HK1109141B

HK1109141B - Pyrrolotriazine derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis

Info

Publication number: HK1109141B
Application number: HK07114075.2A
Authority: HK
Inventors: Julie A. Dixon; Catherine Brennan; Karl Miranda; Brent Chandler; Barton Phillips; Jianmei Fan; Michael Brands; Andrea Mcclure; Benjamin Jones; Wenlang Fu; Donald Bierer; Steven Magnuson; Harold C. E. Kluender
Original assignee: Bayer Healthcare Llc
Priority date: 2004-06-03
Filing date: 2005-06-03
Publication date: 2011-01-14

Description

Pyrrolotriazine derivatives useful for the treatment of hyperproliferative disorders and diseases associated with angiogenesis

The present invention relates to novel pyrrolotriazine compounds, pharmaceutical compositions containing such compounds, and the use of these compounds and compositions for the prevention and/or treatment of hyperproliferative disorders and diseases associated with angiogenesis.

Background

To support a size of more than 1-2mm³The tumor cells are recognized to require a functional matrix, a supporting structure consisting of fibroblasts, smooth muscle cells, endothelial cells, extracellular matrix proteins and soluble factors (Folkman, j., Semin Oncol, 2002.29(6 Suppl 16), 15-8). Tumors induce the formation of stromal tissue by secreting soluble growth factors such as PDGF and transforming growth factor beta (TGF- β), which in turn stimulate host cells to secrete complement factors such as Fibroblast Growth Factor (FGF), Epidermal Growth Factor (EGF), and Vascular Endothelial Growth Factor (VEGF). These stimulatory factors induce the formation of new blood vessels or angiogenesis that bring oxygen and nutrients to the tumor, allowing the tumor to grow and providing a metastatic pathway. Certain treatments targeted at inhibiting stromal formation are believed to inhibit the growth of epithelial tumors in various tissue types (George, d. semin Oncol, 2001.28(5 Suppl 17), 27-33; Shaheen, r.m., et al, Cancer Res, 2001.61(4), 1464-8; Shaheen, r.m., et al, Cancer Res, 1999.59(21), 5412-6). However, drugs targeting a single pathway are limited in their efficacy due to the intrinsic complexity and diversity of growth factors involved in angiogenesis and tumor progression. It is desirable to provide treatments that are resistant to several key signaling pathways used by tumors to induce angiogenesis in the host stroma. These include PDGF, a matrix form Potent stimulators of angiogenesis (Ostman, A.and C.H.Heldin, Adv Cancer Res, 2001, 80, 1-38), FGF, a chemoattractor and mitogen for fibroblasts and endothelial cells, and VEGF, a potent regulator of angiogenesis.

The major regulator of angiogenesis and vasculogenesis in embryonic development and certain angiogenic-dependent diseases is vascular endothelial growth factor (VEGF; also known as vascular permeability factor, VPF). VEGF represents a family of mitogen isoforms that exist as homodimers as a result of alternative RNA splicing. The VEGF isoforms have been reported to be highly specific for vascular endothelial cells (see Farrara et al, Endocr. Rev.1992, 13, 18; Neufield et al, FASEB J.1999, 13, 9).

VEGF expression has been reported to be induced by hypoxia (Shweiki et al Nature 1992, 359, 843) and by various cytokines and growth factors such as interleukin-1, interleukin-6, epidermal growth factor and transforming growth factor. To date, VEGF and VEGF family members have been reported to bind to one or more of the three transmembrane receptor tyrosine kinases (Mustonen et al j. cell biol., 1995, 129, 895), VEGF receptor-1 (also known as flt-1 (fms-like tyrosine kinase-1)), VEGFR-2 (also known as a kinase insert domain containing receptor (KDR)); murine analogs of KDR are known as fetal liver kinase-1 (flk-1)), and VEGFR-3 (also known as flt-4)). KDR and flt-1 have been shown to have different signalling properties (Waltenberger et al J.biol.chem.1994, 269, 26988; Park et al Oncogene 1995, 10, 135). Thus, KDR undergoes strong ligand-dependent tyrosine phosphorylation in intact cells, but flt-1 shows a weak response. Therefore, binding to KDR is believed to be a critical requirement for the induction of various VEGF-mediated biological responses.

In vivo, VEGF plays a major role in angiogenesis and induces angiogenesis and vascular permeability. Uncontrolled VEGF expression is responsible for the development of a variety of diseases characterized by abnormal angiogenesis and/or hyperpermeable processes. Modulation of the VEGF-mediated signaling cascade with certain agents is believed to provide a useful means for controlling aberrant angiogenesis and/or hyperpermeability processes.

Vascular endothelial growth factors (VEGF, VEGF-C, VEGF-D) and their receptors (VEGFR2, VEGFR3) are key regulators of not only tumor angiogenesis but also lymphatic angiogenesis. In most tumors, VEGF-C and VEGF-D are predominantly expressed during tumor growth, and are usually expressed at significantly elevated levels. VEGF expression is stimulated by hypoxia, cytokines, tumor genes such as ras, or by inactivation of tumor suppressor genes (McMahon, G.Oncologenist 2000, 5(suppl.1), 3-10; McDonald, N.Q.; Hendrickson, W.A.Cell 1993, 73, 421-.

The biological activity of VEGF is mediated by binding to their receptors. VEGFR3 (also known as Flt-4) is expressed primarily on lymphatic endothelium in normal adult tissues. VEGFR3 function is required for neovascularization, but not for maintenance of existing lymph. VEGFR3 is also upregulated on the vascular endothelium in tumors. Recently, ligands for VEGF-C and VEGF-D, VEGFR3, have been found to be modulators of lymphatic angiogenesis in mammals. The lymphatic angiogenesis induced by the tumor-associated lymphatic angiogenic factors can promote the growth of new blood vessels into tumors, which allow tumor cells to enter the systemic circulation. Cells invading the lymph can find their way into the blood stream via the chest catheter. Tumor expression studies have enabled direct comparison of VEGF-C, VEGF-D and VEGFR3 expression using clinical pathology factors that are directly related to the ability of the primary tumor to spread (e.g., lymph node involvement, lymph invasion, secondary metastasis, and disease-free survival). In many instances, these studies demonstrated a statistical correlation between the expression of lymphoangiogenic factors and the ability of primary solid tumors to metastasize (Skobe, M. et al. Nature Med.2001, 7(2), 192-.

Hypoxia appears to be an important stimulus for the production of VEGF in malignant cells. Activation of p38MAP kinase is essential for VEGF induction in tumor cells in response to hypoxia (Blascoke, F. et al. biochem. Biophys. Res. Commun.2002, 296, 890-. In addition to involvement in angiogenesis by regulation of VEGF secretion, p38MAP kinase also promotes malignant cell invasion and migration of different tumor types by regulating collagenase activity and urokinase plasminogen activator expression (Laferriere, J. et al. J. biol. chem.2001, 276, 33762-. Furthermore, VEGF activates extracellular signal-regulated protein kinase (ERK) in Human Umbilical Vein Endothelial Cells (HUVEC) (Yu, Y.; Sato, D.J. cell Physiol 1999, 178, 235-246).

PDGF is a key regulator of matrix formation secreted by many tumors in a paracrine manner and is believed to promote the growth of fibroblasts, smooth muscle and endothelial cells, thereby promoting matrix formation and angiogenesis. PDGF was originally identified as the v-sis oncogene product of the simian sarcoma virus (Heldin, C.H., et al, J Cell Sci Suppl, 1985, 3, 65-76). The growth factor is composed of two peptide chains called a or B chains, which share 60% homology in their primary amino acid sequence. The chains are disulfide-crosslinked to form a 30kDa mature protein composed of AA, BB or AB homodimers or heterodimers. PDGF is present at high levels in platelets and is expressed by endothelial cells and vascular smooth muscle cells. In addition, PDGF production is upregulated in hypoxic states such as those present in vascularized deficient tumor tissue (koremembanas, s., et al, KidneyInt, 1997, 51(2), 438-43). PDGF binds with high affinity to the PDGF receptor, an 1106 amino acid 124kDa transmembrane tyrosine kinase receptor (helldin, c.h., a.ostman, and l.ronnstrand, Biochim biophysis Acta, 1998.1378(1), 79-113). PDGFR exists as homo-or heterodimeric chains with 30% homology throughout their amino acid sequence and 64% homology between their kinase domains (Heldin, C.H., et al. Embo J, 1988, 7(5), 1387-93). PDGFR is a member of the family of tyrosine kinase receptors with split kinase domains, which includes VEGFR2(KDR), VEGFR3(Flt4), c-Kit, and FLT 3. PDGF receptors are expressed primarily on fibroblasts, smooth muscle cells and pericytes, and to a lesser extent on neuronal cells of the central nervous system, mesangial cells, leydig cells and schwann cells. Upon binding to the receptor, PDGF induces receptor dimerization and undergoes autophosphorylation and transphosphorylation of tyrosine residues, which increases the kinase activity of the receptor and promotes recruitment of downstream effectors through activation of the SH2 protein binding domain. A variety of signaling molecules form complexes with activated PDGFR, including PI-3-kinase, phospholipase C-. gamma., src, and GAP (GTPase activating protein of p 21-ras) (Soskic, V., et al. Biochemistry, 1999, 38(6), 1757-64). PDGF activates Rho signaling pathways that induce cell motility and migration through PI-3-kinase activation, and induces mitogenesis through activation of the p21-ras and MAPK signaling pathways through activation of GAP.

In adults, the primary function of PDGF is believed to be to promote and enhance the rate of Wound healing and maintain vascular homeostasis (Baker, E.A. and D.J.Leaper, Wound repair Regen, 2000.8(5), 392-8; Yu, J., A.Moon, and H.R.Kim, biochem Biophys Res Commun, 2001.282(3), 697-one 700). PDGF is present in high concentrations in platelets and is a potent chemoattractor for fibroblasts, smooth muscle cells, neutrophils and macrophages. In addition to its role in wound healing, PDGF is known to help maintain vascular homeostasis. During the development of new blood vessels, PDGF recruits pericytes and smooth muscle cells necessary for structural integrity of the blood vessels. PDGF is thought to play a similar role in the neovascularization of tumors. Due in part to its role in angiogenesis, PDGF controls intercellular fluid pressure and thereby regulates vascular permeability by regulating the interaction between connective tissue cells and the extracellular matrix. Inhibition of PDGF activity can reduce stromal stress and facilitate cytotoxic influx into tumors, thereby improving the antitumor effects of these drugs (Pietraras, K., et al. Cancer Res, 2002.62(19), 5476-84; Pietraras, K., et al. Cancer Res, 2001.61(7), 2929-34).

PDGF can promote tumor growth directly by paracrine or autocrine stimulation of PDGFR receptors on stromal or tumor cells, or by recombination to amplify or activate receptors. It is postulated that overexpressed PDGF is capable of transforming human melanoma cells and keratinocytes through its direct effect on matrix formation and induction of angiogenesis (Forsberg, k., et al, Proc Natl Acad Sci U S a., 1993.90(2), 393-7; Skobe, m.and n.e. fusenig, Proc Natl Acad Sci U S a, 1998.95(3), 1050-5), two cell types that do not express the PDGF receptor. This paracrine stimulation of the tumor stroma has also been observed in tumors expressing PDGF but not the receptor for colon, lung, breast and prostate cancers (Bhardwaj, B., et al. Clin Cancer Res, 1996, 2(4), 773-82; Nakanishi, K., et al. Mod Pathol, 1997, 10(4), 341-7; Sundberg, C., et al. Am J Pathol, 1997, 151(2), 479-92; Lindmark, G., et al. Labinvest, 1993, 69(6), 682-9; Vignaud, J.M., et al. Cancer Res, 1994, 54(20), 5455-63). Expression of ligands for PDGF has been mostly reported in glioblastoma (Fleming, t.p., et al. Cancer Res, 1992, 52(16), 4550-3), soft tissue sarcoma (Wang, j., m.d.coltrera, and a.m.go, Cancer Res, 1994, 54(2), 560-4), ovarian Cancer (Henriksen, r., et al. Cancer Res, 1993, 53(19), 4550-4), prostate Cancer (Fudge, k., c.y.wang, and m.e.stearns, Mod pages, 1994, 7(5), 54), pancreatic Cancer (Funa, k., et al. Cancer Res, 1990, 50(3), 748-53), and lung Cancer (antoniads, h.n., et al, Proc Natl Acad, Sci, us, 1992, 89 (3942), wherein tumor receptors have been expressed by stimulating tumor growth. Ligand-independent activation of the receptor was found to a lesser extent, but has been reported in chronic myelomonocytic leukemia (CMML), where chromosomal translocation events form fusion proteins between the Ets-like transcription factor TEL and the PDGF receptor. In addition, activating mutations in PDGFR have been found in gastrointestinal stromal tumors in which c-Kit activation is not implicated (Heinrich, m.c., et al, Science, 2003, 9, 9).

Certain PDGFR inhibitors are capable of interfering with the development of tumor stroma, and are therefore believed to inhibit tumor growth and metastasis.

The link between activity in vitro tumor cell proliferation assays and antitumor activity in the clinic is well established in the art. For example, taxol (Silvestrini et al, StemCells 1993, 11(6), 528-35), taxotere (Bissery et al, Anti Cancer Drugs1995, 6(3), 339) and topoisomerase inhibitors (Edelman et al, Cancer Chemother for therapeutic use.

Cells protect their DNA by adopting a higher-order complex called chromatin. Chromatin condensation is evident during mitosis and cell death induced by dephagization, but chromatin deagglomeration is essential for replication, repair, recombination and transcription. Histones belong to certain DNA binding proteins involved in the regulation of DNA coagulation; and post-transcriptional modification of the histone tail plays a key role in the kinetic coagulation/de-coagulation that occurs during the cell cycle. Phosphorylation of the histone H3 tail is involved in transcription and cell division (Prigent et al j. cell Science2003, 116, 3677). A number of protein kinases have been reported to phosphorylate histone H3, and these kinases function as signal transduction and mitotic kinases.

Pyrrolotriazine derivatives having kinase inhibitory activity have been described in the following documents: US patent application 10/289,010, US patent 6,670,357, WO 2001/19828, WO2003/042172, WO 2004/009542, WO 2004/009601, WO 2004/009784 and WO 2004/013145.

In one embodiment, the present invention provides a compound of formula (I)

Wherein

R¹Selected from the group consisting of aryl, benzyl, and heteroaryl,

wherein aryl and heteroaryl may be optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from

·(C₁-C₄) Alkyl radical, wherein (C)₁-C₄) The alkyl group may be substituted by 0, 1, 2 or 3 halogens, 0 or 1 heterocyclic group or 0 or 1 (C)₁-C₃) Alkoxy is substituted, wherein

(C₁-C₃) Alkoxy may optionally be substituted by (C)₁-C₃) The alkyl amino group is substituted by the alkyl amino group,

·(C₁-C₃) Alkoxy radical, wherein (C)₁-C₃) Alkoxy may optionally be substituted by (C)₁-C₃) The alkyl amino group is substituted by the alkyl amino group,

the presence of a halogen, in particular,

a trifluoromethyl group,

the presence of a trifluoromethoxy group,

·(C₃-C₆) A cycloalkyl group,

phenyl, said phenyl being optionally substituted by 1 or 2 halogens,

·wherein X is CH₂O, S or NR^1-1And wherein R is^1-1Is hydrogen or (C)₁-C₆) An alkyl group, a carboxyl group,

the nitro group(s) of the compound,

a cyano group, in the form of a cyano group,

·(C₁-C₃) An alkylthio group is a group of one or more,

a trifluoromethylthio group (CTS-S-),

·(C₁-C₃) An alkyl-carbonyl group, a carboxyl group,

·(C₁-C₆) Alkoxycarbonyl, and

a phenoxy group, wherein the phenoxy group may optionally be selected by 0, 1 or 2 independently from (C) ₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethoxy and halogen,

and is

Wherein benzyl can be substituted by 0, 1, 2 or 3 substituents selected from halogen, (C)₁-C₃) Alkyl and (C)₁-C₃) A radical substitution of alkoxy;

R²selected from hydrogen, halogen, (C)₁-C₄) Alkyl and (C)₁-C₄) An alkoxy group;

R³is selected from

A carboxyl group,

the formyl radical,

·(C₁-C₆) Alkylcarbonyl group of (C)₁-C₆) Alkylcarbonyl is optionally substituted by 0, 1, 2 or 3 substituents selected from fluoro, chloro, hydroxy, (C)₁-C₆) Alkoxy and heterocyclic ring, and the like,

·(C₃-C₆) A cycloalkyl-carbonyl group,

·(C₁-C₆) Alkoxycarbonyl group of said (C)₁-C₆) Alkoxycarbonyl is optionally substituted by 0, 1, 2 or 3 groups selected from amino and (C)₁-C₆) The radical of an alkoxycarbonyl group is substituted,

an amino-carbonyl group, or a carbonyl group,

·(C₁-C₆) Alkylaminocarbonyl radical, in which (C)₁-C₆) The alkylaminocarbonyl group may be optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of: (C)₃-C₆) Cycloalkyl, halogen, amino, (C)₁-C₆) Alkylamino, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) Alkylthio group, (C)₁-C₆) Alkoxycarbonylamino and methylsulfonyl, and wherein (C)₁-C₆) The alkylaminocarbonyl group may be optionally substituted with 0 or 1 heterocyclic group, wherein the heterocyclic group may be optionally substituted with 0 or 1 (C)₁-C₆) Alkyl is substituted, and wherein (C)₁-C₆) The alkylaminocarbonyl radical may optionally be substituted by 0 or 1 phenyl, where phenyl may optionally be substituted by 0 or 1 halogen, (C) ₁-C₆) Alkyl or (C)₁-C₆) The substitution of alkoxy groups is carried out,

a heterocyclylcarbonyl group, optionally substituted by 0 or 1 amino group, (C)₁-C₆) Alkylamino, cycloalkyl or (C)₁-C₆) Alkyl substitution (C)₁-C₆) Alkyl may optionally be substituted by 0 or 1 amino group or (C)₁-C₆) The alkyl amino group is substituted by the alkyl amino group,

·(C₁-C₆) Alkyl group of (C)₁-C₆) The alkyl group is optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of

a) A hydroxyl group(s),

b) an amino group, a carboxyl group,

c)(C₁-C₆) Alkylamino radical, in which (C)₁-C₆) The alkylamino group may be substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of: halogen, amino, alkylamino, methoxy, methylthio and methylsulfonyl,

d) arylamino, wherein arylThe amino group may be substituted with 0, 1 or 2 substituents independently selected from the group consisting of: (C)₁-C₆) Alkyl, (C)₁-C₆) An alkoxy group and a trifluoromethyl group,

e) heterocyclyl, wherein heterocyclyl may be substituted by 0, 1 or 2 (C)₁-C₆) Alkyl is substituted, wherein (C)₁-C₆) Alkyl may be substituted with 0, 1 or 2 hydroxy, methoxy or pyridyl,

f) an imidazole group which is a group having a structure represented by,

g) a pyridylamino group,

h)(C₁-C₃) Alkoxy group of the formula (C)₁-C₃) Alkoxy is optionally substituted up to the full-fluorine level by fluorine or by a heterocycle, wherein the heterocycle may optionally be substituted by 0 or 1 (C)₁-C₆) The substitution of the alkyl group is carried out,

i)(C₁-C₃) Alkoxy (C) ₂-C₃) Alkoxy, and

j)(C₁-C₆) An alkoxycarbonyl group, a carbonyl group,

k)(C₃-C₆) Cycloalkyl radicals

l) a cyano group,

·(C₁-C₆) Alkoxy group of the formula (C)₁-C₆) Alkoxy is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of: amino group, (C)₁-C₆) Alkylamino and heterocyclyl, wherein the heterocyclyl may be substituted by 0, 1, 2 or 3 (C)₁-C₆) The substitution of the alkyl group is carried out,

·(C₃-C₆) Cycloalkylaminocarbonyl group of₃-C₆) Cycloalkylaminocarbonyl is optionally substituted by (C)₁-C₃) The substitution of the alkyl group is carried out,

a cyano group, in the form of a cyano group,

heteroaryl, wherein heteroaryl may be substituted with 0, 1, 2 or 3 groups independently selected from

a)(C₁-C₆) Alkyl radical, wherein (C)₁-C₆) Alkyl may be substituted by 0, 1, 2 or 3 halogens, 0 or 1 heterocyclyl, 0 or 1 alkylamino, or 0 or 1 hydroxy or methoxy,

b) the halogen(s) are selected from the group consisting of,

c) an amino group, a carboxyl group,

d) an alkylamino group,

e)(C₁-C₆) Alkoxycarbonyl, and

f)(C₃-C₆) A cycloalkyl group,

an arylcarbonyl group, said arylcarbonyl group being independently selected from (C) by 0, 1, 2 or 3₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl and halogen, and the like, in the presence of a halogen,

a heterocyclyl group, wherein the heterocyclyl group may be independently selected from 0, 1, 2 or 3 (C)₁-C₆) Alkyl and (C)₁-C₆) Substituted with a group of alkoxycarbonyl; and is

R⁴Selected from hydrogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy and halogen;

or a pharmaceutically acceptable salt thereof.

Depending on their structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to enantiomers or diastereomers and to the respective mixtures thereof. Mixtures of said enantiomers and/or diastereomers may be separated into individual stereoisomers by known methods.

The invention also relates to tautomers of the compounds, depending on the structure of the compounds.

For the purposes of the present invention, a salt is a pharmaceutically acceptable salt of a compound of the invention.

Pharmaceutically acceptable salts of compound (I) include acid addition salts of inorganic acids, carboxylic and sulfonic acids, for example salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.

Pharmaceutically acceptable salts of the compounds of formula (I) also include salts with common bases, such as alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, arginine, lysine, ethylenediamine and methylpiperidine.

For the purposes of the present invention, solvates are in the form of compounds which coordinate with solvent molecules to form solid or liquid complexes. Hydrates are solvates of a particular form, in which coordination is with water.

For the purposes of the present invention, unless otherwise specified, the substituents have the following meanings:

alkyl represents straight or branched chain alkyl groups typically having 1 to 6, 1 to 4 or 1 to 3 carbon atoms, illustratively methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy generally denotes a straight-chain or branched hydrocarbon radical which generally has 1 to 6, 1 to 4 or 1 to 3 carbon atoms and is bonded via an oxygen atom. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isobutoxy, hexoxy, isohexoxy. The terms "alkoxy" and "alkyloxy" may be used synonymously.

Alkylamino denotes an amino group having one or two (independently selected) alkyl substituents, illustratively methylamino, ethylamino, N-propylamino, isopropylamino, tert-butylamino, N-pentylamino, N-hexylamino, N-dimethylamino, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-isopropyl-N-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-pentylamino and N-hexyl-N-methylamino.

Alkylthio generally denotes a straight-chain or branched hydrocarbon radical having 1 to 6 carbon atoms and being linked via a sulfur atom. Non-limiting examples include methylthio and ethylthio.

Arylamino refers to an amino group having one and two (independently selected) aryl substituents, illustratively phenylamino.

Aminoalkyl represents an alkyl group substituted by an amino group. Non-limiting examples include aminomethyl and aminoethyl.

Aminocarbonyl represents a free amide group.

Alkylcarbonyl represents a carbonyl group having an alkyl substituent. Non-limiting examples include acetyl, propionyl, butyryl, 2-methylpropionoyl, and hexanoyl.

Alkylaminocarbonyl denotes aminocarbonyl (free amide) having one and two (independently selected) alkyl substituents, illustratively methylaminocarbonyl, ethylaminocarbonyl, N-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, N-pentylaminocarbonyl, N-hexylaminocarbonyl, N-dimethylaminocarbonyl, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-N-propylaminocarbonyl, N-isopropyl-N-N-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-N-N-pentylaminocarbonyl and N-N-hexyl-N-methylaminocarbonyl.

Alkoxycarbonyl represents a carbonyl group having an alkoxy substituent. These are exemplified by methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl and n-hexyloxycarbonyl.

Cycloalkyl means monocyclic cycloalkyl groups typically having 3 to 8 or 5 to 7 carbon atoms, illustratively cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Aryl denotes mono-or bicyclic carbocyclic groups which are aromatic in at least one ring, usually having 6 to 10 carbon atoms, illustratively phenyl and naphthyl.

Heteroaryl represents a mono-or bicyclic group having typically 5 to 10 or 5 to 6 ring atoms and up to 5, in further embodiments up to 4 heteroatoms selected from nitrogen, oxygen and sulfur, said mono-or bicyclic group being aromatic in at least one ring. Which may be attached via a ring carbon atom or a ring nitrogen atom. If bicyclic, where one ring is aromatic and the other is not, it may be attached to either ring. Illustrative examples are thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuryl, benzimidazolyl, benzothienyl, quinolinyl, isoquinolinyl, 1, 3-benzodioxinyl, 1, 4-benzodioxinyl or benzodioxolyl.

Heteroarylcarbonyl represents a heteroaryl residue attached via a carbonyl carbon atom.

Heterocyclyl represents a non-aromatic (i.e., saturated or partially unsaturated) mono-or bicyclic group, in one embodiment a monocyclic group, typically having 4 to 10 or 5 to 8 ring atoms and up to 3, and in another embodiment up to 2 ring atoms selected from nitrogen, oxygen and sulfur, CO, SO and SO₂A heteroatom and/or a heterogroup of (a). If bicyclic, it may be a fused or spiro-linked bicyclic ring. The bicyclic ring can be attached via a ring carbon atom or a ring nitrogen atom. Illustrative examples are tetrahydrofuran-2-yl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, morpholinyl, perhydroazepinylAnd (4) a base.

Heterocyclylcarbonyl represents the residue of a heterocyclyl group attached via the carbonyl carbon atom.

Methylsulfonyl represents-S (O)₂CH₃And (c) a residue.

Halogen or halo represents a substituent selected from fluorine, chlorine, bromine and iodine, in further embodiments fluorine and chlorine.

(C₁-C₃) Alkoxy (C)₂-C₃) Alkoxy means alkoxy having 2 to 3 carbons substituted at the 2 or 3 position with alkoxy having 1 to 3 carbons, illustratively 2-methoxyethoxy (CH)₃-O-CH₂CH₂-O-), 3-ethoxypropoxy (CH)₃CH₂-O-CH₂CH₂CH₂-O-), 2-methoxypropoxy (CH) ₃-O(CH₃)CHCH₂-O-), 2-isopropoxyethoxy (CH)₃(CH₃)CH-O-CH₂CH₂-O-), 2-methoxy-1-methylethoxy (CH)₃OCH₂(CH₃) CH-O-) or 3-propoxyethoxy (CH)₃CH₂CH₂-O-CH₂CH₂-O-)。

Optionally quilt (C)₁-C₃) Alkyl substituted (C)₃-C₆) Cycloalkylaminocarbonyl denotes aminocarbonyl (free amide) having one (independently selected) cycloalkyl substituent, which cycloalkyl group may optionally be substituted on the nitrogen atom by (C)₁-C₃) Alkyl substituted, and independently substituted by 1 or 2 (C) on any available carbon atom₁-C₃) Alkyl substitutions are exemplified by N-cyclopropylaminocarbonyl, N-cyclopropyl-N-methylaminocarbonyl, N- (2-methylcyclopropyl) aminocarbonyl, N-cyclobutylaminocarbonyl, N- (2, 2-dimethyl) cyclopropyl) aminocarbonyl, cyclopentylaminocarbonyl, N- (3-ethylcyclopentyl) aminocarbonyl, N-cyclohexylaminocarbonyl, N-cyclohexyl-N-ethylaminocarbonyl, N- (3-propylcyclohexyl) aminocarbonyl and N- (4, 4-dimethylcyclohexyl) aminocarbonyl.

The legend immediately following the bond indicates the point of attachment in the molecule.

Alternatively, the dotted line (- - - -) means that the bond is attached to the rest of the molecule via a group.

When such as (C)₁-C₄) When a generic prefix is used before a substituent, it means that the number of carbon atoms is varied, e.g. in (C)₁-C₄) In the case of (B) 1 to 4 carbon atoms.

When more than one substituent is selected from a group, the selections may be independent of each other. Unless the maximum number of substituents is indicated, substitution can occur up to the maximum number of possible substitution positions, e.g., for halo, up to the perhalogenated level.

In a further embodiment, the present invention provides a compound of formula (I),

wherein

R¹Selected from phenyl and monocyclic heteroaryl having 5 or 6 ring atoms,

wherein phenyl and heteroaryl may be optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from

·(C₁-C₄) Alkyl radical, wherein (C)₁-C₄) Alkyl groups may be substituted by 0, 1, 2 or 3 halogens, 0 or 1 pyrrolidinyl, 0 or 1 morpholinyl, or 0 or 1 (C)₁-C₃) Alkoxy is substituted, wherein

the presence of a halogen, in particular,

a trifluoromethyl group,

the presence of a trifluoromethoxy group,

·(C₃-C₆) A cycloalkyl group,

phenyl, said phenyl being optionally substituted by 1 or 2 halogens,

trifluoromethylthio;

R³is selected from

A carboxyl group,

the formyl radical,

·(C₁-C₆) Alkylcarbonyl group of (C)₁-C₆) Alkylcarbonyl is optionally substituted with 0, 1, 2 or 3 groups selected from: fluorine, chlorine, hydroxy, (C) ₁-C₆) Alkoxy and monocyclic heterocycles having 5 or 6 ring atoms,

·(C₃-C₆) A cycloalkyl-carbonyl group,

an amino-carbonyl group, or a carbonyl group,

·(C₁-C₆) Alkylaminocarbonyl radical, in which (C)₁-C₆) The alkylaminocarbonyl group may be optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of: (C)₃-C₆) Cycloalkyl, halogen, amino, (C)₁-C₆) Alkylamino, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) Alkylthio group, (C)₁-C₆) Alkoxycarbonylamino and methylsulfonyl, and wherein (C)₁-C₆) The alkylaminocarbonyl radical may optionally be substituted by 0 or 1 hydroxyl groupOr 0 or 1 monocyclic heterocyclyl having 5 or 6 ring atoms, wherein heterocyclyl may optionally be substituted by 0 or 1 (C)₁-C₆) Alkyl is substituted, and wherein (C)₁-C₆) The alkylaminocarbonyl radical may optionally be substituted by 0 or 1 phenyl, where phenyl may optionally be substituted by 0 or 1 halogen or (C)₁-C₆) The substitution of the alkyl group is carried out,

a monocyclic heterocyclylcarbonyl group having 5 or 6 ring atoms, optionally substituted by 0 or 1 amino, (C)₁-C₆) Alkylamino radical, (C)₃-C₆) Cycloalkyl or (C)₁-C₆) Alkyl is substituted, wherein (C)₁-C₆) Alkyl may optionally be substituted by 0 or 1 amino group or (C) ₁-C₆) The alkyl amino group is substituted by the alkyl amino group,

a) A hydroxyl group(s),

b) an amino group, a carboxyl group,

e) a monocyclic heterocyclic group having 5 or 6 ring atoms, wherein the heterocyclic group may be substituted by 0, 1 or 2 (C)₁-C₆) Alkyl is substituted, wherein (C)₁-C₆) Alkyl may be substituted with 0, 1 or 2 hydroxy, methoxy or pyridyl,

f) an imidazole group which is a group having a structure represented by,

h)(C₁-C₃) Alkoxy group of the formula (C)₁-C₃) Alkoxy is optionally substituted with up to a full-fluorine level by fluorine or by a monocyclic heterocycle having 5 or 6 ring atoms, wherein the heterocycle may optionally be substituted with 0 or 1: (a)C₁-C₆) The substitution of the alkyl group is carried out,

i)(C₁-C₃) Alkoxy (C)₂-C₃) Alkoxy, and

j)(C₁-C₆) An alkoxycarbonyl group, a carbonyl group,

k)(C₃-C₆) A cycloalkyl group,

l) a cyano group,

a cyano group, in the form of a cyano group,

a)(C₁-C₆) Alkyl radical, wherein (C)₁-C₆) Alkyl may be substituted with 0, 1, 2 or 3 halogens, 0 or 1 monocyclic heterocyclyl containing 5 or 6 ring atoms, 0 or 1 alkylamino, or 0 or 1 hydroxy or methoxy,

b) The halogen(s) are selected from the group consisting of,

e)(C₁-C₆) Alkoxycarbonyl, and

f)(C₃-C₆) A cycloalkyl group,

monocyclic heteroaryl carbonyl having 5 or 6 ring atoms,

a monocyclic heterocyclyl having 5 or 6 ring atoms, wherein heterocyclyl may be substituted by 0, 1, 2 or 3 independently selected from (C)₁-C₆) Alkyl and (C)₁-C₆) Substituted with a group of alkoxycarbonyl; and

R⁴selected from hydrogen and halogen;

or a pharmaceutically acceptable salt thereof.

wherein

R¹Selected from the group consisting of phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl and pyrimidinyl, wherein phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl and pyrimidinyl may be optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of

·(C₁-C₄) Alkyl radical, wherein (C)₁-C₄) Alkyl groups may be substituted with 0, 1, 2 or 3 halogens,

the presence of a halogen, in particular,

a trifluoromethyl group,

the presence of a trifluoromethoxy group,

the number of the cyclopropyl groups,

phenyl, optionally substituted by 1 or 2 halogens;

R²selected from hydrogen, fluorine and chlorine;

R³is selected from

·(C₁-C₆) Alkylcarbonyl group of (C)₁-C₆) Alkylcarbonyl is optionally substituted with 0, 1, 2 or 3 groups selected from: fluorine, chlorine, hydroxy, (C) ₁-C₆) Alkoxy, piperazinyl, morpholinyl, pyrrolidinyl, and piperidinyl,

a cyclopropyl carbonyl group, in which the carbonyl group is a carbonyl group,

an amino-carbonyl group, or a carbonyl group,

·(C₁-C₆) Alkylaminocarbonyl radical, whichIn (C)₁-C₆) The alkylaminocarbonyl group may be optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of: (C)₃-C₆) Cycloalkyl, halogen, amino, (C)₁-C₆) Alkylamino, hydroxy, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) Alkylthio group, (C)₁-C₆) Alkoxycarbonylamino and methylsulfonyl, and wherein (C)₁-C₆) Alkylaminocarbonyl may be optionally substituted with 0 or 1 hydroxy, piperazinyl, morpholinyl, pyrrolidinyl or piperidinyl, wherein piperazinyl, morpholinyl, pyrrolidinyl or piperidinyl may be optionally substituted with 0 or 1 (C)₁-C₆) Alkyl is substituted, and wherein (C)₁-C₆) The alkylaminocarbonyl radical may optionally be substituted by 0 or 1 phenyl, where phenyl may optionally be substituted by 0 or 1 halogen or (C)₁-C₆) The substitution of the alkyl group is carried out,

heterocyclylcarbonyl selected from piperazinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl or piperidinylcarbonyl, said groups optionally substituted by 0 or 1 amino, (C)₁-C₆) Alkylamino radical, (C)₃-C₆) Cycloalkyl or (C)₁-C₆) Alkyl is substituted, wherein (C)₁-C₆) Alkyl may optionally be substituted by 0 or 1 amino group or (C)₁-C₆) The alkyl amino group is substituted by the alkyl amino group,

a) A hydroxyl group(s),

c)(C₁-C₆) Alkylamino radical, in which (C)₁-C₆) The alkylamino group may be substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, alkylamino and methoxy,

e) piperazinyl, morpholinyl, pyrrolidinyl or piperidinyl, wherein piperazinyl, morpholinyl, pyrrolidinyl or piperidinylThe radicals may be substituted by 0, 1 or 2 (C)₁-C₆) Alkyl is substituted, wherein (C)₁-C₆) Alkyl may be substituted with 0, 1 or 2 hydroxy or methoxy groups,

f) an imidazole group which is a group having a structure represented by,

h)(C₁-C₃) Alkoxy group of the formula (C)₁-C₃) Alkoxy is optionally substituted with up to a full-fluorine level, or with a monocyclic heterocycle having 5 or 6 ring atoms, wherein the heterocycle may optionally be substituted with 0 or 1 (C)₁-C₆) The substitution of the alkyl group is carried out,

i)(C₁-C₃) Alkoxy (C)₂-C₃) Alkoxy, and

j)(C₁-C₆) An alkoxycarbonyl group, a carbonyl group,

k)(C₃-C₆) A cycloalkyl group,

l) a cyano group,

a cyano group, in the form of a cyano group,

pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, imidazolyl or pyrimidinyl, wherein the pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, imidazolyl or pyrimidinyl may be substituted with 0, 1, 2 or 3 groups independently selected from

a)(C₁-C₆) Alkyl radical, wherein (C)₁-C₆) Alkyl may be substituted with 0, 1, 2 or 3 halogens, 0 or 1 alkylamino, or 0 or 1 methoxy,

b) halogen, and

f)(C₃-C₆) A cycloalkyl group,

pyrazolyl carbonyl, oxazolyl carbonyl, isoxazolyl carbonyl, thiazolyl carbonyl, pyridinyl carbonyl or pyrimidinyl carbonyl; and is

R⁴Selected from hydrogen and fluorine;

or a pharmaceutically acceptable salt thereof.

wherein

R¹Selected from the group consisting of phenyl and monocyclic heteroaryl,

·(C₁-C₄) Alkyl radical, wherein (C)₁-C₄) Alkyl may be substituted by 0, 1, 2 or 3 halogens, 0 or 1 pyrrolidinyl or morpholinyl, or 0 or 1 (C)₁-C₃) Alkoxy is substituted, wherein

(C₁-C₃) Alkoxy may optionally be substituted by (C)₁-C₃) Substituted by alkylamino

the presence of a halogen, in particular,

a trifluoromethyl group,

the presence of a trifluoromethoxy group,

·(C₃-C₆) A cycloalkyl group,

·(C₁-C₃) Alkylthio radicals, and

a phenoxy group, wherein the phenoxy group may be optionally substituted with 0, 1 or 2 groups independently selected from: (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, trifluoromethoxy and halogen,

R²selected from hydrogen, halogen, (C) ₁-C₄) Alkyl and (C)₁-C₄) An alkoxy group;

R³is selected from

A carboxyl group,

·(C₁-C₆) Alkylcarbonyl group of (C)₁-C₆) Alkylcarbonyl is optionally substituted with 0, 1, 2 or 3 groups selected from: fluorine, chlorine, hydroxy, (C)₁-C₆) Alkoxy and a heterocyclic ring, and a pharmaceutically acceptable salt thereof,

·(C₃-C₆) A cycloalkyl-carbonyl group,

·(C₁-C₆) An alkoxycarbonyl group, a carbonyl group,

an amino-carbonyl group, or a carbonyl group,

·(C₁-C₆) Alkylaminocarbonyl radical, in which (C)₁-C₆) The alkylaminocarbonyl group may be optionally substituted with 0, 1, 2 or 3 groups independently selected from: (C)₃-C₆) Cycloalkyl, halogen, (C)₁-C₆) Alkylamino, hydroxy and (C)₁-C₆) Alkoxy, and wherein (C)₁-C₆) The alkylaminocarbonyl group may be optionally substituted with 0 or 1 heterocyclic group, wherein the heterocyclic group may be optionally substituted with 0 or 1 (C)₁-C₆) Alkyl is substituted, and wherein (C)₁-C₆) The alkylaminocarbonyl radical may optionally be substituted by 0 or 1 phenyl, where phenyl may optionally be substituted by 0 or 1 halogen, (C)₁-C₆) Alkyl or (C)₁-C₆) The substitution of alkoxy groups is carried out,

a heterocyclylcarbonyl group, optionally substituted by 0 or 1 amino group, (C)₁-C₆) Alkylamino, cycloalkyl or (C)₁-C₆) Alkyl is substituted, wherein (C)₁-C₆) Alkyl may optionally be substituted by 0 or 1 amino group or (C)₁-C₆) The alkyl amino group is substituted by the alkyl amino group,

·(C₁-C₆) Alkyl group of (C)₁-C₆) Alkyl is optionally substituted with 0, 1, 2 or 3 groups independently selected from

a) A hydroxyl group(s),

c)(C₁-C₆) Alkylamino radical, in which (C) ₁-C₆) The alkylamino group may be substituted with 0, 1, 2, 3 or 4 groups independently selected from: halogen, amino, alkylamino, methoxy, methylthio and methylsulfonyl,

f) an imidazole group which is a group having a structure represented by,

h)(C₁-C₃) Alkoxy group of the formula (C)₁-C₃) Alkoxy is optionally substituted with up to a full-fluorine level, or with a heterocycle, wherein the heterocycle may optionally be substituted with 0 or 1 (C)₁-C₆) The substitution of the alkyl group is carried out,

i)(C₁-C₃) Alkoxy (C)₂-C₃) Alkoxy, and

j)(C₁-C₆) An alkoxycarbonyl group, a carbonyl group,

k)(C₃-C₆) A cycloalkyl group,

a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein the heteroaryl group may be substituted with 0, 1, 2 or 3 groups independently selected from

g)(C₁-C₆) Alkyl radical, wherein (C)₁-C₆) The alkyl group may be substituted by0. 1, 2 or 3 halogen, 0 or 1 heterocyclyl, 0 or 1 alkylamino, or 0 or 1 hydroxy and methoxy,

h) the halogen(s) are selected from the group consisting of,

i) an amino group, a carboxyl group,

j) an alkylamino group,

k)(C₁-C₆) Alkoxycarbonyl, and

l)(C₃-C₆) A cycloalkyl group,

monocyclic heteroaryl carbonyl having 5 or 6 ring atoms,

A monocyclic heterocyclylcarbonyl group having 5 or 6 ring atoms,

wherein heterocyclyl may be selected from 0, 1, 2 or 3 independently₁-C₆) Alkyl and (C)₁-C₆) Substituted with a group of alkoxycarbonyl; and

R⁴is hydrogen or fluorine;

or a pharmaceutically acceptable salt thereof.

wherein

·(C₁-C₃) An alkoxy group,

the presence of a halogen, in particular,

trifluoromethyl, and

a phenoxy group, wherein the phenoxy group may be optionally substituted with 0, 1 or 2 groups independently selected from: alkyl, (C)₁-C₆) Alkoxy, trifluoromethoxy and halo;

R²is hydrogen, fluoro, chloro, methyl, ethyl or methoxy;

R³is selected from

·(C₁-C₆) An alkoxycarbonyl group, a carbonyl group,

·(C₁-C₆) Alkylaminocarbonyl radical, in which (C)₁-C₆) The alkylaminocarbonyl group may be optionally substituted with 0, 1, 2 or 3 groups independently selected from halogen, and

·(C₃-C₆) Cycloalkylaminocarbonyl group of ₃-C₆) Cycloalkylaminocarbonyl is optionally substituted by (C)₁-C₃) The substitution of the alkyl group is carried out,

piperazinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, or piperidinylcarbonyl; and is

R⁴Is hydrogen;

or a pharmaceutically acceptable salt thereof.

wherein

R¹Selected from phenyl, pyrazolyl, thiazolyl, pyridyl and pyrimidinyl,

wherein the phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl and pyrimidinyl may be optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of

Methyl, ethyl, propyl or butyl, where methyl, ethyl, propyl or butyl may be substituted by 0, 1, 2 or 3 fluorine or chlorine,

the presence of fluorine or chlorine, or of chlorine,

trifluoromethyl, and

a phenoxy group, wherein the phenoxy group may be optionally substituted with 0, 1 or 2 substituents independently selected from the group consisting of: methyl, ethyl, propyl or butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, fluoro and chloro;

R²is hydrogen;

R³is selected from

Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl,

·(C₁-C₄) Alkylaminocarbonyl radical, in which (C)₁-C₄) The alkylaminocarbonyl group may be optionally substituted with 0, 1, 2 or 3 fluoro, and

cyclopropylaminocarbonyl optionally substituted by methyl, ethyl or propyl,

Pyrrolidinylcarbonyl or piperidinyl carbonyl; and is

R⁴Is hydrogen;

or a pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention provides a compound of formula (Ic),

wherein

R¹Selected from the group consisting of aryl, benzyl and heteroaryl,

wherein aryl and heteroaryl may be optionally substituted with 1, 2, 3 or 4 substituents independently selected from

the presence of a halogen, in particular,

a trifluoromethyl group,

the presence of a trifluoromethoxy group,

·(C₃-C₆) A cycloalkyl group,

phenyl, said phenyl being optionally substituted by 1 or 2 halogens,

the nitro group(s) of the compound,

a cyano group, in the form of a cyano group,

·(C₁-C₃) An alkylthio group is a group of one or more,

a trifluoromethylthio group (CTS-S-),

·(C₁-C₃) An alkyl-carbonyl group, a carboxyl group,

·(C₁-C₆) Alkoxycarbonyl, and

phenoxy radical

And is

R²selected from hydrogen, halogen, alkyl and alkoxy;

R³is selected from

A carboxyl group,

the formyl radical,

·(C₁-C₆) Alkylcarbonyl optionally substituted with 1, 2 or 3 fluoro,

·(C₁-C₆) An alkoxycarbonyl group, a carbonyl group,

an amino-carbonyl group, or a carbonyl group,

·(C₁-C₆) Alkylaminocarbonyl radical, in which (C)₁-C₆) The alkylaminocarbonyl group may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: halogen, amino, alkylamino, methoxy and methylsulfonyl, and wherein (C)₁-C₆) The alkylaminocarbonyl group may be substituted with 0 or 1 hydroxyl group or 0 or 1 heterocyclic group,

a heterocyclic carbonyl group,

·(C₁-C₆) Alkyl group of (C)₁-C₆) The alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of

a) A hydroxyl group(s),

b) an amino group, a carboxyl group,

d) arylamino, whereinThe arylamino group may be substituted with 0, 1 or 2 substituents independently selected from the group consisting of: (C)₁-C₆) Alkyl, (C)₁-C₆) An alkoxy group and a trifluoromethyl group,

e) heterocyclyl, wherein heterocyclyl may be substituted by 0, 1 or 2 (C)₁-C₆) Alkyl is substituted, wherein (C)₁-C₆) Alkyl may be substituted with 0, 1 or 2 methoxy or pyridyl,

f) an imidazole group which is a group having a structure represented by,

g) a pyridylamino group,

h)(C₁-C₃) Alkoxy group of the formula (C) ₁-C₃) Alkoxy groups are optionally substituted with up to a perfluoro level with fluorine,

i)(C₁-C₃) Alkoxy (C)₂-C₃) Alkoxy, and

j)(C₁-C₆) An alkoxycarbonyl group, a carbonyl group,

·(C₁-C₆) Alkoxy group of the formula (C)₁-C₆) Alkoxy is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: amino group, (C)₁-C₆) Alkylamino and heterocyclyl, wherein the heterocyclyl may be substituted by 0, 1, 2 or 3 (C)₁-C₆) Alkyl substitution;

·(C₃-C₆) Cycloalkylaminocarbonyl optionally substituted by (C)₁-C₃) The substitution of the alkyl group is carried out,

cyano, and

m)(C₁-C₆) Alkyl radical, wherein (C)₁-C₆) Alkyl may be substituted with 0, 1, 2 or 3 halogens, 0 or 1 heterocyclyl, 0 or 1 alkylamino, or 0 or 1 methoxy,

n) a halogen, and (c) a halogen,

o) an amino group, and

p) alkylamino;

or a pharmaceutically acceptable salt thereof.

In further embodiments, the present invention provides compounds of formula (Ic):

wherein

R¹Selected from the group consisting of aryl and heteroaryl,

wherein aryl and heteroaryl may be substituted with 0, 1, 2, 3 or 4 substituents independently selected from

(C₁-C₄) An alkyl group, a carboxyl group,

(C₁-C₃) An alkoxy group,

the halogen(s) are selected from the group consisting of,

a trifluoromethyl group,

a trifluoro-methoxyl group,

(C₃-C₆) A cycloalkyl group,

phenyl, said phenyl being optionally substituted with 0, 1 or 2 halogens, and

wherein X is CH ₂O, S or NR^1-1(ii) a And wherein R^1-1Is hydrogen or (C)₁-C₆) An alkyl group;

R²selected from hydrogen, halogen, alkyl and alkoxy;

R³selected from carboxyl, (C)₁-C₆) Alkoxycarbonyl, aminocarbonyl, (C)₁-C₆) An alkylaminocarbonyl group and a heterocyclylcarbonyl group,

wherein (C)₁-C₆) The alkylaminocarbonyl group may be optionally substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of: halogen, amino, alkylamino, methoxy and methylsulfonyl, or R³Is (C)₁-C₆) Alkyl group of (C)₁-C₆) Alkyl is optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of: hydroxy, amino, (C)₁-C₆) Alkylamino, arylamino, heterocyclyl, pyridyl and pyridylamino,

wherein (C)₁-C₆) The alkylamino group may be optionally substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of: halogen, amino, alkylamino, methoxy, methylthio and methylsulfonyl, and wherein the heterocyclic radical may optionally be substituted by 0, 1 or 2 (C)₁-C₆) Alkyl is substituted, wherein (C)₁-C₆) Alkyl may be optionally substituted with 1 or 2 methoxy or pyridyl,

and wherein arylamino may be optionally substituted with 0, 1 or 2 substituents independently selected from: (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy and trifluoromethyl, or

R³Is (C)₁-C₆) Alkoxy group of the formula (C) ₁-C₆) Alkoxy is optionally substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of: amino group, (C)₁-C₆) Alkylamino and heterocyclyl, wherein heterocyclyl may optionally be substituted by 0, 1, 2 or 3 (C)₁-C₆) Alkyl substitution;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides compounds of formula (I)

Wherein

R¹Selected from phenyl and mono-or bicyclic heteroaryl containing 5, 6, 9 or 10 ring atoms and up to 2 heteroatoms selected from nitrogen, oxygen and sulfur,

wherein phenyl and heteroaryl may be substituted with 0, 1 or 2 substituents independently selected from: (C)₁-C₄) Alkyl radical, C₁-C₃) Alkoxy, halogen, trifluoromethyl, trifluoromethoxy, (C)₃-C₆) Cycloalkyl, phenyl optionally substituted by trifluoromethyl andwherein

X is CH₂O, S or NR^1-1；

Wherein R is^1-1Is hydrogen or (C)₁-C₆) An alkyl group;

R²selected from hydrogen, fluoro, chloro, methyl and methoxy;

R³selected from carboxyl, (C)₁-C₆) Alkoxycarbonyl, aminocarbonyl and (C)₁-C₆) Alkylaminocarbonyl radical, in which (C)₁-C₆) The alkylaminocarbonyl group may be optionally substituted with 0, 1 or 2 substituents independently selected from the group consisting of: halogen, amino, alkylamino, methoxy and methylsulfonyl, or R³Is substituted by amino, (C)₁-C₆) Alkylamino, pyridyl or 5-to 6-membered heterocyclyl substituted (C) ₁-C₆) Alkyl, said 5-or 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, wherein (C)₁-C₆) The alkylamino group may be optionally substituted with 0, 1 or 2 substituents independently selected from the group consisting of: halogen, amino, alkylamino, methoxy and methylsulfonyl, and wherein the heterocyclyl may optionally be substituted by 0, 1 or 2 (C)₁-C₆) Alkyl is substituted, wherein (C)₁-C₆) Alkyl may be optionally substituted with 0 or 1 methoxy or pyridyl, or

R³Is (C)₁-C₆) Alkoxy group of the formula (C)₁-C₆) Alkoxy is optionally substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of: amino group, (C)₁-C₆) Alkylamino and a 5-to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl may optionally be substituted with 0, 1, 2 or 3 (C)₁-C₆) Alkyl substitution;

or a pharmaceutically acceptable salt thereof.

wherein

R¹Is selected from

A phenyl group, optionally substituted with 1-2 groups selected from: halogen, (C)₁-C₄) Alkyl radical, OCF₃、CF₃And, andwherein X is CH₂O, S or NR^1-1Wherein R is^1-1Is hydrogen or (C)₁-C₆) An alkyl group, a carboxyl group,

pyridyl optionally substituted by CF₃The substitution is carried out by the following steps,

pyrazolyl, optionally substituted with 1-2 groups selected from:

(C₁-C₄) Alkyl, (C)₃-C₆) Cycloalkyl and phenyl, optionally substituted with CF₃The substitution is carried out by the following steps,

an isoxazolyl group optionally substituted by (C)₁-C₄) Alkyl substitution，

Pyrimidin-4-yl, said pyrimidin-4-yl being optionally (C)₁-C₃) The substitution of alkoxy groups is carried out,

indazolyl, optionally substituted on N (C)₁-C₄) Alkyl substitution;

R²is hydrogen;

R³is selected from

·CO₂R^3-1

·CONR^3-2R^3-3

·-(CH₂)_mNR^3-4R^3-5

·Wherein X is O or NH, or a salt thereof,

·wherein X is O or NH, or a salt thereof,

·

and

·

m is 1, 2 or 3;

n is 1, 2 or 3;

p is 1, 2 or 3;

q is 2 or 3;

r is 2 or 3;

s is 1, 2 or 3;

t is 0, 1 or 2;

u is 1, 2 or 3;

R^3-1is H or (C)₁-C₆) An alkyl group;

R^3-2and R^3-3Independently selected from H and (C)₁-C₆) An alkyl group;

R^3-4and R^3-5Independently selected from H and (C)₁-C₆) An alkyl group;

R^3-6is CF₃、(C₁-C₄) Alkoxy or (C)₁-C₄) An alkyl group;

or a pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention provides a compound of formula (Ia),

wherein

R³Is selected from

·Wherein X is O or NH, or a salt thereof,

·wherein X is O or NH, and

aminocarbonyl or (C)₁-C₆) An alkylaminocarbonyl group, said group being substituted as described above;

n is 1, 2 or 3;

R⁵independently selected from fluoro, chloro, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoromethoxy and morpholino; and is

v is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of formula (Ib)

Or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of formula (Ic), wherein R is¹To represent

In another embodiment, the present invention provides a compound of formula (Ic), wherein R is³Represents an ethoxycarbonyl group.

In another embodiment, the present invention provides a compound of formula (Ic), wherein R is³Is (C)₁-C₆) An alkyl amino carbonyl group,

wherein (C)₁-C₆) The alkylaminocarbonyl group may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, amino, alkylamino, methoxy and methylsulfonyl, and wherein arylamino may be optionally substituted with 1 or 2 methoxy or trifluoromethyl groups.

In further embodiments, the invention provides compounds as described in the working examples section of this application.

In a further embodiment, the invention relates to compounds which are metabolized or hydrolyzed under physiological conditions to compounds of formula (I). These compounds include, for example, ester and amide derivatives (which can be hydrolyzed to the corresponding acids, alcohols, and amines, respectively) and orthoester and aminal esters (which can be hydrolyzed to the corresponding acids, respectively), acetals, and hemiacetals (which can be hydrolyzed to the corresponding keto derivatives, such as the oxo group of the 4-oxopyrimidine ring moiety).

In a further embodiment, the present invention provides a process for the preparation of a compound of formula (I), wherein a compound of formula (II) is reacted

Wherein R is²、R³And R⁴Has the meaning as described above and which is,

with isocyanate compounds of the formula (III)

R¹-NCO(III)

Or with carbamates of the formula (VI)

R¹-NH-C (O) -OPh (VI),

wherein R is¹Have the meaning described above; or

Reacting a compound of formula (IV)

Wherein R is¹、R²、R³And R⁴Has the meaning as described above and which is,

with amines of the formula (V)

R¹-NH₂(V)，

Wherein R is¹Have the meaning indicated above.

The preparation of the compounds of the present invention can be illustrated by the following synthetic schemes. Unless otherwise specifically defined, such as R¹To R³The symbols of substituents of one class have the meanings indicated above.

Processes for the preparation of pyrrolotriazines are also disclosed in published US application 10/289,010 (publication No. US 2003-0186982A1), US patent 6,670,357(US application 10/036,293) and WO 2003/042172, WO2004/009542, WO2004/009601, WO 2004/009784 and WO 2004/013145, all of which are incorporated herein by reference in their entirety.

General methods for preparing Compounds of the invention

The compounds of formula (I) according to the invention can be suitably prepared from the corresponding amino compounds of formula (II) by the straightforward procedures as described in the reaction schemes below, or by methods well known to those skilled in the art. In these reaction schemes, R unless otherwise indicated ¹-R³、R^3-2、R^3-3、R^3-4、R⁴And r have the same meanings as described above.

Reaction scheme 1 describes a general procedure for the preparation of compounds of formula (I) from the corresponding amino compounds of formula (II) by standard methods of urea formation. In this reaction scheme, a compound of formula (II) is reacted with an isocyanate of formula (III) or more preferably a carbamate of formula (VI), typically in an inert solvent, to directly produce a compound of formula (I). Alternatively, the amine of formula (II) may be first treated with a chloroformate of formula (VII) in an inert solvent to provide a carbamate intermediate of formula (IV). The compound of formula (IV) is then reacted with an amine of formula (V) in an inert solvent to provide the compound of formula (I).

Reaction scheme 1

A more specific example of the process of reaction scheme 1 is described in reaction scheme 2 below. In this reaction scheme, an amine of the formula (II-1) [ formula (II), wherein R³Is CO₂Et]As starting material, it is reacted with an isocyanate (III), a carbamate (VI) or in two steps using in succession a compound of formula (VII) and subsequently a compound of formula (V) to yield a compound of formula (I-1) [ formula (I), wherein R³Is CO₂Et]. The compound of formula (I-1) can then be used as a starting material to prepare other compounds of formula (I) as shown, for example, in reaction scheme 3 below.

Reaction scheme 2

Reaction scheme 3 illustrates the reaction scheme from which R³Is CO₂Et to the compound of formula (I-1) wherein R³Are various substituents of the compounds of formula (I). For example, hydrolysis of (I-1) in an aqueous base or acid solution gives a carboxylic acid compound of the formula (I-2). Reacting the acid with a compound of formula (R)^3-2)(R^3-3) NH amine coupling to produce the amide of formula (I-3).

Reducing agent for the ester of formula (I-1)E.g., DIBAL reduction, the alcohol of formula (I-4) is obtained. The alcohol is oxidized by standard methods, such as Dess-Martin periodinane (periodinane), to produce the aldehyde of formula (I-5). The aldehyde is converted to the amine compound of formula (I-6) by a reductive amination procedure. In this procedure, the compound of formula R is reacted in the presence of acetic acid^3-4-NH₂The addition of a primary amine to the compound of formula (I-5) does not isolate the intermediate imine compound, but is selectively reduced with a reducing agent such as sodium triacetoxyborohydride to produce the amine of formula (I-6).

Reaction scheme 3

The alcohol of the formula (I-4) is further constructed in the following reaction scheme 4, and the aldehyde of the formula (I-5) is further constructed in the following reaction scheme 5.

In scheme 4, the alcohol is converted to the homologous aldehyde by standard methods, i.e., using tosyl chloride or mesyl chloride, respectively, and a base such as pyridine or Et ₃N to tosylate and mesylate to yield the intermediate of formula (I-7). (I-7) is reacted with a cyanide source, such as KCN or NaCN, in a polar solvent, such as DMF, to produce the nitrile of formula (I-8). Selective reduction using DIBAL followed by hydrolytic workup yields an aldehyde of formula (I-9). (ii) conversion of the aldehyde of formula (I-9) to the Compound of formula (I-10) [ (I) wherein R is³Is (R)^3-4)NHCH₂CH₂-]。

Reaction scheme 4

The aldehyde of formula (I-5) is used as a starting material to prepare additional compounds of formula (I) as shown in reaction scheme 5 below. (I-5) reacting with a phosphonate ester and a strong base such as LiH, Wadsworth-Emmons type to produce an unsaturated ester of formula (I-11); the ester is reduced to the saturated compound of formula (I-12) by hydrogenation in acetic acid using a platinum oxide catalyst. The ester is reduced to the alcohol of formula (I-13) and then oxidized to the compound of formula (I-14), which is the 2-carbon homologue of the aldehyde of formula (I-5). Reductive amination of (I-14) as described in reaction schemes 3 and 4 above, to produce a compound of formula (I-15) [ formula (I), wherein R³Is (R)^3-4)NHCH₂CH₂CH₂-]。

Reaction scheme 5

General procedure for the preparation of intermediates

The preparation of the key intermediate (II-1) used as the starting material in reaction scheme 2 as described above is shown in reaction scheme 6 below. The 4-nitrocinnamate of formula (VIII) is reacted with an isocyanide reagent of formula (IX) in the presence of a strong base such as Lithium Hexamethyldisilazide (LHMDS) in an aprotic solvent such as THF to produce the substituted pyrrole of formula (X). Subjecting (X) to Vilsmeier conditions (e.g. DMF, POCl) ₃) Formylating to produce a 2-formylpyrrole of formula (XI). Aldehyde (XI) is converted to a nitrile of formula (XII) by: with hydroxylamine hydrochloride to form an oxime intermediate, which is dehydrated in situ using a reagent such as acetic anhydride to produce a nitrile of formula (XII). Then using a strong base such as NaH and an amination reagent such as (Ph)₂P(O)-O-NH₂N-aminating the nitrile of formula (XII) to produce an N-aminonitrile of formula (XIII). Reacting (XIII) with formamide [ HC (O) NH₂]To produce a pyrrolotriazine intermediate of formula (XIV-1). In the final step, the nitro substituent on the phenyl ring is optionally further substituted in THF using a catalyst such as Raney nickelThus, intermediate (II-1) was produced. These same reduction conditions are used to convert the addition compounds of formula (XIV), prepared as shown in schemes 8-11 below, to the corresponding intermediates of formula (II).

Reaction scheme 6

The cinnamate esters of formula (VIII) are either commercially available or prepared as shown in reaction scheme 7. In this procedure, a substituted nitrotoluene of formula (XV) is oxidized using a reagent such as potassium permanganate to produce the corresponding acid of formula (XVI); the acid is reduced to the alcohol of formula (XVII) using a reducing agent such as borane and then oxidized to the aldehyde of formula (XVIII) using a reagent such as Dess-Martin periodinane (periodinane). Use (EtO) ₂P(O)CH₂CO₂Et and a strong base such as LiH, (XVIII) of the Wadsworth-Emmons type to produce a cinnamate ester of formula (VIII).

Reaction scheme 7

The following reaction scheme 8 shows the use of intermediate (XIV-1) for the preparation of intermediates of formula (II-2). Reacting the compound of formula (XIV-1) with an excess of methyl Grignard reagent to produce a tertiary alcohol of formula (XIX). Using hydrogen peroxide and Lewis acids such as BF₃This compound is subjected to oxidative rearrangement and hydrolysis to produce a hydroxy compound of formula (XX). (XX) is reacted with a substituted alcohol of formula (XXI) under Mitsunobu conditions such as DEAD, TPP to produce an intermediate of formula (XIV-2). As described for the preparation of formula (II-1) in reaction scheme 6, reduction of the nitro group in formula (XIV-2) produces an intermediate of formula (II-2) [ formula (II), wherein R³Is R' N (CH)₂)_rO-, and R "and R' are as described in reaction scheme 8]。

Compounds of formula (II-2) can be used to prepare compounds of formula (I) [ wherein R is³Is of the formula R' N (CH)₂)_rThe group of O-, and R 'and R' are as described in reaction scheme 8]。

Reaction scheme 8

Wherein R ', R' are independently selected from H and (C)₁-C₆) Alkyl, or

R 'and R' may be joined together to form a 5 or 6 membered heterocyclic ring containing the additional N, O or S atom, and may optionally be substituted with (C) ₁-C₆) Alkyl substitution

As shown in scheme 9 below, various other intermediates of formula (IV-3) - (XIV-7) are prepared using compounds of formula (XIV-1) prepared as shown in scheme 6. For example, the ester group in formula (XIV-1) is selectively reduced in THF using, for example, DIBAL, to produce the compound of formula (XIV-3). The alcohol (XIV-3) is oxidized to the aldehyde of formula (XIV-4) using standard conditions, for example, Dess-Martin periodinane (periodinane) in dichloromethane. The compound of formula (XIV-3) can also be converted to the corresponding chloride of formula (XIV-5) using, for example, thionyl chloride. The nitro group and chlorine in formula (XIV-5) are reduced using Ra-Ni to obtain an intermediate of formula (II-3). Reacting a compound of formula (XIV-5) with a compound of formula R^3-9-OH alcohol and a base such as sodium hydride to produce an ether of formula (XIV-6).

Reaction scheme 9

As shown in the following reaction scheme 9, the compound of formula (XIV-4) can also be used for preparing a nitrile of formula (XIV-7) by a two-step process: with hydroxylamine hydrochloride and pyridine, followed by dehydration of the intermediate oxime using acetic anhydride. The aldehyde of formula (XIV-4) can also be converted to an isoxazole intermediate of formula (XIV-8) by: with tosylmethyl isocyanide (TosMIC) in a protic solvent such as methanol in the presence of a base such as potassium carbonate.

Reaction scheme 10

As shown in scheme 11, intermediates of formula (XIV-1) can also be used to prepare other amides and heterocyclic compounds. (XIV-1) is hydrolyzed under standard conditions to the corresponding acid of formula (XIV-9) and then the formula R is used^3-11-1-NH₂Is directly converted into the amide of the formula (XIV-11), or is first converted into the acid chloride of the formula (XIV-10) and then reacted with the compound of the formula R^3-11-1-NH₂The amine of (2) is reacted. The acid chlorides of formula (XIV-10) are also used to prepare oxadiazole compounds of formulae (XIV-12) and (XIV-13) by the following method: 1) with hydrazine and trimethyl orthoformate to form oxadiazoles of the formula (XIV-12), 2) with hydrazine, formula R^3-11-2-CO₂Carboxylic acid of H and dehydrating agent such as POCl₃To produce a substituted oxadiazole of the formula (XIV-13).

Reaction scheme 11

The intermediates of formula (XIV-1) - (XIV-13) can then be reduced as desired to provide the corresponding amino compounds of formula (II) before obtaining the compounds of formula (I).

Reaction scheme 12

Wherein R ', R' are independently selected from H and (C)₁-C₆) Alkyl, or

R 'and R' may be joined together to form a 5 or 6 membered heterocyclic ring containing the additional N, O or S atom, and may optionally be substituted with (C)₁-C₆) Alkyl substitution

Reaction scheme 13

Wherein R ', R' are independently selected from substituted (C) ₁-C₆) Alkyl and (C)₃-C₆) Cycloalkyl radicals

It is also understood that the starting materials are commercially available or can be readily prepared by standard methods well known in the art. Such methods include, but are not limited to, the transformation methods set forth herein.

Unless otherwise indicated, the reaction is generally carried out in an inert organic solvent which does not change under the reaction conditions. These solvents include ethers, such as diethyl ether, 1, 4-dioxane or tetrahydrofuran, halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane or tetrachloroethane, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, alcohols, such as methanol, ethanol or isopropanol, nitromethane, dimethylformamide or acetonitrile. Mixtures of solvents may also be used.

The reaction is generally carried out at a temperature of from 0 ℃ to 150 ℃, preferably from 0 ℃ to 70 ℃. The reaction can be carried out at normal pressure, elevated pressure or reduced pressure (e.g. 0.5 to 5 bar). The reaction is usually carried out under atmospheric air or an inert gas (typically nitrogen).

Prodrugs of the invention may generally be prepared by conventional methods well known in the art. For example, a hydroxy group can be converted to an ester by reacting the compound with an acid chloride or anhydride under standard conditions. Hydroxy groups can be converted to carbonates by reacting the compounds with chloroformates under standard conditions.

Salts of the compounds identified herein may be obtained by isolating the compound as the hydrochloride salt by treating the free base with a solution of anhydrous HCl in a suitable solvent, such as THF. In general, the desired salts of the compounds of the present invention may be prepared in situ during the final isolation and purification of the compounds by methods well known in the art. Alternatively, the desired salt may be prepared by reacting the purified compound in its free base form with a suitable organic or inorganic acid, respectively, and isolating the salt thus formed. These methods are conventional and will be apparent to those skilled in the art.

In addition, sensitive or reactive groups on the compounds of the present invention may need to be protected and deprotected during any of the above methods. In general, protecting Groups can be added and removed by conventional methods known in the art (see, e.g., T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis; Wiley: New York, (1999).

If used as active compounds, the compounds of the invention are preferably isolated in substantially pure form, that is to say substantially free of residues from the synthesis. Purity can be determined by methods known to those skilled in chemistry or pharmacy (see, inter alia, Remington's pharmaceutical Sciences, 18) ^thed.1990, Mack Publishing Group, Enolo). Preferably, the compounds have a purity (w/w) of greater than 99%, if desiredIf desired, purities of greater than 95%, 90% or 85% may be employed.

The compounds of the invention exhibit an unexpected and useful spectrum of pharmacological and pharmacokinetic activity and can therefore be suitably used as medicaments for the treatment and/or prophylaxis of human and animal disorders.

Due to their antiproliferative properties, the compounds of the present invention may be used, alone or in combination with other active ingredients, for the treatment and/or prevention of hyperproliferative disorders in mammals. A hyperproliferative disorder-mediated indication refers to a disorder or condition whose development is at least in part via proliferation.

The invention also relates to methods of using the compounds or compositions described herein to treat or prevent hyperproliferative diseases in mammals, or to prepare medicaments for treating or preventing hyperproliferative disorders in mammals. The method comprises administering to a patient (or mammal), including a human being, in need thereof an amount of a compound of the present invention, a pharmaceutically acceptable salt or ester thereof, or a composition thereof effective to treat or prevent the disorder.

The invention also relates to methods of using the compounds of the invention as prophylactic or chemopreventive agents for the prevention of hyperproliferative disorders in mammals as described herein. The method comprises administering to a mammal, including a human, in need thereof an amount of a compound of the present invention, or a pharmaceutically acceptable salt or ester thereof, effective to delay or reduce the onset of the condition.

Hyperproliferative disorders include, but are not limited to, solid tumors, such as breast cancer, respiratory tract cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and their distant metastases. These conditions also include lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of respiratory tract cancers include, but are not limited to, small cell and non-small cell lung cancers, as well as bronchial adenomas and pleuropneumocytomas.

Examples of brain cancers include, but are not limited to, brainstem and hypothalamic (hypophtalmic) gliomas, cerebellar and cerebral astrocytomas, medulloblastomas, ependymomas, and neuroectodermal and pineal tumors.

Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer. Tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancers, as well as uterine sarcomas.

Tumors of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic duct, rectal, small intestine, and salivary gland cancers.

Urinary tract cancers include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, and urinary tract cancers.

Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

Liver cancers include, but are not limited to, hepatocellular carcinoma (with or without fibrolamellar variants), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to, squamous cell carcinoma, kaposi's sarcoma, malignant melanoma, merkel cell skin cancer, and non-malignant skin cancer.

Head and neck cancers include, but are not limited to, laryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and lip and oral cancer.

Lymphomas include, but are not limited to, aids-related lymphoma, non-hodgkin's lymphoma, cutaneous T-cell lymphoma, hodgkin's disease, and central nervous system lymphoma.

Sarcomas include, but are not limited to, soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lymphosarcomas, and rhabdomyosarcomas.

Leukemias include, but are not limited to, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

These conditions are typical in humans and are also present with similar etiologies in other mammals, which may also be treated by administration of the compounds and/or pharmaceutical compositions of the present invention.

The assay described herein is a method by which the activity of a compound relevant to the treatment of a condition identified herein can be determined.

In another embodiment, the present invention provides a medicament containing at least one compound of the present invention. In a further embodiment, the present invention provides a medicament containing at least one compound of the invention and one or more pharmaceutically acceptable (pharmacologically acceptable and pharmaceutically safe) excipients or carrier substances, such as hydroxypropylcellulose, and its use as such.

The active ingredient may act systemically and/or locally. For this purpose, the active ingredient may be administered in a suitable manner, for example orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, transdermally, conjunctivally, otically or via an implant.

For these routes of use, the active compounds can be administered in a suitable form of use. A summary of the forms of use is disclosed in Remington's Pharmaceutical Sciences, 18^thed.1990，Mack Publishing Group，Enolo。

Useful oral administration forms includeThe active ingredients are released rapidly in the form of use and/or in modified form, for example in the form of tablets (uncoated tablets and coated tablets, for example enteric coatings), capsules, sugar-coated tablets, granules, pills, powders, emulsions, suspensions, liquids and aerosols. Such sustained release pharmaceutical compositions are described in Part 8, Chapter 91of Remington's pharmaceutical Sciences, 18^th ed.1990，Mack Publishing Group，Enolo。

Parenteral use can be carried out by avoiding absorption steps (intravenous, intra-arterial, intracardiac, intraspinal or intralumbar) or by means involving absorption (intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal). Useful forms for parenteral use include injection and infusion solutions, suspensions, emulsions, lyophilisates and preparations in the form of sterile powders. Such parenteral Pharmaceutical compositions are described in Part 8, Chapter84of Remington's Pharmaceutical Sciences, 18^th ed.1990，MackPublishing Group，Enolo。

In one embodiment, the invention relates to the intravenous (i.v.) use of the active compounds, for example by bolus injection (i.e. as a single dose, e.g. per syringe), short-term infusion (e.g. up to one hour) or long-term infusion (e.g. over one hour). Use may also be by intermittent administration. The amount used may vary depending on the situation, and is usually 0,5-30 or 1-20ml for bolus injection, 25-500 or 50-250ml for short time infusion, and 50-1000 or 100-500ml for long time infusion.

The form of use must be sterile or pyrogen free. The use form can be based on an aqueous solvent or a mixture of an aqueous solvent and an organic solvent. Examples are ethanol, polyethylene glycol (PEG)300 or 400, with cyclodextrins or emulsifiers such as lecithin, PluronicSolutolOrAn aqueous solution of (a). Aqueous solutions are preferred.

For intravenous use, the solution is typically isotonic and euhydrac, e.g., having a pH of 3-11, 6-8, or about 7.4.

Glass or plastic containers may be used as packaging for the i.v. solution, such as rubber-sealed vials. They may contain a liquid volume of 1-1000 or 5-50 ml. The solution can be drawn directly from the vial for use in a patient. For this purpose, it may be advantageous to provide the active compound in solid form (e.g. as a lyophilisate) and to dissolve the active compound by adding a solvent to the vial immediately prior to administration.

Solutions for infusion may conveniently be packaged in containers made of glass or plastic, such as bottles or collapsible containers like bags. They may contain a liquid volume of 1-1000 or 50-500 ml.

Forms suitable for other routes of use include, for example, inhalation pharmaceutical forms (including powder inhalers, nebulizers), nasal drops/solutions, sprays; tablets or capsules for lingual, sublingual or buccal administration, suppositories, otic and ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixes), lipophilic suspensions, ointments, creams, emulsions, pastes, dusting powders or implants.

The active ingredients can be converted into the cited forms of use in a manner known per se. This is done using inert, non-toxic pharmaceutically acceptable excipients. These include in particular carriers (for example microcrystalline cellulose), solvents (for example liquid polyethylene glycol), emulsifiers (for example sodium lauryl sulfate), dispersants (for example polyvinylpyrrolidone), synthetic or natural biopolymers (for example albumin), stabilizers (for example antioxidants such as ascorbic acid), colorants (for example inorganic pigments such as iron oxide) or taste and/or odour flavours.

For human use, in the case of oral administration, a dosage of 0.001-100mg/kg or 0.01-20mg/kg is recommended. In the case of parenteral administration, for example intravenous or nasal, buccal or inhalational administration via the mucosa, a dosage of 0.001 to 0.60mg/kg, in particular 0.01 to 30mg/kg, is recommended.

Nevertheless, it may be necessary in some cases to vary the amounts indicated above, i.e. as a function of the body weight, the route of use, the individual's performance of the active ingredient, the manner of preparation and the time between uses. For example, in some cases it may be sufficient to use a minimum amount below that stated, while in other cases it may be necessary to exceed the stated upper limit. In case larger amounts are used, it is appropriate to divide them into several daily single doses.

The percentages in the following tests and examples, unless otherwise indicated, are by weight; parts are by weight. The solvent ratios, dilution ratios and concentrations reported for the liquid/liquid solutions are on a volume basis, respectively.

A. Examples of the embodiments

General preparation method

Unless otherwise indicated, the term "concentration under reduced pressure" means the use of a Buchi rotary evaporator at about 15mm Hg.

Thin Layer Chromatography (TLC) is carried out inPre-coated glass-based silica gel 60 AF-254250 μm plates, the visualization of which is performed by one or more of the following techniques: (a) ultraviolet irradiation, (b) exposure to iodine vapor, (c) immersing the plate in a solution of 10% phosphomolybdic acid in ethanol, followed by heating, and/or (d) immersing the plate in a solution of cerium sulfate, followed by heating. The column chromatography (flash chromatography) is implemented by using 230-400 mesh EMSilica gel.

"shaker block" refers to the use of a BTS3000 shaker from J-Kem Scientific at 150- "180" speed.

Proton (1H) Nuclear Magnetic Resonance (NMR) spectra were measured using a Varian 400Mercury Plus (400MHz) spectrometer using Me₄Si (. delta.0.00) or residual protonated solvent (CHCl)₃δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard. Carbon (C) ¹³C) NMR spectra were determined using a Varian 400Mercury Plus (400MHz) (100MHz) spectrometer using solvent (CDCl)₃δ77.0；d₃-MeOD；δ49.0；d₆-DMSO δ 39.5) as standard.

HPLC-electrospray mass spectrometry (HPLC ES-MS) for identification was obtained with a Gilson HPLC system equipped with a variable wavelength detector set at 254nm, a YMC pro C-18 column (2X 23mm, 120A) and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120 to 1200amu using variable ion times depending on the number of ions in the source. The eluent is A: 2% acetonitrile in water containing 0.02% TFA, and B: 2% aqueous acetonitrile containing 0.018% TFA. Gradient elution was performed from 10% B to 95% B over 3.5 minutes at a flow rate of 1.0 mL/min, with an initial hold of 0.5 minutes and a final hold of 0.5 minutes at 95% B. The total run time was 6.5 minutes.

Preparative High Performance Liquid Chromatography (HPLC) was performed on a Gilson 215Liquid Handler equipped with a Gilson 322 pump and a Gilson UV-VIS-155 detector set at 254nM or a Shimadzu LC-8A pump with a Shimadzu SPD-10A detector set at 220nM, both equipped with a YMC Pac Pr0C18 column (150X 20mm), as required. Eluent a was acetonitrile containing 0.01% trifluoroacetic acid and eluent B was water containing 0.01% trifluoroacetic acid. Typically, a gradient from 10% A/90% B to 90% A/10% B is run over 15-25 minutes. The desired fractions were collected and the solvent was removed in vacuo to afford the final compound as the trifluoroacetate salt.

HPLC using a chiral column can be used to separate the enantiomers. Analytical conditions Chiralcel was used on Shimadzu HPLC(4.6X 150mm) column. 30% eluent A ═ hexane (0.1% Et)₃N) and 70% eluent B ═ 1: 1MeOH-EtOH (0.1% Et)₃N), 15 min, flow rate 1.0 mL/min, detection by UV at 235 nm. Preparation conditions Chiralcel was used on a Gilson215HPLC(20X 150mm) column. 30% eluent A ═ hexane (0.1% Et)₃N) and 70% eluent B ═ 1: 1MeOH-EtOH (0.1% Et)₃N), 15 minutes, flow rate of 1.0 mL/min, detection by UV at 235nm, using about 75mg of material per injection.

RPMI growth medium was obtained from

The IUPAC nomenclature was generated using ACD/Name Version 7.0 from Advanced Chemistry Development (U.S.A.).

Abbreviations and acronyms combinations

¹H-NMR proton nuclear magnetic resonance spectrum

³¹P-NMR phosphorus-31 nuclear magnetic resonance spectrum

AcOH acetic acid

(Ac)₂O acetic anhydride

abs anhydrous

aq water content

ap is about

atm atmospheric pressure

br width

BOP benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate

Bu butyl

ACN acetonitrile

Ac₂O acetic anhydride

AcOH acetic acid

Diatomaceous earth trademark from Celite corp

CD₃CN acetonitrile-d₃

CD₃OD methanol-d₄

d double peak

DCE Dichloroethane

DCM dichloromethane

dd double doublet

DIBAL diisobutylaluminum hydride

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

DMSO-d₆Dimethyl sulfoxide-d₆

equiv equivalent(s)

ES-MS electrospray mass spectrometry

Et₃N-Triethylamine

Et₂O Ether

EtOAc ethyl acetate

EtOH ethanol

FBS fetal bovine serum

g

h hours

HPLC high performance liquid chromatography

Hz

J NMR coupling constant

L liter

LCMS liquid chromatography-mass spectrometry

LHMDS hexamethyldisilazane-based aminolithium salt

M molarity

Me methyl group

MeOH methanol

mg of

MHz

min for

mL of

mmol millimole

MPLC Medium pressure liquid chromatography

MS Mass Spectrometry

Ms methanesulfonyl

N equivalent (standard)

nM nanomolar

Pr propyl group

Benzotriazol-1-yl-oxytripyrrolidinophosphonium py-BOP hexafluorophosphate

q quartet peak

Raney nickel of Ra-Ni

R_fTLC retention factor

Rochelle's salt potassium sodium tartrate

RPMI Roswell Park Memorial Institute

Retention time of RT

rt Room temperature

s single peak

t triplet peak

TEA Triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TosMIC tosylmethyl isocyanide

TPP triphenylphosphine

Ts p-toluenesulfonyl group

v/v volume/volume ratio

v/v/v volume/volume ratio

Microliter of μ L

Micron diameter of

Preparation of intermediates

An intermediate A: preparation of 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid ethyl ester

Step 1: preparation of 4- (4-Nitrophenyl) -1H-pyrrole-3-carboxylic acid ethyl ester

To a solution of 1M lithium hexamethyldisilazide in THF (102.4mL, 102.4mmol) cooled to-77 deg.C was added dropwise 1- [ (isocyanomethyl) sulfonyl group over 30 minutes]-a solution of 4-toluene (20.0g, 102.4mmol) in THF (100 mL). The solution was stirred for an additional 15 minutes, then a solution of ethyl (2E) -3- (4-nitrophenyl) acrylate (22.66g, 102.4mmol) in THF (250mL) was added dropwise over 1 hour. The reaction was allowed to warm to room temperature over 17 hours. Saturated NaHCO₃Aqueous solution (200mL) was added to the reaction mixture, followed by EtOAc (500 mL). The solution was transferred to a separatory funnel, the organic layer was separated and washed with H₂O (100mL) wash. The aqueous layer was back-extracted with EtOAc (2X 150 mL). The combined organic layers were collected and dried (MgSO)₄) Concentrated onto silica gel and purified by column chromatography (100% CH)₂Cl₂To 95: 5v/v CH₂Cl₂-EtOAc) to yield 16.65g of the above compound as an orange/yellow solid (63.98mmol, 62% yield).

¹H-NMR(DMSO-d₆) δ 11.78(brs, 1H), 8.19to 8.15(m, 2H), 7.76 to 7.73(m, 2H), 7.57 to 7.56(m, 1H), 7.22 to 7.21(m, 1H), 4.18 to 4.13(q, J ═ 7.1Hz, 2H), 1.21(t, J ═ 7.1Hz, 3H);

LCMS RT＝2.90min；TLC R_f＝0.47(95∶5v/v CH₂Cl₂-EtOAc).

step 2: preparation of 5-formyl-4- (nitrophenyl) -1H-pyrrole-3-carboxylic acid ethyl ester

To a solution of DCE (100mL) was added DMF cooled in an ice-salt bath (14.96mL, 194.4 mmol). After slow addition of POCl₃A white precipitate formed (18.12mL, 194.4 mmol). The solution was warmed to room temperature while stirring vigorously for 30 minutes. The slurry was re-cooled in an ice-salt bath. A suspension of 4- (4-nitrophenyl) -1H-pyrrole-3-carboxylic acid ethyl ester (46.00g, 176.8mmol) in DCE (500mL) was added. The reaction was allowed to proceed for 1 hour while cooling in an ice-salt bath and then warmed to room temperature over 17 hours. A mixture of sodium acetate (79.75g, 972.2mmol) in water (600mL) was added to the reaction and the solution was heated at 80 ℃ for 1 hour. Cooling to room temperature, transferring the solution to a separating funnel, separating the organic layer while using CH₂Cl₂The aqueous layer was back-extracted (2X 150 mL). The combined organic layers were collected and dried (MgSO)₄) Filtered and concentrated to dryness. The crude product was heated to reflux in toluene (2L) and hexane (200mL) was added to the hot solution. The solution was allowed to cool slowly and crystals formed over the next 2 days. Collecting the crystals and using Et ₂O (500mL) and dried in vacuo to afford 25.53g of the above compound as golden needles (88.57mmol, 50% yield).

¹H-NMR(DMSO-d₆)δ12.94(br s，1H)，9.29(d，J＝0.8Hz，1H)，8.25to 8.22(m，2H)，7.81(d，J ═ 2.7Hz, 1H), 7.74 to 7.71(m, 2H), 4.12 to 4.06(q, J ═ 7.1Hz, 2H), 1.15 to 1.11(t, J ═ 7.0Hz, 3H); LCMS RT 2.75 min; TLC R_f＝0.16(95∶5v/v CH₂Cl₂-EtOAc).

And step 3: preparation of 5-cyano-4- (nitrophenyl) -1H-pyrrole-3-carboxylic acid ethyl ester

To a solution of pyridine (400mL) was added 5-formyl-4- (nitrophenyl) -1H-pyrrole-3-carboxylic acid ethyl ester (24.55g, 85.17mmol), followed by hydroxylamine hydrochloride (6.51g, 93.7 mmol). The solution was stirred at room temperature for 2h, acetic anhydride (17.68mL, 187.4mmol) was added, and the solution was heated to 80 ℃ for 17 h. Cooled to room temperature, the reaction mixture was partially concentrated in vacuo, then diluted with EtOAc (300mL) and H₂Dilution with O (300 mL). The solution was transferred to a separatory funnel and the organic layer was separated while the aqueous layer was back-extracted with EtOAc (2X 100 mL). The combined organic layers were collected and dried (Na)₂SO₄) Filtered and concentrated to dryness. Then the crude product is treated with CH₂Cl₂-Et₂O (1: 1v/v, 300 mL). The solid was collected and used for Et₂O (150mL) and dried in vacuo to afford 18.94g of the above compound as a fluffy white solid (66.40mmol, 78% yield).

¹H-NMR(DMSO-d₆) δ 13.24(br s, 1H), 8.30 to 8.27(m, 2H), 7.92(s, 1H), 7.74 to 7.71(m, 2H), 4.16 to 4.10(q, J ═ 7.2Hz, 2H), 1.18 to 1.15(t, J ═ 7.0Hz, 3H); LCMS RT 2.97 min; TLC R_f＝0.20(95∶5v/v CH₂Cl₂-EtOAc).

And 4, step 4: preparation of (aminooxy) (diphenyl) phosphine oxides

To a solution of hydroxylamine hydrochloride (15.86g, 228.2mmol) in H cooled in an ice salt bath₂To the mixture in O (35mL) was added 7.1N NaOH (27.4mL, 194.4mmol), followed by 1, 4-dioxane (100 mL). The solution was stirred vigorously for 15 minutes, then a solution of chlorodiphenylphosphine oxide (20.00g, 84.52mmol) in 1, 4-dioxane (100mL) was added. The solution was stirred for a further 15 minutes, a white precipitate formed and was filtered. The solid was suspended in 0.25N NaOH (250mL) while stirring in a ice-salt bath for 1 hour. Then collecting the solid with H₂O (100mL) was washed and dried thoroughly in vacuo to give 7.09g of the above compound as a white powder (30.4mmol, 36% yield).

¹H-NMR(DMSO-d₆) δ 7.72 to 7.67(m, 4H), 7.50 to 7.40(m, 6H);³¹P-NMR(DMSO-d₆)δ23.11(br s，1P).

and 5: preparation of l-amino-5-cyano-4- (nitrophenyl) -1H-pyrrole-3-carboxylic acid ethyl ester

To a solution of DMF (625mL) was added 5-cyano-4- (nitrophenyl) -1H-pyrrole-3-carboxylic acid ethyl ester (17.97g, 63.00mmol), followed by a 60% dispersion of NaH in mineral oil (3.02g, 75.59 mmol). The solution was stirred at room temperature for 15 minutes, then (aminooxy) (diphenyl) phosphine oxide (17.63g, 75.59mmol) was added and the solution was heated to 80 ℃ for 17 hours. Cooled to room temperature and saturated NaHCO was added ₃Aqueous (500mL), followed by addition of EtOAc (400 mL). The solution was transferred to a separatory funnel and the organic layer was separated while the aqueous layer was back-extracted with EtOAc (2X 200 mL). The combined organic layers were collected and dried (Na)₂SO₄) Filtered and concentrated to dryness. Then the crude product is treated with CH₂Cl₂Trituration with hexane (1: 1v/v 400 mL). CollectingThe solid was washed with hexanes (100mL), dried under vacuum, suspended in EtOAc, and heated to reflux for 15 min before filtration. The filtrate was concentrated in vacuo and then dried in vacuo to give 14.15g of the above compound as a yellow powder (47.12mmol, 75% yield).

¹H-NMR(DMSO-d₆) δ 8.29 to 8.27(m, 2H), 7.73(s, 1H), 7.71 to 7.69(m, 2H), 6.71(br s, 2H), 4.14 to 4.09(q, J ═ 7.1Hz, 2H), 1.17 to 1.14(t, J ═ 7.1Hz, 3H); LCMS RT 2.91 min; TLCR_f＝0.30(95∶5v/vCH₂Cl₂-EtOAc).

Step 6: preparation of the title Compound

To a solution of formamide (74.9mL, 1.88mol) was added ethyl 1-amino-5-cyano-4- (nitrophenyl) -1H-pyrrole-3-carboxylate (14.15g, 47.12 mmol). The solution was heated to 195 ℃ for 2 hours and then cooled to room temperature over 17 hours. The crystalline solid was collected with EtOAc (2X 100mL) followed by H₂O (100mL) wash. The solid was dried under vacuum to obtain 10.20g of the above compound as a bronze colored crystalline solid (31.16mmol, 66% yield).

¹H-NMR(DMSO-d₆) δ 8.27 to 8.25(m, 2H), 8.20(s, 1H), 8.05(br s, 1H), 7.97(s, 1H), 7.66 to 7.64(m, 2H), 5.52(br s, 1H), 4.10 to 4.05(q, J ═ 7.1Hz, 2H), 1.11 to 1.07(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝328；LCMS RT＝2.51min；TLCR_f＝0.20(3∶1v/v CH₂Cl₂-EtOAc).

An intermediate B: preparation of 4-amino-5- (4-aminophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid ethyl ester

Raney nickel was added to a flask containing 20mL of anhydrous EtOH. Using anhydrous EtOH (3 as a template) as a catalyst20 mL). The 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f][1，2，4]A suspension of triazine-6-carboxylic acid ethyl ester (4.0g, 12.2mmol) in anhydrous EtOH (600mL)/THF (200mL) was added to the flask containing the catalyst. The flask was evacuated and refilled with hydrogen (3 ×), and then the reaction was placed under a hydrogen atmosphere (1atm) and stirred at room temperature overnight. The reaction is carried out byThe pad was filtered and washed with copious amounts of EtOH/THF (3: 1) to give 3.60g of the above compound as a brown solid (96% yield).

¹H-NMR(DMSO-d₆)δ8.05(s，1H)，8.04(brs，2H)，7.88(s，1H)，7.01(d，J＝8.0Hz，2H)，6.61(d，J＝8.0Hz，2H)，5.31(br s，2H)，4.07(q，J＝7.4Hz，2H)，1.12(t，J＝7.2Hz，3H)；MS[M+H]⁺＝298；LCMS RT＝1.64min；TLCR_f0.30 (acetone/CH)₂Cl₂ 1∶3).

An intermediate C: preparation of ethyl 4-amino-5- {4- [ (phenoxycarbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

To a stirred solution of intermediate B (1.0g, 3.4mmol) in THF (33mL) at-40 deg.C was added pyridine (0.33mL, 4.0mmol) followed by phenyl chloroformate (0.42mL, 3.4 mmol). Some solids precipitated out. The mixture was stirred at room temperature for 2 hours. Phenyl chloroformate (0.02mL, 0.10mmol) was then added and the mixture was stirred at room temperature for an additional half an hour. The reaction was filtered and washed with water (3X 5mL) and EtOAc-hexane (9: 1v/v) (3X 5mL) to give the above compound as a pale yellow solid (600mg, 43%). The filtrate was concentrated in vacuo and further purified by column chromatography (30: 70: 1-80: 20: 1v/v/v EtOAc-hexane-NH) ₄OH), more of the title compound was obtained(570mg，40％)。

¹H-NMR(DMSO-d₆) δ 10.42(s, 1H), 8.13(s, 1H), 8.06(br s, 1H), 7.93(s, 1H), 7.58(d, J ═ 8.4Hz, 2H), 7.46 to 7.39(m, 2H), 7.35(d, J ═ 8.5Hz, 2H), 7.29 to 7.21(m, 3H), 5.07(br s, 1H), 4.06(q, J ═ 7.2Hz, 2H), 1.08(t, J ═ 7.2Hz, 3H); MS [ M + H ]]⁺＝418；LCMS RT＝2.81min.

An intermediate D: preparation of ethyl 4-amino-5- (4- { [ (4-nitrophenoxy) carbonyl ] amino } phenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of intermediate C was used to prepare the title compound by substituting phenyl 4-nitrochloroformate for phenyl chloroformate.

¹H-NMR(DMSO-d₆)δ10.66(s，1H)，8.32(d，J＝9.3Hz，2H)，8.16(s，1H)，7.95(s，1H)，7.61(d，J＝8.8Hz，2H)，7.56(d，J＝8.9Hz，2H)，7.38(d，J＝8.9Hz，2H)，4.07(q，J＝7.2Hz，2H)，1.09(t，J＝7.2Hz，3H)；MS[M+H]⁺＝463；LCMS RT＝3.29min.

Intermediate E: preparation of ethyl 4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

To a suspension of intermediate C (210mg, 0.45mmol) in THF: DMF 4: 1(8mL) was added Et₃N (0.20mL, 1.4mmol) and 2-fluoro-5- (trifluoromethyl) aniline (0.18mL, 1.36 mmol). The mixture was stirred at room temperature untilUntil the reaction was complete, at which time the reaction was evaporated to dryness and purified by HPLC (10-90% ACN/H)₂O), the product was obtained as a yellow solid (80mg, 35%).

¹H-NMR(DMSO-d₆)δ9.33(s，1H)，8.97(d，J＝4.0Hz，1H)，8.62(d，J＝12.0Hz，1H)，8.12(s，1H)，8.11(br s，1H)，7.92(s，1H)，7.6-7.3(m，5H)，4.10(q，J＝8.0Hz，2H)，1.11(t，J＝8.0Hz，3H)；MS[M+H]⁺＝503；LCMS RT＝3.50min；TLCR_f＝0.40(3∶1v/vCH₂Cl₂-acetone).

An intermediate F: preparation of N- [4- (4-amino-6-formylpyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Step 1: preparation of N- {4- [ 4-amino-6- (hydroxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

To a solution of THF (8.0mL) was added intermediate E (80.0mg, 0.16mmol), followed by DIBAL (0.8mL, 0.8mmol, 1.0M in THF). The reaction was stirred at rt while DIBAL (2.4mL, 2.4mmol, 1.0M in THF) was added in three portions until the reaction was complete as indicated by HPLC. The reaction was diluted with EtOAc and quenched with saturated rochelle brine solution. The reaction was extracted with EtOAc (4 ×). The organic layer was dried (Na)₂SO₄) And evaporated to give a crude oil which was purified by HPLC (10-90% ACN/H)₂O) to yield a yellow solid (40.0mg, 55%).

¹H-NMR(CD₃CN)δ8.61(d，J＝8.0Hz，1H)，7.80(s，1H)，7.66-7.60(m，3H)，7.42-7.32(m，4H)，4.50(s，2H)；MS[M+H]⁺＝461；LCMS RT＝2.87min.

Step 2: preparation of the title Compound

Mixing N- {4- [ 4-amino-6- (hydroxymethyl) pyrrolo [2, 1-f)][1，2，4]Triazin-5-yl]Phenyl) -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl]Urea (40.0mg, 0.09mmol) was dissolved in THF (5.0mL) and Dess-Martin periodinane reagent (44.0mg, 0.10mmol) was added thereto. The reaction was stirred at room temperature until HPLC indicated completion of the reaction. The reaction was diluted with EtOAc and saturated NaHCO₃/Na₂S₂O₃1: 1 (3X) aqueous solution. The aqueous layer was back-extracted with EtOAc (2X). The organic layer was dried (Na) ₂SO₄) And evaporated to give a crude oil which was purified by HPLC (10-90% ACN/H)₂O) to yield a yellow solid (35.0mg, 88%).

¹H-NMR(CD₃OD)δ9.76(s，1H)，8.61(d，J＝8.0Hz，1H)，8.11(s，1H)，7.87(s，1H)，7.65(d，J＝8.0Hz，1H)，7.46(d，J＝8.0Hz，1H)，7.30(d，J＝8.0Hz，1H)；MS[M+H]⁺＝459；LCMS RT＝2.95min.

Intermediate G: preparation of 4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid

To a solution of intermediate E (720.0mg, 1.433mmoL) in 5mL MeOH and 3mL THF was added 1M NaOH (3.58mL, 3.58mmoL) and the reaction was stirred at 60 ℃ for 12 hours. The reaction mixture was cooled and placed in CHCl₃And pH 2 sulfate buffer. The organic layer was washed with brineWashing and drying (Na)₂SO₄) And concentrated to give a brown solid (623mg, 92% yield).

¹H-NMR(DMSO-d₆)δ12.17(bs，1H)，9.34(s，1H)，8.98(d，J＝2Hz，1H)，8.62(dd，J＝2Hz，8Hz，1H)，8.07(3，1H)，8.0(bs，1H)，7.91(s，1H)，7.53(d，J＝8Hz，2H)，7.55-7.45(m，1H)，7.42-7.35(m，1H)，7.32(d，J＝8Hz，2H)，5.0(bs，1H)；MS[M+H]⁺＝475.2；LCMSRT＝2.56min，TLCR_f＝0.26(1∶1∶0.02v/v/v THF∶CH₂Cl₂∶MeOH).

Intermediate H: preparation of ethyl 3- [ 4-amino-5- (4-aminophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl ] propionate

Step 1: preparation of [ 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl ] methanol

To a solution of THF (10mL) was added intermediate A (500mg, 1.53mmol), followed by DIBAL (3mL, 3mmol, 1.0M in toluene). The reaction was stirred at room temperature for 1 hour. Additional DIBAL (1.5mL, 1.5mmol, 1.0M in toluene) was added and stirred at room temperature for an additional 1 hour. The reaction was diluted with EtOAc and quenched with saturated rochelle brine solution. The reaction was extracted with EtOAc (4 ×). The organic layer was dried (Na) ₂SO₄) And evaporated to give a crude solid (435mg, 100%) which was used directly in the next step without further purification.

¹H-NMR(DMSO-d₆)δ8.29(d，J＝9.2Hz，2H)，7.89(s，1H)，7.73(s，1H)，7.67(d，J＝9.3Hz，2H)，5.07(t，J＝5.5Hz，1H)，4.38(d，J＝5.2Hz，2H)；MS[M+H]⁺＝286；LCMS RT＝0.59min.

Step 2: preparation of 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carbaldehyde

To a solution of THF (80mL) was added 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f][1，2，4]Triazin-6-yl]Methanol (435mg, 1.53mmol) followed by Dess-Martin periodinane reagent (4mL, 1.89mmol, 15% wt in CH)₂Cl₂Solution of (1). The reaction was stirred at room temperature until HPLC indicated completion (5 hours). The reaction was diluted with EtOAc and saturated NaHCO₃/Na₂S₂O₃Aqueous (1: 1v/v) (3X) wash. The aqueous layer was back-extracted with EtOAc (2X). The organic layer was dried (Na)₂SO₄) And evaporated to give a crude yellow solid (433mg, 100%) which was used directly in the next step without further purification.

¹H-NMR(DMSO-d₆)δ9.79(s，1H)，8.39(s，1H)，8.29(d，J＝8.7Hz，2H)，8.00(s，1H)，7.73(d，J＝8.8Hz，2H)；MS[M+H]⁺＝284；LCMS RT＝2.48min.

And step 3: preparation of ethyl (2E) -3- [ 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl ] acrylate

In N₂To a solution of lithium hydride (68mg, 4.0mmol) in THF (5mL) was added triethyl phosphonoacetate (498mg, 2) under an atmosphere.22 mmol). The mixture was stirred at room temperature for 30 minutes, and 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f ] was added to the reaction mixture ][1，2，4]Slurry of triazine-6-carbaldehyde (433mg, 1.53mmol) in THF (15 ml). The mixture was heated at reflux for 2 hours. After cooling to room temperature, NaHCO was slowly added₃Aqueous solution, followed by addition of EtOAc. The organic layer was collected and the aqueous layer was back-extracted with EtOAc (2 ×). The combined organic layers were dried (Na)₂SO₄) And evaporated to give a crude yellow solid which was purified by column chromatography (10: 90-90: 10v/v EtOAc-hexane) to give the title compound (480mg, 89%).

¹H-NMR(CD₃OD)δ8.42(d，J＝8.0Hz，2H)，8.17(s，1H)，7.88(s，1H)，7.68(d，J＝8.0Hz，2H)，7.43(d，J＝16Hz，1H)，6.36(d，J＝16Hz，1H)，4.16(q，J＝7.1Hz，2H)，1.23(t，J＝7.1Hz，3H)；MS[M+H]⁺＝354；LCMS RT＝3.12min.

And 4, step 4: preparation of the title Compound

In N₂Under the atmosphere, adding PtO₂(16mg, 0.070mmol) of a suspension in acetic acid (0.5ml) was added to (2E) -3- [ 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f)][1，2，4]Triazin-6-yl]Suspension of ethyl acrylate (144mg, 0.408mmol) in acetic acid (2 ml). The flask was evacuated, refilled with hydrogen (3 ×), and the reaction was carried out under a hydrogen atmosphere (1atm) for 1 day. PtO was further added to acetic acid (0.5ml)₂(50mg, 0.22mmol), and the reaction was further carried out under a hydrogen atmosphere for 1 day. The reaction was filtered through a pad of celite and washed with MeOH. It was evaporated to dryness, diluted with EtOAc and taken over Na₂CO₃And (4) washing with an aqueous solution. The aqueous layer was back-extracted with EtOAc (2X). The organic layer was dried (Na)₂SO₄) Filtered and evaporated to dryness to give the above compound as a yellow solid (120mg, 90% yield).

¹H-NMR(CD₃OD)δ7.70(s，1H)，7.47(s，1H)，7.12(d，J＝8.3Hz，2H)，6.84(d，J＝8.3Hz，2H)，4.06(q，J＝7.8Hz，2H)，2.82(t，J＝7.8Hz，2H)，2.48(t，J＝7.7Hz，2H)，1.18(t，J＝7.8Hz，3H)；MS[M+H]⁺＝326；LCMS RT＝1.20min.

Intermediate I: preparation of N- {4- [ 4-amino-6- (3-oxopropyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Step 1: preparation of phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate

To a stirred solution of 2-fluoro-5- (trifluoromethyl) aniline (3.00g, 16.7mmol) in THF (80mL) at room temperature was added pyridine (2.71mL, 33.5mmol), followed by phenyl chloroformate (3.15mL, 25.1 mmol). Some solids precipitated out. The mixture was stirred at room temperature overnight. Water was added to the reaction and it was extracted with EtOAc. The organic solution was washed with water (2X) and MgSO₄Dried and filtered. The filtrate was concentrated in vacuo and purified by column chromatography (10: 90-30: 70v/v EtOAc-hexane) to afford the title compound (3.1g, 62%).

¹H-NMR(DMSO-d₆) δ 10.36(br s, 1H), 8.15(d, J ═ 7.1Hz, 1H), 7.59 to 7.47(m, 2H), 7.46 to 7.38(m, 2H), 7.30 to 7.20(m, 3H); TLCR_f0.39 (9: 1v/v hexanes-EtOAc).

Step 2: preparation of ethyl 3- (4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl) propanoate

To a solution of THF (2.0mL) was added intermediate H (80mg, 0.25mmol), followed by phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate (74mg, 0.25mmol) and triethylamine (34. mu.L, 0.25 mmol). The reaction was stirred at 0 ℃ and slowly warmed to room temperature and held overnight. The solution was concentrated to dryness in vacuo and then purified by column chromatography (5: 95-50: 50v/v EtOAc-hexane) to give the title compound (66mg, 50%).

¹H-NMR(CD₃OD) δ 8.62(d, J ═ 7.4Hz, 1H), 7.74(s, 1H), 7.63(d, J ═ 8.6Hz, 2H), 7.52(s, 1H), 7.40 to 7.31(m, 4H), 4.06(q, J ═ 7.0Hz, 2H), 2.84(t, J ═ 7.5Hz, 2H), 2.50(t, J ═ 7.4Hz, 2H), 1.18(t, J ═ 7.0Hz, 3H); MS [ M + H ]]⁺＝531；LCMS RT＝3.29min.

And step 3: preparation of N- {4- [ 4-amino-6- (3-hydroxypropyl) pyrrolo [2, 1-f) [1, 2, 4] triazin-5-yl ] phenyl) -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

To a solution of THF (6mL) was added 3- (4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] phenyl)]Amino } carbonyl) amino]Phenyl } pyrrolo [2, 1-f][1，2，4]Triazin-6-yl) propionic acid ethyl ester (62mg, 0.12mmol) followed by DIBAL (0.6mL, 0.6mmol, 1.0M in toluene). The reaction was stirred at room temperature for 1 hour. DIBAL (1.2mL, 1.2mmol, 1.0M in toluene) was added and stirred at room temperature for an additional 1 hour. The reaction was diluted with EtOAc and quenched with saturated rochelle brine solution. The reaction was extracted with EtOAc (4 ×). The combined organic layers were dried (Na)₂SO₄) Filtered and evaporated to dryness to give a crude yellow solid (56mg, 98%), which was used directly in the next step without further purification。

¹H-NMR(CD₃OD) δ 8.62(d, J ═ 7.6Hz, 1H), 7.74(s, 1H), 7.61(d, J ═ 7.6Hz, 2H), 7.52(s, 1H), 7.38 to 7.31(m, 4H), 3.50(t, J ═ 7.1Hz, 2H), 2.61(t, J ═ 7.8Hz, 2H), 1.77 to 1.65(m, 2H); MS [ M + H ] ]⁺＝489；LCMSRT＝2.50min.

And 4, step 4: preparation of the title Compound

To a solution of THF (5mL) was added N- {4- [ 4-amino-6- (3-hydroxypropyl) pyrrolo [2, 1-f ]][1，2，4]Triazin-5-yl]Phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl]Urea (55mg, 0.11mmol) followed by the addition of Dess-Martin periodinane reagent (0.29mL, 0.14mmol, 15% wt in CH₂Cl₂In (1). The reaction was stirred until HPLC indicated completion (2 hours). The reaction was diluted with EtOAc and with NaHCO₃/Na₂S₂O₃Wash with 1: 1 aqueous solution (3X). The aqueous layer was back-extracted with EtOAc (2X). The combined organic layers were dried (Na)₂SO₄) Filtered and evaporated to give a crude yellow solid (53mg, 96%) which was used without further purification.

¹H-NMR(DMSO-d₆) δ 9.35(s, 1H), 8.98(s, 1H), 8.62(d, J ═ 7.2Hz, 1H), 7.80(s, 1H), 7.62 to 7.28(m, 6H), 2.71(t, J ═ 7.5Hz, 2H), 2.41(t, J ═ 7.4Hz, 2H); MS [ M + H ]]⁺＝487；LCMS RT＝2.62min.

Intermediate J: preparation of 4-amino-5- {4- [ ({ [ 2-chloro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid

Step 1: preparation of ethyl 4-amino-5- {4- [ ({ [ 2-chloro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

To a solution of DCE (5mL) was added intermediate B (300mg, 1.01mmol) followed by 2-chloro-1-isocyanato-4- (trifluoromethyl) benzene (0.32mL, 2.12 mmol). Will react in N₂After stirring at room temperature for 1 hour under an atmosphere, 2N aqueous HCl (0.50mL, 1.01mmol) was added to the reaction followed by DMF (5 mL). The solution was heated at 80 ℃ for 1 hour. Cooled to room temperature, the solution was diluted with EtOAc, transferred to a separatory funnel, and saturated NaHCO₃And (4) washing with an aqueous solution. The aqueous layer was back extracted with EtOAc. The combined organic layers were collected, dried, concentrated, and purified by column chromatography (95: 5 v/vCH)₂Cl₂-MeOH). The resulting fractions containing the product were concentrated and used with CH₂Cl₂And hexane. The product was filtered and dried in vacuo to give 408mg of the above compound as a white solid (0.79mmol, 78% yield).

¹H-NMR(DMSO-d₆) δ 9.72(s, 1H), 8.67(s, 1H), 8.64(s, 1H), 8.13(s, 1H), 8.08(br s, 1H), 7.93(s, 1H), 7.72(d, J ═ 8.5Hz, 1H), 7.56(d, J ═ 8.8Hz, 2H), 7.39 to 7.36(m, 1H), 7.34(d, J ═ 8.6Hz, 2H), 5.10(br s, 1H), 4.09(q, J ═ 7.0Hz, 2H), 1.12(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝519；LCMS RT＝3.58min；TLCR_f＝0.26(95∶5v/v CH₂Cl₂-MeOH).

Step 2: preparation of the title Compound

To a solution of MeOH (20mL) and THF (50mL) was added 4-amino-5- {4- [ ({ [ 2-chloro-5- (trifluoromethyl) phenyl ] phenyl ]Amino } carbonyl) amino]Phenyl } pyrrolo [2, 1-f][1，2，4]Triazine-6-carboxylic acid ethyl ester (381mg, 0.73mmol) followed by the addition of 1N aqueous NaOH (7.34mL, 7.34 mmol). Then reacting at N₂The mixture was heated at 60 ℃ for 17 hours under an atmosphere. Cooling downTo room temperature, the solution was partially rotary evaporated and then treated with 1N HCl (7.34mL, 7.34 mmol). The precipitate formed was collected and washed with water to obtain 324mg of the above compound as a white solid (0.66mmol, yield 90%).

¹H-NMR(DMSO-d₆)δ12.29(br s，1H)，9.75(s，1H)，8.69(s，1H)，8.63(s，1H)，8.08(s，1H)，8.03(br s，1H)，7.92(s，1H)，7.72(d，J＝8.3Hz，1H)，7.55(d，J＝8.4Hz，2H)，7.37(m，1H)，7.33(d，J＝8.6Hz，2H)，5.05(br s，1H)；MS[M+H]⁺＝491；LCMS RT＝3.15min；TLCR_f＜0.1(5∶4∶1v/v/v CH₂Cl₂-EtOAc-MeOH).

An intermediate K: preparation of 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid

A suspension of intermediate A (1.04g, 3.18mmol) in EtOH (10mL), THF (5mL) and 1N NaOH (5.56mL, 5.56mmol) was stirred at 80 ℃ for 6 h. The homogeneous solution was cooled to room temperature and treated dropwise with 1N HCl (5.56 mL). The reaction was concentrated in vacuo and the resulting solid was triturated with water to give the above compound as a tan solid.

MS[M+H]⁺＝300.2；LCMS RT＝1.37min.

Intermediate L: preparation of 4-amino-5- (4-aminophenyl) -N- (tert-butyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

Step 1: preparation of 4-amino-N- (tert-butyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

To a solution of toluene (10mL) was added 2M trimethylaluminum in hexane (1.37mL, 2.75mmol), followed by 2-methylpropan-2-amine (0.14mL, 1.37 mmol). The solution was stirred at room temperature for 15 min, then intermediate A (300mg, 0.92mmol) was added. The solution was heated at 110 ℃ for 17 hours. Cool to room temperature and slowly add 1N HCl until bubbling ceases. Addition of EtOAc followed by careful addition of NaHCO ₃An aqueous solution. The solution was transferred to a separatory funnel, the organic layer was collected and the aqueous layer was back-extracted with EtOAc (3X 20 mL). The combined organic layers were dried (MgSO)₄) Concentrated and purified by column chromatography (50: 45: 5 v/v/vCH)₂Cl₂EtOAc/MeOH) to yield 181mg of the above compound (0.51mmol, 56% yield).

¹H-NMR(DMSO-d₆)8.25(d，J＝8.9Hz，2H)，8.16(s，1H)，7.94(s，1H)，7.59(d，J＝8.8Hz，2H)，7.39(s，1H)1.25(s，9H)；MS[M+H]⁺＝355；LCMS RT＝2.42min.

Step 2 preparation of the title Compound

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting 4-amino-N- (tert-butyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide for intermediate a.

¹H-NMR(DMSO-d₆)δ7.91(s，1H)，7.89(br s，1H)，7.84(s，1H)，7.07(d，J＝8.2Hz，2H)，6.69(d，J＝8.3Hz，2H)，6.15(s，1H)，5.44(s，2H)，5.04(br s，1H)，1.14(s，9H)；MS[M+H]⁺＝325；LCMS RT＝1.38min；TLCR_f＝0.15(95∶5v/v CH₂Cl₂-MeOH).

An intermediate M: preparation of 4-amino-5- (4-aminophenyl) -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

Step 1: preparation of 4-amino-5- (4-nitrophenyl) -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

Intermediate K (495mg, 1.73mmol) was added to a solution of thionyl chloride (15mL) and heated at 50 ℃ for 3 hours. Cool to room temperature, concentrate the reaction mixture to dryness and treat finely with THF (Chasing). The reaction mixture was then diluted with 2, 2, 2-trifluoro-ethylamine hydrochloride (587mg, 4.33mmol) and triethylamine (1.15mL, 8.66mmol) in THF (8mL) and stirred at rt overnight. The solution was rotary evaporated to dryness, diluted with EtOAc (50mL), transferred to a separatory funnel, and washed with water (50 mL). The aqueous layer was back-extracted with EtOAc (4X 20mL) and dried (Na) ₂SO₄) Filtered and concentrated to dryness. It was then triturated with EtOAc/MeOH. The product was collected to yield 490mg of the above compound as a yellow solid (74% yield).

¹H-NMR(DMSO-d₆) δ 8.77(t, J ═ 6.2Hz, 1H), 8.29(s, 1H), 8.23(d, J ═ 8.9Hz, 2H), 7.97(s, 1H), 7.59(d, J ═ 8.9Hz, 2H), 3.97 to 3.91(m, 2H); MS [ M + H ]]⁺＝381.1；LCMS RT＝2.33min).

Step 2: preparation of the title Compound

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting 4-amino-5- (4-nitrophenyl) -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide for intermediate a.

¹H-NMR(CD₃OD) δ 8.00(s, 1H), 7.81(s, 1H), 7.17(d, J ═ 8.5Hz, 2H), 6.84(d, J ═ 8.6Hz, 2H), 4.03 to 3.85(m, 2H); MS [ M + H ]]⁺＝351.2；LCMS RT＝1.14min.

An intermediate N: preparation of 2- (trimethylsilyl) ethyl (5- (4-aminophenyl) -6- { [ (2-methoxyethyl) amino ] carbonyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-yl) carbamate

Step 1: preparation of 4-amino-N- (2-methoxyethyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of 4-amino-N- (tert-butyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide (intermediate L step 1) was used to prepare the title compound using 2-methoxyethylamine instead of 2-methylpropan-2-amine.

¹H-NMR(DMSO-d₆) δ 8.22(d, J ═ 8.7Hz, 2H), 8.18(s, 1H), 8.11(t, J ═ 5.6Hz, 1H), 7.93(s, 1H), 7.58(d, J ═ 8.9Hz, 2H), 3.28 to 3.26(m, 2H), 3.21(s, 3H), 3.16 to 3.14(m, 2H); MS [ M + H ]]⁺＝357；LCMS RT＝1.83min.

Step 2: preparation of 2- (trimethylsilyl) ethyl [6- { [ (2-methoxyethyl) amino ] carbonyl } -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-yl ] carbamate

To a solution of DMF (100mL) was added 4-amino-N- (2-methoxyethyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f][1，2，4]Triazine-6-carboxamide (4.03g, 11.3mmol) followed by the addition of 60% by weight NaH (1.13g, 28.3mmol) in mineral oil. The solution was stirred for 15 minutes, then 4-nitrophenyl 2- (trimethylsilyl) ethyl carbonate (3.52g, 12.4mmol) was added. The solution is placed in N₂Stirred under atmosphere for 2 hours. MeOH was added to the reaction until bubbling ceased, then EtOAc (50mL) was added. The solution was transferred to a separatory funnel and washed with 1N NaOH (20mL) and water (20 mL). The organic layer was collected and dried (Na)₂SO₄) And purified by column chromatography to give 3.60 g of the above compound (7.15mmol, yield 63%).

¹H-NMR(CDCl₃) δ 8.38(d, J ═ 8.5Hz, 2H), 8.16(s, 1H), 8.14(s, 1H), 7.69(d, J ═ 8.5Hz, 2H), 5.87 to 5.86(m, 1H), 4.17(t, J ═ 8.3Hz, 2H), 3.48 to 3.46(m, 2H), 3.36(t, J ═ 5.0Hz 2H), 3.21(s, 3H), 0.93(t, J ═ 8.1Hz 2H), -0.01(s, 9H); MS [ M + H ] ]⁺＝501；LCMS RT＝3.17min.

And step 3: preparation of the title Compound

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting [6- { [ (2-methoxyethyl) amino ] carbonyl } -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-yl ] carbamic acid 2- (trimethylsilyl) ethyl ester for intermediate a.

¹H-NMR(DMSO-d₆) δ 8.26(s, 1H), 8.23(s, 1H), 8.16(s, 1H), 7.42(br s, 1H), 7.04(d, J ═ 8.3Hz, 2H), 6.61(d, J ═ 8.3Hz, 2H), 5.36(br s, 2H), 3.99(t, J ═ 8.3Hz, 2H), 3.29 to 3.25(m, 4H), 3.18(s, 3H), 0.88 to 0.84(m, 2H), -0.01(s, 9H); MS [ M + H ]]⁺＝471；LCMS RT＝3.04min.

Intermediate O: preparation of 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carbonitrile

To a solution of pyridine (8.75mL) was added 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f][1，2，4]Triazine-6-carbaldehyde (intermediate H, step 2) (500mg, 1.77mmol) was added followed by hydroxylamine hydrochloride (135mg, 1.94 mmol). The solution was stirred at room temperature for 1 hour, acetic anhydride (.366mL, 3.88mmol) was added, and the solution was heated at 80 ℃ for 17 hours. Cooled to room temperature, the reaction mixture was partially rotary evaporated and then treated with EtOAc (50mL) and H₂Dilution with O (50 mL). The solution was transferred to a separatory funnel and the organic layer was separated while the aqueous layer was back-extracted with EtOAc (2X 25 mL). The combined organic layers were collected and dried (Na) ₂SO₄) Filtered and concentrated to dryness to give a brown solid. The solid was confirmed to be the title compound and N- [ 6-cyano-5- (4-nitro-phenyl) -pyrrolo [2, 1-f ] in a 1: 1 ratio][1，2，4]Triazin-4-yl]-an acetamide.

¹H-NMR(DMSO-d₆) δ 10.67(s, 1H), 8.96(s, 1H), 8.62(s, 1H), 8.57(s, 1H), 8.40 to 8.30(m, 4H), 8.05(s, 1H), 7.79 to 7.68(m, 4H), 1.74(s, 3H); MS [ M + H ]]⁺＝281.2，323.0；LCMS RT＝2.48min.

An intermediate P: preparation of 4-amino-5- (4-aminophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carbonitrile

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting intermediate O for intermediate a.

¹H-NMR(CD₃OD)δ8.29(s，1H)，7.98(s，1H)，7.57(d，J＝9.0Hz，2H)，7.33(d，J＝9.0Hz，2H)；MS[M+H]⁺＝251.3；LCMS RT＝0.40min.

Intermediate Q: preparation of 4-amino-5- (4-aminophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

Step 1: preparation of 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

A mixture of intermediate O (80mg, 0.29mmol) in sulfuric acid (1mL) was stirred at room temperature overnight. The reaction mixture was slowly quenched with saturated sodium bicarbonate solution until gas evolution ceased. The reaction mixture was then extracted with EtOAc (3X 5mL) and THF (3X 5mL) and dried (Na)₂SO₄) Filtered and concentrated to dryness to give a brown solid.

¹H-NMR(CD₃OD)δ8.22(d，J＝9.0Hz，2H)，8.04(s，1H)，7.80(s，1H)，7.59(d，J＝8.6Hz，2H)；MS[M+H]⁺＝299.1；LCMS RT＝1.15min.

Step 2: preparation of the title Compound

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide for intermediate a.

¹H-NMR(CD₃OD)δ8.26(s，1H)，8.02(s，1H)，7.98(br s，2H)，7.53(d，J＝9.0Hz，2H)，7.33(d，J＝9.0Hz，2H)；MS[M+H]⁺＝269.3；LCMS RT＝0.19min.

Intermediate R: preparation of [ 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl ] methanol

To a solution of THF (10mL) was added intermediate A (500mg, 1.53mmol), followed by DIBAL (3mL, 3mmol, 1.0M in toluene). The reaction was stirred at room temperature for 1 hour. DIBAL (1.5mL, 1.5mmol, 1.0M in toluene) was added and stirred at room temperature for an additional 1 hour. The reaction was diluted with EtOAc and quenched with saturated rochelle brine solution. The reaction was extracted with EtOAc (4 ×), and the organic layer was dried (Na)₂SO₄) And evaporated to give a crude solid (435mg, 100%) which was used directly in the next step without further purification.

An intermediate S: preparation of 6- (chloromethyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine

A mixture of intermediate R (522mg, 1.83mmol) in thionyl chloride (10mL) was stirred at 50 ℃ for 1 h. The mixture was concentrated to dryness to give a brown solid.

¹H-NMR(DMSO-d₆)δ8.37(d，J＝8.9Hz，2H)，8.19(s，1H)，8.16(s，1H)，7.74(d，J＝8.9Hz，2H)，4.70(s，2H)；MS[M+H]⁺＝304.3；LCMS RT＝2.44min.

An intermediate T: preparation of 5- (4-aminophenyl) -6-methylpyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting intermediate S for intermediate a.

¹H-NMR(CD₃OD)δ7.74(s，1H)，7.52(s，1H)，7.13(d，J＝8.2Hz，2H)，6.86(d，J＝8.5Hz，2H)，2.11(s，3H)；MS[M+H]⁺＝240.3；LCMS RT＝1.06min.

An intermediate U: preparation of 5- (4-aminophenyl) -6- (methoxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine

Step 1: preparation of 6- (methoxymethyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine

To a solution of thionyl chloride (20mL) was added intermediate R (873mg, 3.06mmol), which was added under N₂Heat to reflux under atmosphere for 2 hours. Cooled to room temperature, the reaction mixture was rotary evaporated to dryness and taken up with CH₂Cl₂And (5) fine processing. The reaction mixture was diluted with MeOH (20mL) and 60 wt% NaH (C) (in mineral oil) was added489mg, 12.2 mmol). The solution was heated to reflux for 6 hours. Cool to room temperature, evaporate the solution to dryness by rotation, dilute with EtOAc (50mL), move to a separatory funnel, and wash with water (50 mL). The aqueous layer was back-extracted with EtOAc (4X 20mL) and dried (MgSO)₄) Filtered and purified by column chromatography (95: 5 v/vCH)₂Cl₂MeOH). The resulting clear fractions were combined, evaporated and washed with CH₂Cl₂Trituration with diethyl ether. The product was collected to yield 470mg of the above compound as a yellow solid (1.57mmol, 51% yield).

¹H-NMR(DMSO-d₆)δ8.30(d，J＝8.9Hz，2H)，7.91(s，1H)，7.84(s，1H)，7.65(d，J＝8.9Hz，2H)，4.29(s，2H)，3.21(s，3H)；MS[M+H]⁺＝300；LCMS RT＝2.07min；TLCR_f＝0.54(95∶5v/v CH₂Cl₂-MeOH).

Step 2: preparation of the title Compound

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting 6- (methoxymethyl) -5- (4-nitrophenyl) pyrrolo [2, 1f ] [1, 2, 4] triazin-4-amine for intermediate a.

¹H-NMR(DMSO-d₆)δ7.79(s，1H)，7.67(s，1H)，7.03(d，J＝8.4Hz，2H)，6.64(d，J＝8.7Hz，2H)，5.30(s，2H)，)，4.24(s，2H)，3.19(s，3H)；MS[M+H]⁺＝270；LCMS RT＝0.26min；TLCR_f＝0.30(95∶5v/v CH₂Cl₂-MeOH).

An intermediate V: preparation of 4-amino-5- (4-aminophenyl) -N- (2, 3-dihydroxypropyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

Step 1: preparation of 4-amino-N- (2, 3-dihydroxypropyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

To a solution of intermediate K (550mg, 1.84mmol), 3-amino-1, 2-propanediol (251mg, 2.76mmol), triethylamine (1.0mL, 7.4mmol) and DMF (20mL) was added py-BOP (1051mg, 2.02mmol) and the reaction was stirred for 1 h. The reaction mixture was concentrated in vacuo and the residue was triturated first with water and then with 30% aqueous ethanol to give 318mg of the above compound as an orange/yellow solid (47% yield)

MS[M+H]⁺＝373.2；LCMS RT＝1.21.

Step 2: preparation of the title Compound

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting 4-amino-N- (2, 3-dihydroxypropyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide for intermediate a.

¹H-NMR(DMSO-d₆) δ 8.02(s, 1H), 7.84(s, 1H), 7.28(t, J ═ 6Hz, 1H)7.02(d, J ═ 8Hz, 2H), 5.34(s, 2H), 5.05(bs, 1H), 4.75(bs, 1H), 4.52(bs, 1H), 4.38 to 3.43(m.1h), 3.36 to 3.16(M, 3H), 3.03 to 2.85(M, 1H) MS [ M + H ] M ]⁺＝343.2；LCMS RT＝1.02min.

Intermediate W: preparation of 4-amino-5- (4-aminophenyl) -N-cyclopropylpyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

Step 1: preparation of 4-amino-N-cyclopropyl-5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of 4-amino-N- (tert-butyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide (intermediate L, step 1) was used to prepare the title compound by substituting cyclopropylamine for 2-methylpropan-2-amine.

¹H-NMR(DMSO-d₆) δ 8.23(d, J ═ 8.8Hz, 2H), 8.14(s, 1H), 8.13(br s, 1H), 7.93(d, J ═ 8.4Hz, 2H), 7.58(s, 1H), 2.67 to 2.59(m, 1H), 0.62 to 0.54(m, 2H), 0.46 to 0.41(m, 2H); MS [ M + H ]]⁺＝339.2；LCMS RT＝1.40min.

Step 2: preparation of the title Compound

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting 4-amino-N-cyclopropyl-5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide for a.

¹H-NMR(CD₃OD) δ 7.68(s, 1H), 7.58(s, 1H), 7.07(s, 1H), 6.73(d, J ═ 8.6Hz, 2H), 6.33(d, J ═ 8.3Hz, 2H), 5.05(s, 2H), 2.38 to 2.28(m, 1H), 0.34 to 0.24(m, 2H), 0.067 to-0.032 (m, 2H); MS [ M + H ]]⁺＝309.3；LCMS RT＝0.23min.

An intermediate X: preparation of 4-amino-5- (4-aminophenyl) -N-methylpyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

Step 1: preparation of 4-amino-N-methyl-5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

Intermediate K (300mg, 1.00mmol) was added to a thionyl chloride solution (10mL) and heated at 50 ℃ for 3 hours. Cool to room temperature, evaporate the reaction mixture to dryness by rotation and work up with THF. The reaction mixture was then diluted with 2M methylamine in THF (40mL) and stirred at rt overnight. The solution was rotary evaporated to dryness, diluted with EtOAc (50mL), transferred to a separatory funnel, and washed with water (50 mL). The aqueous layer was back-extracted with EtOAc (4X 20mL) and dried (Na)₂SO₄) Filtered and evaporated to dryness by rotation. It was then triturated with EtOAc/MeOH. The product was collected to yield 240mg of the above compound as a yellow solid (240mg, 76% yield).

¹H-NMR(DMSO-d₆) δ 8.22(d, J ═ 8.9Hz, 2H), 8.15(s, 1H), 7.94(s, 1H), 7.58(d, J ═ 8.9Hz, 2H), 3.60 to 3.55(m, 1H), 2.62(d, J ═ 4.6Hz, 3H); MS [ M + H ]]⁺＝313.2；LCMS RT＝0.58min).

Step 2: preparation of the title Compound

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting 4-amino-N-methyl-5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide for intermediate a.

¹H-NMR(DMSO-d₆) δ 8.00(s, 1H), 7.84(s, 1H), 7.00(d, J ═ 8.4Hz, 2H), 6.61(d, J ═ 8.5Hz, 2H), 5.31(s, 2H), 4.19 to 4.12(m, 1H), 2.59(d, J ═ 4.6Hz, 3H); MS [ M + H ] ]⁺＝281.3；LCMS RT＝1.03min

Intermediate Y: preparation of 4-amino-5- (4-aminophenyl) -N- (2-morpholin-4-ylethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

Step 1: preparation of 4-amino-N- (2-morpholin-4-ylethyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of 4-amino-N-methyl-5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide (intermediate X step 1) was used to prepare the title compound, replacing methylamine with 2-morpholin-4-yl-ethylamine.

¹H-NMR(CD₃OD) δ 8.34(d, J ═ 8.8Hz, 2H), 8.07(s, 1H), 7.89(s, 1H), 7.69(d, J ═ 8.8Hz, 2H), 3.66 to 3.61(m, 4H), 3.39(t, J ═ 6.6Hz, 2H), 2.49 to 2.40(m, 6H); MS [ M + H ]]⁺＝412.2；LCMS RT＝0.28min.

Step 2: preparation of the title Compound

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting 4-amino-N- (2-morpholin-4-ylethyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide for intermediate a.

¹H-NMR(CD₃OD) δ 8.04(br s, 2H), 7.99(s, 1H), 7.80(s, 1H), 7.20(d, J ═ 8.4Hz, 2H), 6.85(d, J ═ 8.4Hz, 2H), 3.64 to 3.57(m, 4H), 3.42 to 3.36(m, 2H), 2.35 to 2.27(m, 6H); MS [ M + H ]]⁺＝382.3；LCMS RT＝0.17min.

An intermediate Z: preparation of 5- (4-aminophenyl) -6- [ (2-methoxyethoxy) methyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine

Step 1: preparation of 6- [ (2-methoxyethoxy) methyl ] -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine

The procedure used for the preparation of 6- (methoxymethyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine (intermediate U, step 1) was used to prepare the title compound by substituting 2-methoxy-ethanol for methanol.

¹H-NMR(CD₃OD) δ 8.35(d, J ═ 8.7Hz, 2H), 7.85(s, 1H), 7.77(s, 1H), 7.75(d, J ═ 8.7Hz, 2H), 4.45(s, 2H), 3.59 to 3.49(m, 4H), 3.33(s, 3H); MS [ M + H ]]⁺＝344.1；LCMS RT＝2.14min.

Step 2: preparation of the title Compound

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting 6- [ (2-methoxyethoxy) methyl ] -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine for intermediate a.

¹H-NMR(CD₃OD) δ 7.74(s, 1H), 7.65(s, 1H), 7.17(d, J ═ 8.5Hz, 2H), 6.81(d, J ═ 8.5Hz, 2H), 4.42(s, 2H), 3.57 to 3.47(m, 4H), 3.32(s, 3H); MS [ M + H ]]⁺＝314.3；LCMSRT＝0.25min.

Intermediate AA: preparation of 5- (4-aminophenyl) -6- [ (2, 2, 2-trifluoroethoxy) methyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine

Step 1: preparation of 5- (4-nitrophenyl) -6- [ (2, 2, 2-trifluoroethoxy) methyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine

The procedure used for the preparation of 6- (methoxymethyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine (intermediate U, step 1) was used to prepare the title compound by substituting 2, 2, 2-trifluoro-ethanol for methanol.

¹H-NMR (acetone-d)₆) δ 8.36(d, J ═ 8.6Hz, 2H), 7.89(s, 1H), 7.85(s, 1H), 7.81(d, J ═ 8.6Hz, 2H), 4.68(s, 2H), 4.04 to 3.94(m, 2H); MS [ M + H ]]⁺＝368.3；LCMS RT＝2.68min.

Step 2: preparation of the title Compound

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting 5- (4-nitrophenyl) -6- [ (2, 2, 2-trifluoroethoxy) methyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine for intermediate a.

¹H-NMR(CD₃OD) δ 7.75(s, 1H), 7.65(s, 1H), 7.15(d, J ═ 8.6Hz, 2H), 6.81(d, J ═ 8.6Hz, 2H), 4.53(s, 2H), 3.93 to 3.72(m, 2H); MS [ M + H ]]⁺＝338.2；LCMS RT＝1.69min.

An intermediate AB: preparation of 5- (4-aminophenyl) -6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine

Step 1: preparation of 5- (4-nitrophenyl) -6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine

To 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f][1，2，4]To a solution of triazine-6-carbaldehyde (intermediate H, step 2) (692mg, 2.44mmol) was added tosylmethyl isocyanide (477mg, 2.44mmol) and potassium carbonate (338mg, 2.44mmol) in MeOH. The solution was stirred at reflux overnight. The solution was dried and diluted with EtOAc (50mL) and THF (50 mL). Water (50mL) was added to the reaction mixture. The solution was transferred to a separatory funnel, and the organic layer was separated and washed with brine (50 mL). The aqueous layer was back-extracted with EtOAc (2X 50 mL). The combined organic layers were collected and dried (Na) ₂SO₄) Concentrated onto silica gel and purified by column chromatography (100% CH)₂Cl₂To 95: 5v/v CH₂Cl₂EtOAc) to yield 310mg of the above compound as a yellow solid (39% yield).

¹H-NMR(DMSO-d₆)δ11.70(s，1H)，8.31(d，J＝8.5Hz，2H)，8.28(s，1H)，8.17(s，1H)，7.66(d，J＝7.1Hz，2H)，6.75(s，1H)；MS[M+H]⁺＝323.2；LCMS RT＝2.57min.

Step 2: preparation of the title Compound

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting 5- (4-nitrophenyl) -6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine for intermediate a.

¹H-NMR(CD₃OD)δ8.11(s，1H)，7.91(s，1H)，7.79(s，1H)，7.15(d，J＝8.6Hz，2H)，6.87(d，J＝8.6Hz，2H)，6.45(s，1H)；MS[M+H]⁺＝293.2；LCMS RT＝1.23min.

An intermediate AC: preparation of 4-amino-5- {4- [ ({ [ 2-chloro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N (1, 1-dimethyl-2-oxoethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of intermediate F (step 2) was used to prepare the title compound by substituting 4-amino-5- {4- [ ({ [ 2-chloro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } } -N- (2-hydroxy-1, 1-dimethylethyl) pyrrolo [2, 1-F ] [1, 2, 4] triazine-6-carboxamide for N- {4- [ 4-amino-6- (hydroxymethyl) pyrrolo [2, 1-F ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea.

¹H-NMR(DMSO-d₆)δ9.69(s，1H)，9.21(s，1H)，8.65(s，1H)，8.62(d，J＝2.1Hz，1H)，8.23(s，1H)，8.20(s，1H)，7.90(s，1H)，7.70(d，J＝8.8Hz，1H)，7.53(d，J＝9.1Hz，2H)，7.35(dd，J＝8.8，1.6Hz，1H)，7.30(d，J＝8.6Hz，2H)，3.30(s，6H)；MS[M+H]⁺＝560.1；LCMS RT＝3.36min.

Intermediate AD: preparation of 5- (4-aminophenyl) -6- (1, 3, 4-oxadiazol-2-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine

Step 1: preparation of 5- (4-nitrophenyl) -6- (1, 3, 4-oxadiazol-2-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine

Intermediate K (183mg, 0.613mmol) was added to a thionyl chloride solution (5mL) and heated at 50 ℃ for 3 hours. Cool to room temperature, evaporate the reaction mixture to dryness by rotation and work up with THF. The reaction mixture was then diluted with pyridine (5mL), hydrazine (100mg, 3.15mmol) was added, and stirred at room temperature overnight. The solution was evaporated to dryness by rotary evaporation, diluted with trimethoxy-methane (10mL) and stirred under reflux for 5 hours. The solution was rotary evaporated to dryness and purified by HPLC to give the title compound (27mg, 14%).

¹H-NMR(CD₃OD)δ8.71(s，1H)，8.24(d，J＝9.1Hz，2H)，8.20(s，1H)，7.84(s，1H)，7.73(d，J＝8.9Hz，2H)；MS[M+H]⁺＝324.2；LCMS RT＝2.07min.

Step 2: preparation of the title Compound

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting 5- (4-nitrophenyl) -6- (1, 3, 4-oxadiazol-2-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine for intermediate a.

¹H-NMR(CD₃OD)δ8.64(s，1H)，8.06(s，1H)，7.75(s，1H)，7.08(d，J＝8.7Hz，2H)，6.66(d，J＝8.9Hz，2H)；MS [M+H]⁺＝294.2；LCMS RT＝0.21min.

Intermediate AE: preparation of 5- (4-amino-phenyl) -6-imidazol-1-ylmethyl-pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-ylamine

Step 1: preparation of 6-imidazol-1-ylmethyl-5- (4-nitro-phenyl) -pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-ylamine

The procedure used for the preparation of 6- (methoxymethyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine (intermediate U, step 1) was used to prepare the title compound, substituting imidazole for methanol.

¹H-NMR (acetone-d)₆)δ8.22(d，J＝8.8Hz，2H)，7.77(s，1H)，7.66(s，1H)，7.54(d，J＝8.8Hz，2H)，7.27(s，1H)，6.82(s，1H)，6.73(s，1H)，5.14(s，2H)；MS[M+H]⁺＝336.0；LCMS RT＝0.25min.

Step 2: preparation of the title Compound

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting 6-imidazol-1-ylmethyl-5- (4-nitro-phenyl) -pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-ylamine for intermediate a.

MS[M+H]⁺＝306.0；LCMS RT＝1.02min.

Intermediate AF: preparation of N- {4- [ 4-amino-6- (hydroxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The compound from example 51 (0.25g, 0.515mmol) was suspended in THF (5mL) and treated with a solution of 1M DIBAL in THF (2mL, 2.06 mmol). The resulting solution was stirred at room temperature for 3 hours and saturated NH₄The Cl solution was stopped. The mixture was stirred for 1 hour. The mixture was transferred to a separatory funnel and the crude product was extracted with EtOAc. The organic layer was then washed with water and saturated NaCl solution. The organic layer was then washed with MgSO₄Dried, filtered, and concentrated under reduced pressure. The residual solid was then triturated with EtOAc and filtered to give 0.22g of product as a tan solid (0.496mmol, 96% yield).

¹H-NMR(DMSO)δ11.66(s，1H)，9.86(s，1H)，9.73(s，1H)，8.53(d，J＝8.7Hz，1H)，8.05(s，1H)，7.82(s，1H)，7.65(s，1H)，7.61(d，J＝6.6Hz，2H)，7.38-7.35(m，3H)，4.95(t，J＝5.2Hz，1H)，4.37(d，J＝5.1Hz，2H)；MS[M+H]⁺＝444.0；LCMS RT＝2.3min.

Intermediate AG: preparation of N- [4- (4-amino-6-formylpyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

Intermediate AF (1.9g, 4.29mmol) was suspended in THF (20mL) and treated with Dess-Martin periodinane (2.0g, 4.71 mmol). The mixture was stirred at room temperature overnight with Na ₂S₂O₃Saturated NHCO of (3)₃The solution was stopped. The mixture was stirred for 1 hour and then transferred to a separatory funnel. The crude product was extracted with EtOAc and washed with water and saturated NaCl solution. The organic layer was then washed with MgSO₄Dried, filtered and concentrated under reduced pressure. The residual solid was then triturated with EtOAc and filtered to give 1.8g of product as a tan solid (4.08mmol, 95% yield).

¹H-NMR(DMSO)δ10.05(bs，1H)，9.82(s，1H)，9.72(s，1H)，8.52(d，J＝5.1Hz，1H)，8.26(s，1H)，8.07(s，1H)，7.95(s，1H)，7.64(d，J＝8.6Hz，2H)，7.44(d，J＝8.6Hz，2H)，7.35(d，J＝5.8Hz，1H)；MS[M+H]⁺＝442.0；LCMS RT＝2.81min.

Intermediate AH: preparation of 4-amino-5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl l pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid

The procedure used for the preparation of intermediate G was used to prepare the title compound by substituting example 144 for intermediate E.

¹H-NMR(DMSO)δ10.29(bs，1H)，8.03to7.96(m，3H)，7.86(s，1H)，7.53(d，J＝8.5Hz，2H)，7.45(d，J＝7.0Hz，1H)，7.33(d，J＝8.6Hz，2H)；MS[M+H]⁺＝458.1；LCMS RT＝2.51min.

Intermediate AI: preparation of 4-amino-5- (3-fluoro-4-nitrophenyl) pyrrolo [2, 1-f ]1, 2, 4] triazine-6-carboxylic acid ethyl ester

Step 1: preparation of 3-fluoro-N-methoxy-N-methyl-4-nitrobenzamide

To CH₂Cl₂(1L) to the solution was added 3-fluoro-4-nitrobenzoic acid (100g, 540mmol) and EDCI (155.3g, 810mmol), followed by NMM (178mL, 1.62mol) and N-methoxymethylaminohydrochloride (79.0g, 810 mmol). The solution is placed in N₂Stirred at room temperature under an atmosphere for 17 hours. The reaction mixture was then diluted with 1N HCl (1L), transferred to a separatory funnel, and separated. The organic phase was washed with 1N NaOH (2X 500mL) and water (250 mL). All aqueous layers were back-extracted with EtOAc (2X 500 mL). The organic layers were combined and dried (MgSO) ₄) Filtered and concentrated in vacuo to afford 102.3g of the above compound as a yellow solid (448mmol, 83% yield).

¹H-NMR(DMSO-d₆) δ 8.22 to 8.18(t,j ═ 8.0Hz, 1H), 7.79 to 7.76(d, J ═ 11.5Hz, 1H), 7.60 to 7.58(d, J ═ 8.3Hz, 1H), 3.56(s, 3H), 3.28(s, 3H); MS [ M + H ]]⁺＝229.1；LCMS RT＝2.27min.

Step 2: preparation of ethyl 3-fluoro-4-nitrobenzaldehyde

To a solution of THF (800mL) cooled in an ice-salt/water bath was added 3 fluoro-N-methoxy-N-methyl-4-nitrobenzamide followed by 1M DIBAL in THF over 30 minutes with an addition funnel. The solution is placed in N₂Stirred under atmosphere for 1 hour. The reaction mixture was then carefully diluted with 1N HCl (500mL) and EtOAc (500mL), transferred to a separatory funnel, and separated. The organic phase was washed with 1N HCl (3X 250mL), 1N NaOH (2X 250mL) and water (250 mL). The entire aqueous layer was stripped with EtOAc (2X 250 mL). The organic layers were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to yield 67g of the above compound (396mmol, 88% yield).

¹H-NMR(DMSO-d₆) δ 10.06(s, 1H), 8.36 to 8.32(t, J ═ 7.8Hz, 1H), 8.06 to 8.03(d, J ═ 11.2Hz, 1H), 7.95 to 7.93(d, J ═ 9.1Hz, 1H).

And step 3: preparation of ethyl (2E) -3- (3-fluoro-4-nitrophenyl) acrylate

The procedure used for the preparation of intermediate H, step 3, was used to prepare the title compound by substituting ethyl 3-fluoro-4-nitrobenzaldehyde for 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carbaldehyde.

1H-pyrrole-3-carboxylic acid ethyl ester, the procedure used for the preparation of intermediate A, step 2, was used to prepare the title compound.

¹H-NMR(DMSO-d₆) δ 12.99(s, 1H), 9.33(s, 1H), 8.17 to 8.13(t, J ═ 8.2Hz, 1H), 7.81 to 7.74(m, 2H), 7.52 to 7.50(d, J ═ 6.6Hz, 1H), 4.13 to 4.07(q, J ═ 7.2Hz, 2H), 1.16 to 1.13(t, J ═ 7.0Hz, 3H); LCMS RT ═ 2.92.

Step 6: preparation of 5-cyano-4- (3-fluoro-4-nitrophenyl) -1H-pyrrole-3-carboxylic acid ethyl ester

The procedure used for the preparation of intermediate a, step 3, was used to prepare the title compound by substituting 4- (3-fluoro-4-nitrophenyl) -5-formyl-1H-pyrrole-3-carboxylic acid ethyl ester for 5-formyl-4- (nitrophenyl) -1H-pyrrole-3-carboxylate.

¹H-NMR(DMSO-d₆) δ 13.29(s, 1H), 8.22 to 8.18(t, J ═ 8.2Hz, 1H), 7.91(s, 1H), 7.74 to 7.71(d, J ═ 10.9Hz, 1H), 7.51 to 7.50(d, J ═ 6.5Hz, 1H), 4.16 to 4.10(q, J ═ 7.0Hz, 2H), 1.18 to 1.15(t, J ═ 7.0Hz, 3H).

And 7: preparation of 1-amino-5-cyano-4- (3-fluoro-4-nitrophenyl) -1H-pyrrole-3-carboxylic acid ethyl ester

Replacement of 5-cyano-4- (3-fluoro-4-nitrophenyl) -1H-pyrrole-3-carboxylic acid ethyl ester

¹H-NMR(DMSO-d₆) δ 8.17 to 8.13(t, J ═ 8.2Hz, 1H), 8.04 to 8.01(d, J ═ 12.7Hz, 1H), 7.79 to 7.77(d, J ═ 8.4Hz, 1H), 7.71 to 7.67(d, J ═ 16.1Hz, 1H), 6.71 to 7.67(d, J ═ 16.1Hz, 1H), 693 to 6.87(d, J ═ 15.9Hz, 1H), 4.24 to 4.18(q, J ═ 7.1Hz, 2H), 1.29 to 1.25(t, J ═ 7.1Hz, 3H); LCMS RT ═ 3.18.

And 4, step 4: preparation of 4- (3-fluoro-4-nitrophenyl) -1H-pyrrole-3-carboxylic acid ethyl ester

The procedure used for the preparation of intermediate a, step 1, was used to prepare the title compound by substituting (2E) -3- (3-fluoro-4-nitrophenyl) acrylate with ethyl (2E) -3- (3-fluoro-4-nitrophenyl) acrylate.

¹H-NMR(DMSO-d₆) δ 11.86(s, 1H), 8.10 to 8.06(t, J ═ 8.5Hz, 1H), 7.74 to 7.71(d, J ═ 13.5Hz, 1H), 7.57 to 7.54(m, 2H), 7.31 to 7.30(m, 1H), 4.18 to 4.13(q, J ═ 7.1Hz, 2H), 1.25 to 1.21(t, J ═ 7.0Hz, 3H); LCMS RT 3.05min.

And 5: preparation of 4- (3-fluoro-4-nitrophenyl) -5-formyl-1H-pyrrole-3-carboxylic acid ethyl ester

The procedure used for the preparation of intermediate a, step 5, was used to prepare the title compound by substituting 4- (3-fluoro-4-nitrophenyl) -1H-pyrrole-3-carboxylic acid ethyl ester for 4- (4-nitrophenyl) - (nitrophenyl) -1H-pyrrole-3-carboxylic acid ethyl ester.

¹H-NMR(DMSO-d₆) δ 8.238.21(t, J ═ 8.3Hz, 1H), 7.72(s, 1H), 7.69(d, J ═ 1.8Hz, 1H), 7.49 to 7.47(d, J ═ 8.5Hz, 1H), 6.72(s, 2H).

And 8: preparation of the title Compound

To EtOH (75mL) solution was added 1-amino group-5-cyano-4- (3-fluoro-4-nitrophenyl) -1H-pyrrole-3-carboxylic acid ethyl ester (1.68g, 5.28mmol) and formamidine acetate (5.49g, 52.8 mmol). The solution was heated to 80 ℃ for 17 hours. Upon cooling to room temperature, the solution was treated with water to form a precipitate, which was filtered and washed with additional water. The solid was then suspended in DCM and Et₂And (4) in O. Collect the solid and use Et₂O wash to obtain 1.22g of an orange-yellow solid (3.52mmol, 67% yield).

¹H-NMR(DMSO-d₆) δ 8.20(s, 1H), 8.18 to 8.14(t, J ═ 8.2Hz, 1H), 7.97(s, 1H), 7.66 to 7.63(d, J ═ 12.4Hz, 1H), 7.41 to 7.39(d, J ═ 8.4Hz, 1H), 4.12 to 4.07(q, J ═ 7.0Hz, 2H), 1.13 to 1.10(t, J ═ 7.0Hz, 3H); MS [ M + H ]]⁺＝346.2；LCMS RT＝2.77min.

Intermediate AJ: preparation of 4-amino-5- (4-amino-3-fluorophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid ethyl ester

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting intermediate 2 for intermediate a.

¹H-NMR(DMSO-d₆) δ 8.07(s, 1H), 7.90(s, 1H), 7.04 to 7.01(d, J ═ 12.3Hz, 1H), 6.88 to 6.85(m, 2H), 6.81 to 6.77(m, 1H), 5.36(s, 2H), 4.11 to 4.06(q, J ═ 7.1Hz, 2H), 1.15 to 1.11(t, J ═ 7.0Hz, 3H); MS [ M + H ] ]⁺＝316.1；LCMS RT＝2.16min.

Intermediate AK: preparation of N- [4- (4-amino-6-formylpyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - (4-methylpyridin-2-yl) urea

The procedure used for the preparation of intermediate F was used to prepare the title compound by substituting example 258 for intermediate E.

¹H-NMR(DMSO-d₆) δ 10.90(s, 1H), 9.74(s, 1H), 9.48(s, 1H), 8.26(s, 1H), 8.15 to 8.14(d, J ═ 5.2Hz, 1H), 7.96(s, 1H), 7.68 to 7.66(d, J ═ 8.6Hz, 2H), 7.45 to 7.43(d, J ═ 8.4Hz, 2H), 7.28(s, 1H), 6.87 to 6.85(m, 1H), 2.30(s, 3H); MS [ M + H ]]⁺＝388.1；LCMS RT＝2.09min.

Intermediate AL: preparation of N- [4- (4-amino-6-formylpyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) -2-fluorophenyl ] -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of intermediate F was used to prepare the title compound by substituting example 242 for intermediate E.

¹H-NMR(DMSO-d₆) δ 10.16(s, 1H), 10.13 to 10.08(br s, 1H), 9.76(s, 1H), 8.55 to 8.54(d, J ═ 5.3Hz, 1H), 8.34 to 8.29(t, J ═ 8.6Hz, 1H), 8.28(s, 1H), 8.01(s, 1H), 7.97(s, 1H), 7.48 to 7.45(d, J ═ 11.2Hz, 1H), 7.39 to 7.38(d, J ═ 5.7Hz, 1H), 7.29 to 7.27(d, J ═ 8.1Hz, 1H); MS [ M + H ]]⁺＝459.9；LCMS RT＝2.96min.

Intermediate AM: preparation of N- {4- [ 4-amino-6- (4-formyl-1, 3-oxazol-2-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of intermediate F was used to prepare the title compound by substituting example 237 for intermediate E.

¹H-NMR(DMSO-d₆) δ 9.79(s, 1H), 9.37(s, 1H), 8.97(s, 1H), 8.87(s, 1H), 8.63 to 8.61(d, J ═ 7.5Hz, 1H), 8.34(s, 1H), 7.96(s, 1H), 7.60 to 7.58(d, J ═ 8.6Hz, 2H), 7.53 to 7.48(m, 1H), 7.42 to 7.40(m, 3H); MS [ M + H ]]⁺＝526.1；LCMS RT＝2.93min.

Intermediate AN: preparation of N- [4- (4-amino-6-formylpyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) -2-fluorophenyl ] -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of intermediate F was used to prepare the title compound by substituting example 249 for intermediate E.

¹H-NMR(DMSO-d₆) δ 9.75(s, 1H), 9.45(s, 1H), 9.33(s, 1H), 8.65 to 8.64(d, J ═ 7.1Hz, 1H), 8.34 to 8.29(m, 2H), 7.97(s, 1H), 7.54 to 7.40(m, 3H), 7.27 to 7.25(d, J ═ 9.4Hz, 1H); MS [ M + H ]]⁺＝477.1；LCMS RT＝3.07min.

Intermediate AO: preparation of phenyl {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } carbamate

The procedure used for the preparation of intermediate C was used to prepare the title compound by substituting intermediate AB for intermediate B.

¹H-NMR(DMSO-d₆) δ 10.48(s, 1H), 8.29(s, 1H), 8.09(s, 1H), 7.90(s, 1H), 7.67 to 7.65(d, J ═ 8.4Hz, 2H), 7.45 to 7.38(m, 4H), 7.28 to 7.23(m, 3H), 6.54(s, 1H); MS [ M + H ] ]⁺＝413.1；LCMS RT＝2.51min.

Example 1: preparation of ethyl 4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

To a solution of DCE (2mL) was added intermediate B (75mg, 0.25mmol) followed by 1-fluoro-2-isocyanato-4- (trifluoromethyl) benzene (52mg, 0.25 mmol). The reaction was stirred at room temperature for 2 hours. The solution was concentrated to dryness in vacuo and then purified by preparative HPLC (10-90% ACN/H)₂O, containing 0.1% TFA). The resulting fractions were transferred to a separatory funnel, diluted with EtOAc (20mL), and diluted with saturated NaHCO₃Aqueous solution (20mL) and H₂O (20mL) wash. The organic layer was separated and dried (MgSO)₄) Filtered, and concentrated to dryness to obtain 30mg of the above compound (0.060mmol, yield 24%).

¹H-NMR(DMSO-d₆) δ 9.33(s, 1H), 8.95(d, J ═ 2.3Hz, 1H), 8.63 to 8.61(m, 1H), 8.13(s, 1H), 8.07(br s, 1H), 7.93(s, 1H), 7.56 to 7.53(m, 2H), 7.51 to 7.48(m, 1H), 7.40(br s, 1H), 7.34 to 7.32(m, 2H), 5.09(br s, 1H), 4.11 to 4.06(q, J ═ 6.9Hz, 2H), 1.13 to 1.10(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝503；LCMS RT＝3.22min；TLC R_f＝0.15(95∶5v/v CH₂Cl₂-MeOH).

Example 2: preparation of ethyl 4-amino-5- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

1-chloro-4-isocyanato-2- (trifluoromethyl) benzene was used in place of 1-fluoro-2-isocyanato-4- (trifluoromethyl) benzene and purified by column chromatography (5: 4: 1v/v/v CH₂Cl₂EtOAc-MeOH) was used to prepare the title compound, the procedure used for the preparation of example 1 was used.

¹H-NMR(DMSO-d₆) δ 9.22(br s, 1H), 9.02(br s, 1H), 8.12(s, 1H), 8.11(d, J ═ 2.4Hz, 1H), 7.92(s, 1H), 7.63(d, J ═ 2.3Hz, 1H), 7.62(s, 1H), 7.55 to 7.53(m, 2H), 7.32 to 7.30(m, 2H), 4.10 to 4.05(q, J ═ 7.1Hz, 2H), 1.12 to 1.09(t, J ═ 7.0Hz, 3H); MS [ M + H ]]⁺＝519；LCMSRT＝3.06min；TLCR_f＝0.48(5∶4∶1v/v/v CH₂Cl₂-EtOAc-MeOH).

Example 3: preparation of ethyl 4-amino-5- {4- [ ({ [ 4-fluoro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

To a solution of THF (1mL) was added intermediate C (55mg, 0.13mmol), followed by 4-fluoro-3- (trifluoromethyl) aniline (30. mu.L, 0.24mmol) and triethylamine (55. mu.L, 0.40 mmol). The reaction was stirred at 40 ℃ for 48 hours. The solution was concentrated to dryness in vacuo and then purified by preparative HPLC (10-100% ACN/H)₂O, containing 0.1% TFA). The resulting fractions were combined, concentrated in vacuo, diluted with EtOAc (5mL), and saturated Na₂CO₃Aqueous (5mL) wash. The aqueous layer was back-extracted with EtOAc (5 mL). The organic layers were combined and dried (Na) ₂SO₄) Filtering and concentratingReduced to dryness to obtain 37mg of the above compound (0.074mmol, yield 56%).

¹H-NMR(CD₃OD) δ 8.08(s, 1H), 7.92(dd, J ═ 6.4, 2.7Hz, 1H), 7.84(s, 1H), 7.69 to 7.62(m, 1H), 7.57(d, J ═ 8.3Hz, 2H), 7.36(d, J ═ 8.7Hz, 2H), 7.26(t, J ═ 8.7Hz, 1H), 4.10(q, J ═ 7.1Hz, 2H), 1.16(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝503；LCMS RT＝3.02min.

Example 4: preparation of ethyl 4-amino-5- [4- ({ [ (2, 2, 4, 4-tetrafluoro-4H-1, 3-benzodioxin-6-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting intermediate D for intermediate C and 2, 2, 4, 4-tetrafluoro-4H-1, 3-benzodioxine-6-amine for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD)δ8.38(s，1H)，8.02(s，1H)，8.01(d，J＝2.2Hz，1H)，7.67(dd，J＝8.5，2.2Hz，1H)，7.62(d，J＝8.2Hz，2H)，7.42(d，J＝8.2Hz，2H)，7.24(d，J＝8.4Hz，1H)，4.17(q，J＝7.2Hz，2H)，1.16(t，J＝7.2Hz，3H)；MS[M+H]⁺＝547；LCMSRT＝3.29min.

EXAMPLE 5 preparation of ethyl 4-amino-5- {4- [ ({ [3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 3- (trifluoromethyl) aniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD)δ8.08(s，1H)，7.93(br s，1H)，7.84(s，1H)，7.63(d，J＝8.4Hz，1H)，7.58(d，J＝8.7Hz，2H)，7.48(t，J＝8.0Hz，1H)，7.38(d，J＝8.4Hz，2H)，7.30(d，J＝8.2Hz，1H)，4.10(q，J＝7.3Hz，2H)，1.16(t，J＝7.3Hz，3H)；MS[M+H]⁺＝485；LCMS RT＝3.43min.

Example 6: preparation of ethyl 4-amino-5- {4- [ ({ [4- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 4- (trifluoromethyl) aniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD) δ 8.07(s, 1H), 7.83(s, 1H), 7.66(d, J ═ 8.3Hz, 2H), 7.60 to 7.55(m, 4H), 7.36(d, J ═ 8.6Hz, 2H), 4.14(q, J ═ 7.2Hz, 2H), 1.16(t, J ═ 7.2Hz, 3H); MS [ M + H ]]⁺＝485；LCMS RT＝3.47min.

Example 7: preparation of ethyl 4-amino-5- {4- [ ({ [2- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 2- (trifluoromethyl) aniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD) δ 8.07(s, 1H), 7.96(d, J ═ 8.7Hz, 1H), 7.83(s, 1H), 7.70 to 7.56(m, 4H), 7.37(d, J ═ 8.7Hz, 2H), 7.30(t, J ═ 7.9Hz, 1H), 4.11(q, J ═ 7.1Hz, 2H), 1.16(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝485；LCMS RT＝2.80min.

Example 8: preparation of ethyl 4-amino-5- {4- [ ({ [2- (trifluoromethoxy) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 2- (trifluoromethoxy) aniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD) δ 8.26(dd, J ═ 8.5, 2.1Hz, 1H), 8.07(s, 1H), 7.83(s, 1H), 7.59(d, J ═ 8.6Hz, 2H), 7.40 to 7.28(m, 4H), 7.14 to 7.07(m, 1H), 4.08(q, J ═ 7.2Hz, 2H), 1.16(t, J ═ 7.2Hz, 3H); MS [ M + H ]]⁺＝501；LCMSRT＝3.07min.

Example 9: preparation of ethyl 4-amino-5- {4- [ ({ [3- (trifluoromethoxy) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 3- (trifluoromethoxy) aniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD)δ8.07(s，1H)，7.83(s，1H)，7.64(br s，1H)7.56(d, J ═ 8.4Hz, 2H), 7.39 to 7.28(m, 5H), 4.10(q, J ═ 7.1Hz, 2H), 1.57(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝501；LCMS RT＝3.08min.

Example 10: preparation of ethyl 4-amino-5- {4- [ ({ [ 4-bromo-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 4-bromo-3- (trifluoromethyl) aniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD) δ 8.07(s, 1H), 8.01(d, J ═ 2.5Hz, 1H), 7.83(s, 1H), 7.68(d, J ═ 8.8Hz, 1H), 7.60 to 7.54(m, 3H), 7.36(d, J ═ 8.5Hz, 2H), 4.08(q, J ═ 7.2Hz, 2H), 1.16(t, J ═ 7.2Hz, 3H); MS [ M + H ] ]⁺＝563；LCMS RT＝3.19min.

Example 11: preparation of ethyl 4-amino-5- {4- [ ({ [4- (trifluoromethoxy) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 4- (trifluoromethoxy) aniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD)δ8.07(s，1H)，7.83(s，1H)，7.57(d，J＝7.3Hz，2H)，7.54(d，J＝6.8Hz，2H)，7.35(d，J＝8.5Hz，2H)，7.20(d，J＝8.8Hz，2H)，4.10(q，J＝7.2Hz，2H)，1.14(t，J＝7.2Hz，3H)；MS[M+H]⁺＝501；LCMSRT＝3.11min.

Example 12: preparation of ethyl 4-amino-5- [4- ({ [ (1-methyl-1H-indazol-5-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 1-methyl-1H-indazol-5-amine for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD) δ 8.12(s, 1H), 7.93(d, J ═ 5.6Hz, 2H), 7.91(s, 1H), 7.59 to 7.51(m, 3H), 7.36(d, J ═ 8.6Hz, 1H), 7.29(d, J ═ 8.6Hz, 2H), 4.07(q, J ═ 7.2Hz, 2H), 4.00(s, 3H), 1.09(t, J ═ 7.2Hz, 3H); MS [ M + H ]]⁺＝471；LCMS RT＝2.90min.

Example 13: preparation of ethyl 4-amino-5- (4- { [ (1, 3-benzodioxol-5-ylamino) carbonyl ] amino } phenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 1, 3-benzodioxol-5-amine for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD)δ8.08(s，1H)，7.84(s，1H)，7.55(d，J＝9.0Hz，2H)，7.35(d，J＝9.0Hz，2H)，7.13(t，J＝1.4Hz，1H)，6.92(br s，1H)，6.76(d，J＝1.2Hz，2H)，5.92(s，2H)，4.08(q，J＝7.1Hz，2H)，1.16(t，J＝7.1Hz，3H)；MS[M+H]⁺＝461；LCMS RT＝3.04min.

Example 14: preparation of ethyl 4-amino-5- [4- ({ [ (2, 2-difluoro-1, 3-benzodioxol-5-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 2, 2-difluoro-1, 3-benzodioxol-5-amine for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD)δ8.08(s，1H)，7.84(s，1H)，7.59(d，J＝2.1Hz，1H)，7.56(d，J＝8.9Hz，2H)，7.36(d，J＝8.9Hz，2H)，7.12(d，J＝8.7Hz，1H)，7.03(dd，J＝8.7，2.1Hz，1H)，6.92(br s，1H)，4.09(q，J＝7.2Hz，2H)，1.15(t，J＝7.2Hz，3H)；MS[M+H]⁺＝497；LCMS RT＝3.44min.

Example 15: preparation of ethyl 4-amino-5- [4- ({ [ (3-chloro-4-fluorophenyl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 3-chloro-4-fluoroaniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD) δ 8.08(s, 1H), 7.84(s, 1H), 7.73(dd, J ═ 6.3, 2.4Hz, 1H), 7.56(d, J ═ 8.8Hz, 2H), 7.36(d, J ═ 8.4Hz, 2H), 7.33 to 7.27(m, 1H), 7.17(t, J ═ 9.2Hz, 1H), 4.09(q, J ═ 7.1Hz, 2H), 1.16(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝469；LCMS RT＝3.37min.

Example 16: preparation of ethyl 4-amino-5- [4- ({ [ (3-isopropylphenyl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 3-isopropylaniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD) δ 8.08(s, 1H), 7.84(s, 1H), 7.56(d, J ═ 8.6Hz, 2H), 7.39 to 7.32(m, 3H), 7.26 to 7.19(m, 2H), 6.92(d, J ═ 7.2Hz, 1H), 4.15(q, J ═ 7.1Hz, 2H), 1.16(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝459；LCMS RT＝3.07min.

Example 17: preparation of ethyl 4-amino-5- [4- ({ [ (4-isopropylphenyl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 4-isopropylaniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD) δ 8.08(s, 1H), 7.84(s, 1H), 7.56(d, J ═ 8.3Hz, 2H), 7.37 to 7.32(m, 4H), 7.18(d, J ═ 8.4Hz, 2H), 4.15(q, J ═ 7.1Hz, 2H), 1.16(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝459；LCMS RT＝3.09min.

Example 18: preparation of ethyl 4-amino-5- [4- ({ [ (3, 4-dichlorophenyl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 3, 4-dichloroaniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD) δ 8.09(s, 1H), 7.84(s, 1H), 7.82(d, J ═ 2.1Hz, 1H), 7.57(d, J ═ 8.3Hz, 2H), 7.44 to 7.29(m, 4H), 6.92(s, 2H), 4.15(q, J ═ 7.2Hz, 2H), 1.16(t, J ═ 7.2Hz, 3H); MS [ M + H ] ]⁺＝485；LCMS RT＝3.14min.

Example 19: preparation of ethyl 4-amino-5- [4- ({ [ (4-bromo-2-fluorophenyl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 4-bromo-2-fluoroaniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD) δ 8.14(s, 1H), 8.12 to 8.07(m, 1H), 7.88(s, 1H), 7.59(d, J ═ 8.7Hz, 2H), 7.42 to 7.27(m, 3H), 6.92(s, 1H), 4.15(q, J ═ 7.1Hz, 2H), 1.16(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝513；LCMS RT＝3.42min.

Example 20: preparation of ethyl 4-amino-5- {4- [ ({ [ 3-methoxy-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 3-methoxy-5- (trifluoromethyl) aniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD) δ 8.08(s, 1H), 7.84(s, 1H), 7.57(d, J ═ 8.9Hz, 2H), 7.40 to 7.35(m, 4H), 6.83(s, 1H), 4.10(q, J ═ 7.1Hz, 2H), 1.16(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝515；LCMS RT＝3.11min.

Example 21: preparation of ethyl 4-amino-5- {4- [ ({ [ 3-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 3-fluoro-5- (trifluoromethyl) aniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD)δ8.08(s，1H)，7.84(s，1H)，7.65(d，J＝10.9Hz，1H)，7.59(s，1H)，7.58(d，J＝8.3Hz，2H)，7.38(d，J＝8.5Hz，2H)，7.05(d，J＝9.1Hz，1H)，4.15(q，J＝7.2Hz，2H)，1.16(t，J＝7.2Hz，3H)；MS[M+H]⁺＝503；LCMS RT＝3.56min.

Example 22: preparation of ethyl 4-amino-5- [4- ({ [ (2, 2, 3, 3-tetrafluoro-2, 3-dihydro-1, 4-benzodioxin-6-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 2, 2, 3, 3-tetrafluoro-2, 3-dihydro-1, 4-benzodioxine-6-amine for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD)δ8.07(s，1H)，7.83(s，1H)，7.63(t，J＝1.3Hz，1H)，7.56(d，J＝8.7Hz，2H)，7.35(d，J＝8.6Hz，2H)，7.20(d，J＝1.3Hz，2H)，4.12(q，J＝7.2Hz，2H)，1.15(t，J＝7.2Hz，3H)；MS[M+H]⁺＝547；LCMS RT＝3.66min.

Example 23: preparation of ethyl 4-amino-5- {4- [ (anilinocarbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting aniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD) δ 8.09(s, 1H), 7.84(s, 1H), 7.56(d, J ═ 8.8Hz, 2H), 7.44(d, J ═ 8.0Hz, 2H), 7.36(d, J ═ 8.8Hz, 2H), 7.33 to 7.27(m, 2H), 7.03(t, J ═ 7.4Hz, 1H), 4.15(q, J ═ 7.1Hz, 2H), 1.15(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝417；LCMS RT＝2.53min.

Example 24: preparation of ethyl 4-amino-5- [4- ({ [ (2-isopropylphenyl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

Step 1: preparation of phenyl (2-isopropylphenyl) carbamate

To a stirred solution of 2-isopropylaniline (200mg, 1.5mmol) in THF (9mL) at room temperature was added pyridine (0.24mL, 3.0mmol) followed by phenyl chloroformate (0.28mL, 2.2 mmol). Some solids precipitated out. The mixture was stirred at room temperature for 4.5 hours. Water was added to the reaction and it was extracted with EtOAc. The organic solution was washed with water (5mL), MgSO₄Dried and then filtered. The filtrate was concentrated in vacuo and crystallized from EtOAc-hexane (1: 9v/v) to give the title compound (130mg, 34%).

¹H-NMR(DMSO-d₆) δ 9.45(s, 1H), 7.44 to 7.36(m, 2H), 7.35 to 7.28(m, 2H), 7.25 to 7.14(m, 5H), 3.27(m, 1H), 1.17(d, J ═ 6.9Hz, 2H); TLCR_f0.33 (9: 1v/v hexane-EtOAc).

Step 2: preparation of the title Compound

Phenyl (2-isopropylphenyl) carbamate (43mg, 0.17mmol) was added to a solution of THF (1.5mL), followed by intermediate B (50mg, 0.17mmol) and triethylamine (23 μ L, 0.17 mmol). The reaction was stirred at 50 ℃ for 36 hours. The solution was concentrated to dryness in vacuo and then purified by preparative HPLC (10-100% ACN/H)₂O, containing 0.1% TFA). The resulting fractions were combined and concentrated in vacuo. EtOAc (5mL) was added and saturated Na ₂CO₃Aqueous (5mL) wash. The aqueous layer was back-extracted with EtOAc (5 mL). The organic layers were combined and dried (Na)₂SO₄) Filtered, and concentrated to dryness to obtain 19mg of the above compound (0.042mmol, yield 25%).

¹H-NMR(CD₃OD) δ 8.08(s, 1H), 7.84(s, 1H), 7.57(d, J ═ 8.6Hz, 2H), 7.53 to 7.49(m, 1H), 7.38 to 7.32(m, 3H), 7.21 to 7.16(m, 2H), 6.92(s, 1H), 4.09(q, J ═ 7.1Hz, 2H), 3.28 to 3.18(m,1H)，1.16(t，J＝7.1Hz，3H)；MS[M+H]⁺＝459；LCMS RT＝3.31min.

example 25: preparation of ethyl 4-amino-5- {4- [ ({ [ 3-tert-butyl-1- (4-fluorophenyl) -1H-pyrazol-5-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 24 was used to prepare the title compound by substituting 3-tert-butyl-1- (4-fluorophenyl) -1H-pyrazol-5-amine for 2-isopropylaniline.

¹H-NMR(DMSO-d₆)δ9.15(s，1H)，8.44(s，1H)，8.12(s，1H)，8.05(br s，1H)，7.93(s，1H)，7.57(dd，J＝9.1，5.0Hz，2H)，7.49(d，J＝8.6Hz，2H)，7.37(t，J＝8.8Hz，2H)，7.28(d，J＝9.1Hz，2H)，6.38(s，1H)，5.05(br s，1H)，4.02(q，J＝7.1Hz，2H)，1.27(s，9H)，1.08(t，J＝7.1Hz，3H)；MS[M+H]⁺＝557；LCMS RT＝3.12min.

Example 26: preparation of ethyl 4-amino-5- {4- [ ({ [3, 5-bis (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 24 was used to prepare the title compound by substituting 3, 5-bis (trifluoromethyl) aniline for 2-isopropylaniline.

¹H-NMR(CD₃OD)δ8.11(s，2H)，8.09(s，1H)，7.86(s，1H)，7.60(d，J＝8.8Hz，2H)，7.52(s，1H)，7.35(d，J＝8.5Hz，2H)，4.07(q，J＝7.1Hz，2H)，1.14(t，J＝7.1Hz，3H)；MS[M+H]⁺＝553；LCMS RT＝3.40min.

Example 27: preparation of ethyl 4-amino-5- {4- [ ({ [ 2-morpholin-4-yl-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 24 was used to prepare the title compound by substituting 2-morpholin-4-yl-5- (trifluoromethyl) aniline for 2-isopropylaniline.

¹H-NMR(CD₃OD) δ 8.50(s, 1H).8.09(s, 1H), 7.85(s, 1H), 7.62(d, J ═ 8.9Hz, 2H), 7.42 to 7.29(d, J ═ 8.7Hz, 4H), 4.08(q, J ═ 7.1Hz, 2H), 3.98 to 3.93(m, 4H), 2.98 to 2.89(m, 4H), 1.16(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝570；LCMS RT＝3.18min.

Example 28: preparation of ethyl 4-amino-5- [4- ({ [ (2, 2, 3, 3-tetrafluoro-2, 3-dihydro-1, 4-benzodioxin-5-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 24 was used to prepare the title compound by substituting 2, 2, 3, 3-tetrafluoro-2, 3-dihydro-1, 4-benzodioxine-5-amine for 2-isopropylaniline.

¹H-NMR(CD₃OD)δ8.10(d，J＝8.0Hz，1H)，8.08(s，1H)，7.84(s，1H)，7.59(d，J＝8.2Hz，2H)，7.38(d，J＝8.2Hz，2H)，7.23(t，J＝8.2Hz，1H)，6.93(d，J＝8.2Hz，1H)，4.10(q，J＝7.1Hz，2H)，1.16(t，J＝7.1Hz，3H)；MS[M+H]⁺＝547；LCMS RT＝3.27min.

Example 29: preparation of ethyl 4-amino-5- [4- ({ [ (6-methoxypyrimidin-4-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 24 was used to prepare the title compound by substituting 6-methoxypyrimidin-4-amine for 2-isopropylaniline.

¹H-NMR(DMSO-d₆)δ9.82(s，1H)，9.60(s，1H)，8.50(s，1H)，8.13(s，1H)，7.93(s，1H)，7.56(d，J＝8.5Hz，2H)，7.33(d，J＝8.5Hz，2H)，7.09(d，J＝1.1Hz，1H)，4.07(q，J＝7.1Hz，2H)，3.89(s，3H)，1.09(t，J＝7.1Hz，3H)；MS[M+H]⁺＝449；LCMS RT＝2.94min.

Example 30: preparation of N- {4- [ 4-amino-6- (morpholin-4-ylmethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

To intermediate F (40.0mg, 0.08mmol) in CH₂Cl₂To a solution (3.0mL) were added AcOH (0.03mL, 0.46mmol) and morpholine (0.01mL, 0.11 mmol). The reaction was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (49.0mg, 0.23mmol) was added. The reaction was stirred at room temperature until completion. Will react with CH₂Cl₂Dilute, move to separatory funnel, and use saturated NaHCO₃Aqueous (2 x) wash. By CH₂Cl₂(2X) back-extracting the aqueous phase. The organic phase was dried (Na)₂SO₄) And evaporated to give a crude oil which is purified by HPLC (10-90% ACN/H)₂O), the title compound (30mg, 70%) was obtained.

¹H-NMR(CD₃OD)δ8.61(d，J＝8.0Hz，1H)，7.76(s，1H)，7.66(s，1H)，7.62(s，1H)，7.60(s，1H)，7.40(d，J＝8.0Hz，2H)，7.33(d，J＝8.0Hz，2H)，3.65-3.62(m，4H)，3.48(s，2H)，2.40-2.36(m，4H)；MS[M+H]⁺＝530；LCMS RT＝2.22min；TLCR_f0.27 (1: 3v/v acetone: CH)₂Cl₂).

Example 31: preparation of N- (4- { 4-amino-6- [ (4-methylpiperazin-1-yl) methyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Replacement of morpholine by 1-methylpiperazine and preparative TLC (20: 180: 1v/v/v MeOH-CH)₂Cl₂-NH₄OH) and the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD)δ8.61(d，J＝8.0Hz，1H)，7.77(s，1H)，7.67(s，1H)，7.61(d，J＝8.0Hz，2H)，7.41-7.33(m，4H)，3.53(s，2H)，3.35(s，3H)，2.50(br s，4H)，2.32(m，4H)；MS[M+H]⁺＝543；LCMS RT＝2.15min；TLCR_f＝0.23(20∶180∶1v/v/v MeOH-CH₂Cl₂-NH₄OH).

Example 32: preparation of N- [4- (4-amino-6- { [ (2-methoxyethyl) amino ] methyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Replacement of morpholine by 2-methoxyethylamine and by use of 0-15% MeOH-CH₂Cl₂Mplc (analogix) of (a) was purified and the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.61 to 8.59(d, J ═ 7.8Hz, 1H), 7.80(s, 1H), 7.79(s, 1H), 7.67 to 7.65(d, J ═ 8.6Hz, 2H), 7.41 to 7.39(d, J ═ 8.6Hz, 2H), 7.35 to 7.33(d, J ═ 8.9Hz, 2H), 3.99(s, 2H), 3.48 to 3.46(t, J ═ 5.1Hz, 2H), 3.31(s, 3H), 2.91 to 2.89(t, J ═ 5.2Hz, 2H); MS [ M + H ]]⁺＝518；LCMS RT＝2.26min；TLCR_f＝0.30(15∶85v/v MeOH-CH₂Cl₂).

Example 33: preparation of N- {4- [ 4-amino-6- ({ [2- (methylthio) ethyl ] amino } methyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Substituting 2- (methylthio) ethylamine for morpholine and by using 0-15% MeOH-CH₂Cl₂Mplc (analogix) of (a) was purified and the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.62 to 8.60(d, J ═ 7.7Hz, 1H), 7.78(s, 1H), 7.71(s, 1H), 7.65 to 7.63(d, J ═ 8.6Hz, 2H), 7.42 to 7.40(d, J ═ 8.5Hz, 2H), 7.35 to 7.33(d, J ═ 8.8Hz, 2H), 3.80(s, 2H), 2.75 to 2.72(t, J ═ 6.5Hz, 2H), 2.58 to 2.55(t, J ═ 6.6Hz, 2H), 1.99(s, 3H); MS [ M + H ] ]⁺＝534；LCMS RT＝2.36min；TLCR_f＝0.50(15∶85v/v MeOH-CH₂Cl₂).

Example 34: preparation of N- [4- (4-amino-6- { [ (2-methoxyethyl) (methyl) amino ] methyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Substituting 2-methoxy-N-methylethylamine for morpholine by using 0-15% MeOH-CH₂Cl₂Mplc (analogix) of (a) was purified and the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.61 to 8.59(d, J ═ 7.9Hz, 1H), 7.80(s, 1H), 7.78(s, 1H), 7.66 to 7.64(d, J ═ 8.6Hz, 2H), 7.40 to 7.38(d, J ═ 8.5Hz, 2H), 7.35 to 7.32(d, J ═ 8.9Hz, 2H), 3.90(s, 2H), 3.47 to 3.44(t, J ═ 5.4Hz, 2H), 3.29(s, 3H), 2.79 to 2.77(t, J ═ 5.4Hz, 2H), 2.39(s, 3H); MS [ M + H ]]⁺＝532；LCMS RT＝2.69min；TLCR_f＝0.16(15∶85v/v MeOH-CH₂Cl₂).

Example 35: preparation of N- {4- [ 4-amino-6- (pyrrolidin-1-ylmethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Pyrrolidine was used instead of morpholine and by using 0-15% MeOH-CH₂Cl₂Mplc (analogix) of (a) was purified and the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.62 to 8.60(d, J ═ 7.8Hz, 1H), 7.78(s, 1H), 7.74(s, 1H), 7.64 to 7.62(d, J ═ 8.4Hz, 2H), 7.39 to 7.37(d, J ═ 8.6Hz, 2H), 7.35 to 7.33(d, J ═ 8.8Hz, 2H), 3.77(s, 2H), 2.63 to 2.60(m, 4H), 1.82 to 1.78(m, 4H); MS [ M + H ] ]⁺＝514；LCMS RT＝2.69min；TLCR_f＝＜0.10(15∶85v/v MeOH-CH₂Cl₂).

Example 36: preparation of N- {4- [ 4-amino-6- ({ [2- (methylsulfonyl) ethyl ] amino } methyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

2- (methylsulfonyl) ethylamine hydrochloride was used in place of morpholine and by using 0-15% MeOH-CH₂Cl₂Mplc (analogix) of (a) was purified and the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.62 to 8.60(d, J ═ 7.5Hz, 1H), 7.77(s, 1H), 7.69(s, 1H), 7.64 to 7.62(d, J ═ 8.7Hz, 2H), 7.42 to 7.40(d, J ═ 8.9Hz, 2H), 7.35 to 7.33(d, J ═ 8.9Hz, 2H), 3.77(s, 2H), 3.22 to 3.19(t, J ═ 6.5Hz, 2H), 3.03 to 2.99(t, J ═ 6.7Hz, 2H), 2.96(s, 3H); MS [ M + H ]]⁺＝566；LCMS RT＝2.25min；TLCR_f＝0.21(15∶85v/vMeOH-CH₂Cl₂).

Example 37: preparation of N- {4- [ 4-amino-6- ({ [2- (dimethylamino) ethyl ] amino } methyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

By substituting N, N-dimethylethane-1, 2-diamineTemorph, and purification by HPLC (10-90% ACN/H)₂O), the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD)δ8.62(d，J＝7.4Hz，1H)，7.77(s，1H)，7.71(s，1H)，7.64(d，J＝8.5Hz，2H)，7.40(d，J＝8.5Hz，2H)，7.33(d，J＝8.0Hz，2H)，3.73(s，2H)，2.61(t，J＝6.5Hz，2H)，2.37(t，J＝6.9Hz，2H)，2.17(s，6H)；MS[M+H]⁺＝531；LCMS RT＝1.96min.

Example 38: preparation of N- {4- [ 4-amino-6- (piperidin-1-ylmethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Piperidine instead of morpholine and purification by HPLC (10-90% ACN/H)₂O), the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.63(d, J ═ 8.2Hz, 1H), 7.77(s, 1H), 7.73(s, 1H), 7.62(d, J ═ 8.6Hz, 2H), 7.37(d, J ═ 8.8Hz, 2H), 7.34(d, J ═ 8.8Hz, 2H), 3.50(s, 2H), 2.36 to 2.27(m, 4H), 1.60 to 1.50(m, 4H), 1.40 to 1.35(m, 2H); MS [ M + H ]]⁺＝528；LCMS RT＝2.34min.

Example 39: preparation of N- [4- (4-amino-6- { [ (3, 3, 3-trifluoropropyl) amino ] methyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

By 3, 3, 3-Trifluoropropan-1-amine instead of morpholine and purification by HPLC (10-90% ACN/H)₂O), the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.62(d, J ═ 7.3Hz, 1H), 7.77(s, 1H), 7.70(s, 1H), 7.63(d, J ═ 8.3Hz, 2H), 7.39(d, J ═ 7.9Hz, 2H), 7.34(d, J ═ 7.4Hz, 2H), 3.73(s, 2H), 2.74(t, J ═ 7.3Hz, 2H), 2.37 to 2.22(m, 2H); MS [ M + H ]]⁺＝556；LCMS RT＝2.41min.

Example 40: preparation of N- [4- (4-amino-6- { [4- (pyridin-4-ylmethyl) piperazin-1-yl ] methyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Replacement of morpholine by 1- (pyridin-4-ylmethyl) piperazine and purification by HPLC (10-90% ACN/H)₂O), the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.62(d, J ═ 7.3Hz, 1H), 8.43(dd, J ═ 4.6, 1.6Hz, 2H), 7.97(s, 1H), 7.77(s, 1H), 7.67(s, 1H), 7.62(d, J ═ 8.5Hz, 2H), 7.41 to 7.31(m, 6H), 3.54(s, 2H), 3.51(s, 2H), 3.32 to 3.29(m, 4H); MS [ M + H ]]⁺＝620；LCMS RT＝2.32min.

Example 41: preparation of N- [4- (4-amino-6- { [4- (2-methoxyethyl) piperazin-1-yl ] methyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Replacement of morpholine by 1- (2-methoxyethyl) piperazine and purification by HPLC (10-90% ACN/H)₂O), the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.61(d, J ═ 7.1Hz, 1H), 7.77(s, 1H), 7.67(s, 1H), 7.62(d, J ═ 8.9Hz, 2H), 7.39(d, J ═ 8.9Hz, 2H), 7.34(d, J ═ 8.3Hz, 2H), 3.50(s, 3H), 3.48(t, J ═ 5.3Hz, 2H), 3.29(s, 2H), 2.58 to 2.38(m, 10H); MS [ M + H ]]⁺＝587；LCMS RT＝2.55min.

Example 42: preparation of N- [4- (4-amino-6- { [ (4-methoxyphenyl) amino ] methyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

4-Methoxyaniline instead of morpholine and purification by HPLC (10-90% ACN/H)₂O), the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.62(d, J ═ 7.4Hz, 1H), 7.75(s, 1H), 7.65 to 7.58(m, 3H), 7.41(d, J ═ 8.1Hz, 2H), 7.34(d, J ═ 8.1Hz, 2H), 6.70(d, J ═ 8.8Hz, 2H), 6.56(d, J ═ 8.9Hz, 2H), 4.16(s, 2H), 3.68(s, 3H); MS [ M + H ]]⁺＝566；LCMS RT＝2.93min.

Example 43: preparation of N- (4- { 4-amino-6- [ (dimethylamino) methyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Replacement of morpholine by N-methyl methylamine and purification by HPLC (10-90% ACN/H)₂O), the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD)δ8.62(d，J＝8.0Hz，1H)，7.78(s，1H)，7.70(s，1H)，7.63(d，J＝8.6Hz，2H)，7.37(d，J＝8.6Hz，2H)，7.34(d，J＝8.4Hz，2H)，3.52(s，2H)，2.18(s，6H)；MS[M+H]⁺＝488；LCMS RT＝2.55min.

Example 44: preparation of N- (4- { 4-amino-6- [ (methylamino) methyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Methylamine instead of morpholine and purification by HPLC (10-90% ACN/H)₂O), the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD)δ8.62(d，J＝7.4Hz，1H)，7.77(s，1H)，7.70(s，1H)，7.64(d，J＝8.6Hz，2H)，7.39(d，J＝8.6Hz，2H)，7.34(d，J＝8.5Hz，2H)，3.70(s，2H)，2.33(s，3H)；MS[M+H]⁺＝474；LCMS RT＝2.55min.

Example 45: preparation of N- {4- [ 4-amino-6- ({ [3- (dimethylamino) propyl ] amino } methyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Using N, N-dimethylethane-1, 2-diamine instead of morpholinePurification by HPLC (10-90% ACN/H)₂O), the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.60(d, J ═ 8.0Hz, 1H), 7.97(s, 1H), 7.84(s, 1H), 7.69(d, J ═ 8.0Hz, 2H), 7.43(d, J ═ 8.0Hz, 2H), 7.35(d, J ═ 8.6Hz, 2H), 4.20(s, 2H), 3.04(t, J ═ 7.3Hz, 2H), 2.94(t, J ═ 7.3Hz, 2H), 2.79(s, 6H), 2.00 to 1.89(m, 2H); MS [ M + H ]]⁺＝545；LCMS RT＝2.28min.

Example 46: preparation of N- {4- [ 4-amino-6- ({ [4- (trifluoromethyl) phenyl ] amino } methyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

4- (trifluoromethyl) aniline instead of morpholine and purification by HPLC (10-90% ACN/H)₂O), the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.68(d, J ═ 8.0Hz, 1H), 7.76(s, 1H), 7.67 to 7.62(m, 3H), 7.43(d, J ═ 8.8Hz, 2H), 7.36 to 7.27(m, 4H), 6.61(d, J ═ 8.7Hz, 2H), 4.67(s, 2H); MS [ M + H ]]⁺＝604；LCMS RT＝3.31min.

Example 47: preparation of N- (4- { 4-amino-6- [ (pyridin-3-ylamino) methyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Replacement of morpholine by pyridin-3-amine and performance by HPLCPurification (10-90% ACN/H₂O), the procedure used for the preparation of example 30 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.61(d, J ═ 8.2Hz, 1H), 7.82(d, J ═ 2.9Hz, 1H), 7.75(s, 1H), 7.72(dd, J ═ 5.5, 1.6Hz, 1H), 7.64 to 7.59(m, 3H), 7.41(d, J ═ 7.8Hz, 2H), 7.33(d, J ═ 8.4Hz, 2H), 7.09(dd, J ═ 8.3, 4.8Hz, 1H), 6.94 to 6.88(m, 1H), 4.24(s, 2H); MS [ M + H ]]⁺＝537；LCMS RT＝2.08min.

Example 48: preparation of ethyl 4-amino-5- {4- [ ({ [5- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

Step 1: preparation of phenyl [5- (trifluoromethyl) pyridin-2-yl ] carbamate

5- (trifluoromethyl) pyridin-2-amine (100mg, 0.617mmol) and N, N-diisopropylethylamine (159.5mg, 215. mu.L, 1.234mmol) at 5mL CH at room temperature₂Cl₂The solution in (1) was treated with phenyl chloroformate (106mg, 85. mu.L, 0.68mmol), and stirred for 3 hours. The solution was diluted with EtOAc, washed 2 times with 1N hci and 1 time with brine. The organic layer was dried (Na)₂SO₄) And concentrated to give a white solid. Trituration with 10% EtOAc in hexane afforded 120mg (69%, 0.42mmol) of the above compound as a white solid.

¹H-NMR(DMSO-d₆) δ 11.26(s, 1H), 8.70(s, 1H), 8.22 to 8.16(m, 1H), 7.99(d, J ═ 8Hz, 1H), 7.45 to 7.40(m, 2H), c) 7.30 to 7.20(m, 3H)

Step 2: preparation of the title Compound

A mixture of intermediate B (57.9mg, 0.195mmol) and triethylamine in 2mL THF was heated to 55 deg.C to form a cloudy solution. Phenyl [5- (trifluoromethyl) pyridin-2-yl ] carbamate (50mg, 0.177mmol) as a solid was added to the solution, and the mixture was stirred overnight. After 16 h, the solid precipitate was filtered, washed with ethyl acetate and dried to yield 66mg (77%, 0.14mmol) of the above compound as a yellow solid.

¹H-NMR(DMSO-d₆) δ 9.33(s, 1H), 8.95(d, J ═ 2.3Hz, 1H), 8.63 to 8.61(m, 1H), 8.13(s, 1H), 8.07(br s, 1H), 7.93(s, 1H), 7.56 to 7.53(m, 2H), 7.51 to 7.48(m, 1H), 7.40(br s, 1H), 7.34 to 7.32(m, 2H), 5.09(br s, 1H), 4.11 to 4.06(q, J ═ 6.9Hz, 2H), 1.13 to 1.10(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝486.0；LCMS RT＝3.36min；TLCR_f＝0.46(100％EtOAc).

Example 49: 4-amino-5- [4- ({ [ (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid ethyl ester

The procedure used for the preparation of example 48 was used to prepare the title compound by substituting 3-tert-butyl-1-methyl-1H-pyrazol-5-amine for 5- (trifluoromethyl) pyridin-2-amine and purifying by recrystallization (EtOAc/EtOH).

¹H-NMR(DMSO-d₆)δ9.08(s，1H)，8.56(s，1H)，8.12(s，1H)，8.11-8.04(bs，1H)，7.92(s，1H)，7.53(d，J＝8.7Hz，2H)，7.30(d，J＝8.7Hz，2H)，6.05(s，1H)，5.14-5.01(bs，1H)4.03(q，J＝7.2Hz，2H)，1.09(t，J＝7.2Hz，3H)；MS[M+H]⁺＝477.2；LCMS RT＝2.60min.

Example 50: preparation of ethyl 4-amino-5- [4- ({ [ (4-tert-butylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

4-tert-Butylpyridin-2-amine instead of 5- (trifluoromethyl) pyridin-2-amine and purification by HPLC (10-90% ACN/H)₂O), the procedure used for the preparation of example 48 was used to prepare the title compound.

¹H-NMR(DMSO-d₆)δ10.88(s，1H)，9.44(s，1H)，8.19(d，J＝5.7Hz)，8.12(s，1H)，8.11-8.10(bs，1H)，7.92(s，1H)，7.61(d，J＝8.4Hz，2H)，7.49(s，1H)，7.32(d，J＝8.4Hz，2H)7.09-7.03(m，1H)，5.01-5,18(bs，1H)，4.07(q，J＝7.2Hz，2H)，1.25(s，9H)，1.08(t，J＝7.2Hz，3H)；MS[M+H]⁺＝474.2；LCMS RT＝2.63min；TLCR_f＝0.27(3∶7v/v THF-CH₂Cl₂).

Example 51: preparation of ethyl 4-amino-5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

Replacement of 5- (trifluoromethyl) pyridin-2-amine with 4- (trifluoromethyl) pyridin-2-amine and purification by flash chromatography (1: 3 v/vTHF-CH)₂Cl₂) The procedure used for the preparation of example 48 was used to prepare the title compound.

¹H-NMR(DMSO-d₆)δ10.19(s，1H)，9.89(s，1H) 8.52(d, J ═ 5.4Hz, 1H), 8.12(s, 1H), 8.12 to 8.10(m, 2H), 7.93(s, 1H), 7.59(d, J ═ 6.9Hz, 2H), 7.48 to 7.30(m, 3H), 5.15 to 5.10(m, 1H), 4.06(q, J ═ 7.2Hz, 2H), 1.11(t, J ═ 7.2Hz, 3H); MS [ M + H ]]⁺＝486.1；LCMS RT＝3.33min；TLCR_f＝0.27(3∶7v/v THF-CH₂Cl₂).

Example 52: preparation of ethyl 4-amino-5- [4- ({ [ (3-tert-butylisoxazol-5-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 48 was used to prepare the title compound by substituting 3-tert-butylisoxazol-5-amine for 5- (trifluoromethyl) pyridin-2-amine and purifying by washing the precipitate formed during the reaction (1: 1v/v EtOAc-hexane).

¹H-NMR(DMSO-d₆)δ10.17(s，1H)，9.02(s，1H)，8.13(s，1H)，8.0-8.1(bs，1H)，7.93(s，1H)，7.54(d，J＝8.7Hz，2H)，7.32(J＝8.7Hz，2H)，6.07(s，1H)，5.2-5.0(bs，1H)，4.07(q，J＝6.9Hz，2H)，1.25(ms，9H)，1.09(t，J＝6.9Hz，3H)；MS[M+H]⁺＝464.2；LCMS RT＝3.25min；TLCR_f＝0.33(3∶7v/v THF-CH₂Cl₂).

Example 53: preparation of 4-amino-5- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid

To a solution of MeOH (1.5mL) was added 4-amino-5- {4- [ ({ [ 4-chloro- ] --3- (trifluoromethyl) phenyl]Amino } carbonyl) amino]Phenyl } pyrrolo [2, 1-f][1，2，4]Triazine-6-carboxylic acid ethyl ester, the compound of example 2 (22mg, 0.042mmol), THF (3.0mL), and 1N NaOH (0.42mL, 0.42 mmol). The reaction was heated to 65 ℃ for 17 hours. Cooling to room temperature and allowing the reaction to pass/silica gel plug filtration with 85: 15v/v CH₂Cl₂-MeOH elution. The filtrate was concentrated to dryness in vacuo and taken up with CH₂Cl₂Diluting and drying (MgSO)₄) Filtered and concentrated to dryness in vacuo to give 3.8mg of the above compound (0.0077mmol, 18% yield).

¹H-NMR(DMSO-d₆) δ 8.18(br s, 1H), 7.98(br s, 1H), 7.88(s, 1H), 7.67(br s, 1H), 7.59 to 7.57(d, J ═ 8.6Hz, 1H), 7.53 to 7.51(d, J ═ 7.7Hz, 2H), 7.34 to 7.32(d, J ═ 8.0Hz, 2H), 6.56(s, 1H), 5.06(br s, 1H); MS [ M + H ]]⁺＝491；LCMS RT＝3.18min；TLCR_f＝0.20(85∶15v/v CH₂Cl₂-MeOH).

Example 54: preparation of ethyl 4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

To a solution in MeOH (4.0mL) was added intermediate E (30mg, 0.060mmol), THF (2.0mL), and 1N NaOH (0.24mL, 0.24 mmol). The reaction was stirred at room temperature for 2 days. The solution was transferred to a Biotage Samplet and dried in a vacuum oven. The product was purified by flash chromatography (Biotage) using 5: 4: 1v/v/v CH ₂Cl₂EtOAc-MeOH elution. The pure fractions were combined and concentrated to dryness in vacuo to give 14mg of the above compound (0.029mmol, 48% yield).

¹H-NMR(DMSO-d₆) δ 9.33(s, 1H), 8.96(d, 1H, J ═ 2.4Hz), 8.63 to 8.61(dd, 7.3Hz, 2.4Hz, 1H), 8.15(s, 1H), 8.09(br s, 1H), 7.93(s, 1H), 7.56 to 7.54(m, 2H), 7.50 to 7.47(m, 1H), 7.40(m, 1H), 7.34 to 7.32(m, 2H), 5.09(br s, 1H), 3.63(s, 3H); MS [ M + H ]]⁺＝489；LCMS RT＝2.85min；TLCR_f＝0.55(5∶4∶1v/v/v CH₂Cl₂-EtOAc-MeOH).

Example 55: preparation of 4-amino-N- [3- (dimethylamino) propyl ] -5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

To a solution of intermediate G (41mg, 0.09mmol) in 0.5mL DMF was added a solution of py-BOP (32.0mg, 0.13mmol) N, N-dimethylpropane-1, 3-diamine (13.25mg, 0.13mmol) in THF, diisopropylethylamine (24.9mg, 0.19mmol) and 4-dimethylaminopyridine (4mg, 0.04 mmol). After 12 hours, the reaction was run at 150mLCH₂Cl₂Diluted, washed with water and brine, and then dried over sodium sulfate. The solution was concentrated and the residue was purified by flash column (20% THF in CH)₂Cl₂Of (b) to obtain 25.4mg of a material containing impurities. Trituration with ethyl acetate afforded 10.3mg of the desired product (0.018mmol, 21 mg).

¹H-NMR(MeOD-d₆) δ 8.60(d, J ═ 8Hz, 1H), 7.97(3, 1H), 7.84(s, 1H), 7.65(d, J ═ 9Hz, 1H), 7.43(d, J ═ 9Hz, 2H), 7.33(d, J ═ 9Hz, 2H), 3.25(t, J ═ 7Hz, 2H), 2.23(t, J ═ 7Hz, 2H), 2.21(s, 6H), 1.61(ap quintuple, J ═ 7Hz, 2H); MS [ M + H ]]⁺＝559.3；LCMS RT＝2.63min；TLCR_f＝0.14(1∶2v/v THF∶CH₂Cl₂).

Example 56: preparation of 4-amino-N- [2- (dimethylamino) ethyl ] -5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The present compound was prepared as described in example 55, substituting N, N-dimethylethane-1, 2-diamine for N, N-dimethylpropane-1, 3-diamine to give 23.7mg of the product as a white solid (0.044mmol, 34% yield).

¹H-NMR(CD₃OD)δ8.62(d，J＝8Hz，1H)，8.01(s，1H)，7.84(s，1H)，7.66(d，J＝8Hz，1H)，7.42(d，J＝8Hz，2H)，7.35(d，J＝8Hz，2H)，3.90(t，J＝7Hz，2H)，2.40(t，J＝7Hz，2H)，2.20(s，6H)；MS[M+H]⁺＝545.2；LCMS RT＝2.13min；TLCR_f＝0.31(1∶3∶9v/v/v 2MNH₃In MeOH/THF/CH₂Cl₂In (1).

Example 57: preparation of N- {4- [ 4-amino-6- (morpholin-4-ylcarbonyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The present compound was prepared by the same procedures as in example 55, using morpholine instead of N, N-dimethylpropane-1, 3-diamine, to obtain 7.2mg of a product as a white solid (0.013mmol, 16%).

¹H-NMR(CD₃OD)δ8.62(d，J＝8Hz，1H)，7.91(s，1H)，7.80(s，1H)，7.66(d，J＝9Hz，1H)，7.43-7.39(m，2H)，7.34(d，J＝9Hz，2H)，3.26-3.45(m，4H)，3.2-3.0(m，4H)，MS[M+H]⁺＝544.6；LCMSRT＝2.49min；TLCR_f＝0.34(1∶2v/v THF∶CH₂Cl₂).

Example 58: preparation of 4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N, N-dimethylpyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The present compound was obtained in the same manner as in example 55, except for using N-methylmethylamine instead of N, N-dimethylpropane-1, 3-diamine, and 7.0mg of a product was obtained as a white solid (0.014mmol, 17%)

¹H-NMR(CD₃OD)δ8.61(d，J＝8Hz，1H)，7.85(s，1H)，7.79(s，1H)，7.60(d，J＝9Hz，1H)，7.38(d，J＝9Hz，2H)，7.34(d，J＝9Hz，2H)，2.93(s，3H)，2.72(s，3H)，MS[M+H]⁺＝502.2；LCMSRT＝2.54min；TLCR_f＝0.29(1∶2v/vTHF∶CH₂Cl₂).

Example 59: preparation of 4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N-methylpyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The present compound was prepared by the same procedures as in example 55, using methylamine instead of N, N-dimethylpropane-1, 3-diamine, to obtain mg of the product as a white solid (mmol, yield)

¹H-NMR(CD₃OD)δ8.61(d，J＝8Hz，1H)，7.85(s，1H)，7.97(s，1H)，7.83(d，J＝9Hz，1H)，7.61(d，J＝9Hz，2H)，7.43-7.39(m，2H)7.34(d，J＝9Hz，2H)，2.93(s，3H)；MS[M+H]⁺＝488.5；LCMS RT＝2.50min；TLCR_f＝0.26(1∶2v/v THF∶CH₂Cl₂).

Example 60: preparation of N- (4- { 4-amino-6- [ (4-methylpiperazin-1-yl) carbonyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The present compound was obtained by the same procedures as in example 55, using 1-methylpiperazine instead of N, N-dimethylpropane-1, 3-diamine, to obtain 6.2mg of a product as a white solid (0.011mmol, 9% yield).

¹H-MR(CD₃OD)δ8.62-8.59(m，1H)，7.86(s，1H)，7.80(d，J＝9Hz，1H)，7.64(d，J＝9Hz，2H)，7.42-7.39(m，2H)7.34(d，J＝9Hz，2H)，3.65-3.57(m，2H)，3.56-3.50(m，2H)，3.20-3.11(m，2H)，2.13(s，3H)；MS[M+H]⁺＝557.0；LCMS RT＝2.13min；TLCR_f＝0.21(1∶1v/v THF∶CH₂Cl₂).

Example 61: preparation of 4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (4-pyrrolidin-1-ylbutyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

Replacement of N, N-dimethylpropane-1, 3-diamine with 4-pyrrolidin-1-ylbutan-1-amine and purification by HPLC (10-90% ACN/H) ₂O), the procedure used for the preparation of example 55 was used to prepare the title compound.

¹H-NMR(CD₃OD)δ8.61(d，J＝7.4Hz，1H)，7.98(s，1H)，7.83(s，1H)，7.66(d，J＝7.3Hz，2H)，7.43(d，J＝8.4Hz，2H)，7.34(d，J＝8.3Hz，2H)，3.24(t，J＝5.8Hz，2H)，2.73to 2.63(m，4H)，2.57(t，J＝5.8Hz，2H)，1.86to 1.78(m，4H)，1.48to 1.39(m，4H)；MS[M+H]⁺＝599；LCMS RT＝2.66min.

Example 62: preparation of 4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (3-pyrrolidin-1-ylpropyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

Replacement of N, N-dimethylpropane-1, 3-diamine with 3-pyrrolidin-1-ylpropan-1-amine and purification by HPLC (10-90% ACN/H)₂O), the procedure used for the preparation of example 55 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.62(d, J ═ 7.7Hz, 1H), 8.03(s, 1H), 7.84(s, 1H), 7.66(d, J ═ 8.0Hz, 2H), 7.43(d, J ═ 8.4Hz, 2H), 7.35(d, J ═ 8.2Hz, 2H), 3.28 to 3.21(m, 2H), 2.64 to 2.55(m, 4H), 2.44 to 2.36(m, 2H), 1.84 to 1.76(m, 4H), 1.71 to 1.60(m, 2H); MS [ M + H ]]⁺＝585；LCMS RT＝2.63min.

Example 63: preparation of 4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2-pyrrolidin-1-ylethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

Replacement of N, N-dimethylpropane-1, 3 with 2-pyrrolidin-1-ylethylamineDiamine and purification by HPLC (10-90% ACN/H)₂O), the procedure used for the preparation of example 55 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.62(d, J ═ 7.6Hz, 1H), 7.97(s, 1H), 7.84(s, lH), 7.66(d, J ═ 7.8Hz, 2H), 7.43(d, J ═ 8.2Hz, 2H), 7.35(d, J ═ 8.5Hz, 2H), 3.25 to 3.20(m, 2H), 2.64 to 2.50(m, 6H), 1.82 to 1.74(m, 4H); MS [ M + H ]]⁺＝571；LCMS RT＝2.23min.

Example 64: preparation of 4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (3-morpholin-4-ylpropyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

Replacement of N, N-dimethylpropane-1, 3-diamine with 3-morpholin-4-ylpropan-1-amine and purification by HPLC (10-90% ACN/H)₂O), the procedure used for the preparation of example 55 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.62(d, J ═ 7.2Hz, 1H), 7.97(s, 1H), 7.84(s, 1H), 7.66(d, J ═ 8.3Hz, 2H), 7.44(d, J ═ 8.3Hz, 2H), 7.34(d, J ═ 8.7Hz, 2H), 3.64(t, J ═ 3.6Hz, 4H), 3.26(t, J ═ 6.1Hz, 2H), 2.43 to 2.37(m, 4H), 2.21(t, J ═ 7.7Hz, 2H), 1.68 to 1.54(m, 2H); MS [ M + H ]]⁺＝601；LCMS RT＝2.21min.

Example 65: preparation of 4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2-morpholin-4-ylethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

2-Morpholin-4-ylethylamine was used instead of N, N-dimethylpropane-1, 3-diamine and purified by HPLC (10-90% ACN/H) ₂O), the procedure used for the preparation of example 55 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.61(d, J ═ 7.8Hz, 1H), 8.03(s, 1H), 7.84(s, 1H), 7.69(d, J ═ 8.4Hz, 2H), 7.46(d, J ═ 8.5Hz, 2H), 7.35(d, J ═ 8.2Hz, 2H), 3.60(t, J ═ 5.0Hz, 4H), 3.39 to 3.33(m, 2H), 2.37 to 2.30(m, 6H); MS [ M + H ]]⁺＝587；LCMS RT＝2.21min.

Example 66: preparation of N- {4- [ 4-amino-6- (3-morpholin-4-ylpropyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

To intermediate I (53mg, 0.11mmol) in CH₂Cl₂To the solution in (3.0mL) were added AcOH (0.036mL, 0.63mmol) and morpholine (0.019mL, 0.22 mmol). The reaction was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (66mg, 0.31mmol) was added. The reaction was stirred at room temperature until completion. Will react with CH₂Cl₂Dilute, move to separatory funnel, and use saturated NaHCO₃Aqueous (2 x) wash. By CH₂Cl₂(2X) back-extracting the aqueous phase. The organic phase was dried (Na)₂SO₄) And evaporated to give a crude oil which is purified by HPLC (10-90% ACN/H)₂O), the title compound (15mg, 24%) was obtained.

¹H-NMR(CD₃OD)δ8.62(d，J＝7.8Hz，1H)，7.74(s，1H)，7.62(d，J＝8.2Hz，2H)，7.53(s，1H)，7.38to7.31(m，4H)，3.62(t，J＝5.2Hz，4H)，2.59(t，J＝7.3Hz，2H)，2.38 to 2.23(m，6H)，1.74to 1.62(m，2H)；MS [M+H]⁺＝558；LCMS RT＝2.18min.

Example 67: preparation of N- {4- [ 4-amino-6- (3-pyrrolidin-1-ylpropyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Pyrrolidine was used instead of morpholine and purification was performed by HPLC (10-90% ACN/H)₂O), the procedure used for the preparation of example 66 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.61(d, J ═ 7.8Hz, 1H), 7.74(s, 1H), 7.63(d, J ═ 8.3Hz, 2H), 7.55(s, 1H), 7.39 to 7.31(m, 4H), 2.72 to 2.55(m, 8H), 1.86 to 1.70(m, 6H); MS [ M + H ]]⁺＝542；LCMS RT＝2.15min.

Example 68: preparation of ethyl 4-amino-5- [4- ({ [ (3, 4-dimethoxyphenyl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 3, 4-dimethoxyaniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD)δ8.27(s，1H)，8.15(s，1H)，8.06(s，1H)，7.98(s，1H)，7.67(d，J＝8Hz，2H)，7.39(d，J＝8Hz，2H)，7.34(s，1H)，6.95(d，J＝9Hz，1H)，6.86(d，J＝9Hz，3H)，4.15(q，j＝7，2H)，3.81(s，3H)，3.78(s，3H)，1.18(t，j＝7Hz，3H)；MS[M+H]⁺＝477.1LCMS RT＝2.50min.

Example 69: preparation of 4-amino-N-cyclopropyl-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

A solution of intermediate G (50mg, 0.105mmol), cyclopropylamine (11. mu.L, 0.106mmol), py-BOP (82mg, 0.158mmol) and triethylamine (22. mu.L, 0.158mmol) was stirred at room temperature for 15 min and then concentrated in vacuo. The residue was purified by using 20% in CH₂Cl₂The THF in (9) was purified by silica gel chromatography, and then the product was triturated with a 30% aqueous methanol solution to obtain 31.5mg of the above compound (0.061mmol, yield 71%).

¹H-NMR(DMSO-d₆) δ 9.32(s, 1H), 8.96(s, 1H), 8.64(bd, J ═ 6Hz, 1H), 8.06(s, 1H), 7.90(s, 1H), 7.85 to 7.82(M, 1H), 7.54(d, J ═ 8Hz, 2H), 7.53 to 7.50(M, 2H), 7.45 to 7.35(M, 1H), 7.31(d, J ═ 8Hz, 1H), 5.03(bs, 1H), 2.63-2.59 (M1H), 0.62 to 0.58(M, 2H), 0.41 to 0.39(M, 2H). MS [ M + H ], 1H, 2H, and M]⁺＝514.2；LCMS RT＝3.11min；TLC R_f＝0.33(2∶1v/v CH₂Cl₂-THF).

Example 70: preparation of 4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 69 was used to prepare the title compound by substituting 2, 2, 2-trifluoroethylamine hydrochloride for cyclopropylamine.

¹H-NMR(DMSO-d₆) δ 9.29(s, 1H), 8.93(s, 1H), 8.64-8.58(M, 1H), 8.51(t, J ═ 6Hz, 1H), 8.18(s, 1H), 8.00(bs, 1H), 7.91(s, 1H), 7.52(d, J ═ 8Hz, 2H), 7.51 to 7.46(M, 1H), 7.40 to 7.30(M, 1H), 7.28(d, J ═ 8Hz, 2H), 5.05(bs, 1H), 4.00 to 3.85(M, 2H), MS [ M + H ]]⁺＝556.2；LCMS RT＝3.32min；TLCR_f＝0.33(2∶1v/v CH₂Cl₂-THF).

Example 71: preparation of 4-amino-N-ethyl-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 69 was used to prepare the title compound by substituting ethylamine for cyclopropylamine.

¹H-NMR(CD₃OD) δ 8.62 to 8.60(m, 1H), 7.98(s, 1H), 7.84(s, 1H), 7.63(d, J ═ 9Hz, 2H), 7.42 to 7.41(m, 1H), 7.34(d, J ═ 7Hz, 2H), 1.04(t, J ═ 7Hz, 3H); MS [ M + H ]]⁺＝502.1；LCMS RT＝2.68min；TLCR_f＝0.44(3∶2v/v CH₂Cl₂-THF).

Example 72: preparation of N- (4- { 4-amino-6- [3- (4-methylpiperazin-1-yl) propyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Replacement of morpholine by 1-methylpiperazine and purification by HPLC (10-90% ACN/H)₂O) will be used in the preparation ofThe procedure used for the preparation of example 66 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.61(d, J ═ 8.0Hz, 1H), 7.74(s, 1H), 7.63(d, J ═ 8.7Hz, 2H), 7.54(s, 1H), 7.37(d, J ═ 8.0Hz, 2H), 7.34(d, J ═ 8.1Hz, 2H), 2.79 to 2.37(m, 12H), 2.47(s, 3H), 1.75to 1.62(m, 2H); MS [ M + H ]]⁺＝571.4；LCMS RT＝2.48.

Example 73: preparation of 4-amino-5- [4- ({ [ (4-tert-butylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] -N-methylpyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

To a solution of DMF (1mL) was added intermediate X (50mg, 0.18mmol), followed by phenyl (4-tert-butylpyridin-2-yl) carbamate (48mg, 0.18mmol) and triethylamine (25. mu.L, 0.18 mmol). The reaction was stirred at room temperature overnight, concentrated to dryness, and purified by HPLC to obtain 22mg of the above compound (0.04mmol, 26% yield).

¹H-NMR(DMSO-d₆)δ10.9(s，1H)，9.48(s，1H)，8.17(d，J＝5.4Hz，1H)，8.06(s，1H)，7.88(s，1H)，7.02(d，J＝5.0Hz，1H)，7.61to 7.54(m，3H)，7.29(d，J＝8.3Hz，2H)，7.04(dd，J＝5.5，1.6Hz，1H)，2.61(d，J＝4.7Hz，3H)，1.25(s，9H)；MS[M+H]⁺＝459.2；LCMS RT＝2.49.

Example 74: preparation of 4-amino-5- {4- [ ({ [ 4-fluoro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N-methylpyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting phenyl [ 4-fluoro-3- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD) δ 7.97(s, 1H), 7.91(dd, J ═ 6.4, 3.0Hz, 1H), 7.83(s, 1H), 7.68 to 7.62(m, 1H), 7.59(d, J ═ 8.3Hz, 2H), 7.40(d, J ═ 8.3Hz, 2H), 7.27(t, J ═ 9.9Hz, 1H), 2.76(s, 3H); MS [ M + H ]]⁺＝488.3；LCMS RT＝2.31.

Example 75: preparation of 4-amino-N- (tert-butyl) -5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 69 was used to prepare the title compound by substituting 2-methylpropan-2-amine for cyclopropylamine.

¹H-NMR(DMSO-d₆)δ9.35(s，1H)，8.95(s，1H)，8.61(d，J＝5Hz，1H)，8.02(s，1H)，7.88(s，1H)，7.98 to 7.92(m，1H)，7.57(d，J＝8Hz，2H)，7.45to 7.44(m，1H)，7.41to 7.36(m，1H)，7.34(d，J＝8Hz，2H)，6.62(s，1H)，1.15(s，9H)；MS[M+H]⁺＝530.3；LCMS RT＝2.94min；TLCR_f＝0.68(3∶2v/v CH₂Cl₂-THF).

Example 76: preparation of 4-amino-5- [4- ({ [ (4-tert-butylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] -N-cyclopropylpyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate W for intermediate X.

¹H-NMR(CD₃OD) δ 8.22(d, J ═ 6.3Hz, 1H), 7.98(s, 1H), 7.83(s, 1H), 7.71(d, J ═ 8.6Hz, 2H), 7.42(d, J ═ 8.6Hz, 2H), 7.21(s, 1H), 7.10(dd, J ═ 5.6, 1.7Hz, 1H), 2.72to2.59(m, 1H), 1.31(s, 9H), 0.72 to 0.62(m, 2H), 0.42 to 0.33(m, 2H); MS [ M + H ]]⁺＝485.3；LCMS RT＝2.70.

Example 77: preparation of 4-amino-5- {4- [ ({ [ 3-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N-methylpyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting phenyl [ 3-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆) δ 8.04(s, 1H), 7.88(s, 1H), 7.70(s, 1H), 7.61(d, J ═ 11.0Hz, 1H), 7.52(d, J ═ 8.6Hz, 2H), 7.29(d, J ═ 8.6Hz, 2H), 7.21(d, J ═ 8.1Hz, 1H), 3.11 to 3.08(m, 1H), 2.62(d, J ═ 3.4Hz, 3H); MS [ M + H ]]⁺＝488.2；LCMS RT＝3.05.

Example 78: preparation of 4-amino-N-cyclopropyl-5- {4- [ ({ [ 4-fluoro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate W for intermediate X and phenyl [ 4-fluoro-3- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD) δ 7.62(s, 1H), 7.55(dd, J ═ 7.8, 2.8Hz, 1H), 7.47(s, 1H), 7.34 to 7.27(m, 1H), 7.24(d, J ═ 8.4Hz, 2H), 7.03(d, J ═ 8.4Hz, 2H), 6.91(t, J ═ 9.8Hz, 1H), 2.36 to 2.24(m, 1H), 0.39 to 0.28(m, 2H), 0.058 to-0.027 (m, 2H); MS [ M + H ]]⁺＝514.2；LCMS RT＝3.11.

Example 79: preparation of 4-amino-N-cyclopropyl-5- {4- [ ({ [ 3-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate W for intermediate X and phenyl [ 3-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR (acetone-d)₆) δ 7.67(s, 1H), 7.51(s, 1H), 7.33(s, 1H), 7.24(d, J ═ 1.5Hz, 1H), 7.15(d, J ═ 9.0Hz, 2H), 6.92(d, J ═ 9.0Hz, 2H), 6.84(d, J ═ 8.6Hz, 1H), 2.74 to 2.69(m, 1H), 2.29 to 2.21(m, 1H), 0.24 to 0.15(m, 2H), 0.045 to-0.021 (m, 2H); MS [ M + H ]]⁺＝514.3；LCMS RT＝3.19.

Example 80: preparation of 4-amino-N-cyclopropyl-5- [4- ({ [ (2, 2, 4, 4-tetrafluoro-4H-1, 3-benzodioxin-6-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate W for intermediate X and phenyl (2, 2, 4, 4-tetrafluoro-4H-1, 3-benzodioxine-6-yl) carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD) δ 8.02(d, J ═ 2.5Hz, 1H), 7.98(s, 1H), 7.84(s, 1H), 7.67(dd, J ═ 9.1, 2.8Hz, 1H), 7.61(d, J ═ 8.8Hz, 2H), 7.40(d, J ═ 8.4Hz, 2H), 7.25(d, J ═ 9.1Hz, 1H), 2.72 to 2.63(m, 1H), 0.73 to 0.65(m, 2H), 0.42 to 0.35(m, 2H); MS [ M + H ]]⁺＝558.2；LCMS RT＝3.29.

Example 81: preparation of 4-amino-N-cyclopropyl-5- {4- [ ({ [3- (2, 2, 2-trifluoroethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate W for intermediate X and phenyl [3- (2, 2, 2-trifluoroethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR (acetone-d)₆) δ 7.64(s, 1H), 7.47(s, 1H), 7.38(d, J ═ 4.0Hz, 1H), 7.11(d, J ═ 8.7Hz, 2H), 7.06(d, J ═ 8.7Hz, 2H), 6.89 to 6.83(m, 4H), 3.22 to 3.09(m, 2H), 2.74 to 2.68(m, 1H), 2.30 to 2.20(m, 1H), 0.25 to 0.17(m 2H), 0.040 to-0.027 (m, 2H); MS [ M + H ] ]⁺＝510.2；LCMS RT＝3.01.

Example 82: preparation of 4-amino-N-cyclopropyl-5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate W for intermediate X and phenyl [4- (trifluoromethyl) pyridin-2-yl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆) δ 8.52(d, J ═ 5.8Hz, 1H), 8.06(s, 1H), 8.04(s, 1H), 7.87(s, 1H), 7.56(d, J ═ 8.4Hz, 2H), 7.34(d, J ═ 5.0Hz, 1H), 7.30(d, J ═ 8.4Hz, 2H), 3.12 to 3.09(m, 1H), 2.68 to 2.60(m, 1H), 0.62 to 0.55(m2H), 0.44 to 0.36(m, 2H); MS [ M + H ]]⁺＝497.2；LCMS RT＝2.94.

Example 83: preparation of 4-amino-5- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N-cyclopropylpyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate W for intermediate X and phenyl [ 4-chloro-3- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆) δ 8.11(d, J ═ 2.4Hz, 1H), 8.04(s, 1H), 7.87(s, 1H), 7.66 to 7.58(m, 2H), 7.52(d, J ═ 8.4Hz, 2H), 7.28(d, J ═ 8.4Hz, 2H), 3.13 to 3.09(m, 1H), 2.69 to 2.60(m, 1H), 0.64 to 0.56(m 2H), 0.43 to 0.37(m, 2H)；MS[M+H]⁺＝530.2；LCMS RT＝3.25.

Example 84: preparation of 4-amino-5- {4- [ ({ [ 4-fluoro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2-methoxyethyl) -N-methylpyrrolido [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 69 was used to prepare the title compound by substituting 2-methoxy-N-methylethylamine for cyclopropylamine.

¹H-NMR(DMSO-d₆) δ 9.07(s, 1H), 8.98 to 8.91(m, 1H), 8.01 to 7.97(m, 1H), 7.90(s, 1H), 7.87 to 7.81(m, 1H), 7.68 to 7.60(m, 1H), 7.59 to 7.50(m, 2H), 7.48 to 7.40(m, 1H), 7.17 to 7.10(m, 1H), 3.44 to 3.40(m, 2H), 3.25 to 3.10(m, 5H), 2.83(s, 3H-rotamer a), 2.65(s, 3H-rotamer b); MS [ M + H ]]⁺＝546.2；LCMS RT＝3.04min；TLCR_f＝0.47(55∶40∶5v/v CH₂Cl₂-THF-EtOH).

Example 85: preparation of N- [4- (4-amino-6-methylpyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate T for intermediate X and phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.61(d，J＝2.6Hz，1H)，7.73(s，1H) 7.62(d, J ═ 8.7Hz, 2H), 7.49(s, 1H), 7.37 to 7.31(m, 4H), 2.14(s, 3H); MS [ M + H ]]⁺＝445.1；LCMS RT＝2.80.

Example 86: preparation of N- [4- (4-amino-6-methylpyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [ 4-chloro-3- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate T for intermediate X and phenyl [ 4-chloro-3- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD) δ 8.05(d, J ═ 2.4Hz, 1H), 7.73(s, 1H), 7.67 to 7.58(m, 3H), 7.50(s, 1H), 7.48(d, J ═ 8.1Hz, 1H), 7.33(d, J ═ 8.7Hz, 2H), 2.18(s, 3H); MS [ M + H ]]⁺＝461.1；LCMS RT＝2.89.

Example 87: preparation of 4-amino-5- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate M for intermediate X and phenyl [ 4-chloro-3- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.04(s，1H)，8.00(d，J＝2.4Hz，1H)，7.84(s，1H)，7.64(dd，J＝8.4，2.8Hz，1H)，7.59(d，J＝8.4Hz，2H)，7.49(d，J＝8.6Hz，1H)，7.38(d，J＝8.4Hz，2H)，3.94(q，J＝9.2Hz，2H)；MS[M+H]⁺＝572.1；LCMS RT＝3.07.

Example 88: preparation of 4-amino-5- {4- [ ({ [ 4-fluoro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate M for intermediate X and phenyl [ 4-fluoro-3- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD) δ 8.04(s, 1H), 7.90(dd, J ═ 6.3, 2.7Hz, 1H), 7.85(s, 1H), 7.68 to 7.63(m, 1H), 7.59(d, J ═ 8.6Hz, 2H), 7.39(d, J ═ 8.7Hz, 2H), 7.26(t, J ═ 9.8Hz, 1H), 3.94(q, J ═ 9.2Hz, 2H); MS [ M + H ]]⁺＝556.1；LCMS RT＝2.94.

Example 89: preparation of 4-amino-5- {4- [ ({ [ 3-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate M for intermediate X and phenyl [ 3-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ804(s, 1H), 7.84(s, 1H), 7.66 to 7.53(m, 4H), 7.38(d, J ═ 8.7Hz, 2H), 7.03(d, J ═ 8.2Hz, 1H), 3.94(q, J ═ 9.2Hz, 2H); MS [ M + H ]]⁺＝556.1；LCMS RT＝3.02.

Example 90: preparation of 4-amino-5- [4- ({ [ (3, 4-dichlorophenyl) amino ] carbonyl } amino) phenyl ] -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate M for intermediate X and phenyl (3, 4-dichlorophenyl) carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD) δ 8.04(s, 1H), 7.85(s, 1H), 7.81(d, J ═ 2.4Hz, 1H), 7.58(d, J ═ 8.8Hz, 2H), 7.43 to 7.37(m, 3H), 7.31(dd, J ═ 8.9, 2.5Hz, 1H), 3.94(q, J ═ 9.2Hz, 2H); MS [ M + H ]]⁺＝538.1；LCMS RT＝2.97.

Example 91: preparation of 4-amino-5- [4- ({ [ (2, 2, 4, 4-tetrafluoro-4H-1, 3-benzodioxin-6-yl) amino ] carbonyl } amino) phenyl ] -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate M for intermediate X and phenyl (2, 2, 4, 4-tetrafluoro-4H-1, 3-benzodioxine-6-yl) carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.04(s，1H)，8.01(d，J＝2.3Hz，1H)，7.84(s，1H)，7.66(dd，J＝9.2，2.8Hz，1H)，7.60(d，J＝8.3Hz，2H)，7.39(d，J＝8.3Hz，2H)，7.23(d，J＝9.3Hz，1H)，3.94(q，J＝9.2Hz，2H)；MS[M+H]⁺＝600.0；LCMS RT＝3.11.

Example 92: preparation of 4-amino-N- (2, 2, 2-trifluoroethyl) -5- {4- [ ({ [3- (2, 2, 2-trifluoroethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate M for intermediate X and phenyl [3- (2, 2, 2-trifluoroethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.04(s，1H)，7.85(s，1H)，7.59(d，J＝8.6Hz，2H)，7.46(d，J＝8.6Hz，2H)，7.38(d，J＝8.5Hz，2H)，7.26(d，J＝8.5Hz，2H)，3.94(q，J＝9.2Hz，2H)，3.42(q，J＝10.2Hz，2H)；MS[M+H]⁺＝552.1；LCMS RT＝2.84.

Example 93: preparation of 4-amino-N- (2, 2, 2-trifluoroethyl) -5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate M for intermediate X and phenyl [4- (trifluoromethyl) pyridin-2-yl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.54(d，J＝5.1Hz，1H)，8.19(s，1H)，8.06(br s，1H)，7.91(s，1H)，7.60(d，J＝8.7Hz，2H)，7.35(d，J＝5.6Hz，2H)，7.31(d，J＝8.9Hz，2H)，3.94(q，J＝9.2Hz，2H)；MS[M+H]⁺＝539.0；LCMS RT＝2.77.

Example 94: preparation of 4-amino-5- [4- ({ [ (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) amino ] carbonyl } amino) phenyl ] -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate M for intermediate X and phenyl (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.04(s，1H)，7.85(s，1H)，7.59(d，J＝8.5Hz，2H)，7.39(d，J＝8.7Hz，2H)，6.13(s，1H)，3.94(q，J＝9.2Hz，2H)，3.70(s，3H)，1.28(s，9H)；MS[M+H]⁺＝530.1；LCMS RT＝2.45.

Example 95: preparation of ethyl 4-amino-5- (4- { [ ({3- [2- (diethylamino) ethoxy ] -4-methoxyphenyl } amino) carbonyl ] amino } phenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 3- [2- (diethylamino) ethoxy ] -4-methoxyaniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD) δ 8.07(s, 1H), 7.83(s, 1H), 7.56(d, J ═ 8.8Hz, 2H), 7.33(d, J ═ 8.9Hz, 2H), 7.26(s, 1H), 6.91(d, J ═ 1.1Hz, 2H), 4.20 to 4.10(m, 4H), 3.81(s, 3H), 3.18 to 2.99(m, 2H), 2.86 to 2.74(m, 4H), 1.18 to 1.10(m, 9H); MS [ M + H ] ]⁺＝562.4；LCMS RT＝2.57.

Example 96: preparation of ethyl 4-amino-5- {4- [ ({ [ 4-methoxy-3- (morpholin-4-ylmethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 4-methoxy-3- (morpholin-4-ylmethyl) aniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD) δ 8.11(s, 1H), 7.91(s, 1H), 7.50(d, J ═ 8.5Hz, 2H), 7.36 to 7.32(m, 2H), 7.27(d, J ═ 8.5Hz, 2H), 6.89(d, J ═ 9.6, 1H), 4.08(q, J ═ 7.3Hz, 2H), 3.71(s, 2H), 3.59 to 3.53(m, 4H), 3.28(s, 3H), 2.39 to 2.33(m, 4H), 1.08(t, J ═ 7.2Hz, 3H); MS [ M + H ]]⁺＝546.2；LCMS RT＝2.47.

Example 97: preparation of ethyl 4-amino-5- {4- [ ({ [4- (pyrrolidin-1-ylmethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting 4- (pyrrolidin-1-ylmethyl) aniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(CD₃OD) δ 8.07(s, 1H), 7.83(s, 1H), 7.56(d, J ═ 8.5Hz, 2H), 7.47(d, J ═ 8.5Hz, 2H), 7.33(t, J ═ 8.9Hz, 4H), 4.13(q, J ═ 7.3Hz, 2H), 3.78(s, 2H), 2.79 to 2.70(m, 4H), 1.91 to 1.84(m, 4H), 1.15(t, J ═ 7.2Hz, 3H); MS [ M + H ] ]⁺＝500.2；LCMS RT＝2.46.

Example 98: preparation of ethyl 4-amino-5- (4- { [ ({3- [2- (diethylamino) ethoxy ] phenyl } amino) carbonyl ] amino } phenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

With 3- [2- (diethylamino) ethoxy]Aniline instead of 4-fluoro-3- (trifluoromethyl) aniline and purified by HPLC (10-90% ACN/H₂O), the procedure used for the preparation of example 3 was used to prepare the title compound.

¹H-NMR(CD₃OD) δ 8.05(s, 1H), 7.82(s, 1H), 7.57(d, J ═ 8.4Hz, 2H), 7.35 to 7.30(m, 3H), 7.20(t, J ═ 8.0Hz, 1H), 6.94(dd, J ═ 7.9, 2.0Hz, 1H), 6.63(dd, J ═ 8.4, 1.9Hz, 1H), 4.17 to 4.03(m, 4H), 3.29 to 3.25(m, 2H), 3.10to 2.97(m, 4H), 1.28 to 1.19(m, 9H); MS [ M + H ]]⁺＝532.4；LCMS RT＝2.57.

Example 99: preparation of N- [4- (4-amino-6-cyanopyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate P for intermediate X and phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.62(d，J＝7.0Hz，1H)，8.19(s，1H)，7.91(s，1H)，7.69(d，J＝8.6Hz，2H)，7.50(d，J＝8.6Hz，2H)，7.34(d，J＝8.7Hz，2H)；MS[M+H]⁺＝456.1；LCMS RT＝3.10.

Example 100: preparation of N- {4- [ 4-amino-6- (methoxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate U for intermediate X and phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.61(d，J＝7.6Hz，1H)，7.78(s，1H)，7.68(s，1H)，7.62(d，J＝8.7Hz，2H)，7.40(d，J＝8.6Hz，2H)，7.33(d，J＝8.7Hz，2H)，4.35(s，2H)，3.30(s，3H)；MS[M+H]⁺＝475.2；LCMS RT＝2.81.

Example 101: preparation of N- {4- [ 4-amino-6- (methoxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate U for intermediate X and phenyl [4- (trifluoromethyl) pyridin-2-yl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD) δ 8.52(d, J ═ 5.4Hz, 1H), 7.79(s, 1H), 7.76(s, 1H), 7.71 to 7.67(m, 3H), 7.43(d, J ═ 8.6Hz, 2H), 7.28(d, J ═ 5.3Hz, 1H), 4.36(s, 2H), 3.29(s, 3H); MS [ M + H ]]⁺＝458.1；LCMS RT＝2.66.

Example 102: preparation of N- {4- [ 4-amino-6- (methoxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 3-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 76 was used to prepare the title compound by substituting intermediate U for intermediate X and phenyl [ 3-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD) δ 7.77(s, 1H), 7.67(s, 1H), 7.66 to 7.60(m, 4H), 7.39(d, J ═ 8.5Hz, 2H), 7.03(d, J ═ 8.9Hz, 1H), 4.34(s, 2H), 3.20(s, 3H); MS [ M + H ]]⁺＝475.2；LCMS RT＝2.88.

Example 103: preparation of N- [4- (4-amino-6-cyanopyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [ 3-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate P for intermediate X and phenyl [ 3-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD) δ 8.18(s, 1H), 7.90(s, 1H), 7.70 to 7.62(m, 3H), 7.59(s, 1H), 7.49(d, J ═ 8.9Hz, 2H), 7.06(d, J ═ 8.9Hz, 1H); MS [ M + H ]]⁺＝456.4；LCMS RT＝3.26.

Example 104: preparation of 4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate Q for intermediate X and phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.61(d，J＝7.9Hz，1H)，8.23(s，1H)，7.99(s，1H)，7.66(d，J＝8.7Hz，2H)，7.46(d，J＝8.7Hz，2H)，7.35(d，J＝8.7Hz，2H)；MS[M+H]⁺＝474.3；LCMS RT＝2.89.

Example 105: preparation of ethyl 4-amino-5- {4- [ ({ [ 2-chloro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

To a solution of DCE (5mL) was added intermediate B (300mg, 1.01mmol) followed by 2-chloro-1-isocyanato-4- (trifluoromethyl) benzene (0.32mL, 2.12 mmol). The reaction was allowed to proceed at room temperature N₂Stirred under the atmosphere for 1 hour, then2N aqueous HCl (0.50mL, 1.01mmol) was added to the reaction, followed by DMF (5 mL). The solution was heated for an additional 1 hour. After cooling to room temperature, the solution was diluted with EtOAc, transferred to a separatory funnel, and saturated NaHCO₃And (4) washing with an aqueous solution. The aqueous layer was back extracted with EtOAc. The combined organic layers were collected, dried, concentrated, and purified by column chromatography (95: 5 v/vCH)₂Cl₂-MeOH). The resulting fractions containing the product were concentrated and treated with CH₂Cl₂And hexane. The product was filtered and dried in vacuo to give 408mg of the above compound as a white solid (0.79mmol, 78% yield).

¹H-NMR(DMSO-d₆) δ 9.72(s, 1H), 8.67(s, 1H), 8.64(s, 1H), 8.13(s, 1H), 8.08(br s, 1H), 7.93(s, 1H), 7.72(d, J ═ 8.5Hz, 1H), 7.56(d, J ═ 8.8Hz, 2H), 7.39 to 7.36(m, 1H), 7.34(d, J ═ 8.6Hz, 2H), 5.10(br s, 1H), 4.09(q, J ═ 7.0Hz, 2H), 1.12(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝519；LCMS RT＝3.58min；TLCR_f＝0.26(95∶5v/vCH₂Cl₂-MeOH).

Example 106: preparation of 4-amino-N- (tert-butyl) -5- {4- [ ({ [ 2-chloro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 105 was used to prepare the title compound by substituting intermediate L for intermediate B.

¹H-NMR(DMSO-d₆)δ9.74(s，1H)，8.67(s，1H)，8.64(d，J＝2.4Hz，1H)，8.03(s，1H)，7.89(s，1H)，7.72(d，J＝7.5Hz，1H)，7.59(d，J＝8.6Hz，2H)，7.39(s，1H)，7.36(d，J＝8.7Hz，2H)，6.64(s，1H)，1.19(s，9H)；MS[M+H]⁺＝546；LCMS RT＝3.09min；TLCR_f＝0.47(9∶1v/v CH₂Cl₂-MeOH).

Example 107: preparation of 4-amino-5- [4- ({ [ (2-fluorophenyl) amino ] carbonyl } amino) phenyl ] -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

To an EPA vial loaded with intermediate N (50mg, 0.11mmol) was added CH₂Cl₂(2 mL). 1-fluoro-2-isocyanatobenzene (15mg, 0.11mmol) was added and the mixture was stirred at room temperature for 20 minutes. The reaction was then heated to 42 ℃ and shaken at this temperature overnight. TLC was run using 3: 7v/v EtOAc-hexanes and the results indicated that the reaction had consumed almost all of the SM. To the vial was added TFA (100. mu.L). It was stirred at room temperature overnight. LCMS showed the desired product formed. The samples were concentrated by GeneVac and DMSO (2mL) was added. The sample was purified by preparative LCMS to yield 27.3mg of the above compound (0.059mmol, 58% yield).

¹H-NMR(DMSO-d₆)δ3.2(s，3H)7.0(m，1H)7.2(t，J＝7.3Hz，1H)7.2(s，1H)7.3(d，J＝7.3Hz，2H)7.6(d，J＝7.8Hz，3H)7.6(s，2H)7.9(s，1H)8.2(m，3H)8.6(s，1H)9.2(s，1H).MS[M+H]⁺＝464；LCMS RT＝2.86min.

Example 108: preparation of 4-amino-5- [4- ({ [ (3-fluorophenyl) amino ] carbonyl } amino) phenyl ] -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-fluoro-3-isocyanatobenzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(d，J＝11.2Hz，2H)3.3(d，J＝11.7Hz，2H)3.3(s，1H)6.8(m，1H)7.1(d，J＝7.8Hz，1H)7.3(d，J＝8.8Hz，1H)7.5(m，4H)7.6(s，2H)7.9(s，1H)8.1(s，2H)9.0(d，J＝19.6Hz，3H)；MS[M+H]⁺＝464；LCMS RT＝2.90min.

Example 109: preparation of 4-amino-N- (2-methoxyethyl) -5- [4- ({ [ (3-methoxyphenyl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-isocyanato-3-methoxybenzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，3H)3.3(m，5H)6.6(d，J＝7.8Hz，1H)7.0(d，J＝8.3Hz，1H)7.2(m，3H)7.3(d，J＝7.8Hz，2H)7.6(d，J＝7.8Hz，3H)7.6(s，1H)7.9(s，1H)8.1(s，2H)8.8(s，1H)8.9(s，1H)；MS [M+H]⁺＝476；LCMS RT＝2.84min.

Example 110: preparation of 4-amino-5- [4- ({ [ (3, 4-dichlorophenyl) amino ] carbonyl } amino) phenyl ] -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1, 2-dichloro-4-isocyanatobenzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，2H)3.3(d，J＝11.7Hz，2H)3.3(s，1H)7.3(m，4H)7.5(t，J＝8.3Hz，4H)7.6(s，2H)7.9(d，J＝13.7Hz，1H)8.1(s，2H)9.0(s，1H)9.1(s，1H)；MS[M+H]⁺＝514；LCMS RT＝3.17min.

Example 111: preparation of 4-amino-5- [4- ({ [ (3-chlorophenyl) amino ] carbonyl } amino) phenyl ] -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-chloro-3-isocyanatobenzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，2H)3.3(d，J＝11.2Hz，3H)3.3(s，2H)7.0(d，J＝6.4Hz，1H)7.3(m，2H)7.6(d，J＝7.8Hz，3H)7.6(s，2H)7.7(s，1H)7.9(s，1H)8.1(s，2H)9.0(d，J＝4.9Hz，3H)；MS[M+H]⁺＝480；LCMS RT＝3.02min.

Example 112: preparation of 4-amino-5- [4- ({ [ (2, 3-dichlorophenyl) amino ] carbonyl } amino) phenyl ] -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1, 2-dichloro-3-isocyanatobenzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，1H)3.3(d，J＝5.9Hz，2H)7.3(s，2H)7.3(d，J＝7.8Hz，4H)7.6(d，J＝8.3Hz，3H)7.6(s，2H)7.9(s，1H)8.1(s，1H)8.2(d，J＝8.3Hz，1H)8.5(s，1H)9.7(s，1H)；MS[M+H]⁺＝514；LCMS RT＝3.12min.

Example 113: preparation of 4-amino-5- [4- ({ [ (3-bromophenyl) amino ] carbonyl } amino) phenyl ] -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-bromo-3-isocyanatobenzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，3H)3.3(m，2H)7.2(d，J＝7.3Hz，1H)7.3(t，J＝7.8Hz，2H)7.3(d，J＝7.3Hz，4H)7.6(d，J＝8.3Hz，3H)7.6(s，1H)7.9(s，1H)7.9(s，1H)8.1(s，1H)9.0(s，3H)；MS[M+H]⁺＝524；LCMS RT＝3.04min.

Example 114: preparation of 4-amino-5- [4- ({ [ (4-fluoro-3-nitrophenyl) amino ] carbonyl } amino) phenyl ] -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-fluoro-4-isocyanato-2-nitrobenzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，3H)3.3(m，2H)7.3(d，J＝8.3Hz，3H)7.5(m，4H)7.7(s，1H)7.7(s，1H)7.9(s，1H)8.1(s，1H)8.5(s，1H)9.1(s，1H)9.3(s，1H)；MS[M+H]⁺＝509；LCMS RT＝2.93min.

Example 115: preparation of 4-amino-N- (2-methoxyethyl) -5- [4- ({ [ (3-nitrophenyl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-isocyanato-3-nitrobenzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，1H)3.3(d，J＝4.4Hz，1H)3.3(s，1H)7.3(d，J＝7.8Hz，3H)7.6(d，J＝7.3Hz，5H)7.7(s，2H)7.7(d，J＝7.8Hz，2H)7.8(d，J＝8.3Hz，2H)8.0(s，1H)8.1(s，1H)8.6(m，1H)9.1(s，1H)9.3(s，1H)；MS[M+H]⁺＝491；LCMS RT＝2.92min.

Example 116: preparation of 4-amino-5- {4- [ ({ [ 2-chloro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-chloro-2-isocyanato-4- (trifluoromethyl) benzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，2H)3.3(d，J＝11.7Hz，2H)3.3(s，1H)7.4(dd，J＝16.9，8.6Hz，3H)7.6(d，J＝7.8Hz，3H)7.7(s，2H)7.7(d，J＝8.3Hz，2H)8.0(s，1H)8.1(s，2H)8.7(d，J＝12.2Hz，3H)9.7(s，1H)；MS[M+H]⁺＝548；LCMS RT＝3.24min.

Example 117: preparation of 4-amino-5- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-chloro-4-isocyanato-2- (trifluoromethyl) benzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，1H)3.3(m，2H)7.3(d，J＝7.3Hz，3H)7.6(d，J＝7.3Hz，3H)7.6(m，4H)7.9(s，1H)8.1(s，3H)9.1(s，1H)9.3(s，2H)；MS[M+H]⁺＝548；LCMS RT＝3.26min.

Example 118: preparation of 4-amino-5- [4- ({ [ (2, 5-difluorophenyl) amino ] carbonyl } amino) phenyl ] -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 2, 4-difluoro-1-isocyanatobenzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δH)6.8(s，1H)7.3(d，J＝7.8Hz，3H)7.6(d，J＝7.8Hz，2H)7.6(s，1H)7.9(s，1H)8.1(s，2H)8.8(s，1H)9.3(s，1H)；MS[M+H]⁺＝482；LCMS RT＝2.97min.

Example 119: preparation of 4-amino-5- [4- ({ [ (3, 5-dichlorophenyl) amino ] carbonyl } amino) phenyl ] -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1, 3-dichloro-5-isocyanatobenzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，3H)3.3(d，J＝17.1Hz，3H)7.2(s，1H)7.3(d，J＝7.8Hz，3H)7.6(s，6H)7.6(s，2H)8.1(s，2H)9.1(s，1H)9.1(s，1H)；MS[M+H]⁺＝514；LCMS RT＝3.23min.

Example 120: preparation of 5- [4- ({ [ (3-acetylphenyl) amino ] carbonyl } amino) phenyl ] -4-amino-N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1- (3-isocyanatophenyl) ethanone for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，1H)3.3(s，1H)3.3(s，1H)7.3(d，J＝7.8Hz，3H)7.5(t，J＝7.6Hz，2H)7.6(m，7H)7.7(d，J＝7.3Hz，2H)8.0(s，1H)8.1(d，J＝15.7Hz，3H)8.9(s，2H)9.0(s，1H)；MS[M+H]⁺＝488；LCMS RT＝2.78min.

Example 121: preparation of 4-amino-5- {4- [ ({ [ 2-fluoro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 2-fluoro-1-isocyanato-3- (trifluoromethyl) benzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，3H)3.3(d，J＝16.6Hz，3H)7.4(m，5H)7.4(s，2H)7.6(d，J＝7.3Hz，4H)7.6(s，2H)7.9(s，1H)8.1(s，2H)8.5(s，2H)8.9(s，1H)9.3(s，2H)；MS[M+H]⁺＝532；LCMS RT＝3.14min.

Example 122: preparation of 4-amino-5- {4- [ ({ [ 4-fluoro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-fluoro-4-isocyanato-2- (trifluoromethyl) benzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ2.5(m，5H)3.4(s，2H)7.3(d，J＝7.8Hz，2H)7.5(t，J＝9.5Hz，1H)7.6(d，J＝7.8Hz，2H)7.6(d，J＝4.9Hz，3H)7.9(s，1H)8.0(d，J＝4.9Hz，1H)8.1(s，1H)9.0(s，1H)9.1(s，1H)；MS[M+H]⁺＝532；LCMS RT＝3.16min.

Example 123: preparation of 4-amino-N- (2-methoxyethyl) -5- (4- { [ (2-naphthylamino) carbonyl ] amino } phenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 2-isocyanatonaphthalene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，2H)3.3(d，J＝14.7Hz，2H)7.4(m，4H)7.5(t，J＝7.3Hz，2H)7.5(d，J＝8.8Hz，2H)7.6(d，J＝8.3Hz，5H)7.8(m，4H)8.1(s，3H)9.0(s，3H)；MS[M+H]⁺＝496；LCMS RT＝3.07min.

Example 124: preparation of 4-amino-5- [4- ({ [ (3, 5-dimethoxyphenyl) amino ] carbonyl } amino) phenyl ] -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-isocyanato-3, 5-dimethoxybenzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.0(s，1H)3.2(s，3H)3.3(m，3H)3.7(s，4H)6.7(s，3H)7.3(d，J＝7.8Hz，3H)7.5(d，J＝7.8Hz，3H)7.6(s，2H)8.1(s，2H)8.7(s，2H)8.8(s，1H)；MS[M+H]⁺＝506；LCMS RT＝2.88min.

Example 125: preparation of 4-amino-5- [4- ({ [ (3-chloro-2-tolyl) amino ] carbonyl } amino) phenyl ] -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-chloro-3-isocyanato-2-toluene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ2.3(s，3H)2.5(d，J＝16.6Hz，9H)3.5(s，1H)5.2(s，1H)7.2(m，2H)7.3(d，J＝7.3Hz，2H)7.6(d，J＝7.8Hz，2H)7.6(s，1H)7.8(d，J＝6.4Hz，1H)7.9(s，1H)8.1(s，1H)8.2(s，1H)9.2(s，1H)；MS[M+H]⁺＝494；LCMS RT＝3.00min.

Example 126: preparation of 4-amino-5- [4- ({ [ (2-fluoro-5-nitrophenyl) amino ] carbonyl } amino) phenyl ] -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-fluoro-2-isocyanatobenzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，2H)3.3(d，J＝5.4Hz，1H)3.3(s，1H)7.4(d，J＝8.3Hz，3H)7.6(t，J＝9.0Hz，5H)7.7(s，2H)7.9(d，J＝11.2Hz，2H)8.1(s，2H)9.1(s，1H)9.2(s，1H)9.4(s，1H)；MS[M+H]⁺＝509；LCMS RT＝2.95min.

Example 127: preparation of 4-amino-5- [4- ({ [ (3, 4-difluorophenyl) amino ] carbonyl } amino) phenyl ] -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1, 2-difluoro-4-isocyanatobenzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，3H)3.3(m，3H)7.1(d，J＝7.8Hz，1H)7.3(m，4H)7.6(d，J＝8.3Hz，3H)7.6(s，3H)7.9(s，1H)8.1(s，1H)9.0(d，J＝11.2Hz，3H)；MS[M+H]⁺＝482；LCMS RT＝2.95min.

Example 128: preparation of 4-amino-5- [4- ({ [ (3-iodophenyl) amino ] carbonyl } amino) phenyl ] -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-iodo-3-isocyanatobenzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，4H)3.3(m，1H)7.1(t，J＝7.6Hz，1H)7.3(m，5H)7.5(m，3H)7.6(s，1H)7.9(s，1H)8.0(s，1H)8.1(s，2H)8.9(d，J＝18.6Hz，3H)；MS[M+H]⁺＝572；LCMS RT＝3.09min.

Example 129: preparation of 4-amino-N- (2-methoxyethyl) -5- {4- [ ({ [3- (methylthio) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-isocyanato-3- (methylthio) benzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，3H)3.3(m，3H)6.9(d，J＝7.3Hz，1H)7.2(m，3H)7.3(d，J＝7.3Hz，3H)7.5(s，2H)7.6(d，J＝7.8Hz，3H)7.6(s，2H)7.9(s，1H)8.1(s，2H)8.8(s，1H)8.9(s，2H)；MS[M+H]⁺＝492；LCMS RT＝2.97min.

Example 130: preparation of methyl 3- [ ({ [4- (4-amino-6- { [ (2-methoxyethyl) amino ] carbonyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] amino } carbonyl) amino ] benzoate

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 3-isocyanatobenzoic acid methyl ester for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，3H)3.3(m，2H)3.9(s，2H)7.3(d，J＝7.8Hz，3H)7.4(t，J＝7.6Hz，1H)7.6(d，J＝7.8Hz，4H)7.6(m，3H)7.9(s，1H)8.1(s，2H)8.2(s，1H)8.9(s，1H)9.0(s，1H)；MS[M+H]⁺＝504；LCMS RT＝2.87min.

Example 131: preparation of 4-amino-N- (2-methoxyethyl) -5- (4- { [ ({3- [ (trifluoromethyl) thio ] phenyl } amino) carbonyl ] amino } phenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-isocyanato-3- [ (trifluoromethyl) thio ] benzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ2.5(d，J＝16.1Hz，9H)5.2(s，1H)7.3(d，J＝7.3Hz，3H)7.5(t，J＝7.6Hz，1H)7.6(d，J＝6.4Hz，3H)7.6(s，1H)7.9(s，1H)8.0(s，1H)8.1(s，1H)9.0(s，1H)9.1(s，1H)；MS[M+H]⁺＝546；LCMS RT＝3.26min.

Example 132: preparation of 4-amino-5- {4- [ ({ [ 3-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-fluoro-3-isocyanato-5- (trifluoromethyl) benzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.5(s，3H)7.2(s，2H)7.3(d，J＝8.3Hz，4H)7.6(s，2H)7.6(s，4H)7.7(s，2H)8.1(s，2H)9.1(s，2H)9.3(s，2H)；MS[M+H]⁺＝532；LCMS RT＝3.22min.

Example 133: preparation of 4-amino-N- (2-methoxyethyl) -5- [4- ({ [ (3-phenoxyphenyl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound from 1-isocyanato-3-phenoxybenzene and 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，2H)3.5(s 2H)6.6(s，1H)7.0(d，J＝7.8Hz，2H)7.2(s，3H)7.3(s，2H)7.3(d，J＝7.8Hz，5H)7.4(s，3H)7.5(s，1H)7.6(s，1H)7.9(s，1H)8.1(s，1H)8.8(d，J＝15.7Hz，3H)；MS[M+H]⁺＝538；LCMSRT＝3.22min.

Example 134: preparation of 4-amino-5- (4- { [ (1, 3-benzodioxol-5-ylamino) carbonyl ] amino } phenyl) -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 5-isocyanato-1, 3-benzodioxole for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.2(s，2H)6.0(s，5H)6.8(s，2H)7.2(s，2H)7.3(d，J＝7.3Hz，5H)7.5(s，2H)8.1(s，2H)8.6(s，2H)8.8(s，2H)；MS[M+H]⁺＝490；LCMS RT＝2.78min.

Example 135: preparation of 4-amino-5- [4- ({ [ (3-fluorobenzyl) amino ] carbonyl } amino) phenyl ] -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-fluoro-3- (isocyanatomethyl) benzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ4.3(s，3H)6.8(s，2H)7.1(s，1H)7.1(s，4H)7.3(s，4H)7.4(s，1H)7.5(s，4H)7.9(s，1H)8.1(s，2H)8.8(s，2H)；MS[M+H]⁺＝478；LCMS RT＝2.82min.

Example 136: preparation of 4-amino-5- (4- { [ (2, 3-dihydro-1, 4-benzodioxine-6-ylamino) carbonyl ] amino } phenyl) -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 6-isocyanato-2, 3-dihydro-1, 4-benzodioxine for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.0(s，3H)3.2(s，2H)3.5(s，2H)6.8(s，2H)7.1(s，1H)7.3(d，J＝7.3Hz，4H)7.5(s，4H)7.9(s，1H)8.1(s，2H)8.5(s，2H)8.8(s，2H)；MS[M+H]⁺＝504；LCMS RT＝2.78min.

Example 137: preparation of 4-amino-N- (2-methoxyethyl) -5- (4- { [ (3-thienylamino) carbonyl ] amino } phenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 3-isocyanatothiophene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.0(s，4H)7.3(s，5H)7.6(s，3H)7.9(s，2H)8.1(s，3H)8.8(s，2H)9.0(s，2H)；MS[M+H]⁺452; LCMS RT 2.77min example 138: preparation of 4-amino-5- [4- ({ [ (2-fluorobenzyl) amino]Carbonyl } amino) phenyl]-N- (2-methoxyethyl) pyrrolo [2, 1-f][1，2，4]Triazine-6-carboxamides

The procedure used for the preparation of example 107 was used to prepare the title compound by substituting 1-fluoro-2- (isocyanatomethyl) benzene for 1-fluoro-2-isocyanatobenzene.

¹H-NMR(DMSO-d₆)δ3.5(s，4H)4.4(s，3H)7.3(d，J＝7.8Hz，9H)7.4(s，2H)7.5(s，H)8.1(s，1H)8.8(s，2H)；MS[M+H]⁺＝478；LCMS RT＝2.82min.

Example 139: preparation of 4-amino-N- (2, 2, 2-trifluoroethyl) -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate M for intermediate X and phenyl [6- (trifluoromethyl) pyridin-2-yl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.05(s，1H)，7.97(s，1H)，7.85(s，1H)，7.67(d，J＝8.7Hz，2H)，7.56(d，J＝8.7Hz，1H)，7.46to 7.41(m，3H)，3.94(q，J＝8.9Hz，2H)；MS[M+H]⁺＝539.0；LCMS RT＝2.71.

Example 140: preparation of 4-amino-N- (2, 2, 2-trifluoroethyl) -5- {4- [ ({ [2- (trifluoromethyl) pyridin-4-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate M for intermediate X and phenyl [2- (trifluoromethyl) pyridin-4-yl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.47(d，J＝5.9Hz，1H)，8.04(s，1H)，8.03(d，J＝2.9Hz，1H)，7.85(s，1H)，7.66(dd，J＝5.4，1.9Hz，1H)，7.62(d，J＝8.9Hz，2H)，7.41(d，J＝8.8Hz，2H)，3.94(q，J＝9.2Hz，2H)；MS[M+H]⁺＝539.0；LCMS RT＝2.56.

Example 141: preparation of 4-amino-N- (tert-butyl) -5- {4- [ ({ [ 3-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 105 was used to prepare the title compound by substituting intermediate L for intermediate B and 1-fluoro-3-isocyanato-5- (trifluoromethyl) benzene for 1-chloro-2-isocyanato-4- (trifluoromethyl) benzene.

¹H-NMR(DMSO-d₆) δ 9.34(s, 1H), 9.14(s, 1H), 8.03(s, 1H), 7.88(s, 1H), 7.72 to 7.70(m, 1H), 7.65 to 7.62(m, 1H), 7.61 to 7.57(m, 2H), 7.35 to 7.34(m, 2H), 7.24 to 7.22(m, 1H), 6.61(m, 1H), 1.18(s, 9H); MS [ M + H ]]⁺＝530；LCMS RT＝3.09min；TLCR_f＝0.54(5∶4∶1v/v/v CH₂Cl₂-EtOAc-MeOH).

Example 142: preparation of 4-amino-N- (tert-butyl) -5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate L for intermediate X and phenyl [4- (trifluoromethyl) pyridin-2-yl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆) δ 9.91(s, 1H), 9.76(s, 1H), 8.54to 8.53(d, J ═ 5.1Hz, 1H), 8.06(s, 1H), 8.03(s, 1H), 7.89(s, 1H), 7.64 to 7.62(d, J ═ 8.6Hz, 2H), 7.37 to 7.35(d, J ═ 8.6Hz, 2H), 6.67(s, 1H), 1.19(s, 9H); MS [ M + H ] ]⁺＝513；LCMS RT＝2.84min；TLCR_f＝0.37(5∶4∶1v/v/v CH₂Cl₂-EtOAc-MeOH).

Example 143: preparation of 4-amino-5- {4- [ ({ [ 2-chloro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2-hydroxy-1, 1-dimethylethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

To a solution of DMF (2mL) was added intermediate J (50mg, 0.10mmol), followed by benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (45mg, 0.10mmol), 4-methylmorpholine (0.01mL, 0.10mmol) and 2-amino-2-methylpropan-1-ol (0.01mL, 0.10 mmol). The solution is placed in N₂Stirred at room temperature under an atmosphere for 17 hours. The reaction mixture was rotary evaporated and then purified by column chromatography (5: 4: 1 v/v/vCH)₂Cl₂EtOAc-MeOH) to yield 38mg of the above compound (0.068mmol, 67% yield).

¹H-NMR(DMSO-d₆) δ 9.73(s, 1H), 8.67(s, 1H), 8.64(d, J ═ 2.2Hz, 1H), 8.03(s, 1H), 7.89(s, 1H), 7.72(d, J ═ 8.5Hz, 1H), 7.59(d, J ═ 8.6Hz, 2H), 7.39 to 7.38(m, 1H), 7.36(d, J ═ 8.5Hz, 2H), 6.52(s, 1H), 4.77(t, J ═ 5.8Hz, 1H), 3.29(d, J ═ 5.9Hz, 2H), 1.12(s, 6H); MS [ M + H ]]⁺＝562；LCMS RT＝3.16min；TLCR_f＝0.32(5∶4∶1v/v/v CH₂Cl₂-EtOAc-MeOH).

Example 144: preparation of ethyl 4-amino-5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate B for intermediate X and phenyl [6- (trifluoromethyl) pyridin-2-yl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆) δ 9.89(s, 1H), 9.74(s, 1H), 8.13(s, 1H), 8.02 to 7.97(m, 2H), 7.92(s, 1H), 7.55(d, J ═ 9Hz, 2H), 7.53 to 7.50(m, 1H), 7.35(d, J ═ 9Hz, 2H), 5.12(bs, 1H), 4.07(q, J ═ 7Hz, 2H), 1.09(t, J ═ 7Hz, 3H); MS [ M + H ]]⁺＝486.0；LCMS RT＝2.92min；TLC R_f＝0.38(3∶1v/v CH₂Cl₂-THF).

Example 145: preparation of 4-amino-N- (2-fluoro-1, 1-dimethylethyl) -5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 69 was used to prepare the title compound by substituting 1-fluoro-2-methylpropan-2-amine for cyclopropylamine.

¹H-NMR(DMSO-d₆) σ 9.20(bs, 1H), 8.60(d, J ═ 7Hz, 1H), 8.07(s, 1H), 7.89(s, 1H), 7.57(d, J ═ 8Hz, 2H), 7.45 to 7.41(m, 1H), 7.40 to 7.30(m, 1H), 7.35(d, J ═ 8Hz,2H)，6.86(s，1H)，5.02(bs，1H)4.39(d，J＝24Hz，2H)，1.15(s，9H)；MS[M+H]⁺＝548.4；LCMS RT＝3.35min；TLCR_f＝0.58(3∶2v/vCH₂Cl₂-THF).

example 146: preparation of 4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (tetrahydrofuran-2-ylmethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 69 was used to prepare the title compound by substituting 1- (tetrahydrofuran-2-yl) methylamine for cyclopropylamine.

¹H-NMR(DMSO-d₆) δ 9.32(s, 1H), 8.94(d, J ═ 3Hz, 1H), 8.63to 8.59(m.1h), 8.08(s, 1H), 7.89(s, 1H), 7.60 to 7.55(m, 1H), 7.54(d, J ═ 8Hz, 2H), 7.50 to 7.45(m, 1H), 7.41 to 7.34(m, 1H), 7.32(d, J ═ 8Hz, 2H), 5.01(bs, 1H), 3.80 to 3.72(m, 1H)3.76 to 3.60(m, 1H), 3.58 to 3.50(m, 1H), 3.20 to 3.12(m, 1H), 1.80 to 1.69(m, 1H); MS [ M + H ]]⁺＝558.3；LCMS RT＝3.13min；TLCR_f＝0.29(3∶2v/v CH₂Cl₂-THF).

Example 147: preparation of 4-amino-5- {4- [ ({ [ 2-chloro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 143 was used to prepare the title compound by substituting 2, 2, 2-trifluoroethylamine for 2-amino-2-methylpropan-1-ol.

¹H-NMR(DMSO-d₆) δ 9.70(s, 1H), 8.67(s, 1H), 8.64(s, 1H), 8.52(t, J ═ 6.2Hz, 1H), 8.19(s, 1H), 7.92(s, 1H), 7.72(d, J ═ 8.3Hz, 1H), 7.54(d, J ═ 8.7Hz, 2H), 7.39 to 7.36(m, 1H), 7.30(d, J ═ 8.5Hz, 2H), 3.98 to 3.91(m, 2H); MS [ M + H ]]⁺＝573；LCMS RT＝3.11min；TLC R_f＝0.43(5∶4∶1v/v/v CH₂Cl₂-EtOAc-MeOH).

Example 148: 4-amino-N- (2, 2-dimethylpropyl) -5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

2, 2-dimethylpropan-1-amine instead of cyclopropylamine, the procedure used for the preparation of example 69 was used to prepare the title compound.

¹H-NMR(DMSO-d₆) δ 9.33(s, 1H), 8.94(d, J ═ 3Hz, 1H), 8.61(dd, J ═ 7,2Hz, 1H), 8.06(s, 1H), 7.89(s, 1H), 7.57(d, J ═ 9Hz, 2H), 7.50 to 7.45(m, 1H), 7.41 to 7.36(m, 1H), 7.35(d, J ═ 9Hz, 2H)7.26(t, J ═ 6Hz, 1H), 5.00(bs, 1H), 2.91(d, J ═ 6Hz, 1H), 0.72(s, 9H); MS [ M + H ]]⁺＝544.5；LCMS RT＝3.13min；TLCR_f＝0.51(3∶2v/v CH₂Cl₂-THF).

Example 149: preparation of 4-amino-5- {4- [ ({ [ 2-chloro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (1, 1-dimethyl-2-morpholin-4-ylethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 66 was used to prepare the title compound by substituting intermediate AC for intermediate I.

¹H-NMR(CD₃OD) δ 8.66(d, J ═ 1.7Hz, 1H), 7.95(s, 1H), 7.83(s, 1H), 7.72(d, J ═ 8.8Hz, 2H), 7.62(d, J ═ 8.7Hz, 1H), 7.47(d, J ═ 8.8Hz, 2H), 7.31(dd, J ═ 8.5, 2.1Hz, 1H), 3.62 to 3.53(m, 4H), 2.44(s, 2H), 2.42 to 2.34(m, 4H), 1.18(s, 6H); MS [ M + H ]]⁺＝631.2；LCMS RT＝2.84.

Example 150: preparation of 4-amino-5- {4- [ ({ [ 2-chloro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- [2- (dimethylamino) -1, 1-dimethylethyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 66 was used to prepare the title compound by substituting intermediate AC for intermediate I and N-methyl methylamine for morpholine.

¹H-NMR(CD₃OD)δ8.66(s，1H)，8.00(s，1H)，7.84(s，1H)，7.71(d，J＝8.4Hz，2H)，7.63(d，J＝8.7Hz，1H)，7.46(d，J＝8.4Hz，2H)，7.32(d，J＝8.9Hz，1H)，2.27(s，2H)，2.04(s，6H)，1.13(s，6H)；MS[M+H]⁺＝456.1；MS[M+H]⁺＝589.4；LCMS RT＝2.50.

Example 151: preparation of N- [4- (4-amino-6-cyanopyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [ 4-fluoro-3- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate P for intermediate X and phenyl [ 4-fluoro-3- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD) δ 8.18(s, 1H), 7.94 to 7.89(m, 2H), 7.69 to 7.64(m, 3H), 7.48(d, J ═ 8.1Hz, 2H), 7.26(t, J ═ 9.9Hz, 1H); MS [ M + H ]]⁺＝456.1；LCMS RT＝3.09.

Example 152: preparation of N- [4- (4-amino-6-cyanopyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [3- (trifluoromethoxy) phenyl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate P for intermediate X and phenyl [3- (trifluoromethoxy) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD) δ 8.17(s, 1H), 7.90(s, 1H), 7.68 to 7.61(m, 3H), 7.48(d, J ═ 8.1Hz, 2H), 7.40 to 7.29(m, 2H), 6.91(d, J ═ 8.0Hz, 1H); MS [ M + H ] ]⁺＝454.1；LCMS RT＝3.11.

Example 153: preparation of N- [4- (4-amino-6-cyanopyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [2- (trifluoromethyl) pyridin-4-yl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate P for intermediate X and phenyl [2- (trifluoromethyl) pyridin-4-yl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD) δ 8.47(d, J ═ 6.1Hz, 1H), 8.18(s, 1H), 8.05(d, J ═ 2.2Hz, 1H), 7.09(s, 1H), 7.71 to 7.64(m, 3H), 7.50(d, J ═ 8.1Hz, 2H); MS [ M + H ]]⁺＝439.0；LCMS RT＝2.72.

Example 154: preparation of N- [4- (4-amino-6-cyanopyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate P for intermediate X and phenyl (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.18(s，1H)，7.90(s，1H)，7.65(d，J＝8.0Hz，2H)，7.47(d，J＝8.0Hz，2H)，7.17(m 1H)，7.11(m，1H)，6.13(s，1H)，3.71(s，3H)，1.28(s，9H)；MS[M+H]⁺＝430.1；LCMS RT＝2.56.

Example 155: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AB for intermediate X and phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.63(d，J＝6.8Hz，1H)，8.13(s，1H)，7.98(s，1H)，7.83(s，1H)，7.69(d，J＝8.5Hz，2H)，7.42(d，J＝8.4Hz，2H)，7.35(d，J＝8.3Hz，2H)，6.49(s，1H)；MS[M+H]⁺＝498.1；LCMS RT＝2.82.

Example 156: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AB for intermediate X and phenyl [4- (trifluoromethyl) pyridin-2-yl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.50(d，J＝5.3Hz，1H)，8.12(s，1H)，7.98(s，1H)，7.84(s，1H)，7.77(s，1H)，7.76(d，J＝8.1Hz，2H)，7.45(d，J＝8.0Hz，2H)，7.29(d，J＝6.3Hz，1H)，6.51(s，1H)；MS[M+H]⁺＝481.0；LCMS RT＝2.70.

Example 157: preparation of N- (4- { 4-amino-6- [ (2-methoxyethoxy) methyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate Z for intermediate X and phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD) δ 8.62(d, J ═ 8.0Hz, 1H), 7.79(s, 1H), 7.71(s, 1H), 7.62(d, J ═ 8.1, 2H), 7.44(d, J ═ 8.2Hz, 2H), 7.34(d, J ═ 9.0Hz, 2H), 4.45(s, 2H), 3.59 to 3.48(m, 4H), 3.33(s, 3H); MS [ M + H ]]⁺＝519.2；LCMSRT＝3.13.

Example 158: preparation of N- (4- { 4-amino-6- [ (2, 2, 2-trifluoroethoxy) methyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AA for intermediate X and phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.53(d，J＝6.7Hz，1H)，7.70(s，1H)，7.63(s，1H)，7.52(d，J＝8.3，2H)，7.33(d，J＝8.3Hz，2H)，7.24(d，J＝8.3Hz，2H)，4.47(s，2H)，4.00(q，J＝7.9Hz，2H)；MS[M+H]⁺＝543.3；LCMS RT＝3.10.

Example 159: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 3-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AB for intermediate X and phenyl [ 3-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD) δ 8.12(s, 1H), 7.97(s, 1H), 7.83(s, 1H), 7.71 to 7.60(m, 4H), 7.42(d, J ═ 8.2Hz, 2H), 7.05(d, J ═ 8.1Hz, 1H), 6.49(s, 1H); MS [ M + H ]]⁺＝498.2；LCMS RT＝2.90.

Example 160: preparation of N- (4- { 4-amino-6- [ (2, 2, 2-trifluoroethoxy) methyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AA for intermediate X and phenyl [4- (trifluoromethyl) pyridin-2-yl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆) δ 9.90(s, 1H), 9.75(s, 1H), 8.53(d, J ═ 4.7Hz, 1H), 8.05(s, 1H), 7.85(s, 1H), 7.82(s, 1H), 7.62(d, J ═ 8.6Hz, 2H), 7.39 to 7.32(m, J ═ 8.0Hz, 3H), 4.49(s, 2H), 3.97(q, J ═ 9.1Hz, 2H); MS [ M + H ]]⁺＝526.0；LCMS RT＝2.90.

Example 161: preparation of N- [4- (4-amino-6-cyanopyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - (3-tert-butylisoxazol-5-yl) urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate P for intermediate X and phenyl (3-tert-butylisoxazol-5-yl) carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.17(s，1H)，7.90(s，1H)，7.68(d，J＝7.8Hz，2H)，7.48(d，J＝7.8Hz，2H)，6.13(s，1H)，1.31(s，9H)；MS[M+H]⁺＝417.1；LCMS RT＝2.87.

Example 162: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 4-fluoro-3- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AB for intermediate X and phenyl [ 4-fluoro-3- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD) δ 8.12(s, 1H), 7.97(s, 1H), 7.92(dd, J ═ 2.7, 6.2Hz, 1H), 7.83(s, 1H), 7.70 to 7.62(m, 3H), 7.41(d, J ═ 8.0Hz, 2H), 7.28(t, J ═ 9.5Hz, 1H), 6.49(s, 1H); MS [ M + H ] ]⁺＝498.2；LCMS RT＝3.14.

Example 163: preparation of N- {4- [ 4-amino-6- (1, 3, 4-oxadiazol-2-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AD for intermediate X and phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.80(s，1H)，8.62(d，J＝6.7Hz，1H)，8.28(s，1H)，7.89(s，1H)，7.64(d，J＝8.2Hz，2H)，7.45(d，J＝8.2Hz，2H)，7.34(d，J＝8.9Hz，2H)；MS[M+H]⁺＝499.2；LCMS RT＝2.82.

Example 164: preparation of 4-amino-N- (tert-butyl) -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate L for intermediate X and phenyl [6- (trifluoromethyl) pyridin-2-yl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆) δ 9.88(s, 1H), 9.73(s, 1H), 8.05 to 7.99(m, 1H), 8.04(d, J ═ 8Hz, H H), 7.88(s, 1H), 7.55(d, J ═ 8Hz, 2H), 7.50 to 7.46(m, 1H), 7.36(d, J ═ 8Hz, 2H), 6.66(s, 1H), 5.00(bs, 1H), 1.16(s, 9H); MS [ M + H ]]⁺＝513.1；LCMS RT＝2.84min；TLCR_f＝0.64(3∶2v/v CH₂Cl₂-THF).

Example 165: preparation of 4-amino-N- (2, 2-dimethylpropyl) -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AE for intermediate X and phenyl [6- (trifluoromethyl) pyridin-2-yl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆) δ 9.87(s, 1H), 9.77(s, 1H), 8.07(s, 1H), 8.06 to 7.81(m, 3H), 7.89(s, 1H), 7.54(d, J ═ 8Hz, 2H), 7.55 to 7.50(m, 1H), 7.36(d, J ═ 8Hz, 2H), 7.28 to 7.20(m, 1H), 4.95(bs, 1H), 2.91(d, J ═ 6Hz, 2H), 0.72(s, 9H); MS [ M + H ]]⁺＝527.1；LCMS RT＝2.89min；TLCR_f＝0.64(3∶2v/v CH₂Cl₂-THF).

Example 166: preparation of 1- [4- (4-amino-6-imidazol-1-ylmethyl-pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) -phenyl ] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AE for intermediate X and phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(CD₃OD)δ8.61(d，J＝7.5Hz，1H)，7.80(s，1H)，7.72(s，1H)，7.61(d，J＝8.6Hz，2H)，7.46(s，1H)，7.34(d，J＝8.6Hz，2H)，7.24(d，J＝8.4Hz，2H)，6.93(d，J＝5.1Hz，2H)，5.17(s，2H)；MS[M+H]⁺＝511.3；LCMS RT＝2.63min.

Example 167: preparation of 4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2-methoxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 69 was used to prepare the title compound by substituting 2-methoxyethylamine for cyclopropylamine.

¹H-NMR(CD₃OD) δ 8.62(d, J ═ 7.5Hz, 1H), 8.03(s, 1H), 7.84(s, 1H), 7.69(d, J ═ 9.0Hz, 2H), 7.45(d, J ═ 9.0, 2H), 7.35(d, J ═ 8.8Hz, 2H), 3.39 to 3.34(m, 4H), 3.24(s, 3H); MS [ M + H ]]⁺＝532.1；LCMS RT＝3.05min.

Example 168: preparation of N- [4- (4-amino-6-cyanopyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [6- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate P for intermediate X and phenyl [6- (trifluoromethyl) pyridin-2-yl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆) δ 9.89(s, 1H), 9.75(s, 1H), 8.51(s, 1H), 8.03 to 7.99(m, 3H), 7.63(d, J ═ 8.4, 2H), 7.51 to 7.44(m, 3H); MS [ M + H ]]⁺＝439；LCMS RT＝2.62min.

Example 169: preparation of ethyl 3- (4-amino-5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl) propanoate

The procedure used for the preparation of intermediate I was used to prepare the title compound by substituting phenyl [6- (trifluoromethyl) pyridin-2-yl ] carbamate for phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate.

¹H-MR(DMSO-d₆) δ 9.88(s1H), 9.73(s, 1H), 8.05 to 7.98(m, 3H), 7.79(s, 1H), 7.61 to 7.57(m, 3H), 7.51 to 7.49(m, 1H), 7.33(d, J ═ 8.7, 2H), 4.03 to 3.97(m, 2H), 2.74 to 2.70(m, 2H), 2.55 to 2.51(m, 2H), 1.15 to 1.11(m, 3H); MS [ M + H ] ]⁺＝514；LCMS RT＝2.65min.

Example 170: preparation of N- {4- [ 4-amino-6- (1H-imidazol-1-ylmethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 3-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 166 was used to prepare the title compound by substituting phenyl [ 3-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate.

¹H-NMR(CD₃OD) δ 8.55 to 8.58(m, 1H), 7.98(s, 1H), 7.97(s, 1H), 7.65 to 7.80(m, 2H), 7.63(d, J ═ 9Hz, 2H), 7.41 to 7.43(m, 1H), 7.2 to 7.4(m, 1H), 7.25(d, J ═ 9Hz, 2H), 7.00tp 7.1(m, 1H), 5.46(s, 2H), 4.89(bs, 4H); MS [ M + H ]]⁺＝511.0；LCMS RT＝2.29min.

Example 171: preparation of ethyl 4-amino-5- [4- ({ [ (3-phenoxyphenyl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 1 was used to prepare the title compound by substituting 3-phenoxyphenyl isocyanate for 1-fluoro-2-isocyanato-4- (trifluoromethyl) benzene.

¹H-NMR(DMSO-d₆) δ 8.60(s, 1H), 8.82(s, 1H), 8.11(s, 1H), 7.91(s, 1H), 7.50 to 7.48(m, 2H), 7.41 to 7.37(m, 2H), 7.29 to 7.25(m, 4H), 7.15 to 7.11(m, 2H), 7.04 to 7.01(m, 2H), 4.10 to 4.04(m, 2H), 1.12 to 1.08(m, 3H); MS [ M + H ] ]⁺＝509.1；LCMS RT＝3.48min.

Example 172: preparation of tert-butyl (3- { [ (4-amino-5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl) carbonyl ] amino } propyl) carbamate

The procedure used for the preparation of example 55 was used to prepare the title compound by substituting tert-butyl (3-aminopropyl) carbamate for N, N-dimethylpropane-1, 3-diamine and phenyl [6- (trifluoromethyl) pyridin-2-yl ] carbamate for phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate.

¹H-NMR(DMS O-d₆) δ 9.88(s, 1H), 9.72(s, 1H), 8.06 to 7.97(m, 3H), 7.89(s, 1H), 7.78 to 7.75(m, 1H), 7.53 to 7.48(m, 3H), 7.33 to 7.31(m, 2H), 6.75 to 6.72(m, 1H), 3.11 to 3.06(m, 2H), 2.91 to 2.86(m, 2H), 1.52 to 1.48(m, 2H), 1.35(s, 9H); MS [ M + H ]]⁺＝614.2；LCMS RT＝2.55min.

Example 173: preparation of 4-amino-N- (3-aminopropyl) -5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

To a solution of DMF (5mL) was added intermediate G (100mg, 0.21mmol) and BOP (93mg, 0.21mmol), followed by NMM (23. mu.L, 0.21mmol) and tert-butyl (3-aminopropyl) carbamate (37mg, 0.21 mmol). Will react in N ₂Stirred at room temperature under an atmosphere for 2 hours. The solution was then washed with EtOAc (20mL) and NaHCO₃The aqueous solution (20mL) was diluted, transferred to a separatory funnel, and separated. The aqueous layer was back-extracted with EtOAc (2X 20 mL). The combined organic layers were dried (MgSO)₄) Filtered and concentrated in vacuo. The crude product was purified by flash chromatography (9: 1v/v CH)₂Cl₂MeOH). The isolated product, (3- { [ (4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl) is isolated]Amino } carbonyl) amino]Phenyl } pyrrolo [2, 1-f][1，2，4]Triazin-6-yl) carbonyl]Amino } propyl) carbamic acid tert-butyl ester with CH₂Cl₂(5mL) and TFA (5mL) and in N₂Stirred at room temperature under an atmosphere for 17 hours. The reaction mixture was then concentrated in vacuo and purified by preparative HPLC (10-90% ACN/H)₂O, containing 0.1% TFA). The resulting purified fractions were purified with EtOAc (20mL) and NaHCO₃The aqueous solution (20mL) was diluted and separated. Subjecting the organic layer to H₂O washing, separating and drying (MgSO)₄) Filtered and concentrated to dryness to give 29mg of the above compound as a white solid (0.055mmol, 26% yield).

¹H-NMR(DMSO-d₆) δ 9.59 to 9.55(br s, 1H), 8.58 to 8.56(d, J ═ 9.7Hz, 1H), 8.05(s, 1H), 7.89(s, 1H), 7.76 to 7.74(m, 1H), 7.57 to 7.55(d, J ═ 8.5Hz, 2H), 7.50 to 7.45(m, 1H), 7.39 to 7.35(m, 1H), 7.32 to 7.29(d, J ═ 8.6Hz, 2H), 3.19 to 3.14(m, 2H), 2.57 to 2.54(m, 2H), 1.57 to 1.50(m, 2H); MS [ M + H ] ]⁺＝531.3；LCMS RT＝2.52min.

Example 174: preparation of 4-amino-N- (3-aminopropyl) -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 173 was used to prepare the title compound by substituting example 250 for intermediate G.

¹H-NMR(CD₃OD) δ 7.99(s, 1H), 7.98 to 7.94(m, 1H), 7.84(s, 1H), 7.68 to 7.65(m, 2H), 7.52(d, J ═ 8.5, 1H), 7.47 to 7.43(m, 3H), 3.35(m, 2H), 2.83 to 2.80(m, 2H), 1.82 to 1.75(m, 2H); MS [ M + H ]]⁺＝514.1；LCMS RT＝1.85min.

Example 175: preparation of 4-amino-N-methyl-5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

A solution of intermediate AH (40mg, 1eq) and HATU (50mg, 1.5eq) in 1ml anhydrous DMF was stirred at room temperature for 0.5 h. The mixture was then added to a solution of 0.2ml of amine (1.5eq) in anhydrous DMF. Triethylamine (26.5mg, 3eq) was added to the reaction and the reaction was stirred at rt overnight. The reaction mixture was purified without work-up on Prep LC-MS, using a gradient elution with water and acetonitrile containing 0.1% TFA as modifier.

MS[M+H]⁺＝471.14；LCMS RT＝2.97min.

Example 176: preparation of 4-amino-N-ethyl-5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting ethylamine for methylamine.

MS[M+H]⁺＝485.16；LCMS RT＝2.91min.

Example 177: preparation of 4-amino-N-cyclopropyl-5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting cyclopropylamine for methylamine.

MS[M+H]⁺＝497.16；LCMS RT＝2.94min.

Example 178: preparation of 4-amino-N- (2-pyrrolidin-1-ylethyl) -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting N- (2-aminoethyl) -pyrrolidine for methylamine.

MS[M+H]⁺＝554.22；LCMS RT＝2.6min.

Example 179: preparation of 4-amino-N- [2- (dimethylamino) ethyl ] -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting N, N-dimethylethylenediamine for methylamine.

MS[M+H]⁺＝528.2；LCMS RT＝2.6min.

Example 180: preparation of 4-amino-N- (3-methoxypropyl) -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 3-methoxypropylamine for methylamine.

MS[M+H]⁺＝528.18；LCMS RT＝2.9min.

Example 181: preparation of 4-amino-N- (2-ethoxyethyl) -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 2-ethoxyethylamine for methylamine.

MS[M+H]⁺＝529.18；LCMS RT＝2.96min.

Example 182: preparation of N- {4- [ 4-amino-6- (morpholin-4-ylcarbonyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [6- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting morpholine for methylamine.

MS[M+H]⁺＝527.17；LCMS RT＝2.84min.

Example 183: preparation of 4-amino-N- (2-morpholin-4-ylethyl) -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 4- (2-aminoethyl) morpholine for methylamine.

MS[M+H]⁺＝570.21；LCMS RT＝2.58min.

Example 184: preparation of N- (4- { 4-amino-6- [ (4-methylpiperazin-1-yl) carbonyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [6- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 1-methylpiperazine for methylamine.

MS[M+H]⁺＝540.2；LCMS RT＝2.55min.

Example 185: preparation of 4-amino-N- [3- (4-methylpiperazin-1-yl) propyl ] -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 1- (3-aminopropyl) -4-methylpiperazine for methylamine.

MS[M+H]⁺＝597.26；LCMS RT＝2.5min.

Example 186: preparation of 4-amino-N- [3- (2-oxopyrrolidin-1-yl) propyl ] -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 1- (3-aminopropyl) -2-pyrrolidone for methylamine.

MS[M+H]⁺＝582.21；LCMS RT＝2.81min.

Example 187: preparation of 4-amino-N- [4- (dimethylamino) -3, 3-dimethylbutyl ] -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

With 2, 2, N^＊1^＊，N^＊1^＊-tetramethyl-butane-1, 4-diamine instead of methylamine, the procedure used for the preparation of example 175 was used to prepare the title compound.

MS[M+H]⁺＝570.25；LCMS RT＝2.65min.

Example 188: preparation of 4-amino-N- [3- (dimethylamino) propyl ] -N-methyl-5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting N, N' -trimethyl-1, 3-propanediamine for methylamine.

MS[M+H]⁺＝556.23；LCMS RT＝2.57min.

Example 189: preparation of 4-amino-N- (3-morpholin-4-ylpropyl) -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 4- (3-aminopropyl) morpholine for methylamine.

MS[M+H]⁺＝584.23；LCMS RT＝2.6min.

Example 190: preparation of 4-amino-N- (4-pyrrolidin-1-ylbutyl) -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 4- (1-pyrrolidine) butylamine for methylamine.

MS[M+H]⁺＝582.25；LCMS RT＝2.6min.

Example 191: preparation of 4-amino-N- [2- (1-methylpyrrolidin-2-yl) ethyl ] -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 2- (2-aminoethyl) -1-methylpyrrolidine for methylamine.

MS[M+H]⁺＝568.23；LCMS RT＝2.6min.

Example 192: preparation of 4-amino-N- [4- (dimethylamino) butyl ] -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 4-dimethylaminobutylamine for methylamine.

MS[M+H]⁺＝556.23；LCMS RT＝2.6min.

Example 193: preparation of N- {4- [ 4-amino-6- ({4- [3- (dimethylamino) propyl ] piperazin-1-yl } carbonyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [6- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 1- (3-dimethylaminopropyl) -piperazine for methylamine.

MS[M+H]⁺＝611.27；LCMS RT＝2.45min.

Example 194: preparation of N- {4- [ 4-amino-6- ({4- [2- (dimethylamino) ethyl ] piperazin-1-yl } carbonyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [6- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 1- (2-dimethylaminoethyl) -piperazine for methylamine.

MS[M+H]⁺＝597.26；LCMS RT＝2.52min.

Example 195: preparation of 4-amino-N- [3- (dimethylamino) propyl ] -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 3- (dimethylamino) propylamine for methylamine.

MS[M+H]⁺＝542.22；LCMS RT＝2.6min.

Example 196: preparation of 4-amino-N- [4- (diethylamino) butyl ] -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 4-diethylaminobutylamine for methylamine.

MS[M+H]⁺＝598.28；LCMS RT＝2.67min.

Example 197: preparation of 4-amino-N, N-bis (2-methoxyethyl) -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting di (2-methoxyethyl) amine for methylamine.

MS[M+H]⁺＝573.21；LCMS RT＝2.93min.

Example 198: preparation of N- {4- [ 4-amino-6- (1, 4-dioxa-8-azaspiro [4.5] decan-8-ylcarbonyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [6- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 1, 4-dioxa-8-azaspiro [4.5] decane for methylamine.

MS[M+H]⁺＝583.2；LCMS RT＝2.93min.

Example 199: preparation of 4-amino-N- (cyclohexylmethyl) -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting cyclohexanemethylamine for methylamine.

MS[M+H]⁺＝553.22；LCMS RT＝3.31min.

Example 200: preparation of 4-amino-N-cyclopentyl-5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting cyclopentylamine for methylamine.

MS[M+H]⁺＝525.19；LCMS RT＝3.1min.

Example 201: preparation of 4-amino-N- (2-isopropoxyethyl) -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 2-aminoethylisopropyl ether for methylamine.

MS[M+H]⁺＝543.2；LCMS RT＝3.05min.

Example 202: preparation of 4-amino-N- [3- (diethylamino) propyl ] -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting N, N-diethyl-1, 3-propanediamine for methylamine.

MS[M+H]⁺＝570.25；LCMS RT＝2.62min.

Example 203: preparation of 4-amino-N- (cyclopropylmethyl) -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting cyclopropanemethylamine for methylamine.

MS[M+H]⁺＝511.17；LCMS RT＝3.04min.

Example 204: preparation of 4-amino-N- [3- (methylthio) propyl ] -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 3- (methylthio) propylamine for methylamine.

MS[M+H]⁺＝545.16；LCMS RT＝3.06min.

Example 205: preparation of 4-amino-N- (3-isopropoxypropyl) -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 3-isopropoxypropylamine for methylamine.

MS[M+H]⁺＝557.22；LCMS RT＝3.05min.

Example 206: preparation of N- (4- { 4-amino-6- [ (4-cyclohexylpiperazin-1-yl) carbonyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [6- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 1-cyclohexylpiperazine for methylamine.

MS[M+H]⁺＝608.26；LCMS RT＝2.63min.

Example 207: preparation of 4-amino-N- [ (1-ethylpyrrolidin-2-yl) methyl ] -5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 2- (aminomethyl) -1-ethylpyrrolidine for methylamine.

MS[M+H]⁺＝568.23；LCMS RT＝2.64min.

Example 208: preparation of N- [4- (4-amino-6- { [3- (dimethylamino) pyrrolidin-1-yl ] carbonyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [6- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 3- (dimethylamino) pyrrolidine for methylamine.

MS[M+H]⁺＝554.22；LCMS RT＝2.54min.

Example 209: preparation of N- (4- { 4-amino-6- [ (4-ethylpiperidin-1-yl) carbonyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [6- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting 4-ethylpiperidine for methylamine.

MS[M+H]⁺＝553.22；LCMS RT＝3.25min.

Example 210: preparation of 4-amino-N-isobutyl-5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting isobutylamine for methylamine.

MS[M+H]⁺＝513.19；LCMS RT＝3.11min.

Example 211: preparation of 4-amino-N-butyl-5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 175 was used to prepare the title compound by substituting N-butylamine for methylamine.

MS[M+H]⁺＝513.19；LCMS RT＝3.14min.

Example 212: preparation of ethyl 4-amino-5- {4- [ ({ [4- (trifluoromethyl) -1, 3-thiazol-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 24 was used to prepare the title compound by substituting 4- (trifluoromethyl) -1, 3-thiazol-2-amine for 2-isopropylaniline.

¹H-NMR(DMSO-d₆) δ 11.0(s, 1H), 9.15(s, 1H), 8.13(s, 1H), 7.93(s, 1H), 7.87(s, 1H), 7.57 to 7.55(m, 2H), 7.35 to 3.33(m, 2H), 1.12 to 1.09(m, 3H); MS [ M + H ]]⁺＝492；LCMS RT＝2.73min.

Example 213: preparation of Ethyl 4-amino-5- {4- [ ({ [4- (trifluoromethyl) -1, 3-thiazol-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid

The procedure used for step 2 to prepare intermediate J was used to prepare the title compound by substituting phenyl [4- (trifluoromethyl) -1, 3-thiazol-2-yl ] carbamate for phenyl [ 2-chloro-5- (trifluoromethyl) phenyl ] carbamate.

¹H-NMR(DMSO-d₆) δ 12.3 to 12.2(br s, 1H), 11.2 to 11.1(br s, 1H), 9.41 to 9.18(br s, 1H), 8.30(s, 1H), 8.29 to 8.1(br s, 1H), 7.90(s, 1H), 7.82(s, 1H), 7.65 to 7.58(m, 2H), 7.55 to 7.30(m, 2H), 5.27 to 4.71(br s, 1H); MS [ M + H ]]⁺＝464；LCMS RT＝2.28min.

Example 214: preparation of 4-amino-N- (2, 2, 2-trifluoroethyl) -5- {4- [ ({ [4- (trifluoromethyl) -1, 3-thiazol-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 69 was used to prepare the title compound by substituting example 213 for intermediate G and 2, 2, 2-trifluoroethylamine for cyclopropylamine.

¹H-NMR(DMSO-d₆) δ 11.0(s, 1H), 9.13(s, 1H), 8.55 to 8.52(m, 1H), 8.19(s, 1H), 7.91(s, 1H), 7.85(s, 1H), 7.55 to 7.52(m, 2H), 7.32 to 7.30(m, 2H), 3.97 to 3.93(m, 2H); MS [ M + H ]]⁺＝544.9；LCMS RT＝2.52min.

Example 215: preparation of ethyl 4-amino-5- {4- [ ({ [ 2-fluoro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 24 was used to prepare the title compound by substituting 2-fluoro-3- (trifluoromethyl) aniline for 2-isopropylaniline.

¹H-NMR(DMSO-d₆) δ 9.33(s, 1H), 8.92(s, 1H), 8.52 to 8.45(m, 1H), 8.16(s, 1H), 8.10(bs, 1H), 7.96(s, 1H), 7.57(d, J ═ 9.0Hz, 2H), 7.40 to 7.34(m, 4H), 5.14(bs, 1H), 4.10(q, J ═ 8.0Hz, 2H), 1.12(q, J ═ 7.8Hz, 3H); MS [ M + H ]]⁺＝503.2；LCMS RT＝3.14min.

Example 216: preparation of Ethyl N- {4- [ 4-amino-6- (methoxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [3- (trifluoromethoxy) phenyl ] urea

The procedure used for the preparation of example 24 was used to prepare the title compound by substituting 3-methoxyaniline for 2-isopropylaniline and intermediate U for intermediate B.

¹H-NMR(DMSO-d₆) δ 7.81(s, 1H), 7.73(s, 1H), 7.65 to 7.71(m, 2H), 7.61(d, J ═ 9Hz, 2H), 7.40((d, J ═ 9Hz, 2H), 7.37(m, 1H), 7.33 to 7.36(m, 2H), 6.90 to 6.95(m, 1H), 4.36(s, 2H), 3.30(s, 3H); MS [ M + H ]]⁺＝473.1；LCMS RT＝2.69min.

Example 217: preparation of N- {4- [ 4-amino-6- (methoxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 3-tert-butyl-1- (4-fluorophenyl) -1H-pyrazol-5-yl ] urea

¹H-NMR(CD₃OD) δ 7.78(s, 1H), 7.68(s, 1H), 7.52 to 7.58(m, 2H), 7.52(d, J ═ 9Hz, 2H)7.37(d, J ═ 9Hz, 2H), 7.28 to 7.31(m, 2H), 6.44(s, 1H), 4.34(s, 2H), 3.30(s, 3H), 1.26(s, 9H); MS [ M + H ]]⁺＝529.2；LCMS RT＝3.04min.

Example 218: preparation of N- {4- [ 4-amino-6- (ethoxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 246 was used to prepare the title compound by substituting phenyl [4- (trifluoromethyl) pyridin-2-yl ] carbamate for 1-fluoro-2-isocyanato-4- (trifluoromethyl) benzene.

¹H-NMR(DMSO-d₆) δ 9.99(s, 1H), 9.82(s, 1H), 8.56(d, J ═ 5Hz, 1H), 8.10(s, 1H), 7.87(s, 1H), 7.77(s, 1H), 7.65(d, J ═ 9Hz, 2H), 7.62 to 7.65(m, 1H), 7.30 to 7.42(m, 4H), 4.32(s, 2H), 3.40(q, J ═ 7Hz, 2H), 1.09(t, J ═ 7Hz, 3H); MS [ M + H ] ]⁺＝472.1；LCMS RT＝2.73min.

Example 219: preparation of N- {4- [ 4-amino-6- (hydroxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [6- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used in step 1 to prepare intermediate F was used to prepare the title compound by substituting example 144 for intermediate E.

¹H-NMR(DMSO-d₆) δ 9.87(s, 1H), 9.71(s, 1H), 8.03 to 7.99(m, 3H), 7.82(s, 1H), 7.65(s, 1H), 7.57 to 7.55(m, 3H), 7.50 to 7.47(m, 1H), 7.37(d, J ═ 8.5Hz, 2H), 4.97 to 4.94(m, 1H), 4.36(d, J ═ 5.2Hz, 2H); MS [ M + H ]]⁺＝444.0；LCMS RT＝224min.

Example 220: preparation of N- [ (4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl) carbonyl ] serine Ethyl ester

The procedure used for the preparation of example 143 was used to prepare the title compound by substituting serine methyl ester hydrochloride for 2-amino-2-methylpropan-1-ol and intermediate G for intermediate J.

¹H-NMR(DMSO-d₆) δ 9.33(s, 1H), 8.95(d, J ═ 2.5Hz, 1H), 8.62 to 8.60(d, J ═ 8.8Hz, 1H), 8.20(s, 1H), 7.91(s, 1H), 7.78 to 7.76(d, J ═ 7.8Hz, 1H), 7.55 to 7.53(d, J ═ 8.7Hz, 2H), 7.50 to 7.47(m, 1H), 7.40 to 7.37(m, 1H), 7.34 to 7.32(d, J ═ 8.4Hz, 2H), 4.98 to 4.95(t, J ═ 5.9Hz, 1H), 4.38 to 4.34(m, 1H), 4.08 to 4.03(q, J ═ 7.2, 2H), 3.70 to 3.70 (t, 3.1H), 3.1H, 1H); MS [ M + H ] ]⁺＝590.0；LCMS RT＝2.69min.

Example 221: preparation of N- [ (4-amino-5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl) carbonyl ] serine Ethyl ester

The procedure used for the preparation of example 143 was used to prepare the title compound by substituting serine methyl ester hydrochloride for 2-amino-2-methylpropan-1-ol and the compound of example 250 for intermediate J.

¹H-NMR(DMSO-d₆) δ 9.87(s, 1H), 9.74(s, 1H), 8.54 to 8.53(d, J ═ 5.4Hz, 1H), 8.20(s, 1H), 8.06(s, 1H), 7.91(s, 1H), 7.79 to 7.77(d, J ═ 7.6Hz, 1H), 7.59 to 7.57(d, J ═ 8.7Hz, 2H), 7.37 to 7.33(m, 3H), 4.98 to 4.95(t, J ═ 5.8Hz, 1H), 4.39 to 4.34(m, 1H), 4.08 to 4.03(q, J ═ 7.0Hz, 2H), 3.72 to 3.61(m, 2H), 1.18to 1.14(t, J ═ 7.1, 3H); MS [ M + H ]]⁺＝573.0；LCMS RT＝2.55min.

Example 222: preparation of N- [4- (4-amino-6-vinylpyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

Potassium tert-butoxide (0.51g, 4.53mmol) was suspended in 1, 4-dioxane (40mL) and treated with methyl (triphenyl) phosphonium bromide (1.6g, 4.53 mmol). The resulting yellow suspension was stirred at room temperature for 30 minutes. The mixture was then treated with intermediate AG (1.0g, 2.27 mmol). The mixture was then stirred at room temperature for 3 hours. The mixture was then poured into water and stirred for 1 hour. The mixture was then filtered and washed with water and methanol. The residual solid was dried under reduced pressure to give 0.62g of product as a light brown solid (1.41mmol, 62% yield).

¹H-NMR(DMSO-d₆)δ10.0(bs，1H)，9.86(bs，1H)，8.53(d，J＝5.1Hz，1H)，8.07(s，1H)，8.04(s，1H)，7.84(s，1H)，7.64(d，J＝8.5Hz，2H)，7.35(d，J＝5.2Hz，H)，7.30(d，J＝8.4Hz，2H)，6.39(q，J＝11.0Hz，1H)，5.63(dd，J＝1.6Hz，1H)，5.11(dd，J＝1.6Hz，1H)；MS[M+H]⁺＝440.0；LCMS RT＝2.89min.

Example 223: preparation of N- [4- (6-acetyl-4-aminopyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 233 was used to prepare the title compound by substituting example XXX for example 269.

¹H-NMR(DMSO-d₆) δ 9.32(s, 1H), 8.95(d, J ═ 2Hz, 1H), 8.61(dd, J ═ 2,5Hz, 1H), 8.37(s, 1H), 8.05(bs, 1H), 7.92(s, 1H), 7.54(d, J ═ 9Hz, 2H), 7.46 to 7.52(m, 1H), 7.36to7.40(m, 1H), 7.31, d, J ═ 9HHz，2H)，5.02(bs，1H)，2.30(s，3H)；MS[M+H]⁺＝473.3；LCMS RT＝2.95min.

Example 224: preparation of 4-amino-5- {4- [ ({ [ 2-fluoro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate M for intermediate X and (2-fluoro-3-trifluoromethyl-phenyl) -carbamic acid phenyl ester for (4-tert-butylpyridin-2-yl) carbamic acid phenyl ester.

¹H-NMR(DMSO-d₆) δ 9.34(s, 1H), 8.94(s, 1H), 8.58 to 8.48(m, 2H), 8.23(s, 1H), 7.98(bs, 1H), 7.96(s, 1H), 7.56(d, J ═ 7.5Hz, 2H), 7.41 to 7.33(m, 4H), 5.11(bs, 1H), 4.10(m, 2H); MS [ M + H ]]⁺＝556.1；LCMSRT＝3.00min.

Example 225: preparation of N- {4- [ 4-amino-6- (morpholin-4-ylmethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N- [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 30 was used to prepare the title compound by substituting intermediate AG for intermediate F.

¹H-NMR(CD₃OD) δ 8.54(s, 1H), 8.06(s, 1H), 8.05(s, 1H), 7.64 to 7.41(m, 2H), 7.39 to 7.38(m, 2H), 3.57 to 3.50(m, 2H), 3.42 to 3.41(m, 2H), 2.67 to 2.66(m, 2H), 2.47 to 2.32(m, 4H); MS [ M + H ]]⁺＝513.0；LCMS RT＝1.92min.

Example 226: preparation of N- {4- [ 4-amino-6- (cyanomethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

Step 1: preparation of [ 4-amino-5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl ] acetonitrile

The procedure used for the preparation of intermediate U, step 1, was used to prepare the title compound by substituting DMF for methanol and sodium cyanide for sodium hydride.

MS[M+H]⁺＝295.4；LCMS RT＝2.11min.

Step 2: preparation of 4-amino-5- (4-aminophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl ] acetonitrile

Reacting 4-amino-5- (4-aminophenyl) pyrrolo [2, 1-f][1，2，4]Triazin-6-yl]A solution of acetonitrile (250mg, 0.85mmol) and tin (II) chloride (1.61g, 8.5mmol) in 75mL EtOH was heated at 80 ℃ for 1 hour. The reaction was then quenched with EtOAc and saturated NaHCO₃And (5) diluting the solution. After 15 minutes, the vigorously stirred mixture was filtered through a pad of celite, washing well with EtOAc. The organic layer was then separated and dried (Na) ₂SO₄) And evaporated to dryness. With Et₂O trituration to yield 210mg of the title compound (93%Yield).

MS[M+H]⁺＝265；LCMS RT＝2.63min.

And step 3: preparation of N- {4- [ 4-amino-6- (cyanomethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 101 was used to prepare the title compound by substituting 4-amino-5- (4-aminophenyl) pyrrolo [2, 1f ] [1, 2, 4] triazin-6-yl ] acetonitrile for intermediate U.

¹H-NMR(DMSO-d₆) δ 8.54(d, J ═ 5Hz, 1H), 8.07(s, 1H), 7.87(s, 1H), 7.77(s, 1H), 7.66(d, J ═ 9Hz, 2H), 7.36(d, J ═ 9Hz, 2H), 7.34 to 7.36(m, 1H), 3.81(s, 2H); MS [ M + H ]]⁺＝453.1；LCMS RT＝2.67min.

Example 227: preparation of N- [4- (4-amino-6- { [ (2, 2, 2-trifluoroethyl) amino ] methyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [6- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 30 was used to prepare the title compound by substituting 2, 2, 2-trifluoroethylamine for morpholine and N- [4- (4-amino-6-formylpyrrolo [2, 1-F ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [6- (trifluoromethyl) pyridin-2-yl ] urea for intermediate F.

¹H-NMR(DMSO-d₆) Δ 9.88(s, 1H), 9.75(s, 1H), 8.02 to 7.99(m, 2H), 7.82(s, 1H), 7.69(s, 1H), 7.57 to 7.48(m, 4H), 7 38 to 3.36(m, 2H), 3.67 to 3.66(s, 2H), 3.28 to 3.14(m, 2H), 2.66 to 2.56(m, 2H); MS [ M + H ]]⁺＝525.0；LCMS RT＝2.10min.

Example 228: preparation of N- [4- (4-amino-6- { [ (2, 2, 2-trifluoroethyl) amino ] methyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 30 was used to prepare the title compound by substituting 2, 2, 2-trifluoroethylamine for morpholine and intermediate AG for intermediate F.

¹H-NMR(CD₃OD) δ 8.51(d, J ═ 5.3Hz, 1H), 7.77(s, 1H), 7.48(br s, 1H), 7.70 to 7.68(m, 3H), 7.44 to 7.42(m, 2H), 7.29 to 7.27(m, 2H), 3.81(s, 2H), 3.18 to 3.11(m, 2H); MS [ M + H ]]⁺＝525.1；LCMS RT＝2.19min.

Example 229: preparation of N- [4- (4-amino-6- { [ (2-methoxyethyl) amino ] methyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 30 was used to prepare the title compound by substituting 2-methoxyethylamine for morpholine and intermediate AG for intermediate F.

¹H-NMR(CD₃OD) δ 8.51(d, J ═ 5.3Hz, 1H), 7.80(s, 1H), 7.78(s, 1H), 7.75 to 7.72(m, 3H), 7.43 to 7.41(m, 2H), 7.28(d, J ═ 5.6Hz, 1H), 3.97(s, 2H), 3.48 to 3.45(m, 2H), 2.89 to 2.86(m, 2H) )；MS[M+H]⁺＝501.0；LCMS RT＝1.99min.

Example 230: preparation of ethyl 2- (4-amino-5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl) -4, 5-dihydro-1, 3-oxazole-4-carboxylate

To a solution of THF (2mL) was added N- [ (4-amino-5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl) cooled to-78 deg.C]Amino } carbonyl) amino]Phenyl } pyrrolo [2, 1-f][1，2，4]Triazin-6-yl) carbonyl]Serine Ethyl ester (example 221) (50mg, 0.09 mmol). In N₂DAST (13. mu.L, 0.10mmol) was added while stirring under atmosphere and the reaction was allowed to proceed for 1 hour. Then adding anhydrous K₂CO₃The solution was warmed to room temperature over 30 minutes. The reaction mixture was transferred to a separatory funnel, diluted with EtOAc (20mL), and saturated NaHCO₃Aqueous solution (20mL) and H₂O (20mL) wash. The organic phase was collected and dried (MgSO)₄) And concentrated in vacuo. The crude product was purified by preparative HPLC (10-90% ACN/H)₂O, containing 0.1% TFA). The fractions were left overnight, partly with new product. The two products were separated by column chromatography (5: 4: 1v/v/v DCM/EtOAc/MeOH) to give 9mg of the title compound isolated (0.016mmol, 18%).

¹H-NMR(DMSO-d₆) δ 9.91(s, 1H), 9.78(s, 1H), 8.54 to 8.53(d, J ═ 5.0Hz, 1H), 8.08(s, 1H), 8.05(s, 1H), 7.91(s, 1H), 7.58 to 7.56(d, J ═ 8.6Hz, 2H), 7.37 to 7.36(d, J ═ 5.1Hz, 1H), 7.34 to 7.32(d, J ═ 8.6Hz, 2H), 4.75to 4.71(m, 1H), 4.38 to 4.29(m, 2H), 4.13 to 4.08(q, J ═ 7.1Hz, 2H), 1.21 to 1.18(t, J ═ 7.0Hz, 3H); MS [ M + H ] ]⁺＝555.1；LCMS RT＝2.84min.

Example 231: preparation of 2-amino-3-ethoxy-3-oxopropyl 4-amino-5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

To a solution of THF (2mL) was added N- [ (4-amino-5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl) cooled to-78 deg.C]Amino } carbonyl) amino]Phenyl } pyrrolo [2, 1-f][1，2，4]Triazin-6-yl) carbonyl]Serine Ethyl ester (example 221) (50mg, 0.09 mmol). In N₂DAST (13. mu.L, 0.10mmol) was added while stirring under atmosphere and the reaction was allowed to proceed for 1 hour. Then adding anhydrous K₂CO₃The solution was warmed to room temperature over 30 minutes. The reaction mixture was transferred to a separatory funnel, diluted with EtOAc (20mL), and saturated NaHCO₃Aqueous solution (20mL) and H₂O (20mL) wash. The organic phase was collected and dried (MgSO)₄) And concentrated in vacuo. The crude product was purified by preparative HPLC (10-90% ACN/H)₂O, containing 0.1% TFA). The fractions were left overnight, partly with new product. The two products were separated by column chromatography (5: 4: 1v/v/v DCM/EtOAc/MeOH) to give 4mg of the title compound isolated (0.0075mmol, 9%).

¹H-NMR(DMSO-d₆) δ 9.92(s, 1H), 9.78(s, 1H), 8.54 to 8.53(d, J ═ 5.4Hz, 1H), 8.15(s, 1H), 8.07(s, 1H), 7.93(s, 1H), 7.60 to 7.58(d, J ═ 8.8Hz, 2H), 7.37 to 7.35(d, J ═ 6.4Hz, 1H), 7.33 to 7.31(d, J ═ 8.6Hz, 2H), 4.25 to 4.21(m, 1H), 4.12 to 4.08(m, 1H), 4.07 to 4.02(q, J ═ 7.0Hz, 2H), 3.55 to 3.52(t, J ═ 4.9Hz, 1H), 1.15 to 1.11(t, J ═ 7.2, 3H); MS [ M + H ] ]⁺＝573.1；LCMS RT＝2.38min.

Example 232: preparation of ethyl 2- (4-amino-5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl) -1, 3-oxazole-4-carboxylate

To a solution of THF (16mL) was added N- [ (4-amino-5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl) cooled to-78 deg.C]Amino } carbonyl) amino]Phenyl } pyrrolo [2, 1-f][1，2，4]Triazin-6-yl) carbonyl]Serine Ethyl ester (example 221) (437mg, 0.76 mmol). In N₂DAST (0.14mL, 1.07mmol) was added while stirring under atmosphere and the reaction was allowed to proceed for 1 hour. DAST (0.14mL, 1.07mmol) was added and the solution was stirred for 30 minutes. The acetone/dry ice cooling bath was replaced with an ice/water bath and DBU (0.41mL, 2.75mmol) and BrCCl were added₃(0.27mL, 2.75mmol) and the solution was warmed to room temperature over 17 hours. DBU (0.41mL, 2.75mmol) and BrCCl were added₃(0.27mL, 2.75mmol) and the solution was stirred for 6 hours. The reaction mixture was transferred to a separatory funnel, diluted with EtOAc (50mL), and washed with NaHCO₃Saturated aqueous solution (50mL) and H₂O (50mL) wash. The aqueous fraction was back extracted with DCM (3X 30 mL). The combined organic layers were dried (MgSO)₄) Evaporation in vacuo and purification by flash chromatography (5: 4: 1v/v/v DCM/EtOAc/MeOH) afforded 33mg of the title compound isolated (0.060mmol, 8% yield).

¹H-NMR(DMSO-d₆) δ 9.93(s, 1H), 9.77(s, 1H), 8.70(s, 1H), 8.55 to 8.54(d, J ═ 5.0Hz, 1H), 8.30(s, 1H), 8.06(s, 1H), 7.95(s, 1H), 7.64 to 7.61(d, J ═ 8.8Hz, 2H), 7.42 to 7.40(d, J ═ 8.8Hz, 2H), 7.38 to 7.36(d, J ═ 6.2Hz, 1H), 4.28 to 4.23(q, J ═ 7.6Hz, 2H), 1.28 to 1.25(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝553.1；LCMS RT＝3.04min.

Example 233: preparation of N- [4- (6-acetyl-4-aminopyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of intermediate F, step 2, was used to prepare the title compound by substituting example 269 for N- {4- [ 4-amino-6- (hydroxymethyl) pyrrolo [2, 1-F ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea.

¹H-NMR(CD₃OD)δ8.51(d，J＝5Hz，1H)，8.15(s，1H)，7.97(s，1H)，7.89(s，1H)，7.77(d，J＝9Hz，2H)，7.38(d，J＝9Hz，2H)，7.26(d，J＝5Hz，1H)，2.29(s，3H)；MS[M+H]⁺＝456.0；LCMS RT＝2.71min.

Example 234: preparation of N- (4- { 4-amino-6- [4- (hydroxymethyl) -1, 3-oxazol-2-yl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 241 was used to prepare the title compound by substituting example 232 for example 237.

¹H-NMR(DMSO-d₆) δ 9.91(s, 1H), 9.76(s, 1H), 8.53(d, J ═ 5.4Hz, 1H), 8.17(s, 1H), 8.05(s, 1H), 7.92(s, 1H), 7.75(s, 1H), 7.62(s, 1H), 7.61(d, J ═ 8.6Hz, 2H), 7.40 to 7.36(m, 3H), 5.14 to 5.11(m, 1H), 4.31(d, J ═ 5.7Hz, 2H); MS [ M + H ] ]⁺＝511.0；LCMSRT＝2.33min.

Example 235: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-2-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

Step 1: preparation of 5- (4-Nitro-phenyl) -6-oxazol-2-yl-pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-ylamine

The first step of the process for the preparation of intermediate M was used to prepare 4-amino-5- (4-nitro-phenyl) -pyrrolo [2, 1-f ] using 2, 2-dimethoxy-ethylamine instead of 2, 2, 2-trifluoro-ethylamine hydrochloride][1，2，4]Triazine-6-carboxylic acid (2, 2-dimethoxy-ethyl) -amide. To a methanesulfonic acid solution (1.5ml) was added P₂O₅(225.0mg, 1.58mmol), followed by the addition of 4-amino-5- (4-nitro-phenyl) -pyrrolo [2, 1-f ]][1，2，4]Triazine-6-carboxylic acid (2, 2-dimethoxy-ethyl) -amide (150mg, 0.388 mmol). The dark brown mixture was heated to 100 ℃ and stirred for 18 hours. The mixture was then poured onto ice (15g), stirred for 15 minutes, and sufficient saturated sodium carbonate solution was added to neutralize the reaction. The white precipitate was filtered and collected (35mg, 27%).

¹H-NMR(DMSO-d₆)δ8.33(s，1H)，8.31(m，2H)，8.03(d，J＝10Hz，2H)，7.73(d，J＝10Hz，2H)，7.28(s，1H).MS[M+H]⁺＝323.2；LCMSRT＝2.51min.

Step 2: preparation of 5- (4-amino-phenyl) -6-oxazol-2-yl-pyrrolo [2, 1f ] [1, 2, 4] triazin-4-ylamine

The procedure used for the preparation of intermediate B was used to prepare the title compound by substituting 5- (4-nitro-phenyl) -6-oxazol-2-yl-pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-ylamine for 4-amino-5- (4-aminophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate.

MS[M+H]⁺＝293.3；LCMS RT＝0.38min.

And step 3: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-2-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting 5- (4-amino-phenyl) -6-oxazol-2-yl-pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-ylamine for intermediate X and phenyl [4- (trifluoromethyl) pyridin-2-yl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆)δ9.94(s，1H)，9.79(s，1H)，8.55(d，J＝6.2Hz，1H)，8.23(s，1H)，8.07(s，1H)，8.00(s，1H)，7.94(s，1H)，7.61(d，J＝7.9Hz，2H)，7.40(d，J＝7.9Hz，2H)，7.36(s，1H)，7.18(s，1H)；MS[M+H]⁺＝481.1；LCMS RT＝3.11min.

Example 236: preparation of ethyl 2- (4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl) -4, 5-dihydro-1, 3-oxazole-4-carboxylate

The procedure used for the preparation of example 230 was used to prepare the title compound by substituting ethyl N- [ (4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenylpyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl) carbonyl ] serine (example 220) for ethyl 2- (4-amino-5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl) -4, 5-dihydro-1, 3-oxazole-4-carboxylate (example 221).

¹H-NMR(DMSO-d₆) δ 9.31(s, 1H), 8.96 to 8.95(d, J ═ 2.9Hz, 1H), 8.63 to 8.61(d, J ═ 7.2Hz, 1H), 8.08(s, 1H), 7.91(s, 1H), 7.54 to 7.52(d, J ═ 8.6Hz, 2H), 7.50 to 7.48(d, J ═ 10.9Hz, 1H), 7.41 to 7.38(m, 1H), 7.33 to 7.31(d, J ═ 8.6Hz, 2H), 4.76 to 4.71(m, 1H), 4.38 to 4.29(m, 2H), 4.13 to 4.08(q, J ═ 6.5Hz, 2H), 1.21 to 1.18(t, J ═ 7.2, 3H); MS [ M + H ] ]⁺＝572.2；LCMS RT＝2.94min.

Example 237: preparation of ethyl 2- (4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl) -1, 3-oxazole-4-carboxylate

To a solution of THF (2mL) and DCM (2mL) cooled in an ice/water bath was added 2- (4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] phenyl]Amino } carbonyl) amino]Phenyl } pyrrolo [2, 1-f][1，2，4]Triazin-6-yl) -4, 5-dihydro-1, 3-oxazole-4-carboxylic acid ethyl ester (example 236) followed by addition of DBU (24. mu.L, 0.16mmol) and BrCCl₃(16. mu.L, 0.16 mmol). The solution is placed in N₂The mixture was stirred under an atmosphere for 1 hour, and then the solution was warmed to room temperature while stirring for 17 hours. The reaction mixture was evaporated in vacuo and purified by flash chromatography (50: 45: 5v/v/vDCM/EtOAc/MeOH) to afford isolated 16mg of the title compound as a white solid (0.028mmol, 65% yield).

¹H-NMR(DMSO-d₆) δ 9.35(s, 1H), 8.96(d, J ═ 2.8Hz, 1H), 8.69(s, 1H), 8.62 to 8.60(d, 1H)J ═ 9.3Hz, 1H), 8.29(s, 1H), 7.94(s, 1H), 7.58 to 7.56(d, J ═ 8.4Hz, 2H), 7.52 to 7.47(m, 1H), 7.40 to 7.37(m, 3H), 4.27 to 4.23(q, J ═ 6.3Hz, 2H), 1.28 to 1.24(t, J ═ 7.1Hz, 3H); MS [ M + H ] ]⁺＝570.1；LCMS RT＝3.16min.

Example 238: preparation of N- [4- (4-amino-6- { [ (1-methylpiperidin-4-yl) methoxy ] methyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 271 was used to prepare the title compound by substituting (1-methylpiperidin-4-yl) methanol for methanol and the product from intermediate F (step 1) for example 262.

¹H-NMR(DMSO-d₆) δ 8.58 to 8.57(m, 1H), 8.05 to 7.93(m, 2H), 1.68 to 7.64(m, 2H), 7.51 to 7.46(m, 1H), 7.38 to 7.36(m, 2H), 4.46(s, 2H), 4.02 to 4.00(m, 1H), 3.27 to 3.09(m, 4H), 2.66(s, 3H), 1.62 to 1.55(m, 2H), 1.25 to 1.15(m, 2H); MS [ M + H ]]⁺＝572.1；LCMS RT＝2.06min.

Example 239: preparation of N- {4- [ 4-amino-6- (hydroxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 3-tert-butyl-1- (4-fluorophenyl) -1H-pyrazol-5-yl ] urea

The procedure used for the preparation of intermediate F, step 1, was used to prepare the title compound by substituting example 25 for intermediate E.

¹H-NMR(DMSO-d₆)δ9.11(s，1H) 8.42(s, 1H), 7.81(s, 1H), 7.64(s, 1H), 7.48 to 7.58(m, 5H), 7.28 to 7.48(m, 5H), 6.36(s, 1H), 4.94(t, J ═ 5Hz, 1H), 4.34(d, J ═ 5Hz, 2H), 1.26(s, 9H); MS [ M + H ] ]⁺＝515.2；LCMS RT＝2.48min.

Example 240: preparation of N- {4- [ 4-amino-6- (cyanomethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 226 was used to prepare the title compound by substituting phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate.

¹H-NMR(DMSO-d₆) δ 9.41(s, 1H), 9.01(d, J ═ 3Hz, 1H), 8.62(d, J ═ 3,8Hz, 1H), 7.81(s, 1H), 7.77(s, 1H), 7.61(d, J ═ 9Hz, 2H), 7.47 to 7.54(m, 1H), 7.38 to 7.42(m, 1H), 7.35(d, J ═ 9Hz, 2H), 5.35(dd, J ═ 2,6Hz), 3.82(s, 2H); MS [ M + H ]]⁺＝470.1；LCMS RT＝2.80min.

Example 241: preparation of N- (4- { 4-amino-6- [4- (hydroxymethyl) -1, 3-oxazol-2-yl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of intermediate F, step 1, was used to prepare the title compound by substituting 2- (4-amino-5- {4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-F ] [1, 2, 4] triazin-6-yl) -1, 3-oxazole-4-carboxylic acid ethyl ester (example 232) for intermediate E.

¹H-NMR(DMSO-d₆) δ 9.35(s, 1H), 8.97 to 8.96(d, J ═ 3.4Hz, 1H), 8.63 to 8.61(d, J ═ 7.4Hz, 1H), 8.17(s, 1H), 7.93(s, 1H), 7.75(s, 1H), 7.58 to 7.56(d, J ═ 8.7Hz, 2H), 7.53 to 7.48(m, 1H), 7.41 to 7.36(m, 3H), 5.16 to 5.13(t, J ═ 5.6Hz, 1H), 4.32 to 4.31(d, J ═ 5.5Hz, 2H); MS [ M + H ] ]⁺＝528.1；LCMS RT＝2.68min.

Example 242: preparation of ethyl 4-amino-5- { 3-fluoro-4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AJ for intermediate X and phenyl [4- (trifluoromethyl) pyridin-2-yl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆) δ 10.14(s, 1H), 10.11 to 10.04(br s, 1H), 8.54 to 8.53(d, J ═ 5.3Hz, 1H), 8.28 to 8.23(t, J ═ 8.4Hz, 1H), 8.14(s, 1H), 8.01(s, 1H), 7.94(s, 1H), 7.39 to 7.33(m, 2H), 7.18 to 7.16(d, J ═ 10.0Hz, 1H), 4.12 to 4.06(q, J ═ 8.3Hz, 2H), 1.14 to 1.10(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝504.1；LCMS RT＝3.12min.

Example 243: preparation of N- {4- [ 4-amino-6- (hydroxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2-fluorophenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of intermediate F, step 1, was used to prepare the title compound by substituting 4-amino-5- { 3-fluoro-4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-F ] [1, 2, 4] triazine-6-carboxylic acid ethyl ester (example 242) for intermediate E.

¹H-NMR(DMSO-d₆) δ 10.13(s, 1H), 10.07 to 10.02(br s, 1H), 8.54 to 8.53(d, J ═ 5.3Hz, 1H), 8.29 to 8.24(t, J ═ 8.5Hz, 1H), 8.03(s, 1H), 7.84(s, 1H), 7.67(s, 1H), 7.39(s, 1H), 7.38 to 7.35(d, J ═ 8.7Hz, 1H), 7.21 to 7.19(d, J ═ 9.7Hz, 1H), 5.02 to 5.00(t, J ═ 5.1Hz, 1H), 4.39to 4.37(d, J ═ 5.2Hz, 2H); MS [ M + H ]]⁺＝462.0；LCMS RT＝2.44min.

Example 244: preparation of N- [4- (4-amino-6-cyanopyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

¹H-NMR(DMSO-d₆)δ9.96(s，1H)，9.78(s，1H)，8.55(d，J＝5Hz，1H)，8.52(s，1H)，8.07(s，1H)，7.99(s，1H)，7.69(d，J＝9Hz，2H)，7.45(d，J＝9Hz，2H)，7.36(d，J＝5Hz，1H)；MS[M+H]⁺＝439.1；LCMS RT＝3.01min.

Example 245: preparation of methyl 4-amino-5- {4- [ ({ [ 3-tert-butyl-1- (4-fluorophenyl) -1H-pyrazol-5-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 25 was used to prepare the title compound by substituting 4-amino-5- (4-aminophenyl) pyrrolo [2, 1f ] [1, 2, 4] triazine-6-carboxylic acid methyl ester for intermediate B.

¹H-NMR(DMSO-d₆) δ 9.14(s, 1H), 8.43(s, 1H), 8.13(s, 1H), 7.92(s, 1H), 7.25 to 7.60(m, 8H), 6.36(s, 1H), 7.32 to 7.40(m, 4H), 7.17 to 7.25(m, 1H), 7.14(bs, 1H), 6.34(s, 1H), 3.61(s, 1H); MS [ M + Na ] ]⁺＝565.2；LCMS RT＝3.13min.

Example 246: preparation of N- {4- [ 4-amino-6- (ethoxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Step 1: preparation of 6- (ethoxymethyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine

The procedure used for the preparation of intermediate U was used to prepare the title compound by substituting ethanol for methanol.

MS[M+H]⁺＝284.1；LCMS RT＝0.35min.

Step 2: preparation of N- {4- [ 4-amino-6- (ethoxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 1 was used to prepare the title compound by substituting 6- (ethoxymethyl) -5- (4-aminophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine for intermediate B.

¹H-NMR(DCM-d₆)δ12.19(s，1H)，8.51(d，J＝7.5Hz，1H)，8.01(s，1H)，7.74(s，1H)，7.4-7.3(bs，1H)，7.29-7.14(m，5H)，6.8(s，1H)，4.34(s，2H)，3.40(q，J＝7.0Hz，2H)，0.80(m，3H)；MS[M+H]⁺＝489.2；LCMS RT＝3.92min.

Example 247: preparation of N- {4- [ 4-amino-6- (methoxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2-fluorophenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 271 was used to prepare the title compound by substituting N- {4- [ 4-amino-6- (hydroxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2-fluorophenyl } -N '- [4- (trifluoromethyl) pyridin-2-yl ] urea (example 243) for N- {4- [ 4-amino-6- (hydroxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (4-methylpyridin-2-yl) urea (example 262).

¹H-NMR(DMSO-d₆) δ 10.14(s, 1H), 10.09 to 10.04(br s, 1H), 8.54 to 8.53(d, J ═ 5.5Hz, 1H), 8.30 to 8.26(t, J ═ 8.5Hz, 1H), 8.00(s, 1H), 7.86(s, 1H), 7.76(s, 1H), 7.39 to 7.38(d, J ═ 5.2Hz, 1H), 7.35 to 7.32(d, J ═ 12.0Hz, 1H), 7.21 to 7.18(d, J ═ 10.2Hz, 1H), 4.28(s, 2H), 3.22(s, 3H); MS [ M + H ]]⁺＝476.1；LCMS RT＝2.77min.

Example 248: preparation of N- (4- { 4-amino-6- [ (2-methoxyethoxy) methyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl) -N' - [ 3-tert-butyl-1- (4-fluorophenyl) -1H-pyrazol-5-yl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate Z for intermediate X and phenyl (3-tert-butyl-1- (4-fluorophenyl) -1H-pyrazol-5-yl) -carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆)δ9.13(s，1H)，8.43(s，1H)，7.83(s，1H)，7.73(s，1H)，7.58-7.49m，4H)，7.38(d，J＝9.4Hz 2H)，7.31(d，J＝9.4Hz，2H)，6.37(s，1H)，4.30(s，2H)，3.46-3.43(m，2H)，3.40-3.37(m，2H)，3.20(s，3H)，1.26(s，9H)；MS[M+H]⁺＝573.1；LCMS RT＝2.71min.

Example 249: preparation of ethyl 4-amino-5- { 3-fluoro-4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AJ for intermediate X and phenyl [ 2-fluoro-5- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆) δ 9.42(s, 1H), 9.28(s, 1H), 8.65 to 8.63(m, 1H), 8.27 to 8.22(m, 1H), 8.13(s, 1H), 7.93(s, 1H), 4.11 to 4.06(m, 2H), 114 to 1.10(m, 3H); MS [ M + H ]]⁺＝521.3；LCMS RT＝2.98min.

Example 250: preparation of 4-amino-5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid

The procedure used for the preparation of intermediate G was used to prepare the title compound by substituting example 51 for intermediate E.

¹H-NMR(DMSO-d₆) δ 12.3(s, 1H), 9.87(s, 1H), 9.75(s, 1H), 8.53(d, J ═ 5.3Hz, 2H), 8.07 to 8.06(m, 3H), 7.86(s, 1H), 7.58 to 7.56(m, 2H), 7.36 to 7.33(m, 3H); MS [ M + H ]]⁺＝458.0；LCMS RT＝2.28min.

Example 251: preparation of N- {4- [ 4-amino-6- (hydroxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2-fluorophenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of intermediate AF was used to prepare the title compound by substituting example 249 for example 51.

¹H-NMR(DMSO-d₆) δ 9.41(s, 1H), 9.40(s, 1H), 9.26 to 8.63(m, 1H), 8.28 to 8.24(m, 1H), 7.83(s, 1H), 7.66(s, 1H), 7.53 to 7.48(m, 1H), 7.41 to 7.33(m, 2H), 7.18(d, J ═ 8.2Hz, 1H), 5.01to 4.98(m, 1H), 4.37(d, J ═ 5.0Hz, 2H); MS [ M + H ] ]⁺＝479.1；LCMSRT＝2.49min.

Example 252: preparation of 4-amino-5- { 3-fluoro-4- [ ({ [ 2-fluoro-5- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid

The procedure used for the preparation of intermediate G was used to prepare the title compound by substituting example 249 for intermediate E.

¹H-NMR(DMSO-d₆) δ 12.3(s, 1H), 9.43(s, 1H), 9.27(s, 1H), 8.65 to 8.63(m, 1H), 8.25 to 8.20(m, 1H), 8.07(s, 1H), 8.02(s, 1H); MS [ M + H ]]⁺＝433.1；LCMS RT＝2.58min.

Example 253: preparation of 4-amino-5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 104 was used to prepare the title compound by substituting phenyl [4- (trifluoromethyl) pyridin-2-yl ] carbamate for phenyl [ 3-fluoro-5- (trifluoromethyl) phenyl ] carbamate.

¹H-NMR(CD₃OD)δ8.52(d，J＝5Hz，1H)，8.06(s，1H)，7.84(s，1H)，7.71(s，1H)，7.70(d，J＝9Hz，2H)，7.46(d，J＝9Hz，2H)，7.28(d，J＝5Hz，1H)；MS[M+H]⁺＝457.0；LCMS RT＝2.36min.

Example 254: preparation of N- {4- [ 4-amino-6- (methoxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2-fluorophenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 271 was used to prepare the title compound by substituting example 251 for example 262.

¹H-NMR(CD₃OD) δ 8.65(d, J ═ 8.0Hz, 1H), 8.31 to 8.27(m, 1H), 7.80(s, 1H), 7.70(s, 1H), 7.35 to 7.23(m, 4H), 4.37(s, 2H), 3.33(s, 3H); MS [ M + H ] ]⁺＝493.1；LCMS RT＝2.84min.

Example 255: preparation of N- {4- [ 4-amino-6- (cyanomethyl) pyrrolo [2, 1-f ] [ I, 2, 4] triazin-5-yl ] -2-fluorophenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 271 was used to prepare the title compound by substituting N- {4- [ 4-amino-6- (hydroxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2-fluorophenyl } -N '- [4- (trifluoromethyl) pyridin-2-yl ] urea (example 243) for N- {4- [ 4-amino-6- (hydroxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (4-methylpyridin-2-yl) urea (example 262) and sodium cyanide for MeOH.

¹H-NMR (acetone-d)₆) δ 10.99(s, 1H), 9.39(s, 1H), 8.59 to 8.58(d, J ═ 5.1Hz, 1H), 8.51 to 8.47(t, J ═ 8.5Hz, 1H), 7.84(s, 1H), 7.82 to 7.81(d, J ═ 6.4Hz, 1H), 7.75(s, 1H), 7.38 to 7.35(m, 2H), 7.30 to 7.28(d, J ═ 8.4Hz, 1H), 3.86(s, 2H); MS [ M + H ]]⁺＝471.0；LCMS RT＝2.75min.

Example 256: preparation of N- [4- (4-amino-6-cyanopyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) -2-fluorophenyl ] -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of intermediate O was used to prepare the title compound by substituting intermediate AN for intermediate H.

¹H-NMR(CD₃OD) δ 8.66 to 8.64(m, 1H), 8.41 to 8.37(m, 1H), 8.20(s, 1H), 7.92(s, 1H), 7.40 to 7.31(m, 4H); MS [ M + H ] ]⁺＝474.1；LCMS RT＝2.92min.

Example 257: preparation of N- (4- { 4-amino-6- [4- (morpholin-4-ylmethyl) -1, 3-oxazol-2-yl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 66 was used to prepare the title compound by substituting intermediate AM for intermediate I.

¹H-NMR(CD₃OD) δ 8.62 to 8.60(d, J ═ 7.6Hz, 1H), 8.15(s, 1H), 7.85(s, 1H), 7.65(s, 1H), 7.61 to 7.59(d, J ═ 8.7Hz, 2H), 7.42 to 7.40(d, J ═ 8.5Hz, 2H), 7.35 to 7.33(m, 2H), 3.69 to 3.66(t, J ═ 4.7Hz, 4H), 3.46(s, 2H), 2.53 to 2.50(t, J ═ 4.6Hz, 4H); MS [ M + H ]]⁺＝597.1；LCMS RT＝2.44min.

Example 258: preparation of ethyl 4-amino-5- [4- ({ [ (4-methylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylate

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate B for intermediate X and (4-methylpyridin-2-yl) iminodicarbonic acid diphenyl ester for (4-tert-butylpyridin-2-yl) carbamic acid phenyl ester.

¹H-NMR(DMSO-d₆) δ 10.83(s, 1H), 9.45(s, 1H), 8.15 to 8.13(d, J ═ 5.3Hz, 1H), 8.13(s, 1H), 7.93(s, 1H), 7.62 to 7.60(d, J ═ 8.3Hz, 2H), 7.34 to 7.32(d, J ═ 8.3Hz, 2H), 7.28(s, 1H), 6.87 to 6.86(d, J ═ 5.3Hz, 1H), 4.11 to 4.06(q, J ═ 7.1Hz, 2H), 2.30(s, 3H)1.13 to 1.10(t, J ═ 7.1Hz, 3H); MS [ M + H ] ]⁺＝432.1；LCMS RT＝2.30min.

Example 259: preparation of N- {4- [ 4-amino-6- (ethoxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-3- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 1 was used to prepare the title compound by substituting 6- (ethoxymethyl) -5- (4-nitrophenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine for intermediate B and 2-fluoro-1-isocyanato-3- (trifluoromethyl) benzene for 1-fluoro-2-isocyanato-4- (trifluoromethyl) benzene.

¹H-NMR(DMSOD6)δ9.28(s，1H)，8.89(s，1H)，8.48-8.42(m，1H)，7.83(s，1H)，7.73(s，1H)，7.59(s，1H)，7.56(s，1H)，7.36-7.32(m，4H)，4.28(s，2H)，3.37(q，J＝5.2Hz，2H)，1.06(t，J＝7Hz，3H)；MS[M+H]⁺＝489.1；LCMS RT＝2.87.

Example 260: preparation of 4-amino-5- [4- ({ [ (4-methylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid

The procedure used for the preparation of intermediate G was used to prepare the title compound by substituting 4-amino-5- [4- ({ [ (4-methylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid ethyl ester (example 258) for intermediate E.

¹H-NMR(DMSO-d₆) δ 12.28(s, 1H)10.82(s, 1H), 9.46(s, 1H), 8.14 to 8.13(d, J ═ 5.4Hz, 1H), 8.07(s, 1H), 7.91(s, 1H), 7.60 to 7.58(d, J ═ 8.6Hz, 2H), 7.34 to 7.31(d, J ═ 8.6Hz, 2H), 7.27(s, 1H), 6.86 to 6.85(d, J ═ 5.9, 1H), 2.30(s, 3H); MS [ M + H ]]⁺＝404.2；LCMS RT＝0.38min.

Example 261: preparation of 4-amino-N- (2-hydroxy-1-methylethyl) -5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 143 was used to prepare the title compound by substituting 1-aminopropan-2-ol for 2-amino-2-methylpropan-1-ol and example 250 for intermediate J.

¹H-NMR(DMSO-d₆) δ 9.87(s, 1H), 9.74(s, 1H), 8.54 to 8.53(d, J ═ 5.0Hz, 1H), 8.11(s, 1H), 8.06(s, 1H), 7.89(s, 1H), 7.59 to 7.57(d, J ═ 8.6Hz, 2H), 7.37 to 7.31(m, 4H), 4.65 to 4.62(t, J ═ 5.8Hz, 1H), 3.85 to 3.79(m, 1H), 3.23 to 3.16(m, 2H), 1.01to 1.00(d, J ═ 6.7Hz, 3H); MS [ M + H ]]⁺＝515.0；LCMS RT＝2.41min.

Example 262: preparation of N- {4- [ 4-amino-6- (hydroxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (4-methylpyridine 2-yl) urea

The procedure used for the preparation of intermediate F, step 1, was used to prepare the title compound by substituting 4-amino-5- [4- ({ [ (4-methylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-F ] [1, 2, 4] triazine-6-carboxylic acid ethyl ester (example 258) for intermediate E.

¹H-NMR(DMSO-d₆) δ 10.84(s, 1H), 9.45(s, 1H), 8.14 to 8.13(d, J ═ 5.6Hz, 1H), 7.82(s, 1H), 7.65(s, 1H), 7.64 to 7.62(d, J ═ 8.5Hz, 2H), 7.37 to 7.35(d, J ═ 8.5Hz, 2H), 7.27(s, 1H), 6.86 to 6.85(d, J ═ 5.1Hz, 1H), 4.97 to 4.95(t, J ═ 5.3Hz, 1H), 4.38 to 4.37(d, J ═ 5.4Hz, 2H), 2.30(s, 3H); MS [ M + H ] ]⁺＝390.0；LCMS RT＝1.51min.

Example 263: preparation of N- (4- { 4-amino-6- [ (2-methoxyethoxy) methyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } -2-fluorophenyl) -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 271 was used to prepare the title compound by substituting 3-methoxypropan-1-ol for methanol and the compound of example 251 for example 262.

¹H-NMR(CD₃OD) δ 8.64(d, J ═ 6.9Hz, 1H), 8.31 to 8.26(m, 1H), 7.79(s, 1H), 7.71(s, 1H), 7.37 to 7.33(m, 3H),7.25(d, J ═ 8.4Hz, 1H), 4.49(s, 2H), 3.54 to 3.52(m, 2H), 3.33(s, 3H); MS [ M + H ]]⁺＝537.1；LCMS RT＝2.82min.

Example 264: preparation of 4-amino-5- [4- ({ [ (4-methylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 143 was used to prepare the title compound by substituting 2, 2, 2-trifluoroethylamine for 2-amino-2-methylpropan-1-ol and 4-amino-5- [4- ({ [ (4-methylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid (example 260) for intermediate J.

¹H-NMR(DMSO-d₆) δ 10.80(s, 1H), 9.44(s, 1H), 8.52 to 8.49(t, J ═ 6.2Hz, 1H), 8.18(s, 1H), 8.14 to 8.13(d, J ═ 5.3Hz, 1H), 7.91(s, 1H), 7.59 to 7.57(d, J ═ 8.6Hz, 2H), 7.31 to 7.28(d, J ═ 8.6Hz, 2H), 7.28(s, 1H), 6.86 to 6.85(d, J ═ 5.2Hz, 1H), 3.97 to 3.93(m, 2H), 2.30(s, 3H); MS [ M + H ] ]⁺＝485.1；LCMS RT＝2.06min.

Example 265: preparation of 4-amino-N-methyl-5- [4- ({ [ (4-methylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 143 was used to prepare the title compound by substituting methylamine for 2-amino-2-methylpropan-1-ol and 4-amino-5- [4- ({ [ (4-methylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid (example 260) for intermediate J.

¹H-NMR(DMSO-d₆) δ 10.80(s, 1H), 9.45(s, 1H), 8.14 to 8.13(d, J ═ 5.4Hz, 1H), 8.05(s, 1H), 7.89(s, 1H), 7.82 to 7.80(m, 1H), 7.59 to 7.57(d, J ═ 8.6Hz, 2H), 7.31 to 7.29(d, J ═ 8.4Hz, 2H), 7.28(s, 1H), 6.86 to 6.85(d, J ═ 5.1Hz, 1H), 2.64 to 2.63(d, J ═ 4.7Hz, 3H), 2.30(s, 3H); MS [ M + H ]]⁺＝417.0；LCMS RT＝1.54min.

Example 266: preparation of 4-amino-N-ethyl-5- [4- ({ [ (4-methylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 143 was used to prepare the title compound by substituting ethylamine for 2-amino-2-methylpropan-1-ol and 4-amino-5- [4- ({ [ (4-methylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid (example 260) for intermediate J.

¹H-NMR(DMSO-d₆) δ 10.80(s, 1H), 9.45(s, 1H), 8.14 to 8.13(d, J ═ 5.1Hz, 1H), 8.06(s, 1H), 7.89(s, 1H), 7.76 to 7.73(t, J ═ 5.9Hz, 1H), 7.59 to 7.57(d, J ═ 8.6Hz, 2H), 7.32 to 7.30(d, J ═ 8.6Hz, 2H), 7.28(s, 1H), 6.86 to 6.85(d, J ═ 6.9Hz, 1H), 3.16 to 3.09(m, 2H), 2.30(s, 3H)1.03 to 1.00(t, J ═ 7.1Hz, 3H); MS [ M + H ]]⁺＝431.1；LCMS RT＝1.80min.

Example 267: preparation of 4-amino-N- (2-hydroxy-1-methylethyl) -5- [4- ({ [ (4-methylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 143 was used to prepare the title compound by substituting 2-aminopropan-1-ol for 2-amino-2-methylpropan-1-ol and 4-amino-5- [4- ({ [ (4-methylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid (example 260) for intermediate J.

¹H-NMR(DMSO-d₆) δ 10.82(s, 1H), 9.45(s, 1H), 8.14 to 8.13(d, J ═ 5.2Hz, 1H), 8.10(s, 1H), 7.89(s, 1H), 7.61 to 7.59(d, J ═ 8.8Hz, 2H), 7.33 to 7.31(d, J ═ 8.6Hz, 2H), 7.30 to 7.28(m, 2H), 6.87 to 6.85(d, J ═ 5.8Hz, 1H), 4.65 to 4.62(t, J ═ 5.7Hz, 1H), 3.84 to 3.78(m, 1H), 3.22 to 3.16(m, 2H), 2.30(s, 3H), 1.01 to 0.99(d, J ═ 6.7, 3H)); MS [ M + H ] ]⁺＝461.1；LCMS RT＝162min.

Example 268: preparation of N- {4- [ 4-amino-6- (1-hydroxy-1-methylethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

A solution of example 51(78mg, 0.155mmol) in 5mL THF was dissolved in methylmagnesium bromide (0.78mL, 2.3mmol, 3N in Et₂O) and heated at 60 ℃ for 4 hours. Quench the reaction with MeOH, dilute with EtOAc, and dilute with saturated NH₄And (5) washing with a Cl solution. The organic layer was dried over sodium sulfate and evaporated to dryness. The residue obtained is taken up in Et₂Trituration with O afforded 64mg of the title product (87% yield).

¹H-NMR(DMSO-d₆)δ9.98(s，1H)，9.79(s，1H)，8.52(d，J＝5Hz，1H)，8.70(s，1H)，7.77(s，1H)，7.58(d，J＝9Hz，2H) 7.56(s, 1H), 7.33(d, J ═ 9Hz, 2H), 7.30 to 7.35(m, 1H), 7.11(bs, 2H), 4.91(s, 1H), 1.24(s, 6H); MS [ M + H ]]⁺＝472.1；LCMS RT＝2.48min.

Example 269: preparation of N- {4- [ 4-amino-6- (1-hydroxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

Step 1: preparation of 4-amino-5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid

The procedure used for the preparation of intermediate F was used to prepare the title compound by substituting example 51 for intermediate E.

¹H-NMR(DMSO-d₆) δ 9.97(s, 1H), 9.78(s, 1H), 9.75(s, 1H), 8.54(d, J ═ 5Hz, 1H), 8.27(s, 1H), 8.07(s, 1H), 7.96(s, 1H), 7.67(d, J ═ 9Hz, 2H), 7.75(d, J ═ 9Hz, 2H), 7.36(d, J ═ 5Hz, 1H), 5.33 to 5.37(m, 1H); MS [ M + H ] ]⁺＝422.0；LCMS RT＝2.77min.

Step 2: preparation of N- {4- [ 4-amino-6- (1-hydroxyethyl) pyrrolo [2, 1f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

4-amino-5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl)]Amino } carbonyl) amino]Phenyl } pyrrolo [2, 1-f][1，2，4]A solution of triazine-6-carboxylic acid (60mg, 0.136mmol) in 5mL THF was prepared by dropwise addition of methylmagnesium bromide (0.68mL, 2.1mmol, 3M in Et over 2 min₂O) to be processed. The reaction was stirred for 15 min, then quenched with MeOH, diluted with EtOAc, and diluted with NH₄And (4) washing with an aqueous Cl solution. The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was taken up in Et₂Trituration with O afforded 50.1mg of the title compound (82% yield).

¹H-NMR(DMSO-d₆)δ10.05(s，1H)，9.82(s，1H)，8.52(d，J＝5Hz，1H)，8.09(s，1H)，7.81(s，1H)，7.64(s，1H)，7.61(d，J＝9Hz，2H)，7.34(d，J＝9Hz，2H)，4.96(d，J＝5Hz，1H)，4.63(dq，J＝5,6Hz，1H)，1.24(d，J＝6Hz，3H)；MS[M+H]⁺＝458.0；LCMSRT＝2.41min.

Example 270: n- [4- (4-amino-6-propionylpyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 233 was used to prepare the title compound by substituting example 274 for example 269.

¹H-NMR(DMSO-d₆) δ 9.98(s, 1H), 9.85(s, 1H), 8.53(d, J ═ 5Hz, 1H), 8.37(s, 1H), 8.07(s, 1H), 8.00 to 8.10(bs, 1H), 7.59(d, J ═ 9Hz, 2H), 7.30 to 7.39(m, 3H), 2.71(d, J ═ 7Hz, 2H), 0.92(t, J ═ 7Hz, 3H); MS [ M + Na ] ]⁺＝492.0；LCMS RT＝2.87min.

Example 271: preparation of N- {4- [ 4-amino-6- (methoxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (4-methylpyridin-2-yl) urea

To a solution of DCM (5mL) was added N- {4- [ 4-amino-6- (hydroxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (4-methylpyridin-2-yl) urea (example 262) (40mg, 0.10mmol), followed by 2M thionyl chloride in DCM (0.51mL, 1.03 mmol). The solution was stirred at room temperature for 1 hour and then evaporated in vacuo. THF (5mL) and MeOH (5mL) were added to the crude reaction, followed by triethylamine (43. mu.L, 0.31 mmol). The solution was heated to 50 ℃ for 3 days then evaporated in vacuo and purified with MPLC (Isco) 0-5% MeOH/DCM. The resulting purified fractions were combined and evaporated to yield 25mg of the title compound (0.061mmol, 60% yield).

¹H-NMR(DMSO-d₆) δ 10.86(s, 1H), 9.46(s, 1H), 8.14 to 8.13(d, J ═ 6.3Hz, 1H), 7.84(s, 1H), 7.75(s, 1H), 7.65 to 7.63(d, J ═ 8.7Hz, 2H), 7.36 to 7.34(d, J ═ 8.6Hz, 2H), 7.27(s, 1H), 6.87 to 6.86(d, J ═ 5.0Hz, 1H), 4.27(s, 2H), 3.20(s, 3H), 2.30(s, 3H); MS [ M + H ]]⁺＝404.0；LCMSRT＝1.99min.

Example 272: preparation of N- (4- { 4-amino-6- [ (2-methoxyethoxy) methyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - (4-methylpyridin-2-yl) urea

The procedure used for the preparation of example 271 was used to prepare the title compound by substituting 2-methoxyethanol for MeOH.

¹H-NMR(DMSO-d₆) δ 10.85(s, 1H), 9.46(s, 1H), 8.14 to 8.13(d, J ═ 5.4Hz, 1H), 7.84(s, 1H)7.75(s, 1H), 7.65 to 7.62(d, J ═ 8.6Hz, 2H), 7.38 to 7.36(d, J ═ 8.1Hz, 2H), 7.26(s, 1H), 6.87 to 6.85(d, J ═ 5.9Hz, 1H), 4.33(s, 2H), 3.49 to 3.46(m, 2H), 3.43 to 3.40(m, 2H), 3.22(s, 2H), 2.30(s, 3H); MS [ M + H ]]⁺＝448.0；LCMS RT＝2.00min.

Example 273: preparation of 4-amino-N-cyclopropyl-5- [4- ({ [ (4-methylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 143 was used to prepare the title compound by substituting cyclopropylamine for 2-amino-2-methylpropan-1-ol and 4-amino-5- [4- ({ [ (4-methylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid (example 260) for intermediate J.

¹H-NMR(DMSO-d₆) δ 10.79(s, 1H), 9.45(s, 1H), 8.15 to 8.13(d, J ═ 5.6Hz, 1H), 8.05(s, 1H), 7.89(s, 1H), 7.83 to 7.82(d, J ═ 3.6Hz, 1H), 7.59 to 7.57(d, J ═ 8.7Hz, 2H), 7.31 to 7.29(m, 3H), 6.86 to 6.85(d, J ═ 5.1Hz, 1H), 2.68 to 2.63(m, 1H), 2.30(s, 3H), 0.63 to 0.58(m, 2H), 0.44 to 0.40(m, 2H); MS [ M + H ] ]⁺＝465.1；LCMS RT＝1.86min.

Example 274: preparation of N- {4- [ 4-amino-6- (1-hydroxypropyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 269 was used to prepare the title compound by substituting ethylmagnesium bromide for methylmagnesium bromide.

¹H-NMR(DMSO-d₆) δ 9.95(s, 1H), 9.77(s, 1H), 8.53(d, J ═ 5Hz, 1H), 8.04(s, 1H),. 1 to 8.2(bs, 1H), 8.05 to 8.10(m, 1H), 7.65(d, J ═ 9Hz, 2H), 7.39(d, J ═ 9Hz, 2H), 7.32to 7.40(m, 1H); MS [ M + H ]]⁺＝472.0；LCMS RT＝2.59min.

Example 275: preparation of N- (4- { 4-amino-6- [ cyclopropyl (hydroxy) methyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 269 was used to prepare the title compound by substituting cyclopropylmagnesium bromide for methylmagnesium bromide.

¹H-NMR(DMSO-d₆) δ 9.95(s, 1H), 9.83(s, 1H), 8.61(d, J ═ 5Hz, 1H), 8.14(s, 1H), 7.91(s, 1H), 7.78(s, 1H), 7.69(d, J ═ 9Hz, 2H), 7.40 to 46(m, 3H), 5.00(d, J ═ 5Hz, 1H), 4.00-4.02(m, 1H), 0.25 to 0.48(m, 3H), 0.00 to 0.08(m, 2H); MS [ M + H ]]⁺＝484.0；LCMS RT＝2.60min.

Example 276: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2-fluorophenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

To a solution of THF (10mL) and MeOH (10mL) cooled in an ice/water bath was added 0.5M sodium methoxide in MeOH (0.96mL, 0.48mmol), followed by TosMIC (93mg, 0.48 mmol). Mixing the solutionStir for 5 min, then add intermediate AL (73mg, 0.16 mmol). The solution was heated to 60 ℃ for 17 hours. The reaction mixture was cooled and transferred to a separatory funnel, diluted with EtOAc (20mL) and NaHCO₃Saturated aqueous solution (20mL) and H₂O (20mL) wash. The aqueous layer was back-extracted with EtOAc (2X 20 mL). The combined organic layers were dried (MgSO)₄) Filtered, evaporated in vacuo and purified by flash chromatography 5: 4: 1v/v/vDCM/EtOAc/MeOH and the resulting purified fractions combined and evaporated to yield 26mg of the title compound as a white solid (0.052mmol, 33% yield).

¹H-NMR(DMSO-d₆) δ 10.18(s, 1H), 10.16 to 10.12(br s, 1H), 8.55 to 8.54(d, J ═ 5.4Hz, 1H), 8.35 to 8.31(t, J ═ 8.3Hz, 1H), 8.30(s, 1H), 8.10(s, 1H), 8.01(s, 1H), 7.91(s, 1H), 7.39 to 7.36(m, 2H), 7.23 to 7.21(d, J ═ 10.4Hz, 1H), 6.63(s, 1H); MS [ M + H ]]⁺＝499.0；LCMS RT＝2.85min.

Example 277: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (4-methylpyridin-2-yl) urea

The procedure used for the preparation of example 276 was used to prepare the title compound by substituting intermediate AK for intermediate 5.

¹H-NMR(DMSO-d₆) δ 10.92(s, 1H), 9.50(s, 1H), 8.29(s, 1H), 8.15 to 8.14(d, J ═ 4.9Hz, 1H), 8.09(s, 1H), 7.90(s, 1H), 7.69 to 7.67(d, J ═ 8.4Hz, 2H), 7.38 to 7.36(d, J ═ 8.5Hz, 2H), 7.27(s, 1H), 6.87 to 6.86(d, J ═ 5.8Hz, 1H), 6.57(s, 1H), 2.30(s, 3H); MS [ M + H ]]⁺＝427.1；LCMS RT＝2.09min.

Example 278: preparation of N- {4- [ 4-amino-6- (cyclopropylcarbonyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 233 was used to prepare the title compound by substituting example 275 for example 269.

¹H-NMR(DMSO-d₆) δ 9.87(s, 1H), 9.74(s, 1H), 8.53(d, J ═ 5Hz, 1H), 8.51(s, 1H), 8.05(s, 1H), 8.00 to 8.05(bs, 1H), 7.57(d, J ═ 9Hx, 2H), 7.30 to 7.40(m, 3H), 2.40(m, 1H), 0.76 to 0.9(m, 4H); MS [ M + H ]]⁺＝482.0；LCMS RT＝2.96min.

Example 279: preparation of 4-amino-N- (2-hydroxy-1, 1-dimethylethyl) -5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

¹H-NMR(DMSO-d₆)δ12.28(bs，1H)，9.87(s，1H)9.75(s1H), 8.53(d, J ═ 5Hz, 1H), 8.07(s, 1H), 8.06(s, 1H), 7.91(s, 1H), 7.57(d, J ═ 9Hz, 2H), 7.34 to 7.37(m, 1H), 7.34(d, J ═ 9Hz, 2H); MS [ M + H ]]⁺＝458.1；LCMS RT＝2.53min.

Step 2: preparation of 4-amino-N- (2-hydroxy-1, 1-dimethylethyl) -5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 143 was used to prepare the title compound by substituting 4-amino-5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid for intermediate J.

¹H-NMR(DMSO-d₆)δ9.92(s，1H)，9.77(s，1H)，8.54(d，J＝5.0Hz，1H)，8.06(s，1H)，8.03(s，1H)，7.89(s，1H)，7.62(d，J＝8.8Hz，2H)，7.36(d，J＝8.8Hz，4H)，6.53(s，1H)，4.75(t，J＝6.2Hz，2H)，3.27(d，J＝5.9Hz，2H)，1.09(s，6H)；MS[M+H]⁺＝529.0；LCMS RT＝2.59min.

Example 280: preparation of N- {4- [ 4-amino-6- (4, 4-dimethyl-4, 5-dihydro-1, 3-oxazol-2-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

Example 279(25mg, 0.047mmol) in 2mL CH₂Cl₂The solution in (1) was treated with thionyl chloride (0.95mmol, 11.2mg) and stirred for 15 minutes. The reaction was diluted with ethyl acetate and washed with sodium bicarbonateAnd (6) washing. The organic layer was dried (Na) ₂SO₄) Filtered and concentrated to dryness. The residue was taken up in Et₂Trituration in O/hexane afforded 19.4mg of the above compound as a yellow solid (81% yield).

¹H-NMR(DMSO-d₆)δ10.40(s，1H)，9.96(s，1H)，8.91(s，1H)，8.54(d，J＝6.2Hz，1H)，8.13(s，1H)，8.07(s，1H)，7.64(d，J＝8.8Hz，2H)，7.44(d，J＝8.8Hz，4H)，7.35(d，J＝5.3Hz，1H)，5.67(bs，1H)，4.54(s，2H)，1.47(s，6H)；MS[M+H]⁺＝511.0；LCMS RT＝2.44min.

Example 281: preparation of N- {4- [ 4-amino-6- (4-methyl-4, 5-dihydro-1, 3-oxazol-2-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 230 was used to prepare the title compound by substituting 4-amino-N- (2-hydroxy-1-methylethyl) -5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide (example 261) for ethyl 2- (4-amino-5- {4- [ ({ [4- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-6-yl) -4, 5-dihydro-1, 3-oxazole-4-carboxylate (example 221).

¹H-NMR(DMSO-d₆) δ 9.89(s, 1H), 9.77(s, 1H), 8.54 to 8.53(d, J ═ 5.3Hz, 1H), 8.05(s, 1H), 8.01(s, 1H), 7.90(s, 1H), 7.58 to 7.56(d, J ═ 8.7Hz, 2H), 7.37 to 7.36(m, 1H), 7.35 to 7.33(d, J ═ 8.6Hz, 2H), 4.28 to 4.24(t, J ═ 8.6Hz, 2H), 4.15 to 4.06(m, 1H), 3.71 to 3.67(t, J ═ 7.9Hz, 2H, 1.13 to 1.11(d, J ═ 6.6Hz, 3H); MS [ M + H ] ]⁺＝497.0；LCMS RT＝2.43min.

Example 282: preparation of N- [4- (4-amino-6- { [ (2-methoxyethyl) amino ] methyl } pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - (4-methylpyridin-2-yl) urea

The procedure used for the preparation of example 66 was used to prepare the title compound by substituting intermediate AK for intermediate I and 2-methoxyethylamine for morpholine.

¹H-NMR(CD₃OD) δ 8.15 to 8.14(d, J ═ 5.3Hz, 1H), 7.81(s, 1H), 7.80(s, 1H), 7.74 to 7.72(d, J ═ 8.7Hz, 2H), 7.42 to 7.40(d, J ═ 8.6Hz, 2H), 7.00(s, 1H), 6.90 to 6.89(d, J ═ 5.3Hz, 1H), 4.04(s, 2H), 3.49 to 3.46(t, J ═ 5.1Hz, 2H), 2.95 to 2.92(t, J ═ 5.1Hz, 2H), 2.37(s, 3H), 1.93(s, 3H); MS [ M + H ]]⁺＝446.9；LCMS RT＝1.25min.

Example 283: preparation of N- {4- [ 4-amino-6- (morpholin-4-ylmethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (4-methylpyridin-2-yl) urea

The procedure used for the preparation of example 66 was used to prepare the title compound by substituting intermediate AK for intermediate I.

¹H-NMR(DMSO-d₆) δ 10.90 to 10.87(br s, 1H), 9.48(s, 1H), 8.14 to 8.13(d, J ═ 5.1Hz, 1H), 7.82(s, 1H), 7.64 to 7.62(d, J ═ 8.5Hz, 2H), 7.40 to 7.38(d, J ═ 8.5Hz, 2H), 7.26(s, 1H), 6.87 to 6.85(d, J ═ 5.6Hz, 1H), 3.55 to 3.50(m, 4H), 3.34 to 3.33(br s, 2H), 2.32 to 2.28(m, 4H), 2.30(s, 3H); MS [ M + H ] ]⁺＝459.0；LCMS RT＝1.16min.

Example 284: preparation of N- {4- [ 4-amino-6- (hydroxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (3-tert-butylisoxazol-5-yl) urea

The procedure used for the preparation of intermediate F was used to prepare the title compound by substituting example 52 for intermediate E.

¹H-NMR(DMSO-d₆)δ10.13(s，1H)，8.96(s，1H)，7.82(s，1H)，7.65(s，1H)，7.56(d，J＝9Hz，2H)，7.35(d，J＝9Hz，2H)，6.05(s，1H)，4.94(t，J＝5Hz，1H)，4.35(d，J＝5Hz，2H)，1.24(s，9H)；MS[M+H]⁺＝422.1；LCMS RT＝2.26min.

Example 285: preparation of N- {4- [ 4-amino-6- (1-hydroxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (3-tert-butylisoxazol-5-yl) urea

The procedure used for the preparation of example 269 was used to prepare the title compound by substituting example 52 for example 51.

¹H-NMR(DMSO-d₆) δ 10.19(s, 1H), 9.07(s, 1H), 8.81(s, 1H), 7.64(s, 1H), 7.56(d, J ═ 8Hz, 2H), 7.30 to 7.40(m, 2H), 6.05(s, 1H), 4.95(m, 1), 4.60 to 4.64(m, 1H), 1.36(m, 2H), 1.23(s, 9H); MS [ M + H ]]⁺＝436.1；LCMS RT＝2.41min.

Example 286: preparation of N- (4- { 4-amino-6- [ cyclopropyl (hydroxy) methyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - (3-tert-butylisoxazol-5-yl) urea

The procedure used for the preparation of example 269 was used to prepare the title compound by substituting example 52 for example 51 and cyclopropylmagnesium bromide for methylmagnesium bromide.

¹H-NMR(DMSO-d₆) δ 10.24(s, 1H), 9.07(s, 1H), 8.81(s, 1H), 7.64(s, 1H), 7.56(d, J ═ 8Hz, 2H), 7.30 to 7.40(m, 2H), 6.05(s, 1H)4.98(d, J ═ 5Hz, 1H), 3.97 to 4.01(m, 1H), 1.28(s, 9H), 0.25 to 0.48(m, 3H), 0.00to 0.08(m, 2H); MS [ M + H ]]⁺＝434.1；LCMSRT＝2.63min.

Example 287: preparation of N- [4- (6-acetyl-4-aminopyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) phenyl ] -N' - (3-tert-butylisoxazol-5-yl) urea

The procedure used for the preparation of example 233 was used to prepare the title compound by substituting example 285 for example 269.

¹H-NMR(DMSO-d₆)δ10.15(s，1H)，8.98(s，1H)，8.37(s，1H)，(8.01(bs，1H)，7.92(s，1H)，7.53(d，J＝9Hz，2H)，7.30(d，J＝9Hz，2H)，6.05(s，1H)，2.27(s，3H)；MS[M+H]⁺＝434.1；LCMS RT＝2.63min.

Example 288: preparation of N- {4- [ 4-amino-6- (cyclopropylcarbonyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (3-tert-butylisoxazol-5-yl) urea

The procedure used for the preparation of example 233 was used to prepare the title compound by substituting example 286 for example 269.

¹H-NMR(DMSO-d₆)δδ10.15(s，1H)，8.98(s，1H)，8.37(s，1H)，(8.01(bs，1H)，7.92(s，1H)，7.53(d，J＝9Hz，2H)，7.30(d，J＝9Hz，2H)，6.05(s，1H)；MS[M+H]⁺＝460.1；LCMS RT＝2.81min.

Example 289: preparation of 4-amino-5- [4- ({ [ (3-tert-butylisoxazol-5-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxylic acid

The procedure used for the preparation of intermediate G was used to prepare the title compound by substituting example 52 for intermediate E.

¹H-NMR(DMSO-d₆)δ10.18(s，1H)，9.04(s，1H)，8.07(s，1H)，7.19(s，1H)，7.52(d，J＝8.2Hz，1H)，7.31(d，J＝8.2Hz，2H)，6.05(s，1H)，5.73(s，1H)，1.24(s，9H)；MS[M+H]⁺＝436.1；LCMS RT＝2.43min.

Example 290: preparation of N- {4- [ 4-amino-6- (isopropoxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 246 was used to prepare the title compound by substituting isopropanol for ethanol.

¹H-NMR(DMSO-d₆)δ12.25(s，1H)，8.48(d，J＝6.8Hz，1H)，8.27(s，1H)，8.04(s，1H)，7.61-7.51(m，3H)，7.18(d，J＝8.2Hz，2H)，6.70(d，J＝8.2Hz，2H)，4.33(s，2H)，3.55(m，1H)，1.04(d，J＝6.2Hz，6H)；MS[M+H]⁺＝503.1；LCMS RT＝3.70min.

Example 291: preparation of 4-amino-5- [4- ({ [ (3-tert-butylisoxazol-5-yl) amino ] carbonyl } amino) phenyl ] -N- (2-hydroxy-1, 1-dimethylethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 143 was used to prepare the title compound by substituting example 289 for intermediate J.

¹H-NMR(DMSO-d₆)δ10.14(s，1H)，9.00(s，1H)，8.03(s，1H)，7.89(s，1H)，7.56(d，J＝8.8Hz，2H)，7.34(d，J＝8.8Hz，4H)，6.51(s，1H)，6.06(s，1H)，5.74(s，1H)，4.75(t，J＝3.8Hz，1H)，3.27(bs，2)1.24(s，9H)，1.09(s，6H)；MS[M+H]⁺＝507.1；LCMSRT＝2.46min.

Example 292: preparation of N- {4- [ 4-amino-6- (4, 4-dimethyl-4, 5-dihydro-1, 3-oxazol-2-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (3-tert-butylisoxazol-5-yl) urea

The procedure used for the preparation of example 280 was used to prepare the title compound by substituting example 291 for example 279.

¹H-NMR(DMSO-d₆)δ10.19(s，1H)，9.43(s，1H)，8.61(s，1H)，8.41(bs，1H)，8.01(s，1H)，7.56(d，J＝8.8Hz，2H)，7.40(d，J＝8.8Hz，2H)，6.12(s，1H)，5.41(bs，1H)，4.45(s，2H)，1.41(s，6H)，1.24(s，9H)；MS[M+H]⁺＝489.1；LCMS RT＝2.36min.

Example 293: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (4-tert-butylpyridin-2-yl) urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AB for intermediate X.

¹H-NMR(DMSO-d₆) δ 10.96 to 10.93(br s, 1H), 9.48(s, 1H), 8.30(s, 1H), 8.20 to 8.18(d, J ═ 6.1Hz, 1H), 8.09(s, 1H), 7.90(s, 1H), 7.70 to 7.68(d, J ═ 8.6Hz, 2H), 7.50(s, 1H), 7.38 to 7.36(d, J ═ 8.5Hz, 2H), 7.08 to 7.06(d, J ═ 5.4Hz, 1H), 6.57(s, 1H), 1.28(s, 9H); MS [ M + H ]]⁺＝469.1；LCMS RT＝2.44min.

Example 294: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 3-tert-butyl-1- (4-fluorophenyl) -1H-pyrazol-5-yl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AB for intermediate X and phenyl [ 3-tert-butyl-1- (4-fluorophenyl) -1H-pyrazol-5-yl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆) δ 9.19(s, 1H), 8.45(s, 1H), 8.28(s, 1H), 8.07(s, 1H), 7.89(s, 1H), 7.58 to 7.54(m, 4H), 7.39 to 7.31(m, 4H), 6.53(s, 1H), 6.36(s, 1H), 1.28(s, 9H); MS [ M + H ]]⁺＝552.1；LCMSRT＝2.88min.

Example 295: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AB for intermediate X and phenyl (3-tert-butyl-1-methyl-1H-pyrazol-5-yl) carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆) δ 9.10(s, 1H), 8.54(s, 1H), 8.29(s, 1H), 8.08(s, 1H), 7.90(s, 1H), 7.62 to 7.59(d, J ═ 8.6Hz, 2H), 7.35 to 7.33(d, J ═ 8.6Hz, 2H), 6.54(s, 1H), 6.05(s, 1H), 3.61(s, 3H), 1.22(s, 9H); MS [ M + H ]]⁺＝472.2；LCMS RT＝2.43min.

Example 296: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (3-tert-butylisoxazol-5-yl) urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AB for intermediate X and phenyl (3-tert-butylisoxazol-5-yl) carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆) δ 10.21(s, 1H), 9.07(s, 1H), 8.29(s, 1H), 8.09(s, 1H), 7.90(s, 1H), 7.62 to 7.60(d, J ═ 8.6Hz, 2H), 7.38 to 7.35(d, J ═ 8.5Hz, 2H), 6.55(s, 1H), 6.07(s, 1H), 1.26(s, 9H); MS [ M + H ]]⁺＝459.1；LCMS RT＝2.65min.

Example 297: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [3- (trifluoromethoxy) phenyl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AB for intermediate X and phenyl [3- (trifluoromethoxy) carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆) δ 9.11(s, 1H), 9.02(s, 1H), 8.30(s, 1H), 8.08(s, 1H), 7.90(s, 1H), 7.71(s, 1H), 7.62 to 7.60(d, J ═ 8.4Hz, 2H), 7.42 to 7.38(t, J ═ 8.1Hz, 1H), 7.36 to 7.34(d, J ═ 8.7Hz, 2H), 7.32 to 7.29(d, J ═ 9.1Hz, 1H), 6.96 to 6.93(d, J ═ 10.6, 1H), 6.55(s, 1H); MS [ M + H ]]⁺＝496.1；LCMSRT＝2.89min.

Example 298: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 4-chloro-3- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate AB for intermediate X and phenyl [ 4-chloro-3- (trifluoromethyl) phenyl ] carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H-NMR(DMSO-d₆) δ 9.26(s, 1H), 9.08(s, 1H), 8.30(s, 1H), 8.12(s, 1H), 8.09(s, 1H), 7.90(s, 1H), 7.64 to 7.61(m, 4H), 7.37 to 7.35(d, J ═ 8.5Hz, 2H), 6.55(s, 1H); MS [ M + H ]]⁺＝514.1；LCMS RT＝3.02min.

Example 299: preparation of N- {4- [ 4-amino-6- (2-thienylcarbonyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (3-tert-butylisoxazol-5-yl) urea

The procedure used for the preparation of example 287 was used to prepare the title compound by substituting 2-thienylmagnesium bromide for methylmagnesium bromide.

¹H-NMR(DMSO-d₆)8.26(s，1H)，7.98(dd，J＝1,4Hz，1H)，7.96(s，1H)，7.75(dd，J＝1,3Hz)，7.53(d，J＝6Hz，2H)，7.30(d，J＝6Hz，2H)，7.19(dd，J＝3,4Hz，1H)，6.05(s，1H)1.25(s，9H)；MS[M+H]⁺＝502.1；LCMS RT＝2.98min.

Example 300: preparation of N- {4- [ 4-amino-6- (1-hydroxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 269 was used to prepare the title compound by substituting example 1 for example 51.

¹H-NMR(DMSO-d₆) δ 9.41(s, 1H), 9.01(d, J ═ 3Hz, 1H), 8.62(d, J ═ 3,8Hz, 1H), 7.81(s, 1H), 7.77(s, 1H), 7.61(d, J ═ 9Hz, 2H), 7.47 to 7.54(m, 1H), 7.38to 7.42(m, 1H), 7.35(d, J ═ 9Hz, 2H); MS [ M + H ]]⁺＝475.1；LCMS RT＝2.59min.

Example 301: preparation of N- {4- [ 4-amino-6- (1, 2-dihydroxyethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

Methanesulfonamide (65mg, 0.683mmol) was dissolved in a 1: 1 solution of tert-butanol: water (5mL) and treated with AD-mix β (1.0 g). The mixture was then treated with example 222(0.3g, 0.683mmol) and the reaction was stirred at room temperature overnight. After completion, the solution was treated with solid sodium sulfite (1.5g) and stirred for 1 hour. The reaction was then transferred to a separatory funnel and the crude product was extracted with EtOAc. The organic layer was washed with water and saturated NaCl solution. The solution was then MgSO ₄Dried, filtered, and concentrated under reduced pressure. The isolated title compound was, without purification, 0.3g tan solid (0.634mmol, 93% yield).

¹H-NMR(DMSO-d₆)δ9.88(bs，1H)，9.76(bs，1H)，8.53(d，J＝5.7Hz，1H)，8.06(s，1H)，7.82(s，1H)，7.63(s，1H)，7.61(d，J＝8.8Hz，2H)，7.37-7.35(m，3H)，5.03(d，J＝4.6Hz，2H)，4.65(t，J＝5.8Hz，1H)，4.47-4.43(m，1H)，3.45-3.38(m，2H)；MS[M+H]⁺＝474.0；LCMS RT＝2.13min.

Example 302: preparation of 4-amino-N, N-dimethyl-5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 69 was used to prepare the title compound by substituting intermediate AH for intermediate G and dimethylamine for cyclopropylamine. The reaction was stirred for 16 hours and purified by HPLC (20-85% acetonitrile in water).

¹H NMR(DMSO-d₆)δ9.87(s，1H)，9.68(s，1H)，8.05to 7.96(m，2H)，7.89(s，1H)，7.85(s，1H)，7.57to7.52(m，2H)，7.49(dd，J＝6.6，1.6Hz，1H)，7.32to 7.27(m，2H)，2.81(s，3H)，2.64(s，3H)；MS[M+H]⁺＝485.0；LCMS RT＝2.43min.

Example 303: preparation of 4-amino-N-ethyl-N-methyl-5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 69 was used to prepare the title compound by substituting intermediate AH for intermediate G and N-ethyl-N-methylamine for cyclopropylamine. The reaction was stirred for 16 hours and purified by HPLC (20-85% acetonitrile in water).

¹H NMR(DMSO-d₆) δ 9.86(s, 1H), 9.68(s, 1H), 8.05 to 7.96(m, 2H), 7.89(s, 1H), 7.85(s, 1H), 7.56 to 7.46(m, 3H), 7.30(d, J ═ 8.1Hz, 2H), 3.31 and 3.06 (diastereomeric quartet, 2H), 2.79 and 2.58 (diastereomeric quartet, 2H), respectively Singlet, 3H), 0.93 and 0.81 (diastereomeric triplet, 3H); MS [ M + H ]]⁺＝499.1；LCMS RT＝2.55min.

Example 304: preparation of 4-amino-N, N-diethyl-5- {4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 69 was used to prepare the title compound by substituting intermediate AH for intermediate G and diethylamine for cyclopropylamine. The reaction was stirred for 16 hours and purified by HPLC (20-85% acetonitrile in water).

¹H NMR(DMSO-d₆) δ 9.85(s, 1H), 9.67(s, 1H), 8.05 to 7.96(m, 2H), 7.89(s, 1H), 7.85(s, 1H), 7.55 to 7.46(m, 3H), 7.33 to 7.28(m, 2H), 3.32 and 3.02 (diastereomeric quartet, 2H), 0.94 and 0.82 (diastereomeric triplet, 3H); MS [ M + H ]]⁺＝513.1；LCMS RT＝2.64min.

Example 305: preparation of N- {4- [ 4-amino-6- (pyrrolidin-1-ylcarbonyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [6- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 69 was used to prepare the title compound by substituting intermediate AH for intermediate G and pyrrolidine for cyclopropylamine. The reaction was stirred for 16 hours and purified by HPLC (20-85% acetonitrile in water).

¹H NMR(DMSO-d₆) Δ 9.86(s, 1H), 9.67(s, 1H), 8.04 to 7.98(m, 2H), 7.91(s, 1H), 7.89(s, 1H), 7.56 to 7.46(m, 3H), 7.34 to 7.29(m, 2H), 3.32(t, J ═ 6.4Hz, 2H), 3.11(t, J ═ 6.4Hz, 2H), 1.77to 1.60(m, 4H); MS [ M + H ]]⁺＝511.1；LCMS RT＝2.53min.

Example 306: preparation of N- {4- [ 4-amino-6- (piperidin-1-ylcarbonyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [6- (trifluoromethyl) pyridin-2-yl ] urea

Intermediate AH instead of intermediate G and piperidine instead of cyclopropylamine will be used in the preparation

The procedure of example 69 was used to prepare the title compound. The reaction was stirred for 16 hours and purified by HPLC (20-85% acetonitrile in water).

¹H NMR(DMSO-d₆) δ 9.86(s, 1H), 9.68(s, 1H), 8.04 to 7.98(m, 2H), 7.89(s, 1H), 7.83(s, 1H), 7.58 to 7.47(m, 3H), 7.33 to 7.28(m, 2H), 3.43(br s, 2H), 3.04(br s, 2H), 1.43 to 1.31(m, 4H), 0.98(br s, 2H); MS [ M + H ]]⁺＝525.1；LCMS RT＝2.73min.

Example 307: preparation of N- (4- { 4-amino-6- [ (2-methylpiperidin-1-yl) carbonyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl } phenyl) -N' - [6- (trifluoromethyl) pyridin-2-yl ] urea

The procedure used for the preparation of example 69 was used to prepare the title compound by substituting intermediate AH for intermediate G and piperidine for cyclopropylamine. The reaction was stirred for 16 hours and purified by HPLC (20-85% acetonitrile in water).

¹H NMR(DMSO-d₆) δ 9.85(s, 1H), 9.68(s, 1H), 8.05 to 7.97(m, 2H), 7.89(s, 1H), 7.83(s, 1H), 7.58 to 7.47(m, 3H), 7.33 to 7.27(m, 2H), 2.69to 2.60(m, 1H), 2.50(br s, 2H), 1.50 to 1.31(m, 4H), 0.99 to 0.90(m, 5H); MS [ M + H ]]⁺＝539.1；LCMS RT＝2.81min.

Example 308: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2-fluorophenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 276 was used to prepare the title compound by substituting intermediate AL for intermediate 7.

¹H-NMR(DMSO-d₆) δ 9.46(s, 1H), 9.32(s, 1H), 8.65 to 8.64(d, J ═ 7.4Hz, 1H), 8.35 to 8.30(t, J ═ 8.5Hz, 1H), 8.30(s, 1H), 8.09(s, 1H), 7.90(s, 1H), 7.53 to 7.48(m, 1H), 7.42 to 7.39(m, 1H), 7.37 to 7.34(d, J ═ 12.0Hz, 1H), 7.21 to 7.19(d, J ═ 8.4Hz, 1H), 6.62(s, 1H); MS [ M + H ]]⁺＝516.1；LCMS RT＝3.01min.

Example 309: preparation of 4-amino-N-cyclopropyl-5- [4- ({ [ (3-methoxyphenyl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate W for intermediate X and phenyl (3-methoxyphenyl) carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H NMR(DMSO-d₆) δ 8.81(s, 1H), 8.75(s, 1H), 8.04(s, 1H), 7.92(br s, 1H), 7.88(d, J ═ 4.3Hz, 1H), 7.54 to 7.48(m, 2H), 7.31 to 7.23(m, 2H), 7.21 to 7.12(m, 2H), 6.96 to 6.90(m, 1H), 6.55(dd d, J ═ 8.1, 2.7, 0.7Hz, 1H), 4.66(br s, 1H), 3.73(s, 3H), 2.70 to 2.62(m, 1H), 0.64 to 0.58(m, 2H), 0.44 to 0.38(m, 2H); MS [ M + H ]]⁺＝458.1；LCMS RT＝2.38min.

Example 310: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [3- (trifluoromethyl) phenyl ] urea

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting intermediate AO for intermediate C and 3- (trifluoromethyl) aniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(DMSO-d₆) δ 9.23 to 9.16(br s, 2H), 8.28(s, 1H), 8.07(s, 1H), 7.89(s, 1H), 7.72(s, 1H), 7.63 to 7.61(d, J ═ 8.6Hz, 2H), 7.34 to 7.28(m, 4H), 7.01 to 6.99(d, J ═ 7.1Hz, 1H), 6.55(s, 1H); MS [ M + H ]]⁺＝480.0；LCMS RT＝2.84min.

Example 311: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (3-chlorophenyl) urea

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting intermediate AO for intermediate C and 3-chloroaniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR(DMSO-d₆) δ 8.29(s, 1H), 8.08(s, 1H), 8.04(s, 1H), 7.90(s, 1H), 7.68 to 7.66(m, 3H), 7.51 to 7.47(t, J ═ 8.1Hz, 1H), 7.34 to 7.32(d, J ═ 8.6Hz, 2H), 7.30 to 7.28(d, J ═ 8.4Hz, 1H), 6.56(s, 1H); MS [ M + H ]]⁺＝446.1；LCMS RT＝2.72min.

Example 312: preparation of N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - (4-chlorophenyl) urea

The procedure used for the preparation of example 3 was used to prepare the title compound by substituting intermediate AO for intermediate C and 4-chloroaniline for 4-fluoro-3- (trifluoromethyl) aniline.

¹H-NMR (DMSO-d₆) δ 8.93(s, 1H), 8.90(s, 1H), 8.29(s, 1H), 8.08(s, 1H), 7.90(s, 1H), 7.61 to 7.59(d, J ═ 8.6Hz, 2H), 7.50 to 7.48(d, J ═ 9.1Hz, 2H), 7.35 to 7.32(m, 4H), 6.55(s, 1H); MS [ M + H ]]⁺＝446.1；LCMS RT＝2.65min.

Example 313: preparation of 4-amino-5- [4- ({ [ (3-methoxyphenyl) amino ] carbonyl } amino) phenyl ] -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

The procedure used for the preparation of example 73 was used to prepare the title compound by substituting intermediate M for intermediate X and phenyl (3-methoxyphenyl) carbamate for phenyl (4-tert-butylpyridin-2-yl) carbamate.

¹H NMR(DMSO-d₆) δ 8.79(s, 1H), 8.72(s, 1H), 8.48(dd, J ═ 6.4, 6.4Hz, 1H), 8.17(s, 1H), 8.00(br s, 1H), 7.91(s, 1H), 7.52 to 7.47(m, 2H), 7.30 to 7.23(m, 2H), 7.21 to 7.12(m, 2H), 6.96 to 6.90(m1H), 6.54(ddd, J ═ 8.2, 2.6, 0.8Hz, 1H), 5.08(br s, 1H), 4.02 to 3.90(m, 2H), 3.73(s, 3H); MS [ M + H ]]⁺＝500.2；LCMS RT＝2.61min.

The following examples can be synthesized following the synthetic methods outlined above:

4-amino-5- [4- ({ [ (3-phenoxyphenyl) amino ] carbonyl } amino) phenyl ] -

N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N-cyclopropyl-5- [4- ({ [ (3-phenoxyphenyl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N- (2, 2, 2-trifluoroethyl) -5- {4- [ ({ [2- (trifluoromethyl) pyrimidin-4-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N-cyclopropyl-5- {4- [ ({ [2- (trifluoromethyl) pyrimidin-4-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N- (2, 2, 2-trifluoroethyl) -5- {4- [ ({ [3- (trifluoromethoxy) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N-cyclopropyl-5- {4- [ ({ [3- (trifluoromethoxy) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-5- (4- { [ (1, 3-benzodioxol-5-ylamino) carbonyl ] amino } phenyl) -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-5- (4- { [ (1, 3-benzodioxol-5-ylamino) carbonyl ] amino } phenyl) -N-cyclopropylpyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-5- [4- ({ [ (6-methylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N-cyclopropyl-5- [4- ({ [ (6-methylpyridin-2-yl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-5- {4- [ ({ [3- (3-ethylphenoxy) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-5- {4- [ ({ [3- (2-chlorophenoxy) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N- (2, 2, 2-trifluoroethyl) -5- (4- { [ ({3- [4- (trifluoromethoxy) phenoxy ] phenyl } amino) carbonyl ] amino } phenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N-cyclopropyl-5- {4- [ ({ [3- (2-methylphenoxy) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N-cyclopropyl-5- {4- [ ({ [3- (4-fluorophenoxy) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N-cyclopropyl-5- {4- [ ({ [3- (3-methoxyphenoxy) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N- (tert-butyl) -5- [4- ({ [ (3-phenoxyphenyl) amino ] carbonyl } amino) phenyl ] pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N- (2, 2, 2-trifluoroethyl) -5- {4- [ ({ [4- (trifluoromethyl) pyrimidin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N-cyclopropyl-5- {4- [ ({ [4- (trifluoromethyl) pyrimidin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-5- { 3-fluoro-4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-5- { 2-methyl-4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-5- { 3-methoxy-4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N-cyclopropyl-5- { 2-fluoro-4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N-cyclopropyl-5- { 3-ethyl-4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N-cyclopropyl-5- {3- (trifluoromethoxy) -4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N- (tert-butyl) -5- { 3-fluoro-4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N- (tert-butyl) -5- { 2-methyl-4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N- (tert-butyl) -5- { 3-methoxy-4- [ ({ [6- (trifluoromethyl) pyridin-2-yl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N- (tert-butyl) -5- {4- [ ({ [3- (2-methylphenoxy) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N- (tert-butyl) -5- {4- [ ({ [3- (4-fluorophenoxy) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

4-amino-N- (tert-butyl) -5- {4- [ ({ [3- (3-methoxyphenoxy) phenyl ] amino } carbonyl) amino ] phenyl } pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2, 6-difluorophenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2, 6-difluorophenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2-chlorophenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2-chlorophenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

N- [4- (6-acetyl-4-aminopyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) -2-fluorophenyl ] -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

N- {4- [ 4-amino-6- (cyclopropylcarbonyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2-fluorophenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

N- [4- (4-amino-6-glycoloylpyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl) -2-fluorophenyl ] -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

N- {4- [ 4-amino-6- (1, 3-thiazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

N- {4- [ 4-amino-6- (4-methyl-1, 3-thiazol-2-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

N- {4- [ 4-amino-6- (1, 3-thiazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

N- {4- [ 4-amino-6- (morpholin-4-ylacetyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

N- {4- [ 4-amino-6- (methoxyacetyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

N- {4- [ 4-amino-6- (1, 2, 4-oxadiazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

N- {4- [ 4-amino-6- (3-methyl-1, 2, 4-oxadiazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

N- {4- [ 4-amino-6- (cyanomethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2-fluorophenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

N- {4- [ 4-amino-6- (cyanomethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2-fluorophenyl } -N' - [4- (trifluoromethyl) pyridin-2-yl ] urea

N- {4- [ 4-amino-6- (5-methylisoxazol-3-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- [ (4-methylpiperazin-1-yl) methyl ] -3- (trifluoromethyl) phenyl ] urea

N- {4- [ 4-amino-6- (methoxymethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] phenyl } -N' - [4- [ (4-methylpiperazin-1-yl) methyl ] -3- (trifluoromethyl) phenyl ] urea

4-amino-5- {4- [ ({ [4- [ (4-methylpiperazin-1-yl) methyl ] -3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenyl } -N- (2, 2, 2-trifluoroethyl) pyrrolo [2, 1-f ] [1, 2, 4] triazine-6-carboxamide

N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2-fluorophenyl } -N' - [4- [ (4-methylpiperazin-1-yl) methyl ] -3- (trifluoromethyl) phenyl ] urea

N- {4- [ 4-amino-6- (1, 3-oxazol-5-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-5-yl ] -2-fluorophenyl } -N' - [4- (morpholin-4-ylmethyl) -3- (trifluoromethyl) phenyl ] urea

B. Evaluation of physiological Activity

The in vitro effect of the compounds of the invention can be demonstrated in the following tests:

growth factor stimulated p-ERK assay in HUVEC

Exponentially growing human endothelial HUVEC cells (human umbilical vein endothelial cells, cat # CC-2517, Cambrex, Walkersville, MD) were seeded at 25000 cells/well in EBM-2MV medium with growth factors (cat # CC-3202, Cambrex) in 96-well plates and at 37 ℃ at 5% CO₂Medium growth. After 16 hours of inoculation, the cells were exchanged into serum-free medium (RPMI 1640 containing 0.1% BSA (bovine serum albumin)), and compounds of different concentrations were added thereto, and cultured for 2 hoursCells were stimulated with 50ng/ml VEGF (vascular endothelial growth factor, Protein Sciences, Meriden, CT) or bFGF (basic fibroblast growth factor cat # PHG0026, Biosource International, Camarillo, Calif.) for 10 min. The remainder of the experiment was carried out according to the manufacturer's instructions for the ERK1/2Bioplex assay (cat #171-304004, Bio-Rad, Hercules, Calif.). After removing the medium by aspiration, the cells were rapidly washed with 100. mu.l of cell washing buffer A to stop the treatment reaction. Immediately thereafter, 80 microliters of cell lysis buffer was added to each well of the 96-well plate placed on ice. The cells in each well were lysed by pipetting up and down 5 times with a multichannel pipette. The plate was then shaken for 20 minutes at 300rpm on a microtiter plate shaker at 4 ℃. The cell debris was pelleted by centrifugation at 4500g for 15 min at 4 ℃ and the supernatant was collected. 45 microliters of supernatant was diluted with an equal volume of Bio-Plex phosphoprotein assay buffer B. The coupled and pigment coated beads were added to a 96 well filter plate and the prepared lysate was added. The bead and lysate mixture was incubated at room temperature for 15-18 hours. On the following day, the plates were vacuum filtered and then washed 3 times. To each well 25 microliters of detection antibody solution was added and the plate was incubated at room temperature for 30 minutes. The plate was then vacuum filtered and washed as described above. To each well 50 microliters of streptavidin-PE solution was added, the plate was incubated at room temperature for 10 minutes, then vacuum filtered, and washed as described above. To each well was added 125. mu.l of resuspension buffer and the data were obtained on a Luminex 100 apparatus (Bio-Rad). In the HUVEC assay, the compounds of examples 1, 8, 9, 12, 23, 27, 30, 32, 49, 59 and 70 showed greater than 50% inhibition at 100nM in VEGF-stimulated Phospho-ERK. In the HUVEC assay, the compounds of examples 11, 22, 24, 26, 29, 37, 39, 41, 47, 66, 75, 85, 93, 99, 100, 131, 143, 146 and 168 showed greater than 50% (at 1. mu.M) but less than 50% (at 100nM) inhibition in VEGF-stimulated Phospho-ERK. In the HUVEC assay, the compounds of examples 14, 18, 62, 96, 98, 104 and 140 showed greater than 50% (at 10. mu.M) but less than 50% (at 100nM and 1. mu.M) inhibition in VEGF-stimulated Phospho-ERK.

BRDU growth factor stimulated proliferation of HUVEC

Exponentially growing human umbilical vein endothelial cells (HUVEC; Cat # CC-2519A, Cambrex, Walkersville, MD) were seeded at 2000 cells/well in Collagen IV-coated 96-well plates (Cat #35-4429, Becton Dickinson, Bedford, MA) in assay medium containing RPMI-1640(Cat #11875-093, Gibco, Carlsbad, CA), 0.5% charcoal-purified serum (Cat # SH30068.03, HyClone, Logan, Utah) and 1% N-2 supplement (Cat #17502-048, Gibco, Carlsbad, CA). Plates were incubated at 37 ℃ in 5% CO₂After 4 hours of medium culture, cells were treated with different concentrations of compound (diluted in test medium at a final DMSO concentration of 0.1%) and then immediately stimulated with either 80ng/ml vascular endothelial growth factor (VEGF, Cat #100-20, PeproTech, Rocky Hill, NJ) or 1.5ng/ml basic fibroblast growth factor (bFGF, Cat #100-18B, PeproTech, Rocky Hill, NJ). The treated cells were incubated at 37 ℃ in 5% CO₂Cultured for 3 days. DNA synthesis was determined by bromodeoxyuridine (BrdU) incorporated into newly synthesized DNA using the Amersham Cell promotion BioTrack ELISA system (Cat # RPN250, Amersham, Piscataway, N.J.). Diluted BrdU solution (20. mu.l BrdU stock, diluted 1: 20 times in assay buffer) was added to each well and incubated at 37 ℃ in 5% CO ₂And culturing for 6 hours. The medium was removed and the cells were fixed at room temperature for 30 minutes according to the instructions of the Amersham test kit. After removal of the fixative, blocking buffer (supplied by Amersham kit; 200. mu.l/well) was added and the plates were stored overnight at 4 ℃. The blocking buffer was removed by pipetting, and peroxidase-labeled anti-BrdU antibody (supplied by Amersham kit; 100. mu.l/well) was added and incubated at room temperature for 3 hours. The plates were washed 3 times with wash buffer (supplied by Amersham kit; 300. mu.l/well/wash). Immediately after washing, 100. mu.l of TMB-substrate was added to each well and further incubated at room temperature for 30 minutes. By adding 25. mu.l of 1M H₂SO₄The reaction is stopped. Plates were immediately read at 450nm using a SpectraMAX 250 spectrometer plate reader (Molecular Devices, Sunnyvale, Calif.).The software used was SoftMAX pro v.2.4.1.

The compounds of examples 70, 101, 218 and 226 showed an IC of less than 10nM in the VEGFR-stimulated HUVEC proliferation assay₅₀. The compounds of examples 103, 151, 155, 157, 159, 162, 223, 233, 234, 239 and 243 exhibited IC's greater than 10nM but less than 100nM in the VEGFR-stimulated HUVEC proliferation assay ₅₀. The compounds of examples 30, 99, 102, 152, 240 and 247 exhibited IC's greater than 100nM but less than 500nM in the VEGFR-stimulated HUVEC proliferation assay₅₀. The compounds of examples 100 and 163 exhibited IC's greater than 500nM but less than 2 μ M in the VEGFR-stimulated HUVEC proliferation assay₅₀。

The compounds of examples 70, 99, 101, 103, 151 and 223 exhibited IC's of less than 100nM in the FGFR stimulated HUVEC proliferation assay₅₀. The compounds of examples 30, 102, 152, 155, 157, 159, 162, 218, 226, 233, 234, 239, 243 and 247 exhibited IC greater than 100nM but less than 500nM in the FGFR stimulated HUVEC proliferation assay₅₀. The compound of example 240 exhibited an IC of greater than 500nM but less than 1 μ M in the FGFR stimulated HUVEC proliferation assay₅₀。

Proliferation of tumor cells

Human tumor cells (e.g., HCT116 or MDA-MB-231 cells) were plated at 3.0X 10³Individual cells/well were seeded into Costar 96-well plates and cultured in 150. mu.l of RPMI complete medium (Invitrogen Corporation, Grand Island, NY) containing 10% fetal bovine serum (Hyclone, Logan, Utah) in 5% CO₂Was grown in an incubator at 37 ℃ for 16 hours. To each well 50 μ l additional growth medium containing compounds at a concentration of 40 μ M to 18nM and 0.4% DMSO was added. Cells were allowed to stand at 5% CO ₂The growth was carried out at 37 ℃ for 72 hours. Mu.l of Alamar Blue (Trek Diagnostic Systems, Inc., Cleveland, Ohio) reagent was added to each well and cultured at 37 ℃ for 3 hours. The plates were read in a spectra MaxGemini (Molecular Devices, CA) at 544nm excitation wavelength and 590nm emission wavelength. By log drug concentrationLinear regression analysis of degree versus percent inhibition to determine IC₅₀The value is obtained.

The compounds of examples 25, 70, 93, 155, 235 and 237 exhibited IC's of less than 500nM in the HCT116 proliferation assay₅₀. The compounds of examples 59, 69, 71, 76, 156, 159, 161, 162, 223, 239, 241, 256 and 257 exhibited IC's greater than 500nM but less than 1.5. mu.M in the HCT116 proliferation assay₅₀. In the HCT116 proliferation assay, the compounds of examples 30, 73, 74, 82, 99, 100, 102, 149, 157, 163, 217, 225, 226, 232, 233, 234, 240, 242, 243, 247, 248, 254 and 255 exhibit an IC of greater than 1.5 μ M but less than 5 μ M₅₀. The compounds of examples 84, 94, 103, 153 and 218 showed IC's of greater than 5 μ M but less than 10 μ M in the HCT116 proliferation assay₅₀。

The compounds of examples 25, 70, 71, 155 and 156 exhibited IC's of less than 500nM in the MDA-MB-231 proliferation assay ₅₀. The compounds of examples 59, 82, 93, 99, 149, 159, 217, 223, 235, 239, 248, 251, 255, 256 and 257 exhibited IC's greater than 500nM but less than 1.5 μ M in the MDA-MB-231 proliferation assay₅₀. The compounds of examples 69, 73, 74, 76, 94, 100, 157, 161, 162, 163, 225, 226, 232, 233, 234, 237, 240, 241, 242, 243, 247, and 254 exhibited IC's greater than 1.5 μ M but less than 5 μ M in the MDA-MB-231 proliferation assay₅₀. The compounds of examples 102, 103, 153 and 218 exhibited IC's greater than 5 μ M but less than 10 μ M in the MDA-MB-231 proliferation assay₅₀。

p-Histone 3

Compounds were tested for inhibition of histone 3 phosphorylation in colon cancer (HCT 116). Briefly, 20,000 cells/well were seeded into 96-well black-walled poly-d-lysine plates in RPMI + 10% FBS at 5% CO₂Incubated overnight at 37 ℃. On the following day, cells were treated with the compound for 24 hours at 37 ℃. After compound treatment, plates were centrifuged at 1000rpm for 2 minutes and washed 2 times with 100 μ 1 cold sterile TBS. Then will beCells were fixed with a cold solution of 3.7% formaldehyde in TBS (4 ℃ for 1 hour) and then permeabilized with a mixture of 0.1% Triton-X-100 in TBS (30 minutes at room temperature). The plate was then washed with 0.25% BSA-TBS and blocked with BSA solution at room temperature for 1 hour with shaking. The supernatant was removed, replaced with primary antibody (anti-phospho-histone 3, serine 10, cell marker) diluted 1: 250 in 0.25% BSA-TBS, and incubated overnight at 4 ℃. The plates were washed and treated with a secondary antibody (anti-rabbit Eu-labeled) diluted 1: 10000 in 0.25% BSA-TBS (room temperature 1 h). The antibody solution was removed from each well and washed 8 times. Wash buffer was replaced with 50 μ l of pre-warmed enhancing solution and mixed on an orbital (orbital) shaker for 10 minutes. Fluorescence was measured using a Victor V fluorescence detector. Data expressed as percent inhibition: % inhibition is 100- ((signal with inhibitor-background)/(signal without inhibitor-background)) × 100. The compounds of examples 88, 92, 139, 164, 165, 171, 176 and 177 showed IC's of less than 500nM in the p-histone 3 assay ₅₀. In the p-histone 3 assay, the compounds of examples 7, 13, 59, 167 and 204 showed IC's of greater than 500nM but less than 1 μ M₅₀。

The in vivo effects of the compounds of the invention may be demonstrated in tumor xenograft experiments such as those described by Wilhelm, s. et al, Cancer res.2004, 64, 7099-09.

C. Working examples for pharmaceutical compositions

The compounds of the invention may be converted into pharmaceutical compositions as follows:

and (3) tablet preparation:

consists of the following components:

100mg of the compound according to example 1, 50mg of lactose (monohydrate), 50mg of corn starch (native), 10mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2mg of magnesium stearate.

The tablet has a weight of 212mg, a diameter of 8mm and a bending radius of 12mm.

Preparation:

the mixture of active ingredient, lactose and starch was granulated using a solution of 5% PVP in water (m/m). After drying, the granules were mixed with magnesium stearate for 5 minutes. The mixture was molded using a conventional tablet press (tablet format, see above). The applied molding pressure is typically 15 kN.

Suspension for oral administration:

consists of the following components:

1000mg of the compound of example 1, 1000mg of ethanol (96%), 400mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99g of water.

A single dose of 100mg of a compound of the invention is provided by 10ml of an oral suspension.

Preparation:

rhodigel was suspended in ethanol and the active ingredient was added to the suspension. Water was added with stirring. Stirring was continued for about 6 hours until swelling of the Rhodigel was complete.

Solution for intravenous administration 1:

consists of the following components:

100-200mg of the compound of example 1, 15g of polyethylene glycol 400 and 250g of water, optionally containing up to 15% Cremophor EL, and optionally up to 15% ethanol, and optionally up to 2 equivalents of a pharmaceutically acceptable acid such as citric acid or hydrochloric acid.

Preparation:

the compound of example 1 and polyethylene glycol 400 were dissolved in water with stirring. The solution was sterile filtered (pore size 0.22 μm) and filled into heat-sterilized infusion bottles under sterile conditions. The infusion bottle was sealed with a rubber seal.

Solution for intravenous administration 2:

consists of the following components:

100-200mg of the compound of example 1, an aqueous salt solution, optionally containing Cremophor EL up to 15% by weight, and optionally ethanol up to 15% by weight, and optionally up to 2 equivalents of a pharmaceutically acceptable acid such as citric acid or hydrochloric acid.

Preparation:

the compound of example 1 was dissolved in brine with stirring. CremophorEL, ethanol or acid is optionally added. The solution was sterile filtered (pore size 0.22 μm) and filled into heat-sterilized infusion bottles under sterile conditions. The infusion bottle was sealed with a rubber seal.

It will be apparent to those skilled in the art that changes and modifications may be made to the present invention without departing from the spirit or scope of the invention as set forth herein.

Claims

1. A compound of formula (I)

Wherein

R¹Selected from the group consisting of aryl, benzyl and heteroaryl,

·C₁-C₄Alkyl radical, wherein C₁-C₄Alkyl may be substituted with 0, 1, 2 or 3 halogens, 0 or 1 heterocyclyl,

·C₁-C₃alkoxy radical, wherein C₁-C₃Alkoxy may optionally be substituted by C₁-C₃The alkyl amino group is substituted by the alkyl amino group,

the presence of a halogen, in particular,

a trifluoromethyl group,

the presence of a trifluoromethoxy group,

phenyl, said phenyl being optionally substituted by 1 or 2 halogens,

·wherein X is O or NR^1-1And wherein R is^1-1Is hydrogen or C₁-C₆An alkyl group, a carboxyl group,

the nitro group(s) of the compound,

a cyano group, in the form of a cyano group,

·C₁-C₃an alkylthio group is a group of one or more,

a trifluoromethylthio group (CTS-S-),

·C₁-C₃an alkyl-carbonyl group, a carboxyl group,

·C₁-C₆alkoxycarbonyl, and

a phenoxy group, wherein the phenoxy group may optionally be selected by 1 independently from C₁-C₆Alkyl radical, C₁-C₆Alkoxy, trifluoromethoxy and halogen,

and is

Wherein benzyl can be substituted by 0, 1, 2 or 3 substituents selected from halogen, C₁-C₃Alkyl and C₁-C₃A radical substitution of alkoxy;

R²is hydrogen;

R³is selected from

A carboxyl group,

the formyl radical,

·C₁-C₆alkylcarbonyl of said C₁-C₆Alkylcarbonyl optionally substituted by 1 atom selected from C₁-C₆Alkoxy and heterocyclic ring, and the like,

·C₃-C₆a cycloalkyl-carbonyl group,

·C₁-C₆alkoxycarbonyl radical, said C₁-C₆Alkoxycarbonyl is optionally substituted by 0, 1, 2 or 3 groups selected from amino and C ₁-C₆The radical of an alkoxycarbonyl group is substituted,

an amino-carbonyl group, or a carbonyl group,

·C₁-C₆alkylaminocarbonyl radical, in which C₁-C₆The alkylaminocarbonyl group may be optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of: c₃-C₆Cycloalkyl, amino, C₁-C₆Alkylamino radical, C₁-C₆Alkoxycarbonyl group, C₁-C₆Alkylthio and C₁-C₆Alkoxycarbonylamino group, or wherein C₁-C₆The alkylaminocarbonyl group may be optionally substituted with 0 or 1 heterocyclic group, wherein the heterocyclic group may be optionally substituted with 0 or 1C₁-C₆Alkyl substitution, or wherein C₁-C₆The alkylaminocarbonyl radical may optionally be substituted by 0 or 1 phenyl, where the phenyl radical may optionally be substituted by 0 or 1 halogen, C₁-C₆Alkyl or C₁-C₆The substitution of alkoxy groups is carried out,

a heterocyclylcarbonyl group, the heterocyclylcarbonyl group being optionally substituted by 0 or 1C₁-C₆Alkylamino, cycloalkyl or C₁-C₆The substitution of the alkyl group is carried out,

·C₁-C₆alkyl radical, said C₁-C₆The alkyl group is optionally substituted with 1 substituent independently selected from the group consisting of

b) An amino group, a carboxyl group,

c)C₁-C₆alkylamino radical, in which C₁-C₆The alkylamino group may be optionally substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of: halogen, amino, alkylamino, methoxy, methylthio and methylsulfonyl,

d) arylamino, wherein arylamino may be substituted with 0, 1 or 2 substituents independently selected from the group consisting of: c ₁-C₆Alkyl radical, C₁-C₆An alkoxy group and a trifluoromethyl group,

e) heterocyclyl, wherein heterocyclyl may be interrupted by 0, 1 or 2C₁-C₆Alkyl substitution, wherein C₁-C₆Alkyl may be substituted with 0, 1 or 2 hydroxy, methoxy or pyridyl,

f) an imidazole group which is a group having a structure represented by,

g) a pyridylamino group,

h)C₁-C₃alkoxy radical, said C₁-C₃Alkoxy is optionally substituted with up to a full-fluorine level, or with a heterocycle, wherein the heterocycle may optionally be substituted with 0 or 1C₁-C₆The substitution of the alkyl group is carried out,

i)C₁-C₃alkoxy radical C₂-C₃Alkoxy, and

j)C₁-C₆an alkoxycarbonyl group, a carbonyl group,

k)C₃-C₆cycloalkyl radicals

l) a cyano group,

·C₁-C₆alkoxy radical, said C₁-C₆Alkoxy is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of: amino group, C₁-C₆Alkylamino and heterocyclyl, wherein heterocyclyl may be interrupted by 0, 1, 2 or 3C₁-C₆The substitution of the alkyl group is carried out,

·C₃-C₆a cycloalkyl-aminocarbonyl group,

a cyano group, in the form of a cyano group,

heteroaryl, wherein heteroaryl may be optionally substituted with 0, 1, 2 or 3 groups independently selected from

a)C₁-C₆Alkyl radical, wherein C₁-C₆Alkyl may be substituted with 0, 1, 2 or 3 halogens, 0 or 1 heterocyclyl, 0 or 1 alkylamino, or 0 or 1 hydroxy or methoxy,

b) the halogen(s) are selected from the group consisting of,

c) an amino group, a carboxyl group,

d) an alkylamino group,

e)C₁-C₆alkoxycarbonyl, and

f)C₃-C₆a cycloalkyl group,

a heteroaryl-carbonyl group, which is a carbonyl group,

heterocyclic radicalWherein heterocyclyl may be substituted by 0, 1, 2 or 3 independently selected from C ₁-C₆Alkyl and C₁-C₆Substituted with a group of alkoxycarbonyl; and is

R⁴Is hydrogen;

wherein the aryl group is a mono-or bicyclic carbocyclic group having 6 to 10 carbon atoms which is aromatic in at least one ring,

heteroaryl is a mono-or bicyclic radical having 5 to 10 ring atoms and up to 5 heteroatoms from the group consisting of nitrogen, oxygen and sulfur, which is aromatic in at least one ring, and heterocyclyl is a non-aromatic mono-or bicyclic radical having 4 to 10 ring atoms and up to 3 heteroatoms from the group consisting of nitrogen, oxygen and sulfur, CO, SO and SO₂A heteroatom and/or a heterogroup of (a);

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein

R¹Selected from phenyl and monocyclic heteroaryl having 5 or 6 ring atoms,

·C₁-C₄Alkyl radical, wherein C₁-C₄Alkyl may be substituted by 0, 1, 2 or 3 halogens, 0 or 1 pyrrolidinyl, 0 or 1 morpholinyl,

the presence of a halogen, in particular,

a trifluoromethyl group,

the presence of a trifluoromethoxy group,

phenyl, said phenyl being optionally substituted by 1 or 2 halogens,

trifluoromethylthio;

R²is hydrogen;

R³is selected from

A carboxyl group,

the formyl radical,

·C₁-C₆alkylcarbonyl of said C₁-C₆Alkylcarbonyl is optionally substituted with 1 group selected from: c₁-C₆Alkoxy and monocyclic heterocycles having 5 or 6 ring atoms,

·C₃-C₆a cycloalkyl-carbonyl group,

·C₁-C₆alkoxycarbonyl radical, said C₁-C₆Alkoxycarbonyl is optionally substituted by 0, 1, 2 or 3 groups selected from amino and C₁-C₆The radical of an alkoxycarbonyl group is substituted,

an amino-carbonyl group, or a carbonyl group,

·C₁-C₆alkylaminocarbonyl radical, in which C₁-C₆The alkylaminocarbonyl group may be optionally substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of: c₃-C₆Cycloalkyl, amino, C₁-C₆Alkylamino radical, C₁-C₆Alkoxycarbonyl group, C₁-C₆Alkylthio and C₁-C₆Alkoxycarbonylamino group, or wherein C₁-C₆The alkylaminocarbonyl radical may optionally be substituted by 0 or 1 hydroxyl group or 0 or 1 monocyclic heterocyclic radical having 5 or 6 ring atoms, where the heterocyclic radical may optionally be substituted by 0 or 1C₁-C₆Alkyl substitution, or wherein C₁-C₆The alkylaminocarbonyl radical may optionally be substituted by 0 or 1 phenyl, where phenyl may optionally be substituted by 0 or 1 halogen or C₁-C₆The substitution of the alkyl group is carried out,

a monocyclic heterocyclylcarbonyl group having 5 or 6 ring atoms, optionally substituted by 0 or 1C₁-C₆Alkylamino radical, C₃-C₆Cycloalkyl or C₁-C₆The substitution of the alkyl group is carried out,

b) An amino group, a carboxyl group,

c)C₁-C₆alkylamino radical, in which C₁-C₆The alkylamino group may be substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of: halogen, aminoAlkylamino, methoxy, methylthio and methylsulfonyl,

e) a monocyclic heterocyclyl having 5 or 6 ring atoms, wherein the heterocyclyl may be interrupted by 0, 1 or 2C₁-C₆Alkyl substitution, wherein C₁-C₆Alkyl may be substituted with 0, 1 or 2 hydroxy, methoxy or pyridyl,

f) an imidazole group which is a group having a structure represented by,

h)C₁-C₃alkoxy radical, said C₁-C₃Alkoxy is optionally substituted by fluorine up to the level of perfluoro or by a monocyclic heterocycle having 5 or 6 ring atoms, wherein the heterocycle may optionally be substituted by 0 or 1C₁-C₆The substitution of the alkyl group is carried out,

i)C₁-C₃alkoxy radical C₂-C₃Alkoxy, and

j)C₁-C₆an alkoxycarbonyl group, a carbonyl group,

k)C₃-C₆a cycloalkyl group,

l) a cyano group,

·C₃-C₆a cycloalkyl-aminocarbonyl group,

a cyano group, in the form of a cyano group,

a)C₁-C₆Alkyl radical, wherein C₁-C₆Alkyl may be substituted with 0, 1, 2 or 3 halogens, 0 or 1 monocyclic heterocyclyl with 5 or 6 ring atoms, 0 or 1 alkylamino, or 0 or 1 hydroxy or methoxy,

b) the halogen(s) are selected from the group consisting of,

e)C₁-C₆alkoxycarbonyl, and

f)C₃-C₆a cycloalkyl group,

monocyclic heteroaryl carbonyl having 5 or 6 ring atoms,

A monocyclic heterocyclyl having 5 or 6 ring atoms, wherein heterocyclyl may be interrupted by 0, 1, 2 or 3 independently selected from C₁-C₆Alkyl and C₁-C₆Substituted with a group of alkoxycarbonyl;and is

R⁴Is hydrogen;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein

·C₁-C₄Alkyl radical, wherein C₁-C₄Alkyl groups may be substituted with 0, 1, 2 or 3 halogens,

the presence of a halogen, in particular,

a trifluoromethyl group,

the presence of a trifluoromethoxy group,

phenyl, optionally substituted by 1 or 2 halogens;

R²is hydrogen;

R³is selected from

·C₁-C₆Alkylcarbonyl of said C₁-C₆Alkylcarbonyl is optionally substituted with 1 group selected from: c₁-C₆Alkoxy, piperazinyl, morpholinyl, pyrrolidinyl, and piperidinyl,

a cyclopropyl carbonyl group, in which the carbonyl group is a carbonyl group,

an amino-carbonyl group, or a carbonyl group,

·C₁-C₆alkylaminocarbonyl radical, in which C₁-C₆The alkylaminocarbonyl group may be optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of: c ₃-C₆Cycloalkyl, amino, C₁-C₆Alkylamino radical, C₁-C₆Alkoxycarbonyl group, C₁-C₆Alkylthio and C₁-C₆Alkoxycarbonylamino group, or wherein C₁-C₆Alkyl radicalAminocarbonyl may be optionally substituted with 0 or 1 hydroxy, piperazinyl, morpholinyl, pyrrolidinyl or piperidinyl, wherein piperazinyl, morpholinyl, pyrrolidinyl or piperidinyl may be optionally substituted with 0 or 1C₁-C₆Alkyl is substituted, and wherein C₁-C₆The alkylaminocarbonyl radical may optionally be substituted by 0 or 1 phenyl, where phenyl may optionally be substituted by 0 or 1 halogen or C₁-C₆The substitution of the alkyl group is carried out,

heterocyclylcarbonyl selected from piperazinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl or piperidinylcarbonyl, said group optionally substituted by 0 or 1C₃-C₆Cycloalkyl or C₁-C₆The substitution of the alkyl group is carried out,

c)C₁-C₆Alkylamino radical, in which C₁-C₆The alkylamino group may be substituted with 0, 1, 2, 3 or 4 substituents independently selected from halogen, alkylamino and methoxy,

e) piperazinyl, morpholinyl, pyrrolidinyl or piperidinyl, wherein piperazinyl, morpholinyl, pyrrolidinyl or piperidinyl may be interrupted by 0, 1 or 2C₁-C₆Alkyl substitution, wherein C₁-C₆Alkyl may be substituted with 0, 1 or 2 hydroxy or methoxy groups,

f) An imidazole group which is a group having a structure represented by,

h)C₁-C₃alkoxy radical, said C₁-C₃Alkoxy is optionally substituted with up to a full-fluorine level, or with a monocyclic heterocycle having 5 or 6 ring atoms, wherein the heterocycle may optionally be substituted with 0 or 1C₁-C₆The substitution of the alkyl group is carried out,

i)C₁-C₃alkoxy radical C₂-C₃Alkoxy, and

j)C₁-C₆an alkoxycarbonyl group, a carbonyl group,

k)C₃-C₆a cycloalkyl group,

l) a cyano group,

·C₃-C₆a cycloalkyl-aminocarbonyl group,

a cyano group, in the form of a cyano group,

a)C₁-C₆Alkyl radical, wherein C₁-C₆Alkyl may be substituted with 0, 1, 2 or 3 halogens, 0 or 1 alkylamino, or 0 or 1 methoxy,

b) halogen, and

f)C₃-C₆a cycloalkyl group,

R⁴Is hydrogen;

or a pharmaceutically acceptable salt thereof.

4. A process for the preparation of a compound of claim 1, wherein

Reacting a compound of formula (II)

Wherein R is²、R³And R⁴Having the meaning as set forth in claim 1,

with an isocyanate compound of the formula (III),

R¹-NCO(III)

Or with a carbamate of formula (VI),

R¹-NH-C(O)-OPh(VI)

wherein R is¹Have the meaning as defined in claim 1; or

Reacting a compound of formula (IV)

Wherein R is¹、R²、R³And R⁴Having the meaning as set forth in claim 1,

with an amine of the formula (V),

R¹-NH₂(V)

wherein R is¹Have the meaning indicated in claim 1.

5. A pharmaceutical composition comprising a compound of claim 1.

6. The pharmaceutical composition of claim 5 in combination with at least one pharmaceutically acceptable carrier or excipient.

7. A process for preparing a pharmaceutical composition according to claim 6, said process comprising combining at least one compound according to claim 1 with at least one pharmaceutically acceptable carrier or excipient, mixing the combination and bringing the combination into a suitable administration form.

8. Use of a compound of claim 1 for the preparation of a pharmaceutical composition for the treatment of a proliferative disorder.

9. Use of a pharmaceutical composition according to claim 5 or 6 in the manufacture of a medicament for the treatment or prevention of a proliferative disorder.

10. Use of a compound of formula (I) according to claim 1 in the manufacture of a medicament for treating a condition or disease in a mammal.

11. The use of claim 10, wherein the condition or disease is cancer.

12. The use of claim 10, wherein the therapeutically effective amount of a compound of formula (I) according to claim 1 shows an effect on angiogenesis.