Sie sind auf Seite 1von 70

COMMUNICATION NI AINA MONO DI TUTTI

US009884839B2

(12) United States Patent ( 10) Patent No.: US 9,884,839 B2


Hartmann et al. (45 ) Date of Patent: Feb . 6 , 2018
(54 ) INHIBITORS OF (56 ) References Cited
17BETA -HYDROXYSTEROID
DEHYDROGENASES TYPE 1 AND TYPE 2 U . S . PATENT DOCUMENTS
(71 ) Applicant: ElexoPharm GmbH , Saarbruecken 4, 197, 309 A * 4/1980 Thuillier .............. C07D 333/22
514 /438
(DE ) 5 ,817 ,691 A 10 / 1998 Barnes et al.
8 ,609,622 B2 * 12/ 2013 Yang .. C07H 7 /04
(72 ) Inventors: Rolf Hartmann , Saarbruecken (DE ); 514 / 23
Martin Frotscher , Sulzbach (DE ); 9 ,434 ,670 B2 * 9 /2016 Deliencourt
Ahmed Saad Abdelsamie Ahmed , Godefroy .............. C07C 43 / 225
Bahteem (EG ); Emmanuel Bey , 2005 /0038053 A1 2 /2005 Hirvelae et al.
Colmar (FR ); Chris J . van Koppen , 2005/0228038 A 10 / 2005 Vander Jagt et al.
Kleve (DE ); Sandrine FOREIGN PATENT DOCUMENTS
Oberwinkler-Marchais, Marburg (DE );
Carsten Börger, Saarbruecken (DE ); DE 102007040243 Al 2 /2009
Lorenz Siebenbürger, Saarbruecken EP 0801058 AL 10 / 1997
(DE ); Victor Hernández Olmos, WO 2004110459 Al 12 /2004
Saarbruecken (DE ) WO
WO
2005037845 Al 4 /2005
2005123671 A1 12 /2005
(73 ) Assignee : ElexoPharm GmbH , Saarbruecken wo 2006063615 A1 6 /2006
WO 2008116920 A2 10 / 2008
(DE) WO 2009002746 Al 12 /2008
WO 2011079772 Al 7 /2011
( * ) Notice : Subject to any disclaimer, the term of this Wo 2012025638 A1 3 /2012
patent is extended or adjusted under 35 WO WO 2012025638 A1 * 3 /2012 .. ... ... CO7D 277/ 24
U .S .C . 154 (b ) by 0 days. WO 2012117097 AL 9 /2012

(21) Appl. No.: 15 /109 ,271 OTHER PUBLICATIONS


(22) PCT Filed: Jan . 5 , 2015 Allan et al., “Novel inhibitors of 17B -hydroxysteroid
dehydrogenase type 1: Templates fordesign ” , Bioorg.Med . Chem .,
PCT/EP2015 /050062 2008 , vol. 16 , pp . 4438 -4456 .
(86 ) PCT No.: Bagi et al., “ Effect of 17B -hydroxysteroid dehydrogenase type 2
$ 371 (c )(1), inhibitor on bone strength in ovariectomized cynomolgus mon
( 2 ) Date: Jun . 30 , 2016 keys” , J. Musculoskelet. Neuronal Interact., 2008 , vol. 8 :3 , pp .
267-280 .
(87 ) PCT Pub . No.: WO2015 /101670 Berube et al., “ Preparation of 16B - Estradiol Derivative Libraries as
Bisubstrate Inhibitors of 17ß -Hydroxysteroid Dehydrogenase Type
PCT Pub. Date: Jul. 9 , 2015 1 Using the Multidetachable Sulfamate Linker” , Molecules, 2010 ,
vol. 15, pp. 1590 -1631.
(65 ) Prior Publication Data Bey et al., “ New Insights into the SAR and Binding Modes of
Bis(hydroxyphenyl)thiophenes and -benzenes: Influence of Addi
US 2016 /0318895 A1 Nov. 3 , 2016 tional Substituents on 17ß -Hydroxysteroid Dehydrogenase Type 1
( 17B -HSD1) Inhibitory Activity and Selectivity ” , J. Med . Chem .,
( 30 ) Foreign Application Priority Data 2009, vol. 52 , pp . 6724 -6743 .
Bulun et al., “ Role of aromatase in endometrial disease ” , J. Steroid
Jan . 3, 2014 ( EP ) ... . . . . . . . .. 14150140 Biochem . Mol. Biol., 2001, vol. 79 , pp . 19 -25 .
( Continued )
(51) Int. Ci.
CO7D 333/22 ( 2006 .01) Primary Examiner — Yevegeny Valenrod
C07D 333 /28 ( 2006 .01)
C07D 409/04 ( 2006 .01 ) (74 ) Attorney, Agent, or Firm — The Webb Law Firm
C07D 409/ 10 ( 2006 .01)
C07D 409/ 12 ( 2006 .01)
(52 ) U .S . CI. (57) ABSTRACT
CPC ......... C070 333/ 22 ( 2013.01); C070 333/ 28 Provided herein are non -steroidal 17beta -hydroxysteroid
( 2013 .01 ); C07D 409 /04 (2013 .01) ; C07D dehydrogenase type 1 and type 2 (17B -HSD1 and 17B
409 / 10 (2013. 01 ); C07D 409/ 12 ( 2013 .01) HSD2) inhibitors, their production and use, especially for
(58 ) Field of Classification Search the treatment and for prophylaxis of hormone- related dis
CPC .. CO7D 333 /22 ; CO7D 333 /28 ; CO7D 409/04 ; eases .
C07D 409 / 10 ; C07D 409 / 12
USPC ............... 514 /231. 5
See application file for complete search history. 14 Claims, No Drawings
US 9 ,884 ,839 B2
Page 2

(56) References Cited Oster et al., “ Novel estrone mimetics with high 17B -HSD1 inhibi
tory activity ” , Bioorg. Med . Chem ., 2010 , vol. 18 , pp . 3494 -3505 .
Pasqualini, “ The selective estrogen enzyme modulators in breast
OTHER PUBLICATIONS cancer: a review ” , Biochim . Biophys. Acta , 2004 , vol. 1654 , pp .
123 - 143.
Bydal et al., “ Steroidal lactones as inhibitors of 17B -hydroxysteroid Perspicace et al., “ Novel N -methylsulfonamide and retro - N
dehydrogenase type 5 : Chemical synthesis, enzyme inhibitory activ methylsulfonamide derivatives as 17B -hydroxysteroid
dehydrogenase type 2 ( 17B -HSD2 ) inhibitors with good ADME
ity, and assessmentof estrogenic and androgenic activities” , Eur. J. related physicochemical parameters" , Eur. J. Med . Chem ., 2013 ,
Med . Chem ., 2009, vol. 44 , pp . 632 -644 . vol. 69, pp . 201 -215 .
Cook et al., “ 4 ,5 -Disubstituted cis-pyrrolidinones as inhibitors of Perspicace et al., “ Synthesis and Biological Evaluation of
17B -hydroxysteroid dehydrogenase II . Part 1: Synthetic approach ” , Thieno [ 3, 2 -d ]-pyrimidinones, Thieno [3 ,2 - d ]pyrimidines and
Tetrahedron Letters, 2005, vol. 46 , pp . 1525 - 1528 . Quinazolinones: Conformationally Restricted 17B -Hydroxysteroid
Elo et al., " Characterization of 17ß -Hydroxysteroid Dehydrogenase Dehydrogenase Type 2 ( 17B -HSD2) Inhibitors" , Molecules, 2013 ,
Isoenzyme Expression in Benign and Malignant Human Prostate ” , vol. 18 , pp . 4487 -4509.
Int. J. Cancer, 1996 , vol. 66 , pp . 37-41.
Poirier et al., “ Inhibitors of type II 17B -hydroxysteroid
dehydrogenase” , Mol. Cell, Endocrinol., 2001 , vol. 171 , pp . 119
Fink et al., “ Association of Testosterone and Estradiol Deficiency 128.
with Osteoporosis and Rapid Bone Loss in Older Men ” , J. Clin . Saloniemi et al., “ Novel Hydroxysteroid ( 173 ) Dehydrogenase 1
Endocrinol.Metab ., 2006 , vol. 91: 10 , pp. 3908- 3915 . Inhibitors Reverse Estrogen -Induced Endometrial Hyperplasia in
Geisler et al., “ Aromatase inhibitors as adjuvant treatment of breast Transgenic Mice ” , Am . J. Pathol., 2010 , vol. 176 :3 , pp . 1443 -1451 .
cancer” , Crit . Rev . Oncol. Hematol., 2006 , vol. 57, pp. 53 -61. Sam et al., “ Steroidal Spiro -y -lactones That Inhibit 17B
Gunn et al., “ 4 ,5 - Disubstituted cis -pyrrolidinones as inhibitors of Hydroxysteroid Dehydrogenase Activity in Human Placental
type II 17B - hydroxysteroid dehydrogenase. Part 2 . SAR ” , Bioorg . Microsomes" , J. Med . Chem ., 1995 , vol. 38 , pp . 4518 -4528 .
Med . Chem . Lett., 2005, vol. 15 , pp . 3053- 3057 . Santner et al., “ In Situ Estrogen Production via the Estrone Sulfatase
Haller et al., “Molecular Framework of Steroid /Retinoid Discrimi Pathway in Breast Tumors : Relative Importance versus the
nation in 17B -Hydroxysteroid Dehydrogenase Type 1 and Photore Aromatase Pathway ” , J. Clin . Endocrinol. Metab ., 1984 , vol. 59 : 1,
ceptor -associated Retinol Dehydrogenase ” , J.Mol . Biol., 2010 , vol. pp . 29 - 33 .
399 , pp . 255 - 267. Schuster et al., “ Discovery of Nonsteroidal 17B -Hydroxysteroid
Hanson et al., “ Sulfatases: Structure ,Mechanism , Biological Activ Dehydrogenase 1 Inhibitors by Pharmacophore -Based Screening of
ity, Inhibition , and Synthetic Utility” , Angew . Chem . Int. Ed ., 2004, Virtual Compound Libraries ”, J. Med . Chem ., 2008 , vol. 51, pp .
vol. 43, pp . 5736 -5763. 4188 -4199 .
Hughes et al., “ 1 , 25- Dihydroxyvitamin D3 Regulates Estrogen Starcevic et al., “ Synthesis and Biological Evaluation of (6 - and
Metabolism in Cultured Keratinocytes ” , Endocrinology , 1997 , vol. 7 - Phenyl) Coumarin Derivatives as Selective Nonsteroidal Inhibi
138 :9 , pp . 3711-3718 . tors of 17ß -Hydroxysteroid Dehydrogenase Type 1” , J. Med .
Labrie, “ At the Cutting Edge Intracrinology " , Mol. Cell. Chem ., 2011, vol. 54 , pp . 248 - 261.
Endocrinol., 1991, vol. 78 , pp . C113 -C118 . Takayama et al., “ Pyrrole derivatives as potent inhibitors of lym
Lawrence et al., “ Novel and Potent 17ß -Hydroxysteroid phocyte -specific kinase: Struture, synthesis , and SAR ” , Bioorg .
Dehydrogenase Type 1 Inhibitors ” , J. Med . Chem ., 2005, vol. 48 , Med . Chem . Lett., 2010 , vol. 20 , pp . 108 -111 .
pp . 2759- 2762. Thakar et al., “ Synthesis and Antifungal Activity of 3 - Furyl and
Lilienkampf et al., “ Synthesis and Biological Evaluation of 17B 3 - Thienyl-substituted -1 ,2 -benzisoxazoles” , J. Indian Chem . Soc.,
Hydroxysteroid Dehydrogenase Type 1 ( 17B -HSD1) Inhibitors 1984 , vol. LXI, pp . 715 -716 .
Based on a Thieno [ 2 , 3 -d ]pyrimidin -4 ( 3H ) - one Core ” , J. Med . Vihko et al., " Structure and function of 17B -hydroxysteroid
Chem ., 2009, vol. 52 , pp . 6660 -6671. dehydrogenase type 1 and type 2 " , Mol. Cell . Endocrinol., 2001,
Marhais -Oberwinkler et al., “ Structural Optimization of 2,5 vol. 171, pp . 71 - 76 .
Thiophene Amides as Highly Potent and Selective 17B Wetzel et al., “ Introduction of an Electron Withdrawing Group on
Hydroxysteroid Dehydrogenase Type 2 Inhibitors for the Treatment the Hydroxyphenylnaphthol Scaffold Improves the Potency of 17B
of Osteoporosis ", J. Med . Chem ., 2013 , vol. 56 , pp . 167- 181. Hydroxysteroid Dehydrogenase Type 2 ( 17B -HSD2 ) Inhibitors ” , J.
Marchais -Oberwinkler et al., “ Substituted 6 - Phenyl - 2 -naphthols . Med . Chem ., 2011, vol. 54 , pp . 7547 - 7557 .
Potent and Selective Nonsteroidal Inhibitors of 17ß -Hydroxysteroid Wetzel et al., “ 17B -HSD2 inhibitors for the treatment of osteopo
Dehydrogenase Type 1 ( 17B -HSD1): Design , Synthesis, Biological rosis: Identification of a promising scaffold ” , Bioorg. Med . Chem .,
Evaluation , and Pharmacokinetics” , J. Med . Chem ., 2008, vol. 51, 2011 , vol. 19 , pp. 807 - 815 .
pp. 4685 -4698. Wood et al., “ 4, 5 -Disubstituted cis-pyrrolidinones as inhibitors of
Messinger et al., “New inhibitors of 17B -hydroxysteroid type II 17B -hydroxysteroid dehydrogenase . Part 3 . Identification of
dehydrogenase type 1” , Mol. Cell. Endocrinol., 2006 , vol. 248, pp . lead candidate ” , Bioorg . Med . Chem . Lett ., 2006 , vol. 16 , pp .
192 -198. 4965 -4968 .
Miyoshi et al., “ Involvement of Up-Regulation of 17B Xie et al., “ Identification of small -molecule inhibitors of the
Hydroxysteroid Dehydrogenase Type 1 in Maintenance of AB -ABAD interaction ” , Bioorg. Med . Chem . Lett ., 2006 , vol. 16 ,
Intratumoral High Estradiol Levels in Postmenopausal Breast Can pp. 4657 -4660 .
cers ”, Int. J. Cancer, 2001, vol. 94 , pp . 685-689. Xu et al., “ Triazole ring - opening leads to the discovery of potent
Oster et al., “ Bicyclic Substituted Hydroxyphenylmethanones as nonsteroidal 17B -hydroxysteroid dehydrogenase type 2 inhibitors” ,
Novel Inhibitors of 17ß -Hydroxysteroid Dehydrogenase Type 1 Eur. J. Med . Chem ., 2011, vol. 46 , pp . 5978 -5990 .
( 17B -HSD1) for the Treatment of Estrogen -Dependent Diseases” , J .
Med . Chem ., 2010 , vol. 53 , pp . 8176 -8186 . * cited by examiner
US 9 ,884 ,839 B2
INHIBITORS OF hyperplasia (Bulun , S . E . et al ., J. Steroid Biochem . Mol.
17BETA -HYDROXYSTEROID Biol., 79: 19 - 25 (2001 ); Miyoshi, Y . et al., Int. J. Cancer, 94 :
DEHYDROGENASES TYPE 1 AND TYPE 2 685 -689 (2001); Gunnarsson , C . et al., Cancer Res., 61:
8448 - 8451 ( 2001); Kitawaki, J., Journal of Steroid Bio
CROSS -REFERENCE TO RELATED 5 chemistry & Molecular Biology , 83 : 149- 155 (2003 ); Vihko ,
APPLICATIONS P . et al., J. Steroid . Biochem .Mol. Biol., 83: 119 - 122 (2002 );
Vihko, P. et al., Mol. Cell. Endocrinol., 215 : 83- 88 ( 2004 );
This application is the United States national phase of Saloniemi T. et al., Am . J. Pathol. 176 : 1443 -1451 (2010 )),
International Application No. PCT/EP2015 /050062 filed ovarian cancer, prostate cancer (Elo et al J. Cancer 66 : 37
Jan . 5 , 2015 , and claims priority to European Patent Appli - 10 (1996 )), acne (Odlind et al., Clin . Endocrinol. 16 : 243-249
cation No. 14150140 .3 filed Jan . 3 , 2014 , the disclosures of ( 1982)), androgen -dependent hair loss and psoriasis
which are hereby incorporated in their entirety by reference . (Hughes et al. Endocrinology 138 : 3711 ( 1997 ) ) .
The invention relates to non - steroidal 17beta - hydroxys - The most potent estrogen is E2 , which is formed in
teroid dehydrogenase type 1 and type 2 ( 17B -HSD1 and premenopausal females ,mainly in the ovaries. On an endo
17ß -HSD2) inhibitors , their production and use , especially 15 crine route , it arrives at the target tissues , where it displays
for the treatment and for prophylaxis of hormone -related its action by means of an interaction with the estrogen
diseases. receptor (ER ) a . After the menopause , the plasma E2 level
decreases to 1/ 10 of the E2 level found in premenopausal
BACKGROUND OF THE INVENTION females ( Santner, S . J. et al., J. Clin . Endocrinol. Metab ., 59 :
20 29 - 33 ( 1984 )). E2 is mainly produced in the peripheral
General Aspects and Inhibition of 17B -HSD1: Steroid tissue , e .g., breast tissue , endometrium , adipose tissue and
hormones are important chemical carriers of information skin , from inactive precursors, such as estrone sulfate -EI- S ),
serving for the longterm and global control of cellular dehydroepiandrosterone (DHEA ) and DHEA - S . These reac
functions . They control the growth and the differentiation tions occur with the participation of various steroidogenic
and function of many organs. On the other hand , they may 25 enzymes (hydroxysteroid dehydrogenases, aromatase ),
also have negative effects and favor the pathogenesis and which are in part more abundantly produced in the periph
proliferation of diseases in the organism , such as mammary eral tissue, where these active estrogens display their action .
and prostate cancers (Deroo , B J . et al., J. Clin . Invest., 116 : As a consequence of such intracrine mechanism for the
561- 570 (2006 ); Fernandez , S . V . et al., Int. J. Cancer, 118 : formation of E2-, its concentration in the peripheral tissue ,
1862- 1868 (2006 )). 30 especially in estrogen -related diseases, is higher than that in
The biosynthesis of steroids takes place in the testes or the healthy tissue. Above all, the growth of many breast
ovaries, where sex hormones are produced . In addition , the cancer cell lines is stimulated by a locally increased E2
production of glucocorticoids and mineral corticoids takes concentration . Further, the occurrence and progress of dis
place in the adrenal glands. Moreover, individual synthetic eases such as endometriosis, leiomyosis, adenomyosis,men
steps also occur outside the glands, namely in the brain or in 35 orrhagia , metrorrhagia and dysmenorrhea is dependent on a
the peripheral tissue , e . g ., adipose tissue (Bulun , S . E . et al., significantly increased -E2 level in accordingly diseased
J. Steroid Biochem .Mol. Biol., 79: 19 - 25 (2001); Gangloff , tissue .
A . et al., Biochem . J., 356 : 269-276 (2001)). In this context, Endometriosis is an estrogen -related disease affecting
Labrie coined the term “ intracrinology ” in 1988 (Labrie , C . about 5 to 10 % of all females of childbearing age (Kitawaki,
et al., Endocrinology , 123: 1412 - 1417 ( 1988 ); Labrie , F. et 40 J., Journal of Steroid Biochemistry & Molecular Biology ,
al., Ann . Endocrinol. (Paris ), 56 : 23 - 29 ( 1995 ); Labrie, F . et 83 : 149 - 155 (2003 )). From 35 to 50 % of the females
al., Horm . Res., 54 : 218 -229 ( 2000)). Attention was thus suffering from abdominal pain and /or sterility show signs of
focused on the synthesis of steroids that are formed locally endometriosis (Urdl, W ., J. Reproduktionsmed . Endokrinol.,
in peripheral tissues and also display their action there 3 : 24 - 30 ( 2006 )). This disease is defined as a histologically
without getting into the blood circulation . The intensity of 45 detected ectopic endometrial glandular and stromal tissue . In
the activity of the hormones is modulated in the target tissue correspondingly severe cases , this chronic disease , which
by means of various enzymes. tends to relapse , leads to pain of different intensities and
Thus, it could be shown that the 17B -hydroxysteroid variable character and possibly to sterility . Three macro
dehydrogenase type 1 ( 17B -HSD1) , which catalyzes the scopic clinical pictures are distinguished : peritoneal endo
conversion of estrone (E1 to estradiol (E2 ), is more abun - 50 metriosis , retroperitoneal deep - infiltrating endometriosis
dant in endometriotic tissue and breast cancer cells while including adenomyosis uteri, and cystic ovarial endometrio
there is a deficiency in 17B -HSD type 2 , which catalyzes the sis. There are various explanatory theories for the pathogen
reverse reaction (Bulun , S . E . et al., J. Steroid Biochem . esis of endometriosis , e . g ., the metaplasia theory , the trans
Mol. Biol., 79 : 19 - 25 (2001); Miyoshi, Y . et al., Int. J. plantation theory and the theory of autotraumatization of the
Cancer, 94 : 685 -689 (2001 )). 55 uterus as established by Leyendecker (Leyendecker, G . et
A major class of steroid hormones is formed by the al., Hum . Reprod., 17 : 2725 - 2736 (2002)).
estrogens, the female sex hormones, whose biosynthesis According to the metaplasia theory (Meyer , R ., Zentralbl.
takes place mainly in the ovaries and reaches its maximum Gynakol., 43 : 745 -750 ( 1919 ); Nap , A . W . et al., Best Pract.
immediately before ovulation . However, estrogens also Res. Clin . Obstet Gynaecol., 18 : 233 -244 ( 2004 )), pluripo
occur in the adipose tissue , muscles and some tumors. Their 60 tent coelomic epithelium is supposed to have the ability to
main functions include a genital activity, i.e., the develop - differentiate and form endometriotic foci even in adults
ment and maintenance of the female sexual characteristics as under certain conditions. This theory is supported by the
well as an extragenital lipid -anabolic activity leading to the observation that endometrioses , in part severe ones, can
development of subcutaneous adipose tissue. In addition , occur in females with lacking uterus and gynastresy . Even in
they are involved in the pathogenesis and proliferation of 65 males who were treated with high estrogen doses due to a
estrogen -related diseases , such as endometriosis , endome- prostate carcinoma, an endometriosis could be detected in
trial carcinoma, adenomyosis, breast cancer and endometrial singular cases .
US 9 ,884 ,839 B2
According to the theory postulated by Sampson (Halme, the use of the non - steroidal aromatase inhibitor letrozole
J. et al., Obstet Gynecol., 64: 151 - 154 ( 1984 ); Sampson, J., leads to a significant reduction of the frequency and severity
Boston Med . Surg . J., 186 : 445 -473 (1922 ); Sampson , J., of dysmenorrheal and dyspareunia and to a reduction of the
Am . J. Obstet. Gynecol., 14 : 422 - 469 ( 1927 )), retrograde endometriosis marker CA125 level ( Soysal, S . et al., Hum .
menstruation results in the discharge ofnormal endometrial 5 Reprod ., 19 : 160 - 167 (2004 )). The side effect profile of
cells or fragments of the eutopic endometrium into the aromatase inhibitors ranges from hot flushes , nausea , fatigue
abdominal cavity with potential implantation of such cells in to osteoporosis and cardiac diseases . Long term effects
the peritoneal space and further development to form endo - cannot be excluded . All the possible therapies mentioned
metriotic foci. Retrograde menstruation could be detected as herein are also employed in the combatting of diseases such
a physiological event . However, not all females with retro - 10 as leiomyosis , adenomyosis ,menorrhagia ,metrorrhagia and
grade menstruation become ill with endometriosis , but vari dysmenorrhea .
ous factors, such as cytokines, enzymes, growth factors Every fourth cancer disease in the female population falls
( e. g ., matrix metalloproteinases ), play a critical role . under the category of mammary cancers . This disease is the
The enhanced autonomous non - cyclical estrogen produc - main cause of death in the western female population at the
tion and activity as well as the reduced estrogen inactivation 15 age of from 35 to 54 years (Nicholls, P. J., Pharm . J., 259 :
are typical peculiarities of endometriotic tissue. This 459 - 470 ( 1997 ) ). Many of these tumors exhibit an estrogen
enhanced local estrogen production and activity is caused by dependent growth and are referred to as so -called HDSC
a significant overexpression of aromatase , expression of (hormone dependent breast cancer ). A distinction is made
17B -HSD1 and reduced inactivation of potent E2 due to a between ER + and ER - tumors. The classification criteria are
lack of 17B -HSD2, as compared to the normal endometrium 20 important to the choice of a suitable therapy . About 50 % of
(Bulun , S . E . et al., J. Steroid Biochem . Mol. Biol., 79 : 19 - 25 the breast cancer cases in premenopausal females and 75 %
( 2001) ; Kitawaki, J., Journal of Steroid Biochemistry & of the breast cancer cases in postmenopausal females are
Molecular Biology, 83 : 149 - 155 ( 2003 ); Karaer, O . et al., ER + (Coulson , C ., Steroid biosynthesis and action , 2nd
Acta . Obstet . Gynecol. Scand ., 83 : 699 - 706 ( 2004 ) ; Zeitoun , edition , 95 - 122 ( 1994 ); Lower , E . et al., Breast Cancer Res.
K . et al., J. Clin . Endocrinol. Metab ., 83 : 4474 - 4480 ( 1998 )). 25 Treat., 58 : 205 -211 (1999 ) ), i. e ., the growth of the tumor is
The polymorphic symptoms caused by endometriosis promoted by as low as physiological concentrations of
include any pain symptoms in the minor pelvis , back pain , est
estrogens
in the diseased tissue .
dyspareunia , dysuria and defecation complaints . The therapy of choice at an early stage of breast cancer is
One of the therapeutic measures employed most fre - surgical measures , if possible , breast-preserving surgery .
quently in endometriosis is the surgical removal of the 30 Only in a minor number of cases, mastectomy is performed .
endometriotic foci (Urdl, W ., J. Reproduktionsmed . In order to avoid relapses , the surgery is followed by
Endokrinol., 3 : 24 - 30 (2006 )). Despite new therapeutic radiotherapy , or else radiotherapy is performed first in order
concepts, medicamental treatment remains in need of to reduce a larger tumor to an operable size . In an advanced
improvement. The purely symptomatic treatment of dys state , or when metastases occur in the lymph nodes, skin or
menorrhea is effected by means of non - steroidal anti -inflam - 35 brain , the objective is no longer to heal the disease , but to
matory drugs (NSAID ), such as acetylsalicylic acid , indo - achieve a palliative control thereof.
methacine, ibuprofen and diclofenac. Since a COX2 The therapy of the mammary carcinoma is dependent on
overexpression could be observed both in malignant tumors the hormone receptor status of the tumor, on the patient' s
and in the eutopic endometrium of females with endometrio hormone status and on the status of the tumor (Paepke , S . et
sis , a therapy with the selective COX2 inhibitors, such as 40 al., Onkologie , 26 Suppl., 7 : 4 - 10 (2003 )). Various thera
celecoxib , suggests itself (Fagotti , A . et al., Hum . Reprod . peutical approaches are available , but all are based on
19 : 393 -397 (2004 ); Hayes, E . C . et al., Obstet. Gynecol. hormone deprivation (deprivation of growth -promoting
Surv., 57 : 768 -780 (2002)). Although they have a better endogenous hormones) or hormone interference (supply of
gastro - intestinal side effect profile as compared to the exogenous hormones ). However, a precondition of such
NSAID , the risk of cardiovascular diseases, infarction and 45 responsiveness is the endocrine sensitivity of the tumors ,
stroke is increases , especially for patients with a predamaged which exists with HDSC ER + tumors . The drugs employed
cardiovascular system (Dogne , J . M . et al., Curr. Pharm . in endocrine therapy include GnRH analogues, anti- estro
Des., 12 : 971 - 975 (2006 )). The causalmedicamental theory gens and aromatase inhibitors . GnRH analogues, such as
is based on estrogen deprivation with related variable side gosereline, will bind to specific membrane receptors in the
effects and a generally contraceptive character. The gesta - 50 target organ , the pituitary gland , which results in an
gens with their anti- estrogenic and antiproliferative effect on increased secretion of FSH and LH . These two hormones in
the endometrium have great therapeutic significance . The turn lead to a reduction of GnRH receptors in a negative
most frequently employed substances include medroxypro - feedback loop in the pituitary cells. The resulting desensi
gesterone acetate , norethisterone , cyproterone acetate . The tization of the pituitary cells towards GnRH leads to an
use of danazole is declining due to its androgenie side effect 55 inhibition of FSH and LH secretion , so that the steroid
profile with potential gain of weight,hirsutism and acne . The hormone feedback loop is interrupted . The side effects of
treatment with GnRH analogues is of key importance in the such therapeutic agents include hot flushes, sweats and
treatment of endometriosis (Rice , V.; Ann . NY Acad . Sei., osteoporosis.
955: 343 - 359 ( 2001 )); however, the duration of the therapy Another therapeutic option is the use of anti- estrogens ,
should not exceed a period of 6 months since a longer term 60 antagonists at the estrogen receptor. Their activity is based
application is associated with irreversible damage and an on the ability to competitively bind to the ER and thus avoid
increased risk of fracture . The side effect profile of the the specific binding of the endogenous estrogen . Thus, the
GnRH analogues includes hot flushes, amenorrhea , loss of natural hormone is no longer able to promote tumor growth .
libido and osteoporosis , the latter mainly within the scope of Today , therapeutic use involves so - called SERM ( selective
a long term treatment. 65 estrogen receptor modulators), which develop estrogen ago
Another therapeutic approach involves the steroidal and nism in tissues such as bones or liver, but have antagonistic
non - steroidal aromatase inhibitors. It could be shown that andjor minimal agonistic effects in breast tissue or uterus
US 9 ,884 ,839 B2
(Holzgrabe , U ., Pharm . Unserer Zeit , 33 : 357 - 359 (2004 ); pathway for the production of E1/E2 by means of the
Pasqualini, J. R ., Biochim . Biophys. Acta ., 1654 : 123 - 143 enzyme steroid sulfatase , an enzyme that catalyzes the
( 2004 ); Sexton , M . J. et al., Prim Care Update Ob Gyns, 8 : conversion of El sulfate and DHEA - S to estrone and
25 - 30 ( 2001 )). Thus, these compounds are not only effective DHEA . In this way, 10 times as much E1 is formed in the
in combatting breast cancer, but also increase the bone 5 target tissue as compared to the aromatase pathway (Santner,
density and reduce the risk of osteoporosis in postmeno - S . J. et al., J. Clin . Endocrinol. Metab ., 59: 29- 33 ( 1984 ) ). E1
pausal females . The use of the SERM tamoxifen is most is then reduced by means of the enzyme 17ß -HSD1 to form
widely spread . However, after about 12 - 18 months of treat- E2 , the most potent estrogen . Steroid sulfatase and 17ß
ment, there is developmentof resistance , an increased risk of HSD1 are new targets in the battle against estrogen -related
endometrial cancers and thrombo - embolic diseases due to 10 diseases, especially for the development of therapeutic
the partial agonistic activity at the ER (Goss , P . E . et al., agents for mammary carcinomas ( Pasqualini, J. R ., Biochim .
Clin . Cancer Res., 10 : 5717 -5723 (2004 ); Nunez , N . P . et al., Biophys . Acta ., 1654: 123 - 143 (2004 ) ) .
Clin . Cancer Res., 10 : 5375 -5380 (2004 )). Numerous steroidal sulfatase inhibitors could be found ,
The enzymatically catalyzed estrogen biosynthesis may including the potent irreversible inhibitor EMATE , which
also be influenced by selective enzyme inhibitors. The 15 exhibited an agonistic activity at the estrogen receptor,
enzyme aromatase , which converts C19 steroids to C18 however (Ciobanu , L . C . et al., Cancer Res., 63: 6442 -6446
steroids, was one of the first targets for lowering the E2 (2003) ; Hanson , S . R . et al., Angew . Chem . Int. Ed . Engl.,
level. This enzyme complex , which belongs to the 43 : 5736 -5763 (2004 )). Some potent non -steroidal sulfatase
cytochrome P -450 enzymes , catalyzes the aromaticzation of inhibitors could also be found, such as COUMATE and
the androgenic A ring to form estrogens. The methyl group 20 derivatives as weil as numerous sulfamate derivatives of
at position 10 of the steroid is thereby cleaved off. The first tetrahydronaphthalene, indanone and tetralone (Hanson , S .
aromatase inhibitor employed for the therapy of breast R . et al., Angew . Chem . Int. Ed. Engl., 43: 5736 -5763
cancer was aminoglutethimide. However , aminoglutethim ( 2004)). Recently , one sulfatase inhibitor has completed a
ide affects several enzymes of the cytochrome P -450 super - phase I clinical trial in postmenopausal women with breast
family and thus inhibits a number of other biochemical 25 cancer (Foster, P . A . et al., Anticancer Agents Med Chem .
conversions. For example, among others, the compound 8 (7 ): 732 -8 ( 2008).
interferes with the steroid production of the adrenal glands The inhibition of 17B -HSD1, a key enzyme in the bio
so heavily that a substitution of both glucocorticoids and synthesis of E2 , the most potent estrogen , could suggest
mineralocorticoids may be necessary. In themeantime,more itself as an option in the therapy of estrogen - related diseases
potent and more selective aromatase inhibitors , which can 30 in both premenopausal and postmenopausal females (Kit
be subdivided into steroidal and non-steroidal compounds, awaki, J., Journal of Steroid Biochemistry & Molecular
are on the market. The steroidal inhibitors include, for Biology , 83 : 149 - 155 ( 2003 ); Allan , G . M . et al., Mol. Cell
example , exemestane, which has a positive effect on the Endocrinol., 248 : 204 - 207 ( 2006 ); Penning, T . M ., Endocr.
bone density, which is associated with its affinity for the Rev ., 18 : 281- 305 ( 1997 ); Sawicki, M . W . et al., Proc . Natl .
androgen receptor (Goss , P . E . et al., Clin . Cancer Res., 10 : 35 Acad . Sci. USA , 96 : 840 -845 (1999 ); Vihko , P . et al., Mol.
5717 -5723 ( 2004 ) ). However, this type of compounds is an Cell. Endocrinol., 171 : 71 - 76 (2001)). An advantage of this
irreversible inhibitor that also has a substantial number of approach is the fact that the intervention is effected in the
side effects, such as hot flushes, nausea , fatigue. However, last step of estrogen biosynthesis , i.e ., the conversion of E1
there are also non steroidal compounds that are employed to the highly potent E2 is inhibited . The intervention is
therapeutically, for example , letrozole. The advantage of 40 effected in the biosynthetic step occurring in the peripheral
these compounds resides in the lesser side effects , they do tissue, so that a reduction of E2 production takes place
not cause uterine hypertrophy , but have no positive effect on locally in the diseased tissue . The use of correspondingly
the bone density and result in an increase of LDL (low selective inhibitors would probably be associated with little
density lipoprotein ), cholesterol and triglyceride levels side effects since the synthesis of other steroids would
(Goss, P. E . et al., Clin . Cancer Res ., 10 : 5717 - 5723 ( 2004 ); 45 remain unaffected . To achieve a selective effect, it would be
Nunez , N . P . et al., Clin . Cancer Res ., 10 : 5375 -5380 important that such inhibitors exhibit no or only very little
( 2004 )) . Today, aromatase inhibitors are predominantly agonistic activity at the ER , especially at the ER a , since
employed as second - line therapeutic agents . In the mean - agonistic binding is accompanied by an activation and thus
time, however, the equivalence or even superiority of aro - proliferation and differentiation of the target cell. In contrast,
matase inhibitors to SERM , such as tamoxifene , has been 50 an antagonistic activity of such compounds at the ER would
proven in clinical studies (Geisler, J. et al., Crit . Rev . Oncol. be tolerated since the inhibitor would prevent the natural
Hematol., 57: 53 -61 ( 2006 ); Howell, A . et al., Lancet, 365 : substrates from binding at the receptor which in turn will
60 -62 (2005 )). Thus , the use of aromatase inhibitors also as result in a further reduction of the proliferation of the target
first- line therapeutical agents is substantiated . cells . The use of selective 17B -HSD1 inhibitors for the
However, the estrogen biosynthesis in the peripheral 55 therapy of numerous estrogen -dependent diseases is dis
tissue also includes other pathways for the production of E1 c ussed , for example , for breast cancer, tumors of the ovaries ,
and the more potent E2 by avoiding the enzyme aromatase prostate carcinoma, endometrial carcinoma, endometriosis ,
that is locally present in the target tissue , for example , breast adenomyosis , endometrial hyperplasia , acne, psoriasis , and
tumors . Two pathways for the production of estrogens in androgen - dependent hair loss . Highly interesting and com
breast cancer tissue are postulated ( Pasqualini, J. R ., Bio - 60 pletely novel is the proposal to employ selective inhibitors
chim . Biophys . Acta ., 1654 : 123 - 143 ( 2004 ) ), the aromatase of 17B -HSD1 for prevention when there is a genetic dispo
pathway ( Abul-Hajj , Y J. et al., Steroids, 33: 205 - 222 s ition for breast cancer (Miettinen , M . et al., J. Mammary
( 1979); Lipton , A . et al., Cancer, 59 : 779- 782 (1987 )) and Gland . Biol. Neoplasia , 5 : 259-270 (2000 )).
the sulfatase pathway (Perei , E . et al. , J. Steroid . Biochem ., Hydroxysteroid dehydrogenases (HSD ) can be subdi
29 : 393 -399 (1988 )) . The aromatase pathway includes the 65 vided into different classes . The 11B -HSD modulate the
production of estrogens from androgens with participation activity of glucocorticoids, 3B -HSD catalyzes the reaction of
of the enzyme aromatase. The sulfatase pathway is the 5 -33 -hydroxysteroids (DHEA or 5 -androstene-3B , 17ß
US 9,884,839 B2
diol) to form A5 -3B -ketosteroids ( androstenedione or tes - chemistry, 34 6003-6013 ( 1995 )). Its designation as assigned
tosterone ). 17B -HSDs convert the less active 17 -ketosteroids by the enzyme commission is E .C .1 .1.1 .62 .
to the corresponding highly active 17 -hydroxy compounds Engel et al. (Langer, L . J. et al., J. Biol. Chem ., 233 :
(androstenedione to testosterone and E1 to E2 ) or conversely 583 - 588 ( 1958 )) were the first to describe this enzyme in the
( Payne, A . H . et al., Endocr. Rev ., 25: 947 - 970 ( 2004 ); 5 1950 ' s . In the 1990 ' s, first crystallization attempts were
Peltoketo , H . et al., J. Mol. Endocrinol., 23 : 1 - 11 ( 1999 );
made, so that a total of 20 crystallographic structures can be
Suzuki, T . et al., Endocr . Relat. Cancer, 12 : 701- 720 ( 2005 )).
recurred to today in the development of inhibitors (Negri, M .
Thus, the HSD play a critical role in both the activation and et al. PLoS ONE 5 (8 ): el2026 . doi: 10 .1371/journal
the inactivation of steroid hormones. Depending on the .pone .0012026 (2010 )). Available are X - ray structures of the
cell's need for steroid hormones, they alter the potency of 10 enzyme alone, but also of binary and ternary complexes of
the sex hormones (Penning, T . M ., Endocr. Rev., 18 : 281 the enzyme with its substrate and other ligands or substrate !
305 ( 1997 )), for example , Ei is converted to the highly
potent E2 by means of 17B -HSD1, while E2 is converted to ligand and cofactor.
the less potent El by means of 17B -HSD2; 17B -HSD2 as a cofactor.is 17B
17B -
HSD1 a soluble cytosolic enzyme. NADPH serves
-HSD1 is encoded by a 3 . 2 kb gene
inactivates E2 while 17B -HSD1 activates El. 15 consisting of 6 exons and 5 introns that is converted to a 2 .2
To date, fourteen different mammalian 17ß -HSDs have kb transcript (Luu - The. V . J. Steroid Biochem . Mol. Biol..
been identified (Haller, F . et al., J. Mol. Biol. doi: 76 : 143 - 151 ( 2001); Labrie , F . et al., J. Mol. Endocrinol., 25 :
10 . 1016jj .jmb .2010 .04 . 002 ( 2010 ); Zhongyi, S . et al ., Endo - 1 - 16 (2000 )). It is constituted by 327 amino acids . The
crinology 148 3827 - 3836 (2007 ); Miyoshi, T . et al., Int. J. molecular weight of the monomer is 34 .9 kDa (Penning , T .
Cancer 94 ( 2001) 685 -689), and twelve of these enzymes 20 M ., Endocr. Rev ., 18 : 281 -305 ( 1997 )) . 17B -HSD1 is
could be cloned (Suzuki, T . et al., Endocr. Relat. Cancer, 12 : expressed in the placenta , liver, ovaries, endometrium , pros
701 -720 ( 2005 ) ) . They all belong to the so - called short chain tate gland , peripheral tissue, such as adipose tissue and
dehydrogenasejreductase (SDR ) family, with the exception breast cancer cells (Penning, T . M ., Endocr. Rev ., 18 :
of 17B -HSD5, which is a ketoreductase . The amino acid 281 - 305 ( 1997 ) ). It was isolated for the first time from
identity between the different 17ß -HSDs is as low as 25 human placenta (Jarabak , J. et al., J. Biol. Chem ., 237 :
20 - 30 % (Luu - The, V ., J. Steroid Biochem . Mol. Biol., 76 : conversion( 1962
345 - 357 )). The main function of 17ß -HSD1 is the
of the less active E1 to the highly potent E2.
143- 151 ( 2001)) , and they are membrane- bound or soluble However, it also catalyzes to a lesser extent the reaction of
enzymes . The X -ray structure of 6 human subtypes is known dehydroepiandrosterone (DHEA ) to 5 - androstene-3B , 17ß
(Ghosh , D . et al., Structure , 3 : 503 -513 ( 1995 ) ; Kissinger, C . diol, an androgen showing estrogenic activity (Labrie, F .,
R . et al., J. Mol. Biol., 342: 943 - 952 ( 2004 ) ; Zhou , M . et al., 30 Mol. Cell. Endocrinol., 78 : CI13 - 118 ( 1991); Poirier, D .,
Acta Crystallogr. D . Biol. Crystallogr ., 58 : 1048 - 1050 Curr . Med . Chem ., 10 : 453 -477 (2003 ); Poulin , R . et al.,
( 2002) . The 17B -HSDs are NAD ( H ) -dependent and NADP Cancer Res., 46 : 4933 -4937 (1986 ) ). In vitro , the enzyme
( H )- dependent enzymes. They play a critical role in the catalyzes the reduction and oxidation between El and E2
hormonal regulation in humans. The enzymes are distin - while it catalyzes only the reduction under physiological
guished by their tissue distribution , catalytic preference 35 conditions . These bisubstrate reactions proceed according to
( oxidation or reduction ), substrate specificity and subcellular a random catalytic mechanism , i. e ., either the steroid or the
localization . The same HSD subtype was found in different cofactor is first to bind to the enzyme (Negri, et al. PLOS
tissues . It is likely that all 17ß -HSDs are expressed in the ONE 5 ( 8 ): e12026 . doi: 10 . 1371/ journal.pone.0012026
different estrogen -dependent tissues , but in different con (a2010 )). The enzyme consists of a substrate binding site and
channel that opens into the cofactor binding site . The
centrations. In diseased tissue, the ratio between the different 40 substrate binding site is a hydrophobie tunnel having a high
subtypes is altered as compared to healthy tissue, some complementarity to the steroid . The 3 -hydroxy and 17 -hy
subtypes being overexpressed while others may be absent. droxy groups in the steroid form four hydrogen bonds to the
This may cause an increase or decrease of the concentration amino acid residues His221, Glu282 , Ser142 and Tyr155 .
of the corresponding steroid . Thus , the 17B -HSDs play an The hydrophobie van der Waals interactions seem to form
extremely important role in the regulation of the activity of 45 the main interactions with the steroid while the hydrogen
the sex hormones. Further, they are involved in the devel - bonds are responsible for the specificity of the steroid for the
opmentof estrogen - sensitive diseases, such as breast cancer, enzyme (Labrie , F . et al., Steroids,62: 148 - 158 (1997 )). Like
ovarian , uterine and endometrial carcinomas, as weil as with all the other enzymes of this family, what is present as
androgenrelated diseases, such as prostate carcinoma. a cofactor binding site is the Rossmann fold , which is a
benign prostate hyperplasia , acne, hirsutism etc . It has been 50 region consisting of ex - helices and ß -sheets ( ß -c -ß - a -ß )) , a
shown that some 17B -HSDs are also involved in the devel generally occurring motif Gly -Xaa -Xaa - Xaa -Gly - Xaa -Gly,
opment of further diseases , e . g., pseudohermaphrodism and a nonsense region Tyr-Xaa-Xaa -Xaa -Lys within the
active site . What is important to the activity is a catalytic
( 17B -HSD3 (Geissler, W . M . et al., Nat. Genet., 7 : 34 - 39 tetrade consisting of Tyr155 -Lys159 -Ser142 -Asnl14 , which
( 1994 ))), bifunctional enzyme deficiency ( 17B -HSD4 (van stabilize the steroid and the ribose in the nicotinamide
Grunsven , E . G . et al., Proc . Natl. Acad. Sci. USA , 95 : 55 during the hydride transfer ( Alho -Richmond , S . et al., Mol.
2128 -2133 ( 1998 ))), polycystic kidney diseases ( 17B-HSD8 Cell Endocrinol., 248 : 208 -213 (2006 ); Labrie, F. et al.,
(Maxwell, M . M . et al., J. Biol. Chem ., 270 : 25213 - 25219 Steroids, 62: 148 - 158 ( 1997) ; Nahoum , V . et al ., Faseb . J.,
( 1995 ))) and Alzheimer's ( 17B -HSD10 (Kissinger, C . R . et 17 : 1334 - 1336 ( 2003 )).
al., J. Mol. Biol., 342: 943- 952 ( 2004 ) ; He, X . Y . et al., J. The gene encoding 17B -HSD1 is linked with the gene for
Biol. Chem ., 274 : 15014 - 15019 ( 1999 ); He, X . Y . et al., Mol . 60 mammary and ovarian carcinomas that is very susceptible to
Cell Endocrinol., 229 : 111 - 117 ( 2005 ) ; He, X . Y . et al., J. mutations and can be inherited , the BRCA1 gene, on chro
Steroid Biochem . Mol. Biol., 87 : 191 - 198 ( 2003 ); Yan , S . D . mosome 17911- 921 (Labrie , F . et al., J. Mol . Endocrinol.,
et al., Nature , 389 : 689 -695 ( 1997 ) )) . The best characterized 25 : 1 - 16 ( 2000 )) . As has been demonstrated , the activity of
member of the 17ß -HSDs is the type 1 17B -HSD . The 17B -HSD1 is higher in endometrial tissue and breast cancer
17B -HSD1 is an enzyme from the SDR family , also referred 65 cells as compared to healthy tissue, which entails high
to as human placenta E2 dehydrogenase (Gangloff , A . et al., intracellular E2 levels, which in turn cause proliferation and
Biochem . J., 356 269 - 276 ( 2001 ); Jomvall, H . et al., Bio differentiation of the diseased tissue (Bulun , S . E . et al., J .
US 9,884 ,839 B2 10

Steroid Biochem . Mol. Biol., 79 : 19 -25 (2001); Miyoshi, Y.


et al., Int. J. Cancer, 94: 685 -689 ( 2001); Kitawaki, J., ??

Journal of Steroid Biochemistry & Molecular Biology , 83 :


149 - 155 ( 2003) ; Pasqualini, J. R ., Biochim . Biophys . Acta .,
1654 : 123 - 143 (2004 ); Vihko , P. et al., Mol. Cell . Endocri- 5
nol., 171: 71-76 ( 2001); Miettinen , M . et al., Breast Cancer
Res. Treat., 57 : 175 -182 ( 1999 ); Sasano , H . et al., J. Clin .
Endocrinol. Metab ., 81: 4042 -4046 ( 1996 ); Yoshimura , N . et HO
al., Breast Cancer Res ., 6 : R46 - 55 ( 2004 ) ) . An inhibition of
17B -HSD1 could result in the E2 level being lowered and 10 S (CH2
5) 0
thus lead to a regression of the estrogen -related diseases.
Further, selective inhibitors of 17B -HSD1 could be used for
prevention when there is a genetic disposition for breast * Bu
cancer (Miettinen , M . et al., J. Mammary Gland. Biol. OH
Neoplasia, 5 : 259 -270 ( 2000 )). 15
Therefore , this enzyme would suggest itself as a target for
the development of novel selective and non-steroidal inhibi D . MIT (CH2)3 — Br
tors as therapeutic agents in the battle against estrogen
related diseases. Recently , in vivo efficacy of 17B -HSD1
inhibitors has been reported in two animal models. Immu- 20
??
nodeficient mice were inoculated either with MCF -7 cells
over -expressing human recombinant 17B -HSD1 enzyme
(Husen , B . et al., Mol. Cell . Endocrinol., 248 , 109 - 113
( 2006 ); Husen , B . et al., Endocrinology, 147 , 5333 - 5339
( 2006 ) ) or with T47D cells naturally expressing 17B -HSD1 25
(Day , J. M . et al.; Int. J. Cancer, 122, 1931- 1940 (2008 ). In
both models , the El induced tumor growth was reduced by
17B -HSD1 inhibitors, validating 17B -HSD1 as a novel target HO
for the treatment of estrogen dependent diseases . Up to date
however, no 17B -HSD1 inhibitor has entered clinical trials. 30
In the literature, only a few compounds have been Another class of compounds which has been described is
described as inhibitors of 17BHSD1 (D . Poirier, Anticancer the so - called hybrid inhibitors (Berube, M . et al., Can . J.
Agents Med . Chem . 9 642 -660 (2009 ) ; Day, J. M . et al., Chem . 87 1180 - 1199 ( 2009) ), compounds that, due to their
Minerva Endocrinol., 35 ( 2 ), 87 - 108 ( 2010 ); D . Poirier, molecular structure , not only attack at the substrate binding
Expert Opin Ther Pat., doi: 10 . 1517 / 13543776 .2010 .505604 35 site , but also undergo interactions with the cofactor binding
( 2010 )). Most inhibitors are steroidal compounds obtained site . The inhibitors have the following structure :
by different variations of the estrogen skeleton (Rouillard , F . adenosine moiety or simplified derivatives that can inter
et al., Open Enzyme Inhib . J., 1 61- 71 (2008 ); D . Poirier, act with the cofactor binding site ;
Anticancer Agents Med . Chem . 9 642 -660 ( 2009 ); Mazum - E2 or El moiety , which interacts with the substrate
dar M . et al.; Biochem J., 424 ( 3 ):357 - 366 ( 2009) ; Möller G 40 binding site ; and
et al. Bioorg Med Chem Lett., 19 (23 ): 6740 -6744 (2009 ); a spacer of varying length as a linking element between

oshington
Berube M . et al. Molecules 15 1590 - 1631 ( 2010 )). the two moieties.

(A )

OH
NA
(CH2) C = 0 OH

EM1745 Ki = 3 . 0 + 0 . 8 nM

Sharo
(B )

HN

HO
IC50 = 27 nM
US 9,884 ,839 B2
11
Among these compounds, inhibitors have been synthe
12
sized that exhibit a good inhibition of the enzyme and a good U - 11 - 100A
selectivity for 17B -HSD2 ( compound B (Lawrence , H . R . et
al., J. Med . Chem ., 48 : 2759 - 2762 ( 2005 ) ). In addition , the 5
inventors consider that a small estrogenic effect can be
achieved by a substitution at the C2 of the steroid skeleton
(Cushman , M . et al., J. Med . Chem ., 38 : 2041- 2049 ( 1995 );
Leese, M . P . et al ., J. Med . Chem ., 48 : 5243 -5256 (2005 )); 10
however, this effect has not yet been demonstrated in tests .
However , a drawback of these steroidal compounds may
be a low selectivity . With steroids, there is a risk that the
compounds will also interfere with other enzymes of the 15
steroid biosynthesis , which would lead to side effects . In
addition , due to their steroidal structure , they may have an Ki = 0 .61 uM
affinity for steroid receptors and function as agonists or
antagonists .
Among the phytoestrogens, which have affinity for the Recently, using a pharmacophore model for 17B -HSD1
egens
estrogen receptor and act as estrogens or anti-estrogens inhibitors Schuster et al. identified some compounds with
depending on the physiological conditions, flavones, isofla (17B -HSD1 inhibitory activity in the micromolar range
Schuster, D . et al., J Med Chem . 51 :4188- 4199 (2008)) .
vones and lignans have been tested for an inhibitory activity 25 Regarding additional non steroidal 17B -HSD1 inhibitors . 5
(Makela , S . et al., Proc . Soc. Exp . Biol. Med ., 217 : 310 -316 templates reveal interesting biological activities: A . Thio
( 1998 ); Makela , S . et al , Proc. Soc . Exp . Biol.Med ., 208 : phenepyrimidinones (US2005 /038053; Messinger , J. et al .,
51-59 (1995); Brooks, J. D . et al., J. Steroid Biochem . Mol. Mol. Cell. Endocrinol., 248 : 192 - 198 ( 2006 ) ;
W02004j110459; Lilienkampf, A . et al., J. Med . Chem . 52:
Biol., 94 : 461 -467 (2005)). Coumestrol was found to be 3030 6660 -6671Med
particularly potent, but of course showed estrogenic activity al. Bioorg (2009. Chem
)); B ..Biphenyl ethanones
16 : 4438-4456 (2008(Allan , G . M . et
): C .Hydroxy
(Nogowski, L ., J. Nutr. Biochem ., 10 : 664 -669 (1999 )). phenylnaphtols (WO /08EP/53672 ; Marchais-Oberwinkler
Gossypol derivatives were also synthesized as inhibitors S . et al., J. Med . Chem ., 51: 4685 - 4698 (2008 )) Marchais
(US2005/0228038 ). In this case , however, the cofactor bind - 35 Oberwinkler
D .
, S . et al., J. Med . Chem ., 54 : 534 -547 , 2011 );
Heterocyclic substituted biphenylols (Oster, A . et al.,
ing site rather than the substrate binding site is chosen as the Bioorg . Med . Chem
target site (Brown, W . M . et al., Chem . Biol. Interact., droxyphenyl) arenes .(,W02009 18 : 3494 - 3505 ( 2010 )) ; E . Bis (hy
143 -144 , 481-491 (2003)), which might entail problems in Chem ., 52: 6724 -6743 ( 2009 )/)02746 .
; Bey, E . et al., J. Med .
selectivity with respect to other enzymes utilizing NAD ( H ) 40
or NADP (H ).

Z
45 R1

50
HOT
Coumestrol IC50 = 0 .2 „ M

In addition to diketones, such as 2 , 3 - butanedione and 55


glyoxal, which were used for studies on the enzyme, suicide
inhibitors were also tested . However, these were found not
to be therapeutically utilizable since the oxidation rate of the HO '
alcohols to the corresponding reactive form , namely the
ketones, was too weak (Poirier, D ., Curr. Med . Chem ., 10 : 60
453- 477 ( 2003 )).
In other studies, Jarabak et al. ( Jarabak , J. et al., Bio
chemistry, 8 : 2203- 2212 (1969 ) ) examined various non 1

steroidal inhibitors for their inhibitory effect, U - 11 -100A HO .


having been found as the most potent compound in this 65
group . However, as compared to other non steroidal com
pounds, U -II- 100A is a weak inhibitor of 17BHSD1.
US 9 ,884,839 B2
13 14
- continued 3 -phenylurea ) are also known to interact with amyloid beta
D (AB) peptide and /or ( AB )-binding alcohol dehydrogenase
ki and are potential anti-Alzheimer agent (Xie , Y . et al., Bioorg .
(Het ) & Med . Chem . Lett . 16 : 4657- 60 (2006 )) .
arom
5 Finally, selective 17B -HSD1 inhibitors with (phenylthi
R2
azolyl) (phenyl)methanone (phenylthienyl)(phenyl)metha
none and (benzothiazolyl) (phenyl)methanone structure are
known from WO2012/025638, and selective 17B-HSD1
OH
inhibitors with (phenyl- 1,3 -thiazol-4 -yl)phenol and (phe
10 nylthienyl phenol structure are known from
E DE102007040243A1.
-R
17Beta-Hydroxysteroid Dehydrogenase Type 2 Inhibi
tors: Estrogens and androgens play a crucial role in the
development, growth and function of all tissues involved in
15 reproduction and fertility . It is also well known, that E2 and
testosterone/dihydrotestosterone ( T /DHT) the most active
estrogen and androgen , respectively , can be involved in a
series ofhormone- sensitive diseases. For example estrogens
or androgens are often responsible for the development of
Most of those classes showed high potency at the protein 20 breast cancer or prostate cancer, respectively, via stimulation
level (IC50 < 20 nM ; W02004 /53424 ) but a limited inhibitory of cell proliferation in the corresponding tissues ( Travis , R .
activity (IC50 > 200 nM ) in cell-based 17ß -HSD1 assays C . et al., Breast Cancer Res., 5 : 239- 247 (2003 ); Wilding, G .,
(Messinger J. et al, Mol. Cell . Endocrinol., 248: 192- 198 Cancer Surv ., 14113 - 14130 ( 1992 )) or insufficient levels of
( 2006 ) and Bey E . et al , J. Med. Chem ., 52 : 6724 -6743 E2 and T /DHT predispose the human skeleton to osteopo
(2009 )), which might be due to poor cell membrane perme - 25 rosis in both men and women (Pietschmann, P. et al.,
ability . Gerontology , 55:3 - 12 (2008)).
Recently described coumarins display only moderate Osteoporosis is a systemic skeletal disease characterized
inhibition of 17B -HSD1 (Star?evi? et al, J. Med . Chem . 54 : by deterioration of bone tissue and low bone mass, resulting
248 - 261 ( 2011) ), whereas bicyclic substituted hydroxyphe - in increased fragility of the bone and higher risk of fractures
nylmethanones have been described as potent inhibitors 30 of the hip , spine and wrist. Osteoporotic fractures lead to
(Oster et al., J. Med . Chem . 53 : 8176 -8186 ( 2010 )). pain , occasional disability and more important, they increase
mortality (Cree , M . et al., J. Am . Geriatr . Soc., 48 :283 - 288
( 2000 )).
In healthy individuals, bone mass is maintained by a
35 balance between bone resorption and bone formation per
hetero formed by the osteoclasts (OCs) and osteoblasts (OBS),
respectively . This process of bone remodelling facilitates
repair of microdamage, provides calcium uptake and there
fore brings stability and strength to the bone .
40 Bone loss is, however, accelerated in post-menopausal
women and in elderly men . The mechanisms by which
elderly people , both men and women , lose bone are not fully
understood and remain under investigation .Decreased quan
F1 tity of sex hormones is one important factor causing bone
45 loss. In women at menopause , estrogen deficiency (Cree , M .
et al., J. Am . Geriatr. Soc., 48 :283- 288 (2000 )) and in older
OH men , estrogen and androgen insufficiency ( Fink , H . A . et al.,
J. Clin . Endocrinol.Metab ., 91 :3908 -3915 ( 2006 );Meier, C .
et al., Arch . Intern . Med ., 168: 47 - 54 (2008)) result in a
50 disproportionate increase in bone loss as compared with
bone formation and often lead to osteoporosis .
Since OBs and OCs express estrogen receptors (Hoyland ,
J. A . et al., Bone , 20 :87- 92 (1997 )) and respond to estrogen
??
treatments, the most potent estrogen , E2 must have a direct
effect on maintenance of bone mineral density . There are
also substantial evidence that androgens like testosterone ( T )
Inhibitors with hydroxybenzothiazole core ( Spadaro et al. and dihydrotestosterone (DHT) may as well be involved in
PLoS ONE 7 : e29252. doi: 10 . 1371/journal.pone . 0029252; bone formation , increasing OB activity and therefore pro
J. Med . Chem . 55 : 2469 - 2473 ( 2012 )) are potent but show tecting the bones against osteoporosis (Vanderschueren , D .
poor pharmacokinetics . Further, 2 -benzoylbenzothiazole 60 et al., Endocr. Rev., 25 :389 -425 ( 2004 ), Vanderschueren , D .
derivatives having lipid lowering activity are known from et al., Curr. Opin . Endocrinol. Diabetes Obes., 15 : 250 -254
EP - A - 735029 , and N -( benzothiazol - 2 -yl)arylcarboxamide (2008 )). T and DHT might act via activation of the androgen
and I-(benzothiazol- 2 -yl)- 3 -(aryl)urea derivatives and their receptor (AR ) which is present in the OBs (Bland , R ., Clin .
use for the inhibition of ubiquitination are known from Sci ., 98 :217 - 240 ( 2000 ) ) or could be the precursor of
WO2005/037845 . Similar N -(benzothiazol- 2 -yl)arylcarbox - 65 estrogens ( the enzyme aromatase, responsible for the trans
amide and 1 -( benzothiazol- 2 -yl) - 3 - (aryl) urea derivatives formation of androgens in estrogens has been identified in
including frentizole (1 -(6 -methoxy -1,3 -benzothiazol-2 -yl) - the OBs ). Controlled increase of E2 and T in bones of
US 9 ,884 ,839 B2
15 16
osteoporotic patients will simultaneously lower bone resorp distribution together with the oxidative activity of 17B
tion ( effect of E2 ) and raise bone formation ( effect of T ) HSD2 suggests that this enzymemay play an essential role
improving bone loss and osteoporotic fractures . Augmenta in the inactivation of highly active estrogens and androgens ,
tion of E2 and T levels in bones might be achieved by resulting in diminished sex hormone action in target tissues.
inhibition of the enzyme 17B -hydroxysteroid dehydrogenase 5 Relatively few inhibitors of 17B -HSD2 have been
type 2 ( 17ß -HSD2) which has been identified in OBS (Dong, described . Sam . K . M .. J. Med. Chem ., 38 :4518- 4528
Y . et al., J. Bone Miner . Res ., 13: 1539-1546 ( 1998 ); Feix , M . (1995 ); Poirier, D . et al ., Mol. Cell. Endocrinol., 171 : 119
et al., Mol. Cell. Endocrinol., 171: 163- 164 ( 2001) ; Janssen , 128 ( 2001) : Bvdal. P . et al., Eur. J .Med . Chem ., 44 :632 -644
J. Met al., J. Cell . Biochem ., 75: 528 - 37 ( 1999 )). A restricted (2009)) reported on the potent steroidal C17 - spirolactone 1
increase in E2 and T in OCs and OBs is important to avoid 10 (inhibitory activity of 70 % at 1 uM and 40 % at 100 nM ).
unwanted side - effects such as induction of breast cancer or Cook et al. ( Cook , J. H . et al., Tetrahedron Letters , 46 : 1525
prostate cancer. This might be achieved via an intracrine 1528 (2005 ); Gunn , D ., Bioorg . Med . Chem . Lett ., 15 : 3053
mechanism (Labrie , F ., Mol. Cell. Endocrinol. 78:C113 - 118 3057 (2005 ); Wood , Jfound
. et alusing
., Bioorg
( 1991)) , i.e ., the transformation of E2 and T in inactive 16 .:4965
16 4965 --4968
1968 (020061
2006 )) found high. through
, using high
Med . Chem
through --put
. Lett .,
put scre
screen
precursors should be blocked dominantly in the bone cells 15 ing methods, the first new class of potent non - steroidal
17B -HSD2 (Wu, L . et al., J. Biol. Chem ., 268: 12964- 12969 inhibitors of 17B -HSD2: the 4 ,5 - disubstituted cis -pyrroli
( 1993 ); Lu, M ., J. Biol. Chem ., 277 :22123 - 22130 ( 2002 )) dines . The most active compound described is 2 (IC . = 10
belongs to the hydroxysteroid dehydrogenase (HSD ) super nM ). It has been recently proven in monkeys, using an
family . The HSD enzymes play pivotal roles not only in the osteoporosis model for in vivo evaluation of the 17B -HSD2
activation but also in the inactivation of steroid hormones . 20 inhibitor 3 . that inhibition of this enzyme helps to maintain
Depending on the need of the cell , they modulate the a sufficient local level of E2 and T in bones when the level
potency of the sex hormones (Penning , T. M . et al., Endocr. of circulating active sex steroid drops (Bagi, C . M . et al., J.
Rev ., 18 : 281- 305 ( 1997 )). For example, 17B -HSD1 acti
vates El into the very potent E2, while 17B -HSD2 oxidizes Musculoskelet. Neuronal Interact., 8 :267 -280 ( 2008 )).
E2 into E1 thus decreasing the action of the potent E2. It is 25
therefore believed that in physiology 17B -HSD2 protects the
cell against excessive level of active estrogen . To date ,
fourteen different 17B -HSDs have been identified (Lukacik ,
P. et al.,Mol. Cell. Endocrinol. 248 :61-71 ( 2006 ); Luu - The ,
V . et al., Best Pract . Res . Clin . Endocrinol. Metab ., 22 : 207 - 30
221 (2008 ) ) and twelve different subtypes have been cloned
from human tissues. They all belong to the Short-Chain 17
Dehydrogenase /Reductase family (except type 5 ). The 17ß
HSDs show little amino acid identity ( 20 - 30 % ) and are
membrane -bound or soluble enzymes. The X - ray structures 35
of six human subtypes (type 1, 4 , 8 , 10 , 11 , 14 ) are known HO 3
(Moeller , G . et al., Mol. Cell. Endocrinol. 301: 7 - 19 (2009 ) ) .
All of them are NAD (H )- or NADP (H ) -dependent. The OH
17ß - HSDs play therefore a key role in hormonal regulation
and function in humans. They differ in tissue distribution , 40
catalytic preference (oxidation or reduction ), substrate
specificity and subcellular localisation . It is likely that all
17B -HSDs, modulating estrogen and androgen action , are
expressed in the different estrogen /androgen -dependent tis
sues but certainly at different concentrations. In diseased 45
tissues , the ratio between the different subtypes is changed
compared to healthy tissues : one enzyme subtype might be
overexpressed or completely absent, leading to higher /lower
concentrations of the specific steroids . Selective inhibition
of one subtype could therefore be a good strategy to influ - 50
ence the level in estrogen and androgen in hormone sensitive
diseases. 17B -HSD2 (EC 1. 1. 1.51 ) is a transmembrane pro
tein localized in the endoplasmic reticulum (Wu, L . et al., J.
Biol. Chem ., 268:12964 -12969 ( 1993 ); Lu, M ., J. Biol.
Chem ., 277 : 22123 - 22130 ( 2002 )). Its 3D -structure remains 55
unknown . 17B -HSD2 shows a broad tissue distribution in
adult: it is expressed in liver, small intestine, endometrium , This modulation of steroid levels might be useful for a
urinary tracts and bone osteoblastic (Dong, Y . et al., J. Bone variety of indications like prevention and treatment of
Miner. Res ., 13 : 1539- 1546 ( 1998 ); Feix , M . et al., Mol. Cell . diseases caused by a misbalance of OB /OC activity like
Endocrinol., 171: 163- 164 (2001); Eyre, L . J. et al., J. Bone 60 osteoporosis, osteopenia and impaired bone fracture healing
Miner. Res., 13 :996 - 1004 (1998 )) and osteoclastic (van der (Undsay, R . et al., Obst. Gynecol., 76 :290 -295 ( 1990 );
Eerden , B . C . J. et al., J. Endocrinol., 180 : 457 -467 (2004) ) Turner, R . T. et al., Endocr. Rev., 16 : 275 - 300 ( 1994 ); Mec
cells . It has a predominant oxidative activity on hydroxy zekalski, B . et al., Gynecol. Endocrinol., 26 :652 -657
groups at the position C17 of the steroids: it converts the (2010 ) ), postmenopausal symptoms, vaginal atrophy
highly active 17ß -hydroxysteroid estrogen E2 as well as the 65 (Klingsberg S . A . et al., Int J Women 's Health , 1: 105 - 111
17ß - hydroxysteroid androgens T and DHT into their inac (2009 ) ; Mac Bride, M . B ., Mayo Clin . Proc ., 85 : 87 - 94
tive keto forms using the cofactor NAD +. The broad tissue (2010 ); Smith , A . L et al., Discov. Med., 10 :500 -510
US 9 ,884 ,839 B2
17 18
(2010 )); colon cancer (Oduwole 0 . O . et al., J. Steroid . enzyme (mouse and rat) which is crucial for proof of
Biochem .Mol. Biol. 87 : 133 - 140 (2003 )), neuronal diseases principle studies. In particular, the introduction of two and
(Behl, C . et al., Biochem . Biophys. Res. Commun ., 216 : three fluorine atoms, respectively, on the benzoylmoiety led
473- 482 ( 1995 )) like Alzheimer (Pike , C . J., Front Neuroen to a dramatic increase in potency towards murine 17beta
docrinol., 30 : 239 -258 (2009 )) and Parkinson 's disease 5 HSD1 and 2 by up to 100 - fold ; in case of the human
(Bourque, M . et al., Front Neuroendocrinol., 30 :142- 157 enzymes , the achieved potencies increase 5 - 1000 - fold . The
( 2009)), depression (Schmidt, P. J. et al., Ann . N . Y . Acad . strong beneficial effects exerted by multiple halogenation of
Sci., 179 :70 - 85 (2009 ) anxiety , hypercholesterolemia (Kar - the benzoylmoiety on human and rodent 17beta -HSD1 and
jalainen , A . et al., Arterioscler. Thromb. Vasc . Biol., 4 : 1101 - 2 inhibition are documented by a direct comparison of
1106 (2000 )), cardiovascular diseases ( Traish , A . M . et al., 10 inhibitory activities displayed by compounds with different
J . Androl., 30: 477 -494 ( 2009) ; Xing D . et al., Arteriosder. degrees of halogenation , see section “ Comparative Data ” .
Thromb . Vasc . Biol., 29 : 289 - 295 ( 2009 )) ; hair loss (Moo - The examples given there also illustrate the fact that difluo
radian , A . D . et al., Endocr. Rev., 8 : 1 - 28 ( 1987 ); Georgala S . rination in general leads to a slight-to - good human 17beta
et al., Dermatology 208 : 178 - 9 ( 2004 )) , non -insulin -depen - HSD1 selectivity whereas trifluorination favours human
dent diabetes mellitus ( Ferrara A . et al., Diabetes Care 25 : 15 17beta -HSD2 selectivity . Both the strong increase in
1144 - 1150 ( 2001 )), rheumatic diseases and inflammatory potency and the modulation of selectivity are surprising in
diseases (Cutolo , M . et al., Ann . N . Y . Sci., 1193 :36 -42 light ofWO 2012 /025638 : The monofluorinated compounds
( 2010 ) ; Islander U . et al., Mol. Cell . Endocrinol. Doi: 7 and 9 of WO 2012 /025638 show insignificant differences
10 . 1016 /j.mce . 2010 .05.018 ( 2010 )). More recently , non - in potency toward human 17beta -HSD1 and are less selec
steroidal 17B -HSD2 inhibitors from different compound 20 tive compared to their non - fluorinated analogs 1 and 4
classes have been described (Wetzel M . et al., Bioorg .Med . (numbering refers to WO 2012 /025638 ). Compounds with
Chem ., 19 : 807-815 ( 2011 ) ; Wetzel M . et al., J. Med . Chem ., more than one fluorine atom attached to the benzoyl moiety
54 : 7547 -7557 ( 2011 ). Wetzel M . et al., Eur. J . Med . Chem ., are not described in WO 2012 /025638 . Thus , the data did not
47 : 1 - 17 ( 2012 ). Xu K . et al., Eur. J. Med . Chem ., 46 : allow the condusion that introduction of two or three fluo
5978 -5990 (2011 ) ; Xu K . et al., Letters in Drug Design & 25 rine atoms increases potencies dramatically . Furthermore ,
Discovery , 8 : 406 -421 ( 2011 ); Al- Soud Y . A . et al, Arch . due to the different architectures of the substrate binding
Pharm . (Weinheim ), 345 : 610 -621 ( 2012 ) ; Marchais -Ober - sites (which are supposed to be the inhibitor binding sites as
winkler et al. S ., J. Med . Chem ., 56 : 167- 181 (2013) ; Per- well ) of human 17beta -HSD1/2 in comparison to murine
spicace E . et al., Eur. J. Med . Chem ., 69:201 -215 (2013 ); 17beta -HSD1/ 2 , the strong inhibition of themurine enzymes
Perspicace E . et al., Molecules, 18 : 4487 -4509 ( 2013 )). 30 is unexpected .
Further, selective 17bHSD1 inhibitors with N -benzyl- N - Moreover , the new inhibitors display improved pharma
methyl(phenyl) thiophene- carboxamide , N -benzyl- N - cokinetic parameters such as solubility and metabolic sta
methyl-(phenyl)- 1,3 -thiazole- carboxamide and N -benzyl- bility . The invention thus provides:
N -methyl-biphenyl-3 -carboxamide structure are known (1 ) A compound ( with 17beta -hydroxysteroid dehydroge
from WO2012117097 . 35 nase type 1 ( 17B -HSD1) or type 2 (17ß -HSD2) inhibitory
Related Structures: Thakar K . A . and Padhye A . M ., J. Ind. activity ) having the formula (I)
Chem . Soc . LXI: 715 -716 (1984 ) discloses certain mono
and dihalogeno -hydroxyphenyl- furyl-ketones , and mono
and di-halogeno -hydroxyphenyl-thienyl-ketones in the syn
thesis of furyland thienyl-substituted benzisoxazoles. 40
Takayama T. et al., Bioorg. & Med . Chem . Lett. 20 : IL Y pour
108- 111 ( 2010 ) and WO2005/ 123671 disclose (3 -amino -4
carboxamido -5 -(4 '-phenoxy )phenyl-pyrrol-2 -yl)-phenyl-ke
tone derivatives that are inhibitors of lymphocyte -specific
kinase and are useful as immunsuppresive agents , e . g . for 45
(R2)n Rz IT
le

the treatment of inflammatory diseases and of organ trans wherein


plant rejection . R1 represents H , OH , alkoxy or acyloxy ;
EP0801058A1 and U . S . Pat. No. 5 ,817 ,691 disclose aryl - n represents an integer of 1 or 2 ;
thio -, arylsulfinyl- and arylsulfonylpyrrole compounds hav R2 at each occurrence independently represents a halogen
ing insecticidal activity . 50 atom ;
WO2011/079772 discloses the one-pot synthesis of cer - R3 represents alkyl, haloalkyl or halogen atom ;
tain 2 ,5 -disubstituted thienes. R4 represents H ; OH ; an alkyl or an alkoxy group, each
of which may carry phenyl and halogen substituents
SUMMARY OF THE INVENTION (wherein said phenyl substituents may carry up to 3 sub
55 stituents independently selected from OH , alkyl,
A new series of non -steroidal inhibitors has been identi - haloalkyl, alkoxy, halogen , amino , CN and — NO2); a
fied . The compounds are structurally derived from the 6 -membered aromatic group which may carry 1 to 3 sub
bicyclic substituted hydroxyphenylmethanones (Oster et al., stituents independently selected from — R , haloalkyl, halo
J. Med . Chem . 53 : 8176 -8186 ( 2010 ) ) mentioned above, but gen , — NO ,, — OR ', — SR ', — CH , R , — COR', — NR 'R ',
display clearly improved properties : They show greatly 60 CN , COOR', - NR 'SO R , SONR 'R ', - NR 'COR ,
enhanced potency toward human 17B-HSD1 and 17B CONR 'R ', OC (O )R ', CH NR 'R ', CHOR ',
HSD2, respectively , at the protein level. The compounds are SO , R and — SOR (wherein R is an alkyl group , a het
the most potent inhibitors of 17B -HSD1 and 17B -HSD2 ever erocyclic ring, an aromatic or non aromatic ring thatmay be
described . This high potency was achieved by the introduc condensed or linked with a 5 - or 6 -membered , aliphatic or
tion of halogen (fluorine) atoms. Selectivity for the type 1 or 65 aromatic heterocyclic ring , a benzyl group , or an aliphatic or
the type 2 enzyme can be adjusted by the substitution aromatic heterocyclic group that may be condensed or
pattern . The compounds are active towards the rodent linked with a benzene ring , each of said groups may be
US 9 ,884 ,839 B2
19 20
substituted with up to 5 substituents independently selected wherein R1, R2, R3, R4, R5, R6 , R7, X and n have the same
from halogen , lower alkyl, lower haloalkyl, OH , — NO , , meaning as in ( 1 ) above, the aryl ring is a heterocyclic
lower alkoxy, lower haloalkoxy, — NH , phenyl, CN , aromatic ring, which carries up to 3 heteroatoms indepen
- COR " , — NHCOR " , CONHR ", — NHSO , R " and dently selected from N , S and O , W and U represent
SONHR " (wherein R " is H , lower alkyl, lower haloalkyl or 5 independently CH or N , preferably the compound has the
phenyl), and R ' at each occurrence is independently selected formula (Ila )
from the groups of R above and H ), or two of said substitu
ents , together with the adjacent carbon atoms of the 6 -mem
bered aromatic group , may form a 5 . or 6 -membered , ( IIa )
aliphatic or aromatic , homocyclic or heterocyclic ring con
densed to said 6 -membered aromatic group, wherein the R7
heterocyclic ring carries up to 3 heteroatoms independently
selected from N , S and 0 , and the third substituent may be aryl
located on the 6 -membered aromatic group or on the ring
condensed thereto ; or a 5 or 6 -membered aliphatic or (R2)n R3 - -- R6,
aromatic heterocyclic group which carries up to 3 heteroa - 13 WTR5
toms independently selected from N , S and O and may carry R4
1 to 3 substituents independently selected from R
haloalkyl, halogen , — NO , OR , SR ', CH R ,
- COR ', NR 'R ', CN , COOR , NR 'SO , R , wherein all the variables are as defined for formula ( II)
— SO , NR 'R ', — NR 'COR ', - NRCOR ', CONR 'R ', OC 20 above .
(O ) R ', — CH NR 'R ', CHOR ', SO , R and — SOR has(3the ) In a preferred embodiment of (2 ) above, the compound
formula (III)
(wherein R and R ' is as defined above ) or two of said
substituents, together with the adjacent carbon atoms of the
5 or 6 -membered aliphatic or aromatic heterocyclic group ,
may form a 6 -membered , aliphatic or aromatic ring con (III)
densed to said 5 or 6 -membered aromatic group , and the
third substituent may be present on the 5 or 6 -membered
aromatic group or on the ring condensed thereto ; and said P arvl
substituent R3 being directly or through a phenylen group 30
bound to the aryl ring ; (R2)n R3
R5, R6 and R7 independently represent H , - R , haloalkyl,
halogen , — NO2, OR , SR , CH R ', COR',
- NR 'R ', _ CN , — COOR ', — NHSO R ', — NRSO , R '
- SO NRR ', - NHCOR ', - NRCOR ', CONRR ', OC WU R62
(O )R ', CH ,NRR', CHOR ', SOZR ' or SOR 35 R5
(wherein R and R ' is as defined above ),
X represents
wherein all the variables are as defined in ( 2 ) above .
(4 ) In a preferred embodiment of ( 1) to (3 ) above, the
O
Rz 40 compound is a compound with 17ß -HSD1 inhibitory activ
=

=
Z
WIN ity, wherein in the formulas (1)- ( III) n is 1 and R2 and R3
independently represent halogen atoms.
(5 ) In a preferred embodiment of ( 1 ) to (3 ) above, the
compound is a compound with 17B -HSD2 inhibitory activ
45 ity, wherein in the formulas (I)-( III)
(i ) n is 1 , R2 is a halogen atom and R3 represents alkyl or
(wherein Y , if present, represents O or S , and R8 represents haloalkyl (preferably R3 represents CH , or CF3); or
H or lower alkyl); and the aryl ring is a 5 -membered ( ii ) n is 2 , R2 and R3 at each occurrence independently
heteroaromatic ring which carries up to 3 heteroatoms represent halogen
independently selected from N , S and 0 , including , but not OP 50 (6 ) A compoundatoms
50 (with
.
17B -HSD1 or 17B -HSD2 inhibi
limited to , a thiadiazole, triazole , oxadiazole , isothiadiazole , tory activity ) having the formula (1)
isooxadiazole, thiazole , oxazole, imidazole, pyrazole, isox
azole , isothiazole , furane , pyrrole or thiophene (thiene ); or a
pharmaceutically acceptable salt thereof.
(2 ) In a preferred embodiment of (1 ) above, the compound 55 Kind
has the formula ( II ) aryl Ro
(R2)n R3 R7
R7
60
ary as defined in any one of ( 1) to (5 ) above , for use in the
treatment and prophylaxis of hormone-related diseases in a
(R2)n R3 - R6 mammal.
W
(7 ) A method for the production of the compound of any
R25 65 one of ( 1) o (5 ) above or a pharmaceutically acceptable salt
thereof, which comprises condensing aromatic precursor
compounds of formula (I) .
US 9,884,839 B2
21 22
( 8 ) A pharmaceutical composition or medicament com 2 ,4 ,6 -trichlorobenzylamino , 2 ,4,6 - triisopropylbenzylamino ,
prising at least one compound of any one of ( 1) to (5 ), or a 2 ,4 ,6 - trifluorobenzylamino , 2 ,6 - dimethoxybenzylamino ,
pharmaceutically acceptable salt thereof, and optionally one 2 ,6 - dichloro - 3 - nitrobenzylamino , 3 -chloro -2 ,6 -difluoroben
or more suitable carriers and/ or excipients. zylamino , 2 - chloro -6 -methylbenzylamino , 2 -chloro -6
(9 ) Use of a compound of any one of (1 ) to (5 ) above , or 5 fluoro -5 -methylbenzylamino , 4 -bromo- 2,6 - fluorobenzy
a pharmaceutically acceptable salt thereof for preparing a lamino , 2 -chloro -3 ,6 -difluorobenzylamino , 2 ,5
medicament for the treatment and prophylaxis of hormone dichlorobenzylamino , 2- bromo -6 -
methylbenzylamino , 2 ,6
related diseases in a mammal. difluoro - 3 -
methylbenzylamino ,
( 10 ) A method for the treatment and prophylaxis of chlorobenzylamino , 2 - fluoro -6 -methoxybenzylamino, 2 ,66 2 -bromo -
hormone-related diseases in a mammal, such as estrogen - 10 dimethyl-4 -fluorobenzylamino , 2 - chloro -6
related diseases, which comprises administering a com methoxybenzylamino ,
pound of any one of ( 1) to (5 ) above , or a pharmaceutically methylbenzylamino , 2-( 2 -( N ,N -dimethylamino)-ethyloxy
2 -chloro -6 fluoro -5
)
acceptable salt thereof to the mammal (i.e ., the patient) in phenyloxy or 3 - ( 2 -( N , N - dimethylamino ) ethyloxy )
need of such treatment or prophylaxis . phenyloxy ;
( 11 ) In a preferred embodiment of (6 ) and (8 ) to (10 ) 15 (iv ) when in the compound of formula (I) the aryl ring is
above , the compound , pharmaceutical composition , medi
cament or method is for the treatment and prophylaxis of N -methyl-3 -amino - 4 -carboxamido - 5 -(4'-phenoxy )phenyl
estrogen -related diseases in a mammal, preferably com pyrrol-2 -yl, and X is CO — , then the phenyl moiety
prises carrying R1-R3 is not 2 ,6 -dichlorophenyl;
(i) a compound having 17B -HSD1 inhibitory activity, e .g . 20 (v ) when in the compound of formula (I) the aryl is a
as defined in ( 4 ) above , and is for use in the treatment and pyrrol and R4 is a phenyl residue substituted with 1 to 3
prophylaxis of endometriosis, endometrial carcinoma, endo
metrial hyperplasia , adenomyosis, breast cancer , prostate substituents independently selected from halogen , — NO2,
cancer, acne , androgen -dependent hair loss, psoriasis, pros CN, C /-zalkyl, C .zhaloalkyland C - alkoxy,and the phenyl
tate cancer, acne , androgen -dependent hair loss , psoriasis 25 moiety carrying R1-R3 is a phenyl substituted with 2 to 4
and ovarian carcinoma; or substituents selected from halogen , — NO , CN , C1- alkyl,
( ii ) a compound having 17ß -HSD2 inhibitory activity , e. g. C1.4haloalkyl and C1-4alkoxy, then X is not — SO — or
as defined in (5 ) above , and is for use in the treatment and
prophylaxis of osteoporosis , osteopenia , impaired bone frac S02 — ; and
ture healing, hair loss, colon cancer, vaginal atrophy ,hyper - 30 ( vi) when in the compound of formula (1) the aryl is a
cholesterolemia , and non - insulin -dependent diabetes melli - thiene, R4 is an aryl group , unsaturated monocyclic hetero
tus. cyclic ring or unsaturated fused heterobicyclic ring, each of
(12 ) In a preferred embodiment of the compound of (1 ) to which may be substituted with 1 to 3 substituents indepen
(5 ) and (11) above,
(i) the compound of formula ( l) is not 2,4 -dichloro -6 - 35 dently selected from halogen , — NO2, amino , cyano ,
hydroxyphenyl-furyl-ketone , 2,4 -dibromo -6 -hydroxyphe- hydroxy , mercapto , carboxyl, C1-4 alkyl, C1-4haloalkyl,
nyl-furyl-ketone , 4 -chloro -2 -hydroxy -6 -methylphenyl- fu - C1-talkoxy, benzyloxy, C1-4alkylthio , C1-4 hydroxyalkyl,
ryl-ketone, 4 -chloro -2 - hydroxy -5 -methylphenyl- furyl C - alkyl amino, bis (C1- alkyl)amino, C - acylamino, car
ketone , 2 ,4 -dichloro -6 -hydroxyphenyl-thienyl-ketone or bamoyl, C1- alkoxycarbonyl, and C -4 alkylsulfonyl, R5 and
4 -chloro -2-hydroxy -6 -methylphenyl-thienyl-ketone;
(ii ) when in the compound of formula (I) the aryl ring is R6 are hydrogen , and the phenylmoiety is a phenyl substi
3 -amino -4 -carboxamido -5 -( 4'-phenoxy)phenyl-pyrrol- 2 - yl, tuted with 2 to 3 substituents selected from halogen ,
and X is Co , then the phenylmoiety carrying R1-R3 is hydroxy, C1-4 alkyl, C1-4 haloalkyl and C1- alkoxy, then X is
not 2 ,6 -difluorophenyl, 2 , 4 ,6 -trifluorophenyl, 2 ,6 - difluoro - not _ CO .
3 -methylphenyl, 2, 5 - difluorophenyl, 3 - fluoro - 2 -methylphe - 45 ( 13 ) In another preferred embodiment of the compound of
nyl, 2 ,3 -difluorophenyl, 2, 3 -dichlorophenyl, 2 ,4 -dichloro
phenyl, 3 ,5 -dichlorophenyl, 2 ,5 -dichlorophenyl. 3 - chloro - 2 - ( 1 ) to (3 ) and ( 11 ) above ,
ethvinhenyl, 33 ,4A -- dichlorophenyl
methylphenyl dichloronhenyl or 3 -bromo - 2 . (i ) when in the compound of formula (I ) the aryl ring is
methylphenyl;
or 3-bromo-2 a furyl or thiene , R3 is methyl or a halogen and X is
(iii ) when in the compound of formula (1) the phenyl 50 CO , then one of R1 and R4 to R7 is not H ;
moiety carrying R1-R3 is 2 ,6 - difluorophenyl and X is ( ii ) in the compound of formula (I) the aryl ring is a not
- C0 — , then the aryl ring is not a 3 -amino -4 -carboxamido pyrrol
5 -( 4 -substituted )phenyl-pyrrol- 2 -yl, in which the substitu - PY carrying an - NH , and a CONH , group in its
ent is methoxy, 2 - pyrimidinyloxy, benzyloxy, 2 ,6 -dichlo positions 3 and 4 ;
robenzyloxy , amino , benzoylamido , benzylamino , 55 ( iii) when in the compound of formula (I) the aryl ring is
cyclohexylmethylamino, 2,6 -dichlorobenzylamino , N -(2 ,6 - a pyrrol, then X is not - SO — or S0 , — ; and
dichlorobenzyl)-N -methylamino , 2 ,5 -dichlorobenzylamino , (iv ) when in the compound of formula (I) the aryl ring is
2 -chloro -6 -methlbenzylamino, 3 -phenylpropylamino , 4 -tri a thiene and X is Co , then R2 and R3 are halogen
fluoromethylbenzylamino , 2 -pyridylmethoxy, 2 -(4 -methyl
piperazin - 1 -yl) ethyloxy, 5 -tifluoromethylpyridin - 2 -yloxy , 60 atoms, preferably R2 and R3 are F and n is 2 .
piperidin -2 -yloxy, 4,6 -dimethylpiperidin -2 -yloxy, piperidin - (14 ) In a preferred embodiment of the composition or
2 -yloxy, 4,6 -dimethoxypiperidin -2 -yloxy, 3 -phenylpropi
onoylamido , 2 - pyridinylcarbamido , 3 - (3 -pyridinyl) propi (i) when in the compound of formula (1) the aryl ring is
onoylamido , 2 -chloro -6 - fluorobenzylamino ,
2 - trifluoromethylbenzylamino , 2 -methylbenzylamino , 2 ,6 - 65 30 3 -amino -4 -carboxamido -5-(4'-phenoxy)phenyl-pyrrol-2-yl,
difluorobenzylamino, 2 ,4 ,6 - trimethylbenzylamino , 2,3 ,5 ,6 and X is - C0 — , then the phenyl moiety carrying R1-R3 is
tetramethylbenzylamino , 2 ,3 , 5,6 - tetrafluorobenzylamino , not 2 ,6 -difluorophenyl, 2 ,4 ,6 -trifluorophenyl, 2 ,6 -difluoro
US 9 ,884 ,839 B2
23 24
3 -methylphenyl, 2 ,5 -difluorophenyl, 3 - fluoro - 2-methylphe more double and /or triple bonds. Of straight-chain or
nyl, 2, 3-difluorophenyl, 2,3 -dichlorophenyl, 2 ,4 -dichloro branched -chain alkyl residues, preferred are those having
phenyl, 3,5 -dichlorophenyl, 2,5 -dichlorophenyl, 3 -chloro -2 from 1 to 10 carbon atoms, more preferably those having
methylphenyl , 3,4 -dichlorophenyl or 3-bromo-2 - 5 from 1 to 6 carbon atoms, even more preferably those having
methylphenyl; from 1 to 3 carbon atoms. Ofthe cyclic alkyl residues, more
( ii ) when in the compound of formula (I) the phenyl preferred are mono - or bicyclic alkyl residues having from
moiety carrying R1-R3 is 2,6 -difluorophenyl and X is 3 to 15 carbon atoms, especially monocyclic alkyl residues
- CO — , then the aryl ring is not a 3 -amino -4 -carboxamido - 10 having from 3 to 8 carbon atoms.
5 -(4 -substituted )phenyl-pyrrol-2 -yl, in which the substitu meaning ofalkyl
“ Lower ” and “ lower alkoxy” residues within the
ent is methoxy, 2 -pyrimidinyloxy, benzyloxy, 2 ,6-dichlo or cyclic saturated lower arealkyl
the invention straight-chain , branched -chain
residues and lower alkoxy
robenzyloxy, amino , benzoylamido , benzylamino, residues or those having a double
cydohexylmethylamino , 2,6 -dichlorobenzylamino , N -(2,6 - 15 straight-chain ones, those having fromor 1triple to 6
bond. Of the
carbon atoms,
dichlorobenzyl )-N -methylamino , 2 ,5 -dichlorobenzylamino , especially 1 to 3 carbon atoms, are particularly preferred .
2 -chloro -6-methlbenzylamino , 3 -phenylpropylamino , 4 -tri “ Aryls ” and “ homocyclic aromatic groups ” within the
fluoromethylbenzylamino , 2-pyridylmethoxy, 2-(4-methyl meaning of the present invention include, if not specified
piperazin -1-yl)ethyloxy, 5-tifluoromethylpyridin1102 -2--yloxy
10ay,, 2020 othe
otherwise,mono -, bi- and tricyclic aryl residues having from
piperidin
piperiam --22--yloxy
yloxy,, 44,,60--dimeny
dimethylpiperidin
piperidin --22--yloxy
yloxy,, Piperidin
piperidin- 3 to 18 ring atoms, which may optionally be anellated with
2 -yloxy, 4,6 -dimethoxypiperidin -2-yloxy, 3 -phenylpropi one or more saturated rings. Particularly preferred are
onoylamido , 2 -pyridinylcarbamido , 3 -( 3 -pyridinyl)propi- anthracenyl, dihydronaphthyl, fluorenyl, hydrindanyl, inda
onoylamido , 2 -chloro -6 - fluorobenzylamino, 25 nyl , indenyl, naphthyl, naphthenyl, phenanthrenyl, phenyl
2 -trifluoromethylbenzylamino , 2 -methylbenzylamino , 2 ,6 - and tetralinyl.
difluorobenzylamino, 2 ,4 ,6 - trimethylbenzylamino , 2,3 ,5 ,6 - Unless stated otherwise , “ heteroaryl” residues and “ het
tetramethylbenzylamino , 2 ,3,5,6 -tetrafluorobenzylamino , erocyclic groups” are mono - or bicyclic heteroaryl residues
2 ,4 ,6 - trichlorobenzylamino , 2 ,4 ,6 -triisopropylbenzylamino , 30 having from 3 to 12 ring atoms and preferably having from
2 ,4 ,6 - trifluorobenzylamino, 2 ,6 - dimethoxybenzylamino, 1 to 5 heteroatoms selected from nitrogen , oxygen and
2 ,6 -dichloro - 3 -nitrobenzylamino, 3 -chloro - 2,6 -difluoroben - sulfur, which may be anellated with one or more saturated
zylamino, 2 -chloro -6 -methylbenzylamino , 2 -chloro -6 rings. The preferred monocyclic and bicyclic heteroaryls
fluoro - 5 -methylbenzylamino , 4 -bromo -2 ,6 - fluorobenzy include benzimidazolyl, benzothiazolyl, benzoxazolyl, ben
lamino , 2-chloro -3,6 -difluorobenzylamino, 2,5 - 3 zisoxazolyl, quinazolinyl, quinolyl, quinoxalinyl, cinnoli
dichlorobenzylamino , 2-bromo-6 -methylbenzylamino, 2,6 nyl, dihydroindolyl , dihydroisoindolyl, dihydropyranyl,
difluoro -3 -methylbenzylamino , 2-bromo-6 dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imida
chlorobenzylamino , 2 -fluoro -6 -methoxybenzylamino, 2 ,6 zolinyl, imidazolyl, indazolyl, indolyl, isoquinolyl, isoindo
dimethyl-4 - fluorobenzylamino , 2 -chloro -6 - 40 lyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl,
methoxybenzylamino, 2 -chloro -6 - fluoro - 5 morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl , phthalazi
methylbenzylamino , 2-(2 -(N ,N -dimethylamino )ethyloxy ) nyl, piperazinyl, piperidyl, pteridinyl, purinyl, pyrazolidinyl,
phenyloxy or 3 -(2 -(N ,N -dimethylamino ylamino )ethyloxy) pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl,
phenyloxy ; and 45 pyrimidyl, pyrrolidinyl, pyrrolidin -2-onyl, pyrrolinyl, pyr
(iii) when in the compound of formula (I) the aryl ring is rolyl, tetrazinyl, tetrazolyl, tetrahydropyrrolyl, thiadiazolyl,
N -methyl-3 -amino -4 -carboxamido -5 - (4'-phenoxy )phenyl- thiazinyl, thiazolidinyl, thiazolyl, triazinyl, triazolyl and
pyrrol-2 -yl, and X is CO — , then the phenyl moiety thiophenyl.
carrying R1-R3 is not 2 ,6 -dichlorophenyl. 50 “ Arylenes” and “ phenylenes” within the meaning of this
( 15 ) In another preferred embodiment of the composition invention include the bivalent equivalents of the above
or medicament of (8 ) and (11) above , in the compound of defined arvl residues .
formula (I) the aryl ring is a not pyrrol carrying an — NH “ Halogen ” includes fluorine, chlorine, bromine and
and a CONH , group in its positions 3 and 4 . 55 iodine .
DETAILED DESCRIPTION OF THE " Halo -” , “ halogenated” or “ optionally halogenated ” resi
INVENTION dues within the meaning of the present invention include any
residues in which one to all H atoms have been replaced by
In the compounds of formulas (I) to (III) of the invention , 60 the above mentioned halogen atomsor combinations of such
the variables and the terms used for their characterization halogen atoms.
have the following meanings: “ Pharmaceutically acceptable salts” and “ salts” within the
“ Alkyl” and “ alkoxy” residues within the meaning of the meaning of the present invention include salts of the com
invention may be straight-chain , branched -chain or cyclic , s pounds with organic acids (such as lactic acid , acetic acid ,
and saturated or (partially ) unsaturated . Preferable alkyl amino acids, oxalic acid etc.), inorganic acids (such as HCI,
residues and alkoxy residues are saturated or have one or HBr, phosphoric acid etc .), and , if the compounds have acid
US 9 ,884 ,839 B2
25 26
substituents , also with organic or inorganic bases including In a particularly preferred embodiment of aspects (1) to
amino acids. Preferred are salts with HCl. (3 ) above, the aryl ring represents a thiophene; R1 is OH ; n
“ Pharmacologically suitable carriers ” within the meaning is 1 or 2 ; R2 is F ; R3 is lower alkyl, lower kaloalkyl or F ;
of the present invention are selected by the skilled person , 5 W and U (if present) are independently selected from CH
depending on the desired dosage form . and N ; R4 represents H , OH , an alkoxy group, which may
In a preferred embodiment of the compound of aspects ( 1) carry up to 3 halogen substituents , CH , R , SO , R ,
to (3) above, the aryl ring, is a thiadiazole, triazole, oxadi — NHSO , R and — NRSO , R ', (wherein R and R ' is as
azole , isothiadiazole, isooxadiazole, thiazole , oxazole , imi 10 defined above); R7 is selected from H and alkyl; and /or R5
dazole , pyrazole, isoxazole , isothiazole, furane, pyrrole or and R6 are independently selected from H , OH , CN ,
thiene (thiophene ); alkyl, alkoxy and halogen .
R1 is - H , OH or lower alkoxy ; W and U ( if present) are In a further preferred embodiment of aspects (1) to (3 )
independently selected from CH or N ; R2 represents halo 15 above, R1 is a hydroxy group in the meta position relative
gen ; R3 represents lower alkyl, lower haloalkyl or halogen ; to the CO — junction , n is 1 or 2 , R2 is F and R3 is CHz,
R7 represents H or lower alkyl;
R5 represent H , R , haloalkyl, halogen , NO2, CF, or F.
_ CH _ R , OR , NR'R ', CN , NR 'SO , R , In a particularly preferred embodiment of aspects (1) to
_ SO . NR 'R ' _ NRICOR ' or CONR'R '. (wherein R is 20 (5 ) above , the compounds are selected from the following
alkyl, aryl, benzyl, an aliphatic or aromatic heterocyclic compounds ( 1)
group , an aliphatic cyclic or heterocyclic ring , each of which [5 -(3 - Aminophenyl)thiophen -2 -yl](2 ,6 -difluoro -3 -hydroxy
may be substituted with up to 5 substituents independently phenyl)methanone (1 ).
selected from halogen , lower alkyl, lower haloalkyl, OH , 254-Bromo- N - { 3 -[5 - (2 ,6 -difluoro -3 -hydroxybenzoyl) thio
— NO ,, lower alkoxy , NH ,, phenyl, CN , COR ", phen - 2 -yl)-phenyl} - 2 - trifluoromethoxybenzenesulfona
- NHCOR " , CONHR " , — NHSO , R " and SO ,NHR " mide (2 ).
(wherein R " is - H , lower alkyl, lower haloalkyl or phenyl); N -{3 -[5 -(2,6 -Difluoro -3 -hydroxybenzoyl)thiophen -2- yl ]
and R ' is R or H ); 30 phenyl) -2 -trifluoromethoxybenzene-sulfonamide (3 ).
R6 is selected from H , OH , lower alkyl, lower alkoxy, N -{3- 15 -(2,6-Difluoro-3-hydroxybenzoyl)thiophen -2-yl]
lower haloalkoxy and halogen ; and /or phenyl) -2 -trifluoromethylbenzene - sulfonamide (4 ).
R4 represents H , OH , an alkyl or an alkoxy group , each Pyridine - 3 -sulfonic acid (3 - [5 -( 2,6 - difluoro - 3 -hydroxy
of which may carry phenyl and halogen substituents, 35 benzoyl)- thiophen - 2 -yl)-phenyl) - amide (5 ).
wherein said phenyl substituents may carry up to 3 substitu - 1 -Methyl- 1H -imidazole- 4 -sulfonic acid ( 3 -15 -(2 ,6 -difluoro
ents independently selected from – OH , alkyl, haloalkyl, 3 -hydroxy-benzoyl) thiophen -2 - yl)-phenyl) -amide (6 ).
alkoxy, halogen , amino , — CN and — NO2, CH R , Cyclopropanesulfonic acid (3 -15 -( 2,6 -difluoro -3 -hydroxy
- NHSO , R and — NHCOR ', (wherein Rand R ' is as defined 40 benzoyl)-thiophen -2 -yl)-phenyl)-amide (7).
above), a 6-membered aromatic or hetero aromatic group (2,6 - Difluoro -3-hydroxy -phenyl)-(5 -pyridin -4 -yl-thiophen
which may carry 1 to 3 substituents independently selected 2 - yl)-methanone (8 ).
from R , haloalkyl, halogen, - NO2, OR , NR'R ', 2,6 -Difluoro -3-hydroxy -phenyl)-(5 -pyridin -3-yl-thiophen
- CN , - NR 'SO2R , SONR'R ', - NR'COR ', CONR 'R ' 45 2 - yl)-methanone (9 ).
(wherein R and R ' is as defined above ) or two of said (2,6 - Difluoro - 3 -hydroxy -phenyl)-[5 -(2 ,4 -difluoro -phenyl)
substituents , together with the adjacent carbon atoms of the thiophen -2 - yl]-methanone (10 ).
6 -membered aromatic group ,may form a 5 - or 6 -membered on - [|5 -- ((33 --Chloro
Chloro --phenyl
aliphatic or aromatic, homocyclic or heterocyclic ring con phenyl))--thiophen
thie - 2 -yl) -( 2 , 0 -ainuoro - 3 -hy
densed to said 6 -membered aromatic group , wherein the 5050
in the droxy
Oxy-phenyl
? )-methanone ( 11 ).
heterocyclic ring carries up to 3 heteroatoms independently 15 - (3 -Chloro - 4 -methoxy-phenyl)- thiophen -2 -yl)-(2 ,6 -dif
selected from N , S and 0 , and wherein the third substituent luoro - 3 -hydroxy-phenyl)methanone (12 ).
may be located on the 6 -membered aromatic group or on the [5 -(3 -Chloro -4 -methoxy- phenyl) -4 -methyl-thiophen -2 -yl)
ring condensed thereto , or a 5 or 6 -membered , aliphatic or 55 (2 ,6 -difluoro -3 -hydroxy-phenyl)-methanone ( 13 ).
aromatic heterocyclic group which carries up to 3 heteroa - [5 -(3 -Chloro - 2-methoxy -phenyl) -thiophen - 2 - yl)-( 2 ,6 -dif
tomsindependently selected from N , S and O and may carry l uoro - 3 -hydroxy-phenyl)methanone (14 ).
1 to 3 substituents independently selected from R, [5 -(3,5-Dichloro-4 -methoxy -phenyl)-thiophen -2 -yl)-(2,6
haloalkyl, halogen , — NO , OR , NR'R ', CN , 60 difluoro -3 -hydroxy -phenyl)-methanone (15 ).
- NR 'SOR, SO NR 'R ', - NR 'COR , CONR 'R ', (2,6 -Difluoro -3 -hydroxy -phenyl)-[5 -(4 -methoxy -3,5 -dim
(wherein R and R ' is as defined above ) or two of said ethyl-phenyl)-thiophen -2 -yl)-methanone (16 ).
substituents , together with the adjacent carbon atoms of the (2 ,6 - Difluoro -3 -hydroxy -phenyl)-[5 -(4 -difluoromethoxy -3 ,
5 or 6 -membered aliphatic or aromatic heterocyclic group, s 5 -difluoro -phenyl) thiophen -2 -yl]-methanone ( 17 ).
may form a 6 -membered , aliphatic or aromatic ring con - 5 -[5 -( 2,6 -Difluoro - 3 -hydroxy -benzoyl)-thiophen - 2 -yl]-2
densed to said 5 or 6 -membered aromatic group. isopropoxy -benzonitrile ( 18 ).
US 9 ,884 ,839 B2
27 28
(2,6 - Difluoro -3 -hydroxy -phenyl )- { 5 -[4 -methoxy -3 -(mor (5 -( 1H -Indol-6 -yl)thiophen - 2 -yl)(2,4 ,5-trifluoro -3 -hy
pholine-4 -sulfonyl)phenyl]-thiophen - 2- yl } -methanone droxyphenyl)methanone (43).
( 19 ) . 3 -(5 -(2,4 ,5 - Trifluoro -3-hydroxybenzoyl)thiophen - 2-yl)ben
[5 -(3 -Chloro -4-hydroxy -phenyl)- thiophen -2 -yl)-(2,6 -dif- 5 zamide (44).
luoro -3 -hydroxy -phenyl)methanone ( 20 ). (5 -(3,5 -Dichloro -4-methoxyphenyl)thiophen -2-yl)(2,4,5
[5 -( 3 -Chloro - 4 -hydroxy-phenyl)-4 -methyl-thiophen - 2 -yl) trifluoro -3 -hydroxyphenyl)methanone (45 ).
(2 ,6 -difluoro -3 -hydroxy -phenyl)-methanone (21). (5 -(4 -Methoxy -3,5 -dimethylphenyl)thiophen -2 -yl)(2 ,4 ,5
[5 -(3 -Chloro -2 -hydroxy-phenyl)- thiophen -2 -yl)-(2 ,6 -dif trifluoro -3 -hydroxyphenyl)methanone ( 46 ).
luoro- 3-hydroxy -phenyl)methanone (22). (5-(3-(Hydroxymethyl)phenyl)thiophen-2-yl)(2,4,5 -trif
[5 -(3,5-Dichloro -4-hydroxy -phenyl)- thiophen -2 -yl)-(2 ,6 -di luoro -3 -hydroxyphenyl)methanone (47).
fluoro -3 -hydroxy -phenyl)-methanone (23 ). 1-Methyl-N -( 3 -(5 -(2 ,4,5 - trifluoro -3 -hydroxybenzoyl)thio
( 2,6 -Difluoro - 3 -hydroxy -phenyl)-[5 -(4 -hydroxy - 3,5 -dim phen - 2-yl)phenyl)-1H -imidazole -4 -sulfonamide (48 ).
ethyl- phenyl)- thiophen -2 -yl)-methanone (24 ). 15 (5 -(3 ,5 -Dichloro -4- hydroxyphenyl) thiophen -2 -yl)(2 ,4,5 -tri
5 -[5 -(2,6 - Difluoro -3 -hydroxy-benzoyl)-thiophen -2 -yl)-2 fluoro -3 -hydroxyphenyl)methanone (49 ).
hydroxy -benzonitnile ( 25) . (5 -(4 -Hydroxy -3 ,5- dimethylphenyl)thiophen - 2- yl)(2,4 ,5
[5 -(3 -Chloro -4 -methoxy-5 -methyl-phenyl )-thiophen - 2 -yl) trifluoro -3 -hydroxyphenyl)methanone (50 ).
(2 ,6 -difluoro -3 -hydroxy -phenyl)-methanone ( 26 ). 20 (5 -(4 -Methoxyphenyl) thiophen - 2 -yl)(2 ,4,5 -trifluoro -3 -hy
[5 -(3 -Chloro -4 -hydroxy -5 -methyl-phenyl)-thiophen -2 -yl ]- droxyphenyl)methanone (51 ).
(2 ,6 -difluoro -3 -hydroxy -phenyl)-methanone (27 ). (5 -(3 -Methoxyphenyl) thiophen -2 -yl)( 2,4,5 - trifluoro -3 -hy
1 -(4 - {3 - Chloro -5 - [5 -(2 ,6 -difluoro - 3 -hydroxy-benzoyl) droxyphenyl)methanone (52 ).
thiophen - 2-yl)-2 -methoxy -benzyl} -piperazin - 1-yl)-etha - 25 (5 -(2 -Methoxyphenyl) thiophen -2 -yl)(2,4 ,5 -trifluoro - 3-hy
none (28 ) . droxyphenyl)methanone (53 ).
1-(4- {3 -Chloro -5-[5-(2,6 -difluoro -3-hydroxy -benzoyl ) N -(3 -(5 -(2,4,5 - Trifluoro -3-hydroxybenzoyl) thiophen -2 -yl)
thiophen - 2-yl)-2-hydroxy -benzyl} -piperazin - 1- yl)-etha phenyl)acetamide (54 ).
none (29 ). 30 (5 -(2- Aminophenyl)thiophen -2-yl)(2 ,4,5- trifluoro -3-hy
[5 -(3 - Chloro -4 -methoxy -5 -piperazin - 1 -ylmethyl-phenyl) droxyphenyl)methanone (55 ) .
thiophen - 2 -yl)-( 2,6 -difluoro -3 -hydroxy -phenyl)-metha (5 - Phenylthiophen -2 -yl)(2 ,4 ,5 -trifluoro - 3 -hydroxyphenyl)
none ( 30 ). methanone (56 ).
[5 -( 3 -Chloro -4 -methoxy -5 -[1,2,3 ]triazol-1 -ylmethyl -phe - 35 (5 -(3 -Amino -4 -methylphenyl)thiophen - 2 -yl)(2 ,4 ,5 -trif
nyl)-thiophen -2-yl]-(2,6-difluoro -3-hydroxy -phenyl) luoro -3 -hydroxyphenyl)methanone (57).
methanone ( 31 ). (5 -(3 - Amino - 2-methylphenyl) thiophen - 2 -yl)( 2,4 ,5 - trif
[5 -(3 -Chloro -4 -hydroxy -5-[ 1,2,3 ] triazol-1 -ylmethyl-phe luoro -3 -hydroxyphenyl)methanone (58 ).
nyl)- thiophen - 2 -yl)-(2 ,6 -difluoro - 3- hydroxy -phenyl ) 40
(5 -(3 - Amino -4 -hydroxyphenyl)thiophen -2 -yl)(2 ,4 ,5 - trif
methanone (32 ). luoro - 3 -hydroxyphenyl)methanone (59 ).
Cyclopropanesulfonic acid {3-[5 -(2 ,6 -difluoro -3-hydroxy - (5 -(3 -Amino -4-methoxyphenyl)thiophen -2 -yl)(2,4,5- trif
benzoyl)- thiophen -2 -yl)-5 -methyl-phenyl)-amide (33 ). luoro -3 -hydroxyphenyl)methanone (60 ).
Cyclopropanesulfonic acid ( 3- [5 -( 2 ,6 -difluoro -3 -hydroxy - (5 -( 1H -Indol- 5 -yl)thiophen - 2 -yl)(2 ,4 ,5 - trifluoro -3 - hy
benzoyl)- thiophen -2-yl]-5-methyl-phenyl}-methyl-amide 45 droxyphenyl)methanone (61).
(34 ). (5 -( 1H -Indol-4 -yl)thiophen - 2-yl)(2,4 ,5- trifluoro -3 -hy
[5-(3- Aminophenyl)thiophen -2-yl](2 ,4,5 -trifluoro -3-hy droxyphenyl)methanone (62).
droxyphenyl)methanone ( 35 ). N -( 3 -(5 - (2 ,4, 5 -trifluoro -3 -hydroxybenzoyl)thiophen - 2 - yl)
4 -Bromo -N - { 3-[ 5 -(2,4 ,5 - trifluoro - 3-hydroxybenzoyl) thio - 50 phenyl)methanesulfonamide (63 ).
phen - 2- yl]phenyl) -2 - trifluoromethoxybenzenesulfona - N -(4 -( 5 -(2,4 ,5 -trifluoro - 3-hydroxybenzoyl)thiophen - 2- yl)
mide (36 ). phenyl) acetamide (64 ).
N -{3-15-(2,4 ,5- Trifluoro-3-hydroxybenzoyl) thiophen -2-yl] (5-(Pyridin-3-yl)thiophen -2-yl)(2,4,5-trifluoro -3-hydroxy
phenyl ) -2 - trifluoro -methoxybenzenesulfonamide ( 37 ). 55 phenyl)methanone (65 ).
N - { 3- [5 -(2 ,4 ,5 - Trifluoro -3 -hydroxybenzoyl)thiophen -2 -yl] (5 -(Quinolin - 7 - yl) thiophen -2 -yl)( 2,4 ,5 -trifluoro -3 -hydroxy
phenyl) -2 - trifluoro -methylbenzenesulfonamide (38 ). phenyl)methanone (66 ).
[5 - (5 -Fluoro -pyridin -3 -yl)-thiophen - 2 -yl)-(2 ,4 ,5 -trifluoro - (5 -( 1H -Benzo [ d ] imidazol-5 -yl)thiophen -2 -yl)( 2,4 ,5 -trif
3 -hydroxy -phenyl)methanone (39 ). 60 luoro - 3 -hydroxyphenyl)methanone (67 ).
[5 -(2,4 -Difluoro - phenyl)-thiophen -2 -yl)-(2 ,4,5 - trifluoro -3 - (5 -(4 -Hydroxyphenyl) thiophen -2 -yl)(2 ,4 ,5 -trifluoro -3 -hy
hydroxy -phenyl)-methanone (40 ). droxyphenyl)methanone (68 ).
(5 -(3 -Chloro - 4 -hydroxyphenyl) thiophen -2 -yl)(2,4 ,5 -trif (5 -(3 -Hydroxyphenyl) thiophen -2 -yl)(2 ,4 ,5 -trifluoro -3 -hy
luoro -3 -hydroxyphenyl)methanone (41). 65 droxyphenyl)methanone (69) .
(5-(3 -Fluoro -4 -hydroxyphenyl) thiophen -2 -yl)(2,4 ,5- trif (5-(2-Hydroxyphenyl)thiophen -2-yl)(2,4,5-trifluoro -3-hy
luoro -3 -hydroxyphenyl)methanone (42 ). droxyphenyl)methanone (70 ).
US 9 ,884 ,839 B2
29
(5-(4-Hydroxy-3,5-dimethylphenyl)thiophen -2-yl)(5
fluoro -3 -hydroxy -2-methyl-phenyl)methanone (71).
(4,5-Difluoro-3-hydroxy-2-methylphenyl)(5 -(4-hydroxy -3 , R 6

5 -dimethylphenyl)thiophen -2 -yl )methanone (72 ). 5


i

(5-Methylthiophen -2-yl)(2,4,5- trifluoro-3-hydroxyphenyl) +

methanone (73 ).
4 -(5 -(2 ,4 ,5- Trifluoro -3 -hydroxybenzoyl )thiophen -2 -yl )phe 10
nyl sulfamate (74 ). le, lg
4 -(5 -(2 ,6 - Difluoro - 3 -hydroxybenzoyl) thiophen - 2 -yl)benze R 6
nesulfonamide (75 ).
3 -(3-(2,6 -Difluoro -3 -hydroxybenzoyl)thiophen -2-yl)benze - 15
nesulfonamide ( 76 ).
(6 - Chloro -2 - fluoro -3 -hydroxyphenyl)(5 -( 3,5 -dichloro -4 OH
methoxyphenyl) thiophen -2 -yl)methanone (77).
(2 -Chloro -6 -fluoro -3-hydroxyphenyl)(5 -(3,5 -dichloro -4 - -20 NH2

methoxyphenyl) thiophen - 2 -yl)methanone (78 ). 1 , 35


(2 -Chloro -3 -hydroxyphenyl)(5 -(4 -hydroxy -3,5 -dimethyl
phenyl)thiophen -2 -yl)methanone (79). 25
Ri 6
Pharmaceutically acceptable a salts of said compounds (1) to
(79 ).
The compound for use in a mammal in the treatment ??
and/or prophylaxis of hormone-related diseases in a mam - 30
mal of aspect (6) above, the pharmaceutical composition or ANHO
medicament of aspect (8 ) above, themedicament of aspect S= 0
(9 ) above and the method for the treatment and /or prophy
laxis of hormone-related diseases in a mammal of aspect
( 10 ) above , all of which include the compounds of aspects
( 1) to (5) above and the particular compounds (1) to (79 ) as
defined above, are particularly suitable for the prophylaxis 40 2 - 4 , 36 - 38

and /or treatment of estrogen -related diseases in a mammal, R6


notably diseases in which a modulation of the estradiol level
is required , such as the treatment and/or prophylaxis of
endometriosis , endometrial carcinoma, endometrial hyper- 45
plasia, adenomyosis , breast cancer, ovarian carcinoma, OH
osteoporosis , osteopenia , impaired bone fracture healing,
prostate cancer, psoriasis , acne, (androgen -dependent) hair
loss, colon cancer , vaginal atrophy, hypercholesterolemia , -
and non -insulin -dependent diabetes mellitus.
The treatment and /or prophylaxis of hormone -related 5 -7 , 33, 34 , 48, 63
diseases in a mammal as referred to in of aspects (6 ) and (8 ) 55
to (11 ) above includes the treatment and /or prophylaxis of
all types ofmammals , such as primates (human beings, apes
etc.), farm animals (cattle, pig , horse, goat, rabbit etc .), Compound Ri R 2 R3 R4
companion animals (dog , cat guinea pig , hamster etc .), 60 le 2,6 -di-F -
rodents (mice , rats etc .) and the like, wherein the treatment
and /or prophylaxis of human beings is particularly pre
ferred .
In the following the chemical structures of the particularly as
preferred inhibitors ( 1) to (79 ) of the invention (hereinafter
2 ,4 ,5 -tri- F
2 ,6 - di- F
2 ,6 -di- F
2 ,6 -di- F
2 ,6 - di- F

4 -Br — 2 -OCF3
2 -OCF3
2 -CF3 11 I I
also “ title compounds ” ) are shown .
US 9, 884 ,839 B2
32
-continued -Ocontinued
Compound R R2 R3 RA Ri 6
2 ,6 - di - F

win
OH
10 K4

2 ,6 -di- F ? ? K6
R5

11 - 27 , 41- 42 , 44 -47 , 49 -60 ,


64 , 68-72, 74 -79

2 ,6 -di- F HH 20 Com
7 pound R R, R, R, R6

33

34
2 ,6 -di-F

2 ,6 -di- F
xxx
yo
to CH2

CH3
H

CH3
25

3030
131
*
9
=
12
13
14
15

18
20
8 2 , 6- di- F
2 ,6 -di- F
4a| 22,,66--didi-- FF
2 ,6 - diF - H
2, 6 - di- F CH?
26dE
2 ,6 - diF - HH
2 ,6 -diF - H
2 ,6 -di- F
26
2 ,6 --di - F
2 ,6 -di- F
2 ,6 -di- F
H
HO CH
H
CH
CF
H
H
OCH
H
H
|End
CH

CH
C

CH3
F
CN
— SO , - 4
morpholine
N
CH
CF
H
OCHZ
??? ,
H
OCHZ
OCHZ
OCHF2
OCH (CH3)2
OCHZ
CI
CH3

H
2 ,6 -di- F H H Cl OH
mi 35
21 2 , 6 - di- F CH? H .
22 2 ,6 -di- F H
23 2 ,6 -diF - H
24
25
2 ,6 -di- F
2 ,6 - diF -
OH

H
OH

OH
OH
OH ?
Hc
CH3
35 2 ,4 ,5 -tri -F 2 ,6 -di- F OCH3 CH3
27 2 ,6 -diF - H ?? CH3
????
????
??
4 - Br — 2 -OCFz
2 , 4 , 5 - tri - F
2 ,4,5 - triF - 2 -OCF3
2 ,4 ,5 - tri -F 2 -CF3
|
| |
|

40
39
40
41
42
2, 4 ,5 -tri- F H
2, 4 ,5 -tri- F H
2,4 ,5 -triF- H
2 , 4 , 5 - tri-F H
2 , 4 , 5 -tri- F H
CH
CF
N
CH
Cl
CONH ,
CH
CF
OH
OH
?
5.DŠEJLT5IED JR5E
CF
CH

48 2 ,4 ,5 - tri -F ? ? 45 2 , 4 ,5 -triF- H Cl OCH3


46 2 ,4 ,5 -tri- F H CH OCHZ CH3
47 2 ,4 ,5 -tri- F H CH ,OH H H
45
49 2 ,4 ,5 -tri-F H ? Cl OH Cl
50 2 ,4 ,5 -triF- H H CH3 OH CH3
51 2 ,4 ,5 -triF- H OCHZ
2 ,4 ,5 -tri-F H OCHZ
2 ,4 , 5 -tri- F H OCH
2 ,4 ,5 -triF- H H NHCOCHZ
50 55 2 ,4 ,5 - tri- F H NH2 H
63 2, 4,5-tri - F CH , ? ?
useyou
canso57
56 2 ,4 ,5 -tri-F H
2 ,4 ,5 -tri-FH
?
?
H
NH2 CH3
58 2 ,4 ,5 -tri- F H CHZ NH2 ?
59 246
2 , 4 , 5 -.tri- F H OH
NH2
60 2, 4 ,5 -tri- F H NH2 OCHZ
55 64 2 ,4 ,5 -tri-F H H ? NHCOCHZ
65 2,4 ,5 -tri- F H N ?
68 2 ,4 ,5 -tri-F H OH
? 69 2 ,4 ,5 -triF- H H OH
2 ,4 , 5 -tri- F H OH ? ?
4 5 - F ,2 - CH2 H H CH3 ?? CH3
60 4 ,5 -di- F, H
2 -CHZ
CH3 ?? CH3
OH 74 2 ,4 ,5 -tri-FH OSO2NH2
75 2 ,6 - diF - H H SO2NH2
76 2 ,6 -diF - H SONH2
R5 77 6 - C1,2 -F H H CI ?Me
78 2 - C1,6 - F H H Cl OMe
65 792 -C1 H H Me ??
8 -10 , 39 , 40 , 65
F
33 US9,84,839 B2
US 9 ,884,839 B2
34 34
Scheme 1: General synthesis of compounds having formula la
5 R5 R4
K2 IRO
RAILR
aryl )
R pony
R3 aryl,
R6
OH R3
a, b
(R2)n

R n = 1, 2, 3
R2n
28 - 30 15
" Reagents and conditions:
-
a method A , A1Cl3 , anhydrous CH2Cl2, 0° C ., 0.5 h and then rt, 3 h.
b method B , BBr3, CH2Cl2, -78° C . to it, overnight.

20
F

Scheme 2 : General synthesis of compounds having formula II


Rs
25 R3 F
Ri (RO)2B
31a, 31 , 32 R5
R3

Compound Ri R2
so y R-Ipiangolarester Log
aryl R = H , pinacolato -ester aryl

35
OCHZ COCHZ
OH COCHZ a a, c, d , e , or f
OCH3 ? VA
5
?
6
8
4
OCHZ ???? , (R2)n (R2n
OCHZ n = 1 , 2, 3 n = 1, 2 , 3
?? H

R 6
EO (RO ), B
Ro
Rio

2 aryl R6 arv ?
OH R2 R = H, 0. ?
pinacolato -ester
43, 61 , 62 , 66 , 67 , 73 b , c , d , e, or f Wilá
W RO

Compound Ri R " Reagents and conditions:


60 a method A , AIC13 , anhydrous CH2Cl2, 0° C ., 0.5 h and then it, 3 h .
43 2 ,4 ,5 -tri- F 1H -indol-6 -yl b method C1, Cs2CO3, Pd (PPh3)4, DME /water ( 1: 1), reflux , 4 h ; or
61 2 ,4 ,5 -tri- F 1H - indol- 5 - yl method C2 , Na2CO3 (2M ), Pd (PPhz)4, toluene/ethanol (1: 1), reflux , overnight.
2 ,4 ,5 -tri- F 1H -indol-4 - yl c method B , BBr3, CH2Cl2, -78° C . to rt, overnight.
2 ,4 ,5 -tri- F quinolin - 7 - yl d method D , pyridine, corresponding sulfonyl chloride, rt, overnight.
va
wNaN
2 ,4 ,5 - tri-F
2 ,4 ,5 -tri- F
1H -benzo [d ] imidazol-5 -yl
CH3
e HCI 6M , reflux , 2 h .
65 f NaH , DMF,Mel, 0° C . to rt , 0.5 h .
US 9 ,884,839 B2
35 36
Scheme 3: Synthesis of compounds le, 1g, 1 -25 , 35- 78a

Ri 6

Ri 6

OH

OH

R6R5 20 -25
8 - 10 , 39 , 40 49 - 50
68 -70

R 6 R 6
in

+
A
? 3
OH

Ro- R
R6
R5
8a - 10a, 40a
11- 19 , 41 -47
51-67, 75 - 78

pl. - popote
S
Ri 6
1
cl T

Br
A
Rj 6

R
1b (R = CH2CH3, R1 = 2 ,6 -di- F , R2 = H )
1c( R = CH2CH3, R1 = 2 ,6 -di- F , R2 = CH3)
1d (R = CH3, R1 = 2 ,4,5 -tri- F , R2 = H )
77a ( R = CH3, R1 = 4 - C1, 2 - F , R2 = H )
78a (R = CH3, R1 = 2 - C1, 4 - F , R2 = H )
Br
A
R16

3
OH
le (R1 = 2 ,6 - di- F , R2 = H )
1f(R1 = 2 ,6 - di- F , R2 = CH3)
1g (R1 = 2 ,4 ,5 -tri - F , R2 = H )
77b (R = CH3, R1 = 4 - CI, 2- F , R2 = H )
78b (R = CH3, R1 = 2- C1, 4- F ,R2 = H )
Br
- R2
US 9,884 ,839 B2
37 -continued
38
38

Ri 6 R 6

5 s

*
w

OR NH NH
OH

NH2

SO la, 35a 1 , 35

R2
2a -4a , 36a- 38a

Ri 6

OH

“Reagents and conditions:


2 -4 , 36 -38
??

a method A , A1C1z, anhydrous CH2Cl2, 0° C ., 0 .5 h and then rt, 3 h .


b method B , BBr3, CH2Cl2, -78° C . to rt,overnight.
Ri 6

OH

egy 5 - 7 , 48

c method C1, corresponding boronic acid for (1 , 1a , 10 - 19 ), Cs2CO3, Pd (PPh3)4, DME /water ( 1: 1 ), reflux , 4 h ; method C2, 4 -pyridinylboronic acid pinacol ester for (Sa ),
Lub=-0
0

3- pyridinylboronic acid for (9a ), 5 - fluoro -3 -pyridinylboronic acid for ( 39 ), (7 -(4 ,4, 5,5 - tetramethyl- 1, 3,2 - dioxaborolan - 2 -yl) quinolone (66a) for (66 ), Na2CO3 ( 2M ),
Pd(PPhz)4, toluene/ethanol (1:1 ), reflux, overnight;method C3, corresponding boronic acid for (41-47, 51-67, 75 -78 ), Cs2CO3, Pd(PPhz)4, toluene/DME /water (0 .7:0.9 :2 ),
85° C ., 16 h .
d method D1, pyridine, corresponding su ;fonyl chloride, rt, overnight;method D2, pyridine, correxponding sulfonyl chloride , CH2Cl2, rt, overnight.

Scheme 4 : Synthesis of compounds 27 -302


FO

Y F
OH
de OH ??

OH

27 26
US 9, 884 ,839 B2
- continued

Br ^ Cl Br ^

OH ??

26c 26b 26a

OH
Br

28
280
28a 28b

OH

OH OH
NH

29 30
" Reagents and conditions:
a NBS, AcOH , rt, overnight.
b CH31, K2CO3, DMF, rt , overnight.
c bispinocolato diborane, PddppCl2, KOAc/DMSO , 2 h .
d method C1, le , Cs2CO3, Pd(PPh3 )4 , DME/water (1: 1 ), reflux , overnight.
e method B , BBr3, CH2Cl2, - 78° C . to it, overnight.
f NBS, DBPO , CC14, reflux, 2 h .
g NEtz, 1 -piperazine - 1 - yl- ethanone.
h HC16M , reflux, 2 h .
US 9 , 884,839 B2
41
Scheme 5 : Synthesis of compounds 31a , 31 , 324

-- C/
. + NaN3
? 3
Br N,
N3
28b 31c 31b

???
0H

0H

32 31 31a

Reagents and conditions:


a DMF, ft, overnight.
b method C1, le, Cs2CO3, Pd (PPh3)4, DME/water (1:1 ), reflux , overnight.
cCH3COOCH = CH ), microwave, 120° C .,
d2M NaOH , THF, rt, 2h.
e method B , BBr3 , CHCl ; - 78°C . to rt , overnight ,

Scheme 6 : Synthesis of compounds 33, 344

??
-

Br N H2 Br )=:?-=0
Br 0
0= ?= 0

33b 34b 33a (R1 = H )


34a(R1 = CH3)
US 9, 884 ,839 B2
43
- continued
z
-
0
O= 's=
0

OH
33 (R1 = H )
34 (R1 = CH3)
" Reagents and conditions:
a method D , pyridine, cyclopropanesulfonyl chloride, rt, overnight.
b bispinacolato diborane, Pd (dppf)Cl2, KOAc/DMSO , 2 h .
c NaH , DMF,Mel , 0° C . to rt, 0.5 h .
d method C1, le, Cs2CO3, Pd(PPh3)4, DME/water (1:1), reflux, 3 days.

Scheme 7: Synthesis of compounds 58a, 59a, 60a , 62a, 66a, 76am

wereto workat
ArylDa

"Reagents and conditions:


-Br Aryl- B

58a , 59a, 60a , 62a ,


66a, 76a
a bispinacolato diborane, Pd(dppf)Cl2 ,KOAc/DMSO or Dioxane, 40 to 80° C .,
30 min to 72 h .
3030

Scheme 8: Synthesis of compound 71a

8
OOH OOH

F V NO2 I NO2 NO2


71a 715 71c
O

HO
HO 20 HO . 20

F HO
HO

718 71f 71e 71d


US 9 ,884 ,839 B2
45 46
- continued
OME OMe

71h 711
ago
"Reagents and conditions:
a H2SO4, HNO3, 0° C ., 1 h .
b BnBr, K2CO3, DMF, 50° C ., 1.5 h .
cH2, Pd/C ,MeOH, rt,41.5 h .
d NaNO2, H2O ,H2SO4, 0°C., 2 h then reflux , 15 min .
e Ac20 , DMAP, rt, 15 h ,
fSOC12, rt, 14 h then 80° C ., 1 h .
g 2-bromothiophene, AlCl3 , DCM , 0°C ., 1 h, rt, 4 h .
h method C3 .
i NaOH , THF, methanol, water, rt, overnight.
j Method B .

Scheme 9 : Synthesis of compound 72a


O= LOH C
Br

OMe F OMe F OMe F Y OMe


-

F
72a 72b
å
en
US 9, 884 ,839 B2
48
- continued
HO Meo

Br

F MeO
Me01 Y MeO
Me01 Y F
F É
72e 72d

"Reagents and conditions:


a Mg, Et20 , reflux , 2 h ,then CO2, THF , 10° C ., 4 h .
b n - BuLi, 2,2,6,6 -tetramethylmpiperidine, THF, -78° C ., 15 min then 0° C ., 1 h, Mel, 0° C ., 20 min then 40° C ., 1.5 h .
c SOCl2 , rt, 14 h .
d method A .
e method C3
f method B .

-continued
Scheme 10 : Synthesis of compound 73a

??

OMe

DALYS
3

#
FY F " Reagents and conditions :
OMe a 2 -Methylthiophene, method A .
b Method B .
73a

Scheme 11 : Synthesis of compound 74a

plocha
OR2
ld (R1 = 2 ,4 ,5 -tri - F , R2 = CH3)
1b (R1 = 2,6 -di-F , R2 = CH2CH3)
Bra
OR

74a (R1 = 2 ,4 ,5 -tri-F ,


R2 = CH3, R3 = p -OH )
49 US9.884359B2 so
US 9 ,884 ,839 B2
50

phoro phone
OR2
74 (R1 = 2,4,5 - tri-F , R2 = CH3, R3 = p -OH )
a Reagents and conditions:
a Method C3.
=
s
=

b Sulfamoyl chloride, N ,N - dimethylacetamide, 0° C ., 2 h .


0

NH2
-continued

OME
=
p=0
- NH2
74b (R1 = 2 ,4,5 -tri- F , R2 = CH3, R3 = p -OH )

c Method B .

Scheme 12 : Synthesis of compound 79a

OMe
4 - 6 - otha
OH
a

OMe
79a
OMe
79b
Br

phroatia
OME

"Reagents and conditions:


a SOC1) , reflux, 1 h .
b Method A .
c Method C1.
79
Me a
- OMe +
d

OMe

79c
- OMe

d Method B .

The invention is further described and illustrated in the the latter case after separation the solvent flow has been split
following examples,which are however not to be construed using a flow splitter and a 515 HPLC pump formakeup flow .
as limiting the invention . 50 Water containing 0 . 1 % formic acid and acetonitrile contain
ing 0 . 1 % formic acid were used as solvents for the analysis
EXAMPLES and separation . A Waters X -Bridge column (C18 , 150x4 .6
mm , 5 uM ) has been used with a flow of 1 ml/min for the
Chemical Methods : Chemical names follow IUPAC analysis and a Waters X - Bridge column (C18 , 150x19 mm ,
nomenclature . Starting materials were purchased from 55 5 uM ) has been used with a flow of 20 ml/min for the
Aldrich , Acros, Lancaster ,Maybridge , Combi Blocks, Merk , separation .
or Fluka and were used without purification . All microwave irradiation experiments were carried out in
Column chromatography (CC ) was performed on silica a CEM -Discover monomode microwave apparatus .
gel (70 -200 um ), reaction progress was monitored by thin ' H NMR and 13C NMR spectra were measured on a
layer chromatography ( TLC ) on Alugram SIL G UV254 60 Bruker AM500 spectrometer (500 MHz) at 300 K or on a
(Macherey -Nagel). Bruker Fourier300 (300 MHz) at 295 .5 K . Chemical shifts
In case of preparative HPLC purification the compounds are reported in d (parts permillion :ppm ), by reference to the
were purified using a setup produced by Waters Corporation hydrogenated residues of deuteriated solvent as internal
containing a 2767 Sample Manager, a 2545 binary gradient standard (CDC13 : 8= 7.24 ppm (' H NMR ) and 6 = 77 ppm
pump, a 2998 PDA detector and a 3100 electron spray mass 65 (13C NMR ), CD , OD : 8 = 3 .35 ppm (' H NMR ) and d = 49.3
spectrometer. The system has been used for a part of the ppm (13C NMR ), CD COCD3: 8 = 2 .05 ppm (' H NMR ) and
analytical analysis as well as the preparative separation. In 8 = 29 .9 ppm ( 13C NMR ), CD3SOCD 8 = 2.50 ppm ( H
US 9 ,884,839 B2
51 52
NMR ) and d = 39.5 ppm (13C NMR )). Signals are described General Procedure for Sulfonamide /Amide Coupling .
as s , br. s, d , t, dd , ddd, m , dt, q, sep for singlet, broad singlet , Method D1: The amino phenyl derivative (1 equiv ) was
doublet, triplet, doublet of doublets , doublet of doublets of dissolved in pyridine absolute and was spiked with sulfonyl
doublets,multiplet, doublet of triplets, quadruplet, and sep chloride/acid chloride ( 1. 5 equiv ). The reaction mixture was
tet respectively . All coupling constants (3 ) are given in hertz 5 stirred overnight at rt ( refluxed in case of amide coupling ).
(Hz). The reaction was quenched by adding 10 mlof 2N HCl and
Mass spectra ( ESI) has been recorded on a TSQ Quantum extracted with ethyl acetate . The organic layers were washed
( Thermo Finnigan ) instrument or on the system mentioned with saturated sodium hydrogenocarbonate and brine, dried
above. over magnesium sulfate , filtered and concentrated to dry
Tested compounds are > 95 % chemical purity as measured n ess. The product was purified by CC .
by HPLC . Method D2: The amino phenyl derivative ( 1 equiv ) and
Example 1 absolute pyridine ( 3 equiv ) was dissolved in dichlorometh
ane and was spiked with sulfonyl chloride (1 .1 equiv ). The
15 reaction mixture was stirred for 24 h at rt and 4 h at reflux .
Preparation of the Title Compounds The reaction was quenched by adding water and extracted
three
General Procedure for Friedel -Crafts Acylation . Method over magnesium times with ethyl acetate . The organic layers were dried
A : An ice -cooled mixture of monosubstituted thiophene ness. The product sulfate was
, filtered and concentrated to dry
purified by preparative HPLC .
derivate ( 1 or 1.5 equiv ), arylcarbonyl chloride (1 equiv), 20
and aluminumtrichloride ( 1 equiv ) in anhydrous dichlo
romethane was warmed to room temperature and stirred for 1b
2 - 4 h . 1M HClwas used to quench the reaction . The aqueous
layer was extracted with ethyl acetate . The combined
organic layers were washed with brine, dried over magne - 25
sium sulfate , filtered , and concentrated to dryness . The Brs
product was purified by CC . F
General Procedure for Ether Cleavage . Method B : To a
solution of methoxybenzene derivative ( 1 equiv ) in anhy
drous dichloromethane at -78 OC (dry ice /acetone- d6 bath ), 30
boron tribromide in dichloromethane (1M , 3 equiv per 5 -Bromo -thiophen -2 - yl )-(3 -ethoxy -2 ,6 - difluoro -phenyl)
methoxy function ) was added dropwise . The reaction mix - methanone (1b ): The title compound was prepared by reac
ture was stirred overnight at room temperature under nitro tion of 2 -bromothiophene (2217 mg, 13 .60 mmol), 2 ,6
gen atmosphere . Water was added to quench the reaction , difluoro -4 -ethoxybenzoyl chloride (3000 mg, 13 .60 mmol)
and the aqueous layer was extracted with ethyl acetate . The 35 and aluminum chloride ( 1813 mg, 13 .60 mmol) according to
combined organic layers were washed with brine, dried over method A . The product was purified by CC (hexane/ ethyl
magnesium sulfate , filtered , and concentrated to dryness . acetate 97 :3 ); yield : 79 % (3740 mg). ' H NMR (300 MHz,
The product was purified by CC . acetone- d ) 8 7 . 34 (dd, J = 4 . 1, 0 . 9 Hz, 1H ), 7 .20 - 7 . 22 (m ,
General Procedure for Suzuki Coupling . Method C1: A
mixture of arylbromide ( 1 equiv ), boronic acid derivative 40 2H ), 6 . 98 ( td , J= 9.0 , 2.0 Hz, 1H ), 4 .05 (q , J= 7 .0 Hz, 2H ),
1.27 (t, J= 7.0 Hz, 3H ); 13C NMR (75 MHz, acetone- d ') &
( 1 . 2 equiv ) , cesium carbonate (4 equiv ) and tetrakis (triph
enylphosphine ) palladium ( 0 .01 equiv ) was suspended in an 179 .03 , 153 .83 , 153 .76 , 150 .63 , 145 .09, 136 .88 , 132.66,
oxygen -free DME/water (1: 1 ) solution and refluxed under 128 . 96 , 124 .50 , 117 .19 , 117 .06 , 65 .44 , 14 .08 ; 13C NMR ( 75
nitrogen atmosphere . The reaction mixture was cooled to MHz, Acetone -d ') & 179 .03 , 152. 19 ( dd , J = 242 .2 , 5 .8 Hz),
room temperature . The aqueous layer was extracted with 45 148 .69 (dd, J = 250 .5 , 7 .4 Hz ), 145 . 09 , 143 . 94 ( dd , J = 10 .6 ,
ethyl acetate. The combined organic layers were washed 3 .3 Hz), 136 .88 , 132 .66 , 128 . 96 , 124.50 , 117 . 11 (dd , J = 9 .3 ,
with brine, dried over magnesium sulfate , filtered and con - 3 . 2 Hz ), 111 .26 (dd , J = 22.6 , 4 . 1 Hz ), 65. 44, 14 . 08 ; MS
centrated to dryness . The product was purified by CC . ( ESI): 448 . 64 ( M + H ) *.
Method C2: A mixture of arylbromide ( 1 equiv ), boronic
acid derivative (1. 2 equiv ), sodium carbonate ( 2 equiv ) and 50
tetrakis (triphenylphosphine ) palladium (0 . 01 equiv ) was lc
suspended in an oxygen -free toluene/ ethanol (1 :1 ) solution
was refluxed for 20 h under nitrogen atmosphere. The F
aqueous layer was extracted with ethyl acetate. The com
bined organic layers were washed with brine, dried over 55 F
magnesium sulfate, filtered and concentrated to dryness . The
product was purified by CC .
Method C3: A mixture of arylbromide (1 equiv ), boronic
acid derivative ( 1 . 1 equiv ), cesium carbonate ( 3 . 5 equiv ) and
tetrakis(triphenylphosphine ) palladium (0 .035 equiv ) was 60 (5 -Bromo-4 -methyl-thiophen -2 -yl)-(3 -ethoxy - 2,6 -dif
suspended in an oxygen - free toluene/DME /water (0 .7 : 0 . 9 : 2 ) luoro - phenyl)-methanone ( 1c ): The title compound was pre
solution and heated under argon atmosphere to 85° C . for 16 pared by reaction of 2 - bromo- 3 -methoxy -thiophene ( 1204
h . The reaction mixture was cooled to room temperature . mg, 6 . 80 mmol) , 2 ,6 - difluoro - 4 - ethoxybenzoyl chloride
Water was added and the aqueous layer was extracted with (1000 mg, 4 .53 mmol) and aluminum chloride (604 mg, 4 .53
ethyl acetate three times. The combined organic layers were 65 mmol) according to method A . The product was purified by
dried over magnesium sulfate , filtered and concentrated to CC (hexanelethyl acetate 97 : 3 ); 49 % (800 mg). MS (ESI):
dryness. The product was purified by preparative HPLC . 362 .09 (M + H ) *
US 9 ,884,839 B2
54
54
ld 18

OH

F
10

( 5 -Bromo -thiophen - 2 -yl) -(2 , 4, 5 - trifluoro - 3 -methoxy (5 -Bromo -thiophen - 2 -yl)-(2 ,4,5 - trifluoro - 3 -hydroxy -phe
phenyl)-methanone ( 1d ): A mixture of 2 -bromothiophene nyl) -methanone (1g ): The title compound was prepared by
(3000 mg, 18.4 mmol), 2,4 ,5 - trifluoro - 3 -methoxybenzoyl . reaction of (5 -bromothiophen - 2 - yl)( 2 ,4 ,5 - trifluoro - 3
chloride (4132 mg, 18 .4 mmol) and aluminiumum chloride chloride 15 methoxyphenyl)methanone (id ) ( 3000 mg, 8 .64 mmol) and
( 2453 mg, 18.4 mmol) in anhydrous dichloromethane was boron tribromide (43. 2 mmol) according to method B . The
stirred at 0° C . for 30 min . The reaction mixture was warmed product was purified by CC ( hexan / ethyl- acetate 9 : 1 ) ; yield :
to rt and stirred for 1 h . HCl 1M was used to quench the 841H %, OH (2310 mg). ' H NMR (300 MHz, acetone - d “) d 9 .85 (s,
), 7 .40 (dd , J = 4 . 1 , 1 . 8 Hz, 1H ), 7 .23 (t, J = 4 . 4 Hz.
reaction . The aqueous layer was extracted with ethyl acetate . 20
The combined organic layers were washed with brine, dried 201H ), 6 .99 (ddd , J= 10 .0 , 8. 1, 5.6 Hz , 1H ); 13C NMR (75
over magnesium sulfate , filtered and concentrated to dry 148 .37, acetone
MHz -d ') & 181. 29 , 148 .81 (dd , J = 11 .1 , 3 . 1 Hz),
(dd, J= 16 . 2, 2 .3 Hz), 144 .80 , 144 .64 (dd , J = 6 .6 , 2 .3
ness. The product was purified by CC (hexan / ethyl acetate
97 : 3 ), yield 75 % (5845 mg); ' H NMR ( 300 MHz, acetone Hz ), 141. 26 (dd , J= 15 . 9, 5 .8 Hz), 136 . 83 (d , J = 2 . 3 Hz),
d ) 8 7 .41 (dd . J = 4 . 1. 1. 9 Hz. 11 ). 7 .28 - 7 . 19 (m , 2H ), 3.97 25 136 .20 (dd , J= 30 .7 , 3 .2 Hz), 132. 40 , 123 .83 , 106 . 16 (dd ,
( t. J = 1 .2 Hz, 3H ) : 13C NMR ( 75 MHz, acetone- d ) 8 180 . 99. J = 21.2 , 3 .0 Hz).
151.02 , 149.48 , 147.76 , 144.68 , 136 .99 , 136 .95 , 132 .45 ,
124 . 04 , 110. 44 , 110 . 12 , 61. 86 .

le 30

Br 35
F ??

[ 5 -(3 - Aminophenyl)thiophen -2 -yl](3 -ethoxy -2 ,6 -difluo


rophenyl)methanone ( la ): The title compound was prepared
(5 -Bromo -thiophen - 2 -yl)-(2 ,6 -difluoro - 3 -hydroxy -phe- 40 by reaction of (5 -bromothiophen - 2 -yl)( 3 - ethoxy -2 ,6 -difluo
nyl)-methanone ( le ): The title compound was prepared by rophenyl)methanone (1b ) (450 mg, 1 .30 mmol) and
reaction of 5 -bromo-thiophen -2 -yl)-(3 -ethoxy -2,6 -difluoro - 3 -aminophenyl-boronic acid ( 213 mg, 1.55 mmol), cesium
phenyl)-methanone (1b ) ( 3000 mg, 8 .64 mmol) and boron carbonate (1689 mg, 5 . 18 mmol) and tetrakis( triphenylphos
tribromide (43 .20 mmol, 5 equiv ) according to method B . phine ) palladium (20 mg, 16 umol) according to method C1.
The product was purified by CC (hexane /ethyl acetate 45 The product was used directly in the subsequent reaction
90 : 10 ); yield : 84 % (2310 mg). MS (ESI): 320 . 12 (M + H )*. without any characterisation ; yield : 88 % (410 mg).
The product was used in the next steps without any char
acterisation .
1
50
if

Br 55 H2N - OH
F OH
??

[5 -(3 -Aminophenyl) thiophen -2 -yl ](2 ,6 - difluoro - 3 -hy


droxyphenyl)methanone ( 1): The title compound was pre
(5 -Bromo- 4 -methyl-thiophen - 2 - yl)- ( 2 ,6 - difluoro -3 - hy - 60 pared by reaction of [5 - ( 3 -aminophenyl) thiophen - 2 - yl )- (3
droxy - phenyl)-methanone ( 1f) : The title compound was ethoxy -2 ,6 - difluorophenyl)methanone (la ) (440 mg, 1. 22
prepared by reaction of (5 -bromo-4 -methyl- thiophen -2 -yl)- mmol) and boron tribromide (3.7 mmol) according to
( 3 -ethoxy- 2 ,6 - difluoro -phenyl)-methanone ( 1c ) (850 mg, method B . The product was purified by CC (dichlorometh
2 . 35 mmol) and boron tribromide ( 11.76 mmol, 5 equiv ) ane /methanol 99.5 :0 . 5) ;yield : 50 % (200 mg). ' H NMR (500
according to method B . The product was used in the next 65 MHz, acetone -d ') 8 9 .02 (br. s, 1H ), 7 .45 (dd , J= 7 .1, 2 .9 Hz,
step without further purification and characterisation ; yield : 1H ), 7 .33 ( d , J = 4 . 1 Hz, 1H ), 7 . 10 (dd , J =41. 1 , 6 .5 Hz, 2H ),
77 % (600 mg). 7 .00 -6 .85 (m , 3H ), 6 .62 ( ddd , J= 8.0 , 2 .1, 0.8 Hz, 1H ), 4.75
US 9 ,884 ,839 B2

? ? ????????
55 56
(br. s, 2H , NH ,); 13C NMR (125 MHz, acetone -d “) 8 179.48 , 126 .34 , 124 .92 (d , J= 1.9 Hz), 123.59, 122 .15, 120. 39 (dd ,
155.98 , 152 .23 (dd, J = 241.6 , 6 .1 Hz), 149 .34 , 148 .66 (dd , J = 9. 1 , 3 .8 Hz ), 120 .08 , 118 . 80 , 118 .01 (dd , J = 24 .0 , 19 .7 Hz),
J = 249. 5 , 7 .7 Hz), 143 . 90 (dd, J = 10 .7 , 3 .2 Hz), 137.34 , 112 .44 (dd , J= 22 .8 , 3 .9 Hz); MS ( ESI): 635 . 43 (M + H ) *.
133.47 , 129 .97 , 125 . 13 , 124 .46 , 121.00, 116 .62 (dd , J = 9 .3 ,
3 .0 Hz), 115 .73 , 114 .65, 111 .62 , 111 . 13 (dd , J = 22 .7 , 4 .1 Hz ); 5 3a
MS (ESI): 332 . 12 (M + H ) *.
F
=

NH

F
O=
S= NH
O
a
17
N - { 3 -[ 5 - (3 -Ethoxy- 2 ,6 -difluorobenzoyl) thiophen - 2 -yl]
20 phenyl) - 2 -trifluoromethoxy -benzene-sulfonamide ( 3a ): The
title compound was prepared by reaction of [5 -(3 -amino
phenyl)thiophen - 2 -yl]( 3 -ethoxy -2 ,6 -difluorophenyl)metha
none (la) (210 mg, 0 .58 mmol) and 2 - trifluoromethoxyben
4 -Bromo-N - { 3- [5 -(3 -ethoxy -2,6 -difluorobenzoyl) thio zenesulfonyl chloride ( 152 mg, 0 .58 mmol) according to
phen - 2 -yl]phenyl} -2 -trifluoro -methoxy -benzenesulfona - 25 method Di. The product was sufficiently pure for use in the
mide (2a): The title compound was prepared by reaction of subsequent reaction ; yield : 66 % (225 mg; yellow oil ).
[ 5 - (3 - aminophenyl) thiophen - 2 - yl] (3 -ethoxy -2 ,6 -difluoro
phenyl)methanone ( la ) (210 mg, 0 .58 mmol) and 4 -bromo
2 -trifluoromethoxybenzenesulfonyl chloride ( 198 mg, 0 .58 3
mmol) according to method D1.; yield : 65 % (250 mg). The 30
product was used in the next steps without any characteri
sation . F

2 35
O= o= 0NH OH

F 40
NH
O=s=0 ??

F N - {3 -[5 -(2,6 -Difluoro -3-hydroxybenzoyl)thiophen -2 -yl]


F phenyl) - 2 -trifluoromethoxy -benzene -sulfonamide (3): The
Tla
title compound was prepared by reaction of N -{3 -[5 -(3
ethoxy -2 ,6 -difluorobenzoyl) thiophen -2 -yl)phenyl)- 2 -trif
luoromethoxybenzene -sulfonamide (3a ) (225 mg, 0. 39
mmol) and boron tribromide (2 .3 mmol) according to
4 -Bromo- N - { 3 -[5 -(2 ,6 -difluoro - 3 -hydroxybenzoyl)thio - 50 method B . The product was purified by CC (dichlorometh
phen -2 -yl)-phenyl) - 2-trifluoromethoxybenzenesulfonamide ane/methanol 99 .5 :0 .5) ; yield : 44 % (142mg). TH NMR (500
(2 ): The title compound was prepared by reaction of
4 -bromo- N - { 3 -[5 -(3 -ethoxy - 2,6 -difluorobenzoyl-thiophen MHz, acetone -d ') d 9.50 (br. s, 1H ), 9.04 (br. s , 1H ),
2 - yl) phenyl } - 2 -trifluoromethoxy -benzenesulfonamide (2a ) 8 . 14 - 8 .09 ( m , 1H ) , 7 .77 (ddd , J = 8 .4 , 7 .5 , 1. 7 Hz, 1H ),
(250 mg, 0.38 mmol) and boron tribromide (2 .3 mmol) 55 7 .68 - 7.65 (m , 1H ), 7 .62 (dt, J= 4.0 , 0.8 Hz, 1H ), 7 .57 -7 .51
according to method B . The product was purified by CC (m , 3H ), 7 .51 -7 .50 (m , 1H ), 7 .38 (tt, J = 4 .6 , 2 .3 Hz, 1H ),
( dichloromethane /methanol 99 . 5 :0 .5 ) ; yield : 75 % (180 mg).
IH NMR (500 MHz, acetone- d ) 8 9 .35 (br. s, 1H ), 8 .58 (br. 7 .34 -7 .30 (m , 1H ), 7.25 -7 .17 (m , 1H ), 7.03 (ddd , J = 10 .5 ,
s, 1H ) , 8 . 03 ( d , J = 8 .5 Hz, 1H ), 7 .76 ( dd , J = 8 .5 , 1. 8 Hz, 1H ), 6 .9 , 1. 9 Hz, 1H ); 13C NMR ( 125 MHz, acetone -d ') & 180 .69 ,
7 .73 ( m . 1H ), 7 .68 - 7 .65 ( m . 1H ) , 7 .62 ( dt. J = 4 . 1. 0 .9 Hz. 60 154 .44 , 152.55 (dd, J = 240 .6 , 5 .8 Hz ), 148 .43 (dd , J = 245. 9 ,
1H ), 7 . 54 (ddd , J = 7 .7 , 1 .8 , 1.0 Hz, 1H ), 7 .52 (d , J = 4 . 1 Hz , 7 .8 Hz), 146 .82 (d , J= 1 .7 Hz), 143 .48 , 142 .66 (dd , J= 12 .9 ,
1H ), 7 . 42 - 7 . 37 ( m , 1H ), 7 . 32 (ddd , J = 8 . 1 , 2 .2 , 1. 0 Hz, 1H ), 3 .2 Hz). 139 . 17 . 138. 18 . 136 .37 . 134 . 77. 132.58 . 132 .25 .
7 . 19 - 721 (m , 1H ), 7 .03 (ddd , J = 9 . 1, 8 .6 , 1. 9 Hz, 1H ) ; 13C
NMR (125 MHz, acetone-d ') & 180 .68 , 154 .32, 152 .55 (dd , 131 .25 , 128 .02 , 126 .26 , 123 .28 , 124 .49 - 120 .18 (m ), 121. 95 ,
J = 240 .6 , 5 .8 Hz), 148 .43 (dd , J= 245 .8 , 7 .7 Hz), 146 .95 (d , 65 53 (d , J= 1.8 Hz), 120 . 39 (dd, J= 9 .1 , 3 .8 Hz), 118 .50 ,
121.
J= 1. 8 Hz ), 143. 55 , 142 .66 (dd, J= 13 . 0 , 3 . 2 Hz ), 138.85 , 118 .02 (dd , J= 23 .9, 19 .7 Hz), 112 .45 (dd , J= 22 .8 , 3. 9 Hz);
138 . 17 , 134 .88 , 133 .83 , 131 .81, 131 .47 , 131.34 , 129 .12 , MS (ESI): 555 . 17 (M ) *.
US 9 ,884,839 B2
en
o

F OH

O=
-= = NH
S=
0
10

OSS
15
N - { 3 -[5 -(3 -Ethoxy -2 ,6 -difluorobenzoyl)thiophen - 2 -yl]
phenyl)-2 -trifluoromethyl-benzene -sulfonamide (4a ). The
title compound was prepared by reaction of [5-(3-amino
phenyl)thiophen - 2 -yl](3 -ethoxy -2 ,6 -difluorophenyl)metha 20 Pyridine- 3 -sulfonic acid (3 - [5 -( 2,6 - difluoro - 3 -hydroxy
none (1a ) (210 mg, 0.58 mmol) and 2-trifluoromethylben
nuoromethylben - benzoyl)- thiophen - 2 -yl)-phenyl) -amide (5 ): The title com
zenesulfonyl chloride ( 143 mg, 0 .58 mmol) according to pound was prepared by reaction of [5 - (3 -aminophenyl)
method D1 yield : 68 % (225 mg). The product was used in thiophen - 2 - yl ](2,6 -difluoro -3 -hydroxyphenyl)methanone
the next steps without any characterisation . ( 1 ) ( 100 mg, 0 .30 mmol) and pyridine - 3 -sulfonyl chloride
25 hydrochloride ( 96 mg, 0 .45 mmol) according to method D1.
The product was purified by CC (dichloromethane/methanol
. 95 : 5 ) ; yield : 35 % (50 mg ). ' H NMR (500 MHz, acetone -dº)
8 8 . 28 ( dd, J = 2 .4 , 0 .8 Hz , 1H ), 8 . 10 ( dd , J = 4 .7 , 1 .6 Hz, 1H ),
7 .52 - 7 .49 (m , 1H ), 6 .96 -6 .94 (m , 1H ), 6 .94 -6 .91 (m , 1H ),
F
30 6 .88 ( d , J = 4 . 1 Hz, 1H ), 6 . 83 ( d , J = 7 .6 Hz, 1H ), 6 . 82 - 6 .80 ( m ,
1H ), 6 .71 (t, J= 7 .9 Hz, 1H ), 6 .55 -6 .47 (m , 2H ), 6 .41 (td ,
J = 9 . 0 , 1.6 Hz, 1H ); 13C NMR ( 125 MHz, acetone- d ') 8
O-
S=
- NH OH
180 .8 , 154 .6 , 154 .4, 148.7 , 143.6 , 139.3, 138 .3, 137.0 ,
toO F 135 . 9 , 135 .0 , 131 .5 , 126 .5 , 125 . 1 , 123.8 , 122.8 , 120 .4 ,
35 119 .4 , 112 .6 , 112.4 ; MS ( ESI): 473 .28 (M + H ) *.
IF

40

OH

N -{ 3 -[5 -(2,6 -Difluoro -3 -hydroxybenzoyl)thiophen - 2 -yl ]


phenyl) -2-trifluoromethyl-benzene -sulfonamide (4 ): The as
title compound was prepared by reaction of N - {3-[5-(3
ethoxy -2 ,6 -difluorobenzoyl)thiophen - 2 -yl]phenyl) -2 - trif
luoromethylbenzenesulfonamide (4a ) (230 mg, 0 .41 mmol)
and boron tribromide (2 .4 mmol) according to method B . OES
The product was purified by CC (dichloromethane/methanol
99 .5 :0 .5 ); yield : 48 % (165 mg). ' H NMR (500 MHz,
acetone- d ) 8 9.39 (br. s, 1H ), 9 .00 (br. s, 1H ), 8 .30 - 8.25 (m ,
1H ), 8.03 -7 .98 (m , 1H ), 7.87 -7.82 (m , 2H ), 7 .68 - 7.65 (m , ss
1H ), 7.62 (dt, J = 4 .1, 0 .9 Hz, 1H ), 7 .55 -7 .51 (m , 2H ),
7 .42 - 7 .37 (m , 1H ), 7 .32 (ddd , J = 8 . 1, 2 .2 , 1.0 Hz, 1H ), 1-Methyl- 1H -imidazole -4 -sulfonic acid ( 3- [5 -( 2 ,6 -dif
7 .19-7 .21 (m , 1H ), 7 .06 -7 .00 (m , 1H ); 13C NMR ( 125 MHz, luoro (6 ):
- 3 -hydroxy - benzoyl)- thiophen - 2 -yl)-phenyl ) -amide
The title compound was prepared by reaction of [ 5 -(3
acetone - d ') & 180 .69 , 152 .54 (dd , J= 240 .6 , 5 .8 Hz), 1480.:42
42 60 aminophenyl )thiophen -2 -yl](2 ,6 -difluoro - 3-hydroxyphe
(dd, J = 245.8 , 7 .8 Hz), 143.51, 142.66 (dd, J= 12 . 9, 3 .2 Hz), nyl)methanone ( 1 ) ( 100 mg, 0 . 30 mmol) and 1-methyl- 1H
139. 14 , 139 . 11 , 138 . 17 , 134 . 83 , 134. 47 , 133 .86 , 132 .78, imidazole -4 -sulfonyl chloride (81 mg, 0 .45 mmol)
131.32 , 129 .56 (q , J= 6 .4 Hz), 128.41, 128 . 15 , 126 . 32, according to method D1. The product was purified by CC
125 .06 , 123 .37 , 122 .88 , 122 .14 , 120 .39 (dd, J = 9 .1, 3 .8 Hz ( dichloromethane/methanol 95 : 5 ); yield : 72 % (103 mg) . ' H
12 )),, 65 NMR (500 MHz, acetone -d ) 8 9 .17 (s, 1H ), 9 .01 (s, 1H ),
118 .73 , 118 .02 (dd , J= 24 .0 , 19.6 Hz ); MS (ESI): 539.32 7 .75-7 .72 (m , 2H ), 7 .64 -7 .61 (m , 2H ), 7.54 (d , J= 4 . 1 Hz,
(M ) . 1H ), 7.50 -7.43 (m , 1H ), 7 .39 -7 .34 (m , 2H ), 7.21 ( td, J = 9 .4 ,
US 9 ,884 ,839 B2
59
5.5 Hz, 1H ), 7 .04 (td, J = 8.8 , 1. 9 Hz, 1H ), 3.76 (s, 3H ); 13C
NMR ( 125 MHz, acetone - d “) & 180 .7 , 155 . 1, 153 .6 , 151 .6 ,
149.5 , 147 .5 , 143 . 3 , 142 . 7 , 140 .7 , 140 . 1 , 138 .3 , 134 .5 ,
130 . 9, 126 .2, 122 .5, 121.9 , 1204 , 118.4 , 112.6 , 112 .4 , 34 .2 ;
MS (ESI): 476 .21 (M + H ) +. F

7 OH
10

OH (2,6 -Difluoro -3-hydroxy -phenyl)-(5 -pyridin -4- yl-thio


phen -2 -yl )-methanone (8 ): The title compound was prepared
F by reaction of (3 -Ethoxy -2 ,6 -difluoro -phenyl)-(5 -pyridin -4
15 yl-thiophen -2-yl)-methanone (8a) (450 mg, 1.30 mmol) and
boron tribromide (7.8 mmol, 6 .0 equiv ) according to method
NH B . The product was purified by CC (dichloromethanel
OES
methanol 90 : 10 ); yield : 24 % ( 100 mg). ' H NMR (500 MHz,
20 DMSO - d “) & 10 .40 (br. s, 1H ), 8.64 (d , J= 6 . 1 Hz, 2H ), 7. 91
(d , J = 4 .1 Hz, 1H ), 7 .77 (dd , J = 4 .6 , 1. 5 Hz, 2H ), 7.69 (d ,
J = 4 .0 Hz, 1H ), 7 . 16 ( td , J = 9 .4 , 5 .6 Hz, 1H ), 7 .08 (t, J = 8 .6
Hz, 1H ); 13C NMR ( 125 MHz, DMSO -d ) 8 180 .32 , 150 .66 ,
Cyclopropanesulfonic acid { 3 -[5 -(2 ,6 -difluoro -3 -hy- 25 150 .49 , 150 .46 (dd , J = 239 .7, 5 .6 Hz), 146 .88 (dd , J= 246 .7 ,
droxy -benzoyl)- thiophen -2 - yl)-phenyl} -amide ( 7): The title 7.5 Hz), 143. 06 , 141. 92 (dd , J = 11. 8, 2 .9 Hz) 139.04 ,
compound was prepared by reaction of [ 5 -(3 -aminophenyl) 137 .82, 128 . 13 , 120 .19 , 119.81 (dd, J = 8 . 9, 3 .9 Hz), 116 .22
thiophen -2 - yl ](2,6 -difluoro -3 -hydroxyphenyl)methanone (dd, J= 23 .4 , 19 .0 Hz), 111.75 (dd , J= 22 .3 , 3 .5 Hz); MS
( 1) ( 100 mg, 0 .30 mmol) and cyclopropanesulfonyl chloride 30 (ESI): 317 .94 (M )+ .
( 1M in dichloromethane ) (63 mg, 0.45 mmol) according to
method D1. The product was purified by CC (dichloro 9a
methane /methanol 95 :5 ); yield : 56 % (73mg). 'H NMR (500
MHz, acetone -d ) d 9 .01 (s, 1H ), 8 .77 (s , 1H ), 7 .80 -7 .78 (m , 35
1H ), 7 .65 (dt, J= 4 .1, 0. 9 Hz, 1H ), 7.61-7 .58 (m , 2H ),
7 .54 -7 .44 (m , 2H ), 7 .21 ( td , J = 9.5 , 5. 4 Hz, 1H ), 7 .04 (td ,
J = 9 .0 , 1. 9 Hz, 1H ), 2 .73 - 2 .67 (m , 1H ), 1.07- 0 . 96 (m , 4H ) ;
13C NMR ( 125 MHz, acetone -d ) 8 188 .7 , 154 .8, 143.5 , 40
140 .6, 138 .3 134 .9 , 131.3 , 126 .3 , 123 .1, 122 .6 , 120 .4, 119 .2,
112 .6 , 112.4 , 32.4 , 5 .8; MS (ESI): 436 .25 (M + H )*.
(3- Ethoxy -2,6 -difluoro -phenyl)-(5 -pyridin -3-yl-thio
Sa
45 phen - 2 -yl)-methanone (9a ): The title compound was pre
pared by reaction of 5 -bromo- thiophen -2 -yl)-(3 -ethoxy-2 ,6
difluoro -phenyl)-methanone ( 1b ) (400 mg, 1. 15 mmol),
pyridine -3 -boronic acid ( 170 mg, 1.38 mmol), sodium car
50 bonate (2.5 ml, 2 M ) and tetrakis (triphenylphosphine ) pal
ladium (5 umol) according to method C2 . The product was
purified by CC (dichloromethane/methanol 99.5:0 .5 ); yield :
50 % ( 200 mg). ' H NMR ( 300 MHz , acetone - d ') / 8 . 90 ( d ,
55 J= 2 .2 Hz , 1H ), 8 .50 (dd, J= 4 .8, 1.4 Hz, 1H ), 8 .04 (ddd ,
(3 -Ethoxy -2,6 -difluoro -phenyl)-(5 -pyridin -4 -yl- thio J = 8. 0, 2.3 , 1. 7 Hz, 1H ), 7 .59 (d , J = 4 . 1 Hz, 1H ), 7 .55 (dd ,
phen -2 - yl) -methanone (8a): The title compound was pre - J = 4 .0, 0 .7 Hz, 1H ), 7 .37 (ddd, J = 8 .0 , 4 .8 , 0.6 Hz, 1H ), 7 .22
pared by reaction of 5 -bromo-thiophen -2 -yl )-(3 -ethoxy -2,6 - (td, J = 9.3 , 5 .3 Hz, 1H ), 6 .99 (td , J= 8 . 9, 2.0 Hz, 1H ), 4.06 (q ,
difluoro -phenyl)-methanone (1b ) (300 mg, 0 .86 mmol), 60 J= 7.0 Hz, 2H ), 1.28 (t, J= 7 .0 Hz, 3H ); 13C NMR (75 MHz,
pyridine -4 -boronic acid pinacol ester (355 mg, 1.73 mmol), acetone -d “) 8 179.71, 152.23 (dd, J= 241.8 , 5.9 Hz ), 150 .81 ,
sodium carbonate (2 .5 ml, 2 M ) and tetrakis (triphenylphos - 148.70 (dd , J = 241.8 , 5 .9 Hz), 147 . 16 , 143 .95 (dd , J= 10 .6 ,
phine) palladium (5 umol) according to method C2. The 3 .3 Hz ), 143.20 , 137.35 , 133.48 , 128. 92, 126 .24, 124 .03 ,
product was purified by CC (dichloromethane/methanol cs 117.40 (dd , J = 22.9 , 3 .2 Hz ), 116 .88 (dd, J= 9.3, 3.1 Hz),
99 .5 :0 .5 ); yield : 91 % (450 mg). The product was used in the 111.22 (dd , J= 22.6 , 4 .2 Hz), 65 .44 (s), 14 .10 (s); MS (ESI):
next steps without any characterisation . 346 .05 ( M ) .
US 9 ,884,839 B2
62
was prepared by reaction of [5 -( 2,4 - difluoro - phenyl)- thio
phen -2 -yl]- (3 -ethoxy -2 ,6 - difluoro -phenyl)-methanone ( 10a )
( 300 mg, 0 .79 mmol) and boron tribromide (3 . 9 mmol, 5 .0
equiv ) according to method B . The product was purified by
F 5 CC ( dichloromethane /methanol 99.75 :0 .25 ); yield : 72 %
( 280 mg). ' H NMR (500 MHz, acetone- d ) 8 8 . 99 ( s, 1H ) ,
7 . 96 (td , J = 8 .8 , 6 . 3 Hz, 1H ) , 7 .68 (ddd , J = 4 .0 , 1. 9 , 0 . 9 Hz,
1H ), 7.65 (dd , v= 4 .1, 0 .9 Hz, 1H ), 7 .29 -7 .23 (m , 1H ),
7 . 23 - 7 . 16 (m , 2H ), 7 .02 -7 .04 ( m , 1H ); 13C NMR ( 125 MHz,
1010 acetone- d ) 8 180 . 88 (s ), 164. 18 (dd , J = 251. 5 , 12 .7 Hz),
(2 ,6 -Difluoro -3 -hydroxy -phenyl)-(5 -pyridin -3 -yl- thio 160 .45 (dd, J = 253.6 , 12 .6 Hz), 152. 56 (dd , J= 240.6 , 5 .8 Hz ),
phen -2 -yl) -methanone (9 ): The title compound was prepared 148 .43 (dd , J= 245 .8 , 7.7 Hz), 145 .46 (dd , J= 361.6 , 3 .6 Hz),
by reaction of ( 3- ethoxy -2 ,6 -difluoro -phenyl)-(5 -pyridin -3 142 .65 (dd, J= 12 . 9, 3 .2 Hz ), 137 .39 , 131.60 (dd , J = 9.8 , 4 . 4
yl-thiophen - 2 -yl)-methanone (9a ) ( 200 mg, 0 .58 mmol) and Hz ), 128 .62, 128 .59, 120 .41 (dd, J = 9 . 1 , 3 . 9 Hz), 118 . 40 (dd ,
boron tribromide (3 .47 mmol, 6 .0 equiv ) according to J = 12 .7 , 4 . 1 Hz ), 118 .04 (dd , J= 24 .0 , 19.6 Hz ), 113 .46 (dd ,
method B . The product was purified by CC (dichlorometh - J = 21 . 1 , 4 .5 Hz ), 112 .46 ( dd , J = 22 .8 , 3 . 9 Hz ), 105 .76 (t,
ane/methanol 90 : 10 ); yield : 17 % ( 31 mg). ' H NMR (500 J= 26 .4 Hz); MS ( ESI): 352 .88 ( M )*.
MHz, DMSO -d ) 8 10 .28 (s, 1H , OH ), 9 .06 (s, 1H ), 8 .64 (d ,
J = 4 .2 Hz, 1H ), 8 . 23 (ddd , J = 8 .0 , 2 .4 , 1 .5 Hz, 1H ), 7 . 81 (d , so
11
J = 4. 1 Hz, 1H ), 7 .71 (d , J = 4 . 1 Hz, 1H ), 7 .53 (dd, J = 8 .0 , 4 .8
Hz, 1H ), 7 . 16 (td , J = 9 .4 , 5 .7 Hz, 1H ), 7 . 10 ( td , J = 8 . 9 , 1. 4 Hz,
1H ); 13C NMR ( 125 MHz, DMSO - d ) 8 180 . 06 , 150 .52 (dd ,
J = 239.6 , 5 .7 Hz), 150 .43 , 150 .25 , 146 . 90 (dd , J = 246 .5 , 7 .6 F
Hz), 146 . 86 , 142 . 30 , 141. 88 (dd , J = 11 . 9 , 3 .0 Hz), 137 . 98 , 25
133 . 83 , 128 .41 , 126 . 98 , 124 . 25 , 119 .60 (dd , J = 9 . 1 , 4 . 0 Hz),
116 . 43 ( dd , J = 23 .5 , 19 .4 Hz), 111. 71 (dd , J = 22 .4 , 3 .6 Hz ); OH
MS (ESI): 317 . 92 (M ) *.
30 [5 -(3 - Chloro -phenyl)- thiophen -2 -yl)-( 2 ,6 -difluoro -3 -hy
10a droxy -phenyl)-methanone ( 11 ): The title compound was
prepared by reaction of (5 -bromo- thiophen -2 -yl)-(2 ,6 -dif
luoro - 3 -hydroxy-phenyl) -methanone (le ) (430 mg, 1. 35
mmol) , 3 -chloro -phenylboronic acid (253 mg, 1.62 mmol),
35 cesium carbonate ( 1756 mg, 5 . 39 mmol) and tetrakis ( triph
enylphosphine ) palladium (5 umol) according to method C1.
The product was purified by CC (hexane /ethyl acetate 9 : 1) ;
]
1
yield : 74 % ( 350 mg). 1H NMR (500 MHz, acetone- d )
9 .02 (s, 1H , OH ), 7 .84 ( tt , J = 2 .4 , 1. 2 Hz, 1H ), 7 .74 -7 . 76 ( m ,
1H ), 7 .69 (d , J = 4 . 1 Hz, 1H ), 7 .66 (dt, J = 4 .1 , 0 .9 Hz, 1H ) ,
7 .50 - 7.52 (m , 1H ), 7 .47 (ddd , J = 8 .0 , 2.0 , 1.1 Hz, 1H ),
7 . 19 - 7 .21 ( m , 1H ), 7 .02 -7 .04 ( m , 1H ); 13C NMR ( 125 MHz.
[5 -( 2,4 -Difluoro - phenyl)- thiophen - 2 -yl)-( 3 -ethoxy -2 ,6 acetone - d ) 180 .77 , 153 .31, 152 . 56 (dd , J = 240 .6 , 5 . 8 Hz),
difluoro -phenyl)-methanone ( 10a ): The title compound was 148 .44 (dd , J= 245.9 , 7 .7 Hz), 143 . 92 , 142 .68 (dd , J= 12 .9 ,
prepared by reaction of 5 -bromo - thiophen - 2 - yl)-( 3 - ethoxy - 45 3 . 2 Hz), 138 . 12 , 135 . 80, 135 .69, 131. 92 , 130 . 20 , 126 . 96 .
2 ,6 -difluoro -phenyl)-methanone ( 1b ) ( 300 mg, 0 . 86 mmol), 126 .90, 125 .81, 120. 42 (dd , J = 9 . 1, 3 .9 Hz ), 117 .97 (dd ,
2 , 4 - difluorophenylboronic acid (164 mg, 1. 04 mmol), J = 23. 9 , 19 .7 Hz), 112 .47 (d , J = 22 .8 Hz); MS (ESI) : 350.63
cesium carbonate ( 1126 mg, 3 .5 mmol) and tetrakis (triph - (M ) " .
enylphosphine ) palladium (5 umol) according to method C1;
yield : 91 % (300 mg). The product was used in the next steps 50 12
without any characterisation .

orcups OH
F
??
no
8

[5 -(3 - Chloro -4 -methoxy -phenyl)- thiophen -2 -yl)-( 2,6 -dif


65 luoro -3 - hydroxy -phenyl)-methanone ( 12 ): The title com
(2 ,6 -Difluoro -3 -hydroxy -phenyl)- [5 -(2 ,4 - difluoro -phe- pound was prepared by reaction of (5 -bromo- thiophen - 2
nyl)- thiophen -2 - yl)-methan -one (10 ): The title compound yl)-(2 ,6 - difluoro - 3 -hydroxy -phenyl)-methanone ( le ) (445
US 9 ,884 ,839 B2
63 64
mg, 1.71 mmol), 3 -chloro - 4 -methoxy -phenylboronic acid according to method C1; yield : 39 % (140 mg). The product
( 382 mg, 2 .05 mmol), cesium carbonate (2226 mg, 6 .83 was used in the next steps without any characterisation .
mmol) and tetrakis ( triphenylphosphine ) palladium (5 umol )
according to method C1. The product was purified by CC
(petroleum ether/ ethyl acetate 8 :2 ); yield :69% (450 mg). 'H 5 15
NMR ( 500 MHz, acetone - d ) 8 8 . 99 ( s, 1H , OH ), 7 . 84 ( d ,
J = 2. 3 Hz, 1H ), 7 .73 (dd , J= 8 .6 , 2 .3 Hz, 1H ), 7 .60 ( dd , J = 3 .0 ,
2 .0 Hz, 1H ), 7 .55 (d , J = 4 .1 Hz, 1H ), 7.23 -7 .17 (m , 2H ), 7.02
( ddd, J= 9 .1 , 8 .6 , 1.9 Hz, 1H ), 3. 97 (s, 3H ); 13C NMR ( 125 F
MHz, acetone -d ') : 180 .50, 157. 07 , 154 .01 , 152 .57 (dd , 10
J= 240.4 , 5 .8 Hz), 148 .43 ( dd , J= 245 .7 , 7 .8 Hz), 142 .81, OH
142.63 (dd , J = 13 .0 , 3 . 2 Hz), 138 .32 , 128 .60 , 127 . 29, 127 .28 ,
125.60 , 123 .74 , 120 .27 (dd , J = 9. 1, 3. 9 Hz), 118 .12 (dd ,
J = 24 .0 , 19 .7 Hz), 113 .93 , 112 . 41 (dd, J= 22 .8 , 3 .9 Hz); MS [5 -(3 ,5 -Dichloro -4 -methoxy -phenyl)-thiophen -2 -yl)-(2 ,
(ESI): 380 .67 (M ) *. 6 -difluoro - 3 -hydroxy -phen -yl)-methanone (15 ): The title
compound was prepared by reaction of (5 - bromo-thiophen
2 -yl)-( 2,6 -difluoro -3 -hydroxy-phenyl)-methanone le ) (300
13 mg, 0. 94 mmol), 3,5 -dichloro -4 -methoxy -phenylboronic
acid (249 mg, 1.13 mmol), cesium carbonate (1225 mg, 3.76
mmol) and tetrakis (triphenylphosphine ) palladium (5 umol)
according to method C1. The product was purified by CC
( dichloro -methane/petroleum ether 90 : 10 ) followed by
washing with petroleum ether; yield : 90 % (350 mg). ' H
25 NMR (500 MHz, acetone- d ) 8 8 . 99 ( s , 1H ; OH ), 7 .83 ( s,
OH 2H ), 7 .67 (d , J= 4 . 1 Hz, 1H ), 7.64 ( d , J = 4 . 1 Hz, 1H ), 7 .21 (td ,
J = 9. 4 , 5 .4 Hz, 1H ), 7 .03 (td , J = 8 .9 , 1.8 Hz, 1H ), 3 .93 ( s, 3H );
13C NMR (125 MHz, acetone - d ') & 180 . 74 (s), 153 .85 (s ),
[5 -(3 -Chloro -4 -methoxy- phenyl)-4 -methyl-thiophen -2 152.57 (dd, J= 240 .7 , 5 .7 Hz), 151.51 (s), 148 . 44 (dd ,
yl]-(2 ,6 -difluoro -3 -hydroxy -phenyl)-methanone (13 ): The 30 J= 246 .0 , 7 .7 Hz), 144 .21 (s ), 142.66 (dd , J= 12 .9, 3. 2 Hz),
title compound was prepared by reaction of (5 -bromo-4 - 138 .06 (s ), 131.62 (s), 130 .85 (s ), 127.68 (s ), 127 .35 (s),
methyl-thiophen - 2 -yl)-( 2,6 -difluoro -3 -hydroxy -phenyl) 120 .48 (dd , J= 9 .1 , 3 .9 Hz), 117 .89 (dd , J= 23 . 8 , 19 .6 Hz),
methanone (1f) (600 mg, 1. 81 mmol), 3 -chloro - 4 -methoxy - 112.47 (dd , J = 22 .8 , 3. 9 Hz), 61. 32 (s ); MS (ESI): 414 .73
phenylboronic acid (507 mg, 2 .72 mmol), cesium carbonate sa (M )*.
(2347 mg, 7 .20 mmol) and tetrakis (triphenylphosphine)
palladium (5 umol) according to method C1. The product
16
was purified by CC (dichloromethane ); yield : 80 % ( 570
mg). ' H NMR (500 MHz, acetone-d ' ) 8 8 .98 ( s, 1H ), 7 .62
( d , J= 2 .2 Hz, 1H ), 7.54 (dd , J = 8 .5 , 2. 3 Hz, 1H ), 7.52 -7 .50 40
( m , 1H ), 7 .27 (d , J = 8 .6 Hz, 1H ), 7 . 17 - 7 . 19 (m , 1H ), 7 .02
(ddd , J= 9 .1 , 8.6 , 1. 9 Hz, 1H ), 3 . 99 (s , 3H ), 2. 32 - 2. 32 ( m , F
F
3H ) ; 13C NMR (125 MHz, acetone - d ') & 180 .54 (s ), 156 . 53
( s), 152.54 (dd, J = 240 .3 , 5 . 9 Hz), 148 .39 (dd , J = 245 .4 , 7 . 9 OH
Hz), 148 .32 (s ), 142 .60 (dd , J= 13. 1, 3.0 Hz), 141.34 (s ), 45
140.62 (s ), 136 .43 (s ), 130 . 96 (s ), 129.76 (s ), 127 .35 (s),
123 . 27 (s ), 120 . 14 ( dd , J = 9 .2 , 3 .8 Hz), 118.23 ( dd , J = 24 .1 , (2 ,6 - Difluoro -3 -hydroxy -phenyl)-[5 -(4 -methoxy -3,5 -di
20 .1 Hz), 113.71 (s), 112 .37 (dd , J= 22 .8, 3 .9 Hz), 56 .75 (s), methyl-phenyl) -thiophen -2 -yl)-methanone (16 ): The title
14 . 96 (s ); MS (ESI): 396 .72 (M + 2H )* . compound was prepared by reaction of (5 -bromo- thiophen
50 2 -yl)-(2 ,6 -difluoro -3 -hydroxy -phenyl)-methanone ( le ) (500
14 mg, 1.57 mmol), 4 -methoxy - 3,5 -dimethyl phenylboronic
acid (338 mg, 1.88 mmol), cesium carbonate (2042 mg, 6 .27
mmol) and tetrakis ( triphenylphosphine) palladium (5 umol )
F 55 according to method C1. The product was purified by CC
(hexane/ethyl acetate 8 :2 ); yield : 78 % (460 mg). ' H NMR
OH
(500 MHz, acetone- d ') 8 8.83 (s, 1H , OH ), 7.48 -7 .46 (m ,
1H ), 7. 37 (d , J = 4 .2 Hz, 3H ), 7 .06 ( td , J = 9 .4 , 5.4 Hz, 1H ),
60 6 .89 (td , J = 8 . 8 , 1. 8 Hz, 1H ), 3 .62 (s, 3H ), 2 . 18 (s, 6H ); 130
[5 -(3 - Chloro -2 -methoxy -phenyl)- thiophen - 2 -yl)-(2 ,6 - dif- NMR (75 MHz, acetone-d ') 8 179 .53 , 158 .58 , 154 .86 ,
luoro - 3 -hydroxy -phenyl)-methanone ( 14 ): The title com 150 .08 (dd , J= 240 .5 , 5 .9 Hz), 145.81 (dd , J= 245.2 , 7 .9 Hz),
pound was prepared by reaction of (5 -bromo- thiophen -2 141.72 (dd , J= 10 .9, 5.4 Hz), 141.65, 137.32 , 131.90 , 128 .40 ,
yl)-( 2,6 -difluoro - 3 -hydroxy -phenyl)-methanone (le ) (300
mg. 0 .94 mmol), 3 - chloro - 2 -methoxy -phenylboronic acid 65 126 .85, 124 .37, 119 .27 (dd , J = 9 .0 , 3 . 8 Hz), 117. 15 (dd .
(210 mg, 1.12 mmol ), cesium carbonate ( 1225 mg, 3 .76 J = 30 .8 , 11. 1 Hz), 111.47 ( dd , J = 22. 9 , 3 .8 Hz ), 59.09 , 15 .27 ;
mmol) and tetrakis ( triphenylphosphine ) palladium (5 umol) MS (ESI): 374 .69 (M ) *.
US 9 ,884,839 B2
65
57 19

OH

(2 ,6 - Difluoro -3 -hydroxy -phenyl)-[5 -(4 -difluoromethoxy


3,5 -difluoro -phenyl)-thiophen - 2- yl )-methanone (17 ): The
title compound was prepared by reaction of (5 -bromo (2,6-Difluoro -3 -hydroxy-phenyl)- {5 -[4 -methoxy -3-(mor
thiophen - 2- yl)-(2,6 -difluoro -3 -hydroxy -phenyl)-methanone 15 pholine-4 -sulfonyl)-phen - yl]-thiophen - 2-yl) -methanone
( le ) (460 mg, 1.44 mmol), 4 -difluoromethoxy -3,5 -diflouro - (19): The title compound was prepared by reaction of
phenylboronic acid (387 mg, 1.73 mmol), cesium carbonate (5 -bromo - thiophen -2 - yl) -(2 ,6 -difluoro -3 -hydroxy-phenyl)
( 1877 mg, 5.77 mmol) and tetrakis( triphenylphosphine ) methanone (le ) (460 mg, 1.44 mmol), 4 -methoxy -3 -(mor
palladium (5 umol) according to method C1. The product 20 pholine - 4 -sulfonyl)-phenylboronic acid (521 mg, 1.73
was purified by CC (DCM ); yield : 84 % (505 mg). ' H NMR mmol), cesium carbonate ( 1877 mg, 5.77 mmol) and tetrakis
(500 MHz, acetone -d ') 8 9 .01 (s, 1H , OH ), 7 .75 (d , J= 4 .1 (triphenylphosphine ) palladium (5 umol) according to
Hz, 1H ), 7.72 -7.65 (m , 1H ), 7.24 -7 .19 (m , 1H ), 7 .11-7 .10 method C1. The product was purified by CC (dichlorometh
(m , 1H ), 7.07 - 7.02 (m , 1H ); 13C NMR ( 125 MHz, acetone - 25os ane /methanol 99.5 :0 .5 ); yield : 56 % (400 mg). ' H NMR (500
d ') & 180.88 (s), 157.04 ( dd , J = 251.3 , 4 .6 Hz), 152 .56 (dd, MHz, acetone - d ) 8 9 .01 (br. s, 1H ), 8 .18 (d , J= 2 .4 Hz, 1H ),
J = 240 .8 . 5 .7 Hz), 151. 23 (t. J = 2 .8 Hz ), 148 . 43 (dd. J = 246 .1 . 8 . 05 (dd , J = 8 .7 , 2 .5 Hz, 1H ), 7 .64 (dt, J = 4 . 1 , 0 . 9 Hz, 1H ) .
7 .6 Hz), 144.71, 142.68 (dd , J= 12 .9, 3 .2 Hz), 138 .02 , 133.47 7 .60 (d , J= 4 . 1 Hz, 1H ), 7 .39 (d , J= 8 .7 Hz, 1H ), 7 .22 - 7 .20 ( m ,
(t, J= 9 .6 Hz), 128 .01, 120 .54 (dd, J= 9. 1, 3 .9 Hz), 117 .79 (dd , 1H ), 7.03 (ddd , J= 9.1 , 8 .6 , 1.9 Hz, 1H ), 4 . 06 (s, 3H ),
J= 23 .6 , 19 .5 Hz), 117 .36 (t, J = 264.6 Hz), 112 .50 (dd, 3 .67 -3 .64 (m , 4H ), 3 .25 -3 .22 (m , 4H ); 13C NMR ( 125 MHz,
J= 22 .7, 3 .9 Hz), 111.64 (d , J= 5.4 Hz), 111.49 (d, J= 5.4 Hz); acetone- d ') d 180 .52 , 158 .93 , 153.70 , 152.55 (dd , J= 240 .5 ,
MS (ESI): 418 .72 (M )*. 5 .8 Hz), 148 .42 (dd , J = 245 .7 , 7 .7 Hz), 143.06 , 142 .65 (dd,
J= 12. 9, 3.2 Hz), 138 .33 , 133 .37, 129.86 , 128 .17 , 126 .22,
35 125 .93 , 120 .33 (dd , J = 9 .1, 3 .9 Hz), 118 .07 (dd , J= 24 .0 , 19 .6
1818 Hz), 114 .83 , 112.43 (dd, J= 22 .8, 3.9 Hz), 67.27 , 56 .86 ,
47 .01; MS (ESI): 495 .74 (M ) *.
F 40
20

OH
HO
5 - [5 -(2 ,6 - Difluoro - 3 -hydroxy -benzoyl)-thiophen -2 -yl]-2 F
isopropoxy -benzonitrile ( 18 ): The title compound was pre OH
pared by reaction of (5 -bromo-thiophen - 2- yl )-(2 ,6 -difluoro
3-hydroxy -phenyl)-methanone (le) (460 mg, 1.44 mmol),
3 -cyano -4 -isopropoxyphenylboronic acid ( 387 mg, 1.73 50 [5 -(3 -Chloro -4 -hydroxy -phenyl) -thiophen -2 - yl)-( 2 ,6 -dif
otrakis luoro -3 - hydroxy -phenyl)-methanone ( 20 ): The title com
mmol), cesium carbonate (1877 mg, 5 .77 mmol) and tetrakis
(triphenylphosphine) palladium (5 umol) according to pound was prepared by reaction of [5 -( 3 -chloro - 4 -methoxy
phenyl)-thiophen - 2 -yl]-(2 ,6 -difluoro -3 -hydroxy -phenyl)
method C1. The product was purified by CC ( dichlorometh - methanone ( 12 ) ( 340 mg, 0 . 89 mmol) and boron tribromide
ane/methanol 99 .5:0 .5 ); yield : 52 % (300 mg). ' H NMR (500 55 (4 .46 mmol, 5.0 equiv ) according to method B . The product
MHz, acetone -d ) 8 8. 99 (s, 1H , OH ), 8. 13 (d , J = 2 .5 Hz, was purified by CC (dichloromethane /methanol 99 .5:0 .5 );
1H ), 8 .03 (dd , J= 8 .9, 2 .4 Hz, 1H ), 7.65-7 .62 (m , 2H ), 7.36 yield : 74 % ( 241 mg). ' H NMR (500 MHz, acetone- d ') &
9 .33 (s, 1H , OH ), 8 . 99 (d , J= 1.4 Hz, 1H , OH ), 7 .82 (t, J= 2 .9
(d , J = 9 .1 Hz, 1H ), 7 .24 -7 .17 (m , 1H ), 7 .03 ( td , J= 8 .9 , 1.9 Hz, Hz, 1H ), 7 .62 (dd , J = 8 .5 , 2. 3 Hz, 1H ), 7 .60 -7 .59 (m , 1H ),
1H ), 4 .92 ( sep , J = 6 .0 Hz, 1H ), 1 .41 (d , J = 6 .0 Hz, 6H ); ' ' C 60 7 .52 ( d . J - 4 . 1 Hz. 1H ), 7 .19 ( ddd . J = 9 .6 . 9 .2 . 5 . 4 Hz, 1H ) .
NMR (125 MHz, acetone- d ') & 180 .58, 161. 32 (s), 153 .11 7 .12 (d, J= 8 .5 Hz, 1H ), 7.06 -6 . 96 (m , 1H ). 13C NMR ( 125
( s ), 152 .56 (dd , J = 240 .7 , 5 .7 Hz), 148.42 (dd , J = 245 .8 , 7 . 9 MHz, acetone -dº ) & 180 .47 , 155 . 24 , 154 .39 , 152.56 (dd ,
Hz), 143 .18 , 142 .64 (dd , J = 13 .0 , 3. 1 Hz), 138 . 32 , 133 .34, JJ == 240 .4 , 5 .8 Hz), 148 .43 (dd, J = 245 .6 , 7 .8 Hz), 142 .63 (dd ,
04 65 125 .30 ,, 122
132.42 , 126 .74 , 126 .07 , 120 .33 (dd , J= 9 .0 , 3 .9 Hz ), 118 .V4 13 . 1 3 .2 Hz), 142 .55 , 138 .36 , 128 .67, 127.32 , 126 .79 ,
.15 , 120 .24 (dd , = 9 .1, 3.8 Hz), 118 .33, 118 . 10
(dd, J = 24 .0 , 19 .8 Hz), 116 .29, 115 .60 , 112 .43 (dd , J = 22.8 , (dd. J= 23 .8 . 19 .6 Hz ), 112 .39 ( dd . J = 22.8 . 3 .9 Hz); MS
3 .8 Hz), 104.38 , 73 .09 , 22.03 ; MS (ESI): 399 .75 (M )* . (ESI) : 366 . 47 (M ) *.
US 9 ,884,839 B2

21 23

HO

??

OH
10
10
[5 -(3 ,5 -Dichloro -4 -hydroxy -phenyl) -thiophen - 2 - yl)-( 2 ,6
[5 -(3- Chloro-4-hydroxy-phenyl)-4 -methyl-thiophen -2 difluoro -3 -hydroxy -phen -yl)-methanone (23 ): The title com
pound was prepared by reaction of [5 - (3, 5 -dichloro -4
yl]-( 2,6- difluoro -3-hydroxy -phenyl)-methanone (21): The methoxy -phenyl)- thiophen - 2 -yl)-(2 ,6 -difluoro - 3- hydroxy
title compound was prepared by reaction of [5-(3 -chloro-4- 15 phenyl)-methanone ( 15) ( 350 mg, 0 .84 mmol) and boron
methoxy -phenyl)-4 -methyl- thiophen -2 -yl]-(2,6 -difluoro -3 tribromide (4 . 12 mmol, 5 .0 equiv ) according to method B .
hydroxy -phen -yl)-methanone (13 ) (520 mg, 1.32 mmol) and The product was purified by CC (dichloromethane/methanol
boron tribromide (6 .58 mmol, 5 .0 equiv ) according to 99.75 : 0 .25 ); yield : 84 % (285 mg). ' H NMR (500 MHz,
method B . The product was purified by CC (dichloro - 20 (dt??, J = 4 .1 , 0 .8 Hz, 1H ), 7 .60 ( d , J = 4 . 1 Hz, 1H ), 7 .20 ( ddd ,
methane/methanol 99.75 :0 .25 ); yield : 82 % (413 mg). ' H J = 9 .6 , 9 .2 , 5 .4 Hz, 1H ), 7 .02 (ddd , J = 9 .1 , 8 .6 , 1. 9 Hz, 1H );
NMR ( 500 MHz, acetone- dº ) 8 . 9 . 25 (s, 1H , OH ), 8 . 97 (d , 13C NMR (125 MHz. acetone- dó ) 8 180 .58. 152. 56 ( dd .
J= 1.4 Hz, 1H ), 7 .58 (d , J = 2 .3 Hz, 1H ), 7.50 - 7.48 (m , 1H ), J = 240 .6 , 5 .8 Hz), 152 .50 , 151 .05 , 148 .43 (dd , J= 245 .8 , 7.8
7 .41 ( dd . J = 8 . 4 . 2 . 2 Hz. 1H ) . 7 .21- 7 . 17 (m . 1H ) . 7 . 15 ( d . 25 Hz ), 143 .32 , 142 .64 ( dd, J = 13 . 0 , 3 .2 Hz ), 138 . 19 , 127 . 32 ,
J = 8 .4 Hz, 1H ), 7 .04 -6 . 98 (m , 1H ), 2. 34 -2 .29 (m , 3H ); 13C (127 .22, 126 .30 , 123.61, 120 .36 (dd , J = 9 .1, 3 .8 Hz), 118 .01
NMR (125 MHz, acetone -d ') & 180 .52, 154 .61, 152 .54 (dd, ( ESI):J=402 dd , 23. 9, 19 .7 Hz), 112 .43 (dd, J= 22.8 , 3. 9 Hz); MS
.59 ( M + H ) *.
J= 240 .2 , 5 .9 Hz), 148 .69, 148.40 (dd , J= 245 .5, 7 .8 Hz),
142.60 (dd , J= 13.0 , 3.2 Hz), 141. 12, 140 .65, 136 .21, 130. 99, 30 24
129.72 , 126 .78 , 121.68 , 120 .12 (dd, J= 9.1 , 3 .8 Hz), 118 .22
( dd , J= 32.7 , 28 .5 Hz), 118 .05 , 112 .36 (dd , J= 22.8 , 3. 9 Hz),
15 .00; MS (ESI): 380 .74 (M ) *. HO
35

22 OH

40
0 (2 ,6 - Difluoro -3 -hydroxy -phenyl )-[5 -(4 -hydroxy- 3,5 -di
F methyl-phenyl)-thiophen - 2- yl]-methanone (24 ): The title
OH compound was prepared by reaction of (2 ,6 -difluoro -3
OH hydroxy -phenyl)- 15 - (4 -methoxy - 3 ,5 - dimethyl-phenyl)-thio
phen - 2 -yl)-methanone ( 16 ) ( 400 mg, 1 .07 mmol) and boron
43 tribromide (5 .34 mmol, 5 .0 equiv ) according to method B .
[5 -( 3- Chloro -2 -hydroxy -phenyl)-thiophen -2 -yl)-(2,6 -dif The product was purified by CC (dichloromethane /methanol
luoro - 3 -hydroxy-phenyl) -methanone ( 22 ): The title com - 99.5 :0 . 5 ); yield : 69 % (266 mg). 'H NMR (500 MHz,
pound was prepared by reaction of [5 -(3-chloro -2 -methoxy acetone- d “ ) 8 8. 82 (br. s, 1H ), 7 .65 (br. s, 1H ), 7 .41 (d , J = 4 .1
Hz, 1H ), 7. 32 -7 . 28 (m , 3H ), 7 .05 ( td , J= 9.4 , 5 .4 Hz, 1H ),
phenyl) -thiophen - 2 - yl) -( 2 ,6 - difluoro - 3 -hydroxy - phenyl) - 50 6 .87 (td , J = 8 .8 . 1 . 8 Hz, 1H ), 2 . 16 (s . 6H ); 13C NMR ( 125
methanone ( 14) ( 140 mg, 0 .37 mmol) and boron tribromide MHz, acetone -d ') 8 179.30 , 155. 99, 155. 18, 151 .66 (dd ,
( 1 . 84 mmol. 5 . 0 equiv ) according to method B . The productJ = 240 .2 , 5 .9 Hz), 147.52 (dd , J = 245 . 3 , 7 .9 Hz), 141.69 (dd .
was purified by CC (dichloromethane/methanol 99 .75 :0.25 ); J= 13.22. 1,, 3119
.3 Hz), 140 .66 , 137 .47 , 126 .63, 124. 95 , 124.42 ,
yield : 76 % ( 102 mg). ' H NMR (500 MHz, acetone - d ') 08 »55 123
1111.42 (dd , J.=1422.(9dd, 3,. 9J =Hz9 . )1,, 153 ..866Hz ), 117 .57 - 117 .07 (m ),
; MS (ESI): 360 .91 (M )*.
9.32 (s, 1H ; OH ), 9. 11 (d , J= 0 .9 Hz, 1H , OH ), 7.80 (dd,
J = 8 . 0 , 1. 4 Hz, 1H ), 7 .77 ( d , J= 4 . 2 Hz, 1H ), 7 .62 (d , J = 4 .2
25
Hz, 1H ), 7.45 ( dd , J= 8. 0 , 1.4 Hz, 1H ), 7 .19 (td , J= 9 .4 , 5 .4
Hz, 1H ), 7 .06 - 6 . 98 (m , 2H ); 13C NMR ( 125 MHz, acetone- 60
d ) & 181.04, 152.52 (dd , J= 240.2, 5 .9 Hz), 150 .46 , 150 . 17 , L

HO
148 .43 (dd , J= 245.6 , 7 .8 Hz), 143 .71, 142.68 (dd, J= 12 .9 ,
3 .2 Hz), 136 .63 , 131. 00 , 128 .18 , 128 .00 , 123 .22 , 122 .89 ,
122 .13 , 120 . 14 (dd , J= 9. 1, 3.9 Hz), 118 .45 (dd , J= 24 .2, 19 9. 5 OH
Hz), 112 .34 (dd , J= 22. 8 , 3. 9 Hz ); MS (ESI): 368. 86
( M + 2H ) .
US 9 ,884 ,839 B2
69 70
5- [5 -(2,6 -Difluoro -3 -hydroxy -benzoyl)-thiophen -2 -yl)-2 - title compound was prepared by reaction of 2 -( 3 -chloro -4
hydroxy -benzonitrile (25 ): The title compound was prepared methoxy-5 -methyl-phenyl)-4 ,4 ,5 ,5 -tetramethyl-(1 ,3 ,2 ]di
by reaction of 5 -[5 -( 2 ,6 - difluoro - 3 -hydroxy -benzoyl) -thio oxaborolane ( 26a ) ( 1000 mg, 3. 53 mmol), (5 -bromo -thio
phen - 2 -yl]-2 -isopropoxy -benzonitrile ( 18 ) ( 220 mg, 0 .55 phen -2 -yl)- (2 ,6 -difluoro -3 -hydroxy -phenyl)-methanone
mmol) and boron tribromide (2.75 mmol, 5 .0 equiv ) accord - 5 (le ) (1000 mg, 3. 13 mmol), cesium carbonate (4000 mg,
ing to method B . The product was purified by CC (dichlo 12.5 mmol) and tetrakis (triphenylphosphine ) palladium (18
romethane/methanol 99 .25:0 .75 ); yield : 59 % (115 mg). ' H mg, 0 . 02 mmol) according to method C1. The product was
NMR (500 MHz, acetone - d ) 8 9 .67 (br. s, 1H ), 8 . 12 - 8 . 07 purified by CC (hexane / ethyl acetate 8 : 2 ); yield : 82 % ( 1000
(m , 1H ), 7 . 93 (dd , J = 8 . 7 , 2 .4 Hz, 1H ), 7 .62 (d , J = 4 . 1 Hz, mg). ' H NMR (500 MHz, acetone - d ) 8 . 98 (s , 1H ), 7 . 72
1H ), 7 .60 (d , J = 4 . 1 Hz, 1H ), 7 .24 - 7 .17 (m , 2H ), 7 .03 (td , " (dd, J = 2 .2 , 0 .6 Hz, 1H ), 7 .65- 7 .60 (m , 2H ), 7 .60 (d , J = 4 .1
J= 8 .9 , 1 .9 Hz, 1H ); 13C NMR ( 125 MHz, acetone-d ') & Hz, 1H ), 7 .20 (td , J = 9 .4 , 5 . 2 Hz, 1H ), 7. 03 ( td , J= 8 . 8, 1. 9 Hz,
180 . 56 , 161.47 , 153.44 , 152 . 56 (dd , J= 240 .4 , 5 .8 Hz), 1H ), 3.86 (s, 3H ), 2 .38 (s, 3H ); 13C NMR (125 MHz,
148. 42 (dd . J = 245 . 7 . 7 .8 Hz). 142. 98 . 142.63 (dd . J = 13 . 0 . acetone- d ) 8 180 .7 , 156 .4 , 153 .6 , 151. 7 , 149.5 , 149.5 ,
3 .2 Hz), 138 . 33 , 133 .37 , 132 .07, 126 . 34 , 125 . 82 , 120 . 31 ( dd , 15- 147 . 5 , 143 . 5 , 142. 8 , 142. 7 , 138 . 3 , 135 .5 , 130 .7 , 129.3 ,
J = 9 . 1 , 3 . 9 Hz), 118 . 08 , 118 .07 (d , J = 43.7 Hz ), 116 .41, 128 .8 , 126 .5 , 120 .4, 112.6 , 112 .4 , 60 .7 , 16 .5 ; MS (ESI):
112 .42 (dd , J= 22. 8, 3 . 9 Hz), 101. 91 ; MS (ESI): 357 .81 (M )* . 395 . 28 ( M + H ) .

268 20

.
HO

B.
25

2 - (3 -Chloro - 4 -methoxy-5 -methyl-phenyl)-4 ,4 ,5 ,5 -te - 3030


tramethyl-[ 1,3, 2] dioxaborolane ( 26a ): 5-bromo- 1 -chloro -2 AF
methoxy -3 -methylbenzene (5.00 g, 20 .2 mmol, 1.00 equiv ),
bis (pinacolato )diboron (8.09 g, 31 .8 mmol, 1.50 equiv), ??
OH
potassium acetate (5 .95 g , 60 .6 mmol, 3 .00 equiv ) and
Pd (dppf) C12 (739 mg, 1.01 mmol, 0 .05 equiv ) were dis [5 -(3 -Chloro -4 -hydroxy -5 -methyl-phenyl)-thiophen -2
solved under N , in 40 ml dry DMSO and the mixture was
stirred at 80° C . for 2 h . The reaction was quenched with yl]-(2 ,6 - difluoro - 3 -hydroxy -phenyl)-methanone (27 ): The
water, diluted with diethyl ether and filtered over celite. The title compound was prepared by reaction of [5 -( 3 -chloro - 4
phases were separated and the aqueous layer was extracted methoxy -5 -methyl-phenyl)-thiophen -2 -yl)-(2 ,6 -difluoro -3
two times with diethyl ether. The combined organic lavers 40 hydroxy -phen -yl) -methanone ( 26 ) ( 104 mg, 0 .26 mmol) and
were washed three times with water; one time with brine, boron tribromide (1.05 mmol, 4 .0 equiv ) according to
dried over magnesium sulfate , filtered and concentrated method B . The product was purified by CC ( hexane/ethyl
under reduced pressure. The crude product was purified by acetate 7 :3 ); yield : 82 % ( 84 mg). ' H NMR (500 MHz,
cc (hexane/ethyl acetate 85 :15); yield : 88 % (4 .71 g ). ' H acetone - d ) 8 8 .96 (d , J = 1. 3 Hz, 1H ), 8 .50 (s , 1H ), 7 .68 -7 .66
NMR (500 MHz. acetone - d6) 87 .54 - 7 .56 ( m . 11 ) . 7 . 48 - 7 . 50 45 (m , 1H ), 7 .60 - 7 .55 (m , 2H ), 7 . 53 ( d , J = 4 . 1 Hz, 1H ), 7 . 19 (td .
(m , 1H ), 3 .82 (s, 3H ), 2.31 (t, J= 0 .6 Hz, 3H ), 1.33 (s, 12H ). J= 9.4 , 5 . 5 Hz, 1H ), 7 .02 ( td , J = 8 . 8, 1.9 Hz, 1H ), 2 .34 (s, 3H );
13C NMR ( 125 MHz, acetone- d ) 8 180 .5 , 154.6 , 153.6 ,
153.2 , 151. 7 , 149.5 , 147. 5 , 142 .7 , 138 . 4 , 128 .7 , 128 .6 ,
26 126 .5 , 125. 8 , 125 .3 , 121. 8 , 120 .3 , 118 .4 , 118 .2 , 112 .5 , 112 .4 ,
50 16 .8 ; MS (ESI): 381.06 (M + H ) +.

28b

55

60

Br
??

65 2 - (3 -Bromomethyl-5 -chloro - 4 -methoxy -phenyl) -4 ,4 , 5 ,5


[5 -(3 - Chloro -4 -methoxy - 5 -methyl-phenyl)-thiophen - 2 - tetramethyl-[ 1,3 ,2 ]dioxaborolane (28b ): 2 -(3 -chloro -4
yl ]-( 2,6 -difluoro -3 -hydroxy -phenyl)-methanone ( 26 ): The methoxy -5 -methylphenyl) - 4 ,4 ,5 ,5 -tetramethyl- 1,3 ,2 - dioxa
US 9 ,884,839 B2
71
borolane (26a ) (200 mg, 0 .71 mmol, 1 .00 equiv ) and none ( 28 ): The title compound was prepared by reaction of
N -bromo-succinimide (113 mg, 0 .63 mmol, 0 .90 equiv ) 1 -(4 -( 3 -chloro - 2 -methoxy -5 -( 4 ,4,5 ,5 -tetramethyl- 1,3 ,2 -di
were dissolved under N2 in 17 ml CC14, followed by a oxaborolan - 2 -yl) benzyl) piperazin - 1 - yl) ethanone ( 28a ) ( 100
catalytic amount of dibenzoyl peroxide. The mixture was mg, 0 .24 mmol, 1.00 equiv ), (5 -bromothiophen - 2- yl)(2 ,6
stirred under reflux for 1 h . The reaction was quenched with 5 difluoro - 3 -hydroxyphenyl) -methanone ( le ) (77 mg, 0 .24
water and extracted three times with dichloromethane . The mmol, 1. 00 equiv ) , cesium carbonate ( 156 mg, 0 .48 mmol)
combined organic layers were washed two times with water, and tetrakis(triphenylphosphine ) palladium (1 mg, 0 .001
one time with brine, dried over sodium sulfate , filtered and mmol, 0 .005 equiv ) according to method C1 . The product
concentrated under reduced pressure . The crude productwas was purified by CC ( ethyl acetate / ethanol 8 : 2 ); yield : 98 %
purified by CC ( hexane/ethyl acetate 85 : 15 ) ; yield : 70 % 10 (55 mg). ' H NMR (500 MHz, DMSO - d ) 89.53 (br. s., 1H ),
( 180 mg). ' H NMR (500 MHz, acetone -d ') 8 7 .75 (d , J= 1 .5 8 . 28 -8 .26 (m , 2H ), 8 . 10 - 8 .03 ( m , 2H ), 7 .66 ( td , J = 9 .4 , 5 . 3
Hz, 1H ), 7 .68 (d , J = 1.5 Hz, 1H ), 4 .71 (s, 2H ), 4 .00 (s , 3H ), Hz, 1H ), 7 .48 ( td , J = 8 . 9, 2 .0 Hz, 1H ), 4 .38 (s, 3H ), 4 . 10 (s,
1. 33 - 1. 35 (m , 12H ) . 2H ), 4 .03 - 3 . 94 ( m , 4H ), 2 .99 (t, J = 5 .0 Hz, 2H ), 2 .93 (t, J = 5 .0
Hz, 2H ), 2 .46 (s, 3H ). 13C NMR ( 125 MHz, DMSO -d ) &
15 180 .7 , 169.0 , 156 .7 , 153 .5 , 151.6 , 149.4 , 147 .4 , 143 .5 ,
28a 142 .7 , 138 .2 , 135 .8 , 130 .6 , 129.6 , 128. 3, 127 .7 , 126 .5 ,
120 . 4 , 118 .0 , 112 .5 , 112 .3 , 61. 8 , 57 . 1 , 54 .0 , 53.7 , 46 . 9 , 42 . 0 ,
21.3 ; MS (ESI): 521 .41 (M + H ) *.
20
29

25

??

OH
ek
en
30

1- { 4 -[3 - Chloro -2 -methoxy -5 -(4 ,4 ,5 ,5 -tetramethyl-[ 1,3 ,2 ]


dioxaborolan - 2 -yl) -benzyl]-piperazin - 1 - yl ) - ethanone (28a ):
2 - ( 3 -(bromomethyl)- 5 -chloro - 4 -methoxyphenyl)-4 ,4 ,5 ,5 -te
tramethyl-1,3 ,2 -dioxaborolane (28b ) ( 180 mg, 0 .50 mmo , 35
1.00 equiv ) was dissolved under N , in 1 ml dry THF and 1 - (4 - { 3 -Chloro -5 -[5 -( 2 ,6 -difluoro -3 -hydroxy -benzoyl)
1 -acetylpiperazine was added . The mixture was stirred for 1 thiophen -2 -yl)-2 -hydroxy-benzyl)-piperazin - 1-yl)-etha
h under reflux . The reaction was quenched with water and none ( 29 ) : The title compound was prepared by reaction of
extracted three times with ethyl acetate . The combined 1 -( 4 - 3 -Chloro -5 - [5 - ( 2 ,6 - difluoro - 3 - hydroxy - benzoyl)
organic layers were washed two times with water, one time 40 thiophen - 2 -yl]-2 -methoxy- benzyl ) -piperazin - 1 -yl) -etha
with brine , dried over MgSO4, filtered and concentrated none (28 ) ( 150 mg, 0 . 29 mmol) and boron tribromide ( 0 . 87
under reduced pressure . The crude product was purified by mmol, 3 .0 equiv ) according to method B . The product was
cc ( ethyl acetate/ ethanol 8 : 2 ), to give the desired product as purified by using preparative TLC (dichloromethane/metha
yellow solid ; yield : 70 % ( 198 mg). ' H NMR (500 MHz, nol 95 : 5 ); yield : 12 % ( 16 mg). ' H NMR (500 MHz, acetone
acetone - d ) 87.69 (d , J = 1 .5 Hz, 1H ), 7 .65 ( d , J = 1 .5 Hz, 1H ), 10 d ) 8 7 . 86 - 7 . 80 (m , 1H ), 7 . 75 ( d , J= 2 . 2 Hz , 1H ), 7 .65 - 7 . 56
3 .90 (s, 3H ), 3.57 (s, 3H ), 2 .77 (t, J = 5. 2 Hz, 2H ), 2 .70 (t, (m , 1H ), 7.54-7 .49 (m , 1H ), 7 .24 - 7 .18 (m , 1H ), 7 .06 -6 . 99
J= 5 .2 Hz, 2H ), 2.47 (t, J= 5 .2 Hz, 2H ), 2 .42 (t, J= 5 .2 Hz, 2H ), (m , 1H ), 3.70 -3 .60 (m , 4H ), 2 .71-2 .52 (m , 4H ), 2 .04 ( s, 3H ) ;
2 .00 (s, 3H ), 1.34 (s, 12H ). 13C NMR ( 125 MHz, acetone- d ' ) & 180 .7 , 169 .9 , 156 .0 ,
154.6 , 153 .5 , 153.5 , 151.6 , 149 .5 , 147.5 , 142 .8 , 142 . 5 ,
138 .4 , 127 .7 , 126 .7 , 125.8 , 125 . 3 , 124.9 , 122.1 , 120.2 ,
28 118.2, 112.5, 112.4 , 61.1, 53 .5 , 52.9, 46.6, 41.8 , 21.3; MS
( ESI): 506.89 ( M + H ) *.

30
55

OH
F
??
NH
65
1 -(4 -{ 3 -Chloro -5 -[5 -(2 ,6 -difluoro -3 -hydroxy -benzoyl)
thiophen - 2 -yl]-2 -methoxy -benzyl) -piperazin - 1 -yl)-etha
US 9 ,884 ,839 B2
73 74
[5 -(3 - Chloro -4 -methoxy -5 -piperazin - 1 -ylmethyl-phe 2 -( 3 - Azidomethyl-5 -chloro -4 -methoxy -phenyl) -4 ,4 ,5 ,5 -te
nyl)- thiophen - 2 -yl)-( 2 ,6 - difluoro - 3 -hydroxy -phenyl) tramethyl-( 1,3 ,2 ]dioxaborolane (31c ) (683 mg, 2 .16 mmol,
methanone ( 30 ): 1- (4 -( 3 - chloro -5 -(5 -(2 ,6 -difluoro - 3 -hy 1 .00 equiv ), (5 -bromothiophen - 2 -yl) (2 ,6 -difluoro -3 -hy
droxybenzoyl)-thiophen -2 -yl)-2 -methoxybenzyl) droxyphenyl)methanone (le) (700 mg, 2 . 16 mmol, 1.00
piperazine - 1 -yl)ethanone ( 28 ) ( 150 mg, 0 .29 mmol, 1.00 5 equiv ), cesium carbonate (2000 mg, 6 .44 mmol, 3 equiv )
equiv ) was dissolved in 20 ml 3 M aqueous HCl and heated and tetrakis (triphenylphosphine) palladium ( 13 mg, 0 . 01
to 80° C . for 3 h . The reaction was washed two times with mmol, 0 .005 equiv ) according to method C1; yield : 84 %
ethyl acetate , the aqueous layer was basified to pH 10 with (785 mg); The product was used in the next steps without
2 M NaOH and washed two times with ethyl acetate . The any characterisation .
aqueous layer was neutralized with 2 M HCl and extracted 10
three times with ethyl acetate . The combined organic layers
were washed one timewith water, one timewith brine , dried 31a
over MgSO4, filtered and concentrated under reduced pres
sure to give the desired pure product in 40 % yield as pale
yellow solid . ' H NMR (500 MHz, acetone -d ' ) 8 7 . 83 -7 .79 15
(m , 2H ), 7.67 -7 .60 (m , 2H ), 7 .19 ( m , 1H ), 7 .00 ( td , J = 9 .0 ,
1 .9 Hz, 1H ), 3 .92 ( s, 3H ), 3.59 (s, 2H ), 2 .89- 2 .81 (m , 4H ),
2 .53 - 2.45 (m , 4H ); 13C NMR ( 125 MHz, acetone - d ) 8
180 .8 , 156 .8 , 153 . 3 , 151.5 , 149. 4 , 147 .5 , 143 .6 , 142 .9 ,
142.7 , 138 .2 , 135 . 4 , 130 .7 , 129 .6 , 128 . 4 , 127 . 9 , 126 . 7 , 20
120 .5 , 118 .1 , 112 .3, 112 .2 , 62.0 , 56 .9 , 50 .4 , 44 .3 ; MS (ESI):
479 . 22 (M + H ) *. N?N
31c 25 Acetic acid 3 -[5 - (3 -chloro - 4 -methoxy-5 -[1 ,2 ,3 ] triazol-1
ylmethyl-phenyl)- thiophene -2 -carbonyl] -2 ,4 -difluoro -phe
nylester (31a ): (5 -( 3 -( azidomethyl)-5 - chloro -4 -methoxy
phenyl)-thiophen - 2 -yl) (2 ,6 - difluoro - 3 - hydroxyphenyl)
methanone (31b ) (50 mg, 0 .11 mmol, 1.00 equiv ), was
30 dissolved in 106 ul vinyl acetate and the reaction was heated
at 120° C . under microwave for 10 h . The reaction was
concentrated under reduced pressure and purified by CC
using ethyl acetate as eluent; yield : 27 % ( 15 mg) . ' H NMR
(500 MHz, DMSO -d “ ) 8 8 .11 (d , J = 0 .9 Hz, 1H ), 7 .92 (d ,
35 J= 2 .5 Hz, 1H ), 7 .70 (d , J = 0 . 9 Hz, 1H ), 7 .68-7 .66 (m , 1H ),
7 .64 - 7 .61 (m , 2H ), 7 .53 (td , J = 8 . 9, 5 .5 Hz, 1H ), 7 . 26 ( td ,
2 - (3 -Azidomethyl-5 -chloro -4 -methoxy - phenyl)-4 , 4 ,5 ,5 J= 8 . 8, 1. 9 Hz, 1H ), 5 .78 (s, 2H ), 3 .89 (s, 3H ), 2 . 34 (s, 3H ) ;
tetramethyl-[ 1,3 ,2 ]dioxaborolane (31c ): 2 -( 3 -(bromom - MS (ESI): 504 .12 (M + H ) *.
ethyl)- 5 - chloro -4 -methoxyphenyl)-4 ,4 ,5 ,5 -tetramethyl- 1,3 ,
2 -dioxaborolane (28b ) (800 mg, 2 . 19 mmol, 1.00 equiv ) was 40
dissolved under N , in 8 mldry DMF and sodium azide (143 31
mg, 2 .19 mmol, 1.00 equiv ) was added . The mixture was
stirred at room temperature overnight. The mixture was
quenched with water and extracted three times with ethyl
acetate . The combined organic layers were washed two 45
times with water, one timewith brine , dried over magnesium F
sulfate , filtered and concentrated under reduced pressure .
The crude product was purified by CC (hexanelethyl acetate OH
8 :2 ); yield : 71 % (503 mg). 'H NMR (500 MHz, acetone -d " )
8 7 .72 (d , J = 1 .6 Hz, 1H ), 7 .69 (d , J= 1.6 Hz, 1H ), 4 . 55 (s , 50
2H ), 3 . 93 (s, 3H ), 1. 34 (s, 12H ).

316 [5 -(3 -Chloro -4 -methoxy- 5 -[ 1,2 ,3 ] triazol- 1-ylmethyl-phe


55 nyl)- thiophen - 2 -yl]-( 2,6 - difluoro -3 -hydroxy -phenyl)
methanone (31): Acetic acid 3 -[5 -(3 -chloro -4 -methoxy -5 -[ 1,
2 ,3 ]triazol- 1 -ylmethyl- phenyl)-thiophene- 2 -carbonyl]- 2,4
difluoro - phenylester (31a ) (110 mg, 0 .24 mmol, 1.00 equiv )
was dissolved under N , in a degased mixture of 5 ml THF
60 and 600 ul of 2M NaOH . The mixture was stirred for 2 h at
OH
room temperature . The reaction was acidified to pH 6 with
1 M HCl and extracted three times with ethyl acetate . The
N3 combined organic layers were washed two times with water,
one time with brine, dried over magnesium sulfate, filtered
[5 -( 3 - Azidomethyl-5 -chloro - 4 -methoxy -phenyl) -thio - 65 and concentrated under reduced pressure to give the desired
phen - 2 -yl)-( 2,6 -difluoro -3 -hydroxy -phenyl) -methanone product; yield : 95 % (90 mg). ' H NMR (500 MHz, acetone
(31b ): The title compound was prepared by reaction of d ') & 9.05 (br. s, 1H ), 8 .11 (d , J= 0 .9 Hz, 1H ), 7 .91 (d, J= 2.2
US 9 ,884 ,839 B2
75 76
Hz), 7 .70 (d , J = 0 .9 Hz, 1H ), 7 .67 (d , J = 2 .2 Hz, 1H ), Cyclopropanesulfonic acid ( 3 -methyl-5 -(4 ,4 ,5 ,5 -tetram
7 .65 -7 .62 (m , 1H ), 7.61- 7.58 ( m , 1H ), 7 .21 (td , J = 8. 9, 5 .5 ethyl-[ 1, 3, 2 ]dioxaborolan - 2 -yl)-phenyl]-amide (33a ):
Hz, 1H ), 7 .03 (td , J = 8 .8 , 1 .9 Hz, 1H ), 5 .78 (s, 2H ), 3 .89 ( s, Cyclopropanesulfonic acid ( 3 -bromo- 5 -methyl-phenyl)
3H ); MS (ESI): 462 . 15 (M + H ) *. amide (33b ) (800 mg, 2 .76 mmol, 1 equiv ) was dissolved in
10 ml dry dimethyl sulfoxide under N2 atmosphere . Bispi
nacolatodiborone (1050 mg, 4 .14 mmol , 1.5 equiv ), potas
sium acetate (8 .28 mmol, 3 equiv ) and Pd(dppf)Cl2 (0 . 14
mmol, 0 .05 equiv ) were added. The reaction mixture was
heated to 80° C . overnight. Reaction mixture was cooled
down to room temperature , quenched with water and diethyl
OH ether, filtered over celite , extracted three times with diethyl
ether, washed three times with water, washed with brine ,
Z 15 dried over magnesium sulfate , filtered and evaporated under
-

Z
reduced pressure . Purified with flash chromatography (di
chloromethane pure to dichloromethane/methanol 8 :2 );
yield : 16 % (150 mg).
[5 -(3 - Chloro -4 -hydroxy -5 -[1 ,2,3 ] triazol- 1- ylmethyl -phe - 20
nyl)- thiophen -2 -yl] -(2 ,6 -difluoro - 3 -hydroxy -phenyl)
methanone (32 ): The title compound was prepared by reac 33
33
tion of | 5 - (3 - Chloro -4 -methoxy -5 - [ 1 , 2 , 3 ]triazol- 1 -ylmethyl
phenyl)-thiophen - 2 -yl)-(2 ,6 - difluoro -3 -hydroxy -phenyl)
methanone (31) (80 mg, 0 . 16 mmol) and boron tribromide 25 OH
( 800 ul, 0 . 80 mmol, 5 .0 equiv ) according to method B . The
product was purified by CC (ethyl acetate / ethanol 9 :1 ); F
yield : 32 % ( 23 mg). ' H NMR (500 MHz, acetone- d ) 8 8 .74
(d , J= 1. 3 Hz, 1H ), 8. 43 (s, 1H ), 8 .03 - 7 . 90 ( m , 2H ), 7 .68 -7 .54 30
(m , 2H ), 7 . 30 ( td , J = 8 . 8 , 5 . 5 Hz, 1H ) , 7 .01 (td , J= 8 . 8 , 1 . 9 Hz,
1H ), 6 . 05 (s, 2H ); 13C NMR ( 125 MHz, acetone- dº) & 180 .7 ,
153.3 , 143 .2 , 138 .3 , 130 .7 , 129 .3 , 129 .2 , 128 . 8 , 127 . 3 , 0= S
126 . 1, 124 .6 , 123 .0 , 120 . 3 , 112.4 , 52 .0 ; MS (ESI): 448 . 12
( M + H ) *. 35

33b
Bra N ito Cyclopropanesulfonic acid {3 -[5 -(2 ,6 -difluoro -3 -hy
droxy-benzoyl)- thiophen -2 -yl)-5-methyl -phenyl] -amide
(33): cyclopropanesulfonic acid [3 -methyl-5-(4,4,5,5- te
tramethyl-[ 1, 3,2 ]dioxaborolan -2 -yl)-phenyl]-amide ( 33a )
(0 .45 mmol, 1.20 equiv ), (5 -bromo- 2 -thienyl)( 2,4 -difluoro
3 -hydroxyphenyl)-methanone le (0 .37 mmol, 1.00 equiv ),
45 mencium carbonater
Cyclopropanesulfonic acid (3 -bromo -5 -methyl-phenyl) 45 ceasium carbonate (1. 11 mmol, 3 . 00 equiv ) and Pd (PPh3) 4
amide ( 33b ): The title compound was prepared by reaction (0 .002 mmol, 0 .005 equiv ) were suspended in a degased
of 3 -bromo -5 -methylaniline ( 1000mg, 5 .38 mmol, 1 equiv ) mixture of 5 ml DME and 5 ml water. The mixture was
and cyclopropanesulfonyl chloride (1013 mg, 8 .07 mmol, heated to reflux for 3 days under N , atmosphere. The
1 . 5 equiv ) according to method D . The product was purified 50 mixture was cooled down to room temperature . quenched
by CC (hexane/ethyl acetate 8 :2 ); yield : 77 % ( 1200mg). ' H with water, filtered over celite , extracted three times with
NMR (500 MHz, acetone - d ) 8 8 .62 (br. s , 1H ), 7 .35 (s, 1H ),
7 . 15 (s, 1H ), 7 .13 (s, 1H ), 2 .65- 2 .61 (m , 1H ), 2 .30 (s, 3H ), ethyl acetate, washed one time with water, one time with
1. 00 - 0 . 95 ( m , 4H ) . brine , dried over sodium sulphate, filtered and evaporated
55 under reduced pressure. The product was purified by mPLC
33a (0 % ethyl acetate to 100 % ethyl acetate ) followed by
preparative TLC (hexane/ethyl acetate 5 :5 ); yield : 18 % (30
mg). ' H NMR (500 MHz, acetone- d ) 8 8 .98 (s, 1H ), 8 .68
60 (s, 1H ), 7.61 (d , v= 4 .0 Hz, 1H ), 7 .57 (s, 1H ), 7.55 (d , v= 4 .0
0 Hz, 1H ), 7 .41 (s, 1H ), 7. 26 (s, 1H ), 7 .21-7 . 15 (m , 1H ), 7.01
S=
( td , J = 8 .8 , 1.8 Hz, 1H ), 2.70 -2 .65 (m , 1H ), 2 .38 (s, 3H ),
1.02 -0. 96 (m , 4H ); 13C NMR (125 MHz, acetone-d ) &
65 180 .6 , 155 .0 , 143 .2 , 141.3 , 140 .4 , 138 .1, 134 .6 , 126 .1 ,
123 .7, 123 .1, 120.3 , 116 .4 , 112.3 , 29 .7, 21.4 , 5 .7 ; MS (ESI):
449.76 ( M + H ) *.
US 9 ,884,839 B2
77
34b
7878 34

OH

10

Cyclopropanesulfonic acid (3 -bromo -5 -methyl-phenyl)


methyl-amide (34b ): Cyclo -propane -sulfonic acid OSS= 0
( 3 -bromo-5 -methyl-phenyl)-amide ( 33b ) ( 100 mg, 0 .345
mmol, 1 equiv ) was dissolved in 1 ml anhydrous dimethyl 15
formamide and cooled to 0° C . under N , atmosphere .
Sodium hydride (10 mg, 0.414 mmol, 1.2 equiv ) was added Cyclopropanesulfonic acid {3 -[5 -( 2 ,6 -difluoro -3 -hy
and the solution was stirred for 10 min . Methyl iodide ( 54 droxy -benzoyl) -thiophen - 2 -v11- 5 -methyl-phenyl } -methyl
mg, 0 .024 ml, 0 .380 mmol, 1. 1 equiv ) was added slowly , the 20 amide (34 ): cyclopropanesulfonic acid methyl-[ 3 -methyl-5
mixture warmed up to room temperature and stirred over (4 ,4, 5,5 -tetramethyl-[ 1,3 ,2 ]dioxaborolan -2 - yl)- phenyl]
night. The mixture was quenched with water, extracted three amide (34a ) (0 .86 mmol, 1 . 00 equiv ), (5 -bromo - 2 -thienyl )
times with diethyl ether , washed 5 times with water, and (12.00 ,4 -difluoro -3 -hydroxyphenyl)-methanone le (0 . 86 mmol,
equiv ), cesium carbonate ( 3 .42 mmol, 4 .00 equiv ) and
subsequently with brine , dried over sodium sulphate , filtered 25 PdOPPh . (0 . 004 mmol. 0 .005 equiv ) were suspended in a
and evaporated under reduced pressure. The product was degased mixture of 5 mlDME and 5 ml water. The mixture
used in the next steps without further purification ; yield : was heated to reflux for 3 days under N2 atmosphere. The
81 % (85 mg). 'H NMR (500 MHz, acetone -d ) 8 7.44 (s, mixture was cooled down to room temperature , quenched
1H ), 7.29 (s, 1H ), 7.16 (s, 1H ), 3.31 (s, 3H ), 2 .56 -2 .54 (mm , 3030 ethyl
with water, filtered over celite , extracted three times with
acetate , washed one time with water, one time with
1H ), 2 .33 (s, 3H ), 0 .99- 0. 96 (m , 4H ). brine , dried over sodium sulphate , filtered and evaporated
under reduced pressure . The product was purified by CC
(hexanelethyl acetate 8 : 2 to 5 :5 ) followed by preparative
348 35 TLC ( dichloromethane /methanol 99 : 1 ); yield : 6 % (25 mg).
H NMR (500 MHz, acetone - d ) 89. 04 ( s, 1H ), 7 .71 ( s , 1H ),
7 .65 - 7.63 (m , 2H ), 7.58 (s, 1H ), 7 .30 (s, 1H ), 7 .23 -7. 18 (m ,
0 1H ), 7 .04 (dt, J= 9 . 0 , 1 .9 Hz, 1H ), 3 .41 (s, 3H ), 2 .68- 2 .65 ( m ,
= 1H ), 2 .43 (s, 3H ), 1 .01- 0 .90 (m , 4H ); 13C NMR (125 MHz,
acetone-d “ ) & 180 .7 , 154 .7, 144.2 , 140 .9 , 138 .1, 134.4 ,
129 .3 , 126 .4 , 122 .5 , 112 . 4 , 38 .7 , 21 . 2 , 4 .9 ; MS (ESI) : 463 .87
( M ) *.
45
35a

Cyclopropanesulfonic acid methyl -[3 -methyl-5 -(4 ,4,5 ,5


tetramethyl-[ 1,3, 2 ]dioxaborolan - 2- yl)-phenyl]-amide (34a ):
Cyclopropanesulfonic acid (3 -bromo-5 -methyl-phenyl)
amide (34b ) (260 mg, 0.86 mmol, 1 equiv ) was dissolved in
3 ml dry dimethyl sulfoxide under N2 atmosphere. Bispina
colatodiborone (326 mg, 1.28 mmol, 1.5 equiv ), potassium H2N
acetate (2.57 mmol, 3 equiv ) and Pd (dppf)Cl2 (0 .04 mmol,
0 .05 equiv ) were added . The reaction mixture was heated to 5 -(3 - Aminophenyl)- thiophen - 2 -yl](2 ,4,5 - trifluoro -3
80° C . overnight. Reaction mixture was cooled down to methoxyphenyl)methanone (35a ): The title compound was
room temperature, quenched with water and diethyl1 ether ether,, 60 prepared by reaction of (5 -bromothiophen - 2 -yl) ( 2,4 ,5 -trif
filtered over celite , extracted three times with diethyl ether , luoro -3 -methoxyphenyl)methanone ( id ) ( 1000 mg, 2 .85
washed three times with water and subsequently with brine , mmol) and 3 - aminophenylboronic acid (468 mg, 3.42
dried over magnesium sulphate, filtered and evaporated mmol), cesium carbonate (3711 mg, 11. 39 mmol) and tet
rakis (triphenylphosphine ) palladium ( 40 mg, 33 umol)
under reduced pressure. Purified with flash chromatography Pay 65 according to method C1; yield : 90 % (930 mg; yellow oil).
( dichloromethane pure to dichloromethane/methanol 8 : 2 ); The product was used directly in the subsequent reaction
yield : 50 % (150 mg). without any characterisation .
US 9 ,884,839 B2
7919 80
36
35
IL

5
- OH
OH

10
NH
HN
F
[5-(3- Aminophenyl)thiophen -2-yl](2,4 ,5 -trifluoro -3-hy - 15 VF
droxyphenyl)methanone (35): The title compound was pre Il
pared by reaction of [5 -(3-aminophenyl)thiophen -2-yl](2 ,4,
5 - trifluoro - 3 -methoxyphenyl)methanone (35a ) (930 mg,
2.56 mmol) and boron tribromide (7 .7 mmol) according to 20 4 -Bromo -N - { 3 - [5 -(2 ,4 ,5 -trifluoro - 3 -hydroxybenzoyl)
method B . The productwas purified by CC (dichlorometh thiophen -2 - yl)phenyl) -2 -trifluoromethoxybenzenesulfona
ane /methanol 99.5 :0 .5 ); yield : 61.5 % (550 mg; yellow oil ); mide ( 36 ): The title compound was prepared by reaction of
' H NMR (500 MHz, acetone-d “ ) 8 7 .66 (ddd , J= 16 .9 , 4 . 1, 4 -bromo -2 -trifluoromethoxy - N - {3 -[5 -( 2 ,4 ,5 -trifluoro - 3
1.8 Hz, 1H ), 7.61 -7.37 (m , 2H ), 7 .19- 7.00 (m , 3H ), 6 .76 25 methoxybenzoyl) thiophen -2 -yl]
( dddd , J = 8.0 , 4 .4 , 2. 1, 1.0 Hz, 1H ) ; 13C NMR (75 MHz, phenyl}benzenesulfonamide ( 36a ) (310 mg, 0 .47 mmol) and
acetone -d “) & 181.53 (s), 149.83 (ddd , J = 14.8 , 9.2, 3.3 Hz), boron tribromide (2 . 3 mmol) according to method B . The
product was purified by CC (dichloromethane/methanol
147 .77- 147 .32 (m ), 145 .75 - 145 .38 (m ), 144 .52 - 143.93 (m ), 99 .5 :0 .5 ); yield : 72.5 % ( 190 mg; yellow oil); ' H NMR (500
138 .27 (ddd, J= 15 .8, 11.0 , 2.4 Hz), 133 .50 , 129. 94 , 124 .29 , 30 MHz, acetone- d “) 89. 97 (br., 1H , NH ), 9 .61 (br. s, 1H , OH ),
123. 20 -122.69 (m ), 120 .91 (d, J = 4 .6 Hz), 117 .16 , 115565 .65 , 8J.=031.6(dHz
, J = 8 .5 Hz, 1H ), 7 .77 (dd , J = 8 .5 , 1.8 Hz, 1H ), 7 .74 (p ,
114 .65 , 111.59, 110 .16 (dd , J= 20 .8 , 3.7 Hz), 61.85; MS 1H ), 7 .54, (1Hddd),, 7J.67 (dd , J= 4 .1 , 1. 8 Hz, 1H ), 7 .67-7 .65 ( m ,
= 7 .8 , 1.8 , 1 .0 Hz, 1H ), 7 .52 (d , J= 4 . 1 Hz,
( ESI): 350.18 ( M + H ) . 1H ), 7 .42 - 7 .37 (m , 1H ), 7 . 31 (ddd , J = 8 . 1, 2 .2 , 1. 0 Hz, 1H ),
35. 7 . 12 (ddd , J = 9 . 9 , 8 . 1 , 5 .6 Hz, 1H ) ; 1°C NMR (125 MHz,
acetone - d ) 8 182. 85 , 148 .56 (ddd , J = 7 . 3 , 6 . 5 , 3 . 3 Hz),
36a 146 .95 (dd , J = 3. 2 , 1 .6 Hz ), 146 .61 (ddd , J= 7 .7 , 6 . 9, 3 .1 Hz),
F 143 .65 (ddd , J= 248 .6 , 15 . 8 , 5 . 8 Hz), 143. 09 , 138.84, 138 .25 ,
138 .23 , 137 .08 (ddd , J = 18 .3 , 12. 9 , 3 .0 Hz), 134 . 94 , 133 .83 ,
20131 .82, 131. 46 , 131 . 32, 129 . 11, 126 . 14 , 124 .91 (d , J = 1 . 9
Hz ), 123. 53, 123 .07 ( ddd, J = 15.7 , 6 . 8 , 3 .9 Hz ), 122.07 ,
121.11 ( q, J = 260 .6 Hz ), 118 .76 , 106 . 96 ( dd , J= 21 .1 , 3.0 Hz);
MS (ESI): 653.32 (M + H ) *.
}
45
37a

OSSO NH

F 50

Br

4 -Bromo- 2 -trifluoromethoxy -N - {3 - [5 -( 2,4 ,5 -trifluoro


methoxybenzoyl)thiophen -2 -yl]
phenyl}benzenesulfonamide (36a ): The title compound was
pro-33.
55
OSSO NH

prepared by reaction of [5 -(3 - aminophenyl)thiophen - 2- yl ]


(2,4 ,5- trifluoro -3 -methoxyphenyl )methanone (35a ) (260
mg, 0 .72 mmol) and 4 -bromo- 2-trifluoromethoxybenzene
sulfonyl chloride (243 mg, 0.72 mmol) according to method benzoyl 2 - Trifluoromethoxy - N - { 3 -[5 -( 2 ,4,5 - trifluoro -3 -methoxy
D ; yield: 65.0 % (310 mg; yellow oil). The productwas used" 65 The title)thiophen -2 -yl]phenyl } benzenesulfonamide (37a ):
compound was prepared by reaction of [5 -(3
directly in the subsequent reaction without any characteri aminophenyl) thiophen - 2 -yl](2 ,4 ,5 - trifluoro - 3 -methoxyphe
sation . nyl)methanone (35a) (260 mg, 0 .72 mmol) and 2 -trifluo
US 9 ,884 ,839 B2
82
romethoxybenzenesulfonyl chloride ( 189 mg, 0 .72 mmol) The title compound was prepared by reaction of [5 -(3
according to method D1; yield : 70 .6 % (260 mg; yellow oil ). aminophenyl) thiophen - 2 -yl](2 ,4 ,5 - trifluoro - 3 -methoxyphe
The product was used directly in the subsequent reaction nyl)methanone (35a ) ( 260 mg, 0 . 72 mmol) and 2 -trifluo
without any characterisation . romethylbenzenesulfonyl chloride ( 177 mg, 0 .72 mmol)
5 according to method D1; yield : 43. 5 % (180 mg; yellow oil ) .
The product was used directly in the subsequent reaction
37 without any characterisation .

10 38

OH

OH

OSSO - NH T

ILI
VF

N - { 3 -[5 -(2 ,4 ,5 - Trifluoro -3 -hydroxybenzoyl) thiophen - 2


20
NH

- CF3

yl]phenyl} -2 - trifluoromethoxybenzenesulfonamide (37):


The title compound was prepared by reaction of 2- trifluo - N - {3 -[5 -(2,4,5 - Trifluoro -3-hydroxybenzoyl) thiophen -2
romethoxy - N - { 3 -[5 -(2 , 4 ,5 -trifluoro - 3 -methoxybenzoyl) yl]phenyl) - 2 - trifluoromethylbenzenesulfonamide (38 ): The
thiophen - 2 - yl ]phenyl }benzenesulfonamide ( 37a ) ( 300 mg, title compound was prepared by reaction of N - { 3 - [5 - ( 2 ,4 ,
0 .51 mmol) and boron tribromide ( 2 .5 mmol) according to 20 5 -trifluoro - 3 -methoxybenzoyl) thiophen - 2 - yl]phenyl ) - 2 -tri
method B . The product was purified by CC (dichlorometh - fluoromethylbenzenesulfonamide ( 38a ) ( 185 mg, 0. 32
ane /methanol 99.5:0 .5 ); yield : 52 .4 % (154 mg; yellow oil ); mmol) and boron tribromide ( 1 .6 mmol) according to
' H NMR (500 MHz, acetone- d “) 89.98 (br. s, 1H , NH ), 9.52 method B . The product was purified by CC (dichlorometh
(br. s , 1H , OH ), 8 . 13 -8 .09 ( m , 1H ) , 7 .78 (ddd , J= 8 .4 , 7 .5 , 1 . 7 ane/methanol 99 .5 :0 .5 ) ; yield : 41.6 % ( 75 mg; yellow oil ) ;
Hz, 1H ), 7 .66 ( ddd , J = 4 .3 , 3 . 1, 1 . 1 Hz, 2H ) , 7 .58 - 7 .53 ( m , 24 H NMR (500 MHz, acetone- d ) 8 9 . 97 (br. s , 1H , NH ), 9 . 40
2H ), 7 .52 -7 .50 (m , 2H ), 7. 38 ( td , J= 7 .9 , 0 .4 Hz, 1H ), 7 . 31 (br. s, 1H , OH ), 8 .30 - 8 .23 (m , 1H ), 8 .04 -7 . 98 (m , 1H ),
( ddd , J = 8 . 1 , 2 .2 , 1 .0 Hz, 1H ), 7 . 12 (ddd, J= 9 .9 , 8 . 1 , 5 .6 Hz, 7 . 89 - 7 .82 (m , 2H ), 7 .67 (dd , J = 4 . 1 , 1 .8 Hz, 1H ), 7 .66 (t,
1H ); 13C NMR ( 125 MHz, acetone- d ' ) & 182 . 85 , 153. 98 , J = 1. 8 Hz, 1H ), 7 . 53 (ddd , J = 7 .8 , 1. 8 , 1 .0 Hz, 1H ), 7 .51 ( d ,
148 . 55 ( ddd, J = 7 .7 , 7 . 0 , 3 .0 Hz ), 146 . 81 (dd, J = 3 . 2 , 1 .6 Hz), J = 4 . 1 Hz, 1H ), 7 .40 (t, J = 7 . 9 Hz , 1H ) , 7 .31 ( ddd , J = 8 . 1 , 2 .2 ,
146 .61 (ddd, J = 7 .6 , 7 . 1 , 3 .0 Hz ), 143.65 (ddd, J = 248 .6 , 15 .9 , 1 1 . 0 Hz, 1H ) , 7 . 12 (ddd , J = 9 . 9 , 8 . 1 , 5 .6 Hz, 1H ); 13C NMR
5 .6 Hz), 143 .03 , 139. 16 , 138.25 (d , J= 2 . 1 Hz ), 137 .09 (ddd , ( 125 MHz, acetone - d ) 8 182 .84 , 153 .91, 148. 57 (ddd ,
J = 18 .2 , 13 . 1 , 3 .3 Hz ), 136 .36 , 134 .84 , 132 .57 , 132 . 27 , J = 16 .0 , 12. 3 , 2 .7 Hz ), 146 .61 (ddd, J = 10 .7 , 9 . 1, 3 . 1 Hz ),
131 . 23 , 128 . 02 , 126 . 06 , 123 . 22 , 123.07 (ddd , J = 15 .6 , 6 .5 , 144 . 89 - 142 .31 ( m ), 143 .06 , 139 . 15 , 138 . 25 (d , J= 2 . 1 Hz),
3 .7 Hz), 121.85, 121.53 (d, J= 1.8 Hz), 121.28 (q , J= 259.2 137.05 (ddd , J= 10 .1, 8.0 , 5 .8 Hz ), 134. 90 , 134.47 , 133.86 ,
(M ) . 88,122.05.2),128.497 133.86
Hz), 118 . 45 , 106 . 94 (dd , J = 21. 1, 3 .0 Hz); MS (ESI ): 573.62 16 132 .76 , 131. 30 , 129 .56 ( q , J = 6 . 4 Hz), 128 . 42, 128 . 16 ,
126 . 11, 125 . 05 , 123 . 31 , 122. 88 , 122 .05 , 118 .69, 106 . 96 ( dd ,
J= 21. 1, 3.0 Hz); MS (ESI): 558 .02 (M + H ) *.
38a
50 39
F

payag
F
F

F. OH
55
F

- NH
SSO 60
[5 -(5 - Fluoro -pyridin - 3 -yl)-thiophen -2 -yl]-( 2,4 ,5 -trif
luoro - 3 -hydroxy- phenyl)-methanone (39): The title com
LCF3 pound was prepared by reaction of (5 -bromo-thiophen -2
yl)-( 2 ,4 ,5 - trifluoro - 3 -hydroxy - phenyl)-methanone ( 1g ) (650
mg, 1. 93 mmol), 5 - fluoro - 3 -pyridinylboronic acid (326 mg,

you are sestelor anthonybann


N - {3 - [5 -( 2,4 ,5 - Trifluoro - 3 -methoxybenzoyl) thiophen -2
65 2 .31 mmol), sodium carbonate (3 .5 ml, 2 M ) and tetrakis
(triphenylphosphine) palladium (5 umol) according to
yl]phenyl ) -2 - trifluoromethylbenzenesulfonamide (38a ): method C2. The productwas purified by CC (dichlorometh
US 9 ,884 ,839 B2
83 84
ane /methanol 9: 1); yield : 26 % ( 180 mg). ' H NMR (500 106 .08 (dd , J= 21 .1, 3. 1 Hz ), 104.85 (t, J = 26 .3 Hz); MS
MHz, DMSO -d “) 8 11 .39 (s, 1H ), 8. 93 (t, J= 1.6 Hz , 1H ), (ESI): 370 .79 (M + H )*.
8 .64 (d , J = 2 .6 Hz, 1H ), 8 .27 (ddd , J= 10 .0 , 2 .6 , 1.9 Hz, 1H ),
7 .89 (d , J= 4 .1 Hz, 1H ), 7.76 (dd , J= 4 .1, 1.5 Hz, 1H ), 7.23 5 41
(dd , J= 14 .6 , 8.9 Hz, 1H ). 13C NMR (126 MHz, DMSO -d )
8 182 .35 , 160 .22, 158. 19 , 147 .81, 147.79, 143 .16 , 143. 13 ,
142.70 , 138 .34 , 138 . 19, 138 .15 , 138 . 14 , 137 .91 , 130 . 11,
130 .08 , 127.90 , 121.43, 120 .48, 120.32 ; MS ( ESI): 354.35 10

, 2013
OH
(M + H )*
HO
40a

qa
F 15

(5 -(3 - Chloro -4 -hydroxyphenyl ) thiophen - 2 -yl)( 2,4 ,5 -trif


luoro -3-hydroxyphenyl)methanone (41): The title com
pound was prepared by reaction of (5 -bromothiophen -2 -yl)
F (2,4,5 -trifluoro -3-hydroxyphenyl)methanone (1g) ( 96 .0 mg,
0 .285 mmol), (3 -chloro -4 -hydroxyphenyl)boronic acid
(51. 7 mg, 0 . 300 mmol), cesium carbonate ( 326 mg, 1.00
[5 -(2 ,4 - Difluoro -phenyl)- thiophen -2 -yl)-(2 ,4 ,5 -trifluoro - 25 mmol) and tetrakis(triphenylphosphine) palladium ( 11.5
3 -methoxy -phenyl)-methanone (40a ): The title compound mg, 9.95 umol ) according to method C3 . The product was
was prepared by reaction of (5 -Bromo-thiophen -2 -yl)-(2,4, purified by preparative HPLC (water with 0 .1 % formic
5 -trifluoro -3 -methoxy -phenyl )-methanone (1d ) (500 mg, acid / acetonitrile with 0 .1 % formic acid 60:40 to 30 :70 ) ;
1.42 mmol), 2 ,4 -difluorophenylboronic acid (270 mg, 1.71 30 yield : 40 % (43 .4 mg); ' H NMR (300 MHz, acetone-d ') 8
mmol),cesium carbonate (1856 mg, 5 .70 mmol) and tetrakis 9.61 (br. s, 1H ), 7 .82 (d , J = 2 .2 Hz, 1H ), 7 .68 -7 .59 (m , 2H ),
( triphenylphosphine ) palladium (40 mg, 33 umol) according 7.53 (d, J= 4 .1 Hz, 1H ), 7 .13 (d , J= 8.6 Hz, 1H ), 7 .18 -7.04 (m ,
to method C1; yield: 86 % (500 mg). The product was used 35
1H ), 7.13 (d, J= 8 .6 Hz, 1H );MS (ESI): 385 .1 (M + H )*.
in the next steps without any characterisation .

ging
42

OH
OH

45
HO

'F

[5 -(2,4 - Difluoro -phenyl)- thiophen -2 -yl]-( 2,4 ,5 -trifluoro 50


3 -hydroxy -phenyl)-methanone (40 ): The title compound (5 -(3 -Fluoro -4-hydroxyphenyl) thiophen -2-yl)(2,4,5- trif
was prepared by reaction of [5 -(2 ,4 - Difluoro -phenyl)- thio - luoro -3 -hydroxyphenyl)methanone (42 ): The title com
phen - 2 -yl)-(2 ,4 ,5 -trifluoro -3 -methoxy -phenyl )-methanone pound was prepared by reaction of (5 -bromothiophen -2 -yl)
(40a ) (500 mg, 1.3 mmol) and boron tribromide (6 .5 mmol) ss (2 ,4 ,5- trifluoro - 3-hydroxyphenyl)methanone (1g) (96 .0 mg,
according to method B . The product was purified by CC 0.285 mmol), (3 - fluoro -4 -hydroxyphenyl )boronic acid (46 .8
(DCM /MeOH 99.5 :0 .5 ); yield : 79 % (380 mg); ' H NMR mg, 0.300 mmol), cesium carbonate (326 mg, 1.00 mmol)
(300 MHz, acetone -d ') d 9.79 (s, 1H , OH ), 7.88 -7 .77 (m , and tetrakis ( triphenylphosphine ) palladium (11.5 mg, 9.95
1H ), 7.59 (dd , J= 4. 1, 0 .7 Hz, 1H ), 7.51 (d, J= 4. 1 Hz, 1H ), cumol) according to method C3 . The product was purified by
7 .18 -6 .95 (m , 3H ). 13C NMR (75 MHz, acetone- d “) preparative HPLC (water with 0. 1 % formic acid /acetonitrile
182. 12 , 170 .11, 163.21 ( dd, J = 251.4 , 12 .8 Hz), 159 .51 (dd , with 0 .1 % formic acid 60 :40 to 30 :70 ); yield : 29 % (30 .8
J= 253 .6 , 12 .4 Hz), 147.81, 145 .54 (dd , J = 3 .2 , 1.7 Hz), mg); ' H NMR (300 MHz, acetone -d ') & 9.55 (br. s, 1H ),
143.62 (dd , J= 146 .3 , 3.6 Hz), 136 .55 , 136 .52 , 130 .63 (dd , 7 .65 (dd, J= 4 .1 , 1.5 Hz, 1H ), 7 .60 (dd , J= 11 .9 , 2 .2 Hz, 1H ),
J = 8 .7 , 5. 5 Hz), 127 .49 (dd , J = 4 .1, 1.8 Hz), 122 .06 , 117 .66 , 7 .52 -7 .48 (m , 1H ), 7 .51 (d , J = 4 . 1 Hz, 1H ), 7 .14 -7 . 06 ( m ,
117.50 (dd, J=6.9, 2.3 Hz), 112.54 (dd, J= 19.9, 5.7 Hz), 1H ), 7.11 (t, J= 8.8 Hz, 1H ); MS (ESI-): 367.1 (M - H ) .
US 9 ,884,839 B2
85
85 86
45

??
F
F
5

NH
?? ??

(5-(1H -Indol-6-yl)thiophen -2-yl)(2,4,5-trifluoro-3-hy - 15


droxyphenyl)methanone (43 ): The title compound was pre
10
MeO
OH

(5 -(3 ,5-Dichloro -4 -methoxyphenyl)thiophen -2-yl)(2,4 ,5


pared by reaction of (5 - bromothiophen -2 -yl)( 2,4 ,5 -trifluoro trifluoro -3 -hydroxyphenyl)methanone (45 ): The title com
3 -hydroxyphenyl)methanone (1g ) ( 96 .0 mg, 0.285 mmol), pound was prepared by reaction of (5-bromothiophen -2 - yl)
( 1H - indol-6 -yl)boronic acid (48 .3 mg, 0 .300 mmol), cesium 200(2 ,4 ,5- trifluoro -3 -hydroxyphenyl)methanone (1g) (96 .0 mg,
carbonate (326 mg, 1.00 mmol) and tetrakis (triphenylphos
phine ) palladium (11.5 mg, 9.95 umol) according to method 0(66.285.3 mg mmol), (3,5 -dichloro -4 -methoxyphenyl)boronic acid
C3. The product was purified by preparative HPLC (water mmol) and, 0 .tetrakis 300 mmol), cesium carbonate ( 326 mg, 1.00
(triphenylphosphine ) palladium (11.5
with 0 .1 % formic acid /acetonitrile with 0 . 1 % formic acid 25 mg, 9. 95 umol) according to method C3 . The product was
50 :50 to 20 :80 ); yield : 81 % ( 85.7 mg); 1H NMR (300 MHz, purified by preparative HPLC (water with 0 .1 % formic
acetone -d “) 8 10 .50 (br. s, 1H ), 7 .91 (m , 1H ), 7.67 (d, J= 8 .4 acid /acetonitrile with 0 . 1 % formic acid 40 :60 to 5 : 95 ); yield :
Hz, 1H ), 7.64 (dd , J = 4 . 1, 1. 9 Hz, 1H ), 7.53 (d , J= 4 .1 Hz, 59 % (73 .2 mg); H NMR (300 MHz, acetone -d ') 8 7 .86 (s,
1H ), 7.51- 7.46 (m , 2H ), 7 .13 - 7.05 (m , 1H ), 6 . 56 -6 .52 (m , SO30 2H1 ), 7.71 -7 .69 (m , 2H ), 7 .13 (ddd , J= 10 .0 , 8 .1 , 5 .7 Hz, 1H ),
1H); MS ( ESI - ): 372.1 ( M - H )". 3 .95 (s , 3H ); MS ( ESI -): 431.0 (M - H ) .

F 44 35
46

???? NH2
OH

3 -(5 -(2,4,5- Trifluoro -3 -hydroxybenzoyl) thiophen -2-yl)


benzamide (44 ): The title compound was prepared by reac -
40
40

45

50
Me0
HzC

H3C
??
(5 -(4 -Methoxy -3 ,5 - dimethylphenyl) thiophen - 2 -yl)(2 ,4 ,5
??

tion of (5 -bromothiophen -2 -yl)-( 2,4 ,5- trifluoro -3 -hydroxy - trifluoro -3 -hydroxyphenyl)methanone (46 ): The title com
phenyl)methanone ( 1g ) ( 96 .0 mg, 0 .285 mmol), pound was prepared by reaction of (5 -bromothiophen - 2 - yl )
(3 -carbamoylphen - yl)boronic acid (49.5 mg, 0 . 300 mmol), ss (2 ,4,5 - trifluoro -3 -hydroxyphenyl)methanone (1g ) ( 96 .0 mg,
cesium carbonate ( 326 mg, 1 .00 mmol) and tetrakis ( triph - 0 .285 mmol), (4 -methoxy -3 ,5 - dimethylphenyl)boronic acid
enylphosphine ) palladium ( 11.5 mg, 9. 95 umol) according to (54.0 mg, 0 .300 mmol), cesium carbonate (326 mg, 1. 00
method C3. The product was purified by preparative HPLC mmol) and tetrakis (triphenylphosphine) palladium (11.5
(water with 0 . 1 % formic acid /acetonitrile with 0 .1 % formicsomg, 9 .95 umol) according to method C3. The product was
acid 70 : 30 to 40 :60 ) giving the formiate of the title com - purified by preparative HPLC (water with 0 . 1 % formic
pound ; yield : 21 % (25 .7 mg); 'H NMR ( 300 MHz, DMSO - acid /acetonitrile with 0 .1 % formic acid 40 :60 to 5 :95 ); yield :
d ') & 11.35 (br. s, 1H ), 8. 28 (t, J= 1.8 Hz, 1H ), 8. 16 (br. s, 73 % (81.5 mg); 'H NMR (300 MHz, CDC13) 8 7.49 (dd,
1H ), 8 .00 - 7 .92 (m , 2H ), 7.77 (d , J = 4 .3 Hz, 1H ), 7 .73 (dd, 65cs J = 3 .9 , 1.7 Hz, 1H ), 7 .34 (s , 2H ), 7 .24 -7 .27 (m , 1H ), 6 .99 (td ,
J = 4 .3 , 1.7 Hz, 1H ), 7 .66 -7 .50 (m , 3H ), 7 .28 -7 .20 (m , 1H ); J = 8 .7, 6 . 1 Hz, 1H ), 3 .76 (s, 3H ), 2 .38 (s, 6H ); MS ( ESI):
MS (ESI-): 376 . 1 (M - H ) . 393 .2 (M + H ) +.
US 9 ,884 ,839 B2
87 88
(5 -(3 ,5 -Dichloro -4 -hydroxyphenyl)thiophen -2 -yl)(2 ,4 ,5
47 trifluoro - 3 -hydroxyphenyl)methanone ( 49 ): The title com
pound was prepared by reaction of (5 -(3 ,5 -dichloro -4
methoxyphenyl)thiophen - 2 - yl)( 2 ,4 ,5 -trifluoro - 3
5 hydroxyphenyl)methanone (45 ) (48 mg, 0 .11 mmol) and
?? boron tribromide (0 .34 mmol, 3.0 equiv) according to
method B . The product was purified by CC (hexane :ethyl
F acetate, 3. 1 > 2 : 1); yield : quantitative (84 mg). 'H NMR
( 300 MHz, acetone - d ) 8 9 .92 ( s, 1 H ); 9 . 30 ( s, 1 H ); 7 . 81
10
(s, 2 H ); 7 .68 (dd , J= 1.8 , 4 . 1 Hz, 1 H ); 7 .65 -7 .61 (m , 1 H );
7 .13 (ddd , J= 5 .6 , 8 . 1, 10 .0 Hz, 1 H ) ; MS (ESI): 420 . 20
OH (M + H ) *
(5 -(3 -(Hydroxymethyl)phenyl)thiophen - 2-yl)( 2,4,5 -trif
luoro -3 -hydroxyphenyl)methanone (47): The title com - 15
pound was prepared by reaction of (5 -bromothiophen - 2- yl )
(2 ,4 ,5 - trifluoro - 3 -hydroxyphenyl)methanone (1g) (96 .0 mg,
0 .285 mmol), (3 -(hydroxymethyl)phenyl)boronic acid (45 .6
mg , 0 . 300 mmol), cesium carbonate ( 326 mg, 1 .00 mmol)
and tetrakis ( triphenylphosphine) palladium (11.5 mg, 9.95 20 H3C OH
umol) according to method C1. The product was purified by
preparative HPLC (water with 0 . 1 % formic acid /acetonitrile
with 0 .1 % formic acid 70:30 to 40 :60); yield : 24 % (25 . 1 HOM
mg); ' H NMR ( 300 MHz,MeOH -d4) 87.75 ( s, 1H ), 7 .65 ( d ,
J = 6 . 7 Hz, 1H ), 7 . 58 (dd , J = 4 .0 , 1. 8 Hz, 1H ), 7 .51 ( d , J = 4 . 1 25 H3C
Hz, 1H ), 7 .47 -7 .37 (m , 2H ), 6 . 97 (ddd , J = 9 .7 , 8 . 1 , 5 .7 Hz,
1H ), 4 .67 (s, 2H ); MS (APCI- ): 364. 1 (M - H ) .
48
(5 -(4 -Hydroxy -3 ,5 -dimethylphenyl)thiophen - 2-yl)(2,4 ,5
30
trifluoro -3 -hydroxyphenyl)methanone (50 ): The title com
pound was prepared by reaction of (5 -(4 -Methoxy -3,5
dimethylphenyl)thiophen - 2- yl )(2 ,4,5 - trifluoro -3
hydroxyphenyl)methanone (46 ) (51 mg, 0 .13 mmol) and
OH
boron tribromide (0 .39 mmol, 3 .0 equiv ) according to
35 method B . The product was purified by CC (hexane:ethyl
acetate , 6 : 4 ); yield : 98 % (51 mg). ' H NMR ( 300 MHz,
CDC13 ): 7 .48 (dd , J = 4 . 1, 2. 0 Hz, 1H ), 7. 32 (br.s, 2H ), 7 .22
( d , J = 4 . 1 Hz, 1H ), 6 . 98 (ddd, J= 9 .6 , 8 .1 , 5 . 8 Hz, 1H ), 4 . 90
(s, 1H ), 2.30 (s, 6H ); MS (ESI): 379 .10 (M + H ) *.
- 40

51

45

1-Methyl- N - (3 -(5 -(2 ,4 ,5 - trifluoro - 3 -hydroxybenzoyl)


thiophen - 2- yl)phenyl)-1H - imidazole-4 -sulfonamide (48 ):
The title compound was prepared by reaction of (5 - (3
aminophenyl) thiophen - 2 -yl)( 2,4 ,5 -trifluoro - 3 -hydroxyphe - 50 OH
nyl)methanone ( 39.4 mg, 113 umol) and 1 -methyl- 1H -imi
dazole -4 -sulfonyl chloride (29 .4 mg, 124 umol) according to
method D .
(5 -(4 -Methoxyphenyl) thiophen - 2 - yl )(2 ,4,5 -trifluoro -3
49 55 ,hydroxyphenyl)methanone (51): The title compound was
prepared by reaction of (5 -bromothiophen - 2 -yl)( 2,4 ,5 -trif

Bay
F
luoro -3 -hydroxyphenyl)methanone ( 1g ) (94 .8 mg, 0 .281
mmol), 4 -methoxyphenylboronic acid (45 .6 mg, 0 .300
OH 60 mmol), cesium carbonate (326 mg, 1.00 mmol) and tetrakis
(triphenylphosphine) palladium ( 11.6 mg, 10 .0 umol)
according to method C3. The product was purified by
HO preparative HPLC (water with 0 . 1 % formic acid /acetonitrile
with 0 .1 % formic acid ); yield : 40 % (40 .7 mg). 1H NMR
65 (300 MHz, acetone -d ): 8 7 .81-7 .70 (m , 2H ), 7 .64 (dd ,
J = 4 . 1 , 1 . 8 Hz, 1H ), 7 .48 ( d , J = 4 . 1 Hz, 1H ), 7 . 17 - 6 . 99 ( m ,
3H ), 3 .87 (s, 3H ); MS (ESI) : 365.2 (M + H ) *.
US 9 ,884,839 B2

54

NH

F F ??

(5 -(3 -Methoxyphenyl) thiophen -2 -yl)(2 ,4,5 - trifluoro -3 - N -(3 -(5 -(2,4 ,5 - Trifluoro -3 -hydroxybenzoyl) thiophen -2
hydroxyphenyl)methanone (52 ): The title compound was yl) phenyl)acetamide (54): The title compound was prepared
prepared by reaction of (5 -bromothiophen -2- yl )( 2,4,5 -trif - 20 by reaction of (5 -bromothiophen -2 -yl)(2,4 ,5 - trifluoro -3 -hy
luoro -3-hydroxyphenyl)methanone (1g) (94.8 mg, 0 .281 droxyphenyl)methanone (1g ) (94 .8 mg, 0 .281 mmol),
mmol), 3-methoxyphenylboronic acid (45.6 mg, 0.300 3 -acetylamidophenylboronic acid (53.7 mg, 0 .300 mmol),
mmol), cesium carbonate (326 mg, 1.00 mmol) and tetrakis cesium carbonate (326 mg, 1.00 mmol) and tetrakis(triph
( triphenylphosphine) palladium (11.6 mg, 10 .0 umol) 25 enylphosphine) palladium (11.6 mg, 10 .0 umol) according to
according to method C3. The product was purified by method C3 . The product was purified by preparative HPLC
preparative HPLC (water with 0 .1 % formic acid /acetonitrile (water with 0 . 1 % formic acid /acetonitrile with 0 .1 % formic
with 0 . 1 % formic acid ); yield : 43 % (44 .0 mg). 'H NMR acid ); yield : 8 % (8 .72 mg). ' H NMR (300 MHz, acetone
( 300 MHz, MeOH -d4): 8 7.81- 7 .48 (m , 2H ), 7 .46 -7 .26 (m , 30 dC ): 8 9 .31 (br. s, 1H ), 8 .21-8 . 14 (m , 1H ), 7 .72 -7 .60 (m , 2H ),
3H ), 7 .09 -6 .95 (m , 2H ), 3.89 (s, 3H ); MS (ESI): 365 .2 7 .60 -7.34 (m , 3H ), 7 .12 (ddd , J= 10 .0 , 8 .1, 5.6 Hz, 1H ), 3 .31
(M + H ) * . (s, 3H ); MS (ESI): 392 .3 (M + H ) *.

53 55

$
NH2

Y OH OH
#

50
(5 -(2 -Methoxyphenyl)thiophen - 2-yl)(2,4,5- trifluoro -3 - (3 -(2 -Aminophenyl)thiophen -2-yl)(2 ,4 ,5 -trifluoro -3-hy
hydroxyphenyl)methanone (53): The title compound was droxyphenyl )methanone (55): The title compound was pre
prepared by reaction of (5 -bromothiophen -2 -yl)(2 ,4 ,5 - trif - pared by reaction of (5 -bromothiophen - 2-yl)(2 ,4,5 -trifluoro
luoro-3-hydroxyphenyl)methanone (19) (94.8 mg, 0.281 < 3-hydroxyphenyl)methanone (19) (94.8 mg, 0.281 mmol),
mmol), 2 -methoxyphenylboronic acid (45 .6 mg, 0 .300 (2 -aminophenyl)boronic acid (41. 1 mg, 0.300 mmol),
mmol), cesium carbonate (326 mg, 1.00 mmol) and tetrakis cesium carbonate (326 mg, 1.00 mmol) and tetrakis(triph
(triphenylphosphine) palladium (11.6 mg, 10.0 umol) enylphosphine) palladium ( 11.6 mg, 10. 0 umol) according to
according to method C3 . The product was purified by a method C3. The product was purified by preparative HPLC
preparative HPLC (water with 0 . 1 % formic acid /acetonitrile (water with 0 .1 % formic acid /acetonitrile with 0 . 1 % formic
with 0 .1 % formic acid ); yield : 68 % (70 .0 mg). 'H NMR acid ); yield : 53 % (52 .1 mg). ' H NMR (300 MHz, MeOH
( 300 MHz, acetone -dº ): 8 7 .87 (dd , J= 7.8 , 1.7 Hz, 1H ), 7 .71 d4): 87.64 (dd, J = 3. 8, 1 .7 Hz, 1H ), 7 .45 -7 .38 (m , 1H ), 7. 33
(d, J = 4.2 Hz, 1H ), 7.63 (dd , J= 4 .2, 1.8 Hz, 1H ), 7.43 (ddd , (dd , J= 7.7 , 1.5 Hz, 1H ), 7 .26 -7 .14 (m , 1H ), 7 .11 -6 .95 ( m ,
J = 8.5 , 7 .2 , 1.6 Hz, 1H ), 7.24 -7 .19 (m , 1H ), 7. 15 -7 .05 (m , 1H ), 6 .90 (d , J= 8 .1 Hz, 1H ), 6 .84-6 .71 (m , 1H ); MS ( ESI):
2H ), 4 .03 (s, 3H ); MS (ESI): 365 .2 (M + H ) *. 350 .2 (M + H ) *.
US 9 ,884,839 B2
92
mmol, 1.0 equiv ), bis (pinacolato ) diboron ( 1. 50 g, 5 .91
56 mmol, 1 . 1 equiv ), potassium acetate ( 1 . 58 g , 16 . 1 mmol, 3 .0
equiv ) and Pd( dppf)C12 (118 mg, 0 . 161 mmol, 0 .03 equiv )
were dissolved under argon atmosphere in 15 mlDMSO and
SV the mixture was stirred at 80° C . for 48 h . Water was added
and the aqueous layer was extracted with ethyl acetate three
times. The combined organic layers were dried over mag
nesium sulfate , filtered and concentrated to dryness . The raw
product was purified by flash chromatography; yield : 39 %
F Y OH 10 (486 mg). ' H NMR ( 300 MHz, acetone-dº): 8 7 .05 (dd ,
J = 7 .3 , 1.3 Hz, 1H ), 6 . 91 (t, J = 7 .6 Hz, 1H ), 6 .77 (dd , J= 7 . 8 ,
1 .4 Hz, 1H ), 2 .33 (s, 3H ), 1.33 (s, 12H ).
(5 -Phenylthiophen - 2 - yl)( 2 ,4 ,5 - trifluoro - 3 -hydroxyphe 58
nyl)methanone (56 ): The title compound was prepared by 15
reaction of (5 -bromothiophen - 2 -yl)(2 ,4 ,5 -trifluoro - 3 -hy
droxyphenyl)methanone (1g) (94 .8 mg, 0 .281 mmol), phe 's
nylboronic acid (36 .6 mg, 0 .300 mmol), cesium carbonate
( 326 mg, 1.00 mmol) and tetrakis( triphenylphosphine ) pal
ladium ( 11.6 mg, 10 .0 umol) according to method C3 . The HN
product was purified by preparative HPLC (water with 0 .1 %
formic acid /acetonitrile with 0 . 1 % formic acid ); yield : 51% Y OH
(47.9 mg). 'H NMR ( 300 MHz, acetone -dº): 8 9. 91 (br. s,
1H ), 7.87 -7.77 (m , 2H ), 7.69 (dd, J= 4 .1, 1.8 Hz, 1H ), 7.61 25
(d , J= 4 . 1 Hz, 1H ), 7 .55 -7 .39 (m , 3H ), 7 .12 (ddd , J = 10 .0 , 8 .1 ,
5.7 Hz, 1H ); MS (ESI): 335.2 (M + H ) *. (5 -(3 -Amino -2 -methylphenyl) thiophen - 2 -yl)(2 ,4 ,5 -trif
luoro -3 -hydroxyphenyl)methanone (58 ): The title com
pound was prepared by reaction of (5 -bromothiophen -2 -yl)
57 30 (2 , 4 ,5 -trifluoro - 3 -hydroxyphenyl)methanone (1g ) ( 94 .8 mg,
0 . 281 mmol), 2 -methyl- 3 - (4 ,4 ,5 , 5 - tetramethyl- 1, 3 ,2 - dioxa
borolan - 2 - yl)aniline (58a ) (69.9 mg, 0 .300 mmol), cesium
carbonate ( 326 mg , 1. 00 mmol) and tetrakis( triphenylphos
phine ) palladium ( 11 .6 mg, 10 .0 umol) according to method
HN
35 C3. The product was purified by preparative HPLC (water
with 0 . 1 % formic acid/ acetonitrile with 0 . 1 % formic acid ) ;
yield : 7 % (7.60 mg).
Y OH ' H NMR (300 MHz, MeOH - d4): 8 7 .58 (dd , J= 3 . 9 , 1.8
Hz, 1H ), 7. 43 (d , J = 4 .0 Hz, 1H ), 7 . 19 -6 .88 (m , 4H ), 2 . 22 (s ,
40 3H ); MS (ESI) : 364.2 ( M + H ) *.
(5 -( 3 - Amino -4 -methylphenyl) thiophen -2 -yl) (2 ,4 ,5 - trif
luoro - 3 -hydroxyphenyl)methanone (57 ): The title com 59a
pound was prepared by reaction of (5 -bromothiophen - 2 -yl)
(2 ,4 ,5 -trifluoro - 3 -hydroxyphenyl)methanone (1g) (94 .8 mg, 45
0 .281 mmol), 3-amino -4 -methylphenylboronic acid (45 .3
mg, 0 .300 mmol) , cesium carbonate (326 mg, 1.00 mmol) WS
and tetrakis (triphenylphosphine) palladium ( 11 .6 mg, 10 .0
umol) according to method C3 . The product was purified by
preparative HPLC (water with 0 . 1 % formic acid /acetonitrile 50
with 0 . 1 % formic acid ); yield : 15 % (15 . 7 mg). ' H NMR
(300 MHz, MeOH - d * ): 8 7 .61 (d , J = 2 .2 Hz, 1H ), 7 .14 (d ,
J = 3. 9 Hz, 1H ), 7. 11 -6 .97 (m , 2H ), 6 .86 (d , J= 7 .8 Hz, 1H ),
6 .80 ( d, J= 7.5 Hz, 1H ), 2 .22 (s, 3H ); MS (ESI): 364 .2 5 -(4 ,4 ,5,5 - Tetramethyl-1,3 ,2 -dioxaborolan - 2 -yl)benzo [ d ]
(M + H ) . 55 oxazole (59a ): 5 -Bromobenzo [d ]oxazole ( 500 mg, 2.53
mmol, 1.0 equiv ), bis(pinacolato ) diboron (706 mg, 2 .78
mmol, 1.1 equiv ), potassium acetate (745 mg, 7.59 mmol,
58a 3 .0 equiv ) and Pd (dppf)C12 (55 .5 mg, 75 . 9 umol, 0 .03 equiv )
were dissolved under argon atmosphere in 7 ml DMSO and
60 the mixture was stirred at 80° C . for 22 h . Water was added
and the aqueous layer was extracted with ethyl acetate three
times. The combined organic layers were dried over mag
HN nesium sulfate , filtered and concentrated to dryness. The raw
product was purified by flash chromatography ; yield : 37 %
65 ( 229 mg). ' H NMR (300 MHz, acetone- dº ): 8 8 . 47 (s , 1H ) ,
2 -Methyl-3 -(4 ,4,5 ,5 -tetramethyl-1,3 ,2 -dioxaborolan -2 8 . 12 (s, 1H ), 7 .86 -7 .80 ( m , 1H ), 7 .72 -7 .64 (m , 1H ), 1.37 (s ,
yl)aniline (58a ): 3 -Bromo -2 -methylaniline (1. 00 g , 5 .37 12H ).
US 9 ,884,839 B2
93 94
94
59 60

O
HO

H?N

Y OH 10 F OH

F F

(5 -(3 - Amino -4 -methoxyphenyl) thiophen -2 -yl) (2,4 ,5 -trif


15 luoro - 3 -hydroxyphenyl)methanone (60 ): The title com
pound was prepared by reaction of (5 -bromothiophen -2 - yl)
(5-(3 -Amino-4 -hydroxyphenyl)thiophen - 2-yl)(2,4,5-trif (2,4 ,5 -trifluoro - 3-hydroxyphenyl)methanone (1g ) (94 .8 mg,
luoro -3-hydroxyphenyl)methanone (59 ): The title com 0oxaborolan .281 mmol), 2 -methoxy -5 -(4 ,4 ,5 ,5 - tetramethyl- 1,3 ,2 - di
- 2 - yl)aniline (60a ) (74 .7 mg, 0 .300 mmol),
pound was prepared by reaction of (5-bromothiophen -2-Yyl!)) .20 cesium carbonate (326 mg, 1.00 mmol) and tetrakis( triph
(2,4 ,5 - trifluoro -3 -hydroxyphenyl)methanone (1g) (94 .8 mg, enylphosphine ) palladium ( 11 .6 mg, 10 .0 umol) according to
0 .281 mmol), 5 - ( 4 , 4 ,5 ,5 -tetramethyl- 1 .3 .2 - dioxaborolan - 2 - method C3. The product was purified by preparative HPLC
yl)benzo [d ]oxazole (59a ) ( 73 .5 mg, 0 .300 mmol), cesium acid (water with 0 . 1 % formic acid /acetonitrile with 0 .1 % formic
); yield : 31 % (33 .3 mg). ' H NMR ( 300 MHz, MeOH
carbonate (326 mg, 1.00 mmol) and tetrakis (triphenylphos - 36 d4): 8 7 .61-7 .52 (m , 1H ), 7 .29 (d , J= 3 .9 Hz, 1H ), 7. 22 - 7. 10
phine ) palladium (11.6 mg, 10 .0 umol) according to method (m , 1H ), 7.05 -6.86 (m , 1H ), 6 .78 (d, J= 8. 1 Hz, 1H ), 4 .61 (br .
C3 . The product was purified by preparative HPLC (water S, 2H ), 3 . 94 (s, 3H ); MS (ESI): 380 .3 (M + H ) *.
with 0. 1 % formic acid /acetonitrile with 0. 1 % formic acid );
yield : 35 % ( 35.7 mg). 30 61
'H NMR (300 MHz, MeOH -d4): 8 7.58 - 7.51 (m , 1H ),
7.33 (d , J= 3 .9 Hz, 1H ), 7 .17 (d , J= 1.5 Hz, 1H ), 7 .04 (dd,
J = 8.0 , 2. 1 Hz, 1H ), 7 .01 -6 . 92 (m , 1H ), 6 .78 (d, J= 8 .1 Hz,
1H); MS ( ESI): 366. 2 ( M + H )* . 35 HN
OH
F
60a

U
(5 -( 1H - Indol-5 -yl)thiophen - 2 -yl)(2 ,4 ,5 - trifluoro - 3 -hy
droxyphenyl)methanone (61): The title compound was pre
pared by reaction of (5 -bromothiophen - 2 -yl)( 2,4 ,5 -trifluoro
3 -hydroxyphenyl )methanone (1g ) (94 .8 mg, 0 .281 mmol),
(1H - indol- 5 -yl) boronic acid (48. 3 mg, 0 . 300 mmol), cesium
carbonate (326 mg, 1.00 mmol) and tetrakis(triphenylphos
NH2 phine ) palladium ( 11.6 mg, 10 .0 umol) according to method
C3. The product was purified by preparative HPLC (water
with 0 . 1 % formic acid /acetonitrile with 0 . 1 % formic acid );
yield : 49 % (51 .6 mg). ' H NMR (500 MHz, acetone - dº ) : 8
50 8 .09 (dd , J= 1.9, 0 .6 Hz, 1H ), 7 .65 (dd , J = 4 .1, 1. 9 Hz, 1H ),
2 -Methoxy -5 -(4 ,4,5,5 - tetramethyl -1,3,2 -dioxaborolan -2 87 ..602 , -57 ..51 (m , 3H ), 7 .47 -7 .41 (m , 1H ), 7 . 11 ( ddd, J= 10 .1,
7 Hz, 1H ), 6 .63 -6 . 57 (m , 1H ); MS (ESI): 374 .3
yl)aniline (60a ): 5- Bromo- 2-methoxyaniline (500 mg, 2 .48 (M + H )*.
mmol, 1.0 equiv ), bis(pinacolato )diboron (691 mg, 2 .72 55
mmol, 1.1 equiv ), potassium acetate (730 mg, 7.44 mmol, 62a
3.0 equiv ) and Pd (dppf)C12 (54 .4 mg, 74 .4 umol, 0 .03 equiv )
were dissolved under Argon atmosphere in 7 ml DMSO and
the mixture was stirred at 80° C . for 48 h . Water was added
and the aqueous layer was extracted with ethyl acetate three
times. The combined organic layers were dried over mag
nesium sulfate , filtered and concentrated to dryness. The raw
product was purified by flash chromatography ; yield : 30 % HN
(184 mg). 'H NMR (300 MHz, acetone -dº): 8 7.11- 7.02 (m ,
2H ), 6.81 (d, J= 7.9 Hz, 1H ), 3.84 (s, 3H ), 1.29 (s, 12H ).
US 9 ,884 ,839 B2
95 96
4 -(4 ,4,5 ,5 - Tetramethyl-1 ,3 ,2 -dioxaborolan - 2 -yl)- 1H - in umol) according to method C3. The product was purified by
dole (62a ): 4 -Bromoindole (1.00 g, 5 .10 mmol, 1.0 equiv ), preparative HPLC (water with 0 .1 % formic acid /acetonitrile
bis (pinacolato )diboron (1 .42 g , 5 .61 mmol, 1. 1 equiv ), with 0 .1 % formic acid ); yield : 53 % (64 .2 mg). ' H -NMR
potassium acetate (1. 50 g , 15 .3 mmol, 3 .0 equiv ) and (500 MHz, acetone-dº ): 89. 95 (br. s, 1H ), 8 .76 (s, 1H ), 7 .76
Pd (dppf)C12 ( 112 mg, 0 .153 mmol, 0 .03 equiv ) were dis - 5 (t, J= 1.9 Hz, 1H ), 7 .71 ( dd , J= 3.9 , 1.7 Hz, 1H ), 7 .63 -7.56 (m ,
solved under Argon atmosphere in 15 ml DMSO and the 2H ), 7.49 (t, J= 7.9 Hz, 1H ), 7.43 (ddd , J= 8.0 , 2 .1, 1.0 Hz,
mixture was stirred at 80° C . for 24 h and afterwards at 40° 1H ), 7 . 13 (ddd , J = 9 .9 , 8 . 1 , 5 . 7 Hz, 1H ), 3 .08 ( s, 3H ); MS
C . for 72 h . Water was added and the aqueous layer was ( ESI): 428. 2 ( M + H ) *.
extracted with ethyl acetate three times. The combined
organic layers were dried over magnesium sulfate , filtered
and concentrated to dryness. The raw product was purified 64
by flash chromatography and by preparative HPLC (water
with 0 . 1 % formic acid / acetonitrile with 0 . 1 % formic acid ); F
yield : 38 % ( 470 mg). 'H NMR (500 MHz, acetone- dº ): 81
10 .21 (br. s, 1H ), 7 .55 - 7 .49 (m , 2H ), 7 .34 (dt, J= 3 .0 , 1 .3 Hz,
1H ), 7 .10 (dd , J = 8 .0 , 7. 1 Hz, 1H ), 6 .93 -6 .91 ( m , 1H ), 1. 37 OH
( s, 12H ) .
HN
6220
HN

N -(4 -( 5 -( 2,4,5 - trifluoro -3 -hydroxybenzoyl) thiophen -2


OH
yl)phenyl)acetamide (64 ): The title compound was prepared
by reaction of (5 -bromothiophen -2 -yl)(2 ,4,5 - trifluoro -3 -hy
droxyphenyl)methanone (1g ) (94 .8 mg, 0.281 mmol),
30 4 -acetylamidophenylboronic acid (53.7 mg, 0.300 mmol),
(5 -( 1H - Indol-4 -yl)thiophen - 2 -yl)( 2,4 ,5 -trifluoro -3 -hy cesium carbonate (319 mg, 0.979 mmol) and tetrakis (triph
droxyphenyl)methanone (62 ): The title compound was pre enylphosphine) palladium (11.3 mg, 9 .78 umol) according to
pared by reaction of (5 -bromothiophen -2 -yl)( 2,4 ,5 -trifluoro method C3 . The product was purified by preparative HPLC
3 -hydroxyphenyl)methanone ( 1g ) (94 .8 mg, 0 .281 mmol), (water with 0 .1 % formic acid /acetonitrile with 0 . 1 % formic
4 -( 4,4,5 ,5 - tetramethyl-1,3 ,2 -dioxaborolan -2 -yl)-1H -indole 35
(62a ) (72 .9 mg, 0 .300 mmol), cesium carbonate (319 mg, acid ); yield : 12 % ( 12 .9 mg). ' H - NMR (300 MHz, DMSO
0 .979 mmol) and tetrakis (triphenylphosphine ) palladium d6 ): 10 . 16 (s, 1H ) 7 .76 (d , J = 8 .9 Hz, 2H ), 7 .69 ( d , J = 8 . 8
(11.3 mg, 9.78 umol) according to method C3 . The product Hz, 2H ), 7 .64 (dd , J = 4. 1, 1.5 Hz, 1H ), 7 .61-7 .56 (m , 1H ),
was purified by preparative HPLC (water with 0 .1 % formic 7.19-7.07 (m , 1H ), 2.07 (s, 3H ); MS (ESI): 392.2 (M + H ) +.
acid /acetonitrile with 0 .1 % formic acid ); yield : 95 % ( 99.6 40
mg) . ' H -NMR (300 MHz, acetone - d ) : 8 10 .67 (br. s , 1H ) ,
7 .73 (dd , J= 4.0 , 1.8 Hz, 1H ), 7 .67 (d , J = 4 .1 Hz, 2H ),
7 .60 -7 .52 (m , 2H ), 7. 48 ( dd , J = 7 .4 , 0 . 9 Hz, 1H ), 7. 28 -7 . 20
( m , 1H ), 7 . 15 (ddd, J= 10 .0 , 8 . 1, 5 .6 Hz, 1H ), 6 . 96 (ddd,
J = 3 . 2 , 2 . 0 , 1. 0 Hz, 1H ); MS (ESI ): 374 . 3 ( M + H ) +. 45
OH
com
os F F
- OH
(5 -(Pyridin -3 -yl) thiophen - 2 -yl)(2 ,4 ,5 -trifluoro - 3 -hy
droxyphenyl)methanone (65 ) : The title compound was pre
55 pared by reaction of (5 -bromothiophen - 2- yl )(2 ,4,5 - trifluoro
NH 3 -hydroxyphenyl)methanone ( 1g ) (94 .8 mg, 0 .281 mmol),
pyridine -3 -boronic acid (36 .9 mg, 0 .300 mmol), cesium
carbonate (326 mg, 1. 00 mmol) and tetrakis(triphenylphos
60 phine) palladium ( 11. 3 mg, 9.78 umol) according to method
N -(3 -(5 -(2 ,4 ,5 -trifluoro - 3 -hydroxybenzoyl) thiophen -2 C3. The product was purified by preparative HPLC (water
yl)phenyl)methanesulfonamide (63 ): The title compound with 0 . 1 % formic acid /acetonitrile with 0 . 1 % formic acid );
was prepared by reaction of (5 -bromothiophen -2 -yl) (2 ,4 ,5 - yield : 15 % ( 14 .2 mg). ' H -NMR (500 MHz, DMSO - dº) : 8
trifluoro - 3 - hydroxyphenyl)methanone ( 1g) ( 94. 8 mg, 0 .281 9 .05 ( d , J = 2 .0 Hz, 1H ), 8 .63 (dd , J = 4 . 8 , 1 . 4 Hz, 1H ), 8 . 22
mmol), 3 -methylsulfonylaminophenylboronic acid (64.5 65 (dt, J = 8 . 0 , 1. 9 Hz, 1H ), 7 .81 (d , J = 4 . 1 Hz, 1H ), 7 .74 (dd ,
mg, 0 .300 mmol), cesium carbonate (319 mg, 0 . 979 mmol) J = 4 . 1 , 1. 4 Hz, 1H ), 7 .67 - 7 . 48 ( m , 1H ), 7 .24 (ddd , J = 10 .0 ,
and tetrakis (triphenylphosphine ) palladium ( 11 .3 mg, 9.78 8 .2 , 5.7 Hz, 1H ); MS (ESI): 336 .3 (M + H ) *.
US 9 ,884,839 B2
97 98
(5 -( 1H -Benzo [d ] imidazol -5 -yl) thiophen - 2 -yl)( 2,4 ,5-trif
66a luoro - 3 -hydroxyphenyl)methanone (67): The title com
pound was prepared by reaction of (5 -bromothiophen -2 - yl)
0 ( 2 ,4 ,5 - trifluoro - 3 -hydroxyphenyl)methanone (1g ) (94 . 8 mg,
- 5 0 . 281 mmol), 1H -benzimidazole -5 -boronic acid pinacol
W
ester (73 .2 mg, 0 .300 mmol), cesium carbonate (320 mg,
0 . 984 mmol) and tetrakis (triphenylphosphine) palladium
(40 .4 mg, 35 .0 umol) according to method C3. The product
was purified by preparative HPLC (water with 0 . 1 % formic
acid / acetonitrile with 0 . 1 % formic acid ); yield : 7 % ( 7 . 6 mg) .
'H -NMR (300 MHz, DMSO -d “): 8 12 .58 (br. s, 1H ), 8 .32 (s,
1H ), 8 .04 (br. s, 1H ), 7 .70 -7 .64 ( m , 4H ), 7. 19 -7 . 11 (m , 1H );
7 -(4 ,4 ,5 ,5 - Tetramethyl-1,3 ,2 -dioxaborolan - 2 -yl)quino MS (ESI): 375 .2 (M + H )* .
line (66a ): 7 -Bromoquinoline (500 mg, 2.36 mmol, 1.0 15
equiv ), bis (pinacolato )diboron (671 mg, 2.64 mmol, 1. 1
equiv ), potassium acetate (707 mg, 7 .20 mmol, 3 .1 equiv )
and Pd (dppf)C12 (52 .7 mg, 72.0 umol, 0.03 equiv ) were
dissolved under Argon atmosphere in 7 ml DMSO and the
mixture was stirred at 80° C . over night. Water was added 20 HO
and the aqueous layer was extracted with ethyl acetate three
times. The combined organic layers were dried over mag
nesium sulfate, filtered and concentrated to dryness . The raw
product was purified by flash chromatography; yield : 52 %
(316 mg). ' H NMR ( 300 MHz, acetone-d ) : 8 8 . 93 (dd , 25 Y
J = 4 . 1, 1 .7 Hz, 1H ), 8 .49 (s , 1H ), 8 .35 - 8 . 27 ( m , 1H ), 7 . 97 F
7 .83 (m , 2H ), 7 .53 (dd , J= 8.3 , 4 .2 Hz, 1H ), 1.39 (s, 12H ).
(5 -(4 -Hydroxyphenyl) thiophen -2 -yl)( 2,4 ,5 -trifluoro -3
66 30 hydroxyphenyl)methanone (68 ): The title compound was
prepared by reaction of (5 -(4 -methoxyphenyl) thiophen - 2
yl) (2 ,4, 5 -trifluoro -3 -hydroxyphenyl)methanone (51) (20 .0
mg, 54.9 umol) and boron tribromide (0 . 165 mmol, 3.0
35 equiv ) according to method B . The product was purified by
preparative HPLC (water with 0 . 1 % formic acid /acetonitrile
OH
with 0 . 1 % formic acid ); yield : 18 % (3 .50 mg) . 'H -NMR
F (300 MHz, acetone-dº ): 8 7 .70 -7 .63 (m , 2H ), 7 .61 (dd ,
J = 4 . 1, 1.9 Hz, 1H ), 7.43 (d , J = 4 . 1 Hz, 1H ), 7 .05 -6 . 91 (m ,
40 3H ); MS (ESI): 351.2 (M + H )*.
(5 -(Quinolin - 7 - yl) thiophen -2 -yl) ( 2 ,4 ,5 - trifluoro - 3 -hy
droxyphenyl)methanone (66 ): The title compound was pre
pared by reaction of (5 -bromothiophen - 2 -yl)(2 ,4 ,5 -trifluoro 69
3 -hydroxyphenyl)methanone ( 1g ) (7 - (4 ,4 , 5 ,5 - tetramethyl- 1 ,
3 ,2 -dioxaborolan -2 -yl) quinoline (66a ) (76 .5 mg, 0 .300 45
mmol), sodium carbonate ( 74 .2 mg, 0 .700 mmol) and tet
rakis (triphenylphosphine ) palladium ( 3 .24 mg, 2 .80 umol)
according to method C2. The product was purified by
preparative HPLC (water with 0 . 1 % formic acid / acetonitrile
with 0 . 1 % formic acid ); yield : 5 % (5 . 9 mg) . ' H -NMR (300 50
MHz, DMSO - dº): 6 8 . 97 (dd , J = 4 . 2, 1.7 Hz, 1H ), 8 .46 - 8 .38 Y OH
( m , 2H ), 8 .20 - 8 .02 ( m , 2H ), 7 . 94 ( d , J = 4 .0 Hz, 1H ) , 7 .74 (dd ,
J = 4 .1 , 1.5 Hz, 1H ), 7 .58 (dd, J= 8 .1 , 4.2 Hz, 1H ), 7 .13 (d ,
J = 6 . 2 Hz, 1H ) ; MS (ESI): 386 . 2 ( M + H ) *.
55
3 (5 -(3 -Hydroxyphenyl) thiophen -2 -yl)(2,4 ,5 - trifluoro - 3
hydroxyphenyl)methanone (69) : The title compound was
prepared by reaction of (5 -(3 -methoxyphenyl)thiophen -2
yl) (2 ,4 ,5 -trifluoro -3 - hydroxyphenyl)methanone (52 ) ( 26 .2
F 60 mg, 71.9 umol) and boron tribromide (0 . 216 mmol, 3.0
equiv ) according to method B . The product was purified by
preparative HPLC (water with 0 . 1 % formic acid /acetonitrile
OH with 0 . 1 % formic acid ); yield : 83 % (21. 0 mg). 1H -NMR
F (500 MHz, acetone-dº): 87.66 (dd, J = 3 .9 , 1. 7 Hz, 1H ), 7 .54
65 (d , J = 4 . 1 Hz, 1H ), 7 . 33 -7 . 26 ( m , 2H ), 7 . 25 -7 .23 (m , 1H ),
7 .11 (ddd , J = 10 .0 , 8 . 1 , 5 . 5 Hz, 1H ), 6 . 95 -6 . 91 (m , 1H ); MS
( ESI ): 351 . 3 ( M + H )* .
US 9 ,884,839 B2
100
mmol, 1.0 equiv ), benzylbromide (665 mg, 3 .89 mmol, 1.2
70 equiv ) and potassium carbonate (558 mg, 3 .89 mmol, 1. 2
equiv ) at 50° C . in 4 .0 mL DMF for 1 .5 hours. The reaction
was stopped by the addition of water and extracted with
ethyl acetate three times. The combined organic layers were
OH
washed with brine and dried with magnesium sulfate . After
concentration in vacuo the crude mixture was purified by
flash chromatography (dichloromethane:n -hexane ) to obtain
the product as an oil; yield : 35 % (328 .1 mg). ' H NMR (300
F OH
10 MHz, CDC12) 8 7 .76 ( dd , J = 8 .2 , 2 .8 Hz, 1H ), 7 .61 (dd ,
J= 7.4, 2 .8 Hz, 1H ), 7.45 -7 .34 (m , 6H ), 5 .38 (s, 2H ), 2.56 (s,
3H ).
(5 -( 2 -Hydroxyphenyl) thiophen - 2 -yl)(2 ,4 ,5 -trifluoro - 3
hydroxyphenyl)methanone ( 70 ): The title compound was 15 71c
prepared by reaction of (5 - (2 -methoxyphenyl) thiophen - 2
yl) (2 ,4 ,5 -trifluoro - 3 - hydroxyphenyl)methanone (53) (34. 3 HO -
HO 1
mg, 94 .1 umol) and boron tribromide (0 .282 mmol, 3 .0
equiv ) according to method B . The product was purified by
preparative HPLC (water with 0 .1 % formic acid /acetonitrile 20 NH2
with 0. 1 % formic acid ); yield : 45 % (14 .7 mg). 'H -NMR
( 300 MHz, acetone -d ) : 87 .82 ( dd , J= 7 . 9 , 1. 5 Hz, 1H ), 7 .75
(d , J = 4 .2 Hz, 1H ), 7 .64 (dd , J = 4 .1, 1.6 Hz, 1H ), 7 .31 -7 .21
(m , 1H ), 7. 15- 7.03 (m , 2H ), 6 . 98 (t, J= 7 .5 Hz, 1H ); MS 25
( ESI): 351. 2 ( M + H ) *. 3 - Amino -5 - fluoro - 2-methylbenzoic acid ( 71c ): The title
compound was prepared by reaction of benzyl 5 - fluoro -2
71a methy
methyl-3 - nitrobenzoate (71b ) (321 mg, 1 . 11 mmol) and
palladium on charcoal ( 10 % Pd , 160 mg) under hydrogen
HO 30 atmosphere in 5.0 mL methanol at room temperature for
41. 5 h . The reaction was stopped by dilution with ethyl
NO2 acetate and filtered through a pad of celite fine . After drying
35
with magnesium sulfate , evaporation of the solvent afforded
F the pure product as solid ; yield : 90 % (167.9 mg). 'H NMR
(300 MHz, MeOH -d4) d 6 . 80 (dd , = 9.4 , 2 .5 Hz, 1H ), 6 .63
5 -fluoro -2 -methyl-3 -nitrobenzoic acid (71a ): The title (dd , J= 10 .5 , 2.3 Hz, 1H ), 2 .32 -2 .28 (m , 3H ) .
compound was prepared by reaction of 5- fluoro - 2-methyl
benzoic acid (500 mg, 3 . 24 mmol, 1 .0 equiv ) in 4 mL 40
sulphuric acid (95 % ) and fuming nitric acid ( 245 . 1 mg, 3 .89 71d
mmol, 1 .2 equiv ) in 0 .7 mL sulphuric acid (95 % ) at - 11° C .
The mixture was warmed to 0° C . and stirred for one hour HO
at this temperature . It was poured into ice cold water,
extracted with ethyl acetate three times , washed with brine 45 ??
and dried over magnesium sulfate , filtered and concentrated
to dryness. The crude product was used in the next step
without any further purification . *

50
71b 5 -Fluoro -3 -hydroxy -2 -methylbenzoic acid ( 71d ): The
title compound was prepared by reaction of 3 -amino -5
fluoro - 2-methylbenzoic acid (71c ) (68 .1 mg, 0 .403 mmol, 1
55 equiv ) in 0 .5 ml water and 1.0 ml sulfuric acid (95 % ) and
sodium nitrite (29. 2 mg, 0 .423 mmol, 1. 05 equiv ) dissolved
in 0 .7 mL water at 0° C . After 2 h of reaction time, the
mixture was added dropwise to a boiling solution of 10 .0 mL
NO2 60 sulfuric acid (50 % ) and refluxed for 15 min . After cooling to
room temperature, the mixture was extracted with ethyl
acetate, washed with brine , dried with magnesium sulfate
and purified by preparative HPLC (water with 0 . 1 % formic
Benzyl 5 - fluoro - 2-methyl-3 -nitrobenzoate (71b ): The title 65 aacid /acetonitrile with 0 . 1 % formic acid ); yield : 40 % (27 .3
ss
compound was prepared by reaction of the crude mixture of mg). ' H NMR (300 MHz, MeOH -d *) 8 7 .02 (dd , J = 9 .4 , 2 .3
5 -fluoro - 2 -methyl- 3- nitrobenzoic acid (71a ) (591 mg, 3 .24 Hz, 1H ), 6 .70 (dd , J= 10 .0 , 2.2 Hz, 1H ), 2.37 (s, 3H ).
US 9 ,884 ,839 B2
101 102
7 .01 (dd, J= 8.0 , 2 .7 Hz, 1H ), 6 .95 (dd , J= 8 .7, 2.6 Hz, 1H ),
71e 2.33 (s, 3H ), 2. 10 - 2.07 (m , 3H ).
HO
71h

10

3 -Acetoxy -5 - fluoro -2 -methylbenzoic acid (71e ): The title


compound was prepared by reaction of 5 -fluoro -3 -hydroxy Meo F
2 -methylbenzoic acid ( 71d ) (39 .2 mg, 0 .230 mmol) in 1 .0 ml
of acetic anhydride in the presence of a catalytic amount of 15
DMAP (~ 2 mg) at room temperature for 15 h . 1 .0 ml of 5 - Fluoro - 3 -(5 - (4 -methoxy - 3 ,5 - dimethylphenyl)thio
water was added and the mixture was stirred for another phene- 2-carbonyl)-2 -methylphenyl acetate ( 71h ): The title
hour. After dilution with water, the crude mixture was compound was prepared by reaction of (3 -(5 -bromothio
extracted with ethyl acetate, dried with magnesium sulfate phene- 2- carbonyl)-5 - fluoro -2 -methylphenyl acetate (719)
and purified by preparative HPLC (water with 0 . 1 % formic 20 (8 .5 mg, 24 umol), 4 -methoxy -3 ,5 -dimethyl phenylboronic
acid /acetonitrile with 0 . 1 % formic acid ) ; yield : 82 % ( 39 . 8 acid (4 .7 mg, 26 umol), cesium carbonate ( 27. 1 mg, 83 .2
mg ); H NMR (300 MHz, MeOH - d . ) 8 7 .54 (dd , J = 9 . 1 , 2 . 8 umol) and tetrakis(triphenylphosphine) palladium (1.00 mg,
Hz, 1H ), 7 .12 ( dd, J = 8.7 , 2.7 Hz, 1H ), 2 .42-2.32 (m , 6H ). 0 . 865 umol) according to method C3. The crude product was
25
used in the next step without further purification .
71f
71i

30

OH

Meo
35
3 -(Chlorocarbonyl)-5 -fluoro -2 -methylphenyl acetate
( 71f): The title compound was prepared by reaction of (5 -Fluoro -3 -hydroxy -2 -methylphenyl)(5 -(4 -methoxy - 3,
3 -acetoxy-5 -fluoro -2 -methylbenzoic acid (71e) (20 .0 mg, 5 - dimethylphenyl )thiophen -2 -yl)methanone (71i): The title
94 .3 umol, 1 equiv ) in 1.0 ml of thionyl chloride at room
temperature for 14 h . The mixture was heated to 80° C . and 40 compound was prepared by reaction of (5 - fluoro -3 - (3 -( 4
stirred for another 1 h . Removal of excess thionyl chloride methoxy - 3,5 -dimethylphenyl )thiophene -2 -carbonyl) -2
by distillation under reduced pressure yielded the crude methylphenyl acetate (71h ) (24 umol) and sodium hydroxide
( 3 .82 mg, 95 .6 umol, 4 equiv ) in 4 ml THF /methanol/water
product , which was used in the next step without further
purification. 1 / 1 / 2 overnight. The mixture was diluted with water,
45 extracted with ethyl acetate , dried with magnesium sulfate ,
concentrated under reduced pressure und purified by flash
71g chromatography; yield : 82 % ( 7 .2 mg); 'H NMR (300 MHz,
acetone- d ' ) 8 7 .51- 7 .41 ( m , 4H ), 6 .80 (dd , J = 10 . 2 , 2 .6 Hz,
1H ), 6 . 73 (dd, J = 8 .6 , 2 .6 Hz, 1H ), 3. 76 (s , 3H ), 2 .32 (s, 6H ),
50 2 . 15 - 2 .09 ( m , 3H ) .
Br

F 55

3 -(5 -Bromothiophene -2 -carbonyl) -5 -fluoro -2 -methyl OH


phenyl acetate (71g ): The title compound was prepared by
reaction of 3 -( chlorocarbonyl)-5 -fluoro - 2 -methylphenyl
acetate (71f) (94 .3 umol, 1 equiv ) aluminum chloride ( 25 . 1 60 ??
mg, 0 . 188 mmol, 2 equiv ) and 2 -bromothiophene (15 .3 mg,
93 .8 umol, 1 equiv. ) at 0° C . for one hour and at room
temperature for 4 h . After dilution with 1 M hydrochloric (5 -(4 -Hydroxy -3,5 -dimethylphenyl) thiophen - 2- yl)(5
acid , the crude mixture was extracted with ethyl acetate , fluoro -3 -hydroxy -2 -methylphenyl)methanone (71): The title
washed with brine , dried with magnesium sulfate and puri - 65 compound was prepared by reaction of (5 -fluoro -3 -hydroxy
fied by flash chromatography ; yield : 25 % (8 .5 mg). ' H NMR 2 -methylphenyl)(5 - (4 -methoxy- 3 ,5 - dimethylphenyl) thio
(300 MHz, CDC1z) 8 7 .16 - 7 .14 (m , 1H ), 7 .11 -7 .07 (m , 1H ), phen -2 -yl)methanone (71i) (7 .2 mg, 19. 4 umol) and boron
US 9 ,884 ,839 B2
103
tribromide (58 .3 umol, 3 .0 equiv ) according to method B .
104
104
The product was purified by preparative HPLC (water with 72c
0 . 1 % formic acid /acetonitrile with 0 . 1 % formic acid ); yield :
97 % (6 .7 mg). 'H NMR (300 MHz, acetone- d ') 8 7 .44 -7 .37
(m , 4H ), 6 .79 ( dd , J= 10 .2 , 2 .6 Hz, 1H ), 6 .72 (dd , J = 8 .6 , 2 .6 5
Hz, 1H ), 2 .30 (s , 6H ), 2 .13 - 2 .10 (m , 3H ); MS (ESI): 357 .2 OMe
(M + H ) *.

F
72a 10
HO 4 ,5 -Difluoro - 3 -methoxy -2 -methylbenzoyl chloride (72c ):
The title compound was prepared by reaction of 4 ,5 -dif
luoro - 3 -methoxy - 2-methylbenzoic acid (72b ) (52 .8 mg,
OMe 15 0 .261 mmol) in 2 ml thionyl chloride at room temperature
for 16 h , and at 80° C . for 1 h . The thionyl chloride was
F F removed by distillation under reduced pressure to obtain the
crude product, which was used in the next step without
further purification .
3,4-Difluoro-5-methoxybenzoic acid (72a): The title com - 20
pound was prepared by reaction of 5 -bromo-1,2 -difluoro -3 72d
methoxybenzene (1.03 g , 4 .62 mmol, 1.0 equiv ) and mag
nesium (112 mg, 4 .61 mmol, 1.0 equiv ) and iodine (~ 2 mg)
in 13 ml diethylether under reflux for 2 h . Carbon dioxide 25 Br
was bubbled through the solution at 10° C . until all solvent - OMe
( 13 ml) was evaporated two times. The crude product was
dissolved in 10 mL THF and carbon dioxide was bubbled
through the solution for additional 1 h . The reaction was 30 F F
quenched with 1 M HCl, extracted with ethyl acetate , dried (5 -Bromothiophen -2 - yl) (4 ,5 -difluoro -3 -methoxy -2
with magnesium sulfate and concentrated under reduced methylphenyl )methanone (72d ): The title compound was
pressure to afford the crude product , which was purified by prepared by reaction of 4,5 -difluoro -3 -methoxy - 2-methyl
flash chromatography ; yield : 31 % (265 mg). ' H NMR (300 35 benzoyl chloride (72c) (0 .261 mmol, 1 equiv), aluminum
MHz,MeOH -d4) 8 7.65-7.45 (m , 2H ), 3.99 (s, 1H ). chloride ( 34 . 8 mg, 0 .261 mmol, 1 equiv ) and 2 -bromothio
phene ( 42 . 7 mg, 0 . 262 mmol, 1 equiv ) at 0° C . for 45 min
and at room temperature for 2 h . After dilution with 1 M
hydrochloric acid , the crude mixture was extracted with
726 10
40 ethy
ethyl acetate , washed with brine, dried with magnesium
HO sulfate and purified by flash chromatography; yield : 47 %
(42 .4 mg). ' H NMR ( 300 MHz, CDC1z ) 8 7 . 18 -7 . 14 (m ,
1H ), 7 . 12 - 7 .08 (m , 1H ), 6 . 80 (dd , J= 7. 4 , 2 .0 Hz, 1H ), 3 .86
OMe 45 (ss,, 31
3H ), 2 .20 (d , J= 2 .5 Hz, 3H ).
F F 72e

4 , 5- Difluoro -3 -methoxy - 2-methylbenzoic acid ( 72b ): The 50


title compound was prepared by reaction of 2 ,2 ,6 ,6 - tetram
ethylpiperidine ( 374 mg, 2 .65 mmol, 5 equiv ) and n -butyl
lithium ( 2. 5 M in n -hexane, 2 .65 mmol, 5 equiv ) in 12 .5 ml OMe
THF at - 78 OC for 15 min . The mixture was warmed to 0° Meo
C . and 3,4 -difluoro -5 -methoxybenzoic acid (72a ) ( 100 mg, 55
0 .532 mmol, 1 equiv ) in 0 . 9 ml THF was added dropwise
and the mixture was stirred for 1 h at 0° C . Methyliodide
( 331 ul, 5 .31 mmol, 10 equiv ) was added dropwise and the (4 ,5 -Difluoro -3 -methoxy - 2-methylphenyl)(5 -(4
mixture was stirred for 20 min at 0° C . and for 1.5 h at 40° methoxy -3 ,5 -dimethylphenyl) thiophen -2 -yl)methanone
C ., quenched with water , acidified with 1 M hydrochloric 60 (72e ): The title compound was prepared by reaction of
acid extracted with ethyl acetate , dried with magnesium (5 - bromothiophen - 2 - yl)(4 ,5 - difluoro - 3 -methoxy - 2-methyl
sulfate and concentrated under reduced pressure to afford the phenyl)methanone (720 ) (42 .4 mg, 0 . 122 mmol),
crude product. This was purified by preparative HPLC 4 -methoxy -3 ,5 -dimethylphenylboronic acid (24 . 1 mg, 0 .134
(water with 0 . 1 % formic acid /acetonitrile with 0 . 1 % formic mmol), cesium carbonate ( 139 mg, 0 .427 mmol) and tetrakis
acid ); yield : 45 % (48 .7 mg). ' H NMR (300 MHz, MeOH - d4) 65 (triphenylphosphine ) palladium (4 .93 mg, 4 .27 umol)
8 7 .50 (dd , J= 8 . 1, 1 .9 Hz, 1H ), 3 .95 (s, 3H ), 2 .48 (d , J = 2 .6 according to method C3. The product was purified by
Hz, 3H ). preparative HPLC (water with 0 . 1 % formic acid /acetonitrile
US 9 ,884 ,839 B2
105 106
with 0 .1 % formic acid ); yield : 92 % (45 .4 mg). ' H NMR (5-Methylthiophen -2 -yl)(2,4,5 -trifluoro -3 -hydroxyphe
( 300 MHz, CDC13) 8 7 . 36 (d , J = 4 .0 Hz, 1H ), 7 .31 (s, 2H ) , nyl)methanone (73 ): The title compound was prepared by
7 .22 (d , J= 4 .0 Hz, 1H ), 6 .85 (dd, J = 7.5 , 2 .0 Hz, 1H ), 3.87 (s, reaction of (5 -methylthiophen - 2- yl)(2,4 ,5-trifluoro -3
3H ), 3 .74 (s , 3H ), 2 .31 (s , 6H ), 2 .22 (d , J= 2.5 Hz, 3H ) .
5 methoxyphenyl )methanone (73a) ( 121 mg, 0 .423 mmol) and
boron tribromide (1.38 mmol, 3.3 equiv) according to
method B . The product was purified by preparative HPLC
(water with 0 .1 % formic acid /acetonitrile with 0. 1 % formic
10 acid ); yield : 55 % (63 .1 mg). ' H -NMR ( 300 MHz, MeOH
- OH d4) 87.47 -7 .43 (m , 1H ), 7 .02 -6 .90 (m , 2H ), 2.62 (s, 3H );MS
HOT ( ESI): 273 . 2 ( M + H )*.
F
15
74a
(4,5 - Difluoro -3 -hydroxy -2 -methylphenyl)(5 -(4 -hydroxy
3 ,5 -dimethylphenyl)thiophen -2 -yl)methanone (72 ): The title
compound was prepared by reaction of (4 ,5 -difluoro -3
methoxy -2 -methylphenyl)(5 -(4 -methoxy -3 ,5-dimethylphe - 20 OMe
nyl) thiophen -2 - yl)methanone ( 72e ) (45 .4 mg, 0 .113 mmol) HO
and boron tribromide (0 .678 mmol, 6 .0 equiv ) according to F F
method B . The product was purified by preparative HPLC
(water with 0 . 1 % formic acid /acetonitrile with 0 . 1 % formic 25 ((5 -(4 -Hydroxyphenyl)thiophen -2 -yl)(2,4 ,5 -trifluoro -3
acid ); yield : 86 % ( 36 .4 mg). ' H -NMR (300 MHz, acetone methoxyphenyl)methanone (74a ): The title compound was
d ) 8 7 .47 -7 .37 (m , 4H ), 6 .98 (dd , J = 7 .9, 2 . 1 Hz, 1H ), 2 .30
(s, 6H ), 2 .18 (d , J= 2.5 Hz, 3H );MS (ESI): 375 .2 (M + H ) *. prepared by reaction of (5-Bromo -thiophen-2-yl)(2,4,5-trif
luoro -3 -methoxyphenyl)methanone ( 1d ) (176 mg, 0 .500
30 mmol), 4 -hydroxyphenylboronic acid (75.9 mg, 0.550
73a mmol), cesium carbonate (569 mg, 1.75 mmol) and tetrakis
( triphenylphosphine ) palladium (20 .2 mg, 17 .5 umol)
according to method C3 . The product was purified by
35
preparative HPLC (water with 0. 1 % formic acid /acetonitrile
with 0 .1 % formic acid ); yield : 17 % (31.1 mg).
OMe
F 40 74b

(5 -Methylthiophen -2- yl )(2,4,5 -trifluoro -3 -methoxyphe


nyl)methanone (73a ): The title compound was prepared by -OMe
reaction of 2-methylthiophene (64 .4 mg, 0 .656 mmol), 2 ,4, 45
5 - trifluoro - 3 -methoxybenzoyl chloride (147.2 mg, 0 .656
mmol) and aluminum chloride (87.5 mg, 0 .656 mmol)
according to method A . The product was purified by flash
chromatography; yield : 69 % ( 130 mg). ' H NMR (300 MHZ, 50 NH2
acetone -dº) 8 7 .49 (dd , J= 3 .8 , 1.8 Hz, 1H ), 7 .29 (ddd , J = 9 .9 ,
8 .3 , 5 .7 Hz, 1H ), 6 . 98 (dd , J = 3 .9 , 1. 0 Hz, 1H ), 4 .04 -4 . 14 (m , 4 -(5 -(2,4 ,5 - Trifluoro -3 -methoxybenzoyl) thiophen - 2 -yl)
3H ), 2 .57 -2 .62 (m , 3H ). phenyl sulfamate (74b ): The title compound was prepared
55 by reaction of (5 -(4 -hydroxyphenyl)thiophen -2 - yl)( 2 ,4, 5
13
trifluoro -3 -methoxyphenyl)methanone (74a ) (31.0 mg, 85. 1
umol) and sulfamoyl chloride (49 .1 mg, 0 .425 mmol) in 1.5
ml N ,N -Dimethylacetamide at 0° C . for 2 h . The reaction
mixture was diluted with water and extracted with ethyl
acetate , dried with magnesium sulphate and concentrated
under reduced pressure to afford the crude product. The
product was purified by preparative HPLC (water with 0 . 1 %
OH formic acid /acetonitrile with 0 . 1 % formic acid ); yield : 56 %
F (21.3 mg). ' H -NMR (300 MHz, MeOH - d * ) 87.86 (d , J= 8 .4
65 Hz , 2H ), 7 .65 - 7 .60 (m , 1H ), 7 . 55 (d , J = 4 .2 Hz, 1H ) , 7 .45 ( d ,
J= 8 .4 Hz , 2H ), 7 .35 -7.25 (m , 1H ), 4 .12 (s, 3H ); MS (ESI):
444.1 (M + H ) *
US 9 ,884,839 B2
107
107
74
108
3 -(4 ,4,5 ,5 - Tetramethyl-1,3 ,2 -dioxaborolan -2 -yl)benzene
sulfonamide ( 76a): 3 - Bromobenzenesulfonamide (580 mg,
2.46 mmol, 1.0 equiv), bis (pinacolato )diboron (1.00 g, 3.94
5 mmol, 1.6 equiv ), potassium acetate (730 mg, 7.44 mmol, 3
OH
equiv ) and Pd (dppf)C12 (92.0 mg, 0 .126 mmol, 0.05 equiv )
were dissolved under N2 in 10 ml dioxane and the mixture
was stirred for 30 minutes under reflux . The reaction was
F 10 quenched with water . The mixture was used directly in the
OSSO NH2
subsequent reaction without any further purification as the
product is unstable .

4 -(5 -(2 ,4 ,5 - Trifluoro - 3 -hydroxybenzoyl)thiophen -2 - yl ) 15 76


phenyl sulfamate (74 ): The title compound was prepared by SO2NH2
reaction of (4 -(5 -( 2 ,4 ,5 -trifluoro - 3 -methoxybenzoyl)thio ]
T

phen - 2 -yl) phenyl sulfamate (74b ) (20 .0 mg, 45 . 1 umol) and -

boron tribromide (0 .135 mmol, 3 .0 equiv ) according to HO


HO .
method B with 3 h reaction time. The product was purified 20
by preparative HPLC (water with 0 .1 % formic acid / acetoni
trile with 0 . 1 % formic acid ) ; yield : 64 % ( 12.4 mg). ' H -NMR F.

(300 MHz, MeOH -d4) 8 7.86 (d , J = 8 .7 Hz, 2H ), 7.66 - 7.60


( m , 1H ), 7.57 - 7.53 (m , 1H ), 7 .45 (d , J = 8. 1 Hz, 2H ), 7 .07- 26 3 -(5 -(2 ,6 -Difluoro -3 -hydroxybenzoyl) thiophen -2 - yl)ben
6. 96 ( m , 1H); MS ( ESI): 430.2 ( M + H )*. zenesulfonamide (76 ): The title compound was prepared by
reaction of (5 -bromo-thiophen - 2-yl)(2,6 -difluoro -3 -hy
F
75 droxyphenyl)methanone (le ) (670 mg, 2 . 10 mmol) and
3 -(4 ,4,5 , 5 -tetramethyl- 1,3 ,2 -dioxaborolan -2 -yl)benzenesul
HO
HO .
NH2 fonamide (76a ) (707 mg, 2 .50 mmol), cesium carbonate
(2 .74 g, 8 .41 mmol) and tetrakis( triphenylphosphine ) palla
dium (26 .0 mg, 22.5 umol) according to method C1. The
product was purified by CC (dichloromethane /methanol
98:2 ); yield : 24 % (200 mg). 'H NMR (500 MHz, DMSO -dº )
4-(5 -(2,306 --Dinuoro
Difluoro --35 --hydroxybenzoyi
hydroxybenzoyl)thiophen --22--ylyl))ben
ben
zenesulfonamide (75 ): The title compoundthiophen
was prepared by- 8 10 .28 (s, 1H ), 8.22 (t, J= 1.7 Hz, 1H ), 8.07 (ddd , J= 7 .8 , 1.8 ,
0 .9 Hz, 1H ), 7.88 (ddd , J= 7 .8 , 1.6 , 1.0 Hz , 1H ), 7.77 (d ,
reaction of (5 -bromo- thiophen - 2 -yl)-(2 ,6 -difluoro -3 -hy
droxy -phenyl) -methanone (le ) ( 319 mg. 1. 00 mmol) and J = 4 . 1 Hz, 1H ), 7. 71 (dd, J= 14 .2 , 6 . 1 Hz, 2H ), 7 .50 (s , 2H ).
(4 -sulfamoylphenyl)boronic acid (241 mg, 1. 20 mmol), 0 7 . 17 ( td , J= 9 .4 , 5 . 7 Hz, 1H ), 7 . 11 ( td , J= 9 .0 , 1.2 Hz, 1H ); 13C
cesium carbonate (1.30 g, 4 .00 mmol) and tetrakis ( triph - NMR (126 MHz, DMSO -d ) 8 180 .04, 152. 19 , 150 .51 (dd ,
enylphosphine) palladium ( 12 .0 mg, 10 .3 umol) according J = 239.5 , 5 .6 Hz ), 146 .89 (dd , J = 246 .5 , 7 .7 Hz), 145 .27 ,
to method C1. The product was purified by CC (dichlo
romethane /methanol 98 :2 ); yield : 81 % ( 320 mg). ' H NMR 142.09, 141.89 (dd , J= 11 .6 , 2. 9 Hz), 138 .06 , 132. 90 , 130 . 26 ,
(500 MHZ. DMSO - 068 10 .28 ( s. 11 ). 8 . 05 - 8 . 00 ( m , 2H ). 45 129 . 42 , 126 .77 , 126 .38 , 123.09, 119 .63 ( dd , J = 9 .0 , 4 .1 Hz ),
7 . 94 -7 .88 (m , 2H ), 7 .81 (d , J = 4 . 1 Hz, 1H ), 7 .71 ( d , J = 4 . 1 Hz, 116 . 43 (dd , J = 23 .4 , 19 . 3 Hz), 111.74 (dd, J = 22 .3 , 3 .6 Hz );
1H ), 7 .48 ( s, 2H ), 7 . 17 ( td , J = 9 .4 , 5 .6 Hz, 1H ) , 7 . 13 - 7 . 08 ( m , MS (ESI): 396 .2 (M + H ) +.
1H ); 13C NMR (126 MHz, DMSO ) & 180 . 08 , 152 . 13 , 150 .52
( dd, J = 239 .6 , 5 .6 Hz), 146 . 90 (dd, J = 246 .6 , 7 .5 Hz ), 144.60 ,
142. 38 , 141. 88 (dd , J = 11 . 8 , 2 . 8 Hz ), 137 . 99 , 135 . 16 , 127 . 20 , 77a
126 .80 , 126 .65 , 119.63 (dd , J = 9 .3 , 4 . 1 Hz), 116 .43 (dd ,
J= 23 .5 , 19 . 1 Hz ), 111 .73 (dd , J= 22 .2 , 3 .6 Hz); MS (ESI): Meo Br
396 . 3 ( M + H ) +.
55
76a ci
SO2NH2
(5 -Bromothiophen -2 - yl)(6 -chloro - 2 - fluoro -3 -methoxy
60 phenyl)methanone (77a ): The title compound was prepared
by reaction of 2-bromothiophene ( 1.22 g , 7.48 mmol),
6 -chloro -2 - fluoro -3 -methoxybenzoyl chloride ( 1. 12 g, 5 .02
mmol) and aluminum chloride (666 mg, 4 .99 mmol) accord
ing to method A . The product was purified by CC (dichlo
romethane /hexane 75:25 ); yield : 60 % ( 1.05 g ). MS (ESI):
350 . 5 (M + H ) *
US 9 ,884,839 B2
109
77b 78b
FO
=
HO . Br HO .

- Br

(5 - Bromothiophen -2 -yl)(6 -chloro -2 -fluoro -3 -hydroxy - 10 (5 - Bromothiophen -2 -yl)( 2 -chloro -6 -fluoro -3 -hydroxy
phenyl)methanone (77b ): The title compound was prepared phenyl )methanone (78b ): The title compound was prepared
by reaction of (5 -bromothiophen -2 -yl)(6 -chloro -2 -fluoro -3 by reaction of (5 -bromothiophen -2 - yl) ( 2 -chloro -6 -fluoro -3
methoxyphenyl)methanone (77a ) (700 mg, 2 .00 mmol) and methoxyphenyl
boron tribromide (6 .00 mmol, 3 equiv ) according to method4 15 boron tribromide)methanone (78a ) (700 mg, 2.00 mmol) and
B . The product was purified by CC (dichloromethane ); B . The product was purified, 3 by (6 . 00 mmol equiv ) according to method
CC (dichloromethane);
yield : 81 % (540 mg ). ' H NMR ( 300 MHz, DMSO - d ' )
10 .61 (s , 1H ), 7.46 - 7.40 ( m , 2H ), 7 .26 (dd , J = 8.8 , 1.3 Hz, 10 .59 (s, 1H ), 7 .41 (q, J= 4 . 1 Hz, 2H ),MHz
yield : 78 % (523 mg ). ' H NMR ( 300 , DMSO - d ') d
7 .27 -7 . 19 (m , 1H ),
1H ), 7. 13 (t, J= 9 .0 Hz, 1H ); MS (ESI): 336 .5 (M + H ) * . 7 .13 (dd , J= 9 . 1, 5 .3 Hz, 1H ); MS (ESI): 336 .5 (M + H ) *.
20
78

HO

Short F OMe

(6 - Chloro - 2- fluoro - 3-hydroxyphenyl)(5 -(3 ,5 -dichloro -4


methoxyphenyl)thiophen -2 - yl)methanone (77 ): The title
25

30
HO

(2 - Chloro -6 - fluoro -3 -hydroxyphenyl)(5 -(3 ,5 -dichloro -4


compound was prepared by reaction of (5 -bromothiophen - methoxyphenyl)thiophen - 2 -yl)methanone ( 78 ): The title
2 - yl) (6 -chloro - 2 - fluoro -3 -hydroxyphenyl)methanone ( 77b ) 36 compound was prepared by reaction of (5 -bromothiophen
OMe

(335 mg, 1.00 mmol) and (3,5 -dichloro - 4 -methoxyphenyl) 2 -yl)(2 -chloro -6 - fluoro - 3 -hydroxyphenyl)methanone (78b )
boronic acid ( 264 mg, 1 .20 mmol), cesium carbonate ( 1.30 ( 335 mg, 1 .00 mmol) and (3 ,5 -dichloro -4 -methoxyphenyl)
g, 3 . 99 mmol) and tetrakis (triphenylphosphine) palladium boronic acid (264 mg, 1.20 mmol), cesium carbonate ( 1.30
( 12 .0 mg, 10 .4 umol) according to method C1. The product g , 3. 99 mmol) and tetrakis ( triphenylphosphine ) palladium
was purified by CC (dichloromethane/methanol 99 .5 :0 .5 ) 40 ( 12 .0 mg, 10 . 4 umol) according to method C1. The product
followed by washing with petroleumIm ether
ether ;; yield
yield :: 89
89 %% ((385
385 was purified by CC (dichloromethane/methanol 99. 25 :0 .75)
mg). ' H NMR ( 300 MHz, DMSO - d ) d 10 .59 ( s, 1H ), 7 .97 followed by washing with petroleum ether; yield : 83 % (360
( s , 2H ), 7 .78 ( d , J = 4 . 1 Hz, 1H ), 7 . 59 (d , J = 4 .0 Hz, 1H ), 7 .27 mg). H NMR (300 MHz, DMSO - d ) 8 10 . 58 ( s, 1H ), 7 . 96
( dd , J = 8 .8 , 1. 4 Hz, 1H ), 7 . 14 (t, J = 9 .0 Hz, 1H ), 3 .88 (s , 3H ); (s, 2H ), 7 .77 (d , J= 4 .1 Hz, 1H ), 7 .57 (d , J = 4 . 1 Hz, 1H ), 7 .24
1°C NMR (75 MHz, DMSO - dº ) d 182.50 , 152 . 80 , 150 . 94 , 45 (t. J = 8 . 8 Hz, 1H ), 7 . 14 (dd , J = 9 . 1 , 5 . 3 Hz, 1H ), 3 . 87 (s , 3H ) ;
148. 14 (d , J = 245 . 2 Hz ), 145 .02 (d , J = 11. 9 Hz ), 142 . 31 , 13C NMR ( 75 MHZ DMSO - 068182 59 152 . 78 . 151. 68 ( d .
138 .29, 130 .75 , 129.80, 127. 91, 127. 37, 127 . 10 , 126 . 24 (d , J = 238 . 3 Hz), 150 .82 , 150 .77 (d , J= 2. 3 Hz), 142 .38 , 138 .10 ,
J = 3 . 3 Hz ), 120 .36 (d , J= 3 .7 Hz), 118 .96 (d , J= 4 .1 Hz), 130 .77, 129 .79 , 127 .87 , 127. 35 , 127. 10 (d , J= 23 .3 Hz),
61. 32; MS (ESI): 432.9 (M + H )*. 118 .52 ( d , J = 8 . 5 Hz ), 117 .04 ( d , J = 6 . 0 Hz ), 115 .81 ( d , J = 22 . 3
SU Hz), 61.32 ; MS ( ESI): 432.8 (M + H )*.
78a
0
Meo . Br 79a
55

(5 -Bromothiophen -2 -yl) (2 - chloro -6 - fluoro - 3 -methoxy - 60


phenyl)methanone (78a): The title compound was prepared
by reaction of 2 -bromothiophene ( 1.22 g , 7 .48 mmol), 2 -Chloro -3 -methoxybenzoyl chloride ( 79a ): 2 -Chloro -3
2 -chloro -6 - fluoro - 3 -methoxybenzoyl chloride ( 1. 12 g , 5 .02 methoxybenzoic acid ( 200 mg, 1 .07 mmol, 1 equiv ) was
mmol) and aluminum chloride (666 mg, 4 .99mmol) accord dissolved in thionyl chloride (2 . 16 g , 18 .2 mmol, 17 equiv )
ing to method A . The product was purified by CC (dichlo - 65 and stirred under reflux for 1 h . The solution was concen
romethane /hexane 75 :25 ); yield : 72 % (1.26 g). MS ( ESI): trated in vacuum and the crude product was used in the next
350 . 5 (M + H ) . step without purification .
US 9 ,884,839 B2
111
111 112
Hz, 1H ), 2.29 (s, 6H ); 13 C -NMR (300 MHz, acetone -d ') &
0 796 186 .75 , 156 .01, 155. 92 , 154 .46 , 141. 53, 141.03 , 138. 10 ,
128 .72 , 127 .53 , 125 .85 , 125.57 , 123 .91, 120 .42 , 118 .77,
118 .05, 16 .65.
Br Example 2
Biological Testing
(5 - Bromothiophen - 2 -yl)( 2 -chloro - 3 -methoxyphenyl) 10 Biological methods: [2 ,4 ,6 ,7 -PH ]- E1 and [ 2 ,4,6 ,7 - H ]-E2
methanone (79b ): The title compound was prepared by were bought from Perkin - Elmer. Quickszint Flow 302 scin
reaction of 2 -chloro - 3 -methoxybenzoyl chloride (79a ) ( 1 .07 tillator fluid was bought from Zinsser Analytic . Human
mmol), 2 -bromothiophene ( 175 mg, 1.07 mmol) and alu - 17B -HSD1 and human 17B -HSD2 were prepared from
minium trichloride ( 143 mg, 1.07 mmol) according to human placenta according to a previously described proce
method A . In contrast, the mixture was stirred at room 15 dure (Marchais- Oberwinkler et al . S ., J. Med . Chem .,
temperature overnight. The crude product was purified by 56 : 167- 181 (2013 )). Fresh human placenta was homog
flash chromatography (SiO2, hexane /ethyl acetate 8 : 2) ; enized , and cytosolic fraction and microsomes were sepa
yield : 76 % (270 mg). ' H NMR (300 MHz, acetone - dº) rated by differential centrifugation at 1,000 g , 10 ,000 g and
7 . 46 (m , 1H ), 7 .33 - 7 . 29 (m , 2H ) , 7 . 24 (d , J = 4 . 1 Hz , 1H ), 150 , 000 g . For the partial purification of 17B -HSD1, the
7 .10 (dd , J= 7 .6 , 1.4 Hz, 1H ), 3. 97 (s, 3H ). 20 cytosolic fraction was precipitated with ammonium sulfate .
17B -HSD2 was obtained from the microsomal fraction .
1. Inhibition of human 17ß -HSD1: Inhibitory activities
790 were evaluated by an established method (Marchais - Ober
0 winkler et al. S ., J. Med . Chem ., 56 : 167 - 181 (2013 )) .
25 Briefly, the cytosolic enzyme preparation was incubated
with NADH ( 500 UM ] in the presence of potential inhibitors
at 37° C . in a phosphate buffer (50 mm ) supplemented with
20 % of glycerol and EDTA (1 mM ). Inhibitor stock solu
tions were prepared in DMSO . The final concentration of
30 DMSO was adjusted to 1 % in all samples. The enzymatic
reaction was started by addition of a mixture of unlabelled
(2 - Chloro - 3-methoxyphenyl)(5 -(4 -methoxy -3 ,5 -dimeth and [2 ,4 ,6 , 7 -PH ]-E1 (final concentration : 500 nM , 0 . 15 uCi).
ylphenyl)thiophen -2 -yl)methanone (79c ): The title com After 10 min , the incubation was stopped with HgCl, and the
mixture was extracted with diethylether. After evaporation ,
pound was prepared by reaction of (5 -bromothiophen - 2- yl )
( 2 - chloro - 3 -methoxyphenylmethanone (795 ) (262 mg 35 the steroids were dissolved in acetonitrile . El and E2 were
0 .790 mmol), 3 ,5 -dimethyl- 4 -methoxyphenylboronic acid separated using acetonitrile /water (45 :55) as mobile phase in
a C18 reverse phase chromatography column (Nucleodur
( 171 mg, 0 .950 mmol), cesium carbonate ( 1.03 g , 3 .16 C18 125 / 3 100 - 5 , Macherey -Nagel) connected to a HPLC
mmol) and tetrakis (triphenylphosphine ) palladium ( 18 .0 system (Agilent 1200 series, Agilent Technologies ). Detec
mg, 15 .6 umol) according to method C1. The crude product vj 40 tion and quantification of the labeled steroids were per
was purified by flash chromatography (SiO2, hexane/ethyl 40 formed using a radioflow detector (Ramona, raytest). The
acetate 9 : 1 to 8 :2 ); yield : 50 % ( 183 mg). ' H NMR (300 conversion rate was calculated after analysis of the resulting
MHz, acetone- d ) 8 7 .51- 7 . 43 ( m , 4H ), 7 . 38 ( d , J = 4 .0 Hz,
1H ), 7. 30 (dd , J= 8.3 , 1.4 Hz, 1H ), 7. 10 (dd , J= 7.5 , 1.4 Hz, chromatograms according to the following equation :
1H ), 3 . 99 (s, 3H ), 3 .76 (s, 3H ), 2 . 32 (s, 6H ). % conversion = [% E2/0% E2+ % E1)]x100.
45
45
2 . Inhibition of human 17B -HSD2: The 17B -HSD2 inhi

puede
79 bition assay was performed similar to the human 17ß -HSD1
procedure . The microsomal fraction was incubated with
NAD + [ 1 ,500 UM ], test compound and a mixture of unla
50 belled - and [ 2 , 4 ,6 ,7 - H ]-E2 (final concentration : 500 nM ,
0 .11 uCi) for 20 min at 37° C . Further treatment of the
?? samples and HPLC separation were carried out as indicated
HO above. The conversion rate was calculated after analysis of
the resulting chromatograms according to the following
55 equation :
(2 - Chloro - 3 -hydroxyphenyl) (5 -(4 -hydroxy-3 ,5 - dimethyl % conversion = [% E1/ % E1 + % E2 )]x100
phenyl)thiophen -2 -yl)methanone (79 ): The title compound 3 . Preparation ofmouse and rat 17B -HSD1 and 2 : Recom
was prepared by reaction of (2 -Chloro - 3 -methoxyphenyl) binant mouse and rat 17B -HSD1 enzymes were produced by
(5 -( 4 -methoxy -3 , 5 - dimethylphenyl)thiophen - 2 - yl)metha - 60 transfection of HEK293 cells with a mouse or rat 17B -HSD1
none ( 79c ) ( 177 mg 0 .457 mmol) and boron tribromide (3 .68 expression plasmid . 48 hours after transfection, cells were
mmol, 8 .0 equiv ) according to method B with 3 h reaction homogenized by ultrasonication ( 3x10 s ) in a buffer con
time. The crude product was purified by preparative TLC taining sucrose (40mM Tris , 250 mM sucrose , 5 mM EDTA ,
(SiO2, hexane/ ethyl acetate 7 : 3 ); yield : 45 % (75 .0 mg). 7 mM DTT , 1 mM PMSF, pH 7 .5 ). Cell lysates were
1H -NMR ( 300 MHz, acetone - d ) 8 9 . 06 (s , 1H ), 7 .74 ( s, 65 centrifuged ( 1 , 000 g , 15 min , 4° C . ) and 20 % glycerol was
1H ), 7 .42 (m , 2H ), 7 .36 - 7 .39 (m , 2H ), 7 . 31 (dd , J= 8 . 1 , 7 .5 added to the supernatant before aliquots were frozen and
Hz, 1H ), 7 .18 (dd , J = 8 .2 , 1.5 Hz, 1H ), 7 .01 (dd, J= 7 .5 , 1.5 stored at -70° C . Microsomal 17B -HSD2 fractions were
US 9 ,884 ,839 B2
113 114
obtained from mouse or rat liver. Fresh liver tissues were TABLE 1 - continued
processed as described for the human placental 17ß -HSD2 Inhibitory effect of compounds 1-79 , 1g, and 31a on human
preparation . The pellet fractions containing the microsomal
17B -HSD2 were used for the determination of E1 formation . and mouse 17ß -HSD1 and 17ß -HSD2.
4 . Inhibition of mouse and rat 17B -HSD1: Inhibitory 5

KH
IC50 [nMja Inhibition @ 1 uM
activities of the compounds towardsmouse or rat 17B -HSD1
were evaluated by a method similar to the human 17B -HSD1 Cpmd h17ß -HSD1 h17B -HSD2 m17B -HSD1 m17B - HSD2
assay . The recombinant enzymepreparations were incubated 16 0 .9 18 59 55
with NADPH (500 uM ), test compound and a mixture of 17 36 47 74
unlabeled - and [ 2 , 4 ,6 ,7 -PH ]-E1 ( final concentration : 10 nM , 10 1918 19 n .db n .d.b
0 . 15 uCi) for 10 min at 37° C . Further treatment of the 79 % @ 1 uM 85 % @ 1 uM 58 44
20 0 .5 20 82
samples and HPLC separation was carried out as mentioned
above . 22 27
0 .8

azna
WNanE 38
46
IC50 : 78 nM
82

antliudh
The conversion rate was calculated after analysis of the 2 .4 23
IC50 :
IC50 : 209 nM
76
resulting chromatograms according to the following equa - 15 24 O

tion :
% conversion = [ % E2/6% E2 + % E1)]x100
26 2333 ON
23 3 .3
0 .4
0.2
1. 4 21
397 nM
23
n.d.
n.d.b
37
40
n. d.)
n .d.b
45
5. Inhibition ofmouse and rat 17B -HSD2: The mouse and 2 .1 11 16 40
rat 17B -HSD2 inhibition assays were performed similarly to 20 30 4 .7 26 25 41
the human 17B -HSD2 procedure . The microsomal fractions 31a 28 % @ 1 UM 32 % @ 1 UM 20 n .d.b
were incubated with NAD + ( 1,500 UM ), test compound and 31 2.1 9 32 84
37 % @4 . 71 uM 30 % @ 1 UM n .i. n .d .b
a mixture of unlabelled - and [2 ,4 ,6 ,7 -PH ]-E2 ( final concen
tration : 10 nM , 0 . 15 uCi) for 20 min at 37° C . Further WN IC50 :
602 nM
IC50 : 122 nM
treatment of the samples and HPLC separation was carried 25 34 5 IC50 : 46 % @ 250 nM
out as mentioned above. 513 nM
80
The conversion rate was calculated after analysis of the ?? 49
2 .4 1 .8 IC50 : 90 nM
resulting chromatograms according to the following equa
tion : ?? iNno
???? 5 .8
4 .8
2 .0
1. 4
IC50 : 79 nM
IC50 : 36 nM
% conversion = [ % E1/( % E1 + % E2)]x100
6 .Metabolic Stability Tests in Human Liver S9 Fraction :
30 39
41
59
7 .2
1 .1
18
1 .4
3. 1
cauta
33
24
IC50 : 326 nM
89

= zat
?
napa
z
3222
,
The compound ( 1 g M ) was incubated with 1 mg/mL pooled 42 2. 5 3 .0 46 84
28 . 8 7 .5 IC50 : IC50 : 113 nM
human liver S9 fraction (BD Gentest), 2 mM NADP, 10 mM
glucose-6 -phosphate , 10 U /ml glucose-6 -phosphate dehy - 35
drogenase , 10 mM MgCl2 , 1 mM UDPGA , and 0 . 1 mM
44 Sa
a
2a 22 . 4 6 .8
1138 nM
10 % @
100 nM
19 % @ 100 nM
PAPS at 37 dr for 0 , 5 , 15 , and 60 min . The incubation was 45 0 .6 2 .6 IC50 : 1732 IC50 : 89 NM
stopped by precipitation of S9 enzymes with 2 volumes of 46 1 .2 2.3 13.4 16 % @ 100 nM
47 5 .9 4 .4 13.8 IC50 : 260 nM
cold acetonitrile containing internal standard . Concentration 48 21. 0 4.1 12. 1 IC50 : 155 nM
of the remaining test compound at the different time points 40 49
ad 9 .1 11. 2 13 . 8
was analyzed by LC -MS/MS and used to determine hal- 50 0 .9 1 .3 IC50 : IC50 : 100 nM
found at the and Clint . 650 nM
Biological Data 47 % @ 10 nM 87 % @ 10 nM n . d .b n.d.
52 75 % @ 10 nM 47 % @ 10 nM n.d.5 15 % @ 50 nM
45 53 81 % @ 10 nM 96 % @ 10 nM n.d.5 34 % @ 50 nM
TABLE 1 54 31 % @ 10 nM 89 % @ 10 nM n.d.5 30 % @ 50 nM

19999
Inhibitory effect of compounds 1 -79 , lg, and 31a on human 55 12 % @ 10 nM 68 % @ 10 nM n.d.) 23 % @ 50 nM
and mouse 17B -HSD1 and 17ß - HSD2. 56 71 % @ 10 nM 93 % @ 10 nM n.db n .d."
57 14 % @ 10 nM 60 % @ 10 nM n.d. n.d.5
IC50 [nMja Inhibition @ 1 UM “
588
1. 1 % @ 10 nM 61 % @ 10 nM n.d.) 40 % @ 50 nM
50 59 48 % @ 10 nM
13 % @ 10 nM
68 % @ 10 nM
51 % @ 10 nM
n .d .
n .d.
27 % @ 50 nM
23 % @ 50 nM
Cpmd h17B -HSD1 h17B - HSD2 m17B - HSD1 m17B -HSD2
48 % @ 10 nM 68 % @ 10 nM n.d b 60 % @ 50 nM
F1 384 18 22 93 % @ 10 nM 100 % @ 10 nM n.d.) 46 % @ 50 nM

ANRum
lg 130 11 44 63 53 % @ 10 nM 77 % @ 10 nM n . d. 38 % @ 50 nM
10 30 n .d." 64 0% @ 10 nM 62 % @ 10 nM n .d. 28 % @ 50 nM
1.7 71 IC50 : 67 nM 55 15 % @ 10 nM 62 % @ 10 nM n.d.5 n.d."
3. 1 IC50 : IC50 : 54 nM 22 % @ 10 nM 83 % @ 10 nM n.d.: n.d.
750 nM 30 % @ 10 nM 86 % @ 10 nM n.d.5 n.d.)
2. 3 6 IC50 : IC50 : 7 nM n.d.6 42 % @ 50 nM
uAWONvAaE 4 3.7
250 nM
47 86
69
66 % @ 10 nM
72 % @ 10 nM
96 % @ 10 nM
95 % @ 10 nM n.d.5 32 % @ 50 nM
5.5 2 .7 10 n.d.
70 19 % @ 10 nM 100 % @ 10 nM n.d. n.d.
1. 8 6 .5 76 91 60 7171????? 12 . 6 nM 50 nM n.d. 79 % @ 50 nM
27 % @ 1 UM 49 % @ 1 UM n.db n.db 44 nM 159 nM n.d.b 22 % @ 50 nM
57 % @ 1 uM 64 % @ 1 UM 14
N
9.1 % @ 56 % @ 100 nM n.d.) n.d."
3 .5 41 100 nM

ouAN
?
?

1.2 60 74 20 % @ 10 nM 72 % @ 10 nM n.d. n.d.5


1. 3 40 18 % @ 10 nM 54 % @ 10 nM n.d. 10 % @ 50 nM
?????? 5. 5 25 65 76 34 % @ 10 nM 26 % @ 10 nM n.d 6 1. 8 % @ 50 nM
0 .6 IC50 : 550 nM 100 % @ 10 nM 45 % @ 10 nM n.d.6 n . d.5
US 9, 884 ,839 B2
115 116
TABLE 1 - continued TABLE 3 - continued
Inhibitory effect of compounds 1 -79 , 1g, and 31a on human Inhibition of rat 17B -HSD1 and 17B -HSD2 by selected compounds.
and mouse 17B -HSD1 and 17B -HSD2.
% Inhibition
ICso [nMja Inhibition @ 1 uM
Cmpd Cmpd conc. r17B -HSD1 r17B -HSD2
Cpmd h17B -HSD1 h17B -HSD2 m17B -HSD1 m17B -HSD2
250 nM 29 31
78 41 % @ 10 nM 54 % @ 10 nM n .d . 76 % @ 50 nM 250 nM 49
79 3 1 % @ 10 nM 64 % @ 10 nM n . d. 70 % @ 50 nM 250 nM 27
250 nM n .i.
.

- 10

AAwNOvW?Na
Mean value of three determinations, standard deviation less than 15 % . 5000 nM 59 n.d.5.
bnot determined . 250 nM 63 35
no inhibition 250 nM n .i. c n .i.
500 nM 51 55
250 nM 39 n.d.b
250 nM n .i. c 66
TABLE 2 15
250 nM 46 100
250 nM 50
Metabolic Stability of selected compounds in human liver S9 fraction 250 nM 29
Human liver S9
250 nM
250 nM
41
58
Cmpd t1/2 (min ) CLint Mean value of three determinations, standard deviation lessthan 15 % .
bn . d ., not determined
F1 3. 6 193.8 n.i., no inhibition .
5 .7 122 . 5

? 4.3
4 .6
18. 1
8 .5
2 .9
129 .4
2 .6
160 . 7
149. 6
38. 3
81. 3
241. 4
5.4
272 .7
Comparative Data
The introduction of two and three fluorine atoms, respec
25 tively, on the benzoylmoiety led to a dramatic increase in
potency towards murine 17beta -HSD1 and 2 by up to
100 - fold ; in case of the human enzymes, the achieved
potencies increase 5 - 1000 - fold . The strong beneficial effects
25 10 . 7 64 . 5
exerted by multiple halogenation of the benzoyl moiety on
6.5 106 .8
11. 3 61.5 30 human and rodent 17beta -HSD1 and 2 inhibition are docu
15 . 0 n . d ." mented by a direct comparison of inhibitory activities dis
24. 9 27. 9 played by compounds with different degrees of halogena
38 .0 18 . 2. tion . These examples also illustrate the fact that
20 .8 33 . 3
48 .9 14 . 2 difluorination in general leads to a slight -to - good human
25 .0 27 .7 35 17beta -HSD1 selectivity whereas trifluorination favours
27.4 25 . 3 human 17beta -HSD2 selectivity.
79 22.0 31.6 Both the strong increase in potency and the modulation of
selectivity are unanticipated in light of WO2012 / 025638:
The monofluorinated compounds 7 and 9 of WO2012 /
TABLE 3 025638 show insignificant differences in potency toward
80 human 17beta -HSD1 and are less selective compared to
Inhibition of rat 17B -HSD1 and 17B-HSD2 by selected compounds. their non -fluorinated analogs 1 and 4 (numbering refers to
WO2012 /025638 ). Compounds with more than one fluorine
% Inhibition atom attached to the benzoyl moiety are not described in
Cmpd Cmpd conc r 17B -HSD1 r17B -HSD2 WO2012 / 025638. Thus, the data did not allow the conclu
45 sion that introduction of two or three fluorine atoms
5000 nM increases potencies dramatically . Furthermore , due to the
250 nM different architectures of the substrate binding sites (which
250 nM
250 nM are supposed to be the inhibitor binding sites as well ) of
uAWNE 100
250
nM
nM
human 17beta -HSD1/2 in comparison to murine 17beta
HSD1/2 , the strong inhibition of the murine enzymes is
unexpected .
TABLE 4
HO HO HO

4
US 9, 884 ,839 B2
117
117 TABLE 4 -continued
118

?? HO
HO

F
F F
10 40

IC50 [NM ] IC50 [nM ] IC50 [nM ] IC50 [nM ] IC50 [nM ] IC50 [nM ]
or % inhibition or % inhibition or % inhibition or % inhibition or % inhibition or % inhibition
Compd h17B -HSD1 h17B -HSD2 m17B -HSD1 m17B -HSD2 r17ß -HSD1 r17B -HSD2
32 % @ 1 UM 35 % @ 1 UM n. d n.d n .d n .d
3427 300 5 % @ 1 UM 18 % @ 1 uM n .d n .d
92 % @ 100 nM 87 % @ 100 nM 18 % @ 1 uM 75 % @ 1 uM 35 % @ 250 nM 20 % @ 250 nM
3 .5 9 .0 41 67. 5 63 % @ 250 nM 66 % @ 250 nM
IBoto 7 .2 1.4 27 .5 80 58 % @ 250 nM 86 % @ 250 nM

TABLES
que
TABLE 5
HO

para HO

(= compd . 17 in WO 2012/025638 )

IC50 [nM ]
HO

IC 50 [nM ]
E

IC 50 [nM ]
HO

IC50 [nM ] Cso [nM ] IC50 [nM ]


or % inhibition or % inhibition or % inhibition or % inhibition or % inhibition or % inhibition
Compd h17B -HSD1 h17B -HSD2 m17B -HSD1 m17B -HSD2 r17B -HSD1 r17B -HSD2
|

??
76 % @ 1 UM
240
240
93 % @ 1 UM
424214%%% @@@ 111 „UMuMM 9 % @ 1 uM
92 % @ 1 uM
d n.
n .d
n .d
n .d
? 0 .5 20 50 % @ 1 uM 95 % @ 1 uM 48 % @ 500 nM 98% @ 500 nM
US 9 ,884, 839 B2
119
119
TABLE 6
120

HO HO HO

F F F

NH , NH2 NH2
L
(

IC50 [NM ] IC50 [nM ] IC50 [nM ] IC50 [nM ] IC50 [nM ] IC50 [nM ]
or % inhibition or % inhibition or % inhibition or % inhibition or % inhibition or % inhibition
Compd h17B -HSD1 h17B -HSD1 m17B -HSD1 m17B -HSD2 r17B - HSD1 r17B -HSD2
I

F 77 % @ 1 uM 68 % @ 1 uM n .d n.d n .d n .d
10 25 30 % @ 1 UM n.d 51 % @ 250 nM 48 % @ 250 nM
I
49 5 13 177 46 % @ 250 nM 100 % @ 250 nM

TABLE 7
HO HO

Compd
Bade Bad
HO
??

IC50
or % inhibition
h17ß -HSD1
72
??

IC50
or % inhibition
h17B -HSD2
IC50
or % inhibition
m17B -HSD1
??)

HO

IC50
or % inhibition
m17B -HSD2
71

50
F
HO

IC50
or % inhibition
r17B -HSD1
IC50
or % inhibition
r17B -HSD2

av
899 NM
12. 6 nM
44 nM
0.9 M 3239 nM
50 nM
159 nM
1 . 3 nM
35 .5 UM
n .d.
n.d .
650 nM
546 nM
79 % @ 50 nM
22 % @ 50 nM
100 nM
n .d .
n .d .
n.d.
n .d .
n .d .
n .d .
n .d .
US 9 ,884, 839 B2
121
TABLE 8
122
122

HO ?? HO

F F F

NH NH
IL NH F
NH
F
0 F F
O=

Br Br Br
36

IC 50 [nM ] IC50 [nM ] IC50 [nM ] IC50 [nM ] IC50 [nM ] IC 50 [nM ]
or % inhibition or % inhibition or % inhibition or % inhibition or % inhibition or % inhibition
Compd h17B -HSD1 h17B -HSD2m17B -HSD1m17B -HSD2 r17B -HSD1 r17B -HSD2
H 199 21 % @ 1 uM 36 % @ 1 UM n.d n .d
1. 7 56 % @ 250 nM 86 % @ 250 nM
38 2 .4
17
1. 8
71 % @ 1 UM
68 % @ 1 UM
100
12 . 5 50 % @ 250 nM 100 % @ 250 nM

TABLE 9
HO HO

F F

Br Br ?

le 1g

IC50 [nM ] IC50 [NM ] IC50 [nM ] IC50 [nM ] 1C50 [nM ] IC50 [nM ]
or % inhibition or % inhibition or % inhibition or % inhibition or % inhibition or % inhibition
Compd h17B -HSD1 h17B-HSD1 m17B -HSD1 m17B -HSD2 r17B -HSD1 r17B -HSD2
le 85 % @ 100 nM 71 % @ 100 nM 5 % @ 1 uM 80 % @ 1 uM 5 % @ 250 nM 60 % @ 250 nM
lg 130 27 11% @ 1 um 44% @ 1 um d n. n .d
US 9 ,884 ,839 B2
123
TABLE 10
124
124
HO HO

F F

0
NH O
M
F F
O= 1 F O=ON F

3 37
IC 50 [nM ] IC50 [NM ] IC50 [nM ] IC50 [nM ] IC50 [nM ] IC50 [nM ]
or % inhibition or % inhibition or % inhibition or % inhibition or % inhibition or % inhibition
Compd h17ß - HSD1h17B -HSD2 m17B -HSD1 m17B -HSD2 r17B -HSD1r17B -HSD2

37 3 5 .8 1 23 13
746746
55 % @ 1 UM 33
33
22 70% @ 250nm 74% @ 250 nM
70 % @ 250 nM 74 % @ 250 nM
29 % @ 250 nM 93 % @ 250 nM

TABLE 11
HO HO

F F

O
NH F F NH . F
| || NH
F
OS 7 ON
+ 38

IC 50 [nM ] IC50 [nM ] IC50 [nm ] IC50 [nm ] IC50 [nM ] IC50 [nM ]
or % inhibition or % inhibition or % inhibition or % inhibition or % inhibition or % inhibition
Compd h17B -HSD1h17B -HSD2 m17B -HSD1 m17B -HSD2 r17B -HSD1 r17B -HSD2
2.3 251 20 59 % @ 100 nM 70 % @ 100 nM
20
38 48 4 1. 8 1 % @ 1 uM 36 41% @ 250 nM 96 % @ 250 nM
US 9,884 ,839 B2
125 126
The invention claimed is : and said substituent R4 being directly or through a
1. A compound having the formula (I) for use in the phenylene group bound to the aryl ring;
treatment of hormone -related diseases in a mammal R5 , R6 and R7 independently represent H , — R ,haloalkyl,
halogen , — NO , OR , SR ', CH , R ', COR ',
5 — NR 'R ', — CN , COOR ', — NHSO , R ', - NRSO , R ',
SO NRR ', NHCOR ', NRCOR ', CONRR ', OC ( O ) R ',
???? CH NRR ', CHOR ', — SO R ' or — SOR ', wherein
aryl - R and R ' is as defined above,
RI X represents
10
(R2in Red O
7
=

0
2
-
v
=
O
wherein Z

R1 represents , OH , alkoxy or acyloxy ; -

n represents an integer of 1 or 2 ; 15
RS
R2 is at each occurrence independently selected from the
group consisting of fluorine , chlorine , and bromine ; wherein Y , if present, representsOor S , and R8 represents
R3 represents alkyl, haloalkyl or halogen atom ; H or lower alkyl; and
R4 represents H ; OH ; an alkyl or an alkoxy group , each the arvl ring is a 5 -membered heteroaromatic ring which
of which may carry phenyl and halogen substituents , carries up to 3 heteroatoms independently selected
wherein said phenyl substituents may carry up to 3 from N , S and O ;
substituents independently selected from — OH , alkyl, or a pharmaceutically acceptable salt thereof.
haloalkyl, alkoxy , halogen , amino, CN and NO2; a 2 . The compound for use in the treatment of hormone
6 -membered aromatic group which may carry 1 to 3 25 related diseases in a mammal of claim 1 , wherein the
substituents independently selected from R , compound has the formula (II )
haloalkyl, halogen , - NO2, ORS, SR ', CH R , COR ',
NR 'R ', CN , COOR ', NR 'SO R , SO NR 'R ', (II)
NR 'COR , CONR 'R ', OC (O )R ', CH NR 'R ', R7
CHOR ', SO , R and SOR , wherein R is an alkyl 30
group, a heterocyclic ring , an aromatic or non aromatic aryl
ring that is optionally condensed or linked with a 5 - or
6 -membered , aliphatic or aromatic heterocyclic ring, a (R2)n R3 - - R6,
benzyl group, or an aliphatic or aromatic heterocyclic U
group that is optionally condensed or linked with a 35 R4 w R5
benzene ring , each of said groups may be substituted
with up to 5 substituents independently selected from
halogen , lower alkyl, lower haloalkyl, OH , NO2, lower wherein R1, R2, R3, R4, R5, R6, R7, X and n have the
alkoxy , lower haloalkoxy, NH ,, phenyl, CN , samemeaning as in claim 1 , the aryl ring is a hetero
COR " , — NHCOR " , CONHR " , NHSO , R " and 40 cyclic aromatic ring , which carries up to 3 heteroatoms
SO NHR " , wherein R " is H , lower alkyl, lower independently selected from N , S and O , W and U
haloalkyl or phenyl, and R ' at each occurrence is represent independently CH or N .
independently selected from the groups of R above and 3 . The compound for use in the treatment of hormone
H , or two of said substituents, together with the adja - related diseases in a mammal of claim 2 , wherein the
cent carbon atoms of the 6 -membered aromatic group, 45 compound has the formula (III)
optionally form a 5 - or 6 -membered , aliphatic or aro
matic , homocyclic or heterocyclic ring condensed to
said 6 -membered aromatic group , wherein the hetero (III)
cyclic ring carries up to 3 heteroatoms independently
selected from N , S and O , and the third substituent is 50 R7
optionally located on the 6 -membered aromatic group aryl
or on the ring condensed thereto ; or a 5 or 6 -membered Ri11
aliphatic or aromatic heterocyclic group which carries
up to 3 heteroatoms independently selected from N , S (R2)n R3
and O and may carry 1 to 3 substituents independently 55
selected from — R , haloalkyl, halogen , — NO2, OR ',
SR ', _ CH _ R , COR , NR'R ', CN , COOR ',
- NR'SO R , SONR'R ', NRCOR ', NRCOR ', R5 R66
CONR 'R ', OC ( O ) R ', CH NR 'R ', CHOR ',
SO , R and — SOR , wherein R and R ' is as defined 60
above , or two of said substituents , together with the wherein all the variables are as defined in claim 2 .
adjacent carbon atomsof the 5 or 6 -membered aliphatic 4 . The compound for use in the treatment of hormone
or aromatic heterocyclic group , optionally form a related diseases in a mammal of claim 2 , wherein
6 -membered , aliphatic or aromatic ring condensed to the aryl ring represents a thiadiazole, triazole , oxadiazole ,
said 5 or 6 -membered aromatic group , and the third 65 isothiadiazole , isooxadiazole , thiazole , oxazole , imida
substituent is optionally present on the 5 or 6 -mem zole ,pyrazole, isoxazole , isothiazole , furane,pyrrole or
bered aromatic group or on the ring condensed thereto ; thiophene;
US 9 ,884 ,839 B2
127 128
W and U represent independently CH or N ; 7 . The compound for use in the treatment of hormone
R1 is OH or lower alkoxy; related diseases in a mammal of claim 1 , wherein the
R3 represents lower alkyl, lower haloalkyl or halogen ; compound has 17B -HSD1 inhibitory activity , and wherein in
R7 represents H or lower alkyl; formula (I) n is 1, R2 and R3 independently represent
R5 represent H , R , haloalkyl, halogen , — NO ,, 5 halogen atoms.
CH . R . OR '. - NR 'R '. CN . - NR 'SO . R . 8 . The compound for use in the treatment of hormone
_ SO NR 'R '. — NRICOR ' or CONR 'R ', wherein R is related diseases in a mammal of claim 1 , wherein the
alkyl, aryl, benzyl, an aliphatic or aromatic heterocyclic compound has 17ß -HSD2 inhibitory activity, and wherein in
group , an aliphatic cyclic or heterocyclic ring , each of formula (1 )
which may be substituted with up to 5 substituents 10 (1) n is 1 , R2 is selected from the group consisting of
independently selected from halogen , lower alkyl, fluorine, chlorine, and bromine and R3 represents alkyl
or haloalkyl; or
lower haloalkyl, OH , NO2, lower alkoxy , - NH2, ( ii ) n is 2 , R2 is at each occurrence independently selected
phenyl, CN , COR ", - NHCOR ", CONHR " , from the group consisting of fluorine, chlorine , and
- NHSO , R " and SO NHR " , wherein R " is H , lower 15 bromine and R3 at each occurrence independently
alkyl, lower haloalkyl or phenyl; and R ' is R or H ; represents a halogen atom .
R6 is selected from H , OH , lower alkyl, lower alkoxy, 9 . The compound for use in the treatment of hormone
lower haloalkoxy and halogen ; and /or related diseases in a mammal of claim 1 , wherein the
R4 represents H , OH , an alkyl or an alkoxy group , each compound is selected from [ 5 -( 3aminophenyl)thiophen - 2
of which optionally carry phenyl and halogen substitu - 20 yl](2 ,6 -difluoro -3 -hydroxyphenyl)methanone , 4 -bromo-N
ents, wherein said phenyl substituents optionally carry {3 - [5 -(2 ,6 -difluoro -3 -hydroxybenzoyl) thiophen - 2 - yl)-phe
up to 3 substituents independently selected from – OH , nyl ) - 2 - trifluoromethoxybenzenesulfonamide , N - {3 -[5 -( 2 ,6
alkyl, haloalkyl, alkoxy , halogen , amino , CN and difluoro - 3 -hydroxybenzoyl) thiophen - 2 -yl)phenyl) - 2
- NO2, CH2R , — NHSO , R and - NHCOR ', trifluoromethoxybenzene -sulfonamide , N - { 3- [5 -(2 ,6
wherein R and R ' is as defined above, a 6 -membered 25 difluoro -3 -hydroxybenzoyl) thiophen - 2 -yl]phenyl )- 2
aromatic or hetero aromatic group which optionally trifluoromethylbenzene - sulfonamide, pyridine -3 -sulfonic
carry 1 to 3 substituents independently selected from acid { 3 -[5 -( 2 ,6 -difluoro -3 -hydroxy-benzoyl)-thiophen -2
- R , haloalkyl, halogen , — NO2, - OR ', NR 'R ', yl]-phenyl} -amide, 1-methyl-1H - imidazole -4 - sulfonic acid
CN , NR 'SO R , SO NR 'R ', NR 'COR ', { 3 -[5 - (2 ,6 -difluoro -3 - hydroxyl-benzoyl)-thiophen - 2 -yl]
CONR 'R ', wherein R and R ' is as defined above , or 30 phenyl ) -amide , cyclopropanesulfonic acid (3 - [5 -( 2 ,6 - dif
two of said substituents , together with the adjacent luoro - 3 -hydroxy- benzoyl)- thiophen - 2 -yl )-phenyl) -amide ,
carbon atoms of the 6 -membered aromatic group , (2 ,6 -difluoro - 3-hydroxy -phenyl )-(5 -pyridin -4 - yl- thiophen
optionally form a 5 - or 6 -membered aliphatic or aro 2 -yl)-methanone, (2 ,6 - difluoro - 3 -hydroxy- phenyl)-(5 -pyri
matic, homocyclic or heterocyclic ring condensed to din - 3 - yl- thiophen -2 -yl) -methanone , (2 ,6 -difluoro -3 -hy
said 6 -membered aromatic group , wherein the hetero - 35 droxy- phenyl)-[5 -( 2 ,4 -difluoro -phenyl) - thiophen - 2 -yl]
cyclic ring carries up to 3 heteroatoms independently methanone , [5 -(3 -chloro -phenyl)- thiophen -2 -yl)-(2 ,6
selected from N , S and 0 , and wherein the third difluoro - 3 -hydroxy -phenyl)-methanone, [5 -( 3 -chloro -4
substituent may be located on the 6 -membered aro - methoxy -phenyl)- thiophen - 2 -yl)-(2 ,6 -difluoro -3 -hydroxy
matic group or on the ring condensed thereto , or a 5 or phenyl)-methanone , [5 -( 3 - chloro -4 -methoxy -phenyl)-4
6 -membered , aliphatic or aromatic heterocyclic group 40 methyl- thiophen - 2 -yl)-(2 ,6 -difluoro - 3 -hydroxy -phenyl)
which carries up to 3 heteroatoms independently methanone, (5 -( 3 - chloro - 2 -methoxy -phenyl)-thiophen - 2
selected from N , S and O and optionally carry 1 to 3 yl]-(2 ,6 - difluoro - 3- hydroxy -phenyl)-methanone , [5 -(3 , 5
substituents independently selected from R , dichloro -4 -methoxy -phenyl)-thiophen - 2 -yl)-( 2 ,6 - difluoro
haloalkyl, halogen , - NO2, — OR ', - NR 'R ', — CN , 3 -hydroxy -phenyl) -methanone, (2,6 -difluoro -3 -hydroxy
- NR 'SOR , — SO NR 'R ', — NR 'COR ', CONR 'R ', 45 phenyl)- [5 -(4 -methoxy -3 ,5 - dimethyl-phenyl) -thiophen -2
wherein R and R ' is as defined above or two of said yl ]-methanone, (2 ,6 - difluoro - 3 -hydroxy -phenyl) - 15 -( 4
substituents , together with the adjacent carbon atoms of difluoromethoxy -3 ,5 -difluoro -phenyl)- thiophen -2 - yl)
the 5 or 6 -membered aliphatic or aromatic heterocyclic methanone , 5 -[5 -(2 ,6 -difluoro - 3 -hydroxy -benzoyl)
group , optionally form a 6 -membered , aliphatic or thiophen -2 - yl]-2 - isopropoxy -benzonitrile, (2 ,6 -difluoro - 3
aromatic ring condensed to said 5 or 6 -membered 50 hydroxy -phenyl)- {5 -[ 4 -methoxy - 3 -(morpholine-4
aromatic group . sulfonyl)-phenyl]-thiophen - 2- yl)-methanone, [5 -(3 -chloro
5 . The compound for use in the treatment of hormone 4 -hydroxy -phenyl)-thiophen -2 - yl)-(2 ,6 -difluoro -3 -hydroxy
related diseases in a mammal of claim 4 , wherein the aryl phenyl)-methanone, [5 -( 3 -chloro -4 -hydroxy-phenyl)-4
ring represents a thiophene ; R1 is OH ; n is 1 or 2 ; R2 is F ; methyl- thiophen - 2 -yl]-(2 ,6 -difluoro - 3-hydroxy -phenyl )
R3 is lower alkyl, lower haloalkyl or F, W and U are 55 methanone , [5 -(3 -chloro -2 -hydroxy -phenyl)-thiophen -2
independently selected from CH and N ; R4 represents H , yl] -( 2 ,6 -difluoro -3 -hydroxy -phenyl) -methanone, (5 -(3 ,5
OH , an alkoxy group , which optionally carry up to 3 halogen dichloro -4 -hydroxy -phenyl)- thiophen - 2 -yl)-(2 ,6 -difluoro -3
substituents , CH2R , SOR , — NHSOZR and hydroxy- phenyl)-methanone , (2 ,6 -difluoro - 3 -hydroxy
- NRSO R ', wherein R and R ' is as defined above; R7 is phenyl)-[5 -(4 -hydroxy -3 ,5 -dimethyl-phenyl) -thiophen -2
selected from H and alkyl; and / or R5 and R6 are indepen - 60 yl]-methanone , 5 - [5 -(2 ,6 - difluoro -3 -hydroxy -benzoyl)
dently selected from H , OH , CN , alkyl, alkoxy and thiophen - 2 - yl]- 2 -hydroxy-benzonitrile , [5 -( 3 -chloro -4
halogen . methoxy - 5 -methyl-phenyl)- thiophen -2 -yl)-(2 ,6 -difluoro - 3
6 . The compound for use in the treatment of hormone - hydroxy -phenyl)-methanone , [5 -(3 - chloro - 4 -hydroxy -5
related diseases in a mammal of claim 3 , wherein in the methyl-phenyl)- thiophen - 2 -yl)-(2 ,6 -difluoro - 3 -hydroxy
compounds of formula (I) R1 is a hydroxy group in the meta 65 phenyl)-methanone, 1- (4 - { 3 -chloro - 5 -[5 -(2 ,6 -difluoro - 3
position relative to the Co — junction , n is 1 or 2 , R2 is hydroxy -benzoyl)-thiophen - 2 -yl ]-2 -methoxy -benzyl)
F and R3 is CH2, CF or F . piperazin - 1 -yl)-ethanone, 1- (4 - {3 - chloro - 5 -[5 -(2 ,6
US 9 ,884,839 B2
129 130
difluoro -3 -hydroxy -benzoyl)- thiophen -2 -yl)-2 -hydroxy phenyl)methanone , (5 -(2 -hydroxyphenyl)thiophen -2 -yl)(2 ,
benzyl) -piperazin - 1- yl) -ethanone, [5 -(3 - chloro - 4 -methoxy 4 ,5 - trifluoro -3 -hydroxyphenyl)methanone, (5 -(4 -hydroxy
5 -piperazin - 1 -ylmethyl- phenyl)-thiophen - 2 -yl)-(2 ,6 3 ,5 - dimethylphenyl) thiophen -2 -yl) (5 - fluoro -3 -hydroxy -2
difluoro - 3 -hydroxy -phenyl)-methanone, [5 -( 3 -chloro -4 methylphenyl)methanone , (4 ,5 -difluoro - 3 -hydroxy - 2
methoxy - 5- [1 ,2 ,3 ]triazol- 1 -ylmethyl-phenyl)-thiophen - 2 - 5 methylphenyl)(5 - (4 -hydroxy -3 ,5 -dimethylphenyl)thiophen
yl]-(2 ,6 - difluoro -3 -hydroxy -phenyl)-methanone, [5 -(3 2 -yl)methanone, (5 -methylthiophen -2 -yl)(2,4 ,5 -trifluoro - 3
chloro -4 -hydroxy -5 -[1,2 ,3 ] triazol- 1- ylmethyl -phenyl) hydroxyphenyl)methanone , 4 -(5 -(2 ,4, 5- trifluoro -3
thiophen - 2 -yl)-(2 ,6 -difluoro - 3 -hydroxy - phenyl) hydroxybenzoyl) thiophen - 2 -yl) phenyl sulfamate , 4 - (5 -(2 ,6
methanone , cyclopropanesulfonic acid { 3-[ 5 -(2,6 -difluoro difluoro - 3 -hydroxybenzoyl) thiophen - 2 -yl)
3 -hydroxy -benzoyl)-thiophen -2 -yl]-5 -methyl-phenyl) - 10 benzenesulfonamide , 3 -( 5 -(2,6 -difluoro -3 -hydroxybenzoyl)
amide, cyclopropanesulfonic acid ( 3 - [5 - (2,6 -difluoro -3 - thiophen -2 -yl)benzenesulfonamide, (6 -chloro - 2- fluoro -3
hydroxy -benzoyl)- thiophen - 2 -yl]-5 -methyl-phenyl) hydroxyphenyl)(5 -(3 ,5 -dichloro -4 -methoxyphenyl)
methyl-amide, [5 -(3 - aminophenyl) thiophen - 2 -yl](2 ,4 ,5 - thiophen -2 - yl)methanone, ( 2 -chloro -6 - fluoro -3
trifluoro -3 -hydroxyphenyl)methanone, 4 -bromo -N - {3 - [5 - hydroxyphenyl)(5 - (3 ,5 -dichloro - 4 -methoxyphenyl)
( 2,4 ,5 -trifluoro - 3-hydroxybenzoyl) thiophen - 2 -yl]phenyl) - 15 thiophen - 2 -yl)methanone, and pharmaceutically acceptable
2 -trifluoromethoxybenzenesulfonamide , N - { 3 -[5 - (2 ,4,5 - salts thereof.
trifluoro -3 -hydroxybenzoyl)thiophen - 2 -yl]phenyl ) -2 10 . A pharmaceutical composition comprising
trifluoromethoxybenzenesulfonamide , N - {3 -[5 -( 2,4 ,5 - a compound having the formula (I)
trifluoro -3 -hydroxybenzoyl) thiophen - 2 - yl)phenyl) -2
trifluoromethylbenzenesulfonamide, [5 -(5 - fluoro -pyridin - 3 - 20
yl)-thiophen - 2 -yl )-(2 ,4 , 5 - trifluoro - 3 -hydroxy -phenyl) (1)
methanone, (5 - ( 2 , 4 - difluoro -phenyl) -thiophen - 2 - yl )- (2 ,4 ,5 2 R4
trifluoro -3 -hydroxy -phenyl)-methanone , (5 -(3 -chloro -4
hydroxyphenyl)thiophen - 2- yl)(2 ,4,5 - trifluoro -3 R1 diyi
Rs
hydroxyphenyl)methanone, (5 -( 3 - fluoro - 4 -hydroxyphenyl) 25 (R2)n R3
thiophen - 2- yl )(2 ,4,5 - trifluoro -3 -hydroxyphenyl)methanone,
(5 -( 1H -indol-6 - yl) thiophen - 2 - yl) (2 ,4 ,5 -trifluoro -3 - hy
droxyphenyl)methanone, 3 - (5 -( 2,4 ,5 -trifluoro -3 -hydroxy wherein
benzoyl) thiophen - 2 -yl)benzamide, (5 -(3 ,5 -dichloro -4 R1 represents , OH , alkoxy or acyloxy ;
methoxyphenyl) thiophen -2 -yl) (2,4 ,5 -trifluoro -3 30 n represents an integer of 1 or 2 ;
hydroxyphenyl)methanone , (5 -(4 -methoxy -3 ,5 R2 is at each occurrence independently selected from the
dimethylphenyl)thiophen - 2 -yl)(2 ,4,5 - trifluoro -3 group consisting of fluorine , chlorine, and bromine;
hydroxyphenyl)methanone, (5 -( 3 -(hydroxymethyl)phenyl) R3 represents alkyl, haloalkyl or halogen atom ;
thiophen -2 - yl) (2 ,4, 5 - trifluoro -3 -hydroxyphenyl)methanone, R4 represents H ; OH ; an alkyl or an alkoxy group , each
1 -methyl- N -( 3 - (5 - (2 ,4 ,5 - trifluoro -3 - hydroxy -benzoyl) thio - 35 of which optionally carry phenyl and halogen substitu
phen -2 -yl)phenyl)-1H - imidazole-4 -sulfonamide, (5 -(3 ,5- di ents , wherein said phenyl substituents optionally carry
chloro -4 -hydroxyphenyl) thiophen - 2 -yl)( 2 ,4 ,5 -trifluoro - 3 up to 3 substituents independently selected from – OH ,
hydroxyphenyl)methanone , (5 - (4 -hydroxy -3 , 5 alkyl, haloalkyl, alkoxy, halogen , amino, CN and
dimethylphenyl) thiophen -2 -yl) (2 ,4 ,5 - trifluoro -3 - NO2; a 6 -membered aromatic group which option
hydroxyphenyl)methanone, (5 -(4 -methoxyphenyl) thiophen - 40 ally carry 1 to 3 substituents independently selected
2 -yl)(2 ,4 ,5 - trifluoro - 3-hydroxyphenyl)methanone , (5 -(3 from - R , haloalkyl, halogen , - NO2, - OR ', — SR ',
methoxyphenyl) thiophen -2 -yl) (2,4 ,5 -trifluoro -3 _ CH , R , COR ', — NR 'R ', CN , COOR',
hydroxyphenyl)methanone, (5 -( 2 -methoxyphenyl)thiophen - NR 'SO2R , SONR 'R ', - NR' COR , CONR'R ',
2 -yl) (2 ,4 ,5 - trifluoro - 3 - hydroxyphenyl)methanone , N -(3 -(5 OC ( O ) R ', CH ,NR ' R ', CHOR ', — SO , R and
(2 ,4 ,5 - trifluoro - 3 -hydroxybenzoyl)thiophen -2 -yl)phenyl) 45 SOR , wherein R is an alkyl group , a heterocyclic
acetamide , (5 -(2 -aminophenyl)thiophen -2 -yl) (2,4 ,5 ring , an aromatic or non aromatic ring that is optionally
trifluoro -3 -hydroxyphenyl)methanone , (5 -phenylthiophen condensed or linked with a 5 - or 6 -membered, aliphatic
2 -yl) ( 2 ,4 ,5 -trifluoro -3 -hydroxyphenyl)methanone, (5 -( 3 or aromatic heterocyclic ring, a benzyl group , or an
Amino -4 -methylphenyl)thiophen -2 -yl) (2 ,4 ,5 - trifluoro - 3 aliphatic or aromatic heterocyclic group that is option
hydroxyphenyl)methanone, (5 -( 3 -amino -2 -methylphenyl) 50 ally condensed or linked with a benzene ring, each of
thiophen - 2 - yl)( 2 ,4 ,5 -trifluoro - 3 -hydroxyphenyl)methanone , said groups is optionally substituted with up to 5
( 5 - (3 - amino -4 -hydroxyphenyl) thiophen -2 -yl) (2 ,4 ,5 - trif substituents independently selected from halogen ,
luoro - 3 -hydroxyphenyl)methanone , (5 -( 3 -amino -4 lower alkyl, lower haloalkyl, OH , NO2, lower
methoxyphenyl)thiophen - 2 -yl) (2 ,4 ,5 -trifluoro -3 - hydroxy alkoxy , lower haloalkoxy, — NH , phenyl, CN ,
phenyl)methanone, (5 -( 1H - indol-5 - yl) thiophen - 2 -yl)( 2,4 ,5 - 55 COR " , — NHCOR " , CONHR " , — NHSO , R " and
trifluoro -3 -hydroxy -phenyl)methanone, (5 -( 1H - indol-4 -yl) SO NHR " , wherein R " is H , lower alkyl, lower
thiophen - 2- yl )(2 ,4,5 - trifluoro -3 -hydroxyphenyl)methanone, haloalkyl or phenyl, and R ' at each occurrence is
N -(3 -( 5 -(2 ,4 ,5 -trifluoro -3 -hydroxybenzoyl)thiophen - 2 -yl) independently selected from the groups of R above and
phenyl)methanesulfonamide, N -(4 -(5 -(2 ,4,5 -trifluoro -3 -hy H , or two of said substituents , together with the adja
droxybenzoyl)thiophen -2 -yl)phenyl)acetamide, (5 -(pyridin - 60 cent carbon atoms of the 6 -membered aromatic group ,
3 -yl) thiophen -2 -yl)( 2,4 ,5- trifluoro -3 -hydroxyphenyl) optionally form a 5 - or 6 -membered , aliphatic or aro
methanone, (5 -( quinolin -7 - yl)thiophen -2 - yl) (2 ,4,5 matic , homocyclic or heterocyclic ring condensed to
trifluoro -3 -hydroxyphenyl)methanone, (5 - 1H -benzo [d ] said 6 -membered aromatic group , wherein the hetero
imidazol- 5 - yl) thiophen - 2 -yl) (2 ,4 ,5 - trifluoro -3 cyclic ring carries up to 3 heteroatoms independently
hydroxyphenyl)methanone, (5 -( 4 -hydroxyphenyl) thiophen - 65 selected from N , S and 0 , and the third substituent is
2 -yl)(2 ,4,5 - trifluoro -3 -hydroxyphenyl)methanone, (5 -(3 optionally located on the 6 -membered aromatic group
hydroxyphenyl)thiophen -2 -yl)( 2,4 ,5 -trifluoro -3 -hydroxy or on the ring condensed thereto ; or a 5 or 6 -membered
US 9 ,884,839 B2
131 132
aliphatic or aromatic heterocyclic group which carries benzylamino, 2,4 ,6 -trimethylbenzylamino , 2,3 ,5 ,6
up to 3 heteroatoms independently selected from N , S tetramethylbenzylamino , 2 ,3 ,5 ,6 - tetrafluoro
and O and optionally carry 1 to 3 substituents indepen benzylamino , 2,4 ,6 -trichlorobenzylamino , 2 ,4,6
dently selected from - R , haloalkyl, halogen , - NO2, triisopropylbenzylamino, 2 ,4 ,6 -trifluorobenzyl-amino,
OR', — SR ', — CH , R , — COR ', — NR'R ', — CN , 5 2 ,6 -dimethoxybenzylamino , 2 ,6 - dichloro -3 -nitroben
COOR ', NR 'SO , R , — SO ,NR' R ', NR 'COR ', zylamino , 3 -chloro - 2 ,6 - difluoro -benzylamino ,
- NRCOR ', — CONR 'R ', OC (O ) R ', — CH NR 'R ', 2 - chloro -6 -methylbenzylamino, 2 -chloro -6 - fluoro -5
CH ,OR ', - SO , R and — SOR , wherein R and R ' is methylbenzylamino , 4 - bromo -2 ,6 - fluorobenzylamino ,
as defined above , or two of said substituents, together 2 - chloro -3 ,6 - difluorobenzylamino , 2 ,5 - dichlorobenzy
with the adjacent carbon atomsof the 5 or 6 -membered lamino, 2 -bromo-6 -methylbenzylamino , 2,6 -difluoro
aliphatic or aromatic heterocyclic group , optionally 3 -methylbenzylamino , 2 -bromo -6 -chloro -benzy
form a 6 -membered , aliphatic or aromatic ring con lamino, 2- fluoro -6 -methoxybenzylamino , 2 ,6
densed to said 5 or 6 -membered aromatic group , and
dimethyl-4 - fluorobenzylamino , 2 -chloro -6
methoxybenzylamino , 2 - chloro -6 - fluoro -5
the third substituent may be present on the 5 or 6 -mem - 15 methylbenzylamino , 2 -( 2 -(N ,N -dimethylamino )
bered aromatic group or on the ring condensed thereto ; ethyloxy )phenyloxy or 3 -( 2 - (N ,N -dimethylamino )
and said substituent R4 being directly or through a ethyloxy )phenyloxy ; and
phenylene group bound to the aryl ring; ( iii ) when in the compound of formula (I) the aryl ring is
R5 , R6 and R7 independently represent H , — R , haloalkyl, N -
methyl - 3 -amino -4 -carboxamido -5 -(4 '-phenoxy)phe
halogen , — NO ,, OR , SR ', CH , R ', COR ', nyl-pyrrol-2 -yl, and X is _ C0 — , then the phenyl
- NR 'R ', CN , COOR ', NHSO , R ', moiety carrying R1- R3 is not 2,6 -dichlorophenyl;
- NRSO , R ' SO ,NRR ', — NHCOR ', — NRCOR ', or a pharmaceutically acceptable salt thereof.
CONRRY, OC( O) R', CHÚNRRY, CHOR', 11 . A compound having the formula (1)
- SOR' or — SOR ', wherein R and R ' is as defined
above, 25
X represents
RA
O Ž aryl >
=

0=Ou
Z
-
30
(R2)n R3 R7
Rs
Z
wherein
R1 represents , OH , alkoxy or acyloxy ;
wherein Y, if present, represents O or S, and R8 represents 35 n represents an integer of 1 or 2 ;
H or lower alkyl; and R2 is at each occurrence independently selected from the
the aryl ring is a 5 -membered heteroaromatic ring which group consisting of fluorine , chlorine , and bromine;
carries up to 3 heteroatoms independently selected R3 represents alkyl, haloalkyl or halogen atom ;
from N , S and O ; R4 represents H ; OH ; an alkyl or an alkoxy group, each
provided that 40 of which optionally carry phenyl and halogen substitu
(i) when in the compound of formula (I) the aryl ring is ents, wherein said phenyl substituents optionally carry
3 -amino -4 -carboxamido -5 -(4 '-phenoxy )phenyl-pyrrol up to 3 substituents independently selected from – OH ,
2 -yl, and X is - CO , then the phenylmoiety carrying alkyl, haloalkyl, alkoxy, halogen , amino , CN and
R1-R3 is not 2 ,6 - difluorophenyl, 2 , 4 ,6 -trifluorophenyl, - NO2; a 6 -membered aromatic group which option
2 ,6 -difluoro - 3 -methylphenyl, 2 ,5 - difluorophenyl, 45 ally carry 1 to 3 substituents independently selected
3 - fluoro - 2 -methylphenyl, 2 ,3 -difluorophenyl, 2,3 -di from — R , haloalkyl, halogen , — NO , - OR ', - SR ',
chlorophenyl, 2 ,4 -dichlorophenyl, 3, 5 -dichlorophenyl, CHR , COR ', NR ' R ', CN , COOR ',
2 ,5 -dichlorophenyl , 3 -chloro -2-methylphenyl, 3 ,4 -di - NR'SO , R , SONR'R ', - NR 'COR , CONR 'R ',
chlorophenyl or 3 -bromo - 2 -methylphenyl; OC (O )R ', CH NR 'R ', CHOR ', SO2R and
(ii) when in the compound of formula (I) the phenyl 50 SOR , wherein R is an alkyl group , a heterocyclic
moiety carrying R1- R3 is 2 ,6 -difluorophenyl and X is ring , an aromatic or non aromatic ring that is optionally
CO — , then the aryl ring is not a 3- amino -4 -carbox condensed or linked with a 5 - or 6 -membered , aliphatic
amido -5 -(4 '-substituted )phenyl-pyrrol-2 - yl, in which or aromatic heterocyclic ring, a benzyl group , or an
the substituent is methoxy, 2 -pyrimidinyloxy, benzy aliphatic or aromatic heterocyclic group that is option
loxy, 2,6 - dichlorobenzyloxy, amino, benzoylamido , 55 ally condensed or linked with a benzene ring, each of
benzylamino , cyclohexylmethylamino , 2,6 -dichlo said groups is optionally substituted with up to 5
robenzylamino, N -(2 ,6 -dichlorobenzyl)-N -methyl substituents independently selected from halogen ,
amino , 2,5 -dichlorobenzylamino , 2 - chloro -6 -methl lower alkyl, lower haloalkyl, OH , NO2, lower
benzylamino , 3 - phenylpropylamino , alkoxy , lower haloalkoxy, — NH ,, phenyl, CN ,
4 - trifluoromethylbenzylamino , 2 -pyridylmethoxy, 60 COR " , — NHCOR " , - CONHR " , — NHSO , R " and
2 -(4 -methylpiperazin - 1- yl)ethyloxy , 5 - tifluoromethyl SO NHR " , wherein R " is H , lower alkyl, lower
pyridin - 2 - yloxy, piperidin - 2 -yloxy, 4 ,6 -dimethylpiperi haloalkyl or phenyl, and R ' at each occurrence is
din - 2 - yloxy, piperidin - 2 - yloxy, 4 ,6 - dimethoxypiperi independently selected from the groups of R above and
din - 2 -yloxy , 3 -phenylpropionoylamido , H , or two of said substituents , together with the adja
2 -pyridinylcarbamido , 3-(3 -pyridinyl)propionoy - 65 cent carbon atoms of the 6 -membered aromatic group ,
lamido , 2 - chloro -6 - fluorobenzylamino, 2 - trifluorom may form a 5 - or 6 -membered , aliphatic or aromatic ,
ethylbenzylamino , 2 -methylbenzylamino , 2 ,6 -difluoro homocyclic or heterocyclic ring condensed to said
US 9 ,884 ,839 B2
133 134
6 -membered aromatic group , wherein the heterocyclic benzylamino, cyclohexylmethylamino, 2 ,6 - dichlo
ring carries up to 3 heteroatoms independently selected robenzylamino, N -(2 ,6 - dichlorobenzyl)- N -methyl
from N , S and 0 , and the third substituent is optionally amino , 2,5 - dichlorobenzylamino , 2 -chloro -6 -methl
located on the 6 -membered aromatic group or on the benzylamino , 3 -phenylpropylamino ,
ring condensed thereto ; or a 5 or 6 -membered aliphatic 5 4 - trifluoromethylbenzylamino , 2 -pyridylmethoxy ,
or aromatic heterocyclic group which carries up to 3 2 - (4 -methylpiperazin - 1 -yl)ethyloxy, 5 -tifluoromethyl
heteroatoms independently selected from N , S and O pyridin - 2 - yloxy, piperidin - 2 -yloxy, 4 ,6 -dimethylpiperi
and optionally carry 1 to 3 substituents independently din - 2 -yloxy, piperidin - 2 -yloxy, 4 ,6 -dimethoxypiperi
selected from R , haloalkyl, halogen , — NO2, - OR ', din -2 -yloxy, 3 -phenylpropionoylamido ,
SR ', CH2R , COR', NR'R ', CN , COOR ', 2 -pyridinylcarbamido , 3 -(3 -pyridinyl) propionoy
- NR'SO R , SONR'R ', — NR 'COR ', NRCOR ', lamido, 2 -chloro -6 -fluorobenzylamino , 2 -trifluorom
CONR'R ', - OC (O ) R ', CH NR 'R ', CHOR ', ethylbenzylamino , 2 -methylbenzylamino , 2,6 -difluoro
SO ,R and SOR , wherein R and R ' is as defined benzylamino , 2,4 ,6 -trimethylbenzylamino , 2 ,3 ,5 ,6
above , or two of said substituents, together with the tetramethylbenzylamino , 2,3 ,5,6 -tetrafluoro
adjacent carbon atoms of the 5 or 6 -membered aliphatic benzylamino , 2,4 ,6 -trichlorobenzylamino , 2 ,4,6
or aromatic heterocyclic group , optionally form a triisopropylbenzylamino, 2 ,4 ,6 -trifluorobenzyl-amino,
6 -membered , aliphatic or aromatic ring condensed to 2 ,6 -dimethoxybenzylamino , 2,6 - dichloro -3 -nitroben
said 5 or 6 -membered aromatic group , and the third zylamino , 3 -chloro -2 ,6 - difluoro -benzylamino,
substituent optionally is present on the 5 or 6 -mem - 20 2 - chloro -6 -methylbenzylamino , 2 -chloro -6 -fluoro -5
bered aromatic group or on the ring condensed thereto ; methylbenzylamino , 4 -bromo- 2 ,6 - fluorobenzylamino ,
and said substituent R4 being directly or through a 2 -chloro - 3,6 -difluorobenzylamino , 2 ,5 -dichlorobenzy
phenylene group bound to the aryl ring ; lamino, 2 - bromo-6 -methylbenzylamino, 2 ,6 -difluoro
R5, R6 and R7 independently represent H , - R , haloalkyl, 3 -methylbenzylamino , 2 -bromo-6 - chlorobenzylamino ,
halogen , - NO2, — OR ', — SR ', CH , R ', COR ', 25 2 - fluoro -6 -methoxybenzylamino, 2,6 - dimethyl-4 - fluo
- NR 'R ', CN , COOR ', NHSO , R ', robenzylamino , 2 -chloro -6 -methoxybenzylamino ,
- NRSO _ R _ SO ,NRR', — NHCOR ', NRCOR ', 2 -chloro -6 - fluoro -5 -methylbenzylamino , 2 -(2 -(N ,N -di
CONRR ', OC (O )R ', — CH NRR ', CH ,OR ', methylamino ) ethyloxy ) phenyloxy or 3 -(2 -( N ,N -dim
SO , R ' or — SOR ', wherein R and R ' is as defined ethylamino )ethyloxy ) phenyloxy ;
above, 30
X represents ( iv ) when in the compound of formula (I) the aryl ring is
N -methyl- 3 -amino -4 -carboxamido- 5 - (4 '-phenoxy ) phe
nyl-pyrrol-2 -yl, and X is _ CO , then the phenyl
O

=
K

moiety carrying R1- R3 is not 2,6 -dichlorophenyl;


v
=
O
?
-
35 (v ) when in the compound of formula (I) the aryl is a
2 pyrrol and R4 is a phenyl residue substituted with 1 to
3 substituents independently selected from halogen ,
- NO2, CN , C1- alkyl , C1-4haloalkyl and C - alkoxy,
and the phenyl moiety carrying R1-R3 is a phenyl
wherein Y , if present, represents O or S , and R8 represents 40 substituted with 2 to 4 substituents selected from halo
H or lower alkyl; and gen , — NO2, CN , C1- alkyl , C1- haloalkyl and
the aryl ring is a 5 -membered heteroaromatic ring which C1-4alkoxy, then X is not SO — or — S02— ; and
carries up to 3 heteroatoms independently selected (vi) when in the compound of formula (1) the aryl is a
from N , S and O ; thiene , R4 is an aryl group , unsaturated monocyclic
provided that 45
45 heterocyclic ring or unsaturated fused heterobicyclic
(i) the compound of formula (I) is not 2 ,4 -dichloro -6 ring, each of which may be substituted with 1 to 3
hydroxyphenyl- furyl-ketone, 2 ,4 -dibromo -6 -hydroxy substituents independently selected from halogen ,
phenyl- furyl-ketone, 4 - chloro - 2 -hydroxy -6 -methyl - NO2, amino, cyano , hydroxy, mercapto , carboxyl,
phenyl- furyl-ketone , 4 - chloro - 2 -hydroxy - 5 C1-4 alkyl, C - haloalkyl, C1-4alkoxy, benzyloxy,
methylphenyl-furyl-ketone, 2 ,4 -dichloro -6 - 50 C1-4alkylthio , C1-4 hydroxyalkyl, Cl alkyl amino , bis
hydroxyphenyl- thienyl-ketone or 4 -chloro -2 -hydroxy (C1- alkyl)amino , C1- acylamino , carbamoyl ,
6 -methylphenyl- thienyl-ketone ; C1-4alkoxycarbonyl, and C1-4 alkylsulfonyl, R5 and R6
( ii ) when in the compound of formula (I) the aryl ring is are hydrogen , and the phenyl moiety is a phenyl
3 -amino -4 -carboxamido- 5 -(4 '-phenoxy ) phenyl-pyrrol substituted with 2 to 3 substituents selected from halo
2 -yl, and X is CO — , then the phenyl moiety carrying 55 gen , hydroxy , C1-4 alkyl, C1-4 haloalkyl and C -4alkoxy,
R1-R3 is not 2,6 -difluorophenyl, 2 ,4 ,6 - trifluorophenyl,
2 ,6 -difluoro - 3 -methylphenyl, 2,5 -difluorophenyl, then X is not — C0 — ;
3 - fluoro - 2 -methylphenyl, 2 ,3 - difluorophenyl, 2 ,3 - di or a pharmaceutically acceptable salt thereof.
chlorophenyl, 2,4 -dichlorophenyl, 3, 5 -dichlorophenyl, 12 . The compound of claim 11, wherein the aryl ring
2 ,5 - dichlorophenyl, 3 -chloro - 2 -methylphenyl, 3 , 4 - di - 60 represents a thiophene and R1 is OH .
chlorophenyl or 3- bromo- 2-methylphenyl; 13 . A method for the production of the compound of claim
( iii ) when in the compound of formula (I) the phenyl 11 or a pharmaceutically acceptable salt thereof, comprising
moiety carrying R1-R3 is 2 ,6 -difluorophenyl and X is condensing an aromatic precursor compound of the com
_ C0 — , then the aryl ring is not a 3 - amino - 4 - carbox - pound of formula ( I).
amido- 5 -(4 '- substituted )phenyl-pyrrol- 2 -yl, in which 65 14 . The compound for use in the treatment of hormone
the substituent is methoxy, 2 - pyrimidinyloxy, benzy - related diseases in a mammal of claim 2 , wherein the
loxy, 2 ,6 - dichlorobenzyloxy , amino , benzoylamido , compound has the formula ( IIa )
US 9 ,884,839 B2
135 136
(IIa )

R7 a
aryl
RI
(R2)n R3 R62
PWT
R " R5 10

and wherein all the variables are as defined in claim 2 .


* * * * *

Das könnte Ihnen auch gefallen