TR201816379T4 - DNA-PK inhibitörleri. - Google Patents

DNA-PK inhibitörleri. Download PDF

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Publication number
TR201816379T4
TR201816379T4 TR2018/16379T TR201816379T TR201816379T4 TR 201816379 T4 TR201816379 T4 TR 201816379T4 TR 2018/16379 T TR2018/16379 T TR 2018/16379T TR 201816379 T TR201816379 T TR 201816379T TR 201816379 T4 TR201816379 T4 TR 201816379T4
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TR
Turkey
Prior art keywords
4alkyl
group
atoms
alkyl
2alkyl
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TR2018/16379T
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English (en)
Inventor
S Charifson Paul
Michael Cottrell Kevin
Deng Hongbo
P Duffy John
Gao Huai
Giroux Simon
Green Jeremy
Lee Jackson Katrina
Patrick Maxwell John
A Morris Mark
Charles Pierce Albert
D Waal Nathan
M Kennedy Joseph
J Lauffer David
Willem Ledeboer Mark
Li Pan
Xu Jinwang
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Vertex Pharma
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Application filed by Vertex Pharma filed Critical Vertex Pharma
Publication of TR201816379T4 publication Critical patent/TR201816379T4/tr

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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers

Abstract

Bu buluş DNA-PK inhibitörleri olarak formül (I)?in bileşiklerine ilişkindir. Buluş ayrıca sözü edilen bileşikleri içeren farmasötik olarak kabul edilebilir bileşimler ve bileşimleri kanser gibi çeşitli hastalıklar, rahatsızlıklar veya bozuklukların tedavisinde kullanmanın usullerini sunmaktadır.

Claims (3)

ISTEMLER
1. Asagidaki formülü haiz bir bilesik: veya bunun farmasötik olarak kabul edilebilir bir tuzu olup, burada 5 Q N veya CH9dir; Rl hidrojen, CH3 veya CHZCH3,tür veya Rl ve bagli oldugu karbon bir C=CH2 grubu olusturur; RA1 ve O C0_4alkil-C(O)OR^lb, C0_4alkil-C(O)Ci-4alkil, C0_4alkil-N(RA'b)C(O)R^'a, C0_4alkil- N(RAlb)(4-6 üyeli-heterosiklil), N(RAlb)C2-4alkil-N(RA1a)2, N(RA1b)C2-4alkil-ORA”, N(R^lb)C1-4alkil-(5-10 üyeli heteroaril), N(R^lb)C1.4alkil-(4-6 üyeli heterosiklil), heieroaril), C0-4alkil-N(R^'a)(4- 6 üyeli heterosiklil) veya C0- 4alki1 N(R^'b)(5 6 üyeli- heteroarilýdir, burada sözü edilen her RA heterosiklil aziridinil, oksetanil, tetrahidrofuranil, tetrahidropiranil, dioksanil, dioksolanil, azetidinil, pirolidinil, pirolidinonil, pirolidinedionil, morfolinil, piperidinil, piperazinil, piperazinonil, izoindolinonil arasindan seçilen bir halka sistemidir, burada sözü edilen her RAl heteroaril furanil, tiofenil, imidazolil, benzoimidazolil, oksazolil, oksadiazolil, tiazolil, pirazolil, tiadiazolil, piridinil, pirimidinil, pirazinil, triazolil ve tetrazolil arasindan seçilen bir halka sistemidir ve burada sözü edilen her RAl alkil, sikloalkil, fenil, heterosiklil ve heteroaril grubu istege bagli olarak en fazla üç F` atomu, en fazla iki Cmalkil grubu, bir C3_(,sikloalkil grubu, bir fenil grubu, bir benzil grubu, bir alkenil-C0_2alkil grubu, bir alkinil-C0_2alkil grubu, en fazla iki C2 grubu, bir SCi-4alkil grubu, bir S(0)zc.aalkil grubu, bir C(0)RA'b grubu, bir C(O)ORA”” grubu, bir C(O)N(RA”“)2 grubu, bir -CN grubu veya oksetanil, tetrahidrofuranil, tetrahidropiranil, piperidinil ve morfolinil arasindan seçilen bir C4_(` heterosiklik halka sistemiyle sübstitüe edilir; her RA” bagimsiz bir sekilde hidrojen, C1_4alkil, C3_6sikloalkil, oksetanil, tetrahidrofuranîl, tetrahidrOpiranil, pirolidinil ve piperidinil arasindan seçilen C4_6heterosiklil, imidazolil, triazolil, tetrazolil, pirazolil, tiofenil, tiazolil, piridinil, pirimidinil ve pirazinil arasindan seçilen C5-6heteroarildir veya iki RAla ve araya giren bir azot atoinu aziridiiiil, azetidinil, pirolidinil, pirolidinonil, piperidinil, piperidinonil, tetrahidropiridinil, piperazinil ve morfolinil arasindan seçilen 3-6 üyeli bir heterosiklik halka olusturur, burada sözü edilen her RAla alkil, sikloalkil, heterosiklil ve heteroaril grubu istege bagli olarak en fazla üç F atomu, en fazla iki Ciaalkil grubu, bir C3-(,sikloalkil grubu, en fazla iki C0-2a1kil-ORAlb grubu, bir C0_2alkil-N(R^'b)2 grubu, bir SCi-4alkil grubu, bir C(0)R^'b grubu, bir C(O)OR^'b grubu, bir C(O)N(R^'b)2 grubu veya bir -CN grubuyla sübstitüe edilir; her RA'b bagimsiz bir sekilde hidrojen, C1_2alkil veya C3-4sikloalkildir; C0.2alkil-C(O)-(4-6 üyeli)heterosik1ildir, burada sözü edilen her heterosiklil oksetanil, tetrahidropiranil, tetrahidrofuranil, dioksanil, dioksolanil, azetidinil, pirolidinil, pirolidinonil, pirolidindionil, morfolinil, piperidinil, piperazinil, piperazinonil ve 1,1- dioksotietanil arasindan seçilir ve hidrojen disinda sözü edilen her RA2 grubu istege bagli olarak en fazla üç F atomu, en fazla iki Ci_2alki1 grubu, bir C3_6sikloalkil grubu, bir alkenil- grubu, bir SCi-4alkil grubu, bir S(O)2Ci-4alkil grubu, bir (:(0)R^2b grubu, bir C(O)ORA2b grubu, bir C(O)N(RA2b)2 grubu veya bir -CN grubuyla sübstitüe edilir; her RA281 bagimsiz bir sekilde, hidrojen, C1_4alkil, imidazolil, triazolil, tetrazolil, pirazolil, tiofenil, tiazolil, piridinil, pirimidinil ve pirazinil arasindan seçilen bir C5_6heteroarildir veya iki RM& ve araya giren bir azot atomu aziridiiiil, azetidinil, pirolidinil, pirolidinonil, piperidinil, piperidinonil, tetrahidropiridinil, piperazinil ve morfolinil arasindan seçilen 3-6 üyeli bir heterosiklik halka olusturur; her R^2b, bagimsiz bir sekilde, hidrojen, Ci-4alki1 veya C3-4sik10a1kildir; RA3 hidrojen veya C1_2alkildir; her RM, bagimsiz bir sekilde, döteryum, halojen, CN, C1-4alkil veya OC1-4alkildir, burada her RA4 alkil istege bagli olarak en fazla 3 F atomu, ikiz olmayan iki OH grubu veya bir OCi-2alkille sübstitüe edilir veya iki RA4 araya giren bir doymus karbon atomuyla birlikte spiroyla bagli bir siklopropil veya siklobütil halkasi olusturur; Halka B asagidakiler arasindan seçilen bir halka sistemidir: GÜRBBU 0 N RB3 OÜ Rss o YRes RB4 /N KN heterosiklil halkasi (burada sözü edilen heterosiklik halka oksetanil, tetrahidrofuranil, tetrahidropiranil, dioksanil, dioksolanil ve pirolidinonil arasindan seçilir), fenil, benzil veya (CH2)1-2(5-6 üyeli)heter0ari1 halkasidir (burada sözü edilen heteroaril halkasi piridinil, imidazolil ve pirazolil arasindan seçilir) ve burada sözü edilen her RBl alkil, sikloalkil, fenil, benzil, heterosiklil ve heteroaril grubu istege bagli olarak en fazla 3 F atomu, en fazla iki Ci_2alkil grubu, ikiz olmayan iki OH grubu veya bir OCi-galkille sübstitüe edilir; RB2 hidrojen, Ci.4alki1 veya OCi_4alkildir; her RB3 bagimsiz bir sekilde, hidrojen, halojen, Ci_4alkil, C2_4alkenil, C2-4alkinil, CN, C(O)NH(CHNHCHztetrahidrofuranil, C(O)NHCHgtetrahidropiranil, C(O)Nernil, C(O)NHbenzi1, C(O)NHOH, C(O)NHOC0.loksetanil, C(O)NHO(CHNHOfenil, C(O)NHObenzil, NHz, NHC(O)C1.4alkil, OC1-4alkil, SC1.4alkil, S(O)Ci-4a1kil veya furanil, tiofenil, imidazolil, pirol, pirazolil ve oksadiazolil arasindan seçilen 5 üyeli heteroaril halkasidir, burada hidrojen veya halojen disinda her RB3 grubu istege bagli olarak C1, en fazla üç F atomu, ikiz olmayan en fazla iki OH grubu, en fazla iki OCi_2alkil, bir NH2, bir NHCi_2alkil, bir NHC(O)Ci_2alkil veya bir N(Ci_2alkil)2,yle sübstitüe edilir; her RB4 bagimsiz bir sekilde, hidrojen, halojen, C1.4alkil, OC1.4alkil, SC1.4alkil, NHZ, C(O)NHC1,4alkil, C(O)N(Ci,4alkil)2, CN, bir morfolinil halkasi veya bir imidazolil halkasidir, burada her RB4 alkil istege bagli olarak en fazla 3 F atomu, ikiz olmayan iki OH grubu veya bir OC1-2alkille sübstitüe edilir; RBS hidrojen, C1-4alkil, C(O)C1-4alkil, C(O)OC1-4alkil, C(O)NH2, C(O)NHC1-4alkil veya C(O)N(Ci-4alkil)2,dir, burada sözü edilen RBS alkil istege bagli olarak en fazla 3 F atomu, ikiz olmayan iki OH grubu veya bir OCi-2alkille sübstitüe edilir ve RB6 F veya Ci-2alkildir veya iki RM` ve araya giren bir karbon atomu bir spirosiklopropil veya spirosiklobütil halkasi olusturur; burada “alkil” veya “alkil grubu” terimi, tamamen doymus olan düz Zincirli (yani dallanmamis) veya dallanmis, sübstitüe edilmis veya edilmemis bir hidrokarbon zincirini belirtmektedir; ve “alkoksi” ve “tioalkil” terimleri, ana karbon zincirine sirasiyla bir oksijen veya kükürt vasitasiyla baglanan bir alkil grubunu belirtir; ve “heterosikl”, “heterosiklil”, “heterosikloalkil” veya “heterosiklik” terimi burada, sistemdeki en az bir halkanin ayni veya farkli olan bir veya daha fazla heteroatom içerdigi ve tamamen doymus olan veya bir veya daha fazla doymamislik birimi içeren, ama aromatik olmayan ve molekülün geri kalanina tek bir baglanti noktasina sahip olan monosiklik, bisiklik veya trisiklik bir halka sistemini belirtmek için kullanilmaktadir.
2. Istem lse uygun bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu olup, asagidaki formülü haizdir:
3. lstem Ve uygun bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu olup, asagidaki formülü haizdir: burada RAl Ci-4alkil, OCi-4alkil veya N(RAla)2'dir, burada her RAla bagimsiz bir sekilde, hidrojen veya C1_4alkildir veya iki RAM ve araya giren bir azot atomu aziridinil, azetidinil, pirolidinil, pirolidinonil, piperidinil, piperidinonil, tetrahidropiridinil, piperazinil ve morfolinil arasindan seçilen 3-6 üyeli bir heterosiklik halka olusturur, burada sözü edilen her RAl alkil ve heterosiklil grubu istege bagli olarak en fazla üç F atomu, en fazla üç 2H atomu, en fazla iki Cmalkil grubu, bir C3-6sikloalkil grubu, en fazla iki C0-2alkil-ORAlb 5 grubu, bir C0-2alkil-N(RA'b)2 grubu, bir SCi-4alkil grubu, bir C(O)RA"° grubu, bir C(O)ORA'bgrubu, bir C(O)N(RA]b)2 grubu veya bir -CN grubuyla sübstitüe edilir, burada RA'b, bagimsiz bir sekilde, hidrojen, Ci.2alki1 veya C3_4sikloalkildir.
4. Istem lle uygun bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu olup, asagidaki formülü haizdir: (14.45)` RA2 (LA-30)` RA2` (LA-31)` /m mN/ ý(RA4)n NA2 l / ) k\Q N/ (RA4)n W N 1R | (l-A-SÜ), veya RA?” (l-A-Sl),
5. Istem l”e uygun bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu olup, asagidaki formülü haizdir: (l-B-l l. (Hi-2). iI-B~3). 0.849!. 2,l0 mn RB4 N R33 RB4 RB4 RB4 `N R8 Rss lN/ÄQ lkNýk® NJso NL`O lI-B-JI I. (FB-32). (HI-33). HNNER:: H WWRM
6. Istem 1 ila 5,in herhangi birine uygun bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu olup, burada ve R1 CH3°tür.
7. istem 1-6”nin herhangi birine uygun bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu olup, burada Q CH”dir.
8. Istem 1-7°nin herhangi birine uygun bilesik veya bunun farmasötik olarak kabul 10 edilebilir bir tuzu olup, burada Halka A bir heterosiklil veya heteroaril halkasi içerir.
9. Istem l-8”in herhangi birine uygun bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu olup, burada Halka A = örnegin, örnegin burada burada sözü edilen her heterosiklil oksetan-Z-il, azetidin-Z-il, piperidin-4-il ve 1,1- dioksotietan-Z-il arasindan seçilir ve sözü edilen her RA2 grubu istege bagli olarak en fazla üç F atomu, en fazla iki Cmalkil grubu, en fazla iki ORAN“ grubu, bir C0-2alkil-N(RA2b)2 grubu, bir C(O)RA2b grubu, bir C(2 grubu veya bir -CN grubu arasindan seçilir; her RAza, bagimsiz bir sekilde, H veya C1_4alkildir veya iki RM“ ve araya giren bir azot atomu aziridinil, azetidinil, pirolidinil, pirolidinonil, piperidinil, piperidinonil, tetrahidropiridinil, piperazinil ve morfolinil arasindan seçilen 3-6 üyeli bir heterosiklik halka olusturur; her RAZb, bagimsiz bir sekilde, H veya C1-4alkildir; ve
10. Istem 8'e uygun bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu olup, burada Halka A = 04 (RA4)n u" \ O. (RM)n örnegin burada burada sözü edilen her heterosiklil oksetan-Z-il, azetidin-Z-il, piperidin-4-il ve 1,1- dioksietan-Z-il arasindan seçilir ve sözü edilen her RA2 grubu istege bagli olarak en fazla üç F atomu, en fazla iki C2 grubu, bir C(O)R^2b grubu, bir (:(0)0RA2b grubu, bir C(O)N(R^2b)2 grubu veya bir -CN grubuyla sübstitüe edilir; her RM&l bagimsiz bir sekilde, H, Ci-4alkildir veya iki RA2a ve araya giren bir azot atomu aziridinil, azetidinil, pirolidinil, pirolidinonil, piperidinil, piperidinonil, tetrahidropiridinil, piperazinil ve morfolinil arasindan seçilen 3-6 üyeli bir heterosiklik halka olusturur; her RAZb bagimsiz bir sekilde, H veya Ci-4alkildir; ve
11. Istem 8,e uygun bilesik veya bunun famlasötik olarak kabul edilebilir bir tuzu olup, burada Halka A = Lßxmmjn /N(R^4)n l N/J`RA1 veya l NAR/`1 ; örnegin burada RA' C.-4alki1, C2 veya N(R^lb)C2.4alkil-N(R^la)2”dir, burada sözü edilen her RAl alkil ve sikloalkil istege bagli olarak en fazla üç F atomu, en fazla üç 2H atomu veya en fazla iki C0,2alkil-ORA1b grubuyla sübstitüe edilir; her RAla bagimsiz bir sekilde, hidrojen veya Cj_4alkildir veya RAla ve araya giren bir azot atomu aziridinil, azetidinil, pirolidinil, pirolidinonil, piperidinil, piperidinonil, tetrahidropiridinil, piperazinil ve morfolinil arasindan seçilen 3-6 üyeli bir heterosiklik halka olusturur, burada RA”, nin sözü edilen her alkil ve heterosiklil grubu istege bagli olarak en fazla üç F atomu, en fazla iki Cj-2alkil grubu, en fazla iki ORAlb grubu veya bir her RAib bagimsiz bir sekilde, hidrojen veya Cj-2alki1dir; her RA4 bagimsiz bir sekilde, halojen, 2n, Cj-4alki1 veya OCj-4a1kildir, burada her R^4 alkil istege bagli olarak en fazla 3 F atomu, ikiz olmayan iki OH grubu veya OCHalkille sübstitüe edilir; ve
12. Istem 8?e uygun bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu olup, burada Halka A = her RA4 bagimsiz bir sekilde, halojen, Cj-4alkil veya OCj-4alkildir, burada her RA4 alkil istege bagli olarak en fazla 3 F atomu, ikiz olmayan iki OH grubu veya OCj-2alkille sübstitüe edilir ve burada 11 0-2ldir.
13. Istem 7,ye uygun bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu olup, burada Halka B bir heterosiklil veya heteroaril halkasi içerir.
14. Istem 139e uygun bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu olup, burada Halka B : OtR°°Iu 1 (R b.` (R )O_2F\^N'RBS örnegin, (RBG)0_2r\/\N'RBS her RB3 ve RB4, bagimsiz bir sekilde, hidrojen, halojen veya Ci-4alkildir, burada sözü edilen her RB3 ve RB4 alkil istege bagli olarak en fazla 3 F atomu, ikiz olmayan iki OH grubu veya bir OC1-2alkille sübstitüe edilir; RB5 hidrojen, CMalkil, C(O)C1,4alkil, C(O)OC1,4alkil, C(O)NH2, C(O)NHC1,4a1kil veya C(O)N(C1-4alkil)2,dir burada sözü edilen RBS alkil istege bagli olarak en fazla 3 F atomu, ikiz olmayan iki OH grubu veya OCi_2alkille sübstitüe edilir; ve R136 F veya C1-2alkildir veya iki RBß ve araya giren bir karbon atomu bir spirosiklopropil veya spirosiklobütil halkasi olusturur; veya b) Halka B = burada R133 C(O)NHC1-4 alkildir, burada sözü edilen alkil istege bagli olarak en fazla üç F atomu, ikiz olmayan en fazla iki OH grubu veya en fazla iki OC1-2alkille sübstitüe edilir; 5 her RB4, bagimsiz bir sekilde, hidrojen, döteryum, halojen, Ci-4alkil veya OCi-4alki1dir, burada RB4 alkil istege bagli olarak en fazla 3 F atomu, ikiz olmayan iki OH grubu veya OCi_2alkille sübstitüe edilir; örnegin burada Halka A = N RAl veya N RA1 , burada sözü edilen heterosiklik halka sistemi oksetanil, tetrahidrofuranil, tetrahidropiranil ve morfolinil arasindan seçilir ve sözü edilen alkil, sikloalkil ve heterosiklilin her biri istege bagli olarak en fazla üç F atomu, en fazla üç 2H atomu veya en fazla iki OC1-2alkille sübstitüe edilir; 15 her RM, bagimsiz bir sekilde, F, 2H veya OC1.4a1ki1dir; ve
15. Asagidaki formülü haiz bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu RB4 RB3 20 burada X N veya CRA57tir; RA' P, Ci-4alkil, C3-ssikloalkil, OCi-4alkil, OC]_4alkil-C3_5sikloalkil, NHZ, NHCi-4alkil, NHC1,4alkil-C3,5sikloalkil veya C0,4alkil-heterosiklildir, burada sözü edilen heterosiklik halka sistemi oksetanil, tetrahidrofuranil, tetrahidropiranil ve morfolinil arasindan seçilir ve sözü edilen alkil, sikloalkil ve heterosiklilin her biri istege bagli olarak en fazla üç F atomu, en fazla üç 2H atomu, ikiz olmayan en fazla iki OH grubu veya en fazla iki her RM, bagimsiz bir sekilde, H veya 2H”dir; RA5 hidrojen, F, Ci-4alkil veya OCi-4alkildir, burada sözü edilen her alkil istege bagli olarak en fazla üç F atomu veya en fazla üç 2H atomuyla sübstitüe edilir; RB3 C(O)NHC1_4 alkildir, burada sözü edilen alkil istege bagli olarak en fazla üç F atomu, en fazla üç 2H atomu, ikiz olmayan en fazla iki OH grubu veya en fazla iki OC 1-2alkille sübstitüe edilir; ve her RB4, bagimsiz bir sekilde, hidrojen, döteryum, F veya C1-4alkildir.
16. Istem l'e uygun bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu olup, X N veya CRA5 StIr; NHC0-4alkil-C3.5sik10alkil veya C0.4alkil-heterosiklildir, burada sözü edilen heterosiklik halka sistemi oksetanil, tetrahidrofuranil, tetrahidropiranil ve morfolinil arasindan seçilir ve sözü edilen alkil, sikloalkil ve heterosiklilin her biri istege bagli olarak en fazla üç F atomu, en fazla üç 2H atomu, ikiz olmayan en fazla iki OH grubu veya en fazla iki her RM, bagimsiz bir sekilde, H veya 2H'dir; R^5 hidrojen, F, C1_4alkil veya OC1-4alkildir, burada sözü edilen her alkil istege bagli olarak, en fazla üç F atomu veya en fazla üç 2H atomuyla sübstitüe edilir; RB3 C(O)NHC1-4 alkildir, burada sözü edilen alkil istege bagli olarak en fazla üç F atomu, en fazla üç 2H atomu, ikiz olmayan en fazla iki OH grubu veya en fazla iki OCi_2alkille sübstitüe edilir; ve her RB4, bagimsiz bir sekilde, hidrojen, döteryum, F veya C1-4alkildir.
17. Istem lie uygun bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu olup, burada bilesik asagidaki formülü haizdir: CH3 çH3 10 11 12 3:) «Jû F 1 6 m { 3 / \ 4. IN MÖ sim. I 261 262 263 H 1\/.I 355 356 357 3 3 *e 3 .N \ /N N \ /N m.. \I\N W nxN 0 Cl/ "mu 0 J m. /NirHv W \I\N N \ ,N um Ni m6 5 6% I 081% I
1. 3 &J
18. Istem lse uygun bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu olup, burada bilesik asagidaki formülü haizdir:
20. Istem l,e uygun bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu olup, burada bilesik asagidaki formülü haizdir:
21. Istem l-20inin herhangi birine uygun bir bilesigi veya bunun farmasötik olarak kabul edilebilir bir tuzunu ve farmasötik olarak kabul edilebilir bir eksipiyan içeren bir farmasötik bilesim.
22. Bir hastada kanser tedavisinde kullanim için istem 1-203nin herhangi birine uygun bir bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu veya sözü edilen bilesigi veya farmasötik olarak kabul edilebilir tuzunu içeren bir farmasötik bilesim.
23. Bir hücrenin bir DNA lezyonuna yol açan bir maddeye duyarli hale getirilmesinde kullanim için, istem l-20°nin herhangi birine uygun bir bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu veya sözü edilen bilesigi veya farmasötik olarak kabul edilebilir tuzunu içeren bir farmasötik bilesim olup, kullanim hücrenin sözü edilen bilesikle temas ettirilmesi asamasini içerir.
24. Bir hastada kanser tedavisi için terapötik bir rejimin güçlendirilmesinde kullaniin için istem l-20'nin herhangi birine uygun bir bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu veya sözü edilen bilesigi veya farmasötik olarak kabul edilebilir tuzunu
25. Istem 23,e uygun kullanim için istem l-20inin herhangi birine uygun bir bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu veya sözü edilen bilesigi veya farmasötik olarak kabul edilebilir tuzunu içeren bir farmasötik bilesim olup, burada bir DNA lezyonuna yol açan madde radyasyon terapisi veya kansere karsi bir kemoterapötik maddedir.
26. Istem 24”e uygun kullanim için istem 1-207nin herhangi birine uygun bir bilesik veya bunun farmasötik olarak kabul edilebilir bir tuzu veya sözü edilen bilesigi veya farmasötik olarak kabul edilebilir tuzunu içeren bir farmasötik bilesim olup, burada terapötik rejim radyasyon terapisini veya kansere karsi bir kemoterapötik maddeyi içerir.
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