Patent Application
20220185793
The pesent invention relates to compounds of formula (I)
pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof and their use for the prevention and treatment of oncovirus induced cancer in a subject.
Cancer is the leading cause of death. About 14 million new cases of cancers are diagnosed every year and leading to 8.8 million cancer related deaths. In addition to genetic and environmental factors, oncoviruses are known to account for about 12-15% of all human cancers. Due to a complex molecular interplay between virus and their host, lack of appropriate preclinical animal models the management of virus-induced cancers remains a high unmet medical need.
There are at least seven oncoviruses known to cause human cancers. The list includes Epstein Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), Human papillomavirus (HPV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human T Cell lymphotrophic virus type 1 (HTLV-1) and Human Immunodeficiency Virus (HIV). Oncoviruses trigger oncogenic transformation of normal cells by hijacking cellular mitogenic pathway as well as evading host immune surveillance (Mesri E A, Feitelson M A, Munger K. 2014. Human viral oncogenesis: A cancer hallmarks analysis. Cell Host & Microbe 15: 266-282).
Common malignancies associated with oncoviruses are as follows:
Epstein Barr Virus associated cancers:
EBV is a double stranded DNA virus and belongs to γ-herpesvirus family of viruses. EBV is primarily known to infect B cells, but in certain instances is also known to infect epithelial cells. Under certain conditions such as immune suppression, EBV viral genes get activated leading to oncogenic transformation of the infected host cells. EBV is associated with several lymphoid malignancies that include Burkitt lymphoma, and classical Hodgkin lymphoma. EBV is also linked with immunodeficiency-associated lymphoproliferative disorders such as post-transplant lymphoproliferative disorder (PTLD), non-Hodgkin lymphoma (NHL).
Examples of EBV associated epithelial tumors consist of Nasopharyngeal Carcinoma (NPC) and gastric tumors.
Kaposi's Sarcoma Herpesvirus (KSHV) driven cancers:
KSHV also known as human herpes virus 8 (HHV-8) also belongs to γ-herpesvirus family of viruses. KSHV is known to cause three main human cancers, namely Kaposi's Sarcoma (KS), Primary Effusion Lymphoma (PEL) and Multicentric Castleman's disease (MCD). All three cancers occur primarily in the context of immune deficiency and/or HIV infection (Dittmer D P, Damania B. 2016. Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy. The Journal of clinical investigation 126: 3165-3175).
Human Papillomavirus (HPV) associated cancers:
HPV is one of the leading causes of virus—induced cancers. This double stranded DNA virus predominantly infects epithelial cells and thereby is an established cause for cervical carcinomas, vulvar, vaginal and oral carcinomas (Mesri E A, Feitelson M A, Munger K. 2014. Human viral oncogenesis: A cancer hallmarks analysis. Cell Host & Microbe 15: 266-282). Hepatitis B and Hepatitis C virus (HBV and HCV) induced human carcinomas: HBV and HCV are major etiological agents for hepatocellular carcinomas (Mesri E A, Feitelson M A, Munger K. 2014. Human viral oncogenesis: A cancer hallmarks analysis. Cell Host & Microbe 15: 266-282).
Human T Cell Lymphotropic Virus-1 (HTLV-1): HTLV-1 is known to cause adult T-cell Leukemia (Mesri E A, Feitelson M A, Munger K. 2014. Human viral oncogenesis: A cancer hallmarks analysis. Cell Host & Microbe 15: 266-282).
Oncoviruses deploy a variety of mechanisms to trigger oncogenic transformation of infected cells. This includes hijacking and activation of cancer-causing cellular pathways, chronic inflammation and induction of genomic instability. Almost all of the oncoviruses are known to express oncogenic viral homologs of host proteins and thereby driving cell survival, proliferation and evasion of immune surveillance. Infection by HBV and HCV is known to cause chronic inflammation of the liver and thereby promote hepatocellular carcinomas (Mesri E A, Feitelson M A, Munger K. 2014. Human viral oncogenesis: A cancer hallmarks analysis. Cell Host & Microbe 15: 266-282).
Several therapeutic strategies have been developed to treat virus-induced human cancers. These can be broadly subdivided into two categories, 1) agents targeting viral oncogenes and 2) agents targeting host proteins. The development of prophylactic vaccine against HPV and several nucleoside analogs represent examples of anti-viral therapies. In addition, several drugs targeting cellular oncogenes have also been used to address virus-induced malignancies, such as inhibitors of PI3K/mTOR signaling, PDGFR, c-kit. However, treatment of oncovirus induced human cancers still poses a major challenge and there is a high need to develop novel therapeutic agents.
The present invention relates to compounds according to formula (I)
pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof,
wherein X is selected from CH2, CF2, CHF, CO, CHOH, CHO(C1-C3) alkyl, NH, N(C1-C3 alkyl), S, SO and O;
wherein Y1, Y2 and Y3 are each independently selected from N and C;
wherein Z is NR10R11;
wherein R10 is selected from H, C1-C6 alkyl, C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, OH, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)NR12R13; and
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, OH, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)NR12R13; wherein R1 is selected from H, halogen, COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl and norbornyl;
wherein R2 is selected from COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C2-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl, norbornyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl;
wherein R3 is selected from H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl;
wherein R4, R5 and R6 are each independently selected from H, OH, halogen, NH2, NO2, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, C1-C6-S-alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl;
wherein R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl when Y1 is C;
wherein R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl when Y3 is C;
wherein R9 is absent when Y2 is N or is selected from H, halogen, COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl and norbornyl when Y2 is C; and
wherein R12 and R13 are each independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl.
The present invention also relates to a pharmaceutical composition comprising the compounds of formula (I) and pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof and the compounds of formula (I) and pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof and pharmaceutical compositions thereof for use in a method for the prevention or treatment of oncovirus induced cancer in a subject. The present invention is useful in methods for preventing and treating oncovirus induced cancer.
The following are definitions of terms used in the present application. The initial definition provided for a group or term herein applies to that group or term throughout the description and the claims, individually or as part of another group, unless otherwise indicated.
The term “alkyl” as used herein refers to a saturated straight or branched chain group of carbon atoms derived from an alkane by the removal of one hydrogen atom. C1-C3 alkyl comprises for example methyl, ethyl, n-propyl, i-propyl. C1-C6 alkyl comprises for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, and n-hexyl. C3-C6 alkyl comprises for example n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl or n-hexyl. C2-C6 alkyl comprises for example ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, and n-hexyl.
The term “heteroalkyl” as used herein refers to an alkyl radical as defined herein wherein one, two, three or four hydrogen atoms have been replaced with a substituent independently selected from the group consisting of ORa, C(O)ORa, NRbRc, C(O)NRbRc, S(O)nRd (wherein n is an integer from 0 to 2) and halogen, with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom, wherein Ra is H, C1-C3 alkylcarbonyl, C1-C3 alkyl, or C3-7 cycloalkyl; Rb and Rc are each independently H, C1-C3 alkylcarbonyl, C1-C3 alkyl, or C3-7 cycloalkyl; and when n is 0, Rd is H, C1-C3 alkyl or C3-7 cycloalkyl, and when n is 1 or 2, Rd is C1-C3 alkyl or C3-7 cycloalkyl. Preferably. the term “heteroalkyl” as used herein refers to an alkyl radical or an alkanediyl radical as defined herein wherein one, two, three or four hydrogen atoms have been replaced with a substituent independently selected from the group consisting of OH, NH2 and halogen, more preferably selected from the group consisting of OH and NH2. Representative examples of C1-C6 heteroalkyl include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2-hydroxy-1-methylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 1-hydroxy-2-methylpropyl, 3-hydroxy-1-(2-hydroxyethyl)-propyl, 2-hydroxy-1-methylpropyl, 1,1,1-trifluoroethyl, 1,1,1-trifluoromethyl, 2,2,3,3-tetrafluoropropyl. Representative examples of C2-C6 heteroalkyl include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2-hydroxy-1-methylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 1-hydroxy-2-methylpropyl, 3-hydroxy-1-(2-hydroxyethyl)-propyl, 2-hydroxy-1-methylpropyl, 1,1,1-trifluoroethyl, 2,2,3,3-tetrafluoropropyl.
The term “C1-C3 cyanoalkyl” as used herein refers to an alkyl radical as defined herein wherein one, two or three hydrogen atoms have been replaced with a CN group. C1-C3 cyanoalkyl is preferably cyanomethyl.
The term “C2-C6 alkenyl” as used herein refers to straight or branched chain hydrocarbon groups having 2 to 10 carbon atoms and at least one double bond.
The term “C2-C6 alkynyl” as used herein refers to straight or branched chain hydrocarbon groups having 2 to10 carbon atoms and at least one triple bond.
The term “C3-C12 cycloalkyl ” as used herein refers to a monovalent saturated monocyclic or bicyclic hydrocarbon group, preferably a monovalent saturated monocyclic goup of 3-12, preferably 3-7 carbons, respectively derived from a cycloalkane by the removal of a single hydrogen atom. A preferred C3-C12 cycloalkyl group is thus a “C3-C7 cycloalkyl” group which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term “C3-C12 cycloalkyl” and “C3-C7 cycloalkyl” “as used herein also includes cycloalkyl groups that comprise a C1-3 alkyl radical. Examples of such groups comprise cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, 2-cyclopentylethyl.
The term “C1-C6 alkoxy” as used herein refers to a radical —OR where R is a C1-C6 alkyl as defined herein. Examples are methoxy, ethoxy, propoxy, butoxy.
The term “C1-C6 alkylamino” as used herein refers to a radical —NRR′ where one of R and R′ represent a C1-C6 alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to methylamino, ethylamino.
The term “C1-C6 dialkylamino” as used herein refers to a radical —NRR′ where R and R′ independently represent a C1-C6 alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to dimethylamino, methylethylamino, di(1-methylethyl)amino, (methyl)(hydroxyethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino.
The term “C1-C3 alkanoyl” as used herein refers to a radical —CO—C1-C3 alkyl wherein the C1-C3 alkyl group is as defined herein.
The term “(C1-C6)alkyl carboxy” as used herein refers to a radical —RC(O)OH, wherein R is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is as defined herein.
The term “C1-C3 alkoxycarbonyl” as used herein refers to radicals —C(O)O C1-C3 alkyl, —C1-C3 alkyl C(O)O C1-C3 alkyl and —OC(O) C1-C3 alkyl and is preferably —C(O)O C1-C3 alkyl wherein the C1-C3 alkyl group is as defined herein.
The term “aryl” as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings, and is preferably a monocyclic carbocyclic ring system having one aromatic ring. The aryl group can also be fused to a cyclohexane, cyclohexene, cyclopentane, or cyclopentene ring or to a cyclohexane, cyclohexene, cyclopentane, or cyclopentene ring comprising a carbonyl group. The aryl groups of this invention can be optionally substituted as further described below. A preferred aryl group and optionally substituted aryl group, respectively of this invention is a phenyl group or substituted phenyl group. Substituents can be e.g. NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C10 heteroalkyl, halogen, CN, CF3, C3-C12 cycloalkyl, CHO, carbonyl(C1-C10 alkyl), C1-C3 alkoxycarbonyl, or (C1-C10 alkyl)carbonyl(C1-C10 alkyl). Preferably such aryl groups are unsubstituted unless otherwise indicated herein.
The term “heteroaryl” as used herein refers to substituted and unsubstituted aromatic 5-, or 6-membered monocyclic groups and 9- or 10-membered bicyclic groups, preferably a substituted and unsubstituted aromatic 5-, or 6- membered monocyclic group, which have at least one heteroatom (O, S or N), preferably one to four N or one to two N and one O, in at least one of the ring(s). Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic group may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. Heteroaryl groups must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. Heteroaryl groups of this invention can be optionally substituted as further described below. Usually, a heteroaryl group and optionally substituted heteroaryl group, respectively of this invention is selected from the group consisting of substituted and/or unsubstituted aromatic 5-, or 6-membered monocyclic groups, which have at least one heteroatom (O, S or N), preferably one to four N or one to two N and one O, in the ring. A preferred heteroaryl group is an optionally substituted heteroaryl group selected from the group consisting of an optionally substituted pyridinyl group, an optionally substituted pyrimidinyl group, an optionally substituted di- or triazole group, an optionally substituted thiazole group, an optionally substituted oxazole group, an optionally substituted oxadiazole group and an optionally substituted imidazole group. Most preferably an optionally substituted pyridinyl group, an optionally substituted pyrimidinyl group, an optionally substituted tetrazole, an optionally substituted oxadiazole group, and/or an optionally substituted imidazole group, is used as heteroaryl group in the present invention, or an optionally substituted pyridinyl group, an optionally substituted pyrimidinyl group, an optionally substituted thiazole, an optionally substituted oxazole group and/or an optionally substituted imidazole group . Substituents can be e.g. NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably NH2. Preferably such heteroaryl groups are unsubstituted unless otherwise indicated herein.
The term “C3-C12 heterocyclyl” as used herein means a saturated, monocyclic ring with 3 to 12, preferably 5 to 6 ring atoms which contains up to 3, preferably 1 or 2 heteroatoms selected independently from nitrogen, oxygen or sulfur, and wherein the remaining ring atoms being carbon atoms. Examples of such saturated heterocycles include [1,3]dioxanyl, [1,3]dioxolanyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, oxazolidinyl, thiazolidinyl, azepanyl and the like. Preferably such heterocyclyl groups are unsubstituted unless otherwise indicated herein.
The terms “halo” or “halogen” as used herein refers to F, Cl, Br, or I and is preferably F, Cl, or Br, more preferably F.
The term ‘optionally substituted’ or ‘substituted’ means that the referenced group is substituted with one or more additional group(s), preferably with one additional group, individually and independently selected from the listed groups.
In one aspect the present invention provides compounds according to formula (I)
pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof,
wherein X is selected from CH2, CF2, CHF, CO, CHOH, CHO(C1-C3) alkyl, NH, N(C1-C3 alkyl), S, SO and O;
wherein Y1, Y2 and Y3 are each independently selected from N and C;
wherein Z is NR10R11;
wherein R10 is selected from H, C1-C6 alkyl, C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, OH, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)NR12R13; and
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, OH, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)NR12R13; wherein R1 is selected from H, halogen, COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl and norbornyl;
wherein R2 is selected from COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C2-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl, norbornyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl;
wherein R3 is selected from H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl;
wherein R4, R5 and R6 are each independently selected from H, OH, halogen, NH2, NO2, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl;
wherein R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl when Y1 is C;
wherein R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl when Y3 is C;
wherein R9 is absent when Y2 is N or is selected from H, halogen, COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl and norbornyl when Y2 is C; and
wherein R12 and R13 are each independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl.
In a further aspect the present invention provides a pharmaceutical composition comprising compounds of formula (I)
pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof,
wherein X is selected from CH2, CF2, CHF, CO, CHOH, CHO(C1-C3) alkyl, NH, N(C1-C3 alkyl), S, SO and O;
wherein Y1, Y2 and Y3 are each independently selected from N and C;
wherein Z is NR10R11;
wherein R10 is selected from H, C1-C6 alkyl, C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, OH, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)NR12R13; and
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, OH, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)NR12R13; wherein R1 is selected from H, halogen, COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl and norbornyl;
wherein R2 is selected from COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C2-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl, norbornyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl;
wherein R3 is selected from H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl;
wherein R4, R5 and R6 are each independently selected from H, OH, halogen, NH2, NO2, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl;
wherein R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl when Y1 is C;
wherein R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl when Y3 is C;
wherein R9 is absent when Y2 is N or is selected from H, halogen, COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl and norbornyl when Y2 is C;
wherein R12 and R13 are each independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl, and a pharmaceutically acceptable carrier.
In a further aspect the present invention provides compounds according to formula (I)
pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof,
wherein X is selected from CH2, CF2, CHF, CO, CHOH, CHO(C1-C3) alkyl, NH, N(C1-C3 alkyl), S, SO and O;
wherein Y1, Y2 and Y3 are each independently selected from N and C;
wherein Z is NR10R11;
wherein R10 is selected from H, C1-C6 alkyl, C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, OH, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)NR12R13; and
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, OH, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)NR12R13;
wherein R1 is selected from H, halogen, COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13; C(O)NR12R13; C1-C6 alkyl-C(O)NR12R13; C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl and norbornyl;
wherein R2 is selected from H, halogen, COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13; C(O)NR12R13; C1-C6 alkyl-C(O)NR12R13; C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl, norbornyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl;
wherein R3 is selected from H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl;
wherein R4, R5 and R6 are each independently selected from H, OH, halogen, NH2, NO2, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl;
wherein R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl when Y1 is C;
wherein R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl when Y3 is C;
wherein R9 is absent when Y2 is N or is selected from H, halogen, COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl and norbornyl when Y2 is C; and
wherein R12 and R13 are each independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl for use in a method for the prevention or treatment of oncovirus induced cancer in a subject.
The following embodiments, preferred embodiments and very preferred embodiments should apply without the need of repetition to all aspects and other embodiments.
In one embodiment X is selected from CH2, CF2, CHF, CHOH, CHO(C1-C3) alkyl and CO.
In a further embodiment X is selected from NH, N(C1-C3-alkyl), S and O. In a further embodiment X is selected from CH2, CF2, CHF, NH, N(C1-C3-alkyl), S and O.
In a preferred embodiment X is selected from CH2, NH and O. In a more preferred embodiment X is selected from NH and O. In a particular embodiment X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O. In a more particular embodiment X is selected from CH2, CHOH, CHO(C1-C3) alkyl, and O, more particular X is selected from CH2, CHOH, CHOCH3, and O. In an even more particular preferred embodiment X is O.
In one embodiment Y1, Y2 and Y3 are each C. In a further embodiment Y1, Y2 and Y3 are each N. In a further embodiment Y1 is C, Y2 is selected from N and C and Y3 is C. In a further embodiment Y1 and Y2 are each C and Y3 is selected from N and C. In a further embodiment Y1 and Y2 are each independently selected from N and C and Y3 is C. In a further embodiment Y1 and Y2 are each independently selected from N and C and Y3 is N. In a further embodiment Y1 and Y3 are each independently selected from N and C and Y2 is C. In a further embodiment Y1 and Y3 are each independently selected from N and C and Y2 is N.
In a further embodiment Y2 and Y3 are each independently selected from N and C and Y1 is C. In a further embodiment Y2 and Y3 are each independently selected from N and C and Y1 is N. In a preferred embodiment Y1 is N or C and Y2 and Y3 are each C. In a more preferred embodiment Y1 is N and Y2 and Y3 are each C. In an even more preferred embodiment Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C.
In one embodiment R1 is selected from C3-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl and norbornyl. In a further embodiment R1 is selected from C3-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, and C3-C12 heterocyclyl. In a further embodiment R1 is selected from C3-C6 alkyl, C3-C6 heteroalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C12 cycloalkyl, and C3-C12 heterocyclyl. In a further embodiment R1 is selected from C4-C6 alkyl, C4-C6 heteroalkyl, C4-C6 alkenyl. C4-C6 alkynyl.
In a preferred embodiment Rlis selected from H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl and C1-C6 alkoxy. In a further preferred embodiment R1 is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH. In a more preferred embodiment R1 is selected from H, halogen, C1-C6 alkyl, C3-C12 cycloalkyl and C1-C6 alkoxy.
In an even more preferred embodiment R1 is selected from H, halogen and C1-C6 alkyl. In a particular preferred embodiment R1 is selected from H, halogen and methyl. In a particular preferred embodiment R1 is selected from H and C1-C6 alkyl, more particular R1 is selected from H and methyl. In an even more particular preferred embodiment R1 is H.
In one embodiment R2 is selected from COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C2-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl, norbornyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl.
In a further embodiment R2 is selected from COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1 or 2, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl, norbornyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl. In a further embodiment R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, CN, halogen, C3-C12 cycloalkyl ,C3-C12 heterocyclyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen.
In a further embodiment R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, CN, halogen, C3-C12 cycloalkyl ,C3-C12 heterocyclyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen. In a preferred embodiment R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen.
In a further preferred embodiment R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen.
In a further preferred embodiment R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are preferably selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl, imidazolyl and thiadiazolyl optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen.
In further preferred embodiment R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are preferably selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl, imidazolyl and thiadiazolyl optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen.
In a further preferred embodiment R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are preferably selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen.In further preferred embodiment R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are preferably selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen.
In a more preferred embodiment R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl. In a further more preferred embodiment R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl and C2-C6 alkynyl. In an even more preferred embodiment R2 is selected from C2-C6 alkyl and C2-C6 heteroalkyl. In an even more preferred embodiment R2 is selected from C2-C6 alkyl and C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2. In a further even preferred embodiment R2 is C2-C6 alkyl, particularly C3-C6 alkyl, most particular tert-butyl.
In a further more preferred embodiment R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by C1-C6 alkyl, halogen, even more preferably by methyl, halogen.
In a further more preferred embodiment R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by C1-C6 alkyl, halogen, even more preferably by methyl, halogen.
In a further even more preferred embodiment R2 is selected from C2-C6 alkyl, C3-C12 cycloalkyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, preferably optionally substituted by C1-C6 alkyl, halogen, more preferably by methyl, halogen.
In a particular embodiment R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are selected from phenyl, pyridyl and thiazolyl, and wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl preferably optionally substituted by C1-C6 alkyl, halogen, more preferably by methyl, halogen.
In a further preferred embodiment R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are selected from phenyl, pyridyl and thiazolyl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by C1-C6 alkyl, halogen, even more preferably by methyl, halogen.
In a further even more preferred embodiment R2 is selected from C2-C6 alkyl, C6 cycloalkyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are selected from phenyl, pyridyl and thiazolyl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, preferably optionally substituted by C1-C6 alkyl, halogen, more preferably by methyl, halogen.
In further embodiment R2 is selected from C3-C6 alkyl, C3-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, CN, halogen, C3-C12 cycloalkyl ,C3-C12 heterocyclyl.
In further embodiment R2 is selected from C3-C6 alkyl, C3-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, CN, halogen, C3-C12 cycloalkyl ,C3-C12 heterocyclyl.
In further embodiment R2 is selected from C3-C6 alkyl, C3-C6 heteroalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are preferably selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl, imidazolyl and thiadiazolyl optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen.
In further embodiment R2 is selected from C3-C6 alkyl, C3-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C3-C6 alkenyl, C3-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are preferably selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl, imidazolyl and thiadiazolyl optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen.
In further embodiment R2 is selected from C3-C6 alkyl, C3-C6 heteroalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are preferably selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen.
In further embodiment R2 is selected from C3-C6 alkyl, C3-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C3-C6 alkenyl, C3-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are preferably selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen. In a further preferred embodiment R2 is selected from C3-C6 alkyl, C3-C6 heteroalkyl, C3-C6 alkenyl, C3-C6 alkynyl. In a further preferred embodiment R2 is selected from C3-C6 alkyl, C3-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C3-C6 alkenyl, C3-C6 alkynyl.
In a further preferred embodiment R2 is selected from C3-C6 alkyl, C3-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by C1-C6 alkyl, halogen, even more preferably by methyl, halogen.
In a further preferred embodiment R2 is selected from C3-C6 alkyl, C3-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by C1-C6 alkyl, halogen, even more preferably by methyl, halogen.
In a further even more preferred embodiment R2 is selected from C3-C6 alkyl, C3-C12 cycloalkyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, preferably optionally substituted by C1-C6 alkyl, halogen, more preferably by methyl, halogen.
In a particular embodiment R2 is selected from C3-C6 alkyl, C3-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are selected from phenyl, pyridyl and thiazolyl, and wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably optionally substituted by C1-C6 alkyl, halogen, more preferably by methyl, halogen.
In a further preferred embodiment R2 is selected from C3-C6 alkyl, C3-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are selected from phenyl, pyridyl and thiazolyl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by C1-C6 alkyl, halogen, even more preferably by methyl, halogen.
In a further even more preferred embodiment R2 is selected from C3-C6 alkyl, C6 cycloalkyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are selected from phenyl, pyridyl and thiazolyl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, preferably optionally substituted by C1-C6 alkyl, halogen, more preferably by methyl, halogen.
In one embodiment R3 is selected from H, halogen, C1-C6 alkyl and C1-C6 heteroalkyl. In a preferred embodiment R3 is selected from H, halogen and C1-C6 alkyl. In a more preferred embodiment R3 is selected from H and halogen. In an even more preferred embodiment R3 is H.
In one embodiment R4, R5 and R6 are each independently selected from H, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl. In a preferred embodiment R4, R5 and R6 are each independently selected from H, halogen, C1-C6 alkoxy and C1-C6 alkyl.
In a more preferred mbodiment R4, R5 and R6 are each independently selected from H, halogen, and C1-C6 alkyl. In an even more preferred embodiment R4, R5 and R6 are each independently selected from H and halogen and are preferably H. In a particular embodiment R4 is selected from H and halogen, and/ or R5 is selected from H and C1-C6 alkyl and/or R6 is selected from H and C1-C6 alkyl. In a more particular embodiment R4 is selected from H and halogen, and/ or R5 is selected from H and methyl and/or R6 is selected from H and methyl.
In one embodiment R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and C1-C6 heteroalkyl when Y1 is C. In a preferred embodiment R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C. In a more preferred embodiment R7 is absent when Y1 is N or is H when Y1 is C.
In one embodiment R8 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and C1-C6 heteroalkyl when Y3 is C. In a preferred embodiment R8 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y3 is C. In a more preferred embodiment R8 is absent when Y1 is N or is H when Y3 is C.
In one embodiment R9 is absent when Y2 is N or is selected from C3-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl and norbornyl when Y2 is C. In a further embodiment R9 is absent when Y2 is N or is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, and C3-C12 heterocyclyl when Y2 is C. In a further embodiment R9 is absent when Y2 is N or is selected from C3-C6 alkyl, C3-C6 heteroalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C12 cycloalkyl, and C3-C12 heterocyclyl when Y2 is C. In a further embodiment R9 is absent when Y2 is N or is selected from C4-C6 alkyl, C4-C6 heteroalkyl, C4-C6 alkenyl. C4-C6 alkynyl when Y2 is C. In a preferred embodiment R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl and C1-C6 alkoxy when Y2 is C. In a further preferred embodiment R9 is absent when Y2 is N or is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH when Y2 is C. In a more preferred embodiment R9 is absent when Y2 is N or is selected from H, halogen C1-C6 alkyl and C1-C6 heteroalkyl when Y2 is C. In a even more preferred embodiment R9 is absent when Y2 is N or is selected from H, halogen and methyl when Y2 is C. In a particular preferred embodiment R9 is absent when Y2 is N or is H when Y2 is C. In a more preferred embodiment Y1 is N and R7 is absent, Y2 and Y3 are each C and R9 and R8 are each H.
In one embodiment R19 is selected from H, C1-C6 alkyl. In a preferred embodiment R10 is H.
In one embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl, preferably is C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl, wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen. In a preferred embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by NH2.
In one embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by heteroaryl, preferably is C1-C6 alkyl substituted by heteroaryl, wherein the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by NH2.
In a further embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, 6 to 10-membered heteroaryl, C3-C12 heterocyclyl, preferably is C1-C6 alkyl substituted by aryl, 6 to 10-membered heteroaryl, C3-C12 heterocyclyl, wherein the aryl, the 6 to 10-membered heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a further embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, or C3-C12 heterocyclyl, wherein the heteroaryl is not 3H-imidazole-4-yl, preferably is C1-C6 alkyl substituted by aryl, heteroaryl, or C3-C12 heterocyclyl, wherein the heteroaryl is not 3H-imidazole-4-yl, and wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a further embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, or C3-C12 heterocyclyl, wherein the heteroaryl is not 3H-imidazole-4-yl and not 1H-imidazole-4-yl, preferably is C1-C6 alkyl substituted by aryl, heteroaryl, or C3-C12 heterocyclyl, wherein the heteroaryl is not 3H-imidazole-4-yl and not 1H-imidazole-4-yl, and wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a further embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl, wherein the heteroaryl is not imidazolyl, preferably is C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl, wherein the heteroaryl is not imidazolyl and wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12-R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a preferred embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or 6 to 10-membered heteroaryl, preferably is C1-C6 alkyl substituted by aryl or 6 to 10-membered heteroaryl, wherein the aryl and the 6 to 10-membered heteroaryl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a further preferred embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the heteroaryl is not 3H-imidazole-4-yl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl, wherein the heteroaryl is not 3H-imidazole-4-yl, and wherein the aryl and the heteroaryl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a further preferred embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the heteroaryl is not 3H-imidazole-4-yl and not 1H-imidazole-4-yl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl, wherein the heteroaryl is not 3H-imidazole-4-yl and not 1H-imidazole-4-yl, and wherein the aryl and the heteroaryl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a further preferred embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the heteroaryl is not imidazolyl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl, wherein the heteroaryl is not imidazolyl and wherein the aryl and the heteroaryl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In one embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by 6 to 10-membered heteroaryl, preferably is C1-C6 alkyl substituted by 6 to 10-membered heteroaryl, wherein the 6 to 10-membered heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl , more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a further embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by heteroaryl, wherein the heteroaryl is not 3H-imidazole-4-yl, preferably is C1-C6 alkyl substituted by heteroaryl, wherein the heteroaryl is not 3H-imidazole-4-yl, and wherein the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a further embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by heteroaryl, wherein the heteroaryl is not 3H-imidazole-4-yl and not 1H-imidazole-4-yl, preferably is C1-C6 alkyl substituted by heteroaryl, wherein the heteroaryl is not 3H-imidazole-4-yl and not 1H-imidazole-4-yl, and wherein the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a further embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by heteroaryl, wherein the heteroaryl is not imidazolyl, preferably is C1-C6 alkyl substituted by heteroaryl, wherein the heteroaryl is not imidazolyl and wherein the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a preferred embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl, wherein the heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl, preferably selected from from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl, and the aryl is phenyl, wherein the aryl and the heteroaryl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a further preferred embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl, wherein the heteroaryl is selected from pyridyl, pyrimidinyl, oxadiazolyl, imidazolyl and tetrazolyl, preferably selected from pyridyl, pyrimidinyl, oxadiazolyl, and tetrazolyl, and the aryl is phenyl, wherein the aryl and the heteroaryl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a further preferred embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by heteroaryl, preferably is C1-C6 alkyl substituted by heteroaryl, wherein the heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl, preferably selected from from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl, and
wherein the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a further preferred embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by heteroaryl, preferably is C1-C6 alkyl substituted by heteroaryl, wherein the heteroaryl is selected from pyridyl, pyrimidinyl, oxadiazolyl, imidazolyl and tetrazolyl, preferably selected from pyridyl, pyrimidinyl, oxadiazolyl, and tetrazolyl, and wherein the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a further preferred embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or 6 to 10-membered heteroaryl, preferably is C1-C6 alkyl substituted by aryl or 6 to 10-membered heteroaryl, wherein the heteroaryl is selected from pyridyl, pyridazinyl, and pyrimidinyl, preferably is selected from pyridyl and pyrimidinyl, and the aryl is phenyl , and wherein the aryl and the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a more preferred embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the heteroaryl is not 3H-imidazole-4-yl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl wherein the heteroaryl is not 3H-imidazole-4-yl, wherein the heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl, preferably selected from from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl, and the aryl is phenyl , and wherein the aryl and the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a more preferred embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the heteroaryl is not 3H-imidazole-4-yl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl wherein the heteroaryl is not 3H-imidazole-4-yl, wherein the heteroaryl is selected from pyridyl, pyrimidinyl, oxadiazolyl, imidazolyl and tetrazolyl, preferably selected from pyridyl, pyrimidinyl, oxadiazolyl, and tetrazolyl, and the aryl is phenyl , and wherein the aryl and the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a further more preferred embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the heteroaryl is not 3H-imidazole-4-yl and not 1H-imidazole-4-yl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl wherein the heteroaryl is not 3H-imidazole-4-yl and not 1H-imidazole-4-yl, wherein the heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl, preferably selected from from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl, and the aryl is phenyl, and wherein the aryl and the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a further more preferred embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the heteroaryl is not 3H-imidazole-4-yl and not 1H-imidazole-4-yl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl wherein the heteroaryl is not 3H-imidazole-4-yl and not 1H-imidazole-4-yl, wherein the heteroaryl is selected from pyridyl, pyrimidinyl, oxadiazolyl, imidazolyl and tetrazolyl, preferably selected from pyridyl, pyrimidinyl, oxadiazolyl, and tetrazolyl, and the aryl is phenyl, and wherein the aryl and the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In a further more preferred embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl and the aryl is phenyl , preferably is C1-C6 alkyl substituted by aryl or heteroaryl wherein the heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl, and the aryl is phenyl, and wherein the aryl and the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
In an even more preferred embodiment R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the heteroaryl is selected from pyridyl, pyrimidinyl, oxadiazolyl, and tetrazolyl and the aryl is phenyl , preferably is C1-C6 alkyl substituted by aryl or heteroaryl wherein the heteroaryl is selected from pyridyl, pyrimidinyl, oxadiazolyl, and tetrazolyl, and the aryl is phenyl, and wherein the aryl and the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)N R12-R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2.
The aryl, the heteroaryl and the C3-C12 heterocyclyl of the substituted C1-C6 alkyl group of R10 and/or R11 are optionally substituted usually in ortho or para position, preferably para position, or in 2 or 3 position, to the C1-C6 alkyl group.
In one embodiment R12 and R13 are each independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl. In further embodiment R12 and R13 are each independently selected from C3-C12 cycloalkyl and C3-C12 heterocyclyl. In a preferred embodiment R12 and R13 are each independently selected from H, C1-C6 alkyl and C1-C6 heteroalkyl. In a more preferred embodiment R12 and R13 are each independently selected from H and C1-C6 alkyl and are preferably H.
In a preferred embodiment
R1 is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH and is preferably selected from H, methyl, ethyl and halogen, more preferably from H, methyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, CN, halogen, C3-C12 cycloalkyl ,C3-C12 heterocyclyl; and
R9 is absent when Y2 is N or is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH, preferably selected from H, methyl, ethyl and halogen when Y2 is C.
In a further preferred embodiment
R1 is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH and is preferably selected from H, methyl, ethyl and halogen, more preferably from H, methyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl wherein the C2-C6 heteroalkyl is preferably C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are preferably selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl; and
R9 is absent when Y2 is N or is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH, preferably selected from H, methyl, ethyl and halogen when Y2 is C .
In a further preferred embodiment
R1 is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH and is preferably selected from H, methyl, ethyl and halogen, more preferably from H, methyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl wherein the C2-C6 heteroalkyl is preferably C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl and C2-C6 alkynyl; and
R9 is absent when Y2 is N or is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH preferably selected from H, methyl, ethyl and halogen when Y2 is C .
In a further preferred embodiment
R1 is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH and is preferably selected from H, methyl, ethyl and halogen, more preferably from H, methyl;
R2 is selected from C2-C6 alkyl and C2-C6 heteroalkyl wherein the C2-C6 heteroalkyl is preferably C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, and is preferably tert-butyl; and
R9 is absent when Y2 is N or is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH, preferably selected from H, methyl, ethyl and halogen when Y2 is C .
In a further preferred embodiment
R1 is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH and is preferably selected from H, methyl, ethyl and halogen, more preferably from H, methyl;
R2 is selected from C3-C6 alkyl, C3-C6 heteroalkyl wherein the C3-C6 heteroalkyl is preferably C3-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C3-C6 alkenyl, C3-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, CN, halogen, C3-C12 cycloalkyl ,C3-C12 heterocyclyl; and
R9 is absent when Y2 is N or is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH, preferably selected from H, methyl, ethyl and halogen when Y2 is C .
In a further preferred embodiment
R1 is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH and is preferably selected from H, methyl, ethyl and halogen and is more preferably H, methyl;
R2 is selected from C3-C6 alkyl, C3-C6 heteroalkyl wherein the C3-C6 heteroalkyl is preferably C3-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C3-C6 alkenyl, C3-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are preferably selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl; and
R9 is absent when Y2 is N or is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH, preferably selected from H, methyl, ethyl and halogen and is more preferably H when Y2 is C .
In a further preferred embodiment
R1 is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH and is preferably selected from H, methyl, ethyl and halogen and is more preferably H, methyl;
R2 is selected from C3-C6 alkyl, C3-C6 heteroalkyl wherein the C3-C6 heteroalkyl is preferably C3-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C3-C6 alkenyl and C3-C6 alkynyl; and
R9 is absent when Y2 is N or is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH, preferably selected from H, methyl, ethyl and halogen and is more preferably H when Y2 is C .
In a further preferred embodiment
R1 is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH and is preferably selected from H, methyl, ethyl and halogen and is more preferably H, methyl;
R2 is selected from C3-C6 alkyl and C3-C6 heteroalkyl wherein the C3-C6 heteroalkyl is preferably C3-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2 wherein R2 is is preferably C3-C6 alkyl more preferably tert-butyl; and
R9 is absent when Y2 is N or is selected from H, methyl, ethyl, halogen, CN, CF3, NH2 and OH preferably selected from H, methyl, ethyl and halogen and is more preferably H when Y2 is C .
In a further preferred embodiment
R1 is selected from H, methyl and ethyl and is more preferably H, methyl;
R2 is selected from C3-C6 alkyl and C3-C6 heteroalkyl wherein the C3-C6 heteroalkyl is preferably C3-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2; and
R9 is absent when Y2 is N or is selected from H, methyl and ethyl when Y2 is C.
In a more preferred embodiment
R1 is selected from H, methyl and ethyl, and is preferably H;
R2 is C3-C6 alkyl, preferably t-butyl; and
R9 is absent when Y2 is N or is selected from H, methyl and ethyl and is preferably H when Y2 is C.
In a particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C;
Z is NR10R11, wherein
R10 is H; and
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl, wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C 1 -C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)NR12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, wherein R11 is preferably selected from C1-C3 cyanoalkyl and C1-C6 alkyl substituted by aryl or heteroaryl, more preferably is C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by NH2;
R1 is selected from H, halogen, C1-C6 alkyl, C3-C12 cycloalkyl and C1-C6 alkoxy, preferably selected from H, halogen and C1-C6 alkyl;
R2 is selected from H, halogen, COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl, norbornyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, wherein R2 is preferably selected from COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1 or 2, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl, norbornyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl;
R3 is selected from H, halogen, C1-C6 alkyl and C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl, preferably selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and Cl-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; and
wherein R12 and R13 are each independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl, preferably selected from H and C1-C6 alkyl.
In a further particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from
N and C, Y2 is selected from N and C and Y3 is C;
Z is NR10R11, wherein
R10 is H; and
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl, wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)NR12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, wherein R11 is preferably selected from C1-C3 cyanoalkyl and C1-C6 alkyl substituted by aryl or heteroaryl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by NH2;
R1 is selected from H, halogen, C1-C6 alkyl, C3-C12 cycloalkyl and C1-C6 alkoxy, preferably selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl wherein the C2-C6 heteroalkyl is preferably C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C1-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, CN, halogen, C3-C12 cycloalkyl ,C3-C12 heterocyclyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R3 is selected from H, halogen, C1-C6 alkyl and C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl, preferably selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; and
wherein R12 and R13 are each independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl, preferably selected from H and C1-C6 alkyl.
In a further particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C;
Z is NR10R11, wherein
R10 is H; and
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl, wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)NR12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, wherein R11 is preferably selected from C1-C3 cyanoalkyl and C1-C6 alkyl substituted by aryl or heteroaryl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by NH2;
R1 is selected from H, halogen, C1-C6 alkyl, C3-C12 cycloalkyl and C1-C6 alkoxy, preferably selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, wherein R2 is preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl; R3 is selected from H, halogen, C1-C6 alkyl and C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl, preferably selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and Cl-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; and
wherein R12 and R13 are each independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl and C3-C12 heterocycly, preferably selected from H, and C1-C6 alkyl.
In a further particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C; Z is NR10R11, wherein
R10 is H; and
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl, wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)NR12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, wherein R11 is preferably selected from C1-C3 cyanoalkyl and C1-C6 alkyl substituted by aryl or heteroaryl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by NH2;
R1 is selected from H, halogen, C1-C6 alkyl, C3-C12 cycloalkyl and C1-C6 alkoxy, preferably selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, wherein R2 is preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl;
R3 is selected from H, halogen, C1-C6 alkyl and C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl, preferably selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; and
wherein R12 and R13 are each independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl and C3-C12 heterocycly, preferably selected from H, and C1-C6 alkyl.
In a particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from
N and C, Y2 is selected from N and C and Y3 is C;
Z is NR10R11, wherein
R10 is H; and
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, 6 to 10-membered heteroaryl, or C3-C12 heterocyclyl, wherein the aryl, the 6 to 10-membered heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13 , preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, wherein R11 is preferably selected from C1-C3 cyanoalkyl and C1-C6 alkyl substituted by c 6 to 10-membered heteroaryl, preferably is C1-C6 alkyl substituted by aryl or 6 to 10-membered heteroaryl, wherein the aryl and the 6 to 10-membered heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by NH2;
R1 is selected from H, halogen, C1-C6 alkyl, C3-C12 cycloalkyl and C1-C6 alkoxy, preferably selected from H, halogen and C1-C6 alkyl;
R2 is selected from COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C2-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl, norbornyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, wherein R2 is preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl,
wherein R2 is more preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl;
R3 is selected from H, halogen, C1-C6 alkyl and C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl, preferably selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and Cl-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; and
wherein R12 and R13 are each independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl, preferably selected from H and C1-C6 alkyl.
In a further particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from
N and C, Y2 is selected from N and C and Y3 is C;
Z is NR10R11, wherein
R10 is H; and
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, or C3-C12 heterocyclyl, wherein the heteroaryl is not imidazolyl and wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, wherein R11 is preferably selected from C1-C3 cyanoalkyl and C1-C6 alkyl substituted by aryl or heteroaryl wherein the heteroaryl is not imidazolyl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl wherein the heteroaryl is not imidazolyl, wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by NH2;
R1 is selected from H, halogen, C1-C6 alkyl, C3-C12 cycloalkyl and C1-C6 alkoxy, preferably selected from H, halogen and C1-C6 alkyl;
R2 is selected from COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C2-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl, norbornyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, wherein R2 is preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, wherein R2 is more preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl;
R3 is selected from H, halogen, C1-C6 alkyl and C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl; R4, R5 and R6 are each independently selected from H, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl, preferably selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and Cl-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; and
wherein R12 and R13 are each independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl, preferably selected from H and C1-C6 alkyl.
In a further particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C; Z is NR10R11, wherein
R10 is H; and
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, or C3-C12 heterocyclyl, wherein the heteroaryl is not 3H-imidazole-4-yl and wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, wherein R11 is preferably selected from C1-C3 cyanoalkyl and C1-C6 alkyl substituted by aryl or heteroaryl wherein the heteroaryl is not 3H-imidazole-4-yl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl wherein the heteroaryl is not 3H-imidazole-4-yl, wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by NH2,
R1 is selected from H, halogen, C1-C6 alkyl, C3-C12 cycloalkyl and C1-C6 alkoxy, preferably selected from H, halogen and C1-C6 alkyl;
R2 is selected from COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C2-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl, norbornyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, wherein R2 is preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl,
wherein R2 is more preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl;
R3 is selected from H, halogen, C1-C6 alkyl and C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl, preferably selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and Cl-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; and
wherein R12 and R13 are each independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl, preferably selected from H and C1-C6 alkyl.
In a further particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from
N and C, Y2 is selected from N and C and Y3 is C;
Z is NR10R11, wherein
R10 is H; and
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, or C3-C12 heterocyclyl, wherein the heteroaryl is not 3H-imidazole-4-yl and not 1H-imidazole-4-yl and wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, wherein R11 is preferably selected from C1-C3 cyanoalkyl and C1-C6 alkyl substituted by aryl or heteroaryl wherein the heteroaryl is not 3H-imidazole-4-yl and not 1H-imidazole-4-yl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl wherein the heteroaryl is not 3H-imidazole-4-yl and not 1H-imidazole-4-yl, wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by NH2;
R1 is selected from H, halogen, C1-C6 alkyl, C3-C12 cycloalkyl and C1-C6 alkoxy, preferably selected from H, halogen and C1-C6 alkyl;
R2 is selected from COC1-C6 alkyl, NH2, OH, CN, SO3H, S(O)n(C1-C6 alkyl) wherein n is 0, 1, or 2, C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C1-C6 alkylamino, C1-C6 dialkylamino, carboxy, C1-C6 alkyl-carboxy, C1-C3 alkyl-NHC(O)OR12, C1-C3 alkyl-OC(O)NR12R13, C(O)NR12R13, C1-C6 alkyl-C(O)NR12R13, C2-C6 alkoxy, C1-C3 alkoxycarbonyl, C1-C6 alkyl-NHCOR12, C1-C3 alkanoyl, adamantyl, norbornyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, wherein R2 is preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl,
wherein R2 is more preferably selected from C2-C6 alkyl, C3-C12 cycloalkyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R3 is selected from H, halogen, C1-C6 alkyl and C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl, preferably selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and Cl-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; and
wherein R12 and R13 are each independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl, preferably selected from H and C1-C6 alkyl.
In a more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from
N and C, Y2 is selected from N and C and Y3 is C; R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl is phenyl and
wherein the heteroaryl is selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, thiophenyl, furanyl and thiadiazolyl, preferably selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl and wherein the aryl and the heteroaryl are optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2;
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, wherein R2 is more preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl, even more preferably selected from C2-C6 alkyl;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and Cl-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; and R12 and R11 are each independently selected from H and C1-C6 alkyl.
In a further more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C; R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by heteroaryl, preferably is C1-C6 alkyl substituted by heteroaryl, wherein the heteroaryl is selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, thiophenyl, furanyl and thiadiazolyl, preferably selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiophenyl, furanyl and thiadiazolyl, and wherein the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2;
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, wherein R2 is more preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl, even more preferably selected from C2-C6 alkyl;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; and
R12 and R13 are each independently selected from H and C1-C6 alkyl.
In a further more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C; R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl is phenyl and wherein the heteroaryl is selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, thiophenyl, furanyl and thiadiazolyl and wherein the aryl and the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2,
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, wherein R2 is more preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl, even more preferably selected from C2-C6 alkyl;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and Cl-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; and
R12 and R13 are each independently selected from H and C1-C6 alkyl.
In a further more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C; R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by heteroaryl, preferably is C1-C6 alkyl substituted by heteroaryl, wherein the heteroaryl is selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, thiophenyl, furanyl and thiadiazolyl, and wherein the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2;
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, wherein R2 is more preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl, even more preferably selected from C2-C6 alkyl;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and Cl-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; and
R12 and R13 are each independently selected from H and C1-C6 alkyl.
In a further more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C; R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by heteroaryl, preferably is C1-C6 alkyl substituted by heteroaryl, wherein the heteroaryl is selected from pyridyl, pyrimidinyl, imidazolyl, oxadiazolyl and tetrazolyl, preferably from pyridyl, pyrimidinyl, oxadiazolyl and tetrazolyl, and wherein the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2;
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, wherein R2 is more preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl, even more preferably selected from C2-C6 alkyl;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and Cl-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; and
R12 and R13 are each independently selected from H and C1-C6 alkyl.
In a further more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C;
R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by heteroaryl, preferably is C1-C6 alkyl substituted by heteroaryl, wherein the heteroaryl is selected from pyridyl, pyrimidinyl, imidazolyl, oxadiazolyl and tetrazolyl, preferably from pyridyl, pyrimidinyl, oxadiazolyl and tetrazolyl, and wherein the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2;
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, wherein R2 is more preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl, even more preferably selected from C2-C6 alkyl;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and Cl-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; and R12 and R13 are each independently selected from H and C1-C6 alkyl.
In a further more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C; R10 is H; R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl is phenyl and wherein the heteroaryl is selected from pyridyl, pyrimidinyl, imidazolyl, oxadiazolyl and tetrazolyl, preferably selected from pyridyl, pyrimidinyl, oxadiazolyl and tetrazolyl, wherein the aryl and the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)OR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2;
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, wherein R2 is more preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl, even more preferably selected from C2-C6 alkyl;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is
N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; andR12 and R13 are each independently selected from H and C1-C6 alkyl.
In a further more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C; R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, preferably is C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl is phenyl and wherein the heteroaryl is selected from pyridyl, pyrimidinyl, imidazolyl, oxadiazolyl and tetrazolyl, preferably selected from pyridyl, pyrimidinyl, oxadiazolyl and tetrazolyl, wherein the aryl and the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2;
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, wherein R2 is more preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl, even more preferably selected from C2-C6 alkyl;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and Cl-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; andR12 and R13 are each independently selected from H and C1-C6 alkyl.
In a further more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C; R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by heteroaryl, preferably is C1-C6 alkyl substituted by heteroaryl, wherein the heteroaryl is selected from pyridyl, pyrimidinyl, imidazolyl, oxadiazolyl and tetrazolyl, preferably selected from pyridyl, pyrimidinyl, oxadiazolyl and tetrazolyl, wherein the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2;,
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, wherein R2 is more preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl, even more preferably selected from C2-C6 alkyl;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and Cl-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; andR12 and R13 are each independently selected from H and C1-C6 alkyl.
In a further more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O and is preferably selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C, preferably Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C; R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by heteroaryl, preferably is C1-C6 alkyl substituted by heteroaryl, wherein the heteroaryl is selected from pyridyl, imidazolyl, oxadiazolyl and tetrazolyl and wherein the heteroaryl is optionally substituted by NH2, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), OH, O(C1-C6) alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, C(O)NR12, C(O)N R12R13, preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, more preferably by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, even more preferably by NH2;,
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl wherein the heterosubstituent is not halogen and is preferably selected from OH and NH2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, wherein R2 is more preferably selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl and C2-C6 alkynyl, even more preferably selected from C2-C6 alkyl;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y1 is C, or R7 is absent when Y1 is N or is selected from H, halogen and Cl-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen, C1-C6 alkyl and, C1-C6 heteroalkyl, preferably selected from H, halogen and C1-C6 alkyl when Y2 is C, or R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C; andR12 and R13 are each independently selected from H and C1-C6 alkyl.
In an even more particular preferred embodiment
X is selected from CH2, CF2, CHF, CO, CHOH, CHO(C1-C3) alkyl, NH, N(C1-C3 alkyl), S, SO and O;
wherein Y1, Y2, and Y3 are each independently selected from N and C;
Z is NR10R11;
R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl, wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, preferably optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R1 is selected from H, halogen, C1-C6 alkyl, C3-C12 cycloalkyl and C1-C6 alkoxy;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by C1-C6 alkyl, halogen, even more preferably by methyl, halogen;
R3 is selected from H, halogen, C1-C6 alkyl and C1-C6 heteroalkyl;
R4, R5 and R6 are each independently selected from H, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl;
R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C.
In a further even more particular preferred embodiment
X is selected from CH2, CF2, CHF, CO, CHOH, CHO(C1-C3) alkyl, NH, N(C1-C3 alkyl), S, SO and O;
wherein Y1, Y2, and Y3 are each independently selected from N and C;
Z is NR10R11;
R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl, wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl, preferably optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R1 is selected from H, halogen, and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl, preferably optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, more preferably by C1-C6 alkyl, halogen, even more preferably by methyl, halogen;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C.
In a further even more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O, preferably X is selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1, Y2, and Y3 are each independently selected from N and C;
Z is NR10R11;
R10 H;
R11 is selected from C1-C3 cyanoalkyl and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R11 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C3-C12 cycloalkyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen and C1-C6 alkyl when Y3 is C; and
R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C.
In a further even more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O, preferably X is selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C;
Z is NR10R11;
R10 is H;
R11 is selected from C1-C3 cyanoalkyl and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C3-C12 cycloalkyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is selected from H, halogen and C1-C6 alkyl; and
R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C.
In a further even more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O, preferably X is selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
wherein Y1, Y2, and Y3 are each independently selected from N and C;
Z is NR10R11;
R19 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl is phenyl and wherein the heteroaryl is selected from pyridyl, pyrimidinyl, imidazolyl, oxadiazolyl and tetrazolyl, wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C3-C12 cycloalkyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen and C1-C6 alkyl when Y3 is C; and
R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C.
In a further even more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O, preferably X is selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C;
Z is NR10R11;
R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl is phenyl and wherein the heteroaryl is selected from pyridyl, pyrimidinyl, imidazolyl, oxadiazolyl and tetrazolyl, wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C3-C12 cycloalkyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is selected from H, halogen and C1-C6 alkyl; and
R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C.
With respect to the even more particular preferred embodiments outlined above, the heteroaryl group of R11 is preferably not 3H-imidazole-4-yl.
With respect to the even more particular preferred embodiments outlined above, the heteroaryl group of R11 is preferably not 3H-imidazole-4-yl and not 1H-imidazole-4-yl.
In a further even more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O;
wherein Y1, Y2, and Y3 are each independently selected from N and C;
Z is NR10R11;
R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl is phenyl and wherein the heteroaryl is selected from pyridyl, pyrimidinyl, oxadiazolyl and tetrazolyl, wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C3-C12 cycloalkyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen and C1-C6 alkyl when Y3 is C; and
R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C.
In a further even more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O, preferably X is selected from CH2, CHOH, CHO(C1-C3) alkyl, and O;
Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C;
Z is NR10R11;
R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl is phenyl and wherein the heteroaryl is selected from pyridyl, pyrimidinyl, oxadiazolyl and tetrazolyl, wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C2-C6 alkyl, C3-C12 cycloalkyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is selected from H, halogen and C1-C6 alkyl; and
R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C.
In a further even more particular preferred embodiment
X is selected from CH2, CF2, CHF, CO, CHOH, CHO(C1-C3) alkyl, NH, N(C1-C3 alkyl), S, SO and O;
wherein Y1, Y2, and Y3 are each independently selected from N and C;
Z is NR10R11;
R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl, wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl;
R1 is selected from H, halogen, C1-C6 alkyl, C3-C12 cycloalkyl and C1-C6 alkoxy;
R2 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl;
R3 is selected from H, halogen, C1-C6 alkyl and C1-C6 heteroalkyl;
R4, R5 and R6 are each independently selected from H, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C12 cycloalkyl and C3-C12 heterocyclyl;
R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C.
In a further even more particular preferred embodiment
X is selected from CH2, CF2, CHF, CO, CHOH, CHO(C1-C3) alkyl, NH, N(C1-C3 alkyl), S, SO and O;
wherein Y1, Y2, and Y3 are each independently selected from N and C;
Z is NR10R11;
R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl, heteroaryl, C3-C12 heterocyclyl, wherein the aryl, the heteroaryl and the C3-C12 heterocyclyl are optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 cycloalkyl, C3-C12 heterocyclyl;
R1 is selected from H, halogen, and C1-C6 alkyl;
R2 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C3-C12 heterocyclyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C12 heterocyclyl, C3-C12 cycloalkyl;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen and C1-C6 alkyl when Y3 is C;
R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C.
In a further even more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O;
Y1, Y2, and Y3 are each independently selected from N and C;
Z is NR10R11;
R10 is H;
R11 is selected from C1-C3 cyanoalkyl and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C1-C6 alkyl, C3-C12 cycloalkyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen and C1-C6 alkyl when Y3 is C; and
R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C.
In a further even more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O;
Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C;
Z is NR19R11;
R10 is H;
R11 is selected from C1-C3 cyanoalkyl and C1-C6 alkyl substituted by aryl or heteroaryl,
wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C1-C6 alkyl, C3-C12 cycloalkyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is selected from H, halogen and C1-C6 alkyl; and
R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C.
In a further even more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O;
wherein Y1, Y2, and Y3 are each independently selected from N and C;
Z is NR10R11;
R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl is phenyl and wherein the heteroaryl is selected from pyridyl, pyrimidinyl, imidazolyl, oxadiazolyl and tetrazolyl, wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C1-C6 alkyl, C3-C12 cycloalkyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
R8 is absent when Y3 is N or is selected from H, halogen and C1-C6 alkyl when Y3 is C; and
R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C.
In a further even more particular preferred embodiment
X is selected from CH2, CO, CHOH, CHO(C1-C3) alkyl, NH and O;
Y1 is selected from N and C, Y2 is selected from N and C and Y3 is C;
Z is NR10R11;
R10 is H;
R11 is selected from C1-C3 cyanoalkyl, and C1-C6 alkyl substituted by aryl or heteroaryl, wherein the aryl is phenyl and wherein the heteroaryl is selected from pyridyl, pyrimidinyl, imidazolyl, oxadiazolyl and tetrazolyl, wherein the aryl and the heteroaryl is optionally substituted by NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R1 is selected from H, halogen and C1-C6 alkyl;
R2 is selected from C1-C6 alkyl, C3-C12 cycloalkyl, aryl and heteroaryl, wherein the aryl and the heteroaryl are optionally substituted by C1-C6 alkyl, C1-C6 heteroalkyl, halogen;
R3 is selected from H, halogen and C1-C6 alkyl;
R4, R5 and R6 are each independently selected from H, halogen and C1-C6 alkyl;
R7 is absent when Y1 is N or is selected from H, halogen and C1-C6 alkyl when Y1 is C;
Rg is selected from H, halogen and C1-C6 alkyl; and
R9 is absent when Y2 is N or is selected from H, halogen and C1-C6 alkyl when Y2 is C.
A most particular preferred embodiment of the invention are the following compounds pharmaceutically-accentahle salts, hydrates, solvates, or stereoisomers thereof:
A further most particular preferred embodiment of the invention are the following compounds pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof:
A further most particular preferred embodiment of the invention are the following compounds pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof:
A further most particular preferred embodiment of the invention are the following compounds pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof:
A further most particular preferred embodiment of the invention are the following compounds pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof:
A particular preferred embodiment of the invention are the following compounds pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof:
The most particular preferred embodiment of the invention are the following compounds pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof:
Preparation of the Compounds
The compounds of the invention may be prepared by the exemplary processes described in the following reaction schemes or by the processes described in the examples. Exemplary reagents and procedures for these reactions appear hereinafter. Starting materials can be purchased or readily prepared by one of ordinary skilled in the art.
The syntheses of the di-arylamino, di-arylether and di-arylthioether analogs is depicted in Scheme 1: The respective amino-aryl moiety of formula (II) (X=NH, eventually monoalkylated) is reacted with the halogenated nitro-aryl precurser of formula (III) in a polar solvent in presence of a base at elevated temperatures. Preferably the solvent is a mixture of DMSO and an alcohol like tBuOH. As a base an alcoholate like tBuOK can be used. Reaction temperatures are between room temperature and 150° C., preferably between 60 and 110° C. The respective hydroxy- or mercapto-aryl moiety of formula (II) (X═O, S) is reacted with the halogenated nitro-aryl precurser of formula (III) in a polar solvent in presence of a base. A preferred reaction condition is carbonate as base in DMF at room temperature. Finally, the nitro function of formula (IV) can be reduced to the respective amine of formula (V) under Béchamp conditions or via catalytic hydrogenation. Preferred Bechamp conditions are Fe powder in a mixture of EtOH, H2O and AcOH under sonication. Catalytic hydrogenation can be performed in presence of Pd/C in a polar solvent like an alcohol. Alternatively, target compounds of formula (VIII) (Y3=N) can be obtained via substitution of the halogene of formula (VI) by the X-containing aryl moiety of formula (VII), eventually in presence of a protection group (PG). Preferred conditions are phosphate as a base in an unpolar aromatic solvent at 100 to 150° C. under ferrocenyl catalysis [see: Advanced Synthesis & Catalysis 353 (2011), 3403].
Scheme 2 depicts the reductive alkylation of amino-derivatives of formula (V): A preferred method is stirring the amine of formula (V) and the respective aldehyde in a polar solvent like an alcohol in presence of a weak acid like acetic acid. Then a reducing reagent like NaBH3CN is added. Basic work-up finally yields compounds of formula (IX). Alternatively, the amine of formula (V) and the aldehyde are mixed in an unpolar solvent like dichloromethane in presence of a base like triethylamine. Then a reducing reagent like NaBH(OAc)3 is added. Aqueous work-up finally yields compounds of formula (IX).
Scheme 3 illustrates the syntheses of carbon-bridged analogs (X═CH2, CF2, CHF, CHOH, CHOAlk, CO): The halogen-aryl moiety of formula (X) is decarboxylatively coupled to the aryl-acetate of formula (XI), catalyzed by a transition metal complex, yielding the nitro derivative of formula (XII). Preferred conditions are XPhos/Pd2(allyl)2Cl2 as the catalyst in a unpolar solvent at elevated temperatures. The methylene bridge (X═CH2) of formula (XII) can be oxidized to the respective di-aryl-ketone of formula (XIV). Preferred conditions are oxygen as the reagent in a mixture of acetic acid and DMSO at elevated temperature, catalyzed by FeCl2.(H2O)4 [analogously to: Angew. Chem. Int. Ed. 51 (2012), 2745]. Reduction of the carbonyl group of formula (XIV) leads to the benzylic alcohol of formula (XVII). A preferred reducing reagent could be sodium borohydride. Alternatively, the benzylic alcohol of formula (XVII) can be obtained via cross coupling of a boronate of formula (XV) with an aryl-aldehyde of formula (XVI). Alkylation of the compound of formula (XVII) with an alkyl-iodide in presence of a strong base (e.g. NaH) in an aprotic polar solvent yields the alkoxy-derivative of formula (XVIII) [analogously to: Example 2 in U.S. Pat. No. 5,965,740]. The mono-fluoro derivative of formula (XIX) can be obtained either by oxidative fluorination of the compound of formula (XII) or hydroxy-substitution in a compound of formula (XVII). The oxidative fluorination can be done under conditions as Jacobsen salene complex, iodosylbenzene, base, tris(hydrogen fluoride) in a polar solvent at elevated temperatures [J. Am. Chem.Soc. 136 (2014), 6842]. Substitution of the benzylic hydroxy group by fluoride can be achieved by applying conditions like activation with trichloroacetimidate, 1,8-diazabicyclo[5.4.0]undec-7-ene in dichloromethane in presence of bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate followed by triethylamine tris(hydrogen fluoride) in a mixture of F3C—C6H5 and tetrahydrofurane at slightly elevated temperatures [Tetrahedron 71 (2015), 5932]. The keto-derivative of formula (XIV) can be converted to the difluoromethylen derivative of formula (XX) with [bis(2-methoxyethyl)amino]-sulfur trifluoride at elevated temperatures [analogously to: US2015246938; Step 2, Preparation of Compound 76; page 55]. Finally, the nitro-groups of compounds of formula (XII), (XIV) and (XVII)-(XX) can be reduced to the respective amino derivatives as described in Scheme 1.
Stereoisomers
Compounds of the present invention can exist as stereoisomers wherein asymmetric or chiral centers are present. These compounds are designated by the symbols“R” or“S”, depending on the configuration of sub stituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art.
These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
Geometric isomers can also exist in the compounds of the present invention. The present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring.
Compounds of the present invention can also exist as racemates which is given the descriptor “rac”. The term racemate, as used herein, means an equimolar mixture of a pair of enantiomers. A racemate is usually formed when synthesis results in the generation of a stereocenter. As used herein, the term racemic mixture means racemate. Compounds of the present invention can also exist as diastereomeric meso forms which is given the descriptor “rel”. The term diastereomeric meso form as used herein means achiral forms with a pseudostereogenic C-atom, which is given the descriptor “r” or “s”, respectively.
Salts
The compounds of the present invention may be used in the form of pharmaceutically-acceptable salts derived from inorganic or organic acids. By “pharmaceutically-acceptable salt”is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically-acceptable salts are well-known in the art. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid.
Representative acid addition salts include, but are not limited to trifluoroacetic acid (TFA), acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides ; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically-acceptable basic addition salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
Solvates/Hydrates
It should be appreciated that solvates and hydrates of the compound according to formula (I) are also within the scope of the present application. Methods of solvation are generally known in the art.
A further embodiment of the present invention may also include compounds, which are identical to the compounds of formula (I) except that one or more atoms are replaced by an atom having an atomic mass number or mass different from the atomic mass number or mass usually found in nature, e.g. compounds enriched in 2H (D), 3H, 13C, 127I etc. These isotopic analogs and their pharmaceutical salts and formulations are considered useful agents in therapy and/or diagnosis, for example, but not limited to, where a fine-tuning of in vivo half-life time could lead to an optimized dosage regimen.
Pharmaceutical Compositions
In a further aspect the present invention provides a pharmaceutical composition comprising compounds of formula (I) according to the invention and a pharmaceutically acceptable diluent, excipient or carrier. In one embodiment the pharmaceutical composition further comprises another pharmaceutical active agent.
In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) according to the invention and a pharmaceutically acceptable diluent, excipient or carrier, wherein said compound of formula (I) is present in a therapeutically effective amount.
Formulations and Modes of Administration
The compounds of the present invention may, in accordance with the invention, be administered in single or divided doses by oral, parenteral, inhalatory, rectal or topical administration including cutaneous, ophthalmic, mucosal scalp, sublingual, buccal and intranasal routes of administration; further, the compounds provided by the invention may be formulated to be used for the treatment of leukocyte populations ex vivo and in vitro.
When the compounds of the present invention are to be administered e.g. by the oral route, they may be administered as medicaments in the form of pharmaceutical compositions which contain them in association with a pharmaceutically acceptable diluent, excipient or carrier material. Thus the present invention also provides a pharmaceutical composition comprising the compounds according to the invention as described supra and one or more pharmaceutically acceptable diluent, excipient or carrier. The pharmaceutical compositions can be prepared in a conventional manner and finished dosage forms can be solid dosage forms, for example, tablets, dragees, capsules, and the like, or liquid dosage forms, for example solutions, suspensions, emulsions and the like. Pharmaceutically acceptable diluent, excipient or carrier include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art.
In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) according to the invention and at least one pharmaceutically acceptable diluent, excipient or carrier, wherein the composition is a tablet or a capsule, preferably a tablet.
Dosing Regimen
An exemplary treatment regime entails administration once daily, twice daily, three times daily, every second day, twice per week, once per week. The composition of the invention is usually administered on multiple occasions. Intervals between single dosages can be, for example, less than a day, daily, every second day, twice per week, or weekly. The composition of the invention may be given as a continous uninterrupted treatment. In an exemplary treatment regime the compound of formula (I) according to the invention can be administered from 0.1-100 mg per day.
Therapeutic Use
The compounds according to the invention as described supra have preventive and therapeutic utility in human and veterinary diseases.
In one aspect of the present invention, the compounds according to the invention as described herein or the pharmaceutical composition as described herein may be used as a medicament, preferably for use in human medicine and/or veterinarian medicine. Accordingly the present invention provides the compounds according to the invention as described herein or a pharmaceutical composition as described herein, for use as a medicament.
The terms “treatment”/“treating” as used herein includes: (1) delaying the appearance of clinical symptoms of the state, disorder or condition developing in an animal, particularly a mammal and especially a human, that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and/or (3) relieving the condition (i.e. causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment.
The term “prevention” comprises prophylactic treatments. In preventive applications, the pharmaceutical combination of the invention is administered to a subject suspected of having, or at risk for developing cancer. In therapeutic applications, the pharmaceutical combination is administered to a subject such as a patient already suffering from cancer, in an amount sufficient to cure or at least partially arrest the symptoms of the disease. Amounts effective for this use will depend on the severity and course of the disease, previous therapy, the subject's health status and response to the drugs, and the judgment of the treating physician.
The term “therapeutically effective amount” refers to an amount of a drug effective to treat a disease or disorder in a mammal. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of tumor or cancer cells, reduce the tumor size; inhibit (i.e., slow to some extert and preferably stop) cancer cells infiltration into peripheral organs; inhibit (i.e., slow to some extert and preferably stop) tumor metastasis; inhibit, to some extert, tumor growth; and/or relieve to some extert one or more of the symptoms associated with the cancer. To the extert the compounds of the present invention may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic.
The term “therapeutically effective amount” as used herein means an amount sufficient to prevent, or preferably reduce by at least about 30 percent, preferably by at least 50 percent, preferably by at least 70 percent, preferably by at least 80 percent, preferably by at least 90%, a clinically significant change in the growth or progression or mitotic activity of a target cellular mass, group of cancer cells, or other feature of pathology.
When provided preventively, compounds of the invention are provided in advance of established disease. The preventive administration of a compound of the present invention serves to prevent or attenuate the evolution of disease. The therapeutic administration of a compound of the present invention serves to attenuate established disease. Thus, in accordance with the invention, a compound of the present invention can be administered either prior to the onset of disease or during the course of disease.
In one aspect of the invention, there are provided the compounds of formula (I) according to the invention for use in a method for the prevention or treatment of oncovirus induced cancer in a subject.
Also provided is the use of the compounds according to the invention as described herein or the pharmaceutical composition as described herein for the manufacture of a medicament for the prevention or treatment of oncovirus induced cancer in a subject.
Also provided is the use of the compounds according to the invention as described herein or the pharmaceutical composition as described herein for the prevention or treatment of oncovirus induced cancer in a subject.
Also provided is a method for the prevention or treatment of oncovirus induced cancer in a subject, comprising administering to said subject a therapeutically effective amount of the compounds according to the invention as described herein or the pharmaceutical composition as described herein.
In a preferred embodiment the oncovirus inducing cancer is selected from Epstein-Barr Virus (EBV), Kaposi's Sarcoma Herpervirus (KSHV), Human Papillomavirus (HPV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human T Cell Lymphotropic Virus-1 (HTLV-1) and Human Immunodeficiency Virus (HIV).
In an even more preferred embodiment the oncovirus inducing cancer is Epstein-Barr Virus (EBV) or Kaposi's Sarcoma Herpervirus (KSHV), in particular Epstein-Barr Virus (EBV). In a particular preferred embodiment the oncovirus induced cancer is selected from the group consisting of angio-immunoblastic T cell lymphomas, T/NK cell lymphomas, Burkitt lymphoma, classical Hodgkin lymphoma, post-transplant lymphoproliferative disorder (PTLD), non-Hodgkin lymphoma (NHL), Nasopharyngeal Carcinoma (NPC), lympho-epithelioma like gastric carcinomas, gastric adenocarcinomas, leiomypsarcomas, X-linked lymphoproliferative dieases, AIDS related lymphoproliferative disease, AIDS-related Kaposi's Sarcoma, classical Kaposi's Sarcoma (KS), Primary Effusion Lymphoma (PEL), Multicentric Castleman's disease (MCD), preferably oncovirus induced cancer selected from the group consisting of Burkitt lymphoma, classical Hodgkin lymphoma, post-transplant lymphoproliferative disorder (PTLD), non-Hodgkin lymphoma (NHL), Nasopharyngeal Carcinoma (NPC), lympho-epithelioma like gastric carcinomas, gastric adenocarcinomas, AIDS related lymphoproliferative disease, AIDS-related Kaposi's Sarcoma, classical Kaposi's Sarcoma (KS), Primary Effusion Lymphoma (PEL), Multicentric Castleman's disease (MCD), angio-immunoblastic T cell lymphomas, T/NK cell lymphomas, more preferably oncovirus induced cancer selected from the group consisting of Burkitt lymphoma, classical Hodgkin lymphoma, post-transplant lymphoproliferative disorder (PTLD), non-Hodgkin lymphoma (NHL), Nasopharyngeal Carcinoma (NPC), lympho-epithelioma like gastric carcinomas, gastric adenocarcinomas.
In a further aspect the present invention provides a kit of parts comprising a container and a package insert, wherein the first container comprises at least one dose of a medicament comprising a compound of formula (I) or a pharmaceutically-acceptable salt, hydrate, solvate, or stereoisomer thereof and optionally one or more pharmaceutically acceptable diluents, excipients or carrier, and the package insert comprises instructions for treating a subject for oncovirus induced cancer using the medicament.
In a further aspect the present invention provides the use of the compound of formula (I) or pharmaceutically-acceptable salt, hydrate, solvate, or stereoisomer thereof or a compound as described supra or a pharmaceutically-acceptable salt, hydrate, solvate, or stereoisomer thereof or the kit as described supra in diagnosing, predicting, and/or monitoring of oncovirus induced cancer in a subject.
Abbreviations
AcOH acetic acid
brine saturated aqueous NaCl solution
CV column volumes
DCE 1,2-dichlorethane
DCM dichloromethane
DME 1,2-dimethoxyethane
DMF dimethylformamide
DMSO-d6 deuterated dimethyl sulfoxide
equiv equivalent(s)
EtOAc ethyl acetate
Et2O diethyl ether
EtOH ethanol
expl. example
Fe iron
h hour(s)
HCl hydrochloric acid
M molar concentration
MeOH methanol
MgSO4 magnesium sulfate
min minute(s)
mL milliliter(s)
Mw molecular weight
NaBH(OAc)3 sodium triacetoxyborohydride
NaHCO3 sodium bicarbonate
Na2SO4 sodium sulfate
Pd/C palladium on carbon
pTSA p-toluenesulfonic acid
RT room temperature
tBuOH tert.-butanol
tBuOK potassium tert.-butylate
TEA triethylamine
THF tetrahydrofurane
TLC thin layer chromatography (Rf. retertion factor)
To the desired aryl alcohol A (1.1 equiv) and the corresponding 4-halo-nitroaryl B (1.0 equiv) in DMF (0.5 M), was added K2CO3 (1.2 equiv). The reaction was stirred at RT. After completion (monitored by TLC with EtOAc/hexanes or EtOAc/cyclohexane as eluent and stained with KMnO4), usually observed after 14 h, the reaction mixture was poured into a mixture of Et2O and a satured aqueous solution of NaHCO3. The layers were separated and the aqueous phase extracted twice with Et2O. The combined organic layers were washed with a saturated aqueous solution of NaHCO3, dried over Na2SO4 or MgSO4, filtered-off and concentrated under reduced pressure. The crude product was purified by combi flash column chromatography using EtOAc/hexanes or EtOAc/cyclohexane as the eluent, to afford the corresponding title compound C.
To the nitro compound C (1.0 equiv) were added Fe powder (5.0 equiv) and EtOH/H2O/AcOH 2:2:1 (0.1 M). The reaction was sonicated until completion (monitored by TLC, with EtOAc/hexanes or EtOAc/cyclohexane as eluent and stained with KMnO4). The obtained brown slurry was filtered through filter paper, rinsed with EtOAc and the organic solvents were evaporated. EtOAc was added followed by careful addition of a saturated aqueous solution of NaHCO3. Layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over MgSO4 or Na2SO4, filtered-off and the solvent was evaporated. The crude product was purified by combi flash column chromatography using EtOAc/hexanes or EtOAc/cyclohexane as the eluent, to afford the corresponding title compound D.
To the HCl salt of the arylamine (E) (1.0 equiv) and the aldehyde (1.0 equiv) in MeOH (0.18 M) under inert atmosphere, was added AcOH (1.2 equiv). After 1 h stirring, NaBH3CN (5.0 equiv) was added. This mixture was stirred until completion (monitored by TLC, with EtOAc/hexanes or EtOAc/cyclohexane as eluent and stained with KMnO4). The reaction was then neutralized by dropwise addition of a 1.0 M aqueous solution of NaOH and the solvent was evaporated. The obtained residue was poured into EtOAc and a 1.0 M aqueous solution of NaOH. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4 or Na2SO4, filtered-off and solvent was evaporated. The crude product was purified by combi flash column chromatography using EtOAc/hexanes or EtOAc/cyclohexane as the eluent, to afford the corresponding title compound F.
General Procedure D: Suzuki Coupling
To a suspension of the desired boronic acid G (1.2 equiv), the desired bromoaryl H (1.0 equiv) and the accurate base (2.0-2.5 equiv) in dioxane/H2O 4:1 (0.05-0.1 M), the palladium catalyst (10% mol) was added. The reaction mixture was stirred at reflux. After 16 h, EtOAc and H2O were added. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4 or Na2SO4, filtered through a pad of celite and concentrated under reduced pressure. The residue was purified by column chromatography using EtOAc/hexanes or EtOAc/cyclohexane as the eluent, to afford the target compound C.
N.B.: This procedure was also applied to Suzuki couplings between G as a bromoaryl derivative and H as aryl boronic acid/ester.
To a suspension of the desired boronic acid G (1.2 equiv), the desired bromoaryl H (1.0 equiv) and K2CO3 (2.0-2.5 equiv) in dioxane: H2O 4:1 (0.05-0.1 M), tetrakis(triphenylphosphine)palladium(0) (10% mol) was added. The reaction mixture was stirred at reflux. After 16 h, EtOAc and H2O were added. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4 or Na2SO4, filtered through a pad of celite and concentrated under reduced pressure. The residue was purified by column chromatography using EtOAc/hexanes or EtOAc/cyclohexane as the eluent, to afford the target compound C.
To a freshly prepared solution of sodium methoxide (Na 5.0 equiv, MeOH 0.1M) under inert atmosphere, the aminoaryl derivative D (1.0 equiv) was added. The reaction was stirred at RT (1 h). Then, the appropriate aldehyde (1.4 equiv) was added followed, after 16 h, by NaBH4 (2.0 equiv). The mixture was stirred until completion (monitored by TLC). MeOH was evaporated and EtOAc followed by saturated aqueous NaHCO3 were added. The layers were separated and the organic layer was washed with brine, dried over MgSO4 or Na2SO4, filtered and evaporated under vacuum. The crude residue was purified by column chromatography using EtOAc/hexanes or EtOAc/cyclohexane as the eluent, to afford the target compound F
To a solution of the nitro compound C (1.0 equiv), at RT, in a 3:1 mixture of acetone/H2O was added NH4Cl (5 equiv). To this stirring solution Zn (5.0 equiv) was added in portions. The reaction mixture was stirred for 1 h (monitored by TLC, with EtOAc/hexanes or EtOAc/cyclohexane as eluent and stained with KMnO4) and then concentrated under reduced pressure. The residue was suspended in EtOAc and filtered through a pad of celite which was washed with EtOAc. The filtrate was washed washed with NaHCO3 (2×), dried over MgSO4 or Na2SO4, filtered-off and the solvent was evaporated to afford the corresponding title compound D.
To a solution of the aminoaryl derivative D (1.0 equiv), in DCE (0.25M), at RT, was added the appropriate aldehyde (1.1 equiv). The mixture was stirred for 5 min before NaBH(OAc)3 (1.5 equiv) was added followed by AcOH (1 equiv) addition. The reaction was stirred at RT overnight. The reaction mixture was quenched by adding 1M NaOH and diluted with H2O and CH2Cl2. The two layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried over MgSO4 or Na2SO4, filtered and evaporated under vacuum. The crude residue was purified by column chromatography using EtOAc/hexanes or EtOAc/cyclohexane as the eluent, to afford the target compound F.
Following the General procedure C, 6-(4-(tert-butyl)phenoxy)-N-(pyridin-4-ylmethyl)pyridin-3-amine was obtained in 72% yield (0.31 mmol, 103 mg) from the HCl salt of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (0.043 mmol, 118 mg).
C21H23N3O; Mw=333.44 g.mol−1; Yellowish sticky oil; 1H NMR (400 MHz, CDCl3) δ 8.60-8.52 (m, 2H), 7.61 (d, J=3.0 Hz, 1H), 7.38-7.31 (m, 2H), 7.31-7.27 (m, 2H), 7.01-6.92 (m, 3H), 6.76 (d, J=8.8 Hz, 1H), 4.36 (s, 2H), 4.09 (s, 1H), 1.30 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 156.73, 150.27, 148.28, 139.95, 132.21, 126.59, 124.80, 122.18, 119.52, 112.52, 77.48, 77.16, 76.84, 47.74, 34.47, 31.63.
The starting material was prepared as follows:
Following the General procedure A, 2-(4-(tert-butyl)phenoxy)-5-nitropyridine was obtained in 72% yield (14.41 mmol, 3.92 g) from 4-(tert-butyl)phenol (19.97 mmol, 3.00 g) and 2-chloro-5-nitropyridine (19.97 mmol, 3.17 g).
C15H16N2O3; Mw=272.30 g.mol−1; Yellow oil; 1H NMR (400 MHz, CDCl3) δ 9.07 (dd, J=2.8, 0.5 Hz, 1H), 8.46 (dd, J=9.1, 2.8 Hz, 1H), 7.50-7.39 (m, 2H), 7.11-7.05 (m, 2H), 7.01 (dd, J=9.1, 0.5 Hz, 1H), 1.36 (s, 9H).
6-(4-(tert-Butyl)phenoxy)pyridin-3-amine was obtained following the General procedure B.
C15H18N2O; Mw=242.32 g.mol−1; 1H 1NMR (400 MHz, CDCl3) δ 7.69 (d, J=3.0 Hz, 1H), 7.39-7.3 1 (m, 2H), 7.03 (dd, J=8.6, 3.0 Hz, 1H), 7.00-6.93 (m, 2H), 6.72 (d, J=8.6 Hz, 1H), 3.48 (s, NH2), 1.31 (s, 9H).
Following the General procedure C, 6-(4-(tert-butyl)phenoxy)-N-(pyridin-3-ylmethyl)pyridin-3-amine was obtained in 86% yield (0.90 mmol, 300 mg) from the HCl salt of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (1.05 mmol, 291 mg).
C21H23N3O; Mw=333.44 g.mol−1; Yellowish sticky oil; 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.54 (d, J=3.7 Hz, 1H), 7.67 (dd, J=12.7, 5.4 Hz, 2H), 7.39-7.31 (m, 2H), 7.31-7.26 (m, 1H), 7.04-6.94 (m, 3H), 6.77 (d, J=8.7 Hz, 1H), 4.34 (s, 2H), 4.07-3.88 (m, 1H), 1.31 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 156.67, 153.29, 149.28, 149.15, 146.51, 140.15, 135.27, 134.33, 132.28, 126.58, 124.95, 123.76, 119.46, 112.57, 77.48, 77.16, 76.84, 46.48, 34.46, 31.63.
Following the General procedure C, 6-(4-(tert-butyl)phenoxy)-N-(pyridin-2-ylmethyl)pyridin-3-amine was obtained in 65% yield (0.23 mmol, 75 mg) from the HCl salt of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (0.36 mmol, 100 mg).
C21H23N3O; Solid; Mw=333.44 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=4.3 Hz, 1H), 7.71 (d, J=3.0 Hz, 1H), 7.67 (td, J=7.7, 1.8 Hz, 1H), 7.34-7.30 (m, 3H), 7.21 (dd, J=7.0, 5.1 Hz, 1H), 7.07 (d, J=8.7, 3.1 Hz, 1H), 7.01-6.95 (m, 2H), 6.78 (d, J=8.7 Hz, 1H), 4.43 (s, 2H), 1.31 (s, 9H).
Following the General procedure C, N-benzyl-6-(4-(tert-butyl)phenoxy)pyridin-3-amine was obtained in 17% yield (0.168 mmol, 56 mg) from the HCl salt of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (0.984 mmol, 274 mg).
C22H24N2O; Mw=332.45 g.mol−1; White solid; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=3.0 Hz, 1H), 7.39-7.26 (m, 7 H), 7.05-6.94 (m, 3H), 6.76 (d, J=8.7 Hz, 1H), 4.31 (s, 2H), 1.31 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 156.27, 153.49, 146.36, 140.73, 138.81, 132.26, 128.89, 127.64, 127.63, 126.56, 124.72, 119.34, 112.55, 77.48, 77.16, 76.84, 48.95, 34.45, 31.64.
To a suspension of the HCl salt of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (1.0 equiv, 1.26 mmol, 350 mg) and 2-aminopyrimidine-5-carbaldehyde (0.95 equiv, 1.19 mmol, 150 mg) in CH2Cl2 (0.2 M, 6.0 mL) under inert atmosphere, was added triethylamine (2.2 equiv, 2.76 mmol, 0.38 mL). The brown suspension was stirred for 1.5 h and NaBH(OAc)3 (2.95 equiv, 3.71 mmol, 810 mg) was added. The so obtained beige suspension was then stirred for 4 h.
The reaction was poured into ice and EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered-off and concentrated. The crude product was purified by combi flash column chromatography using Et0Ac/MeOH as the eluent, to afford 5-(((6-(4-(tert-butyl)phenoxy)pyridin-3-yl)amino)methyl)pyrimidin-2-amine (0.48 mmol, 166 mg, 38% yield).
C20H23N5O; Mw=349.44 g.mol−1; 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 2H), 7.55 (d, J=2.9 Hz, 1H), 7.34 (d, J=8.7 Hz, 2H), 7.13 (dd, J=8.7, 3.0 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 6.79 (d, J=8.7 Hz, 1H), 6.53 (s, 2H), 6.03 (t, J=5.9 Hz, 1H), 4.03 (d, J=5.8 Hz, 2H), 1.27 (s, 9H).
To a suspension of the HCl salt of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (1.0 equiv, 1.04 mmol, 290 mg) and Cs2CO3 (2.5 equiv, 2.60 mmol, 847 mg) in DMF (0.4 M, 2.5 mL) under inert atmosphere, bromoacetonitrile (1.0 equiv, 1.04 mmol, 72 μL) was added. The yellow suspension was stirred 16 h at 80° C. The reaction mixture was poured into a stirred mixture of EtOAc and water. The layers were separated and the organic layer was washed with water, dried over Na2SO4 or MgSO4, filtered-off and concentrated under reduced pressure. The crude product was purified by combi flash column chromatography using toluene/EtOAc as the eluent, to afford 2-((6-(4-(tert-butyl)phenoxy)pyridin-3-yl)amino)acetonitrile (0.10 mmol, 28 mg, 10% yield).
C17H19N3O; Mw=281,36 g.mol−1; 1H NMR (400 MHz, DMSO-d6) δ 7.78-7.75 (m, 1H), 7.40-7.36 (m, 2H), 7.14 (dd, J=8.8, 3.1 Hz, 1H), 7.04-6.99 (m, 2H), 6.87 (dd, J=8.7, 0.7 Hz, 1H), 4.10 (s, 2H), 1.32 (s, 9H).
To a stirred 9:1 mixture of DMF and MeOH (0.4 M, 0.45 mL) in a microwave tube, 2-((6-(4-(tert-butyl)phenoxy)pyridin-3-yl)amino)acetonitrile (1.0 equiv, 0.17 mmol, 44 mg), copper(I) bromide (0.07 equiv, 12 μmol, 1.7 mg) and azidotrimethylsilane (1.5 equiv, 0.26 mmol, 34 μL) were added. The tube was sealed and N2 was bubbled through the mixture. The yellow suspension was stirred 16 h at 85° C. The reaction mixture was poured into a stirred mixture of EtOAc and water. The layers were separated and the organic layer was washed with water, dried over Na2SO4 or MgSO4, filtered-off and concentrated under reduced pressure. The crude product was purified by combi flash column chromatography using CH2Cl2/MeOH as the eluent, to afford N-((2H-tetrazol-5-yl)methyl)-6-(4-(tert-butyl)phenoxy)pyridin-3-amine (0.07 mmol, 22 mg, 40% yield).
C17H20N6O; Mw=324.39 g.mol−1; 1H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J=3.0 Hz, 1H), 7.37-7.32 (m, 2H), 7.15 (dd, J=8.7, 3.1 Hz, 1H), 6.91-6.86 (m, 2H), 6.82 (d, J=8.7 Hz, 1H), 6.35 (t, J=5.9 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 1.27 (s, 9H).
A solution of 2-((6-(4-(tert-butyl)phenoxy)pyridin-3-yl)amino)acetohydrazide (1.0 equiv, 350 μmol, 110 mg) and formic acid (1.0 equiv, 350 μmol, 13 μL) in DCE (0.3 M, 1 mL) in a sealed microwave vial was stirred 30 min, then POCl3 (1.0 equiv, 350 μmol, 33 μL) was added. The yellow solution was stirred 16 h at 85° C. Volatiles were removed and the crude product was purified by combi flash column chromatography using cyclohexane/EtOAc as the eluent, to afford N-((1,3,4-oxadiazol-2-yl)methyl)-6-(4-(tert-butyl)phenoxy)pyridin-3-amine (43 μmol, 14 mg, 12% yield).
C18H20N4O2; Mw=324.38 g.mol−1; 1H I NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.05 (d, J=2.6 Hz, 1H), 7.78 (dd, J=9.0, 3.1 Hz, 1H), 7.47 (s, 1H), 7.43-7.39 (m, 2H), 7.05 (dd, J=8.9, 0.5 Hz, 1H), 7.03-6.99 (m, 2H), 4.19 (s, 2H), 1.30 (s, 9H).
The starting material was prepared as follows:
To a suspension of the HCl salt of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (1.0 equiv, 3.62 mmol, 1.0 g) and K2CO3 (1.3 equiv, 4.60 mmol, 640 mg) in DMF (0.3 M, 12 mL) under inert atmosphere, bromomethyl acetate (1.3 equiv, 4.60 mmol, 0.45 mL) was added. The pink suspension was stirred 60 h at RT. The reaction mixture was poured into a stirred mixture of EtOAc and water. The layers were separated and the organic layer was washed with water, dried over Na2SO4 or MgSO4, filtered-off and concentrated under reduced pressure. The crude product was purified by combi flash column chromatography using cyclohexane/EtOAc as the eluent, to afford methyl (6-(4-(tert-butyl)phenoxy)pyridin-3-yl)glycinate (3.28 mmol, 1.0 g, 90% yield).
C18H22N2O3; Mw=314.39 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J=3.2, 0.6 Hz, 1H), 7.38-7.33 (m, 2H), 7.02 (dd, J=8.8, 3.1 Hz, 1H), 7.00-6.96 (m, 2H), 6.79 (dd, J=8.7, 0.6 Hz, 1H), 3.90 (s, 2H), 3.79 (s, 3H), 1.31 (s, 9H).
To a solution of methyl (6-(4-(tert-butyl)phenoxy)pyridin-3-yl)glycinate (1.0 equiv, 1.72 mmol, 540 mg) in EtOH (0.1 M, 18 mL), hydrazine monohydrate (1.6 equiv, 2.78 mmol, 0.21 mL) was added. The colorless solution was stirred 5 h at 80° C. Volatiles were removed and the crude product was purified by combi flash column chromatography using CH2Cl2/MeOH as the eluent, to afford 2-((6-(4-(tert-butyl)phenoxy)pyridin-3-yl)amino)acetohydrazide (1.27 mmol, 400 mg, 74% yield).
C17H22N4O2; Mw=314.39 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=3.1 Hz, 1H), 7.38-7.33 (m, 2H), 6.99 (m, 3H), 6.79 (d, J=8.8 Hz, 1H), 3.85 (s, 2H), 1.31 (s, 9H).
2-((6-(4-(tert-Butyl)phenoxy)pyridin-3-yl)amino)acetohydrazide (1.0 equiv, 80 μmol, 25 mg), BrCN (1.2 equiv, 95 μmol, 10 mg), and NaHCO3 (1.2 equiv, 95 μmol, 8 mg) were added to a 5:2 mixture of dioxane and water (0.05 M, 1.4 mL) in a sealed microwave vial. The yellow suspension was sonicated for 5 h. The reaction mixture was poured into a mixture of EtOAc and sat. aq. NaHCO3. The layers were separated and the organic layer was washed with brine, dried over Na2SO4 or MgSO4, filtered-off and concentrated under reduced pressure. The crude product was purified by combi flash column chromatography using CH2Cl2/MeOH as the eluent, to afford 5-(((6-(4-(tert-butyl)phenoxy)pyridin-3-yl)amino)methyl)-1,3,4-oxadiazol-2-amine (35 μmol, 12 mg, 43% yield).
C18H21N5O2; Mw=339.40 g.mol−1; 1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J=3.0 Hz, 1H), 7.37-7.32 (m, 2H), 7.18 (dd, J=8.8, 3.1 Hz, 1H), 6.96 (s, 2H), 6.91-6.86 (m, 2H), 6.82 (d, J=8.7 Hz, 1H), 6.29 (t, J=6.3 Hz, 1H), 4.32 (d, J=6.3 Hz, 2H), 1.27 (s, 9H).
Following the General procedure C, N-((1H-imidazol-4-yl)methyl)-6-(4-(tert-butyl)phenoxy)pyridin-3-amine was obtained in 32% yield (0.12 mmol, 37 mg) from the HCl salt of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (0.36 mmol, 100 mg).
C19H22N4O; Mw=322.41 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=3.0 Hz, 1H), 7.62 (s, 1H), 7.37-7.32 (m, 2H), 7.07 (dd, J=8.7, 3.0 Hz, 1H), 6.99-6.94 (m, 3H), 6.77 (d, J=8.7 Hz, 1H), 4.29 (s, 2H), 1.31 (s, 9H).
Following the General procedure F, 6-((4′-fluoro-[1,1′-biphenyl]-4-yl)oxy)-4-methyl-N-(pyridin-3-ylmethyl)pyridin-3-amine was obtained in 45% yield (0.15 mmol, 0.047 g) from 6-((4′-fluoro-[1,1′-biphenyl]-4-yl)oxy)-4-methylpyridin-3-amine (0.340 mmol, 0.100 mg). C24H20FN3O; Mw=385.43 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.49 (d, J=4.1 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.46-7.39 (m, 4H), 7.22 (dd, J=7.8, 4.9 Hz, 2H), 7.07-6.99 (m, 4H), 6.70 (s, 1H), 4.33 (s, 2H), 3.58 (s, 1H), 2.15 (s, 3H).
The starting materials were prepared as followed:
Following the General procedure A, 2-(4-bromophenoxy)-4-methyl-5-nitropyridine was obtained in 40% yield (11 mmol, 3.50 g) from 4-bromophenol (31.9 mmol, 5.51 g) and 2-chloro-4-methyl-5-nitropyridine (29 mmol, 5.00 g).
C12H9BrN2O3; Mw=309.12 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 7.55 (d, J=8.9 Hz, 2H), 7.04 (d, J=8.9 Hz, 2H), 6.86 (d, J=1.0 Hz, 1H), 2.68 (app d, J=1.0 Hz, 3H).
Following the General procedure E, 2-((4′-fluoro-[1,1′-biphenyl]-4-yl)oxy)-4-methyl-5-nitropyridine was obtained in 82% yield (1.13 mmol, 0.30 g) from 2-(4-bromophenoxy)-4-methyl-5-nitropyridine (1.13 mmol, 0.350 mg) and (4-fluorophenyl)boronic acid (1.70 mmol, 0.238 mg).
C18H13FN2O3; Mw=324.31 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 7.63-7.58 (m, 2H), 7.57-7.52 (m, 2H), 7.23-7.19 (m, 2H), 7.17-7.11 (m, 2H), 6.89 (d, J=0.9 Hz, 1H), 2.69 (s, 3H).
Following the General procedure B, 6-((4′-fluoro-[1,1′-biphenyl]-4-yl)oxy)-4-methylpyridin-3-amine was obtained in 86% yield (476 mmol, 0.140 g) from 24(4′-fluoro-[1,1′-biphenyl]-4-yl)oxy)-4-methyl-5-nitropyridine (555 mmol, 0.180 g).
C18H15FN2O; Mw=294.33 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.54-7.46 (m, 4H), 7.14-7.06 (m, 4H), 6.72 (s, 1H), 2.20 (s, 3H), 2.07 (s, 2H).
Following the General procedure F, 6-((4′-fluoro-[1,1′-biphenyl]-4-yl)oxy)-2-methyl-N-(pyridin-3-ylmethyl)pyridin-3-amine was obtained in 32% yield (0.088 mmol, 34 mg) from 6-((4′-fluoro-[1,1′-biphenyl]-4-yl)oxy)-2-methylpyridin-3-amine (0.27 mmol, 80 mg).
C24H20FN3O; Mw=385.44 g mol−1; 1H NMR (400 MHz, DMSO-d6) δ 8.63-8.57 (m, 1H), 8.44 (dd, J=4.8, 1.7 Hz, 1H), 7.77 (dt, J=7.8, 1.9 Hz, 1H), 7.71-7.63 (m, 2H), 7.62-7.54 (m, 2H), 7.35 (ddd, J=7.8, 4.8, 0.8 Hz, 1H), 7.31-7.21 (m, 2H), 7.01-6.94 (m, 2H), 6.91 (d, J=8.6 Hz, 1H), 6.68 (d, J=8.5 Hz, 1H), 5.85 (t, J=6.1 Hz, 1H), 4.39 (d, J=6.1 Hz, 2H), 2.30 (s, 3H).
The starting materials were prepared as followed:
Following the General procedure A, 6-(4-bromophenoxy)-2-methyl-3-nitropyridine was obtained in 93% yield (26.9 mmol, 8.31 g) from 6-chloro-2-methyl-3-nitropyridine (29 mmol, 5.00 g) and 4-bromophenol (32 mmol, 5.50 g).
C12H9BrN2O3; Mw=309.12 g mol−1; lNMR (400 MHz, CDCl3) δ 8.38 (d, J=8.9 Hz, 1H), 7.72-7.42 (m, 2H), 7.15-6.99 (m, 2H), 6.84 (d, J=8.9 Hz, 1H), 2.73 (s, 3H).
Following the General procedure E, a mixture of (4-fluorophenyl)boronic acid (4.85 mmol, 679 mg), 6-(4-bromophenoxy)-2-methyl-3-nitropyridine (3.23 mmol, 1.00 g), K2CO3 (8.09 mmol, 1.12 g), and Pd(PPh3)4 (0.162 mmol, 187 mg, 5% mol) in 4:1 mixture of dioxane/H2O (0.1 M) was converted to 6-((4′-fluoro-[1,1′-biphenyl]-4-yl)oxy)-2-methyl-3-nitropyridine in 90% yield (2.94 mmol, 900 mg).
C18H13FN2O3; Mw=324.31 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=8.9 Hz, 1H), 7.62-7.58 (m, 2H), 7.58-7.53 (m, 2H), 7.25-7.21 (m, 2H), 7.19-7.11 (m, 2H), 6.84 (dd, J=8.9, 0.7 Hz, 1H), 2.77 (s, 3H).
Following the General procedure B, 6-((4′-fluoro-[1,1′-biphenyl]-4-yl)oxy)-2-methylpyridin-3-amine was obtained in 72% yield (1.11 mmol, 330 mg) from 6-((4′-fluoro-[1,1′-biphenyl]-4-yl)oxy)-2-methyl-3-nitropyridine (1.54 mmol, 500 mg).
C18H15FN2O; Mw=294.33 g.mol−1; 1H NMR (400 MHz, DMSO-d6) δ 7.71-7.63 (m, 2H), 7.63-7.56 (m, 2H), 7.32-7.22 (m, 2H), 7.08 (d, J=8.3 Hz, 1H), 7.02-6.96 (m, 2H), 6.67 (d, J=8.3 Hz, 1H), 4.90 (s, 2H), 2.18 (s, 3H).
Following the General procedure F, 4-methyl-N-(pyridin-3-ylmethyl)-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine was obtained in 28% yield (80 mmol, 0.030 g) from 4-methyl-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine (0.28 mmol, 0.080 g).
C21H18N4OS; Mw=374.46 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.66 (s, 1H), 8.56 (s, 1H), 8.00 (s, 1H), 7.71 (dt, J=7.9, 1.9 Hz, 1H), 7.57-7.49 (m, 3H), 7.30 (dd, J=7.8, 4.8 Hz, 1H), 7.12-7.06 (m, 2H), 6.77 (s, 1H), 4.40 (d, J=3.2 Hz, 2H), 3.68 (s, 1H), 2.22 (s, 3H).
The starting material was prepared as follows:
Following the General procedure A, 2-(4-bromophenoxy)-4-methyl-5-nitropyridine was obtained in 40% yield (11 mmol, 3.50 g) from 4-bromophenol (31.9 mmol, 5.51 g) and 2-chloro-4-methyl-5-nitropyridine (29 mmol, 5.00 g).
C12H9BrN2O3; Mw=309.12 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 7.55 (d, J=8.9 Hz, 2H), 7.04 (d, J=8.9 Hz, 2H), 6.86 (d, J=1.0 Hz, 1H), 2.68 (app d, J=1.0 Hz, 3H).
Following the General procedure E, 5-(4-((4-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole was obtained in 40% yield (1.02 mmol, 0.320 g) from 5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)thiazole (3.78 mmol, 0.799 mg) and 2-(4-bromophenoxy)-4-methyl-5-nitropyridine (2.52 mmol, 0.780 g).
C15H11N3O3S; Mw=313.33 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.78 (s, 1H), 8.07 (s, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.21 (d, J=8.7 Hz, 2H), 6.90 (s, 1H), 2.69 (s, 3H).
Following the General procedure B, 4-methyl-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine was obtained in 33% yield (0.424 mmol, 0.120 g) from 5-(4-((4-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole (1.02 mmol, 0.320 g).
C15H13N3OS; Mw=283.35 g.mol−1; lH NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.00 (s, 1H), 7.67 (s, 1H), 7.54 (d, J=8.7 Hz, 2H), 7.09 (d, J=8.7 Hz, 2H), 6.73 (s, 1H), 2.21 (s, 3H), 2.04 (s, 2H).
Following the General procedure F, 2-methyl-N-(pyridin-3-ylmethyl)-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine was obtained in 61% yield (0.15 mmol, 56 mg) from 2-methyl-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine (0.25 mmol, 70 mg).
C21H18N4OS; Mw=374.46 g mol−1; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J=0.7 Hz, 1H), 8.67-8.52 (m, 1H), 8.44 (dd, J=4.8, 1.7 Hz, 1H), 8.22 (d, J=0.7 Hz, 1H), 7.77 (dt, J=7.9, 2.0 Hz, 1H), 7.63 (d, J=8.7 Hz, 2H), 7.35 (ddd, J=7.9, 4.8, 0.9 Hz, 1H), 7.00-6.95 (m, 2H), 6.91 (d, J=8.6 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 5.87 (t, J=6.1 Hz, 1H), 4.39 (d, J=6.1 Hz, 2H), 2.30 (s, 3H).
The starting material was prepared as follows:
Following the General procedure D, a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (4.89 mmol, 1.03 g), 6-(4-bromophenoxy)-2-methyl-3-nitropyridine (3.26 mmol, 1.01 g; expl. 12, Step 1), Na2CO3 (8.15 mmol, 864 mg), and Pd(PPh3)4 (0.163 mmol, 188 mg, 5% mol) in a 4:1 mixture of dioxane/H2O (0.06 M) was converted to 5-(4-((6-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole in 20% yield (0.67 mmol, 209 mg).
C15H11N3O3S; Mw=313.33 g.mol−1; 1H NMR (400 MHz, DMSO-d6) δ 9.10 (app d, J=0.7 Hz, 1H), 8.52 (d, J=8.9 Hz, 1H), 8.33 (s, 1H), 7.91-7.71 (m, 2H), 7.40-7.21 (m, 2H), 7.11 (d, J=8.9 Hz, 1H), 2.60 (s, 3H).
Following the General procedure B, 2-methyl-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine was obtained in 64% yield (0.42 mmol, 120 mg) from 5-(4-((6-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole (0.66 mmol, 206 mg).
C15H13N3OS; Mw=283.35 g.mol−1; lNMR (400 MHz, DMSO-d6) δ 9.04 (d, J=0.7 Hz, 1H), 8.22 (d, J=0.7 Hz, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.3 Hz, 1H), 6.99 (d, J=8.7 Hz, 2H), 6.68 (d, J=8.4 Hz, 1H), 4.92 (s, 2H), 2.17 (s, 3H).
Following the General procedure F, 6-((2,2′-dimethyl-[1,1′-biphenyl]-4-yl)oxy)-2-methyl-N-(pyridin-3-ylmethyl)pyridin-3-amine was obtained in 30% yield (0.09 mmol, 35 mg) from 6-((2,2′-dimethyl-[1,1′-biphenyl]-4-yl)oxy)-2-methylpyridin-3-amine (0.30 mmol, 90 mg).
C26H25N3O; Mw=395.51 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.59 (d, J=4.3 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.40 (dd, J=7.7, 5.0 Hz, 1H), 7.25-7.18 (m, 3H), 7.10 (d, J=6.8 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.93 (d, J=2.5 Hz, 1H), 6.89-6.82 (m, 2H), 6.64 (d, J=8.4 Hz, 1H), 4.44 (s, 2H), 3.88 (s, 1H), 2.43 (s, 3H), 2.07 (s, 3H), 2.01 (s, 3H).
The starting material was prepared as follows:
Following the General procedure A, 6-(4-bromo-3-methylphenoxy)-2-methyl-3-nitropyridine was obtained in 94% yield (5.46 mmol, 1.76 g) from 6-chloro-2-methyl-3-nitropyridine (5.79 mmol, 1.00 g) and 4-bromo-3-methylphenol (6.37 mmol, 1.19 g).
C13H11BrN2O3; Mw=323.15 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=8.9 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.05 (d, J=2.6 Hz, 1H), 6.88 (dd, J=8.6, 2.6 Hz, 1H), 6.80 (d, J=8.9 Hz, 1H), 2.74 (s, 3H), 2.42 (s, 3H).
Following the General procedure D, a mixture of o-tolylboronic acid (3.71 mmol, 505 mg), 6-(4-bromo-3-methylphenoxy)-2-methyl-3-nitropyridine (2.48 mmol, 800 mg), Na2CO3 (4.95 mmol, 525 mg), and Pd(PPh3)4 (0.124 mmol, 143 mg, 5% mol) in a 3:1 mixture of DME/H2O (0.43 M) was converted to 64(2,2′-dimethyl-[1,1′-biphenyl]-4-yl)oxy)-2-methyl-3-nitropyridine in 90% yield (2.24 mmol, 750 mg).
C20H18N2O3; Mw=334.38 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=8.9 Hz, 1H), 7.33-7.21 (m, 3H), 7.19-7.09 (m, 2H), 7.07 (d, J=2.5 Hz, 1H), 7.02 (dd, J=8.2, 2.5 Hz, 1H), 6.81 (d, J=8.9 Hz, 1H), 2.81 (s, 3H), 2.10 (s, 3H), 2.08 (s, 3H).
Following the General procedure B, 6-((2,2′-dimethyl-[1,1′-biphenyl]-4-yl)oxy)-2-methylpyridin-3-amine was obtained in 80% yield (0.60 mmol, 183 mg) from 64(2,2′-dimethyl-[1,1′-biphenyl]-4-yl)oxy)-2-methyl-3-nitropyridine (0.75 mmol, 250 mg).
C20H20N2O; Mw=304.39 g.mol−1; 1H NMR (400 MHz, methanol-d4) δ 7.29-7.16 (m, 4H), 7.06-7.03 (m, 1H), 7.01 (d, J=8.3 Hz, 1H), 6.88 (d, J=2.6 Hz, 1H), 6.80 (dd, J=8.3, 2.6 Hz, 1H), 6.63 (dd, J=8.5, 0.7 Hz, 1H), 2.33 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H).
Following the General procedure F, 2-methyl-N-(pyridin-3-ylmethyl)-6-(4-(thiazol-2-yl)phenoxy)pyridin-3-amine was obtained in 35% yield (0.16 mmol, 0.060 g) from 2-methyl-6-(4-(thiazol-2-yl)phenoxy)pyridin-3-amine (452 mmol, 0.128 g).
C21H18N4OS; Mw=374.46 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.70-8.67 (m, 1H), 8.60 (dd, J=4.8, 1.3 Hz, 1H), 7.96-7.90 (m, 2H), 7.85 (d, J=3.3 Hz, 1H), 7.76-7.69 (m, 1H), 7.34 (dd, J=7.6, 4.9 Hz, 1H), 7.30 (d, J=3.3 Hz, 1H), 7.11-7.05 (m, 2H), 6.94 (d, J=8.6 Hz, 1H), 6.71 (d, J=8.6 Hz, 1H), 4.43 (d, J=2.7 Hz, 2H), 3.87 (s, 1H), 2.41 (s, 3H).
The starting material was prepared as follows:
Following the General procedure A, 2-(4-((6-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole was obtained in 51% yield (1.44 mmol, 0.450 g) from 4-(2-thiazolyl)phenol (2.82 mmol, 500 mg) and 6-chloro-2-methyl-3-nitropyridine (3.10 mmol, 536 mg).
C15H11N3O3S; Mw=313.33 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=8.9 Hz, 1H), 8.04 (d, J=8.5 Hz, 2H), 7.88 (s, 1H), 7.36 (s, 1H), 7.25 (d, J=8.2 Hz, 2H), 6.87 (d, J=8.9 Hz, 1H), 2.74 (s, 3H).
Following the General procedure B, 2-methyl-6-(4-(thiazol-2-yl)phenoxy)pyridin-3-amine was obtained in 68% yield (0.434 mmol, 123 mg) from 2-(4-((6-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole (0.638 mmol, 200 mg).
C15H13N3OS; Mw=283.35 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=8.8 Hz, 2H), 7.76 (d, J=3.3 Hz, 1H), 7.22 (d, J=3.3 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.4 Hz, 1H), 6.59 (d, J=8.4 Hz, 1H), 2.30 (s, 3H).
Following the General procedure F, 2-methyl-6-((6-phenylpyridin-3-yl)oxy)-N-(pyridin-3-ylmethyl)pyridin-3-amine was obtained in 71% yield (0.20 mmol, 75 mg) from 2-methyl-6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine (0.29 mmol, 80 mg).
C23H20N4O; Mw=368.44 g mol−1; 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J=2.2 Hz, 1H), 8.44 (dd, J=4.8, 1.6 Hz, 1H), 8.39 (d, J=2.8 Hz, 1H), 8.10-8.01 (m, 2H), 7.93 (d, J=8.8 Hz, 1H), 7.77 (dd, J=7.9, 2.0 Hz, 1H), 7.52-7.44 (m, 3H), 7.43-7.40 (m, 1H), 7.39-7.32 (m, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.76 (d, J=8.5 Hz, 1H), 5.88 (t, J=6.2 Hz, 1H), 4.40 (d, J=6.1 Hz, 2H), 2.29 (s, 3H).
The starting material was prepared as follows:
Following the General procedure D, a mixture of phenylboronic acid (11.49 mmol, 1.40 g), 6-bromopyridin-3-ol (5.75 mmol, 1.00 g), Na2CO3 (11.49 mmol, 1.22 g), and Pd(PPh3)4 (0.287 mmol, 332 mg) in a 3:1 mixture of DME/H2O (0.32 M) was converted to 6-phenylpyridin-3-ol in 61% yield (3.50 mmol, 600 mg).
C11H9NO; Mw=171.20 g mol−1; 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.40-7.34 (m, 1H), 7.15-7.09 (m, 2H), 6.95 (dd, J=8.6, 0.7 Hz, 1H), 6.65-6.57 (m, 2H), 6.54-6.49 (m, 1H), 6.40 (dd, J=8.6, 2.9 Hz, 1H).
Following the General procedure A, 2-methyl-3-nitro-6((6-phenylpyridin-3-yl)oxy)pyridine was obtained in 95% yield (1.22 mmol, 374 mg) from 6-chloro-2-methyl-3-nitropyridine (1.27 mmol, 220 mg).
C17H13N3O3; Mw=307.31 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.60 (dd, J=2.8, 0.7 Hz, 1H), 8.42 (d, J=8.9 Hz, 1H), 8.09-7.93 (m, 2H), 7.82 (dd, J=8.7, 0.7 Hz, 1H), 7.62 (dd, J=8.7, 2.8 Hz, 1H), 7.56-7.40 (m, 3H), 6.96 (d, J=8.9 Hz, 1H), 2.73 (s, 3H).
Following the General procedure B, 2-methyl-6((6-phenylpyridin-3-yl)oxy)pyridin-3-amine was obtained in 89% yield (1.08 mmol, 300 mg) from 2-methyl-3-nitro-6-((6-phenylpyridin-3-yl)oxy)pyridine (1.22 mmol, 374 mg).
C17H15N3O; Mw=277.33 g.mol−1; 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J=2.5 Hz, 1H), 8.15-7.98 (m, 2H), 7.94 (d, J=8.7 Hz, 1H), 7.55-7.45(m, 3H), 7.44-7.37 (m, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 4.93 (s, 2H), 2.17 (s, 3H).
Following the General procedure H, 4-(4-(tert-butyl)phenoxy)-3-fluoro-N-(pyridin-3-ylmethyl)aniline was obtained in 40% yield (0.23 mmol, 80 mg) from 4-(4-(tert-butyl)phenoxy)-3-fluoroaniline (0.578 mmol, 150 mg; preparation see: WO 2013 093885).
C22H23FN2O; Mw=350.44 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.65-8.63 (m, 1H), 8.57-8.53 (m, 1H), 7.73-7.68 (m, 1H), 7.32-7.26 (m, 3H), 6.94 (t, J=8.9 Hz, 1H), 6.86-6.80 (m, 2H), 6.46-6.41 (m, 1H), 6.39-6.34 (m , 1H), 4.34 (s, 2H), 4.14 (s, 1H), 1.29 (s, 9H).
Following the General procedure H, 4-(4-cyclohexylphenoxy)-3-fluoro-N-(pyridin-3-ylmethyl)aniline was obtained in 61% yield (0.21 mmol, 80 mg) from 4-(4-cyclohexylphenoxy)-3-fluoroaniline (0.35 mmol, 100 mg; preparation see: WO 2013 093885).
C24H25FN2O; Mw=376.48 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.58-8.54 (m, 1H), 7.74-7.69 (m, 1H), 7.33-7.28 (m, 1H), 7.12-7.07 (m, 2H), 6.93 (t, J=8.9 Hz, 1H), 6.86-6.79 (m, 2H), 6.47-6.41 (m, 1H), 6.38-6.34 (m, 1H), 4.35 (s, 2H), 4.10 (bs, 1H), 2.49-2.41(m, 1H), 1.88-1.78 (m, 4H), 1.77-1.70 (m, 2H), 1.41-1.32 (m, 4H).
Following the General procedure H, 6-([1,1′-biphenyl]-4-yloxy)-N-(pyridin-3-ylmethyl)pyridin-3-amine was obtained in 25% yield (0.14 mmol, 50 mg) from 6-([1,1′-biphenyl]-4-yloxy)pyridin-3-amine (0.572 mmol, 150 mg).
C23H19N3O; Mw=253.43 g mol−1; 1H NMR1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.55 (d, J=5.0 Hz, 1H), 7.73-7.66 (m, 2H), 7.60-7.52 (m, 4H), 7.47-7.38 (m, 2H), 7.35-7.27 (m, 2H), 7.14-7.10 (m, 2H), 7.06-7.01 (m, 1H), 6.85-6.81 (m, 1H), 4.36 (s, 2H), 4.02 (s, 1H).
The starting material was prepared as follows:
Following the General procedure A, 2-([1,1′-biphenyl]-4-yloxy)-5-nitropyridine was obtained in 99% yield without purification (4.65 mmol, 1.36 g) from [1,1′-biphenyl]-4-ol (4.70 mmol, 800 mg) and 2-chloro-5-nitropyridine (4.70 mmol, 745 mg).
C17H12N2O3; Mw=292.29 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 9.08 (d, J=2.8 Hz, 1H), 8.50 (dd, J=9.1, 2.8 Hz, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.60 (dd, J=8.3, 1.2 Hz, 2H), 7.46 (dd, J=8.2, 6.8 Hz, 2H), 7.40-7.33 (m, 1H), 7.26-7.20 (m, 2H), 7.08 (dd, J=9.1, 0.5 Hz, 1 H).
Following the General procedure B, 6-([1,1′-biphenyl]-4-yloxy)pyridin-3-amine was obtained in 97% yield (1.66 mmol, 434 mg) from 2-([1,1′-biphenyl]-4-yloxy)-5-nitropyridine (1.71 mmol, 500 mg).
C17H14N2O; Mw=262.31 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J=3.0, 0.6 Hz, 1H), 7.61-7.52 (m, 4 H), 7.47-7.39 (m, 2H), 7.36-7.29 (m, 1H), 7.17-7.06 (m, 3H), 6.82 (dd, J=8.6, 0.6 Hz, 1H).
Following the General procedure H, 6-((6-phenylpyridin-3-yl)oxy)-N-(pyridin-3-ylmethyl)pyridin-3-amine was obtained in 49% yield (0.282 mmol, 100 mg) from 6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine (0.576 mmol, 152 mg).
C22H18N4O; Mw=354.41 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.59-8.54 (m, 1H), 8.52 (d, J=2.8 Hz, 1H), 7.97-7.92 (m, 2H), 7.79-7.74 (m, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.62 (d, J=3.0 Hz, 1H), 7.54-7.50 (m, 1H), 7.49-7.42 (m, 2H), 7.42-7.33 (m, 2H), 7.09-7.04 (m, 1H), 6.89 (d, J=8.7 Hz, 1H), 4.40 (s, 2H), 4.06 (s, 1H).
The starting material was prepared as follows:
Following the General procedure A, 5-nitro-2-((6-phenylpyridin-3-yl)oxy)pyridine was obtained in 93% yield (2.63 mmol, 0.77 g) from 6-phenylpyridin-3-ol (2.92 mmol, 0.51 g) and 2-chloro-5-nitropyridine (2.84 mmol, 0.45 g).
C16H11N3O3; Mw=293.28 g.mol−1; Solid; 1H NMR (400 MHz, CDCl3) δ 9.04 (d, J=2.7 Hz, 1H), 8.59 (d, J=2.6 Hz, 1H), 8.54 (dd, J=9.0, 2.8 Hz, 1H), 8.04-7.97 (m, 2H), 7.83 (d, J=8.6 Hz, 1H), 7.62 (dd, J=8.6, 2.8 Hz, 1H), 7.52-7.47 (m, 2H), 7.45 (dd, J=4.9, 3.6 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H).
Following the General procedure B, 6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine was obtained in 93% yield (2.43 mmol, 0.64 g) from 5-nitro-2-((6-phenylpyridin-3-yl)oxy)pyridine (2.63 mmol, 0.77 g).
C16H13N3O; Mw=263.30 g.mol−1; Solid; 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J=2.7 Hz, 1H), 7.96 (d, J=7.3 Hz, 2H), 7.71 (dd, J=7.9, 5.9 Hz, 2H), 7.51 (dd, J=8.6, 2.7 Hz, 1H), 7.46 (t, J=7.5 Hz, 2H), 7.39 (t, J=7.3 Hz, 1H), 7.13 (dd, J=8.6, 2.9 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 3.63 (s, 2H).
Following the General procedure H, 6-([1,1′-biphenyl]-4-yloxy)-4-methyl-N-(pyridin-3-ylmethyl)pyridin-3-amine was obtained in 44% yield (0.24 mmol, 90 mg) from 6-([1,1′-biphenyl]-4-yloxy)-4-methylpyridin-3-amine (0.543 mmol, 150 mg).
C24H21N3O; Mw=367.45 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J=2.2 Hz, 1H), 8.57-8.53 (m, 1H), 7.73-7.69 (m, 1H), 7.58-7.51 (m, 5H), 7.45-7.38 (m, 2H), 7.35-7.27 (m, 2H), 7.15-7.09 (m, 2H), 6.79-6.75 (m, 1H), 4.40 (s, 2H), 3.66 (s, 1H), 2.22 (s, 3H).
The starting material was prepared as follows:
Following the General procedure A, 6-([1,1′-biphenyl]-4-yloxy)-4-methyl-3-nitropyridine was obtained in 38% yield (2.3 mmol, 0.71 g) from [1,1′-biphenyl]-4-ol (5.9 mmol, 1.00 g) and 6-chloro-4-methyl-3-nitropyridine (5.8 mmol, 1.00 g).
C18H14N2O3; Mw=306.32 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.69-7.63 (m, 2H), 7.63-7.57 (m, 2H), 7.49-7.42 (m, 2H), 7.40-7.34 (m, 1H), 7.25-7.20 (m, 2H), 6.88 (d, J=0.9 Hz, 1H), 2.69 (d, J=0.8 Hz, 3H).
Following the General procedure B, 6-([1,1′-biphenyl]-4-yloxy)-4-methylpyridin-3-amine was obtained in 74% yield (1.5 mmol, 410 mg) from 6-([1,1′-biphenyl]-4-yloxy)-4-methyl-3-nitropyridine (2.0 mmol, 600 mg).
C18H16N2O; Mw=276.34 g.mol−1; 1HNMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.61-7.52 (m, 4H), 7.42 (t, J=7.6 Hz, 2H), 7.33 (dt, J=9.2, 4.3 Hz, 1H), 7.12 (d, J=8.7 Hz, 2H), 6.72 (s, 1H), 3.03 (s, 2H), 2.21 (d, J=0.5 Hz, 3H).
Following the General procedure H, 6-([1,1′-biphenyl]-4-yloxy)-2-methyl-N-(pyridin-3-ylmethyl)pyridin-3-amine was obtained in 60% yield (0.326 mmol, 120 mg) from 6-([1,1′-biphenyl]-4-yloxy)-2-methylpyridin-3-amine (0.543 mmol, 150 mg).
C24H21N3O; Mw=367.45 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.67-8.65 (m, 1H), 8.59-8.54 (m, 1H), 7.75-7.71 (m, 1H), 7.58-7.51 (m, 4H), 7.45-7.39 (m, 2H), 7.35-7.29 (m, 2H), 7.12-7.05 (m, 2H), 6.91-6.87 (m, 1H), 6.67-6.63 (m, 1H), 4.40 (s, 2H), 3.83 (s, 1H), 2.40 (s, 3H).
The starting material was prepared as follows:
Following the General procedure A, 6-([1,1′-biphenyl]-4-yloxy)-2-methyl-3-nitropyridine was obtained in 89% yield (5.3 mmol, 1.63 g) from [1,1′-biphenyl]-4-ol (5.9 mmol, 1.00 g) and 6-chloro-2-methyl-3-nitropyridine (5.8 mmol, 1.00 g).
C18H14N2O3; Mw=306.32 g.mol−1; 1HNMR (400 MHz, CDCl3) δ 8.38 (d, J=8.9 Hz, 1H), 7.63 (dd, J=16.5, 7.9 Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (dd, J=8.3, 6.4 Hz, 1H), 7.24 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.9 Hz, 1H), 2.78 (s, 3H).
Following the General procedure B, 6-([1,1′-biphenyl]-4-yloxy)-2-methylpyridin-3-amine was obtained in 90% yield (4.7 mmol, 1.31 g) from 6-([1,1′-biphenyl]-4-yloxy)-2-methyl-3-nitropyridine (5.3 mmol, 1.61 g).
C18H16N2O; Mw=276.34 g.mol−1; 1HNMR (400 MHz, CDCl3) δ 7.59-7.52 (m, 4H), 7.42 (t, J=7.6 Hz, 2H), 7.32 (ddd, J=7.4, 3.9, 1.2 Hz, 1H), 7.10 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 3.49 (s, 2H), 2.37 (s, 3H).
Following the General procedure H, 6-((4′-fluoro-[1,1′-biphenyl]-4-yl)oxy)-N-(pyridin-3-ylmethyl)pyridin-3-amine was obtained in 51% yield (0.18 mmol, 68 mg) from 6-((4′-fluoro-[1,1′-biphenyl]-4-yl)oxy)pyridin-3-amine (0.35 mmol, 100 mg).
C23H18FN3O; Mw=371.42 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.56 (d, J=4.9 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.66 (d, J=2.9 Hz, 1H), 7.59-7.46 (m, 4H), 7.34 (dd, J=7.9, 4.9 Hz, 1H), 7.17-7.00 (m, 5H), 6.84 (dd, J=8.8, 0.6 Hz, 1H), 4.38 (s, 2H), 4.02 (s, 1H).
The starting material was prepared as follows:
Following the General procedure A, 2-(4-bromophenoxy)-5-nitropyridine was obtained in 89% yield (37.2 mmol, 10.97 g) from 4-bromophenol (42.8 mmol, 7.40 g) and 2-chloro-5-nitropyridine (41.6 mmol, 6.60 g).
C11H7BrN2O3; Mw=295.09 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 9.03 (d, J=2.6 Hz, 1H), 8.49 (dd, J=9.0, 2.8 Hz, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.06 (m, 3H).
Following the General procedure E, a mixture of 4-fluorophenylboronic acid (8.9 mmol, 1.25 g), 2-(4-bromophenoxy)-5-nitropyridine (7.8 mmol, 2.30 g), K2CO3 (19.5 mmol, 2.70 g) and Pd(PPh3)4 (10% mol) in dioxane/H2O 4:1 (0.05-0.1 M) was converted to 24(4′-fluoro-[1,1′-biphenyl]-4-yl)oxy)-5-nitropyridine in 87% yield (6.8 mmol, 2.10 g).
C17H11FN2O3; Mw=310.28 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 9.07 (d, J=2.7 Hz, 1H), 8.50 (dd, J=9.0, 2.7 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.55 (dd, J=8.5, 5.4 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 7.14 (t, J=8.6 Hz, 2H), 7.09 (d, J=9.0 Hz, 1H).
Following the General procedure B, 6-((4′-fluoro-[1,1′-biphenyl]-4-yl)oxy)pyridin-3-amine was obtained in 58% yield (3.9 mmol, 1.10 g) from 2-((4′-fluoro-[1,1′-biphenyl]-4-yl)oxy)-5-nitropyridine (6.8 mmol, 2.10 g).
C17H13FN2O; Mw=280.30 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J=3.0 Hz, 1H), 7.51 (m, 4H), 7.16-7.07 (m, 5H), 6.82 (d, J=8.6 Hz, 1H).
Following the General procedure H, 3-fluoro-4-(4-(pyridin-2-yl)phenoxy)-N-(pyridin-3-ylmethyl)aniline was obtained in 78% yield (0.27 mmol, 103 mg) from 3-fluoro-4-(4-(pyridin-2-yl)phenoxy)aniline (0.35 mmol, 100 mg).
C23H18FN3O; Mw=371.42 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.65 (ddd, J=4.8, 1.8, 1.0 Hz, 2H), 8.57 (d, J=4.9 Hz, 1H), 7.99-7.87 (m, 2H), 7.79-7.62 (m, 3H), 7.32 (dd, J=7.9, 4.8 Hz, 1H), 7.19 (ddd, J=7.2, 4.9, 1.4 Hz, 1H), 7.05-6.92 (m, 3H), 6.56-6.35 (m, 2H), 4.37 (s, 2H), 4.16 (s, 1H).
The starting material was prepared as follows:
Following the General procedure A, 2-(4-(2-fluoro-4-nitrophenoxy)phenyl)pyridine was obtained in 30% yield (4.38 mmol, 1.36 g) from 4-(pyridin-2-yl)phenol (14.6 mmol, 2.50 g) and 1,2-difluoro-4-nitrobenzene (14.3 mmol, 2.28 g).
C17H11FN2O3; Mw=310.28 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.71 (ddd, J=4.9, 1.8, 0.9 Hz, 1H), 8.12 (dd, J=10.2, 2.6 Hz, 1H), 8.10-8.04 (m, 2H), 8.01 (ddd, J=9.0, 2.6, 1.5 Hz, 1H), 7.84-7.76 (m, 1H), 7.76-7.71 (m, 1H), 7.29 (s, 1H), 7.23-7.16 (m, 2H), 7.06 (dd, J=9.1, 7.9 Hz, 1H).
Following the General procedure B, 3-fluoro-4-(4-(pyridin-2-yl)phenoxy)aniline was obtained in 42% yield (1.8 mmol, 0.51 g) from 2-(4-(2-fluoro-4-nitrophenoxy)phenyl)pyridine (4.38 mmol, 1.36 g).
C17H13FN2O; Mw=280.30 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J=5.0 Hz, 1H), 7.90 (d, J=8.5 Hz, 2H), 7.75 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.28 (m, 1H), 7.02-6.94 (m, 2H), 6.90 (t, J=8.8 Hz, 1H), 6.46 (dd, J=12.0, 2.7 Hz, 1H), 6.39 (ddd, J=8.6, 2.7, 1.3 Hz, 1H).
Following the General procedure H, 3-fluoro-4-(4-(pyridin-3-yl)phenoxy)-N-(pyridin-3-ylmethyl)aniline was obtained in 63% yield (0.22 mmol, 84 mg) from 3-fluoro-4-(4-(pyridin-3-yl)phenoxy)aniline (0.35 mmol, 100 mg).
C23H18FN3O; Mw=371.42 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J=2.3 Hz, 1H), 8.71-8.51 (m, 3H), 7.83 (ddd, J=7.9, 2.4, 1.6 Hz, 1H), 7.72 (dd, J=7.8, 1.9 Hz, 1H), 7.54-7.43 (m, 2H), 7.33 (ddd, J=12.4, 7.8, 4.8 Hz, 2H), 7.07-6.93 (m, 3H), 6.54-6.34 (m, 2H), 4.37 (s, 2H).
The starting material was prepared as follows:
Following the General procedure A, 3-(4-(2-fluoro-4-nitrophenoxy)phenyl)pyridine was obtained in 79% yield (17.7 mmol, 5.48 g) from 4-(pyridin-3-yl)phenol (22.4 mmol, 3.84 g) and 1,2-difluoro-4-nitrobenzene (22.0 mmol, 3.50 g).
C17H11FN2O3; Mw=310.28 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.64 (d, J=5.0 Hz, 1H), 8.13 (dd, J=10.2, 2.7 Hz, 1H), 8.09-7.98 (m, 2H), 7.69-7.61 (m, 2H), 7.55-7.48 (m, 1H), 7.23-7.17 (m, 2H), 7.11 (dd, J=9.0, 7.8 Hz, 1H).
Following the General procedure B, 3-fluoro-4-(4-(pyridin-3-yl)phenoxy)aniline was obtained in 63% yield (11.1 mmol, 3.1 g) from 3-(4-(2-fluoro-4-nitrophenoxy)phenyl)pyridine (17.7 mmol, 5.48 g).
C17H13FN2O; Mw=280.30 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J=2.4 Hz, 1H), 8.57 (dd, J=5.0, 1.5 Hz, 1H), 7.95 (s, 1H), 7.52-7.47 (m, 2H), 7.45 (s, 1H), 7.06-7.00 (m, 2H), 6.97 (t, J=8.7 Hz, 1H), 6.54 (dd, J=12.0, 2.7 Hz, 1H), 6.46 (ddd, J=8.6, 2.7, 1.2 Hz, 1H).
Following the General procedure H, N-(pyridin-3-ylmethyl)-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine was obtained in 31% yield (0.11 mmol, 42 mg) from 6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine (0.37 mmol, 100 mg).
C20H16N4OS; Mw=360.44 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.68-8.51 (m, 2H), 8.00 (s, 1H), 7.78-7.63 (m, 2H), 7.59-7.50 (m, 2H), 7.30 (d, J=5.8 Hz, 1H), 7.14-7.01 (m, 3H), 6.84 (dd, J=8.7, 0.6 Hz, 1H), 4.36 (s, 2H).
The starting material was prepared as follows:
To a suspension of 2-(4-bromophenoxy)-5-nitropyridine (20.6 mmol, 6.08 g; expl. 24, Step 1), CH3COOK (61.1 mmol, 6.00 g) and bis(pinacolato)diboron (30.5 mmol, 7.75 g) in dioxane (0.1 M, 150 mL) under inert atmosphere, Pd(dppf)Cl2′CH2Cl2 (5% mol) was added. The red mixture was stirred 16 h at 105° C. The reaction mixture was filtered through a pad of celite. Water was added to the filtrate and the mixture was extracted with EtOAc (2x). The organic layer was washed with sat. aq. NaHCO3, brine, dried over Na2SO4, filtered-off and concentrated. The crude product was purified by combi flash column chromatography using EtOAc/cyclohexane (1% to 20%) as the eluent, to afford 5-nitro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine (15.6 mmol, 5.93 g, 76% yield).
C17H19BN2O5; Mw=342.16 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 9.04 (d, J=2.5 Hz, 1H), 8.47 (dd, J=9.1, 2.8 Hz, 1H), 7.94-7.88 (m, 2H), 7.20-7.13 (m, 2H), 7.06-7.01 (m, 1H), 1.35 (s, 12H).
Following the General procedure D, a mixture of 5-nitro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine (9.2 mmol, 3.50 g), 5-bromothiazole (7.4 mmol, 1.25 g), Cs2CO3 (15.0 mmol, 4.90 g) and PdCl2(PPh3)2 (10% mol) in dioxane/H2O 4:1 (0.05-0.1 M) was converted to 5-(4-((5-nitropyridin-2-yl)oxy)phenyl)thiazole in 52% yield (3.8 mmol, 1.15 g).
C14H9N3O3S; Mw=299.30 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 9.05 (d, J=2.6 Hz, 1H), 8.78 (s, 1H), 8.51 (dd, J=9.1, 2.8 Hz, 1H), 8.08 (s, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.10 (d, J=9.0 Hz, 1H).
Following the General procedure B, 6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine was obtained in 46% yield (1.8 mmol, 0.48 g) from 5-(4-((5-nitropyridin-2-yl)oxy)phenyl)thiazole (3.8 mmol, 1.15 g).
C14H11N3OS; Mw=269.32 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.95 (s, 1H), 7.67 (d, J=3.0 Hz, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.05 (m, 3H), 6.76 (d, J=8.6 Hz, 1H).
Following the General procedure H, 4-((2,2′-dimethyl-[1,1′-biphenyl]-4-yl)oxy)-N-(pyridin-3-ylmethyl)aniline was obtained in 51% yield (0.15 mmol, 68 mg) from 44((2,2′-dimethyl-[1,1′-biphenyl]-4-yl)oxy)aniline (0.34 mmol, 100 mg).
C26H24N2O; Mw=380.49 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.67 (dd, J=2.3, 0.8 Hz, 1H), 8.56 (dd, J=4.9, 1.7 Hz, 1H), 7.83-7.75 (m, 1H), 7.34 (ddd, J=7.9, 4.9, 0.8 Hz, 1H), 7.26-7.23 (m, 2H), 7.23-7.18 (m, 1H), 7.12-7.06 (m, 1H), 7.03-6.92 (m, 3H), 6.87-6.83 (m, 1H), 6.76 (ddd, J=8.3, 2.6, 0.6 Hz, 1H), 6.68-6.61 (m, 2H), 4.39 (s, 2H), 2.06 (s, 3H), 2.00 (s, 3H).
The starting material was prepared as follows:
Following the General procedure A, 1-bromo-2-methyl-4-(4-nitrophenoxy)benzene was obtained in 91% yield (27.1 mmol, 8.34 g) from 4-bromo-3-methyl-phenol (31.5 mmol, 6.01 g) and 4-fluoro-nitrobenzene (29.9 mmol, 4.22 g).
C13H10BrNO3; Mw=308.13 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.24-8.18 (m, 2H), 7.57 (d, J=8.6 Hz, 1H), 7.05-6.96 (m, 3H), 6.80 (dd, J=8.6, 2.9 Hz, 1H), 2.41 (s, 3H).
Following the General procedure E, a mixture of o-tolylboronic acid (30.9 mmol, 4.20 g), 1-bromo-2-methyl-4-(4-nitrophenoxy)benzene (27.1 mmol, 8.34 g), K2CO3 (55.0 mmol, 7.60 g) and Pd(PPh3)4 (10% mol) in dioxane/H2O 4:1 (0.05-0.1 M) was converted to 2,2′-dimethyl-4-(4-nitrophenoxy)-1,1′-biphenyl in 92% yield (24.9 mmol, 7.96 g). C20H17NO3; Mw=319.36 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.26-8.21 (m, 2H), 7.31-7.27 (m, 2H), 7.24 (d, J=4.8 Hz, 1H), 7.14 (dd, J=14.2, 7.6 Hz, 2H), 7.11-7.04 (m, 2H), 7.00 (d, J=2.5 Hz, 1H), 6.95 (dd, J=8.2, 2.2 Hz, 1H), 2.09 (s, 3H), 2.07 (s, 3H).
Following the General procedure B, 4-((2,2′-dimethyl-[1,1′-biphenyl]-4-yl)oxy)aniline was obtained in 88% yield (21.9 mmol, 6.33 g) from 2,2′-dimethyl-4-(4-nitrophenoxy)-1,1′-biphenyl (24.9 mmol, 7.96 g).
C20H19NO; Mw=289.38 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 7.26-7.24 (m, 2H), 7.23-7.18 (m, 1H), 7.10 (d, J=6.8 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 6.96-6.91 (m, 2H), 6.84 (d, J=2.5 Hz, 1H), 6.77 (dd, J=8.4, 2.6 Hz, 1H), 6.75-6.71 (m, 2H), 2.07 (s, 3H), 2.00 (s, 3H).
Following the General procedure H, 6-((2,2′-dimethyl-[1,1′-biphenyl]-4-yl)oxy)-N-(pyridin-3-ylmethyl)pyridin-3-amine was obtained in 49% yield (0.17 mmol, 65 mg) from 6-((2,2′-dimethyl-[1,1′-biphenyl]-4-yl)oxy)pyridin-3-amine (0.345 mmol, 100 mg).
C25H23N3O; Mw=381.48 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.60-8.56 (m 1H), 7.76-7.72 (m, 2H), 7.36-7.31 (m, 1H), 7.30-7.26 (m, 2H), 7.24-7.20 (m, 1H), 7.15-7.11 (m, 1H), 7.10-7.04 (m, 2H), 6.99-6.96 (m, 1H), 6.94-6.89 (m, 1H), 6.87-6.84 (m, 1H), 4.40 (s, 2H), 4.02 (s, 1H), 2.10 (s, 3H), 2.04 (s, 3H).
The starting material was prepared as follows:
Following the General procedure A, 2-(4-bromo-3-methylphenoxy)-5-nitropyridine was obtained in 98% yield (6.2 mmol, 1.93 g) from 4-bromo-3-methyl-phenol (6.8 mmol, 1.28 g) and 2-chloro-5-nitropyridine (6.4 mmol, 1.01 g).
C12H9BrN2O3; Mw=309.12 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 9.04 (d, J=2.7 Hz, 1H), 8.49 (dd, J=9.0, 2.9 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.10-7.01 (m, 2H), 6.88 (dd, J=8.6, 2.8 Hz, 1H), 2.42 (s, 3H).
Following the General procedure E, a mixture of o-tolylboronic acid (1.9 mmol, 264 mg), 2-(4-bromo-3-methylphenoxy)-5-nitropyridine (1.3 mmol, 400 mg), K2CO3 (2.6 mmol, 358 mg) and Pd(PPh3)4 (10% mol) in dioxane/H2O 4:1 (0.05-0.1 M) was converted to 2-((2,2′-dimethyl-[1,1′-biphenyl]-4-yl)oxy)-5-nitropyridine in 95% yield (1.2 mmol, 392 mg).
C19H16N2O3; Mw=320.35 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 9.11 (d, J=2.8 Hz, 1H), 8.49 (dd, J=9.1, 2.8 Hz, 1H), 7.35-7.31 (m, 1H), 7.29 (m, 1H), 7.25-7.22 (m, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.15 (dt, J=7.0, 1.2 Hz, 1H), 7.09-7.00 (m, 3H), 2.10 (s, 3H), 2.09 (s, 3H).
Following the General procedure B, 6-((2,2′-dimethyl-[1,1′-biphenyl]-4-yl)oxy)pyridin-3-amine was obtained in 37% yield (0.5 mmol, 132 mg) from 2-((2,2′-dimethyl-[1,1′-biphenyl]-4-yl)oxy)-5-nitropyridine (1.2 mmol, 392 mg).
C19H18N2O; Mw=290.37 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=2.8 Hz, 1H), 7.25 (s, 2H), 7.23-7.18 (m, 1H), 7.12 (t, J=6.2 Hz, 2H), 7.06 (d, J=8.2 Hz, 1H), 6.96 (d, J=1.9 Hz, 1H), 6.90 (dd, J=8.3, 2.3 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 2.85 (s, 2H), 2.08 (s, 3H), 2.02 (s, 3H).
Following the General procedure H, (4′-fluoro-[1,1′-biphenyl]-4-yl)(4-((pyridin-3-ylmethyl)-amino)phenyl)methanol was obtained in 78% yield with purification (0.20 mmol, 0.078 g) from (4-aminophenyl)(4′-fluoro-[1,1′-biphenyl]-4-yl)methanol (0.51 mmol, 0.150 g).
C25H21FN2O; Mw=384.45 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.65-8.58 (m, 1H), 8.52 (dd, J=4.8, 1.6 Hz, 1H), 7.69 (dt, J=7.9, 1.9 Hz, 1H), 7.55-7.45(m, 4H), 7.47-7.41 (m, 2H), 7.30-7.26 (m, 1H), 7.23-7.17 (m, 2H), 7.16-7.07 (m, 2H), 6.66-6.57 (m, 2H), 5.80 (s, 1H), 4.36 (s, 2H).
The starting material was prepared as follows:
To a solution of 4-bromo-4′-fluoro-1,1′-biphenyl (1.99 mmol, 0.500 g), in dry THF (19.9 ml), at −78° C., under inert atmosphere, tert-butyllithium (2.390 mmol, 1.4 ml) was added dropwise. The reaction mixture was stirred at −78° C. for 20 min before trimethyl borate (1.99 mmol, 0.222 ml) was added dropwise. After stirring for 1 h the reaction mixture was brought to RT and quenched with 1N HCl and stirred for 30 min. The reaction mixture was concentrated under vacuo and the observed precipitate was filtered off and air dried to get (4′-fluoro-[1,1′-biphenyl]-4-yl)boronic acid (1.852 mmol, 0.400 g) in 93% yield as a white powder. The NMR spectra was identical to the previously reported one (Neya, et al., WO 2003 022842).
To a solution of chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.093 mmol, 0.046 g) in dry dioxane (12.3 ml), at RT, under inert atmosphere, was added potassium hydroxide (1.852 mmol, 1.234 ml) and the mixture stirred for 3 min. To this solution (4′-fluoro-[1,1′-biphenyl]-4-yl)boronic acid (1.852 mmol, 0.400 g) was added followed by 4-nitrobenzaldehyde (3.760 mmol, 0.560 g). The mixture was stirred for 14 h at RT and then quenched by addition of brine. The mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage KP-Sil 50 g, hexane/EtOAc, 0-20%) to afford (4′-fluoro-[1,1′-biphenyl]-4-yl)(4-nitrophenyl)methanol (1.46 mmol, 0.473 g) in 79% yield as a white solid. C19H14FNO3; Mw=323.32 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.25-8.16 (m, 2H), 7.65-7.59 (m, 2H), 7.56-7.48 (m, 4H), 7.44-7.39 (m, 2H), 7.17-7.06 (m, 2H), 5.97 (s, 1H), 2.41 (s, 1H). 19F NMR (377 MHz, CDCl3) δ-115.19.
Following the General procedure G, (4-aminophenyl)(4′-fluoro-[1,1′-biphenyl]-4-yl)methanol was obtained in 98% yield with purification (1.55 mmol, 0.445 g) from (4′-fluoro-[1,1′-biphenyl]-4-yl)(4-nitrophenyl)methanol (1.52 mmol, 0.500 g).
C19H16FNO; Mw=293.33 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 7.56-7.48 (m, 4H), 7.47-7.41 (m, 2H), 7.22-7.15 (m, 2H), 7.13-7.07 (m, 2H), 6.71-6.60 (m, 2H), 5.80 (s, 1H).
Following the General procedure H, 4-((4′-fluoro-[1,1′-biphenyl]-4-yl)(methoxy)methyl)-N-(pyridin-3-ylmethyl)aniline was obtained in 52% yield with purification (0.25 mmol, 0.102 g) from 4-((4′-fluoro-[1,1′-biphenyl]-4-yl)(methoxy)methyl)aniline (0.51 mmol, 0.150 g).
C26H23FN2O; Mw=398.47 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J=2.2 Hz, 1H), 8.52 (dd, J=4.9, 1.6 Hz, 1H), 7.69 (dtd, J=7.8, 1.7, 1.0 Hz, 1H), 7.55-7.46 (m, 4H), 7.43-7.36 (m, 2H), 7.26 (s, 1H), 7.19-7.14 (m, 2H), 7.13-7.07 (m, 2H), 6.62-6.57 (m, 2H), 5.19 (s, 1H), 4.35 (s, 2H), 3.38 (s, 3H).
The starting material was prepared as follows:
To a solution of (4′-fluoro-[1,1′-biphenyl]-4-yl)(4-nitrophenyl)methanol (0.464 mmol, 0.15 g; expl. 30, Step 2), in acetone (4.64 ml), was added Cs2CO3 (1.392 mmol, 0.453 g) followed by iodomethane (0.696 mmol, 0.044 ml). The reaction mixture was refluxed for 4 h in a sealed tube at 60° C. The cooled reaction mixture was directly loaded on silica and the residue purified by flash chromatograpy (Biotage KP-Sil 25 g, hexane/EtOAc, 0-20%) to afford 4-fluoro-4′-(methoxy(4-nitrophenyl)methyl)-1,1′-biphenyl (0.406 mmol, 0.137 g) in 88% yield.
C20H16FNO3; Mw=337.34 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.22-8.17 (m, 2H), 7.61-7.48 (m, 6H), 7.41-7.36 (m, 2H), 7.15-7.07 (m, 2H), 5.36 (s, 1H), 3.43 (s, 3H).
Following the General procedure G, 4-((4′-fluoro-[1,1′-biphenyl]-4-yl)(methoxy)methyl)-aniline was obtained in 78% yield with purification (1.30 mmol, 0.400 g) from 4-fluoro-4′-(methoxy(4-nitrophenyl)methyl)-1,1′-biphenyl (1.78 mmol, 0.600 g).
C20H18FNO; Mw=307.37 g.mol−1; 1H NMR (300 MHz, Chloroform-d) δ 7.59-7.44 (m, 4H), 7.45-7.33 (m, 2H), 7.22-7.00 (m, 4H), 6.76-6.55 (m, 2H), 5.19 (s, 1H), 3.38 (s, 3H).
Following the General procedure H, 4-((4′-fluoro-[1,1′-biphenyl]-4-yl)methyl)-N-(pyridin-3-ylmethyl)aniline was obtained in 87% yield (0.27 mmol, 115 mg) from 4-((4′-fluoro-[1,1′-biphenyl]-4-yl)methyl)aniline (0.36 mmol, 100 mg).
C25H21FN2; Mw=368.46 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.54 (d, J=4.9 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.55-7.47 (m, 2H), 7.48-7.41 (m, 2H), 7.31 (t, J=6.3 Hz, 1H), 7.26-7.21 (m, 3H), 7.15-7.07 (m, 2H), 7.06-7.00 (m, 2H), 6.62-6.54 (m, 2H), 4.37 (s, 2H), 3.91 (s, 2H).
The starting material was prepared as follows:
To a solution of (4′-fluoro-[1,1′-biphenyl]-4-yl)(4-nitrophenyl)methanol (1.54 mmol, 0.500 g; expl. 30, Step 2), in dry DCM (7.73 ml), under inert atmosphere, at −78° C., was added dropwise diethylamino-sulfur-trifluoride (1.85 mmol, 0.245 ml). The reaction mixture was stirred at the same temperature for 2 h then brought to RT. The reaction was then quenched using saturated NaHCO3 solution. The two layers were separated, and the aqueous layer was extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford 4-fluoro-4′-(fluoro(4-nitrophenyl)methyl)-1,1′-biphenyl (1.38 mmol, 0.450 g) in 89% yield as yellow solid.
C19H13F2NO2; Mw=325.31 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 8.29-8.22 (m, 2H), 7.59-7.49 (m, 6H), 7.42-7.36 (m, 2H), 7.17-7.09 (m, 2H), 6.58 (d, J=47.0 Hz, 1H).
Following the General procedure G, 4((4′-fluoro-[1,1′-biphenyl]-4-yl)methyl)aniline was obtained in 60% yield with purification (1.30 mmol, 0.154 g) from 4-fluoro-4′-(fluoro(4-nitrophenyl)methyl)-1,1′-biphenyl (0.92 mmol, 0.300 g).
C19H16FN; Mw=277.34 g.mol−1; 1H NMR (400 MHz, CDCl3) δ 7.56-7.50 (m, 2H), 7.49-7.44 (m, 2H), 7.27-7.24 (m, 2H), 7.16-7.09 (m, 2H), 7.06-7.01 (m, 2H), 6.71-6.66 (m, 2H), 3.94 (s, 2H).
Following the General procedure H, 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-2-methyl-N-(pyridin-3-ylmethyl)pyridin-3-amine was obtained in 20% yield with purification (0.22 mmol, 86 mg) from 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-2-methylpyridin-3-amine (1.155 mmol, 0.341 g) and nicotinaldehyde (1.60 mmol, 1.40 eq.).
C23H19FN4O; MW=386.43 g mol-1; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.44 (d, J=4.7 Hz, 1H), 8.39-8.34 (m, 1H), 8.10-8.05 (m, 2H), 7.92 (d, J=8.7 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.47 (dd, J=8.7, 2.8 Hz, 1H), 7.36-7.26 (m, 3H), 6.98-6.90 (m, 1H), 6.76 (d, J=8.5 Hz, 1H), 5.88 (t, J=6.1 Hz, 1H), 4.40 (d, J=6.0 Hz, 2H), 2.29 (s, 3H).
The starting material was prepared as follows:
To a solution of 6-bromopyridin-3-ol (29 mmol, 5.0 g), in dry DMF (29 mL), under N2, at 0° C., was added portionwise NaH (29 mmol, 1.1 g, 60% wt). The mixture was stirred at 0° C. for 1 h. Methyl chloromethyl ether (29 mmol, 2.3 g, 2.2 mL,) was then slowly added. The mixture was stirred at 0° C. for 1 h and then allowed to warm to RT over the weekend. The reaction mixture was cooled to 0° C. and saturated NaHCO3 solution was added. The mixture was warmed to RT and diluted with H2O. The mixture was extracted with AcOEt (3×). The combined organic layers were washed with H2O (3×) and brine. The mixture was dried over MgSO4, filtered and concentrated under reduced pressure. The product, 2-bromo-5-(methoxymethoxy)pyridine (29 mmol, 6.3 g), was isolated as a colorless oil in quantitative yield.
C7H8BrNO2; Mw=218.05 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.15 (dd, J=3.1, 0.6 Hz, 1H), 7.35 (dd, J=8.7, 0.6 Hz, 1H), 7.27-7.20 (m, 1H), 5.15 (s, 2H), 3.46 (s, 3H).
Following the General procedure D, a mixture of (4-fluorophenyl)boronic acid (32.0 mmol, 4.4 g), 2-bromo-5-(methoxymethoxy)pyridine (29.0 mmol, 6.3 g), K2CO3 (58.0 mmol, 8.0 g), and Pd(PPh3)2Cl2 (2.9 mmol, 2.0 g) in 4:1 mixture of 2-propanol/H2O (0.1 M) was converted to 2-(4-fluorophenyl)-5-(methoxymethoxy)pyridine in 56% yield (16.20 mmol, 3.79 g).
C13H12FNO2; Mw=233.24 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.46 (dd, J=2.9, 0.7 Hz, 1H), 7.97-7.83 (m, 2H), 7.60 (dd, J=8.7, 0.7 Hz, 1H), 7.43 (dd, J=8.7, 2.9 Hz, 1H), 7.13 (dd, J=8.9, 8.5 Hz, 2H), 5.23 (s, 2H), 3.51 (s, 3H).
To a solution of 2-(4-fluorophenyl)-5-(methoxymethoxy)pyridine (16.20 mmol, 3.79 g), in dioxane (20 mL), at RT was added a 4M HCl (146 mmol, 36.6 mL) dioxane solution. The mixture was heated at 80° C. overnight. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was dissolved in H2O and extracted with DCM (3×). The aqueous layer was neutralized to pH=6-7 with solid Na2CO3. The precipitated white solid was filtered off, washed with hexane and dried under vacuo for 2 h, to afford 6-(4-fluorophenyl)pyridin-3-ol (15.0 mmol, 2.83 g) in 92% yield.
C11H8FNO; Mw=189.19 g mol−1; 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.20 (dd, J=2.9, 0.7 Hz, 1H), 8.09-7.93 (m, 2H), 7.78 (dd, J=8.7, 0.7 Hz, 1H), 7.33-7.15 (m, 3H).
Following the General procedure A, 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-2-methyl-3-nitropyridine was obtained in 100% yield (3.00 mmol, 900 mg) from 6-(4-fluorophenyl)pyridin-3-ol (3.00 mmol, 600 mg) and 6-chloro-2-methyl-3-nitropyridine (3.00 mmol, 500 mg).
C17H12FN3O3; Mw=325.29 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.58 (dd, J=2.7, 0.7 Hz, 1H), 8.42 (d, J=8.9 Hz, 1H), 8.03-7.96 (m, 2H), 7.76 (dd, J=8.7, 0.7 Hz, 1H), 7.60 (dd, J=8.7, 2.7 Hz, 1H), 7.20-7.14 (m, 2H), 6.96 (dd, J=8.9, 0.7 Hz, 1H), 2.72 (s, 3H).
Following the General procedure B, 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-2-methylpyridin-3-amine was obtained in 89% yield (2.80 mmol, 732 mg) from 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-2-methyl-3-nitropyridine (2.80 mmol, 910 mg).
C17H14FN3O; Mw=295.31 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.49 (dd, J=2.8, 0.7 Hz, 1H), 7.98-7.88 (m, 2H), 7.64 (dd, J=8.4, 0.7 Hz, 1H), 7.45 (dd, J=8.7, 2.8 Hz, 1H), 7.19-7.08 (m, 2H), 7.04 (d, J=8.4 Hz, 1H), 6.68 (dd, J=8.4, 0.7 Hz, 1H), 3.50 (s, 2H), 2.33 (s, 3H).
Following the General procedure H, 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-4-methyl-N-(pyridin-3-ylmethyl)pyridin-3-amine was obtained in 84% yield after purification (0.964 mmol, 0.373 g) from 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-4-methylpyridin-3-amine (1.14 mmol, 0.337 g) and nicotinaldehyde (1.617 mmol, 1.40 eq.).
C23H19FN4O; MW=386.43 g mol-1; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J=1.8 Hz, 1H), 8.44 (dd, J=4.8, 1.5 Hz, 1H), 8.37 (d, J=2.7 Hz, 1H), 8.11-8.02 (m, 2H), 7.91 (d, J=8.7 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.50 (dd, J=8.7, 2.8 Hz, 1H), 7.37-7.24 (m, 4H), 6.89 (s, 1H), 5.80 (t, J=6.1 Hz, 1H), 4.39 (d, J=6.1 Hz, 2H), 2.24 (s, 3H).
The starting material was prepared as follows:
Following the General procedure A, 2-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-4-methyl-5-nitropyridin was obtained in 90% yield (2.70 mmol, 900 mg) from 6-(4-fluorophenyl)pyridin-3-01 (3.00 mmol, 600 mg; expl. 33, Step 3) and 2-chloro-4-methyl-5-nitropyridine (5.00 mmol, 800 mg).
C17H12FN3O3; Mw=325.29 g mol−1; H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.55 (dd, J=2.8, 0.6 Hz, 1H), 8.01-7.95 (m, 2H), 7.76 (dd, J=8.7, 0.6 Hz, 1H), 7.60 (dd, J=8.6, 2.8 Hz, 1H), 7.17 (app t, J=8.8 Hz, 2H), 6.97 (s, 1H), 2.72 (s, 3H).
Following the General procedure B, 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-4-methylpyridin-3-amine was obtained in 96% yield (2.58 mmol, 763 mg) from 2-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-4-methyl-5-nitropyridine (2.70 mmol, 900 mg).
C17H14FN3O; Mw=295.31 g mol−1; 1H NMR (400 MHz, CDCl3) δ 8.48 (dd, J=2.8, 0.6 Hz, 1H), 7.95-7.89 (m, 2H),7.66 (dd, J=8.1, 0.6 Hz, 1H), 7.64 (s, 1H), 7.47 (dd, J=8.7, 2.8 Hz, 1H), 7.19 (app t, J=8.7 Hz, 2H), 6.77 (s, 1H), 3.48 (s, 2H), 2.22 (s, 3H).
Identification of Novel Compounds to Target Oncovirus Positive and Driven Human Cancers
In order to identify novel compounds with an ability to block growth of oncovirus driven human cancers, the two EBV positive cell lines LCL070903 and HG-3 (Rosén A, Bergh AC, Gogok P, Evaldsson C, Myhrinder A L, Hellqvist E, Rasul A, Bjorkholm M, Jansson M, Mansouri L, Liu A, Teh B T, Rosenquist R, Klein E. Lymphoblastoid cell line with B1 cell characteristics established from a chronic lymphocytic leukemia clone by in vitro EBV infection Oncoimmunology. 2012 Jan. 1; 1(1):18-27) were used as representative cell lines. A set of compounds were tested for their ability to block growth and downregulate EBV target (cellular and viral) genes as described in following sections.
Cell Culture
One million human EBV positive lymphoma cell lines HG3 and LCL070903 (Rosén et al., 2012) were cultured in RPMI1640 media supplemented with 10% FCS. For RNA expression analysis cells were treated with compounds at 10 μM concentration and for proliferation assay cells were treated at a concentration range of 0.01-100 μM. Following treatment cells were harvested and washed with 1× PBS. Total RNA was extracted as described below.
RNA Extraction
Total RNA was extracted from cells using TRIzol® extraction kit (Invitrogen). Briefly, 1×106 cells were washed with ice-cold 1× PBS and lysed in 1 ml of TRIzol® solution for 5 minutes at room temperature to dissociate nucleoprotein complexes. Lysed cells were then treated with 200 μl of chloroform and shaked vigorously for 15-30 seconds and incubated at room temperature for 2-3 minutes. The samples were centrifuged at 14000 rpm using Eppendorf table top centrifuge for 10 minutes at 4° C. Following centrifugation, upper aqueous phase was transferred to new eppendorf tubes. To precipitate total RNA 500 μl of isomyl alcohol was added to the separated aqueous phase and incubated at room temperature for 10 minutes. A RNA pellet was obtained by centrifuging the samples at 4° C. for 10 minutes. RNA pellet obtained was washed with 1 ml ice cold 75% ethanol and spun down at 14000 rpm at 4° C. RNA pellet was dried off of excess of ethanol and resuspended in 40 IA DPEC water.
cDNA Synthesis
Total RNA extracted from the cell was used to synthesize cDNA by reverse transcription reaction. Reverse transcription was performed according to one of the two following protocols.
In first protocol, SuperScript™ RT (Invitrogen) was used for reverse transcription reaction. RNA concentration was measured using NanoDrop®ND-1000 spectrophotometer (Witec AG) and 500 ng of total RNA was mixed with a 10 mM mix of dNTPs and 100 ng of random primers. The reaction mix was incubated at 65° C. for 5 minutes and quickly incubated on ice for 1 minute. Following incubation on ice, 5× first strand buffer and 0.1M DTT were added and mix was incubated for 2 minutes at 25° C. To start the reverse transcription reaction, 200U of SuperScrip™ II RT was added to the reaction mix and incubated at 42° C. for 50 minutes. The reaction was stopped by incubating the reaction mix at 75° C. for 15 minutes.
In second protocol, reverse transcription was performed using PrimeScript RT Master Mix (Takara). RNA concentration was measured using NanoDrop®ND-1000 spectrophotometer (Witec AG) and 1 μg of total RNA was mixed with 4 μL 5X PrimeScript RT Master Mix in a total reaction volume of 20 μL. The reaction mix was incubated at 37° C. for 15 minutes followed by heat inactivation at 85° C. for 5 seconds.
Quantitative Real Time PCR Analyses
QRT-PCR was carried out using 7900 HT Fast Real-Time PCR system (Applied Biosystems) or QuantStudio 3 system (ThermoFisher). Briefly, 12.5 ng of template cDNA was used with a primer concentration of 0.5 μM each and lx SYBR Green dye in a final volume of 10 μL in a 96 well or 384 well plate format.
Alamarblue/Prestoblue Proliferation Assay
Alamarblue® and PrestoBlue proliferation assays were performed to determine the growth kinetics of EBV inhibitor treated cells. Alamar blue® and PrestoBlue consists of a cell permeable substrate resazurin. In metabolically active and proliferating cells, resazurin is converted to resorufin due to an intrinsic reducing power of live cells and produces a red fluorescence. Therefore production of resorufin serves as an indicator of the viability of the cell population.
Proliferation assays were performed by seeding 5000 cells/well in a 96 well plate. Cells were treated with DMSO or compounds for 72 hours using concentration ranges of 0.01-100 μM. Each concentration was tested in 4 replicates. To determine the growth kinetics, 10 μl of Alamar blue® or PrestoBlue (Invitrogen) was added to each well and incubated for 4 hours. Readout was taken using Tecan F500 (Tecan) multiplate reader or Varioskan LUX (ThermoFisher) multiplate reader.
In order to determine anti-cancer activity of compounds in oncoviral driven cells, an EBV infected human Chronic Lymphocytic Leukemia cell line HG-3 was used (Rosen et al., 2012). In brief, HG-3 cells were plated in a 96 well plate and treated with an increasing concentration of compounds. As shown in
Upon infection of human cells, EBV is known to induce cancerous transformation of cells via upregulation of host as well as viral genes (e.g LMP1, RUNX3, EBNA2, BATF1 and CD21).
To determine the ability of compounds to downregulate EBV driven gene expression, HG-3 cells were treated with selected compounds and percentage inhibition of EBV target genes was determined by quantitative PCR. As shown in Table 2, compounds down regulate EBV target genes such as LMP1, RUNX3, EBNA2, BATF1 and CD21. To further determine the anti-oncoviral specificity of compounds, these compounds were tested for their ability to downregulate a NOTCH target gene HES1 in a NOTCH1 positive (EBV negative) human leukemic cell line RPMI8402. As shown in table 3, while a comparative compound 6-(4-tert-Butylphenoxy)pyridin-3-amine described in WO 2013/093885 effectively downregulates HES1, compounds 6-(4-(tert-Butyl)phenoxy)-N-(pyridin-4-ylmethyl)pyridin-3-amine, 6-(4-(tert-Butyl)phenoxy)-N-(pyridin-3-ylmethyl)pyridin-3-amine, 6-(4-(tert-Butyl)phenoxy)-N-(pyridin-2-ylmethyl)pyridin-3-amine), N-((1H-Imidazol-4-yl)methyl)-6-(4-(tert-butyl)phenoxy)pyridin-3-amine and 5-(((6-(4-(tert-Butyl)phenoxy)pyridin-3-yl)amino)methyl)pyrimidin-2-amine do not modulate expression of this gene. This data confirms specificity of these compounds in targeting EBV driven tumors.
In order to determine anti-cancer activity of compounds in oncoviral driven cells, EBV infected human Chronic Lymphocytic Leukemia cell line HG-3 was used (Rosen et al., 2012).
In brief, HG-3 cells were plated in a 96 well plate and treated with an increasing concentration of compounds. As shown in
Upon infection of human cells, EBV is known to induce cancerous transformation of cells via upregulation of host as well as viral genes (e.g LMP1, EBNA2, BATF1, BMI1 and CD21). To determine the ability of compounds to downregulate EBV driven gene expression, HG-3 and LCL070903 cells were treated with selected compounds and percentage inhibition of EBV target genes was determined by quantitative PCR. As shown in Table 5 and Table 6, compounds down regulate EBV target genes such as BMI1 in HG-3 and LCL070903 cells, respectively (
| Number | Date | Country | Kind |
|---|---|---|---|
| 19168505.6 | Apr 2019 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2020/060149 | 4/9/2020 | WO | 00 |
