EP3630778A1 - Nouveaux inhibiteurs de map4k1 - Google Patents

Nouveaux inhibiteurs de map4k1

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Publication number
EP3630778A1
EP3630778A1 EP18728587.9A EP18728587A EP3630778A1 EP 3630778 A1 EP3630778 A1 EP 3630778A1 EP 18728587 A EP18728587 A EP 18728587A EP 3630778 A1 EP3630778 A1 EP 3630778A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
oxy
trifluoromethyl
oxazin
dihydro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP18728587.9A
Other languages
German (de)
English (en)
Inventor
Vinod Patel
Venkateshwar REDDY
Laxmikant Atmaram Gharat
Sachin Sundarlal Chaudhari
Sanjib Das
Ranganadh VELGALETI
Daisy Manish Shah
Malini Bajpai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ichnos Sciences SA
Original Assignee
Ichnos Sciences SA
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Filing date
Publication date
Application filed by Ichnos Sciences SA filed Critical Ichnos Sciences SA
Publication of EP3630778A1 publication Critical patent/EP3630778A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present patent application is directed to novel inhibitors of the mitogen-activated protein kinase kinase kinase kinase kinase 1, also known as MAP4K1 or HPK1 (hematopoietic progenitor kinase 1). BACKGROUND OF THE INVENTION
  • Protein kinases represent a large family of proteins which play a variety of crucial roles in the regulation of a wide range of cellular processes. Such kinases include 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, especially selective inhibition, has become an important strategy in treating many diseases and disorders.
  • MAP4K1 is a serine/threonine kinase of the Ste20 family.
  • MAP4K enzymes MAP kinase kinases
  • a MAP4K will phosphorylate and activate a particular substrate which is a MAP3K (a MAP kinase kinase).
  • a MAP3K in turn phosphorylates and activates a MAP2K (a MAP kinase kinase).
  • a MAP2K in turn phosphorylates and activates a MAPK (MAP kinase).
  • the MAP kinase is the final effector of the pathway and it in turn phosphorylates a substrate to control key cellular processes such as cell proliferation, cell differentiation, gene expression, transcription regulation, and apoptosis.
  • the substrate of MAPK is generally a nuclear protein, such as nuclear factor kappa-B (NF-excellentB). Activation of the MAPK by its phosphorylation by an MAP2K results in translocation of this final enzyme in the cascade into the nucleus.
  • MAP4K1 also known as HPK1
  • HPK1 is primarily expressed in the immune system’s Tcells and B cells, which are critical in regulation of the immune system. Overstimulation of T cell and B cell activation pathways can result in auto-immune diseases, while understimulation of these pathways can result in immune dysfunction, susceptibility to viral and bacterial infection and increased susceptibility to cancer.
  • MAP4K1 is activated by its interaction with activated T cell receptors (TCRs) and B cell receptors (BCRs), so MAP4K1 activation serves to convey the cellular activation signal from the surface of a T or B cell to the effector proteins in the nucleus.
  • TCRs T cell receptors
  • BCRs B cell receptors
  • MAP4K1 activation ultimately results in activation of several identified nuclear effector proteins, including those involved in the NF-excellent1, AP-1, ERK2, and Fos signaling pathways.
  • MAP4K1 is considered a negative regulator of T cell receptor (TCR) activation signals, and it is one of the effector molecules that mediates immunosuppression of T cell responses upon exposure to prostaglandin E2 (PGE2).
  • PGE2 prostaglandin E2
  • MAP4K1 regulates the MAP3K’s MEKK1, TAK1 and MLK3. These in turn regulate the MAP2K’s MKK4 and MKK7. These in turn regulate the 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 has been implicated in apoptosis, neurodegeneration, cell differentiation and proliferation, inflammatory conditions and cytokine production.
  • the JNK signal transduction pathway is activated in response to environmental stress and by the engagement of several classes of cell surface receptors, including cytokine receptors, serpentine receptors and receptor tyrosine kinases.
  • the JNK pathway has been implicated in biological processes such as oncogenic transformation and mediating adaptive responses to environmental stress.
  • JNK has also been associated with modulating immune responses, including maturation and differentiation of immune cells, as well as effecting programmed cell death in cells identified for destruction by the immune system.
  • JNK signaling is particularly implicated in ischemic stroke and Parkinson's disease, but also in other diseases as mentioned further below.
  • JNK signaling has also been implicated in diseases such as excitotoxicity of hippocampal neurons, liver ischemia, reperfusion, neurodegenerative diseases, hearing loss, deafness, neural tube birth defects, cancer, chronic inflammatory diseases, obesity, diabetes, in particular, insulin-resistant diabetes, and it has been proposed that selective JNK inhibitors
  • MAP4K1 is an upstream regulator of JNK
  • effective inhibitors of MAP4K1 would be useful in treating the same diseases which have been suggested or implicated for JNK inhibitors, especially where such disease or dysfunction is manifested in hematopoietic cells such as T cells and B cells.
  • HPK1 MAP4K1
  • PGE2 prostaglandin E2
  • MAP4K1 and PGE2 are particularly noteworthy because PGE2 is the predominant eicosanoid product released by cancer cells, including lung, colon and breast cancer cells. Tumor-produced PGE2 is known to contribute significantly to tumor- mediated immune suppression.
  • MAP4K1 small molecule inhibitors of MAP4K1 have been reported, but they do not inhibit MAP4K1 selectively, or even preferentially.
  • inhibitors include staurosporine, bosutinib, sunitinib, lestaurtinib, crizotinib, foretinib, dovitinib and KW-2449.
  • Staurosporine for example, broadly inhibits a wide range of protein kinases across both the serine/threonine and tyrosine kinase families.
  • Bosutinib is primarily an inhibitor of the tyrosine kinase BCR- Abl, with additional activity against the Src family tyrosine kinases.
  • Sunitinib is a broad inhibitor of tyrosine kinases. Lestaurtinib is primarily an inhibitor of the FLT, JAK and TRK family tyrosine kinases. Crizotinib is primarily an inhibitor of the c-met and ALK tyrosine kinases. Foretinib was under study as an inhibitor of the c-Met and VEGFR tyrosine kinases. Dovitinib is primarily an inhibitor of the FGFR receptor tyrosine kinase. KW-2449 is an experimental inhibitor primarily of the FLT3 tyrosine kinase.
  • Sunitinib inhibits MAP4K1 at nanomolar concentrations, but it is a broad-spectrum receptor tyrosine kinase inhibitor. Treating T-cells with sunitinib results in enhanced cytokine product similar to that observed with HPK1 ⁇ / ⁇ T cells, which suggests that in T cells a selective MAP4K1 inhibitor could produce the same enhanced immune response phenotype.
  • the major challenge currently faced in the field is the lack of MAP4K1 specific inhibitors.
  • the present disclosure provides novel, highly effective small-molecule inhibitors of MAP4K1.
  • the present invention relates to a compound of formula (I)
  • 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, CH2, CHOH and CO;
  • each occurrence of R 5 is selected from hydrogen, halogen, cyano, hydroxyl and C 1- 8 alkyl;
  • R 7 is selected from hydrogen and C1-8alkyl
  • each occurrence of R 6 is selected from halogen, cyano, hydroxyl, C 1-8 alkyl, haloC 1- 8 alkyl, hydroxyC 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkoxyC 1-8 alkyl, C 3-6 cycloalkyl and C 3- 6cycloalkylC1-8alkyl;
  • R 1 , R 2 , R 3 and R 4 which may be same or different, are each independently selected from hydrogen, amine, C 1-8 alkyl, C 3-6 cycloalkyl, haloC 1-8 alkyl, hydroxyC 1-8 alkyl, C 3- 6cycloalkylC1-8alkyl, C1-8alkoxy, 3-15 membered heterocyclyl, C1-8alkyl3-15 membered heterocyclyl and CR a R b NR a R b ;
  • R a and R b which may be the same or different, are each independently selected from hydrogen and C 1-8 alkyl;
  • Z is selected from O, NH and S;
  • L is selected from and
  • Ring Q is selected from
  • each occurrence of R 8 is selected from halogen, cyano, cyanoC1-8alkyl, cyanohaloC1- 8alkyl, cyanoC 3-6 cycloalkyl, C 1-8 alkyl, haloC 1-8 alkyl, hydroxyC 1-8 alkyl, hydroxyC 1-8 haloalkyl, and -SO 2 R 1 ;
  • each occurrence of R 9 is selected from halogen, cyano, hydroxyl, C1-8alkyl, haloC1-
  • R 10 is selected from halogen, hydroxyl, cyano, C1-8alkyl, haloC1-8alkyl, C3-6cycloalkyl 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 0, 1 or 2
  • ‘p’ is 0 or 1
  • ‘t’ is 1 or 2.
  • the compounds of formula (I) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (I) as defined above wherein A is N (according to an embodiment defined below); F is O (according to another embodiment defined below); R 7 is hydrogen (according to yet another embodiment defined below).
  • R 1 is hydrogen or C 1-8 alkyl (e.g. methyl) and R 2 is hydrogen, C 1-8 alkyl (e.g. methyl, ethyl or isopropyl), hydroxyC 1-8 alkyl (e.g. hydroxyl methyl), C 1-8 alkoxyC 1- 8alkyl (e.g. methoxymethyl), 3-15 membered heterocyclylC1-8alkyl (e.g. or CR a R b NR a R b .
  • R a and R b are independently hydrogen or methyl.
  • R a and R b are hydrogen.
  • R a and R b are methyl.
  • R 3 is hydrogen or C 1-8 alkyl (e.g. methyl) and R 4 is hydrogen or C 1-8 alkyl (e.g. methyl) and‘m’ is 1 or 2.
  • R 5 is hydrogen, halogen (e.g. chloro) or cyano.
  • R 7 is hydrogen or C 1-8 alkyl (e.g. methyl).
  • R 6 is halogen (e.g. chloro or fluoro), C 1-8 alkyl (e.g. methyl), haloC 1- 8alkyl (e.g. trifluoromethyl) or C1-8alkoxy (e.g. methoxy).
  • R 6 is halogen (e.g. chloro or fluoro), C 1-8 alkyl (e.g. methyl), haloC 1- 8alkyl (e.g. trifluoromethyl) or C1-8alkoxy (e.g. methoxy).
  • R 6 is chloro, fluoro, methyl, trifluoromethyl or methoxy.
  • R 8 is halogen (e.g. chloro or bromo), cyano, cyanoC1-8alkyl (e.g. cyanomethyl or cyanoisopropyl), cyanohaloC1-8alkyl (e.g. cyanodifluoromethyl), cyanoC3- 6cycloalkyl (e.g. cyanocyclopropane), C 1-8 alkyl (e.g. methyl), haloC 1-8 alkyl (e.g. trifluoromethyl or difluoromethyl), hydroxyC1-8haloalkyl (e.g. hydroxyl difluoromethyl) or - SO2R 1 .
  • R 1 is C1-8alkyl (e.g. methyl, ethyl or amine).
  • R 8 is chloro, bromo, cyano, cyanomethyl, cyanoisopropyl, cyanodifluoromethyl, cyanocyclopropane, methyl, trifluoromethyl, difluoromethyl, hydroxyl difluoromethyl, -SO 2 Me, -SO 2 Et or -SO 2 NH 2 .
  • R 9 is halogen (e.g. fluoro or bromo), cyano, hydroxyl, C1-8alkyl (e.g. methyl), haloC 1-8 alkyl (e.g. trifluoromethyl), C 1-8 alkoxy (e.g. methoxy),
  • Ring Q is In this embodiment, R 10 is C 1-8 alkyl (e.g. methyl) or haloC 1-8 alkyl (e.g. trifluoromethyl). In yet another embodiment,‘t’ is 2.
  • R 10 is C1-8alkyl (e.g. methyl) or C6-14aryl.
  • C6-14aryl is optionally substituted with one or more substituents selected from cyano, or amide.
  • 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-
  • E is CH2, CH-CH3, C(CH3)2, (CH2)2, N-CH3 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
  • ‘m’ is 1 or 2;
  • ‘n’ is 0, 1 or 2.
  • compounds of formula (I) with an IC50 value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM, with respect to MAP4K1 inhibition.
  • the present application also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described
  • the compounds described herein may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a tablet, capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient such as a carrier or a diluent
  • a carrier or enclosed within a carrier which can be in the form of a tablet, capsule, sachet, paper or other container.
  • Dosages employed in practicing the present invention will of course vary depending, e.g. on the particular disease or condition to be treated, the particular compound used, the mode of administration, and the therapy desired.
  • the compound may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation.
  • satisfactory results, e.g. for the treatment of diseases as hereinbefore set forth are indicated to be obtained on oral administration at dosages of the order from about 0.01 to 2.0 mg/kg.
  • an indicated daily dosage for oral administration will accordingly be in the range of from about 0.75 to 300 mg, conveniently administered once, or in divided doses 2 to 4 times, daily or in sustained release form.
  • Unit dosage forms for oral administration thus for example may comprise from about 0.2 to 75 or 150 mg or 300 mg, e.g. from about 0.2 or 2.0 to 10, 25, 50, 75, 100, 150, 200 or 300 mg of the compound disclosed herein, together with a pharmaceutically acceptable diluent or carrier therefor.
  • compositions comprising Compounds of the Invention may be prepared using conventional diluents or excipients and techniques known in the galenic art.
  • oral dosage forms may include tablets, capsules, solutions, suspensions and the like.
  • halogen or“halo” means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).
  • alkyl refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. C 1-8 alkyl), and which is attached to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).
  • C1-6alkyl refers to an alkyl chain having 1 to 6 carbon atoms.
  • C 1-4 alkyl refers to an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. C1-8 alkoxy).
  • Representative examples of such groups are -OCH3 and -
  • alkoxyalkyl or“alkyloxyalkyl” refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. C1-8alkoxyC1-8alkyl or C 1-8 alkyloxyC 1-8 alkyl).
  • alkoxyalkyl moiety includes, but are not limited to, - CH 2 OCH 3 (methoxymethyl) and -CH 2 OC 2 H 5 (ethoxymethyl). Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched.
  • haloalkyl refers to at least one halo group (selected from F, Cl, Br or I), linked to an alkyl group as defined above (i.e. haloC 1-8 alkyl). Examples of such haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups.
  • haloC1-4alkyl refers to at least one halo group linked an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloC 1-8 alkoxy).
  • haloalkoxy include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy.
  • all haloalkoxy groups described herein may be straight chain or branched.
  • hydroxyC1-8alkyl refers to a C1-8alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyC 1-4 alkyl).
  • hydroxyC 1-4 alkyl moieties include, but are not limited to
  • cyanoalkyl refers to a alkyl group as defined above directly bonded to cyano group (i.e. cyanoC 1-8 alkyl). Examples of such cyanoC 1-8 alkyl moiety include, but are not limited to, cyanomethyl, cyanoethyl and cyanoisopropyl. Unless set forth or recited to the contrary, all cyanoalkyl groups described herein may be straight chain or branched.
  • cyanohaloalkyl refers to cyanoalkyl group substituted with one or more halogen atoms (i.e.cyanohaloC 1-8 alkyl).
  • halogen atoms i.e.cyanohaloC 1-8 alkyl
  • Example of cyanohaloalkyl include but are not limited to cyanodifluoromethyl. Unless set forth or recited to the contrary, all cyanohaloalkyl groups described herein may be straight chain or branched.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.C3-12cycloalkyl).
  • monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl.
  • the term“C 3-6 cycloalkyl” refers to the cyclic ring having 3 to 6 carbon atoms.
  • Examples of“C 3- 6cycloalkyl” include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to an alkyl group (i.e. C3-6cycloalkylC1-8alkyl).
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • cyanocycloalkyl refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to cyano group (i.e.“cyanoC 3-6 cycloalkyl).
  • Non- limiting example of such groups include cyanocyclopropane.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C6- 14 aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • heterocyclic ring or“heterocyclyl” unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e. 3 to 15 membered heterocyclyl) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
  • heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- oxoazepinyl, octahydroin
  • heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. 3 to 15 membered heterocyclylC1-8alkyl).
  • the 20 heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • heteroaryl refers to 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S (i.e. 5 to 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 that results in the creation of a stable structure.
  • heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, iso
  • salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulf
  • treating or“treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non-domestic animals such as wildlife.
  • A“therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • The“therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • the compounds of formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolysing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • Enantiomers can also be separated by use of chiral HPLC column.
  • the chiral centres of the present invention can have the S or R configuration as defined by the IUPAC 1974.
  • salt or “solvate”, and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers or racemates of the inventive compounds.
  • compositions can be prepared using procedures well
  • compositions described herein comprise one or more compounds described herein and one or more pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • the pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.
  • suitable carriers include, but are not limited to, 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.
  • compositions described herein may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.
  • compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
  • Administration of the compounds of the invention, in pure form or in an appropriate 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 which effectively transports the active compound of the patent application to the 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 liquids, such as suspensions or solutions.
  • Topical dosage forms of the compounds include, but are not limited to, ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.
  • Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art.
  • MAP4K1 inhibitors according to the invention are highly effective inhibitors of the MAP4K1 kinase, producing inhibition at nanomolar concentrations.
  • MAP4K1 inhibitors according to the invention are therefore useful for treatment and prophylaxis of diseases associated with protein kinase signaling dysfunction. Accordingly, without being bound by any theory, it is believed that inhibition of MAP4K1 could, for example, reverse or prevent the cellular dysfunction associated with perturbations of the JNK signaling pathway, especially in T and B cells.
  • a MAP4K1 inhibitor as described herein could provide a potential means to regulate MAPK signal transduction pathways, especially the JNK pathway, and by extension provide a treatment for a variety of diseases and disorders including autoimmune, neurodegenerative, neurological, inflammatory, hyperproliferative, and cardiovascular diseases and disorders.
  • selective MAP4K1 inhibition may provide a novel means of cancer treatment.
  • Traditional signal transduction strategies relate to interference with the pathways that promote tumor cell proliferation or metastasis.
  • the present invention provides instead a means of enhancing the activity and effectiveness of the body’s T cells, for example, to overcome the immunosuppressive strategies used by many cancers.
  • the U.S. Food and Drug Administration (FDA) has recently approved some monoclonal antibody-based treatments that achieve the same result by interfering with T-cell surface receptors which promote inhibition of TCR activity (e.g., anti-CTLA-4 and anti-PD-1 antibodies, marketed as Ipilimumab and Pembrolizumab, respectively).
  • the success of the treatments demonstrate proof of the concept that cancer can be effectively treated by interfering with pathways which
  • the invention provides a method for the treatment or prophylaxis of a disease or disorder which may be ameliorated by modulating (e.g., inhibiting) MAP4K1-dependent signaling pathways, including the JNK pathway, e.g., autoimmune, neurodegenerative, neurological, inflammatory, hyperproliferative, and cardiovascular diseases and disorders, comprising administering to a patient in need thereof an effective amount of the compound of Formula I as described herein, in free or pharmaceutically acceptable salt form.
  • modulating e.g., inhibiting
  • MAP4K1-dependent signaling pathways including the JNK pathway, e.g., autoimmune, neurodegenerative, neurological, inflammatory, hyperproliferative, and cardiovascular diseases and disorders
  • administration of the compound of Formula I results in enhanced T cell receptor (TCR) signaling, such as resulting in an enhanced T cell-mediated immune response (e.g., increased T cell cytokine production).
  • TCR T cell receptor
  • administration of the compound of Formula I results in increased T cell resistance to PGE2-mediated T cell suppression.
  • the disease or disorder may be selected from the group consisting of: neurodegenerative diseases, such as Parkinson's disease or Alzheimer's disease; stroke and associated memory loss; autoimmune diseases such as arthritis; allergies and asthma; diabetes, especially insulin-resistant diabetes; other conditions characterized by inflammation, including chronic inflammatory diseases; liver ischemia; reperfusion injury; hearing loss or deafness; neural tube birth defects; obesity; hyperproliferative disorders including malignancies, such as leukemias, e.g. chronic myelogenous leukemia (CML); oxidative damage to organs such as the liver and kidney; heart diseases; and transplant rejections.
  • the disease or disorder to be treated may also relate to impaired MAP4K1-dependent signaling.
  • Impaired MAP4K1 signaling can lead to reduced immune cell, e.g. T and B cell, function which can permit or enhance the escape of nascent cancer cells from immune surveillance.
  • Restoration of T and B cell function via treatment with a MAP4K1-inhibitor can therefore promote the clearance of carcinogenic and pre- carcinogenic cells from the body.
  • the invention provides a method for the treatment or prevention of hyperproliferative diseases, such as cancer, including melanomas, thyroid cancers, adenocarcinoma, breast cancer, central nervous system cancers such as glioblastomas, astrocytomas and ependymomas, colorectal cancer, squamous cell carcinomas, small and non-small cell lung cancers, ovarian cancer, endometrial cancer, pancreatic cancer, prostate cancer, sarcoma and skin cancers.
  • hyperproliferative diseases such as cancer, including melanomas, thyroid cancers, adenocarcinoma, breast cancer, central nervous system cancers such as glioblastomas, astrocytomas and ependymomas, colorectal cancer, squamous cell carcinomas, small and non-small cell lung cancers, ovarian cancer, endometrial cancer, pancreatic cancer, prostate cancer, sarcoma and skin cancers.
  • the invention provides a method of treatment or prevention of hematologic cancers such as leukemias, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia (CML), Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, megakaryoblastic leukemia, and multiple myeloma.
  • hematologic cancers such as leukemias, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia (CML), Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, megakaryoblastic leukemia, and multiple myeloma.
  • MAP4K1 inhibitor compounds described herein for the treatment or prophylaxis of disease or disorder according to the foregoing methods may be used as a sole therapeutic agent or may be used in combination with one or more other therapeutic agents useful for the treatment of said diseases or disorders.
  • Such other agents include inhibitors of other protein kinases in the JNK pathway, including, for example, inhibitors of JNK (e.g., JNK1 or JNK2), MKK4, MKK7, p38, MEKK (e.g., MEKK1, MEKK2, MEKK5), and GCK,
  • the MAP4K1 inhibitor of the invention may be administered in combination with inhibitors of JNK (e.g., JNK1 or JNK2), MKK4, MKK7, p38, MEKK (e.g., MEKK1, MEKK2, MEKK5), and GCK.
  • JNK e.g., JNK1 or JNK2
  • MKK4 MKK7, p38 e.g., MKK4, MKK7, p38
  • MEKK e.g., MEKK1, MEKK2, MEKK5
  • the invention provides the following:
  • the reaction may be carried out in the presence of suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride etc., and the solvent can be selected from DMF, DMSO, acetonitrile, 1,4-dioxane or a mixture thereof.
  • the reaction can also be performed by Buchwald reaction using a suitable base such as tripotassium phosphate, sodium or potassium tert-butoxide, cesium carbonate, etc., in the presence of palladium acetate as catalyst and a suitable hindered ligand (eg.
  • suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride etc.
  • the solvent can be selected from DMF, DMSO, acetonitrile, 1,4-dioxane or a mixture thereof.
  • the reaction can also be performed by Buchwald reaction using a suitable base such as tripotassium phosphate, sodium or potassium tert-butoxide, cesium carbonate, etc., in the presence of palladium acetate as catalyst and a suitable hindered ligand (eg. XPhos, di-tBuXPhos, JohnPhos, DavePhos, Sphos, etc.) in an appropriate solvent such as toluene, 1,4-doxane, water or a mixture thereof.
  • a suitable hindered ligand eg. XPhos, di-tBuXPhos, JohnPhos, DavePhos, Sphos, etc.
  • the coupling reaction of the ester of formula (7) with amine of formula (4) in the presence of a suitable reagent and solvent directly affords the deprotected final compound of general formula (IIa).
  • the suitable base used in the reaction may be potassium tert-butoxide or trimethyl aluminium solution.
  • the coupling reaction may be carried out in a suitable solvent or mixture thereof.
  • the suitable solvent may be selected from dichloromethane, THF, toluene, or a combination thereof.
  • the coupling reaction of compound of formula (1) with the amine of formula (4) gives amide of formula (5) which on substitution reaction with compound of formula (6) followed by deprotection furnishes the compound of general formula (IIa).
  • the reaction conditions for the alternative sequence may remain the same as described in scheme 1.
  • Deprotection reaction may be carried out using hydrochloric acid or trifluoroacetic acid in suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc.
  • suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc.
  • the benzoic acid derivative of formula (8) on coupling reaction with ethyl 2-(3- aminophenyl)-2,2-difluoroacetate (9) yields the amide derivative of formula (10).
  • the reaction may be carried out via acid chloride formation using oxalyl chloride or thionyl
  • the suitable base for the reaction may be triethylamine, N,N-diisopropylethylamine, pyridine or DMAP and solvent may be selected from THF, chloroform, dichloromethane or 1,4- dioxane.
  • the reductive amination and deprotection of compound of formula (10) using ammonia solution in methanol at elevated temperature (above 50 °C) affords the compound of formula (11).
  • Substitution of compound of formula (11) with halogen derivative (2) yields the compound of formula (12).
  • the reaction may be carried out in the presence of suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride etc.; and the solvent can be selected from DMF, DMSO, acetonitrile, 1,4-dioxane or a mixture thereof.
  • suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride etc.
  • the solvent can be selected from DMF, DMSO, acetonitrile, 1,4-dioxane or a mixture thereof.
  • the amide group of compound of formula (12) converts to the nitrile group by reaction with Burgess Reagent to give compound of general formula (IIb).
  • the reaction may be carried out in a suitable solvent such as dichloromethane.
  • the amino phenol compound of formula (13) on reaction with compound of formula (6) yields the compound of formula (14).
  • the reaction may be carried out in the presence of suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride etc.; and the solvent can be selected from DMF, DMSO, toluene, acetonitrile, 1,4- dioxane or a mixture thereof.
  • suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride etc.
  • the solvent can be selected from DMF, DMSO, toluene, acetonitrile, 1,4- dioxane or a mixture thereof.
  • the amine compound of formula (14) on step wise reaction with triphosgene and amine of formula (4) in THF; followed by deprotection yields the urea derivative of general formula (IIIa).
  • Deprotection reaction may be carried out using hydrochloric acid or trifluoroacetic acid in suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc.
  • suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc.
  • Compound of general formula (IIIa) may be synthesized by the reaction of a carbamate derivative of amine (4’) with compound (14) in the presence of a suitable base and solvent.
  • the suitable base for the reaction may be triethylamine, DIPEA, etc. and the suitable solvent may be DMSO.
  • Compound of general formula (IIIa) can also be synthesized by an alternative sequence of reaction starting from Z- protected analogue (13’) of compound (13).
  • the amine of formula (14) on reaction with acid compound of formula (4’) yields the amide compound of formula (15).
  • the coupling reaction may be carried out in the presence of suitable coupling agent such as HATU, EDCI.HCl with or without HOBt, T3P or DCC.
  • suitable coupling agent such as HATU, EDCI.HCl with or without HOBt, T3P or DCC.
  • the reaction may be carried out in suitable solvent selected from THF, dichloromethane, dichloroethane, chloroform, 1,4-dioxane or a mixture thereof.
  • the compound of formula (16) on deprotection yields the compound of general formula (IIIb).
  • Deprotection reaction may be carried out using hydrochloric acid or trifluoroacetic acid in suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc.
  • suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, F, Q and n are as defined in the general description
  • R’ Me or Et
  • P protecting group, like Boc or PMB
  • the coupling reaction of the nitro ester of formula (16) with amine of formula (4) in the presence of a suitable reagent and solvent affords the compound of general formula (17).
  • the suitable base used in the reaction may be potassium tert-butoxide or trimethyl aluminium solution.
  • the coupling reaction may be carried out in a suitable solvent or mixture thereof.
  • the suitable solvent may be selected from dichloromethane, THF, toluene, or a combination thereof.
  • Nitro reduction compound of formula (17) yields the amine of formula (18).
  • the reaction may be carried out using iron powder in the presence of acetic acid or ammonium chloride in appropriate solvent such as methanol, ethanol, THF, water or a mixture thereof.
  • the substitution reaction of compound of formula (18) with halogen bearing compound of formula (6) in the presence of a suitable reagent and solvent yields the compound of formula (19).
  • the reaction may be performed using Buchwald coupling method in the presence of suitable base, catalyst, ligand and solvent.
  • the reaction may be performed using base such as sodium or potassium tert-butoxide, cesium or potassium carbonate, etc.
  • palladium acetate can be used as a catalyst along with a suitable ligand (eg. XPhos, t-BuXPhos, JohnPhos) and appropriate solvent can be selected from 1,4-dioxane, toluene, water or a mixture thereof.
  • a suitable ligand eg. XPhos, t-BuXPhos, JohnPhos
  • appropriate solvent can be selected from 1,4-dioxane, toluene, water or a mixture thereof.
  • the compound of formula (19) on deprotection yields the compound of general formula (II
  • Deprotection reaction may be carried out using hydrochloric acid or trifluoroacetic acid in suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc.
  • suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc.
  • the reaction may be carried out in the presence of suitable base and solvent.
  • Suitable base may be potassium carbonate, cesium carbonate, cesium fluoride etc. and the suitable solvent may be DMF, DMSO, 1,4-dioxane, etc.
  • the compound of formula (21) on N-deprotection affords the compound of general formula (IId).
  • Deprotection reaction may be carried out using hydrochloric acid or trifluoroacetic acid in suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc.
  • compound of formula (21) on reaction with sodium borohydride in a suitable solvent yields the gives the hydroxyl derivative of formula (22).
  • the suitable solvent for the reaction may be THF, methanol or a mixture thereof.
  • the compound (22) undergoes further reduction in the presence of trimethylsilane and trifluoroacetic acid followed by N- deprotection to furnish the compound of general formula (IIf).
  • Deprotection reaction may be carried out using hydrochloric acid or trifluoroacetic acid in suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc.
  • the compound of general formula (IId) on reduction using sodium borohydride yields the compound of general formula (IIe).
  • the suitable solvent for the reaction may be THF, methanol or a mixture thereof.
  • the compound of formula (5a) on reaction with formyl derivative of formula (23) in the presence of base and solvent affords the compound of formula (24).
  • Suitable base may be potassium carbonate, cesium carbonate, cesium fluoride etc. and the suitable solvent may be DMF, DMSO, 1,4-dioxane, etc.
  • 4,6-Dichloro-5-methoxypyrimidine (25) on reaction with appropriately substituted ethanolamine derivative of formula (26) in the presence of suitable base and solvent yields the compound of formula (27).
  • the suitable base for the reaction may be potassium carbonate and solvent may be DMF or 1,4-dioxane.
  • boron tribromide in a suitable solvent such as THF, affords either of the compound of formula (28) or (29) or a mixture thereof in varied ratio, which on reaction with a suitable protecting agent in the presence of a suitable base and solvent furnishes the compound of formula (2a).
  • the N-protecting agent can be tert-butyl dicarbonate (Boc anhydride) or 4- methoxybenzylchloride (PMB-Cl).
  • the suitable base for the reaction may be triethylamine, DIPEA, DMAP, or a mixture thereof and solvent can be selected from THF, dichloromethane, 1,4-dioxane, DMF or a mixture thereof.
  • a general approach for the preparation of compounds of the formula (2b) (wherein R 3 and R 4 are as defined in the general description) is depicted in synthetic scheme 8.
  • the suitable base for the reaction may be triethylamine, DIPEA, DMAP, or a mixture thereof and solvent can be selected from DMF, 1,4-dioxane, DMSO or a mixture thereof.
  • the N- protecting agent can be tert-butyl dicarbonate (Boc anhydride) or 4-methoxybenzylchloride (PMB-Cl).
  • the suitable base for the reaction may be triethylamine, DIPEA, DMAP, or a mixture thereof and solvent can be selected from THF, dichloromethane, 1,4-dioxane, DMF or a mixture thereof.
  • the compound of formula (34) on self-Mitsunobu reaction yields the cyclized compound of formula (2d).
  • the N-protecting agent can be tert-butyl dicarbonate (Boc anhydride) or 4-methoxybenzylchloride (PMB-Cl).
  • the suitable base for the reaction may be LiHMDS, triethylamine, DIPEA, DMAP, or a mixture thereof.
  • the suitable solvent can be selected from THF, dichloromethane, 1,4-dioxane, DMF or a mixture thereof.
  • 2-amino-4-bromopyridin-3-ol hydrobromide (36) undergoes cyclization with chloroacetyl chloride (39) at elevated temperature (> 50 °C) in the presence of suitable base solvent to yield 8-bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (40).
  • the suitable base for the reaction may be sodium bicarbonate and solvent may be 2-butanone, water or a mixture thereof.
  • Compound (40) on N-protection with a suitable protecting agent in the presence of suitable base and solvent furnishes the compound of formula (2f).
  • the N-protecting agent can be tert-butyl dicarbonate (Boc anhydride) or 4-methoxybenzylchloride (PMB-Cl).
  • the suitable base for the reaction may be cesium carbonate, and solvent can be selected from THF, 1,4-dioxane, DMF or a mixture thereof.
  • a general approach for the preparation of compounds of the formula (2g) is depicted in synthetic scheme 11.
  • the compound of formula (45) on reaction with benzyl alcohol (46) in the presence of suitable base and solvent yields the compound of formula (47).
  • the suitable base for the reaction may be potassium tert-butoxide and solvent may be DMSO.
  • the compound of formula (47) undergoes esterification using sulfuric acid in methanol under reflux conditions to give the compound of formula (48) which on palladium (palladium on carbon 5-10%, 50% wet) catalyzed hydrogenation affords the compound of formula (1a).
  • the hydrogenation reaction may be performed in a suitable solvent such as ethanol, methanol, ethyl acetate, or a combination thereof.
  • the suitable solvent for the reaction is water.
  • a general approach for the preparation of compounds of the formula (4a) (wherein R 8 and R 9 are as defined in the general description) is depicted in synthetic scheme 14.
  • the reaction may be done in the presence of suitable base and solvent.
  • the suitable base may be sodium, potassium or cesium carbonate, sodium or potassium tert-butoxide, sodium hydride, cesium fluoride, etc.
  • the solvent may be selected from THF, DMF, toluene, DMSO, chloroform, dichloromethane, acetonitrile, dichloroethane, 1,4-dioxane or a mixture thereof. Nitro reduction of compound (55) yields the compound of formula (4a).
  • the reaction may be carried out using iron powder in the presence of acetic acid or ammonium chloride in appropriate solvent such as methanol, ethanol, THF, water or a mixture thereof. Nitro reduction can also be done by palladium (palladium on carbon 5-10%, 50% wet) catalyzed hydrogenation.
  • the hydrogenation reaction may be performed in a suitable solvent such as ethanol, methanol, ethyl acetate, or a combination thereof.
  • step 1 intermediate 2-((6-chloro-5-methoxypyrimidin-4-yl)amino)ethanol (step 1 intermediate) (6.0 g, 29.4 mmol) and boron tribromide in dichloromethane (1.0M, 100 mL) was refluxed for 3-4 h. 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 in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to yield 4.0 g of the desired compound.
  • Step 3 tert-Butyl 4-chloro-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate
  • step 2 intermediate 4-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (step 2 intermediate) (4.0 g, 23.3 mmol) in dichloromethane (40 mL) were added di-tert-butyl dicarbonate (Boc anhydride) (7.6 g, 34.9 mmol) at 0 °C followed by triethylamine (9.7 mL) and the mixture was stirred at 0 °C for 3 h and then 1 h at RT.
  • DMAP (1.4 g, 11.6 mmol) was
  • step 1 intermediate a mixture of 4,6-dichloropyrimidin-5-ol (step 1 intermediate) (4.0 g, 24.2 mmol), ethyl glycolate (3.02 g, 29.1 mmol) and triphenylphosphine (12.7 g, 48.5 mmol) in THF (40 mL) was slowly added diethyl azodicarboxylate (DEAD) (9.8 g, 48.5 mmol) at RT. The mixture was stirred overnight at RT. The mixture was diluted with diethyl ether and filtered off the precipitated solid. 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.
  • Step 3 4-Chloro-8-(4-methoxybenzyl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one
  • ethyl 2-((4,6-dichloropyrimidin-5-yl)oxy)acetate (1.0 g, 3.98 mmol) in DMF (10 mL) were added 4-methoxybenzylamine (818 mg, 5.97 mmol) followed by DIPEA (513 g, 3.98 mmol) at 0 °C.
  • the mixture was stirred overnight at RT and the 1 h at 130 °C.
  • the mixture was cooled and quenched with water.
  • step 1 intermediate A mixture of (S)-1-((6-chloro-5-methoxypyrimidin-4-yl)amino)propan-2-ol (step 1 intermediate) (4.8 g, 22.1 mmol) and boron tribromide (1M in dichloromethane, 25 mL) was heated at 80 °C for 18 h. The solvent was removed under reduced pressure and the residue was quenched with ice-cooled water. The aqueous solution was neutralized using 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.
  • Step 3 (S)-tert-Butyl 4-chloro-6-methyl-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate
  • the titled compound was prepared by the reaction of (S)-4-((2-bromopropyl)amino)-6- chloropyrimidin-5-ol (step 2 intermediate) (500 mg, 2.69 mmol) with di-tert-butyl dicarbonate (881 mg, 4.84 mmol) in the presence of DMAP (296 mg, 2.48 mmol) in dichloromethane (10 mL) as per the procedure described in step 3 of Intermediate A1 to yield 154 mg of the compound.
  • step 1 intermediate 2-((6-chloro-5-methoxypyrimidin-4-yl)amino)-2-methylpropan-1-ol (step 1 intermediate) (3.5 g, 15.1 mmol) in dichloromethane (35 mL) was added boron tribromide (1M in THF, 75.8 mL) 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.
  • Step 3 tert-Butyl (6-chloro-5-hydroxypyrimidin-4-yl)(1-hydroxy-2-methylpropan-2- yl)carbamate
  • step 2 intermediate 4-chloro-6-((1-hydroxy-2-methylpropan-2-yl)amino)pyrimidin-5-ol (step 2 intermediate) (2.5 g, 11.4 mmol) in dichloromethane (25 mL) were 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.
  • 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 (step 3 intermediate) (1.9 g, 5.97 mmol) in anhydrous THF (20 mL) were added triphenylphosphine (1.88 g, 7.18 mmol) and diisopropyl azodicarboxylate (DIAD) (1.39 mL, 7.17 mmol) at 0 °C under nitrogen atmosphere.
  • DIAD diisopropyl azodicarboxylate
  • step 1 intermediate 2-amino-4-bromopyridin-3-ol hydrobromide (step 1 intermediate) (15 g, 58.6 mmol) in acetonitrile (150 mL) were added cesium carbonate (57.1 g, 175 mmol) followed by 1,2-dibromoethane (16.4 g, 87.7 mmol) and the mixture was refluxed for 48 h. The mixture was filtered and the filtrates was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 3.0 g of the titled compound.
  • step 2 intermediate 8-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (step 2 intermediate) (2.1 g, 9.76 mmol) in anhydrous THF (20 mL) were dropwise added lithium bis(trimethylsilyl)amide (LiHMDS) (1M, 11.6 mL, 11.7 mmol) followed by di-tert-butyl dicarbonate (3.3 mL, 14.6 mmol) at 0 °C and the mixture was stirred at the same temperature for 1 h. The reaction was quenched with saturated ammonium chloride solution and extracted
  • LiHMDS lithium bis(trimethylsilyl)amide
  • step 1-Intermediate A7 To a solution of 2-amino-4-bromopyridin-3-ol hydrobromide (step 1-Intermediate A7) (12 g, 63.4 mmol) in a mixture of 2-butanone and water (1:1, 120 mL) was added aqueous solution of sodium bicarbonate (16 g, 190 mmol) at 0 °C and the mixture was stirred for 10 min. Chloroacetyl chloride (7.16 g, 63.4 mmol) was added to the mixture and stirred for 3-4 h at 0 °C. Then the mixture was heated to 80 °C and stirred for 10 h. The mixture was cooled to RT and extracted twice with ethyl acetate.
  • Step 2 8-Bromo-4-(4-methoxybenzyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one
  • step 1 intermediate 8-bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one
  • step 1 intermediate 8-bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one
  • step 1 intermediate 250 mg, 1.09 mmol
  • DMF 5.0 mL
  • 4-methoxybenzyl chloride 256 mg, 1.63 mmol
  • step 1 intermediate 1-(4,6-dichloropyrimidin-5-yl)prop-2-en-1-ol (step 1 intermediate) (100 mg, 0.49 mmol) in dichloromethane (5.0 mL) was added Dess–Martin periodinane (415 mg, 0.97 mmol) at 0 °C and the mixture was stirred overnight at RT. The mixture was filtered
  • Step 3 4-Chloro-8-(4-methoxybenzyl)-7,8-dihydropyrido[2,3-d]pyrimidin-5(6H)-one
  • step 2 intermediate 1-(4,6-dichloropyrimidin-5-yl)prop-2-en-1-one (step 2 intermediate)
  • step 2 intermediate 4-methoxybenzylamine (1.1 g, 8.12 mmol) at RT.
  • the mixture was stirred overnight at 50 °C.
  • the mixture was cooled and quenched with water.
  • the aqueous mixture was extracted twice with ethyl acetate.
  • Step 1 (R)-Methyl 2-((tert-butoxycarbon l amino -3- meth lsulfonyl)oxy)propanoate
  • step 1 intermediate To a stirred solution of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3- ((methylsulfonyl)oxy)propanoate (step 1 intermediate) (2.9 g, 9.76 mmol) in dichloromethane (20 mL) were 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 stirred at RT for 18 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography to yield 1.46 g of the desired product.
  • DIPEA N,N- diisopropylethylamine
  • step 2 intermediate To a solution of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-morpholinopropanoate (step 2 intermediate) (1.4 g, 4.86 mmol) in THF (15 mL) was added DIBAL solution (1M in toluene, 19.4 mL, 19.4 mmol) at -78 °C and the mixture was stirred at the same temperature for 2 h. The reaction was quenched with brine and stirred for 1 h. The solution was filtered and washed with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by column chromatography to yield 1.2 g of the desired product.
  • Step 4 (R)-tert-Butyl (1-((4,6-dichloropyrimidin-5-yl)oxy)-3-morpholinopropan-2- yl)carbamate
  • the titled compound was prepared by the reaction of (R)-tert-butyl (1-hydroxy-3- morpholinopropan-2-yl)carbamate (step 3 intermediate) (1.2 g, 4.61 mmol) with 4,6- dichloropyrimidin-5-ol (step 1 of Intermediate A2) (912 mg, 5.51 mmol) in the presence of DIAD (1.4 g, 6.92 mmol) and triphenylphosphine (1.8 g, 6.92 mmol) in THF (10 mL) as per
  • step 4 intermediate To a solution of (R)-tert-butyl (1-((4,6-dichloropyrimidin-5-yl)oxy)-3-morpholinopropan-2- yl)carbamate (step 4 intermediate) (2.9 g, 7.13 mmol) in ethyl acetate (10 mL) was added hydrochloric acid in 1,4-dioxane (4M, 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.
  • step 5 intermediate To a solution of (R)-1-((4,6-dichloropyrimidin-5-yl)oxy)-3-morpholinopropan-2-amine hydrochloride (step 5 intermediate) (520 mg, 1.51 mmol) in DMF (5.0 mL) was added DIPEA (2.6 mL, 15.1 mmol) and the mixture was stirred overnight at RT. 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 yield 271 mg of the desired product.
  • Step 7 (R)-tert-Butyl 4-chloro-7-(morpholinomethyl)-6H-pyrimido[5,4-b][1,4]oxazine- 8(7H)-carboxylate
  • the titled compound was prepared by the reaction of (R)-4-chloro-7-(morpholinomethyl)-7,8- dihydro-6H-pyrimido[5,4-b][1,4]oxazine (step 6 intermediate) (260 mg, 0.96 mmol) with di-
  • Step 2 (S)-1-(4-Chloro-7-(hydroxymethyl)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)- yl)ethanone
  • step 1 intermediate N-(6-chloro-5-hydroxypyrimidin-4-yl)acetamide (step 1 intermediate) (500 mg, 2.67 mmol) followed by (2R)-(-)-glycidyl tosylate (669 mg, 2.93 mmol) 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.
  • step 2 intermediate A solution of (S)-1-(4-chloro-7-(hydroxymethyl)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)- yl)ethanone (step 2 intermediate) (150 mg, 0.62 mmol) in hydrochloric acid in 1,4-dioxane (3.0 mL) 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 using saturated sodium
  • Step 4 (S)-tert-Butyl 7-(((tert-butoxycarbonyl)oxy)methyl)-4-chloro-6H-pyrimido[5,4- b][1,4]oxazine-8(7H)-carboxylate
  • the titled compound was prepared by the reaction of (S)-(4-chloro-7,8-dihydro-6H- pyrimido[5,4-b][1,4]oxazin-7-yl)methanol (step 3 intermediate) (170 mg, 0.84 mmol) with di-tert-butyl dicarbonate (476 mg, 2.18 mmol) in the presence of DMAP (246 mg, 2.01 mmol) in dichloromethane (10 mL) as per the procedure described in step 3 of Intermediate A1 to yield 100 mg of the compound.
  • the titled compound was prepared by the reaction of 2-amino-4-bromopyridin-3-ol hydrobromide (step 1 of Intermediate A7) (1.0 g, 3.90 mmol) and 1-bromo-3-chloropropane (925 mg, 5.80 mmol) in the presence of cesium carbonate (3.8 g, 11.7 mmol) in acetonitrile (10 mL) as per the procedure described in step 2 of Intermediate A7 to yield 400 mg of the compound.
  • step 1 intermediate 4-bromo-3-(3-chloropropoxy)pyridin-2-amine (step 1 intermediate) (400 mg, 1.20 mmol) in DMF (5.0 mL) was added sodium hydride (60% w/w, 96 mg, 2.40 mmol) at RT. The mixture 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 combined organic layers were 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.
  • Step 3 tert-Butyl 9-bromo-3,4-dihydropyrido[3,2-b][1,4]oxazepine-5(2H)-carboxylate
  • the titled compound was prepared by the reaction of 9-bromo-2,3,4,5-tetrahydropyrido[3,2- b][1,4]oxazepine (step 2 intermediate) (2.0 g, 8.77 mmol) and di-tert-butyl dicarbonate (2.84 g, 13.0 mmol) in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) (1M, 11 mL, 10.6 mmol) in anhydrous THF (20 mL) as per the procedure described in step 3 of Intermediate A7 to yield 2.1 g of the compound.
  • LiHMDS lithium bis(trimethylsilyl)amide
  • step 2 of Intermediate A7 To a solution of 8-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (step 2 of Intermediate A7) (802 mg, 3.73 mmol) in trifluoroacetic acid (5.0 mL) was added potassium nitrate (415 mg, 4.10 mmol) at 0 °C. The mixture was gradually warmed to RT and stirred overnight at RT. The mixture was quenched with ice-water and neutralized with aqueous sodium hydroxide solution at 0 °C. The precipitated solid was filtered, washed with water and dried. The crude solid was triturated with diethyl ether and dried well to yield 732 mg of the desired
  • Step 2 tert-Butyl 8-bromo-7-nitro-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxylate
  • the titled compound was prepared by the reaction of 8-bromo-7-nitro-3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazine (step 1 intermediate) (875 mg, 3.36 mmol) with di-tert-butyl dicarbonate (1.15 mL, 5.04 mmol) in the presence of triethylamine (0.94 mL, 6.72 mmol) and DMAP (41 mg, 0.34 mmol) in dichloromethane (20 mL) as per the procedure described in step 3 of Intermediate A4 to yield 1.02 g of the compound.
  • step 1 intermediate A solution of methyl 3-(benzyloxy)-4-(trifluoromethyl)benzoate (step 1 intermediate) (500 mg, 2.27 mmol) in methanol (5.0 mL) with catalytic amount of 10% palladium on carbon (50% wet) was hydrogenated at RT for 16 h. The mixture was filtered through celite and the celite bed was rinsed with methanol. The combined filtrate and washings were concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 400 mg of the desired product.
  • step 1 intermediate 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (step 1 intermediate) (4.0 g, 14.1 mmol) in dichloromethane (40 mL) were added N-ethylpiperazine (1.88 mL, 14.7 mmol) followed by N,N-diisopropylethylamine (DIPEA) (3.27 mL, 19.1 mmol) at RT. The mixture 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.
  • DIPEA N,N-diisopropylethylamine
  • step 2 intermediate A solution of 1-ethyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine (step 2 intermediate) (800 mg, 2.52 mmol) in methanol (20 mL) with catalytic amount of 10% palladium on carbon (50% wet) was hydrogenated at RT for 16 h. The mixture was filtered through celite and the celite bed was rinsed with methanol. The combined filtrate and washings were concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 600 mg of the desired product.
  • the titled compound was prepared by the catalytic hydrogenation reaction of N,N-dimethyl- 2-(4-nitro-2-(trifluoromethyl)phenoxy)ethanamine (2.2 g, 7.91 mmol) in methanol (15 mL) as per the procedure described in step 3 of Intermediate C1 to yield 1.8 g of the compound.
  • Step 1 1-Methyl-4-(4-nitro-2-(trifluoromethyl)phenyl)piperazine A mixture of 2-fluoro-5-nitrobenzotrifluride (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 layer was 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.
  • the titled compound was prepared by the catalytic hydrogenation reaction of 1-methyl-4-(4- nitro-2-(trifluoromethyl)phenyl)piperazine (step 1 intermediate) (5.0 g, 17.3 mmol) in methanol (200 mL) as per the procedure described in step 3 of Intermediate C1 to yield 4.12 g of the compound.
  • Step 1 tert-Butyl 4-(4-nitro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate
  • Step 2 tert-Butyl 4-(4-amino-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate
  • the titled compound was prepared by the catalytic hydrogenation reaction of tert-butyl 4-(4- nitro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (step 1 intermediate) (3.0 g, 8.00 mmol) in methanol (200 mL) as per the procedure described in step 3 of Intermediate C1 to yield 2.3 g of the compound.
  • Step 1 1-Ethyl-4-(4-nitrobenzyl)pip r zin
  • the titled compound was prepared by the reaction of 1-(bromomethyl)-4-nitrobenzene (1.8 g, 8.32 mmol) with N-ethylpiperazine (1.16 mL, 9.16 mmol) in the presence of N,N- diisopropylethylamine (DIPEA) (2.15 mL, 12.5 mmol) in dichloromethane (10 mL) as per the procedure described in step 2 of Intermediate C1 to yield 1.23 g of the compound.
  • DIPEA N,N- diisopropylethylamine
  • step 1 intermediate 1-ethyl-4-(4-nitrobenzyl)piperazine (step 1 intermediate) (200 mg, 0.88 mmol) in a mixture of methanol and water (1:1, 20 mL) were added ammonium chloride (215 mg, 4.08 mmol) followed by iron powder (224 mg. 4.028 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 layer was separated and washed with water followed by brine and dried over anhydrous sodium sulfate.
  • step 1 intermediate tert-butyl (4-methyl-3-(trifluoromethyl)phenyl)carbamate (step 1 intermediate) (3.8 g, 13.8 mmol) in carbon tetrachloride (30 mL) were added N- bromosuccinimide (4.13 g, 27.6 mmol) and AIBN (226 mg, 1.38 mmol) at RT 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.
  • Step 3 tert-Butyl (4-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-3- (trifluoromethyl)phenyl)carbamate
  • step 2 intermediate To a solution of tert-butyl (4-(bromomethyl)-3-(trifluoromethyl)phenyl)carbamate (step 2 intermediate) (200 mg, 0.56 mmol) in THF (10 mL) were added N,N,N’- trimethylethylenediamine (176 ⁇ L, 1.35 mmol) and triethylamine (236 ⁇ L, 1.69 mmol) at RT and the reaction mixture was stirred at RT for 2 h. 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.
  • N,N,N’- trimethylethylenediamine 176 ⁇ L, 1.35 mmol
  • triethylamine 236 ⁇ L, 1.69 mmol
  • step 3 intermediate To a solution of tert-butyl (4-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-3- (trifluoromethyl)phenyl)carbamate (step 3 intermediate) (300 mg, 0.80 mmol) in dichloromethane (5.0 mL) 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.
  • Step 1 Di-tert-butyl (3-bromo-5-(trifluoromethyl)phenyl)imidodicarbonate
  • the titled compound was prepared by the reaction of 3-bromo-5-trifluoromethylaniline (5.0 g, 20.8 mmol) with di-tert-butyl dicarbonate (11.3 g, 52.1 mmol) in the presence of DMAP (254 mg, 2.08 mmol) in dichloromethane (20 mL) as per the procedure described in step 3 of Intermediate A1 to yield 3.8 g of the product.
  • Step 2 Di-tert-butyl (3-((2-(dimethylamino)ethyl](methyl)amino)-5- (trifluoromethyl)phenyl)imidodicarbonate
  • step 1 intermediate di-tert-butyl (3-bromo-5-(trifluoromethyl)phenyl)imidodicarbonate (step 1 intermediate) (2.2 g, 4.89 mmol) in 1,4-dioxane (20 mL) were added N,N,N’- trimethylethylenediamine (636 ⁇ L, 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, 1.47mmol) at RT and the reaction mixture was stirred at 45 °C for 4 h.
  • N,N,N’- trimethylethylenediamine 636 ⁇ L, 4.89 mmol
  • sodium tert-butoxide (1.40
  • Step 3 N 1 -(2-(Dimethylamino)ethyl)-N 1 -methyl-5-(trifluoromethyl)benzene-1,3-diamine
  • the titled compound was prepared by the reaction of di-tert-butyl (3-((2- (dimethylamino)ethyl](methyl)amino)-5-(trifluoromethyl)phenyl)imidodicarbonate (step 2 intermediate) (100 mg, 0.22 mmol) with trifluoroacetic acid (0.5 mL) in dichloromethane (3.0 mL) as per the procedure described in step 4 of Intermediate C33 to yield 50 mg of the compound.
  • Step 1 1-(3-Nitrophenyl)cyclopropanec r ni ril
  • step 1 intermediate 1-(3-nitrophenyl)cyclopropanecarbonitrile (step 1 intermediate) (630 mg, 3.35 mmol) in a mixture of ethyl acetate and water (1:1, 20 mL) were added ammonium chloride (1.79 g, 33.4 mmol) followed by 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 layer was separated and washed with water followed by brine and dried over anhydrous sodium sulfate.
  • Step 1 (S)-3-Fluoro-1-(3-nitro-5-(trifluoromethyl)phenyl)pyrrolidine
  • the titled compound was prepared by the reaction of 1-bromo-3-nitro-5- (trifluoromethyl)benzene (1.2 g, 4.44 mmol) with (S)-3-fluoropyrrolidine (593 mg, 6.66 mmol) in the presence of cesium carbonate (4.34 g, 13.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (81 mg, 0.09 mmol) and ( ⁇ )-2,2′- bis(diphenylphosphino)-1,1′-binaphthalene (rac-BINAP) (83 mg, 0.13 mmol) in 1,4-dioxane (20 mL) as per the procedure described in step 2 of Intermediate C34 to yield 109 mg of the desired compound.
  • 1 H NMR 400 MHz, DMSO-d6) ⁇ 2.16-2.22 (m, 1H), 2.27-2.33 (m, 1H),
  • the titled compound was prepared by the catalytic hydrogenation of (S)-3-fluoro-1-(3-nitro- 5-(trifluoromethyl)phenyl)pyrrolidine (step 1 intermediate) (100 mg, 0.36 mmol) in the presence of palladium on carbon (10% w/w, 50% wet) as per the procedure described in step 3 of Intermediate C1 to yield 55 mg of the compound.
  • 1 H NMR 400 MHz, DMSO-d6) ⁇ 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, 2H), 6.18 (s, 1H).
  • Step 1 tert-Butyl 4-(3-nitro-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)- carboxylate
  • Step 2 tert-Butyl 4-(3-amino-5-(trifluoromethyl)phenyl)piperidine-1-carboxylate
  • the titled compound was prepared by the catalytic hydrogenation of tert-butyl 4-(3-nitro-5- (trifluoromethyl)phenyl)piperidine-1-carboxylate (step 1 intermediate) (880 mg, 2.35 mmol) in the presence of palladium on carbon (10% w/w, 50% wet) (catalytic) as per the procedure described in step 3 of Intermediate C1 to yield 728 mg of the compound.
  • the titled compound was prepared by the reaction of 1-bromo-3-nitro-5- (trifluoromethyl)benzene (2.0 g, 7.40 mmol) with thiomorpholine (1.1 g, 11.1 mmol) in the presence of cesium carbonate (7.2 g, 22.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ) (135 mg, 0.15 mmol) and ( ⁇ )-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (rac-BINAP) (138 mg, 0.22 mmol) in 1,4-dioxane (30 mL) as per the procedure described in step 2 of Intermediate C34 to yield 1.05 g of the desired compound.
  • cesium carbonate 7.2 g, 22.2 mmol
  • Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium(0)
  • step 1 intermediate 4-(3-nitro-5-(trifluoromethyl)phenyl)thiomorpholine (step 1 intermediate) (1.0 g, 3.42 mmol) in dichloromethane (20 mL) was added mCPBA (1.7 g, 10.3 mmol) at RT and the mixture was stirred at RT for 2 h. 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 yield 523 mg of the desired product. 1 H NMR (400 MHz,
  • Step 3 4-(3-Amino-5-(trifluoromethyl)phenyl)thiomorpholine 1,1-dioxide
  • the titled compound was prepared by the catalytic hydrogenation of 4-(3-nitro-5- (trifluoromethyl)phenyl)thiomorpholine 1,1-dioxide (step 2 intermediate) (510 mg, 1.57 mmol) in the presence of palladium on carbon (10% w/w, 50% wet) (catalytic) as per the procedure described in step 3 of Intermediate C1 to yield 346 mg of the compound.
  • the titled compound was prepared by the catalytic hydrogenation of N-(2- (dimethylamino)ethyl)-4-nitro-2-(trifluoromethyl)benzamide (step 1 intermediate) (300 mg, 0.98 mmol) in the presence of palladium on carbon (10% w/w, 50% wet) in methanol (10 mL) as per the procedure described in step 3 of Intermediate C1 to yield 151 mg of the compound.
  • the titled compound was prepared by the catalytic hydrogenation of (4-ethylpiperazin-1- yl)(4-nitro-2-(trifluoromethyl)phenyl)methanone (step 1 intermediate) (2.0 g, 6.04 mmol) in the presence of 10% palladium on carbon (50% wet) in methanol (50 mL) as per the procedure described in step 3 of Intermediate C1 to yield 1.9 g of the compound.
  • the titled compound was prepared by the reaction of ethyl 2,2-difluoro-2-(3- nitrophenyl)acetate (step 1 intermediate) (600 mg, 2.44 mmol) with iron powder (567 mg, 10.2 mmol) and ammonium chloride (1.30 g, 24.4 mmol) in a mixture of ethyl acetate and water (7:2, 9.0 mL) as per the procedure described in step 2 of Intermediate C28 to yield 350 mg of the compound.
  • the titled compound was prepared by the reaction of 1-bromo-3-nitro-5- (trifluoromethyl)benzene (250 mg, 0.93 mmol) with 4,4-difluoropiperidine (354 mg, 2.77
  • the titled compound was prepared by the catalytic hydrogenation of 4,4-difluoro-1-(3-nitro- 5-(trifluoromethyl)phenyl)piperidine (step 1 intermediate) (220 mg, 0.71 mmol) in the presence of palladium on carbon (10% w/w, 50% wet) in methanol (5.0 mL) as per the procedure described in step 3 of Intermediate C1 to yield 70 mg of the compound.
  • 1 H NMR 400 MHz, DMSO-d6) ⁇ 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) + .
  • step 1 intermediate A solution of diethyl 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)malonate (step 1 intermediate) (5.0 g, 14.3 mmol) in 50% sulfuric acid (50 mL) was heated at 85-90 °C for 2-3 h. 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, concentrated to yield 3.2 g of the desired product.
  • the titled compound was prepared by the reaction of 2-methyl-5-nitro-3- (trifluoromethyl)pyridine (250 mg, 1.21 mmol) with iron powder (679 mg, 12.1 mmol) and ammonium chloride (519 mg, 9.70 mmol) in a mixture of ethanol and water (6:1, 3.5 mL) as per the procedure described in step 2 of Intermediate C28 to yield 170 mg of the compound.
  • Step 1 tert-Butyl 4-(3-nitro-5-(trifluoromethyl)phenyl)-1,4-diazepane-1-carboxylate
  • the titled compound was prepared by the reaction of 1-bromo-3-nitro-5- (trifluoromethyl)benzene (100 mg, 0.37 mmol) with tert-butyl 1,4-diazepane-1-carboxylate
  • Step 2 tert-Butyl 4-(3-amino-5-(trifluoromethyl)phenyl)-1,4-diazepane-1-carboxylate
  • step 1 intermediate tert-butyl 4-(3-nitro-5- (trifluoromethyl)phenyl)-1,4-diazepane-1-carboxylate
  • iron powder 114 mg, 2.05 mmol
  • ammonium chloride 88 mg, 1.64 mmol
  • step 1- A solution of tert-butyl 4-(3-nitro-5-(trifluoromethyl)phenyl)-1,4-diazepane-1-carboxylate (step 1-Intermediate C52) (600 mg, 1.54 mmol) in hydrochloric acid in 1,4-dioxane (5.0 mL) 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 using saturated sodium bicarbonate solution till pH 8-9 at -20 °C. 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 was as such carried forward to the next step.
  • step 1 intermediate 1-(3-nitro-5-(trifluoromethyl)phenyl)-1,4-diazepane (step 1 intermediate) (250 mg, 0.87 mmol) in acetonitrile (35 mL) were added methyl iodide (126 mg, 0.89 mmol) and potassium carbonate (125 mg, 0.91 mmol) at 0 °C and the mixture was stirred overnight at RT. 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.
  • the titled compound was prepared by the reaction of 1-methyl-4-(3-nitro-5- (trifluoromethyl)phenyl)-1,4-diazepane (step 2 intermediate ) (180 mg, 0.59 mmol) with iron powder (331 mg, 5.92 mmol) and ammonium chloride (253 mg, 4.73 mmol) in ethanol (3.0 mL) as per the procedure described in step 2 of Intermediate C28 to 140 mg of the compound.
  • the crude amine was as such carried forward to the next step due to poor solubility and instability in solution form.
  • Step 1 1-(3-Nitro-5-(trifluoromethyl)phenyl)-4-(oxetan-3-yl)piperazine
  • the titled compound was prepared by the reaction of 1-(3-nitro-5-(trifluoromethyl)phenyl)-4- (oxetan-3-yl)piperazine (step 1 intermediate ) (100 mg, 0.30 mmol) with iron powder (179 mg, 3.19 mmol) and ammonium chloride (138 mg, 2.55 mmol) in ethanol (4.0 mL) as per the procedure described in step 2 of Intermediate C28 to 70 mg of the compound.
  • Step 2 tert-Butyl isopropyl(3-nitro-5-(trifluoromethyl)benzyl)carbamate
  • the titled compound was prepared by the reaction of N-(3-nitro-5- (trifluoromethyl)benzyl)propan-2-amine (step 1 intermediate) (170 mg, 0.65 mmol) with di- tert-butyl dicarbonate (156 mg, 0.71 mmol) in the presence of DIPEA (168 mg, 1.30 mmol) in dichloromethane (5.0 mL) as per the procedure described in step 3 of Intermediate A1 to yield 240 mg of the product.
  • Step 3 tert-Butyl 3-amino-5-(trifluoromethyl)benzyl(isopropyl)carbamate
  • the titled compound was prepared by the reaction of tert-butyl isopropyl(3-nitro-5- (trifluoromethyl)benzyl)carbamate (step 2 intermediate ) (235 mg, 0.65 mmol) with iron powder (363 mg, 6.50 mmol) and ammonium chloride (278 mg, 5.20 mmol) in ethanol (5.0 mL) and water (1.5 mL) as per the procedure described in step 2 of Intermediate C28 to 170 mg of the compound.
  • Step 1 4-(3-Nitro-5-(trifluoromethyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole
  • the titled compound was prepared by the reaction of 1-bromo-3-nitro-5- (trifluoromethyl)benzene (1.0 g, 3.70 mmol) with 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.12 g, 4.07 mmol) in the presence of cesium carbonate (1.80 g, 5.50 mmol), and 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (150 mg, 0.18 mmol) in 1,4-dioxane (10 mL) and water (2.0 mL) as per the procedure described in step 2 of Intermediate C34 to yield 730 mg of the desired compound 1 H NMR (400 MHz, DMSO-d6) ⁇ 1.53-1.68 (m, 2H), 1.69- 1.74 (m, 1
  • the titled compound was prepared by the reaction of 4-(3-nitro-5-(trifluoromethyl)phenyl)-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazole (step 1 intermediate) (350 mg, 1.03 mmol) with hydrochloric acid in ethyl acetate (10 mL) in methanol (5.0 mL) as per the procedure described in step 1 of Intermediate C57 to yield 257 mg of the compound.
  • Step 3 1-Methyl-4-(3-nitro-5-(trifluorometh l hen l)-1H-pyrazole
  • the titled compound was prepared by the reaction of 4-(3-nitro-5-(trifluoromethyl)phenyl)- 1H-pyrazole (step 2 intermediate) (100 mg, 0.39 mmol) with methyl iodide (82 mg, 0.58 mmol) in the presence of sodium hydride (60% w/w, 17 mg, 0.42 mmol) in DMF (5.0 mL) as per the procedure described in step 2 of Intermediate C57 to yield 60 mg of the compound.
  • 1H NMR 400 MHz, DMSO-d6) ⁇ 3.89 (s, 3H), 8.24 (s, 2H), 8.41 (s, 1H), 8.59 (s, 1H), 8.66 (s, 1H).
  • the titled compound was prepared by the catalytic hydrogenation of 1-methyl-4-(3-nitro-5- (trifluoromethyl)phenyl)-1H-pyrazole (step 3 intermediate) (55 mg, 0.20 mmol) in the presence of palladium on carbon (10% w/w, 50% wet, 20 mg) in methanol (5.0 mL) and THF (2.0 mL) as per the procedure described in step 3 of Intermediate C1 to yield 35 mg of the compound.
  • 1 H NMR 400 MHz, DMSO-d6) ⁇ 3.85 (s, 3H), 5.56 (s, 2H), 6.68 (s, 1H), 6.95 (s, 2H), 7.79 (s, 1H), 8.12 (s, 1H).
  • Step 1 tert-Butyl 3-(3-nitro-5-(trifluorometh l henox )azetidine-1-carboxylate
  • the titled compound was prepared by the reaction of 3-nitro-5-(trifluoromethyl)phenol (1.0 g, 4.83 mmol) with N-Boc-3-hydroxyazetidine (1.0 g, 5.80 mmol) 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) as per the procedure described in step 2 of Intermediate A2 to yield 1.52 g of the compound.
  • triphenylphosphine 1.9 g, 7.20 mmol
  • DIAD diisopropyl azodicarboxylate
  • the titled compound was prepared by the reaction of tert-butyl 3-(3-nitro-5- (trifluoromethyl)phenoxy)azetidine-1-carboxylate (step 1 intermediate) (1.50 g, 5.73 mmol) with hydrochloric acid in ethyl acetate (20 mL) in ethyl acetate (4.0 mL) as per the procedure described in step 1 of Intermediate C57 to yield 918 mg of the compound (isolated a hydrochloride salt).
  • step 2 intermediate 3-(3-nitro-5-(trifluoromethyl)phenoxy)azetidine hydrochloride (step 2 intermediate) (900 mg, 3.01 mmol) in dichloroethane (10 mL) were added formaldehyde (37%, 135 mg, 4.52 mmol) and sodium triacetoxyborohydride (STAB) (958 mg, 4.52 mmol) 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
  • the titled compound was prepared by the reaction of 1-methyl-3-(3-nitro-5- (trifluoromethyl)phenoxy)azetidine (step 3 intermediate ) (780 mg, 2.82 mmol) with iron powder (780 mg, 14.1 mmol) and ammonium chloride (1.5 g, 28.2 mmol) in methanol (10 mL) and water (10 mL) as per the procedure described in step 2 of Intermediate C28 to 623 mg of the compound.
  • Step 1 (1S,4S)-tert-Butyl 5-(3-nitro-5-(trifluoromethyl)phenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • the titled compound was prepared by the reaction of 1-bromo-3-nitro-5- (trifluoromethyl)benzene (2.7 g, 13.6 mmol) with (1S,4S)-tert-butyl 2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (500 mg, 2.52 mmol) in the presence of sodium tert-butoxide (350 mg, 3.64 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (138 mg, 0.15 mmol) and Xantphos (175 mg, 0.30 mmol) in toluene (10 mL) as per the procedure described in step 2 of Intermediate C34 to yield 840 mg of the desired compound.
  • the titled compound was prepared by the reaction of (1S,4S)-tert-butyl 5-(3-nitro-5- (trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (step 1 intermediate) (400 mg, 1.13 mmol) with hydrochloric acid in 1,4-dioxane (4.0 mL) in ethanol (8.0 mL) as per the procedure described in step 1 of Intermediate C57 to yield 280 mg of the compound.
  • the crude amine was as such carried forward to the next step.
  • the titled compound was prepared by the reaction of (1S,4S)-2-(3-nitro-5- (trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane hydrochloride (step 2 intermediate) (275 mg, 0.94 mmol) with methyl iodide (147 mg, 1.03 mmol) in the presence of potassium carbonate (142 mg, 1.03 mmol) in acetonitrile (12 mL) as per the procedure described in step 2 of Intermediate C57 to yield 60 mg of the compound.
  • the crude amine was as such carried forward to the next step.
  • Step 4 3-((1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-(trifluoromethyl)aniline
  • the titled compound was prepared by the catalytic hydrogenation of (1S,4S)-2-methyl-5-(3- nitro-5-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane (step 3 intermediate) (60 mg, 0.19 mmol) in the presence of palladium on carbon (10% w/w, 50% wet, 20 mg) in methanol (10 mL) as per the procedure described in step 3 of Intermediate C1 to yield 60 mg (crude) of the compound.
  • the crude amine was as such carried forward to the next step due to poor solubility and instability in solution form.
  • the titled compound was prepared by the reaction of 1-bromo-3-nitro-5- (trifluoromethyl)benzene (2.0 g, 7.40 mmol) with morpholine (1.61 g, 18.5 mmol) in the presence of N,N-diisopropylethylamine (DIPEA) (2.7 mL, 14.8 mmol) in DMSO (10 mL) as per the procedure described in step 2 of Intermediate C1 to yield 1.1 g of the compound.
  • DIPEA N,N-diisopropylethylamine
  • step 1 intermediate A suspension of 4-(3-nitro-5-(trifluoromethyl)phenyl)morpholine (step 1 intermediate) (1.1 g, 3.98 mmol), benzyltributylammonium chloride (7.5 g, 23.9 mmol) and KMnO4 (3.77 g, 23.9 mmol) in dichloromethane (70 mL) was heated overnight at 70 °C. 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 combined filtrate and washings were concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography
  • the titled compound was prepared by the reaction of 4-(3-nitro-5- (trifluoromethyl)phenyl)morpholin-3-one (step 2 intermediate ) (300 mg, 1.14 mmol) with iron powder (636 mg, 11.3 mmol) and ammonium chloride (487 mg, 9.10 mmol) in ethanol (10 mL) and water (4.0 mL) as per the procedure described in step 2 of Intermediate C28 to 150 mg of the compound.
  • the titled compound was prepared by the reaction of 3'-nitro-5'-(trifluoromethyl)-[1,1'- biphenyl]-4-carbonitrile (step 2 intermediate ) (150 mg, 0.51 mmol) with iron powder (286 mg, 5.13 mmol) and ammonium chloride (219 mg, 4.10 mmol) in ethanol (5.0 mL) and water (2.0 mL) as per the procedure described in step 2 of Intermediate C28 to 50 mg of the compound.
  • step 1 intermediate 1-(4-nitro-2-(trifluoromethyl)phenyl)ethanone (step 1 intermediate) (120 mg, 0.52 mmol) in methanol (5.0 mL) was added sodium borohydride (20 mg, 0.52 mmol) at 0 °C 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.
  • step 2 intermediate 1-(4-nitro-2-(trifluoromethyl)phenyl)ethanol (step 2 intermediate) (600 mg, 2.56 mmol) in dichloromethane (5.0 mL) were added triethylamine (1.0 mL, 7.68 mmol) followed by methanesulfonyl chloride (Mesyl chloride) (587 mg, 5.12 mmol) 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 under reduced pressure at 25 °C.
  • triethylamine 1.0 mL, 7.68 mmol
  • Mesyl chloride methanesulfonyl chloride
  • Step 4 4-(1-(4-Ethylpiperazin-1-yl)ethyl)-3-(trifluoromethyl)aniline
  • the titled compound was prepared by the reaction of 1-ethyl-4-(1-(4-nitro-2- (trifluoromethyl)phenyl)ethyl)piperazine (step 3 intermediate ) (220 mg, 0.66 mmol) with iron powder (371 mg, 6.64 mmol) and ammonium chloride (283 mg, 5.31 mmol) in ethanol (5.0 mL) and water (1.0 mL) as per the procedure described in step 2 of Intermediate C28 to 80 mg of the compound.
  • the titled compound was prepared by the reaction of N-(3-bromo-5- (trifluoromethyl)phenyl)propionamide (step 1 intermediate) (1.0 g, 3.37 mmol) with benzophenone imine (918 mg, 5.06 mmol) in the presence of cesium carbonate (2.2 g, 6.76
  • the titled compound was prepared by the reaction of N-(3-((diphenylmethylene)amino)-5- (trifluoromethyl)phenyl)propionamide (step 2 intermediate) (1.0 g, 2.53 mmol) with hydrochloric acid in 1,4-dioxane (5.0 mL) in THF (10 mL) as per the procedure described in step 1 of Intermediate C57 to yield 431 mg of the compound.
  • step 1 intermediate 2-(4-nitro-2-(trifluoromethyl)phenyl)acetonitrile (step 1 intermediate) (500 mg, 2.17 mmol) in THF (15 mL) were added methyl iodide (925 mg, 6.51 mmol) followed by potassium tert-butoxide solution (1M, 6.5 mL, 6.51 mmol) 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 and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the titled compound was prepared by the reaction of 2-methyl-2-(4-nitro-2- (trifluoromethyl)phenyl)propanenitrile (step 2 intermediate) (300 mg, 1.15 mmol) with iron powder (321 mg, 5.76 mmol) and ammonium chloride (308 mg, 5.76 mmol) in methanol (10 mL) and water (10 mL) as per the procedure described in step 2 of Intermediate C28 to 137 mg of the compound.
  • the titled compound was prepared by the reaction of 5-(trifluoromethyl)benzene-1,3-diamine (1.1 g, 6.26 mmol) with N,N-dimethylglycine (644 mg, 6.25 mmol) 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) as per the procedure described in step 1 of Intermediate C82 to yield 230 mg of the compound.
  • Step 1 N,N-Dimethyl-1-(3-nitro-5-(trifluorometh l henyl)azetidin-3-amine
  • the titled compound was prepared by the reaction of 1-bromo-3-nitro-5- (trifluoromethyl)benzene (200 mg, 0.74 mmol) with N,N-dimethylazetidin-3-amine hydrochloride (256 mg, 1.48 mmol) in the presence of sodium tert-butoxide (355 mg, 3.70 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ) (34 mg, 0.04 mmol) and Xantphos (30 mg, 0. 05 mmol) in 1,4-dioxane (4.0 mL) as per the procedure described in
  • step 2 of Intermediate C34 to yield 155 mg of the desired compound.
  • the titled compound was prepared by the reaction of N,N-dimethyl-1-(3-nitro-5- (trifluoromethyl)phenyl)azetidin-3-amine (step 1 intermediate) (150 mg, 0.52 mmol) with iron powder (290 mg, 5.19 mmol) and ammonium chloride (222 mg, 4.15 mmol) in ethanol (4.0 mL) and water (2.0 mL) as per the procedure described in step 2 of Intermediate C28 to 95 mg of the compound.
  • step 1 intermediate 3-(3-nitro-5-(trifluoromethyl)phenyl)propiolamide (step 1 intermediate) (201 mg, 0.78 mmol) in a mixture of methanol and water (3:1, 10 mL) was added ammonium chloride (416 mg, 7.78 mmol) and the mixture was heated to 80 °C.
  • Zinc dust (254 mg, 3.84 mmol) was added to the mixture in small portions and stirred at for 1 h at 80 °C.
  • 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 combined organic layers were washed with water, followed by brine.
  • the titled compound was prepared by the reaction of 3-(3-nitro-5- (trifluoromethyl)phenyl)propiolamide (Intermediate C87-step 1 intermediate) (200 mg, 0.77 mmol) with iron powder (216 mg, 3.87 mmol) and ammonium chloride (42 mg, 0.77 mmol) in a mixture of ethanol, THF and water (2:1:1, 10 mL) as per the procedure described in step 2 of Intermediate C28 to yield 110 mg of the compound.
  • 1 H NMR 400 MHz, DMSO-d6) ⁇ 5.90 (s, 2H), 714-7.21 (m, 3H), 7.71 (s, 1H), 8.17 (s, 1H).
  • the titled compound was prepared by the catalytic hydrogenation of 1-(methylsulfonyl)-3- nitrobenzene (step 1 intermediate) (351 mg, 1.74 mmol) in the presence of 10% palladium on carbon (50% wet, 150 mg) in methanol (5.0 mL) as per the procedure described in step 3 of Intermediate C1 to yield 230 mg of the compound.
  • ESI-MS m/z 172 (M+H) + .
  • Step 1 3-(3-Nitro-5-(trifluoromethyl)phenyl)prop-2-yn-1-ol
  • the titled compound was prepared by the reaction of 1-bromo-3-nitro-5- (trifluoromethyl)benzene (502 mg, 1.86 mmol) with propargyl alcohol (219 ⁇ L, 3.72 mmol) in the presence of bis(triphenylphosphine)palladium(II)dichloride (65 mg, 0.09 mmol), copper iodide (35 mg, 0.18 mmol) and triethylamine (0.8 mL, 5.58 mmol) in DMF (5.0 mL) as per the procedure described in step 1 of Intermediate C87 to yield 205 mg of the compound.
  • the titled compound was prepared by the reaction of 3-(3-Nitro-5- (trifluoromethyl)phenyl)prop-2-yn-1-ol (step 1 intermediate) (738 mg, 3.01 mmol) with methyl iodide (0.37 mL, 6.02 mmol) in the presence of sodium hydride (60%w/w, 240 mg, 6.02 mmol) in THF (10 mL) as per the procedure described in step 2 of Intermediate C57 to yield 390 mg of the compound.
  • 1 H NMR 400 MHz, DMSO-d6) ⁇ 3.38 (s, 3H), 4.41 (s, 2H), 8.36 (s, 1H), 8.49 (s, 1H), 8.53 (s, 1H).
  • the titled compound was prepared by the reaction of 1-(3-methoxyprop-1-yn-1-yl)-3-nitro-5- (trifluoromethyl)benzene (step 2 intermediate) (465 mg, 1.79 mmol) with iron powder (501 mg, 8.97 mmol) and ammonium chloride (95 mg, 1.79 mmol) in a mixture of ethanol, THF and water (3:2:1, 12 mL) as per the procedure described in step 2 of Intermediate C28 to yield 312 mg of the compound.
  • the titled compound was prepared by the catalytic hydrogenation of 1-(difluoromethyl)-3- nitrobenzene (step 1 intermediate) (320 mg, 1.85 mmol) in the presence of 10% palladium on carbon (50% wet, 100 mg) in methanol (5.0 mL) as per the procedure described in step 3 of Intermediate C1 to yield 160 mg of the compound.
  • ESI-MS m/z 144 (M+H) + .
  • the titled compound was prepared by the reaction of ethyl 2,2-difluoro-2-(3- nitrophenyl)acetate (Step 1 of C45) (408 mg, 1.66 mmol) with sodium borohydride (126 mg, 3.32 mmol) in ethanol (10 mL) as per the procedure described in step 2 of Intermediate C81 to yield 271 mg of the compound.
  • the titled compound was prepared by the catalytic hydrogenation of 2,2-difluoro-2-(3- nitrophenyl)ethanol (step 1 intermediate) (260 mg, 1.28 mmol) in the presence of 10% palladium on carbon (50% wet, 100 mg) in methanol (8.0 mL) as per the procedure described in step 3 of Intermediate C1 to yield 75 mg of the compound.
  • step 1 of C87 3-(3-nitro-5-(trifluoromethyl)phenyl)propiolamide (step 1 of C87) (100 mg, 0.38 mmol) in anhydrous dichloromethane (5.0 mL) was added Burgess reagent (110 mg, 0.46 mmol) 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 titled compound.
  • the titled compound was prepared by the reaction of 3-(3-nitro-5- (trifluoromethyl)phenyl)propiolonitrile (step 1 intermediate) (251 mg, 1.04 mmol) with iron powder (292 mg, 5.22 mmol) and ammonium chloride (56 mg, 1.04 mmol) in a mixture of ethanol, THF and water (2:2:1, 25 mL) as per the procedure described in step 2 of Intermediate C28 to yield 121 mg of the compound.
  • 1 H NMR 400 MHz, DMSO-d6) ⁇ 6.04 (s, 2H), 7.06-7.11 (m, 2H), 7.20 (s, 1H).
  • the titled compound was prepared by the reaction 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) as per the procedure described in step 1 of Intermediate C24 to yield 901 mg of the compound.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 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, 1H); ESI-MS (m/z) 348 (M+H) + .
  • the titled compound was prepared by the reaction of 1-(3-iodo-5-nitrophenyl)-4- methylpiperazine (step 1 intermediate) (481 mg, 1.38 mmol) with sodium methanesulfinate (282 mg, 2.77 mmol), in the presence of N,N-dimethylethylenediamine (73 mg, 0.83 mmol) and copper(I)trifluoromethane sulfonate toluene complex (215 mg, 0.42 mmol) as per the procedure described in step 1 of Intermediate C94 to yield 310 mg of the compound.
  • the titled compound was prepared by the catalytic hydrogenation of 1-methyl-4-(3- (methylsulfonyl)-5-nitrophenyl)piperazine (step 2 intermediate) (301 mg, 1.00 mmol) in the presence of 10% palladium on carbon (50% wet, 150 mg) in methanol (10 mL) as per the procedure described in step 3 of Intermediate C1 to yield 110 mg of the compound.
  • Step 1 N-(4-((4-Ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3- hydroxybenzamide
  • Step 2 tert-Butyl 4-(3-((4-((4-ethylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)carbamoyl)phenoxy)-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)- carboxylate
  • step 1 intermediate N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3- hydroxybenzamide (step 1 intermediate) (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) in DMF (5.0 mL) was added cesium carbonate (241 mg, 0.74 mmol) and the mixture was stirred at 130 °C for 2 h.
  • Step 3 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
  • step 2 intermediate tert-butyl 4-(3-((4-((4-ethylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)carbamoyl)phenoxy)-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)- carboxylate (step 2 intermediate) (220 mg, 0.34 mmol) in ethanol (3.0 mL) was added hydrochloric acid in 1,4-dioxane (7.0 mL) at 0 °C 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 followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 105 mg of the desired product.
  • Step 1 tert-Butyl 4-(2-chloro-5-(methoxycarbonyl)phenoxy)-6H-pyrimido[5,4- b][1,4]oxazine-8(7H)-carboxylate
  • 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
  • the titled compound was prepared by the reaction of tert-butyl 4-(2-chloro-5- (methoxycarbonyl)phenoxy)-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (step 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) in the presence of potassium tert-butoxide (1M, 1.42 mL, 1.42 mmol) in anhydrous THF (20 mL) as per the procedure described in step 1 of Method A to yield 20 mg of the product.
  • step 1 intermediate 100 mg, 0.24 mmol
  • 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
  • the titled compound was prepared by the reaction of tert-butyl 4-(2-chloro-5- (methoxycarbonyl)phenoxy)-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (step 1- Method B) (150 mg, 0.34 mmol) and tert-butyl 4-(3-amino-5- (trifluoromethyl)phenyl)piperazine-1-carboxylate (Intermediate C39) (107 mg, 0.31 mmol) in the presence of potassium tert-butoxide (1M, 2.0 mL, 2.06 mmol) in anhydrous THF (10 mL) as per the procedure described in step 1 of Method A to yield 118 mg of the product.
  • the titled compound was prepared by the reaction of 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 (step 1 intermediate) (110 mg, 0.17 mmol) with hydrochloric acid in 1,4-dioxane (4M, 20 mL) in ethanol (4.0 mL) as per the procedure described in step 3 of Method A to yield 54 mg of the product.
  • Step 1 4-Chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3- nitrobenzamide
  • step 1 intermediate 4-chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)-3-nitrobenzamide (step 1 intermediate) (1.4 g, 2.97 mmol) in a mixture of ethyl methanol and water (1:1, 60 mL) were 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.
  • 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
  • step 2 intermediate 3-amino-4-chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)benzamide (step 2 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 toluene (5.0 mL) were added sodium tert-butoxide (36 mg, 0.37 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (12 mg, 0.01 mmol) and ( ⁇ )-2,2′- bis(diphenylphosphino)-1,1′-binaphthalene (rac-BINAP) (13 mg, 0.02 mmol) and the mixture was stirred at 140
  • 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
  • the titled compound was prepared by the reaction of 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 (step 3 intermediate) (60 mg, 0.09 mmol) with hydrochloric acid in 1,4-dioxane (4.0 mL) in ethanol (4.0 mL) as per the procedure described in step 3 of Method A to yield 19 mg of the product.
  • Step 1-Method B 100 mg, 0.24 mmol
  • 2-(3-aminophenyl)acetonitrile 31 mg, 0.24 mmol
  • trimethyl aluminium solution 2M, 237 ⁇ L, 0.47 mmol
  • Step 1 Ethyl 2-(3-(3-((tert-butyldimethylsilyl)oxy)-4-chlorobenzamido)phenyl)-2,2- difluoroacetate
  • step 1 intermediate A mixture of ethyl 2-(3-(3-((tert-butyldimethylsilyl)oxy)-4-chlorobenzamido)phenyl)-2,2- difluoroacetate (step 1 intermediate) (650 mg, 1.34 mmol) and ammonia solution (7M in methanol, 10 mL) was heated at 80 °C for 4 h in a sealed tube. The reaction mixture was cooled and concentrated under reduced pressure to yield 560 mg of the desired product.
  • 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
  • step 2 intermediate N-(3-(2-amino-1,1-difluoro-2-oxoethyl)phenyl)-4-chloro-3- hydroxybenzamide (step 2 intermediate) (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) in DMF (5.0 mL) was added cesium carbonate (360 mg, 1.10 mmol) and the mixture was stirred at 130 °C for 3 h.
  • Step 4 4-Chloro-N-(3-(cyanodifluoromethyl)phenyl)-3-((7,8-dihydro-6H-pyrimido[5,4- b][1,4]oxazin-4-yl)oxy)benzamide
  • step 3 intermediate 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 (step 3 intermediate) (40 mg, 0.08 mmol) in dichloromethane (3.0 mL) was added Burgess reagent (76.8 mg, 0.32 mmol) and the mixture was stirred at RT for 3 h. The reaction mixture was concentrated under reduced
  • Step 1 4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-methoxy-5- (trifluoromethyl)phenyl)benzamide
  • the titled compound was prepared by the reaction of tert-butyl 4-(2-chloro-5- (methoxycarbonyl)phenoxy)-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (step 1-) (100 mg, 0.24 mmol) and 3-methoxy-5-(trifluoromethyl)aniline (45 mg, 0.24 mmol) in the presence of potassium tert-butoxide (1M, 1.42 mL, 1.42 mmol) in anhydrous THF (3.0 mL) as per the procedure described in step 1 of Method A to yield 75 mg of the product.
  • Step 2 4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-hydroxy-5- (trifluoromethyl)phenyl)benzamide
  • step 1 intermediate 4-chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3- methoxy-5-(trifluoromethyl)phenyl)benzamide (step 1 intermediate) (70 mg, 0.14 mmol) in dichloromethane (2.0 mL) was added boron tribromide (1M in dichloromethane, 1.2 mL, 1.16 mmol) at 0 °C and the mixture was stirred at RT for 4 h. The reaction mixture was quenched with methanol at 0 °C and concentrated under reduced pressure.
  • Step 1 4-Chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3- hydroxybenzamide
  • the titled compound was prepared by the reaction of methyl 4-chloro-3-hydroxybenzoate (Intermediate B1) (260 mg, 1.39 mmol) and 4-((4-ethylpiperazin-1-yl)methyl)-3- (trifluoromethyl)aniline (Intermediate C1) (400 mg, 1.39 mmol) in the presence of potassium tert-butoxide (1M, 8.4 mL, 8.39 mmol) in anhydrous THF (8.0 mL) as per the procedure described in step 1 of Method A to yield 200 mg of the product.
  • 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
  • step 1 intermediate 4-chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)-3-hydroxybenzamide (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 A9) (600 mg, 1.97 mmol) in DMF (20 mL) was added cesium carbonate (3.2 g, 9.85 mmol) and the mixture was stirred at 50 °C for 3 h. The mixture was cooled to RT 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
  • 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
  • step 2 A solution of 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 (step 2 intermediate) (40 mg, 0.06 mmol) in a mixture of dichloroethane and trifluoroacetic acid (1:1, 600 ⁇ L) was stirred overnight at 80 °C. The mixture was cooled to RT and then to 0 °C before the addition of aqueous sodium bicarbonate solution till pH 7-8.

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Abstract

L'invention concerne de nouveaux inhibiteurs de MAP4K1 (HPK1) utiles pour le traitement de maladies ou de troubles caractérisés par un dérèglement des voies de transduction de signal associées à l'activation MAPK, y compris des maladies hyperprolifératives, des maladies du dysfonctionnement du système immunitaire, des troubles inflammatoires, des maladies neurologiques et des maladies cardiovasculaires. L'invention concerne en outre des compositions pharmaceutiques comprenant lesdits inhibiteurs et des méthodes de traitement desdites maladies et troubles. Les inhibiteurs de l'invention sont représentés par la formule (I), dans laquelle les définitions pour A, D, E, F, R5, R6, R7, Z, le cycle Q, n, x et y sont tels que définis dans la description.
EP18728587.9A 2017-05-26 2018-05-28 Nouveaux inhibiteurs de map4k1 Withdrawn EP3630778A1 (fr)

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CA2932351A1 (fr) 2013-12-13 2015-06-18 Dana-Farber Cancer Institute, Inc. Procede pour traiter un lymphome lymphoplasmocytaire
AU2019372046B2 (en) 2018-10-31 2022-05-26 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds as HPK1 inhibitors
EP3873608A1 (fr) 2018-10-31 2021-09-08 Gilead Sciences, Inc. Composés 6-azabenzimidazole substitués ayant une activité inhibitrice de hpk1
US20220047603A1 (en) 2018-12-11 2022-02-17 Bayer Aktiengesellschaft Substituted pyrrolopyridine-derivatives
TW202102500A (zh) 2019-03-26 2021-01-16 比利時商健生藥品公司 二環ｈｐｋ１抑制劑
US20220177458A1 (en) 2019-03-26 2022-06-09 Janssen Pharmaceutica Nv Hpk1 inhibitors
US11453681B2 (en) 2019-05-23 2022-09-27 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof
CA3140017A1 (fr) 2019-07-19 2021-01-28 Aurore HICK Derives d'uree polyaromatiques et leur utilisation dans le traitement de maladies musculaires
JP2023524597A (ja) 2020-05-08 2023-06-12 ハリア・セラピューティクス・インコーポレイテッド Ｎｅｋ７キナーゼの阻害剤
WO2021249913A1 (fr) 2020-06-09 2021-12-16 Bayer Aktiengesellschaft Dérivés de 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azétidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate et des composés apparentés servant d'inhibiteurs de map4k1 (hpk1) pour le traitement du cancer
US20240190891A1 (en) 2020-07-15 2024-06-13 Chiesi Farmaceutici S.P.A. Pyrido oxazine amino derivatives as alk5 inhibitors
CN112225748B (zh) * 2020-10-20 2021-11-30 四川大学华西医院 一种具有flt3激酶抑制活性的小分子化合物及其应用
CN114539065B (zh) * 2020-11-25 2023-07-25 帕潘纳(北京)科技有限公司 制备4-硝基-2-三氟甲基苯乙酮的方法
US20240116948A1 (en) 2020-12-23 2024-04-11 Chiesi Farmaceutici S.P.A. Pyrido oxazine derivatives as alk5 inhibitors
EP4029501A1 (fr) 2021-01-19 2022-07-20 Anagenesis Biotechnologies Combinaison de dérivés polyaromatiques de l'urée et d'inhibiteur glucocorticoïde ou hdac pour le traitement de maladies ou d'affections associées aux cellules musculaires et/ou aux cellules satellites
EP4288437A1 (fr) 2021-02-05 2023-12-13 Bayer Aktiengesellschaft Inhibiteurs de map4k1
JP2024513227A (ja) 2021-04-05 2024-03-22 ハリア・セラピューティクス・インコーポレイテッド Ｎｅｋ７阻害剤
WO2022226182A1 (fr) 2021-04-22 2022-10-27 Halia Therapeutics, Inc. Inhibiteurs de nek7
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CN116410203B (zh) * 2021-12-29 2024-06-25 四川大学 具有trk及其耐药突变抑制活性的化合物及其应用
CN114751874A (zh) * 2022-05-30 2022-07-15 江南大学 作为TRPV4-KCa2.3促耦联剂的1-苄基-4-乙基哌嗪衍生物及其应用
EP4289427A1 (fr) * 2022-06-10 2023-12-13 Anagenesis Biotechnologies Dihydro[1,8]naphthyridin-7-one et pyrido[3,2-b][1,4]oxazin-3-one pour une utilisation dans le traitement du cancer, et des métastases en particulier.
US20240158394A1 (en) 2022-09-14 2024-05-16 Halia Therapeutics, Inc. Nek7 inhibitors
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