1, R2 and R3 are as defined above, can be carried out as described in Scheme 4b below.

Option 4b

According to Scheme 4b, the intermediate of formula (IVb) can be prepared by the following reaction:

Step i): reacting an intermediate of formula (XVIIIa) with an intermediate of formula (XVI) wherein R1 and R2 are as defined above to obtain an intermediate of formula (XXV) wherein R1 and R2 are as defined above;

Step k): reacting the obtained intermediate of formula (XXV) with an intermediate of formula (XX), wherein Z is iodine, bromine, mesylate, tosylate, triflate, hydroxyl, boronic acid or boronic ester, and R3 is as defined above, to obtain an intermediate of formula (XXVI), wherein R1, R2 and R3 are as defined above;

Step e): halogenating the obtained intermediate of formula (XXVI) to obtain an intermediate of formula (XXVII), wherein Hal is iodine or bromine, and R1, R2 and R3 are as defined above;

Step g): the obtained intermediate of formula (XXVII) is reacted with an intermediate of formula (XI), wherein Q is boronic acid or boronic ester or stannane, and R4 is (C ₂ -C ₆ )alkenyl, aryl, heteroaryl or heterocyclic group, or when R4 is (C ₂ -C ₆ )alkenyl, Q is hydrogen, to obtain an intermediate of formula (XXVIII), wherein R4 is (C ₂ -C ₆ )alkenyl, aryl, heteroaryl or heterocyclic group, and R1, R2 and R3 are as defined above;

Step j): Halogenate the intermediate of formula (XXVIII) to obtain the intermediate of formula (IVb), wherein Hal is iodine or bromine, R4 is (C ₂ -C ₆ )alkenyl, aryl, heteroaryl or heterocyclic, and R1, R2 and R3 are as defined above, i.e., the intermediate of formula (IVb).

According to step i) of scheme 4b, the reaction can be carried out as described in step i) of scheme 3.

According to step k) of scheme 4b, the reaction can be carried out as described in steps k) and k') of scheme 4a.

According to step e) of scheme 4b, halogenation can be carried out as described in step e) of scheme 2a (see Bioorg. Med. Chem. Lett. 2000, 2171-2174; Chem. Commun. 1997, 695-696).

According to step f) of scheme 4b, the reaction is carried out as described in step f) of scheme 2.

According to step j) of scheme 4b, the halogenation can be carried out as described in step j) of scheme 4a.

The preparation of intermediates of formula (V) can be carried out as described in Scheme 5 below, wherein R7 is a boronic acid or boronic ester, and A, B, R5, R6, X and Y are as defined above.

Option 5

According to Scheme 5, the intermediate of formula (V) can be prepared by the following reaction:

Step d) reaction of an intermediate of formula (VIII), wherein Y is carbon, R7 is boronic acid or boronic ester, R10 is linear or branched (C ₁ -C ₄ ) alkyl, A, B and X are as defined above, to obtain an intermediate of formula (XXIX), wherein Y is carbon, R7 is boronic acid or boronic ester, A, B and X are as defined above;

Step a) reacting the obtained intermediate of formula (XXIX) with an intermediate of formula (VI) wherein R5 and R6 are as defined above to obtain an intermediate of formula (V) wherein Y is carbon, R7 is boronic acid or boronic acid ester, and A, B, R5, R6 and X are as defined above;

Optionally

Step b) an intermediate of formula (XIIa), wherein Y is nitrogen, B is a 5- or 6-membered heteroaryl ring, R7 is a boronic acid or boronic ester, and A and X are as defined above, reacted with an intermediate of formula (VI), wherein R5 and R6 are as defined above, to obtain an intermediate of formula (V), wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, R7 is a boronic acid or boronic ester, and A, R5, R6 and X are as defined above;

Optionally

Step b') an intermediate of formula (XIIa) wherein Y is nitrogen, B is a 5- or 6-membered heteroaryl ring, R7 is a boronic acid or boronic ester, and A and X are as defined above, reacted with an intermediate of formula (VII) wherein R6 is as defined above to give an intermediate of formula (V) wherein Y is nitrogen, B is a 5- or 6-membered heteroaryl ring, R5 is hydrogen, R7 is a boronic acid or boronic ester, and A, R6 and X are as defined above;

Optionally

Step g) reducing the intermediate of formula (XIIa), wherein Y is nitrogen, B is a 5- or 6-membered heteroaryl ring, R7 is a boronic acid or boronic ester, A and X are as defined above, to obtain the intermediate of formula (XXX), wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, R7 is a boronic acid or boronic ester, A and X are as defined above;

or

Step h) reaction of an intermediate of formula (XIIb), wherein Y is nitrogen, B is a 5- or 6-membered heteroaryl ring, R7 is boronic acid or boronic ester, R8 is a suitable protecting group COR10 or COOR10, wherein R10 is a linear or branched (C ₁ -C ₄ ) alkyl group, and A and X are as defined above, to obtain an intermediate of formula (XXX) as defined above;

Then

Step b) reacting the obtained intermediate of formula (XXX) with an intermediate of formula (VI) wherein R5 and R6 are as defined above to obtain an intermediate of formula (V) wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, R7 is boronic acid or boronic ester, and A, R5, R6 and X are as defined above;

or

Step b') reacting the obtained intermediate of formula (XXX) with an intermediate of formula (VII) wherein R6 is as defined above to obtain an intermediate of formula (V) wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, R5 is hydrogen, R7 is boronic acid or boronic ester, and A, R6 and X are as defined above;

Optionally

Step p) Reaction of an intermediate of formula (XXXI) wherein R11 is hydrogen, iodine, bromine or chlorine, A, B, R5, R6, Y and X are as defined above, to obtain an intermediate of formula (V) wherein R7 is boronic acid or boronic ester, A, B, R5, R6, Y and X are as defined above.

According to step d) of scheme 5, the reaction is carried out as described in step d) of scheme 2.

According to steps a), b) and b') of scheme 5, the reaction is carried out as described in steps a), b) and b') of scheme 1.

According to steps g) and h) of scheme 5, the reaction is carried out as described in steps g) and h) of scheme 3.

According to step p) of Scheme 5, a catalyst such as Pd(0), PdCl 2 dppf, PdCl ₂ (CH 3 CN) 2 , Pd(OAc) ₂ , Pd(dba) ₂ is reacted with a ligand such as diphenylphosphinoferrocene (dppf), bis(2-di-tert-butylphosphinophenyl) ether, tricyclohexylphosphine (PCy ₃ ), _2- (biphenyl ₎ di-cyclopentylphosphane (PCy ₂ (o-biph), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), a suitable base such as potassium acetate (AcOK), triethylamine (TEA) and bispinacolato diboron (B ₂ pin 2 ) in a suitable organic solvent such as dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, 1,2-dimethoxyethane, ethanol, _toluene , _etc. at a temperature ranging from room temperature to reflux. ), pinacolborane (HBpin) or diboronic acid [B(OH) ₂ ] ₂ , the reaction of the intermediate of formula (XXXI) is carried out for a period of 1 hour to 48 hours to obtain the intermediate of formula (V).

Alternatively, when R11 is hydrogen, the reaction can also be carried out in a solvent such as 1,2-dimethoxyethane, tetrahydrofuran, benzene, hexane, octane, etc., using a catalyst such as [Ir(COD)(OMe) ₂ ], [Ir(COD)Cl ₂ ] and a ligand such as 2,2′-bipyridine (bpy), 4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy) at a temperature range of room temperature to reflux for a period of 1 to 48 hours (Angew. Chem. Int. Ed. 2002, 41, 3056-3058; Tetrahedron Lett. 2002, 43, 5649-5651).

The preparation of intermediates of formula (VIII) can be carried out as described in Scheme 6 below, wherein Y is carbon, R7 is a boronic acid or boronic ester, R10 is a linear or branched ( _C1 - _C4 ) alkyl group, and A, B, and X are as defined above. Intermediate (VIII) can be commercially available or prepared according to methods described in the literature and well known to those skilled in the art (Med. Chem. Lett., 2014, 5, 592-597).

Option 6

According to Scheme 6, the intermediate of formula (VIII) can be prepared by the following reaction:

Step q): reaction of an intermediate of formula (XXXII), wherein Y is carbon, R11 is hydrogen, iodine, bromine or chlorine, and A, B and X are as defined above, to obtain an intermediate of formula (XXXIII), wherein Y is carbon, R11 is hydrogen, iodine, bromine or chlorine, R10 is a linear or branched (C ₁ -C ₄ ) alkyl group, and A, B and X are as defined above;

Step p): reacting the obtained intermediate of formula (XXXIII) to obtain the intermediate of formula (VIII), wherein Y is carbon, R7 is boronic acid or boronic ester, R10 is linear or branched (C ₁ -C ₄ ) alkyl, and A, B and X are as defined above;

Optionally

Step r): Reaction of an intermediate of formula (XXXIV), wherein Y is carbon, R10 is a linear or branched (C ₁ -C ₄ ) alkyl group, and A, B, and X are as defined above, to obtain an intermediate of formula (XXXV), wherein Y is carbon, R10 is a linear or branched (C ₁ -C ₄ ) alkyl group, OTf is trifluoromethanesylfonate, and A, B, and X are as defined above;

Step p'): reacting the intermediate of formula (XXXV) obtained to obtain the intermediate of formula (VIII) wherein Y is carbon, R7 is boronic acid or boronic ester, R10 is linear or branched ( _C1 - _C4 ) alkyl, and A, B and X are as defined above.

According to step q) of scheme 6, the intermediate of formula (XXXII) is esterified in the presence of an acid catalyst such as p-toluenesulfonic acid, sulfonic acid, methanesulfonic acid in an alcohol such as methanol, ethanol, propanol, etc. at room temperature to reflux for a period of 1 hour to 48 hours.

Alternatively, the intermediate of formula (XXXII) can be converted to the corresponding acid chloride in the presence of thionyl chloride or oxalyl chloride with or without catalytic amount of dimethylaminopyridine (DMAP) at a temperature ranging from room temperature to reflux, in the absence of solvent or in a solvent such as dichloromethane, toluene, and then treated with an alcohol such as methanol, ethanol, propanol, etc.

Alternatively, the reaction can be carried out at a temperature ranging from zero to room temperature in a solvent such as dichloromethane, dimethylformamide, etc., in the presence of a catalytic amount of dimethylaminopyridine (DMAP) using a coupling agent such as dicyclohexylcarbodiimide (DCC) for a period of 1 hour to 48 hours.

According to steps p) and p') of scheme 6, the reaction can be carried out as described in step p) of scheme 5.

According to step r) of Scheme 6, the reaction can be carried out in a solvent such as dichloromethane, tetrahydrofuran, in trifluoromethanesulfonic anhydride, N-phenyl-bis(trifluoromethanesulfonimide) using a base such as diisopropylethylamine (DIPEA), triethylamine (TEA) with or without a catalytic amount of dimethylaminopyridine (DMAP) at a temperature ranging from -78°C to room temperature for a period of 1 hour to 48 hours.

The preparation of intermediates of formula (XIIa), wherein Y is nitrogen, B is a 5- or 6-membered heteroaryl ring, R7 is a boronic acid or boronic ester, and A and X are as defined above, or the preparation of intermediates of formula (XIIb), wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, R7 is a boronic acid or boronic ester, R8 is a suitable protecting group COR10 or COOR10, wherein R10 is a linear or branched ( _C1 - _C4 ) alkyl group, and A and X are as defined above, can be carried out as described in Scheme 7 below. Intermediates (XIIa) and (XIIb) can be commercially available or prepared according to methods described in the literature and well known to those skilled in the art.

Option 7

According to Scheme 7, the intermediate of formula (XIIa) can be prepared by the following reaction:

Step p): Reaction of an intermediate of formula (XXXVIa) wherein Y is nitrogen, B is a 5- or 6-membered heteroaryl ring, Hal is iodine or bromine, A and X are as defined above, to obtain an intermediate of formula (XIIa) wherein Y is nitrogen, B is a 5- or 6-membered heteroaryl ring, R7 is boronic acid or boronic ester, and A and X are as defined above.

According to Scheme 7, the intermediate of formula (XIIb) can be prepared by the following reaction:

Step s): Protection of the intermediate of formula (XXXVIb), wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, Hal is iodine or bromine, A and X are as defined above, to obtain the intermediate of formula (XXXVII), wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, Hal is iodine or bromine, R8 is a suitable protecting group COR10 or COOR10, wherein R10 is a straight chain or (C ₁ -C ₄ ) alkyl, and A and X are as defined above;

Step p'): reacting the obtained intermediate of formula (XXXVII) to obtain the intermediate of formula (XIIb), wherein Y is nitrogen, B is a 5- or 6-membered heterocyclic ring, R7 is boronic acid or boronic ester, R8 is a suitable protecting group COR10 or COOR10, wherein R10 is a linear or branched (C ₁ -C ₄ ) alkyl group, and A and X are as defined above.

According to steps p) and p') of scheme 7, the reaction can be carried out as described in step p) of scheme 5.

According to step s) of Scheme 7, the protection of the intermediate of formula (XXXVIb) to the intermediate of formula (XXXVII) can be carried out at a temperature ranging from -78°C to room temperature in a solvent such as dichloromethane, tetrahydrofuran, toluene, etc., in the presence of a base such as triethylamine (TEA), diisopropylamine (DIPEA), sodium hydride (NaH), pyridine, with or without a catalyst such as dimethylaminopyridine (DMAP), using a reagent such as acid chloride, acetic anhydride, trifluoroacetic anhydride, di-tert-butylcarbamate or ethyl chloroformate for a period of 1 hour to 48 hours.

The preparation of intermediates of formula (XXXI) wherein R is hydrogen, iodine, bromine or chlorine and A, B, R, R, X and Y are as defined above can be carried out as described in Scheme 8 below. Intermediates (XXXVIII) and (XXXIX) can be commercially available or prepared according to methods described in the literature or known to those skilled in the art.

Option 8

Step a): an intermediate of formula (XXXVIII), wherein Y is carbon, R11 is hydrogen, iodine, bromine or chlorine, and A, B and X are as defined above, reacted with an intermediate of formula (VI), wherein R5 and R6 are as defined above, to obtain an intermediate of formula (XXXI), wherein Y is carbon, R11 is hydrogen, iodine, bromine or chlorine, and A, B, R5, R6 and X are as defined above;

Optionally

Step b): an intermediate of formula (XXXIXa) wherein Y is nitrogen, B is a 5- or 6-membered heteroaryl ring, R11 is hydrogen, iodine, bromine or chlorine, and A and X are as defined above, reacted with an intermediate of formula (VI) wherein R5 and R6 are as defined above to obtain an intermediate of formula (XXXI) wherein Y is nitrogen, B is a 5- or 6-membered heteroaryl ring, R11 is hydrogen, iodine, bromine or chlorine, and A, R5, R6 and X are as defined above;

or

Step b'): an intermediate of formula (XXXIXa) wherein Y is nitrogen, B is a 5- or 6-membered heteroaryl ring, R11 is hydrogen, iodine, bromine or chlorine, and A and X are as defined above, reacted with an intermediate of formula (VII) wherein R6 is as defined above to obtain an intermediate of formula (XXXI) wherein Y is nitrogen, B is a 5- or 6-membered heteroaryl ring, R11 is hydrogen, iodine, bromine or chlorine, R5 is hydrogen, and R6, A and X are as defined above;

Optionally

Step b): an intermediate of formula (XXXIXb) wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, R11 is hydrogen, iodine, bromine or chlorine, and A and X are as defined above, reacted with an intermediate of formula (VI) wherein R5 and R6 are as defined above to obtain an intermediate of formula (XXXI) wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, R11 is hydrogen, iodine, bromine or chlorine, and A, R5, R6 and X are as defined above;

or

Step b'): An intermediate of formula (XXXIXb) wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, R11 is hydrogen, iodine, bromine or chlorine, and A and X are as defined above, is reacted with an intermediate of formula (VII) wherein R6 is as defined above to give an intermediate of formula (XXXI) wherein Y is nitrogen, B is a 5- or 6-membered heterocyclyl ring, R11 is hydrogen, iodine, bromine or chlorine, R5 is hydrogen, and R6, A and X are as defined above.

According to steps a), b) and b') of Scheme 8, the reaction is carried out as described in steps a), b) and b') of Scheme 1.

The starting materials, in any of their wide possible variations, and any reactants object of the process of the present invention are known compounds and, if not commercially available per se, can be prepared according to well-known methods or as described in the experimental part below.

Pharmacology

In vitro cell proliferation assay

To evaluate the antiproliferative activity of compounds of formula (I), the following human cell lines were used: A2780 ovarian carcinoma; TT medullary thyroid carcinoma with a mutated RET-C634W receptor; and LC-2/ad human lung adenocarcinoma with a CCDC6-RET fusion protein. Exponentially growing cells were seeded and cultured at 37°C in a humidified 5% _CO2 atmosphere using appropriate culture medium supplemented with 10% fetal bovine serum. Twenty-four hours after cell plating, a scalar dose of the compound dissolved in 0.1% DMSO was added to the culture medium and, depending on their different proliferation rates, cells were exposed to the drug for 72 hours (A2780) or 144 hours (TT and LC-2/ad). At the end of treatment, cell proliferation was measured using an intracellular ATP monitoring system (CellTiterGlo - Promega) according to the manufacturer's instructions, using an Envision instrument (PerkinElmer) as a reader. Data from compound-treated and vehicle-treated cells were compared using Assay Explorer software (Symyx Technologies Inc). _IC50 values were calculated using sigmoidal interpolation curve fitting.

In Table A below, representative compounds of Formula (I) are reported for their antiproliferative activity against a medullary thyroid carcinoma cell line expressing the aforementioned RET mutant form (TT) and a lung adenocarcinoma cell line harboring the aforementioned RET fusion form (LC-2/ad). As a control, the antiproliferative activity of the same compounds against an irrelevant RET-independent cell line (A2780) is reported. All of these compounds showed significant activity against RET-driven cell models compared to irrelevant cell models.

Table A

According to all the above results, the novel compounds of formula (I) of the present invention appear to be particularly advantageous in the treatment of diseases caused by deregulated protein kinase activity, such as cancer.

The compounds of the invention can be administered as a single agent, or alternatively, in combination with known anti-cancer treatments such as radiation or chemotherapy regimens, in combination with, for example, anti-hormonal agents, such as antiestrogens, anti-androgens and aromatase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, agents that target microtubules, platinum-based agents, alkylating agents, DNA damaging or intercalating agents, anti-tumor antimetabolites, other kinase inhibitors, other anti-angiogenic agents, kinesin inhibitors, therapeutic monoclonal antibodies, mTOR inhibitors, histone deacetylase inhibitors, farnesyl transferase inhibitors, and inhibitors of the hypoxic response.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range.

When a combination formulation is inappropriate, the compounds of formula (I) may be used sequentially with known anticancer agents.

The compound of formula (I) of the present invention suitable for administration to mammals such as humans can be administered by conventional routes, and the dosage level depends on the patient's age, weight, and condition and the administration route.

For example, a suitable dosage of a compound of formula (I) suitable for oral administration may be about 10 mg to about 1 gram per dose, 1 to 5 times a day. The compounds of the present invention may be administered in various dosage forms, for example, orally in the form of tablets, capsules, sugar-coated or film-coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, for example, intramuscularly or via intravenous and/or intrathecal and/or intraspinal injection or infusion.

The present invention also provides a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient may be a carrier or a diluent.

Pharmaceutical compositions containing the compounds of the present invention are generally prepared according to conventional methods and administered in suitable pharmaceutical forms.

For example, solid oral forms may contain, together with the active compound, the following substances: diluents such as lactose, glucose, saccharose, sucrose, cellulose, corn starch or potato starch; lubricants such as silicon dioxide, talc, stearic acid, magnesium stearate or calcium stearate and/or polyethylene glycols; binders such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrants such as starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; dyes; sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulfate; and generally non-toxic and pharmacologically inactive substances used in pharmaceutical preparations. These pharmaceutical preparations can be prepared in a known manner, for example, by mixing, granulating, tabletting, sugar coating or film coating processes.

Liquid dispersions for oral administration may be, for example, syrups, emulsions and suspensions.

As an example, a syrup may contain sucrose or sucrose with glycerol and/or mannitol and sorbitol as a carrier.

Suspensions and emulsions may contain natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol as examples of carriers.

The suspension or solution for intramuscular injection may contain, together with the active compound, a pharmaceutically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol and, if desired, an appropriate amount of lidocaine hydrochloride.

Solutions for intravenous injection or infusion may contain sterile water as a carrier, or preferably they may be in the form of sterile isotonic saline solutions, or they may contain propylene glycol as a carrier.

Suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier such as cocoa butter, polyethylene glycol, polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

Experimental part

See the experimental section and claims for any specific compound of formula (I) of the present invention, optionally in pharmaceutically acceptable salt form. With respect to the examples below, the compounds of the present invention were synthesized using the methods described herein or other methods well known in the art.

The abbreviations and abbreviations used in this document have the following meanings:

g (gram) mg (milligram)

mL (milliliter) μL (microliter)

mM (millimole) mmol (millimole)

μM (micromolar) R _t (retention time)

h (hour) MHz (megahertz)

mm (millimeter) Hz (hertz)

M (mole) min (minute)

mol (mole) TLC (thin layer chromatography)

r.t. (room temperature) TEA (triethylamine)

DMAP (dimethylaminopyridine) DME (dimethoxyethane)

Na ₂ SO ₄ (sodium sulfate) AcOEt (ethyl acetate)

Na ₂ CO ₃ (sodium carbonate) K ₂ CO ₃ (potassium carbonate)

DMF (N,N-dimethylformamide) DCM (dichloromethane)

DIPEA(N,N-diisopropyl-N-ethylamine) Hex(hexane)

THF (tetrahydrofuran) DMSO (dimethyl sulfoxide)

MeOH (methanol) ESI (electrospray ionization)

NaHCO ₃ (sodium bicarbonate) OTf (trifluoromethanesulfonate)

HCl (hydrochloric acid solution) NH ₃ (33% aqueous solution of ammonium hydroxide)

LiOH (lithium hydroxide) KOH (potassium hydroxide)

EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride)

TBTU (N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate)

HBTU (N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate)

RP-HPLC (reverse phase high performance liquid chromatography).

In order to better illustrate the present invention, the following examples are now given without constituting any limitation to the present invention.

As used herein, the symbols and conventions used in the methods, schemes, and examples are consistent with those used in contemporary scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry.

Unless otherwise noted, all materials were obtained from commercial suppliers, of the best grade, and used without further purification. Anhydrous solvents such as DMF, THF, DCM, and toluene were obtained from Aldrich Chemical Company. All reactions involving air- or moisture-sensitive compounds were performed under nitrogen or argon atmosphere.

General purification and analytical methods

Flash chromatography was performed using silica gel (Merck grade 9395, 60A).

HPLC was performed on a Waters X Terra RP 18 (4.6 x 50 mm, 3.5 μm) column using a Waters 2790 HPLC system equipped with a 996 Waters PDA detector and a Micromass mod. ZQ single quadrupole mass spectrometer equipped with an electrospray (ESI) ion source. Mobile phase A was 5 mM ammonium acetate buffer (acetic acid-acetonitrile 95:5, pH 5.2), and mobile phase B was water-acetonitrile (5:95). The gradient was 10 to 90% B over 8 minutes, holding at 90% B for 2 minutes. UV detection was performed at 220 nm and 254 nm. The flow rate was 1 mL/min. The injection volume was 10 μL. A full scan was performed with a mass range of 100 to 800 amu. The capillary voltage was 2.5 kV; the source temperature was 120°C; and the arc cone was 10 V. Masses are given as m/z ratios.

When necessary, compounds were purified by preparative HPLC on a Waters Symmetry C18 (19 x 50 mm, 5 μm) column or a Waters X Terra RP18 (30 x 150 mm, 5 μm) column using a Waters Preparative HPLC 600 equipped with a 996 Waters PDA detector and a Waters ZQ single quadrupole mass spectrometer with electrospray ionization in positive mode. Mobile phase A was water/0.1% TFA, and mobile phase B was acetonitrile. The gradient was from 10 to 90% B over 8 minutes, with a hold of 90% B for 2 minutes. The flow rate was 20 mL/min. Alternatively, mobile phase A was water/0.05% _NH3 , and mobile phase B was acetonitrile. The gradient was from 10 to 100% B over 8 minutes, with a hold of 100% B for 2 minutes. The flow rate was 20 mL/min. ¹ H-NMR spectra ( ¹ H{ ¹⁵ N- ³¹ P}) were recorded at a constant temperature of 28° C. on a Varian INOVA 400 spectrometer operating at 400.50 MHz and equipped with a 5 mm z-axis PFG indirect detection probe.

Chemical shifts are referenced to the residual solvent signal (DMSO- _d6 : 2.50 ppm ^for1H , unless otherwise specified). Data are reported as follows: chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, br.s = broad singlet, dd = doublet of doublet, ddd = doublet of doublet of doublet, dt = double of triplet, td = triplet of doublet, qd = quartet of doublet, tt = triplet of triplet, m = multiplet, spt = septet), coupling constant (J, Hz), and number of protons.

ESI(+) high-resolution mass spectra (HRMS) were obtained on a Q-Tof Ultima (Waters, Manchester, UK) mass spectrometer directly connected to an Agilent 1100 micro-HPLC system (Palo Alto, US) as previously reported (M. Colombo, F. R. Sirtori, V. Rizzo, Rapid Commun Mass Spectrom 2004, 18(4), 511-517).

Preparation Example 1

Scheme 4a, step k

4-Chloro-5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine

The intermediates can be prepared according to the methods described in patents WO2009114874 and WO2011044157.

Y＝96％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.47 (d, J＝6.7Hz, 6H) 4.92-5.15 (m, 1H) 8.16 (s, 1H) 8.63 (s, 1H)

HRMS (ESI) calcd for C ₉ H ₁₀ ClIN ₃ [(M+H) ⁺ ]: 321.9603; found: 321.9605

Following this same methodology, but using appropriate commercially available reagents, the following intermediates were prepared:

4-Chloro-7-cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

Y＝92％

¹ H NMR(401MHz, DMSO-d ₆ )δppm 1.61-1.74(m,2H)1.81-2.03(m,4H)2.06-2.22(m,2H)5.04-5.20(m,1H)8.10(s,1H)8.63(s,1H)

HRMS (ESI) calcd. for C ₁₁ H ₁₂ ClIN ₃ [(M+H) ⁺ ]: 347.9759; found: 347.9753

4-Chloro-7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

Y＝45％

HRMS (ESI) calcd. for C ₁₀ H ₁₀ ClIN ₃ [(M+H) ⁺ ]: 333.9603; found: 333.9615

4-Chloro-5-iodo-7-(tetrahydropyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine

Y＝68％

HRMS (ESI) calcd. for C ₁₁ H ₁₂ ClIN ₃ O [(M+H) ⁺ ]: 364.9708; found: 364.9701

4-Chloro-5-iodo-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine

Y＝98％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 5.23 (q, J＝9.1Hz, 2H) 8.05 (s, 1H) 8.74 (s, 1H)

HRMS (ESI) calcd for C ₈ H ₅ ClF ₃ IN ₃ [(M+H) ⁺ ]: 361.9164; found: 361.9170

4-Chloro-7-cyclopropylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

Y＝83％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 0.39-0.46 (m, 2H) 0.48-0.55 (m, 2H) 1.27 (d, J = 7.8Hz, 1H) 4.12 (d, J = 7.3Hz, 2H) 8.09 (s, 1H) 8.64 (s, 1H)

HRMS (ESI) calcd. for C ₁₀ H ₁₀ ClIN ₃ [(M+H) ⁺ ]: 333.9603; found: 333.9604

4-Chloro-7-cyclobutylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

Y＝93％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.68-1.99 (m, 6H) 2.73-2.88 (m, 1H) 4.29 (d, J = 7.4Hz, 2H) 8.02 (s, 1H) 8.63 (s, 1H)

HRMS (ESI) calcd. for C ₁₁ H ₁₂ ClIN ₃ [(M+H) ⁺ ]: 347.9759; found: 347.9770

4-Chloro-7-(4,4-difluoro-cyclohexyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

Y＝35％

HRMS (ESI) calcd for C ₁₂ H ₁₂ ClF ₂ IN ₃ [(M+H) ⁺ ]: 397.9727; found: 397.9715

Preparation Example 2

Scheme 4a, step i

5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

A solution of 4-chloro-5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.31 mmol) in dioxane (0.47 mL) and aqueous _NH₄OH (0.35 mL) was heated in a microwave at 100°C for 4 hours. The solvent was removed under reduced pressure, and the residue was collected with AcOEt and washed with distilled water and brine. The organic layer was dried _over anhydrous _Na₂SO₄ and evaporated to dryness, yielding a pure white solid.

Y＝95％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.40 (d, J＝6.7Hz, 7H) 4.76-4.96 (m, 1H) 6.55 (br.s., 2H) 7.57 (s, 1H) 8.08 (s, 1H)

HRMS (ESI) calcd for C ₉ H ₁₂ IN ₄ [(M+H) ⁺ ]: 303.0101; found: 303.0104

Following this same procedure, but using the appropriate intermediates, the following intermediates were prepared:

7-Cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Y＝73％

¹ H NMR(401MHz, DMSO-d ₆ )δppm 1.52-1.73(m,2H)1.75-1.91(m,4H)1.98-2.16(m,2H)4.90-5.06(m,1H)6.55(br.s.,2H)7.52(s,1H)8.08(s,1H)

HRMS (ESI) calcd for C ₁₁ H ₁₄ IN ₄ [(M+H) ⁺ ]: 329.0258; found: 329.0254

7-Cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Y＝75％

HRMS (ESI) calcd for C ₁₀ H ₁₂ IN ₄ [(M+H) ⁺ ]: 315.0101; found: 315.0104

5-iodo-7-(tetrahydropyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Y＝62％

HRMS (ESI) Calcd for C ₁₁ H ₁₄ IN ₄ O [(M+H) ⁺ ]: 345.0207; Found: 345.0203

5-iodo-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Y＝95％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 5.03 (q, J＝9.3Hz, 2H) 6.73 (br.s., 2H) 7.49 (d, J＝1.1Hz, 1H) 8.15 (s, 1H)

HRMS (ESI) Calcd for C ₈ H ₇ F ₃ IN ₄ [(M+H) ⁺ ]: 342.9662; Found: 342.9663

7-Cyclopropylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Y＝71％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 0.35-0.40 (m, 2H) 0.44-0.54 (m, 2H) 1.15-1.29 (m, 1H) 3.95 (d, J = 7.1Hz, 2H) 6.57 (br.s., 2H) 7.52 (s, 1H) 8.09 (s, 1H)

HRMS (ESI) calcd for C ₁₀ H ₁₂ IN ₄ [(M+H) ⁺ ]: 315.0101; found: 315.0096

7-Cyclobutylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Y＝94％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.59-2.02 (m, 6H) 2.73 (quin, J = 7.6Hz, 1H) 4.12 (d, J = 7.4Hz, 2H) 6.57 (br.s., 2H) 7.39-7.47 (m, 1H) 8.09 (s, 1H)

HRMS (ESI) calcd for C ₁₁ H ₁₄ IN ₄ [(M+H) ⁺ ]: 329.0258; found: 329.0269

7-(4,4-Difluoro-cyclohexyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Y＝42％

HRMS (ESI) Calcd for C ₁₂ H ₁₄ F ₂ IN ₄ [(M+H) ⁺ ]: 379.0226; Found: 379.0229

Preparation Example 3

Scheme 6, step q

6-Hydroxy-naphthalene-1-carboxylic acid methyl ester

The intermediates were prepared according to the method described in Med. Chem. Lett. 2014, 5, 592-597.

Y＝95％

HRMS (ESI) Calcd for C ₁₂ H ₁₁ O ₃ [(M+H) ⁺ ]: 203.0703; Found: 203.0707

Following this same procedure, but using appropriate starting materials, the following intermediates were prepared:

6-Hydroxy-naphthalene-2-carboxylic acid methyl ester

Y＝96％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 3.88 (s, 3H) 7.12-7.22 (m, 2H) 7.74-7.80 (m, 1H) 7.84-7.89 (m, 1H) 7.98 (d, J = 8.7Hz, 1H) 8.49 (s, 1H) 10.17 (s, 1H)

HRMS (ESI) Calcd for C ₁₂ H ₁₁ O ₃ [(M+H) ⁺ ]: 203.0703; Found: 203.0699

Preparation Example 4

Scheme 6, step r

6-Trifluoromethanesulfonyloxy-naphthalene-1-carboxylic acid methyl ester

The intermediate can be prepared according to the method described in Med. Chem. Lett. 2014, 5, 592-597 using trifluoromethanesulfonic anhydride (Y=97%), or according to the method described in patent WO/2007/104538 using N-phenyltrifluoromethanesulfonimide (Y=93%).

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 3.96(s,3H)7.72-7.82(m,2H)8.27(dd,J＝7.3,1.3Hz,1H)8.30(d,J＝2.7Hz,1H)8.36(d,J＝8.3Hz,1H)8.94(d,J＝9.5Hz,1H)

HRMS (ESI) Calcd. for C ₁₃ H ₁₀ F ₃ O ₅ S [(M+H) ⁺ ]: 335.0196; Found: 335.0177

Following this same procedure, but using appropriate starting materials, the following intermediates were prepared:

6-Trifluoromethanesulfonyloxy-naphthalene-2-carboxylic acid methyl ester

Y＝97％

HRMS (ESI) Calcd. for C ₁₃ H ₁₀ F ₃ O ₅ S [(M+H) ⁺ ]: 335.0196; Found: 335.0185

Preparation Example 5

Scheme 6, step p′

6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalene-1-carboxylic acid methyl ester

The intermediate can be prepared according to the method described in Med. Chem. Lett. 2014, 5, 592-597.

Y＝54％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.33-1.38(m,12H)3.93-3.97(m,3H)7.61-7.67(m,1H)7.83-7.87(m,1H )8.17-8.21(m,1H)8.28-8.33(m,1H)8.39-8.43(m,1H)8.70-8.76(m,1H)

HRMS (ESI) calcd for C ₁₈ H ₂₂ BO ₄ [(M+H) ⁺ ]: 312.1642; found: 312.1647

Following this same procedure, but using appropriate starting materials, the following intermediates were prepared:

6-(4,4,5,5-Tetramethyl-[1,3,2]]dioxaborolan-2-yl)-naphthalene-2-carboxylic acid methyl ester

Y＝84％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.35(s,12H)3.93(s,3H)7.80(dd,J＝8.3,1.1Hz,1H)7.99(dd,J＝8.6,1.8Hz,1H)8.13(dd,J＝11.0,8.8Hz,2H)8.39(s,1H)8.63(s,1H)

HRMS (ESI) calcd for C ₁₈ H ₂₂ BO ₄ [(M+H) ⁺ ]: 312.1606; found: 312.1600

Preparation Example 6

Scheme 5, step d

6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalene-1-carboxylic acid

The intermediate can be prepared according to the method described in Med. Chem. Lett. 2014, 5, 592-597.

Y＝48％

HRMS (ESI) calcd for C ₁₇ H ₂₀ BO ₄ [(M+H) ⁺ ]: 299.1449; found: 299.1452

Following this same procedure, but using appropriate starting materials, the following intermediates were prepared:

6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalene-2-carboxylic acid

Y＝93％

HRMS (ESI) Calcd for C ₁₇ H ₂₀ BO ₄ [(M+H) ⁺ ]: 299.1449; Found: 299.1447

6-(Dihydroxyboryl)naphthalene-1-carboxylic acid

Y＝49％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 7.54(t,J＝7.7Hz,1H)7.95(dd,J＝8.7,1.1Hz,1H)8.11(dd,J＝7.6,3.1Hz,2H)8.23(s,2H)8.41(s,1H)8.75(d,J＝8.8Hz,1H)13.05(br.s.,1H)

HRMS (ESI) Calcd for C ₁₁ H ₁₀ BO ₄ [(M+H) ⁺ ]: 217.0667; Found: 217.0661

Preparation Example 7

Scheme 5, step a

6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalene-1-carboxylic acid cyclopropylamide

To a solution of 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalene-1-carboxylic acid (100 mg, 0.34 mmol) in anhydrous DMF (1 mL) was added DIPEA (0.114 mL, 0.67 mmol), TBTU (215 mg, 0.67 mmol) and cyclopropylamine (0.046 mL, 0.67 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was collected with AcOEt and washed with acidic water and brine solution. The organic layer was dried _over anhydrous _Na2SO4 and evaporated to dryness. The product was isolated as a white solid.

Y＝53％

HRMS (ESI) calcd for C ₂₀ H ₂₅ BNO ₃ [(M+H) ⁺ ]: 338.1922; found: 338.1917

Following this same procedure, but using appropriate starting materials, the following intermediates were prepared:

6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalene-2-carboxylic acid cyclopropylamide

Y＝63％

HRMS (ESI) calcd for C ₂₀ H ₂₅ BNO ₃ [(M+H) ⁺ ]: 338.1922; found: 338.1921

[5-(Cyclopropylcarbamoyl)naphthalen-2-yl]boronic acid

Y＝98％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 0.55-0.62(m,2H)0.69-0.77(m,2H)2.90-2.99(m,1H)7.41(ddd,J＝8.3,7.0,0.9Hz,1H)7.52(t,J＝8.1Hz,1H)7.55(dd,J＝7.0,1.5Hz,1H)7.71 (dt,J＝8.3,1.0Hz,1H)7.90(dd,J＝8.5,1.3Hz,1H)7.98(d,J＝7.8Hz,1H)8.10(d,J＝8.5Hz,1H)8.20(s,2H)8.39(br.s,1H)8.52(d,J＝4.3Hz,1H)

HRMS (ESI) calcd. for C ₁₄ H ₁₅ BNO ₃ [(M+H) ⁺ ]: 255.1176; found: 255.1175

Preparation Example 8

Solution 2, step c

6-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid methyl ester

5-Iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (100 mg, 0.33 mmol) was dissolved in a mixture of DME (2.4 mL) and distilled water (1.5 mL). Under an argon atmosphere, _Na₂CO₃ (140 _mg , 1.32 mmol), 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2-yl)-naphthalene-1-carboxylic acid methyl ester (113 mg, 0.36 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.01 mmol) were added to the reaction medium. The mixture was heated under reflux for 3 hours. The solvent was removed under reduced pressure, and the residue was collected with AcOEt and washed with distilled water and brine solution. The organic layer was dried _over anhydrous _Na₂SO₄ and evaporated to dryness. The crude material was purified by flash chromatography (AcOEt) to give the title compound after trituration with diethyl ether.

Y＝66％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.50(d,J＝6.8Hz,6H)3.97(s,3H)5.01(quin,J＝6.8Hz,1H)6.13(br.s.,2H)7.60-7.67(m,2H)7.82(dd,J＝8.9,2. 0Hz,1H)8.10(d,J＝2.0Hz,1H)8.13(dd,J＝7.3,1.3Hz,1H)8.17(s,1H)8.23(d,J＝8.3Hz,1H)8.82(d,J＝8.9Hz,1H)

HRMS (ESI) calcd. for C ₂₁ H ₂₁ N ₄ O ₂ [(M+H) ⁺ ]: 361.1659; found: 361.1665

Following this same procedure, but using appropriate starting materials, the following intermediates were prepared:

5-(1H-indol-5-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Y＝85％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.47(d,J＝6.7Hz,6H)4.97(quin,J＝6.7Hz,1H)6.00(br.s.,2H)6.47(ddd,J＝3.0,2.0,0.9Hz,1H)7.19(dd,J＝8.2,1 .6Hz,1H)7.33-7.36(m,1H)7.39(t,J＝2.7Hz,1H)7.47-7.52(m,1H)7.59-7.62(m,1H)8.12(s,1H)11.17(br.s.,1H)

HRMS (ESI) calcd for C ₁₇ H ₁₈ N ₅ [(M+H) ⁺ ]: 292.1557; found: 292.1550

5-(1H-indol-6-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Y＝83％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.46-1.51(m,6H)4.99(quin,J＝6.8Hz,1H)6.06(br.s.,2H)6.47(dd,J＝2.5,1.5Hz,1H)7.12(dd,J＝8.1,1 .6Hz,1H)7.38(t,J＝2.7Hz,1H)7.40(s,1H)7.46(s,1H)7.63(d,J＝8.1Hz,1H)8.13(s,1H)11.16(br.s.,1H)

HRMS (ESI) calcd for C ₁₇ H ₁₈ N ₅ [(M+H) ⁺ ]: 292.1557; found: 292.1547

1-[6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,4-dihydro-2H-quinolin-1-yl]-ethanone

Y＝78％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.39-1.50(m,6H)1.91(quin,J＝6.4Hz,3H)2.21(s,3H)2.76(t,J＝6.5Hz,2H)3.71(t,J＝6.3Hz ,2H)4.97(quin,J＝6.8Hz,1H)6.06(br.s.,2H)7.16-7.32(m,2H)7.34-7.78(m,3H)8.13(s,1H)

HRMS (ESI) Calcd. for C ₂₀ H ₂₄ N ₅ O [(M+H) ⁺ ]: 350.1976; Found: 350.1980

5-(1H-indazol-6-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

¹ H NMR (600MHz, DMSO-d ₆ ) δppm 3.76(s,3H)6.13(br.s.,2H)7.23(dd,J＝8.2,1.3Hz,1H)7.38(s,1H)7.53(s,1H)7.84(d,J＝8.2Hz,1H)8.09(s,1H)8.17(s,1H)13.08(s,1H)

HRMS (ESI) calcd. for C ₁₄ H ₁₃ N ₆ [(M+H) ⁺ ]: 265.1196; found: 265.1205

Preparation Example 9

Solution 2, step d

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid

To a solution of methyl 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylate (100 mg, 0.28 mmol) in THF (0.9 mL) and distilled water (0.9 mL) was added LiOH (20 mg, 0.83 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the alkaline aqueous phase was washed twice with AcOEt to remove organic impurities. The aqueous layer was then acidified with 2N HCl to yield the title compound as a crystalline precipitate.

Y＝91％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.53(d,J＝6.8Hz,6H)5.08(quin,J＝6.7Hz,1H)7.64(dd,J＝8.2,7.3Hz,1H)7.79(dd,J＝8.9,2.0Hz,1H)7.95(s,1H)8.1 1(d,J＝1.8Hz,1H)8.18(dd,J＝7.3,1.3Hz,1H)8.21(d,J＝8.2Hz,1H)8.47(s,1H)8.98(d,J＝8.9Hz,1H)13.20(br.s.,1H)

HRMS (ESI) Calcd for C ₂₀ H ₁₉ N ₄ O ₂ [(M+H) ⁺ ]: 347.1503; Found: 347.1506

Preparation Example 10

Option 3, step g

5-(2,3-Dihydro-1H-indol-5-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

The intermediates can be prepared according to the method described in patent WO2014/072220.

Y＝72％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.44(d,J＝6.71Hz,6H)2.96(t,J＝8.5Hz,2H)3.46(td,J＝8.5,1.8Hz,2H)4.94(quin,J＝6.7Hz,1H)5.57(s,1H )5.96(br.s.,2H)6.58(d,J＝7.9Hz,1H)6.99(dd,J＝7.9,1.8Hz,1H)7.12(s,1H)7.17-7.36(m,1H)8.09(s,1H)

HRMS (ESI) calcd for C ₁₇ H ₂₀ N ₅ [(M+H) ⁺ ]: 294.1713; found: 294.1712

Following this same procedure, but using appropriate starting materials, the following intermediates were prepared:

5-(2,3-Dihydro-1H-indol-6-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Y＝65％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.45(d,J＝6.7Hz,6H)2.94(t,J＝8.4Hz,2H)3.46(t,J＝8.5Hz,2H)4.94(quin,J＝6.8Hz,1H)5.62(s,1H)6.08 (br.s.,2H)6.56(d,J＝1.2Hz,1H)6.59(dd,J＝7.3,1.5Hz,1H)7.09(d,J＝7.2Hz,1H)7.31(s,1H)8.11(s,1H)

HRMS (ESI) calcd for C ₁₇ H ₂₀ N ₅ [(M+H) ⁺ ]: 294.1713; found: 294.1709

Preparation Example 11

Scheme 3, step h

7-Isopropyl-5-(1,2,3,4-tetrahydro-quinolin-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

To a solution of 1-[6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,4-dihydro-2H-quinolin-1-yl]-ethanone (100 mg, 0.29 mmol) in MeOH (9.4 mL) and distilled water (4.8 mL) was added KOH (321 mg, 5.73 mmol). The mixture was heated to reflux for 19 hours. The solvent was removed under reduced pressure, the residue was collected with DCM, and washed with distilled water and brine solution. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to dryness. The crude material was purified by flash chromatography (AcOEt/Hex 8/2-9/1) to give the title compound (63 mg) as a yellow oil.

Y＝65％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.43(d,J＝6.6Hz,6H)1.82(quin,J＝5.9Hz,2H)2.68-2.73(m,2H)3.17-3.24(m,2H)4.93(quin,J＝6.8Hz,1H)5 .74(s,1H)6.06(br.s.,2H)6.51(d,J＝9.15Hz,1H)6.87-7.00(m,2H)7.20(s,1H)7.23(br.s.,1H)8.08(s,1H)

HRMS (ESI) calcd. for C ₁₈ H ₂₂ N ₅ [(M+H) ⁺ ]: 308.1870; found: 308.1873

Example 1

Scheme 1, step c

6-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (Compound 1)

The compound can be prepared according to the method described in Preparation 8.

Y＝69％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 0.58-0.63(m,2H)0.71-0.78(m,2H)1.50(d,J＝6.71Hz,6H)2.96(td,J＝7.48,3.72Hz,1H)5.01(quin,J＝6.80Hz,1H)6.09(br.s.,2H)7 .51-7.57(m,2H)7.60(s,1H)7.72(dd,J＝8.73,1.77Hz,1H)7.98-8.07(m,2H)8.17(s,1H)8.29(d,J＝8.67Hz,1H)8.56(d,J＝4.52Hz,1H)

HRMS (ESI) calcd. for C ₂₃ H ₂₄ N ₅ O [(M+H) ⁺ ]: 386.1976; found: 386.1972

Following this same procedure, but using the appropriate intermediates, the following compounds were prepared:

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-2-carboxylic acid cyclopropylamide (Compound 2)

Y＝49％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 0.53-0.64(m,2H)0.67-0.76(m,2H)1.47(d,J＝6.84Hz,6H)2.89(td,J＝7.45,3.78Hz,1H)4.98(quin,J＝6.71Hz,1H)6.11(br.s.,2H)7.61(s,1H)7 .70(dd,J＝8.36,1.65Hz,1H)7.85-7.92(m,1H)7.94-7.98(m,1H)7.99(s, 1H)8.06(d,J＝8.54Hz,1H)8.14(s,1H)8.41(s,1H)8.56(d,J＝4.15Hz,1H)

HRMS (ESI) calcd. for C ₂₃ H ₂₄ N ₅ O [(M+H) ⁺ ]: 386.1976; found: 386.1971

6-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (Compound 3)

Y＝25％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 0.53-0.65(m,2H)0.70-0.79(m,2H)1.61-1.77(m,2H)1.80-2.04(m,4H )2.08-2.24(m,2H)2.96(td,J＝11.47,3.97,3.36Hz,1H)5.02-5.25(m,1 H)6.09(br.s.,2H)7.51-7.61(m,3H)7.72(dd,J＝8.67,1.83Hz,1H)7.95-8.08(m,2H)8.17(s,1H)8.28(d,J＝8.79Hz,1H)8.56(d,J＝4.39Hz,1H)

HRMS (ESI) Calcd. for C ₂₅ H ₂₆ N ₅ O [(M+H) ⁺ ]: 412.2132; Found: 412.2133

6-[4-Amino-7-(tetrahydropyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-naphthalene-1-carboxylic acid cyclopropylamide (Compound 8)

Y＝20％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 0.59-0.64(m,2H)0.71-0.78(m,2H)1.91(dd,J＝12.14,2.62Hz,2H)2.15(qd,J＝12.25, 4.39Hz,2H)2.92-3.01(m,1H)3.51-3.59(m,2H)4.02(dd,J＝11.11,4.15Hz,2H)4.87(tt ,J＝11.95,4.04Hz,1H)6.13(br.s.,2H)7.52-7.58(m,2H)7.63(s,1H)7.72(dd,J＝8.79, 1.83Hz,1H)7.98-8.06(m,2H)8.18(s,1H)8.29(d,J＝8.79Hz,1H)8.57(d,J＝4.39Hz,1H)

HRMS (ESI) calcd. for C ₂₅ H ₂₆ N ₅ O ₂ [(M+H) ⁺ ]: 428.2081; found: 428.2091

6-(4-Amino-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (Compound 12)

Y＝15％

HRMS (ESI) calcd. for C ₂₄ H ₂₅ N ₅ O [(M+H) ⁺ ]: 398.1976; found: 398.1979

6-(4-Amino-7-cyclopropylmethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (Compound 13)

Y＝47％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 0.42-0.48(m,2H)0.48-0.56(m,2H)0.58-0.64(m,2H)0.71-0.78(m,2H )1.26-1.38(m,1H)2.92-3.01(m,1H)4.07(d,J＝7.20Hz,2H)6.11(br.s .,2H)7.54-7.56(m,2H)7.56(s,1H)7.71(dd,J＝8.73,1.89Hz,1H)7.99-8.07(m,2H)8.17(s,1H)8.29(d,J＝8.79Hz,1H)8.57(d,J＝4.39Hz,1H)

HRMS (ESI) calcd. for C ₂₄ H ₂₄ N ₅ O [(M+H) ⁺ ]: 398.1976; found: 398.1974

6-(4-Amino-7-cyclobutylmethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (Compound 14)

Y＝46％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 0.58-0.64(m,2H)0.71-0.78(m,2H)1.74-2.06(m,6H)2.84(quin,J＝7.63 Hz,1H)2.92-3.01(m,1H)4.23(d,J＝7.45Hz,2H)6.10(br.s.,2H)7.47(s,1 H)7.52-7.57(m,2H)7.69(dd,J＝8.79,1.83Hz,1H)8.00(d,J＝1.83Hz,1H)8 .01-8.06(m,1H)8.17(s,1H)8.28(d,J＝8.79Hz,1H)8.56(d,J＝4.39Hz,1H)

HRMS (ESI) Calcd. for C ₂₅ H ₂₆ N ₅ O [(M+H) ⁺ ]: 412.2132; Found: 412.2134

6-[4-Amino-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-naphthalene-1-carboxylic acid cyclopropylamide (Compound 15)

Y＝56％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 0.58-0.65(m,2H)0.71-0.77(m,2H)2.97(td,J＝7.29,4.09Hz,1H)5.14(q,J＝9.28Hz,2H)6.28(br.s.,2H)7.49-7.52(m,1H) 7.55-7.59(m,2H)7.70(dd,J＝8.73,1.89Hz,1H)8.02-8.10(m,2H)8.24(s,1H)8.31(d,J＝8.79Hz,1H)8.58(d,J＝4.39Hz,1H)

HRMS (ESI) Calcd for C _{2 2} H _{1 9} F ₃ N ₅ O [(M+H) ⁺ ]: 426.1536; Found: 426.1537

6-[4-Amino-7-(4,4-difluoro-cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-naphthalene-1-carboxylic acid cyclopropylamide (Compound 30)

Y＝30％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 0.56-0.62(m,2H)0.71-0.77(m,2H)2.02-2.21(m,8H)2.95(td,J＝7.29,4.09Hz,1H)4.83(m,1H)6.16(br.s.,2H)7.54-7.55 (m,2H)7.64(s,1H)7.71(dd,J＝8.69,1.68Hz,1H)8.01-8.03(m,2H)8.18(s,1H)8.28(d,J＝8.85Hz,1H)8.60(d,J＝4.12Hz,1H)

HRMS (ESI) Calcd. for C ₂₆ H ₂₆ F ₂ N ₅ O [(M+H) ⁺ ]: 462.21; Found: 462.2112

Example 2

Solution 1, step a

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxamide (Compound 4)

To a solution of 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid (100 mg, 0.29 mmol) in anhydrous DMF (3.3 mL) was added DIPEA (0.198 mL, 1.16 mmol), EDCI (90 mg, 0.58 mmol) and 1-hydroxy-1H-benzotriazole ammonium salt (88 mg, 0.58 mmol). The reaction mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, the residue was collected with AcOEt, and washed with saturated NaHCO ₃ solution, HCl 0.5M and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to dryness. The crude material was purified by flash chromatography (AcOEt/MeOH 95/5) to give the title compound after trituration with diethyl ether.

Y＝57％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.50(d,J＝6.71Hz,6H)5.01(quin,J＝6.80Hz,1H)6.10(br.s.,2H)7.55(dd,J＝8.18,7.08Hz,1H)7.58(br.s.,1H) 7.61(s,1H)7.63-7.66(m,1H)7.72(dd,J＝8.79,1.83Hz,1H)7.95-8.08(m,3H)8.17(s,1H)8.41(d,J＝8.79Hz,1H)

HRMS (ESI) Calcd. for C ₂₀ H ₂₀ N ₅ O [(M+H) ⁺ ]: 346.1663; Found: 346.1669

Example 3

Solution 1, step a

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid isopropylamide (Compound 5)

To a solution of 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid (100 mg, 0.29 mmol) in anhydrous DMF (3.3 mL) was added DIPEA (0.198 mL, 1.16 mmol), HBTU (220 mg, 0.58 mmol) and isopropylamine (0.05 mL, 0.58 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was collected with AcOEt and washed with saturated NaHCO ₃ solution, water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to dryness. The crude material was purified by flash chromatography (AcOEt/MeOH 99/1) to give the title compound after trituration with diethyl ether.

Y＝76％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.22(d,J＝6.59Hz,6H)1.50(d,J＝6.84Hz,6H)4.14-4.25(m,1H)4.93-5.09(quin,J＝6.77Hz,1H)6.09(br.s.,2H)7.52-7.58 (m,2H)7.60(s,1H)7.72(dd,J＝8.79,1.83Hz,1H)7.97-8.06(m,2H)8.17(s,1H)8.27(d,J＝8.67Hz,1H)8.39(d,J＝7.93Hz,1H)

HRMS (ESI) calcd. for C ₂₃ H ₂₆ N ₅ O [(M+H) ⁺ ]: 388.2132; found: 388.2130

Following this same procedure, but using the appropriate intermediates, the following compounds were prepared:

6-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid methylamide (Compound 6)

Y＝65％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.50(d,J＝6.84Hz,6H)2.87(d,J＝4.64Hz,3H)5.01(quin,J＝6.71Hz,1H)6.09(br.s.,2H)7.53-7.57(m,1H)7.58-7.60(m, 1H)7.60(s,1H)7.71(dd,J＝8.79,1.83Hz,1H)7.97-8.06(m,2H)8.17(s,1H)8.31(d,J＝8.67Hz,1H)8.46(q,J＝4.35Hz,1H)

HRMS (ESI) calculated value: C ₂₁ H ₂₂ N ₅ O [(M+H) ⁺ ]: 360.1819; found value: 360.1831

6-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid (2,2,2-trifluoroethyl)-amide (Compound 7)

Y＝45％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.50(d,J＝6.71Hz,6H)4.18(qd,J＝9.70,6.41Hz,2H)5.01(quin,J＝6.74Hz,1H)6.11(br.s.,2H)7.57-7.64(m,3H)7.75(d d,J＝8.79,1.95Hz,1H)8.06(d,J＝1.71Hz,1H)8.08-8.12(m,1H)8.17(s,1H)8.24(d,J＝8.79Hz,1H)9.24(t,J＝6.35Hz,1H)

HRMS (ESI) Calcd. for C ₂₂ H ₂₁ F ₃ N ₅ O [(M+H) ⁺ ]: 428.1693; Found: 428.1698

6-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopentylamide (Compound 9)

Y＝53％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.50(d,J＝6.84Hz,6H)1.52-1.76(m,6H)1.87-2.03(m,2H)4.28-4.39(m,1H)4.97-5.06(m,1H)6.09(br.s.,2H)7.52-7.59( m,2H)7.61(s,1H)7.71(dd,J＝8.73,1.89Hz,1H)7.98-8.07(m,2H)8.17(s,1H)8.25(d,J＝8.67Hz,1H)8.48(d,J＝7.32Hz,1H)

HRMS (ESI) Calcd. for C ₂₅ H ₂₈ N ₅ O [(M+H) ⁺ ]: 414.2289; Found: 414.2297

6-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid [4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide (Compound 10)

Y＝25％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.47(d,J＝6.71Hz,6H)2.14(s,3H)2.24-2.45(m,8H)3.56(s,2H)4.88-5.14(m,1H)6.08(br.s.,2H)7.55-7.66(m,2H)7.68- 7.79(m,3H)8.00(d,J＝7.45Hz,1H)8.06(d,J＝1.46Hz,1H)8.11(d,J＝8.18Hz,1H)8.15(s,1H)8.21-8.33(m,2H)10.82(s,1H)

HRMS (ESI) Calcd. for C ₃₃ H ₃₅ F ₃ N ₇ O [(M+H) ⁺ ]: 602.2850; Found: 602.2867

6-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclobutylamide (Compound 11)

Y＝30％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.50(d,J＝6.71Hz,6H)1.65-1.77(m,2H)1.98-2.16(m,2H)2.23-2.37(m,2H)4.44-4.62(m,1H)4.94-5.08(m,1H)6.09(br.s.,2H)7.52 -7.64(m,3H)7.68-7.74(dd,J＝8.79,2.2Hz,1H)7.99-8.07(m,2H)8.17(s,1H)8.24-8.28(d,J＝8.79Hz,1H)8.72-8.83(d,J＝7.81Hz,1H)

HRMS (ESI) calcd. for C ₂₄ H ₂₆ N ₅ O [(M+H) ⁺ ]: 400.2132; found: 400.2128

Example 4

Solution 1, step b

5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclopropylamide (Compound 16)

To a suspension of triphosgene (124 mg, 0.42 mmol) and Na2CO3 (106 mg, 2.52 mmol) in DCM (20 mL) maintained at 0°C under argon was added cyclopropylamine (0.087 mL, 1.26 mmol). The reaction was monitored by HPLC (after treating a sample of the reaction mixture with 3-methylaniline to form 1-cyclopropyl-3-(3-methylphenyl)urea). After 1 hour, 5-(2,3-dihydro-1H-indol-5-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine was added at 0°C, and the reaction was stirred at room temperature for 2.5 hours. The mixture was diluted with DCM, washed with water (3×10 mL) and brine, dried over anhydrous _{Na2SO4 ,} and concentrated under vacuum. Purification by flash column chromatography (AcOEt to AcOEt/MeOH 95/5) gave the product as a yellow solid.

Y＝66％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 0.44-0.54(m,2H)0.60-0.66(m,2H)1.45(d,J＝6.71Hz,7H)2.57-2.66(m,1H)3.14(t,J＝8.73Hz,3H)3.87(t,J＝8.79Hz,2H)4.95(quin,J＝6.77Hz ,1H)6.02(br.s.,2H)6.72(d,J＝2.93Hz,1H)7.17(dd,J＝8.24,1.89Hz,1H)7.23(d,J＝1.34Hz,1H)7.35(s,1H)7.90(d,J＝8.30Hz,1H)8.11(s,1H)

HRMS (ESI) calcd. for C ₂₁ H ₂₅ N ₆ O [(M+H) ⁺ ]: 377.2085; found: 377.2093

Following this same procedure, but using the appropriate intermediates (III and VI), the following compounds were prepared:

6-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclopropylamide (Compound 17)

Y＝49％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 0.45-0.51(m,2H)0.59-0.64(m,2H)1.46(d,J＝6.71Hz,6H)2.57-2.64(m,1H)3.12(t,J＝8.61Hz,2H)3.88(t,J＝8.73Hz,2H)4.97(quin,J＝6.71Hz ,1H)6.08(br.s.,1H)6.74(d,J＝2.69Hz,1H)6.92(dd,J＝7.51,1.65Hz,1H)7.22(d,J＝7.57Hz,1H)7.35(s,1H)7.97(d,J＝1.46Hz,1H)8.12(s,1H)

HRMS (ESI) calcd. for C ₂₁ H ₂₅ N ₆ O [(M+H) ⁺ ]: 377.2085; found: 377.2086

5-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclopropylmethyl-amide (Compound 18)

Y＝44％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 0.20-0.24(m,2H)0.36-0.44(m,2H)0.96-1.06(m,1H)1.42-1.48(d,J＝6.71 Hz,6H)3.02(t,J＝6.10Hz,2H)3.17(t,J＝8.54Hz,2H)3.93(t,J＝8.73Hz,2H)4 .95(quin,J＝6.77Hz,1H)5.99(br.s.,2H)6.72(t,J＝5.68Hz,1H)7.16(dd,J＝ 8.18,1.83Hz,1H)7.24(s,1H)7.34(s,1H)7.90(d,J＝8.30Hz,1H)8.11(s,1H)

HRMS (ESI) calcd. for C _{2 2} H _{2 7} N ₆ O [(M+H) ⁺ ]: 391.2241; found: 391.2249

5-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclobutylamide (Compound 19)

Y＝40％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.45(d,J＝6.84Hz,6H)1.53-1.70(m,2H)1.99-2.11(m,2H)2.13-2.23(m,2H)3. 15(t,J＝8.61Hz,2H)3.94(t,J＝8.79Hz,2H)4.14-4.28(m,1H)4.95(quin,J＝6.7 4Hz,1H)6.00(br.s.,2H)6.74(d,J＝7.57Hz,1H)7.15(dd,J＝8.24,1.89Hz,1H)7 .24(d,J＝1.22Hz,1H)7.32-7.37(m,1H)7.88(d,J＝8.18Hz,1H)8.10-8.13(m,1H)

HRMS (ESI) Calcd. for C _{2 2} H _{2 7} N ₆ O [(M+H) ⁺ ]: 391.2241; Found: 391.2252

5-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclohexylamide (Compound 20)

Y＝65％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.10(d,J＝12.08Hz,1H)1.21-1.34(m,4H)1.39-1.49(d,J＝6.71Hz,6H)1.60(d,J＝1 1.84Hz,1H)1.66-1.95(m,4H)3.15(t,J＝8.67Hz,2H)3.47-3.62(m,1H)3.92(t,J＝8 .67Hz,2H)4.95(quin,J＝6.68Hz,1H)5.99(br.s.,2H)6.25(d,J＝7.81Hz,1H)7.15( dd,J＝8.24,1.89Hz,1H)7.23(s,1H)7.34(s,1H)7.88(d,J＝8.30Hz,1H)8.11(s,1H)

HRMS (ESI) calcd. for C ₂₄ H ₃₁ N ₆ O [(M+H) ⁺ ]: 419.2554; found: 419.2555

5-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclohexylmethyl-amide (Compound 21)

Y＝18％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 0.79-0.95(m,2H)1.09-1.26(m,3H)1.45(d,J＝6.96Hz,6H)1.43-1.55(m,1H)1. 56-1.77(m,4H)2.98(t,J＝6.29Hz,2H)3.16(t,J＝8.48Hz,2H)3.93(t,J＝8.73Hz ,2H)4.96(quin,J＝6.71Hz,1H)6.08(br.s.,2H)6.61(t,J＝5.74Hz,1H)7.15(dd ,J＝8.36,1.77Hz,1H)7.23(s,1H)7.36(s,1H)7.89(d,J＝8.30Hz,1H)8.13(s,1H)

HRMS (ESI) Calcd. for C ₂₅ H ₃₃ N ₆ O [(M+H) ⁺ ]: 433.2711; Found: 433.2718

5-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclopentylamide (Compound 22)

Y＝29％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.41-1.47(m,7H)1.51(td,J＝7.35,4.09Hz,4H)1.59-1.76(m,3H)1.80-1.9 0(m,2H)3.15(t,J＝8.61Hz,2H)3.93(t,J＝8.73Hz,2H)3.98-4.10(m,1H)4.9 6(quin,J＝6.74Hz,1H)6.04(br.s.,2H)6.33(d,J＝7.20Hz,1H)7.16(dd,J＝8 .30,1.83Hz,1H)7.23(s,1H)7.35(s,1H)7.89(d,J＝8.30Hz,1H)8.12(s,1H)

HRMS (ESI) Calcd for C ₂₃ H ₂₉ N ₆ O [(M+H) ⁺ ]: 405.2398; Found: 405.2397

5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid (tetrahydropyran-4-yl)-amide (Compound 23)

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.45(d,J＝6.71Hz,6H)1.51-1.64(m,2H)1.75(dd,J＝12.51,2.26Hz,2H)3.16(t,J＝8 .61Hz,2H)3.35-3.40(m,2H)3.71-3.82(m,1H)3.87(dd,J＝11.53,2.75Hz,2H)3.94(t ,J＝8.73Hz,2H)4.95(quin,J＝6.77Hz,1H)5.99(br.s.,2H)6.40(d,J＝7.69Hz,1H)7.1 6(dd,J＝8.30,1.71Hz,1H)7.24(s,1H)7.34(s,1H)7.89(d,J＝8.18Hz,1H)8.11(s,1H)

HRMS (ESI) Calcd for C ₂₃ H ₂₉ N ₆ O ₂ [(M+H) ⁺ ]: 421.2347; Found: 421.2357

5-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (Compound 24)

Y＝47％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.46(d,J＝6.71Hz,6H)3.22-3.29(m,2H)4.21(t,J＝8.67Hz,2H)4.97(quin,J＝6.74Hz,1H)6.03(br.s.,2H)7.24(dd,J＝8.36,1.77Hz,1H)7.32(s ,1H)7.35(d,J＝7.69Hz,1H)7.39(s,1H)7.54(t,J＝7.87Hz,1H)7.89(d,J ＝8.79Hz,1H)7.96(d,J＝8.18Hz,1H)8.05(s,1H)8.12(s,1H)8.87(s,1H)

HRMS (ESI) Calcd. for C ₂₅ H ₂₄ F ₃ N ₆ O [(M+H) ⁺ ]: 481.1958; Found: 481.1965

5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid isopropylamide (Compound 25)

Y＝62％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.12(d,J＝6.59Hz,6H)1.42(d,J＝6.71Hz,6H)3.12(t,J＝8.61Hz,2H)3.80-3.93(m,3H)4.92(quin,J＝6.74Hz,1H)5.96(b r.s.,2H)6.25(d,J＝7.81Hz,1H)7.13(dd,J＝8.24,1.77Hz,1H)7.20(s,1H)7.31(s,1H)7.87(d,J＝8.18Hz,1H)8.08(s,1H)

HRMS (ESI) Calcd. for C ₂₁ H ₂₇ N ₆ O [(M+H) ⁺ ]: 379.2241; Found: 379.2257

5-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid (1-methyl-piperidin-4-yl)-amide (Compound 26)

Y＝25％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 1.45(d,J＝6.71Hz,6H)1.55(qd,J＝12.00,3.78Hz,2H)1.74(d,J＝9.76Hz,2H)1.87-1.9 6(m,2H)2.15(s,3H)2.75(d,J＝11.84Hz,2H)3.15(t,J＝8.61Hz,2H)3.43-3.59(m,1H)3. 93(t,J＝8.73Hz,2H)4.95(quin,J＝6.77Hz,1H)5.99(br.s.,2H)6.31(d,J＝7.57Hz,1H)7 .16(dd,J＝8.24,1.77Hz,1H)7.23(s,1H)7.34(s,1H)7.88(d,J＝8.18Hz,1H)8.11(s,1H)

HRMS (ESI) Calcd. for C ₂₄ H ₃₂ N ₇ O [(M+H) ⁺ ]: 434.2663; Found: 434.2660

6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,4-dihydro-2H-quinoline-1-carboxylic acid cyclopropylamide (Compound 27)

Y＝20％

¹ H NMR (401MHz, DMSO-d ₆ ) δppm 0.44-0.51(m,2H)0.56-0.63(m,2H)1.45(d,J＝6.71Hz,6H)1.84(quin,J＝6.29 Hz,2H)2.56-2.64(m,1H)2.73(t,J＝6.41Hz,2H)3.57(t,J＝6.23Hz,2H)4.96(qu in,J＝6.80Hz,1H)6.08(br.s.,2H)6.84(d,J＝2.93Hz,1H)7.15(dd,J＝8.42,2. 20Hz,1H)7.19(d,J＝2.07Hz,1H)7.37(s,1H)7.47(d,J＝8.42Hz,1H)8.11(s,1H)

HRMS (ESI) Calcd. for C _{2 2} H _{2 7} N ₆ O [(M+H) ⁺ ]: 391.2241; Found: 391.2241

Claims (9)

1. Compounds of formula (I) in R1 and R2 are hydrogen; R3 is hydrogen or optionally substituted with a group selected from the following: straight-chain or branched _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl and 3- to 7-membered heterocyclic rings; R4 is hydrogen; Ring A and ring B fuse together to form a bicyclic system, which is selected from naphthalene, 2,3-dihydroindole, isoquinoline and quinoline; Y represents carbon or nitrogen; X is hydrogen; R5 is hydrogen; and R6 is hydrogen or optionally substituted with a group selected from the following: straight-chain or branched _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, and phenyl; Or its medicinal salt. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from: 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (compound 1), 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-2-carboxylic acid cyclopropylamide (Compound 2) 6-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (compound 3), 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylate (compound 4), 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid isopropylamide (compound 5), 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid methylamide (compound 6), 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid (2,2,2-trifluoroethyl)-amide (compound 7), 6-[4-amino-7-(tetrahydropyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]naphthalene-1-carboxylic acid cyclopropylamide (compound 8), 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopentylamide (compound 9), 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthyl-1-carboxylic acid [4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide (compound 10), 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclobutylamide (compound 11), 6-(4-amino-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (compound 12), 6-(4-amino-7-cyclopropylmethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (compound 13), 6-(4-amino-7-cyclobutylmethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (compound 14), 6-[4-amino-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]naphthalene-1-carboxylic acid cyclopropylamide (compound 15), 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclopropylamide (compound 16) 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclopropylamide (compound 17) 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclopropylmethyl-amide (compound 18) 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclobutylamide (compound 19) 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclohexylamide (compound 20) 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclohexylmethyl-amide (compound 21) 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclopentylamide (compound 22) 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (compound 24), 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid isopropylamide (compound 25) 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,4-dihydro-2H-quinoline-1-carboxylic acid cyclopropylamide (compound 27) 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-isoquinoline-1-carboxylic acid cyclopropylamide (compound 28), 6-(4-amino-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (compound 29), 6-[4-amino-7-(4,4-difluoro-cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]naphthalene-1-carboxylic acid cyclopropylamide (compound 30), 6-[4-amino-7-(1-methyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]naphthalene-1-carboxylic acid cyclopropylamide (compound 31), 6-[4-amino-7-(1-cyclopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]naphthalene-1-carboxylic acid cyclopropylamide (compound 32), 6-{4-amino-7-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-naphth-1-carboxylic acid cyclopropylamide (compound 33), 6-[7-(1-acetyl-piperidin-4-yl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl]naphthalene-1-carboxylic acid cyclopropylamide (compound 34), 6-[4-amino-7-(2,2,6,6-tetramethyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]naphthalene-1-carboxylic acid cyclopropylamide (compound 35), 6-[4-amino-7-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]naphthalene-1-carboxylic acid cyclopropylamide (compound 36), 6-[4-amino-7-(1-methyl-piperidin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]naphthalene-1-carboxylic acid cyclopropylamide (compound 37), 6-[4-amino-7-(1-methyl-azacyclobutane-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]naphthalene-1-carboxylic acid cyclopropylamide (compound 38), 6-[4-amino-7-(1-cyclopropyl-azacyclobutane-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]naphthalene-1-carboxylic acid cyclopropylamide (compound 39), 6-[7-(1-acetyl-azacyclobutane-3-ylmethyl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl]naphthalene-1-carboxylic acid cyclopropylamide (compound 40), and 6-{4-amino-7-[1-(2-hydroxy-ethyl)-azacyclobutane-3-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-naphth-1-carboxylic acid cyclopropylamide (compound 41). 3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, selected from: 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (compound 1), 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-2-carboxylic acid cyclopropylamide (Compound 2) 6-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (compound 3), 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylate (compound 4), 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid isopropylamide (compound 5), 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid methylamide (compound 6), 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid (2,2,2-trifluoroethyl)-amide (compound 7), 6-[4-amino-7-(tetrahydropyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]naphthalene-1-carboxylic acid cyclopropylamide (compound 8), 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopentylamide (compound 9), 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthyl-1-carboxylic acid [4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide (compound 10), 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclobutylamide (compound 11), 6-(4-amino-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (compound 12), 6-(4-amino-7-cyclopropylmethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (compound 13), 6-(4-amino-7-cyclobutylmethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-naphthalene-1-carboxylic acid cyclopropylamide (compound 14), 6-[4-amino-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]naphthalene-1-carboxylic acid cyclopropylamide (compound 15), 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclopropylamide (compound 16) 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclopropylamide (compound 17) 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclopropylmethyl-amide (compound 18) 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclobutylamide (compound 19) 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclohexylamide (compound 20) 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclohexylmethyl-amide (compound 21) 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid cyclopentylamide (compound 22) 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (compound 24), 5-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindole-1-carboxylic acid isopropylamide (compound 25) 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,4-dihydro-2H-quinoline-1-carboxylic acid cyclopropylamide (compound 27), and 6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-isoquinoline-1-carboxylic acid cyclopropylamide (compound 28). 4. A method for preparing a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, comprising the following steps: Step a): Make the intermediate of equation (II) Where Y is carbon, and A, B, R1, R2, R3, R4, and X are intermediates as defined in claim 1 that react with formula (VI). HNR5R6 (VI) Wherein R5 and R6 are compounds as defined in claim 1, yielding formula (I); optional Step b): Make the intermediate of equation (III) Where Y is nitrogen, and A, B, R1, R2, R3, R4, and X are, as defined in claim 1, intermediates that react with formula (VI). HNR5R6 (VI) Where R5 and R6 are as defined above, the compound of formula (I) is obtained; or Step b′: React the intermediate of formula (III), wherein Y is nitrogen and A, B, R1, R2, R3, R4 and X are as defined above, with the intermediate of formula (VII). R6NCO (VII) Where R6 is as defined above, resulting in the compound of formula (I); optional Step c): Make the intermediate of formula (IV) R1, R2, R3, and R4 are as defined above, and Hal is iodine or bromine, undergoing a cross-coupling reaction with the intermediate of formula (V). Where R7 is boric acid or borate ester, and A, B, R5, R6, X and Y are as defined above, the compound of formula (I) is obtained; Optionally, a compound of formula (I) may be converted into another compound of formula (I), and if desired, a compound of formula (I) may be converted into its pharmaceutically usable salt, or a salt may be converted into free compound (I). 5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, carrier and/or diluent. 6. The pharmaceutical composition according to claim 5, further comprising one or more chemotherapeutic agents. 7. The use of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a reagent for an in vitro method of inhibiting the activity of RET family proteins. 8. A product comprising a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof and one or more chemotherapeutic agents, as a combination preparation for simultaneous, separate or sequential use in anticancer therapy. 9. Use of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament having anticancer activity.