OA17193A

OA17193A - New thienopyrimidine derivatives, a process for their preparation and pharmaceutical compositions containing them.

Info

Publication number: OA17193A
Application number: OA1201400559
Authority: OA
Inventors: KOTSCHY Andràs; SZLAVIK Zoltàn; CSEKEI Màrton; Paczal Attila; SZABO Zoltàn; Sipos Szabolcs; RADICS Gàbor; Proszenyak Agnes; BALINT Balàzs; Bruno Alain; Geneste Olivier; Edward Paul Davidson James; Brooke Murray James; Chen I-Jen; Perron-Sierra Françoise
Original assignee: Les Laboratoires Servier; Vernalis (R&D) Ltd.
Priority date: 2013-12-23
Filing date: 2014-12-18
Publication date: 2016-04-05

Abstract

Compounds of formula (I):

Description

The présent invention relates to new indolizine compounds, to a process for their préparation and to pharmaceutical compositions containîng them.

The compounds of the présent invention are new and bave very valuable pharmacological characteristics in the field of apoptosis and cancerology.

Apoptosis, or programmed cell death, is a physiological process that is crucial for embryonic development and maintenance of tissue homeostasis.

Apoptotic-type cell death involves morphological changes such as condensation of the nucléus, DNA fragmentation and also biochemical phenomena such as the activation of caspases which cause damage to key structural components of the cell, so inducing its 10 disassembly and death. Régulation of the process of apoptosis is complex and involves the activation or repression of several intracellular signalling pathways (Cory S. et al., Nature Review Cancer, 2002,2,647-656).

Deregulation of apoptosis is involved in certain pathologies. Increased apoptosis is associated with neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s 15 disease and ischaemia. Conversely, déficits in the implémentation of apoptosis play a significant rôle in the development of cancers and their chemoresistance, in auto-immune diseases, inflammatory diseases and viral infections. Accordingly, absence of apoptosis is one of the phenotypic signatures of cancer (Hanahan D. et al., Cell 2000,100, 57-70).

The anti-apoptotic proteins of the Bcl-2 family are associated with numerous pathologies.

The involvement of proteins of the Bcl-2 family is described in numerous types of cancer, such as colon cancer, breast cancer, small-cell lung cancer, non-small-cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphoid leukaemia, lymphoma, myeloma, acute myeloid leukemia, pancreatic cancer, prostate cancer, etc. Overexpression of the anti-apoptotic proteins of the Bcl-2 family is involved in tumorigenesis, in résistance to chemotherapy and in the clînical prognosis of patients affected by cancer. Notably, Mcl1, an anti-apoptotic Bcl-2 family member, is overexpressed in various types of cancer (Beroukhim R. et al., Nature 2010, 899-905). There is, therefore, a therapeutic need for compounds that inhibit the anti-apoptotic activity of the proteins of the Bcl-2 family.

-2In addition to being new, the compounds of the présent invention hâve pro-apoptotic properties making it possible to use them in pathologies involving a defect in apoptosis, such as, for exampie, in the treatment of cancer and of immune and auto-immune diseases.

The présent invention relates more especially to compounds of formula (I):

wherein:

♦ A represents a lincar or branched (C|-Cg)alkyl group or an halogen atom, ♦ Ri, R-2, R3, R4 and R5 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-Cé)alkyl group, a linear or branched (C₂Cô)alkenyl group, a linear or branched (C2-Cô)alkynyl group, a linear or branched (Ci-C₆)polyhaloalkyl, a hydroxy group, a linear or branched (Ci-Ci)alkoxy group, -S-(C]-C₆)alkyl group, a cyano, a nitro group, -alkylfCo-CéJ-NRgRg’, -O-Cyi, -alkyl(Co-C₆)-Cyi, -alkenyl(C₂-C₆)-Cyi, -alkynyl(C₂-C₆)-Cy_b -O-alkyl(C_l-C₆)-R₅, -COORg, -OC(O)R₈, -C(O)NRgRg’, -NR₈C(O)-R₈’, -NRgC(O)-ORg’, -alkyl(Ci-C₆)-NRgC(O)-R₈’, -SO₂-NR₈R₈’, -SO_ralkyl(Ci-C₆), or the substituents of one of the pairs (Ri,R₂), (R₂, R3), (Ri, R3), (R4, R5) when grafted onto two adjacent carbon atoms, form together with the carbon atoms carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain from one to 3 hetero atoms selected from oxygen, sulphur and nitrogen, it being understood that resulting ring may be substituted by a group selected from a lincar or branched (CrCc)alkyl group, -NRioRio’, -alkyl(Coe

-3ΙΟ

Cfi)-Cyi or an oxo,

X represents a carbon or a nitrogen atom,

Rô represents a hydrogen, a linear or branched (Ci-C6)alkyl group, an aryl, an heteroaryl group, an arylalkylfCi-Cg) group, an heteroarylalkyXCi-Ce) group,

R7 represents a linear or branched (Cf-Côjalkyl group, a linear or branched (C₂Cô)alkenyl group, a linear or branched (C₂-C6)alkynyl group, -Cy3, -alkyl(C[-C6)Cy3, -alkenyl(C₂-Cô)-Cy3, -alkynyl(C₂-C₆)-Cy₃, -Cy₃~Cy4, -Cy₃-alkyl(C₀-C₆)-Oalkyl(Co-Cf,)-Cy4, an halogen atom, a cyano, -C(O)-Rn, -C(O)NRnRn’,

R_g and R₈’ independently of one another represent a hydrogen atom, a linear or branched (CrCû)alkyl group, or -alkyl(Co-C6)-Cyi, or (R«, R#’) form together with the nitrogen atom carrying them an aromatic or nonaromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from one to 3 hetero atoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (CiCô)alkyl group,

R§ represents -Cyi, -Cyi-alkyl(Co-C<j)-Cy₂, -Cyralkyl(C₀-C6)-O-alkyl(Cû-C6)-Cy₂, -Cyi-alkyl(C_o-C₆)-NR₈-alkyl(Co-C6)-Cy₂, -CfOJ-NRgRg’, -NR₈Rg’,

-NR&C(O)Rs’, -OR₈, O-alkyl(C|-C₆)-OR₈, -SO₂-Rs, -C(O)-OR_g, -NH-C(O)-NH-R_g, Rio, Rio’, Ri 1 and Ru’ independently of one another represent a hydrogen atom or an optionally substituted linear or branched (Ci-Cejalkyl group,

Ri₂ represents a hydrogen or a hydroxy group,

Cyi, Cy_2i Cyî and Cy^ independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl or an heteroaryl group, it being understood that:

- aryl means a phenyl, naphthyl, biphenyl or indenyl group,

- heteroaiyl means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 3 hetero atoms selected from oxygen, sulphur and nitrogen, cycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, e

-4- “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, and containing from 1 to 3 hetero atoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring Systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy, to be substituted by from 1 to 4 groups selected from optionally substituted linear or branched (Ci-Côjalkyl, optionally substituted linear or branched (C2-C6)alkenyl group, optionally substituted linear or branched (C2-C₆)alkynyl group, optionally substituted linear or branched (Ci-Cô)alkoxy, optionally substituted (CiCô)alkyl-S-, hydroxy, oxo (or //-oxide where appropriate), nitro, cyano, -COOR', -OCOR’, -CONR’R”, -NR'R, -(C=NR')-OR”, linear or branched (Ci-C₆)polyhaloalkyl, trifluoromethoxy, or halogen, it being understood that R' and R independently of one anolher represent a hydrogen atom or an optionally substituted linear or branched (CiC₆)alkyl group, their enantiomers, diastereoisomers and atropoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartane acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid etc.

Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, toŸ-butylamine etc.

Advantageously, at least one of the groups selected from R;, R2, and R3 does not represent a hydrogen atom.

In the preferred compounds of the invention, A represents a linear or branched (Ci17193

-5Cô)alkyl group.

Preferably, X represents a carbon atom.

In some preferred embodiments,

In other embodiments,

Preferably, R<> represents a hydrogen or a linear or branched (Ci-Cg)alkyl group.

In the preferred compounds of the invention, R; represents a linear or branched (CiCô)alkyl group, a linear or branched (C2-Cé)alkenyl group, a linear or branched (C210 Cfi)alkynyl group, an aryl or an heteroaryl group.

The invention relates also to a process for the préparation of compounds of formula (I), which process is characterised in that there is used as starting material the compound of formula (Il-a):

-6wherein R7 is as defîned for formula (I), which compound of formula (ΙΙ-a) is subjected to coupling with a compound of formula (III):

(III) wherein R4, R5 and R12 are as defîned for formula (I), and

Alk represents a linear or branched (Ci-Cô)alkyl group, to yield the compound of formula (IV):

wherein R4, R_s, R7 and are as defîned for formula (I) and Alk is as defîned before, compound of formula (IV) which is further subjected to coupling with compound of formula (V):

wherein R|, 1<2, Rj, X and A are as defined for formula (I), and

Rbi and Rbj represent a hydrogen, a linear or branched (C’i-Cô) alkyl group, or Rbi and Rb2 form with the oxygen carrying them an optionally methylated ring, to yield the compound of formula (VI):

wherein R], R₂, R3, R4, Rs, R7, R12, X and A are as defined for formula (I) and Alk is as defined before, the Alk-O-C(O)- ester function of which compound of formula (VI) is hydrolysed to yield *

-8the carboxylic acid, which may optionally be optionally be reacted with an alcohol of formula R₆OH wherein R₆ is as defined in formula (I), to yield the compound of formula (I), which may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino...) of the starting reagents or of the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.

In an other embodiment of the invention, compounds of formula (I) may be obtained using an alternative process, which process is characterised in that there is used as starting material the compound of formula (Il-b):

(Ihb) which compound of formula (ΙΙ-b) is converted into compound of formula (II-c) :

(ll-c) which compound of formula (Π-c) is subjected to coupling with a compound of formula (V):

e

(V) wherein Ri, R₂, R3, X and A are as defined for formula (I), and

Rbi and R_B2 represent a hydrogen, a linear or branched (Cj-Cs) alkyl group, or Rbj and Rr? form with the oxygen carrying them an optionally methylated ring, to yield the compound of formula (VI):

(VI) wherein Rj, R₂, R3, A and X are as defined in formula (I), which compound of formula (VI) is further subjected to the action of I₂ in the présence of lithium diisopropylamide (strong base) to yield compound of formula (VII):

-ίο-

(VII)

17193 >

wherein Rj, R2, R3, A and X are as defined in formula (I), which compound of formula (VII) is further subjected to coupling with a compound of formula (VIII):

(VIII) wherein R7 is as defined for formula (I), and

Rb3 and Rb₄ represent a hydrogen, a linear or branched (Ci -Q) alkyl group, or R_B3 and R_B4form with the oxygen carrying them an optionally methylated ring, to yield compound of formula (IX):

(IX)

-11wherein Ri, R₂, R₃, A, X and R7 are as defined in formula (I), which compound of formula (IX) is further subjected to coupling with a compound of formula (III):

(III) wherein R^, R_s, and Rp are as defined for formula (I), and

Alk represents a linear or branched (Ci-Cg)alkyl group, to yield the compound of formula (VI):

(VI) wherein R_(> R₂, R₃, R4, R5, R7, R12, X and A are as defined for formula (I) and Alk is as defined before, the ester function of which compound of formula (VI) is hydrolysed to yield the carboxylic

- 12acid, which may optionally be optionally be reacted with an alcohol of formula RgOH wherein Ré is as defined in formula (I), to yield the compound of formula (I), which may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino...) of the starting reagents or of the synthesis inteimediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.

The compounds of formulae (Il-a), (ΙΙ-b), (III), (V), (VIII) and the amine NHR3R4 are either commercially available or can be obtained by the person skilled in the art using conventional chemical reactions described in the literature.

Pharmacological study of the compounds of the invention has shown that they hâve proapoptotic properties. The ability to reactivate the apoptotic process in cancerous cells is of major therapeutic interest in the treatment of cancers and of immune and auto-immune diseases.

More especially, the compounds according to the invention will be useful in the treatment of chemo- or radio-resistant cancers.

Among the cancer treatments envisaged there may be mentioned, without implying any limitation, treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

fe

-13The présent invention relates also to phannaceutical compositions comprising at least one compound of formula (I) in combination with one or more pharmaceutically acceptable excipients.

Among the phannaceutical compositions according to the invention there may be 5 mentioned more especially those that are suitable for oral, parentéral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets or dragées, sublingual tablets, sachets, paquets, capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.

The dosage varies according to the sex, âge and weight of the patient, the administration 10 route, the nature of the therapeutic indication, or of any associated treatments, and ranges from 0.01 mg to 1 g per 24 hours in one or more administrations.

Furthermore, the présent invention relates also to the association of a compound of formula (I) with an anticancer agent selected from genotoxic agents, mitotic poisons, antimetabolites, protéasome inhibitors, kinase inhibitors and antibodies, and also to 15 pharmaccutical compositions comprising that type of association and their use in the manufacture of médicaments for use in the treatment of cancer.

The compounds of the invention may also be used in association with radiotherapy in the treatment of cancer.

The following Préparations and Examples illustrate the invention but do not limit it in any 20 way.

General Procedures

Ail reagents obtained from commercial sources were used without further purification. 25 Anhydrous solvents were obtained from commercial sources and used without further drying.

17193 4

-14Flash chromatography was performed on ISCO CombiFlash Rf 200i with pre-packed silica-gel cartridges (RediiS'ep®Æf Gold High Performance).

Thin layer chromatography was conducted with 5 x 10 cm plates coated with Merck Type 60 F254 silica-gel.

Microwave heating was performed in an Anton Pair MonoWave or CEM Discover® instrument.

Préparative HPLC purifications were performed on an Armen Spot Liquid Chromatography system with a Gemini-NX® 10 μΜ C18, 250 mm x 50 inm i.d. column running at a flow rate of H8 mL min’¹ with UV diode array détection (210 - 400 nm) using 25 mM aqueous NH4HCO3 solution and MeCN as eluents unless specified otherwise.

Analytical LC-MS: The compounds of the présent invention were characterized by high performance liquid chromatography-mass spectroscopy (HPLC-MS) on Agilent HP1200 with Agilent 6140 quadrupole LC/MS, operating in positive or négative ion electrospray ionisation mode. Molecular weight scan range is 100 to 1350. Parallel UV détection was done at 210 nm and 254 nm. Samples were supplied as a 1 mM solution in ACN, or in THF/H2O (1:1) with 5 pL loop injection. LCMS analyses were performed on two instruments, one of which was operated with basic, and the other with acidic eluents.

Basic LCMS: Gemini-NX, 3 pm, C18, 50 mm x 3.00 mm i.d. column at 23 °C, at a flow rate of 1 mL min’¹ using 5 mM ammonium bicarbonate (Solvent A) and acetonitrile (Solvent B) with a gradient starting from 100% Solvent A and finishing at 100% Solvent B over various/certain duration of time.

Acidic LCMS: ZORBAX Eclipse XDB-C18, 1.8 pm, 50 mm x 4.6 mm i.d. column ai 40 °C, at a flow rate of 1 mL min’¹ using 0.02% v/v aqueous formic acid (Solvent A) and 0.02% v/v formic acid in acetonitrile (Solvent B) with a gradient starting from 100% Solvent A and finishing at 100% Solvent B over various/certain duration of time.

- 15'Η-NMR measurements were performed on Broker Avance III 500 MHz spectrometer and Broker Avance III 400 MHz spectrometer, using DMSO-df, or CDCh as solvent. ‘H NMR data is in the form of delta values, given in part per million (ppm), using the residual peak of the solvent (2.50 ppm for DMSO-dô and 7.26 ppm for CDCI3) as internai standard. Splitting patterns are designated as: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br s (broad singlet), dd (doublet of doublets), td (triplet of doublets), dt (doublet of triplets), ddd (doublet of doublet of doublets).

Combination gas chromatography and low resolution mass spectrometry were performed 011 Agilent 6850 gas chromatograph and Agilent 5975C mass spectrometer using 15 m x 0.25 mm column with 0.25 pm HP-5MS coating and hélium as carrier gas. Ion source: EI⁺, 70 eV, 230°C, quadrupole: 150°C, interface: 300°C.

HRMS were determined on a Shimadzu IT-TOF, ion source température 200°C, ESI +/-, ionization voltage: (+-)4.5 kV. Mass resolution min. 10000.

Elementary analyses were performed on a Thermo Flash EA 1112 Elemental Analyzer.

List of abbreviations

abbreviation	name
2-Me-THF	2-methyl-tetrahydrofurane
Ac	acetyl
Ad	adamantyl
AIBN	2-((1 -cyano-1 -methyl-ethyl)azo]-2-methyl-propanenitrile
AtaPhos	bis(di-i^,e/7-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II)
CuTC	copper(I) thiophene-2-carboxylate
DAST	diethylaminosulfur trifhioridc
dba	dibenzylideneacetone
DCM	methylene chloride
Dess-Martin periodinane	l,l,l-tris(acetyloxy)-l,l-dihydro-l,2-benziodoxol-3-(l£/)one
DIPA	diisopropylamine
DIPEA	diisopropylethylamine
DME	1,2-dimethoxyethane
DMF	dimethylformamide
dppf	1,1 -bis(diphenylphosphino)fenOcene
eq.	équivalent

Et HMDS 'Pr LDA Me MeCN NBS Bu NCS Ph PyBOP	ethyl hexamethyldisilazane isopropyl lithium diisopropylamide methyl acetonitrile N-bromosuccinimide n-butyl N-chlorosuccinimide phenyl benzotriazol-1 -yloxy(tripyrrolidin-1 -yl)phosphonium hexafluorophosphate
rt Selectfluor	room température 1 -ch loromethy 1-4-fl uoro-1,4-diazoniabicy cio [2.2.2] octane bis(tetrafluoroboiate)
SPhos TBAF TBAOH ‘Bu /BuXPhos TEA TFA THF TIPSC1	2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl tetrabutil ammonium fluoride tetrabutil ammonium hydroxyde /e/V-butyl 2-di(toV-butylphosphino)-2^l,4^,,6'-triisopropylbihenyl triethylamine trifluoroacetic acid tetrahydrofurane triisopropylsilyl chloride

Préparation la: 5-Bromo-4-chloro-6-iodo-thieno[2,3-rflpyrimidine

Step A: 6~Iodo-3H-thieno[2,3-]pyrimidin-4-one

A 2 L round bottomed flask equipped with mechanical stirrer, thermometer and reflux condenser was charged with the solution of 433 mL acetic acid, 13 mL sulfuric acid and 87 mL water. 69.3 g 3/7-thieno[2,3-<flpyrimidin-4-one (0.46 mol), 51.9 g periodic acid (0.23 mol) and 104 g iodine (0.41 mol) were added to the stirred solution heated to 60 °C for lh. The resulting suspension was cooled to room température, fîltered off, washed with a mixture of acetic acid and water (5:1) and then with diethyl ether. The resulting beige crystalline solid was air dried. NMR (500 MHz, DMSO-de): 12.57 (brs, 1H), 8.09 (s, 1H), 7.65 (s, 1H).

Step B: 4-Chloro-6-iodo-thieno[2,3-d]pyrimidirie

A 1 L round bottomed flask equipped with mechanical stirrer, thermometer, reflux condenser and a CaCh-tube was charged with 113 mL phosphorous oxychloride and 35

- 17mL A./V-dimethylaniline (0.29 mol). 75.54g 6-iodo-3//-thieno[2,3-if|pyrimÎdin-4-one (0.27 mol) was added to the mixture in portions during 5 minutes. The reaction mixture was stirred at 105 °C for 1 hour. The resulting suspension was cooled to 10 °C, filtered and washed with hexane. The crude product was added to ice water and stirred for 10 minutes, filtered off, washed with cold water, diethyl ether and air dried. Beige crystalline solid was obtained. *H NMR (400 MHz, DMSO-dfi): 8.89 (s, IH), 7.98 (s, IH).

Step C: 5-Bromo-4-chloro-6-iodo-thieno[2,3-d]pyrimidine

A 2 L round bottomed flask equipped with mechanical stirrer, thermometer and a bubbler was charged with 600 mL acetonitrile. 84.9 g 4-chloro-6-iodo-thieno[2,3-<7]pyrimidine (0.29 mol), 50.9 g NBS (0.29 mol) and 8.5 mL tetrafluoroboric acid diethyl ether complex were added. The reaction mixture was stirred at room température for 16 hours. Further

22.9 g (0.12 mol) NBS was added to the mixture in three portions. After cooling the suspension to 0 °C and stirring for further 1 hour the precipitate was filtered off, washed with acetonitrile and air dried. The product was obtained as beige crystalline solid. 'H NMR (500 MHz, DMSO-d₆): 8.88 (s, IH).

Préparation lb: 4-Chloro-5,6-diiodo-thieno[2,3-rf|pyrimidine

Step A: S,6-Diiodo-3H-thieno[2,3-d]pyrimidin~4-one

To a well stirred slurry of 61.3 g 3//-thieno[2,3-i/]pyrimidin-4-one (396 mmol), 92.4 g periodic acid (405 mmol), 1 L acetic acid, 200 mL water and 6 mL cc. sulfuric acid was added 203 g iodine (799 mmol). The reaction mixture was heated to 110 °C and stirred for 3 hours. The suspension was cooled to room température then 940 mL diethyl ether was added and stirred further at 10 °C for 30 minutes. The precipitate was filtered off washed with a 2:1 mixture of diethyl ether and éthanol (100 mL), finally with diethyl ether (3 x 250 mL) and air dried to give the product as a tan powder.

Step B: 4-Chloro-5,6-diiodo-thieno[2,3-d]pyrimidme

To a well stirred slurry of 180 g 5,6-diiodo-3Æ-thieno[2,3-i/]pyrimidin-4-one (445 mmol) in 2.5 L phosphorous oxychloride was added 64 mL 7V,A-dimethylaniline. The réaction mixture was heated to 105 °C and stirred for 1.5 hours. The resulting suspension was

-18cooled to room température and l .5 L hexane was added and it was stirred further for 20 minutes. The precipitate was fîltered off, washed with hexane (3 x 500 ml) and water (3 x 100 mL) then air dried to give the product as a grey crystalline solid. NMR (400 MHz, DMSO-de): 8.88 (s, IH).

Préparation le; 4-Chloro-5-iodO“thienol2.3-</|pyrÎmidînc

52.8 g 4-chloro-5,6-diiodO'thieno[2.3-c/]pyrimidine (Préparation lb) (125 mmol) was dissolved in 400 mL abs. THF and cooled to 0 °C. 100 ml 'BuMgCl (200 mmol, 2 M in diethyl ether) was added over 15 minutes. 50 mL water was added then the solution was decanted and concentrated under reduced pressure. The crude product was sonicated in a mixture of acetonitrile and water (3:l) and then collected by filtration. ^JH NMR (400 MHz, DMSO-dû): 8.95 (s, IH), 8.45 (s, IH).

Préparation Id: 4-Chloro-6-ethvl-5-iodo-thien()l2.3-f/lnvrimidine

Step A: 6-Ethyl-3H~thieno[2,3-d]pyrimidin-4-one

The mixture of 701 g 2-amino-5-ethyl-thiophene-3-carboxylic acid ethyl ester (3.52 mol) and 2200 mL formamide was heated to 200 °C and the lower boiling point solvents were distilled off. After 2 hours further 250 mL formamide was added and the mixture was stirred at the same température for another hour then at room température for 16 hours. The resulting mixture was poured into 7.5 L water and the precipitate was fîltered off, washed with 1.5 L toluene and 3 L water then air dried to give the product as a brown crystalline solid.

Step B: 6-Ethyl-5-iodo-3H-thieno[2,3-d]pyriimdin-4-one

The mixture of 301 g 6-ethyl-3//-thieno[2,3-rf]pyrimÎdin-4-one, 847 g iodïne, 1040 g silver sulfate and 1.7 L éthanol was stirred at room température for 3 days. The resulting precipitate was fîltered off and washed with éthanol (3 x 400 ml). The product was eluted from the filter cake with the following procedure: the filter cake was stirred with 800 niL Λ/Ν-dimethylformamide at 50 ^UC for 1 hour then the suspension was fîltered. This sequence was repeated 6 times. The combined organic layer was evaporated to dryness to give the product as a tan crystalline solid.

e

-19Slep C: 4-Chlo)'o-6-eihyl-5-iodo-fhieno[2,3-d]pyrimidine

The mixture of stirred 880 ml phosphorous oxychloride and 102 mL A'Àf-dimethylaniiine was heated to 95 °C and 220 g 6-ethyl-5-iodo-3Af-thieno[2,3-<7|pyrimidin-4-one (0.719 mol) was added quickly at the same température and then stirred for further 15 minutes. The reaction mixture was cooled to 80 °C and poured on a stirred mixture of water (1 L), crushed ice (2 kg) and DCM (700 ml). The resulting mixture was stirred for further 30 minutes while the température was kept below 20 °C. The phases were separated, the inorganic layer was extracted with DCM (100 ml) and the organic layer was washed with water (100 ml). The combined organic layer was dried with MgSCU and concentrated under reduced pressure to give the product as a tan crystalline solid. *Η NMR (400 MHz, DMSO-d₆): 8.79 (s, 1H), 3.02 (q, 2H), 1.39 (t, 3H).

Préparation le: 6-Bromo-4-chtoro-5iodo-thieno[2,3-rf|pyrimidine

Step A: 6-Bromo-3H-thieno[2,3-d]pyrimidin-4-one

The mixture of 60.1 g 3/Athieno[2,3-iZjpyrimidin-4-one (0.395 mol), 605 mL acetic acid and 24 mL bromine (0.468 mol) was stirred at room température for 16 hours. The reaction mixture was monitored by LCMS. Further bromine was added in three portions (12 mL, 5 mL, 10 mL) until the conversion exceeded 95%. The precipitate was filtered off, washed with acetic acid (3x50 mL), diethyl ether (3x100 mL) and then air dried to give the product as a tan powder.

Step B: 6-Bromo-5-iodo-3H-thieno[2,3-d]pyrimidin-4-one

L cc. sulfuric acid was cooled with ice-water bath and 72.0 g potassium iodide (0.434 mol) was added in portions during 15 minutes and then 32.4 g sodium periodate (0.151 mol) during a 10 minutes period. The resulting mixture was stirred at room température for 30 minutes then 80.0 g 6-bromo-3H-thieno[2,3-t(|pyiimidin-4-one (0.346 mol) was added to the mixture in portions in 30 minutes while the internai température was kept between 21 °C and -19 °C. The reaction mixture was stirred at -20 °C for 1.5 hours. Ice (3 kg) was added to the suspension then the precipitate was filtered off, washed with water (3x500

-20mL), finally with diethyl ether (3x200 mL) and air dried to give the product as a tan crystalline solid.

Step C: 6-Bromo-4-chloro-5-iodo-thieno[2,3-d]pyrimidine

To a well stirred slurry of 116 g 6-brorno-5-iodo-3Æ-thieno[2,3-d]pyrirnidin-4-one (0.324 mol) in 910 mL phosphorous oxychloride 41 mL Λζ/V-dimethylaniline was added. The stirred reaction mixture was heated to 100 °C for 1.5 hours. The resulting suspension was cooled to room température, hexane (1100 mL) was added and it was stirred for further 20 minutes. The precipitate was filtered off, washed with hexane (3x500 mL), water (3x100 mL) and diisopropyl ether (2x200 mL), finally air dried to give the Préparation le as a green shaded powder. ^!H NMR (400 MHz, DMSO-d_â): 8.95 (s, IH)

Préparation 2a: 5-BiOmo-4-chloro-6-(4-fluoiOphenyl)thieno[2,3-i/]pyrimidine

75.08 g 5-bromo-4-chloro-6-iodo-thieno[2,3-i/]pyrimidme (Préparation la) (200 mmol), 53.63 g 2-(4-fluoiOphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (240 mmol), 130 g césium carbonate (400 mmol), 2.245 g Pd(OAc)2 (10 mmol) and 8.50 g 'BuX-Phos (20 mmol) were placed in a 2 L flask. 600 mL THF and 200 mL water were added, and then stirred ovemight at 70°C under argon atmosphère. THF was evaporated, and then the product was collected by filtration. Crude product was sonicated in 250 mL acetonitrile and filtered again. Then Préparation 2a was crystalized from EtOH / THF (2:1).

'HNMR(400 MHz, DMSO-d₆): 9.02 (s, IH), 7.80-7.77 (m, 2H), 7.47-7.43 (m, 2H).

Préparation 2b: 5-Bromo-4-chloro-6-(5-fluoro-2-furyl)thieno[23-rf]pyrimidine

112,6 g (300 mmol) 5-bromo-4-chIoro-6-iodo-thieno[2,3-<7jpyrimidine (Préparation la), 254.4 g (1200 mmol) 2-(5-fluoiO-2-furyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane, 195.5 g (600 mmol) césium carbonate, 3.36 g (15 mmol) Pd(OAc)2, 12.74 g (30 mmol) 'BuX-Phos were placed in a 2 L flask. 1000 mL THF and 400 mL water were added, and then stirred ovemight at 70°C under argon atmosphère. THF was evaporated, and then the product was collected by filtration. Crude product was dissolved in THF, and then celite was added and the volatiles were evaporated under reduced pressure. The solid residue was purified by flash chromatography on silica gel using heptane / EtOAc as eluents.

‘H NMR (400 MHz, DMSO-d₆): 8.95 (s, IH), 7.55 (t, IH), 6.23 (dd, IH).

-21Préparation 2c; 5-BiOmo-4-chIoro-6-(2“furyl)thieno[2,3«rf]pyriniidine

H2.6 g 5-bromo-4-chloro-6-iodo-thieno[2,3-</]pyrimidine (Préparation la) (300 mmol), 93.14 g 2-(2-furyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (480 mmol), 215.0 g césium carbonate (660 mmol), 3.367 g Pd(OAc)₂ (15 mmol) and 12.74 g 'BuX-Phos (20 mmol) were placed in a 2 L flask. 1000 mL THF and 300 mL water were added, and then stirred for 7 hours at 70°C under argon atmosphère. THF was evaporated, and then the product was collected by filtration. Crude product was sonicated in 250 mL acetonitrile and filtered again. Then Préparation 2c was crystalized from EtOH / THF (2:1).

'H NMR (400 MHz, DMSO-d₀): 8.96 (s, IH), 8.05 (dd, IH), 7.59 (dd, IH), 6.86 (dd, IH).

Préparation 2d; 5-Bromo-4-chloro-6-(5-chloro-2-ftiryl)thieno[2,3-rf]pyriinidine

33.29 g 5-bromo-4-chloro-6-(2-furyl)thieno[2,3-i(jpyrimidine (Préparation 2c) (105.7 mmol) and 16.90 g NCS (126.6 mmol) were placed in a 1 L flask. 400 mL THF and 20 mL TFA were added, and the stirred for 2 hours at room température. Réaction mixture was washed with saturated NaHCCh. The organic phas was dried over MgSO-», filtered and concentrated to give Préparation 2d.

'il NMR (400 MHz, CDC1₃): 8.84 (s, IH), 7.52 (d, IH), 6.45 (d, IH).

Préparation 2c: 5-Bromo-4-chloro-6-(4-fluoro-3-methoxy-phenyl)thieno[23JJpyrimidine

15.01 g 5-bromo-4-chloro-6-iodo-thieno[2,3-if]pyrimidine (Préparation la) (40 mmol),

12.10 g 2-(4-fluoro-3-methoxy-phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (44 mmol), 32.58 g césium carbonate (100 mmol), 1.463 g Pd(dppf)CI₂ (2 mmol) were placed in an 1 L flask. 150 mL THF and 150 mL water were added, and then stirred ovemight at 70°C under argon atmosphère. To the reaction mixture brine was added and the pH was set to 6 with 2 M HCl, and then extracted with DCM. The volatiles from the organic phase were evaporated under reduced pressure and the crude product was purified by flash chromatography on silica gel using heptane I DCM as eluents.

'H NMR (400 MHz, DMSO-d₆): 8.94 (s, IH), 7.42 (dd, IH), 7.36 (dd, IH), 7.24-7.20 (m, IH), 3.90(s, 3H).

-22Preparation 2f; 4-Chloro-5-iodo-6-(prop-l -ynyl)-thien o [2,3-//] py ri ni id i n e

42.24 g 4-chloiO-5,6-diiodo-thieno[2,3-i/]pyrirtiidine (Préparation lb) (l 00 mmol), 3.509 g Pd(PPh₃)2Cl (5 mmol) and 1.904 g Cul (10 mmol) were dissolved in 400 mL DIP A, then propyne was bubbled through the reaction mixture, which was stirred for 6 hours at room température. After full conversion the volatiles were evaporated under reduced pressure and the crude product was purified by flash chromatography on silica gel using heptane / EtOAc as eluents.

‘H NMR (400 MHz, DMSO-di): 8.92 (s, IH), 2.25 (s, 3H).

Préparation 2g: 5-Bromo-4-chlorO6-(3.4-difluorophenvl)thienol23-d|pvriniidine

9.39 g 5-bromo-4-chloro-6-iodo-thieno[2,3-<7]pyrimidine (Préparation la) (25 mmol), 9.00 g 2-(3,4-difluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (37.5 mmol), 16.29 g césium carbonate (50 mmol), 912 mg Pd(dppf)Ch (1.25 mmol) were placed in a 250 mL flask. 100 mL THF and 50 mL water were added, and then stirred for 2 hours at 70°C under argon atmosphère. THF was evaporated, and then it was extracted with EtOAc. The organic layer was dried over NaiSO^ filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using DCM and MeOH as eluents.

'H NMR (400 MHz, DMSO-d₆): 9.06 (s, 1 H), 7.91 (m, IH), 7.71 (m, IH), 7.60 (m, IH).

Unless otherwise specified, most of the compounds of Préparation 3aa to 3bo were obtained using General procedures 3A, 3B or 3C described below.

General procedure 3A:

Step A:

1.0 eq. ethyl (2A)-2-acetoxy-3-(2-hydroxyphenyl)propanoate (Préparation 3aa-(7?)), 2.0 eq. of the appropriate alcohol and 2.0 eq. triphenylphosphine were dissolved in dry toluene (0.2 M for the phénol), then 2.0 eq. di-Ze/7-butyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen. After reaching an appropriate conversion the volatiles were removed under reduced pressure, the crude intermediate was purified via flash chromatography using heptane / EtOAc as eluents.

-23Step B:

The obtained intermediate was dissolved in éthanol (0.5 M for the Step A product) then sodium ethoxide solution (1.0 M in éthanol) was added (2-5 mol%). The resulting mixture 5 was stirred at room température. Additional sodium ethoxide solution was added if conversion was not complété. The mixture was concentrated to half of its volume, then water and brine was added, and it was extracted with ethyl acetate. The combined organics were dried over Na₂SC>4, filtered and evaporated under reduced pressure then it was purified via flash chromatography using heptane / EtOAc as eluents or other solvents, if 10 indicated.

General procedure 3B; (Tetrahedron Lett. 1994,35, 5205-5208.)

Step A:

To a stirred mixture of 1.0 eq. of the appropriate carbaldehyde and 1.25 eq. ethyl chloroacetate in THF (1.0 M for the carbaldehyde) at -78°C 1.25 eq. sodium bis(trimethyisilyl-amide) solution (1.0 M in THF) was added dropwise. After addition température was allowed to rcach room température. When the reaction Teached an appropriate conversion to the oxirane the mixture was quenched with saturated NH4CI, the 20 layers were separated, the aqueous layer was extracted with EtîO, the combined organics were dried over NaîSCU filtered and concentrated.

Step B;

The crude oxirane was dissolved in THF or EtOAc (1.0 M) and transferred to a 25 hydrogenating vessel, 5 mol% of Pd(OH)2 was added and the mixture was hydrogenated at

3-4.5 bars of hydrogen pressure. In case of a low conversion glacial acetic acid and Pd(OH)2 were added to the mixture and hydrogénation was continued. When the appropriate réduction occurred, the mixture was filtered through a pad of celite, the filtrate was concentrated under reduced pressure and purified via flash chromatography using 30 heptane / EtOAc as eluents (or other solvents, if indicated).

General procedure 3C:

-24Step A:

To a stirred mixture of water / to7-butanol (1:1, 0.2 M for the cinnamate dérivative), 1.0 eq. methane sulfonamîde, 1 g/mmol AD-mix-α and 1.0 eq. cinnamate dérivative were added at room température. The mixture was stirred at room température until no further conversion was observed, and then the mixture was cooled to 0-5 °C and 2.5 eq. sodium metabisulfite was added in small portions, then stirring was continued for 30 minutes at room température. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na₂SO4, filtered and evaporated under reduced pressure. The residue was purified via flash chromatography using DCM / methanol as eluents to obtain the appropriate dihydroxy compound.

Step B:

The solution of the dihydroxy compound in dichloromethane ! trifluoroacetic anhydride (4:1, 0.25 M) was stirred at room température for 1 hour. The mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (~ 0.25 M), 5 mol% Pd/C (10 m/m%) was added, and then it was stirred ovemight at room température under atmospheric hydrogen pressure. The reaction mixture was filtered through a pad of celite and purified via flash chromatography using hexane / chloroform as eluents or other solvents, if indicated.

Préparation 3nn-(rac}: Ethyl 2-acetoxy-3-(2-hydroxyphenyl)propanoate

Step A: [2-(Bromomethyl)phenyl]acetate

60.07 g 2-methylphenyl acetate (400 mmol) and 106.8 g NBS (600 mmol) were placed in a 1 L flask. 500 mL cyclohexane was added, and then with intensive stirring 3,284 g AIBN (20 mmol) was added over 30 min. The mixture was stirred at 80°C until no further conversion was observed, then cooled to room température. The precipitate was filtered off and washed with cyclohexane. The motlier liquor was concentrated under reduced pressure, and the crude product was used in Step B without further purification.

Step B: Ethyl 2-acetoxy~3-(2~hydroxyphenyl)propanoate ♦

-2523.ΙΟ g anhydrous LiCl (545 mmol) and 65.36 g anhydrous ZnCl₂ (479.6 mmol) were placcd in a 2 L flask, then dried at 160°C under O.l Hgmm for 1 hour. After cooling to room température under argon atmosphère, 26.49 g magnésium turnings (1090 mmol) and 1 L dry pre-cooled (0°C) THF were added. The resulting mixture was immersed into an ice-bath, and then stirred for 30 min.

100 g [2-(bromomethyl)phenyl] acetate -crude product from Step A- (~ 436 mmol) was dissolved in 120 mL dry THF and was added to the precooled inorganics over 15 min. After addition of the reagent the resulting mixture was stirred for 45 min while keeping the température between 0-5°C. To the mixture 64.82 mL ethyl 2-oxoacetate (654 mmol, 50% in toluene) was added over 5 mins and the resulting mixture was stined for another 15 mins.

From the mixture the remaining inorganics were removed by filtration, and then 500 mL MeOH was added to the filtrate. This mixture was stirred untii the intramolecular acetyl group migration from the phenolic oxygen to the alkyl oxygen was completed. To the mixture 30 mL acetic acid was added then the volatiles were evaporated under reduced pressure. To the residue 350 mL water was added and it was extracted with EtOAc. The combined organic layers wcrc washed with saturated NaHCOa and with brine, and then dried over MgSO^, filtered and evaporated under reduced pressure. To the residue 100 mL hexane was added and it was stirred for 30 mins at 0°C. The formed white crystals were collected by filtration and washed with hexane yielding Préparation 3aa-(r«c). *H NMR (500 MHz, DMSO-dé) δ 9.53 (s, IH), 7.06 (t, IH), 7.04 (d, IH), 6.79 (d, IH), 6.71 (t, IH),

5.10 (dd, IH), 4.05 (q, 2H), 3.06 (dd, 1 H), 2.94 (dd, IH), 2.00 (s, 3H), 1.09 (t, 3H).

Préparation 3aa-6S): Ethyl (2S)-2-acetoxy-3-(2-hydroxyphenyI)propanoate and

Préparation 3aa-(R).* Ethyl (2Æ)-2-acetoxy-3-(2-hydroxyphenyl)propanoate

Enantiomers of Préparation 3aa-(r«c) were separated via chiral chromatography. Column: OD; Eluents: heptane / EtOI-l; the enantiomer eluting earlier was collected as Préparation 3aa-(S) with 99.8% ee and the enantiomer eluting later was collected as Préparation 3aa-(Æ) with 99.9% ee.

-26Préparation_______3ab: Ethyl (2R)-2-hydroxy-3-(2-fetrahydropyran-2yloxyphenyl)propanoate

Step A: Ethvl (2R)-2-acetoxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate

103.3 g ethyl (27?)-2-acetoxy-3-(2-hydroxyphenyl)piOpanoate (Préparation 3aa-(7?)) (409 mmol) was dissolved in 280 mL 3,4-dihydro-27f-pyran. 300 mg /wo-toluenesulfonic acid monohydrate was added and the mixture was stirred until no further conversion was observed. Then it was diluted with l L ethyl acetate, washed with 200 mL saturated NaHCCh solution, then with 200 mL water. Combined organic layers were dried over NaîSCL, fîltered and concentrated. Then it was purified via flash chromatography using heptane / EtOAc.

Step B: Ethvl (2R)-2-hydroxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate

137.57 g ethyl (2Â)-2-acetoxy-3-(2“teti'ahydiOpyran-2-yloxyphenyl)propanoate (409 mmol) was dissolved in 600 mL éthanol, then 20 mL sodium ethoxide solution (l .0 M in éthanol) was added and it was stirred until no further conversion was observed. The mixture was concentrated to half of its volume, then 300 mL water and 300 mL brine was added, and it was extracted with ethyl acctatc. The combined organics were dried over sodium sulfate, fîltered and concentrated. The enantiopurity of the starting material was conserved. ‘H NMR (500 MHz, DMSO-dô, l:l mixture of diastereomers) Ô 7.16 (t, IH), 7.13 (d, IH), 7.04 (d, IH), 6.87 (t, IH), 5.51/5.47 (m, IH), 4.27 (m, IH), 4.04/4.02 (q, 2H), 3.73/3.56 (m, 2H), 3.06/3.04/2.74/2.71 (dd, 2H), 1.95/1.64 (m, 2H), 1.79 (m, 2H), 1.65/1.50 (m, 2H), 1.12/1.10 (t, 3H).

Préparation 3ac: Ethvl (27?)-2-hydroxy-3-[2-(pyrazin-2-ylmcthoxy)phenyî]propanoate Using General procedure 3A and pyrazin-2-ylmethanol as the appropriate alcohol Préparation 3ac was obtained. The product was purified by column chromatography using DCM / methanol.

*H NMR (400 MHz, DMSO-d_fi,) δ 8.88 (s, IH), 8.64 (dd, 2H), 7.22-7.16 (m, 2H), 7.06 (d, IH), 6.89 (t, IH), 5.46 (d, IH), 5.27 (dd, 2H), 4.29 (dq, IH), 4.00 (q, 2H), 3.09 (dd, IH),

2.79 (dd, IH), 1.08 (t,3H).

-27Préparation 3ad: Ethyl (2Æ)-2-hydroxy-3-(2-methoxyphenyl)propanoate and

Préparation 3bi: Ethyl (2S)-2-hydroxy-3-(2-methoxyphenyl)propanoate

Using General procedure 3B and 2-methoxy-benzaldehyde as the appropriate carbaldehyde the lactic ester was obtained in racemic form. 'H NMR (400 MHz, CDCI3) δ 7.23 (dt, ÎH), 7.12 (dd, 1H), 6.89-6.84 (m, 2H), 5.26 (dd, III), 4.14 (dq, 211), 3.24 (dd, III), 3.03 (dd, IH), 2.04 (s, 3H), 1.19 (t, 3H).

Enantiomers were separated via chiral chromatography; Column: AD, Eluent: 2-PrOH; the enantiomer eluting earlier was collected as Préparation 3ad with 99.8% ee and the enantiomer eluting earlier was collected as Préparation 3bi with 97.8% ee.

Préparation 3ae: Ethyl (27?)-2-hydroxy-3-[2-[(4-methoxyphenyl)niethoxy] phenyl] propanoa te

Using General procedure 3A and (4-methoxyphenyl)methanol as the appropriate alcohol Préparation 3ae was obtained. ‘H NMR (400 MHz, CDC1₃) δ 7.38 (d, 2H), 7.21 (dt, 1H), 7.15 (dd, 1H), 6.92-6.88 (m, 4H), 5.29 (dd, 1H), 5.05 (d, 1H), 5.01 (d, 1H), 4.12 (dq, 2H),

3.31 (dd, 1H), 3.04 (dd, 1H), 2.02 (s, 3H), 1.16 (t, 3H).

Préparation 3af; Ethyl (27?)-2-hydroxy-3-[2-[[(25)-tetrahydrofuran-2-yljmethoxy] phenyl]propanoate and

Préparation 3bî: Ethyl (2tf)-2-hydroxy-3-[2-[[(2J?)tetrahydrofuran-2-yl]methoxy] phenyljpropanoate

Using General procedure 3A and tetrahydrofuran-2-ylmethanol as the appropriate alcohol diastereoisomer mixture of the lactic esters were obtained. Diastereoisomers were separated by chiral chromatography. Column: IC. Eluents: heptane / EtOH; the diastereoisomer eluting earlier was collected as Préparation 3af with 99.6% de; *H NMR (400 MHz, CDC13) δ 7.26-7.24 (m, 2I-I), 6.92 (dt, 1H), 6.87 (d, 1H), 4.46-4.41 (m, 1H), 4.35-4.29 (m, 1H), 4.20 (dq, 2H), 4.04 (dd, 1H), 3.99-3.93 (m, 2H), 3.88-3.82 (m, 1H),

3.32 (d, 1H), 3.17 (dd, 1H), 3.00 (dd, 1H), 2.14-2.05 (m, 1H), 2.03-1.90 (m, 2H), 1.85-1.76 (m, 1H), 1.25 (t, 3H) and the diastereoisomer eluting later was collected as Préparation 3bj with 99.5% de; *H NMR (400 MHz, CDC13) δ 7.23-7.15 (m, 2H), 6.91 (dt, 1H), 6.86

-28(d, IH), 4.48-4,44 (m, IH), 4.33-4.27 (m, IH), 4.18 (dq, 2H), 4.06-3.97 (m, 3H), 3.87-3.82 (m, IH), 3.35 (d, IH), 3.18 (dd, IH), 3.00 (dd, IH), 2.14-2.05 (m, IH), 2.04-1.92 (m, 2H), 1.90-1.82 (m, IH), 1.24 (t, 3H)

Préparation 3ag: Methyl (2I?)-2-hydroxy-3-phenyl-propanoate

1.66 g (2/?)-2-hydroxy-3-phenyl-propanoic acid (10 mmol) was dissolved in 30 mL dry methanol and stirred at in presence of catalytic amount of concentrated sulfuric acid until no further conversion was observed. Reaction mixture was concentrated under reduced pressure, to the residue 50 mL EtOAc was added and washed with saturated NaHCOj and 10 with brine. Organic phase was dried over MgSCL, filtered and evaporated under reduced pressure to yield Préparation 3ag. ’H NMR (400 MHz, CDCh) δ 7.33-7.21 (m, 5H), 4.46 (q, IH), 3.78 (s, 3H), 3.14 (dd, IH), 2.98 (dd, IH), 2.77 (d, IH).

Préparation 3ah:Ethvl (2Æ)-2-hydroxy-3-[2-[(2-methoxypyrimidin-4-yl)inethoxy] phenyljpropanoate

Using General procedure 3A and (2-methoxypyrimidin-4-yl)methanol as the appropriate alcohol Préparation 3ah was obtaincd. 'H NMR (400 MHz, CDCI3) δ 8.64 (d, III), 7.29 (d, IH), 7.21-7.17 (m, 2H), 6.98 (d, IH), 6.89 (dt, IH), 5.52 (d, IH), 5.17 (d, IH), 5.13 (d, IH), 4.34-4.30 (m, IH), 4.04 (dq, 2H), 3.92 (s, 3H), 3.11 (dd, IH), 2.83 (dd, IH), 1.10 (t,

3H).

Préparation 3ai: Methyl (2Æ)-2-hydroxy-3-{2-(trifluoroniethoxy)phenyl]propanoate

Using General procedure 3C and methyl (2Æ)-3-[2-(trifluoromethoxy)phenyl]prop-2enoate as the appropriate cinnamic acid dérivative Préparation 3ai was obtained with 25 99.4% ee; ^JH NMR (400 MHz, CDC1₃) δ 7.41-7.33 (m, IH), 7.34-7.16 (m, 3H), 4.46 (ddd,

IH), 3.80 (s, 3H), 3.22 (dd, IH), 3.03 (dd, IH), 2.75 (d, IH).

Préparation 3ai: Methyl (2Æ)-3-[2-(difluoromethoxy)phenyl]-2-hydroxy-piOpanoate

Using General procedure 3C and methyl (2E)-3-[2-(difluoromethoxy)phenyl]prop-2-enoate as the appropriate cinnamic acid dérivative Préparation 3aj was obtained with 99.9% ee; 'H NMR (500 MHz, CDC1₃) δ 7.31 (dd, IH), 7.29-7.24 (m, IH), 7.21-7.15 (m, IH), 7.11

-29(d, IH), 6.53 (t, IH), 4.46 (dd, IH), 3.80 (s, 3H), 3.21 (dd, IH), 3.03 (dd, IH), 2.68 (br s, IH).

Préparation 3ak: Methyl (2R)-3-(3-fluorophenyl)-2-hydroxy-propanoate

Using General procedure 3C and methyl (2E)-3-(3-fluorophenyl)prop-2-enoate as the appropriate cinnamic acid dérivative Préparation 3ak was obtained with 98.6% cc; *H NMR (500 MHz, CDCl₃) δ 7.27-7.24 (m, IH), 7.00 (d, IH), 6.97-6.92 (m, 2H), 4.46 (dd, IH), 3.79 (s, 3H), 3.13 (dd, lH),2.96(dd, IH),2.64 (brs, IH).

Préparation 3ak Methyl (2/î)-2-hydroxy-3-(3-methoxyphenyl)propanoate

Using General procedure 3C and methyl (22?)-3-(3-methoxyphenyl)prop-2-enoate as the appropriate cinnamic acid dérivative Préparation 3al was obtained with 97.3% ee;

NMR (500 MHz, CDCl₃) δ 7.23 (t, IH), 6.83-6.77 (m, 3H), 4.48 (dd, IH), 3.81 (s, 3H),

3.80 (s, 3H), 3.12 (dd, IH), 2.96 (dd, IH), 2.33 (br s, IH).

Préparation 3am; Methvl (2^)-3-(2,3-difluorophenyl)-2-hydroxy-propanoate

Using General procedure 3C and methyl (2E)-3-(2,3-difluorophenyl)prop-2-enoate as the appropriate cinnamic acid dérivative Préparation 3am was obtained with 96.9% ee; *H NMR (500 MHz, CDC1₃) 8 7.19-6.93 (m, 3H), 4.48 (dd, IH), 3.82 (s, 3H), 3.20 (dd, IH), 3.06 (dd, 1H),2.73 (brs, IH).

Préparation 3an: Methvl (2jR)-2-hydroxy-3-[2-(trifluoron»ethyl)phenyl]propanoate

Using General procedure 3C and methyl (2£)-3-[2-(trifluoromethyl)phenyI]piOp-2-enoate as the appropriate cinnamic acid dérivative Préparation 3an was obtained with 99.6% ee; ΉNMR (500 MHz, CDC1₃) δ 7.67 (d, 1 H), 7.53-7.47 (m, 2H), 7.37 (t, IH), 4.43 (dd, IH),

3.81 (s, 3H), 3.40 (dd, IH), 3.01 (dd, IH), 2.70 (br s, IH).

Préparation 3ao: Methyl (2Æ)-2-hydroxy-3-(o-tolyl)propanoate

Using General procedure 3C and methyl (2£)-3-(o-tolyl)prop-2-enoate as the appropriate cinnamic acid dérivative Préparation 3ao was obtained with 99.3% ee; ^lH NMR (500 MHz, CDC1₃) δ 7.20-7.14 (m, 4H), 4.44 (dd, IH), 3.80 (s, 3H), 3.18 (dd, III), 2.95 (dd, 1 H), 2.59 (br s, 1 H), 2.37 (s, 3H).

-30Préparation 3ap: Methyl (27f)-2-hydroxy-3-(w-tolyl)propanoate

Using General procedure 3C and methyl (2£)-3-(w-tolyl)prop-2-enoate as the appropriate cinnamic acid dérivative Préparation 3ap was obtained with 96.7% ee; *H NMR (500 5 MHz, CDCl₃) δ 7.20 (t, IH), 7.07 (d, IH), 7.05 (s, IH), 7.02 (d, IH), 4.46 (dd, IH), 3.79 (s,

3II), 3.11 (dd, III), 2.94 (dd, IH), 2.54 (br s, IH), 2.35 (s, 3H).

Préparation 3aq: Ethvl (2Æ)-3-(3-fluoro-2-methoxy-phenyl)-2-hydroxy-propanoate

Using General procedure 3C and ethyl (2£)-3-(3-fluoro-2-methoxy-phenyl)prop-2-enoate J0 as the appropriate cinnamic acid dérivative Préparation 3aq was obtained with 99.9% ee;

'HNMR (400 MHz, CDCl₃) δ 7.04-6.03 (m, 3H), 4.44 (q, IH), 4.23 (dq, 2H), 3.96 (d, 3H), 3.17 (dd, IH), 3.02 (dd, IH), 1.27 (t, 3H).

Préparation 3ar: Ethvl (2R)-3-(5-fluoro-2-methoxy-phenyI)-2-hydroxy-propanoate

Using General procedure 3C and ethyl (2Æ)-3-(5-fluoro-2-methoxy-phenyl)prop-2-enoate as the appropriate cinnamic acid dérivative Préparation 3ar was obtained with 99.9% ee;

’H NMR (400 MHz, CDCI3) δ 6.95-6.90 (m, 2H), 6.81-6.78 (m, IH), 4.47 (q, IH), 4.22 (dq, 2H), 3.83 (s, 3H), 3.14 (dd, IH), 2.97 (dd, IH), 1.28 (t, 3H).

Préparation 3as: Ethyl (2Æ)-3-(4-fluoro-2-methoxy-phenyl)-2-hydroxy-propanoate

Using General procedure 3C and ethyl (2£)-3-(4-fluoro-2-methoxy-phenyl)piOp-2-enoate as the appropriate cinnamic acid dérivative Préparation 3as was obtained with 99.9% ee; ‘H NMR (500 MHz, CDC1₃) δ 7.10 (t, IH), 6.61-6,57 (m, 2H), 4.42 (q, IH), 4.19 (dq, 2H),

3.82 (s, 3H), 3.07 (dd, IH), 2.96 (dd, IH), 2.80 (d, IH), 1.25 (t, 3H).

Préparation 3at: Ethvl (2Â)-2-hydroxy-3-(2-methoxy-5-methyl-phenyl)propanoate

Using General procedure 3C and ethyl (2£^,)-3-(2-methoxy-5-methyl-phenyl)prop-2-enoate as the appropriate cinnamic acid dérivative Préparation 3at was obtained with 99.9% ee; ^]H NMR (400 MHz, CDC1₃) δ 7.04 (dd, IH), 6.99 (d, IH), 6.78 (d, IH), 4.47 (dd, IH), 30 4.21 (dq, 2H), 3.79 (s, 3H), 3,14 (dd, IH), 2.98 (dd, IH), 2.28 (s, 3H), 1.27 (t, 3H).

Préparation 3au; Ethvl (2R)-2-hydroxy-3-(2-methoxy-3-methyl-phenyl)propanoate

-3l Using General procedure 3C and ethyl (2£)-3-(2-mcthoxy-3-methyl-phcnyl)prop-2-cnoatc as tire appropriate cinnamic acid dérivative Préparation 3au was obtained with 99.8% ee; *H NMR (500 MHz, CDClj) δ 7.10-7.03 (m, 2H), 6.97 (t, IH), 4.45 (q, IH), 4.21 (dq, 2H), 3.26 (s, 3H), 3.16 (dd, IH), 3.01 (d, IH), 2.31 (s, 3H), 1.25 (t, 3H).

Préparation 3av: Ëthyl (2j?)-3-[2-(/er/-butoxycarbonylamino)phenyI]-2-hydroxypropanoate

Using General procedure 3C and ethyl (2£)-3-[2-(tert-butoxycarbonyIamino)phenyl]prop2-enoate as the appropriate cinnamic acid dérivative Préparation 3av was obtained with 99.8% ee; ’H NMR (500 MHz, CDC1₃) δ 7.92 (br s, IH), 7.75 (d, IH), 7.24 (t, IH), 7.10 (d, IH), 7.01 (t, IH), 4.51 (q, IH), 4.27 (q, 2H), 3.34 (br s, 1 H), 3.25 (dd, IH), 3.01 (dd, IH), 1.52 (s, 9H), 1.35 (t, 3H).

Préparation 3aw: Ethyl (2jR)-3-[2-[(te/Ÿ-butoxycarbonylamino)methyl]phenyl]-2hy d roxy-p ropa noate

Using General procedure 3C and ethyl (2£)-3-[2-[(ter/buloxycarbonylamino)melhyl]phenyl]prop-2-enoate as the appropriate cinnamic acid dérivative Préparation 3aw was obtained with 98.8% ee; *H NMR (500 MHz, CDCI3) δ 7.34 (m, IH), 5.63 (br s, IH), 4.44-4.35 (m, 3H), 4.26 (q, 2H), 3.21 (dd, IH), 3.10 (dd, IH), 1.45 (s, 9H), 1.32 (t,3H).

Préparation 3ax; Ethyl (2S)-2-bydroxy-3-[2-(2,2,2-trifluoroethylsulfanyl)phenyl] propanoate and

Préparation 3av: Ethvl (2JÏ)“2-hydroxy-3-[2-(2,2,2-trifliioroetby]sulfanyl)phenyl] propanoate

Step A: l-Methyl-2-(2,2,2-trifluoroethylsvlfanyl)benzene

To a solution of 2.357 mL 2-methylbenzenethiol (20 mmol) in 30 mL dry DMF, 8.292 g potassium carbonate (40 mmol) was added. After 5 min stirring 3.168 mL 2,2,2trifluoroethyl trifluoromethanesulfonate (28 mmol) was added over 5 mins. The resulting mixture was stirred until no further conversion was observed. Brine was added and the

-32mixture was extracted with ethyl acetate. The combined organic layers were dried over MgSOi, filtered and evaporated under reduced pressure. The residue was purified via flash chromatography using heptane / EtOAc as eluents. *H NMR (400 MHz, CDCI3) δ 7.48 (dd, 1H), 7.24-7.13 (m, 3H), 3.40 (q, 2H), 2.48 (s, 3H).

Step B: l-(Bromomethyl)-2-(2,2,2-trifluoroethylsulfanyl)benzene

3.100 g l-methyl-2-(2,2,2-trifluoroethylsulfanyl)benzene (15 mmol) and 4.005 g NBS (22.50 mmol) were placed in a 25 mL flask. 10 mL CCI4 was added, and then 49.2 mg AIBN was added over 5 mins. Mixture was stirred at 80°C ovemight, then cooled to room température; the precipitate was filtered off and washed with hexane. The mother liquor was concentrated, and used in the next step without further purification.

Step C: Ethyl (2R)-2-hydroxy-3-[2-(2,2_l2-trifluoroethylsulfanyl)phenyl]propanoate

632 mg anhydrous LiCl (14.90 mmol) and 1.787 g anhydrous ZnCl₂ (13.11 mmol) were placed in a 250 mL flask, then dried at 160°C under 0.1 Hgmm for 1 hour. After cooling to room température under argon atmosphère 725 mg magnésium turnings (29.81 mmol) and 80 mL dry, pre-cooled (0°C) THF were added. The resulting mixture was immersed into an ice-bath, and then 3.400 g l-(bromomethyl)-2-(2,2,2-trifluoroethylsulfanyl)benzene (~ 11.92 mmol, from Step B) dissolved in 20 mL dry THF and was added to the pre-cooled inorganics over 10 min. The réaction mixture was stirred for 45 min between 0-5°C. To the prepared zinc organic compound 3.546 mL ethyl 2-oxoacetate (3.652 mmol, 50% in toluene) was added over 5 min and further was stirred for 15 min. From the mixture the remained inorganics were removed by filtration, and after addition of saturated NH4CI the mixture was extracted with ethyl acetate. The combined organic phase was dried over Mg₂SO4, filtered and evaporated under reduced pressure. The residue was purified via flash chromatography using heptane / ethyl acetate as eluents giving the appropriate lactic ester in racemic form. *H NMR (400 MHz, CDCI3) δ 7.59 (dd, 1H), 7.33-7.23 (m, 3H), 4.48.4.43 (m, 1H), 4.29-4.22 (m, 2H), 3.46-3.39 (m, 3H), 3.21 (dd, 1H), 2.78 (d, 1H), 1.29 (t, 1H).

Enantiomers were separated via chiral chromatography. Column: AS-V, Eluents: heptane / 2-PrOH; the enantiomer eluting earlier was collected as Préparation 3ax with 99.6% ee and the enantiomer eluting later was collected as Préparation 3ay with 99.5% ee.

♦

-33Preparation 3az:Ethvl (25)-3-i2-fluorophenvl)-2-hvdroxv-propanoate and

Préparation 3ba: Ethyl (2/f)-3-(2-fluorophenyl)-2-hydroxy-propanoate

Using General procedure 3B and 2-fluorobenzaldéhyde as the appropriate carbaldehyde lactic ester was obtained in racemic form. *H NMR (400 MHz, DMSO) δ 7.34-7.22 (m, 2H), 7.16-7.07 (m, 2H), 5.60 (d, 1H), 4.23 (dd, 1H), 4.05 (q, 2H), 2.99 (dd, 1H), 2.86 (dd, 1H), 1.12 (t, 3H).

Enantiomers were separated via chiral chromatography. Column: AS-V, Eluents: heptane / 10 2-BuOH; the enantiomer eluting earlier was collected as Préparation 3az with 99.8% ee and the enantiomer eluting later was collected as Préparation 3ba with 99.4% ee.

Préparation 3bb: Ethyl 3-(benzofuran-7-yl)-2-hydroxy-propanoate

Using General procedure 3B and benzofuran-7-carbaldehyde as the appropriate carbaldehyde Préparation 3bb was obtained. Upon réduction the saturation of the furan moiely was also observed, thus hydrogenolysis was stopped at the point, when the desired product was présent with the highest concentration in the mixture. The product was purified via flash chromatography using DCM / EtOAc as eluents. ^]H NMR (500 MHz, DMSO) δ 7.98 (d, 1H), 7.51 (m, 1H), 7.16 (m, 2H), 6.94 (d, 1H), 5.63 (d, 1H), 4.40 (dd,

1H), 4.02 (q, 2H), 3.25 (dd, 1H), 3.09 (dd, 1H), 1.07 (t, 3H).

Préparation 3bc; Ethyl 3-(benzofuran-4-yl)-2-hydroxy-propanoate

Using General procedure 3B and benzoftuan-4-carbaldehyde as the appropriate carbaldehyde Préparation 3bc was obtained. ’H NMR (400 MHz, CDCI3) δ 7.62 (d, 1H),

7.41 (d, 1H), 7.23 (t, 1H), 7.10 (d, 1H), 6.85 (dd, 1H), 4.53 (dd, 1H), 4.24-4.12 (m, 2H),

3.37 (dd, 1H), 3.21 (dd, 1H), 2.80 (bs, 1H), 1.24 (t, 3H).

Préparation 3bd: Ethvl (2R)-3-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-propanoate and

Préparation 3be; Ethyl (25)-3-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-propanoate

Using General procedure 3B and benzofuian-7-caibaldehyde as tire appropriate carbaldehyde. Applying longer reaction time in Step B the partially saturated lactic ester

-34was obtained as the main product in racemic form, which was purified via flash chiomatography using DCM / EtOAc as eluents. 'H NMR (500 MHz, DMSO) δ 7.07 (m,

IH), 6.92 (m, IH), 6.72 (t, IH), 5.49 (d, IH), 4.50 (m, 2H), 4.23 (m, IH), 4.04 (q, 2H), 3.15 (t, 2H), 2.88 (dd, IH), 2.71 (dd, IH), 1.12 (t, 3H)

Enantiomère were separated via chiral chromatography. Column: OJ-H, Eluents: heptane / l-PrOH; the enantiomer eluting earlier was collected as Préparation 3bd with 99.6% cc and the enantiomer eluting later was collected as Préparation 3be with 92.4% ee.

Préparation 3bf; Ethyl (21?)-3-[4-fluoro-2-(methoxymethoxy)phenyl]-2-hydroxy10 propanoate

Step A: 4-Fhtoro-2-(methoxvmelhoxv)benzaldehyde

To a solution of 1.242 g 4-fluoro-2-hydroxy-benzaldehyde (8.86 mmol) in 10 mL dry acetone 2.444 g K2CO3 (17.7 mmol) and 1.01 mL chloromethyl-methyl-ether (13.3 mmol) were added and stin-ed at room température until no further conversion was observed. The mixture was diluted with ethyl acetate and it was extracted with water and with brine. The organic phase was dried over Na₂SO4, filtered and concentrated under reduced pressure giving 4-fluoro-2-(methoxymethoxy)benzaldehyde. *H NMR (400 MHz, CDCI3) δ 10.39 (s, IH), 7.87 (dd, IH), 6.96 (dd, IH), 6.78 (dt, IH), 5.29 (s, 2H), 3.53 (s, 3H).

Step B: Ethyl (2R)-3-[4-fluoro-2-(methoxymethoxy)phenyl]-2-hydroxy-propanoate

Using General procedure 3B and 4-Fluoro-2-(methoxymethoxy)benzaldehyde as the appropriate carbaldehyde the desired lactic ester was obtained in racemic form. Enantiomers were separated via chiral chromatography. Column: AS-V, Eluents: heptane / 25 EtOH; the enantiomer eluting later was collected as Préparation 3bf with 96.6% ee. 'H

NMR (500 MHz, DMSO) δ 7.16 (dd, IH), 6.90 (dd, IH), 6.73 (m, IH), 5.52 (brs, IH), 5.24 (s, 2H), 4.22 (brm, IH), 4.03 (q, 2H), 3.40 (s, 3H), 2.94 (dd, IH), 2.77 (dd, IH), 1.10 (t 3 H).

Préparation 3bg: Ethyl (2/f)-3-(l,3-benzodioxol-4-yl)-2-hydroxy-propanoate and

Préparation 3bh; Ethyl (25)-3-(1,3-benzodioxoI-4-yI)-2-hydroxy-propanoate ♦

-35(Tetrcihedron Lett. 1994, 35, 5205-5208.) l,3-Benzodioxole-4-carbaldehyde was reacted according to General method B with the exception, that in Step A after the formation of the oxirane the aqueous workup was completely omitted and the solution was directly carried further to in Step B resulting the title compound in racemîc form. ^!H NMR (500 MHz, DMSO) δ 6.78 (dd, IH), 6.74 (t, IH), 6.71 (dd, IH), 5.96 (d, 2H), 5.59 (d, IH), 4.25 (m, IH), 4.05 (q, 2H), 2.91 (dd, IH), 2.76 (dd, IH), 1.13 (t, 3H).

Enantiomers were separated via chiral chromatography. Column: AS-V, Eluents: heptane / 1-BuOH; the enantiomer eluting eaiiier was collected as Préparation 3bg with 99.4% ee and the enantiomer eluting later was collected as Préparation 3bh with 99.8% ee.

Préparation 3bk: Ethyl (2f?)-2-hydroxy-3-[2-[2-(4-naethylpiperazin-lyl)ethoxy]phenyl]propanoate and

Préparation 3bo: Ethyl (2S)-2-hydroxy-3-[2-[2“(4-methylpiperazin-lyl)ethoxy]phenyl]propanoate

Using General procedure 3A starting from ethyl 2-acetoxy-3-(2-hydroxyphenyl)propanoate (Préparation 3aa-(r«c)) and 2-(4-methyIpiperazin-l-yl)ethanol as the appropriate alcohol the lactic ester was obtained in racemîc form. ^XH NMR (500 MHz, DMSO-d₍₎) δ 7.17 (m, IH), 7.10 (dm, IH), 6.94 (dm, IH), 6.83 (m, IH), 5.4 (d, IH), 4.28 (m, IH), 4.06 (t, 2H), 4.02 (m, 2H), 2.97 (dd, 111), 2.71 (dd, IH), 2.69 (t, 211), 2.49 (brs, 411), 2.30 (brs, 411), 2.13 (s, 3H), 1.11 (t, 3H).

Enantiomers were separated via chiral chromatography. Column: OD, Eluents: heptane / 1PrOH; the enantiomer eluting earlier was collected as Préparation 3bk with 99.8% ee and the enantiomer eluting later was collected as Préparation 3bo with 99.6% ee.

Préparation 3bl: Ethyl (2Æ)-2-hydroxy-3-[2-(2,2^-trifluoroethoxy)phenyl]propanoate

Step A: Ethyl (2R)-2-hydroxy-3-(2-hydroxyphenyI)propanoate

To a solution of 13.633 g ethyl (2R)-2-acetoxy-3-(2-hydiOxyphenyl)propanoate (Préparation 3aa-(Æ)) (54 mmol) in 200 mL dry éthanol 30 mL sodium ethoxide (1.0 M) solution was added and stirred at room température. If needed, the addition of the sodium

-36ethoxide solution was repeated until the cleavage of the acetyl group was complété, The mixture was diluted with 600 mL water and it was extracted with ethyl acetate. The combined organic layers were dried over Na2SC>4 fîltered and evaporated under reduced pressure. The obtained material was used in the next step without purification.

Step B: Ethyl (2R)-2-hydroxy-3-[2-(2,2,2-trifluoi'oethoxy)phenyl]propanoate

To a solution of 9.18 g ethyl (272)-2-hydiOxy-3-(2-hydroxyphenyl)propanoate (43.7 mmol) in 130 mL dry DMF, 6.040 g potassium carbonate (43.7 mmol) was added. After 5 mins stirring 7.7 mL 2,2,2-trifluoroethyl trifluoromethanesulfonate (48 mmol) was added over 5 mins. The resulting mixture was stirred until no further conversion was observed. The reaction mixture was extracted with brine / EtOAc. The combined organic layers were dried over NaïSCL, fîltered and evaporated under reduced pressure. The product was purified via flash chromatography using heptane / EtOAc as eluents. *H NMR (500 MHz, DMSO-de) δ 7.23 (t, IH), 7.18 (d, IH), 7.06 (d, IH), 6.95 (t, IH), 5.50 (d, IH), 4.75 (q, 2H), 4.22 (m, IH), 4.02 (q, 2H), 3.00 (dd, IH), 2.76 (dd, IH), 1.09 (t, 3H).

Préparation 3bm; Ethyl (25)-2-hydroxy-3-|2-[[(27?)-tetrahydrofuran-2yl] methoxy ] phen yl]propanoate

Using General procedure 3A starting from ethyl (2S)-2-acetoxy-3-(2hydroxyphenyl)propanoate (Préparation 3aa-(ô)) and [(27?)-tetrahydrofuran-2yljmethanol as the appropriate alcohol Préparation 3bm was obtained. ’H NMR (400 MHz, CDC13) δ 7.26-7.24 (m, 2H), 6.92 (dt, IH), 6.87 (d, IH), 4.46-4.41 (m, IH), 4.354.29 (m, IH), 4.20 (dq, 2H), 4.04 (dd, IH), 3.99-3.93 (m, 2H), 3.88-3.82 (m, IH), 3.32 (d, IH), 3.17 (dd, IH), 3.00 (dd, IH), 2.14-2.05 (m, IH), 2.03-1.90 (m, 2H), 1.85-1.76 (m, IH), 1.25 (t,3H).

Préparation 3bn; Ethvl (2J?)-2-hydroxy-3-|2-(2-pyridylBiethoxy)phenyl]propanoate

Using General procedure 3A and 2-pyridylmethanol as the appropriate alcohol Préparation 3bn was obtained. *H NMR (500 MHz, DMSO-dé) δ 8.58 (dm, IH), 7.85 (td, IH), 7.59 (d, IH), 7.35 (ddd, IH), 7.19 (td, IH), 7.17 (dd, IH), 7.01 (d, IH), 6.88 (td, IH), 5.52 (d, IH), 5.21 (d, IH), 5.17 (d, IH), 4.32 (m, IH), 4.02 (m, 2H), 3.09 (dd, IH), 2.83 (dd, IH), 1.09 (t, 3H).

♦

-37Préparation 4a: Ethyl (2/?)-2-[5-bromo-6-(4-fluorophenyl)thicno[2,3-i/]pyrimidin-4yl]oxy-3-(2-tetra-hydropyran-2-yloxyphenyI)propanoate

48.45 g 5-biOmo-4-chloro-6-(4-fluorophenyl)thieno[2,3-</]pyiimidine (Préparation 2a) (I4l mmol), 45.63 g ethyl (2Æ)-2-hydiOxy-3-(2-tetrahydiOpyran-25 yloxyphenyl)propanoatc (Préparation 3ab) (155 mmol) and 137.8 g Cs₂CO₃ (423 mmol) were placed in a 2 L flask. 1.4 L fert-butanol was added and the mixture was stirred at 70°C under N2 until no further conversion was observed. Approximately 1 L solvent was evaporated under reduced pressure, then it was diluted with water, the pH was set to 8 with

M HCl, and then it was extracted with DCM. The combined organic layers were dried over Na2SÛ4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4a as a mixture of diastereoisomers. *H NMR (500 MHz, DMSO-dô): 8.67/8.66 (s, IH), 7.75 (m, 2H), 7.43 (dm, IH), 7.41 (m, 2H), 7.19 (m, IH), 7.08/7.06 (dm, IH), 6.89 (m, IH), 5.87/5.70 (dd, IH), 5.60/5.55 (m, IH), 4.23-4.08 (m, 2H), 3.80-3.48 (m,

2H), 3.52/3.49 (dd, IH), 3.19/3.17 (dd, IH), 2.09-1.49 (m, 6H), 1.15/1.10 (t, 3H). HRMS calculated for C₂sH26BrFN2O5S: 600.0730, found: 601.0809/601.0798 (M+H).

Préparation 4b: Ethyl (2R)-2-j5-bromo-6-(4-fluorophenyl)thieno[2,3-rf]pyrimidin-4yl]oxy-3-[2-(pyrazin-2-ylmcthoxy)phcnyl]propanoate

1.718 g 5-bromo-4-chloro-6-(4-fluorophenyl)thieno[2,3-J]pyrimidine (Préparation 2a) (5.00 mmol), 1.512 g ethyl (2/?)-2-hydroxy-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoate (Préparation 3ac) (5.00 mmol) and 5.700 g CS2CO3 (17.5 mmol) were placed in a 50 mL flask. 15 mL ferAbutanol was added and the mixture was stirred at 70°C under N₂ until no further conversion was observed. The reaction mixture was diluted with water, the pH was set between 6-7 with 2 M HCl, and then it was extracted with DCM. The combined organic layers were dried over Na₂SO4, filtered and concentrated under reduced pressure, The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4b. MS: (M+H)⁺ = 609.0.

Préparation 4c: Ethyl (2R)-2-[5-bromo-6-(5-fluoro-2-furyI)thieno[2,3-i/]pyrimidin-4yl]oxy-3-(2-tetrahydropyran-2-yloxypheny!)propanoate ♦

-3850.03 g 5-bromo-4-chioiO-6-(5-fluoiO-2-ftnyl)thieno[2,3-i(|pyrimidine (Préparation 2b) (150 mmol), 44.15 g ethyl (2Æ)-2-hydiOxy-3-(2-tetrahydropyran-2yloxyphenyl)propanoate (Préparation 3ab) (150 mmol) and 146.6 g CS2CO3 (450 mmol) were placed in a 2 L flask. 1.5 L ter/-butanol was added and the mixture was stirred at

70°C under N₂ until no further conversion was observed. Approximately 1 L solvent was evaporated, then it was diluted with DCM and water, the pH was set to 8 with 2 M HCl, and then it was extracted with DCM. The combined organic layers were dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4c as a mixture of diastereoisomers. 'H NMR (500 MHz, DMSO-cL): 8.63/8.62 (s, IH), 7.44 (dm, IH), 7.42 (m, IH), 7.19 (tm, IH), 7.07 (d, IH), 6.90 (t, IH), 6.17 (m, IH), 5.80/5.68 (dd, IH), 5.61/5.55 (t, IH), 4.14 (m, 2H), 3.78-3.40 (m, 2H), 3.51 (m, IH), 3.18 (m, IH), 2.00 (m, IH), 1,82 (m, 2H), 1.68-1.37 (m, 2H), 1.66 (m, IH), 1.14/1.11 (t, 3H) . HRMS calculated for C₂₆H24BrFN₂O6S: 590.0522, found: 591.0599 (M+H).

Préparation 4d: Ethyl (2Æ)-2-[5-broino-6-(2-fiiryl)thieno[2,3-iflpyrinudin-4-yl]oxy-3(2-tetrahydropyran-2-yloxyphenyl)propanoate

36.87 g 5-bromo-4-chloiO-6-(2-furyl)thieno[2,3-<7]pyrimidine (Préparation 2c) (117 mmol), 37.83 g ethyl (2J?)-2-hydroxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 3ab) (129 mmol) and 98.00 g Cs₂CO₃ (300 mmol) were placed in a 1 L flask. 400 mL /er/-butanol was added and the mixture was stirred at 50°C under N₂ until 110 further conversion was observed. The reaction mixture was diluted with DCM and brine, and then it was extracted with DCM. The combined organic layers were dried over Na₂SC>4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4d as a mixture of diastereoisomers. MS: (M+H)⁺ = 609.0.

Préparation 4e; Ethyl (2R)-2-[5-bronio-6-(2-furyl)thieno[2,3-i/|pyriinidiu-4-yI]oxy-3(2-methoxyphenyI)propanoate

0.631 g 5-bromo-4-chloro-6-(2-furyl)thieno[2,3-6/]pyrirnidine (Préparation 2c) (2.00 mmol), 0.673 g ethyl (2Æ)-2-hydroxy-3-(2-methoxyphenyl)propanoate (Préparation 3ad) (3.00 mmol) and 0.195 g CS2CO3 (6.00 mmol) were placed in a 25 mL flask. 10 mL tert17193 ♦

-39butanol was added and the mixture was stirred at 60°C under N₂ until no further conversion was observed. The reaction mixture was diluted with DCM and brine, and then ït was extracted with DCM. The combined organic layers were dried over N^SOj, fïltered and concentrated under reduced pressure. The crude product was purified via flash 5 chromatography using heptane and EtOAc as eluents to obtain Préparation 4e. *H NMR (400 MHz, DMSO-de): 8.60 (s, 1H), 7.94 (d, III), 7.43 (d, III), 7.37 (dd, III), 7.22 (td, IH), 6.96 (d, ÎH), 6.86 (td, IH), 6.77 (dd, IH), 5.64 (dd, ÎH), 4.10 (q, 2H), 3.79 (s, 3H), 3.87 (dd, IH), 3.24 (dd, IH), 1.10 (t, 3H).

Préparation 4f; Ethyl (2R)-2-[5-bromo-6-(5-chloro-2-furyl)thieno[2,3-rf]pyrimidin-4yl]oxy-3-[2-[(4-methoxyphenyl)methoxy)phenyl]propanoate

6.05 g 5“bromo-4-chloiO~6-(5-chloro-2furyl)thieno[2,3-if]pyiimidÎne (Préparation 2d) (17.3 mmol), 6.28 g ethyl (2R)-2-hydroxy-3-[2-((4methoxyphenyl)methoxy]phenyl]propanoate (Préparation 3ae) (19.0 mmol) and 19.7 g

CS2CO3 (60.5 mmol) were placed in a 250 mL flask. 60 mL fôr/-butanol was added and the mixture was stirred at 80^uC under N₂ until no further conversion was observed. Water was added, then it was extracted with EtOAc. The combined organic layers were dried over

Na₂SO4, fïltered and concentrated under reduced pressure to obtain Préparation 4f. MS: (M+H)⁺ = 643.0.

Préparation 4g; Ethyl (2/f)-2-[5-l>romo-6-(5-chloro-2-furyl)thieno[2,3-rf]pyriniidin-4yIJoxy-3-(2-[[(25)-tetrahydrofiiran-2-yl]niethoxy]phenyl]propanoate

0.315 g 5-bromo-4-chloro-6-(5-chloro-2-furyl)thieno[2,3-(/|pyrimidine (Préparation 2d) (0.90 mmol), 0.267 g ethyl (2R)-2-hydroxy-3-[2-[[(2S)-tetrahydrofuran-225 yljmethoxyjphenyljpropanoate (Préparation 3af) (0.90 mmol) and 0.977 g Cs₂COj (3.00 mmol) were placed in a 25 mL flask. 5 mL /er/-butanol was added and the mixture was stirred at 65°C under N₂ until no further conversion was observed. Water was added, the pH was set to 8 with 2 M HCl, then it was extracted with DCM, The combined organic layers were dried over Na₂SO4, fïltered, concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4g. MS: (M+H)⁺ = 607.0.

-40Préparation 4h: Ethyl (2J?)-2-[5-brüm«-6-(4-fluoro-3-methoxy-phenyl)thieno[2,3rf|pyriinidin-4-yI]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate

24.00 g 5-bromo-4-chloro-6-(4-fluoiO-3-rnethoxy-phenyl)thieno[2,3-iZ]pyrimidme (Préparation 2e) (64.0 mmol), 22.69 g ethyl (2Æ)-2-hydroxy-3-(2-tetrahydiOpyran-2yloxyphenyl)propanoate (Préparation 3ab) (77.0 mmol) and 62.8 g CS2CO3 (63.0 mmol) were placed in a 250 mL flask. 150 mL feH-butanol was added and the mixture was stirred at 70°C under N?_ until no further conversion was observed Water was added, then it was extracted with DCM. The combined organic layers were dried over Na₂SO4, filtered, concentrated and purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4h as a mixture of diastereoisomers. MS: (M+H)⁺ = 631.0.

Préparation 4i: Methyl (21?)-2-(6-ethyl-5-iodo-thîeno [2,3-d]pyiïniidin-4-yl)oxy-3phenyl-propanoate

5.00 g 4-chlorO“6-ethyl-5-iodo-thieno[2₁3-i/]pyrimidine (Préparation ld) (15.4 mmol), 3.47 g methyl (2Æ)-2-hydiOxy-3-phenyl-propanoate (Préparation 3ag) (19.3 mmol) and 6.28 g Cs₂CO₃ (19.3 mmol) were placed in a 50 mL flask. 15 mL DMSO was added and the mixture was stirred at 60°C under N₂ until no further conversion was observed. The reaction mixture was poured onto ice, the pH was adjusted to 4 with 2M HCl and the mixture was extracted with DCM. The combined organic layers were dried over MgSOi, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4L ’H NMR (400 MHz, CDC1₃): 8.48 (s, 1H), 7.42 (d, 2H), 7.30 (t, 2H), 7.23 (m, 1H), 5.75 (dd, 1H), 3.73 (s, 3H), 3.44-3.40 (m, 2H), 2.93 (q, 2H), 1.33 (t, 3H).

Préparation 4i: Ethyl (ZT/l-l-iô-ethyl-S-iodo-thieno[2,3-(/]pyrimidin-4-yI)oxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate

3.25 g 4-chloro-6-ethyl-5-iodo-thieno[2,3-i/]pyrirnïdine (Préparation Id) (10.0 mmol), 3.24 g ethyl (2Æ)-2-hydroxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 3ab) (11.0 mmol) and 9.77 g Cs₂CO₃ (30.0 mmol) were placed in a 100 mL flask. 50 mL fe/7-butanol was added and the mixture was stirred at 70°C under N₂ until no further conversion was observed. Brine was added, then it was extracted with DCM. The combined organic layers were dried over Na₂SCU, filtered and concentrated under reduced

-41pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4j as a mixture of diastereoisomers. MS: (M+H)¹= 583.0.

Préparation 4k: Ethyl (2Æ)-2-(5-iodo-6-prop“l-ynyl-thieno[2,3-r/Jpyrimidin-4-yl)oxy3-(2-methoxyphenyI)propanoate

0.669 g 4-chloiO-5-iodo-6-prop-l-ynyl-thieno[2,3-i(|pyrimidine (Préparation 2f) (2.00 mmol), 0.673 g ethyl (2/?)-2-hydroxy-3-(2-mcthoxyphenyl)propanoate (Préparation 3ad) (3.00 mmol) and 1.955 g CS2CO3 (6.00 mmol) were placed in a 25 mL flask. 10 mL tert· butanol was added and the mixture was stirred at 60°C under N2 until no further conversion was observed The reaction mixture was diluted with brine, and then it was extracted with DCM. The combined organic layers were dried over NaaSO.», filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4k. ’H NMR (400 MHz, CDCh): 8.52 (s, IH), 7.36 (dd, IH), 7.23 (dd, IH), 6.89-6.84 (m, 2H), 5.78 (dd, IH), 4.23-4.12 (m, 2H), 3.84 (s, 3H), 3.49 (dd, IH), 3.39 (dd, IH), 2.19 (s, 3H), 1.18 (t, 3H). MS: (M+H)⁺ = 523.0.

Préparation 41: Ethvl (2J?)-2-(5-iodo-6-prop-l-ynyl-thieno|23-d]pyrimidin-4-yl)oxy-3(2-tetrahydropyran-2-yloxyphenyl)propanoate

8.92 g 4-chlorO5-iodo-6-prop-l-ynyl-thieno[2,3-c/]pyrimidine (Préparation 2f) (26.7 mmol), 8.83 g ethyl (2Æ)-2-hydiOxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoale (Préparation 3ab) (30.0 mmol) and 29.3 g CS2CO3 (90.0 mmol) were placed in a 500 mL flask. 300 mL toV-butanol was added and the mixture was stirred at 65°C under N2 until no further conversion was observed. Brine was added, then it was extracted with DCM. The combined organic layers were dried over Na2SÛ4, filtered, concentrated under reduced pressure. The crade product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 41 as a mixture of diastereoisomers. MS: (M+H)⁺-593.0

Préparation 4m: 2-(6-Ethyl-5-iodo-thieno[2,3-rf]pyrimidin-4-yl)oxy-3-phenylpropanoic acid

17193 φ.

-42500 mg (2Æ)-2-hydroxy-3-phenyl-pi’opanoic acid (2.77 mmol) was dissolved in 3 mL dry DMF, then 133 mg sodium hydride (3.32 mmol, 60% in minerai oil) was added and it was stirred for 15 minutes at room température. It was added dropwise to a DMF solution (5 mL) of 650 mg 4-chloro-6-ethyl-5-iodo-thïeno[2,3-d]pyrimidine (Préparation Id) (2.00 mmol) and the mixture was stirred for l hour. Then 2,5 mL 10% NaOH solution was added and the réaction mixture was stirred for 30 minutes. It was diluted with water and washed with Et₂O. The aqueous phase was acidified and the yellow precipitate was filtered and dried to obtain Préparation 4m. 'H NMR (500 MHz, DMSO-dô): 13.29 (s, 1H), 8.57 (s, 1H), 7.51 (m, 2H), 7.29 (m, 2H), 7.21 (m, 1H), 5.62 (dd, 1H), 3.36 (dd, 1H), 3.29 (dd, 1H), 2.91 (q, 2H), 1.26 (t, 3H). HRMS calculated for C_I7H_1S1N₂O₃S: 453.9848, found: 454.9918 (M+H).

Préparation 4n: Ethyl (21î)-2-|5-bromo-6-(4-fluorophenyl)thieno[23-rf]pyriniidin-4yl]oxy-3-(2-methoxyphenyl)propanoate

687 mg 5-bromo-4-chloro-6-(4-fluorophenyl)thieno[2,3-iZ]pyrÎmidÎne (Préparation 2a) (2.00 mmol), 673 mg ethyl (2Æ)-2-hydroxy-3-(2-methoxyphenyl)propanoate (Préparation 3ad) (3.00 mmol) and 1.955 g Cs₂CO₃ (6.00 mmol) were placed in a 25 mL flask. 10 mL terr-butanol was added and the mixture was stirred at 60°C under N₂ until no further conversion was observed. The reaction mixture was diluted with brine, and then it was extracted with DCM. The combined organic layers were dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4n. MS: (M+H)⁺ = 531.0.

Préparation 4n: Ethyl (2/î)-2-[5-bromo-6-(3,4-difluorophenyl)thieno[2,3-rf]pyr^,imidin4-yl]oxy-3-(2-tetrahydropyran-2-yIoxyphenyl)propanoate

6.0 g 5-bromo-4-chloiO-6-(3,4-difluorophenyl)thieno[2,3-i/|pyrimidine (Préparation 2g) (16.59 mmol), 5.97 g ethyl (27?)-2-hydroxy-3-(2-tetialiydropyran-2yloxyphenyl)propanoate (Préparation 3ab) (18.25 mmol) and 18.93 g Cs₂CO3 (58.1 mmol) were placed in a 250 mL flask. 100 mL tert-butanol was added and the mixture was stirred at 60°C under N₂ until no further conversion was observed. Approximately 50 mL solvent was evaporated under reduced pressure, then it was diluted with water, the pH was fl·

-43 set to 8 with 2 M HCl, and then it was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure, The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4o as a mixture of diastereoisomers. *H NMR (400 MHz, DMSO-de):

8.69 (d, IH), 7.87 (m, IH), 7.67 (m, IH), 7.57 (m, IH), 7.44 (m, IH), 7.20 (m, IH), 7.07 (m, IH), 6.90 (t, IH), 5.82/5.70 (dd, IH), 5.62/5.56 (t, IH), 4.22-4.08 (m, 2H), 3.75/3.65 (td, IH), 3.61-3.45 (m, 2H), 3.20/3.16 (d, IH), 2.10-1.48 (m, 6H), 1.17/1.14 (t, 3H).

Préparation 4p; Ethyl (2/?)-2-[5-bromo-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-410 yl]oxy-3-[2-|[(2Æ)-tetrahydrofuran-2-yl]niethoxy]phenyl]propanoate

4.12 g 5-bromo-4-chloiO-6-(4-fluorophenyl)thieno[2,3-Jjpyrimidine (Préparation 2a) (12.0 mmol) and 3.80 g ethyl (2J?)-2-hydroxy-3-[2-[[(2/?)-tetrahydrofuran-2yljmethoxyjphenyljpropanoate (Préparation 3b|) (12.9 mmol) were dissolved in 30 mL rer/-butanol, then 13.03 g CS2CO3 (40.0 mmol) was added and the mixture was stirred at

65°C under N₂ until no further conversion was observed. Then it was poured onto icy water, the pH was set to 6 with 2 M HCl, and it was filtered and washed with water to obtain Préparation 4p. 'H NMR (400 MHz, DMSO-d₆): 8.67 (s, IH), 7.76 (m, 2H), 7.42 (m, 2H), 7.38 (dd, IH), 7.21 (dt, IH), 6.98 (d, IH), 6.86 (t, IH), 5.71 (dd, IH), 4.20-4.09 (m, 3H), 4.04-3.96 (m, 2H), 3.79-3.73 (m, IH), 3.69-3.64 (m, IH), 3.40 (dd, IH), 3.22 (dd,

IH), 2.04-1.78 (m, 4H), 1.12 (t, 3H).

Préparation 4q: Ethyl (2R)-2-(6-ethyl-5-iodo-thieno[2,3-d]pyrimidin-4-yl)oxy-3-(2methoxyphenyl)propanoate

2.809 g 4-chloro-6-ethyl-5-iodo-thieno[2,3-t/]pyrimidine (Préparation Id) (8.92 mmol), 25 1.00 g ethyl (2Æ)-2-hydroxy-3-(2-methoxyphenyl)propanoate (Préparation 3ad) (4.46 mmol) and 1.598 g CS2CO3 (4.91 mmol) were dissolved in 5 mL dry DMSO and heated at 60°C until no further conversion was observed. Then it was diluted with water, the pH was set to 7 with 2 M HCl, and then it was extracted with DCM. The combined organic layers were dried over Na₂SO4, filtered and concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4q. MS: (M+H)⁺ = 513.0. '

-44Préparation 4r: Ethyl (25)-2-(6-ethyl-5-iodo-thieno[23-rflpyrimidin-4-yl)oxy-3(2methoxyphenyl)propanoate

2.809 g 4-chtoro-6-ethyl-5-iodo-thieno[2,3-iZ]pyrimidine (Préparation ld) (8.92 mmol), l.OO g ethyl (2S)-2-hydroxy-3-(2-methoxyphenyl)propanoate (Préparation 3bi) (4.46 mmol) and 1.598 g CS2CO3 (4.91 mmol) were dissolved in 5 mL dry DMSO and heated at 60°C until no further conversion was observed. Then it was diluted with water, the pH was set to 7 with 2 M HCl, and then it was extracted with DCM. The combined organic layers were dried over Na2SC>4, fîltered and concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4r. MS: (M+H)⁺= 513.0.

Préparation 4s: Ethyl (2^)-2-[5-bromo-6-(4-fluorophenyI)thieno[23-d]pyrimi<lin-4ylJoxy-3-[2-(2,2,2-trifluoroethoxy)phenyl]propanoate

5.39 g 5-biOmo-4“Chloro-6-(4-fluoiOphenyl)thieno[2,3-d]pyrimidine (Préparation 2a) (15.7 mmol) and 5.50 g ethyl (2R)-2-hydroxy-3-[2-(2,2,2trifluoroethoxy)phenyl]propanoate (Préparation 3bl) (I8.8 mmol) were dissolved in 60 mL feri-butanol, then 15.32 g CS2CO3 (47.0 mmol) was added and the mixture was stirred at 60°C under N2 until no further conversion was observed. Then it was poured onto icy water, the pH was set to 6 with 2 M HCl, and it was fîltered, washed with water to obtain Préparation 4s. 'H NMR (400 MHz, CDCl₃): 8.53 (s, IH), 7.64 (m, 2H), 7.43 (d, IH), 7.27-7.16 (m, 3H), 6.97 (t, IH), 6.82 (d, IH), 5.75 (dd, III), 4.45-4.38 (m, 211), 4.22 (q, 2H), 3.55 (dd, IH), 3.33 (dd, IH), 1.24 (t, 3H).

Préparation 5a: 2-Chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3_s2-dioxaborolan-2yl)phenol

Step A: (4-Bromo-2-chloro-phenoxy)-trimethyl-silane

20.8 g 4-bromo-2-chloro-phenol (100 mmol) was dissolved in 150 mL dry THF then 24.2 g HMDS (150 mmol) was added. The reaction mixture was stirred at 85°C under argon atmosphère for 1.5 hours then concentrated under reduced pressure resulting in the product used without further purification. 'HNMR (200 MHz, CDCI3): 7.49 (d, IH), 7.23 (dd, IH), 6.75 (d, IH), 0.26 (s, 9H).

Step B: 4-Bromo-2-cMoi'o-3-inethyl-phenol mL BuLi solution in hexanes (2.5 M, 120 mmol) was added dropwise to a solution of

I2.l g dry DIP A (120 mmol) in 250 mL dry THF at -78°C under argon atmosphère. The mixture was stirred for 30 minutes at the same température then 28.0 g (4-bïomo-2-chlorophenoxy)-trimethyl-silane (100 mmol) was added dropwise. After 2.5 hours 21.3 g Mel (150 mmol) was added dropwise then the cooling bath was removed and the mixture was stirred ovemight. The reaction was quenched with 100 mL NH4OH solution and 200 mL NH4CI solution and extracted with EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting dark mass was refluxed with pure hexane several times (150-150 mL aliquots) and decanted leaving a black tar behind. Combined organic phases were concentrated under reduced pressure affording 19.0 g crude product used without further purification. ’H NMR (200 MHz, CDCI3): 7.32 (d, IH), 6.76 (d, IH), 5.62 (s, IH), 2.49 (s, 3H).

Step C: (4-Bromo-2-chloro-3-methyl-phenoxy)-trimethyl-silane

20.8 g HMDS (129 mmol) was added to the solution of 19.0 g 4-bromo-2-chloro-3-methylphenol (86.0 mmol) in 150 mL dry THF. The mixture was stirred at 85°C under argon balloon for 1.5 hours and then concentrated under reduced pressure. The obtained product was used without further purification. ’H NMR (200 MHz, CDCR): 7.30 (d, IH), 6.63 (d, IH), 2.50 (s, 3H), 0.28 (s, 9H).

Step D: 2-Chloro-3-melkyl-4-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolari-2-yl)phenol

A solution of 25.2 g (4-bromo-2-chloro-3-methyl-phenoxy)-trimethyl-silane (86,0 mmol) in 250 mL dry THF was cooled to -78°C under argon and then 38 mL ⁿBuLi in hexanes (2.5 M, 94.6 mmol) was added dropwise. After 5 minutes 19.2 g 2-isopropoxy-4,4,5,5tetramethyl-l,3,2-dioxaborolane (103 mmol) was added dropwise. The cooling bath was removed and the mixture was slowly allowed to warm up to room température. Then the mixture was added to 200 mL NH4CI solution and extracted with EtOAc. Combined organic layers were concentrated under reduced pressure and passed through a pad of silica gel using hexane and EtOAc as eluents. The crude product was recrystallized from a

-46mixture of EtOAc and liexane to obtain Préparation 5a. ’H NMR (500 MHz, DMSO-dô): 10.40 (s, ÎH), 7.42 (d, ÎH), 6.80 (d, IH), 2.49 (s, 3H), 1.27 (s, 12H).

Préparation 5b: l-[2-[2-Chloro-3-niethyl-4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-25 y])phenoxy]ethyl]-4-methyl-piperazine

10.0 g 2-chloro-3'inethyl-4-(4,4,5,5-tetrainethyl-l ,3,2-dioxaboiOlan-2-yl)phenol (Préparation 5a) (37.2 mmol), 8.7 g 2-(4-methylpiperazin-l-yl)ethanol (60.3 mmol) and

15.8 g PPh₃ (60.3 mmol) were dissolved in 100 mL dry toluene and then 27 mL diethyl azodicarboxylate (60.3 mmol, 40% solution in toluene) was added dropwise. The mixture was stirred at 50°C under argon for 1.5 hours. The volatiles were evaporated under reduced pressure and 100 mL Et₂O was added. The precipitated white crystals were fîltered off and washed with Et₂O. The filtrate was concentrated under reduced pressure and purified via flash chromatography using CHC1₃ and MeOH as eluents. The resulting light brown oil was crystallized from hexane to give Préparation 5b as an off-white solid. *H NMR (500

MHz, DMSO-cL): 7.56 (d, 1H), 6.99 (d, 1H), 4.15 (t, 2H), 2.72 (t, 2H), 2.51 (s, 3H), 2.50 (br s, 4H), 2.29 (br s, 4H), 2.13 (s, 3H), 1.29 (s, 12H).

Préparation 5c: [2-Chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dÎoxaborolan-2yl)phenoxy]-tr iisopropyl-silan e

Step A: (4-Bromo-2-chloro-phenüxy)-ti'iisopropylsilane

200 g 4-broino-2-chloiO-phenol (0.97 mol) and 126 mL TIPSC1 (1.18 mol) were dissolved in 1.6 L DCM. 167 g imidazole (2.45 mol) was added and the mixture was stirred at room température for 2 hours. The volatiles were evaporated under reduced pressure and the 25 residue was dissolved in 1.5 L EtOAc. The mixture was washed with brine, dried over

Na₂SO4, fîltered and concentrated under reduced pressure. The triisopi-opylsilyl hydroxide impurity was removed by distillation (120°C at 0.01 mmHg). The residue was fîltered through a short pad of silica with hexane and concentrated under reduced pressure. The product (colourless oil) was used in the next step without further purification. *H NMR 30 (400 MHz, CDCb): 7.49 (d, 1H), 7.21 (dd, 1H), 6.78 (d, 1H), 1.31 (septet, 3H), 1.14 (d,

18H). MS (El, 70 eV) m/z (% relative intensity, [ion]): 63 (30), 79 (24), 93 (41), 170 (17), 235 (19), 251 (16), 265 (24), 293 (23), 319 (77), 321 (100), 323 (28), 362 (1, [M⁺]).

-47Step B: (4-Broino-2-chloro-3-methyl-phenoxy)driisopropyl-silane

76.0 mL dry DIPA (0.54 mol) was dissolved in 1.2 L dry THF under argon atmosphère and

51,2 mL BuLi solution (10 M in hexanes, 0.512 mol) was added dropwise at -78°C. The 5 mixture was stirred for 45 minutes at the same température. 178 g (4-bromo-2-chlorophenoxy)-triisopropyl-silane (0.488 mol) was added dropwise at -78°C and the white suspension was stirred for 8 hours. 36.5 mL Mel (0.586 mmol) was added at this température and the reaction mixture was stirred ovemight without further cooling. The volatiles were evaporated under reduced pressure. The residue was dissolved in 1.5 L 10 EtOAc, washed with brine, dried over I^SO^ filtered and concentrated under reduced pressure. The crude product was filtered through a short pad of silica using hexane as eluent and concentrated under reduced pressure to obtain the product as pale yellow oil. ’H NMR (400 MHz, CDC1₃): 7.30 (d, IH), 6.68 (d, IH), 2.53 (s, 3H), 1.32 (septet, 3H), 1.14 (d, 18H).

Step C: [2-Chloro-3-methyl-4-(4,4,5,5-tetramethyl~l,3,2-dioxaborolan-2-yl)phenoxy]triisopropyl-silane

178 g (4-bromo-2-chloiO-3-methyl-phenoxy)-triisopropyl-silane (0.472 mol) was dissolved in 1.4 L dry THF under argon atmosphère and 52 mL BuLi solution (10 M in hexanes, 20 0.52 mol) was added dropwise at -78°C. The mixture was stirred for 5 minutes at this température. Then 116 mL 2-isopiOpoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.569 mol) was added and the mixture was allowed to warm up to room température. The volatiles were evaporated under reduced pressure. The residue was dissolved in 1.5 L EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated under reduced 25 pressure. The 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane impurity was removed by distillation (80°C at 0.01 mrnHg), The crude product was triturated in MeOH affording Préparation 5c as a white solid. ’H NMR (400 MHz, CDCI3): 7.53 (d, IH), 6.74 (d, IH), 2.60 (s, 3H), 1.34 (s, 12H), 1.32 (m, 3H), 1.12 (d, 18H).

Préparation 5d: 2-(3-ChIoro-4-methoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-l,3,2dioxaborolane

-485.371 g 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (20.0 mmol) and 15.74 g PPI13 (60.0 mmol) were dissolved in 50 mL dry MeOH under N₂, then 13.82 g di/er/butyl azodicarboxylate (60.0 mmol) was added and the mixture was stirred at 50°C for 2 hours. Then it was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 5d. *H NMR (400 MHz, DMSO-d₆): 7.59 (d, 1H), 6.98 (d, 1H), 3.85 (s, 3H), 2.52 (s, 3H), 1.29 (s, 12H). MS (El, 70 eV) m/z (% relative intensity, [ion]): 77 (21), 82 (100), 225 (29), 267 (18), 282 (32, [M]⁺), 284 (11, [M]⁺).

Préparation 5e: [2-Chloro-3-ethyl-4-(4,4,5,5-tetramethyl-l,3^-dioxaborolan-2y l)phenoxy] -triisopropyl-silane

Step A; (4-Bromo~2-chlorû-3-ethyl-phenuxy)-lriisopropyl-silane

7.07 g (4-bromo-2-chloro-phenoxy)-triisopropyl-silane (19.4 mmol, see Step A at Préparation 5c) was dissolved in 60 mL dry THF under N₂ and was cooled to -78°C with dry ice-acetone. 11.7 mL LDA (23.3 mmol in 2 M THF, EtPh) was added and the mixture was stirred for 1 hour. Then 4.23 g ethyl iodide (38.9 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with saturated NH4CI solution, extracted with EtOAc, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane as eluent to obtain a mixture of product and starting material. They were separated via reversed phase chromatography using pure MeCN as eluent. MS (El, 70 eV) m/z (% relative intensity, [ion]): 63 (15), 93 (65), 121 (26), 161 (15), 183 (13), 263 (10), 279 (14), 347 (71), 349 (100), 351 (28), 390 (1, [M⁺]), 392 (1, [M⁺]).

Step B: [2-Chloi'o-3-elhyl~4-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)phenoxy]~ triisopropyl-silane

1.08 g (4-biOmo-2-chloiO-3-ethyl-phenoxy)-tiiisopropyl-silane (2.76 mmol) was dissolved in 20 mL dry THF under N₂ and was cooled to -78°C with dry ice-acetone. 1.9 mL BuLi (3.03 mmol in 1.6 M hexanes) was added and the mixture was stirred for 5 minutes, then 1.02 mL 2-isopropoxy-4,4,5,5“tetramethyl-l,3,2-dioxaborolane (4.00 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with

-49saturated NH4CI solution, extracted with EtOAc, dried over Na2SÜ4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 5e. MS (El, 70 eV) m/z (% relative intensity, [ion]): 55 (25), 83 (100), 93 (50), 225 (14), 295 (9), 395 (67), 397 (26).

Préparation 5f; l-|2-[2-Chloro-3-fluoro-4-(4,4,5,5-tetramethyl4,3,2-dioxaborolan-2yl)phenoxy] ethyl] -4-methy 1-piperazine

Step A: l-[2-(4-Bromo-3-fliioro-phenoxy)ethyl]-4-melhyl-piperazine

1.91 g 4-bromo-3-fluoro-phenol (10.0 mmol), 1.73 g 2-(4-methylpiperazin-l-yl)ethanol (12.0 mmol) and 5.00 g immobilized PPI13 (15.0 mmol) were dissolved in 30 mL dry toluene under N?., then 2.99 g diter/bulyl azodicarboxylate (13.0 mmol) was added and the mixture was stirred at 50°C for 6 hours. Then it was filtered, the filtrate was concentrated 15 under reduced pressure and purified via flash chromatography using EtOAc and MeOH as eluents to obtain l-[2-(4-bromo-3-fluoro-phenoxy)ethyl]-4-inethyl-piperazine. MS (M+H): 317.2.

Step B: l-[2-(4-Bromo-2~chloro~3-fluoro-phenoxy)ethyl]-4-methyl-piperazine

2.35 g l-[2-(4-bromo-3-fluoro-phenoxy)ethyl]-4-methyl-piperazine (7.41 mmol) was dissolved in 40 mL dry THF under N2 and was cooled to -78°C with dry ice-acetone. 7.2 mL LDA (14.4 mmol in 2 M THF, EtPh) was added and the mixture was stirred for 1 hour, then 2.10 g 1,1,1,2,2,2-hexachloroethane (8.89 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with brine, extracted with

DCM, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using EtOAc and MeOH as eluents to obtain l-[2-(4-biOmo-2-chloro-3-fluoro-phenoxy)ethyl]-4-methyl-piperazine. MS (M+H): 351.0.

Step______C: l-l2-[2-Chloro-3-jluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenoxy]ethyl]-4-methyl-piperazine

-501.94 g l-[2-(4-bromo-2-chloiO-3-fluoiO-phenoxy)ethyl]-4-methyl-piperazine (5.50 mmol) was dissolved in 25 ml, dry THF under N₂ and was cooled to -78°C with dry ice-acetone.

4.2 mL BuLi (6.60 mmol in 1.6 M hexanes) was added and the mixture was stirred for 5 minutes, then 2.04 mL 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (10.0 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with brine, extracted with DCM, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using EtOAc and MeOH as eluents to obtain Préparation 5f. MS (M+H): 399.2.

Préparation 5g; 2-Fiuoro-3-methyl-4-(4,4,5,5-teiramethyI-l,3,2-dioxaborolan-2yl)phenoi

Step A: (4-Bromo-2-fluoro-phenoxy)-triisopropyl-silane

3.82 g 4-bromo-2-fluoro-phenol (20.0 mmol) was dissolved in 50 mL DCM, then 5.14 mL TIPSC1 (24.0 mmol) and 2.72 g imidazole (40.0 mmol) was added and the mixture was stirred at room température for 1 hour. Then it was concentrated under reduced pressure and purified via flash chromatography using heptane as eluent to obtain (4-bromo-2fluoro-phenoxy)-triisopropyl-silane. MS (El, 70 eV) m/z (% relative intensity, [ion]): 63 (35), 77 (100), 105 (44), 153 (43), 182 (25), 233 (75), 235 (75), 261 (9), 263 (9), 303 (17), 305 (17), 346 (3, [M*]), 348 (3, [M*]).

Step B: (4-Bromo-2-fluoro-3-methyl-phenoxy)-ti'iisopropyl-silane

6.50 g (4-bromo-2-fluoro-phenoxy)-1riisopropyl-silane (18.7 mmol) was dissolved in 60 mL dry THF under N₂ and was cooled to -78°C with dry ice-acetone. 11.2 mL LDA was added (22.5 mmol in 2 M THF, EtPh) and the mixture was stirred for 1 hour, then 2.3 mL Mel (37.4 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with saturated NH4CI solution, extracted with EtOAc, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane as eluent to obtain (4-bromo-2-fluoiO-3-methyl-phenoxy)triisopropyl-silane. MS (El, 70 eV) m/z (% relative intensity, [ion]): 63 (21), 77 (100), 61 (105), 167 (52), 196 (43), 247 (60), 249 (59), 275 (25), 277 (25), 317 (14), 319 (14), 360 (5,[M⁺J), 362(5, [M⁴]).

-51Step C: l2-b'luoro-3-methyl-4-(4,4,5, S-tetramethyl-l, 3,2-dioxaborolcm-2-yl)phenoxy]triisopropyl-sïlane

6.61 g (4-bromo-2-fluoro-3-methyl-phenoxy)-triisopropyl-silane (18.3 mmol) was dissolved in 80 mL dry THF under N₂ and was cooled to -78°C with dry ice-acetone. 13.8 mL BuLi (22.0 mmol in 1.6 M hexanes) was added and the mixture was stirred for 10 minutes, then 5,6 mL 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaboiOlane (27.4 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with saturated NH4CI solution, extracted with Et₂O, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain [2-fluoro-3-methyl-4(4,4,5,5-tetramethyl-l,3,2-dioxaboiOlan-2-yl)phenoxy]-triisopiOpyl-silane. MS (El, 70 eV) m/z (% relative intensity, [ion]): 77 (39), 83 (100), 195 (26), 223 (20), 241 (10), 323 (4), 365 (4).

Step D: 2-Fluoro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

6.00 g [2-fluoro-3-methyI-4~(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenoxy]triisopropyl-silane (14.7 mmol) was dissolved in 20 mL THF, then 16.2 mL TBAF (16.2 mmol in 1 M THF) was added and the mixture was stirred for 10 minutes. Then it was diluted with EtOAc and Et₂O, washed with water and brine, dried over Na₂SO<i, filtered and concentrated under reduced pressure. The crade product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 5g. '11 NMR (400 MHz, DMSO-de): 10.09 (s, 1H), 7.27 (dd, 1H), 6.75 (t, 1H), 2.36 (d, 3H), 1.27 (s, 12H). MS (Ef, 70 eV) m/z (% relative intensity, [ion]): 152 (100), 166 (18), 195 (21), 237 (18), 252(19, [M⁺]).

Préparation 5h: l-Methyl-4-[2-[4-methyl-3-(4,4,5,5-tetraniethyH,3,2-dioxaborolan-2y l)phenoxy ] ethy I Jpiperazine

Step A: 1 -[2-(3-Bromo-4-melhyl-phenoxy)ethyl]-4-methyl-pîperazine

0.50 g 3-bromo-4-methyl-phenol (2.67 mmol), 0.46 g 2-(4-methylpiperazin-l-yl)ethanol (3.21 mmol) and 0.84 g PPI13 (3.21 mmol) was dissolved in 10 mL dry THF under N₂, then

-521.47 mL diethyl azodicarboxylate (3.21 mmol, 40% in toluene) was added and the mixture was stirred at room température for 2 hours. Then it was concentrated under reduced pressure and purified via reversed phase chromatography using aqueous 0.1% TFA solution and MeCN as eluents to obtain l-[2-(3-bromo-4-methyl-phenoxy)ethyl]-4-methyl5 piperazine. MS (M+H): 313.1.

Step______B: 1 -Methyl-4-[2-[4-methyl-3-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2ytyphenoxy] ethyl]piperazine

1.70 g l-[2-(3-bromo-4-methyl-phenoxy)ethyl]-4-methyI-piperazine (5.43 mmol), 1.52 g 10 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-l ,3,2-dioxaborolane (5.97 mmol), 395 mg PdCl₂ x dppf (0.54 mmol) and 1.60 g ICOAc (16.3 mmol) were dissolved in 20 mL dry DMF under N₂. The mixture was stirred at 85°C for 5 hours, then it was filtered through celite, diluted with Et₂O, washed with water, dried over Na₂SC>4, filtered and concentrated under reduced pressure. Then heptane was added, the solid 15 impurities were filtered and the fïltrate was concentrated under reduced pressure. The crade product was used as Préparation 5h without further purification. MS (M+H): 361.2.

Préparation______Si; 2-(3-Chloro-5-fluoro-4-methoxy-2-methyI-phenyi)-4,4,5,5tetramethyl-1,3,2-dioxaborolane

Step A: l-Bromo-3-chloro-5-fluoro-4-methoxy-2-methyl-benzene

13.01 g 3-chloro-l-fluoro-2-methoxy-4-methyl-benzene (74.5 mmol) was dissolved in 200 mL AcOH, then 4.1 mL bromine (80.0 mmol) was added and the mixture was stirred at room température. Additional 6 mL bromine needed to reach complété conversion. Then 25 the mixture was poured onto icy water, the pH was carefully set to 8 with solid KOH and

K.₂CO₃, then saturated Na₂S₂O₃ solution was added untii the brown color of bromine disappeared. Then it was extracted with Et₂O. The combined organics were washed with water, then brine, then dried over Na₂SO4, filtered and concentrated under reduced pressure to give l-bromo-3-chloro-5-fluorO“4-methoxy-2-methyI-benzene. ’H NMR (400 30 MHz, CDCh): 7.29 (d, 1I-I), 3.95 (d, 3H), 2.47 (d, 3H). MS (El, 70 eV) m/z (% relative intensity, [ion]): 75 (26), 95 (42), 107 (25), 130 (96), 132 (35), 237 (57), 239 (74), 252 (77, [M*]), 254 (100, [M⁴]), 256 (23, [M]).

-53Step B: 2-(3-Chloro-5-fluoro-4-methoxy-2-methyl-phenyl)-4,4,5,5-teiramethyl-l,3,2dioxaborolane

761 mg l-bromo-3-chloro-5-fluoro-4-methoxy-2-methyl-benzene (3.0 mmol) was dissolved in 15 mL dry THF under N₂ and was cooled to -78°C w'ith dry ice-acetone. 2.1 mL BuLi (3.3 mmol in 1.6 M hexanes) was added and the mixture was stirred for 10 minutes, then 0.69 mL 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dïoxaborolane (3.4 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with saturated NH4CI solution, extracted with DCM, dried over Na2SO₄, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 5i. MS (El, 70 eV) m/z (% relative intensity, [ion]): 200 (100), 201 (57), 243 (52), 285 (26), 300 (35, [M⁴]), 302 (11, [M⁴]).

Préparation 5i: l-[3-Chloro-2-methoxy-4-inethyl-5-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)phenyl]-4-methyl-piperazine

Step A: l-(5-Bromo-3-chloro-2-methoxy-4-methyl-phenyl)-4-methyl-piperazme

1.27 g l-bromo-3-chloiO-5-fluoro-4-methoxy-2-methyl-benzene (5.00 mmol, see Step A at Préparation 5i) was dissolved in 15 mL dry THF under N₂ and was cooled to -78°C with dry ice-acetone. Separately 0.58 mL 1-methylpiperazine (5.25 mmol) was dissolved also in 15 mL dry THF under N2 and was cooled to 0°C with icy water. Then 3.3 mL ⁿBuLi (5.25 mmol in 1.6 M hexanes) was added and the mixture was stirred for 10 minutes, then it was cooled to -78°C with dry ice-acetone. This latter mixture was transferred to the THF solution of l-bromo-3-chloro-5-fluoro-4-methoxy-2-methyl-benzene and the mixture was allowed to warm up to room température. Water and brine were added and the mixture was extracted with DCM, dried over Na2SO₄, filtered and concentrated under reduced pressure. The crude product was purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. MS (M+H): 333.0.

Step B: 1 -[3-Chloro-2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolcm-2yl)phenyl]-4-methyl-piperazine ♦

-54334 mg l-(5-bromo-3-chloro-2-methoxy-4-methyl-phenyl)-4-methyl-piperazine (1.00 mmol) was dissolved in 10 mL dry THF under N2 and was cooled to -78^UC with dry iceacetone. 0.66 mL BuLi (1.05 mmol in 1.6 M hexanes) was added and the mixture was stirred for 15 minutes, then 0.25 mL 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.20 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with brine, extracted with DCM, dried over Na2SO4, fîltered and concentrated under reduced pressure and used as Préparation 5j without further purification. MS (M+H): 381.2.

Préparation 5k: 2-CliIoro-6-methoxy-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)phenol

Step A: 4-Bromo~2-methoxy-5-methyl-phenol

1.38 g 2-methoxy-5-methyl-phenol (10.0 mmol) was dissolved in 20 mL THF, then 1.87 g NBS (10.5 mmol) was added and the mixture was stirred at room température for 2 hours. Then it was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain 4-bromo-2-methoxy-5-methyl-phenol. ^!H NMR (400 MHz, CDCI3): 7.00 (s, 1H), 6.82 (s, IH), 5.46 (s, IH), 3.87 (s, 3H), 2.30 (s, 3H). MS (El, 70 eV) m/z (% relative intensity, [ion]): 51 (44), 65 (40), 94 (88), 137 (22), 173 (29), 175 (30), 201 (83), 203 (78), 216 (100, [M⁴]), 218 (96, [M⁺]).

Step B: 4-Bromo-2-chloro-6-methoxy-3-methyl-phenol

1.09 g 4-bromo-2-methoxy-5-methyl-phenol (5.00 mmol) was dissolved in 20 mL THF, then 701 mg NCS (5.25 mmol) was added and the mixture was stirred at room température for 1 day. Then it was concentrated under reduced pressure and purified via reversed phase chromatography using aqueous 0.1% TFA solution and MeCN as eluents to obtain 4bromo-2-chloro-6-methoxy-3-methyl-phenol. ^]H NMR (400 MHz, CDCI3): 6.98 (s, IH), 5.81 (s, IH), 3.88 (s, 3H), 2.43 (s, 3H). MS (El, 70 eV) m/z (% relative intensity, [ion]): 63 (37), 128 (53), 171 (42), 209 (26), 237 (67), 250 (77, [M⁴]), 252 (100, [M⁴]), 254 (24, [M⁴]).

Step C: (4-Bromo-2-chloro-6-methoxy-3-methyl-pherioxy)-triisopropyl-silarie

-55772 mg 4-bromo-2-chloro-6-methoxy-3-methyl-phenol (3.07 mmol) and 788 pL TIPSCl (3.68 mmol) were dissolved in 10 mL DCM. 418 mg imidazole (6.14 mmol) was added and the mixture was stirred at room température ovemight. Then it was concentrated under reduced pressure and purified via flash chromatography using heptane as eluent to obtain (4-bromo-2-chloro-6-methoxy-3-methyl-phenoxy)-triisopropyl-silane. ’H NMR (400 MHz, CDCJj): 6.95 (s, IH), 3.77 (s, 3H), 2.44 (s, 3H), 1.30 (scptct, 3I-I), 1.10 (d, 18H). MS (El, 70 eV) m/z (% relative intensity, [ion]); 59 (19), 183 (15), 279 (27), 308 (13), 348 (76), 350 (100), 352 (28), 363 (66), 365 (89), 367 (24).

Step D: [2-Chloro-6-methoxy-3-melhyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenoxy]-triisopropyl-silane

3.07 mmol (4-bromo-2-chloro-6-methoxy-3-methyl-phenoxy)-triisopropyl-silane was dissolved in 20 mL dry THF under N2 and was cooled to -78°C with dry ice-acetone. 2.1 mL ⁿBuLi (3.40 mmol in 1.6 M hexanes) was added and the mixture was stirred for 5 minutes, then 820 pL 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (4.00 mmol, dissolved in 5 mL dry THF) was added and the mixture was allowed to warm up to room température. It was quenched with saturated NH4CI solution, extracted with EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain [2-chloro6-methoxy-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]triisopropyl-silane. MS (El, 70 eV) m/z (% relative intensity, [ion]): 225 (14), 254 (10), 296 (13), 396 (67), 398 (26), 411 (100), 413 (39).

Step E: 2-C.hloro-6-methoxy-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2ytyphenol

3.07 mmol [2-chloro-6-methoxy-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenoxy]-triisopropyl-silane was dissolved in 5 mL THF, then 3.5 mL TBAF (3.50 mmol in 1 M THF) was added and the mixture was stirred for 10 minutes. Then it was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 5k. ^lH NMR (400 MHz, DMSO-dfi): 9.71 (s, IH), 7.09 (s, IH), 3.79 (s, 3H), 2.44 (s, 3H), 1.28 (s, 12H).

e

-56MS (El, 70 eV) m/z (% relative intensity, [ion]): 183 (23), 198 (100), 199 (52), 223 (13), 241 (9), 283 (6), 298 (51, [M¹]), 300 (17, [M¹]).

Préparation 51: 2-Chloro-3,6-dimethyl-4-(4,4,5,5-tetrainethyM,3,2-dioxaborolan-25 yl)phenol

Step A: (4-Bromo-2-chloro-6-methyl-phenoxy)-lriisopropyl-silane

5.00 g 4-bromo-2-chloro-6-methyl-phenol (22.6 mmol) and 5.80 mL TIPSC1 (27.1 mmol) were dissolved in 50 mL DCM. 3.07 g imidazole (45.1 mmol) was added and the mixture was stirred at room température ovemight. Then it was concentrated under reduced pressure and purified via flash chromatography using heptane as eluent to obtain (4-bromo2-chloro-6-methyl-phenoxy)-triisopropyl-siIane. *H NMR (400 MHz, CDCI3): 7.31 (s,

IH), 7.15 (s, IH), 2.62 (s, 3H), 1.39 (septet, 3H), 1.13 (d, 18H). MS (El, 70 eV) m/z (% relative intensity, [ion]): 93 (33), 183 (30), 307 (14), 333 (87), 335 (100), 337 (30).

StepB; (4-Bromo-2-chloro-3,6-dimeihyl-phenoxy)-lriisopropyl-silane

6.70 g (4-bromo-2-chloro-6-methyl-phenoxy)-triisopropyl-silane (17.7 mmol) was dissolved in 80 mL dry THF under N₂ and was cooled to -78°C with dry ice-acetone. 10.6 mL LD A was added (21.2 mmol in 2 M THF, EtPh) and the mixture was stirred for 1 hour, 20 then 2.2 mL Mel (35.4 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with saturated NH4CI solution, extracted with Et₂O, dried over Na₂SO4, fïltered and concentrated under reduced pressure. The crade product was purified via flash chromatography using heptane as eluent. The unreacted starting material was separated via reversed phase chromatography using MeCN as eluent to obtain (425 biOmo-2-chloro-3,6-dimethyl-phenoxy)-triisopropyl-silane. 'H NMR (400 MHz, CDCI3):

7.23 (s, IH), 2.47 (s, 3H), 2.24 (s, 3H), 1.40 (septet, 3H), 1.13 (d, 18H). MS (El, 70 eV) m/z (% relative intensity, [ion]): 93 (23), 146 (17), 197 (26), 347 (76), 349 (100), 351 (27).

Step C: [2-Chloro-3,6-dimethyl-4-(4,4,5,5-tetfamethyl-i,3,2-dioxahorolan-2-yl)phenoxy]30 triisopropyl-silane

1.18 g (4-bromo-2-chloiO-3,6-dimethyl-phenoxy)-triisopiOpyl-silane (3.00 mmol) was dissolved in 15 mL dry THF under N₂ and was cooled to -78°C with dry ice-acetone. 2.25 mL ⁿBuLi (3.60 mmol in 1.6 M hexanes) was added and the mixture was stirred for 15 minutes, then 1.02 mL 2-isopiOpoxy-4,4,5,5-tetramethyl-l,3,2-dioxaboiOlane (5.00 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with saturated NH4CI solution, extracted with Et₂O, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain [2-chloro-3,6-dimethyl-4(4,4,5,5-tetramethyI-l,3,2-dioxaborolan-2-yl)phenoxy]-triisopiOpyl-silane. MS (El, 70 eV) m/z (% relative intensity, [ion]): 83 (100), 101 (30), 225 (14), 395 (54), 397 (21).

Step D: 2-Chloro-3,6-dimethyl-4-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)phenol

968 mg [2-chloro-3,6-dimethyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenoxy]triisopropyl-silane (2.20 mmol) was dissolved in 10 mL THF, then 2.4 mL TBAF (2,40 mmol in 1 M THF) was added and the mixture was stirred for 5 minutes. Then it was diluted with Et₂O and EtOAc, washed with water and brine, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 51. *H NMR (400 MHz, CDClj): 7.48 (s, IH), 5.89 (s, IH), 2.58 (s, 3H), 2.26 (s, 3H), 1.35 (s, 12H). MS (El, 70 eV) m/z (% relative intensity, [ion]): 91 (14), 147 (22), 182 (100), 183 (61), 225 (43), 267 (14), 282 (26, [M⁺]), 284 (9, [M¹]).

Préparation Sm: 2-Chloro-6-fluoro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)phenol

Step A: 4-Bromo-2-chloro-6~fluoro-3-methyl-phenol

3.21 g 2-chloro-6-fluoro-3-methyi-phénol (20.0 mmol) was dissolved in 60 mL THF, then 3.74 g NBS (21.0 mmol) was added and the mixture was stirred at room température for 10 minutes. Then it was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain 4-bromo-2-chloro-6-fluoro3-methyl-phenol. *H NMR (400 MHz, CDC1₃): 7.25 (d, IH), 5.63 (s, IH), 2.44 (d, 3H). MS (El, 70 eV) m/z (% relative intensity, [ion]): 75 (37), 95 (36), 159 (100), 161 (31), 238 (47, [M⁺]), 240 (61, [M⁺]), 242 (15, [M⁺]).

-58Sien B; (4-Bromo-2-chloro-6-flιιυι υ-3-melhyl-phenoxy)-Irïisopropyl-silane

4.06 g 4-bromo-2-chloro-6-fluoiO-3-methyl-phenol (19.9 mmol) and 4.35 mL TIPSCl (20.3 mmol) were dissolved in 50 mL DCM. 2.31 g imidazole (33.9 mmol) was added and the mixture was stirred at room température for 1 hour. Then it was concentrated under reduced pressure and purified via flash chromatography using heptane as eluent. to obtain (4-bromo-2-chloro-6-fluoro-3-methyl-phenoxy)-triisopiOpyl-silane. 4-1 NMR (400 MHz, CDClj): 7.21 (d, IH), 2.45 (d, 3H), 1.32 (septet, 3H), 1.10 (d, 18H). MS (El, 70 eV) m/z (% relative intensity, [ion]): 77 (100), 97 (37), 187 (22), 215 (58), 267 (42), 269 (54), 311 (13),351 (32), 353 (43).

Step C; [2-Chloro-6-jhioro-3-methyl-4-(4,4,5,5-letramethyl-l, 3,2-dioxaborolan-2yl)phenoxy]-tfïisopropyl-silane

6.22 g (4-bromo-2-chloro-6-fluoro-3-methyl-phenoxy)-triisopropyl-silane (15.7 mmol) was dissolved in 65 mL dry THF under N₂ and was cooled to -78°C with dry ice-acetone.

11.8 mL ⁿBuLi (18.9 mmol in 1.6 M hexanes) was added and the mixture was stirred for 30 minutes, then 5.34 mL 2-isopiOpoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (26.2 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with saturated NI-I4CI solution, extracted with DCM, dried over hJa₂SÜ4, fïltered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain [2-chloiO-6-fluoro-3methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-triisopiOpyl-silane. ¹H NMR (400 MHz, CDCI3): 7.37 (d, IH), 2.54 (d, 3H), 1.33 (m, 15H), 1.10 (d, 18H). MS (El, 70 eV) m/z (% relative intensity, [ion]): 83 (100), 101 (18), 275 (8), 399 (7).

Step D: 2-Chloro-6~fluoro-3-methyl~4~(4_>4,3,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol

5.18 g [2-chloiO-6-fluoiO-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenoxy]-triisopropyl-silane (11.7 mmol) was dissolved in 15 mL THF, then 12.9 mL TB AF (12.9 mmol in 1 M THF) was added and the mixture was stirred for 5 minutes. Then it was diluted with EtOAc, washed with pH 5 HCl solution, water and brine, dried over Na₂SO4, fïltered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 5m. ’H NMR (400 MHz, CDCI3): 7.45 (d, IH), 5.74 (s, IH), 2.56 (d, 3H), 1.34 (s, 12H). MS

-59(El, 70 eV) m/z (% relative intensity, [ion]): 59 (30), 85 (17), 151 (23), 186 (100), 187 (63), 229 (49), 272 (25), 286 (22, [M¹]), 288 (7, [M¹]).

Préparation 5n: 3-[2-Chloro-3-methyl-4-(4,4,5^-tetramethyl-l,3,2-dioxaborolan-2yl)phenylJ-AV/V-dimethyl-propan-l-amine

Step A: l-Bromo-3-chloro-4-iodo-2-methyl-benzene

7.93 g 4-bromo-2-chloro-l -iodo-benzene (25.0 mmol) was dissolved in 300 mL dry THF under N₂ and was cooled to -78°C with dry ice-acetone. 13.8 mL LDA was added (27.5 mmol in 2 M THF, EtPh) and the mixture was stirred for 75 minutes, then 3.1 mL Mel (50.0 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with saturated NH4CI solution and most of the volatiles were evaporated under reduced pressure. Then it was extracted with DCM, dried over Na₂SÛ4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane as eluent to obtain l-biOmo-3-chloro-4-iodo-2-methylbenzene. 'HNMR (400 MHz, CDC1₃): 7.55 (d, 1H), 7.17 (d, 1H), 2.62 (s, 3H). MS (El, 70 eV) m/z (% relative intensity, [ion]): 63 (27), 89 (47), 124 (35), 251 (43), 330 (81, [M¹]), 332 (100, [M*]), 334 (25, [M⁺]).

Step B: 3-(4-Bromo-2-chloro-3-methyl-phenyl)-N,N-dimethyl-prop-2-yn-l-amine

1.66 g l-bromo-3-chloro-4-iodo-2-methyl-benzene (5.00 minol), 626 pL N,Ndimethylprop-2-yn-l -amine (7.00 mmol), 176 mg PdCl₂(PPh₃)₂ (0.25 mmol) and 95 mg copper(I) iodide (0.50 mmol) were dissolved in 26 mL dry DIPA and the mixture was stirred at 40°C under N₂ for 30 minutes. Then it was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents. Then it was further purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain 3-(4-bromo-2-chloro-3-methyl-phenyl)-A^zA^rdimethyl-prop-2-yn-l-amine. *H NMR (400 MHz, CDCh): 7.38 (d, 1H), 7.16 (d, 1H), 3.52 (s, 2H), 2.52 (s, 3H), 2.38 (s, 6H). MS (M+H): 286.0.

Step C: 3-(4-Bfomo-2-chloro-3-methvl-phenvl)-N,N-dimethyl-propan-]-amine

-60641 mg 3-(4-bromo-2-chloiO-3-methyl-phenyl)-N,N-dimethyl-prop-2-yn-l-amine (2.13 mmol) was dissolved in 3 mL AcOH, then 300 mg red phosphorus and 5 mL HI (67% aqueous solution) was added. The mixture was heated to 180°C for 20 minutes via microwave irradiation. After cooling to room température it was neutralized with 2 M NaOH, extracted with DCM, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain 3-(4-bromo-2-chloro-3methyl-phenyl)-MN-dimethyl-propan-l-amine. 'H NMR (400 MHz, CDCI3): 7.35 (d, IH), 6.92 (d, IH), 2.70 (t, 2H), 2.51 (s, 3H), 2.29 (t, 2H), 2.21 (s, 6H), 1.74 (quint, 2H). MS (M+H): 290.0.

Step D: 3 -[2-Chloro-3-methyl-4-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)phenyl] N,N-dimethyl-propan~l-amine

378 mg 3-(4-bromo-2-chloiO-3-methyl-phenyl)-A^r,À^r-dimethyl-propan-l-amine (1.30 mmol) was dissolved in 5 mL dry THF under N₂ and was cooled to -78°C with dry iceacetone. 0.94 mL BuLi (1.50 mmol in 1.6 M hexanes) was added and the mixture was stirred for 5 minutes, then 370 pL 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.80 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with water and brine, extracted with EtOAc, dried over Na₂SO₄, filtered and concentrated under rcduccd pressure and used as Préparation 5n without further purification. MS (M+H): 338.2.

Préparation 5o: [2-Bromo-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenoxy]-triisopropyl-silane

Step A: (2,4-Dibromophenoxy)-triisopropyl-silane

7.56 g 2,4-dibromophenol (30.0 mmol) and 7.7 mL TIPSC1 (36.0 mmol) were dissolved in 100 mL DCM. 4.08 g imidazole (60.0 mmol) was added and the mixture was stirred at room température ovemight. Then it was concentrated under reduced pressure and purified via flash chromatography using heptane as eluent to obtain (2,4-dibromophenoxy)triisopropyl-silane. MS (El, 70 eV) m/z (% relative intensity, [ion]): 109 (39), 137 (43), 201 (22), 279 (24), 309 (27), 337 (20), 363 (48), 365 (100), 367 (52).

- 61 Step B: (2,4-Dibromo-3-methyl-pher}oxy)-trnsopropyl-silane

11. 15 g (2,4-dibromophenoxy)-triisopiOpyl-silane (27.3 mmol) was dissolved in 100 mL dry THF under N₂ and was cooled to -78°C with dry ice-acetone. 16.4 mL LDA (32.8 mmol in 2 M THF, EtPh) was added and the mixture was stirred for 1 hour, then 3.4 mL Mel (54.6 mmol) was added and the mixture was allowed to waim up to room température. It was quenched with saturated NH4CI solution, extracted with EtOAc, dried over Na₂SC>4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane as eluent to obtain (2,4-dibromo-3-methyl-phenoxy)triisopropyl-silane. MS (El, 70 eV) m/z (% relative intensity, [ion]): 139 (19), 161 (14), 351 (13), 377 (54 ), 379 (100), 381 (53).

Step C: [2-Bromo-3-methyl-4-(4_l4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]triisopropyl-silane

8.70 g (2,4-dibromo-3-methyl-phenoxy)-triisopropyl-silane (20.6 mmol) was dissolved in 50 mL dry THF under N₂ and was cooled to -78°C with dry ice-acetone. 14.2 mL ⁿBuLi (22.7 mmol in 1.6 M hexanes) was added and the mixture was stirred for 1 minute, then 6.1 mL 2-isopiOpoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (30.0 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with saturated NH4CI solution, extracted with EtOAc, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified via reversed phase chromatography using MeCN as eluent to obtain Préparation 5o. ’H NMR (400 MHz, CDCI3): 7.57 (d, 1H), 6.71 (d, 1H), 2.65 (s, 3H), 1.37-1.27 (m, 15H), 1.13 (d, 18H). MS (El, 70 eV) m/z (% relative intensity, [ion]): 55 (54), 83 (100), 139 (27), 425 (53), 427 (54).

Préparation 5n: l-[2-[2,3-Dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenoxy]ethyl]-4-methy!-piperazine

St en A: 4-Bromo-2,3-dichloro-phenol

1.63 g 2,3-dichlorophenol (10.0 mmol) was dissolved in 30 mL DCM and was cooled to 0°C. Then 512 pL bromine (10.0 mmol) was added and the mixture was allowed to warm up to room température and the mixture was stirred at room température ovemight. Then it

17193 «

-62was washed with saturated Nap^C^ solution, dried over NaîSCU, fîltered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain a mixture of 6-bromo-2,3-dichloro-phenol and 4bromo-2,3-dichloro-phenol. MS (M-H): 239.0.

Step B: l-[2-(4-Bromo-2,3-dichloro-phenoxy)ethyl]-4-methyl-piperazine

1.90 g mixture of 6-bromo-2,3-dichloro-phenol and 4-bromo-2,3-dichloro-phenol (7.85 mmol), 2.27 g 2-(4-methylpiperazin-l-yl)ethanol (15.7 mmol) and 4.12 g PPfo (15.7 mmol) were dissolved in 20 mL dry toluene under N2, then 3.62 g diter/butyl azodicarboxylate (15.7 mmol) was added and the mixture was stirred at room température ovemight. Then it was concentrated under reduced pressure and the regioisomers were separated via flash chromatography using EtOAc and MeOH as eluents. The desired isomer was further purified via reversed phase chromatography using water and MeCN as eluents to obtain l-[2-(4-bromo-2,3-dïchloro-phenoxy)ethyl]-4-methyl-piperazine. ’H

NMR (400 MHz, DMSO-d₆): 7.69 (d, IH), 7.16 (d, IH), 4.20 (t, 2H), 2.72 (t, 2H), 2.42-

2.18 (m, 8H), 2.13 (s, 3H). MS (M+H): 367.0.

Step_________C: 1 - [2-[2,3-Dichloro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2yl)phenoxy] ethyl]-4-methyl-piperazine

2.10 g l-[2-(4-bromo-2,3-dichloiO-phenoxy)ethyl]-4-methyl-piperazine (5.70 mmol) was dissolved in 25 mL dry THF under N2 and was cooled to -78°C with dry ice-acetone. 3.9 mL ⁿBuLi (6.28 mmol in 1.6 M hexanes) was added and the mixture was stirred for 5 minutes, then 2.0 mL 2-isopropoxy-4,4,5₎5-tetramethyl-l₎3,2-dioxaboiOlane (10.0 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with brine, extracted with DCM, dried over Na2SO4, fîltered and concentrated under reduced pressure. The crude product was purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Préparation 5p. MS (M+H): 415.2.

Préparation 5q: l-[2-[[3-€hl()ro-4-niethyl-5-(4,4,5,5-tetraniethyl-l,3,2-dioxaborolan-2yl)-2-pyridyl]oxy]ethyI]-4-methyl-piperazine ♦

-63Step A: 5’ΒΓοηιο~3~νΜοΓϋ-4-τηεΛνΙ·’ρντί(Ιΐη~2-οΙ

4.86 g 5-bromo-4-methyi-pyridin-2-ol (25.8 mmol) was dîssolved in 250 mL THF, then

4.49 g NCS (33.6 mmol) was added and the mixture was stirred at 60°C in dark for 45 minutes. Then it was concentrated under reduced pressure and crystallized from Et₂O and heptane to get an overweight product, which was crystallized from 100 mL MeC-N to give 5-bromo-3-chloro-4-methyl-pyridin-2-ol. ’H NMR (400 MHz, DMSO-de): 11.50 (br s, IH), 7.74 (s, IH), 2.36 (s, 3H). MS (M+H): 222.0, (M-H): 220.0.

Step B: l-[2-[(5-Bromo-3-chloro-4-melhyl-2-pyridyl)oxy]ethyl]-4-methyl-piperazine

2.326 g 5-bromo-3-chloro-4-methyl-pyridin-2-ol (10.45 mmol), 2.163 g 2-(4methylpiperazin-l-yl)ethanol (15.00 mmol) and 3.935 g PPhj (15.00 mmol) were dîssolved in 30 mL dry toluene under N₂, then 3.454 g ditertbutyl azodicarboxylate (15.00 mmol) was added and the mixture was stirred at room température under N₂ for 20 minutes. Then it was concentrated under reduced pressure and the structural isomers were separated via flash chromatography using EtOAc and MeOH as eluents. The isomer eluting earlier was collected as l-[2-[(5-bromo-3-chloiO-4-rnethyl-2-pyridyl)oxy]ethyl]-4-methyl-piperazîne.

4-1 NMR (400 MHz, DMSO-d_fi): 8.24 (s, IH), 4.41 (t, 2H), 2.68 (t, 2H), 2.48-2.15 (m, 1 IH), 2.12 (s, 3H). MS (M+H): 348.0.

²⁰ Step & l-[2^[343hloro-4-methyl-5-(4,4,5,5rfetrameth)4-l,3,2^ioxaborolan-2-yl)-2pyridyl]oxy]elhyl]-4-methyl-piperazine

1.917 g l-[2-[(5-bromo-3“Chloro-4-methyl-2-pyridyl)oxy]ethyl]-4-methyl-piperazine (5.50 mmol) was dîssolved in 30 mL dry THF under N₂ and was cooled to -78°C with dry iceacetone. 4.1 mL BuLi (6.60 mmol in 1.6 M hexanes) was added and the mixture was stii+ed for 5 minutes, then 1.46 mL 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (7.15 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with brine, extracted with DCM, dried over Na₂SÛ4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using EtOAc and MeOH as eluents to obtain Préparation 5q. MS (M+H): 396.2.

-64Préparation 5r: l-[3-|2-Chloro-3-methyl-4-(4,4,5,5-tetramethyl-13,2-dioxaborolan-2yl)phenyl]propylj-4-methyl-piperazine

Step A: 3-(4-Bromo-2-chloro-3-methyl-phenyl)prop-2-yn-l-ol

17.43 g l-bromo-3-chloro-4-ïodo-2-methyl-benzene (52.60 mmol, see Step A at Préparation 5n), 3.37 mL prop-2-yn-l-ol (57.86 mmol), 369 mg PdCl₂(PPh3)₂ (0.53 mmol) and 501 mg copper(I) iodide (2.63 mmol) were dissolved in 100 mL dry DIPA and the mixture was stirred at 40°C under N₂ for 20 minutes. Then it was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain 3-(4-bromo-2-chloro-3-methyl-phenyl)prop-2-yn-l-ol. 'H NMR (400 MHz, CDC1₃): 7.40 (d, IH), 7.16 (d, IH), 4.54 (d, 2H), 2.53 (s, 3H), 1.87 (t, IH). MS (El, 70 eV) m/z (% relative intensity, [ion]): 63 (35), 115 (100), 223 (56), 258 (15, [M⁴]), 260 (18, [M⁴]), 262 (5, [M⁴]).

Step B: 3-(4-Bromo-2-chloro-3-methyl-phenyl)prop-2-ynyl methcmesulfonate

5.427 g 3-(4-bromo-2-chloro-3-methyl-phenyl)prop-2-yn-l-ol (20.9 mmol) and 4.37 mL DIPEA (25.1 mmol) was dissolved in 50 mL dry DCM under N₂, then 1.78 mL methanesulfonyl chloride (23.0 mmol) was added carefully and the mixture was stirred for 10 minutes. Then it was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain 3-(4-bromo-2-chloro-3methyl-phenyl)prop-2-ynyl methanesulfonate. ^lH NMR (400 MHz, CDCI3): 7.45 (d, III),

7.19 (d, IH), 5.12 (s, 2H), 3.18 (s, 3H), 2.53 (s, 3H).

Step C: l-[3-(4-Bromo-2-chloro-3-methyl-phenyl)prop-2-ynyl]-4-methyl-piperazine

4.31 g 3-(4-bromo-2-chloro-3-methyl-phenyl)prop-2-ynyl methanesulfonate (12.8 mmol) was dissolved in 120 mL MeCN, and the mixture was added to the stirred mixture of 2.65 g K₂CO₃ (19.2 mmol), 14.2 mL 1-methylpiperazine (127.7 mmol) and 120 mL MeCN. The mixture was stirred for 30 minutes, then it was filtered and the filtrate was concentrated under reduced pressure. Brine was added and the mixture was extracted with DCM, dried over Na₂SO4, filtered and concentrated under reduced pressure to obtain 1 -[3-(4-bromo-2chloro-3-methyl-phenyl)prop-2-ynyl]-4-methyl-piperazine. MS (M+H): 341.0.

-65Step D: l-[3~(4~Bromo-2-chloro-3-methyl-phenyl)propyl]-4-methyl-piperazine

l.5l g l-[3-(4-biOmo-2-chloiO-3-methyl-phenyl)prop-2-ynylJ-4-methyi-piperazine (4.42 mmol) was dissolved in 15 mL AcOH, then 500 mg red phosphorus and 10 mL HI (67% aqueous solution) was added. The mixture was heated to 18O°C for 5 minutes via 5 microwave irradiation. After cooling to room température it was neutralized with 2 M NaOH_s extracted with DCM, dried over Na₂SÛ4, filtered and concentrated under reduced pressure. The crude product was purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain l-[3-(4-bromo-2-chloro-3methyl-phenyl)propyl]-4-methyl-piperazine. *H NMR (400MHz, DMSO-dô): 7.50 (d, IH),

7.13 (d, IH), 2.68 (t, 2H), 2.47 (s, 3H), 2.46-2.15 (m, 10H), 2.13 (s, 3H), 1.67 (quint, 2H).

MS (M+H): 345.0.

Step______E: l-[3-[2-Chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenyl]propyl]-4-methyl-piperazine

708 mg l-[3-(4-bromo-2-chloro-3-methyI-phenyl)propyl]-4-methyl-piperazine (2.04 mmol) was dissolved in 10 mL dry THF under N₂ and was cooled to -78°C with dry iceacetone. 1.7 mL ⁿBuLi (2.70 mmol in 1.6 M hexanes) was added and the mixture was stirred for 5 minutes, then 0.6l mL 2-ïsopropoxy-4,4,5,5-tetrametliyl-l,3,2-dioxaborolane (3,00 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with brine, extracted with DCM, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Préparation 5r. MS (M+H): 393.4.

Préparation 5s: 1 -[2-[2,3-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)pbenoxy]ethyl]-4-methyl-piperazine

Step A: 4-Bromo-2,3-dimethyl-phenol

1.22 g 2,3-dimethylphenol (10.0 mmol) was dissolved in 50 mL MeCN, then 1.78 g NBS 30 (10.0 mmol) was added and the mixture was stirred at room température ovemight. Then it was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain 4-bromo-2,3-dimethyl-phenol. ’H NMR (400

-66MHz, CDC1₃): 7.24 (d, 1H), 6.52 (d, 1H), 4.68 (s, 1H), 2.37 (s, 3H), 2.22 (s, 3H), MS (El, 70 eV) m/z (% relative intensity, [ion]): 77 (45), 91 (62), 121 (100), 200 (76, [M]⁺), 202 (74, [M]⁺).

Step B: l-[2-(4-Bromo-2,3-dimethyl-phenoxy)ethyl]-4-methyl-piperazme

1.54 g 4-biOmo-2,3-dimethyl-phetiol (7.66 mmol), 2.21 g 2-(4-methylpiperazin-lyl)ethanol (15.3 mmol) and 6.03 g PPh₂ (23.0 mmol) were dissolved in 20 mL dry toluene under N₂, then 5.29 g di/er/butyl azodicarboxylate (23.0 mmol) was added and tlie mixture was stirred at 45°C for 2 hours. Then it was concentrated under reduced pressure and purified via flash chromatography using EtOAc and MeOH as eluents to obtain l-[2-(4bromo-2,3-dimethyl-phenoxy)ethyl]-4-methyl-piperazine. ^!H NMR (400 MHz, CDCI3): 7.31 (d, 1H), 6.58 (d, 1H), 4.06 (t, 2H), 2.83 (t, 2H), 2.70-2.38 (m, 8H), 2.36 (s, 3H), 2.29 (s, 3H), 2.20 (s, 3H).

Step_________C: l-[2-[2,3-Dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenoxy]ethyl]-4-methyl-piperazme

2.10 g l-[2-(4-bromo-2,3-dimethyl-phenoxy)ethyl]-4-methyl-piperazine (6.42 mmol) was dissolved in 25 mL dry THF under N₂ and was cooled to -78°C with dry ice-acetone. 4.2 mL ⁿBuLi (6.74 mmol in 1.6 M hexanes) was added and the mixture was stirred for 15 minutes, then 1.44 mL 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (7.06 mmol) was added and the mixture was allowed to warm up to room température. It was quenched with brine, extracted with DCM, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 5s. *H NMR (400 MHz, DMSO-dô): 7.46 (d, 1H), 6.75 (d, 1H), 4.02 (t, 2H), 2.68 (t, 2H), 2.48 (br s, 4H), 2.38 (s, 3H), 2.30 (br s, 4H), 2.13 (s, 3H), 2.05 (s, 3H), 1.26 (s, 12H). MS (M+H): 375.4.

Préparation 5t: 2-(4-Bromo-3-chloro-2-inethyl-phenyl)-4,4,5,5-tetianiethyl-l,3,2dioxaborolane

2.92 g l-biOmo-2-chloro-4-iodo-3-methyl-benzene (8.81 mmol) was dissolved in 30 mL dry THF under N₂ and 4.8 mL EtMgCl (9.69 mmol in 2 M THF) was added dropwise at room température. It was stirred for 10 minutes, then 5.4 mL 2-isopropoxy-4,4,5,517193

-67tetramethyl-l,3,2-dioxaborolan.e (26.4 mmol) was added and the mixture was stirred for 10 minutes. Then it was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 5t. 'H NMR (400 MHz, DMSO-dô): 7.49 (d, IH), 7.45 (d, IH), 2.66 (s, 3H), 1.34 (s, 12H).

Préparation 6a; Ethyl (2R)-2-[(5S^, _â)-5(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(4fluorophenyl)thieno [2_t3-4]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2yloxyphenyl)propanoate

186.6 g ethyl (27?)-2-[5-bromo-6-(4-fluoropheayl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-(2tetra-hydropyran-2-yloxyphenyl)propanoate (Préparation 4a) (310.3 mmol) and 99.99 g 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (372.3 mmol) were dissolved in 1.2 L THF, then 202.2 g CS2CO3 (620.6 mmol) dissolved in 300 mL water was added. Then 11.0 g AtaPhos (15.51 mmol) was added, and the mixture was stirred under nitrogen at reflux température until no further conversion was observed. Most of the volatiles were evaporated under reduced pressure, then it was diluted with dichloromethane and brine. After shaking the pH of the aqueous phase was set to 8 with 2 M HCl. After phase séparation the aqueous phase was extracted with dichloromethane. The organic layers were combined and dried over Na2SÛ4, filtered and concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer pair eiuting later was collected as Préparation 6a. ’H NMR (500 MHz, DMSO-dô, 1:1 mixture of diastereomers): 10.27 (br s, IH), 8.60 (s, IH), 7.30 (m, 2H), 7.22 (m, 2H), 7.16/7.14 (d, IH), 7.12 (m ,1H), 7.00 (d, IH), 6.96 (d, IH), 6.74/6.73 (t, IH), 6.34/6.36 (d, IH), 5.55/5.52 (m, IH), 5.54/5.41 (dd, IH), 4.06 (q, 2H), 3.68/3.54 (m, 2H), 3.10/3.07 (dd, IH), 2.44 (dd, IH), 1.98/1.90 (br s, IH), 1.85/1.83 (s, 3H), 1.79 (br s, 2H), 1.64 (br s, IH), 1.59 (br s, IH), 1.54 (br s, IH), 1.09/1.08 (t, 3H). HRMS: (M+H) = 663.1728 and 663.1717.

Préparation 6b; Ethyl (2R)-2-[(5S’₍,)-5“(3-ch!oro-4-hydroxy-2-methyl-phenyl)-6-(4fliiorophenyl)thieno[2,3-//]pyrimidin-4-yl|oxy-3-[2-(pyrazin-2ylmethoxy)phenyl]propanoate

2.52 g ethyl (2/?)-2-[5-bromo-6-(4-fluorophenyl)tliieno[2,3-c(]pyrimidin-4-yl]oxy-3-[2(pyrazin-2-ylmethoxy)phenyl]propanoate (Préparation 4b) (4.1 mmol) and 2.2 g 217193

-68chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (8.2 mmol) were dissolved in 30 mL l,4-dioxane, then 2.67 g CS2CO3 (8.2 mmol) dissolved in 15 mL water was added. Then 284 mg AtaPhos (0.41 mmol) was added, and the mixture was stirred under nitrogen at 100°C until no further conversion was observed. Most of the volatiles were evaporated under reduced pressure, then it was diluted with dichloromethane and brine. After shaking the pH of the aqueous phase was set to 7 with 2 M HCl. After phase séparation the aqueous phase was extracted with dichloromethane. The organic layers were combined and dried over NaîSCU, fîltered and concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting later was collected as Préparation 6b. 'H NMR (500 MHz, DMSO-d₆): 10.27 (s, 1H), 8.92 (d, 1H), 8.76-8.61 (m, 2H), 8.58 (s, 1H), 7.30 (m, 2H), 7.22 (m, 2H), 7.19 (m, 1H), 7.16 (d, 1H), 7.07 (dm, 1H), 6.97 (d, 1H), 6.76 (m, 1H), 6.30 (dm, 1H), 5.46 (dd, 1H), 5.30 (d, 1H), 5.25 (d, 1H), 4.07 (m, 1H), 4.04 (m, 1H), 3.16 (dd, 1H), 2.49 (dd, 1H), 1.80 (s, 3H), 1.08 (t, 3H). HRMS: (M+H) = 671.1533.

Préparation 6c: Ethyl f2^-2-[(5S(T)-5-(3-chloi'o-4-liydroxy-2-inethyl-phenyl)-6-(5fluoro-2-fury l)thieno [2,3-//] py ri midi n-4-yI] oxy-3-(2-tetrahyd ropyran-2yloxyphenyl)propanoate and

Préparation 6q: Ethyl (2R)-2-[(5_JR«)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(5fluoro-2-furyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2yloxyphenyl)propanoate

174.0 g ethyl (2Æ/2-[5-bromo-6-(5-fluoro-2-furyl)thieno[2,3-c/]pyrimidin-4-yl]oxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 4c) (294.2 mmol) and 94.81 g 2chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (353.0 mmol) were dissolved in 1.18 L THF, then 191.7 g CS2CO3 (588.4 mmol) dissolved in 300 mL water was added. Then 10.41 g AtaPhos (14.71 mmol) was added, and the mixture was stirred under nitrogen at 60°C until no further conversion was observed. Most of the volatiles were evaporated under reduced pressure, then it was diluted with dichloromethane and brine. After shaking the pH of the aqueous phase was set to 8 with 2 M HCL After phase séparation the aqueous phase was extracted with dichloromethane .

-69The organic layers were combined and dried over Na2SO₄, fîltered and concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents.

The diastereoisomer pair eluting earlier was collected as Préparation 6q. 'H NMR (500 MHz, DMSO-dô, l:l mixture of diastereomers): 10.44 (s, IH), 8.58 (s, IH), 7.11 (t, IH), 7.02/7.00 (d, IH), 6.98 (d, IH), 6.95/6.94 (d, IH), 6.73 (t, IH), 6.21/6.19 (d, IH), 5.87 (dd, IH), 5.71 (t, IH), 5.55/5.49 (t, IH), 5.47/5.34 (dd, IH), 4.10 (q, IH), 4.08 (q, IH), 3.66 (m, IH), 3.52 (m, IH), 3.23 (dd, IH), 2.33 (dd, IH), 2.22/2.21 (t, 3H), 2.03-1.49 (m, 6H), 1.11/1.10 (t, 3H). ). HRMS: (M+H) = 653.1518

The diastereoisomer pair eluting later was collected as Préparation 6c. ’H NMR (500 MHz, DMSO-dg, 1:1 mixture of diastereomers): 10.40 (s, IH), 8.58 (s, IH), 7.15 (t, IH), 7.10 (d, IH), 7.04 (d, IH), 7.01 (d, IH), 6.81/6.80 (t, IH), 6.38/6.36 (d, IH), 5.89(dd, IH), 5.69 (t IH), 5.56/5.52 (t, IH), 5.56/5.43 (dd, IH), 4.05 (q, 2H), 3.68 (m, IH), 3.54 (m, IH), 3.13 (dd, IH), 2.36 (dd, IH), 1.95/1.94 (s, 3H), 1.82-1.51 (m, 6H), 1.09 (t, 3H). HRMS: (M+H) = 653.1485 and 653.1492.

Préparation 6d; Ethyl (2R)-2- [(55_ff)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(2fu ry l)thieno [2,3-rf] py rimidin-4-yi J oxy-3-(2-tetrahydropy ran-2yloxyphenyl)propanoate

36.3 g ethyl (2Â7-2-[5-bromo-6-(2-furyl)thieno[2,3-rf]pyrimidin-4-yl]oxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 4d) (63.3 mmol) and 18.7 g 2chloro-3-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (69.6 mmol) were dissolved in 400 mL THF, then 32.6 g CS2CO3 (100.0 mmol) dissolved in 100 mL water was added. Then 1.8 g AtaPhos (2.5 mmol) was added, and the mixture was stirred under nitrogen at reflux température until no further conversion was observed. Then it was diluted with dichloromethane and brine. After shaldng the pH of the aqueous phase was set to 8 with 2 M HCl. After phase séparation the aqueous phase was extracted with dichloromethane . The organic layers were combined and dried over Na2SO₄, fîltered and concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer pair eluting later was collected as Préparation 6d. ’H NMR (400 MHz, DMSO-de, 1:1 mixture of diastereomers): 10.40 (s, IH), 8.58/8.57 (s, IH), 7.80/7.79 (d, IH), 7.15 (tm, IH), 7.10

-70(d, IH), 7.05 (d, IH), 7.02 (d, IH), 6.81 (m, IH), 6.54 (dd, IH), 6.39 (dm, IH), 5.69 (dm, IH), 5.57 (m, IH), 5.55/5.43 (ddd, IH), 4.06 (m, 2H), 3.68 (m, IH), 3.54 (m, IH), 3.33 (s, 3H), 3.13 (td IH), 2.36 (m, IH), 1.94/1.93 (s, 3H), 1.80 (m, 2H), 1.71-1.48 (m, 3H), 1.09 (td, 3H). MS: (M+H)⁺ = 635.0.

Préparation 6e: Ethyl (2Æ_>)-2-](5S'„)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(2furyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2-nietlioxyphenyl)propanoate

2.013 g ethyl (27?J-2-[5-biOmo-6-(2-fuiyl)thieno[2,3-<7]pyrimidin-4-yl]oxy-3-(2methoxyphenyl)propanoate (Préparation 4e) (4.0 mmol) and 1.396 g 2-chloro-3-methyl4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (5.2 mmol) were dissolved in 16 mL 1,4-dioxane, then 2.607 g Cs₂CO₃ (8.0 mmol) dissolved in 4 mL water was added. Then 57 mg AtaPhos (0.08 mmol) was added, rinsed with nitrogen, and heated at 110°C via microwave irradiation until no further conversion was observed. Then it was diluted with dichlorométhane and brine. After shaking the pH of the aqueous phase was set to 5 with 2 M HCl. After phase séparation the aqueous phase was extracted with dichlorométhane . The organic layers were combined and dried over NaiSCL, filtered and concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting later was collected as Préparation 6e, ^!H NMR (500 MHz, DMSO-dô): 10.40 (br s, IH), 8.57 (s, IH), 7.79 (d, IH), 7.18 (td, IH), 7.08 (d, IH), 7.04 (d, IH), 6.91 (d, IH), 6.77 (t, IH), 6.53 (dd, IH), 6.36 (dd, IH), 5.67 (d, III), 5.40 (dd, III), 4.04 (m, 2H), 3.77 (s, 3H), 3.00 (dd, IH), 2.42 (dd, IH), 1.92 (s, 3H), 1.07 (l, 3H). HRMS: (M+H) - 565.1187.

Préparation 6f: Ethyl (2/f/2-[6-(5-chloro-2-furyl)-(55„)-5-(3-chloro-4-hydroxy-2methyl-ph eny l)-th ien o {2,3-//] py ri m idin -4-yl] oxy-3- [2-((4methoxyphenyl)methoxy]phenyl]propanoate

11.11 g ethyl f2J^-2-[5-bromo-6-(5-chloiO-2-fiiryl)thieno[2,3--d]pyrirnidin-4-yl]oxy-3-[2[(4-methoxyphenyl)methoxy]phenyl]propanoate (Préparation 4f) (17.28 mmol) and 7.0 g 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (26.0 mmol) were dissolved in 100 mL 1,4-dioxane, then 11.4 g CS2CO3 (35.0 mmol) dissolved in 50 mL water was added. Then 1.22 g AtaPhos (1.73 mmol) was added, and the mixture was stirred under nitrogen at reflux température until no further conversion

-71 was observed. Then it was diluted with dichloromethane and brine. After shaking the pH of the aqueous phase was set to 6 with 2 M HCl. After phase séparation the aqueous phase was extracted with dichloromethane. The organic layers were combined and dried over Na₂SO4, filtered and concentrated under reduced pressure. The diastereoisomers were 5 separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting later was collected as Préparation 6f. MS: (M+H) = 705.0.

Préparation 6g; Ethyl (2R)-2-[6-(5-chloro-2-furj'I)-(55_u)-5-(3-chloro-4-hydroxy-2ïnethyl-phenyl)-thieno[2,3-rf|pyriinidin-4-yl]oxy-3-[2-[[(2S)-tetrahydrofuran-210 yl]methoxy]phenyl]propanoate

547 mg ethyl f2jy-2-[5-bromo-6-(5-chloro-2-furyl)thieno[2,3-if]pyrimidin-4-yl]oxy-3-[2[[(2S)-tetrahydrofuran-2-yl]methoxy]phenyl]propanoate (Préparation 4g) (0.752 mmol) and 403 mg 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation Sa) (1.5 mmol) were dissolved in the mixture of 5 mL THF and 5 mL 1,415 dioxane, then 652 mg Cs?CÛ3 (2.0 mmol) dissolved in 5 mL water was added. Then 53 g

AtaPhos (0.075 mmol) was added, rinsed with nitrogen, heated at 100°C via microwave irradiation untii no further conversion was observed. Then it was diluted with dichloromethane and brine. After shaking the pH of the aqueous phase was set to 6 with 2 M HCl. After phase séparation the aqueous phase was extracted with dichloromethane. The 20 organic layers were combined and dried over Na₂SC>4, filtered and concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting later was collected as Préparation 6g. MS: (M+H) = 669.0.

Préparation 6h: Ethyl (2/f/-2-[(5iÇ₍,)-5-(3-chloro-4-hydroxy-2-methyl-phenyi)“6-(4fluoro-3-methoxy-phenyl)thieno[23-rf]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2yloxyphenyftpropanoate

22.0 g ethyl f2Æ9-2-[5-brorno-6-(4-fluoro-3-methoxy-phenyl)thieno[2,3-d]pyrimidin-4yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 4h) (34.84 mmol) 30 and 11.23 g 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation Sa) (41.80 mmol) were dissolved in 200 mL THF, then 34.05 g CS2CO3 (104.5 mmol) dissolved in 200 mL water was added. Then 2.46 g AtaPhos (3.48 mmol)

-72was added, and the mixture was stirred under nitrogen at 60°C until no further conversion was observed. Then it was diluted with dichloromethanc and brine. After shaking the pH of the aqueous phase was set to 7 with 2 M HCl. After phase séparation the aqueous phase was extracted with dichloromethane. The organic layers were combined and dried over Na2SO4, filtered and concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer pair eluting later was collected as Préparation 6h. ’H NMR (400 MHz, DMSO-dfi, l:l mixture of diastereomers): 10.30 (s, IH), 8.61/8.60 (s, IH), 7.26/7.23 (d, IH), 7.19/7.17 (d, IH), 7.13 (m, IH), 7.01 (d, IH), 6.99 (d, IH), 6.94 (m, IH), 6.87 (dd, IH), 6.74 (m, IH), 6.30 (m, IH), 5.56/5.53 (m, IH), 5.53/5.42 (m, IH), 4.07 (m, 2H), 3.68/3.56 (m, 2H), 3.59/3.58 (s, 3H), 3.15 (m, IH), 2.42 (dd, IH), 2.03-1.89 (br s, IH), 1.86/1.84 (s, 3H), 1.79 (br s, 2H), 1.71-1.48 (br s, 3H), 1.10 (td, 3H). MS: (M+H) = 693.0.

Préparation 6i: Methvl (2Λ)-2-[(55_Λ)-5-(3-ε1ιΙθΓθ-4-1ιγΰπ)χγ-2-ιηεί1ιγΙ-ρ1ΐ£ηγ1)-6-6ί1ιγΙtirieno[2,3-if]pyriinidin-4-y!]oxy-3-plienyl-propanoate and

Préparation 6n; Methyl (2JÎ)-2-[(52?_rt)’(3-chloro-4-hydiOxy-2-methyl-phenyl)-6-ethylthieiio[2,3-(/]pyriniidin-4-yl]oxy-3-phenyl-propanoate

13.17 g methyl f2RJ-2-(6-ethyI-5-iodo-thieno[2,3-if]pyrimidin-4-yl)oxy-3-phenylpropanoate (Préparation 4i) (28.12 mmol) and 10.57 g 2-chloro-3-methyl-4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (39.37 mmol) were dissolved in 100 ml, 2-Me-THF, then 40 mL TBAOH (1 M aqueous solution) was added. Then 893 mg AtaPhos (1.406 mmol) was added, and the mixture was stirred under nitrogen at reflux température until no further conversion was observed. It was diluted with EtOAc and 1 mL HCl (2 M aqueous solution), then it was washed with water and brine. The organic layer was dried over Na₂SO4, filtered and concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting earlier was collected as Préparation 6n. 'H NMR (500 MHz, DMSO-d₆): 10.22 (br,s IH), 8.53 (s, IH), 7.16 (m, 3H), 7.07 (d, IH), 7.00 (d, IH), 6.66 (m, 2H), 5.45 (dd, IH), 3.54 (s, 3H), 2.93 (dd, IH), 2.66 (dd, IH), 2.62 (m, 2H), 1.99 (s, 3H), 1.15 (t, 3H). HRMS: (M+H) = 483.1137.

e

-73The diastereoisomer eluting later was collected as Préparation 6i. ’H NMR (500 MHz, DMSO-de): 10.26 (br s, 1H), 8.52 (s, 1H), 7.14 (m, 3H), 6.97 (d, 1H), 6.94 (d, IH), 6.65 (m, 2H), 5.30 (dd, 1H), 3.64 (s, 3H), 2.99 (dd, 1H), 2.66 (m, 2H), 2.54 (dd, 1H), 2.17 (s, 3H), 1.15 (t, 3H). HRMS: (M+H) = 483.1126.

Préparation 6i: Methyl (2Æ)-2-|6-ethyl-(5S_i()-5-(4-hydrcxy-2-inetliylphenyl)thieno[2,3-i7]pyriiiiidin-4-yljoxy-3-phenyl-propanoate and

Préparation 6o; Methyl (2Æ)-2-[6-ethyl-(5/?„)-5-(4-hydroxy-2-mcthyl· phenyl)thieno[2,3-rf]pyrimidin-4-yl]oxy-3-phenyl-propanoate

2.25 g methyl (2^7-2-(6-ethyl-5-iodo-thieno[2.3-i/]pyrimidin-4-yl)oxy-3-phenylpropanoate (Préparation 4i) (2.67 mmol) and 1.76 g 3-methy 1-4-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)phenol (8.0 mmol) were dissolved in 15 mL 2-Me-THF, then 2.75 g Ag₂CO₃ (10.0 mmol) was added. Then 309 mg Pd(PPh3)₄ (0.267 mmol) was added, rinsed with nitrogen, heated at 100°C via microwave irradiation until no further conversion was observed. It was diluted with ethyl acetate and brine. After shaking the pH of the aqueous phase was set to 5 with 2 M HCl. After phase séparation the organic layer was dried over Na2SO₄, filtered and concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting carlicr was collected as Préparation 6j. *H NMR (500 MHz, DMSO-dfi): 9.44 (s, 1H), 8.52 (s, 1H), 7.16 (ni, 3H), 7.05 (d, 1H), 6.78 (d, 1H), 6.76 (dd, 1H), 6.70 (m, 2H), 5.47 (dd, 1H), 3.54 (s, 3H), 2.95 (dd, 1H), 2.68 (dd, 1H), 2.62 (m, 2H), 1.84 (s, 3H), 1.15 (t, 3H). HRMS: (M+H) = 449.1509.

The diastereoisomer eluting later was collected as Préparation 6o. *H NMR (500 MHz, DMSO-di):9.64 (s, 1H), 8.50 (s, 1H), 7.14 (m, 3H), 6.94 (d, 1H), 6.82 (d, 1H), 6.77 (dd, 1H), 6.66 (m, 2H), 5.28 (dd, 1H), 3.64 (s, 3H), 2.97 (dd, 1H), 2.64 (m, 2H), 2.58 (dd, 1H), 2.08 (s, 3H), 1.14 (st, 3H). HRMS: (M+H) = 449.1540.

Préparation 6k: Ethyl (2R)-2-[(5S«)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethylthieno[2,3-d]pyrimidin-4-yljoxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate

5.0 g ethyl f2RJ-2-(6-ethyl-5-iodo-thieno[2,3-</Jpyriniidin-4-yl)oxy-3-(2-tetrahydrûpyran2-yloxyphenyI)propanoate (Préparation 4j) (9.33 mmol) and 3.22 g 2-chloro-3-methyl-417193

-74(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (12.0 mmol) were dissolved in 60 mL THF, then 6.52 g CS2CO3 (20.0 mmol) dissolved in 20 mL water was added. Then 330 mg AtaPhos (0.466 mmol) was added, and the mixture was stirred under nitrogen at 65 °C until no further conversion was observed. Then it was diluted with dichloromethane and brine. After shaking the pH of the aqueous phase was set to 8 with 2 M IICl. After phase séparation the aqueous phase was extracted with dichloromethane. The organic layers were combined and dried over Na2SO4, filtered and concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer pair eluting later was collected as Préparation 6k. ’H NMR (400 MHz, DMSO-dô, l:l mixture of diastereomers): 10.24 (br s, IH), 8.52/8.51 (s, IH), 7.13 (m, IH) 7.05 (d, IH), 7.01 (dm, IH), 6.98 (d, IH), 6.79 (m, IH), 6.35 (m, IH), 5.55/5.51 (m, IH), 5.50 (dd, IH), 5.37 (dd, IH), 4.03 (m, 2H), 3.67 (m, IH), 3.53 (m, IH), 3.06 (dd, IH), 2.65 (dd, IH), 2.58 (m, IH), 2.41 (m, IH), 1.98/1.97 (s, 3H), 1.79 (m, 2H), 1.68-1.47 (m, 3H), 1.15 (t, 3H), 1.06 (td, 3H). MS: (M+H) = 597.2.

Préparation 6k Ethyl (22/)-2-[(5₍S’_rt)-5-(3-chloro-4-hydroxy-2-inethyl-phenyl)-6-prop-lynyl-thieno[2₎3-i/]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate

472 mg ethyl ('27î)-2-(5-iodo-6-prop-l-ynyl-thieno[2,3-i/]pyrimidin-4-yl)oxy-3-(2methoxyphenyl)propanoate (Préparation 4k) (0.90 mmol) and 403 mg 2-chloro-3-meÎhyl4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (1.5 mmol) were dissolved in 10 mL 1,4-dioxane, then 652 mg CS2CO3 (2.0 mmol) dissolved in 2 mL water was added. Then 64 mg AtaPhos (0.09 mmol) was added, rinsed with nitrogen, heated at 110°C via microwave irradiation until no further conversion was observed. Then it was diluted with dichloromethane and brine. After shaking the pH of the aqueous phase was set to 5 with 2 M HCl. After phase séparation the aqueous phase was extracted with dichloromethane. The organic layers were combined and dried over Na2SO4, filtered and concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting later was collected as Préparation 61. ’HNMR (500 MHz, DMSO-de): 10.34 (br s, IH), 8.61 (s, IH), 7.16 (m, IH), 7.09 (d, IH), 6.98 (d, IH), 6.89 (dm, IH), 6.69 (m, IH), 6.19 (dm, IH), 5.34 (dd, IH), 4.08 (m, IH), 4.03 (m, IH), 3.75 (s, 3H), 3.01 (dd, IH), 2.49 (dd, IH), 2.08 (s, 3H), 2.03 (s, 3H), 1.07 (t, 3H). HRMS: (M+H) = 537.1247.

-75Preparation 6m; Ethyl (2/i)-2-[(5S^,„)-5-(3-chloro-4-hydroxy-2-nicthyl-phenyl)-6-propl-ynyl-thieno[23-rf]pyrimidin-4-yl]oxy-3-(2“tetrahydropyran-2yloxyphenyl)propanoate

10.59 g ethyl f2Æ)-2-(5-iodo-6-prop-l-ynyl-thieno[2,3-<fjpyrimidin-4-yl)oxy-3-(2tetrahydropyran-2-yloxyphcnyl)propanoatc (Préparation 41) (17.87 mmol) and 5.76 g 2chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (21.45 mmol) were dissolved in 100 mL THF, then 11.64 g Cs₂CÛ3 (35.74 mmol) dissolved in 30 mL water was added. Then 1.26 g AtaPhos (1.79 mmol) was added, and the mixture was stirred under nitrogen at 60C until no further conversion was obseived. Then it was diluted with dichloromethane and brine. After shaking the pH of the aqueous phase was set to 8 with 2 M HCl. After phase séparation the aqueous phase was extracted with dichloromethane. The organic layers were combined and dried over Na₂SO₄, filtered and concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer pair eluting later was collected as Préparation 6m. MS: (M+H) = 607.0.

Préparation 6p: Ethyl f27?)-2-i(55„)-5 (3-chloro-4-hydroxy-2-methyl-pheny!)-6-(3,4difluorophenyl)thieno[2,3-//Jpyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2yloxyphenyl)propanoatc

9.18 g ethyl (2Æ)-2-[(5.S'_a)-5-bromo-6-(3,4-difluorophenyl)thieno[2,3-J]pyrimidin-4yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 4o) (14.82 mmol) and 5.17 g 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (19.26 mmol) were dissolved in 50 mL THF, then 6.52 g Cs₂CO₃ (20 mmol) dissolved in 20 mL water was added. Then 525 mg AtaPhos (0.74 mmol) was added, and the mixture was stirred under nitrogen at reflux température until no further conversion was observed. Most of the volatiles were evaporated under reduced pressure, then it was diluted with dichloromethane and brine. After shaking the pH of the aqueous phase was set to 8 with 2 M HCl. After phase séparation the aqueous phase was extracted with dichloromethane. The organic layers were combined and dried over Na₂SO₄, filtered and concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer pair

-76eluting later was collected as Préparation 6p. ‘H NMR (500 MHz, DMSO-dé, 1:1 mixture of diastereomers): 10.33 (br s, IH), 8.63/8.62 (s, IH), 7.47 (m, IH), 7.30 (m, IH), 7.19/7.17 (d, IH), 7.13 (m ,2H), 7.00 (m, 2H), 6.76/6.76 (dd, IH), 6.34/6.29 (d, IH), 5.56/5.53 (m, IH), 5.54/5.42 (dd, IH), 4,07 (m, 2H), 3.68/3.54 (m, 2H), 3.11/3.08 (dd, IH), 2.44 (dd, IH), 2.05-1.89 (m, IH), 1.86/1.84 (s, 3H), 1.80 (m, 2H), 1.72-1.45 (m, 3H), 1.09/1.08 (t, 311). MS: (Μ III) = 681.0

Préparation 6r: Ethyl f27?_?)-2-[(55'_fl)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(4fluorophenyl)thieno[2,3-rf]pyrimidin-4-ylJoxy-3-[2-[[(2Æ)-tetrahydrofuran-2y 1] methoxy] phenyl] propa noate

7.22 g ethyl (2JÎ_/)-2-[5-bromo-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-[2[[(2/?_/)-tetrahydrofuran-2-yl]methoxy]phenyl]propanoate (Préparation 4p) (12.00 mmol) and 4.83 g 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (18.00 mmol) were dissolved in 60 mL dioxane, then 7.82 g CS2CO3 (24.00 mmol) dissolved in 30 mL water was added. Then 708 mg AtaPhos (1.00 mmol) was added, and the mixture was stirred under nitrogen at reflux température until no further conversion was observed. Most of the volatiles were evaporated under reduced pressure, then it was diluted with dichloromethane and brine. After shaking the pH of the aqueous phase was set to 6 with 2 M HCl. After phase séparation the aqueous phase was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, fïltered and concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting later was collected as Préparation 6r. NMR (500 MHz, DMSO-de): 10.25 (br s, IH), 8.60 (s, IH), 7.30 (m, 2H), 7.21 (m, 2H), 7.14 (t, IH), 7.12 (d, IH), 6.95 (d, IH), 6.90 (d, IH), 6.70 (t, IH), 6.32 (d, IH), 5.43 (dd, IH), 4.15 (m, IH), 4.03 (m, 2H), 3.97 (dd, IH), 3.93 (dd, IH), 3.74 (m, IH), 3.66 (m, IH), 2.97 (dd, IH), 2.48 (dd, IH), 1.99 (m, IH), 1.88 (m, IH), 1.85 (s, 3H), 1.82 (m, IH), 1.81 (m, IH), 1.05 (t, 3H).

Préparation 6s: Ethyl (2i?)-2-[5-(3-chloro-4-hydroxy-2-inethyl-phenyl)-6-(4fluoropheny l)thieno J 2,3--/7] py rimidin-4-y 1] oxy-3-[2-(2,2,2trifluoroethoxy)phenyl]propanoate (mixture of diastereoisomers) *

-779.17 g ethyl (2Â9-2-[5-bromo-6-(4-iluorophenyl)lhieno[2,3-iZ]pyrimidin-4-yl]oxy-3-[2(2,2,2-trifluoroethoxy)phenyl]propanoate (Préparation 4s) (15.35 mmol) and 4.95 g 2chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (18.42 mmol) were dissolved in 50 mL THF, then 15.00 g CS2CO3 (46.05 mmol) dissolved in 50 mL water was added. Then 1.09 g AtaPhos (1.54 mmol) was added, and the mixture was stirred under nitrogen at 60°C until no further conversion was observed. Then the most of the volatiles were evaporated under reduced pressure and it was diluted with brine. The pH was set to 6 with 2 M HCI, and the mixture was extracted with dichloromethane . The combined organic layers were dried over Na2SÛ4, filtered and concentrated under reduced pressure and purified via flash chromatography using heptane and ethyl acetate as eluents to Préparation 6s as a mixture of diastereoisomers. ’H NMR (400 MHz, DMSO-dâ): 10.26 (br s, IH), 8.60 (s, IH), 7.32-7.26 (m, 2H), 7.24-7.17 (m, 3H), 7.15-7.11 (m, IH), 7.03-6.94 (m, 2H), 6.82-6.68 (m, IH), 6.33/6.19 (dd, IH), 5.36/5.29 (dd, IH), 4.83-4.64 (m, 2H), 4.09/4.04 (q, 2H), 3.15/3.01 (dd, IH), 2.50/2.37 (dd, IH), 2.32/1.85 (s, 3H), 1.11/1.07 (t,3H).

Préparation 7a; Ethyl (2Æ)-2-[(55„)-5-[3-chIoro-2-methyl-4-[2-(4-metliylpiperazin-lyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-rf]pyrimidin-4~yl]oxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate

132.3 g ethyl (2Æ)-2-[(5_JS'„)-5-(3-chloro-4-hydroxy-2-methyI-phenyl)-6-(4-fluorophenyI)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2-tetrahydiOpyran-2-yloxyphenyl)propanoate (Préparation 6a) (199.5 mmol), 43.17 g 2-(4-methylpipcrazin-l-yl)cthanol (299.3 mmol) and 94.20 g PPhj (359,1 mmol) were dissolved in 1 L dry toluene, then 78.09 g di/er/butyl azodicarboxylate (339.2 mmol) was added. The mixture was stirred at 50°C under N₂ until no further conversion was observed. 980 mL toluene was evaporated, then 500 mL Et20 was added, and the mixture was stirred and sonicated. The precipitated white crystals were filtered, washed with Et₂O to give 65.9 g pure triphenylphosphineoxide. The filtrate was concentrated under reduced pressure and purified via flash chromatography using EtOAc and MeOH as eluents to obtain Préparation 7a. MS: (M+H)⁺ “ 789.2.

-78Préparation 7b; Ethyl (2Æ_y)-2-|(&S^, _fi)-5-|3-chloro-2-methyl-4-[2-(4-inethylpiperazin-lyl)ethoxy]phcnyl]-6-(5-fluoro-2-furyl)thieno[2,3-rf|pyrimidin-4-yl]oxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate

4.94 g ethyl (2.K)-2-[(5S'₍₇)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(4-fluoiOphenyl)thieno[2,3-i/Jpyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)piOpanoate (Préparation 6a) (7.5 mmol), 1.34 g 2-(dimethylamino)ethanol (15 mmol) and 3.94 g PPh₃ (15 mmol) were dissolved in 30 mL dry toluene, then 3.45 g di/er/butyl azodicarboxylate (15 mmol) was added. The mixture was stined at 50°C under N₂ until no further conversion was observed. The toluene was evaporated under reduced pressure and the residue was purified via flash chromatography using DCM and MeOH as eluents to obtain Préparation 7b. MS: (M+H)⁴ = 734.2.

Préparation 7c; Ethyl (2Æj-2-[(5S^, _rt)-5-[3-chloro-2-methyl-4-[2-(4-methylpÎperazin-l yl)ethoxy]phenyl]-6-(5-fluoro-2-furyl)thieno[2,3rfJpyrimidin-4-yl]oxy-3-(2tetrahydropyran-2-y!oxyphenyl)propanoate

11.55 g ethyl (27?)-2-[(50'_iî)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(5-fluoro-2furyl)thieno[2,3-i(]pyrimidin-4-yl]oxy-3-(2-tetrahydiOpyran-2-yloxyphenyl)piOpanoate (Préparation 6c) (7.5 mmol), 5.77 g 2-(4-methylpiperazin-l-yl)ethanol (40 mmol), and 10.49 g PPh₃ (40 mmol) were dissolved in 100 mL dry toluene, then 9.21 g di/er/butyl azodicarboxylate (40 mmol) was added. The mixture was stiired at 50°C under N₂ until no further conversion was observed. The toluene was evaporated under reduced pressure and the residue was purified via flash chromatography using DCM and MeOH as eluents to obtain Préparation 7c. MS: (M+H)⁴ = 695.2.

Préparation 7d: Ethyl (27?J-'2-[(5.S^, _iï)-5-[3-chloro-4-(2-dimeihylaminoethyloxy)-2methyl-phenyl]-6-(5-fluoiO-2-furyl)thieno[23-rf]pyriniidin-4-yl]oxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate

2,87 g ethyl (2Â)-2-[(50'_i7)-5-(3-chloro-4-hydroxy-2-metliyl-phenyl)-6'(5-fluoro-2furyl)thieno[2,3-i/]pyrÎmidin-4-yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)piOpanoate (Préparation 6c) (5.05 mmol), 1.35 g 2-(dimethylamino)ethanol (15.15 mmol) and 3.98 g PPh₃ (15.15 mmol) were dissolved in 100 mL dry toluene, then 3.49 g dito+butyl azodicarboxylate (15.15 mmol) was added. The mixture was stiired at 50°C under N₂ until

-79no further conversion was observed. The toluene was evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents to obtain Préparation 7d. MS: (M+H)⁺ = 724.2.

⁵ Préparation 7c: Ethyl ('2R)-2-[(5>S'_e)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(2-furyl)thieno[23-i/}pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2yloxyphenyl)propanoate

19.05 g ethyl (27î)-2-[(5S_n)-5-(3-chloro-4-hydiOxy-2-metliyl-phenyl)-6-(2-furyl)thieno[2_!3</|pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 6d) 10 (30 mmol), 8.65 g 2-(4-methylpiperazin-l-yl)ethanol (60 mmol) and 15.74 g PPh₃ (60 mmol) were dissolved in 200 mL dry toluene, then 13.81 g ditertbutyl azodicarboxylate (60 mmol) was added. The mixture was stirred at 50°C under N₂ until no further conversion was observed. The toluene was evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents to 15 obtain Préparation 7e. MS: (M+H)⁺ = 761.2.

Préparation 7f: Ethyl (2R)-2-[(5₁S_e)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenylJ-6-(4-fluoro-3-methoxy-phenyl)thieno[2,3-rf|pyrimidin-4-yl]oxy-3(2-tetrahydropyran-2-yloxyphenyï)propanoate

13.5 g ethyl (2/î)-2-[(5S_fl)'5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(4-fluoro-3methoxy-phenyl)thieno[2,3-i/Jpyriinidin-4-yl]oxy-3-(2-tetrahydropyran-2yloxyphenyl)propanoate (Préparation 6h) (13.5 mmol), 5.62 g 2-(4-methylpiperazin-lyl)ethanol (39 mmol) and 10.22 g PPh₃ (39 mmol) were dissolved in 250 mL dry toluene, then 10.22 g difertbutyl azodicarboxylate (39 mmol) was added. The mixture was stirred at 25 50°C under N₂ until no further conversion was observed. The toluene was evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents to obtain Préparation 7f. MS: (M+H)⁺ - 819.0.

Préparation 7g: Ethyl (2iî)-2-[(55^)'5-[3-ehloro-2--methyl~4-[2-(4-methylpÎpciazin-l30 yi)ethoxyJphenyIJ-6-ethyl-thieno[23-rf]pyriiuidin-4-ylJoxy-3-(2-tetrahydropyran-2yloxyphenyl)propanoate

-809.86 g ethyl (2R7“2“[(5iS'_e)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethyl-thieno[2,3<Z]pyrimidin-4-yl]oxy-3-(2-tetrahydiOpyran-2-yloxyphenyl)propanoate (Préparation 6k) (6.46 mmol), 1.73 g 2-(4-methylpiperazin-l-yl)ethanol (12.0 mmol) and 3.15 g PPI13 (12.0 mmol) were dissolved in 40 mL dry toluene, then 2.76 g di/erfbutyl azodicarboxylate (12.0 mmol) was added. The mixture was stirred at 50°C under N₂ until no further conversion was observed. Toluene was evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents to obtain Préparation 7g. MS: (M+H)⁺ “ 723.2.

Préparation 7h: Ethyl (2R)-2-[(5S„)-5-[3-chIoro-2-niethyl-4-[2-(4-niethyipiperazin-lyl)ethoxy]phenyl]-6-prop-l-ynyl-thieno[2,3-iflpyrimidin-4-yl]oxy-3-(2tetrahydropyran-2-yioxyphenyl)propanoate

6.60 g ethyl ('2J?)-2-[(55_fl)-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-prop-l-ynylthieno[2,3-i/]pyrimidin-4-yl]oxy-3-(2-tetfahydrc>pyran-2-yloxyphenyl)propanoate (Préparation 6m) (10.87 mmol), 2.88 g 2-(4-methylpiperazin-l-yl)ethanol (20 mmol) and 5.25 g PPI13 (20 mmol) were dissolved in 450 mL dry toluene, then 4.61 g diter/butyl azodicarboxylate (20 mmol) was added. The mixture was stirred at 50°C under N₂ until no further conversion was observed. The toluene was evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents to obtain Préparation 7h. MS: (M+H)⁺ = 733.2.

Préparation 7i; Ethyl (2/î)-2-[6-(S-chloiO-2-furyl)-5-(5>S_rt)-[3-chloro-2-niethyl-4-(2-(4methylpiperazin~l-yl)ethoxy]phenyl]thieno[2,3-'/]pyrimidin-4-yl]oxy-3-[2-[(4methoxyphenyl)methoxy]phenyl]propanoate

5.30 g ethyl f2R)-2-[6-(5-chJoro-2-furyl)-5-(5S_fl)-(3-chloro-4-hydiOxy-2-methylphenyl)thieno[2,3-ifjpyrimidin-4-yl]oxy-3-r2-f(4-methoxyphenyl)methoxy]phenyl] propanoate (Préparation 6f) (7.5 mmol), 2.16 g 2-(4-methylpiperazin-l-yl)ethanol (15 mmol) and 3.93 g PPh₃ (15 mmol) were dissolved in 30 mL dry toluene, then 3.45 g diferfbutyl azodicarboxylate (15 mmol) was added. The mixture was stirred at 50°C under N₂ until no further conversion was observed. The toluene was evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents to obtain Préparation 7i. MS: (M+H)^4- = 831.0.

-δΐPréparation 7î: Ethyl (2J?)-2-[(5S_ff)-5-f3-chloro-2-methyl4-[2-(4>methylpiperazin-lyl)ethoxy]phenylJ-6-(3,4-difluorophenyl)thieno[2,3-rfjpyrimidin-4-yljoxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate

6.85 g ethyl (2RJ-2-[(5S'_e)-5-(3-chloro~4-hydroxy-2-methyl-phenyl)-6-(3,4difluorophenyl)thieno[2,3-</]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2· yloxyphenyl)propanoate (Préparation 6p) (10.06 mmol), 2,90 g 2-(4-methylpiperazin-lyl)ethanol (20.12 mmol) and 5.27 g PPh₃ (20.12 mmol) were dissolved in 20 mL dry toluene, then 4.63 g difër/butyl azodicarboxylate (20.12 mmol) was added. The mixture was stirred at 50°C under N₂ until no further conversion was observed. The toluene was evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents to obtain Préparation 7j. MS: (M+H)⁺ = 681.0.

Préparation 7k: Ethyl (2Æ)-2-[(5iSfl)-5-[3-chloro-2-methyl-4-[2“(4-methyIpiperazm-l yl)ethoxy]phenyl]-6-(2,3-difluorophenyl)thieno[23-dlpyrimidin-4-yl]oxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate

Step A: 5-Bromo-4-chloro-6-(2,3-difluorophenyl)thieno[2,3-dJpyrvmidine

9.39 g 5-bromo-4-chloro-6-iodo-thieno[2,3-û(]pyrimidine (Préparation la) (25 mmol), 9.00 g 2-(2,3-difluorophcnyl)-4,4,5,5-tctramcthyl-l,3,2-dioxaborolanc (37.5 mmol), 16.29 g Cs₂CO₃ (50 mmol), and 0.912 g Pd(dppf)Cl₂ (1.25 mmol) were placed in a 250 mL flask. 100 mL THF and 50 mL water were added, and then stirred at 70°C under N₂ until no further conversion was observed. The reaction mixture was extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using DCM and MeOH as eluents.

*H NMR (500 MHz, DMSO-d_fi): 9.07 (s, IH), 7.71 (m, IH), 7.46 (m, 2H). HRMS calculated for C|₂H₄BrClF₂N₂S: 359.8935, found: 360.9013 (M+H).

Step B: Ethyl (2R)-2-[5-bromo-6-(2,3-difiuorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3(2-tetrahydropyran-2-yloxyphenyl)propanoate

-828.3 g 5-biOmo-4“ChlorO“6-(2,3-difluorophenyl)thieno[2,3-<7]pyrimidine (23 mmol), 7.48 g ethyl (2Â)-2-hydroxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 3ab) (25.4 mmol) and 26.23 g CS2CO3 (80.5 mmol) were piaced in a 250 mL flask. 100 mL tertbutanol was added and the mixture was stirred at 60°C under N2 until no further conversion was observed. The reaction mixture was diluted with brine, the pH was set between 6-7 with 2 M HCl, and then it was extracted with DCM. The combined organic layers were dried over Na2SO4, fîltered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain the product of Step B as a mixture of diastereoisomers. ^lH NMR (500 MHz, DMSO-da): 8.71 (d, IH), 7.69 (m, IH), 7.43 (m, 3H), 7.19 (m, IH), 7.07 (m, IH), 6.89 (t, IH), 5.83/5.71 (dd, IH), 5.60/5.56 (t, IH), 4.15 (m, 2H), 3.75-3.18 (m, 4H), 1.99-1.56 (m, 4H), 1.82 (m, 2H), 1.15/1.16 (t, 3H). HRMS calculated for CzeHzsBrFatyOsS: 618.0636, found: 619.0695 (M+H).

Step C: Ethyl (2R)-2-[(5S_a)b-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(2,3difluorophenyl)thieno[2,3-d]pyrimidm-4-yî]oxy-3-(2-tetrahydropyran-2yloxyphenyl)propcmoate

8.75 g ethyl f2/?)-2-[(5S_ZJ)-5-bromo-6-(2₁3-difluoiOphenyi)th!eno[2,3-d]pyrimidin-4yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate (14.1 mmol) and 4.92 g 2-chloro3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboiOlan-2-yl)phenol (Préparation 5a) (18.3 mmol) were dissolved in 50 mL THF, then 6.11 g CS2CO3 (18.8 mmol) dissolved in 20 mL water was added. Then 0.5 g AtaPhos (0.7 mmol) was added, and the mixture was stirred under N2 at reflux température until no further conversion was observed. The reaction mixture was diluted with brine and extracted with DCM. The organic combined layers were dried over Na₂SO4, fîltered and concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and EtOAc as eluents. The diastereoisomer pair eluting later was collected as the product of Step C. 'H NMR (500 MHz, DMSO-cL, 1:1 mixture of diastereomers): 10.24 (br s, IH), 8.66/8.65 (s, IH), 7.48 (m, IH), 7.22 (m, IH), 7.13 (m, 2H), 7.08 (d, IH), 7.01 (d, IH), 6.89 (d, IH), 6.74 (t, IH), 6.38/6.32 (d, IH), 5.55 (m, IH), 5.45 (dd, IH), 4.04 (m, 2H), 3.68/3.54 (m, 2H), 3.32 (dd, IH), 2.47 (dd, IH), 2.06-1.48 (m, 6H), 1.90/1.88 (s, 3H), 1.07/1.06 (t, 3H). HRMS calculated for C₃5H3iClF₂N2O₆S: 680.1559, found: 681.1618/681.1624 (M+H).

♦

-83Step D: Ethyl (2R)-2-[(5Sa)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazÎn-lyl)ethoxy]phenyl]-6-(3,4-difluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2tetrahydropyran-2-yloxyphenyl)propcmoate

6.49 g ethyl (2/?)-2-[(55₀)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(2,3difluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-(2-tetraliydropyran-2-yloxyphcnyl) propanoate (9.5 mmol), 2.75 g 2*(4-methylpiperazin-l-yl)ethanol (19 mmol) and 4.98 g PPI13 (19 mmol) were dissolved in 20 mL dry toluene, then 4,38 g di/er/butyl azodicarboxylate (19 mmol) was added. The mixture was stirred at 50°C under N₂ until no further conversion was observed. The toluene was evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents to obtain Préparation 7k. *H NMR (500 MHz, DMSO-de, 1:1 mixture of diastereomers): 8.67 (s, 1H), 7.48 (m, 1H), 7.22-7.17 (m, 3H), 7.13 (t, 1H), 7.10 (d, 1H), 7.01 (d, 1H), 6.72 (t, 1H), 6.33/6.28 (d, 1H), 5.54/5.51 (m, 1H), 5.45 (dd, 1H), 4.18 (m, 2H), 4.03 (m, 2H), 3.68/3.54 (m, 2H), 3.02/2.99 (dd, 1H), 2.69 (t, 2H), 2.56 (m, 1H), 2.46 (br s, 4H), 2.22 (br s, 4H), 2.08 (s, 3H), 2.03-1.46 (m, 6H), 1.93/1.92 (s, 3H), 1.05 (t, 3H). HRMS calculated for C4₂H4₃C1F₂N2O₆S: 806.2716, found: 807.2763/807.2793 (M+H).

Préparation 8a; Ethyl f2_JR)-2-[(5S_e)-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(4-flnorophenyl)thieno[2,3-«r]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate

199.5 mmol ethyl (27?)-2-[(55'„)-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)elhoxyJphenyl]-6-(4-fluorophenyl)thieno[2,3-iflpyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)-propanoate (Préparation 7a) was dissolved in 1 L EtOH, then 1 L 1.25 M HCl in EtOH was added and the mixture was stirred at room température until no further conversion was observed. Most of the EtOH was evaporated, then Et₂O was added and the precipitated HCl sait (white solid) was filtered, washed with Et₂O. The HCl sait was carefully treated with saturated NaHCO.3 solution, extracted with DCM, the combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure to give Préparation 8a. 'H NMR (400 MHz, DMSO-de): 9.53 (br s, 1H), 8.60 (s, 1H),

7.30 (m, 2H), 7.28 (d, 1H), 7.21 (m, 2H), 7.16 (d, IH), 6.97 (t, 1H), 6.72 (d, 1H), 6.53 (t, 1H), 6.20 (d, 1H), 5.46 (dd, 1H), 4.22 (m, 2H), 4.04 (m, 2I-I), 2.92 (dd, 1H), 2.75 (m, 2H),

-842.53 (br s, 4H), 2.44 (dd, IH), 2.36 (br s, 4H), 2.17 (s, 3H), 1.88 (s, 3H), 1.06 (t, 3H). HRMS calculated for C₃7H_3SC1FN₄O₅S: 704.2235, found: 705.2288 (M+H).

Préparation 8b: Ethyl (27?_/)-2-|(55_rt)-[3-chloro-4-(2-diinethylaininoethyloxy)-2-methylphenyl]“6-(4-fluoropheiiyl)thÎeno[2,3-i/|pyriniidin-4-yl]oxy-3-(2hydroxyphenyl)propanoatc

5.60 mmol ethyl (27f)-2-[(55^l _ir)-5-[3-chloiO-4-(2-dimethylaminoethyloxy)-2-methyl· phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyiïmidin-4-yl]oxy-3-(2-tetrahydiOpyran-2yloxyphenyl)propanoate (Préparation 7b) was dissolved in 40 mL EtOH, then 20 mL 1.25 M HCl in EtOH was added and the mixture was stirred until no further conversion was observed. Water and saturated NaHCO₃ solution were added catefully and the mixture was extracted with DCM, the combined organic phases were dried over Na₂SO₄, fîltered and concentrated under reduced pressure. The crude product was purified via flash chromatography using DCM and EtOAc as eluents to obtain Préparation 8b. ^!H NMR (500 MHz, DMSO-de): 9.53 (br s, IH), 8.61 (s, IH), 7.30 (m, 2H), 7.29 (d, IH), 7.31 (m, 2H), 7.16 (d, IH), 6.97 (m, IH), 6.71 (dm, IH), 6.52 (m, IH), 6.18 (dm, IH), 5.46 (dd, IH), 4.20 (t, 2I-I), 4.04 (m, 2H), 2.92 (dd, IH), 2.69 (t, 2H), 2.43 (dd, IH), 2.22 (s, 6H), 1.88 (s, 3H), 1.06 (t, 3H). HRMS calculated for C34H33CIFN3O5S: 649.1813, found: 650.1887 (M+H).

Préparation 8c: Ethyl (2jî)-2-[(53'_rt)-5-[3-chloro-2-inethyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(5-fluoro-2-furyl)thieno[2^-rf]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate

184 mmol ethyl f2Æ)-2-[(55_rt)-5-[3-chloiO-2-methyl-4-[2-(4-methy lpiperazin-1yl)ethoxy]phenyl]-6-(5-fluoro-2-furyl)thieno[2,3-t/]pyrimidin-4-yl]oxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 7c) was dissolved in I L EtOH, then 1 L 1.25 M HCl in EtOH was added and the mixture was stirred at room température until no further conversion was observed. Most of the EtOH was evaporated, then Et₂O was added and the precipitated HCl sait (white solid) was filtered, washed with Et₂O. The HCl sait was carefiilly treated with saturated NaHCO₃ solution, extracted with DCM, the combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using DCM and MeOH

-85as eluents to obtain Préparation 8c. ’H NMR (500 MHz, DMSO-d₍₎): 9.55 (s, IH), 8.58 (s, IH), 7.25 (s, 2H), 6.99 (t, IH), 6.72 (d, IH), 6.59 (t, IH), 6.23 (d, IH), 5.88 (dd, IH), 5.72 (t, IH), 5.47 (dd, IH), 4.27 (t, 2H), 4.04 (m, 2H), 2.95 (dd, IH), 2.77 (t, 2H), 2.53 (br s, 4H), 2.35 (dd, IH), 2.30 (br s, 4H), 2.13 (s, 3H), 1.97 (s, 3H), 1.06 (t, 3H). HRM.S calculated for C^CFN^S: 694.2028, found: 695.2106 (M+H).

Préparation 8d; Ethyl (2R)-2-[(5S_n)>5-[3-chloro>4-(2-dimethylaminoethyloxy)-2methyl-phenyl]-6-(5-fluoro-2-furyl)thieno[2,3-rfJpyrimidin-4-yl]oxy-3-(2hyd roxy pheny l)propanoate

30 mL 1.25 M HCl in EtOH was added to 1.5 mmol ethyl (2iî)-2-[(5iS'_fl)-5-|'3-chloro-4-(2dimethylamÎnoethyloxy)-2-methyl-phenyl]-6-(5-fluoro-2-furyl)thieno[2,3V!pyrimidin-4yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate (Pi-eparation 7d) and the mixture was stirred until no further conversion was observed. The reaction mixture was carefully diluted with saturated NaHCO₃ solution and the mixture was extracted with DCM, the combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure. The crade product was purified via flash chromatography using EtOAc and MeOH as eluents to obtain Préparation 8d. ‘H NMR (500 MHz, DMSO-dé): 9.56 (br s,

IH), 8.58 (s, IH), 7.25 (s, 2H), 6.99 (td, IH), 6.72 (dd, IH), 6.59 (td, IH), 6.23 (dd, IH), 5.88 (dd, IH), 5.71 (t, IH), 5.48 (dd, IH), 4.25 (m, 2H), 4.04 (m, 2H), 2.96 (dd, IH), 2.71 (t, 2H), 2.35 (dd, III), 2.23 (s, 6H), 1.98 (s, 3H), 1.06 (t, 3H). HRMS calculated for

C₃2H₃|C1FN.,O₆S: 639.1606, found: 640.1679 (M+H).

Préparation 8e: Ethyl (2R)-2-[(55_n)-5-[3-chIoro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]pheny]J-6-(2-furyl)thienoJ2,3-//|pyrimidin-4-yl]oxy-3-(2-hydroxyphenyl) propanoate mmol ethyl (2^)-2-[(55_ff)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(2-iuryl)thieno[2,3-i7jpyriinidin-4-yl]oxy-3-(2-tetrahydropyran-2yloxyphenyl)propanoate (Préparation 7e) was dissolved in 200 mL EtOH, then 200 mL

1.25 M HCl in EtOH was added and the mixture was stirred at room température until no further conversion was observed. Saturated NaHCO3 solution was added, and the reaction mixture was extracted with DCM. The combined organic layers were dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash

-86chromatography using DCM and MeOH as eluents to obtain Préparation 8e. *H NMR (500 MHz, DMSO-de): 9.55 (s, 1H), 8.58 (s, 1H), 7.80 (d, 1H), 7.26 (d, 1H), 7.24 (d, 1H), 6.99 (t, 1H), 6.72 (d, 1H), 6.60 (t, 1H), 6.53 (dd, 1H), 6.24 (d, 1H), 5.69 (d, 1H), 5.48 (dd, 1H), 4.28 (t, 2H), 4.04 (m, 2H), 2.95 (dd, 1H), 2.78 (t, 2H), 2.51 (br s, 4H), 2.34 (dd, 1H),

2.31 (br s, 4H), 2.13 (br s, 3H), 1.96 (s, 3H), 1.06 (t, 3H). HRMS calculated for C35II37CIN4O6S: 676.2122, found: 677.2194 (M+H).

Préparation 8f: Ethyl (2ft)-2-[(55«)-6-(5-chloro-2-furyl)-5-[3-chloro-2-inethyl-4-[2-(4methylpiperazin-l-yl)ethoxy]plienyl]thieno[2,3-r/]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate

200 mL 1.25 M HCI in EtOH was added to 7 mmol ethyl (2Æ)-2-[6-(5-chloiO-2-furyl)-5(5S'₍₁)-[3-chloiO-2-methyl-4-[2-(4-methylpiperazm-l-yl)ethoxy]phenyl]thieno[2,3<7]pyrimidin-4-yl]oxy-3-[2-[(4-niethoxyphenyl)methoxy]phenyl]propanoate (Préparation 7i) and the mixture was stirred at 80°C until no further conversion was observed. Saturated NaHCÛ3 solution was added to the réaction mixture, and it was extracted with DCM. The combined organic layers were dried over Na2SO4, fîltered and concentrated under reduced pressure and purified via flash chromatography using DCM and MeOH as eluents to obtain Préparation 8f. ‘H NMR (500 MHz, DMSO-d₆): 9.56 (br s, 1H), 8.59 (s, 1H), 7.25 (s, 2I-I), 6.99 (t, 1H), 6.72 (d, 1H), 6.59 (t, 1H), 6.55 (d, 1H), 6.23 (d, 1H), 5.74 (d, 1H), 5.48 (dd, 1H), 4.28 (t, 2H), 4.04 (m, 2H), 2.95 (dd, 1H), 2.79 (t, 2H), 2.58 (br s, 4H), 2.44 (br s, 41-1), 2.35 (dd, 1H), 2.23 (br s, 3H), 1.96 (s, 311), 1.06 (t, 311). HRMS calculated for C35H36CI2N4O6S: 710.1733, found: 711.1797 (M+H).

Préparation 8g: Ethyl (22?)-2-[(55„)-5-[3-chloro-2-methyl-4-|2-(4-mcthylpiperazin-lyI)ethoxy]phenyl]-6-(4-fluoro-3-methoxy-phenyl)thieno[2,3-rf]pyrimÎdin-4-yl]oxy-3(2-hydroxyphenyl)propanoate mmol ethyl f27?J-2-[(5S„)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(4-fluoro-3-methoxy-phenyl)thieno[2₃3-</|pyrimidin-4-yl]oxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 7f) was dissolved in 300 mL EtOH, then 150 mL 1.25 M HCl in EtOH was added and the mixture was stirred at room température until no further conversion was observed. Saturated NaHCO₃ solution was added and the mixture was extracted with DCM. The combined organic layers were dried

-87over Na2SÛ4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using DCM and MeOH as eluents to obtain Préparation 8g. ’H NMR (500 MHz, DMSO-d₆): 9.57 (br s, IH), 8.61 (s, IH), 7.31 (d, IH), 7.24 (dd, IH), 7.19 (d, IH), 6.97 (td, IH), 6.93 (ddd, IH), 6.86 (dd, IH), 6.71 (d, IH), 5 6.53 (t, IH), 6.16 (d, IH), 5.46 (dd, IH), 4.23 (m, 2H), 4.05 (m, 2H), 3.57 (s, 3H), 2.95 (dd, IH), 2.73 (m, 2H), 2.72 (br s, 4H), 2.68 (br s, 4H), 2.41 (dd, IH), 2.10 (s, 3H), 1.88 (s, 3H), 1.07 (t, 3H). ). HRMS calculated for C₃₈H₄₀ClFN₄O₆S: 734.2341, found: 735.2406 (M+H).

Préparation 8h; Ethyl (2R)-2-[(55_rt)-5-[3-chloro-2-methyl-4-[2-(4-niethyipiperazin-lyl)ethoxy|phenyi|-6-ethyi-thieiio[2,3-R]pyiimÎdin-4-yljoxy-3-(2hydroxyphenyl)propanoate mmol ethyl (2J?/2-[(5S_a)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-ethyl-thieno|2,3-i/Jpyrimidin-4-yl]oxy-3-(2-tetrahydropyran-215 yloxyphenyl)propanoate (Préparation 7g) was dissolved in 100 mL EtOH, then 40 mL

1.25 M HCl in EtOH was added and the mixture was stirred at room température until no further conversion was observed. Saturated NaHCO₃ solution was added and the reaction was extracted with DCM. The combincd organic layers were dried over Na2SO₄, filtered and concentrated under reduced pressure. The crude product was purified via flash 20 chromatography using DCM and MeOH as eluents to obtain Préparation 8h. *H NMR (500 MHz, DMSO-de): 9.53 (s, IH), 8.53 (s, IH), 7.21 (d, IH), 7.18 (d, IH), 6.99 (t, IH), 6.72 (d, IH), 6.58 (t, IH), 6.22 (d, IH), 5.42 (dd, IH), 4.25 (m, 2H), 4.02 (m, 2H), 2.90 (dd, IH), 2.76 (m, 2H), 2.67 (m, IH), 2.60 (m, IH), 2.49 (br s, 4H), 2.41 (dd, IH), 2.27 (br s, 4H), 2.11 (s, 3H), 2.01 (s, 3H), 1.17 (t, 3H), 1.05 (t, 3H). HRMS calculated for 25 C₃₃H₃₉C1FN₄O₅S: 638.2330, found: 639.2377 (M+H).

Préparation 81; Ethyl (27?>-2-|(55_i,)-5-[3-chloro-2-inethyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyi]-6-prop-l-ynyl-thieno[2,3-rf]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate

10 mmol ethyl (2Æ)-2-[(5S_a)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-prop-l-ynyl-thieno[2,3-i7|pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2yloxyphenyl)propanoate (Préparation 7h) was dissolved in 100 mL EtOH, then 40 mL

1.25 M HCl in EtOH was added and the mixture was stirred at room température untii no further conversion was observed. The most of the EtOII was evaporated then saturated NaHCOj solution was added and the mixture was extracted with DCM. The combined organic layers were dried over Na₂SÛ4, filtered and concentrated under reduced pressure 5 and purified via flash chromatography using DCM and MeOH as eluents to obtain Préparation 8i. *1-1 NMR (500 MHz, DMSO-d₆): 9.53 (s, IH), 8.62 (s, IH), 7.24 (d, IH), 7.19 (d, IH), 6.97 (m, IH), 6.70 (dm, IH), 6.52 (m, IH), 6.05 (dm, IH), 5.41 (dd, IH),

4.25 (t, 2H), 4.05 (m, 2H), 2.97 (dd, IH), 2.76 (m, IH), 2.74 (m, IH), 2.51 (br s, 4H), 2.42 (dd, IH), 2.26 (br s, 4H), 2.11 (s, 3H), 2.10 (s, 3H), 2.03 (s, 3H), 1.08 (t, 3H). HRMS calculated for C₃4H₃₇C1N₄O₅S: 648.2173, found: 649.2275 (M+H).

Préparation 8j; Ethyl (2R)-2-[5-|5-chloro-4-methyl-6-[2“(4-methyIpiperazin-lyl)ethoxy]-3-pyridyl]-6-(4-fluorophenyl)thieno[2,3-rf]pyriimdiii-4-ylJoxy-3-(2hydroxyphenyl)propanoate (mixture of diastereoisomers)

Step A: Ethyl (2R)-2-[5-[5-chloro-4-methyl-6-[2-(4-meihylpiperazind-yl)ethoxy]-3pyridyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2-tetrahydropyrari-2yloxyphenyl)propanoate

1.504 g ethyl (2Æ)-2-[5-bromo-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-(220 tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 4a) (2.50 mmol) and 1.052 g 1[2-[[3-chloro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2~ pyridyl]oxy]ethyl]-4-methyl-piperazine (Préparation 5q) (2.66 mmol) were dissolved in 15 mL THF, then 1.63 g Cs₂CO₃ (5.00 mmol) dissolved in 5 mL water was added. Then 177 mg AtaPhos (0.25 mmol) was added, and the mixture was stirred under nitrogen at 25 reflux température untii no further conversion was observed. Then the mixture was diluted with brine, extracted with DCM, the combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure, then purified via flash chromatography using EtOAc and MeOH as eluents.

Step B: Ethyl (2R)-2-[5-[5-chloro-4-methyl-6-[2-(4-methylpiperaziri-l-yl)ethoxy]-3pyridyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2~hydroxyphenyl) propcmoate (mixture of diastereoisomers) e

-89The obtained ethyl (2^-2-['5-[5-chioro-4-methyl-6-[2-(4-methylpiperazin-I-yi)ethoxy]-3pyridylJ-6-(4-fluorophenyl)thieno[2,3-tf]pyrimidin-4-yl]oxy~3-(2-tetrahydiOpyran-2yloxyphcnyl)propanoate was dîssolved in 50 mL EtOH, then 10 mL 1.25 M HCl in EtOH was added and the mixture was stirred at room température until no further conversion was observed. Saturated NaHCCh solution was added carefully and the mixture was extracted with DCM, the combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using DCM and MeOH as eluents to give Préparation 8j as a mixture of distereoisomers. ’H NMR (400 MHz, DMSO-d₆): 9.57 (br s, IH), 8.65/8.64 (s, IH),

8.07/7.68 (s, IH), 7.37-7.31 (m, 2H), 7.27-7.22 (m, 2H), 6.98/6.96 (td, IH), 6.72/6.70 (dd,

IH), 6.54/6.48 (td, IH), 6.29/6.05 (dd, IH), 5.55/5.42 (dd, IH), 4.60-4.41 (m, 2H), 4.074.01 (m, 2H), 3.05/2.92 (dd, IH), 2.72/2.69 (t, 2H), 2.48-2.12 (m, 9H), 2.09 (s, 3H), 2.08/1.90 (s, 3H), 1.10/1.05 (t, 3H). MS (M+H): 706.2.

Préparation 8k: Ethyl (2Æ)-2-[(55^, _/r)-5-[3-chIoro-2-methyM-[2-(4-methylpiperazin-lyl)ethoxy]phenylJ-6-(3,4-difluorophcnyl)thieno[23-rf]pyrÎmidin-4-ylJoxy-3-(2hydroxyphenyl)propanoate

7.85 g ethyl (2R>-2-[(5S₀)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(3,4-difluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(220 tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 7j) (9.72 mmol) was dîssolved in 70 mL EtOII, then 50 mL 1.25 M HCl in EtOH was added and the mixture was stirred at room température until no further conversion was observed. The most of the EtOII was evaporated then water and saturated NalICCb solution were added and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using DCM and MeOH as eluents to obtain Préparation 8k. *H NMR (500 MHz, DMSO-dô): 9.54 (s, IH), 8.63 (s, IH), 7.46 (m, IH), 7.32 (m, IH), 7.30 (d, IH), 7.18 (d, IH), 7.11 (m, IH), 6.97 (t, IH), 6.71 (d, IH), 6.53 (t, IH), 6.19 (d, IH), 5.46 (dd,

IH), 4.23 (m, 2H), 4.04 (m, 2H), 2.92 (dd, IH), 2.73 (m, 2H), 2.50 (br s, 4I-I), 2.43 (dd,

IH), 2.25 (br s, 4H), 2.10 (s, 3H), 1.89 (s, 3H), 1.06 (t, 3H). HRMS calculated for C37H37CIF2N4O5S: 722.2141, found: 723.2211 (M+H).

-90Préparation 81: Ethyl (27î)-2-[(55_w)-5-(3-ehloro-4-methoxy-2-niethyl-phenyl)-6-(4fluorophenyl)thieno[2,3-rf]pyrimidin-4-yl]oxy-3-(2-hydroxyphenyl)propanoate

Step A: Ethyl (2R)-2-[(5S_a)-5-(3-chloro-4-methoxy-2-me.thyl-phenyl)-6-(4fuorophenyl)thieno[2,3-d]pyrimidm-4-yl]oxy-3-(2-tetrahydropyran-2yloxyphenyl)propanoate

12.47 g ethyl (2Â/2-[5-biOmo-6-(4-fluorophenyl)thieno[2,3-i/]pyiimidin-4-ylJoxy-3“(2tetra-hydropyran-2-yloxyphenyl)propanoate (Préparation 4a) (20.7 mmol) and 8.20 g 2(3-chloiO-4-methoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Préparation 5d) (29.0 mmol) were dissolved in 145 mL THF. then 13.50 g Cs₂CO₃(41.50 mmol) dissolved in 48 mL water was added. Then 1.17 g AtaPhos (1.66 mmol) was added, and the mixture was stirred under nitrogen at reflux température until no further conversion was observed. Then most of the volatiles were evaporated and the residue was diluted with brine. The pH was set to 6 with 2 M HCl, and the mixture was extracted with DCM. The combined organic layers were dried over Na₂SO4, filtered and concentrated under reduced pressure, then purified via flash chromatography using heptane and EtOAc as eluents. The diastereoisomer pair eluting later was collected as ethyl (2À)-2-[(5X)-5-(3chloiO-4-methoxy-2-methyl-phenyl)-6-(4-fluoiOphenyl)thieno[2,3-i(]pyrimidin-4-yl]oxy-3(2-tetrahydropyran-2-yloxyphenyl)propanoate.

Step______B: Ethyl (2R)-2-[(5S_c)-5-(3-chloro-4-methoxy-2-methyl-pheiiyl)-6-(4fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2-hydroxyphenyl)propanoate

The product of Step A was dissolved in 300 mL EtOH, then 150 mL 1.25 M HCl in EtOH was added and the mixture was stirred at room température until no further conversion was observed. Most of the EtOH was evaporated, then saturated NaHCO₃ solution was added carefully, and the mixture was extracted with DCM, dried over Na₂SÛ4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using DCM and MeOH as eluents to give Préparation 81. ’H NMR (500 MHz, DMSO-d₆): 9.52 (s, IH), 8.61 (s, IH), 7.30 (m, 3H), 7.22 (t, 2H), 7.14 (d, IH), 6.97 (t, IH), 6.71 (d, IH), 6.53 (t, IH), 6.18 (d, IH), 5.45 (dd, IH), 4.04 (m, 2H), 3.90 (s, 3H), 2.91 (dd, IH), 2.44 (dd, IH), 1.89 (s, 3H), 1.06 (t, 3H). HRMS calculated for C₃iH26C1FN₂O_sS: 592.1235; found 593.1307 (M+H).

-91Prepa ration 8m: Ethyl (2_JR)-2-((55^, _e)-5-[3-chloro-2-inethyl-4-|2-(4-methy!piperazin-lyl)ethoxy]phenyl]-6-(23-difluorophenyl)thieno[2,3-rf]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate

9.72 mmol ethyl (2/?)-2-[(55'_a)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)cthoxy]phcnyl]-6-(2,3-difluoiOphcnyl)thicno[2,3-i/]pyrimidin-4-yl]oxy-3-(2tetrahydropyran-2-yloxyphenyI)propanoate (Préparation 7k) was dissolved in 70 mL EtOH, then 60 mL 1.25 M HCl in EtOH was added and the mixture was stirred at room température until no further conversion was observed. Ice and saturated NaHCO₃ solution were added and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using EtOAc and MeOH as eluents to obtain Préparation 8m. *H NMR (500 MHz, OMSO-dg): 9.54 (br s, IH), 8.66 (s, IH), 7.48 (m, IH), 7.22-7.18 (m, 3H), 7.09 (m, IH), 6.97 (t, IH), 6.72 (d, IH), 6.52 (t, IH), 6.21 (d, IH), 5.47 (dd, IH), 4.18 (m, 2H), 4.02 (m, 2H), 2.86 (dd, IH), 2.72 (m, 2H), 2.53 (dd, IH), 2.51 (br s, 4H), 2.39 (br s, 4H), 2.19 (br s, 3H), 1.94 (s, 3H), 1.04 (t, 3H). HRMS calculated for C₃₇H₃₇C1F₂N₄O₅S: 722.2141; found 723.2177 (M+H).

Unless otherwise specifîed, most of the compounds of Préparation 9aa to 9ei were obtained using General procedures 9A to 9H described below.

General procedure 9A:

The appropriate acetal (1.0 eq.) was stirred with 2N HCl solution (3 mL/mmol) at 60°C until no further conversion was observed. Reaction mixture was cooled to 0°C, then NaOH (5.7 eq.) was added portionwise. The pH was adjusted to 8 using 10% K₂CO₃ solution, then sodium borohydride (2.0 eq.) was added portionwise keeping the température under 5°C and the mixture was stirred for 30 min at 0°C. Reaction mixture was extracted with EtOAc, the combined organic phases were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crade product was purified via flash chromatography using heptane and EtOAc as eluents.

92General procedure 9B:

The appropriate acetal (1.0 eq.) was stirred with IN HCl solution (3 mL/mmol) at 50°C for 45 min. Reaction mixture was cooled to 0°C, then NaOH (2.85 eq.) was added portionwise. The pH was adjusted to 8 using 10% K2CO3 solution, then sodium borohydridc (2.0 cq.) was added portionwise keeping the température under 5°C and stirred for 30 min at 0°C. Reaction mixture was extracted with EtOAc, the combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents.

General procedure 9C;

To the mixture of the appropriate amidine hydrochloride (1.2 eq.) and (£)-415 (dimethylamino)-l,l-dimethoxy-but-3-en-2-one (Préparation 9a 1, 1.0 eq.) in dry methanol (0.5 mL/mmol) sodium methoxide (1.2 eq.) was added portionwise and the mixture was stirred at 75 °C for 2 h. The reaction mixture was cooled and concentrated under reduced pressure. To the residue water \vas added and it was extracted with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents.

General procedure 9D;

To the mixture of the appropriate hydrazine hydrochloride (1.2 eq.) and (E)-4(dimethylamino)-l,l-dimethoxy-but-3-en-2-one (Préparation 9al, 1.0 eq.) in dry methanol (0.5 mL/mmol) sodium methoxide (1.2 eq.) was added portionwise and the mixture was stirred at 75 °C for 2 h. The reaction mixture was cooled and concentrated under reduced pressure. To the residue water was added and it was extracted with DCM.

The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents.

*

-93General procedure 9E;

To the solution of the appropriate methylsulfonyl dérivative (Préparation 9a3 l.O eq.) in 5 dry acetonitrile (3ml/mmol) K2CO3 (2.0 eq.) and the appropriate amine (1.5 eq.) were added, and stirred at 70°C until no further conversion was observed. The reaction mixture was cooled, filtered, the precipitate was washed with EtOAc, then the filtrate was concentrated under reduced pressure. Crude product was purified via flash chromatography using heptane and EtOAc as eluents.

I0

General procedure 9F:

To the solution of ΙΗ-pyrazole (l .0 eq.) in DMF (0.5 mL/mmol) KOH (l.0 eq.) was added, then it was cooled to 0°C, and the appropriate halide was added (1.0 eq.) dropwise. The 15 mixture was stirred at room température until no further conversion was observed. The mixture was diluted with DCM and washed with water. The organic layer was dried over MgSÛ4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents.

²⁰ General procedure 9G:

To the suspension of sodium hydride (1.10 eq.) in tetrahydrofurane (0.20 mL/mmol) was added the solution of pyrazolc (1) (1.0 eq.) in tetrahydrofurane (0.12 mL/mmol) dropwise, while the température was kept under 20 °C. After the mixture was stirred at room 25 température for 30 minutes, the appropriate halide (1.20 eq.) was added and the mixture was stirred further at same température for 16 hours. Next, the reaction mixture was refluxed for 15 hours. After completion the resulting precipitate was filtered off, the filtrate was concentrated then the residue was poured onto a mixture of water and ethyl acetate.

The phases were separated, and the aqueous layer was extracted with ethyl acetate. The 30 combined organic layers were dried over Na₂SÜ4, filtered and concentrated under reduced pressure. The crude product was purified via distillation.

-94General procedure 9H:

To the solution of appropriate alkyl pyrazole (l.O eq.) in dry tetrahydrofurane (1.5 mL/mmol) n-butyllithium (1.10 eq.) was added dropwise at -70 °C. The mixture was stirred further at same température for 30 minutes; afterwards allowed to warm up to 0 °C in approx. 30 minutes, and cooled in a dry icc bath. N.N-dirnethylformamide (1.10 eq.) was added dropwise at -70 °C, then the reaction mixture was stirred at room température overnight. The mixture was cooled to 15 °C, and saturated ammonium chloride solution was added dropwise to the mixture at 15 °C, then the mixture was poured into saturated ammonium chloride solution. The phases were separated, the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na₂SÛ4, and concentrated under reduced pressure. The residue was used in tire next step without further purification. To the solution of the appropriate crude aldéhyde (1.0 eq.) in éthanol (0.5 mL/mmol) sodium borohydride (1.30 eq.) was added portionwise at -15 °C then the reaction mixture was stirred at room température for 1 h. The mixture was poured onto crushed ice and stirred for 16 hours. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The oily phase was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na₂SÛ4, and concentrated to dryness.

Préparation 9al: (£)4-(Dimethylamino)-l,l-diniethoxy-but-3-en-2-one

502.1 g l,l-dimethoxypropan-2-one (4.25 mol) and 506.4 g 1 ,l-diinethoxy-A,ÀMirnethylmethanamine (4.25 mol) were mixed in a 2 L flask and stirred at 105°C for 3 hours. The formed MeOH was removed continuously via distillation. When MeOH formation stopped (at 65°C head température) the reaction mixture was vacuum distilled (decreasing the pressure slowly to 30 mbar) to remove side products and unreacted starting materials. The crade product was distilled at 0.1 mbar. Fractions were collected between 107-118°C head température (bath température 160-165°C) to give a yellow oil. *H NMR (500 MHz, DMSO-dô): 7.59 (d, III), 5.17 (d, 1H), 4.42 (s, 1H), 3.25 (s, 6H), 3.09 (s, 3H), 2.78 (s, 3H).

Préparation 9a2; 4-(Dimethoxymethyl)-2-methyIsulfanyl-pyrnnidinc

-95198 g sodium methoxide (3,67 mmol) was dissolved in 3 L MeOH and cooled to 0°C. 322 g thiocarbamide (4.23 mol) was added portionwise and the mixture was stirred for 1 hour. Then 488 g (E)-4-(dimethylamino)-l,l-dimethoxy-but-3-en-2-one (Préparation 9al) (2.82 mol) was added dropwise at 0°C, then it was heated to 70°C for 4 hours. It was cooled to room température, 237 mL methyl iodide (3.81 mol) was added dropwise, kccping the température below 28°C, and the resulting mixture was stirred ovemight at room température. It was fïltered, the filtrate was concentrated under reduced pressure, diluted with EtOAc, washed with water and brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over Na₂SO4, fïltered and concentrated under reduced pressure. The residue was dissolved in 500 mL Et₂O, fïltered through a pad of silica, using Et₂O as eluent. The filtrate was concentrated under reduced pressure to give a light brown oil. *H NMR (400 MHz, DMSO-d₆): 8.69 (d, IH), 7.23 (d, IH), 5.22 (s, IH), 3.33 (s, 6H), 2.52 (s, 3H).

Préparation 9a3:4-(Dimethoxyinethyl)-2-methylsu!fonyl-pyrîmidine

To solution of 180 g 4-(dimethoxymethyl)-2-methylsulfanyl-pyrimidine (Préparation 9a2, 940 mmol) in 1.5 L methanol and 1.5 L H₂O 752 g Oxone (potassium peroxymonosulfaie, 1220 mmol) was added portionwise at -5°C, then stirred at 0°C ovemight. The reaction mixture was concentrated under reduced pressure to half volume using a 30°C bath and then the mixture was fïltered, and the précipitâtes were was washed with DCM. The filtrate was extracted with DCM. The combined organic layers were dried over MgSÛ4, fïltered and concentrated under reduced pressure to give a light brown oil. *H NMR (400 MHz, CDCh): 8.98 (d, IH), 7.97 (d, IH), 5.36 (s, IH), 3.47 (s, 6H), 3.39 (s, 3H).

Préparation 9a4: 2-Methvlsulfonvl-4-(tetrahydronvran-2-yloxymcthyl)pyrimidine

Step A:

To solution of 7.24 g (2-methylsulfanylpyrimidin-4-yl)methanol (Préparation 9aa, 47.5 mmol) and 30.0 g 3,4-dihydro-2H-pyran (357 mmol) in 150 mL DCM 452 mg of ptoluenesulfonic acid monohydrate (2.30 mmol) was added and it was stirred at room température for 2h. The reaction mixrture was diluted with DCM, then it was washed with water and saturated aq. NaHCO₃. The organic layer was dried over Na₂SO4 and

-96concentrated under reduced pressure. The residue was purified via flash chi'omatography using heptane and EtOAc as eluents to give 2-methyIsulfanyI-4-(tetrahydropyran-2yloxymethyl)pyrimidine. MS: (M+H)⁺ = 241.2.

Step B:

To solution of 11.4 g 2-methylsulfanyl-4-(tetrahydropyran-2-yloxymcthyl)pyrimidine (47.5 mmol) in 500 mL DCM 24.6 g MCPBA (3-chloroperoxybenzoic acid, 143 mmol) was added portionwise at 0°C and stirred at this température for 1 h. The précipitâtes were filtered off, and the filtrate was washed water and saturated aq. NaHCOj. The organic layer was dried over Na₂SO4 and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to give the title product. *H NMR (400 MHz, CDC1₃): 9.05 (d, 1H), 7.86 (d, 1H), 4.83 (d, 1H), 4.80 (m, 1H), 4.74 (d, 1H), 3.77 (m, 1H), 3.48 (m, 1H), 3.41 (s, 3H), 1.88-1.40 (m, 6H).

Préparation 9a5:5-(Dimethoxymethyl)-lH-pyrazole

To the mixture of the 4.11 g hydrazine hydrochloride (60.0 mmol) and 8.66 g (£)-4(dimethylamino)-1,l-dimethoxy-but-3-en-2-one (Préparation 9al, 50.0 mmol) in dry methanol 3.241 g sodium methoxide (60.0 mmol) was added portionwise and the mixture was stirred at 50°C for 45 min. The reaction mixture was cooled and concentrated under reduced pressure. To the residue water was added and it was extracted with DCM. The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give the title product. *H NMR (400 MHz, CDCI3): 12.78 (br s, 1H), 7.68 (s, 1H), 6.22 (d, 1H), 5.37 (s, 1H), 3.24 (s, 6H).

Préparation 9aa; (2-Mcthvlsulfanvlpyrimidin-4-yl)methanol

Starting from 4-(dimethoxymethyl)-2-methylsulfanyl-pyrimidine (Préparation 9a2) using General procedure 9A the title product was obtained as white ciystals. *H NMR (400 MHz, DMSO-d₆): 8.61 (d, 1H), 7.25 (d, 1H), 5.63 (t, 1H), 4.49 (d, 2H), 2.49 (s, 3H).

Préparation 9ab: [2-(2-Methoxyethylsulfanyl)pyrimidin-4-yl]methanol

-97StepA:

1.51 g sodium methoxide (28.0 mmol) was dissolved in 15 mL MeOH and cooled to 0°C.

2.44 g thiocarbamide (32.0 mol) was added portionwise and the mixture was stirred for 1 hour. Then 3.46 g (Æ)-4-(dimethylamino)-l,1-dimethoxy-but-3-en-2-one (Préparation 9al) (20.0 mol) was added dropwise at 0°C, then it was heated to 80°C and stirred there for 2 hours. It was cooled to room température, 4.17 g 1-bromo-2-methoxy-ethane (30 mmol) was added and the mixture was stiired for 1 hour at 50°C, then ovemight at room température. It was filtered, the filtrate was concentrated under reduced pressure, diluted with EtOAc, washed with water and brine. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl-acetate as eluents to give a light yellow oil (4-(dimethoxymethyl)2-(2-methoxyethylsulfanyl)pyrimidine). ’H NMR (400 MHz, DMSO-dè): 8.68 (d, IH), 7.24 (d, IH), 5.23 (s, IH), 3.59 (t, 2H), 3.33 (s, 6H), 3.32 (t, 2H), 3.28 (s, 3H).

Step B:

Starting from this material using General procedure 9A the title product was obtained. 'H NMR(400 MHz, DMSO-d_fi): 8.60 (d, IH), 7.25 (d, IH), 5.63 (t, IH), 4.48 (d, 2H), 3.57 (t, 2H), 3.29 (t, 2H), 3.27 (s, 3H).

Préparation 9ac: [2-(3-Methoxypropylsulfanyl)pyrimidïn-4-yI] methanol

Step A:

1.51 g sodium methoxide (28.0 mmol) was dissolved in 15 mL MeOH and cooled to 0°C. 2.44 g thiocarbamide (32.0 mol) was added portionwise and the mixture was stirred for I hour. Then 3.46 g (E)-4-(dimethylamino)-l,l-dimethoxy-but-3-en-2-one (Préparation 9al) (20.0 mol) was added dropwise at 0°C, then it was heated at 80°C for 2 hours. It was cooled to room température, 4.59 g l-bromo-3-methoxy-propane (30 mmol) was added and was stirred 1 hour at 50°C, then ovemight at room température. It was filtered, the filtrate was concentrated under reduced pressure, diluted with EtOAc, washed with water and brine. The organic layer was dried over Na₂SO4, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography using heptane and ethyl-acetate as eluents to give a light yellow oil (4-(dimethoxymethyl)-2-(317193

-98methoxypropylsulfanyl)pyrimidine). ⁱII NMR (400 MHz, DMSO-d^): 8.68 (d, IH), 7.23 (d, IH), 5.22 (s, IH), 3.43 (t, 2H), 3.33 (s, 6H), 3.24 (s, 3H), 3.14 (m, 2H), 1.90 (m, 2H).

Siep B:

Starting from this material using General procedure 9A the title product was obtained. *H NMR (400 MHz, DMSO-d₆): 8.60 (d, IH), 7.24 (d, IH), 5.63 (t, IH), 4.48 (d, 2H), 3.42 (t, 2H), 3.24 (s, 3H), 3.12 (t, 2H) 1.88 (m, 2H).

Préparation 9ad: (2-Ethoxypyrimidin-4-yl)methanol

Step A:

To the solution of 1500 mg 4-(dimethoxymethyl)-2-rnethylsulfonyl-pyrimidine (Préparation 9a3, 6.46 mmol) in 60 mL éthanol 527 mg sodium ethoxide (7.75 mmol) was added and stirred at room température for lh. The volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to give 4-(dimethoxymethyl)-2-ethoxy-pyrimidine. MS: (M+H)⁺ = 199.2.

Step B:

Starting from this material using General procedure 9A the title product was obtained. MS: (M+H)⁺ = 155.2

Préparation 9ae: (2-Isopropoxypyrimidin-4-yl)methanol

Step A:

To the solution of 1500 mg 4-(dimethoxyinethyl)-2-methylsulfonyl-pyrimidine (Préparation 9a3, 6.46 mmol) in 50 mL propan-2-ol the solution of 310 mg sodium hydride (60%, 7.75 mmol) in 10ml propan-2-ol was added and stirred at room température for lh. The volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to give 4(dimethoxymethyl)-2-isopropoxy-pyriniidine. MS: (M+H)⁺ = 213.2.

Step B:

-99Starting from this material using General procedure 9A the title product was obtained.

MS: (M+H)⁺- 169.2

Préparation 9af; (2-Propoxypyrimidin-4-yl)methanol

Step A:

To the solution of 1500 mg 4-(dimethoxymethyl)-2-methylsulfonyl-pyrimidine (Préparation 9a3, 6.46 mmol) in 50 mL propan-l-ol the solution of 310 mg sodium hydride (60%, 7.75 mmol) in 10ml propan-l-ol was added and stirred at room température for lh. The volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to give 4(dimethoxymethyl)-2-propoxy-pyrimidine. MS: (M+H)⁺ = 213.2.

StepJL

Starting from this material using General procedure 9A the title product was obtained. MS: (M+H)⁺= 169.2

Préparation 9ag: [2-(2-Methoxyethoxy)pyrimidin-4-yl]methanol

Step A:

2-Methoxyethanol (10 mL) was cooled to 0°C and 413 mg of sodium hydride (60%, 10.33 mmol) was added portionwise, then 2.00 g 4-(dimethoxymethyl)-2-methylsulfonylpyrimidine (Préparation 9a3) (8.61 mmol) was added and stirred at room température for lh. The reaction mixture was concentrated under reduced pressure. To the residue water was added and it was extracted with DCM. The combined organic layers were dried over MgSCL and concentrated under reduced pressure to give 4-(dimethoxymethyl)-2-(2methoxyethoxy)pyrimidine. MS: (M+H)⁺ = 229.2.

Step B:

Starting from this material using General procedure 9A the title product was obtained. MS: (M+H)⁺= 185.2

- I00 Préparation 9ah: [2-(2-Ethoxyethoxy)pyrimidin-4-yl]methanol

Step A:

mL 2-ethoxyethanol was cooled to 0°C, then 240 mg sodium hydride (6.00 mmol) was added portionwise and the mixture was stirred at this température for 15 min. The solution of I.l6 g 4-(dimethoxymethyl)-2-methylsulfonyl-pyrimidme (Préparation 9a3, 5.00 mmol) in 3 mL 2-ethoxyethanol was added, then cooling was removed and reaction mixture was stirred at room température for 2h. Brine was added then the mixture was extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to give 4-(dimethoxymethyl)-2-(2ethoxyethoxy)pyrimidine. ^]H NMR (400 MHz, CDCl₃): 8.54 (d, ÎH), 7.17 (d, 1H), 5.18 (s, 1H), 4.53 (t, 2H), 3.82 (t, 2H), 3.59 (q, 2H), 3.42 (s, 6H), 1.22 (t, 3H).

Step B:

Starting from this material using General procedure 9A the title product was obtained. *H NMR (400 MHz, CDClj): 8.47 (d, 1H), 6.95 (d, 1H), 4.71 (br s, 2H), 4.56 (t, 2H), 3.84 (t, 2H), 3.62 (q, 2H), 1.25 (t, 3H).

Préparation 9ai: [2-(2,2,2-Trifluoroethoxy)pyrinudin-4-yI]niethanol

Step A:

To the solution of 5.00 g 4-(dimethoxymethyl)-2-methylsulfonyl-pyrimidine (Préparation 9a3,21.5 mmol) in 54 ml dry acetonitrile 5.95 g K2CO3 (43.1 mmol) and 3.24 g 2,2,2trifluoroethanol (32.3 mmol) were added, and stirred at 60°C until no further conversion was observed. The reaction mixture was cooled, filtered, the precipitate was washed with EtOAc, then the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give 4(dimethoxymcthyl)-2-(2,2,2-trifluoiOethoxy)pyrimidine. *11 NMR (400 MHz, DMSO-ds): 8.74 (d, 1H), 7.32 (d, 1H), 5.25 (s, 1H), 5.05 (q, 2H), 3.34 (s, 6H).

Step B:

e

- ΙΟΙ Starting from this material using General procedure 9A lhe tille product was obtained. ’H NMR (400 MHz, DMSO-d₆): 8.65 (d, IH), 7.32 (d, IH), 5.69 (t, IH), 5.02 (q, 2H), 4.51 (d, 2H).

⁵ Préparation 9ai: [2-(3,3,3-Trifhioropropoxy)pyriinidin-4-yl]methanol

Step A:

To the solution of 2.00 g Préparation 9a3 (8.61 mmol) in acetonitrile 2.38 g K2CO3 (17.2 mmol), then 3,3,3-trifluoropropan-l-ol were added and the so obtained mixture was stirred for lOh at 60°C. The reaction mixture was cooled, filtered and the filtrate concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl-acetate as eluents to give 4-(dimethoxymethyl)-2-(3,3,3trifluoropropoxy)pyrimidine. ’HNMR (400 MHz, DMSO-df,): 8.68 (d, IH), 7.22 (d, IH), 5.22 (s, IH), 4.53 (t, 2H), 3.33 (s, 6H), 2.83 (m, 2H).

Step B:

Starting from this material using General procedure 9A the title product was obtained.¹H NMR (400 MHz, DMSO-d₆): 8.59 (d, IH), 7.22 (d, IH), 5.63 (t, IH), 4.49 (m, 4H), 2.81 (m, 2H).

Préparation 9ak: (2-PhcnoxvPYrimidin~4-yl)nicthanol

Step A:

To the solution of 1.50 g Préparation 9a3 (6.46 mmol) in 50 mL THF 2.14 g K2CO3 (15.5 25 mmol), then 729 mg of phénol (7.75 mmol) were added and the so obtained mixture was stirred for 3 days at room température. The reaction mixture was concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl-acetate as eluents to give 4-(dimethoxymethyl)-2-phenoxy-pyrimidine. MS: (M+H)⁺= 247.2.

Step B:

Starting from this material using General procedure 9A the title product was obtained.

MS: (M+Hf = 203.2

-102Préparation 9al; (2-Aminopyrimidin-4-yl)methanol

Step A:

To the stirred mixture of 2.29 g of guanidine hydrochloride (24.0 mmol) and 8 mL of methanol 130 g sodium methoxide (24.0 mmol) and 3.46 g Préparation 9al (20.0 mmol) were added, then stirred at 75 °C for 2 h. The reaction mixture was cooled, concentrated under reduced pressure, then 30 mL water was added. The formed precipitate was filtered, washed with water and dried to give 4-(dimethoxymethyl)pyrimidin-2-amine. ’H NMR (400 MHz, DMSO-d₆): 8.26 (d, 1H), 6.71 (br s, 2H), 6.61 (d, 1H), 5.00 (s, 1H), 3.28 (s,

6H).

Step B:

The solution of 5.01 g 4-(dimethoxymethyl)pyrimidin-2-amine (29.5 mmol) in 100 mL 2N aq. HCl was stirred at 60°C for 5h. Reaction mixture was cooled to 0°C, then 7.60 g NaOH (190 mmol) was added portionwise. The pH was adjusted to 8 using 10% K2CO3 solution, then 2.24 g sodium borohydride (59.0 mmol) was added portionwise keeping the température under 5°C and stirred for 30 min at 0°C. The reaction mixture was extracted with EtOAc, the combined organic phases were dried over Na₂SO4 and concentrated under reduced pressure. The crude product was purified via flash chromatography (MeOH containing 1%NH3- and DCM)· 'H NMR (400 MHz, DMSO-d₆): 8.20 (d, 1H), 6.66 (d, 1H), 6.49 (br s, 211), 5.35 (t, 1H), 4.30 (d, 2H).

Préparation 9am: [2-(Methylainino)pyrimidin-4-yl]incthanol

To the 2M solution of methylamine in THF (3 mL) 232 mg 4-(dimethoxymethyl)-2methylsulfonyl-pyrimidine (Préparation 9a3, 1.00 mmol) was added and it was stirred at room température for lh. The reaction mixture was concentrated under reduced pressure, the residue was diluted with EtOAc and washed with brine. The organic layer was dried 30 over MgSÛ4 and concentrated under reduced pressure. To the residue 3 mL 2N HCl was added and it was stirred at 60°C for 2h. Than it was cooled to 0°C, the pH was adjusted to 9 using 2N NaOH solution, and then 76 mg sodium borohydride (2.0 mmol) was added

-103and the mixture was stirred for lh. The reaction mixture was extracted with EtOAc, the combined organic layers were dried over MgSO₄ and concentrated under reduced pressure to give the title product. MS: (M+2H)⁴ = 141.4.

Préparation 9an: [2-(Dimethylamino)pyriniidin-4-yl]niethanoi

To 3 mL dimethylamine solution (2M in THF, 6 mmol) 232 mg 4-(dimethoxymethyl)-2methylsulfonyl-pyrimidine (Préparation 9a3, 1,00 mmol) was added and it was stiiTed at room température for lh. The reaction mixture was concentrated under reduced pressure, the residue was diluted with EtOAc and washed with brine. The organic layer was dried 10 over MgSO₄ and concentrated under reduced pressure. To the residue 3 mL 2N HCl was added and it was stirred at 60°C for 2h. It was cooled to 0°C, the pH was adjusted to 9 using 2N NaOH solution, and then 76 mg sodium borohydride (2.0 mmol) was added and stirred for lh. The reaction mixture was extracted with EtOAc, and the combined organic layers were dried over MgSO₄ and concentrated under reduced pressure to give the title 15 product. MS: (M+H)⁺ = 154.4.

Préparation 9ao: [2-(2-Metïioxyethylamino)py rimidin-4-yI|methanol

Step A:

Starting from 4-(dimethoxymethyl)-2-methylsulfonyl-pyrimidine (Préparation 9a3) and 2-mcthoxycthanaminc using General procedure 9E 4-(dimethoxymethyl)-N-(2methoxyethyl)pyrimidin-2-amine was obtained. 'HNMR (400 MHz, CDC1₃): 8.32 (d, IH), 6.73 (d, IH), 5.61 (br s, IH), 5.08 (s, IH), 3.62 (m, 2H) 3.56 (m, 2H), 3.38 (s, 6H), 3.36 (s, 3H).

Step B:

Starting from this material using General procedure 9A the title product was obtained. ’H NMR (400 MHz, CDC1₃): 8.22 (d, IH), 6.48 (d, IH), 5.64 (br s, IH), 4.57 (s, 2I-I), 3.65 (m, 2H) 3.58 (m, 2H), 3.49 (s, IH), 3.39 (s, 3H).

Préparation 9an: [2-[2“Methoxyethyl(methyl)aminoJpyrimidÎn-4-yl]inethanol

-104Step A:

Starting from 4-(dimethoxymethyl)-2-methylsulfonyl-pyrimidine (Préparation 9a3) and 2-methoxy-N-methyl-ethanarnine as amine reagent using General procedure 9E 4(dimethoxymethyl)-jV-(2“methoxyethyl)-jV-methyl-pyrimÎdin-2-ainine was obtained. ^JH NMR (400 MHz, CDC1₃): 8.32 (d, IH), 6.66 (d, IH), 5.04 (s, 1H), 3.82 (t, 2H) 3.58 (t, 2H), 3.40 (s, 6H), 3.34 (s, 3H), 3.21 (s, 3H).

Step B:

Starting from this product using General procedure 9A the title product was obtained. *H NMR (400 MHz, CDC1₃): 8.25 (d, IH), 6.39 (d, IH), 4.57 (d, 2H), 3.90 (br s, IH), 3.85 (t, 2H) 3.61 (t, 2H), 3.37 (s, 3H), 3.24 (s, 3H).

Préparation 9aq: [2-(4-Methylpiperazin-1 -yl)pyrimidin-4-yl]methanol

Step A:

Starting from 4-(dimethoxymethyl)-2-methylsulfonyl-pyrimidine (Préparation 9a3) and 1-methylpiperazine using General procedure 9E 4-(dimethoxymethyl)-2-(4methylpiperazin-l-yl)pyrimidine was obtained. ’HNMR (400 MHz, CDCI3): 8.34 (d, ÎI-I), 6.70 (d, IH), 5.06 (s, IH), 3.85 (m, 4H), 3.41 (s, 6H), 2.46 (m, 4H), 2.34 (s, 3H).

Step B:

Slarling from 4-(dimelhoxymethyl)-2-(4-methyipiperazin-l-yl)pyiimidine using General procedure 9A the title product was obtained. ’H NMR (400 MHz, DMSO-dé): 8.33 (d, IH), 6.72 (d, IH), 5.41 (t, IH), 4.35 (d, 2H), 3.70 (m, 4H), 2.36 (m, 4H), 2.22 (s, 3H).

Préparation 9ar: (2-(Morpholin-4-yl)pyrimidin-4-yl)methanol

Step A:

3.50 g Préparation 9a3 (15.1 mmol) was stirred in 23 mL morpholine at room température for 2h. The reaction mixture was concentrated under reduced pressure and the residue was purified via flash cliromatography using heptane and ethyl-acetate as eluents to e

-105 give 4-[4-(dimethoxymethyl)pyrimidin-2~yl]morpholine. *H NMR (400 MHz, DMSO-dû); 8.42 (d, IH), 6.71 (d, IH), 5.06 (s, IH), 3.67 (m, 8H), 3.31 (s, 6H).

Step B:

Starting from 4-[4’(dimethoxymethyl)pyrirnidin-2-yl]morpholine using General procedure 9A the title product was obtained. *H NMR (400 MHz, DMSO-d₆): 8.36 (d, IH), 6.76 (d, IH), 5.43 (t, IH), 4.36 (d, 2H), 3.65 (m, 8H).

Préparation 9as: |2-(Hf-[l,2,3]Triazol-l-yl)pyriinidin-4-yI]niethanol

Step A:

To the solution of 829 mg 1 H-[ 1,2,3]triazole (12.0 mmol) in acetone 2.07 g K2CO3 (15.0 mmol), then Préparation 9a3 were added and the mixture was stirred for 2h at room température. The reaction mixture was fïltered and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl-acetate as eluents to give 4-(dimethoxymethyl)-2-(127-[l,2,3]triazol-l-yl)pyrimidine as while crystals. *H NMR (400 MHz, DMSO-d₆): 9.06 (d, IH), 8.89 (d, IH), 8.01 (d, IH), 7.70 (d, IH), 5.44 (s, IH), 3.40 (s, 6H).

Note: 4-(dimethoxymethyl)-2-(l//-[l,2,3]triazol-2-yl)pyrimidine was also obtained. NMR (400 MHz, DMSO-d₆): 9.03 (d, IH), 8.24 (s, 2H), 7.66 (d, IH), 5.42 (s, IH), 3.39 (s, 6H).

Step B:

Starting from 1.40 g 4-(dimethoxymethyl)-2-(17A[l,2,3]triazol-l-yl)pyrimidine using General procedure 9A the title product was obtained. ’H NMR (400 MHz, DMSO-dô): 8.97 (d, IH), 8.88 (d, IH), 7.99 (d, 1 H), 7.70 (d, IH), 5.86 (t, IH), 4.69 (d, 2H).

Préparation 9at: [2-(Benzylamino)pyrimidm-4-yl]inethanol

To the solution of 0.32 mL benzylamine in 4 mL DCM 460 mg 4-(dimethoxymethyl)-2methylsulfonyl-pyrimidine (Préparation 9a3, 2.00 mmol) was added and it was stirred at 40°C for 16h. The reaction mixture was diluted with DCM and washed with brine. The

-106organic layer was dried over MgSO<i and concentrated under reduced pressure. To the residue 6 mL 2N HCl was added and it was stirred at 60°C for 2h. It was cooled to 0°C, the pH was adjusted to 9 using 2N NaOH solution, and then 152 mg sodium borohydride (2.0 mmol) was added and stirred for lh, The reaction mixture was extracted with EtOAc, the combined organic layers were dried over MgSOd lïltered and concentrated under reduced pressure to give the title product. MS: (M+H)⁺ =? 216.2.

Préparation 9au: [2-(Cyclopropylmethoxy)pyrimidin-4-yl]mcthanol

Step A:

mL cyclopropylmethanol was cooled to 0°C, then 1.10 g sodium hydride (27.5 mmol) was added portionwise and the mixture was stirred at this température for 30 min. This mixture was added to 953 mg of 2-methylsulfonyl-4-(tetrahydropyran-2yloxymethyl)pyrimidine (Préparation 9a4, 3.50 mmol) and it was stirred at room température for 30 min. Water was added then the mixture was extracted with DCM. The combined organic layers wcrc dried over MgSÛ4, fïltered and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to give 2-(cyclopropylmethoxy)-4-(tetrahydropyran-2-yloxymethyl)pyrimidine. MS: (M+H)⁺= 265.2.

Step B:

To the solution of 732 mg of 2-(cycloprapylmethoxy)-4-(tetrahydropyi’an-2yloxymethyl)pyrimidine (2.77 mmol) in 50 mL EtOH 160 mg pyridinium ptoluenesulfonate (0.64 mmol) was added and the mixture was stirred at 50°C for 16h. The mixture was concentrated under reduced pressure, the residue was purified via flash chromatography using heptane and EtOAc as eluents to give the title product. 4-1 NMR (400 MHz, DMSO-dô): 8.55 (d, IH), 7.16 (d, IH), 5.59 (t, IH), 4.45 (m, 2H), 4.11 (d, 2H), 1.25 (m, IH), 0.55 (m, 2H), 0.33 (m, 2H).

Préparation 9aw: [2-(4-Pyridylmethoxy)pyrimidin-4-yl]methanol

To the solution of 164 mg of 4-pyridylmethanol (1.50 mmol) in 3 mL DMF 80 mg of sodium hydride (60%, 2.0 mmol) was added at 0°C and stirred al room température for 30

-107min. This mixture was added to the solution of 272 mg of 2-methylsulfonyl-4(tetrahydiOpyran-2-yloxymethyl)pyrimidine (Préparation 9a4, l.OO mmol) in l mL DMF. The mixture was stirred at room température for lh, then it was diluted with water, and extracted with DCM. The combined organic layers were dried over Na₂SO4 and 5 concentrated under reduced pressure. The residue was dissolved in 15 mL EtOH then 160 mg pyridinium p-toluenesulfonate (0.64 mmol) was added and stirred at 50°C for 16h. The mixture was concentrated under reduced pressure, the residue diluted with water, and extracted with DCM. The combined organic layers were dried over Na₂SO4 and concentrated under reduced pressure. The residue was purified via flash chromatography 10 using heptane and EtOAc as eluents to give the title product. MS: (M+H)⁺ = 218.2.

Préparation 9ax: (2-Benzyloxypyrïmidin-4-yl)methanol

Step A:

To 4.25 mL phenylmethanol cooled to 0°C 545 mg sodium hydride (13.6 mmol) was added portionwise and the mixture was stirred at room température for 30 min. This mixture was added to 460 mg of 2-methylsulfonyl-4-(tetrahydiOpyran-2yloxymethyl)pyrimidine (Préparation 9a4, 1.69 mmol) and it was stirred at room température for lh. Water was added then the mixture was extracted with DCM. The 20 combined organic layers were dried over MgSÛ4 and concentrated under reduced pressure.

The residue was purified via flash chromatography using heptane and EtOAc as eluents to give 2-benzyloxy-4-(letrahydiOpyran-2-yloxymethyl)pyrimidine. MS: (M+H)⁺ = 301.2.

Step B:

To the solution of 408 mg of 2-benzyloxy-4-(tetrahydiOpyran-2-yloxymethyl)pyrimidine (1.36 mmol) in 50 mL EtOH 79 mg pyridinium/?-toluenesulfonate (0.30 mmol) was added and the mixture was stirred at 50°C for 16h. The mixture was concentrated under reduced pressure, the residue was purified via flash chromatography using heptane and EtOAc as eluents to give the title product. ’H NMR (400 MHz, DMSO-dé): 8.59 (d, IH), 7.47-7.30 (m, 5H), 7.21 (d, IH), 5.62 (t, IH), 5.37 (s, 2H), 4.49 (m, 2H).

Préparation 9av: {2-[(l-methyl-l/f-imidazol-5-yl)methoxy]pyrnnidin-4-yl}methanol e

-108To the solution of 224 mg of (l-methyl-l/7-imidazol-5-yl)inethanol (2.00 mmol) in 5 mL DMF 158 mg of sodium hydride (60%, 3.95 mmol) was added at 0°C and it was stirred at room température for 30 min. This mixture was added to the solution of 500 mg of 2methylsulfony1-4-(tetrahydropyran-2-yloxymethyl)pyrimidine (Préparation 9a4, 1.84 mmol) in 1 mL DMF. The reaction mixture was stirred at room température for 1h, then it was diluted with water, and extracted with DCM. The combined organic layers were dried over Na₂SO4 and concentrated under reduced pressure. The residue was dissolved in 5 mL HCl in EtOH (1.25M) and stirred at room température for lh. The mixture was concentrated under reduced pressure, the residue diluted with water, and extracted with DCM. The combined organic layers were dried over Na₂SO4 and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to give the title product. MS: (M+H)⁺ = 221.2.

Préparation 9ba: (2-Ethylpyrimidin-4-yl)methanol

Step A:

Starting from propanamidine hydrochloride using General procedure 9C 4(dimethoxymethyl)-2-ethyl-pyrimidine was obtained. MS: (M+H)⁺ = 183.2.

Step B:

Starting from this material using General procedure 9A the title product was obtained. 'il NMR (400 MHz, DMSO-d₆): 8.69 (d, 1H), 7.37 (d, 1H), 5.59 (t, 1H), 4.52 (d, 2H), 2.84 (q, 2H), 1.25 (t,3H).

Préparation 9bt>: (2-Propylnvrimidin-4-vDmethanol

Step A:

Starting from butanamidine hydrochloride using General procedure 9C 4(dimethoxymethyl)-2-propyl-pyrimidine was obtained. MS: (M+H)⁺ - 197.2.

Step B:

-109 Starting from this material using General procedure 9 A the title product was obtained. NMR (40Ü MHz, DMSO-d₆): 8.68 (d, ÎH), 7.36 (d, ÎH), 5.59 (t, IH), 4.51 (d, 2H), 2.79 (t, 2H), 1.75 (h, 2H), 0.90 (t, 3H).

Préparation 9bc; (2-Butylpyrimidin-4-yl)inethanol

Step A:

Starting from n-pentanamidine hydrochloride using General procedure 9C 2-butyl-4(dimethoxymethyl)pyrimidine was obtained. 'H NMR (400 MHz, DMSO-dô): 8.77 (d, ÎH), 7.36 (d, IH), 5.25 (s, ÎH), 3.32 (s, 6H), 2.87 (t, 2H), 1.73 (m, 2H), 1.32 (m, 2H), 0.90 (t, 3H).

Step B:

Starting from this material using General procedure 9A the title product was obtained. ’H NMR (400 MHz, DMSO-d₆): 8.70 (d, IH), 7.36 (d, IH), 5.59 (t, 1H), 4.51 (d, 2H), 2.81 (t, 2H), 1.70 (m, 2H), 1.31 (m, 2H), 0.89 (t, 3H).

Préparation 9bd; (2-IsoproDvlpvrnnidin-4-vl)methanol

Step A:

Starting from 2-methylpropanamidine hydrochloride using General procedure 9C 4(dimethoxymethyl)-2-isopropyl-pyrimidine was obtained. 'il NMR (400 MHz, DMSO-de): 8.79 (d, IH), 7.36 (d, IH), 5.25 (s, IH), 3.34 (s, 6H), 3.14 (h, IH), 1.27 (d, 6H).

StepJL

Starting from this material using General procedure 9A the title product was obtained. ’H NMR (400 MHz, DMSO-d₆): 8.70 (d, IH), 7.37 (d, IH), 5.59 (t, IH), 4.52 (d, 2H), 3.08 (h, IH), 1.25 (d, 6H).

Préparation 9be; (2-Cyclopropvlpyrimidin-4-yl)methanol

Step A:

- lio Starting from cyclopropanecarboxamidine hydrochloride using General procedure 9C 2cyclopiOpyl-4-(dimethoxymethyl)pyrimidine was obtained. 'H NMR (400 MHz, DMSOd<): 8.67 (d, IH), 7.28 (d, IH), 5.20 (s, IH), 3.31 (s, 6H), 2.20 (m, IH), 1.07-0.96 (m, 4H).

Step B:

Starting from this material using General procedure 9A the title product was obtained. ’H NMR (400 MHz, DMSO-d₆): 8.59 (d, IH), 7.29 (d, IH), 5.56 (t, IH), 4.47 (d, 2H), 2.14 (m, IH), l.03-0.92 (m, 4H).

!0 Préparation 9bf: (2-Isobutylpyrimidin-4-yl)methanol

Step A:

Starting from 3-methylbutanamidine hydrochloride using General procedure 9C 4(dimethoxymethyl)-2-isobutyl-pyrimidine was obtained. ^!H NMR (400 MHz, DMSO-dô):

8.77 (d, IH), 7.36 (d, IH), 5.25 (s, IH), 3.32 (s, 6H), 2.75 (d, 2H), 2.22 (m, IH), 0.89 (d,

6H).

Step B:

NMR (400 MHz, DMSO-d₆): 8.69 (d, IH), 7.37 (d, IH), 5.59 (t, IH), 4.51 (d, 2H), 2.69 (d, 2H), 2.19 (m, IH), 0.88 (d, 6H).

Préparation 9bg; |2-(Cyclopropylmethyl)pyrimidin-4-yl]methanol

Step A;

Starting from 2-cyclopropylacetamidine hydrochloride using General procedure 9C 2(cyclopropylmethyl)~4-(dimethoxymethyl)pyrimidine was obtained. *H NMR (400 MHz, DMSO-dô): 8.79 (d, IH), 7.38 (d, IH), 5.26 (s, IH), 3.34 (s, 6H), 2.78 (d, 2H), 1.18 (m, IH), 0.46 (m, 2H), 0.22 (m, 2I-I).

Step B:

- lll Starting from this material using General procedure 9A the title product was obtained. ’H NMR (400 MHz, DMSO-d₆): 8.70 (d, IH), 7.39 (d, IH), 5.59 (t, IH), 4.52 (d, 2H), 2.71 (d, 2H), 1.17 (m, IH), 0.45 (m, 2H), 0.25 (m, 2H).

⁵ Préparation 9bh: (2-tert~Butylpyrimidin-4-yl)niethanol

Step A:

Starting from 2,2-dimethylpropanamidine hydrochloride using General procedure 9C 2tert-butyl-4-(dimethoxymethyl)pyrimidine was obtained. ’H NMR (400 MHz, DMSO-cU):

8.80 (d, IH), 7.34 (d, IH), 5.25 (s, IH), 3.34 (s, 6H), 1.35 (s, 9H).

Step B:

Starting from this material using General procedure 9A the title product was obtained. ’H NMR (400 MHz, DMSO-d_e): 8.72 (d, IH), 7.35 (d, IH), 5,57 (t, IH), 4.52 (d, 2H), 1.33 (s, 15 9H).

Préparation 9bi: (2-Cvciopentvlpyrimidin-4-yl)methanoI

Step A:

Starting from cyclopentanecaiboxamidine hydrochloride using General procedure 9C 2cyclopentyl-4-(dimethoxymethyl)pyrimidine was obtained. MS: (M+H)⁺ = 223.2.

Step B:

Starting from this material using General procedure 9A the title product was obtained. ^lH 25 NMR (400 MHz, DMSO-d₆): 8.68 (d, IH), 7.34 (d, IH), 5.57 (t, IH), 4.51 (d, 2H), 3.25 (p,

IH), 1.98 (m, 2H), 1.87-1.57 (m, 6H).

Préparation 9bj: [2-(Trifluoromethyl)pyrïmidin-4-yl]methanoI

3θ Step A:

The mixture of 500 mg Préparation 9al (2.89 mmol) and 356 mg 2,2,2trifluoroacetamidine (3.18 mmol) was heated at 110°C for 40 min in a microwave reactor.

-112The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give 4-(dimethoxymethyl)-2-(trifluoiOmethyl)pyrimidine. 'H NMR (400 MHz, CDClj): 8.97 (d, IH), 7.77 (d, IH), 5.36 (s, IH), 3.48 (s, 6H).

Step B :

Starting from this material using General procedure 9A the title product was obtained. ’H NMR(400 MHz, CDCh): 8.90 (d, IH), 7.65 (d, IH), 5.87 (br s, IH), 4.91 (d, 2H).

Préparation 9bk; [2-(Methoxy methyl)pyrimidin-4-yl] methanol

Step A:

Starting from 2-methoxyacetamidine hydrochloride using General procedure 9C 4(dimethoxymethyl)-2-(methoxymethyl)pyrimidine was obtained. *H NMR (400 MHz, DMSO-dc): 8.86 (d, IH), 7.47 (d, IH), 5.30 (s, IH), 4.58 (s, 2H), 3.37 (s, 3H), 3.34 (s, 6H).

Step B:

Starting from this material using General procedure 9A the title product was obtained. *H NMR (400 MHz, DMSO-d₆): 8.77 (d, IH), 7.47 (d, IH), 5.66 (t, IH), 4.55 (d, 2H), 4.53 (s, 2H), 3.36 (s, 3H).

Préparation 9bl: [2-(2-Methoxyethyl)pyrimidin-4-yl]mcthanol

Step A:

Starting from 3-methoxypropanamidine hydrochloride using General procedure 9C 4(dimethoxymethyl)-2-(2-methoxyethyl)pyrimidine was obtained. ^jH NMR (400 MHz, DMSO-d₆): 8.78 (d, IH), 7.38 (d, JH), 5.25 (s, 1 H), 3.80 (t, 2H), 3.33 (s, 6H), 3.22 (s, 3H), 3.11 (t, 2H).

Note: 2-[4-(dimethoxymethyl)pyrimidin-2-yl]-A^r,?/-dimethyl-ethanamine was also obtained. MS: (M+H)⁺ = 226.2. (See also at Step A of Préparation 9bm)

Sien B:

- 113Starting from this material using General procedure 9A the title product was obtained. ^lH NMR (400 MHz, DMSO-d₆): 8.70 (d, IH), 7.39 (d, IH), 5.60 (t, IH), 4.52 (d, 2H), 3.78 (t, 2H), 3.22 (s, 3H),3.06(t, 2H).

Préparation 9bm; [2-(2-Dimetbylaminoethyl)pyrimidin-4-yl]methanol

Step A:

To the mixture of l .63 g 3-(dimethylamino)propanamidine dihydrochloride (8.67 mmol) and 1.25 g (jE)-4-(dimethylamino)-l,l-dimethoxy-but-3-en-2-one (Préparation 9al, 7.23 mmol) in 4 mL dry methanol sodium methoxide (17.3 mmol) was added portionwise and the mixture was srirred at 75 °C for 2 h. The reaction mixture was cooled and concentrated under reduced pressure. Water was added to the residue and it was extracted with EtOAc. The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure to give 2-[4-(dimethoxymethyl)pyrimidin-2-yl]-N’,N-dimethyl-ethanamine. MS: (M+H)⁺ = 226.2.

Step B:

1.474 g crude 2-[4-(dimethoxymethyl)pyrimidin-2-yl]-jV,_JV-dimethyl-ethanamine obtained in Step A was stirred with 20 mL 2N HCl solution at 60°C for 2h. The reaction mixture was cooled to 0°C, then 1.52 NaOH (3.8 mmol) was added portionwise. The pH was adjusted to 8 using 10% K2CO3 solution, then 492 mg sodium borohydride (13.0 mmol) was added portionwise keeping the température under 5°C and stirred for 30 min at 0°C. Reaction mixture was salted (4g NaCl) then extracted with 2-Me-THF. The combined organic layers were dried over NaîSO₄ and concentrated under reduced pressure to give the title product.

^!H NMR (400 MHz, DMSO-d₆): 8.69 (d, IH), 7.39 (d, IH), 5.64 (br s, IH), 4.52 (s, 2H), 3.01 (m, 2H), 2.80 (m, 2H), 2.25 (s, 6H).

Préparation 9bn: [2-(Ethoxymethyl)pyrimidin-4-yl]inethanol

Step A:

-114 Starting from 2-ethoxyacetamidine hydrochloride using General procedure 9C 4(dimethoxymethyl)-2-(ethoxymethyl)pyrimidine was obtained. *H NMR (400 MHz, DMSO-dô): 8.86 (d, IH), 7.46 (d, IH), 5.29 (s, IH), 4.61 (s, 2H), 3.58 (q, 2H), 3.33 (s, 6H), 1.16 (t, 3 H).

Step B:

Starting from this material using General procedure 9A the title product was obtained. *H NMR (400 MHz, DMSO-d₆): 8.77 (d, IH), 7.47 (d, IH), 5.65 (t, IH), 4.56 (m, 4H), 3.57 (q,2H), 1.14 (t,3H).

Préparation 9bo: [2-(4-Chlorophenyl)pyrimidin-4-yl]methanol

Step A:

Starting from 4-chlorobenzamidine hydrochloride using General procedure 9C 2-(4chloiOphenyl)-4-(dimethoxymethyl)pyrimidine was obtained. *H NMR (400 MHz, DMSOd«): 8.97 (d, IH), 8.40 (m, 2H), 7.61 (m, 2H), 7.50 (d, IH), 5.38 (s, IH), 3.39 (s, 6H).

Step B:

Starting from this material using General procedure 9A the title product was obtained. ’H NMR (400 MHz, DMSO-d₆): 8.89 (d, IH), 8.39 (m, 2H), 7.59 (m, 2H), 7.52 (d, IH), 5.71 (t, IH), 4.64 (d,2H).

Préparation 9bp; [2-(2-MethoxypIienyl)pyrinudin-4-yl]niethanol

Step A:

Starting from 2-methoxybenzamidine acetic acid sait using General procedure 9C 4(dimethoxymethyl)-2-(2-methoxyphenyl)pyrimidine was obtained. *H NMR (400 MHz, DMSO-dfi): 8.93 (d, IH), 7.55-7.44 (m, 3H), 7.16 (d, IH), 7.06 (m, IH), 5.31 (s, IH), 3.76 (s, 3H), 3.37 (s, 6H).

Step B:

*

- 115 261 mg4-(dimethoxymethyl)-2-(2-methoxyphenyl)pyrimidine (1.00 mmol) was dissolved in 2 mL HCl in dioxane (4M solution), then 2 mL water was added and this mixture was stirred at 50 °C for 16h. The reaction mixture was cooled to 0°C, then 320 rngNaOH (8.0 mmol) was added portionwise. The pH was adjusted to 8 using 10% K₂CO₃ solution, then 76 mg sodium borohydride (2.0 mmol) was added and the mixture was stirred for 30 min at 0°C. The reaction mixture was diluted with 5 mL water and extracted with EtOAc. The combined organic phases were dried over Na₂SO4 and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give the title product. *H NMR (400 MHz, DMLSO-dô): 8.84 (d, IH), 7.50-7.42 (m, 3H), 7.14 (d, IH), 7.03 (m, IH), 5.66 (t, IH), 4.58 (d, 2H), 3.75 (s, 3H).

Préparation 9bq; [2-(2-Pyridyl)pyrimidin-4-yl]methanol

Step A:

Starting from pyridine-2-carboxamidine hydrochloride using General procedure 9C 4(dimethoxymethyl)-2-(2-pyridyl)pyrimidine was obtained. MS: (M+H)⁺ ~ 232.2.

Step B:

Starting from this material using General procedure 9A the titie product was obtained. *H NMR (400 MHz, DMSO-d₆): 8.94 (d, IH), 8.74 (d, IH), 8.37 (d, IH), 7.97 (m, IH), 7.60 (d, 111), 7.52 (m, III), 5.74 (t, IH), 4.67 (d, 2H).

Préparation 9br; [2-(3-Pyridyl)pyrimidin-4-yJJniethanol

Step A:

Starting from pyridine-3-carboxamidine hydrochloride using General procedure 9C 4(dimethoxymethyl)-2-(3-pyridyl)pyrimidine was obtained. MS: (M+H)⁺ = 232.2.

Step B:

Starting from this material using General procedure 9A the title product was obtained. 'H NMR (400 MHz, DMSO-d₆): 9.51 (dd, IH), 8.93 (d, IH), 8.72 (dd, IH), 8.66 (m, IH), 7.56 (m, 2H), 5.73 (t, IH), 4.67 (d, 2H).

-116Préparation 9bs: [2-(4-Pyridyl)pyrimidin-4-yl]methanol

Step A:

Starting from pyridine-4-carboxamidine hydrochloride using General procedure 9C 4(dimcthoxymethyl)-2-(4-pyridyl)pyrimidine was obtained. MS: (M+H)⁺ = 232.2.

Step B:

'H NMR (400 MHz, DMSO-d_fi): 8.98 (d, 1H), 8.77 (m, 2H), 8.25 (m, 2H), 7.63 (d, ÎH), 5.76 (t, ÎH), 4.68 (d, 2H).

Préparation 9bt: [2-(3-Furyl)pyrimidin-4-yl]methanol

Step A:

Starting from furan-3-carboxamidine hydrochloride using General procedure 9C 4(dimethoxymethyl)-2-(3-l’uryl)pyrimidine was obtained. *H NMR (400 MHz, DMSO-dr,): 8.85 (d, ÎH), 8.43 (br s, ÎH), 7.83 (dd, 1H), 7.39 (d, 1H), 7.04 (dd, ÎH), 5.31 (s, 1H), 3.36 (s, 6H).

Step B:

Starting from this material using General procedure 9A the title product was obtained. ’H NMR (400 MHz, DMSO-d₆): 8.77 (d, 1H), 8.39 (br s, 1H), 7.80 (dd, 1H), 7.40 (d, 1H), 7.02 (dd, 1H), 5.65 (t, 1H), 4.58 (d, 2H).

Préparation 9bu: [2-(3-Thienyl)pyriinidin-4-yl]methanol

Step A:

Starting from thiophene-3-carboxamidine hydrochloride using General procedure 9C 4(dimethoxymethyl)-2-(3-thienyl)pyrimidine was obtained. *H NMR (400 MHz, DMSOd₆): 8.89 (d, 1H), 8.39 (dd, 1H), 7.81 (dd, 1H), 7.67 (dd, 1H), 7.40 (d, 1H), 5.33 (s, 1H), 3.38 (s, 6H).

-117Step B:

Starting from this material using General procedure 9A the title product was obtained. ’H NMR (400 MHz, DMSO-d₆): 8.81 (d, IH), 8.36 (dd, IH), 7.80 (dd, IH), 7.65 (dd, IH), 7.42 (d, IH), 5.66 (t, IH), 4.60 (d, 2H).

Préparation 9bv; [2-(2-ThienyI)pyrinudin-4-yl]inethanol

Step A:

Starting from thiophene-2-carboxamidine hydrochloride using General procedure 9C 4(dimethoxymethyl)-2-(2-thienyl)pyrimidine was obtained. MS: (M+H)⁺ = 237.2.

Step B:

Starting from this material using General procedure 9A the title product was obtained. 'H NMR (400 MHz, DMSO-dg): 8.77 (d, IH), 7.93 (dd, IH), 7.76 (dd, IH), 7.40 (d, IH), 7.20 (dd, III), 5.68 (t, III), 4.58 (d, 211).

Préparation 9bw: (2-flZ/-Pvrazol-l-vl)pYrimidin-4-yl)methanol

Step A:

To the stirred mixture of 4.18 g of pyrazole-l-carboxamidine hydrochloride (28.5 mmol) and 120 mL of éthanol 4.05 g ofNa2HPO₄ (28.5 mmol) and 4.12 g of Préparation 9al (23.78 mmol) were added, then it was stirred at 85 °C for 10 h. The reaction mixture was cooled, concentrated under reduced pressure, and the crude product was purified via flash chromatography using heptane and EtOAc as eluents to give 4-(dimethoxymethyl)-2-(17A pyrazol-l-yl)-pyrimidine. *H NMR (400 MHz, DMSO-dé): 8.92 (d, IH), 8.65 (d, IH), 7.87 (br s, IH), 7.50 (d, IH), 6.62 (dd, IH), 5.36 (s, IH), 3.38 (s, 6H).

Step B:

Starting from this material using General procedure 9A the title product was obtained. ^lH NMR (400 MHz, DMSO-d₆): 8.84 (d, IH), 8.65 (d, IH), 7.84 (br s, IH), 7.51 (d, IH), 6.59 (dd, IH), 5.77 (t, IH), 4.63 (d, 2H).

-lisPréparation 9bx; (2-Thiazol-2-ylpyrimidin-4-y l)methanol

Step A:

To the stirred mixture of 1.00 g of thiazole-2-carboxamidine hydrochloride (6.11 mmol) and 3 mL of methanol 330 mg sodium methoxide (6.11 mmol) and 1.05 g of Préparation 9al (6.11 mmol) were added, then it was stirred at 75 °C for 7 h. The reaction mixture was cooled, concentrated under reduced pressure, brine was added and it was extracted with DCM. The combined organic phases were dried over Na₂SC>4 and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give 2-[4-(dimethoxymethyl)pyrimidin-2-yl]thiazole. MS: (M+H)⁺ = 238.2.

Step B:

Starting from this material using General procedure 9A the title product was obtained. ^lH NMR (400 MHz, DMSO-d₆): 8.91 (d, 1H), 8.03 (dd, 2H), 7.61 (d, 1H), 5.78 (t, 1H), 4.65 (d, 2H).

Préparation 9by: (2-Benzylpyrimidin-4-yl)methanol

Step A:

Starting from 2-phenylacetamidine hydrochloride using General procedure 9C 2-benzyl4-(dimethoxymethyl)pyrimidine was obtained. MS: (M+H)^4- = 245.2.

Step B:

Starting from this material using General procedure 9A the title product was obtained. ’H NMR (400 MHz, DMSO-d₆): 8.71 (d, 1H), 7.39 (d, 1H), 7.28 (m, 4H), 7.20 (m, 1H), 5.61 (t, 1H), 4.52 (d, 2H), 4.16 (s, 2H).

Préparation 9bz: [2-(Phenoxymethyl)pyriinidin-4-yl]methanol

Step A:

-119Starting from 2-phenoxyacetamidine hydrochloride using General procedure 9C 4(dimethoxymethyl)-2-(phenoxymethyl)pyrimidine was obtained. MS: (M+H)⁺ = 261.2,

Step B:

Starting from this material using General procedure 9A the title product was obtained. ’H NMR (400 MHz, DMSO-d₆): 8.81 (d, IH), 7.51 (d, IH), 7.28 (m, 2H), 6.95 (m, 3H), 5.68 (t, IH), 5.21 (s, 2H), 4.57 (d,2H).

Préparation 9ca: (5-Bromopyrimidin-4-yl)metlianoi

Step A:

To the solution of 3.90 g of 4-(dimethoxymethyl)pyrimidine (25.3 mmol) in 100 AcOH 4.15 g sodium acetate (50.6 mmol) and 8.08 g bromine (50.6 mmol) were added and the mixture was stirred at 40°C for 7 h. Reaction mixture was concentrated under reduced pressure, DCM was added to the residue, and it was washed with saturated aq. NaHCCh. The organic phase was dried over Na₂SO4 and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give 5-bromo-4-(dimethoxymethyl)pyrimidine. ’H NMR (400 MHz, DMSO-d₆): 9.18 (s, IH), 9.06 (s, IH), 5.51 (s, IH), 3.40 (s, 6H).

Step B:

Starting from this material using General procedure 9A the title product was obtained. ^lH NMR (400 MHz, DMSO-d₆): 9.14 (s, IH), 8.94 (s, IH), 5.49 (t, IH), 4.62 (d, 2H).

Préparation 9cb: (5-Bromo-2-methoxv-nvrimidin-4-vBmethanol

Step A:

Starting from methyl carbamimidate hydrochloride using General procedure 9C 4(dimethoxymethyl)-2-methoxy-pyrimidine was obtained. ^]H NMR (400 MHz, DMSO-dô): 8.66 (d, IH), 7.18 (d, IH), 5.20 (s, IH), 3.92 (s, 3H) 3.33 (s, 6H).

Step B:

-120 To the solution of 5.49 g of 4-(dimethoxymethyl)-2-methoxy-pyrimidine (30.0 mmol) in 100 AcOH 4.92 g sodium acetate (60.0 mmol) and 9.59 g bromine (60.0 mmol) were added and stirred at 40°C for 24 h. The reaction mixture was concentrated under reduced pressure, to the residue DCM was added, and it was washed with saturated aq. NaHCCh. The organic phase was dried over Na₂SO4 and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give 5-bromo-4-(dimethoxyrnethyl)-2-methoxy-pyrimidine. ’H NMR (400 MHz, DMSO-d₆): 8.79 (s, IH), 5.41 (s, IH), 3.93 (s, 3H), 3.40 (s, 6H).

Step C:

Starting from this material using General procedure 9A the title product was obtained. 'H NMR (400 MHz, DMSO-d₆): 8.68 (s, IH), 5.41 (t, IH), 4.54 (d, 2H), 3.94 (s, 3H).

Préparation 9cc; [2-Methoxy-5-(3-thienyl)pyriinidin-4-yl] methanol

Step A:

To the solution of 766 mg of 5-bromo-4-(dimethoxymethyl)-2-niethoxy-pyriniidine (the product of Préparation 9cb, Step B, 2.91 mmol) in 15 mL THF-water (1:1) 934 mg 4,4,5,5-tetramethyl-2-(3-thienyl)-l,3,2-dioxaboiOlane (4.45 mmol), 1.96 g CS2CO3 (6.00 mmol) and 522 mg tetrakis(triphenylphosphine)palladium(0) (0.450 mmol) were added and the mixture was heated under N₂ in a tnicrowave reactor at 110°C for 30 h. The réaction mixture was filtered; the filtrate was concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl-acetate as eluents to give 4-(dimethoxymethyl)-2-methoxy-5-(3-thienyl)pyrimidine. MS: (M+H)⁺ = 267.2.

Step B:

‘H NMR (400 MHz, DMSO-d₆): 8.62 (s, IH), 7.76 (m, IH), 7.70 (m, IH), 7.39 (dd, IH), 5.39 (t, IH), 4.49 (d, 2H), 3.98 (s, 3H).

Préparation 9cd: (2,6-Dimetlioxypyrimidin-4-yl)methanol

-121Step A:

To the mixture of 12.16 g O-methylisouiea hydrochloride (110 mmol) and 20.0 g ethyl 4,4-dimethoxy-3-oxo-butanoate (91.6 mmol) in dry methanol 5.94 g sodium methoxide (110 mmol) was added portionwise and the mixture was stirred at 75 °C for 2 h. The reaction mixture was cooled, celite was added and the volatiles were removed under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give 4-(dimethoxymethyI)-2-methoxy-lZY-pyrimidin-6-one. *H NMR (400 MHz, DMSO-d₆); 12.37 (br s, 1H), 6.03 (s, 1H), 5.08 (s, 1H), 3.87 (s, 3H), 3.57 (m, 4H), 1.15 (t,6H).

Step B:

To the solution of 2.00 g 4-(dimethoxymethyl)-2-methoxy-lZ7-pyrimidin-6-one (8.76 mmol) in 8 mL DMF 1612 mg phosphoryl chloride (10.5 mmol) was added dropwise at 0°C and it was stirred at this température for 30 min. The mixture was diluted with 40 mL DCM and it was poured onto ice. The organic layer was washed with water, then it was dried over MgSÛ4 and concentrated under reduced pressure. The residue was dissolved in 30 mL methanol and 946 mg sodium methoxide (17.52 mmol) was added at 0°C, and it was stin-ed at this température for lh. Celite was added and the volatiles were removed under under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give 4-(dimethoxymethyl)-2,6-dimethoxypyrimidine. MS: (M+H)⁺ = 243.2.

Step C:

4-1 NMR (400 MHz, DMSO-di): 6.53 (br s, 1H), 5.53 (t, 1H), 4.40 (dd, 2H), 3.89 (s, 3H), 3.86 (s, 3H).

Préparation 9ce: (6-Chloropyrimidin-4-yl)methanol

Step A:

To the solution of 3.00 g chloromethyl benzoate (17.59 mmol) in 21 mL MeCN 5.799 g Nal (38.69 mmol) was added. l’he réaction mixture was stirred at room température for

- 122I4h. The precipitate was filtered and the organic phase was concentrated to give iodomethyl benzoate as a yellow oil.

Slep B:

Préparation of activated zinc. Zinc was washed quîckly with 10% HCl followed with water tlien éthanol then diethyl ether. The activated zinc was stored under argon.

An excess of activated zinc was suspended in 3 mL THF, treated with 349 mg 1,2dibromoethane (160 uL, 1.857 mmol) and the resulting mixture was heated at 60 °C under argon for 30 minutes. The reaction mixture was allowed to cool to room température, 10 treated with 154 mg trimethylchlorosilane (180 uL, 1.418 mmol) and the resulting mixture was stirred at room température for 30 minutes. The reaction mixture was treated with 64.5 mg LiCl (1.521 mmol) and the resulting mixture was stirred at room température for 30 minutes.

A solution of iodomethyl benzoate (1.60 g, 6.11 mmol) in 3 mL THF was added and the 15 resulting mixture was stined at room température for 1.5 h. This réaction mixture was added to a solution of 537 mg 4,6-dichloropyrimidine (3.605 mmol) and 502 mg tris[tris(3,5-bis(trifluoromethyl)-phenyl)phosphine]palladium(0) {Superstable Pd(0)

Catalyst} (0.180 mmol) in 6mL THF and the resulting mixture was stirred at room température under argon for 18 h. The reaction mixture was filtered through celite, diluted 20 with saturated ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate layers were combined, dried on magnésium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography.

Step C:

To the solution of 800 mg (6-chloropyrimidin-4-yl)methyl benzoate (3.217 mmol) in 32 mL MeOH 17 mg NaOMe (0.315 mmol) was added. It was stirred at room température for 2.5h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography to give the title product. *H NMR (200 MHz, CDCI3): 8.94 (s, IH), 7.47 (s, IH), 4.76 (s, 2H).

Préparation 9cf: (2-Methoxy-6-nicthyl-pyriniidin-4-yl)methanoj

- 123 To the solution of l.OO g methyl 2-mcthoxy-6-mcthyl-pyrimidine-4-carboxylate (5.49 mmol) in 15 mL abs THF 12 mL DIBAL-H (IM in THF) was added and it was stirred at room température for 30 min, then further 12 mL DIBAL-H was added. After l h the excess of DIBAL-H was quenched with propan-2-ol, then with water. Saturated aq. NaF 5 solution was added to the reaction mixture, then it was extracted with DCM. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The crade product was purified via flash chromatography using heptane and EtOAc as eluents to give the title product. 'H NMR (400 MHz, DMSO-d₆): 7.07 (s, IH), 5.55 (t, IH), 4.43 (m, 2H), 3.86 (s, 3H), 2.40 (s, 3H).

I0

Préparation 9cg: (6-PhenYlnvrimidin-4-yl)methanol

To the solution of l.OO g ethyl 6-phenylpyrimidine-4-carboxylate (4.38 mmol) in 15 mL MeOH 175 mg NaBH₄ (4.63 mmol) was added at room température and it was stirred at 70°C for 3 h. The reaction mixture was concentrated, and the residue was diluted with 15 saturated aq. K₂CÛ3 and it was extracted with DCM. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give the title product. *H NMR (400 MHz, CDCI3): 8.97 (s, IH), 8.11 (d, 2H), 7.68-7.45 (m, 4H), 5.45 (d, 2H).

Préparation 9ch; (2-Chloronvrimidin-4-vDmethanol

To the solution of 1860 mg methyl 2-chloropyrimidine-4-carboxyiate (10.78 mmol) in 11 mL THF 21.6 mL DIBAL-H (IM in THF, 21.6 mmol) was added dropwise at -70°C and it was stirred at this température for 16 h. 5 mL MeOH was added to it at -50°C, then 5 mL 25 water was added to it at 0°C. It was fïltered through celite. The filtrate was concentrated under reduced pressure, and then it was purified via flash chromatography using heptane and EtOAc as eluents. *H NMR (200 MHz, CDCI3): 8.60 (d, IH), 7.38 (d, IH), 4.79 (s, 2H).

Préparation 9da; ( 1 -Ethy 1-17/-pyrazol-5-yI)methanol

Step A:

-124Using bromoethane in General procedure 9G 1 -ethyl- ΙΗ-pyrazole was obtained.

Step B:

Starting from 1-ethyl-IH-pyrazole using General procedure 9H the title product was 5 obtained. 'H NMR (400 MHz, CDC1₃): 7.36 (d, 1H), 6.15 (d, 1H), 4.66 (br s, 2H), 4.18 (q, 2H), 2.99 (br s, 1H), 1.42 (t, 3H).

Préparation 9db: (l-Propyl-l//-pyrazol-5-yl)methanol

Step A:

Using 1-bromopropane in General procedure 9G 1-propylpyrazole was obtained. MS: (M+H)⁺= 111.2.

Step B:

Starting from 1-propyl-IH-pyrazole using General procedure 9H the title product was obtained. ^lH NMR (400 MHz, CDC1₃): 7.34 (d, 1H), 6.14 (d, 1H), 4.64 (s, 2H), 4.07 (dd, 2H), 1.85 (m, 2H), 0.89 (t, 3H). MS: (M+H)⁺ = 141.2.

Préparation 9dc: [l-(Propan-2-yl)-lH-pyrazol-5-yl]methanol

Using 2-bromopropane in General procedure 9G 1-isopropylpyrazole was obtained.

Step B:,

Starting from 1-isopropylpyrazole using General procedure 9H the title product was obtained. ’H NMR (400 MHz, DMSO-d₆): 7.32 (d, 1H), 6.10 (d, 1H), 5.21 (t, 1H), 4.60 (h, 1H), 4.50 (d, 2H), 1.36 (d, 6H). MS: (M+H)⁺ = 141.2.

Préparation 9dd: (l-Butyl-lH-pyrazol-5-yl)mcthanol

Starting from 1-butylpyrazole using General procedure 9H the title product was obtained. 'H NMR (400 MHz, DMSO-d₆): 7.30 (d, 1H), 6.12 (d, 1H), 5.23 (t, 1H), 4.49 (d, 2H), 4.06 (t, 2H), 1.72 (m, 2H), 1.26 (m, 2H), 0.88 (t, 3H). MS: (M+H)⁺ = 155.2.

W

- 125Prepa ration 9de: il-l3-Methylbutyi)-l/ï-pyrazol-5-yl]niethanol

Step A:

Using l-bromo-3-methyl-butane in General procedure 9F l-(3-methylbutyl)-l/7-pyrazole was obtained. *H NMR (400 MHz, DMSO-d₆): 7.71 (d, IH), 7.40 (d, IH), 6.20 (t, IH), 4.11 (t, 2H), 1.65 (q, 2H), 1.44 (h, IH), 0.89 (d, 6H).

Step B:

Starting from l-(3-methylbutyl)-l//-pyrazole using General procedure 9H the title product was obtained. *H NMR (400 MHz, DMSO-de): 7.30 (d, IH), 6.12 (d, IH), 5.25 (t, IH), 4.49 (d, 2H), 4.08 (m, 2H), 1.63 (m, 2H), 1.55 (h, IH), 0.90 (d, 6H).

Préparation 9df: [1 -(Cyclopropylmethyl)-l /7-pyrazol-5-yî]inethano!

Starting from l-(cyclopropylmethyl)-17f-pyrazole using General procedure 9H the title product was obtained. ’H NMR (400 MHz, DMSO-dô): 7.31 (d, IH), 6.14 (d, IH), 5.26 (t, IH), 4.51 (d, 2H), 3.96 (d, 2H), 1.24 (m, IH), Ü.51-0.24 (m, 4H). MS: (M+H)⁺ = 153.2.

Préparation 9dg: (l-Cyclopentvl-lH-pyrazol-5-yl)methanol

SîsrAl

Using bromocyclopentane in General procedure 9G l-cyclopentyl-l//-pyrazole was obtained.

StepJL

Starting from l-cyclopentyl-lJ/-pyrazole using General procedure 9H the title product was obtained. ^{H NMR (400 MHz, DMSO-d₆): 7.31 (d, IH), 6.11 (d, IH), 5.20 (t, IH), 4.77 (p, IH), 4.51 (d, 2H), 1.99 (m, 2H), 1.91 (m, 2H), 1.82 (m, 2H), 1.61 (m, 2H). MS: (M+H)⁺= 167.2.

Préparation 9dh; (l-Cvclohexvl-lff-pyrazol-S-yDmethanol

-126Step A:

Using bromocyclohexane in General procedure 9G 1-cyclohexyl-l/f-pyrazole was obtained. MS: (M+H)⁺ =151.2.

Step B:

Starting from l-cyclohcxyl-17/-pyrazole using General procedure 9H the title product was obtained. ^lH NMR (400 MHz, CDC1₃): 7.44 (s, IH), 6.17 (s, IH), 4.70 (d, 2H), 4.20 (m, IH), 2.05-1.21 (m, 10H). MS: (M+H)⁺= 181.2.

Préparation 9di; (l-(Tetrahydro-2/7-pyran-4-yl)-1 H-pyrazol-5-yl)méthanol

Step A:

The mixture of 596 mg pyrazole (8.75 mmol), 2.89 g 4-biOino-tetrahydiOpyran (17.5 mmol) and 1.47 g sodium hydrogen carbonate (17.5 mmol) was stirred at 120 °C for 10 days. After completion it was diluted with diethyl ether (30 mL), the precipitate was filtered off and the volatiles were removed under reduced pressure at room température. The crude oil was diluted with diethyl ether (20 mL) and washed with water. The aqueous phase was extracted with ethyl acetate, The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dîchloromethane:ethanol=100:l) to give l-(tetrahydro-2/7-pyran4-yl)-l//-pyrazole. MS: (M+II)⁺= 153.2.

Step B:

Starting from l-(tetrahydiO-2H-pyran-4-yl)-lff-pyrazole using General procedure 9H the title product was obtained. 'HNMR (400 MHz, CDC1₃): 7.46 (d, IH), 6.19 (d, IH), 4.71 (s, 2H), 4.46 (m, IH), 4.12 (dd, 2H), 3.55 (m, 2H), 2.34 (m, 2H), 1.88 (m, 2H). MS: (M+H)⁺ = 183.1.

Préparation 9dj: {l-[2-(Dimetliylaiiiino)ethyl]-l/f-pyrazf>l-5-yl}methanol

Step A:

-127The mixture of 5 g lH-pyrazole (79.44 mmol), 11.64 g 2-chloro-A⁷^V-dimethylethylamine hydrochloride (80.79 mmol) and 30.0 g potassium carbonate (220.32 mmol) in 100 mL DMF was stirred at 60 °C for 14 hours. After completion the volatiles were removed under reduced pressure. The residue was diluted with chloroform (100 mL) and washed with water. The organic layer was dried over NasSCL and concentrated under reduced pressure. The residue was diluted with cthanol (20 mL) and 34 mL HCl (5N in EtOH) was added. The precipitate was fîltered off, washed with diethyl ether and dried to give MY-dimethyl2-(l/f-pyrazol-l-yl)-ethanamine. MS: (M+H)⁺= 140.2.

Step B:

Starting from A(?/-dimethyl-2-(l//-pyrazol-l-yl)-ethanamine using General procedure 9H the title product was obtained. *H NMR (400 MHz, CDCI3): 7.47 (br s, IH), 6.25 (br s, IH), 4.54 (s, 2H), 4.27 (m, 2H), 2.73 (m, 2H), 2.21 (s, 6H), MS: (M+H)⁺ = 170.1.

Préparation 9dk: [l-(4-Methoxybenzyl)4//-pyrazol-5-yl]inethanol

Step A:

Using l-(bromomethyl)-4-methoxy-benzene in General procedure 9G l-(4methoxybenzyl)-lf/’-pyrazole was obtained.

Step B:

Starting from l-(4-methoxybenzyl)-l/7-pyrazole using General procedure 9H the title product was obtained. *H NMR (400 MHz, CDCl₃): 7.47 (d, IH), 7.14 (m, 2H), 6.85 (m, 2H), 6.24 (d, IH), 5.35 (s, 2H), 4.60 (s, 2H), 3.78 (s, 3H). MS: (M+H)⁺ = 219.1.

Préparation 9dl: [l-(4,4,4-Trifluorobutyl)-lH-pyrazol-5-yl]methanol

Step A:

Using 4-bromo-l,l,l-trifluoro-butane in General procedure 9F 1 -(4,4,4-trifluorobutyl)lH-pyrazole was obtained. ’H NMR (400 MHz, DMSO-dô): 7.75 (d, IH), 7.46 (d, IH),

6.24 (t, III), 4.19 (t, 2H), 2.26-2.13 (m, 2H), 1.98 (m, 2H).

- 128Step B:

Starting from 1-(4,4,4-trifluorobutyl)-l//-pyrazole using General procedure 9H the title product was obtained. ’H NMR (400 MHz, DMSO-d₆): 7.36 (d, IH), 6.16 (d, IH), 5.29 (br s, IH), 4.50 (d, 2H), 4.16 (t, 2H), 2.31-2.18 (m, 2H), 1.99 (m, 2H).

Préparation 9dm: (l-Pentvl-lÆ-nvrazol-5-vDmethanoi

Step A:

Using 1-bromopentane in General procedure 9F 1-pentyl-lH-pyrazole was obtained. *H NMR (400 MHz, DMSO-d₆): 7.70 (d, IH), 7.41 (d, IH), 6.20 (t, IH), 4.08 (t, 2H), 1.75 (p, 2I-I), 1.28 (m, 2H), 1.17 (m, 2H), 0.84 (t, 3H).

Step B;

Starting from l-pentyl-l/7-pyrazole using General procedure 9H the title product was obtained. NMR (400 MHz, DMSO-d₆): 7.31 (d, IH), 6.12 (d, IH), 5.25 (t, IH), 4.49 (d, 2H), 4.05 (t, 2H), 1.74 (p, 2H), 1.34-1.17 (m, 4H), 0.86 (t, 3H).

Préparation 9dn and Préparation 9do: (1Λ or 5)-l-(l-pentyl-lZT-pyrazol-5-yl)ethanol and (IS or.Æ)-l-(l-pentyl-lH-pyrazol-5-yl)ethanol

To the solution of 2.00 g l-pentyl-177-pyrazole (Préparation 9dm, Step A, 14.47 mmol) in 30 mL dry THF 10 mL n-BuLi (1.6 M, 16 mmol) was added dropwisc at -78°C and the mixture was stirred for 1 h at this température, then 848 mg acetaldehyde (20.0 mmol) was added dropwise and stirred for 90 min at -78°C. The mixture was poured into cooled saturated aq. NH₄C1 solution. Phases were separated; the aqueous phase was extracted with F.tOAc. The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to give l-(2-penty!pyrazol-3-yl)ethanol. ’H NMR (400 MHz, DMSO-dô): 7.30 (d, IH), 6.11 (d, IH), 5.24 (d, IH), 4.80 (m, IH), 4.08 (m, 2H), 1.75 (p, 2H), 1.41 (d, 3H), 1.35-1.15 (m, 4H), 0.86 (t, 3H). The enantiomers were separated via chiral chromatography column: AD, eluents: heptane / EtOH. The product eluting earlier was collected as Préparation 9dn, and the product eluting later was collected as Préparation 9do.

-129Preparation 9dp; [ 1 -(2-Methoxyethyl)-12/-pyrazol-5-ylJmethanol

Starting from 5-(dimethoxymethyl)-l//-pyrazole (Préparation 9a5) and l-bromo-2mcthoxy-cthanc using General procedure 9F 5-(dimethoxymethyl)-l-(2-methoxyethyl)177-pyrazole was obtained. *H NMR (400 MHz, DMSO-d₆): 7.40 (d, IH), 6.25 (d, IH), 5.62 (s, IH), 4.25 (t, 2H), 3.65 (t, 2H), 3.24 (s, 6H), 3.22 (s, 3H).

Note: 3-(dimethoxymethyl)-l-(2-methoxyethyl)-17T-pyrazole was also obtained. ’H NMR (400 MHz, DMSO-dô): ): 7.65 (d, IH), 6.18 (d, IH), 5.33 (s, 1H),4.22 (t, 2H), 3.65 (t, 2H),

3.24 (s, 6H), 3.21 (s, 3H).

Step B:

Starting from 5-(dimethoxymethyl)-l-(2-methoxyethyl)-l//-pyrazole using General procedure 9B the title product was obtained. ’H NMR (400 MHz, DMSO-de): 7.33 (d, IH), 6.13 (d, IH), 5.22 (t, IH), 4.50 (d, 2H), 4.24 (t, 2H), 3.65 (t, 2H), 3.20 (s, 3H).

Préparation 9dq: [ 1 -(3-Methoxypropyl)-1 77-py razol-5-yl] methanol

Step A:

Starting from 5-(dïmethoxymethyl)-l//’-pyrazole (Préparation 9a5) and l-bromo-3methoxy-propane using General procedure 9F 5-(diniethoxymethyl)-l-(3methoxypropyl)-17Z-pyrazole was obtained. ’H NMR (400 MHz, DMSO-d$): 7.40 (d, IH),

6.25 (d, IH), 5.59 (s, IH), 4.12 (t, 2H), 3.29 (t, 2H), 3.25 (s, 6H), 3.23 (s, 3H), 1.96 (m, 2H).

Note: 3-(dimethoxymethyl)-l-(3-methoxypiOpyl)-l//-pyrazole was also obtained. ’H NMR (400 MHz, DMSO-d₆): 7.66 (d, IH), 6.18 (d, IH), 5.33 (s, IH), 4.11 (t, 2H), 3.25 (t, 2H), 3.23 (s, 6H), 3.21 (s, 3H), 1.97 (m, 2H).

Step B:

Starting from 5-(dimethoxymethy 1)-1-(3-rnethoxypropyl)-l/-/-pyrazole using General procedure 9B the title product was obtained. ’H NMR (400 MHz, DMSO-dô): 7.33 (d,

-1301H), 6.13 (d, IH), 5.24 (t, IH), 4.48 (d, 2H), 4.11 (t, 2H), 3.28 (ζ 2H), 3.22 (s, 3H), 1.97 (m, 2H).

Préparation 9dr; [l-(2-Ethoxyethyl)-lfT-pyrazol-5-yl]methanol

Step A:

Starting from 5-(dimethoxymethyl)-l//-pyrazole (Préparation 9a5) and l-bromo-2ethoxy-ethane using General procedure 9F 5-(dimethoxymethyl)-l-(2-ethoxyethyl)-lHpyrazole was obtained. *H NMR (400 MHz, DMSO-d₆): 7.40 (d, IH), 6.25 (d, IH), 5.65 (s, 10 IH), 4.24 (t, 2H), 3.68 (t, 2H), 3.38 (m, 2H), 3.24 (s, 6H), 1.06 (t, 3H). Note: 3(dimethoxymethyl)-l-(2-ethoxyethyl)pyrazole was also obtained. *H NMR (400 MHz, DMSO-d₆): 7.65 (d, IH), 6.19 (d, IH), 5.33 (s, IH), 4.21 (t, 2H), 3.69 (t, 2H), 3.39 (q, 2H),

3.24 (s, 6H), 1.05 (t, 3H).

Step B:

Starting from 5-(dimethoxymethyl)-l-(2-ethoxyethyl)-lZZ-pyrazole using General procedure 9B the title product was obtained. ’H NMR (400 MHz, DMSO-dg): 7.33 (d, IH), 6.13 (d, IH), 5.20 (t, IH), 4.51 (d, 2H), 4.23 (t, 2H), 3.68 (t, 2H), 3.38 (q, 2H), 1.05 (t, 3H).

Préparation 9ds: (l-[2-(2-Methoxyethoxy)ethyl]-lH-pyrazol-5-yl}methanol

Step A:

Starting from 5-(dimethoxymethyl)-l//-pyrazole (Préparation 9a5) and l-(225 bromoethoxy)-2-methoxy-ethane using General procedure 9F 5-(dimethoxy methyl)-1 -[2(2-methoxyethoxy)ethyl]-l/7-pyrazole was obtained. ’HNMR (400 MHz, DMSO-dô): 7.40 (d, IH), 6.25 (d, IH), 5.67 (s, IH), 4.25 (t, 2H), 3.72 (t, 2H), 3.47 (m, 2H), 3.39 (m, 2H),

3.25 (s, 6I-I), 3.21 (s, 3H).

Note: 3-(dimethoxymethy 1)-1-(2-(2-methoxyethoxy)ethyl]-177-pyrazole was also obtained.

¹1-I NMR (400 MHz, DMSO-dc): 7.66 (d, 1 H), 6,19 (d, 1 H), 5.33 (s, 1 H), 4.22 (t, 2H), 3.74 (t, 2H), 3.48 (m, 2H), 3.39 (m, 2H), 3.24 (s, 6H), 3.21 (s, 3H).

e

-131StepB:

Starting from 5-(dimethoxymethyl)-l-[2-(2-methoxyethoxy)ethyl]-lZ/-pyrazole using General procedure 9B the title product was obtained. 'H NMR (400 MHz, DMSO-dfi): 7.33 (d, IH), 6.13 (d, IH), 5.19 (t, IH), 4.51 (d, 2H), 4.24 (t, 2H), 3.72 (t, 2H), 3.46 (m, 2H),3.38(m, 2H), 3.20 (s, 3H).

Préparation 9dt: (1 -/er/-Butyl-lZZ-pyrazol-5-yJ)methanol

Step A:

Starting from terf-butylhydrazine hydrochloride using General procedure 9D 1-ferr-butyl5-(dimethoxymethyl)-l/Z-pyrazole was obtained. *H NMR (400 MHz, DMSO-de): 7.34 (d, IH), 6.34 (d, IH), 5.74 (s, IH), 3.24 (s, 6H), 1.57 (s, 9H).

Note: l-/e/'/-butyl-3-(dimethoxymethyl)-lAT-pyrazole was also obtained. ^!H NMR (400 MHz, DMSO-dô): 7.75 (d, IH), 6.18 (d, IH), 5.34 (s, IH), 3.24 (s, 6H), 1.50 (s, 9H).

Step B:

Starting from l-tert-butyl-5-(dimethoxymethyl)-lf/-pyrazole using General procedure 9B the titleproduct was obtained. ^!H NMR (400 MHz, DMSO-de): 7.27 (d, IH), 6.19 (d, IH), 5.31 (t, IH), 4.61 (d, 2H), 1.56 (s, 9H).

Préparation 9du: [l-(2,2,2-Trifluoroethyl)-lZZ-pyrazol-5-ylJmethanol

Step A:

Starting from 2,2,2-trifluoroethylhydrazine (70 w/w% in water) using General procedure 9D in absence of sodium methoxide 5-(dimethoxymethyl)-1-(2,2,2-trifluoroethyl)-4,5dihydro-177-pyrazol-5-ol was obtained. ’HNMR (400 MHz, DMSO-dg): 6.83 (t, IH), 6.03 (s, IH), 4.30 (s, IH), 3.95 (m, IH), 3.47 (m, IH), 3.40 (d, 6H), 2.88 (m, IH), 2.50 (m, IH).

Step B:

Starting from 5-(dimethoxymethyl)-l-(2,2,2-trifluoroethyl)-4,5-dihydiO-l/Z-pyrazol-5-ol using General procedure 9B the title product was obtained. ’H NMR (400 MHz, DMSOd₆): 7.48 (d, IH), 6.27 (d, IH), 5.46 (t, IH), 5.08 (q, 2H), 4.56 (d, 2H).

-132Preparation 9dv; [l-(cyclohexylmethyl)-ljff-pyrazol-5-yl]methanol and

Préparation 9dw; [ 1 -(cyclohexylmethyl)-17/-pyrazol-3-y 1J m ethanol

Step A:

Starting from cyclohexylmethylhydrazine hydrochloride using General procedure 9D 1(cyclohexylmethyl)-5-(dimethoxymethyl)-17/-pyrazole was obtained. This product eluted first. 'H NMR (400 MHz, DMSO-d₆): 7.38 (d, IH), 6.25 (d, IH), 5.59 (s, IH), 3.91 (d,

2H), 3.24 (s, 6H), 1.89 (m, IH), 1.66 (m, 2H), 1.61 (m, 2H), 1.48 (d, 2H), 1.16 (m, 2H),

0.95 (dd, 2H).

Note: The secondly eluted product was the l-(cyclohexylmethyl)-3-(dimethoxymethyl)lÆ-pyrazole. ^!H NMR(400 MHz, DMSO-d₆): 7.64 (d, IH), 7.17 (d, IH), 5.33 (s, IH), 3.91 (d, 2H), 3.23 (s, 6H), 1.77 (m, IH), 1.66 (m, 2H), 1.60 (m, 2H), 1.47 (d, 2H), 1.16 (m, 2H), 15 0.92(dd,2H).

Step Bl:

Starting from l-(cyclohexylmethyl)-5-(dimethoxymethyl)-lH-pyrazole using General procedure 9B [l-(cyclohexylmethyl)-ll/-pyrazol-5-yl]methanol was obtained. ’H NMR (400 MHz, DMSO-dû): 7.31 (d, IH), 6.12 (d, IH), 5.24 (l, IH), 4.48 (d, 2H), 3.90 (d, 2H),

1.84 (m, III) 1.69-1.55 (m, 3H), 1.49 (m, 2H), 1.15 (m, 3H), 0.96 (m, 2H).

Step B2:

Starting from l-(cyclohexylmethyl)-3-(dimethoxymethyl)-l/f-pyrazole using General 25 procedure 9B [l-(cyclohexylmethyl)-l/Apyrazol-3-yl]methanol was obtained. ’H NMR (400 MHz, DMSO-dé): 7.56 (d, IH), 6.13 (d, IH), 4.94 (t, IH), 4.37 (d, 2H), 3.85 (d, 2H), 1.75 (m, IH) 1.69-1.56 (m, 3H), 1.49 (m, 2H), 1.15 (m, 3H), 0.91 (m, 2H).

Préparation 9ea: [6-(2-Furyl)-2-pyridyl]methanol

To the solution of 940 mg (6-bromo-2-pyridyl)methanol (5.00 mmol) in 20 mL dioxane

1.94 g 2-(2-furyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (10.0 mmol), 4.89 g CS2CO3 (15.0 mmol) and 577 mg tetrakis(triphenylphosphine)palladium(0) (0.50 mmol) were »

-133added, and it was· stirred under N₂ at 70°C for 16 h. The réaction mixture was concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl-acetate as eluents to give the title product. MS: (M+H)⁺ = 176.2.

Préparation 9eb; [6-(2-Thienyl)-2-pyridyl]methanol

To the solution of 624 mg (6-bromo-2-pyridyl)methanol (3.30 mmol) in 15 mL dioxane 850 mg 2-thienylboronic acid (6.60 mmol), 3.25 g Cs₂CO3 (10.0 mmol) and 385 mg tetrakis(triphenylphosphine)palIadium(0) (0.33 mmol) were added, and it was stirred under N₂ at 70°C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl-acetate as eluents to give the title product. MS: (M+H)⁺ = 192.2.

Préparation 9ec: (l-Butyl-lW-l,2,3-triazol-5-yl)methanol

Step A:

To the solution of 690 mg 1 ff-[l,2,3]triazole (10.0 mmol) in 5 mL DMF 1.50 g K₂CO₃(11.0 mmol) and 1.50 g bromobutane (11.0 mmol) were added and the mixture was stirred at room température for 16 h. The reaction mixture was poured into 50 mL water and extracted with DCM. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The regioisomers were separated via flash chromatography using heptane and EtOAc as eluents: 2-butyl-2Æ-[l,2,3]triazole eluted first then l-butyl-l//-[l,2,3]triazole. 'H NMR (400 MHz, DMSO-d₆) of l-butyl-1/7- [l,2,3]triazole: 7.62 (m, IH), 7.53 (m, IH), 4.32 (m, 2H), 1.82 (m, 2H), 1.27 (m, 2H), 0.87 (m, 3H).

Step B:

To the cooled solution of 428 mg l-butyl-l//-[l,2,3]triazole (3.40 mmol) in 15 mL THF under N₂ 2.35 mL BuLi (1.6M, 3.74 mmol) was added at -78°C, and it was stirred for 15 min, then 0.300 mL DMF (3.74 mmol) was added. The reaction mixture was stirred at room température for 24 h. It was poured onto 50 mL ice-water, and extracted with EtOAc. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was dissolved in 20 mL EtOH and 250 mg sodium borohydride (6.50

17193 «

-134mmol) was added at O°C and stirred for 1 h at this température, then it was stirred at room température for 16 h. Then 1 mL water was added, and the volatiles were removed under reduced pressure. The residue was diluted with EtOAc and washed with brine. The organic phase was dried over Na₂SO4 and concentrated under reduced pressure. The residue was 5 purified via flash chromatography using heptane and EtOAc as eluents to give the title product. 7.59 (s, IH), 5.46 (t, IH), 4.58 (d, 2H), 4.32 (t, 2H), 1.79 (m, 2H), 1.29 (m, 2H), 0.90 (m, 3H).

Préparation 9ed: 11-(3-Methoxypropy 1)-1//-1,2,3-triazol-5-yl|inethanol

Step A:

To the solution of 690 mg l/7-[l,2,3]triazole (10.0 mmol) in 5 mL acetonitrile 1.50 g K₂CO3 (11.0 mmol) and 1.68 g 1 -bromo-3-methoxy-propane (11.0 mmol) were added and the mixture was stirred at room température for 24 h. The reaction mixture was filtered and 15 concentrated under reduced pressure. The regioisomers were separated via flash chromatography using heptane and EtOAc as eluents: 2-(3-methoxypropyI)-lH- [1,2,3]triazole eluted first then l-(3-methoxypropyl)-lH-[l,2,3]tiiazole. ’H NMR (400 MHz, DMSO-dfi) of l-(3-methoxypropyl)-lH-[l,2,3]triazole: 8.12 (d, IH), 7.72 (d, IH), 4.42 (t, 2H), 3.29 (t, 2H), 3.23 (s, 3H), 2.04 (m, 2H).

Step B:

To the cooled solution of 378 mg l-(3-methoxypropyl)-l//-[l,2,3]triazole (2.70 mmol) in mL THF under N₂ 1.90 mL BuLi (1.6M, 3.04 mmol) was added at -78°C, and it was stirred for 30 min, then 0.220 mL DMF (3.00 mmol) was added. The reaction mixture was 25 stirred at room température for 4 h. It was poured onto 40 mL ice-water, and extracted with EtOAc. The combined organic phases were dried over Na₂SC>4 and concentrated under reduced pressure. The residue was dissolved in 16 mL EtOH and 200 mg sodium borohydride (5.29 mmol) was added at 0°C and stirred for 1 h at this température, then it was stirred at room température for 16 h. Then 1 mL water was added, and the volatiles were removed under reduced pressure. The residue was diluted with EtOAc and washed with brine. The organic phase was dried over Na₂SÛ4 and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as

-135eluents to give the title product. ^!H NMR (400 MHz, DMSO-dô): 7.60 (s, 1H), 5.46 (t, 1H),

4.57 (d, 2H), 4.37 (t, 2H), 3.31 (t, 2H), 3.23 (s, 3 H), 2.04 (m, 2H).

Préparation 9ee: (l-PhenvM//-Î.2.3-triazol-5-vi)methanol

Step A: (Tang. Bo-Xiao et alSynthesis 2008,1707)

The mixture of 207 mg 17/-[l,2,3]triazole (3.00 mmol), 735 ing iodobenzene (3.60 mmol), mg copper(I)oxide (0.60 mmol), 216 mg 1,10-phenantroline (1.20 mmol), and 2.35 g TBAF hydrate (9.00 mmol) was heated at 115 °C for 22 h under argon. The reaction mixture was diluted with EtOAc and washed with brine. The organic phase was dried over

Na₂SO4 and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to give 1-phenyl-1Æ-[1,2,3]triazole. ‘H NMR (400 MHz, OMSO-d^): 8.84 (d, 1H), 7.99 (d, 1H), 7.92 (m, 2H), 7.61 (m, 2H), 7.49 (m, 1H).

Step B:

To the cooled solution of 216 mg l-phenyl-H7-[l,2,3]triazole (1.50 mmol) in 7 mL THF under N₂ 1.00 mL BuLi (1.6M, 1.60 mmol) was added at -78°C, and it was stirred for 15 min, then 0.130 mL DMF (1.63 mmol) was added. The reaction mixture was stirred at 20 room température for 90min. It was poured onto 30 mL ice-water, and extracted with

EtOAc. The combined organic phases wcrc dried over Na₂SO4 and concentrated under reduced pressure. The residue was dissolved in 9 mL EtOlI and 111 mg sodium borohydride (2.94 mmol) was added at 0°C and stirred for 1 h at this température, then it was stirred at room température for 16 h. Then 1 mL water was added and the reaction 25 mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with brine. The organic phase was dried over Na₂SÛ4 and concentrated under reduced pressure to give the title product. MS: (M+H)⁺ = 176.2.

Préparation 9ef: [l-(2-MethoxyethyI)-lH-l,2,3-triazol-5-yl)methanol

Step A:

-136To the solution of 2.50 g ethyl lH-[l,2,3]triazole-5-carboxylate (17.7 mmol) in 20 mL acetonitrile and in 3 mL DMF 3.19 g K2CO3 (23.1 mmol) and 3.20 g l-bromo-2-methoxyethane (23.1 mmol) were added and the mixture was stirred at 35°C for 24 h, Then it was filtered and concentrated under reduced pressure. The regioisomers were separated via flash chromatography using heptane and EtOAc as eluents: ethyl 2-(2-methoxyethyl)-2H- [l,2,3]triazolc-4-carboxylatc clutcd first followed by ethyl l-(2-methoxyethyl)-177-l,2,3triazole-5-carboxylate. ^!H NMR (400 MHz, DMSO-dr,) of ethyl l-(2-methoxyethyl)-17/l,2,3-triazole-5-carboxylate: 8.22 (s, IH), 4.59 (t, 2H), 4.43 (q, 2H), 3.76 (t, 2H), 3.36 (s, 3H), 1.42 (t, 3H).

Step B:

To the solution of 223 mg ethyl l-(2-methoxyethyl)-l/7’-l,2,3-triazole-5-carboxylate (1.12 mmol) in 5 mL EtOH 105 mg sodium borohydride (2.78 mmol) was added at 0°C and the mixture was stirred for 1 h at this température, then it was stirred at room température for 16 h. Then 1 mL water was added, and the reaction mixture was concentrated under reduced pressure. The residue was digerated with DCM, the solids were filtered off and the filtrate was concentrated under reduced pressure to give the title product as yellow oil. 7.64 (s, IH), 4.69 (s, 2H), 4.61 (t, 2H), 3.85 (t, 2H), 3.37 (s, 3H).

Préparation 9cg; 4-(2-Hydroxycthyl)-l-methyl-piperazin-2-one

To the mixture of 450 mg l-methylpiperazin-2-one (3.00 mmol) and 1.00 g K₂CO₃ (7.24 mmol) in 5 mL THF 1 mL 2-bromoelhanol (14.Immol) was added and the mixture was stirred at 65°C for 16h. The mixture was cooled to room température, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography using DCM and MeOH to give 4-(2-hydroxyethyl)-l-methyl-piperazin-2-one. MS: (M+H)⁺ = 159.4.

Préparation 9eh: 2-(4-(2,2,2-Trifluoroethyl)piperazin-l -yljethanol

Step A:

To a solution of 5.208 g 2-piperazin-l-ylethanol (40 mmol) in 250 mL dry éthanol 8.063 g 4-dimethylaminopyridine (66 mmol) and 12.1 mL (2,2,2-trifluoroacetyl) 2,2,2a

-137trifluoroacctate (87 mmol) was added in portions and the mixture was stirred at room température until no further conversion was observed. The mixture was concentrated under reduced pressure and purified via flash chromatography using EtOAc and MeOH as eluents to give 2,2,2-trifluoro-l-[4-(2-hydroxyethyl)piperazin-l-yl]ethanone.

Step B:

To a mixture of 3.300 g 2,2.2-trifluoiO-l-[4-(2-hydroxyethyl)piperazin-l-yl]ethanone (14.6 mmol) and 1.988 g imidazole (29.2 mmol) in 50 mL THF 4.7 mL chloro(triisopropyl)silane (21.9 mmol) was added dropwise and it was stirred at room 10 température until no further conversion was observed. Then the volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to give 2,2,2-trifluoiO-1-(4-(2triisopropylsilyloxyethyl)piperazin-l-yl]ethanone. MS (El, 70 eV) m/z (% relative intensity, [ion]): 166 (5), 195 (100), 339 (11), 382 (1, [M*])·

SifiJlÇL

To a solution of 1.55 g 2,2,2-trifluoro-l-[4-(2-triisopropylsilyloxyethyl)piperazin-lyl]ethanone (4.0 mmol) in 15 mL THF 12 mL BH3XTHF (1.0 M in THF, 12 mmol) was added with stirring and it was heated at 45°C until no further conversion was observed.

The mixture was cooled to room température, the excess of BHj was decomposed hy the addition of MeOH. The volatiles were evaporated under reduced pressure and the residue was co-cvaporatcd with MeOH again. Then the crude product was purified via flash chromatography using heptane and EtOAc as eluents to give triisopropyl-[2-[4-(2,2,2trifluoroethyl)piperazin-l-yl]ethoxy]silane. MS (El, 70 eV) m/z (% relative intensity, [ion]): 138 (7), 165 (5), 181 (100) 325 (9), 368 (4, [M⁺]).

Slep D:

To a solution of 0.536 g triisopropyl-[2-[4-(2,2,2-triiluoroethyl)piperazin-lyl]ethoxy]silane (1.45 mmol) in 10 mL THF 1.52 mL TBAF (1.0 M in THF) was added 30 and it was stireed at room température until no further conversion was observed. The volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents to give the title product. ’H NMR (400

-138MHz, CDCh): 3.64 (t, 2H), 3.06 (br s, 2H), 2.98 (q, 2H), 2.78-2.68 (m, 4H), 2.63-2.53 (m, 5H).

Préparation 9ei: 2-i4-(2.2-Difliwroethvl)i)iperazin-l-vllethanol

Step A:

To a solution of 3.254 g 2-piperazin-l-ylethanol (25 mmol) in 60 mL dry éthanol 7.82 g 4dimethylaminopyridine (64 mmol) and 8 mL (2,2-difluoroacetyl) 2,2-difluoroacetate (64 mmol) was added and stirred at room température. Later a second portion of 7.82 g 4dimethylaminopyridine (64 mmol) and 8 mL (2,2-difluoroacetyl) 2,2-difluoroacetate (64 mmol) were added and the mixture was stirred at room température until no further conversion was observed. The mixture was concentrated under reduced pressure and purified via flash chromatography using EtOAc and MeOH as eluents to give 2,2-difluoro1 - [4-(2-hydroxyethyl)piperazin-1 -yljethanone.

Step B:

1.800 g 2,2-difluoro-l-[4-(2-hydroxyethyl)piperazin-l -yljethanone (8.65 mmol) and L. 178 g imidazole (17.3 mmol) were dissolved in 25 mL THF and 2.8 mL chloro(triisopropyl)silane (13.0 mmol) was added dropwise to the solution, which was stirred at room température until no further conversion was observed. Then the volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to give 2,2-difluoro-l-[4-(2triisopropylsilyloxyethyl)piperazin-l-yl]ethanone. MS (El, 70 eV) m/z (% relative intensity, [ion]): 148 (4), 177 (100), 321 (5), 364 (1, [M*]).

Step C:

To a solution of 1.40 g 2,2-difluoi'O“l-[4-(2-triisopropylsilyloxyethyl)piperazin-lyljethanone (3.84 mmol) in 15 mL THF 7.7 mL BH3XTHF (1.0 M in THF) was added with stirring and the mixture was heated at 45°C until no further conversion was observed. After cooling to room température the excess of BH3 was decomposed by the addition of MeOH. The volatiles were evaporated under reduced pressure and the residue was co-evaporated with MeOH again. Then the crude product was purified via flash chromatography using

-139heptane and EtOAc as eluents to give 2-(4-(2,2-difluoiOethyl)piperazin-l-yl]ethoxytriisopropyl-silane. MS (El, 70 eV) m/z (% relative intensity, [ion]): 59 (5), 70 (7), 97 (5), 120 (9), 147 (3), 163 (100), 307 (3) 350 (1, [M¹]).

Step I):

To a solution of 0.547 g 2-(4-(2,2-difluoroethyl)piperazin-l-yl]ethoxy-triisopropyl-silane (1.56 mmol) in 10 mL THF 1.64 mL TBAF (1.0 M in THF) was added and the mixture was stirred at room température until no further conversion was observed. The volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents to give the title product. ^JH NMR (400 MHz, CDC1₃): 5.87 (tt, IH), 3.60 (t, 2H), 2.74 (td, 2H), 2.66-2.41 (m, 10H).

Préparation 10a: Ethyl (2jf)-2-[(5S'_i,)-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[(2“ methy lsulfanylpyrim id in-4-yl)methoxy] pheny 1] propanoate

1.77 g ethyl (2/?)-2-[(55'_a)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 8a) (2.5 mmol), 1.17 g (2methylsulfanylpyrimidin-4-yl)methanol (Préparation 9aa) (7.5 mmol) and 1.97 g PPI13 (7.5 mmol) were dissolved in 50 mL dry toluene, then 1.74 g diteributy 1 azodicarboxylate (7.5 mmol) was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The toluene was evaporated under reduced pressure and the residue was purified via flash chromatography using DCM and MeOH as eluents. 'H NMR (500 MHz, DMSO-d₆): 8.70 (d, IH), 8.58 (s, IH), 7.34 (d, IH), 7.31 (d, IH), 7.30 (m, 2H), 7.22 (m, 2I-I), 7.17 (t, IH), 7.16 (d, IH), 6.98 (d, IH), 6.74 (t, IH), 6.31 (d, IH), 5.47 (dd, IH), 5.17 (d, IH), 5.11 (d, IH), 4.20 (m, IH), 4.16 (m, IH), 4.06 (m, 2H), 3.12 (dd, IH), 2.69 (m, 2H), 2.56 (dd, IH), 2.50 (s, 3H), 2.46 (br s, 4H), 2.24 (br s, 4H), 2.10 (s, 3H), 1.86 (s, 3H), 1.06 (t, 3H). HRMS calculated for C₄3H44C1FN₆O₅S2: 842.2487, found: 843.2660 (M+H).

17193 «

-140Préparation 10b: Ethyl (2A)-2-|(5S^,„)-5'[3-ehloro-4-(2-diniethylaniinoethyloxy)-2methyi-phenyl]-6-(4-fluorophenyl)thieno[2,3-rf]pyrimidin-4-yl]oxy-3-[2-[(2mefhylsu]fanylpyrimidin-4-yl)methoxy]phenyl]propanoate

0.975 g ethyl (2J?_/)-2-[(5S'„)-5-[3-chloiO-4-(2-dimethylaminoethyloxy)-2-methyl-phenyl]-6(4-fluorophenyl)thieno[2,3-iZ]pyrimidin-4-yl]oxy-3-(2-hydroxyphenyl)propanoate (Préparation 8b) (1.5 mmol), 0.702 g (2-methylsulfanylpyrimidin-4-yl)methanol (Préparation 9aa) (4.5 mmol) and 1.180 g PPh₃ (4.5 mmol) were dissolved in 50 mL dry toluene, then 1.036 g di/er/butyl azodicarboxylate (4.5 mmol) was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The toluene was evaporated under reduced pressure, Et₂O was added, and the mixture was stirred and sonicated. The precipitated white crystals were filtered, washed with Et₂O. The filtrate was concentrated and purified via flash chromatography using DCM and MeOH as eluents. ^!H NMR (500 MHz, DMSO-d₆): 8.69 (d, IH), 8.60 (s, IH), 7.34 (d, IH), 7.30 (d, IH), 7.30 (dd, 2H), 7.23 (t, 2H), 7.17 (d, IH), 7.16 (t, IH), 6.98 (d, IH), 6.74 (t, IH), 6.29 (dd, IH), 5.47 (dd, IH), 5.17 (d, IH), 5.11 (d, IH), 4.19 (t, IH), 4.15 (t, IH), 4.08 (m, IH), 4.05 (m, IH), 3.13 (d, IH), 2.64 (t, 2H), 2.56 (d, IH), 2.50 (s, 3H), 2.19 (s, 6H), 1.85 (s, 3H), 1.06 (t, 3H). HRMS calculated for C₄₀H₃9ClFN₅O5S₂: 787.2065, found: 788.2148 (M+H).

Préparation 10c: Ethyl (2Æ)-2-[(5S_e)-5-[3-chloro-2-methyl-4-[2-(4-inethylpiperazin-lyl)cthoxy]phcnyl]-6-(5-fluoro-2-ftiryl)thieno[2,3-rf]pyriniidin-4-yl]oxy-3-[2-[(2“ methylsulfanylpyrimidin-4“yl)methoxy]phenyl]propanoate

1.39 g ethyl (2J?A2-[(5S_rt)-5-[3-chloro-2“niethyl-4-[2~(4-methylpiperazm-ly l)ethoxy]phenyl] -6-(5 -fluoro-2-fury l)thieno [2,3 -rf]py rimidin-4-y 1] oxy-3 -(2hydroxyphenyl)propanoate (Préparation 8c) (2.00 mmol), 0.94 g (2methylsulfanylpyrimidin-4-yl)methanol (Préparation 9aa) (6.00 mmol) and 1.57 g PPh₃(6.00 mmol) were dissolved in 40 mL dry toluene, then 1.38 g di/er/butyl azodicarboxylate (6.00 mmol) was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The toluene was evaporated under reduced pressure and the residue was purified via flash chromatography using DCM and MeOH as eluents. ^]H NMR (500 MHz, DMSO-dô): 8.70 (d, IH), 8.57 (s, IH), 7.35 (d, IH), 7.27 (d, IH), 7.25 (d, IH), 7.19 (m, IH), 7.00 (dm, IH), 6.81 (m, IH), 6.35 (dm, IH), 5.89 (dd, IH), 5.71 (t, IH), 5.48 (dd, IH), 5.18 (d, IH), 5.12 (d, IH), 4.26 (m, IH), 4.22 (m, IH), 4.08 (m, IH), 4.05 (m,

- I4l 1H), 3.15 (dd, 1H), 2.50 (s, 3H), 2.50 (br s, 4H), 2.49 (dd, 1H), 2.27 (br s, 4H), 2.11 (s, 3H), 1.95 (s, 3H), 1.06 (t, 3H). HRMS calculated for C^CIFNeC^: 832.2280, found: 833.2332 (M+H).

Préparation lia; Ethyl (2Æ)-2-[5-(3-chloro-2-ethyI-4-hydroxy-phenyl)-6-(25 furyl)thieno[2,3-<7Jpyriniidin-4-yl]oxy-3-(2-jnethoxyphenyl)propanoatc (mixture of diastereoisomers)

403 mg ethyl (27?)-2-[5-biOnio-6-(2-furyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-(2methoxyphenyl)propanoate (Préparation 4e) (0.80 mmol), 371 mg [2-chloro-3-ethyl-4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]-triisopropyl-silane (Préparation

Se) (0.85 mmol), 57 mg Ataphos (0.08 mmol) and 652 mg CS2CO3 (2.00 mmol) were dissolved in 8 mL dioxane and 2 mL water. The mixture was heated to 110°C for 15 minutes via microwave irradiation. Then water was added and the pH was set to 6 with 2

M HCl. Then it was extracted with DCM, dried over Na₂SO4, filtered and concentrated under reduced pressure and purified via reversed phase chromatography, using MeCN as eluent to obtain ethyl (2Æ)-2-[5-(3-chloro-2-ethyl-4-triisopropylsilyloxy-phenyl)-6-(2furyl)thieno[2,3-i(|pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate (MS (M+H): 735.2). Then it was dissolved in 2 mL toluene, 0.45 mL TBAF (0.45 mmol in 1 M THF) was added and the mixture was stirred for 5 minutes. Then it was diluted with DCM, washed with water and brine, dried over Na₂SC>4, filtered and concentrated under reduced pressure. The crade product was purified via flash chromatography, using heptane and

EtOAc as eluents to obtain Préparation lia as a mixture of diastereoisomers. MS (M+H): 579.2 for both diastereomers.

Préparation H b; Ethyl (2R)-2-f 5-(3-fluoro-4-hy droxy-2-methyl-pheny 1)-6-(225 furyI)thieno[2,3-rfjpyrimidin-4-ylJoxy-3'(2-methoxyphenyl)propanoate (mixture of diastereoisomers)

503 mg ethyl (2Æ)-2-[5-bromo-6-(2-furyl)thieno[2,3iZ]pyrimidin-4-yl]oxy-3-(2methoxyphenyl)propanoate (Préparation 4e) (1.00 mmol), 378 mg 2-fluoro-3-methyl-4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5g) (1.50 mmol), 21 mg

Ataphos (0.03 mmol) and 652 mg CS2CO3 (2.00 mmol) were dissolved in 8 mL dioxane and 2 mL water. The mixture was heated to 110°C for 10 minutes via microwave

-142irradiation. Then water was added and the pH was set to 6 with 2 M HCl. Then it was extracted with DCM, dried over NaîSO^ fîltered and concentrated under reduced pressure. The crude product was purified via flash chromatography, using heptane and EtOAc as eluents to obtain Préparation 11b as a mixture of diastereoisomers. MS (M+H): 549.0, (M-H): 547.0 for both diastereomers.

Préparation______12; 4-Chloro-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]thieno[2,3-rf]pyrimidine

25.00 g 4-chloiO-5-iodo-thieno[2,3-i/]pyrimidine (Préparation le) (84.31 mmol), 39.94 g 1-[2-[2-ϋΜοΐΌ-3-ΐΏ6ί1ιγ1--4·-(4,4,5,5-·ί6ΐΓ8!η6ΐ1^1-1₎3_ΐ2-άίοχ3ΒοΐΌ13η“2··γ1)ρ1ιεηοχγ]6ί1ιν1]-4methyl-piperazine (Préparation 5b) (101.2 mmol) and 53.69 g K3PO4 (252.9 mmol) were dissolved in 300 mL DME and 200 mL water. 946 mg palladium acetate (4.221 mmol) and 3.021 g BuPAd2 (8.433 mmol) were added, and then the mixture was stirred at 60°C under argon atmosphère until no further conversion was observed. Then the DME was evaporated and the precipitated solid was fîltered off and washed with water. To the fîltered solid 100 mL MeCN was added and it was sonicated, and then it was fîltered to give a pale yellow solid as Préparation 12. ^lH NMR (400 MHz, DMSO-dg): 8.98 (s, 1H), 7.97 (s, 1H), 7.22 (d, 1H), 7.09 (s, 1H), 4.25-4.16 (m, 2H), 2.76 (t, 2H), 2.54 (br s, 4H), 2.32 (br s, 4H), 2.14 (s, 3H), 2.06 (s, 3H).

Préparation______13: 4-Cliloro-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazïn-lyI)ethoxy]pheiiyl]-6-Îo(fo-thieno[2,3-tf]pyr:midine

21.95 g 4-chloro-5-[3-chloiO-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl] thieno-[2,3-<Z]pyrimidine (Préparation 12) (50.20 mmol) was dissolved in 500 mL dry THF under N2 and then it was cooled to -78°C. 50.20 mL lithium diisopropylamide (100.4 mmol, 2 M in THF, EtPh, hexanes) was added and the mixture was stirred at -78°C for 1 hour. Then 25.48 g iodine (100.4 mmol) was added and the mixture was allowed to warm up to room température. The volatiles were evaporated; the residue was diluted with DCM, washed with 10% sodium thiosulphate solution. The aqueous layer was extracted with DCM. The combined organic phases were dried overNa₂SO4, fîltered and concentrated. 50 mL MeCN was added and it was sonicated for 10 minutes, fîltered, washed with MeCN to give a pale yellow solid as Préparation 13. ^fH NMR (500 MHz, DMSO-dg): 8.93 (s, 1H),

-143 7.15 (d, IH), 7.13 (d, IH), 4.22 (t, 2H), 2.77 (t, 2H), 2.56 (br s, 4H), 2.34 (br s, 4H), 2.16 (s, 3H), 2.00 (s, 3H).

Préparation______14: 4-Chloro-5-[3-chloro-2-methyl-4-[2-(4-uiethylpiperazin-l5 yl)ethoxy]phenyl]-6-(2-furyl)thieno[2,3-(/]pyrimidme

3.00 g 4-chloiO-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6iodo-thieno[2,3-</]pyrÎmidine (Préparation 13) (5.32 mmol), 2.06 g 2-(2-furyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane (9.05 mmol), 377 mg AtaPhos (0.53 mmol) and 5.205 g césium carbonate (15.97 mmol) were placed in an 250 mL flask. 80 mL dioxane and 20 10 mL water were added, and then stirred at 70°C under argon atmosphère until no further conversion was observed. Brine was added to the reaction mixture and it was extracted with EtOAc. The combined organic phases were dried over MgSO4, fïltered and evaporated under reduced pressure, and then purified by flash chromatography using DCM / MeOH as eluents to give Préparation 14. ’H NMR (500 MHz, DMSO-d^): 8.93 (s, IH), 15 7.86 (d, IH), 7.24 (d, IH), 7.19 (d, IH), 6.55 (d, IH), 5.65 (d, IH), 4.23 (t, 2H), 2.78 (t,

2H), 2.15 (s, 3H), 2.04 (s, 3H).

Préparation 15a: Methyl (2R)-2-[(55„)-5-(3-ch!oro-4-hydroxy-2-methyl-5-nitrophenyl)-6-ethyl-thieno[2,3-</jpyrimidin-4-yi]oxy-3-phenyl-propanoate

483 mg methyl (2Æ)-2-[(55_a)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethyl-thieno[2,3i/)pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 6i) (1.00 mmol) was dissolved in mL MeCN, then 139 mg nitronium lelrafluoroborate (1.05 mmol) suspended in 10 mL MeCN was added and the mixture was stirred at 0°C for 50 minutes. The volatiles were evaporated under reduced pressure and the crude product was purified via flash 25 chromatography, using heptane and EtOAc as eluents to obtain Préparation 15a. *H NMR (400 MHz, DMSO-d₆): 11.19 (br s, IH), 8.59 (s, IH), 7.87 (s, JH), 7.14 (m, 3H), 6.72 (m, 2H), 5.59 (dd, IH), 3.53 (s, 3H), 2.97 (dd, IH), 2.74-2.61 (m, 3H), 2.07 (s, 3H), 1.18 (t, 3 H). HRMS calculated for C₂5H22CIN₃O₆S: 527.0918, found: 528.0986 (M+H).

Préparation 15b: Methyl (2R)-2-[(55_(/)-5-(5-amino-3-chioro-4-hydroxy-2-inethylphenyl)-6-ethyi-thieno[23-if]pyrimidin-4-yl]oxy-3-phenyl-propanoate

17193] _β

-144 1.339 g methyl (27?/2-[(5S’₀)-5-(3-chloiO-4-hydiOxy-2-methyl-5-nitro-phenyl)-6-ethylthieno[2,3-<7]pyrirnidin-4-ylJoxy-3-phenyl-propanoate (Préparation 15a) (2.536 mmol) was dissolved in 40 mL MeOH. 270 mg Selcat Q6 was added and the mixture was stirred at 40°C under 4 atm. H₂ pressure for 90 minutes. Then it was filtered through celite and the volatiles were evaporated under reduced pressure. The crade product was purified via flash chromatography, using heptane and EtOAc as eluents to obtain Préparation 15b. 'H NMR (400 MHz, DMSO-d₆): 8.78 (br s, IH), 8.52 (s, IH), 7.16 (m, 3H), 6.67 (m, 2H), 6.58 (s, IH), 5.45 (dd, IH), 4.88 (br s, 2H), 3.51 (s, 3H), 2.92 (dd, IH), 2.78 (dd, IH), 2.72-2.59 (m, 2H), 1.86 (s, 3H), 1.17 (t, 3H). HRMS calculated for C25H24CIN3O4S: 497.1176, found: 498.1259 (M+H).

Préparation 15c: Methyl (2Â)-2-[(55'_(l)-5-[7-chloro-2-(chloromethyl)-6-mcthyl-l,3benzoxazol-5-yl]-6-ethyl-thieno[2,3-rf|pyrimidin-4-yl]oxy-3-phenyl-propanoate

100 mg methyl (27?)~2-[(50'_rt)-5-(5-amino-3-chloro-4-hydiOxy-2-niethyl-phenyl)-6-ethyl15 thieno[2,3-<flpyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 15b) (0.20 mmol) was dissolved in 0.5 mL dry toluene under N₂. 57 pL triethyl-ortochloroacetate (0.30 mmol) was added and the mixture was stirred at 100°C for 1 hour. The volatiles were evaporated under reduced pressure. The crude product was purified via flash chromatography, using heptane and EtOAc as eluents to obtain Préparation 15c. MS (M+H): 556.0.

Préparation 15d: Methyl (2ff)-2-[(5S_ff)-5-(3-chloro-4-hydroxy-5-iodo-2-meihylphenyl)-6-ethyl-thieno[2,3-i/]pyrimidin-4-yl]oxy-3-phenyI-propanoate

483 mg methyl (27?J-2-[(5S_a)-5-(3-chloro-4“hydiOxy-2-methyl-phenyi)-6-ethyl-thieno[2,3<7jpyrimidin-4-y1]oxy-3-phenyl-propanoate (Préparation 6i) (1.0 mmol) was dissolved in

5 mL EtOH, then 305 mg iodine (1.2 mmol) and 405 mg Ag₂SO4 (1.3 mmol) were added and the mixture was stirred at room température for 90 minutes. Then it was filtered, the filtrate was concentrated under reduced pressure and the crude product was purified via flash chromatography, using heptane and EtOAc as eluents to obtain Préparation 15d. *H NMR (400 MHz, DMSO-d₆): 10.10 (br s, IH), 8.55 (s, IH), 7.64 (s, IH), 7.15 (m, 3H),

6.63 (m, 2H), 5.49 (dd, IH), 3.58 (s, IH), 3.00 (dd, IH), 2.69 (dd, IH), 2.65 (m, 2H), 1.99 (s, 3H), 1.17 (t, 3H). HRMS calculated for C₂5H₂₂CIIN₂O4S: 608.0034, found: 609.0130 (M+H).

-145 Préparation 15e; Methyl (2/?)-2-|(5A)_f)-5-(3,5-dichloro-4-hydroxy-2-melhyl-phenyl)-6ethyl“thienoi2,3i/]pyrimidm-4-yl]oxy-3-plienyl-propanoate

483 mg methyl (2Æ)-2-[(5S'₍,)-5-(3-chloro-4-hydiOxy-2-methyl-pheny1)-6-ethyI-thieno[2,3i/]pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 6i) (1.0 mmol) was dissolved in 5 mL THF, then 147 mg NCS (1.1 mmol) was added and the mixture was stirred at 50°C for 3 hours. The volatiles were evaporated under reduced pressure and the crude product was purified via flash chromatography, using heptane and EtOAc as eluents to obtain Préparation 15e. *H NMR (400 MHz, DMSO-d₆): 10.21 (s, IH), 8.56 (s, IH), 7.33 (s, IH), 7.16 (m, 3H), 6.66 (m, 2H), 5.52 (dd, IH), 3.55 (s, 3H), 2.98 (dd, IH), 2.70-2.60 (m, 3H), 1.99 (s, 3H), 1.17 (t, 3H). HRMS calculated for C₂₅H₂₂C1₂N₂O4S: 516.0677, found: 517.0772 (M+H).

Préparation 15f; Methyl (2/î)-2-[(5*S'(.)-5-(5-broino-3-chloro-4-hydroxy-2-methylphenyl)-6-ethyl-thieno[2,3-//]pyriinidin-4-ylJoxy-3-phenyl-propanoate

169 mg methyl (2R)-2-[(5S₀)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethyl-thieno[2,3</]pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 6i) (0.35 mmol) was dissolved in 2 mL THF, then 64 mg NBS (0.36 mmol) was added and the mixture was stirred at 50°C for 10 minutes. The volatiles were evaporated under reduced pressure and the crude product was purified via flash chromatography, using heptane and EtOAc as eluents to obtain Préparation 15f. ’ll NMR (400 MHz, DMSO-d^): 10.10 (br s, IH), 8.54 (s, IH), 7.44 (s, IH), 7.15 (m, 3H), 6.65 (m, 2H), 5.50 (dd, IH), 3.55 (s, 3H), 2.98 (dd, III), 2.702.59 (m, 3H), 1.97 (s, 1 H), 1.16 (t, 3H). MS (M+H): 561.0, (M-H): 559.0.

Unless otherwise specified, compounds of Préparation 16a to 16g were obtained using General procedure 16A described below.

General procedure 16A;

2.5 eq. 4-chloro-6-ethyl-5-iodo-thieno[2,3-i/]pyrimidine (Préparation Id), 1.0 eq. of the appropriate alcohol and 1.5 eq. césium carbonate were dissolved in dry DMSO (0.25 M for Préparation ld). The mixture was stirred at 100°C under nitrogen until no further

-146conversion was observed. The reaction mixture was cooied to room température, it was diluted with water, the pH was set to 7 with 2 M HCl, and then it was extracted with ethyl acetate. The combined organic phases were dried over Na₂SO4, filtered, concentrated under reduced pressure and purified via flash chromatography using heptane and ethyl acetate as 5 eluents.

Préparation 16a: Ethyi (2.ff)-3-(l,3-benzodioxol-4-yI)-2-(6-ethyl-5-iodo-thieno[2,3d]pyrimidin-4-yl)oxy-propanoate

Using General procedure 16A and ethyl (2Æ)-3-(l,3-benzodioxol-4-yl)-2-hydroxy10 propanoate (Préparation 3bg) as the appropriate alcohol we obtained Préparation 16a.

’HNMR (400 MHz, CDC1₃): 8.49 (s, 1H), 6.90 (dd, 1H), 6.75 (t, 1H), 6.73 (dt, 1H), 5.92 (dd, 2H), 5.82 (t, 1H), 4.20 (dq, 2H), 3.40 (d, 2H), 2.93 (q, 2H), 1.33 (t, 3 H), 1.21 (t, 3H).

Préparation 16b: Ethyl (2Æ)-3-(2,3-dihydrobenzofuran-7-yl)-2-(6-ethyl-5-iodo15 thieno[2,3-<Zjpyrimidin-4-yl)oxy-propanoate

Using General procedure 16A and ethyl (2Æ)-3-(2,3-dihydrobenzofuran-7-yl)-2-hydroxypropanoate (Préparation 3bd) as the appropriate alcohol we obtained Préparation 16b. ’H NMR (400 MHz, CDC1₃): 8.48 (s, 1H), 7.17 (d, 1H), 7.08 (d, 1H), 6.76 (t, 1H), 5.81 (dd, 1 H), 4.54 (dt, 2H), 4.19 (dq, 2H), 3.44-3.32 (m, 2H), 3.19 (t, 2H), 2.92 (q, 2H), 1.32 (t, 20 3H), 1.20 (t,3H).

Préparation 16c: Ethyl (25)-3-(2,3-dihydrobenzofuran-7-yl)-2-(6-ethyl-5-iodothieno[2,3-rf]pyrimidin-4-yl)oxy-propanoate

Using General procedure 16A and ethyl (25)-3-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy25 propanoate (Préparation 3be) as the appropriate alcohol we obtained Préparation 16c. ’H

NMR (400 MHz, CDC1₃): 8.48 (s, 1H), 7.17 (d, 1H), 7.08 (d, 1H), 6.76 (t, 1H), 5.81 (dd, 1H), 4.54 (dt, 2H), 4.19 (dq, 2H), 3.44-3.32 (m, 2H), 3.19 (t, 2H), 2.92 (q, 2H), 1.32 (t, 3H), 1.20 (t,3H).

Préparation 16d: Ethyl 3-(benzofuran-7-yl)-2-(6-ethyl-5-iodo-thieno[2,3~d|pyriniidin4-yI)oxy-propanoate

-147Using General procedure 16A and ethyl 3-(benzofuran-7-yl)-2-hydroxy-propanoate (Préparation 3bb) as the appropriate alcohol we obtained Préparation 16d. *H NMR (400 MHz, CDCl₃): 8.47 (s, IH), 7.61 (d, IH), 7.49 (d, IH), 7.36 (d, IH), 7.16 (t, IH), 6.76 (d, IH), 5.94 (dd, IH), 4.18 (dq, 2H), 3.79-3.66 (m, 2H), 2.90 (q, 2H), l.3l (t, 3H), 1.16 (t, 3H).

Préparation 16e: Ethyl (25)-2-(6-ethyl-5-iodo-thieno[2,3-rf]pyrimidin-4-yI)oxy-3-(2fluorophenyl)propanoate

Using General procedure 16A and ethyl (25)-3-(2-fluorophenyl)-2-hydroxy-propanoate (Préparation 3az) as the appropriate alcohol we obtained Préparation 16e. ^!H NMR (400 MHz, CDCI₃): 8.48 (s, IH), 7.45 (dt, IH), 7.23 (m, IH), 7.06 (t, IH), 7.04 (t, IH), 5.78 (dd, IH), 4.19 (m, 2H), 3.53-3.41 (m, 2H), 2.92 (q, 2H), 1.33 (t, 3H), 1.20 (t, 3H).

Préparation 16f: Ethyl (2Æ)-2-(6-ethyl-5-iodo-thieno[2,3-/f]pyriinidin-4-yl)oxy-3-(2fluorophenyl)propanoate

Using General procedure 16A and ethyl (2J?)-3-(2-fluorophenyl)-2-hydroxy-propanoate (Préparation 3ba) as the appropriate alcohol we obtained Préparation 16f. *H NMR (400 MIIz, CDClj): 8.48 (s, IH), 7.45 (dt, IH), 7.23 (m, IH), 7.06 (t, IH), 7.04 (t, III), 5.78 (dd, IH), 4.19 (m, 2H), 3.53-3.41 (m, 2H), 2.92 (q, 2H), 1.33 (t, 3H), 1.20 (t, 3H).

Préparation 16g: Ethyl (25)-3-(1,3-benzodioxol-4-yl)-2-(6-ethyl-5-iodo-thieno[2,3i/]pyrimidin-4-yl)oxy-propanoate

Using General procedure 16A and ethyl (25)-3-(1,3-benzodioxol-4-yl)-2-hydroxypropanoate (Préparation 3bh) as the appropriate alcohol we obtained Préparation 16g. ‘H NMR (400 MHz, CDCI3): 8.49 (s, IH), 6.90 (dd, IH), 6.75 (t, IH), 6.73 (dt, IH), 5.92 (dd, 2H), 5.82 (t, IH), 4.20 (dq, 2H), 3.40 (d, 2H), 2.93 (q, 2H), 1.33 (t, 3H), 1.21 (t, 3H).

Préparation 17a: Ethyl (2/?)-3-(l ,3-benzodioxol-4-yl)-2-[(5R_ff)-5-(3-chloro-4-hydroxy2-inethyl-phenyl)-6-ethyl-thieno[2,3-d|pyrimidin-4-yl]oxy-propanoate and

Préparation 17b: Ethyl (2Æ)-3-(l,3-benzodioxol-4-yl)-2-[(55_ff)-5-(3-chloro-4-hydroxy2-methyl-phenyl)-6-ethyl-thieno[2,3-d]pyrimidin-4-ylJoxy-propanoate . 1480.482 g ethyl (2R)-3-(l,3-benzodioxol-4-yl)-2-(6-ethyl-5-iodo-thieno[2,3-d]pyrimidin-4yl)oxy-propanoate (Préparation 16a) (0.92 mmol), 0.737 g 2-chloro-3-methyl-4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation Sa) (2.74 mmol), 0.041g Pd(OAc)2 (0.18 mmol) 0.130g BuPAd₂ (0.36 mmol), 2.7 mL Bu₄NOH solution (2.7 mmol, 1.0 M in water) and 6.6 mL DME were heated under nitrogen at 100^QC for 10 min in microwave reactor with stirring. The pH of the mixture was set to 6 with 2 M HCl, and then it was extracted with MTBE. The combined organic phases were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The diastereomers were separated via flash chromatography using heptane and EtOAc as eluents, collecting the diastereomer eluting earlier as Préparation 17a, and the diastereomer eluting later as Préparation 17b. Préparation 17a: *H NMR (500 MHz, DMSO-d₆): 10.28 (br s, IH), 8.53 (s, IH), 6.91 (d, IH), 6.88 (d, IH), 6.73 (d, IH), 6.58 (t, IH), 5.95 (s, 2H), 5.82 (d, IH), 5.30 (dd, IH), 4.09 (m, 2H), 2.97 (dd, IH), 2.65 (m, 2H), 2.44 (dd, IH), 2.15 (s, 3H), 1.15 (t, 3H), 1.09 (t, 3H). Préparation 17b: ’HNMR (500 MHz, DMSO-d_fi): 10.23 (br s, IH), 8.54 (s, IH), 7.03 (d, IH), 6.96 (d, IH), 6.75 (d, IH), 6.62 (t, IH), 5.96 (s, IH), 5.94 (s, IH), 5.92 (d, IH), 5.43 (dd, IH), 4.02 (m, 2H), 2.86 (dd, IH), 2.62 (m, 2H), 2.58 (dd, IH), 1.95 (s, 3H), 1.15 (t, 3H), 1.04 (t, 3H).

Préparation 17c: Ethyl (27î)-2-|(50'_rt)-5-(3-chloro-4-hydiOxy-2-niethyl-phenyl)-6-ethylthieno[2_s3-i/]pyrimidüi-4-yl]oxy-3-(2,3-dihydrobenzofiiran-7-yI)propanoate

0.525 g ethyl (2J?)-3-(2,3-dihydiObenzofuran-7-yl)-2-(6-ethyl-5-iodo-thieno[2,3</jpyrimidin-4-yl)oxy-piOpanoate (Préparation 16b) (1.0 mmol), 0.670 g 2-chloro-3methyl-4“(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (2.5 mmol), 0.063 g AtaPhos (0.09 mmol), 2.5 mL Bu₄NOH solution (2.5 mmol, 1.0 M in water) and 4.5 mL 2-MeTHF were heated under nitrogen at 100°C for 10 mins in a microwave reactor with stirring. The pH of the mixture was set to 6 with 2 M HCl, and then it was extracted with MTBE. The combined organic phases were dried over Na2SO₄, filtered and concentrated under reduced pressure. The diastereomers were separated via flash chromatography using heptane and EtOAc as eluents, collecting the diastereomer eluting later as Préparation 17c. 'H NMR (500 MHz. DMSO-d₆): 10.23 (br s, IH), 8.52 (s, IH), 7.04 (d, IH), 7.02 (d, IH), 6.96 (d, IH), 6.62 (t, IH), 6.12 (d, IH), 5.38 (dd, IH),

-1494.49 (m, 2H), 4.02 (m, 2H), 3.11 (t, 2H), 2.87 (dd, IH), 2.61 (m, 2H), 2.45 (dd, IH), 1.95 (s, 3H), 1.15 (t, 3H), 1.05 (t,3H).

Préparation 17d: Ethyl (2S)-2-((52?_ff)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethylthieno|2_J3-</Jpyrimidin-4-yl]oxy-3-(2,3-dihydrobenzofuran-7-yl)propanoate

0.525 g ethyl (2S)-3-(2,3-dihydrobenzofuran-7-yl)-2-(6-ethyl-5-iodo-thieno[2,3fZ]pyriniidin-4-yl)oxy-propanoate (Préparation 16c) (1.0 mmol), 0.670 g 2-chloro-3methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (2.5 mmol), 0.063 g AtaPhos (0.09 mmol), 2,5 mL BtqNOH solution (2.5 mmol, 1.0 M in water) and 4.5 mL 2-MeTHF were heated under nitrogen at 100°C for 10 mins in a microwave reactor with stirring. The pH of the mixture was set to 6 with 2 M HCl, and then it was extracted with MTBE. The combined organic phases were dried over NajSCL, fîltered and concentrated under reduced pressure. The diastereomers were separated via flash chromatography using heptane and EtOAc as eluents, collecting the diastereomer eluting later as Préparation 17d. ‘H NMR (500 MHz, DMSO-d₆): 10.23 (br s, IH), 8.52 (s, IH), 7.04 (d, IH), 7.02 (d, IH), 6.96 (d, IH), 6.62 (t, IH), 6.12 (d, IH), 5.38 (dd, IH), 4.49 (m, 2H), 4.02 (m, 2H), 3.11 (t, 2H), 2.87 (dd, IH), 2.61 (m, 2H), 2.45 (dd, IH), 1.95 (s, 3H), 1.15 (t, 3H), 1.05 (t, 3H).

Préparation 17e: Ethyl (2Æ)-3-(benzofuran“7-yI)-2-[(5S_fl)-5-(3-chloro-4-hydroxy-2methyl-phenyl)-6-ethyl-thieno[23“<f|pyHmidm-4-yl]oxy-propanoate and

Préparation 17f: Ethyl (2S)3-(benzofuran-7“yI)-2-[(5iî₍,)-5-(3-chloro-4-hydroxy-2methyl-phenyl)-6-ethyLthÎcno[2,3-z/]pyrimidin-4-yl]oxy-propanoate

0.647 g Ethyl 3-(benzofuran-7-yl)-2-(6-ethyl-5-iodo-thieno[2,3-£7]pyrimidin-4-yl)oxypropanoate (Préparation 16d) (1.24 mmol), 0.766 g 2-chloro-3-methyl-4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (2.85 mmol), 0.087 g AtaPhos (0.12 mmol), 2.5 mL BU4NOH solution (2.5 mmol, 1.0 M in water) and 5 mL 2MeTHF were heated under nitrogen at 100°C for 10 mins in a micro wave reactor with stirring. The pH of the mixture was set to 6 with 2 M HCl, it was fîltered through a pad of celite, and the pad was washed both with water and MTBE. The phases were then separated, the aqueous layer was extracted with MTBE. The combined organic phases

-150were dried over Na₂SO4, filtered and concentrated. The foui^- stereoisomer containing mixture was first separated via flash chromatography using heptane and EtOAc as eluents, and collecting the pair of compounds eluting later as diastereomer 2 racemate. Then further séparation of diastereomer 2 racemate was accomplished by chiral chromatography, Column: AD, Eluents: heptane / EtOH. The enantiomer eluting earlier was collected as Préparation 17e with ee> 99.8% and the enantiomer eluting later was collected as Préparation 17f with ee: 99.6%.

'H NMR (500 MHz, DMSO-d₆): 10.25 (br s, IH), 8.52 (s, IH), 7.97 (d, IH), 7.49 (m, IH), 7.06 (d, IH), 7.04 (t, IH), 7.01 (d, IH), 6.91 (d, IH), 6.36 (m, IH), 5.57 (dd, IH), 3.98 (m, IH), 3.93 (m, IH), 3.22 (dd, IH), 2.90 (dd, IH), 2.65 (m, IH), 2.60 (m, IH), 1.96 (s, 3H), 1.15 (t, 3H), 0.94 (t,3H).

Préparation 17g; Ethyl (2S)-2-[(5ZO-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethylth ieno [2,3-rfj pyrimid in-4-y 1] oxy-3-(2-flu oropheny l)prop anoate

0,425 g Ethyl (2S)-2-(6-ethyl-5-iodo-thieno[2,3-i(Jpyrimidm-4-yl)oxy-3-(2fluorophenyl)propanoate (Préparation 16e) (0.85 mmol), 0.570 g 2-chloro-3-methyl-4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (2.12 mmol), 0.053 g AtaPhos (0.075 mmol), 2.13 mL B114NOH solution (2.13 mmol, 1.0 M in water) and 4 mL 2-MeTHF were heated under nitrogen at 100°C for 10 mins in a micro wave reactor with stirring. The pH of the mixture was set to 6 with 2 M HCl, it was filtered through a pad of celite, the pad was washed both with water and MTBE. The phases were then separated, the aqueous layer was extracted with MTBE. The combined organic phases were dried over Na₂SÜ4, filtered and concentrated under reduced pressure. The diastereomers were separated via flash chromatography using heptane and EtOAc as eluents, collecting the diastereomer eluting later as Préparation 17g. *H NMR (500 MHz, DMSO-Üg): 10.23 (s, IH), 8.54 (s, IH), 7.24 (m, IH), 7.09 (ddd, IH), 7.05 (d, IH), 6.98 (d, IH), 6.97 (td, IH), 6.45 (td, IH), 5.42 (dd, IH), 4.00 (m, 2H), 2.93 (dd, IH), 2.72 (dd, IH),

2.63 (m, 2H), 1.97 (s, 3H), 1.15 (t, 3H), 1.02 (t, 3H).

Préparation 17h: Ethvl (21î)-2-[(5₁S'_fl)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethylthieno[2,3Wjpyrimidin-4-yl]oxy-3-(2-fluorophenyl)propanoate

- I5l 0.425 g Ethyl (2fî)-2-(6-ethyl-5-iodo-thieno[2,3-i(]pyrimidin-4-yl)oxy-3-(2fluorophenyl)propanoate (Préparation 16f) (0.85 mmol), 0.570 g 2-chloro-3-methyl-4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (2.12 mmol), 0.053 g AtaPhos (0.075 mmol), 2.13 mL B114NOH solution (2.13 mmol, 1.0 M in water) and 4 mL 2-MeTHF were heated under nitrogen at 100°C for 10 mins in a microwave reactor with stiiïing. The pH of the mixture was set to 6 with 2 M HCl, it was filtered through a pad of celite, the pad was washed both with water and MTBE. The phases were then separated, the aqueous layer was extracted with MTBE. The combined organic phases were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The diastereomers were separated via flash chromatography using heptane and EtOAc as eluents, coliecting the diastereomer eluting iater as Préparation 17h. *H NMR (500 MHz, DMSO-d₆): 10.23 (s, 1H), 8.54 (s, 1H), 7.24 (m, 1H), 7.09 (ddd, 1H), 7.05 (d, 1H), 6.98 (d,

1H), 6.97 (td, 1H), 6.45 (td, 1H), 5.42 (dd, 1H), 4.00 (m, 2H), 2.93 (dd, 1H), 2.72 (dd, 1H),

2.63 (m, 2H), 1.97 (s, 3H), 1.15 (t, 3H), 1.02 (t, 3H).

Préparation 17i: Ethvl (25)-3-(1,3-benzodioxol-4-yl)-2-((55«)-5-(3-chloro-4-hydroxy-2methyl-phcnyl)-6-ethyl-thieno[2,3-rf]pyrimidin-4-yl]oxy-propanoate and

Préparation 17i: Ethyl (25)-3-(1,3-benzodioxol-4-yl)-2-{(5i₍,)-5-(3-chloro-4-hydroxy20 2-methyl-phenyl)-6-ethyl-thieno[2,3-rf]pyrimidin-4-ylJoxy-propanoate

0.482 g ethyl (25)-3-(1,3-benzodioxol-4-yl)-2-(6-ethyl-5-iodo-thieno[2,3-J)pyrimidin-4· yl)oxy-propanoate (Préparation 16g) (0.92 mmol), 0.737 g 2-chloro-3-methyl-4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (2.74 mmol), 0.041g Pd(OAc)₂ (0.18 mmol), 0.130g BuPAd₂ (0.36 mmol), 2.7 mL Bu₄NOH solution (2.7 25 mmol, 1.0 M in water) and 6.6 mL DME were heated under nitrogen at 100°C for 10 mins in a microwave reactor with stirring. The pH of the mixture was set to 6 with 2 M HCl, and then it was extracted with MTBE. The combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure. The diastereomers were separated via flash chromatography using heptane and EtOAc as eluents, coliecting the diastereomer 30 eluting earlier as Préparation 17i, and the diastereomer eluting Iater as Préparation 17j.

-152Preparation 17i: ’H NMR (500 MHz, DMSO-d_ô): 10.28 (br s, IH), 8.53 (s, IH), 6.91 (d, IH), 6.88 (d, IH), 6.73 (d, IH), 6.58 (t, IH), 5.95 (s, 2H), 5.82 (d, IH), 5.30 (dd, IH), 4.09 (m, 2H), 2.97 (dd, IH), 2.65 (m, 2H), 2.44 (dd, IH), 2.15 (s, 3H), 1.15 (t, 3H), 1.09 (t, 3H). Préparation 17j: 'H NMR (500 MHz, DMSO-dô): 10.23 (br s, IH), 8.54 (s, IH), 7.03 (d, IH), 6.96 (d, IH), 6.75 (d, IH), 6.62 (t, IH), 5.96 (s, IH), 5.94 (s, IH), 5.92 (d, 1I-I), 5.43 (dd, IH), 4.02 (m, 2H), 2.86 (dd, IH), 2.62 (m, 2H), 2.58 (dd, IH), 1.95 (s, 3H), 1.15 (t, 3H), 1.04 (t, 3H).

Préparation 18a: Ethyl (2R)-2- [(55'„)-5-(3-chloro-4-hydioxy-5-methoxy-2-methylphenyl)-6-prop-l-ynyl-thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2methoxyphenyl)propanoate

444 mg ethyl (2R)-2-(5-iodo-6-prop-l-ynyl-thieno[2,3-</]pyrimidin-4-yl)oxy-3-(2methoxyphenyl)propanoate (Préparation 4k) (0.85 mmol), 297 mg 2-chloro-6-methoxy3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5k) (1.00 mmol), 62 mg PdCl₂ x dppf (0.085 mmol) and 326 mg Cs₂CO₃ (1.00 mmol) were dissolved in 8 mL dioxanc and 2 mL water. The mixture was heated to 110°C for 10 minutes via microwave irradiation. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography, using heptane and EtOAc as eluents. The diastereoisomer eluting earlier was collected as Préparation 18a. ‘H NMR (400 MHz, DMSO-d₆): 9.60 (br s, IH), 8.62 (s, IH), 7.15 (t, IH), 6.89 (s, IH), 6.87 (d, IH), 6.66 (t, IH), 6.05 (dd, IH), 5.32 (dd, IH), 4.11 (m, 2H), 3.86 (s, 3H), 3.75 (s, 3H), 3.10 (dd, IH), 2.37 (dd, IH), 2.06 (s, 3H), 2.05 (s, 314), 1.11 (t, 3H). HRMS calculated for C29H27CIN2O6S; 566.1278, found: 567.1360 (M+H).

Préparation 18b; Ethyl (27f)-2-[5-(3-chloro-4-hydroxy-2,5-dimethyl-phenyl)-6-prop-lynyl-thienoi2,3-rf(pyrimidin-4-y!]oxy-3-(2“methoxyphenyl)propanoate (mixture of diastereoisomers)

522 mg ethyl (2/2)-2-(5-iodo-6-prop-l-ynyl-thieno[2,3-<Z]pyrimidin-4-yl)oxy-3-(2methoxyphenyl)propanoate (Préparation 4k) (1.00 mmol), 351 mg 2-chloro-3,6-dimethyl4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 51) (1.24 mmol), 73 mg PdCl₂ x dppf (0,10 mmol) and 489 mg Cs₂CO₃ (1.50 mmol) were dissolved in 8 mL

-153dioxane and 2 mL water. The mixture was heated to 11O°C for 12 minutes via microwave irradiation. Then it was diluted with brine, neutralized with 2 MIIC1, extracted with DCM, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography, using heptane and EtOAc as eluents to obtain

Préparation 18b as a mixture of diastereoisomers. ’l l NMR (400 MHz, DMSO-df,): 9.25 (br s, IH), 8.61 (s, IH), 7.14 (t, IH), 7.06/6.94 (s, IH), 6.87 (d, IH), 6.65/6.61 (t, IH), 6.11/6.06 (dd, IH), 5.33/5.25 (dd, IH), 4.14-4.02 (m, 2H), 3.75 (s, 3H), 3.09/3.05 (dd, IH), 2.44-2.34 (m, IH), 2.27/2.26 (s, 3H), 2.18/2.09 (s, 3H), 2.04/2.02 (s, 3H), 1.09 (t, 3H). HRMS calculated for C₂₉H₂7C1N₂O₅S: 550.1329, found: 551.1412 (M+H).

Préparation 18c; Ethyl (2A)-2-[(55„)-5-(3-chloro-5-fluoro-4-hydroxy-2-methylphenyI)-6-prop-l -ynyl-thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2methoxyphenyl)propanoate

522 mg ethyl (2Æ)-2-(5-iodo-6-prop-l-ynyl-thieno[2,3-iZ]pyrimidin-4-yl)oxy-3-(215 methoxyphenyl)propanoate (Préparation 4k) (1.00 mmol), 403 mg 2-chloro-6-fluoro-3methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5m) (1.5 mmol), 71 mg AtaPhos (0.1 mmol) and 652 mg Cs₂CO₃ (2.00 mmol) were dissolved in 8 mL dioxane and 2 mL water. The mixture was heated to 100°C for 15 minutes via microwave irradiation. Then it was diluted with brine, neutralized with 2 M HCl, extracted 20 with DCM, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography, using heptane and .EtOAc as eluents. The diastereoisomer eluting later was collected as Préparation 18c. ’H NMR (400 MHz, DMSO-d₆): 10.56 (br s, IH), 8.64 (s, IH), 7.17 (dt, IH), 7.13 (d, IH), 6.90 (d, IH), 6.69 (t, IH), 6.23 (dd, IH), 5.41 (dd, IH), 4.11-4.01 (m, 2H), 3.75 (s, 3H), 3.03 (dd, IH), 2.52 (dd, 25 IH), 2.06 (m, 6H), 1.08 (t, 3H). HRMS calculated for C₂₈H₂4C1FN₂O₅S: 554.1078, found:

555.1166 (M+H).

Préparation 19a; Ethyl 3-(benzofuran-4-yl)-2-(5-iodo-6-prop-l-ynyl-thieno[2,3d]pyrimidin-4-yl)oxy-propanoate

2.676 g 4-chloro-5-iodo-6-prop-l-ynyl-thieno[2,3-r7]pyrimidine (Préparation 2f) (8 30 mmol), 0.937 g ethyl 3-(benzofuran-4-yl)-2-hydroxy-propanoate (Préparation 3bc) (4 mmol) and 1,955 g Cs₂CO₃ (6 mmol) were placed in a flask. 20 mL dry DMSO was added

-154and the mixture was stirred at room température until no further conversion was observed, It was diluted with water, the pli was set to 8 with 2 MIIC1, and then it was extracted with DCM. The combined organic phases were dried over Na2SO<i filtered and concentrated under reduced pressure and purified via flash chromatography using heptane and ethyl acetate as eluents to give Préparation 19a. ’H NMR (400 MHz, CDCI3): 8.50 (s, IH),

7.64 (d, IH), 7.40 (d, IH), 7.33 (d, IH), 7.22 (t, IH), 6.94 (d, IH), 5.82 (dd, IH), 4.17 (ni, 2H), 3.71-3.59 (m, 2H), 2.18 (s, 3H).

Préparation 20a: Ethyl (2/i)-3-(beiizofuran-4-yI)-2-|(55₍,)-5-(3-chloro-4-hydroxy-2methyl-phenyl)-6-prop-l-ynyl-thieno[2,3-</|pyriinidin-4-yl]oxy-propanoate and

Préparation 20b: Ethyl (2*S)-3-(benzofuran-4-yl)-2-[(5iî„)-5-(3-chloro-4-hydroxy-2methyl-phenyl)-6-prop-l-ynyl-thieno[2,3-rf]pyrimidxn-4-ylJoxy-propanoate

0.850 g ethyl 3-(benzofuran-4-yl)-2-(5-iodo-6-prop-l-ynyl-thieno[2,3-Jjpyrimidin-4yl)oxy-propanoate (Préparation 19a) (1.6 mmol), 0.859 g 2-chloro-3-methyl-4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (3.2 mmol), 0.110 g AtaPhos (0.16 mmol) and 1.043 g CS2CO3 (3.2 mmol) were placed in a niicrowave reactor tube. 16 mL Dioxane and 4.8 mL HjO were added and the mixture was heated under nitrogen at 80°C for 10 mins in microwave reactor. The mixture was filtered through a pad of celite, the pad was washed both with water and MTBE. The pH of the filtrate was adjusted to 7 with 2 M HCl, and then it was shaken. The aqueous phase was extracted with MTBE, the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The mixture containing four stereoisomers was first separated via flash chromatography using heptane and EtOAc as eluents and the diastereomeric pair eluting later was collected as diastereomer 2 racemate. Then the diastereomer 2 racemate was separated by chiral chromatography, Column: AD, Eluents: heptane / éthanol. The product eluting earlier was collected as Préparation 20a with ee: 96.8%, the product eluting later was collected as Préparation 20b with ee>99.8%. ’H NMR (500 MHz, DMSO-d₆): 10.31 (br s, IH), 8.62 (s, IH), 7.95 (dd, IH), 7.41 (dd, IH), 7.13 (dd, IH), 7.05 (dd, IH), 7.00 (dd, IH), 6.82 (dd, IH), 6.28 (dd, IH), 5.49 (dd, IH), 3.98 (m, IH), 3.91 (m, IH), 3.16 (dd, IH), 2.98 (dd, IH), 2.09 (s, 3H), 2.03 (s, 3H), 0.97 (t, 3H).

-155Préparation 21: Methyl (2Æ)-2-(6-bromo-5-iodo-thicno[2,3-ï/|pyrimidin-4-yl)oxy-3phenyl-propanoate

15.39 g 6-bromo-4-chloro-5-iodo-thieno[2,3-iflpyrimidine (Préparation le) (41 mmol),

11.08 g methyl (2Æ)-2-hydroxy-3-phenyl-propanoate (61.5 mmol) and 26.71 g césium 5 carbonate (82 mmol) were placed in a 100 mL flask. 40 mL dry DMSO was added and the mixture was stirred at 70°C under argon atmosphère until no further conversion was observed. The reaction mixture was poured onto 200 mL water, and then pH was set to ~5. The precipitated product was collected by filtration. MS (M+H) = 519.0.

Préparation 22; Methyl (21î)-2-[6-bromo-(5<S^, _s)“5-(3-chloro-4“hydroxy-2-niethyl10 phenyI)thieno[2,3-rf|pyriinidin-4-yl]oxy-3-phenyI-propanoate

1.557 g methyl (27?)-2-(6-bromo-5-iodo-thieno[2,3-i/jpyrimidin-4-yl)oxy-3-phenylpropanoate (Préparation 21) (3.0 mmol), 1.289 g 2-chloro-3-methyl-4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (4.8 mmol), 219 mg Pd(ddpf)C12 (0.3 mmol) and 2.931 g césium carbonate (9.0 mmol) were placed in a 30 mL 15 microwavc tube. After addition of 12 mL dioxanc and 6 mL water reaction was heated at

120°C under nitrogen with stirring for 25 min in a microwave reactor. Water was added to the reaction mixture and the pH was set to 5 with 2 M HCl. The resulting mixture was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. Diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eiuting later was collected as Préparation 22. MS (M+H) ~ 532.0.

Préparation 23a; [2-Chloro-4-(4~chlorothien o [2,3-rfj py rimidin-5-yl)-3-niethy 1phenoxy]-triisopropyl-silane

34.50 g 4-chloiO-5-iodo-Îhieno[2,3-</]pyriinidine (Préparation le) (116.3 mmol), 59.32 g [2-chloro-3-methyl-4-(4,4_>5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]-triisopropylsilane (Préparation 5c) (139.6 mmol), 653 mg Pd(OAc)2 (2.908 mmol), 2.085 g BuPAd2 (5.817 mmol) and 74.09 g K3PO4 (349.0 mmol) were placed in a 1 L flask. After addition of 450 mL DME and 150 mL water the reaction was stirred under nitrogen at 60°C until no further conversion was observed. To the reaction mixture saturated aq. NH4CI was added and then it was extracted with EtOAc. The combined organic layers were dried over

-156MgSÛ4 and concentrated under reduced pressure. The obtained solid was sonicated in acetonitrile / water (3:1) and collected by filtration to give Préparation 23a. ^]H NMR (400 MHz, DMSO-di): 8.95 (s, 1H), 7.98 (s, 1H), 7.13 (d, 1H), 6.91 (d, 1H), 2.05 (s, 3H), 1.401.29 (ni, 3H), 1.10 (dd, 18H).

Préparation 23b: 4-Chloro-5-(3-chloro-2-methyl-phenyl)thieno|2,3-rf]pyrimidine

Step A:

The mixture of 4.26 g (3-chloro-2-methyl-phenyl)boiOnic acid (25.0 mmol) and 2.954 g 2,3-dimethylbutane-2,3-diol (25,0 mmol) was dissolved in 125 mL 2-Me-THF and 0.2 g dry Amberlyst 15 H* ion-exchange resin (previously co-evaporated with toluene) was added and the mixture was stirred at room température until no further conversion was observed. The solution was fîltered through a pad of celite, it was washed with 2-MeTHF and the filtrate was evaporated under reduced pressure to give 2-(3-chloro-2-methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaboiOlane. The obtained material was used without further purification.

Step B:

3.558 g 4-chloro-5-iodo-thieno[2,3-</]pyrimidine (Préparation le) (12.0 mmol), 3.636 g 2-(3-chloiO-2-methyl-phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaboiOlane (Step A, 14.4 mmol), 67.4 mg Pd(OAc)2 (0.3 mmol), 0.215 g BuPAda (0.6 mmol) and 7.645 g K3PO4 (36.0 mmol) were placed in a flask. After the addition of 45 mL DME and 15 mL water the mixture was stirred under nitrogen at 60°C until no further conversion was observed. To the réaction mixture saturated aq. NH4CI was added and it was extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude material was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 23b. 'H NMR (400 MHz, CDC1₃): 8.89 (s, 1H), 7.47 (dd, 1H), 7.43 (s, 1H), 7.20 (t, 1H), 7.14 (dd, 1H), 2.14 (s, 3H).

Préparation 24a: [2-ChIoro-4-(4-chloro-6-iodo-thieno[2,3-rf]pyrimidin-5-yl)-3-methylphenoxyj-triisopropyl-silane

-15738.00 g [2-chloro-4-(4-chlorothicno[2,3-</]pyriinidin-5-yl)-3-methyl-phenoxy]triisopropyl-silane (Préparation 23a) (81.27 mmol) was dissolved in l L dry THF then cooled to -78°C under argon atmosphère. 48.76 mL lithium diisopropylamide (97.53 mmol, 2 M in THF, EtPh, hexanes) was added and the mixture was stirred at -78°C for l hour. Then 24.75 g iodine (97.53 mmol) was added and the mixture was allowed to warm up to room température. Saturated aq. NH4CI was added to the reaction mixture and it was extracted with EtOAc. The combined organic layers were washed with NaiSîOj solution, then dried over Na₂SO4 and concentrated under reduced pressure. The obtained solid was sonicated in acetonitrile / water (3:l) and collected by filtration. ’H NMR (400 MHz, 10 DMSO-d₆): 8.91 (s, IH), 7.05 (d, IH), 6.97 (d, IH), 1.99 (s, 3H), 1.39-1.30 (m, 3H), 1.10 (dd, 18H).

Préparation______24b: 4-ChloiO-5-(3-chloro-2-niethyI-pheny!)-6-iodo-thieno[2,3.'/Jpyrimidine

L48 g 4-chloro-5-(3-chloro-2-methyl-phenyl)thieno[2,3-6flpyrimidine (Préparation 23b) (5.0 mmol) was dissolved in 30 mL dry TUF then cooled to -78°C under argon atmosphère. 2.75 mL lithium diisopropylamide (5.5 mmol, 2 M in THF, EtPh, hexanes) was added and the mixture was stirred at -78°C for 1 hour. Then 1.675 g iodine (6.5 mmol) was added and the mixture was allowed to warm up to room température. Saturated aq, 20 NI-I4CI was added to the reaction mixture and it was extracted with EtOAc. The combined organic layers were washed with Na₂S₂O3 solution, then dried over NaaSÛ4 and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 24b. ’H NMR (400 MHz, CDCI3): 8.82 (s, IH), 7.52 (dd, IH), 7.25 (t, IH), 7.05 (dd, IH), 2.09 (s, 3H).

Préparation 25: Ethyl (2R)-2-I(5S_e)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-iodothieno[2,3-rf]pyriinidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate

37.85 g [2-chloro-4-(4-chloro-6-iodo-thieno[2,3-J]pyrimidin-5-yl)-3-methyl-phenoxy]triisopropyl-silane (Préparation 24a) (63.7 mmol), 15.71 g methyi (2Æ)-2-hydroxy-3-(2methoxyphenyl)propanoate (Préparation 3ad) (70 mmol) and 62.3 g CS2CO3 (191 mmol) 30 were placed in a 500 mL flask. 150 mL te/7-butanol was added and the mixture was stirred at 65°C until no further conversion was observed. It was diluted with icy water, the pH was

-158set to 6 with 2 MIIC1, and then it was extracted with ethyl acctatc. The combined organic layers were dried over Na₂SO4 and concentrated under reduced pressure. The residue was dissolved in 100 mL THF, 76.4 mL TBAF (IM in THF) was added and the mixture was stirred at room température until no further conversion was observed. Approximately 50 mL solvent was evaporated under reduced pressure, then it was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure and purified via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting later was collected as Préparation 25. *H NMR (500 MHz, DMSO-d₆): 10.33 (s, IH), 8.55 (s, IH), 7.18 (t, IH), 7.00 (d, IH), 6.98 (d, IH), 6.90 (d, IH), 6.75 (t, IH), 6.29 (d, IH), 5.36 (dd, IH), 4.03 (m, 2H), 3.76 (s, 3H), 2.99 (dd, IH), 2.42 (dd, IH), 1.97 (s, 3H), 1.06 (t, 3H). HRMS: (M+H) = 625.0055.

Préparation 26a: Ethyl (2Jf)-2-[5-[3-chloro-2-methyl-4-(2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-iodo-tliieiio|2,3-r/]pyriniidin-4-yl|oxy-3-(2-tetrahydropyran-2yloxyph enyl)propan oa te

7.1 g 4-chloro-5-[3-chloiO-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-iodothieno[2,3-üf]pyrimidine (Préparation 13) (12.6 mmol), 4.45 g ethyl (2R)-2-hydroxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 3ab) (15.12 mmol) and 12.32 g Cs₂CO3 (32.81 mmol) were placed in a 250 mL flask. 100 mL /er/-butanol and 50 mL DMSO was added and the mixture was stirred at 90°C until no further conversion was observed. It was diluted with ethyl acetate and then it was washed with brine. The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure and purified via flash chromatography using ethyl acetate and methanol as eluents to obtain Préparation 26a as a mixture of diastereomers. MS: (M+H) = 821.0.

Préparation 26b: Ethyl (27f)‘2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-iodo-thieno[2,3-i/}pyrimidin-4-yl]oxy-3-(2-hydroxyphenyl) propanoate

6.7 g ethyl (2J?)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6iodo-thieno[2,3-ù(]pyrimidin-4-yl]oxy-3-(2-tetrahydiOpyran-2-yloxyphenyl)piOpanoate (Préparation 26a) (8.15 mmol) was dissolved in 75 mL éthanol, then 75 mL HCl (1.25 M in éthanol) was added and the mixture was stirred at room température until no further

- 159conversion was observed. It was concentrated under reduced pressure and purified via flash chromatography using ethyl acetate and methanol as eluents to obtain Préparation 26b as a mixture of diastereomers. MS: (M+H) = 737.0.

Préparation 26c: Ethyl (2Æ)-3-[2-[(bbutyl-lff-pyrazol-5-yl)methoxy]phenyl]-2-[5-l3chIoro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-iodo-thieuo[2,3d]pyriinidin-4-yl]oxy-propanoate

5.5 g ethyl (2R)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6iodo-thieno[2,3-<7)pyrimidin-4-yl]oxy-3-(2-hyditOxyphenyI)propanoate (Préparation 26b) (7.46 mmol), 2.3 g (l-butyl-l77-pyrazol-5-yl)methanol (Préparation 9dd) (14.92 mmol) and 3.91 g triphenyl phosphine (14.92 mmol) were dissolved in 100 mL abs. toluene, then

2.6 g diier/buty! azodicarboxylate (14.92 mmol) was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. It was concentrated under reduced pressure and purified via flash chromatography using ethyl acetate and methanol as eluents to obtain Préparation 26c as a mixture of diastereomers. MS: (M+H)⁺ = 873.0.

Préparation 27: Ethyl (2JÎ)-2>[(5S_<,)-5-[3“Chloro-2-methyl-4-[2-(4-methylpiperaziiilyl)ethoxy]phenyl]-6-(4-fluoro-3-methoxy-phenyl)thieno[2,3-d]pynmidin-4-yl]oxy-3[2- K2-methoxypyrimid in-4-yl)methoxy]phenyl] propanoa te

441 mg ethyl (2/?)-2-[(5_tS^, _a)-5-[3-ch1oro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(4-fluoro-3-methoxy-phenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 8g) (0.6 mmol), 252 mg (2-methoxypyrimidin-4yl)methanol (1.8 mmol) and 472 mg triphenyl phosphine (1.8 mmol) were dissolved in 10 mL abs. toluene, then 414 mg dito/butyl azodicarboxylate (1.8 mmol) was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. It was concentrated under reduced pressure and purified via flash chromatography using dichloromethane and methanol as eluents to obtain Préparation 27. MS: (M+H) = 856.6.

Préparation 28a: Ethyl (2Æ)-2-[(55^, _n)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin'lyl)ethoxy]phenyl]-6-(4-fluoro-3-hydroxy-phenyl)thieno[2,3-rf]pyrimidin-4-yljoxy-3-[2|(2-methoxypyrimidin-4-yl)methoxy]phenyl]propanoate

-160857 mg ethyl (2Æ)-2-[(5^)-5-[3-chloro-2-methyl-4-[2-(4-rnethyIpiperazin-l--yl)cthc>xy] phenyJ]-6-(4-fluoro-3-melhoxy-phenyl)lhienu[2,3-iZ]pyriniidin-4-yl]oxy-3-[2-[(2-inetlioxy pyrimidin-4-yl)methoxy]phenyl]propanoate (Préparation 27) (1.0 mmol) was dissolved in 20 mL DCM, and 5.3 mL BBr₃ (IM in DCM, 5.3 mmol) was added at 0°C, The mixture was stirred at 0°C until no further conversion was observed. It was diluted with water, the pH was set to 6 with NaHCO₃ (saturated aqueous solution), and then it was extracted with dichloromethane. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure and purified via flash chromatography using dichloromethane and methanol as eluents to obtain Préparation 28a. ’H NMR (400 MHz, DMSO-dâ): 10.15 (br s, IH), 8.66 (d, IH), 8.59 (s, IH), 7.29 (d, IH), 7.28 (d, IH), 7.17 (t, IH), 7.16 (d, IH), 7.13 (dd, IH), 6.99 (d, IH), 6.87 (dd, IH), 6.75 (t, IH), 6.65 (m, IH), 6.32 (d, IH), 5.48 (dd, IH), 5.16 (d, IH), 5.10 (d, IH), 4.23 (m, IH), 4.17 (m, 1 H), 4.05 (m, 2H), 3.91 (s, 3H), 3.11 (dd, IH), 2.89-2.47 (br s, 8H), 2.77 (br s, 2H), 2.57 (dd, IH), 2.42 (br s, 3H), 1.89 (s, 3H), 1.05 (t, 3H). MS: (M+H) = 843.2.

Préparation 28b: Ethyl (2fi)-2-[5-(3-chloro-4-niethoxy-2-methyl-phenyl)-6-(4-fluoro3-hydroxy-phenyl)thieno[2,3-rf]pyrimidin-4-ylJoxy-3-|2-[(2-methoxypyriniidin-4yl)methoxy]phenyl]propanoate

Step A:

To the solution of 3.212 g 4-chloro-5-iodo-thieno[2,3-<(]pyrimidine (Préparation le, 10.83 mmol), 6.897 g K₃PO₄ (32.49 mmol), 388 mg bis(l-adamantyl)-butyl-phosphane (1.083 mmol) in 50 ml dimethoxyethane and 15 ml water 4.609 g 2-(3-chloiO-4-methoxy2-methyl-phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Préparation 5d, 16.31 mmol) and 729 mg palladium(II) acetate (1.083 mmol) was added, and it was stirred at 60°C for 2h under nitrogen atmosphère. The reaction mixture was diluted with water and the pH was adjusted to 7 using 2N HCl. It was extracted with DCM, the combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to give 4-chloro-5(3-chloro-4-methoxy-2-methyl-phenyl)lhieno[2,3-i/]pyiïnudine. ’H NMR (400 MHz, DMSO-d₆): 8.98 (s, IH), 7.98 (s, IH), 7.25 (d, IH), 7.09 (d, IH), 3.91 (s, 3H), 2.07 (s, 3H).

-161Step B :

2.706 g of the product of Step A (8.35 mmol) was dissolved in 50 ml THF, the mixture was cooled to -78°C and 5 mL lithium diisopropylamide (2M in THF, 10 mmol) was added dropwise and the mixture was stirred at this température for 30 minutes, Additional 4.5 mL lithium diisopropylamide (2M in THF, 9 mmol) was added dropwise, and the stirring was continued at -78°C for 30 minutes and then 4.223 g of iodine (16.64 mmol) was added to the reaction mixture. After 30 minutes ït was left to warm to room température. Water then saturated aq. NH4CI solution was added to the mixture and then it was extracted with diethylether. The combined organic phases were dried over Na₂SO4 and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to give 4-chloiO-5-(3-chloro-4-methoxy-2-methylphenyl)-6-iodo-thieno[2,3-d]pyrimidine. MS: (M+H)⁺ = 452.0.

Step C:

2.055 g of the product of Step B (4.57 mmol), 1.540 g 2-[4-fluoro-3(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (Préparation BAS, 5.459 mmol) and 2.965 g césium carbonate (9.10 mmol) were dissolved in 30 mL dioxane and 10 mL water, and 322 mg bis(di-ter/-butyl(4dimethylaminophenyl)phosphine)dichloropalladium(II) (AtaPhos, 0.4548 mmol) was added. The reaction mixture was stirred under nitrogen at 55°C until no further conversion was observed. The reaction mixture was cooled to room température, it was diluted with water and the pH was adjusted to 7 using 2 M HCl. It was extracted with DCM, the combined organic phases were dried over Na₂SC>4 and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to give 4-chloro-5-(3-chloro-4-methoxy-2-methyl-phenyl)-6-[4-fluoro-3(methoxymethoxy)phenyl]thieno [2,3-ii]pyrimidine. MS: (M+H)⁴ = 479.0.

Step D:

To 1.824 g of the product of Step C (3.805 mmol) and 2,529 g ethyl (2R)-2-hydroxy-3-[2[(2-methoxypyrimidin-4-yl)methoxy]phenyl]propanoate (Préparation 3ah, 7.610 mmol) in 40 mL /erZ-butanol 5.005 g césium carbonate (15.36 mmol) was added and it was stirred at 65°C until no further conversion was obtained. The reaction mixture was cooled to room

-162température, it was diluted with water and the pH was adjusted to 7 using 2 M HCl. It was extracted with DCM, the combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to give ethyl (2R)-2- [5-(3-chloro-4-methoxy-2methyl-phenyl)-6-[4-fluoiO-3-(methoxymethoxy)phenyl]thieno[2,3-i/jpyrimidin-4-yl]oxy3-[2“[(2-methoxypyrimidin-4-yl)methoxy]phenyl]propanoate. MS: (M+H)⁺ = 775.0.

Sien E:

1.373 g of the product of Step D (l .771 mmol) was dissolved in 50 mL HCl (1.25 M in EtOH) and the mixture was stirred at 50°C until no further conversion was observed. It was cooled to room température then saturated aq. NaHCO₃ solution was added to the réaction mixture, and it was extracted with DCM. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to give Préparation 28b. HRMS calculated for C₃₇H₃₂ClFN₄O₇S: 730.1664; found 731.1746 (M+H).

Préparation BAI; 4,4,5,5-tetramethyl-2-thieno[3^-b]thiophen-3-yl-l,3>2dioxaborolane

0.782 g 3-bromothieno[3,2-b]thiophene (3.6 mmol), 3.626 g 4,4,5,5-tetramethyl-2-(4,4,5,5lelramelhyl-l,3,2-dioxaboiOlan-2-yl)-l,3,2-dioxaboiOlane (14 mmol), 0.783 g PdCl₂*dppf (1.07 mmol) and 2.102 g KOAc (21.4 mmol) were dissolved in 4 mL dioxane under N₂. It was heated to 60°C for 5 hours. The reaction mixture was cooled down and filtered through celite. The filtrate was concentrated and purified via flash chromatography using heptane and EtOAc as eluents to give Préparation BAI. ’H NMR (500 MHz, DMSO-dû): 8.11 (d, IH), 7.67 (dd, 1H), 7.45 (d, IH), 1.32 (s, 12H). HRMS calculated for C₁₂Hi₅BO₂S₂: 266.0607, found: 267.0682 (M+H).

Préparation_______BA2; 4,4,5,5-tetramethyl-2-thieno[3,2-bJthiophen-2-yl-l,3,2dioxaborolane

0.982 g thieno[3,2-b]thiophene (7.0 mmol) was dissolved in 40 mL THF under N₂ and cooled to -78°C. 7 ml BuLi (1.6 M in hexanes, 7.0 mmol) was added and the mixture was stirred at -78°C for 1 hour. Then 1.6 mL 2-isopropoxy-4,4,5,5-tetramethyl-l,3,217193

-163dioxaborolane (7.7 minol) was added and after 10 minutes stirring the mixture was allowed to warm up to room température. It was quenched with saturated aq. NH₄C1 solution, then extracted with THF, dried over Na₂SO4, filtered and concentrated and purified via flash chromatography using heptane and EtOAc as eluents to give Préparation BA2. MS (El, s 70 eV) m/z (% relative intensity, [ion]): 120 (19), 165 (25), 166 (100), 167 (44), 180 (17), 206 (22), 223 (60), 266 (68, [M⁺]).

Préparation BA3; 2-[4-fluoro-3-(methoxyniethyl)phenyl]-4,4,5,5-tetramethyl-l,3,2dioxaborolanc

0.801 g LiCl (19 mmol) was heated at 250°C for 10 minutes under N₂. Then it was cooled to room température and the flask was charged with 0.911 g Mg (38 mmol) and 30 mL dry THF. The Mg was activated with 0.15 mL ?Bu₂AlH (1 M in THF, 0.15 mmol) for 10 minutes, then it was cooled to 0°C and 3.313 g 4-bromo-l-fluoro-2(methoxymethyl)benzene (15 mmol) was added. After formation of the Grignard reagent (appr. 30 minutes) at 0°C 4 mL 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (20 mmol) was added and the réaction mixture was stirred for 30 minutes, then filtered through celite, diluted with EtOAc and washed with saturated aq. NH4CI. The aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over Na₂SÛ4, filtered, concentrated and purified via flash chromatography using heptane and EtOAc as 20 eluents to give Préparation BA3. MS (El, 70 eV) m/z (% relative intensity, [ion]): 59 (21), 85 (20), 134 (24), 135 (100), 136 (28), 150 (30), 165 (24), 166 (43), 167 (95), 192 (20), 251 (44, [M*]).

Préparation BA4: 2-(5-fluoro-2-furyl)-4,4,5,5-tetramethyI-l,3,2-dioxaboroIane

In a 2 L flask 57.7 g 5-bromo-2-furoic acid (300 mmol) and 108.1 g Selectfluor (300 mmol) were added to 900 mL pentane, than 270 mL saturated NaHCOs solution (300 mmol) was added in portions. The reaction mixture was stirred at room température for 1 hour. The layers were separated, and the aqueous layer was extracted with pentane. The combined organic layers were dried over MgSC>4, than filtered into a dried 3-necked 4 L flask. The resulting solution was diluted with 450 mL dry THF under N₂, than cooled to 78°C. 18 mL ⁿBuLi (10 M in hexanes, 180 mmol) was added dropwise (T < -65°C) than the reaction mixture was stirred for 5 minutes. 36 mL 2-isopropoxy-4,4,5,5-tetramethyl17193

-164 1,3,2-dioxaborolane (180 mmol) was added slowly (T < -70°C) and the reaction mixture was stirred for 10 minutes. Cooiing was removed, and the reaction mixture was warmed up to -15°C than quenched with 600 mL saturated aq. NH4CI solution and stirred for 15 minutes. The layers were separated and the aqueous layer was extracted with Et?O. The combined organic layers were dried over MgSO^, filtered and concentrated to give Préparation BA4.

Préparation BA5; 2-[4-fluoiO-3-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-l,3,2dioxaborolane

Step A:

1.91 g 5-bromo-2-fIuoro-phenol (10 mmol) was dissolved in acetone (5 mL). 1.20 g chloro(methoxy)methane (15 mmol) and 2.76 g K2CO3 (20 mmol) was added and the reaction mixture was stirred at room température until no further conversion was observed. The volatiles were evaporated under reduced pressure, and the residue was diluted with water and extracted with DCM. The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain 4-bromo-l-fluoro-2(methoxymethoxy)benzene. *H NMR (400 MHz, CDC1₃):7.37 (dd, IH), 7.13-7.09 (m, IH), 6.99 (dd, IH), 5.22 (s, 2H), 3.54 (s, 3H). MS (El, 70 eV) m/z (% relative intensity, [ion]): 63 (40), 81 (71), 82 (45), 94 (100), 96 (35), 161 (91), 163 (87), 175 (34), 177 (35), 204 (28), 206 (27), 234 (91, [M⁺]), 236 (89, [M⁺]).

Step B:

0.319 g LiCl (7.5 mmol) was heated at 250°C for 10 minutes under N₂. Then it was cooled to room température and the flask was charged with 0.366 g Mg (15 mmol) and 15 mL dry THF. The Mg was activated with 0.06 mL /Bu₂AII-I (1 M in THF, 0.06 mmol) for 10 minutes, then it was cooled to 0°C and 1.416 g 4-bromo-l-fluoro-2(methoxymethoxy)benzene (6 mmol) was added. After formation of the Grignard reagent (appr. 30 minutes) at 0°C 1.5 mL 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (7.5 mmol) was added and the réaction mixture was stirred for 30 minutes, then filtered through celite, diluted with EtOAc and washed with saturated aq. NH4CI. The aqueous

-165phase was extracted with EtOAc. The combined organic phases were dried over Na₂SO4 and concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation BA5. 'H NMR (400 MHz, CDCI3): 7.60 (dd, IH), 7.48-7.44 (m, IH), 7.10 (dd, IH), 5.27 (s, 2H), 3.56 (s, 3H), 1.35 (s, 12H).

MS (El, 70 eV) m/z (% relative intensity, [ion]): 57 (42), 59 (54), 83 (31), 85 (30), 138 (40), 151 (51), 152 (54), 153 (42), 166 (100), 237 (31), 252 (69), 282 (49, [M⁺]).

Compounds of the invention display axial chirality. They can be isolated as a mixture of atropoisomers or as individual atropoisomers (S_a or R_a~).

General procedure (la)

Step A:

eq. ethyl (2Æ)-2-[(5S'_a)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrîmidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 8a), 2 eq. of the appropriate alcohol and 2 e.q triphenyl phosphine were dissolved in abs. toluene (0.2 M for the phénol), then 2 eq. di/er/butyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using ethyl acctatc and methanol as eluents.

Step B:

The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq LiOH x H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, 25 extracted with dichloromethane. The combined organic phases were dried over Na₂SC>4, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

General procedure (Ib)

-166Step A:

eq. ethyl (2À)-2-[(5S_û)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-</]pyrimidm-4-yl]oxy-3-[2-[(2methylsulfanylpyrimidin“4-yl)methoxy]phenyl]propanoate (Préparation 10a), 3.0 eq. of the appropriate boronic acid dérivative and 3.0 eq. copper(I) thiophenecarboxylate were dissolved in dry THF (0.1 M for Préparation 10a), then 0,15 eq. Pd(PPh3)₄ was added.

The mixture was stirred at 70°C under nitrogen until no further conversion was observed. Then it was concentrated under reduced pressure and the crude intermediate was purified via flash chromatography using dichloromethane and methanol as eluents.

Step B:

The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq LiOI-I x H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, 15 extracted with DCM, The combined organic phases were dried over Na2SO₄, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous NHjHCOj solution and MeCN as eluents.

Exampie 1 (2/?)-2-{[(5S_n)-5- {3-chlora-2-methyI-4-[2-(4-methylpiperazin-1 20 yl)ethoxy]phenyl}-6-(4~fluorophenyl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3“(2methoxyphenyl)propanoic acid

Using General procedure la and methanol as the appropriate alcohol Example 1 was obtained. HRMS calculated for C36H3gClFN₄O5S: 690.2079; found 691.2147 (M+H).

Example 2 (27?)-2- {[(5S<,)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(27?)tetrahydrofuran-2 -ylmethoxyjpheny 1} propanoi c acid

Using General procedure (la) and [(2RJ-tetrahydrofuran-2-yl]methanol as the appropriate alcohol Example 2 was obtained. HRMS calculated for C₄oH₄2ClFN₄06S: 760.2498; found 761.2550 (M+H).

-167Exampie 3 (2R)-2-{[(5S_n)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin4-yl]oxy}-3-[2-(2,2,2trifluoroethoxy)phenyl]propanoic acid

Step A:

211 mg ethyl (2Æ)-2-[(55„)-[3-chloro-2-methyl-4-[2-(4-methylpÎperazin-lyl)ethoxy]phenyl]-6-(4-fluorophenyI)thieno[2,3-rf]pyrimÎdin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 8a) (0.3 mmol) and 138 mg K2CO3 (1.0 mmol) were dissolved in 2 mL DMF, then 232 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.0 mmol) was added. The mixture was stirred at room température under nitrogen until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with dichloromethane, dried over Na₂SO4, filtered and concentrated under reduced pressure.

Step B:

The obtained intermediate was dissolved in 8 mL dioxane-water 1:1 and 150 mg LiOH x H2O (3.57 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with dichloromethane, dried over Na₂SO4, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 3. HRMS calculated for C37H35CIF4N4O5S: 758.1953; found 759.1999 (M+H).

Exampie 4 (2Æ>2-{[(5S_a)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/)pyrimidin-4-yl]oxy}-3-[2-(2,2difluoroethoxy)phenyl]propanoic acid

Using General procedure (la) and 2,2-difluoi'oethanol as the appropriate alcohol Example 4 was obtained. HRMS calculated for C37H36CIF3N4O5S: 740.2047; found 741.2119 (M+H).

-168Exampie 5 (2R)-2- {[(55_α)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-ùflpyrimidin-4-ylJoxy}-3-{2-[(7Æ or 5J-l( l -pentyl- lH-pyrazol-5 -yl)ethoxy]phenyl Jpropanoic acid

Using General procedure (la) and (IR or 5)-l-(l-pentyl-lH-pyrazol-5-yl)ethanol (Préparation 9dn) as the appropriate alcohol Exampie 5 was obtained. HRMS calculated for C45H50CIFN6O5S: 840.3236; found 421.1674 (M+2H).

Exampie 6 (2R)-2- {[(55„)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyI}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(75 or 7?)-l( 1 -pentyl-1 H-pyrazol-5 -y l)ethoxy]phenyl} propanoic acid

Using General procedure (la) and (IS or 7?)-l-(l-pentyl-1 H-pyrazol-5-yl)ethanol (Préparation 9do) as the appropriate alcohol Example 6 was obtained. HRMS calculated for C45H₅₀ClFN₆O₅S: 840.3236; found 421.1679 (M+2H).

Example 7 (2R)-2-{[(55(,)-5- {3-chloro-2-methyl-4-|2-(4-methyIpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrîmidin-4-yl]oxy}-3-{2-[(6-methoxy2-phenylpyrimidin-4-yl)methoxy]phenyl}pi’opanoic acid

Using General procedure (la) and (6-methoxy-2-phenyl-pyrimidin-4-yl)methanol (prepared according to Tabei, Kalsumi; Kawasiina, Etsuko; Toyozo, Takaza; Kato, Tetsuzo J. Heterocyclic Chem., 22, 569-574, 1985) as the appropriate alcohol Example 7 was obtained. HRMS calculated for C47H44C1FN₆O_cS: 874.2716; found 438.1444 (M+2H).

Example 8 (2Æ)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-{2-[(2,6diniethoxypyrimidin-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (la) and (2,6-dimethoxypyrimidin-4-yl)methanol (Préparation 9cd) as the appropriate alcohol Example 8 was obtained. HRMS calculated for C42H42CIFN6O7S: 828.2508; found 415.1340 (M+2H).

f

-169 Example 9 (2R)-2-{ [(5Sa)-5-[3-chloro-2-methyl-4-[2-(4-niethylpiperazin-1 yl)ethoxy]phenyl)-6-(4-fkiorophenyl)thieno[2,3-<Z]pyrnnidin-4-yl]oxy}-3-{2-[(5-methyll,2-oxazol-3-yl)methoxy]phenyl}propanoic acid

Using General procedure (la) and (5-mcthyl-l,2-isoxazol-3-yl)methanol as the appropriate alcohol Example 9 was obtained. HRMS calculated for C40H39CIFN5O6S: 771.2294; found 386.6226 (M+2H).

Example 10 (2Â)-2-{ [(55,)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 y l)ethoxy ] phenyl} -6-(4-fluorophenyl)thieno [2,3 - JJpyr imidin-4-yl] oxy} -3 - {2- [(5 fluoropyridin-2-yl)methoxy]phenyl}propanoic acid

Using General procedure (la) and (5-fluoro-2-pyridyl)methanol as the appropriate alcohol

Example 10 was obtained. HRMS calculated for C41H38CIF2N5O5S: 785.2250; found 393.6212 (M+2H).

Example 11 (2J?)-2-{[(55,)-5- {3-chloro-2-methyl-4-[2-(4-methyipiperazin-lyl]ethoxy]phenyl}-6-(4-fluorophenyl)thieno[23-</Jpyrimidin-4-yl]oxy}-3-(2-{[6-(furan-2yl)pyridin-2-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [6-(2-furyl)-2-pyridyl]inethauol (Préparation 9ea) as the appropriate alcohol Example 11 was obtained. HRMS calculated for C^HnClFNsOéS: 833.2450; found 417.6304 (M+2H).

Example 12 (2J?)-2-{[(55,)-5-{3-chloro-2-methyl-4~[2-(4-methylpiperazin-lyl)ethoxy]phenyl}“6-(4-fluorophenyl)thieno[2,3-i(]pyriniidin-4-yl]oxy}-3-(2-{[6(morpholin-4-yl)pyridin-2-yl]methoxy} phenyl)propanoic acid

Using General procedure (la) and (6-(morpholin-4-yl)-pyridin-2-yl)methanol (prepared according to WO 02/42305 Al) as the appropriate alcohol Example 12 was obtained. HRMS calculated for C45H46C1FN₆O₆S: 852.2872; found 427.1494 (M+2H).

170Example 13 (2R)-2- {[(55_α)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2.3-</]pyrimidin-4-yl] oxy} -3 - {2-((6ethoxypyridin-2-yl)methoxy]phenyl}propanoic acid

Using General procedure (la) and (6-ethoxy-2-pyridyl)methanol as the appropriate alcohol Example 13 was obtained. HRMS calculated for C43H43CIFN5O6S: 811.2607; found 406.6361 (M+2H).

Example 14 (2.R)-2-{[(5S_fl)-5-{3~chloro-2-methyl-4-[2~(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-(pyridin-2ylmethoxy)phenyl]propanoic acid

Using General procedure (la) and 2-pyridylmethanol as the appropriate alcohol Example 15 14 was obtained. HRMS calculated for C41H39CIFN5O5S: 767.2344; found 384.6257 (M+2H).

Example 15 (2Â)-2-{[(5S_a)-5-{3-chloro-2-niethyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-<7]pyrimidin-4-yl]oxy}-3-(2-{[l20 (cyclohexyl methyl)-1 H-pyrazol-3-yl]methoxy }phenyl)propanoic acid

Using General procedure (la) and [l-(cyclohexyImethyl)-l/7-pyrazol-3-yl]methanol (Préparation 9dw) as the appropriate alcohol Example 15 was obtained. HRMS calculated for C46H₅ûC1FN6O₅S: 852.3236; found 427.1688 (M+2H).

Example 16 (27?)-2-{[(5_>S^,„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2methylpyridin-4-yl)methoxy]phenyl} propanoic acid

Using General procedure (la) and (2-methyl-4-pyridyl)methanol as the appropriate alcohol Example 16 was obtained. HRMS calculated for C42H41CIFN5O5S: 781.2501; found 391.6327 (M+2H).

- 171 Exemple 17 (2Λ)-2-{ [(55^)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-I yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2(trifluoromethyl)pyridin-4-yl]methoxy} phenyl)propanoic acid

Using General procedure (la) and [2-(trifluoromcthyl)-4-pyridyl]methanol as the appropriate alcohol Example 17 was obtained, HRMS calculated for C42H38CIF4N5O5S: 835.2218; found 836.2334 (M+H).

Example 18 (2^)-2-( [(5SJ-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-J|pyrimÎdin-4-yl]oxy}-3-(2-{[2(thiophen-2-yl)pyridin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [2-(2-thienyl)-4-pyridyl]methanol (Préparation 9eb) as the appropriate alcohol Example 18 was obtained. HRMS calculated for C45H41CIFN5O5S2: 849.2222; found 425.6192 (M+2H).

Exemple 19 (2Æ)-2-{ [(5S_a)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2chloiOpyridin-4-yl)methoxy] phenyl }propanoic acid

Using General procedure (la) and (2-chloro-4-pyridyl)methanol as lhe appropriate alcohol Example 19 was obtained. HRMS calculated for C41H38CI2FN5O5S: 801.1955; found 802.2017 (M+H).

Example 20 (2R)-2- {[(5SJ-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2(morpholin-4-yl)pyridin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [2-(morpholin-4-yl)pyridin-4-yl]methanol as the appropriate alcohol Exampie 20 was obtained. HRMS calculated for C4sH46C1FNôO6S: 852.2872; found 427.1490 (M+2H).

-172Example 21 (2Â)-2-{[(5S'_i7)-5-{3-chloiO-2-methyl-4-[2-(4-niethylpiperazin-lyl)ethoxy] phenyl} -6-(4-fluoiOphenyl)thieno [2,3 -àflpyrimi din-4 -y l]oxy} -3 - (2 - [(2methoxypyridin-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (la) and (2-methoxy-4-pyridyl)methanol as the appropriate alcohol Example 21 was obtained. HRMS calculated for C42H41CIFN5O6S: 797.2450; found 399.6302 (M+2H).

Example 22 (2/?)-2-{[(55'_fl)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i7|pyrÎmidin-4-yl]oxy}-3-(2-{[2-(2methoxyethoxy )pyr idin-4-y 1]methoxy }phenyl)propanoic acid

Using General procedure (la) and [2-(2-methoxyethoxy)pyridin-4-yl]methanol as the 15 appropriate alcohol Example 22 was obtained. HRMS calculated for C44H45CIFN5O7S: 841.2712; found 421.6410 (M+2H).

Example 23 (2R)-3-{2-[(2-/er7-butylpyrimidin-4-yl)methoxy]phenyl}-2-{[(55_f,)-5-{3chloro-2-inethyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl} -6-(4-fluorophenyl)thieno [2,3-i/]pyrimidin-4-y]]oxy}propanoic acid

Using General procedure (la) and (2-/err-butylpyrimidin-4-yl)methanol (Préparation 9bh) as the appropriate alcohol Example 23 was obtained. HRMS calculated for C44H₄6C1FN₆O₅S: 824.2923; found 413.1528 (M+2H).

Example 24 (2^)-2-(((5^)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-<7]pyrimidin-4-yl]oxy}-3-(2-{[2-(propan-

2-yl)pyrîmidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and (2-isopropylpyrimidin-4-yl)inethanol (Préparation 9bd) as the appropriate alcohol Example 24 was obtained. HRMS calculated for

C₄3H44C1FN₆O_SS; 810.2766; found 406.1465 (M+2H).

-173Example 25 (2Â)-2-{[(55a)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fiuoiOphenyl)thieno[2,3-<7|pyrimidÎn-4-yl]oxy}-3-(2-{[2(trifluoromethyl)pyrimidin-4-yl]methoxy}phenyl)piOpanoic acid

Using General procedure (la) and (2-trifluoromethylpyrimidin-4-yl)methanol (Préparation 9bj) as the appropriate alcohol Example 25 was obtained. HRMS calculated for C41H37CIF4N6O5S: 836.2171 ; found 837.2295 (M+H).

Example 26 (27?)-2-{[(55_fl)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[23-<flpyrimidin-4-yl]oxy}-3-{2-[(2cyclopropylpyrimidin-4-yl)methoxy]phenyl}propanoicacid

Using General procedure (la) and (2-cyclopropylpyrimidin-4-yl)methanol (Préparation 9be) as the appropriate alcohol Exemple 26 was obtained. HRMS calculated for C43H42CIFN6O5S: 808.2610; found 405.1363 (M+2H).

Example 27 (2R)-2-{ [(55„)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i7]pyrimidin-4-yl]oxy}-3-(2-{[2-(4chIorophenyl)pyrimidin-4-y IJmethoxy] phenyl)propanoic acid

Using General procedure (la) and [2-(4-chlorophenyl)pyrimidin-4-yl]methanol (Préparation 9bo) as the appropriate alcohol Example 27 was obtained. HRMS calculated forC4₆H4iCl₇.FN₆O₅S: 878.2220; found 879.2355 (M+H).

Example 28 (27?)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-niethy1piperazin-lyl)ethoxy]phenyl)-6-(4-fluorophenyl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-{2-[(2cyclopentylpyiimidin-4-yl)methoxy]phenyl Jpropanoic acid

Using General procedure (la) and (2-cyclopentylpyrimidin-4-yl)methanol (Préparation

9bi) as the appropriate alcohol Example 28 was obtained. HRMS calculated for

C45H46CIFN6O5S: 836.2923; found 419.1537 (M+2H).

-174Example 29 (2/?)-2-{ [(5<S'_i7)-5-{3-clilorO'2-methyl-4-[2-(4-methy]piperazin-1 y l)ethoxy]pheny 1} -6- (4-fluorophenyl)thieno [2,3 -d]pyrimidin-4-yl] oxy} -3 - {2- [(2phenylpyrimidin-4-yl)methoxy]phenyl}piOpanoic acid

Using General procedure (la) and (2-phenylpyrimidin-4-yl)methanol as the appropriate alcohol Exampie 29 was obtained. HRMS calculated for C46H42CIFN6O5S: 844.2610; found 423.1363 (M+2H).

Example 30 (2R)-2- {[(5<S^, _ZT)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i(]pyrimidin-4-yl]oxy}~3-(2-{[2-(2methoxyphenyl)pyrimidin-4-yl]niethoxy}phenyl)propanoic acid

Using General procedure (la) and [2-(2-methoxyphenyl)pyrimidin-4-yl]methanol (Préparation 9bp) as the appropriate alcohol Example 30 was obtained. HRMS calculated for C47H44CJFN6O6S: 874.2716; found 438.1415 (M+2H).

Exampie 31 (2Æ)-2-{[(5S_e)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-(2-{[2-(pyridin-

2- yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [2-(2-pyridyl)pyrimidin-4-yl]mcthanol (Préparation 9bq) as the appropriate alcohol Exampie 31 was obtained. HRMS calculated for C₄₅H4iClFN₇O5S: 845.2562; found 423.6373 (M+2H).

Example 32 (27?)-2- {[(55„)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-<flpyrimidin-4-ylJoxy}-3-(2-{[2-(pyridin-

3- yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [2-(3-pyridyI)pyrimidin-4-yl]inethanol (Préparation

9br) as the appropriate alcohol Example 32 was obtained. HRMS calculated for

C45H41CIFN7O5S: 845.2562; found 423.6337 (M+2H).

-175Example 33 (212)-2- {|.(55_σ)-5 - (3 -chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimÎdin-4-yl]oxy}-3-(2-{[2(thiophen-2-yl)pyrimidin-4-yl]methoxy)phenyl)propanoic acid

Using General procedure (la) and [2-(2-thicnyl)pyrimidin-4-yl]methanol (Préparation 9bv) as the appropriate alcohol Example 33 was obtained. HRMS calculated for C44H4oClFN₆O_sS2,· 850.2174; found 851.2245 (M+H).

Example 34 (2À)-2-{[(5S„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i(|pyriniidin-4-yl]oxy}-3-(2-{[2-(pyridin-

4-yl)pyrinûdin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [2-(4-pyridyl)pyrimidin-4-yl]niethanol (Préparation

9bs) as the appropriate alcohol Example 34 was obtained. HRMS calculated for C4_SH₄|C1FN₇O₅S: 845.2562; found 423.6358 (M+2H).

Example 35 (212)-2-{[(5LS'_a)-5-{3-chloro-2-methyl-4-[2(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno[2,3~d]pyrimidin-4-yl]oxy}-3-(2-{[2-(furan-320 yl)pyrimidin-4-yl]methoxy)phenyl)propanoic acid

Using General procedure (la) and [2-(3-furyl)pyrimidin-4-yl]fnethanol (Préparation 9bt) as the appropriate alcohol Example 35 was obtained. HRMS calculated for C44H4oClFN_fi0₆S: 834.2403; found 835.2443 (M+H).

Example 36 (212)-2- {[(55_e)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-</|pyritnidin-4-yl]oxy}-3-(2-{[2-(l,3thiazol-2-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [2-(2-thiazolyl)pyrimidin-4-yl]methanol (Préparation

9bx) as the appropriate alcohol Example 36 was obtained. HRMS calculated for

C43H39CIFN7O5S2: 851.2127; found 426.6120 (M+2H).

-176Example 37 (27?)-2-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i7]pyrimidin-4-yljoxy}-3-{2-[(2ethylpyrimidin-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (la) and (2-cthylpyrirnidin-4-yl)methanol (Préparation 9ba) as the appropriate alcohol Example 37 was obtained. HRMS calculated for C42H42CIFN6O5S: 796.2610; found 399.1381 (M+2H).

Example 38 (27?)-2-{[(5>S'_n)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-ùQpyrimidin-4-yl]oxy} -3-(2- {[2-(2methylpropyl)pyrimidin-4-yl] methoxy} phenyl)propanoic acid

Using General procedure (la) and [2-(2-methylpropyl)pyrimidin-4-yl]methanol (Préparation 9bf) as the appropriate alcohol Example 38 was obtained. HRMS calculated for CWUClFNeOjS: 824.2923; found 825.2998 (M+H).

Example 39 (2R)-2- {[(5S„)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{[2(cyclopropylmethyl)pyrimidin-4-yl]methoxy} phenyl)propanoic acid

Using General procedure (la) and [2-(cyclopropyhnethyl)pyrùnidin-4-yl] methanol (Préparation 9bg) as the appropriate alcohol Example 39 was obtained. HRMS calculated for C44H44CIFN6O5S: 822.2766; found 412.1458 (M+2H).

Example 40 (2Æ)-3-{2-[(2-benzylpyrimidin-4-yl)methoxy]phenyl}-2-{[(5₁S^, _a)-5-{3-chloro2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3i/]pyrimidin-4-yl]oxy}propanoic acid

Using General procedure (la) and (2-benzylpyrimidin-4-yl)methanol (Préparation 9by) as the appropriate alcohol Example 40 was obtained. HRMS calculated for C47H44CIFN6O5S:

858.2766; found 430.1471 (M+2H). .

-177Example 41 (27?)-2-{L(50’_n)-5-{3-chloro~2-niethyJ-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-idpyiimidin-4-yl]oxy}-3-{2-[(2propylpyrimidin-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (la) and (2-propylpyrimidin-4-yl)methanol (Préparation 9bb) as the appropriate alcohol Exampie 41 was obtained. HRMS calculated for C43H44CIFN6O5S: 810.2766; found 406.1459 (M+2H).

Example 42 (270-3-{2-[(2-butyIpyrimidin-4-yl)methoxy]phenyl}-2-{[(5S„)-5-{3-chloro-2methyM-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno[2,3d]pyrimidin-4-yl]oxy}propanoic acid

Using General procedure (la) and (2-butylpyrimidin-4-yl)methanol (Préparation 9bc) as the appropriate alcohol Exampie 42 was obtained. HRMS calculated for C44H46ClFNeO5S: 824.2923; found 413.1500 (M+2H).

Exampie 43 (2Æ)-2-{[(5S_n)-5-{3-chloro-2-methyl-4-[2-(4-rnethylpiperazin-lyl)ethoxy]pheny)}-6-(4-fluorophenyl)thieno[2_>3-J]pyriinidin-4-yl]oxy}-3-[2-({2-[2(dimethylamino)ethyl]pyrimidin-4-yl}methoxy)phenyl]propanoicacid

Using General procedure (la) and [2-[2-(dimethylainino)ethyl]pyrimidin-4-yl]methanol (Préparation 9bm) as the appropriate alcohol Exampie 43 was obtained. HRMS calculated for C44H47CIFN7O5S: 839.3032; found 420.6614 (M+2H).

Example 44 (2Æ)-2-{[(5S_o)-5· {3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-iZ]pyrimïdïn-4-yl]oxy}-3-(2-{[2-(2methoxyethyl)pyrimidin-4-yl]methoxy} phenyl)propanoic acid

Using General procedure (la) and [2-(2-methoxyethyl)pyrimidin-4-yl]methanol (Préparation 9bl) as the appropriate alcohol Example 44 was obtained. HRMS calculated for C43H4₄C1FN₆O₆S: 826.2716; found 414.1439 (M+2H).

-178Example 45 (2R)-2-{ ((55,,)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno(2_!3-i(|pyrimidin-4-yl]oxy}-3-(2-{[2(methoxymethyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [2-(2-methoxymethyl)pyrimidin-4-yl]methanol (Préparation 9bk) as the appropriate alcohol Example 45 was obtained. HRMS calculated forC₄2H42ClFN₆O₆S: 8I2.2559; found 813.2622 (M+H).

Example 46 (2^)-2-(((55,,)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno(2,3-J]pyrimidin-4-yl]oxy}-3-(2-{[2(phenoxymethyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [2-(phenoxymethyl)pyrimidin-4-yl]methanol (Préparation 9bz) as the appropriate alcohol Example 46 was obtained. HRMS calculated for C47H44CIFN6O6S: 874.2716; found 875.2790 (M+H).

Example 47 (27?)-2-([(55_fl)-5- (3-chloro-2-methyl-4-(2-(4-methylpiperazin-1 yl)ethoxy]phenyl} -6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy} -3-(2- {(2(ethoxymethyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and (2-(ethoxymethyl)pyriinidin-4-yl]methanol (Préparation 9bn) as the appropriate alcohol Example 47 was obtained. HRMS calculated for C43H44CIFN6O6S: 826.2716; found 827.2783 (M+H).

Example 48 (2Æ)-2-{[(55„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno(2,3-if]pyrimidin-4-yl]oxy}-3-[2-({2-[(2inethoxyethyl)(inethyl)amino]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Using General procedure (la) and (2-[2-methoxyethyl(methyl)amino]pyrimidin-4yl]methanol (Préparation 9ap) as the appropriate alcohol Example 48 was obtained, HRMS calculated for C44H4₇C1FN7O₆S·. 855.2981; found 428.6583 (M+2H).

-179 Example 49 (2//)-2-{[(55_a)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)cthoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-<Z}pyrimidin-4-yl]oxy}-3-(2-{[2-(lHpyrazol-1 -yl)pyrimidin-4-yl]methoxy }phenyl)propanoic acid

Using General procedure (la) and (2-(l//-pyrazol-l-yl)pyrimidin-4-yI)methanol (Préparation 9bw) as the appropriate alcohol Example 49 was obtained. HRMS calculated for C43H40CIFN8O5S: 834.2515; found 418.1327 (M+2H).

Example 50 (2Λ)-2- {[(5^)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(4methylpiperazin- l-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [2-(4-mcthylpiperazin-l-yl)pyrimidin-4-yl]methanol (Préparation 9aq) as the appropriate alcohol Example 50 was obtained. HRMS calculated for C4₅H4₈C1FN₈O₅S.· 866.3141 ; found 434.1640 (M+2H).

Example 51 (27?)-2-{[(5₁S'_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl} -6-(4-fluorophenyl)thieno[2,3-i/Jpyrimidin-4-yl]oxy} -3-(2- {[2-(l H1,2,3 -triazol-1 -yl)pyrimidin-4-yl]methoxy) phenyl)propanoic acid

Using General procedure (la) and [2-(1//-1,2₎3-triazol-l-yl)pyriniidin-4-yl]methanol (Préparation 9as) as the appropriate alcohol Example 51 was obtained. HRMS calculated for C42H39CIFN9O5S: 835.2467; found 418.6292 (M+2H).

Example 52 (2R)-2- {[(55₀)-5- {3-chloro-2-methyl-4-[2-(4-methyipiperazin-1yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-(2-{[2(morphol ïn-4-yl)pyrimidin-4-yl]methoxy} phenyl)propanoic acid

Using General procedure (la) and (2-(morpholin-4-yl)pyrimidin-4-yl)methanol (Préparation 9ar) as the appropriate alcohol Example 52 was obtained. HRMS calculated for C44H45CIFN7O6S: 853.2825; found 427.6484 (M+2H).

-180Example 53 (2Λ)-2-{[(55^)-5- {3-chloiO-2-methy!-4-[2-(4-methylpiperazin-1 yl)etlioxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-<7]pyrimidin-4-yI]oxy}-3-[2-({2-[(2methoxyethyl)amino]pyiimidin-4-yl} methoxy)phenyl Jpropan oie aci d

Using General procedure (la) and [2-(2-methoxyethylamino)pyrimidin-4-yl]methanol (Préparation 9ao) as the appropriate alcohol Example 53 was obtained. HRMS calculated for C43H45CIFN7O6S: 841.2825; found 421.6505 (M+2H).

Example 54 (2R)-2- {[(55^,)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2_J3-JJpyrimidin-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxy]pheny 1} propanoic acid

Using General procedure (la) and (2-methoxypyrimidin-4-yl)methanol as the appropriate alcohol Example 54 was obtained. HRMS calculated for C41H40CIFN6O6S: 798.2403; found 400.1284 (M+2H).

Example 55 (2Â)-2-{[(5<S^, ₀)-5-{3-chloro-2-methyl-4-[2-(4-inethylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno[2₎3-a']pyrimidin-4-y]]oxy}-3-(2-{[2-(propan2-yloxy)pyrimidïn-4-yl]methoxy} phenyl)propanoic acid

Using General procedure (la) and (2-isopropoxypyrimidin-4-yl)methanol (Préparation 9ae) as the appropriate alcohol Example 55 was obtained. HRMS calculated for C₄₃H₄₄C1FN₆O₆S: 826.2716; found 414.1442 (M+2H).

Example 56 (2Æ)-2-[[(55„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno[2,3-<7]pyriniÎdin'4-yl]oxy}-3-{2-[(2phenoxypyiïmidin-4-yl)tnethoxy]phenyl}propanoic acid

Using General procedure (la) and (2-phenoxypyrimidin-4-yl)methanol (Préparation 9ak) as the appropriate alcohol Exemple 56 was obtained. HRMS calculated for

C46H42C1FN₆O₆S.· 860.2559; found 431.1333 (M+2H).

- 181 Example 57 (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-iZ]pyrimidin-4-yl]oxy}-3-{2-[(2ethoxypy ri ni id in-4-yl)methoxy]phenyl} propanoic acid

Using General procedure (la) and (2-ethoxypyrimidin-4-yl)methanol (Préparation 9ad) as the appropriate alcohol Example 57 was obtained. HRMS calculated for C42H42CIFN6O6S: 812.2559; found 407.1342 (M+2H).

Example 58 (2R)-2~ {[(5S_a)-5- [3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-rf]pyrÎmidin-4-yI]oxy}-3-(2-{[2-(2,2,2trifluoroethoxy)pyrimidm-4-yl]methoxy)phenyl)propanoic acid

Using General procedure (la) and [2-(2,2,2-trifluoiOethoxy)pyrimidin-4-yl]methanol (Préparation 9ai) as the appropriate alcohol Example 58 was obtained. HRMS calculated for C42H39CIF4N6O6S: 866.2276; found 434.1195 (M+2H).

Example 59 (2R)-2.-{ [(55),)-5- {3-chloro-2-methyl-4-[2-(4~methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{[2-(pyridin4-ylmethoxy)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [2-(4-pyridylmethoxy)pyrimidin-4-yl]mcthanol (Préparation 9aw) as the appropriate alcohol Example 59 was obtained. HRMS calculated for C4₆H43C1FN₇O₆S: 875.2668; found 438.6442 (M+2H).

Example 60 (21î)-2-{[(5S’_n)-5-{3-chIoro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-iZ]pyrimidin-4-yl]oxy}-3-[2-({2-[(lmethyl-1 H-imidazo 1 -5 -y 1 )m ethoxy] pyri midin-4-yl} methoxy)phenyl] propanoic acid

Using General procedure (la) and {2-[(l -methyl-l//-imidazol-5-yI)methoxy]pyrimidin-4yl}methanol (Préparation 9ay) as the appropriate alcohol Example 60 was obtained. HRMS calculated for C45H44CIFN8O6S: 878.2777; found 440.1451 (M+2H).

-182Example 61 (2R)-2-{[(5SJ-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl) -6-(4-fluorophenyl)thieno [2,3-d]pyrirnidin-4-yl]oxy } -3- {2 - [(2piOpoxypyrïmidin-4-yl)nTethoxy]phenyl jpropanoic acid

Using General procedure (la) and (2-propoxypyrimidin-4-yl)methanol (Préparation 9af) as the appropriate alcohol Example 61 was obtained. HRMS calculated for C43H44CIFN6O6S: 826.2716; found 414.1423 (M+2H).

Example 62 (2/?)-2- {[(5^)-5- {3--chloro-2-methy]-4-[2-(4-tnethylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(3,3,3trifluoropiOpoxy)pyiiniidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [2-(3_}3,3-tiifluoiOpropoxy)pyrimidin-4-yl]methanol (Préparation 9aj) as the appropriate alcohol Example 62 was obtained. HRMS calculated for C₄₃H4|C1F₄N₆O₆S: 880.2433; found 441.1294 (M+2H).

Example 63 (2R)-2- {[(55„)-5- {3-chloro-2-methyl-4-[2-(4-înethylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{[2-(2methoxyethoxy)pyrimidin-4-yl]methoxy)phenyI)propanoic acid

Using General procedure (la) and [2-(2-inethoxyethoxy)pyrimidin-4-yl]methanol (Préparation 9ag) as the appropriate alcohol Example 63 was obtained. HRMS calculated forC₄₃H44ClFN₆O₇S: 842.2665; found 422.1385 (M+2H).

Example 64 (2/2)-2-{[(5S_a)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno[2,3-d]pyrimidÎn-4-yl]oxy} -3-(2-((2-(2ethoxyethoxy)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [2-(2-ethoxyethoxy)pyrimidin-4-yl]methanol (Préparation 9ah) as the appropriate alcohol Example 64 was obtained. HRMS calculated for C44H46C1FN₆O₇S: 856.2821; found 429.1497 (M+2H).

-183 Example 65 (2/()-2“{[(5LS'_£,)-5-{3-cliloro-2-methyl-4-[2-(4-methylpipei^,azin-lyl)ethoxy]phenyl} -6-(4-fluorophenyl)thieno[2,3-<ZJpyrimidin-4-yl]oxy} >3-(2- {[2(methylsulfanyl)pyrimidin-4-yl]methoxy)phenyl)propanoic acid

Using General procedure (la) and (2-methylsulfanylpyrimidin-4-yl)methanol (Préparation 9aa) as the approprîate alcohol Example 65 was obtained. HRMS calculated for C4JH40CIFN6O5S2: 814.2174; found 815.2260 (M+H).

Example 66 (2Æ)-2-{[(5S_rt)-5-(3-chloro-2-methyl-4-[2-(4-methyIpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/|pyrimidin-4-yl]oxy}-3-[2-({2-[(3methoxypropyl)sulfanyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Using General procedure (la) and [2-(3-methoxypropylsulfanyl)pyrimidin-4-yI]methanol (Préparation 9ac) as the approprîate alcohol Example 66 was obtained. HRMS calculated for C44H46CIFN6O6S2: 872.2593; found 437.1384 (M+2H).

Example 67 (2j?)-2-{ [(5S„)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-({2“[(2methoxyethyl)sulfanyi]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Using General procedure (la) and [2-(2-methoxyethylsulfanyl)pyrimidin-4-yl]methanol (Préparation 9ab) as the approprîate alcohol Example 67 was obtained. HRMS calculated for C₄3H₄₄ClFN_fiO₆S₂: 858.2436; found 430.1286 (M+2H).

Example 68 (2R)-2-{[(55„)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-</]pyi'imidin-4-yI]oxy}-3-[2-(pyrimidin-4ylm.ethoxy)phenyl]propanoic acid

Using General procedure (la) and pyrimidin-4-ylmethanol as the approprîate alcohol Example 68 was obtained. HRMS calculated for C^HssClFNâOsS: 768,2297; found 769.2358 (M+H).

- 184Example 69 (2R)-2- {[(50'_rt)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl} -6-(4-fluoiOphenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy} -3-{2-[( l -methyll H-p yrazol -5 -yl)methoxy ] phenyl} propanoic acid

Using General procedure (la) and (l-methyl-l//-imidazol-5-yl)niethanol as the appropriate alcohol Example 69 was obtained. HRMS calculated for C4OH40CIFN6O5S: 770.2453; found 771.2527 (M+H).

Example 70 (2R)-3-{2-[(i-/er/-butyl-lH-pyrazol-5-yl)methoxy]plienyl}-2-{f(5>.S'„)-5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(4fluorophenyl)thieno[2.3-4/]pyrimidin-4-yl]oxy}propanoic acid

Using General procedure (la) and (l-taŸ-butyl-17/-pyrazol-5-yl)methano! (Préparation 15 9dt) as the appropriate alcohol Exampie 70 was obtained. HRMS calculated for C₄3H46C1FN6O5S: 812.2923; found 813.3030 (M+H).

Example 71 (27?)-2-{[(55_a)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyriinidin-4-yl]oxy}-3-(2-{[l-(propan20 2-yl)-lH-pyrazol-5-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [l-(propan-2-yl)-lZZ-pyrazol-5-yl]methanol (Préparation 9dc) as the appropriate alcohol Example 71 was obtained. HRMS calculated for C42H44CIFN6O5S: 798.2766; found 400.1469 (M+2H).

Example 72 (2Æ)-2- {[(5S_a)-5 - { 3 - chl oro-2-m ethy 1-4- [2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno[2,3-z/]pyrimidin-4-yl]oxy}-3-{2-[(lcyclopentyl-lH-pyrazol-5-yl)methoxy]phenyl}propanoic acid

Using General procedure (la) and (l-cyclopentyl-lH-pyrazol-5-yl)methanol (Préparation

9dg) as the appropriate alcohol Example 72 was obtained. HRMS calculated for

C44H46C1FN₆O₅S: 824.2923; found 413.1559 (M+2H).

-185 Example 73 (2R)-2-{[(5₁S'_(ï)-5-{3-chloro-2-methy]-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thjeno[2,3-ri]pyrimidin-4-yl]oxy} -3-(2-(( 1 cyclohexyl-1 H-pyrazol-5-yl)methoxy]phenyl}propanoic acid

Using General procedure (la) and (l-cyclohexyl-l//-pyrazol-5-yl)methanol (Préparation 9dh) as the appropriate alcohol Example 73 was obtained. HRMS calculated for C₄5H48C1FN₆O₅S: 838.3079; found 839.3165 (M+H).

Example 74 (2R)-2- {[(5S_fl)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(l-phenyl1 H-pyrazol-5-yl)methoxy]phenyl} propanoic acid

Using General procedure (la) and (l-phenyMH-pyrazol-5-yl)methanol as the appropriate alcohol Example 74 was obtained. HRMS calculated for C45H42CIFN6O5S: 832.2610; found 833.2656 (M+H).

Example 75 (2R)-2-{[(55₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-<Z]pyrimidin-4-yl]oxy}-3-(2-([l(tetrahydiO-2H-pyran-4-yl)-lH-pyrazol-5-yl]methoxy}phenyl)propanoicacid

Using General procedure (la) and (l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5yl)methanol (Préparation 9di) as the appropriate alcohol Example 75 was obtained. HRMS calculated foi^^ClFNôOeS: 840.2872; found 841.2913 (M+H).

Example 76 (2R)-2- {[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-{2-[(l-ethy]-lHpyiazol-5-yl)methoxy]phenyI}propanoic acid

Using General procedure (la) and (l-ethyl-lH-pyrazol-5-yl)methanol (Préparation 9da) as the appropriate alcohol Example 76 was obtained. HRMS calculated for

C4JH42CIFN6O5S: 784.2610; found 785.2679 (M+H).

-186Example 77 (271)-2- {[(55,,)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl)-6-(4-fluoiOphenyl)thieno[2,3-z/]pyrimidiri-4-yl]oxy}-3-(2-{[l-(2,2,2trifluoroethyl)-1 H-pyrazol-5 -yljmethoxy} phenyl)propanoic acid

Using General procedure (la) and [l-(2_J2,2-trifluoroethyl)-lH-pyrazol-5-yl]methanol (Préparation 9du) as the appropriate alcohol Exampie 77 was obtained. HRMS calculated for C41H39CIF4N6O5S: 838.2327; found 839.2389 (M+H).

Example 78 (27?)-2-{[(55₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidÎn-4-yl]oxy}-3-(2-{[l(cyclopropylmethyl)-1 H-pyrazol-5-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [l-(cyclopropylmethyl)-lH-pyrazol-5-yl]methanol (Préparation 9df) as the appropriate alcohol Example 78 was obtained. HRMS calculated for C43H44CIFN6O5S: 810.2766; found 406.1464 (M+2H).

Example 79 (27?)-2-{[(55_fl)-5-{3-chloro-2-HÎethyI-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno[2,3-i7]pyrnnÎdin-4-yl]oxy}-3-(2-{[l-(420 methoxybenzyl)-lH-pyrazol-5-yl]mcthoxy)phenyl)propanoicacid

Using General procedure (la) and [l-(4-methoxybenzyl)-lH-pyrazol-5-yl]methanol (Préparation 9dk) as the appropriate alcohol Example 79 was obtained. HRMS calculated foi^HifiClFNcOeS: 876.2872; found 439.1531 (M+2H).

Example 80 (27î)-2- {[(55_σ)-5 - {3 -chloro-2 -methyl-4- [2-(4-methy lpiperazin-1 yl)ethoxy]phenyl} -6-(4-fluorophenyl)thieno[2,3-iZ]pyrimidin-4-yl]oxy}-3-(2- {[ 1 (cyclohexylmethyl)-1 H-pyrazol-5-yl]methoxy }phenyl)propanoic acid

Using General procedure (la) and [l-(cyclohexylmethyl)-177-pyrazol-5-yl]methanol (Préparation 9dv) as the appropriate alcohol Example 80 was obtained. HRMS calculated for C₄6H5qC1FN₆O_sS.· 852.3236; found 427.1679 (M+2H).

- 187 Example 81 (2R)-2-{ [(55^)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-iZ]pyrimidin-4“yl]oxy}-3-{2-[(l-propyl1 H-py razol-5 -y l)methoxy Jphenyl} propanoic acid

Using General procedure (la) and (l-propyl-l/7-pyrazol-5-yl)methanol (Préparation 9db) as the appropriate alcohol Example 81 was obtained. HRMS calculated for C|₂H44C1FN₆O_sS: 798.2766; found 400.1433 (M+2H).

Example 82 (2R)-2-{ [(55_fl)-5- {3-chIoro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno[2,3-rfJpyrimidin-4-yl]oxy}-3-(2-{[l-(3methylbutyl)- lH-pyrazol-5-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [l-(3-methylbutyl)-lH-pyrazol-5-yl]methanol (Préparation 9de) as the appropriate alcohol Example 82 was obtained. HRMS calculated for C44H4SCIFN6O5S: 826.3079; found 827.3123 (M+H).

Example 83 (2R)- 3- {2-[( 1 -butyl-1 H-pyrazol -5-yl)methoxy] phenyl} -2- {[(55^)-5 - {3 chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(4fluoropheny l)thieno [2,3 -cf] pyrimidin-4-y l]oxy} propanoic acî d

Using General procedure (la) and (l-butyl-177-pyrazol-5-yl)methanol (Préparation 9dd) as the appropriate alcohol Example 83 was obtained. HRMS calculated for C₄3H46C1FN₆O₅S: 812.2923; found 407.1551 (M+2H).

Example 84 (2Æ)-2-{[(5S_n)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{[l-(4,4,4trifluorobutyl)-1 H-pyrazol-5-yl]methoxy} phenyl)propanoic acid

Using General procedure (la) and [l-(4,4,4-trifluorobutyl)-lH-pyrazol-5-yl]methanol (Préparation 9dl) as the appropriate alcohol Example 84 was obtained. HRMS calculated for C43H4₃CIF₄N₆O₅S: 866.2640; found 434.1385 (M+2II).

-188Example 85 (2Λ)-2-{[(55,)-5-(3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl} -6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy} -3 - {2-[( l -pentyllH-pyrazol-5-yl)methoxy]phenyl}propanoic acid

Using General procedure (la) and (l-pentyl-lH-pyrazol-5-yl)niethanol (Préparation 9dm) as the appropriate alcohol Example 85 was obtained. HRMS calculated for C44H_4gClFN₆O₅S: 826.3079; found 827.3206 (M+H).

Example 86 (28)-2-( [(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i7Jpyi-imidin-4-yl]oxy}-3-(2-{[l-(3methoxypropy l)-1 H-pyrazol -5 -yljmethoxy} phenyl)propanoic acid

Using General procedure (la) and [l-(3-methoxypropyl)-lZ/-pyrazol-5-yl]methanol (Préparation 9dq) as the appropriate alcohol Example 86 was obtained. HRMS calculated for C₄3H46ClFN₆O₆S: 828.2872; found 415.1505 (M+2H).

Example 87 (28)-2 - {[(55,)-5- {3 -ch loro-2-methyl-4- [2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-[2-({l-[2(dimethylamino)ethyl)-1 H-pyrazoI-5-yl }methoxy)phenyl]propanoic acid

Using General procedure (la) and {l-[2-(dimethylamino)ethyl]-lH-pyrazol-5-yl}methanol (Préparation 9dj) as tlie appropriate alcohol Example 87 was obtained. HRMS calculated for C43H4₇CIFN₇O_sS: 827.3032; found 414.6592 (M+2H),

Example 88 (28)-2-{[(55,)-5- {3-chloiO-2-methyl-4-[2-(4-methy Ipiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thicno[2,3-</]pyrimidin-4-yl]oxy}-3-(2-{[l-(2methoxyethyl)- l//-pyrazol-5-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [l-(2-methoxyethyl)-l//-pyrazol-5-yl]methanol (Préparation 9dp) as the appropriate alcohol Example 88 was obtained. HRMS calculated for C42H44CIFN6O6S: 814.2716; found 408.1423 (M+2H).

-189Example 89 (272)-2-([(5S'_e)-5-{3-chloro-2-methyl-4-[2-(4-methyipiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-c(]pyrimidin-4-yl]oxy}-3-(2-([l-(2ethoxysthyl)-1 H-pyrazol-5-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [l-(2-ethoxyethyl)-lZ/-pyrazol-5-yl]methanol (Préparation 9dr) as the appropriate alcohol Exemple 89 was obtained. HRMS calculated forC₄3H46ClFN₆O₆S: 828.2872; found 415.1510 (M+2H).

Example 90 (272)-2- ([(55^)-5- (3-chîoro-2-methyl-4-[2~(4-methylpiperazin-1yl)ethoxy] phenyl} -6-(4-fluorophenyl)thieno [2,3 -ifJpyrimidin-4-y IJoxy } -3 - [2-( {I - [2-(2methoxyethoxy)ethyl]-1 H-pyrazol-5-yl}methoxy)phenyl]propanoic acid

Using General procedure (la) and (l-[2-(2-methoxyethoxy)ethyl]-lH-pyrazol-5yljmethanol (Préparation 9ds) as the appropriate alcohol Example 90 was obtained. HRMS calculated for C44H₄gClFN₆O₇S: 858.2978; found 430.1571 (M+2H).

Example 91 (272)-2-(((55^)-5- (3-chloro-2-methyl-4-(2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-[2-(pyrazin-2ylmethoxy)phenyl]propanoic acid

Using General procedure (la) and pyrazin-2-ylmethanol as the appropriate alcohol

Example 91 was obtained. HRMS calculated for C4oH38C1FN60sS: 768.2297; found 769.2422 (M+H).

Example 92 (272)-2-( [(55^)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}“6-(4-fluorophenyl)thieno[2,3-cZjpyrimidin-4-yl]oxy)-3-{2-[(l-inethyl1 H-imidazol-5-yl)methoxy]phenyl}piOpanoic acid

Using General procedure (la) and (l-methyl-l#-imidazol-5-yl)rnethanol as the appropriate alcohol Example 92 was obtained. HRMS calculated for C40H40CIFN6O5S: 770.2453; found 771.2523 (M+H).

-190Exampie 93 (2R)-2-{ [(5S₍₇)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-l yi)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i(]pyiirriidin-4-yl]oxy}-3-[2-(pyrimidin-5ylmethoxy)phenyl]propanoic acid

Using General procedure (la) and pyrimidin-5-ylmethanol as the appropriate alcohol

Example 93 was obtained. HRMS calculated for C40H38CIFNÛO5S: 768.2297; found 769.2379 (M+H).

Example 94 (2/?)-2-([(55_a)-5-(3-chloro-2-inethyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl} -6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy} -3- {2-[(l -phenyl1H-1,2,3-triazol-5-yl)methoxy]phenyl}propanoic acid

Using General procedure (la) and (l-phenyl-lH-l,2,3-triazol-5-yl)methanol (Préparation

9ee) as the appropriate alcohol Exampie 94 was obtained. HRMS calculated for C₄₄H_4iClFN₇O₅S: 833.2562; found 834.2620 (M+H).

Example 95 (2Æ)-3-(2-[(l-butyl-lH-l,2_>3-triazol-5-yl)methoxy]phenyl}-2-([(55_fl)-5-(3chloro-2-methyl-4- [2-(4-methy lpiperazin-1 -y 1 ) e thoxy] phenyl} -6 - (4 fluorophenyI)thieno[2,3-t(|pyrimidin-4-yl]oxy}propanoic acid

Using General procedure (la) and (l-butyl-lH-l,2,3-triazol-5-yl)methanol (Préparation 9ec) as the appropriate alcohol Example 95 was obtained. HRMS calculated for C₄₂H₄₅C1FN₇O₅S: 813.2875; found 814.2964 (M+H).

Example 96 (2R)-2- {[(55_a)-5 - (3-chloro-2-methyl-4- [2-(4-methy lpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-if|pyrimidin-4-yl]oxy}-3-(2-([l-(3methoxypiOpyl)-lH-l,2,3-triazol-5-yl]methoxy}phenyl)piOpanoic acid

Using General procedure (la) and [l-(3-methoxypropyl)-lH-l_}2,3-triazol-5-yl]methanol (Préparation 9ed) as the appropriate alcohol Example 96 was obtained. HRMS calculated for C₄₂H₄₅C1FN₇O₆S: 829.2825; found 830.2876 (M+H).

- I9l Example 97 (2/?)-2-{[(55^, _a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl} -6-(4-fluorophenyl)thieno[2,3-iZ}pyrimidin-4-yl]oxy} -3-(2-{ [ l -(2methoxyethyl)-lH-l,2,3-triazol-5-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [l-(2-methoxyethyl)-lH-l,2,3-triazol-5-yl]mcthanol (Préparation 9ef) as the appropriate alcohol Example 97 was obtained. HRMS calculated for C41H43CIFN7O6S: 815.2668; found 408.6427 (M+2H).

Example 98 (2R)-2- {[(50^)-5- {3-chloro-2-methyl -4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-<7]pyrimidin-4-yl]oxy}-3-[2-(l₎3-oxazol-

4- ylmethoxy)phenyl]propanoic acid

Using General procedure (la) and oxazol-4-ylmethanol as the appropriate alcohol Example 98 was obtained. HRMS calculated for C39H37CIFN5O6S: 757.2137; found 758.2245 (M+H).

Example 99 (27?)-3-{2-[(5-bromo-2-methoxypyrimidin-4-yl)methoxy]phenyl}-2-{[(5S₀)-

5- {3-chloro-2-methyl-4-[2-(4-methylpîperazïn-l-yl)ethoxy]phenyl}-6-(4fluorophenyl)thieno[2,3-i/]pyrirnidin-4-yl]oxy}propanoic acid

Using General procedure (la) and (5-bromo-2-methoxy-pyritnidin-4-yl)methanol (Préparation 9cb) as the appropriate alcohol Example 99 was obtained. HRMS calculated for C4iH₃₉BrClFN₆O₆S: 876.1508; found 439.0864 (M+2H).

Example 100 (2R)-2- {[(55^)-5- {3 -chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno[2,3-i/]pyrimidÎn-4-yl]oxy}-3-(2-{[2-methoxy5-(thiophen-3-yl)pyrimidin-4-yl]methoxy} phenyl)propanoic acid

Using General procedure (la) and [2-methoxy-5-(3-thienyl)pyrimidin-4-yl]methanol (Préparation 9cc) as the appropriate alcohol Example 100 was obtained. HRMS calculated for C4₅H4₂C1FN₆O₆S₂: 880.2280; found 441.1229 (M+2H).

-192Example 101 (2/?)-3-{2-[(5-biOmopyrimidin-4-yl)methoxy]phenyl}-2-{[(55„)-5-{3chloiO-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl} -6-(4fluorophenyl)thieno[2,3-</]pyrimidin-4-yl]oxy}propanoic acid

Using General procedure (la) and (5-bromopyrimidin-4-yl)methanol (Préparation 9ca) as the appropriate alcohol Example 101 was obtained. HRMS calculated for C₄oH37BrClFN60₅S: 846.1402; found 424.0775 (M+2H).

Example 102 (2J?)-2-{[(5S^, ₍₇)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2_J3-d]pyrimidin-4-yI]oxy}-3-{2-[(4-metliyl4H-1,2_}4-triazol-3-yl)methoxy]phenyl}propanoic acid

Using General procedure (la) and (4-methyl-4/Al,2,4-triazol-3~yl)methanol as the appropriate alcohol Example 102 was obtained. HRMS calculated for C₃₉H₃9C1FN7O$S: 771.2406; found 772.2411 (M+H).

Example 103 (27?)-2-{[(55'₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxyJphenyl}-6-(4-fluorophenyl)thieno[2_J3-//]pyrimidin-4-yl]oxy}-3-[2-(2fluoroethoxy)phenyl]propanoic acid

Using General procedure (la) and 2-fluoroethanol as the appropriate alcohol Example 103 was obtained. HRMS calculated for C37H37CIF2N4O5S: 722.2141; found 723.2244 (M+H).

Example 104 (2Æ)-2-{[(55_fi)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-(2methoxyethoxy)phenyl]propanoic acid

Using General procedure (la) and 2-methoxy éthanol as the appropriate alcohol Example 104 was obtained. I-IRMS calculated for CjsHjoClFN^S: 734.2341; found 735.2455 (M+H).

- 193 Example 105 (2R)-2-{ [(5S'a)-5-{3-chIoro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2.3-J]pyrimidin-4-yl]oxy}-3-{2-[2-(2methoxyethoxy)ethoxy]phenyl} propanoi c acid

Using General procedure (la) and 2-(2-methoxyethoxy)ethanol as the appropriate alcohol Example 105 was obtained. HRMS calculated for C40H44CIFN4O7S: 778.2603; found 390.1362 (M+2H).

Example 106 (2Æ)-2-{ [(5&)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/lpyrimidin-4-yl]oxy}-3-(2-{2-[2-(2methoxyethoxy)ethoxy]ethoxy} phenyl)propanoic acid

Using General procedure (la) and 2-[2-(2-methoxyethoxy)ethoxy]ethanol as the appropriate alcohol Example 106 was obtained. HRMS calculated for C42H48CIFN4O8S: 822.2865; found 412.1520 (M+2H).

Example 107 (2R)-2- {[(5&)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-</]pyrimidin-4-yl]oxy} -3-(2- {[2-(4methoxyphenyl)pyrimidÎn-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (Ib) and (4-methoxyphenyl)boronic acid as the appropriate boronic acid dérivative Example 107 was obtained. HRMS calculated for C4₇H44C1FN₆O₆S: 874.2716; found 438.1407 (M+2H).

Example 108 (2^)-2-{[(5.S'_e)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy] phenyl} -6-(4-fluorophenyl)thieno [2,3 -h]pyrim i d i n-4-yljoxy} -3 -(2- {[2-(6Tnethylpyridin-3-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (Ib) and (6-methyl-3-pyridyl)boronic acid as the appropriate boronic acid dérivative Example 108 was obtained. HRMS calculated for

C46H4₃C1FN₇O₅S·. 859.2719; found 430.6436 (M+2H).

-194Example 109 (27?)-2-{[(56'„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-[2-({2-l6(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl}methoxy)phenyl]propanoicacid

Using General procedure (lb) and [6-(trifluoroinethyl)-3-pyridyl]boiOnic acid as the appropriate boronic acid dérivative Example 109 was obtained. HRMS calculated for C46H40CIF4N7O5S: 913.2436; found 914.2521 (M+H).

Example 110 (2Λ)-2-{ [(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyI}-6-(4-fluoiOphenyl)thieno[2₅3-i7]pyrimidin-4-yl]oxy}-3-(2-{[2-(6chloropyridin-3-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (lb) and (6-chloro-3-pyridyl)boronic acid as the appropriate boronic acid dérivative Example 110 was obtained. HRMS calculated for C₄₅H4oC12FN₇0₅S: 879.2173; found 440.6161 (M+2H).

Example 111 (2/?)-2- {[(5S_c)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2₃3-i7]pyrÎmidin-4-y]]oxy}-3-(2-{[2-(6meÎhoxypyridin-3-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (lb) and (6-methoxy-3-pyridyl)boronic acid as the appropriate boronic acid dérivative Example 111 was obtained. HRMS calculated for C46H43CIFN7O6S: 875.2668; found 438.6403 (M+2H).

Example 112 (2/?)-2-{[(55„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-c/]pyrimidin-4-yl]oxy}-3-(2-{[2-(3methoxyphenyI)pyrimidin-4-yl]methoxy}phenyl)piOpanoic acid

Using General procedure (lb) and (3-methoxyphenyl)boronic acid as the appropriate boronic acid dérivative Example 112 was obtained. HRMS calculated for

C₄7H44C1FN₆O₆S: 874.2716; found 875.2836 (M+H).

B

-195 Exampie 113 (272)-2-( [(5SJ-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)eÎhoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrirnidin-4-yl]oxy}-3-(2“{[2-(2methylphenyl)pyrimidin-4-yl]methoxy} phenyl)propanoic acid

Using General procedure (Ib) and o-tolylhoronic acid as the appropriate boronic acid dérivative Example 113 was obtained. HRMS calculated for C47H44CIFN6O5S: 858.2766; found 430.1464 (M+2H).

Example 114 (2R)-2-{ [(5<%)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl)-6-(4-fluorophenyl)thieno[2,3-ù(Ipyrimidin-4-yl]oxy}-3-(2-{[2-(2fluorophenyl)pyrimidin-4-yi]methoxy}phenyl)propanoic acid

Using General procedure (Ib) and (2-fluorophenyl)boronic acid as the appropriate boronic acid dérivative Example 114 was obtained. HRMS calculated for C46H_4lCIF2N6O5S: 862.2516; found 432.1342 (M+2H).

Exampie 115 (2Æ)-2- {[(55_o)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}’6-(4-fluorophenyl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-(2-{[2-(2ethoxyphenyl)pyrimidin-4-yl]methoxy} phenyl)propanoic acid

Using General procedure (Ib) and (2-ethoxyphenyl)boronic acid as the appropriate boronic acid dérivative Example 115 was obtained. HRMS calculated for C39H38CIFN6O7S: 788.2195; found 395.1179 (M+2H).

Example 116 (2/?)-2~ {((55^)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{[2-(2methylpyridin-3-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (Ib) and (2-methyl-3-pyridyl)boronic acid as the appropriate boronic acid dérivative Example 116 was obtained. HRMS calculated for

C4ûH₄3C1FN₇O₅S: 859.2719; found 430.6429 (M+2H).

• 196Example 117 (2R)-2-([(5SJ-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yj|]oxy}-3-(2-{[2-(ftiran-2yl)pyrimidin-4-yl]methoxy}phenyl)piOpanoic acid

Using General procedure (Ib) and 2-furylboronic acid as the appropriate boronic acid dérivative Example 117 was obtained. IIRMS calculated for C44H4oClFN₆O_âS: 834.2403; found 418.1278 (M+2H).

Example 118 (2R)-2-{[(55_n)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl)-6-(4-fluorophenyl)thieno[2,3-iZ]pyrimidin-4-yl]oxy}-3-(2-{[2-(2methylpyridin-4-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (Ib) and (2-inethyl-4-pyridyl)boronic acid as the appropriate boronic acid dérivative Example 118 was obtained. HRMS calculated for C46H43CIFN7O5S: 859.2719; found 430.6409 (M+2H).

Example 119 (2R)-2-{ [(5S’_a)-5-{3-chloro-2-m.ethyl-4-[2-(4-methylpiperazin-I yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/Spyrimidin-4-yl]oxy}-3-(2-{[2-(2chloropyridin-4-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (Ib) and (2-chloro-4-pyridyl)boronic acid as the appropriate boronic acid dérivative Example 119 was obtained. HRMS calculated for C45H40CI2FN7O5S: 879.2173; found 440.6186 (M+2H).

Example 120 (2R)-2-{[(5S_o)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyi}-6-(4-fluorophenyl)thieno[2,3-iZ]pyrimidin-4-yl]oxy}-3-(2-{[2-(3methylpyridin-4 -yl)pyrimidin-4-yl] methoxy} phenyl)propanoic acid

Using General procedure (Ib) and (3-methyl-4-pyridyl)boronic acid as the appropriate boronic acid dérivative Example 120 was obtained. HRMS calculated for

C46H43CIFN7O5S: 859.2719; found 860.2808 (M+H).

e

-197 Example 121 (2Æ)-2-{[(55J-5-(3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{[2-(2methylthiophen-3-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (Ib) and (2-methyl-3-thienyl)boronic acid as the appropriate boronic acid dérivative Example 121 was obtained. HRMS calculated for C₄₅H4₂C1FN₆O5S₂: 864.2331; found 433.1239 (M+2H).

Example 122 (2R)-2-{ [(55_σ)-5- (3-chloiO-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-iZ}pyrimidin-4-yl]oxy}-3-(2-{[2-(5methylpyridin-3-yl)pyrimidin-4-yl]niethoxy}phenyl)propanoic acid

Using General procedure (Ib) and (5-methyl-3-pyridyl)boronic acid as the appropriate boronic acid dérivative Example 122 was obtained. HRMS calculated for C^HzbCIFNtOsS: 859.2719; found 430.6450 (M+2H).

Example 123 (2R)-2- {[(55_σ)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl} -6-(4-fluorophenyI)thieno[2,3-<Z]pyrimidin-4-yl]oxy} -3-(2-( [2-(4methylpyridin-3-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (Ib) and (4-methyl-3-pyridyl)boronic acid as the appropriate boronic acid dérivative Example 123 was obtained. HRMS calculated for C₄6H₄jC1FN₇O₅S: 859.2719; found 430.6434 (M+2H).

Example 124 (2Λ)-2- {[(5SJ-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-f!uorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{[2-(4methyithiophen-3-yl)pyrimidm-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (1b) and (4-methyl-3-thienyl)boronic acid as the appropriate boronic acid dérivative Example 124 was obtained. HRMS calculated for

C₄₅H₄₂C1FN₆O₅S₂: 864.2331 ; found 433.1256 (M+2H).

-198Example 125 (2À)-2-{[(5SJ-5-{3-chloro-2-methyl-4-[2-(4-rnethylpiperazin-lyl)ethoxy]pheny]}-6-(4-fluorophenyI)thieno|2,3-i/Jpyrijnidin-4-yl]oxy}-3-[2-(lH-pyrazol5 -ylmethoxy)phenyl]propanoi c acid

Step A:

1.058 g ethyl (27?)-2-[(5iS'_iï)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 8a) (1.5 mmol), 982 mg [l-(4-methoxybenzyl)17f-pyrazol-5-yl]methanol (Préparation 9dk) (4.5 mmol) and 1.18 g PPh₃ (4.5 mmol) were dissolved in 30 mL dry toluene, then 1.036 g di/er/butyl azodicarboxylate (4.5 mmol) was added. The mixture was stirred at 50°C under nitrogen untii no further conversion was observed. The volatiles were evaporated under reduced pressure, and the crude intermediate was purified via flash chromatography using dichloromethane and methanol as eluents.

Step B:

226 mg (0.25 mmol) from the obtained intermediate was dissolved in 13 mL TFA and it was stirred at 100°C for 1 hour. The volatiles were evaporated under reduced pressure, then the residue was diluted with DCM, washed with saturated aqueous NaHCO₃ solution. The organic layer was dried over Na₂SO4, filtered and concentrated under reduced pressure.

Step C:

The obtained crude intermediate was dissolved in 6 mL dioxane-water 1:1 and 105 mg LiOH x H₂O (2.5 mmol) was added. The mixture was stirred at room température untii no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM, dried over Na₂SÛ4, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to give Example 125. HRMS calculated for C₃₉H38C1FN₆O5S: 756.2297; found 757.2303 (M+H).

General procedure (lia) ♦

-199StepA:

eq. ethyl (2R)-2-[(55’_<,)-5-[3-chloro-4-(2-dimethylaminoethyloxy)-2-methyl-phenyl]-6-(4fluoiOphenyl)thieno[2,3-i7]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)piOpanoate (Préparation 8b), 2 eq. of the appropriate alcohol and 2 eq. triphenyl phosphine were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. di/ertbutyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents.

Step B:

The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq LiOH x H2O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na₂SO4, fïltered and concentrated under reduced pressure. The crade product was purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents.

General procedure (Ilb)

Step A:

eq. ethyl (2R)-2-[(5S_a)-5-[3-chloro-4-(2-dimethylaminoethyloxy)-2-methyl-phenyl]-6-(4fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-[2-[(2-methylsulfanylpyrimidin-4yl)methoxy]phenyl]propanoate (Préparation 10b), 3.0 eq. of the appropriate boronic acid dérivative and 3.0 eq. copper(I) thiophenecarboxylate were dissolved in dry THF (0.1 M for Préparation 10b), then 0.15 eq. Pd(PPh3)4 was added. The mixture was stirred at 70°C under nitrogen until no further conversion was observed. Then it was concentrated under reduced pressure and the crude intermediate was purified via flash chromatography using dichloromethane and methanol as eluents.

Step B:

-200The obtained intermediate was dissolved in dioxane-water 1:1 (10 ml/mmol) and 10 eq LiOH x H₂O was added. The mixture was stirred at until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous NH₄HCÛ3 solution and MeCN as eluents.

Example 126 (2R)-2-{ [(56),)-5- {3-chloro-4- [2-(dimethylamino)ethoxy] -2-methylphenyl} 6-(4-fluoiOphenyl)thieno[2,3-i7}pyrimidin-4-yl]oxy}-3-{2-[(2Æ)-tetrahydiOfuran-2yhnethoxy]phenyl }propanoic acid

Using General procedure (lia) and [(27î)-tetraliydrofuran-2-yl]methanol as the appropriate alcohol Example 126 was obtained. HRMS calculated for C37H37CIFN3O6S: 705.2076; found 706.2163 (M+H).

Example 127 (2/?)-2-{[(50'_a)-5-{3-chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}6-(4-fluoiOphenyl)thieno[2,3-^pyrimidin-4-yl]oxy}-3-[2-(2,2,2trifluoroethoxy)phenyl]propanoic acid

Step À:

195 mg ethyl (2JÎ)-2-[(5₎S'_a)-5-[3-chloiO-4-(2-dimethylaminoethyloxy)-2-methyl-phenyl]-6(4-fluorophenyl)thieno[2,3-£(]pyi'imidin-4-yl]oxy-3-(2-hydroxyphenyl)propanoate (Préparation 8b) (0.3 mmol) and 138 mg K₂CÛ3 (1.0 mmol) were dissolved in 2 mL DMF, then 232 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.0 mmol) was added. The mixture was stirred at room température under nitrogen until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SÛ4, filtered and concentrated under reduced pressure.

Stet) B:

The obtained intermediate was dissolved in 8 mL dioxane-water 1:1 and 150 mg LiOH x

H₂O (3.57 mmol) was added. The mixture was stirred at room température until no further

S

-201 conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na2SO₄, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain 5 Example 127. HRMS calculated for C34H30CIF4N3O5S: 703.1531; found 704.1634 (M+H).

Example 128 (2R)-2- {[(5S_n)-5 - { 3 -chloro-4- [2-(dimethylamino)ethoxy]-2-methylphenyl} 6-(4-fluoiOphenyl)thieno[2,3-<f]pyrimidin-4-yl]oxy}-3-(2-{[2-(pyridin-4-yl)pyrimidin-4yl]methoxy}phenyl)propanoic acid

Using General procedure (lia) and [2-(4-pyridyl)pyrimidin-4-yl]methanol (Préparation 9bs) as the approprîate alcohol Example 128 was obtained. HRMS calculated for C₄2H36C1FN₆O₅S: 790.2140; found 396.1147 (M+2H).

Example 129 (27?)-2-{[(5S_a)-5-{3“Chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}“ 6-(4-fluorophenyl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-(2-{[2-(morpholin-4-yl)pyrimidin4-yl]methoxy)phenyl)propanoic acid

Using General procedure (lia) and (2-(morpholin-4-yl)pyrimidin-4-yl)methanoI 20 (Préparation 9ar) as the approprîate alcohol Example 129 was obtained. HRMS calculated for C₄₁H4oClFN_â0₆S: 798.2403; found 799.2458 (M+H).

Example 130 (2j'?)-2-{[(5_lS'_n)-5-{3-chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}6-(4-fluorophenyl)thieno[2,3-rf]pyrimidin-4-yl]oxy]-3-{2-[(2-ethoxypyrimidin-425 yl)methoxy]phenyl}propanoic acid

Using General procedure (Ha) and (2-ethoxypyrimidin-4-yl)methanol (Préparation 9ad) as the approprîate alcohol Example 130 was obtained. HRMS calculated for

C39H37CIFN5O6S: 757.2137; found 758.2212 (M+H).

e

-202Example 131 (2R)-2- {[(55_a)-5- {3-chloiO-4-[2-(dimcthylamino)cthoxy]-2-mcthylphenyl}6-(4-fluorophenyl)thieno[2,3-i/Jpyriniidin-4-yl]oxy}-3-(2-{[2-(2,2,2trifluoroethoxy)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (lia) and [2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]methanol (Préparation 9ai) as the appropriate alcohol Example 131 was obtained. HRMS calculated for C39H34CIF4N5O6S: 811.1854; found 812.1956 (M+H).

Example 132 (2IÎ)-2-{[(55'_iï)-5-{3-chloiO-4-[2-(dimethylainino)ethoxy]-2-methylphenyl}6-(4-fluorophenyl)thicno[2,3-ùf)pyrimidin-4-yl]oxy}-3-(2-{[1-(2,2,2-trifluoroethyl)-1 Hpyrazol-5-yl]methoxy)phenyl)propanoic acid

Using General procedure (lia) and [l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl]methanol (Préparation 9du) as the appropriate alcohol Example 132 was obtained. HRMS calculated for Css^CW^OsS: 783.1905; found 784.1969 (M+H).

Example 133 (2R)-3- (2-[(l -buty I-l H-pyrazol-5-yl)methoxy]phenyl} -2- {[(5S_a)-5- {3chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}-6-(4-fluorophenyl)thieno[2,3iZjpy rimidin-4-y l]oxy} propanoic acid

Using General procedure (lia) and (l-butyl-lH-pyrazol-5-yl)methanol (Préparation 9dd) as the appropriate alcohol Example 133 was obtained. HRMS calculated for C40H41CIFN5O5S: 757.2501; found 758.2596 (M+H).

Example 134 (27?)-2-{[(5S_a)-5-{3-chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}6“(4-fluorophenyl)thieno[2,3-iZ|pyriiîiidin-4-yl]oxy}-3“[2-(pyrazin-2ylmethoxy)phenyl]propanoic acid

Using General procedure (lia) and pyrazin-2-yhnethanol as the appropriate alcohol

Example 134 was obtained. HRMS calculated for C37H33CIFN5O5S: 713.1875; found

714.1931 (M+H).

203 Example 135 (2Æ)-2-{[(j7^)-5-{3-chloro-4-[2-(dimcthylamino)ethoxy]-2-methylphenyl)6-(4-fluorophenyl)tliieno[2,3-i/]pyiiinidiii-4-yl]oxy} -3 -(2- {[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)piOpanoic acid

Using General procedure (Ilb) and (2-methoxyphenyl)boronic acid as the appropriate boronic acid Example 135 was obtained. HRMS calculated for C44H39CIFN5O6S: 819.2294; found 410.6206 (M+2H).

Example 136 (2R)-2-{[(5S„)-5-{3-chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}10 6-(4-fluorophenyl)thieno[2,3“i(|pyrimidin-4-yl]oxy}-3-(2-{[2-(2-meîhylpyridiri-4yl)pyrimidin-4-yl]methoxy} phenyl)propanoic acid

Using General procedure (Ilb) and (2-methyl-4-pyridy])boronic acid as the appropriate boronic acid Example 136 was obtained. HRMS calculated for C43H38CIFN6O5S: 15 804.2297; found 403.1234 (M+2H).

Example 137 (27î)-2-{[(55'_a)-5-{3-chloro-4-[2-(dimelhylatnino)ethoxy]-2-methylphenyl}6-(4-fluorophenyl)thieno[2,3-i/Jpyrimidin-4-yl]oxy}-3-(2- {[2-(3-methylpyridin-4yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (Ilb) and (3-methyl-4-pyridyl)boronic acid as the appropriate boronic acid Example 137 was obtained. HRMS calculated for C43H38CIFN6O5S: 804.2297; found 403.1237 (M+2H).

Example 138 (2/?)-2-{[(5S„)-5-{3-chloro-4-[2-(dimethylarnino)ethoxy]-2-methylphenyl}6-(4-fluorophenyl)thieno f2,3-i/]pyrimidin-4-yl]oxy )-3-(2-{[2-(4-methylpyridin-3yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (Ilb) and (4-methyl-3-pyridyl)boronic acid as the appropriate boronic acid Example 138 was obtained. HRMS calculated for C43H38CIFN6O5S: 804.2297; found 403.1220 (M+2H).

-204General procedure (ΠΙα)

l.O eq. of ethyl (2R)-2-[(5S_n)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(4fluorophenyl)thieno [2,3 -<7] py rimidin-4-yl] oxy-3 - [2 -(pyrazi n-2ylmethoxy)phenyl]propanoate (Préparation 6b), 2.0 eq. of the appropriate alcohol and 2.0 eq. triphenylphosphine were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. difer/butyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents. The obtained intermediate was dissolved in dioxane-water l :l (10 mL/mmol) and 10 eq LiOH * H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na2SO₄, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NfL^HCOs solution and MeCN as eluents.

Exampie 139 (22?)-2-{[(55_o)-5-(3-chloro-2-methyl-4-{[(3Â)-l-methylpyrrolidin-3yl]methoxy}phenyl)-6-(4-fluorophenyl)thieno[2,3-r/]pyrimidin-4-yl]oxy}-3-[2-(pyrazin-2ylmethoxy)phenyl]propanoic acid

Using General procedure (Ilia) and [(3Æ)-l-methyIpyrrolidin-3-yl]methanol as the appropriate alcohol Example 139 was obtained. HRMS calculated for C39H35CIFN5O5S: 739.2031; found 740.2136 (M+H).

Example 140 (2R)-2-{ [(5S_a)-5-(3-chloro-2-methyl-4- {[(35)-1 -methylpynOlidin-3yl]methoxy}phenyl)-6-(4-fluoiOphenyl)thieno[2,3-if]pyrimidin-4-yl]oxy}-3-[2-(pyrazin-2ylmethoxy)phenyl]propanoic acid

Using General procedure (Ilia) and [(35)-l-methylpyrrolidin-3-yl]methanol as the appropriate alcohol Example 140 was obtained. HRMS calculated for C39H35CIFN5O5S:

739.2031; found 740.2095 (M+H).

W

-205Example 141 (27?)-2-{[(5S_e)-5-{3-chloro-2-methyl-4-[((35 or 7?)-l-methylpiperidin-3yl)oxy]phenyl}-6-(4-fluoiOphenyI)thieno[2,3-i/]pyrÎmidin-4-yl]oxy}-3-[2-(pyrazin~2ylmethoxy)phenyl]propanoic acid and

Exampie 142 (2/?)-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[((3Jî or S)-1-methylpiperidin-3yl)oxy]phenyJ}-6-(4-fluoiOphenyl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-[2-(pyrazin-2ylmethoxy)phenyl]propanoic acid and

Example 143 (2Æ)-2-([(55_a)-5-{3-chloro-2-methyl-4-[(l -methylpyrrolidin-2yl)methoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-[2-(pyrazin-2ylmethoxy)phenyl]propanoic acid (mixture of diastereoisomers)

0.470 g ethyl (2Æ)-2-[(55a)-5-(3-chloro-4-hydroxy-2methyI-phenyl)-6-(4fluorophenyl)thieno[2,3-t/]pyrimidin-4-yl]oxy-3-[2-(pyrazin-2ylmethoxy)phenyl]propanoate (Préparation 6b) (0.7 mmol), 0.330 g l-methylpipcridin-3ol (2.0 mmol), and 0.524 g triphenyl phosphine (2.0 mmol) were dissolved in 15 mL dry toluene, then 0.461 g diter/butyl azodicarboxylate (2.0 mmol) was added. The mixture was stirred at 50°C under nitrogen. During the reaction rearrangement of the methylpiperidine moiety was also observed. When no further conversion was observed the volatiles were evaporated under reduced pressure, and the constitutional isomers were separated via flash chromatography using DCM and MeOH as eluents. The mixture of compounds eluting earlier were the precursors of Example 141 and 142, while the mixture of compounds eluting later were the precursors of Example 143. The obtained precursor dérivatives were separately dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq LiOH x H₂O was added. The mixtures were stirred at room température until no further conversion was observed. Then they were individually diluted with brine, neutralized with 2 M HCl, extracted with DCM, The combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure and purified separately via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 141 [HRMS calculated for C39H35CIFN5O5S: 739.2031; found 740.2119 (M+H)], Example 142 [HRMS calculated for C39H35CIFN5O5S: 739.2031; found

I

-206740.2088 (M+H)], and Example 143 [HRMS calculated for C₃9H₃₅C1FN₅O₅S: 739.2031; found 740.2101 and 740.2078 (M+H)].

Example 144 (2R)-2-{[(5S'₍₇)-5-{3-chloro-2-methyl-4-[(l-methylazepan-3yl)methoxy]phenyl}-6-(4-f!uoiOphenyl)thieno[2,3-J]pyrimidin“4-yl]oxy}-3-[2-(pyrazin-2ylmethoxy)phenyl]propanoic acid (mixture of diastereoisomeis)

Using General procedure (Ilia) and 2-(l-methyl-2-piperidyl)ethanol as the appropriate alcohol in the course of the reaction the ring-expansion of the piperidyl moiety was observed, thus Example 144 was obtained. HRMS calculated for C41H39CIFN5O5S: 767.2344; found 768.2399 and 768.2398 (M+H).

Example 145 (2R)-2· {[(55„)-5 - {3 -chloro-2 -methy 1-4 - [( 1 -methy lpyrrolidin-3 yl)methoxy] phenyl} -6-(4-fluorophenyl)thieno [2,3-d] py rimid i n-4-y 1] oxy} -3 - [2-(pyrazin-2ylmethoxy)phenyl]propanoic acid (mixture of diastereoisomeis)

Using General procedure (Ilia) and (l-methylpyrrolidin-3-yl)methanol as the appropriate alcohol Example 145 was obtained. HRMS calculated for C39H35CIFN5O5S: 739.2031;

found 740.2081 (M+H).

Example 146 (2R)-2-{ [(5^,)-5-{3-chloro-2-methyl-4-[3-(l-methylpyrrolidin-2yl)piOpoxy]phcnyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}“3-[2-(pyrazin-2ylmethoxy)phenyl]propanoîc acid (mixture of diastereoisomeis)

Using General procedure (Ilia) and 2-(l-methyl-3-piperidyl)ethanol as the appropriate alcohol in the course of the reaction the ring-contraction of the piperidyl moiety was observed, thus Example 146 was obtained. HRMS calculated for C41H39CIFN5O5S: 767.2344; found 768.2454 (M+H).

Example 147 (2R)-2-{ [(5S^, _<r)-5-{3-chloro-4-[3-(dimethylamino)propoxy]-2methylphenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-(pyrazin-2ylmethoxy)phenyl]propanoic acid «

-207Using General procedure (Ilia) and 3-(dimethylamino)propan-l-ol as the appropriate alcohol Example 147 was obtained. HRMS calculated for C38H35CIFN5O5S: 727.2031; found 728.2085 (M+H).

Example 148 (2Æ)-2-{[(5S_rt)-5-{3-chloro-2-methyl-4-[2-(morphoIin-4-yl)ethoxy]phenyl}6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-[2-(pyrazin-2ylmethoxy)phenyl]propanoic acid

Using General procedure (Ilia) and 2-(morpholin-4-yl)ethanol as the appropriate alcohol Example 148 was obtained. HRMS calculated for C39H35CIFN5O6S: 755.1981; found 756.2052 (M+H).

General procedure (IVa) ¹⁵ Sien A:

eq. ethyl (2R)-2-[(5S_n)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(5-fluoro-2-furyl)thieno[2,3-</]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 8c), 2 eq. of the appropriate alcohol and 2 eq. triphenyl phosphine were dissolved in dry toluene (0.2 M for the phénol), then 2 eq.

di/er/butyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents.

Step B:

The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq LiOH x H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na₂SO4, filtered and 30 concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

/>

-208Example 149 (2Æ)-2-{ [(5^)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(5-fluoiOfuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

IJsing General procedure (IVa) and méthanol as the appropriate alcohol Example 149 was obtained. HRMS calculated for C34H34CIFN.AS: 680.1872; found 681.1947 (M+H).

Example 150 (2Æ)-2-{[(5S’_(y)-5-{3ChloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(5-fluoiOfuran-2-yl)thieno[2,3-c/]pyrimidin-4-yl]oxy}-3-{2-[(2/?)tetrahydrofuran-2-ylmethoxy]phenyl} propanoi c acid

Using General procedure (IVa) and [(27?)-ietrahydrofuran-2-yl]methanol as the appropriate alcohol Example 150 was obtained. HRMS calculated for C_3SH4oClFN407S: 750.2290; found 751.2375 (M+H).

Example 151 (2R)-2-{[(5S_a)-5-{3-chloro-2-inethyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-<i]pyrimidÎn-4-yl]oxy}-3-{2-[2(methylamino)-2-oxoethoxy]phenyl}piOpanoic acid

Using General procedure (IVa) and 2-hydroxy-V-methyl-acetamide as the appropriate alcohol Example 151 was obtained. HRMS calculated for C₃₆H₃7C1FN5O7S: 737.2086; found 738.2195 (M+H).

Example 152 (2Â)-2-{[(5S₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(5-iluoiOfuran-2-yl)thieno[2_s3-i7]pyrimidin-4-yl]oxy}-3-{2-[2(cyclopentylamino)-2-oxoethoxy]phenyl}propanoic acid

Using General procedure (IVa) and jV-cyclopentyl-2-hydroxy-acetamide as the appropriate alcohol Example 152 was obtained. HRMS calculated for C40I-I43CIFN5O7S: 791.2556;

found 792.2658 (M+H).

-209Example 153 (2/?)-3-{2-[2-(benzylamino)-2-oxoethoxy]phenyl}-2-{[(5S_e)-5-{3-chloro-2methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl} -6-(5-fluorofuran-2-yl)thieno[2,3d] py rim idin-4-yl] oxy Jpropanoic acid

Using General procedure (IVa) and N-benzyl-2-hydroxy-acetamide as the appropriate alcohol Example 153 was obtained. HRMS calculated for C42I-I41CIFN5O7S: 813.2399; found 814.2492 (M+H).

Example 154 (2Æ)-2-{[(55J-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l 10 yl)ethoxy]phenyl}-6“(5-fluorofiiran-2-yl)thieno[2,3-i(Jpyrimidin“4-yl]oxy}-3-{2-[2-oxo-2(propylamino)ethoxy]phenyl}propanoic acid

Using General procedure (IVa) and 2-hydroxy-N-propyl-acetamide as the appropriate alcohol Example 154 was obtained. HRMS calculated for C38H41CIFN5O7S: 765.2399;

found 766.2459 (M+H).

Example 155 (2R)-2-{ [(5S_fl)-5- {3-chloro-2-methyl-4- [2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(5-fluoroftiran-2-yl)thieno[2₎3-i/]pyrimidin-4-yl]oxy}-3-(2-{2-oxo-2[(2-phenylethyl)amino]ethoxy}phenyl)propanoic acid

Using General procedure (IVa) and 2-hydroxy-N-2-phenylethyl-acetamide as the appropriate alcohol Example 155 was obtained. IIRMS calculated for C43H43CIFN5O7S: 827.2556; found 828.2580 (M+H).

Example 156 (2R)-3-(2-[2-(butylamino)-2-oxoethoxy]phenyl}-2-{[(5S„)-5-{3-chloro-2· methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(5fiuoiOÎuran-2-yl)thÎeno[2,3z7]pyrimidin-4-yl]oxy}propanoic acid

Using General procedure (IVa) and V-butyl-2-hydroxy-acetamide as the appropriate alcohol Example 156 was obtained. HRMS calculated for C39H43CIFN5O7S: 779.2556;

found 780.2614 (M+H).

-210Example 157 (2Λ)-2-{ [(55^)-5-( 3-chloro-2-methy l-4-[2-(4-methy Ipiperazin-1yl)ethoxy]phenyl}-6-(5-fluoiOfuran-2-yl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3“(2-{2-[(2methoxyethyl)amino]-2-oxoethoxy}phenyl)propanoic acid

Using General procedure (IVa) and 2-hydroxy-À^r-(2-methoxyethyl)acetamide as the appropriate alcohol Example 157 was obtained. HRMS calculated for CagHuClFNsOgS: 781.2348; found 782.2478 (M+H).

Example 158 (2Æ)-2-{[(5S'_(J)-5-{3-chloro-2-methyL4“[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(5-fluoiOfuran-2-yl)thieno[2,3-£f|pyrimidin-4-yl]oxy}-3-[2-(2,2_J2trifluoroethoxy)phenyl]propanoic acid

Step A:

209 mg ethyl (27?)-2-[(5₁S^, _n)-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(4-fhiorophenyl)thieno[2,3-c(|pyrimidin-4~yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 8c) (0.3 mmol) and 138 mg K₂CO₃ (1.0 mmol) were dissolved in 2 mL DMF, then 232 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.0 mmol) was added. The mixture was stirred at room température under nitrogen until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na₂SÛ4, filtered and concentrated under reduced pressure.

Step B:

The obtained intermediate was dissolved in 8 mL dioxane-water 1:1 and 150 mg LiOH x H₂O (3.57 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 158. HRMS calculated for C35H33CIF4N4O6S: 748.1745; found 749.1819 (M+H).

-211Example 159 (2R)-2- {[(55J-5- { 3 -chloro-2-methyl-4-[2-(4-rnethylpiperazin-1 yl)ethoxy]pheny!}-6-(5-fluorofuran-2-yl)thieno[2,3“<^pyrimidin-4-yl]oxy}-3-(2-{[4(trifluoroniethyl)pyridin-2-yl]inethoxy} phenyljpropanoic acid

Using General procedure (IVa) and [4-(trifluoromethyl)-2-pyridyl]methanol as the appropriate alcohol Example 159 was obtained. I-IRMS calculated for C40H36CIF4N5O6S: 825.2011; found 413.6085 (M+2H).

Example 160 (22?)-2-{[(55_a)-5-{3-chloro-2-niethyl-4-[2-(4-niethylpiperazin-l10 yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thienof2,3-iZ]pyriniidin-4-yl]oxy}-3-{2-[(2methoxy-6-methylpyiimidin-4-yl)niethoxy]phenyl}propanoic acid

Using General procedure (IVa) and (2-methoxy-6-methyl-pyrimidin-4-yl)methanol (Préparation 9cf) as the appropriate alcohol Example 160 was obtained, HRMS 15 calculated for C4oH4oC1FN₆0₇S: 802.2352; found 402.1241 (M+2H).

Example .161 (2À)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-cflpyrimidin-4-yI]oxy}-3-{2-[(6methylpyrimidin-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (IVa) and (6-methylpyrimidin-4-yl)methanol as the appropriate alcohol Example 161 was obtained. HRMS calculated for C39II38CIFN&O6S: 772.2246; found 387.1188 (M+2H).

Example 162 (27?)-2-{[(55«)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-i7Jpyrimidin-4-yl]oxy}-3-{2-[(6methoxypyrimidin-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (IVa) and (6-methoxypyrimidin-4-yl)methanol (Préparation

9ce) as the appropriate alcohol Example 162 was obtained. HRMS calculated for

C3₉H3_gClFN₆O₇S: 788.2195; found 395.1165 (M+2H).

λ

-212Exampie 163 (27?)-2-{ [(5^)-5-{3-chloro~2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxyJphenyl}-6-(5“fluoiOfuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(5fluoropyridin-2-yl)methoxy]phenyl}propanoicacid

Using General procedure (IVa) and (5-fluoro-2-pyridyl)methanol as the appropriate alcohol Exampie 163 was obtained. HRMS calculated for Cj^sC^NsOeS: 775.2043; found 776.2161 (M+H).

Example 164 (2À)-2- {[(5S„)-5-{3-chloro-2-methyl-4-[2-(4-rnethylpiperazin-l 10 yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-i/|pyiimidin-4-yl]oxy}-3-(2-{[6(trifluoroinethyl)pyridin-2-yl]inethoxy}phenyl)piOpanoic acid

Using General procedure (IVa) and [6-(trifluoromethyl)-2-pyridyl]methanol as the appropriate alcohol Example 164 was obtained. HRMS calculated for C40H36CIF4N5O6S:

825.2011; found 826.2100 (M+H).

Exampie 165 (2R)-2-{[(5Æ_o)-5- {3 -chloro-2-methy 1-4- [2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-iZ|pyrimidin-4-yl]oxy}-3-[2-(pyridÎn2-ylmethoxy)phenyl]propanoic acid and

Example 166 (2R)-2-{[(5S^, _a)-5-{3-chloro-2-methyl-4-[2-(4-methylpipcrazin-lyl)ethoxy]phenyl}-6-(5-nuorofuran-2-yl)thieno[2,3-rZ]pyriinidin-4-yl]oxy}-3-[2-(pyridin2-ylmethoxy)phenyl]piOpanoic acid

Step A:

591 mg 4-chloro-5-[3-chloro-2-methyl“4-[2-(4-methylpiperazin-l -yl)ethoxy]phenyl]-6iodo-thieno[2,3-i/]pyrimidine (Préparation 13) (1.05 mmol), 915 mg ethyl (2Æ)-2hydroxy-3-[2-(2-pyridylmethoxy)phenyl]piopanoate (Préparation 3bn) (1.045 mmol) and

977 mg CS2CO3 (3.0 mmol) were placed in a flask. 10 mL /er/-butanol was added and the mixture was stirred at 60°C until no further conversion was observed. Then it was diluted with brine and extracted with dichloromethane. The combined organic phases were dried over Na₂SO₄, filtered and concentrated under reduced pressure and purified via préparative e

-213 reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain ethyl (2Æ)-2-[5-[3-chloro-2-methyI-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-iodo-thieno[2,3-i/Jpyrimidin-4-yI]oxy-3-[2-(2pyridylmethoxy)phenyl]propanoate as a mixture of diastereoisomers. MS: (M+H) - 828.0.

Step B:

518 mg ethyl (2R)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]6-iodo-thieno[2,3-i(]pyrimidin-4-yl]oxy-3-[2-(2-pyridylmethoxy)phenyl]propanoate (0.625 mmol) and 565 mg 2-(5-fluoro-2-furyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.66 mmol) were dissolved in 5 ml 1,4-dioxane, then 407 mg CS2CO3 (1.25 mmol) dissolved in 1 mL water was added. Then 46 mg PdCl₂ x dppf (0.0625 mmol)was added. The mixture was heated at 100°C via microwave irradiation until no further conversion was observed. Then it was diluted with brine, extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents.

Step C:

The obtained intermediate was dissolved in 10 mL dioxane-water 1:1 (10 mL/mmol) and 200 mg LiOH χ H2O (4.77 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, ncutralized with 2 M HCl, extracted with DCM, dried over Na2SO4, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents. The diastereoisomer eluting earlier was collected as Example 165. HRMS calculated for C39H37CIFN5O6S: 757.2137; found 379.6156 (M+2H). The diastereoisomer eluting later was collected as Example 166. HRMS calculated for C39H37CIFN5O6S: 757.2137; found 379.6159 (M+2H).

Exemple 167 (27?)-2- {[(55„)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-l y 1 )ethoxy] phenyl )-6-(5 -fluorofuran-2-yl)thieno [2,3-</Jpyrimidin-4 -y l]oxy} -3 -(2- ( [2(triiluoromethyl)pyridin-4-yl]methoxy)phenyl)propanoicacid

- 214 Using General procedure (IVa) and [2-(lriiluoromethyl)-4-pyridyl]methanol as the appropriate alcohol Example 167 was obtained. HRMS calculated for C40H36CIF4N5O6S: 825.2011; found 826.2124 (M+H).

Example 168 (2R)-2-{[(5S/)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-i(}pyrinüdin-4-yl]oxy}-3-{2-[(2methoxypyridin-4-yl)methoxy]phenyl }propanoi c acid

Using General procedure (IVa) and (2-methoxy-4-pyridyl)methanol as the appropriate 10 alcohol Example 168 was obtained. HRMS calculated for C4QH39CIFN5O7S: 787.2243;

found 394.6210 (M+2H).

Example 169 (2Λ)-2- {[(55/)-5- {3 -chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-J}pyrimidin-4-yl]oxy}-3-(2-{[215 (trifluoiOmethyI)pyrimidin-4-yI]methoxy}phenyl)piOpanoic acid

Using General procedure (IVa) and [2-(trifluoromethyl)pyrimidin-4-yl]methanol (Préparation 9bj) as the appropriate alcohol Example 169 was obtained. HRMS calculated for C39H35CIF4N6O6S: 826.1963; found 827.2059 (M+H).

Example 170 (27?)-2- {[(50/)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl} -6-(5-fluoiOfuran-2-yl)thieno[2,3-</]pyiimidin-4-yl]oxy} -3- {2-[(2cyclopropylpyrimidin-4-yl)niethoxy]phenyl}propanoic acid

Using General procedure (IVa) and (2-cyclopropylpyrimidin-4-yl)methanol (Préparation 9be) as the appropriate alcohol Example 170 was obtained. HRMS calculated for C4iH4oClFN₆0₆S.· 798.2403; found 400.1265 (M+2H).

Example 171 (2R)-2-{[(55/)-5 - {3 -chloiO-2-methyl-4-[2-(4-methylpiperazin-1 30 yl)ethoxy]phenyl}-6-(5-fiuoiOfuran-2-yl)thieno[2,3-c7]pyrimidin-4-yl]oxy}-3-(2-{[2(thiophen-2-yI)pyrimidin-4-yl]methoxy}phenyl)piOpanoic acid

-2I5Using General procedure (IVa) and [2-(2-thienyl)pyrimidin-4-yl]methanol (Préparation 9bv) as the appropriate alcohol Example 171 was obtained. HRMS calculated for C₄₂H₃₈C1FN₆O₆S₂: 840.1967; found 421.1070 (M+2H).

Example 172 (27?)-2-{ [(55,,)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phcnyl }-6-(5-fluorofuran-2-yl)thicno[2,3-J]pyriinidin-4-yl]oxy} -3-(2- {[2(pyridin-4-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (IVa) and [2-(4-pyridyl)pyrimidin-4-yl]methanol (Préparation 9bs) as the appropriate alcohol Example 172 was obtained. HRMS calculated for C₄₃H₃9C1FN₇O₆S: 835.2355; found 418.6246 (M+2H).

Example 173 (2R)-2-{ [(55_n)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phcnyl}-6-(5-fluorofuran-2-yl)thieno[2,3-i(|pyrimidin-4-yl]oxy}-3-(2-{[2(thiophen-3-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (IVa) and [2-(3-thienyl)pyriinidin-4-yl]inethanol (Préparation 9bu) as the appropriate alcohol Example 173 was obtained. HRMS calculated for C₄₂H₃sC1FN₆O₆S₂: 840.1967; found 841.2059 (M+H),

Example 174 (2R)-2-{ [(55„)-5- [3-chloro-2-methyl-4-[2-(4-methylpipcrazin-1 yl)ethoxy]phenyl)-6-(5-fluorofuran-2-yl)thieno[2,3-i(|pyrimidin-4-yl]oxy}-3-(2-{[2-(2methoxyethyl)pyrimidin-4-yl]methoxy) phenyl)propanoic acid

Using General procedure (IVa) and [2-(2-methoxyethyl)pyrimidin-4-yl]methanol (Préparation 9bi) as tire appropriate alcohol Exampie 174 was obtained. HRMS calculated for QiH^ClW^S: 816.2508; found 409.1335 (M+2H).

Example 175 (2R)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-<7jpyrimidin-4-yl]oxy}-3-(2-{[2(morpholin-4-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

-2I6Using General procedure (IVa) and (2-(morpholin-4-yl)pyrimidin-4-yl)methanol (Préparation 9ar) as the appropriate alcohol Example 175 was obtained. HRMS calculated for C₄₂H₄₃C1FN₇O₇S: 843.2617; found 422.6360 (M+2H).

Example 176 (27()-2-(((.5.9,,)-5- (3-chloiO-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl)-6-(5-fhiorofuran-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-y l)methoxy]phenyl} propanoic acid

Using General procedure (IVa) and (2-methoxypyrimidin-4-yl)methanol as the appropriate alcohol Example 176 was obtained. HRMS calculated for C^HssNôChFSCl: 788.2195; found 789.2289 (M+H).

Example 177 (2R)-2- {[(5S„)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(2ethoxypyri mid in-4 -yl)methoxy]phenyl} propanoic acid

Using General procedure (IVa) and (2-ethoxypyrimidin-4-yl)methanol (Préparation 9ad) as the appropriate alcohol Example 177 was obtained. HRMS calculated for C₄oH4₀C1FN₆0₇S: 802.2352; found 402.1255 (M+2H).

Example 178 (2R)-2-{ [(5S_a)-5-{ 3 -chloro-2-niethyl-4-[2-(4-methy lpiperazin-1 yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-i/]pyriinidin-4-yl]oxy}-3-(2-{[2(2,2,2-trifluoiOethoxy)pyrimidin-4-yl]methoxy}phenyl)piOpanoicacid

Using General procedure (IVa) and [2-(2,2,2-trifluoroethoxy)pyriinidin-4-yl]inethanol (Préparation 9ai) as the appropriate alcohol Example 178 was obtained. HRMS calculated for C₄₀H₃₇ClF₄N₆O₇S: 856.2069; found 857.2110 (M+H).

Example 179 (2R)-2- {[(55J-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl} -6-(5-fkiorofuran-2-yl)thieno[2,3-iZ]pyrimidin-4-yl]oxy} -3 - [2(pyrimidin-4-ylmethoxy)phenyI]propanoic aci d

-217Using General procedure (ÏVa) and pyrimidin-4-ylmethanol as the appropriate alcohol Example 179 was obtained. HRMS calculated for CjgHaûClFNôOôS: 758.2090; found 759.2166 (M+H).

Example 180 (272)-2-{[(5S_a)-5-{3-chlorO“2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-<7]pyrimidin-4-yl]oxy}-3-{2-[(lmethyl-1 H-pyrazol-5-yl)methoxy]phenyl} propanoic acid

Using General procedure (IVa) and (l-methyl-l//-pyrazol-5-yl)methanol as the appropriate 10 alcohol Example 180 was obtained. HRMS calculated for CîsHasClFNcOôS: 760.2246;

found 761.2343 (M+H).

Example 181 (272)-3- {2-[( 1 -tert-butyl-1 H-pyrazol-5-yl)methoxy]phenyl )-2-( [(55_fl)-5- ( 3chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(5-fluorofuran-215 yl)thieno[2,3-i/)pyrimidin-4-yl]oxy}propanoic acid

Using General procedure (IVa) and (1-tert-butyl-177-pyrazol-5-yl)methanol (Préparation 9dt) as the appropriate alcohol Example 181 was obtained, HRMS calculated for C₄₁H44ClFN_âO₆S: 802.2716; found 402.1422 (M+2H).

Example 182 (272)-2-{[(5S_fl>5-(3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl) -6-(5-fluoiOfuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy} -3-(2- ( [ 1 (piOpan-2-yl)-lH-pyrazol-5-yl]methoxy}phenyl)piOpanoic acid

Using General procedure (IVa) and [l-(propan-2-yl)-177-pyrazol-5-y)]methanol (Préparation 9dc) as the appropriate alcohol Example 182 was obtained. HRMS calculated for C₄oH4₂C1FN₆0₆S: 788.2559; found 789.2663 (M+H).

Example 183 (272)-2- {[(55^)-5-(3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 30 yI)ethoxy]phenyl}-6-(5-fluoroftiran-2-yl)thieno[2,3-(Z|pyrimidin-4-yl]oxy}-3-{2-[(lcyclopentyI-lH-pyrazol-5-yl)methoxy]phenyl}propanoic acid

-2I8Using General procedure (IVa) and (l-cyclopentyl-lH-pyrazol-5-yl)methanol (Préparation 9dg) as the appropriate alcohol Example 183 was obtained. HRMS calculated for C₄₂H₄₄C1FN₆O₆S: 814.2716; found 815.2796 (M+H).

Example 184 (2Æ)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-rnethylpiperazin-lyl)ethoxy]phenyl ) -6-(5-fluorofuran-2-y l)thieno[2,3-</]pyrimidin-4-yl]oxy} -3 - [2-[( 1 -ethyl 1 H-pyrazol-5 -yl)methoxy] phenyl} propanoic acid

Using General procedure (IVa) and (l-ethyl-lH-pyrazol-5-yl)methanol (Préparation 9da) 10 as the appropriate alcohol Example 184 was obtained. HRMS calculated for CjçHioCIFNôOsS: 774.2403; found 388.1265 (M+2H).

Example 185 (2R)-2- {[(5SJ-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl} -6-(5-fluoroiüran-2-yl)thieno[2,3-if]pyrimidin-4-yl]oxy} -3-(2- {[ 1 15 (2,2,2-trifluoroethyl)-1 H-pyrazol-5-yl]methoxy)phenyl)propanoic acid

Using General procedure (IVa) and [1-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl]methanol (Préparation 9du) as the appropriate alcohol Example 185 was obtained. HRMS calculated for C₃₉H₃₇C1F₄N₆O₆S: 828.2120; found 415.1131 (M+2H).

Example 186 (22?)-2- {[(55_n)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-i/]pyiimidin-4-yl]oxy} -3-(2-{[l (cyclopropylmelhyl)-lH-pyrazol-5-yl]methoxy}phenyl)propanoic acid

Using General procedure (IVa) and [l-(cyclopropylmethy1)-lH-pyrazol-5-yl]methanol (Préparation 9df) as the appropriate alcohol Example 186 was obtained. HRMS calculated for ChH^CIFNôOôS: 800.2559; found 401.1355 (M+2H).

Example 187 (2/?)-2-{[(5_<$^, _n)-5-{3-chloro-2-methyl-4-[2-(4-methylpÎperazin-l30 yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-<7]pyrimidin-4-yl]oxy}-3-{2-[(lpropyl-lH-pyrazol-5-yl)methoxy]phenyl}propanoic acid

-219Using General procedure (IVa) and (l-propyl-lf/-pyrazol-5-yl)methanol (Préparation 9db) as the approprîate alcohol Example 187 was obtained. HRMS calculated for C4cH42C1FN₆0ûS: 788.2559; found 395.1357 (M+2H).

Example 188 (2R)-3 - {2-[( 1 -butyl-lH-pyrazol-5-yl)methoxy]phenyl}-2- {[(5S_n)-5- {3chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(5-fluorofuran-2yl)thieno[2,3-if]pyrimidin-4-yl]oxy}propanoic acid

Using General procedure (IVa) and (l-butyl-l//-pyrazol-5-yl)methanol (Préparation 9dd) as the approprîate alcohol Exemple 188 was obtained. HRMS calculated for C4iH4₄ClFN₆O₆S: 802.2716; found 402.1447 (M+2H).

Example 189 (2R)-2- {[(55^)-5- {3 -chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yI)thieno[2,3-(71pyrimidîn~4-yl]oxy}-3-[2-(pyrazin2 -y lmethoxy )phenyl]propanoic acid

Using General procedure (IVa) and pyrazin-2-ylmethanol as the approprîate alcohol Example 189 was obtained. HRMS calculated for CssHmCIFNôOgS: 758.2090; found 759.2159 (M+H).

Example 190 (2R)-2-{[(5S_a)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)elhoxy]phenyl}-6-(5-fhioiOfuran-2-yl)thieno[2,3rf]pyrimidin-4-yl]oxy}-3-[2 (pyrimidin-5-ylmethoxy)phenyl]propanoic acid

Using General procedure (IVa) and pyrimidin-5-ylmethanol as the approprîate alcohol Example 190 was obtained. HRMS calculated for CagHjgClFNeOôS: 758.2090; found 759.2198 (M+H).

Example 191 (2Æ)-2- {[(5SJ-5-{3-chloro-2-methyl-4-[2-(4-methyIpiperazin-1 yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-i/^r|pyrimidin-4-yl]oxy}-3-[2-(l_>3oxazol-4-ylmethoxy)phenyl]propanoic acid

-220Using General procedure (IVa) and l,3-oxazol-4-ylmethanol as the appropriate alcohol

Exampie 191 was obtained. HRMS calculated for C37H35CIFN5O7S: 747.1930; found 748.1970 (M+H).

Exemple 192 (27()-2- {[(5S_a)-5- {3-chloro-2-methy]-4-[2-(4-methylpiperazÎn-1 y l)ethoxy] phenyl}-6-(5-fluorofuran-2-y 1) th i eno [2,3 -d] py rimi d i n-4-yl]oxy } -3 - [2- [2(dimethylamino)ethoxy]phenyl}propanoic acid

Using General procedure (IVa) and 2-(dimethylamino)ethanol as the appropriate alcohol Example 192 was obtained. HRMS calculated for C37H41CIFN5O6S: 737.2450; found 369.6277 (M+2FI).

Example 193 (2À)-2-{[(5S^, _a)-5-{3-chloiO-2-inethyl-4-[2-(4-methylpiperazin“lyI)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-t7]pyriinidin-4-yl]oxy}-3-[2-(2hydroxyethoxy)phenyl]propanoic acid

Using General procedure (IVa) and ethylene glycol as the appropriate alcohol Exampie

193 was obtained. HRMS calculated for C35H36CIFN4O7S: 710.1977; found 711.2037 (M+H).

Example 194 (27()-2- {[(5S_a)-5- {3 -chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl} -6-(5-fluorofuran-2-yl)thieno[2,3-(f]pyriînidin-4-y IJoxy} -3 -[2-(2methoxyethoxy)phenyl]propanoic acid

Using General procedure (IVa) and 2-methoxyethanol as the appropriate alcohol Example

194 was obtained. HRMS calculated for C36H₃«C1FN4O7S: 724.2134; found 725.2224 (M+H).

Example 195 (27()-2- {[(55_a)-5- {3-chloro-2-niethyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-{2-[2-(2hydroxyethoxy)ethoxy]phenyl} propanoic acid

- 221 Using General procedure (IVa) and 2-(2-hydroxyethoxy)ethanol as the appropriate alcohol Example 195 was obtained. HRMS calculated for C37H40CIFN4O8S: 754.2239; found 755.2279 (M+H).

Exampie 196 (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-inethylpiperazin-lyl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[2-(2methoxyethoxy)ethoxy]phenyl}propanoic acid

Using General procedure (IVa) and 2-(2-methoxyethoxy)ethanol as the appropriate alcohol 10 Example 196 was obtained. HRMS calculated for C38H42CIFN4O8S: 768.2396; found 769.2481 (M+H).

Example 197 (27?)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpÎperazin-ly])ethoxy]phenyl}-6-(5-fluorofuran-2“yl)thieno[2,3-JJpyrimidin-4-yl]oxy}-3“(2-{2-[2-(215 methoxyethoxy)ethoxy]ethoxy}phenyl)propanoic acid

Using General procedure (IVa) and 2-[2-(2-methoxyethoxy)ethoxy]ethanol as the appropriate alcohol Exampie 197 was obtained. HRMS calculated for C40H46CIFN4O9S: 812.2658; found 407.1384 (M+2H).

Exampie 198 (21î)-2- {[(5S_a)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)eihoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-(2-{[2-(3methylpyridin-4-yl)pyrimidin-4-yl]metlioxy}phenyl)propanoic acid

Step A:

417 mg ethyl (2Æ)-2-[(5S_n)-5-[3-chloro-2-methyl-4-[2-(4-methylpipera7.in-lyl)ethoxy]phenyl]-6-(5-fluoro-2-furyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[(2methylsulfanylpyrimidin-4-yl)methoxy]phenyl]piOpanoate (Préparation 10c) (0.5 mmol),

205 mg (3-methyl-4-pyridyl)boronic acid (1.5 mmol) and 286 mg copper(I) thiophenecarboxylate (1.5 mmol) were dissolved in 5 mL dry THF, then 58 mg Pd(PPh3)₄(0.05 mmol) was added. The mixture was stirred at 70°C under nitrogen until no further

-222conversion was observed. Then it was concentrated under reduced pressure and the crude intermediate was purified via flash chromatography using DCM and MeOH as eluents.

Step B:

The obtained intermediate was dissolved in 3 mL methanol and 150 mg NaOH (3.75 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 198. HRMS calculated for C44H4iClFN₇O₆S: 849.2512; found 425.6338 (M+2H),

General procedure (Va)

Step A:

eq. ethyl (2Æ)-2-[(5Sa)-5-[3-chloro-4-(2-dimethylarnmoethyloxy)-2-mcthyl-phcnyl]-6-(5fluoro-2-furyl)lhieno[2,3-dJpyrimidin-4-yl]oxy-3-(2-hydroxyphenyl)propanoate (Préparation 8d), 2 eq. of the appropriate alcohol and 2 eq. triphenyl phosphine were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. diter/butyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents.

Step B:

The obtained intermédiare was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH x H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with dichloromethane. The combined organic phases were dried over Na₂SO₄, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

-223Example 199 (2R)-2-{[(55_a)-5-{3-chloro-4-[2-(dimethyIamino)ethoxy]-2-methylphenyl}6-(5-fluorofuran-2-yl)thieno[2_>3-i/Jpyrimidin-4-yi]oxy}-3-(2-methoxyphenyl)propanoic acid

Using General procedure (Va) and methanol as the appropriate alcohol Exampie 199 was obtained. HRMS calculated for C31II29CIFN3O6S: 625.1450; found 626.1509 (M+H).

Example 200 (25)-2-{[(55_a)-5-{3-chloro-4-[2-(diniethylamino)ethoxy]-2-mcthylphenyl}6-(5-fiuorofuran-2-yl)thieno[2,3-iflpyrimidin-4-yl]oxy}-3-[2-(2,2,2trifluoroethoxy)phenyl]propanoic acid

Step A;

192 mg (2R)-2-[(55₀)-5-[3-chloro-4-(2-dimethylaminoethyloxy)-2-meth.yl-phenyl]-6-(5fluoro-2-furyl)thieno[2,3-J]pyrÎinidin-4-yl]oxy-3-(2-hydiOxyphcnyl)propanoate (Préparation 8d) (0.3 mmol) and 138 mg K2CO3 (1.0 mmol) were dissolved in 2 mL DMF, then 232 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.0 mmol) was added, The mixture was stirred at room température under nitrogen until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM, dried over Na₂SO4, filtered and concentrated under reduced pressure.

Step B;

The obtained intermediate was dissolved in 8 mL dioxane-water 1:1 and 150 mg LiOH * Η2Ο (3.57 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diiuted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 200. HRMS calculated for C32H28CIF4N3O6S: 693.1323; found 694.1382 (M+H).

Exampie 201 (2/?)-2-{[(55_fl)-5-{3-chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}6-(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2(trifluoiOmethyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

-224Using General procedure (Va) and [2-(tritluoromethyl)pyrimidin-4-yl]methanol (Préparation 9bj) as the appropriate alcohol Example 201 was obtained. HRMS calculated for C₃₆H₃₀ClF₄N₅O₆S: 771.1541; found 772.1604 (M+H).

Example 202 (27?)-2-{[(55_fl)-5-{3-chloro-4-[2-(dimcthylamino)cthoxy]-2-methylphenyl)6-(5-fIuorofuran-2-yl)thieno[2.3-6f]pyrimidin-4-yl]oxy}-3-(2-{[2-(morpholin-4yl)pyrimidin-4-yl]methoxy}phenyl)piOpanoicacid

Using General procedure (Va) and (2-(morpholin-4-y])pyrimidin-4-yl)methanol (Préparation 9ar) as the appropriate alcohol Example 202 was obtained. HRMS calculated for C₃9H_3SC1FN₆O₇S: 788.2195; found 395.1179 (M+2H).

Example 203 (22î)-2-{[(5S_n)-5-{3-chloro-4-[2-(dimethylamino)ethoxy]-2-methyIphenyl}6-(5-fluoiOfuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2,2,2tiifluoroethoxy)pyrimidin-4-yl]methoxy}phenyl)piOpanoic acid

Using General procedure (Va) and [2-(2,2,2-trifluoiOethoxy)pyrimidin-4-yl]methanol (Préparation 9ai) as the appropriate alcohol Example 203 was obtained. HRMS calculated for C.37H32CIF4N5O7S: 801.1647; found 802.1706 (M+H).

Example 204 (27?)-2-{[(5S'₍₇)-5-{3-chloro-4-[2-(dimethylamino)elhoxy]-2-inethylplienyl}6-(5-fluorofuran-2-y l)thieno [2,3 -d]pyrimidin-4-y 1] oxy} -3 - {2-[( 1 - ethyl -1 H-pyrazol- 5 yl)methoxy]phenyl}propanoic acid

Using General procedure (Va) and (l-ethyl-lZ/-pyrazol-5-yl)methanol (Préparation 9da) as the appropriate alcohol Example 204 was obtained. HRMS calculated for C₃6H₃₅C1FN₅O₆S.· 719.1981; found 720.2064 (M+H).

Example 205 (27?)-2-{[(55_iI)'5-{3-chloro-4-[2-(dimethylamino)ethoxy]-2-niethylphenyl}6-(5-fluorofuran-2-yl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-(2-{[l-(2,2,2-trifluoiOethyl)-lHpyrazol-5-yl]methoxy}phenyl)piopanoic acid

-225Using General procedure (Va) and [l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl]methanol (Préparation 9du) as the appropriate alcohol Example 205 was obtained. HRMS calculated for C₃₆H32ClF₄N₅O₆S: 773.1698; found 774.1771 (M+H).

Example 206 (27?)-2-{[(5S₀)-5-{3-chloro-4-[2-(dimethylarnino)ethoxy]-2-methylphenyl}6-(5-fluoiOfuran-2-yl)thieno[2,3-<7]pyrimidin-4-yl]oxy}-3-[2-(pyrazin-2ylmethoxy)phenyl]propanoic acid

Using General procedure (Va) and pyrazin-2-ylmethanoi as the appropriate alcohol Example 206 was obtained. HRMS calculated for C35H31CIFN5O6S: 703.1668; found 704.1726 (M+H).

General procedure (Via)

Step A;

eq. ethyl (2Æ)“2-[(5S_n)-5-[3-chIoro-2-rnethyl-4-|2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(2-furyl)thieno[2,3-rf]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 8e), 2 eq. of the appropriate alcohol and 2 eq. triphenylphosphine were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. ditertbutyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. Then it was concentrated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents.

Step B:

The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH x H2O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with dichloromethane. The combined organic phases were dried over Na2SO₄, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH₄HCO₃ solution and MeCN as eluents.

-226Example 207 (2R)-2-{[-[(5iS^, ₍₇)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(fu ran-2 -yl )thieno [2,3-J]pyrimidin-4 -yl] oxy} -3-(2hydroxyphenyl)propanoic acid

Ethyl (2R)-2-[(5S'_/J)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6(2-furyl)thieno[2,3-</|pynniidin-4-yl]oxy-3-(2-hydroxyphenyl)pi'opanoate (Préparation 8e) was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH ^x H2O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with dichloromethane. The combined organic phases were dried over NajSCL, fïltered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 207. HRMS calculated for C₃3H33C1N₄O₆S: 648.1809; found 649.1862 (M+H).

Example 208 (2R)-2-{ [(55J-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl} -6-(furan-2-yl)thieno[2,3 - J]pyrimidin-4-yl]oxy} -3- {2-[(JR)-1 -(pyridin4-yl)ethoxy]phenyl}propanoic acid

Using General procedure (Via) and (/7?)-l-(4-pyridyl)ethanol as the appropriate alcohol Example 208 was obtained. HRMS calculated for C4oH4oC1Ns0₆S: 753.2388; found 377.6276 (M+2H).

Example 209 (2J?)-2- {[(5SJ-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i7]pyiimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General procedure (Via) and methanol as the appropriate aicohol Example 209 was obtained. HRMS calculated for C34H35CIN4O6S: 662.1966; found 663.2028 (M+H).

-227Example 210 (2/()-2- {[(56^)-5- {3 -chloro-2-methyl-4-(2 -(4-methylpiperazin-1 yI)ethoxy]phenyl}-6‘(furan-2-yl)thieno[2,3-i7Jpyrimidin-4-yl]oxy}-3-[2-(propan-2yloxy)phenyl]propanoic acid

Using General procedure (Via) and 2-propanol as the appropriate alcohol Example 210 was obtained. IIRMS calculated for C₃₆H39C1N₄O₆S: 690.2279; found 691.2344 (M+H).

Example 211 (2/()-2- {[(55^)-5- {3-chloiO-2-methyl-4-[2-(4-methylpiperazÎn-1 yl)ethoxy]phenyl }-6-(furan-2-yl)thieno[2,3-i/]pyriinidin-4-yl]oxy} -3-(2-((2/()tetrahydrofuran-2-ylmethoxy]phenyl} propanoic acid

Using General procedure (Via) and [(2J?)-tetrahydrofuran-2-yl]methanol as the appropriate alcohol Example 211 was obtained. HRMS calculated for C₃8H₄iC1N₄O₇S: 732.2384; found 733.2453 (M+H).

Example 212 (2/()-2-( [(5S₀)-5- {3-chloro-2-methyl-4-(2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-</jpyrimidin-4-yl]oxy}-3-(2(cyclopentyloxy)phenyl]propanoicacid

Using General procedure (Via) and cyclopentanol as the appropriate alcohol Example 212 was obtained. HRMS calculated for C₃8H₄₁C1N₄O₆S: 716.2435; found 717.2481 (M+H).

Example 213 (2/()-2- {[(5S_a)-5- (3 -chloro-2-methyl-4-[2-(4-methylpiperazin-1 y l)ethoxy] phenyl} -6-(furan-2-yl)thieno [2,3-r(|pyrimidin-4-yl] oxy} -3 - [2-(5,6,7,8tetrahydroquinolin-8-yloxy)phenyl]propanoic acid

Using General procedure (Via) and 5,6,7,8-tetrahydroquinolin-8-ol as the appropriate alcohol Example 213 was obtained as mixture of the diastereoisomers. HRMS calculated for C42H42CIN5O6S: 779.2544; found 390.6369 (M+2H) and 390.6355 (M+2H).

-228Example 214 (21?)-2-{[(55₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl} -6-(fiiran-2-yl)thieno[2,3-<7jpyrimÎdin-4-yI]oxy} -3 - [2-[(lmethylpyiTolidin-3-yl)oxy]phenyl}piOpanoic acid

Using General procedure (Via) and l-methylpyrrolidin-3-ol as the appropriate alcohol

Example 214 was obtained as mixture of the diastereoisomers. HRMS calculated for

C_3SH42C1N₅O₆S; 731.2544; found 366.6362 (M+2H) and 366.6354 (M+2H).

Exa mple 215 (2R)-2 - {[(55„)-5 - {3 -chloro-2-methyl-4- [2-(4-methy lpiperazin-1 yl)ethoxy]phenyl}~6-(furan-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2ethoxyphenyl)propanoic acid

Using General procedure (Via) and éthanol as the appropriate alcohol Example 215 was obtained. HRMS calculated for C35H37CIN4O6S: 676.2122; found 677.2216 (M+H).

Example 216 (2Æ)-2-{ [(55),)-5-{3-chloro-2-methyl-4- [2-(4-methylpiperazin-1yl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3-<f]pyrimidin-4-yl]oxy}-3-[2-(piOp-2-yn-lyloxy)phenyl]propanoic acid

Using General procedure (Via) and prop-2-yn-l-ol as the appropriate alcohol Example

216 was obtained. HRMS calculated for C36H35C1N4O(îS: 686.1966; found 687.2056 (M+H).

Example 217 (2R)-2-{[(55),)-5- [3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-</jpyrimidin-4-yl]oxy}-3-{2-[2(dimethylamino)-2-oxoethoxy]phenyl }propanoic acid

Using General procedure (Via) and 2-hydroxy-A)?/-dimethyl-acetamide as the appropriate alcohol Example 217 was obtained. HRMS calculated for C37H40CIN5O7S: 733.2337;

found 734.2407 (M+H).

- 229 Example 218 (2Â)-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i7]pyrimidin-4-ylJoxy}-3-{2-[2(methylamino)-2-oxoethoxy]phenyl)propanoic acid

Using General procedure (Via) and 2-hydroxy-V-methyl-acetamide as the appropriate alcohol Example 218 was obtained. HRMS calculated for C36H38CIN5O7S: 719.2180; found 720.2263 (M+H).

Example 219 (2R)-2-{[(55J-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 10 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-{2-[2-OXO-2(phenylamino)ethoxy]phenyl}propanoic acid

Using General procedure (Via) and 2-hydroxy-V-phenyl-acetamide as the appropriate alcohol Example 219 was obtained. HRMS calculated for C41H4QCIN5O7S: 781.2337;

found 391.6225 (M+2H).

Example 220 (2j?)-3-{2-[2-(butylamino)-2-oxoethoxy]phenyl}-2-{[(5S_a)-5-{3-chloro-2methyl-4-[2-(4-methylpipei^,azin-l-yl)ethoxy]phenyl}-6-(furan-2-yl)thïeno[2_>3d]pyrimidin-4-yl]oxy}propanoic acid

Using General procedure (Via) and V-butyl-2-hydroxy-acetamide as the appropriate alcohol Example 220 was obtained. HRMS calculated for C39H44CIN5O7S: 761.2650; found 762.2703 (M+H).

Example 221 (2/?)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-(2,2,2trifluoroethoxy)phenyl]propanoic acid

Step A:

677 mg ethyl (2Æ)-2-[(5SJ-5-[3-chloiO-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyI]-6-(2-furyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 8e) (1 mmol) and 276 mg K.2CO3 (2.0 mmol)

-230were dissolved in 5 mL DMF, then 141 pL 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.2 mmol) was added. The mixture was stirred at room température under nitrogen until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with dichioromethane, and the combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure.

Step B:

The obtained intermediate was dissolved in 10 mL dioxane-water 1:1 and 420 mg LiOH * H₂O (10.0 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with dichioromethane, the combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NI-I4HCO3 solution and MeCN as eluents to obtain Example 207. HRMS calculated for C35H34CIF3N4O6S: 730.1840; found 731.1875 (M+H).

Example 222 (2Æ)-2-{[(5S_n)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(füran-2-yl)thieno[2,3-d'Jpyrimidin-4-yl]oxy}-3-{2-[(4-chloiOpyridin2-y l)methoxy]phenyl} propanoic acid

Using General procedure (Via) and (4-chloro-2-pyridyl)methanol as the appropriate alcohol Example 222 was obtained. HRMS calculated for C39H37Cl₂NsO6S: 773.1842; found 387.6008 (M+2H).

Example 223 (27?)-2-{[(55_/)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyI}-6-(furan-2-yl)thieno[2,3-tZ]pyrimidin-4-yl]oxy}-3-{2-[(4methoxypyridin-2-yl)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (4-methoxy-2-pyridyl)methanol as the appropriate alcohol Example 223 was obtained. HRMS calculated for C4QH4QCIN5O7S: 769.2337;

found 385.6252 (M+2I-I).

- 231 Example 224 (2R)-2-{[(5₁S'₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(6phenylpyrimidin-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (6-phenylpyrimidin-4-yl)methanol (Préparation 9cg) as the appropriate alcohol Example 224 was obtained. HRMS calculated for C₄₄H4iClN₆O₆S: 816.2497; found 409.1321 (M+2H).

Example 225 (27?)-2-{[(55^, ₍₇)-5-{3~chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-J]pyrimidin-4-yl]oxy}3-{2-[(l,3-dimethyllH-pyrazoi-5-yl)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (l,3-dimethyl-l/f-pyrazoI-5-yl)methanol as the appropriate alcohol Example 225 was obtained. HRMS calculated for CjULiCiNôOfiS: 756.2497; found 379.1313 (M+2H).

Example 226 (2Æ)-2-{[(55_<I)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(3-cyclopropyl1 -methyl-1 H-pyrazol-5-yl)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (3-cyclopropyl-l-methyl-lH-pyrazol-5-yl)mcthanol as the appropriate alcohol Example 226 was obtained. HRMS calculated for C41H43CIN6O6S: 782.2653; found 392.1398 (M+2H).

Example 227 (2)?)-2-{[(5₁S^, ₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i/jpyrirnidin-4-yl]oxy}-3-{2-[(l-rnethyl-3phenyl-1 H-pyrazol-5-yI)methoxy]phenyl Jpropanoic acid

Using General procedure (Via) and (l-methyl-3-phenyl-lH-pyrazol-5-yl)methanol as the appropriate alcohol Example 227 was obtained. HRMS calculated for C44H43CIN6O6S:

818.2653; found 819.2735 (M+H).

-232Example 228 (27?)-2-{[(5S_ii)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(fuian-2-yl)thieno[2,3-<Z]pyrimidin-4-yl]oxy}-3-(2-{[3-(furan-2-yl)-lmethyl-lH-pyrazol-5-yl]methoxy}phenyl)propanoic acid

Using General procedure (Via) and [3-(ftiran-2-y])-l-methyl-l77-pyrazol-5-yl]methanol as the appropriate alcohol Example 228 was obtained. HRMS calculated for C42H41CIN6O7S: 808.2446; found 809.2524 (M+H).

Example 229 (2R)-2- {[(.56/)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2(cyclopropylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and cyclopropylmethanol as the appropriate alcohol

Example 229 was obtained. HRMS calculated for C37H39N4O6SCI: 702.2279; found 703.2374 (M+H).

Example 230 (2Æ)-2- {[(55/)-5- {3-chloiO-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yi)thieno[2,3-i(]pyriinidin-4-yl]oxy)-3-[2-(isoquinolin-3ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and isoquinolin-3-ylmethanol as the appropriate alcohol

Example 230 was obtained. HRMS calculated for C43II40CIN5O6S: 789.2388; found 395.6256 (M+2H).

Example 231 (2R)-2-{[(5iS/)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-JJpyrimidin-4-yl]oxy}-3-{2-[(5-chloiOpyridin2-yl)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (5-chloro-2-pyridyl)methanol as the appropriate alcohol Example 231 was obtained. HRMS calculated for C39H37CI2N5O6S: 773.1842;

found 774.1921 (M+H).

-233 Example 232 (2A)-2-{ [(55J-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-<7]pyrirnidiri-4-ylJoxy}-3-{2-[(5-fluoropyridin2-yl)inethoxy]phenyl} propanoic acid

Using General procedure (Via) and (5-fluoro-2-pyridyl)methanol as the appropriate alcohol Exemple 232 was obtained. HRMS calculated for C39H37CIFN5O6S: 757.2137; found 758.2199 (M+H).

Example 233 (2Æ)-2-{[(5S_e)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-û?]pyrimidin-4-yl]oxy}-3-{2-[(5methoxypyridin-2-yl)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (5-methoxy-2-pyridyl)methanol as the appropriate alcohol Example 233 was obtained. HRMS calculated for C40H40CIN5O7S: 769.2337; found 385.6241 (M+2H).

Example 234 (27?)-2-{[(55_a)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyI}-6-(furan-2-yl)thieno[2,3-i7|pyrimidin-4-yl]oxy}-3-[2-(quinolin-2ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and quinolin-2-ylmethanol as the appropriate alcohol

Example 234 was obtained. HRMS calculated for C43H40CIN5O6S: 789.2388; found 395.6253 (M+2H).

Example 235 (2/?)-2-{[(55_n)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-J]pyrimjdin-4-yl]oxy}-3-{2-[(6methylpyridin-2-yl)methoxy]phenyl}piOpanoic acid

Using General procedure (Via) and (6-methyl-2-pyridyl)methanol as the appropriate alcohol Example 235 was obtained. HRMS calculated for C40H40CIN5O6S: 753.2388;

found 377.6262 (M+2H).

-234Example 236 (2JÎ)-2-{[(5S'_(/)-5-{3-chloro-2-niethyl-4-[2-(4-methylpiperazin-l yl)cthoxy]phcnyl}-6-(furan-2-yl)thicno[2,3-i/]pyrimÎdin-4-ylJoxy}-3-{2-[(6-chloiOpyiidin2-yl)methoxy]phenyl) propanoic acid

Using General procedure (Via) and (6-chloro-2-pyridyl)niethanol as the appropriate alcohol Example 236 was obtained. HRMS calculated for C39H37CI2N5O6S: 773.1842; found 774.1906 (M+H).

Exampie 237 (2Æ)-2- {[(5iS)_I)-5-{3-chloro-2-methyl-4-[2-(4-niethylpiperazin-1 yl)ethoxy]phenyl] -6-(furan-2-yl)thieno[2,3-<7]pyrimidin-4-yl]oxy} -3-(2- {[6-(pyrrolidin-1yl)pyridin-2-yl]methoxy}phenyl)propanoic acid

Using General procedure (Via) and (6-pyiTolidin-l-yl-2-pyridyl)methanol as the appropriate alcohol Example 237 was obtained. HRMS calculated for C43H45CIN6O6S: 808.2810; found 405.1472 (M+2H).

Example 238 (2R)-2-{[(5S₀)-5- (3 -chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-4/]pyriinidin-4-yl]oxy}-3-{2-[(6methoxypyridin-2-yl)methoxy]phenyl} propanoic acid

Using General procedure (Via) and (6-methoxy-2-pyridyl)methanol as the appropriate alcohol Example 238 was obtained. HRMS calculated for C.4ÛH40CIN5O7S: 769.2337; found 770.2432 (M+H).

Example 239 (2/?)-2-{[(55_rt)-5-{3-chloro-2-methyl-4-[2-(4-niethylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-iÎ)pyrimidin-4-yl]oxy}-3-[2(cyclopentylmethoxy)phenylJpiOpanoic acid

Using General procedure (Via) and cyclopentylmethanol as the appropriate alcohol

Example 239 was obtained. HRMS calculated for C39II43CIN4O6S: 730.2592; found

731.2639 (M+H).

-235Exa mple 240 (2R)-3- [2-(benzy loxy)phenyl]-2- {[(5S_a)-5 - {3 -chloro-2-methyl-4- [2-(4methylpiperazin-l-yl)ethoxy]phenyl}-6-(iuran-2-yf)thieno[2,3-<7]pyrimidin-4yl]oxy}propanoic acid

Using General procedure (Via) and phenylmethanol as the appropriate alcohol Example

240 was obtained. HRMS calculated for C4QH39CIN4O6S: 738.2279; found 739.2319 (M+H).

Example 241 (2R)-2-{ [(55^)-5- {3-chloro-2-methyl-4-[2-(4-methyIpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-<7|pyrimïdÎn-4-yl]oxy}-3-[2-(pyridin-2ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and 2-pyridylmethanol as the appropriate alcohol Example

241 was obtained. HRMS calculated for C39H38CIN5O6S: 739.2231; found 370.6197 (M+2H).

Example 242 (22?)-2-{[(5&)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}6-(furan-2-yl)thieno[2,3-J]pyrimidin-4-yl]oxy}-3-[2-(pyridin-3ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and 3-pyridylmethanol as the appropriate alcohol Exemple

242 was obtained. HRMS calculated for C39H38CIN5O6S: 739.2231; found 370.6178 (M+2H).

Example 243 (27?)-2- {[(55«)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3-</jpyrimidin-4-yl]oxy}-3-[2-(pyiidazin-3ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and pyridazin-3-ylmethanol as the appropriate alcohol

Example 243 was obtained. HRMS calculated for C38H37CIN6O6S: 740.2184; found

741.2227 (M+H).

-236Example 244 (2Æ)-2-{[(5₁S'_n)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl} -6-(furan-2-yl)thieno[2,3 -i/]pyrimidin-4-yl]oxy} -3 - |2-(i uran-2ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and 2-furylmethanol as the appropriate alcohol Example

244 was obtained. IIRMS calculated for C3SH37CIN4O7S: 728.2071; found 729.2112 (M+H).

Example 245 (2/()-2- {[(55^, _a)-5-{3-chloro-2-methyl-4-f2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(fui-an-2-yl)thieno[2_s3-i/lpyrimidin-4-yl]oxy}“3-[2-(thiophen-2ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and 2-thienylmethanol as the appropriate alcohol Example

245 was obtained. HRMS calculated for C38H37CIN4O6S2: 744.1843; found 745.1895 (M+H).

Example 246 (27?)-2-{[(5S_o)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(l-niethyl-lHpyrazol-3-yl)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (1 -methyl- 17Apyrazol-3-yl)methanol as the appropriate alcohol Example 246 was obtained. HRMS calculated for C38H39CIN6O6S: 742.2340; found 372.1234 (M+2H).

Example 247 (2/?)-2-{[(5,S'_a)-5-{3-cliloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2_}3-J]pyrimidin-4-yl]oxy}-3-{2-[(2methylpyrimidin-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (2-methylpyrimidin-4-yl)methanol as the appropriate alcohol Example 247 was obtained. HRMS calculated for C39H39CIN6O6S: 754.2340;

found 755.2446 (M+H).

-237Example 248 (2R)-2-{ [(55,)-5- {3-chloro-2-methyl-4-[2-(4-melhy lpiperazin-1 yl)ethoxy]pheny l} -6-(furan-2-yl)thieno[2,3 -/Z]pyrimidin-4-yl]oxy} -3 -(2- {[2(trifluoromethyl)pyrimidin-4-yl]methoxy} phenyl)propanoic acid

Using General procedure (Via) and [2-(trifluoromethyl)pyrimidin-4-yl]methanol (Préparation 9bj) as the appropriate alcohol Example 248 was obtained. HRMS calculated for CsgHjôC^NôOeS: 808.2058; found 809.2126 (M+H).

Example 249 (27?)-2- {[(55_a)-5 - {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 10 yl)ethoxy]phenyl}-6-(ftiran-2-yl)thieno[2,3-if|pyrimidin-4-yl]oxy}-3-{2-[(2chloropyrimidin-4-yl)methoxy]phenyl}piOpanoic acid

Using General procedure (Via) and (2-chloropyrimidin-4-yl)methanol (Préparation 9ch) as the appropriate alcohol Example 249 was obtained. HRMS calculated for 15 CjgHjûChNôOôS: 774.1794; found 775.1863 (M+H).

Example 250 (22f)-3- {2-[(2-aminopyrimidin-4-yl)methoxy]phenyl}-2-{ [(55J-5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3ri] py rimidin-4-yl] oxy} propanoic acid

Using General procedure (Via) and (2-aminopyrimidin-4-yl)methanol (Préparation 9al) as the appropriate alcohol Example 250 was obtained. IIRMS calculated for CjsHjgCltyOôS: 755.2293; found 378.6217 (M+2H).

Example 251 (2/?)-2-{[(55_fi)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-ly l)ethoxy]pheny 1} -6-(furan-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy } -3 -(2- {[2(dimethylamino)pyrimidin-4-yl]methoxy}phenyl)piOpanoic acid

Using General procedure (Via) and [2-(dimethylamino)pyrimidin-4-yl]methanol (Préparation 9an) as the appropriate alcohol Example 251 was obtained. HRMS calculated forC^H^ClNvOeS: 783.2606; found 392.6366 (M+2H).

-238Example 252 (27?)-2-{[(5LS'_fi)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-rf]pyriniidin-4-yljoxy}-3-(2-{[2-(morpholin-4yl)pyrimidin-4-yl]methoxy}phenyl)piOpanoic acid

Using General procedure (Via) and (2-(morpholin-4-yl)pyrimidin-4-yl)methanol (Préparation 9ar) as the appropriate alcohol Example 252 was obtained. HRMS calculated for C42H44CIN7O7S: 825.2711; found 413.6424 (M+2H).

Example 253 (2R)-2-{ [(55_a)-5 - {3 -chlor o-2-methyl-4- [2 -(4-methylpiperazi η-1 10 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy} -3-(2- {[2(methylamino)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (Via) and [2-(methylamino)pyrimidin-4-yl]methanol (Préparation 9am) as the appropriate alcohol Example 253 was obtained. HRMS 15 calculated for C39H40CIN7O6S: 769.2449; found 385.6305 (M+2H).

Example 254 (2Â)-3-(2-{[2-(benzylamino)pyrimidin-4-yl]methoxy}phenyl)-2-{[(55_a)-5{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl }-6-(furan-2yl)thieno[2,3 -rf)py rimidi n-4-y 1] oxy) propanoic acid

Using General procedure (Via) and [2-(benzylamino)pyrimidin-4-yl]mcthanol (Préparation 9at) as the appropriate alcohol Example 254 was obtained. HRMS calculated for C45H44CIN7O6S: 845.2762; found 423.6479 (M+2H).

Example 255 (2/?)-2-{[(55₀)-5-{3-chloiO-2-rnethyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3-d]pyrÎmÎdin-4-yl]oxy}~3“{2-[(2methoxypyrimidÎn-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (2-methoxypyrimidin-4-yl)methanol as the appropriate alcohol Example 255 was obtained. HRMS calculated for C39I-I39CIN6O7S: 770.2289;

found 771.2344 (M+H).

-239Example 256 (27?)-2- {[(55,,)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl} -6-(furan-2-yl)thieno[2,3-i7]pyrimidin-4-yl]oxy} -3 -(2- {[2(cyclopropylmethoxy)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (Via) and [2-(cyclopiOpylmethoxy)pyrimidin-4-yl]methanol (Préparation 9au) as the appropriate alcohol Example 256 was obtained. HRMS calculated for C42H43CIN6O7S: 810.2602; found 406.1380 (M+2H).

Example 257 (2Λ)-3-(2-{[2-(benzyloxy)pyrimidin-4-yl]methoxy}phenyl)-2- {[(55,,)-5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl) -6-(furan-2-yl)thieno[2,3<f]pyrinüdin-4-yl]oxy}propanoic acid

Using General procedure (Via) and (2-benzyloxypyrimidin-4-yl)methanol as the appropriate alcohol Example 257 was obtained. HRMS calculated for C45H43CIN6O7S: 846.2602; found 424.1407 (M+2H).

Example 258 (2Λ)-2- {[(55,,)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyI}-6-(furan-2-yl)thieno[2,3-J]pyriniidin-4-yl]oxy}-3-[2-(pyridin-4ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and 4-pyridylmethanol as the appropriate alcohol Example

258 was obtained. HRMS calculated for C^HsgClNsOâS: 739.2231; found 370.6187 (M+2H).

Example 259 (2R)-2-{[(55„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-ly!)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-J]pyritnidin-4-yl]oxy}-3-[2-(pyrnnidin-4ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and pyrimidin-4-ylmethanol as the appropriate alcohol

Example 259 was obtained. HRMS calculated for C38H37CIN6O6S: 740.2184; found

741.2259 (M+H).

-240Example 260 (2R)-2-{[(55_iZ)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy] phenyl} -6-(furan-2-yl)thieno|2,3-i/]pynmidm-4-yl]oxy} -3- (2-[( l -methyl-1Hpyrazol-5-yl)methoxy]phenyl}piOpanoic acid

Using General procedure (Via) and (1-methyl-177-pyrazol-5-yl)methanol as the appropriate alcohol Example 260 was obtained. HRMS calculated for C_3gH₃₉CIN6O6S: 742.2340; found 743.2404 (M+H).

Example 261 (2R)-2-{ f(5^,)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l 10 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i7]pyrimidin-4-yl]oxy}-3-(2-{[l-(propan-2-yl)1 H-pyrazol-5-yl]methoxy}phenyl)piOpanoic acid

Using General procedure (Via) and [l-(propan-2-yl)-l/Z-pyrazol-5-yl]methanol (Préparation 9dc) as the appropriate alcohol Example 261 was obtained. HRMS calculated for C^H^CINôOôS: 770.2653; found 771.2726 (M+H).

Example 262 (272)-2- {[(55^)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(l-cyclopentyllH-pyrazol-5-yl)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (l-cyclopentyI-lH-pyrazol-5-yl)mcthanol (Préparation 9dg) as the appropriate alcohol Example 262 was obtained. HRMS calculated for C42H45CIN6O6S: 796,2810; found 797.2835 (M+H).

Example 263 (272)-2-{[(55„)-5-{3-chloiO-2-methyl-4-[2-(4-methylpipei‘azin-lyl)ethoxy]phenyI}-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(l-phenyl-1Hpyrazol -5-yl)methoxy]phenyl} propanoi c acid

Using General procedure (Via) and (1-phenyl-177-pyrazol-5-yl)methanol as the appropriate alcohol Example 263 was obtained. HRMS calculated for C4₃H₄iC1N6O₆S: 804.2497;

found 805.2575 (M+H).

«

- 241 Exampie 264 (2R)-2- {[(55„)-5- {3-cHoro-2-rnethyl-4-[2-(4-rnethyIpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-y]]oxy}-3-{2-[(I-ethyl-lHpyrazol-5-yl)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (l-ethyl-l/7-pyrazol-5-yI)methanol (Préparation 9da) as the appropriate alcohol Example 264 was obtained. HRMS calculated for C^HuClNgOgS; 756.2497; found 757.2597 (M+H).

Example 265 (2R)-2-{ [(5S_a)-5· {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 10 yl)ethoxy]phenyl} -6-(furan-2-yl)thieno[2,3-i/|pyrimidin-4-yl]oxy}-3-(2-{ [ 1 -(2,2,2trifluoroethyl)-1 H-pyrazol-5-yl]methoxy} phenyl)propanoic acid

Using General procedure (Via) and [l-(2,2,2-trifluoroethyl)-lZZ-pyrazol-5-yl]methanol (Préparation 9du) as the appropriate alcohol Example 265 was obtained. HRMS 15 calculated for C₃9H₃8C1F₃N₆O₆S: 810.2214; found 406.1175 (M+2H).

Exampie 266 (2R)-2- {[(55₀)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl)-6“(furan-2-yI)thieno[2,3-<ZJpyiimidin-4-yl]oxy)-3-[2-(oxetan-2ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and oxetan-2-ylniethanol as the appropriate alcohol

Example 266 was obtained as a mixture of diastereoisomers. HRMS calculated for

C₃7H₃9C1N4O₇S: 718.2228; found 719.2296 (M+H) and found 719.2283 (M+H).

Example 267 (2Æ)-2-{[(5S_a)-5-{3-chIoro-2-methyl-4-[2-(4-methyIpiperazin-Iyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-J]pyrimidin-4-yl]oxy}-3-{2-[(l -methyl- IHimidazol-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (1 -methyl- l/7-imidazoi-4-yl)methanol as the appropriate alcohol Example 267 was obtained. HRMS calculated for CssHwClNéOéS:

742.2340; found 372.1233 (M+2H).

-242Examplc 268 (2Λ)-2- {[(55_ü)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-d]pyriinidin-4-yl]oxy}-3-{2-[(5methylpyrazin-2-yl)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (5-methylpyrazin-2-yl)methanol as the appropriate alcohol Exampie 268 was obtained. IIRMS calculated for C39H39CIN6O6S: 754.2340; found 755.2408 (M+H).

Example 269 (2À)-2-{[(55_i7)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-t7]pyrimidin-4-yl]oxy}-3-{2-[(5-chloropyrazin“ 2-yl)methoxy] phenyl} propanoi c acid

Using General procedure (Via) and (5-chloropyrazin-2-yl)methanol as the appropriate alcohol Example 269 was obtained. HRMS calculated for CjgHasChNôOôS: 774.1794; found 775.1817 (M+H).

Example 270 (2R)-2- {[(55^)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(fijran-2-yl)thieno[2,3-rZ]pyrimidin-4-yl]oxy}-3-{2-[(5methoxypyrazin-2-yl)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (5-methoxypyrazin-2-yl)methanol as the appropriate alcohol Example 270 was obtained. HRMS calculated for C39H39QN6O7S: 770.2289; found 771.2329 (M+H).

Exampie 271 (2À)-2-{[(55_rt)-5-(3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(2methylpyrimidin-5-yl)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (2-methylpyrimidin-5-yl)methanol as the appropriate alcohol Example 271 was obtained. HRMS calculated for C39H39CIN6O6S: 754.2340;

found 755.2422 (M+H).

f

-243Examplc 272 (2Λ)-2- {[(5S_fl)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl }-6-(fùran-2-yl)thieno[2,3-J]pyrimidin-4-yl]oxy} -3-(2-{[2-(pyrrolidin-1 yl)pyrimidin-5-yl]methoxy}phenyl)propanoic acid

Using General procedure (Via) and (2-pyrrolidin-l-ylpyrimidin-5-yl)methanol as the approprîate alcohol Example 272 was obtained. HRMS calculated for C42H44CIN7O6S: 809.2762; found 405.6443 (M+2H).

Example 273 (2Æ)-2- {[(5S_O>5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 10 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-iZ]pyriniidin-4-yl]oxy}-3-(2-{[2-(niorpholin-4yl)pyrimidi n- 5 -yljmethoxy} phenyl)propanoic acid

Using General procedure (Via) and (2-(morpholin-4-yl)pyrimidin-5-yl)methanol as the approprîate alcohol Example 273 was obtained. HRMS calculated for C42H44CIN7O7S:

825.2711; found 413.6424 (M+2H).

Example 274 (2/?)-2- {[(5&)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-c(jpyrimidin-4-yl]oxy}-3-{2-[(2methoxypyrimidin-5 -yl)methoxy]phenyl} propanoic acid

Using General procedure (Via) and (2-methoxypyrimidin-5-yl)methanol as the approprîate alcohol Example 274 was obtained, HRMS calculated for C39H39CIN6O7S: 770.2289; found 771.2398 (M+H).

Example 275 (2Æ)-2-{[(5S₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-J]pyrimidin-4-yl]oxy}-3-[2-(pyrazin-2ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and pyrazin-2-ylmethanol as the approprîate alcohol

Example 275 was obtained. HRMS calculated for C38H37CIN6O6S: 740.2184; found

741.2255 (M+H).

»

-244Example 276 (2R)-2- {[(55,)-5- {3-chloro-2-methyl-4- [2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(fuian-2-yl)thieno[2,3-i7]pyrimidin-4-yl]oxy}-3-{2-[(l-melhyl-lHimidazol-5 -yl)methoxy]phenyl} propanoi c acid

Using General procedure (Via) and (l-methyl-l//-imidazol-5-yl)methanol as the appropriate alcohol Example 276 was obtained. HRMS calculated for C38H39CIN6O6S: 742.2340; found 372.1237 (M+2H).

Example 277 (27?)-2-{[(55)-5-{3-chloro-2-methyl-4-[2-(4-inethylpiperazin-l10 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-iZ]pyrimidin-4-yl]oxy}“3-[2-(pyrimidin-5ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and pyriinidin-5-ylmethanol as the appropriate alcohol

Example 277 was obtained. HRMS calculated for CssHtzCINcOôS: 740.2184; found

741.2266 (M+H).

Example 278 (2/?)-2-{[(55,)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl} -6-(furan-2-yl)thieno[2_J3-tZjpyrimidin-4-yl]oxy }-3-[2-( 1,3 -thiazol-5 yltnethoxy)phenyl]propanoic acid

Using General procedure (Via) and I,3-thiazol-5-ylmethanol as the appropriate alcohol

Examplc 278 was obtained. HRMS calculated for C37H36CIN5 0^82: 745.1796; found 746.1855 (M+H).

Example 279 (2Æ)-2-{[(55?)-5-{3-chloro-2-methyl-4-[2-(4-methylpïperazin-lyl)ethoxy]phenyl}-6-(iuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(l-methyl-lHpy razol-4-y 1 )methoxy] phenyl} propanoic acid

Using General procedure (Via) and (1 -methyl- lH-pyrazol-4-yl)methanol as the appropriate alcohol Example 279 was obtained. HRMS calculated for C38H39CIN6O6S: 742.2340;

found 372,1243 (M+2H).

*4

-245Example 280 (2R)-2- {[(55^)-5- [3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3-i/Jpyrimidin-4-yl]oxy}3-[2-(l,3-oxazol-4ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and 1,3-oxazoM-ylmethanol as the appropriate alcohol

Example 280 was obtained. HRMS calculated for C37H36CIN5O7S: 729.2024; found 730.2116 (M+H).

Example 281 (22J)-2-{[(5S'_a)-5-{3-chloro-2-inethyl-4-[2-(4-inethylpiperazin-l10 yl)ethoxy]phenyl} -6-(furan-2-yl)thieno[2,3-iZ]pyrimidin-4-yl]oxy}-3-[2-( 1,3-thiazol-4ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and l,3-thiazol-4-ylmethanol as the appropriate alcohol

Example 281 was obtained. HRMS calculated for C37H36CIN5O6S2: 745.1796; found 15 746.1867 (M+H).

Example 282 (2R)-2-{[(5S₀)-5-{3-chIoro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl} -6-(furan-2-yl)thieno [2,3 - J]pyrimidin-4-yl] oxy} -3 - {2- [(2-methyl'2Hindazol-3-yI)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (2-methyl-22/-indazol-3-yl)methanol as the appropriate alcohol Example 282 was obtained. HRMS calculated for C42H41CIN6O6S: 792.2497; found 397.1336 (M+2H).

Example 283 (2R)-2-[[(5^)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-{2-[(5phenylpyrimidin-2-yl)methoxy]phenyl}propanoic acid

Using General procedure (Via) and (5-phenylpyrimidin-2-yl)methanol as the appropriate alcohol Example 283 was obtained. HRMS calculated for C44H41CIN6O6S: 816.2497;

found 817.2539 (M+H).

-246Example 284 (2/?)-2-{[(55^, _<7)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-ly l)ethoxy Jpheny l} -6-(furan-2-yl)thieno [2,3 -d]pyrimidin-4-y l] oxy} -3 - [2-(isoquinolin-1 ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and isoquinolin-l-ylmethanol as the appropriate alcohol Example 284 was obtained. HRMS calculated for C43H40CIN5O6S: 789.2388; found 395.6266 (M+2H).

Example 285 (2Λ)-2- {[(55^)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-{2-[(3-chloropyridin2-yl)methoxy]phenyl [propanoic acid

Using General procedure (Via) and (3-chloro-2-pyridyl)methanol as the appropriate alcohol Exainple 285 was obtained. HRMS calculated for C39H37CI2N5O6S: 773.1842; found 774.1881 (M+H).

Example 286 (2Æ)-2-{[(55₀)-5-{3-chioro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(fuian-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-(pyrimidin-2ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and pyrimidin-2-ylmethanol as the appropriate alcohol Exampie 286 was obtained. HRMS calculated for CasffnClNôOùS: 740.2184; found 741.2229 (M+H).

Example 287 (27?)-2-{[(55_<J)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl} -6-(furan-2-yl)thieno[2,3-i/]pyiimidin-4-yl]oxy }-3-{2-[(l -methyl-1Himidazol-2-yl)methoxy]phenyl} propanoic acid

Using General procedure (Via) and (I-methyl-177-imidazol-2-yl)methanol as the appropriate alcohol Exampie 287 was obtained. HRMS calculated for C38H39CIN6O6S:

742.2340; found 372.1246 (M+2H).

-247Exainple 288 (2Æ)-2- {[(56_a)-5-{3-chloro-2-methyl-4-[2-(4-rnethylpiperazin-l yl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-(3,3,3trifluoropropoxy)phenyl]propanoic acid

Using General procedure (Via) and 3,3,3-trifluoropropan-l-oI as the appropriate alcohol Example 288 was obtained. HRMS calculated for C36H36CIF3N4O6S: 744.1996; found 745.2037 (M+H).

Example 289 (2R)-2- {[(5S/)-5- {3 -chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl} -6-(furan-2-yl)thieno[2,3-<Z]pyrimidin-4-yl]oxy} -3-{2-[2-(pyridin-2yl)ethoxy]phenyl}propanoic acid

Using General procedure (Via) and 2-(2-pyridyl)ethanol as the appropriate alcohol Example 289 was obtained. HRMS calculated for C40H40CIN5O6S: 753.2388; found 377.6280 (M+2H).

Example 290 (2R)-2-{[(55„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxyjphenyl) -6-(furan-2-yl)thienol2,3 -i/|pyrimidin-4-yl]oxy} -3-(2-(2methoxyethoxy)phenyi]propanoic acid

Using General procedure (Via) and 2-methoxyethanol as the appropriate alcohol Example

290 was obtained. HRMS calculated for C36H39CIN4O7S: 706.2228; found 707.2279 (M+H).

Example 291 (2/?)-2-{[(5S_fi)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yI)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-(2phenoxyethoxy)phenyl]propanoic acid

Using General procedure (Via) and 2-phenoxyethanol as the appropriate alcohol Example

291 was obtained. HRMS calculated for C41H41CIN4O7S: 768.2384; found 769.2459 (M+H).

-248Example 292 (2/?)-3-{2-[2-(benzyIoxy)ethoxy]phenyl}-2-[[(5S_a)-5-{3-chloiO-2-methyl-4[2-(4-methylpiperazi η-1 -yl)ethoxy] phenyl} -6-(furan-2 -yl)thieno [2,3-e/]pyrimi din-4yljoxyjpropanoic acid

Using General procedure (Via) and 2-benzyloxyethanol as the appropriate alcohol Example 292 was obtained. HRMS calculated for C4TI43CIN4O7S: 782.2541; found 392.1344 (M+2H).

Example 293 (25)-2- {[(55_a)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-t7]pyrimidin-4-yl]oxy}-3-{2-[(2Æ)tetrahydrofuran-2-ylmethoxyjphenyl) propanoic acid

503 mg 4-chloio-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(2furyl)thieno[2,3-c(jpyrimidine (Préparation 14) (1 mmol), 353 mg ethyl (25)-2-hydroxy-3[2-[[(27?)-tetrahydrofuran-2-yl]methoxy]phenyl]propanoate (Préparation 3bm) (1.2 mmol) and 986 mg césium carbonate (3 mmol) were dissolved in 10 mL dry tertbutanol. The mixture was stirred at 60°C under nitrogen until no further conversion was observed. The reaction mixture was cooled to room température, then 5 mL 2 M LiOH solution was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na₂SÛ4, filtered and concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. Diastereoisomer eluting later was collected as Example 293. HRMS calculated for C38H41CIN4O7S: 732.2384; found 733.2476 (M+H).

Examp le 294 (2A)-3 - {2- [( 1 -benzyl-1 H-1,2,3 -triazol-4-yl)methoxy]phenyl} -2 - {[(55„)-5(3-chIoro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl) -6-(furan-2yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}propanoic acid and

-249Example 295 (27?)-3-{2-[(l-benzyl-lH-l^,3-triazol-5-yl)methoxy]phenyl)-2-{[(55_n)-5{3-chloiO-2-methyl-4-[2-(4-methylpÎperazin-1-yl)ethoxy]phenyl}-6-(furan-2yl)thieno[2,3-i(]pyrimidin-4-yl]oxy}propanoic acid

To a THF solution of 310 mg ethyl (2R)-2-[(55„)-5-[3-chloro-2-methyl-4-[2-(4methylpiperazin-I-yl)ethoxy]phenyl]-6-(2-furyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-(2prop-2-ynoxyphenyl)propanoate (see Step A of Example 216) (0.433 mmol), 86 mg benzyl azide (0.649 mmol) and 3 mg Cp*Ru(PPh3)₂Cl were added and the mixture was stirred at 70°C until no further conversion was observed. Then it was concentrated under reduced pressure and the crude product was purified via flash chromatography using DCM and MeOH as eluents to obtain the mixture of triazole regioisomers. Then 185 mg of this mixture (0.218 mmol) was dissolved in 5 mL dioxane / water (1:1) and 92 mg LiOH x H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with

DCM. The combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure. The regioisomers were separated and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. Regioisomer eluting earlier was collected as Example 294. HRMS calculated for

C43H42CIN7O6S: 819.2606; found 410.6375 (M+2H), Regioisomer eluting later was collected as Example 295. HRMS calculated for C43H4₂ClN70éS: 819.2606; found 410.6381 (M+2H).

Example 296 (2R)-2-{[(55_e)-5-{3-chloro-2-methyl-4-[2-(4-methyl-4-oxidopiperazin-lyl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3-iZ]pyrimidin-4-yl]oxy}-3-(225 methoxyphenyl)propanoic acid

During the synthesis of Example 209, Example 296 was formed and isolated as a side product. HRMS calculated for C34H₃₅C1N4O₇S: 678.1915; found 679.1966 (M+H).

Example 297 (2/0-2-{[(5.S\)-5-{3-chloro-2-methyl-4-[2-(4-rnethyl-l,4-dioxidopiperazinl-yl)ethoxy]phenyl)-6-(furan-2-yI)thieno[2,3-i/Jpyrimidin-4-yl]oxy )-3-(2methoxyphenyl)propanoic acid

-250200 mg (2Æ)-2-{ [(5Sa)-5-{3-chloiO-2-methyl-4-[2-(4-rnethylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-J]pyrimidin-4-yl]oxy}-3-(2-methoxyphenyl) propanoic acid (Example 209) was dissolved in 1 mL methanol and 5 pL 50% aqueous hydrogen peroxide solution was added. The reaction mixture was stirred at room température ovemight. Then water was added and the mixture was extracted with DCM. The organic phase was dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 297.

HRMS calculated for C34H35CIN4O8S: 694.1864; found 695.1911 (M+H).

General procedure (VHa)

Step A:

1.0 eq. of ethyl (2K)-2-[(5S_ÎJ)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(215 furyl)thieno[2,3-r/]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate (Préparation 6e),

2.0 eq. of the appropriate alcohol and 2.0 eq. triphenylphosphine were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. di/er/butyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure, the crade ester was purified via flash 20 chromatography using DCM and MeOH as eluents.

Step B:

The obtained ester was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH x

H2O was added. The mixture was stirred at room température until 110 further conversion 25 was observed. The reaction mixture was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na₂SO₄₅ concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

251 Example 298 (27?)-2-{[(55_σ)-5-(3-ο1ύθΓθ-2-ηκώγ1*4-{[(25/1-ιη6ΐ1ν1ργιτο1ΐάΐη-2yi]methoxy}phenyl)-6-(furan-2-yl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-(2methoxyphenyi)propanoic acid

Using General procedure (Vlîa) and [(2$- 1-methylpyrrolidin-2-yl]methanol as the appropriate alcohol Example 298 was obtained. HRMS calculated for C33H32CIN3O6S: 633.1700; found 634.1771 (M+H)

Example 299 (2R)-2- {[(5S_tf)-5-(3 -chloro-2-methyl-4- {[(2R)-1 -methylpyrro!idin-2yl]methoxy}phenyl)-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General procedure (Vlîa) and [(2Æ)-l-methylpyrrolidin-2-yl]methanol as the appropriate alcohol Example 299 was obtained. HRMS calculated for C33H32CIN3O6S: 633.1700; found 634.1774 (M+H)

Example 300 (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[(3Æ or S)-(l-methylazepan-3y!)oxy]phenyl}-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General procedure (Vlîa) and (l-methyI-2-piperidyl)methanol as the appropriate alcohol Example 300 was obtained collecting only the later eluting diastereomer (absolute configuration not confîrmed). HRMS calculated for C34H34CIN3O6S: 647.1857; found 648.1916 (M+H)

Example 301 (2/?)-2-{[(5S_fl)-5-{3-chloro-2-niethyl-4-[((3Æ or S)-l-methyIpiperidin-3yI)oxy]phenyl}-6-(furan-2-yl)thieno[2_s3-i7]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid and

Example 302 (2Æ)-2-{[(55_e)-5 -{3-chloro-2-inethyl-4-[((3S or Æ)-l-methylpiperidin-3yl)oxy]phenyl}-6-(furan-2-y])thieno[2,3-i/)pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

-252Using General procedure (Vlla) and l-methylpiperidin-3-ol as the appropriate alcohol

Example 301 was obtained collecting the earlier eluting diastereomer (absolute configuration not determined). HRMS calculated for C33H32CIN3O6S: 633.1700; found

634.1771 (M+H) and Example 302 was obtained collecting the later eluting diastereomer (absolute configuration not determined). HRMS calculated for C33H32CIN3O0S: 633.1700; found 634.1763 (M+H)

Example 303 (2Æ)-2-{[(5S_rt)-5-{3-chloiO-2-methyl-4-[(l-methylpyriOlidin-310 yl)oxy]phenyl}-6-(furan-2-yl)thieno[2,3-(/|pyrimidin-4-yl]oxy}“3-(2-methoxyphenyl) propanoic acid

Using General procedure (Vlla) and l-methylpyrrolidin~3-ol as the appropriate alcohol

Example 303 was obtained. HRMS calculated for C32FI30CIN3O6S: 619.1500; found 15 620.1544 (M+H)

Example 304 (2R)-2- {[(55₀)-5- {3-chloro-2-methyl-4-[(l -methylpiperidin-4yl)oxy]phenyl}-6-(furan-2-yl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-(2-methoxyphenyI) propanoic acid

Using General procedure (Vlla) and l-methylpiperidin-4-ol as the appropriate alcohol Example 304 was obtained. HRMS calculated for C33H32CIN3O6S: 633.1700; found 634.1753 (M+H)

Example 305 (27?)-2-({(5S_£,)-5-[3-chloro-2-metliyl-4-((3S' or Â)-pyrrolidin-3yloxy)phenyl]-6-(furan-2-yl)thieno[2,3-iZ|pyrimidin-4-yl}oxy)-3-(2-methoxyphenyI) propanoic acid and

Example 306 (2R)-2-({(5S_£J)-5-[3-chloro-2-methyl-4-((35' or Æ)-pyrrolidin-330 yloxy)phenyl]-6-(furan-2-yl)thieno[2,3-</]pyrimidin-4-yl}oxy)-3-(2-methoxyphenyl) propanoic acid

-253Using General procedure (Vlla) and pyrrolidin-3-ol as the appropriate alcohol Example 305 was obtained collecting the earlier eiuting diastereomer (absolute configuration not confirmed). HRMS calculated for C₃iH₂gCIN₃O₆S: 605.1387; found 606.1472 (M+H), and Example 306 was obtained collecting the later eiuting diastereomer (absolute configuration not confirmed). HRMS calculated for C31H28CIN3O6S: 605.1387; found 606.1461 (M+H)

Example 307 (222)-2-(((55^)-5-(4-((35 or Â)-l-azabicyclo[2.2.2]oct-3-yloxy)-3-chloro-2methylphenyl]-6-(furan-2-yl)thieno[2,3-</]pyrimidin-4-yl} oxy)-3 -(2methoxyphenyl)propanoic acid and

Example 308 (222)-2-(((55_Λ)-5-[4-((322 or S)-l-azabicyclo[2.2.2]oct-3-yloxy)-3-chloro-2methylphenyl]-6-(furan-2-yl)thieno[2,3-if]pyrimidin-4-yl}oxy)-3-(2methoxyphenyl)propanoic acid

Using General procedure (Vlla) and quinuclidin-3-ol as the appropriate alcohol Example 307 was obtained collecting the earlier eiuting diastereomer (absolute configuration not confirmed). HRMS calculated for C34H32CIN3O6S: 645.1700; found 646.1799 (M+H), and Exampie 308 was obtained collecting the later eiuting diastereomer (absolute configuration not confirmed). HRMS calculated for C34H32CIN3O6S: 645.1700; found 646.1746 (M+H)

Example 309 (22?)-2-{[(55_rt)-5-(3-chloro-2-nietbyl-4-[((25 or 22)-1-methylpiperidin-2yl)methoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i(|pyrimidin-4-yl]oxy}-3-(2-methoxyphenyl) propanoic acid

Using General procedure (Vlla) and (l-methyl-2-piperidyl)methanol as the appropriate alcohol Example 309 was obtained collecting the earlier eiuting diastereomer (absolute configuration not confirmed). HRMS calculated for C34H34CIN3O6S: 647.1857; found 648.1934 (M+H)

-254Example 310 (2R)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[(l-methylpyrrolidin-3-yl)methoxy] phenyl}-6-(furan-2-yl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-(2-methoxyphenyl) propanoic acid

Using General procedure (Vlla) and (l-methylpyrrolidin-3-yl)methanol as the appropriate alcohol Example 310 was obtained. HRMS calculated for C33H32CIN3O6S: 633.1700; found 634.1775 (M+H)

Example 311 (2J?)-2-{[(50’_a)-5-{3-chloro-2-methyl-4-[(l-methylpiperidin-4-yl)methoxy] phenyl}-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yi]oxy}-3-(2-methoxyphenyl) propanoic acid

Using General procedure (Vlla) and (1-methyl-4-piperidyl)methanol as the appropriate . alcohol Example 311 was obtained. HRMS calculated for C34H34CIN3O6S: 647.1857;

found 648.1911 (M+H)

Example 312 (27?)-2-{[(55_a)-5-(3-chloro-4-{[l-(2-methoxyethyl)pyrrolidin-3-yl]methoxy} -2-methylpheny l)-6-(furan-2-yl)thieno [2,3 -i/]pyri midin-4-yl] oxy} -3 -(2-methoxyphenyl) propanoic acid

Using General procedure (Vlla) and [l-(2-methoxyethyl)pyriOlidin-3-yl]methanol as the appropriate alcohol Example 312 was obtained. HRMS calculated for C35H36CIN3O7S: 677.1962; found 678.2026 (M+H)

Example 313 (2Â)-2~{[(5S₀)-5-{3-chloro-4-[(l,4-dimethylpiperazin-2-yl)methoxy]-2methylphenyl}-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-methoxyphenyl) propanoic acid

-255Using General procedure (Vlla) and (l^-dimethylpiperazin^-yOmethanol as the appropriate alcohol Example 313 was obtained. HRMS calculated for C34H35CIN4O5S: 662.1966; found 663.2004 (M+H)

Example 314 (2/f)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[(4-methylmorpholïn-2-yl)niethoxy] phenyl}-6-(furan-2-yl)thieno[2,3-<Zjpyrimidin-4-yl]oxy}-3-(2-methoxyphenyl) propanoic acid

Using General procedure (Vlla) and (4-methylmorpholin-2-yl)methanol as the appropriate alcohol Example 314 was obtained. HRMS calculated for C33H32CIN3O7S: 649.1649; found 650.1710 (M+H)

Example 315 (27?)-2-({(5S_ff)-5-[3-chloro-2-methyl-4-(morpholin-2-ylmethoxy)phenyl]-615 (furan-2-yl)thieno[2,3-i/}pyrimidin-4-yl)oxy)-3-(2-methoxyphenyl)propanoic acid

Using General procedure (Vlla) and morpholin-2-ylmethanol as the appropriate alcohol Example 315 was obtained. HRMS calculated for C32H30CIN3O7S: 635.1493; found 636.1518 (M+H)

Example 316 (2J?)-2-{[(55_fl)-5-{3-chloro-2-methyl-4-[2-(l -methylpyrrolidin-2-yl)ethoxy] phcnyl} -6-(furan-2-y l)thieno [2,3 -i/Jpyri m id in-4-yl]oxy} -3 -(2-methoxyphenyl) propanoic acid

Using General procedure (Vlla) and 2-(l-methylpyrrolidin-2-yl)ethanol as the appropriate alcohol Example 316 was obtained. HRMS calculated for C34H3₄ClN30fiS: 647.1857; found 648.1909 (M+H)

Example 317 (22?)-2-{[(5SJ-5-{3-chloro-2-methyl-4-[2-(l -methylpiperidin-430 yl)ethoxy]phenyl) -6-(fuian-2-yl)thieno[2,3-t/}pyrimidin-4-yl]oxy} -3 -(2methoxyphenyl)propanoic acid

-256Using General procedure (VHa) and 2-(l-methyl-4-piperidyl)ethanol as the appropriate alcohol Example 317 was obtained. HRMS calculated for C35H36CIN3O6S; 661.2013; found 662.2056 (M+H)

Example 318 (2j?)-2-{[(5SJ-5-{3-chloiO-2-methyl-4-[2-(4-methylmorpholin-2yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2_i3-i/|pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General procedure (Vlla) and 2-(4-methylmorpholin-2-yl)ethanol as the appropriate alcohol Example 318 was obtained collecting only the later eluting diastereomer (absolute configuration not confirmed). HRMS calculated for C34H34CIN3O7S: 663.1806; found 664.1881 (M+H)

Example 319 (2R)-2-({ (55_Λ)-5-[4-(2 -aminoethoxy)-3-chloro-2-methylphenyl]-6-(furan-2yl)thieno[2,3-ifjpyrimidin-4-yl}oxy)-3-(2-methoxyphenyl)propanoic acid

Using General procedure (Vlla) and 2-aminoethanol as the appropriate alcohol Example 319 was obtained. HRMS calculated for C29H26CIN3O6S: 579.1231; found 580.1301 (M+H)

Example 320 (27?)-2-{[(5S_a)-5-{3-chloro-4-[2-(dirnethylamino)ethoxy]-2“methylphenyl}6-(furan-2-yl)thieno[2,3-c/]pyrimÎdin-4-yl]oxy}-3-(2-methoxyphenyl)propanoic acid

Using General procedure (Vlla) and 2-(dimethylamino)ethanol as the appropriate alcohol Example 320 was obtained. HRMS calculated for C₃₁H₃oC1N306S: 607.1544; found 608.1617 (M+H)

Example 321 (2Æ)-2-{[(5S_a)-5-{3-chloiO-2-methyl-4-[2-(4-methyl-3-oxopiperazin-l yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-4/]pyriniidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

-257Using General procedure (Vlla) and 4-(2-hydroxyethyl)-l-methyl-piperazin-2-one (Préparation 9eg) as the appropriate alcohol Example 321 was obtained. HRMS calculated for C34H33CIN4O7S: 676.1758; found 677.1850 (M+H)

Ex ample 322 (2R)-2- {[(55^)-5 - {3 -chloro-4- [2-(4-ethy lpiperazin-1 -yl)ethoxy] -2methylphcnyl}-6-(furan-2-yl)thicno[2,3-i7]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General procedure (Vlla) and 2-(4-ethylpiperazin-l-yl)ethanol as the appropriate alcohol Example 322 was obtained. HRMS calculated for C35H37CIN4O6S: 676.2122; found 677.2186 (M+H)

Example 323 (2R)-2- {[(5^)-5- (4-[2-(4-acetyIpiperazin- l-yl)ethoxy]-3-chloro-2methylphcnyl}-6-(furan-2-yl)thieno[2,3-<Z]pyriinidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Step A:

141 mg ethyl (27?)-2-[(5S_a)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(2-furyl)thieno[2,3d]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate (Préparation 6e) (0.25 mmol), 0.092 mL 2-piperazin-l-ylethanol (0.75 mmol) and 197 mg triphenylphosphine (0.75 mmol) were dissolved in 5 mL dry tolucnc, then 173 mg di/er/butyl azodicarboxylate (0.75 mmol) was added. The mixture was stirred at 50°C under nitrogen untii no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude ester was purified via flash chromatography using DCM and MeOH as eluents resulting the intermediate product ethyl (2J?)-2-[(5S^)-5-[3-chloro-2-methyl-4-(2-piperazinl-ylethoxy)phenyl]-6-(2-furyl)thieno[2,3-iZ]pyrimidin-4-yl]oxy-3-(2methoxyphenyl)propanoate. ^!H NMR (500 MHz, DMSO-dô): 8.58 (s , IH), 7.79 (dd, IH), 7.25 (d, IH), 7.24 (d, IH), 7.18 (m, IH), 6.91 (d, IH), 6.75 (m, IH), 6.52 (dd, IH), 6.33 (d, IH), 5.69 (dd, IH), 5.41 (dd, IH), 4.27 (m, 2II), 4.05 (m, IH), 4.02 (m, IH), 3.76 (s, 3H), 2.97 (dd, IH), 2.73 (t, 2H), 2.64 (m, 4H), 2.43 (bim, 4H), 2.43 (dd, IH), 1.94 (s, 3H), 1.06 (t, 3H).

- 258 Step B:

mg ethyl (2A)-2-[(5₁S'„)-5-[3-chloro-2-methyl-4-(2-piperazin-l-ylethoxy)phenyl]-6-(2furyl)thieno[2,3-i(]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)piOpanoate (0.13 mmol) and 0.036 mL triethylamirie (0.26 mmol) were dissolved in 1 mL dry DCM at room température. 0.018 mL acetyl chloride (0.26 mmol) was added and the reaction mixture was stirred until no further conversion was observed. The reaction was quenched with water and the mixture was extracted with DCM. The combined organic phases were washed with water, dried with Na₂SÛ4 and concentrated under reduced pressure. Crude ethyl (2Â)-2-[(5>S'₍₇)-5-[4-[2-(4-acetylpiperazin-l-yl)ethoxy]-3-chloro-2-methyl-phenyl]-6(2-furyl)thieno[2,3-(/Jpyrimidin-4-yl]oxy-3-(2-methoxyphenyi)propanoate was dissolved in a mixture of 1 mL dioxane and 1 mL water and 11 mg LiOH x H₂O (0.26 mmol) was added. The mixture was stirred at room température until no further conversion was observed. The reaction mixture was diluted with brine, neutralized with 2 M HCl, extracted with DCM, dried with Na₂SO₄, concentrated under reduced pressure and purified via preparative reversed phase chromatography resulting Example 323. HRMS calculated for C35H35CIN4O7S: 690.1915; found 691.1996 (M+H)

Example 324 (2À)-2-{[(5₁S'_a)-5~(3-chloro-2-methyl-4-{2-[4-(propan-2-yl)piperazin-l yl]ethoxy}phenyl)-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4“yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General procedure (Vlla) and 2-(4-isopropylpiperazin-l-yl)ethanol as the appropriate alcohol Example 324 was obtained. HRMS calculated for C36H39CIN4O6S: 690.2279; found 691.2335 (M+H)

Example 325 (2R)~2-{[(55^)-5-(3-chloro-2-methyl-4-[2-(4-phenylpiperazin-1 yl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General procedure (Vlla) and 2-(4-phenylpiperazin-l-yl)ethano! as the appropriate alcohol Example 325 was obtained. HRMS calculated for C39H37CIN4O6S: 724.2122; found 725.2187 (M+H)

-259Exemple 326 (2Æ)-2-{[(5<S)i)-5-(4-{2-[4-(2-amino-2-oxoethyl)piperazin-l-yl]ethoxy}-3chloro-2-methylphenyl)-6-(fiiran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid mg ethyl (2Æ)-2-[(5S_a)-5-[3-cliloro-2-methyl-4-(2-piperazin-l-ylethoxy)phenyl]-6-(2furyl)thieno[2,3-J)pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate (as described in Step A of Example 323) (0.12 mmol) was dissolved in 2 mL dry THF. 41 mg 2bromoacetamide (0.30 mmol) and 98 mg CS2CO3 (0.30 mmol) were added at room température and the mixture was heated at 70 °C until no further conversion was observed. The mixture was concentrated under reduced pressure and the crude product was hydrolyzed by the addition of 3 mL NaOH solution (10 m/m%) in aqueous methanol (90% methanol). The mixture was stirred at room température until no further conversion was observed. The reaction mixture was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na2SO₄, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents resulting Example 326. HRMS calculated for C35H36CIN5O7S: 705.2024; found 706.2112 (M+H)

Example 327 (2/î)-2-([(5_<S^, _ft)-5-(3-chloro-2-methyl-4-{2-[4-(2,2,2-trifluoroethyl)piperazinl-yl]ethoxy}phenyl)-6-(furan-2-yl)thieno[2,3-ifjpyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General procedure (Vlla) and 2-(4-(2,2,2-trifluoroethyl)piperazin-l-yl]ethanol (Préparation 9eh) as the appropriate alcohol Example 327 was obtained. HRMS calculated for C35H34CIF3N4O6S: 730.1840; found 731.1919 (M+H)

Example 328 (2R)-2-{[(5S_fl)-5-(3-chloro-4-{2-[4-(2,2-difluoroethyl)piperazin-lyljethoxy} -2-methylphenyl)-6-(fùran-2-yl)thieno[2,3-i(]pyrimidin-4-yl]oxy} -3-(2methoxyphenyl)propanoic acid

-260Using General procedure (Vlla) and 2-[4-(2,2-difluorocîhyl)pipcrazin-l-yl]cthanol (Préparation 9ei) as the appropriate alcohol Exampie 328 was obtained. HRMS calculated for CasHsiCHÙNAS: 712.1934; found 713.1978 (M+H)

Example 329 (27?)-2-{[(5S„)-5-(4-[2-(4-benzylpiperazin-l-yl)ethoxy]-3-chloro-2methylphenyl}-6-(furan-2-yl)thieno[2,3iZ]pyriinidin-4-yI]oxy}-3-(2methoxyphenyl)propanoic acid

Step A:

mg ethyl (2R)-2-[(5>S'_(i)-5-[3-chloro-2-methyl-4-(2-piperazin-l-yIethoxy)phenyl]-6-(2furyl)thieno[2,3-i(|pyrimidin“4-yl]oxy-3-(2-methoxyphenyl)propanoate (as described in Step A of Example 323) (0.115 mmol) and 0.013 mL benzaldehyde (0.127 mmol) were dissolved in 1 mL dry DCM. 37 mg sodium triacetoxyborohydride (0.173 mmol) was added and the reaction mixture was stin-ed at room température until no further conversion was observed. The reaction was quenched with NaHCO₃ solution and extracted with DCM. The combined organic phases wcrc dried with Na₂SÛ4 and concentrated under reduced pressure. The crude product was purified using flash chromatography eluting with DCMMeOH gradient.

Step B:

The ester (product of Step A) was hydrolyzed by the addition of 3 mL NaOH solution (10 m/m%) in aqueous methanol (90% methanol). The mixture was stirred at room température until no further conversion was observed. The reaction mixture was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents resulting Example 329. HRMS calculated for C40H39CIN4O6S: 738.2279; found 739.2322 (M+H)

Example 330 (27?)-2-{((55_a)-5“(3-chloro-4“{2-[4-(2-methoxyethyl)piperazin- l-yl]ethoxy}2-methylphenyl)-6-(furan-2-yl)thieno[2,3-<7]pyriniidin-4-yl]oxy}-3-(2methoxyphenyl)piOpanoic acid

-26!Step A:

135 mg ethyl (2R)-2-[(5S„)-5-[3-chloro-2-methyl-4-(2-piperazin-l-ylethoxy)phenyl]-6-(2furyl)thieno[2,3-£/]pyriniidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate (as described in Step A of Exampie 323) (0.20 mmol) was dissoleved in 1.5 mL dry THF. 0.040 mL 1bromo-2-methoxy-ethane (0.40 mmol) and 130 mg Cs₂CÛ3 (0.40 mmol) were added at room température and the mixture was heated at 70 °C until no further conversion was observed. The mixture was concentrated under reduced pressure and the crude product was purified using flash chromatography eluting with a DCM-MeOH gradient.

Step B:

The ester obtained in Step A was hydrolyzed by adding 3 mL NaOH solution (10 m/m%) in aqueous methanol (90% methanol). The mixture was stirred at room température until no further conversion was observed. The reaction mixture was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried with Na₂SO₄, concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents resulting Example 330. HRMS calculated for C36H39CIN4O7S: 706.2228; found 707.2273 (M+H)

Example 331 (2/?)-2- {[(55₀)-5- {3-chloro-2-methyl-4-[2-(methylamino)ethoxy]phenyl} -6(furan-2-yl)thieno[2,3-d]pyrimidin-4-yI]oxy}-3-(2-methoxyphenyl)propanoic acid

Using General procedure (Vlla) and 2-(methylamino)ethanol as the appropriate alcohol Exampie 331 was obtained. HRMS calculated for C30H28CIN3O6S; 593.1387; found 594.1455 (M+H)

Exampie 332 (2R)-2-{ [(5S_a)-5-(3-chloio-2-methyl-4- {[(4-methylpiperazin-1 yl)acetyl]oxy}phenyl)-6-(furan-2-yl)thieno[2,3-<Z]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

-262100 mg ethyl (2Æ)-2-[(5S_n)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(2-furyl)thieno[2,3i/Jpyrimidin-4-yl]oxy-3-(2-methoxyphenyl)piOpanoate (Préparation 6e) (0.18 mmol) was dissolved in 0.5 mL dioxane and a solution of 37 mg LiOH x I-I₂O (0.88 mmol) in 0.5 mL water was added to it. The mixture was stirred at room température for 30 minutes, quenched with water, acidified with dilute hydrochloric acid solution and extracted with DCM. The combined organic phases were dried with Na₂SO₄ and concentrated under reduced pressure. The crude product was re-dissolved in 2 mL dry DCM, 64 mg 2-(4methylpiperazin-l-yl)acetic acid (0.40 mmol), 208 mg PyBOP (0.40 mmol) and 0.060 mL triethylamine (0.44 mmol) were added. The mixture was stirred at room température until no further conversion was observed. Further DCM was added and the organic phase was washed with water, dried with Na₂SO₄ and concentrated under reduced pressure. The crade product was purified with préparative HPLC resulting Example 332. HRMS calculated for C₃₄H33C1N₄O₇S: 676.1758; found 677.1846 (M+H)

Example 333 (2/?)-2-{[(5Æ₀)-5-{3-fluoro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(ftiran-2-yl)thieno[2,3-rZ]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid and

Example 334 (27?)-2- {[(5^)-5- {3-fluoro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-d]pyriinidin-4-yl]oxy}-3-(2mcthoxyphcnyl)propanoic acid

501 mg ethyl (2Æ)-2-[5-(3-fluoro-4-hydroxy-2-methyl-phenyl)-6-(2-furyl)thieno[2,3£Z]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)piOpanoate (Préparation 11b, mixture of diastereomers) (0.913 mmol), 198 mg 2-(4-methylpiperazin-l-yl)ethanol (1.37 mmol) and 480 mg triphenylphosphine (1.83 mmol) were dissolved in 10 mL dry toluene, then 420 mg difôrtbutyl azodicarboxylate (1.83 mmol) was added. The mixture was stirred at 50°C under nitrogen for 45 minutes. The volatiles were evaporated under reduced pressure and the crude ester was purified using flash chromatography (eluents: EtOAc and MeOH). The obtained ester was dissolved in a mixture of 4 mL dioxane and 2 mL water and 200 mg LiOH x H₂O was added. The reaction mixture was stirred at room température for 1.5 hours, quenched by the addition of brine and neutralized with 2 M HCL The mixture was

-263extracted with DCM, dried with Na₂SC)4, concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. Example 333 was obtained as the diastereoisomer eluting earlier from the préparative HPLC column [HRMS calculated for C.34H35FN4O6S: 646.2261; found 647.2365 (M+H)], and Example 334 was obtained as the diastereoisomer eluting later from the préparative HPLC column [HRMS calculated for C34H35FN4O6S: 646.2261; found 647.2302 (M+H)].

Example 335 (2^)-2-(((5^)-5- (3-chloro-2-ethyl-4-[2-(4-methylpiperazin- 1 yl)ethoxy]phenyl}-6-(furan-2-yI)thieno[2,3-rf]pyriinidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid and

Example 336 (2R)-2-([(5R_fl)-5-(3-chloro-2-ethyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-iZ]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

250 mg ethyl ((2R)-2-[5-(3-chloro-2-ethyl-4-hydroxy-phenyl)-6-(2-furyl)thieno[2,3</]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate (Préparation lia, mixture of diastereomers) (0.40 mmol), 115 mg 2-(4-methylpiperazin-l-yl)ethanol (0.80 mmol) and 210 mg triphenylphosphine (0.80 mmol) were dissolved in 5 mL dry toluene, then 184 mg ditertbutyl azodicarboxylate (0.80 mmol) was added. The mixture was stirred at 50°C under nitrogen for 1 hour. The volatiles were evaporated under reduced pressure and the crude ester was purified using flash chromatography (eluents: EtOAc and MeOH). The obtained ester was dissolved in a mixture of 4 mL dioxane and 2 mL water and 100 mg LiOH x H2O was added. The reaction mixture was stirred at 30 °C for 1 hour. Water was added to the mixture and pH was set to 4-5 with 2 M HCl. The mixture was extracted with DCM, dried with Na2SÛ4, concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NI-I4HCO3 solution and MeCN as eluents. Example 335 was obtained as the diastereoisomer eluting later from the préparative HPLC column [HRMS calculated for C35H37CIN4O6S: 676.2122; found 677.2204 (M+H)], while Example 336 was obtained as the diastereoisomer eluting earlier

-264from the préparative HPLC column [HRMS calculated for C35H37CIN4O6S; 676.2122; found 677.2181 (M+H)]

Example 33 7 (2R)-2- {[5-{3 -chloro-2 -fluoro -4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-ri]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid (mixture of diastereoisomers)

503 mg ethyl (2À)-2-[5-bromo-6-(2-furyl)thieno[2,3-d]pyrimidïn-4-yl]oxy-3-(2methoxyphenyl)propanoate (Préparation 4e) (1.00 mmol), 900 mg l-[2-[2-chloro-3fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboiOlan“2-yI)phenoxy]ethyl]-4-methyl-piperazine (Préparation 5f) (2.20 mmol), 35 mg Ataphos (0.05 mmol) and 977 mg Cs₂CO₃ (3.00 mmol) were dissolved in 10 mL dioxane and 2 mL water. It was heated to 110°C for 15 minutes via microwave in-adiation. Then it was diluted with brine, extracted with DCM, and the combined organic phases were dried over Na₂SÛ4, filtered and concentrated under reduced pressure and purified via reversed phase chromatography, using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. The obtained ester was dissolved in a mixture of 5 mL dioxane and 5 mL water and 200 mg LiOH * H₂O was added. The reaction mixture was stirred at room température until no further conversion was observed. Water was added to the mixture and pH was set between 4-5 with 2 M HCl. The mixture was extracted with DCM, and the combined organic phases were dried with Na₂SÛ4, concentrated under reduced pressure and purified via préparative reversed phase chromatography resulting Exampie 337. HRMS calculated for C33H32CIFN4O6S: 666.1715; found 667.1792 (M+H)

General procedure (Villa)

Step A:

1.0 eq. 4-chloro-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(2fui-yl)thieno[2,3-t/]pyrimidine (Préparation 14), 1.2 eq. of the appropriate alcohol and 3.0 eq. césium carbonate were dissolved in dry /er/butanol or dry DMSO (0.2 M for Préparation 14). The mixture was stirred at 60°C under nitrogen until no further conversion was observed. The reaction mixture was cooled to room température then it ♦

-265was diluted with brine and extracted with DCM. The combined organic phases were dried over MgSO₄ and evaporated under reduced pressure. The crade product was purified via flash chromatography using EtOAc / MeOH as eluents.

The product of Step A was dissolved in dioxane / H₂O (1:1, 0.2 M for the product of Step A) and 10 eq. LiOH x H₂O was added then it was stirred at room température until no further conversion was observed. The reaction mixture was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄, concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

Exampie 338 (2R)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2(difluoromethoxy)phenyl]propanoic acid

Using General procedure (Villa) and methyl (2R)-3-[2-(difluoromethoxy)phenyl]-2· hydroxy-propanoate (Préparation 3aj) as the appropriate alcohol; the diastereoisomer eluting later was collected as Example 338. HRMS calculated for Cm^CIF^OîS: 698.1777; found 699.1866 (M+H)

Example 339 (2R)- {[(5/^)-5- {3-chIoro-2-mcthyl-4-[2-(4-mcthylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-<7Jpyrimidin-4-yl]oxy}(phenyl)ethanoicacid and

Example 340 (2R)- {[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl} -6-(furan-2-yl)thieno[2,3-<flpyrimidin-4-yl]oxy} (phenyl)ethanoic acid

Using General procedure (Villa) and methyl (2Æ)-2-hydroxy-2-phenyl-acetate as the appropriate alcohol; the diastereoisomer eluting earlier was collected as Example 339 and the diastereoisomer eluting later was collected as Example 340. HRMS calculated for

C₃₂H_3lCIN₄O₅S: 618.1704; found 619.1766 (M+H) and 619.1768 (M+H) ♦

-266Exampie 341 (25)-2- {[(52^)-5-(3 -chl oro-2-methyl -4 - [2-(4-methylpiperazin -1 yl)ethoxy]phenyl} -6-(fiiran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3 -(2fluorophenyl)propanoic acid

Using General procedure (Villa) and ethyl (25)-3 -(2-fluorophenyl)-2-hydroxy-propanoate (Préparation 3az) as the appropriate alcohol; the diastcrcoisomer eluting later was collected as Example 341. HRMS calculated for C33H32CIFN4O5S: 650.1766; found 651.1825 (M+H)

Example 342 (2R, 35)-2-( [(5Æ„)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i7]pyrimidin-4-y]]oxy}-3-hydiOxy-3phenylpropanoic acid and

Example 343 (22î,35)-2-([(55_£ï)-5-(3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]pheny 1}-6-(furan-2-yl)thieno [2,3-iTJpyrim îd i n-4-yl]oxy}-3-hydroxy-3phenylpropanoic acid

Using General procedure (Villa) and methyl (2 R,35)-2,3-dihydroxy-3-phenyl-propanoate as the appropriate alcohol; the diastereoisomer eluting earlier was collected as Example 342 and the diastereoisomer eluting later was collected as Example 343. HRMS calculated for C₃3ll33ClN₄O₆S: 648.1809; found 649.1879 (M+H) and 649.1875 (M+H)

Example 344 (2Æ)-2-{[(55_<l)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-(2-methoxy-5methylphenyl)propanoic acid

Using General procedure (Villa) and ethyl (2J?)-2-hydroxy-3-(2-methoxy-5-methylphenyl)propanoate (Préparation 3at) as the appropriate alcohol; the diastereoisomer eluting later was collected as Example 344. HRMS calculated for C35H37CIN4O6S:

676.2122; found 677.2176 (M+H)

-267Example 345 (2R)-2-{[(5S₍,)-5-{3-chloiO-2-methyl-4-[2-(4-methylpïperazin-l yl)ethoxy]phenyl}-6-(furan-2-yi)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(5-fluoro-2methoxyphenyl)propanoic acid

Using General procedure (Villa) and ethyl (2/?)-3-(5-fluoro-2-methoxy-phenyI)-2hydroxy-propanoate (Préparation 3ar) as the appropriate alcohol; the diastereoisomer eluting Iater was collected as Example 345. HRMS calculated for C34H34CIFN4O6S: 680.1872; found 681.1947 (M+H)

Example 346 (2R)-2-{[(55_fl)-5-{3-chloro-2-methyl-4-[2-(4--methylpiperazin-lyl)ethoxy]phenyl}“6-(furan-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(4-fluoro-2methoxyphenyl)propanoic acid

Using General procedure (Villa) and ethyl (2R)-3-(4-fluoro-2-methoxy-phenyl)-2hydroxy-propanoate (Préparation 3as) as the appropriate alcohol; the diastereoisomer eluting Iater was collected as Example 346. HRMS calculated for C.34H34CIFN4O6S: 680.1872; found 681.1915 (M+H)

Exemple 347 (2R)-2-{[(55,)-5- {3 -chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(3methylphenyl)propanoic acid

Using General procedure (Villa) and methyl (25)-2-hydroxy-3-(m-tolyI)propanoate (Préparation 3ap) as the appropriate alcohol; the diastereoisomer eluting Iater was collected as Example 347. HRMS calculated for C34H35CÎN4O5S: 646.2017; found 647.2073 (M+H)

Example348 (2R)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-(3fluorophenyl)piOpanoic acid

-268Using General procedure (Villa) and methyl (2R)-3-(3-fluorophenyl)-2-hydroxypropanoate (Préparation 3ak) as the appropriate alcohol; the diastereoisomer eluting later was collected as Example 348. HRMS calculated for C33H32CIFN4O5S: 650.1766; found 651.1818 (M+H)

Example 349 (2R)-2-{[(55/)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-(3methoxyphenyl)propanoic acid

Using General procedure (Villa) and methyl (2Æ)-2-hydroxy-3-(3methoxyphenyl)propanoate (Préparation 3al) as the appropriate alcohol; the diastereoisomer eluting later was collected as Example 349. HRMS calculated for C₃4H3₅C1N₄O₆S.· 662.1966; found 663.2043 (M+H)

Example 350 (2R)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]pheny 1} -6-(furan-2-yl)thieno[2,3 +/| py rimidin-4-y 1 ] oxy )-3-(2,3difluorophenyl)piOpanoic acid

Using General procedure (Villa) and methyl (27?)-3-(2,3-difluorophenyl)-2-hydroxy· propanoate (Préparation 3am) as the appropriate alcohol; the diastereoisomer eluting later was collected as Example 350. HRMS calculated for C33H31CIF2N4O5S: 668.1672; found 669.1729 (M+H)

Example 351 (27?)-2-{[(55/)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-methoxy-3methylphenyl)propanoic acid

Using General procedure (Villa) and ethyl (27?)-2-hydroxy-3-(2-methoxy-3-methylphenyl)propanoate (Préparation 3au) as the appropriate alcohol; the diastereoisomer eluting later was collected as Example 351. HRMS calculated for C35H37CIN4O6S:

676.2122; found 677.2221 (M+H)

-269Example 352 (2R)-2- {[(5S₀)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)elhoxy]phenyl}-6-(furan-2-yl)lhieno[2,3-iZ]pyiimidin-4-yl]üxy)“3-(3-fluoro-2methoxyphenyl)propanoic acid

Using General procedure (Villa) and ethyl (222)-3-(3-fluoro-2-methoxy-phenyl)-2hydroxy-propanoate (Préparation 3aq) as the appropriate alcohol; the diastereoisomer eluting later was collected as Example 352. HRMS calculated for C34H34CIFN4O6S: 680.1872; found 681.1963 (M+H)

Example 353 (22?)-2-([(55_t,)-5-(3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-[2(trifluoroniethyl)phenyl]propanoic acid

Using General procedure (Villa) and methyl (2À)-2-hydroxy-3-[215 (trifluoromethyl)phenyl]propanoate (Préparation San) as the appropriate alcohol; the diastereoisomer eluting later was collected as Example 353. HRMS calculated for C34H32CIF3N4O5S: 700.1734; found 701.1803 (M+H)

Example 354 (222)-2-( [(55_σ)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 20 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-J]pyrimidin-4-yl]oxy}-3-(2methylphenyl)propanoic acid

Using General procedure (Villa) and methyl (222)-2-hydroxy-3-(o-tolyl)propanoate (Préparation 3ao) as the appropriate alcohol; the diastereoisomer eluting later was collected as Example 354. HRMS calculated for C34H35CIN4O5S: 646.2017; found 647.2087 (M+H)

Example 355 (22?)-3-[2-(aminomethyl)phenyl]-2-([(5S_ti)-5-(3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2₅3-iZ|pyrimidin-430 yl]oxy}propanoic acid

Step A:

-270252 mg 4-chloro-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(2furyl)thieno[2,3-djpyrimidine (Préparation 14) (0,50 mmol), 196 mg ethyl (272)-3-(2((terZ-butoxycarbonylamino)methyl]phenyl]-2-hydroxy-propanoate (Préparation 3aw) (0.60 mmol) and 488 mg césium carbonate (1.50 mmol) were dissolved in dry ter/butanol (0.1 M for Préparation 14). The mixture was stirred at 60°C under nitrogen until no further conversion was observed. The mixture was cooled to room température, then it was diluted with brine and extracted with EtOAc. The combined organic phases were dried over MgSO₄, filtered and concentrated, and then purified by flash chromatography on silica gel using EtOAc / MeOH as eluents to give ethyl (272)-3-[2-((terT butoxycarbonylamino)methyl]phenyl]-2-(5-[3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(2-furyl)thieno[2,3-rf|pyrimidin-4-yl]oxy-piOpanoate.

Step B:

198 mg ethyl (27î)-3-[2-[(Zez7-butoxycaibonylamino)methyl]phenyl]-2-[5-[3-chloro-2methyl-4-[2-(4-methy]piperazin-l-yi)ethoxy]phenyl]-6-(2-furyl)thieno[2,3-i(]pyrimidin-4yljoxy-propanoate (0.250 mmol) was dissolved in 10 mL dry DCM, then 1 mL TFA was added and it was stirred at room température until no further conversion was observed, and then reaction mixture was washed with saturated NaHCO3. The organic layer was dried over MgSÛ4, filtered and the volatiles were evaporated under reduced pressure to give ethyl (2Æ)-3-(2-(aminomethyl)phenyl]-2-(5-(3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(2-furyl)thieno(2,3-tZ(pyrimidin-4-yl]oxy-piOpanoatc.

Step C:

mg ethyl (2R)-3-(2-(aminomethyl)phenyl]-2-(5-[3-chloiO-2-methyl-4-(2-(4methylpiperazin-l-yl)ethoxy]phenyl]-6-(2-furyl)thieno[2,3-d]pyrimidin-4-yl]oxypropanoate (0.081 mmol) was dissolved in 1 mL dioxane/water (1:1) and 68 mg LiOH x H2O was added. The mixture was stirred at room température until no further conversion was obseived. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na2SO₄, filtered, concentrated and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. The diastereoisomer eiuting later was collected as Example 355. HRMS calculated for C34II36CIN5O5S: 661.2126; found 331.6148 (M+2H)

-27IExample 356 (27?)-3-{2-[(acetylamino)methyl]phenyl}“2-{[(5<S’_i,)-5-{3-chloro-2-methyl-4[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-<7]pyrimidin-4yl]oxy}propanoic acid

Step A:

100 mg ethyl (2R)-3-[2-(aminomethyl)phenyl]-2-[5-[3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl]-6-(2-furyl)thieno[2,3-i7]pyrimidin-4-yl]oxypropanoate (0.145 mmol) (Step B of Example 355) and 61 μΐ triethyl amine (435 pmol) were dissolved in 5 mL DCM, and then 12 μΐ acetyl chloride (174 pmol) was added. Reaction mixture was stirred at room température until no further conversion was observed. The crude mixture was purified via flash chromatography using EtOAc / MeOH as eluents to give ethyl (2Æ)-3-[2-(acetamidomethyl)phenyl]-2-[5-[3-chloro-2-methyl-4-[2(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(2-furyl)thieno[2,3-iZ]pyrimidin-4-yl]oxy15 propanoate.

Sien B:

mg ethyl (2Æ)-3-[2-(acetarnidomethyl)phenyl]-2-[5-[3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl]-6-(2-furyl)thieno[2,3-t7]pyrimidin-4-yl]oxy20 propanoate (0.10 mmol) was dissolved in 2 mL dioxane / water (1:1) and 84 mg LiOH * H₂O (2.0 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na₂SO4, fîltered and concentrated and purified via préparative reverse phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. The diastereoisomer eluting later was collected as Example 356. HRMS calculated for C36H38CIN5O6S: 703.2231; found 704.231 (M+H)

Example 357 (2R)-2- {[(55^)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 30 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-rf]pyrimidin-4“yl]oxy}-3-(2lluoiOphenyl)propanoic acid

-272Using General procedure (Villa) and ethyl (2Æ)-3-(2-fluorophenyl)-2-hydroxy-propanoate (Préparation 3ba) as the appropriate alcohol; the diastereoisomer eluting later was collected as Exampie 357. HRMS calculated for C33H32CIFN4O5S: 650.1766; found 651.1827 (M+H)

Exemple 358 (27?)-3-{2-[(rcr/-butoxycarbonyl)amino]phenyl}-2-([(5S₀)-5-{3-chloro-2methyl-4-[2-(4-methylpiperazin-l -yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3i/Jpyri midin-4-yl] oxy}propanoic acid

Using General procedure (Villa) and ethyl (27?)-3-[2-(/er/-butoxycarbonylamino)phenylJ2-hydroxy-propanoate (Préparation 3av) as the appropriate alcohol; the diastereoisomer eluting later was collected as Example 358. HRMS calculated for C38H42CIN5O7S: 747.2493; found 748.2538 (M+H)

Exemple 359 (27?)-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-ly4)ethoxy]phenyl}-6~(furan-2-yl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3--(2,3-dihydro-· 1 benzofuran-7-yl)propanoic acid

Using General procedure (Villa) and ethyl (2À)-3-(2,3-dihydrobenzofuran-7-yl)-220 hydroxy-propanoate (Préparation 3bd) as the appropriate alcohol; the diastereoisomer eluting later was collected as Exemple 359. HRMS calculated for C35H35CIN4O6S: 674.1966; found 675.2033 (M+H)

Example 360 (25)-( [(57?„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l25 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-<7|pyrimidin-4-yl]oxy}-3-(2,3-dihydiO-1 benzofuran-7-yl)propanoic acid

Using General procedure (Villa) and ethyl (25)-3-(2,3-dihydiObenzofuran-7-yl)-2hydroxy-propanoate (Préparation 3be) as the appropriate alcohol the diastereoisomer eluting later was collected as Exampie 360. HRMS calculated for C35H35CIN4O6S: 674.1966; found 675.2025 (M+H) *

-273 Example 361 (2S)-{ [(5K„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-iflpyrimidm-4-yl]oxy}-3-{2-[(2,2,2trifluoroethyl)sulfanyl]phenyl)propanoic acid

Using General procedure (Villa) and ethyl (2S)-2-hydroxy-3-[2-(2,2,2trifluoroethylsulfanyl)phenyl]propanoate (Préparation 3ax) as the appropriate alcohol; the diastereoisomer eluting later was collected as Example 361. HRMS calculated for C35H34CIF3N4O5S2: 746.1611; found 747.1678 (M+H)

Example 362 (2J?)-{[(55^, _<J)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-tZ]pyrimidin-4-yl]oxy}-3-{2-[(2,2,2trifluoroethyl)sulfanyl]phenyl}propanoicacid

Using General procedure (Villa) and ethyl (2K)-2-hydroxy-3-[2-(2,2,215 trifluoroethylsulfanyl)phenyl]propanoate (Préparation 3ay) as the appropriate alcohol the diastereoisomer eluting later was collected as Example 362 was obtained. HRMS calculated for C35H34CIF3N4O5S2: 746.1611; found 747.1682 (M+H)

General procedure (IXa)

Step A:

eq, of ethyl (2/?)-2-[6-(5-chloro-2-iuryl)-(55_</)-5-[3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl]thieno[2,3-i/]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 81), 2 eq. of the appropriate alcohol and 2 eq. PPh₃ were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. di/er/butyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen. After no further conversion observed the volatiles were evaporated under reduced pressure and the crude ester was purified via flash chromatography using EtOAc and MeOH as eluents.

Step B:

The product of Step A was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH x H₂O was added. The mixture was stirred at room température until no further conversion

17193φ

-274was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with

DCM. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified via prepaiative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

Example 363 (27?)-2-{[6-(5-chloiOfuran-2-yl)-(55_fl)-5-(3-chloiO-2-mcthyl-4-[2-(4methylpiperazin-1 -yl)ethoxy]phenyl}thieno[2,3-i/]pyrimidin-4-yl]oxy} -3-(2methoxyphenyl)propanoic acid

Using General procedure (IXa) and methanol as the appropriate alcohol Example 363 was obtained. HRMS calculated for C₃4H₃4Cl₂N₄O₆S: 696.1576; found 697.1656 (M+H)

Example 364 (2J?)-2-{[6-(5-chlorofuran-2-yl)-(55_a)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyI}thieno[2,3-JJpyrimidin-4-yl]oxy}-3-{2'[(2Æ)tetrahydrofüian-2-ylmethoxy]phenyl}propanoic acid

Using General procedure (IXa) and [(2Æ)-tetrahydrofuran-2-yl]methanol as the appropriate alcohol Example 364 was obtained. HRMS calculated for C₃8H₄oCl₂N₄07S: 766.1995;

found 767.2056 (M+H)

Example 365 (27?)-2-{[6-(5-chlorofuran-2-yl)-(55_fl)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3-iZ|pyrimidÎn-4-yl]oxy}-3-[2-(2,2,2trifluoroethoxy)phenyl]propanoic acid

214 mg ethyl (2Æ)-2-|‘6-(5-chloro-2-furyl)-(55_CT)-5-[3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl]thieno[2,3-c(|pyrimidin-4-yl]oxy-3-(2-hydiOxy phenyl)propanoate (Préparation 8f) (0.300 mmol) and 138 mg K₂CO₃ (1.00 mmol) were dissolved in 2 mL DMF, then 232 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.00 mmol) was added. The mixture was stirred at room température under nitrogen for 7 hours. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The crade product was dissolved in 8 mL dioxane-water (1:1) and 126 mg LiOH x H₂O (3.00 mmol) was added. The mixture was stirred at room température for 1 hour.

-275Then it was diluted with brine, neutralized with 2 M HCI, and extracted with DCM. The combined organic phases were dried over Na₂SO₄, concentrated under reduced pressure and the residue was purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to give Example 365. HRMS calculated for C₃₅H₃₃Cl₂F₃N₄O₆S: 764.145; found 765.1523 (M+H)

Exampie 366 (2R)-2-{[6~(5-chlorofuran-2-y!)-(5S_a)-5“[3-chloiO-2-methyl-4-[2-(4methylpiperazin-l-yI)ethoxy]phenyl}thieno[2,3-</jpyrimidin-4-yl]oxy}-3-[2-(pyridin-2ylmethoxy)phenyl]propanoic acid

Using General procedure (IXa) and 2-pyridyimethanol as the appropriate alcohol Example 366 was obtained. HRMS calculated for C₃9H₃7C1₂N5O6S: 773.1842; found 387.5992 (M+2H)

Example 367 (2R)-2-{ [6-(5-chlorofuran-2-yl)-(55'_ff)-5-{3”Chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl)thieno[2,3-i(jpyrimidin-4-yl]oxy}-3-(2-{[2(trifluoromethyl)pyrimidin-4-yl]methoxy}phenyl)propanoicacid

Using General procedure (IXa) and [2-(trifluoromethyl)pyrimidin-4-yl]methanol (Préparation 9bj) as the appropriate alcohol Example 367 was obtained. HRMS calculated for C₃9H₃5C1₂F₃N(>O6S: 842.1668; found 843.175 (M+H)

Example 368 (27?)-2-{[6-(5-chlorofuran-2-yl)-(55_fl)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-1 -yl)ethoxy]phenyl} thieno[2,3-^pyrimidin-4-yl]oxy}-3-(2- {[2(morpholin-4-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (IXa) and (2-(morpholin-4-yl)pyrimidin-4-yl)methanol (Préparation 9ar) as the appropriate alcohol Example 368 was obtained. HRMS calculated for C₄₂H4₃C1₂N₇O₇S: 859.2322; found 430.6247 (M+2H) *

-276Example 369 (27?)-2-{(6-(5-chlorofuran-2-yl)-(5S_i,)-5-(3-chloro-2 -methyl-4-(2-(4methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxy]phenyl }propanoic acid

Using General procedure (IXa) and (2-methoxypyrimidin-4-yl)methanol as the appropriate alcohol Example 369 was obtained. HRMS calculated for C39H38CI2N6O7S: 804.19; found 805.2032 (M+H)

Example 370 (2A)-2-( [6-(5-chlorofuran-2-yl)-(5S_fl)-5-(3-chloiO-2-methyl-4-[2-(4methyIpiperazin-l-yl)ethoxy]phenyl}thieno(2,3-i(]pyrimidin-4-yl]oxy}-3-[2-(pyrimidin-4ylmethoxy)phenyl]propanoic acid

Using General procedure (IXa) and pyrimidm-4-ylmethanol as the appropriate alcohol

Example 370 was obtained. HRMS calculated for C3₈H₃6Cl₂NfiOfiS: 774.1794; found 775.182 (M+H)

Example 371 (2Â)-2-{[6-(5-chlorofuran-2-yl)-(55_a)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-(2-[(l-niethyllH-pyrazol-5-yl)methoxy]phenyl}piOpanoic acid

Using General procedure (IXa) and (1 -methyl-177-pyrazol-5-yl)methanol as the appropriate alcohol Example 371 was obtained. HRMS calculated for CjgHagChNeOgS: 776.1951;

found 777.1999 (M+H)

Example 372 (2R)-2-{[6-(5-chlorofuran-2-yl)-(5S_fl)-5-(3-chloro-2-niethyl-4-[2-(4methylpiperazin-1 -yl)ethoxy]phenyl}thieno[2,3-iZ]pyrimidin-4-yl]oxy} -3-(2-(( 1 -ethyl-1//pyrazol-5-yl)methoxy]pheny 1} propanoic acid

Using General procedure (IXa) and (l-ethyl-17Z-pyrazol-5-yl)methanol (Préparation 9da) as the appropriate alcohol Example 372 was obtained. HRMS calculated for

C₃9H4oC12N₆0₆S: 790.2107; found 396.1113 (M+2H)

-277Example 373 (2R)-2-{[6-(5-chlorofuran-2-yl)-(5₁S'_i,)-5-{3-cliloro-2-methyl-4-[2-(4metliylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3-i(|pyrimidin-4-yl]oxy}-3-(2-{[]-(2,2,2trifluoroethyl)-l H-pyrazol-5-yl]methoxy}phenyl)propanoic acid

IJsing General procedure (TXa) and [l-(2,2,2-trifluoroethyl)-l//-pyrazol-5-yl]methanol (Préparation 9du) as the appropriate alcohol Example 373 was obtained. HRMS calculated for C₃9H₃₇C1₂F₃N₆O₀S: 844.1824; found 845.186 (M+I-I)

Example 374 (2R)-2-[[6-(5-chloiOfuran-2-yl)-(55'_rt)-5-{3-chloiO-2-methyl-4-[2-(4methylpiperazin“l-yl)ethoxy]phenyl}thieno[2,3-<s]pyriinidin-4-yl]oxy}-3-[2-(pyrazin-2ylmethoxy)phenyl]propanoic acid

Using General procedure (IXa) and pyrazin-2-ylmethanol as the appropriate alcohol Example 374 was obtained. HRMS calculated for CasHaôChNôO^S: 774.1794; found 775.1824 (M+H)

Example 375 (2R)-2-{[6-(5-chlorofuran-2-yl)-(55₀)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl]thieno[2,3-i/]pyrimidÎn-4-yl]oxy}-3-[2-(pyrimidin-5ylmethoxy)phenyl]propanoic acid

Using General procedure (IXa) and pyrimidin-5-ylmethanol as the appropriate alcohol

Example 375 was obtained. HRMS calculated for CaaH^ChNôOeS: 774.1794; found 775.1869 (M+H)

Example 376 (27?)-2-{[6-(5-chlorofuran-2-yl)-(5iS^, _rt)-5-{3-chloro-2-methyI-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3-o']pyrimidin-4-yl]oxy}-3-[2-(l,3-oxazol-4· ylmethoxy)phenyl]propanoic acid

Using General procedure (IXa) and l,3-oxazol-4-ylmethanol as the appropriate alcohol

Example 376 was obtained. HRMS calculated for CnHasChNsOîS: 763.1634; found 764.1685 (M+H)

-284conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM, and the combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

General procedure (Xld)

Step A;

l eq. methyl (2/?)-2-[6-ethyl-(5^)-5-(4-hydroxy-2-methyl-phenyl)thieno[2,3-i/Jpyrimidin4-yl]oxy-3-phenyl-propanoate (Préparation 60), 2 eq. ofthe appropriate alcohol and 2 eq. PPI13 were dissolved in dry toluene (0.2 M for the phénol), then 2. eq di/eributyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents.

Step B:

The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH * H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM, and the combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

General procedure (XIe)

Step A:

eq. phénol dérivative, 2 eq. of the appropriate alcohol and 2 eq. PPh₃ were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. di/er/butyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crade intermediate was purified via flash chromatography using EtOAc and MeOH as eluents.

-279and the crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents.

Step B:

The obtained intermediate was dissolved in dioxane-water l:l (10 mL/mmol) and 10 eq LiOH x H₂O was added. The mixture was stirred at room température untii no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na2SO₄, concentrated under reduced pressure and purified via préparative reversed phase chromatography using K) 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

Example 378 (27?)-2-{[(55_Λ)-5-{3-οΜθΓθ-2^β^1-4-[2-(4^βΛγ1ρϊρβΓ3ζΐη-1yi)ethoxy]phenyl}-6-(4-fluoro-3-metlioxyphenyl)thieno[2,3-i(]pyiimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General procedure (Xa) and methanol as the appropriate alcohol Example 378 was obtained. HRMS calculated for C37H38CIFN4O6S: 720.2185; found 721.2243 (M+H).

Example 379 (2R)-2-{[(55₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 20 yI)ethoxy]phenyl}-6-(4-fluoro-3-mcthoxyphcnyl)thieno[2,3-<7)pyTÎmidm-4-yl]oxy}-3-{2[(2R)-letrahydrofuran-2-yImethoxy]phenyl}propanoïc acid

Using General procedure (Xa) and [(2Æ)-tetrahydrofuran-2-yl]methanol as the appropriate alcohol Example 379 was obtained. HRMS calculated for C4jH44ClFN₄O7S: 790.2603;

found 791.2670 (M+H).

Example 380 (2R)-2-{[(55^)-5 - {3 -chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluoiO-3-methoxyphenyi)thieno[2,3-iZ]pyrimidin-4-yl]oxy}-3-[2(2,2,2-trifluoroethoxy)phenyl]propanoicacid

Step__A_:

-280221 mg ethyl (2R)-2-[(55_i/)-5-[3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(4-fluoiO-3-methoxy-phenyl)thieno[2,3-<yjpyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 8g) (0.3 mmol) and 138 mg K₂CO₃ (l.O mmol) were dissolved in 2 mL DMF, then 232 mg 2,2,2-trifluoiOethyl trifluoromethanesulfonate (l.O mmol) was added. The mixture was stirred at room température under nitrogen until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and concentrated under reduced pressure.

IO step B:

The obtained intermediate was dissolved in 8 mL dioxane-water J:l and 150 mg LiOH x

H₂O (3.57 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and 15 concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 380. HRMS calculated for C38H37CIF4N4O6S: 788.2058; found 789.2133 (M+H).

Example 381 (2J?)-2-{[(5S'₀)-5-{3-chloro-2-metliyl-4-[2“(4-methylpiperazin-l20 yl)ethoxy]phenyl}-6-(4-fluoiO-3-methoxyphenyl)thieno[2,3-i/Jpyrimidin-4-yl]oxy}-3-[2(pyridin-2-ylmethoxy)phenyl]propanoic acid

Using General procedure (Xa) and 2-pyridylmethanol as the approprîate alcohol Example 381 was obtained. HRMS calculated for C4₂H4|C1FN5O6S: 797.2450; found 399.6308 25 (M+2H).

Example 382 (2R)-2- {[(5^)-5- {3 -chloro-2-methyl-4-[2-(4-methylpiperazïn-1 yl)ethoxy]phenyl}-6-(4-fluoro-3-methoxyphenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2{[2-(trifluoromethyl)pyrimidin-4-yl]methoxy}phenyl)piOpanoic acid

-281Using General procedure (Xa) and [2-(trifluoromethyl)pyrimidin-4-yl]methanol (Préparation 9bj) as the appropriate alcohol Exampie 382 was obtained, HRMS calculated for C₄₂H39ClF₄N₆O₆S: 866.2276; found 867.2352 (M+H).

Example 383 (2R)-2-{[(5<S^, _fl)-5-{3-chloro-2-inethyl-4-[2-(4-methylpiperazÎn-lyl)ethoxy]phenyl}-6-(4-fluoro-3-methoxyphenyl)thieno[2,3-6/]pyrimidin-4-yl]oxy}-3-{2[(2-methoxypyrimidin-4-yI)methoxy]phenyl}propanoicacid

Using General procedure (Xa) and (2-methoxypyrimidin-4-yl)methanol as the appropriate alcohol Exampie 383 was obtained. HRMS calculated for C^HttClFNôChS: 828.2508; found 415.1343 (M+2H),

Example 384 (2J?)-2-{[(55_a)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(4-fluoiO-3-methoxyphenyl)thieno[2,3-ifjpyrimidin-4-yl]oxy}-3-{2[(l -ethyl-1 H-pyrazol-5-yl)methoxy]phenyl}propanoic acid

Using General procedure (Xa) and (l -ethyl-l£f-pyrazol-5-yI)methanol (Préparation 9da) as the appropriate alcohol Exampie 384 was obtained. HRMS calculated for C₄₂H₄₄ClFN₆O₆S: 814.2716; found 408.1436 (M+2H).

Exampie 385 (2Æ)-2-{[(5S'_û)-5-{3-chloro-2-methyl-4-[2-(4-niethylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluoiO-3-methoxyphenyl)thieno[2,3-i7|pyrimidin-4-yl]oxy}-3-{2[(1 -propyl-1 H-pyrazol-5-yl)methoxy]phenyl }propanoic acid

Using General procedure (Xa) and (1-propyl-1H-pyrazol-5-yl)methanol (Préparation 9db) as the appropriate alcohol Example 385 was obtained. HRMS calculated for C^FUeClFNeOôS: 828.2872; found 415.1536 (M+2H).

Example 386 (2Æ)-2-{[(55a)-5-{3-chloro-2-methyl-4-[2-(4-methyIpiperazin-lyl)ethoxy]phenyl}-6-(4-fluoro-3-methoxyphenyl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-[2(pyrazin-2-ylmethoxy)phenyl]propanoic acid

-282Using General procedure (Xa) and pyrazin-2-ylmethanol as the appropriate alcohol Example 386 was obtained. HRMS calculated for CijfyoClFNôOgS: 798.2403: found 799.2474 (M+H).

Example 387 (2/î)-2-{[(5S^,„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]pheny l} -6 -(4-fluoro- 3 -methoxypheny l)thieno [2,3 -</] pyrimidin-4-y l] oxy} -3 -[2(2-methoxyethoxy)phenyl]propanoic acid

Using General procedure (Xa) and 2-methoxyethanol as the appropriate alcohol Example 387 was obtained. HRMS calculated for C39H42CIFN4O7S: 764.2447; found 765.2502 (M+H).

General procedure (Xla)

Step A:

l eq. methyl (2R)-2-[(55_<7)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethyl-thieno[2,34]pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 6i), 2 eq. of the appropriate alcohol and 2 eq. PPI13 were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. di/er/butyl azodicarboxylate was added. The mixture was stiired at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents.

Step B;

The obtained intermedlate was dissolved in dioxane-water l:l (10 mL/mmol) and 10 eq, LiOH x H2O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM, and the combined organic phases were dried over Na₂SO₄, fîltered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

General procedure (Xlb)

-283 Step Λ:

l eq. methyl (22?)-2-[(52?_a)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethyl-thieno[2,3<7]pyrimidin-4-yl]oxy-3-phenyl-piOpanoate (Préparation 6n), 2 eq. of the appropriate alcohol and 2 eq. PPh₃ were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. dite/Tbutyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents.

Step B:

The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq LiOH x H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM, and the combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

General procedure (XIc)

Step A:

eq. methyl (2/?)-2-[6-etliyl-(5\,)-5-(4-hydroxy-2-methyl-phenyl)thieno[2,3-iZ]pyrimidin4-yl]oxy-3-phenyl-propanoate (Préparation 6j), 2 eq. of the appropriate alcohol and 2 eq. PPh₃ were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. di/er/butyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents.

Step B:

The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOII x II₂O was added. The mixture was stirred at room température until no further

-284conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM, and the combined organic phases were dried over NaîSCL, fîltered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

General procedure (Xld)

Step A:

l eq. methyl (2Æ)-2-[6-ethyl-(5Æ_a)-5-(4-hydroxy-2-methyl-phenyl)thieno[2,3-rf]pyrimidin4-yl]oxy-3-phenyI-propanoate (Préparation 60), 2 eq. of the appropriate alcohol and 2 eq. PPI13 were dissolved in dry toluene (0.2 M for the phénol), then 2. eq di/ertbutyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents.

Step B:

The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH x H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM, and the combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

General procedure (XJe)

Step A:

eq. phénol dérivative, 2 eq. of the appropriate alcohol and 2 eq. PPh₃ were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. diteributyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents.

- 285 Step B;

The obtained intermediate was dissolved in dioxane-water l:l (10 mL/mmol) and 10 eq. LiOH x H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM, and the combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

Gen eral procedure (Xlf) eq. ester was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH x H₂O was added and the mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM, and the combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure. If necessary it was purified via préparative reversed phase chromatography using MeCN and 25 mM aqueous NH4HCO3 solution as eluents.

Example 388 (2Æ)-2-{[(5S_a)-5-(3-chloro-4-hydroxy-2-methylphenyl)-6-ethylthieno[2,3</]pyrimidin-4-yl]oxy} -3-phcnylpropanoic acid

Methyl (2/?)-2-[(55_fl)-5-(3-chloiO-4-hydroxy-2-methyl-phenyl)-6-ethyl-thieno[2,3i/]pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 6i) was hydrolyzed according to General procedure (Xlf) to give Example 388. HRMS calculated for C₂4H₂iClN₂O4S: 468.0911; found 469.0997 (M+H).

Exampie 389 (2R)-2- {[(5Æ_o)-5-(3-chloro-4-hydroxy-2-niethylphenyl)-6-ethylthieno[2,3c/]pyrimÎdin-4-yl]oxy} -3 -phenylpropanoic acid

Methyl (2Æ)-2-[(5R_fl)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethyl-thieno[2,3</|pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 6n) was hydrolyzed according to

17193 *

-286General procedure (Xlf) to give Example 389. HRMS calculated for C24H21CIN2O4S: 468.0911 ; found 469.0982 (M+H).

Example 390 (2Æ)-2-[((55_n)-5-{3-chloiO-4-[2-(dimethylamino)-2-oxoethoxy]-2methylphenyl}-6-ethylthieno[2,3-d]pyrimidin-4-yl)oxy]-3-phenylpiOpanoic acid

Using General procedure (Xla) and 2-hydroxy-MV-dimethyl-acetamide as the appropriate alcohol Example 390 was obtained. HRMS calculated for C28H28CIN3O5S: 553.1438; found 554.1538 (M+H).

Example 391 (25)-2-(((55,)-5- {3-chloro-2-methyl-4-[2-oxo-2-(pyrrolidin-1 yl)ethoxy]phenyl}-6-ethylthieno[2,3-</]pyrimidin-4-yl)oxy]-3-phenylpiOpanoic acid

Using General procedure (Xla) and 2-hydiOxy-l-pyrrolidin-l-yl-ethanone as the appropriate alcohol Example 391 was obtained. HRMS calculated for C30H30CIN3O5S: 579.1595; found 580.1673 (M+H).

Example 392 (27?)-2-[((55_I)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)-2oxoethoxy]phenyl}-6-ethylthieiio[2,3-d]pyrimidin-4-yl)oxy]-3-phenylpropanoic acid

Using General procedure (Xla) and 2-hydroxy-l-(4-methylpiperazin-l-yl)ethanone as the appropriate alcohol Example 392 was obtained. HRMS calculated for C31H33CIN4O5S: 608.1860; found 609.1948 (M+H).

.Example 393 (2//)-2-(((55,)-5- {3-chloro-2-methyl-4-[2-(morpholin-4-yl)-2oxoethoxy]phenyl}-6-ethylthieno[2,3-<7|pyi’imidm-4-yl)oxy]-3-phenylpiOpanoic acid

Using General procedure (Xla) and 2-hydroxy-l-(inorpholin-4-yl)ethanone as the appropriate alcohol Example 393 was obtained. HRMS calculated for C30H30CIN3O6S:

595.1544; found 596.1626

-287Exampie 394 (2À)-2-({(5S_a)-5-[4-(benzyloxy)-3-chioiO-2-methylphenyl]-6ethylthieno[2,3-iZ]pyrimidin-4-yl }oxy)-3-phenylpropanoic acid

Using General procedure (Xla) and phenylmethanol as the appropriate alcohol Example

394 was obtained. HRMS calculated for C31H27CIN2O4S: 558.1380; found 559.1465 (M+H).

Example 395 (22?)-2-({(55_n)-5-[3-chloro-2-methyl-4-(pyridin-4-ylmethoxy)phenyl]-6ethyltliieno[2,3-if|pyrimidin-4-yl} oxy)-3-phenylpropanoic acid

Using General procedure (Xla) and 4-pyridylmethanol as the appropriate alcohol Example

395 was obtained. HRMS calculated for C3ÛH26CIN3O4S: 559.1333; found 560.1396 (M+H).

Example 396 (2Æ)-2-[((5S₀)-5-{3-chloro-2-methyl-4-[2-(pyridin-3-yl)ethoxy]phenyl}-6ethylthieno[2,3-i/Jpyrimidin-4-yl)oxy]-3-phenylpropanoic acid

Using General procedure (Xla) and 2-(3-pyridyl)ethanol as the appropriate alcohol Exampie 396 was obtained. HRMS calculated for C31H28CIN3O4S: 573.1489; found 574.1559 (M+H).

Example 397 (2/?)-2-[((55„)-5-{3-chloiO-2-melhyl-4-[2-(pyridin-4-yl)ethoxy]phenyl}-6ethy lthieno [2,3 -(flpyrimidin-4-y l)oxy] -3 -phenylpropanoic acid

Using General procedure (Xla) and 2-(4-pyridyl)ethanol as the appropriate alcohol Example 397 was obtained. HRMS calculated for C31H28CIN3O4S: 573.1489; found 574.1562 (M+H).

Example 398 (27?)-2-{[(55„)-5-(4-butoxy-3-chloiO-2-methylphenyl)-6-ethylthieno[2,3ùQpyrimidin-4-yl]oxy} -3 -phenylpropanoic acid

-288Using General procedure (Xla) and butan-l-ol as the appropriate alcohol Example 398 was obtained. HRMS calculated for C28H29CIN2O4S: 524.1537; found 525.1619 (M+H).

Example 399 (2Z?)-2-[((5S/)-5-{3-chloro-2-methyl-4-[3-(pyridin-4-yl)propoxy]phenyl}-6ethylthieno[2,3-ô(|pyrimidin-4-yl)oxy]-3-phenylpropanoic acid

Using General procedure (Xla) and 3-(4-pyridyl)propan-l-ol as the appropriate alcohol Example 399 was obtained. HRMS calculated for C32I-I30CIN3O4S: 587.1646; found 588.1732 (M+H).

Example 400 (2Æ)-2-[((5S/)-5-{3-chloro-4-[3-(dimethylammo)propoxy]-2methylphenyl}-6-ethylthieno[2,3-if|pyrimidin-4-yl)oxy]-3-phenylpropanoic acid

Using General procedure (Xla) and 3-(dimethylamino)propan-l-ol as the appropriate alcohol Example 400 was obtained. HRMS calculated for C29H32CIN3O4S: 553.1802; found 554.1891 (M+H).

Example 401 (2R )-2- [((5S/)-5 - {3 -chloro-2-methyl-4- [3 - ( 2 -oxopyrrolidi η-1 yl)propoxy]phenyl}-6-ethylthieno[2,3-i/]pyrimidin-4-yl)oxy]-3-phenylpiOpanoic acid

Using General procedure (Xla) and l-(3-hydroxypropyl)pyrrolidin-2-one as the appropriate alcohol Example 401 was obtained. HRMS calculated for C31H32CIN3O5S: 593.1751 ; found 594.1826 (M+H).

Example 402 (2R)-2-[((5Sa)-5-(3-chloro-2-methyl-4- [3-(4-methylpiperazin-1 yl)propoxy]phenyl}-6-ethylthieno[2,3-i7]pyriniidin-4-yJ)oxy]-3-phenylpropanoic acid

Using General procedure (Xla) and 3-(4-methylpiperazin-l-yl)piOpan-l-ol as the appropriate alcohol Example 402 was obtained. HRMS calculated for C32H37CIN4O4S:

608.2224; found 609.2304

-289Example 403 (2Æ)-2-[((.5S_a)-5-{3-chloro-4-[3-(lH-iinidazol-l -yl)propoxy]-2methylphenyl} -6-ethylthieno[2,3-<Z]pyrimidin-4-yl)oxy]-3-pheny]propanoic acid

Using General procedure (Xla) and 3-(U/imidazol-l-yl)propan-l»ol as the appropriate alcohol Example 403 was obtained. HRMS calculated for C30H29CIN4O4S: 576.1598; found 577.1698 (ΜιII).

Example 404 (2R)-2-{ [(5S'_i,)-5-(3-chloiO-4-{3-[(ethyIcarbamoyI)amino]propoxy}-2methylphenyl)-6-ethylthieno[2,3-d]pyrimidin-4-yl]oxy}-3-phenylpropanoic acid

Using General procedure (Xla) and l-ethyl-3-(3-hydroxypropyl)urea as the appropriate alcohol Example 404 was obtained. HRMS calculated for C30H33CIN4O5S: 596.1860; found 597.1943 (M+H).

Example 405 (2Æ)-2-(((5>S^, _a)-5-[3-chloro-4-(3-hydroxypropoxy)-2-methylphenyl]-6ethy ithieno [2,3 -rZJpyrimidin-4-yl} oxy)-3 -phenylpropanoic acid

Using General procedure (Xla) and propane- 1,3-diol as the appropriate alcohol Example 405 was obtained. HRMS calculated for C27H27CIN2O5S: 526.1329; found 527.1402 (M+H).

Example 406 (2Æ)-2-[((5S_a)-5- {3-chloro-2-methyl-4-[3-(niethylsulfonyl)piOpoxy]phenyl} -6-ethylthieno[2,3-rZ]pyrimidin-4-yl)oxy]-3-phenylpropanoic acid

Using General procedure (Xla) and 3-methylsulfonylpropan-l-ol as the appropriate alcohol Example 406 was obtained. HRMS calculated for C28H29CÎN2O6S2: 588.1156; found 589.1242 (M+H).

Example 407 (2Æ)-2-[((5S_a)-5-(3-chloiO-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}30 6-ethylthieno[2,3-d]pyrinudin-4-yl)oxy]-3-phenylpropanoic acid

-290Using General procedure (Xla) and 2-(dimethylamino)ethanol as the appropriate alcohol Example 407 was obtained. HRMS calculated for C₂8H3₀ClN3O4S: 539.1646; found 540.1742 (M+H).

Example 408 (222)-2-[((52?_ff)-5-{3-chloro-4-(2-(dimethylamino)ethoxy]-2-methyIphenyl}6-ethylthieno[2,3-i(]pyrimidin-4-yl)oxy]-3-phenylpropanoic acid

Using General procedure (Xlb) and 2-(dimethylamino)ethanol as the appropriate alcohol Example 408 was obtained. HRMS calculated for C28H3ÛCIN3O4S: 539.1646; found 10 540.1744 (M+H).

Example 409 (222)-2-(((55,,)-5- {4-[2-(dimethylammo)ethoxy]-2-methylphenyl} -6ethylthieno [2,3 -«^r]pyrimidin-4-y l)oxy]-3 -phenylpropanoic acid

Using General procedure (XIc) and 2-(dimethylamino)ethanol as the appropriate alcohol Example 409 was obtained. HRMS calculated for C28H3₁N₃O₄S: 505.2035; found 506.2096 (M+H).

Example 410 (222)-2-(((522^)-5- (4-[2-(dimethylamino)ethoxy]-2-methylphenyl}-620 ethylthieno[2,3-JJpyrimidin-4-yl)oxy]-3-phenylpropanoic acid

Using General procedure (Xld) and 2-(diniethylamino)ethanol as the appropriate alcohol Example 410 was obtained. HRMS calculated for C28H31N3O4S: 505.2035; found 506.2109 (M+H).

Example 411 (222)-2-([(55„)-5-(3-chloro-4-(2-[(2-hydiOxyethyl)(methyl)amino]ethoxy}2-methylphenyl)-6-ethylthieno[2,3-i(]pyriniidin-4-yl]oxy}-3-phenylpropanoic acid

Using General procedure (Xla) and 2-[2-hydroxyethyl(methyl)amino]ethanol as the appropriate alcohol Example 411 was obtained. HRMS calculated for C29H32C1N₃O₅S: 569.1751; found 570.1837 (M+H).

- 291 Example 412 (2R)-2-{[(55„)-5(4-{2-[bis(2-hydroxyethyl)amino]ethoxy}-3-chloro-2methylphenyl)-6-ethylthieno[2,3-i/]pyrimidin-4-yl]oxy}-3-phenylpropanoic acid

Using General procedure (Xla) and 2-[bis(2-hydroxyethyl)amino]ethanol as the appropriate alcohol Example 412 was obtained. HRMS calculated for C30H34CIN3O6S: 599.1857; found 600.1939 (M+H).

Example 413 (2/f)-2-[((55_ÎJ)-5-{3-chloro-4-[2-(4-hydroxypiperidin-1 -yl)ethoxy]-2methylphenyl}-6-ethylthieno[2,3-(ZJpyrirnidin-4-yl)oxy]-3-phenylpropanoic acid

Using General procedure (Xla) and l-(2-hydroxyethyl)piperidin-4-ol as the appropriate alcohol Example 413 was obtained. HRMS calculated for C31H34CIN3O5S: 595.1908; found 596.1976 (M+H).

Example 414 (2^)-2-[((5^_a)-5-{3-chloro-2-methyl-4-[2~(4-methylpiperazin-lyl)ethoxy]phenyl} -6-ethyltbieno [2,3-djpyrimidin-4-yl)oxy]-3 -phenylpropanoic acid

Using General procedure (Xlb) and 2-(4-methylpiperazin-l-yl)ethanol as the appropriate alcohol Example 414 was obtained. HRMS calculated for C31H35CIN4O4S: 594.2068; found 595.2138 (M+H).

Example 415 (2Æ)-2-[((55_a)-5-{3-chloro-2-methyl-4-[2-(4-melhylpiperazin-lyl)ethoxy]phenyl}-6-ethylthieno[2,3-i(lpyrimidin-4-yl)oxy]-3-phenylpropanoic acid

Using General procedure (Xla) and 2-(4-methylpiperazin-l-yl)ethanol as the appropriate alcohol Example 415 was obtained. HRMS calculated for C.31H35CIN4O4S: 594.2068; found 595.2148 (M+H).

Example 416 (2^)-2-[(6-είίψ1-(5Λ,)-5- {2-methyl-4-[2-(4-methy lpiperazin-1 yl)ethoxy]phenyl]thieno[2,3-(Z]pyrÎmidin-4-yl)oxy]-3-phenylpropanoic acid

-292Using General procedure (Xld) and 2-(4-methylpiperazin-l-yl)ethanol as the appropriate alcohol Example 416 was obtained. HRMS calculated for C3iH₃₆N₄O4S: 560.2457; found 561.2524 (M+H).

Example 417 (2Â)-2-[(6-ethyl-(55₀)-5-{2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}thieno[2,3-rf|pyrimidin-4-yl)oxy]-3-phenylpropanoic acid

Using General procedure (XIc) and 2-(4-methylpiperazin-l-yl)ethanol as the appropriate alcohol Example 417 was obtained. HRMS calculated for C31H36N4O4S: 560.2457; found 561.2536 (M+H).

Example 418 (22?)-2-[((5S_a)-5- {3-chloro-4-[2-(177-imidazol-l -yl)ethoxy]-2methylphenyl}-6-ethylthieno[2,3-i/]pyrimidin-4-yl)oxy]-3-phenylpiOpanoic acid

Using General procedure (Xla) and 2-(l#-imidazol-l-yl)ethanol as the appropriate alcohol Example 418 was obtained, HRMS calculated for C29H27CIN4O4S: 562.1442; found 563.1537 (M+H).

Example 419 (21?)-2-[((55_n)-5-{3-chloiO-2-niethyl-4-[2-(2-oxoimidazolidin“lyl)cthoxy]phenyl}-6-ethylthieno[2,3-</]pyrimidÎn-4-yl)oxy]-3-phenylpropanoic acid

Using General procedure (Xla) and l-(2-hydroxyethyl)imidazolidin-2-one as the appropriate alcohol Example 419 was obtained. HRMS calculated for C29H29CIN4O5S: 580.1547; found 581.1613 (M+H).

Example 420 (2R)-2-[((55),)-5-{3-chloro-2-methyl-4-[2-(morpholin-4-yl)ethoxy]pheny 1}6-ethylthieno[2,3-i7]pyrimidin-4-yl)oxy]-3-phenylpropanoic acid

Using General procedure (Xla) and 2-(morpholin-4-yl)ethanol as the appropriate alcohol Example 420 was obtained. HRMS calculated for C30H32CIN3O5S: 581.1751; found 582.1847 (M+H).

»

- 293 Example 421 (2/?)-2-[((5A_f,)-5-{3-chloro-2-methyl-4-[2-(morpholin-4-yl)ethoxy]phenyl)6-ethylthieno[2,3-</lpyrimidin-4-yl)oxy]-3-phenylpropanoic acid

Using General procedure (Xlb) and 2-(morpholin-4-yl)ethanol as the approprîate alcohol Example 421 was obtained. HRMS calculated for C30H32CIN3O5S: 581.1751; found 582.1853 (M+Il).

Example 422 (2Æ)-2-[((5S_n)-5-{4-[2-(acetylamino)ethoxy]-3-chloro-2-methylphenyl}-6ethylthieno[2,3-iZ]pyrimidin-4-yl)oxy]-3-phenylpropanoicacid

Using General procedure (Xla) and /V-(2-hydroxyethyl)acetamide as the approprîate alcohol Example 422 was obtained. HRMS calculated for C28H28CIN3O5S: 553.1438; found 554.1511 (M+H).

Example 423 (2/?)-2-({(55_fl)-5-[3-chloro-4-(2-hydi’oxyethoxy)-2-methylphenyl]-6ethylthieno[2,3-t/]pyrimidin-4-yl}oxy)-3-phenylpropanoic acid

Using General procedure (Xla) and ethylene glycol as the approprîate alcohol Example

423 was obtained. HRMS calculated for Cag^sCJNzOjS: 512.1173; found 513.1256 (M+H).

Example 424 (2R)-2-({(5S_fl)-5-[3-chloro-4-(2-inethoxye(hoxy)-2-methylphenyl]-6ethylthieno[2,3 -<ZJpyrimidin-4-yl} oxy)-3 -phenylpropanoic acid

Using General procedure (Xla) and 2-methoxyethanol as the approprîate alcohol Example

424 was obtained. HRMS calculated for C27H27CIN2O5S: 526.1329; found 527.1400 (M+H).

Example 425 (2/l)-2-[((56_a)-5- {3-chloro-4-[2-(2-methoxyethoxy)ethoxy]-2methylphenyl}-6-ethylthieno[2,3-ii]pyrinridin-4-yl)oxy]-3-phenylpropanoic acid

-294Using General procedure (Xla) and 2-(2-methoxyethoxy)ethanol as the appropriate alcohol Exampie 425 was obtained. HRMS calculated for C29H31CIN2O6S: 570.1591; found 57l.l690(M+H).

Exampie 426 (27?)-2-{[(55_a)-5-(3-chloro-4-hydiOxy-2-methyl-5-nitrophenyl)-6ethylthieno[2,3-</|pyrimidÎn-4-yl]oxy}-3-phenylpiOpanoic acid

Methyl (272)-2“[(55„)-5-(3-chloro-4-hydiOxy-2-methyl-5-nitro-phenyl)-6-ethyl-thieno[2,3i/jpyrimidin-4-ylJoxy-3-phenyl-propanoate (Préparation 15a) was hydrolyzed according to General procedure (Xlf) to give Example 426. HRMS calculated for C2₄H2cClN30éS: 513.0761; found 514.0840 (M+H).

Example 427 (2/2)-2-{[(55_ÎI)-5-(5-bromo-3-chloiO-4-hydroxy-2-inethylphenyl)-6ethylthieno [2,3 -iZjpyrimi dïn-4-yl] oxy} -3 -phenylpropanoic acid

Methyl (2Æ)-2-[(50'„)-5-(5-bromo-3-chloiO-4-hydroxy-2-methyl-phenyl)-6-ethylthieno[2,3-i7]pyrimîdin-4-yl]oxy-3-phenyl-piOpanoate (Préparation 15f) was hydrolyzed according to General procedure (Xlf) to give Example 427. HRMS calculated for C₂₄H₂oBrClN₂04S: 546.0016; found 547.0106 (M+H).

Exampie 428 (27t)-2-{[(5Sa)-5-(3,5-dichloro-4-hydiOxy-2-methylphenyl)-6ethylthieno[2,3-<7]pyrimidin-4-yl]oxy} -3-phenylpropanoic acid

Methyl (27?)-2-[(55_i,)-5-(3,5-dichloro-4-hydiOxy-2-methyl-phenyl)-6-ethyl-thieno[2,3c/[pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 15e) was hydrolyzed according to General procedure (Xlf) to give Example 428. HRMS calculated for C2₄H2oC12N₂0₄S: 502.0521; found 503.0582 (M+H).

Example 429 (2/i)-2-{[(5Æ„)-5-(3,5-dichloiO-4-hydroxy-2-methylphenyl)-6ethylthieno[2,3-iZ]pyrimidin-4-yl]oxy}-3-phenylpropanoic acid »

- 295 40 mg methyl (2Â)-2-[6-ethyl-(5Æ_fl)-5-(4-hydroxy-2-rnethyl-phenyl)thieno[2,3i^pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 6o) (0.089 mmol) was dissolved in 2 mL THF and 26 mg NCS (0.193 mmol) was added. The mixture was stirred at 55°C until no further conversion was observed. Then the volatiles were evaporated under reduced pressure and the crade intermediate was purified via flash chromatography using heptane and EtOAc as eluents. The obtained intermediate was hydrolyzed according to General procedure (Xlf) to give Example 429. HRMS calculated for C24H20CI2N2O4S: 502.0521; found 503.0587 (M+H).

Example 430 (27î)-2[((5S^, _ÎI)-5-{3-chloro-4-hydroxy-2~methyl-5-[(4-methylpiperazïn-Iyl)methyl]phenyl}-6-ethyIthieno[2,3-i/]pyrimidin-4-yl)oxy]-3-phenylpropanoicacid

483 mg methyl (2^)-2-[(55'_if)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethyl-thieno[2,3<7]pyrimidin-4-yl]oxy“3-phenyl-propanoate (Préparation 6i) (1.0 mmol) and 140 mg hexamethylenetetramine (1.0 mmol) were dissolved in 10 mL TFA and stirred at 90°C for 3 hours. The cooled reaction mixture was poured onto 100 mL icy water and the precipitated solid was fîltered and dried. Then it was dissolved in 20 mL EtOH, 167 pL 1methylpiperazine (1.5 mmol) and 636 mg Na(OAc)₃H (3.0 mmol) were added and the mixture was stirred at room température until no further conversion was observed. Then it was diluted with water, extracted with DCM, combined organic phases were dried over Na2SÛ4, fîltered and concentrated under reduced pressure. The crude intermediate was purified via reversed phase chromatography using aqueous 0.1% TFA solution and MeCN as eluents. The intermediate obtained in Step A was hydrolyzed according to General procedure (Xlf) to give Example 430. HRMS calculated for C30H33CIN4O4S: 580.1911; found 581.1972 (M+H).

Example 431 (2R)-2- {[(55₄₇)-5-(5-amino-3-chloro-4-hydiOxy-2-methylphenyl)-6ethylthieno[2,3-i/]pyrimidin-4-yl]oxy}-3-phenylpropanoic acid

Methyl (2/?)-2-[(5S^, _f()-5-(5-amino-3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethylthieno[2,3-rf]pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 15b) was hydrolyzed

-296according to General procedure (Xlf) to give Example 431. HRMS calculated for C24H22CIN3O4S: 483.1020; found 484.1083 (M+H).

Example 432 (2R)-2-({(5S^, ₀)-5-[3-chloro-4-hydroxy-2-methyl-5'(4-methylpiperazin-l yl)phenyl]-6-ethylthieno[2,3-J|pyrimidin-4-yl}oxy)-3-phenylpiOpanoic acid

1.00 g immobilized PPh₃ (3.00 mmol) and 761 mg iodine (3.00 mmol) were dissolved in 5 mL DCM and stirred for 15 minutes, then 272 mg imidazole (4.00 mmol) was added, and the mixture was stirred for 10 minutes. Then 115 pL 2-[2hydroxyethyl(methyl)amino]ethanol (1.00 mmol) was added, and the mixture was stirred for 1 hour. Then it was filtered, the filtrate was washed with saturated Na2S₂O3 solution and brine, dried over Na2SÛ4, filtered and concentrated under reduced pressure. To the formed 2-iodo-V-(2-iodoethyI)-iV-methyl-ethanamine 100 mg methyl (2R)-2-[(5Sa)-5-(5amino-3-chloro-4-hydroxy-2-methyl“phenyl)-6-ethyl-thieno[2,3-d]pyrimidin-4-yl]oxy-3phenyl-propanoate (Préparation 15b) (0.20 mmol), 42 mg NaHCO₃ (0.50 mmol) and 2 mL EtOH were added and the mixture was stirred at reflux température ovemight. Then it was diluted with EtOAc, washed with water and brine. The combined organic phases were dried . over Na₂SO4, filtered and concentrated under reduced pressure. The crude intermediate was purified via flash chromatography, using EtOAc and MeOH as eluents. The obtained intermediate was hydrolyzed according to General procedure (Xlf) to give Example 432. HRMS calculated for C29H31CIN4O4S: 566.1755; found 567.1794 (M+H).

Example 433 (27?)-2-({(5₁S'_fl)-5-[3-chloro-5-(formylamino)-4-hydiOxy-2-methylphenyl]-6ethylthieno[2,3-iZ]pyrimidin-4-yl}oxy)-3-phenylpropanoic acid mg methyl (2/?)-2-[(5S_a)-5-(5-amino-3-chloiO-4-hydroxy-2-methyl-phenyl)-6-ethylthieno[2,3-cZ]pyrimidin-4-yl]oxy-3-phenyl-piOpanoate (Préparation 15b) (0.07 mmol) was dissolved in 0.5 mL dry toluene under N2. 23 pL triethyl-or/7zoformate (0.136 mmol) was added and the mixture was stirred at 100°C for 2.5 hours. Then the volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography, using heptane and EtOAc as eluents. The obtained intermediate was hydrolyzed according

-297to General procedure (Xlt) to give Example 433. HRMS calculated for C25H22CIN3O5S: 511.0969; found 512.1048 (M+H).

Exemple 434 (2Æ)-2-[((5S_a)-5-(3-chloro-4-methoxy-2-methyl-5-[(4-methylpiperazin-1yl)methy]]phenyl}-6-ethylthicno[2,3-i/]pyrimidin-4-yl)oxy]-3-phenylpropanoic acid

Step A:

408 mg methyl (2A)-2-[(55_ÎJ)-5-(5-bromo-3-chloiO-4-hydroxy-2-methyl-phenyl)-6-ethylthieno[2,3-<7Jpyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 15f) (0.73 mmol) was dissolved in 4 mL MeOH, then 444 mg immobilized PPh₃ (1.33 mmol) and 306 mg di/er/butyl azodicarboxylate (1.33 mmol) were added and the mixture was stirred at 50°C under nitrogen until no further conversion was observed. Then the mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain methyl (27?)-2-[(5S_a)-5-(5bromo-3-chloro-4-methoxy-2-methyl-phenyl)-6-ethyI-thieno[2,3-c(]pyrÎmidin-4-yl]oxy~3phenyl-propanoate.

Step B:

195 mg of the bromo dérivative (0.34 mmol) synthesized in step A was dissolved in 3 mL THF, then 309 mg potassium l-methyl-4-trifluoroboratomethylpipcrazinc (1.70 mmol), 8 mg Pd(OAc)₂ (0.034 mmol), 28 mg SPhos (0.068 mmol), 665 mg CS2CO3 (2.04 mmol) and 0.3 mL water were added, and the mixture was heated to 90°C for 10 minutes via microwave irradiation. Then the volatiles were evaporated under Teduced pressure, the residue was diluted with brine, extracted DCM, and the combined organic phases were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The obtained intermediate was hydrolyzed according to General procedure (Xlf) to give Example 434. HRMS calculated for C31H35CIN4O4S: 594.2068; found 595.2145 (M+H).

Exampie 435 (27?)-2-[((5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yi)ethoxy]5-nitrophenyl}-6-ethylthieno[2,3-i/]pyrimidin-4-yl)oxy]-3-phenylpropanoic acid

-298Using General procedure (Xle), methyl (2J?)-2-[(55'_fl)-5-(3“Chloro-4-hydroxy-2-methyl-5nitro-phenyl)-6-ethyl-thieno[2,3-i/]pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 15a) as the phénol and 2-(4-methylpiperazin-l-yl)ethanol as the appropriate alcohol Example 435 was obtained. HRMS calculated for C31H34CIN5O6S: 639.1918; found 640.1984 (M+H).

Example 436 (2/î)-2-[((50'_n)-5-{3,5-dichloiO-2-methyl“4-[2-(4-niethylpiperazin-1 yl)ethoxy]phenyJ}-6-ethylthieno[2,3-<7jpyrimidin-4-yl)oxy]-3-phenylpiOpanoic acid

Using General procedure (Xle) with methyl (27?)-2-[(50'_i7)-5-(3,5-dichloiO-4-hydroxy-2methyl-phenyl)-6-ethyl-thieno[2₎3-d]pyrimidin-4-yl]oxy“3phenyl-piOpanoate (Préparation 15e) as the phénol and 2-(4-methylpiperazin-l-yl)ethanol as the appropriate alcohol Example 436 was obtained. HRMS calculated for C31H34CI2N4O4S: 628.1678; found 629.1776 (M+H).

Example 437 (2Æ)-2-[((5S_a)-5-{5-amino-3-chloiO-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-ethylthieno[2,3-i7]pyrimidin-4-yl)oxy]-3-phenylpropanoic acid

Using General procedure (Xle) with methyl (2/?)-2-[(55_a)-5-(5-amino-3-chloiO-4-hydroxy2-methyl-phenyl)-6-ethyl-tliieno[2,3-i/]pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 15b) as the phénol and 2-(4-methylpïperazin-l-yl)ethanol as the appropriate alcohol Example 437 was obtained. HRMS calculated for C31H36CIN5O4S: 609.2177; found 610.2226 (M+H).

Example 438 (2R)-2-{[(5S'_a)-5-(5-chloro-4-hydroxy-2-methylphenyl)-6-ethylthieno[2,3c(]pyrimidin-4-yl]oxy} -3-phenylpropanoic acid

100 mg methyl (2/?)-2-[6-ethyl-(55^, ₍,)-5-(4-hydiOxy-2-methyl-phenyl)thieno[2_>3b]pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 6j) (0.223 mmol) was dissolved in 5 mL THF, then 31 mg NOS (0.234 mmol) was added. The reaction mixture was stirred at 60°C ovemight, Two monochlorinated and a dichlorinated intermediate were formed. The volatiles were evaporated under reduced pressure and the isomers were separated via

-299préparative reversed phase chromatography using 40 mM aqueous NFI₄OAc solution (pH was set to 4 with AcOH) and MeCN as eluents. The monochlorinated regioisomer eluting earlier was collected. The obtained intermediate was hydrolyzed according to General procedure (Xlf) to give Example 438. HRMS calculated for CMH21CIN2O4S: 468.0911;

found 469.0981 (M+H).

Example 439 (2J?)-2-{[(5/?_o)-5-(5-chloro-4-hydiOxy-2-methylphenyl)-6-ethylthieno[2,3i/]pyrimidin-4-yl]oxy}-3-phenyipropanoicacid

105 mg methyl (27?)-2-[6-ethyl-(5/?_a)-5-(4-hydroxy-2-methyl-phenyl)thieno[2,3</Jpyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 6o) (0.234 mmol) was dissolved in 5 mL THF, then 34 mg NCS (0.257 mmol) was added. The mixture was stirred at 60°C ovemight. Two monochlorinated and a dichlorinated intermediate were formed. The volatiles were evaporated under reduced pressure, and the mixture was hydrolyzed according to General procedure (Xlf). The isomer mixture was separated via préparative reversed phase chromatography using 40 mM aqueous NH₄OAc solution (pH was set to 4 with AcOH) and MeCN as eluents. The monochlorinated regioisomer eluting later was collected as Example 439. HRMS calculated for C₂₄H2iCIN2O₄S: 468.0911; found 469.0987 (M+H).

Example 440 (2J?)-2-[(6-ethyl-(55_n)-5-(2-methyl-5-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}thieno[2,3-J|pyrimidin-4-yl)oxy]-3-phenylpropanoic acid and (25)-2[(6-ethyl-(5À_a)-5-{2-methyl-5-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3iZ]pyrimidin-4-yl)oxy]-3-phenylpropanoic acid (racemîc) mg 2-(6-ethyl-5-iodo-thieno[2₎3-(7]pyrimidin-4-yl)oxy-3-phenyl-propanoic acid (Préparation 4m) (0.10 mmol), 108 mg l-rnethyl-4-[2-[4-methyl-3-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)phenoxy]ethyl]piperazine (Préparation 5h) (0.30 mmol), 18 mg Pd2dba₃ (0.02 mmol), 14 mg BuPAd2 (0.04 mmol) and 55 mg K2CO3 (0.40 mmol) were dissolved in 2 mL DME and 0.5 mL water. The mixture was heated to 120°C for 10 minutes via microwave irradiation. Then the mixture was cooled to room température, fïltered, washed with saturated NaHCCb solution. The filtrate was washed with Et2O, then

-300it was acidified with 2 M HCl and extracted with DCM. The combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure. The diastereomers were separated and purified via préparative reversed phase chromatography using 40 mM aqueous NI-I4OAC solution (pH was set to 4 with AcOH) and MeCN as 5 eluents. The diastereoisomer pair eluting later was collected as Exampie 440. HRMS calculated for C31H36N4O4S: 560.2457; found 561.2549 (M+H).

Exampie 441 (2X)-2-{[(5S_a)-5-(8-chloro-7-methyl-3-oxo-3_#4-dihydro-2H-l₅4-benzoxazin6-yl)-6-ethylthieno[2,3-i/]pyrirnidin-4-yl]oxy}-3-phenylpiOpanoic acid

100 mg methyl (2J?)-2-[(55_a)-5-(5-amino-3-chloro-4-hydroxy-2-methyl-phenyI)-6-ethylthieno[2,3-iZ|pyiimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 15b) (0.20 mmol) was dîssolved in 1 mL dry THF under N₂ and was cooled to 0ⁿC. Then 42 mg K₂CO₃ (0.30 mmol) and 19 pL bromoacetyl bromide (0.22 mmol) were added and the mixture was 15 stirred for 30 minutes, then heated to 50°C and stirred overnight. Then it was concentrated under reduced pressure and purified via flash chromatography, using heptane and EtOAc as eluents. The obtained ester was hydrolyzed according to General procedure (Xlf) to give Example 441. HRMS calculated for C₂₆H2₂C1N₃O₅S: 523.0969; found 524.1062 (M+H).

Example 442 (27?)-2-[((55_a)-5-(7-chloro-2-[(dimethylamino)methyl]-6-methyl-lbenzofuran-5-yl}-6-ethylthieno[2,3-i/]pyrimidin-4-yl)oxy]-3-phenylpropanoic acid

152 mg methyl (2Æ)-2-[(55,)-5-(3-chloro-4-hydroxy-5-iodo-2-methyl-phenyl)-6-ethylthieno[2,3-</|pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 15d) (0.25 mmol), 33 mg N,2V-dirnethylprop-2-yn-l-amine (0.40 mmol), 18 mg PdCl₂(PPh₃)₂ (0.025 mmol) and 5 mg copper(I) iodide (0.025 mmol) were dîssolved in 1 mL DIPA under N₂. The mixture was stiired at 50°C for 30 minutes. Then it was concentrated under reduced pressure and purified via flash chromatography, using heptane and EtOAc as eluents. The obtained intermediate was hydrolyzed according to General procedure (Xlf) to give Example 442.

HRMS calculated for C29H28CIN3O4S: 549.1489; found 505.0959 (M+H - Me₂NH).

ί»

-301 Exampie 443 (2/?)-2-{[(55_ï)-5-(7-chloro-6-methyl-l-benzofuran-5-yl)-6-ethylthieno[2,3d]pyrimidin-4-yl]oxy} -3-phcnylpropanoic acid

HO mg methyl (27?)-2-[(55«)-5-(3-chloro-4-hydroxy-5-iodo-2-methyl-phenyl)-6-ethyl5 thieno[2,3-if]pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 15d) (0.18 mmol), 51 pL ethynyl(trimethyl)silane (0.36 mmol), 6.3 mg PdCI₂(PPh3)₂ (0.009 mmol) and l .7 mg copper(l) iodide (0.009 mmol) were dissolved in 2 mL DIPA under N₂. The mixture was stirred at 50°C for 10 minutes, then 0.22 mL TBAF (l M in THF, 0.22 mmol) was added and the mixture was stirred for additional 20 minutes. Then the volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography, using heptane and EtOAc as eluents. The obtained intermediate was hydrolyzed according to General procedure (Xlf) to give Example 443. HRMS calculated for C₂fiH₂iClN₂O4S: 492.0911; found 493.0999 (M+H).

Example 444 (2/?)-2-{[(557)-5-(7-chloro-2,6-dimethyl-l,3-benzoxazol-5-yl)-6ethylthieno[2,3-iZ|pyrimidin-4-yl]oxy} -3-phenylpropanoic acid mg methyl (2Æ)-2-[(5S_o)-5-(5-amino-3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethylthieno[2,3-t/]pyrimidin-4-yI]oxy~3-phenyI-propanoate (Préparation 15b) (0,10 mmol) was dissolved in 0.5 mL dry toluene under N₂. 27 pL triethyl-or/Aoacetate (0.15 mmol) was added and the mixture was stirred at 100°C for 2.5 hours. Then the volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography, using heptane and EtOAc as eluents. The obtained intermediate was hydrolyzed according to General procedure (Xlf) to give Exampie 444. HRMS calculated for C26H22CIN3O4S:

507.1020; found 508.1114 (M+H).

Exampie 445 (2R)-2-[((5S_a)-5-{7-chloro-6-methyl-2-[(4-methylpiperazin-1 -yl)methyl]l,3-benzoxazol-5-yl}-6-ethylthieno[2,3-J]pyrimidin-4-yl)oxy]-3-phenylpropanoic acid

56 mg methyl (27?)-2-[(55a)-5-[7-chloiO2-(chloiOmethyl)-6-methyl“l,3-benzoxazol-5-yl]6-ethyl-thieno[2,3-d]pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 15c) (0.10 mmol) was dissolved in 2 mL dry THF under N₂. 20 mg 4-ιη6ΐ1ψ1-ρίρεΓαζΐη6 (0.20 mmol)

-302was added and the mixture was stirred at room température for 1 hour. Then the volatiles were evaporated under reduced pressure and the obtained crude intermediate was hydrolyzed according to General procedure (Xlf) to give Example 445. HRMS calculated for C₃₁H₃₂C1N5O4S: 605.1864; found 606.1937 (M+H).

Example 446 (2/?)-2“({(5_LS’_ÎI)-5“[7-chloro-6-rnethyl-2-(morpholin-4-ylmethyl)-l ,3benzoxazol-5-yl]-6-ethylthieno[2,3-</]pyrimidin-4-yl}oxy)-3-phenylpiOpanoic acid mg methyi (2R)-2-[(55'_d7)5-[7-chloiO-2-(chloiOmethyl)-6-methyl-l,3-benzoxazol-5-yl]6-ethyl-thieno[2,3-<7]pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 15c) (0.10 mmol) was dissolved in 2 mL dry THF under N₂. 18 mg morpholine (0.20 mmol) was added and the mixture was stirred at room température overnight. The volatiles were evaporated under reduced pressure and the obtained crude intermediate was hydrolyzed according to General procedure (Xlf) to give Example 446. HRMS calculated for C₃oH₂₉C1N₄0₅S: 592.1547; found 593.1613 (M+H).

Example 447 (27?)“2“{[6-ethyl-(5_iS'_(i)-5-(4-hydroxy-2-melhylphenyl)thieno[2,3i(Jpyrimidin-4-yl]oxy}-3-phenylpropanoic acid

Methyl (2Æ)-2-[6-ethyl-(5SJ-5-(4-hydroxy-2-methyl-phenyl)thieno[2,3-<7]pyriinidin-4yl]oxy-3-phenyl-propanoate (Préparation 6j) was hydrolyzed according to General procedure (Xlf) to give Example 447. HRMS calculated for C24H22N2O4S: 434.1300; found 435.1358 (M+H).

Example 448 (27?)-2-{[6-ethyl-(5R_rt)-5-(4-hydiOxy-2-methylphenyl)thieno[2.3eZjpyrimidin-4-yl]oxy} -3-phenylpropanoic acid

Methyl (27?)-2-[6-ethyl-(5R_iJ)-5-(4-hydroxy-2-methyl-phenyl)thieno[2,3-rt]pyrimidin-4yl]oxy-3-phenyl-propanoate (Préparation 60) was hydrolyzed according to General procedure (Xlf) to give Example 448. HRMS calculated for C24H22N2O4S: 434.1300; found 435.1369 (M+H).

-303Exampie 449 (2R)-2-{[(55_a)-5-(3-chloro-2-methylphenyl)-6-ethylthieno[2,3-ri]pyrimidïn4-yl]oxy}-3-phenylpropanoïc acid and (2S)-2-{[(5Â_n)-5-(3-chloro-2-inethylphenyl)-6ethylthieno[2,3-t/]pyrimidÎn-4-yl]oxy}-3-phenylpropanoic acid (racemic)

373 mg 2-(6-ethyl-5-iodo-thieno[2,3-d]pyrimidin-4-yl)oxy-3-phenyl-propanoic acid (Préparation 4m) (0.82 mmol), 280 mg (3-chloro-2-methyl-phenyl)boronic acid (1.64 mmol), I5l mg Pd₂dba3 (0.164 mmol), 118 mg BuPAd₂ (0.329 mmol) and 795 mg K₂CO3 (5.75 mmol) were dissolved in 15 mL DME and 3 mL water. The mixture was heated to 80°C for 30 minutes via microwave irradiation. Then it was cooled to room température, filtered, washed with saturated NaHCO₃ solution. The filtrate was washed with Et₂O, then it was acidified with 2 M HCl and extracted with DCM, the combined organic phases were dried over Na₂SO4, filtered and concentrated under reduced pressure. The diastereomers were separated and purified via préparative reversed phase chromatography using 40 mM aqueous NH₄OAc solution (pH was set to 4 with AcOH) and MeCN as eluents. Diastereoisomer pair eluting earlier was collected as Example 449. HRMS calculated for C₂₄H₂₁C1N₂O3S: 452.0961; found 453.1045 (M+H).

Exampie 450 (211)-2-{[(55_a)-5-(3-chloro-2-methylphenyl)-6-ethylthieno[2,3-i/Jpyrimidin4-yl]oxy}-3-phenylpropanoic acid and

Example 451 (211)-2-{[(5/?_fl)-5-(3-chloro-2-methylphenyl)-6-ethylthieno[2,3-i(]pyrimidin4-yl]oxy}-3-phenylpropanoic acid

150 mg methyi (27î)-2-(6-ethyl-5-iodo-thieno[2,3-rf]pyrimidÎn-4-yl)oxy-3-phenylpropanoate (Préparation 4i) (0.320 mmol), 164 mg (3-chloro-2-methyl-phenyl)boronic acid (0.961 mmol). 74 mg Pd(PPh₃)₄ (0.064 mmol), and 265 mg Ag₂CO₃ (0.961 mmol) were dissolved in 6 mL DME, It was heated to 100°C for 10 minutes via microwave irradiation. Then the mixture was cooled to room température, and the volatiles were evaporated under reduced pressure. The diastereoisomers were separated via flash chromatography, using heptane and EtOAc as eluents. The diastereoisomer eluting earlier was collected and hydrolyzed according to General procedure (Xlf) to give Example 450. HRMS calculated for C₂4H2_fClN₂O₃S: 452.0961; found 453.1040 (M+H). The

-304diastereoisomer eluting Iater was collected and hydrolyzcd according to General procedure (Xlf) to give Example 451. HRMS calculated for C24H21CIN2O3S: 452.0961; found 453.1044 (M+H).

Exemple 452 (27/)-2-{[6-ethyl-(5S„)-5-(3-hy droxy-2-methylpheny l)thieno[2,3d]pyrimidin-4-yl]f)xy}-3-plienylpropanoic acid and (2₁S)-2-{[6-ethyl-(57?_fl)-5-(3-hydroxy-2methylphenyl)thieno[2,3-if|pyrimidin-4-yl]oxy}-3-phenylpiOpanoic acid (racemic) mg 2-(6-ethyl-5-iodo-thieno[2,3-<7]pyrimidÎn-4-yl)oxy-3-phenyl-propanoic acid (Préparation 4m) (0.10 nunol), 70 mg 2-methyl-3-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)phenol (0.30 mmol), 18 mg Pd2dba3 (0.02 mmol), 14 mg ⁿBuPAd2 (0.04 mmol) and 55 mg K2CO3 (0.40 mmol) were dissolved in 2 mL DME and 0.5 mL water. It was heated to 90°C for 30 minutes via microwave irradiation. Then the mixture was cooled to room température, filtered, washed with saturated NaHCCh solution. The filtrate was washed with Et2Û, then it was acidified with 2 M HCl and extracted with DCM. The combined organic phases were dried over Na2SC>4, filtered and concentrated under reduced pressure. The diastereomers were separated and purified via préparative reversed phase chromatography using 40 mM aqueous NH4OAC solution (pH was set to 4 with AcOH) and MeCN as eluents. The diastereoisomer pair eluting earlier was collected as Example 452. HRMS calculated for C24H22N2O4S: 434.1300; found 435.1371 (M+H).

General procedure (Xlla)

Step A:

eq. ethyl (27/)-2-[(55?)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyI]-6-ethyl-thieno[2,3-if|pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 8h), 2 eq. of the appropriate alcohol and 2. eq triphenyl phosphine were dissolved in abs. toluene (0.2 M for the phénol), then 2 eq diter/butyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents.

-305Step B:

The product of Step A was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq LiOH x H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄, concentrated under reduced pressure and the residue was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

General procedure (Xllb )

Step A:

eq. of the appropriate phénol, 2 eq. 2-(4-methylpiperazin-l-yl)ethanol and 2 eq. triphenyl phosphine were dissolved in abs. toluene (5 mL/mmol), then 2 eq. ditertbutyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents.

Step B:

The product of Step A was dissolved in dioxane-water 1:1(10 mL/mmol) and 10 eq LiOH x H₂O was added. The mixture was stirred ai room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated under reduced 25 pressure and the residue was purified via préparative reversed phase chromatography using mM aqueous NH4HCO3 solution and MeCN as eluents.

Example 453 (2Æ)-2-[((55a)-5-{3-chloiO-2-methyl-4-[2-(4-methylpipei^,azÎn-l yl)ethoxy]phenyl}-6-ethylthieno[2,3-i/]pyrimidin-4-yl)oxy]-3-(230 methoxyphenyl)propanoic acid

17193 ·

- 306 Using General procedure (Xlla) and methanol as the appropriate alcohol Exampie 453 was obtained. HRMS calculated for C32H37CIN4O5S: 624.2173; found 625.2259 (M+H)

Exampie 454 (2À)-2-[((55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-ethylthieno[2,3-iflpyrimidin-4-yl)oxy]-3-[2-(2,2,2tri fl uoroethoxy)pheny I Jpropanoi c aci d

Step À:

192 mg ethyl (2/?)“2-[(5S_a)-5-[3“Ch]ofo-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-ethyl-thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2-hydroxyphenyl) propanoate (Préparation 8h) (0.3 mmol) and 138 mg K₂CO₃ (1.0 mmol) were dissolved in 2 mL DMF, then 232 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.0 mmol) was added. The mixture was stirred at room température under nitrogen until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM The combined organic phases were dried over Na₂SO4 and concentrated under reduced pressure.

Step B;

The product of Step A was dissolved in 8 mL dioxane-water 1:1 and 150 mg LiOFI x H₂O (3.57 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure and the residue was purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 454. HRMS calculated for C₃3H3₆C1F3N₄O₅S: 692.2047; found 693.2151 (M+H)

Example 455 (2Æ)-2-[((5S„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-ethylthieno[2,3-</]pyrimidin-4-yl)oxy]-3-{2-[(2-methoxypyrimidin-4yl)methoxy]phenyl} propanoic acid

-307Using General procedure (Xlla) and (2-mcthoxypyrimidin-4-yl)methanol as the approprîate alcohol Example 455 was obtained. HRMS calculated for C37H41CIN6O6S: 732.2497; found 367.1311 (M+2H)

Example 456 (2/?)-2-[((55'₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin“lyl)ethoxy]phenyl}-6-ethylthieno[2,3-</jpyrimidin-4-yl)oxy]-3-{2-[(l-ethyl-lH-pyrazol-5y 1 )methoxy]phenyl} propanoic acid

Using General procedure (Xlla) and (l-cthyl-17/-pyrazol-5-yl)mcthanol (Préparation 9da) as the approprîate alcohol Example 456 was obtained. HRMS calculated for C37H43CIN6O5S: 718.2704; found 360.144 (M+2H)

Example 457 (2Æ)-2-[((5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-ethylthieno[2,3-ûT]pyi-iniidin-4-yl)oxy]-3-[2-(2methoxyethoxy)phenyl]propanoic acid

Using General procedure (Xlla) and 2-methoxyethanol as the approprîate alcohol Example

457 was obtained. HRMS calculated for C34H41CIN4O6S: 668.2435; found 335.1297 (M+2H)

Example 458 (2Æ)-2-[((56\)-5-(3-chloiO-2-methy1-4-[2-(4-tnethylpiperazin-l yl)ethoxy]phenyl)-6-ethylthieno[2,3-i(|pyrimidin-4-yl)oxy]-3-(2,3-dihydiO-l-benzofuran7-yl)propanoic acid

Using General procedure (Xllb) and ethyl (2jR)-2-[(55i7)-5-(3-chloro-4-hydroxy-2-methylphenyl)-6-ethyl-thieno[2,3-<7]pyrimidin-4-yl]oxy-3-(2,3-dihydiObenzofuran-7yl)propanoate (Préparation I7c) as the approprîate phénol Example 458 were obtained.

HRMS calculated for C33H37CIN4O5S: 636.2173; found 637.2233 (M+H)

Example 459 (2S)-2-[((57î„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-ethylthieno[2,3-i/]pyrimidÎn-4-yl)oxy]-3-(2,3-dihydro-l-benzofuran7-yI)propanoic acid

-308Using General procedure (Xllb) and ethyl (25)-2-[(55_a)-5-(3-cIiIoiO-4-hydiOxy-2-niethylphenyl)-6-ethyl-thieno[2,3-z7]pyrimidin-4-y]]oxy-3-(2,3-dihydrobenzofuran-7yl)propanoate (Préparation 17d) as the appropriate phénol Example 459 were obtained.

HRMS calculated for C33H37CIN4O5S: 636.2173; found 637.2236 (M+H)

Example 460 (272)-3-(1,3-benzodioxol-4-yl)-2-[((55„)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-6-ethylthieno[2,3-d]pyriniidin-4-yl)oxy]propanoic acid

Using General procedure (Xllb) and ethyl (272)-3-(l,3-benzodioxol-4-yl)-2-[(55_a)-5-(3chloiO-4-hydiOxy-2-methyl-phenyl)-6-ethyl-thieno[2₅3-<7]pyrimidin-4-yl]oxy-piOpanoate (Préparation 17b) as the appropriate phénol Example 460 was obtained. HRMS calculated for C32H35CIN4O6S: 638.1966; found 639.2067 (M+H)

Example 461 (272)-3-(1 -benzofuran-7-yl)-2-[((55_ff)-5- (3-chloro-2-methyl-4-[2-(4methylpiperazin-1 -yl)ethoxy]phenyl} -6-ethylthieno[2,3 -i7jpyrimidin-4-yl)oxy]piOpanoic acid

Using General procedure (Xllb) and ethyl (27?)-3-(benzofuran-7-yl)-2-[(55„)-5-(3-chloro4-hydroxy-2-methyl-phenyl)-6-ethyl-thieno[2,3-i7]pyrimidin-4-yl]oxy-piOpanoate (Préparation 17e) as the appropriate phénol Example 461 was obtained. HRMS calculated for C33H35CIN4O5S: 634.2017; found 635.2069 (M+H)

Example 462 (25)-3-(1 -benzofuian-7-yl)-2-[((51?_a)-5-{3-chloro-2-methyl-4-[2-(4rtiethylpiperazin-I-yl)ethoxy]phenyl}-6-ethylthieno[2,3-<7]pyrimidin-4-yl)oxy]propanoic acid

Using General procedure (Xllb) and ethyl (2S)-3-(benzofuran-7-yl)-2-[(57?_a)-5-(3-chloro4-hydroxy-2-methyl-phenyl)-6-ethyl-thieno[2,3-iZ]pyrimidin-4-yl]oxy-propanoate (Préparation 171) as the appropriate phénol Example 462 was obtained. HRMS calculated for C33H35CIN4O5S: 634.2017; found (M+H)

-309Exainpie 463 (27?)-2-[((5iS/)-5-{3-cldoro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl)-6-ethylthieno[2,3-<7]pyrimidin-4-yl)oxy]-3-(2-fluoiOphenyl)propanoic acid

Using General procedure (Xllb) and ethyl (2Æ)-2-[(5S_a)-5-(3-chloro-4-hydroxy-2-methylphenyl)-6-ethyl-thieno[2,3-c(|pyrimidin-4-yl]oxy-3-(2-fluorophenyl)propanoate (Preparationl7h) as the phénol Example 463 was obtained. HRMS calculated for C31H34CIFN4O4S: 612.1973; found 613.205 (M+H)

Example 464 (2S)-2-[((5Â_ff)-5-{3-chIoro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-ethylthieno[2,3-i(|pyrimidin-4-yl)oxy]-3-(2-fluorophenyl)propanoic acid

Using General procedure (Xllb) and ethyl (2iS)-2-[(5R₀)-5-(3-chloro-4-hydroxy-2-methylphcnyl)-6-cthyl-thicno[2,3-JJpyrimidin-4-yl]oxy-3-(2-fluorophcnyl)propanoate (Preparationl7g) as the phénol Example 464 was obtained. HRMS calculated for C31H34CIFN4O4S: 612.1973; found 613.2053 (M+H)

General procedure (XHIa)

StepA:

eq. ethyl (22f)-2-[(5S₀)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-prop'l-ynylthieno[2,3-âQpyrimidln-4-yl]oxy-3-(2-methoxyphenyl)propanoate (Préparation 61), 2 eq. of the appropriate alcohol and 2 eq. PPI13 were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. diteributyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents.

Step B:

-310The product of Step A was dissolved in dioxane-water l :l (10 mL/mmol) and 10 eq. LiOII x H2O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na2SO4, concentrated under reduced pressure and the residue was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

General procedure (XlIIb)

Step A:

eq. phénol dérivative, 2 eq. of the appropriate alcohol and 2 eq. PPI13 were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. diter/butyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents.

Step B:

The product of Step A was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH x H2O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na2SÛ4, concentrated under reduced pressure and the residue was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

General procedure (SIIle) eq. ester was dissolved in dioxane-water 1:1 (10 mL / mmol) and 10 eq. LiOH x H2O was added and the mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCI, and extracted with DCM. The combined organic phases were dried over Na2SO₄ and concentrated under reduced pressure. If necessary the product was purified via préparative reversed phase chromatography using MeCN and 25 mM aqueous NH4HCO3 solution as eluents.

- 311 Exampie 465 (22?)-2-{[(55_n)-5-{3-chloro'2-methyl-4-[2-(l-methylpiperidin-4yl)ethoxy]phenyl}-6-(prop-l-yn-l-yl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General procedure (XHIa) and 2-(l-methyl-4-piperidyl)ethanol as the appropriate alcohol Example 465 was obtained. HRMS calculated for C34H36CIN3O5S: 633.2064; found 634.2136 (M+H).

Example 466 (2R)-2-{[(5S_n)-5-(3-chlorO”4-{2-[di(propan-2-yl)amino]ethoxy}-2methylphenyl)-6-(prop-1 -yn-1 -yl)thieno[2,3-rf]pyrimidin-4-yl]oxy }-3-(2methoxyphenyl)propanoic acid

Using General procedure (XlIIa) and 2-(diisopropylamino)ethanol as the appropriate alcohol Example 466 was obtained. HRMS calculated for C34H38CIN3O5S: 635.2221; found 636.2310 (M+H).

Example 467 (2R)-2- {[(55J-5- (3-chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl} 6-(prop-l -yn-1 -yl)thieno[2,3-d]pyrimidin-4-yl]oxy) -3-(2-methoxyphenyI)propanoic acid

Using General procedure (XlIIa) and 2-(dimethylamino)ethanol as the appropriate alcohol Example 467 was obtained. HRMS calculated for C30H30CIN3O5S: 579.1595; found 580.1663 (M+H).

Example 468 (2R)-2- {[(55_fl)-5- {3 -chloro-2-methyl-4- [2-(pyrrolidin-1 -yl)ethoxy]phenyl} 6“(piOp-l-yn-l-yl)thieno[2,3-^pyrimidin-4-yl]oxy}-3-(2-methoxyphenyl)propanoic acid

Using General procedure (XlIIa) and 2-pyrrolidin-l-ylethanol as the appropriate alcohol Example 468 was obtained. HRMS calculated for C32H32CIN3O5S: 605.1751; found 606.1822 (M+H).

-312Example 469 (2Æ)-2-{[(5S_n)-5-{3-chloro-2-methyl-4-[2-(pïperidin-l-yl)ethoxy]phenyl}-6(prop-l-yn-l-yl)lhieno[2,3-iZ]pyrimidin-4-yl]oxy}-3-(2-methüxyphenyl)propanoicacÎd

Using General procedure (XlIIa) and 2-(l-piperidyl)ethanol as the appropriate alcohol Example 469 was obtained. HRMS calculated for C33H34CIN3O5S: 619.1908; found 620.2011 (M+H).

Example 470(2Æ)-2-{[(5J?_a)-5-(3-chloro-5-fluoiO-4-methoxy-2-methylphenyl)-6-(prop-lyn-1 -yl)thieno[2,3-i/]pyriniidin-4-yl]oxy}-3-(2-methoxyphenyl)propanoic acid and

Example 471 (2JÎ)-2-{[(5S'_<z)-5-(3-chloro-5-fluoro4-methoxy-2-methylphenyl)-6-(prop-lyn-l-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-methoxyphenyl)propanoic acid

522 mg ethyl (2Æ)-2-(5-iodo-6-prop-l-ynyl-thieno[2,3-i/jpyrimidin-4-yl)oxy-3-(2methoxyphenyl)propanoate (Préparation 4k) (1.00 mmol), 451 mg 2-(3-chloro-5-fluoro4-methoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Préparation 5i) (1.50 mmol), 73 mg PdCh * dppf (0.10 mmol) and 652 mg CS2CO3 (2.00 mmol) were dissolved in 10 mL dioxane and 2.5 mL water, and heated under nitrogen at 110°C for 10 minutes in a microwave reactor. Then reaction mixture was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na2SO4, concentrated under reduced pressure and the residue was purified via flash chromatography, using heptane and EtOAc as eluents, then it was hydrolyzed according to General procedure (XIIIc). The diastereoisomer eluting earlier was collected as Example 470. HRMS calculated for C27H₂₂C1FN₂O₅S: 540.0922; found 541.0987 (M+H). The diastereoisomer eluting later was collected as Example 471. HRMS calculated for C27H22CIFN2O5S: 540.0922; found 541.1009 (M+H).

Example 472 (2R)-2-(((5J?_n)-5-[3-chloro-4-methoxy-2-methyl-5-(4-methylpiperazin-1yl)phenyl] -6-(prop-1 -yn-1 -y l)thieno [2,3 -i/]pyrimidin-4-yl} oxy)-3 -(2methoxyphenyl)propanoic acid and

-313Example 473 (27?)-2-({(5S_a)-5-[3-chloiO-4-methoxy-2-methyl-5-(4-inethylpiperazin-lyl)phenyl]-6-(prop-1 -yn-1 -yl)thieno[2,3-i/]pyrimidin-4-yl}oxy)-3-(2methoxyphenyl)propanoic acid

418 mg ethyl (2À)-2-(5-iodo-6-prop-l-ynyl-thieno[2,3-J|pyrimidin-4-yl)oxy-3-(2methoxyphenyl)propanoate (Préparation 4k) (0.80 mmol), 381 mg l-[3-chloro-2methoxy-4-methyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl]-4-methylpiperazine (Préparation 5j) (1.00 mmol), 58 mg PdCl₂ x dppf (0.08 mmol) and 391 mg Cs₂CO₃ (1.20 mmol) were dissolved in 10 mL dioxane and 2 mL water and was heated under nitrogen at 110°C for 10 minutes in a microwave reactor. Then reaction mixture was diluted with brine, and extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure and the residue was purified via flash chromatography, using heptane and EtOAc as eluents, then it was hydrolyzed according to General procedure (XIIIc). The diastereoisomer eluting earlier was collected as Example 472. HRMS calculated for C32H33CIN4O5S: 620.1860; found 621.1929 (M+H). The diastereoisomer eluting later was collected as Example 473. HRMS calculated for C32H33CIN4O5S: 620.1860; found 621.1929 (M+H).

Example 474 (2/?)-2-{[(5Æ_a)-5-{3-chloro-2,5-dimethyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(prop-l-yn-l-yl)thieno[2,3<7]pyriinidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid and

Example 475 (2R)-2-{[(5S₀)-5-{3-chloro-2,5-dimethyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl)-6-(prop-l-yn-l-yl)thieno[2,3-if|pyrÎmidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General procedure (Xfflb), diastereoisomer mixture of ethyl (2Æ)-2-[5-(3-chloro-4hydiOxy-2,5-dimethyl-phenyl)-6-prop-l-ynyl-thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2methoxyphenyl)propanoate (Préparation 18b) as the phénol and 2-(4-methyIpiperazin-lyl)ethanol as the appropriate alcohol Example 474 and Example 475 were obtained. The diastereoisomer eluting earlier was collected as Example 474. HRMS calculated for C34H37CIN4O5S: 648.2173; found 649.2252 (M+H). The diastereoisomer eluting later was

-314collected as Exampie 475. HRMS calculated for C34H37CIN4O5S: 648.2173; found 649.2251 (M+H).

Example 476 (2R)-2-{ [(5S_a)-5-{3-chloro-5-fluoro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl) -6-(prop-1 -yn-1 -yl)thieno[2,3-<7jpyrimÎdin-4-y]]oxy) -3 -(2methoxyphenyl)propanoic acid

Using General procedure (XlIIb), ethyl (2j?)-2-[(5S_i7)-5-(3-chloro-5-fluoro-4-hydroxy-2methyl-phenyl)-6-piOp-l-ynyl-thieno[2,3-t(|pyrimidin-4-yl]oxy-3-(2methoxyphenyl)propanoate (Préparation 18c) as the phénol and 2-(4-methylpiperazin-lyl)ethanol as the appropriate alcohol Exampie 476 was obtained. HRMS calculated for C₃3H34C1FN₄O₅S: 652.1922; found 653.2005 (M+H).

Example 477 (27?)-2-{[(58'_n)-5-{3-chIoro-5-methoxy-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(prop-l-yn-l-yl)thieno[2,3-(7|pyrirnidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

To 57 mg ethyl (2/?)-2-[(5_lS'_i,)-5-(3-chloiO-4-hydroxy-5-methoxy-2-methyl-phenyl)-6-piOpl-ynyl“thieno[2,3-£/]pyrimidm-4-yl]oxy-3-(2-methoxyphenyl)propanoate (Préparation 18a) (0.10 mmol), 29 mg 2-(4-methylpiperazin-l-yl)ethanol (0.20 mmol) and 100 mg immobilized PPI13 (0.30 mmol) 1 mL dry toluene was added followed by 52 mg 3(dimethylcarbamoylimino)-l,l-dimethyl-urea (0.30 mmol). The mixture was stirred at 50°Ç under nitrogen until no further conversion was observed. Then the mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents. The obtained intermediate was hydrolyzed according to General procedure (XIIIc) to give Example 477. HRMS calculated for C34H₃₇C1N4O₆S: 664.2122; found 665.2200 (M+H).

Example 478 (2Â)-2-{[(5/?₍₇)-5-{3-chloiO-4-[3-(dimethylamino)propyl]-2-methylphenyl}6-(piOp-l-yn-l-yl)thieno[2,3-i/Jpyrimidin-4-yl]oxy}-3-(2-methoxyphenyl)piOpanoic acid and

-315Example 479 (2/()-2- {[(58'_α)-5- (3-chioro-4-[3-(dimethyIamino)propyl]-2-methylphenyl} 6-(prop-l -yn-1 -yl)thieno[2,3-if]pyrimidin-4-yl]oxy}-3-(2-methoxyphenyl)propanoic acid

522 mg ethyl (2/()-2-(5-iodo-6-prop-l-ynyl-thieno[2,3-i/]pyrimidin-4-yl)oxy-3-(25 methoxyphenyl)propanoate (Préparation 4k) (1.00 mmol), 1.30 mmol 3-[2-chloro-3methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-V,V-dimethyl-propan-lamine (Préparation 5n), 71 mg AtaPhos (0.10 mmol) and 652 mg CS2CO3 (2,00 mmol) were dissolved in 8 mL dioxane and 2 mL water, and heated under nitrogen at 100°C for 15 minutes in a microwave reactor. The reaction mixture was diluted with brine and extracted with DCM. The combined organic phases were dried over Na₂SO₄, concentrated under reduced pressure and the residue was purified via flash chromatography, using EtOAc and MeOH as eluents. The obtained intermediate was hydrolyzed according to General procedure (XIIIc). The diastereoisomer eluting earlier was collected as Example 478. HRMS calculated for C31H32CIN3O4S: 577.1802; found 578.1876 (M+H). The diastereoisomer eluting later was collected as Example 479. HRMS calculated for C31H32CIN3O4S: 577.1802; found 578.1881 (M+H).

Example 480 (2/()-2- {[(5S₀)-5-(3-cWoro-4-hydroxy-2-methylphenyl)-6-(piOp- 1-yn-1 yl)thieno[2,3-(7]pyrimidin-4-yl]oxy}-3-(2-methoxyphenyl)propanoic acid

Ethyl (2/?)-2-[(5S_(I)-5-(3-chloro-4-hydroxy-2-methyl-phenyI)-6-prop-l-ynyl-thieno[2,3i/]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate (Préparation 61) was hydrolyzed according to General procedure (XIIIc) to give Example 480. HRMS calculated for C₂₆H₂₁C1N2O₅S: 508.0860; found 509.0940 (M+H).

General procedure (XlVa)

Step A:

eq. ethyl (2K)-2-[(55_a)-5-[3-chloro-2-iïiethyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-prop-l-ynyl-thieno[2,3-tZ]pyrimidin-4-yl]oxy-3-(230 hydroxyphenyl)propanoate (Préparation 8i), 2 eq. of the appropriate alcohol and 2 eq. triphenyl phosphine were dissolved in abs. toluene (0.2 M for the phénol), then 2 eq.

e

-316difôr/butyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversionwas observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents.

Step B :

The product of Step A was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH x H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure and the residue was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

Example 481 (2R)-2-{[(5SJ-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}“6-(prop-l-yn-l-yl)thieno[2,3-<7}pyriinidin-4-yl]oxy}-3-(2ethoxyphenyl)propanoic acid

Using General procedure (XlVa) and éthanol as the appropriate alcohol Exampie 481 was obtained.

HRMS calculated for C34H37CIN4O5S: 648.2173; found 649.2249 (M+H).

Exampie 482 (25)-2- {[(55_α)-5- {3 -chloro-2-methy 1-4-(2-(4-methylpiperazin-1 y l)ethoxy]phenyl} -6-(prop-1 -yn-1 -y l)thieno [2,3 -i(]pyiïmidin-4-yl]oxy} -3 -(2- {[2 -(2 methoxyphenyl)pyrimidin-4-yl]methoxy} phenyl)propanoic acid

Using General procedure (XlVa) and [2-(2-methoxyphenyl)pyrimidin-4-yl]methanol (Préparation 9bp) as the appropriate alcohol Exampie 482 was obtained. HRMS calculated for C44H43C1N₆O₆S: 818.2653; found 410.1394 (M+2H).

Example 483 (2R)-2-{[(55_n)-5-{3-chloro-2-methyl-4-(2“(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(prop-l-yn-l-yl)thieno[2,3-J]pyrimidin-4-yl]oxy}-3-(2-((2-(3methylpyridin-4-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid »

-317StepA:

1.30 g ethyl (2Æ)-2-[(55_fl)-5-[3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-prop-l-ynyl-thieno[2,3-if)pyrimidin-4-yl]oxy-3-(25 hydroxyphenyl)propanoate (Préparation 8i) (2.0 mmol), 0.94 g (2methylsulfanylpyrimidin-4-yl)methanol (Préparation 9aa) (6.0 mmol) and 1.57 g PPI13 (6.0 mmol) were dissolved in 40 mL dry toluene, then 1.38 g di-fé/7-butyl azodicarboxylate (6.0 mmol) was added. The mixture was stirred at 50°C under nitrogen. If needed, the addition of (2-methylsulfanylpyrimidin-4-yl)methanol (Préparation 9aa) (6.0 mmol), 10 PPh3 (6.0 mmol) and difer/butyl azodicarboxylate (6.0 mmol) can be repeated. When no further conversion was observed the volatiles were evaporated and the residue was purified via flash chromatography using DCM and MeOH as eluents, to obtain ethyl (2Â)-2-[(55₀)5- [3 -chloro-2-methyl-4- [2-(4-methy lpiperazin-1 -yl)ethoxy]phenyl]-6-prop-1 -ynylthieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[(2-methylsulfanylpyrimidin-4is yl)methoxy]phenyl]propanoate. HRMS calculated for C40H43CIN6O5S2: 787.2498; found 787.2464 (M+H).

Step B:

0.572 g ethyl (2Â)-2-[(55„)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l20 yl)ethoxy]phenyl]-6-prop-1 -ynyl-thieno[2,3-J]pyrimidin-4-yl]oxy-3-[2-[(2methylsulfanylpyrimidin-4-yl)methoxy]phenyl]propanoate (0.44 mmol), 0.179 g (3methyl-4-pyridyl)boronic acid (1.31 mmol), 0.25 g copper(I) thiophene-2-carboxylate (1.31 mmol) and 51 mg Pd(PPh₃)₄ were dissolved in 5 mL dry THF heated under nitrogen at 70 °C. If needed, the addition of reagents was repeated. When no further conversion was 25 observed the volatiles were evaporated and the residue was purified via flash chromatography using DCM and MeOH as eluents.

Step C:

The product of Step B was dissolved in 5 mL dioxane-water 1:1 and 10 eq. LiOH x H₂O 30 was added, The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄, concentrated under reduced

-318pressure and the residue was purified via préparative reverse phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to fumish Example 483. HRMS calculated for C43H42CIN7O5S: 803.2657; found 402.6401 (M+2H).

Example 484 (2Æ)-2-{[(55_a)-5-(3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl} -6-(prop-1 -yn-1 -yl)thieno [2,3 -rf]pyrimidin-4-yl]oxy} -3 - (2 - {[2- (2methoxyethyl)pyrimidin-4-yl]methoxy } phenyl)propanoic acid

Using General procedure (XlVa) and [2-(2-methoxyethyl)pyrimidin-4-yl]methanol (Préparation 9bl) as the appropriate alcohol Example 484 was obtained. HRMS calculated for C₄₀H43ClN₆O_âS: 770.2653; found 386.1410 (M+2H).

Example 485 (27?)-2-{[(55„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyI)ethoxy]phenyl}-6-(prop-l -yn-1 -yl)thieno[2,3-û(]pyrimidin-4-yl]oxy}-3-(2-{[2(morpholin-4-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (XlVa) and (2-(morpholin-4-yI)pyrimidin-4-yl)methanol (Préparation 9ar) as the appropriate alcohol Example 485 was obtained. HRMS calculated for C41H44C1N7O6S: 797.2762; found 399.6446 (M+2H).

Example 486 (2Æ)-2- {[(55,,)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl) -6-(prop-1 -yn-1 -yl)thieno[2,3-i(jpyrimidîn-4-yl]oxy} -3-{2-[(2methoxypyrimidin-4-yl)methoxy]pheny 1} propanoic acid

Using General procedure (XlVa) and (2-methoxypyrimidin-4-yl)methanol as the appropriate alcohol Example 486 was obtained. HRMS calculated for C38H39CIN6O6S: 742.2340; found 743.2424 (M+H).

Example 487 (2J?)-2- {[(55^)-5- {3 -chloro-2 -methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl} -6-(prop-1 -yn-1 -yl)thieno [2,3-d]pyrimidin-4-yl]oxy} -3-(2- {[2-(2,2,2trifluoroethoxy)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

- 319 Using General procedure (XIVa) and [2-(2,2₎2-trifluoroethoxy)pyiimidin-4-yr]methanol (Préparation 9ai) as the appropriate alcohol Example 487 was obtained. HRMS calculated forCjçHsgClFaNôOôS: 810.2214; found 811.2323 (M+H).

Example 488 (2Æ)-3-[2-[(l-/erZ-butyl-lH-pyrazol-5-yl)niethoxy]phenyl}-2-{[(5₁S_a)-5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-1-yi)ethoxy] phenyl}-6-(prop-1-yn-1 yl)thieno[2,3-i(jpyrimidin-4-yl]oxy}propanoic acid

Using General procedure (XlVa) and (l-/er/-butyl-lH-pyrazol-5-yl)methanol (Préparation 9dt) as the appropriate alcohol Example 488 was obtained. HRMS calculated for C^ClNeOsS: 756.2861; found 379.1485 (M+2H).

Example 489 (2R)-2- {[(53),)-5- (3-chloro-2-meihyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl }-6-(prop-1 -yn-1 -yl)thieno[2,3-J]pyrimidin-4-yl]oxy} -3 -(2- {[ 1 -(2,2,2trifluoroethyl)-177-pyrazol-5-yl]methoxy}phenyl)propanoic acid

Using General procedure (XlVa) and [l-(2,2₎2-trifluoroethyl)-lH-pyrazol-5-yl]methanol (Préparation 9du) as the appropriate alcohol Example 489 was obtained. HRMS calculated for C₃₈H₃gCIF₃N6O_sS: 782.2265; found 783.2353 (M+H).

Example 490 (2Æ)-3- [2-[(l -butyl-1 H-pyrazol-5-yl)methoxy]phenylJ -2-{[(5S_a)-5- (3chloro-2-methyl-4-[2-(4-methylpipcrazin-1 -y l)cthoxy]phcnyl} -6-(prop- 1-yn-1 yl)thieno[2,3-<7}pyrirnidin-4-yl]oxy}propanoic acid

Using General procedure (XlVa) and (l-butyl-l//-pyrazol-5-yl)methanol (Préparation 9dd) as the appropriate alcohol Example 490 was obtained. HRMS calculated for C40H45CIN6O5S: 756.2861 ; found 757.2953 (M+H).

Example 491 (23)-3-(1 -benzofuran-4-yl)-2-{[(5Æ_a)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-1 -yl)ethoxy]phenyl}-6-(prop-l -yn-1 -yl)thieno[2,3-rfJpyrimidin-4yl]oxy}propanoic acid

-320 Step A:

0.137 g ethyl (25)-3-(benzofuran-4-yl)-2-[(57?_n)5-(3-chlora-4-hydroxy-2-m.ethyl-phenyl)-6prop-l-ynyl-thieno[2,3-c/]pyrimidin-4-yl]oxy-propanoate (Préparation 20b) (0.25 mmol), 0.072 g 2-(4-methylpiperazin-l-yl)ethanol (0.5 mmol) and 0.166 g PPh₂ (0.5 mmol) were dissolved in 4 ml, dry toluene and 0.115 g di/er/butyl azodicarboxylate (0.5 mmol) was added and it was heated at 50°C. If needed, the addition of reagents can be repeated. When no further conversion was observed the volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents.

Step B:

The product of Step A was dissolved in 10 mL dioxane-water 1:1 and 0.200 g LiOH χ H2O (5.88 mmol) was added. The mixture was stirred at room température until no further conversion was obseived. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄, concentrated under reduced pressure and the residue was purified via preparative reverse phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to fumish Example 491. HRMS calculated for C34H33CIN4O5S: 644.1860; found 645.1934 (M+H).

Example 492 (2R)-3-(l-benzofuran-4-yl)-2-{[(5_lS'₍,)-5-{3-chloiO-2-methyl-4-[2-(4methylpiperazin-1 -yl)ethoxy]phenyl} -6-(prop-1 -yn-1 -yl)thieno[2,3-J]pyrimidin-4yl]oxy}propanoic acid

Step A:

0.137 g ethyl (2R)-3-(benzofuran-4-yl)-2-[(55_fl)5-(3-chloro-4-hydroxy-2-methyI-phenyl)-6prop-l-ynyl-thieno[2,3-ôZ]pyrimidin-4-yl]oxy-propanoate (Préparation 20a) (0.25 mmol), 0.072 g 2-(4-methylpiperazin-l-yl)ethanol (0.5 mmol) and 0.166 g PPhj (0.5 mmol) were dissolved in 4 mL dry toluene and 0.115 g di/erZbutyl azodicarboxylate (0.5 mmol) was added and it was heated at 50°C. If needed, the addition of reagents can be repeated. When no further conversion was observed the volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents.

Step B:

-321The product of Step A was dissolved in 10 mL dioxane-water 1:1 and 0.200 g LiOH * H₂O (5.88 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated 5 under reduced pressure and the residue was purified via préparative reverse phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to furnish Example 492. HRMS calculated for C34H33CIN4O5S: 644.1860; found 645.1935 (M+H).

General procedure (XVa)

Step A:

eq. methyl (2R)-2-[6-bromo-(5.S„)-5-(3-chloiO-4-hydroxy-2-methyl-phenyl)thieno[2,3JJpyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 22), 2.5 eq. of the appropriate boronic ester or boronic acid and 2.5 eq. Cs₂CO₃ were dissolved in THF-water (4:1) (12.5 ml/mmol of Préparation 22), then 0.1 eq Pd(dppf)C12 was added. The mixture was heated 15 under nitrogen at 110°C in a microwave reactor until no further conversion was observed.

Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na2SÜ4, concentrated under reduced pressure and the residue was purified via flash chromatography using heptane and ethyl acetate as eluents.

Step B:

eq. of the product of Step A, 2 eq. 2-(4-methylpiperazin-l-yl)ethanol and 2 eq. PPh₃ were dissolved in dry toluene (5 mL/mmol of the product of Step A), then 2 eq. direr/buty 1 azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crade intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents.

Step C:

The product of Step B was dissolved in dioxane-water 1:1(10 mL/mmol product of Step

B) and 10 eq. LiOH x H₂O was added. The mixture was stirred at room température until

-322no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na2SO4, concentrated under reduced pressure and the residue was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

General procedure (XVb)

Step A:

l eq. phénol dérivative, 2 eq. 2-(4-methylpiperazin-l-yl)ethanol and 2 eq. triphenyl phosphine were dîssolved in dry toluene (5 mL/mmol of phénol), then 2 eq. diter/butyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents.

Step B:

The product of Step A was dîssolved in dioxane-water 1:1 (10 mL/mmol product of Step A) and 10 eq. LiOH * H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄₎concentrated under reduced pressure and the residue was purified via préparative reversed phase chromatography using 25 mM aqueous NH4I-ICO3 solution and MeCN as eluents.

Example 493 (2Æ)-2-[(6-[(l Z)-but-l -en-l-yl]-(55_f,)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3-i(]pyrimidin-4-yl)oxy]-3-phenyIpiOpanoic acid

Step A:

8.45 g 4-chloro-5,6-diiodo-thieno[2,3-ù(]pyrimidine (Préparation lb) (20 mmol), 5.41 g methyl (2Æ)-2-hydroxy-3-phenyl-propanoate (Préparation 3ag) (30 mmol) and 13.03 g Cs₂CO₃ (40 mmol) were placed in a flask. 20 mL DMSO was added and the mixture was stirred at 60°C until no further conversion was observed. It was diluted with water, the pH

-323 was set to 5 with 2 M HCl, and then it was extracted with dichlorométhane, The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure, and purified via flash chromatography using heptane and ethyl acetate as eluents to obtain methyl (2À)2-(5_s6-diiodothieno[2,3-i(lpyrimidin-4-yl)oxy-3-phenyl-propanoate. *H NMR (400 MHz, DMSO-de): 8.49 (s, IH), 7.42 (m, 2H), 7.30 (m, 2H), 7.25 (m, IH), 5.78 (dd, IH), 3.75 (s, 3H), 3.50-3.35 (m, 2H).

Step B:

230 mg methyl (2Æ)-2-(5,6-diiodothieno[2,3-d]pyrimidin-4-yl)oxy-3-phenyl-propanoate (0.4 mmol), 14 mg Pd(PPh3)2Cl (0.02 mmol) and 4 mg Cul (0.02 mmol) were dissolved in 3 mL D1PA, then but-1 -yne was bubbled through the reaction mixture, which was stirred at 30°C until no further conversion was observed. The reaction mixture was concentrated under reduced pressure and purified via flash chromatography using heptane and ethyl acetate as eluents to obtain methyl (2Æ)-2-(6-but-l-ynyl-5-iodo-thieno[2,3-d]pyrimidin-4yl)oxy-3-phenyl-propanoate. NMR (400 MHz, CDCI3): 8.52 (s, IH), 7.43 (m, 2H), 7.29 (m, 2H), 7.22 (m, IH), 5.76 (dd, IH), 3.73 (s, 3H), 3.49-3.35 (m, 2H), 2.54 (q, 2H), 1.31 (t, 3H).

Step C:

189 mg methyl (2Â)-2-(6-but-l-ynyl-5-iodo-thieno[2,3-<7]pyrimidin-4-yl)oxy-3-phenylpropanoate (0.383 mmol) and 155 mg 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaboro!an-2-yl)phcnol (Préparation 5a) (0.6 mmol) were dissolved in 3 mL 2-methyltetrahydrofurane, 600 pL tetrabutyl ammonium hydroxyde (IM in water, 0.6 mmol) was added. Then 27 mg AtaPhos (0.038 mmol) was added and the reaction mixture was heated under nitrogen at 110°C in a microwave reactor until no further conversion was observed. Then reaction mixture was diluted with dichlorométhane and brine, the pH was set to 5 with 2 M HCl, and extracted with dichlorométhane. The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting later was collected as methyl (2/?)-2-[6-but-l-ynyl-5-(2-chloro-4-hydroxy-3methyl-phenyl)thieno[2,3-<7]pyrimidin-4-yl]oxy-3-phenyl-propanoate. MS: (M+H) =

507.0.

-324Step D:

mg methyi (27?)-2-[6-but-l-ynyl-5-(2-chloro-4-hydroxy-3-methyl-phenyl)thieno[2,3</jpyrimidin-4-yl]oxy-3-phenyl-propanoate (O.l mmol) and 2 mg Pd/BaCO₃ (5 m/m%) (0.001 mmol) was dissolved in 10 mL methanol. Then 2.5 mL H₂ was added and the réaction mixture was stirred at room température until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN to obtain methyi (2A)-2-[6-[(lZ)-but-l-enyl]-5-(2-chloro-4-hydiOxy-3methyl-phenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-phenyl-piOpanoate. *H NMR (500 MHz, DMSO-dû): 10.35 (br s, IH), 8.54 (s, IH), 7.15 (m, 3H), 7.07 (d, IH), 7.01 (d, IH), 6.65 (m, 2H), 6.31 (dt, IH), 6.14 (d, IH), 5.44 (dd, IH), 3.56 (s, 3H), 2.95 (dd, IH), 2.65 (dd, IH), 2.16 (g, 2H), 2.00 (s, 3H), 0.96 (t, 3H). HRMS: (M+H) = 509.1324.

Step E:

mg methyi (2Æ)-2-[6-[(lZ)-but-l-enyl]-5-(2-chloro-4-hydroxy-3-inethylphenyl)thieno[2,3-ri]pyrimidin-4-yl]oxy-3-phenyl-propanoate (0.039 mmol), 12 mg 2-(4methylpiperazin-l-yl)ethanol (0.08 mmol) and 26 mg triphenyl phosphine (0.08 mmol) were dissolved in 3 mL dry toluene, then 18 mg di/e/7butyl azodicarboxylate (0.08 mmol) was added. The mixture was stirred at 40°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using ethyl acctatc and methanol as eluents.

Step F:

The product of Step E was dissolved in 1 mL dioxane-water (1:1) and 17 mg LiOH x H₂O (0.4 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄, concentrated under reduced pressure, and the residue was purified via préparative reversed phase chromatography using 25 mM aqueous NH₄HCO₃ solution and MeCN as eluents to obtain Example 493. HRMS calculated for C₃₃H37C1N₄O₄S: 620.2224; found (M+H)

-325Exampie 494 (2R)-2-{ [(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-inethylpiperazin-1 yl)ethoxy]phenyl}-6-(2-methylprop-l-en-l-yl)thieno[2,3-djpyrirnidin-4-yl]oxy}-3phenylpropanoic acid

Using General procedure (XVa) and 4,4,5,5-tetramethyl-2-(2-methylprop-l-enyl)-l,3,2dioxaborolane as the appropriate boronic ester Exampie 494 was obtained. HRMS calculated for C33H37CIN4O4S: 620.2224; found 621.2287 (M+H)

Example 495 (21?)-2-{ [(5S'_a)-5-{3-chloiO-2-methyl-4-[2-(4-methyIpiperazin-1 10 yl)ethoxy]phenyl}-6-(4-methylthiophen-2-yl)thieno[2,3-<(]pyrimidin-4-yI]oxy}-3phenylpropanoic acid

Using General procedure (XVa) and4,4,5,5-tetramethyi-2-(4-methyl-2-thienyl)-I,3,2dioxaborolane as the appropriate boronic ester Example 495 was obtained. HRMS !5 calculated for C34H35CIN4O4S2: 662.1788; found 663.1884 (M+H)

Example 496 (2R)-2-{[6-(l-benzofüran-2-yl)-(55„)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-1 -yl)ethoxy]phenyi}tbieno[2,3-</)pyrimidin-4-yl]oxy} -3-phenyIpropanoic acid

Using General procedure (XVa) and 2-(benzofuran-2-yl)-4,4,5,5-tetramethyl-l,3,2dioxaborolane as the appropriate boronic ester Example 496 was obtained. HRMS calculated for C37H35CIN4O5S: 682.2017; found 683.2084 (M+H)

Exampie 497 (2R)-2-{[6-(I-benzothiophen-2-yl)-(55_a)-5-{3-chloiO-2-methyl-4-[2-(4methy 1 piperazin-1 -y l)ethoxy]phenyl} thieno[2,3 -d]pyrimidin-4-y I]oxy} -3 -pheny Ipropanoic acid

Using General procedure (XVa) and 2-(benzothiophen-2-yl)-4,4,5,5-tetramethyl-l,3,230 dioxaborolane as the appropriate boronic ester Example 497 was obtained. HRMS calculated for C37H35CIN4O4S2: 698.1788; found 699.1879 (M+H)

-326Example 498 (2R)-2- {[(56),)-5-{3-chloro-2-melhyl-4-[2-(4-rnethylpiperazin-1 yl)ethoxy]phenyl)-6-(4-fluorophenyl)thieno[2,3-iZ|pyrimidin-4-yl]oxy}-3-plieriylpropanoic acid

Using General procedure (XVa) and 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2dioxaborolane as the appropriate boronic ester Example 498 was obtained. HRMS calculated for C35H34CIFN4O4S: 660.1973; found 661.2042 (M+H)

Example 499 (2R)-2- {[(56,,)-5- {3 -chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(5-methylfuran-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3phenylpropanoic acid

Using General procedure (XVa) and 4,4,5,5-tetramethyl-2-(5-methyl-2-furyl)-l,3,2dioxaborolane as the appropriate boronic ester Example 499 was obtained. HRMS calculated for C34H35CIN4O5S: 646.2017; found 647.2091 (M+H)

Example 500 (2Æ)-2-{[(5S,7)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl} -6-(5-methylthiophen-2-yl)thieno[2,3 -d]pyriniidin-4-yl]oxy} -3 phenylpropanoic acid

Using General procedure (XVa) and 4,4,5,5-tetramethyl-2-(5-methyl-2-thienyl)-1,3,2dioxaborolane as the appropriate boronic ester Example 500 was obtained. HRMS calculated for C34H35CIN4O4S2: 662.1788; found 663.1874 (M+H)

Example 501 (2R)-2-{[(55„)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy’|phenyl}-6-(5-chlorothiophen-2-yl)thieno[2,3-<Z]pyrimidin-4-yl]oxy}-3phenylpropanoic acid

Using General procedure (XVa) and (5-chloro-2-thienyl)boronic acid as the appropriate boronic acid Exemple 501 was obtained. HRMS calculated for C33H32CI2N4O4S2: 682.1242; found 683.1308 (M+H)

-327Examp le 502 (2Λ)-2- [((55,)-5 - {3 -chloro-2-methyl-4- [2-(4-methylpiperazin-1 yl)ethoxy]phenyl} -6-pheny lthieno[2,3 -cflpyrimidin-4-yl)oxy]-3 -phenylpropanoic acid

Using General procedure (XVa) and 4,4₅5,5-tetramethyl-2-phenyl-l,3,2-dioxaborolane as the appropriate boronic ester Example 502 was obtained, HRMS calculated for C35H35CIN4O4S: 642,2068; found 643.2135 (M+H)

Example 503 (25)-2- {[(55,)-5- {3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl)-6-(l-methyl-lH-pynOl-2-yl)thieno[2,3-iZ]pyrimidin-4-yl]oxy}-3phenylpropanoic acid

Using General procedure (XVa) and l-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)-lH-pyrrole as the appropriate boronic ester Example 503 was obtained. HRMS calculated for C₃4H36C1N₅O4S: 645.2177; found 646.2222 (M+H)

Example 504 (2//)-2- {[(55,)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(fi.iran-2-yl)thieno[2,3-iZ]pyrimidin-4-yl]oxy}-3-phenylpropanoicacid

Using General procedure (XVa) and 2-(2-furyl)-4,4_s5,5-tetramethyl-l ,3,2-dioxaborolane as the appropriate boronic ester Example 504 was obtained. HRMS calculated for C33H33CIN4O5S: 632.186; found 633.1939 (M+H)

Example 505 (2//)-2-{[(55_l)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(thiophen-2-yl)thieno[2.,3-<7]pyrimidin-4-yl]oxy}-3-phenylpropanoic acid

Using General procedure (XVa) and 2-thienylboronic acid as the appropriate boronic acid

Example 505 was obtained. HRMS calculated for C33H33CIN4O4S2:648.1632; found 649.172 (M+H)

-328Example 506 (2R)-2- {[(55),)-5 - (3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(l-methyl-lH-pyrazol-3-yl)thieno[2,3-if|pyrimidin-4-yl]oxy}-3phenylpropanoic acid

Using General procedure (XVa) and l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)-lÆ-pyrazole as the approprîate boronic ester Example 506 was obtained. HRMS calculated for C₃3H35ClN₆O₄S: 646.2129; found 647.2195 (M+H)

Example 507 (2IÎ)-2-{[(55'_fl)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-l10 yl)ethoxy]phenyl}-6-(pyridin-4-yl)thieno[2,3-<|pyrimidin-4-yl]oxy}-3-phenylpropanoic acid

Using General procedure (XVa) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)pyridine as the approprîate boronic ester Example 507 was obtained. HRMS calculated for C34H34CIN5O4S; 643.202; found 644.2089 (M+H)

Example 508 (2Æ)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(l-methy]4H-pyrazol-5-yl)thieno[2,3-iZjpyrimidin-4-yl]oxy}-3phenylpropanoic acid

Using General procedure (XVa) and l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)-lH-pyrazole as the approprîate boronic ester Example 508 was obtained. HRMS calculated for C33H3₅C1N₆O₄S: 646,2129; found 647.222 (M+H)

Example 509 (27?)-2-{[(55_ÎT)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-3-yl)thieno[2,3-</]pyrimidinⁱ-4-yl]oxy}-3-phenylpiOpanoicacid

Using General procedure (XVa) and 2-(3-furyl)-4,4,5,5-tetramethyl-l,3,2-dioxaboroIane as the approprîate boronic ester Example 509 was obtained. HRMS calculated for

C₃3H₃₃C1N4O₅S: 632.186; found 633.196 (M+H) *

-329Example 510 (2Λ)-2-{ [(55_a)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(thiophen-3-yl)thieno[2,3-iZ)pyrimidin-4-yl]oxy}-3-phenylpropanoic acid

Using General procedure (XVa) and 4,4,5,5-tetramethyl-2-(3-thienyl)-l ,3,2-dioxaborolane as the appropriate boronic ester Exampie 510 was obtained. HRMS calculated for C33H33CIN4O4S2: 648.1632; found 649.1711 (M+H)

Example 511 (2R)-2-([(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazÎn-l10 yl)ethoxy]phenyl}-6~(2-methylthiophen-3-yI)thieno[2,3-(/]pyriinidm-4-yl]oxy}-3phenylpropanoic acid

Using General procedure (XVa) and 4,4,5,5-tetramethyl-2-(2-methyl-3-thienyl)-l,3,2dioxaborolane as the appropriate boronic ester Example 511 was obtained. HRMS calculated for C34H35CIN4O4S2: 662.1788; found 663.1864 (M+H)

Example 512 (2R)-2-{[(55₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(l,3-thiazol-5-yI)thieno[2,3-</Jpyrimidin-4-yl]oxy}-3phenylpropanoic acid

Using General procedure (XVa) and 5-(4,4,5,5-tetramethyl-l,3,2~dioxaborolan-2-yl)-l,3thiazolc as the appropriate boronic ester Exampie 512 was obtained. HRMS calculated for C32H32CIN5O4S2: 649.1584; found 650.1654 (M+H)

Example 513 (2/i)-2-{[(5S_n)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl} -6-(l -methyl-1 H-py razol-4-yl)thieno[2,3-d]pyrimidin-4-yl]oxy} -3 phenylpropanoic acid

Using General procedure (XVa) and l-methyl-4-(4₎4,5,5-tetramethyl-l,3,2-dioxaborolan30 2-yl)-lH-pyrazole as the appropriate boronic ester Example 513 was obtained. HRMS calculated for C3₃H₃5C1N₆O₄S; 646.2129; found 647.2199 (M+H) >

-330Example 514 (2Æ)-2-{[(5S/)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl} -6-(5-methylthiophen-3-yl)thieno[2,3 -zZjpyri m id i n-4-y 1 Joxy} -3 phenylpropanoic acid

StepA:

531 mg 4-bromo-2-methyl-thiophene (3.0 mmol), 813 mg 2-(5,5-dimethyl-1,3,2dioxaborinan-2-yl)-5,5-dimethyl-l,3,2-dioxaborinane (3.6 mmol) and 883 mg KOAc (9.0 mmol) were dissolved in 15 mL 1,4-dioxane, then 219 mg Pd(dppf)Ch (0.3 mmol) was added. The mixture was heated under nitrogen at 120°C in a micro wave reactor until no further conversion was observed. The volatiles were evaporated under reduced pressure and purified via flash chromatography using heptane and ethyl acetate as eluents to obtain 5,5-dimethyl-2“(5-methyl-3-thienyl)-l,3,2-dioxaborinane. ^!H NMR (500 MHz, CDCI3): 7.59 (d, IH), 7.00 (dd, 1H), 3.73 (s, 4H), 2.49 (d, 3H), 1.02 (s, 6H).

Step B:

Using General procedure (XVa) and 5,5-dimethyl-2-(5-methyl-3-thienyl)-l,3,2dioxaborinane as the appropriate boronic ester Example 514 was obtained. HRMS calculated for C34H35CIN4O4S2: 662.1788; found 663.1884 (M+H)

Example 515 (2R)-2- {[(55/)-5- {3-chIoiO-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}“6-(2-methyl-l,3-thiazol-4-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3phenylpropanoic acid

Using General procedure (XVa) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-y 1)-1,3-thiazole as the appropriate boronic ester Example 515 was obtained. HRMS calculated for C33H34CIN5O4S2: 663.1741; found 664.1823 (M+H)

Example 516 (27?)-2-{[(55/)-5-{3-chloro-2-niethyl-4-[2-(4-inethyIpiperazin-l yl)ethoxy]phenyl}-6-(4-methylthiophen-3-yl)thieno[2,3-dJpyiimidin-4-yl]oxy}-3phenylpropanoic acid %

-331Using General procedure (XVa) and 4,4,5,5-tetramethyl-2-(4-methyl-3-thienyl)-l,3,2dioxaborolane as the appropriate boronic ester Example 516 was obtained. HRMS calculated for C34H35CIN4O4S2: 662.1788; found 663.1863 (M+H)

Example 517 (272)-2- {[(5S„)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-l y l)ethoxy]phenyl} -6-(3 -methy lthiophen-2-y l)thieno [2,3-t(|pyrimidin-4-yl]oxy} -3 phenylpropanoic acid

Using General procedure (XVa) and 4,4,5,5-tetramethyl-2-(3-methyl-2-thienyl)-l,3,210 dioxaborolane as the appropriate boronic ester Example 517 was obtained. HRMS calculated for C34H35CIN4O4S2: 662.1788; found 663.1882 (M+H)

Example 518 (272)-2-[(6-bromo-(5S₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}thieno[2,3-J]pyrimidin-4-yl)oxy]-3-phenylpropanoic acid

StepA:

180 mg methyl (272)-2-[6-bromo-(55₀)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)thieno[2,3i/|pyrimidin-4-yljoxy-3-phenyl-propanoate (Préparation 22) (0.335 mmol), 96 mg 2-(4methylpiperazin-l-yl)ethanol (0.672 mmol) and 177 mg PPI13 (0,672 mmol) were dissolved in 6 mL dry toluene, then 145 mg di/er/butyl azodicarboxylate (0.672 mmol) was added.

The mixture was stirred at 50°C under nitrogen until no further conversion was observed.

The volatiles wcrc evaporated under rcduccd pressure and the residue was purified via flash chromatography using ethyl acetate and methanol as eluents.

Step B:

The product of Step A was dissolved in 5 ml methanol and 50 mg NaOH (1.25 mmol) was added. The mixture was stin-ed at 50°C until no further conversion was observed. It was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure, and the 30 residue was purified via préparative reversed phase chromatography using 25 mM aqueous

NH4HCO3 solution and MeCN as eluents to obtain Example 518. HRMS calculated for

C2₉H₃oBrClN404S: 644.086; found 645.0942 (M+H)

-332Example 519 (2R)-2-{ [(55_π)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl} -6-(prop-1 -yn-1 -yl)thieno[2,3-cZ]pyrimidin-4-yl]oxy} -3-phenylpropanoic acid

Step A:

8.45 g 4-chloiO-5,6-diiodo-thieno[2,3-i7]pyrïmidine (Préparation lb) (20 mmol), 5.41 g methyl (25)-2-hydroxy-3-phenyl-propanoate (Préparation 3ag) (30 mmol) and 13.03 g CS2CO3 (40 mmol) were placed in a flask. 20 mL DMSO was added and the mixture was stirred at 60°C until no further conversion was observed. The reaction mixture was diluted with water, the pH was set to 5 with 2 M HCl, and then it was extracted with dichloromethane. The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure, and the residue was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain methyl (25)-2-(5,6-diiodothieno[2,3i/]pyrimidin-4-yl)oxy-3-phenyl-propanoate. 'H NMR (400 MHz, DMSO-dô): 8,49 (s, 1H), 7.42 (m, 2H), 7.30 (m, 2H), 7.25 (m, IH), 5.78 (dd, IH), 3.75 (s, 3H), 3.50-3.35 (m, 2H).

Step B:

1.132 g methyl (25)-2-(5,6-diiodothieno[2,3-rZ|pyrimidin-4-yl)oxy-3-phenyl-propanoate (2 mmol), 70 mg Pd(PPha)₂Cl (0.1 mmol) and 38 mg Cul (0.2 mmol) were dissolved in 10 mL DIPA, then propyne was bubbled through the reaction mixture, which was stirred at 45°C until no further conversion was observed. It was concentrated under reduced pressure and purified via flash chromatography using heptane and ethyl acetate as eluents to obtain methyl (25)-2-(5-iodo-6-prop-l-ynyl-thieno[2,3-zf|pyrimidin-4-yl)oxy-3-phenylpropanoate. MS: (M+H) - 479.0.

Step C:

469 mg methyl (25)-2-(5-iodo-6-prop-l-ynyl-thieno[2,3-J]pyriinidin-4-yl)oxy-3-phenylpropanoate (0.98 mmol) and 537 mg 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenol (Préparation 5a) (2.0 mmol) were dissolved in 10 mL 1,4dioxane, then 815 mg CS2CO3 (2.5 mmol) dissolved in 2 mL water was added followed by 71 mg AtaPhos (0.1 mmol) and the mixture was heated under nitrogen at 110°C in a

- 333 microwave reactor until no further conversion was observed. After dilution with dichloromethane and brine lhe pH was sel to 5 with 2 M HCl and lhe aqueous phase was extracted with dichloromethane. The combined organic layers were dried over Na2SO₄, concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting later was collected as methyl (27?)-2-[5-(2-chloro-4-hydiOxy--3-methyl-phenyl)-6-piOp-lynyl-thieno[2,3-J]pyrimidin-4-yl]oxy-3-phenyl-propanoate. MS: (M+H) - 493.0.

Step D:

360 mg methyl (2Â)-2-[5-(2-clfloro-4-hydroxy-3-methyl-phenyl)-6-piOp-l-ynylthieno[2,3-i/Jpyrimidin-4-yl]oxy-3-pheny]-pi’opanoate (0.73 mmol), 211 mg 2-(4methylpiperazin-l-yl)ethanol (1.46 mmol) and 487 mg triphenyl phosphine (1.46 mmol) were dissolved in 5 mL dry toluene, then 336 mg diterZbutyl azodicarboxylate (1.46 mmol) was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents.

Step E:

The product of Step D was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH x H2O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic layers were dried over Na2SC>4, concentrated under reduced pressure, and the residue was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 519. HRMS calculated for C32H33CIN4O4S: 604.1911; found 605.2 (M+H)

Example 520 (2Æ)-2-{[(55„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin--l yl)ethoxy]phenyl}-6-(cyclopropylethynyl)thieno[2,3-i/]pyrimidÎn-4-yl]oxy}-3phenylpropanoic acid

Step A:

-3341.132 g methyl (2Â)-2-(5,6-diiodothieno[2,3-</]pyrimidÎn-4-yl)oxy-3-phenyl-propanoate (from Step A of Example 519, 2 mmol), 152 mg ethynylcyclopropane (2.3 mmol), 70 mg Pd(PPh3)2Cl (0.1 mmol) and 38 mg Cul (0.2 mmol) were dissolved in 4 mL DIPA and the mixture was stirred uinder nitrogen at 40°C until no further conversion was observed. The reaction was concentrated under reduced pressure and purified Ma flash chromatography using heptane and ethyl acetate as eluents to obtain methyl (27?)-2-[6-(2cyclopropyIethynyl)-5-iodo-thierio[2,3-iZ]pyrimidin-4-yl]oxy-3-phenyl-propanoate. MS: (M+H) = 505.0.

Step B:

968 mg methyl (2Æ)-2-[6-(2-cyclopiOpylethynyl)-5-iodo-thieno[2,3-r/]pyrimidin-4-yl]oxy3-phenyl-propanoate (1.92 mmol) and 670 mg 2-chIoro-3-methyl-4-(4,4,5,S-tétraméthylia,2-dioxaborolan-2-yl)plienol (Préparation 5a) (2.5 mmol) were dissolved in 8 mL 2methyl-tetrahydrofurane and 2.5 mL tetrabutylammonium hydroxyde (1M in water, 2.5 mmol) was added followed by 68 mg AtaPhos (0.096 mmol). The mixture was heated under nitrogen at 110°C in a microwave reactor until no further conversion was observed. Then it was diluted with dichloromethane and brine, the pH was set to 5 with 2 M HCl and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting later was collected as methyl (2Æ)-2-[5-(2-chloro-4-hydiOxy-3methyl-phenyl)-6-(2-cyclopiOpylelhynyl)thieno[2,3-i/)pyrimidin-4-yl]oxy-3-phenylpropanoate. MS: (M+H) = 519.0.

Step C:

156 mg methyl (2Æ)-2-[5-(2-chloro-4-hydiOxy-3-methyl-phenyl)-6-(2cyclopropylethynyl)thieno[2,3-rZ]pyrimidin-4-yl]oxy-3-phenyl-propanoate (0.3 mmol), 87 mg 2-(4-methylpiperazin-l-yl)ethanol (0.6 mmol) and 158 mg triphenyl phosphine (0.6 mmol) were dissolved in 3 mL dry toluene, then 138 mg diter/butyl azodicarboxylate (0.6 mmol) was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the

-335crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents.

Step D:

The product of Step C was dissolved in 5 mL methanol and 200 mg LiOH x H₂O (4.76 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM, dried over Na₂SO4, fïltered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 520. HRMS calculated for C34H35CIN4O4S: 630.2068; found 631.2096 (M+H)

Example 521 (2R)-2-[((5S_fl)-5-{3-chloro-2-methyl-4-[2-(4-niethylpiperazin-lyl)ethoxy]phenyl}-6-cyanothieno[2,3-iZ]pyrimidin-4-yl)oxy]-3-phenylpropanoicacid

Step A:

5 mg [2-chloro-4-(4-chloiOthieno[2,3-t/Jpyrimidin-5-yl)-3-methyl-phenoxy]triisopropyl-silane (Préparation 23a) (2.0 mmol) was dissolved in 20 mL dry THF then cooled to ~78°C under argon atmosphère. 1.2 mL lithium diisopropylamide (2.4 mmol, 2 M in THF, EtPh, hexanes) was added and the mixture was stirred at -78°C for 1 hour. Then 471 mg p-tolylsulfonylformonitrile (2.6 mmol) was added and the mixture was allowed to wann up to room température. To the reaction mixture saturated aq. NII4CI was added and then extracted with ethyl acetate. Organic layer was dried over Mg₂SO4, fïltered and concentrated under reduced pressure. The crude intermediate was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain 4-chIoro-5-(3-chloro2-methyl-4-triisopropylsilyloxy-phenyl)thieno[2,3-rf]pyrimidine-6-carbonitrile.

‘H NMR (400 MHz, DMSO-d₆): 9.16 (s, IH), 7.26 (d, IH), 7.03 (d, IH), 2.10 (s, 3H), 1.42-1.30 (m, 3H), 1.10 (dd, 18H).

Step B:

380 mg 4-chloro-5-(3-chloiO-2-methyl-4-triisopiOpylsilyloxy-phenyl)thieno[2,3i/]pyrimidine-6-carbonitrile (0.77 mmol) was dissolved in 7 mL ’PrOH, 166 mg methyl

-336(2R)-2-hydroxy-3-phenyl-propanoate (Préparation 3ag) (0.92 mmol) and 753 mg CS2CO3 (2.31 mmol) was added and the mixture was stirred at room température until no further conversion was observed. It was diluted with water, the pH of the mixture was set to 4 with 2 M HCl, and extracted with DCM. The combined organic layers were dried over Na₂SO4, concentrated under reduced pressure, and the residue was purified via flash chromatography using heptane and ethyl acetate as eluents.

Step C:

The product of Step B was dissolved in IO mL THF, 0.8 mL TBAF (IM in THF) (0.8 mmol) was added and the mixture was stirred until no further conversion was observed. Then it was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over Na₂SO4, filtered and concentrated under reduced pressure and purified via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting later was collected to obtain methyl (2A)-2-[(5S_a)-5-(3-chloiO-4-hydroxy-2-methylphenyl)-6-cyano-thieno[2,3-<7]pyrimidin-4-yl]oxy-3-phenyI-piopanoate. MS: (M+H) = 480.0.

Step D:

Using General procedure (XVb) and methyl (2Æ)-2-[(5S„)-5-(3-chloro-4-hydiOxy-2methyl-phenyl)-6-cyano-thieno[2,3-i7]pyrimidm“4-yl]oxy-3-phenyl-propanoate as the appropriate phénol Exampie 521 was obtained. HRMS calculated for C30H30CIN5O4S: 591.1707; found 592.1786 (M+H)

Example 522 (2Æ)-2-[(6-acetyl-(5S_a)-5-{3-chloro-2-methyl-4“[2-(4-methylpiperazinlyl)ethoxy]phenyl}thieno[2,3-tZ]pyrimidin-4-yl)oxy]-3-phenylpiOpanoicacid

Step A:

935 mg [2-chloro-4-(4-chlorothieno[2,3-iZ|pyrimidin-5-yl)-3-methyl-phenoxy]triisopropyl-silane (Préparation 23a) (2.0 mmol) was dissolved in 20 mL dry THF then cooled to -78°C under argon atmosphère. 1.2 mL lithium diisopropylamide (2.4 mmol, 2 M in THF, EtPh, hexanes) was added and the mixture was stirred at -78°C for 1 hour. Then 265 mg acetic anhydride (2.6 mmol) was added and the mixture was allowed to warm up

- 337to room température. To the reaction mixture saturated NH4CI was added and then extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure, and the residue purified via flash chromatography, using heptane and EtOAc as eluents to obtain l-[4-chloro-5-(3-chloro-2-methyl-45 triisopropylsilyloxy-phenyI)thieno[2,3-J]pyrimidin-6-yl]ethanone. *H NMR (400 MHz,

CDCh): 8.94 (s, IH), 6.98 (d, IH), 6.95 (d, IH), 2.17 (s, IH), 2.03 (s, IH), 1.44-1.32 (m, 3 H), 1.17 (d, 18H).

Step B:

278 mg l-[4-chloro-5-(3-chloiO-2-methyl-4-triisopropyIsilyloxy-phenyl)thieno[2,3i/Jpyrimidin-6-yl]ethanone (0.55 mmol) was dissolved in 5 mL ’PrOH, 118 mg methyl (2R)-2-hydroxy-3-pheny]-propanoate (Préparation 3ag) (0.65 mmol) and 538 mg CS2CO3 (1.65 mmol) was added and the mixture was stirred at room température until no further conversion was observed. It was diluted with water, the pH of the mixture was set to 4 with

2 M HCl, and extracted with dichloromethane. The combined organic layers were dried over Na2SO₄, concentrated under reduced pressure, and the residue was purified via flash chromatography using heptane and ethyl acetate as eluents.

Step C;

The product of Step B was dissolved in 10 mL THF, 6 mL TBAF (IM in THF) (0.6 mmol) was added and the mixture was stirred at room température until no further conversion was observed. Then it was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over Na2SO₄, concentrated under reduced pressure and purified via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting later was collected to obtain methyl (2/?)-2-[6-acetyL5-(3-chloro-4-hydroxy-2-methylphenyl)thieno[2,3-<Z]pyrimidin-4-yl]oxy-3-phenyl-propanoate. *H NMR (500 MHz, DMSO-de): 10.44 (br s, IH), 8.71 (s, IH), 7.20 (m, 3H), 7.16 (d, IH), 7.03 (d, IH), 6.82 (m, 2H), 5.46 (dd, IH), 4.75 (m, IH), 2.87 (dd, IH), 2.64 (dd, IH), 2.03 (s, 3H), 1.94 (s, 3H), 1.07 (d, 3H), 0.91 (d, 3H). HRMS: (M+H) = 525.1244

Step D:

-338Using General procedure (XVb) and methyl (2Æ)-2-[6-acetyl-5-(3-chloro-4-hydroxy-2methyl-phenyl)thieno[2,3-d]pyrimidin-4“yl]oxy-3-phenyl-piOpanoate as the appropriate phénol Example 522 was obtained. HRMS calculated for C31H33CIN4O5S: 608.186; found 609.194 (M+H)

General Procedure (XVI)

Step A:

2.5 eq. of the appropriate boronic acid was dissolved in dry dioxane (5 mL/mmol Préparation 25), then 2.5 eq pinacol and dry acidic Amberlyst (100 mg/mmol boronic acid) were added and the mixture was stirred at room température ovemight, then it was fîltered (if the appropriate boronic ester was available, then it was dissolved in dioxane (5 mL /mmol Préparation 25) and this solution was used instead of the filtrate). 1 eq. ethyl (27?)-2-[(5.S'_fl)-5-(3~chloro-4-hydroxy-2-methyl-phenyl)-6-iodo-thieno[2,3-i/]pyrimidin-4yl]oxy-3-(2-methoxyphenyl)piopanoate (Préparation 25), 0.1 eq. PdCl₂ * dppf, 2.5 eq. Cs₂CO₃ and water (2.5 mL/mmol) were added to the filtrate and the mixture was heated under nitrogen at 110°C in a microwave reactor until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO4 and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents.

Step B:

eq. of the product of Step A, 2 eq. of 2-(4-methyIpiperazin-l-yl)ethanol and 2 eq. PPh3 were dissolved in dry toluene (0.2 M for the product of Step A), then 2 eq. diter/butyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents.

Step C:

The product of Step B was dissolved in dioxane-water (1:1, 10 mL/mmol) and 10 eq. LiOH x H₂O was added. The mixture was stirred at room température until no further ♦

- 339conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as 5 eluents.

Example 523 (27?)-2-{[(5S'_a)-5-{3-chloro-2-methyl-4-[2-(4-mcthylpiperazin-lyl)ethoxy]phenyl)-6-(3,4,5-trifluorophenyl)thieno[2,3-iZJpyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-(3,4,5-trifluorophenyl)-1,3,2dioxaborolane as the appropriate boronic acid dérivative Example 523 was obtained. HRMS calculated for 726.1891; found 727.1963 (M+H).

Example 524 (27?)-2-{[(55₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(3,4-difluoro-5-methoxyphenyl)thieno[2,3-û(|pyrimidin-4-yl]oxy}-3(2-methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(3,4-difluoro-5-methoxy-phenyl)-4,4,5,520 tetramethyl-l,3,2-dioxaborolane as the appropriate boronic acid dérivative Example 524 was obtained. HRMS calculated for C₃7H37C1F₂N₄O₆S: 738.2090; found 739.2158 (M+H).

Example 525 (2R)-2-{ [(5S_a)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(2,3,4,5-tetrafluorophenyl)thieno[2,3-d]pyriniidin-4-yl]oxy}-3-(225 methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-(2,3,4,5-tetrafluorophenyl)-

1,3,2-dioxaborolane as the appropriate boronic acid dérivative Example 525 was obtained. HRMS calculated for C36H33CIF4N4O5S: 744.1796; found 745.1873 (M+H).

-340Exampie 526 (2/?)-2-{[6-(3-chloiO-5-fluoiOphenyl)-(55_a)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl)thieno[2,3-r/]pyrimidin-4-yl]oxy)-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(3-chloro-5-fluoiO-phenyl)-4,4,5,5-tetramethyl-

1,3,2-dioxaborolane as the appropriate boronic acid dérivative Exampie 526 was obtained. HRMS calculated for C₃₆H35C1₂FN₄O₅S: 724.1689; found 725.1766 (M+H).

Example 527 (2/?)-2-{[(55_fl)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl)-6-(3,5-difluorophenyl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(3,5-difluorophenyl)-4,4,5,5-tetramethyl-l,3,2dioxaborolane as the appropriate boronic acid dérivative Example 527 was obtained. HRMS calculated for C₃6H3₅C1F₂N₄O₅S: 708.1985; found 709.2054 (M+H).

Example 528 (2R)-2- {[(55_a)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 y l)ethoxy]phenyl )-6-(3 -fluoro-5 -methoxyphenyl)thieno [2,3 -riJpyrimidin-4-yl] oxy} -3 -(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(3-fluoro-5-methoxy-phenyl)-4,4,5,5-tetramethyl-

1,3,2-dioxaborolane as the appropriate boronic acid dérivative Example 528 was obtained. HRMS calculated for C₃7H₃8C1FN₄O(îS: 720.2185; found 721,2259 (M+H).

Example 529 (2R)-2- {[(55,,)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyI)-6-(4-methylfuran-2-yl)thieno[2,3-ri]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-(4-methyl-2-furyl)-l,3,2dioxaborolane as the appropriate boronic acid dérivative Example 529 was obtained. HRMS calculated for C₃₅H37C1N₄O₆S: 676.2122; found 677.2239 (M+H).

-341Example 530 (2R)-2- {[(55„)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxyJphenyl}-6-(thieno[3,2-bjthiophen-2-yl)thieno[2,3-i/]pyriinidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Step A:

982 mg thicno[3,2-b]thiophcnc (7.0 mmol) was dissolved in 40 mL dry THF and cooled to -78°C under argon atmosphère. 11.2 mL BuLi (7.0 mmol, 1.6 M in hexanes) was added and the mixture was stirred at -78°C for 1 hour. Then 1.6 mL 2-isopropoxy-4,4,5,5tetramethyl-l,3,2-dioxaborolane (7.7 mmol) was added and the mixture was allowed to warm up to room température, then it was quenched with saturated aq. NH4CI solution, then extracted with THF, dried over Na₂SO4, filtered and concentrated and purified via flash chromatography using heptane and EtOAc as eluents to give 4,4,5,5-tetramethyl-2thieno[3,2-b]thiophen-2-yl-l,3,2-dioxaborolane. MS (El, 70 eV) m/z (% relative intensity, [ion]): 120 (19), 165 (25), 166 (100), 167 (44), 180 (17), 206 (22), 223 (60), 266 (68, [M⁺]).

Step B:

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-thieno[3,2-b]thiophen-2-yl-

1,3,2-dioxaborolane as the appropriate boronic acid dérivative Exampie 530 was obtained. HRMS calculated for C36H35CIN4O5S3: 734.1458; found 735.1553 (M+H).

Exa mple 531 (2R)-2-[(55₀)-(5 - {3 -chloro-2-methyl-4- [2-(4-methy Ipiperazin-1 yl)ethoxy]phenyl}-6-[4-fluoiO-3-(trifluoromethyl)phenyl]thieno[2,3-d]pyrimidin-4yl)oxy]-3-(2-methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-[4-fluoro-3-(trifluoiOmethyl)phenyl]-4,4,5,5tetramethyl-l,3,2-dioxaborolane as the appropriate boronic acid dérivative Example 531 was obtained. HRMS calculated for C37H35CIF4N4O5S: 758.1953; found 759.2031 (M+H).

Example 532 (2R)-2-[[6-(3-chloro-4-fluorophenyl)-(5iS'_tJ)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

-342Using General Procedure (XVI) and 2-(3-chloro-4-fluoro-phenyl)-4,4,5,S-tétraméthylia ,2-dioxaborolane as the appropriate boronic acid dérivative Example 532 was obtained.

HRMS calculated for C36H3SCI2FN4O5S: 724.1689; found 725.1761 (M+H).

Example 533 (27?)-2- {[(55,,)-5- {3-chloiO-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(3,4-difluoiOphenyl)thieno[2,3-c(|pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(3,4-difluorophenyl)-4,4,5,5-tetramethyl-l,3,2dioxaborolane as the appropriate boronic acid dérivative Example 533 was obtained. HRMS calculated for C₃₆H35C1F₂N₄O₅S: 708.1985; found 709.2055 (M+H).

Example 534 (2R)-2-{ [(55,,)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl) -6-(4-fluoro-3-hydroxyphenyI)ihieno[2,3-£/Jpyrimidin-4-yl]oxy} -3 -(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenol as the appropriate boronic acid dérivative Example 534 was obtained. HRMS calculated for C3₆H₃₆C1FN4O(5S: 706.2028; found 707.2087 (M+H).

Example 535 (2À)-2-[(55_a)-5-{3-chloiO-2-methyl-4-[2-(4-niethylpiperazin-l yl)ethoxy]phenyl)-6-[4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl]thieno[2,3-ri]pyrimidin-4yl)oxy]-3-(2-methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-[4-fluoiO-3-(2_}2,2-trifluoroethoxy)phenyll-4,4,5,5tetramethyl-l ,3,2-dioxaborolane as the appropriate boronic acid dérivative Example 535 was obtained. HRMS calculated for C38H37CIF4N4O6S: 788.2058; found 789.2125 (M+H).

Example 536 (27?)-2-{[6-(3-chloro-2,4-difluorophenyl)-(55_n)-5-{3-chioro-2-methyl-4-[2(4-methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2methoxyphenyljpropanoïc acid

4»

-343Using General Procedure (XVI) and 2-(3-chloro-2,4-difluoro-phenyl)-4,4,5,S-tétraméthylia,2-dioxaborolane as the appropriate boronic acid dérivative Example 536 was obtained.

HRMS calculated for C^Cy^OsS: 742.1595; found 743.1645 (M+H).

Exemple 537 (2R)-2-{[(5Sn)-5-{3-chloro-2-methyl-4-[2-(4-rnethylpiperazin-lyl)ethoxy]phenyl} -6-(2,3,4-trifluorophenyl)thieno [2,3-<7]pyrimidin-4-yl]oxy} -3 -(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-(2,3,4-trifluorophenyl)-l,3,2dioxaborolane as the appropriate boronic acid dérivative Example 537 was obtained. HRMS calculated for C^ClFslWjS: 726.1891; found 727.1963 (M+H).

Exa mple 538 (2R)-2- {[(5S_a)- 5- {3 -chloro-2-methyl-4- [2-(4-methy lpiperazin-1 yl)ethoxy]phenyl)-6-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-(p-tolyl)-l,3,2-dioxaboiOlane as the appropriate boronic acid dérivative Example 538 was obtained. HRMS calculated for C37H39CIN4O5S: 686.2330; found 687.2405 (M+H).

Example 539 (2R)-2-{ [(5SJ-5- [3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(4-chlorophenyl)thieno[2,3-tf]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane as the appropriate boronic acid dérivative Example 539 was obtained. HRMS calculated for C₃6H₃6C1₂N4O₅S: 706.1783; found 707.1865 (M+H).

Example 540 (2Æ)-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(2,4-difluorophenyl)thieno[2,3-d]pyrHnidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

-344Using General Procedure (XVI) and 2-(2,4-diiluorophenyi)-4,4,5,5-tetramethyl-1,3,2dioxaborolane as the appropriate boronic acid dérivative Example 540 was obtained.

HRMS calculated for C₃6H₃₅C1F₂N₄O₅S·. 708.1985; found 709.2055 (M+H).

Exampie 541 (2R)-2- {[(55,,)-5- {3 -chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl)-6-(5-methylfuran-2-yl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-(5-methyl-2-furyl)-l,3,2dioxaborolane as the appropriate boronic acid dérivative Example 541 was obtained. HRMS calculated for CjsHjyCIWeS: 676.2122; found 677.2198 (M+H).

Example 542 (2R)-2-[((55_n)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-[5-(dimethoxymethyl)furan-2-yl]thieno[2,3-a^r]pyrimÎdÎn-4-yl)oxy]-3(2-methoxyphenyl)propanoic acid

Using Step A and Step B of General Procedure (XVI) and (5-fonnyl-2-furyl)boronic acid as the appropriate boronic acid dérivative ethyl (2Â)-2-[(55_fl)-5-[3-chIoro-2-methyl-4-[2(4-methyIpiperazin-l-yl)ethoxy]phenyl]-6-(5-formyl-2-furyl)thieno[2,3-i/]pyrimidin-4yl]oxy-3-(2-methoxyphenyl)propanoate was obtained. It was dissolved in mcthanol-water (9:1) conlaining 5 m/m% NaOH (10 eq.) and the mixture was stirred at 50°C until no further conversion was observed. Then the mixture was diluted with water and the pH was adjusted to 6 by the addition of 2 M HCl solution. The mixture was extracted with DCM, the combined organic phases dried over Na₂SO₄₎and concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 542. HRMS calculated for C₃₇H4iClN₄O₈S: 736.2334; found 737.2416 (M+H).

Exampie 543 (2R)-2-{ [(55J-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-l y l)ethoxy ] phenyl} -6- (5 -ethyl furan-2-yl) thieno [2,3 -rf]py rimidin-4-yl ]oxy} -3 -(2methoxyphenyl)propanoic acid

- 345 Using General Procedure (XVI) and 2-(5-ethyl-2-furyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane as the appropriate boronic acid dérivative Example 543 was obtained. HRMS calculated for C₃₆H₃₉C1N4O₆S: 690.2279; found 691.2343 (M+H).

Example 544 (27?)-2-{[(53_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}“6-(5-methoxyfiiran-2-yl)thieno[2,3-t7]pyriinidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(5-methoxy-2-furyl)-4,4,5,5-tetramethyi-l,3,2dioxaborolane as the appropriate boronic acid dérivative Example 544 was obtained. HRMS calculated for C₃₅H₃₇C1N4O₇S: 692.2071; found 693.2122 (M+H).

Example 545 (2Æ)-2- {[(55),)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 15 y 1 )ethoxy]phenyl) -6-(3 -nitrophenyl)thieno[2,3 ~d] pyri midin-4-yl] oxy ) -3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-(3-nitrophenyl)-1,3,2dioxaborolane as the appropriate boronic acid dérivative Example 545 was obtained.

HRMS calculated for C₃₆H₃₆C1N₅O₇S: 717.2024; found 718.2101 (M+H).

Example 546 (27?)-2-{[(55_e)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-ly l)ethoxy]phenyl )-6-(3 -methylphenyl)thieno[2,3 -rf]pyrimidin-4-yl] oxy} -3 -(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-(/M-tolyl)-l,3,2-dioxaboiOlane as the appropriate boronic acid dérivative Example 546 was obtained. HRMS calculated for C₃₇H3₉C1N4O₅S: 686.2330; found 687.2401 (M+H).

Example 547 (2/?)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-ly])ethoxy]phenyl)-6-(3-ethynylphenyl)thieno[2,3-ii|pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

- 346Using General Procedure (XVI) and tiimethyl-[2-[3-(4,4,5₁5-tetramethyl-l,3,2dioxaborolan-2-yl)phenyl]ethynyl]silane as the appropriate boronic acid dérivative Example 547 was obtained. HRMS calculated for C38H37CIN4O5S: 696.2173; found 697.2234 (M+H).

Example 548 (2/?)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(3-cyanophenyl)thieno[2,3-û(Jpyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 3-(4,4,5,5-tetramethyl-l,3,2-dioxaboiOlan-2yl)benzonitrile as the appropriate boronic acid dérivative Example 548 was obtained. HRMS calculated for C3₇H3₆ClN₅O₅S: 697.2126; found 698.2188 (M+H).

Example 549 (2Â)-2-[((55a)-5-{3-chloro-2-methyl-4-[2-(4-rnethylpiperazin-lyl)ethoxy]pheny]}-6-[3-(trifluoiOmethyl)phenyl]thieno[2,3-i(Jpyiimidin-4-yl)oxy]-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-[3-(tiifluoromethyl)phenyl]-

1,3,2-dioxaborolane as the appropriate boronic acid dérivative Example 549 was obtained. HRMS calculated for C₃₇H3₆C1F₃N4O₅S: 740.2047; found 741.2125 (Ml II).

Example 550 (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(3-chlorophenyl)thieno[2,3-<7Ipyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(3-chloiOphenyl)-4,4,5,5-tetrainethyl-l,3,2dioxaborolane as the appropriate boronic acid dérivative Example 550 was obtained. HRMS calculated for C36H36CI2N4O5S: 706.1783; found 707.1860 (M+H).

-347Example 551 (27?)-2 - {[(55J-5- {3-chloiO-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyI}-6-(3-fluoiOphenyl)thieno[2,3-iZ}pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(3-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2dioxaborolane as the appropriate boronic acid dérivative Exampie 551 was obtained. HRMS calculated for C₃₆H₃₆C1FN₄O₅S: 690.2079; found 691.2152 (M+H).

Example 552 (2/?)-2-[((55_n)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-[3-(dÎmethylamino)phenyl]thieno[2,3-<7]pyrimidin-4-yI)oxy]-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and N,?/-diniethyl-3-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)aniline as the appropriate boronic acid dérivative Exampie 552 was obtained. HRMS calculated for C38H42CIN5O5S: 715.2595; found 716.2681 (M+H).

Example 553 (2Æ)-2~([(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(3-hydroxyphenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 3-(4,4,5,5-(etramelhyl-l,3,2-dioxabofolan-2-yl)phenol as the appropriate boronic acid dérivative Example 553 was obtained. HRMS calculated for C₃₆H37C1N₄O₆S: 688.2122; found 689.2204 (M+H).

Example 554 (2R)-2-{[(5SJ-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl)-6-(3-methoxyphenyl)thieno[2,3-(/|pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane as the appropriate boronic acid dérivative Example 554 was obtained.

HRMS calculated for C₃₇H₃<>C1N₄O₆S: 702.2279; found 703.2358 (M+H).

348 Example 555 (2./2)-2-(((55^)-5- (3-chloro-2-niethyl-4-[2-(4-mcthylpipcrazin-1 yl)elhoxy]phenyl}-6-(3-(lrinuoroinethoxy)phenyl]tliieno[2,3-c/]pyriinidin-4-yl)oxy]-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramethyi-2-[3-(trif]uoiOmethoxy)phenyl]-

1,3,2-dioxaborolane as the appropriate boronic acid dérivative Example 555 was obtained. HRMS calculated for C₃7H_3ÉC1F₃N4O₀S: 756.1996; found 757.2067 (M+H).

Example 556 (27?)-2-(((55_i,)-5-(3-chloiO-2-methyl-4-(2-(4-methylpipeiazin-lyl)ethoxy]phenyl}-6-[3-(4-fluoiOphenoxy)phenyl]thieno[2,3-iîQpyrimidin-4-yl)oxy]-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(3-(4-fluorophenoxy)phenyI]-4,4,5,S-tétraméthylia,2-dioxaborolane as the appropriate boronic acid dérivative Example 556 was obtained. HRMS calculated for C42H40CIFN4O6S.· 782.2341; found 783.2412 (M+H).

Example 557 (272)-2-{[(55_fl)-5-{3-chloro-2-methyl-4-[2-(4-melhylpiperazin-l yl)ethoxy]phenyl} -6-(3-ethoxyphenyl)thieno[2,3-i/]pyrimidin-4-y 1] oxy} -3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(3-ethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane as the appropriate boronic acid dérivative Example 557 was obtained. HRMS calculated for Css^iCINîOôS: 716.2435; found 717.2505 (M+H).

Example 558 (2/2)-2-[((55_a)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-[3-(methylsulfanyl)phenyl}thieno[2,3-iZ|pyrimidin-4-yl)oxy]-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-(3-methylsulfanylphenyl)-l,3,2dioxaborolane as the appropriate boronic acid dérivative Example 558 was obtained.

HRMS calculated for ¢3^39^0582: 718.2050; found 719.2113 (M+H).

♦

- 349 Example 559 (212)-2- ([6-(3-chloro-2-fluorophenyl)-(55_e)-5-(3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3-cZ]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(3-chloro-2-fluoro-phenyl)-4,4,5,S-tétraméthylia, 2-dioxaborolane as the appropriate boronic acid dérivative Example 559 was obtained. HRMS calculated for C₃₆H₃5Cl₂FN₄O_sS: 724.1689; found 725.1765 (M+H).

Example 560 (212)-2-( [(55_a)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-l 10 yl)ethoxy]phenyl}-6-(2,3-difluorophenyl)thïeno[2,3-i7jpyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(2,3-difluorophenyl)-4,4,5,5-tetramethyl-l,3,2dioxaborolane as the appropriate boronic acid dérivative Example 560 was obtained.

HRMS calculated for C36H35CIF2N4O5S: 708.1985; found 709.2052 (M+H).

Example 561 (27?)-2-{[(55_n)-5-(3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)cthoxy]phcny 1} -6-(2-fl uoro-3 -methoxyphenyl)thieno [2,3 -i(|pyrimidin-4-yl]oxy} -3 -(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(2-fluoro-3-methoxy-phenyl)-4,4,5,5-tetramethyI-

1,3,2-dioxaborolane as the appropriate boronic acid dérivative Example 561 was obtained. HRMS calculated for C37H38CIFN4O6S: 720.2185; found 721.2281 (M+H).

Example 562 (272)-2-[((55_<,)-5-{3-chloro-2-rnethyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-[2-fluoro-3-(trifluoromethoxy)phenyl]thieno[2,3-d]pyrimidin-4yl)oxy] -3-(2-methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-[2-fluoiO-3-(trifluoromethoxy)phenyl]-4,4,5,530 tetramethyl-1,3,2-dioxaborolane as the appropriate boronic acid dérivative Example 562 was obtained. HRMS calculated for C37H35CIF4N4O6S: 774.1902; found 775.1974 (M+H).

-350Example 563 (27?)-2-{[6-(l-benzofui^-an-4-yl)-(5S),)-5-{3-chIoro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3-7]pyi'imidin-4-y]]oxy}-3-(2methoxyphenyl)piOpanoic acid

Using General Procedure (XVI) and 2-(benzofuran-4-yl)-4,4,5,5-tetramethyl-l,3,2dioxaborolane as the appropriate boronic acid dérivative Example 563 was obtained. HRMS calculated for C₃₈H37ClN₄O₆S: 712.2122; found 713.2193 (M+H).

Example 564 (2Jf)-2-[((55^, _n)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-phenylthieno[2,3-d]pynmidin-4-yl)oxy]-3-(2methoxyphenyl)piopanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetiamethyl-2-phenyl-l,3,2-dioxaborolane as the appropriate boronic acid dérivative Example 564 was obtained. HRMS calculated for C36H37CIN4O5S: 672.2173; found 673.2258 (M+H).

Example 565 (2/?)-2-{[(5S_e)-5-{3 -chloiO-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(2-chlorophenyl)thieno[2,3-i/]pyrirnidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(2-chlorophenyl)-4,4,5,5-tetramethyl-l,3,2dioxaborolane as the appropriate boronic acid dérivative Example 565 was obtained. HRMS calculated for C_3ÉH₃₆C1₂N₄O₅S: 706.1783; found 707.1860 (M+H).

Example 566 (21î)-2-{[(5₁S)₇)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(2-fluorophenyl)thieno[2,3-idpyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(2-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2dioxaborolane as the appropriate boronic acid dérivative Example 566 was obtained.

HRMS calculated for C₃6H₃₆C1FN₄O₅S: 690.2079; found 691.2169 (M+H).

♦

-351 Exampie 567 (2R)-2- {[(5S_u)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(pyridin-3-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)pyridine as the appropriate boronic acid dérivative Example 567 was obtained. HRMS calculated for CjsH^CINsOsS: 673.2126; found 674.2205 (M+H).

Example 568 (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l10 yl)ethoxy]phenyl}-6-(thiophen-3-yl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-(3-thienyl)-l,3,2-dioxaborolane as the appropriate boronic acid dérivative Exampie 568 was obtained. HRMS calculated 15 for CgÆsCINRDsSa: 678.1737; found 679.1808 (M+H).

Exampie 569 (2/?)-2-{[(5>S'_a)-5-{3-chloro-2-mcthyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(l,3-oxazol-5-yl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3oxazole as the appropriate boronic acid dérivative Example 569 was obtained. HRMS calculated for C₃₃H₃4C1N₅O₆S: 663.1918; found 664.1997 (M+H).

Example 570 (2Æ)-2-{[(5i%)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(5-chlorothiophen-3-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(5-chloro-3-thienyl)-4,4,5,5-tetramethyl-1,3,230 dioxaborolane as the appropriate boronic acid dérivative Example 570 was obtained.

HRMS calculated for C₃4H₃4C1₂N₄O₅S₂: 712.1348; found 713.1423 (M+H).

-352Exaniple 571 (27/)-2-( [(55,)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(thieno[3,2-b]thiophen-3-yl)thieno[2,3-<7]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Step A:

782 mg 3-bromothieno[3,2-b]thiophene (3.6 mmol), 3.626 g 4,4,5,5-tetramethyl-2(4,4,5,5-tetiamethyi-l,3,2-dioxaboiOlan-2-yl)-l,3,2-dioxaboiOlane (14 mmol), 0.783 g PdChxdppf (1.07 mmol) and 2.102 g KOAc (21.4 mmol) were dissolved in 4 mL dioxane. The mixture was heated to 60°C and stirred under argon atmosphère until no further conversion was observed. The reaction mixture was cooled to room température and filtered through a pad of celite. The filtrate was concentrated and purified via flash chromatography using heptane and EtOAc as eluents to give 4,4,5,5-tetramethyl-2thieno[3,2-b]thiophen-3-yl-l,3,2-dioxaborolane. ^lH NMR (500 MHz, DMSO-cL): 8.11 (d, 1H), 7.67 (dd, 1H), 7.45 (d, 1H), 1.32 (s, 12H). HRMS calculated for Ci₂H₁₃BO₂S₂: 266.0607, found: 267.0682 (M+H).

Step B:

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-thieno|3,2-b]thiophen-3-yl-

1,3,2-dioxaborolane as the appropriate boronic acid dérivative Example 571 was obtained. HRMS calculated for 734.1458; found 735.1531 (M+H).

Example 572 (27?)-2-{[(5S’_a)-5-{3-chloro-2-mcthyl-4-[2“(4-mcthylpipcrazin-lyl)ethoxy]phenyl}-6-(prop-l-yn-l-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using Step B and C of General Procedure (XVI) and ethyl (2//)-2-[(55,)-5-(3-chloro-4hydroxy-2-methyl-pheny l)-6-prop-1 -ynyl-th ieno [2,3 -JJpyrimidin-4-yl] oxy- 3 -(2methoxyphenyl)propanoate (Préparation 61) as the phénol dérivative, Example 572 was obtained. HRMS calculated for C33H35CIN4O5S: 634.2017; found 635.2082 (M+H).

- 353 Example 573 (2Æ)-2-([6-(but-l-yn-l-yl)-(5S_o)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3+dpyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Step A:

625 mg ethyl (27()-2-[(5S'_a)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-iodo-thieno(2,3<Z]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)piOpanoate (Préparation 25) (1.0 mmol), 35 mg Pd(PPh3)₂C12 (0.05 mmol) and 19 mg Cul (0.1 mmol) were dissolved in 4 mL DIPA, then but-l-yne was bubbled through the reaction mixture, which was stirred at 50°C until no further conversion was observed. Then the volatiles were evaporated under reduced pressure and the crude intermediate was purified by flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2Æ)-2-[6-but-l-ynyI-(5S_a)-5-(3-chloro-4-hydroxy-2methyl-phenyl)thieno[2,3-i7]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate.

Step B:

Using Step B and C of General Procedure (XVI) and ethyl (27()-2-[6-but-l-ynyl-(5S_a)-5(3 -chloro-4-hydroxy-2-methyl-phenyI)thieno [2,3 -ί/Jpy rim i di n-4-y I] oxy-3 -(2methoxyphenyl)propanoate as the phénol dérivative, Example 573 was obtained. HRMS calculated for CwHayClhUOsS: 648.2173; found 649.2251 (M+H).

Example 574 (2/()-2- {[(57(_u)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(dimethylcarbamoyl)thieno[2,3-£(|pyrimidin-4~yI]oxy}-3-(2methoxyphenyl)propanoic acid and

Example 575 (2/()-2-{[(5S„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(dimethylcarbarnoyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Step A:

2.195 g 4-chloiO-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl] thieno-[2,3-</]pyrimidme (Préparation 12) (5.02 mmol) was dissolved in 50 mL dry THF and then it was cooled to -78°C under argon atmosphère. 5.2 mL lithium diisopropylamide

-354(10.4 mmol, 2 M in THF, EtPh, hexanes) was added and the mixture was stirred at -78^DC for l hour. Then 5.00 g dry-ice was added and the mixture was allowed to warm up to room température and it was stirred until no further conversion was observed. The mixture was quenched with saturated aq. NH4CI and extracted with DCM. The combined organic phases were dried over Na₂SO4 and concentrated under reduced pressure. The residue was purified via flash chiOmatography using DCM and MeOH as eluents to obtain 4-chloro-5[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]thieno[2,3-iZ]pyrimidine~ 6-carboxylîc acid.

Step B:

1.444 g 4-chloiO-5-[3-chloiO-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl] thieno[2,3-d]pyrimidine-6-carboxylic acid (3.0 mmol), 444 mg ethyl (2R)-2-hydroxy-3-(2methoxyphenyl)propanoate (Préparation 3ad) (2.0 mmol) and 987 mg césium carbonate (9.0 mmol) were stirred in 30 mL dry /er/butanol at 70°C until no further conversion was observed. The reaction mixture was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO4 and concentrated under reduced pressure. The crude intermediate was purified via flash chiOmatography using DCM and MeOH as eluents to obtain 5-[3-chloro-2-methyl-4-[2-(4methylpiperazin-l'yl)ethoxy]phenyl]-4-[(22?)-2-ethoxy-l-[(2-methoxyphenyl)methyl]-2oxo-ethoxy]thieno[2,3-iflpyiimidine-6-carboxyHc acid.

Step C:

669 mg 5-[3-chloro-2-methyl-4-[2-(4-niethylpiperazin- l-yl)ethoxy]phenyl]-4-[(7Æ)-2ethoxy-l“[(2-methoxyphenyl)methyl]-2-oxo-ethoxy]thieno[2,3-i/]pyrimidine-6-carboxylic acid (1.0 mmol), 1 mL dimethylamine (2 mmol, 2 M in THF) and DIPA were dissolved in 5 mL dry DCM, then 520 mg PyBOP (1.0 mmol) was added and the mixture was stirred at room température until no further conversion was observed. The volatiles were removed under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2Æ)-2-[5-[3-chloiO-2-methyl-4-[2-(4methylpiperazin-1 -yl)ethoxy]phenyl]-6-(dimethylcarbamoyl)thieno[2,3 -</]pyrimidin-4yl] oxy-3 -(2-methoxyphenyl)propanoate.

-355 Step D:

Ethyl (25)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6(dimethylcarbamoyl)thieno[2,3-iZJpyrimidin-4-yl]oxy-3-(2-methoxyphenyl)piOpanoate was hydrolyzed according to Step C of General Procedure (XVI). The diastereoisomer eiuting earlier was collected as Exampie 574. HRMS calculated for C33H38CIN5O6S: 667.2231; found 668.2287 (M+H). The diastereoisomer eiuting later was collected as Example 575. HRMS calculated for C33H₃₈C1N₅O₆S: 667.2231 ; found 668.2280 (M+H).

Example 576 (25)-2- {[(55,,)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 10 yl)ethoxy]phenyl}-6-(l,l-difluoiOethyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Step A:

4.22 g 4-chloiO-5,6-diiodo-thieno[2_J3-iZJpyrimidine (Préparation lb) (10.0 mmol) was 15 dissolved in 160 mL dry THF, then cooled to -78°C under argon atmosphère. 5 mL ethylmagnesium chloride (2 M in THF) (10.0 mmol) was added and the mixture was stirred at -78°C for 10 minutes. Then 1,321 g acetaldehyde (30.0 mmol) was added and the mixture was allowed to warm up to room température. Saturated aq. NH4CI was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over 20 Na₂SO4 and concentrated under reduced pressure. The crude product was purified via flash chromatography using DCM and MeOH as eluents to obtain l-(4-chloro-5-iodothieno[2,3-d]pyrimidin-6-yl)ethanol. *H NMR (400 MHz, DMSO-dô): 8.89 (s, IH), 6.38 (d, IH), 5.15 (m, IH), 1.44 (d, 3H).

Step B:

2.1 g l-(4-chloro-5-iodo-thieno[2,3-i(]pyrimidin-6-yl)ethanol (6.17 mmol) was dissolved in

100 mL dichloromethane, then cooled to 0°C under argon atmosphère. Then 2.75 g DessMartin periodinane (6.47 mmol) was added and strirred until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate 30 was purified via flash chromatography using DCM as eluent to obtain l-(4-chloro-5-iodothieno[2,3-i/jpyrimidin-6-yl)ethanone. ’H NMR (400 MHz, DMSO-dé): 9.04 (s, IH), 2.80 (s, 3H).

-356Step C:

1.02 g l-(4-chloiO-5-iodo-thieno[2,3-c/]pyrimidin-6-yl)ethanone (3.01 mmol) was dîssolved in 25 mL dichloromethane, then 3.22 g DAST (20.0 mmol) was added. The mixture was stirred at 50°C under argon atmosphère until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using dichloromethane as eluent to obtain 4-chloro6-(l,l-difluoiOethyl)-5-iodo-thieno[2,3-J]pyrimidine. 'H NMR (400 MHz, DMSO-dô): 9.02 (s, IH), 2.22 (t, 3H).

Step D:

880 mg 4-chloro-6-(l,l-difluoroethyl)-5-iodo-thieno[2,3-i/]pyrimidine (2.44 mmol), 821 mg ethyl (2Æ)-2-hydroxy-3-(2-methoxyphenyl)propanoate (Préparation 3ad) (3.66 mmol) and 1.59 g CS2CO3 (4.88 mmol) were stirred at 50°C in 2.5 mL DMSO until no further conversion was observed. The reaction mixture was diluted with brine, then it was extracted with EtOAc. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain ethyl (27?)-2-[6-(l,l-difluoroethyl)-5-iodothieno[2,3-i/]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate. ’H NMR (400 MHz, DMSO-d₆): 8.70 (s, IH), 7.44 (dd, IH), 7.25 (td, IH), 6.98 (d, IH), 6.88 (t, IH), 5.69 (dd, IH), 4.10 (q, 2H), 3.80 (s, 3H), 3.41 (dd, IH), 3.26 (dd, IH), 2.20 (t, 3H), 1.09 (t, 3H).

Step E:

920 mg ethyl (2/?)-2-[6-(l,l-difluoroethyl)-5-iodo-thieno[2,3-cf|pyrimidin-4-yl]oxy-3-(2methoxyphenyl)propanoate (1.68 mmol) and 676 mg 2-chloro-3-methyl-4-(4,4,5,5teÎramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (2.52 mmol) were dîssolved in 7 mL 2-Me-THF, then 2.52 mL tetrabutylammonium hydroxide (2.52 mmol, 1 M in water) and 119 mg AtaPhos (0.168 mmol) were added and the mixture was heated under nitrogen at 110°C in a micro wave reactor until no further conversion was observed. Then it was diluted with brine and extracted with dichloromethane. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure, and the crude intermediate was purified via flash chromatography using heptane and EtOAc as eluents to

-357obtain ethyl (2R)-2-[5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(l, l ~ difluoroetliyl)tlüeno[2,3-i7]pyriniidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate as a mixture of diastereoisomers, *H NMR (400 MHz, DMSO-dfi): 10,34 (br s, IH), 8.68 (s, IH), 7.20 (td, IH), 7.04 (d, IH), 6.96 (d, IH), 6.93 (d, IH), 6.81 (t, IH), 6.55 (dd, IH), 5.42 (dd, IH), 3.98 (m, 2H), 3.76 (s, 3H), 2.87 (dd, IH), 2.46 (dd, IH), 1.93 (s, 3H), 1.72 (t, 3H), 1.00 (t, 3H).

Step F:

100 mg ethyl (2Æ)-2-[5-(3-chloro-4-hydtOxy-2-methyl-phenyl)-6-(l,ldifluoroethyl)thieno[2,3-tZ]pyrimidin-4-yI]oxy-3-(2“methoxyphenyl)propanoate (0.178 mmol), 51 mg 2-(4-methylpiperazin-l-yl)ethanol (0.355 mmol) and 534 mg triphenyl phosphine (0.534 mmol) were dissolved in 4 mL dry toluene, then 123 mg ditertbutyl azodicarboxylate (0.534 mmol) was added. The mixture was stirred at 45°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and methanol as eluents to obtain ethyl (2R)-2-[5-[3-chloro-2-mcthyl-4-[2-(4methylpiperazin-1 -yl)elhoxy]pheny l]-6-( 1,1 -difluoroethyl)thieno[2,3 -c7]pyrimidin~4yl]oxy-3-(2-methoxyphenyl)propanoate.

Step G:

The intermediate obtained in Step F was dissolved in 3 mL methanol and 100 mg LiOH x H?.O (2.38 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO4 and concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. The diastereoisomer eluting later was collected as Example 576. HRMS calculated for C^HasClFz^OsS: 660.1985; found 661.2059 (M+H).

Example 577 (2R)-2-{[6-(5-biOmofuran-2-yl)-(55'₀)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3-i7]pyriinidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

-358 1.326 g (2/?)-2-{[(5_lS^, _fi)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l“ yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2.,3-i/]pyrimidin-4-yl]oxy}-3-(2-methoxyphenyl) propanoic acid (Example 209) (2 mmol) was dissolved in 20 mL chloroform, then 534 mg NBS (3 mmol) was added. The resulting mixture was stirred at 0°C untii no further conversion was observed. Tlien the mixture was diluted with water and the pH was adjusted to 6 by the addition of 2 M HCl solution. The mixture was extracted with DCM, the combined organic phases were dried over Na₂SÛ4 and concentrated under reduced pressure. The crude product was purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 577. HRMS calculated for C₃4H₃₄BrClN4O₆S: 740.1071; found 741.1165 (M+H).

Example 578 (2Â)-2-{[(5.?_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(5-ethynylfuran-2-yl)thieno[2,3-iZ|pyrimidin-4-yI]oxy}-3-(2methoxyphenyl)propanoic acid mg (2/?)-2-{[6-(5-bromofuran-2-yl)-(55'_fl)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl)thieno[2,3-if]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid (Example 577) (0.07 mmol), 96 mg butyl-dimethyl-[2(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)ethynyl]silane (0.36 mmol), 120 mg Cs₂CO₃(0.36 mmol) and 6 mg PdCl₂ ^x dppf (0.008 mmol) were dissolved in a mixture of 0.80 mL dioxane and 0.20 mL water. The reaction mixture was stirred at 70°C untii no further conversion was observed. The reaction was quenched at room température with water and the mixture was extracted with DCM. The combined organic phases were dried over Na₂SÛ4 and concentrated under reduced pressure. The residue was dissolved in 0.50 mL TI-IF, then 50 pL TBAF (1 M in THF) was added and the reaction mixture was stirred at room température untii no further conversion was observed. Then the mixture was concentrated under reduced pressure and purified via reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 578. HRMS calculated for C₃₆H₃5C1N₄O₆S: 686.1966; found 687.2039 (M+H).

e

-359Example 579 (2A)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-mcthylpipcrazin-lyl)ethoxy]phenyl}-6-(5-cyanofuran-2-yl)lhieno[2,3-ri]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

StepAx

250 mg ethyl (2Æ)-2-[(5S_a)-5-(3-chloro-4-hydiOxy-2-methyl-phenyl)-6-iodo-thieno[2,3i/]pyrimidin-4-yl]oxy-3-(2-methoxyphenyI)propanoate (Préparation 25) (0.40 mmol), 315 mg PPI13 (1.20 mmol), 276 mg di/e/Vbutyl azodicarboxylate (1.20 mmol) and 173 mg 2-(4methylpiperazin-l-yl)ethanol (1.20 mmol) were dissolved in 10 ml dry toluene and the reaction mixture was stirred at 50°C under nitrogen until no further conversion was observed. The mixture was concentrated under reduced pressure and the crude product was purified via flash chromatography using DCM and MeOH as eluents. The obtained product was hydrolyzed in 3 mL methanol-water (9:1) containing NaOH (5m/m%) at room température. The mixture was diluted with water, thê pH was adjusted to 6 by the addition of 2 M HCl solution, and it was extracted with DCM. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified using reverse phase préparative HPLC resulting (2Â)-2-[(55n)-5-[3-chloro-2methyl-4-[2-(4-meÎhylpiperazin-l-yI)ethoxy]phenyl]-6-iodo-thieno[2,3-i(]pyrimidin-4yl]oxy-3-(2-methoxyphenyl)propanoicacid.

Step B:

mg (2Æ)-2-[(5S_a)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl]-6iodo-thieno[2,3-i/jpyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoic acid (0.10 mmol), 66 mg 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)furan-2-carbonitrile (0.30 mmol), 18 mg AtaPhos (0.025 mmol) and 98 mg CS2CO3 (0.30 mmol) were dissolved in a mixture of 0.75 mL THF and 0.25 mL water and heated under nitrogen at 100 °C for 10 minutes in a microwave reactor. The crude reaction mixture was diluted with water and the pH was adjusted to 6 by the addition of 2N HCl solution. The mixture was extracted with DCM, the combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 579. HRMS calculated for C35H34CIN5O6S: 687.1918; found 688.2001 (M+H),

360Exampie 580 (2Λ)-2-[((55_Λ)-5- {3-chloro-2-methyI-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-[5-(methoxycarbonoimidoyl)furan-2-yl]thieno[2,3-ii]pyrimidin-4yl)oxy] -3 -(2-methoxyphenyl)propanoic acid

222 mg (2R)-2-{ [(55_</)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}“6“(5“Cyanofuran-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-rnethoxy phenylpropanoic acid (Example 579) (0.032 mmol) was hydrolyzed in 3 mL methanolwater (9:l) containing NaOH (5m/m%) at room température. After évaporation of the volatiles under reduced pressure the multicomponent mixture was purified using reversed phase chromatography with 25 mM aqueous NH4HCO3 solution and MeCN as eluents to give Example 580 as one of the products. HRMS calculated for C36H38CIN5O7S: 719.2180; found 360.6152 (M+2H).

Example 581 (2Æ)-2-{[6-(5-carbamoylfuran-2-yI)-(55₀)-5-{3-chloro-2-methyl-4-[2-(4methy lpiperazin-1 -yl)ethoxy]phenyl} thieno[2,3-d]pyiimidin-4-yl]oxy } -3-(2methoxyphenyl)propanoic acid

Hydrolysis of (2/?)-2- {[(55),)-5- [3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(5-cyanofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid (Example 579) was performed as described in Example 580. Exampie 581 was obtained as one of the products of the multicomponent mixture following séparation by reversed phase chromatography with 25 mM aqueous NH4HCO3 solution and MeCN as eluents. HRMS calculated for C35H36CIN5O7S: 705.2024; found 706.2105 (M+H)

Example 582 (2/?)-2-[((55'_B)-5-{3-chloiO-2-methyl-4[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-[5-(dimethylcarbamoyl)furan-2-yl]thieno[2,3-i(]pyrimidin-4-yl)oxy]3 -(2-methoxypheny l)propanoic acid

Step A:

-361 984 mg 4-chloro-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]thieno[2,3-ri]pyrimidine (Préparation 12) (2.25 mmol) was dissolved in 20 mL dry THF under N₂ and cooled to -78°C. 2.25 mL LDA (2 M in THF, 4.5 mmol) was added at -78°C and the reaction mixture was stirred for 1 h at this température, then 9 mL chloro(trimethyl)stannane (1 M in THF, 9 mmol) was added and stirred for 20 min at 78°C, then the reaction mixture was allowed to warm up to room température. Saturated aq. NH₄C1 was added and the mixture was extracted with diethyl ether. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was dissolved in 60 mL EtOAc and following the addition of 40 mL saturated aq. NaF solution it was stirred ovemight and filtered. The aqueous phase was extracted with EtOAc and the combined organic phases were dried over Na₂SO4, and evaporated under reduced pressure. The crude product was purified via flash chromatography using DCM and MeOH as eluents to obtain [4-chloro-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]thieno[2,3-if]pyrimidin-6-yl]-trimethyl-stannane. ’H NMR (500 MHz, DMSO-de): 8.90 (s, IH), 7.13 (d, IH), 7.11 (d, IH), 4.22 (m, 2H), 2.77 (t, 2H), 2.57 (br s, 4H), 2.41 (br s, 4H), 2.21 (br s, 3H), 1.97 (s, 3H), 0.14 (s, 9H). HRMS calculated for C₂₃H₃₀Cl₂N₄OSSn: 600.0539; found 601.0584 (M+H).

Step B:

1.91g 5-bromofùran-2-carboxylic acid (10 mmol), 10 mL dimethylamine (2 M in THF, 20 mmol), 5.42 g PyBOP (10.4 mmol) and 3.5 mL DIPA (20 mmol) were dissolved in 20 mL dry DCM and stirred at room température under N₂ until no further conversion was observed. The DCM was evaporated under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 5-bromo-MAdimethyl-furan-2-carboxamide. MS: (M+H)⁺ = 218.2.

Step C:

400 mg [4-chloro-5-[3 -chloiO-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl]thieno[2,3-JJpyrimidin-6-yI]-tiïmethyl-stannane (product of Step A) (0.6 mmol), 291 mg 5-biOmo-7/₁À^r-dimethyl-furan-2-carboxamide (product of Step B) (1.3 mmol), 12 mg Pd(PhCN)₂Cl₂ (0.03 mmol), 13 mg Cul (0.06 mmol) and 20 mg Ph₃As (0.06 mmol) were dissolved in 1 mL NMP and stirred at 100°C under N₂ until no further

-362 conversion was observed. The mixture was diluted with EtOAc and washed with saturated aq. NaF solution. The aqueous phase was extracted with EtOAc and the combined organic phases were dried over Na2SÜ4 and evaporated under reduced pressure. The crude product was purified via flash chromatography using DCM and MeOH as eluents to obtain 5-[4chloro-5-[3-chloro-2-methyI-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]thieno[2,3rf]pyrimidin-6-yl]-.MA^r-dimethyl-furan-2-carboxamide. ’H NMR (500 MHz, DMSO-cU): 8.97 (s, IH), 7.26 (d, IH), 7.20 (d, IH), 7.04 (d, IH), 5.80 (d, IH), 4.24 (t, 2H), 3.13 (br s, 3H), 2.97 (br s, 3H), 2.79 (t, 2H), 2.57 (br s, 4H), 2.35 (br s, 4H), 2.17 (s, 3H), 2.06 (s, 3H). HRMS calculated for C27H29CI2N5O3S: 573.1368; found 574.1463 (M+H).

Step D:

0.255 g 5-[4-chloro-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl]thieno[2,3-<7]pyrimidin-6-yl]-JV;V-dimethyl-furan-2-carboxamide (0.4 mmol), 0.134 g ethyl (2Æ)-2-hydroxy-3-(2-methoxyphenyl)propanoate (Préparation 3ad) (0.6 mmol) and 0.391 g CS2CO3 (1.2 mmol) were placed in a 100 mL flask. 35 mL propan2-ol was added and the mixture was stirred at 50°C under N2 until no further conversion was observed. 1 mL water and 0.336 g LiOHx^O (8 mmol) were added and the mixture was stirred at 50°C until no further conversion was observed. The reaction was diluted with water; the pH was adjusted between 4-5 using 2 M HCl and extracted with DCM. The combined organic phases were dried over Na2SO₄ and evaporated under reduced pressure. The diastereomers were separated via préparative reversed phase chromatography using 20 mM aqueous NH4HCO3 solution and MeCN as eluents; the diastereomer eluting later was collected as Example 582. HRMS calculated for C37H40CIN5O7S: 733.2337; found 734.2450 (M+H).

Example 583 (2/?)-2-[((5S_a)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-[5-(methoxycarbonyl)furan-2-yl]thieno[2,3-d]pyrimidin-4-yl)oxy]-3(2-methoxyphenyl)propanoic acid

Hydrolysis of (2R)-2~ {[(5S„)-5- {3-chloiO-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl} -6-(5-cyanofuian-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy} -3-(2methoxyphenyl)propanoic acid (Example 579) was performed as described in Example

-363580. Example 583 was obtained as one of the products of the multicomponent mixture following séparation by reversed phase chromatography with 25 mM aqueous NH4HCO3 solution and MeCN as eluents. HRMS calculated for C36H37CIN4O8S: 720.2021; found 721.2104 (M+H).

Example 584 (2/2)-2- {[(55₍,)-5- {3 -chloro-2-methyl-4- [2-(4-methylpiperazin-1 yI)ethoxy]phenyl}-6-(5-ethenylfiiran-2-yl)thieno[2,3-i7Jpyrimidin-4-yl]oxy} -3-(2methoxyphenyl)propanoic acid

27 mg (2/2)-2-{[6-(5-bromofuran-2-yl)-(55_e)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid (Example 577) (0.036 mmol), 28 mg 4,4,5,5-tetramethyl2-vinyl-l,3,2-dioxaborolane (0.18 mmol), 23 mg CS2CO3 (0.072 mmol) and 3 mg AtaPhos (0,004 mmol) were dissolved in a mixture of 0.40 mL dioxane and 0.10 mL water. The reaction mixture was stirred at 70 °C until no further conversion was observed. The reaction mixture was quenched at room température with water and the pH was set to 5 using 2 M HCl solution. The mixture was extracted with DCM, and the combined organic phases were dried over Na2SO₄ and concentrated under reduced pressure. The crude product was purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 20 solution and MeCN as eluents to obtain Example 584. HRMS calculated for

C36H37CIN4O6S: 688.2122; found 689.2178 (M+H).

Example 585 (2Æ)-2-{[(5S_(I)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(5-cyclopropylfuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(225 methoxyphenyl)propanoic acid

283 mg (2/2)-2- {[6-(5-bromofui^-an-2-yl)-(5S_fl)-5-{3-chloro-2-methyl-4-[2-(4methyipiperazin-l-yl)ethoxy]phenyl}tbieno[2,3-d]pyrimidm-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid (Example 577) (0.38 mmol), 0.70 mL 2-cyclopropyl30 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3.8 mmol), 0.62 g CS2CO3 (1.9 mmol) and 29 mg

PdCh ^x dppf (0.04 mmol) were dissolved in a mixture of 4 mL dioxane and 1 mL water.

The mixture was heated under nitrogen at 100 °C in a microwave reactor until no further

- 364 conversion was observed. The reaction was quenched at room température with water and the pH was set to 6 using 2 M HCl solution. The mixture was extracted with DCM, the combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 585. HRMS calculated for C37H39CIN4O6S: 702.2279; found 703.2337 (M+H).

Example 586 (2À)-2- {[(55_a)-5- {3 -chloro-2-methyl-4-[2 -(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(5-phenylfuran-2-yl)thieno[2,3-<Z|pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

200 mg (2R)-2-{ [6-(5-bromofuran-2-yl)-(55„)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3-<7]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid (Example 577) (0.27 mmol), 275 mg 4,4,5,5-tetramethyl2-phenyl-l,3,2-dioxaborolane (1.35 mmol), 440 mg Cs₂CO₃ (l.35mmol) and 19 mg AtaPhos (0.027 mmol) were dissolved in a mixture of 3 mL dioxane and 0.75 mL water. The reaction mixture was stirred under nitrogen at 70 °C for 1 hour. The réaction was quenched at room température with water and the pH was set to 5 using 2 M HCl solution. The mixture was extracted with DCM, the combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 586. HRMS calculated for C40H39CIN4OÛS: 738.2279; found 739.2358 (M+H).

Example 587 (2R)-2-[((55),)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]pheny!}-6-[3-(pyridin-4-ylmethoxy)phenyl]thieno[2,3-7]pyrimidin-4-yI)oxy]-3(2-methoxyphenyl)propanoic acid

Step A:

500 mg ethyl (2Â)-2-[(55),)-5-(3-chloiO-4-hydroxy-2-methyl-phenyl)-6-iodo-thieno[2,37]pyrimidîn-4-yl]oxy-3-(2-methoxyphenyl)propanoate (Préparation 25) (0.80 mmol), 630 mg PPI13 (2.40 mmol), 352 mg di/er/butyl azodicarboxylate (2.40 mmol) and 346 mg 2-(417193

-365methylpiperazin-l-yl)ethanol (2.40 ininol) were dissolved in 20 ml dry toluene and the reaction mixture was stirred at 50 °C under nitrogen atmosphère until no further conversion was observed. The mixture was concentrated under reduced pressure and the residue was purified via flash chromatography using DCM and MeOH as eluents to give ethyl (27?)-2-[(5>S'₀)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-y1)ethoxy]phenyl]-6iodo-thieno[2,3W]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate.

Step B:

445 mg ethyl (2Æ)-2-[(5S_i7)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-iodo-thieno[2_>3-i(|pyrimidin-4-yl]oxy~3-(2methoxyphenyl)propanoate (0.59 mmol), 264 mg 3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenol (1.20 mmol), 106 mg AtaPhos (0.15 mmol) and 391 mg CS2CO3 (1.20 mmol) were dissolved in a mixture of 4.5 mL THF and 4.5 mL water. The mixture was heated under nitrogen at 100 °C in a microwave reactor until no further conversion was observed. The crude reaction mixture was diluted with water and the pH was adjusted lo 6 by the addition of 2 M HCl solution. The mixture was extracted with DCM, the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified via flash chi'omatography using DCM and MeOH as eluents to give ethyl (2Æ)-2-[(5S_o)-5-[3-chloro-2-methyl-4-[2-(4-methyIpiperazin-lyl)ethoxy]phenyl]-6-(3-hydroxyphenyl)thieno[2,3-</[pyrimidin-4~yl]oxy-3-(2methoxyphenyl)propanoate.

Step C:

mg ethyl (2Jî)-2-[(55^, _fl)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyll-6-(3-hydroxyphenyl)thieno[2,3-if]pyrimidin-4-yl]oxy-3-(2methoxyphenyl)propanoate (0.10 mmol), 80 mg PPhj (0.30 mmol), 70 mg di/er/butyl azodicarboxylate (0.30 mmol) and 33 mg 4-pyridylmethanol (0.30 mmol) were dissolved in 3 ml dry toluene and the reaction mixture was stirred under nitrogen at 50°C until no further conversion was observed. The mixture was concentrated under reduced pressure and the crade product was purified via flash chromatography using DCM and MeOH as eluents. The obtained product was hydrolyzed in 3 mL methanol-water (9:1) containîng NaOH (5m/m%) at room température. The mixture was diluted with water and the pH was

-366adjusted to 6 by the addition of 2 M HCl. The mixture was extracted with DCM, the combined organic phases were dried over Na₂SO4 and concentrated under reduced pressure. The crude product was purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 587. HRMS calculated for C₄2H42ClN_sO₆S: 779.2544; found 390.6339 (M+2H).

Exampie 588 (25)-2-[((55J-5-{3-chloro-2-methyl-4-[2-(4-niethylpiperazin-lyl)ethoxy]phenyl}-6-(3-[2-(morpholin-4-yl)ethoxy]phenyl}thieno[2,3-</]pyrimidin-4yl)oxy]-3-(2-methoxyphenyl)propanoic acid

Using the same procedures as described for Example 587 and replacing 4-pyridylmethanol with 2-(morpholin-4-yl)ethanol in Step C Example 588 was obtained. HRMS calculated for C₄2H_4gClN5O₇S.· 801.2963; found 401.6554 (M+2H).

Example 589 (25)-2-[((55_fl)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-[3-(2-niethoxyethoxy)phenyl]thieno[2,3-i7]pyrimidin-4-yl)oxy]-3-(2methoxyphenyl)propanoic acid

Using the same procedures as described for Example 587 and replacing 4-pyridylmethanol 20 with 2-methoxyethanol in Step C Example 589 was obtained.

HRMS calculated for C39H43CIN4O7S: 746.2541; found 747.26 (M+H).

Example 590 (25)-2-( [(55,,)- 5 - {3 -chloro-2-methy 1-4- [2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-((25 or 5)-tetrahydrofuran-2-yl)thieno[2₎3-</]pyrimidin-4-yl]oxy}-325 (2-methoxyphenyl)propanoic acid and

Example 591 (25)-2- {[(55„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl]-6-((25 or 5)-tetrahydrofuran-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3(2-methoxyphenyl)propanoic acid

Slep A:

-367To a solution of 565 mg Préparation 6e (l.OO mmol) in 90 ml EtOH 1298 mg palladium hydcoxide on carbon (Pearlman’s catalyst 20 wt. %) was added. The réaction mixture was flushed with nitrogen, and then it was flushed with hydrogen and stirred under hydrogen atmosphère (10 bar) at room température for 4 days. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to give ethyl (2R)-2-[(55'<?)-5-(3-chloro-4hydroxy-2-methyl-phenyl)-6-tetrahydrofuran-2-yl-thieno[2,3-iZ]pyrimidin-4-yI]oxy-3-(2methoxyphenyl)propanoate diastereomers. ’H NMR (500 MHz, DMSO-dé) of the ÎO diastereomer eluted eaiiier: 10.26 (s, ÎH), 8.54 (s, 1H), 7.18 (td, 1H), 7.02 (d, 1H), 6.97 (d,

1H), 6.90 (dd, 1H), 6,75 (t, 1H), 6.32 (dd, 1H), 5.35 (dd, 1H), 4.70 (t, 1H), 4.03-3.96 (m, 3H), 3.76 (s, 3H), 3.73 (m, 1H), 2.95 (m, 1H), 2.45 (dd, 1H), 2.07 (m, 1H), 1.99 (s, 3H), 1.96 (m, 1H), 1.89 (m, 1H), 1.74 (m, 1H), 1.05 (t, 3H).

*H NMR (500 MHz, DMSO-dô) of the diastereomer eluted later: 10.26 (br s, 1H), 8.55 (s, 15 1H), 7.19 (td, 1H), 7.05 (d, 1H), 6.96 (d, 1H), 6.91 (d, 1H), 6,77 (td, 1H), 6.46 (dd, 1H),

5.36 (dd, 1H), 4.82 (t, 1H), 4.05-3.93 (m, 3H), 3.76 (s, 3H), 3.71 (m, 1H), 2.85 (dd, 1H), 2.57 (m, 1H), 2.04 (m, 1H), 1.95 (m, 1H), 1.94 (s, 3H), 1.88 (m, 1H), 1.66 (m, 1H), 1.00 (t, 3H).

Step B:

Using the Step B and Step C of General Procedure (XVI), starting from the earlier eluted diastereomer in Step A Example 590 was obtained. HRMS calculated for C34H39CIN4O6S: 666.2279; found 667.2349 (M+H); Starting from the later eluted diastereomer in Step A Exampie 591 was obtained. HRMS calculated for C34H39CIN4O6S: 666.2279; found 25 667.2315 (M+H).

Example 592 (27?)-2-[((5Æ₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-ethylthieno[2,3-iZ]pyrimidin-4-yl)oxy]-3-(2methoxyphenyl)propanoic acid

Step A:

17193 ·

-368649 mg 4-chloro-6-ethyl-5-iodo-thieno[2,3-if]pyrimidine (Préparation ld) (2.0 mmol), 538 mg ethyl (27?)-2-hydroxy-3-(2-methoxyphenyl)propanoate (Préparation 3ad) (2.4 mmol) and 1.955 g césium carbonate (6.0 mmol) were stirred at 70°C in 10 mL dry fëributanol until no further conversion was observed. The mixture was cooled to room température, and then 10 ml, water, 947 mg l-[2-[2-chloro-3-methyl-4-(4,4,5,5tetramethyl-l,3,2dioxaborolan-2-yl)phenoxy]ethyl]-4-methyi-piperazine (Préparation 5b) (2.4 mmol) and I4l mg AtaPhos (0.2 mmol) were added. The mixture was stirred under nitrogen at 60°C until no further conversion was observed. Then brine was added and the mixture was extracted with EtOAc. The combined organic phases were dried over MgSOzj and concentrated under reduced pressure. The residue was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2Λ)-2-(5-(3-chloro-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-ethyl-thieno[2,3-</]pyrimidin-4yl]oxy-3-(2-methoxyphenyl)propanoate.

Step B:

The product of Step A was hydrolyzed according to Step C of General Procedure (XVI); the diastereoisomer eluting earlier was collected as Example 592. HRMS calculated for C32H37CIN4O5S; 624.2173; found 625.2255 (M+H).

Example 593 (25)-2-(((55),)5- {3-chloro-2-methyl-4-[2-(4-inethylpiperazin-1 . yl)ethoxy]phenyl} -6-ethylthieno[2,3-<7]pyrimidin-4-yl)oxy]-3-(2methoxyphenyl)propanoic acid

Step A:

649 mg 4-chloro-6-ethyl-5-iodo-thieno[2,3-J]pyrirnidine (Préparation ld) (2.0 mmol), 538 mg ethyl (2S)-2-hydroxy-3-(2-methoxyphenyl)propanoate (Préparation 3bi) (2.4 mmol) and 1.955 g césium carbonate (6.0 mmol) were stirred at 70°C in 10 mL dry ter/butanol until no further conversion was observed. The mixture was cooled to room température, and then 10 mL water, 947 mg l-[2-(2-chloro-3-methyl-4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-methyl-piperazine (Préparation 5b) (2.4 mmol) and 141 mg AtaPhos (0.2 mmol) were added. The mixture was stirred at 60°C until no further conversion was observed. Then brine was added and the mixture was

-369extracted with EtOAc. The combined organic phases were dried over MgSO₄, filtered and concentrated under reduced pressure. The crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2>S)-2-[5-[3-chloro-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-ethyl-thieno[2,3-Ê(]pyrimidin-45 yl]oxy-3-(2-methoxyphenyl)propanoate.

Step B:

The product of Step A was hydrolyzed according to Step C of General Procedure (XVI); the diastereoisomer eluting earlier was collected as Exampie 592. HRMS calculated for 10 C₃₂H₃7ClN4O₅S: 624.2173; found 625.2239 (M+H).

General Procedure (XVIIa)

Step A:

eq. ethyl (27?)-2-[(55_a)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l15 yl)ethoxy]phenyl]-6-(4-fluoro-3-hydroxy-phenyl)thieno[2,3-<Z]pyrimidin-4-yl]oxy-3-[2[(2-methoxypyrimidin-4-yl)methoxy]phenyl]propanoate (Préparation 28a), 2 eq. of the appropriate alcohol and 2 eq. triphenyl phosphine were dissolved in dry toluene (5 mL/mmol), then 2 eq. di/er/butyl azodicarboxylate was added. The mixture was stirred at 50°C. under nitrogen until no further conversion was observed. The volatiles were 20 evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents.

Step B:

The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. 25 LiOH ^x H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH₄HCO₃ solution and MeCN as eluents.

- 370 Example 594 (2A)-2-[((5S_n)-5-{3-chloiO-2-methyl-4-[2-(4-methylpipcrazin-lyl)ethoxy]phenyl}-6-[4-nuoro-3-(methoxymelhyl)phenyl]lhieno[2,3-iZ]pyriinidin-4yl)oxy] -3 - {2- [(2-methoxypyrimidin-4 -yl)methoxy] phenyl} propanoic acid

Step A:

0.801 g LiCl (19 mmol) was heated at 250°C for 10 minutes under N₂. Then it was cooled to room température and the flask was charged with 0.911 g Mg (38 mmol) and 30 mL dry THF. The Mg was activated with 0.15 mL /Bu₂A1H (1 M in THF, 0.15 mmol) for 10 minutes, then it was cooled to 0°C and 3.313 g 4-bromo-l-fluoro-2(methoxymethyl)benzene (15 mmol) was added. After 30 minutes stirring at 0°C 4 mL 2isopiOpoxy-4,4,5,5-tetramethyl-l,3₅2-dioxaborolane (20 mmol) was added and the reaction mixture was stirred for 30 minutes, then filtered through celite, diluted with EtOAc and washed with saturated aq. NH4CI. The aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure and the residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 2-[4-fluoro-3-(methoxymethyl)phenyl]-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane. MS (El, 70 eV) m/z (% relative intensity, [ion]): 59 (21), 85 (20), 134 (24), 135 (100), 136 (28), 150 (30), 165 (24), 166 (43), 167 (95), 192 (20), 251 (44, [M⁺]).

Step B:

3.94 g 4-chloro-5-[3-chloiO-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6iodo-thieno[2,3-i/]pyrimidine (Préparation 13) (7 mmol), 2.11 g 2-[4-fluoro-3(methoxymethyl)phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (8.4 mmol), 4.56 g Cs₂CO₃ (14 mmol), and 0.496 g AtaPhos (0.7 mmol) were placed in a 100 mL flask. 45 mL dioxane and 15 mL water were added, and the mixture was stirred under N₂ at 70°C until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure, and the crude product was purified via flash chromatography using DCM and MeOH as eluents to obtain 4-chloro-5-[3-chloro-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-[4-fluoiO-3-(methoxyniethyl) phenyl]thieno[2,3-ri]pyrimidine. MS: (M+H) = 575.2.

-371 Step C:

2.615 g 4-chloro-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-[4fluoro-3-(methoxymethyl)phenyl]thieno[2,3-fiT|pyrimidme (4.5 mmol), 1.61 g ethyl (212)-2hydroxy-3-(2-tetrahydiOpyran-2-yloxyphenyl)propanoate (Préparation 3ab) (5.5 mmol) and 4.40 g CS2CO3 (13.5 mmol) were placed in a 100 mL flask. 50 mL terr-butanol was added and the mixture was stirred at 80°C under N₂ until no further conversion was observed. The mixture was diluted with water, the pH was set to 7 with 2 M HCl, and then it was extracted with DCM, The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (21?)-2-[5-[3-chloro-2methyl-4-[2-(4-methyIpiperazin-1 -yl)ethoxy]pheny 1] -6- [4-fluoro -3-(methoxymethyl) phenyl]thieno[2,3-i(]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate as a mixture of diastereoisomers. MS: (M+H) = 833.2.

Step D:

2.36 g ethyl (212)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6[4-fluoro-3-(methoxymethyl)phenyl]thieno[2,3-<7]pyrimidin-4-yl]oxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate (28.3 mmol) was dissolved in 15 mL EtOH, then 20 mL 1.25 M HCl in EtOH was added and the mixture was stiired at room température until no further conversion was observed. Saturated aq. NaHCOs solution was added and the reaction mixture was extracted with DCM. The combined organic layers wcrc dried over Na₂SO4 and concentrated under reduced pressure. The crude product was purified via flash chromatography using DCM and MeOH as eluents to obtain ethyl (212)2- [5- [3 -chloro-2-methyl -4- [2-(4-methylpiperazi η-1 -yl)ethoxy]phenyl] -6- [4-fluoro-3 (methoxymethyl) phenyllthieno[2,3-i7]pyrimidin-4-yl]oxy-3-(2-hydroxyphenyl)propanoate as a mixture of diastereomers. MS: (M+H) =749.2.

Step E:

0.375 g ethyl (272)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]6-[4-fluoiO-3-(inethoxymethyl)phenyl]thieno[2.3-</]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (0.5 mmol), 0.21 g (2-methoxypyrimidin-4-yl)methanol (1.5 mmol) and 0.393 g PPI13 (1.5 mmol) were dissolved in 10 mL dry toluene, then 0.345 g

17193 · •372di/er/butyl azodicarboxylate (1.5 mmol) was added. The mixture was stirred at 50°C under N₂ until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using DCM and methanol as eluents to obtain ethyl (25)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazinl-yl)ethoxy]phenyl]-6-[4-fluoiO-3-(methoxyinethyl)phenyl]thieno[2_s3-d]pyrimidin-4yl]oxy-3-[2-[(2-tnethoxypyiimidin-4-yl)methoxy]phenyl]propanoate as a mixture of diastereomers. MS: (M+H) ~ 871.2.

Step F:

The product of Step E was dissolved in 10 mL dioxane-water (l : l ) and 0.21 g LiOH x H₂O (5 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure and purified via préparative reverse phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. The diastereomer eluting Iater was collected as Example 594. HRMS calculated for C43H44CIFN6O7S: 842.2665; found 422.1408 (M+2H).

Example 595 (2Æ)-2-{[(55,)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluoro-3-hydroxyphenyl)thieno[2,3-rf]pyiïmidin-4-yl]oxy}-3-{2[(2-methoxypyrimidin-4-yl)methoxy]phenyl}propanoic acid

316 mg ethyl (2R)-2-[(55,)-5-[3-chloro-2-methyl-4-[2-(4-rnethylpïperazin-lyl)ethoxy]phenyl]-6-(4-fluoro-3-hydroxy-phenyl)thieno[2,3-i/|pyrimidin-4-yl]oxy-3-[2[(2-methoxypyrimidin-4-yl)methoxy]phenyl]propanoate (Préparation 28a) (0.375 mmol) was dissolved in 10 mL dioxane-water 1:1 and 157 mg LiOH x H₂O (3.75 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄, concentrated under reduced pressure and purified via préparative reversed phase chromatography using MeCN and 25 mM aqueous NH4HCO3 solution as eluents to obtain Example 595. HRMS calculated for C₄₁H4oClFN₆07S: 814.2352; found 408.1254 (M+2H).

e

-373Example 596 (2Æ)-2-[((5S/)-5- {3-chloro-2-methyl-4-[2-(4-methyIpiperazin-1 yl)ethoxy]phenyI}-6-{4-fluoro-3-[2-(morpholin-4-yl)ethoxy]phenyl}thieno[2,3i/jpyrimidin-4-yl)oxy]-3-{2-[(2-methoxypyrimidin-4-yl)methoxy]phenyl}piOpanoic acid

Using General Procedure (XVIIa) and 2-(morpholin-4-yl)ethanol as the appropriate alcohol Example 596 was obtained. HRMS calculated for C47H51CIFN7O8S: 927.3192; found 464.6657 (M+2H).

Example 597 (2R)-2-[((5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-[4-fluoro-3-(2-hydroxyethoxy)phenyl]thieno[2,3-d]pyrimidin-4yl)oxy]-3-{2-[(2“methoxypyrimidin-4-yl)methoxy]phenyl)propanoic acid

Using General Procedure (XVIIa) and ethylene glycol as the appropriate alcohol Example 597 was obtained. HRMS calculated for C43H44CIFN6O8S: 858.2614; found 430.1402 (M+2H).

Example 598 (2R)-2-[((5S_rt)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyI}-6-[4-fluoro-3-(2-methoxyethoxy)phenyl]thieno[2,3-ii]pyrimidin-4yl)oxy]-3-{2-[(2-methoxypyrimidin-4-yl)methoxy]phenyl}propanoic acid

Using General Procedure (XVIIa) and 2-methoxyethanol as the appropriate alcohol Example 598 was obtained. HRMS calculated for C44H4ÊCIFN6O8S: 872.277; found 437.1468 (M+2H).

Example 599 (2R)-2- {[(5S'„)-5-{3-chloro-2-methyl-4-[2-(4-methyIpiperazin-1 yl )ethoxy] phenyl }-6-(3 -methoxypropyl)thieno [2,3 -iTJpyrim idin-4-y 1] oxy} - 3 - {2- [(2methoxypyrimidin-4-yl)methoxy]phenyl}propanoic acid

Slep A:

3.754 g 5-bromo-4-chloro-6-iodo-thieno[2,3-iZ]pyriinidine (Préparation la) (10.0 mmol), 1198 mg 3-methoxyprop-l-yne (17.1 mmol), 702 mg Pd(PPh₃)2Cl (1.0 mmol), 288 mg Cul

17193 ·

-374(2.0 mmol) and 2.8 mL TEA (20 mmol) were dissolved in 50 mL THF, and the mixture was stirred under nitrogen at room température until no further conversion was observed. It was concentrated under reduced pressure and purified via flash chromatography using heptane and ethyl acetate as eluents to obtain 5-bromo-4-chloiO-6-(3-methoxyprop-lynyl)thieno[2,3-<7]pyrimidine. ^!H NMR (400 MHz, DMSO-d₆): 9.04 (s, IH), 4.50 (s, 2H), 3.40 (s, 3H).

Step B:

2.07 g 5-bromo-4-chloiO-6-(3-methoxyprop-l-ynyl)thieno[2,3-i7]pyriinidine (6.517 mmol), 2. Il g ethyl (2R)-2-hydiOxy-3-(2-tetrahydropyran-2-yIoxyphenyl)propanoate (Préparation 3ab) (7.17 mmol) and 6.58 g CS2CO3 (20 mmol) were placed in a flask. 70 mL ferf-butanol was added and the mixture was stirred under nitrogen at 65°C until no further conversion was observed. It was diluted with water and extracted with dichloromethane. The combined organic layers were dried over Na₂SÛ4 and concentrated under reduced pressure to obtain ethyl (2Æ)-2-[5-brorno-6-(3-methoxyprop-lynyl)thien0[2,3-c/]pyrimidin-4-yl]oxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate. It was used innext step without further purification. MS: (M+H) = 575.0.

Step C:

The product of Step B and 2.6 g 2“chloiO-3-methyI-4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)phenol (Préparation 5a) (9.68 mmol) were dissolved in 21 mL THF, then 5.24 g CS2CO3 (16.08 mmol) dissolved in 7 mL water was added followed by 431 mg AtaPhos (0.6l mmol), and the mixture was stirred under nitrogen at 65 °C until no further conversion was observed. Then it was diluted with dichloromethane and brine. After phase séparation the aqueous phase was extracted with dichloromethane. The organic layers were combined and dried over Na2SÛ4 and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain ethyl (2Æ)-2-[5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(3-methoxyprop-l-ynyl)thieno [2,3-<7]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)piOpanoate as a mixture of diastereomers. MS: (M+H) = 637.2.

Step D:

-3752,765 g ethyl (27?)-2-[5-(3-chloro-4-hydioxy-2-methyl-phenyl)-6-(3-methoxypiOp-lynyl)thieno[2,3-i/)pyrimÎdÎn-4-yl]oxy-3-(2-tetrahydiOpyran-2-yloxyphenyl)propanoate (4.34 mmol), 1.3 g 2-(4-methylpiperazin-l-yl)ethanol (9.0 mmol) and 2.623 g triphenyl phosphine (10.0 mmol) were dissolved in 40 mL dry toluene, then 2.303 g di/er/butyl azodicarboxylate (10.0 mmol) was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using ethyl acetate and methanol as eluents to obtain ethyl (2Æ)‘2-[5-[3-chlorO“2-methyl-4-[2-(4-methylpiperazinl-yl)ethoxy]phenyi]-6«(3-methoxyprop-l-ynyl)thieno[2,3-iZ]pyiimidin-4-yl]oxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate as a mixture of diastereomers. MS: (M+H) = 763.2.

StepE:

3.59 g ethyl (2J?)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6(3-methoxyprop-l-ynyl)thieno[2,3-<Z]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2yloxyphenyl)propanoate (4.3 mmol) and 458 mg Selcat Q6 were dissolved in 50 mL methanol, then 1.87 g ZerAbutylamine borane (21.5 mmol) was added. The mixture was stirred at room température until no further conversion was observed. It was fïltered through a plug of celite and the volatiles were evaporated under reduced pressure to obtain ethyl (2Æ)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(3methoxypropyl) thieno[2,3-<7]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2yloxyphenyl)propanoate as a mixture of diastereomers that was used in next step without further purification. MS: (M+H) = 767.2.

Step F:

The product of Step E was dissolved in 20 mL EtOH, then 20 mL 1.25 M HCl in. EtOH was added and the mixture was stirred at room température until no further conversion was observed. Most of the EtOH was evaporated under reduced pressure then water and saturated aq. NaHCO₃ solution were added and the mixture was extracted with DCM. The combined organic layers were dried over Na₂SO4 and concentrated under reduced pressure. The crude product was purified via flash chromatography using DCM and MeOH as eluents to obtain ethyl (21?)-2-[5-[3-chloro-2-methyl-4-[2-(4-iïiethylpiperazin-l17193 ₉

-376yl)ethoxy]phenyl]-6-(3-niethoxypropyl)thieno[2,3-i7]pyrimidin“4-yl]oxy-3-(2hydroxyphenyl)propanoate as a mixture of diastereomers. MS: (M+H) ~ 683.2.

Step G:

479 mg ethyl (2/?)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]~

6-(3-methoxypropyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-(2-hydiOxyphenyl)propanoate (0.7 mmol), 280 mg (2-methoxypyrimidin-4-yl)methanol (2.0 mmol) and 525 mg triphenyl phosphine (2.0 mmol) were dissolved in 10 mL dry toluene, then 461 mg di/c/butyl azodicarboxylate (2.0 mmol) was added. The mixture was stirred at 50°C under nitrogen untii no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents.

Step H:

The product of Step G was dissolved in 30 mL dioxane-water (1:1) and 250 mg LiOH x H₂O (5.95 inmol) was added. The mixture was stirred at room température untii no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with dichloromethane. The combined organic phases were dried over Na₂SC>4, concentrated under reduced pressure, and purified via préparative reversed phase 20 chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. The diastereoisomer eluting later was collected as Example 599. HRMS calculated for C39H45CIN6O7S: 776.2759; found 777.2796 (M+H).

General Procedure (XVIIIa)

Step A:

eq. ethyl (2Æ)-3-[2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chloiO-2-mcthyl4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-iodo-thieno[2,3-iZ]pyrimidin-4-yl]oxypropanoate (Préparation 26c), 2 eq. of the appropriate boronic acid dérivative and 2,5 eq. Cs₂CO₃ were dissolved in THF-water (1:1) (0.1 M for Préparation 26c), then 0.1 eq.

PdCl₂xdppf was added. The mixture was heated under nitrogen at 100°C in a microwave reactor untii no further conversion was observed. Then it was diluted with brine and

-377extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure, and purified via flash chromatography using EtOAc and MeOH as eiuents.

Step B:

The product of Step A was dissolved in dioxane-water l:l (10 mL/mmol) and 10 eq, LiOH * H2O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated under reduced 10 pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eiuents separating the diastereoisomers.

Example 600 (2Æ)-3- (2-[( 1 -butyl-1 H-pyrazol-5-yI)methoxy]phenyl} -2- {[(55^)-5- (3chloro-2-methyl-4- [2-(4-methylpiperazin-1 -yl)ethoxy]pheny 1} -6-(4 15 cyanophenyl)thieno[2,3-c7]pyrimidin-4-yl]oxy}propanoic acid

Using General Procedure (XVIIIa) and (4-cyanophenyl)boronic acid as the appropriate boronic acid dérivative, the diastereoisomer eluting later was collected as Example 600. HRMS calculated for C44H46CIN7O5S: 819.2970; found 410.6565 (M+2H).

Example 601 (2Æ)-3- (2-[( 1 -butyl-1 H-pyrazol-5-yl)methoxy]phenyl}-2- ([(55^)-5-(3chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl }-6-(4ethylphenyl)thieno[2,3-<7]pynmidin-4-yl]oxy}propanoic acid

Using General Procedure (XVIIIa) and (4-ethylphenyl)boronic acid as the appropriate boronic acid dérivative, the diastereoisomer eluting later was collected as Example 601. HRMS calculated for C45H_5IC1N₆O₅S: 822.3330; found 412.1729 (M+2H).

Example 602 (2A)-3-(2-[(l -butyl-lH-pyrazol-5-yl)methoxy]phenyl}-2-([(55„)-5-(330 chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl} -6-(4hydroxyphenyl)thieno[2_s3-£7]pyrimidin-4-y]]oxy} propanoic acid

17193 ·

-378 Using General Procedure (XVIIIa) and (4-hydroxyphenyl)boronic acid as the appropriate boronic acid dérivative, the diastereoisomer eluting later was collected as Example 602. HRMS calculated for C₄₃H₄7ClN₆O₆S: 810.2966; found 406.1541 (M+2H).

Example 603 (22?)-3-{2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl}-2-{[(55₀)-5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(4methoxyphenyl)thieno[2,3-i/)pyrimidin-4-yl]oxy}piOpanoic acid

Using General Procedure (XVIIIa) and (4-methoxyphenyl)boronic acid as the appropriate boronic acid dérivative, the diastereoisomer eluting later was collected as Example 603. HRMS calculated for C₄₄H₄₉C1N₆O6S: 824.3123; found 413.1648 (M+2H).

Example 604 (2R)-3-{2-[( 1 -butyl-1 H-pyrazol-5-yl)methoxy]phenyl} -2- {[(55),)-5- {3 chloiO-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl)-6-(4-ethoxyphenyl)thieno [2,3-rijpyrimidin-4-yl]oxy)propanoic acid

Using General Procedure (XVIIIa) and (4-ethoxyphenyl)boionic acid as the appropriate boronic acid dérivative, the diastereoisomer eluting later was collected as Example 604. HRMS calculated for C₄5H_s1C1N₆O₆S.· 838.3279; found 420.1700 (M+2H).

Exampie 605 (2Λ)-3 - {2-[(l -butyl-1 H-pyrazol-5-y l)methoxy]phenyl} -2- {[6-(6'-chloro-2,3bipyridin-5-yl)-(55_lï)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl} thieno[2,3-ri|pyrimidin-4-yl]oxy}propanoic acid and

Exampie 606 (2Â)-3-{2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl}-2-{[(55₀)-5-{3chloiO-2-methyI-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(6-chloropyridin-3yl)thieno[2,3-JJpyrimidin-4-yl]oxy}propanoic acid

Using General Procedure (XVIIIa) and (6-chloro-3-pyridyl)boronic acid as the appropriate boronic acid dérivative Example 606 was collected as the secondly eluting diastereoisomer. HRMS calculated for C₄2H₄5C12N₇O5S: 829.2580; found 415.6359 (M+2H). Overreaction at the Suzuki coupling was also observed and the later eluting «

-379diastereoisomer of this side product was collected as Example 605. HRMS calculated for C47H48CI2N8O5S: 906.2845; found 454.1481 (M+2H).

Exampie 607 (2R)-3 - {2- [( 1 -butyl -1 H-pyrazol-5-y l)methoxy]phenyl} -2- {[(55^)-5 - {3 5 chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(6-fluoropyridin-3yl)thieno[2,3-r/|pyrimidin-4-yl]oxy}propanoic acid

Using General Procedure (XVIIIa) and (6-fluoro-3-pyridyl)boronic acid as the appropriate boronic acid dérivative, the diastereoisomer eluting later was collected as Example 607.

HRMS calculated for C42H45CIFN7O5S: 813.2875; found 407.6496 (M+2H).

Exampie 608 (2R)-3~{2-[( 1 -butyl-1 H-pyrazol-5-yl)methoxy]phenyl}-2- {[(5X)-5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(6-methoxypyridin-3yl)thieno[2,3-J]pyrimidin-4-yl]oxy}propanoic acid

Using General Procedure (XVIIIa) and (6-methoxy-3-pyridyl)boronic acid as the appropriate boronic acid dérivative, the diastereoisomer eluting later was collected as Example 608. HRMS calculated for C₄3H₄8C1N₇O₆S: 825.3075; found 413.6608 (M+2H).

Example 609 (2J?)-3-{2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl}-2-{[(5>S'_a)-5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(pyridin-3-yl)thieno[2,3i/]pyrimidin-4-yl]oxy} propanoic acid

Using General Procedure (XVIIIa) and 3-pyridylboronic acid as the appropriate boronic acid dérivative, the diastereoisomer eluting later was collected as Example 609. HRMS calculated for C42H46CIN7O5S: 795.2970; found 398.6572 (M+2H).

Example 610 (2/?)-3-{2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl}-2-{[(5S_a)-5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl} -6-(l -methyl-1 H-pyrazol-330 yl)thieno[2,3-i/Jpyrimidin-4-yl]oxy}propanoic acid

-380Using General Procedure (XVIIIa) and l-methyl-3-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)pyrazole as the appropriate boronic acid dérivative, the diastereoisomer eluting later was collected as Example 610. HRMS calculated for C41H47CIN8O5S: 798.3079; found 400.1599 (M+2H).

Example 611 (2Æ)-3-{2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl}-2-[((55_rt)-5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-ethynylthieno[2,3i/]pyrimidin-4-yl)oxy]propanoic acid

Step A:

437 mg ethyl (2Æ)-3-[2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chloro-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-iodo-thieno[2,3W]pyrimidin-4yl]oxy-propanoate (Préparation 26c) (0.5 mmol), 139 pL ethynyl(trimethyl)silane (1.0 mmol), 35 mg Pd/PPhs^CL (0.05 mmol) and 19 mg copper(I) iodide (0.1 mmol) were dissolved in 5 mL DIPA, then the mixture was stirred under nitrogen at 60°C until no further conversion was observed. The reaction mixture was cooled to room température and 600 μΐ TBAF (0.6 mmol, 1 M in THF) was added and it was stirred for 30 minutes. Then the volatiles were evaporated under reduced pressure and the crade product was purified by flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2R)3-[2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chloro-2-methyJ-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl] -6-ethynyl-thieno[2,3-z/]pyrimidin-4-yl]oxypropanoate.

Step B:

The product of Step A was hydrolyzed according to Step B of General Procedure (XVIIIa) and the diastereoisomer eluting later was collected as Example 611. HRMS calculated for C39H43CIN6O5S: 742.2704; found 743.2789 (M+H).

Example 612 (2Æ)-3-{2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl}-2-{[6-(but-l-yn-lyl)-(5S₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3i/]pyrimidÎn-4-yl]oxy}piOpanoic acid

-381 Step A:

437 mg ethyl (2Λ)-3-[2-[(1-butyl-1 H-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chloro-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-iodo-thieno[2,3-i(]pyrimidin-4yljoxy-propanoate (Préparation 26c) (0.5 mmol), 35 mg Pd(PPh₃)2C12 (0.05 mmol) and 19 mg copper(I) iodide (0.1 mmol) were dissolved in 5 mL DIPA, then but-l-yne was bubbled through the reaction mixture, which was stirred at 60°C until no further conversion was observed. Then the volatiles were evaporated under reduced pressure and the crude product was purified by flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2Æ)-3-[2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl]-2-[6-but-ly nyl-5 - [3 -chloro-2-methyl-4-[2 -(4 -methylpiperazin-1 -y l)ethoxy] pheny I ]thieno[2,3 i(]pyrimidin-4-yl]oxy-propanoate.

Step B:

The obtained intermediate was hydrolyzed according to Step B of General Procedure (XVIIIa) and the diastereoisomer eluting later was collected as Example 612. HRMS calculated for C41H47CIN6O5S: 770.3017; found 386.1594 (M+2H).

Exampie 613 (2Æ)-3-{2-[(l -butyl- lH-pyrazol-5-y])methoxy]phenyl}-2-{[(5.S^, _fl)-5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(3-methoxyprop-l-yn-lyl)thieno[2,3-iZ|pyrimidin-4-yl]oxy}propanoic acid

Step A:

437 mg ethyl (27?)-3-[2-[(l -butyl-1 H-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chloro-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-iodo-thieno[2,3-i(]pyrimidin-4yljoxy-propanoate (Préparation 26c) (0.5 mmol), 70 mg 3-methoxyprop-l-yne (1.0 mmol), 35 mg Pd(PPh₃)2C12 (0.05 mmol) and 19 mg Cul (0.1 mmol) were dissolved in 5 mL DIPA and stirred under nitrogen at 60°C until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crade product was purified by flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2Λ)-3-[2-[(1butyl-lH-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chioro-2-methyl-4-[2-(4-methylpiperazinl-yl)ethoxy]phenyl]-6-(3-methoxypiOp-l-ynyl)thieno[2,3-J]pyrimidin-4-yl]oxypropanoate.

17193 *

-382Step B:

The product of Step A was hydrolyzed according to Step B of General Procedure (XVIIIa); the diastereoisomer eluting later was collected as Example 613. HRMS calculated for C₄|H₄7C1N₆O₆S: 786.2966; found 787.3040 (M+H).

Example 614 (2/?)-3-{2-[(l-butyl-l H-pyrazol-5-yl)methoxy]phenyl}-2-(((55^)-5-(3chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-cyanothieno[2,3d]pyrimidin-4-yl)oxy]piOpanoic acid

Step A:

437 mg ethyl (2A)-3-[2-[(l-butyl-lH~pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chloiO-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-iodo-thieno[2,3-<7]pyrimidin-4yljoxy-propanoate (Préparation 26c) (0.5 mmol) and 224 mg CuCN (2.5 mmol) were stirred at 100°C in 5 mL dry DMF until no further conversion was observed. Brine was added and the mixture was extracted with DCM. The combined organic phases were washed with brine, then dried over MgSO₄ and concentrated under reduced pressure. The residue was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2Æ)-3-[2-[(l -butyl-lH-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chloro-2methyl-4- [2- (4-methylpiperazin-1 -y l)ethoxy]pheny 1] -6-cyano-thieno [2,3 -if] pyrim idi n-4yljoxy-propanoate.

Step B:

The obtained intermediate was hydrolyzed according to Step B of General Procedure (XVIIIa) and the diastereoisomer eluting later was collected as Example 614. HRMS calculated for C38H42CIN7O5S: 743.2657; found 372.6390 (M+2H).

Example 615 (2JÎ)-3-{2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl} -2-{[(55„)-5-{3chloro-2-methyl-4- [2-(4-methylpiperazin-1 -yl)ethoxy]phenyl} -6(trifluoromethyl)thieno[2,3-i7]pyrimidin-4-yl]oxy}piOpanoic acid

Step A:

-383437 mg ethyl (25)-3-[2-[(l-butyl-lH-pyrazoI-5-yl)methoxy]phenyl]-2-[5-[3-chloro-2methyl-4-[2-(4-metliylpiperazïn-l-yl)ethoxy]phenyl]-6-iodo-thieno[2₍3-iZ]pyrimidin-4yijoxy-propanoate (Préparation 26c) (0,75 mmol), 28.2 mg 1,10-phenanthroline (0.156 mmol), 29.7 mg copper(I) iodide (0.156 mmol), 130 mg potassium fluoride (2.23 mmol), 330 gL trimethyl(trifluoromethyl)silane (2.23 mmol) and 250 pL trimethyl borate (2.23 mmol) were dissolved in 5 mL dry DMSO and the mixture was stirred at room température ovemight under argon atmosphère. Then brine was added and the mixture was extracted with DCM. The combined organic phases were washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The crade product was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (25)-3-(2-((1 -butyl1 H-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpïperazin-1 yl)ethoxy] phenyl]-6-(trifluoromethyl)thieno[2,3-rf]pyrimidin-4-yl]oxy-propanoate.

Step B:

The product of Step A was hydrolyzed according to Step B of General Procedure (XVIIIa) and the diastereoisomer eiuting later was collected as Example 615. HRMS calculated for C38H42CIF3N6O5S: 786.2578; found 394.1372 (M+2H).

Example 616 (25)-3-{2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl}-2-[((5S^, _fl)-5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-{4-[2-(morpholin-4yl)ethoxy]phenyl}thieno[2,3-rf]pyrimidin-4-yl)oxy]propanoic acid

Step A:

420 mg ethyl (25)-3-(2-((1-butyl-1 H-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chloro-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(4-hydroxyphenyl)thieno(2,3iZjpyrimidin-4-yl]oxy-propanoate (see Step A of Example 602) (0.5 mmol), 182 μΐ 2(morpholin-4-yl)ethanol (1.5 mmol) and 393 mg triphenylphosphine (3.0 mmol) were dissolved in 10 mL dry toluene, then 261 mg diter/butyl azodicarboxylate (3.0 mmol) was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. Then the volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents to give ethyl (25)-3(2-((1-butyl-lH-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chloro-2-methyl-4-[2-(4-methyl

17193 _e

-384piperazin-l-yl)ethoxy]phenyl]-6-[4-(2-(morpholin-4-yl)ethoxy)phenyl]thieno[2,3ùQpyrimidin-4-yl]oxy-propanoate.

Step B:

The product of Step A was hydrolyzed according to Step B of General Procedure (XVIIIa) and the diastereoisomer eluting later was collected as Example 616. HRMS calculated for C49H58CIN7O7S: 923.3807; found 462.6977 (M+2H).

Example 617 (2R)-3 - {2- [( 1 -butyl-1 H-pyrazol-5 -yl)methoxyjpheny 1} -2- {[(50^)-5 - {3chloiO-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(3methoxypropyl)thieno[2,3-i(]pyrimidin-4-yl]oxy} propanoic acid

350 mg ethyl (2Æ)-3-{2-[(l-butyl-lH-pyrazol-5-yl)methoxyjphenyl}-2-{[(5₁S^, _(î)-5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy] phenyl} -6-(3-methoxyprop-1 -yn-1 yl)thieno[2,3-i/}pyrimidin-4-yl]oxy}propanoic acid (Example 613) (0.43 mmol) and 46 mg Selcat Q6 were dissolved in 5 mL méthanol, then 187 mg ZerLbutylamine borane (2.2 mmol) was added and the mixture was stirred at room température until no further conversion was observed. The mixture was fîltered through celite, then the filtrate was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na^SCht and concentrated under reduced pressure. The residue was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 617. HRMS calculated for C4₁H_5IC1N₆O₆S: 790.3279; found 791.3329 (M+H).

Example 618 (27?)-2-{[6-(6-aminopyridin-3-yl)-(5S_fl)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-1 -yl)ethoxy]phenyl} thieno [2,3 -<7]pyrimidin-4-y ljoxy} -3 - {2- [( 1 -butyl-1Hpyrazol-5-yi)methoxyJphenyl }propanoic acid

Using General Procedure (XVIIIa) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboiOlan-2yl)pyridin-2-amine as the appropriate boronic acid dérivative; the diastereoisomer eluting later was collected as Example 618. HRMS calculated for C42H47CIN8O5S: 810.3079; found 811.3129 (M+H).

♦

-385Exemple 619 (2Λ)-3-{2-[(1 -butyl-lH-pyrazol-5-yl)methoxy]phenyl}-2-[((5S'_fl)-5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-[6-(morpho!in-4yl)pyi‘idin-3-y]]thieno[2,3-<7]pyrimidin-4-yl)oxy]piOpanoic acid

Step A:

250 mg ethyl (27f)-3-[2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl]-2-[5~[3-chloro-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(6-fluoiO-3-pyndyl)thieno[2,3i(jpyrimidin-4-yl]oxy-piOpanoate (see Step A of Example 607) (0.29 mmol) and 258 pL morpholine (2.90 mmol) were heated at 150°C in a microwave reactor until no further conversion was observed. The volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents to give ethyl (2R)-3-[2-[( 1 -butyi-1 H-pyrazol-5-yl)methoxy]pheny 1]-2-[5-[3-chloro-2-methy 1 -4-[2(4-methylpiperazin-1 -yl)ethoxy]phenyl]-6-(6-morpholino-3 -pyridyl)thieno[2,3tZJpyrimidin-4-yljoxy-propanoate.

Step B:

The product of Step A was hydrolyzed according to Step B of General Procedure (XVilla) and the diastereoisomer eluting later was collected as Example 619. HRMS calculated for C46H₅₃ClN_gO₆S: 880.3497; found 441.1825 (M+2H).

Exampie 620 (27?)-3-{2-[(l-butyl-lH-pyrazol-5-yl)mcthoxy]phcnyl}2-[((55a)-5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-]-yl)ethoxy]phenyl}-6-{6-[(2methoxyethyl)amino]pyiïdin-3-yl}thieno[2,3-/Z|pyrimidin-4-yl)oxy]propanoÎc acid

Step A:

300 mg ethyl (2i?)-3-[2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chloro-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(6-fluoro-3-pyridyl)thieno[2,3d]pyrimidin-4-yl]oxy-propanoate (see Step A of Example 607) (0.35 mmol) and 258 pL 2methoxyethanamine (3.50 mmol) were heated at 150°C in a micro wave reactor until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude product was purified via flash chromatography using EtOAc and MeOH as

17193 *

-386eluents lu give ethyl (2/?)-3-[2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chloro2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-[6-(2-nrethoxyethylamino)-3pyridyl]thieno[2,3-i/jpyrimidin-4-yl]oxy-propanoate.

Step B:

The product of Step A was hydrolyzed according to Step B of General Procedure (XVIIIa) and the diastereoisomer eluting later was collected as Example 620. HRMS calculated for C45H53CIN8O6S: 868.3497; found 435.1839 (M+2H).

Example 621 (27?)-3“{2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl}-2-[((55'„)-5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-{6-[2-(morpholin-4yl)e±oxy]pyridin-3-yl}thieno[2,3-i/]pyrimidin-4-yl)oxy]piOpanoic acid

Step A:

260 mg ethyl (2J?)-3-[2-[(l-butyl-lH-pyrazol-5-yl)inethoxy]phenyl]2-[5-[3-chloro-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyI]-6-(6-fluoro-3-pyridyl)thieno[2,3rf)pyrimidin-4-yl]oxy-propanoate (Step A of Example 607) (0.31 mmol), 405 mg 2(morpholin-4-yl)ethanol (3.10 mmol) and 293 mg césium carbonate (0.93 mmol) were stirred at 60°C in 10 mL dry /e/ Abutanol until no further conversion was observed. Brine was added and the mixture was extracted with DCM. The combined organic phases were washed with brine, then dried over MgSO₄, and concentrated under reduced pressure. The residue was purified via flash chiomatography using EtOAc and MeOH as eluents to give ethyl (27?)-3-[2-[(l-butyl-lH-pyrazol-5-yI)methoxy]phenyl]-2-[5-[3-chloro-2-methyl-4-[2(4-methylpiperazin-Lyl)ethoxy]phenyl]-6-[6-(2-morpholinoethoxy)-3-pyridyl]thieno[2,325 i/|pyrim idin-4-yl] oxy-propanoate.

Step B:

The product of Step A was hydrolyzed according to Step B of General Procedure (XVIIIa) and the diastereoisomer eluting later was collected as Example 621. HRMS calculated for

C48H57CIN8O7S: 924.3759; found 463.1961 (M+2H).

♦

-387Example 622 (2/2)-3-{2-[(l -butyl-l H-pyrazol-5-yl)methoxy]phenyl}-2-[((55_ü)-5- {3chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)cthoxy]phcnyl}-6-[6-(2-methoxyethoxy) pyridin-3-yl]thieno[2,3-i7Jpyrimidin-4-yl)oxy]propanoic acid

Step A:

200 mg ethyl (2/?)-3-[2-[(l “butyl-l H-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chloro-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(6-fluoro-3-pyridyl)thieno[2,3£/|pyrimidin-4-yl]oxy-propanoate (see Step A of Example 607) (0.24 mmol), 56 pL 2methoxyethanol (0.72 mmol) and 232 mg césium carbonate (0.72 mmol) were stirred at

70°C in 5 mL dry Zert-butanol until no further conversion was observed. Brine was added and the mixture was extracted with DCM. The combined organic phases were washed with brine, then dried over MgSO₄, and concentrated under reduced pressure. The residue was purified via flash chromatography using EtOAc and MeOH as eluents to give ethyl (2/2)-3[2- [( 1 -butyl-1 H-pyrazol-5 -yl)methoxy]phenyl] -2- [5 - [3 -chloro-2-methyl-4- [2 -(415 methylpiperazin-1 -yl)ethoxy]phenyl]-6-[6-(2-methoxyethoxy)-3-pyiidyl]thieno[2,3«dpyrimidi n-4-yl]oxy-propanoate.

Step B:

The product of Step A was hydrolyzed according to Step B of General Procedure (XVIIIa) 20 and the diastereoisomer eluting later was collected as Example 622. HRMS calculated for C4₅H52C1N₇O₇S: 869.3337; found 435.6737 (M+2H).

General procedure (XXa)

The appropriate acid was dissolved in éthanol (20 mL/g) contaînîng 1% cc. sulfùric acid and the mixture was stirred at 70°C until no further conversion was observed. Water was added to the mixture and it was neutralized with NaHCO3, extracted with DCM. the combined organic phases were dried with Na2SO₄ and concentrated under reduced pressure. The crude ester was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

17193 φ t

- 388 Example 623 ethyl (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{[l(propan-2-yl)-lH-pyrazol-5-yl]methoxy}phenyl)piOpanoate

Starting from Example 182 using General procedure (XXa) Example 623 was obtained.

HRMS calculated for C^CIFNôOôS: 816.2872; found 409.1516 (M+2H)

Example 624 ethyl (27()-2- {[(5^)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{[l-(propan10 2-yl)-lH-pyrazol-5-yl]methoxy}phenyl)propanoate

Starting from Example 71 using General procedure (XXa) Example 624 was obtained.

HRMS calculated for C^FLisCIFNôOsS: 826.3079; found 414.1627 (M+2H)

Example 625 ethyl (2/?)-2-{[(55’₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-i7]pyrimidin-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxy]phcnyl} propanoatc

Starting from Example 176 using General procedure (XXa) Example 625 was obtained.

HRMS calculated for C41H42CIFN6O7S: 816.2508; found 817.2629 (M+H)

Example 626 ethyl (2/?)-2-{[(5₁S^, _a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-<7]pyrimidm-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxy]phenyl}propanoate

Starting from Example 54 using General procedure (XXa) Example 626 was obtained.

HRMS calculated for C43H44CIFN6O6S: 826.2716; found 414.1440 (M+2H)

Example 627 ethyl (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-niethylpiperazin-l30 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i7]pyrimidin-4-yl]oxy}-3-(2-methoxy phenyl)propanoate

- 389Starting from Example 209 using General procedure (XXa) Example 627 was obtained. HRMS calculated for C36H39CIN4O6S: 690.2279; found 691.2347 (M+H)

Example 628 ethyl (2^)-2-(((5^)-5-{3-chloro-2-methyl-4-(2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-ù0pyrimidin-4-yl]oxy}-3-{2-((2J?)tetrahydrofuran-2-yl m ethoxy] phenyl }propanoate

Starting from Example 2 using General procedure (XXa) Example 628 was obtained.

HRMS calculated for C42H46CIFN4O6S: 788.2811; found 789.2875 (M+H)

Example 629 ethyl (27?)-2-{[(55_a)-5-{3-chioro-2-methyl-4-[2-(inorpholin-4yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(2R)tetrahydrofuran-2-ylmethoxy]phenyl}propanoate

Starting from Example 648 using General procedure (XXa) Example 629 was obtained. HRMS calculated for C^Î-hijClFNjOyS: 775.2494; found 776.2560 (M+H)

Example 630 ethyl (27?)-2-{[(5>S)_Î)-5-{3-cMoro-4-[2-(dimethylamîno)ethoxy]-2methylphenyl}-6-(4-fluorophenyl)thieno(2,3-if]pyriniidin-4-yl]oxy}-3-{2-[(2R)tetrahydrofuran-2-ylmethoxy]phenyl} propanoate

Starting from Example 126 using General procedure (XXa) Example 630 was obtained. HRMS calculated for Cs^iCIFNîOôS: 733.2389; found 734.2469 (M+H)

Example 631 ethyl (2R)-2-{[(5>%)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-c?]pyrimidin-4-yl]oxy}-3-[2-(pyrazin-2ylmethoxy)phenyl]propanoate

Starting from Example 91 using General procedure (XXa) Example 631 was obtained.

HRMS calculated for C42H42CIFN6O5S: 796.2610; found 797.2695 (M+H)

-390Example 632 ethyl (25)-2-{[(55,)-5-{3-chloio-2-methyl-4-[2-(morpholin-4yl)ethoxy]phenyl}-6-(4-fluorophenyl)thïeno[2,3-i/]pyrimidin-4-yl]oxy}-3-[2-(pyi^,azin-2ylmethoxy)phenyl]propanoate

Starting from Example 148 using General procedure (XXa) Example 632 was obtained. HRMS calculated for C₄|H₃9C1FN₅O6S: 783.2294; found 784.2387 (M+H)

Example 633 ethyl (2/?)-2-{[(50^, ₍₇)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl)-6-(thiophen-3-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(210 methoxyphenyl)piopanoate

Starting from Example 568 using General procedure (XXa) Example 633 was obtained.

HRMS calculated for C₃6H₃9C1N₄O_sS₂: 706.2050; found 707.2111 (M+H)

Example 634 ethyl (25)-2-{[(55_fl)-5-{3-chloro-4-[2-(dimethylamino)ethoxy]-2methylphenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-(2,2,2trifl uorocthoxy)phcnyl] propanoatc

Starting from Example 127 using General procedure (XXa) Example 634 was obtained.

HRMS calculated for C₃₆H3₄C1F₄N₃O5S: 731.1844; found 732.1929 (M+H)

Example 635 ethyl (25)-2-{[(55z)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fhiorophenyl)thieno[2_s3-i7]pyrimidm-4-yl]oxy} -3-(2-(2,2,2trifluoroethoxy)phenyl]propanoate

Starting from Example 3 using General procedure (XXa) Example 635 was obtained.

HRMS calculated for C₃9H3₉C1F₄N₄O₅S: 786.2266; found 787.2334 (M+H)

Example 636 ethyl (25)-2-{[(55_fl)-5-(3-chloro-4-hydroxy-2-methylphenyl)-6-(thiophen-330 yl)thieno[2,3-</jpyrimidin-4-yl]oxy}-3-(2-methoxyphenyl)propanoate

-391Starting from Example 715 using General procedure (XXa) Exampie 636 was obtained.

HRMS calculated for C29H25CIN2O5S2: 580.0893; found 581.0953 (M+H)

Example 637 ethyl (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(morpholin-4yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-<7]pyrimidin-4-yl]oxy}-3-[2-(2,2,2trifluoroethoxy)phenyl]propanoate

Starting from Example 657 using General procedure (XXa) Example 637 was obtained.

HRMS calculated for CssHse^NaOeS: 773.1949; found 774.2023 (M+H)

Example 638 ethyl (27?)-2-{[(5S₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-(2-{[2-(2,2_>2trifluoroethoxy)py ri midin-4-y ljmethoxy} phenyl)propanoate

Starting from Example 58 using General procedure (XXa) Example 638 was obtained.

HRMS calculated for C^H^C^NeOeS: 894.2589; found 895.2688 (M+H)

Example 639 ethyl (2iî)-2-{[(5S^, _i,)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-iZ]pyrimidm-4-yi]oxy}-3-(2-{[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}phenyI)propanoate

Starting from Example 30 using General procedure (XXa) Example 639 was obtained.

HRMS calculated for CÆCIFNôOôS·. 902.3029; found 452.1594 (M+2H)

Exampie 640 2,3-dihydro-lH-inden-5-yl (2R)-2-{[(5S^, ₀)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l“yl)ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno[2,3-<7]pyrimidin-4yl]oxy}-3-(2-methoxyphenyl)propanoate mg (2Æ)-2-[(5S_a)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6(4-fluoiOphenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoic acid (Example 1) (0.10 mmol), 20 mg 2,3-dihydro-lH-inden-5-ol (0.15 mmol), 0.028 mL triethylamine (0.20 mmol) and 78 mg PyBOP (0.15 mmol) wcrc dissolved in 3 mL DCM

-392and the reaction mixture was stirred at room température until no further conversion was observed. Water was added and the mixture was extracted with DCM, and the combined organic phases were dried with Na₂SO₄ and concentrated under reduced pressure. The crade ester was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents resulting Example 640. HRMS calculated for C45H44CIFN4O5S: 806.2705; found 807.2820 (M+H)

Example 641 2,2,2-trifluoroethyl (2/?)-2-{[(55_n)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-</|pyrimidÎn-4yl]oxy}-3-(2-methoxyphenyl)propanoate mg (2R)-2-[(55'₀)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6(4-fluorophenyl)thieno[2,3-</]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoic acid (Example 1) (0.10 mmol), 0.011 mL trifluoroethanol (0.15 mmol), 0.028 mL triethylamine (0.20 mmol) and 78 mg PyBOP (0.15 mmol) were dissolved in 3 mL DCM and the réaction mixture was stirred at room température until no further conversion was observed. Water was added and the mixture was extracted with DCM, and the combined organic phases were dried with Na₂SO₄ and concentrated under reduced pressure. The crude ester was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents resulting Example 641. HRMS calculated for C38H3₇C1F₄N₄O₅S: 772.2109; found 773.2188 (M+H)

Example 642 ethyl (2Æ)-2-{[(5S_n)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-iyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-tf]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoate

Starting from Example 1 using General procedure (XXa) Example 642 was obtained. HRMS calculated for Cse^oClFN^jS: 718.2392; found 719.2475 (M+H)

Example 643 {[(2R)-2-{[(5S_o)-5-{3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-<(|pyrimidin-4-yl]oxy} -3-(2methoxyphenyl)propanoyl]oxy}methyl2,2-dimethylpropanoate

-39369 mg (2Æ)-2-[(55J-5“[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2~methoxyphenyl)propanoic acid (Example 1) (0.10 mmol), 15 mg chloromethyl 2,2-dimethylpropanoate (0.10 mmol), 30 mg sodium iodide (0.20 mmol) and 65 mg Cs2COj (0.20 mmol) were dissolved in 1 mL DMF and the reaction mixture was stirred at room température until no further conversion was observed. Water was added and the mixture was extracted with DCM, and the combined organic phases were dried with Na₂SO4 and concentrated under reduced pressure. The crude ester was purified via préparative reversed phase chromatography using 25 mM aqueous TFA solution and MeCN as eluents resulting Example 643. HRMS calculated for C42H46CIFN4O7S: 804.2760; found 805.2822 (M+H)

Example 644 (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl (272)-2-{[(55_a)-5-{3-chloro-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3iZ]pyrimidin-4-yl]oxy}-3-(2-methoxyphenyl)propanoate mg (2Æ)-2-[(5S_a)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl]-6(4-fluorophenyl)thieno[2,3-iZJpyrimidin~4-yl]oxy-3-(2-methoxyphenyl)propanoic acid (Example 1) (0.10 mmol), 15 mg 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one (0.10 mmol), 30 mg sodium iodide (0.20 mmol) and 65 mg Cs₂CÜ3 (0.20 mmol) were dissolved in 1 mL DMF and the reaction mixture was stirred at room température until no further conversion was observed. Water was added and the mixture was extracted with DCM, and the combined organic phases were dried with Na₂SO₄ and concentrated under reduced pressure. The crude ester was purified via préparative reversed phase chromatography using 25 mM aqueous TFA solution and MeCN as eluents resulting Example 644. HRMS calculated for C41H40N4O8FSCI: 802.2239; found 803.2298 (M+H)

General procedure (XXIa)

Step A:

eq. phénol dérivative, 2 eq. of the appropriate alcohol and 2 eq. PPh3 were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. diterrbuty] azodicarboxylate was added. The

-394mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents.

Step B:

The product of Step A was dîssolved in dioxane-water (l:l, 10 mL/mmol) and 10 eq. LiOH x H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated 10 under reduced pressure, and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

General procedure (XXIb) eq. ester was dîssolved in dioxane-water (1:1, 10 mL/mmol) and 10 eq. LiOH x H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄, concentrated under reduced pressure. If necessary the crude product was purified via préparative reversed phase chromatography using MeCN and 25 mM aqueous NH4HCO3 solution as eluents.

Example 645 (27?)-2-{[(55_i/)-5-(4-{2-[4-(4-aminobutyl)piperazin-l-yl]ethoxy}-3-chloiO-2methylphenyl)-6-(4-fluorophenyl)thieno[2,3-c/]pyrimidin-4-yl]oxy}-3-{2-[(2R)tetrahydrofuran-2-ylmethoxy]phenyl}propanoic acid

Using General procedure (XXIa), ethyl (2/?)-2-[(55,)-5-(3-chloro-4-hydroxy-2-methylphenyl)-6-(4-fluorophenyl)thieno[2,3-c?]pyrimidin-4-yl]oxy-3-[2-[[(2X)-tetrahydrofuran-2yl]methoxy]phenyl]propanoate (Préparation 6r) as the phénol and 2-(4-(4aminobutyl)piperazin-l-yl]ethanol as the appropriate alcohol, Example 645 was obtained. HRMS calculated for C43H₄₉C1FN₅O6S: 817.3076; found 818.3129 (M+H).

-395Example 646 (27î)-2-{[(55_fl)-5-{3-bromo-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

StepA:

531 mg ethyl (27?)-2-[5-bromo-6-(4-fluorophenyl)thieno[2,3-i7}pyrimidin-4-yl]oxy-3-(2methoxyphenyl)propanoate (Préparation 4n) (l .00 mmol), 598 mg [2-bromo-3-methyl-4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]-triisopropyl-silane (Préparation 5o) (1.27 mmol), 71 mg AtaPhos (0.10 mmol) and 652 mg CS2CO3 (2.00 mmol) were dissolved in 8 mL dioxane and 2 mL water, The mixture was heated under nitrogen at 110°C for 15 minutes in a microwave reactor. Then 1.2 mL TBAF (1.20 mmol in 1 M THF) was added and the mixture was stirred for 5 minutes at room température. Then it was diluted with water, acidified to pH 4 with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SÛ4 and concentrated under reduced pressure. The crude intermediate was purified via flash chromatography using heptane and EtOAc as eluents and the diastereoisomer eluting later was collected as ethyl (2Â)-2-[(55_a)5-(3-bromo-4-hydroxy-2-methyl-phenyl)-6-(4-fluorophenyl)thieno[2,3-if]pyrimidin-4yl]oxy-3-(2-methoxyphenyl)propanoate.

Stepjl·

Using the product of Step A as the phénol and 2-(4-methylpiperazin-l-yl)ethanol as the appropriate alcohol in General procedure (XXIa), Example 646 was obtained. HRMS calculated for C36H3<;BrFN4O5S: 734.1574; found 735.1637 (M+H).

Example 647 (2R)-2- {[(55«)-5- {2,3-dichloro-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyi}-6-(4-fluorophenyl)thieno[2,3-iZ]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Step A:

266 mg ethyl (2R)2-[5-bromo-6-(4-fluorophenyI)thieno[2,3-i/]pyiimidin-4-yl]oxy-3-(2methoxyphenyl)propanoate (Préparation 4n) (0.50 mmol), 298 mg l-[2-[2,3-dichloro-4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-methyl-piperazine • 396(Préparation 5p) (0.70 mmol), 35 mg AtaPhos (0.05 mmol) and 489 mg CS2CO3 (1.50 mmol) were dissolved in 4 mL dioxane and 1 mL water, and the mixture was heated under nitrogen at 110°C for 8 minutes in a microwave reactor. Then it was diluted with brine and extracted with DCM. The combined organic phases were dried over Na2SO4, concentrated under reduced pressure, and purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

Step B:

The product of Step A was hydrolyzed according to General Procedure 21b and the diastereoisomer eluting later was collected as Example 647. HRMS calculated for CasHjsClaF^OsS: 710.1533; found 711.1604 (M+H).

Example 648 (2R)-2-{[(55/)-5-{3-chloro-2-methyl-4-[2-(morphoIin-4-yl)ethoxy]phenyl}6-(4-fluorophenyl)thieno [2,3 -d] pyr imidin-4-y ljoxy} -3 - {2- [(2Æ)-tetrahy drofuran-2 ylmethoxy]phenyl}propanoic acid

Using General procedure (XXIa) with ethyl (2R)-2-[(55_fl)-5-(3-chloro-4-hydroxy-2methyl-phenyl)-6-(4-fluorophenyl)thieno[2,3-J]pyrimidin-4-yl]oxy-3-[2-[[(27?)tetrahydrofuran-2-yl]methoxy]phenyl]propanoate (Préparation 6r) as the phénol and 2(morpholin-4-yl)ethanol as the appropriate alcohol, Example 648 was obtained. HRMS calculated for C39H39CIFN3O7S: 747.2181; found 748.2237 (M+H).

Example 649 (2À)-2-{[(5S^,«)-5-{3-chloro-2-methyl-4-[(l-methylpyrrolidin-3yl)methoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-<7]pyrimidin-4-yl]oxy}-3-{2-[(2À)tetrahydiOfuran-2-ylmethoxy]phenyl}propanoic acid (mixture of diastereoisomers)

Using General procedure (XXIa) with ethyl (2/?)-2[(55'_n)-5-(3-chloro-4-hydroxy-2methyLphenyl)-6--(4-fluorophenyl)thierio[2,3“i7]pyrimidin-4-yl]oxy-3-[2-[[(27?)tetrahydiOfuran-2-yl]methoxy]phenyl]propanoate (Préparation 6r) as the phénol and (1methylpyrrolidin-3-yl)methanol as the appropriate alcohol, Example 649 was obtained. HRMS calculated for C39H39CIFN3O6S: 731.2232; found 732.2297 (M+H).

-397Exainple 650 (27?)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[((3 R. or >S)-l-methylpiperidm-3-yl) oxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-{2-[(2Æ)tetrahydrofuran-2-yImethoxy]phenyl}propanoic acid

Using General procedure (XXIa) with ethyl (2Æ)-2-[(5S„)-5-(3-chloro-4-hydroxy-2Tnethyl-phenyl)-6-(4-fluorophenyl)thieno[2,3-<f]pyrimidin-4-yl]oxy-3-[2-[[(2/?)tetrahydrofuran-2-yl]methoxy]phenyl]propanoate (Préparation 6r) as the phénol and 1methylpiperidin-3-ol as the appropriate alcohol, Exemple 650 was obtained as a single diastereoisomer (the absolute configuration of the l-methylpiperidin-3-yI moiety was not determined). HRMS calculated for C39H39CIFN3O6S: 731.2232; found 732.2319 (M+H).

Example 651 (2JÎ)-2-{[(5R_a)-5-{5-chloro-4-metliyl-6-[2-(4-methylpiperazin-lyl)ethoxy]pyridin-3-yl}-6-(4-fluorophenyl)thieno[2,3-ri]pyrimidin-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxy]phenyl} propanoic acid

Using General procedure (XXIa) with ethyl (2A)-2-[5-[5-chloro-4-methyl-6-[2-(4methyIpiperazin-l-yl)ethoxy]-3-pyridyl]-6-(4-fluorophenyl)thieno[2,3-iZ]pyrimidin-4yl]oxy-3-(2-hydroxyphenyl)propanoate (Préparation 8j) as the phénol and (2methoxypyrimidin-4-yl)methanol as the appropriate alcohol Example 651 was obtained as the later eluting diastereoisomer. HRMS calculated for C40H39CIFN7OÎS: 799.2355; found 400.6259 (M+2H).

Example 652 (2À)-2-{[(57?_n)-5-{5-chloro-4-methyl-6-[2-(4-methylpiperazin-lyl)ethoxy]pyridin-3-yl}-6-(4-fluorophenyl)thieno[2,3-ri]pyrimidin-4-yl]oxy}-3-{2-[(lethyl-lI-I-pyrazol-5-yl)methoxy]phenyl}propanoic acid

Using General procedure (XXIa) with ethyl (2R)-2-[5-[5-chloro-4-methyl-6-[2-(4methylpiperazin-l-yl)ethoxy]-3-pyridyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4yl]oxy-3-(2-hydroxyphenyl)propanoate (Préparation 8j) as the phénol and (1-ethyl-lHpyrazol-5-yl)methanol (Préparation 9da) as the appropriate alcohol Example 652 was obtained as the later eluting diastereoisomer. HRMS calculated for C40H41CIFN7O5S: 785.2562; found 393.6355 (M+2H).

-398Example 653 (2R)-2~ {[(55,,)-5- {3-chloro-2-methyl-4-[3-(4-methylpiperazin-1 yl)propyl]phenyl}-6-(4-fluoiOpheny])thieno[2,3-<7]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid and

Example 654 (27?)-2-{[(5Æ_n)-5-{3-chloro-2-methyl-4-[3-(4-methylpiperazin-lyl)piOpyl]phenyl}-6-(4-fluoiOphenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Step A:

531 mg ethyl (2^)-2-[5-bromo-6--(4-fluorophenyl)thieno[2₎3-h]pyrimidin-4-yl]oxy-3-(2methoxyphenyl)propanoate (Préparation 4n) (1.00 mmol), 393 mg l-[3-[2-chloro-3methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]piOpyl]-4-methyl-piperazine (Préparation 5r) (1.00 mmol), 71 mg AtaPhos (0.10 mmol) and 652 mg CS2CO3 (2.00 mmol) were dissolved in 8 mL dioxane and 2 mL water, and the mixture was heated under nitrogen at 110°C for 7 minutes in a microwave reactor. Then it was diluted with brine and extracted with DCM. The combined organic phases were dried over Na2SO₄, concentrated under reduced pressure, and purified via reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

Step B:

The product of Step B was hydrolyzed according to General Procedure 21b. The diastereoisomer eluting earlier was collected as Example 654. HRMS calculated for C37H38CIFN4O4S: 688.2286; found 689.2396 (M+H). The diastereoisomer eluting later was collected as Example 653. HRMS calculated for C37H38CIFN4O4S: 688.2286; found 689.2358 (M+H).

Example 655 (2/?)-2-{[(55_fl)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-<ZJpyrimidin-4-yl]oxy}-3-[2-(3methoxypiOpyl)phenyl]propanoic acid

Step A:

-399l.OO g ethyl (2/?)-2-[(55_rt)-[3-chloro-2-mcthyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-<7|pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 8a) (1.4I mmol) and 594 pL TEA (4.25 mmol) were dissolved in 10 mL dry DCM, then 477 pL trifluoromethylsulfonyl trifluoromethanesulfonate (2.00 mmol) was added and the mixture was stirred at room température for 10 minutes. Then it was concentrated under reduced pressure and the residue was dissolved in 10 mL dry DMSO. 156 mg PdChxdppf (0.21 mmol), 81 mg copper(ï) iodide (0.42 mmol), 1.17 mL 3-methoxyprop-l-yne (14.2 mmol) and 903 mg K3PO4 (3.00 mmol) were added and the mixture was stirred under nitrogen at 80°C for 8 hours. Then it was diluted with EtOAc and filtered through celite. The filtrate was washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The residue was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2R)2-[(5S_a)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenylJ-6-(4fluoropheny l)thieno [2,3 -</]pyrimidin-4-yl]oxy- 3 - [2-(3 -methoxyprop-1 -yny l)pheny 1] propanoate.

Step B:

326 mg ethyl (2Æ)-2-[(5S_a)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-[2-(3methoxyprop-l-ynyl)phenyl]propanoate (0.43 mmol) and 46 mg Selcat Q6 were dissolved in 5 mL methanol, then 187 mg terAbutylamine borane (2.2 mmol) was added and the mixture was stirred at room température until no further conversion was observed. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure,

Step C:

The product of Step B was hydrolyzed according to General procedure (XXIb) to give Example 655. HRMS calculated for C39H42CIFN4O5S: 732.2548; found 733.2614 (M+H).

Example 656 (2R)-2-{[(5S_fl)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyi}-6-(4-fluorophenyl)thieno[2,3-<7]pyrÎmidin-4-yl]oxy}-3-[2-(3methoxyprop-1 -yn-1 -yl)phcnyl]propanoic acid

-400Ethyl (2Æ)-2-[(5S₀)-5“[3-chloro-2-methyl-4-[2-(4-rnethylpiperazin-l-yl)ethoxy]phenyl]-6(4-fluorophenyl)thieno[2,3-</Jpyrimidin-4-yl]oxy-3-[2-(3-methoxypiOp-l-ynyl)phenyl] propanoate (see Step A of Exampie 655) was hydrolyzed according to General procedure (XXIb) to give Example 656. HRMS calculated for C39H38CIFN4O5S: 728.2235; found 729.2301 (M+H).

Example 657 (2/Î)-2-{[(5S_<,)-5-{3-chloro-2-methyl-4-[2-(morpholin-4-yl)ethoxy]phenyl}6-(4-fluorophenyl)thieno[2,3-û']pyiiinidin-4-yl]oxy}-3-[2-(2₅2,2trifluoroethoxy)phenyl] propanoic acid

Using General procedure (XXIa) with ethyl (2R)-2-[5-(3-chloiO-4-hydroxy-2-methylphenyl)-6-(4-fluorophenyl)thieno[2,3-i7]pyrimidin-4-ylJoxy-3-[2-(2,2,2trifluoroethoxy)phenyl]propanoate (Préparation 6s) as the phénol and 2-(morpholin-4yl)ethanol as the appropriate alcohol, Example 657 was obtained as the secondly eluting diastereoisomer. HRMS calculated for C36H32CIF4N3O6S: 745.1636; found 746.1686 (M+H).

Exampie 658 (2/f)-2-{[(5S_fJ-5-{3-chloro-2-methyl-4-[((2 S or R)-l-methylpyrrolidin-2yl)methoxy]phenyl}-6-(4-fluorophenyl)thieno[2_i3-^]pyrimidin-4-yl]oxy}-3-[2-(2_}2,2trifluoroethoxy)phenyl]propanoic acid (single diastereoisomer) and

Example 659 (2/?)-2-{[(5S^, _a)-5-{3-chloro-2-methyl-4-[((2 R or S)-l-methylpyrrolidin-2yl)methoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/lpyrimidin-4-yl]oxy}“3-[2-(2,2,2trifluoroethoxy)phenyl]propanoic acid (single diastereoisomer)

Using General procedure (XXIa) with ethyl (2Æ)-2-[5-(3-chloiO-4-hydroxy-2-methylphenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-(2_}2,2-trifluoroethoxy) phenyijpropanoate (Préparation 6s) as the phénol and l-methylpiperidin-3-ol as the appropriate alcohol a rearrangement was observed during the Mitsunobu coupling. Example 658 and Example 659 were isolated as the thirdly and fourthly eluting diastereoisomers differing in the absolute configuration of the l-methylpyrrolidin-2-yl moiety, which was not determined. Example 658 HRMS calculated for C36H32CIF4N3O5S:

-401 729.1687; found 730.1762 (M+H) and 730.1716 (M+H). Example 659 HRMS calculated for C36H32CIF4N3O5S: 729.1687; found 730.1716 (M+H).

Example 660 (2K)-2- {[(5&)-5-(3-chloro-4-niethoxy-2-methylphenyl)-6-(4fluorophenyl)thieno[2_}3-d]pyriniidin-4-yl]oxy}-3-(2-{[2-(dimethylamino)pyrÎmidin-4yl]methoxy}phenyl)propanoic acid

Using General procedure (XXIa) with ethyl (2Æ)-2-[(55_rt)-5-(3-chloro-4-methoxy-2methyl-phenyl)-6-(4-fluorophenyl)thieno[2,3-i(|pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 81) as the phénol and [2(dimethylamino)pyrimidin-4-yl]methanol (Préparation 9an) as the appropriate alcohol, Example 660 was obtained. HRMS calculated for C36H31CIFN5O5S: 699.1718; found 700.1805 (M+H).

Example 661 (2R)-2- {[(5S_a)-5-(3-chloro4-methoxy-2-methylpheny 1)-6-(4fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[2-(4-methyIpiperazin-lyl)ethoxy}phenyl}propanoic acid

Using General procedure (XXIa) with ethyl (2R)-2-[(5S_a)-5-(3-chloro-4-methoxy-2methyl-phenyl)-6-(4-fluorophenyl)thieno[2,3-(/]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 81) as the phénol and 2-(4-methylpiperazin-lyl)ethanol as the appropriate alcohol, Example 661 was obtained. HRMS calculated for C₃6H₃₆C1FN4O₅S.· 690.2079; found 691.2141 (M+H).

Example 662 (2R)-2-{ [(5&)-5-(3-chloiO-4-methoxy-2-methylphenyl)-6-(4fluorophenyl)thieno[2,3-i(|pyriniidin-4-yl]oxy} -3-(2-(2(dimethylamino)ethoxy]phenyl} propanoic acid

Using General procedure (XXIa) with ethyl (25)-2-[(5S_a)-5-(3-chloro-4-methoxy-2methyl-phenyl)-6-(4-fluorophenyl)thieno[2,3-É7]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 81) as the phénol and 2-(dimethylamino)ethanol

-402as the appropriate alcohol, Example 662 was obtained. HRMS calculated for C33HÎ1CIFN3O5S: 635.1657; found 636.1770 (M+H).

Example 663 (2Æ)-2-{[(55„)-5-(3-chloro-4-methoxy-2-methylphenyl)-6-(4fluorophenyl)thieno[2,3-tZ]pyrimidin-4-yl]oxy} -3-[2-( {1 -[2-(dimethylamino)ethyll-1Hpyrazol-5-yl} methoxy)phenyl]propanoic acid

Using General procedure (XXIa) with ethyl (27?)-2-[(55_a)-5-(3-chloro-4-methoxy-2methyl-phenyl)-6-(4-fluorophenyl)thieno [2,3 -djpyrimidi n-4-y 1] oxy-3 - (2hydroxyphenyl)propanoate (Préparation 81) as the phénol and {l-[2(dimethylamino)ethyl]-lH-pyrazol-5-yl}methanol (Préparation 9dj) as the appropriate alcohol, Example 663 was obtained. HRMS calculated for C37H₃5C1FN$OsS: 715.2031; found 716.2157 (M+H).

Example 664 (27?)-2-{[(55_<,)-5-{3-chloro-5-fluoro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl)-6-(4-fluorophenyl)thieno[2,3-<7Jpyrimidin-4-yl]oxy}-3-(2rnethoxyphenyl)propanoic acid and

Example 665 (2R)-2-{ [(5ÆJ-5-{3-chIoro-5-fluoro-2-inethyl-4[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i7]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Step A:

531 mg ethyl (2R)-2-[5-bromo-6-(4-fluoiOphenyl)thieno[2,3-c(]pyrimidin-4-yl]oxy-3-(2methoxyphenyl)propanoate (Préparation 4n) (1.00 mmol), 380 mg 2-chloro-6-fluoro-3methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5m) (1.33 mmol), 71 mg AtaPhos (0.10 mmol) and 652 mg CS2CO3 (2.00 mmol) were dissolved in 8 mL dioxane and 2 mL water. The mixture was heated under nitrogen at 110°C for 10 minutes in a microwave reactor. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified via flash chromatography, using heptane and EtOAc as eluents to obtain a mixture of diastereoisomers.

-403Step B:

Using the product of Step A as the phénol and 2-(4-methylpiperazin-l-yl)ethanol as the appropriate alcohol in General procedure (XXIa) the diastereoisomer eluting earlier was collected as Example 665. HRMS calculated for C36H35CIF2N4O5S: 708.1985; found 709.2042 (M+H). The diastereoisomer eluting later was collected as Example 664. HRMS calculated for C3₆H35C1F₂N₄O₅S: 708.1985; found 709.2037 (M+H).

General procedure (XXIIa)

Step A:

eq. ethyl (2Æ)-2-[(5S_a)-5-(3-chIoro-4-hydroxy-2-methyi-phenyl)-6-(2-furyl)thieno[2,3c7]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 6d), 2 eq. of the appropriate alcohol and 2 eq. triphenyl phosphine were dissolved in dry toluene (5 ml/mmol), then 2 eq. ditertbutyl azodicarboxylate was added. The mixture was stirred at

50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents.

Step R:

The product of Step A was dissolved in éthanol (5 mL/mmol), then HCl (1.25 M in éthanol) was added (5 mL/mmol) and the mixture was stirred at room température until no further conversion was observed. Most of the éthanol was evaporated under reduced pressure. The réaction mixture was treated carefully with saturated aq. NaHCCh solution and extracted with DCM. The combined organic phases were dried over Na2SO₄ and 25 concentrated under reduced pressure.

Step C:

eq. of the product of Step B, 2 eq. of the appropriate alcohol and 2 eq. triphenyl phosphine were dissolved in dry toluene (5 ml,/mmol), then 2 eq. di/er/butyl 30 azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure

-404and the residue was purified via flash chromatography using ethyl acetate and methanol as eluents.

Step D:

The product of Step C was dissolved in dioxane-water l :l (10 mL/mmol) and 10 eq. LiOH x H₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCI, and extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure, and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

Exampie 666 (25)-2- {[(55_a)-5-(3-chloro-2-methylphenyl)-6-(fuian-2-yl)thieno[2,3J]pyrimidÎn-4-yl]oxy}-3-{2-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}propanoic acid

Step A:

251 mg 5-bromo-4-chloro-6-iodo-thieno[2,3-c/]pyrimidine (Préparation la) (0.668 mmol), 270 mg ethyl (25)-2-hydroxy-3-[2-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]propanoate (Préparation 3bk) (0.8 mmol) and 871 mg Cs₂CO₃ (2.67 mmol) were placed in a flask. 7 mL ter/-butanol was added and the mixture was stirred at 60°C until no further conversion was observed. Then it was concentrated under reduced pressure and purified via flash chromatography using ethyl acetate and methanol as eluents to obtain ethyl (25)-2-(5-bromo-6-iodo-thieno[2,3-</|pyrimidin-4-yl)oxy-3-[2-[2-(4methylpiperazin-1 -yl)ethoxy]phenyl]propanoate.

Step B:

420 mg ethyl (2A)-2-(5-bromo-6-iodo-thieno[2,3-i/]pyrimidin-4-yl)oxy-3-[2-[2“(4-methyl piperazin-l-yl)ethoxy]phenyl]propanoate (0.62 mmol), 360 mg 2-(2-furyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane (1.86 mmol), 606 mg césium carbonate (1.86 mmol), and 74 mg Pd(dppf)Cl₂ (0.124 mmol) were placed in a flask. 8 mL 1,4-dioxane and 2 mL water were added, and the mixture was stirred at 40°C under argon until no further conversion was observed. The réaction mixture was concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution

-405and MeCN as eluents to obtain ethyl (2l?)-2-[5-bromo-6-(2-furyl)thieno[2,3-d]pyrimidin-4yl]oxy-3-[2-[2«(4-methylpiperazin-l-yl)ethoxy]phenyl]propanoate. MS: (M+H) = 615.0.

Step C:

189 mg ethyl (2Æ)-2-[5-bromo-6-(2-furyl)thieno[2,3-iZ]pyrimidin-4-yl]oxy-3-[2-[2-(4methylpiperazin-l-yl)ethoxy]phenyl]propanoate (0.3 mmol) and 146 mg 2-(3-chloro-2methyl-phenyl)-5,5-dimethyl-l,3,2-dioxaborinane (0.6 mmol) were dissolved in 2.5 mL 1,4-dioxane, then 195 mg CS2CO3 (0.6 mmol) dissolved in 0.6 mL water was added followed by 21 mg AtaPhos (0.021 mmol), and the mixture was heated under nitrogen at 110°C in a microwave reactor untii no further conversion was observed. Then it was diluted with brine and extracted with dichloromethane. The combined organic phases were dried over Na₂SO₄, concentrated under reduced pressure, and purified via flash chromatography using dichloromethane and methanol as eluents.

Step D:

The product of Step C was dissolved in 4 mL dioxane-water (1:1) and 126 mg LiOH x H₂O (3.0 mmol) was added. The mixture was stirred at room température untii no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified via préparative reversed phase chromatography using MeCN and 25 mM aqueous NELHCCh solution as eluents. The diastereoisomer eluting later was collected to obtain Example 666. HRMS calculated for C33H₃3C1N₄O₅S: 632.1860; found 633.1962 (M+H)

Example 667 (2S)-2-{[(5A_fl)-5-(3-chloro-2-methylphenyl)-6-(furan-2-yl)thieno[2,3</]pyrimidin-4-yl]oxy}-3-{2-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}piOpanoic acid

Step A:

260 mg 5-bromo-4-chloro-6iodo-thieno[2,3-i/]pyrimidine (Préparation la) (0.69 mmol), 280 mg ethyl (2S)-2-hydiOxy-3-[2-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]propanoate (Préparation 3bo) (0.83 mmol) and 899 mg Cs2CO₃ (2.76 mmol) were placed in a flask. 7 mL /ezï-butanol was added and the mixture was stirred at 60°C untii no further conversion

-406was observed. Then it was concentrated under reduced pressure and purified via flash chromatography using ethyl acetate and methanol as eluents to obtain ethyl (2S)-2-(5bromo-6-iodo--thÎeno[2,3-</Jpyrimidin-4-yl)oxy-3-[2-[2-(4-niethylpiperazÎn-lyl)ethoxy]phenyl]propanoate.

Step B:

420 mg ethyl (2S)-2-(5-bromo-6-iodo-thieno[2,3-(7|pyiimidin-4-yl)oxy-3-[2-[2-(4methylpiperazin-l-yl)ethoxy]phenyl]piOpanoate (0.62 mmol), 360 mg 2-(2-furyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane (l .86 mmol), 606 mg césium carbonate (1.86 mmol), and 74 mg Pd(dppf)C12 (0.124 mmol) were placed in a flask. 8 mL 1,4-dioxane and 2 mL water were added, and the mixture was stirred at 40°C under argon until no further conversion was observed. The reaction mixture was concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain. ethyl (2S)-2-[5-bromo-6-(2-furyl)thieno[2,3-i(]pyrimidin4-yl]oxy-3-[2-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]propanoate. MS: (M+H) = 615.0.

Step C:

189 mg ethyl (2S)-2-[5-bromo-6-(2-furyl)thieno[2,3-<Z]pyrimidin-4-yl]oxy-3-[2-[2-(4methylpiperazin-l-yl)ethoxy]phenyl]propanoate (0.3 mmol) and 146 mg 2-(3-chloro-2methyI-phenyl)-5,5-dimethyl-l,3,2-dioxaborinane (0.6 mmol) were dissolved in 2.5 mL 1,4-dioxane, then 195 mg CS2CO3 (0.6 mmol) dissolved in 0.6 mL water was added followed by 21 mg AtaPhos (0.021 mmol), and the mixture was heated under nitrogen at 110°C in a microwave reactor until no further conversion was observed. Then it was diluted with brine and extracted with dichloromethane. The combined organic phases were dried over Na₂SC>4, concentrated under reduced pressure, and purified via flash chromatography using dichloromethane and methanol as eluents.

Step D:

The product of Step C was dissolved in 4 mL dioxane-water (1:1) and 126 mg LiOH x H₂O (3.0 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases wcrc dried over Na₂SO4 and

-407concentrated under reduced pressure. The residue was purified via préparative reversed phase chromatography using MeCN and 25 mM aqueous NH4HCO3 solution as eluents. The diastereoisomer eluting later was collected to obtain Exampie 667. HRMS calculated for C33H33CIN4O5S: 632.1860; found 633.1959 (M+H)

Example 668 (2/?)-2- {[(55_o)-5- (3-chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl }6-(furan-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(l-methyl-lH-pyrazol-5yl)methoxy]phenyl}propanoic acid

Using General procedure (XXIIa) with 2-(dimethylamino)ethanol as the appropriate alcohol in Step A and (1-methyl-lH-pyrazol-5-yl)methanol as the appropriate alcohol in Step C Example 668 was obtained. HRMS calculated for C35H34CIN5O6S: 687.1918; found 688.1996 (M+H)

Example 669 (2Æ)-2-{[(5S«)-5-{3-chloiO-4-[2-(4-ethylpiperazin-l-yl)ethoxy]-2methylphcnyl}-6-(furan-2-yl)thicno[2,3-J|pyrimidin-4-yl]oxy}-3-[2-(2methoxyethoxy)phenyl]propanoic acid

Using General procedure (XXIIa) with 2-(4-ethylpiperazin-l-yl)ethanol as the appropriate alcohol in Step A and 2-methoxyethanol as the appropriate alcohol in Step C Example 669 was obtained. HRMS calculated for C37H41CIN4O7S: 720.2384; found 721.2455 (M+H)

Example 670 (2Æ)-2-{[(55_a)-5-{3-chloro-4-[2-(4-ethylpiperazin-l-yl)ethoxy]-2methylphenyl}-6-(furan-2-yl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-{2-[(225 methoxypyrimidin-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (XXIIa) with 2-(4-ethylpiperazin-l-yl)ethanol as the appropriate alcohol in Step A and (2-methoxypyrimidin-4-yl)methanol as the appropriate alcohol in Step C Example 670 was obtained. HRMS calculated for C,_toH4)ClN607S: 784.2446;

found 393.1312 (M+2H)

-408Example 671 (2R)-2- {[(5S_e)-5-(3-chloro-2-methyl-4- {2-[4-(propan-2-yl)piperazin-1 yl]ethoxy}phenyl)-6-(furan-2-yl)thieno[2,3-t()pyrimidin-4-yl]oxy}-3-[2-(2methoxyethoxy)phenyl]propanoic acid

Using General procedure (XXIIa) with 2-(4-isopropylpiperazin-l-yl)ethanol as the appropriate alcohol in Step A and 2-methoxyethanol as the appropriate alcohol in Step C Example 671 was obtained, HRMS calculated for C38H43CIN4O7S: 734.2541; found 735.2639 (M+H)

Example 672 (2R)-2-{[(55_n)-5-(3-chloro-2-methyl-4-{2-[4-(propan-2-yl)piperazin-lyl]ethoxy}pheriyl)-6-(furan-2-yI)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (XXIIa) with 2-(4-isopropylpiperazin-l-yl)ethanol as the appropriate alcohol in Step A and (2-methoxypyrimidin-4-yl)methanol as the appropriate alcohol in Step C Example 672 was obtained. HRMS calculated for C41H43CIN6O7S: 798.2602; found 799.2644 (M+H)

Example 673 (27î)-2-[(55_ff)-5-[2,3-dimethyl-4-[2-(4-methylpiperazin-l-yI)ethoxy]phenyl]6-(2-furyl)thieno[2,3-d]pyrimidin-4-yI]oxy-3-[2-(2,2,2-trifluoroethoxy)phenyl]propanoic acid

Step A:

574 mg ethyl (2R)-2-[5-bromo-6-(2-furyl)thieno[2,3-c(]pyrimidin-4-yl]oxy--3-(2tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 4d) (1.0 mmol), 562 mg l-[2[2,3-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-methylpiperazine (Préparation 5s) (1.5 mmol), 71 mg AtaPhos (0.1 mmol) and 652 mg CS2CO3 (2.0 mmol) were dissolved in a mixture of 5 mL THF and 5 mL water. The reaction was heated under nitrogen at 110°C in a microwave reactor until no further conversion was observed, Then it was diluted with brine, neutralized with 2 M HCl, and extracted with dichloromethane. The combined organic phases were dried over Na₂SO4, concentrated

-409under reduced pressure, and purified via flash chromatography, using ethyl acetate and methanol as eluents.

Step B:

The product of Step A was dissolved in 5 mL éthanol, then 20 mL HCl solution (1.25 M in éthanol) was added and it was stirred at room température until no further conversion was observed. Saturated aq. NaHCOj solution was added carefully and it was extracted with dichloromethane. The combined organic phases were dried over Na2SÛ4, concentrated under reduced pressure, and purified via flash chromatography using ethyl acetate and methanol as eluents to obtain ethyl (2Æ)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazinl-yl)ethoxy]phenyl]-6-(2-furyl)thieno[2,3-iflpyrimidin-4-yl]oxy-3-(2“hydroxyphenyl) propanoate as mixture of diastereoisomers. MS: (M+H) = 641.4.

StepÇi.

The product of Step B was dissolved in 5 mL DMF, 276 mg K₂CO₃ (2.00 mmol) and 232 mg 2,2,2-tiifluoroethyl trifluoromethanesulfonate (l.OO mmol) were added and the mixture was stirred at room température until no further conversion was observed. It was diluted with brine and extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure, and purified via flash chromatography using ethyl acetate and methanol as eluents.

Step D:

The product of Step C was dissolved in 12 mL dioxane-water (1:1) and 300 mg LiOH x H₂O (7.14 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na^SCU and concentrated under reduced pressure. The residue was purified via préparative reversed phase chromatography using MeCN and 25 mM aqueous NH<|HCO₃ solution as eluents. The diastereoisomer eluting later was collected as Exampie 673. HRMS calculated for C₃6H₃₇F₃N4O₆S: 710.2386; found 711.2442 (M+H)

- 410 Example 674 (2R)-2-{ [5-(3-chloro-4-hydroxy-2-methylplienyl)-6-(furan-2-yl)thieno[2,3t7]pyrimidin-4-yl]oxy}-3-[2-(pyridiii-2-ylmethoxy)phenyl]piOpanoic acid

Step A:

488 mg 5-bromo-4-chloro-6-(2-furyl)thieno[2,3-i/Jpyrimidine (Préparation 2c) (1.3 mmol), 471 mg ethyl ethyl (27?)-2-hydroxy-3-[2-(2-pyridylmethoxy)phenyi]piOpanoate (Préparation 3bn) (1.56 mmol) and 1.27 g Cs₂CO₃ (3.9 mmol) were placed in a flask. 20 mL te/Ÿ-butanol was added and the mixture was stirred at 70°C until no further conversion was observed. The solvent was evaporated under reduced pressure, the residue was diluted with water, the pH was set to 8 with 2 M HCl, and then it was extracted with DCM. The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure, and purified via flash chromatography using heptane and ethyl acetate as eluents.

Step B:

The product of Step A and 83.27 mg 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yI)phenol (Préparation 5a) (0.31 mmol) were dissolved in 2 mL THF, then 252 mg CS2CO3 (0.78 mmol) dissolved in 2 mL water was added followed by 18 mg AtaPhos (0.03 mmol), and the mixture was heated under nitrogen at 100°C in a microwave reactor until no further conversion was observed. It was diluted with ethyl acetate and brine, the organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl acetate as eluents. MS: (M+H) = 641.4.

Step C:

The product of Step B was dissolved in 4 mL dioxane-water (1:1) and 59 mg LiOH x H₂O (1.4 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified via préparative reversed phase chromatography using MeCN and 25 mM aqueous NHL1HCO3 solution as eluents.

The diastereoisomer eluting Iater was collected as Example 674. HRMS calculated for C₃₂H₂₄C1N₃O₆S: 613.1074; found 614.1152 (M+H).

*

-4I1 General procedure (XXI Ha)

Το l eq. of the appropriate ester in MeOH (24 mL/mmol) 28 eq. LiOHxH₂O (5.96 mmol) was added and the mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, ncutralized with 2 M HCI, and extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure and purified via préparative reversed phase chromatography using 0.1% aqueous TFA solution and MeCN as eluents

Example 675 (2/()-3-(1,3-benzodioxol-4-yl)-2-{[(55'_a)-5-(3-chloiO-4-hydiOxy-2methylphenyl)-6-ethylthieno[2,3-ô(|pyrimidin-4-yl]oxy}piOpanoic acid

Ethyl (2/()-3-(1,3-benzodioxol-4-yl)-2-[(55_a)-5-(3-chloro-4-hydiOxy-2-methyl-phenyl)-6ethyl-thieno[2,3-<Z]pyrimidin-4-yl]oxy-propanoate (Préparation 17b) in General procedure (XXIIIa) gave Example 675. HRMS calculated for C^HîiCft^OgS: 512,0809; found 513.0869 (M+H)

Example 676 (25)-3-(1,3-benzodioxol-4-yI)-2-{[(5S_a)-5-(3-chloro-4-hydroxy-2methylphenyl)-6-ethylthieno[2,3-iZ]pyrimidin-4-yl]oxy}propanoic acid

Ethyl (25)-3-(1,3-benzodioxol-4-yl)-2-[(55_a)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6ethyl-thieno[2,3-d]pyrimidin-4-yi]oxy-propanoate (Préparation 17i) in General procedure (XXIIIa) gave Example 676. HRMS calculated for C₂5H₂iC1N₂O6S: 512.0809; found 513.0877 (M+H)

Example 677 (25)-3-(1,3 -benzodioxol-4-yl)-2- {[(5/?_a)-5-(3-chloro-4-hydroxy-2methylphenyl)-6-ethylthieno[2,3-if|pyrimidin-4-yl]oxy}piOpanoic acid

Ethyl (25)-3-(1,3-benzodioxol-4-yl)-2-[(5/(_fl)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6ethyl-thieno[2,3-c(|pyrimidin-4-yl]oxy-piOpanoate (Préparation 17j) in General procedure

-412(XXIIIa) gave Example 677. HRMS calculated for C25H21CIN2O6S: 512.0809; found 513.089 (M+H)

Example 678 (^Rj-S-QB-benzodioxoM-yÎ^-JifJR^-S-p-chloro-A-hydroxy^5 methylphenyl)-6-ethylthieno[2,3-iflpyiïmidin-4-yl]oxy}piOpanoic acid

Ethyl (2Æ)-3-(l,3-benzodioxol-4-yi)-2-[(5Â_a)-5-(3-chloro-4-hydiOxy-2-rnethyl-phenyl)-6ethyl-thieno[2,3-c/]pyriinidin-4-yl]oxy-propanoate (Preparatîonlîa) in General procedure (XXIIIa) gave Example 678. HRMS calculated for C25H21CIN2O6S: 512.0809; found 10 513.0868 (M+H)

Example 679 (2_IS)-2-{[(57?„)-5-(3-chloiO-4-hydroxy-2-methylphenyl)-6-ethylthieno[2,3i7Jpyrimidin-4-yl]oxy} -3-(2-methoxyphenyl)propanoic acid and

Example 680 (25)-2- {[(55_(i)-5-(3-chloro-4-hydroxy-2-methylphenyl)-6-ethylthieno[2,3<7Jpyrimidin-4-yl]oxy} -3-(2-rnethoxyphenyl)propanoic acid

Step A:

0.61 g ethyl (25)-2-(6-ethyl-5-iodo-thieno[2,3-if]pyrimidin-4-yl)oxy-3-(220 methoxyphenyl)propanoate (Préparation 4r) (1.19 mmol), 0.480 g 2-chloro-3-methyl-4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (1.79 mmol), 0.218 g Pd₂(dba)3 (0-24 mmol), 0.171 g BuPAd₂ (0.48 mmol), 1.79 mL BujNOH solution (1.79 mmol, 1 M in water) and 7 mL 2-Me-THF were heated with stining at 110°C under argon for 10 mins in a microwave reactor. The pH of the mixture was set to 6 with 2 M HCl, and 25 then it was extracted with MTBE. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure, and purified via flash chromatography using heptane and EtOAc as eluents, yielding ethyl (25)-2-[5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6ethyl-thieno[2,3-<f]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)piOpanoate as a mixture of diastereomers. MS: (M+H)⁺ = 527.2.

Step B:

- 413 Το 0,529 g of the product of Step A (1.0 mmol) dissolved in 6 mL TIIF-water (1:1) 0.250g LiOHxI^O (5.96 mmol) was added and the mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure and purified via préparative reverse phase chromatography using 0.1% aqueous TFA solution and MeCN as eluents to obtain Example 680 as the product eluting earlier [HRMS calculated for C25H23CIN2O5S: 498.1016; found 499.1079 (M+H)], and Example 679 as the product eluting later [HRMS calculated for C25H23CIN2O5S: 498.1016; found 499.1097 (M+H)].

Example 681 (2Â)-2-{ [(5S_e)5-(3-chloro-4-hydroxy-2-methylphenyl)-6-ethylthieno[2,3i/]pyrimidin-4-y!]oxy}-3-(2-methoxyphenyl)piOpanoic acid and

Example 682 (22?)-2-{[(51?_f/)-5-(3-chloro-4-hydroxy-2-methylphenyl)-6-ethylthieno[2,315 d]pyrimidin-4-yl]oxy}-3-(2-methoxyphenyI)propanoic acid

Step A:

0.50 g ethyl (2Æ)-2-(6-ethyl-5-iodo-thieno[2,3-d]pyrimidm-4-yl)oxy-3-(2methoxyphenyl)propanoate (Préparation 4q) (0.98 mmol), 0.393 g 2-chloro-3-methyl-420 (4,4,5,5-tetramethyl-1,3,2-dioxaboro1an-2-yl)phenol (Préparation 5a) (1.46 mmol), 0.179 g Pd₂(dba)₃ (0.2 mmol), 0.140 g BuPAd₂ (0.39 mmol), 1.46 mL BU4NOH solution (1.46 mmol, 1 M in water) and 5 mL 2-Me-THF were heated under nitrogen with stirring at 110°C for 10 mins in a microwave reactor. The pH of the mixture was set to 6 with 2 M HCl, and then it was extracted with MTBE. The combined organic phases were dried over 25 Na2SO₄, concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to yield ethyl (27?)-2-[5-(3-chloro-4-hydroxy-2-methylphenyl)-6-ethyl-thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate as a mixture of diastereomers. MS: (M+I-l)⁺ = 527.2.

Step B:

To 0.454g of the product of Step A (0.86 mmol) dissolved in 6 mL THF-water (1:1) 0.250g LiOHxH₂O (5.96 mmol) was added and the mixture was stirred at room

-414température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na^SCL, concentrated under reduced pressure, and purified via préparative reverse phase chromatography using 0.1% aqueous TFA solution and MeCN as eluents to obtain Example 682 as the product eluting earlier [HRMS calculated for C25H23CIN2O5S: 498.1016; found 499.1091 (M+H)⁺], and Example 681 as the product eluting later [HRMS calculated for C2₅H23C1N₂O₅S: 498.1016; found 499.1074 (M+H)⁴].

Example 683 (2<S)-2-[(5R_n)-(5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-ethylthieno[2,3-i7}pyriniidin-4-yl)oxy]-3-(2methoxyphenyl)propanoic acid

StepA:

0.2 g (25)-2- {[(5Jf_a)-5-(3-chloiO-4-hydiOxy-2-methylphenyl)-6-ethylthieno[2,3i(]pyrimidin-4-yl]oxy}-3-(2-methoxyphenyl)propanoic acid (Example 679) (0.4 mmol) was dissolved in 2 mL dry methanol and 20 pL concentrated sulfirric acid was added and it was stirred at room température until no further conversion was obseived. Then the mixture was concentrated, the residue was dissolved in EtOAc and it was washed with saturated aq. NaHCO3 solution. The organic layer was dried over Na₂SÛ4 and concentrated under reduced pressure to give methyl (25)-2-{[(57?_a)-5-(3-chloro-4-hydroxy-2methylphenyl)-6-ethylthieno[2,3-i7Jpyrimidin-4-yl]oxy}-3-(2-methoxyphenyl)propanoate, which was used without further purification.

Step B:

The mixture of 0.232 g of the product of Step A (0.45 mmol), 0.13 g 2-(4-methylpiperazinl-yl)ethanol (0.9 mmol), 0.208 g ditertbutyl azodicarboxylate (0.9 mmol) and 0.301 g resin bound triphenylphosphine (3 mmol/g, 0.9 mmol) was stirred in 3 mL dry toluene at 50°C until no further conversion was observed. Then the mixture was filtered through a pad of Celite, the pad was washed with EtOAc and the filtrate was concentrated under reduced pressure. The residue was dissolved in 4 mL methanol and 0.108 g LiOHxH₂O (2.57 mmol) was added and the mixture was stirred at room température until no further conversion was obseived. Then it was diluted with brine, neutralized with 2 M HCl. and

-415 extracted with DCM. The combined organic phases were dried over Na2SO4, concentrated under reduced pressure and purified via préparative reverse phase chromatography using 40 mM aqueous NH4OAC solution (pH set to 4 with AcOH) and MeCN as eluents to obtain Example 683. HRMS calculated for C32H37CIN4O5S: 624.2173; found 625.2253 (M+H)⁺.

General procedure (XXIVa)

Step A:

l eq. phénol dérivative, 2 eq. of the appropriate alcohol and 2 eq. PPh₃ were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. difërfbutyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was obseived. The volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents.

Step B:

The obtained intermediate was dissolved in dioxane-waler (l: l, 10 mL/mmol) and 10 eq. LiOHxH₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na2SÛ4, concentrated under reduced pressure, and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

Example 684 (25)-2-{[(55_a)-5-{3-chloro-2-niethyl-4-[2-(piperazin-l-yl)ethoxy]pheny]}-6(prop-1 -yn-1 -yl)thieno[2,3-i7]pyrimidin-4-yl]oxy}-3-(2-methoxyphenyl)propanoic acid

Using General procedure (XXIVa), ethyl (2Æ)-2-[(5S_n)-5-(3-chloro-4-hydroxy-2-methylphenyl)-6-prop-l-ynyl-thieno[2,3-</]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate (Préparation 61) as the phénol and 2-piperazin-l-ylethanol as the appropriate alcohol Example 684 was obtained. HRMS calculated for C32H33CIN4O5S: 620.1860; found 621.1944 (M+H).

-416Example 685 (2R)-2-{[(55^)-5-{3-chloiO-2-methyl-4-[2-(morpholin-4-yl)ethoxy]phenyl}6-(prop-1 -yn-1 -yl)lhieno[2,3-i/]pyrimidin-4-yl]oxy} -3-(2-methoxyphenyl)propanoic acid

Using General procedure (XXIVa), ethyl (2Æ)-2-[(5S„)-5-(3-chloiO-4-hydroxy-2-methylphenyl)-6-piOp-l-ynyl-tliieno[2,3-i7]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate (Préparation 61) as the phénol and 2-(morpholin-4-yl)ethanol as the appropriate alcohol Example 685 was obtained. HRMS calculated for C32H32CIN3O6S: 621.1700; found 622.1776 (M+H).

Example 686 (2Æ)-2-([(57?_a)-5-{3-fluoro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl} -6-(prop-1 -yn-1 -yl)thieno[2,3-i/]pyrimidin-4-yl]oxy} -3 -(2methoxyphenyl)propanoic acid and

Example 687 (2/?)-2-{[(55₀)-5-{3-fluoro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl) -6-(prop-1 -yn-1 -yl)thieno[2,3-d]pyriniidin-4-yl]oxy} -3 -(2methoxyphenyl)propanoic acid

Step A:

522 mg ethyl (2A)-2-(5-iodo-6-prop-l-ynyl-thieno[2_:3-i/jpyrimidin-4-yl)oxy-3-(2methoxyphenyl)propanoate (Préparation 4k) (1.00 mmol), 378 mg 2-fluoro-3-methyl-4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5g) (1.50 mmol), 73 mg PdCl₂*dppf (0.10 mmol) and 489 mg Cs₂CO₃ (1.50 mmol) were dissolved in 8 mL dioxane and 2 mL water. The mixture was heated under nitrogen at 110°C for 10 minutes in a microwave reactor. The reaction was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SC>4, concentrated under reduced pressure and purified via flash chromatography, using heptane and EtOAc as eluents to give a mixture of diastereoisomers.

Step B:

Using General procedure (XXIVa) with the product of Step A as the phénol and 2-(4methylpiperazin-l-yl)ethanol as the appropriate alcohol Example 686 and Example 687 were obtained. The diastereoisomer eluting earlier was collected as Example 686. HRMS

-417calculaled for C33H35FN4O5S: 618.2312; found 619.2398 (M+H). The diastereoisomer eluting later was collected as Exampie 687. HRMS calculated for C33H35FN4O5S: 618.2312; found 619.2396 (M+H).

Exampie 688 (2/2)-2-{[(5J?_e)-5-{3-chloro-2-methyl-4-[2-(moipholin-4-yl)ethoxy]phenyl}5 6-(5-fluoiOfuran-2-yl)thieno[2,3-d]pyrÎmidin-4-yl]oxy}-3-[2-(2,2,24rifluoroethoxy) phenyl]propanoic acid

Step A:

667 mg of ethyl (2Æ)-2-[(57?_a)-5-(3-chloiO-4-hydiOxy-2-methyl-phenyl)-6-(5-fluoro-210 fuiyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2-y]oxyphenyl)piOpanoate (Préparation 6q) (1.00 mmol), 262 mg 2-(morpholin-4-yl)ethanol (2.00 mmol), and 525 mg PPh₃ (2.00 mmol) were dissolved in 5 mL dry toluene, then 461 mg diter/butyl azodicarboxylate (2.00 mmol) was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced 15 pressure and the residue was purified via flash chromatography using EtOAc and methanol as eluents to give ethyl (2/?)-2-[(5/?_a)-5-[3-chloro-2-methyl-4-(2morpholinoethoxy)phenyl]-6-(5-fluoro-2-furyl)thieno[2,3-//]pyiimidin-4-yl]oxy-3-(2 tetrahydropyran-2-yloxyphenyl)propanoate.

Step B:

The product of Step A was dissolved in 35 mL IIC1 (1.25 M in EtOH) and the mixture was stirred at 60°C for 2h. Saturated aq. NaHCO₃ solution was added to the reaction mixture, and it was extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure and purified via flash chromatography using DCM 25 and methanol as eluents to give ethyl (2Æ)-2-[(5Æ„)-5-[3-chloro-2-rnethyl-4-(2-(morpholin4-yl)ethoxy)phenyl]-6-(5-fluoro-2-furyl)thieno[2,3-iZ]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate.

Step C:

The product of Step B (232 mg, 0.34 mmol) was dissolved in 2 ml DMF, 138 mg K₂CO₃(1.0 mmol) and 77 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.0 mmol) were

-418added. The mixture was stirred at room température under nitrogen for 7 hours. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The obtained ester was dissolved in 5 mL dioxane-water (l:l) and 142 mg Li0H*H₂O (3.40 mmol) was added. The mixture was stirred at room température for l hour, then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄, concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and MeCN as eluents to give Exampie 688. HRMS calculated for C34H30CIF4N3O7S: 735.1429; found 736.1469 (M+H)

Example 689 (25)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(moipholin-4-yl)ethoxy]phenyl}6-(5-fluorofuran-2-yl)thieno|2,3-r/Jpyrimidin-4-yl]oxy}-3-[2-(2,2,2trifluoroethoxy)phenyl]propanoicacid

Starting from ethyl (25)-2-[(55₀)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(5-fluoro-2furyl)thicno[2,3-iZ]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 6c) and using the same steps as described for Example 688 gave Example 689. HRMS calculated for C34H30CIF4N3O7S: 735.1429; found 736.1501 (M+H).

Example 690 (25)-2- {[(55,,)-5- {3 -chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(5-fluoiOfuran-2-yl)thieno[2,3-i/]pyi'iniidin-4-yl]oxy}-3-[4-fluoiO-2(methoxymethoxy)phenyl]propanoicacid

Step A:

2.816 g 4-Chloro-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l -yl)ethoxy]phenyl]-6iodo-thieno[2,3-i(]pyrimidine (Préparation 13) (5.00 mmol), 1.634 g ethyl (25)-3-[4fluoro-2-(methoxymethoxy)phenyl]-2-hydroxy-propanoate (Préparation 3bf) (6.00 mmol) and 4.88 g Cs₂CO₃ (15.0 mmol) were placed in a 50 mL flask. 15 mL Ze/7-butanol was added and the mixture was stirred at 35°C under N₂ for 16 hours. The reaction mixture was diluted with water, the pH was set to 7 with 2 M HCl, and it was extracted with DCM. The combined organic phases were dried over Na₂SO₄, concentrated under reduced pressure

-419and purified via flash chromatography using EtOAc and methanol as eluents to obtain ethyl (25)-2-[5-[3-chlorO'2-mcthyl-4-[2-(4-mcthylpipcrazin‘ 1 -yl)cthoxy]phcnyl]-6-iodothieno[2,3-i7)pyrimidin-4-yl]oxy-3-[4-fluoro-2-(methoxymethoxy)phenyI]propanoate as a mixture of diastereoisomers.

Step B:.

1.075 g of the product of Step A (1.35 mmol), 0.856 g 2-(5-fluoro-2-furyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane (4.04 mmol), 0.880 g césium carbonate (2.70 mmol), and 99 mg [l,r-bis(diphenylphoshino)ferrocene]dichloropalladium(II) (0.135 mmol) were dissolved in 12 mL dioxane and 3 mL water, and the mixture was heated under argon at 110°C for 15 min in a microwave reactor. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified via flash chromatography using EtOAc and methanol as eluents to obtain ethyl (27?)-2-[5-[3-chloro-2-methy!-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl]-6(5-fluoro-2-furyl)thieno[2₃3-c/]pyrimidin-4-yl]oxy-3-[4-fluoro-2-(methoxymethoxy) phenyljpropanoate. HRMS calculated for C37H39CIF2N4O7S: 756.2196044; found 757.2255 (M+H).

Step C:

To the solution of 350 mg of the product of Step A (0.462 mmol) in 10 ml methanol 200 mg LiOHxHîO (4.77 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with EtOAc. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure. The residue was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. The diastereomer eluting Iater was collected as Example 690. HRMS calculated for C35H35CIF2N4O7S: 728.1883; found 729.1955 (M+H)

Example 691 (2Æ)-2-{[(5S_<I)-5-{3-chloro-2-methyl-4-[2-(4-methylpipeiazin-lyl)ethoxy]phenyl}-6-(5-fluorofiiran-2-yl)thieno[2,3-if|pyrimidin-4-yl]oxy}-3-[4-fluoro-2(pyrazin-2-ylmethoxy)phenyl]propanoic acid

-420StepA:

mL HCI (1.25 M in EtOII) was added to 396 mg ethyl (2Jî)-2-[5-[3-chloro-2-methyl-4[2-(4-methylpiperazin“l“yl)ethoxyJphenyl]-6-(5-fluoiO-2-furyl)thieno[2₎3-i?^r]pyrÎmidin-4yl]oxy-3-[4'fluoro-2-(methoxymethoxy)phenyl]propanoate (0.522 mmol, product of Step B of Example 690) and the mixture was stirred at room température for 48h. Saturated aq. NaFICO₃ solution was added to the reaction mixture, and it was extracted with EtOAc. The combined organic layers were dried over Na₂SO₄ and concentrated. The residue was purified via flash chiOmatography using DCM and methanol as eluents to give ethyl (2R)2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(5-fluoiO-2ftiryl)thieno[2,3-i7]pyrimidin-4-yl]oxy-3-(4-fluoro-2-hydroxyphenyl)propanoate. HRMS calculated for C3₅H₃₅ClF₂N4O₆S.· 712.1933897; found 713.2005 (M+H).

Step B:

200 mg of the product of Step A (0.281 mmol), 61.8 mg pyrazin-2-ylmethanol (0.562 mmol) and 147 mg PPh₃ (0.562 mmol) were dissolved in 2 mL dry toluene, then 129 mg di/er/butyl azodicarboxylate (0.562 mmol) was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crade intermediate was purified via flash chromatography using EtOAc and MeOH as eluents.

Sien C:

The product of Step B was dissolved in 4 mL dioxane-water (1:1) and 109 mg LiOH*H₂O (2.60 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with EtOAc. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. The diastereomer eluting later was collected as Example 691. HRMS calculated for C₃8H₃₅CIF₂N₆O₆S: 776.1995; found 777.209 (M+I-I)

-421 Example 692 (2Æ)-2-{[(5S₀)-5-(3-cHoro-2-methyl-4-[2-(4-methy!piperazin-lyl)cthoxy]phcnyl}-6-(5-fluorofuran-2-yl)thieno[2,3-iZ]pyrimidin-4-yl]oxy}-3-(4-fluoro-2methoxyphenyl)propanoic acid

Step A:

200 mg ethyl (27?)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]6-(5-fluoro-2-furyl)thieno[2,3-i7]pyrimidin-4-yl]oxy-3-(4-fluoro-2-hydroxyphenyl) propanoate (Step A of Example 691, 0.281 mmol), 22.7 μΐ methanol (0.562 mmol) and

147 mg PPh3 (0.562 mmol) were dissolved in 2 mL dry toluene, then 129 mg ditertbutyl 10 azodicarboxylate (0.562 mmol) was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents.

Step B:

The product of Step A was dissolved in 4 mL dioxane-water (1:1) and 109 mg LiOH*H₂O (2.60 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with EtOAc. The combined organic phases were dried over Na?SO₄ and 20 concentrated under reduced pressure. The residue was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

The diastereomer eluting later was collected as Example 692. HRMS calculated for C34H33C1F₂N₄O₆S: 698.1777; found 699.1846 (M+H)

Example 693 (2R)-2-{[(55_o)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l 25 yl)ethoxy]phenyl}-6-(6-fluoropyridin-3-yl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-(2-{[](2,2,2-trifluoroethyl)-lH-pyrazol-5-yl]methoxy)phenyl)piOpanoic acid

Step A:

2.88 g ethyl (27?)-2-[5-[3-chloro-2-methyl-4-[2-(4-niethylpiperazin-l-yl)ethoxy]phenyl]-630 iodo-thieno[2,3-(Z]pyrimidin-4-yl]oxy-3-(2-hydiOxyphenyl)piOpanoate (Préparation 26b) (4 mmol), 1.80 g [l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl]methanol (Préparation 9du)

17193 φ

-422(ΙΟ mmol) and 2.62 g PPh₃ were dissolved in dry toluene (0.2 M for Préparation 26b), then 2.30 g dizer/butyl azodicarboxylate was added. The mixture was stirred at 50°C under argon atmosphère. After reaching appropriate conversion the volatiles were evaporated under reduced pressure and the crude ester was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (27?)-2-[5-[3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl]-6-iodo-thieno[2,3-<7]pyrimidin-4-yl]oxy-3-[2-[[l(2,2,2-trifluoiOethyl)-lH-pyrazol-5-yl]methoxy]phenyl]propanoate.

Step B:

1.35 g of the product of Step A (1.5 mmol), 254 mg (6-fluoro-3-pyridyl)boronic acid (1.8 mmol), 110 mg Pd(dppf)C12 (0.15 mmol) and 1.59 g césium carbonate (4.5 mmol) were dissolved in 10 mL THF-water (1:1 ). The mixture was heated under nitrogen at 100°C in a microwave reactor untii no further conversion was observed. Then it was diluted with brine and extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crade product was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2Æ)-2-[5-[3-chloro-2methyl-4“[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(6-fluoiO-3-pyridyl)thieno[2,3-d] pyrimidin-4-yl]oxy-3-[2-[[2-(2,2,2-trifluoiOethyl)pyrazol-3-yl]methoxy]phenyl] propanoate.

Step C:

250 mg of the product of Step B (0.29 mmol) was dissolved in 3 mL dioxane-water (1:1, 10 mL/mmol) and 122 mg LiOH x H₂O (2.9 mmol, 10 eq.) was added. The mixture was stirred at room température untii no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄ and concentrated. The residue was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO₃ solution and MeCN as eluents. The diastereoisomer eluting later was collected as Example 693. HRMS calculated for C40H38CIF4N7O5S: 839.2280; found 840.2366 (M+H) «

-423Examplc 694 (2j?)-2-[((5S_fl)-5-{3-chloro-2-mcthyl-4-[2-(4-mcthylpiperazin-lyl)ethoxy]phenyl}-6-[6-(2-methoxyethoxy)pyridin-3-yl]thieno[2,3-c/]pyrimidin-4-yl)oxy]3-(2- {[ î -(2,2,2-trifluoroethyl)- lH-pyrazol-5-yl]methoxy }phenyl)propanoic acid

Step A:

416 mg ethyl (2Æ)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yI)ethoxy]phenyl]6-(6~fluoro-3-pyridyl)thieno[2,3-i/jpyrimidin-4-yl]oxy-3-[2-[[l-(2,2,2-trifluoroethyl)-lHpyrazol-5-yl]methoxy]phenyl]propanoate (product of Step B of Exampie 693) (0.48 mmol), 112 pL 2-methoxyethanoI (1.44 mmol) and 464 mg césium carbonate (1.44 mmol) were stirred at 70°C in 5 mL dry /er/-butanol until no further conversion was obsei'ved. Brine was added and the mixture was extracted with DCM. The combined organic phases were washed with brine, then dried over MgSO₄ and concentrated under reduced pressure. The residue was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2Æ)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6[6-(2-methoxyethoxy)-3-pyridyl]thieno[2,3-J]pyrimidin-4-yl]oxy-3-[2-[[l-(2,2,2trifluoroethyl)-1 H-pyrazol-5-yl]mcthoxy]phcnyl]propanoatc.

StejiBi

The product of Step A was hydrolyzed according to Step C of Example 693; the diastereoisomer eluting later was collected as Example 694. HRMS calculated for C4₃H45C1F₃N7O₇S: 895.2742; found 896.2801 (M+H)

Example 695 (2Λ)-2-[((55_η)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]thieno[2,3-if]pyrimidin-4yl)oxy]-3-(2- {[ 1 -(2,2,2-trifluoroethyl)-l H-pyrazol-5-yl]methoxy }phenyl)propanoic acid

Step A:

434 mg ethyl (2A)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenylJ6-(6-fluoro-3-pyridyl)thieno[2,3-i7]pyrimidin-4-yl]oxy-3-[2-[[l-(2,2,2-trifluoroethyl)-lHpyrazol-5-yl]methoxy]phenyl]propanoate (product of Step B of Example 693) (0.50 mmol), 510 pL 2,2,2-trifluoroethanol (7.0 mmol) and 489 mg césium carbonate (1.5 mmol) were stirred at 70°C in 5 mL dry 'BuOII until no further conversion was observed.

17193 *

-424Brine was added and the mixture was extracted with DCM. The organic phase was washed with brine, then dried over MgSÛ4 and concentrated under reduced pressure. The residue was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2R)-2-[5-[3-chloro-2-metliyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-[6-(2,2,2trifluoroethoxy)-3-pyridyl]thieno[2,3-i/lpyrimidin“4-yI]oxy-3-[2-[[l-(2,2,2trifluoiOethyl)lH-pyrazol-5-yl]methoxy]phenyl]propanoate.

Step B:

The product of Step A was hydrolyzed according to Step C of Example 693; the diastereoisomer eluting later was collected as Example 695. HRMS calculated for C₄2H4oClF₆N₇06S: 919.2353; found 920.2414 (M+H)

Example 696 (2Æ)-2-{[(5S„)-5-{3-chloro-2-methyl-4-[2-(4-methylpïperazin-lyl)ethoxy]phenyl}-6-(6-methoxypyridin-3-yl)thieno[2,3-<7)pyrimidin-4-yl]oxy}-3-(2-{[l(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl]methoxy}phenyl)propanoic acid

Step A:

450 mg (2R)-2-[5- [3 -chloiO-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl] -6iodo-thieno[2,3-i(]pyi'imidin-4-yl]oxy-3-[2-[[l-(2,2,2-trifluoiOethyl)-lH-pyrazol-5yl]methoxy]phenyl]propanoate (product of Step A of Example 693) (0.5 mmol), 92 mg (6methoxy-3-pyridyl)boronic acid (0.6 mmol), 37 mg Pd(dppf)Cl₂ (0.05 mmol) and 530 mg césium carbonate (1.5 mmol) were dissolved in 5 mL THF-water (1:1) and the mixture was heated under nitrogen at 100°C in a microwave reactor until no further conversion was observed. Then it was diluted with brine and extracted with DCM. The combined organic phases were dried over Na2SC>4 and concentrated under reduced pressure. The crude product was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (27?)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l -yl)ethoxy]phenyl]-6(6-methoxy-3-pyridyl)thieno[2,3-â(|pyrimidÎn-4-yl]oxy-3-[2-[[l-(2,2,2-trifluoiOethyl)-lHpyrazol-5-yl]methoxy]phenyl]propanoate

Step B:

-425The product of Step A was hydrolyzcd according to Step C of Example 693; the diastereoisomer eluting later was collected as Example 696. HRMS calculated for C₄|H4iClF₃N₇O₆S: 851.2480; found 852.2514 (M+H)

General procedure (XXVIIa)

Step A:

eq. ethyl (27?)“2-[5-(3-chloro-4-methoxy-2-inethyl-phenyl)-6-(4-fluoro-3-hydroxyphenyl)thieno[2,3-J]pyrimidin-4-yl]oxy-3-[2-[(2-methoxypyrimidin-4-yl)methoxy]phenyl] propanoate (Préparation 28b), 2 eq. of the appropriate alcohol and 2 eq. PPh₃ were 10 dissolved in dry toluene (0.2 M for the phénol), then 2 eq. diteributyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using DCM and MeOH as eluents.

Siep B:

The product of Step A was dissolved in dioxane-water (1:1, 10 mL/mmol) and 10 eq. LiOHxHaO was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic layers were dried over Na2SO₄ and 20 concentrated under reduced pressure. The residue was purified via préparative reversed phase chromatography using 25 mM aqueous NH₄HCO3 solution and MeCN as eluents. The diastereoisomers were separated at this stage.

Example 697 (27?)-2-{[(5R_ff)-5-(3-chloiO-4-methoxy-2-methylphenyl)-6-{4-fluoiO-3-[225 (4-methylpiperazin-1-yl)ethoxy]phenyl}thienof2,3-i(|pyrimidin-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxy]phenyl}piOpanoic acid

Using General procedure (XXVIIa) starting from 2-(4-methylpiperazin-l-yl)ethanol as the appropriate alcohol Example 697 was obtained as the diastereomer eluting earlier. HRMS 30 calculated for C^ClFNeOyS: 828.2508; found 415.1324 (M+2H)

-426Example 698 (25)-2-{[(5S_a)-5-(3-chloro-4-methoxy“2-methylphenyl)-6-{4-f1uoiO-3-[2-(4methylpiperazin-l-yl)elhoxyjphenyl}thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxy]phenyl} propanoic acid

Using General procedure (XXVIIa) starting from 2-(4-methylpiperazin-1 -yl)ethanol as the appropriate alcohol Example 698 was obtained as the diastereomer eluting later. HRMS calculated for C^CIFNôOjS: 828.2508; found 415.1343 (M+2H)

Example 699 (2Æ)-2-{[(5Æ_a)-5-(3-chloiO-4-methoxy-2-inethylphenyl)-6-{4-fluoro-3-[210 (moipholin-4-yl)ethoxy]phenyl)thieno[2,3-dJpyrimidin-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (XXVIIa) starting from 2-(morpholin-4-yl)ethanol as the appropriate alcohol Example 699 was obtained as the diastereomer eluting earlier. HRMS 15 calculated for C41H39CIFN5O8S: 815.2192; found 408.6163 (M+2H)

Example 700 (25)-2-{[(5S_rt)-5-(3-chloro-4-inethoxy-2-methyIphenyl)-6- {4-fluoro-3-[2(morpholin-4-yl)ethoxy]phenyl}thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxy]phenyl}propanoicacid

Using General procedure (XXVIIa) starting from 2-(morpholin-4-yl)ethanol as the appropriate alcohol Example 700 was obtained as the diastereomer eluting later. HRMS calculated for C4iH3₉CIFN₅O₈S: 815.2192; found 408.6173 (M+2H)

Example 701 (27?)-2-{[(55„)-5-(3-chloro-4-methoxy-2-methylphenyl)-6-{3-[2(dimethylamino)ethoxy]-4-fluoiOphenyl}thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (XXVIIa) starting from 2-(dimethylamino)ethanol as the appropriate alcohol Example 701 was obtained as the diastereomer eluting earlier. HRMS calculated for C3₉H3₇C1FN₃O₇S: 773.2086; found 387.6122 (M+2H)

-427Example 702 (2Λ)-2-{[(5S_n)-5-(3-chloro-4-methoxy-2-methylphenyl)-6- {3-[2(dimethylamino)ethoxy]-4-fluorophenyl}thieno[2.3-i7]pyrimidin-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxy]phenyl }propanoic acid

Using General procedure (XXVITa) starting from 2-(dimethylamino)ethanol as the appropriate alcohol Example 702 was obtained as the diastereomer eluting later. HRMS calculated for Cs^ClFNjOvS: 773.2086; found 387.6114 (M+2H)

General procedure (XXXIa)

Step A:

eq. ethyl (2/?)-2-[(55_a)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyJ]-6-(2,3-r/ifluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2-hydroxy phenyl)propanoate (Préparation 8m), 3 eq. of the appropriate alcohol and 3 eq. triphenyl phosphine were dissolved in dry toluene (20 mL/mmol), then 3 eq. diie/7butyi azodicarboxylate was added. The mixture was slirTed at 50°C under N₂ until no further conversion was observed. The volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using DCM and methanol as eluents.

Step R:

The product of Step A was dissolved in dioxane-water (1:1, 10 mL/mmol) and 10 eq. LiOHxH₂O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combibed organic phases were dried over Na2SO₄, concentrated under reduced pressure and purified via préparative reverse phase chromatography using 25 mM aqueous NH₄HCO₃ solution and MeCN as eluents.

Example 703 (27?)-2- {[(55₀)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyI)-6-(2,3-difluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxy]phenyl} propanoic acid

17193 ·

-428 Using General procedure (XXXIa) and (2-methoxypyrimidin-4-yl)methanol as the appropriate alcohol Example 703 was obtained. HRMS calculated for C/hHjôC^NôOgS: 816.2308; found 817.2434 (M+H).

Example 704 (272)-2-{[(55„)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(2,3-difluorophenyl)thieno[2,3-i7]pyrimidin-4-yl]oxy}-3-{2-[(l-ethyllH-pyrazol-5-yl)methoxy]phenyl}propanoic acid

Using General procedure (XXXIa) and (1 -ethyl-lH-pyrazol-5-yl)methanol (Préparation

9da) as the appropriate alcohol Example 704 was obtained. HRMS calculated for C4iH4iClF₂N₆O₅S: 802.2516; found 803.2607 (M+H).

Example 705 (272)-2- {[(55_o)-5- {3 -chloro-2-methyl-4- [2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(2,3-difluorophenyl)thieno[2,3-</|pyrimidin-4-ylJoxy}-3-(2-{[215 (trifluoromethyI)pyrÎmidin-4-yl]methoxy }phenyl)propanoic acid

Using General procedure (XXXIa) and [2-(trifluoromethyl)pyrimidin-4-yl]methanol (Préparation 9bj ) as the appropriate alcohol Example 705 was obtained. HRMS calculated for C_4îH3₆C1F_sN₆O5S: 854.2077; found 855.2121 (M+H).

General procedure (XXXIIa)

Step A:

eq. ethyl (27?)-2-[(55_e)-5-[3-chloiO-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(3,4-difluorophenyl)thieno[2,3-</]pyrimidin-4-yl]oxy-3-(225 hydroxyphenyl)propanoate (Préparation 8k), 2 eq. of the appropriate alcohol and 2 eq. triphenyl phosphine were dissolved in abs. toluene (5 ml/mmol), then 2 eq. di/er/butyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using ethyl acetate and 30 methanol as eluents.

-429SggJL

The product of Step A was dissolved in dioxane-water (l:l, I0 mL/mmol ) and 10 eq, L1OHXH2O was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄, concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

Example 706 (2R)-2- {[(5S_e)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl)-6-(3,4-difluorophenyl)thieno[2,3-i(Jpyrimidin-4-yI]oxy}-3-{2-[(2methoxypyrimidin-4-yj)methoxy]phenyl}propanoic acid

Using General procedure (XXXIIa) and (2-methoxypyrimidin-4-yl)methanol as the appropriate alcohol Example 706 was obtained. HRMS calculated for C4jH39ClF₂N6O6S: 816.2308; found 817.2389 (M+H)

Example 707 (2Λ)-2- {[(55_σ)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(3,4-difluorophenyl)thieno[2,3-i(]pyriinidin-4-yl]oxy}-3-(2-{|2(trifluoromethyl)pyrimidin-4-yl]methoxy} phenylpropanoic acid

Using General procedure (XXXIIa) and [2-(trifluoromethyl)pyrimidin-4-yl]methanol (Préparation 9bj) as the appropriate alcohol Exampie 707 was obtained. HRMS calculated for C41H36CIF5N6O5S: 854.2077; found 855.2146 (M+H)

Example 708 (2R)-2-[[(5S_n)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(3,4-difluorophenyl)thieno[2,3-//]pyrimidin-4-yl]oxy}-3-{2-[(l-ethyl1 H-pyrazol-5-yl)methoxy]phenyl)propanoic acid

Using General procedure (XXXIIa) and (1-ethyl-lH-pyrazol-5-yl)methanol (Préparation 9da) as the appropriate alcohol Example 708 was obtained. HRMS calculated for C41H41CIF2N6O5S: 802.2516; found 803.2561 (M+H)

17193 ·

-430Example 709 (27?)-2-{[(5S'_rt)-5-{3-chloro-2-methyl-4-[2-(4-mcthylpipcrazin-lyl)ethoxy]phenyl}-6-(3-fluoiOphenyl)thieno[2,3-c/]pyriinidin-4-yl]oxy}-3-[2-(piOpan-2yloxy)phenyl]propanoic acid

Step A:

3.75 g 5-biOmo-4-chloiO-6-iodo-thieno[2,3-i'/]pyrùriidine (Préparation la) (10 mmol), 2.44 g 2-(3-fluoro-phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (11 mmol), 8.15 g Cs₂CO₃ (25 mmol), and 366 mg Pd(dppf)Cl₂ (0.5 mmol) were placed in a 250 mL flask. 40 mL THF and 40 mL water were added, and then stirred ovemight at 70°C under N₂. To the reaction mixture brine was added, the pH was set to 6 with 2 M HCl and it was extracted with DCM. The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain 5-biomo-4-chloro-6-(3-fluorophenyl)thieno[2,3Jjpyrimidine. 'H NMR (500 MHz, DMSO-d₆): 9.04 (s, 1H), 7.66-7.60 (m, 2H), 7.56 (d, 1H), 7.44 (td, 1H). HRMS calculated for C_l2H₅ClFBrN₂S: 341.9029; found 342.9093 (M+H).

Step B:

2.62 g of the product of Step A (7.6 mmol), 3.78 g ethyl (2Æ)-2-hydroxy-3-[2-[(4methoxyphenyl)methoxy]phenyl]propanoate (Préparation 3ae) (11.5 mmol) and 7.46 g Cs₂CO3 (22.9 mmol) were placed in a 250 mL flask. 150 mL toï-butanol was added and the mixture was stirred at 60°C under N₂ until no further conversion was observed. Water was added to the mixture and it was extracted with DCM. The combined organic layers were dried over Na₂SO₄, concentrated, and purified via flash chiomatography using heptane and EtOAc as eluents to obtain ethyl (2/?)-2-[5-bromo-6-(3fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-[2-[(4-methoxyphenyl)methoxylphenyI] propanoate. ‘H NMR (500 MHz, DMSO-d₆): 8.67 (s, 1H), 7.62-7.54 (m, 3H), 7.40 (m, 4H), 7.22 (td, 1H), 7.08 (d, 1H), 6.90 (d, 2H), 6.88 (td, 1H), 5.71 (dd, IH), 5.10 (d, 1H), 5.06 (d, 1H), 4.11 (m, 2H), 3.74 (s, 3H), 3.45 (dd, 1H), 3.21 (dd, 1H), 1.10 (t, 3H). HRMS calculated for C3iH₂₆BrFN₂O₅S: 636.0730; found 637.0815 (M+H).

Step C:

-431 0.152 g of the product of Step B (0.24 mmol), 0.160 g 2-chloro-3-methyl-4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Préparation 5a) (0.60 mmol), and 0.017 g Ataphos (0.024 mmol) were dissolved in 1.7 mL 2-Me-THF, and 0.6 mL tetrabutylammonium hydroxide (IM in H₂O, 0.6 mmol) was added. The mixture was heated under nitrogen at 110 °C for 10 min in a microwave reactor. The reaction was diluted with water, the pH was adjusted to 4 by the addition of 2 M HCl, and it was extracted with DCM. The combined organic phases were dried over Na₂SO4 and concentrated under reduced pressure. The mixture of diastereomers was separated via flash chromatography using heptane and EtOAc as eluents. The diastereomer eluting later was collected as ethyl (21?)-2-[(55'«)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(3fluorophenyl)thieno[2,3-i(lpyrimidin-4-yl]oxy-3-[2-[(4-methoxyphenyl)metlioxy]phenyl] propanoate. *H NMR (500 MHz, DMSO-d₆): 10.28 (s, IH), 8.62 (s, IH), 7.41-7.39 (m, 3H), 7.20-7.12 (m, 4H), 7.01-6.96 (m, 3H), 6.90 (d, 2H), 6.71 (td, IH), 6.33 (dd, IH), 5.43 (dd, IH), 5.05 (d, IH), 5.01 (d, IH), 4.03 (q, 2H), 3.73 (s, 3H), 3.04 (dd, IH), 2.46 (dd, IH), 1.79 (s, 3H), 1.04 (t, 3H). HRMS calculated for C38H₃₂C1FN₂O₆S: 698.1654; found 699.1754 (M+H).

Sien D:

0.966 g of the product of Step C (1.4 mmol), 0.60 g 2-(4-methylpiperazin-l-yl)ethanol (4.1 mmol) were dissolved in 20 mL dry toluene, then 1.38 g PPh₃ polymer (3 mmol/g, 4.1 mmol) and 0.95 g di-terAbutyl azodicarboxylate (4.1 mmol) was added. The mixture was stirred at 50°C under N₂ until no further conversion was observed. The polymer was filtered off, toluene was evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2/()-2-((55^)5-(3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yI)ethoxy]phenyl]-6-(3fluorophenyl)thieno[2,3-i(]pyrimidin-4-yl]oxy-3-[2-[(4-methoxyphenyl)methoxy]phenyl] propanoate. 'l-I NMR(500 MHz, DMSO-d₆): 8.64 (s, IH), 7.41-7.38 (m, 3H), 7.29 (d, IH), 7.20-7.12 (m, 4H), 7.03-7.01 (m, 2H), 6.90 (d, 2H), 6.70 (t, IH), 6.31 (dd, IH), 5.42 (dd, IH), 5.04 (d, IH), 5.00 (d, IH), 4.19 (m, 2H), 4.02 (q, 2H), 3.73 (s, 3H), 2.99 (dd, IH), 2.70 (t, 2H), 2.50 (dd, IH), 2.46 (br s, 4H), 2.22 (br s, 4H), 2.08 (s, 3H), 1.82 (s, 3H), 1.02 (t, 3H). HRMS calculated for C4_SH4₆C1FN4O₆S: 824.2811; found 825.2899 (M+H).

17193 *

-432Step E:

0.20 g ofthe product of Step D (0.24 mmol) was dîssolved în 0.5 mL DCM and cooled to 0°C. 4 mL HBr (33 % solution in acetic acid) was added and the mixture was stirred for 10 min. Water was added and the pH was adjusted to 4 by the addition of saturated aq. NaHCO₃ solution. The mixture was extracted with DCM, the combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was dîssolved in 20 mL EtOH and 0.2 mL cc. H₂SO₄ was added. The reaction mixture was stirred at 50°C until no further conversion was observed. Brine was added and the mixture was extracted with DCM. The combined organic phases were dried over Na2SO₄ and concentrated under reduced pressure. The crade product was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2Λ)-2-[(55_α)-5-[3chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(3-fluoiOphenyl)thieno [2,3-cdpyrimidin-4-yl]oxy-3-(2-hydroxyphenyl)propanoate. HRMS calculated for C₃₇H4₆FN₄O₆S: 704.2235; found 705.2307 (M+H).

Step F:

mg of the product of Step E (0.13 mmol), 94 mg PPh₃ (0.39 mmol), 96 mg di/er/butyl azodicarboxylate (0.39 mmol) and 32 pL propan-2-ol (0.39 mmol) were dîssolved in 2 ml dry toluene and the reaction mixture was stirred at 50°C under N₂ until no further conversion was observed. The mixture was concentrated under reduced pressure. The residue was dîssolved in 5 mL MeOH, 252 mg LiOHxH₂O (6.0 mmol) was added and it was stirred at room température until no further conversion was observed. The methanol was evaporated under reduced pressure, water was added to the residue, the pH was adjusted to 4 by the addition of 2 M HCl solution, and it was extracted with DCM. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The crade product was purified via préparative reverse phase chromatography using 25 mM aqueous NH₄HCO₃ solution and MeCN as eluents to obtain Exampie 709. HRMS calculated for C₃₈H₄oClFN₄O_sS: 718.2392; found 719.2469 (M+H).

Example 710 (2/?)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(3-fluorophenyI)thieno[2,3-i(|pyrimidin-4-yl]oxy}-3“{2-[(4-methoxybenzyl) oxyjphenyljpropanoic acid

-433 100 mg of the product of Step D in Example 709 (0.12 mmol) was dissolved in 5 mL MeOH. 252 mg LiOHxH₂O (6 mmol) was added and the mixture was stirred at room température until no further conversion was observed. The methanol was evaporated under reduced pressure, water was added, and the pH was adjusted to 4 by the addition of 2 M HCl. The precipitated crude product was filtered, dried and purified via préparative reverse phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 710. HRMS calculated for C43H4₂C1FN₄O₆S: 796.2498; found 797.2565 (M+H).

Example 711 (2R)-2- {[(5S₀)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(3-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2hydroxyphenyl)propanoic acid

100 mg of the product of Step E in Example 709 (0.14 mmol) was dissolved in 5 mL MeOH, 252 mg LiOH*H₂0 (6 mmol) was added and the mixture was stirred at room température until no further conversion was observed. The methanol was evaporated under reduced pressure, water was added, and the pH was adjusted to 4 by the addition of 2 M HCl. The precipitated crude product was filtered, dried and purified via préparative reverse phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 711. HRMS calculated for C35H34CIFN4O5S: 676,1922; found 677.2005 (M+H).

Example 712 (2Æ)-2-{[(5S_w)-5-{3-chloro-2-methyI-4-[2-(niorpholin-4-yl)ethoxy]phenyl}6-(l-methyl-lH-pyrazol-4-yl)thieno[2,3-d]pyrimidin-4-yl]oxy)-3-phenylpiOpanoic acid

Slep A:

266 mg methyl (2/?)-2-[6-bromo-(55_fl)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)thieno[2,3<7jpyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 22) (0.50 mmol), 312 mg 1methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (1.50 mmol), 488 mg Cs₂CO3 (1.50 mmol), and 54 mg Pd(dppf)CI₂ (0.075 mmol) were dissolved in a mixture of 8 mL 2-Me-THF and 1 mL water and the mixture was heated under nitrogen at 100 ^UC for

17193 ·

-43430 minutes in a microwave reactor. The reaction was diluted with water, the pH was adjusted between 3-4 by the addition of 2 M HCl, and the mixture was extracted with DCM. The combined organic phases were dried over Na₂SO4 and concentrated under reduced pressure. The residue was purified via flash cliiOmatography using DCM and MeOH as eluents to give methyl (2^)-2-[(5S_a)-5-(3-chloro-4-hydtOxy-2-methyl-phenyl)-6(l-methylpyrazol-4-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-phenyl-propanoate. HRMS calculated for C^H^CllSL^S: 534.1129; found 535.1210 (M+H).

Step B:

mg methyl (27?)-2-f(55_n)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(l-methylpyrazol4-yl)thieno[2,3-</Jpyrimidin-4-yl]oxy-3-phenyl-propanoate (0.185 mmol), 97 mg PPhj (0.37 mmol), 85 mg di/er/butyl azodicarboxylate (0.37 mmol) and 53 mg 2-(morpholin-4yl)ethanol (0.37 mmol) were dissolved in 3 ml dry toluene and the reaction mixture was stirred at 50 °C under nitrogen atmosphère for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified via flash chromatography using DCM and MeOH as eluents.

Step C:

The product of Step B was hydrolyzed at room température in 5 mL methanol-water (9:1) containîng NaOH (5m/m%). After completîon the mixture was diluted with water, the pH was adjusted to 6 by the addition of 2 M HCl, and the mixture was extracted with DCM. The combined organic phases were dried over Na₂SO4 and concentrated under reduced pressure. The crude product was purified using reverse phase préparative HPLC resulting Example 712. HRMS calculated for C₃₂H₃₂C1N5O₅S: 633.1813; found 634.1894 (M+H).

Example 713 (2Æ)-2-{[(55_£,)-5-(3-chloiO-4-methoxy-2-methylphenyl)-6-{3-[2-(4methylpiperazin-1 -yl)ethoxy]phenyl} thieno[2,3-d]pyrimidin-4-yl]oxy} -3-(2methoxyphenyl)propanoic acid

Step A:

250 mg ethyl (27?)-2-[(5S„)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-iodo-thieno[2,3<7]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)piOpanoate (Préparation 25) (0.40 mmol), 315

- 435 mg PPh₃ (1.20 mmol) and 276 mg di/ez7butyl azodicarboxylate (1.20 mmol) were dissolved in 3 mL methanol. The mixture was stirred at 50 °C under nitrogen atmosphère for 30 minutes. The mixture was concentrated under reduced pressure and the crude product was purified via flash chromatography using heptane and EtOAc as eluents to give 5 ethyl (2Æ)-2-[(5S_a)-5-(3-chloro-4-methoxy-2-methyl-phenyl)-6-iodo-thieno[2,3c/jpyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate. HRMS calculated for C₂6H24C1IN₂O₅S: 638.0139; found 639.0222 (M+H).

Step B:

291 mg of the product of Step A (0.40 mmol), 352 mg 3-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)phenol (1.60 mmol), 652 mg Cs₂CO₃ (2.00 mmol) and 19 mg Pd(dppl)Cl₂ (0.04 mmol) were dissolved in a mixture of 2.4 mL dioxane and 1.2 mL water, and the mixture was heated under nitrogen at 110 °C for 10 minutes in a microwave reactor. The reaction was diluted with water, the pH was adjusted between 3-4 by the addition of 2 M HCl, and the mixture was extracted with DCM. The combined organic phases were dried over Na₂SO4 and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to give ethyl (2R)2-[(55_a)-5-(3-chloro-4-methoxy-2-methyl-phenyl)-6-(3-hydroxyphenyl)thieno[2,3-d] pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate. HRMS calculated for

C₃₂H₂₉C1N₂O₆S: 604.1435; found 605.1518 (M+H).

Step C:

146 mg of the product of Step B (0.24 mmol), 197 mg PPh₃ (0.75 mmol), 152 mg ditez+butyl azodicarboxylate (0.75 mmol) and 108 mg 2-(4-methylpiperazin-l-yl)ethanol 25 (0.75 mmol) were dissolved in 4 ml dry toluene and the reaction mixture was stirred at 50 °C under nitrogen for 30 minutes. The mixture was concentrated under reduced pressure and the obtained crude product was hydrolyzed at room température in 5 mL methanolwater (9:1) containing NaOH (5m/m%). After completion the mixture was diluted with water, the pH was adjusted to 6 by the addition of 2 M HCl, and the mixture was extracted 30 with DCM. The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified using reverse phase préparative HPLC

17193 ·

-436 resulting Exampie 713. HRMS calculated for C37H39CIN4O6S: 702.2279; found 703.2362 (M+H).

Exampie 714 (2R)-2-{[6-(5-chlorofuran-2-yl)-(55„)-5-{3-chloiO-2-methyl-4-[2-(45 methylpiperazin-1-yl)ethoxy]phenyl}thÎeno[2,3-</}pyrimidin-4-yl]oxy}-3-(5-chloro-2inethoxyphenyl)propanoic acid

A mixture of 200 mg (27?)-2-[(55_rt)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(2-fuiyl)thieno[2,3-i(]pyrimidin-4-yl]oxy-3-(210 methoxyphenyl)propanoic acid (Exampie 209) (0.30 mmol) and 300 mg NCS (2.25 mmol) in 5 mL chlorofonn was stirred ovemight under nitrogen at room température. The mixture was diluted with water and extracted with DCM. The combined organic phases were dried over Na₂SC>4 and concentrated under reduced pressure. The crude product was purified using reverse phase préparative HPLC to give Example 714. I-lRMS calculated for

C34H3₃C13N₄O₆S: 730.1186; found 731.1251 (M+H).

Example 715 (2Λ)-2- {[(55_n)-5-(3-chloro-4-hydroxy-2-methylphenyl)-6-(thiophen-3yl)thieno[2,3-«0pyrimidin-4-yl]oxy}-3-(2-me±oxyphenyl)propanoic acid

Step A:

462 mg ethyl (27?)-2-[(55₀)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-iodo-thieno[2,3iZ|pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)piOpanoatc (Préparation 25) (0.8 mmol), 336 mg 4,4,5,5-tetrametliyl-2-(3-thienyl)-l,3,2-dioxaborolane (1.6 mmol), 58 mg Pd(dppf)Cl₂(0.08 mmol), and 521 mg césium carbonate (1.6 mmol) was dissolved in 8 mL dioxane and

2 mL water and it was heated under nitrogen at 110°C for 7 min in a micro wave reactor.

Water was added to the reaction, the pH was adjusted between 4-5 with 2 M HCl, and it was extracted with DCM. The combined organic phases were dried over Na2SO4, concentrated under reduced pressure, and purified via flash chromatography using heptane and ethyl acetate as eluents.

Step B:

-437140 mg of the product of Step A (0.24 mmol) was dissolved in 10 mL MeOH, 202 mg LiOHxHiO (4.80 mmol) was added and it was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure, and purified via préparative reversed phase chromatography using 40 mM aqueous NH4OAc solution (pH set to 4 with AcOH) and MeCN as eluents to obtain Example 715. HRMS calculated for C₂₇H₂₁C1N₂O₅S₂: 552.0580; found 553.0647 (M+H).

Example 716 (25)-2- {[(55,,)-5 - {3 -chloro-2-methyl-4- [3 -(4-methylpiperazin-1 -yl)prop-1 yn-l-yl]phenyl}-6-(2,3-difluorophenyl)thieno[2,3-if]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid and

Example 717 (25)-2-{[(55_o)-5-{3-chloiO-2-methyl-4-[3-(4-methylpiperazin-l -yl)prop-l yn-l-yl]phenyl}-6-(2,3-difluorophenyl)thieno[2,3-</]pyrimidin-4-yI]oxy )-3-(2methoxyphenyl)propanoic acid

Step A:

297 mg 4-chloiO-5-iodo-thieno[2,3-i/]pyrimidine (Préparation le) (1.00 mmol), 398 mg 2-(4-bromo-3-chloro-2-methyl-phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Préparation 5t) (1.20 mmol), 73 mg PdCl₂ x dppf (0.10 mmol) and 978 mg Cs₂CO₃ (3.00 mmol) were dissolved in 10 mL dioxane and 2.5 mL water, and heated under nitrogen at 60°C for 90 minutes in a microwavc rcactor. The réaction mixture was concentrated under reduced pressure and purified via flash chromatography, using heptane and EtOAc as eluents to obtain 5-(4-bromo-3-chloiO-2-methyl-phenyl)-4-chloiO-thieno[2,3-tZ]pyrimidine.

Step B:_

192 mg of the product of Step A (0.51 mmol) was dissolved in 5 mL dry THF under N₂and was cooled to -78°C with dry ice-aceton. 308 pL LDA (0.62 mmol in 2 M THF, EtPh) was added and it was stirred for 1 hour, then 163 mg iodine (0.64 mmol) was added and the mixture was allowed to warm up to room température. It was diluted with Et₂O, washed with saturated Na₂S₂O3 solution, dried over Na₂SC>4, filtered and concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as

17193 *

-438eluents to obtain 5-(4-bromo-3-chloiO-2-methyl-phenyl)-4-chloiO-6-iodo-thieno[2,3rfjpyrimidine.

Step C:

mg of the product of Step B (O.l mmol) was dissolved in 2 mL dioxane, then 72 mg 2(2,3-difluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.30 mmol), 7.3 mg Pd(dppf)Cl₂ (0.01 mmol), 98 mg Cs₂CO₃ (0.30 mmol) and 0.5 mL water were added. The mixture was heated under nitrogen to 60°C for 30 minutes in a microwave reactor. Then it was concentrated under reduced pressure and purified via flash chromatography, using heptane and EtOAc as eluents to obtain 5-(4-bromo-3-chloro-2-methyl-phenyl)-4-chloro-6(2.3-difluorophenyl)thieno[2,3-<7]pyrimidine.

Step D:

165 mg of the product of Step C was dissolved in 2 mL isopropanol. 112 mg ethyl (2R)-2hydroxy-3-(2-methoxyphenyl)propanoate (Préparation 3ad) (0.50 mmol) and 326 mg Cs₂CO₃ (1.00 mmol) were added and the mixture was stirred at 50°C for 2 hours, Then it was diluted with water, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SÜ4 and concentrated under reduced pressure. Then it was dissolved in 5 mL MeOH, 141 mg LiOHxH₂O (3.35 mmol) was added and it was stirred at room température for 1 hour. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO₄, concentrated under reduced pressure and purified via préparative reversed phase chromatography using 40 mM aqueous NH4OAC solution (pH set to 4 with AcOH) and MeCN as eluents to obtain (27?)-2-[5-(4-bromo-3-chloro-2-methyl-phenyl)-6-(2,3difluoiOphenyl)thieno[2,3-<7] pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoic acid as a mixture of diastereomers.

Step E:

To 77 mg of the product of Step D (0.12 mmol), 82 mg l-methyl-4-prop-2-ynyl-piperazine (0.60 mmol), 2.7 mg Pd(OAc)₂ (0.012 mmol), 8.5 mg BuPAd₂ (0.024 mmol), and 2.3 mg copper(l) iodide (0.012 mmol) 1 mL DIP A wase added and the mixture was heated under nitrogen to 120°C for 40 minutes in a microwave reactor. The reaction mixture was

-439concentrated under reduced pressure and purified via préparative reversed phase chromatography using 40 mM aqueous NH₄OAc solution (pH was set to 4 with AcOH) and MeCN as eluents to obtain Example 716 and Example 717. The diastereoisomer eluting earlier was collected as Example 716. HRMS calculated for C37H3₃C1F2N₄O₄S: 702.1879; found 703.1963 (M+H). The diastereoisomer eluting Iater was collected as Example 717. HRMS calculated for C37H33C1F₂N₄O₄S: 702.1879; found 703.1947 (M+H).

Example 718 (2Æ)-2-{[6-(5-chlorofuran-2-yl)-(557)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(4-fluoro-2methoxyphenyl)propanoic acid

Step A:

700 mg 5-bromo-4-chloro-6-(5-chloro-2-furyl)thieno[2,3-i/]pyrimidine (Préparation 2d) (2.0 mmol), 581 mg ethyl (27î)-3-(4-fluoro-2-methoxy-phenyl)-2-hydroxy-propanoate (Préparation Sas) (2.4 mmol) and 1.955 g césium carbonate (6.0 mmol) were stirred at 70°C in 10 mL dry tertbutanol until no further conversion was observed. The mixture was cooled to room température, and then 10 mL water, 947 mg l-[2-[2-chloro-3-methyl-4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-methyl-piperazine (Préparation 5b) (2.4 mmol) and 141 mg AtaPhos (0.2 mmol) were added. The mixture was stirred under nitrogen at 60°C until no further conversion was observed. Then brine was added and the mixture was extracted with EtOAc. The combined organic phases were dried over MgSO₄ and concentrated under reduced pressure. The crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (27?)2-[6-(5-chloro-2-furyl)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]thieno [2,3 -d]pyrimidin-4-yl]oxy-3 -(4-fluoro-2-methoxypheny I )propanoate.

Step B:

560 mg of the product of Step A (0.75 mmol) was dissolved in 20 mL dioxane-water (1:1) and 632 mg LiOHxH2O (15.1 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were

17193 f

-440dried over Na₂SO4, filtered and concentrated. The residue was purified via préparaiive reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents; the diastereoisomer eluting later was collected as Example 718. HRMS calculated for C34H33CI2FN4O6S: 714.1482; found 715.1553 (M+H).

Example 719 (27?)-2-{[(5Æ₀)-5-(3-chloro-2-methylphenyl)-6-(prop-l-en-2-yl)thieno[2,3-£7]pyrimidin-4yl]oxy}-3-phenylpropanoic acid and

Example 720 (2Æ)-2-{[(5S„)-5-(3-chloro-2-methylphenyl)-6-(prop-l-en-2-yl)thieno[2,3-d]pyrimidïn-4yl]oxy}-3-phenylpropanoic acid

Step A:

The mixture of 0.421 g 4-Chloro-5-(3-chloro-2-methyl-phenyl)-6-iodo-thieno[2,3Jjpyrimidine (Préparation 24b) (1.0 mmol), 0.207 mL 2-Ϊ3ορΐΌρβηγ1“4,4,5,5-ΙβΐΓ^6Λγ11,3,2-dioxaborolane (1.1 mmol), 0.303 g Ag₂CC>3 (El mmol), 0.173 g Pd(PPh3)₄ (0.15 mmol), and 5 mL 2-MeTHF was heated under nitrogen at 100°C for 15 min in a microwave reactor. The reaction was diluted with 50 mL DCM and it was filtered through a pad of celite. The celite was washed with DCM and the filtrate was evaporated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to give 4-chloro-5-(3-chloro-2-methyl-phenyl)-6-isopropenyI-thieno[2,3iTJpyrimidîne. 'H NMR (500 MHz, DMSO-d₆): 8.95 (s, IH), 7.56 (dd, IH), 7.31 (t, IH), 7.25 (dd, IH), 5.33 (m, IH), 5.22 (m, IH), 2.08 (s, 3H), 1.77 (m IH).

Step B:

The mixture of 0.12 g product of Step A (0.36 mmol), 0,193 g methyl (2/?)-2-hydroxy-3phenyl-propanoate (Préparation 3ag) (1.07 mmol), 0.466 g Cs₂CO₃ (1.43 mmol), and 4 mL dry DMSO was heated at 80°C untii no further conversion was observed. The mixture was cooled to room température, it was diluted with DCM and brine, neutralized with 2 M HCl, and it was extracted with DCM. The combined organic layers were dried over Na2SÛ4 and evaporated under reduced pressure. The obtained crude material was dissolved

-44I in I0 mL MeOH-THF (l:l), 227 mg LiOHx^O (5.5 mmol) was added and the mixture was stirred at 45 °C until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO4 and concentrated under reduced pressure. The residue was purified via préparative reverse phase chromatography using 0.1% aqueous TFA solution and MeCN as eluents to obtain Example 719, as the diastereomer eluting earlier [HRMS calculated for Czs^Cl^OsS: 464.0961; found 465.1054 (M+H)], and Example 720, as the diastereomer eluting later [HRMS calculated for C25H21CIN2O3S: 464.0961; found 465.1028 (M+H)].

Example 721 (2R)-2- {[(5S_n)-5-(3-chloro-2-methylphenyl)-6-ethenylthieno[2,3d]pyrimidin-4-yl]oxy}-3-phenylpropanoic acid

Step A:

The mixture of 550 mg 4-chloro-5-(3-chloro-2-methyl-phenyl)-6-iodo-thieno[2,3i/Jpyrimidine (Préparation 24b) (1.3 mmol), 0.245 mL 4,4,5,5-tetramethyl-2-vinyI-l,3,2dioxaborolane (1.43 mmol), 0.397 g AgiCCh (1.43 mmol), 0.227 g Pd(PPh₃)₄ (0.195 mmol), and 6 mL 2-MeTHF was heated under nitrogen at 100°C for 15 min in a microwave reactor. The mixture was diluted with 50 mL DCM and it was filtered through a pad of celite. The celite was washed with DCM and the filtrate was evaporated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to give 4-chloro-5-(3-chloiO-2-methyl-phenyl)-6-vinyl-thieno[2,3Opyrimidine. ‘H NMR (500 MHz, DMSO-d₆): 8.94 (s, IH), 7.59 (dm, IH), 7.35 (t, IH), 7.24 (dm, IH), 6.44 (dd, IH), 5.90 (d, IH), 5.54 (d, IH), 2.04 (s, 3H).

Step B:

The mixture of 150 mg product of Step A (0.47 mmol), 0.252 g methyl (2Æ)-2-hydroxy-3phenyl-propanoate (Préparation 3ag) (1.4 mmol), 0.456 g CS2CO3 (1.40 mmol), and 5 mL dry DMSO was heated at 80°C until no further conversion was observed. The mixture was cooled to room température, it was diluted with DCM and brine, neutralized with 2 M HCl, and the phases were separated. The aqueous layer was extracted with DCM, the combined organic layers were dried over Na₂SO₄, and evaporated under reduced pressure. The crude

17193 *

-442product was dissolved in 10 mL MeOH-THF (l:l), 0.196 g LiOHxH₂O (4.67 mmol) was added and the mixture was stirred at 45°C until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, and extracted with DCM. The combined organic phases were dried over Na₂SO4 and concentrated under reduced 5 pressure. The residue was purified via préparative reverse phase chromatography using

0.1% aqueous TFA solution and MeCN as eluents to obtain Example 721 as the diastereomer eluting later. HRMS calculated for C₂₄Hi9ClN₂O3S: 450.0805; found 451.0893 (M+H).

»

-443PHARMACOLOGICAL STUDY

EXAMPLE A: Inhibition of Mcl-ί by the fluorescence polarisation technique

The relative binding potency of each compound was determined via Fluorescence Polarisation (FP). The method utilised a Fluorescein labelled ligand (Fluorescein-PAlaAhx-AREIGAQLRRMADDLNAQY-OH ; mw 2,765) which binds to the Mcl-1 protein leading to an increased anisotropy measured in milli-polarisation (mP) units using a reader. The addition of a compound which binds competitively to the same site as the ligand will resuit in a greater proportion of unbound ligand in the System indicated by a decrease in mP units.

Method 1: An 11 point serial dilution of each compound was prepared in DMSO and 2μ1 transferred into flat bottomed, low binding, 384-well plate (final DMSO concentration 5%). 38μ1 of buffer (10 mM 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid [HEPES], 150mM NaCl, 0.05% Tween 20, pH 7.4), containing the Fluorescein labelled ligand (final concentration lnM) and Mcl-1 protein (final concentration 5nM) was then added.

Assay plates were incubated ~2 hours at room température before FP was measured on a Biomek Synergy2 reader (Ex. 528nm, Em. 640nm, Cut off 510nm) and mP units calculated. The binding of increasing doses of test compound was expressed as a percentage réduction in mP compared to a window established between ‘5% DMSO only’ and ‘100% inhibition’ (10μΜ Example 38) controls. 11-point dose response curves were plotted with XL-Fit software using a 4-Parameter Logistic Model (Sigmoidal DoseResponse Model) and the inhibitory concentrations that gave a 50% réduction in mP (IC50) were determined. Results obtained using Method I are presented in Table 1 below; IC₅o of Mcl-1 inhibition obtained using Method 1 are not underlined.

Method 2\ An 11 point serial dilution of each compound was prepared in DMSO and 2μ1 transferred into fiat bottomed, low binding, 384-well plate (final DMSO concentration 5%). 38μ1 of buffer (20 mM Na₂PO₄, ImM EDTA, 50mM NaC12, pH 7.4), containing the Fluorescein labelled ligand (final concentration lOnM) and Mcl-1 protein (final

17193 φ

-444concentration ΙΟηΜ) was then added.

Assay plates were incubated ~2 hours at room température before FP was measured on a Biomek Synergy2 reader (Ex. 528nm, Em. 640nm, Cut off 5l0nm) and mP units calculated. The binding of increasing doses of test compound was expressed as a percentage réduction in mP comparcd to a window established between ‘5% DMSO only’ and ‘100% inhibition’ controls (50μΜ unlabelled ligand). 11-point dose response curves were plotted with XL-Fit software using a 4-Parameter Logistic Model (Sigmoidal DoseResponse Model) and the inhibitory concentrations that gave a 50% réduction in mP (IC50) were deteimined. Results obtained using Method 2 are presented in Table 1 below; ICsq of Mcl-1 inhibition obtained usina Method 2 are underlined.

The results show that the compounds of the invention inhîbit interaction between the Mcl-1 protein and the fluorescent peptide described hereinbefore.

EXAMPLE B: Iti vitro cytotoxicitv

The cytotoxicity studies were carried out on the H929 multiple myeloina tumour line.

The cells aie distributed onto microplates and exposed to the test compounds for 48 hours. The cell viabilïty is then quantified by a colorimétrie assay, the Microculture Tétrazolium Assay (Cancer Res., 1987,47,939-942).

The results are expressed in IC50 (the concentration of compound that inhibits cell viability by 50%) and are presented in Table 1 below.

The results show that the compounds of the invention are cytotoxic.

-445-

Table 1: IQn of M.cl-1 inhibition (fluorescence polarisation test) and of cytotoxicity for H929 cells

Note : ICso ofMcl-I inhibition obtained usingMethod2 are underlined.

	IC» (M) Mçl-1 FP	JCs» (pM) MÎT H929		ÎC_S0(M)McI-l FP	ICs, (jiM) MTTH929
Example 1	8,0E-08	0,16	Example 29	3,3E-09	0,007
Example 2	l,2E-08	0,136	Example 30	2,8E-09	0,003
Example 3	8,9E-09	0,114	Example 31	5,6E-09	0,012
Example 4	l,6E-08	0,192	Example 32	#N/A	0,006
Example 5	6,2E-09	0,418	Example 33	7,8E-O9	0,017
Example 6	4,9E-09	0,332	Example 34	3,3 ΕΌ9	0,004
1 Example 7	8,6E-09	0,066	Example 35	4,8E-09	0,027
Example 8	l,6E-08	0,145	Example 36	1,1E-O8	0,015
Example 9	9,3E-09	0,363	Example 37	6,ÛE-09	0,014
Example 10	9,7E-09	0,275	Example 38	l,9E-09	0,016
Example 11	4,4E-08	0,13	Example 39	4,8E-09	0,015
Example 12	l,6E-08	0,076	Example 40	5,6E-09	0,008
Example 13	2,2E-08	0,146	Example 41	2,9E-09	0,007
Example 14	1.3E-O8	0,168	Example 42	3,2E-09	0,012
Example 15	3,7E-08	0,494	Example 43	9,8E-09	0,465
Example 16	5,9E-09	0,095	Example 44	#N/A	0,006
Example 17	l,2E-08	0,062	Example 45	6,7E-09	0,009
Example 18	8,3E-09	0,076	Example 46	7,3E-09	0,024
Example 19	4,4E-09	0,064	Example 47	7,8E-09	0,005
Example 20	6,4E-09	0,08	Example 48	Ι,ΙΕ-08	0,122
Example 21	1.6E-08	0,162	Example 49	2,5E-09	0,012
Example 22	8.3E-09	0,092	Example 50	7,6E-09	0,076
Example 23	2,4E-08	0,054	Example 51	3,5E-09	0,038
Example 24	8,1E-O9	0,012	Example 52	5.6E-09	0,014
Example 25	5,6E-09	0,074	Example 53	3,4E-09	0,015
Example 26	1,1E-O8	0,028	Example 54	5,7E-09	0,024
Example 27	6,6E-09	0,045	Example 55	5,8E-09	0,007
Example 28	4,5E-09	0,021	Example 56	4,4E-09	0,022

-44617193 φ /

	ICm(M)McI-1 FF	fCso (\|iM) ΜΤΤ H929		IC_S0(M)Mcl-J fp	JC» QiM) ΜΊΤ H929
Example 57	5.0E-09	0,008	Example 88	4,2E-09	0,062
Example 58	4,0E-09	0,01	Example 89	6,5E-09	0,027
Example 59	4.0E-09	0,021	Example 90	3,2E-O9	0,058
Example 60	2,4E-09	0,17	Example 91	7,3E-09	0,042
Example 61	6,7E-09	0,01	Example 92	l,2E-08
Example 62	3,9E-09	0,008	Example 93	l,4E-08	0,087
Example 63	4.5E-09	0,009	Example 94	l,9E-09	0,085
Example 64	4,4E-09	0,018	Example 95	4,2E-09	0,022
Example 65	1,OE-08	0,043	Example 96	3,8E-09	0,034
Example 66	4,6E-09	0,037	Example 97	3,3E-09	0,075
Example 67	3,4E-09	0,03	Example 98	3,3E-07	0,118
Example 68	9JE-09	0,035	Example 99	2,0E-08
Example 69	9,7E-08	0,114	Example 100	l,2E-08
1 Example 70	l,6E-09	0,018	Example 101	8,0E-09	0,398
i Example 71	9,4E-09	0,032	Example 102	9,5E-09
! Example 72	9,3E-09	0,04	Example 103	2,4E-08	0,214
Example 73	8,3EO9	0,122	Example 104	7,5E-09	0,386
Example 74	l,6E-08		Example 105	l,2E-08	0,251
Example 75	4,0E-09	0,11	Example 106	l,2E-08	0,195
Example 76	l,6E-08	0,044	Example 107	5.3E-09	0,007
Example 77	5,9E-09	0,042	Example 108	3,5E-09	0,007
Example 78	6,6E-09	0,033	Example 109	8,4E-09	0,108
Example 79	1.3E-08	0,168	Example 110	4,3E-09	0,022
Example 80	4,5E-09	0,035	Example 111	3,3E-09	0,008
Example 81	#N/A	0,034	Example 112	5,6E-09	0,011
Example 82	5,lE-09	0,078	Example 113	2,6E-09	0,005
Example 83	5,1E-O9	0,016	Example 114	2,1E-O9	0,005
Example 84	3,8E-09	0,018	Example 115	2,6E-09	0,003
Example 85	3,6E-09	0,063	Example 116	2,9E-09	0,007
Example 86	2,9E-09	0,063	Example 117	6,1E-O9	0,008
Example 87	7,0E-09	0,274	Example 118	5,5E-09	0,006

-447-

	IC_JU (M) Mcl-1 FP	IC_m(\|iM)MU'H929		lCso(nM) Mcl-1 FP	1C_W (\|iM) MTT H929 \|
Example 119	4,8E-09	0,02	Example 150	9,3E-O9	0,027
Example 120	3,8E-O9	0,003	Example 151	3,6E-O9	0,309
Example 121	5,6E-O9	0,015	Example 152	9,9E-09	0,19
Example 122	3,8E-09	0,01	Example 153	5,0E-09	0,146
Example 123	4,3E-09	0,002	Example 154	6,6E-09	0,1
Example 124	4,3E-09	0,024	Example 155	7,6E-09	0,189
Example 125	7,3E-09	0,354	Example 156	7,0E-09	0,092
Example 126	l,4E-08	0,7	Example 157	7,0E-O9	0,286
Example 127	2,0E-08	0,558	Example 158	4,6E-09	0,033
Example 128	4,OE-O9	0,018	Example 159	9,8E-09	0,246
Example 129	2,2E-09	0,069	Example 160	5,0E-O9	0,021
Example 130	3,4E-09	0,065	Example 161	3,9E-09	0,081
Example 131	7,9E-O9	0,039	Example 162	9,9E-09	0,027
Example 132	4,8E-O9	0,102	Example 163	l,2E-08	0,047
Example 133	3,4E-09	0,099	Example 164	8,2E-09	0,046
Example 134	l,3E-08	0,193	Example 165	l,6E-06
Example 135	8,6E-09	0,005	Example 166	6,OE-O9	0,036
Example 136	7,7E-09	0,015	Example 167	4,6E-09	0,01
Example 137	5,5E-09	0,007	Example 168	2,8E-09	0,025
Example 138	8,9E-09	0,013	Example 169	9,OE-09	0,009
Example 139	8.5E-O8	0,636	Example 170	5.3E-09	0,006
Example 140	2,2E-08	0,205	Example 171	4,1E-O9	0,003
Example 141	3,1E-O8	0,27	Example 172	3,OE-09	0,004
Example 142	4,2E-08	1,67	Example 173	3.1E-09	0,004
Example 143	2,6E-08	1,61	Example 174	2,3E-09	0,005
Example 144	1,6E-O8	1,6	Example 175	3,9E~09	0,003
Example 145	1,1E-O8	0,293	Example 176	3,1E-O9	0,016
Example 146	3,5E-O8	1,16	Example 177	2,8E-09	0,005
Example 147	2,4E-08	0,787	Example 178	6,3E-09	0,002
Example 148	3,1E-O8		Example 179	5,0E-09	0,03
Example 149	1.2E-O8	0,092	Example 180	8,9E-09	0,042

-448-

	)C» (M) Mcl-1 FP	IC» (μΜ) MTT H929		IC» (M) Mcl-1 FP	IC» (μΜ) MTT H929
Example 181	4,8E-09	0,008	Example 212	l,6E-08	0,616
Example 182	4,4E-09	0,013	Example 213	1,8E-O8
Example 183	5,7E-09	0,012	Example 214	9,3E-09	0,897
Example 184	6,0E-09	0,022	Example 215	8,0E-09	0,203
Example 185	4,8EO9	0,012	Example 216	8,5E-09	0,217
Example 186	4,3E-09	0,013	Example 217	5,3E-O9	1,48
Example 187	2,8E-09	0,02	Example 218	6,5E-O9	0,805
Example 188	6,4E-09	0,005	Example 219	9,9E-09	0,191
Example 189	5,5E-09	0,034	Example 220	9,0E-09	0,277
Example 190	7,5E-09	0,037	Example 221	6,3E-09	0,059
Example 191	6,5E-09	0,063	Example 222	7,4E-09	0,314
Example 192	7,7E-09	0,848	Example 223	l,4E-08	0,346
Example 193	5,4E-09	0,116	Example 224	3,7E-09	0,049
Example 194	8,0E-09	0,058	Example 225	8,4E-09	0,105
Example 195	5,5E-09	0,311	Example 226	2,4E-08	0,311
Example 196	5,6E-09	0,076	Example 227	2.0E-08	0,192
Example 197	5,4E-09	0,07	Example 228	2,2E-O8	0,166
Example 198	7,7E-09	0,002	Example 229	4,5E-09	0,134
Example 199	6,6E-Û9	0,28	Example 230	1,2E-O8	0,312
Example 200	6,1E-O9	0,106	Example 231	l,0E-O8	0,116
Example 201	5,8EO9	0,027	Example 232	9,OE-09	0,046
Example 202	3.5E-O9	0,009	Exemple 233	3,4EO9	0,099
Example 203	9,1E-O9	0,005	Example 234	1,1E-O8	0,135
Example 204	4,9E-09	0,034	Example 235	5,1E-O9	0,098
Example 205	3.8E-09	0,028	Example 236	7,4E-09	0,137
Example 206	8,0EO9	0,135	Example 237	l,5E-08	0,186
Example 207	6,5E-09	0,186	Example 238	5,9E-09	0,077
Example 208	5.5E-09	0,571	Example 239	1,1E-O8	0,55
Example 209	9,8E-O9	0,115	Example 24Û	7,2E-09	0,225
Example 210	l,0E-08	0,406	Example 241	5,5E-09	0,074
j Example 211	5,2E-O9	0,063	Example 242	7,3E-09	0,09

-449-

	1C_5O (M) Mcl-1 Fl’	!C₅u(mM) MIT! 1929		ICso (M) Mcl-1 IP	1C_5O (\|lM) MTT H929 II
Example 243	5,6E-09	0,211	Example 274	7,7E-09	0,131 \|
Example 244	8,6E-09	0,205	Example 275	4,5E-09	0,051 \|
Example 245	5,8E-09	0,099	Example 276	6,2 ΕΌ9
Example 246	9,1E-O9	0,324	Example 277	4,8E-09	0,07
Example 247	8,0E-09	0,022	Example 278	6,7E-09	0,202
Example 248	6,9E-09	0,015	Example 279	8,0E-O9	0,406
Example 249	4,0E-09	0,023	Example 280	4,0E-09	0,071
Example 250	3,6E-09	0,499	Example 281	7,9E-09	0,081
Example 251	6.3E-09	0,035	Example 282	4.0E-08	0,601
Example 252	4,2E-09	0,009	Example 283	2,6E-08	0,25
Example 253	3,1E-O9	0,041	Example 284	4,8E-08	1,79
Example 254	3,3E-09	0,044	Example 285	l,7E-08	0,588
Exemple 255	7,5E-09	0,018	Example 286	7,6E-09	0,508
Example 256	4,8E-09	0,006	Example 287	8,3E-O9	0,667
\| Example 257	5,0E-09	0,019	Example 288	1,2E-O8	0,086
Example 258	6,6E-09	0,069	Example 289	l,4E-08	0,18
Example 259	5,2E-09	0,07	Example 290	5,8E-09	0,097
Example 260	6.7E-09	0,033	Example 291	3,8E-08	1,3
Example 261	l,7E-09	0,018	Example 292	9,3E-09	0,192
Example 262	3.9E-09	0,023	Example 293	8,9E-07
Example 263	2,0E-09	0,126	Example 294	l,6E-08	0,886
Example 264	9,1E-O9	0,034	Example 295	4,7E-09	0,021
Example 265	3,5E-09	0,016	Example 296	9.3E-09
Example 266	5,7E-09	0,093	Example 297	6,6E-09
Example 267	8,8E-09	1,6	Example 298	l,2E-08	1,14
Example 268	8,2E-09	0,086	Example 299	l,6E-08	1,03
Example 269	1,1E-O8	0,069	Example 300	3,7E-08
Example 270	l,2E-08	0,068	Example 301	l,2E-08	0,108
Example 271	l,6E-08	0,197	Example 302	1.4E-08	1,59
Example 272	2,2E-08	0,822	Example 303	9,3E-09	0,998
Example 273	9,2E-09	0,905	Example 304	1,1E-O8	1,7

-450-

	fC_M(M) Mcl-1 l'P	1C_SO (μΜ) MTT H929		IC» (M) Mcl-l FP	IC_M (μΜ) ΜΠΉ929
Example 305	6,9E-08	1,64	Example 336	43,2% @ 10 uM
Example 306	l,4E-08	1,12	Example 337	3,8EO8	1,87
Example 307	8,3E-O9	0,998	Example 338	3,0E-08	1,04
Example 308	5,9E-09	1,5	Example 339	18,85% @ 10 uM
Example 309	l,0E-08	1,48	Example 340	6,7E-07
Example 310	1.4E-08	0,26	Example 341	3,5E-08	0,706
Example 311	l,5E-08	1,59	Example 342	3.5E-07
Example 312	8,9E-09	1	Example 343	2.5E-07
Exampie 313	l,0E-08	0,886	Example 344	l,6E-08	0,22
Example 314	6,9E-09	1,82	Example 345	8,6E-09	0,322
Example 315	2,2E-08		Example 346	l,7E-08	0,063
Example 316	7,7E-09	1,46	Example 347	l,4E-08	0,25
Example 317	l,8E-08	0,852	Example 348	2.1E-08	0,346
Example 318	3,0E-08		Example 349	2,7E-08	2,46
Example 319	l,5E-08	0,834	Example 350	2,8E-08
Example 320	6,5E-09	0,471	Example 351	l,5E-08	0,526
\| Example 321	6,0E-09		Example 352	l,4E-08	0,91
Example 322	4,3E-09	0,113	Example 353	2,8E-08
Example 323	8.8E-09		Example 354	1,1E-O8	0,544
Example 324	l,5E-08	0,254	Example 355	3,0E-08
Example 325	5,2E-08		Example 356	1,1E-O8
Example 326	7,9E-09		Example 357	5,5E-07	3,39
Example 327	l,5E-08		Example 358	9,5E-09	1,61
Example 328	5,OE-09	3,03	Example 359	6,6E-09	0,336
Example 329	6,0E-08	3,31	Example 360	2,0E-07
Example 330	8,3E-09	1,17	Example 361	7,1E-O7
Example 331	6,0E-09	0,394	Example 362	2,6E-08	1
Example 332	l,3E-08		Example 363	7,7E-09	0,071
Example 333	7,9E-07		Example 364	5,1E-O9	0,052
Example 334	1.4E-08	0,968	Exampie 365	5,9E-09	0,026
Example 335	l,2E-08	0,217	Example 366	8,6E-09	0,346

-451-

	ICso (M) Mcl-1 FP	IC,_u(pM)MTTH929		FP	ICso(hM) Mît H929
Example 367	3,2E-09	0,015	Example 398	l,5E-06	23,8
Example 368	l,4E-08	0,005	Example 399	1.4E-08
Example 369	5,1EO9	0,009	Example 400	8,4E-08	14,4
Example 370	8,7E-09	0,018	Example 401	4,9E-08	22,3
Example 371	5,6E-09	0,027	Example 402	6,6E-08	10,4
Example 372	9,7E-09	0,018	Example 403	1.4E-08
Example 373	4,6E-09	0,012	Example 404	5,7E-08	21,6
Example 374	9,2E-09	0,038	Example 405	7.4E-09
Example 375	5,6E-09	0,081	Example 406	3,5E-08	21,9
Example 376	2,0E-09	0,076	Example 407	1,1E-O7	7,33
Example 377	3,8E-09	0,047	Example 408	26,25% @ 10 uM	15,9
Example 378	3.2E-O9	0,202	Example 409	2.0E-07
Example 379	1,3E-O8	0,174	Example 410	2.2E-06
Example 380	1,1E-O8	0,162	Example 411	3,4E-08	19
Example 381	l,3E-08	0,119	Example 412	5,lE-08	28,7
Example 382	7.1E-09	0,033	Example 413	1.3E-08	15,8
Example 383	5,6E-09	0,03	Example 414	21,35% @ 10 uM	27,2
Example 384	3,8E-09	0,053	Example 415	5,0E-08	‘ 6,41
Example 385	3.5E-09	0,048	Example 416	7.0E-07	π
Example 386	l,0E-08	0,075	Example 417	1.5E-07
Example 387	4,0E-09	0,202	Example 418	5,6E-08	13,3
Example 388	2.3E-08		Example 419	3,4E-08	21,5
Example 389	1.2E-O6		Example 420	4,0E-08	15,6
Example 390	4,0E-08	20	Example 421	38,1% @ 10 uM
Example 391	3/7E-O8	22,1	Example 422	1.4E-08	14,4
Example 392	3,0E-08	17,1	Example 423	5,3E-08
Example 393	4,1E-O8	16,6	Example 424	9,6E-08
Example 394	3.4E-08		Example 425	9.6E-09
Example 395	1.6ΕΌ8		Example 426	4.6E-09
Example 396	9,9E-08	16,1	Example 427	4.7E-09
Example 397	8.0E-09	15,7	Example 428	7.5E-09

-452-

	ICsu(M)Mcl-l FP	lCjo(pM) MTTH929		IC_W (M) Mcl-1 FP	1C_JC (jiM) MTT H929
Example 429	5.3E-08		Example 460	l,3E-07	6,82
Example 430	l,4E-07	15,5	Example 461	8,5E-08	4,86
Example 431	3,2E-08		Example 462	65.15 %@ 10 uM
Example 432	6,8E-08	13,6	Example 463	4,6E-08	5,11
Example 433	#N/A		Example 464	3.9E-07
Example 434	l,7E-07	11,3	Example 465	2.5E-08
Example 435	3,2E-O7	11,1	Example 466	3,9E-08	3,35 1
Example 436	2.9E-08	15,1	Example 467	ί,ΙΕ-08	0,502
Example 437	4,5E-08	20,3	Example 468	8,6E-09	2,02
Example 438	8.5E-O8		Example 469	l,5E-08	3,06
Example 439	2.5E-O7		Example 470	4.8E-07
Example 440	3.0E-07		Example 471	6.3E-09
Example 441	2.7E-08		Example 472	13,05% @ 10 UM
Example 442	1,1E-O7	20,4	Example 473	5,0E-08
Example 443	1.8E-08		Example 474	5.5E-07
Example 444	1.2E-08		Example 475	6.8E-09	1,12
Example 445	l,3E-07	21	Example 476	2,0E-08	1,03
Example 446	1,1E-O7	25,7	Example 477	5.6E-08	2,57
Example 447	6.8E-08		Example 478	5,3E-07
Example 448	4.4E-07		Example 479	1,1E-O8
Example 449	2.8E-08		Example 480	2.8E-08
\| Example 450	2.6E-08		Example 481	5,4E-09	0,643
Example 451	5.8E-07		Example 482	7,4E-09	0,004 \|
Example 452	3.0E-07		Example 483	5,2E-09	0,003 \|
Example 453	2,6E-08	3	Example 484	3,4E-09	0,014 \|
Example 454	l,2E-08		Example 485	4,3E-09	0,012
Example 455	6,2E-O9	0,339	Example 486	l,9E-09	0,146
Example 456	8,0E-09	0,513	Example 487	6,5E-09	0,004
Example 457	3,4E-08		Example 488	5,4E-09	0,014
Example 458	3,2E-O8	2,73	Example 489	l,2E-09	0,026
Example 459	3,7E-06		Example 490	3,0E-09	0,018

- 453 -

	IC_w(M)Mcl-l FP	ICsu (μΜ) MÎT H929		IC» (M) Mcî-1 FP	IC» (μΜ) MTT H929
Example 491	28,3% @ 10 uM		Example 522	7.5E-08
Example 492	9,0E-08	2,19	Example 523	1.8E-09	0,532
Exampie 493	5.0E-09		Example 524	3,1E-O8	0,417
Exampie 494	4,4E-08	2,56	Example 525	3.3E-09	0,755
Exampie 495	3,6E-O8	1,19	Example 526	4.1E-09	0,835
Example 496	2,0E-07	3,39	Example 527	7,1E-O8	0,272
Exampie 497	9,lE-07	5,95	Example 528	l,6E-08	0,334
Example 498	7,4E-08		Example 529	l,3E-08	0,308
Example 499	l,0E-07	1,5	Example 530	X2E-07	1,59
Example 500	8,0E-08	2,25	Example 531	3.5E-09	1,22
Example 501	2,8E-07	2,84	Example 532	5,9E-08	0,323
Example 502	l,9E-08	0,766	Example 533	2,8E-08	0,201
Example 503	5.0E-07	7,02	Example 534	l,6E-08	0,413
Exampie 504	2,9E-08	0,324	Example 535	l,3E-07	1,84
Example 505	5,8E-08	0,954	Example 536	7,7E-08	0,797
Example 506	7,5E-08	8,29	Example 537	4,3E-08	0,208
Example 507	2,2E-07		Example 538	4,7E-08	0,672
Example 508	3,7E-07		Example 539	7,2E-08	0,731
Example 509	6,2E-08	1,46	Example 540	3.2E-09	0,311
Exampie 510	3,9E-08	0,639	Example 541	2,9E-08	0,329
Example 511	4,8E-07		Example 542	4,3E-07
Example 512	l,3E-07	7,42	Example 543	4,2E-08	0,766
Example 513	3,7E-07		Example 544	l,4E-08	0,274
Example 514	9,6E-08	1,7	Example 545	3,9E-08	1,1
Example 515	8,4E-08	2,95	Example 546	l,7E-08	0,416
Example 516	l,3E-07	5,07	Example 547	3,3E-08	0,475
Example 517	5,1E-O7	6,09	Example 548	l,8E-08	0,497
Example 518	3,5E-08	9,18	Example 549	1,3E-O7	1,5
Example 519	2.3E-08	0,523	Example 550	4,8E-08	0,203
Example 520	4,1E-O8	1,13	Example 551	2,8E-08	0,201
Example 521	2,4E-07		Example 552	4,1E-O8	0,784

17193 »

-454-

	IC_J0 (M) Mcl-1 FP	IC» (μΜ) MÎT H929		1C_5O (M) Mcl-11-T	IC» (μΜ) MÎT H929
Example 553	1,1E-O8	0,585	Example 584	2,9E-08	0,902
Example 554	2,4E-08	0,177	Example 585	8,5E-08	2,92
Example 555	3,9E-07		Example 586	l,4E-06
Example 556	1.2E-O8		Example 587	2,6E-08	0,539
Example 557	4.5E-09	0,475	Example 588	8,0E-09	0,256
Example 558	5,9E-08	0,742	Example 589	8,7E-09	0,233
Example 559	5.2E-09	0,293	Example 590	8,4E-08
Example 560	1,1E-O8	0,128	Example 591	6,5E-08	1,67
Example 561	2,7E-08	0,61	Example 592	2.4E-06
Example 562	5,1E-O7		Example 593	1.9E-06
Example 563	7,4E-08	1,16	Example 594	6,1E-O9	0,13
\| Example 564	8.5E-10	0,202	Example 595	6,2E-09	0,114
Example 565	4,8E-07	1,96	Example 596	2.7E-09	0,12
Example 566	3,0E-08	0,233	Example 597	#N/A	0,449
Example 567	2,1E-O8	1,04	Example 598	7,8E-09	0,097
Example 568	2,5E-O8	0,22	Example 599	1,1E-O8
Example 569	3,9E-08	1,73	Example 600	4,1E-O9	0,031
Example 570	2,0E-08	0,324	Example 601	l,2E-08	0,133
Example 571	4,4E-08	0,559	Example 602	3,7E-09	0,156
Example 572	l,9E-08	0,394	Example 603	5,0E-09	0,036
Exampie 573	1,1E-O8	0,366	Example 604	5,7E-09	0,064
Example 574	24,3% @ 10 uM		Example 605	8,2E-09	0,254
Example 575	46,8% @ 10 uM		Example 606	4,0E-09	0,064
Example 576	6,2E-08	1,51	Example 607	3,5E-09	0,04
Example 577	7,6E-09	0,119	Example 608	4,2E-09	0,021
Example 578	3,8E-08	0,347	Example 609	3,5E-09	0,063
Example 579	8.5E-09	0,463	Example 610	3,5E-09	0,091
Example 580	3,7E-O8		Example 611	3,9E-09	0,23
Example 581	4,2E-07		Example 612	3,5E-09	0,02
Example 582	8,4E-08		Example 613	3,5E-09	0,158
Example 583	1,1E-O7		Example 614	8,4E-09

-455-

	1C_SO (M) Mcl-1 FP	IC₅₁₎ (μΜ) MTT H929		ICsüCMJMcI-I FP	1C«, (μΜ) MTT H929
Example 615	8,0E-10	0,292	Example 646	2,1E-O8	0,298 \|
Example 616	4,0E-09	0,07	Example 647	2,3E-08	0,498
Example 617	5,4 E-09	0,277	Example 648	l,4E-08
Example 618	5,6E-09		Example 649	2,3E-08	0,341
Example 619	7,0E-09	0,336	Example 650	5,1E-O8
Example 620	5,9E-09	0,532	Example 651	6,8 E-09	0,282
Example 621	5,3 E-09	0,095	Example 652	4,7EO9	0,059
Example 622	1,1E-O8	0,109	Example 653	1,6EO8
Example 623	67,8% @ 10 uM		Example 654	4,0E-08	2,08
Example 624	26,95% @ 10 uM		Example 655	2,6E-08
\| Example 625	74,85% @ 10 uM	0,62	Example 656	6,1E-O8	0,523
Example 626	39,45% @ 10 uM		Example 657	2,1E-O8
Example 627	4.9E-07		Example 658	1,8E-O8	^1,71
Example 628	33,2% @ 10 UM		Example 659	2,2E-08
Example 629	14,95% @ 10 UM		Example 660	5,1E-O8
Example 630	27,95% @ 10 uM		Example 661	l,0E-07
Example 631	56% @ 10 UM		Example 662	2,7E-07
Example 632	41,8% @ 10 uM		Example 663	2,5E-O8
Example 633	40.2 %(® 10 uM		Example 664	53,9% @ 10 uM
Example 634	10,7% @ 10 uM		Example 665	3,9E-06
Example 635	50,75% @ 10 uM		Example 666	7,7E-08
Example 636	29.975 10 uM		Example 667	2.1ΕΌ6
Example 637	5,9% @ 10 uM		Example 668	1,1E-O8	0,13
Example 638	34,5% @ 10 uM		Example 669	4,9E-09	0,108
Example 639	66,25% © 10 uM		Example 670	3,2 E-09	0,027
Example 640	42,4% @ 10 uM		Example 671	6,9E-O9	0,107
Example 641	9,6E-O7		Example 672	4,3E-09	0,019
Example 642	11% @ 10 uM		Example 673	1,1E-O8	0,576
Example 643	6,6E-07	0,303	Example 674	2,1E-O8
Example 644	3,7E-07	0,248	Example 675	2.2E-08
Example 645	2,2E-O8		Example 676	71.5 %@ 10 uM

-456-

	IC₅„ (M) Mcl-1 FP	Κ\>(μΜ) MTTH929		IC«, (M) Mcl-I FP	ICso(gM) MTTH929
Example 677	2.2E-06		Example 708	9,6E-09	0,055
Example 678	1.8E-O6		Example 709	3,2E-08	0,518
Example 679	8.9E-07		Example 710	2.4E-09	0,384
Example 680	61.55 %(® 10 uM		Example 711	3.7E-09	0,591
Example 681	6.7E-09		Example 712	4,1E-O7
Example 682	5.1E-07		Example 713	l,6E-08
Example 6S3	3.3E-06		Example 714	3,4E-08	0,188
Example 684	l,9E-08	2,23	Example 715	1.6E-09
Example 685	l,2E-08		Example 716	l,5E-06
Example 686	l,0E-06		Example 717	2,7E-08	0,865
Example 687	2,9E-08	3,66	Example 718	l,2E-08	0,082
Example 688	3,3E-07		Example 719	2.7E-06
Example 689	8,5E-O9	0,657	Example 720	4.4E-08
Example 690	2,3E-08	0,178	Example 721	7.6E-08
Example 691	9,6E-09	0,037
Example 692	l,0E-08	0,059
Example 693	9,3E-10	0,101
Example 694	6,4E-09	0,183
Example 695	l,6E-08	0,268
Example 696	9,6E-09	0,05
Example 697	45,55% @ 1 uM
Example 698	7,3E-09
Example 699	28,5% @ 1 uM
Example 700	l,2E-08
Example 701	40,75% @ 1 uM
Example 702	9,4E-09
Example 703	9,3E-09	0,03
Example 704	9,9E-09	0,025
Example 705	l,7E-08	0,02
Example 706	3,6E-09	0,04
Example 707	l,4E-08	0,042

I

-457EXAMPLE C: Quantification of the cleaved form of PARP in vivo

The ability of the compounds of the invention to induce apoptosis, by measuring cleaved PARP levels, is evaluated in a xenograft model of AMO-l multiple myeloma cells.

I.IO⁷ AMO-l cells are grafted sub-cutaneously into immunosuppressed mice (SCID strain). 12 to 14 days after the graft, the animais are treated by intraveinous or oral routes with the various compounds. After treatment, the tumour masses are recovered and lysed, and the cleaved form of PARP is quantiiîed in the tumour lysâtes.

The quantification is carried out using the Meso Scale Discovery (MSD) ELISA platform test, which specifically assays the cleaved form of PARP. It is expressed in the form of an activation factor corresponding to the ratio between the quantity of cleaved PARP in the treated mice divided by the quantity of cleaved PARP in the control mice.

The results show that the compounds of the invention are capable of inducing apoptosis in AMO-l tumour cells in vivo.

EXAMPLE D: Anti-tumour activity in vivo

The anti-tumour activity of the compounds of the invention is evaluated in a xenograft model of AMO-l multiple myeloma cells.

lxlO⁷ AMO-l cells are grafted sub-cutaneously into immunosuppressed mice (SCID strain).

to 8 days after the graft, when the tumour mass has reached about 150 mm³, the mice are treated with the various compounds in a daily schedule (5-day treatment). The tumour mass is measured twice weekly from the start of treatment.

The compounds of the invention hâve anti-tumour activities (tumour régression) in the AMO-l multiple myeloma model with ΔΤ/C (qualification parameter of the activity of a product, which is defined as the ratio tumour volume of the treated group / tumour volume of the untreated control group) ranging from -26 to -100%. The results obtained show that the compounds of the invention induce significant tumour régression during the treatment period.

17193 ·

-458EXAMPLE F: Pharmaceutical composition: Tablets

1000 tablets containing a dose of 5 mg of a compound selected from Examples 1 to 721 5g

Wheat starch............................................................................................................ 20g

Maize starch............................................................................................................ 20g

Lactose.................................................................................................................... 30g

Magnésium stéarate................................................................................................. 2g

Silica........................................................................................................................ 1g

Hydroxypropylcellulose.......................................................................................... 2g e

Claims

CLÂIMS

1- Compound of formula (I):

wherein:

♦ A represents a linear or branched (Ci-Q)alkyl group or an halogen atom,

5 ♦ R_b R₂, R3, R4 and Rs independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-C₆)alkyl group, a linear or branched (C₂Csjalkenyl group, a linear or branched (C₂-Cs)alkynyl group, a linear or branched (C]-C<5)polyhaloalkyl, a hydroxy group, a linear or branched (Ci-Ccjalkoxy group, -S-(Ci-C6)alkyl group, a cyano, a nitro group, -alky^Co-C^-NRsRg’, -O-Cyi, 10 -alkyl(Co-C6)-Cyi, -alkenyl(C₂-C6)-Cy_1} -alkynyl(C₂-C6)-Cy_b -O-alkyl(Ci-C6)-R9,

-COOR₈, -OC(O)R₈, -C(O)NR8R₈’, -NR₈C(O)-R₈’, -NR₈C(O)-OR₈’,

-alkyl(C₁-C₆)-NR₈C(O)-R₈’, -SOz-NRsR*’, -SO₂-alkyl(Ci-C₆), or the substituents of one of the pairs (Ri,R?.), (R?., Rs), (Ri> Ra), (R4, Rs) when grafted onto two adjacent carbon atoms, form together with the carbon atoms 15 carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain from one to 3 hetero atoms selected from oxygen, sulphur and nitrogen, it being understood that resulting ring may be substituted by a group selected from a linear or branched (Ci-C^alkyl group, -NRkjRio’, -alkyl(CoCô)-Cyi or an oxo,

-460- ♦ X represents a carbon or a nitrogen atom, ♦ Re represents a hydrogen, a linear or branched (Ci-Cô)alkyl group, an aryl, an heteroaryl group, an arylalkyl(Ci-C6) group, an heteroarylalkyl(C|-C6) group,

4 R7 represents a linear or branched (Ci-Cé)alkyl group, a linear or branched (C₂5 Cé)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, -Cy₃, -alkyl(Ci-Cfi)Cy₃, -alkenyl(C₂-C₆)-Cy3, -alkynyl(C₂-C₆)-Cy₃, -Cy₃-Cy₄, -Cy₃-alkyl(Co-C₆)-0alkyl(C₀-C6)-Cy₄, an halogen atom, a cyano, -C(O)-Rn, -C(O)NRj ,Ri j ♦ Rg and Rs’ independently of one another represent a hydrogen atom, a linear or branched (Ci-Cgjalkyl group, or -alkyl(Co-C6)-Cy_b

10 or (R§, Rs’) form together with the nitrogen atom carrying them an aromatic or nonaromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from one to 3 hetero atoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (Ci15 C₆)alkyl group, ♦ Rç represents -Cy_b -Cyi-alkyl(C₀-C₆)-Cy₂, -Cyi-alkyl(Co-C₆)-0-alkyl(C₀-C6)-Cy₂,

-Cy_l-alkyl(C₀-C₆)-NR₈-alkyl(C₀-C₆)-Cy₂, -C(O)-NR₈Rg’, -NR_gRg’,

-NRsC(O)R₈’, -ORg, O-alkyl(Ci-C₆)-OR₈, -SO₂-R_g, -C(O)-ORg, -NH-C(O)-NH-Rg, ♦ Rio, Rio’, Ru and Ru’ independently of one another represent a hydrogen atom or

20 an optionally substituted linear or branched (Ci-Ce)alkyl group, ♦ Ri₂ represents a hydrogen or a hydroxy group, ♦ Cyi, Cy_2> Cy₃ and Cy₄, independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an ai*yl or an heteroaryl group, it being understood that:

25 - aryl means a phenyl, naphthyl, biphenyl or indenyl group,

- heteroaryl means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from l to 3 hetero atoms selected from oxygen, sulphur and nitrogen,

- cycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group

30 containing from 3 to 10 ring members, “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group

-461 containing from 3 to 10 ring members, and containing from l to 3 hetero atoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring Systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy, to be substituted by from 1 to 4 groups selected from optionally substituted linear or branched (C[-Cô)alkyl, optionally substituted linear or branched (C₂-C(s)alkenyl group, optionally substituted linear or branched (C₂-C6)alkynyl group, optionally substituted linear or branched (Ci-Cô)alkoxy, optionally substituted (C|Cô)alkyl-S>, hydroxy, oxo (or IV-oxide where appropriate), nitro, cyano, -COOR', -OCOR’, -CONR’R”, -NR'R, -(C=NR')-OR”, linear or branched (Ci-C₆)polyhaloalkyl, trifluoromethoxy, or halogen, it being understood that R' and R independently of one another represent a hydrogen atom or an optionally substituted linear or branched (CiC₆)alkyl group, their enantiomers, diastereoisomers and atropoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
2- Compounds according to claim 1 wherein at least one of the groups selected from Ri, R₂ and R₃ does not represent a hydrogen atom.
3- Compounds according to claim 1 wherein A represents a linear or branched (Cr Cô)alkyl group.
4- Compounds according to claim 1 wherein X represents a carbon atom.

I^e
5- Compounds according to claim 1 wherein : I represents

-462wherein R# and R’s are as defined in claim l.

wherein Rg is as defined in claim l.
7- Compounds according to claim l wherein R₄ represents a hydrogen or a iînear or

5 branched (Ci-Cô)alkyl group.
8- Compounds according to claim 1 wherein R7 represents a linear or branched (C|Cé)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2C₆)alkynyl group, an aryl or an heteroaryl group.
9- Process for the préparation of a compound of formula (I) characterised in that there
10 is used as starting material the compound of formula (Il-a):

(ll-a) wherein R7 is as defined for formula (I), which compound of formula (Π-a) is subjected to coupling with a compound of formula (III):

-463- wherein R4, R5 and R12 are as defined for formula (I), and

Alk représenta a linear or branched (Ci-C^alkyl group,

5 to yield the compound of formula (IV):

wherein R4, R5, R7 and R12 are as defined for formula (I) and Alk is as defined before, compound of formula (IV) which is further subjected to coupling with compound of formula (V):

wherein Ri, R₂, Ri, X and A are as defïned for formula (I), and

Rbi and Rb₂ represent ahydrogen, a linear or branched (Ci-Ce) alkyl group, or Rm and R_B2form with the oxygen carrying them an optionally methylated ring, to yield the compound of formula (VI):

wherein Rj, R2, R3, R4, R5, R?, R12, X and A are as defïned for formula (I) and Alk is as

20 defïned before, the Alk-O-C(O)- ester function of which compound of formula (VI) is hydrolysed to yield the carboxylic acid, which may optionally be optionally be reacted with an alcohol of formula R(,OH wherein Re is as defïned in formula (I),

-465to yield the compound of formula (I), which may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino...) of the starting reagents or of the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.

10- Process for the préparation of a compound of formula (I) characterised in that there is used as starting material the compound of formula (Il-b):

which compound of formula (ΙΙ-b) is converted into compound of formula (II-c):

(ll-c) which compound of formula (II-c) is subjected to coupling with a compound of formula (V):

-466- (V) wherein R_h R₂, R₃, X and A are as defined for formula (I), and

Rbi and Rb₂ represent a hydrogen, a linear or branched (Ci-C<j) alkyl group, or Rbi and Rb₂form with the oxygen carrying them an optionally methylated ring, to yield the compound of formula (VI): (VI) wherein Rj, R₂, R₃, A and X are as defined in formula (I), which compound of formula (VI) is further subjected to the action of I₂ in the presence of lithium diisopropylamide (strong base) to yield compound of formula (VII):

(VII) wherein Rj, R₂, R₃, A and X are as defined in formula (I), which compound of formula (VII) is further subjected to coupling with a compound of formula (VIII):

(VIII) wherein R7 is as defined for formula (I), and

Rb3 and R_B4 represent a hydrogen, a linear or branched (C|-C₆) alkyl group, or Rb3 and Rb₄form with the oxygen carrying them an optionally methylated ring, lo yield compound of formula (IX):

(IX)

-468wherein R_b R₂, R₃, Λ, X and R₇ are as defined in formula (I), which compound of formula (IX) is further subjected to coupling with a compound of formula (III):

(III) wherein R4, R₅, and Ri₂ are as defined for formula (I), and

Alk represents a linear or branched (Ci-C6)alkyl group, to yield the compound of formula (VI):

wherein R|, R₂, R₃, R4, R₅, R₇, R|₂, X and A are as defined for formula (I) and Alk is as defined before, the ester fonction of which compound of formula (VI) is hydrolysed to yield the carboxylic »

-469acid, which may optionally be optionally be reacted with an alcohol of formula R^OH wherein Rg is as defïned in formula (I), to yield the compound of formula (I), which may be purified according to a conventional

5 séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino...) of the starting reagents or of 10 the synthesis intermediates can be protected, subsequently deprotected and fimctionalized, as required by the synthesis.
11- Pharmaceutical composition comprising a compound of formula (I) according to any one of daims 1 to 8 or an addition sait thereof with a pharmaceutically acceptable acid

15 or base in combination with one or more pharmaceutically acceptable excipients.
12- Pharmaceutical composition according to claim 11 for use as pro-apoplolic agents.
13- Pharmaceutical composition according to claim 12 for use in the treatment of cancers and of auto-immune and immune System diseases.
14- Pharmaceutical composition according to claim 13 for use in the treatment of 20 cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lyrnphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-smallcell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
15- Use of a pharmaceutical composition according to claim 11 in the manufacture of 25 médicaments for use as pro-apoptotic agents.
16- Use of a pharmaceutical composition according to claim 11 in the manufacture of médicaments for use in the treatment of cancers and of auto-immune and immune system

-470diseases.
17- Use of a pharmaceutical composition according to daim 11 in the manufacture of médicaments for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
18- Compound of formula (I) according to any one of daims 1 to 8, or an addition sait thereof with a pharmaceuticaily acceptable acid or base, for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
19- Use of a compound of formula (I) according to any one of daims 1 to 8 or an addition sait thereof with a pharmaceuticaily acceptable acid or base, in the manufacture of médicaments for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
20- Association of a compound of formula (1) according to any one of daims 1 to 8 with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, protéasome inhibitors, kinase inhibitors and antibodies.
21- Pharmaceutical composition comprising an association according to daim 20 in combination with one or more pharmaceuticaily acceptable excipients.
22- Association according to daim 20 for use in the treatment of cancers.

>

-471 -
23- Use of an association according to claim 20 in the manufacture of médicaments for use in the treatment of cancers.
24- Compound of formula (I) according to any one of daims l to 8 for use in association in the treatment of cancers requiring radiotherapy.