KR20200011965A - Novel Inhibitors of MAP4K1 - Google Patents

Abstract

The present invention relates to the treatment of MAP4K1 (HPK1) useful for the treatment of diseases or disorders characterized by dysregulation of signaling pathways associated with MAPK activation, including hyperproliferative disorders, immune system dysfunction disorders, inflammatory disorders, neurological disorders and cardiovascular diseases It relates to a novel inhibitor. The invention also relates to pharmaceutical compositions comprising said inhibitors and methods of treating said diseases and disorders. The inhibitor is a compound of formula (I) as defined herein for A, D, E, F, R ⁵ , R ⁶ , R ⁷ , Z, rings Q, n, x and y.

Description

Novel Inhibitors of MAP4K1

This patent application relates to novel inhibitors of mitogen-activated protein kinase kinase kinase kinase 1, also known as MAP4K1 or HPK1 (hematopoietic precursor kinase 1).

Protein kinases represent a large family of proteins that play a variety of important roles in the regulation of a wide range of cellular processes. These kinases are Akt, Axl, Aurora A, Aurora B, DYRK2, EPHAa2, FGFR3, FLT-3, VEGFr3, IGFLr, IKK2, JNK3, VEGFr2, MEK1, MET, P70s6K, Plk1, RSK1, Src, TrkA, Zap70, cKit , bRaf, EGFR, Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK, PDGFR, TAK1, LimK, Flt1, PDK1, Erk and RON. Inhibition of various protein kinases, particularly selective inhibition, has become an important strategy in the treatment of many diseases and disorders.

MAP4K1 is a serine / threonine kinase of the Ste20 family. MAP4K enzymes (MAP kinase kinases) are generally involved at the highest levels of the mostly linear kinase activation pathway. MAP4K will phosphorylate and activate certain substrates that are MAP3K (MAP kinase kinase). MAP3K then phosphorylates and activates MAP2K (MAP kinase kinase). MAP2K then phosphorylates and activates MAPK (MAP kinase). The MAP kinase is the final effector of the pathway and then phosphorylates the substrate to control key cellular processes such as cell proliferation, cell differentiation, gene expression, transcriptional regulation and apoptosis. The substrate of MAPK is generally a nuclear protein such as nuclear factor kappa-B (NF-кB). Activation of MAPK by phosphorylation by MAP2K translocations this final enzyme to the nucleus by cascade.

MAP4K1, also known as HPK1, is expressed mainly in T cells and B cells of the immune system, which is important for the regulation of the immune system. Congestion of the T cell and B cell activation pathways can lead to auto-immune diseases, while understimulation of these pathways may lead to immune dysfunction, susceptibility to viral and bacterial infections, and increased sensitivity to cancer. Can be. Since MAP4K1 is activated by interaction with activated T cell receptors (TCRs) and B cell receptors (BCRs), MAP4K1 activation plays a role in transferring cell activation signals from the surface of T or B cells to the effector proteins of the nucleus. . There is also evidence that MAP4K1 can be activated via TGF-β receptor, erythropoietin receptor and FAS protein (associated with apoptosis signaling). MAP4K1 activation ultimately results in the activation of several identified nuclear effector proteins, including those involved in NF-k1, AP-1, ERK2 and Fos signaling pathways.

MAP4K1 is considered a negative regulator of T cell receptor (TCR) activation signals and is one of the effector molecules that mediate immunosuppression of T cell responses upon exposure to prostaglandin E2 (PGE2). Studies have shown that MAPK1 activity weakens the strength of T cell receptor signal transduction cascade, whereby targeted gene disruption of MAP4K1 results in enhanced TCR activation signals.

One particularly important pathway that appears to be involved with MAP4K1 is the JNK pathway. MAP4K1 regulates MEKK1, TAK1 and MLK3 of MAP3K. They then regulate MKK4 and MKK7 of MAP2K. Then they regulate MAPK JNK. JNK then regulates important transcription factors and other proteins including p53, SMAD4, NFAT-2, NFAT-4, ELK1, ATF2, HSF1, c-Jun and JunD. JNK is implicated in apoptosis, neurodegeneration, cell differentiation and proliferation, inflammatory symptoms and cytokine production.

The JNK signaling pathway is activated in response to environmental stress and also by the involvement of several classes of cell surface receptors, including cytokine receptors, serpentine receptors and receptor tyrosine kinases. In mammalian cells, the JNK pathway has been implicated in biological processes such as carcinogenic transformation and mediated an adaptive response to environmental stress. JNK is also involved in regulating immune responses, including maturation and differentiation of immune cells, as well as influencing programmed cell death in cells identified as being destroyed by the immune system. Among some neurological disorders, JNK signaling is particularly implicated in ischemic stroke and Parkinson's disease as well as other diseases mentioned further below.

It is noteworthy that the MAPK p38alpha has been shown to inhibit cell proliferation by antagonizing the JNK-c-Jun-path. p38alpha appears to be active in inhibiting proliferation in both normal and cancer cells, strongly suggesting the involvement of JNK in hyperproliferative diseases (see, eg, Hui et al., Nature Genetics, Vol. 39, No. 6, June 2007]). JNK signaling is also associated with excitatory toxicity of hippocampal neurons, hepatic ischemia, reperfusion, neurodegenerative diseases, hearing loss, deafness, neural tube birth defects, cancer, chronic inflammatory diseases, obesity, diabetes, especially insulin-resistant diabetes. It has been suggested that selective JNK inhibitors are required for the treatment of various diseases, implicated in the disease, nontoxic and highly specific.

Since MAP4K1 is an upstream regulator of JNK, an effective inhibitor of MAP4K1 treats the same disease as suggested or implicated in JNK inhibitors, particularly where the disease or dysfunction occurs in hematopoietic cells, such as T cells and B cells. Would be useful.

Targeted disruption of the MAP4K1 (HPK1) allele has been shown to impart increased Th1 cytokine production to T cells in response to TCR engagement. Burakoff et al., Immunologic Research, 54 (1): 262-265 (2012). HPK1-/-T cells were found to proliferate faster than haplotype-matched wild type counterparts and were resistant to prostaglandin E2 (PGE2) -mediated inhibition. Most surprisingly, mice that received adoptive delivery of HPK1-/-T cells became resistant to lung tumor growth. In addition, the loss of HPK1 from dendritic cells (DC) conferred them with excellent antigen presenting ability, allowing HPK1-/-DCs to elicit stronger anti-tumor immune responses when used as cancer vaccines. Blocking MAP4K1 kinase activity by small molecule inhibitors was believed to activate good antitumor activity of both cell types, resulting in synergistic amplification of anti-tumor potential. If MAP4K1 is not expressed in any major organ, the selective inhibitor of MAP4K1 is less likely to cause any serious side effects.

The relationship between MAP4K1 and PGE2 is particularly noteworthy because PGE2 is the dominant eicosanoid product released by cancer cells, including lung, colon and breast cancer cells. Tumor-generated PGE2 is known to significantly contribute to tumor-mediated immune suppression.

Zhang et al., J. Autoimmunity, 37: 180-189 (2011) describe HPK1 expression in CD4 T cells of lupus patients due to the selective loss of JMJD3 histone demethylase binding to the HPK1 locus. The reduction is described. This suggests that HPK1 is one of the key molecules involved in maintaining peripheral resistance. Peripheral resistance is one of the major obstacles to the development of effective anti-tumor immunity.

Although some small molecule inhibitors of MAP4K1 have been reported, they do not selectively or even preferentially inhibit MAP4K1. Such inhibitors include staurosporine, bosutinib, sunitinib, resutaurtinib, crizotinib, foretinib, dovitinib, and KW Contains -2449. For example, staurosporin widely inhibits a wide range of protein kinases across both serine / threonine and tyrosine kinase families. Conservinib is primarily an inhibitor of tyrosine kinase BCR-Abl and has additional activity against Src family tyrosine kinases. Sunitinib is a broad inhibitor of tyrosine kinases. Restautinib is primarily an inhibitor of FLT, JAK and TRK family tyrosine kinases. Crizotinib is primarily an inhibitor of c-met and ALK tyrosine kinases. Poretinib is being studied as an inhibitor of c-Met and VEGFR tyrosine kinases. Dobitinib is mainly an inhibitor of FGFR receptor tyrosine kinase. KW-2449 is an experimental inhibitor mainly of FLT3 tyrosine kinase.

Sunitinib inhibits MAP4K1 at nanomolar concentrations, but it is a broad spectrum of receptor tyrosine kinase inhibitors. Treatment of T-cells with sunitinib results in an increase in cytokine product similar to that observed in HPK1-/-T cells, suggesting that selective MAP4K1 inhibitors in T cells can produce the same enhanced immune response phenotype. Suggest.

At present, there is a largely unmet requirement for an effective way of treating diseases and disorders associated with disrupted protein kinase signaling. Autoimmune diseases, inflammatory diseases, nervous and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma are all diseases and disorders that can be affected by dysfunctional protein kinase signaling. There is an urgent need for improved therapeutic compounds, compositions and methods for the treatment of these diseases and disorders. MAP4K1 inhibition is a particularly attractive target of cancer immunotherapy.

The major challenge currently faced in the art is the lack of MAP4K1 specific inhibitors. The present invention provides novel and very effective small molecule inhibitors of MAP4K1.

In one aspect, the invention relates to compounds of formula (I), stereoisomers, diastereomers, enantiomers or pharmaceutically acceptable salts thereof:

In the above,

A is selected from CH and N;

D is selected from CR ¹ R ² and CO;

E is selected from (CR ³ R ⁴ ) _m , NR ¹ and CO;

F is selected from O, CH ₂ , CHOH and CO;

Each instance of R ⁵ is selected from hydrogen, halogen, cyano, hydroxyl and C _1-8 alkyl;

R ⁷ is selected from hydrogen and C _1-8 alkyl;

Each instance of R ⁶ is halogen, cyano, hydroxyl, C _1-8 alkyl, halo C _1-8 alkyl, hydroxy C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy C _1-8 Alkyl, C _3-6 cycloalkyl, and C _3-6 cycloalkyl C _1-8 alkyl;

R ¹ , R ² , R ³ and R ⁴ , which may be the same or different, are each independently hydrogen, amine, C _1-8 alkyl, C _3-6 cycloalkyl, halo C _1-8 alkyl, hydroxy C _{1- 8} alkyl, C _3-6 cycloalkyl C _1-8 alkyl, C _1-8 alkoxy, 3-15 membered heterocyclyl, C _1-8 alkyl 3-15 membered heterocyclyl and CR ^a R ^b NR ^a R ^b Independently selected from;

R ^a and R ^b may be the same or different and are each independently selected from hydrogen and C _1-8 alkyl;

Z is selected from O, NH and S;

및

로부터 선택되고;L is

And

Is selected from;

x and y indicate the point of attachment;

및

로부터 선택되고;Ring Q is

And

Is selected from;

Each instance of R ⁸ is halogen, cyano, cyano C _1-8 alkyl, cyanohalo C _1-8 alkyl, cyano C _3-6 cycloalkyl, C _1-8 alkyl, halo C _1-8 alkyl , Hydroxy C _1-8 alkyl, hydroxy C _1-8 haloalkyl and -SO ₂ R ¹ ;

Each occurrence of R ⁹ is halogen, cyano, hydroxyl, C _1-8 alkyl, halo C _1-8 alkyl, hydroxy C _1-8 alkyl, C _1-8 alkoxy,

Is selected from;

R ¹⁰ is selected from halogen, hydroxyl, cyano, C _1-8 alkyl, halo C _1-8 alkyl, C _3-6 cycloalkyl and C _6-14 aryl; Wherein C _6-14 aryl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amide or C _1-8 alkyl;

'M' is 1 or 2;

'N' is 0, 1 or 2;

'P' is 0 or 1;

'Q' is 0 or 1;

'T' is either 1 or 2.

The compound of formula (I) may comprise one or more embodiments. It is to be understood that the following embodiments are illustrative of the invention and are not intended to limit the claims to the particular embodiments illustrated. It should also be understood that the embodiments defined herein may be used independently or in conjunction with any definitions, any other embodiments defined herein. Accordingly, the present invention contemplates all possible combinations and replacements of the various independently described embodiments. For example, the present invention provides that A is N (according to the embodiments defined below); F is O (according to another embodiment defined below) F; R ⁷ provides a compound of formula (I) as defined above, according to another embodiment defined below.

According to one embodiment, specifically provided are compounds of the formula (I), in which A is CH.

According to another embodiment, specifically provided are compounds of the formula (I), in which A is N.

According to yet another embodiment, specifically provided are compounds of the formula (I), in which D is CR ¹ R ² or CO.

) 또는 CR^aR^bNR^aR^b인 화학식 (I)의 화합물이 구체적으로 제공된다. 이 실시양태에서, R^a 및 R^b는 독립적으로 수소 또는 메틸이다. 또 다른 실시양태에서, R^a 및 R^b는 수소이다. 추가적인 또 다른 실시양태에서, R^a 및 R^b는 메틸이다. According to yet another embodiment, R ¹ is hydrogen or C _1-8 alkyl (eg methyl) and R ² is hydrogen, C _1-8 alkyl (eg methyl, ethyl or isopropyl), hydroxy C _{1- 8} alkyl (eg hydroxyl methyl), C _1-8 alkoxy C _1-8 alkyl (eg methoxymethyl), 3-15 membered heterocyclyl C _1-8 alkyl (eg

Or compounds of formula (I) wherein CR ^a R ^b NR ^a R ^b are specifically provided. In this embodiment, R ^a and R ^b are independently hydrogen or methyl. In another embodiment, R ^a and R ^b are hydrogen. In yet another embodiment, R ^a and R ^b are methyl.

, CH-CH₂-N(CH₃)₂ 또는 CO인 화학식 (I)의 화합물이 구체적으로 제공된다.According to yet another embodiment, D is CH ₂ , CH—CH ₃ , CH—CH ₂ —CH ₃ , C (CH ₃ ) ₂ , CH—CH (CH ₃ ) ₂ , CH—CH ₂ OH, CH— CH ₂ -O-CH ₃ ,

Specifically provided are compounds of formula (I), which are CH-CH ₂ -N (CH ₃ ) ₂ or CO.

According to yet another embodiment, specifically provided are compounds of the formula (I), in which E is (CR ³ R ⁴ ) _m , NR ¹ or CO.

According to yet another embodiment, a formula wherein R ³ is hydrogen or C _1-8 alkyl (eg methyl) and R ⁴ is hydrogen or C _1-8 alkyl (eg methyl) and 'm' is 1 or 2 ( Specifically provided are compounds of I).

According to yet another embodiment, specifically provided are compounds of the formula (I), wherein E is CH ₂ , CH-CH ₃ , C (CH ₃ ) ₂ , (CH ₂ ) ₂ , N-CH ₃ or CO.

According to yet another embodiment, specifically provided are compounds of the formula (I), wherein F is O, CH ₂ , CHOH or CO.

According to yet another embodiment, specifically provided are compounds of the formula (I) in which R ⁵ is hydrogen, halogen (eg chloro) or cyano.

According to yet another embodiment, specifically provided are compounds of the formula (I) in which R ⁵ is hydrogen, chloro or cyano.

According to yet another embodiment, specifically provided are compounds of the formula (I) in which R ⁷ is hydrogen or C _1-8 alkyl (eg methyl).

According to yet another embodiment, specifically provided are compounds of the formula (I) in which R ⁷ is hydrogen or methyl.

According to yet another embodiment, specifically provided are compounds of the formula (I), wherein Z is O.

According to yet another embodiment, specifically provided are compounds of the formula (I), wherein Z is NH.

According to yet another embodiment, specifically provided are compounds of the formula (I), wherein Z is S.

According to yet another embodiment, R ⁶ is halogen (eg chloro or fluoro), C _1-8 alkyl (eg methyl), halo C _1-8 alkyl (eg trifluoromethyl) or C _{1- 8} alkoxy (e.g., methoxy), the compound of formula (I) is provided specifically.

According to yet another embodiment, specifically provided are compounds of the formula (I) in which R ⁶ is chloro, fluoro, methyl, trifluoromethyl or methoxy.

According to yet another embodiment, specifically provided are compounds of the formula (I) in which 'n' is 0, 1 or 2.

이고; x 및 y가 부착 지점을 표시하는 화학식 (I)의 화합물이 구체적으로 제공된다.According to yet another embodiment, L is

ego; Specifically provided are compounds of formula (I), wherein x and y represent points of attachment.

이고; x 및 y가 부착 지점을 표시하는 화학식 (I)의 화합물이 구체적으로 제공된다.According to yet another embodiment, L is

ego; Specifically provided are compounds of formula (I), wherein x and y represent points of attachment.

이고; x 및 y가 부착 지점을 표시하는 화학식 (I)의 화합물이 구체적으로 제공된다.According to yet another embodiment, L is

ego; Specifically provided are compounds of formula (I), wherein x and y represent points of attachment.

이고; x 및 y가 부착 지점을 표시하는 화학식 (I)의 화합물이 구체적으로 제공된다.According to yet another embodiment, L is

ego; Specifically provided are compounds of formula (I), wherein x and y represent points of attachment.

인 화학식 (I)의 화합물이 구체적으로 제공된다. According to yet another embodiment, ring Q is

Specifically provided are compounds of formula (I).

인 화학식 (I)의 화합물이 구체적으로 제공된다. According to yet another embodiment, ring Q is

Specifically provided are compounds of formula (I).

인 화학식 (I)의 화합물이 구체적으로 제공된다. According to yet another embodiment, ring Q is

Specifically provided are compounds of formula (I).

According to yet another embodiment, R ⁸ is halogen (eg chloro or bromo), cyano, cyano C _1-8 alkyl (eg cyanomethyl or cyanoisopropyl), cyanohalo C _{1 -8} alkyl (eg cyanodifluoromethyl), cyano C _3-6 cycloalkyl (eg cyanocyclopropane), C _1-8 alkyl (eg methyl), halo C _1-8 alkyl (eg Specifically provided are compounds of formula (I), which are trifluoromethyl or difluoromethyl), hydroxy C _1-8 haloalkyl (eg, hydroxyl difluoromethyl) or -SO ₂ R ¹ . In this embodiment, R ¹ is C _1-8 alkyl (eg methyl, ethyl or amine).

According to yet another embodiment, R ⁸ is chloro, bromo, cyano, cyanomethyl, cyanoisopropyl, cyanodifluoromethyl, cyanocyclopropane, methyl, trifluoromethyl, difluoromethyl Specifically provided are compounds of formula (I), which are hydroxyl difluoromethyl, -SO ₂ Me, -SO ₂ Et, or -SO ₂ NH ₂ .

According to yet another embodiment, R ⁹ is halogen (eg fluoro or bromo), cyano, hydroxyl, C _1-8 alkyl (eg methyl), halo C _1-8 alkyl (eg trifluoro Romethyl) C _1-8 alkoxy (eg methoxy),

Specifically provided are compounds of formula (I).

According to yet another embodiment, R ⁹ is fluoro, bromo, cyano, hydroxyl, methyl, trifluoromethyl, methoxy,

Specifically provided are compounds of formula (I).

According to yet another embodiment, ring Q is

Specifically provided are compounds of formula (I).

인 화학식 (I)의 화합물이 구체적으로 제공된다. 이 실시양태에서, R¹⁰이 C_1-8 알킬 (예: 메틸) 또는 할로 C_1-8 알킬(예: 트리플루오로메틸)이다. 추가적인 또 다른 실시양태에서,‘t’는 2이다. According to yet another embodiment, ring Q is

Specifically provided are compounds of formula (I). In this embodiment, R ¹⁰ is C _1-8 alkyl (eg methyl) or halo C _1-8 alkyl (eg trifluoromethyl). In yet another embodiment, 't' is 2.

인 화학식 (I)의 화합물이 구체적으로 제공된다.According to yet another embodiment, ring Q is

Specifically provided are compounds of formula (I).

인 화학식 (I)의 화합물이 구체적으로 제공된다.According to yet another embodiment, ring Q is

Specifically provided are compounds of formula (I).

인 화학식 (I)의 화합물이 구체적으로 제공된다.According to yet another embodiment, ring Q is

Specifically provided are compounds of formula (I).

According to yet another embodiment, specifically provided are compounds of the formula (I) in which R ¹⁰ is C _1-8 alkyl (eg methyl) or C _6-14 aryl. In this embodiment, C _6-14 aryl is optionally substituted with one or more substituents selected from cyano or amide.

또는

인 화학식 (I)의 화합물이 구체적으로 제공된다.According to another embodiment, ring Q is

or

Specifically provided are compounds of formula (I).

According to another embodiment, specifically provided are compounds of the formula (I), in which 'p' is 0 or 1.

According to another embodiment, specifically provided are compounds of formula (I), in which 'q' is 0 or 1.

According to another embodiment,

A is CH or N;

, CH-CH₂-N(CH₃)₂, CO 또는 사이클로알킬이고; D is CH ₂ , CH—CH ₃ , CH—CH ₂ —CH ₃ , C (CH ₃ ) ₂ , CH—CH (CH ₃ ) ₂ , CH—CH ₂ OH, CH—CH ₂ —O—CH ₃ ,

, CH-CH ₂ -N (CH ₃ ) ₂ , CO or cycloalkyl;

E is CH ₂ , CH—CH ₃ , C (CH ₃ ) ₂ , (CH ₂ ) ₂ , N—CH ₃ or CO;

F is O, CH ₂ , CHOH or CO;

R ⁵ is hydrogen, chloro or cyano;

R ⁷ is hydrogen or methyl;

Z is O, NH or S;

R ⁶ is chloro, fluoro, methyl, trifluoromethyl or methoxy;

이고;L is

ego;

Ring Q is

ego;

'M' is 1 or 2;

'N' is specifically provided for compounds of formula (I) wherein 0, 1 or 2.

According to one embodiment, specifically provided are compounds of the formula (I) which have an IC ₅₀ value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM with respect to MAP4K1 inhibition.

Compounds of the present invention include the compounds in Examples 1-261. It is to be understood that Formula (I) structurally encompasses all geometric isomers, stereoisomers, enantiomers and diastereomers, N-oxides, and pharmaceutically acceptable salts that may be considered from the compound structures of the types described herein. .

The present application also provides a pharmaceutical composition comprising at least one compound described herein and at least one pharmaceutically acceptable excipient (eg, a pharmaceutically acceptable carrier or diluent). Preferably the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compounds described herein may be associated with pharmaceutically acceptable excipients (such as carriers or diluents), or may be diluted in carriers, or enclosed in carriers which may be in the form of tablets, capsules, sachets, paper or other containers. Can be.

It is obvious that the dosages used to practice the invention will vary depending, for example, on the particular disease or condition to be treated, the specific compound used, the mode of administration and the desired therapy. The compound may be administered by any suitable route including oral, parenteral, transdermal or inhalation. In general, it is indicated that satisfactory results are obtained upon oral administration, for example, in dosages of about 0.01 to 2.0 mg / kg for the treatment of diseases as described above. Thus, in large mammals, such as humans, the indicated daily dosage for oral administration is about 0.75 to 300 mg, which is administered once for convenience in daily or sustained release form or divided into two to four divided doses. Thus, the unit dosage form for oral administration is, for example, about 0.2 to 75 or 150 mg or 300 mg, for example about 0.2 or 2.0 to 10, 25, 50, 75, 100, 150, 200 or 300 mg of a compound described herein may be included with its pharmaceutically acceptable diluent or carrier.

Pharmaceutical compositions comprising the compounds of the present invention may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus, oral dosage forms may include tablets, capsules, solutions, suspensions, and the like.

Justice

The term "halogen" or "halo" means fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).

The term "alkyl" does not contain unsaturation and hydrocarbons containing only carbon and hydrogen atoms in the main chain having 1 to 8 carbon atoms (ie, C _1-8 alkyl) and attached to the rest of the molecule by a single bond Chain radicals such as but not limited to methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and 1,1-dimethylethyl (t-butyl), The term "C _1-6 Alkyl "refers to an alkyl chain having 1 to 6 carbon atoms. The term" C _1-4 alkyl "refers to an alkyl chain having 1 to 4 carbon atoms. Unless otherwise stated or cited, herein All alkyl groups described or claimed may be straight chain or branched.

The term "alkoxy" refers to an alkyl group (ie, C _1-8 alkoxy) attached to the rest of the molecule via an oxygen bond. Representative examples of such groups are -OCH ₃ and -OC ₂ H ₅ . Unless stated or recited, all alkoxy groups described or claimed herein may be straight chained or branched.

The term "alkoxyalkyl" or "alkyloxyalkyl" refers to an alkoxy or alkyloxy group as defined above (ie, C _1-8 alkoxy C _1-8 alkyl or C _1- directly bonded to an alkyl group as defined above). ₈ alkyloxy C _1-8 alkyl). Examples of such alkoxyalkyl moieties include, but are not limited to, -CH ₂ OCH ₃ (methoxymethyl) and -CH ₂ OC ₂ H ₅ (ethoxymethyl). Unless stated or recited, all alkoxyalkyl groups described herein may be straight chained or branched.

The term “haloalkyl” refers to at least one halo group (selected from F, Cl, Br or I) (ie halo C _1-8 alkyl) linked to an alkyl group as defined above. Examples of such haloalkyl moieties include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. The term “halo C _1-4 alkyl” refers to an alkyl chain having 1 to 4 carbon atoms and at least one halo group linked thereto. Unless stated or recited, all haloalkyl groups described herein may be straight chained or branched.

The term “haloalkoxy” refers to an alkoxy group substituted with one or more halogen atoms (ie halo C _1-8 alkoxy). Examples of "haloalkoxy" include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorometh Methoxy, trichloromethoxy and 1-bromoethoxy. Unless stated or recited, all haloalkoxy groups described herein may be straight chained or branched.

The term “hydroxy C _1-8 alkyl” refers to a C _1-8 alkyl group as defined above (ie hydroxy C _1-4 alkyl) in which one to three hydrogen atoms on different carbon atoms are replaced with hydroxyl groups. Refers to. Examples of hydroxy C _1-4 alkyl residues include, but are not limited to, -CH ₂ OH and -C ₂ H ₄ OH.

The term “cyanoalkyl” refers to an alkyl group as defined above (ie cyano C _1-8 alkyl) directly bonded to a cyano group. Examples of such cyano C _1-8 alkyl residues include, but are not limited to, cyanomethyl, cyanoethyl, and cyanoisopropyl. Unless stated or recited, all cyanoalkyl groups described herein may be straight chained or branched.

The term "cyanohaloalkyl" refers to a cyanoalkyl group substituted with one or more halogen atoms (ie, cyanohalo C _1-8 alkyl). Examples of cyanohaloalkyl include but are not limited to cyanodifluoromethyl. Unless stated or recited, all cyanohaloalkyl groups described herein may be straight chained or branched.

The term "cycloalkyl" refers to a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms (ie, C _3-12 cycloalkyl). Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include perhydronaphthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups such as spiro (4,4) non-2 Includes, but is not limited to: The term "C _3-6 cycloalkyl" refers to a cyclic ring having 3 to 6 carbon atoms. Examples of "C _3-6 cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term “cycloalkylalkyl” refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to an alkyl group (ie, C _3-6 cycloalkyl C _1-8 alkyl). The cycloalkylalkyl group can be attached to the main structure at any carbon atom of the alkyl group such that a stable structure is formed. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl and cyclopentylethyl.

The term "cyanocycloalkyl" refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to a cyano group (ie, "cyano C _3-6 cycloalkyl"). Non-limiting examples of such groups include cyanocyclopropane.

The term "aryl" refers to aromatic radicals having 6 to 14 carbon atoms (ie, C _6-14 aryl), including monocyclic, bicyclic and tricyclic aromatic systems, for example phenyl, naphthyl, tetrahydro Naphthyl, indanyl and biphenyl.

Unless stated otherwise, the term "heterocyclic ring" or "heterocyclyl" refers to a substituted or unsubstituted non-aromatic 3 to 3 consisting of carbon atoms and 1 to 5 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. 15-membered ring radical (ie, 3-15 membered heterocyclyl). The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include a fused, bridged or spiro ring system, and the nitrogen, phosphorus, carbon, oxygen of the heterocyclic ring radical Or sulfur atoms may optionally be oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; In addition, unless otherwise defined by the definition, the heterocyclic ring or heterocyclyl may optionally contain one or more olefin bond (s). Examples of such heterocyclic ring radicals include azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphosphonyl, decahydroisoquinolyl, indanyl, indolinyl , Isoindolinyl, isochromenyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopy Lolidinyl, 2-oxoazinyl, octahydroindolyl, octahydroisoindolyl, perhydroazinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenthiazinyl, phenoxa Genyl, quinuclidinyl, tetrahydroquinquinyl, tetrahydrofuryl or tetrahydrofuranyl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamopolyyl, thiamopolyyl sulfoxide and thiamopolyyl Including but not limited to sulfones It is not. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom such that a stable structure is formed.

The term “heterocyclylalkyl” refers to a heterocyclic ring radical (ie, 3 to 15 membered heterocyclyl C _1-8 alkyl) directly bonded to an alkyl group. The 20 heterocyclylalkyl radical may be attached to the main structure at any carbon atom of the alkyl group such that a stable structure is formed.

Unless otherwise specified, the term “heteroaryl” refers to a 5-14 membered aromatic heterocyclic ring radical having one or more heteroatom (s) independently selected from N, O or S (ie, 5-14 membered Heteroaryl). The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom, such that a stable structure is formed. Examples of such heteroaryl ring radicals are oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindoleyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadizolyl, thiazolyl, Isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, qui Nolinyl, isoquinolinyl, quinazolinyl, cynolinyl, naphthyridinyl, pterridinyl, furinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolinyl, arc Include, but are not limited to, ridinyl, phenazinyl, and phthalazinyl.

The term "pharmaceutically acceptable salts" includes salts prepared from pharmaceutically acceptable bases or acids, including inorganic or organic bases and inorganic or organic acids. Examples of such salts are acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edicyl Elate, estoleate, ecylate, fumarate, glutceptate, gluconate, glutamate, glycolylarsanylate, hexyl resornate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide Id, isothionate, lactate, lactobionate, laurate, maleate, maleate, mandelate, mesylate, methyl bromide, methylnitrate, methylsulfate, no mate, lead sillate, nitrate, N-methyl Glucamine Ammonium Salt, Oleate, Oxalate, Pamoate (M ), Palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theocate, tosylate, Triethiodide and valerate, including but not limited to. Examples of salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, mangamous, potassium, sodium and zinc, However, the present invention is not limited thereto.

The term “treating” or “treatment” of a condition, disorder or symptom includes: (a) a condition, disorder or symptom that has not yet experienced or exhibited clinical or subclinical signs of the condition, disorder or symptom. Preventing or delaying the appearance of clinical signs of a condition, disorder or symptom arising in a subject that may or may be susceptible, (b) inhibiting the condition, disorder or symptom, ie the disease or at least one of said diseases Stopping or reducing the onset of clinical or subclinical signs of; Or (c) alleviate the disease, i.e. cause regression of at least one of the condition, disorder or symptom or clinical or subclinical signs thereof.

The term "subject" includes mammals (especially humans) and other animals, such as livestock (e.g. pets, including cats and dogs) and non-animal animals (e.g., wild animals).

A "therapeutically effective amount" means an amount of a compound that is sufficient to achieve such treatment when administered to a subject to treat a condition, disorder or condition. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity, and the age, weight, physical symptoms and responsiveness of the subject to be treated.

Compounds of formula (I) may contain asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of formula (I) as well as their mixtures, including racemic mixtures, are intended to form part of the present invention. In addition, the present invention encompasses all geometric and positional isomers. Diastereomeric mixtures can be separated into individual diastereomers on the basis of physicochemical differences by methods well known to those skilled in the art, for example by chromatography and / or fractional crystallization. Enantiomers convert the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral adjuvant such as chiral alcohol or Mosher acid chloride), separate the diastereoisomer, and Individual diastereomers can be separated by conversion (eg hydrolysis) into the corresponding pure enantiomers. Enantiomers can also be separated by the use of chiral HPLC columns. The chiral center of the present invention may have an S or R configuration defined by IUPAC 1974.

The terms “salt” or “solvate” and the like refer to enantiomers, stereoisomers, rotamers, tautomers, positional isomers or salts, solvates and prodrugs of the compounds of the invention. It is intended to apply equally to

Pharmaceutical composition

Compounds of the invention are typically administered in the form of pharmaceutical compositions. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention. The pharmaceutical compositions described herein comprise one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, the pharmaceutically acceptable excipient is approved by regulatory authorities or generally considered safe for human or animal use. Such pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, lubricants and lubricants, preservatives, buffers, chelating agents, polymers, gelling agents, viscosity agents, solvents, and the like.

Examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin Agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters and polyoxyethylene.

The pharmaceutical compositions described herein may also include one or more pharmaceutically acceptable adjuvants, wetting agents, suspending agents, preservatives, buffers, sweetening agents, flavoring agents, coloring agents or any combination thereof.

The pharmaceutical composition may be in conventional form, eg, capsules, tablets, solutions, suspensions, injections or products for topical application. In addition, the pharmaceutical compositions of the present invention may be formulated to provide the desired release profile.

Administration of the compounds of the present invention in neat form or in a suitable pharmaceutical composition can be carried out using any of the accepted routes of administration of such compounds or pharmaceutical compositions. The route of administration may be any route that effectively transports the active compound of the present patent application to an appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular and topical.

Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.

Liquid formulations include, but are not limited to, syrups, emulsions and sterile injectable solutions, such as suspensions or solutions.

Topical dosage forms of the compounds include, but are not limited to, ointments, pastes, creams, lotions, powders, solutions, eye drops or ear drops, impregnated dressings, and suitable conventional additives such as preservatives, solvents to aid drug penetration. It may contain.

Suitable dosages of the compounds for use in the treatment of the diseases and disorders described herein can be determined by one of ordinary skill in the art. Therapeutic dosages are generally identified through dose range studies in humans based on preliminary evidence derived from animal studies. The dosage should be sufficient to generate the desired therapeutic benefit without causing unwanted side effects. Modes of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art.

How to treat

Compounds of formula (I) as described herein are very effective inhibitors of MAP4K1 kinase and give rise to inhibition at nanomolar concentrations. Thus, the MAP4K1 inhibitor according to the present invention is useful for the treatment and prevention of diseases associated with protein kinase signaling dysfunction. Thus, without being bound by any theory, it is believed that inhibition of MAP4K1 can reverse or prevent, for example, cellular dysfunction associated with perturbation of JNK signaling pathways, particularly in T and B cells. Therefore, administration of a MAP4K1 inhibitor as described herein may provide a potential means of modulating the MAPK signaling pathway, particularly the JNK pathway, and furthermore, autoimmune, neurodegenerative, neurological, inflammatory, hyperproliferative and cardiovascular disease And treatment for various diseases and disorders, including disorders.

In addition, without being bound by theory, selective MAP4K1 inhibition as provided by the compounds of the present invention may provide new means of treating cancer. Traditional signal transduction strategies involve interference of pathways that promote tumor cell proliferation or metastasis. Rather, the present invention provides a means of enhancing the activity and effectiveness of T cells in the body, for example to overcome the immunosuppressive strategies employed by many cancers. The US Food and Drug Administration (FDA) has determined that some monoclonal antibody-based therapies (eg, Ipilimumab and Pemb, respectively) achieve the same result by interfering with T-cell surface receptors that promote inhibition of TCR activity. Anti-CTLA-4 and anti-PD-1 antibodies sold commercially as rolizumab (Pembrolizumab). The success of this treatment demonstrates the proof of concept that cancer can be effectively treated by interfering with pathways that inhibit TCR signaling. Targeting these routes using small molecule inhibitors of MAP4K1 should produce improved results using more patient-friendly dosing techniques.

Therefore, in a third aspect, the invention encompasses the JNK route comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as described herein in free or pharmaceutically acceptable salt form To treat or prevent diseases or disorders that may be ameliorated by modulating (eg, inhibiting) MAP4K1-dependent signaling pathways, such as autoimmune, neurodegenerative, neurological, inflammatory, hyperproliferative and cardiovascular diseases and disorders. Provide a method.

In certain embodiments, administration of a compound of Formula (I) results in enhanced T cell receptor (TCR) signaling, such as resulting in an enhanced T cell-mediated immune response (eg, increased T cell cytokine production). .

In certain other embodiments, administration of a compound of Formula (I) results in increased T cell resistance to PGE2-mediated T cell inhibition.

Such diseases or disorders include neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease; Stroke and related memory loss; Autoimmune diseases such as arthritis; Allergies and asthma; Diabetes, in particular insulin-resistant diabetes; Other conditions characterized by inflammation, including chronic inflammatory diseases; Liver ischemia; Reperfusion injury; Deafness or hearing impairment; Neural tube birth defects; obesity; Hyperproliferative disorders, including malignant tumors such as leukemia, for example chronic myeloid leukemia (CML); Oxidative damage to organs such as the liver and kidneys; heart disease; And transplant rejection. In certain embodiments, the disease or disorder to be treated may also be associated with impaired MAP4K1-dependent signaling. Impaired MAP4K1 signaling may lead to a decrease in the function of immune cells, such as T and B cells, which may allow or increase early cancer cells to deviate from immune surveillance. Therefore, restoration of T and B cell function through treatment with K1-inhibitors may promote the removal of carcinogenic and pre-carcinogenic cells from the body. Thus, in certain embodiments, the invention relates to melanoma, thyroid cancer, adenocarcinoma, breast cancer, central nervous system cancers such as glioblastoma, astrocytoma and edema, colorectal cancer, squamous cell carcinoma, small cell and non-small cell lung cancer, ovarian cancer Provided are methods for the treatment or prevention of hyperproliferative diseases, such as cancer, including endometrial cancer, pancreatic cancer, prostate cancer, sarcoma, and skin cancer. In certain embodiments, due to the unique role of immune cell dysfunction in blood cancer, The present invention provides a method of treating or preventing hematological cancers such as leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome, chronic myelogenous leukemia (CML), Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryogenic leukemia and multiple myeloma To provide.

The MAP4K1 inhibitor compounds described herein for the treatment or prevention of a disease or disorder according to the methods described above can be used as a single therapeutic agent or in combination with one or more other therapeutic agents useful for the treatment of the disease or disorder. Such other agents include inhibitors of other protein kinases in the JNK pathway, including, for example, inhibitors of JNK (eg JNK1 or JNK2), MKK4, MKK7, p38, MEKK (eg MEKK1, MEKK2, MEKK5) and GCK.

Therefore, in certain embodiments, the MAP4K1 inhibitors of the invention can be administered in combination with inhibitors of JNK (eg, JNK1 or JNK2), MKK4, MKK7, p38, MEKK (eg, MEKK1, MEKK2, MEKK5) and GCK.

In another aspect, the present invention provides:

(i) a compound of formula (I) as described herein in free or pharmaceutically acceptable salt form for use in any method as set forth herein or in the treatment or prevention of any disease or disorder,

(ii) a MAP4K1 inhibitor of the invention in free or pharmaceutically acceptable salt form, for example a compound of Formula I as described herein and a second therapeutic agent useful for the treatment or prevention of any disease or disorder presented herein Combinations as described above comprising;

(iii) the use (in the manufacture of a medicament) of a compound of formula (I) in free or pharmaceutically acceptable salt form, or a combination described herein, for the treatment or prevention of any disease or condition as presented herein,

(iv) a compound of formula I in the form of a free or pharmaceutically acceptable salt as described above for use in the treatment or prevention of any disease or condition as set forth herein, the combinations described herein or the pharmaceutical of the invention Composition.

Overall manufacturing method

Compounds described herein, including compounds of Formula (I), intermediates and certain examples, are prepared via synthetic methods as depicted in Schemes 1-14. In addition, in the following schemes in which specific acids, bases, reagents, coupling reagents, solvents, and the like are mentioned, other suitable acids, bases, reagents, coupling reagents, solvents, and the like can be used and are understood to be within the scope of the present invention. . Modifications to reaction conditions, such as temperature, reaction duration or combinations thereof, are envisioned as part of the present invention. Compounds obtained using the overall reaction sequence may have insufficient purity. These compounds can be purified using any method for purification of organic compounds known to those skilled in the art, for example crystallization or alumina column chromatography using silica gel or different solvents in suitable ratios. All possible geometric isomers and stereoisomers are contemplated within the scope of the present invention.

General Schemes

The overall approach for the preparation of compounds of formula (Ia) wherein R ⁵ , R ⁶ , R ⁷ , A, E, F, D, Z, Q and n are as defined in the general description is given in Synthesis Scheme 1 Depicted in

Synthetic Scheme 1

Substitution reactions of the compound of formula (1), wherein R ′ = Me or Et, with a halogen containing compound of formula (2) in the presence of a suitable reagent and solvent result in a compound of formula (3). The reaction can be carried out in the presence of a suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride and the like, the solvent being selected from DMF, DMSO, acetonitrile, 1,4-dioxane or mixtures thereof. Can be. The reaction is also carried out in the presence of palladium acetate and suitable hindered ligands (e.g. XPhos, di-tBuXPhos, JohnPhos, DavePhos, Sphos, etc.) as catalysts, toluene, 1,4-dioxane, water or mixtures thereof In a suitable solvent such as tripotassium phosphate, sodium or potassium tert-butoxide, cesium carbonate, and the like, by a Buchwald reaction. (Angew. Chem. Int. Ed. 2006, 45, 4321). The coupling reaction of the ester of formula (3) with the amine of formula (4) in the presence of a suitable reagent and solvent provides a compound of formula (la). Suitable bases used in the reaction may be potassium tert-butoxide or trimethyl aluminum solution. The coupling reaction can be carried out in a suitable solvent or mixtures thereof. The suitable solvent can be selected from dichloromethane, THF, toluene or combinations thereof. Alternatively, the coupling reaction of the compound of formula (1) with the amine of formula (4) gives the amide of formula (5), which in turn is replaced by a substitution reaction with the compound of formula (2) The compound of I) is provided.

Compounds of formula (IIa), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, F, Z, Q and n are as defined in the general description) (and P = Boc Or a general approach for the preparation of protecting groups such as PMB) is described in Synthesis 2.

Synthetic Scheme 2

Substitution reactions of compounds of formula (1) with R '= Me or Et, in the presence of suitable reagents and solvents, with a halogen-containing compound of formula (6) give a compound of formula (7). The reaction can be carried out in the presence of a suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride and the like, the solvent being selected from DMF, DMSO, acetonitrile, 1,4-dioxane or mixtures thereof. Can be. The reaction is also carried out in the presence of palladium acetate and suitable hindered ligands (e.g. XPhos, di-tBuXPhos, JohnPhos, DavePhos, Sphos, etc.) as catalysts in suitable solvents such as toluene, 1,4-dioxane, water or mixtures thereof. Under a suitable base such as tripotassium phosphate, sodium or potassium tert-butoxide, cesium carbonate and the like. The coupling reaction of the ester of formula (7) with the amine of formula (4) in the presence of suitable reagents and solvents directly provides the deprotected final compound of formula (IIa). Suitable bases used in the reaction may be potassium tert-butoxide or trimethyl aluminum solution. The coupling reaction can be carried out in a suitable solvent or mixtures thereof. The suitable solvent can be selected from dichloromethane, THF, toluene or combinations thereof. Alternatively, the coupling reaction of the compound of formula (1) with the amine of formula (4) provides an amide of formula (5), which is substituted by deprotection followed by deprotection It provides a compound of (IIa). Reaction conditions for an alternative sequence can be maintained the same as described in Synthesis 1. The deprotection reaction can be carried out using hydrochloric acid or trifluoroacetic acid in a suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane and the like.

A general approach for the preparation of compounds of formula (IIb), wherein R ⁵ , R ⁶ , R ⁷ , A, E, F, D and n are as defined in the general description, is depicted in Synthesis 3 .

Synthesis Scheme 3

The benzoic acid derivative of formula (8) in the coupling reaction with ethyl 2- (3-aminophenyl) -2,2-difluoroacetate (9) produces an amide derivative of formula (10). The reaction can be carried out using oxalyl chloride or thionyl chloride via acid chloride formation followed by coupling with an amine in the presence of a suitable base and solvent. Suitable bases for the reaction can be triethylamine, N, N-diisopropylethylamine, pyridine or DMAP and the solvent can be selected from THF, chloroform, dichloromethane or 1,4-dioxane. Reductive amination and deprotection of the compound of formula (10) using an ammonia solution in methanol at elevated temperature (above 50 ° C.) affords the compound of formula (11). Compound of formula (11) is substituted with halogen derivative (2) to produce compound of formula (12). The reaction can be carried out in the presence of a suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride and the like; The solvent may be selected from DMF, DMSO, acetonitrile, 1,4-dioxane or mixtures thereof. Amide groups of the compounds of formula (12) are converted to nitrile groups by reaction with Burges reagent to provide compounds of formula (IIb). The reaction can be carried out in a suitable solvent such as dichloromethane.

Of compounds of formulas (IIIa) and (IIIb), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, F, Z, Q and n are as defined in the general description The overall approach for production (also here R '= Me or Et and protecting groups such as P = Cbz, Boc or PMB) is described in Synthesis 4.

Synthetic Scheme 4

Upon reaction with the compound of formula (6) the amino phenolic compound of formula (13) produces a compound of formula (14). The reaction can be carried out in the presence of a suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride and the like; The solvent may be selected from DMF, DMSO, toluene, acetonitrile, 1,4-dioxane or mixtures thereof. The amine compound of formula (14) can be prepared by the stepwise reaction of triphosgene with the amine of formula (4) in THF; Deprotection then yields urea derivatives of formula (IIIa). The deprotection reaction can be carried out using hydrochloric acid or trifluoroacetic acid in a suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane and the like. Alternatively, compounds of formula (IIIa) can be synthesized by reaction of carbamate derivatives of amines (4 ') with compound (14) in the presence of a suitable base and solvent. Suitable bases for the reaction may be triethylamine, DIPEA, and the like, and the suitable solvent may be DMSO. Compounds of formula (IIIa) can also be synthesized by alternative reaction sequences starting from the Z-protected analog (13 ') of compound (13). Compounds of formula (13 ') include stepwise reaction of triphosgene with amines of formula (4) in THF; Z-deprotection then yields urea derivatives of formula (14 '). Upon reaction with the compound of formula (6), compound (14 ') produces a compound of formula (IIIa). The reaction conditions can be kept the same as discussed above.

Alternatively, the amine of formula (14) upon reaction with an acid compound of formula (4 ') produces an amide compound of formula (15). The coupling reaction can be carried out in the presence of a suitable coupling agent such as HATU, EDCI.HCl with or without HOBt, T3P or DCC. The reaction can be carried out in a suitable solvent selected from THF, dichloromethane, dichloroethane, chloroform, 1,4-dioxane or mixtures thereof. The compound of formula 16 produces a compound of formula (IIIb) upon deprotection. The deprotection reaction can be carried out using hydrochloric acid or trifluoroacetic acid in a suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane and the like.

Overall approach for compounds of formula (IIc), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, F, Q and n are as defined in the general description (also here R '= Me or Et; a protecting group such as P = Boc or PMB) is depicted in Synthesis 5.

Synthetic Scheme 5

The coupling reaction of the nitro ester of formula (16) with the amine of formula (4) in the presence of a suitable reagent and solvent provides the compound of formula (17). Suitable bases used in the reaction may be potassium tert-butoxide or trimethyl aluminum solution. The coupling reaction can be carried out in a suitable solvent or mixtures thereof. The suitable solvent can be selected from dichloromethane, THF, toluene or combinations thereof. The nitro reducing compound of formula (17) produces an amine of formula (18). The reaction can be carried out using iron powder in the presence of acetic acid or ammonium chloride in a suitable solvent such as methanol, ethanol, THF, water or mixtures thereof. Substitution of the compound of formula (18) with a halogen containing compound of formula (6) in the presence of a suitable reagent and solvent produces a compound of formula (19). The reaction can be carried out using the Buchwald coupling method in the presence of a suitable base, catalyst, ligand and solvent. The reaction can be carried out using a base such as sodium or potassium tert-butoxide, cesium or potassium carbonate and the like. Palladium acetate can be used as a catalyst with suitable ligands (eg XPhos, t-BuXPhos, JohnPhos) and suitable solvents can be selected from 1,4-dioxane, toluene, water or mixtures thereof. Compounds of formula (19) give compounds of formula (IIc) upon deprotection. The deprotection reaction can be carried out using hydrochloric acid or trifluoroacetic acid in a suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane and the like.

Compounds of formulas (IId) and (IIe), (IIf) and (IIg), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, Q and n are defined in the general description The overall approach (also protecting groups such as P = Boc or PMB) for the preparation of the same is shown in Synthesis 6.

Synthesis Scheme 6

Compounds of formula (5a) having phenolic hydroxyl groups produce ethers of formula (21) upon substitution by halogen containing compounds of formula (20). The reaction can be carried out in the presence of a suitable base and solvent. Suitable bases can be potassium carbonate, cesium carbonate, cesium fluoride and the like, and the suitable solvent can be DMF, DMSO, 1,4-dioxane and the like. Compounds of formula (21) provide compounds of formula (IId) upon N-deprotection. The deprotection reaction can be carried out using hydrochloric acid or trifluoroacetic acid in a suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane and the like.

Alternatively, the compound of formula (21) provides a hydroxyl derivative of formula (22) upon reaction with sodium borohydride in a suitable solvent. Suitable solvents for the reaction may be THF, methanol or mixtures thereof. Compound (22) provides a compound of Formula (IIf) by further reduction in the presence of trimethylsilane and trifluoroacetic acid, followed by N-deprotection. The deprotection reaction can be carried out using hydrochloric acid or trifluoroacetic acid in a suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane and the like.

Compounds of formula (IId) produce compounds of formula (IIe) upon reduction with sodium borohydride. Suitable solvents for the reaction may be THF, methanol or mixtures thereof. In another embodiment, the compound of formula (5a) in the presence of a base and a solvent provides the compound of formula (24) upon reaction with formyl derivative of formula (23). Suitable bases can be potassium carbonate, cesium carbonate, cesium fluoride and the like, and the suitable solvent can be DMF, DMSO, 1,4-dioxane and the like.

The reaction of the compound of formula (24) with a methylamine solution in the presence of a catalytic amount of acetic acid followed by N-deprotection gives the compound of formula (IIg). The deprotection reaction can be carried out using hydrochloric acid or trifluoroacetic acid in a suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane and the like.

The overall approach (also protecting groups such as P = Boc or PMB) for the preparation of compounds of formula (2a) wherein R ¹ , R ² , R ³ and R ⁴ are as defined in the general description is given in Synthesis 7 Depicted in

Synthetic Scheme 7

4,6-dichloro-5-methoxypyrimidine (25) produces a compound of formula (27) upon reaction with an appropriately substituted ethanolamine derivative of formula (26) in the presence of a suitable base and a solvent. Suitable bases for the reaction may be potassium carbonate and the solvent may be DMF or 1,4-dioxane. In order to cyclize the compound of formula (27) using boron tribromide in a suitable solvent such as THF, the compound of formula (28) or (29) or mixtures thereof is provided in various ratios, and they are in the presence of suitable bases and solvents Under reaction with an appropriate protective agent to give the compound of formula (2a). The N-protectant may be tert-butyl dicarbonate (Boc anhydride) or 4-methoxybenzylchloride (PMB-Cl). Suitable bases for the reaction can be triethylamine, DIPEA, DMAP or mixtures thereof and the solvent can be selected from THF, dichloromethane, 1,4-dioxane, DMF or mixtures thereof.

A general approach for the preparation of compounds of formula (2b), wherein R ³ and R ⁴ are as defined in the general description, is depicted in Synthesis 8.

Synthesis Scheme 8

Demethylation of 4,6-dichloro-5-methoxypyrimidine (25) with aluminum chloride in a suitable solvent such as dichloroethane gives 4,6-dichloropyrimidin-5-ol (30), which is When reacted with an appropriately substituted glycolate ester of formula (31) under conditions of Mitsunobu, the ethyloxy-ester of formula (32) is provided. The Mitsunobu reaction can be carried out in the presence of triphenylphosphine, diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) in THF as a solvent. Compounds of formula (32) provide cyclized compounds of formula (2b) upon reaction with 4-methoxybenzylamine (PMBA) at elevated temperatures (above 100 ° C.) in the presence of a suitable base and solvent. Suitable bases for the reaction can be triethylamine, DIPEA, DMAP or mixtures thereof, and the solvent can be selected from DMF, 1,4-dioxane, DMSO or mixtures thereof.

An overall approach (also protecting groups such as P = Boc or PMB) for the preparation of compounds of formula (2d), wherein R ¹ and R ² are as defined in the general description, is depicted in Synthesis 9.

Synthesis Scheme 9

4,6-dichloro-5-methoxypyrimidine (25) produces a compound of formula (27a) upon reaction with an appropriately substituted ethanolamine derivative of formula (26a) in the presence of a suitable base and a solvent. Suitable bases for the reaction may be potassium carbonate and the solvent may be DMF or 1,4-dioxane. Compounds of formula (33) are provided to cyclize compounds of formula (27a) with boron tribromide in a suitable solvent such as THF, which is N-protected with a suitable protecting agent in the presence of a suitable base and solvent to The compound of 34) is provided. The N-protectant may be tert-butyl dicarbonate (Boc anhydride) or 4-methoxybenzylchloride (PMB-Cl). Suitable bases for the reaction can be triethylamine, DIPEA, DMAP or mixtures thereof and the solvent can be selected from THF, dichloromethane, 1,4-dioxane, DMF or mixtures thereof. Compounds of formula (34) produce cyclized compounds of formula (2d) by a self-Mitsunobu reaction.

The overall approach for the preparation of compounds of formulas (2e) and (2f), wherein protecting groups such as P = Boc or PMB, is depicted in Synthesis 10.

Synthesis Scheme 10

Bromination of 2-aminopyridin-3-ol (35) with bromine in anhydrous ethanol yields the hydrobromide salt of 2-amino-4-bromopyridin-3-ol (36). Compound (36) is reacted with dibromoethane (37) at elevated temperature (> 50 ° C.) in the presence of a suitable base and solvent to 8-bromo-3,4-dihydro-2H-pyrido [3,2 -b] [1,4] oxazine (38) is produced. Suitable bases for the reaction may be potassium or cesium carbonate and the solvent may be selected from acetonitrile, dichloromethane, 1,4-dioxane, THF or mixtures thereof. Compound (38) provides a compound of Formula (2e) by N-protection with a suitable protecting agent in the presence of a suitable base and solvent. The N-protectant may be tert-butyl dicarbonate (Boc anhydride) or 4-methoxybenzylchloride (PMB-Cl). Suitable bases for the reaction may be LiHMDS, triethylamine, DIPEA, DMAP or mixtures thereof. The suitable solvent can be selected from THF, dichloromethane, 1,4-dioxane, DMF or mixtures thereof. Alternatively, 2-amino-4-bromopyridin-3-ol hydrobromide 36 is cyclized by chloroacetyl chloride 39 at elevated temperature (> 50 ° C.) in the presence of a suitable base solvent, 8- Bromo-2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one (40) is produced. Suitable bases for the reaction may be sodium bicarbonate and the solvent may be 2-butanone, water or mixtures thereof. Compound (40) is N-protected with a suitable protecting agent in the presence of a suitable base and solvent to provide a compound of formula (2f). The N-protectant may be tert-butyl dicarbonate (Boc anhydride) or 4-methoxybenzylchloride (PMB-Cl). Suitable bases for the reaction may be cesium carbonate and the solvent may be selected from THF, 1,4-dioxane, DMF or mixtures thereof.

The overall approach for the preparation of the compound of formula (2 g) is depicted in Synthesis 11.

Synthesis Scheme 11

4,6-Dichloropyrimidine-5-carbaldehyde (41) is reacted with vinylmagnesium chloride (42) in THF to 1- (4,6-dichloropyrimidin-5-yl) prop-2-ene- 1-ol (43), which provides 1- (4,6-dichloropyrimidin-5-yl) prop-2-en-1-one (43) by oxidation, wherein the oxidation reaction is It can be carried out using Des-Martin periodinane in dichloromethane. Compounds of formula (44) provide cyclized compounds of formula (2 g) by reaction with 4-methoxybenzylamine at elevated temperature (> 45 ° C.) in the presence of a suitable base (optional) and a solvent. Suitable bases for the reaction can be triethylamine, DIPEA, DMAP or mixtures thereof and the solvent can be selected from DMF, 1,4-dioxane, DMSO or mixtures thereof.

A general approach for the preparation of compounds of formula (1a), wherein R ⁶ and n are as defined in the general description, is depicted in Synthesis 12 and X is halogen.

Synthesis Scheme 12

Compounds of formula (45) produce compounds of formula (47) by reaction with benzyl alcohol (46) in the presence of a suitable base and solvent. Suitable bases for the reaction may be potassium tert-butoxide and the solvent may be DMSO. Compounds of formula (47) are esterified with sulfuric acid in methanol under reflux conditions to give compounds of formula (48), which are subject to palladium (5-10% palladium on carbon, 50% wet) catalyzed hydrogenation Thereby supplying the compound of formula (1a). The hydrogenation reaction can be carried out in a suitable solvent such as ethanol, methanol, ethyl acetate or combinations thereof. Alternatively, the benzoic acid of formula (49) provides the methyl ester of formula (1a) by esterification with sulfuric acid in methanol.

A general approach for the preparation of compounds of formula (1a), wherein R ⁶ and n are as defined in the general description, is depicted in Synthesis 13 and X is halogen.

Synthesis 13

The amino benzoic acid derivative of formula (50) is a thiophenol-benzoic acid of formula (52) by diazotization reaction with sodium nitrite and hydrochloric acid, followed by reaction with potassium ethyl xanthate (51) in the presence of a suitable base such as sodium bicarbonate. Will generate). Suitable solvent for this reaction is water. Benzoic acid of formula (52) provides the methyl ester of formula (1b) by esterification with sulfuric acid in methanol.

A general approach for the preparation of compounds of formula 4a, wherein R ⁸ and R ⁹ are as defined in the general description, is depicted in Synthesis 14.

Synthesis Scheme 14

Compound of formula (53), wherein "hal" = halogen, provides a compound of formula (55) upon reaction with a compound of formula (54). The reaction can be carried out in the presence of a suitable base and solvent. The suitable base may be sodium, potassium or cesium carbonate, sodium or potassium tert-butoxide, sodium hydride, cesium fluoride and the like. The solvent may be selected from THF, DMF, toluene, DMSO, chloroform, dichloromethane, acetonitrile, dichloroethane, 1,4-dioxane or mixtures thereof. Nitro reduction of compound (55) yields a compound of formula (4a). The reaction can be carried out using iron powder in the presence of acetic acid or ammonium chloride in a suitable solvent such as methanol, ethanol, THF, water or mixtures thereof. Nitro reduction may also be carried out by palladium (palladium on carbon 5-10%, 50% wet) catalyzed hydrogenation. The hydrogenation reaction can be carried out in a suitable solvent such as ethanol, methanol, ethyl acetate or a combination thereof.

Intermediate

Synthesis of Intermediate A

Intermediate A1

tert-butyl 4-chloro-6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate

Step 1 : 2-((6-chloro-5-methoxypyrimidin-4-yl) amino) ethanol

To a stirred solution of 4,6-dichloro-5-methoxypyrimidine (10 g, 55.8 mmol) in 1,4-dioxane (100 mL) ethanolamine (3.42 mL, 56.9 mmol) and potassium carbonate (9.26 g , 67.0 mmol) were added and the mixture was refluxed at 125 ° C for 8 h. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layers were separated and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to yield 10.5 g of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.44 (t, J = 5.6 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.72 (s, 3H), 4.80-4.85 (br s , 1H), 7.55 (s, 1 H), 8.04 (s, 1 H); ESI-MS (m / z) 204 (M + H) ⁺ .

Step 2 : 4-chloro-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazine

Mixture of 2-((6-chloro-5-methoxypyrimidin-4-yl) amino) ethanol (stage 1 intermediate) (6.0 g, 29.4 mmol) and boron tribromide in dichloromethane (1.0M, 100 mL) Was refluxed for 3-4 hours. The mixture was concentrated and the residue was diluted with water. The solution was neutralized with saturated sodium bicarbonate solution and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to yield 4.0 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.02 (t, J = 10.4 Hz, 2H), 4.66 (t, J = 10.0 Hz, 2H), 8.46 (s, 1H), 10.31 (br s, 1H ).

Step 3 : tert-Butyl 4-chloro-6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate

Stirring of 4-chloro-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazine (2-step intermediate) (4.0 g, 23.3 mmol) in dichloromethane (40 mL) Di-tert-butyl dicarbonate (Boc anhydride) (7.6 g, 34.9 mmol) was added to the prepared solution at 0 ° C., followed by triethylamine (9.7 mL), and the mixture was stirred at 0 ° C. for 3 hours. Then stirred at room temperature for 1 hour. DMAP (1.4 g, 11.6 mmol) was added to the reaction mixture in small portions at 0 ° C. and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was diluted with ice water mixture. The aqueous mixture was neutralized using sodium bicarbonate solution and the product was extracted in dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to yield 1.5 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.49 (s, 9H), 3.92 (t, J = 4.8 Hz, 2H), 4.12 (t, J = 4.4 Hz, 2H), 8.31 (s, 1H) .

Intermediate A2

4-chloro-8- (4-methoxybenzyl) -6H-pyrimido [5,4-b] [1,4] oxazin-7 (8H) -one

Step 1 : 4,6-dichloropyrimidin-5-ol

A suspension of 4,6-dichloro-5-methoxypyrimidine (2.0 g, 11.2 mmol) and aluminum chloride (2.0 g, 15.0 mmol) in DCE (10 mL) was heated to reflux for 3-4 hours. The mixture was concentrated under reduced pressure, cooled to 0 ° C. and quenched with ice water. The mixture was diluted with 1M HCl (10 mL). The precipitated solid was filtered off and dried well to yield 1.0 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (s, 1H), 11.67 (br s, 1H).

Step 2 : ethyl 2-((4,6-dichloropyrimidin-5-yl) oxy) acetate

4,6-dichloropyrimidin-5-ol (stage 1 intermediate) (4.0 g, 24.2 mmol) in THF (40 mL), ethyl glycolate (3.02 g, 29.1 mmol) and triphenylphosphine (12.7 g, 48.5 mmol) was slowly added diethyl azodicarboxylate (DEAD) (9.8 g, 48.5 mmol) at room temperature. The mixture was stirred at rt overnight. The mixture was diluted with diethyl ether and the precipitated solid was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield 450 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.34 (t, J = 7.2 Hz, 3H), 4.31 (q, J = 7.2 Hz, 2H), 4.80 (s, 2H), 8.51 (s, 1H) .

Step 3 : 4-chloro-8- (4-methoxybenzyl) -6H-pyrimido [5,4-b] [1,4] oxazin-7 (8H) -one

4-methoxybenzylamine (818 mg) in a solution of ethyl 2-((4,6-dichloropyrimidin-5-yl) oxy) acetate (2 step intermediate) (1.0 g, 3.98 mmol) in DMF (10 mL) , 5.97 mmol) was added, followed by DIPEA (513 g, 3.98 mmol) at 0 ° C. The mixture was stirred at rt overnight and at 130 ° C. for 1 h. The mixture was cooled and quenched with water. The aqueous mixture was extracted twice with dichloromethane. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue was purified by silica gel column chromatography to yield 660 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.71 (s, 3H), 5.05 (s, 2H), 5.12 (s, 2H), 6.86 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 8.44 (s, 1H).

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 1 below.

Intermediate A3

(S) -tert-butyl 4-chloro-6-methyl-6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate

Step 1 : (S) -1-((6-chloro-5-methoxypyrimidin-4-yl) amino) propan-2-ol

To a stirred solution of 4,6-dichloro-5-methoxypyrimidine (5.0 g, 27.9 mmol) in 1,4-dioxane (50 mL) was added potassium carbonate (4.6 g, 33.5 mmol) followed by (S)- (+)-1-Amino-2-propanol (2.3 g, 30.7 mmol) was added at room temperature. The resulting mixture was stirred at 125 ° C. for 8 hours. The mixture was cooled to rt and diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated to yield 4.85 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.05 (d, J = 6.4 Hz, 3H), 3.28-3.34 (m, 2H), 3.73 (s, 3H), 3.78-3.87 (m, 1H), 4.77 (d, J = 4.8 Hz, 1H), 7.46 (t, J = 5.6 Hz, 1H), 8.04 (s, 1H); ESI-MS (m / z) 218 (M + H) ⁺ .

Step 2 : (S) -4-((2-bromopropyl) amino) -6-chloropyrimidin-5-ol

(S) -1-((6-chloro-5-methoxypyrimidin-4-yl) amino) propan-2-ol (stage 1 intermediate) (4.8 g, 22.1 mmol) and boron tribromide (in dichloromethane 1M, 25 mL) was heated at 80 ° C for 18 h. The solvent was removed under reduced pressure and the residue was quenched with ice water. The aqueous solution was neutralized with sodium bicarbonate and extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to yield 3.9 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.63 (d, J = 6.4 Hz, 3H), 3.58-3.64 (m, 1H), 3.72-3.79 (m, 1H), 4.39-4.47 (m, 1H ), 7.48 (t, J = 5.6 Hz, 1H), 7.86 (s, 1H), 9.99 (br s, 1H).

Step 3 : (S) -tert-butyl 4-chloro-6-methyl-6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate

(S) -4-((2-bromopropyl) amino) -6-chloropyrimidine in the presence of DMAP (296 mg, 2.48 mmol) in dichloromethane (10 mL) according to the procedure described in step 3 of intermediate A1. The title compound was prepared by reaction of -5-ol (2 step intermediate) (500 mg, 2.69 mmol) with di-tert-butyl dicarbonate (881 mg, 4.84 mmol) to afford about 154 mg of the compound. . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.50 (s, 9H), 1.63 (d, J = 6.8 Hz, 3H), 3.57-3.63 (m, 1H), 3.75-3.81 (m, 1H), 4.39 (q, J = 6.8 Hz, 1 H), 8.27-8.33 (m, 1 H); ESI-MS (m / z) 285 (M) ⁺ .

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 2 below.

Intermediate A4

tert-butyl 4-chloro-7,7-dimethyl-6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate

Step 1 : 2-((6-chloro-5-methoxypyrimidin-4-yl) amino) -2-methylpropan-1-ol

To a stirred solution of 4,6-dichloro-5-methoxypyrimidine (5.0 g, 27.9 mmol) in 1,4-dioxane (50 mL) was added potassium carbonate (4.6 g, 33.5 mmol) followed by 2-amino- 2-methylpropanol (2.71 mL, 28.4 mmol) was added at room temperature. The resulting mixture was stirred at 125 ° C. for 8 hours. The mixture was cooled to rt and diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated to yield 3.5 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.37 (s, 6H), 3.50 (d, J = 5.6 Hz, 2H), 3.74 (s, 3H), 5.10 (t, J = 6.0 Hz, 1H) , 6.30 (s, 1 H), 8.06 (s, 1 H).

Step 2 : 4-chloro-6-((1-hydroxy-2-methylpropan-2-yl) amino) pyrimidin-5-ol

Of 2-((6-chloro-5-methoxypyrimidin-4-yl) amino) -2-methylpropan-1-ol (stage 1 intermediate) (3.5 g, 15.1 mmol) in dichloromethane (35 mL) To the solution boron tribromide (1M in THF, 75.8 mL) was added at 0 ° C. and the mixture was stirred at rt for 16 h. The reaction mixture was quenched with methanol at 0 ° C. and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to yield 2.5 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.36 (s, 6H), 3.48 (s, 2H), 5.13-5.15 (br s, 1H), 6.11 (s, 1H), 7.88 (s, 1H) ), 9.97 (s, 1 H).

Step 3 : tert-butyl (6-chloro-5-hydroxypyrimidin-4-yl) (1-hydroxy-2-methylpropan-2-yl) carbamate

Of 4-chloro-6-((1-hydroxy-2-methylpropan-2-yl) amino) pyrimidin-5-ol (2 step intermediate) (2.5 g, 11.4 mmol) in dichloromethane (25 mL) To the stirred solution was added di-tert-butyl dicarbonate (2.5 g, 11.4 mmol) at 0 ° C followed by triethylamine (2.4 mL, 17.1 mmol) and the mixture was stirred at rt for 15 h. The solvent was evaporated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography to yield 1.9 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.36 (br s, 6H), 1.50 (br s, 9H), 3.50 (d, J = 6.0 Hz, 2H), 5.06 (t, J = 10.0 Hz, 1H), 6.55 (s, 1 H), 8.20 (s, 1 H).

Step 4 : tert-Butyl 4-chloro-7,7-dimethyl-6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate

Tert-butyl (6-chloro-5-hydroxypyrimidin-4-yl) (1-hydroxy-2-methylpropan-2-yl) carbamate (3-step intermediate) in anhydrous THF (20 mL) (1.9 g, 5.97 mmol) was added triphenylphosphine (1.88 g, 7.18 mmol) and diisopropyl azodicarboxylate (DIAD) (1.39 mL, 7.17 mmol) at 0 ° C. under a nitrogen atmosphere. The mixture was stirred at 0 ° C for 1 h. The solvent was evaporated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography to yield 350 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.36 (s, 6H), 1.51 (s, 9H), 4.13 (s, 2H), 8.19 (s, 1H); ESI-MS (m / z) 300 (M + H) ⁺ .

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 3 below.

Table 3 : Compound Names, Structural Formulas and Analytical Data of Intermediates A5-A6 and A11-A14

Intermediate A7

tert-butyl 8-bromo-2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate

Step 1 : 2-amino-4-bromopyridin-3-ol hydrobromide

Bromine (64 mL, 818 mmol) is added dropwise to a solution of 2-aminopyridin-3-ol (45 g, 409 mmol) in anhydrous ethanol (225 mL) at 0-10 ° C. and the mixture is stirred at room temperature for 3 days. It was. The solvent was removed under reduced pressure at low temperature and the residue was cooled to 0 ° C. Ethyl acetate was added to the residue and stirred for 1 hour. The solid was filtered and dried well to yield 48 g of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.94 (br s, 2H), 6.65 (d, J = 5.6 Hz, 1H), 7.23 (d, J = 5.6 Hz, 1H).

Step 2 : 8-bromo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine

To a solution of 2-amino-4-bromopyridin-3-ol hydrobromide (one step intermediate) (15 g, 58.6 mmol) in acetonitrile (150 mL) cesium carbonate (57.1 g, 175 mmol) followed by 1, 2-dibromoethane (16.4 g, 87.7 mmol) was added and the mixture was refluxed for 48 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 3.0 g of the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.33-3.43 (m, 2H), 4.13-4.20 (m, 2H), 6.71 (d, J = 5.2 Hz, 1H), 7.02 (s, 1H), 7.40 (d, J = 5.2 Hz, 1 H); ESI-MS (m / z) 215 (M + H) ⁺ .

Step 3 : tert-Butyl 8-bromo-2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate

Solution of 8-bromo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxa (2-step intermediate) (2.1 g, 9.76 mmol) in dry THF (20 mL) To lithium bis (trimethylsilyl) amide (LiHMDS) (1 M, 11.6 mL, 11.7 mmol) was added dropwise di-tert-butyl dicarbonate (3.3 mL, 14.6 mmol) at 0 ° C. and the mixture at 1 at the same temperature. Stir for hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography to yield 2.4 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.46 (s, 9H), 3.86 (d, J = 4.4 Hz, 2H), 4.35 (d, J = 4.4 Hz, 2H), 7.38 (d, J = 5.2 Hz, 1H), 7.81 (d, J = 5.2 Hz, 1H); ESI-MS (m / z) 316 (M + H) ⁺ .

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 4 below.

Intermediate A8

8-bromo-4- (4-methoxybenzyl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one

Stage 1 : 8-bromo-2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one

Sodium bicarbonate in a solution of 2-amino-4-bromopyridin-3-ol hydrobromide (stage 1-intermediate A7) (12 g, 63.4 mmol) in a mixture of 2-butanone and water (1: 1, 120 mL) An aqueous solution of (16 g, 190 mmol) was added at 0 ° C and the mixture was stirred for 10 minutes. Chloroacetyl chloride (7.16 g, 63.4 mmol) was added to the mixture and stirred at 0 ° C for 3-4 h. The mixture was then heated to 80 ° C. and stirred for 10 hours. The mixture was cooled to rt and extracted twice with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue thus obtained was purified by silica gel column chromatography to yield 2.5 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.77 (s, 2H), 7.26 (d, J = 5.2 Hz, 1H), 7.75 (d, J = 5.2 Hz, 1H), 11.44 (s, 1H) ; ESI-MS (m / z) 229 (M + H) ⁺ .

Step 2 : 8-bromo-4- (4-methoxybenzyl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one

Solution of 8-bromo-2H-pyrido in DMF (5.0 mL) [3,2-b] [1,4] oxazin-3 (4H) -one (stage 1 intermediate) (250 mg, 1.09 mmol) To the solution of cesium carbonate (709 mg, 2.18 mmol) was added followed by 4-methoxybenzyl chloride (256 mg, 1.63 mmol) and the mixture was stirred at rt for 3 h. The mixture was quenched with water and the product was extracted twice in ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 270 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.78 (s, 3H), 4.80 (s, 2H), 5.30 (s, 2H), 6.83 (d, J = 5.2 Hz, 2H), 7.16 (d, J = 5.2 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 5.2 Hz, 1H).

Intermediate A9

4-chloro-8- (4-methoxybenzyl) -7,8-dihydropyrido [2,3-d] pyrimidin-5 (6H) -one

Step 1 : 1- (4,6-dichloropyrimidin-5-yl) prop-2-en-1-ol

To a stirred solution of 4,6-dichloropyrimidine-5-carbaldehyde (10 g, 56.5 mmol) in anhydrous THF (100 mL) was slowly added vinylmagnesium chloride (1M, 67.6 mL, 67.8 mmol) at -20 ° C. The mixture was stirred at rt for 3 h. The reaction mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to yield 5.0 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.36-5.39 (m, 1H), 5.43 (s, 1H), 5.90-5.92 (br s, 1H), 6.15-6.23 (m, 1H), 8.73 ( s, 1 H).

Step 2 : 1- (4,6-dichloropyrimidin-5-yl) prop-2-en-1-one

To a stirred solution of 1- (4,6-dichloropyrimidin-5-yl) prop-2-en-1-ol (stage 1 intermediate) (100 mg, 0.49 mmol) in dichloromethane (5.0 mL) Des-Martin periodinan (415 mg, 0.97 mmol) was added at ° C and the mixture was stirred at rt overnight. The mixture was filtered through celite and the filtrate was washed with water. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to yield 20 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.10 (d, J = 17.6 Hz, 1H), 6.33 (d, J = 10.8 Hz, 1H), 6.62-6.69 (m, 1H), 8.89 (s 1H ).

Step 3 : 4-chloro-8- (4-methoxybenzyl) -7,8-dihydropyrido [2,3-d] pyrimidin-5 (6H) -one

To a solution of 1- (4,6-dichloropyrimidin-5-yl) prop-2-en-1-one (2-step intermediate) (1.1 g, 5.40 mmol) in DMF (28 mL) 4- at room temperature Methoxybenzylamine (1.1 g, 8.12 mmol) was added. The mixture was stirred at 50 ° C overnight. The mixture was cooled down and quenched with water. The aqueous mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue was purified by silica gel column chromatography to yield 900 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.29 (t, J = 6.0 Hz, 2H), 3.78-3.82 (m, 5H), 4.66 (d, J = 5.6 Hz, 2H), 6.89 (dd, J ₁ = 2.0 Hz, J ₂ = 6.8 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H), 8.38 (s, 1H).

Intermediate A18

(R) -tert-Butyl 4-chloro-7- (morpholinomethyl) -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate

Step 1 : (R) -methyl 2-((tert-butoxycarbonyl) amino) -3-((methylsulfonyl) oxy) propanoate

(R) -methyl 2-((tert-butoxycarbonyl) amino) -3-hydroxypropanoate (2.0 g, 9.13 mmol) in dichloromethane (20 mL) to a stirred solution DIPEA (3.9 mL, 22.8 mmol), and then methanesulfonyl chloride (mesyl chloride) (850 μl, 10.9 mmol) was added at 0 ° C. and the mixture was stirred at 0 ° C. for 1 hour. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with water, then brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to yield 2.95 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.41 (s, 9H), 3.20 (s, 3H), 3.67 (s, 3H), 4.35-4.45 (m, 3H), 7.53 (d, J = 8.0 Hz, 1H).

Step 2 : (R) -methyl 2-((tert-butoxycarbonyl) amino) -3-morpholinopropanoate

(R) -methyl 2-((tert-butoxycarbonyl) amino) -3-((methylsulfonyl) oxy) propanoate (one step intermediate) in dichloromethane (20 mL) (2.9 g, 9.76 mmol To a stirred solution of) was added morpholine (1.7 mL, 19.5 mmol) followed by N, N-diisopropylethylamine (DIPEA) (3.3 mL, 19.5 mmol) at 0 ° C. The mixture was stirred at rt for 18 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography to give 1.46 g of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.96 (t, J = 7.2 Hz, 3H), 2.28-2.51 (m, 10H), 3.72 (s, 2H), 8.09 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H), 8.51 (dd, J ₁ = 2.4 Hz, J ₂ = 8.8 Hz, 1H).

Step 3 : (R) -tert-butyl (1-hydroxy-3-morpholinopropan-2-yl) carbamate

DIBAL solution in a solution of (R) -methyl 2-((tert-butoxycarbonyl) amino) -3-morpholinopropanoate (2 step intermediate) (1.4 g, 4.86 mmol) in THF (15 mL) (1M in toluene, 19.4 mL, 19.4 mmol) was added at -78 ° C and the mixture was stirred at the same temperature for 2 hours. The reaction was quenched with brine and stirred for 1 hour. The solution was filtered and washed with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by column chromatography to give 1.2 g of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.38 (s, 9H), 2.20-2.38 (m, 6H), 3.52-3.60 (m, 6H), 4.60 (t, J = 5.6 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1 H), 8.32 (s, 1 H); ESI-MS (m / z) 260 (M + H) ⁺ .

Step 4 : (R) -tert-butyl (1-((4,6-dichloropyrimidin-5-yl) oxy) -3-morpholinopropan-2-yl) carbamate

(R) -tert-butyl (1-hydr) in the presence of DIAD (1.4 g, 6.92 mmol) and triphenylphosphine (1.8 g, 6.92 mmol) in THF (10 mL) according to the procedure described in step 2 of intermediate A2. Roxy-3-morpholinopropan-2-yl) carbamate (3 step intermediate) (1.2 g, 4.61 mmol) and 4,6-dichloropyrimidin-5-ol (1 step of intermediate A2) (912 mg, 5.51 mmol) gave the title compound to yield 2.96 g of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.18 (d, J = 6.0 Hz, 9H), 2.50-2.51 (m, 4H), 3.50-3.55 (m, 4H), 3.90-4.0 (m, 1H ), 4.09-4.13 (m, 1H), 4.21-4.23 (m, 1H), 4.74-4.80 (m, 2H), 8.32 (s, 1H); ESI-MS (m / z) 406 (M + H) ⁺ .

Step 5 : (R) -1-((4,6-dichloropyrimidin-5-yl) oxy) -3-morpholinopropan-2-amine hydrochloride

(R) -tert-butyl (1-((4,6-dichloropyrimidin-5-yl) oxy) -3-morpholinopropan-2-yl) carbamate in ethyl acetate (10 mL) (4 steps Intermediate) (2.9 g, 7.13 mmol) was added hydrochloric acid in 1,4-dioxane (4 M, 40 mL) and the mixture was stirred at rt for 3 h. The mixture was concentrated under reduced pressure to give 536 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.28-3.66 (m, 6H), 3.90-4.05 (m, 4H), 4.44-4.48 (m, 3H), 8.76 (s, 1H), 9.01 (br s, 3H).

Step 6 : (R) -4-chloro-7- (morpholinomethyl) -7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazine

(R) -1-((4,6-dichloropyrimidin-5-yl) oxy) -3-morpholinopropan-2-amine hydrochloride (5-step intermediate) in DMF (5.0 mL) (520 mg, 1.51 mmol) was added DIPEA (2.6 mL, 15.1 mmol) and the mixture was stirred at rt overnight. The mixture was quenched with water and extracted twice with ethyl acetate. The combined organic extracts were washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue obtained was purified by column chromatography to give 271 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.38-2.46 (m, 4H), 2.49-2.51 (m, 2H), 3.57 (t, J = 4.8 Hz, 4H), 3.77-3.82 (m, 1H ), 4.15-4.16 (s, 2H), 7.89 (s, 1H), 8.09 (s, 1H); ESI-MS (m / z) 271 (M + H) ⁺ .

Step 7 : (R) -tert-butyl 4-chloro-7- (morpholinomethyl) -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate

(R) -4-chloro-7- (morpholinomethyl) -7,8-di in the presence of DMAP (106 mg, 0.86 mmol) in dichloromethane (20 mL) according to the procedure described in step 3 of intermediate A1. By reaction of hydro-6H-pyrimido [5,4-b] [1,4] oxazine (six-step intermediate) (260 mg, 0.96 mmol) with tert-butyl dicarbonate (230 mg, 1.05 mmol) Compounds were prepared to yield 231 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.50 (s, 9H), 3.51-2.29 (m, 6H), 3.52 (d, J = 4.4 Hz, 4H), 4.03 (q, J = 7.2 Hz, 1H), 4.21 (dd, J ₁ = 2.4 Hz, J ₂ = 11.2 Hz, 1H), 8.27-8.33 (m, 1H); ESI-MS (m / z) 285 (M) ⁺ .

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 5 below.

Intermediate A19

(S) -tert-butyl 7-((((tert-butoxycarbonyl) oxy) methyl) -4-chloro-6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H ) -Carboxylate

Step 1 : N- (6-chloro-5-hydroxypyrimidin-4-yl) acetamide

To a solution of 4-amino-6-chloropyrimidin-5-ol (1.5 g, 10.3 mmol) in dichloromethane (15 mL) was added acetyl chloride (0.8 mL, 10.3 mmol), followed by triethylamine (4.2 mL , 30.9 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 790 mg of the desired compound. ESI-MS (m / z) 188 (M + H) ⁺ .

Step 2 : (S) -1- (4-chloro-7- (hydroxymethyl) -6H-pyrimido [5,4-b] [1,4] oxazin-8 (7H) -yl) ethanone

To a suspension of potassium carbonate (1.47 g, 10.7 mmol) in acetonitrile (20 mL) N- (6-chloro-5-hydroxypyrimidin-4-yl) acetamide (stage 1 intermediate) (500 mg, 2.67 mmol ), Then (2R)-(-)-glycidyl tosylate (669 mg, 2.93 mmol) was added and the mixture was refluxed for 24 h. The mixture was cooled to rt and diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 270 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.12 (s, 3H), 3.96-4.16 (m, 1H), 4.16-4.30 (m, 4H), 6.23 (s, 1H), 8.06 (s, 1H ).

Step 3 : (S)-(4-Chloro-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-7 yl) methanol

(S) -1- (4-chloro-7- (hydroxymethyl) -6H-pyrimido [5,4-b] [1,4] oxazine in hydrochloric acid in 1,4-dioxane (3.0 mL) A solution of -8 (7H) -yl) ethanone (two stage intermediate) (150 mg, 0.62 mmol) was stirred at rt for 3 h. The mixture was concentrated under reduced pressure and the residue was diluted with water. The aqueous mixture was basified to pH 8-9 at -20 ° C with saturated sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 170 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.34-3.41 (m, 1H), 3.47-3.57 (m, 2H), 4.11-4.32 (m, 2H), 5.09 (t, J = 5.6 Hz, 1H ), 7.88 (s, 1 H), 8.21-8.22 (br s, 1 H).

Step 4 : (S) -tert-butyl 7-((((tert-butoxycarbonyl) oxy) methyl) -4-chloro-6H-pyrimido [5,4-b] [1,4] oxazine- 8 (7H) -carboxylate

(S)-(4-chloro-7,8-dihydro-6H-pyrimido [5] in the presence of DMAP (246 mg, 2.01 mmol) in dichloromethane (10 mL) according to the procedure described in step 3 of intermediate A1. , 4-b] [1,4] oxazin-7-yl) methanol (3-step intermediate) (170 mg, 0.84 mmol) with di-tert-butyl dicarbonate (476 mg, 2.18 mmol) titled Compounds were prepared to yield 100 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.37 (s, 9H), 1.50 (s, 9H), 4.02-4.13 (m, 1H), 4.15-4.35 (m, 1H), 4.31 (dd, J ₁ = 2.8 Hz, J ₂ = 11.2 Hz, 1H), 4.55-4.79 (m, 1H), 4.80-4.81 (m, 1H), 8.33 (s, 1H).

Intermediate A20

tert-butyl 9-bromo-3,4-dihydropyrido [3,2-b] [1,4] oxazepine-5 (2H) -carboxylate

Step 1 : 4-bromo-3- (3-chloropropoxy) pyridin-2-amine

Step 1 of 2-amino-4-bromopyridin-3-ol hydrobromide (intermediate A7) in the presence of cesium carbonate (3.8 g, 11.7 mmol) in acetonitrile (10 mL) according to the procedure described in step 2 of intermediate A7. ) (1.0 g, 3.90 mmol) and 1-bromo-3-chloropropane (925 mg, 5.80 mmol) gave the title compound, resulting in 400 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.19-2.25 (m, 2H), 3.95 (t, J = 6.0 Hz, 2H), 4.39 (t, J = 5.6 Hz, 2H), 6.17 (s, 2H), 6.74 (d, J = 5.6 Hz, 1H), 7.55 (d, J = 5.6 Hz, 1H).

Step 2 : 9-bromo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine

To a stirred solution of 4-bromo-3- (3-chloropropoxy) pyridin-2-amine (stage 1 intermediate) (400 mg, 1.20 mmol) in DMF (5.0 mL) sodium hydride (60% w / w, 96 mg, 2.40 mmol) was added at room temperature. The mixture was stirred at 80 ° C for 1 h. The reaction mixture was quenched with water and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined and washed with saturated sodium bicarbonate solution followed by brine. The organic layer was dried over anhydrous sodium, filtered and concentrated under reduced pressure to yield 250 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.94-1.98 (m, 2H), 3.25-3.29 (m, 2H) 4.15 (t, J = 6.0 Hz, 2H), 6.39 (br s, 1H), 6.86 (d, J = 5.6 Hz, 1H), 7.52 (d, J = 5.2 Hz, 1H),

Step 3 : tert-Butyl 9-bromo-3,4-dihydropyrido [3,2-b] [1,4] oxazepine-5 (2H) -carboxylate

9-Bromo-2,3,4, in the presence of lithium bis (trimethylsilyl) amide (LiHMDS) (1M, 11 mL, 10.6 mmol) in dry THF (20 mL) according to the procedure described in step 3 of intermediate A7. To the reaction of 5-tetrahydropyrido [3,2-b] [1,4] oxazepine (2-step intermediate) (2.0 g, 8.77 mmol) with di-tert-butyl dicarbonate (2.84 g, 13.0 mmol) The title compound was prepared to yield 2.1 g of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.35 (s, 9H), 1.94-1.97 (m, 2H), 3.60-3.63 (br s, 2H), 4.12-4.14 (br s, 2H), 7.63 (d, J = 5.2 Hz, 1H), 8.02 (d, J = 5.2 Hz, 1H).

Intermediate A21

tert-butyl 8-bromo-7-nitro-2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate

Step 1 : 8-bromo-7-nitro-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine

8-Bromo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine in trifluoroacetic acid (5.0 mL) (2 steps of Intermediate A7) (802 mg, 3.73 mmol) was added potassium nitrate (415 mg, 4.10 mmol) at 0 ° C. The mixture was slowly warmed to rt and stirred at rt overnight. The mixture was quenched with ice water and neutralized with aqueous sodium hydroxide solution at 0 ° C. The precipitated solid was filtered off, washed with water and dried. The crude solid was triturated with diethyl ether and dried well to yield 732 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.52 (t, J = 4.0 Hz, 2H), 4.26 (t, J = 4.0 Hz, 2H), 8.46 (s, 1H), 8.60 (s, 1H) .

Step 2 : tert-butyl 8-bromo-7-nitro-2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate

8-bromo-7-nitro-3, in the presence of triethylamine (0.94 mL, 6.72 mmol) and DMAP (41 mg, 0.34 mmol) in dichloromethane (20 mL) according to the procedure described in step 3 of intermediate A4. 4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine (stage 1 intermediate) (875 mg, 3.36 mmol) and di-tert-butyl dicarbonate (1.15 mL, 5.04 mmol) The title compound was prepared by the reaction of to yield 1.02 g of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.49 (s, 9H), 3.94 (t, J = 4.4 Hz, 2H), 4.46 (t, J = 4.4 Hz, 2H), 8.58 (s, 1H) .

Synthesis of Intermediate B

Intermediate B1

Preparation of Methyl 4-chloro-3-hydroxybenzoate

To a stirred solution of 4-chloro-3-hydroxybenzoic acid (690 mg, 4.00 mmol) in methanol (8.0 mL) was added sulfuric acid (10 μL, 0.20 mmol) and the mixture was heated at 75 ° C. for 14 h. The mixture was concentrated, the residue was cooled to 0 ° C. and neutralized with aqueous sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to yield 902 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.91 (s, 3H), 5.66 (d, J = 4.4 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.56 (dd, J = 8.3, 2.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H); ESI-MS (m / z) 187 (M + H) ⁺ .

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 6 below.

Intermediate B13

Methyl 3-hydroxy-4- (trifluoromethyl) benzoate

Step 1 : methyl 3- (benzyloxy) -4- (trifluoromethyl) benzoate

A mixture of 3-fluoro-4- (trifluoromethyl) benzoic acid (1.0 g, 4.80 mmol) and benzyl alcohol (3.67 mL, 36.4 mmol) and potassium tert-butoxide (1.58 g, 14.2 mmol) in DMSO was stirred at room temperature. Stirred for 2 days. The mixture was diluted with ethyl acetate and water. The aqueous layers were separated, acidified with concentrated HCl and extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated. The residue was dissolved in methanol (5.0 mL). Sulfuric acid (0.5 mL) was added to the mixture and refluxed for 3 hours. The mixture was concentrated, the residue was cooled to 0 ° C. and neutralized with aqueous sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to yield 510 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.97 (s, 3H), 5.27 (s, 2H), 7.35-7.50 (m, 5H), 7.69-7.70 (m, 2H), 7.74 (s, 1H ).

Step 2 : Methyl 3-hydroxy-4- (trifluoromethyl) benzoate

Of methyl 3- (benzyloxy) -4- (trifluoromethyl) benzoate (stage 1 intermediate) (500 mg, 2.27 mmol) in methanol (5.0 mL) with a catalytic amount of 10% palladium (50% wet) on carbon The solution was hydrogenated at room temperature for 16 hours. The mixture was filtered through celite and the celite bed was rinsed with methanol. The filtrates were combined and the washings were concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 400 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.87 (s, 3H), 7.47 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H) , 11.12 (br s, 1 H).

Intermediate B14

Methyl 3-mercapto-4-methylbenzoate

Step 1 : 3-mercapto-4-methylbenzoic acid

Sodium nitrite (958 mg, 13.88) in water (20 mL) at 0 ° C. in a stirred suspension of 3-amino-4-methylbenzoic acid (2.0 g, 13.22 mmol) in concentrated hydrochloric acid (8.0 mL) and water (20 mL). mmol) was added over 20 minutes. The diazotization mixture was added in large portions over 20 minutes to a stirred mixture of potassium ethyl xanthate (2.5 g, 15.8 mmol) and 2M aqueous sodium carbonate solution (22 mL, 43.6 mmol). The mixture was heated at 45 ° C. for 1 hour. The mixture was acidified with concentrated hydrochloric acid and the product was extracted twice in ethyl acetate. The combined organic extracts were washed with water and dried over anhydrous sodium sulfate. The residue obtained after removal of the solvent was refluxed overnight with potassium hydroxide (2.9 g, 52.9 mmol) in a mixture of ethanol and water (1: 1, 20 mL). The reaction mixture was cooled to room temperature, acidified with concentrated hydrochloric acid and extracted three times with ethyl acetate. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to yield 760 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.23 (s, 3H), 5.64 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.60 (dd, J ₁ = 1.6 Hz, J ₂ = 8.0 Hz, 1H), 7.98 (s, 1H), 12.90 (s, 1H); ESI-MS (m / z) 167 (M ⁻ H) ⁻ .

Step 2 : Methyl 3-mercapto-4-methylbenzoate

To a stirred solution of 3-mercapto-4-methylbenzoic acid (760 g, 4.52 mmol) in methanol (10 mL) was added sulfuric acid (250 μL) and the mixture was refluxed for 2 hours. The mixture was concentrated, the residue was cooled to 0 ° C. and neutralized with aqueous sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to yield 502 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.28 (s, 3H), 3.83 (s, 3H), 5.75 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.62 (dd, J ₁ = 1.6 Hz, J ₂ = 7.6 Hz, 1H), 8.01 (s, 1H).

Synthesis of Intermediate C

Intermediate C1

4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline

Step 1 : 1- (bromomethyl) -4-nitro-2- (trifluoromethyl) benzene

N-bromosuccinimide (8.6 g, 48.5) in a solution of 2-methyl-5-nitrobenzotrifluoride (10 g, 48.5 mmol) and AIBN (800 mg, 4.85 mmol) in ethylene dichloride (150 mL) mmol) was added at room temperature and the reaction mixture was refluxed for 18 hours. The mixture was concentrated and the residue was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography to give 6.21 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.88 (s, 2H), 8.04 (d, J = 8.4 Hz, 1H), 8.43 (s, 1H), 8.54 (dd, J ₁ = 2.4 Hz, J ₂ = 8.4 Hz, 1H).

Step 2 : 1-ethyl-4- (4-nitro-2- (trifluoromethyl) benzyl) piperazine

N-ethylpiperazine in a stirred solution of 1- (bromomethyl) -4-nitro-2- (trifluoromethyl) benzene (stage 1 intermediate) (4.0 g, 14.1 mmol) in dichloromethane (40 mL) (1.88 mL, 14.7 mmol) followed by N, N-diisopropylethylamine (DIPEA) (3.27 mL, 19.1 mmol) at room temperature. The mixture was stirred at rt for 16 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution followed by brine. The organic layer was dried over anhydrous sodium, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography to give 3.5 g of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.96 (t, J = 7.2 Hz, 3H), 2.28-2.51 (m, 10H), 3.72 (s, 2H), 8.09 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H), 8.51 (dd, J ₁ = 2.4 Hz, J ₂ = 8.8 Hz, 1H).

Step 3 : 4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline

1-ethyl-4- (4-nitro-2- (trifluoromethyl) benzyl) piperazine (2 step intermediate) (800) in methanol (20 mL) with a catalytic amount of 10% palladium on carbon (50% wet) mg, 2.52 mmol) were hydrogenated at room temperature for 16 hours. The mixture was filtered through celite and the celite bed was rinsed with methanol. The filtrates were combined and the washings were concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 600 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.97 (t, J = 7.2 Hz, 3H), 2.26-2.51 (m, 10H), 3.38 (s, 2H), 5.44 (s, 2H), 6.74 ( dd, J ₁ = 2.4 Hz, J ₂ = 8.4 Hz, 1H), 6.85 (s, 1H), 7.29 (t, J = 8.4 Hz, 1H).

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 7 below.

Intermediate C16

4- (2- (dimethylamino) ethoxy) -3- (trifluoromethyl) aniline

Step 1 : N, N-dimethyl-2- (4-nitro-2- (trifluoromethyl) phenoxy) ethanamine

To a stirred solution of N, N-dimethylethanolamine (2.9 mL, 48.6 mmol) in DMF (10 mL) was added sodium hydride (60% w / w, 421 mg, 10.5 mmol) at 0 ° C and 30 min Was stirred. 1-fluoro-4-nitro-2- (trifluoromethyl) benzene (2.0 g, 9.56 mmol) was added to the mixture and stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous sodium, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography to give 2.3 g of the desired product. The compound proceeded to the next step without characterization.

Step 2 : 4- (2- (dimethylamino) ethoxy) -3- (trifluoromethyl) aniline

Of N, N-dimethyl-2- (4-nitro-2- (trifluoromethyl) phenoxy) ethanamine (2.2 g, 7.91 mmol) in methanol (15 mL) following the procedure described in step 3 of intermediate C1. The title compound was prepared by catalytic hydrogenation, yielding 1.8 g of compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.20 (s, 6H), 2.58 (t, J = 6.0 Hz, 2H), 4.0 (t, J = 6.0 Hz, 2H), 5.03 (s, 2H) , 6.77 (dd, J ₁ = 2.8 Hz, J ₁ = 8.4 Hz, 1H), 6.81-6.82 (br s, 1H), 6.97 (d, J = 8.8 Hz, 1H).

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 8 below.

Intermediate C18

3- (4-isopropylpiperazin-1-yl) -5- (trifluoromethyl) aniline

To a stirred solution of 3-bromo-5- (trifluoromethyl) aniline (1.5 g, 6.25 mmol) in DMF (10 mL) 1-isopropylpiperazine (3.6 mL, 24.4 mmol), cesium carbonate (4.06 g, 12.5 mmol), cuprous iodide (595 mg, 3.12 mmol) and 8-hydroxyquinoline (272 mg, 1.87 mmol) were added at room temperature. The mixture was heated at 120 ° C. for 16 h in a sealed test tube. The reaction mixture was cooled to rt and diluted with ethyl acetate. The solution was washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography to give 660 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.00 (d, J = 6.4 Hz, 6H), 2.50-2.55 (m, 4H), 2.62-2.69 (m, 1H), 3.07 (t, J = 4.8 Hz, 4H), 5.33-5.35 (br s, 2H), 6.28 (s, 1H), 6.32 (s, 2H); ESI-MS (m / z) 288 (M + H) ⁺ .

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 9 below.

Intermediate C24

4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) aniline

Step 1 : 1-methyl-4- (4-nitro-2- (trifluoromethyl) phenyl) piperazine

A mixture of 2-fluoro-5-nitrobenzotrifluoride (5.0 g, 23.9 mmol) and 1-methylpiperazine (7.18 g, 71.7 mmol) in DMSO (20 mL) was heated at 100 ° C for 5 h. The mixture was cooled to rt and diluted with ethyl acetate and water. The organic layers were separated; And the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water followed by brine and concentrated under reduced pressure to give 5.2 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.23 (s, 3H), 2.45-2.51 (m, 4H), 3.13 (t, J = 4.8 Hz, 4H), 7.54 (d, J = 8.8 Hz, 1H), 8.38 (d, J = 2.8 Hz, 1H), 8.40 (d, J = 1.6 Hz, 1H).

Step 2 : 4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) aniline

1-methyl-4- (4-nitro-2- (trifluoromethyl) phenyl) piperazine (one step intermediate) in methanol (200 mL) according to the procedure described in step 3 of intermediate C1 (5.0 g, 17.3 mmol) The title compound was prepared by the catalytic hydrogenation reaction of) to yield 4.12 g of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.19 (s, 3H), 2.49-2.51 (m, 4H), 2.71 (t, J = 4.4 Hz, 4H), 5.34 (s, 2H), 6.76 ( d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.4 Hz, 1H); ESI-MS (m / z) 260 (M + H) ⁺ .

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 10 below.

Intermediate C27

tert-butyl 4- (4-amino-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate

Step 1 : tert-butyl 4- (4-nitro-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate

To a stirred solution of 2-fluoro-5-nitrobenzotrifluoride (5.0 g, 23.9 mmol) in acetonitrile (50 mL) potassium carbonate (6.6 g, 47.8 mmol) and tert-butyl piperazine-1-carboxyl Rate (4.9 g, 26.3 mmol) was added at room temperature and the mixture was refluxed for 24 h. The mixture was cooled to rt and diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water followed by brine and concentrated under reduced pressure to give 5.23 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.43 (s, 9H), 3.06 (t, J = 5.2 Hz, 4H), 3.47 (t, J = 4.4 Hz, 4H), 7.61 (d, J = 8.8 Hz, 1 H), 8.39-8.45 (m, 2 H).

Step 2 : tert-butyl 4- (4-amino-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate

Tert-butyl 4- (4-nitro-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate (stage 1 intermediate) in methanol (200 mL) according to the procedure described in step 3 of intermediate C1. g, 8.00 mmol) in the catalytic hydrogenation reaction to give the title compound, resulting in 2.3 g of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.41 (s, 9H), 2.66 (t, J = 4.8 Hz, 4H), 3.34 (s, 4H), 5.38 (m, 2H), 6.75 (dd J ₁ = 2.4 Hz, J ₂ = 8.4 Hz, 1H), 6.81 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H); ESI-MS (m / z) 346 (M + H) ⁺ .

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 11 below.

Intermediate C28

4-((4-ethylpiperazin-1-yl) methyl) aniline

Step 1 : 1-ethyl-4- (4-nitrobenzyl) piperazine

1- (bromomethyl) -4-nitro in the presence of N, N-diisopropylethylamine (DIPEA) (2.5 mL, 12.5 mmol) in dichloromethane (10 mL) according to the procedure described in step 2 of intermediate C1. The title compound was prepared by reaction of benzene (1.8 g, 8.32 mmol) with N-ethylpiperazine (1.16 mL, 9.16 mmol) to give 1.23 g of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.98 (t, J = 7.2 Hz, 3H), 2.34-2.40 (m, 10H), 3.59 (s, 2H), 7.58 (d, J = 8.4 Hz, 2H), 8.19 (d, J = 8.4 Hz, 2H).

Step 2 : 4-((4-ethylpiperazin-1-yl) methyl) aniline

To a stirred solution of 1-ethyl-4- (4-nitrobenzyl) piperazine (one step intermediate) (200 mg, 0.88 mmol) in a mixture of methanol and water (1: 1, 20 mL) was added ammonium chloride (215 mg, 4.08 mmol), then iron powder (224 mg. 4.028 mmol) was added in small portions at 100 ° C. The mixture was stirred at 100 ° C for 2 h. The mixture was concentrated and the residue was diluted with a mixture of ethyl acetate and water. The organic layers were separated, washed with water, then brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue obtained was purified by column chromatography to yield 3.5 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.95 (t, J = 7.2 Hz, 3H), 2.24-2.29 (m, 10H), 3.23 (s, 2H), 4.93 (br s, 2H), 6.48 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H).

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 12 below.

Intermediate C33

N ^1- (4-amino-2- (trifluoromethyl) benzyl) -N ¹ , N ² , N ² -trimethylethane-1,2-diamine

Step 1 : tert-butyl (4-methyl-3- (trifluoromethyl) phenyl) carbamate

Sodium carbonate (2.3 g, 21.3 mmol) in a solution of 4-methyl-3- (trifluoromethyl) aniline (2.5 g, 14.2 mmol) in a mixture of 1,4-dioxane (20 mL) and water (20 mL) ) And di-tert-butyl dicarbonate (3.72 g, 17.0 mmol) were added and the mixture was stirred at rt for 16 h. The reaction mixture was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated to yield 3.85 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.48 (s, 9H), 2.35 (s, 3H), 7.31 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H) , 7.87 (s, 1 H), 9.59 (s, 1 H).

Step 2 : tert-butyl (4- (bromomethyl) -3- (trifluoromethyl) phenyl) carbamate

N-bromosuccinimide (4.13) in a solution of tert-butyl (4-methyl-3- (trifluoromethyl) phenyl) carbamate (stage 1 intermediate) (3.8 g, 13.8 mmol) in carbon tetrachloride (30 mL) g, 27.6 mmol) and AIBN (226 mg, 1.38 mmol) were added at room temperature and the reaction mixture was refluxed for 16 h. The mixture was concentrated and the residue was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 3.05 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.49 (s, 9H), 4.62 (s, 2H), 6.68 (s, 1H), 7.49-7.57 (m, 2H), 7.71 (s, 1H).

Step 3 : tert-butyl (4-(((2- (dimethylamino) ethyl) (methyl) amino) methyl) -3- (trifluoromethyl) phenyl) carbamate

N, N, N in a solution of tert-butyl (4- (bromomethyl) -3- (trifluoromethyl) phenyl) carbamate (2-step intermediate) (200 mg, 0.56 mmol) in THF (10 mL) '-Trimethylethylenediamine (176 μL, 1.35 mmol) and triethylamine (236 μL, 1.69 mmol) were added at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 315 mg of the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.48 (s, 9H), 2.12 (s, 9H), 2.35 (q, J = 4.4 Hz, 2H), 2.41-2.44 (m, 2H), 3.53 ( s, 2H), 7.62 (s, 2H), 7.87 (s, 1H), 9.66 (s, 1H); ESI-MS (m / z) 376 (M + H) ⁺ .

Step 4 : N ^1- (4-amino-2- (trifluoromethyl) benzyl) -N ¹ , N ² , N ² -trimethylethane-1,2-diamine

Tert-butyl (4-(((2- (dimethylamino) ethyl) (methyl) amino) methyl) -3- (trifluoromethyl) phenyl) carbamate (3-step intermediate) in dichloromethane (5.0 mL) ( To 300 mg, 0.80 mmol) was added trifluoroacetic acid (2.0 mL) and the mixture was stirred at rt for 3 h. The reaction mixture was diluted with ethyl acetate and the organic solution was washed with saturated sodium bicarbonate solution followed by water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated to yield 102 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.11 (s, 9H), 2.34-2.39 (m, 4H), 3.33-3.40 (br s, 2H), 5.42 (s, 2H), 6.75 (dd, J ₁ = 2.0 Hz, J ₂ = 8.0 Hz, 1H), 6.85 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H).

Intermediate C34

N ^1- (2- (dimethylamino) ethyl) -N ¹ -methyl-5- (trifluoromethyl) benzene-1,3-diamine

Step 1 : di-tert-butyl (3-bromo-5- (trifluoromethyl) phenyl) imidodicarbonate

3-bromo-5-trifluoromethylaniline (5.0 g, 20.8 mmol) and di- in the presence of DMAP (254 mg, 2.08 mmol) in dichloromethane (20 mL) according to the procedure described in step 3 of intermediate A1. The title compound was prepared by the reaction of tert-butyl dicarbonate (11.3 g, 52.1 mmol), resulting in 3.8 g of the product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.41 (s, 18H), 7.77 (d, J = 6.0 Hz, 1H), 7.93-7.96 (m, 1H), 8.05 (s, 1H).

Step 2 : di-tert-butyl (3-((2- (dimethylamino) ethyl] (methyl) amino) -5- (trifluoromethyl) phenyl) imidodicarbonate

To a solution of di-tert-butyl (3-bromo-5- (trifluoromethyl) phenyl) imidodicarbonate (1 step intermediate) (2.2 g, 4.89 mmol) in 1,4-dioxane (20 mL) N, N, N'-trimethylethylenediamine (636 μL, 4.89 mmol), sodium tert-butoxide (1.40 g, 14.7 mmol), tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) ₃ ) ₍ 447 mg, 0.49 mmol) and (2-biphenyl) di-tert-butylphosphinetriethylamine (JohnPhos) (37 mg, 1.47 mmol) were added at room temperature and the reaction mixture was stirred at 45 ° C. for 4 hours. Stirred The mixture was cooled to rt and filtered through celite. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic solution was washed with 0.1 N HCl, then water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 2.01 g of the desired compound. The compound proceeded to the next step without characterization.

Step 3 : N ^1- (2- (dimethylamino) ethyl) -N ¹ -methyl-5- (trifluoromethyl) benzene-1,3-diamine

Di-tert-butyl (3-((2- (dimethylamino) ethyl] (methyl) amino) -5- (trifluoromethyl) phenyl in dichloromethane (3.0 mL) following the procedure described in step 4 of intermediate C33. The title compound was prepared by reaction of imidodicarbonate (2 step intermediate) (100 mg, 0.22 mmol)) with trifluoroacetic acid (0.5 mL) to yield 50 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.17 (s, 6H), 2.34 (t, J = 7.2 Hz, 2H), 3.3-3.37 (m, 5H), 5.29 (s, 2H), 6.07 ( s, 1 H), 6.10 (s, 1 H), 6.14 (s, 1 H); ESI-MS (m / z) 262 (M + H) ⁺ .

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 13 below.

Intermediate C36

1- (3-aminophenyl) cyclopropanecarbonitrile

Step 1 : 1- (3-nitrophenyl) cyclopropanecarbonitrile

To a stirred solution of 2- (3-nitrophenyl) acetonitrile (500 mg, 3.08 mmol) in DMSO (10 mL) 1,2-dibromoethane (266 μL, 3.08 mmol) and sodium hydride (60% w / w, 123 mg, 3.08 mmol) was added at room temperature. The mixture was stirred at rt for 16 h. The reaction mixture was quenched with aqueous sodium sulfate solution, diluted with ethyl acetate and the organic layer was washed with saturated sodium bicarbonate solution followed by brine. The organic layer was dried over anhydrous sodium, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography to give 635 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.69 (t, J = 2.8 Hz, 2H), 1.87 (t, J = 2.8 Hz, 2H), 7.70 (t, J = 8.0 Hz, 1H), 7.78 -7.80 (m, 1 H), 8.17-8.19 (m, 2 H).

Step 2 : 1- (3-aminophenyl) cyclopropanecarbonitrile

Ammonium chloride (1.79 g, 33.4) in a stirred solution of 1- (3-nitrophenyl) cyclopropanecarbonitrile (one-step intermediate) (630 mg, 3.35 mmol) in a mixture of ethyl acetate and water (1: 1, 20 mL) mmol) and then iron powder (747 mg. 13.4 mmol) in small portions at 100 ° C. The mixture was stirred at 100 ° C for 2 h. The mixture was concentrated and the residue was diluted with a mixture of ethyl acetate and water. The organic layers were separated, washed with water, then brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue obtained was purified by column chromatography to give 350 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.36 (t, J = 4.8 Hz, 2H), 1.66 (t, J = 4.8 Hz, 2H), 5.22 (br s, 2H), 6.36-6.38 (m , 1H), 6.46-6.48 (m, 1H), 6.57 (s, 1H), 6.99 (t, J = 4.0 Hz, 1H).

Intermediate C37

(S) -3- (3-fluoropyrrolidin-1-yl) -5- (trifluoromethyl) aniline

Step 1 : (S) -3-fluoro-1- (3-nitro-5- (trifluoromethyl) phenyl) pyrrolidine

Cesium carbonate (4.34 g, 13.3 mmol), tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) _{3 in} 1,4-dioxane (20 mL) following the procedure described in step 2 of intermediate C34 ) (81 mg, 0.09 mmol) and (±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthalene (rac-BINAP) (83 mg, 0.13 mmol) Preparation of the title compound by reaction of bromo-3-nitro-5- (trifluoromethyl) benzene (1.2 g, 4.44 mmol) with (S) -3-fluoropyrrolidine (593 mg, 6.66 mmol). This resulted in 109 mg of the target compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.16-2.22 (m, 1H), 2.27-2.33 (m, 1H), 3.47-3.58 (m, 1H), 3.60-3.67 (m, 2H), 3.72 (s, 1 H), 5.43-5.57 (m, 1 H), 7.20 (s, 1 H), 7.52 (s, 1 H), 7.62 (s 1 H); ESI-MS (m / z) 279 (M + H) ⁺ .

Step 2 : (S) -3- (3-fluoropyrrolidin-1-yl) -5- (trifluoromethyl) aniline

(S) -3-fluoro-1- (3-nitro-5- (trifluoromethyl) in the presence of palladium on carbon (10% w / w, 50% wet) according to the procedure described in step 3 of intermediate C1 The title compound was prepared by catalytic hydrogenation of) phenyl) pyrrolidine (one step intermediate) (100 mg, 0.36 mmol) to give 55 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.10-2.26 (m, 2H), 3.27-3.57 (m, 4H), 5.33-5.36 (br s, 2H), 5.49 (br s, 1H), 5.98 (s, 2 H), 6.18 (s, 1 H).

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 14 below.

Intermediate C40

tert-butyl 4- (3-amino-5- (trifluoromethyl) phenyl) piperidine-1-carboxylate

Step 1 : tert-butyl 4- (3-nitro-5- (trifluoromethyl) phenyl) -5,6-dihydropyridine-1 (2H) -carboxylate

Tert-butyl 4- (4,4,5) in a solution of 1-bromo-3-nitro-5- (trifluoromethyl) benzene (1.0 g, 3.70 mmol) in 1,4-dioxane (35 mL) , 5) -tetramethyl-1,3,2-dioxaborolan-2-yl) -5,6-dihydropyridine-1 (2H) -carboxylate (1.1 g, 3.70 mmol), tetrakis (tri Phenylphosphine) palladium (0) (213 mg, 0.18 mmol) and saturated aqueous sodium bicarbonate solution (15 mL) were added and the mixture was heated at 120 ° C for 6 h. The mixture was cooled to rt and diluted with ethyl acetate. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 891 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.52 (s, 9H), 2.60 (br s, 2H), 3.71 (t, J = 5.6 Hz, 2H), 4.18 (br s, 2H), 6.32 ( br s, 1 H), 7.94 (s, 1 H), 8.39 (s, 1 H), 8.42 (s, 1 H).

Step 2 : tert-butyl 4- (3-amino-5- (trifluoromethyl) phenyl) piperidine-1-carboxylate

Tert-butyl 4- (3-nitro-5- (trifluoromethyl) phenyl in the presence of palladium on carbon (10% w / w, 50% wet) (catalytic) according to the procedure described in step 3 of intermediate C1 The title compound was prepared by catalytic hydrogenation of piperidine-1-carboxylate (one step intermediate) (880 mg, 2.35 mmol) to yield 728 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.50 (s, 9H), 1.55-1.66 (m, 2H), 1.82 (d, J = 12.4 Hz, 2H), 2.58-2.66 (m, 1H), 2.80 (t, J = 12.0 Hz, 2H), 4.26 (br s, 2H), 6.69 (s, 1H), 6.78 (s, 1H), 6.86 (s, 1H).

Intermediate C41

3- (1-methylpiperidin-4-yl) -5- (trifluoromethyl) aniline

To a stirred suspension of lithium aluminum hydride (275 mg, 7.25 mmol) in THF (20 mL), tert-butyl 4- (3-amino-5- (trifluoromethyl) phenyl) pi in THF (20 mL) A solution of ferridine-1-carboxylate (intermediate C40) (500 mg, 1.45 mmol) was added slowly at room temperature and the mixture was heated at 90 ° C. for 18 hours. The mixture was cooled to room temperature and quenched with saturated aqueous sodium sulfate solution. The mixture was filtered and the filtrate was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 181 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.56-1.59 (m, 2H), 1.62-1.71 (m, 2H), 1.89-1.90 (m, 2H), 2.17 (s, 3H), 2.3-2.51 (m, 1H), 2.83 (d, J = 7.6 Hz, 2H), 5.48 (s, 2H), 6.29 (s, 1H), 6.73 (s, 2H).

Intermediate C42

4- (3-amino-5- (trifluoromethyl) phenyl) thiomorpholine 1,1-dioxide

Step 1 : 4- (3-nitro-5- (trifluoromethyl) phenyl) thiomorpholine

Cesium carbonate (7.2 g, 22.2 mmol), tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) _{3 in} 1,4-dioxane (30 mL) following the procedure described in step 2 of intermediate C34 ) (135 mg, 0.15 mmol) and (±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthalene (rac-BINAP) (138 mg, 0.22 mmol), 1 The title compound was prepared by reaction of bromo-3-nitro-5- (trifluoromethyl) benzene (2.0 g, 7.40 mmol) with thiomorpholine (1.1 g, 11.1 mmol) to give 1.05 g of the desired compound. Produced. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.66-2.69 (m, 4H), 3.79-3.81 (m, 4H), 7.60 (s, 1H), 7.69 (s, 1H), 7.86 (s, 1H ).

Step 2 : 4- (3-nitro-5- (trifluoromethyl) phenyl) thiomorpholine 1,1-dioxide

MCPBA (1.7 g, 10.3 mmol) in a solution of 4- (3-nitro-5- (trifluoromethyl) phenyl) thiomorpholine (stage 1 intermediate) (1.0 g, 3.42 mmol) in dichloromethane (20 mL) Was added at room temperature and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with saturated sodium bicarbonate solution and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue was purified by silica gel column chromatography to give 523 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.19 (t, J = 5.2 Hz, 4H), 4.01 19 (t, J = 5.2 Hz, 4H), 7.75 (s, 1H), 7.97 (s, 1H ), 8.0 (s, 1 H).

Step 3 : 4- (3-amino-5- (trifluoromethyl) phenyl) thiomorpholine 1,1-dioxide

4- (3-nitro-5- (trifluoromethyl) phenyl) thiomo in the presence of palladium on carbon (10% w / w, 50% wet) (catalytic) according to the procedure described in step 3 of intermediate C1 The title compound was prepared by catalytic hydrogenation of Pauline 1,1-dioxide (2-step intermediate) (510 mg, 1.57 mmol) to give 346 mg of compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.12 (s, 4H), 3.72 (s, 4H), 5.43 (s, 2H), 6.35 (s, 1H), 6.42 (d, J = 6.8 Hz 2H ).

Intermediate C43

4-amino-N- (2- (dimethylamino) ethyl) -2- (trifluoromethyl) benzamide

Step 1 : N- (2- (dimethylamino) ethyl) -4-nitro-2- (trifluoromethyl) benzamide

To a stirred solution of 4-nitro-2- (trifluoromethyl) benzoic acid (500 mg, 2.12 mmol) in dichloromethane (20 mL) triethylamine (612 μL, 4.24 mmol), N ¹ , N ¹ -dimethyl Ethane-1,2-diamine hydrochloride (633 μL, 5.0 mmol) was added followed by HATU (967 mg, 2.54 mmol) at room temperature. The mixture was stirred at rt for 18 h and then quenched with water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 311 mg of the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.23 (s, 6H), 2.45-2.50 (m, 2H), 3.33-3.38 (m, 2H), 7.80 (d, J = 8.4 Hz, 1H), 8.49 (s, 1 H), 8.56 (dd, J ₁ = 2.0 Hz, J ₂ = 8.4 Hz, 1H), 8.76 (t, J = 5.2 Hz, 1H); ESI-MS (m / z) 306 (M + H) ⁺ .

Step 2 : 4-amino-N- (2- (dimethylamino) ethyl) -2- (trifluoromethyl) benzamide

N- (2- (dimethylamino) ethyl) -4-nitro-2 in the presence of palladium on carbon (10% w / w, 50% wet) in methanol (10 mL) according to the procedure described in step 3 of intermediate C1. The title compound was prepared by catalytic hydrogenation of-(trifluoromethyl) benzamide (one step intermediate) (300 mg, 0.98 mmol), resulting in 151 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.16 (s, 6H), 2.33 (t, J = 7.2 Hz, 2H), 3.18-3. 26 (m, 2H), 5.79 (s, 2H), 6.73 (dd, J ₁ = 2.0 Hz, J ₂ = 10 Hz, 1H), 6.87 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H ), 8.0 (t, J = 5.6 Hz, 1H); ESI-MS (m / z) 276 (M + H) ⁺ .

Intermediate C44

(4-amino-2- (trifluoromethyl) phenyl) (4-ethylpiperazin-1-yl) methanone

Step 1 : (4-ethylpiperazin-1-yl) (4-nitro-2- (trifluoromethyl) phenyl) methanone

To a stirred solution of 4-nitro-2- (trifluoromethyl) benzoic acid (2.0 g, 8.51 mmol) in dichloromethane (20 mL) triethylamine (8.5 mL, 59.5 mmol), N-ethylpiperazine (1.24 mL, 9.35 mmol), then T3P (11.1 mL, 18.7 mmol) was added at room temperature. The mixture was stirred at rt for 16 h and then quenched with water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 2.2 g of the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.99 (d, J = 6.8 Hz, 3H), 2.19-2.50 (m, 6H), 3.03-3.16 (m, 2H), 3.58-3.72 (m, 2H ), 7.82 (d, J = 8.4 Hz, 1H), 8.53-8.58 (m, 2H).

Step 2 : (4-amino-2- (trifluoromethyl) phenyl) (4-ethylpiperazin-1-yl) methanone

(4-ethylpiperazin-1-yl) (4-nitro-2- (trifluoro) in the presence of 10% palladium (50% wet) on carbon in methanol (50 mL) following the procedure described in step 3 of intermediate C1. The title compound was prepared by catalytic hydrogenation of romethyl) phenyl) methanone (one step intermediate) (2.0 g, 6.04 mmol), resulting in 1.9 g of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.98 (t, J = 7.2 Hz, 3H), 2.19-2.50 (m, 6H), 3.09-3.18 (m, 2H), 3.57-3.58 (m, 2H ), 5.78 (s, 2H), 6.78 (dd, J ₁ = 2.0 Hz, J ₂ = 8.4 Hz, 1H), 6.88 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H).

Intermediate C45

Ethyl 2- (3-aminophenyl) -2,2-difluoroacetate

Step 1 : ethyl 2,2-difluoro-2- (3-nitrophenyl) acetate

To a stirred suspension of 1-iodo-3-nitrobenzene (5.0 g, 20.1 mmol) and copper powder (5.0 g, 80.3 mmol) in DMSO (20 mL) ethyl 2-bromo-2,2-difluoro Acetate (5.1 mL 40.2 mmol) was added at room temperature. The mixture was stirred overnight at 60 ° C. in a sealed test tube. The reaction mixture was cooled to room temperature and quenched with aqueous ammonium chloride solution. The aqueous mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material obtained was purified by silica gel column chromatography to yield 3.2 g of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.23 (t, J = 7.2 Hz, 3H), 4.26 (q, J = 7.2 Hz, 2H), 7.89 (t, J = 8.4 Hz, 1H), 8.09 (dd, J ₁ = 0.8 Hz, J ₂ = 8.0 Hz, 1H), 8.33 (t, J = 2.0 Hz, 1H), 8.47 (dd, J ₁ = 0.8 Hz, J ₂ = 6.8 Hz, 1H); ESI-MS (m / z) 245 (M + H) ⁺ .

Step 2 : ethyl 2- (3-aminophenyl) -2,2-difluoroacetate

Ethyl 2,2-difluoro-2- (3-nitrophenyl) acetate (stage 1 intermediate) in a mixture of ethyl acetate and water (7: 2, 9.0 mL) according to the procedure described in step 2 of intermediate C28 (600 mg) , 2.44 mmol) and iron powder (567 mg, 10.2 mmol) and ammonium chloride (1.30 g, 24.4 mmol) gave the title compound, resulting in 350 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.23 (t, J = 7.2 Hz, 3H), 4.20 (q, J = 7.2 Hz, 2H), 5.53 (br s, 2H), 6.65 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.75 (s, 1H), 7.15 (t, J = 7.6 Hz, 1H); ESI-MS (m / z) 216 (M + H) ⁺ .

Intermediate C46

3- (4,4-difluoropiperidin-1-yl) -5- (trifluoromethyl) aniline

Step 1 : 4,4-difluoro-1- (3-nitro-5- (trifluoromethyl) phenyl) piperidine

Sodium tert-butoxide (140 mg, 1.45 mmol), tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ () in 1,4-dioxane (3.0 mL) according to the procedure described in step 2 of intermediate C34. dba) ₃ ) (44 mg, 0.05 mmol) and 1,1-bis (diphenylphosphinoferrocene (54 mg, 0.10 mmol) in 1-bromo-3-nitro-5- (trifluoromethyl) The title compound was prepared by reaction of benzene (250 mg, 0.93 mmol) with 4,4-difluoropiperidine (354 mg, 2.77 mmol), resulting in 150 mg of the desired compound ¹ H NMR (400). MHz, DMSO-d ₆ ) δ 2.06 2.09 (m, 4H), 3.60 (t, J = 5.60 Hz, 4H), 7.72 (s, 1H), 7.67 (s, 1H), 7.97 (s, 1H).

Step 2 : 3- (4,4-difluoropiperidin-1-yl) -5- (trifluoromethyl) aniline

4,4-difluoro-1- (3-nitro-5- in the presence of palladium on carbon (10% w / w, 50% wet) in methanol (5.0 mL) according to the procedure described in step 3 of intermediate C1. The title compound was prepared by catalytic hydrogenation of (trifluoromethyl) phenyl) piperidine (one step intermediate) (220 mg, 0.71 mmol) to yield 70 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.97-2.07 (m, 4H), 3.28-3.33 (m, 4H), 5.39 (s, 2H), 6.32 (s, 1H), 6.40 (s, 2H ); ESI-MS (m / z) 281 (M + H) ⁺ .

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 15 below.

Intermediate C50

N- (3-amino-5- (trifluoromethyl) phenyl) acrylamide

To a stirred solution of 5- (trifluoromethyl) benzene-1,3-diamine (200 mg, 1.13 mmol) in dichloromethane (9.0 mL) triethylamine (164 μL, 1.13 mmol) followed by acryloyl chloride (31 μL, 0.34 mmol) was added at 0 ° C. The mixture was stirred at rt overnight. The mixture was quenched with water and extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue was purified by silica gel column chromatography to yield 60 mg of the desired product. ESI-MS (m / z) 231 (M + H) ⁺ .

Intermediate C51

6-methyl-5- (trifluoromethyl) pyridin-3-amine

Step 1 : diethyl 2- (5-nitro-3- (trifluoromethyl) pyridin-2-yl) malonate

To a stirred solution of diethylmalonate (5.0 g, 23.5 mmol) in THF (25 mL) was added potassium tert-butoxide (1M in THF, 70.5 mmol) at −10 ° C. and the mixture was stirred for 10 minutes at the same temperature. After stirring for 30 minutes at room temperature. A solution of 2-chloro-5-nitro-3- (trifluoromethyl) pyridine (5.0 g, 23.52 mmol) in THF (25 mL) was added slowly to the mixture at 0 ° C. and the resulting mixture was added 4 Stir at room temperature for 5 h. The mixture was quenched with aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to yield 5.1 g of the desired product. The crude amine proceeded to the next step as it was.

Step 2 : 2-methyl-5-nitro-3- (trifluoromethyl) pyridine

A solution of diethyl 2- (5-nitro-3- (trifluoromethyl) pyridin-2-yl) malonate (stage 1 intermediate) (5.0 g, 14.3 mmol) in 50% sulfuric acid (50 mL) was 85 to Heated at 90 ° C. for 2-3 hours. The mixture was cooled to 0 ° C and basified with 3N NaOH solution. The aqueous solution was extracted twice with diethyl ether. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to yield 3.2 g of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.79 (s, 3H), 8.73 (d, J = 2.4 Hz, 1H), 9.50 (d, J = 2.4 Hz, 1H).

Step 3 : 6-methyl-5- (trifluoromethyl) pyridin-3-amine

Iron powder with 2-methyl-5-nitro-3- (trifluoromethyl) pyridine (250 mg, 1.21 mmol) in a mixture of ethanol and water (6: 1, 3.5 mL) according to the procedure described in step 2 of intermediate C28. (679 mg, 12.1 mmol) and ammonium chloride (519 mg, 9.70 mmol) gave the title compound to give 170 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.41 (s, 3H), 5.57 (br s, 2H), 7.19 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H ).

Intermediate C52

tert-butyl 4- (3-amino-5- (trifluoromethyl) phenyl) -1,4-diazepane-1-carboxylate

Step 1 : tert-butyl 4- (3-nitro-5- (trifluoromethyl) phenyl) -1,4-diazepane-1-carboxylate

Sodium tert-butoxide (53 mg, 0.55 mmol), tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ ( ₂ ) in 1,4-dioxane (1.0 mL) according to the procedure described in step 2 of intermediate C34. dba) ₃ ) (20 mg, 0.02 mmol) and 1-bromo-3-nitro-5- (trifluoromethyl) in the presence of 1,1-bis (diphenylphosphinoferrocene (24 mg, 0.04 mmol) benzene (100 mg, 0.37 mmol) and tert- butyl 1,4-diazepane-1-carboxylate to give the titled compound by the reaction of (222 mg, 1.11 mmol), to give the target compound as a 85 mg. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.42 (s, 9H), 1.630 (br s, 2H), 1.99-2.02 (m, 2H), 3.30-3.40 (m, 2H), 3.67-3.69 (m , 4H), 7.14 (s, 1 H), 7.66 (s, 1 H), 7.74 (s, 1 H).

Step 2 : tert-butyl 4- (3-amino-5- (trifluoromethyl) phenyl) -1,4-diazepane-1-carboxylate

Tert-butyl 4- (3-nitro-5- (trifluoromethyl) phenyl) -1,4-diazepane-1-carboxylate (1) in ethanol (2.0 mL) following the procedure described in step 2 of intermediate C28. Step intermediate) (80 mg, 0.21 mmol) with iron powder (114 mg, 2.05 mmol) and ammonium chloride (88 mg, 1.64 mmol) gave the title compound to produce 35 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.34 (s, 9H), 1.71-1.99 (m, 2H), 3.16-3.32 (m, 2H), 3.45-3.56 (m, 4H), 5.23-5.24 (m, 4 H), 6.12-6.15 (m, 3 H).

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 16 below.

Intermediate C57

3- (4-methyl-1,4-diazepan-1-yl) -5- (trifluoromethyl) aniline

Step 1 : 1- (3-nitro-5- (trifluoromethyl) phenyl) -1,4-diazepane

Tert-butyl 4- (3-nitro-5- (trifluoromethyl) phenyl) -1,4-diazepane-1-carboxylate in 1,4-dioxane (5.0 mL) (stage 1-intermediate) C52) (600 mg, 1.54 mmol) was stirred at rt for 3 h. The mixture was concentrated under reduced pressure and the residue was diluted with water. The aqueous mixture was basified to pH 8-9 at -20 ° C with saturated sodium bicarbonate solution. The mixture was extracted twice with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 250 mg of the desired product. The crude amine proceeded to the next step as it was.

Step 2 : 1-methyl-4- (3-nitro-5- (trifluoromethyl) phenyl) -1,4-diazepane

Methyl urine in a stirred solution of 1- (3-nitro-5- (trifluoromethyl) phenyl) -1,4-diazepane (stage 1 intermediate) (250 mg, 0.87 mmol) in acetonitrile (35 mL) Odide (126 mg, 0.89 mmol) and potassium carbonate (125 mg, 0.91 mmol) were added at 0 ° C. and the mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 160 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.90-1.92 (m, 2H), 2.26 (s, 3H), 2.26-2.51 (m, 2H), 2.64 (t, J = 4.8 Hz, 2H), 3.55 (t, J = 6.0 Hz, 2H), 3.65 (t, J = 4.8 Hz, 2H), 7.32 (s, 1H), 7.56 (s, 1H), 7.63 (t, J = 2.0 Hz, 1H); ESI-MS (m / z) 304 (M + H) ⁺ .

Step 3 : 3- (4-methyl-1,4-diazepan-1-yl) -5- (trifluoromethyl) aniline

1-methyl-4- (3-nitro-5- (trifluoromethyl) phenyl) -1,4-diazepane (two step intermediate) in ethanol (3.0 mL) following the procedure described in step 2 of intermediate C28 ( The title compound was prepared by reaction of 180 mg, 0.59 mmol) with iron powder (331 mg, 5.92 mmol) and ammonium chloride (253 mg, 4.73 mmol), resulting in 140 mg of the compound. The crude amine proceeded to the next stage as it was due to poor solubility and instability in solution form.

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 17 below.

Intermediate C59

3- (4- (oxetan-3-yl) piperazin-1-yl) -5- (trifluoromethyl) aniline

Step 1 : 1- (3-nitro-5- (trifluoromethyl) phenyl) -4- (oxetan-3-yl) piperazine

A mixture of zinc chloride (277 mg, 2.03 mmol) and molecular sieve (200 mg) was vacuum dried and then 1- (3-nitro-5- (trifluoromethyl) phenyl) pipet in methanol (1.0 mL) Lazine hydrochloride (100 mg, 0.40 mmol) and oxetan-3-one (150 mg, 2.08 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0 ° C and sodium cyanoborohydride (126 mg, 2.08 mmol) was added in small portions. The mixture was stirred at rt for 2 h. The mixture was filtered through celite and the filtrate was diluted with sodium bicarbonate solution. The mixture was passed through celite again and the filtrate was diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 90 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.42-2.51 (m, 4H), 3.43-3.47 (m, 4H), 4.34-4.37 (m, 1H), 4.48 (t, J = 6.0 Hz, 2H ), 4.56-4.68 (m, 2H), 7.64 (s, 1H), 7.75 (s, 1H), 7.90 (t, J = 2.0 Hz, 1H).

Step 2 : 3- (4- (oxetan-3-yl) piperazin-1-yl) -5- (trifluoromethyl) aniline

1- (3-nitro-5- (trifluoromethyl) phenyl) -4- (oxetan-3-yl) piperazine (one step intermediate) in ethanol (4.0 mL) following the procedure described in step 2 of intermediate C28 ) (100 mg, 0.30 mmol) with iron powder (179 mg, 3.19 mmol) and ammonium chloride (138 mg, 2.55 mmol) to produce the title compound, resulting in 70 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.388 (t, J = 4.8 Hz, 4H), 3.12 (t, J = 4.8 Hz, 4H), 3.42-3.45 (m, 1H), 4.47 (t, J = 5.6 Hz, 2H), 4.56 (t, J = 6.4 Hz, 2H), 5.37 (s, 2H), 6.30 (s, 1H), 6.34 (s, 2H).

Intermediate C60

(R) -1- (3-amino-5- (trifluoromethyl) phenyl) -N, N-dimethylpyrrolidin-3-amine

3-bromo-5- (trifluoromethyl) aniline (200 mg, 0.83 mmol) and (R) -N, N-dimethylpyrrolidin-3-amine (200 mg, 1.75 mmol) in DMF (2.0 mL) Copper iodide (83 mg, 0.44 mmol) followed by 8-hydroxyquinoline (40 mg, 0.26 mmol) was added at room temperature in a test tube sealed to a stirred solution of. The mixture was stirred at 120 ° C overnight. The mixture was cooled to rt and diluted with water. The aqueous mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 80 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.73-1.83 (m, 1H), 2.12-2.17 (m, 6H), 2.74-2.78 (m, 1H), 2.98 (t, J = 8.4 Hz, 1H ), 3.16-3.22 (m, 1H), 3.33-3.41 (m, 4H), 5.28 (s, 2H), 5.95 (s, 1H), 6.14 (s, 1H); ESI-MS (m / z) 274 (M + H) ⁺ .

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 18 below.

Intermediate C62

tert-butyl 3-amino-5- (trifluoromethyl) benzyl (isopropyl) carbamate

Step 1 : N- (3-nitro-5- (trifluoromethyl) benzyl) propan-2-amine

A solution of 2-propanamine (408 mg, 7.04 mmol) in dichloromethane (5.0 mL) was cooled to 0 ° C, to which 1- (bromomethyl) -3-nitro-5- in dichloromethane (5.0 mL) A solution of (trifluoromethyl) benzene (500 mg, 1.76 mmol) was added slowly. The mixture was allowed to warm to rt and stirred for 18 h. The mixture was poured into water and the layers separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 170 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.13 (d, J = 6.0 Hz, 6H), 2.96 (br s, 1H), 4.11 (br s, 2H), 8.32 (s, 1H), 8.43 ( s, 1 H), 8.64 (s, 1 H).

Step 2 : tert-butyl isopropyl (3-nitro-5- (trifluoromethyl) benzyl) carbamate

N- (3-nitro-5- (trifluoromethyl) benzyl) propan-2-amine in the presence of DIPEA (168 mg, 1.30 mmol) in dichloromethane (5.0 mL) according to the procedure described in step 3 of intermediate A1. (Step 1 intermediate) (170 mg, 0.65 mmol) with di-tert-butyl dicarbonate (156 mg, 0.71 mmol) gave the title compound to yield 240 mg of product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.15 (d, J = 6.8 Hz, 6H), 1.57 (s, 9H), 4.47 (br s, 3H), 7.85 (s, 1H), 8.32 (s , 1H), 8.38 (s, 1H).

Step 3 : tert-butyl 3-amino-5- (trifluoromethyl) benzyl (isopropyl) carbamate

Tert-butyl isopropyl (3-nitro-5- (trifluoromethyl) benzyl) carbamate (2-step intermediate) in ethanol (5.0 mL) and water (1.5 mL) according to the procedure described in step 2 of intermediate C28 ( The title compound was prepared by the reaction of 235 mg, 0.65 mmol) with iron powder (363 mg, 6.50 mmol) and ammonium chloride (278 mg, 5.20 mmol) to afford 170 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.05 (d, J = 6.8 Hz, 6H), 1.42 (s, 9H), 4.21 (br s, 3H), 5.56 (s, 2H), 6.62 (s , 1H), 6.67 (d, J = 8.4 Hz, 2H).

Intermediate C64

3- (1-methyl-1H-pyrazol-4-yl) -5- (trifluoromethyl) aniline

Step 1 : 4- (3-nitro-5- (trifluoromethyl) phenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole

Cesium carbonate (1.80 g, 5.50 mmol) and 1,1'-bis (diphenylphosphino) ferrocene in 1,4-dioxane (10 mL) and water (2.0 mL) following the procedure described in step 2 of intermediate C34. 1-bromo-3-nitro-5- (trifluoromethyl) benzene (1.0 g, 3.70 mmol) and 1- (tetra) in the presence of -palladium (II) dichloride dichloromethane complex (150 mg, 0.18 mmol) Hydro-2H-pyran-2-yl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (1.12 g, 4.07 mmol) gave the title compound to yield 730 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.53-1.68 (m, 2H), 1.69-1.74 (m, 1H), 1.95-2.0 (m, 2H), 2.07-2.10 (m, 1H), 3.65 -3.70 (m, 1H), 3.94-3.97 (m, 1H), 5.45 (dd, J ₁ = 2.4 Hz, J ₂ = 10.0 Hz, 1H), 7.86 (s, 1H), 8.32 (s, 1H), 8.51 (s, 1 H), 8.75 (s, 1 H), 8.87 (s, 1 H).

Step 2 : 4- (3-nitro-5- (trifluoromethyl) phenyl) -1H-pyrazole

4- (3-nitro-5- (trifluoromethyl) phenyl) -1- (tetrahydro-2H) with hydrochloric acid in ethyl acetate (10 mL) in methanol (5.0 mL) following the procedure described in step 1 of intermediate C57. The title compound was prepared by the reaction of -pyran-2-yl) -1H-pyrazole (one step intermediate) (350 mg, 1.03 mmol), resulting in 257 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.25 (s, 1H), 8.29 (s, 1H), 8.65 (s, 1H), 8.71 (s, 1H), 8.72 (d, J = 2.0 Hz, 1H), 13.24 (s, 1 H).

Step 3 : 1-methyl-4- (3-nitro-5- (trifluoromethyl) phenyl) -1H-pyrazole

4- (3-nitro-5- (trifluoromethyl) in the presence of sodium hydride (60% w / w, 17 mg, 0.42 mmol) in DMF (5.0 mL) according to the procedure described in step 2 of intermediate C57. The title compound was prepared by reaction of phenyl) -1H-pyrazole (2-step intermediate) (100 mg, 0.39 mmol) with methyl iodide (82 mg, 0.58 mmol) to give 60 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.89 (s, 3H), 8.24 (s, 2H), 8.41 (s, 1H), 8.59 (s, 1H), 8.66 (s, 1H).

Step 4 : 3- (1-methyl-1H-pyrazol-4-yl) -5- (trifluoromethyl) aniline

1-methyl-4- (3) in the presence of palladium on carbon (10% w / w, 50% wet, 20 mg) in methanol (5.0 mL) and THF (2.0 mL) according to the procedure described in step 3 of intermediate C1. The title compound was prepared by catalytic hydrogenation of -nitro-5- (trifluoromethyl) phenyl) -1H-pyrazole (3-step intermediate) (55 mg, 0.20 mmol) to yield 35 mg of the compound. . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.85 (s, 3H), 5.56 (s, 2H), 6.68 (s, 1H), 6.95 (s, 2H), 7.79 (s, 1H), 8.12 ( s, 1 H).

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above (steps 1 and 4) are provided in Table 19 below.

Intermediate C66

3-((1-methylazetidin-3-yl) oxy) -5- (trifluoromethyl) aniline

Step 1 : tert-butyl 3- (3-nitro-5- (trifluoromethyl) phenoxy) azetidine-1-carboxylate

3- in the presence of triphenylphosphine (1.9 g, 7.20 mmol) and diisopropyl azodicarboxylate (DIAD) (1.35 mL, 7.20 mmol) in THF (10 mL) according to the procedure described in step 2 of intermediate A2. The title compound was prepared by reaction of nitro-5- (trifluoromethyl) phenol (1.0 g, 4.83 mmol) with N-Boc-3-hydroxyazetidine (1.0 g, 5.80 mmol), yielding 1.52 g of the above. The compound was produced. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.39 (s, 9H), 3.84-3.88 (m, 2H), 4.36 (br s, 2H), 5.27-5.32 (m, 1H), 7.82 (s, 1H), 7.88-7.90 (m, 1H), 8.11 (s, 1H).

Step 2 : 3- (3-nitro-5- (trifluoromethyl) phenoxy) azetidine hydrochloride

Hydrochloric acid and tert-butyl 3- (3-nitro-5- (trifluoromethyl) phenoxy) azetidine- in ethyl acetate (20 mL) in ethyl acetate (4.0 mL) following the procedure described in step 1 of intermediate C57. The title compound was prepared by reaction of 1-carboxylate (one step intermediate) (1.50 g, 5.73 mmol), resulting in 918 mg of the compound (isolated from hydrochloric acid salts). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.02-4.06 (m, 2H), 4.46-4.51 (m, 2H), 5.39-5.42 (m, 1H), 7.77 (d, J = 1.5 Hz, 1H ), 7.95 (t, J = 2.0 Hz, 1H), 8.14 (s, 1H), 9.68 (br s, 2H); ESI-MS (m / z) 263 (M + H-HCl) ⁺ .

Step 3 : 1-methyl-3- (3-nitro-5- (trifluoromethyl) phenoxy) azetidine

To a stirred solution of 3- (3-nitro-5- (trifluoromethyl) phenoxy) azetidine hydrochloride (2-step intermediate) (900 mg, 3.01 mmol) in dichloroethane (10 mL) formaldehyde (37 %, 135 mg, 4.52 mmol) and sodium triacetoxyborohydride (STAB) (958 mg, 4.52 mmol) were added and the mixture was stirred at rt for 18 h. The mixture was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 790 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.29 (s, 3H), 3.02-3.06 (m, 2H), 3.72-3.76 (m, 2H), 5.08 (t, J = 5.6 Hz, 1H), 7.67 (s, 1 H), 7.85 (t, J = 2.0 Hz, 1 H), 8.07 (s, 1 H); ESI-MS (m / z) 277 (M + H) ⁺ .

Step 4 : 3-((1-methylazetidin-3-yl) oxy) -5- (trifluoromethyl) aniline

1-methyl-3- (3-nitro-5- (trifluoromethyl) phenoxy) azetidine (3-step intermediate in methanol (10 mL) and water (10 mL) according to the procedure described in step 2 of intermediate C28 ) (780 mg, 2.82 mmol) with iron powder (780 mg, 14.1 mmol) and ammonium chloride (1.5 g, 28.2 mmol) to prepare the title compound to yield 623 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.27 (s, 3H), 2.92-2.95 (m, 2H), 3.69 (dt, J ₁ = 2.0 Hz, J ₁ = 6.0 Hz, 2H), 4.67- 4.70 (m, 1 H), 5.61 (s, 2 H), 6.17 (s, 1 H), 6.23 (t, J = 1.6 Hz, 1 H), 6.45 (s, 1 H); ESI-MS (m / z) 247 (M + H) ⁺ .

Intermediate C68

1-((4-fluorophenyl) carbamoyl) cyclopropanecarboxylic acid

To a stirred solution of cyclopropane-1,1-dicarboxylic acid (400 mg, 3.05 mmol) in dichloromethane (10 mL) is added thionyl chloride (222 μL, 3.05 mmol), followed by catalytic amount of DMF, and the mixture is brought to room temperature. Stirred for 2 h. The mixture was concentrated under reduced pressure and the residue was dissolved in THF (10 mL). The solution was cooled to 0 ° C; 4-fluoroaniline (0.29 mL, 3.05 mmol) was added to the reaction mixture, followed by triethylamine (0.43 mL, 3.08 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate solution, water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by column chromatography to yield 270 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.41 (s, 4H), 7.12-7.17 (m, 2H), 7.61-7.64 (m, 2H), 10.51 (s, 1H), 12.81 (s, 1H ).

Intermediate C71

3-((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) -5- (trifluoromethyl) aniline

Step 1 : (1S, 4S) -tert-butyl 5- (3-nitro-5- (trifluoromethyl) phenyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate

Sodium tert-butoxide (350 mg, 3.64 mmol), tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) ₃ ) in toluene (10 mL) according to the procedure described in step 2 of intermediate C34 ( 138 mg, 0.15 mmol) and 1-bromo-3-nitro-5- (trifluoromethyl) benzene (2.7 g, 13.6 mmol) and (1S) in the presence of Xantphos (175 mg, 0.30 mmol). The title compound was prepared by reaction of 4S) -tert-butyl 2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (500 mg, 2.52 mmol) to yield 840 mg of the title compound. . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.60 (s, 9H), 2.06 (d, J = 5.2 Hz, 2H), 3.26-3.51 (m, 4H), 4.52 (s, 1H), 4.61- 4.75 (m, 1 H), 6.99 (s, 1 H), 7.51 (s, 1 H), 7.76 (s, 1 H).

Step 2 : (1S, 4S) -2- (3-nitro-5- (trifluoromethyl) phenyl) -2,5-diazabicyclo [2.2.1] heptane hydrochloride

(1S, 4S) -tert-butyl 5- (3-nitro-5- (trifluoro) with hydrochloric acid in 1,4-dioxane (4.0 mL) in ethanol (8.0 mL) following the procedure described in step 1 of intermediate C57. Romethyl) phenyl) -2,5-diazabicyclo [2.2.1] heptan-2-carboxylate (stage 1 intermediate) (400 mg, 1.13 mmol) to prepare the title compound, yielding 280 mg of the above compound. The compound was produced. The crude amine proceeded to the next step as it was.

Step 3 : (1S, 4S) -2-methyl-5- (3-nitro-5- (trifluoromethyl) phenyl) -2,5-diazabicyclo [2.2.1] heptane

(1S, 4S) -2- (3-nitro-5- (trifluoromethyl) phenyl in the presence of potassium carbonate (142 mg, 1.03 mmol) in acetonitrile (12 mL) according to the procedure described in step 2 of intermediate C57. ) The title compound was prepared by the reaction of 2,5-diazabicyclo [2.2.1] heptane hydrochloride (2 step intermediate) (275 mg, 0.94 mmol) with methyl iodide (147 mg, 1.03 mmol). , 60 mg of the compound were produced. The crude amine proceeded to the next step as it was.

Step 4 : 3-((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) -5- (trifluoromethyl) aniline

(1S, 4S) -2-methyl-5- (3 in the presence of palladium on carbon (10% w / w, 50% wet, 20 mg) in methanol (10 mL) according to the procedure described in step 3 of intermediate C1. The title compound was prepared by catalytic hydrogenation of -nitro-5- (trifluoromethyl) phenyl) -2,5-diazabicyclo [2.2.1] heptane (3-step intermediate) (60 mg, 0.19 mmol) , 60 mg (crude) of the compound were produced. The crude amine proceeded to the next step as it was due to poor solubility and instability in solution form.

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 20 below.

Intermediate C74

4- (3-amino-5- (trifluoromethyl) phenyl) morpholin-3-one

Step 1 : 4- (3-nitro-5- (trifluoromethyl) phenyl) morpholine

1-bromo-3-nitro-5- (in the presence of N, N-diisopropylethylamine (DIPEA) (2.7 mL, 14.8 mmol) in DMSO (10 mL) according to the procedure described in step 2 of intermediate C1. The title compound was prepared by reaction of trifluoromethyl) benzene (2.0 g, 7.40 mmol) with morpholine (1.61 g, 18.5 mmol) to give 1.1 g of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.36 (t, J = 5.2 Hz, 4H), 3.75 (t, J = 4.8 Hz, 4H), 7.64 (s, 1H), 7.78 (s, 1H) , 7.91 (t, J = 2.4 Hz, 1H).

Step 2 : 4- (3-nitro-5- (trifluoromethyl) phenyl) morpholin-3-one

4- (3-nitro-5- (trifluoromethyl) phenyl) morpholine (stage 1 intermediate) (1.1 g, 3.98 mmol), benzyltributylammonium chloride (7.5 g, 23.9 mmol in dichloromethane (70 mL) ) And KMnO ₄ (3.77 g, 23.9 mmol) were heated at 70 ° C. overnight. The mixture was cooled to rt and diluted with ethyl acetate. The suspension was filtered through celite and the bed was washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 340 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.91-3.94 (m, 2H), 3.94-4.03 (m, 2H), 4.29 (s, 2H), 8.37 (d, J = 10.8 Hz, 2H), 8.66 (t, J = 1.6 Hz, 1H).

Step 3 : 4- (3-amino-5- (trifluoromethyl) phenyl) morpholin-3-one

4- (3-nitro-5- (trifluoromethyl) phenyl) morpholin-3-one (2-step intermediate) in ethanol (10 mL) and water (4.0 mL) following the procedure described in step 2 of intermediate C28 (300 mg, 1.14 mmol) with iron powder (636 mg, 11.3 mmol) and ammonium chloride (487 mg, 9.10 mmol) gave the title compound to yield 150 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.69 (t, J = 5.2 Hz, 2H), 3.95 (t, J = 4.8 Hz, 2H), 4.19 (s, 2H), 5.72 (s, 2H) ), 6.76 (s, 2H), 6.82 (d, J = 12.4 Hz, 2H).

Intermediate C79

3'-amino-5 '-(trifluoromethyl)-[1,1'-biphenyl] -4-carbonitrile

Step 1 : 3'-nitro-5 '-(trifluoromethyl)-[1,1'-biphenyl] -4-carbonitrile

To a solution of 1-bromo-3-nitro-5- (trifluoromethyl) benzene (250 mg, 0.92 mmol) in 1,4-dioxane (10 mL) and water (1.0 mL), 4- (4, [1,1 ′ with 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzonitrile (215 mg, 0.94 mmol), dichloromethane (39 mg, 0.05 mmol) -Bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex and potassium carbonate (269 mg, 1.95 mmol) were added and the mixture was heated at 100 ° C for 18 h. The mixture was cooled to rt and diluted with ethyl acetate. The solution was filtered through celite. The filtrate was washed with water followed by brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 350 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (dd, J ₁ = 1.6 Hz, J ₂ = 3.6 Hz, 2H), 8.14 (dd, J ₁ = 2.0 Hz, J ₂ = 6.4 Hz, 2H) , 8.60 (s, 2 H), 8.81 (t, J = 1.6 Hz, 1 H).

Step 2 : 3'-amino-5 '-(trifluoromethyl)-[1,1'-biphenyl] -4-carbonitrile

3'-nitro-5 '-(trifluoromethyl)-[1,1'-biphenyl] -4-carbo in ethanol (5.0 mL) and water (2.0 mL) following the procedure described in step 2 of intermediate C28 The title compound is prepared by reaction of nitrile (2 step intermediate) (150 mg, 0.51 mmol) with iron powder (286 mg, 5.13 mmol) and ammonium chloride (219 mg, 4.10 mmol) to yield 50 mg of the compound. It was. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.80 (s, 2H), 6.92 (s, 1H), 7.08 (s, 1H), 7.12 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H).

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 21 below.

Intermediate C81

4- (1- (4-ethylpiperazin-1-yl) ethyl) -3- (trifluoromethyl) aniline

Step 1 : 1- (4-nitro-2- (trifluoromethyl) phenyl) ethanone

After purging argon for 15 minutes, 1-bromo-4-nitro-2- (trifluoromethyl) benzene (500 mg, 1.85 mmol) and tributyl (1-ethoxyvinyl) tin in DMF (5.0 mL) To a stirred solution of (806 mg, 2.22 mmol) was added tetrakis (triphenylphosphine) palladium (0) (136 mg, 0.09 mmol). The mixture was heated at 90 ° C for 18 h. The mixture was cooled to room temperature and poured into dilute hydrochloric acid (50 mL). The solution was stirred at rt for 1 h. The aqueous mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 125 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.65 (s, 3H), 7.66 (d, J = 8.4 Hz, 1H), 8.50 (m, 1H), 78.60 (s, 1H).

Step 2 : 1- (4-nitro-2- (trifluoromethyl) phenyl) ethanol

To a solution of 1- (4-nitro-2- (trifluoromethyl) phenyl) ethanone (1 step intermediate) (120 mg, 0.52 mmol) in methanol (5.0 mL) sodium borohydride (20 mg) at 0 ° C. , 0.52 mmol) was added and the mixture was stirred at rt for 3 h. The reaction was quenched with acetone (2.0 mL) and diluted with water. The aqueous mixture was extracted twice with chloroform. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 120 mg of the desired compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.53 (d, J = 6.4 Hz, 3H), 2.15 (d, J = 2.8 Hz, 1H), 5.42-5.43 (br s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 8.46 (dd, J ₁ = 2.4 Hz, J ₂ = 8.8 Hz, 1H), 8.52 (s, 1H).

Step 3 : 1-ethyl-4- (1- (4-nitro-2- (trifluoromethyl) phenyl) ethyl) piperazine

To a stirred solution of 1- (4-nitro-2- (trifluoromethyl) phenyl) ethanol (2-step intermediate) (600 mg, 2.56 mmol) in dichloromethane (5.0 mL) triethylamine (1.0 mL, 7.68 mmol), and then methanesulfonyl chloride (mesyl chloride) (587 mg, 5.12 mmol) was added at 0 ° C. and the mixture was stirred at rt for 1 h. The reaction was quenched with ice water mixture and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated at 25 ° C. under reduced pressure. The residue was dissolved in DMF (10 mL) and cooled to 0 ° C. To this solution was added potassium carbonate (706 mg, 5.12 mmol) followed by N-ethylpiperazine (292 mg, 2.56 mmol) and the mixture was stirred at rt overnight. The reaction was quenched with ice water mixture and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 320 mg of the desired compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.09 (t, J = 7.2 Hz, 3H), 1.32 (d, J = 10.4 Hz, 3H), 2.30-2.46 (m, 10H), 3.77 (q, J = 4.8 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.40 (dd, J ₁ = 2.4 Hz, J ₂ = 8.8 Hz, 1H), 8.51 (s, 1H).

Step 4 : 4- (1- (4-ethylpiperazin-1-yl) ethyl) -3- (trifluoromethyl) aniline

1-ethyl-4- (1- (4-nitro-2- (trifluoromethyl) phenyl) ethyl) piperazine in ethanol (5.0 mL) and water (1.0 mL) following the procedure described in step 2 of intermediate C28 The title compound was prepared by the reaction of (3-step intermediate) (220 mg, 0.66 mmol) with iron powder (371 mg, 6.64 mmol) and ammonium chloride (283 mg, 5.31 mmol), resulting in 80 mg of the compound. . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.03 (t, J = 6.4 Hz, 3H), 1.17-1.23 (m, 5H), 2.51-2.92 (m, 7H), 3.36 (m, 2H), 5.76 (s, 2 H), 6.78-6.81 (br s, 2 H), 7.38 (d, J = 8.4 Hz, 1 H).

Intermediate C82

N- (3-amino-5- (trifluoromethyl) phenyl) propionamide

Step 1 : N- (3-bromo-5- (trifluoromethyl) phenyl) propionamide

EDCI, HCl (7.9 g, 41.6) to a stirred mixture of propionic acid (1.54 g, 20.8 mmol) and 3-bromo-5- (trifluoromethyl) aniline (5.0 g, 20.8 mmol) in dichloromethane (15 mL) mmol), HOBt (2.8 g, 20.8 mmol) and DIPEA (7.0 mL, 41.6 mmol) were added at 0 ° C. The mixture was stirred at rt for 3 h. The mixture was diluted with water and ethyl acetate. The organic layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 2.3 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.90 (t, J = 7.2 Hz, 3H), 2.36 (q, J = 7.6 Hz, 2H), 7.60 (s, 1H), 7.98 (s, 1H) , 8.11 (s, 1 H), 10.35 (s, 1 H).

Step 2 : N- (3-((diphenylmethylene) amino) -5- (trifluoromethyl) phenyl) propionamide

Cesium carbonate (2.2 g, 6.76 mmol), tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) _{3 in} 1,4-dioxane (10 mL) following the procedure described in step 2 of intermediate C34 ) (232 mg, 0.25 mmol) and (±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthalene (rac-BINAP intermediate 1) (105 mg, 0.16 mmol) The title compound was prepared by reaction of N- (3-bromo-5- (trifluoromethyl) phenyl) propionamide (one step intermediate) (1.0 g, 3.37 mmol) with benzophenone imine (918 mg, 5.06 mmol). To give 1.05 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.05 (t, J = 7.6 Hz, 3H), 2.30 (q, J = 7.6 Hz, 2H), 6.61 (s, 1H), 7.17-7.36 (m, 3H), 7.47-7.69 (m, 9H), 1.06 (s, 1H); ESI-MS (m / z) 397 (M + H) ⁺ .

Step 3 : N- (3-amino-5- (trifluoromethyl) phenyl) propionamide

Hydrochloric acid in 1,4-dioxane (5.0 mL) in THF (10 mL) and N- (3-((diphenylmethylene) amino) -5- (trifluoromethyl) according to the procedure described in step 1 of intermediate C57. The title compound was prepared by reaction of) phenyl) propionamide (two step intermediate) (1.0 g, 2.53 mmol), resulting in 431 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.06 (t, J = 7.6 Hz, 3H), 2.29 (q, J = 7.6 Hz, 2H), 5.58 (s, 2H), 6.51 (s, 1H) , 7.07 (s, 1 H), 7.10 (s, 1 H), 9.84 (s, 1 H).

Intermediate C83

2- (4-amino-2- (trifluoromethyl) phenyl) -2-methylpropanenitrile

Step 1 : 2- (4-nitro-2- (trifluoromethyl) phenyl) acetonitrile

2-chloro-5-nitrobenzotrifluoride (3.0 g, 13.3 mmol), potassium carbonate (367 mg, 2.66 mmol), potassium iodide (3.3 g, 19.9 mmol) and ethyl cyanoacetate (1.80 g, 15.9 in DMF) mmol) (20 mL) was stirred at rt for 72 h. The mixture was quenched with 10% aqueous citric acid solution and extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was dissolved in a mixture of water (25 mL) and acetic acid (10 mL) and 37% hydrochloric acid was added at room temperature. The mixture was heated to 100 ° C for 30 h. The reaction mixture was cooled to room temperature and quenched with 10% aqueous potassium carbonate solution. The aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 2.3 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) 4.40 (s, 2H), 8.02 (d, J = 8.8 Hz, 1H), 8.49 (s, 1H), 8.60 (dd, J ₁ = 2.4 Hz, J ₂ = 8.4 Hz, 1 H); ESI-MS (m / z) 229 (M ⁻ H) ⁻ .

Step 2 : 2-methyl-2- (4-nitro-2- (trifluoromethyl) phenyl) propanenitrile

To a stirred solution of 2- (4-nitro-2- (trifluoromethyl) phenyl) acetonitrile (500 mg, 2.17 mmol) in THF (15 mL) methyl iodide (925 mg, 6.51 mmol), then potassium tert-butoxide solution (1 M, 6.5 mL, 6.51 mmol) was added at 0 ° C. and the mixture was stirred at rt for 18 h. The mixture was diluted with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 70 mg of the desired compound (fraction) with 400 mg of 2- (4-nitro-2- (trifluoromethyl) phenyl) propanenitrile (fraction-2). -1) was generated. Fraction-2 (400 mg, 1.64 mmol) was dissolved in methyl iodide (465 mg, 3.27) in the presence of potassium tert-butoxide solution (1 M, 3.27 mL, 3.27 mmol) in THF (20 mL) according to the procedure described above. mmol) to give 310 mg of the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.88 (s, 6H), 8.11 (d, J = 9.2 Hz, 1H), 8.55 (s, 2H).

Step 3 : 2- (4-amino-2- (trifluoromethyl) phenyl) -2-methylpropanenitrile

2-methyl-2- (4-nitro-2- (trifluoromethyl) phenyl) propanenitrile (2-step intermediate) in methanol (10 mL) and water (10 mL) following the procedure described in step 2 of intermediate C28 (300 mg, 1.15 mmol) with iron powder (321 mg, 5.76 mmol) and ammonium chloride (308 mg, 5.76 mmol) gave the title compound to yield 137 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.72 (s, 6H), 5.71 (s, 2H), 6.79 (dd, J ₁ = 1.6 Hz, J ₂ = 8.4 Hz, 1H), 6.99 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H); ESI-MS (m / z) 229 (M + H) ⁺ .

Intermediate C84

N- (3-amino-5- (trifluoromethyl) phenyl) -2- (dimethylamino) acetamide

5- in the presence of EDCI, HCl (2.39 mg, 12.5 mmol), HOBt (843 mg, 6.25 mmol) and DIPEA (2.15 mL, 12.5 mmol) in dichloromethane (10 mL) according to the procedure described in step 1 of intermediate C82. The title compound was prepared by reaction of (trifluoromethyl) benzene-1,3-diamine (1.1 g, 6.26 mmol) with N, N-dimethylglycine (644 mg, 6.25 mmol) to give 230 mg of the compound. Generated. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.62 (s, 6H), 3.04 (s, 2H), 5.60 (s, 2H), 6.52 (s, 1H), 7.13 (s, 1H), 7.18 ( s, 1 H), 9.72 (s, 1 H); ESI-MS (m / z) 3261 (M + H) ⁺ .

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 22 below.

Intermediate C86

1- (3-amino-5- (trifluoromethyl) phenyl) -N, N-dimethylazetidin-3-amine

Step 1 : N, N-dimethyl-1- (3-nitro-5- (trifluoromethyl) phenyl) azetidin-3-amine

Sodium tert-butoxide (355 mg, 3.70 mmol), tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ () in 1,4-dioxane (4.0 mL) following the procedure described in step 2 of intermediate C34. dba) ₃ ) (34 mg, 0.04 mmol) and xantose (30 mg, 0.05 mmol) with 1-bromo-3-nitro-5- (trifluoromethyl) benzene (200 mg, 0.74 mmol) The title compound was prepared by reaction of N, N-dimethylazetidin-3-amine hydrochloride (256 mg, 1.48 mmol) to give 155 mg of the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.13 (s, 6H), 3.24-3.27 (m, 1H), 3.79 (t, J = 5.2 Hz, 2H), 4.08 (t, J = 7.6 Hz, 2H), 7.07 (s, 1 H), 7.37 (s, 1 H), 7.63 (s, 1 H); ESI-MS (m / z) 290 (M + H) ⁺ .

Step 2 : 1- (3-amino-5- (trifluoromethyl) phenyl) -N, N-dimethylazetidin-3-amine

N, N-dimethyl-1- (3-nitro-5- (trifluoromethyl) phenyl) azetidine-3- in ethanol (4.0 mL) and water (2.0 mL) following the procedure described in step 2 of intermediate C28. The title compound is prepared by the reaction of an amine (one step intermediate) (150 mg, 0.52 mmol) with iron powder (290 mg, 5.19 mmol) and ammonium chloride (222 mg, 4.15 mmol) to yield 95 mg of the compound. It was. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.14 (s, 6H), 3.13-3.18 (m, 1H), 3.50 (t, J = 5.6 Hz, 2H), 3.86 (t, J = 7.2 Hz, 2H), 5.36 (s, 2H), 5.82 (s, 2H), 6.19 (s, 1H); ESI-MS (m / z) 260 (M + H) ⁺ .

Intermediate C87

(E) -3- (3-amino-5- (trifluoromethyl) phenyl) acrylamide

Step 1 : 3- (3-nitro-5- (trifluoromethyl) phenyl) propionamide

To a solution of 1-bromo-3-nitro-5- (trifluoromethyl) benzene (1.0 g, 3.70 mmol) in degassed DMF (10 mL), propiolamide (511 mg, 7.40 mmol), bis (tri Phenylphosphine) palladium (II) dichloride (129 mg, 0.18 mmol), cupric iodide (71 mg, 0.37 mmol) and triethylamine (1.54 mL, 11.1 mmol) were added at room temperature. The resulting mixture was heated in a microwave reactor at 120 ° C. for 30 minutes. The mixture was cooled to room temperature and quenched with water. The product was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 480 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.92 (br s, 2H), 8.32 (s, 1H), 8.46 (s, 1H), 8.57-8.66 (m, 1H).

Step 2 : (E) -3- (3-amino-5- (trifluoromethyl) phenyl) acrylamide

To a stirred solution of 3- (3-nitro-5- (trifluoromethyl) phenyl) propionolamide (stage 1 intermediate) (201 mg, 0.78 mmol) in a mixture of methanol and water (3: 1, 10 mL) Ammonium chloride (416 mg, 7.78 mmol) was added and the mixture was heated to 80 ° C. Zinc dust (254 mg, 3.84 mmol) was added in small portions to the mixture and stirred at 80 ° C. for 1 hour. The mixture was cooled to rt and diluted with ethyl acetate. The solution was filtered through celite. The filtrate was washed with ethyl acetate and the organic layers were combined and washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by column chromatography to yield 65 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.73 (s, 2H), 6.58 (d, J = 16.0 Hz, 1H), 6.84 (s, 1H), 6.95 (d, J = 7.6 Hz, 2H) , 7.16 (s, 1 H), 7.30 (d, J = 15.6 Hz, 1 H), 7.55 (s, 1 H).

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 23 below.

Intermediate C89

3- (3-amino-5- (trifluoromethyl) phenyl) propionamide

3- (3-nitro-5- (trifluoromethyl) phenyl) propionamide (intermediate C87) in a mixture of ethanol, THF and water (2: 1: 1, 10 mL) following the procedure described in step 2 of intermediate C28 The title compound was prepared by reaction of step 1 intermediate) (200 mg, 0.77 mmol) with iron powder (216 mg, 3.87 mmol) and ammonium chloride (42 mg, 0.77 mmol) to give 110 mg of the compound. . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.90 (s, 2H), 714-7.21 (m, 3H), 7.71 (s, 1H), 8.17 (s, 1H).

Intermediate C90

(E) -3- (3-amino-5- (trifluoromethyl) phenyl) acrylonitrile

To a solution of 3-bromo-5- (trifluoromethyl) aniline (502 mg, 2.09 mmol) in degassed DMF (5.0 mL) acrylonitrile (97 μL, 2.51 mmol), tetrakis (triphenylphosphine Palladium (0) (121 mg, 0.10 mmol) and triethylamine (0.87 mL, 6.27 mmol) were added at room temperature. The resulting mixture was heated in a microwave reactor at 130 ° C. for 30 minutes. The mixture was cooled to room temperature and quenched with water. The product was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 206 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.79 (s, 2H), 7.44 (d, J = 16.8 Hz, 1H), 7.92-7.96 (m, 2H), 7.12 (s, 1H), 7.59 ( d, J = 16.8 Hz, 1H).

Intermediate C91

4- (5-amino-3- (tert-butyl) -1H-pyrazol-1-yl) benzonitrile

To a solution of 4-hydrazinylbenzonitrile (3.0 g, 22.55 mmol) in ethanol (30 mL) is added pivaloyl acetonitrile (3.38 g, 37.1 mmol) followed by PTSA (6.42 g, 33.8 mmol) and the mixture Was heated to reflux for 16 hours using Dean-Stark equipment. The precipitated solid was filtered and dried to yield 3.5 g of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.22 (s, 9H), 5.50 (s, 2H), 7.83-7.93 (m, 5H); ESI-MS (m / z) 241 (M + H) ⁺ .

Intermediate C92

3- (5-amino-3- (tert-butyl) -1H-pyrazol-1-yl) benzonitrile

To a solution of 3-hydrazinylbenzonitrile (500 mg, 3.75 mmol) in hydrochloric acid in 1,4-dioxane (10 mL) was added pivaloyl acetonitrile (565 mg, 4.51 mmol) and the mixture was stirred for 16 hours. Heated to reflux. The mixture was cooled to rt and diluted with water. The solution was basified with saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 830 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.22 (s, 9H), 5.45 (s, 2H), 7.62-7.73 (m, 2H), 7.94-8.03 (m, 3H); ESI-MS (m / z) 241 (M + H) ⁺ .

Intermediate C94

3- (methylsulfonyl) aniline

Step 1 : 1- (methylsulfonyl) -3-nitrobenzene

To a solution of 1-iodo-3-nitrobenzene (500 mg, 2.01 mmol) in degassed DMSO (5.0 mL) sodium methanesulfinate (413 mg, 4.01 mmol), N, N-dimethylethylenediamine (106 mg, 1.20 mmol) copper (I) trifluoromethane sulfonate toluene complex (311 mg, 0.60 mmol) was added and the mixture was evacuated and flushed with nitrogen three times. The mixture was heated at 120 ° C. for 3 hours. The mixture was cooled to rt, quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 360 mg of the desired compound. The compound proceeded to the next step as it was without characterization.

Step 2 : 3- (methylsulfonyl) aniline

1- (methylsulfonyl) -3-nitrobenzene (stage 1 intermediate) in the presence of 10% palladium on carbon (50% wet, 150 mg) in methanol (5.0 mL) according to the procedure described in step 3 of intermediate C1 ( 351 mg, 1.74 mmol) was subjected to catalytic hydrogenation to yield the title compound, resulting in 230 mg of the compound. ESI-MS (m / z) 172 (M + H) ⁺ .

Compound structural formulas, names and analytical data of intermediates prepared according to the procedures described above are provided in Table 24 below.

Intermediate C95

3- (3-methoxyprop-1-ynin-1-yl) -5- (trifluoromethyl) aniline

Step 1 : 3- (3-nitro-5- (trifluoromethyl) phenyl) prop-2-ynin-1-ol

Bis (triphenylphosphine) palladium (II) dichloride (65 mg, 0.09 mmol), copper iodide (35 mg, 0.18 mmol) and triethylamine in DMF (5.0 mL) according to the procedure described in step 1 of intermediate C87. By reaction of 1-bromo-3-nitro-5- (trifluoromethyl) benzene (502 mg, 1.86 mmol) with propargyl alcohol (219 μL, 3.72 mmol) in the presence of (0.8 mL, 5.58 mmol). The title compound was prepared, resulting in 205 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.37 (d, J = 6.0 Hz, 2H), 5.50 (t, J = 6.0 Hz, 1H), 8.26 (s, 1H), 8.46 (d, J = 2.0 Hz, 2H).

Step 2 : 1- (3-methoxyprop-1-ynin-1-yl) -3-nitro-5- (trifluoromethyl) benzene

3- (3-nitro-5- (trifluoromethyl) in the presence of sodium hydride (60% w / w, 240 mg, 6.02 mmol) in THF (10 mL) according to the procedure described in step 2 of intermediate C57. ) Phenyl) prop-2-ynin-1-ol (stage 1 intermediate) (738 mg, 3.01 mmol) with methyl iodide (0.37 mL, 6.02 mmol) prepared the title compound to give 390 mg of The compound was produced. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.38 (s, 3H), 4.41 (s, 2H), 8.36 (s, 1H), 8.49 (s, 1H), 8.53 (s, 1H).

Step 3 : 3- (3-methoxyprop-1-ynin-1-yl) -5- (trifluoromethyl) aniline

1- (3-methoxyprop-1-ynin-1-yl) -3-nitro- in a mixture of ethanol, THF and water (3: 2: 1, 12 mL) following the procedure described in step 2 of intermediate C28 The title compound was prepared by the reaction of 5- (trifluoromethyl) benzene (2 step intermediate) (465 mg, 1.79 mmol) with iron powder (501 mg, 8.97 mmol) and ammonium chloride (95 mg, 1.79 mmol). , 312 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.34 (s, 3H), 4.31 (s, 2H), 5.78 (s, 2H), 7.54 6.81 (s, 1H), 6.86 (s, 1H), 6.87 (s, 1 H); ESI-MS (m / z) 230 (M + H) ⁺ .

Intermediate C97

3- (difluoromethyl) aniline

Step 1 : 1- (difluoromethyl) -3-nitrobenzene

To a stirred solution of 3-nitrobenzaldehyde (506 mg, 3.35 mmol) in anhydrous dichloromethane (10 mL) was added dropwise DAST (1.32 mL, 10.04 mmol) at -78 ° C. The mixture was slowly warmed to rt and stirred for 3 h. The mixture was quenched with saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 332 mg of the desired compound. The compound proceeded to the next step as is without characterization.

Step 2 : 3- (difluoromethyl) aniline

1- (difluoromethyl) -3-nitrobenzene (stage 1 intermediate) in the presence of 10% palladium on carbon (50% wet, 100 mg) in methanol (5.0 mL) according to the procedure described in step 3 of intermediate C1. The title compound was prepared by catalytic hydrogenation of (320 mg, 1.85 mmol) to yield 160 mg of the compound. ESI-MS (m / z) 144 (M + H) ⁺ .

Intermediate C100

2- (3-aminophenyl) -2,2-difluoroethanol

Step 1 : 2,2-difluoro-2- (3-nitrophenyl) ethanol

Ethyl 2,2-difluoro-2- (3-nitrophenyl) acetate (stage 1 of C45) (408 mg, 1.66 mmol) and sodium boro in ethanol (10 mL) following the procedure described in step 2 of intermediate C81. The title compound was prepared by the reaction of hydride (126 mg, 3.32 mmol), resulting in 271 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.89-4.01 (m, 2H), 5.76 (t, J = 6.4 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 8.01 (dd, J ₁ = 0.4 Hz, J ₂ = 7.6 Hz, 1H), 8.31 (s, 1H), 8.36-8.41 (m, 1H).

Step 2 : 2- (3-aminophenyl) -2,2-difluoroethanol

2,2-difluoro-2- (3-nitrophenyl) ethanol in the presence of 10% palladium on carbon (50% wet, 100 mg) in methanol (8.0 mL) according to the procedure described in step 3 of intermediate C1 ( Title compound was prepared by catalytic hydrogenation of 1 step intermediate) (260 mg, 1.28 mmol) to yield 75 mg of the compound. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.70-3.77 (m, 2H), 5.31 (s, 2H), 5.53 (s, 1H), 6.58-6.65 (m, 2H), 6.68 (s, 1H ), 7.05-7.10 (m, 1 H); ESI-MS (m / z) 174 (M + H) ⁺ .

Intermediate C101

3- (3-amino-5- (trifluoromethyl) phenyl) propiononitrile

Step 1 : 3- (3-nitro-5- (trifluoromethyl) phenyl) propiononitrile

Burgess reagent (110) in a stirred solution of 3- (3-nitro-5- (trifluoromethyl) phenyl) propionamide (1 step of C87) (100 mg, 0.38 mmol) in anhydrous dichloromethane (5.0 mL) mg, 0.46 mmol) was added at 0 ° C. and the mixture was stirred at rt for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield 60 mg of the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.72 (d, J = 1.2 Hz, 1H), 8.77 (s, 1H), (d, J = 1.2 Hz, 1H), 8.99 (dd, J ₁ = 1.6 Hz, J ₂ = 2.4 Hz, 1H).

Step 2 : 3- (3-amino-5- (trifluoromethyl) phenyl) propiononitrile

3- (3-nitro-5- (trifluoromethyl) phenyl) propioronitrile (1 in a mixture of ethanol, THF and water (2: 2: 1, 25 mL) according to the procedure described in step 2 of intermediate C28 Step intermediate) (251 mg, 1.04 mmol) with iron powder (292 mg, 5.22 mmol) and ammonium chloride (56 mg, 1.04 mmol) to prepare the title compound to give 121 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.04 (s, 2H), 7.06-7.11 (m, 2H), 7.20 (s, 1H).

Intermediate C106

3- (4-methylpiperazin-1-yl) -5- (methylsulfonyl) aniline

Step 1 : 1- (3-iodo-5-nitrophenyl) -4-methylpiperazine

Of 1-fluoro-3-iodo-5-nitrobenzene (1.0 g, 3.75 mmol) 1-methylpiperazine (1.9 g, 18.7 mmol) in DMSO (10 mL) according to the procedure described in step 1 of intermediate C24. The title compound was prepared by the reaction to yield 901 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.20 (s, 3H), 2.40-2.45 (m, 4H), 3.25-3.30 (m, 4H), 7.61-7.67 (m, 2H), 7.77-7.80 (m, 1 H); ESI-MS (m / z) 348 (M + H) ⁺ .

Step 2 : 1-methyl-4- (3- (methylsulfonyl) -5-nitrophenyl) piperazine

In the presence of N, N-dimethylethylenediamine (73 mg, 0.83 mmol) and copper (I) trifluoromethane sulfonate toluene complex (215 mg, 0.42 mmol) according to the procedure described in step 1 of intermediate C94, The title compound was prepared by reaction of (3-iodo-5-nitrophenyl) -4-methylpiperazine (one step intermediate) (481 mg, 1.38 mmol) with sodium methanesulfinate (282 mg, 2.77 mmol) , 310 mg of the compound were produced. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.20 (s, 3H), 2.44-2.49 (m, 4H), 2.54 (s, 3H), 3.38-3.42 (m, 4H), 7.74-7.77 (m , 1H), 7.89-7. 94 (m, 2H); ESI-MS (m / z) 300 (M + H) ⁺ .

Step 3 : 3- (4-methylpiperazin-1-yl) -5- (methylsulfonyl) aniline

1-methyl-4- (3- (methylsulfonyl) -5-nitro in the presence of 10% palladium on carbon (50% wet, 150 mg) in methanol (10 mL) according to the procedure described in step 3 of intermediate C1. The title compound was prepared by catalytic hydrogenation of phenyl) piperazine (2-step intermediate) (301 mg, 1.00 mmol) to give 110 mg of this compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.22 (s, 3H), 2.41-2.47 (m, 4H), 3.08 (s, 3H), 3.09-3.14 (m, 4H), 5.45 (s, 2H ), 6.36-6.39 (m, 1 H), 6.51-6.57 (m, 2H); ESI-MS (m / z) 270 (M + H) ⁺ .

Example

The overall procedure for the synthesis of the examples is described in Methods A-R. All examples were prepared according to any of the methods described below from the appropriate combination of intermediates. The names, structural formulas, intermediates / methods and characterization data used for each example are provided in Table 25.

Method A

3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4-ethylpiperazin- Preparation of 1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide

Step 1 : N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-hydroxybenzamide

4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline (intermediate C1) (500 g, 1.74 mmol) and methyl 3-hydroxy in anhydrous THF (5.0 mL) A mixture of benzoate (intermediate B2) (317 mg, 1.91 mmol) was cooled to -20 ° C and potassium tert-butoxide (1 M, 10 mL, 10.44 mmol) was added. The mixture was stirred at rt for 3 h. The reaction mixture was cooled to -20 ° C and quenched with saturated sodium bicarbonate solution. The aqueous mixture was extracted twice with ethyl acetate and the organic layers combined and washed with water, then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to yield 220 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.98 (t, J = 6.8 Hz, 3H), 2.31-2.50 (m, 8H), 2.51 (br s, 2H), 3.56 (s, 2H), 6.98 -7.01 (br d, 1H), 7.31-7.35 (m, 2H), 7.39 (d, J = 6.4 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.4 Hz , 1H), 8.21 (s, 1H), 9.79 (s, 1H), 10.42 (s, 1H); ESI-MS (m / z) 408 (M + H) ⁺ .

Step 2 : tert-butyl 4- (3-((4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) carbamoyl) phenoxy) -6H-pyri Mido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate

N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-hydroxybenzamide (stage 1 intermediate) in DMF (5.0 mL) (200 mg, 0.49 mmol) and tert-butyl 4-chloro-6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate (intermediate A1) (134 mg, 0.49 mmol) Cesium carbonate (241 mg, 0.74 mmol) was added to the stirred solution of and the mixture was stirred at 130 ° C for 2 h. The mixture was cooled to rt and diluted with a mixture of ethyl acetate and water. The organic layers were separated and washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to give 245 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.98 (t, J = 7.2 Hz, 3H), 1.50 (s, 9H), 2.39-2.50 (m, 10H), 3.56 (s, 2H), 3.91 ( t, J = 4.0 Hz, 2H), 4.39 (t, J = 4.0 Hz, 2H), 7.46 (dd, J ₁ = 1.6 Hz, J ₂ = 8.0 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 8.04 (d, J = 8.0 Hz, 2H), 8.20 (s, 1H), 10.52 (s, 1H); ESI-MS (m / z) 643 (M + H) ⁺ .

Step 3 : 3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4-ethyl Piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide

Tert-butyl 4- (3-((4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) carbamoyl) phenoxy)-in ethanol (3.0 mL)- To a stirred solution of 6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate (two-step intermediate) (220 mg, 0.34 mmol) at 1,4- Hydrochloric acid in dioxane (7.0 mL) was added and the mixture was stirred at rt for 3 h. The mixture was diluted with ethyl acetate and water. The organic layer was washed with water, saturated sodium bicarbonate solution and then brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 105 mg of the desired product.

Method B

4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-(((2 Preparation of-(dimethylamino) ethyl) (methyl) amino) methyl) -3- (trifluoromethyl) phenyl) benzamide

Step 1 : tert-butyl 4- (2-chloro-5- (methoxycarbonyl) phenoxy) -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxyl Rate

Methyl 4-chloro-3-hydroxybenzoate (Intermediate B1) (226 mg, 1.21 mmol) and tert-butyl 4-chloro-6H-pyrimido [5,4-b] [1, in DMF (10 mL) 4] Cesium carbonate (540 mg, 1.65 mmol) is added to a stirred solution of oxazine-8 (7H) -carboxylate (Intermediate A1) (300 mg, 1.10 mmol) and the mixture is stirred at 130 ° C. for 3 hours. It was. The mixture was cooled to room temperature and quenched with saturated aqueous solution of sodium bicarbonate. The aqueous mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 334 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.50 (s, 9H), 3.86 (s, 3H), 3.94 (t, J = 4.4 Hz, 2H), 4.40 (t, J = 4.0 Hz, 2H) , 7.79 (d, J = 8.4 Hz, 1H), 7.85-7.88 (m, 2H), 8.04 (s, 1H).

Step 2 : 4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4- ( ((2- (dimethylamino) ethyl) (methyl) amino) methyl) -3- (trifluoromethyl) phenyl) benzamide

Tert-butyl 4- (2-chloro-5- (methoxy) in the presence of potassium tert-butoxide (1 M, 1.42 mL, 1.42 mmol) in dry THF (20 mL) according to the procedure described in step 1 of Method A Carbonyl) phenoxy) -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate (stage 1 intermediate) (100 mg, 0.24 mmol) and N ^1- ( 4-amino-2- (trifluoromethyl) benzyl) -N ¹ , N ² , N ² -trimethylethane-1,2-diamine (intermediate C33) (58 mg, 0.22 mmol) gave the title compound. To give 20 mg of product.

Method B '

4-Chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (piperazin- Preparation of 1-yl) -5- (trifluoromethyl) phenyl) benzamide

Step 1 : tert-butyl 4- (3- (4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) Oxy) benzamido) -5- (trifluoromethyl) phenyl) piperazine-1-carboxylate

Tert-butyl 4- (2-chloro-5- (methoxy) in the presence of potassium tert-butoxide (1 M, 2.0 mL, 2.06 mmol) in dry THF (10 mL) according to the procedure described in step 1 of Method A Carbonyl) phenoxy) -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate (Step 1-Method B) (150 mg, 0.34 mmol) and tert- The title compound is prepared by the reaction of butyl 4- (3-amino-5- (trifluoromethyl) phenyl) piperazine-1-carboxylate (Intermediate C39) (107 mg, 0.31 mmol) to give 118 mg of the product. Produced. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.43 (s, 9H), 3.19-3.21 (m, 4H), 3.46-3.52 (m, 6H), 4.21 (t, J = 4.0 Hz, 2H) 6.99 (s, 1 H), 7.61-7.89 (m, 7 H), 10.40 (s, 1 H); ESI-MS (m / z) 635 (M + H) ⁺ .

Step 2 : 4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- ( Piperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide

Hydrochloric acid (4 M, 20 mL) in 1,4-dioxane in ethanol (4.0 mL) and tert-butyl 4- (3- (4-chloro-3-((7)) following the procedure described in step 3 of Method A , 8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamido) -5- (trifluoromethyl) phenyl) piperazine-1 The title compound was prepared by reaction of carboxylate (one step intermediate) (110 mg, 0.17 mmol) to give 54 mg of product.

Method C

4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) amino) -N- (4-((4- Preparation of ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide

Step 1 : 4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-nitrobenzamide

To a stirred solution of 4-chloro-3-nitrobenzoic acid (1.0 g, 4.97 mmol) in dichloromethane (10 mL) was added oxalyl chloride (500 μL, 5.30 mmol) followed by a catalytic amount of DMF and the mixture at room temperature. Stir for 2 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The solution was cooled to 0 ° C .; 4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline (intermediate C1) (1.0 g, 3.30 mmol) was added to the reaction mixture followed by DIPEA (1.5 mL, 8.30 mmol) was added. The resulting mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted twice with ethyl acetate. The organic extracts were combined and washed with saturated sodium bicarbonate solution, water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by column chromatography to yield 1.43 g of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.98 (t, J = 7.2 Hz, 3H), 2.28-2.39 (m, 10H), 3.57 (s, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.98-8.04 (m, 2H), 8.16 (s, 1H), 8.27 (dd, J ₁ = 2.4 Hz, J ₂ = 8.4 Hz, 1H), 8.65 (s, 1H), 10.77 (s, 1H ).

Step 2 : 3-amino-4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide

4-Chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3 in a mixture of ethyl methanol and water (1: 1, 60 mL) To a stirred solution of nitrobenzamide (one step intermediate) (1.4 g, 2.97 mmol) was added ammonium chloride (1.6 g, 29.7 mmol) followed by iron powder (830 mg, 14.8 mmol) in small portions at 80 ° C. The mixture was stirred at 80 ° C for 2 h. The mixture was cooled to rt, filtered and concentrated. The residue was diluted with a mixture of ethyl acetate and water. The organic layers were separated, washed with water, then brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue obtained was purified by column chromatography to yield 732 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.98 (t, J = 7.2 Hz, 3H), 2.28-2.39 (m, 10H), 3.55 (s, 2H), 5.60 (s, 2H), 7.13 ( dd, J ₁ = 2.4 Hz, J ₂ = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 1H), 8.01 (dd, J ₁ = 2.0 Hz , J ₂ = 8.8 Hz, 1H), 8.18 (s, 1H), 10.41 (s, 1H); ESI-MS (m / z) 441 (M + H) ⁺ .

Step 3 : tert-butyl 4-((2-chloro-5-((4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) carbamoyl) phenyl) Amino) -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate

3-amino-4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide in toluene (5.0 mL) (2 step intermediate) ) (150 mg, 0.34 mmol) and tert-butyl 4-chloro-6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate (intermediate A1) (102 mg, 0.37 mmol) in a stirred solution of sodium tert-butoxide (36 mg, 0.37 mmol), tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) ₃ ) (12 mg, 0.01 mmol) and ( ±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthalene (rac-BINAP) (13 mg, 0.02 mmol) is added and the mixture is 25 h at 140 ° C. in a sealed test tube. Was stirred. The mixture was diluted with ethyl acetate and the organic mixture was washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by column chromatography to yield 67 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.98 (t, J = 6.8 Hz, 3H), 1.49 (s, 9H), 2.30-2.39 (m, 10H), 3.57 (s, 2H), 3.90 ( t, J = 8.0 Hz, 2H), 4.15 (t, J = 8.0 Hz, 2H), 7.72 (t, J = 7.2 Hz, 2H), 7.78 (m, 1H), 8.02-8.04 (m, 2H), 8.20 (s, 1 H), 8.43 (s, 1 H), 8.55 (s, 1 H), 10.56 (s, 1 H); ESI-MS (m / z) 674 (M ⁻ H) ⁻ .

Step 4 : 4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) amino) -N- (4- ( (4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide

Hydrochloric acid and 1,4-dioxane (4.0 mL) in ethanol (4.0 mL) and tert-butyl 4-((2-chloro-5-((4-((4- Ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) carbamoyl) phenyl) amino) -6H-pyrimido [5,4-b] [1,4] oxazine-8 ( The title compound was prepared by reaction of 7H) -carboxylate (3 step intermediate) (60 mg, 0.09 mmol) to give 19 mg of product.

Method D

4-chloro-N- (3- (cyanomethyl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl Preparation of oxy) benzamide

Tert-butyl 4- (2-chloro-5- (methoxycarbonyl) phenoxy) -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) in toluene (5.0 mL) To a stirred solution of) -carboxylate (Step 1-Method B) (100 mg, 0.24 mmol) 2- (3-aminophenyl) acetonitrile (31 mg, 0.24 mmol) and trimethyl aluminum solution (2 M, 237 μL) , 0.47 mmol) was added at 0 ° C. The mixture was stirred at rt for 2 h. The mixture was poured into ice water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 68 mg of the desired product.

Method E

4-chloro-N- (3- (cyanodifluoromethyl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazine-4 Preparation of -yl) oxy) benzamide

Step 1 : ethyl 2- (3- (3-((tert-butyldimethylsilyl) oxy) -4-chlorobenzamido) phenyl) -2,2-difluoroacetate

Oxalyl chloride (364 μL, 4.19 mmol) in a stirred solution of 3-((tert-butyldimethylsilyl) oxy) -4-chlorobenzoic acid (600 mg, 2.09 mmol) in dichloromethane (10 mL) followed by a catalytic amount DMF was added and the mixture was stirred at rt for 2 h. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (10 mL). The solution was cooled to 0 ° C; Ethyl 2- (3-aminophenyl) -2,2-difluoroacetate (intermediate C45) (495 mg, 2.30 mmol) was added to the reaction mixture followed by DIPEA (1.12 mL, 6.27 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate solution, water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by column chromatography to yield 655 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.27-0.35 (m, 6H), 1.02 (s, 9H), 1.27 (t, J = 6.8 Hz, 3H), 4.33 (q, J = 7.2 Hz, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.51-7.64 (m, 4H), 7.97 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 10.54 (s, 1H); ESI-MS (m / z) 484 (M + H) < + >.

Step 2 : N- (3- (2-amino-1, 1-difluoro-2-oxoethyl) phenyl) -4-chloro-3-hydroxybenzamide

Ethyl 2- (3- (3-((tert-butyldimethylsilyl) oxy) -4-chlorobenzamido) phenyl) -2,2-difluoroacetate (stage 1 intermediate) (650 mg, 1.34 mmol) And a mixture of ammonia solution (7M in methanol, 10 mL) were heated in a sealed test tube at 80 ° C. for 4 hours. The reaction mixture was cooled down and concentrated under reduced pressure to yield 560 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.32 (d, J = 8.0 Hz, 1H), 7.43-7.53 (m, 4H), 7.92 (d, J = 8.4 Hz, 1H), 8.03 (s, 2H), 8.37 (s, 1 H), 10.47 (s, 1 H), 10.51 (s, 1 H); ESI-MS (m / z) 341 (M + H) ⁺ .

Step 3 : N- (3- (2-amino-1, 1-difluoro-2-oxoethyl) phenyl) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5 , 4-b] [1,4] oxazin-4-yl) oxy) benzamide

N- (3- (2-amino-1, 1-difluoro-2-oxoethyl) phenyl) -4-chloro-3-hydroxybenzamide (2-step intermediate) in DMF (5.0 mL) (250 mg) , 0.73 mmol) and tert-butyl 4-chloro-6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate (intermediate A1) (200 mg, 0.74 mmol) Cesium carbonate (360 mg, 1.10 mmol) was added to the stirred solution and the mixture was stirred at 130 ° C. for 3 hours. The mixture was cooled to room temperature and quenched with saturated aqueous solution of sodium bicarbonate. The aqueous mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 45 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.51 (br s, 2H), 4.19-4.22 (m, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.4 Hz , 1H), 7.66-7.91 (m, 6H), 7.94 (d, J = 8.0 Hz, 1H), 8.07 (m, 1H), 8.38 (s, 1H), 10.52 (s, 1H); ESI-MS (m / z) 476 (M + H) ⁺ .

Step 4 : 4-chloro-N- (3- (cyanodifluoromethyl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] jade Photo-4-yl) oxy benzamide

N- (3- (2-amino-1, 1-difluoro-2-oxoethyl) phenyl) -4-chloro-3-((7,8-dihydro-6H-) in dichloromethane (3.0 mL) To a solution of pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide (3 step intermediate) (40 mg, 0.08 mmol) was added Burgess reagent (76.8 mg, 0.32 mmol). Was added and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography to yield 7.0 mg of the desired compound.

Method F

4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3-hydroxy-5 Preparation of-(trifluoromethyl) phenyl) benzamide

Step 1 : 4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3-meth Methoxy-5- (trifluoromethyl) phenyl) benzamide

Tert-butyl 4- (2-chloro-5- (methoxy) in the presence of potassium tert-butoxide (1 M, 1.42 mL, 1.42 mmol) in dry THF (3.0 mL) according to the procedure described in step 1 of Method A Carbonyl) phenoxy) -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate (Step 1-Method B) (100 mg, 0.24 mmol) and 3- The title compound was prepared by reaction of methoxy-5- (trifluoromethyl) aniline (45 mg, 0.24 mmol), resulting in 75 mg of product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.51 (br s, 2H), 3.83 (s, 3H), 4.20 (t, J = 4.0 Hz, 2H), 7.00 (s, 1H), 7.69-7.90 (m, 7 H), 10.56 (s, 1 H); ESI-MS (m / z) 481 (M + H) ⁺ .

Step 2 : 4-Chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3-hydro Roxy-5- (trifluoromethyl) phenyl) benzamide

4-Chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- in dichloromethane (2.0 mL) To a solution of (3-methoxy-5- (trifluoromethyl) phenyl) benzamide (stage 1 intermediate) (70 mg, 0.14 mmol) was added 0 boron tribromide (1M in dichloromethane, 1.2 mL, 1.16 mmol) to 0 Add at C and stir the mixture for 4 h at room temperature. The reaction mixture was quenched with methanol at 0 ° C. and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue was purified by flash column chromatography to yield 25 mg of the desired compound.

Method G

4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((5-oxo-5,6,7,8 Preparation of Tetrahydropyrido [2,3-d] pyrimidin-4-yl) oxy) benzamide

Step 1 : 4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-hydroxybenzamide

Methyl 4-chloro-3-hydroxybenzoate (Intermediate B1) in the presence of potassium tert-butoxide (1 M, 8.4 mL, 8.39 mmol) in dry THF (8.0 mL) according to the procedure described in step 1 of Method A. By the reaction of (260 mg, 1.39 mmol) and 4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline (intermediate C1) (400 mg, 1.39 mmol) The compound was prepared, resulting in 200 mg of product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.98 (t, J = 7.2 Hz, 3H), 2.33-2.55 (m, 6H), 3.33 (br s, 4H), 3.56 (s, 2H), 7.42 -7.53 (m, 3H), 7.70 (d, J = 8.4 Hz, 1H), 8.01 (dd, J ₁ = 2.0 Hz, J ₂ = 8.4 Hz, 1H), 8.32 (s, 1H), 10.50 (s, 1H), 10.60 (br s, 1H).

Step 2 : 4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((8- (4-methoxybenzyl ) -5-oxo-5,6,7,8-tetrahydropyrido [2,3-d] pyrimidin-4-yl) oxy) benzamide

4-Chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-hydroxybenzamide in step 1 (20 mL) (Step 1 Intermediate) (872 mg, 1.97 mmol) and 4-chloro-8- (4-methoxybenzyl) -7,8-dihydropyrido [2,3-d] pyrimidin-5 (6H) -one (intermediate) To a stirred solution of A9) (600 mg, 1.97 mmol) cesium carbonate (3.2 g, 9.85 mmol) was added and the mixture was stirred at 50 ° C for 3 h. The mixture was cooled to room temperature and quenched with water. The aqueous mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 400 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.99 (t, J = 7.2 Hz, 3H), 2.40-2.51 (m, 10H), 2.68 (t, J = 7.6 Hz, 2H), 3.57 (s, 2H), 3.65 (t, J = 6.8 Hz, 2H), 3.74 (s, 3H), 4.90 (s, 2H), 6.92 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.91-7.94 (br s, 2H), 8.04 (dd, J ₁ = 1.6 Hz, J ₂ = 8.4 Hz, 1H), 8.18 (s, 1H), 8.24 (s, 1H), 10.58 (s, 1H); ESI-MS (m / z) 709 (M + H) ⁺ .

Step 3 : 4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((5-oxo-5,6, 7,8-tetrahydropyrido [2,3-d] pyrimidin-4-yl) oxy) benzamide

4-Chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) in a mixture of dichloroethane and trifluoroacetic acid (1: 1, 600 μL) Phenyl) -3-((8- (4-methoxybenzyl) -5-oxo-5,6,7,8-tetrahydropyrido [2,3-d] pyrimidin-4-yl) oxy) benz A solution of amide (2 step intermediate) (40 mg, 0.06 mmol) was stirred at 80 ° C overnight. The mixture was cooled to room temperature and then cooled back to 0 ° C. and aqueous sodium bicarbonate solution was added until pH 7-8. The aqueous mixture was extracted twice with dichloromethane and the organic layers combined and washed with water, then brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to give 12 mg of the desired product.

Method G '

4-chloro-N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) -3-((7-oxo-7,8-dihydro-6H-pyri Preparation of Mido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide

Step 1 : 4-chloro-3-hydroxy-N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide

Methyl 4-chloro-3-hydroxybenzoate (Intermediate B1) in the presence of potassium tert-butoxide (1 M, 115 mL, 115 mmol) in dry THF (50 mL) according to the procedure described in step 1 of Method A (3.6 g, 19.3 mmol) and 3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) aniline (intermediate C19) (5.0 g, 19.3 mmol) gave the title compound. This gave 2.6 g of product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.23 (s, 3H), 2.47 (s, 4H), 3.21 (br s, 4H), 6.95 (s, 1H), 7.42-7.44 (m, 1H) , 7.51-7.53 (m, 2H), 7.60 (s, 1H), 7.65 (s, 1H), 10.32 (s, 1H), 10.60 (s, 1H).

Step 2 : 4-chloro-3-((8- (4-methoxybenzyl) -7-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazine -4-yl) oxy) -N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide

4-Chloro-3-hydroxy-N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide (one-step intermediate) in DMSO (0.5 mL) ( 80 mg, 0.19 mmol) and 4-chloro-8- (4-methoxybenzyl) -6H-pyrimido [5,4-b] [1,4] oxazin-7 (8H) -one (intermediate A2) To a stirred solution of (118 mg, 0.38 mmol), cesium fluoride (88 mg, 0.58 mmol) was added and the mixture was stirred at 118 ° C for 5-7 h. The mixture was cooled to room temperature and quenched with water. The precipitated solid was collected through filtration and dried in vacuo. The crude compound was purified by flash column chromatography to yield 110 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.24 (s, 3H), 2.52-2.56 (m, 4H), 3.18-3.22 (m, 4H), 3.72 (s, 3H), 5.04 (s, 2H ), 5.15 (s, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.97 (s, 1H), 7.32 (d, J = 8.8 Hz, 2H), 7.59 (s, 1H), 7.64 (s , 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.93-7.98 (m, 2H), 8.22 (s, 1H), 10.41 (s, 1H).

Step 3 : 4-chloro-N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) -3-((7-oxo-7,8-dihydro- 6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide

4-chloro-3-((8- (4-methoxybenzyl) -7-oxo-7,8-dihydro-6H-pyrimido [5,4-b] following the procedure described in step 3 of method G [1,4] oxazin-4-yl) oxy) -N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide (2-step intermediate) ( 100 mg, 0.15 mmol) and trifluoroacetic acid (2.0 mL) prepared the title compound to yield 40 mg of product.

Method H

4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((5,6,7,8-tetrahydropyripy Preparation of [[2,3-d] pyrimidin-4-yl) oxy) benzamide

Step 1 : 4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((5-hydroxy-8- ( 4-methoxybenzyl) -5,6,7,8-tetrahydropyrido [2,3-d] pyrimidin-4-yl) oxy) benzamide

4-Chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((8- in THF (5.0 mL) at 0 ° C) (4-methoxybenzyl) -5-oxo-5,6,7,8-tetrahydropyrido [2,3-d] pyrimidin-4-yl) oxy) benzamide (Step 2-Method G) ( To a solution of 500 mg, 0.76 mmol) sodium borohydride (54 mg, 0.71 mmol) was added followed by the dropwise addition of methanol (1.0 mL). The mixture was stirred at rt for 3-4 h. The reaction was quenched with water and extracted twice with chloroform. The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 400 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (t, J = 7.2 Hz, 3H), 1.70-1.74 (m, 1H), 1.92 (d, J = 2.8 Hz, 1H), 2.45-2.56 (m , 10H), 3.50-3.60 (m, 4H), 3.78 (s, 3H), 4.77 (d, J = 14.8 Hz, 1H), 4.89 (d, J = 15.2 Hz, 1H), 5.03 (br s, 1H ), 5.26 (d, J = 4.4 Hz, 1H), 6.90 (dd, J ₁ = 2.0 Hz, J ₁ = 6.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.71-8.18 (m , 7H), 10.59 (s, 1 H); ESI-MS (m / z) 711 (M + H) ⁺ .

Step 2 : 4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((8- (4-methoxybenzyl ) -5,6,7,8-tetrahydropyrido [2,3-d] pyrimidin-4-yl) oxy) benzamide

4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((in triethylsilane (16 mL) at 0 ° C. 5-hydroxy-8- (4-methoxybenzyl) -5,6,7,8-tetrahydropyrido [2,3-d] pyrimidin-4-yl) oxy) benzamide (stage 1 intermediate) Trifluoroacetic acid (8.0 mL) was added dropwise to (400 mg, 0.56 mmol) of the stirred mixture, and the mixture was stirred at room temperature for 3-4 hours. The mixture was cooled to 0 ° C. and neutralized with aqueous sodium bicarbonate solution. The aqueous mixture was extracted twice with chloroform. The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 200 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.09 (m, 3H), 1.89 (m, 2H), 2.50 (br s, 10H), 2.76 (m, 2H), 3.51-3.62 (m, 4H) , 3.73 (s, 3H), 4.78 (s, 2H), 6.90 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 7.71-7.92 (m, 4H), 8.00 ( s, 1 H), 8.06 (d, J = 7.2 Hz, 1 H), 8.18 (s, 1 H), 10.57 (s, 1 H); ESI-MS (m / z) 695 (M + H) ⁺ .

Step 3 : 4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((5,6,7,8- Tetrahydropyrido [2,3-d] pyrimidin-4-yl) oxy) benzamide

4-Chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((8 according to the procedure described in step 3 of method G) -(4-methoxybenzyl) -5,6,7,8-tetrahydropyrido [2,3-d] pyrimidin-4-yl) oxy) benzamide (2-step intermediate) (100 mg, 0.14 mmol ) And trifluoroacetic acid (2.0 mL) produced the title compound, resulting in 25 mg of product.

Method I

1- (4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -3- (4 Preparation of-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea

Step 1 : tert-butyl 4- (5-amino-2-chlorophenoxy) -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate

5-amino-2-chlorophenol (80 mg, 0.55 mmol) and tert-butyl 4-chloro in the presence of cesium carbonate (540 mg, 1.65 mmol) in DMF (3.0 mL) according to the procedure described in step 2 of Method G. 130 mg of the title compound was prepared by reaction of -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate (intermediate A1) (150 mg, 0.55 mmol), 130 mg The compound of ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.50 (s, 9H), 3.92 (t, J = 4.4 Hz, 2H), 4.37 (t, J = 4.0 Hz, 2H), 5.44 (s, 2H) , 6.41 (d, J = 6.4 Hz, 1H), 6.47 (dd, J ₁ = 2.4 Hz, J ₂ = 8.4 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H) ; ESI-MS (m / z) 379 (M + H) ⁺ .

Step 2 : tert-butyl 4- (2-chloro-5- (3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) ureido) phenoxy C) -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate

Triphosgene in a stirred solution of 4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline (intermediate C1) (150 mg, 0.52 mmol) in THF (20 mL) (54 mg, 0.18 mmol) was added and the resulting mixture was stirred at 70 ° C. After heating for 1 hour, the mixture was concentrated under reduced pressure and the residue was dissolved in THF (20 mL). This solution was converted to tert-butyl 4- (5-amino-2-chlorophenoxy) -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) in THF (20 mL). To a stirred mixture of carboxylate (one step intermediate) (150 mg, 0.40 mmol) and triethylamine (172 μL, 1.19 mmol) was added dropwise at room temperature. The resulting mixture was stirred at 70 ° C. for 2 hours. The mixture was cooled to room temperature and quenched with water. The aqueous mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 100 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.09 (t, J = 7.2 Hz, 3H), 1.50 (s, 9H), 2.42-2.51 (m, 10H), 3.54 (br s, 2H), 3.94 (t, J = 8.4 Hz, 2H), 4.40 (t, J = 7.6 Hz, 2H), 7.29 (dd, J ₁ = 2.4 Hz, J ₂ = 8.0 Hz, 1H), 7.48 (d, J = 8.8 Hz , 1H), 7.55-7.94 (m, 3H), 7.95 (s, 1H), 8.05 (s, 1H), 9.15 (s, 1H), 9.20 (s, 1H).

Step 3 : 1- (4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -3 -(4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea

Hydrochloric acid and tert-butyl 4- (2-chloro-5- (3- (4-((4-ethylpiperazin-1) in 1,4-dioxane (2.0 mL) following the procedure described in step 3 of Method A -Yl) methyl) -3- (trifluoromethyl) phenyl) ureido) phenoxy) -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate ( The title compound was prepared by the reaction of two step intermediate) (100 mg, 0.14 mmol), resulting in 52 mg of product.

Method I '

1- (4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -3- (3- (trifluor Preparation of rhomethyl) phenyl) urea

Step 1 : benzyl (4- (3- (3- (trifluoromethyl) phenyl) ureido) phenyl) carbonate

3- (trifluoromethyl) aniline (218 mg, 1.34 mmol), triphosgene (138 in the presence of triethylamine (361 mg, 3.57 mmol) in THF (5.0 mL) according to the procedure described in step 2 of Method I mg, 0.47 mmol) and 4-aminophenylbenzylcarbonate (250 mg, 0.89 mmol) gave the title compound to yield 200 mg of the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.07 (s, 2H), 6.95 (d, J = 2.0 Hz, 2H), 7.29-7.57 (m, 10H), 8.01 (s, 1H), 8.61 ( s, 1 H), 8.98 (s, 1 H).

Step 2 : 1- (4-hydroxyphenyl) -3- (3- (trifluoromethyl) phenyl) urea

Benzyl (4- (3- (3- (trifluoromethyl) phenyl) ureido) phenyl) carbonate in methanol (5.0 mL) with a catalytic amount of 10% palladium on carbon (50% wet, 200 mg) (stage 1) Intermediate) (200 mg, 0.47 mmol) was hydrogenated at room temperature for 18 hours. The mixture was filtered through celite and celite beds and diluted with chloroform. The filtrate was concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 48 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.69 (d, J = 6.8 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 7.6 Hz, 1H), 7.48 -7.53 (m, 2H), 8.0 (s, 1H), 8.44 (s, 1H), 8.91 (s, 1H), 9.11 (s, 1H); ESI-MS (m / z) 397 (M + H) ⁺ .

Step 3 : tert-butyl 4- (4- (3- (3- (3-fluorotrimethyl) phenyl) ureido) phenoxy) -6H-pyrimido [5,4-b] [1,4] oxazine -8 (7H) -carboxylate

1- (4-hydroxyphenyl) -3- (3- (trifluoromethyl) phenyl in the presence of cesium carbonate (109 mg, 0.34 mmol) in DMF (0.5 mL) according to the procedure described in step 2 of Method G. Urea (two-step intermediate) (50 mg, 0.17 mmol) and tert-butyl 4-chloro-6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate (intermediate) The title compound was prepared by the reaction of A1) (59 mg, 0.22 mmol), resulting in 30 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.48 (s, 9H), 3.34-3.39 (m, 1H), 3.91 (t, J = 4.4 Hz, 2H), 4.36 (t, J = 4.0 Hz, 2H), 7.10-7.12 (m, 2H), 7.50-7.58 (m, 4H), 8.02-8.04 (br s, 2H), 8.67 (s, 1H), 9.07 (s, 1H); ESI-MS (m / z) 432 (M + H) ⁺ .

Step 4 : 1- (4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -3- (3- (Trifluoromethyl) phenyl) urea

Hydrochloric acid and tert-butyl 4- (4- (4- (3- (3- (trifluoromethyl) phenyl) ureido) phenoxy in 1,4-dioxane (1.0 mL) according to the procedure described in step 3 of Method A ) The title compound is prepared by the reaction of) -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate (3-step intermediate) (30 mg, 0.06 mmol), 11 mg of product were produced.

Method I ”

1- (3- (tert-butyl) -1- (4-cyanophenyl) -1H-pyrazol-5-yl) -3- (4-((3,4-dihydro-2H-pyrido [ Preparation of 3,2-b] [1,4] oxazin-8-yl) oxy) phenyl) urea

Step 1 : tert-butyl 8- (4-(((benzyloxy) carbonyl) amino) phenoxy) -2H-pyrido [3,2-b] [1,4] oxazine-4 (3H)- Carboxylate

Tert-butyl 8-bromo-2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate (intermediate A7) (400 mg, 1.27 mmol in toluene (10 mL) ), Benzyl (4-hydroxyphenyl) carbamate (370 mg, 1.52 mmol) and tripotassium phosphate (966 mg, 4.56 mmol) were degassed and palladium acetate (52 mg, 0.24 mmol) followed by 2-di tert-butylphosphino 2 ', 4', 6'-triisopropylbiphenyl (t-BuXPhos) (129 mg, 0.30 mmol) was added at room temperature. The mixture was refluxed at 120 ° C. for 16 hours. The mixture was cooled to rt, diluted with diethyl ether and filtered through celite. The filtrate was concentrated and the residue thus obtained was purified by flash column chromatography to yield 198 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.47 (s, 9H), 3.86 (t, J = 4.4 Hz, 2H), 4.27 (t, J = 4.4 Hz, 2H), 5.16 (s, 2H) , 6.45 (d, J = 5.6 Hz, 1H), 7.04-7.09 (m, 2H), 7.34-7.46 (m, 5H), 7.52 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 5.6 Hz, 1H), 9.86 (s, 1H); ESI-MS (m / z) 478 (M + H) ⁺ .

Step 2 : tert-butyl 8- (4-aminophenoxy) -2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate

Tert-butyl 8- (4-(((benzyloxy) carbonyl) amino) phenoxy)-in the presence of 10% palladium on carbon (50% wet, 40 mg) according to the procedure described in step 2 of method I '. The title compound was prepared by the hydrogenation of 2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate (one step intermediate) (230 mg, 0.48 mmol), 127 mg of the target compound were produced. The compound proceeded to the next step as is without characterization.

Step 3 : tert-butyl 8- (4- (3- (3- (tert-butyl) -1- (4-cyanophenyl) -1H-pyrazol-5-yl) ureido) phenoxy) -2H -Pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate

4- (5-amino-3- (tert-butyl) -1H-pyrazol-1-yl) benzonitrile (intermediate C91) in a mixture of dichloromethane (6.0 mL) and saturated sodium bicarbonate solution (4.0 mL) ( To 50 mg, 0.21 mmol) of the stirred solution was added diphosgene (100 μL, 0.83 mmol) at 0 ° C. and the mixture was stirred at rt for 1.5 h. The mixture was diluted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give isocyanate. The isocyanate intermediate was suspended in a mixture of THF (10 mL) and acetonitrile (1.0 mL) and cooled to 0 ° C. To this mixture was added tert-butyl 8- (4-aminophenoxy) -2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate (2-step intermediate) (71 mg). , 0.21 mmol), then DIPEA (142 μL, 0.83 mmol), and the resulting mixture was stirred at rt for 16 h. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 52 mg of the desired compound. ESI-MS (m / z) 610 (M + H) ⁺ .

Step 3 : 1- (3- (tert-butyl) -1- (4-cyanophenyl) -1H-pyrazol-5-yl) -3- (4-((3,4-dihydro-2H- Pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) phenyl) urea

Hydrochloric acid and tert-butyl 8- (4- (3- (3- (tert-butyl) -1) in 1,4-dioxane (3.0 mL) in methanol (0.5 mL) according to the procedure described in step 3 of Method A -(4-cyanophenyl) -1H-pyrazol-5-yl) ureido) phenoxy) -2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxyl The title compound was prepared by reaction of the rate (2 step intermediate) (50 mg, 0.08 mmol) to give 7.0 mg of product.

Method J

4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((7-oxo-7,8-dihydro- Preparation of 6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide

Step 1 : Methyl 4-chloro-3-((8- (4-methoxybenzyl) -7-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] ox Photo-4-yl) oxy) benzoate

4-chloro-8- (4-methoxybenzyl) -6H-pyrimido [5 in the presence of cesium fluoride (328 mg, 2.16 mmol) in DMSO (2.0 mL) according to the procedure described in step 2 of Method G '. , 4-b] [1,4] oxazin-7 (8H) -one (intermediate A2) (330 mg, 1.08 mmol) and 4-chloro-3-hydroxybenzoate (intermediate B1) (261 mg, 1.40 mmol) gave the title compound to yield 210 mg of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.72 (s, 3H), 3.86 (s, 3H), 5.02 (s, 2H), 5.14 (s, 2H), 6.87 (dd, J ₁ = 2.0 Hz , J ₂ = 6.4 Hz, 2H), 7.31 (d, J = 6.8 Hz, 2H), 7.79 (d, J = 8.8 Hz, 1H), 7.88-7.90 (m, 2H), 8.19 (s, 1H).

Step 2 : 4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((8- (4-methoxybenzyl ) -7-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide

Methyl 4-chloro-3-((8- (4-methoxybenzyl) -7-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1, in toluene (3.0 mL) 4] oxazin-4-yl) oxy) benzoate (stage 1 intermediate) (210 mg, 0.46 mmol) and 4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl To a solution of aniline (intermediate C1) (110 mg, 0.38 mmol) was added dropwise trimethyl aluminum solution (2M in toluene, 768 μL, 1.54 mmol) at room temperature. The mixture was stirred at room temperature for 3-5 hours. The mixture was quenched with aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 115 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.99 (t, J = 7.2 Hz, 3H), 2.40-2.51 (m, 10H), 3.57 (s, 2H), 3.72 (s, 3H), 5.04 ( s, 2H), 5.15 (s, 2H), 6.87 (dd, J ₁ = 2.0 Hz, J ₂ = 6.4 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.94-8.0 (m, 3H), 8.17 (s, 1H), 8.22 (s, 1H), 10.58 (s, 1H); ESI-MS (m / z) 711 (M + H) ⁺ .

Step 3 : 4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((7-oxo-7,8- Dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide

4-Chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((8 according to the procedure described in step 3 of method G) -(4-methoxybenzyl) -7-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide (2 steps Intermediate) (100 mg, 0.14 mmol) and trifluoroacetic acid (3.0 mL) produced the title compound, resulting in 29 mg of product.

Method J '

N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -4-methyl-3-((7-oxo-7,8-dihydro- Preparation of 6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide

Step 1 : Methyl 3-((8- (4-methoxybenzyl) -7-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazine-4- Yl) oxy) -4-methylbenzoate

4-Chloro-8- (4-methoxybenzyl) -6H-pyrimido [5,4-b] [1,4] oxazin-7 (8H) -one (intermediate A2) in toluene (4.0 mL) ( 370 mg, 1.21 mmol), a suspension of methyl 3-hydroxy-4-methylbenzoate (intermediate B3) (261 mg, 1.57 mmol) and tripotassium phosphate (513 mg, 2.42 mmol) was degassed and palladium acetate (54 mg, 0.24 mmol), then 2-di-tert-butylphosphino-2 ', 4', 6'-triisopropylbiphenyl (t-BuXPhos) (77 mg, 0.18 mmol) was added at room temperature. The mixture was refluxed for 3-5 hours. The mixture was cooled to rt, diluted with diethyl ether and filtered through celite. The filtrate was concentrated and the residue thus obtained was purified by flash column chromatography to yield 309 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.19 (s, 3H), 3.72 (s, 3H), 3.83 (s, 3H), 5.01 (s, 2H), 5.14 (s, 2H), 6.88 ( d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.79 (dd, J ₁ = 2.0 Hz , J ₂ = 8.0 Hz, 1H), 8.17 (s, 1H).

Step 2 : N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((8- (4-methoxybenzyl) -7- Oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methylbenzamide

Methyl 3-((8- (4-methoxybenzyl) -7- in the presence of trimethyl aluminum solution (2M in toluene, 970 μL, 1.94 mmol) in toluene (3.0 mL) according to the procedure described in step 2 of Method J Oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methylbenzoate (stage 1 intermediate) (270 mg, 0.62 mmol) and 4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline (intermediate C1) (140 mg, 0.49 mmol) to prepare the title compound, 210 mg of the compound were produced. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.98 (t, J = 8.4 Hz, 3H), 2.19 (s, 3H), 2.40-2.51 (m, 10H), 3.56 (br s, 2H), 3.72 (s, 3H), 5.02 (s, 2H), 5.15 (s, 2H), 6.88 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 7.2 Hz , 1H), 8.17-8.19 (br s, 2H), 10.44 (s, 1H).

Step 3 : N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -4-methyl-3-((7-oxo-7,8- Dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide

N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((8- (4-) according to the procedure described in step 3 of method G. Methoxybenzyl) -7-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methylbenzamide (2 steps Intermediate) (150 mg, 0.22 mmol) and trifluoroacetic acid (3.0 mL) produced the title compound, resulting in 18.0 mg of product.

Method K

4-chloro-N- (4-((4- (2-cyanoacetyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((7,8-di Preparation of hydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide

To a solution of 2-cyanoacetic acid (20 mg, 0.18 mmol) in acetonitrile (5.0 mL) was added DIPEA (0.1 mL, 0.56 mmol), followed by TBTU (50 mg, 0.18 mmol) at 0 ° C and the mixture was 30 Stir for minutes. 4-Chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4- (piperazin- 1-ylmethyl) -3- (trifluoromethyl) phenyl) benzamide (dihydrochloride salt) (80 mg, 0.14 mmol) was added to the mixture and stirred at room temperature for 3 hours. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 6.0 mg of the desired product.

Method L

4-chloro-3-((8-methyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- Preparation of (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide

Step 1 : Methyl 4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzoate

Hydrochloric acid and tert-butyl 4- (2-chloro-5- (methoxycarbonyl) phenoxy) -6H-pyridine in ethyl acetate (25 mL) in methanol (5.0 mL) according to the procedure described in step 3 of Method A The title compound was prepared by reaction of mino [5,4-b] [1,4] oxazine-8 (7H) -carboxylate (Step 1-Method B) (500 mg, 1.18 mmol), yielding 307 mg of The product was produced. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.83-3.87 (m, 2H), 4.04 (s, 3H), 4.17-4.21 (m, 2H), 7.68-7.74 (m, 3H), 7.81 (br s, 2H).

Step 2 : methyl 4-chloro-3-((8-methyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzoate

Methyl 4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzoate in DMF (5.0 mL) ( To a stirred solution of 1 st intermediate) (300 mg, 0.93 mmol) was added methyl iodide (132 mg, 0.93 mmol) followed by sodium hydride (60% w / w, 41 mg, 1.03 mmol) at 0 ° C. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 105 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.34 (s, 3H), 3.58 (t, J = 4.8 Hz, 2H), 3.85 (s, 3H), 4.27 (t, J = 4.4 Hz, 2H) , 7.71-7.78 (m, 2 H), 7.80-7.83 (m, 2 H).

Step 3 : 4-chloro-3-((8-methyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide

Methyl 4-chloro-3-((8-methyl-7,8) in the presence of potassium tert-butoxide (1M, 1.9 mL, 1.8 mmol) in dry THF (5.0 mL) according to the procedure described in step 1 of Method A. -Dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzoate (2 step intermediate) (100 mg, 0.30 mmol) and 3- (4-methyl The title compound was prepared by reaction of piperazin-1-yl) -5- (trifluoromethyl) aniline (intermediate C19) (78 mg, 0.30 mmol), resulting in 81 mg of product.

Method M

N- (4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -N- ( Preparation of 4-fluorophenyl) cyclopropane-1,1-dicarboxamide

Step 1 : tert-Butyl 4- (4-amino-2-fluorophenoxy) -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate

Tert-butyl 4-chloro-6H-pyrimido [5,4-b] [1,4 in the presence of cesium carbonate (1.2 g, 3.67 mmol) in DMF (10 mL) according to the procedure described in step 2 of Method A ] The title compound is prepared by the reaction of oxazine-8 (7H) -carboxylate (intermediate A1) (500 mg, 1.83 mmol) with 4-amino-2-fluorophenol (350 mg, 2.76 mmol), 361. mg of the compound was produced. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.49 (s, 9H), 3.90 (t, J = 4.4 Hz, 2H), 4.35 (t, J = 4.0 Hz, 2H), 5.36 (s, 2H) , 6.36 (dd, J ₁ = 2.5 Hz, J ₂ = 6.8 Hz, 1H), 6.48 (dd, J ₁ = 2.8 Hz, J ₂ = 13.2 Hz, 1H), 6.92 (t, J = 8.8 Hz, 1H) , 7.95 (s, 1 H); ESI-MS (m / z) 363 (M + H) ⁺ .

Stage 2 : tert-butyl 4- (2-fluoro-4- (1-((4-fluorophenyl) carbamoyl) cyclopropane carboxamido) phenoxy) -6H-pyrimido [5,4- b] [1,4] oxazine-8 (7H) -carboxylate

Tert-butyl 4- (4-amino-2-fluorophenoxy) -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxyl in dichloromethane (5.0 mL) DIPEA (138 μL, 0.80 mmol), 1-((4-fluorophenyl) carbamoyl) cyclopropanecarboxylic acid (Intermediate C68) (100 mg) in a stirred solution of rate (1 step intermediate) (161 mg, 0.45 mmol) , 0.45 mmol mmol), then HATU (305 mg, 0.80 mmol) was added at room temperature. The mixture was stirred at rt for 18 h before it was quenched with water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to yield 75 mg of the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.45-1.46 (br s, 4H), 1.49 (s, 9H), 3.92 (t, J = 4.4 Hz, 2H), 4.38 (t, J = 3.6 Hz , 2H), 7.15 (t, J = 9.2 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.62-7.89 (m, 3H), 8.03 (s, 1 H), 10.02 (s, 1 H), 10.30 (s, 1 H).

Step 3 : N- (4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl)- N- (4-fluorophenyl) cyclopropane-1,1-dicarboxamide

Hydrochloric acid and tert-butyl 4- (2-fluoro-4- (1-((4-fluoro) in 1,4-dioxane (8.0 mL) in ethanol (5.0 mL) according to the procedure described in step 3 of Method A Rophenyl) carbamoyl) cyclopropanecarboxamido) phenoxy) -6H-pyrimido [5,4-b] [1,4] oxazine-8 (7H) -carboxylate (2-step intermediate) (65 mg, 0.11 mmol) to give the title compound, which yields 20 mg of product.

Method N

4-chloro-3-((3-methyl-2-oxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidin-5-yl) oxy) -N- (3- Preparation of (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide

Step 1 : tert-butyl (4- (2-chloro-5-((3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) carbamoyl) phenoxy) -3 -Formylpyridin-2-yl) carbamate

4-Chloro-3-hydroxy-N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide in DMF (3.0 mL) (Step 1-Method G Cesium carbonate (314 mg, 0.97 mmol) was added to a solution of ') (200 mg, 0.48 mmol) and the mixture was stirred for 30 minutes. The solution was cooled to 0 ° C. and tert-butyl (3-chloro-2-formylphenyl) carbamate (CAS # 1260667-07-9) (186 mg, 0.73 mmol) was added at the same temperature. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with ice and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography to yield 220 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.48 (s, 9H), 2.23 (s, 3H), 2.45-2.51 (m, 4H), 3.21 (t, J = 4.8 Hz, 4H), 6.45 ( d, J = 6.0 Hz, 1H), 6.98 (s, 1H), 7.59 (s, 1H), 7.62 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 8.01 (dd, J ₁ = 2.0 Hz, J ₂ = 8.4 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 8.37 (d, J = 5.6 Hz, 1H), 10.40 (s, 2H), 10.48 (s, 1H); ESI-MS (m / z) 534 (M + H-BOC) ⁺ .

Step 2 : 4-chloro-3-((3-methyl-2-oxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidin-5-yl) oxy) -N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide

Tert-butyl (4- (2-chloro-5-((3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) carbamoyl) phenoxy in THF (1.0 mL) To a stirred solution of) -3-formylpyridin-2-yl) carbamate (stage 1 intermediate) (50 mg, 0.08 mmol), a methylamine solution (33% in ethanol, 0.1 mL, 0.8 mmol), followed by one Drops of acetic acid were added and the mixture was stirred at rt overnight. The precipitated solid was filtered, dried and purified by silica gel column chromatography to yield 12 mg of the desired compound.

Method O

4-chloro-3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) -N- (3- (4-methyl Preparation of Piperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide

Step 1 : 8-Bromo-7-nitro-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine (nitro adduct)

8-Bromo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine in sulfuric acid (8 mL) (Step 2-Intermediate A7) (2.0 g, 9.30 mmol) To a stirred solution of was added dropwise a mixture of sulfuric acid and nitric acid (1: 1, 14 mL) at 0 ° C. over 15 minutes. The mixture was poured into crushed ice and stirred to give a yellow solid. Aqueous sodium hydroxide solution was added to the mixture until pH 8-9. The solid was filtered off, washed with water and dried well. The crude solid was purified by recrystallization from acetone to yield 1.2 g of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.50-4.52 (m, 2H), 4.56-4.59 (m, 2H), 8.76 (s, 1H).

Step 2 : 4-chloro-N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) -3-((7-nitro-3,4-dihydro- 2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) benzamide

8-Bromo-7-nitro-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine (nitro adduct) in DMF (12 mL) (stage 1 intermediate) (202 mg, 0.66 mmol) and 4-chloro-3-hydroxy-N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide (Step 1- To a stirred solution of Method G ') (246 mg, 0.59 mmol) was added potassium carbonate (275 mg, 1.98 mmol) and the mixture was stirred at 105 ° C for 2 h. The mixture was cooled to room temperature and quenched with water. The aqueous mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 368 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.32 (s, 3H), 2.51-2.59 (br s, 4H), 3.23 (br s, 4H), 4.40-4.42 (m, 2H), 4.46-4.48 (m, 2H), 6.97 (s, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.55 (s, 1H), 7.59 (s, 1H), 7.78-7.83 (m, 2H), 8.99 ( s, 1 H), 10.40 (s, 1 H).

Step 3 : tert-butyl 8- (2-chloro-5-((3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) carbamoyl) phenoxy) -7- Nitro-2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate

4-chloro-N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) -3-((7-nitro-3,4 in dichloromethane (15 mL) Triethylamine in a solution of -dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) benzamide (two-step intermediate) (361 mg, 0.66 mmol) (183 μL, 1.31 mmol), then di-tert-butyl dicarbonate (227 μL, 0.99 mmol) was added and the mixture was stirred for 5 minutes before DMAP (8 mg, 0.06 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with dichloromethane and washed with water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to give 287 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.52 (s, 9H), 2.22 (s, 3H), 2.40-2.51 (m, 4H), 3.16-3.20 (m, 4H), 3.91 (d, J = 4.4 Hz, 2H), 4.28 (d, J = 4.0 Hz, 2H), 6.94 (s, 1H), 7.31 (d, J = 1.6 Hz, 1H), 7.55 (s, 1H), 7.57 (s, 1H ), 7.77-7.81 (m, 2 H), 8.80 (s, 1 H), 10.36 (s, 1 H).

Step 4 : tert-butyl 7-amino-8- (2-chloro-5-((3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) carbamoyl) phenoxy ) -2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate

Tert-butyl 8- (2-chloro-5-((3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl in a mixture of methanol and water (3: 1, 20 mL) ) Carbamoyl) phenoxy) -7-nitro-2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) carboxylate (3 step intermediate) (280 mg, 0.40 mmol) To the stirred solution, ammonium chloride (215 mg, 4.05 mmol) was added and the mixture was heated to 80 ° C. Zinc dust (135 mg, 2.06 mmol) was added in small portions and the mixture was stirred at 80 ° C. for 1 hour. The mixture was cooled to room temperature and poured into aqueous sodium bicarbonate solution. The aqueous mixture was extracted twice with a 5% mixture of methanol in chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by column chromatography to give 174 mg of the target compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.45 (s, 9H), 2.24 (s, 3H), 2.40 (br s, 4H), 3.21 (br s, 4H), 3.72 (t, J = 4.4 Hz, 2H), 4.08 (t, J = 4.0 Hz, 2H), 5.15 (s, 2H), 6.94 (s, 1H), 7.14 (s, 1H), 7.55-7.75 (m, 5H), 10.38 (s 1H).

Step 5 : 4-chloro-3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) -N- (3- ( 4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide

Tert-butyl 7-amino-8- (2-chloro-5-((3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) carba in dichloromethane (5.0 mL) Mole) phenoxy) -2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate (4 step intermediate) (119 mg, 0.18 mmol) in a stirred solution of- BF ₃ -etherate (50%, 135 μL, 0.54 mmol) was added at 20 ° C. and the mixture was stirred for 5 minutes. Then a solution of tert-butyl nitrite (43 μL, 0.36 mmol) in DCM (5.0 mL) was added dropwise to the reaction mixture over 10 minutes. The resulting mixture was stirred at -20 ° C for 30 minutes. The mixture was warmed up to 10 ° C. and nitrogen gas was blown to remove the solvent. The crude black residue was dissolved in DMF (5.0 mL) and added to a stirred solution of iron sulfate (55 mg, 0.19 mmol) in DMF (5.0 mL) and the mixture was stirred at rt for 5 min. Poured into aqueous sodium bicarbonate solution and extracted the product twice in ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by column chromatography to give 28 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.27 (s, 3H), 2.44-2.47 (br s, 4H), 3.19-3.21 (br s, 4H), 3.43 (br s, 2H), 4.10 ( t, J = 4.0 Hz, 2H), 6.10 (d, J = 5.6 Hz, 1H), 6.96 (s, 2H), 7.53 (d, J = 5.6 Hz, 1H), 7.59 (s, 3H), 7.78- 7.85 (m, 2 H), 10.38 (s, 1 H); ESI-MS (m / z) 548 (M + H) ⁺ .

Method P

1- (4-((7-cyano-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) phenyl) -3- ( Preparation of 4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea

Step 1 : tert-butyl 8- (4-(((benzyloxy) carbonyl) amino) phenoxy) -7-nitro-2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate

Tert-butyl 8-bromo-7-nitro-2H-pyrido [3, in the presence of cesium fluoride (1.9 g, 12.5 mmol) in DMSO (40 mL) according to the procedure described in step 2 of Method G '. 2-b] [1,4] oxazine-4 (3H) -carboxylate (intermediate A22) (1.5 g, 4.16 mmol) and benzyl (4-hydroxyphenyl) carbamate (1.11 mg, 4.58 mmol) The title compound was prepared to yield 1.39 g of the compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.51 (s, 9H), 3.89 (t, J = 4.4 Hz, 2H), 4.25 (t, J = 4.0 Hz, 2H), 5.14 (s, 2H) , 6.92 (d, J = 9.2 Hz, 2H), 7.34-7.43 (m, 7H), 8.69 (s, 1H), 9.72 (s, 1H).

Step 2 : tert-butyl 7-amino-8- (4-(((benzyloxy) carbonyl) amino) phenoxy) -2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate

Tert-butyl 8- (4-(((benzyloxy) carbonyl) amino) phenoxy) -7-nitro- in a mixture of methanol and water (3: 1, 40 mL) according to the procedure described in step 4 of Method O 2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate (stage 1 intermediate) (1.35 g, 2.58 mmol) with zinc dust (844 mg, 12.9 mmol) and ammonium The title compound was prepared by the reaction of chloride (1.38 g, 25.8 mmol) to give 921 mg of product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.45 (s, 9H), 3.73 (t, J = 4.4 Hz, 2H), 4.07 (t, J = 4.0 Hz, 2H), 4.94 (s, 2H) , 5.13 (s, 2H), 6.79 (d, J = 9.2 Hz, 2H), 7.34-7.39 (m, 7H), 8.32 (s, 1H), 9.64 (s, 1H); ESI-MS (m / z) 492 (M + H) ⁺ .

Step 3 : tert-Butyl 8- (4-(((benzyloxy) carbonyl) amino) phenoxy) -7-iodo-2H-pyrido [3,2-b] [1,4] oxazine- 4 (3H) -carboxylate

Tert-butyl 7-amino-8- (4-(((benzyloxy) carbonyl) amino) phenoxy) -2H-pyrido [3,2-b] [1,4] in acetonitrile (8.0 mL) PTSA (232 mg, 1.22 mmol) was added to a stirred suspension of oxazine-4 (3H) -carboxylate (2-step intermediate) (200 mg, 0.41 mmol) and stirred at room temperature for 10-15 minutes. To this mixture was added a solution of sodium nitrite (56 mg, 0.81 mmol) and potassium iodide (169 mg, 1.05 mmol) in water (1.0 mL) at 10-15 ° C. The reaction mixture was slowly brought to room temperature and poured into aqueous sodium bicarbonate solution. The aqueous mixture was extracted twice with ethyl acetate and the organic extracts combined and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by column chromatography to yield 102 mg of the desired compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.48 (s, 9H), 3.83 (t, J = 4.4 Hz, 2H), 4.16 (t, J = 3.6 Hz, 2H), 5.13 (m, 2H) , 6.79 (d, J = 8.8 Hz, 2H), 7.34-7.43 (m, 7H), 8.27 (s, 1H), 9.70 (s, 1H).

Step 4 : tert-Butyl 8- (4-(((benzyloxy) carbonyl) amino) phenoxy) -7-cyano-2H-pyrido [3,2-b] [1,4] oxazine- 4 (3H) -carboxylate

Tert-butyl 8- (4-(((benzyloxy) carbonyl) amino) phenoxy) -7-iodo-2H-pyrido [3,2-b] [1,4] in DMF (5.0 mL) To a solution of oxazine-4 (3H) -carboxylate (3-step intermediate) (52 mg, 0.08 mmol) zinc cyanide (10 mg, 0.09 mmol), [1,1'-bis (diphenylphosphino) ferrocene] Dichloropalladium (II) (10 mg, 0.017 mmol) was added followed by water (10 μL) and the mixture was degassed for 5 minutes before tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) ₃ ) (8.0 mg, 0.008 mmol) was added. The resulting mixture was heated to 145 ° C. for 15 minutes in a microwave reactor. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by column chromatography to yield 19 mg of Boc-deprotected compound. The Boc group was recovered by reaction of the compound with di-tert-butyl dicarbonate (1.5 equiv) in the presence of LiHMDS (1.5 equiv) in THF (5.0 vol) following the procedure described in step 3 of intermediate A7 to obtain the title compound. Generated. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ δ 1.50 (s, 9H), 3.88 (t, J = 3.6 Hz, 2H), 4.21 (t, J = 4.4 Hz, 2H), 5.14 (m, 2H ), 6.97 (d, J = 8.0 Hz, 2H), 7.33-7.44 (m, 7H), 8.41 (s, 1H), 9.78 (s, 1H).

Step 5 : tert-Butyl 8- (4-aminophenoxy) -7-cyano-2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate

Tert-butyl 8- (4-(((benzyloxy) carbonyl) amino) phenoxy) -7-sia in methanol (12 mL) with a catalytic amount of 10% palladium on carbon (50% wet, 60 mg) A solution of no-2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate (4-step intermediate) (120 mg, 0.24 mmol) was hydrogenated at room temperature for 1 hour. . The mixture was filtered through celite and the celite bed was rinsed with methanol. The filtrate and washings were combined and concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 48 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.50 (s, 9H), 3.87 (t, J = 4.4 Hz, 2H), 4.22 (t, J = 4.0 Hz, 2H), 6.92 (dd, J ₁ = 2.0 Hz, J ₂ = 6.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 9.34 (s, 1H).

Step 6 : tert-butyl 7-cyano-8- (4- (3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) ureido) Phenoxy) -2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate

Tert-butyl 8- (4-aminophenoxy by using triphosgene (13 mg, 0.04 mmol) and triethylamine (71 μL, 0.37 mmol) in THF (10 mL) according to the procedure described in step 2 of Method I ) -7-cyano-2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate (5-step intermediate) (45 mg, 0.12 mmol) and 4-(( The title compound is prepared by reaction of 4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) aniline (intermediate C1) (35 mg, 0.12 mmol) to give 53 mg of the compound. It was. ESI-MS (m / z) 682 (M + H) ⁺ .

Step 7 : 1- (4-((7-Cyano-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) phenyl)- 3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea

Hydrochloric acid and tert-butyl 7-cyano-8- in 1,4-dioxane (2.5 mL) in 1,4-dioxane (2.0 mL) and methanol (0.5 mL) according to the procedure described in step 3 of Method A. (4- (3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) ureido) phenoxy-2H-pyrido [3,2-b ] The title compound was prepared by reaction of [1,4] oxazine-4 (3H) -carboxylate (stage 6 intermediate) (52 mg, 0.07 mmol), resulting in 11 mg of product ¹ H NMR ( 400 MHz, DMSO-d ₆ ) δ 1.01 (t, J = 7.2 Hz, 3H), 2.42 (br s, 10H), 3.33 (br s, 2H), 3.54 (br s, 2H), 4.04 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 9.2 Hz, 2H), 7.41 (d, J = 9.2 Hz, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 8.10 (s, 2H), 8.79 (s, 1H), 9.04 (s, 1H); ESI-MS (m / z) 582 (M + H) ⁺ .

Method Q

1- (3- (tert-butyl) -1- (3-cyanophenyl) -1H-pyrazol-5-yl) -3- (4-((3,4-dihydro-2H-pyrido [ Preparation of 3,2-b] [1,4] oxazin-8-yl) oxy) phenyl) urea

Step 1 : Phenyl (3- (tert-butyl) -1- (3-cyanophenyl) -1H-pyrazol-5-yl) carbamate

3- (5-amino-3- (tert-butyl) -1H-pyrazol-1-yl) benzonitrile (intermediate C92) (150 mg, 0.62 mmol) and pyridine (0.1 mL, 1.25 in THF (10 mL) To the stirred solution of mmol) was added phenyl chloroformate (0.12 mL, 0.94 mmol) at 0 ° C. The mixture was stirred at rt for 2 h and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue obtained was purified by silica gel column chromatography to yield 79 mg of the desired product. ESI-MS (m / z) 361 (M + H) ⁺ .

Step 2 : tert-butyl 8- (4- (3- (3- (tert-butyl) -1- (3-cyanophenyl) -1H-pyrazol-5-yl) ureido) phenoxy) -2H -Pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate

Tert-butyl 8- (4-aminophenoxy) -2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate (method I ") in DMSO (5.0 mL) Step 2) (60 mg, 0.17 mmol) in a cooled (10 ° C.) solution of triethylamine (75 μL, 0.53 mmol) followed by phenyl (3- (tert-butyl) -1- (3-cyanophenyl) -1H-pyrazol-5-yl) carbamate (stage 1 intermediate) (70 mg, 0.19 mmol) was added and the mixture was stirred at rt for 16 h The mixture was diluted with ethyl acetate, water, saturated ammonium and washed with chloride solution and brine. the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified the resulting residue by silica gel column chromatography gave the desired product in 69 mg. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.30 (s, 9H), 1.47 (s, 9H), 3.86 (t, J = 4.0 Hz, 2H), 4.27 (t, J = 4.0 Hz, 2H), 6.41 ( s, 1H), 6.47 (d, J = 3.2 Hz, 1H), 7.03 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.71-7.77 ( m, 1H), 7.80 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 8.53 ( s, 1 H), 9.10 (s, 1 H); ESI-MS (m / z) 610 (M + H) ⁺ .

Step 3 : 1- (3- (tert-butyl) -1- (3-cyanophenyl) -1H-pyrazol-5-yl) -3- (4-((3,4-dihydro-2H- Pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) phenyl) urea

Tert-butyl 8- (4- (3- (3- (tert-butyl) -1- (3-cyanophenyl) -1H-pyrazol-5-yl) ureido) phenoxy in acetonitrile (10 mL) PTSA (200 mg) in a stirred solution of -2H-pyrido [3,2-b] [1,4] oxazine-4 (3H) -carboxylate (2-step intermediate) (64 mg, 0.11 mmol) , 1.05 mmol), 2-3 drops of methanol were added and the mixture was stirred at rt for 16 h. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and the residue obtained was purified by silica gel column chromatography to yield 21 mg of the desired product.

Method R

1- (3- (tert-butyl) -1- (4-cyanophenyl) -1H-pyrazol-5-yl) -3- (2-fluoro-4-((2,3,4,5 Preparation of Tetrahydropyrido) [3,2-b] [1,4] oxazepin-9-yl) oxy) phenyl) urea (Example 228)

Step 1 : tert-butyl 9- (4- (3- (3- (tert-butyl) -1- (4-cyanophenyl) -1H-pyrazol-5-yl) ureido) -3-fluoro Phenoxy) -3,4-dihydropyrido [3,2-b] [1,4] oxazepine-5 (2H) -carboxylate

1,1 in a solution of 4- (5-amino-3- (tert-butyl) -1H-pyrazol-1-yl) benzonitrile (Intermediate 91) (120 mg, 0.34 mmol) in dichloromethane (10 mL) '-Carbonyldiimidazole (CDI) (55 mg, 0.34 mmol) was added and the mixture was stirred at 50 ° C. for 1 hour and then at room temperature overnight. To this mixture was added 2-fluoro-4-((2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepin-9-yl) oxy) aniline (method I " (81 mg, 0.34 mmol) was added at room temperature and stirred for 16 hours The reaction was quenched with water and extracted twice with dichloromethane. The combined was dried over anhydrous sodium sulfate, filtered and concentrated The residue was purified by silica gel column chromatography to give 60 mg of the title compound ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.29 ( s, 9H), 1.36 (s, 9H), 1.90-1.93 (m, 2H), 3.60-3.68 (m, 2H), 3.96-4.02 (m, 2H), 6.42 (s, 1H), 6.66 (d, J = 5.6 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 9.2 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.97-8.02 (m, 2H), 8.58 (s, 1 H), 9.14 (s, 1 H); ESI-MS (m / z) 541 (M + H-Boc) ⁺ .

Step 2 : 1- (3- (tert-butyl) -1- (4-cyanophenyl) -1H-pyrazol-5-yl) -3- (2-fluoro-4-((2,3, 4,5-tetrahydropyrido [3,2-b] [1,4] oxazepin-9-yl) oxy) phenyl) urea

Hydrochloric acid and tert-butyl 9- (4- (3- (3- (tert-butyl) -1- (4-cyano) in 1,4-dioxane (5.0 mL) according to the procedure described in step 3 of Method A Phenyl) -1H-pyrazol-5-yl) ureido) -3-fluorophenoxy) -3,4-dihydropyrido [3,2-b] [1,4] oxazepine-5 (2H The title compound was prepared by reaction of) -carboxylate (one step intermediate) (50 mg, 0.08 mmol) to give 18 mg of product.

Pharmacological activity

This is a one-step binding assay based on the binding and displacement of the labeled tracer, wherein the compound addition adds anti-GST tagged europium (Eu) as donor and Alexa Fluor labeled tracer as acceptor. Simultaneous binding of both tracer and GST-antibody to the kinase domain of HPK1 resulted in a high degree of FRET (fluorescence resonance energy transfer) from the anti-GST tagged Europium (Eu) fluorophore on the kinase tracer to the Alexa Fluor® 647 fluorophore. And this signal is reduced in the presence of an inhibitor that can be measured.

Test compounds or reference compounds, such as sunitinib, were dissolved in dimethylsulfoxide (DMSO) to prepare a 10.0 mM stock solution and diluted to the desired concentration. The final concentration of DMSO in the reaction was 3% (v / v). 6 nM Eu-Anti-GST antibody in kinase buffer containing 50 mM HEPES (pH 7.5), 10 mM MgCl ₂ , 1 mM EGTA, 0.01% Brij-35, with or without the desired concentration of the compound An assay mixture was prepared by mixing with 15 nM MAP4K-1 enzyme. The reaction was incubated for 15 minutes on ice. The pre-incubation step was terminated by adding 30 nM kinase tracer 222 to the reaction mixture. After shaking for 5 minutes, the reaction was further incubated for 1 hour at room temperature, which was kept at 4 ° C. in the ARTEMIS reader and read according to the kit instructions (Thermo). Inhibition of test compounds was calculated based on the FRET ratio of 665/615. Activity was calculated as a percentage of control response. IC50 values were calculated from dose response curves by nonlinear regression analysis using GraphPad Prism software.

The prepared compounds were tested using the above assay procedure and the results obtained are provided in Table 26. Percent inhibition at 1.0 μM and 10.0 μM concentrations are provided in the table below with IC ₅₀ (nM) details for the selected samples.

The IC ₅₀ (nM) values are listed in Table 26, where “A” refers to IC ₅₀ values of less than 50 nM, “B” refers to IC ₅₀ values in the range of 50.01 to 100.0 nM, and “C” "denotes an IC ₅₀ value of greater than 100.01 to about 500 nM, and," D "refers to an IC ₅₀ value of 500 nM exceeded.

Although the present invention has been described with reference to specific embodiments, it should be understood that these embodiments merely illustrate the principles and applications of the present invention. Therefore, it should be understood that many modifications may be made to the exemplary embodiments, and that other configurations may be devised without departing from the spirit and scope of the invention as described above.

All publications and patent applications cited in this application are incorporated herein by reference to the same extent as each individual publication or patent application is specifically and individually indicated to be incorporated herein by reference.

Claims (42)

Compounds of formula (I), stereoisomers, diastereomers, enantiomers or pharmaceutically acceptable salts thereof:

In the formula,
A is selected from CH and N;
D is selected from CR ¹ R ² and CO;
E is selected from (CR ³ R ⁴ ) _m , NR ¹ and CO;
F is selected from O, CH ₂ , CHOH and CO;
Each instance of R ⁵ is selected from hydrogen, halogen, cyano, hydroxyl and C _1-8 alkyl;
R ⁷ is selected from hydrogen and C _1-8 alkyl;
Each instance of R ⁶ is halogen, cyano, hydroxyl, C _1-8 alkyl, halo C _1-8 alkyl, hydroxy C _1-8 alkyl, C _1-8 alkoxy, C _1-8 alkoxy C _1-8 Alkyl, C _3-6 cycloalkyl, and C _3-6 cycloalkyl C _1-8 alkyl;
R ¹ , R ² , R ³ and R ⁴ , which may be the same or different, are each independently hydrogen, amine, C _1-8 alkyl, C _3-6 cycloalkyl, halo C _1-8 alkyl, hydroxy C _{1- 8} alkyl, C _3-6 cycloalkyl C _1-8 alkyl, C _1-8 alkoxy, 3-15 membered heterocyclyl, C _1-8 alkyl 3-15 membered heterocyclyl and CR ^a R ^b NR ^a R ^b Independently selected from;
R ^a and R ^b may be the same or different and are each independently selected from hydrogen and C _1-8 alkyl;
Z is selected from O, NH and S;
L is

And

Is selected from;
x and y represent the point of attachment;
Ring Q is

And

Is selected from;
Each instance of R ⁸ is halogen, cyano, cyano C _1-8 alkyl, cyanohalo C _1-8 alkyl, cyano C _3-6 cycloalkyl, C _1-8 alkyl, halo C _1-8 alkyl , Hydroxy C _1-8 alkyl, hydroxy C _1-8 haloalkyl and -SO ₂ R ¹ ;
Each occurrence of R ⁹ is halogen, cyano, hydroxyl, C _1-8 alkyl, halo C _1-8 alkyl, hydroxy C _1-8 alkyl, C _1-8 alkoxy,

Is selected from;
R ¹⁰ is selected from halogen, hydroxyl, cyano, C _1-8 alkyl, halo C _1-8 alkyl, C _3-6 cycloalkyl and C _6-14 aryl; Wherein C _6-14 aryl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amide or C _1-8 alkyl;
'm' is 1 or 2;
'n' is 0, 1 or 2;
'p' is 0 or 1;
'q' is 0 or 1; And
't' is 1 or 2. The compound of claim 1, wherein A is CH. The compound of claim 1, wherein A is N. 7. The compound of claim 1, wherein D is CR ¹ R ² or CO. The compound of claim 1, wherein E is (CR ³ R ⁴ ) _m , NR ¹ or CO. The compound of claim 1, wherein F is O, CH ₂ , CHOH or CO. The compound of any one of claims 1-6, wherein R ⁵ is hydrogen, chloro or cyano. The compound of any one of claims 1-6, wherein R ⁷ is hydrogen or methyl. The compound of any one of claims 1-8, wherein R ³ is hydrogen or methyl. The compound of any one of claims 1-9 wherein R ⁴ is hydrogen or methyl. The compound of any one of claims 1-10, wherein 'm' is 1 or 2. The compound of claim 1, wherein Z is O. The compound of claim 1, wherein Z is NH. The compound of claim 1, wherein Z is S. 7. The compound of claim 1, wherein R ⁶ is chloro, fluoro, methyl, trifluoromethyl or methoxy. 13. The compound of claim 1 or 12, wherein 'n' is 0, 1 or 2. The compound of claim 1, wherein L is

Phosphorus compounds. The compound of claim 1, wherein L is

Phosphorus compounds. The compound of claim 1, wherein L is

Phosphorus compounds. The compound of claim 1, wherein L is

Phosphorus compounds The compound of claim 1, wherein ring Q is

Phosphorus compounds The compound of any one of claims 1-21, wherein R ⁸ is chloro, bromo, cyano, cyanomethyl, cyanoisopropyl, cyanodifluoromethyl, cyanocyclopropane, methyl, trifluoro. Methyl, difluoromethyl, hydroxyl difluoromethyl or -SO ₂ R ¹ . The compound of any one of claims 1-22, wherein R ¹ is hydrogen, methyl, ethyl or amine. 24. The compound of claim 1, wherein R ² is hydrogen, methyl, ethyl, isopropyl, hydroxyl methyl, methoxymethyl, 3-15 membered heterocyclyl C _1-8 alkyl or CR ^a R ^b NR ^a R ^b compound. The compound of any one of claims 1-24, wherein R ^a and R ^b are hydrogen or methyl. The method of claim 1, wherein D is CH ₂ , CH—CH ₃ , CH—CH ₂ —CH ₃ , C (CH ₃ ) ₂ , CH—CH (CH ₃ ) ₂ , CH— CH ₂ OH, CH—CH ₂ —O—CH ₃ ,

, CH-CH ₂ -N (CH ₃ ) ₂ or CO. 27. The compound of any one of claims 1 to 26, wherein R ⁹ is fluoro, bromo, cyano, hydroxyl, methyl, trifluoromethyl, methoxy,

Phosphorus compounds. The compound of any one of claims 1-27 wherein R ¹⁰ is methyl, trifluoromethyl or C _6-14 aryl. The compound of any one of claims 1-28 wherein 't' is 2. 30. The compound of any one of the preceding claims, wherein 'p' is 0 or 1. 31. The compound of any one of claims 1-30, wherein 'q' is 0 or 1. The method of any one of claims 1 to 31,
A is CH or N;
D is CH ₂ , CH—CH ₃ , CH—CH ₂ —CH ₃ , C (CH ₃ ) ₂ , CH—CH (CH ₃ ) ₂ , CH—CH ₂ OH, CH—CH ₂ —O—CH ₃ ,

, CH-CH ₂ -N (CH ₃ ) ₂ , CO or cycloalkyl;
E is CH ₂ , CH—CH ₃ , C (CH ₃ ) ₂ , (CH ₂ ) ₂ , N—CH ₃ or CO;
F is O, CH ₂ , CHOH or CO;
R ⁵ is hydrogen, chloro or cyano;
R ⁷ is hydrogen or methyl;
Z is O, NH or S;
R ⁶ is chloro, fluoro, methyl, trifluoromethyl or methoxy;
L is

or

ego;
Ring Q is

ego;
'm' is 1 or 2;
'n' is 0, 1 or 2; A compound selected from the following compounds and their pharmaceutically acceptable salts:
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4-ethylpiperazin- 1) -yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4-4-ethylpipe Razin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -4-fluorobenzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4- Methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4- Isopropylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4- Methylpiperidin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4- (morpholino Methyl) -3- (trifluoromethyl) phenyl) benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4- (piperazin- 1-ylmethyl) -3- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-(((2 -(Dimethylamino) ethyl) (methyl) amino) methyl) -3- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4- (4-methyl Piperazin-1-yl) -3- (trifluoromethyl) phenyl) benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4- (piperazin- 1-yl) -3- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-morpholino- 3- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4- Ethyl piperazin-1-yl) methyl) phenyl) benzamide;
4-chloro-N- (3-chloro-4-((4-ethylpiperazin-1-yl) methyl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5,4- b] [1,4] oxazin-4-yl) oxy) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4- Ethyl piperazin-1-yl) methyl) -3-methylphenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4-methyl Piperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
N- (3-bromo-5- (trifluoromethyl) phenyl) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] Oxazin-4-yl) oxy) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4- (4-ethyl Piperazine-1-carbonyl) -3- (trifluoromethyl) phenyl) benzamide;
N- (4-((4-acetylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
N- (3-bromo-4-((4-ethylpiperazin-1-yl) methyl) phenyl) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4 -b] [1,4] oxazin-4-yl) oxy) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4- (2- ( Dimethylamino) ethoxy) -3- (trifluoromethyl) phenyl) benzamide;
4- (4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamido) -N- (2- (dimethylamino) ethyl) -2- (trifluoromethyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (trifluoro Methyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((1- Ethylpiperidin-4-yl) oxy) -3- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4-ethyl Piperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4-iso Propylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4- Propylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4-propyl Piperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-N- (3- (4- (cyclopropylmethyl) piperazin-1-yl) -5- (trifluoromethyl) phenyl) -3-((7,8-dihydro-6H-pyri Mido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3-((4- Ethylpiperazin-1-yl) methyl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4- ( Dimethylamino) piperidin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3-((2- (Dimethylamino) ethyl) (methyl) amino) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-N- (3- (2-cyanopropan-2-yl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] Oxazin-4-yl) oxy) benzamide;
4-chloro-N- (3- (1-cyanocyclopropyl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazine- 4-yl) oxy) benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (piperazin- 1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4-methyl Piperidin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (piperidine -4-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (1-methyl Piperidin-4-yl) -5- (trifluoromethyl) phenyl) benzamide;
(S) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3-fluoropyrrolidin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (1,1 -Dioxidothiomorpholino) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3-((dimethylamino ) Methyl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-N- (3- (cyanomethyl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl ) Oxy) benzamide;
4-chloro-N- (3- (cyanodifluoromethyl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazine-4 -Yl) oxy) benzamide;
(R) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3-fluoropyrrolidin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((3- (Dimethylamino) pyrrolidin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
(S) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
(R) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
(R) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4- ((3- (methylamino) pyrrolidin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
(S) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4- ((3- (methylamino) pyrrolidin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (2-fluoro-3 -(Trifluoromethyl) phenyl) benzamide;
4-chloro-N- (4-cyano-3- (trifluoromethyl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] Oxazin-4-yl) oxy) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4- (trifluoro Methyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (6-methyl-5- (Trifluoromethyl) pyridin-3-yl) benzamide;
4-chloro-N- (3-cyano-5- (trifluoromethyl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] Oxazin-4-yl) oxy) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3-methoxy-5 -(Trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3-fluoro-5 -(Trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3-hydroxy-5 -(Trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (2-methoxy-5 -(Trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3-morpholino- 5- (trifluoromethyl) phenyl) benzamide;
(R) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3- (dimethylamino) pyrrolidin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
(S) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3- (dimethylamino) pyrrolidin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-N- (3- (4,4-difluoropiperidin-1-yl) -5- (trifluoromethyl) phenyl) -3-((7,8-dihydro-6H- Pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
(R) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3-hydroxypyrrolidin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
N- (3- (1,4-diazepane-1-yl) -5- (trifluoromethyl) phenyl) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5 , 4-b] [1,4] oxazin-4-yl) oxy) benzamide hydrochloride;
4-chloro-N- (4-((4- (2-cyanoacetyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((7,8-di Hydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
N- (3-((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -5- (trifluoromethyl) phenyl) -4-chloro-3-(( 7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide hydrochloride;
4-chloro-N- (3- (4-cyclopropylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5 , 4-b] [1,4] oxazin-4-yl) oxy) benzamide;
N- (3-acrylamido-5- (trifluoromethyl) phenyl) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4 ] Oxazin-4-yl) oxy) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4- ( Oxetan-3-yl) piperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
(S) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3-hydroxypyrrolidin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3-((isopropyl Amino) methyl) -5- (trifluoromethyl) phenyl) benzamide;
(S) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide hydrochloride;
(R) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide hydrochloride;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4- ( Prop-2-ynin-1-yl) piperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4-fluoro Ropiperidin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4-methyl -1,4-diazepan-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) -3-((7-oxo-7,8-dihydro-6H-pyri Mido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((7-oxo-7,8-dihydro- 6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
(S) -4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((6-methyl-7,8 -Dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
(S) -4-chloro-3-((6-methyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N -(3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
(R) -4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((7-methyl-7,8 -Dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
(S) -4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((7-methyl-7,8 -Dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
4-chloro-3-((7,7-dimethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- ( 4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,7-dimethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- ( 3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methyl-N- (4-((4- Methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4-ethylpiperazin-1 -Yl) -5- (trifluoromethyl) phenyl) -4-methylbenzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4-isopropylpiperazin -1-yl) methyl) -3- (trifluoromethyl) phenyl) -4-methylbenzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methyl-N- (3- (4-methyl Piperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4-isopropylpiperazin- 1-yl) -5- (trifluoromethyl) phenyl) -4-methylbenzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methyl-N- (3- (4-propyl Piperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
N- (3- (4- (cyclopropylmethyl) piperazin-1-yl) -5- (trifluoromethyl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5, 4-b] [1,4] oxazin-4-yl) oxy) -4-methylbenzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3-((4-ethylpiperazin- 1-yl) methyl) -5- (trifluoromethyl) phenyl) -4-methylbenzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methyl-N- (4- (trifluoro Methyl) phenyl) benzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methyl-N- (3-morpholino- 5- (trifluoromethyl) phenyl) benzamide;
(R) -3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3- ( Dimethylamino) pyrrolidin-1-yl) -5- (trifluoromethyl) phenyl) -4-methylbenzamide;
N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -4-methyl-3-((7-oxo-7,8-dihydro- 6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
(S) -N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -4-methyl-3-((6-methyl-7,8 -Dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) amino) -N- (4-((4- Ethyl piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) thio) -N- (4-((4-ethylpiperazin- 1-yl) methyl) -3- (trifluoromethyl) phenyl) -4-methylbenzamide;
3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) -N- (4-((4-ethylpiperazin- 1-yl) methyl) -3- (trifluoromethyl) phenyl) -4-methylbenzamide;
3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) -N- (3-((4-ethylpiperazin- 1-yl) methyl) -5- (trifluoromethyl) phenyl) -4-methylbenzamide;
3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) -N- (3- (4-ethylpiperazin-1 -Yl) -5- (trifluoromethyl) phenyl) -4-methylbenzamide;
3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) -N- (4-((1-ethylpiperidine -4-yl) oxy) -3- (trifluoromethyl) phenyl) -4-methylbenzamide;
3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) -4-methyl-N- (3- (4-methyl Piperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -4-methyl-3-((3-oxo-3,4-dihydro- 2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) benzamide;
4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((5-oxo-5,6,7,8 Tetrahydropyrido [2,3-d] pyrimidin-4-yl) oxy) benzamide;
4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((5,6,7,8-tetrahydropyripy Degree [2,3-d] pyrimidin-4-yl) oxy) benzamide;
4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((5-hydroxy-5,6,7, 8-tetrahydropyrido [2,3-d] pyrimidin-4-yl) oxy) benzamide;
N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -4-methyl-3-((5,6,7,8-tetrahydropyripy Degree [2,3-d] pyrimidin-4-yl) oxy) benzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4-ethylpiperazin- 1-yl) methyl) -3- (trifluoromethyl) phenyl) -4-methoxybenzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4-ethylpiperazin- 1-yl) methyl) -3- (trifluoromethyl) phenyl) -5- (trifluoromethyl) benzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4-ethylpiperazin- 1-yl) methyl) -3- (trifluoromethyl) phenyl) -2-methylbenzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4-ethylpiperazin- 1-yl) methyl) -3- (trifluoromethyl) phenyl) -4- (trifluoromethyl) benzamide;
2-chloro-5-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4- Ethyl piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4- Ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -2-methylbenzamide;
5-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4-ethylpiperazin- 1-yl) methyl) -3- (trifluoromethyl) phenyl) -2-fluorobenzamide;
3-chloro-5-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4- Ethyl piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
1- (4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -3- (4 -((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea;
N- (4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -4-(( 4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3-((2R, 6S) -2,6-dimethylmorpholino) -5- (trifluoromethyl) phenyl) benzamide;
(S) -4-chloro-3-((7-methyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N -(3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
(R) -4-chloro-3-((7-methyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N -(3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
(R) -4-chloro-3-((6-methyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N -(3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
(R) -4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((6-methyl-7,8 -Dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
(S) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (2-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
(R) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (2-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3-jade Consuming polyno) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3-((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) -5- (trifluoromethyl) phenyl) benzamide;
(R) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3,4-dimethylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
(S) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3,4-dimethylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) -4-methyl-N- (3-morpholino- 5- (trifluoromethyl) phenyl) benzamide;
(S) -3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) -N- (3- (3- ( Dimethylamino) pyrrolidin-1-yl) -5- (trifluoromethyl) phenyl) -4-methylbenzamide;
1- (4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -3- (3 -(4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) urea;
(S) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (2,4-dimethylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
(R) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (2,4-dimethylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3-((1- Methylazetidin-3-yl) oxy) -5- (trifluoromethyl) phenyl) benzamide;
(R) -4-methyl-3-((7-methyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N -(3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
3-((7,7-dimethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methyl-N- ( 3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (1-methyl -1H-pyrazol-4-yl) -5- (trifluoromethyl) phenyl) benzamide;
1- (4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -3- (3- (4- Methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) urea;
(R) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -5- (trifluoromethyl) phenyl) benzamide;
(S) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -5- (trifluoromethyl) phenyl) benzamide;
(R) -4-chloro-3-((6-methyl-7-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) Oxy) -N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
(R) -4-chloro-3-((7-ethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N -(3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
(R) -3-((7-ethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methyl-N -(3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
(S) -4-chloro-3-((7-ethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N -(3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
(S) -3-((7-ethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methyl-N -(3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
N- (4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -3-fluorophenyl) -N- ( 4-fluorophenyl) cyclopropane-1,1-dicarboxamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (2-((1- Methylpiperidin-4-yl) oxy) -5- (trifluoromethyl) phenyl) benzamide;
(S) -4-chloro-3-((6-methyl-7-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) Oxy) -N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((6,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
1- (4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -3- (4-((4 Ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea;
3-chloro-4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4-methyl Piperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
3-chloro-4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4- Ethyl piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
1- (4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -3-methylphenyl) -3- (4- ((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea;
3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) -4-methyl-N- (3- (4- ( Oxetan-3-yl) piperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
1- (4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -3-methylphenyl) -3- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) urea;
1- (3-chloro-4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -3- (4 -((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea;
1- (3-chloro-4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -3- (3 -(4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) urea;
4-chloro-3-((8-methyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
N- (3- (1H-pyrazol-4-yl) -5- (trifluoromethyl) phenyl) -4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4 -b] [1,4] oxazin-4-yl) oxy) benzamide;
(R) -4-chloro-3-((7-isopropyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy)- N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
(S) -4-chloro-3-((7-isopropyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy)- N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-N- (4- (1- (4-ethylpiperazin-1-yl) ethyl) -3- (trifluoromethyl) phenyl) -3-(((R) -7-methyl-7 , 8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
4-chloro-N- (4'-cyano-5- (trifluoromethyl)-[1,1'-biphenyl] -3-yl) -3-((7,8-dihydro-6H- Pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
4-chloro-N- (3'-cyano-5- (trifluoromethyl)-[1,1'-biphenyl] -3-yl) -3-((7,8-dihydro-6H- Pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
4-chloro-3-((3-methyl-2-oxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidin-5-yl) oxy) -N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
(R) -4-chloro-3-((7-ethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N -(4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3-propionamido- 5- (trifluoromethyl) phenyl) benzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methyl-N- (3- (4-methyl -1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4-methyl -1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (2-fluoro-5- (trifluoro Rhomethyl) phenyl) -4-methylbenzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (2-fluoro-5 -(Trifluoromethyl) phenyl) benzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4-ethylpiperazin- 1-yl) methyl) -3- (trifluoromethyl) phenyl) -4-methylbenzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4- Ethyl piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) -N- (3- (4- ( Oxetan-3-yl) piperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) -N- (3- (4-methyl Piperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
1- (3-chloro-4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -3- (3 -(Trifluoromethyl) phenyl) urea;
1- (4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -3- (3- (trifluor Rhomethyl) phenyl) urea;
1- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] jade Photo-4-yl) oxy) phenyl) urea;
4-chloro-N- (4- (2-cyanopropan-2-yl) -3- (trifluoromethyl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5, 4-b] [1,4] oxazin-4-yl) oxy) benzamide;
(R) -4-chloro-3-((7- (morpholinomethyl) -7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl ) Oxy) -N- (3- (trifluoromethyl) phenyl) benzamide;
1- (3-cyano-5- (trifluoromethyl) phenyl) -3- (4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] jade Photo-4-yl) oxy) phenyl) urea;
(R) -1- (3-chloro-4-((7-methyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy ) Phenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea;
1- (4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -2-fluorophenyl) -3- ( 3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) urea;
4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4-methylpiperazin-1 -Yl) -5- (trifluoromethyl) phenyl) benzamide;
4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4-ethylpiperazin- 1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
1- (4-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) phenyl) -3- (3- (4- Methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) urea;
1- (4-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) phenyl) -3- (4-((4 Ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (2- ( Dimethylamino) acetamido) -5- (trifluoromethyl) phenyl) benzamide;
N- (3- (4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamido) ) -5- (trifluoromethyl) phenyl) -1-isopropylazetidine-3-carboxamide;
(S) -4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((7- (hydroxymethyl) -7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (4-methylpiperazin-1 -Yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (pyridine-4 -Ylethynyl) -5- (trifluoromethyl) phenyl) benzamide;
1- (4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -2-fluorophenyl) -3- ( 4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3- ( Dimethylamino) azetidin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
4-chloro-3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) -N- (4-((4- Ethyl piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
1- (4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -3- (4-((4 Ethylpiperazin-1-yl) methyl) phenyl) urea;
1- (2-chloro-4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -3- (4 -((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea;
1- (4-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) phenyl) -3- (4-((4 Ethylpiperazin-1-yl) methyl) phenyl) urea;
(E) -N- (3- (3-amino-3-oxoprop-1-en-1-yl) -5- (trifluoromethyl) phenyl) -3-((7,8-dihydro -6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methylbenzamide;
N- (3- (3-amino-3-oxoprop-1-ynin-1-yl) -5- (trifluoromethyl) phenyl) -3-((7,8-dihydro-6H-pyri Mido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methylbenzamide;
1- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (4-((2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepin-9-yl) oxy) phenyl) urea;
1- (4-((7-cyano-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) phenyl) -3- ( 4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea;
(E) -N- (3- (2-cyanovinyl) -5- (trifluoromethyl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazine 4-yl) oxy) -4-methylbenzamide;
1- (4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -3- (3-((4 -Ethylpiperazin-1-yl) methyl) -5- (trifluoromethyl) phenyl) urea hydrochloride;
(R) -1- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (4-((7-methyl-7,8- Dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) urea;
4-chloro-N- (4- (1- (4-ethylpiperazin-1-yl) ethyl) -3- (trifluoromethyl) phenyl) -3-(((R) -7-methyl-7 , 8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide (isomer I);
4-chloro-N- (4- (1- (4-ethylpiperazin-1-yl) ethyl) -3- (trifluoromethyl) phenyl) -3-(((R) -7-methyl-7 , 8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide (isomer II);
1- (3- (tert-butyl) -1- (4-cyanophenyl) -1H-pyrazol-5-yl) -3- (4-((3,4-dihydro-2H-pyrido [ 3,2-b] [1,4] oxazin-8-yl) oxy) phenyl) urea;
(R) -1- (5- (tert-butyl) isoxazol-3-yl) -3- (3-chloro-4-((7-methyl-7,8-dihydro-6H-pyrimido [5 , 4-b] [1,4] oxazin-4-yl) oxy) phenyl) urea;
1- (5- (tert-butyl) isoxazol-3-yl) -3- (4-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine -8-yl) oxy) phenyl) urea;
1- (4-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) oxy) phenyl) -3- (4-((4 Ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea;
N- (5- (tert-butyl) isoxazol-3-yl) -3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-8- Yl) oxy) -4-methylbenzamide;
(R) -4-chloro-N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3-((7- (methoxymethyl) -7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
(R) -4-chloro-3-((7-((dimethylamino) methyl) -7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazine-4- Yl) oxy) -N- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
(R) -1- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (3-fluoro-4-((7-methyl -7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) urea;
1- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (2-fluoro-4-((2,3,4,5 Tetrahydropyrido [3,2-b] [1,4] oxazepin-9-yl) oxy) phenyl) urea;
N- (3- (tert-butyl) -1- (3-cyanophenyl) -1H-pyrazol-5-yl) -3-((3,4-dihydro-2H-pyrido [3,2 -b] [1,4] oxazin-8-yl) oxy) -4-methylbenzamide;
N- (3- (tert-butyl) -1- (4-cyanophenyl) -1H-pyrazol-5-yl) -3-((3,4-dihydro-2H-pyrido [3,2 -b] [1,4] oxazin-8-yl) oxy) -4-methylbenzamide;
(R) -4-chloro-3-((7-methyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N -(3- (4-methylpiperazin-1-yl) phenyl) benzamide;
(R) -4-chloro-3-((7-methyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N -(2- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3-hydroxyprop- 1-Ayn-1-yl) -5- (trifluoromethyl) phenyl) -4-methylbenzamide;
(R) -1- (2-chloro-4-((7-methyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy ) Phenyl) -3-cyclopropylurea;
4-chloro-3-((2-chloro-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4- ((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
1- (4-((7,7-dimethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea;
1- (3- (tert-butyl) -1- (4-cyanophenyl) -1H-pyrazol-5-yl) -3- (2-fluoro-4-((2,3,4,5 Tetrahydropyrido [3,2-b] [1,4] oxazepin-9-yl) oxy) phenyl) urea;
N- (3- (tert-butyl) -1- (3-cyanophenyl) -1H-pyrazol-5-yl) -4-chloro-3-((7,7-dimethyl-7,8-di Hydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
1- (4-((7,7-dimethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -3-fluoro Phenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea;
1- (5- (tert-butyl) isoxazol-3-yl) -3- (3-chloro-4-((7,7-dimethyl-7,8-dihydro-6H-pyrimido [5,4 -b] [1,4] oxazin-4-yl) oxy) phenyl) urea;
1- (3- (tert-butyl) -1- (4-cyanophenyl) -1H-pyrazol-5-yl) -3- (3-chloro-4-((7,7-dimethyl-7, 8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) urea;
1- (3-chloro-4-((7,7-dimethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl ) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea;
1- (4-((7,7-dimethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -3-methylphenyl) -3- (4-((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) urea;
1- (3- (tert-butyl) -1- (3-cyanophenyl) -1H-pyrazol-5-yl) -3- (3-chloro-4-((7,7-dimethyl-7, 8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) urea;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methyl-N- (3- (methylsulfonyl ) Phenyl) benzamide;
3-((7,7-dimethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-(( 4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -4-methylbenzamide;
1- (3- (tert-butyl) -1- (3-cyanophenyl) -1H-pyrazol-5-yl) -3- (4-((3,4-dihydro-2H-pyrido [ 3,2-b] [1,4] oxazin-8-yl) oxy) phenyl) urea;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3-hydroxy-3- Methylbut-1-ynin-1-yl) -5- (trifluoromethyl) phenyl) -4-methylbenzamide;
N- (3- (difluoromethyl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methylbenzamide;
3- (3- (tert-butyl) -5- (3- (2-fluoro-4-((2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazin-9-yl) oxy) phenyl) ureido) -1H-pyrazol-1-yl) benzamide;
(R) -N- (5- (tert-butyl) isoxazol-3-yl) -4-chloro-3-((7-methyl-7,8-dihydro-6H-pyrimido [5,4- b] [1,4] oxazin-4-yl) oxy) benzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (ethyl sulfonyl) phenyl)- 4-methylbenzamide;
3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3-methoxyprop- 1-Ayn-1-yl) -5- (trifluoromethyl) phenyl) -4-methylbenzamide;
1- (4-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) phenyl) -3- (3- (methylsul Ponyl) phenyl) urea;
N- (3- (1,1-difluoro-2-hydroxyethyl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] Oxazin-4-yl) oxy) -4-methylbenzamide;
N- (3- (cyanoethynyl) -5- (trifluoromethyl) phenyl) -3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] Oxazin-4-yl) oxy) -4-methylbenzamide;
1- (4-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) phenyl) -3- (3- (ethylsulfur Phonyl) phenyl) urea;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (3- (3-hydro Oxybut-1-ynin-1-yl) -5- (trifluoromethyl) phenyl) benzamide;
3- (3- (4-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) phenyl ureido) benzenesulfonamide;
N- (5- (tert-butyl) isoxazol-3-yl) -4-chloro-3-((7,7-dimethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) benzamide;
1- (3- (tert-butyl) -1-methyl-1H-pyrazol-5-yl) -3- (4-chloro-3-((7,7-dimethyl-7,8-dihydro-6H -Pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) urea;
4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4-((4- Ethylpiperazin-1-yl) methyl) -3- (methylsulfonyl) phenyl) benzamide;
1- (3- (tert-butyl) -1- (3-cyanophenyl) -1H-pyrazol-5-yl) -3- (2-fluoro-4-((2,3,4,5 Tetrahydropyrido [3,2-b] [1,4] oxazepin-9-yl) oxy) phenyl) urea;
3-((7,7-dimethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4- (3 -Hydroxybut-1-ynin-1-yl) -3- (trifluoromethyl) phenyl) -4-methylbenzamide;
1- (3- (tert-butyl) -1- (3-cyanophenyl) -1H-pyrazol-5-yl) -3- (4-((7,7-dimethyl-7,8-dihydro -6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) phenyl) urea;
4-methyl-N- (3- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) -3-((2,3,4,5-tetrahydropyrido [3 , 2-b] [1,4] oxazepin-9-yl) oxy) benzamide;
3-((7,7-dimethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- (4- (4 -Hydroxybut-1-ynin-1-yl) -3- (trifluoromethyl) phenyl) -4-methylbenzamide;
3-((7,7-dimethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -4-methyl-N- ( 3- (4-methylpiperazin-1-yl) -5- (methylsulfonyl) phenyl) benzamide;
1- (4-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8yl) oxy) phenyl) -3- (3- (4-methyl Piperazin-1-yl) -5- (methylsulfonyl) phenyl) urea;
1- (4-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl) oxy) phenyl) -3- (4-((4 Ethylpiperazin-1-yl) methyl) -3- (methylsulfonyl) phenyl) urea;
4-chloro-3-((7,7-dimethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- ( 4- (1- (4-ethylpiperazin-1-yl) ethyl) -3- (trifluoromethyl) phenyl) benzamide (isomer I);
4-chloro-3-((7,7-dimethyl-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl) oxy) -N- ( 4- (1- (4-ethylpiperazin-1-yl) ethyl) -3- (trifluoromethyl) phenyl) benzamide (isomer II). Chemical formula

Of a compound or a pharmaceutically acceptable salt thereof. Chemical formula

Of a compound or a pharmaceutically acceptable salt thereof. Chemical formula

Of a compound or a pharmaceutically acceptable salt thereof. 37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36 and a pharmaceutically acceptable excipient. The pharmaceutical composition of claim 37, wherein the pharmaceutically acceptable excipient is a carrier or diluent. A method of treating MAP4K1 (HPK1) mediated disease, disorder, syndrome or condition in a subject,
A method of treating MAP4K1 (HPK1) mediated disease, disorder, syndrome or condition in a subject, comprising administering an effective amount of a compound according to any one of claims 1 to 36. 40. The method of claim 39, wherein said disease, disorder, syndrome or condition is an autoimmune, neurodegenerative, nervous system, inflammatory, hyperproliferative and cardiovascular disease. The method of claim 39, wherein the disease, disorder, syndrome, or condition is Parkinson's disease, Alzheimer's disease, stroke and related memory loss, arthritis, allergy, asthma, diabetes, insulin-resistant diabetes, liver ischemia, reperfusion injury, deafness or hearing impairment Central nervous system cancers such as neural tube, congenital defects, obesity, chronic myelogenous leukemia (CML), oxidative damage of liver and kidney, melanoma, thyroid cancer, adenocarcinoma, breast cancer, glioblastoma, astrocytoma and central nervous system, colorectal cancer, squamous Epithelial cell carcinoma, small cell and non-small cell lung cancer, ovarian cancer, endometrial cancer, pancreatic cancer, prostate cancer, sarcoma and skin cancer. The method of claim 39, wherein the disease, disorder, syndrome or symptom is cancer.