OA17201A

OA17201A - Tris(hetero)arylpyrazoles and use thereof.

Info

Publication number: OA17201A
Application number: OA1201500051
Authority: OA
Inventors: Steffen Wildum; Burkhard Klenke; Astrid Wendt
Original assignee: Aicuris Gmbh & Co. Kg
Priority date: 2012-08-17
Filing date: 2013-08-16
Publication date: 2016-04-05

Abstract

The present invention relates to novel tris(hetero)arylpyrazoles, to processes for preparation thereof, to the use thereof for treatment and/or prophylaxis of diseases and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially of retroviral disorders, in man and/or animals.

Description

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

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

S 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 moiphological 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. el al., Nature Review Cancer, 2002,2,647-656).

Deregulation of apoptosis is învolved 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 signifïcant 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. el al., Cell 2000,100,57-70).

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

The învolvement of proteins of the Bcl-2 family is described in numerous types of cancer, such as colon cancer, breast cancer, small-cell Jung cancer, non-small-cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphoid leukaemia, lymphoma, myeloma, acute myeloid leukemïa, pancreatic cancer, prostate cancer, etc. Overexpression of the anti-apoptotic proteins of the Bcl-2 family is învolved in tumorigenesis, in résistance to chemotherapy and in the clinical prognosls of patients aflected by cancer. Notably, Mcl1, an anti-apoptotic Bc!-2 family member, is overexpressed in various types of cancer (Beroukhim R. el 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.

I

-3Cs)*Cyi or an oxo, ♦ X represents a carbon or a nitrogen atom, ♦ Re represents a hydrogen, a linear or branched (C|-Ce)alky1 group, an aryl, an heteroaryl group, an arylalkyl(Ci-C_e) group, an heteroarylalkyl(Cj-C_e) group, ♦ R7 represents a linear or branched (C|-Ce)alkyl group, a linear or branched (C2Cô)alkenyl group, a linear or branched (C₂-C₆)alkynyl group, -Cy₃, -alkyKCi-Ce)Cy₃, -alkenyl(C2-C6)-Cy₃, -alkynyl(C₂-C_é)-Cy₃, -Cy₃-Cy₄, -Cy₃-alkyl(Co-C₆)-0alkyl(Cc'Ci)-Cy4, an halogen atom, acyano, -C(0)-Rn, -C(0)NRnRn\ ♦ Rg and Rg’ independently of one another represent a hydrogen atom, a linear or branched (C_t-C6)alkyl group, or -alkyl(Cc-C6)-Cyi, or (Rg, Rg’) 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 15 substituted by a group representing a hydrogen atom, a linear or branched (CiCg)alkyJ group, ♦ R9 represents -Cyi, -Cyralkyl(C₀-C₆)-Cy2, -Cyj-alkyltCo-C^-O-alkylCCo-CfO-Cyî,

-Cy_ralkyl(Co-C₆)-NRralkyl(Cû-C6)-Cy₂, -C(O)-NRgRg’, -NRjRg’,

-NRgC(O)Rg’, -ORg, 0-alkyl(Cj-C6)-0Rg, -SO₂-Rg, -C(O)-ORg, -NH-C(O).NH-R_S, ♦ Rio, Rio*, Ri 1 and Ru* independently of one another represent a hydrogen atom or an optionally substituted linear or branched (Cj-C^alkyl group, ♦ Ru represents a hydrogen or a hydroxy group, ♦ Cyj, Cy₂, Cy₃ and Cy_4> 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,

- 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 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,

-5Ce)alky 1 group.

Preferably, X represents a carbon atom.

In some preferred embodiments,

In other embodiments,

Preferably, Re represents a hydrogen or a linear or branched (C_rCe)alkyl group.

In the preferred compounds of the invention, R7 represents a linear or branched (CiCé)alkyl group, a linear or branched (C2*Ci)alkenyl group, a linear or branched (C210 Q)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 (11-a):

(B-a)

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

Rbi and Rm represent a hydrogen, a linear or branched (Ci-Ce) alkyl group, or Rai and Rm form with the oxygen earrying them an optionally mcthylated ring, to yield the compound of formula (VI):

(VI) wherein Rt, R₂, Rj, R4, Rj, R7, Ru, X and A are as dcfined for formula (I) and Alk is as defined before, the Alk-O-C(O)- ester fonction of which compound of formula (VI) is hydrolysed to yiel d «

Re₂O '^ORbi (V) whercinRi, R₂, R3, X and A arc as defined for formula (I), and

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

wherein Ri, R₂, R3, A and X arc as defined in formula (I), which compound of formula (VI) is further subjected to the action of h in the presence of lithium dïisopropylamide (strong base) lo yield compound of formula (VU):

-nwherein Rj, Rï, 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):

wherein R4, Rs, and R12 are as defined for formula (I), and

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

(VI) wherein Ri, Ri, Rj, R», Rs, R7, Ru» 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 çarboxylic *

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

Among the pharmaceutical compositions according to the invention thcre may be 5 mentioned more cspccîally those that are suitable for oral, parentéral, nasal, per- or trans-cutancous, rectal, perlingual, ocular or respiratory administration, especîally 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 to route, the nature of the thcrapeutic indication, or of any associated treatments, and ranges from 0.0! 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, mîtotic poisons, antimetabolites, protéasome inhibitors, kinase inhibitors and antibodies, and also to 15 pharmaceutical 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 iliustrate the invention but do not iimit it in any 20 way.

General Procedures

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

-15’H-NMR measurements were performed on Broker Avance III500 MHz spectrometer and Broker Avance III400 MHz spectrometer, using DMSO-d_A or CDCh as solvent. ’H NMR data is in the form of delta values, given in part per million (ppm), using the residuai pcak of the solvent (2.50 ppm for DMSO-de and 7.26 ppm for CDCh) as internai standard.

Splitting patterns are designated as: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintct), 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 cliromatography and low resolution mass spectrometry were performed on Agîlcnl 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: ΕΓ, 70 eV, 230°C, quadrupole: 150°C, interface: 300°C.

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

Elemcntary analyses were performed on a Thermo Flash EA 1112 Elemcntal Analyzer.

20	List of abbreviations
abbreviation	name
	2-Me-THF	2-methyl-tetrahydrofurane
	Ac	acetyl
	Ad	adamantyl
25	AIBN	2-[(l -cyano-1 •methyl-ethyl)azo]-2-melhyl-propanenitrilc
	AtaPhos	bïs(di-ier/-butyl(4- dimethylaminophcnyl)phosphine)dichloropalladium(ll)
	CuTC	copper(I) thiophene-2-carboxylate
	DAST	diethylaminosulfur trifluoridc
30	dba	dibenzylideneacetone
	DCM	methylene chloride
	Dcss-Martin periodinane	1,1,1 -tris(acetyloxy)-1,1 -di hydro-1,2-benziodoxol-3-(l //)· one
	DIPA	diisopropylainine
35	DIPEA	diisopropylethylamîne
	DME	1,2-dimethoxyethane
	DMF	dimethylformamide
	dppf	1,1 *-bis(diphcnyIphosphino)ferrocene
	eq.	équivalent

Φ

-17mL jV.jV-dimethylaniline (0.29 mol). 75.54g 6-iodo-3ff-thieno[2,3-/]pyrimidin-4-one (0.27 mol) was added to the mixture in portions during 5 minutes. The réaction mixture was stirred at 105 °C for 1 hour. The resulting suspension was cooled to 10 ^eC, filtered and washed withhexane. 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. ’HNMR(400MHz,DMSO-dé): 8.89 (s, IH), 7.98 (s, IH).

Step C; 5-Brnmo-4-chloro-6-iodo-thleno[2.3-d]pyrim!dine

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-/]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 1b: 4-Chloro-5.6-dliodo-thlenol23-rflpvrimldinc

St en A: 5,6-Diiodo-3H-thieno[2,3-d]pyrimidin-4-one

To a well stirred slurry of 61.3 g 3//-thieno[2_I3-/]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-S, 6-dilodo-thieno[2,3-d]pyrlmidine

To a well stirred slurry of 180 g 5,6-diiodo-3H-thieno[2,3-/]pyrimidin-4-one (445 mmol) in 2.5 L phosphorous oxychloridc was added 64 mL jV.jV-dimcthylaniline. The reaction mixture was heated to 105 °C and stirred for 1.5 hours. The resulting suspension was f

-19Sien C: 4-ChIoro-6-ethyl-5-iodo-thleno[2,3-d]pyrimidine

The mixture of stirred 880 ml phosphorous oxychloride and 102 mL A^-di methyl aniline was heated to 95 °C and 220 g 6-ethyl-5-iodo-3Zf-thieno[2,3-J]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 MgSO₄ and concentrated under reduced pressure to give the product as a tan crystalline solid. *H NMR (400 MHz, DMSO-de): 8.79 (s, IH), 3.02 (q, 2H), 1.39(t, 3H).

Préparation 1 ci 6-Dromo-4-chloro-5lodo-thlenol23-rf|pyrfmldlne

Step A: 6-Bromn~3H~lhieno[2,3-d]pyrlmldin-4-ûne

The mixture of 60.1 g 3/7-thieno[2,3-</]pyrimidin-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 réaction 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 fïltered off, washed with acetic acid (3x50 mL), dicthyl ether (3x100 mL) and then air dried to give the product as a tan powder.

Step B: 6-Bromo-5~lodo-3H~thleno[2,3-d]pyrimidin-4-one

Lcc. sulfuric acid was cooled with ice-water bath and 72.0 g potassium ïodide (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-i/]pyrimidin-4-onc (0.346 mol) was added to the mixture in portions in 30 minutes while the internai température was kept between 21 ^eC and -19 °C. The reaction mixture was stirred at -20 °C for 1.5 hours. Ice (3 kg) was added to lhe suspension then the precipitate was fïltered ofT, washed with water (3x500 *

-21Préparation 2c; 5-Bromo-4-chloro-6-(2-furvDthlenof23-rflDvrimidine

112.6 g 5-bromo-4-chloro-6-iodo-thieno[2,3-i/]pyrimidine (Préparation la) (300 mmol), 93.14 g 2-(2-furyl)-4,4,5,5-tetramethy!-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 v.os 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-d_e): 8.96 (s, 1H), 8.05 (dd, 1H), 7.59 (dd, 1H), 6.86 (dd, 1H).

Préparation 2d: 5-Bn>mo-4-chloro-6-(5-chtoro-2-furvDthicnof23-rflpvrimldine

33.29 g 5-bromo-4-chIoro-6-(2-fiiryl)thieno[2,3-i/]pyrimidine (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 15 TFA were added, and the stirred for 2 hours at room température. Reaction mixture was washed with saturated NaHCOj. The organic phas was dried over MgSO₄, filtered and concentrated to give Préparation 2d.

‘H NMR (400 MHz, CDClj): 8.84 (s, 1H), 7.52 (d, 1H), 6.45 (d, 1H).

Préparation 2e; 5-Bromo-4-chloro>6-(4-fluoro-3-methoxy-phenyI)thieno[2,3rf]pyrlmldine

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

12.10 g 2-(4-fluoro-3-melhoxy-phenyI)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (44 mmol), 32.58 g césium carbonate (100 mmol), 1.463 g Pd(dppf)C]₂ (2 mmol) were placed 25 in an 1 L flask. 150 mL THF and 150 mL water were added, and then stirred ovemight at 70^eC under argon atmosphère. To the réaction 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 / DCM as eluents.

'H NMR (400 MHz, DMSO-d<): 8.94 (s, 1H), 7.42 (dd, 1H), 7.36 (dd, 1H), 7.24-7.20 (m, IH), 3.90 (s, 3H).

-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 complète. 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 NajSOx, 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 Left. 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(trimethylsilyl-amide) solution (1,0 M in THF) was added dropwise. After addition température was allowed to rcach room température. When the reaction reached an appropriate conversion to the oxirane the mixture was quenched with saturated NH4CI, the 20 layers were separaled, the aqueous layer was extracted with EhO, 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)î was added and the mixture was hydrogenated at

3-4.5 bars of hydrogen pressure. In case of a low conversion glacial acctic 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 édité, 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;

23.10 g anhydrous LiCl (545 mmol) and 65.36 g anhydrous ZnCh (479.6 mmol) were placed în a 2 L flask, then dried at 160°C under 0.1 Hgmm for 1 hour. After cooling to room température under argon atmosphère, 26.49 g magnésium tumlngs (1090 mmol) and 1 L dry pre-cooled (0°C) THF were added. The resulting mixture was immersed into an 5 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 whîle keeping the température between 0-5°C. To the mixture 64,82 mL ethyl 2-oxoacetate (654 mmol, 50% to In toluène) was added over 5 min s and the resulting mixture was stirred for another 15 mins.

From the mixture the remaining inorganics were removed by filtration, and then 500 mL MeOH was added to the filtrate. l’his mixture was stirred untii the intramolecular acetyl group migration from the phenolic oxygen to the alkyl oxygen was completed. To the 15 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 NaHCOj and with brine, and then dried over MgSO₄₁ 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 20 collected by filtration and washed with hexane yielding Préparation 3aa-(rnc). *H NMR (500 MHz, DMSO-dc) 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, IH), 2.94 (dd, IH), 2.00 (s, 3H), 1.09 (t, 3H).

Préparation 3aa-ffl,· Ethyl (25)-2-acetoxy-3-(2-hydroxyphcnyI)propanoate and

Préparation 3na-fff); Ethyl (2/?)-2-acctoxy-3-(2-hydroxyphenyl)propanoate

Enantiomers of Préparation 3aa-(rac) were separated via chiral chromatography. Cohtmn: OD; Eluents: heptane / EtOH; the enantiomer eluting earlier was collected as Préparation 3aa-(5) with 99.8% ee and the enantiomer eluting later was collected as 30 Préparation 3aa-(Æ) with 99.9% ee.

*

-27Préparation 3ad; Ethyl (2A)-2-hydroxy-3-(2-mcthoxyphenyI)propanoate and

Préparation 3bk 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, CDCIj) 5 7.23 (dt, IH),

7.12 (dd, IH), 6.89-6.84 (m, 2H), 5.26 (dd, 111), 4.14 (dq, 2Π), 3.24 (dd, 111), 3.03 (dd, 111),2.04 (s, 3H), 1.19 (t, 311).

Enantiomers were separated via chiral chromatography; Coiumn: AD, Eluent: 2-PrOH; the enantiomer eiuting earlier was collected as Préparation 3a<! with 99.8% ee and the enantiomer eiuting earlier was collected as Préparation 3bi with 97.8% ee.

Préparation 3ae: Ethyl (2J?)-2-hydroxy-3-[2-[(4-methoxyphenyl)incthoxyl phenylfpropanoate

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

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

Préparation 3af; Ethyl (XR)*2-hydroxy-3-[2-I[(25)-tetrahydrofuran-2-yl]methoxyJ phenyl] propanoa te and

Préparation 3bl ; Ethvl (2R)-2-hydroxy-3-|2-[[(2R)-tetrahydrofuran-2-yl]methoxyl phenyl] propanoatc

Using General procedure 3A and tetrahydrofuran-2-ylmcthanol as the appropriate alcohol diastereoisomer mixture of the lactic esters were obtained. Diastereoisomers were separated by chiral chromatography. Cohimn: IC, Eluents: heptane / EtOH; the diastereoisomer eiuting earlier was collected as Préparation 3af with 99.6% de; *H NMR (400 MHz, CDC13) δ 7.26-7.24 (m, 211). 6.92 (dt, IH). 6.87 (d, IH), 4.46-4.41 (m, IH), 4.35-4.29 (m, IH), 4.20 (dq, 2H), 4.04 (dd, IH), 3.99-3.93 (m, 2H), 3.88-3.82 (m, (H),

3.32 (d, IH), 3.17 (dd, lH),3.00(dd, 111), 2.14-2.05 (m, 111), 2.03-1.90 (m,2H), 1.85-1.76 (m, IH), 1.25 (t, 3H) and the diastereoisomer eiuting 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, IH). 6.86 è

-29(d, IH), 6.53 (t, !H), 4.46 (dd, IH), 3.80 (s, 3H), 3.21 (dd, 1 H), 3.03 (dd, IH), 2.68 (br s, IH).

Préparation 3alt: Methyl (2R)-3-(3-iluorophenyl)-2-hydroxy-propanoate

Using General procedure 3C and methyl (2E)-3-(3-fluorophcnyl)prop-2-cnoate as the appropriate cinnamic acid dérivative Préparation 3ak was obtained with 98.6% cc; *H NMR (500 MHz, CDClj) 8 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, IH),2.96 (dd, IH),2.64 (brs, IH).

Préparation 3alî Methyl (2Æ)-2-hydroxy-3-(3-methoxyphenyl)propanoate

Using General procedure 3C and methyl (2E)-3-(3-methoxyphenyl)prop-2-enoate as the appropriate cinnamic acid dérivative Préparation 3al was obtained with 97.3% ee; *H NMR (500 MHz, CDClj) 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, 1 H), 2.96 (dd, I H), 2.33 (br s, I H).

Préparation 3am; Methyl (2/f)-3-(23-dHluorophenyl)-2-hydroxy-propanoate

Using General procedure 3C and methyl (2£)-3-(2,3-dinuorophenyl)prop-2-enoate as the appropriate cinnamic acid dérivative Préparation 3am was obtained with 96.9% ee; ’H NMR (500 MHz, CDClj) 5 7.19-6.93 (m, 3H), 4.48 (dd, IH), 3.82 (s, 3H), 3.20 (dd, IH), 3.06 (dd, IH), 2.73 (brs, IH).

Préparation 3a n; Methyl (21ï)-2-hydroxy-3-|2-(trinuoromelhyl)pheny!]propanoate Using General procedure 3C and methyl (2E)-3-[2-(trifluoromcthyl)phenyl]prop-2-enoate as the appropriate cinnamic acid dérivative Préparation 3an was obtained with 99.6% ce; ’H NMR (500 MHz, CDClj) 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, 111), 2.70 (brs, IH).

Préparation 3ao: Methyl (2R)-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; ’H NMR (500 MHz, CDClj) δ 7.20-7.14 (m, 4H), 4.44 (dd, IH), 3.80 (s, 3H), 3.18 (dd, 11-1), 2.95 (dd, 111),2.59 (brs, 1H),2.37(s,3H).

-31Using General procedure 3C and ethyl (2£)-3-(2-mcthoxy-3-mcthyl-phcnyl)prop-2-cnoatc as tlie appropriate cinnainic acid dérivative Préparation 3>u was obtained with 99.8% ee; ‘H NMR (500 MHz, CDC1₃) δ 7.10-7.03 (m, 2H), 6.97 (t, 1H), 4.45 (q, 1H), 4.21 (dq, 2H), 3.26 (s, 3H), 3.16 (dd, 1H), 3.01 (d, 1H), 2.31 (s, 3H), 1.25 (t,3H).

Préparation 3av; Ethyl (2R)-3-[2-(fer/-butoxyearbonylainino)phenyi]-2-hydroxypropanoate

Using General procedure 3C and ethyl (2E)-3-[2-(fc/7-butoxycarbonylamino)phenyl]prop2-enoate as the appropriate cinnamic acid dérivative Préparation 3av was obtained with 10 99.8% ee; ’H NMR (500 MHz, CDCI3) δ 7.92 (br s, 1H), 7.75 (d, I H), 7.24 (t, 1H), 7.10 (d, IH), 7.01 (t, 1H), 4.51 (q, 1H), 4.27 (q, 2H), 3.34 (br s, IH), 3.25 (dd, 1H), 3.01 (dd, lift 1.52 (s, 9H), 1.35 (t, 3H).

Préparation 3aw; Ethyl (2R)-3-[2-[(/err-butoxycarbonylamino)methyl]phenyl]-215 hydroxy-propnnoate

Using General procedure 3C and ethyl (2E)-3-[2-[(ferfbutoxycarbonylamino)melhyl]phenyl]prop-2-enoale as the appropriate cinnamic acid dérivative Préparation 3aw was obtained with 98.8% ee; *H NMR (500 MHz, CDClj) 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, 20 1 H), 1.45 (s, 9H), 1.32 (ζ 311).

Préparation 3ax; Ethyl (2S)-2-hydroxy-3-[2-(2,2,2-trinuoroethylsulfany!)phenyl] propanoate and

Préparation 3av; Ethvl (2R)-2-hydroxy-3-[2-(2,2,2-trifluoroethylsulfanyl)phenyl] propanoate

StenA' l-Methyl-2-(2,2,2-trifuoroethylsulfanyl)benzene

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

-33Préparation 3az:Ethvl (251-342-11 uoroplienvlÎ-2-hydroxy-propanoate and

Préparation 3ba: Ethyl (2/î)-3-(2-fluorophenyI)-2-hydroxy-propnnoate

Using General procedure 3R 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, IH), 4.23 (dd, IH), 4.05 (q, 2H), 2.99 (dd, IH), 2.86 (dd, IH), 1.12 (t, 3 H).

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

Préparation 3bbi 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 nwiety 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, IH), 7.51 (m, IH), 7.16 (m, 2H), 6.94 (d, IH), 5.63 (d, IH), 4.40 (dd, 20 IH),4.02 (q,2H), 3.25 (dd, IH), 3.09 (dd, IH), 1.07 (t, 3H).

Préparation 3bc: Ethyl 3-(benMfuran-4-yl)-2-hydroxy-propanoatc

Using General procedure 3B and benzofuran-4-carbaldehyde as the appropriate carbaldehyde Préparation 3bc was obtained. ^JH NMR (400 MHz, CDClj) δ 7.62 (d, IH),

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

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

Préparation 3bdt Ethyl (2R)-3-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-propanoate and

Préparation 3be: Ethyl (25)-3-(23-dihydrobenzofuran-7-yl)-2-hydroxy-propanoate

Using General procedure 3B and benzofuran-7-carbaldehyde as the appropriate carbaldehyde. Applyîng longer reaction time In Step B the partially saturated lactic ester ♦

-35(Tetrahedron Lett. 1994,35,5205-5208.)

13-Benzodioxo!e-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 racemic form. ^lH NMR (500 MHz, DMSO) δ 6.78 (dd, ! H), 6.74 (t, IH), 6.7! (dd, IH), 5.96 (d, 2H), 5.59 (d, 1H), 4.25 (m, IH), 4.05 (q, 2H), 2.9! (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 earlier 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 (2R)-2-hydroxy*3-[2-[2-(4-methylpiperazln-lyl)ethoxy]phcnyl|propanoatc and

Préparation 3bo: Ethyl (2S>2-hyclroxy-3-|2-|2-(4-methylplperazln-lyl)ethoxy]phenyl]propanoate

Using General procedure 3A starting from ethyl 2-acetoxy-3-(2-hydroxyphenyl)propanoate (Préparation 3aa-(rnc)) and 2-(4-methylpiperazin-l-yl)cthanol as the appropriate alcohol the lactic ester was oblaîned in racemic form. ^lH NMR (500 MHz, DMSO-ds) δ 7.17 (m, IH), 7.10 (dm, IH), 6.94 (dm, IH), 6.83 (m, 1H), 5.4 (d, IH), 4.28 (m, IH), 4.06 (t, 2H), 4.02 (m, 211), 2.97 (dd, ΠΙ), 2.7! (dd, !H), 2.69 (t,211), 2.49 (brs, 411), 2.30 (brs, 411),2.13 (s, 3H), 1.11 (t, 311).

Enanliomers were separated via chiral chromatography. Column: OD, Eluents: heptane / !· PrOH; 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 3blr Ethyl (2R)-2-hydroxy-3-|2-(2,2,2-trinuorocthoxy)phenyl]propanoate

Step A: Ethyl (2R)-2-hydroxy-3-(2-hydroxyphenyl)propanoale

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

-37Préparation 4n: Ethyl (27?)-2-[5-bromo-6-(4-fluon)phenyl)thleno[23-</]pyrimIdln-4yl]oxy-3-(2-tetra'hydropyran-2-yIoxyphenyI)pn)panoate

48.45 g 5-bromo-4-chloro-6-(4-fluorophenyl)thicno[2,3-(/]pyrimidine (Préparation 2a) (141 mmol), 45.63 g ethyl (2Æ)-2-hydroxy-3-(2-tetrahydropyran-25 yloxyphenyljpropanoatc (Préparation 3ab) (155 mmol) and 137,8 g Cs₂COj (423 mmol) were placed in a 2 L flask. 1.4 L /er/-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 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 Préparation 4a as a mixture of diastereoisomers. ’H NMR (500 MHz, DMSO-de): 8.67/8.66 (s, 1H), 7.75 (m, 2H), 7.43 (dm, 1H), 7.41 (m, 2H), 7.19 (m, IH), 7.08/7.06 (dm, IH), 6.89 (m, 1H), 5.87/5.70 (dd, 1H), 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 C₃sH₂₆BrFNiOîS: 600.0730, found: 601.0809/601.0798 (M+H).

Préparation 4b? Ethyl (2R)-2-[5-bromo-6-(4-Îluorophenyl)thieno|23-4/]pyrîmldin-4yI]oxy-3-|2-(pyrazln-2-y!mcthoxy)phcnyl]propnnootc

1.718 g 5-bromo-4-chloro-6-(4-fluorophenyl)thïeno[2,3-i/]pyrimidÎne (Préparation 2a) (5.00 mmol), 1.512 g ethyl (2Æ)-2-hydroxy-3-[2-(pyrazin-2-ylmethoxy)phenyl]propanoate (Préparation 3ac) (5.00 mmol) and 5.700 g CsjCOj (17.5 mmol) were placed h a 50 mL flask. 15 mL /erZ-butanol 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, fîltered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as cluent3 to obtain Préparation 4b. MS: (M+H)⁺ 609.0.

Préparation 4c; Ethyl (2Æ)-2-|5-bromo-6-(5-nuoro-2-ft!ryl)thleno[23*rf]pyrhnIdin-4yI]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoatc ♦

-39butanol was added and the mixture was stirred at 60°C under N₂ unti! 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 Na₂SO<, fîltered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4e. *H NMR (400 MHz, DMSO-de): 8.60 (s, IH), 7.94 (d, IH), 7.43 (d, HJ), 7.37 (dd, III), 7.22 (td, IH), 6.96 (d, IH), 6.86 (td, IH), 6.77 (dd, IH), 5.64 (dd, IH), 4.10 (q, 2H), 3.79 (s, 3H), 3.87 (dd, IH), 3.24 (dd, IH), 1.10(t, 3H).

Préparation _4f; Ethyl (2Æ)-2-[5-bronio-6-(S-chloro-2-fury))thleno[2,3-d]pyrlmldin-4yl]oxy-3-[2-|(4-mcthoxypheny))methoxy]phenyl]propanoate

6.05 g 5-bromo-4-chloro-6-(5-chloro-2-furyl)thieno[2,3-Jjpyrïmidine (Préparation 2d) (17.3 mmol), 6.28 g ethyl (2A)-2-hydroxy-3-[2-[(4methoxyphenyl)methoxy] phenyl] propanoate (Préparation 3ae) (19.0 mmol) and 19.7 g Cs₂COj (60.5 mmol) were piaced in a 250 mL flask. 60 mL /m-butanol was added and the mixture was stirred at 8(TC under N₂ until no further conversion was observed. Water was added, then it was extracted with EtOAc. The combined organic layers were dried over Na₂SO«, fîltered and concentrated under reduced pressure to obtain Préparation 4f. MS: (M+H)⁺ - 643.0.

Préparation 4g: Ethyl (2/f)-2-J5-bromo-6-(5-cliloro-2-furyl)thleno|23*i/]pyrimidiu-4yl]oxy-3-|2-[|(2S)-tetrahydroftiran-2-yl]methoxy]phenyl]propanoate

0,315 g 5-bromo-4-chloro-6-(5-chloro-2-furyi)thieno[2,3-</]pyrimidine (Préparation 2d) (0.90 mmol), 0.267 g ethyl (2A)-2-hydroxy-3-[2-[[(25)-tetrahydrofuran-2yl]methoxy]phenyl]propanoate (Préparation 3af) (0.90 mmol) and 0.977 g Cs₂CO3 (3.00 mmol) were piaced in a 25 mL flask. 5 mL /err-butanol was added and the mixture was stirred at 65°C under N₂ until no further conversion was observed. Water was added, the pli was set to 8 with 2 M HCl, then it was extracted with DCM. The combined organic layers were dried over Na₂SO.|, fîltered, concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4g. MS: (M+Il)* = 607.0.

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

Préparation 4k; Ethyl (27?)-2-(5-iodo-6-prop-l‘ynyl-thieno[23-</]pyrimidh-4-yI)oxy3-(2-niethoxyphenyl)propanoate

0.669 g 4-chloro-5-iodo-6-prop-l-ynyi-thieno[2,3-i/]pyrimtdine (Préparation 2f) (2.00 mmol), 0.673 g ethyl (2/î)-2-hydroxy-3-(2-methoxyphcnyi)propanoate (Préparation 3ad) (3.00 mmol) and 1.955 g CS2CO3 (6.00 mmol) were placed in a 25 mL flask. 10 mL terl10 butanol was added and the mixture was stirred at 60°C under Nj 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 4k. ’H NMR 15 (400 MHz, CDClj): 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, 311), 3.49 (dd, III), 3.39 (dd, IH), 2.19 (s, 3H), 1.18 (t, 3H). MS: (M+H)* = 523.0.

Préparation 41: Ethvl (2JÎ)-2-(5-lodo-6-prop-l-ynyl-thieno[23-<flpyi*imidin-4-yl)oxy-320 (2-tetrahydropyran-2-yloxyphenyl)propanoate

8.92 g 4-chloro-5-iodo-6-prop-l-ynyl-thieno[2,3-d]pyrimidine (Préparation 21) (26.7 mmol), 8.83 g ethyl (2A)-2-hydroxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoale (Préparation 3ab) (30.0 mmol) and 293 g CS2CO3 (90.0 mmol) were placed in a 500 mL flask. 300 mL /ert-butanol was added and the mixture was stirred at 65°C under N2 until no 25 further conversion was observed. Brine was added, then it was extracted with DCM. The combined organic layers were dried over Na₂SO₄, filtered, concentrated under reduced pressure. The crude 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-Î6-Ethyl-5-iodo-thicno[23-*ftpy<’l^midin-4-yl)oxy-3-phcnylpropanoic acid

-43set to 8 with 2 M HCl, and then it was extracted with DCM. The combined organic layers were dried over Na₂SO_4> 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-dû): 5 8.69 (d, 1H), 7.87 (ni, 1H), 7.67 (m, JH), 7.57 (m, 1H), 7.44 (m, 1H), 7.20 (m, IH), 7.07 (m, 1H), 6.90 (t, 1 H), 5.82/5.70 (dd, IH), 5.62/5.56 (t, 1H), 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 4n: Ethyl (2R)-2-[5-bromo-6-(4-fluorophenyl)thienoP,3-rf]pyrimldin-410 yi]oxy-3-[2-[[(2R)‘tctrahydrofuran-2-yl]methoxy]phenyl]propanoate

4.12 g 5-bromo-4-chloro-6-(4-fluorophenyl)thieno[2,3-ri]pyrimidÎne (Préparation 2a) (12.0 mmol) and 3.80 g ethyl (2/î)-2-hydroxy-3-[2-[[(2Æ)-tetrahydrofuran-2yljmethoxyjphenyljpropanoate (Préparation 3bj) (12.9 mmol) were dissolved in 30 mL Zert-butanol, then 13.03 g Cs₂COj (40.0 mmol) was added and the mixture was stirred at 15 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-dé): 8.67 (s, IH), 7.76 (m, 2H), 7.42 (m, 2H), 7.38 (dd, ill), 7.21 (dt, iH), 6.98 (d, IH), 6.86 (t, IH), 5.71 (dd, IH), 4.20-4.09 (m, 311), 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, 20 iH), 2.04-1.78 (m, 4H), 1.12 (t, 3H).

Préparation 4q: Ethyl (2R)-2-(6-ethyi-5-iodo-tlileno[2,3-rf]pyrimldln-4-yl)oxy-3-(2methoxyphenyi)propanoate

2.809 g 4-chloro-6-ethyl-5-iodo-thicno[2,3-i/]pyrimidine (Préparation Jd) (8.92 mmol), 25 1.00 g ethyl (2/î)-2-hydroxy-3-(2-methoxyphenyl)propanoate (Préparation 3ad) (4.46 mmol) and 1.598 g Cs₂COj (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 overNa₂SO₄, filtered and concentrated under reduced pressure and purified via 30 flash chromatography using heptane and EtOAc as eluents to obtain Préparation 4q. MS:

(M+H)* = 513.0. ‘ f·

-45Step B; 4~Bromo-2-chloro-3-methyl-phenol mL BuLi solution in hcxanes (2.5 M, 120 mmol) was added dropwise to a solution of 12.1 g dry DIPA (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-bromo-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 réaction was quenched with 100 mL NH4OH solution and 200 mL NH4CI solution and extracted with EtOAc, dried over NajSO^ filtered and concentrated under reduced pressure. The resultîng 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 afïording 19.0 g crude product used without further purification. ’H NMR (200 MHz, CDClj): 7.32 (d, IH), 6.76 (d, IH), 5.62 (s, IH), 2.49 (s, 3H).

StepC: (4~Bromo~2-ch!oro~3-methvl-phenoxy)-lrlmethyl-silanc

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, CDCIi); 7.30 (d, IH), 6.63 (d, IH), 2.50 (s,3H), 0.28 (s, 9H).

Step D: 2-Chloro-3-melhyl-4-(4,4,5_t5-lelrameihyl-l,3,2-dioxaborolan-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 BuLÎ 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 passcd through a pad of silica gel using hexane and EtOAc as eluents. The crude product was recrystallized from a

-47Step B: (4-Bromo-2-chloro-3-mefhyl-phenoxy)-trilsopropyl-silanc

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

51.2 mL BuLÎ solution (10 M in hexanes, 0.512 mol) was added dropwise at -78°C. The 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 et this température and the reaction mixture was stirred ovemight without further cooling. The volatiles were evaporated under reduced pressure. The residue was dissolved în 1.5 L

EtOAc, washed with brine, dried over NaîSO^, 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. ^lH NMR (400 MHz, CDClj): 7.30 (d, IH), 6.68 (d, IH), 2.53 (s, 3H), 1.32 (septet, 3H), 1.14 (d, 18H).

Sten C: P-Chloro-3-methyl-4-(4,4,5,5-tetramefhyl-l,3,2-dioxaborolan-2-yl)phenoxy]tri isopropyl-s liane

178 g (4-bromo-2-ch1oro-3-methyl-phei»xy)-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^OC. The mixture was stirred for 5 minutes at this température. Then 116 mL 2-isopropoxy-4,4,5,5-tetramethy 1-1,3,2-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 13>2-dioxaborolane impurity was removed by distillation (80°C at 0.01 mmllg). The crude product was triturated in MeOH afîording Préparation 5c as a white solid. ’H NMR (400 MHz, CDCIj): 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-Chïoro-4-methoxy-2-methyLphcnyl)-4,4,5,5-tetraniethyI-133dloxaborolane

Λ

-49saturated NH4CI solution, extracted with EtOAc, 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 5e. MS (El, 70 eV) m/z (% relative intensity, [ion]): 55 (25), 83 (100), 93 (50), 225 (14), 295 (9), 395 5 (67),397(26).

Préparation 5f: l-|2-|2-Chloro-3-fIuoro-4-(4,4,5,5-tctrflniethyl-l,3,2-dioxaborolan-2yl)phenoxy]ethyl]-4-methyl-plperazlne

Sien Λ · l-[2-(4-Bromo-3-fluoro-phenoxy)ethyl]-4-methyl-piperazine

1.9! g 4-bromo-3-fluoro-phenoI (10.0 mmol), 1.73 g 2-(4-methylpiperazin-l-yl)ethanol (12.0 mmol) and 5.00 g immobilized PPhj (15.0 mmol) were dissolved in 30 mL dry toluene under N₂, then 2.99 g di/er/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-methyl-pipera2ine. MS (M+H): 317.2.

StenB: l-r2-i4-Bromo-2-chloro-3-fluoro-phenoxv)elhvll-4-methvl-niperazine

2.35 g l-[2-(4-bromo-3-fluoro-phcnoxy)ethyl]-4-methyl-piperazinc (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-bromo-2-chloro-3-fluoro-phcnoxy)ethyl]-4-methyl-piperazine. MS (M+H): 351.0.

Step C: ]-l2-[2-Chloro-3-Jluoro‘4-(4,4,5,5’telramethyl-l,3,2-dioxaborolan-2yl)phenoxy]ethyl]-4-methyl-piperazine

-51Step C: 12-ΕΙιιογο-3-ρκ^Ι-4-(4,4,5,5-tetramelhyl-l, 3,2-dioxaborolan-2-yI)phenoxy]~ triisopropyl-silane

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^-tetramethyl-l,3,2-dioxaboroIane (27.4 mmol) was added and the mixture was allowed to warm up to room température. Jt 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-methy]-4(4_i4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yJ)phenoxy]-triisopropyl-silane. MS (El, 70 cV) m/z (% relative intensity, [ion]): 77 (39), 83 (100), 195 (26), 223 (20), 241 (10), 323 (4), 365 (4).

StepD: 2-Fluoro-3-methyî-4-(4,4.5.5-tetramethyi-1.3.2-dioxaborolan-2-vl)phenol

6.00 g [2-fluoro-3-methyl-4-(4,4,5,5-tetramelhyl-1,3,2-dioxaborolan-2-yI)phenoxy]triisopropyl-silane (14.7 mmol) was dissolved in 20 mL THF, then 16.2 mL TBAF (16.2 mmol in I 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 Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 5g. ’lï NMR (400 MHz, DMSO-de): 10.09 (s, JH), 7.27 (dd, IH), 6.75 (t, IH), 2.36 (d, 3H), 1.27 (s, 12H), MS (El, 70 eV) m/z (% relative intensity, [ion]): 152 (100), 166 (18), 195 (21), 237 (18), 252(19, [M⁺]).

Prenaration 5h; l-Methyl-4-|2-[4-methyl-3-(4,4,5,5-tetramethyl-13>2-dioxaborolan-2yl)phenoxy]ethyl]piperazine

Step A: l-[2-(3-Bromo-4-melhy!-phenoxy)elhyl]-4-melhyl-piperazine

0.50 g 3-bromo-4-methyl-phenoI (2.67 mmol), 0.46 g 2-(4-melhylpiperazin-J-yl)ethano! (3.21 mmol) and 0.84 g PPhj (3.21 mmol) was dissolved in 10 mL dry THF under N₂, then ♦

-53Slep B: 2-(3-Ch!oro-5-fluoro-4-methoxy-2-methyl-phenyl)-4,4,5,5~ietramelhyl-l,3,2dioxaborolane

761 mg l-bromo-3-chloro-5-fluoro-4-methoxy-2-methyl-benzene (3.0 mmol) was dissolved în 15 mL dry THF under N₂ and was cooied to -78°C with 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-tetramethyJ-l,3^-dioxaborolane (3.4 mmol) was added and the mixture was allowed to warm up to room température. Tt 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 51. MS (El, 70 eV) m/z (% relative intensity, [ion]): 200 (100), 201 (57), 243 (52), 285 (26), 300 (35, [M*]),302(ll,[M*]).

Préparation 51; l-[3-Chloro-2-methoxy-4-methyl-5-(4,4,5,5-tdramethyl-l,3,2dioxaborolan-2-yl)phcnyl|-4-methyl-piperazine

SlepA: l-(5-Bromo-3-chloro-2-me(hoxy-4-mefhyl-phenyl)-4-methyl-piperazbie

1.27 g l-bromo-3-chloro-5-fluoro-4-methoxy-2-methyl-benzene (5.00 mmol, see Step A at 20 Préparation 51) was dissolved in 15 mL dry THF under N₂ and was cooied to -78“C with dry ice-acetone. Separately 0.58 mL i-mcthylpiperazine (5.25 mmol) was dissolved also in mL dry THF under N₂ and was cooied to 0°C with icy water. Then 3.3 mL BuLi (5.25 mmol in 1.6 M hexanes) was added and the mixture was stirred for 10 minutes, then it was cooied to -78^eC with dry ice-acetone. This latter mixture was transferred to the THF 25 solution of l-bromo-3-chloro-5-fliioro-4-methoxy-2-nnethyl-ben7ene 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.

Sien B: l-[3-Chloro-2-methoxy-4-methyl-5‘ (4,4,5,5-ielramelhyl-1,3,2-dioxaboro lan-2yl)phenyl]-4-methyl-piperazirte

-55772 mg 4-bromo-2-chloro-6-mcthoxy-3-methyl-phenol (3.07 mmol) and 788 pL TIPSC1 (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 5 (4-bromo-2-chloro-6-methoxy-3-methyl-phenoxy)-triisopropyl-silane. ’H NMR (400 MHz,

CDClj): 6.95 (s, IH), 3.77 (s, 3H), 2.44 (s, 3H), 1.30 (septet, 3H), 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).

Sten D: [2-Chloro-6-methoxy-3-methyl-4-(4,4.5,5-tetramethyl4.3,2-dioxaboro!an-2yl)phenoxy]-triisopropyl-si!ane

3.07 mmol (4-bromo-2-chloro-6-methoxy-3-methyI-phenoxy)-triisopropyl-silane was dissolved in 20 mL dry THF under Ni and was cooled to -78°C with dry ice-acetone. 2.1 mL BuLi (3.40 mmol in 1.6 M hexanes) was added and the mixture was stirred for 5 15 minutes, then 820 pL 2-isopropoxy-4,4,5,5-tetramethyl-l,3^-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-chloro20 6-metlioxy-3-inethyl-4-(4,4,5,5-tetramethyl-13i2-dioxaboroIan-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-Chloro-ti-meihnxy-3-methyl-4-(4.4,5,5-telramelhyl-1.3,2-dÎoxaboroIan‘225 yljpheno!

3.07 mmol [2-chloro-6-methoxy-3-methyl-4-(4,4,5,5-tetramethyl-l,3^-dioxaborolan-2yl)phcnoxy]-trïisopropyl-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 30 concentrated under reduced pressure, The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 5k. ^lH NMR (400MHz, DMSO-di): 9.71 (s, IH), 7.09 (s, IH), 3.79 (s, 3H),2.44 (s, 3H), 1.28 (s, 12H).

-57mL “BuLi (3.60 mmol in 1.6 M hexanes) was added and the mixture was stirred for 15 minutes, then 1.02 mL 2-îsopropoxy-4,4,5,5-tetramethyU,3»2-dÎoxaborolanc (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’tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]-triisopropyl-silane. MS (El, 70 eV) m/z (% relative Intensity, [ion]): 83 (100), 101 (30), 225 (14), 395 (54), 397 (21).

SispJlL 2-Chloro-3,6-dimelhyl-4-(4,4,5,5-ieiramethy!-l,3,2-dioxaborolan-2-y!)pheno!

968 mg [2-chloro-3,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]· triïsopropyl-silane (220 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 El₂O and EtOAc, washed with water and brine, dried over Na₂SO<, 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, III), 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, [M*]).

Préparation______5m: 2-CI>loro-6-nuoro-3-methyl-4-(4,43»5-tetraincthyl-l,3»2’ dioxaborolan-2-yl)phcnol

Sien À: 4-Bromo-2-chloro-6-fluoro-3-methyl-phenol

3.21 g 2-ehloro-6-fluoro-3-mcthyl-phenol (20.0 mmol) was dissolved in 60 mL THF, lhen 3.74 g NBS (21.0 mmol) was added and the mixture was stirred at room température for 10 minutes. Then ït was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain 4-bromo-2-chloro-6-fluoro· 3-mcthyi-phenol. ^lH 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*]).

-59(Eï, 70 cV) 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 Sn: 3-|2-Ch!oro-3-methyl-4-(4,4,5,5-tetramethy!-l,3,2-dioxaborolan-2y!)pheny!]-7V,/V-dlmethyl-propan-l-amine

Step A: l-Bromo-3-ch!oro-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 Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane as eluent to obtain l-bromo-3-chloro-4-iodo-2-methylbenzene. *H NMR (400 MHz, CDCI3): 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, [M^hJ), 332 (100, [M*]), 334 (25, [M*]).

Step B: 3-(4-Bromo-2-chloro-3-methy!-phenyl)-N, N-dimcthyl-prop-2-yn-1-amine

1.66 g l-brumo-3-chluro-4-iodo-2-inethyl-benzene (5.00 mmol), 626 pL N,Hdimethylprop-2-yn-l-amine (7,00 mmol), 176 mg PdCl₂(PPh3)2 (0.25 mmol) and 95 mg coppcr(I) iodide (0.50 mmol) were dissolved in 26 mL dry D1PA and the mixture was stirred at 40°C under N: 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)-M/V· dimethyl-prop-2-yn-l-amine. *H NMR (400 MHz, CDCI3): 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.

Sien C: 3-f4-Bromo-2-chloro-3-methvl-phenvl)-N.N-dimethyI-propan-l~amine

-61Step B: (2,4~Dibromo-3-melhyl~phenoxy)-triisopropy!-silane

11.15 g (2,4-dibromophenoxy)-triisopropyl-silane (27.3 mmol) was dissolved in 100 mL dry THF under N₂ and was cooled to -78^eC 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 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 (2,4-dibromo-3-methyl-phenoxy)10 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-(4,4,5,5-le!ramelhyl-l,3,2-dioxaborolan-2-yl)phenoyy]tri Isopropyl-silane

8.70 g (2,4-dibromO’3-tnethy)-phenoxy)-triisopropyl-silane (20.6 mmol) was dissolved in mL dry THF under N₂ and was cooled to -78°C with dry ice-acetone. 14.2 mL BuLi (22.7 mmol in 1.6 M hexanes) was added and the mixture was stirred for I minute, then

6.1 mL 2-Îsopropoxy-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 20 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, CDClj): 7.57 (d,

IH), 6.71 (d, IH), 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-Dlchloro-4-(4,4,5,5-tetraiuethyl-l,3,2-<lioxabQrolan-2yl)phenoxy]ethyl]-4-mcthyl-piperazitie

Step A: 4-Bromo~2,3-dichloro-phenol

1.63 g 2,3-dichlorophenol (iO.O 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 τοοιη température ovemight. Then it

-63Step Al 5-Bromo-3-chloro-4-methyl-pyridin-2-ol

4.86 g 5-bromo-4-methyl-pyridin-2-ol (25.8 mmol) was dissolved 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 crystallîzed from Et₂O and heptane to get an overweight product, which was crystallized from 100 mL MeCN to give 5-bromo-3-chloro-4-methy!-pyridin-2-oI. ’H NMR (400 MHz, DMSO-d_e): 11.50 (br s, IH), 7.74 (s, IH), 2.36 (s, 311). MS (M+Il): 222.0, (M-H): 220.0.

Step B: ! -[2-[(5-Bromo-3-chloro-4-methyl-2-pyrldyl)oxy]ethylJ-4-methyl-plperazlne

2.326 g 5-bromo-3-chIoro-4-methyl-pyridin-2-ol (10,45 mmol), 2.163 g 2-(4melhylpiperazin-l-yl)ethanol (15.00 mmol) and 3.935 g PPhj (15.00 mmol) were dissolved în 30 mL dry toluene under Nj, then 3.454 g di/er/butyl azodicarboxylate (15.00 mmol) was added and the mixture was stirred at room température under N₂ for 20 minutes. Then ît 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 Ι-[2-[(5-ΒΓοηιο-3<1ιΙθΓθ-4-πΐΐ11ιγΙ-2-ργΓΪάγΙ)οχγ]εΐ1ιγ1]-4-ιηεΐΗγ!·ρΐρεΓ3ζΐηο. Ή NMR (400 MHz, DMSO-d₆): 8.24 (s, IH), 4.41 (t, 211), 2.68 (t, 2H), 2.48-2.15 (m, 1III), 2.12 (s, 3H). MS (M+H): 348.0.

Step C: l-[2-[[3-Chhro-4-methyl-5-(4,4,5_l5-tetramethyl-l,3_l2-dioxaborolan-2-y!)-2pyrldyl]oxy]cthyl]-4-mcthyl-pipcrazinc

1.917 g l-[2-[(5-bromo-3-chloro-4-methyl-2-pyridyl)oxy]elhy!]-4-methyl-piperazine (5.50 mmol) was dissolved in 30 mL dry THF under N₂ and was cooled to -78°C with dry iceacetonc. 4.1 mL BuLi (6.60 mmol in 1.6 M hexanes) was added and the mixture was stirred for 5 minutes, then 1.46 mL 2-isopropoxy-4,4,5,5-tctramethyl-l,3,2-dioxaboro!ane (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 Na₂SO₄, 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.

-65SrepD: l-[3-(4-Bromo-2-chloro-3-me!hvl-phenvl)prom>!l-4-mefhyl-piperazine

1.51 g l-[3-(4-bromo-2-chloro-3-methyl-pheny1)prop-2-ynylJ-4-methyl-piperazine (4.42 mmol) was dissolved in 15 mL AcOll, then 500 mg red phosphores and 10 mL H1 (67% aqueous solution) was added. The mixture was heated to 180°C for 5 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 NfyHCCb solution and MeCN as eluents to obtain l-[3-(4-bromo-2-ch!oro-3methyl-phenyl)propyll-4-methyl-pipcrazine. *H NMR (400MHz, DMSO-de): 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: 1 -[3-(2-ChIoro-3-methyl-4 -(4,4,5,5-tetramethyl-l, 3,2-dioxaboro lan-2yl)phenyl]propyl]~4~methyl-plperazine

708 mg l-[3-(4-bromo-2-chloro-3-methyl-phenyl)propyl]-4-methyl-piperazinc (2.04 mmol) was dissolved in I0 mL dry THF under N₂ and was cooled to -78°C with dry iceacetone. 1.7 mL BuLi (2.70 mmol in 1.6 M hexanes) was added and the mixture was stirred for 5 minutes, then 0.61 mL 2-isopropoxy-4,4,5,5-tetramethyl-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 NH1HCO3 solution and MeCN as eluents to obtain Préparation 5r. MS (M+H): 393.4.

Préparation 5s: l*|2-[23-dlmethyI-4-(4,4^^-tetramethyl-13i2*dlox»borohn-2y l)ph enoxy] ethyl | -4-m e t h y 1-p i pentzinc

St en A: 4-Bromo-2,3-dimethyl-phenol i .22 g 2,3-dîmethylphénol (10.0 mmol) was dissolved in 50 mL MeCN, then 1.78 g NBS (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-dimetliyl-phcno!. ’H NMR (40û|

-67tetramethyl-1,3,2-dioxaborolanc (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-de): 7.49 (d, IH), 7.45 (d, IH), 2.66 (s, 3H), 1.34 (s, 12H).

Préparation 6a; Ethyl (2R)-2-[(5S^, _d)-5-(3-cliloro-4-hydroxy-2-methyl-phenyl)-6-(4fluorophenyl)thleno [2_f3-ⁱ/]pyriniidin-4-yl]oxy-3-(2-tetrahydropyran-2· y loxypheny I)propan oat e

186.6 g ethyl (2Æ)-2-[5-bromo-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-ylloxy-3-(2tctra-hydropyran-2-yloxyphcnyl)propanoatc (Préparation 4a) (310.3 mmol) and 99.99 g 2«ch!oro-3-methy!-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 shakîng the pH ofthe 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 Na₂SOe, fïltered 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 6a. *H NMR (500 MHz, DMSO-de, 1:1 mixture of diastereomers): 10.27 (br s, IH), 8.60 (s, 111), 7.30 (m, 2H), 7.22 (m, 2H), 7.16/7.14 (d, IH), 7.12 (m ,1H), 7.00 (d, III), 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 (brs, IH), 1.85/1.83 (s, 3H), 1.79 (brs, 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-[(55^, _e)-S-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(4fluorophenyl)tblenoI2,3-rf]pyrimldin-4-yI]oxy-3-12-(pyrazln-2ylmcthoxy)phenyl]propanoate

2.52 g ethyl (2Æ)-2-[5-bromo-6-(4-fluorophenyl)thîeno[2,3-rf]pyrimidin-4-yl]oxy-3-[2(pyrazin-2-ylmethoxy)phenyl]propanoate (Préparation 4b) (4.1 mmol) and 2.2 g 217201

-69The 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 earlier was collected as Préparation 6q. NMR (500 MHz, DMSO-de, 1:1 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-de, 1:1 mixture of diastereomers): 10.40 (s, IH), 8.58 (s, IH), 7.15 (t, IH), 7.10 (d, 1H),7.O4 (d, 1 H), 7.01 (d, IH),6.81/6.80 (t, IH), 638/636 (d, 1H),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), 236 (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 (2Κ)-2-|(53;)-5-(3·€ΐιΙοπ>-4-Ι^(ΐΓθχγ-2-ιηβί1ιγ1-ρ1^1)-6-(2furyl)thieno[23’</]pyrimldin-4-yl]oxy-3-(2-tetrahydropyran-2yloxyphenyl)propanoate

363 g ethyl (27?/2-[5-bromo-6-(2-furyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 4d) (633 mmol) and 18.7 g 2chloro-3-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-diuxaburolan-2-yi)phenol (Préparation 5a) (69.6 mmol) were dissolved în 400 mL THF, then 32.6 g CsîCOj (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 end brine. After shakîng 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 6d. *HNMR (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

-71was observed. Then it was diluted with dichloromethane and brine. After shaklng the pH of the aqueous phase was set to 6 with 2 M HCI. 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 (27f)-2-[6-(5-chloro-2-furyl)-(55_ff)-5-(3-ch!oro-4-hydroxy-2rnethyl-phenyl)-thleno[23-rf]pyrimidin-4-yl]oxy-3-I2-I[(2S)-tctrahydrofuran-210 yl]methoxy]phenyl]propanoate

547 mg ethyl (2Â)-2-(5-bromo-6-(5-chloro-2-furyI)thieno[2,3-rf]pyrimidin-4-yl]oxy-3-[2[[(2S)-tetrahydrofuran-2-yl]methoxy]phcnyl]propanoate (Préparation 4g) (0.752 mmol) and 403 mg 2-chloro-3-methyl-4-(4₎4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yI)phenol (Préparation 5a) (1.5 mmol) were dissolved in the mixture of 5 mL THF and 5 mL 1,415 dïoxane, then 652 mg CS2CO3 (2.0 mmol) dissolved in 5 mL water was added. Then 53 g

AtaPhos (0.075 mmol) was added, rînsed with nitrogen, heated at lOO’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 6 with 2 M HCl. After phase séparation the aqueous phase was extracted with dichloromethane. The 20 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 6g. MS: (M+H) « 669.0.

Préparation 6h: Ethyl (2/?J-2-|(5.Ç_(f)-5'(3’Chloro-4-hydroxy-2-methykphenyI)-6-(4fluoro-3-mcfhoxy-phenyl)thleno[23-rf]pyrimldin-4-yl]oxy-3-(2-tetrahydropyran-2yloxyplienyl)propanoafe

22.0 g ethyl (2Æ)-2-[5-bromo-6-(4-fluoro-3-methoxy-phenyl)thieno[2,3-</]pyTimÎdin-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 5a) (41,80 mmol) were dissolved in 200 mL THF, then 34.05 g Cs₂COj (104.5 mmol) dissolved in 200 mL water was added. Then 2.46 g AtaPhos (3.48 mmol)

-73The diastereoîsomer eluting later was collected as Préparation 61. 'H NMR (500 MHz, DMSO-de): 10.26 (br s, IH), 8.52 (s, IH), 7.14 (m, 3H), 6.97 (d, IH), 6.94 (d, IH), 6.65 (m, 2H), 5.30 (dd, IH), 3.64 (s, 3H), 2.99 (dd, IH), 2.66 (m, 2H), 2.54 (dd, IH), 2.17 (s, 3H), 1.15 (t, 3H). HRMS: (M+H) = 483.1126.

Préparation______6j; Methyl (2/?)-2-|6-ethyl-(55_e)-5-(4-hydroxy-2-inethylphenyI)thleno[23-d]pyrimldin-4-ylloxy-3-phcnyl-propanoatc and

Préparation 6o; Methyl f?ÆJ-2-|6-ethyl-(5R₍,)-5-(4-hydroxy-2-niethylphenyl)thieno[23-rf]pyrimldin-4-yI]oxy-3-phenyl-propanoaic

2.25 g methyl (7i)-2-(6-ethyl-5-iodo-thieno|2,3-i/]pyrimtdin-4-yl)oxy-3-phenylpropanoate (Préparation 41) (2.67 mmol) and 1.76 g 3-methyl-4-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)phenol (8.0 mmol) were dîssolved în 15 mL 2-Me-THF, then 2.75 g AgîCOj (10.0 mmol) was added. Then 309 mg Pd(PPhj).( (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 diastercoisomcr eluting carlîcr was collected as Préparation 6j. ’ll NMR (500 MHz, DMSO-de): 9.44 (s, IH). 8.52 (s, IH), 7.16 (m, 3H), 7.05 (d, IH), 6.78 (d, IH), 6.76 (dd, IH), 6.70 (m, 2H), 5.47 (dd, IH), 3.54 (s, 3H), 2.95 (dd, IH), 2.68 (dd, IH), 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-de):9.64 (s, IH), 8.50 (s, IH), 7.14 (m, 3W), 6.94 (d, IH), 6.82 (d, IH), 6.77 (dd, IH), 6.66 (m, 2H), 5.28 (dd, IH), 3.64 (s, 3H), 2.97 (dd, IH), 2.64 (m, 2H), 2.58 (dd, IH), 2.08 (s, 3H), 1.14 (st, 3H). HRMS: (M+H) = 449.1540.

Préparation 6k; Ethyl (2R)-2-|(5S'_l,)-5-(3-chloro-4-hydroxy-2-mcthyl-phenyI)-6-ethyl· thieno|23-rf]pyrlmldln-4-yI|oxy-3-(2-tetrahydropyran-2-yloxyphenyI)propanoatc 5.0 g ethyl f2/f)-2-(6-ethyl-5-îodo-thieno[2,3-i/Jpyrimidin-4-yl)oxy-3-(2-tetrahydropyran· 2-yloxyphenyI)propanoate (Préparation 4j) (9.33 mmol) and 3.22 g 2-chloro-3-methyl-417201

-75Préparation 6m; Ethyl (2JI>2-[(5£₍)-5-(3-ehloro-4-hydroxy-2*nicthyl-phenyl)-6-propl-ynyLthieno[2,3-if]pyrlniidin-4-yl]oxy-3-(2-tetrahydropyran-2yloxyphenyljpropanoate

10.59 g ethyl (2J?J-2-(5-iodo-6-prop-l-yny!-thieno[2,3-Î/]pyrimidin-4-y])oxy-3-(2tetrahydropyran-2-yloxyphcnyl)propanoatc (Préparation 41) (17.87 mmol) and 5.76 g 2chloro-3-methyl-4-(4,4,5,5-tctramethyl-l,3,2’dioxaborolan-2-yl)phenol (Préparation Sa) (21.45 mmol) were dissolved in 100 mL THF, then 11.64 g CS2CO3 (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 observed.

Then it was diluted with dichloromethane and brine. Afïer 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 Na^SO^ filtered and concentrated under reduced pressure. The diastereolsomers were separated via flash 15 chromatography using heptane and ethyi acetate as eluents. The diastereoisomer pair eluting later was collected as Préparation 6m. MS: (M+H) = 607.0.

Préparation 6n; Ethyl (2Jî)-2-[(55’_f)-5-(3-chloro-4-hydroxy-2-niefhyl-phenyl)-6-(3,4dlfluorophenyl)thleno[23-//]pyrim!din-4-yl]oxy-3-(2-tetrahydropynm-220 ytoxyphenyl)propanoatc

9.18 g ethyl (2/y-2-[(5S'_e)-5-bromo-6-(3,4-dÎfluorophenyl)lhieno[2,3-<f|pyrimidin-4· yl]oxy-3-(2'tctrahydropyran-2-yloxyphenyl)propanoale (Préparation 4o) (14.82 mmol) and 5.17 g 2-ch!oro-3-mcthyl-4-(4,4,5_I5-tetramethyl-l,3,2-dioxaborolan-2-y!)phenoI (Préparation 5a) (19.26 mmol) were dissolved in 50 mL THF, then 6.52 g CsiCOj (20 25 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. Afïer shaking the pH of the aqueous phase was set to 8 with 2 M HCl. After phase séparation the aqueous phase was extracted 30 with dichloromethane. The organic layers were combined and dried over NajSO₄, filtered and concentrated under reduced pressure. The diastercoïsomers were separated via flash chromatography using heptane and ethyl acetaie as eluents. The diastereoisomer pair

-779.17 g ethyl (2JîJ-2-[5-bromo-6-(4-nuon)phenyl)(hieno[2,3-i/]pyrimidin-4-y]Joxy-3-[2(2,2,2-trifluoroethoxy)pheny]Jpropanoate (Préparation 4s) (15.35 mmol) and 4.95 g 2chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pheno] (Préparation 5a) (18.42 mmol) were dissolved In 50 mL THF, then 15.00 g Cs₂CO₂ (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 ofthe volatiles were evaporated under reduced pressure and it was diluted with brine. The pH was set to 6 with 2 M HCl, and the mixture was extracted with dichloromethane. The combined organic layers were dried over Na₂SOi, 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-ds): 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 (2R)-2-[(55_e)-5-|3-chloro-2-methyl-4-|2-(4-methylplperazln-lyI)ethoxy]phenyll-6-(4-fluoropheny])thieno|23-dlpyrlmid]n-4-yl]oxy-3-(2tetrahydropyran-2-yloxyphenyl)propnnoate

132.3 g ethyl (2R)-2-[(5S'_e)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(4-fluorophenyl)thieno[2,3-rf]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 6a) (199.5 mmol), 43.17 g 2-(4-methylpipcrazin-l-yl)cthanol (299.3 mmol) and 94.20 g PPh3 (359.1 mmol) were dissolved in 1 L dry toluene, then 78.09 g direr/butyl azodicarboxylate (3392 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 Et₂O was added, and the mixture was stirred and sonicated. The precipîtated white crystais 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.

-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.

Préparation 7c; Ethyl (2/y-2-[(&9_a)-5-[3-chloro-2-methyl-4-[2-(4-methylplperazin-lyl)ethoxy]phenyl]-6-(2-furyI)thicno[23A]pyrinildin-4-yl]oxy-3-(2-tctrahydropyran-2yloxyphenyl)propanoate

19.05 g ethyl (7Æ)-2-[(5S_<I)-5-(3’Chloro-4-hydroxy-2-metliyl-phenyl)-6-(2-furyl)thieno[2,3i(]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 6d) (30 mmol), 8.65 g 2-(4-methylpîperazin-l-yl)ethanol (60 mmol) and 15.74 g PPhj (60 mmol) were dissolved in 200 mL dry toluene, then 13.81 g difcrtbutyl 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 obtain Préparation 7e. MS: (M+H)* = 761.2.

Préparation 7f; Ethyl (2R)*2-[(5S'₄)-5-[3-chIoro-2-methy1-4-|2-(4’methylpiperazin-lyI)ethoxylphenyl]-6-(4-fluoro-3-methoxy-phenyI)thieno|23-d]pyrimidln-4-yl]oxy*3(2-tetrahydropyran-2-yloxyphenyI)propanoate

13.5 g ethyl (7Æ)-2’[(5&)-5-(3<hloro-4-hydroxy-2-methyl-phenyl)-6-(4-fluoro-3methoxy-phenyl)thicno[2,3A]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran'2yioxyphenyl)propanoate (Préparation 6h) (13.5 mmol), 5.62 g 2-(4-methylpiperazin-lyl)ethanol (39 mmol) and 10.22 g PPhj (39 mmol) were dissolved in 250 mL dry toluene, then 10.22 g diter/butyl azodicarboxylate (39 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 7f. MS: (M+H)* = 819.0.

Préparation 7e; Ethyl (2/t)-2-[(55'_e)'5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]ρhenyl|-6-ethyl·thi¢no|23-rf]ρyrimidin-4-yl|oχy-3-(2-tetrahydroρyran-2· yloxyphenyl)propnnoate

-81Prenaration_7i; Ethyl (21î)-2-[(5S_ï)-5-[3-chloro-2-metliyl~4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl|-6-(3,4-difluorophcnyl)thieno|2,3-d]pyriinidin*4-yl]oxy-3-(2tctrahydropyran-2-yloxyphenyl)propanoate

6.85 g ethyl (2/?J-2-[(55'_û)-5-(3-chloro-4-hydroxy-2-mcthyl-plieny!)-6-(3,4dinuorophcnyl)thïcno[2,3-if]pyrimidin-4-yl]oxy-3-(2-tctrahydiOpyran’2yloxyphcnyl)propanoate (Préparation 6p) (10.06 mmol), 2.90 g 2-(4-methyipiperazin-lyljethanol (20.12 mmol) and 5.27 g PPhj (20.12 mmol) were dissolved In 20 mL dry toluene, then 4.63 g diferfbutyl azodicarboxylate (20.12 mmol) was added. The mixture to was stirred at 50°C under Ni 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 (2Jî_j)-2-[(5S'_ff)-5-|3-chloro-2-niethyl-4-|2-(4-niethylpipcn»zin«l15 yI)ethoxy[phcnyl]-6-(2,3*difluorophenyl)thicno|2,3-d]pyrlmldin-4-yl]oxy-3-(2tetrahydropyran-2-yloxyphenyl)prOpanoate

Step À: 5-Bromo-4-chloro-6-(2,3-difluorophenyl)thleno[2,3-dJpyrimld'ne

9.39 g 5-bromo-4-chloro-6-iodo-thieno[2,3-if]pyrimïdine (Préparation la) (25 mmol), 20 9.00 g 2-(2,3-dïfluorophcnyl)’4,4,5,5-tctramcthyl-l,3,2-dioxaborolanc (37.5 mmol), 16.29 g CS3CO3 (50 mmol), and 0.912 g Pd(dppf)Cli (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 Ni 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 25 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 CnIUBrCIFiNiS: 359.8935, found: 360.9013 (M+H).

Sten B: Ethyl (2R)-2~[5-bromo-6-(2,3~dlfluorophenyl)thleno[2,3-d]pyrlmldin-4'yl]oxy-3~ (2-tetrahydropyran-2-yloxyphenyl)propanoate

-83Sfep D; Ethyl (2R)-2f(5Sa)-5-[3-chloro-2-tnethyl-4-[2~(4-meihylpiperazin~]yl)ethoxy]phenyl]-6-(3.4-àifl tiorophenytythl eno[2,3-d]pyrimidin -4-yl]oxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate

S 6.49 g ethyl f2Â_/)-2-[(5S_i,)-5-(3-chloro-4-hydroxy-2-methyl-pheny])-6-(2,3difluorophcnyl)thicno[2,3-i/]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2-yloxyphcnyl) propanoate (9.5 mmol), 2.75 g 2-(4-methylpiperazin-l-yl)ethanol (19 mmol) and 4.98 g

PPhj (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-dfi, 1:1 mixture of diastereomers):

8.67 (s, 1 H), 7.48 (m, IH), 7.22-7.17 (m, 3H), 7.13 (t, 1 H), 7.10 (d, 1H), 7.01 (d, IH), 6.72 (t, IH), 6.33/6.28 (d, IH), 5.54/5.51 (m, IH), 5.45 (dd, IH), 4.18 (m, 2H), 4.03 (m, 2H),

3.68/3.54 (m, 2H), 3.02/2.99 (dd, IH), 2.69 (t, 2H), 2.56 (m, IH), 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 C4₂H4sCIF₃N2O_eS: 806.2716, found: 8073763/807.2793 (M+H).

Préparation 8a; Elhyl f2/î)-2-[(5S'_i7)-[3-chloro-2-methyl-4-|2-(4-methylplperazin-lyI)elhoxy]phenylJ-6-(4-fIuorophenyl)thleno[2,3’<flpyrimldin-4-ylIoxy-3-(220 hydroxyphenyl)propanoate

199.5 mmol ethyl (2/y-2-[(55^, _tf)-[3-chIoro-2-methyl-4-[2-(4-methylpiperazin-l-yl)elhuxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-y!Joxy-3-(2-tetrahydropyran-2-yloxyphenyl)-propanoate (Préparation 7a) was dissolved in i L EtOH, then 1 L 1.25 M HCl in E1OH was added and the mixture was stirred al room température until no further 25 conversion was observed. Most of the EtOH was evaporated, then Et2Û was added and the precipitated HCl sait (white solid) was fîltered, washed with Et₂O. The HCl sait was carefolly treated with saturated NaHCOj solution, extracted with DCM, the combined organic phases were dried over Na₂SÛ4, fîltered and concentrated under reduced pressure to give Préparation 8a. 'H NMR (400 MHz, DMSO-d₆): 9.53 (br s, IH), 8.60 (s, IH), 30 7.30 (m, 2H), 7.28 (d. IH), 7.21 (m, 2H), 7.16 (d, 1 H), 6.97 (t, 1 H), 6.72 (d, JH), 6.53 (I,

JH), 6.20 (d, JH), 5.46 (dd, IH), 4.22 (m, 2H), 4.04 (m, 2H), 2.92 (dd, JH), 2.75 (m, 2H),

-85as eluents to obtain Préparation 8c. ’H NMR (500 MHz, DMSO-de): 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). HRMS calculated for C_îîH₃₆CIFN₄0ûS: 694.2028, found: 695.2106 (M+H),

Préparation 8d; Ethyl (2jy-2-I(5S'_fl)-5-J3-chloro-4-(2-dimethylamÎnoethyloxy)-2· mcthyl-phenyl]-6-(5-fluoro-2-furyl)thleno|23-</Jpyrimidin-4-yl]oxy-3-(2hydroxypheny1)propanoate

30 mL 1.25 M HCi in EtOH was added to 1.5 mmol ethyl (25)-2-[(5S_a)-5-[3-chloro-4-(2dimethylaminoethy!oxy)-2-inethyi-phenyl]-6-(5-fluoro-2-furyl)thieno[2,3-</]pyrimidÎn-4yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 7d) and the mixture was stirred until no further conversion was observed. The reaction mixture was carefully diluted with saturated NaHCOj solution 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 EtOAc and MeOH as eluents to obtain Préparation 8d. ’HNMR (500 MHz, DMSO-dé): 9.56 (br s, IH), 8.58 (s, 1H), 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 (1, 2H), 2.35 (dd, IH), 2.23 (s, 6H), 1.98 (s, 3H), 1.06 (t, 3H). HRMS calculated for

CjiHjiCiFNjOfiS: 639.1606, found: 640.1679 (M+H).

Préparation 8c: Ethyl (2Æ)-2-[(55(,)-5-13-chloro-2-methyl-4-[2-(4-niethyIpiperazin-lyl)ethoxy]phenyl]-6-(2-furyl)thlenoJ23-rf|pyrimldin-4-yI]oxy-3-(2-hydroxyphenyl) propanoate mmol ethyl (2i)-2-[(5S_tf)- 5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(2-furyI)thieno[2,3-i/]pyrimîdin-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 NaHCOj solution was added, and the reaction mixture was extracted with DCM. The combined organic layers were dried over NaîSO₄, liltered and concentrated under reduced pressure. The crude product was purified via flash

-87over Na₂SO₄, filtered and concentrated under reduced pressure. The cnide 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), 3 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(brs,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 CajHwClFN^S: 734.2341, found: 735.2406 (M+H).

Préparation 8h; Ethyl (2R)-2-[(5S’_rt)-5'[3-chloro-2-methyl-4-[2-(4-inethylpipernzin-l· yl)ethoxyIphenyl[-6-ethyl-thleno[2,3-<Z]pyrinildin-4-yl]oxy-3-(2hydroxyphenyl)propanoate mmol ethyl f2R)-2-[(55_e)-5-[3-ch!oro-2-methyl-4-[2-(4-methylpiperazin-ly!)ethoxy]phenyi]-6-cthy!-thieno|2,3-i/Jpyrimidin-4-ylJoxy-3-(2-tetrahydropyran-2t5 yloxyphenyljpropanoate (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 NaHCOj solution was added and the réaction 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 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 CîîHjîCIFN^OjS: 638.2330, found: 639.2377 (M+H).

Préparation 81; Ethyl (2A)-2-[(55_e)-5-[3-chloro-2-methyl-4-[2-(4-methylplpenizln-ly l)ethoxy ] ph en y l]-6-pro p-1-y nyl-thlen o[2,3-rf] py rlm Id in-4-y 11 oxy-3-(2hydroxyphenyljpropanoate

10 mmol ethyl (2R)-2-[(5S_e)-5-[3-chloro-2-methyl-4-[2-(4-methylpîperazin-ly 1 Jethoxy ] p heny I ]-6-prop-1 -yny 1 -thieno[2,3 -c/J py ri mid in-4-yl]oxy-3 -(2-tctrahyd ropyran-2 yloxyphenyljpropanoate (Préparation 7h) was dissolved in 100 mL EtOH, then 40 mL

-89The obtained ethyl (27y-2-[5-[5-chloro-4-methyl-6-[2-(4-methylpiperazin-l-yl)ethoxy]-3pyridylJ-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidÎn-4-yl]oxy-3-(2-tetrahydtOpyran-2· yloxyphenyl)propanoate was dissolved in 50 mL EtOH, then 10 mL 1.25 M HCl in EtOH was added and the mixture was stirred at room température untii no further conversion was observed. Saturated NaHCOj solution was added carefully and the mixture was extracted with DCM, the combined organic phases were dried over Na₂SO<, 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, LH),

J0 8.07/7.68 (s, LH), 7.37-7.31 (m, 2H), 7.27-7.22 (m, 2H), 6.98/6.96 (td, LH), 6.72/6.70 (dd, IH), 6.54/6.48 (td, LH), 6.29/6.05 (dd, LH), 5.55/5.42 (dd, LH), 4.60-4.41 (m, 2H), 4.074.0L (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 (2/?J-2-[(55,)-5-[3-chIoro-2-mctliyI-4-{2-(4-methylpipcrazin-lyI)ethoxy]phenyI|-6-(3,4-difluorophenyl)thicno[23-d]pyrlmidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate

7.85 g ethyl (2/y-2-[(55_e)-5-[3-chloro-2-methyl-4-|2-(4-methylpiperazin-ly])ethoxy]phenyl]-6-(3,4-difluorophcnyl)thieno[2,3-</]pyrimidin-4-yl]oxy-3-(220 tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 7j) (9.72 mmol) was dissolved in 70 mL EtOIl, then 50 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 EtOIl was evaporated then water and saturated NaHCOj solution were added and the mixture was extracted with DCM. The combined organic layers were dried over Na₂SOi, 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-de): 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, JH), 6.97 (t, IH), 6.71 (d, JH), 6.53 (t, IH), 6.19 (d, IH), 5.46 (dd, IH), 4.23 (m, 2H), 4.04 (m, 2H), 2.92 (dd, III), 2.73 (m, 2H), 2.50 (br s, 4H), 2,43 (dd,

JH), 2.25 (br s, 4H), 2.10 (s, 3H), 1.89 (s, 3H), 1.06 (t, 3H). HRMS calculated for C37HJ7CIF2N4O5S: 722.2141, found: 723.2211 (M+H).

-91Préparation 8m: Ethyl f27?)-2-[(55'_i)'5'|3-chIoro-2-methyl-4-|2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(23-dinuorophenyl)thIenol23-rf]pyrlmidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate

9.72 mmol ethyl (2/î)-2-[(5S'a)-5-[3-chloro-2-methyI-4-[2-(4-methy!piperazin-lyl)cthoxy]phcnyl]-6«(2,3-difluorophcnyl)thicno[2,3-</]pyrimidin-4-yl]oxy-3-(2tetrahydropyran-2-y!oxypheny!)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 NaHCOj solution were added and the mixture was extracted with DCM. The combined organic layers were dried over NaiSQ», filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using EtOAc and MeOH as eluents to obtain Préparation 8m. ^lH NMR (500 MHz, DMSO-d₆): 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, 1 H), 6.52 (ζ 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 C37H37CIFÎN4OJS: 722.2141; found 723.2177 (M+H).

Unless otherwise specified, most of the compounds of Préparation 9aa to 9ei were obtained using Gcncrnl 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. Réaction mixture was cooled to 0°C, then NaOH (5.7 eq.) was added portionwise. The pH was adjusted to 8 using 10% KîCQj solution, then sodium borohydridc (2.0 eq.) was added portionwise keeping the température under 5“C and the mixture was stirred for 30 min at 0°C. Réaction mixture was extracted with EtOAc, the combined organic phases were dried over NaîSO^ filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents.

-93General procédure 9E;

To the solution of the appropriate methylsulfonyl dérivative (Préparation 9a3 1.0 eq.) in dry acetonîtrile (3ml/mmol) K.2CO3 (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 fïltrate was concentrated under reduced pressure. Crude product was purified via flash chromatography using heptane and EtOAc as eluents.

General procedure 9F;

To the solution of 1 H-pyrazole (1.0 eq.) in DMF (0.5 mL/mmol) KOH (1.0 eq.) was added, then it was cooled to 0^eC, and the appropriate halide was added (1.0 eq.) dropwise. The 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 MgSO4, filtered and concentrated under reduced pressure, 'llie crude product was purified via flash chromatography using heptane and EtOAc as eluents.

General procedure 9G;

To the suspension of sodium hydride (1.10 eq.) in tetrahydrofurane (0.20 mL/mmol) was added the solution of pyrazole (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 température for 30 minutes, the appropriate halide (1.20 eq.) was added and the mixture was stirred further at same température for 16 hours. Ncxt, the réaction mixture was refluxed for 15 hours. After completîon the resulting precipitate was filtered off, the fïltrate 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 combined organic layers were dried over NaîSO4, filtered and concentrated under reduced pressure. The crude product was purified via distillation.

-95198 g sodium methoxide (3,67 mmol) was dissolved in 3 L MeOH and cooled to O’C. 322 g thiocarbamide (4.23 mol) was added portionwise and the mixture was stirred for 1 hour. Then 488 g (£)-4-(dimethyIamino)-l,l-dimethoxy-but-3-en-2-one (Préparation 9al) (2.82 mol) was added dropwise at O^eC, 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, keeping the température below 28°C, and the resulting mixture was stirred ovemight at room température. It was filtered, 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 iayers were dried over Na₂SO<, filtered and concentrated under reduced pressure. The residue was dissolved in 500 mL Et₂O, filtered 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-d_fi): 8.69 (d, IH), 7.23 (d, IH), 5.22 (s, IH), 3.33 (s, 6H), 2.52 (s, 3H).

Préparation 9a3; 4-(Dimethoxymethyl)-2-methylsulfonyl-pyrlmidlne

To solution of 180 g 4-(dimethoxymethyl)-2-methylsulfanyI-pyrimidine (Préparation 9a2, 940 mmol) in 1.5 L methanol and 1.5 L H₂O 752 g Oxone (potassium pcroxymonosulfate, 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 filtered, and the précipitâtes were was washed with DCM. The filtrate was extracted with DCM. The combined organic layers were dried over MgSO₄, filtered and concentrated under reduced pressure to give a light brown oil. *H NMR (400 MHz, CDGî): 8.98 (d, IH), 7.97 (d, IH), 5.36 (s, IH), 3.47 (s, 6H), 3.39 (s, 3H).

Préparation 9a4; 2-Methvbulfonvl-4-(tctrahvdronvran-2-vloxvmethvl)nyrlmldine

SfepA:

To solution of 7.24 g (2-methyIsuIfanyIpyrimidin-4-yi)methanol (Préparation 9aa, 47.5 mmol) and 30.0 g 3,4-dihydro-2H-pyran (357 mmol) in 150 mL DCM 452 mg of p30 toluenesulfonic acid monohydrate (230 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

-97Step 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 1 hour. Then 3,46 g (E)-4-(dimetbylamino)-l,1-dimethoxy-but-3-en-2-onc (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 l -bromo-2-methoxy*ethane (30 mmol) was added and the mixture was stirred 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 NajSO^ and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl-acctate as eluents to give a light yellow oil (4-(dimcthoxymethyl)2-(2-methoxyethylsulfany!)pyrimidine). ’H NMR. (400 MHz, DMSO-di): 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(i): 8.60 (d, IH), 7.25 (d, IH), 5.63 (t, IH), 4.48 (d, 2H), 3.57 (t, 2H), 3.29(1,2H), 3.27 (s, 3H).

Préparation 9«cî [2-(3-Methoxypropylsulfanyl)pyrimidin-4-yl]methanol

RepAi

2.44 g thiocarbamide (32.0 mol) was added portionwise and the mixture was stirred for 1 25 hour. Then 3.46 g (£)-4-(dimethylamino)-l,l-dimethoxy-but-3-en-2-one (Préparation

9n1) (20.0 mol) was added dropwise at 0°C, then it was heated at 80°C for 2 bouts. 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 NaîSO^, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography using heptane and cthyl-acetate as eluents to give a light yellow oil (4-(dimethoxymethyl)-2-(317201

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

MS: (M+H)⁴ -169.2

Préparation 9af; (2-PronoxvnvrimldÎn-4-vI)methanol

Step A:

To the solution of 1500 mg 4-(dimcthoxymethyl>2-methylsulfonyl-pyrimidine (Préparation 9a3, 6.46 mmol) in 50 mL propan-l-ol the solution of 310 mg sodium hydridc (60%, 7.75 mmol) in 10ml propan-l-ol was added and stirred at room température 10 for lh. Tho 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-pyrimïdÎne. MS: (M+H)⁴ “ 213.2,

Step PL

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-yI]methanol

Step Ai

2-Methoxyethanol (10 mL) was cooled to 0°C and 413 mg of sodium hydridc (60%, 10.33 mmol) was added portîonwise, then 2,00 g 4-(dimethoxymethyl)-2-methylsulfonylpyrimidine (Préparation 9a3) (8.61 mmol) was added and stirred at room température for 1h. The reaction mixture was concentrated under reduced pressure. To the residue water 25 was added and it was extracted with DCM. The combined organic layers were dried over

MgSO₄ and concentrated under reduced pressure to give 4-(dimethoxymethyl)-2-(2methoxyethoxy)pyrimidine. MS: (Μ+Π)⁴ - 229.2.

Step B:

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

MS: (M+H)⁴ -185.2

-ιοίStarting from this material using General procedure 9A the title pruduct was obtained. ’H NMR (400MHz,DMSO-d₆): 8.65 (d, IH),7.32(d, IH), 5.69(ζ IH),5.02 (q,2H),4.51 (d, 2H).

Préparation 9a|; [2-(333-Trifluoropropoxy)pyriinidln-4-yl]incthanol

StepA;

To the solution of 2.00 g Préparation 9a3 (8.61 mmol) in acetonitrile 2.38 g K2CO3 (17.2 mmol), then 33.3-trifluoropropan-l-ol were added and the so obtained mixture was stirred for ί Oh at 60°C. The reaction mixture was cooled, filtered and the filtrale concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl-acetate as eluents to give 4-(dimethoxymethyl)-2-(333trifluoropropoxy)pyrimidine. ’HNMR (400 MHz, DMSO-da): 8.68 (d, IH), 7.22 (d, IH), 5.22 (s, IH), 4.53 (t, 2H), 3.33 (s, 6H), 2.83 (m, 2H).

Starting from this material using General procedure 9A the title product was obtained.’H NMR (400 MHz, DMSO-d_fi): 8.59 (d, IH), 7.22 (d, IH), 5.63 (t, IH), 4.49 (m, 4H), 2.81 (m,2H).

Préparation 9ak: (2-Phcnoxy pyrimid in-4-yt)mcthanot

Step A;

To the solution of 1.50 g Préparation 9a3 (6.46 mmol) in 50 mLTHF 2.14 gKjCOî (15.5 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 réaction 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-phcnoxy-pyriinidine. MS: (M+H)⁺= 247.2.

Step B:

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

MS: (M+Hf “203.2

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)* = 141.4.

Préparation 9an; [2-(Dlmethylamlno)pyrlinidin-4-yl]mcthanol

To 3 mL dimethylamine solution (2M in THF, 6 mmoi) 232 mg 4-(dimethoxymethyl)-2methylsulfonyl-pyrîmidine (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 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 product. MS: (M+H)⁺= 154.4.

Préparation 9ao; [2-(2-MethMyethy!amlno)pyrimidin-4-yl]me(IianoI

Step A:

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

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

Préparation 9ap; l2-l2-Mcthoxvcthvl(methvl)aminoInvrimidln-4-vilmethanol

-105give 4-[4-(dimethoxymcthyl)pyrimIdin-2-yl]morpho!ine. *H NMR (400 MHz, DMSO-de): 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-(dÎmethoxymethyl)pyrimidin-2-yl]morpholine using General procedure 9A the title product was obtained. ’H NMR (400 MHz, DMSO-de): 8.36 (d, IH), 6.76 (d, IH), 5.43 (t, IH),4.36 (d,2H),3.65(m, 8H).

Préparation 9ast [2-(lΗ·\ 1,23]Triazol-l-yl)pyrimidin-4-yl]méthanol

Step A:

To the solution of 829 mg IH-[l,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 filtered and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl-acetate as eluents to give 4-(dimethoxymethyl)-2-(lff-[l,2,3]triazol-l-yI)pyrimidine as white crystals, 'H NMR (400 MHz, DMSO-de): 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-(!#-[!,2,3]triazol-2-yl)pyrimidine was also obtained. ’H NMR (400 MHz, DMSO-de): 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-(l/A[l,2,3]triazol-l-y!)pyrimidine using General procedure 9A the title product was obtained. ^lH NMR (400 MHz, DMSO-de): 8.97 (d, IH), 8.88 (d, IH), 7.99 (d, IH), 7.70 (d, IH), 5.86 (t, IH), 4.69 (d, 2H).

Préparation 9at: [2-(Benzylamlno)pyrimldin-4-y1]mcthanol

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

-107min. This mixture was added to the solution of 272 mg of 2-methylsulfonyl-4(tctrahydropyran-2-yloxymethyl)pyrimidinc (Préparation 9a4,1.00 mmol) in 1 mL DMF.

The mixture was stirred at room température for 1 h» then it was diluted with water, and extracted with DCM. The combined organic layers were dried over Na^SO* and 5 concentrated under reduced pressure. The residue was dissolved in 15 mL EtOH then 160 mg pyridinium p-to!uenesulfonate (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 NajSOi 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-Benzvloxvnvrimldin-4-vDmethanol t5 To 4.25 mL phenylmethano! 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-(tetrahydropyran-2yloxymethyljpyrimidine (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 MgSO₄ and concentrated under reduced pressure.

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

Step B:.

To the solution of 408 mg of 2-benzy!oxy-4-(tetrahydropyran-2-yloxymcthyI)pyrimidinc (1.36 mmol) in 50 mL EtOH 79 mg pyridiniump-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-dô): 8.59 (d, IH), 7.47-730 (m, 5H), 7.21 (d, IH), 5.62 (t, IH), 537 (s, 2H), 4.49 (m, 2H).

Préparation 9av; {2-[(l-methyl-lff-imidazol-5-yl)methoxy]pyrimidin-4-yi}methanol

-109- .

Starting from this material using General procedure 9A the title product was obtained. ^lH NMR (400 MHz, DMSO-de): 8.68 (d, IH), 7.36 (d, 1 H), 5.59 (t, IH), 4.51 (d, 2H),2.79(t, 2H), 1.75 (h, 2H), 0.90 (t, 3H).

⁵ 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-de): 8.77 (d, 10 IH), 7.36 (d, !H), 5.25 (s, IH), 3.32 (s. 6H), 2.87 (t, 2H), 1.73 (m, 2H), 1.32 (m, 2H), 0.90 (t,3H).

Step

Starting from this material using General procedure 9A the title product was obtained. ^lH 15 NMR (400 MHz, DMSO-de): 8.70 (d, IH), 7.36 (d, IH), 5.59 (t, IH), 4.51 (d, 2H),2.81 (t, 2H), 1.70 (m, 2H), 1.31 (m, 2H), 0.89 (t, 3H).

Préparation 9bd: (2-lsopronvlDvrimldln-4-y|)methanol

Step A;

Starting from 2-methyipropanamidine hydrochloride using General procedure 9C 4(diniethoxymethyi)-2-isopropyl-pyrimidine was obtained. ’llNMR(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).

Step B:

Starting from this material using General procedure 9A the title product was obtained. *H NMR (400 MHz, DMSO-de): 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 9bc: (2-Cyclopropylpyrimldin-4-yl)methanol

Step A:

-lllStarting 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, 1H), 4.52 (d, 2H), 2.71 (d, 2H), 1.17 (m, IH), 0.45 (m, 2H), 0.25 (m, 2H).

Préparation 9bh: (2-ferf-Butylpyrlmidin-4-yl)méthanol

SlepA:

Starting from 2,2-dimethyIpropanamidine hydrochloride using General procedure 9C 2tert-butyl-4-(dimethoxymethyl)pyrimidine was obtained. *H NMR (400 MHz, DMSO-di): 8.80 (d, IH), 7.34(d, IH), 5.25 (s, IH),3.34 (s, 610,1.35 (s, 9H).

SïepB:

Starting from this material using General procedure 9A the title product was obtained. *H NMR (400 MHz, DMSO-d_fi): 8.72 (d, III), 7.35 (d, IH), 5.57 (t, IH), 4.52 (d, 2H), 1.33 (s, 9H).

Préparation ?bl; (2-CvclonentvlnYrimidin-4-vDmcthanol

Step Ai

Starting from cyclopentanecarboxamidine hydrochloride using General procedure 9C 2· cyclopentyM-fdimethoxymethyOpyrimidine was obtained. MS: (M+H)⁴ 223.2.

Step B:

Starting from this material using General procedure 9A the title product was obtained. ’H NMR (400 MHz, DMSO-dfi): 8.68 (d, IH), 7.34 (d, IH), 5,57 (t, IH), 4.51 (d, 2H), 3.25 (p. 1 H), 1.98 (m, 2H), 1.87-1.57 (m, 6H).

Préparation 9b|; l2-iTrifluoromcthvl)nvrimidin-4.Yl|methanoi

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.

-113 Starting from this material using General procedure 9A the title product was obtained. ’ll NMR(400 MHz,DMS0-d₆): 8.70(d, 1 H), 7.39 (d, IH),5.60 (t, IH),4,52 (d, 2H), 3.7S (t, 2H), 3.22 (s, 3 H), 3.06 (t, 2H).

Préparation 9bnu [2-(2-DlmethylaminoethyI)pyrimidin-4-yI|methanol

Step A ’

To the mixture of 1.63 g 3-(dimethylamino)propanamidine dihydrochloride (8.67 mmol) and 1.25 g (E)-4-(dimethylamino)-l,l-dimethoxy-but-3-en-2-one (Préparation 9al, 723 mmol) in 4 mL dry methanol sodium methoxide (17.3 mmol) was added porlionwise and the mixture was stirred 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-(dimethoxymcthyl)pyrimidin-2-yl]-AT, V-dimethyl-ethanamïne. MS: (M+H)⁺ = 226.2.

1.474 g crude 2-[4-(dimethoxymethyl)pyrimidin-2-yl]-jV,jV-<limethyl-ethanarnine 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% K₂COj 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 Na₂SO₄ and concentrated under reduced pressure to give the title product.

Ή NMR (400 MHz, DMSO-d₆): 8.69 (d, III), 7.39 (d, IH), 5.64 (br s. 111), 4.52 (s, 2H), 3.01 (m, 2H), 2.80 (m, 2H), 2.25 (s, 6H).

Préparation 9bn; [2-(Ethoxymethy!)pyrlml<Wn-4-y!Itnethanol

Step A:

-115261 mg 4-(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 mg NaOH (8.0 mmol) was added portionwise. The pH was adjusted to 8 using 10% KjCOa 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 tille product. *H NMR (400 MHz, DMSO-ds): 8.84 (d, IH),

7.50-7.42 (m, 3H), 7.14 (d, !H), 7.03 (m, IH), 5.66 (t, IH), 4.58 (d, 2H), 3.75 (s, 3H).

Préparation 9bn: |2-(2-Pyridvl)Dvrlmldln-4-vl1methanol

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

Sltp B;.

Starting from this material using General procedure 9A the title product was obtained. *H 20 NMR (400 MHz, DMSO-dô): 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)pyrlm!dln-4-yl]methanoI

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-d_fi): 9.51 (dd, IH), 8.93 (d, IH), 8.72 (dd, IH), 8.66 (m, IH), 7.56 (m, 2H), 5.73 (L IH), 4.67 (d, 2H).

-117Step B:

Starting from this material using General procedure 9A the title product was obtained. NMR (400 MHz, DMSO-dô): 8.81 (d, IH), 8.36 (dd, IH), 7.80 (dd, III), 7.65 (dd, JH), 7.42 (d, IH), 5.66 (t, IH), 4.60 (d, 2H).

Préparation 9bvî [2-(2-Thlcnyl)pyriniidÎn-4-yi]methanol

Step A:

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

SiszJL

Starting from this material using General procedure 9A the title product was obtained. *H NMR (400 MHz, DMSO-de): 8.77(d, IH), 7.93 (dd, IH), 7.76 (dd, IH), 7.40(d, IH), 7.20 (dd, 111),5.68 (t, III), 4.58 (d,2II).

Préparation 9bw: (2-fl£M^Tazol-l-yl)pyrlmidln-4-yl)methanol

Step A:

To the stirred mixture of 4.18 g of pyrazole-t-caiboxamidïne hydrochloride (28.5 mmol) and 120 mL of éthanol 4.05 g ofNajHPO^ (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 usîng heptane and EtOAc as eluents to give 4-(dimethoxymethyl)-2-(lHpyrazol-l-yl)-pyrimidine. NMR (400 MHz, DMSO-de): 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. *H 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 (ζ IH), 4.63 (d, 2H).

-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-de): 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)mcthanol

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. Réaction mixture was concentrated under reduced pressure, DCM was added to the residue, and it was washed with saturated aq. NaHCOj.

The organic phase was dried over Na^SCL 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. ’HNMR (400 MHz, DMSO-de): 9.18 (s, IH), 9.06(s, IH),5.51 (s, IH), 3.40(s,6H).

StepBt.

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

Préparation 9cb; (5-Bromo-2-mcthoxy-pyrlmidin-4-yl)methanol

Step A:

Starting from methyl carbamimidate hydrochloride using General procedure 9C 4(dimethoxymethyl)-2-mcthoxy-pyrimidÎne was obtained. *H NMR (400 MHz, DMSO-de):

8.66 (d, 1 H), 7.18 (d, IH), 5.20 (s, IH), 3.92 (s, 3H) 3.33 (s, 6H).

SlepJb

-121Step A;

To the mixture of 12.16 g O-methylîsourea hydrochloride (110 mmol) and 20.0 g ethyl 4,4-dimethoxy-3-oxo-butanoate (91.6 mmol) in dry méthanol 5.94 g sodium methoxide (110 mmol) was added portionwise and the mixture was stirred at 75 °C for 2 h. The 5 réaction 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-(dimcthoxymethyl)-2-methoxy-lZ7-pyrimÎdin-6-one. *H NMR (400 MHz, DMSO-de): 12.37 (br s, IH), 6.03 (s, IH), 5.08 (s, IH), 3.87 (s, 3H), 3.57 (m,4H), 1.15 (t,6H).

SleeJk

To the solution of 2.00 g 4-(dimethoxymethyl)-2-methoxy-1H-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 15 DCM and it was poured onto îce. The organic layer was washed with water, then it was dried over MgSO< and concentrated under reduced pressure. The residue was dissolved in 30 mL méthanol and 946 mg sodium methoxide (17.52 mmol) was added at 0°C, and it was stirred at this température for Ih. Celite was added and the volatiles were removed under under reduced pressure. The crude product was purified via flash chromatography 20 using heptane and EtOAc as eluents to give 4-(dimethoxymethyl)-2,6-dimethoxypyrîmidine. MS: (M+H)⁺ = 243.2.

Slep_&.

*11 NMR (400 MHz, DMSO-cU): 6.53 (br s, IH), 5.53 (t, IH), 4.40 (dd, 2H), 3.89 (s, 3H),

3.86 (s,3H).

Préparation 9ce: (6-Chloropyrlmidin-4-yl)methano!

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. The reaction mixture was stirred at room température for .123To the solution of 1.00 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 I 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 oTganic phases were dried over NajSO^ 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, DMSO-d₆): 7.07 (s, IH), 5.55 (t, IH), 4,43 (m, 2H), 3.86 (s, 3H), 2.40 (s, 3H).

Préparation 9cg; (6-Phenylpyrimidin-4-y!)methanol

To the solution of 1.00 g ethyl 6-phenylpyrimidinc-4-carboxylate (4.38 mmol) in 15 mL MeOH 175 mg NaBH-i (4.63 mmol) was added at room température and it was stirred at 70°C for 3h. The reaction mixture was concentrated, and the residue was diluted with 15 saturated aq. K2CO3 and it was extracted with DCM. The combined organic phases were drîed over Na₂SO4 and concentrated under reduced pressure. The crude product was purified via flash chrumalography using heptane and EtOAc as eluents to give tire title product. *H NMR (400 MHz, CDClj): 8.97 (s, IH), 8.11 (d, 2H), 7.68-7.45 (m, 4H), 5.45 (d, 2H).

Préparation 9 ch: (2-Chloropyrimidin-4-yl)methanol

To the solution of 1860 mg methyl 2-chloropyrimidine-4-carboxylatc (10.78 mmol) In 11 mL THF 21.6 mL DIBAL-H (IM in THF, 21.6 mmol) was added dropwise at -70’0 and it was stirred at this température for 16 h. 5 mL MeOH was added to it at ·50°Ο, then 5 mL 25 water was added to it at 0°C. It was filtered 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, CDClj): 8.60 (d, IH), 7.38 (d, IH), 4.79 (s, 2H).

Préparation 9da: (l-Ethyl-l/Apyrazol-5-yl)methanol

Step A:

-125Préparation 9de: [1 -(3-Methylbutyl)-l//-pyrazol-5-yl]methanol

Step A:

Using l-bromo-3-methyI-butane in General procedure 9F l-(3-mcthylbutyl)-l//-pyrazole was obtained. 'H NMR (400 MHz, DMSO-d₆): 7.71 (d, IH), 7.40 (d, IH), 620 (t, IH), 4.11 (t,2H), 1.65 (q, 2H), 1.44 (h, IH), 0.89 (d, 6H).

Step B;

Starting from l-(3-methyIbutyl)-l//-pyrazole using General procedure 911 the title product was obtained. ‘1-1 NMR (400 MHz, DMSO-d₆): 7.30 (d, IH), 6.12 (d, IH), 5.25 (ζ IH), 4.49 (d, 2H), 4.08 (m, 2H), 1.63 (m, 2H), 1.55 (h, 1 H), 0.90 (d, 6H).

Préparation 9df: [1 -(Cyclopropy!methyl)-1 W-pyrazol-5-yl] methanol

Starting from J-(cyclopiOpylmethyl)-IZf-pyrazole using General procedure 9Π the title product was obtained. ⁽H NMR (400 MHz, DMSO-d«): 7.31 (d, IH), 6.14 (d, 1H), 5.26 (t, IH), 4.51 (d, 2H), 3.96 (d,2H), 1.24 (m, IH), 0.51-0.24 (m,4H). MS: (M+H)*= 153.2.

Préparation 9dg: (Î-Cvclopentvl-lH-nvrazol-5-vllmethanoI

Step A:

Using bromocyclopentane in General procedure 9G l-cyclopentyl-l//-pyrazoie was obtained.

StepJPi

Starting from l-cyclopentyl-IH-pyrazole using General procedure 911 the title product was obtained. 'H NMR (400 MHz, DMSO-d₄): 7.31 (d, IH), 6.11 (d, IH), 520 (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 9dht (t-CyclohcxyMZZ-pyrazol-5-yl)metlianoI

-127The mixture of 5 g lH-pyrazolc (79.44 mmol), 11.64 g 2-chloro-A\N-dirnethylethylamine 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. Afler 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 Na₂SO₄ 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 filtered off, washed with diethyl ether and dried to give N,jV-dimethyl2-(l/Apyrazol-l-yl)-ethanamine. MS: (M+H)⁺= 140.2.

Slep B:

Starting from ?7,?7-dimethyl-2-(lIf-pyrazol-l-yl)-cthanamine using General procedure 9H the title product was obtained. *H NMR (400 MHz, CDClj): 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)-lH-pyrazol-5-yl]methanol

Ster>A:

Using l-(bromomethyl)-4-methoxy-benzene in General procedure 9G l-(4methoxybcnzyl)-lH-pyrazole was obtained.

Step B;

Starting from l-(4-methoxybenzyl)-lH-pyrazole using General procedure 9H the title product was obtained. 'H NMR (400 MHz, CDCI₃): 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-Trinuorobutyl)-lH-pyrflzol-5-yl]methanol

Step A ·

Using 4-bromo-l,l,I-trifluoro-butane in General procedure 9F 1 -(4,4,4-trifluorobutyl)* lH-pyrazole was obtained. 'H NMR (400 MHz, DMSO-d₆): 7.75 (d, IH), 7.46 (d, IH), 6.24 (t, 111), 4.19 (t. 2H), 2.26-2.13 (m, 2H), 1.98 (m, 2H).

-129Préparation 9dp; [l-(2-Mcthoxyethyl)-l//-pyrazol-5-yl]methanoI

S ftp A;.

Starting from 5-(dimethoxymethyl)-l//-pyrazole (Préparation 9a5) and l-bromo-2mcthoxy-cthanc using General procedure 9F 5-(dimethoxymethyl)-l-(2-methoxyethyl)IH-pyrazole was obtained. 'H NMR (400 MHz, DMSO-de): 7.40 (d, III), 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-(diniethoxymethyi)-l-(2-methoxyethyl)-l/f-pyrazole was also obtained. ’H NMR iO (400 MHz, DMSO-d₆): ): 7.65 (d, IH), 6.18 (d, IH), 533 (s, IH),4.22 (t, 2H), 3.65 (t, 211),

334 (s, 6H), 3.21 (s, 3H).

Step D:

Starting from 5-(dimethoxymethyl)-l-(2-mcthoxyethyl)-l//-pyrazolc using General 15 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)-1ΛΓ-pyrazol-S-y 1]methanol

Step A:

Starting from 5-(dimethoxymethyl)-lZApyrazolc (Préparation 9a5) and l-bromo-3methoxy-propane using General procedure 9F 5-(di methoxymethyl )-l-(3methoxypropyl)-lZ/-pyrazole was obtained. ’H NMR (400 MHz, DMSO-de): 7.40 (d, 111), 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, 25 2H).

Note: 3-(dimethoxymethyl)-l-(3-methoxypropyl)-lZ/*pyrazole was also ohtained. ’H NMR (400 MHz, DMSO-de): 7,66 (d, IH), 6.18 (d, IH), 533 (s, IH), 4.11 (t, 2H), 3.25 (t, 211), 3.23 (s, 6H), 3.21 (s, 3H), 1.97 (m, 2H).

Step B:

Starting from 5-(dimcthoxymethyl)-l-(3-mcthoxypropyl)-IZf-pyrazole using General procedure 9B the title product was obtained. ’H NMR (400 MHz, DMSO-de): 7.33 (d,

W

-131 Step B:

Starting from 5-(dimethoxymcthyl)-l-[2-(2-methoxycthoxy)ethyt]-Ij7-pyrazoIe using General procedure 9B the title product was obtained. ’H NMR (400 MHz, DMSO-de): 7.33 (d, IH), 6.13 (d, IH), 5.19 (t, JH), 4.51 (d, 2H), 424 (t, 2H), 3.72 (t, 2H), 3.46 (m, 2H), 3.38 (m, 2H), 3.20 (s, 3H).

Préparation 9dt; (l-/er/-ButvM7f-pYrazoI-5-vDniethanol

Sien A:

Starting fromterf-butylhydrazinehydrochloride using General procedure 9D l-fer/-butyl5-(dimelhoxymethyl)-l//-pyrazole was obtained. ’H NMR (400 MHz, DMSO-de): 7.34 (d, IH), 6.34 (d, IH), 5.74 (s, 111), 3.24 (s, 6H), 1.57 (s, 9H).

Note: l-/er/-butyl-3-(dimclhoxymethyl)-lH-pyrazole was also obtained. ’H NMR (400 MHz, DMSO-d_s): 7.75 (d, 1 H), 6.18 (d, IH), 5.34 (s, IH), 3.24 (s, 6H), 1.50 (s, 9H).

Step B:

Starting from l-ter/-butyl-5-(dimelhoxymethyl)-lf/-pyrazole using General procedure 9B the title product was obtained. *H NMR (400 MHz, DMSO-de): 7.27 (d, IH), 6.19 (d, IH), 5.31 (t, 1 H). 4.61 (d, 2H), 1.56 (s, 9H).

Préparation 9du; [l-(2,2,2-Trlfluoroethyl)-l J7-pyrazol-5-yl]methanol

Stepjfc

Starting from 2,2,2-trifluoroethylhydrazine (70 w/w% in water) using General procedure 9D in absence of sodium methoxide 5·(άίπιβΐ1ιοχγτηβ11ιγΙ)-1·(2.2,2-ΐΓΪί1ιιθΓθ€ΐΙιγΙ)-4,5dihydro-lZZ-pyrazol-5-ol was obtained. ’H NMR (400 MHz, DMSO-de): 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, 111), 2.50 (m, IH).

Step B:

Starting from 5-(dimethoxymethyl)-l-(2_l2,2-trifluoroethyI)-4,5-dihydiO-lW-pyrazol-5-ol using General procedure 9B the title product was obtained. ’H NMR (400 MHz, DMSOde): 7.48 (d, IH), 6.27 (d, IH), 5.46 (t, 1 H), 5.08 (q, 2H), 4.56 (d, 2H).

*

-133added, and it wasstirred under Nj 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)⁺ = 1762.

Préparation 9ebÎ [6-(2-Thienyi)-2-pyridyI]mcthanoI

To the solution of 624 mg (6-bromo-2-pyridyl)methanoi (3.30 mmol) in 15 mL dioxane 850 mg 2-thîenylboronic acid (6.60 mmol), 3.25 g Cs₂COj (10.0 mmol) and 385 mg tetrakis(triphenylphosphinc)pal1adium(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 9ee; (l-Butvi-l/Z-1.23-triazol-5-vl)mcthanol

StepA,·

To the solution of 690 mg JH-[l,2,3]triazole (10.0 mmol) in 5 mL DMF 1.50 g K₂CO₂(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 Na₂SOx and concentrated under reduced pressure. The regioisomers were separated via flash chromatography using heptane and EtOAc as eluents: 2-butyl-2H-[l,2,3]triazole eluted first then l-butyl-ίH-[l2,3]triazole. 'H NMR (400 MHz, DMSO-d₆) of 1-butyl-lH[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).

Siep B:_

To the cooled solution of 428 mg 1 -butyl-1 Il-[1,2,3]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 réaction 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 Na₂SÛ4 and concentrated under reduced pressure. The residue was dissolved in 20 mL EtOH and 250 mg sodium borohydride (6.50

-135eluents to give the title product. *H NMR (400 MHz, DMSO-de): 7.60 (s, IH), 5.46 (t, IH), 4.57 (d, 2H), 4.37 (t, 2H), 3.31 (t, 2H), 323 (s, 3H), 2.04 (m, 2H).

Préparation 9ee: (l-Phenvl-17/-1.23-triazol-5-yl)methanol

Step A: (Tan g. Bo-Xiao et al Synthesis 1707)

The mixture of207 mg lZ/-[l^,3]triazole (3.00 mmol), 735 mg iodobenzene (3.60 mmol), mg copper(l)oxide (0.60 mmol), 216 mg 1,10-phcnantroline (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 l-phenyl-l/A[l,2,3]triazole.

‘H NMR (400 MHz, DMSO-Λ): S.84 (d, IH), 7.99 (d, IH), 7.92 (m, 2H), 7.61 (m, 2H), 7.49 (m, IH),

Step B:

To the cooled solution of 216 mg 1 -phenyl-lH-[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.(30 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 were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was dissolved in 9 mL EtOll 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 Na₂SO4 and concentrated under reduced pressure to give the title product. MS: (M+H)⁺ = 176.2.

Préparation 9ef; [l-(2-Methoxyethyl)-llI-l,23-trlazol-5-ylJmethanol

Step Al *

-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)pÎperazin-l-yl]cthanone.

Step B:

To a mixture of3.300 g 2,2,2-trifluoro-l-[4-(2-hydroxyethyl)piperazin-l-yl]ethanone (14.6 mmol) and 1.988 g imidazole (29.2 mmol) ïn 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 23.2-trifluoro-l-[4-(2triisopropylsilyloxyethyl)piperazin-l-yl]ethanone. MS (El, 70 eV) m/z (% relative intensity, [ion]).· 166 (5), 195 (100), 339 (11), 382 (I, [M*]).

To a solution of 1.55 g 2,2,2-trifluoro-l-[4-(2-trilsopropylsilyloxycthyl)piperazin-l· yl]ethanone (4.0 mmol) in 15 mL THF 12 mL BIIjxTHF (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)piperazîn-l-yl]ethoxy]silane. MS (El, 70 eV) m/z (% relative intensity, 25 [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-trifluoroethyl)pïperazin-lyl]ethoxy]silane (1.45 mmol) in 10 mL THF 1.52 mL TBAF (1.0 M în THF) was added and il 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 *H NMR (400

-139heptane and EtOAc as eluents to give 2-(4-(2,2-difluoroethy!)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 (I, [M*]).

Step D:

To a solution of 0.547 g 2-(4-(2,2-difluoroethy!)piperazin-l-yl]ethoxy-triisopropy!-si!ane (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 ’H NMR (400 MHz, CDCh): 5.87 (tt, IH), 3.60 (t, 2H), 2.74 (td, 211), 2.66-2.41 (m, 10H).

Préparation 10a; Ethyl (2/y-2-[(55^, _e)-[3-chloro-2-methyl-4-[2-(4-methylplperazln-lyl)ethoxy]phenyl]-6-(4-flnorophenyl)thleno[2,3-rf]pyrimidin-4-yl]oxy-3-[2-|(2methybu!fanylpyrimldln-4-yl)methoxy]phenyl]propanoate

1.77 g ethyl (27?7-2-[(5S_ÎJ)'5-[3-chloro-2-meihyl-4-[2-(4-methy!pipcrazin'l· y!)ethoxy]phcnyl]-6-(4-fluorophenyl)thicno[2,3-/]pyrimidin-4-ylJoxy-3-(2hydroxypheny!)propanoate (Préparation 8a) (2.5 mmol), 1.17 g (2methylsu!fany!pyrimidin-4-yl)mcthanol (Préparation 9aa) (7.5 mmol) and 1.97 g PPhj (7.5 mmol) were dissolved in 50 mL dry toluene, then 1.74 g direr/butyl 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-dfi): 8.70 (d, IH), 8.58 (s, IH), 7.34 (d, IH), 7.31 (d, IH), 7.30 (m, 2H), 7.22 (m, 2H), 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, JH), 4.06 (m, 2H), 3.12 (dd, IH), 2.69 (m, 2H), 2.56 (dd, IH), 2.50(s, 3H),2.46 (brs,4H), 2.24 (br s,4H), 2.10(s, 3H), 1.86 (s, 3H), 1.06 (t, 3H). HRMS calculated for CcH_MClFN_sO₃Si: 842.2487, found: 843.2660 (M+H).

-141 IH), 3,15 (dd, IH), 2.50 (s, 3H), 2.50 (br s, 4H), 2.49 (dd, IH), 2.27 (br s, 4H), 2.11 (s, 3H), 1.95 (s, 3H), 1.06 (t, 3H). HRMS calculated for C41H42CIFNAS2: 832.2280, found: 833.2332 (M+H).

Préparation lia; Ethyl (2R)-2-[5-(3-chloro-2-ethyl-4-hydroxy-phcnyl)-6-(25 fuiyl)thieno[2,3-<7]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoatc (mixture of diastereoisomers)

403 mg ethyl (2Æ)-2-[5-bromo-6-(2-fùryl)thieno[2,3-<71pyrimidin-4-yl]oxy-3-(2mcthoxyphenyl)propanoate (Préparation 4c) (0.80 mmol), 371 mg [2-chloro-3-ethyl-4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]-triisopropyl-si!anc (Préparation

5e) (0.85 mmol), 57 mg Ataphos (0.08 mmol) and 652 mg Cs₂COj (2.00 mmol) were dissolved in 8 mL dioxane and 2 mL water. The mixture was heated to 1 IO^qC for 15 minutes via microwave irradiation. Then water was added and the pH was set to 6 wilh 2 M HCl. Then it was extracted with DCM, dried over Na₂SO4, fïltered and concentrated under reduced pressure and purified via reversed phase chromatography, using MeCN as eluent to obtain ethyl (2/y-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 diluled with DCM, washed with water and brine, dried over NaîSCh, fïltered and concentrated under reduced ' 20 pressure. The crude product was purified via flash chromatography, using heptane and

EtOAc as eluents to obtain Préparation lia ns a mixlure of diastereoisomers. MS (M+H): 579.2 for both diastereomers.

Préparation 11 h; Ethyl (2/?)-2-[5-(3-fluoro-4-hydroxy-2-mcthyl-pheny 1)-6-(225 furyl)thieno(23-<npyrlmldin-4-yl]oxy-3-(2-methoxyphenyl)propftnoate (mixture of diastereoisomers)

503 mg ethyl (2/ï)-2-[5’bromo-6-(2-furyl)lhieno[2,3-J]pyrimidin-4-y1]oxy-3-(2methoxyphcnyljpropanoate (Préparation 4e) (1.00 mmol), 378 mg 2-fIuoro-3-methy 1-4(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 H0°C for 10 minutes via microwave

-143 7.15 (d, IH), 7.13 (d, IH), 4.22 (ζ 2Η), 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-me(hyl-4-[2-(4-incthy|pipcra7in-15 yl)ethoxy]phcnyI]-6-(2-furyl)(hieno|2,3-</]pyrlmidine

3.00 g 4-chloro-5-I3-chloro-2-methyl-4-[2-(4-methyipipcrazin-l -yl)ethoxy]phenyl]-6iodo-thieno[2,3-i/]pyrimidÎne (Préparation 13) (5.32 mmol), 2.06 g 2-(2-furyl)-4,4,5,5tctTamethyI-l,3,2-dioxaborolanc (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 MgSO<, filtered and evaporated under reduced pressure, and then purified by flash chromatography using DCM !MeOH as eluents to give Préparation 14. *HNMR (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-[(5S'_e)-5-(3-chloro-4-hydroxy-2-metliyl-5-nltrophenyl)-6-ethyI-thIeno[2,3-i/]py^rlmidin-4-yl]oxy-3-phenyl-propanoate

483 mg methyl (2Æ)-2-[(5.S'_£I)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethyl-thieno[2,3i/Jpyrimidin-4-yl]oxy-3-phenyl’propanoate (Préparation 6i) (1.00 mmol) was dissolved in 10 mL MeCN, then 139 mg nilronium letrafluoroborate (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, IH), 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 (l, 3H). HRMS calculated for C2sH₂₂C1N₃O₆S: 527.0918, found: 528.0986 (M+H).

Préparation 15b: Methyl (2/?)-2-[(5S,)-5-(5-amIno-3-chloro-4-hydroxy-2-ine(hylphcnyJ)-6-cthyI-thicno[23-i/]pyrimidin-4-yl]oiy-3-phcnyl-propanoate

-145Rreparation 15e: Methyl (l/ÎJ-Z-KS^jl-S-fStS-dicliloro^-hydroxy-l-methyl-phenylJ-ecthyl-thieno[2,3~rf]pyrimidin*4-yl]oxy-3-plienyl-propanoate

483 mg methyl (2?î)-2-[(55'_i7)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethyl-tiiieno[2,35 i(|pyrimÎdin-4-yl]oxy-3-phcnyl-propanoate (Préparation 61) (1.0 mmol) was dissolved in 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 I5e. ‘H NMR (400 MHz, DMSO-d_fi): 10.21 (s, IH), 8.56 (s, IH), 7.33 (s,

III), 7.16 (m, 3H), 6.66 (m, 2H), 5.52 (dd, IH), 3.55 (s, 311), 298 (dd, IH), 270-260 (m, 3H), 1.99 (s, 3H), 1.17 (t, 3H). HRMS calculated for C25H22CI2N2O4S: 516.0677, found: 517.0772 (M+H).

Préparation 15f; Methyl (2R)-2-|(5S'₍i)-5-(5-bromo-3-chloro-4-liydroxy-2-niethyl15 phcnyl)-6-ethyl-thicno[2,3-<Z]pyrin)tdin-4-yl]oxy-3-phenyl-propanoate

169 mg methyl (2R)-2-[(5S_£2)-5-(3-chloro-4-hydroxy-2-mcthyi-phenyÎ)-6-ethy1-thicno[2,3iflpyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 61) (0.35 mmol) was dissolved in 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. 'il 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, 111), 2.702.59 (m, 3H), 1.97 (s, IH), 1.16(t, 3H). MS (M+H): 561.0, (M-H): 559.0.

Unless otherwise specificd, compounds of Préparation 16a to 16g were obtained using 25 General procedure 16A described below.

General procedure 16A;

2.5 eq. 4-chloro-6-ethyl-5-iodo-thieno[2,3-i/lpyrimidine (Préparation Id), 1.0 eq. ofthe 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

-147Using Général 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, CDCh): 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), 1.31 (t, 3H), 1.16 (t, 5 3H).

Préparation 16e; Ethyl (25)-2-(6-ethyl-5-fodo-thlenoI2,3-rf|pyriTnidin-4-yI)oxy-3-(2fluorophenyl)propanoate

Using General procedure 16A and ethyi (25)-3-(2-fluorophenyl>2-hydroxy-propanoate 10 (Préparation 3az) as the appropriate alcohol we obtained Préparation 16e. *H NMR (400

MHz, CDCh): 8.48 (s, IH), 7.45 (dt, IH), 7.23 (m, IH), 7.06 (t, 1H), 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 (2Z?)-2-(6-ethyl-5-iodo-tbicno|2,3-if]pyrimidin-4-yi)oxy-3-(215 fluorophenyl)propanoate

Using General procedure 16A and ethyl (2Î)-3-(2-fluorophenyl)-2-hydroxy-propanoate (Préparation 3ba) as the appropriate alcohol we obtained Préparation 16f. ’H NMR (400 MHz, CDCIî): 8.48 (s, IH), 7.45 (dt, IH), 7.23 (m, JH), 7.06 (t, IH), 7.04 (t, 111), 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 16e; Ethyl (25)-3-(l,3’benzodioxol-4-yl)-2-(6-ethyJ-5-iodo-thieno[2,3· rf]pyrimidin-4-yl)oxy-propanoate

Using General procedure 16A and ethyl (25)-3-(1,3-benzodioxo!-4-yl)-2-hydroxypropanoate (Préparation 3bh) as the appropriate aicohol we obtained Préparation 16g.

*H NMR (400 MHz, CDCIj): 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 (2Æ)-3-(13'benzodioxol-4-yl)-2-[(5/r_fl)-5-(3-ehloro-4-hydroxy2-methyl-phenyJ)-6-ethyl-thieno|23-rf|nyrimidin-4-yl|oxy-propanoate and

Préparation 17b: Ethyl (21î)-3-(13'benzodloxol-4-yl)-2-|(55_(t)-5-(3-chloro-4-hydroxy2-TnethyJ-phenyi)-6-ethyJ-thicnol2,3-rf]pyrimidm-4-ylJoxy-propanoate

-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-((5R_ff)-5-(3-ehloro-4-hydroxy-2-methyl-phenyl)-6-ethylthleno|2,3-i/]pyrimldÎn-4-yl]oxy-3-(2,3-dihydrobenzofuran-7-yl)propanoatc

0.525 g ethyl (2S)-3-(2,3-dîhydrobenzofuran-7-yl)-2-(6-ethyl-5-iodo-thieno[2,3</]pyrimidin-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 BiljNOH solution (2.5 mmol, 1.0 M in water) and 4.5 mL 2-MeTHF were heated under nitrogen at !00°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 17d. ’H NMR (500 MHz, DMSO-de): 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, III), 1.95 (s, 3H), 1.15 (t, 3H), 1.05 (t, 3H).

Préparation 17c; Ethyl (2R)-3-(benzofuran-7-yl)-2-|(5S_e)-5-(3-chloro-4-hydroxy-2methyl-phenyl)-6-cthyl-thlcno[23-^]pyrlmldiii-4-yl]oxy-propanoate and

Préparation 17f: Ethyl (2S)-3-(benzofuran-7-yI)-2-|(5R,)-5-(3-chloro-4-hydroxy-2methyl-phenyl)-6-elhyl-thieno|23-^pyrimldin-4-yl]oxy-propanonie

0.647 g Ethyl 3-(benzofuran-7-yl)-2-(6-ethyl-5-iodo-thîeno[2,3-i(]pyrimidin-4-yl)oxypropanoate (Préparation 16d) (124 mmol), 0.766 g 2-chloro-3-methyl-4-(4,4,5,5tctnimethyl-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 microwave reactor with stirring. The pH of the mixture was set to 6 with 2 M HCl, it was filtered 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

-1510.425 g Ethyl ^^-(ô-cthyl-S-iodo-thicno^.S-i/JpyrÎmidinA-yOoxy-S-Pfluorophenyljpropanoate (Préparation 161) (0.85 mmol), 0.570 g 2-chloro-3-methyl-4(4,4,5,5-tetramethy!-l,3,2-dioxaborolan-2-y!)phenol (Préparation 5a) (2.12 mmol), 0.053 g AtaPhos (0.075 mmol), 2.13 mL BmNOH 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 stirring. The pH of the mixture was set to 6 wtth 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 Na₂SO«, 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 17h. *H NMR (500 MHz, DMSO-da): 10.23 (s, 1H), 8.54 (s, 1H), 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 171: Ethvl (25)-3-(13^_benzodioxol-4-y!)-2-[(5S'_w)-5-(3-ch!oro-4-hydroxy-2methyI-phenyl)-6-ethyl-thtcno[2,3-rf]pyrimidln-4-y!]oxy-propanoatc and

Préparation 17j; Ethyl (2S>X134)enzodioxo!-4-yl)-2-I(51ÏJ5-(3-chloro-4-hydroxy2-methyI-phenyl)-6-ethy!-thIeno|23-rf]pyrimldin-4-y!]oxy-propanoate

0.482 g ethyl (2S)-3-(l,3-benzodioxol-4-yl)-2-(6-ethyl-5-iodo-thieno[2,3-</]pyrimidin-4· yl)oxy-propanoate (Préparation 16g) (0.92 mmol), 0.737 g 2-chloro-3-methyl-4-(4,4,5,5tctramcthyl-I,3,2-dioxaboroIan-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 B114NOH solution (2.7 mmol, 1.0 M in water) and 6.6 mL DME were heated under nitrogen at 100°C for 10 mins in a microwavc 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 Na₂SO«, 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 17i, and the diastereomer eluting later as Préparation 17j.

-153dioxane and 2 mL water. The mixture was heated to 1 IO°C for 12 minutes via microwave irradiation. Then it was diluted with brine, neutralized with 2 MIIC1, extracted with DCM, dried over NaîSOe, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography, using heptane and EtOAc as eluents to obtain 5 Préparation 18b as a mixture of dîastereoisomcrs. *H NMR (400 MHz, DMSO-de): 9.25 (br s, JH), 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 CmHjtCINîOîS: 550.1329, found: 551.1412 (M+H).

Préparation 18c: Ethyl (2J0-2-[(&S_e)-5-(3-chtoro-5-Îluor(>-4-liydroxy-2-niethyl· phenyl)-6-prop-l-ynyl-thleno|23-tf|pyrimidin-4-yl]oxy-3-(2methoxyphcnyl)propanoate

522 mg ethyl (2/î)-2-(5-iodo-6-prop·l·ynyl-thieno[2,3-ίήρyrimidίn-4-yl)oxy-3-(215 methoxyphenyl)propanoate (Préparation 4k) (1.00 mmol), 403 mg 2-chloro-6-fluoro-3mcthyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yI)phenoI (Préparation 5m) (L5 mmol), 71 mg AtaPhos (0.1 mmol) and 652 mg CS2CO3 (2.00 mmol) were dîssolved in 8 mL dioxane and 2 mL water. The mixture was heated to I00°C for 15 minutes via microwave irradiation. Then it was diluted with brine, neutralized with 2 M HCl, extracted 20 with DCM, dried over NajSth, 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 CjsHmCIFNjOîS: 554.1078, found: 555.1166 (M+H).

Préparation 19a: Ethyl 3-(benzofuran-4-yI)-2-(5-io(lo-6-prop-l-ynyMhieno[23* J|pyrimidin-4-yl)oxy-propanoate

2.676 g 4-chloro-5-iodo-6-prop-l-ynyl-thieno[2,3-<flpyrimidine (Préparation 2t) (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

-155Préparation 21; Methyl (2Æ)-2-(6-bromo-5-lodo-thicno[2,3-</Îpyrimidin-4-yl)oxy-3phenyl-propanoate

15.39 g 6-bromo-4-chloro-5-iodo-thieno{2,3-i(]pyrimidinc (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^eC 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 (2Λ)-2- [6-brom 0-(55,, )-5-(3-chloro-4-hydroxy-2-methy ΙΙΟ phenyl)thleno[23-rf]pyrlmidin-4-yl]oxy-3-phenyl-propanoatc ‘ 1.557 g methyl (2Æ)-2-(6-bromo-5-iodo-thieno[2,3-i/]pyrLmidin-4-yl)oxy-3-phenylpropanoate (Préparation 21) (3.0 mmol), J.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)Clî (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 dioxane and 6 mL water réaction 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 Na₃SO4, fîltered and concentrated under reduced pressure. Diastereoisomers were separated via flash 20 chromatography using heptane and ethyl acetate as eluents. The diastereoisomer eluting later was collected as Préparation 22. MS (M+H) 532.0.

Préparation 23a; [2-Chloro-4-(4-chlorothleno[2^-rf]pyrlmldln-5-yl)-3-methyiphenoxyj-trlisopropyi-siianc

34.50 g 4-chloro-5-iodo-thieno[2,3-i/]pyrimidine (Préparation le) (116.3 mmol), 59.32 g 25 [2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]-triisopropylsilane (Préparation 5e) (139.6 mmol), 653 mgPd(OAc)î (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 réaction was stirred under nitrogen at 60^eC until no further conversion was observed. To the reaction mixture saturated aq. NH₄C1 was added 30 and then it was extracted with EtOAc. The combined organic layers were dried over

-15738.00 g [2-chloro-4-(4-chlorothicno[2,3-if]pyrimÎdin-5-yl)-3-methyl-phenoxy]triisopropyl-silane (Préparation 23a) (81.27 mmol) was dissolved in 1 L dry THF then cooled to -78°C under argon atmosphère. 48.76 mL lithium diisopropylamidc (97.53 mmol, 2 M in THF, EtPh, hexanes) was added and the mixture was stirred at -78°C for 1 hour. Then 24.75 g îodine (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 NaiSiOj solution, then dried over NaiSO4 and concentrated under reduced pressure. The obtained solid was sonicated in acetonitrile / water (3:1) and collected by filtration. ’H NMR (400 MHz, DMSO-de): 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-Chloro-5-(3-chloro-2-methyl-plienyl)-6-iodo-thieno[2_l3rfjpyrimidine

i.48 g 4-cldoro-5-(3-chloro-2-methyi-phenyl)thÎeno[2,3-d]pyrimidîne (Préparation 23b) (5.0 mmol) was dissolved in 30 mL dry THF then cooled to -78°C under argon atmosphère. 2.75 mL lithium diisopropylamidc (5.5 mmol, 2 M in THF, EtPh, hexanes) was added and the mixture was stirred at -78°C for i hour. Then 1.675 g iodine (6.5 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 NaîSîOj solution, then dried over Na₂SO4 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, CDClj): 8.82 (s, IH), 7.52 (dd, IH), 7.25 (t, IH), 7.05 (dd, IH), 2.09 (s, 3H).

Préparation 25; Ethyl (2/?)-2-I(&S'_w)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-iodothicno|2,3-d]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate

37.85 g [2-chloro-4-(4-chloro-6-iodo-thieno[2,3-if]pyrimidin-5-yl)-3-methyl-phenoxy]· triisopropyl-silane (Préparation 24a) (63.7 mmol), 15.71 g methyl (2R)-2-hydroxy-3-(2methoxyphenyl)propanoate (Préparation 3ad) (70 mmol) and 62,3 gCs₂COj (191 mmol) were placed in a 500 mL flask. i50 mL /er/-butanol was added and the mixture was stirred at 65°C until no further conversion was observed. It was diluted with îcy water, the pH was

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-[(l-butyl-tH-pyrazol-5-yl)methoxy]pheny]]-2-[5-[3chloro-2-methyl-4-[2-(4-methyIplpcrazin-l-yl)cthoxyJphenyl]-6-lo(lo-thieuo[2,3rf]pyrimidin-4-yl]oxy-propanoate

5.5 g ethyl (2)î)-2-[5-[3-chloro-2-methy]-4-[2-(4-methylpïperazin-l-yl)ethoxy]phenyl]-6iodo-thieno[2,3-if]pyrimidin-4-yl]oxy-3-(2-hydiOxyphenyl)propanoate (Préparation 26b) to (7,46 mmol), 2.3 g (i-butyl-i/f-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 dirertbutyl 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.

Prcparatlon 27: Ethyl (2A)-2-[(55»)-5-]3-ch]oro-2-methyl-4-[2-(4-inethylpipcrazln-lyI)ethoxy]phenyl]-6-(4-tluoro-3-inethoxy-phenyJ)thleno[2,3-rflpy^rlmldin-4-yl]oxy-3[2-[(2-methoxypyriinldin-4-yl)niethoxy]phenyl]propanoate

441 mg ethyl (2/î)-2-[(5.S'₄)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-I20 yi)ethoxy]phenyl]-6-(4-fluoro-3-methoxy-phenyl)thÎeno[2,3-i/]pyrÎmidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 8g) (0.6 mmol), 252 mg (2-methoxypyrimîdin-4yl)methanol (1.8 mmol) and 472 mg triphenyl phosphine (1.8 mmol) were dissolved in 10 mL abs. toluene, then 414 mg di/er/butyl azodicarboxylate (1.8 mmol) was added, The mixture was stirred at 50°C under nitrogen until no further conversion was observed. Il 25 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 (2IÎ)-2-[(55_e)-5-[3-chloro-2-methy]-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(4-fluoro-3-hy<lroxy-phenyl)thicno]23-rf]pyrimldin-4-yt[oxy-3-[2[(2-mcthoxypyrimid!n-4-yl)methoxy]pheny!|propanoate

-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 dropwîse and the mixture was stirred at this température for 30 minutes. Additional 4.5 mL lithium diisopropylamide (2M in THF, 9 mmol) was added dropwîse, 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 it was left to warm to room température. Water then saturated aq. NH4CI solution was added to the mixture and then it was extracted with dicthylether. The combined organic phases were dried over Na₂SO< 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-methylphcnyl)-6-iodo-thieno[2,3 AJpyrimidine. 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(mcthoxymcthoxy)phenyl]-4,4,5,5-tetraincthyl-l ,3,2-dioxaboroIane (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-/er/-butyl(4dimethylaminophenyl)phosphine)dichloropalladium(il) (AtaPhos, 0.4548 mmol) was added. Tlie réaction mixture was stirred under nitrogen at 55^eC 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 HCI. 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)-6-[4-fluoro-3(methoxymethoxy)phenyljthicno [2,3-t/]pyrimidine. MS: (M+H)⁺ 479.0.

Step D:

To 1.824 g of the product of Step C (3.805 mmol) and 2.529 g ethyl (2Jî)-2-hydroxy-3-[2[(2-methoxypyrimidin-4-yl)mcthoxy]phenyl]propanoate (Préparation 3ah, 7.610 mmol) in 40 mL /erAbutanol 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 • 163dioxaborolane (7.7 mmol) was added and after 10 minutes stirring the mixture was allowed to warm up to room température. 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 Préparation BA2. MS (El, 5 70 eV) m/z (% relative intensity, [ion]): 120 (19), 165 (25), 166 (100), 167 (44), 180 (17),

206 (22), 223 (60), 266 (68, [M⁴]).

Préparation BA3: 2-[4-fluoro-3-(methoxymethyl)phenyl]-4_t4,5,5-tetramethyH,3,2· dioxaborolane

0.801 g LiCl (19 mmol) was heated at 250°C for 10 minutes under Ni. 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 ï'BuîAIH (! M in THF, 0.15 mmol) for 10 minutes, then it was cooled to 0°C and 3.313 g 4-bromo-1-fluoro-2(methoxymcthyl)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-dioxaborolanc (20 mmol) was added and lhe réaction mixture was stirred for 30 minutes, then filtered through celite, diluted with EtOAc and washed with saturated aq. NH4CL The aqueous phase was back-extracted with EtOAc. 'llie combined organic phases were dried over Na₂SO4, filtered, concentrated and purified via flash chromatography using heptane and EtOAc as eluents to give Préparation ΒΛ3. 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, [M⁴]).

Préparation BA4; 2-(5-fluoro-2-furvD-4.4,5,5-tetra>nethyl-1.3.2-dloxaborolnne

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 NaHCOj solution (300 mmol) was added in portions. The réaction mixture was stined 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 MgSÛ4, 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 BuLi (10 M in hexancs, 180 mmol) was added dropwise (T < -65°C) than the reaction mixture was stirred for 5 minutes. 36 mL 2-ïsopropoxy-4,4,5,5-tetramethyl·

-165 phase was extracted with EtOAc. The combined organic phases were dried over Na₂SO₄and concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation BAS. *H NMR (400 MHz, CDCh): 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, [M⁴]).

Compounds of the invention display axial chirality. They can be isolated as a mixture of atropoisomers or as individual atropoisomers ($_fl or Λο).

General procedure (la)

Sty Al eq. ethyl (2Æ)-2-[(5S_e)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxyJphenylJ-6-(4-fluorophenyl)thieno[2,3-rf]pyrimidÎn-4-ylJoxy-3-(2hydroxyphenyl)propanoate (Préparation 8a), 2 eq. of the appropriate alcohol and 2 e.q triphenyl phosphate 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 * HjO 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 NH^ICOj solution and MeCN as eluents.

General procedure (Ib)

-167Example 3 (2Λ)-2-{ [(55’_<f)-5-(3-chloro-2-methyl-4-[2-(4-methylpÎperazin-1 · yl)eihoxy]phenyl)-6-(4-nuorophcnyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-[2-(2,2_l2tri fluoroethoxy)phenyl]propanoic acid

StenA:

211 mg ethyl (2A)-2-[(55'₀)-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l· yl)ethoxy]phenyl]-6-(4-nuoropheny1)thieno[2,3-d]pyrimidin-4-y]]oxy-3-(2hydroxyphenyljpropanoate (Préparation 8a) (0.3 mmol) and 138 mg K₂COj (1.0 mmol) were dissolved in 2 mL DMF, then 232 mg 22,2-trÎfiuoroethyl 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 NajSO^, filtered and concentrated under reduced pressure and purified via preparative reversed phase chromatography using 5 mM aqueous NlLHCOj solution and MeCN as eluents to obtain Example 3. HRMS calculated for C37HÎ5CIF4N4O5S: 758.1953; found 759.1999 (M+H).

Example 4 (2/?)-2-{[(5S_I7)-5-{3-chloro-2-methyl-4-[2-(4-methylpipcraziii-ly!)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-<(]pyrimidin-4-yl]oxy}-3-[2-(2,2ditluoroethoxy)phenyl]propanoicacid

Using General procedure (la) and 2,2-difluoroethanol as the appropriate alcohol Example 4 was obtained. HRMS calculated for C37H36CIF3N4O5S: 740.2047; found 741.2119 (M+H).

-16917201

Example 9 (2R)-2-{[(5S'_(I)-5-{3-chloro-2-methyl-4-[2-(4-methylpipcrazin-l· yl)ethoxy]phenyl)-6-(4-fluorophenyl)thieno[2,3-rfJpyrimidin-4-yl]oxy)-3-{2-[(5-methyl1,2-oxazol-3-yl)methoxy]phenyl)propanoic acid

Using General procedure (la) and (5-mcthyl-13-isoxazol-3-yl)methanol as the appropriate alcohol Example 9 was obtained. HRMS calculated for CioHaoCIFNsOeS: 771.2294; found 386.6226 (M+2H).

to Exemple 10 (2Æ)-2-{[(5S_rt)-5-(3-ch1oro-2-methÿl-4-[2-(4-mcthylpiperazin-lyl)cthoxy]phenyl}-6-(4-fluorophenyl)thieno[2₁3-rfJpyrÎmidin-4-yl]oxy}-3-{2-[(5fluoropyridin-2-yl)methoxy]phenyI}propanoic acid

Using General procedure (la) and (5-fluoro-2-pyridyl)methanol as the appropriate alcohol 15 Example 10 was obtained. HRMS calculated for CiiHjgClFîNjOiS: 785.2250; found 393.6212 (M+2H).

t

Example 11 (2/f)-2-{[(5S^, _e)-5-{3-chloro-2-mcthyl-4-[2-(4-niethylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluoropheny1)thieno[23-rfJpyrimïdîn-4-yl]oxy}-3-(2-{[6-(furan-220 yl)pyridîn-2-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [6-(2-furyl)-2-pyridyl]methanol (Préparation 9ea) as the appropriate alcohol Example 11 was obtained. HRMS calculated for CmsHuCIFNîOîS: 833.2450; found 417.6304 (M+2H).

Example 12 (2R)-2-{[(5S^,<_I)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[23-d]pyTimÎdin-4-yJ]oxy}-3-(2-{[6(morpholin-4-yl)pyridïn-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 C4_SH4₆C1FN_SO₆S: 852.2872; found 427.1494 (M+2H).

-171Example 17 (2Æ)-2-{[(5&)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl }-6- (4-Π uoropheny l)th ieno[2,3 -djpyri midin-4-yl]oxy) -3-(2- {[2(triiluoromethyl)pyridin-4-yl]methoxy) phenyljpropanoic acid

Using General procedure (la) and [2-(trifluoromcthyl)-4-pyridyl]mcthanol as the appropriate alcohol Example 17 was obtained. HRMS calculated for CuHjgC^NjOsS: 835.2218; found 836.2334 (M+H).

Example 18 (2Æ)-2-{((5₁S^, _fl)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l· y ])ethoxy] phenyl} •6-(4-fluorophenyl)thieno[23-d]pyⁱimidin-4-yl]oxy} -3-(2-( [2(thiophen-2-y))pyridin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [2-(2-thienyl)-4-pyridyl]methanol (Préparation 9eb) as 15 the appropriate alcohol Exampie 18 was obtained. HRMS calculated for C4sH4iCIFN_sO_sS₂:849.2222; found 425.6192 (M+2H).

Exemple 19 (2 Æ )-2 - {[(55^)-5- {3 -chloro-2 -methy 1-4 · [2-(4-methy Ipîperazin-1 y|)ethoxy]phenyl}-6-(4-fluorophenyl)thîeno[2,3-</]pyrïmidin-4-yl]oxy}-3-{2-[(220 chIoropyridin-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (la) and (2-chloro-4-pyridy!)methanol as lhe appropriate alcohol Example 19 was obtained. HRMS calculated for C^HjgCliFNjOjS: 801.1955; found 802.2017 (M+II).

Exemple 20 (2Λ>2-{ [(5SJ-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)cthoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2(morpholin-4-yl)pyridin-4-yl]methoxy} phenyljpropanoic acid

Using General procedure (la) and [2-(moipholln-4-y))pyridïn-4-yl]methanol as the appropriate alcohol Example 20 was obtained. HRMS calculated for CijHiiClFNeOôS: 852.2872; found 427.1490 (M+2H).

• 173Example 25 (2R)-2-{ [(55^)-5- {3-chloro-2-methyI-4-[2-(4-rnethy!pipera2in- ! yI)elhoxy]phenyl}-6-(4-fIuorophenyl)thieno[23-i/]pyrÎmÎdin-4-yl]oxy}-3-(2-{[2(lrifluoromethyl)pyrimidin-4-yl]methoxy}pheny!)propanoic acid

Using General procedure (la) and (2-trifluoromethy!pyrimidin-4-yl)methanol (Préparation 9bj) as the appropriate alcohol Example 25 was obtained. HRMS calculated forC^CIWOjS: 836.2171; found 837.2295 (M+H).

Example 26 (2Jî)-2-{[(55'₍,)-5-{3-chloro-2-meihyl-4-[2-(4-methylpipcrazin-lyl)ethoxy]phenyl)-6-(4-fluorophenyI)lhieno[23-i/]pyrimidin-4’yl]oxy}-3-{2-[(2cyc!opropylpyrimîdin-4-yl)methoxy]phcnyl) propanoic acid

Using General procedure (la) and (2-cyclopropylpyrimidin-4-yl)methanol (Préparation 9be) as the appropriate alcohol Example 26 was obtained. HRMS calculated for C₄₃HuC1FN₆O₅S: 808.2610; found 405.1363 (M+2H).

Example 27 (2^)-2-(((55^)-5- {3-chloro-2-mcthyl-4-(2-(4-methylpiperazin-lyl)ethoxy]phenyl)-6-(4-fluorophenyI)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(4chlorophenyl)pyrîmidin-4-yl]methoxy) phenyl)propanoic acid

Using General procedure (la) and [2-(4-chlorophenyl)pyrîmidin-4-yl]methano! (Préparation 9bo) as the appropriate alcohol Example 27 was obtained. HRMS calculated forC«H4iChFN₆O₅S: 878.2220; found 879.2355 (M+II).

Example 28 (2Λ)-2-{ [(55_fl)-5-(3-chloro-2-methyl-4-[2-(4-mclhy]piperazin-lyl)ethoxy]phenyl)-6-(4-fluorophenyl)thîeno[2,3-rf|pyrïmidin-4-yl]oxy}-3-{2-[(2cy cl openty Ipyrimi d in-4-y 1) methoxyjpheny 1 ) propanoic acid

Using General procedure (la) and (2-cyclopentylpyrimidin-4-yl)methanol (Préparation

9b!) as the appropriate alcohol Example 28 was obtained. HRMS calculated for

C4SH46C1FN6OJS: 836.2923; found 419.1537 (M+2H).

-175Exampie 33 (2Æ)-2-{l(55'_e)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-ly!)ethoxy]pheny!)-6-(4-Îluorophenyl)thieno[2,3-d]pyrimidin-4-yI]oxy}-3-(2-{[2(thiophen-2-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procédure (la) and [2-(2-thicnyl)pyrimidin-4-ylJmethanoI (Préparation 9bv) as the appropriate alcohol Example 33 was obtained. HRMS calculated for C₄₄H«C1FN₆O₅S2:850.2174; found 851.2245 (M+H).

Exampie 34 (2Æ)-2-{[(5S^, _n>5-{3<hloro-2-methyI-4-[2-(4-methy!piperazin-l· yI)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-rf|pyrimidin-4-y!]oxy}-3-(2-{[2-(pyridin4-yl)pyrirnÎdin-4-ylJmethoxy}phenyl)propanoic acid

Using General procedure (la) and [2-(4-pyridyl)pyrimidin-4-yl]methanol (Préparation 15 9bs) as the appropriate alcohol Example 34 was obtained. HRMS calculated for (^s^iCIFNjOîS: 845.2562; found 423.6358 (M+2H).

Example 35 (2£>2-{[(55«)-5-{3-ch!oro-2-inethyl-4-[2-(4-methylpiperazin-ly])ethoxy]phenyI}-6-(4-fluorophenyl)1hieno[2,3-</]pyriniidin-4-yl]oxy}-3-(2-{[2-(furan-320 yl)pyrimidin-4-yl]methoxy)phenyi)propanoic acid

Using General procedure (la) and [2-(3-furyl)pyrimîdin-4-yl]inethanol (Préparation 9bt) as the appropriate alcohol Example 35 was obtained. HRMS calculated for CwHwClFNftC^S: 834.2403; found 835.2443 (M+H).

Example 36 (2/?)-2- {[(55^)-5-{3-chIoro-2-methyi-4-[2-(4-methylpiperazin-1 y]Jethoxy]pheny!)-6-(4-fluorophenyl)thieno[2,3-iiJpyrimïdin-4-yi]oxy}-3-(2-{[2-(l,3thiazol^-yljpyrimidin^yljmethoxy) pheny!)propanoic acid

Using General procedure (la) and [2-(2-thiazolyl)pyrimidin-4-y!]methanol (Préparation

9bx) as the appropriate alcohol Example 36 was obtained. HRMS calculated for

CuHaîCIFNTOiSî: 851.2127; found 426.6120 (M+2H).

-177Exa mple 41 (25)-2- {1(55,)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl)-6-(4-fluorophenyl)thieno[2_f3-i/]pyrimidin-4-yl]oxy}-3-{2-[(2propylpyrïmidin-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (la) and (2-propylpyrimidin-4-yl)methanol (Préparation 9bb) as the appropriate alcohol Exemple 41 was obtained. HRMS calculated for C^H^CIFNèOjS: 810.2766; found 406.1459 (M+2H).

Example 42 (2JÎ)-3-{2-[(2-butylpyrimidin-4-yl)methoxylphenyl}-2-{[(5S’₍,)-5-{3-chloro-2methy 1 -4- [2-(4 -methylpi perazin-1 -y l)ethoxy]phenyl} -6-(4-fluoropheny 1) thi eno[2_f 3iZ]pyrimïdin-4-yi]oxy}propanoicacid

Using General procedure (la) and (2-buty1pyrimidin-4-yl)methanol (Préparation 9bc) as the appropriate alcohol Example 42 was obtained. HRMS calculated for C^H^ClFNfiOjS: 824.2923 ; found 413. ! 500 (M+2H).

Example 43 (25)-2- {[(55,)-5- {3-chloro-2-mcthyI-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl)-6-(4-fluorophenyl)thieno[2,3-J]pyrimidÎn-4-y!]oxy}-3-[2-({2-[220 (dimethylamino)ethyI]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Using General procedure (la) and [2-[2-(diniethylainino)ethyl]pyrïmidin-4-yl]mcthanol (Préparation 9bm) as the appropriate alcohol Exemple 43 was obtained. HRMS calculated for Cxri^ClFNîOjS·. 839 3032; found 420.6614 (M+2H).

Example 44 (25)-2-{[(55_ï)-5-{3-chloro-2-methyl-4-[2-(4-methy!piperazm-lyl)ethoxy]phenyl)-6-(4-fluoropheny!)thieno[23-iflpyrimidin-4-yl]oxy)-3-(2-{[2-(2mcthoxyethyl)pyrimidin-4-yl[methoxy}pheny])propanoic acid

Using General procedure (la) and [2-(2-methoxyethyl)pyrimidin-4-yl]methanol (Préparation 9bl) as the appropriate alcohol Exampie 44 was obtained. HRMS calculated for C4iH₄4ClFN₆O₆S: 826.2716; found 414.1439 (M+2H).

•179Exemple 49 (2Æ)-2-{[(55e)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl)-6-(4-fluorophenyl)thieTio[2,3-4]pyrÎmidin-4-yl]oxy}-3-(2-([2-(l/fpyrazol-1 -yl)pyrimidin-4-yl]methoxy} phenylpropanoic Rcid

Using General procedure (la) and (2-(lH-pyrazol-l-yl)pyrimidin-4-yl)methanol (Préparation 9bw) as the appropriate alcohol Example 49 was obtained. HRMS calculated for CijHtoCIFNiOsS: 834.2515; found 418.1327 (M+2H).

Example 50 (2Λ)-2-{[(55_Λ)-5- {3-chloro-2-methyl-4-[2-(4-methyIpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno(2,3-/]pyrimidÎn-4-yl]oxy}-3-(2-{ (2-(4methylpiperazin-l-yl)pyrimidin-4-yl]methoxy}phenyl)propanoîc acid

Using General procedure (la) and [2-(4-methylpiperazin-J-yl)pyrimidin-4-yl]inethanol (Préparation 9aq) as the appropriate alcohol Example 50 was obtained. HRMS calculated for C^lLigClFNaOiS: 866.3141; found 434.1640 (M+2H).

Example 51 (2Æ)-2-{K5&)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl)-6-(4-fluorophenyl)thteno[2^-/]pyrimidÎn-4-yl]oxy}-3-(2-{(2-(lHl,2,3-triazol-l-yl)pyrimidin-4-yl]methoxy)phenyl)propanoic acid

Using General procedure (la) and [2-(lW-l_l2_l3-triazoH-yl)pyrimÎdin-4-yl]methanol (Préparation 9as) as the appropriate alcohol Example 51 was obtained. HRMS calculated for CxîHjçCIFNçOjS: 835.2467; found 418.6292 (M+2H).

Example 52 (2Æ)-2-{ [(5S_fl)-5-{3-chloro-2-methyl-4-[2-(4-inethylpiperazin-lyl)ethoxy]phenyl)-6-(4-fluorophenyl)thieno(2_l3-/]pyrimidin-4-yl]oxy}-3-(2-{[2(morphol i n-4-y l)pyrim i di n-4-y 1] methoxy} phenyl) propanoic aci d

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 forQMjCIFtyOôS: 853.2825; found 427.6484 (M+2H).

-181Example 57 (2/?)-2-{[(55₀)-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-((2etht>xypyrimidin-4-yl)methoxyJphenyl) propanoic acîd

Using General procedure (la) and (2-ethoxypyrimîdin-4-yl)methanol (Préparation 9ad) as the appropriate alcohol Exampie 57 was obtained. HRMS calculated for C42H42CIFN6O6S: 812.2559; found 407.1342 (M+2H).

Example 58 (2/f)-2-{[(5₁S'_e)’5’{3-chloro-2-methyl-4-[2-(4-methylpîperaz!n-l· yl)ethoxy]phenyl}-6-(4-fluorophenyl)thienop,3-rf]pyrimidin-4-yl]oxy}-3-(2-{[2-(2,23· trifluoroethoxy)pyrimidin-4-y1]methoxy)phenyl)propanoic acîd

Using General procedure (la) and [2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]methanol (Préparation 9ai) as the appropriate alcohol Example 58 was obtained. HRMS calculated for C42IIJ9CIF4N6O6S: 866.2276; found 434.1195 (M+2H).

Example 59 (2Æ)-2-{[(5_<S^, _fl)-5-(3-chloro-2-methy!-4-[2-(4-methylpÎperazin·!yl)ethoxy]phenyl)-6-(4-fluorophenyl)thîeno[2,3-rf)pynmidin-4-yl]oxy}-3-(2-{[2-(pyridin4-y!methoxy)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [2-(4-pyridylmethoxy)pyrîmidïn-4-yl]mcthanol (Préparation 9aw) as the appropriate alcohol Example 59 was obtained. HRMS calculated for C₄6H4îC1FNïOîS: 875.2668; found 438.6442 (M+2H).

Example 60 (2R)-2- {[(55^)-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-((1mcthyl-lH-imidazol-5-yl)methoxy]pyrimidin-4-yl}methoxy)phenyl]propanoicacid

Using General procedure (la) and {2-[(l-methyl-l/Z-imidazol-5-yI)methoxy]pyrimîdin-4yljmethanol (Préparation 9ay) as the appropriate alcohol Example 60 was obtained.

HRMS calculated for C4_îH₄₄CIFN_iO₆S: 878.2777; found 440.1451 (M+2H).

-183Example 65 (2/f)-2-{ [(5lV₀)-5- {3-cliloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophcnyl)thieno[2₍3-rf]pyTimîdin-4-yl]oxy}-3-(2-( [2(methyl$ulfanyl)pyrimidin-4-y]]methoxy)pheny])propanoîc acid

Using General procedure (la) and (2-mcthylsu1fanylpyrimidin-4-yl)methanol (Préparation

9aa) as the appropriate alcohol Example 65 was obtained. HRMS calculated for C4iH4oClFN(iO_sS₂: 814.2174; found 815.2260 (M+H).

Example 66 (2Æ)-2-([(5S_(i)-5-(3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[23-i(]pyrimidin-4-yl]oxy}-3-[2-({2-I(3methoxypropyl)sulfanyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Using General procedure (la) and [2-(3-methoxypropyl3ulfanyl)pyrimidin-4-yI]methanol (Préparation 9ac) as the appropriate alcohol Exemple 66 was obtained. HRMS calculated for C44H46CIFN₆O₆S₂: 872.2593; found 437.1384 (M+2H).

Example 67 (2Λ)-2- ([(5S_rt)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin- ! yl)ethoxy]phenyl)-6-(4-fluorophenyl)thieno[2,3-</]pyûmidin-4-yl]oxy}-3-[2-({2-[(220 methoxyethy|)sulfanyl]pyrimidin-4-yl}methoxy)phenyl]propanoic acid

Using General procedure (la) and [2-(2-melhoxyethylsulfanyl)pyrimidin-4-yl]methanol (Préparation 9ab) as the appropriate alcohol Example 67 was obtained. HRMS calculated for C4jH44ClFNiO(jS₂: 858.2436; found 430.1286 (M+2H).

Example 68 (2i)-2-{[(5S₀)-5-(3-chloro-2-methyl-4-(2-(4-methylpipera2in-lyl)ethoxy]phenyl}-6-(4-fluorophcnyl)thienoI23-<fJpyrimidin-4-yl]oxy}-3-[2-(pyrîmidin-4ylmethoxy)phenyl]propanoic acid

Using General procedure (la) and pyrimidîn-4-ylmethanol as the appropriate alcohol

Example 68 was obtained. HRMS calculated for (^oHjaClFNiOjS: 768.2297; found 769.2358 (M+Il).

-185Exa mple 73 (2R)-2-{[(5^)-5-(3 · chloro-2-methyl-4-[2-(4-methylpiperazin-1 y!)cthoxy]phenyl}-6-(4-fluoropheny!)thieno[2,3A|pyrimidin-4-yl]oxy}-3-{2-[(lcyclohexy 1-1 H-pyrazol-5-yl)methoxy]phenyl) propanoic acid

Using General procedure (la) and (l-cyclohexyl-l/f-pyrazol-5-yl)methano! (Préparation 9dh) as the appropriate alcohol Example 73 was obtained. HRMS calculated for qslIisClFNiOjS: 838.3079; found 839.3165 (M+H).

Ex a mple 74 (2R)-2 -{[(5S_a)-5- (3 -chloro-2-methy 1-4-(2-(4-methy!piperazin-l · yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3A]pyrimïdin-4-yl]oxy}-3-{2-[(l-phenyl1 H-pyrazol-5-yl)methoxy]phenyI) propanoic acid

Using General procedure (la) and (I-phenyl-lH-pyrazol-5-yl)methanoI as the appropriate alcohol Example 74 was obtained. HRMS calculated for CclhnClFNeOjS: 832.2610; found 833.2656 (M+H).

Example 75 (2Â)-2-{[(5_<S'_i/)-5-{3-chloro-2-methyl-4-[2-(4-methylpÎperazin-lyl)cthoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3’<(]pyrimidin-4-yl]oxy)-3-(2-{[120 (tetrahydro-2H-pyran-4-yl)-l H-pyrazol-5-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and (l-(tetrahydro-2II-pyran-4-yI)-lH-pyrazol-5yljmcthano! (Préparation 9di) as the appropriate alcohol Example 75 was obtained. HRMS calculated for QJLîCIFNîOîS: 840.2872; found 841.2913 (M+H).

Example 76 (2Λ)-2- {[(5S_e)- 5- (3 -chloro-2-methyl-4- [2-(4-methylpiperazin-1 yl)ethoxy]phenyl)-6-(4-fluorophenyl)thicno[2,3-</]pyrimidin-4-yl]oxy}-3-{2-[(l-ethyl-lHpyrazol-5-y!)methoxy]phenyl) propanoic acid

Using General procedure (la) and (I-ethyl-lH-pyrazol-5-yl)methanol (Préparation 9da) as the appropriate alcohol Example 76 was obtained. HRMS calculated for CuH^CIFNôOjS: 7842610; found 785.2679 (M+H).

-187 Example 81 (2Â)-2-{[(-5*S'_<J)-5'{3-chloro-2-methyl’4-[2-(4-methylpiperazin-lyî)ethoxy] phenyl} -6-(4-fluoropheny l)thieno[2,3 -cfjpy rimidin -4-y IJoxy} -3-(2-((1 -propy 1lH-pyrazol-5-yl)methoxy]phenyl)propanoic acid

Using General procedure (la) and (l-propyMH-pyrazol-5-yl)methanol (Préparation 9db) as the appropriate alcohol Example 81 was obtained. HRMS calculated for C«H44C1FNîO_sS: 798.2766; found 400.1433 (Μ+2Η).

Example 82 (2Æ)-2-{[(55'_o)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]pheny!}-6-(4-fluorophenyl)thieno [2,3-iZ]pyrimidm-4-yl]oxy}-3-(2-{[ 1-(3methylbutyl)- lH-pyrazo!-5-yl]methoxy}phenyl)propanoic acid

Using General procedure (la) and [l-(3-methy!butyl)-lH-pyrazol-5-yl]metlianol (Préparation 9de) as the appropriate alcohol Example 82 was obtained. HRMS calculated for C^iLîClFNéOjS: 826.3079; found 827.3123 (M+H).

Example 83 (2^)-3-{2-[(l-butyl-IH-pyrazol-5-yl)inethoxy]phenyl)-2-{[(55^, _e)-5-{3chloro-2-methyl-4-[2-(4-mcthylpiperazin-1 -yl)ethoxy]phenyl} -6-(4fluoropheny I)thieno [2,3 -tf] pyrimidin-4-y l]oxy} propanoic acid

Using General procedure (la) and (1 -butyl- lH-pyrazol-5-yl)methanol (Préparation 9dd) as the appropriate alcohol Example 83 was obtained. HRMS calculated for C₄₃H4₆CIFN_sO₃S: 8122923; found 407.1551 (M+2H).

Example 84 (2Æ)-2-([(5_<S^, _e)-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-{[l-(4_I4,4trifluorobutyl)-lH-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 C4₃H_4jCIF₄N₆O₃S: 866.2640; found 434.1385 (M+211).

-189Exemple 89 (22?)-2 - {[(5^)-5- {3-cliloro-2-methy l-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl)-6-(4.fluorophenyl)thieno[2,3-J]pyrimidin-4-yl]oxy)-3-(2-( [1-(2ethoxyethyl)-! H-pyrazol-5-yl]methoxy)phenyl)propanoîc acid

Using General procedure (la) and [l'(2-ethoxyethyl)-17/-pyrazol-5-yl]methanol (Préparation 9dr) as the appropriate alcohol Example 89 was obtained. HRMS calculated for CoH^ClFNôOiS: 828.2872; found 415.1510 (M+2H).

Example 90 (2/?)-2-{[(55_e)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l· yl)ethoxy]phenyl}-6-(4-fluorophenyl)thÎeno[2,3-J]pyrimidin-4-yl]oxy}-3-[2-({l-[2-(2methoxyethoxy)ethyl]-1 H-pyrazol-5-yl)methoxy)phenyl]propanoic acid

Using General procedure (la) and (l-[2-(2-methoxyethoxy)ethyl]-lH-pyrazol-515 yljmethanol (Préparation 9ds) as the appropriate alcohol Example 90 was obtained. HRMS calculatedfor C44H4gClFN₆O₇S: 8582978; found 430.1571 (M+2H).

Example 91 (2JÎ)-2-{[(5S'_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl ] -6-(4-fluorophenyl)thieno[2,3-J]pyrïmidÎn-4-yl]oxy} -3-[2-(pyrazin-220 ylmethoxy)phenyl]propanoic acid

Using General procedure (la) and pyrazin-2-ylmethanol as the appropriate alcohol

Example 91 was obtained. HRMS calculated for C40H3JCIFN6O5S: 768.2297; found 769.2422 (M+H).

Example 92 (2Æ)-2-{[(5S_lï)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)etlioxy]phenyl)-6-(4-fluorophenyl)thÎeno[2,3-</]pyrîmidin-4-yl]oxy} -3- (2-[( 1-methyllH-imidazol-5-yl)methoxy]phenyl}propanoîc acid

Using General procedure (la) and (l-methyl-lH-imidazol-5-yl)iricthanol as the appropriate alcohol Example 92 was obtained. HRMS calculated for C40H4ÛCIFN6O5S: 770.2453; found 771.2523 (M+H).

-191 Exemple 97 (2Â)-2-{[(5SJ-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl)-6-(4-fluorophenyl)thïeno[2,3-i/]pyrimidÎn-4-yl]oxy}-3-(2-{[l-(2methoxyethyl)-lH-l₍2,3-triazol-5-y!]methoxy)phenyl)propanoic acid

Using General procedure (la) and [l-(2-methoxyethyl)-lH-l,2,3-triazol-5-yl]methanol (Préparation 9ef) as the appropriate alcohol Example 97 was obtained. HRMS calculated for C41H4ÎCIFN7O6S: 815.2668; found 408.6427 (M+2H).

Example 98 (2Æ)-2-([(55_e)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)cthoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-J]pyrimidin-4-yl]oxy)-3-[2-(l,3-oxazol·

4- ylmethoxy)phenyl]propanoic acid

Using General procedure 0a) and oxazol-4-ylmcthanol as the appropriate alcohol Example was obtained. HRMS calculated for CîçHnClFNsOeS: 757.2137; found 758.2245 (M+H).

Example 99 (2Î)-3-{2-[(5-bromo-2-methoxypyrimidin4-yl)mcthoxy]phenyl}-2-([(55_i,)-

5- {3-chloro-2*methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}«6-(4fluorophenyl)thieno[2,3</)pyrimidin-4-yl]oxy) propanoic acid

Using General procedure 0a) and (5-bromo-2-methoxy-pyrimldin-4-y!)methanol (Préparation 9cb) as the appropriate alcohol Example 99 was obtained. HRMS calculated for CmHjsRrCIFNfiOiS: 876.1508; found 439.0864 (M+2H).

Example 100 (2Λ)-2- {[(5S_d)-5-(3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thicno[2,3-î/]pyrimidin-4-y!]oxy}-3-(2-{[2-methoxy5-(thÎophen-3-yl)pyrimidin-4-yl]methoxy)phenyl)propanoic acid

Using General procedure (la) and [2-methoxy-5-(3-thienyl)pyrimidm-4-yl]methanol (Préparation 9cc) as the appropriate alcohol Example 100 was obtained. HRMS calculated for C4jH42C1FNîO6S2: 880.2280; found 441.1229 (M+2H).

-193Example 105 (2i)-2-([(55_<I)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-<f]pyrimidin-4-yl]oxy}-3-(242-(2methoxyethoxy)ethoxy]phenyl] propanoic acid

Using General procedure (la) and 2-(2-methoxyetlioxy)ethanol as the appropriate alcohol Example 105 was obtained. HRMS calculated for C40H44CIFN4O7S: 778.2603; found 390.1362 (M+2H).

Example 106 (2Λ)-2· {[(55,)-5- {3-chloro- 2-methyl-4-[2-(4-methylpiperazin-ly l)ethoxy] phenyl} -6-(4- fluorophenyl Jthieno [2,3-i/]pyrimi dîn-4 -yl] oxy} -3 -(2- {2- [2-(2methoxyethoxy)ethoxy]ethoxy]phenyl)propanoic acid

Using General procedure (la) and 2-[2-(2-methoxyethoxy)cthoxy]ethanol as the appropriate alcohol Example 106 was obtained. HRMS calculated for CufysCIFNiOgS: 822.2865; found 412.1520 (M+2H).

Example 107 (2Â)-2-([(5S_e)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l· yl)ethoxy]phenyl)-6-(4-fluorophenyI)thieno[2,3-rf|pyrimidin-4-y1]oxy}-3-(2-{[2-(4methoxyphenyl)pyrimîdîn-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (Ib) and (4-methoxyphenyl)boronic acid as the appropriate boronic acid dérivative Exampie 107 was obtained. HRMS calculated for C47H44CIFNÙO6S: 874.2716; found 438.1407 (M+2H).

Example 108 (2Jî)-2-{[(5.S'_e)-5-{3-chloro-2-methyl4-[2-(4-methyJpiperazin-lyl)ethoxy]pheny!)-6-(4-fluoropheny1)thieno[2,3-rf]pyrimidin-4-y1]oxy}-3-(2-{[2-(6methy1pyridin-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

CiiHxjCIFtyOîS: 859.2719; found 430.6436 (M+2H).

-195Exampie 113 (2Æ)-2-{[(5S_a)-5-{3<hloro-2-mclhyl-4-[2-(4-methylpiperazin-ly!Jethoxy]phenyl}-6-(4-fluorophenyl)lhiçno[2,3-<f)pyrimidÎn-4-yl]oxy}-3-(2-{[2'(2methylphenyl)pyrimidin-4-yl]methoxy) phenylpropanoic acid

Using General procedure (lh) and o-tolylboronic acid as the appropriate boronic acid dérivative Example 113 was obtained. HRMS calculated for C47H44C1FNsO_sS: 858.2766; found 430.1464 (M+2H).

Example 114 (2Æ)-2-{[(5S_a)-5-{3-ch!oro-2-mc[hyl-4-[2-(4-methylpiperazin-ly l)ethoxy] phenyl} -6-(4-fluorophenyl)thieno [2,3-</Jpyrimidin-4-yl]oxy) -3-(2- {[2-(2fluorophenyl)pyrimidin-4-yl]methoxy}pheny!)propanoic acid

Using General procedure (1b) and (2-fluoropheny!)boronic acid as the appropriate boronic acid dérivative Exemple 114 was obtained. HRMS calculated for C4îH<(|C1F2N^OjS: 862.2516; found 432.1342 (M+2H).

Example 115 (2/î)-2-{[(55_e)-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-(2ethoxyphenyl)pyrimidin-4-yl]methoxy)phenyl)propanoicacid

Using General procedure (Ib) and (2-ethoxyphenyl)boronic acid as the appropriate boronic acid dérivative Exampie 115 was obtained. HRMS calculated for CjçHjjClFNeC^S; 788.2195; found 395.1179 (M+2H).

Example 116 (2Λ)-2- {[(5^)-5- (3-chloro-2-methyl-4-[2-(4-methyIpiperazin-1 yl)elhoxy]phenyl)-6-(4-fluorophenyl)lhïeno[2,3-<Z]pyrimidin-4-yl]oxy}-3-(2-{[2-(2methy!pyridin-3-yl)pyrimidin-4-y!]methoxy}phenyl)propanoicacid

Using General procedure (Ib) and (2-methyl-3-pyridyl)boronic acid as the appropriate boronic acid dérivative Example 116 was obtained. HRMS calculated for

C4ûH«CIFN7O_sS: 859.2719; found 430.6429 (M+2H).

-197Exampie 121 (2Æ)-2-{[(5S₀)-5-{3-chloro-2-rnethyl-4-[2-(4-methylpiperazïn-lyl )ethoxy ] phenyl} -6-(4-fluorophenyI)thieno [2,3 -</] pyr i midin-4-ylJoxy} -3-{2- {[2-(2methylthîophen-3-yl)pyrimidin-4-yI]methoxy}pheny])propanoic acid

Using General procedure (Ib) and (2-methyl-3-thienyI)boronic acid as the appropriate boronic acid dérivative Exampie 121 was obtained. HRMS calculated for QjHiîCIFNeOsSj: 864.2331; found 433.1239 (M+2H).

Example 122 (2Æ)-2-{[(5S'_<,)-5-(3-chloro-2-methyI-4-[2-(4-methylpiperazÎn-lyl)ethoxy]phenyl}-6-(4-fluorophenyI)thieno[2,3-if]pyrimÎdin-4-yl]oxy}-3-(2-{[2-{5methylpyridin-3-yl)pyrimidin-4-yI]methoxy}phenyl)propanoic acid

Using General procedure (lb) and (5-methyï-3-pyridyI)boronic acid as the appropriate boronic acid dérivative Example 122 was obtained. HRMS calculated for C46H«CIFN₇O₅S: 859.2719; found 430.6450 (M+2H).

Example 123 (2/?)-2-{[(5^)-5-{3-cWoro-2-methy!-4-[2-(4-methylpipcrazin-lyl)ethoxy]phenyl}-6-(4-fluoropheny!)thieno[2,3-<f]pyrimÎdin-4-yI]oxy}-3-(2-{[2-(4methylpyridin-3-yï)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Usîng General procedure (lb) and (4-methyl-3-pyridyl)boronic acid as the appropriate boronic acid dérivative Exampie 123 was obtained. HRMS calculated for C₄₆H«CIFN₇O₃S: 859.2719; found 430.6434 (M+2H).

Example 124 (2Æ)-2-{[(5S_(I)-5-{3-chloro-2-methyl-4-[2-(4-methylpipcrazin-ly l)ethoxy]ph eny I} - 6-(4-fl uorophenyl) thieno [2,3-t/]py rimidin-4-y ljoxy} -3 -(2- {[2-(4methylthiophen-3-yl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

Using General procedure (lb) and (4-methyl-3-thienyl)boronic acid as the appropriate boronic acid dérivative Example 124 was obtained. HRMS calculated for

C^HuClFNeOsSiî 864.2331; found 433.1256 (M+2H).

-199 Step Al.

eq. ethyl (2Æ)-2-[(5SJ-5-[3-chloro-4-(2-dimethylaminoethyloxy)-2-methyl-phenyl]-6-(4fluorophenyl)thieno[2,3-if]pyrimidin-4'yl]oxy“3-(2-hydroxyphenyl)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/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 * 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, 15 extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 5 mM aqueous NH₄IICOj solution and MeCN as eluents.

General procedure (IIb)

SîepÀL eq. ethyl (2Æ)-2-[(5S_e)-5-[3-chloro-4-(2-ifimethylaminoethyloxy)-2-methyI-phenyI]-6-(4fl uorop henyl)thie no [2,3-J]pyr imidin-4-y l]oxy-3 - [2-[(2-me thylsulfanyl pyrimid in-425 yl)methoxy]phenyljpropanoate (Préparation 10b), 3.0 eq. of the appropriate boronic acid dérivative and 3.0 eq. copper(l) thiophenecarboxylate were dissolved in dry THF (0.1 M for Préparation 10b), then 0.15 eq. Pd(PPhj)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 30 dichloromethane and methanol as eluents.

Step B'

-201conversion was observed. Then ît 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 NH^HCOj solution and MeCN as eluents to obtain 5 Example 127. HRMS calculated for CmHjoCIFMOîS: 703.1531; found 704.1634 (M+H).

Example 128 (2/î)-2-{[(55'₍,)-5-{3-chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}6-(4-fluorophenyl)thicno[2,3-if]pyrÎmidin-4-yI]oxy)-3-(2-{[2-(pyridin-4-yl)pyrimidin-4yl]methoxy}phenyl)propanoic acid

Using General procedure (fia) and [2-(4-pyrîdyl)pyrïmidin-4-yl]methanol (Préparation 9bs) as the appropriate alcohol Example 128 was obtained. HRMS calculated for ^HjôCIFNèOjS: 790.2140; found 396.H47 (M+2H).

Example 129 (2/î)-2-{[(55,)-5-{3-chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-y[]oxy}-3-(2-{[2-(morpholin-4-y1)pyrimidin4-yl]mcthoxy}phenyl)propanoic acid

Using General procedure (lia) and (2-(morpholin-4-yl)pyrimidin-4-y[)methanol 20 (Préparation 9ar) as the appropriate alcohol Example 129 was obtained. HRMS calculated for C4jH₄oClFN_fi0₆S! 7982403; found 799.2458 (M+H).

Example 130 (2Λ)-2-{[(5S_fl)-5-{3-chloro-4-[2-(dÎmethylamÎno)ethoxy]-2-methy1phenyl}6-(4-fl uorop heny l)thieno[2,3 -d] pyrimid in-4«yi ]oxy)-3-(2- [(2-et hoxypy rimidi n-425 yl)methoxy]phenyl}propanoic acid

Using General procedure (lia) and (2-ethoxypyrimidin-4-yl)methanol (Préparation 9ad) as the appropriate alcohol Example 130 was obtained. HRMS calculated for CaoHpClFNAS: 757.2137; found 758.2212 (M+H).

-203Example 135 (2R)-2-{[(5S^, _(I)-5-{3-chloro-4-[2-(dimcthylamino)ethoxy]-2-methylphenyl}6-(4 -fl uoropheny l)thîeno [2,3 -rf]pyrimidin-4-y IJoxy )-3-(2-( [2-(2methoxyphenyljpyr ί mi dîn-4-y I ] methoxy} phenyl)propanoic acid

Using General procedure (11b) and (2-metlwxyphenyl)boronic acid as the appropriate horonic acid Exemple 135 was obtained. HRMS calculated for ChHjçCIFNjOîS: 819.2294; found 410.6206 (M+2H).

Example 136 (2R)-2-{[(5iS'_fl)-5-{3-chloro-4-[2-(dimethylamino)ethoxy]-2-methyIphenyl}6-(4-fluorophenyl)thieno[2,3-rf]pyrimidin-4-yI]oxy}-3-(2-{[2-(2-methylpyridin-4yl)pyrimidin-4-yl]methoxy)phenyl)propanoicacid

Using General procedure (11b) and (2-methyl-4-pyridyl)boronic acid as the appropriate boronic acid Example 136 was obtained. HRMS calculated for C^HjgCIFNiOjS: 804.2297; found 403.1234 (M+2H).

Example 137 (2R)-2-{[(5S_ff)-5-{3-chIuro-4-[2-(dimelhyIamino)ethoxy]-2-methylphenyI}6-(4-fluorophenyl)thîeno(2,3-d]pyriniÎdin-4-yl]oxy}-3-(2-{[2-(3-niethylpyridin-4yl)pyrimidin-4-yl]methoxy)phenyl)propanoicacid

Using General procedure (Hb) and (3-methyI-4-pyridyl)boronic acid as the appropriate boronic acid Example 137 was obtained. HRMS calculated for C^jHjgClFNeOjS: 804.2297; found 403.1237 (M+2H).

Example 138 (2R)-2-([(5S„)-5-{3-chloro-4-[2-(dimethyIamino)ethoxy]-2-niethyIphcnyI}6-(4-fluorophenyl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-(2-{(2-(4-methyIpyridin-3yI)pyrimidïn-4-yl]methoxy}phenyl)propanoicacid

Using General procedure (llb) and (4-methyI-3-pyridyl)boronic acid as the appropriate boronic acid Example 138 was obtained. HRMS calculated for QjHjgClFNâOjS: 804.2297; found 403.1220 (M+2H).

-205Example 141 (2R)-2-{[(55_tf)-5-{3-chloro-2-methyl-4-[((35 or R)-l-methyIpiperidin-3yl)oxy]phenyl}-6-(4-fluorophcnyl)thieno[2₎3-rf]pyrimidin-4-yI]oxy}-3-[2-(pyrazin-2ylmethcxy)phcnyl]propanoic acid and

Example 142 (2R)-2-{[(55,)-5-(3-chloro-2-methyl-4-[((3R or S)-1-methylpiperidin-3yl)oxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-{pyrazîn-2ylmethoxy)phenyl]propanoic acid and

Example 143 (2Λ>2- {[(55,,)-5-[3-chloro-2-mcthyl-4-[(l -methylpyrrolidin-2yl)methoxy]phenyl}-6-(4-fluorophcnyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-[2-(pyrazÎn-2ylmethoxy)phenyl]propanoic acid (mixture of diastereoisomers)

0.470 g ethyl (2Λ)-2-[(55_e)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(4fluo ropheny 1 )t hieno [2,3 -t/]py rimid in-4 -y l] oxy-3 - [2-(pyrazin-2ylmethoxy)pheny!]propanoate (Préparation 6b) (0.7 mmol), 0.330 g l-methylpipcridin-3ol (2.0 mmol), and 0.524 g tripheny! phosphine (2.0 mmol) were dissolved in 15 mL dry toluene, then 0.461 g di/er/butyl azodicarboxyîate (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 constitutiona! isomers were separated via flash chromatography using DCM and MeOH as eluents. The mixture of compounds eluting earlier were the precursors of Exemple 141 and 142, while the mixture of compounds eluting later were the precursors of Exemple 143. The obtained prccursor dérivatives were separately dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq LiOH χ 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 Exemple 141 [HRMS calculated for CjçHîîCIFNsOîS: 739.2031; found 7402119 (M+H)], Exemple 142 [HRMS calculated for CjsHjsCIFNîOîS: 739.2031; found

-207Using General procedure (IHa) and 3-(dimethylamino)propan-l-ol as the appropriate alcohol Example 147 was obtained. HRMS calculated for CjgHjjClFNiOjS: 727.2031; found 728.2085 (M+H).

Exampie 148 (2/?)-2-{[(5S_fl)-5-(3-chloro-2-methyl-4-[2-(morpholin-4-yl)ethoxy]pheny!}6-(4 -fluoropheny l)t hieno [2,3 -rf] pyrimidin-4-y IJ oxy} -3 [2-(pyrnzi n-2y1methoxy)phenyl] propanoic acid

Using General procedure (Ilia) and 2-(morpholin-4-yl)ethanol as the appropriate alcohol Example 148 was obtained. HRMS calculated for CjîHjsCIFNsOûS: 755.1981; found 756.2052 (M+H).

General procedure (IVa)

Step A:

eq. ethyl (2/?)-2-[(5S^, _rt)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperaan-lyl)cthoxy]phenyl]-6-(5-fluoro-2-furyl)thieno[2,3-rf]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.

S(?P B:

The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmo!) and 10 eq LiOH x HîO 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 NajSO^, filtered and 30 concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

-209Example 153 (2Æ)-3-{2-[2-(benzylaniino)-2-üxüethoxy]phenyl}-2-{[(5S_fl)-5-{3-chloro-2methyl-4-[2-(4-methylpiperazin-1-yl)elhoxy]phenyl}-6-(5-fluorofiiran-2-yl)thieno[2,3i/]pyrïmîdÎn-4-yl]oxy}propanoÎc acid

Using General procedure (IVa) and N-benzyl-2-hydroxy-acetamide as the appropriate alcohol Example 153 was obtained. HRMS calculated for CL12H41CIFN5O7S: 813.2399; found 814.2492 (M+H).

Example 154 (2/Î)-2-{[(55_<,)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-ly!)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-{2-[2-oxo-2(propylamino)ethoxy]phenyl)propanoic acid

Using General procedure (IVa) and 2-hydroxy-A/-propyl-acetamide as the appropriate alcohol Example 154 was obtained. HRMS calculated for CîjILiCIFNsOjS: 765.2399; found 766.2459 (M+H).

Example 155 (2/Î)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(5-fluoroftiran-2-yl)thieno[2,3-i/]pyrinitdin-4-yî]oxy}-3-(2-{2-oxo-2[(2-phenylethyl)amino]ethoxy}phenyl)propanoicacid

Using General procedure (IVa) and 2-hydroxy-À/-2-phenylethyl-acetamtde as the appropriate alcohol Example 155 was obtained. HRMS calculated for CmîHoCIFNjOtS: 827.2556; found 828.2580 (M+H).

Example 156 (2R)-3-(2-[2-(butylamino)-2-oxoethoxy]phenyl}-2-{[(>5‘5_i,)-5-{3-chloro-2methy14-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl)-6-(5-fluorofuran-2-yl)thÎeno[2,3zf| py rimidi n-4-y l]ox y} propanoic acid

Using General procedure (IVa) and Mbutyl-2-hydroxy-acetamide as the appropriate alcohol Exemple 156 was obtained. HRMS calculated for C39H43CÎFN5O7S: 779.2556; found 780.2614 (M+H).

-211Exemple 159 (25)-2- {[(55,)-5- {3 -chlcro-2-mcthy 1-4- [2-(4-melhylpiperazin-1 yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)tlueno[2,3-<Z]pyrimÎdin-4-yl]oxy}-3-(2-{[4(trifluoromethyl)pyridin-2-yl]methoxy) pheny IJpropanoïc acid

Using General procedure (IVa) and [4-(trifluoromethyl)-2-pyridyl]methanol as the appropriate alcohol Exampie 159 was obtained. HRMS calculated for CmHjêCI^NjOcS: 825.2011; found 413.6085 (M+2H).

Exemple 160 (25)-2-{[(55_I)-5-{3-ch!oro-2-methyl-4-[2-(4-methylpiperazin-l· yl)ethoxyjphenyi}-6-(5-nuorofuran-2-yl)thieno[2,3-d|pyriniidin-4-yl]oxy}-3-{2-[(2methoxy-6-methylpyrimidin-4'yl)methoxy]phenyl)propanoic acid

Using General procedure (IVa) and (2-methoxy-6-methyl-pyrimidin-4-yl)methanol (Préparation 9cf) as the appropriate alcohol Exemple 160 was obtained. HRMS 15 calculated for CuHwClFNAS: 802.2352; found 402.1241 (M+2H).

Example 161 (25)-2-{[(55ï)-5-{3-chloro-2-methyI-4-[2-(4-methylpiperazin-1yl)ethoxy]phcnyl)-6-(5-fluorofuran-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy)-3-{2-[(6methyipyrimidin-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 CjÿlIjsCIFNôObS: 772.2246; found 387.1188 (M+2H).

Example 162 (25)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxyÎphenyl}-6-(5-fluarofuran-2-yl)thieno[2,3-d]pyrimÎdin-4-yl]oxy}-3-{2-[(6methoxypyrimidin-4-yl)methoxy]phenyl}propanoicacid

Using General procedure (IVa) and (6-mcthoxypyrimidin-4-yl)methanol (Préparation

9ce) as the appropriate alcohol Example 162 was obtained. HRMS calculated for

C₃₉H3gCIFN₆O₇S: 788.2)95; found 395.1165 (M+2H).

-213reversed phase chromatography using 5 mM aqueous NILJICOj solution and MeCN as eluents to obtain ethyl (2À)-2-[5-[3-chIoro-2-mcthyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-iodo-lhieno[2,3-i/]pyrimidin-4-yt]oxy-3-[2-(2pyridylmethoxy)phenyl]propanoate as a mixture of diastereoisomers. MS: (M+H) “ 828.0.

$f?P B;

518 mg ethyl (2A)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]· 6-lodo-thicno[2,3-d]pyrimidm-4-yl]oxy-3-[2-(2-pyridylmcthoxy)phcnyl]propanoate (0.625 mmol) and 565 mg 2-(5-fluoro-2-furyl)-4,4,5,5-tetrametliyl-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 PdCh x dppf (0.0625 mmol)was added. The mixture was heated at 100°C via microwave irradiation untii 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 NH₄HCOj solution and MeCN as eluents.

Step C:

The obtained intermediate was dissolved in 10 mL dioxane-water 1:1 (10 mL/mmol) and 20 200 mg LiOH x H2O (4.77 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 Na2SO₄, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous NIL1HCO3 solution and MeCN as eluents. The diastereoisomer eluting earlier was 25 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 CjslfoClFNjOeS: 757.2137; found 379.6159 (M+2H).

Example 167 (2Æ)-2-[[(55T)-5-{3-chloro-2-methyI-4-[2-(4-methylpiperazin-l30 yl)ethoxy]phenyl}-6-(5-fluorofûran-2-yl)thieno[2,3-J]pyrimidin-4-yl]oxy}-3-(2-{[2(trifluoromethyt)pyridui-4-yl]methoxy} phenyl)propanoic acid

-215Using General procedure (IVa) and [2-(2-thienyI)pyrimidin-4-yl]methanol (Préparation 9bv) as the appropriate alcohol Example 171 was obtained. HRMS calculated for C42H3îC1FN₆O₆S₂: 840.1967; found 421.1070 (M+2H).

Example 172 (2Æ)-2-{[(5S_d)-5-{3-chIoro-2-methyl-4-[2-(4-methylpiperazin-l· yl)ethoxy]phenyl}-6-(5-nuorofuran-2-yl)thicno[2,3-<(]pyrimidin-4-yl]oxy}-3-(2-([2(pyridin-4-yl)pyrimidin-4-ylJmethoxy) phenylpropanoic acid

Using General procedure (IVa) and [2-(4-pyridyl)pyrimidin-4-yl]methanol (Préparation 10 9bs) as the appropriate alcohol Example 172 was obtained. HRMS calculated for C«H3₉C1FN₇O6S: 835.2355; found 418.6246 (M+2H).

Example 173 (2R)-2-{ [(55’_<1)-5-{3-chloro-2-mcthyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl)-6-(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[215 (thiophen-3-yl)pyrimidin-4-yl]methoxy}pbenyl)propanoic acid

Using General procedure (IVa) and [2-(3-thienyi)pyrimidin-4-yl]methanol (Préparation 9bu) as the appropriate alcohol Exampie 173 was obtained. HRMS calculated for CuHjgCIFNiOiSj: 840.1967; found 841.2059 (M+H).

Example 174 (2R)-2-{[(5S'_fl)-5-{3-chloro-2-mcthyl-4-[2-(4-methylpipcrazin-1yl)ethoxy] phenyi}-6-(5’fluorofuran-2-yl)thieno[2,3-<(] pyrimidin-4-y I]oxy}-3-(2-( [2-(2methoxyethyl)pyrimidin-4-yl]methoxy} phenylpropanoic acid

Using General procedure (IVa) and [2-(2-methoxyethyl)pyrimidin-4-yl]methanol (Préparation 9bl) as tlie appropriate alcohol Example 174 was obtained. HRMS calculated for QiIUCIFNfiChS: 816.2508; found 409.1335 (M+2H).

Example 175 (2Æ).2-{[(5SX5-{3-chloro-2-methyl-4-[2-(4-mcthylpipcrazin-l· yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[23-i/lpyrimidin-4-yl]oxy}-3-(2-{[2(morphoIin-4-yl)pyrimîdin-4-yl]methoxy}phenyl)propanoic acid

-217Using General procedure (IVa) and pyriniîdïn-4-ylmethannl as the appropriate alcohol Example 179 was obtained. HRMS calculated for CmHwCIFNéOùS: 758.2090; found 759.2166 (M+H).

Exampie 180 (2/ï)-2-{[(55'_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazÎn-lyl)ethoxy)phenyl}-6-(5-fluorofüran-2-yl)thieno[2,3-<f]pyrÎmidin-4-yl]oxy)-3-{2-[(imethyl-I H-pyrazol-5-yl)methoxy]phenyl)propanoic acid

Using General procedure (IVa) and (l-methyl-l/7-pyrazol-5-yl)methanol as the appropriate 10 alcohol Example 180 was obtained. HRMS calculated for CjbHjïCIFNôOîS: 760.2246;

found 761.2343 (M+H).

Example 181 (2JÎ)-3-{2-[(l-fôri-butyl-lH-pyrazoJ-5-yl)methoxyJphenyl)-2-{[(55'_(î)-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 -teri-butyl-l/f-pyrazol-5-yl)methanol (Préparation 9dt) as the appropriate alcohol Exampie 181 was obtained, HRMS calculated for C_4lH44CIFN₆O₆S: 802.2716; found 402.1422 (M+2H).

Exampie 182 (2/î)-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[2-(4-methylpipcrazin-iyl)ethoxy]phenyl)-6-(5-fluorofuran-2-yl)thieno[2,3-<flpyrimÎdin-4-y1]oxy)-3-(2-{[l(propan-2-yl)-l H-pyrazoI-5-yl]methoxy}phenyl)propanoic acid

Using General procedure (IVa) and [l-(propan-2-yl)-lÂApyrazol-5-yl]methanol (Préparation 9dc) as the appropriate alcohol Example 182 was obtained. HRMS calculated for Cmo^îCIFNîOîS: 788.2559; found 789.2663 (M+H).

Example 183 (2/î)-2-{[(55'_fl)-5-{3-chloro-2-methyl-4-[2-(4-niethylpiperazin-l· yl)ethoxy}phenyl}-6-(5-fluorofuran-2'yl)thicno[2,3-</]pyrimidin-4-yl]oxy) -3-(2-((1cyclopenty 1 -111-pyrazol- 5-y l)mcthoxy] phenyl} pro panoic acid

-219Using General procedure (IVa) and (l-propy]-lif-pyrazol-5-yl)methanol (Préparation 9db) as the appropriate alcohol Example 187 was obtained. HRMS calculated for CwILüCIFNeOfiS: 788.2559; found 395.1357 (M+2H).

Example 188 (2Æ)-3-{2-[(l-butyl-lH-pyrazol-5-yI)mcthoxy]phenyl)-2-{[(5S_rt)-5-{3ch!oro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl) -6-(5-fluorofuran-2yl)thicno[2,3-i(]pyrimîdin-4-yl]oxy}propanoic acid

Using General procedure (IVa) and (l-butyl-I//-pyrazol-5-yl)mcthanol (Préparation 9dd) 10 as the appropriate alcohol Example 188 was obtained. HRMS calculated for C^FUCIFNôOôS.· 802.2716; found 402.1447 (M+2H).

Example 189 (2Λ)-2-{ [(5S₍,)-5-{3-chloro-2-methyl-4-[2-(4-methylpipcrazïn-lyl)ethoxy]phenyl}-6-(5-fluorofiiran-2-yl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-[2-(pyrazin15 2-y1methoxy)phenyl]propanoic acid

Using General procedure (IVa) and pyrazin-2-ylmethanot as the appropriate alcohol Example 189 was obtained. HRMS calculated for CjsHjjCIFNîOîS: 7582090; found 759.2159 (M+H).

Example 190 (2/î)-2-{[(5&)-5-{3-ehloro-2-methyI-4-[2-(4-methylpiperazm-lyl)elhoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-i(|pyrimidin-4-y1]oxy}-3-[2(pyrimidin-5*ylmethoxy)phenyl]propanoîc acid

Using General procedure (IVa) and pyrimidin-5-ylmethanol as the appropriate alcohol Example 190 was obtained. HRMS calculated for CjiHjeCIFNfiOfiS: 7582090; found 759.2198 (M+H).

Example 191 (2Æ)-2-{[(5S_tf)-5-{3-chIoro-2-methyl-4-[2-(4-methylpÎperazÎn-l30 yt)ethoxy]pheny1}-6-(5-fluorofuran-2-yl)thieno[2,3-c/]pyrimidin-4-y1]oxy}-3-[2-(l,3oxazol-4-ylmethoxy)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).

Example 196 (2/î)-2-{[(5S’_fl)-5-{3-chloro-2-methyl-4-[2-(4’methylpiperazin-lyl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-i/Ipyrimidin-4-yl]oxy}-3-{2-[2-(2methoxyethoxy)ethoxy]phenyl}propanoicacid

Using General procedure (IVa) and 2-(2-methoxycthoxy)ethanol as the appropriate alcohol 10 Example 196 was oblained. HRMS calculated for C3JH42CIFN4O8S: 768.2396; found 769.2481 (M+H).

Example 197 (2JÎ)-2-{[(5S_tf)-5-{3-chloro-2-methyl-4-[2-(4-methy|piperazin-1yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yI)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{2-[2-(215 methoxyethoxy)ethoxy]cthoxy} phenylpropanoic acid

Using General procedure (IVa) and 2-[2-(2-methoxyethoxy)ethoxy]elhanol as the appropriate alcohol Example 197 was obtained. HRMS calculated for C4oH4sClFN409S.· 812.2658; found 407.1384 (M+2H).

Example 198 (2Æ)-2-{ [(5^)-5-(3 -chloro-2-methyl-4-[2-(4-methylpipcrazin-1yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3’iZIpyrimidin-4-yl]üxy}-3-(2-{[2-(3methylpyridin-4-yl)pyrimidÎn*4-yl]metlioxy)phenyl)propanoicacid

StepÀL

417 mg ethyl (2/î)-2-[(5S'_e)-5-[3-chloro-2-methyl-4-[2-(4-methy|pipera7in-1yljethoxy Jphcny 1] - 6-(5-fluoro>2- furyl)thieno [2,3-J]pyrimi din-4-yl]oxy-3- [2- [(2methyIsulfanylpyrimidin-4-yl)methoxy]phenyl]propanoate (Préparation 10c) (0.5 mmol),

205 mg (3-methyI-4-pyridyl)boronic acid (1.5 mmol) and 286 mg copperfl) thiophcnecarboxylate (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

-223Exemple 199 (2Λ)-2-{[(5^)-5-{3-chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}6'(5-iluorofuran-2-yl)thieno[2,3-/|pyrimidÎn-4-yl]oxy}-3-(2’methoxyphenyl)propanoÎc acid

Using General procedure (Va) and methanol as the appropriate alcohol Example 199 was obtained. HRMS calculated for CîiIImCIFNjOôS: 625.1450; found 626.1509 (M+H).

Exampie 200 (2Λ)-2· {[(55,)-5-( 3-chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}· 6-(5-fluorofuran-2-yl)lhieno[2,3-d]pyrimidin-4-ylJoxy)-3-[2-(2,2^10 trifluoroethoxy)phcnyl]propanoic acid

SlepAL

192 mg (25)-2-[(5S_e)-5-[3-chlorO'4-(2-dimethylaminoethyloxy)-2-methyl-phcnyl]-6-(5fluoro-2-furyl)thieno[2,3-J]pyrimidÎn-4-yt]oxy-3-(2-hydroxyphenyl)propanoate (Préparation 8d) (0.3 mmol) and 138 mg K₂COj (1.0 mmol) were dissolved in 2 mL DMF, then 232 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate (LO 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 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 Na₂SC>4, filtered and concentrated under reduced pressure and purified via prcparative reversed phase chromatography using 5 mM aqueous NH4HCOJ solution and MeCN as eluents to obtain Example 200. HRMS calculated for C3₂H₂gClF4N3O6S: 693.1323; found 694.1382 (M+H).

Example 201 (25)-2-( [(55.)'5-{3-ch!oro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}6-(5-fluorofuran-2-yl)thÎeno[2,3-<f]pyrimidin-4-yl]oxy}-3'(2-{[2(trifluoromethyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid

-22SUsing General procedure (Va) and (l-(2,2,2-trifluorocthyl)-lH-pyrazol-5-yl]methanol (Préparation 9du) as the appropriate alcohol Exemple 205 was obtained. HRMS calculated for CjJUClFiNsCUS.· 773.1698; found 774.1771 (M+H).

Example 206 (2Æ)-2-{[(5_lS'_i,)-5-{3-chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}6-(5-fluoiOfuran-2-yl)thieno[2,3-i/]pyrinudin-4-yl]oxy}-3-[2-(pyrazin-2ylmethoxy)pheny1]propanoic acid

Using General procedure (Va) and pyrazin-2-yl methanol as the appropriate alcohol Example 206 was obtained. HRMS calculated for CjjHjiClFNjOeS: 703.1668; found 704.1726 (M+H).

General procedure (Via) ftep-A;

I eq. ethyl (2Æ>2-[(5S_n)-5-[3<hloro-2-rnethyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(2-furyl)thieno[2,3-/]pyritnidin-4-yl]oxy-3-(2hydroxyphenyljpropanoate (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. diter/butyl 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 If

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.

-227Example 210 (2i)-2-{[(55'_rt)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-dJpyrimidin-4-yl]oxy)-3-[2-(propan-2y!oxy)phcnyl]propanoîc acid

Using General procedure (Via) and 2-propanol as the appropriate alcohol Example 210 was obtained. 1IRMS calculated for CjJIjyCltyOsS: 690.2279; found 691.2344 (M+H).

Example 211 (2JÎ)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazÎn-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy)-3-(2-[(2JÏ)· tetrahydrofuran-2-ylmethoxy]phenyl} propanoic acid

Using General procedure (Via) and [(2Æ)-tetrahydrofuran-2-yl]methanol as the appropriate alcohol Example 211 was obtained. HRMS calculated for C3JH41CIN4O7S: 732.2384; found 733.2453 (M+H).

Example 212 (2JÎ)-2-{[(55'<7)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)cthoxy]phenyl}-6-(furan-2-yl)thieno[2,3-rf|pyrimidin-4-yl]oxy}-3-l2(cyclopentyloxy)phenyl]propanoicacid

Using General procedure (Via) and cyclopenlanol as the appropriale alcohol Example 212 was obtained. HRMS calculated for CjsH^CIN^OéS: 716.2435; found 717.2481 (M+H).

Example 213 (2Λ)-2-{[(55_β)-5-(3-chloro-2-methyl4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-rflpyrimidin-4-yl]oxy}-3-f2-(5,6,7,8tetrahydroquinolin-8-yloxy)phenyI]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 lhe diastereoisomers. HRMS calculated for C42II42CIN3O0S: 779.2544; found 390.6369 (M+2H) and 390.6355 (M+2H).

-229Exemple 218 ' (2/ï)-2-{[(,5Si,)-5-{3-chïoro-2-methyl-4-[2-(4-mcthy[piperazin-lyl)ethoxy]phenyl}-6-(furan*2-yl)thieno[2,3-<7]pyrimidÎn-4-yl]oxy}-3-{2*[2· (mcthylamino)-2 -oxoethoxy]phenyl} propanoic acid

Using General procedure (Via) and 2-hydroxy-N-methyl-acetamide as the appropriate alcohol Example 218 was obtained. HRMS calculated for C36H3JCIN5O7S: 719.2180; found 720.2263 (M+H).

Example 219 (2/ï)-2-{[(5S_e)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazÎn-lyl)ethoxy]phenyl)-6-(furan-2-yI)thieno[2,3-if]pyrimidin-4-yl]oxy}-3-{2-[2-oxo-2(phenylamino)ethoxy]phenyl) propanoic acid

Using General procedure (Via) and 2-hydroxy-V-phenyI-acetamide as the appropriate alcohol Example 219 was obtained. HRMS calculated for C41II40CINJO7S: 781.2337; found 391.6225 (M+2H).

Example 220 (2Â)-3-{2-[2-(butylamino)-2-oxoet]ioxy]phenyl}-2-{[(55^, _fl)-5-{3-chloro-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(furan-2-yl)thîeno[2,3i/]pyrimidin-4-y!]oxy)propanoie acid

Using General procedure (Via) and y-butyl-2-hydroxy-acetamide as the appropriate alcohol Example 220 was obtained. HRMS calculated fur C39H44CIN5O7S: 761.2650; found 762.2703 (M+H).

Example 221 (2/î)-2-{[(5,Ç_e)-5-{3-chloro-2-methyl’4-[2-(4-methylpiperazin-l· yl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3“d]pyrimidin-4-yl]oxy}-3-[2-(2,2,2tri fl uoroethoxy)phenyl] propanoic acid

SkpAl

677 mg ethyl (2Æ>2-[(5S’J-5-[3-chloro-2-mcthyl-4-[2-(4-methylpiperazin-ly!)ethoxy]phcnyl]-6-(2-furyl)thicno[2,3-rf]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 8e) (1 mmol) and 276 mg K2CO3 (2.0 mmol)

-231 Example 224 (2Λ)-2- {[(55_β)-5- {3 -chloro-2-methy 1-4-[2-(4-mcthylpiperazi η-1yl)ethoxy]phenyl}-6-(furan-2-yl)thienoP,3-d]pyrîmidin-4-yl]oxy}-3-{2-[(6phenylpyrîmidin-4-yl)methoxy]phenyl} propanoic acid

Using General procedure (Via) and (6-phenyIpyrimidin-4-yl)methanol (Préparation 9cg) as the appropriate alcohol Exampie 224 was obtained. HRMS calculated for C44H4iCIN₆O₆S: 816.2497; found 409.1321 (M+2H).

Example 225 (2/Q-2-{[(5S„)-5-{3-chloro-2-methyl-4-[2-(4-methylpipcrazin-l10 yl)ethoxy]phenyl }-6-(furan-2-yl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-(2-[(l ,3-dimcthyl1 H-pyrazol-5-yl)methoxy] phenyl) propanoic acid

Using General procedure (Via) and (l,3-dimethyl-lff-pyrazol-5-yl)methanol as the appropriate alcohol Example 225 was obtained. HRMS calculated for Cj^ILuCINaO^S: 15 756.2497; found 379.1313 (M+2H).

Example 226 (2Λ)-2- {[(55,,)-5- {3 -chloro-2-methyl -4-L2-(4-methy 1 piperazin-1 yI)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-pyrazûl-5-yl)methanol as the appropriate alcohol Example 226 was obtained. HRMS calculated for CLnfyjClNjOiS: 782.2653; found 392.1398 (M+2H).

Exampie 227 (2/f)-2-([(5₁9_e)-5-{3-clüoro-2-melhyl-4-[2-(4-methylpipcrazin-l· yl)ethoxy]phenyl)-6-(furan-2-yl)thïeno[2,3-i(|pyrimidin-4-yl]oxy}-3-{2-[(l-methyl-3phenyl-1 H-pyrazol-5*yl)methoxy]phenyl) propanoic acid

Using General procedure (Via) and (l-methyl-3-phenyl-lZApyrazol-5-yl)mcthanol as the appropriate alcohol Exemple 227 was obtalned. HRMS calculated for C^HuClNaOeS:

818.2653; found 819.2735 (M+H).

-233Example 232 (2Λ)-2-{ [(5S_n)'5-{3-chloro-2-methyl-4-[2-(4-mcthyIpiperûzin-l yl)ethoxy]phenyI}-6-(furan-2-yl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-{2-[(5-fluoropyridin2-yI)methoxy]phenyl) propanoic acid

Using General procedure (Via) and (5-fluoro-2-pyridyl)methanoI as the appropriate alcohol Example 232 was obtained. HRMS calculated for C39H37CIFN5O6S: 757.2137; found 758.2199 (M+H).

Exa mp le 233 (2R>2- {[(55J-5- {3 -chIoro-2-methy I -4-[2-(4-methy Ipiperazin-1 10 y])ethoxy]pheny])-6-(furan-2-yl)thÎeno[2,3-</]pyrimidin-4-yl]oxy}-3-{2-[(5methoxypyridin-2-y!)methoxy]phenyl) propanoic acid

Using General procedure (Via) and (5-methoxy-2-pyridyl)methanoI as the appropriate alcohol Example 233 was obtained. HRMS calculated for CAL10CIN5O7S: 769.2337;

found 385.6241 (M+2H).

Example 234 (2R)-2-{[(5S^, _e)-5’{3-chiorO'2-mcthyl-4-[2-(4-methylpiperazin·!y!)ethoxy]phenyI}-6-(furan-2-yI)thieno[2,3-<(]pyrimidin-4-yl]oxy)-3-[2-(quinoIin-2ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and quinoIin-2-ylmethanol as the appropriate alcohol

Example 234 was obtained. HRMS calculated for CîjH^oCINjOûS: 789.2388; found 395.6253 (M+2H).

Example 235 (2/f)-2-{[(55^, _n)-5-{3-chloro-2-methyl-4-[2-(4-methylpÎperazin-lyl)ethoxy]phenyI)-6-(furan-2-y!)thieno[2,3-<Z]pyrimidin-4-yl]oxy}’3-{2-[(6methylpyridin-2-yl)methoxy]phenyl) propanoic acid

Using General procedure (Via) and (6-methyl-2-pyTidyl)methanol as the appropriate alcohol Example 235 was obtained. HRMS calculated for (WUoCINjOîS: 753.2388;

found 377.6262 (M+2H).

-235Exemple 240 (2Æ)-3-[2-(benzyIoxy)phenyl]-2-{[(55'_(f)-5-{3-chloro-2-methyI-4-[2-(4methylpiperazin-l-yl)ethoxy]phcnyl}-6-(iùran-2-yl)thieno[2,3-J]pyrimidin-4yljoxyjpropanoîc acid

Using General procedure (Via) and phenylmethanol as the appropriate alcohol Example

240 was obtained. HRMS calculated for C40H39CIN4O6S: 738.2279; found 739.2319 (M+H).

Example 241 (2Λ>2- {[(5£)-5- {3<hloro-2-methy]-4-[2-(4-methylpipcrazin-l· yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-rf]pyrimidin-4-y]]oxy}-3-[2-(pyridin-2ylmethoxy)pheny1]propanoic acid

Using General procedure (Via) and 2-pyridylmethanol as the appropriate alcohol Example

241 was obiained. HRMS calculated for C39H33CINSO6S: 7392231; found 370.6197 (M+2H).

Example 242 (2/î)-2-{[(55'_iI)-5-{3-chloro-2-methyl-4-12-(4-methylpiperazin-lyl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3-i/]pyrimÎdin-4-yl]oxy}-3-[2-(pyridin-3ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and 3-pyridylmethanol as the appropriate alcohol Example

242 was obtained. HRMS calculated for CîsHsîCINjOèS: 739.2231; found 370.6178 (M+2H).

Example 243 (2R)-2- {[(5&)-5- (3-chloro-2-methyI-4-[2-(4-îriethylpÎpcrazin-1 yl)ethoxy]phenyI)-6-(furan-2-yl)thÎeno[2,3-i(]pyrimidin-4-yl]oxy)-3-[2-(pyrida7in-3ylmethoxy)phenyl]propanoic acid

Usîng General procedure (Via) and pyridazin-3-y 1 methanol as the appropriate alcohol

Example 243 was obtained. HRMS calculated for Cjj^CINîOîS: 7402184; found

741.2227 (M+H).

-237Example 248 (2Â)-2-{[(5S_e)-5-{3-ch!oro-2-methyl-4-[2-(4-me(hylpiperazin-l yI)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3A]pyrimidin-4-yI]oxy}-3-(2-{[2(trifluoromethyl)pyrimidin-4-yl]methoxy}phenyI)propanoic acid

Using General procedure (Via) and [2-(trifluoromethyl)pyrimidin-4-yl]methano! (Préparation 9bj) as the appropriate alcohol Exemple 248 was obtained. HRMS calculated for CjsHjûCIFjNAS: 808.2058; found 8092126 (M+H).

Example 249 (2Æ)-2-{[(5&)-5-{3-chIoro-2-jnetfiyI-4-[2-(4-mcthyIpipcrazin· 1yl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3AIpyrimidin-4-yl]oxy}-3-{2-[(2chloropyrimidin-4-yl)methoxy]phenyl}propanoÎc acid

Using General procedure (Via) and (2-chloropyrimidin-4-yl)methanol (Préparation 9ch) as the appropriate alcohol Exemple 249 was obtained. HRMS calculated for CjgHjiCbNAS: 774.1794; found 775.1863 (M+H).

Exam pie 250 (2λ!)-3- {2 -[(2-amÎnopyrimidin-4-yl)methoxy]phenyl) -2- {[(55^)-5- {3chIoro-2-methyl-4-[2-(4-melhylpiperazin-l-yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3i/]pyriniidin-4-yl]oxy} propanoic acid

Using General procedure (Via) and (2-aminopyrimidin-4-yl)methano! (Préparation 9al) as the appropriate alcohol Example 250 was obtained. IJRMS calculated for C₃sH_3îC1N₇O₆S: 755.2293; found 378.6217 (M+2H).

Example 251 (2i)-2-{[(55’₍,)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-ly 1 )et hox y] phenyl} -6-( fùran-2-y l)thieno [2,3 A] pyrimidi n-4-y ljoxy} -3 -(2- {[2(dimethylamino)pyrimidin-4-yl]methoxy}phenyi)propanoic acid

Using General procedure (Via) and [2-(dimethyIamino)pyrimidin-4-yI]methanol (Préparation 9an) as the appropriate alcohol Example 25) was obtained. HRMS calculated for C^kCltyOsS: 783.2606; found 392.6366 (M+2H).

-239Example 256 (2/0-2-(((5^,)-5- {3-chloro-2-methyl-4-[2-(4-mcthylpÎperaan-1 yl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3-</]pyrimidÎn-4-yl]oxy}-3-(2-{[2(cyclopropylmethoxy)pyrimidin-4-yl]methoxy)phenyl)propanoic acid

Using General procedure (Via) and [2-(cyclopropylmethoxy)pyrimidin-4-yl]methanol (Préparation 9au) as the appropriate alcohol Exampie 256 was obtained. HRMS calculated for C^H^ClNaOjS: 810.2602; found 406.1380 (M+2H).

Exampie 257 (2/î)-3-(2-{[2-(benzyloxy)pyrÎmidin-4-yl]methoxy}phenyl)-2-{((5S_<,)-5-{310 chloro-2-methyl-4-[2-(4-methylpipcrazin-l-yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[23if]pyrimidin-4-yl]oxy}propanoic acid

Using General procedure (Via) and (2-benzy!oxypyrimidin-4-yl)methanoI as the appropriate alcohol Exampie 257 was obtained. HRMS calculated for C45H43QN6O7S: 15 846.2602; found 424.1407 (Μ1-2Η).

Example 258 (2Æ)-2-{[(5₁%)-5-{3-chloro-2-methyl-4-[2-(4-melhylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-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 C39H38CIN5O6S: 7392231; found 370.6187 (M+2H).

Example 259 (2i)-2-([(5S^, ₀)-5-{3-chloro-2-melhyl-4-[2-(4-melhy!piperazin-lyl)ethoxy]phenyl)-6-(furan-2-yl)tliieno[2,3-d]pyrimidin-4-yl]oxy}-3-[2-(pyrimidin-4ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and pyrimidin-4-y!methanol as the appropriate alcohol

Example 259 was obtained. HRMS calculated for CjgHjjClNôOôS: 7402184; found

741.2259 (M+H).

«

-241Example 264 (25)-2-(((,53^)-5- {3-chloro-2-methyl-4-[2-(4-methyIplperazin-l yl)ethoxy]phenyl}-6-(furan-2-yl)thieno(2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(t-ethyl-lHpyrazol-5-yl)methoxy]phenyl)propanoic acid

Using General procedure (VJa) and (1 -ethyl-t/7-pyrazol-5-yl)methanol (Préparation 9da) as the appropriate alcohol Example 264 was obtained. HRMS calculated for C₃₉H(iClN6O₆S: 756.2497; found 757.2597 (M+H).

Example 265 (25)-2-([(5S^, ₄)-5-{3-chloro-2-methyI-4-[2-(4-methylpiperazin-lyl)ethoxy]pheny!)-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yI]oxy}-3-(2-{[l-(2,2,2trifluorocthyl)-lH-pyrazo]-5-yl]methoxy}phenyl)propanoic acid

Using General procedure (Via) and [ 1-(2,2,2-trîfluoroethyiyiH-pyrazol-5-yl]methanol (Préparation 9du) as the appropriate alcohol Example 265 was obtained. HRMS calculated for C₃9H₃₈C1F₃N₆O₆S: 810.2214; found 406.1175 (M+2H).

Example 266 (25)-2-( ((55,)-5- {3-chloro-2-methy)-4-[2-(4-methyIpipcrazin-1 yl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3-<Zlpyrimidin-4-yl]oxy}-3-(2-(oxetan-2ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and oxetan-2-yl methanol as the appropriate alcohol

Example 266 was obtained as a mixture of diastereoisomers. HRMS calculated for

C_Î7H₃₉C1N4O₇S: 718.2228; found 719.2296 (M+H) and found 719.2283 (M+H).

Example 267 (25)-2- ([(5S_a)-5-{3-chIoro-2-methy l-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3-d]pyrimïdin-4-yl]oxy)-3- (2-[(l-methyl-1 Hlmidazol-4-yl)methoxy]phcnyl)propanoic acid

Using General procedure (Via) and (l-methy!-If/-imidazol-4-yl)mcthanol as the appropriate alcohol Example 267 was obtained. HRMS calculated for C₃8H₃₉C1NéO6S:

742.2340; found 372.1233 (M+2H).

-243Exampie 272 (2/?)-2-{[(5S_o)-5-{3-chloro-2-methyl-4-[2-(4-mcthylpiperazin-lyl)etboxy]phenyl}-6-(ftiran-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2'{[2-(pyrrolidin-lyl)pyrimidin-5-yl]methoxy}pheny!)propanoic acid

Using General procedure (Via) and (2-pyrrolÎdin-l-y!pyrimidin-5’yl)methanol as the appropriate alcohol Exampie 272 was obtained. HRMS calculated for C42H44CIN7O6S: 809.2762; found 405.6443 (M+2H).

Example 273 (2A)-2-{ [(55^)-5- {3-chloro-2-methy l-4-[2-(4-methylpiperazin-1y!)ethoxy] phenyl}-6-(furan-2-yl)thieno [2,3 -</]pyriïnidin-4-y l]oxy) -3-(2-{[2-(morpholin-4y!)pyrimidin-5-yl]methoxy)phenyl)propanoic acid

Using General procedure (Vïa) and (2-(morpholin-4-yl)pyrimidin-5-yl)methanol as the appropriate alcohol Exemple 273 was obtained. HRMS calculated for C42II44CIN7O7S: 825.27 H; found 413.6424 (M+2H).

Exampie 274 (2/Î)-2-{[(5S_e)-5-{3-chloro-2-methyl-4-[2-(4’methylpiperazin-lyl)ethoxy]pheny]}-6-(furan-2-yl)thÎeno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2*[(2methoxypyrimïdin-5-yl)methoxy]phenyl}propanoicacid

Using General procedure (Via) and (2-methoxypyrimidin-5-yl)methanol as the appropriate alcohol Example 274 was obtained. HRMS calculated for CiiHjgClNsChS: 770.2289; found 771.2398 (M+H).

Exemple 275 (2/î)-2-{[(5_IS'_i/)-5-{3-chloro-2-methyl-4-[2-(4-methylpïperazin-l· yljethoxy] phenyl}-6-(furan-2-y!)thi eno[2,3-</]pyrimid i n-4-yl]oxy) -3-[2-(pyrazln-2ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and pyrazin-2-ylmcthanol as the appropriate alcohol

Example 275 was obtained. HRMS calculated for CîgHpClNeOûS: 740.2184; found

741.2255 (M+H).

Μ

-245Example 280 (2-/0-2-{[(5S_fl)’5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-d]pyrimidin-4-ylJoxy}-3-[2-(l,3-oxazol-4ylmcthoxy)phcnyl]propanoic acid

Using General procedure (Via) and l,3-oxazoI-4-ylmethanoI as the appropriate alcohol Example 280 was obtained. HRMS calculated for C37H36CIN5O7S: 729.2024; found 730.2 Π 6 (M+H).

Example 281 (2Æ)-2- {[(5S_o)-5- {3-ch!oro-2-methyI-4-[2-(4-methylpiperazÎn- ΙΙΟ yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-</]pyrimidin-4-y]]oxy}-3-[2-(l,3-thiazoI-4ylmethoxy)phenyl]propanoic acid

Using General procedure (Via) and l,3-thîazol-4-ylmethanoI as the appropriate alcohol

Example 281 was obtained. HRMS calculated for C37H36CIN3O6S1: 745.1796; found 15 746.1867(M+H).

Example 282 (2Æ)-2-{ [(55,)-5- (3-chloro-2-mcthyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thÎeno[2,3-</Jpyrimidin-4-yl]oxy}-3-{2-[(2-methyl-2Hindazo 1-3 -y l)methoxy]pheny 1} propanoi c aci d

Using General procedure (Via) and (2-inethyl-2/f-indazol-3-yl)inethano! as the appropriate alcohol Example 282 was obtained. HRMS calculated for CuHuCINfiOeS: 792.2497; found 397.1336 (M+2H).

Example 283 (2Æ)-2-{[(5S*)-5-{3-chloro-2-inethyl-4-[2-(4-methylpiperazin-l· yl)cthoxy]phenyl}-6-(furan-2-yl)thicno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(5phenylpyrimidin-2-yI)methoxy]phenyl) propanoic acid

Using General procedure (Via) and (5-phenylpyrimÎdin-2-yl)mcthanol as the appropriate alcohol Example 283 was obtained. HRMS calculated for C^H^iCINîOèS: 816.2497;

found 817.2539 (M+H).

-247Example 288 (2Λ)-2- ([(55_e)-5-{3-chloro-2-methyl-4-[2-(4-methylpÎperazin-lyI)ethoxy]phenyI}-6-(furan-2-yl)thieno[2,3-t/]pyrimidin-4-yl]oxy}-3-[2 -(3,3,3trifl uoro propoxy)p heny Ijpropanoic aci d

Using General procedure (Via) and 3,3,3-trifluoropropan-1-o) as the appropriate alcohol

Example 288 was obtained. HRMS calculated for CîcHjoCIFjN^OîS: 744.1996; found 745.2037 (M+H).

Exemple 289 (2Æ)-2-([(55_fl)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-y!)thieno[2,3-d]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

Exemple 289 was obtained. HRMS calculated for C^HwCINjOîS: 753.2388; found 377.6280 (M+2H).

Exemple 290 (2Æ)-2-{[(5SJ-5-(3-chloro-2-mcthyl-4-[2-(4-methylpiperazin-1yl)ethoxyJphenyl}-6-(furan-2-yl)thïeno[2,3-i/Jpyrimidin-4-yl]oxy}-3-[2-(2methoxyethoxy)phenyl ] propanoi c 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).

Exemple 291 (2Æ)-2-{[(55,,)-5-( 3-chloro-2-methy 1-4-[2-(4-methylpi perazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-</]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 C41II41CIN4O7S: 768.2384; found 769.2459 (M+H).

•249Example 295 (25)-3-{2-[(l-benzyl-lH-13.3-lriazol-5-yl)methoxy]phenyl}-2-{[(55_n)-5(3-chloro-2-methyl-4-[2-(4-methylpipera7.in-1-y1)ethoxy]phenyl}-6-(furan-2y 1 ) th îeno [2,3-<ή pyrimidin-4-yl] oxy) propanoic acid

To a THF solution of 310 mg ethyl (25)-2-[(55_J)-5-[3-ch1oro-2-methyl-4-[2-(4mcthy1piperazin-l-yl)ethoxy]phenyl]-6-(2-furyl)thîcno[2,3-i7]pyrinudin-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 LÏOH x H₂O was added. The mixture was stirred at rooin 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 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 Exemple 294. HRMS calculated for

C«H4₂C1N₇O₆S: 819.2606; found 410.6375 (M+2H). Regioisomer eluting later was collected as Example 295. HRMS calculated for C43H4₂CJN₇O6S: 819.2606; found 410.6381 (M+2H).

Example 296 (25)-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[2-(4-methyf-4-oxidopiperazin-lyf)ethoxy]phenyf} •6-(furan-2-yl)thieno[2,3-rilpyrimidin-4-yl]oxy )-3-(225 methoxyphenyl)propanoïc acid

During the synthesis of Example 209, Exampie 296 was formed and isolated as a side product. HRMS calculated for CsityjCINiChS: 678.1915; found 679.1966 (M+H).

Example 297 (25)-2-{l(55_ÎJ)-5-{3-chloro-2-methyl-442-(4-methyl-l_>4-dioxidopiperazinl-yl)ethoxy]phenyl}-6-(fijran-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3’(2methoxyphenyl)propanoic acid

-251Example 298 (25)-2-{[(55_e)-5-(3-chloro-2-mcthyl-4-([(2S/-l -methyIpyTrolidin-2yl]methoxy}phenyI)-6-(furan-2-yl)thieno[2,3-i/]pyrimidÎn-4-yl]oxy}-3-(2methoxyphenyljpropanoic acid

IJsing General procedure (Vlla) and [(25/-l-methylpyrrolidin-2-yl]methanol as the appropriate alcohol Example 298 was obtained. HRMS calculated for CjîHjiCINjOîS: 633.1700; found 634.1771 (M+H)

Example 299 (25)-2-{[(55_tf)-5-(3-chloro-2-methyl-4-{[(2R)- ! -methylpyrrolidin-210 yl]methoxy}phenyl)-6-(furan-2-yl)thieno[2,3-tf]pyrimidin-4-yl]oxy}-3»(2methoxypheny!)propanoic acid

Using General procedure (Vlla) and [(25)-1-methy!pyrrûlidin-2-yl]methanol as the appropriate alcohol Example 299 was obtained. HRMS calculated for C33H32CIN3O6S: 15 633.1700; found 634.1774 (M+H)

Example 300 (25)-2-{[(55_a)-5-{3-chloro-2-mcthyl-4-[(35 or S)-(l-methylazepan-3yl)oxy]phcⁿyl}-6-(furan-2-yl)thieno[2_t3-if|pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General procedure (Vlla) and (l-methy!-2-piperidyl)methanol as the appropriate alcohol Example 300 was obtained coliecting only the Iater eluting diastereomer (absolute configuration not confirmed). HRMS calculated for Cs^Hj^CINjOîS: 647.1857; found 648.1916 (M+H)

Exemple 301 (25)-2-{[(55_a)-5-(3-chloro-2-methyl-4-[((35 0 r S)-1 -methyl piperidin-3yl)oxy]pheny!}-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2methoxypheny!)propanoic acid and

Example 302 (25)-2-{[(55_a)-5-(3-chloro-2-methyl-4-[((35 or 5)-l-methylpiperidin-3yl)oxy]pheny 1} -6-(furan-2-yl)thieno [2,3-</]pyri midin-4-yl]oxy} -3 -(2methoxyphenyljpropanolc acid

-253Using General procedure (Vlla) and pyrrolidin-3-ol as the appropriate alcohol Example

305 was obtained collecting the earlier eluting diastereomer (absolute configuration not confumed). HRMS calculated for Cji^jCINjOéS: 605.1387; found 606.1472 (M+H), and

Example 306 was obtained collecting the later eluting diastereomer (absolute 5 configuration not confirmcd). HRMS calculated for CjiIhsClNjOaS: 605.1387; found

606.1461 (M+H)

Example 307 (2R)-2-(((5S_e)-5-[4-((35 or R)-I-azabicyclo[2.2.2]oct-3-yloxy)-3-chloro-2methylphcnyl]-6-(furan’2-yl)thieno[2,3-iflpyrimidÎn-4-yl}oxy)-3-(2>

met hoxypheny l)propanoi c acid and

Example 308 (2R)-2-({ (5S_e)-5-[4-((3R or S)-l -azabicydo[2.2.2]oct-3-yloxy)-3-chloro-2methylphenyl]-6-(furan-2-yl)thieno[2,3-if|pyrimidin-4-yl}oxy)-3’(2· methoxyphenyl)propanoic acid

Using General procedure (Vlla) and quinuclidin-3-ol as the appropriate alcohol Example

307 was obtained collecting the earlier eluting diastereomer (absolute configuration not confirmed). HRMS calculated for CmI^CINjOûS: 645.1700; found 646.1799 (M+H), and

Example 308 was obtained collecting the later eluting diastereomer (absolute 20 configuration not confirmed). HRMS calculated for C34H32CIN3O6S: 645.1700; found

646.1746 (M+H)

Example 309 (2R>2-([(JS„)-5-{3-chloro-2-methyl-4-[((2S or R>l-methylpiperidin-2yI)methoxy]phenyl)-6-(furan-2-yl)thieno[2,3-if|pyrimidin-4-yl]oxy}-3-(2-methoxypheny!) 25 propanoic acid

Using General procedure (Vlla) and (l-methyl-2-pipcridyl)methanol as the appropriate alcohol Example 309 was obtained collecting the earlier eluting diastereomer (absolute configuration not confirmed). HRMS calculated for CnH^ClNjOaS.· 647.1857; found 30 648.1934 (M+H)

-255Using General procedure (VITa) and (l_t4-dimethylpiperazin-2*yl)methanol as the appropriate alcohol Example 313 was obtained. HRMS calculated for CuH^ClNtOeS: 662.1966; found 663.2004 (M+H)

Exemple 314 (25)-2-{[(5S_il)-5-{3-chIoro-2-methyl-4-[(4-methylinorpholin-2-yl)methoxy] phenyl}-6-(furan-2-yl)thleno[2,3-/]pyrimidin-4-yl]oxy}-3-(2-methoxypheny!) propanoïc acid

Using General procedure (Vüa) and (4-methylmorpholin-2-yl)methanoI as the appropriate alcohol Example 314 was obtained. HRMS calculated for C33H32CIN3O7S: 649.1649; found 650.1710 (M+H)

Example 315 (2Æ)-2-({(5S_ff)-5-[3-chloro-2-methyl-4-(morpholîn-2-ylmethoxy)phenyl]-615 (furan-2-yl)thieno[2,3-/]pyrimidin’4-yl}oxy)-3-(2-methoxyphcnyl)propanoÎcacid

Using General procedure (Vlla) and morpholin-2-yl methanol as the appropriate alcohol Example 315 was obtained. HRMS calculated for C33HÎ0CIN3O7S: 635.1493; found 636.1518 (M+H)

Example 316 (2Jï)-2-{[(5S_(t)-5-{3«chloro-2-methyM-[2-(!-methylpyrrolidin-2-yl)ethoxy] phcnyl}-6’(furan-2-yI)thieno[2,3-/Jpyrimidin-4-yl]oxy}-3-(2-melhoxypheny1) propanoic acid

Using General procedure (Vlla) and 2’(I-mcthylpyrrolidin-2-yI)ethanol as the appropriate alcohol Example 316 was obtained. HRMS calculated for C.uHs^CINaOeS: 647.1857; found 648.1909 (M+H)

Exam pie 317 (2Λ)-2- ([(5S_e)-5- (3-chloro-2-mcthyl-4-[2-( ! -methylpipcridinA3 0 y ljethoxy] phenyl} -6-(furan-2-yl)thi eno[2,3 -/Jpyri m id in-4-yl]oxy | -3 -(2 methoxyphenyljpropanoic acid

-257Using General procedure (Vlîa) and 4-(2-hydroxyethyl)-l-mcthyl-pÎperazin-2-one (Préparation 9eg) as the appropriate alcohol Example 321 was obtained. HRMS calculated for C₃₄H₃₃CIN₄O₇S: 676.1758; found 677.1850 (M+H)

Exempte 322 (23î)-2-{[(55_i)-5-{3-chloro-4-[2-(4-ethylpiperazin-1-yl)ethoxy]-2methylphcnyl }-6-(furan-2-yl)thicno[2,3-e/]pyrimidin-4-yl]oxy} -3-(2methoxyphenyl)propanoic acid

Using General procedure (Vlîa) and 2-(4-ethylpiperazÎn-l-yl)ethanol as the appropriate 10 alcohol Example 322 was obtained. HRMS calculated for C35H17CIN4O6S: 676.2122;

found 677.2186 (M+H)

Example 323 (2R)-2- {[(55_a)-5-{4-[2-(4-acetylpiperazin-1 -yl)ethoxy]-3-ch1oro-2me thy Iphenyl) - 6-(furan-2-y l)thieno [2,3-</]pyrimi din-4-yl]oxy }-3-(213 methoxyphenyljpropanoic acid

Step Ai

141 mg ethyl (2/î)-2-[(5SJ-5-(3-chloro-4-hydroxy-2-methyI-phenyl)-6-(2-furyl)thieno[2,3</]pyrimidin-4-yl]oxy-3-(2-methoxypheny!)propanoate (Préparation 6e) (0.25 mmol), 20 0.092 mL 2-piperazïn-l-ylethanol (0.75 mmol) and 197 mg triphenylphosphine (0.75 mmol) were dissolved in 5 mL dry toluene, then 173 mg diferfbutyl azodicarboxylate (0.75 mmul) 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 ester was purified via flash chromatography using DCM and MeOH as eluents 23 resulting the intermediate product ethyl (27?)-2-[(5S^)-5-[3-chloro-2-methyl-4-(2-pipcrazinl-ylethoxy)phenyl]-6-(2-fiiryl)thieno[2,3-i/]pyrimÎdin-4-yl]oxy-3-(2methoxyphenyl)propanoate. 'H NMR (500 MHz, DMSO-d_s): 8.58 (s, IH), 7.79 (dd, IH),

7.25 (d, IH), 7.24 (d, JH), 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, ! H). 4.27 (m, 211), 4.05 (m, IH), 4.02 (m, IH), 3.76 (s, 30 3H), 2.97 (dd, IH), 2.73 (t, 2H), 2.64 (m, 4H), 2.43 (brm, 4H), 2.43 (dd, 1 H), 1.94 (s, 3H),

1.06 (t, 3H).

-259 Exemple 326 (2/?)-2-{[(5S_rt)-5-(4-{2-[4-(2-amino-2-oxoethyl)piperazîn-l-yl]ethoxy}-3chloro-2-methylphenyl)-6-(furan-2-yl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoîc acid mg ethyl ^^-[(JSAS-Achloro^-methyM-Apiperazin-l-ylethoxyJphenylJ-ô-^furyl)thieno[2,3-rf]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 NaîSO^, filtered and concenlraled 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 C3SH36CIN3O7S: 705.2024; found 706.2112 (M+H)

Exampie 327 (2Λ)-2-{ [(55^, _e)-5-(3-chlnro-2-melhyl-4-{2-[4-(2,2,2-trifluoroe(hyl)piperazinl-yl]ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3-if]pyrimidin-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 CsîI^CIFs^OîS: 730.1840; found 731.1919 (M+H)

Exampie 328 (2Æ)-2-[[(5S_rt)-5-(3-chloro-4-{2-[4-(2,2-dÎfluoracthy0piperazin-lylJethoxy)-2-methyIphenyI)-6-(ftiran-2-yl)thieno[2,3-</]pyrimidin-4-yl]oxy}-3-(2methoxyphcnyljpropanoic acid

-261 StepA;

135 mg ethyl (2R)-2-[(5S'₍,)-5-[3-chloro-2-meihyl-4-(2-piperazin-l-ylethoxy)phenyl]-6-(2furyl)thieno[2,3-d]pyrîmïdin-4-yl]oxy-3-(2-methoxyphenyl)propanoate (as described in Step A of Example 323) (0.20 mmol) was dissoleved in 1.5 mL dry THF. 0.040 mL l· bromo-2-methoxy-ethane (0.40 mmol) and 130 mg Cs₂COj (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.

SisrMl

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 wîth 2 M HCl, extracted with DCM. The combined organic phases were dried with Na₂SO₄, concentrated under reduced pressure and purified via préparative reversed pliase chromatography using 25 mM aqueous NIUHCOj solution and MeCN as eluents resulting Example 330. HRMS calculated for CjeHjîCINiOjS: 706.2228; found 707.2273 (M+H)

Example 331 (2R)-2-{[(5S_a)-5’{3-chloro-2-mcthyl-4-[2-(niethylamlno)ethoxy]phenyl)-6(furan-2-yl)thieno[2,3-<f]pyriniidin-4-yl]oxy}-3-(2-methoxyphenyl)propanoic acid

Using General procedure (Vlla) and 2-(methylamîno)ethanol as the appropriate alcohol Example 331 was obtained. HRMS calculated for CaoHîsCINjOiS: 593.1387; found 594.1455 (M+H)

Example 332 (2R)-2-{ [(55^, _J)-5-(3-chloro-2-methyl-4-{[(4-methylpipcrazin-1 yl)acetyl]oxy)phenyl)-6-(furan-2-yl)thleno[2,3-<(]pyrimidin-4-yl]oxy}-3-(2methoxyphcnyl)propanoic acid

-263extracted with DCM, dried with Na₂SO4, 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 CîîHjjFN^OèS: 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 C34HJ5FN4O6S: 646.2261; found 647.2302 (M+H)].

Example 335 (25)-2-{[(5S_rt)-5-(3-chloro-2-ethyl-4-[2-(4-mcthylpiperazin-I10 yl)ethoxy]phcnyl}-6-(furan-2-yl)thieno[2,3-rf]pyrimidin-4-yl]oxyï-3-(2methoxyphcnyljpropanoic acid and

Examp!e336 (25)-2 -{[(55_fl)-5- (3-chloro-2-ethyl-4-[2-(4 -methy Ipiperazin -1 yl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-(215 mcthoxyphcnyl)propanoic acid

250 mg ethyl ((25)-2-[5-(3-chloro-2-ethyl-4-hydroxy-phenyI)-6-(2-luryl)thieno[2,3i7Jpyrimidin-4-y!]oxy-3-(2-methoxyphenyl)propanoate (Préparation lia, mixture of diastereomers) (0.40 mmol), 115 mg 2-(4-methylpipcrazin-l-yl)ethanol (0.80 mmol) and 20 210 mg triphenylphosphinc (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 25 LiOH * H₂O was added. The reaction mixture was stirred at 30 °C for I hour. Water was added ta the mixture and pH was set to 4-5 with 2 M HCl. The mixture was extracted with

DCM, dried with Na₂SO4, concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. Example 335 was obtained as the diastereoisomer eluting later from the 30 préparative HPLC column [HRMS calculated for C3ÎH37CIN4O6S: 676.2122; found

677.2204 (M+H)], while Example 336 was obtained as the diastereoisomer eluting earlier ♦

-265was diluted with brine and extracted with DCM. The combined organic phases were dried over MgSÛ4 and evaporated under reduced pressure. The crude product was purified via flash chromatography using EtOAc / MeOH as eluents.

St?P B;

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 NajSOj, concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

Exemple 338 (2^)-2-(((55^)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phcnyl}-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-[2(difluoromethoxy)phcny!]propanoic acid

Using General procedure (Villa) and methyl (2/î)-3-[2-(difluoromcthoxy)phenyl]-2hydroxy-propanoate (Préparation 3aJ) as the appropriate alcohol; the diastereoisomer eluting later was collected as Example 338. HRMS calculated for C34H33CIF2N4O6S: 698.1777; found 699.1866 (M+H)

Example 339 (2/î)-{[(5/ï_ff)-5-{3-chloro-2-mcthyl-4-[2-(4-mcthylpiperazin-lyl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3-</]pyrimidin-4-yl]oxy}(pheny!)ethanoicacld and

Example 340 (2Æ)-{[(5&)-5-{3-chloro-2-methyl-4-[2-(4-methy!piperazm-1yl)cthoxy]phenyl}-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}(phenyl)cthanoic 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

C32H31CIN4O5S: 618.1704; found 619.1766 (M+H) and 619.1768 (M+H)

-267Example 345 (2Æ)-2-([(5S_rt)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazÎn-lyl)ethoxy]phenyl}-6-(ftiran-2-yl)thieno[2,3-if|pyrimidÎn-4-yl]oxy}-3-(5-fluoro-2methoxyphenyl)propanoic acid

Using General procedure (Villa) and ethyl (2Æ)-3-(5-fliioro-2-methoxy-phenyl)-2hydroxy-propanoate (Préparation 3ar) as the appropriate alcohol; the diastereoisomer eluting later was collected as Example 345. HRMS calculated for C34H34CIFN4O6S: 680.1872; found 681.1947 (M+H)

Example 346 (2Λ)-2- {[(5$_fl)-5- {3-chloro-2-methyl-4-[2-(4“methylpîperazin-lyl)elhoxy]phenyl}’6-(furan-2-yI)thieno[2_>3-rf]pyrimidin-4-yI]oxy}-3-(4-fluoro-2methoxyphenyljpropanoîc acid

Using General procedure (Villa) and ethyl (2/ï)-3-(4-fluoro-2-methoxy-phenyl)-2hydroxy-propanoate (Préparation 3as) as the appropriate alcohol; the diastereoisomer eluting later was collected as Example 346. HRMS calculated for C3₄H34CIFN₄0îS: 680.1872; found 681.1915 (M+H)

Example 347 (2Λ)-2-{ [(5$_β)-5· (3<hloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phcnyl}-6-(furan-2-yl)(hieno[2,3-cf]pyrimidin-4-yl]oxy}-3-(3methylphenyl)propanoïc acid

Using General procedure (Villa) and methyl (2Æ)-2-hydiOxy-3-(m-tolyl)propanoate (Préparation 3ap) as the appropriate alcohol; the diastereoisomer eluting later was collected as Example 347. HRMS calculated for C3₄H3jCIN40jS: 646.2017; found 647.2073 (M+H)

Example 348 (2A)-2-{[(5S_e)-5-{3-chloro-2-methyl-4-[2'(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(furan-2-yl)thieno[2,3-rf]pyrimidin*4-ylloxy}-3-(3fluorophenyl)propanoic acid *

-269Example 352 (2Æ)-2-{[(5S₀)-5-(3-chloro-2-methyi-4-P-(4-methyipiperazin-!y!)elhoxy]phenyl}-6-(furan-2-y!)thieno[2,3-i/Jpyrimidin-4-yl]oxy}-3-(3-fluoro-2methoxyphenyl)propanolc acid

Using General procedure (Villa) and ethyl (27t)-3-(3-fluoro-2-methoxy-phenyl)-2hydroxy-propanoate (Préparation 3aq) as the appropriate alcohol; the diastereoisomer eiuting later was collected as Exampie 352. HRMS calculated for C34H34CIFN4O6S: 680.1872; found 681.1963 (M+H)

Exampie 353 (2Λ)-2-{ [(5^)-5-{3-chioro-2-methyl-4-[2-(4-methylpiperazin-1y!)ethoxy]phcnyl)-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yI]oxy}‘3-[2(tri fluoro me lhyl)pheny l] propanoic acid

Using General procedure (VIIFa) and methyl (2R)-2-hydroxy-3-[215 (trifluoromethyl)phenyl]propanoate (Préparation 3an) as the appropriate alcohol; the diastereoisomer eiuting later was collected as Exampie 353. HRMS calculated for C34H₃2C1F₃N₄O_sS: 700.1734; found 701.1803 (M+H)

Exemple 354 (2i)-2-[[(5S_fl)-5-{3-chloro-2-methyl-4-[2-(4-mcthylpiperazin-!20 yl)ethoxy]pheny!)-6-(furan-2-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2methylphenyl)propanoic acîd

Using General procedure (Villa) and methyl (2Æ)-2-hydroxy-3-(o-tolyl)propanoate (Préparation 3ao) as the appropriate alcohol; the diastereoisomer eiuting later was collected as Example 354. HRMS calculated for C34H3JCIN4OSS: 6462017; found 647.2087 (M+H)

Example 355 (2/0-3-[2-(ammomethyl)phenyl]-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-!-yl)ethoxy]phenyl)-6-(furan-2-yl)thieno[2,3-d]pyrÎmidin-430 yl]oxy)propanoic acid

Step A:

-271Exampie 356 (2/î)-3-{2-[(acctylamino)melhyljphenyI}-2-{l(55₃)-5-{3-chIoro-2-mcthyl-4[2-(4-methylpipcrazin-l-yJ)ethoxy]phcnyl)-6-(furan-2-yl)thieno[2,3-</JpyrÎmidin-4yljoxyjpropanoîc acid

Sien A:

100 mg ethyl (2A)-3-[2-(amïnomethy])phcny 1)-2-(5-[3-chloro-2-methy 1-4-(2-(4methylpiperazin-l-yl)ethoxy]phenyl)-6-(2-furyl)thieno[23-<Zlpyrimidin-4-y|]oxypropanoate (0,145 mmol) (Step B of Example 355) and 6! μ! tri ethyl amine (435 pmol) were dîssolved in 5 mL DCM, and then 12 μΐ acetyl chloride (174 μτηοΐ) 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 (2R)-3-[2-(acetamidomethyl)phenyl]-2-[5-[3-chloro-2-methyl-4-[2(4-methylpiperazin-l-yl)ethoxy]pheny]]-6-(2-furyl)thieno[2,3-i/lpyrimÎdin-4-yl]oxypropanoate.

SlepBj mg ethyl (2R)-3-[2-(acetamidomethyl)phenyl]-2-[5-[3-chloro-2-methyl-4-[2-(4mcthyIpipcrezin-l-yl)cthoxy]phenyl]-6-(2-furyI)thieno[23-<Z]py^rÎmidin-4-yl]oxypropanoate (0.10 mmol) was dîssolved ïn 2 mL dioxane / water (1:1) and 84 mg LiOH x 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, filtered and concentrated and purified via préparative reverse phase chromatography using 25 mM aquenus NH^HCOj solution and MeCN as eluents. The diastereoisomer eluting later was collected as Exampie 356. HRMS calculated for Cj^HjiClNjOtS: 7032231; found 704.231 (M+H)

Example 357 (2R)-2-{ [(5S_a)-5- (3-chloro-2-methyl-4-[2-(4-methyIpiperazin-1 yl)ethoxy]phenyl)-6-(furan-2-yI)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-(2iluorophenyl)propanoic acid *

-273Example 361 (2S)-{[(51?_n)-5-{3-chtoro-2'methyl-4-[2-(4-methylpiperazjn-lyl)ethoxy]phcnyl}-6-(furan-2-yl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-{2-[(2^,2triiluorocthyl)sulfanyl]phenyl)propanoic acid

Using General procedure (Villa) and ethyl (25)-2-hydroxy-3-[2-(2,2,2· trifluorocthylsulfanyl)phenyl]propanoate (Préparation 3ax) as the appropriate alcohol; the diastereoisomer eluting later was collected as Example 361. HRMS calculated for C3SH34CIF3N4O5S2:746.1611; found 747.1678 (M+H)

Example 362 (2Æ)-{[(5S'_<I)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl}-6-(furan-2-yl)thieno(2,3-rf]pyrimidin-4-yl]oxy}-3’{2-[(2_t2_t2trifluoroethyl)sulfanyl]phenyl)propanoicacid

Using General procedure (Villa) and ethyl (2Æ>2-hydroxy-3-[2-(2,2,2t5 trifluoroethylsulfanyljphenyljpropanoate (Préparation 3ay) as the appropriate alcohol the diastereoisomer eluting later was collected as Example 362 was obtained. HRMS calculated for C35II34CIF3N4O3S2·. 746.1611; found 747.1682 (M+H)

General procedure (IXa)

Step A:

eq. of ethyl (2/î)-2-[6-(5-chloro-2-furyl)-(5S’₀)-5-[3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)cthoxy]phenyl]thieno[2,3-i/]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 81), 2 eq. of the appropriate alcohol and 2 eq. PPÏ13 were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. di/er/butyi azodicarboxylate was added. The mixture was stined 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 i:i (10 mL/mmol) and 10 eq. LiOH x HjO was added. The mixture was stirred at room température until no further conversion

-275Then it was diluted with brine, neutralized with 2 M HCI, and extracted with DCM. The combined organic phases were dried over Na₂SC>4, 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 5 for C₃3H33C1₂FjN4O_sS: 764.145; found 765.1523 (M+H)

Example 366 (27î)-2-{[6-(5-chlorofuran-2-yl)-(5iS’_ÎI)-5-{3-chloro-2-methyl-4-[2-(4methy]piperazïn-]-yl)ethoxy]pheny]}thieno[2,3Ajpyrimidin-4-yl]oxy}-3-[2-(pyridin-2ylmethoxy)phcnyl]propanoic acid

Using General procedure (IXa) and 2-pyridylmethanol as the appropriate alcohol Example

366 was obtained. HRMS calculated for C39II37CI2N5O6S: 773.1842; found387.5992 (M+2H)

Exemple 367 (27î)-2-{[6-(5-chlorofuran-2-yl)-(5S_a)-5-{3-chloro-2-methyl-4-[2-(4meLhylpiperazin-l-yl)cthoxy]phcnyl)thieno[2,3A]pyrimïdin-4-yl]oxy}-3-(2-{[2(trifluoromethyl)pyrimidin-4-yl]methoxy)phenyl)propanoicacid

Using General procedure (IXa) and [2-(trifluoromethyl)pyriniidin-4-yl]methanol (Préparation 9bj) as the appropriate alcohol Example 367 was obtained. HRMS calculated for CsiHjsChFjNAS: 842.1668; found 843.175 (M+H)

Exemple 368 (2Jî)-2-{[6-(5-chlorofùran-2-yl)-(5S_a)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}thieno[2,3A]pyrimidin-4-yl]oxy}-3-(2-{[225 (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 (^UChtyOjS: 859.2322; found 430.6247 (M+2H) *

-277Example 373 (25)-2-{[6-(5-chlorofuran-2-yl)-(5S^, _tf)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]pheny!}thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-(2-{[1-(2,2,2trifluoroethyl)-! H-pyrazol-5-yl]methoxy)phenyl)propanoic acid

IJsing General procedure (TXa) and [l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl]methanol (Préparation 9du) as the appropriate alcohol Example 373 was obtained. HRMS calculated for CwHnCbFjNiOiS: 844.1824; found 845.186 (M+H)

Example 374 (25)-2-( [6-(5-chlorofuran-2-yl)-(5$,)-5-{3-chloro-2-methyl-4-[2-(410 methylpipcrazin-1 -y l)ethoxy]phenyl ] thieno[2,3-rf]pyrimidin-4-yl]oxy }-3-(2-(pyrazin-2ylmcthoxy)phenyl]propanoic acid

Using General procedure (lXa) and pyrazîn-2-yïmethanol as the appropriate alcohol

Example 374 was obtained. HRMS calculated for CjjHjîCIîNîOôS: 774.1794; found

775.1824 (M+H)

Example 375 (25)-2-( [6-(5-chlorofuran-2-y!)-(5S'_iï)-5-{3-chloro-2-methyl-4-[2-(4methylplpcrazin-l-yl)ethoxy]phenyl}thieno[2,3-rf]pyrimidin-4-yI]oxy}-3-(2-(pyrimidin-5ylmethoxy)pheny!]propanoic acid

Using General procedure (IXa) and pyrimidin-5-ylmethanol as the appropriate alcohol

Example 375 was obtained. HRMS calculated for CjeHjeCliNiOiS: 774.1794; found

775.1869 (M+H) ‘

Exemple 376 (25)-2-{[6-(5-chIorofuran-2-yl)-(5S_e)-5-{3-chloro-2-methy!-4-[2-(4methylpiperazin-1-yl)ethoxy]pheny!}thieno[2,3-rf]pyrimidin-4-yl]oxy)-3-[2-( l,3-oxazol-4ylmethoxy)phenyl]propanoîc acid

Using General procedure (IXa) and l,3-oxazol-4-ylmethanol as the appropriate alcohol

Exemple 376 was obtained. HRMS calculated for CjîHjjCbNjOyS: 763.1634; found

764.1685 (M+H) >

-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-watcr 1:1 (10 mL/mmol) and 10 eq LiOH * 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 10 25 mM aqueous NHJICOj solution and MeCN as eluents.

Exemple 378 (2Æ)-2-([(5S_ff)-5-{3-chloro-2-mcthy!-4-[2-(4-nicthylpîperazin-lyl)ethoxy]phenyl}-6-(4-fluoro-3-mctlioxyphenyl)thîeno[2,3-J]pyrimidin-4-yl]oxy}-3-(2· methoxyphenyljpropanoic acid t5 '

Using General procedure (Xa) and methanol as the appropriate alcohol Example 378 was obtained. HRMS calculated for CïtHïsCIFN-AS: 720.2185; found 721.2243 (M+H).

Example 379 (2Æ)-2-{ [(55,)-5-(3-chloro-2-methyl-4-[2-(4-methylpiperazin-l 20 yl)ethoxy]phenyl)-6-(4-fluoro-3-mcthoxyphcnyl)thieno[2,3-d]pyrimidin-4-yI]oxy)-3-{2[(2R)-tetrahydrofuran-2-ylmethoxy]phenyl}propanoic acid

Using General procedure (Xa) and [(2R)-tetrahydrofuran-2-yI]methanol as the appropriate alcohol Example 379 was obtained. HRMS calculated for C4]HmC1FN₄O₂S: 790.2603; 25 found 791.2670 (M+H).

Exemple 380 (2Æ>2-{ [(55>)-5-{3<hloro-2-methyl-4-[2-(4-mcthylpiperazin-1 yl)cthoxy] phenyl ) -6-(4-fluoro-3-methoxyphenyl)thieno[2,3 -</] pyrîmid jn-4-y!]oxy} -3 -[2(2,2,2-trifluoroethoxy)phenylJpropanoicacid

Step A:

-281Using General procedure (Xa) and [2-(trifluoromethyl)pyrimidin-4-yI]methanol (Préparation 9bj) as the appropriate alcohol Exemple 382 was obtained. HRMS calculated for CuHaClFiNiOéS: 866.2276; found 867.2352 (M+H).

Example 383 (2J?)-2-{[(55_rt)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperaztn-1yl)ethoxy]phenyl)-6-(4-fluoro-3-methoxyphenyl)thieno[2₁3-iZ]pyrimidin-4-yl]oxy}-3-{2[(2-methoxypyrimidin-4-y1)methoxy]phenyl)propanoicacid

Using General procedure (Xa) and (2-methoxypyrimidin-4-yl)methanol as the appropriate 10 alcohol Example 383 was obtained. HRMS calculated for CiîH^ClFNfiOjS: 828.2508;

found 415.1343 (M+2H).

Example 384 (2Â)-2-{[(5S_ù)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl)-6-(4-fluoro-3-methoxypheny1)thieno[2,3-rf]pyrÎmidin-4-yl]oxy}-3-{215 [(I -elhyl-1 H-pyrazol-5-yl)methoxy]phenyl)propanoic acid

Using General procedure (Xa) and (l-ethyl-17/-pyrazol-5-yl)melhanol (Préparation 9da) as the appropriate alcohol Exampie 384 was obtained. HRMS calculated for C4₂H44C1FN₆O₆S: 814.2716; found 408.1436 (M+2H).

Example 385 (2Λ)-2- {[(55^)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-(4-fluoro-3-methoxyphenyl)thieno[2_>3-rflpyrimidin-4-yl]oxy}-3-{2[( 1 -propyl-1 H-pyrazol-5 -y l)methoxy] pheny 1} propanoic aci d

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 CijttjsClFNàOeS: 828.2872; found 415.1536 (M+2H).

Example 386(2JÎ)-2-{[(5S'_e}-5-{3-chloro-2-melhyl-4-[2-(4-methytpiperazin-l30 yl)ethoxy]phenyl}-6-(4-fluoro-3-methoxyphenyl)thieno[2₁3-if]pyrtmidin-4-yl]oxy}-3-[2(pyrazin-2-ylmethoxy)phenyl]propanoic acid

-283StepA;.

eq. methyi (2J?)-2-[(5J?₁,)-5-(3'Chloro-4-hydroxy-2-methyl-phcnyl)-6-ethyl-thteno[2,3d]pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 6n), 2 eq. of the appropriate alcohol and 2 eq. PPh₃ were dissolved in dry toluène (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.

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 Na2SO«, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography usîng 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

General procedure (XIc)

S/wA:

eq. methyi (2R)-2-[6-etliyl-(55'_n)-5-(4-hydmxy-2-methyl-phenyl)thieno[2,3-i/]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.

Sf?P 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

-285Sfep 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 vîa préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

General procedure (XIJ) eq. ester was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH * 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 (25>2-{[(55,)-5-(3-chloro-4-hydroxy-2-methylphenyl)-6-ethylthieno[2,3i(]pyrimÎdin-4-yl]oxy}-3-phcnylpropanoicacÎd

Methyl (25)-2-[(5S_a)-5-(3-ch]oro-4-hydroxy-2-methyl-phenyl)-6-ethyl-thieno[2₁3J]pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 61) was hydrolyzed according to General procedure (Xlf) to give Example 388. HRMS calculated for C₂4H₂iC1N₂O₄S: 468.0911; found 469.0997 (M+H).

Example 389 (25)-2-{[(J^-S-O^hloro^-hydroxy^-methylphenylJ-ô-ethylthienop.St/]pyrimidin-4-yl]oxy}-3-phenylpropanoÎcacid

Methyl (25)-2-[(55_rt)-5-(3-chloro-4-hydroxy-2-methyI-pheny])-6-ethyI-thieno[2,3ri]pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 6n) was hydrolyzed according to

-287Example 394 (2A)-2-({(5S_a)-5-[4-(benzyloxy)-3-chloiO-2-methylphenyl]-6ethylthieno[2,3-J]pyriniidin-4-yl}oxy)-3-pheny]propanoic acid

Using General procedure (Xla) and phenylmethanol as the appropriate alcohol Exemple

394 was obtained, HRMS calculated for CjiHrClNîOiS: 558.13B0; found 559.1465 (M+H).

Example 395 (2/Î)-2-({(5S_it)-5-[3-chloro-2-mcthyl-4-(pyridin-4-ylmethoxy)phcnyl]-6ethylthieno [2,3 -/] py ri midin-4-yl} oxy)-3-phenyl propanoic acid

Using General procedure (Xla) and 4-pyridylmethanol as the appropriate alcohol Example

395 was obtained. HRMS calculated for CjoHifiClNjC^S: 559.1333; found 560.1396 (M+H).

Example 396 (2Λ>2-[((55_σ)-5- {3-chloro-2-methyl4-[2-(pyridin-3-y!)ethoxy]phenyl}-6ethyIthieno[2,3-/]pyrimidin-4-yl)oxy]-3-phenylpropanoicacid

Using General procedure (Xla) and 2-(3-pyridy))ethano] as the appropriate alcohol Example 396 was obtained. HRMS calculated for C₃iH2aCIN₃O₄S: 573.14B9; found 574.1559 (M+H).

Example 397 (2/?)-2-[((5S_ff>5-{3-chloiO-2-mdhyl-4-[2-(pyridIn-4-yl)ethûxy]phcnyl}-6cthylthieno[2,3-/]pyriinidin-4-yl)oxy]'3-phenylpropanoic acid

Using General procedure (Xla) and 2-(4-pyridyl)ethanol as the appropriate alcohol Example 397 was obtained. HRMS calculated for C₃|H2gClNjO₄S: 573.14B9; found 574.1562 (M+M).

Example 398 (2/0-2-{[(5SJ-5-(4-butoxy-3-ch]oro-2’methylphenyl)-6-ethylthieno[2,3/]pyrimidm-4-yl]oxy}-3-phenylpropanoic acid

-289Example 403 (25)-2-[((55_e)-5-(3-chloro-4-[3-(l H-imidazol-1 -yl)propoxy]-2methylphenyl}-6-ethylthieno[2,3-rfJpyrimidin-4-yl)oxy]-3-pheny)propanoic acid

Using General procedure (Xla) and 3-(l//-imidazol-l-yl)propan-l-ol as the appropriate 5 alcohol Example 403 was obtained. HRMS calculated for C30H29CIN4O.1S: 576.1598;

found 577.1698 (ΜιII).

Exampie 404 (25)-2-{[(55_F)-5-(3-chloro-4-{3-[(ethy]carbamoyl)amino]propoxy}-2methylphenyl)-6-ethylthieno[2,3-rf]pyrimidin-4-yl]oxy}-3-phenylpropanoic acid

Using General procedure (Xla) and l-ethyl-3-(3-hydroxypropyl)urea as the appropriate alcohol Exampie 404 was obtained. HRMS calculated for C30H33CIN4OJS: 596.1860; found 597.1943 (M+H).

Example 405 (25)-2-({(55_fl)-5-[3-chloro-4-(3-hydroxypropoxy)-2-methylpheny]]-6ethylthieno[2,3-d]pyrimidin-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 CîfHiïClNiOjS: 526.1329; found 527.1402 20 (M+H).

Example 406 (25)-2-[((55t)-5-(3-chloro-2-methyl-4-[3-(niethylsulfonyl)prüpüxy]phenyl} -6-cthylthieno[2,3-if]pyrimidin-4-yl)oxy]-3-phenylpropanoicacid

Using General procedure (Xla) and 3-methylsulfonylpropan-l-ol as the appropriate alcohol Example 406 was obtained. HRMS calculated for CîjHæCINîOeSi: 588.1156; found 589.1242 (M+H).

Example 407 (25)-2-[((55i)-5-{3-chloro-4-[2-(dimethylaniino)ethoxy]-2-methylphenyl}30 6-ethylthieno[2,3-<(]pyrimidin-4-yl)oxy]-3-phenylpropanoic acid

-291Example 412 (2R)-2-{[(5S_o)-5«(4«{2-[bis(2-hydroxyethyl)amino]ethoxy}-3-chloro-2methylphenyl)-6-ethylthîeno[2,3-i/]pyriniidin-4-yl]oxy}-3-phenylpropanoic acid

Using General procedure (Xla) and 2-[bis(2-hydroxycthyl)amino]ethanol as the 5 appropriate alcohol Example 412 was obtained. HRMS calculated for CîoHmCINjOîS: 599.1857; found 600.1939 (M+H).

Example 413 (2Æ)-2-[((5S_J)-5-{3-chloro-4-[2-(4-hydroxypiperidin-l-yl)ethoxy]-2methylphenyl}-6-ethylthieno[2,3-i/]pyrimidin-4-y!)oxy]-3-phenylpropanoic acid

Usïng General procedure (Xla) and l-(2-hydroxyethy!)piperidÎn-4-ol as the appropriate alcohol Example 413 was obtained. HRMS calculated for CjiF^CINjOjS: 595.1908; found 596.1976 (M+H).

Example 414 (2R)-2-[((5R_e)-5-{3-chloro-2-methyl-4-[2-(4-mcthy!piperazin-lyl)ethoxy]phcnyl}-6-ethylthicno[2,3-i/]pyrimidÎn-4-yl)oxy]-3-phenylpropanoic acid

Using General procedure (Xlb) and 2-(4-mcthylpiperazin-l-y!)ethanol as the appropriate alcohol Example 414 was obtained. HRMS calculated for CnHjsClN^S: 594.2068;

found 595.2138 (M+H).

Example 415 (2R)-2-[((55_û)-5-{3-chloro-2-methyM-[2-(4-methylpiperaziii-l· yI)ethoxy]phenyl}-6-ethylthieno[2₍3-£(]pyrimidin-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 C31H35CIN4O4S: 594.2068; found 595.2148 (M+H).

Example 416 (2R)-2-[(6-ethyl-(5/t_e)-5-{2-methyl-4-[2-(4-mcthylpiperazin-l · yl)ethoxy]phenyI}thieno[2,3-iZ]pyrimidin-4-yl)oxy]«3-phenylpropanoicacid

-293Example 421 (25)-2-[((5R_fl)-5-{3-chloro-2-methyl-4-[2-(morpholin-4-y])ethoxy]phenyl)6-ethy!thieno[2,3-iflpyrimidin-4-yI)oxy]-3-phenylpropanoic acid

Using General procedure (Xlb) and 2-(morpholin-4-yl)ethanol as the appropriate alcohol 5 Example 421 was obtained. HRMS calculated for C30H31CIN3O3S: 581.1751; found 582.1853 (M+ll).

Example 422 (2Æ)-2-[((5S_e)-5-{4-[2-(acetylamino)ethoxy]-3-chloro-2-methylphenyl }-6ethylthieno[2,3-if]pyrimidin-4-yl)oxy]-3-phenylpropanoÎc acid

Using General procedure (Xla) and W-(2-hydroxyethyl)acetamide as the appropriate alcohol Example 422 was obtained. HRMS calculated for CîgHîgClNsOjS: 553.1438; found 554.1511 (M+H).

Example 423 (2/î)-2-({(5S_fl>5-[3-chloro-4-(2-hydroxyethoxy)-2-methylphenyl]-6ethylthieno[2,3-i/]pyrimidin-4-yI}oxy)-3-phenylpropanoic acid

Using Ocneral procedure (Xla) and ethylene glycol as the appropriate alcohol Example

423 was obtained. HRMS calculated for C26H25CIN2O3S: 512.1173; found 513.1256 (M+H).

Example 424 (2R)-2-(((5S_d>5-[3-chloro-4-(2-meihoxyelhuxy)-2-meihylphenyl]-6ethylthieno[2,3<f]pyrimidm-4-yl)oxy)-3-phenylpropanoic acid

Using General procedure (Xla) and 2-methoxyethanol as the appropriate alcohol Example

424 was obtained. HRMS calculated for C27H27CIN2O5S: 526.1329; found 527.1400 (M+H).

Exemple 425 (2R)-2-[((55J-5-{3-chloro-4-[2-(2-methoxyethoxy)ethoxy]-230 methylphenyl)-6-ethylthieno[2,3-<f]pyrimÎdin-4-yl)oxy]-3-phenylpropanoicacid

-29540 mg methyl (2Æ)-2-[6-ethyl-(5/ï_<,)-5-(4-hydroxy-2-methyl-phenyl)thieno[2_l3rf]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 crude 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 (2Λ)-2-[((5&)-5-{3-chloro-4-hydroxy-2-mcthyl-5-[(4-m:thylpiperazjn-1yl)methyl]phenyl)-6-ethylthieno[2,3-if]pyrimidin-4-yl)oxy]-3-phenylpropanoicacid

483 mg methyl (2/ï)-2-[(5₁S^,e)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethyI-thieno[2l3if]pyrimidm-4-yl]oxy-3-phcnyl-propanoate (Préparation 6i) (1.0 mmol) and 140 mg hexamethylenctetraminc (1.0 mmol) were dissolved in 10 mL TFA and stirred at 90^QC for 3 hours, The cooled reaction mixture was poured onto 100 mL icy water and the precîpitated solid was fïltered and dried. Then it was dissolved in 20 mL EtOH, 167 pL 1· methylpiperazine (1.5 mmol) and 636 mg NafOAcJjH (3.0 mmol) were added and the mixture was stirred at room température until no further conversion was observed. Then tt was diluted with water, extracted with DCM, combined organic phases were dried over Na2SO4, fïltered 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).

Exemple 431 (2Æ)-2-{[(5S_fl)-5-(Samino-3-chloro-4-hydroxy-2-mcthy]phcnyl)-6ethylthieno[2,3-J]pyrimidin-4-yl]oxy}-3-phenyIpropanoic acid

Methyl (2Æ)-2-[(5₁S^, _e)-5-(5-amino-3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethylthieno[2,3-iflpyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 15b) was hydrolyzed

-297to General procedure (Xlf) to give Exampie 433. HRMS calculated for C25H22CIN3O5S: 511.0969; found 512.1048 (M+H).

Example 434 (2/?)-2-[((55'_rt)-5-{3-chloro-4-methoxy-2-methyl-5-[(4-niethylpiperazin-15 yljmethyl Jpheny 1 ) -6-ethylth i cno [2,3 -d] p yrimidin-4-y l)o x y]-3 -pheny lpropano ic acid

Step A:

408 mg methyl (2/f)-2-[(5S'₍,)-5-(5-bromo-3-chloro-4-hydroxy-2-mcthyl-phenyl)-6-ethylthieno[2,3-d]pyrimidin-4-yl]oxy-3-phenyl-propanoate (Préparation 151) (0.73 mmol) was 10 dissolved in 4 mL MeOH, then 444 mg immobilized PPhj (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 (2^)-2-((55^)-5-(515 bromo-3-chloro-4-mclhoxy-2-methyl-phenyl)-6-ethyl-thieno[2,3-d]pyrimidin-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 20 THF, then 309 mg potassium l-methyl-4-trifluoroboratomethylpipcrazinc (1.70 mmol), 8 mg Pd(OAc)î (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 reduced pressure, the residue was diluted with brine, extracted DCM, and the combined organic phases were 25 dried over Na₂SO₄, filtered and concentrated under reduced pressure. The ohtained intermediate was hydrolyzed according to General procedure (Xlf) to give Exampie 434. HRMS calculated for C31H3JCIN4O4S: 594.2068; found 595.2145 (M+H).

Exampie 435 (2Æ)-2-[((5&)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazÎn-l-yl)ethoxy]30 5-nitrophenyl)-6-ethylthieno[2,3-d]pyrimidin-4-yl)oxy]-3-phenylpropanoicacid

-299préparative reversed phase chromatography using 40 mM aqueous NH«0Ac solution (pH was set to 4 with AcOH) and MeCN as eluents. The monochlorinated regîoisomer eluting earlier was collected. The obtained intermediate was hydrolyzed according to General procedure (Xlf) to give Example 438. HRMS calculated for C24H21CIN2O4S: 468.0911;

found 469.098! (M+H).

Example 439 (2Λ )-2-([(5Æ_rt)-5-(5-chloro-4-hydroxy-2-nicthylpheny!)-6-ethylthieno[2,3i/]pyrimidin-4-yl]oxy}-3-phenylpropanoic acid

105 mg methyl (2Æ)-2-[6-ethy]-(5Æ_a)-5-(4-hydroxy-2-mcthyl-phenyl)thieno[2,3</jpyrimidin-4-yl]oxy-3-phcnyl-propanoate (Préparation 60) (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 preparative reversed phase chromatography using 40 mM aqueous NfyOAc solution (pH was set to 4 with AcOH) and MeCN as eluents. The monochlorinated regîoisomer eluting later was collected as Example 439. HRMS calculated for C24H₂tClN2O4S.· 468.0911; found 469.0987 (M+H).

Example 440 (2Æ)-2-[(6-ethyl-(5S₄)-5-{2-methyl-5-[2-(4-methy)piperazin-l · yl)ethoxy]phenyl}thicno[2,3-<Zjpyrimidin-4-yl)oxy]’3-phenylpropanoie acid and (25)-2[(6-ethyl-(5J?a)-5 - {2-methyI-5-[2-(4-methylpiperazin-1 -y l)ethoxy]phenyl} thieno [2,3</]pyrimidin-4-yl)oxy]-3-phenylpropanoic acid (racemlc) mg 2-(6-ethyI-5-iodo-thieno[2,3-rf]pyrimidin-4-yI)oxy-3’phenyl-propanoic acid (Préparation 4m) (0.10 mmol), 108 mg l-methy!-4-[2-[4-methyl-3-(4,4,5_I5-tetramethyl· l,3,2-dioxaborolan-2-yl)phenoxy]ethyl]pipcrazine (Préparation 5h) (0.30 mmol), 18 mg

Pdidbaj (0.02 mmol), 14 mg BuPAd2 (0.04 mmol) and 55 mg K2CO3 (0.40 mmol) were 30 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, filtered, washed with saturated NaHCOj solution. The filtrate was washed with Et₂O, then

-301 Example 443 (2Æ)-2-{[(55_rt)-5-(7-chloro-6-methyl-1 -benzofuran-5-yl)-6-ethylthîeno[2,3rf]pyrimidin-4-yl]oxy}-3-phcnylpropanoic acid

110 mg methyl (2R)-2-[(55_e)-5-(3-chloro-4-hydroxy-5-iodo-2-methyl-phenyl)-6-ethyl5 thieno[23-<flpyrimidin-4-yî]oxy-3-phenyl-propanoate (Préparation 15d) (0.18 mmol), 51 pL ethynyl(trimethyl)silane (0.36 mmol), 6.3 mg PdCl₂(PPhj)2 (0.009 mmol) and 1.7 mg copper(I) iodide (0.009 mmol) were dissolved in 2 mL D1PA under N₂. The mixture was stirred at 50°C for 10 minutes, then 0.22 mL TBAF (1 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 C2ÛH21CIN2O4S: 492.0911 ; found 493.0999 (M+H).

Example 444 (2Λ)-2-{[(55_Λ)-5-(7-οΜθΓθ-2,6^ύηβΛχ1-1,3-Βεηζοχβζο1-5^1)-6ethylthleno[2,3-i/]pyrimidin-4-yl]oxy)-3-phenylpropanoic acid mg methyl (2Æ)-2-[(5S₀)-5-(5-amino-3-chloro-4-hydroxy-2-methyl-phenyl)-6-ethyIthieno[2,3-i/]pyrimidin-4-yl]oxy-3-phenyl-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^eC 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 Example 444. HRMS calculated for C26H22CIN3O4S:

507.1020; found 508.1114 (M+H).

Example 445 (2R)-2-[((5S_e)-5-{7-chloro-6-methyl-2-[(4-inethylpiperazin-l-y!)methyl]1,3 -benzoxazol-5-yl}-6-cthylthicno [2,3-</] py rimidin-4-yl)oxy]’3-phenylpropanoic aci d

56 mg methyl (2Æ)-2-[(5S_tf)-5-[7’Chloro-2-(chloromethyl)-6-methyl-l,3-bcnzoxazo!-5-yl]6-ethyl-thieno[2,3-i7]pyrimidin-4-yl]oxy-3-phenyl’propanoatc (Préparation 15c) (0.10 mmol) was dissolved in 2 mL dry THF under N₂. 20 mg 4-methyl-piperazine (0.20 mmol)

-303Example 449 (2/t)-2-{[(5S_e)-5-(3-chloro-2-niethyIphenyI)-6-ethyIthieno[2,3-<(]pyrimidin4-yl]oxy)-3-phenyIpropanoic acid and (2S)-2-{[(5/?_ÎJ)-5-(3-ch!oro-2-metIiyIphenyl)-6ethylthieno[2,3-rf]pyrimîdin-4-yl]oxy}-3-phenyIpropanoic acid (racemic)

373 mg 2-{6-ethyl-5-iodo-thieno[2,3-d]pyrimidin-4-yI)oxy-3-phenyl-propanoic acid (Préparation 4m) (0.82 mmol), 280 mg (3-chloro-2-methyl-phenyl)horonic acid (1.64 mmol), 151 mg Pd₂dba₃ (0.164 mmol), 118 mg ⁿBuPAd₂ (0.329 mmol) and 795 mg K₂COj (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 NaHCOj solution. The filtrate was washed with Et₂O, then it was acidified with 2 M HCI 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 NlfiOAc solution (pH was set to 4 with AcOH) and MeCN as eluents.

Diastereoisomer pair eluting earlier was collected as Example 449. HRMS calculated for C_mH₂₁C1N₂0jS: 452,0961; found 453.1045 (Md H).

Example 450 (2Æ)-2-{[(55_tf)-5-(3-chloro-2-methyIphenyl)-6’ethylthieno[2,3-iflpyriniidin4-yl]oxy)-3-phenyl propanoic acid and

Example 451 (2Jî)-2-{[(5A_tf)-5-(3-chIoro-2-methyIphenyl)-6-ethyhhieno[2,3-iflpyTimïdin4-yI]oxy)-3-phenylpropanoic acid

150 mg methyl (2Λ)-2-(6-ethyl·5-iodo-thieno[2,3-ΰ(]pyrimid!n-4-yl)oxy-3-phenyl25 propanoate (Préparation 41) (0.320 mmol), 164 mg (3-chloro-2-mcthyl-phcnyI)boronic acid (0.961 mmol), 74 mg Pd(PPhj)« (0.064 mmol), and 265 mg AgjCOj (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 (Xif) to give Example 450. HRMS calculated for CmHîiCINîOjS: 452.0961; found 453.1040 (M+H). The

-305Step B:

The product of Step A was dissolved in dioxane-water 1:1 (10 mL/mmoI) and 10 eq LiOH x HjO 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 Na₂SOi, 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 (XHb )

SlepA:

eq. ofthe appropriate phénol, 2 eq. 2-(4-methylpiperazin-1 -yljethanol and 2 eq. triphenyl phosphine were dissolved in abs. toluene (5 mL/nunol), then 2 eq. direr/butyl azodicarboxylate was added. The mixture was stirred at 50°C under nitrogen until no further conversion was observed. The volatiles were evaporated under rcduccd pressure and the crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents.

Step B:

TheproductofStep A wasdissolvedindioxane-water 1:1 (IOmL/mmol)and lOeqLiOH ^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 Na₂SOq, 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 453 (2Æ)-2-[((5S_e)-5-(3-chloro-2-methyl-4-[2-(4-methylpiperazÎn-l· yl)ethoxy]phenyl}-6-ethylthicno[2,3-<7]pyrimidin-4-yl)oxy]-3-(2methoxyphenyl)propanoic acid

-307Using General procedure (Xlla) and (2-mcthoxypyrimidin-4-yl)mcthanol as the appropriate alcohol Exemple 455 was obtained. HRMS calculated for CjîHiiClNcOeS: 732.2497; found 367.1311 (M+2H)

Exemple 456 (27î)-2-[((5₁S’_fl)-5-{3-chloro-2-mcthyl-4-[2-(4-methylpipcrazin-l yl)cthoxy] phenyl}-6-ethylthïeno[2,3-cf|pyrïmidin~4-yl)oxy]-3 - {2-[( 1 -ethyl-1 H-pyrazol-5yl)methoxy] phenyl) propanoic acid

Using General procedure (Xlla) and (l-ethyl-1//-pyrazol-5-yl)methanol (Préparation 9da) as the appropriate alcohol Example 456 was obtained. HRMS calculated for C₃₇H43C1N₆O_SS: 718.2704; found 360.144 (M+2H)

Example 457 (2j?)-2-[((55‘J-5-{3-chloro-2-mcthyl-4-[2-(4-mcthylpÎperazin-Iyl)ethoxy]phcnyl}-6-ethylthÎeno[2,3-Jjpyrimidin-4-yl)oxy]-3-[2-(2methoxyethoxy)phenyl]propanoic acid

Using General procedure (Xlla) and 2-methoxyethanol as the appropriate alcohol Example

457 was obtained. HRMS calculated for ÇjiH^CIN^OîS: 668.2435; found 335.1297 (M+2H)

Example 458 (27î)-2-[((55'₍,)-5-{3-chloro-2-methyl-4-[2-(4-methylpÎperazin-l yl)ethoxy]phenyI}-6-ethylthieno[2,3-<f]pyrimidin-4-yI)oxy]-3-(2,3-dihydro-l-benzofuran7-yI)propanoic acid

Using General procedure (XHb) and ethyl (2Æ)-2-[(55a)-5-(3-chloro-4-hydroxy-2-methylphenyl)-6-ethyl-thieno[2,3-</]pyrimidin-4-yl]oxy-3-(2,3-dihydrobenzofiiran-7yl)propanoate (Préparation 17c) as the appropriatephénol Example 458 were obtained.

HRMS calculated for C₃₃H_3ïClN₄0jS: 636.2173; found 637.2233 (M+H)

Example 459 (2S)-2-[((57î₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l’ yl)ethoxy]phcnyl)-6-ethylthieno[2,3-i/]pyrimidin-4-yl)oxy]-3-(2,3-dihydro-l-benzofuran7-yl)propanoic acid

-309Example 463 (2/?)-2-[((55_a)-5-{3-€ldoro-2-!iiethyl-4-[2-(4-Lncthy!pÎperazin'l · yl)ethoxyJphenyl)-6-ethy!thieno[2,3-<7]pyrimldin-4-yl)oxyJ-3-(2-fluorophenyl)propanoic acid

Using General procedure (Xllb) and ethyl (2K)-2-[(5.Ç_e)-5-(3-chloro-4-hydroxy-2-methyl· phenyl)-6-ethyl-thieno[2,3-i7]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 (2*S)-2-[((57î_e)-5-{3>chIoro-2-methy!-4-[2-(4-methylpiperazin-lyl)ethoxy]pheny!}-6-ethylthieno[2,3'<(]pyriniidin-4-yI)oxy]-3>(2-fluorophenyl)propanoic acid

Using General procedure (Xllb) and ethyl (25)-2-[(5i_ff)-5-(3-chloro-4-hydroxy-2-methylphcnyl)-6-cthyl-thicno[2,3-i/]pyrimidin-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 (XIIfa)

Step A:

I eq. ethyl (2/?)-2-[(55_a)-5-(3-chloro-4-hydroxy-2-methy!-phenyl)-6-prop-l-ynylthieno[2,3-i(]pyriniidin-4’yl]oxy-3-(2-niethoxyphcnyl)propanoatc (Préparation 61), 2 eq. of the appropriate alcohol and 2 eq. PPhj were dissolved in dry toluene (0.2 M for the 25 phénol), then 2 eq. di/er/butyl azodicarboxyiate 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.

St en B:

311 Exampie 465 (22?)-2-{[(55'₍₇)-5-{3-chIoro-2-methyl-4’[2-(l’methylpiperidin-4yl)ethoxy]phenyl}-6-(prDp-l-yn-l-yl)thieno[2_J3-d]pyrimidin-4-yl]oxy}-3-(2methoxyphenyljpropanoic acid

Using General procedure (Xllla) and 2-(l-methyl-4-piperidyl)ethanol as the appropriate alcohol Example 465 was obtained. HRMS calculated for C34M36CIN3O5S: 633.2064; found 634.2136 (M+H).

Example 466 (2ÆJ-2-([(5iS'_i,)-5-(3-chloro-4-{2-[di(propan-2-yl)amino]ethoxy}-2methylphcnyl)-6-(prop-1 -yn-1 -yl)thieno[2,3-i/]pyrimidin-4-yt]oxy} -3-(2methoxyphenyl)propanoic acid

Using General procedure (Xllla) and 2-(diisopropylamîno)ethanol as the appropriate alcohol Exampie 466 was obtained. HRMS calculated for CnHjsCItyOjS: 635.2221; found 636.2310 (M+H).

Example 467 (2/ï)-2«{[(5S',,)-5-{3-ch!oro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}6-(prop-l-yn-l-yl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3'(2-methoxyphenyl)propanoic acid

Using General procedure (Xllla) and 2-(dimethy]amino)ethano] as the appropriate alcohol Exampie 467 was obtained. HRMS calculated for CjûHjoCINjOjS: 579.1595; found 580.1663 (M+H).

Example 468 (2/î)-2-{[(5¾)-5-{3-chloro-2·methyl-4-[2-(pyπΌlίdin·l·yl)ethoxy]phenyl}6-(prop-l-yIv·l·yl)thieno[2,3-d]pyriπüdin-4-yt]oxy}-3-(2-mcthoxyphenyl)propanoic acid

Using General procedure (Xllla) and 2-pyrrolidÎn-l-ylethanol as the appropriate alcohol Example 468 was obtained. HRMS calculated for C32H32CIN3O5S: 605.1751; found 606.1822 (M+H).

•313Example 473 (25)-2-({(55_ff)-5-[3-chloro-4-Tnethoxy-2-mcthy]-5-(4-mcthylpiperazin-lyI)phenyl]-6-(prop-l-yn-l-yl)thieno[2,3-i/]pyrimidin-4-y!}oxy)-3-(2methoxyphcnyl)propanoic acid

418 mg ethyl (25)-2<5-iodo-6-prop-l-ynyl-thieno[2,3-d]pyrimidïn-4-yl)oxy-3-(2methoxyphenyljpropanoate (Préparation 4k) (0.80 mmol), 381 mg l-[3-chloro-2methoxy-4-methyl-5-(4,4^₍5-tetrnmethyl-l,3,2-dioxaboro!an-2-yl)phenyl]-4-methyIpipcrazine (Préparation 5j) (1.00 mmol), 58 mg PdClj x dppf (0.08 mmol) and 391 mg CS2CO3 (1.20 mmol) were dissolved in 10 mL dîoxanc and 2 mL water and was heated 10 under nitrogen at 110°C for 10 minutes ίη a microwavc reactor. Then reaction mixture was diluted with brine, and extracted with DCM. The combined organic phases were dried over NaîSO<, 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 (Xlllc). The diastereoisomer eluting earlier was collected as Example

472. HRMS calculated for C32H33CIN4O5S: 620.1860; found 621.1929 (M+H). The diastereoisomer eluting Iater was collected as Example 473. HRMS calculated for Cj₂Hj3CIN₄0jS: 620.1860; found 621.1929 (M+H).

Example 474 (25)-2-{[(55_e>5-{3-chloro-2,5-dimethyl-4-[2-(4-methyIpiperazin-l20 y I )e t hoxy ] phenyl) -6-(prop-1 -yn-1 -yl)thicno [2,3-if]pyrimid in-4-yl]oxy) -3 -(2methoxyphenyl)propanoic acid and

Example 475 (2A)-2-{[(5S_e)-5-(3-chloro-2,5-dimethyl-4-[2-(4-mcthylpipcrazin-ly IJcthoxy] phenyl}-6-(prop-1 -yn-1 -y ])thieno[2,3 -rfjpyrimi d i n-4-y 1 ]oxy ) -3 -(225 methoxyphcnyljpropanoic acid

Using General procedure (XlIIb), diastereoisomer mixture of ethyl (25>2-[5-(3-ch]oro-4hydroxy-2,5-dimethyl-phenyl)-6-prop-I-ynyl-thieno[2,3-iflpyrimidin-4-yl]oxy-3-(2methoxyphcnyl)propanoate (Préparation 18b) as the phénol and 2-(4-niethylpÎperazin-130 yljcthanol as the appropriate alcohol Example 474 and Example 475 were obtained. The diastereoisomer eluting earlier was collected as Example 474. HRMS calculated for Cj₄H37C|N₄0jS: 648.2173; found 649.2252 (M+H). The diastereoisomer eluting Iater was

-315Example 479 (2Æ)-2-{[(5S₀)-5-{3-chloro-4-[3-(dimcthylamino)propyl]-2-methylphenyl}6-(prop-l -yn-1 -yl)thieno[2,3-<f|pyrimidÎn-4’yl]oxy}-3-(2’methoxypheny l)propanoic acîd

522 mg ethyl (2Æ)-2-(5-iodo-6-prop-l-ynyI-thicno[2,3-/flpyrimidin-4-yI)oxy’3-(25 methoxyphenyl)propanoate (Préparation 4k) (1,00 mmol), 1.30 mmol 3-[2-chloro-3methyi-4-(4,4,5,5-tetramcthyI-l,3,2-dioxaborolan-2-yi)phenyl]W,W-dimethyl-propan-Iamine (Préparation 5n), 7i mg AtaPhos (0.10 mmol) and 652 mg Cs₂CO₃ (2.00 mmol) were dîssolved in 8 mL dioxane and 2 mL water, and heated under nitrogen at 100°C for 15 minutes in a microwave reactor. The réaction mixture was diluted with brine and extracted with DCM. The combined organic phases were dried over NajSO^ 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 diastercoisomer eluting eariier was collected as Exampie 478. HRMS calculated for C_3IH₃₂CIN₃O₄S: 577.1802; found 578.1876 (M+H). The diastercoisomer eluting later was collected as Exampie 479. HRMS calculated for C₃|H₃₂C1N₃O₄S; 577.1802; found 578.1881 (M+H).

Exa m pic 480 (2Λ)-2- {[( 5S_rt)-5 - (3 -chloro-4-hy droxy-2-methylph enyl)-6-(prop- i -yn-1 yl)thïeno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-methoxyphenyl)propanoicacid

Ethyl (2tf)-2-[(5S„)-5-(3-chloro-4-hydroxy-2-melhyl-phenyl)-6-prop-l-ynyl-thieno[2,3J]pyrimidin-4-yl]oxy-3-(2-methoxyphenyI)propanoate (Préparation 61) was hydrolyzed according to General procedure (Xlilc) to give Example 480. HRMS calculated for CîîHîiCINiOsS: 508.0860; found 509.0940 (M+H).

General procedure (XJ Va)

Step A:

eq. ethyl (2Æ)-2-[(5S_a)-5-[3-chloro-2-mcthyi-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-prop-l-ynybthieno[2,3-iflpyrimidin-4-yl]oxy^3-(230 hydroxyphenyl)propanoate (Préparation 81), 2 eq. of the appropriate alcohol and 2 eq. triphenyl phosphine were dîssolved in abs. toluene (0.2 M for the phénol), then 2 eq.

-317Sien A;

1.30 g ethyl (25)-2-[(55»)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazÎn-lyl)ethoxy]phenyl]-6-prop-l-ynyl-thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2hydroxyphenyljpropanoate (Préparation 81) (2.0 mmol), 0.94 g (2methylsulfanylpyrimidin-4-yl)methanol (Préparation 9aa) (6.0 mmol) and 1.57 g PPhî (6.0 mmol) were dissolved in 40 mL dry toluene, then 1.38 g di-fer/-butyl azodicarboxylate (6.0 mmol) was added. The mixture was stirred at 50°C under nitrogen. If needed, the addition of (2-methylsulfany!pyrimidin-4-yl)methanol (Préparation 9aa) (6.0 mmol), PPh3 (6.0 mmol) and di/Wbutyl 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 (25)-2-((5505-[3-chloro-2-methyl-4-[2-(4-methy!piperazin-l-yl)ethoxy]phenyl]-6-prop-l-ynylthieno[2,3-i(]pyrÎmidin-4-yl]oxy-3-[2-[(2-methy!sulfanylpyrimidm-4yl)methoxy]phenyl]propanoate. HRMS calculated for C₄oH«C1NîOsS₂: 787.2498; found 787.2464 (M+H).

Sten B:

0.572 g ethyl (25)-2-[(55i)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-ly!)ethoxy]phenyl]-6-prop-l-ynyl-thieno[2,3-iZ]pyrimîdin-4-y1]oxy-3-[2-[(2methylsu!fanylpyrÎmidin-4-yl)methoxy]phenyl]propanoate (0.44 mmol), 0.179 g (3methyl-4-pyridy!)boronic acid (1.31 mmol), 0.25 g copper(I) thiophene-2-carboxylate (1.31 mmol) and 51 mg Pd(PPhj)<i were dissolved in 5 mL dry THF heated under nitrogen at 70 °C. If needed, the additionof reagents was 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.

Step C:

The product of Step B was dissolved in 5 mL dioxane-water 1:1 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 Na₂SO<, concentrated under reduced

-319Using General procedure (XlVa) and [2-(2,2,2-trifluoroethoxy)pyriinidin-4-yI]niethanol (Préparation 9ai) as the appropriate alcohol Example 487 was obtained. HRMS calculated for C_WH_3SC1F₃N6O₆S: 810.2214; found 811.2323 (M+H).

Example 488 (2R)-3-{2-[(!-/CJ7-butyl-IH-pyrazol-5-yl)methoxy]phenyl}-2-{[(55i)-5-{3chlo ro-2-methyl-4-[2-(4-methyl piperazin-1 -yl)ethoxy] pheny I} -6-(prop-1 -yn-! y])thieno[2,3-i(]pyrimidin-4-y!]oxy}propanoic acid

Using General procedure (XlVa) and (l-/er/-butyI-lW-pyrazol-5-yI)methanol (Préparation 9dt) as the appropriate alcohol Example 488 was obtained. HRMS calculated for C^H^ClNfiOjS: 756.2861; found 379.1485 (M+2H).

Example 489 (2R)-2-{ [(55,)-5- (3-chloro-2-methy!-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl} -6-(prop-1 -yn-1 -yl)thieno[2,3-i(Jpyri midin-4-y l]oxy} -3-(2- {[ 1 -(2,2,2trifluoroethyl)-1 Âf-pyrazoI-5-yl] methoxy} phenyljpropanoic acid

Using General procedure (XlVa) and [!-(2,2,2-trifluoroethyI)-lAApyrazol-5-yl]methanol (Préparation 9du) as the appropriate alcohol Example 489 was obtained. HRMS calculated for CjgHjgClFaNeOîS: 782.2265; found 783.2353 (M+H).

Exemple 490 (2R)-3- {2- [(1 -butyl-1 Ff-pyrazoI-5-yl)melhoxy]phenyl) -2- {[(550-5-( 3 chloro-2-methy!-4-[2-(4-methylpipcrazin-1 -yl)cthoxy]phcnyI)-6-(prop-l-yn-l yl)thieno[2,3-d]pyrimidin-4-yl]oxy) propanoic acid

Using General procedure (XlVa) and (1-butyl-!H-pyrazol-5-yl)methanol (Préparation 9dd) as the appropriate alcohol Example 490 was obtained. HRMS calculated for QoH^jClNeOsS: 756.2861; found 757.2953 (M+H).

E xa mp le 491 (2S) -3-( 1 -benzo furan-4-yl)-2- {[(5R_a)-5-(3 -c hloro-2-methyl -4-(2-(4methylpipcrazin-1-yl)cthoxy]phenyI}-6-(prop-l-yn-l-yl)thieno[2,3-i(]pyrimidin-4yl]oxy}propanoic acid ?

-321The product of Step A was dissolved in 10 mL dioxane-watcr 1:1 and 0.200 g LiOH x H₂O (5.88 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, concentrated 5 under reduced pressure and the residue was purified via préparative reverse phase chromatography using 25 mM aqueous NH₄HCOj solution and MeCN as eluents to fumish Example 492. HRMS calculated for C₃₁H33C1N₄O₅S: 644.1860; found 645.1935 (M+H).

General procedure (XVa)

Step A:

eq. methyl (25)-2-[6-bromo-(55r)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)thieno[23d]pyrimidin-4-yl]oxy-3-phenyI-propanoate (Préparation 22), 2.5 eq. of the appropriate boronic ester or boronic acid and 2.5 eq. Cs₂COj were dissolved in THF-water (4:1) (12.5 ml/mmoi of Préparation 22), then 0.1 eq Pd(dppf)Ciî was added. The mixture was heated 15 under nitrogen at 110°C in a microwave reactor until no further conversion was ubserved.

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 flash chromatography using heptane and ethyl acetate as eluents.

Step B:

I eq. of the product of Step A, 2 eq. 2-(4-methy!piperazin-l-yI) éthanol and 2 eq. PPih were dissolved in dry toluene (5 mL/mmol of the product of Step A), 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.

S(ep 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

-323was set to 5 with 2 M HCl, and then it was extracted with dichlorométhane. The combined organic layers were dried over NajSCXf, concentrated under reduced pressure, and purified via flash chromatography using heptane and ethyl acetate as eluents to obtain methyl (2Λ)2-(5,6-diiodothieno[2,3-rf]pyrimidin-4-yl)oxy-3-phenyl-propanoatc. ’H NMR (400 MHz, 5 DMSO-de): 8.49 (s, JH), 7.42 (m, 2H), 7.30 (m, 2H), 7.25 (m, ÎH), 5.78 (dd, 1 H), 3.75 (s, 3H), 3.50-3.35 (m, 2H).

Step B:

230 mg methyl (2Æ)-2-(5,6-diiodothÎeno[2,3-i(]pyrimidin-4-y!)oxy-3-phenyl-propanoate 10 (0.4 mmol), 14 mg Pd(PPhj)2Cl (0.02 mmol) and 4 mg Cul (0.02 mmol) were dissolved in mL D1PA, then but-l-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-Î(]pyrimidïn-415 yl)oxy-3-phenyl-propanoate. ’H NMR (400 MHz, CDCI₃): 8.52 (s, JH), 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 (2Æ)-2-(6-but-l-ynyl-5-ïodo-thieno[2,3-i(]pyrimidin-4-yl)oxy-3-phenylpropanoate (0.383 mmol) and 155 mg 2-chloro-3-methyI-4-(4,4,5,5-tetramethy!-l,3,2« dioxaboro!an-2-yI)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 30 eluting later was collected as methyl (2Æ)-2-[6-but-l-ynyl-5-(2-chloro-4-hydroxy-3methyl-phenyl)thicno[2,3-<f]pyrimidin-4-y!]oxy-3-phenyI-propanoale. MS: (M+H) = 507.0.

-325Example 494 (2R)-2· {[(55,,)-5- { 3-chloro-2 -methy l-4-[2-(4-melhylpipcrazin-1 yl)ethoxy]phenyl}-6-(2-mcthylprop-l-en-l-yl)thîeno[2,3-iZ|pyrimidin-4-yl]oxy}-3phenylpropanoic acid

Using General procedure (XVa) and 4,4^,S-tetramethyl-2-(2-methylprop- 1-enyl)-1,3,2dioxaborolane as the appropriate boronic ester Exemple 494 was obtained. HRMS calculated for C₃₃H₃₇C1N₄O₄S: 620,2224; found 621.2287 (M+H)

Example 495 (25)-2-{[(55_e)-5-(3-chloro-2-methyl-4-[2-(4-methylpÎpcrazin-lto yl)ethoxy]phenyl)-6-(4-methylthiophen-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3phenylpropanoîc acid

Using General procedure (XVa) and 4,4,5,5-tetramethyl-2-(4-methyl-2-thienyl)-l,3,2dioxaborolane as the appropriate boronic ester Example 495 was obtained. HRMS ts calculated for C₃₄H₃₃CIN₄O₄S₂: 662.1788; found 663.1884 (M+H)

Example 496 (25)-2-( [6-(l -benzofuran-2-yl)-(55„)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)cthoxy]phenyl}thieno[2,3-i/|pyrimidin-4-yl]oxy}-3-phenylpropanoic 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 C₃₇H₃₃CIN₄O₃S: 682.2017; found 683.2084 (M+ll)

Example 497 (25)-2-{[6-(l -benzothiophen-2-yl>(55_fl)-5-i3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)cthoxy]phenyl)tliÎeno[2,3-iflpyrimÎdin-4-yl]oxy}-3-phenylpropanoic acid

Using General procedure (XVa) and2-(benzothiophen-2-yl)-4,4,5,5-tetramethyl-l,3,230 dioxaborolane as the appropriate boronic ester Example 497 was obtained. HRMS calculated for C₃7H₃₅C1N₄O₄Si: 698.1788; found 699.1879 (M+H)

-327Exampte 502 (2A)-2-[((55_rt)-5-{3-chloro-2-methyl-4-[2-(4-methylpipcrazin-lyl)ethoxy]phenyl}-6-phenylthieno[2,3-i/]pyrimidin-4-yl}oxy]-3-phenylpropanoic acid

Using General procedure (XVa) and 4,4,5,5-tctramethyl-2-phenyl-l,3₁2-dioxaborolane as the appropriate boronic ester Example 502 was obtained. HRMS calculated for C35H33CIN4O4S: 642.2068; found 643.2135 (M+H)

Example 503 (2A)-2-{[(5S₀)-5-{3-cliloro-2-methyl-4-[2-(4-methyIpiperazin-lyl)ethoxy]phenyl}-6-(l-methyl-lH-pyrro1-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3phenylpropanoic acid

Using General procedure (XVa) and l-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)-IH-pyrrole as the appropriate boronic ester Exemple 503 was obtained. HRMS calculated for Cs^ClNjt^S: 645.2177; found 646.2222 (M+H)

Example 504 (22î)-2-{[(55_<)>5-{3-chloro-2-methyl-4-[2-(4-methy!piperazin-ly 1 Jet hoxy] phenyl} - 6-(furan-2-y l)lhieno[2,3A] pyrimi din-4-yl ] oxy} -3 -pheny I propanoic ac ïd

Using General procedure (XVa) and 2-(2-furyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane as the appropriate boronic ester Example 504 was obtained. HRMS calculated for CjjHjîCIWjS: 632.186; found 633.1939 (M+H)

Example 505 (2Â)-2-{[(5S_n)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyÎ}-6-(thiophen-2-yl)thieno[2,3A]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)

-329Exemple 510 (2J?)-2-{[(5S_a)-5-{3-chloro-2-rr>cthyl-4-[2-(4-mcthylpiperazin-Iyl)ethoxy]phenyl}-6-(thiophcn-3-yl)thieno[2,3-d]pyrimidin-4-yl]oxy)-3-phenylpropanoic acid

Using General procedure (XVa) and 4,4,5,5-tetramethyl-2-(3-thienyl)-l 3,2-dtoxaborolane as the appropriate boronic ester Example 510 was obtained. HRMS calculated for CjjHjjCIWîSî: 648.1632; found 649.17! 1 (M+H)

Example 511 (2R)-2-([(55_fl)-5-{3-ch!oro-2-methyl-4-[2-(4-methy!pipcrazin-l10 yl)ethoxy]phenyl}-6-(2-methy!thiophen-3-y!)thieno[2,3-d]pyrimidin-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 t5 calculated for C3₄H3_SaN₄O₄S₂:662.1788; found 663.1864 (M+H)

Example 512 (2R)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(l,3-thiazo!-5-yi)thieno[23-d]pyrimidîn-4-yl]oxy}-3phenylpropanoic acid

Using General procedure (XVa) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-13· thiazolc as the appropriate boronic ester Example 512 was obtained. HRMS calculated for C32H_î2C1N5O₄S₂: 649.1584; found 650.1654 (M+H)

Example 513 (2R)-2-{[(55,)-5-(3-chloro-2-methyl-4-[2-(4-methylpiperazin-l· yl)ethoxy]phenyl}-6-(l-methyl-lH-pyrazo!-4-yl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3phenyl propanoic acid

Using General procedure (XVa) and l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboro!an30 2-yl)-lH-pyrazole as the appropriate boronic ester Example 513 was obtained. HRMS calculated for C33H3₅C1N₆O₄S: 646.2129; found 647.2199 (M+H) •331Using General procedure(XVa) and 4,4,5,5-tetramethyl-2-(4-methyl-3-thienyl)-l,3,2dioxaborolane as the appropriate boronic ester Exampie 516 was obtained. HRMS calculated for C34H3SCIN4O4S2: 662.1788; found 663.1863 (M+H)

Example 517 (2^)-2-(((5^)-5- {3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxy]phenyl)-6-(3-methy!thiophen-2-yl)thieno(2,3-J)pyrimidin-4-y]]oxy)-3phenylpropanoic acid

Using General procedure (XVa) and 4,4,5,5-tetramethyl-2-(3-mcthyl-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 (27?)-2-[(6-bromo-(5S_<,)-5-{3-chloro-2-methyl-4-[2-(4-metliylpiperazin-lyI)ethoxy]phenyl}thieno[2^-dJpyrimidin-4-yl)oxy]-3-phenylpropanoicacïd

Step A:

180 mg methyl (2Λ)-2-[6-^οιηο-(5₁$'₍,)-5-(3-ο1ι1οΐΌ-4·1^Γθχγ-2·πκώγ]-ρ1ιεηγ1)ύιΪ6ηο[2,3i/|pyrimidin-4-yl]oxy-3-pheny!-propanoatc (Préparation 22) (0.335 mmol), 96 mg 2-(4methylpiperazin-l-yHethanol (0.672 mmol) and 177 mg PPI13 (0.672 mmol) were dissolved 20 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 reduced pressure and the residue was purified via flash chromatography using ethyl acetate and methanol as eluents.

Sien B:

The product of Step A was dissolved in 5 ml methanol and 50 mg NaOH (1.25 mmol) was added. The mixture was stirred 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

CîtjHsoBrClNAS: 644.086; found 645.0942 (M+H)

-333microwave reactor until no further conversion was observed. After dilution with dichloromethane and brine the pH was sel to 5 with 2 M HCl and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried over NaîSQi, 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 (25)-2-[5-(2-chloro-4-hydroxy-3-methyl-phenyl)-6-prop·!· ynyl-thieno[2,3-<Z]pyrimidin-4-yl]oxy-3-phenyl-propanoate. MS: (M+H) ~ 493.0.

SfepD:

360 mg methyl (25)-2-[5-(2-chlofo-4-hydroxy-3-methyl-phenyl)-6-prop-l-ynylthieno[2,3-£/]pyrimidin-4-yl]oxy-3-phcnyl-propanoate (0.73 mmol), 211 mg 2-(4methylpipcrazin-l-y))clhanol (1.46 mmol) and 487 mg triphenyl phosphinc (1.46 mmol) were dissolved in 5 mL dry toluene, then 336 mg dirertbutyl 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 HiO 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 NaîSO^ concentrated under reduced pressure, and lhe residue was purified via preparalive reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents to obtain Example 519. HRMS calculated for CjiHjîCIN^S: 604.1911; found 605.2 (M+H)

Example 520 (25)-2-{[(55_T)-5-{3-chloro-2-nielhyl-4-[2-(4-melhylpiperazin-l yl)elhoxy]phenyl)-6-(cyclopropylethynyl)thieno[2,3-J]pyrimidin-4-yl]oxy}’3phenylpropanoic acid

Step. A:.

-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) wus 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 NbîSO*, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NHJICOj solution 10 and MeCN as eluents to obtain Example 520. HRMS calculated for C34H3JCIN4O4S: 630.2068; found 631.2096 (M+H)

Exemple 521 (2/?)-2-[((5$₍,)-5-{3-chloro-2-niethyl-4-[2-(4-nicthylpiperazin-lyl)ethoxy]phenyl}-6-cyanothieno[2,3-</]pyrimidin-4-y!)oxy]-3-pheny!propanoicacid

Step A:.

935 mg [2-chl oro-4-(4-ch!orothieno[2,3 pyri mid in-5-y l)-3 -methyl-phenoxy]triisopropyl-silane (Préparation 23a) (2.0 mmol) was dissolved in 20 mL dry THF lhen cooled to -78°C under argon atmosphère. 1.2 mL lithium diisopropylamide (2.4 mmol, 2 M 20 ïn THF, EtPh, hexanes) was added and the mixture was stirred at -7£°C for I hour. Then

471 mgp-tolylsulfonylformonitrile (2.6 mmol) was added and the mixture was allowed to warm up to room température. To the reaction mixture saturated aq. NII4CI was added and then extracted with ethyl acetate. Organic layer was dried over MgjSO^ filtered and concentrated under reduced pressure. The crude intermediate was purified via flash 25 chromatography using heptane and ethyl acetate as eluents to obtain 4-chloro*5-(3-chloro2-methyl-4-triisopropylsilyloxy-phenyl)thieno[2,3-d]pyrimÎdÎne-6-carbonitrile.

'H NMR (400 MHz, DMSO-dfi): 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).

St.epBj

380 mg 4-chloro-5-(3-ch!oro-2-methyl-4-triisopropylsilyloxy-phenyl)thieno[2,3rfjpyrimidine-6-carbonitrile (0.77 mmol) was dissolved in 7 mL *PrOH, 166 mg methyl

-337to room température. To the reaction mixture saturated NlI₄Ci was added and then extracted with ethyl acetate. The combined organic Jayers 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 triisopropyJsilyloxy-phenyl)thicno[2,3-/|pyrimidin-6-yl]ethanone. Ή NMR (400 MHz,

CDCIj): 8.94 (s, JH), 6.98 (d, IH), 6.95 (d, IH), 2.17 (s, IH), 2.03 (s, IH), 1.44-J.32 (m, 3H), 1.17 (d, 18H).

Step B:

278 mg ]-[4-chioro-5-(3-chloro-2-methyl-4-triisopropyisilyloxy-phenyl)thieno[2,3d]pyrimidin-6-yl]ethanone (0,55 mmol) was dissolved in 5 mL ’PrOH, 118 mg methyJ (2Æ)-2-hydroxy-3-phenyl-propanoale (Préparation 3ag) (0.65 mmol) and 538 mg Cs₂COj (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.

StepC:

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 slirred at room température until no further conversion was observed. Then it was diluted wilh 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 (2Jf)-2-[6-acetyl-5-(3-chloro-4-hydroxy-2-methylphenyl)thieno[2,3-J]pyrimïdin-4-yl]oxy-3-phenyl-propanoatc. *H NMR (500 MHz, DMSO-di): 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, 1 H), 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, 311). HRMS: (M+H) « 525.1244

Step D:

Φ

339 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 Hnd concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 25 mM aqueous NtyHCOj solution and MeCN as 5 eluents.

Exa m p le 523 (2Λ)-2- {[ (55^)-5 - {3-ch!oro -2-m ethyl-4 - [2-(4-mc thy Ipiperazin-1 yl)ethoxy]phenyl}-6-(3,4,5-trifluorophenyl)thieno[23-d]pyrimidin-4-yl]oxy}-3-(2methoxyphenyljpropanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-(3,4,5-lriiluorophenyl)-l,3,2dioxaborolane as the appropriate boronic acid dérivative Example 523 was obtained. HRMS calculated for CjéHj^ClFjN^S: 726.1891; found 727.1963 (M+H).

Example 524 (2JÎ)-2-([(5S^, ₀)'5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl)-6-(3,4-ifiiluoro-5-methoxyphenyl)thÎeno[2,3-i/]pyrimidin-4-y!]oxy}-3(2-methoxypheny!)propanoic acid

Using General Procedure (XVI) and 2-(3,4-difluorû-5-methoxy-phenyl)-4,4,5,520 tetramethyl-l,3,2-dïoxaborolane as the appropriate boronic acid dérivative Example 524 was obtained. HRMS calculated for C37H37CIF2N4O6S: 738.2090; found 739.2158 (M+H).

Example 525 (2^>2-([(5S^, _û)-5-(3-chloro-2-mcthyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(2,3,4,5-tetrailuorophenyl)thieno[23-i/]pyrimidin-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 Exemple 525 was obtained. HRMS calculated for C36H33CIF4N4OÎS: 744.1796; found 745.1873 (M+H).

-341Example 530 (25)-2-(((550-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxyJphenyl}-6-(thienol3,2-b|thÎophen-2-yl)thieno(2,3-i/]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid ⁵ 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-1,3,2-dioxaborolane (7.7 mmol) was added and the mixture was allowed to 10 warm up to room température, then it was quenched with saturated aq. NH4CI solution, then extracted with THF, dried over NajSO₄, 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-dïoxaborolane. MS (ET, 70 eV) m/z (% relative întensîty, [ion]): 120 (19), 165 (25), 166 (100), 167 (44), 180 (17), 206 (22), 223 (60), 266 (68, 15 [M*]).

iSte/iÆ

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. 20 HRMS calculated for C₃₆H₃₃C1N₄O5S₃: 734.1458; found 735.1553 (M+H).

Example 531 (25)-2-((55,)-(5- (3-chloro-2-methyl-4-[2-(4-methylpipcrazin-lyl)ethoxy]phenyl}-6-[4-fluoro-3-(trifluoromethyl)phenyl]thieno[2,3-cr|pyrimidin-4yl)oxy] -3 -(2-methoxypheny !)propanoic acid

Using General Procedure (XVI) and 2-[4-fluoro-3-(trifluoromethyl)pheny1]-4,4,5,5tetramethyl-1,3,2-dioxaborolane as the appropriate boronic acid dérivative Exampie 531 was obtained. HRMS calculated for C₃₇H_3SC1F4N4O_SS: 758.1953; found 759.2031 (M+H).

Example 532 (25)-2-([6-(3-chloro-4-fluorophenyl)-(55ï)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazîn-1-y I)cthoxy] phenyl }thieno[2,3-i/]pyrimidin-4-yl]oxy) -3-(2methoxyphenyl)propanoic acid *

-343Using General Procedure (XVI) and 2-(3-chloro-2,4-di fl uoro-phenyl)-4,4,5,S-tétraméthylia ,2-dioxaborolane as the appropriate boronic acid dérivative Example 536 was obtained. HRMS calculated for CjJWjFjNAS: 742.1595; found 743.1645 (M+H).

Example 537 (2JÎ)-2-{[(55'_fl)-5-{3-chIoro-2-methyl-4-[2-(4-methylpiperazin-1 y I)e tho x y] phenyl )-6-(2,3,4-trifluorophenyl)thien o [2,3 -e/Jpyri mi d i n-4 -y l]oxy} -3 -(2methoxyphenyl)propanoîc 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 Exampie 537 was obtained. HRMS calculated for Cj^HmCIFîNAS: 726.1891; found 727.1963 (M+H).

Exemple 538 (2A)-2-([(5S_i,)-5-(3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phcnyl}-6-(4-methylphenyl)thieno[2₁3-i/|pyTimidin-4-yl]oxy}-3-(2· methoxyphenyljpropanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-(p-tolyl)-l,3_>2-dioxaborolane as the appropriate boronic acid dcrivatîve Example 538 was obtained. HRMS calculated for C37H39CIN4O5S: 686.2330; found 687.2405 (M+H).

Example 539 (2Λ)-2-{ [(5S_a)-5-{3-chloro-2-niethyl4-[2-(4-methylpipcrazin-lyl)ethoxy] phenyl} -6-(4-chlorophenyl)thieno [2,3-ri]pyrimidÎn-4-y]]oxy}-3-(2methoxypheny!)propanoic acid

Using General Procedure (XVI) and 2-(4-chlorophcnyl)-4,4,5,5-tetramethyl-l,3,2dioxaborolane as the appropriate boronic acid dcrivatîve Exemple 539 was obtained. HRMS calculated for CsJIjtChNjOjS: 706.1783; found 707.1865 (M+H).

Example 540 (2A)-2-{[(5S₍,)-5-(3-chloro-2-mcthyl-4-[2-(4-methy]piperazin-lyl Jethoxy] pheny 1)-6-(2,4 -difluorophenyljthieno [2,3 -ifjpyrimidi n-4-yl ]ox y} -3-(2methoxyphenyl)propanoic acid

-345 Using General Procedure (XVI) and 2-(5-ethyl-2-furyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolanc as lhe appropriate boronic acid dérivative Example 543 was obtained. HRMS calculated for C₃₀H_WC1N₄O₆S: 690.2279; found 691.2343 (M+H).

Example 544 (2K)-2-{ [(5^)-5-{3-chloro-2-mcthyl-4-[2-(4-methylpipcrazin-lyl)ethoxy]phenyl}-6-(5-methoxyfiiran-2-yl)thieno[2,3-i/]pyrimidÎn-4-yl]oxy)-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(5-methoxy-2-furyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane as the appropriate boronic acid dérivative Example 544 was obtained. HRMS calculated for C3ÎH37CIN4O7S: 692.2071; found 693.2122 (M+H).

Example 545 (2R)-2-{[(5S'_tf)-5-{3-chloro-2-methy1-4-[2-(4-metliy[piperazin-l15 yl)ethoxy]phenyI)-6-(3-nitrophenyl)thieno[2,3-i/lpyrimidÎn-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-(3-nitrophenyl)-l,3,2dioxaborolane as the appropriate boronic acid dérivative Example 545 was obtained.

HRMS calculated for CseHjiClNjChS: 717.2024; found 718.2101 (M+H).

Example 546 (2R)-2-{[(5S'_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpipcrazin-lyl)ethoxy]phenyl)-6-(3-methyIphenyl)thicno[2,3-i/]pyrimidin-4-y]]oxy}-3-(2methoxyphenyljpropanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramethyl-2-(m-tolyl)-l,3,2-dioxaborolane as the appropriate boronic acid dérivative Example 546 was obtained. HRMS calculated for C37H39CIN4OSS: 686.2330; found 687.2401 (M+H).

Example 547 (2R)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-mcthylpipcrazin-lyI)ethoxy]phenyl}-6-(3-ethynylphenyl)thieno[2,3-i/]pyrimîdin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid ♦

-347Exemple 551 (2Λ)-2-{ [(55),)-5- {3-chloro-2-methyl-4-(2-(4-methylpiperazin-1yl)ethoxy]phenyl}-6-(3-fluorophenyl)thieno[2,3-</]pyrimidin-4-ylJoxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(3-fluorophenyl)-4,4,5,5-tetramethyl-l,3^dioxaborolane as the appropriate boronic acid dérivative Example 551 was obtained. HRMS calculated for C₃₆H₃₆CIFN4O₅S: 690.2079; found 691.2152 (M+H).

Example 552 (2Λ)-2-[((55_η)-5-(3 -chloro-2-methyl-4-[2 -(4-methyl piperazin-1yl)ethoxy]phenyl}-6-[3-(dÎmethylamino)phenyl]thieno[2,3-J]pyrimidin-4-yl)oxy]-3-(2methoxypheny!)propanoic acid

Using General Procedure (XVI) and V,?/-dimethyl-3-(4₎4,5,5-tetramcthyl'I,3,2dioxaborolan-2-yl)aniline as the appropriate boronic acid dérivative Example 552 was obtained. HRMS calculated for CjsH^CINjOjS: 715.2595; found 716.2681 (M+H).

Example 553 (2Æ)-2- ([(55,,)-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-l y l)ethoxy] phenyl} -6- (3-hydrox ypheny IJthieno [2,3 -î/J pyrimîdin-4-yl J oxy )-3-(2methoxyphenyljpropanoic acid

Using General Procedure (XVI) and 3-(4,4,5,5-telrameLhy 1-1,3,2-dioxaborolan-2-yl) phénol as the appropriate boronic acid dérivative Example 553 was obtained. IIRMS calculated for C₃₆H₃₇CIN4O6S.· 688.2122; found 689.2204 (M+H).

Exemple 554 (2J?)-2-{((55J-5-{3-chloro-2-methyl-4-[2-(4-methylpipera7.in-1yl)elhoxy]phenyl}-6-(3-methoxyphenyl)thieno(2,3-c?Jpyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoïc acid

Using General Procedure (XVI) and 2-(3-methoxyphenyI)-4,4,5,5-tetramethyI-l,3,2dioxaborolane as the appropriate boronic acid dérivative Example 554 was obtained.

HRMS calculated for C₃₇H₃₉C1N4O₆S: 702.2279; found 703.2358 (M+H).

-349Example 559 (2JÎ)-2-{[6-(3-chloro-2-fluorophenyl)-(5S'_tf)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}thieno[23-</lpyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 2-(3-chloro-2-fluoro-phenyl)-4,4,5,5-tetramethyl-

1,3,2-dioxaborolane as the appropriate boronic acid dérivative Example 559 was obtained. HRMS calculated for CsfiHssChFNAS: 724.1689; found 725.1765 (M+H).

Example 560 (2/ï)-2-{[(5S^, _e)-5-{3-chloro-2-inethyl-4-[2-(4*melhylpiperazin-l10 yl)cthoxy]phenyl} -6-(2,3-difluorophenyl)thïeno [2,3 -t/J pyrimidin-4-yl]oxy} -3-(2methoxyphenyl)propanoïc acid

Using General Procedure (XVI) and 2-(2,3-difluorophenyl)-4,4,5,5-tetramethyI-1,3,2dioxaborolane as the appropriate boronic acid dérivative Exemple 560 was obtained.

HRMS calculated for CjfiHjjCIFaWsS: 708.1985; found 709.2052 (M+H).

Example 561 (2i)-2-{[(5S^)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l· yl)cthoxy]phcnyl}-6-(2-fluoro-3-nielhoxyphenyl)thieno[2,3-J]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVJ) and 2-(2-fluoro-3-methoxy-phenyl)-4,4,5,5-tetramethyl-

1,3,2-dioxaborolane as the appropriate boronic acid dérivative Example 561 was obtained. HRMS calculated for CjîHjjCIFNAS: 720.2185; found 721.2281 (M+H).

Example 562 (2i)-2-[((5S'_e)-5-{3-chloro-2-mcthyI-4-[2-(4-melhylpiperazin-lyl)ethoxy]phenyl)-6-[2-fluoro-3-(trifluoromethoxy)phenyl]thieno[2,3-<(Ipyrimidin-4yl)oxyJ-3-(2-methoxyphenyl)propanoîc acid

Using General Procedure (XVI) and 2-[2-fluoro-3-(trifluoromethoxy)phenylJ-4,4,5,530 tetramethyl-l,3,2-dioxaborolane as the appropriate boronic acid dérivative Example 562 was obtained. HRMS calculated for C37H35CIF4N4O6S: 774.1902; found 775.1974 (M+H).

♦

-351Exemple 567 (2/0-2-([(5SJ-5-{3<hloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl)-6-(pyridin-3-yl)thieno[2,3-i7]pyrimidin-4-yl]oxy}-3-(2methoxyphcnyl)propanoic acid

Using General Procedure (XVI) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyridine as the appropriate boronic acid dérivative Example 567 was obtained. HRMS calculated for CjsHjsCINjOîS: 673.2126; found 674.22Û5 (M+H).

Exemple 568 (2/0-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l 10 yl)ethoxy]phenyl} -6-(thiophen-3-yl)thieno[2,3-<7]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 4,4,5,5-tetramcthyl-2-(3-thienyl)-l,3,2-dioxaborolane as the appropriate boronic acid dérivative Example 568 was obtained. HRMS calculated 15 for C34H35CIN4O5S2: 678.1737; found 679.1808 (M+II).

Exa m pic 569 (2Æ)-2- {[(55^)-5 - (3-chloro-2-mcthyl -4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(l,3-oxazol-5-yl)thieno[2,3-rf]pyrimÎdin-4-y]]oxy}-3-(2methoxyphenyl)propanoic acid

Using General Procedure (XVI) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yJ)-1,3oxazole as the appropriate boronic acid dérivative Example 569 was obtained. HRMS calculated for C₃₃H₃4C1N₅O₆S: 663.1918; found 664.1997 (M+H).

Example 570 (2A)-2-{[(55_e)-5-{3-chloro-2-methyJ-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(5-chlorothiophen-3-yl)thieno[2,3-i7)pyrimidin-4-yl]oxy)-3-(2· methoxyphcnyl)propanoic acid

Using General Procedure (XVI) and 2-(5-chloro-3-thîenyl)-4,4,5,5-tetramethyl-1,3,230 dioxaborolane as the appropriate boronic acid dérivative Example 570 was obtained.

HRMS calculated for Cj^ChNASi: 712.1348; found 713.1423 (M+H).

fi

-353Exampie 573 (2Λ)-2- {[6-(but-1 -yn-1-yl)-(5S_e)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin«l-yl)ethoxy]phenyl}thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-(2methoxypheny!)propanoic acid

Sî£J2À2

625 mg ethyl (2/?)-2-[(55_lJ)-5-(3-chloro-4-hydroxy-2-nicthyl-pheny!)-6-iodo-thÎeno[2_l3(ZJpyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate (Préparation 25) (1.0 mmol), 35 mg Pd(PPh₃)₂Cl2 (0.05 mmol) and 19 mg Cul (0.1 mmol) were dissolved in 4 mL DIPA, then but-1-yne was bubbled through the reaction mixture, which was stirred at 50^eC until no further conversion was observed. Then tire 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-ynyl-{5S_a)-5-(3-ch1oro-4-hydroxy-2methyl-pheny!)thieno[2,3-i(]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate.

Sien B:

Using Step B and C of General Procedure (XVI) and ethyl (2Â)-2-[6-but-l-ynyl-(5S'_a)-5(3-chloro-4-hydroxy-2-methyI-phcnyl)thicno[2,3-rf]pyrimidin-4-yl]oxy-3-(2methoxyphenyl)propanoate as the phénol dérivative, Example 573 was obtained. HRMS calculated for C^Hj^ClNAS: 648.2173; found 649.2251 (M+H).

Exemple 574 (2/î)-2-{[(5^«)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)e thox yjphenyl}- 6- (d imethy Icarbamoy l)thieno [2,3-r/Jpyrimid i n-4-y 1 ]oxy} -3-(2methoxyphenyl)propanoîc acid and

Exemple 575 (2Jî)-2-{[(55₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)cthoxy]phenyl}-6-(dimethyIcarbamoyl)thieno[2,3-d]pyrimidin-4-y]]oxy}-3-(2methoxyphenyl)propanoic acid

Step At

2.195 g 4-chloro-5-[3-chIoro-2-methyl-4-[2-(4-methylpÎperazin-l-y!)cthoxy]phenyl] thieno-[2,3-<f]pyrimidine (Préparation 12) (5.02 mmol) was dissolved in 50 mL dry THF and then it was cooled to -78^eC under argon atmosphère. 5.2 mL lithium diisopropylamidc

-355Sub D.

Ethyl (25)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazïn-l-yl)ethoxy]phenyl]-6(dirncthylcarbamoyl)lhieno[2,3-d]pyrimidÎn-4-yl]oxy-3-(2-methoxyphenyl)propanoate was hydrolyzed according to Step C of General Procedure (XVI). The diastereoisomer eluting earlier was collected as Example 574. HRMS calculated for CajHjgCINjOiS: 667.2231; found 668.2287 (M+H). The diastereoisomer eluting later was collected as Exampie 575. HRMS calculated for CjjHjgCINjOeS: 667.2231; found 668.2280 (M+H).

Example 576 (25)-2-{[(55^, _fl)-5-{3-chloro-2-mcthyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(l, l-difluoroethyi)thieno[23-rf]pyrimidÎn-4-y!]oxy}-3-(2methoxypheny!)propanoic acid

Step A:

4.22 g 4-chloro-5,6-diiodo-thicno[2,3-iZ]pyrimidine (Préparation lb) (10.0 mmol) was 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. NII₄C1 was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over NajSCh 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-iodothîeno[23-</]pyrimidin-6-yl)ethanol. *H NMR (400 MHz, DMSO-de).· 8.89 (s, IH), 6.38 (d, IH), 5.15 (m, IH), 1.44 (d, 3H).

SftpJk.

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 was purified via flash chromatography using DCM as eluent to obtain l-(4-chloro-5-îodothieno[2,3-cf|pyrimidin-6-y!)ethanone. ’H NMR (400 MHz, DMSO-di): 9.04 (s, IH), 2.80 (s, 3H).

• 357obtain ethyl (2R)-2-[5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(l,ldi fluo roetliy l)Üiïeno[2,3 -ri] py rîm idin -4 -yl]oxy-3 -(2-methoxyphenyl)propanoate as a mixture of diastereoisomers. *H NMR (400 MHz, DMSO-dù): 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 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 (2R)-2-[5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(l,l10 difluorocthyl)thîeno[2,3-ri]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoate (0.178 mmol), 51 mg 2-(4-methylpiperazin-l-yl)cthanol (0.355 mmol) and 534 mg triphenyl phosphine (0.534 mmol) were dîssolved in 4 mL dry toluene, then 123 mg difôrtbutyl 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 15 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-(4methylpîperazin-1 •yl)elhoxy]phenyl]-6-(l, l-dîfluoroethyl)thieno[2,3-ri]pyrÎmidin-4yl] oxy-3-(2 - methoxypheny 1 Jpropanoate.

Step G:

The intermediate obtained in Step F was dîssolved in 3 mL methanol and 100 mg LiOH x HiO (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 NaîSO₄ and 25 concentrated under reduced pressure. The crude product was purified via preparative reversed phase chromatography using 25 mM aqueous NHJICOj solution and MeCN as eluents. The diastercoisomer eluting later was collected as Example 576. HRMS calculated for Cj2H3_SCIF₂N₄O₅S: 660.1985; found 661.2059 (M+H).

Example 577 (2R)-2-{[6-(5-bromofwan-2-yl)-(5S<,)-5-(3-chloro-2-methyl-4-[2-(4me thy I pi perazin-1 -y l)ethoxy ] phenyl} thieno [2,3-ri] pyri mi din-4-yl ] oxy) -3-(2methoxyphenyljpropanoic acid

-359Example 579 (25)-2-( [(5S_rt)-5-{3-çhloro-2-mcthyl-4-[2-(4-mcthylpipcrazin4yl)ethoxy]phenyl}-6-(5-cyanüfuran-2-yl)thieno[2,3-i(|pyrimidin-4-y!]oxy}-3-(2methoxyphenyljpropanoic acid

SteRÀ:

250 mg ethyl (25)-2-[(55₀)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-iodo-thicno[2,3i/Jpyrimîdin-4-yl]oxy-3-(2-methoxyphenyl)propanoate (Préparation 25) (0.40 mmol), 315 mg PPhj (1.20 mmol), 276 mg di/er/butyl azodicarboxylate (1.20 mmol) and 173 mg 2-(4methylpiperazin-l-yl)ethanol (1.20 mmol) were dissolved in 10 ml dry toluene and the 10 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-watcr (9:1) containing NaOH (5m/m%) at room température. The mixture was diluted with water, the pH was adjusted to 6 by the addition 15 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 (25)-2-[(5S_a)-5-[3-chloro-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-iodo-thieno[23-dJpyrimidÎn-4yI]oxy-3-(2-methoxyphenyl)propanoicacid.

mg (25)-2-[(5S’_a)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phcnyl]-6iodo-thieno[2,3-i/Jpyrimidin-4-yI]oxy-3-(2-methoxyphenyt)propanoÎc acid (0.10 mmol), 66 mg 5-(4,4,5,5-tetramethyM,3,2-dioxaborolan-2-yl)furan-2-carbonitrile (0.30 mmol), 18 25 mg AtaPhos (0,025 mmol) and 98 mg Cs₂COj (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 30 pressure. The crude product was purified via reversed phase chromatography using 25 mM aqueous NH₄HCOj solution and MeCN as eluents to obtain Example 579. HRMS calculated for CjjHmCINjOèS: 687.1918; found 688.2001 (M+H).

• 361984 mg 4-chloro-5-[3-chloro-2-mcthy!-4-[2-(4-methylpiperazin-!· y!)ethoxy]phcnyl]thieno[2,3-d]pyrimidine (Préparation 12) (2.25 mmol) was dissolved in 20 mL dry THF under N₂ and cooied 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 dicthyl 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 overnight 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-methylptperazin-lyl)ethoxy]phenyl]thïeno[2,3-i/lpyrÎmidÎn-6*yl]-trimethyl-stannane. *H NMR. (500 MHz, DMSO-de): 8.90 (s, IH), 7.13 (d, !H), 7.11 (d, IH), 4.22 (m, 2H), 2.77 (t, 2H), 2.57 (br s, 4H), 2.41 (br s, 411), 2.21 (br s, 3H), 1.97 (s, 3H), 0.14 (s, 9H). HRMS calculated for C₂₃H_MCl₂N₄OSSn: 600.0539; found 601.0584 (M+H).

S&L&

1,91g 5-bromofuran-2-carboxylîc acid (10 mmol), 10 mL dimethylamine (2 M in THF, 20 mmol), 5.42 g PyBOP (10.4 mmol) and 3.5 mL D1PA (20 mmol) were dissolved in 20 mL dty DCM and stirred at room température under N₂ untii 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-WM dimcthyl-furan-2-carboxamide. MS: (M+H)⁺ = 218.2.

Sfep.CL

400 mg [4-ch!oro-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phcnyl]thicno[2,3-</]pyrimidin-6-yl]-trimethyl-stannane (product of Step A) (0.6 mmol), 291 mg 5-bromo-N^,.Mdimethy!-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 PhjAs (0.06 mmol) were dissolved in 1 mL NMP and stirred at 100°C under N₂ untii no further

-363 580. Example 583 was obtained as one of the products of the multicomponent mixture following séparation by reversed phase chromatography with 25 mM aqueous NH₄HCOj solution and MeCN as eluents. HRMS calculated for CssHsiCltyOgS: 720.2021; found 721.2104 (M+H).

Exemple 584 (25)-2-{[(5S_e)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl)-6-(5-ethenylfuran-2-yl)thieno[2,3-/]pyrimidin-4-yl]oxy)-3-(2· mcthoxyphcnyljpropanoic acid mg (25)-2-{[6-(5-bromofuran-2-yl)-(55’_£I)-5-{3-chloro-2-mcthyl-4-[2-(4· methylpiperazin-l-yl)ethoxy]phenyl)thieno[2J-rf]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 solution and MeCN as eluents to obtain Example 584. HRMS calculated for C36H3₇C1N₄O₆S: 688.2122; found 689.2178 (M+H).

Example 585 (25)-2-( [(5^)-5-(3-chloro-2-mcthyl-4-[2-(4-mcthylpiperazin-l yl)cthoxy]phcnyl}-6-(5-cyclopropylfuran-2-yl)th.icno[2,3-/]pyrimidin-4-y!]oxy}-3-(2methoxyphenyl)propanoic acid

283 mg (25)-2-{[6-(5-bromofuran-2-yl)-(5S^, _a)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl)thieno[2,3-<f]pyrimidin-4-yl]oxy}-3-(2methoxyphenyl)propanoic acid (Example 577) (0.38 mmol), 0.70 mL 2-cyclopropyl4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3.8 mmol), 0.62 g Cs₂CO3 (1.9 mmol) and 29 mg PdCl₂ 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

-365mcthylpiperazin-l-yl)cthanol (2.40 mmol) were dissolved in 20 ml dry toluène 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 usîng DCM and MeOH as eluente to give ethyl (27î)-2-[(5S’_i,)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl]-6iodo-thÎeno[2,3-d]pyrimÎdin-4-yl]oxy-3-(2-methoxyphenyl)propanoate.

Step B:

445 mg ethyl (2^)-2-((5^)-5-[3-chloro-2-methyl-4-[2’(4-methylpiperazin-ΙΙΟ yl)ethoxy]phenyI]-6-iodo-thieno[2,3-i(]pyrimidin-4-yl]oxy-3-(2methoxyphenyljpropanoate (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 Cs₂COj (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

J5 was observed. The crude reaction 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 Na₂SO4 and concentrated under reduced pressure. The residue was purified via flash chromatography using DCM and MeOH as eluents to give ethyl (2J?)-2-((5S_<i)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l20 yI)ethoxy]phenyl]-6-(3-hydroxyphenyl)thieno[2,3A]pyriniidin-4-yl]oxy-3-(2methoxyphenyl)propanoate.

Step C:

mg ethyl (2Â)-2-[(55’_fl)-5-[3-chloro-2-methyl-4-[2-(4-methylpÎperazin-l25 yI)ethoxy]phenyl]-6-(3-hydroxyphenyl)thieno[2,3A]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 wns observed. The mixture was concentrated under reduced pressure 30 and the crude product was purified via flash chromatography using DCM and MeOH as eluents. The obtained product was hydrolyzcd in 3 mL methanol-water (9:1) contaînîng

NaOH (5m/m%) at room température. The mixture was diluted with water and the pH was •367To a solution of 565 mg Préparation 6e (1.00 mmol) in 90 ml EtOH 1298 mg palladium hydroxide on carbon (Pcarlman’s catalyst 20 wt. %) was added. The reaction 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 réaction mixture was filtered 5 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 NH^HCOî solution and MeCN as eluents to give ethyl (2Â)-2-[(5Sn)-5-(3-chloro-4hydroxy-2-methyl-phenyl)-6-tetrahydrofuran-2-yl-thieno[23-</]pyrimidin-4-yl]oxy-3-(2methoxyphenyljpropanoate diastereomers. 'H NMR (500 MHz, DMSO-d<$) of the 10 diastereomer eluted earlier: 10.26 (s, IH), 8.54 (s, IH), 7.18 (td, IH), 7.02 (d, IH), 6.97 (d,

IH), 6.90 (dd, IH), 6,75 (t, IH), 6.32 (dd, IH), 5.35 (dd, IH), 4.70 (t, IH), 4.03-3.96 (m, 3H), 3.76 (s, 3H), 3.73 (m, IH), 2.95 (m, IH), 2.45 (dd, IH), 2.07 (m, IH), 1.99 (s, 3H), 1.96 (m, IH), 1.89 (m, IH), 1.74 (m, IH), 1.05 (t, 3H).

’H NMR (500 MHz, DMSO-de) ofthe diastereomer eluted later: 10.26 (br s, IH), 8.55 (s, 15 IH), 7.19 (td, iH), 7.05 (d, IH), 6.96 (d, IH), 6.91 (d, IH), 6,77 (td, IH), 6.46 (dd, IH),

5.36 (dd, IH), 4.82 (l, IH), 4.05-3.93 (m, 3H), 3.76 (s, 3H), 3.71 (m, IH), 2.85 (dd, IH),

2.57 (m, IH), 2.04(m, IH), 1.95 (m, IH), 1.94 (s, 3H), 1.88 (m, IH), 1.66 (m, IH), 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 CJ4H39CIN4O6S: 666.2279; found 667.2349 (M+H); Starting from the later eluted diastereomer in Step A Example 591 was obtained. HRMS calculated for C^H^CltyOeS: 666.2279; found 25 667.2315 (M+H).

Exemple 592 (2/î)-2-[((5/î_o)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)ethoxyJphenyl}-6-ethylthicno[2,3-i/]pyrimidin-4-yl)oxy]-3-(2methoxyphenyljpropanoic acid

Sien A17201

-369extracted with EtOAc. The combined organic phases were dried over MgSO«, filtered and concentrated under reduced pressure. The crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (25)-2-[5-[3-chloro-2methyl-4-[2-(4-methylpiperazm-I-yl)ethoxy]phenyl]-6-ethyI-thieno[2,3’i(]pyTiniÎdin-4yl]oxy-3-(2-methnxyphenyl)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 C32HJ7CIN4O5S: 624.2173; found 6252239 (M+H).

General Procedure (XVIÏa)

Step. Al eq. ethyl (2R)-2-[(55’_a)-5-[3-chloro-2-mclhyl-4-[2-(4-methyIpiperazin-lyl)ethüxy]phenyl]-6-(4-nuoro-3-hydroxy-plïenyl)tlïieno[2,3-d]pyrimidin-4-yI]oxy-3-[2[(2-methoxypyrimidin-4-yl)methoxy]phenyI]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/buty] 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. LÎOH ^x HiO 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.

- 371 Step Çj

2.615 g 4-chloro'5-[3-chloro-2-methyl-4-[2-(4-mcthylpiperazin-! -yl)ethoxy]phenyl]-6-[4fluoro-3-(methoxymethyl)phenyl]thieno[2^-c/]pyrimidine (4.5 mmol), 1.61 g ethyl (25)-2hydroxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 3ab) (5.5 mmol) 5 and 4.40 g CS2CO3 (13.5 mmol) were placed in a 100 ml. flask. 50 mT, /ert-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 pli was set to 7 with 2 M HCl, and then it was extracted with DCM. The combined organic layers were dried over Na2SO< and concentrated under reduced pressure. The crude product was purified via flash 10 chromatography using EtOAc and MeOH as eluents to obtain ethyl (25)-2-[5-[3-chloro-2· methyl-4-[2-(4-methylpiperazin4-yl)ethoxy]phenyl]-6-[4-fluoro-3-(methoxymethyl) phenyl]thieno[2,3-cf]pyrimÎdin-4-yi]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate as a mixture of diastereoisomers. MS: (M+H) - 833.2.

Step D.·

2.36 g ethyl (25)-2-[5-[3-chloro-2-melhyl-4-[2-(4-methylpiperazin-!-yl)ethoxy]phenyl]-6[4-fluoro-3-(melhoxymethyl)pheny!]thieno[2,3-J|pyrimidin-4-yl]oxy-3-(2tctrahydropyran-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 stirred at room 20 température until no further conversion was observed. Saturated aq. NaHCCh solution was added and the reaction 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 (25)2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6'[4-fluoro-325 (methoxymethyl) pheny!lthieno[2,3-cflpyrimidin-4-yl]oxy-3-(2-hydroxyphenyl)propanoate as a mixture of diastereomers. MS: (M+H) =749.2.

Stepjb

0.375 g ethyl (25)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-y!)cthoxy]phenyl]30 6-[4-fluoro-3-(methoxymethyl)phenyl]thïeno[2,3-if|pyrimidÎn-4’yl]oxy-3-(2hydroxyphenyl)propanoate (0.5 mmol), 0.2! g (2-methoxypyrimidin-4-y!)methanol (1.5 mmol) and 0.393 g PPhj (1.5 mmol) were dissolved in 10 mL dry toluene, then 0.345 g

-373 Example 596 (2/?)-2-[((55₀)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyI)ethoxy]phenyl)-6-{4-fluoro-3-[2-(morpholin-4-yl)ethoxy]phenyl}thieno[2,3d]pyrimtdin-4-yl)oxy]-3-{2-[(2-methoxypyrimÎdin-4-yI)niethoxy]phenyl}propanoicacid

Using General Procedure (XVIIa) and 2-(morpholin-4-yl)ethanol as the appropriate alcohol Example 596 was obtained. HRMS calculated for C^HjiCIFNtOîS: 927.3192; found 464.6657 (M+2H).

Example 597 (2/?)-2-[((5S_n)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l· yl)ethoxy]phenyl}-6-[4-fluoro-3-(2-hydroxyethoxy)phenyl]thieno[2,3-</]pyrimidin-4· yl)oxy]-3 - (2-[(2-methoxypyrî midi n-4-yl)meth oxyjpheny I} propano ic acid

Using General Procedure (XVIIa) and ethylene glycol as the appropriate alcohol Example 597 was obtained. HRMS calculated for C^H^CIFNûOîS: 858.2614; found 430.1402 (M+2H).

Example 598 (25)-2-[((5SJ-5-{3-chloro-2-mcthyl-4-[2-(4-methylpiperazin-l· yl)ethoxy]phenyl}-6-[4-fluoro-3-(2-methoxyethoxy)phenyl]thieno[2,3-iflpyrimÎdin-4yl)oxy]-3-{2-[(2-methoxypyrimidin-4-yl)methoxy]phenyl}propanoîc acid

Using General Procedure (XVIIa) and 2-methoxyethanol as the appropriate alcohol Example 598 was obtained. HRMS calculated for C^H^ClFNsOgS: 872.277; found 437.1468 (M+2H).

Example 599 (25)-2-{[(55_rt)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l · yl)ethoxy]phenyl}-6-(3-methoxypropyl)thieno[2,3-</]pyrimÎdin-4-yl]oxy}-3-{2-[(2methoxypyrimïdin-4-yl)methoxy]phenyl)propanoic acid

SlepA:

3.754 g 5-bromo-4-chloro-6-iodo-thicno[2,3-</]pyrimtdine (Préparation la) (10.0 mmol), 1198 mg 3-methoxyprop-l-yne (17.1 mmol), 702 mgPd(PPh₃)2CI (1.0 mmol), 288 mg Cul

I

-3752.765 g ethyl (2Â)-2-[5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(3-methoxyprop-lynyl)thieno[2^-i/]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2-yloxypheny[)propanoate (4.34 mmol), 1.3 g 2-(4-methylpiperazin-1-yl)ethanol (9.0 mmol) and 2.623 g triphenyl phosphinc (10.0 mmol) were dissolved in 40 mL dry toluene, then 2.303 g di/er/butyl azodicarhoxylate (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 (2Â)-2-[5-[3-chloro-2-mcthyl-4-[2-(4-methylpiperazÎnl-yl)ethoxy]phcnyl]-6-(3-methoxyprop-l-ynyl)ihicno[2,3-J]pyrimidin-4-yl]oxy-3-(210 tetrahydropyran-2-yloxyphenyl)propanoate as a mixture of diastereomers. MS: (M+H) = 763.2.

Step

3.59 g ethyl (2Æ)-2-[5-[3-chloro-2-methyl-4-[2-(4-mcthylpiperazin-l-yl)ethoxy]phenyl]-615 (3-methoxyprop-l -ynyl)thieno[2,3-</]pyrirnidin-4'yl]oxy’3-(2-tctrahydropyran-2yloxyphenyljpropanoate (4.3 mmol) and 458 mg Selcat Q6 were dissolved in 50 mL methanol, then 1,87 g rerr-butylaminc borane (21.5 mmol) was added. The mixture was stirred at room température until no further conversion was observed. It was filtered 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-methylpîperazin-l-yl)ethoxy]phenyl]-6-(3methoxypropyl) thicno[2,3-</]pyrimidin-4-yl]oxy-3-(2-tctrahydropyran-2yloxyphenyl)propanoute as a mixture of diastereomers that was used in next step without further purification. MS: (M+H) - 767.2,

Sien 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. NaHCOj 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 (2/?)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l17201

-377extracted with DCM. The combined organic phases were dried over NaîSOi, concentrated under reduced pressure, and purified via flash chromatography using EtOAc and MeOH as eluents.

Sien R:

The product of Step A was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH ^x HîO 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 NaïSO<, concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents separating the diastereoisomers.

Example 600 (2Æ)-3- {2-[(l -butyl- lH-pyrazol-5-yl)methoxy]phenyl)-2-{[(55_e)-5-{3chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyI}-6-(4cyanophenyl)thieno[2,3-i7]pyrimidin-4-yI]ûxy} propanoic actd

Using General Procedure (XVIIIa) and (4-cyanophenyl)boronlc acid as the appropriate boronic acid dérivative, the diastereoisomer eluting later was collected as Example 600. HRMS calculated for CMLîCINîOsS: 819.2970; found 410,6565 (M+2H).

Example 601 (2Æ)-3-{2-[(l -butyl-1 H-pyrazol-5-yl)mcthoxy]phenyl) -2-{[(55^)-5- (3chloro-2-methyl-4-[2-(4-methyIpiperazin-l -y!)ethoxy]pheny!} -6-(4ethylphenyl)thÎeno[2,3-(flpyrimÎdin-4-yl]oxy)propanoic acid

Using General Procedure (XVIIIa) and (4-ethy!phenyI)boronic acid as the appropriate boronic acid dérivative, the diastereoisomer eluting later was collected as Example 601. HRMS calculated for C^HjiCINîOsS: 822.3330; found 412.1729 (M+2H).

Example 602 (2Λ)-3- {2-[( 1 -butyl-1 H-pyrazol-5-yl)me thoxy] phenyl} -2 - {[(55^)-5- {3chloro-2-methyl-4-[2-(4-mcthylpipcrazin-1 -yl)ethoxy]phenyl )-6-(4hydroxyphenyl)thicno(2,3-i(]pyrimidin-4-yI]oxy} propanoic acid <

-379diastereoisomer of this side product was collected as Example 605. HRMS calculated for

C47H4₈Cl₂N₈O_sS: 906.2845; found 454.1481 (M+2H).

Exampie 607 (2/?)-3-{2-[(l-butyl-Iiï-pyrazoI-5-yl)methoxy]phenyl}-25 chloro-2-methyl-4-[2-(4-methyIpiperazin-l -yl)ethoxy]phenyl} -6-(6-fluoropyridin-3yl)thîeno[2,3-£(|pyrimidin-4-yl]oxy} propanoic acid

Using General Procedure (XVlIla) and (6-fluoro-3’pyridyl)boronic acid as the appropriate boronic acid dérivative, the diastereoisomer eiuting later was collected as Example 607.

HRMS calculated for C42H45CIFN7OSS: 813.2875; found 407.6496 (M+2H).

Example 608 (2A)-3-(2-[(l-butyl-lH-pyrazoI-5-yl)methoxy]phenyl)-2-{[(5S_fl)-5-{3chloro-2-methyI-4-[2-(4-methylpipcrazin-I-yI)ethoxy]phenyl}-6-(6-niethoxypyridin-3yl)thieno[2,3-rf]pyrimidÎn-4-yl]oxy}propanoic acid

Using General Procedure (XVlIla) and (6-methoxy-3-pyridyl)boronic acid as the appropriate boronic acid dérivative, the diastereoisomer eiuting later was collected as Example 608. HRMS calculated for C^HieClNAS.· 825.3075; found 413.6608 (M+2H).

Example 609 (2/?)-3-(2-[(I-butyl-l H-pyrazol-5-yl)methoxy]phcnyl}-2-{ (3chloro-2-methyl-4-[2-(4-methylpÎperazin-l-yl)ethoxy]phenyl}-6-(pyridin-3-yI)thieno[2,3d]pyrimidin-4-yl]oxy} propanoic acid

Using General Procedure (XVlIla) and 3-pyridylboronic acid as the appropriate boronic 25 acid derîvative, the diastereoisomer eiuting later was collected as Example 609. HRMS calculated for C^HmCINtOsS: 795.2970; found 398.6572 (M+2H).

Example 6t 0 (27^)-3-{2-[(l·butyl-]H-pyrazol-5-yl)methoxy]ρhenyl}-2-{[(5S_fl)-5-(3chloro-2-methyl-4-[2-(4-methylpÎperazin-l -yl)ethoxy]phenyl}-6-(l -methyl-I H-pyrazol-330 yl)thieno[2,3-<7|pyrimidin-4-yl]oxy} propanoic acid *

-381Step A:

437 mg ethyl (2Λ)-3-[2-[(1-butyl-1 H-pyrazol-5-yl)methoxy]phenyI]-2-[5-[3-chloru-2methyl-4-[2-(4-methy]piperazin-l-yl)ethoxy]phenyl]-6-iodo-thieno[23-<f]pyrimidin-4yljoxy-propanoate (Préparation 26c) (0.5 mmol), 35 mg Pd(PPhi)iCli (0.05 mmol) and 19 mg copper(I) iodide (0.1 mmol) were dissolved in 5 mL D1PA, 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)mcthoxy]phenyl]-2-[6-but-lynyl-5-[3-chloro-2-methyl-4-[2-(4-methylpipcrazîn-l-yl)ethoxy]phenyl]thieno[2,3</[pyrimidin-4-yl]oxy-propanoate.

The obtained intermediate was hydrolyzed according to Step B of General Procedure (XVIlIa) and the diastereoisomer eluting later was collected as Example 612. HRMS calculated for Qi^ïCINîOsS: 770.3017; found 386.1594 (M+2H).

Example 613 (2Æ>3-{2-[(l-butyl-IH-pyrazol-5-yl)methoxy]phenyl)-2-{[(5Sa)-5-{3chloro-2-methyl-4- [ 2-(4-methyl pîperazïn-1 -y l)ethoxy]pheny 1}-6-(3 -methoxyprop-1 -yn-1 yl)thieno[2,3-rf]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[2,3-<fJpyrimidÎn-4yljoxy-propanoate (Préparation 26c) (0.5 mmol), 70 mg 3-methoxyprop-1-yne (1.0 mmol), 35 mg PdfPPh^Ch (0.05 mmol) and 19 mg Cul (0.1 mmol) were dissolved in 5 mL D1PA and stirred under nitrogen at 60°C until no further conversion was observed. 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 (2Λ)-3-[2-[(1· butyl-lH-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazinl-yl)ethoxy]phenyl]-6-(3-methoxyprop-l-ynyl)thieno[2,3-<f]pyrimidin-4-y]]oxypropanoate.

-383437 mg ethyl (25)-3-[2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phcnyl]-2-[5-[3-chloro-2methyl-4-[2-(4-metliylpiperazin-l-yl)cthoxy]phenyl]-6-iodo-thieno[2,3-i/]pyrimidin-4yl]oxy-propanoate (Préparation 26c) (0,75 mmol), 28.2 mg 1,10-phenanthrolîne (0.156 mmol), 29.7 mg copper(I) iodidc (0.156 mmol), 130 mg potassium fluoride (2.23 mmol), 330 gL trimcthyl(trîfluoromcthyl)silane (2.23 mmol) and 250 pL trimcthyl 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 crude product was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (25)-3-[2-[(1-butyllH-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chIoro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy] phenyI]-6-(trÎfluoromethyi)thieno[2,3-d]pyrimidin-4-y]]oxy-propanoate.

Step R:

Tire product of Step A was hydrolyzed according to Step B of General Procedure (XVIIIa) and the diastereoisomer eluting later was collected as Exampie 615. HRMS calculated for C_3ïH4îC1F₃N₆0_sS: 786.2578; found 394.1372 (M+2H).

Example 616 (25)-3-{2-[( 1-butyl- lH-pyrazol-5-yl)methoxy]pheny]}-2-[((5S'_rt)-5-{3chloro-2-methyl-4-[2-(4-methy]piperazin-1-yl)ethoxy]phenyl}-6-{4-[2-(morpholin-4yl)ethoxyïphenyl}thieno[2,3-rflpyrimidm“4-yl)oxy]propanoic acid

Step A:

420 mg ethyl (25)-3-[2-[(1-butyl-lH-pyrazol-5-yl)mcthoxy]phenyl]-2-[5-[3-chloro-2methyl-4-[2-(4-mcthylpiperazin-l-yl)ethoxy]phenyl]-6-(4-hydroxyphenyl)thieno[2,3dJpyrimidin-4-ylJoxy-propanoate (see Step A of Exemple 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- IH-pyrazoI-5-yl)methoxy]phenyl]-2-[5-[3-chloro-2-mctliyl-4-[2-(4-methyl

-385Exemple 619 (2R)-3-(2-[(l-butyl-lH-pyrazol-5-yl)methoxy]phenyl)-2-[((5S'_e)-5-{3chIoro-2-methyI-4-[2-(4-methyIpiperazin-l-yl)ethoxy]phenyl}-6-[6-(morpholin-4yl)pyridin-3-yl]thieno[2,3-i/]pyTimÎdin-4-yl)oxy]propanoic acid

Step A:

250 mg ethyl (27?)-3-[2-[(l-butyl-lH-pyrazol-5-yl}methoxy]phcnyl]-2-[5-[3-chloro-2· methy!-4-[2-(4-methy!piperazin-l-yl)ethoxy]phenyl]-6-(6-fluoro-3-pyridyl)thieno[2,3</]pyrimidin-4-yl]oxy-propanoatc (sec Step A of Example 607) (029 mmol) and 258 pL morpholine (2.90 mmol) were heated at I5O°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-[(l-butyMH-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chloro-2-methyl-4-[2(4-methyl pipe razin-1 -y I)ethoxy] phenyl] -6 -(6-morpholino-3 -pyri dy l)thï eno[2,3 i/]pyrÎmidin-4-y1]oxy-propanoatc.

Step B:

The product of Step A was hydrolyzed according to Step B of General Procedure (XVIMa) and the diastereoisomer eluting later was collected as Example 619. HRMS calculated for CuHsiCINgOôS·. 880.3497; found 441.1825 (M+2H).

Example 620 (2Æ)-3-{2-[(l-butyl-l H-pyrazol-5-yl)mcthoxy]phcnyl}-2-[((5S_a)-5-{3chIoro-2-methyl-4«[2-(4-methy!piperazin-l-yl)ethoxy]phenyI}-6-{6-[(2methoxyethyl)amino]pyridin-3-yl}thieno[2,3-i/lpyrimidin-4-yl)oxy]propanoicacid

SlepA;.

300 mg ethyl (2R)-3-[2-[(l-butyl-IH-pyrazo!-5-yl)methoxy]phenylJ-2-[5-[3-chloro-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(6-fluoro-3-pyridyl)thieno[2,3t/]pyrimidÎn-4-yl]oxy-propanoate (see Step A of Example 607) (035 mmol) and 258 pL 2methoxycthanamine (3.50 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 crude product was purified via flash chromatography using EtOAc and MeOH as

-387Exemple 622 (2Λ)-3-{2-[(1-butyl-1 H-pyrazol-5-yl)methoxy]phenyl}-2-[((5S_d)-5- (3chloro-2-mcthy!-4-[2-(4-methy)piperazin-l-y!)cthoxy]phcnyl}-6-[6-(2-methoxyethoxy) pyridin-3-yl]thicno[2,3-i/]pyrimidin-4-yI)oxy]propanoic acid

Step A:

200 mg ethyl (2/l)-3-[2-[(l-butyl-IH-pyrazoI-5-yl)methoxy]phenyl]-2-[5-[3-chloro-2methyl-4· [2-(4-methylpiperazin-1-y l)ethoxy]phenyl]-6-(6-fluoro-3-pyridy IJthïeno [2,3i/]pyrimidin-4-yl]oxy-propanoate (see Step A of Example 607) (0.24 mmol), 56 pL 2methoxycthanol (0.72 mmol) and 232 mg césium carbonate (0.72 mmol) were stirred at 70°C in 5 mL dry /ert-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 MgSO<, and concentrated under reduced pressure. The residue was purified via flash chromatography using EtOAc and MeOH as eluents to give ethyl (2Λ)-3[2-[(l-butyl-!H-pyrazol-5-yl)methoxy]phenyl]-2-[5-[3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl]-6-[6-{2-methoxyethoxy)-3-pyridyl]thÎeno[2,3</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 622. HRMS calculated for C^HsiClNîOiS: 869.3337; found 435.6737 (M+2H).

General procedure (XXa)

The appropriate acid was dissolved în éthanol (20 ml/g) containing 1% cc. sulfuric 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 NaHCOj, 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.

-389Starling from Example 209 using General procedure (XXa) Exampie 627 was obtained.

HRMS calculated fur CjîHjoCIWîS: 690.2279; found 691.2347 (M+H)

Exampie 628 ethyl (2JÏ)-2-{[(5S’_fl)’5-{3-ch!oro-2-methyl-4-[2-(4-methyIpiperazin-lyl)ethoxy]phenyl}-6-(4-nuorophenyl)thieno[23-ri]pyrimÎdin-4-yl]oxy}-3-(2-[(2Â)tetrah ydro furan-2- yl m ethoxyjpbeny 1} propanoate

Starting from Example 2 using General procedure (XXa) Example 628 was obtained.

HRMS calculated for C«H46C1FN₄O₆S: 7882811; found 789.2875 (M+H)

Example 629 clhyl (2Λ)-2-{ [(55^)-5-(3-chloro-2-mcthyl-4-[2-(moipholin-4yl)ethoxy]phenyl}-6-(4-nuorophenyI)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2Â)telrahydrofuran-2-ylmethoxy]phenyl)propanoate

Starting from Example 648 using General procedure (XXa) Example 629 was obtained. HRMS calculated for C₄iH_4JC1FNjO₇S: 775.2494; found 776.2560 (M+H)

Exampie 630 ethyl (2A)-2-([(55'₍,)>5-{3-cldoro-4-[2-(dimcthylamino)ethoxy]-2methylphenyl)-6-(4-fluorophenyI)thieno[23-rf]pyrimidÎn-4-yl]oxy}-3-{2-[(2/Î)tetrahydrofuran-2-yImethoxy]phenyl)propanoate

Starting from Exemple 126 using General procedure (XXa) Exemple 630 was obtained.

HRMS calculated for CjsH^ClFNjOeS: 733.2389; found 734.2469 (M+H)

Example 631 ethyl (2A)-2-{[(55_a)-5-{3-chIoro-2-methy!-4-[2-(4-methylpiperazin-l· yl)ethoxy]phenyl}-6-(4-fluorophenyI)thieno[2,3-<7]pyrîmidin-4-yI]oxy}-3-[2-(pyrazin-2ylmcthoxy)pheny!]propanoatc

Starting from Exampie 91 using General procedure (XXa) Exampie 631 was obtained.

HRMS calculated for C^kClFNéCSS: 796.2610; found 797.2695 (M+H)

391 Starting from Example 715 using General procedure (XXa) Example €36 was obtained.

HRMS calculated for CîoHmCINiOjSî: 580.0893; found 581.0953 (M+H)

Example 637 ethyl (2/î)-2-{[(5S^, _a)-5-{3-chloTO-2-methy!-4-[2-(morpholin-4yl)ethoxy]phenyl}-6-(4-tluorophenyI)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-[2-(2,2,2trifluoroethoxyjphenyljpropanoate

Starting from Example 657 using General procedure (XXa) Example 637 was obtained. HRMS calculated for CjaHacŒWAS: 773.1949; found 774.2023 (M+H)

Example 638 ethyl (2i)-2-{[(5S^, _a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-Jyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-y!]oxy}-3-(2-{[2-(2,2,2trifluoroethoxy)pyrimidin-4-yl]methoxy}phcnyl)propanoate

Starting from Example 58 using General procedure (XXa) Example 638 was obtained. HRMS calculated for C₄₄H₄₃C1F₄N₆O₆S: 894.2589; found 895.2688 (M+H)

Example 639 ethyl (2Æ)-2-{[(5S_a)-5-{3-chloro-2-methyl-4-[2-(4-mcthylpiperazin-!yl)ethoxy]phenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimîdin-4-yl]oxy}-3-(2-{[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy)phenyl)propanoate

Starting from Example 30 using General procedure (XXa) Example 639 was obtained.

HRMS calculated for C^lLjClFNAS: 902.3029; found 452.1594 (M+2H)

Example 640 2,3-dihydro-lH-inden-5-yl (2Λ)-2-([(JV5-(3-chloro-2-methy 1-4-(2-(4methy 1 pi perazin- J -yl)ctboxy] pheny J} -6-(4 -fluoropheny l)thieno[2,3 -d] pyrimid in-4yl]oxy)-3-(2-methoxyphenyl)propanoate mg (2Æ)-2-[(5S'_rt)-5-[3-chloro-2-mcthyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6(4-fluoropheny!)thieno[2,3-rf]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoic acid (Example 1) (0.10 mmol), 20 mg 2,3-dihydro-l//-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

-39369 mg (2Æ)-2-[(55,)-5-[3-chloro-2-methyM-p^-methylpiperazin-l-ylJethoxylphenylJ-ô(4-nuorophenyl)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 Cs₂CO₃ (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 Na₂SO< and concentrated under reduced pressure. The crude ester was purified via préparative reversed phase chromatography to using 25 mM aqueous TFA solution and MeCN as eluents resulting Example 643. HRMS calculated for C^CIFN^S: 804.2760; found 805.2822 (M+H)

Example 644 (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl (2R)-2-{[(5.y_e)-5-(3-chloro-2methyl-4-[2-(4-methylpiperazin-I-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,315 </]pyrimidin-4’yl]oxy}-3-(2-methoxyphenyl)propanoate mg (2R)-2-[(55_fl)-5-[3-cWoro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6(4-fluorophenyl)thieno[2,3-iZ]pyrimidin-4-yl]oxy’3-(2-methoxyphenyl)propanoic acid (Example 1) (0.10 mmol), 15 mg 4<chloromethyl)-5-methyl-13-dioxol-2-one (0.10 mmol), 30 mg sodium iodide (0,20 mmol) and 65 mg Cs₂COj (020 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 C^NAFSCl: 8022239; found 8032298 (M+H)

General procedure (XXIa)

StepA:

I eq. phénol dérivative, 2 eq. of the appropriate alcohol and 2 eq. PPhj were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. difôrfbuty 1 azodicarboxylate was added. The

-395 Example 646 (2Λ)-2- {[(5S₀)-5- {3 -bromo-2-methy I -4-[2-(4-methy lpiperazin-1 yl)ethoxy] phenyl }-6-(4-fluoro phenyl )thieno [2,3-J] pyrim idin-4-yl ] oxy} -3-(2methoxyphenyl)propanoic acid

Step A:

531 mg ethyl (22î)-2-[5-bromo-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-(2methoxyphenyl)propanoate (Préparation 4n) (1.00 mmol), 598 mg [2-bromo-3-methyl-4(4,4,5,5-tetramethyl-1,3,2-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 13 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, acîdified to pH 4 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 chromatography usîng heptane and EtOAc as eluents and the diastereoisomer eluting later was collected as ethyl (2A)-2-[(55_a)5-(3-bromo-4-hydroxy-2-methyl-phenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4ylJoxy-3-(2-methoxyphenyl)propanoate.

frep fr.

Using the product of Step A as the phénol and 2-(4-methylpiperazin-l-yl)ethanol as the appropriate alcohol in General procedure (XXIa), Exemple 646 was obtained. HRMS calculated for C₃₆H_3(îBrFN₄O_JS: 734.1574; found 735.1637 (M+H).

Example 647 (2Λ)-2-([(55_β)-5-{2,3-dichloro-4-[2-(4-melhylpiperazm-1yl)ethoxy]phenyl}-6-(4-fluorophenyl)thicno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2· methoxyphenyl)propanoic acid

Step A:

266 mg ethyl (2Î)-2-[5-bromo-6-(4-fluorophcnyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-(2· methoxyphenyljpropanoatc (Préparation 4n) (0.50 mmol), 298 mg 1-(2-(2,3-dichloro-4(4,4,5,5-tctramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-methyl-pÎpcrazine

-397Exampie 650 (25)-2-{[($50-5-{3-chloro-2-methyl-4-[((3 5 or S)-l-methylpipcridin-3-yl) oxyjphenyl}-6-(4-fluorophenyl)thieno[2,3-rf] pyrimïdin-4-yl]oxy}-3-{2-((25)tetrahydrofuran-2-ylmethoxy]phenyl)propanoic acid

Using General procedure (XXIa) with ethyl (25)-2-(($5>)-5-(3-chloro-4-hydroxy-2methyl-phenyl>6-(4-iluorophenyl)thîeno[2,3-ifIpyrimidÎn-4-yl]oxy-3-[2-[((25)tetrahydrofuran-2-yl]mcthoxy]phenyl]propanoate (Préparation 6r) as the phénol and 1mcthylpiperidin-3-ol as the appropriate alcohol, Example 650 was obtained as a single diastereoisomer (the absolute configuration of the l-methylpiperidin-3-yl moiety was not determined). HRMS calculated for C39H39CIFN3OÎS: 731.2232; found 732.2319 (M+H).

Example 651 (25)-2-{[(55^)-5-{5-chloro-4-methyl-6-[2-(4-mcthylpiperazin-1yl)ethoxy]pyridin-3-yl}-6-(4-fluorophenyl)thïeno[2,3-J]pyrimidin-4-yl]oxy}-3-{2-[(2rnethoxypyrimidin-4-yl)methoxy]phenyl} propanoic acid

Using General procedure (XXIa) with ethyl (25)-2-[5-[5-chloro-4-methyl-6-[2-(4melhylpiperazin-l-yl)ethoxy]-3-pyridyl]-6-(4-fluorophenyl)thieno(2,3-i/]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 20 the later eluting diastereoisomer. HRMS calculated for C40H39CIFN7O6S: 799.2355; found 400.6259 (M+2H).

Example 652 (25>2-{[(55_fl)-5-{5-chloro-4-methyl-6-[2-(4-methylpiperazin-lyl)ethoxy]pyridin-3-yl)-6-(4-fluorophenyl)thieno[2,3-J]pyrimidin-4-yl]oxy}-3-{2-[(l25 ethyl-1 H-pyrazol-5-yl)methoxy]phenyl)propanoic acid

Using General procedure (XXIa) with ethyl (25)-2-[5-(5-chloro-4-methy!-6-(2-(4methylpiperazin-1 -y l)ethoxy]-3-pyri dy !]-6 -(4- fluorophenyljthieno [2,3 -rfjpyrimid i n-4yl]oxy-3-(2-hydroxyphenyl)propanoate (Préparation 8j) as the phénol and (I-ethyl-1 H30 pyrazol-5-yl)melhanol (Préparation 9da) as the appropriate alcohol Example 652 was obtained as the later eluting diastereoisomer. HRMS calculated for C^H^CIFNiOsS: 785.2562; found 393.6355 (M+2H).

-399 1.00 g ethyl (25)-2-[(55_rt)-[3-chloro-2-methy]-4-[2-(4-niethylpÎperazm-lyl)cthoxy]phenyl]-6-(4-fiuorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 8a) (1,41 mmol) and 594 pL TEA (4.25 mmol) were dissolved in 10 mL dry DCM, then 477 pL trifluoromethylsulfonyl 5 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 PdCljxdppf (0.21 mmol), 81 mg copper(I) 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 10 hours. Then it was diluted with EtOAc and filtered through colite. 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 (25)2-[(5S_a)-5-[3-chloro-2-methyI-4-[2-(4-mcthyIpÎperazLn-l-yl)cthoxyJphcnyl]-6-(4fluorophcnyl)thieno [2,3-rf]pyrimÎdÎn-4-yl]oxy-3-[2-(3-methoxyprop-l-yny1)phcnyl] 15 propanoate.

Step B:

326 mg ethyl (25)-2-[(55_n)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-IyI)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-(3· methoxyprop-l-ynyl)pheny1]propanoate (0.43 mmol) and 46 mg Selcat Q6 were dissolved in 5 mL methanol, then 187 mg /er/-butyl amine 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 Ç;

The product of Step B was hydrolyzed according to General procedure (XXIb) to give Example 655. HRMS calculated for CjoH^CIFN^OjS: 732.2548; found 733.2614 (M+H).

Example 656 (25)-2-{[(55_a)-5-(3-chloro-2-methyI-4-[2-(4-methylpiperazin-l· yl)cthoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrÎmidin-4-yI]oxy}-3-[2-(3methoxyprop-1 -yn-1 -yl)phcny IJpropanoic acid

-401 729.1687; fourni 730.1762 (M+H) and 730.1716 (M+H). Example 659 HRMS calculated for C36H32CIF4NJO5S: 729.1687; found 730.1716 (M+H).

Example 660 (2/?)-2-{[(55'_n)-5-(3-chloro-4-methoxy-2-methylphcnyl)-6-(4' fluorophenyl)thieno[2,3-d]pyrimidïn-4-yl]oxy}-3-(2-([2-(dïmethylamino)pyrÎmidin-4yl]methoxy)phenyl)propanoic acid

Using General procedure (XXIa) with ethyl (2/f)-2-[(55_fl)-5-(3-chloro-4-methoxy-2methyl-phenyl)-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-(210 hydroxyphenyl)propanoatc (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 CîôHjiCIFNjOjS: 699.1718; found 700.1805 (M+H).

Example 661 (22î)-2-{[(55_e)-5-(3-chloro-4-methoxy-2-mcthyIphenyi)-6-(4fluorophcnyi)thIeno[2,3-d]pyrimldÎn-4-yl]oxy}-3-{2-[2-(4-methylpipenizin-lyl)ethoxy]phenyl)propanoic acid

Using General procedure (XXIa) with ethyl (2JÏ)-2-[(5S_e)-5-(3-chIoro-4-methoxy-220 methyI-phenyi)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidîn-4-yl]oxy-3-(2hydroxyphenyl)propanoate (Préparation 81) as the phénol and 2-(4-methylpipcrazin-lyl)ethanol as the appropriate alcohol, Example 661 was obtained. HRMS calculated for CîoHjeClFNiOsS: 690.2079; found 691.2141 (M+H).

Example 662 (2/?)-2-{[(55_n)-5-(3-chloro-4-methoxy-2-mcthylphenyl)-6-(4· fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[2(dimethylamino)ethoxy]phenyl)propanoicacid

Using General procedure (XXIa) with ethyl (2/f)-2-[(5S₄)-5-(3-chloro-4-methoxy-230 methyl-phenyl)-6-{4-fluoropheny!)thieno[2,3-rf]pyiïmÎdin-4-yl]oxy-3-(2· hydroxyphenyl)propanoate (Préparation 81) as the phénol and 2-(dimethylamlno)ethanol

-403Stev B:

Usîng lhe product of Step A as the phénol and 2-(4-methylpipcrazin-l-yl)ethano! as the appropriate alcohol in General procedure (XXla) the diastereoisomer eluting earlier was 5 collected as Example 665. HRMS calculated for CîîHjjCIFiNjOjS: 708.1985; found

709.2042 (M+H). The diastereoisomer eluting later was collected as Example 664. HRMS calculated for C36H35CIF2N4O5S: 708.1985; found 709.2037 (M+H).

General procedure (XXIIa) to Step A: .

eq. ethyl (2A)-2-[(55'_ü)-5-(3-ch!oro-4-hydroxy-2-methyl-phenyl)-6-(2-furyI)thieno[2,3i/|pyriniidin-4-yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyt)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. diterrbutyl azodicarboxylate was added. The mixture was stirred at t5 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 methano! as eluents.

Sfen 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. NaHCOj solution and extracted with DCM. The combined organic phases were dried over Na₂SÜ4 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

-405and MeCN as eluents to obtain ethyl (25)-2-[5-bromo-6-(2-furyl)thieno[2,3-/]pyrimidin-4yl]oxy-3-[2-[2«(4*methylpîperazin-l-yl)cthoxy]phenyl]propanoate. MS: (M+H) - 615.0.

&pC:

189 mg ethyl (25)-2-[5-bromo-6-(2-furyl)thienc[2,3-/]pyrimidin-4-yl]oxy-3-[2-[2-(4inethy]pipcrazin-l-yl)ethoxy]phcnyl]propanoate (0.3 mmol) and 146 mg 2-(3-chloro-2mcthyl-phenyl)-5,5-dïmethyl-1,3,2-dioxaborinane (0.6 mmol) were dissolved in 2.5 mL 1,4-dîoxane, then 195 mg Cs₂CO₃ (0.6 mmol) dissolved in 0.6 mL water was added followed by 2] mg AtaPhos (0.021 mmol), and the mixture was heated under nitrogen at 110°C ïn 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 Na₂SO4, concentrated under reduced pressure, and purified via flash chromatography using dichloromethane and methanol as eluents.

Step P;

The product of Step C was dissolved in 4 mL dioxanc-water (1:1) and 126 mg LIOH * HjO (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 were dried over Na₂SO4 and concentrated under reduced pressure. The residue was purified via préparative reversed phase chromatography using MeCN and 25 mM aqueous NH^HCOj solution as eluents. The diastereoisomer eluting later was collected to obtain Example 666. HRMS calculated for CjjHjjCIN^jS: 632.1860; found 633.1962 (M+H)

Example 667 (2S)-2-{[(5Æe)-5-(3’Chloro-2-melhylphenyl)-6-(furan-2-yl)thieno[2,3/]pyrimidin-4-yl]oxy}-3-{2-[2-(4-methylplperazin-l-yl)ethoxy]phenyl}propanoicactd

SiwA;

260 mg 5-bromo-4-chloro-6-iodo-thieno[2,3-/|pyrimidine (Préparation la) (0.69 mmol), 280 mg ethyl (2S')-2-hydroxy-3-[2-[2-(4-methylpiperazin-l-y!)ethoxy}phenyl]propanoate (Préparation 3bo) (0.83 mmol) and 899 mg Cs₂CO₃ (2.76 mmol) were placed in a flask. 7 mL /cri-butanol was added and the mixture was stirred at 60°C until no further conversion

-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 Example 667. HRMS calculated for C33H33CIN4O5S: 632.1860; found 633.1959 (M+H)

Example 668 (2/7)-2-( [(55,)-5- {3-chloro-4«[2-(dimethy!amîno)ethoxy]«2-mcthylphenyl}6-(furan-2-yl)thieno[2,3-d)pyrimÎdin-4-yl]oxy}-3-{2-[(l-methyI-lH-pyrazol-5yl)methoxy]phenyl) propanoic acid

Using General procedure (XXIIa) with 2-(dimethylamino)ethanol as the appropriate alcohol in Step A and (I-methyl-IH-pyrazol-S-yl)methanol as the appropriate alcohol in Step C Example 668 was obtained. HRMS calculated for C3SH34CIN5O6S: 687.1918; found 688.1996 (M+H)

Example 669 (2/?)-2-{[(5.S’₍₇)-5-{3-chloro-4-[2-(4-ethylpiperazin-l-yl)ethoxy]-2methyIphcnyI)-6-(furan-2-yI)thicno [2,3-J]pyrimidÎn-4-yl]oxy)-3-(2-(2methoxyethoxy)phenyl]propanoic acid

Using General procedure (XXIIa) with 2-(4-elhylpiperazin-I-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 C37H4)C1N₄O7S: 720.2384; found 721.2455 (M+H)

Example 670 (2R)-2-{[(55r)-5-{3-chloro-4-[2-(4-ethylpiperazin-l -yl)ethoxy]-2methylphenyl}-6-(furan-2-yl)thicno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(223 methoxypyrimidin-4-yl)methoxy]phenyl}propanoic acid

Using General procedure (XXIIa) with 2-(4-ethylpiperazin-l-yI)ethanol as the appropriate alcohol in Step A and (2-methoxypyrimidin-4-yl)methanol as the appropriate alcohol in Step C Exemple 670 was obtained. HRMS calculated for C^HoClNdCbS·. 784.2446;

found 393.1312 (M+2H) •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 NaîSCh, concentrated under reduced pressure, and purified via flash chromatography using ethyl acetate and methanol as eluents to obtain ethyl (25)-2-[5-[3-chlorO’2-methyI-4-[2-(4-methylpiperazinI-yl)ethoxy]phenyl]-6-(2-furyl)thieno[2,3-</]pyrîmîdin-4’yl]oxy-3(2-hydroxyphenyl) propanoate as mixture of diastereoisomers. MS: (M+H) = 641.4.

Step C.·

The product of Step B was dissolved in 5 mL DMF, 276 mg K₂COj (2.00 mmol) and 232 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.00 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 LÎOH * 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 Na2SO4 and concentrated 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 as Example 673. HRMS calculated for CjeHjîFjNéOôS: 710.2386; found 711.2442 (M+II) e

-4ΠGencral procedure (XXI Ha)

Το 1 eq. of the appropriate ester in MeOH (24 mL/mmol) 28 eq. LiOHxHjO (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 HCI, and extracted with DCM. The combined organic phases were dried over Na₂SO₄, concentrated under reduced pressure and purified via preparative reversed phase chromatography using 0.1% aqueous TFA solution and MeCN as eluents

Example 675 (25)-3-(l3-benzodioxol-4-yl)-2-([(55_fl)-5-(3-chloro-4-hydroxy-2methylphenyl)-6-cthylthieno[2,3-i/JpyrimÎdin-4-yl]oxy}propanoÎc acid

Ethyl (25)-3-(1,3-benzodioxol-4-yl)-2-[(55_fl)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6ethyl-thieno[2,3-i/Jpyrimidin-4*yl]oxy-propanoate (Préparation 17b) in General procedure (XXIIIa) gave Example 675. HRMS calculated for C₂jH₂|C1N₂Û6S: 512.0809; found 513,0869 (M+H)

Exemple 676 (25)-3-(1,3-benzodioxol-4-yl)-2-{[(55_ff)-5-(3-chloro-4-hydroxy-2methylphenyl)-6-ethylthieno[2,3-i/Jpyrimidin-4-yl]oxy}propanoic acid

Ethyl (25)-3-( 1,3-bcnzodïoxol-4-yl)-2-((55_e)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6ethyl-thicno[2,3-i/JpyrimidÎn-4-yl]oxy-propanoate (Préparation 17i) in General procedure (XXIIIa) gave Example 676. HRMS calculated for C_2jH₂|ClN₂O₆S: 512.0809; found 513.0877 (M+H)

Exemple 677 (25)-3-(13-benzodioxoi-4-y!)-2-{[(55₀)-5-(3-chloro-4-hydroxy-2methylphenyl)-6-ethylthieno[2,3-i/JpyrimÎdin-4-yl]oxy}propanoicacld

Ethyl (25)-3-(1,3-benzodioxol-4-yl)-2-[(55₀)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-630 ethyl-tliieno[2,3-i/JpyrimÎdin-4-yl]oxy-propanoatc (Préparation 17J) in General procedure

-413Το 0.529 g of the product ofStcp A (1.0 mmol) dissolved in 6 mL TlIF-water (1:1) 0.250g LîOHxH₂O (5.96 mmol) was added and the mixture was stirred at room température until no further conversion was observed. Then il was diluted with brine, neutralized with 2 M HCI, and extracted with DCM. The combined organic phases were dried over Na₂SO4, 5 concentrated under reduced pressure and purified via préparative reverse phase chromatography using 0.1% aqueous TFA solution and MeCN as eluents to obtain Exemple 680 as the product eluting earlier [HRMS calculated for C₂jHaCIN₂0jS: 498.1016; found 499.1079 (M+H)], and Exemple 679 as the product eluting later [HRMS calculated for C₂jH2jClN₂O$S: 498.1016; found 499.1097 (M+H)].

Exam pl e 681 (2R)-2~ {[(5S_fl)5-(3-chloro-4-hydroxy-2-methylpheny l)-6-ethylthieno[2,3i/]pyrimidin-4-yl]oxy}-3-(2-methoxyphenyl)propanoic acid and

Exemple 682 (2Λ)-2-{ [(5Jî₀)-5-(3-chloro-4-hydroxy-2-methylphenyl)-6-ethylthieno[2,315 rf]pyrimidin-4-yl]oxy}-3-(2-methoxyphenyl)propanoic acid

Sjep-Az

0.50 g ethyl (2Æ)-2-(6-elhyl-5-iodo-thieno[2,3-<(]pyrimidin-4-yl)oxy-3-(2methoxyphenyljpropanoatc (Préparation 4q) (0.98 mmol), 0.393 g 2-ch!oro-3-methyl-420 (4,4,5,5-telramethyl-13,2-dÎoxaboro1an-2-yl)plieno1 (Préparation 5a) (1.46 mmol), 0.179 g Pd₂(dba)j (0.2 mmol), 0.140 g BuPAd₂ (0.39 mmol), 1.46 mL BujNOH solution (1.46 mmol, I M in water) and 5 mL 2-Me-THF were heated under nitrogen with stimng al 110°C for 10 mins in a microwave reactor. The pH of the mixture was set to 6 with 2 M HCl, and then il 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 (2Æ)-2-[5-(3-chloro-4-hydroxy-2-methylphenyl)-6-ethyl-thieno[2,3-rf]pyrimidin-4-yl]oxy-3-(2-melhoxyphenyl)propanoate as a mixture of diastereomers. MS: (M+H)⁺ = 527.2.

Step B:

To 0.454g of the product of Step A (0.86 mmol) dissolved in 6 mL THF-water (kl) 0.250g LÎ0HxH₂0 (5.96 mmol) was added and the mixture was stirred at room

-415extracted with DCM. The combined organic phases were dried over NajSOj, concentrated under reduced pressure and purified via préparative reverse phase chromatography using 40 mM aqueous NfyOAc solution (pH set to 4 with AcOH) and MeCN as eluents to obtain Example 683. HRMS calculated for CjîHnClNiOjS: 624.2173; found 625.2253 (M+H)⁺.

General procedure (XXIVa)

Step A:

eq. phénol dérivative, 2 eq. of the appropriate alcohol and 2 eq. PPhj were dissolved in dry toluene (0.2 M for the phénol), then 2 eq. di/ertbutyl azodicarboxylate was added. The to 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.

S!.ep B;_

The obtained intermediate was dissolved in dioxane-water (1:1, 10 mL/mmol) and 10 eq. LiOHxHiO was added. Oie 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 Na^SOx, concentrated under reduced pressure, and purified via préparative reversed phase chromatography using 20 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

Example 684 (2Æ)-2-{[(5&)-5-{3-chloro-2-methyl-4-[2-(pîperazin-l-yI)ethoxy]phenyl}-6(prop-l-yn-l-yI)thieno[2,3-d]pyrimidin-4-y!]oxy}-3-(2-methoxyphenyl)propanoic acid

Using General procedure (XXIVa), ethyl (2Æ)-2-[(55_tt)-5-(3-chloro-4-hydroxy-2-mcthylphenyl)-6-prop-l-ynyl-thieno[2,3-i/]pyrîmidin-4-yl]oxy-3-(2-methoxyphcnyl)propanoate (Préparation 61) as the phénol and 2-piperazin-I-ylethanol as the appropriate alcohol Example 684 was obtained. HRMS calculated for CJ2II3JCIN4O5S: 620.1860; found 621.1944 (M+H).

-417calculated for C33H33FN4O3S: 618.2312; found 619.2398 (M+H). The diastereoisomer eluting later was collected as Example 687. HRMS calculated for C33H35FN4OÎS: 618.2312; found 619.2396 (M+H).

Exa m pl e 68 8 (2Æ)-2- {( (5Æ_O)-5 - {3 -chloro-2-methy I -4-[2-(moiphol în-4-yl)ethoxy]pheny 1} 5 6-(5-fluorofuran-2-yl)thieno[2,3A]pyrimidin-4-yl]oxy} -3-(2-(2,2,2-trifluoroethoxy) phenyl] propanoic acid

SlgRÀL

667 mg of ethyl (2/f)-2-[(5/f_ff)-5-(3-chloro-4-hydroxy-2-methyl-pheny))-6-(5-fluoro-210 furyl)thieno[2,3A]pyrimidin-4-y]]oxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate (Préparation 6q) (1.00 mmol), 262 mg 2-(moipholin-4-yl)ethanoI (2.00 mmol], and 525 mg PPh₃ (2.00 mmol) were dissolved in 5 mL dry toluene, then 461 mg dîter/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 (2i)-2-[(57ï_(I)-5-[3-chloro-2-methyl-4-(2morpholinoethoxy)pheny!]-6-(5-iluoro-2-furyl)thieno[2,3-ù^r]pyiimidÎn-4-y]]oxy-3-(2tetrahydropyran-2-yloxyphenyl)propanoate.

StçpP;

The product of Step A was dissolved in 35 mL IICI (1.25 M in EtOH) and the mixture was stirred at 60^eC for 2h. Saturated aq. NaHCOj solution was added to the réaction mixture, and it was extracted with DCM. The combined organic phases were dried over Na₂SO<, concentrated under reduced pressure and purified via flash chromatography using DCM 25 and methanol as eluents to give ethyl (2/f)-2-[(5i_ii)-5-p-chloro-2-melhy!-4-(2-(morpholin4-yl)ethoxy)phenyl]-6-(5-fluoro-2-fiiryl)thieno(2,3A]pyrimidin-4-y1]oxy-3-(2hydroxyphenyl)propanoate.

Step C:

The product of Step B (232 mg, 0.34 mmol) was dissolved in 2 ml DMF, 138 mg K₂COj (1.0 mmol) and 77 mg 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.0 mmol) were

-419and purified via flash chromatography using EtOAc and methanol as eluents to obtain ethyl (2/0-2-[5-[3-chlorO’2-mcthyM-[2*(4-mcthylpipcfazin-l-yl)cthoxy]phcnyl]-6-iodothieno[2,3-c/]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,l'-bis(diphenylphoshino)ferrocene]dichloropalladium(Il) (0.135 mmol) were to 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 (2Æ)-2-[5’[3-chloro-2-methyl-4-(2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6· 15 (5-fluoro-2-furyl)thieno[2,3-rf]pyrimÎdin-4-ylJoxy-3-[4-fluoro-2-(methoxymethoxy) phcnyl]propanoate. HRMS calculated for C37H39CIFÎN4O7S: 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 LiOHxHjO (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 25 phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents.

The diastereomer eiuting later was collected as Example 690. HRMS calculated for C_3JH_3ÎCIF₂N₄O7S: 728.1883; found 729.1955 (M+H)

Example 691 (2/î)-2-([(5S^, _rt)-5-(3-chloro-2-methyI-4-(2-(4-methylpiperazin-l30 yl)e(hoxyjphenyl)-6-(5-fluorofuran-2-yl)<hieno[2,3-if]pyrimidin-4-ynoxy}-3-[4’fluoro-2(pyrazin-2-ylmethoxy)phenyl]propanoic acid

-421Example 692 (2R)-2-{[(55r)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l yl)cthoxy]phcnyl)-6-(5-fluoiOfuran-2-yl)thieno[2,3-<7]pyrimidin-4-yl]oxy}-3-(4-fluoro-2methoxyphenyl)propanoic acid

200 mg ethyl (2R)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]6-(5-11uoro-2-furyl)thieno[2,3-d]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 PPhj (0.562 mmol) were dissolved in 2 mL dry toluene, then 129 mg diferrbutyl 10 azodicaiboxylate (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^xH₂O (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 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 C34H₃3C1F₂N4O_êS·. 698.1777; found 699.1846 (M+H)

Example 693 (2R)-2-{[(55_fl)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin· 125 yl)ethoxylphenyl)-6-(6-fluoropyridin-3-yl)thieno[2,3-i(]pyrimidin-4-yl]oxy}-3-(2-{[tÇZ^^-trifluoroethy^l H-pyrazol-5-ynme1hoxy}phenyl)propanoic acid

StepA:

2.88 g ethyl (2R)-2-[5-[3-chIoro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-630 iodo-thieno[2,3-</]pyrimidin-4-yl]oxy-3-(2-hydroxyphenyl)propanoate (Préparation 26b) (4 mmol), 1.80 g [1-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl]methanol (Préparation 9du)

-423Exnmplc 694 (25)-2-[((55_e)-5-{3-chloro-2-mcthyl-4-[2-(4-mcthylpipcrazin-lyl)ethoxy]phenyl)-6-[6-(2-methoxyethoxy)pyridin-3-yl]thieno[2,3-i/]pyrÎmidin-4-yl)oxy]3-(2- {[ 1 -(2,2,2-trifluoroethyl)-1 H-pyrazol-5-yl]methoxy} phenyljpropanoic acid

Step A:

416 mg ethyl (25)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-I-yl)ethoxy]phenyl]6-(6-fluoro-3-pyridyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3’[2-[[l-(2,2,2-trifluoroethyl)-IHpyrazol-5-yl]methoxy]phenyl]propanoate (product of Step B of Example 693) (0.48 mmol), 112 pL 2-methoxyethanol (1.44 mmol) and 464 mg césium carbonate (1.44 mmol) 10 were stirred at 70°C in 5 mL dry retf-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 obtain ethyl (25)-2-[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yI)ethoxy]phenyl]-615 [6-(2-methoxyethoxy)-3-pyridyl]thieno[2,3-</]pyrimidin-4-yl]oxy-3-[2-[[l-(2,2,2trifluoroethylJ-lH’pyrazoI-S-yllmcthoxyJphcnylJpropanoatc.

Step BThe product of Step A was hydrolyzed according to Step C of Example 693; the 20 diastereoisomer eluting later was collected as Example 694. HRMS calculated for C^HcCIFjNjOïS: 895.2742; found 896.2801 (M+H)

Example 695 (25)-2-[((55>)-5-{3-chloro-2-melhyl-4-[2-(4-methylpiperazm-lyl)cthoxy]phenyl}-6-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]thieno[2,3-if]pyTimidin-425 yI)oxy]-3'(2-{[l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl]methoxy}phenyl)propanoicacid

Step Ai

434 mg ethyl (25)-2-[5-[3-chloro-2-mcthyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl)6-(6-fluoro-3-pyridyl)thieno[2,3-J]pyrÎmidm-4’yl]oxy-3-[2-[[l-(2,2,2-trifluoroethyl)-lH30 pyrazol-5-yl]methoxy]phenyllpropanoate (product of Step B of Example 693) (0.50 mmol), 510 pL 2,2,2-trifluoroethanol (7.0 nimol) and 489 mg césium carbonate (1.5 mmol) were stirred at 70°C in 5 mL dry 'DuOlI until no further conversion was observed.

-425 The product of Step A was hydrolyzed according to Step C of Example 693; the diastereoisomer eluting later was collected as Example 696. HRMS calculated for C41H41CIF3N7O6S: 851.2480; found 852.2514 (M+H)

General procedure (XXVHa)

Step A:

I eq. ethyl (2Æ)-2-[5-(3-chlojO-4-methoxy-2-methy!-phenyl)-6-(4-fluoro-3-hydroxyphenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-[2-[(2-methoxypyrimîdÎn-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. diter/buty! 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.

Sien B:

The product of Step A was dissolved in dioxane-water (1:1, 10 mL/mmol) and 10 eq. Li0HxII₂O 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 diastereo isomers were separated at this stage.

Exampie 697 (2Æ)-2-{[(5/E_e)-5-(3-chloro-4-methoxy-2-methylphenyl)-6-{4-iluoro-3-[225 (4-methylpiperazin-l-yl)ethoxy]phenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxy]phenyl) propanoic acid

Using General procedure (XXVIIa) starting from 2-(4-methylpiperazin-l-yI)ethanol as the appropriate alcohol Example 697 was obtained as the diastereomer eluting earlier. HRMS 30 calculated for C42H42CIFN6O7S: 828.2508; found 415.1324 (M+2H)

-427Example 702 (2Λ)-2- {[(5S_e)-5-(3-ch!oro-4-methoxy-2-methylphcnyl)-6-{3-[2(dimethylamino)ethoxy]-4-fluorophcnyl}thicno[2,3-rf]pyrimidin’4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxy]phcnyl}propanoic acid

Using General procedure (XXVHa) starting from 2-(dîmcthyIamino)ethanol as the appropriate alcohol Example 702 was obtained as the diastereomer eluting later. HRMS calculated for Cj^ClENAS: 773.2086; found 387.6114 (M+2H)

General procedure (XXXIa)

1Û Step A:

eq. ethyl (2i)-2-[(55_<I)-5-[3-chloro-2-mcthyl-4-[2-(4-methylpïperazin-lyl)ethoxy]phenyl]-6-(2,3-difluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2-hydroxy phcnyl)propanoate (Préparation 8m), 3 eq. of the appropriate alcohol and 3 eq. triphenyl phosphine were dîssolved in dry toluene (20 mL/mmol), then 3 eq. dîter/butyl 15 azodicarboxylate 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 residue was purified via flash chromatography using ÜCM and methanol as eluents.

Step_R;_

The product of Step A was dîssolved în dioxane-water (1:1, 10 mL/mmol) and 10 eq. LiOHxHiO 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 25 mM aqueous NH4HCO1 solution and MeCN as eluents.

Example 703 (2Λ)-2-{ [(5SJ-5-(3-chloro-2-methyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(2,3-difluorophcnyl)thieno[2,3-d]pyrimidÎn-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxy]phenyl} propanoic acid

-429SttP. B;

The product of Step A was dissolved in dioxane-water (1:1, 10 mL/mmol ) and 10 eq. LiOHxlIîO 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 5 extracted with DCM. The combined organic phases were dried over Na₂SO4, concentrated under reduced pressure and purified vïa préparative reversed phase chromatography using 25 mM aqueous NH4HCOJ solution and MeCN as eluents.

Example 706 (2/î)-2-{[(5S_fl)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l10 yl)ethoxy]phenyl)-6-(3,4-difluorophenyl)thieno[2,3-if|pyrimidin-4-yl]oxy}-3-{2-[(2methoxypyrimidin-4-yl)methoxyJphenyl} propanoic acid

Using Oeneral procedure (XXXHa) and (2-methoxypyrimidin-4-yl) méthanol as the appropriate alcohol Example 706 was obtained. HRMS calculated for C4iH₃<)CIF2N6O6S:

816.2308; found 817.2389 (M+H)

Example 707 (2/J)-2-([(5S_a)-5-{3-chIoro-2-mclhyl-4-[2*(4-methylpîperazin-lyl)ethoxyjpheny! }-6- (3,4-d ifluorophenyl)thieno[2,3-if] pyrimidin-4*yl]oxy} -3-(2- {12(trifluoromethyl)pyrimidin-4-yl]methoxy}phenyl)propanoicacid

Using Oeneral procedure (XXXHa) and [2-(trifluoromcthyl)pyrimidin-4-yl]methanol (Préparation 9bj) as the appropriate alcohol Example 707 was obtained. HRMS calculated for C4jH3éCIF$N60jS: 854.2077; found 855.2146 (M+H)

Example 708 (2Æ)-2- {[(5S_rt)-5- {3-ch!oro-2-methyl-4-[2-(4-methylpiperazin-l yI)ethoxy]phenyt}-6-(3_>4-difiuorophenyI)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-{2-[(l-cthyllH-pyrazol-5-yl)methoxyJphenyl)propanoic acid

Using General procedure (XXXHa) and (l-ethyl-lH-pyrazol-5-yl)methanol (Préparation

9da) as the appropriate alcohol Example 708 was obtained. HRMS calculated for

C41H41CIF2NGO5S: 802.2516; found 803.2561 (M+H)

-4310.152 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)phcnol (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 HjO, 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 Iater was collected as ethyl (25)-2-[(55_e)-5-(3-chIoro-4-hydroxy-2-methyl-phenyl)-6-(3fluorophenyl)thieno[2,3-i/]pyrimidin-4-yI]oxy-3-[2-[(4-methoxyphenyl)methoxy]phenyl] propanoate. ’H NMR (500 MHz, DMSO-de): 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 C_3iH₃₂CIFN₂O₆S: 698.1654; found 699.1754 (M+H).

Step D:

0.966 g of theproduct 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 PPhj polymer (3 mmol/g, 4.1 mmol) and 0.95 g di-ferf-butyl 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 (25)-2-[(55_ff)5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(3fluorophenyI)thieno[2,3-iflpyrimidin-4-yl]oxy-3-[2-[(4-methoxyphenyl)methoxy]phcnyl] propanoate. *H NMR (500 MHz, DMSO-d<): 8.64 (s, IH), 7.41-738 (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, lH),2.46(brs,4H),2.22(brs,4H),2.08(s,3H), 1.82 (s, 31D, 1.02 (t, 3H). HRMS calculated for C^IUClFN^sS: 824.2811; found 825.2899 (M+H).

-433100 mg of the product of Step D in Example 709 (0.12 mmol) was dissolved in 5 mL MeOH. 252 mg LiOHxHjO (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 précipitatcd crude product was filtered, dried and purified via préparative reverse phase chromatography using 25 mM aqueous NH₄HCOj solution and MeCN as eluents to obtain Example 710. HRMS calculated for C43H42CIFN4O6S: 796.2498; found 797.2565 (M+H).

Example 711 (2R)-2-([(3S_n)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(3-fluorophenyl)lhieno[2,3-i/]pyrimidin-4-y!]oxy}-3-(2hydroxyphcnyljpropanoic acid

100 mg of the product of Step E în Example 709 (0.14 mmol) was dissolved in 5 mL MeOH, 252 mg LlOHxHjO (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 precipîtated 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 6772005 (M+H).

Example 712 (2R)-2-{[(3S’_fl)-5-{3-chloro-2-methyl4-[2-(morphonn-4-yl)ethoxy]phenyl}6-(l-methyl-lH-pyrazol-4-yl)thieno[23-<0pyriniidin-4-yl]oxy}-3-phenylpropanoic acid

Step A:

266 mg methyl (2R>2-[6-bromo-(5S’rt)-5-(3-ch!oro-4-hydroxy-2-methyl-phenyl)thieno[23rf]pyrimidin-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)C12 (0.075 mmol) were dissolved in a mixture of 8 mL 2-Me-THE and 1 mL water and the mixture was heated under nitrogen at 100 °C for

-435mg PPh₃ (1.20 mmol) and 276 mg di/er/butyl azodicarboxylate (1.20 mmol) were dissolved ïn 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 ethyi (27?)-2-[(5S_rt)-5-(3-chloro-4-incthoxy-2-methyl-phenyl)-6-iodo-thieno[2,3rf|pyrimÎdin-4-yl]oxy-3-(2-methoxyphenyl)propanoate. HRMS calculated for C^CIINAS: 638.0139; found 639.0222 (M+H).

Step B;

to 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 Cs₂COj (2.00 mmol) and 19 mg Pd(dppf)Cla (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 réaction 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 cliromatography using heptane and EtOAc as eluents to give ethyl (2Λ)2-[(5S_a)-5-(3-chloro-4-methoxy-2-methyi-phenyi)-6-(3-hydroxypheny))thieno[2J-<Z] pyrîmÎdin-4-ylloxy-3-(2-methoxyphenyl)propanoate. HRMS calculated for

C«H_WC1NAS: 604.1435; found 605.1518 (M+H).

SfepC:

146 mg of the product of Step B (0.24 mmol), 197 mg PPhj (0.75 mmol), 152 mg difeributyl 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

-437140 mg of the product of Step A (0.24 mmol) was dissolved in 10 mL MeOH, 202 mg LIOHxHîO (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 NajSO^ 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 C₂₇H₂|C]N₂0jS₂: 552.0580; found 553.0647 (M+H).

Exam pie 716 (2R)-2-{[(5A_fl)-5- ( 3-ch)oro-2-methyl-4-[3-(4-methylpiperazin’ 1 -yl)prop-1 yn-l-yl]phenyl)-6-(2,3-dïfluorophenyl)thicno[2,3-J]pyrimidin-4-yl]oxy}-3-(2methoxyphenyljpropanoic acid and

Example 717(2/ï)-2-([(5S'_rt)-5-(3-chloro-2-methyl-4-[3-(4-methylpÎperazÎn-l-yl)prop-lyn-l-yl]phenyl}-6-(2,3-difluorophenyl)thieno[2,3-/]pyrimidin-4-yI]oxy}-3-(2methoxypheny!)propanoic acid

Sien A:

297 mg 4-chloro-5-iodo-thieno[2,3-/Jpyrimidine (Préparation le) (1.00 mmol), 398 mg 2-(4-bromo-3-chloro-2-methyl-phenyI)-4,4,5,5-tetramethyl-13.2-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 reactor. 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-chloro-2-methyI-phenyl)-4-ch!oro-thieno[2,3-/]pyrimidinc.

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 Na₂SÛ4, filtered and concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as f

-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 Exemple 717. The diastereoisomer eluting earlier was collected as Example 716. HRMS calculated for C37H33CIF2N4O4S: 5 702.1879; found 703.1963 (M+H). The diastereoisomer eluting later was collected as

Example 717. HRMS calculated for C37H33CIF2N4O4S: 702.1879; found 703.1947 (M+H).

Example 718(2JÏ)-2-{[6-(5-chlorofuran-2-yl)-(5₁S'_ff)-5-{3-chloro-2-methyI-4-[2-(4methyIpiperazïn-l-yl)ethoxy]phcnyl}thieno(2,3-</]pyrimidin’4-yl]oxy)-3-(4-fluoro-2to methoxyphenyl)propanoic acid

SfezAz

700 mg 5-bromo-4-chloro-6-(5-chloro-2-furyl)thieno[2,3-Î/]pyrimidÎne (Préparation 2d) (2.0 mmol), 581 mg ethyl (2Æ)-3-(4-fluoro-2-methoxy-phenyI)-2-hydroxy-propanoate 15 (Préparation 3as) (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 I-[2-[2-chloro-3-methy]-4(4,4,5,5-tetramethyl·!,3,2-dioxaborolan-2-yl)phenoxy]ethy]]-4-methyl-piperazine (Préparation 5b) (2.4 mmol) and 141 mg AtaPhos (0.2 mmol) were added. The mixture 20 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 MgSÛ4 and concentrated under reduced pressure. The crude intermediate was purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2R)~ 2-[6-(5-chIoro-2-furyl)-5-[3-chloro-2-methyl-4-[2-(4-methylpÎperaztn-l25 yl)ethoxy]phenyl]thleno [2,3-i/]pyrimidin-4-ylloxy-3-(4-fluoro-2-methoxyphenyl) propane atc.

Slep B:

560 mg of the product of Step A (0.75 mmol) was dtssolved in 20 mL dioxane-water (I:I) and 632 mg LiOH^HaO (I5.I 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

-441in 10 mL McOH-THF (1:1), 227 mg LiOH*H2O (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 Na₂SÛ4 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 C2SH21CIN2O3S: 464.0961; found 465.1054 (M+H)], and Example 720, as the diastereomer eluting later [HRMS calculated for C2jH₂]C1N2O₃S: 464.0961; found 465.1028 (M+H)].

Example 721 (2Æ)-2-{[(5S'_fl)-5-(3-chIoro-2-methylpheny])-6-ethcnylthieno[2,3</]pyrimîdÎn-4-y]]oxy}*3-phenylpropanoicacid

Step A:

The mixture of 550 mg 4-chloro-5-(3-chloro-2-methy]-phenyl)-6-iodo-thieno[2,3i/]pyrimidine (Préparation 24b) (1.3 mmol), 0.245 mL 4,4,5,5-tetramethyl-2-viny!-!,3,2dioxaborolane (1.43 mmol), 0.397 g AgîCÛ3 (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 1o give 4-chIoro-5-(3-chloro-2-methyl-phenyl)-6-vinyl-thieno[2,3i/Jpyrimidine. '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, !t 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 Na2SÛ4, and evaporated under reduced pressure. The crude r

-443PITARMACOLOCICAL STIIDY

EX AMPLE Ai Inhibition of Mcl-1 by the fluorescence polarisation technique

The relative binding potency uf each compound was determined via Fluorescence Polarisation (FP). The method utilîsed a Fluorescein labelled ligand (Fluoresceîn-pAla5 Ahx-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 fiat bottomed, low binding, 384-weli plate (final DMSO concentration 5%). 38μΙ of buffer (10 mM 4-(2-hydroxyethyl)-l-pîperazineethanesulfbnic acid [HEPES], 150mM NaCI, 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 Syncrgy2 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* (ΙΟμΜ Example 38) controls. 1 l-point dose response curves were 20 plotted with XL-Fit software using a 4-Parameter Logistic Model (Sigmoidal DoseResponse Model) and the inhibitory concentrations lhat gave a 50% réduction in mP (1C50) were determined. Results obtained using Method I are presented in Table 1 below; ICjo 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 2μΙ transferred into fiat bottomed, low binding, 384-welI 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

-445-

Table I; IC<n of Mcl-1 Inhibition (fluorescence polarisation test) and of cvtotoxicity for H929 cells

Hôte : ICso of Mcl-l inhibition obtained usingMethod 2 are underlined.

	JCn (M) Md-1 FF	ICj,(jtM)MTTH929		ICn(M)McI-) FP	IC* (μΜ) MTT H929
Example 1	8,0E-08	0,16	Example 29	3,3E-09	0,007
Example 2	l,2E-08	0,136	Example 30	2,8 E-09	0,003
Example 3	8,9 E-09	0,114	Example 31	5,6E-09	0,012
Example 4	1.6E-08	0,192	Exampie 32	#N/A	0,006
Example 5	6,2 E-09	0,418	Example 33	7.8E-09	0,017
Example 6	4,9 E-09	0,332	Example 34	3,3E-09	0,004
Example 7	8.6E-09	0,066	Example 35	4.8E-09	0,027
Example 8	1.6E-08	0,145	Example 36	1,1E-O8	0,015
Example 9	9,3 E-09	0,363	Example 37	6,0E-09	0,014
Example 10	9,7E-O9	0,275	Example 38	l,9E-09	0,016
Example 11	4,4E-O8	0,13	Example 39	4,8 E-09	0,015
Example 12	l,6E-08	0,076	Example 40	5,6E-09	0,008
Example 13	2,2E-08	0,146	Exampie 41	2,9E-09	0,007
Example 14	1,3 E-08	0,168	Example 42	3,2 E-09	0,012
Example IS	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-O9	0,009
Example 18	8,3E-09	0,076	Example 46	7.3E-O9	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	1.1E-08	0,122
Example 21	l,6E-08	0,162	Example 49	2,5E-09	0,012
Example 22	8,3 E-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

-447-

	ICj,(M)Mcl-l F?	Κ.»(μΜ)ΜΓΓ 11929		lC»(nM) Mcl-l FP	IC„(\|iM)MTTH929
Example 119	4,8E-O9	0,02	Example 150	9,3 E-09	0,027
Exampfe 120	3,8E-O9	0,003	Example 151	3,6E-O9	0,309
Example 121	5.6E-09	0,015	Example 152	9,9E-O9	0,19
Example 122	3,8E-09	0,01	Example 153	5,OE-O9	0,146
Example 123	4,3E-O9	0,002	Example 154	6,6E-O9	0,1
Example 124	4,3E-09	0,024	Example 155	7,6E-09	0,189
Example 125	7,3E-O9	0,354	Example 156	7,0E-O9	0,092
Example 126	1,4E-O8	0,7	Example 157	7,0E-O9	0,286
Example 127	2.0ΕΌ8	0,558	Example 158	4.6E-09	0,033
Example 128	4,0 E-09	0,018	Example 159	9,8E-O9	0,246
Example 129	2,2 E-09	0,069	Example 160	5,0E-09	0,021
Example 130	3,4E-O9	0,065	Example 161	3,9 E-09	0,081
Example 131	7,9E-O9	0,039	Example 162	9,9E-O9	0,027
Example 132	4,8Ε·09	0,102	Example 163	1,2E-O8	0,047
\| Example 133	3,4E-09	0,099	Example 164	8,2E-O9	0,046
Exampfe 134	1,3E-O8	0,193	Example 165	1,6E-O6
Example 135	8,6E-O9	0,005	Example 166	6,0E-O9	0,036
Example 136	7,7E-O9	0,015	Example 167	4,6E-O9	0,01
Example 137	5,5E-09	0,007	Example 168	2,8E-O9	0,025
Example 138	8.9E-O9	0,013	Example 169	9.0E-09	0,009
Example 139	8,5E-O8	0,636	Example 170	5.3E-O9	0,006
Example 140	2,2E-O8	0,205	Example 171	4,1E-O9	0,003
Example 141	3,1E-O8	0,27	Example 172	3,OE-O9	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	3,9Ε·09	0,003
Example 145	1,1E-O8	0,293	Example 176	3,1Ε·Ο9	0,016
Example 146	3,5E-O8	1,16	Example 177	2,8ΕΌ9	0,005
Example 147	2,4 E-08	0,787	Example 178	6.3E-O9	0,002
Example 148	3,lE-08		Example 179	5,0E-09	0,03
Example 149	1.2E-08	0,092	Example 180	8,9ΕΌ9	0,042

-449-

	ic„(M)Md-i rr	rc*iO»M)Mrr H929		TCjctMjMcl-l \|P	IC» (;;M) MÎT H929
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	6.2E-O9
Example 246	9.1E-09	0,324	Example 277	4,EE-09	0,07
Example 247	8,OE-09	0,022	Example 278	6,7E-O9	0,202
Example 248	6,9E-09	0,015	Example 279	8,OE-09	0,406
Example 249	4.0E-09	0,023	Example 280	4,0E-O9	0,071
Example 250	3,6E-09	0,499	Example 281	7,9E-O9	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	4,8 E-08	1,79
Example 254	3,3E-09	0,044	Example 285	l,7E-08	0,588
1 Example 255	7,SE-09	0,018	Example 286	7,6E-09	0,508
B Example 256	4.8E-09	0,006	Example 287	8,3E-09	0,667
Example 257	5,0E-O9	0,019	Example 288	1,2E-O8	0,086
Example 258	6,6E-09	0,069	Example 289	1,4E-O8	0,18
Example 259	5.2E-09	0,07	Example 290	5,8E-O9	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-O9	0,192
Example 262	. 3,9E-09	0,023	Example 293	8,96-07
Example 263	2,0E-09	0,126	Example 294	1,6E-O8	0,886
Example 264	9,16-09	0,034	Example 295	4,7E-O9	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	1,2E-O8	1,14
Example 268	8,2E-09	0,086	Example 299	l,6E-08	1,03
Example 269	1.1E-08	0,069	Example 300	3,7E-08
Example 270	l,2E-08	0,068	Example 301	1,26-08	0,108
Example 271	1,66-08	0,197	Example 302	1,4E-O8	1,59
Example 272	2.2E-O8	0,822	Example 303	9,3E-O9	0,998
Example 273	9.2E-O9	0,905	Example 304	1,1E-O8	1,7

-451-

	IC_m(M)McM FP	1C„ (μΜ) MTT H9Ï9		IC»(M) Mcl-1 FP	IC» (μΜ) MIT H929
Example 367	3.2E-O9	0,015	Example 398	1.5E-06	23,8
Example 368	14E-08	0,005	Example 399	1.4E-08
Example 369	5.1E-09	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-O9	0,012	Example 404	5,7E-08	21,6
Example 374	9.2E-O9	0,038	Example 405	L4Î439
Example 375	5.6E-O9	0,081	Example 406	3,5E-O8	21,9
Example 376	2.OE-O9	0,076	Example 407	Ι,ΙΕ-07	7,33
Example 377	3,8E-09	0,047	Example 408	26,25% @ 10 uM	15,9
Example 378		0,202	Example 409	2.0EO7
Example 379	l,3E-08	0,174	Example 410	2.2E-O6
Example 380	1,1E-O8	0,162	Example 411	3,4E-08	19
Example 381	1.3E-08	0,119	Example 412	5,1E-O8	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-O9	0,053	Example 415	5,0E-08	‘ 6,41
Example 385	3,5E-09 .	0,048	Example 416	7.0E-07
Example 386	Ι,ΟΕ-08	0,075	Example 417	1.5E-O7
Example 387	4.0E-09	0,202	Example 418	5,6E-08	13,3
Example 388	2JE-O8		Example 419	3,4E-08	21,5
Example 389	L2E-06		Example 420	4,0E-08	15,6
Example 390	4,0E-08	20	Example 421	38,1% @ 10 uM
Example 391	3,7E-08	22,1	Example 422	L4E48	14,4
Example 392	3.0E-08	17,1	Example 423	5,3E-0B
Example 393	4,1E-O8	16,6	Example 424	9,6E-08
Example 394	3.4E-Ç3		Example 425	9.6E-09
Example 395	istoe		Example 426	.4.6^-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

-453-

I	FP	ICj, (χΜ) MÎT H 929		IC_e(M)Mcl-\| FP	IC»()iM)MTTH929
I Example 491	28,3% @ 10 uM		Example 522	7.5E-08
Example 492	9.CE-08	2,19	Example 523	1.8E-09	0,532
Example 493	s.ofcoa		Example 524	3,1E-O8	0,417
Example 494	4,4E-08	2,56	Example 525	3.3Î-O?	0,755
Example 495	3,6E-08	1,19	Example 526	4.1E-09	0,835
Example 496	2.0E-07	3,39	Example 527	7,1E-O8	0,272
Exemple 497	9.1E-O7	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	1.2E-O7	1,59
Example 500	8.0E-08	2,25	Example 531	3.5E-09	1,22
Example 501	2,8E-O7	2,84	Example 532	5,9E-08	0,323
Example 502	1.9E-O8	0,766	Example 533	2,8E-O8	0,201
Exampie 503	5,0E-07	7,02	Example 534	l,6E-08	0,413
Example 504	2.9E-08	0,324	Example 535	1.3E-07	1,84
Example 505	5,8E-08	0,954	Example 536	7.7E-0S	0,797
Example 506	7,5E-O8	8,29	Example 537	4,3E-08	0,208
Example 507	2.2E-O7		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	3.2EtS9	0,311
Example 510	3,9E-08	0,639	Example 541	2,9E-O8	0,329
Example 511	4,8E-07		Example 542	4.3E-07
Example 512	1.3E-O7	7,42	Example 543	4.2E-08	0,766
Example 513	3,7E-07		Example 544	1.4E-08	0,274
Example 514	9.6E-08	1,7	Example 545	3,9E-O8	1,1
Example 515	8,4E-08	2,95	Example 546	l,7E-08	0,416
Example 516	1,3E-O7	5,07	Example 547	3,3E-O8	0,475
Example 517	5.1E-07	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-O8	0,523	Example 550	4,8 E-08	0,203
Example 520	4.1E-08	1,13	Example 551	2.8E-O8	0,201
Example 521	2.4E-O7		Example 552	4,1E-O8	0,784

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- SSf17201

-457 EXAMPLE 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 ïn a xenograft model of AMO-1 multiple myeloma cells.

1.10⁷ AMO-1 cells are grafted sub-cutaneously into immunosuppressed mice (SC1D 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 quantifiée! in the tumour lysâtes.

The quantification is carried out using the Meso Scale Discovery (MSD) EL1SA 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 arc capable of inducing apoptosis in AMO-1 tumour cells/w vivo.

EXAMPLE I); Antl-tumour activitv in vivo

The anti-tumour activity of the compounds of the invention is evaluated in a xenograft model of AMO-1 multiple myeloma cells.

lxIO⁷ AMO-1 cells are grafted sub-cutaneously into immunosuppressed mice (SC1D strain).

to 8 days after the graft, when the tumow mass has reached about 150 mm³, the mice are treated with the various compounds in a datly schedule (5-day treatment). The tumour mass is measured twice weekly from the start of treatment.

The compounds of the invention have anti-tumour activities (tumour régression) in the AMO-1 multiple myeloma model with ΔΤ/C (qualification parameter of tlic 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.

Claims

1· Compound of formula (I):

wherein:

♦ A represents a linear or branched (C|-C<)alkyl group or an haiogen atom,

5 ♦ Ri, Rî, Rj, R< and Rj independentiy of one another represent a hydrogen atom, a haiogen atom, a linear or branched (Ci-C«)alkyl group, a linear or branched (CiCe)alkenyl group, a linear or branched (Ci-Ci)alkynyl group, a linear or branched (Cî-Ciïpolyhaloalkyl, a hydroxy group, a linear or branched (Ci-Ci)alkoxy group, -SXCfCtOalkyl group, a cyano, a nitro group, -alkyl(Co-C6)-NR«Rj’, -O-Cyi, 10 -alkyl(Co-Ce)-Cyi, -alkeny1(C2-Cs)-Cyi, -alkynyl(Cî-C6)-Cyt_f •O-alkylÎCi-CeJ-Rfc

-COOR», -OC(O)R», -C(O)NRsR_s’, -NR₈C(O)-R_g’_t -NRgC(O)-OR₈*,

-alkyl(Ct-C«)*NRsC(O)-Rg’, -SOrNRsR?» -SOï-alkyl(Ci-Cfi), or the substituents of one of the pairs (Ri,R₂), (R;, Ri), (Ri, Ri)» (R«_t 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-Ci)alkyl group, -NRioRio’, -alkyl(CoCi)-Cyt or an oxo,

-461 containing from 3 to 10 ring members, and containing from 1 to 3 hetero atoms selected from oxygen, sulphur and nitrogen, which may include fiised, bridged or spiro ring Systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined

5 and the alkyl, alkenyl, alkynyl, alkoxy, to be substituted by from 1 to 4 groups selected from optionally substituted linear or branched (Ci-Cejalkyl, optionally substituted linear or branched (Cj-Cs)alkenyl group, optionally substituted linear or branched (Cï-Ci)alkynyl group, optionally substituted linear or branched (Cj-Ceialkoxy, optionally substituted (CiC^alkyl-S-, hydroxy, oxo (or JV-oxide where appropriate), nitro, cyano, -COOR', -0C0R’,

10 -CONR’R”, -NR'R, -(C=NR’)-OR”, linear or branched (C_rC₆)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 (CiC^alkyl group, their enantiomers, diastereoisomers and atropoisomers, and addition salts thereof with a 15 pharmaceutically acceptable acid or base.

2- Compounds according to claim 1 wherein at least one of the groups selected from Ri, Rî and R₃ does not represent a hydrogen atom.

3- Compounds according to claim 1 wherein A represents a linear or branched (CiCe)alkyl group.

20

4- Compounds according to claim 1 wherein X represents a carbon atom.

. . ?

5- Compounds according to claim 1 wherein : J

A represents (III) wherein R4, Rj and Riz are as defined for formula (I), and

Alk represents a tinear or branched (C 1 -Ce)alkyl group, (IV) wherein R», Rj, R7 and Riz are as defined for formula (I) and Alk is as defined bcforc, compound of formula (IV) which is further subjccted to coupling with compound of

20 formula (V):

-465to yield the compound of formula (I), which may be purified according to a conventiona! 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 conventiona! séparation technique,

5 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 10- Process for tire préparation ofa compound of formula (I) characterised in that therc is used as starting material the compound of formula (Π-b):

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

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

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

(VIII)

R^O 'ORea

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

Rbj and Rbh represent a hydrogen, a linear or branched (Cj-Cg) alkyl group, or Rb3 and Rb4 form with the oxygen carrying them an optionally methylated ring, (IX) »

-469acid, which may optionaily bc optionaily bc reacted with an alcohol of formula R$0H wherein R< is as defined 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 8cid or base and which is optionaily 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 ïntermediates can be protected, subsequently deprotected and functionalizcd, as required by the synthesis.

11- Pharmaceutical composition comprising a compound of formula (I) according to any one of claims 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-apuptotic agents.

13- Pharmaceutical composition according to claim 12 for use in the treatment of cancers and of auto-immune and immune System diseascs.

14- Pharmaceutical composition according to claim 13 for use in the treatment of 20 cancers of the bladder, brain, breast and utérus, chronic lymphoid lcukacmïas, cancer of the colon, œsophagus and livcr, lymphoblastic leukaemias, acute myeloid lcukacmïas, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-smallcell lung cancer, prostate cancer, pancreatic cancer and small-ccll 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 în the manufacture of médicaments for use în the treatment of cancers and of auto-immune and immune syslem ♦

-47123- Use of an association according to claim 20 in the manufacture of médicaments for use in the treatment of cancers.

24- Compound of formula (1) according to any one of claïms 1 to 8 for use in association in the treatment of cancers requiring radiotherapy.