[1,3]Diazino[5,4-d]pyrimidines as HER2 inhibitors

Abstract

The present invention relates to a compound represented by the following formula (I): [Formula 1] JPEG2023512175000047.jpg100117 (wherein the group R 1 , R 2 , R 3 and R 4 has the meaning given in the claims and in the description), to novel [1,3]diazino[5,4-d]pyrimidines and derivatives thereof, to their use as inhibitors of HER2 and its mutants, to pharmaceutical compositions containing said compounds and to their use as medicaments, in particular as medicaments for the treatment and / or prophylaxis of tumor diseases.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to a compound represented by the following formula (I):

[0002] [ka]

[0003] (In the formula, the group R 1 , R 2 , R 3 and R 4 has the meaning given in the claims and herein) The present invention relates to novel [1,3]diazino[5,4-d]pyrimidines and derivatives of the formula (I), their use as inhibitors of HER2 and its mutants, pharmaceutical compositions containing said compounds and their use as medicaments, in particular as medicaments for the treatment and / or prophylaxis of neoplastic diseases. [Background technology]

[0004] 2. Background of the Invention The family of ERBB transmembrane receptor tyrosine kinases (RTKs) consists of four members EGFR (ERBB1), HER2 (Neu, ERBB2), HER3 (ERBB3) and HER4 (ERBB4) that perform essential functions during development (Citri et al., Nat. Rev. Mol. Cell. Biol., 2006, 7(7), 505-516; Hynes et al., Curr. Opin. Cell. Biol., 2009, 21(2), 177-184; Wang, Z., Methods Mol. Biol., 2017, 1652, 3-35). ERBB signaling is initiated by binding of the extracellular domains of EGFR, HER3 or HER4 to their respective ligands and subsequent homo- or heterodimerization of ERBB family members. HER2, whose ligand has not been identified, is the preferred dimerization partner for other ERBB members. Upon formation of an active ligand-receptor complex, the intracellular tyrosine kinase domains of EGFR, HER2 or HER4 are activated by autophosphorylation or transphosphorylation, subsequently triggering signaling cascades that most notably engage the mitogen-activated protein (MAP) kinase and / or phosphoinositide 3-kinase (PI3K) pathways (Citri et al, Nat. Rev. Mol. Cell. Biol., 2006, 7(7), 505-516; Hynes et al., Curr. Opin. Cell. Biol., 2009, 21(2), 177-184; Wang, Z., Methods Mol. Biol., 2017, 1652, 3-35.).

[0005] Aberrant ERBB signaling is implicated in several pathophysiological conditions, including cancer or neurological diseases. In cancer, ERBB signaling is overactivated through mutations that render RTKs constitutively active by promoting dimerization or shifting the equilibrium to the active conformer of the kinase, and / or through amplification and subsequent overexpression of RTKs. Both oncogenic mechanisms increase the net output of ERBB signaling, thereby promoting cell survival, cell growth and proliferation (Arteaga et al., Cancer Cell, 2014, 25(3), 282-303). Aberrant HER2 signaling is observed in a wide variety of human malignancies. Oncogenic mutations have been described in the extracellular, (juxtamembrane) and intracellular regions of the protein. Collectively, these mutations render HER2 constitutively active, fueling cancer initiation, tumor maintenance and growth (Connell et al., ESMO Open, 2017, 2(5), e000279). Similarly, overexpression of HER2 increases HER2 signaling and underlies neoplastic transformation and tumor maintenance in various indications, including breast, gastric or lung cancer.

[0006] Consequently, disruption of HER2 oncogenic signaling leads to inhibition of tumor growth. Targeted therapies incorporate HER2-directed antibodies (including trastuzumab and pertuzumab), HER2-directed antibody-drug conjugates (trastuzumab-DM1 (T-DM1, trastuzumab emtansine)) and small molecules that inhibit the HER2 kinase domain (afatinib, neratinib, lapatinib). Ultimately, tumors driven by oncogenic mutations in HER2 or HER2 wild-type amplification may benefit from HER2-specific tyrosine kinase inhibitors (TKIs). Collectively, HER2 alterations affect up to 6-7% of all human cancers, and EGFR wild-type sparing TKIs may emerge as an effective treatment option. Although there are HER2 wild-type inhibitors that are selective over EGFR wild-type, such as tucatinib, these inhibitors have no efficacy against HER2 carrying exon 20 mutations. Other selective wild-type HER2 inhibitors are disclosed in the prior art documents WO 2003 / 049740, WO 2007 / 059257, WO 2005 / 044302. HER2 exon 20 mutations constitute a subset of HER2 gain-of-function mutations that result in enhanced kinase activity (Wang et al. Cancer Cell, 2006, 10(1): 25-38). This enhanced HER2 kinase activity engages downstream signaling cascades to stimulate neoplastic transformation through enhanced growth, proliferation, and survival of mutant cells.

[0007] Studies in genetically engineered mouse models have demonstrated that the most common HER2 exon 20 mutation in NSCLC, the four amino acid duplication YVMA (p.A775_G776insYVMA), is necessary and sufficient to drive oncogenic growth (Perera et al., Proc. Natl. Acad. Sci. USA, 2009, 106(2), 474-479). Loss of HER2-YVMA expression was associated with tumor shrinkage, suggesting that this oncogenic variant of HER2 is required for tumor maintenance (Perera et al. 2009). Furthermore, this study demonstrated that the pan-ERBB blocker afatinib is effective in vivo and can disrupt HER2-YVMA oncogenic signaling in mouse models (Perera et al. 2009). Oncogenic mutations of HER2 in NSCLC mainly affect the tyrosine kinase domain of HER2 and are clustered in exon 20 of the ERBB2 gene (Stephens et al., Nature, 2004, 431(7008), 525-6). It is estimated that 2-4% of lung cancer patients carry activating mutations in HER2 exon 20. Clinically approved ERBB-targeted tyrosine kinase inhibitors are ineffective in these patients because they are limited by EGFR wild-type mediated dose-limiting toxicity. Afatinib and other pan-ERBB blockers have shown limited efficacy in patients with HER2 exon 20-mutated NSCLC, mainly due to limitations in reaching an effective dose. In particular, EGFR wild-type mediated toxicity limits effective dosing.

[0008] Alitinib, ibrutinib, neratinib, poziotinib and pyrotinib are known pan-ERBB inhibitors of mutated HER2 exon 20. Further inhibitors of mutated HER2 exon 20 are disclosed in the prior art documents WO 2015 / 175632, WO 2015 / 195228, WO 2016 / 183278 and WO 2019 / 046775. There is a strong unmet medical need for compounds that selectively target HER2 exon 20 mutant proteins while sparing EGFR wild-type to overcome the drawbacks of EGFR wild-type mediated dose-limiting toxicity. The compounds of the present invention have been found to bind to the tyrosine kinase domain of wild-type HER2 and mutant HER2 exon 20 in an orthosteric and covalent manner, while sparing wild-type EGFR, and act as selective inhibitors of wild-type HER2 and mutant HER2 harboring a mutation in exon 20. Summary of the Invention

[0009] Summary of the Invention The object of the present invention is to provide novel inhibitors of mutant HER2 exon 20 that are selective over wild-type EGFR. The compounds of the present invention act as selective inhibitors of HER2 exon 20 and show improved wild-type EGFR-sparing efficacy profiles in addition to high selectivity over wild-type EGFR compared to prior art compounds. Furthermore, some compounds of the present invention show improved pharmacokinetic and pharmacological profiles, such as good metabolic stability. The compounds of the present invention are useful in the prevention and / or treatment of diseases and / or conditions characterised by excessive or abnormal cell proliferation, in particular the treatment and / or prevention of cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Detailed Description of the Invention The present invention relates to a compound represented by the following formula (I):

[0011] [ka]

[0012] (In the formula, (A0) R 1 is selected from the group consisting of hydrogen, -CH3, -CCH, -OCH3 and halogen. (B0) R 2 is hydrogen or halogen (C0) R 3 is hydrogen or halogen (D0) R 4 is hydrogen or -CH3 And R 1 , R 2 and R 3 At least one of these is not hydrogen. Novel [1,3]diazino[5,4-d]pyrimidines and derivatives or a salt thereof.

[0013] In another embodiment (A1), the present invention relates to R1 is selected from the group consisting of -CH3, -CCH, -OCH3 and halogen; The present invention relates to a compound of formula (I) or a salt thereof. In another embodiment (A2), the present invention relates to a method for producing a composition comprising the steps of: R 1 is selected from the group consisting of -CH3 and halogen; The present invention relates to a compound of formula (I) or a salt thereof. In another embodiment (A3), the present invention relates to a method for producing a composition comprising the steps of: R 1 is selected from the group consisting of -CH3, chlorine and fluorine; The present invention relates to a compound of formula (I) or a salt thereof. In another embodiment (A4), the present invention relates to a method for producing a composition comprising the steps of: R 1 is hydrogen, The present invention relates to a compound of formula (I) or a salt thereof. In another embodiment (A5), the present invention relates to a method for producing a composition comprising the steps of: R 1 is -CH3, The present invention relates to a compound of formula (I) or a salt thereof. In another embodiment (A6), the present invention relates to a method for producing a composition comprising the steps of: R 1 is selected from the group consisting of chlorine, bromine and fluorine; The present invention relates to a compound of formula (I) or a salt thereof. In another embodiment (A7), the present invention relates to a method for producing a composition comprising the steps of: R 1 is chlorine, The present invention relates to a compound of formula (I) or a salt thereof. In another embodiment (A8), the present invention relates to a method for producing a composition comprising the steps of: R 1 is fluorine; The present invention relates to a compound of formula (I) or a salt thereof.

[0014] In another embodiment (B1), the present invention relates to a method for producing a composition comprising the steps of: R 2 is hydrogen, The present invention relates to a compound of formula (I) or a salt thereof. In another embodiment (B2), the present invention relates to a method for producing a composition comprising the steps of: R 2 is a halogen, The present invention relates to a compound of formula (I) or a salt thereof. In another embodiment (B3), the present invention relates to a method for producing a composition comprising the steps of: R 2 is selected from the group consisting of chlorine, bromine and fluorine; The present invention relates to a compound of formula (I) or a salt thereof. In another embodiment (B4), the present invention relates to a method for producing a composition comprising the steps of: R 2 is chlorine, The present invention relates to a compound of formula (I) or a salt thereof. In another embodiment (B5), the present invention relates to a method for producing a composition comprising the steps of: R 2 is fluorine; The present invention relates to a compound of formula (I) or a salt thereof.

[0015] In another embodiment (C1), the present invention relates to a method for producing a composition comprising the steps of: R 3 is hydrogen, The present invention relates to a compound of formula (I) or a salt thereof. In another embodiment (C2), the present invention relates to a method for producing a composition comprising the steps of: R 3 is a halogen, The present invention relates to a compound of formula (I) or a salt thereof. In another embodiment (C3), the present invention relates to a method for producing a composition comprising the steps of: R 3 is chlorine, The present invention relates to a compound of formula (I) or a salt thereof. In another embodiment (C4), the present invention relates to a method for producing a composition comprising the steps of: R 3 is fluorine; The present invention relates to a compound of formula (I) or a salt thereof.

[0016] In another embodiment (D1), the present invention relates to a method for producing a composition comprising the steps of: R 4 is hydrogen, The present invention relates to a compound of formula (I) or a salt thereof. In another embodiment (D2), the present invention relates to a method for producing a composition comprising the steps of: R 4 is -CH3, The present invention relates to a compound of formula (I) or a salt thereof.

[0017] The above individual embodiments represent the structural subgroups (A0)-(A8), (B0)-(B5), (C0)-(C2) and (D0)-(D2) of compounds of formula (I). These structural subgroups can be combined with each other, such as (A), (B), (C) and (D), to clearly define further embodiments of the invention of compounds of formula (I). Thus, further embodiments of the invention are defined herein as compounds of formula (I) as combinations of specific structural subgroups (A), (B), (C) and (D), where (A) is selected from (A0)-(A8); (B) is selected from (B0)-(B5); (C) is selected from (C0)-(C4) and (D) is selected from (D0)-(D2). The present invention further relates to hydrates, solvates, polymorphs, metabolites and prodrugs of these compounds of formula (I). In another embodiment, the present invention relates to pharma- ceutically acceptable salts of the compounds of formula (I). A preferred embodiment of the present invention is the above-mentioned compound of formula (I) or a salt thereof, selected from the group consisting of Examples I-01 to I-8 below.

[0018] [ka] JPEG0007626774000004.jpg178153

[0019] Further preferred embodiments of the present invention are pharma- ceutically acceptable salts of the above compounds of formula (I), selected from the group consisting of Examples I-01 to I-8. A further preferred embodiment of the present invention is the compound of Example I-01. A further preferred embodiment of the present invention is the compound of Example I-02. A further preferred embodiment of the present invention is the compound of Example I-03. A further preferred embodiment of the present invention is the compound of Example I-04. A further preferred embodiment of the present invention is the compound of Example I-05. A further preferred embodiment of the present invention is the compound of Example I-06. A further preferred embodiment of the present invention is the compound of Example I-07. A further preferred embodiment of the present invention is the compound of Example I-08.

[0020] Further preferred embodiments of the present invention are pharma- ceutically acceptable salts of the compounds of Example I-01. Further preferred embodiments of the present invention are pharma- ceutically acceptable salts of the compounds of Example I-02. Further preferred embodiments of the present invention are pharma- ceutically acceptable salts of the compounds of Example I-03. Further preferred embodiments of the present invention are pharma- ceutically acceptable salts of the compounds of Example I-04. Further preferred embodiments of the present invention are pharma- ceutically acceptable salts of the compounds of Example I-05. Further preferred embodiments of the present invention are pharma- ceutically acceptable salts of the compounds of Example I-06. Further preferred embodiments of the present invention are pharma- ceutically acceptable salts of the compounds of Example I-07. Further preferred embodiments of the present invention are pharma- ceutically acceptable salts of the compounds of Example I-08.

[0021] In another aspect, the present invention relates to a method for inhibiting wild type and / or mutant HER2 in a cell, the method comprising contacting the cell with a compound of formula (I). In another embodiment, the present invention relates to a method for inhibiting HER2 having an exon 20 mutation in a cell, preferably comprising contacting the cell with a compound of formula (I). In another aspect, the invention relates to a method for inhibiting phosphorylation of wild type and / or mutant HER2 in a cell, comprising contacting a cell with a compound of formula (I). In another embodiment, the invention relates to a method for inhibiting phosphorylation of HER2 exon 20 mutant in a cell, comprising contacting a cell with a compound of formula (I). In another aspect, the present invention relates to the use of compounds of formula (I) or pharma- ceutically acceptable salts thereof for the treatment and / or prevention of diseases and / or conditions in which inhibition of wild-type and / or mutant HER2 is a therapeutic effect. In another embodiment, the present invention relates to the use of compounds of formula (I) or pharma-ceutically acceptable salts thereof for the treatment and / or prevention of diseases and / or conditions in which inhibition of HER2 exon 20 mutant proteins is a therapeutic effect. In another aspect, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in a method of inhibiting wild-type and / or mutant HER2 in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In another embodiment, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in a method of inhibiting HER2 exon 20 mutant in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0022] In another aspect, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use as a medicament. In another aspect, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the treatment and / or prevention of cancer. In another embodiment, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the treatment and / or prevention of cancer, wherein the cancer is caused by HER2 overexpression and / or HER2 proliferation. In another embodiment, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the treatment and / or prevention of cancer, wherein the cancer is a HER2 exon 20 mutant cancer. In another embodiment, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the treatment and / or prevention of cancer, wherein the HER2 overexpressing, HER2 amplified and / or HER2 exon 20 mutant cancer is selected from brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, colorectal cancer, endometrial cancer, skin cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.

[0023] In another aspect, the invention relates to a method for the treatment and / or prevention of the above mentioned diseases and conditions, which comprises administering to a human a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In another aspect, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prophylaxis of the above mentioned diseases and conditions. In another aspect, the invention relates to the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for the treatment and / or prevention of the abovementioned diseases and conditions.

[0024] Additionally, the following cancers, tumors and other proliferative disorders can be treated with the compounds of the present invention, including, but not limited to: Cancers / tumours / carcinomas of the head and neck: e.g. tumours / carcinomas of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lips, gingiva, alveolar ridge, retromolar triangle, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of tongue, tonsils, tonsillar pilar, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands); Lung cancer / tumor / carcinoma: e.g. non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchoalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, combined oat cell carcinoma); Mediastinal neoplasms: e.g. neurogenic tumors (including neurofibroma, schwannoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma, ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, nonseminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangioleiomyoma); Cancers / Tumors / Carcinomas of the Gastrointestinal (GI) Tract: e.g., esophagus, stomach (gastric carcinoma), pancreas, liver and bile duct (including hepatocellular carcinoma (HCC), e.g., childhood HCC, fibrolamellar HCC, hybrid HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocarcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma; leiomyosarcoma, malignant Schwannoma, fibrosarcoma, Clark's tumor), gallbladder, extrahepatic bile duct, small intestine (including duodenum, jejunum, ileum) Cancers / carcinomas / tumors of the large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stromal tumor (GIST)); genitourinary system (kidney, e.g., renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), adrenal gland, Grabitz tumor; ureter; bladder, e.g., urachal carcinoma, urothelial carcinoma; urethra, e.g., distal, bulbomembranous, prostatic; prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-refractory), penis); Cancer / tumor / carcinoma of the testis: e.g. seminoma, non-seminoma; Gynaecological cancers / tumours / carcinomas: e.g. tumours / carcinomas / cancer of the ovaries, fallopian tubes, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, basalis); Cancers / tumors / carcinomas of the breast: e.g. breast cancer (invasive, colloidal, lobular infiltrating, tubular, adenoid cystic, papillary, medullary, mucinous), hormone receptor positive breast cancer (estrogen receptor positive breast cancer, progesterone receptor positive breast cancer), HER2 positive breast cancer, triple negative breast cancer, Paget's disease of the breast; Cancers / tumors / carcinomas of the endocrine system: e.g. tumors / tumors / carcinomas of the endocrine glands (thyroid carcinoma / tumors; papillary, follicular, anaplastic, medullary), parathyroid gland (parathyroid carcinoma / tumors), adrenal cortex (adrenocortical carcinoma / tumors), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal gland, pineal gland, carotid body, islet cell tumors, paraganglia, pancreatic endocrine tumors (PET; non-functional (nonfluorineunctional) PET, Ppoma, gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors; Sarcomas of soft tissues: e.g. fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon sheath, solitary fibrous tumor of pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, pigmented schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor; Sarcomas of bone; e.g. myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, and mesenchymal chondrosarcomas), osteosarcoma (including parosteal, periosteal, high-grade surface, small cell, radiation-induced osteosarcoma, and Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantinoma, (fibro)histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid, osteoblastoma, eosinophilic granuloma, and chondroblastoma; Mesothelioma: e.g. pleural mesothelioma, peritoneal mesothelioma; Cancers of the skin: e.g. basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentigo, nodular, and intraocular melanoma), actinic keratosis, and eyelid cancer; Neoplasms of the central nervous system and brain: e.g. astrocytoma (cerebral, cerebellar, diffuse, fibrous, anaplastic, pilocytic, protoplasmic, gemistocytary), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, ganglioneuroma, neuroblastoma, retinoblastoma, schwannoma (e.g. auditory), spinal axis tumor; Lymphomas and leukemias: e.g., B-cell non-Hodgkin's lymphoma (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt's lymphoma (BL)), T-cell non-Hodgkin's lymphoma (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)) ), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytoma, chronic B-cell lymphocytic leukemia (BchlorineL), chronic T-cell lymphocytic leukemia (TchlorineL), B-cell small lymphocytic lymphoma (B-SLL), cutaneous T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (nodular lymphocyte predominant type) lymphocyte predominance HD (NLPHD), nodular sclerosis HD (NSHD), mixed cellularity HD (MCHD), lymphocyte-rich classical HD, lymphopenic HD (LDHD), large granular lymphocyte leukemia (LGL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphocytic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myelogenous leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML); Carcinoma of unknown primary site (CUP).

[0025] All of the above cancers / tumors / carcinomas characterised by their specific location / origin within the body are meant to include both primary tumours and metastatic tumours derived from them. All the above cancers / tumors / carcinomas can be further differentiated according to their histopathological classification as follows: Epithelial cancers, such as squamous cell carcinoma (SCC) (carcinoma in situ, superficial invasive, verrucous, pseudosarcoma, undifferentiated, transitional cell, lymphoid epithelium), adenocarcinoma (AC) (well differentiated, mucinous, papillary, pleomorphic giant cell, tubular, small cell, signet ring cell, spindle cell) spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cyst), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumor (small cell carcinoma, paraganglioma, carcinoid); oncocytic carcinoma; Non-epithelial carcinomas, such as sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, hemangiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed and undifferentiated carcinomas.

[0026] In another aspect the invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of cancer, wherein the compound is administered in combination with a cytostatic and / or cytotoxic active substance and / or in combination with radiotherapy and / or immunotherapy. In another aspect, the present invention relates to combinations of compounds of formula (I) or pharma- ceutical acceptable salts thereof with cytostatic and / or cytotoxic active substances for use in the treatment and / or prevention of cancer and / or combinations of compounds of formula (I) or pharma-ceutical acceptable salts thereof with cytostatic and / or cytotoxic active substances for use in the treatment and / or prevention of cancer in combination with radiotherapy and / or immunotherapy. In another aspect, the present invention relates to a method for the treatment and / or prevention of cancer, said method comprising the administration of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with a cytostatic and / or cytotoxic active substance and / or in combination with radiation therapy and / or immunotherapy.

[0027] The compounds of the present invention may be used alone or in combination with one or several other pharmacologically active substances, such as state-of-the-art or standard of care compounds, such as cell proliferation inhibitors, anti-angiogenic agents, steroids or immunomodulatory agents / checkpoint inhibitors.Pharmacologically active agents which may be administered in combination with the compounds of the invention include, but are not limited to, hormones, hormone analogs and antihormonal agents (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g., anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g., goserelin acetate, luprolide), growth factors and / or their corresponding receptors (growth factors, e.g., platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IG ... F), inhibitors of human epidermal growth factor (HER, e.g. HER2, HER3, HER4) and hepatocyte growth factor (HGF) and / or their corresponding receptors, such as inhibitors of (anti)growth factor antibodies, (anti)growth factor receptor antibodies and tyrosine kinase inhibitors, e.g. cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab, pertuzumab and trastuzumab; antimetabolites (e.g. antifolates, e.g. methotrexate, raltitrexed, pyrimidine analogues, e.g. 5-fluorouracil (5 fluorine U), ribonucleoside and deoxyribonucleoside analogues, capecitabine and gemcitabine, purine and adenosine analogues, e.g. mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (arabinose), C), fludarabine); antitumor antibiotics (e.g. anthracyclines such as doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride, myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin, carboplatin);Alkylating agents (e.g. estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as carmustine and lomustine, thiotepa); mitotic inhibitors (e.g. vinca alkaloids such as vinblastine, vindesine, vinorelbine and vincristine; and taxanes such as paclitaxel, docetaxel); angiogenesis inhibitors (e.g. tasquinimod), tubulin inhibitors;DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g. epipodophyllotoxins such as etoposide and etopofos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors (e.g. PDK1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors) Anti-cancer drugs, dual mTOR / PI3K inhibitors, STK33 inhibitors, AKT inhibitors, PLK1 inhibitors, CDK inhibitors, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g. PTK2 / FAK inhibitors), protein-protein interaction inhibitors (e.g. IAP activators, Mcl-1, MDM2 / MDMX), MEK inhibitors, ERK inhibitors, FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bc l-2 inhibitors, Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogues (e.g. everolimus, temsirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors, immunotherapeutics, e.g. immune checkpoint inhibitors, cross-linking inhibitors (e.g. CTLA4, PD1, PD-L1, PD-L2, LAG3, and TIM3 binding molecules / immunoglobulins such as ipilimumab, nivolumab, pembrolizumab, etc.), ADCC (antibody-dependent cell-mediated cytotoxicity) activators (e.g. anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), T cell engagers (e.g. bispecific T cell engagers (BiTEs®), e.g. CD3 x BCMA, CD3 x CD33, CD3 x CD19, etc., PSMA x CD3), tumor vaccines, and various chemotherapeutic drugs such as amifostine, anagrelide, clodronate, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer;

[0028] In another aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula (I) or a pharma- ceutically acceptable salt thereof, and optionally at least one pharma- ceutically acceptable carrier. In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one other cytostatic and / or cytotoxic active substance. In another aspect, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of formula (I) or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients. Suitable formulations for administration of the compounds of the invention will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, liquids, particularly injection (sc, iv, im) and infusion solutions (injectable solutions), elixirs, syrups, sachets, emulsions, inhalants or dispersible powders. Suitable tablets can be obtained, for example, by mixing one or more compounds of formula (I) with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants.

[0029] The daily applicable dosage range of the compound of formula (I) is usually 1 mg to 2000 mg, preferably 10 to 1000 mg. Suitable dosages for intravenous use are between 1 mg and 1000 mg at various infusion rates, preferably between 5 mg and 500 mg at various infusion rates. However, it may be necessary to deviate from the prescribed amount depending on the body weight, age, route of administration, severity of the disease, individual response to the drug, the nature of its formulation and the time and interval at which the drug is administered (continuous or intermittent treatment with one or multiple doses per day). Thus, it may be sufficient to use less than the minimum dose mentioned above, whereas in other cases the upper limit must be exceeded. When administering larger amounts, it may be wise to divide them into several smaller doses over the course of the day.

[0030] general definition Terms not specifically defined herein should be given the meaning that one of ordinary skill in the art would give them in light of the present disclosure and the context. However, as used herein, unless otherwise specified, the following terms have the indicated meanings and adhere to the following conventions. In the groups, radicals, or moieties defined below, the radical is often preceded by a specific number of carbon atoms, e.g., C 1-6 Alkyl means an alkyl group having 1 to 6 carbon atoms. For groups such as OH, NH2, S(O), S(O)2, CN (cyano), COOH, CF3, etc., one of skill in the art will recognize the point of attachment of the group to the molecule from the free valence of the group itself. When the compounds of the invention are depicted in the form of chemical names and as formulas, the formulas shall prevail in the case of any discrepancies. Subformulas may use asterisks to indicate bonds that are attached to the core molecule as defined. Numbering of substituent atoms begins with the atom closest to the core or group to which the substituent is attached. The term "halogen" refers to fluorine, chlorine, bromine and / or iodine atoms. As used herein, the term "substituted" means that any one or more hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the normal valence of the designated atom is not exceeded and that the substitution results in a stable compound.

[0031] Unless otherwise indicated, throughout this specification and the appended claims, a given chemical formula or name is intended to encompass tautomers and all stereo, optical and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) thereof, as well as racemates thereof as well as mixtures of the individual enantiomers in different ratios, mixtures of diastereomers, or mixtures of any of the aforementioned forms in which said isomers and enantiomers are present, as well as pharmacologic acceptable salts thereof and solvates thereof, such as hydrates, including solvates and hydrates of the free compounds or solvates and hydrates of the salts of the compounds. In general, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example, by separation of the corresponding mixtures, by the use of stereochemically pure starting materials and / or by stereoselective synthesis. It is well known in the art how to prepare optically active forms, for example, by resolution of racemic forms or by synthesis, for example, by starting from optically active starting materials and / or using chiral reagents.

[0032] Enantiomerically pure compounds or intermediates of the present invention can be prepared, for example, by the preparation and subsequent separation of suitable diastereomeric compounds or intermediates which can be separated by known methods (e.g. by chromatographic separation or crystallization) and / or via asymmetric synthesis by using chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaries. Furthermore, the skilled person knows how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, for example by chromatographic separation on chiral stationary phases, or by resolution of the racemic mixtures using suitable resolving agents, for example by formation of diastereomeric salts of the racemates with optically active acids or bases followed by separation of the salts and liberation of the desired compound from the salts, or by derivatization of the corresponding racemates with an optically active chiral auxiliary reagent followed by diastereomeric separation and removal of the chiral auxiliary, or by kinetic resolution of the racemates (for example enzymatic resolution); by enantioselective crystallization from a consortium of enantiomorphous crystals under suitable conditions, or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0033] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human tissue without undue toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutical acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound is modified by making an acid or base salt thereof. Examples of pharmaceutical acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, the salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid.

[0034] Further pharma- ceutically acceptable salts can be formed with cations from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium and tris(hydroxymethyl)-aminomethane. The pharma- ceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, the salts can be prepared by reacting the free acid or free base forms of these compounds with a sufficient amount of the appropriate base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Salts of acids other than those mentioned above, for example those useful for the purification or isolation of the compounds of the invention (eg trifluoroacetates), also form part of the invention. For divalent groups where it is important to determine which adjacent group is bonded to which valency, the corresponding bond partner is shown in parentheses, as in the representation below, where necessary for clarity.

[0035] [ka]

[0036] A group or substituent is a corresponding group name, e.g., R a, R b etc.) It is pointed out that when such a group is used repeatedly in different parts of the molecule to define a compound of the invention, the various uses are to be considered totally independent of each other. As used herein, the term "therapeutically effective amount" refers to that amount of a substance that can eliminate or alleviate the symptoms of a disease or prolong the survival of a treated patient.

[0037] As used herein, the term "prodrug" refers to either (i) an inactive form of a drug that exerts its effects after metabolic processes that convert the drug into a usable or active form in the body, or (ii) a substance that is not itself active, but gives rise to a pharmacologically active metabolite (i.e., an inactive precursor). The term "prodrug" or "prodrug derivative" refers to a covalent derivative, carrier, or precursor of a parent compound or active drug substance, which undergoes at least some biotransformation before exerting its pharmacological action. Both prodrugs have metabolically cleavable or otherwise convertible groups that are rapidly biotransformed to the parent compound, for example, by hydrolysis in blood or by activation by oxidation, as in the case of a thioether group. The most common prodrugs include ester and amide analogs of the parent compound. Prodrugs are formulated for the purposes of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, extended duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and / or reduced side effects (e.g., toxicity). Generally, the prodrug itself has little or no biological activity and is stable under normal conditions.Prodrugs can be readily prepared from the parent compound using methods well known in the art, such as those described in the following references, each of which is incorporated herein by reference in its entirety: A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, especially Chapter 5: "Design and Applications of Prodrugs"; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, KB Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, especially pp. 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995, especially Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, EB Roche (ed.), Elsevier, 1987. As used herein, the term "pharmaceutical acceptable prodrugs" refers to prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and which are effective for their intended use, as well as, where possible, in zwitterionic form.

[0038] As used herein, the term "compound selective over wild-type EGFR" refers to a compound that exhibits greater potency towards HER2 compared to EGFR, the potency of which can be determined in a biological assay such as the BA / F3 proliferation assay described below, or a tumor cell line proliferation assay. As used herein, the term "EGFR wild-type sparing" or "EGFR wild-type sparing activity" refers to the reduced potency of a compound on EGFR wild-type, which can be determined in a biological assay such as the BA / F3 proliferation assay described below, or a tumor cell line proliferation assay. As used herein, the term "HER2 amplified cancer" refers to a cancer in which the cancer cells express more than two gene copies of ERBB2. As used herein, the term "HER2-overexpressing cancer" refers to a cancer in which cells of the cancer express HER2 at levels detectable by immunohistochemistry and / or methods that assay for ERBB2 message RNA. As used herein, the term "mutated HER2" or "HER2 harboring an exon 20 mutation" refers to a mutated HER2 protein and the corresponding mutant DNA variant, while the term "HER2 exon 20 mutant" as used herein refers to a HER2 exon 20 mutant protein and the corresponding mutant DNA variant. The term "HER2 mutated cancer" or "HER2 mutated cancer" refers to a cancer in which the cancer or tumor cells harbor a HER2 mutation, including but not limited to the mutations listed in Tables 1 and 2. As used herein, the term "HER2 exon 20 mutated cancer" or "HER2 exon 20 mutated cancer" refers to a cancer in which the cancer or tumor cells harbor at least one HER2 exon 20 mutation, including but not limited to the mutations listed in Table 1. ERBB2 (HER2) exon 20 encodes a portion of the kinase domain and spans amino acids 769 to 835. Any mutation, insertion, duplication, or deletion within this region is defined as an exon 20 mutation, including those listed in Table 1. Additionally, oncogenic HER2 mutations exist outside of exon 20, including those listed in Table 2.

[0039] Table 1. ERBB2 (HER2) exon 20 mutations ("p." refers to the HER2 protein) [Table 1]

[0040] Table 2. Alternative HER2 mutations ("p." refers to the HER2 protein) [Table 2]

[0041] List of abbreviations [Table 3]

[0042] Features and advantages of the present invention will become apparent from the following detailed examples which demonstrate, by way of example, the principles of the invention without limiting its scope. Preparation of the Compounds of the Invention General rules The compounds of the present invention and their intermediates can be obtained by utilizing synthetic methods known to those skilled in the art and described in the organic synthesis literature.Preferably, the compounds are obtained in a manner similar to the preparation methods described more fully below, especially as described in the experimental section.In some cases, the order of carrying out the reaction steps may be different.Variants of reaction methods known to those skilled in the art but not detailed here may also be used. General processes for preparing compounds of the invention will be apparent to those skilled in the art upon examination of the schemes below. Starting materials may be prepared by methods described in the literature or herein, or may be prepared by analogous or similar methods. Any functional group of the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at an appropriate stage in the reaction sequence using methods familiar to those skilled in the art. General reaction scheme and overview of the synthetic route

[0043] [ka] Scheme 1. General Route 1 for the Synthesis of Compound C

[0044] Compounds C of the present invention can be synthesized starting from commercially available para-fluoronitrobenzene (A) and an alcohol, which react by substitution of the nitro group and subsequent reduction to give the corresponding amines C (see, e.g., Ishikawa et al., J. Med. Chem. 2011, 54 (23), 8030-8050; McDaniel et al., J. Med. Chem. 2017, 60 (20), 8369-8384).

[0045] [ka] Scheme 2. General Route 1 for the Synthesis of Compound G

[0046] [ka] Scheme 3. General Route 2 for the Synthesis of Compound G

[0047] Compound G of the present invention can be synthesized from compound E or F according to general route 1 (see, for example, Wang et al., Bioorg. Med. Chem. Lett. 2016, 26 (11), 2589-2593, Wan et al., Org. Lett. 2006, 8, 11, 2425-2428). Alternatively, compound G of the invention can be synthesized from compound H according to general route 2, where compound H is substituted with an appropriate amine (see, e.g., Wang et al., Bioorg. Med. Chem. Lett. 2016, 26 (11), 2589-2593), followed by oxidation of the alkyl sulfide to a sulfoxide or sulfone and substitution with a substituted or unsubstituted piperazine (see, e.g., Del Bello et al., Bioorg. Med. Chem. 2015, 23 (17), 5725-5733).

[0048] [ka] Scheme 4. Synthesis of compounds of formula (I)

[0049] The compounds of formula (I) of the present invention can be synthesized from compound G by deprotection of the Boc-protected substituted or unsubstituted piperazine and subsequent reaction with acryloyl chloride or acryloyl anhydride (see, for example, Zhang et al., Eur. J. Med. Chem. 2019, 178, 417-432). Unless otherwise specified, all reactions are carried out in commercially available equipment using methods commonly used in chemical laboratories. Air- and / or moisture-sensitive starting materials are stored under protective gas and the corresponding reactions and operations using them are carried out under protective gas (nitrogen or argon). The compounds of the present invention are named according to the CAS rules using the software AutoNom (Beilstein) or MarvinSketch (ChemAxon, product version 17.24.3). When a compound is represented both by a structural formula and by its nomenclature, in case of discrepancy, the structural formula is decisive.

[0050] The exemplary compounds of formula (I), I-1 to I-8, and intermediates are prepared by the synthetic methods described below, in which the substituents of the general formula have the meanings given above. These methods are intended to be considered as illustrative of the present invention without limiting the scope of the invention and the compounds claimed therein to these examples. Where no description is given of the preparation of starting compounds, they may be obtained commercially or their synthesis has been described in the prior art or they may be prepared analogously to known prior art compounds or methods described herein. That is, it is within the skill of an organic chemist to synthesize these compounds. Substances described in the literature may be prepared according to published synthetic methods.

[0051] Chromatography Thin layer chromatography is performed using ready-made silica gel 60 TLC on Merck glass (with fluorescent indicator F-254). Preparative high pressure chromatography (RP HPLC) of the example compounds is performed on an Agilent or Gilson system using Waters columns named: SunFire™ Prep C18, OBD™ 10 μm, 50×150 mm or SunFire™ Prep C18 OBD™ 5 μm, 30×50 mm or Xbridge™ Prep C18, OBD™ 10 μm, 50×150 mm or Xbridge™ Prep C18, OBD™ 5 μm, 30×150 mm or Xbridge™ Prep C18, OBD™ 5 μm, 30×50 mm) and YMC named: Actus-Triart Prep C18, 5 μm, 30×50 mm. Compounds are eluted using various gradients of HO / acetonitrile with the addition of 5% acidic modifier (20 mL HCOOH to 1 L HO / acetonitrile (1 / 1)) to water (acidic conditions) on the Agilent system and 0.1% HCOOH to water on the Gilson system. For chromatography under basic conditions on the Agilent system, a H2O / acetonitrile gradient is also used with 5% basic modifier added to the aqueous eluent (50 g NH4HCO3 + 50 mL NH3 (25% in H2O) + H2O for 1 L aqueous eluent). On the Gilson system the aqueous eluent consists of 5 mL of NH4HCO3 solution (158 g in 1 L H2O) and 2 mL of NH3 (28% in H2O) made up to 1 L with H2O. The HPLC-MS columns used were from Waters (Xbridge™ C18, 2.5 μm, 2.1×20 mm or Xbridge™ C18, 2.5 μm, 2.1×30 mm or Aquity UPLC BEH C18, 1.7 μm, 2.1×50 mm), from YMC (Triart C18, 3.0 μm, 2.0×30 mm) and from Phenomenex (Luna C18, 5.0 μm, 2.0×30 mm). HPLC-Mass spectrometry / UV spectroscopy Using an HPLC-MS system (high performance liquid chromatography and mass detector), retention time / MS-ESI was used to characterize the exemplary compounds of the present invention. + The compounds eluting in the injection peak have retention times t Ret. =0.00.

[0052] Method 1 [Table 4]

[0053] Method 2 [Table 5]

[0054] Method 3 [Table 6]

[0055] Method 4 [Table 7]

[0056] Synthesis of compounds C-1 to C-4

[0057] Method 1 [ka]

[0058] [1,2,4]Triazolo[1,5-a]pyridin-7-ol (1.00 g, 7.40 mmol), 1-fluoro-2-methyl-4-nitrobenzene (1.49 g, 9.62 mmol) and potassium carbonate (2.55 g, 18.5 mmol) in DMF (10 mL) are stirred at 80 °C for 16 h. The mixture is poured onto water (150 mL) and extracted with ethyl acetate. The combined organic layers are washed with water, dried (MgSO4), filtered and concentrated in vacuum. The crude product is purified by column chromatography (SiO2, cyclohexane / ethyl acetate gradient) to give the intermediate (1.79 g). This intermediate (1.79 g, 6.62 mmol) and 10% Pd / C (500 mg) in ethanol (50 mL) are stirred under hydrogen atmosphere (4 bar) at a temperature of 18-25 °C for 16 h. The reaction mixture is filtered and concentrated in vacuum. The crude product is purified by column chromatography (SiO2, cyclohexane / ethyl acetate gradient) to give product C-1 (1.36 g).

[0059] Method 2 [1,2,4]Triazolo[1,5-a]pyridin-7-ol (500 mg, 3.70 mmol), 1,3-dichloro-2-fluoro-5-nitrobenzene (1.01 g, 4.81 mmol) and potassium carbonate (1.28 g; 9.25 mmol) are suspended in N,N-dimethylformamide (DMF) (10 mL). The resulting reaction mixture is stirred at 80 °C for 18 h, and HPLC-MS indicates complete conversion. The reaction mixture is concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, cyclohexane / ethyl acetate gradient) to give the intermediate (1.10 g). This intermediate (1.10 g, 3.38 mmol) and iron powder (0.945 g, 16.9 mmol) are suspended in ethanol (10 mL) and water (5 mL). Saturated aqueous ammonium chloride solution (5 mL) is added and the resulting reaction mixture is stirred at 80 °C for 3 h. The solids are removed by filtration. The filtrate is concentrated under reduced pressure and purified by column chromatography (SiO2, dichloromethane / methanol gradient) to give the product C-3 (860 mg). Compounds C-2 and C-4 (Table 3) were synthesized analogously to Method 2 above.

[0060] [Table 8]

[0061] Compounds G-1 to G-8 can be prepared according to General Route 1 or General Route 2 shown below. Synthesis of Compounds G-1 to G-8 According to General Route 1 (Scheme 2)

[0062] Synthesis of compound E) [ka]

[0063] 6-Methanesulfinyl[1,3]diazino[5,4-d]pyrimidin-4-ol (10.30 g, 49.0 mmol, prepared according to WO 97 / 32880) and tert-butyl piperazine-1-carboxylate (11.29 g, 186.3 mmol) in dioxane (200 mL) are stirred at reflux for 16 h. The reaction mixture is concentrated under reduced pressure. The crude product is stirred in DMSO (200 mL) at 80° C. for 30 min, poured onto ice water (1 L) and stirred for an additional 30 min. The solid is collected by filtration, triturated with water and redissolved in dichloromethane / methanol (9 / 1). The organic layer is subsequently washed with 1N aqueous HCl (200 mL) and brine (200 mL), dried (MgSO4), filtered and concentrated in vacuo to give compound E (11.1 g).

[0064] Table 4 [Table 9]

[0065] Synthesis of compound F [ka]

[0066] E (2.0 g, 6.02 mmol) is suspended in dry dichloromethane (50 mL) and DMF (0.76 mL, 9.79 mmol) is added. Then, oxalyl chloride (1.1 mL, 12 mmol) in dry dichloromethane (10 mL) is added dropwise to the stirred reaction mixture. The reaction mixture is stirred at a temperature between 18-25 °C for 1 h and then concentrated in vacuo. The crude product is purified by column chromatography (SiO2, cyclohexane / ethyl acetate gradient) to give product F (1.2 g).

[0067] Table 5 [Table 10]

[0068] Synthesis of compound G [ka]

[0069] F (250 mg, 0.64 mmol) and C-4 (197 mg, 0.71 mmol) in isopropanol (5 mL) are stirred at 50° C. for 16 h. The reaction mixture is poured onto water and the solid is collected by filtration. The crude product is purified by column chromatography (SiO2, dichloromethane / methanol gradient) to give product G-4 (350 mg). Compounds G-1 to G-3 (Table 8) were synthesized similarly to the above procedure. Synthesis of Compounds G-1 to G-8 According to General Route 2 (Scheme 3) Compounds G-1 to G-8 can also be prepared according to general route 2.

[0070] Synthesis of compound J [ka]

[0071] 8-Chloro-2-(methylthio)pyrimido[5,4-d]pyrimidine (1.97 g, 8.32 mmol) and C-1 (2.0 g, 8.32 mmol) in isopropanol (300 mL) are stirred for 1 h at 45° C. The product J-1 is isolated by filtration, washed with isopropanol, and dried in vacuum (3.4 g).

[0072] [Table 11]

[0073] Synthesis of compound K [ka]

[0074] To J-1 (5.40 g, 9.08 mmol) in dichloromethane (150 mL) is added m-chloroperbenzoic acid (77%, 3.05 g, 13.6 mmol) at 5 °C and the reaction mixture is stirred at a temperature of 18-25 °C for 2 h. Saturated aqueous NaHCO3 (200 mL) is added and the aqueous layer is extracted with dichloromethane. The combined organic layers are washed with water, dried (MgSO4), filtered and concentrated in vacuo. The crude product K-1 is used in the next step without further purification (3.0 g).

[0075] Table 7 [Table 12]

[0076] Synthesis of compound G [ka]

[0077] K-1 (500 mg, 1.06 mmol), tert-butyl piperazine-1-carboxylate (244 mg, 1.27 mmol), and diisoproylethylamine (240 μL, 1.4 mmol) in DMF (10 mL) are stirred at 70 °C for 1 h and then at a temperature of 18-25 °C overnight. The reaction mixture is poured onto water and extracted several times with ethyl acetate. The combined organic layers are dried (Na2SO4) and concentrated. The crude product is purified by column chromatography (SiO2, dichloromethane / ammonia in methanol gradient) to give product G-1 (360 mg). Compounds G-5 to G-8 (Table 8) were synthesized similarly to the above procedure.

[0078] Table 8 [Table 13] JPEG0007626774000030.jpg206153

[0079] Synthesis of compounds L-1 to L-8 [ka]

[0080] G-1 (8.7 g, 15.7 mmol) was dissolved in a mixture of dichloromethane (400 mL) and methanol (100 mL) and the resulting solution was cooled to 4 °C. HCl (4 N in dioxane, 20 mL) was added dropwise to the stirred reaction mixture. The reaction mixture was then warmed to a temperature of 18-25 °C and stirred overnight at a temperature of 18-25 °C. The reaction mixture was concentrated and the crude product was purified by column chromatography (SiO2, dichloromethane / ammonia in methanol gradient) to give product L-1 (5.3 g). Compounds L-2 to L-8 (Table 9) were synthesized similarly to the above procedure.

[0081] Table 9 [Table 14] JPEG0007626774000033.jpg206153

[0082] Synthesis of compounds I-1 to I-8 [ka]

[0083] Dissolve L-1 (4.66 g, 10.25 mmol) in dichloromethane (100 mL) and trimethylamine (2.9 mL, 21 mmol). Cool the resulting solution to 4 °C. Add acryloyl chloride (840 μL, 10.2 mmol) in dichloromethane (10 mL) dropwise to the stirred reaction mixture. Stir the resulting reaction mixture at 4 °C for 2 h and then warm to a temperature of 18-25 °C. Then partition the reaction mixture between saturated aqueous NaHCO3 and dichloromethane. Dry the organic layer (MgSO4) and concentrate. Purify the crude product by column chromatography (SiO2, 5% methanol in dichloromethane, isocratic) to give the product (2.95 g). Compounds I-1 to I-8 (Table 8) are synthesized similarly to the above procedure. Alternative reagents for the introduction of acrylamide may be used, such as acryloyl anhydride.

[0084] Table 8 [Table 15] JPEG0007626774000036.jpg178153

[0085] Biological assays Ba / F3 cell model generation and proliferation assay Ba / F3 cells were ordered from DSMZ (ACC300) and grown in RPMI-1640 (ATCC 30-2001) + 10% FBS + 10 ng / ml IL-3 at 37 °C in a 5% CO2 atmosphere. Plasmids containing HER2 mutants and EGFR WT were obtained from GeneScript. To generate EGFR / HER2-dependent Ba / F3 models, Ba / F3 cells were transduced with retroviruses containing vectors harboring EGFR WT, HER2 WT or HER2 mutant (YVMA). Platinum-E cells (Cell Biolabs) were used for retrovirus packaging. Retroviruses were added to Ba / F3 cells. To ensure infection, 4 μg / mL polybrene was added to spinfect the cells. Infection efficiency was confirmed by measuring GFP-positive cells using a cell analyzer. Cells with infection efficiency of 10%-20% were further cultured and puromycin selection was initiated at 1 μg / mL. As a control, parental Ba / F3 cells were used to evaluate the selection status. Selection was considered successful when the parental Ba / F3 cell culture died. To investigate the transforming potential of the HER2 mutations, the growth medium was no longer supplemented with IL-3. Ba / F3 cells harboring an empty vector were used as a control. The switch from IL-3 to EGF was performed on Ba / F3 cells using EGFR WT, known for its dependency on EGF ligand. Puromycin was removed approximately 10 days before the experiment was performed. For proliferation assays (data in Tables 12 and 14), Ba / F3 cells were cultured at 5 × 10 3Cells / 100 μL were seeded in 96-well plates. Compounds were added using an HP D3000 digital dispenser. All treatments were performed in technical triplicate. Treated cells were incubated for 72 hours at 37° C. with 5% CO2. The CellTiter-Glo® Luminescent Cell Viability Assay (Promega) was performed and chemiluminescence was measured using a multilabel plate reader VICTOR X4. Raw data were imported and analyzed with Boehringer Ingelheim proprietary software MegaLab (curve fitting based on the program PRISM, GraphPad Inc.).

[0086] pEGFR assay This assay quantifies the phosphorylation of EGFR at Tyr1068 and was utilized to measure the inhibitory effect of compounds on transgenic EGFR wild-type (WT) protein expressed in HEK cells. Human HEK cells (ATCC CRL-1573) were grown in Eagle's Minimum Essential Medium, MEM Eagle EBSS lacking L-glutamine and containing non-essential amino acids and sodium pyruvate (MEM Lonza BE12-662F) + 5ml GlutaMax (Gibco 35050-038; L-alanyl-L-glutamine) + 5ml Sodium Pyruvat (Gibco 11360-039; 100mM) + 10% FBS at 37°C in a 5% CO2 atmosphere and transduced with a retroviral vector encoding EGFR WT. Transduced cells were selected with puromycin. p-EGFR Tyr1068 was measured using the AlphaScreen Surefire pEGF Receptor (Tyr1068) Assay (PerkinElmer, TGRERS). For this assay, HEK EGFR WT cells were seeded in MEM medium containing 10% FBS. 60 nL of compound dilutions were added to each well of a Greiner TC 384 plate using the Echo platform. Subsequently, 60.000 cells / well in 60 μL were added. Cells were incubated with compounds for 4 h at 37 °C. After centrifugation and removal of the medium supernatant, 20 μL of 1.6x lysis buffer from the TGR / Perkin Elmer kit containing protease inhibitors was added. The mixture was incubated for 20 min with shaking (700 rpm) at a temperature of 20-25 °C. After centrifugation, 4 μL of lysate was transferred to a Proxiplate. 5 μL of acceptor mix (activation buffer diluted 1:25 in combined reaction buffer 1 and reaction buffer 2 (TGRERS Assay Kit, PerkinElmer) + 1:50 Protein A Acceptor Beads 6760137, Perkin Elmer) was added to each well. The plate was shaken (1400 rpm) for 1 min and incubated in the dark at 20-25°C for 2 h. 3 μL of donor mix (AlphaScreen Streptavidin-Coated Donor Beads (6760002, PerkinElmer) diluted 1:50 in dilution buffer (TGRERS Assay Kit, PerkinElmer) was added to each well.The plates were shaken (1400 rpm) for 1 hour and incubated in the dark at a temperature of 20-25°C for 2 hours. Afterwards the plates were analyzed using the Envision reader platform. The results were computed as follows: the ratio of the test compound value to the negative control (DMSO) value was calculated. MEGASTAR IC. 50 In the application, a four-parametric logistic model was used to calculate the IC 50 Calculate the value. This cellular phospho-EGFR (pEGFR) compound dose-response assay quantifies phosphorylation of EGFR at Tyr1068 in HEK cells expressing EGFR WT. The results of the assay are reported as IC 50 The pEGFR IC for a given compound is given as a value. 50 The higher the value, the greater the EGFR WT-preserving activity.

[0087] pHER2(ERBB2) YVMA assay This assay quantifies the phosphorylation of HER2 YVMA at Tyr1221 / 1222 and was utilized to measure the inhibitory effects of compounds on transgenic HER2 YVMA protein expressed in HEK cells using a doxycycline-inducible expression system. Human HEK cells were grown in Eagle's Minimum Essential Medium, MEM Eagle EBSS lacking L-glutamine and containing non-essential amino acids and sodium pyruvate (MEM Lonza BE12-662F) + 5 ml GlutaMax (Gibco 35050-038; L-alanyl-L-glutamine) + 5 ml Sodium Pyruvat (Gibco 11360-039; 100 mM) + 10% FBS at 37°C in a 5% CO2 atmosphere and transduced with a retroviral vector encoding HER2 YVMA. Transduced cells were selected with puromycin. p-HER2 Tyr1221 / 1222 was measured using the AlphaScreen Surefire ErbB2 (Tyr1221 / 1222) assay (PerkinElmer, TGREB2S). For this assay, HEK HER2 YVMA cells were seeded in MEM medium containing 10% FBS. HER2 YVMA expression was induced with 1 μg / ml doxycycline 4 hours prior to compound addition. 60 nL of compound dilutions were added to each well of a Greiner TC 384 plate using the Echo platform. Subsequently, 60.000 cells / well in 60 μL were added. Cells were incubated with compounds for 4 hours at 37 °C. After centrifugation and removal of the medium supernatant, 20 μL of 1.6x lysis buffer from the TGR / Perkin Elmer kit containing protease inhibitors was added. The mixture was incubated for 20 minutes with shaking (700 rpm) at a temperature of 20-25 °C. After centrifugation, 4 μL of lysate was transferred to Proxiplates. 5 μL of acceptor mix (activation buffer diluted 1:25 in combined reaction buffer 1 and reaction buffer 2 (TGREB2S Assay Kit, PerkinElmer) + 1:50 Protein A Acceptor Beads 6760137, PerkinElmer) was added to each well. The plate was shaken (1400 rpm) for 1 min and incubated in the dark at 20-25 °C for 2 h.3 μL of donor mix (AlphaScreen Streptavidin-Coated Donor Beads (6760002, PerkinElmer) diluted 1:50 in dilution buffer (TGRERS Assay Kit, PerkinElmer) was added to each well. The plate was shaken (1400 rpm) for 1 min and incubated in the dark at 20-25°C for 2 h. The plate was then analyzed using the Envision reader platform. The results were computed as follows: the ratio of the test compound value to the negative control (DMSO) value was calculated. From these values, the MEGASTAR IC was calculated. 50 IC using a four-parametric logistic model in an application 50 Calculate the value. This cellular phospho-HER2 YVMA (pHER2 YVMA) compound dose-response assay quantifies phosphorylation of HER2 YVMA at Tyr1221 / 1222 in HEK cells expressing HER2 YVMA. The results of the assay are reported as IC 50 The pHER2 YVMA IC values ​​reported for a given compound are given. 50 The lower the value, the stronger the inhibitory effect of the compound on HER2 YVMA kinase activity.

[0088] HER2 YVMA tumor cell line model generation and proliferation assay HER2 WT-dependent NCI-H2170 cells were ordered from (ATCC, CRL-5928) and grown in RPMI-1640 (Gibco # A10491) ATCC-Formulation + 10% FBS at 37°C in a 5% CO2 atmosphere. Homology-directed genome engineering was used to insert a 12-nucleotide sequence encoding YVMA into exon 20 of the genomic HER2 locus of NCI-H2170 cells. This resulted in a change from HER2 WT to the HER2 YVMA variant, i.e., HER2 p.A775_G776insYVMA. Template DNA containing the HER2 exon 20 YVMA insertion variant was obtained from GenScript. PCR followed by Sanger sequencing was used to confirm the presence of the 12-nucleotide insertion in HER2 exon 20, resulting in the YVMA amino acid duplication. For proliferation assays, NCI-H2170 (HER2 wild type), NCI-H2170 HER2 YVMA and EGFR WT dependent A431 cells were used. NCI-H2170 HER2 YVMA or NCI-H2170 cells were seeded in 96-well plates at 750 cells / 60 μL in growth medium (RPMI ATCC + 10% FBS, + penicillin / streptomycin). A431 cells (ATCC CRL-1555) (DMEM (Sigma #D6429) + 5 ml Sodium Pyruvat Gibco 11360-039) were plated at a density of 5000 cells per well (200 μl) of a 96-well plate. Compounds were added using a HP D3000 digital dispenser the day after cells were plated. All treatments were performed in technical triplicate. Treated cells were incubated for 72 hours at 37°C with 5% CO2. The CellTiter-Glo® Luminescent Cell Viability Assay (Promega) was performed and chemiluminescence was measured using a multilabel plate reader VICTOR X4. Raw data were imported and analyzed with Boehringer Ingelheim proprietary software MegaLab (curve fitting based on the program PRISM, GraphPad Inc.).

[0089] Table 11. Biomarker assays [Table 16]

[0090] Table 12. Tumor cell proliferation assays [Table 17]

[0091] Table 13 [Table 18] JPEG0007626774000040.jpg206153

[0092] Table 14. Tumor cell proliferation assays [Table 19]

[0093] Pharmaceutical Formulation Examples [Table 20]

[0094] The active substance is milled and mixed with lactose and a portion of the corn starch. The mixture is screened and then wet-granulated with a solution of polyvinylpyrrolidone. These granules, the remaining corn starch and magnesium stearate are mixed together. The mixture is compressed to produce tablets of suitable shape and size. Preferred aspects of the present invention are as follows. [1] Formula (I) JPEG0007626774000043.jpg8498 (In the formula, R 1 is hydrogen, -CH 3 , -CCH, -OCH 3 and halogen; R 2 is hydrogen or halogen, R 3 is hydrogen or halogen, R 4 is hydrogen or -CH 3 and And R 1 、R 2 and R 3 At least one of these is not hydrogen. or a salt thereof. 〔2〕R 1 But -CH 3 The compound or salt thereof according to [1] above, wherein the aryl group is selected from the group consisting of aryl, aryl, aryl and halogen. 〔3〕R 1 But -CH 3 The compound or salt thereof according to the above [1], wherein the halogen atom is selected from the group consisting of chlorine and fluorine. 〔4〕R 2 is hydrogen, or a salt thereof, according to [1] above. 〔5〕R 2 is chlorine, or a salt thereof, according to [1] above. 〔6〕R 2 is fluorine, 〔7〕R 3 is hydrogen, or a salt thereof, according to [1] above. 〔8〕R 4 is hydrogen, or a salt thereof, according to [1] above. 〔9〕R 4 But -CH 3 The compound or salt thereof according to [1] above,

[10] The following compound: JPEG0007626774000044.jpg225153 JPEG0007626774000045.jpg183153 The compound or salt thereof according to [1] above,

[11] A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I) described in any one of [1] to

[10] above or a pharma- ceutical acceptable salt thereof, and one or more pharma-ceutical acceptable excipients.

[12] The compound according to any one or more of the above [1] to

[10] , or a pharma- ceutically acceptable salt thereof, for use as a drug.

[13] Use of the compound according to any one or more of the above [1] to

[10] for treating patients suffering from brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, colorectal cancer, endometrial cancer, skin cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer or prostate cancer.

[14] A pharmaceutical composition comprising, in addition to the compound of formula (I), a medicamentously active compound selected from the group consisting of cytostatic and cytotoxic substances.

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, R 1 is hydrogen, -CH 3 , -CCH, -OCH 3 and halogen; R 2 is hydrogen or halogen, R 3 is hydrogen or halogen, R 4 is hydrogen or -CH 3 and And R 1 , R 2 and R 3 At least one of these is not hydrogen. or a salt thereof.

2. R 1 But -CH 3 2. The compound or salt thereof according to claim 1, wherein said compound or salt is selected from the group consisting of:

3. R 1 But -CH 3 2. The compound or salt thereof according to claim 1, wherein said at least one atom is selected from the group consisting of chlorine and fluorine.

4. R 2 The compound or salt thereof according to claim 1, wherein is hydrogen.

5. R 2 The compound or salt thereof according to claim 1, wherein is chlorine.

6. R 2 The compound or salt thereof according to claim 1, wherein is fluorine.

7. R 3 The compound or salt thereof according to claim 1, wherein is hydrogen.

8. R 4 The compound or salt thereof according to claim 1, wherein is hydrogen.

9. R 4 But -CH 3 2. The compound according to claim 1, or a salt thereof,

10. The following compound: 【Chemistry 2】 【change】 The compound or salt thereof according to claim 1, selected from:

11. A compound having the following structure:

12. A pharma- ceutically acceptable salt of a compound having the structure:

13. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I) according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof.

15. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof for treating a patient suffering from brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, colorectal cancer, endometrial cancer, skin cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer or prostate cancer.

16. A pharmaceutical composition comprising, in addition to a compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 12, a pharma- ceutical active compound selected from the group consisting of cytostatic and cytotoxic substances.

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